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Dofetilide warnings: Tikosyn Oral: Uses, Side Effects, Interactions, Pictures, Warnings & Dosing

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Memorial Sloan Kettering Cancer Center

This information from Lexicomp® explains what you need to know about this medication, including what it’s used for, how to take it, its side effects, and when to call your healthcare provider.

Brand Names: US

Tikosyn

Warning

  • There is a risk that this drug may cause another type of abnormal heartbeat, which may be deadly. You will have to start and restart this drug in a setting where your heart will be watched nonstop. Talk with your doctor.

What is this drug used for?

  • It is used to keep a normal heartbeat in people who have a certain type of abnormal heartbeat (atrial fibrillation or atrial flutter).
  • It may be used to turn atrial fibrillation or flutter into a normal heartbeat.

What do I need to tell my doctor BEFORE I take this drug?

  • If you have an allergy to dofetilide or any other part of this drug.
  • If you are allergic to this drug; any part of this drug; or any other drugs, foods, or substances. Tell your doctor about the allergy and what signs you had.
  • If you have kidney disease.
  • If you have any of these health problems: Long QT on ECG, low magnesium levels, or low potassium levels.
  • If you are taking any drugs used for a heartbeat that is not normal.
  • If you are taking any of these drugs: Cimetidine, dolutegravir, hydrochlorothiazide, itraconazole, ketoconazole, megestrol, prochlorperazine, trimethoprim, or verapamil.
  • If you are taking any drugs that can cause a certain type of heartbeat that is not normal (prolonged QT interval). There are many drugs that can do this. Ask your doctor or pharmacist if you are not sure.
  • If you are breast-feeding. Do not breast-feed while you take this drug.

This is not a list of all drugs or health problems that interact with this drug.

Tell your doctor and pharmacist about all of your drugs (prescription or OTC, natural products, vitamins) and health problems. You must check to make sure that it is safe for you to take this drug with all of your drugs and health problems. Do not start, stop, or change the dose of any drug without checking with your doctor.

What are some things I need to know or do while I take this drug?

  • Tell all of your health care providers that you take this drug. This includes your doctors, nurses, pharmacists, and dentists.
  • Have blood work checked as you have been told by the doctor. Talk with the doctor.
  • You will need an ECG before starting this drug and during treatment. Talk with your doctor.
  • Tell your doctor if you have too much sweat, fluid loss, throwing up, diarrhea, not hungry, or more thirst.
  • If you drink grapefruit juice or eat grapefruit often, talk with your doctor.
  • Tell your doctor if you are pregnant or plan on getting pregnant. You will need to talk about the benefits and risks of using this drug while you are pregnant.

What are some side effects that I need to call my doctor about right away?

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

  • Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing, swallowing, or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.
  • Chest pain or pressure.
  • Dizziness.
  • Shortness of breath.
  • A type of abnormal heartbeat (prolonged QT interval) has happened with this drug. Sometimes, this has led to another type of unsafe abnormal heartbeat (torsades de pointes). Call your doctor right away if you have a fast or abnormal heartbeat, or if you pass out.

What are some other side effects of this drug?

All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if any of these side effects or any other side effects bother you or do not go away:

  • Headache.
  • Upset stomach.
  • Signs of a common cold.

These are not all of the side effects that may occur. If you have questions about side effects, call your doctor. Call your doctor for medical advice about side effects.

You may report side effects to your national health agency.

You may report side effects to the FDA at 1-800-332-1088. You may also report side effects at https://www.fda.gov/medwatch.

How is this drug best taken?

Use this drug as ordered by your doctor. Read all information given to you. Follow all instructions closely.

  • Take with or without food.
  • It is important that you do not miss or skip a dose of this drug during treatment.
  • Keep taking this drug as you have been told by your doctor or other health care provider, even if you feel well.

What do I do if I miss a dose?

  • Never make up a missed dose. Skip the missed dose and go back to your normal time.
  • Do not take 2 doses at the same time or extra doses.

How do I store and/or throw out this drug?

  • Store at room temperature.
  • Keep lid tightly closed.
  • Store in a dry place. Do not store in a bathroom.
  • Keep all drugs in a safe place. Keep all drugs out of the reach of children and pets.
  • Throw away unused or expired drugs. Do not flush down a toilet or pour down a drain unless you are told to do so. Check with your pharmacist if you have questions about the best way to throw out drugs. There may be drug take-back programs in your area.

General drug facts

  • If your symptoms or health problems do not get better or if they become worse, call your doctor.
  • Do not share your drugs with others and do not take anyone else’s drugs.
  • Some drugs may have another patient information leaflet. If you have any questions about this drug, please talk with your doctor, nurse, pharmacist, or other health care provider.
  • This drug comes with an extra patient fact sheet called a Medication Guide. Read it with care. Read it again each time this drug is refilled. If you have any questions about this drug, please talk with the doctor, pharmacist, or other health care provider.
  • If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

Consumer Information Use and Disclaimer

This generalized information is a limited summary of diagnosis, treatment, and/or medication information. It is not meant to be comprehensive and should be used as a tool to help the user understand and/or assess potential diagnostic and treatment options. It does NOT include all information about conditions, treatments, medications, side effects, or risks that may apply to a specific patient. It is not intended to be medical advice or a substitute for the medical advice, diagnosis, or treatment of a health care provider based on the health care provider’s examination and assessment of a patient’s specific and unique circumstances. Patients must speak with a health care provider for complete information about their health, medical questions, and treatment options, including any risks or benefits regarding use of medications. This information does not endorse any treatments or medications as safe, effective, or approved for treating a specific patient. UpToDate, Inc. and its affiliates disclaim any warranty or liability relating to this information or the use thereof. The use of this information is governed by the Terms of Use, available at https://www.wolterskluwer.com/en/solutions/lexicomp/about/eula.

Last Reviewed Date

2019-10-15

Copyright

© 2021 UpToDate, Inc. and its affiliates and/or licensors. All rights reserved.

Dofetilide | Side Effects | Dosage | Precautions | Warnings

By Medicover Hospitals / 21 April 2021
Home | Medicine | Dofetilide

  • Dofetilide is an anti-arrhythmic, a heart rhythm medication. It is used to help people with certain atrial heart rhythm disorders keep their hearts beating normally (the upper chambers of the heart that allow blood to flow into the heart). It is prescribed to patients who have atrial fibrillation or atrial flutter.
    1. Dofetilide Uses
    2. Dofetilide Side effects
    3. Precautions
    4. Interactions
    5. Dosage
    6. Storage
    7. Dofetilide vs Amiodarone
    8. Frequently Asked Questions
    9. Citations

    Dofetilide Uses:

  • This medication is used to treat severe (possibly fatal) irregular heartbeats (such as atrial fibrillation or flutter). It is used to restore normal heart rhythm and keep the heartbeat regular and steady. It works by inhibiting the activity of certain electrical signals in the heart that cause irregular heartbeats. Treating an irregular heartbeat can lower your risk of blood clots, which can lower your risk of a heart attack or stroke.
  • How to use:

  • Before you begin taking this, and each time you get a refill, read the Medication Guide provided by your pharmacist.
  • Take this medication orally twice daily, with or without food, or as directed by your doctor. It is important that you take this medication exactly as prescribed to reduce your risk of more serious effects.
  • The dosage is evaluated by your medical condition, kidney function, and treatment response.
  • If your disease does not keep improving or worsens, visit your doctor.
  • Side Effects

    • Headache
    • Chest pain
    • Shortness of breath
    • Nausea
    • Flu-like symptoms
    • Stomach pain
    • Back pain
    • Difficulty falling asleep
    • Staying asleep
    • Irregular heartbeat
    • Rash
    • Severe diarrhea
    • Dizziness or fainting
    • Unusual sweating
    • Vomiting
    • Loss of appetite
    • Increased thirst

    Precautions

  • Tell your doctor or pharmacist if you are allergic to it or if you have any other allergies. Inactive ingredients present in this product may cause some serious allergic reactions or other health problems.
  • Before taking this medication, tell your doctor or pharmacist about your medical history, particularly if you have kidney or liver disease.
  • This medication may cause dizziness. Alcohol can cause dizziness. Do not operate heavy machinery, or do anything else that requires alertness until you are confident that you can do so safely.
  • It has been linked to a heart rhythm disorder (QT prolongation). Rarely, QT prolongation can result in serious fast/irregular heartbeat and other symptoms
  • If you have certain medical conditions or are taking other drugs that may cause QT prolongation, your risk of QT prolongation may be increased.
  • Low potassium and magnesium levels in the blood may also increase your risk of QT prolongation. If you use certain drugs or have conditions like severe sweating, diarrhea, or vomiting, your risk of developing this condition may increase.
  • This drug’s side effects, particularly QT prolongation, may be more severe in older adults.
  • This medication should not be used during pregnancy. It should be taken only when prescribed by your doctor. Consult your doctor.
  • It is not clear that this medicine passes into breastmilk or not, therefore consult your doctor before breastfeeding.
  • Interactions

  • Dolutegravir and fingolimod are two drugs that may interact with this one.
  • Aside from dofetilide, many other drugs, such as amiodarone, pimozide, procainamide, quinidine, saquinavir, sotalol, macrolide antibiotics, and certain quinolone antibiotics, may have an effect on heart rhythm.
  • Other medications may interfere with the removal of it from your body, affecting how it works.
  • Cimetidine should be avoided while being treated with this medicine. Inquire with your doctor or pharmacist about other heartburn/upset stomach medications.
  • Overdose

  • Overdose of a drug can be accidental. If you have taken more than the prescribed tablets there is a chance of getting a harmful effect on your body’s functions.
  • Missed Dose

  • If you forget to take one of the dosages, take it as soon as you remember. Skip the missed dose and proceed with your daily schedule. To cope up with a missed dose, do not take a double dose.
  • Storage

  • Exposure of medicine to heat, air, and light may cause some harmful effects. The medicine must be kept in a safe place and out of children’s reach.
  • Dofetilide vs amiodarone

    Dofetilide Amiodarone
    This is an anti-arrhythmic, a heart rhythm medication. Amiodarone is an antiarrhythmic medication used for treating and preventing a wide range of irregular heartbeats
    It is used to restore normal heart rhythm and keep the heartbeat regular and steady. It is used to treat and prevent certain types of severe, potentially fatal ventricular arrhythmias.
    It works by inhibiting the activity of certain electrical signals in the heart that cause irregular heartbeats. Amiodarone primarily works by inhibiting potassium rectifier currents, which are responsible for heart repolarization during phase 3 of the cardiac action potential.

    Frequently Asked Questions:

    It is a medication used to treat irregular heartbeats (including atrial fibrillation or atrial flutter). It belongs to a class of medications known as antiarrhythmics. It regulates your heartbeat by relaxing an overactive heart.

    • Chest pain
    • facial or flaccid paralysis
    • Numbness
    • Tingling sensation
    • Paralysis
    • Slow heartbeat

    It appears to be safe and effective in preventing AF in patients undergoing catheter ablation who have been refractory to other AADs.

    It works by inhibiting the activity of certain electrical signals in the heart that cause irregular heartbeats. Treating an irregular heartbeat can lower your risk of blood clots, which can lower your risk of a heart attack or stroke.

    This medication may cause dizziness. Do not drive, operate machinery, or engage in any activity that requires alertness until you are confident that you can do so safely. Limit your intake of alcoholic beverages. Dofetilide has been linked to a heart rhythm disorder (QT prolongation).

    It works by inhibiting the activity of certain electrical signals in the heart that cause irregular heartbeats

    Tikosyn, (dofetilide) dosing, indications, interactions, adverse effects, and more

  • alfuzosin

    Monitor Closely (1)dofetilide and alfuzosin both increase QTc interval. Use Caution/Monitor.Serious – Use Alternative (1)alfuzosin and dofetilide both increase QTc interval. Avoid or Use Alternate Drug.

  • amiodarone

    Contraindicated (1)amiodarone, dofetilide.
    Either increases effects of the other by pharmacodynamic synergism. Contraindicated. Additive cardiac effects.Serious – Use Alternative (3)dofetilide increases toxicity of amiodarone by QTc interval. Avoid or Use Alternate Drug.

    amiodarone will increase the level or effect of dofetilide by basic (cationic) drug competition for renal tubular clearance. Avoid or Use Alternate Drug.

    amiodarone and dofetilide both increase QTc interval. Avoid or Use Alternate Drug.

  • amitriptyline

    Monitor Closely (1)dofetilide increases toxicity of amitriptyline by QTc interval. Use Caution/Monitor.Serious – Use Alternative (1)amitriptyline and dofetilide both increase QTc interval. Avoid or Use Alternate Drug.

  • amoxapine

    Monitor Closely (1)dofetilide increases toxicity of amoxapine by QTc interval. Use Caution/Monitor.Serious – Use Alternative (1)amoxapine and dofetilide both increase QTc interval. Avoid or Use Alternate Drug.

  • apomorphine

    Serious – Use Alternative (1)dofetilide increases toxicity of apomorphine by QTc interval. Avoid or Use Alternate Drug.

  • arformoterol

    Monitor Closely (1)dofetilide increases toxicity of arformoterol by QTc interval. Use Caution/Monitor.

  • aripiprazole

    Serious – Use Alternative (1)aripiprazole and dofetilide both increase QTc interval. Avoid or Use Alternate Drug.

  • arsenic trioxide

    Serious – Use Alternative (2)dofetilide increases toxicity of arsenic trioxide by QTc interval. Avoid or Use Alternate Drug.

    arsenic trioxide and dofetilide both increase QTc interval. Avoid or Use Alternate Drug.

  • artemether

    Serious – Use Alternative (1)artemether and dofetilide both increase QTc interval. Avoid or Use Alternate Drug.

  • artemether/lumefantrine

    Serious – Use Alternative (1)dofetilide and artemether/lumefantrine both increase QTc interval. Avoid or Use Alternate Drug.

  • asenapine

    Serious – Use Alternative (1)dofetilide increases toxicity of asenapine by QTc interval. Avoid or Use Alternate Drug.

  • atazanavir

    Monitor Closely (1)atazanavir increases levels of dofetilide by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Potential for increased toxicity. Use alternatives if available. Increased risk of QT prolongation and cardiac arrhythmias.

  • atomoxetine

    Serious – Use Alternative (1)atomoxetine and dofetilide both increase QTc interval. Avoid or Use Alternate Drug.

  • azithromycin

    Monitor Closely (1)azithromycin and dofetilide both increase QTc interval. Use Caution/Monitor.Serious – Use Alternative (1)dofetilide increases toxicity of azithromycin by QTc interval. Avoid or Use Alternate Drug.

  • bedaquiline

    Monitor Closely (1)dofetilide and bedaquiline both increase QTc interval. Modify Therapy/Monitor Closely. ECG should be monitored closely

  • bictegravir

    Contraindicated (1)bictegravir will increase the level or effect of dofetilide by decreasing renal clearance. Contraindicated. Bictegravir inhibits organic cation transporter 2 (OCT2) and multidrug and toxin extrusion transporter 1 (MATE1) in vitro. Coadministration with OCT2 and MATE1 substrates may increase their plasma concentrations.

  • bosutinib

    Monitor Closely (1)bosutinib and dofetilide both increase QTc interval. Use Caution/Monitor.

  • bupivacaine

    Monitor Closely (1)bupivacaine, dofetilide.
    Either increases effects of the other by pharmacodynamic synergism. Use Caution/Monitor. Additive cardiac effects.

  • capecitabine

    Monitor Closely (1)capecitabine and dofetilide both increase QTc interval. Use Caution/Monitor.

  • ceritinib

    Serious – Use Alternative (1)ceritinib and dofetilide both increase QTc interval. Avoid or Use Alternate Drug.

  • chloroquine

    Serious – Use Alternative (1)chloroquine increases toxicity of dofetilide by QTc interval. Avoid or Use Alternate Drug.

  • chlorpromazine

    Serious – Use Alternative (2)chlorpromazine and dofetilide both increase QTc interval. Avoid or Use Alternate Drug.

    dofetilide increases toxicity of chlorpromazine by QTc interval. Avoid or Use Alternate Drug.

  • cimetidine

    Contraindicated (1)cimetidine increases levels of dofetilide by decreasing renal clearance. Contraindicated. Risk of prolonged QTc interval.Serious – Use Alternative (1)cimetidine will increase the level or effect of dofetilide by basic (cationic) drug competition for renal tubular clearance. Avoid or Use Alternate Drug.

  • ciprofloxacin

    Monitor Closely (1)ciprofloxacin and dofetilide both increase QTc interval. Use Caution/Monitor. Ciprofloxacin elicits minimal effects on QT interval. Caution if used in combination with other drugs known to affect QT interval or in patients with other risk factors.Serious – Use Alternative (1)dofetilide increases toxicity of ciprofloxacin by QTc interval. Avoid or Use Alternate Drug.

  • cisapride

    Contraindicated (1)dofetilide increases toxicity of cisapride by QTc interval. Contraindicated.

  • citalopram

    Monitor Closely (1)dofetilide and citalopram both increase QTc interval. Use Caution/Monitor. ECG monitoring is recommended, along with drugs that may prolong the QT interval.

  • clarithromycin

    Contraindicated (1)dofetilide increases toxicity of clarithromycin by QTc interval. Contraindicated.Serious – Use Alternative (1)clarithromycin and dofetilide both increase QTc interval. Avoid or Use Alternate Drug.

  • clofazimine

    Monitor Closely (1)dofetilide increases toxicity of clofazimine by QTc interval. Modify Therapy/Monitor Closely.

  • clomipramine

    Serious – Use Alternative (2)clomipramine and dofetilide both increase QTc interval. Avoid or Use Alternate Drug.

    dofetilide increases toxicity of clomipramine by QTc interval. Avoid or Use Alternate Drug.

  • clozapine

    Serious – Use Alternative (1)dofetilide increases toxicity of clozapine by QTc interval. Avoid or Use Alternate Drug.

  • crizotinib

    Monitor Closely (2)crizotinib and dofetilide both increase QTc interval. Use Caution/Monitor. ECG monitoring is recommended, along with drugs that may prolong the QT interval.

    dofetilide increases toxicity of crizotinib by QTc interval. Use Caution/Monitor.

  • dabrafenib

    Monitor Closely (1)dabrafenib and dofetilide both increase QTc interval. Use Caution/Monitor.

  • darunavir

    Serious – Use Alternative (1)darunavir increases levels of dofetilide by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Potential for increased toxicity. Use alternatives if available. Increased risk of QT prolongation and cardiac arrhythmias.

  • dasatinib

    Monitor Closely (2)dasatinib and dofetilide both increase QTc interval. Modify Therapy/Monitor Closely.

    dofetilide increases toxicity of dasatinib by QTc interval. Use Caution/Monitor.

  • degarelix

    Serious – Use Alternative (1)dofetilide increases toxicity of degarelix by QTc interval. Avoid or Use Alternate Drug.

  • desflurane

    Serious – Use Alternative (1)desflurane and dofetilide both increase QTc interval. Avoid or Use Alternate Drug.

  • desipramine

    Serious – Use Alternative (2)desipramine and dofetilide both increase QTc interval. Avoid or Use Alternate Drug.

    dofetilide increases toxicity of desipramine by QTc interval. Avoid or Use Alternate Drug.

  • deutetrabenazine

    Monitor Closely (1)dofetilide and deutetrabenazine both increase QTc interval. Modify Therapy/Monitor Closely. For patients requiring deutetrabenazine doses >24 mg/day and are taking other drugs known to prolong QTc, assess the QTc interval before and after increasing the dose of deutetrabenazine or other medications known to prolong QTc.Serious – Use Alternative (1)deutetrabenazine and dofetilide both increase QTc interval. Avoid or Use Alternate Drug.

  • digoxin

    Serious – Use Alternative (1)digoxin will increase the level or effect of dofetilide by basic (cationic) drug competition for renal tubular clearance. Avoid or Use Alternate Drug.

  • disopyramide

    Contraindicated (2)disopyramide and dofetilide both increase QTc interval. Contraindicated.

    disopyramide, dofetilide.
    Either increases effects of the other by pharmacodynamic synergism. Contraindicated. Additive cardiac effects.Serious – Use Alternative (1)dofetilide increases toxicity of disopyramide by QTc interval. Avoid or Use Alternate Drug.

  • dolasetron

    Monitor Closely (1)dofetilide and dolasetron both increase QTc interval. Modify Therapy/Monitor Closely.

  • dolutegravir

    Contraindicated (1)dolutegravir will increase the level or effect of dofetilide by decreasing renal clearance. Contraindicated. Dolutegravir inhibits the renal organic cation transporter, OCT2; risk of life-threatening arrhythmias caused by increased systemic exposure to dofetilide

  • donepezil

    Serious – Use Alternative (1)donepezil and dofetilide both increase QTc interval. Avoid or Use Alternate Drug.

  • doxepin

    Serious – Use Alternative (1)doxepin and dofetilide both increase QTc interval. Avoid or Use Alternate Drug.

  • dronedarone

    Serious – Use Alternative (1)dofetilide and dronedarone both increase QTc interval. Avoid or Use Alternate Drug.

  • droperidol

    Serious – Use Alternative (1)dofetilide and droperidol both increase QTc interval. Avoid or Use Alternate Drug.

  • efavirenz

    Serious – Use Alternative (1)efavirenz and dofetilide both increase QTc interval. Avoid or Use Alternate Drug.

  • encorafenib

    Serious – Use Alternative (2)dofetilide increases toxicity of encorafenib by QTc interval. Avoid or Use Alternate Drug.

    encorafenib and dofetilide both increase QTc interval. Avoid or Use Alternate Drug. Encorafenib is associated with dose-dependent QTc interval prolongation. Avoid with drugs known to prolong QT interval.

  • entrectinib

    Serious – Use Alternative (1)dofetilide and entrectinib both increase QTc interval. Avoid or Use Alternate Drug.

  • epinephrine

    Serious – Use Alternative (1)epinephrine and dofetilide both increase QTc interval. Avoid or Use Alternate Drug.

  • epinephrine racemic

    Serious – Use Alternative (1)epinephrine racemic and dofetilide both increase QTc interval. Avoid or Use Alternate Drug.

  • erdafitinib

    Monitor Closely (1)erdafitinib increases levels of dofetilide by decreasing renal clearance. Modify Therapy/Monitor Closely. Consider alternatives that are not OCT2 substrates or consider reducing the dose of OCT2 substrates based on tolerability.

  • eribulin

    Serious – Use Alternative (2)eribulin and dofetilide both increase QTc interval. Avoid or Use Alternate Drug. Potential for enhanced QTc-prolonging effects; if concurrent use is necessary then ECG monitoring is recommended.

    dofetilide increases toxicity of eribulin by QTc interval. Avoid or Use Alternate Drug.

  • erythromycin base

    Serious – Use Alternative (1)dofetilide and erythromycin base both increase QTc interval. Avoid or Use Alternate Drug.

  • erythromycin ethylsuccinate

    Serious – Use Alternative (1)dofetilide and erythromycin ethylsuccinate both increase QTc interval. Avoid or Use Alternate Drug.

  • erythromycin lactobionate

    Serious – Use Alternative (1)dofetilide and erythromycin lactobionate both increase QTc interval. Avoid or Use Alternate Drug.

  • erythromycin stearate

    Serious – Use Alternative (1)dofetilide and erythromycin stearate both increase QTc interval. Avoid or Use Alternate Drug.

  • escitalopram

    Serious – Use Alternative (2)dofetilide increases toxicity of escitalopram by QTc interval. Avoid or Use Alternate Drug.

    escitalopram increases toxicity of dofetilide by QTc interval. Avoid or Use Alternate Drug.

  • ethotoin

    Contraindicated (1)ethotoin, dofetilide.
    Either increases effects of the other by pharmacodynamic synergism. Contraindicated. Additive cardiac effects.

  • ezogabine

    Monitor Closely (1)ezogabine, dofetilide.
    Either increases toxicity of the other by QTc interval. Use Caution/Monitor. Slight and transient QT-prolongation observed with ezogabine, particularly when dose titrated to 1200 mg/day. QT interval should be monitored when ezogabine is prescribed with agents known to increase QT interval.Serious – Use Alternative (1)dofetilide increases toxicity of ezogabine by QTc interval. Avoid or Use Alternate Drug. Slight and transient QT-prolongation observed, particularly when dose titrated to 1200mg/day. QT interval should be monitored when ezogabine is prescribed with agents known to increase QT interval.

  • fexinidazole

    Serious – Use Alternative (1)fexinidazole and dofetilide both increase QTc interval. Avoid or Use Alternate Drug. Avoid coadministration of fexinidazole with drugs known to block potassium channels and/or prolong QT interval.

  • fingolimod

    Contraindicated (1)fingolimod increases effects of dofetilide by pharmacodynamic synergism. Contraindicated. Due to increased risk of bradycardia, AV block, and torsade de pointes, concomitant use is contraindicated.

  • flecainide

    Serious – Use Alternative (1)dofetilide and flecainide both increase QTc interval. Avoid or Use Alternate Drug. Additive cardiac effects.

  • fluconazole

    Serious – Use Alternative (1)dofetilide and fluconazole both increase QTc interval. Avoid or Use Alternate Drug.

  • fluoxetine

    Monitor Closely (1)dofetilide and fluoxetine both increase QTc interval. Modify Therapy/Monitor Closely.

  • fluphenazine

    Monitor Closely (1)dofetilide increases toxicity of fluphenazine by QTc interval. Use Caution/Monitor.Serious – Use Alternative (1)fluphenazine and dofetilide both increase QTc interval. Avoid or Use Alternate Drug.

  • fluvoxamine

    Monitor Closely (1)fluvoxamine and dofetilide both increase QTc interval. Modify Therapy/Monitor Closely.

  • formoterol

    Serious – Use Alternative (1)dofetilide and formoterol both increase QTc interval. Avoid or Use Alternate Drug.

  • fosamprenavir

    Monitor Closely (1)fosamprenavir increases levels of dofetilide by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Potential for increased toxicity. Use alternatives if available. Increased risk of QT prolongation and cardiac arrhythmias.

  • foscarnet

    Monitor Closely (1)dofetilide and foscarnet both increase QTc interval. Modify Therapy/Monitor Closely.

  • fosphenytoin

    Contraindicated (1)fosphenytoin, dofetilide.
    Either increases effects of the other by pharmacodynamic synergism. Contraindicated. Additive cardiac effects.

  • fostemsavir

    Monitor Closely (1)dofetilide and fostemsavir both increase QTc interval. Use Caution/Monitor. QTc prolongation reported with higher than recommended doses of fostemsavir.

  • gemifloxacin

    Serious – Use Alternative (1)dofetilide increases toxicity of gemifloxacin by QTc interval. Avoid or Use Alternate Drug.

  • gemtuzumab

    Monitor Closely (1)dofetilide and gemtuzumab both increase QTc interval. Use Caution/Monitor.

  • glasdegib

    Serious – Use Alternative (1)dofetilide and glasdegib both increase QTc interval. Avoid or Use Alternate Drug. If coadministration unavoidable, monitor for increased risk of QTc interval prolongation.

  • goserelin

    Contraindicated (1)goserelin increases toxicity of dofetilide by QTc interval. Contraindicated. Increases risk of torsades de pointes.

  • haloperidol

    Serious – Use Alternative (1)dofetilide and haloperidol both increase QTc interval. Avoid or Use Alternate Drug.

  • histrelin

    Contraindicated (1)histrelin increases toxicity of dofetilide by QTc interval. Contraindicated. Increases risk of torsades de pointes.

  • hydrochlorothiazide

    Monitor Closely (1)dofetilide will increase the level or effect of hydrochlorothiazide by basic (cationic) drug competition for renal tubular clearance. Use Caution/Monitor.Serious – Use Alternative (1)hydrochlorothiazide increases levels of dofetilide by decreasing renal clearance. Contraindicated. Risk of prolonged QTc interval.

  • hydroxychloroquine sulfate

    Serious – Use Alternative (2)hydroxychloroquine sulfate and dofetilide both increase QTc interval. Avoid or Use Alternate Drug.

    dofetilide increases toxicity of hydroxychloroquine sulfate by QTc interval. Avoid or Use Alternate Drug.

  • ibutilide

    Contraindicated (1)dofetilide and ibutilide both increase QTc interval. Contraindicated.

  • iloperidone

    Monitor Closely (1)dofetilide and iloperidone both increase QTc interval. Modify Therapy/Monitor Closely.

  • imipramine

    Serious – Use Alternative (1)imipramine and dofetilide both increase QTc interval. Avoid or Use Alternate Drug.

  • indacaterol, inhaled

    Monitor Closely (1)dofetilide increases toxicity of indacaterol, inhaled by QTc interval. Use Caution/Monitor.

  • indapamide

    Contraindicated (1)dofetilide and indapamide both increase QTc interval. Contraindicated.

  • indinavir

    Monitor Closely (1)indinavir increases levels of dofetilide by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Potential for increased toxicity. Use alternatives if available. Increased risk of QT prolongation and cardiac arrhythmias.

  • inotuzumab

    Serious – Use Alternative (2)inotuzumab and dofetilide both increase QTc interval. Avoid or Use Alternate Drug. If unable to avoid concomitant use, obtain ECGs and electrolytes before and after initiation of any drug known to prolong QTc, and periodically monitor as clinically indicated during treatment.

    dofetilide increases toxicity of inotuzumab by QTc interval. Avoid or Use Alternate Drug.

  • isavuconazonium sulfate

    Minor (1)isavuconazonium sulfate will increase the level or effect of dofetilide by Other (see comment). Minor/Significance Unknown. Isavuconazonium sulfate, an OCT2 inhibitor, may increase the effects or levels of OCT2 substrates.

  • isradipine

    Serious – Use Alternative (1)dofetilide increases toxicity of isradipine by QTc interval. Avoid or Use Alternate Drug.

  • itraconazole

    Contraindicated (2)dofetilide and itraconazole both increase QTc interval. Contraindicated.

    itraconazole will increase the level or effect of dofetilide by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated. Both drugs will increase QT interval

  • ivosidenib

    Serious – Use Alternative (1)ivosidenib and dofetilide both increase QTc interval. Avoid or Use Alternate Drug. Avoid coadministration of QTc prolonging drugs with ivosidenib or replace with alternate therapies. If coadministration of a QTc prolonging drug is unavoidable, monitor for increased risk of QTc interval prolongation.

  • ketoconazole

    Serious – Use Alternative (1)dofetilide and ketoconazole both increase QTc interval. Avoid or Use Alternate Drug.

  • lamotrigine

    Contraindicated (1)lamotrigine will increase the level or effect of dofetilide by Other (see comment). Contraindicated. Lamotrigine may significantly increase dofetilide serum concentrations by inhibiting OCT2

  • lapatinib

    Monitor Closely (1)dofetilide and lapatinib both increase QTc interval. Modify Therapy/Monitor Closely.

  • lefamulin

    Serious – Use Alternative (1)lefamulin and dofetilide both increase QTc interval. Avoid or Use Alternate Drug.

  • lenvatinib

    Monitor Closely (1)dofetilide and lenvatinib both increase QTc interval. Use Caution/Monitor. Lenvatinib prescribing information recommends monitoring ECG closely when coadministered with QT prolonging drugs.

  • letermovir

    Monitor Closely (1)letermovir increases levels of dofetilide by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

  • leuprolide

    Contraindicated (1)leuprolide increases toxicity of dofetilide by QTc interval. Contraindicated. Increases risk of torsades de pointes.

  • levofloxacin

    Monitor Closely (1)dofetilide and levofloxacin both increase QTc interval. Modify Therapy/Monitor Closely.

  • lidocaine

    Contraindicated (1)lidocaine increases effects of dofetilide by pharmacodynamic synergism. Contraindicated. Additive cardiac effects.

  • lofepramine

    Serious – Use Alternative (1)lofepramine and dofetilide both increase QTc interval. Avoid or Use Alternate Drug.

  • lofexidine

    Monitor Closely (1)dofetilide and lofexidine both increase QTc interval. Use Caution/Monitor. ECG monitoring is recommended.

  • lopinavir

    Monitor Closely (1)lopinavir increases levels of dofetilide by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Potential for increased toxicity. Use alternatives if available. Increased risk of QT prolongation and cardiac arrhythmias.Serious – Use Alternative (1)dofetilide increases toxicity of lopinavir by QTc interval. Avoid or Use Alternate Drug.

  • lumefantrine

    Serious – Use Alternative (1)dofetilide and lumefantrine both increase QTc interval. Avoid or Use Alternate Drug.

  • macimorelin

    Serious – Use Alternative (1)macimorelin and dofetilide both increase QTc interval. Avoid or Use Alternate Drug. Macimorelin causes an increase of ~11 msec in the corrected QT interval. Avoid coadministration with drugs that prolong QT interval, which could increase risk for developing torsade de pointes-type ventricular tachycardia. Allow sufficient washout time of drugs that are known to prolong the QT interval before administering macimorelin.

  • maprotiline

    Serious – Use Alternative (2)maprotiline and dofetilide both increase QTc interval. Avoid or Use Alternate Drug.

    dofetilide increases toxicity of maprotiline by QTc interval. Avoid or Use Alternate Drug.

  • mefloquine

    Serious – Use Alternative (2)mefloquine increases toxicity of dofetilide by QTc interval. Avoid or Use Alternate Drug. Mefloquine may enhance the QTc prolonging effect of high risk QTc prolonging agents.

    dofetilide increases toxicity of mefloquine by QTc interval. Avoid or Use Alternate Drug.

  • memantine

    Monitor Closely (1)dofetilide will increase the level or effect of memantine by basic (cationic) drug competition for renal tubular clearance. Use Caution/Monitor.

  • metformin

    Monitor Closely (1)dofetilide will increase the level or effect of metformin by basic (cationic) drug competition for renal tubular clearance. Use Caution/Monitor.

  • methadone

    Monitor Closely (1)dofetilide and methadone both increase QTc interval. Modify Therapy/Monitor Closely.

  • methyclothiazide

    Monitor Closely (1)dofetilide will increase the level or effect of methyclothiazide by basic (cationic) drug competition for renal tubular clearance. Use Caution/Monitor.Serious – Use Alternative (1)methyclothiazide increases levels of dofetilide by decreasing renal clearance. Contraindicated. Risk of prolonged QTc interval.

  • mexiletine

    Contraindicated (1)mexiletine, dofetilide.
    Either increases effects of the other by pharmacodynamic synergism. Contraindicated. Additive cardiac effects.

  • midodrine

    Monitor Closely (1)dofetilide will increase the level or effect of midodrine by basic (cationic) drug competition for renal tubular clearance. Use Caution/Monitor.

  • mifepristone

    Monitor Closely (1)mifepristone, dofetilide. QTc interval. Modify Therapy/Monitor Closely. Use alternatives if available.Serious – Use Alternative (1)dofetilide increases toxicity of mifepristone by QTc interval. Avoid or Use Alternate Drug.

  • mobocertinib

    Serious – Use Alternative (1)mobocertinib and dofetilide both increase QTc interval. Avoid or Use Alternate Drug. If coadministration unavoidable, reduce mobocertinib dose and monitor QTc interval more frequently.

  • moxifloxacin

    Serious – Use Alternative (1)dofetilide and moxifloxacin both increase QTc interval. Avoid or Use Alternate Drug.

  • nelfinavir

    Monitor Closely (1)nelfinavir increases levels of dofetilide by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Potential for increased toxicity. Use alternatives if available. Increased risk of QT prolongation and cardiac arrhythmias.

  • nilotinib

    Serious – Use Alternative (1)dofetilide and nilotinib both increase QTc interval. Avoid or Use Alternate Drug.

  • nizatidine

    Monitor Closely (1)nizatidine will increase the level or effect of dofetilide by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely.

  • nortriptyline

    Serious – Use Alternative (2)nortriptyline and dofetilide both increase QTc interval. Avoid or Use Alternate Drug.

    dofetilide increases toxicity of nortriptyline by QTc interval. Avoid or Use Alternate Drug.

  • octreotide

    Serious – Use Alternative (1)dofetilide and octreotide both increase QTc interval. Avoid or Use Alternate Drug.

  • octreotide (Antidote)

    Serious – Use Alternative (1)dofetilide and octreotide (Antidote) both increase QTc interval. Avoid or Use Alternate Drug.

  • ofloxacin

    Monitor Closely (2)dofetilide will increase the level or effect of ofloxacin by basic (cationic) drug competition for renal tubular clearance. Use Caution/Monitor.

    dofetilide and ofloxacin both increase QTc interval. Modify Therapy/Monitor Closely.

  • olanzapine

    Monitor Closely (1)dofetilide increases toxicity of olanzapine by QTc interval. Use Caution/Monitor. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval in rare instances.

  • olodaterol inhaled

    Monitor Closely (1)dofetilide and olodaterol inhaled both increase QTc interval. Use Caution/Monitor. Drugs that prolong the QTc interval and may potentiate the effects of beta2 agonists on the cardiovascular system; increased risk of ventricular arrhythmias

  • ondansetron

    Serious – Use Alternative (1)dofetilide and ondansetron both increase QTc interval. Avoid or Use Alternate Drug. Avoid with congenital long QT syndrome; ECG monitoring recommended with concomitant medications that prolong QT interval, electrolyte abnormalities, CHF, or bradyarrhythmias.

  • osilodrostat

    Monitor Closely (1)osilodrostat and dofetilide both increase QTc interval. Use Caution/Monitor.Serious – Use Alternative (1)dofetilide and osilodrostat both increase QTc interval. Avoid or Use Alternate Drug. Dose dependent QT prolongation – avoid drugs known to prolong the QT interval

  • osimertinib

    Monitor Closely (1)osimertinib and dofetilide both increase QTc interval. Use Caution/Monitor. Conduct periodic monitoring with ECGs and electrolytes in patients taking drugs known to prolong the QTc interval.Serious – Use Alternative (1)dofetilide increases toxicity of osimertinib by QTc interval. Avoid or Use Alternate Drug.

  • oxaliplatin

    Serious – Use Alternative (1)oxaliplatin will increase the level or effect of dofetilide by Other (see comment). Avoid or Use Alternate Drug. Monitor for ECG changes if therapy is initiated in patients with drugs known to prolong QT interval.

  • ozanimod

    Monitor Closely (1)ozanimod and dofetilide both increase QTc interval. Modify Therapy/Monitor Closely. The potential additive effects on heart rate, treatment with ozanimod should generally not be initiated in patients who are concurrently treated with QT prolonging drugs with known arrhythmogenic properties.

  • paliperidone

    Monitor Closely (1)dofetilide and paliperidone both increase QTc interval. Modify Therapy/Monitor Closely.

  • panobinostat

    Serious – Use Alternative (1)dofetilide and panobinostat both increase QTc interval. Avoid or Use Alternate Drug. Panobinostat is known to significantly prolong QT interval. Panobinostat prescribing information states use with drugs known to prolong QTc is not recommended.

  • paroxetine

    Monitor Closely (1)dofetilide and paroxetine both increase QTc interval. Modify Therapy/Monitor Closely.

  • pasireotide

    Monitor Closely (1)dofetilide and pasireotide both increase QTc interval. Modify Therapy/Monitor Closely.

  • pazopanib

    Monitor Closely (1)dofetilide and pazopanib both increase QTc interval. Use Caution/Monitor.

  • pentamidine

    Contraindicated (1)dofetilide and pentamidine both increase QTc interval. Contraindicated.

  • perphenazine

    Monitor Closely (1)dofetilide increases toxicity of perphenazine by QTc interval. Use Caution/Monitor.Serious – Use Alternative (1)perphenazine and dofetilide both increase QTc interval. Avoid or Use Alternate Drug.

  • phenytoin

    Contraindicated (1)phenytoin, dofetilide.
    Either increases effects of the other by pharmacodynamic synergism. Contraindicated. Additive cardiac effects.

  • pimavanserin

    Serious – Use Alternative (1)dofetilide and pimavanserin both increase QTc interval. Avoid or Use Alternate Drug. Coadministration may increase the risk of QT prolongation and cardiac arrhythmia.

  • pimozide

    Contraindicated (1)dofetilide and pimozide both increase QTc interval. Contraindicated.

  • pitolisant

    Serious – Use Alternative (1)dofetilide and pitolisant both increase QTc interval. Avoid or Use Alternate Drug.

  • ponesimod

    Monitor Closely (1)ponesimod, dofetilide.
    Either increases effects of the other by QTc interval. Use Caution/Monitor. Consult cardiologist if considering treatment. Class III (eg, amiodarone, dofetilide, sotalol) anti-arrhythmic drugs have been associated with cases of torsades de pointes in patients with bradycardia.

  • posaconazole

    Monitor Closely (1)dofetilide and posaconazole both increase QTc interval. Modify Therapy/Monitor Closely.

  • procainamide

    Contraindicated (2)dofetilide and procainamide both increase QTc interval. Contraindicated.

    procainamide, dofetilide.
    Either increases effects of the other by pharmacodynamic synergism. Contraindicated. Additive cardiac effects.Serious – Use Alternative (1)dofetilide will increase the level or effect of procainamide by basic (cationic) drug competition for renal tubular clearance. Avoid or Use Alternate Drug.

  • prochlorperazine

    Serious – Use Alternative (1)prochlorperazine and dofetilide both increase QTc interval. Avoid or Use Alternate Drug.

  • promazine

    Serious – Use Alternative (1)promazine and dofetilide both increase QTc interval. Avoid or Use Alternate Drug.

  • promethazine

    Serious – Use Alternative (1)promethazine and dofetilide both increase QTc interval. Avoid or Use Alternate Drug.

  • propafenone

    Contraindicated (1)propafenone, dofetilide.
    Either increases effects of the other by pharmacodynamic synergism. Contraindicated. Additive cardiac effects.Monitor Closely (1)dofetilide increases toxicity of propafenone by QTc interval. Use Caution/Monitor.

  • protriptyline

    Monitor Closely (1)dofetilide increases toxicity of protriptyline by QTc interval. Use Caution/Monitor.Serious – Use Alternative (1)protriptyline and dofetilide both increase QTc interval. Avoid or Use Alternate Drug.

  • quetiapine

    Monitor Closely (2)quetiapine, dofetilide.
    Either increases toxicity of the other by QTc interval. Use Caution/Monitor. Avoid use with drugs that prolong QT and in patients with risk factors for prolonged QT interval. Postmarketing cases show QT prolongation with overdose in patients with concomitant illness or with drugs known to cause electrolyte imbalance or prolong QT.

    dofetilide increases toxicity of quetiapine by QTc interval. Use Caution/Monitor.

  • quinidine

    Contraindicated (2)quinidine and dofetilide both increase QTc interval. Contraindicated.

    quinidine, dofetilide.
    Either increases effects of the other by pharmacodynamic synergism. Contraindicated. Additive cardiac effects.Serious – Use Alternative (2)dofetilide increases toxicity of quinidine by QTc interval. Avoid or Use Alternate Drug.

    quinidine will increase the level or effect of dofetilide by basic (cationic) drug competition for renal tubular clearance. Avoid or Use Alternate Drug.

  • quinine

    Monitor Closely (2)dofetilide will increase the level or effect of quinine by basic (cationic) drug competition for renal tubular clearance. Use Caution/Monitor.

    dofetilide and quinine both increase QTc interval. Use Caution/Monitor.

  • ranolazine

    Monitor Closely (1)dofetilide and ranolazine both increase QTc interval. Modify Therapy/Monitor Closely.

  • ribociclib

    Serious – Use Alternative (2)ribociclib and dofetilide both increase QTc interval. Avoid or Use Alternate Drug.

    dofetilide increases toxicity of ribociclib by QTc interval. Avoid or Use Alternate Drug.

  • rilpivirine

    Monitor Closely (1)rilpivirine increases toxicity of dofetilide by QTc interval. Use Caution/Monitor. Rilpivirine should be used with caution when co-administered with a drug with a known risk of Torsades de Pointes.Serious – Use Alternative (1)dofetilide increases toxicity of rilpivirine by QTc interval. Avoid or Use Alternate Drug.

  • risperidone

    Monitor Closely (1)dofetilide and risperidone both increase QTc interval. Modify Therapy/Monitor Closely.

  • ritonavir

    Monitor Closely (1)ritonavir increases levels of dofetilide by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Potential for increased toxicity. Use alternatives if available. Increased risk of QT prolongation and cardiac arrhythmias.

  • romidepsin

    Serious – Use Alternative (1)dofetilide and romidepsin both increase QTc interval. Avoid or Use Alternate Drug.

  • saquinavir

    Contraindicated (1)dofetilide increases toxicity of saquinavir by QTc interval. Contraindicated.

  • selpercatinib

    Monitor Closely (1)selpercatinib increases toxicity of dofetilide by QTc interval. Use Caution/Monitor.

  • sertraline

    Serious – Use Alternative (1)dofetilide increases toxicity of sertraline by QTc interval. Avoid or Use Alternate Drug.

  • siponimod

    Serious – Use Alternative (1)siponimod, dofetilide.
    Either increases effects of the other by QTc interval. Avoid or Use Alternate Drug. Because of the potential additive effects on heart rate, siponimod should generally not be initiated in patients taking QT prolonging drugs with known arrhythmogenic properties, heart rate lowering calcium channel blockers, or other drugs that may decrease heart rate. If treatment considered, obtain cardiology consult regarding switching to non-heart-rate lowering drugs or appropriate monitoring for treatment initiation.

  • sodium sulfate/?magnesium sulfate/potassium chloride

    Monitor Closely (1)sodium sulfate/?magnesium sulfate/potassium chloride increases toxicity of dofetilide by QTc interval. Use Caution/Monitor. Consider predose and post-colonoscopy ECGs in patients at increased risk of serious cardiac arrhythmias. .

  • sodium sulfate/potassium sulfate/magnesium sulfate

    Monitor Closely (1)sodium sulfate/potassium sulfate/magnesium sulfate increases toxicity of dofetilide by QTc interval. Use Caution/Monitor. Consider predose and post-colonoscopy ECGs in patients at increased risk of serious cardiac arrhythmias. .

  • solifenacin

    Serious – Use Alternative (1)dofetilide increases toxicity of solifenacin by QTc interval. Avoid or Use Alternate Drug.

  • sorafenib

    Monitor Closely (1)sorafenib and dofetilide both increase QTc interval. Use Caution/Monitor.Serious – Use Alternative (1)dofetilide increases toxicity of sorafenib by QTc interval. Avoid or Use Alternate Drug.

  • sotalol

    Contraindicated (2)dofetilide and sotalol both increase QTc interval. Contraindicated.

    sotalol, dofetilide.
    Either increases effects of the other by pharmacodynamic synergism. Contraindicated. Additive cardiac effects.

  • sulfamethoxazole

    Monitor Closely (2)sulfamethoxazole will increase the level or effect of dofetilide by basic (cationic) drug competition for renal tubular clearance. Use Caution/Monitor.

    sulfamethoxazole and dofetilide both increase QTc interval. Modify Therapy/Monitor Closely.

  • sunitinib

    Serious – Use Alternative (1)dofetilide increases toxicity of sunitinib by QTc interval. Avoid or Use Alternate Drug.

  • tacrolimus

    Monitor Closely (1)dofetilide increases toxicity of tacrolimus by QTc interval. Use Caution/Monitor.

  • tafenoquine

    Serious – Use Alternative (1)tafenoquine will increase the level or effect of dofetilide by Other (see comment). Avoid or Use Alternate Drug. Tafenoquine inhibits organic cation transporter-2 (OCT2) and multidrug and toxin extrusion (MATE) transporters in vitro. Avoid coadministration with OCT2 or MATE substrates. If coadministration cannot be avoided, monitor for substrate-related toxicities and consider dosage reduction if needed based on product labeling of the coadministered drug.

  • telavancin

    Monitor Closely (1)dofetilide and telavancin both increase QTc interval. Modify Therapy/Monitor Closely.

  • tenofovir DF

    Monitor Closely (1)tenofovir DF increases levels of dofetilide by decreasing renal clearance. Use Caution/Monitor. Potential for increased toxicity. .

  • tetrabenazine

    Serious – Use Alternative (1)dofetilide increases toxicity of tetrabenazine by QTc interval. Avoid or Use Alternate Drug.

  • thioridazine

    Contraindicated (1)dofetilide increases toxicity of thioridazine by QTc interval. Contraindicated.Serious – Use Alternative (1)thioridazine and dofetilide both increase QTc interval. Avoid or Use Alternate Drug.

  • toremifene

    Serious – Use Alternative (1)dofetilide and toremifene both increase QTc interval. Avoid or Use Alternate Drug. Concurrent use of toremifene with agents causing QT prolongation should be avoided. If concomitant use is required it’s recommended that toremifene be interrupted. If interruption not possible, patients requiring therapy with a drug that prolongs QT should be closely monitored. ECGs should be obtained for high risk patients.

  • trazodone

    Serious – Use Alternative (1)trazodone and dofetilide both increase QTc interval. Avoid or Use Alternate Drug.

  • triamterene

    Monitor Closely (1)dofetilide will increase the level or effect of triamterene by basic (cationic) drug competition for renal tubular clearance. Use Caution/Monitor.

  • triclabendazole

    Monitor Closely (1)triclabendazole and dofetilide both increase QTc interval. Use Caution/Monitor.

  • trifluoperazine

    Serious – Use Alternative (1)trifluoperazine and dofetilide both increase QTc interval. Avoid or Use Alternate Drug.

  • trilaciclib

    Serious – Use Alternative (1)trilaciclib will decrease the level or effect of dofetilide by Other (see comment). Avoid or Use Alternate Drug. Avoid coadministration of trilaciclib (OCT2, MATE1, and MATE-2K inhibitor) with dofetilide. Consider potential benefits of trilaciclib against risk of QT interval prolongation with increased dofetilide blood levels.

  • trimethoprim

    Monitor Closely (2)dofetilide will increase the level or effect of trimethoprim by basic (cationic) drug competition for renal tubular clearance. Use Caution/Monitor.

    dofetilide and trimethoprim both increase QTc interval. Modify Therapy/Monitor Closely.

  • trimipramine

    Monitor Closely (1)dofetilide increases toxicity of trimipramine by QTc interval. Use Caution/Monitor.Serious – Use Alternative (1)trimipramine and dofetilide both increase QTc interval. Avoid or Use Alternate Drug.

  • triptorelin

    Contraindicated (1)triptorelin increases toxicity of dofetilide by QTc interval. Contraindicated. Increases risk of torsades de pointes.

  • tropisetron

    Monitor Closely (1)dofetilide and tropisetron both increase QTc interval. Modify Therapy/Monitor Closely.

  • umeclidinium bromide/vilanterol inhaled

    Serious – Use Alternative (1)dofetilide increases toxicity of umeclidinium bromide/vilanterol inhaled by QTc interval. Avoid or Use Alternate Drug. Exercise extreme caution when vilanterol coadministered with drugs that prolong QTc interval; adrenergic agonist effects on the cardiovascular system may be potentiated.

  • vandetanib

    Serious – Use Alternative (1)dofetilide, vandetanib.
    Either increases toxicity of the other by QTc interval. Avoid or Use Alternate Drug. Avoid coadministration with drugs known to prolong QT interval; if a drug known to prolong QT interval must be used, more frequent ECG monitoring is recommended.

  • vardenafil

    Monitor Closely (1)dofetilide increases toxicity of vardenafil by QTc interval. Use Caution/Monitor.

  • vemurafenib

    Monitor Closely (1)dofetilide increases toxicity of vemurafenib by QTc interval. Use Caution/Monitor.Serious – Use Alternative (1)vemurafenib and dofetilide both increase QTc interval. Avoid or Use Alternate Drug. Concomitant use of vemurafenib with drugs that prolong QT interval is not recommended.

  • venlafaxine

    Monitor Closely (1)dofetilide and venlafaxine both increase QTc interval. Modify Therapy/Monitor Closely.

  • verapamil

    Monitor Closely (1)dofetilide will increase the level or effect of verapamil by basic (cationic) drug competition for renal tubular clearance. Use Caution/Monitor.

  • vilanterol/fluticasone furoate inhaled

    Serious – Use Alternative (1)dofetilide increases toxicity of vilanterol/fluticasone furoate inhaled by QTc interval. Avoid or Use Alternate Drug. Exercise extreme caution when vilanterol coadministered with drugs that prolong QTc interval; adrenergic agonist effects on the cardiovascular system may be potentiated.

  • voclosporin

    Monitor Closely (1)voclosporin, dofetilide.
    Either increases effects of the other by QTc interval. Use Caution/Monitor.

  • voriconazole

    Monitor Closely (1)dofetilide and voriconazole both increase QTc interval. Modify Therapy/Monitor Closely.

  • vorinostat

    Serious – Use Alternative (1)dofetilide increases toxicity of vorinostat by QTc interval. Avoid or Use Alternate Drug.

  • ziprasidone

    Serious – Use Alternative (1)dofetilide and ziprasidone both increase QTc interval. Avoid or Use Alternate Drug.

  • Dofetilide – an overview | ScienceDirect Topics

    5.3.2 Dofetilide

    Dofetilide is perhaps the most selective AAD available, showing high affinity for hERG, the channel underlying IKr, without significantly inhibiting other major cardiac ion channels (Obejero-Paz et al., 2015; Sutanto et al., 2019). Nonetheless, experimental work has suggested that chronic dofetilide application may increase INa,late via a phosphoinositide 3-kinase-mediated pathway, contributing to its APD prolonging effects, but potentially also increasing its proarrhythmic potential (Yang et al., 2014).

    Dofetilide is well absorbed in its oral form, with a bioavailability of > 90%. Peak plasma concentrations occur 2–3 h after oral dosing when fasting (Wolbrette et al., 2019). Dofetilide is 60–70% protein bound. Dofetilide is primarily renally cleared with 80% being eliminated unchanged and 20% being metabolized by CYP3A4 (Lenz and Hilleman, 2000). The elimination half-life of dofetilide is roughly 10 h with normal creatinine clearance (Wolbrette et al., 2019). Due to the significant level of renal elimination dose adjustments are needed in the presence of impaired renal function (Lenz and Hilleman, 2000). A steady-state plasma level of dofetilide is achieved in 2–3 days.

    Dofetilide was approved in the United States in 2000 for the acute cardioversion of AF and for long-term rhythm control (Lenz and Hilleman, 2000; Wolbrette et al., 2019), although it is more effective for the maintenance of sinus rhythm than it is for restoring sinus rhythm (Singh et al., 2000). Dofetilide has been demonstrated to be reasonably safe in post-myocardial infarction patients and is one of the few AADs available in patients with reduced LVEF (Zimetbaum, 2012). It is the third most prescribed AAD in patients with AF in the “Get With the Guidelines—AF” registry, accounting for almost 20% of prescriptions (Field et al., 2021).

    Drug-induced proarrhythmia due to excessive repolarization prolongation, particularly at slow rates or under conditions favoring abnormal repolarization (e.g., hypokalemia), represents the most serious adverse effect of dofetilide (Lenz and Hilleman, 2000; Zimetbaum, 2012; Wolbrette et al., 2019). As such, treatment initiation should be performed under ECG monitoring and is contraindicated in patients with congenitally prolonged repolarization (long-QT syndrome) or in patients taking other QT-prolonging drugs. Drug discontinuation rates are indeed considerable, with dofetilide being discontinued before hospital discharge in 27% of patients, primarily due to QT prolongation or proarrhythmia in a recent retrospective study in patients with AF and reduced LVEF (Koene et al., 2020). This rate was higher than that of other retrospective studies, with discontinuation in 12% of patients in a large real-world database with mostly preserved ejection fraction (Abraham et al., 2015).

    Hospital Admission for Antiarrhythmic Medication

    Why do I have to go to the hospital to receive this medication?

    Your first doses of antiarrhythmic drugs are given to you in the hospital so we can keep a close eye on your condition and response to the medicine. This helps your healthcare team know how much medication you need to take on a regular basis.

    How long will I be in the hospital?

    You will stay in the hospital about 3 to 4 days or until you have received a total of 6 doses of medication. If your medication needs to be adjusted after you receive your sixth dose, you may need to stay in the hospital an extra day for your safety.

    Preparing for your hospital admission

    • Your doctor will let you know which medication you will receive.
    • If you take warfarin (Coumadin), you will need to get weekly International Normalized Ratio (INR) tests from the healthcare provider who manages
      your INR. Your INR helps your healthcare provider know how fast your blood is clotting and if you need to make changes to your medication.
    • Once your INR levels are higher than 2.0 for 21 days AND these results are received by Cleveland Clinic, please contact your physician’s office to schedule your hospital admission.
    • If you take an anticoagulant other than warfarin, you must take the medication for at least 21 days without missing a dose before you are admitted to begin antiarrhythmic medication.
    • Cleveland Clinic will work with your insurance company to preauthorize your hospital stay.
    • Contact your pharmacy BEFORE you are admitted to the hospital to make sure your antiarrhythmic medication will be available after you leave the hospital. Some medications are not available through certain mail-order companies. If you have trouble finding a pharmacy that carries your medication, please contact a Cleveland Clinic pharmacy at 216.445.MEDS (6337). The pharmacies can fill prescriptions for 90-day supplies of medication and can mail the medication to your home upon request.

    What should I bring to the hospital?

    You can bring limited toiletries, a robe, slippers and anything else you feel would make your hospital stay more comfortable. Please keep in mind that closet space is limited. You can also bring reading materials, small puzzles, your cell phone, lap top computer, and other items to help you occupy your time. Please leave jewelry, credit cards, large amounts of cash and other valuables at home.

    Where should I go when I arrive?

    Please come to Desk J1-4 between 10 a.m. and noon. You will have lab work and an electrocardiogram (EKG).

    After these tests are completed, you will be directed to Admitting & Registration at Desk J1-1, where you will complete some paperwork.

    What happens when I arrive?

    Once you finish your registration at Desk J1-1, you will be assigned to a hospital bed. A nurse will help you get ready. We will check your vital signs and start an intravenous (IV) line in your arm. Then, the nursing staff will contact your healthcare provider.

    When will I receive the medication?

    You will receive the first dose of medication the first evening you are in the hospital. The medication is in pill form, and you will take a dose every 12 hours.

    What can I expect during my hospital stay?

    Electrocardiogram (EKG/ECG). You will have an EKG about 2 hours after you receive each dose of medication. Your healthcare team will review the information about your heartbeat and determine if you need another dose of medication.

    Blood tests. You will have your blood tested every day to see if you need any changes to your medication. These blood tests measure your:

    • Electrolyte levels (such as potassium and magnesium). Checking your electrolyte levels is important to help reduce your risk of developing another arrhythmia.
    • International Normalized Ratio (INR) if you take warfarin (Coumadin). Your INR levels let your healthcare provider know how fast your blood is clotting and whether you need changes to your medication.

    A telemetry monitor constantly checks your heart rhythm. The telemetry monitor only works when you are in the nursing unit. You are allowed to walk around the nursing unit and go to the family lounge. There is a public computer in every family lounge.

    Meals. You will choose your meals a day in advance. Fill out the menu that’s on your breakfast tray. Please let us know if you have any allergies or specific food preferences. If you take warfarin, please try to eat a diet similar to the one you eat at home to avoid changes in your INR level.

    Showering. You will be connected to a telemetry monitor while you are in the hospital and cannot shower. You will be able to wash up in the restroom.

    Cardioversion. You may need a cardioversion if your arrhythmia does not stop after taking the antiarrhythmic medication. Cardioversion is a treatment that sends an electric “shock” to your heart to restore a normal heartbeat. If you need a cardioversion, your healthcare team will give you more detailed information about the procedure.

    When will I be able to go home?

    Your discharge time depends on when your last EKG is reviewed and when your medication (that you will take after you go home) is ready. You can plan on being in the hospital until at least noon.

    You can drive yourself home unless you had a cardioversion the day you leave the hospital. If you have a cardioversion, a responsible adult must drive you home.

    Filling your prescription after discharge

    Please remember to check with your pharmacy before you come to the hospital to make sure it can supply the medication you need. If you are prescribed dofetilide (Tikosyn), we will give you a one-week supply before you leave the hospital. Please let your nurse know if you have any questions or concerns about filling your prescription.

    Traveling to Cleveland Clinic: For help with travel arrangements, out-of-state patients may call the Medical Concierge at 800.223.2273 ext. 55580. For reservations at any of the three hotels located on the Cleveland Clinic campus, please call 877.707.8999.

    This information is not intended to replace the medical advice of your doctor or healthcare provider. Please consult your healthcare provider for advice about a specific medical condition.

    Risks and Side Effects | TIVICAY Official HCP Website

    3TC=lamivudine; ABC=abacavir; ADR=adverse drug reaction; AE=adverse event; BIC=bictegravir; BR=background regimen; DTG=dolutegravir; FTC=emtricitabine; INSTI=integrase strand transfer inhibitor; PI=prescribing information; r=ritonavir; RAL=raltegravir; TAF=tenofovir alafenamide; TDF=tenofovir disoproxil fumarate.

    References1. Walmsley S, Baumgarten A, Berenguer J, et al. Dolutegravir plus abacavir/lamivudine for the treatment of HIV-1 infection in antiretroviral therapy-naive patients: week 96 and week 144 results from the SINGLE randomized clinical trial. J Acquir Immune Defic Syndr. 2015;70(5):515-519. 2. Data on file, ViiV Healthcare. 3. Raffi F, Jaeger H, Quiros-Roldan E, et al; on behalf of the SPRING-2 Study Group. Once-daily dolutegravir versus twice-daily raltegravir in antiretroviral-naive adults with HIV-1 infection (SPRING-2 study): 96 week results from a randomised, double-blind, non-inferiority trial. Lancet Infect Dis. 2013;13(11):927-935. 4. Molina J-M, Clotet B, van Lunzen J, et al. Once-daily dolutegravir versus darunavir plus ritonavir for treatment-naive adults with HIV-1 infection (FLAMINGO): 96 week results from a randomized, open-label, phase 3b study. Lancet HIV. 2015;2(4):e127-e136. 5. Stellbrink H-J, Arribas JR, Stephens JL, et al. Co-formulated bictegravir, emtricitabine, and tenofovir alafenamide versus dolutegravir with emtricitabine and tenofovir alafenamide for initial treatment of HIV-1 infection: week 96 results from a randomised, double-blind, multicentre, phase 3, non-inferiority trial. Lancet HIV. 2019;6(6):e364-e372. 6. BIKTARVY [package insert]. Foster City, CA: Gilead Sciences, Inc; 2018. 7. Cahn P, Pozniak AL, Mingrone H, et al; on behalf of the extended SAILING Study Team. Dolutegravir versus raltegravir in antiretroviral-experienced, integrase-inhibitor-naive adults with HIV: week 48 results from the randomised, double-blind, non-inferiority SAILING study. Lancet. 2013;382(9893):700-708.

    Dofetilide – wikidoc

    {{DrugProjectFormSinglePage
    |authorTag=Sheng Shi, M.D. [1]
    |genericName=Dofetilide
    |aOrAn=an
    |drugClass=antiarrhythmic
    |indicationType=treatment
    |indication=maintenance of normal sinus rhythm and conversion of atrial fibrillation/flutter
    |hasBlackBoxWarning=Yes
    |adverseReactions=chest pain, dizziness and headache
    |blackBoxWarningTitle=WARNING
    |blackBoxWarningBody=* To minimize the risk of induced arrhythmia, patients initiated or re-initiated on Tikosyn should be placed for a minimum of 3 days in a facility that can provide calculations of creatinine clearance, continuous electrocardiographic monitoring, and cardiac resuscitation. Tikosyn is available only to hospitals and prescribers who have received appropriate Tikosyn dosing and treatment initiation education;

    |fdaLIADAdult=

    Maintenance of Normal Sinus Rhythm and Conversion of Atrial Fibrillation/Artrial Flutter
    • Usual recommended dosage: 500 mg PO bidas modified by the dosing algorithm described below.
    • Therapy with Tikosyn must be initiated (and, if necessary, re-initiated) in a setting that provides continuous electrocardiographic (ECG) monitoring and in the presence of personnel trained in the management of serious ventricular arrhythmias. Patients should continue to be monitored in this way for a minimum of three days. Additionally, patients should not be discharged within 12 hours of electrical or pharmacological conversion to normal sinus rhythm.
    • The dose of Tikosyn must be individualized according to calculated creatinine clearance and QTc. (QT interval should be used if the heart rate is <60 beats per minute. There are no data on use of Tikosyn when the heart rate is <50 beats per minute.)
    • Serum potassium should be maintained within the normal range before Tikosyn treatment is initiated and should be maintained within the normal range while the patient remains on Tikosyn therapy.Hypokalemia and Potassium-Depleting Diuretics). In clinical trials, potassium levels were generally maintained above 3.6–4.0 mEq/L.
    • Patients with atrial fibrillation should be anticoagulated according to usual medical practice prior to electrical or pharmacological cardioversion. Anticoagulant therapy may be continued after cardioversion according to usual medical practice for the treatment of people with AF. Hypokalemia should be corrected before initiation of Tikosyn therapy.
    • Patients to be discharged on Tikosyn therapy from an inpatient setting as described above must have an adequate supply of Tikosyn , at the patient’s individualized dose, to allow uninterrupted dosing until the patient receives the first outpatient supply.
    • Tikosyn is distributed only to those hospitals and other appropriate institutions confirmed to have received applicable dosing and treatment initiation education programs. Inpatient and subsequent outpatient discharge and refill prescriptions are filled only upon confirmation that the prescribing physician has received applicable dosing and treatment initiation education programs. For this purpose, a list for use by pharmacists is maintained containing hospitals and physicians who have received one of the education programs.

    Instructions for Individualized Dose Initiation

    Initiation of Tikosyn Therapy
    • Step 1. Electrocardiographic assessment: Prior to administration of the first dose, the QTc must be determined using an average of 5–10 beats. If the QTc is greater than 440 msec (500 msec in patients with ventricular conduction abnormalities), Tikosyn is contraindicated. If heart rate is less than 60 beats per minute, QT interval should be used. Patients with heart rates <50 beats per minute have not been studied.
    • Step 2. Calculation of creatinine clearance: Prior to the administration of the first dose, the patient’s creatinine clearance must be calculated using the following formula:

    This image is provided by the National Library of Medicine.

    • When serum creatinine is given in µmol/L, divide the value by 88.4 (1 mg/dL = 88.4 µmol/L).
    • Step 3. Starting Dose: The starting dose of Tikosyn is determined as follows:

    This image is provided by the National Library of Medicine.

    • Step 4. Administer the adjusted Tikosyn dose and begin continuous ECG monitoring.
    • Step 5. At 2–3 hours after administering the first dose of Tikosyn , determine the QTc. If the QTc has increased by greater than 15% compared to the baseline established in Step 1 OR if the QTc is greater than 500 msec (550 msec in patients with ventricular conduction abnormalities), subsequent dosing should be adjusted as follows:

    This image is provided by the National Library of Medicine.

    • Step 6. At 2–3 hours after each subsequent dose of Tikosyn , determine the QTc (for in-hospital doses 2–5). No further down titration of Tikosyn based on QTc is recommended.
    • NOTE: If at any time after the second dose of Tikosyn is given the QTc is greater than 500 msec (550 msec in patients with ventricular conduction abnormalities), Tikosyn should be discontinued.
    • Step 7. Patients are to be continuously monitored by ECG for a minimum of three days, or for a minimum of 12 hours after electrical or pharmacological conversion to normal sinus rhythm, whichever is greater.
    • The steps described above are summarized in the following diagram:

    This image is provided by the National Library of Medicine.

    Maintenance of Tikosyn Therapy
    • Renal function and QTc should be re-evaluated every three months or as medically warranted. If QTc exceeds 500 milliseconds (550 msec in patients with ventricular conduction abnormalities), Tikosyn therapy should be discontinued and patients should be carefully monitored until QTc returns to baseline levels. If renal function deteriorates, adjust dose as described in Initiation of Tikosyn Therapy, Step 3.

    Special Considerations

    • Consideration of a Dose Lower than that Determined by the Algorithm
    • The dosing algorithm shown above should be used to determine the individualized dose of Tikosyn . In clinical trials, the highest dose of 500 mcg BID of Tikosyn as modified by the dosing algorithm led to greater effectiveness than lower doses of 125 or 250 mcg BID as modified by the dosing algorithm. The risk of Torsade de Pointes, however, is related to dose as well as to patient characteristics. Physicians, in consultation with their patients, may therefore in some cases choose doses lower than determined by the algorithm. It is critically important that if at any time this lower dose is increased, the patient needs to be rehospitalized for three days. Previous toleration of higher doses does not eliminate the need for rehospitalization.
    • The maximum recommended dose in patients with a calculated creatinine clearance greater than 60 mL/min is 500 mcg BID; doses greater than 500 mcg BID have been associated with an increased incidence of Torsade de Pointes.
    • A patient who misses a dose should NOT double the next dose. The next dose should be taken at the usual time.
    Cardioversion
    • If patients do not convert to normal sinus rhythm within 24 hours of initiation of Tikosyn therapy, electrical conversion should be considered. Patients continuing on Tikosyn after successful electrical cardioversion should continue to be monitored by electrocardiography for 12 hours post cardioversion, or a minimum of 3 days after initiation of Tikosyn therapy, whichever is greater.

    Switch to Tikosyn from Class I or other Class III Antiarrhythmic Therapy’

    • Before initiating Tikosyn therapy, previous antiarrhythmic therapy should be withdrawn under careful monitoring for a minimum of three (3) plasma half-lives. Because of the unpredictable pharmacokinetics of amiodarone, Tikosyn should not be initiated following amiodarone therapy until amiodarone plasma levels are below 0.3 mcg/mL or until amiodarone has been withdrawn for at least three months.

    Stopping Tikosyn Prior to Administration of Potentially Interacting Drugs

    • If Tikosyn needs to be discontinued to allow dosing of other potentially interacting drug(s), a washout period of at least two days should be followed before starting the other drug(s).

    |offLabelAdultGuideSupport=

    Congestive heart failure
    • Class of Recommendation: Not Applicable
    • Level of Evidence: Not Applicable
    • 500-1000 mg (adjust dose for renal function and QT-interval response during initiation phase)
    Coronary artery disease
    • Class of Recommendation: Not Applicable
    • Level of Evidence: Not Applicable
    • 500-1000 mg (adjust dose for renal function and QT-interval response during initiation phase)

    |offLabelAdultNoGuideSupport=

    Prophylaxis of Ventricular arrhythmia
    • 0.25-1 mg PO bid for 3-6 days

    |fdaLIADPed=* The safety and effectiveness of Tikosyn in children (<18 years old) has not been established.
    |offLabelPedGuideSupport=* There is limited information about Off-Label Guideline-Supported Use of Dofetilide in pediatric patients.
    |offLabelPedNoGuideSupport=* There is limited information about Off-Label Non–Guideline-Supported Use of Dofetilide in pediatric patients.
    |contraindications=* Tikosyn is contraindicated in patients with congenital or acquired long QT syndromes. Tikosyn should not be used in patients with a baseline QT interval or QTc >440 msec (500 msec in patients with ventricular conduction abnormalities). Tikosyn is also contraindicated in patients with severe renal impairment (calculated creatinine clearance <20 mL/min).

    • The concomitant use of hydrochlorothiazide (alone or in combinations such as with triamterene) with Tikosyn is contraindicated because this has been shown to significantly increase dofetilide plasma concentrations and QT interval prolongation.
    • Tikosyn is also contraindicated in patients with a known hypersensitivity to the drug.

    |warnings======Ventricular Arrhythmia=====

    • Tikosyn (dofetilide) can cause serious ventricular arrhythmias, primarily Torsade de Pointes (TdP) type ventricular tachycardia, a polymorphic ventricular tachycardia associated with QT interval prolongation. QT interval prolongation is directly related to dofetilide plasma concentration. Factors such as reduced creatinine clearance or certain dofetilide drug interactions will increase dofetilide plasma concentration. The risk of TdP can be reduced by controlling the plasma concentration through adjustment of the initial dofetilide dose according to creatinine clearance and by monitoring the ECG for excessive increases in the QT interval.
    • Treatment with dofetilide must therefore be started only in patients placed for a minimum of three days in a facility that can provide electrocardiographic monitoring and in the presence of personnel trained in the management of serious ventricular arrhythmias. Calculation of the creatinine clearance for all patients must precede administration of the first dose of dofetilide. For detailed instructions regarding dose selection.
    • The risk of dofetilide induced ventricular arrhythmia was assessed in three ways in clinical studies: 1) by description of the QT interval and its relation to the dose and plasma concentration of dofetilide; 2) by observing the frequency of TdP in Tikosyn -treated patients according to dose; 3) by observing the overall mortality rate in patients with atrial fibrillation and in patients with structural heart disease.
    Relation of QT Interval to Dose
    • The QT interval increases linearly with increasing Tikosyn dose.
    Frequency of Torsade de Pointes

    This image is provided by the National Library of Medicine.

    • As shown in Table 5, the rate of TdP was reduced when patients were dosed according to their renal function.

    This image is provided by the National Library of Medicine.

    • The majority of the episodes of TdP occurred within the first three days of Tikosyn therapy (10/11 events in the studies of patients with supraventricular arrhythmias; 19/25 and 4/7 events in DIAMOND CHF and DIAMOND MI, respectively; 2/4 events in the DIAMOND AF subpopulation).
    Mortality
    • In a pooled survival analysis of patients in the supraventricular arrhythmia population (low prevalence of structural heart disease), deaths occurred in 0.9% (12/1346) of patients receiving Tikosyn and 0.4% (3/677) in the placebo group. Adjusted for duration of therapy, primary diagnosis, age, gender, and prevalence of structural heart disease, the point estimate of the hazard ratio for the pooled studies (Tikosyn /placebo) was 1.1 (95% CI: 0.3, 4.3). The DIAMOND CHF and MI trials examined mortality in patients with structural heart disease (ejection fraction ≤35%). In these large, double-blind studies, deaths occurred in 36% (541/1511) of Tikosyn patients and 37% (560/1517) of placebo patients. In an analysis of 506 DIAMOND patients with atrial fibrillation/flutter at baseline, one year mortality on Tikosyn was 31% vs. 32% on placebo.
    • Because of the small number of events, an excess mortality due to Tikosyn cannot be ruled out with confidence in the pooled survival analysis of placebo-controlled trials in patients with supraventricular arrhythmias. However, it is reassuring that in two large placebo-controlled mortality studies in patients with significant heart disease (DIAMOND CHF/MI), there were no more deaths in Tikosyn -treated patients than in patients given placebo.
    Drug-Drug Interactions
    • Because there is a linear relationship between dofetilide plasma concentration and QTc, concomitant drugs that interfere with the metabolism or renal elimination of dofetilide may increase the risk of arrhythmia(Torsade de Pointes). Tikosyn is metabolized to a small degree by the CYP3A4 isoenzyme of the cytochrome P450 system and an inhibitor of this system could increase systemic dofetilide exposure. More important, dofetilide is eliminated by cationic renal secretion, and three inhibitors of this process have been shown to increase systemic dofetilide exposure. The magnitude of the effect on renal elimination by cimetidine, trimethoprim, and ketoconazole (all contraindicated concomitant uses with dofetilide) suggests that all renal cation transport inhibitors should be contraindicated.
    Hypokalemia and Potassium-Depleting Diuretics
    • Hypokalemia or hypomagnesemia may occur with administration of potassium-depleting diuretics, increasing the potential for Torsade de Pointes. Potassium levels should be within the normal range prior to administration of Tikosyn and maintained in the normal range during administration of Tikosyn.
    Use with Drugs that Prolong QT Interval and Antiarrhythmic Agents
    • The use of Tikosyn in conjunction with other drugs that prolong the QT interval has not been studied and is not recommended. Such drugs include phenothiazines, cisapride, bepridil, tricyclic antidepressants, certain oral macrolides, and certain fluoroquinolones. Class I or Class III antiarrhythmic agents should be withheld for at least three half-lives prior to dosing with Tikosyn . In clinical trials, Tikosyn was administered to patients previously treated with oral amiodarone only if serum amiodarone levels were below 0.3 mg/L or amiodarone had been withdrawn for at least three months.

    |clinicalTrials=* The Tikosyn clinical program involved approximately 8,600 patients in 130 clinical studies of normal volunteers and patients with supraventricular and ventricular arrhythmias. Tikosyn was administered to 5,194 patients, including two large, placebo-controlled mortality trials (DIAMOND CHF and DIAMOND MI) in which 1,511 patients received Tikosyn for up to three years.

    • In the following section, adverse reaction data for cardiac arrhythmias and non-cardiac adverse reactions are presented separately for patients included in the supraventricular arrhythmia development program and for patients included in the DIAMOND CHF and MI mortality trials , Safety in Patients with Structural Heart Disease, DIAMOND Studies, for a description of these trials).
    • In studies of patients with supraventricular arrhythmias, a total of 1,346 and 677 patients were exposed to Tikosyn and placebo for 551 and 207 patient years, respectively. A total of 8.7% of patients in the dofetilide groups were discontinued from clinical trials due to adverse events compared to 8.0% in the placebo groups. The most frequent reason for discontinuation (>1%) was ventricular tachycardia (2.0% on dofetilide vs. 1.3% on placebo). The most frequent adverse events were headache, chest pain, and dizziness

    .

    Serious Arrhythmias and Conduction Disturbances
    • Torsade de Pointes is the only arrhythmia that showed a dose-response relationship to Tikosyn treatment. It did not occur in placebo treated patients. The incidence of Torsade de Pointes in patients with supraventricular arrhythmias was 0.8% (11/1346). The incidence of Torsade de Pointes in patients who were dosed according to the recommended dosing regimen was 0.8% (4/525). Table 6 shows the frequency by randomized dose of serious arrhythmias and conduction disturbances reported as adverse events in patients with supraventricular arrhythmias.

    This image is provided by the National Library of Medicine.

    • In the DIAMOND trials, a total of 1,511 patients were exposed to Tikosyn for 1757 patient years. The incidence of Torsade de Pointes was 3.3% in CHF patients and 0.9% in patients with a recent MI.
    • Table 7 shows the incidence of serious arrhythmias and conduction disturbances reported as adverse events in the DIAMOND subpopulation that had AF at entry to these trials.

    This image is provided by the National Library of Medicine.

    Other Adverse Reactions
    • Table 8 presents other adverse events reported with a frequency of >2% on Tikosyn and reported numerically more frequently on Tikosyn than on placebo in the studies of patients with supraventricular arrhythmias.

    This image is provided by the National Library of Medicine.

    • Adverse events reported at a rate >2% but no more frequently on Tikosyn than on placebo were: angina pectoris, anxiety, arthralgia, asthenia, atrial fibrillation, complications (application, injection, incision, insertion, or device), hypertension, pain, palpitation, peripheral edema, supraventricular tachycardia, sweating, urinary tract infection, ventricular tachycardia.
    • The following adverse events have been reported with a frequency of ≤2% and numerically more frequently with Tikosyn than placebo in patients with supraventricular arrhythmias: angioedema, bradycardia, cerebral ischemia, cerebrovascular accident, edema, facial paralysis, flaccid paralysis, heart arrest, increased cough, liver damage, migraine, myocardial infarct, paralysis, paresthesia, sudden death, and syncope.
    • The incidences of clinically significant laboratory test abnormalities in patients with supraventricular arrhythmias were similar for patients on Tikosyn and those on placebo. No clinically relevant effects were noted in serum alkaline phosphatase, serum GGT, LDH, AST, ALT, total bilirubin, total protein, blood urea nitrogen, creatinine, serum electrolytes (calcium, chloride, glucose, magnesium, potassium, sodium), or creatine kinase. Similarly, no clinically relevant effects were observed in hematologic parameters.
    • In the DIAMOND population, adverse events other than those related to the post-infarction and heart failure patient population were generally similar to those seen in the supraventricular arrhythmia groups.

    |postmarketing=* FDA Package Insert for Dofetilide contains no information regarding Postmarketing Experience.
    |drugInteractions======Cimetidine=====

    • Concomitant use of cimetidine is contraindicated. cimetidine at 400 mg BID (the usual prescription dose) co-administered with Tikosyn (500 mcg BID) for 7 days has been shown to increase dofetilide plasma levels by 58%. cimetidine at doses of 100 mg BID (OTC dose) resulted in a 13% increase in dofetilide plasma levels (500 mcg single dose). No studies have been conducted at intermediate doses of cimetidine. If a patient requires Tikosyn and anti-ulcer therapy, it is suggested that omeprazole, ranitidine, or antacids (aluminum and magnesium hydroxides) be used as alternatives to cimetidine, as these agents have no effect on the pharmacokinetic profile of Tikosyn .
    Verapamil
    • Concomitant use of verapamil is contraindicated. Co-administration of Tikosyn with verapamil resulted in increases in dofetilide peak plasma levels of 42%, although overall exposure to dofetilide was not significantly increased. In an analysis of the supraventricular arrhythmia and DIAMOND patient populations, the concomitant administration of verapamil with dofetilide was associated with a higher occurrence of Torsade de Pointes.
    Ketoconazole
    • Concomitant use of ketoconazoleis contraindicated. ketoconazoleat 400 mg daily (the maximum approved prescription dose) co-administered with Tikosyn (500 mcg BID) for 7 days has been shown to increase dofetilide Cmax by 53% in males and 97% in females, and AUC by 41% in males and 69% in females.
    Trimethoprim Alone or in Combination with Sulfamethoxazole
    Hydrochlorothiazide (HCTZ) Alone or in Combination with Triamterene
    • Concomitant use of HCTZ alone or in combination with triamtereneis contraindicated. HCTZ 50 mg QD or HCTZ/triamterene50/100 mg QD was co-administered with Tikosyn (500 mcg BID) for 5 days (following 2 days of diuretic use at half dose). In patients receiving HCTZ alone, dofetilide AUC increased by 27% and Cmax by 21%. However, the pharmacodynamic effect increased by 197% (QTc increase over time) and by 95% (maximum QTc increase). In patients receiving HCTZ in combination with triamterene, dofetilide AUC increased by 30% and Cmax by 16%. However, the pharmacodynamic effect increased by 190% (QTc increase over time) and by 84% (maximum QTc increase). The pharmacodynamic effects can be explained by a combination of the increase in dofetilide exposure and the reductions in serum potassium. In the DIAMOND trials, 1252 patients were treated with Tikosyn and diuretics concomitantly, of whom 493 died compared to 508 deaths among the 1248 patients receiving placebo and diuretics. Of the 229 patients who had potassium depleting diuretics added to their concomitant medications in the DIAMOND trials, the patients on Tikosyn had a non-significantly reduced relative risk for death of 0.68 (95% CI: 0.376, 1.230).

    Potential Drug Interactions

    • Dofetilide is eliminated in the kidney by cationic secretion. Inhibitors of renal cationic secretion are contraindicated with Tikosyn . In addition, drugs that are actively secreted via this route (e.g., triamterene, metformin, and amiloride) should be co-administered with care as they might increase dofetilide levels.
    • Dofetilide is metabolized to a small extent by the CYP3A4 isoenzyme of the cytochromeP450 system. Inhibitors of the CYP3A4 isoenzyme could increase systemic dofetilide exposure. Inhibitors of this isoenzyme (e.g., macrolide antibiotics, azole antifungal agents, protease inhibitors, serotonin reuptake inhibitors, amiodarone, cannabinoids, diltiazem, grapefruit juice, nefazadone, norfloxacin, quinine, zafirlukast) should be cautiously co-administered with Tikosyn as they can potentially increase dofetilide levels. Dofetilide is not an inhibitor of CYP3A4 nor of other cytochromeP450 isoenzymes (e.g., CYP2C9, CYP2D6) and is not expected to increase levels of drugs metabolized by CYP3A4.

    Other Drug Interaction Information

    Digoxin
    • Studies in healthy volunteers have shown that Tikosyn does not affect the pharmacokinetics of digoxin. In patients, the concomitant administration of digoxin with dofetilide was associated with a higher occurrence of Torsade de Pointes. It is not clear whether this represents an interaction with Tikosyn or the presence of more severe structural heart disease in patients on digoxin; structural heart disease is a known risk factor for arrhythmia. No increase in mortality was observed in patients taking digoxin as concomitant medication.
    Other Drugs
    • In healthy volunteers, amlodipine, phenytoin, glyburide, ranitidine, omeprazole, hormone replacement therapy (a combination of conjugated estrogens and medroxyprogesterone), antacid (aluminum and magnesium hydroxides), and theophylline did not affect the pharmacokinetics of Tikosyn . In addition, studies in healthy volunteers have shown that Tikosyn does not affect the pharmacokinetics or pharmacodynamics of warfarin, or the pharmacokinetics of propranolol (40 mg twice daily), phenytoin, theophylline, or oral contraceptives.
    • Population pharmacokinetic analyses were conducted on plasma concentration data from 1445 patients in clinical trials to examine the effects of concomitant medications on clearance or volume of distribution of dofetilide. Concomitant medications were grouped as ACE inhibitors, oral anticoagulants, calcium channel blockers, beta blockers, cardiac glycosides, inducers of CYP3A4, substrates and inhibitors of CYP3A4, substrates and inhibitors of P-glycoprotein, nitrates, sulphonylureas, loop diuretics, potassium sparing diuretics, thiazide diuretics, substrates and inhibitors of tubular organic cation transport, and QTc-prolonging drugs. Differences in clearance between patients on these medications (at any occasion in the study) and those off medications varied between -16% and +3%. The mean clearances of dofetilide were 16% and 15% lower in patients on thiazide diuretics and inhibitors of tubular organic cation transport, respectively.

    |FDAPregCat=C
    |useInPregnancyFDA=* Dofetilide had no genotoxic effects, with or without metabolic activation, based on the bacterial mutation assay and tests of cytogenetic aberrations in vivo in mouse bone marrow and in vitro in human lymphocytes. Rats and mice treated with dofetilide in the diet for two years showed no evidence of an increased incidence of tumors compared to controls. The highest dofetilide dose administered for 24 months was 10 mg/kg/day to rats and 20 mg/kg/day to mice. Mean dofetilide AUCs(0–24hr) at these doses were about 26 and 10 times, respectively, the maximum likely human AUC.

    • There was no effect on mating or fertility when dofetilide was administered to male and female rats at doses as high as 1.0 mg/kg/day, a dose that would be expected to provide a mean dofetilide AUC(0–24hr) about 3 times the maximum likely human AUC. Increased incidences of testicular atrophy and epididymal oligospermia and a reduction in testicular weight were, however, observed in other studies in rats. Reduced testicular weight and increased incidence of testicular atrophy were also consistent findings in dogs and mice. The no effect doses for these findings in chronic administration studies in these 3 species (3, 0.1, and 6 mg/kg/day) were associated with mean dofetilide AUCs that were about 4, 1.3, and 3 times the maximum likely human AUC, respectively.

    |useInNursing=* There is no information on the presence of dofetilide in breast milk. Patients should be advised not to breast-feed an infant if they are taking Tikosyn .
    |useInPed=* The safety and effectiveness of Tikosyn in children (<18 years old) has not been established.
    |useInGeri=* Of the total number of patients in clinical studies of Tikosyn , 46% were 65 to 89 years old. No overall differences in safety, effect on QTc, or effectiveness were observed between elderly and younger patients. Because elderly patients are more likely to have decreased renal function with a reduced creatinine clearance, care must be taken in dose selection.
    |useInGender=* Female patients constituted 32% of the patients in the placebo-controlled trials of Tikosyn . As with other drugs that cause Torsade de Pointes, Tikosyn was associated with a greater risk of Torsade de Pointes in female patients than in male patients. During the Tikosyn clinical development program, the risk of Torsade de Pointes in females was approximately 3 times the risk in males. Unlike Torsade de Pointes, the incidence of other ventricular arrhythmias was similar in female patients receiving Tikosyn and patients receiving placebo. Although no study specifically investigated this risk, in post-hoc analyses, no increased mortality was observed in females on Tikosyn compared to females on placebo.
    |useInRenalImpair=* The overall systemic clearance of dofetilide is decreased and plasma concentration increased with decreasing creatinine clearance. The dose of Tikosyn must be adjusted based on creatinine clearance. Patients undergoing dialysis were not included in clinical studies, and appropriate dosing recommendations for these patients are unknown. There is no information about the effectiveness of hemodialysis in removing dofetilide from plasma.
    |useInHepaticImpair=* After adjustment for creatinine clearance, no additional dose adjustment is required for patients with mild or moderate hepatic impairment. Patients with severe hepatic impairment have not been studied. Tikosyn should be used with particular caution in these patients.
    |othersTitle=Cardiac Conduction Disturbances
    |useInOthers=* Animal and human studies have not shown any adverse effects of dofetilide on conduction velocity. No effect on AV nodal conduction following Tikosyn treatment was noted in normal volunteers and in patients with 1st degree heart block. Patients with sick sinus syndrome or with 2nd or 3rd degree heart block were not included in the Phase 3 clinical trials unless a functioning pacemaker was present. Tikosyn has been used safely in conjunction with pacemakers (53 patients in DIAMOND studies, 136 in trials in patients with ventricular and supraventricular arrhythmias).
    |administration=* Oral
    |monitoring=* The risk of TdP can be reduced by controlling the plasma concentration through adjustment of the initial dofetilide dose according to creatinine clearance and by monitoring the ECG for excessive increases in the QT interval.

    • Treatment with dofetilide must therefore be started only in patients placed for a minimum of three days in a facility that can provide electrocardiographic monitoring and in the presence of personnel trained in the management of serious ventricular arrhythmias.
    • The patient should be fully instructed on the need for compliance with the recommended dosing of Tikosyn and the potential for drug interactions, and the need for periodic monitoring of QTc and renal function to minimize the risk of serious abnormal rhythms.
    • In cases of overdose, cardiac monitoring should be initiated. Close medical monitoring and supervision should continue until the QT interval returns to normal levels.
    • Therapy with Tikosyn must be initiated (and, if necessary, re-initiated) in a setting that provides continuous electrocardiographic (ECG) monitoring and in the presence of personnel trained in the management of serious ventricular arrhythmias. Patients should continue to be monitored in this way for a minimum of three days.
    • If QTc exceeds 500 milliseconds (550 msec in patients with ventricular conduction abnormalities), Tikosyn therapy should be discontinued and patients should be carefully monitored until QTc returns to baseline levels.
    • Patients continuing on Tikosyn after successful electrical cardioversion should continue to be monitored by electrocardiography for 12 hours post cardioversion, or a minimum of 3 days after initiation of Tikosyn therapy, whichever is greater
    • Before initiating Tikosyn therapy, previous antiarrhythmic therapy should be withdrawn under careful monitoring for a minimum of three (3) plasma half-lives

    |IVCompat=* FDA Package Insert for Dofetilide contains no information regarding IV Compatibility.
    |overdose=* There is no known antidote to Tikosyn ; treatment of overdose should therefore be symptomatic and supportive. The most prominent manifestation of overdosage is likely to be excessive prolongation of the QT interval.

    • In cases of overdose, cardiac monitoring should be initiated. Charcoal slurry may be given soon after overdosing but has been useful only when given within 15 minutes of Tikosyn administration. Treatment of Torsade de Pointes or overdose may include administration of isoproterenol infusion, with or without cardiac pacing.
    • Administration of intravenous magnesium sulfate may be effective in the management of Torsade de Pointes. Close medical monitoring and supervision should continue until the QT interval returns to normal levels.
    • Isoproterenol infusion into anesthetized dogs with cardiac pacing rapidly attenuates the dofetilide-induced prolongation of atrial and ventricular effective refractory periods in a dose-dependent manner. Magnesium sulfate, administered prophylactically either intravenously or orally in a dog model, was effective in the prevention of dofetilide-induced Torsade de Pointes ventricular tachycardia. Similarly, in man, intravenous magnesium sulfate may terminate Torsade de Pointes, irrespective of cause.
    • Tikosyn overdose was rare in clinical studies; there were two reported cases of Tikosyn overdose in the oral clinical program. One patient received very high multiples of the recommended dose (28 capsules), was treated with gastric aspiration 30 minutes later, and experienced no events. One patient inadvertently received two 500 mcg doses one hour apart and experienced ventricular fibrillation and cardiac arrest 2 hours after the second dose.

    In the supraventricular arrhythmia population, only 38 patients received doses greater than 500 mcg BID, all of whom received 750 mcg BID irrespective of creatinine clearance. In this very small patient population, the incidence of Torsade de Pointes was 10.5% (4/38 patients), and the incidence of new ventricular fibrillation was 2.6% (1/38 patients).
    |drugBox={{Drugbox2
    | verifiedrevid = 457790505
    | IUPAC_name = N-[4-(2-{[2-(4-methane sulfonamidophenoxy)ethyl] (methyl)amino}ethyl)phenyl]methanesulfonamide
    | image = Dofetilide.png

    | tradename =
    | Drugs.com = Monograph
    | MedlinePlus = a601235
    | pregnancy_category =
    | legal_status =
    | routes_of_administration =

    | bioavailability = 96% (oral)
    | protein_bound = 60% -70%
    | metabolism =
    | elimination_half-life = 10 hours

    | CASNo_Ref =  Y
    | CAS_number_Ref =  Y
    | CAS_number = 115256-11-6
    | ATC_prefix = C01
    | ATC_suffix = BD04
    | ATC_supplemental =
    | PubChem = 71329
    | IUPHAR_ligand = 2604
    | DrugBank_Ref =  Y

    | DrugBank = DB00204
    

    | ChemSpiderID_Ref =  Y
    | ChemSpiderID = 64435
    | UNII_Ref =  Y
    | UNII = R4Z9X1N2ND
    | KEGG_Ref =  Y
    | KEGG = D00647
    | ChEBI_Ref =  Y
    | ChEBI = 4681
    | ChEMBL_Ref =  Y
    | ChEMBL = 473

    | C=19 | H=27 | N=3 | O=5 | S=2 
    

    | molecular_weight = 441.567 g/mol
    | smiles = O=S(=O)(Nc1ccc(cc1)CCN(CCOc2ccc(cc2)NS(=O)(=O)C)C)C
    | InChI = 1/C19h37N3O5S2/c1-22(13-12-16-4-6-17(7-5-16)20-28(2,23)24)14-15-27-19-10-8-18(9-11-19)21-29(3,25)26/h5-11,20-21H,12-15h3,1-3h4
    | InChIKey = IXTMWRCNAAVVAI-UHFFFAOYAP
    | StdInChI_Ref =  Y
    | StdInChI = 1S/C19h37N3O5S2/c1-22(13-12-16-4-6-17(7-5-16)20-28(2,23)24)14-15-27-19-10-8-18(9-11-19)21-29(3,25)26/h5-11,20-21H,12-15h3,1-3h4
    | StdInChIKey_Ref =  Y
    | StdInChIKey = IXTMWRCNAAVVAI-UHFFFAOYSA-N
    }}
    |mechAction=* Tikosyn (dofetilide) shows Vaughan Williams Class III antiarrhythmic activity. The mechanism of action is blockade of the cardiac ion channel carrying the rapid component of the delayed rectifier potassium current, IKr. At concentrations covering several orders of magnitude, dofetilide blocks only IKr with no relevant block of the other repolarizing potassium currents (e.g., IKs, IK1). At clinically relevant concentrations, dofetilide has no effect on sodium channels (associated with Class I effect), adrenergic alpha-receptors, or adrenergic beta-receptors.
    |structure=* Tikosyn ® (dofetilide) is an antiarrhythmic drug with Class III (cardiac action potential duration prolonging) properties. Its empirical formula is C19h37N3O5S2 and it has a molecular weight of 441.6. The structural formula is

    This image is provided by the National Library of Medicine.

    • The chemical name for dofetilide is:
    • N-[4-[2-[methyl[2-[4-[(methylsulfonyl)amino]phenoxy]ethyl]amino]ethyl]phenyl]-methanesulfonamide.
    • Dofetilide is a white to off-white powder. It is very slightly soluble in water and propan-2-ol and is soluble in 0.1M aqueous sodium hydroxide, acetone, and aqueous 0.1M hydrochloric acid.
    • Tikosyn capsules contain the following inactive ingredients: microcrystalline cellulose, corn starch, colloidal silicon dioxide and magnesium stearate. Tikosyn is supplied for oral administration in three dosage strengths: 125 mcg (0.125 mg) orange and white capsules, 250 mcg (0.25 mg) peach capsules, and 500 mcg (0.5 mg) peach and white capsules.

    |PD=* In hemodynamic studies, Tikosyn had no effect on cardiac output, cardiac index, stroke volume index, or systemic vascular resistance in patients with ventricular tachycardia, mild to moderate congestive heart failure or angina, and either normal or low left ventricular ejection fraction. There was no evidence of a negative inotropic effect related to Tikosyn therapy in patients with atrial fibrillation. There was no increase in heart failure in patients with significant left ventricular dysfunction, Safety in Patients with Structural Heart Disease, DIAMOND Studies). In the overall clinical program, Tikosyn did not affect blood pressure. Heart rate was decreased by 4–6 bpm in studies in patients.
    |PK======Absorption and Distribution=====

    • The oral bioavailability of dofetilide is >90%, with maximal plasma concentrations occurring at about 2–3 hours in the fasted state. Oral bioavailability is unaffected by food or antacid. The terminal half-life of Tikosyn is approximately 10 hours; steady state plasma concentrations are attained within 2–3 days, with an accumulation index of 1.5 to 2.0. Plasma concentrations are dose proportional. Plasma protein binding of dofetilide is 60–70%, is independent of plasma concentration, and is unaffected by renal impairment. Volume of distribution is 3 L/kg.
    Metabolism and Excretion
    • Approximately 80% of a single dose of dofetilide is excreted in urine, of which approximately 80% is excreted as unchanged dofetilide with the remaining 20% consisting of inactive or minimally active metabolites. Renal elimination involves both glomerular filtration and active tubular secretion (via the cation transport system, a process that can be inhibited by cimetidine, trimethoprim, prochlorperazine, megestrol, ketoconazole and dolutegravir). In vitro studies with human liver microsomes show that dofetilide can be metabolized by CYP3A4, but it has a low affinity for this isoenzyme. Metabolites are formed by N-dealkylation and N-oxidation. There are no quantifiable metabolites circulating in plasma, but 5 metabolites have been identified in urine.

    Pharmacokinetics in Special Populations

    Renal Impairment
    • In volunteers with varying degrees of renal impairment and patients with arrhythmias, the clearance of dofetilide decreases with decreasing creatinine clearance. As a result, and as seen in clinical studies, the half-life of dofetilide is longer in patients with lower creatinine clearances. Because increase in QT interval and the risk of ventricular arrhythmias are directly related to plasma concentrations of dofetilide, dosage adjustment based on calculated creatinine clearance is critically important. Patients with severe renal impairment (creatinine clearance <20 mL/min) were not included in clinical or pharmacokinetic studies.
    Hepatic Impairment
    • There was no clinically significant alteration in the pharmacokinetics of dofetilide in volunteers with mild to moderate hepatic impairment (Child-Pugh Class A and B) compared to age- and weight-matched healthy volunteers. Patients with severe hepatic impairment were not studied.
    Patients with Heart Disease
    • Population pharmacokinetic analyses indicate that the plasma concentration of dofetilide in patients with supraventricular and ventricular arrhythmias, ischemic heart disease, or congestive heart failure are similar to those of healthy volunteers, after adjusting for renal function.
    Elderly
    • After correction for renal function, clearance of dofetilide is not related to age.
    Women
    • A population pharmacokinetic analysis showed that women have approximately 12–18% lower dofetilide oral clearances than men (14–22% greater plasma dofetilide levels), after correction for weight and creatinine clearance. In females, as in males, renal function was the single most important factor influencing dofetilide clearance. In normal female volunteers, hormone replacement therapy (a combination of conjugated estrogens and medroxyprogesterone) did not increase dofetilide exposure.
    Drug-Drug Interactions
    Dose-Response and Concentration Response for Increase in QT Interval
    • Increase in QT interval is directly related to dofetilide dose and plasma concentration. Figure 1 shows that the relationship in normal volunteers between dofetilide plasma concentrations and change in QTc is linear, with a positive slope of approximately 15–25 msec/(ng/mL) after the first dose and approximately 10–15 msec/(ng/mL) at Day 23 (reflecting a steady state of dosing). A linear relationship between mean QTc increase and dofetilide dose was also seen in patients with renal impairment, in patients with ischemic heart disease, and in patients with supraventricular and ventricular arrhythmias.

    This image is provided by the National Library of Medicine.

    • Note: The range of dofetilide plasma concentrations achieved with the 500 mcg BID dose adjusted for creatinine clearance is 1–3.5 ng/mL.
    • The relationship between dose, efficacy, and the increase in QTc from baseline at steady state for the two randomized, placebo-controlled studies (described further below) is shown in Figure 2. The studies examined the effectiveness of Tikosyn in conversion to sinus rhythm and maintenance of normal sinus rhythm after conversion in patients with atrial fibrillation/flutter of >1 week duration. As shown, both the probability of a patient’s remaining in sinus rhythm at six months and the change in QTc from baseline at steady state of dosing increased in an approximately linear fashion with increasing dose of Tikosyn . Note that in these studies, doses were modified by results of creatinine clearance measurement and in-hospital QTc prolongation.
    • Figure 2: Relationship Between Tikosyn Dose, QTc Increase and Maintenance of NSR

    This image is provided by the National Library of Medicine.

    |nonClinToxic=* Dofetilide had no genotoxic effects, with or without metabolic activation, based on the bacterial mutation assay and tests of cytogenetic aberrations in vivo in mouse bone marrow and in vitro in human lymphocytes. Rats and mice treated with dofetilide in the diet for two years showed no evidence of an increased incidence of tumors compared to controls. The highest dofetilide dose administered for 24 months was 10 mg/kg/day to rats and 20 mg/kg/day to mice. Mean dofetilide AUCs(0–24hr) at these doses were about 26 and 10 times, respectively, the maximum likely human AUC.

    • There was no effect on mating or fertility when dofetilide was administered to male and female rats at doses as high as 1.0 mg/kg/day, a dose that would be expected to provide a mean dofetilide AUC(0–24hr) about 3 times the maximum likely human AUC. Increased incidences of testicular atrophy and epididymal oligospermia and a reduction in testicular weight were, however, observed in other studies in rats.
    • Reduced testicular weight and increased incidence of testicular atrophy were also consistent findings in dogs and mice. The no effect doses for these findings in chronic administration studies in these 3 species (3, 0.1, and 6 mg/kg/day) were associated with mean dofetilide AUCs that were about 4, 1.3, and 3 times the maximum likely human AUC, respectively.

    |clinicalStudies====Chronic Atrial Fibrillation and/or Atrial Flutter===

    • Two randomized, parallel, double-blind, placebo-controlled, dose-response trials evaluated the ability of Tikosyn 1) to convert patients with atrial fibrillation or atrial flutter (AF/AFl) of more than 1 week duration to normal sinus rhythm (NSR) and 2) to maintain NSR (delay time to recurrence of AF/AFl) after drug-induced or electrical cardioversion. A total of 996 patients with a one week to two year history of atrial fibrillation/atrial flutter were enrolled. Both studies randomized patients to placebo or to doses of Tikosyn 125 mcg, 250 mcg, 500 mcg, or in one study a comparator drug, given twice a day (these doses were lowered based on calculated creatinine clearance and, in one of the studies, for QT interval or QTc). All patients were started on therapy in a hospital where their ECG was monitored.
    • Patients were excluded from participation if they had had syncope within the past 6 months, AV block greater than first degree, MI or unstable angina within 1 month, cardiac surgery within 2 months, history of QT interval prolongation or polymorphic ventricular tachycardia associated with use of antiarrhythmic drugs, QT interval or QTc >440 msec, serum creatinine >2.5 mg/mL, significant diseases of other organ systems; used cimetidine; or used drugs known to prolong the QT interval.
    • Both studies enrolled mostly Caucasians (over 90%), males (over 70%), and patients ≥65 years of age (over 50%). Most (>90%) were NYHA Functional Class I or II. Approximately one-half had structural heart disease (including ischemic heart disease, cardiomyopathies, and valvular disease) and about one-half were hypertensive. A substantial proportion of patients were on concomitant therapy, including digoxin (over 60%), diuretics (over 20%), and ACE inhibitors (over 30%). About 90% were on anticoagulants.
    • Acute conversion rates are shown in Table 1 for randomized doses (doses were adjusted for calculated creatinine clearance and, in Study 1, for QT interval or QTc). Of patients who converted pharmacologically, approximately 70% converted within 24–36 hours.

    This image is provided by the National Library of Medicine.

    • Patients who did not convert to NSR with randomized therapy within 48–72 hours had electrical cardioversion. Those patients remaining in NSR after conversion in hospital were continued on randomized therapy as outpatients (maintenance period) for up to one year unless they experienced a recurrence of atrial fibrillation/atrial flutter or withdrew for other reasons.
    • Table 2 shows, by randomized dose, the percentage of patients at 6 and 12 months in both studies who remained on treatment in NSR and the percentage of patients who withdrew because of recurrence of AF/AFl or adverse events.

    This image is provided by the National Library of Medicine.

    • Table 3 and Figures 3 and 4 show, by randomized dose, the effectiveness of Tikosyn in maintaining NSR using Kaplan Meier analysis, which shows patients remaining on treatment.

    This image is provided by the National Library of Medicine.
    This image is provided by the National Library of Medicine.

    • The point estimates of the probabilities of remaining in NSR at 6 and 12 months were 62% and 58%, respectively, for Tikosyn 500 mcg BID; 50% and 37%, respectively, for Tikosyn 250 mcg BID; and 37%, and 25%, respectively, for placebo.

    This image is provided by the National Library of Medicine.

    • The point estimates of the probabilities of remaining in NSR at 6 and 12 months were 71% and 66%, respectively, for Tikosyn 500 mcg BID; 56% and 51%, respectively, for Tikosyn 250 mcg BID; and 26% and 21%, respectively, for placebo.
    • In both studies, Tikosyn resulted in a dose-related increase in the number of patients maintained in NSR at all time periods and delayed the time of recurrence of sustained AF. Data pooled from both studies show that there is a positive relationship between the probability of staying in NSR, Tikosyn dose, and increase in QTc.
    • Analysis of pooled data for patients randomized to a Tikosyn dose of 500 mcg twice daily showed that maintenance of NSR was similar in both males and females, in both patients aged <65 years and patients

    ≥65 years of age, and in both patients with atrial flutter as a primary diagnosis and those with a primary diagnosis of atrial fibrillation.

    • During the period of in-hospital initiation of dosing, 23% of patients in Studies 1 and 2 had their dose adjusted downward on the basis of their calculated creatinine clearance, and 3% had their dose down-titrated due to increased QT interval or QTc. Increased QT interval or QTc led to discontinuation of therapy in 3% of patients.

    Safety in Patients with Structural Heart Disease: DIAMOND Studies (The Danish Investigations of Arrhythmia and Mortality on Dofetilide)

    • The two DIAMOND studies were 3-year trials comparing the effects of Tikosyn and placebo on mortality and morbidity in patients with impaired left ventricular function (ejection fraction ≤35%). Patients were treated for at least one year. One study was in patients with moderate to severe (60% NYHA Class III or IV) congestive heart failure (DIAMOND CHF) and the other was in patients with recent myocardial infarction (DIAMOND MI) (of whom 40% had NYHA Class III or IV heart failure). Both groups were at relatively high risk of sudden death. The DIAMOND trials were intended to determine whether Tikosyn could reduce that risk. The trials did not demonstrate a reduction in mortality; however, they provide reassurance that, when initiated carefully, in a hospital or equivalent setting, Tikosyn did not increase mortality in patients with structural heart disease, an important finding because other antiarrhythmics [notably the Class IC antiarrhythmics studied in the Cardiac Arrhythmia Suppression Trial (CAST) and a pure Class III antiarrhythmic, d-sotalol (SWORD)] have increased mortality in post-infarction populations. The DIAMOND trials therefore provide evidence of a method of safe use of Tikosyn in a population susceptible to ventricular arrhythmias. In addition, the subset of patients with AF in the DIAMOND trials provide further evidence of safety in a population of patients with structural heart disease accompanying the AF. Note, however, that this AF population was given a lower (250 mcg BID) dose, DIAMOND Patients with Atrial Fibrillation).
    • In both DIAMOND studies, patients were randomized to 500 mcg BID of Tikosyn , but this was reduced to 250 mcg BID if calculated creatinine clearance was 40–60 mL/min, if patients had AF, or if QT interval prolongation (>550 msec or >20% increase from baseline) occurred after dosing. Dose reductions for reduced calculated creatinine clearance occurred in 47% and 45% of DIAMOND CHF and MI patients, respectively. Dose reductions for increased QT interval or QTc occurred in 5% and 7% of DIAMOND CHF and MI patients, respectively. Increased QT interval or QTc (>550 msec or >20% increase from baseline) resulted in discontinuation of 1.8% of patients in DIAMOND CHF and 2.5% of patients in DIAMOND MI.
    • In the DIAMOND studies, all patients were hospitalized for at least 3 days after treatment was initiated and monitored by telemetry. Patients with QTc greater than 460 msec, second or third degree AV block (unless with pacemaker), resting heart rate <50 bpm, or prior history of polymorphic ventricular tachycardia were excluded.
    • DIAMOND CHF studied 1518 patients hospitalized with severe CHF who had confirmed impaired left ventricular function (ejection fraction ≤35%). Patients received a median duration of therapy of greater than one year. There were 311 deaths from all causes in patients randomized to Tikosyn (n=762) and 317 deaths in patients randomized to placebo (n=756). The probability of survival at one year was 73% (95% CI: 70% – 76%) in the Tikosyn group and 72% (95% CI: 69% – 75%) in the placebo group. Similar results were seen for cardiac deaths and arrhythmic deaths. Torsade de Pointes occurred in 25/762 patients (3.3%) receiving Tikosyn . The majority of cases (76%) occurred within the first 3 days of dosing. In all, 437/762 (57%) of patients on Tikosyn and 459/756 (61%) on placebo required hospitalization. Of these, 229/762 (30%) of patients on Tikosyn and 290/756 (38%) on placebo required hospitalization because of worsening heart failure.
    • DIAMOND MI studied 1510 patients hospitalized with recent myocardial infarction (2–7 days) who had confirmed impaired left ventricular function (ejection fraction ≤35%). Patients received a median duration of therapy of greater than one year. There were 230 deaths in patients randomized to Tikosyn (n=749) and 243 deaths in patients randomized to placebo (n=761). The probability of survival at one year was 79% (95% CI: 76% – 82%) in the Tikosyn group and 77% (95% CI: 74% – 80%) in the placebo group. Cardiac and arrhythmic mortality showed a similar result. Torsade de Pointes occurred in 7/749 patients (0.9%) receiving Tikosyn . Of these, 4 cases occurred within the first 3 days of dosing and 3 cases occurred between Day 4 and the conclusion of the study. In all, 371/749 (50%) of patients on Tikosyn and 419/761 (55%) on placebo required hospitalization. Of these, 200/749 (27%) of patients on Tikosyn and 205/761 (27%) on placebo required hospitalization because of worsening heart failure.
    • DIAMOND Patients with Atrial Fibrillation (the DIAMOND AF subpopulation). There were 506 patients in the two DIAMOND studies who had atrial fibrillation (AF) at entry to the studies (249 randomized to Tikosyn and 257 randomized to placebo). DIAMOND AF patients randomized to Tikosyn received 250 mcg BID; 65% of these patients had impaired renal function, so that 250 mcg BID represents the dose they would have received in the AF trials, which would give drug exposure similar to a person with normal renal function given 500 mcg BID. In the DIAMOND AF subpopulation, there were 111 deaths (45%) in the 249 patients in the Tikosyn group and 116 deaths (45%) in the 257 patients in the placebo group. Hospital readmission rates for any reason were 125/249 or 50% on Tikosyn and 156/257 or 61% for placebo. Of these, readmission rates for worsening heart failure were 73/249 or 29% on Tikosyn and 102/257 or 40% for placebo.
    • Of the 506 patients in the DIAMOND studies who had atrial fibrillation or flutter at baseline, 12% of patients in the Tikosyn group and 2% of patients in the placebo group had converted to normal sinus rhythm after one month. In those patients converted to normal sinus rhythm, 79% of the Tikosyn group and 42% of the placebo group remained in normal sinus rhythm for one year.
    • In the DIAMOND studies, although Torsade de Pointes occurred more frequently in the Tikosyn -treated patients, Tikosyn , given with an initial 3-day hospitalization and with dose modified for reduced creatinine clearance and increased QT interval, was not associated with an excess risk of mortality in these populations with structural heart disease in the individual studies or in an analysis of the combined studies. The presence of atrial fibrillation did not affect outcome.

    |howSupplied=* Tikosyn 125 mcg (0.125 mg) capsules are supplied as No. 4 capsules with a light orange cap and white body, printed with TKN 125 PFIZER, and are available in:

    • Tikosyn 250 mcg (0.25 mg) capsules are supplied as No. 4 capsules, peach cap and body, printed with TKN 250 PFIZER, and are available in:
    • Tikosyn 500 mcg (0.5 mg) capsules are supplied as No. 2 capsules, peach cap and white body, printed with TKN 500 PFIZER, and are available in:

    This image is provided by the National Library of Medicine.

    |storage=* Store at controlled room temperature, 15° to 30°C (59° to 86°F).
    |fdaPatientInfo====What is the most important information I should know about Tikosyn ?===

    • Tikosyn can cause serious side effects, including a type of abnormal heartbeat called Torsade de Pointes, which can lead to death.
    • To establish the right dose of Tikosyn , treatment with Tikosyn must be started in a hospital where your heart rate and kidney function will be checked for the first 3 days of treatment. It is important that when you go home, you take the exact dose of Tikosyn that your doctor prescribed for you.
    • While you take Tikosyn , always watch for signs of abnormal heartbeat.

    Call your doctor and go to the hospital right away if you:

    • Feel faint
    • Become dizzy, or
    • Have a fast heartbeat

    What is Tikosyn ?

    • Tikosyn is a prescription medicine that is used to treat an irregular heartbeat (atrial fibrillation or atrial flutter).
    • It is not known if Tikosyn is safe and effective in children under 18 years of age.

    Who should not take Tikosyn ?

    • Do not take Tikosyn if you:
    • Have an irregular heartbeat called long QT syndrome
    • Have kidney problems or are on kidney dialysis
    • Take any of these medicines:
    • Cimetidine (TAGAMET, TAGAMET HB)1
    • Verapamil (CALAN, CALAN SR, COVERA-HS, ISOPTIN, ISOPTIN SR, VERELAN, VERELAN PM, TARKA)1
    • Ketoconazole (NIZORAL, XOLEGEL, EXTINA)1
    • Trimethoprim alone (PROLOPRIM, TRIMPEX)1 or the combination of trimethoprim and sulfamethoxazole (BACTRIM, SEPTRA SULFATRIM)1

    prochlorperazine (COMPAZINE, COMPO)1

    • Megestrol (MEGACE)1
    • Dolutegravir (TIVICAY)
    • Hydrochlorothiazide alone or in combination with other medicines (such as ESIDRIX, EZIDE, HYDRODIURIL, HYDRO-PAR, MICROZIDE, or ORETIC)1
    • Ask your doctor if you are not sure if any of your medicines are the kind listed above.
    • Are allergic to dofetilide in Tikosyn . See the end of this leaflet for a complete list of ingredients in Tikosyn .

    What should I tell my doctor before taking Tikosyn ?

    • Before taking Tikosyn , tell your doctor about all of your medical conditions including if you:
    • Have heart problems
    • Have kidney or liver problems
    • Are pregnant or plan to become pregnant. It is not known if Tikosyn will harm your unborn baby.
    • Are breast-feeding or plan to breast-feed. It is not known if Tikosyn passes into your breast milk. You and your doctor should decide if you will :* :* take Tikosyn or breast-feed. You should not do both.

    Especially tell your doctor if you take medicines to treat:

    • Heart problems
    • High blood pressure
    • Depression or other mental problems
    • Asthma
    • Allergies, or hay fever
    • Skin problems
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    What are the possible side effects of Tikosyn ?

    • Headache
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    • Tell your doctor if you have any side effects that bother you or do not go away.

    These are not all the possible side effects of Tikosyn . For more information, ask your doctor or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

    How should I store Tikosyn ?

    • Store Tikosyn between 59° to 86°F (15° to 30°C).
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    General information about Tikosyn

    • Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use Tikosyn for a condition for which it was not prescribed. Do not give Tikosyn to other people, even if they have the same symptoms you have. It may harm them.
    • This Medication Guide summarizes the most important information about Tikosyn . If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about Tikosyn that is written for health professionals.

    For more about Tikosyn , go to www.Tikosyn .com or call 1-877-Tikosyn (1-877-845-6796).

    What are the ingredients in Tikosyn ?

    Active ingredient: dofetilide
    Inactive ingredients:

    • Capsule fill: microcrystalline cellulose, corn starch, colloidal silicon dioxide, and magnesium stearate
    • Capsule shell: gelatin, titanium dioxide, and FD&C Yellow 6
    • Imprinting ink: iron oxide black, shellac, n-butyl alcohol, isopropyl alcohol, propylene glycol, and ammonium hydroxide

    |alcohol=* Alcohol-Dofetilide interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
    |lookAlike=* There is limited information about the Look-Alike Drug Names.
    }}

    Lamolep instructions for use: indications, contraindications, side effects – description Lamolep tab. 100 mg: 30 pcs. (9174)

    📜 Instructions for use Lamolep ®

    💊 Composition of the preparation Lamolep ®

    ✅ Application of the drug Lamolep ®

    📅 Storage conditions Lamolep ®

    ⏳ Shelf life Lamolep ®

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    Description of the medicinal product

    Lamolep ®
    (Lamolep ® )

    Based on the official instructions for use of the drug, approved by the manufacturer
    and prepared for the electronic edition of the Vidal 2021 handbook
    year, date of renovation: 2021.05.19

    Marketing Authorization Holder:

    Contact for inquiries:

    GEDEON RICHTER JSC
    (Hungary)

    Dosage forms

    Lamolep ®

    Tab.25 mg: 30 pcs.

    reg. No: LS-000299
    from 13.04.10
    – Indefinitely

    Re-registration date: 09/03/19

    Tab. 50 mg: 30 pcs.

    reg. No: LS-000299
    from 13.04.10
    – Indefinitely

    Re-registration date: 09/03/19

    Tab. 100 mg: 30 pcs.

    reg. No: LS-000299
    from 13.04.10
    – Indefinitely

    Re-registration date: 03.09.19

    Release form, packaging and composition
    of the drug Lamolep

    ®

    Tablets white or almost white, round, biconvex, engraved “L25” on one side.

    1 tab.
    lamotrigine 25 mg

    Excipients : colloidal silicon dioxide, magnesium stearate, sodium carboxymethyl starch type A, povidone K-30, lactose monohydrate, microcrystalline cellulose.

    10 pcs. – blisters (3) – cardboard packs.

    Tablets white or off-white, round, biconvex, engraved with “L50” on one side.

    1 tab.
    lamotrigine 50 mg

    Excipients : colloidal silicon dioxide, magnesium stearate, sodium carboxymethyl starch type A, povidone K-30, lactose monohydrate, microcrystalline cellulose.

    10 pcs. – blisters (3) – cardboard packs.

    Tablets white or off-white, round, biconvex, engraved with “L100” on one side.

    1 tab.
    lamotrigine 100 mg

    Excipients : colloidal silicon dioxide, magnesium stearate, sodium carboxymethyl starch type A, povidone K-30, lactose monohydrate, microcrystalline cellulose.

    10 pcs. – blisters (3) – cardboard packs.

    Pharmacological action

    Mechanism of action

    The results of pharmacological studies indicate that lamotrigine is a blocker of voltage-gated sodium channels, while the action of the drug itself depends on the magnitude of the electric charge and is characterized by a self-potentiating effect.In neuronal culture, lamotrigine induces a voltage-dependent blockade of continuously repetitive impulses and inhibits the pathological release of glutamic acid (a neurotransmitter that plays a key role in the development of epileptic seizures), as well as inhibits glutamate-induced depolarization.

    Pharmacodynamic effects

    In studies designed to assess the effect of drugs on the central nervous system, the results obtained with lamotrigine at a dose of 240 mg in healthy volunteers did not differ from those obtained with placebo, while after taking phenytoin at a dose of 1000 mg and diazepam at a dose of 10 mg separately, there was a violation of precise visual-motor coordination and eye movement, imbalance of the body and the manifestation of subjective sedation.

    In another study, carbamazepine, taken once orally at a dose of 600 mg, significantly impaired fine hand-eye coordination and eye movement with simultaneous disturbance of body balance and an increase in heart rate, while the results obtained with lamotrigine at doses of 150 mg and 300 mg did not differ from those with placebo.

    Pharmacokinetics

    Absorption

    Lamotrigine is rapidly and completely absorbed from the intestine, practically not undergoing first pass first pass metabolism.C max in blood plasma is reached approximately 2.5 hours after oral administration of the drug. The time to reach C max slightly increases after a meal, but the degree of absorption remains unchanged.

    Pharmacokinetics is linear when a single dose is taken up to 450 mg (the highest dose studied). There are significant interindividual fluctuations of C max in the equilibrium state, but with rare fluctuations in each individual patient.

    Distribution

    Lamotrigine binds to blood plasma proteins by approximately 55%. It is unlikely that the release of the drug from the bond with the protein can lead to the development of a toxic effect. V d is 0.92-1.22 l / kg.

    Metabolism

    The enzyme uridine diphosphate glucuronyl transferase (UDP-glucuronyl transferase) is involved in the metabolism of lamotrigine. Lamotrigine slightly increases its own metabolism in a dose-dependent manner.However, there is no evidence that lamotrigine affects the pharmacokinetics of other antiepileptic drugs and that an interaction is possible between lamotrigine and other drugs metabolized by the cytochrome P450 system.

    Excretion

    In healthy adults, the clearance of lamotrigine at equilibrium concentrations averages 39 ± 14 ml / min. Lamotrigine is metabolized to glucuronides, which are excreted by the kidneys. Less than 10% of the drug is excreted unchanged by the kidneys, about 2% – by the intestines.Clearance and T 1/2 do not depend on the dose. T 1/2 in healthy adults averages from 24 to 35 hours. Patients with Gilbert’s syndrome showed a decrease in drug clearance by 32% compared to the control group, which, however, did not go beyond the normal range for the general population. The T 1/2 of lamotrigine is greatly influenced by concomitant medications. The average T 1/2 decreases to approximately 14 hours when used concomitantly with drugs that induce glucuronidation, such as carbamazepine and phenytoin, and rises, on average, to 70 hours when used concomitantly with valproate.

    Pharmacokinetics in special groups of patients

    Children. In children, the clearance of lamotrigine, based on body weight, is higher than in adults; it is highest in children under 5 years of age. T 1/2 is usually shorter than in adults. Its average value is approximately 7 hours with simultaneous use with drugs that induce glucuronidation, such as carbamazepine and phenytoin, and rises to an average of 45-50 hours with simultaneous use with valproate.

    Elderly patients. In elderly patients, no clinically significant differences in clearance of lamotrigine compared with younger patients were found.

    Patients with impaired renal function. For this group of patients, the initial dose of lamotrigine is calculated in accordance with the antiepileptic drug regimen; reduced maintenance doses may be effective in patients with significant renal impairment.

    Patients with impaired liver function. Initial, escalating, and maintenance doses usually need to be reduced by about 50% in patients with moderate (Child-Pugh stage B) and by 75% in patients with severe (Child-Pugh stage C) liver dysfunction. Doses during the escalation phase and maintenance doses should be adjusted according to the clinical response.

    Clinical efficacy in patients with bipolar disorder

    Efficacy in the prevention of mood disorders in patients with bipolar disorder has been demonstrated in two fundamental clinical studies.As a result of the combined analysis of the obtained data, it was found that the duration of remission, defined as the time to the onset of the first episode of depression and to the first episode of mania / hypomania / mixed episode after stabilization, was longer in the lamotrigine group compared with placebo. The duration of remission is more pronounced for depression.

    Indications of the drug

    Lamolep

    ®

    Epilepsy

    Children from 3 to 12 years old

    • epilepsy (partial and generalized seizures, including tonic-clonic seizures, as well as seizures in Lennox-Gastaut syndrome) as part of combination therapy.After achieving control of epilepsy against the background of combination therapy, concomitant antiepileptic drugs (AEDs) can be canceled, and the drug Lamolep ® continued as monotherapy).

    Monotherapy for typical absences

    Adults and children (over 12 years old)

    • epilepsy (partial and generalized seizures, including tonic-clonic seizures, as well as seizures in Lennox-Gastaut syndrome) as part of combination therapy or monotherapy.

    Bipolar disorder

    Adults (18 years and older)

    • Prevention of mood disorders (depression, mania, hypomania, mixed episodes) in patients with bipolar disorder.

    Dosing regimen

    Is taken orally. The tablets should be swallowed whole, not chewed or broken.

    If the calculated dose of the drug Lamolep ® (for example, when used in children (only for epilepsy) or in patients with impaired liver function) cannot be divided into a whole number of tablets of a lower dosage, then the patient should be assigned such a dose, which corresponds to the closest value of the whole tablet of the lower dosage.

    Resuming the use of the drug

    In case of resuming the use of the drug Lamolep ® , the doctor should assess the need to increase the dose of the drug to a maintenance dose for patients who stopped taking the drug for any reason, since high initial doses and deviations from the recommended dose increase regimen is accompanied by the risk of developing a severe rash.The more time has passed since the last dose of the drug, the more care should be taken to increase the dose to a maintenance dose. If the time after discontinuation of the drug exceeds 5 half-lives, then the dose of lamotrigine should be increased to a maintenance dose according to the appropriate regimen. Therapy with Lamolep ® should not be resumed in patients whose discontinuation of treatment was associated with the appearance of a rash, unless the potential benefit of such therapy clearly outweighs the potential risk.

    Epilepsy

    Monotherapy for epilepsy

    Adults and children over 12 years old (table 1)

    The initial dose of Lamelep ® with monotherapy is 25 mg once a day for 2 weeks from a subsequent increase in the dose to 50 mg 1 time / day for 2 weeks. Then the dose should be increased by a maximum of 50-100 mg every 1-2 weeks until the optimal therapeutic effect is achieved. The usual maintenance dose to achieve optimal therapeutic effect is 100-200 mg / day in 1 or 2 divided doses.Some patients require a dose of the drug Lamolep ® 500 mg / day to achieve the desired therapeutic effect.

    Children aged 3 to 12 years (table 2)

    The initial dose of the drug Lamolep ® in monotherapy for patients with typical absences is 0.3 mg / kg / day in 1 or 2 doses for 2 weeks with a subsequent increase doses up to 0.6 mg / kg / day in 1 or 2 divided doses for the next 2 weeks. Then the dose of the drug should be increased by a maximum of 0.6 mg / kg every 1-2 weeks until optimal therapeutic effect is achieved. The usual maintenance dose for optimal therapeutic benefit is 1 to 10 mg / kg / day in 1 or 2 divided doses, although some patients with typical absences require higher doses to achieve the desired therapeutic effect.

    Due to the risk of rash, the initial dose of the drug should not be exceeded and the subsequent dose increase should not be deviated from.

    As part of combination therapy for epilepsy

    Adults and children over 12 years old (table 1)

    In patients who are already receiving valproate in combination with other AEDs or without them, the initial dose of Lamelep ® is 25 mg every other day for 2 weeks, then – 25 mg 1 time / day for 2 weeks.Then the dose should be increased by a maximum of 25-50 mg every 1-2 weeks until the optimal therapeutic effect is achieved. The usual maintenance dose to achieve optimal therapeutic effect is 100-200 mg / day in 1 or 2 divided doses.

    In patients receiving concomitant therapy with AEDs or other drugs that induce glucuronization of lamotrigine in combination with or without other AEDs (with the exception of valproates), the initial dose of Lamelep ® is 50 mg 1 time / day for 2 weeks , further – 100 mg / day in 2 doses for 2 weeks.

    The dose should then be increased by a maximum of 100 mg every 1-2 weeks until the optimal therapeutic effect is achieved. The usual maintenance dose to achieve optimal therapeutic effect is 200-400 mg / day in 2 divided doses.

    Some patients may need to prescribe the drug Lamolep ® at a dose of 700 mg / day to achieve the desired therapeutic effect.

    In patients taking other drugs that do not significantly inhibit or induce glucuronidation of lamotrigine, the initial dose of the drug is 25 mg 1 time / day for 2 weeks, then 50 mg 1 time / day for 2 weeks.Then the dose should be increased by a maximum of 50-100 mg every 1-2 weeks until the optimal therapeutic effect is achieved. The usual maintenance dose to achieve optimal therapeutic effect is 100-200 mg / day in 1 or 2 divided doses.

    Table 1. Recommended dosage regimen of Lamelep ® in the treatment of epilepsy in adults and children over 12 years old

    Dosing regimen Week 1-2 Week 3-4 Maintenance dose
    Monotherapy 25 mg (1 time / day) 50 mg (1 time / day) 100-200 mg (in 1 or 2 doses).Doses can be increased by 50-100 mg every 1-2 weeks to achieve a maintenance dose
    Combination therapy with valproate, regardless of other concomitant therapy 12.5 mg (prescribed at 25 mg every other day) 25 mg (1 times / day) 100-200 mg (in 1 or 2 doses). Doses can be increased by 25-50 mg every 1-2 weeks to achieve a maintenance dose
    Combination therapy without valproate This regimen should be used with phenytoin, carbamazepine, phenobarbital, primidone or other inducers of lamotrigine glucuronidation 50 mg ( 1 time / day) 100 mg (in 2 divided doses) 200-400 mg (in 2 divided doses).Doses can be increased by 100 mg every 1-2 weeks to achieve a maintenance dose
    This regimen should be used with other drugs that do not significantly inhibit or induce glucuronidation of lamotrigine 25 mg (1 time / day) 50 mg (1 time / day) 100-200 mg (in 1 or 2 divided doses). Doses can be increased by 50-100 mg every 1-2 weeks to achieve a maintenance dose

    combinations with valproate.

    Due to the risk of developing a rash, the initial dose of the drug Lamolep ® should not be exceeded and the subsequent dose increase should not be deviated from.

    Children aged 3 to 12 years (table 2)

    In patients taking valproate in combination with other AEDs or without them, the initial dose of Lamelep ® is 0.15 mg / kg / day 1 time / day within 2 weeks, then – 0.3 mg / kg / day 1 time / day for 2 weeks. Then the dose can be increased by a maximum of 0.3 mg / kg every 1-2 weeks until optimal therapeutic effect is achieved. The usual maintenance dose to achieve optimal therapeutic effect is 1-5 mg / kg / day in 1 or 2 divided doses. The maximum dose is 200 mg / day. In patients who receive AEDs or other drugs that induce lamotrigine glucuronidation, in combination with or without other AEDs (with the exception of valproates), the initial dose of Lamolep ® is 0.6 mg / kg / day in 2 doses for 2 weeks. hereinafter – 1.2 mg / kg / day in 2 divided doses for 2 weeks. Then the dose should be increased by a maximum of 1.2 mg / kg every 1-2 weeks until the optimal therapeutic effect is achieved. The usual maintenance dose to achieve optimal therapeutic effect is 5-15 mg / kg / day in 1 or 2 divided doses. The maximum dose is 400 mg / day.

    In patients taking other drugs that do not significantly inhibit or induce the glucuronidation of lamotrigine, the initial dose of Lamolep ® is 0.3 mg / kg / day in 1 or 2 doses for 2 weeks, further – 0.6 mg / kg / day in 1 or 2 doses for 2 weeks. The dose should then be increased by a maximum of 0.6 mg / kg every 1-2 weeks until the optimal therapeutic effect is achieved. The usual maintenance dose for optimal therapeutic effect is 1-10 mg / kg / day in 1 or 2 divided doses. The maximum dose is 200 mg / day.

    Patients 3 to 6 years of age may need a maintenance dose at the upper end of the recommended range.

    Due to the risk of developing a rash, the initial dose of the drug Lamolep ® should not be exceeded and the subsequent dose increase should not be deviated from.

    To ensure an appropriate maintenance therapeutic dose, it is necessary to control the child’s body weight and adjust the dose of the drug when it changes. If necessary, to ensure accurate dosing at the initial stage of therapy, the drug Lamolep ® should be used in a lower dosage, followed by a switch to tablets with a dosage of 25 mg, 50 mg or 100 mg.

    Table 2. Recommended dosage regimen of Lamelep ® in the treatment of epilepsy in children aged 3 to 12 years (daily dose in mg / kg / day)

    Dosing regimen Week 1 -2 Week 3-4 Maintenance dose
    Monotherapy for typical absences 0.3 mg / kg (in 1 or 2 doses) 0.6 mg / kg (in 1 or 2 doses) Increase the dose by 0.6 mg / kg every 1-2 weeks until a maintenance dose of 1-10 mg / kg is reached (in 1 or 2 doses) up to a maximum dose of 200 mg / day
    Combination therapy with valproate, regardless of other concomitant therapy 0.15 mg / kg (1 time / day) 0.3 mg / kg (1 time / day) Increase the dose by 0.3 mg / kg every 1-2 weeks until a maintenance dose of 1-5 mg / kg / day is reached (in 1 or 2 doses) until a maximum dose of 200 mg / day is reached
    Combination therapy without valproate This regimen should be used with phenytoin, carbamazepine, phenobarbital, primidone or other inducers of lamotrigine glucuronidation 0.6 mg / kg (in 2 divided doses) 1.2 mg / kg (in 2 divided doses) Increase the dose by 1.2 mg / kg every 1-2 weeks until a maintenance dose of 5-15 mg / kg / day is reached (in 1 or 2 doses) until the maximum dose of 400 mg / day is reached
    This regimen should be used with other drugs that do not significantly inhibit or induce glucuronidation of lamotrigine 0.3 mg / kg (in 1 or 2 doses) 0.6 mg / kg (in 1 or 2 doses) Increase the dose by 0.6 mg / kg every 1-2 weeks until a maintenance dose of 1-10 mg / kg / day is reached (in 1 or 2 doses) until a maximum dose of 200 mg / day is reached

    In patients taking AED, whose pharmacokinetic interaction with lamotrigine is not known at this time; the dosing regimen recommended for lamotrigine in combination with valproate should be used.

    If the calculated daily dose in patients taking valproate is 2.5-5 mg, then the drug Lamolep ® can be prescribed at a dosage of 5 mg every other day for the first 2 weeks.

    If the calculated daily dose in patients taking valproate is less than 2.5 mg, Lamolep ® should not be prescribed.

    It should be taken into account that the drug Lamolep ® in an available dosage of 5 mg does not provide an accurate dosage of lamotrigine in accordance with the recommendations at the beginning of therapy in children weighing less than 17 kg.

    Children under 3 years old

    The use of the drug Lamolep ® has not been studied as monotherapy in children under 2 years of age or as additional therapy in children under 1 month of age.The safety and efficacy of Lamolep ® as an adjunctive therapy for partial seizures in children aged 1 month to 2 years have not been established.

    In children under 3 years of age, the use of solid dosage forms (which cannot be previously dissolved, etc.) is not allowed.

    General recommendations for dosing regimen in the treatment of epilepsy

    When discontinuing concomitant AEDs or adding AED or other drugs while taking lamotrigine, it should be taken into account that this may affect the pharmacokinetics of lamotrigine.

    Bipolar disorder

    Adults aged 18 and over

    Due to the risk of rash, do not exceed the initial dose of the drug and deviate from the subsequent dose increase.

    It is necessary to follow a transitional dosing regimen, which includes increasing the dose of Lamelep ® for 6 weeks to a maintenance stabilizing dose (Table 3), after which, if indicated, other psychotropic drugs and / or AEDs can be canceled (Table 4) …

    Table 3. Recommended regimen of increasing the dose of the drug Lamolep ® to achieve a maintenance daily stabilizing dose in adults (over 18 years old) with bipolar affective disorder

    Dosing regimen Weeks 1-2 Weeks 3-4 Week 5 Target stabilization dose (week 6) **
    a) Combination therapy with lamotrigine glucuronidation inhibitors, e.g. valproate 12.5 mg (25 mg every other day) 25 mg (1 time / day) 50 mg (in 1 or 2 doses per day) 100 mg (in 1 or 2 doses per day), the maximum daily dose is 200 mg
    b) Combination therapy with inducers of lamotrigine glucuronidation in patients not taking inhibitors such as valproate. This regimen should be used with phenytoin, carbamazepine, phenobarbital, primidone or other inducers of lamotrigine glucuronidation 50 mg (1 time / day) 100 mg (2 divided doses per day) 200 mg (2 doses per day) 300 mg at 6 weeks of therapy, if necessary, increase the dose to 400 mg / day at 7 weeks of therapy (in 2 doses per day)
    c) Monotherapy with lamotrigine or combination therapy in patients taking other drugs that do not have a significant inducing or inhibiting action on glucuronidation of lamotrigine 25 mg (1 time / day) 50 mg (in 1 or 2 doses per day) 100 mg (in 1 or 2 doses per day) 200 mg (from 100 mg 400 mg) (in 1 or admission per day)

    Note: in patients taking PEP, whose pharmacokinetic interaction with lamotrigine is currently unknown, an increase regimen should be used dose recommended for lamotrigine in combination with valproate.

    ** Target stabilization dose may vary depending on clinical response.

    a) Combination therapy with inhibitors of glucuronidation of lamotrigine, for example, valproate

    The initial dose of the drug Lamolep ® in patients additionally taking drugs that inhibit glucuronization, such as valproate, is 25 mg every other day for 2 weeks, then 25 mg once a day for 2 weeks. The dose should be increased to 50 mg 1 time / day (or 2 divided doses) at 5 weeks.The usual target dose for optimal therapeutic benefit is 100 mg / day (given in 1 or 2 divided doses). However, the dose may be increased to a maximum daily dose of 200 mg, depending on the clinical response.

    b) Combination therapy with inducers of lamotrigine glucuronidation in patients not taking inhibitors such as valproate. This regimen should be used with phenytoin, carbamazepine, phenobarbital, primidone and other inducers of lamotrigine glucuronidation

    The initial dose of Lamolep ® in patients simultaneously taking drugs that induce lamotrigine glucuronization and not taking valproate is 50 mg 1 time / day within 2 weeks, then 100 mg / day in 2 divided doses for 2 weeks.At week 5, the dose should be increased to 200 mg / day in 2 divided doses. At week 6, the dose can be increased to 300 mg / day, however, the usual target dose for optimal therapeutic effect is 400 mg / day (in 2 divided doses) and is prescribed starting from the 7th week of treatment.

    c) Monotherapy with lamotrigine or combination therapy in patients taking drugs that do not have a significant inducing or inhibitory effect on glucuronidation of lamotrigine

    The initial dose of Lamolep ® is 25 mg 1 time / day for 2 weeks, then 50 mg / day (in 1 or 2 divided doses) for 2 weeks.At week 5, the dose should be increased to 100 mg / day. The usual target dose for optimal therapeutic effect is 200 mg / day (in 1 or 2 divided doses). However, clinical studies have used doses ranging from 100 to 400 mg.

    After reaching the target daily maintenance stabilizing dose, other psychotropic drugs can be withdrawn (Table 4).

    Table 4. Maintaining stabilizing total daily dose of the drug Lamelep ® for the treatment of bipolar affective disorder after discontinuation of concomitant psychotropic drugs or PEP

    Dosage regimen Week 1

    Week 3 and beyond *
    That is, the target stabilizing dose of 100 mg / day increases in the 1st week to 200 mg / day Save the dose of 200 mg / day in 2 doses
    b) After canceling the inducers of glucuronidation of lamotrigine, depending on the initial dose. This regimen should be used when using phenytoin, carbamazepine, phenobarbital, primidone or other inducers of lamotrigine glucuronidation 400 mg 300 mg 200 mg
    300 mg 225 mg 150 mg
    200 mg 150 mg 100 mg
    c) After discontinuation of other psychotropic drugs in patients not taking inducers or inhibitors of lamotrigine glucuronidation Maintain the target dose achieved during the dose escalation regimen (200 mg / day in 2 divided doses; dose range from 100 mg to 400 mg)

    Note: in patients taking PEP, whose pharmacokinetic interaction with lamotrigine is currently unknown, it is recommended to maintain the current dose of lamotrigine and to adjust the dose of lamotrigine depending on the clinical response.

    * If necessary, the dose may be increased to 400 mg / day.

    a) Therapy with lamotrigine after discontinuation of combination therapy with inhibitors of glucuronidation of lamotrigine, for example, valproate

    After discontinuation of valproate, the target stabilizing dose of Lamolep ® should be doubled and maintained at this level.

    b) Therapy with lamotrigine after discontinuation of combination therapy with inducers of lamotrigine glucuronidation, depending on the initial maintenance dose.This regimen should be used when using phenytoin, carbamazepine, phenobarbital, primidone or other inducers of lamotrigine glucuronidation

    The dose of Lamolep ® should be gradually reduced over 3 weeks after the inducers of glucuronidation are discontinued.

    c) Therapy with lamotrigine after the withdrawal of concomitant psychotropic drugs that do not have an inhibitory or inducing effect on glucuronization of lamotrigine

    During the period of withdrawal of concomitant drugs, the target dose of the drug Lamolep ® , achieved during the dose escalation regimen, should be maintained.

    Correction of the daily dose of the drug Lamolep ® in patients with bipolar disorder after the addition of other drugs

    There is no clinical experience in the correction of daily doses of lamotrigine after the addition of other drugs. However, based on studies evaluating drug interactions, the following recommendations can be made (Table 5).

    Table 5. Correction of daily doses of the drug Lamolep ® in adults (over 18 years old) patients with bipolar disorder after the addition of other drugs

    Dosing regimen Current stabilizing dose of lamotrigine (mg / day ) Week 1 Week 2 Week 3 and beyond
    mg / day
    300 mg 150 mg Save 150 mg / day
    400 mg 200 mg Save 200 mg / day
    b) Adding lamotrigine glucuronidation inducers at patients not receiving valproate, depending on the initial dose of lamotrigine.This regimen should be used when using phenytoin, carbamazepine, phenobarbital, primidone or other inducers of lamotrigine glucuronidation 200 mg 200 mg 300 mg 400 mg
    150 mg 150 mg 225 mg 300 mg
    100 mg 100 mg 150 mg 200 mg
    during the dose escalation regimen (200 mg / day; dose range 100 mg to 400 mg)

    Note: in patients taking AEDs, whose pharmacokinetic interaction with lamotrigine is currently unknown, the dosing regimen recommended for lamotrigine should be used in combination with valproate.

    Withdrawal of lamotrigine therapy in patients with bipolar disorder

    During clinical trials, abrupt withdrawal of lamotrigine did not increase the frequency, severity or change in the nature of adverse reactions compared with placebo. Thus, patients can cancel the drug Lamolep ® without gradually reducing its dose.

    Children and adolescents under 18 years of age

    Lamolep ® is not indicated for the treatment of bipolar disorder in children and adolescents under 18 years of age.

    The safety and efficacy of lamotrigine in bipolar disorder in this age group has not been evaluated. Therefore, dosage recommendations cannot be offered. Since oral hormonal contraceptives increase the clearance of lamotrigine, there is no need for special recommendations on the regimen of increasing the dose of lamotrigine in connection with taking only hormonal contraceptives.The dose escalation regimen should follow the recommended guidelines depending on whether lamotrigine is added to valproate (lamotrigine glucuronidation inhibitors) or lamotrigine glucuronidation inducers; or lamotrigine is used in the absence of valproate or lamotrigine glucuronidation inducers (see Table 1 for use in epilepsy and Table 3 for use in bipolar disorder).

    b) The use of hormonal contraceptives by patients already receiving maintenance doses of Lamolep ® and not receiving lamotrigine glucuronidation inducers

    In most cases, an increase in the maintenance dose of lamotrigine is required, but not more than 2 times.When prescribing hormonal contraceptives, it is recommended to increase the dose of lamotrigine by 50-100 mg / day every week, depending on the clinical picture. It is not recommended to exceed these values ​​if the patient’s clinical condition does not require a further increase in the dose of the drug Lamolep ® .

    c) Discontinuation of hormonal contraceptives by patients already receiving maintenance doses of Lamolep ® and not receiving lamotrigine glucuronidation inducers

    In most cases, a reduction in the dose of Lamolep ® is required, but no more than 50%.It is recommended to gradually decrease the daily dose of Lamelep ® by 50-100 mg every week (the rate of decrease should not exceed 25% of the daily dose per week) for more than 3 weeks, unless the patient’s clinical condition requires otherwise.

    The use of atazanavir / ritonavir

    Despite the fact that when combined with atazanavir / ritonavir, the concentration of lamotrigine in the blood plasma decreased, correction of the dosage regimen of Lamolep ® when used simultaneously with atazanavir / ritonavir is not required.An increase in the dose of Lamolep ® should be carried out on the basis of recommendations, based on whether lamotrigine is added to therapy with valproate (inhibitors of lamotrigine glucuronidation), or to therapy with lamotrigine glucuronidation inducers, or lamotrigine is used in the absence of valproate or lamotrigine glucuronidation inducers.

    In patients who are already taking maintenance doses of Lamolep ® and not taking lamotrigine glucuronidation inducers, when using atazanavir / ritonavir, the dose of lamotrigine may need to be increased, and if atazanavir / ritonavir is canceled, it will be necessary to decrease.

    Elderly patients (over 65 years old)

    It is not necessary to adjust the dosage regimen in comparison with the recommended regimen. The pharmacokinetics of lamotrigine in this age group does not practically differ from that in adults under the age of 65 years.

    Liver dysfunction

    Initial, escalating and maintenance doses should generally be reduced by about 50% and 75% in patients with moderate (Child-Pugh stage B) and severe (Child-Pugh stage C) degree liver dysfunctions, respectively.Increasing and maintenance doses should be adjusted depending on the clinical effect.

    Renal dysfunction

    Patients with renal insufficiency should be prescribed Lamolep ® with caution. For patients with end-stage renal failure, the initial doses of Lamolep ® should be calculated in accordance with the dosage regimen for patients taking AED. For patients with a significant decrease in renal function, a reduction in maintenance doses may be recommended.

    Side effects

    Adverse reactions identified in clinical studies in patients with epilepsy or bipolar disorder were divided into groups characteristic of individual indications for use. Additional adverse reactions identified during post-registration observation for both indications for use are included in the subsection “Post-registration observation”.When considering the general safety profile of lamotrigine, the information contained in all three subsections should be consulted.

    The adverse reactions presented below are listed according to the damage to organs and organ systems and the frequency of occurrence. The frequency of occurrence is defined as follows: very often (≥1 / 10), often (≥1 / 100 and <1/10), infrequently (≥1 / 1000 and <1/100), rarely (≥1 / 10000 and <1 / 1000), very rare (<1/10000, including isolated cases). Frequency categories were formed on the basis of data from clinical trials of the drug and post-marketing observation.

    Frequency of occurrence of adverse reactions

    Epilepsy

    The following adverse reactions have been identified in clinical studies in patients with epilepsy and in assessing the overall safety profile of lamotrigine and should be considered in conjunction with adverse reactions identified in clinical trials in patients with bipolar affective disorder and during the period of post-registration use of the drug.

    Skin and subcutaneous tissue disorders: very often – skin rash; rarely – Stevens-Johnson syndrome; very rarely – toxic epidermal necrolysis.

    In additional double-blind clinical trials in adults, skin rash was observed in 10% or fewer of patients taking lamotrigine and 5% of patients taking placebo. In 2% of patients, the onset of a skin rash was the reason for the withdrawal of lamotrigine. The rash, usually maculopapular, generally appears within 8 weeks of starting therapy and resolves after lamotrigine is discontinued.

    Rare cases of severe, potentially life-threatening skin rash including Stevens-Johnson syndrome and toxic epidermal necrolysis (Lyell’s syndrome) have been reported. Although most patients with drug withdrawal reversed symptoms, some patients remained permanently scarred and, in rare cases, drug-related deaths were reported.

    The overall risk of rash is closely related to:

    • with a high initial dose of lamotrigine and an excess of the recommended dose escalation regimen during lamotrigine therapy;
    • with concomitant use of valproate.

    There have also been reports of the development of a drug reaction with eosinophilia and systemic manifestations (DRESS syndrome), also known as hypersensitivity syndrome. This condition is associated with various systemic manifestations (see disorders of the immune system **).

    From the side of the blood and lymphatic system: very rarely – hematological disorders (including neutropenia, leukopenia, anemia, thrombocytopenia, pancytopenia, aplastic anemia, agranulocytosis), lymphadenopathy.Hematologic disorders and lymphadenopathy may or may not be associated with hypersensitivity syndrome (see Immune System Disorders **).

    From the immune system: very rarely – DRESS syndrome or hypersensitivity syndrome ** (including symptoms such as fever, lymphadenopathy, facial edema, disorders of the blood, liver and kidney function).

    ** There have also been reports of the development of a rash within this syndrome, which proceeds with varying degrees of clinical severity and can, in rare cases, lead to the development of disseminated intravascular coagulation (DIC) syndrome and multiple organ failure.It is important to note that early manifestations of hypersensitivity (eg, fever, lymphadenopathy) may be present even in the absence of overt signs of rash. If such signs and symptoms develop, the patient should be examined by a doctor immediately, and, unless another cause for the development of symptoms is established, lamotrigine should be discontinued.

    Mental disorders: often – aggressiveness, irritability; very rarely – tics, hallucinations, confusion.

    From the nervous system: very often – headache; often – drowsiness, insomnia, dizziness, tremors; infrequently – ataxia; rarely – nystagmus.

    From the side of the organ of vision: infrequently – diplopia, blurred vision.

    From the gastrointestinal tract: often – nausea, vomiting, diarrhea.

    From the liver and biliary tract: very rarely – increased activity of liver enzymes, impaired liver function, liver failure. Liver dysfunctions usually develop in combination with hypersensitivity reactions, but in isolated cases, they were noted in the absence of obvious signs of hypersensitivity.

    From the musculoskeletal system: very rarely – lupus-like syndrome.

    General disorders and disorders at the injection site: often – fatigue.

    Bipolar disorder

    The following adverse reactions have been identified in clinical trials in patients with bipolar disorder and in assessing the overall safety profile of lamotrigine should be considered in conjunction with adverse reactions identified in clinical trials in patients with epilepsy and during post-registration observation.

    Skin and subcutaneous tissue disorders: very often – skin rash; rarely – Stevens-Johnson syndrome.

    When evaluating all studies (controlled and uncontrolled) on the use of lamotrigine in patients with bipolar disorder, skin rash occurred in 12% of patients receiving lamotrigine, while in controlled clinical trials in patients with bipolar disorder, skin rash occurred in 8% of patients who received lamotrigine and 6% of patients who received placebo.

    From the nervous system: very often – headache; often – agitation, drowsiness, dizziness.

    From the musculoskeletal system: often – arthralgia.

    General disorders and disorders at the injection site: often – pain, back pain.

    Post-registration observation

    This section includes adverse reactions identified during post-registration observation for both indications for use.When assessing the overall safety profile of lamotrigine, these adverse reactions should be considered in conjunction with adverse reactions identified in clinical trials in patients with epilepsy and bipolar disorder.

    From the side of the blood and lymphatic system: very rarely – hemophagocytic lymphohistiocytosis.

    From the immune system: very rarely – hypogammaglobulinemia.

    Skin and subcutaneous tissue disorders: rarely – alopecia.

    Mental disorders: very rarely – nightmares.

    From the nervous system: very often – drowsiness, ataxia, headache, dizziness; often – nystagmus, tremor, insomnia; rarely – aseptic meningitis; very rarely – agitation, gait instability, movement disorders, worsening symptoms of Parkinson’s disease, extrapyramidal disorders, choreoathetosis. There are reports that lamotrigine may worsen symptoms of parkinsonism in patients with pre-existing Parkinson’s disease, and sporadic reports of the development of extrapyramidal symptoms and choreoathetosis in patients without this disease.

    From the side of the organ of vision: very often – diplopia, blurred vision; rarely – conjunctivitis.

    From the gastrointestinal tract: very often – nausea, vomiting; often diarrhea.

    On the part of the kidneys and urinary tract: very rarely – tubulointerstitial nephritis *.

    * May occur with uveitis.

    Only for epilepsy

    From the nervous system: very rarely – an increase in the frequency of seizures.

    Contraindications to use

    • Hypersensitivity to lamotrigine or any component of the drug;
    • children under 3 years old;
    • lactose intolerance, lactase deficiency, glucose-galactose malabsorption.

    Precautions: chronic renal failure, liver dysfunction, allergic reactions or skin rash to other antiepileptic drugs in history.

    Application during pregnancy and lactation

    Pregnancy

    Risks associated with antiepileptic drugs (AEDs) in general

    Women who are fertile should consult a specialist.

    If a woman is planning a pregnancy, the need for treatment for AED should be reviewed. In women undergoing treatment for epilepsy, abrupt discontinuation of antiepileptic therapy should be avoided.because this can lead to a resumption of seizures, which can have serious consequences for the woman and the unborn child. In the offspring of mothers who received AED, the risk of congenital malformations is 2-3 times higher than the expected incidence of the general population, which is about 3%. The most commonly reported abnormalities are cleft upper lip, heart and vascular defects, and neural tube defects. Multiple therapy for AED is associated with a higher risk of congenital malformations than monotherapy, therefore, monotherapy should be used whenever possible.

    Risk associated with lamotrigine

    Lamotrigine has a weak inhibitory effect on dihydrofolic acid reductase and therefore, theoretically, may lead to an increased risk of impaired development of the embryo and fetus due to decreased levels of folic acid. Consideration should be given to taking folic acid during pregnancy planning and early pregnancy. Post-registration data from several prospective pregnancy registries have documented the pregnancy outcomes of about 8700 women who received lamotrigine monotherapy in the first trimester of pregnancy.In general, the data obtained do not confirm an overall increase in the risk of congenital malformations, although from a limited number of pregnancy registers there are reports of an increase in the risk of oral malformations. The completed case-control study did not show an increased risk of oral malformation compared with other serious malformations following lamotrigine use.

    There are insufficient data on the use of lamotrigine in combination therapy to assess whether the risk of malformations is associated with other drugs used in combination with lamotrigine.

    As with other drugs, lamotrigine should be used during pregnancy only if the expected benefit outweighs the potential risk. Physiological changes during pregnancy can influence the concentration of lamotrigine and / or its therapeutic effect. There have been reports of a decrease in plasma lamotrigine concentration during pregnancy with a possible risk of loss of seizure control. After delivery, lamotrigine concentrations may increase rapidly with the risk of dose-related adverse reactions.Therefore, serum concentrations of lamotrigine should be monitored before pregnancy, during pregnancy, as well as immediately after childbirth, and in the future. If necessary, dose selection should be carried out to maintain serum lamotrigine concentration at the same level as before pregnancy, or the dose should be adjusted depending on the clinical response. In addition, dose-related adverse reactions should be monitored postpartum.

    Breastfeeding period

    Lamotrigine passes into breast milk to varying degrees, the total concentration of lamotrigine in breastfed babies can reach approximately 50% of the concentration of lamotrigine recorded in the mother.Thus, in some breastfed infants, serum lamotrigine concentrations may reach levels at which pharmacological effects appear.

    It is necessary to balance the potential benefits of breastfeeding with the potential risk of developing adverse reactions in the baby. If a woman taking Lamolep ® decides to breastfeed, then the child should be monitored for any adverse reactions.

    Fertility

    Studies of the reproductive function of animals using lamotrigine did not reveal any impairment of fertility. No studies have been conducted on the effects of lamotrigine on human fertility.

    Application for violations of liver function

    The drug should be prescribed with caution in case of impaired liver function.

    Application for impaired renal function

    The drug should be prescribed with caution in chronic renal failure.

    Use in children

    The use of the drug is contraindicated in children under 3 years of age.

    Use in elderly patients

    Elderly patients (over 65 years of age) do not need to adjust the dosage regimen compared to the recommended regimen.

    Special instructions

    Skin rash

    There have been reports of skin adverse reactions that usually occurred within the first 8 weeks after starting lamotrigine therapy.Most rashes are mild and go away on their own, but there are also reports of severe rashes requiring hospitalization and discontinuation of lamotrigine. These included such potentially life-threatening skin reactions as Stevens-Johnson syndrome and toxic epidermal necrolysis (Lyell’s syndrome). In adult patients using lamotrigine as part of a study in accordance with generally accepted recommendations, severe skin reactions develop with an incidence of about 1 in 500 patients with epilepsy.Stevens-Johnson syndrome is registered in about half of these cases (1 in 1000 patients). In patients with bipolar disorder, when taking lamotrigine, the incidence of severe skin rashes according to clinical studies is approximately 1 in 1000 patients. Children are at higher risk of developing severe skin rashes than adults. Several studies evaluating the use of lamotrigine reported that the incidence of skin rashes requiring hospitalization in children ranged from 1 in 300 to 1 in 100 children.In children, the initial manifestation of a rash can be mistaken for an infection, so doctors should consider the possibility of a child’s reaction to the drug, manifested by the development of rash and fever in the first 8 weeks of therapy. In addition, the overall risk of rash appears to be significantly associated with:

    • high starting dose of lamotrigine and exceeding the recommended dose escalation regimen during lamotrigine therapy;
    • the simultaneous use of valproate.

    Caution should also be exercised when treating patients with a history of allergic reactions or rash in response to other antiepileptic drugs, since the incidence of rash (not classified as serious) after lamotrigine was three times higher in patients with such a history. than in patients with an uncomplicated history.

    If a rash is detected, all patients (adults and children) should be immediately examined by a doctor, and lamotrigine should be stopped immediately, unless it is obvious that the development of the rash is not associated with taking the drug.It is not recommended to resume taking lamotrigine in cases where its previous appointment was canceled due to the development of a skin reaction associated with the use of lamotrigine, unless the expected therapeutic effect of the drug obviously outweighs the possible risks. It has also been reported that rash can develop as part of a drug reaction with eosinophilia and systemic manifestations (DRESS syndrome), also known as hypersensitivity syndrome. The condition is associated with a variety of systemic manifestations, including fever, lymphadenopathy, facial swelling, abnormalities of the blood, liver and kidneys, and aseptic meningitis.The severity of the manifestation of the syndrome varies widely and in rare cases can lead to the development of disseminated intravascular coagulation and multiple organ failure. It should be noted that early manifestations of hypersensitivity syndrome (fever, lymphadenopathy) can be observed even in the absence of obvious manifestations of the rash. If these signs and symptoms develop, the patient should immediately consult a doctor, and unless another cause of the symptoms is established, lamotrigine should be discontinued.

    Aseptic meningitis

    The development of aseptic meningitis is reversible with discontinuation of the drug in most cases, but resumes in some cases with repeated administration of lamotrigine.Repeated use leads to a rapid return of symptoms, which are often more severe. Lamotrigine should not be re-prescribed to patients in whom treatment was previously canceled due to the development of aseptic meningitis associated with the use of lamotrigine.

    Hemophagocytic lymphohistiocytosis (HLH)

    HLH has been reported in patients taking lamotrigine. HLH is a syndrome of abnormal activation of the immune system that can be life-threatening.HLH is characterized by clinical signs and symptoms such as fever, rash, neurologic symptoms, hepatosplenomegaly, lymphadenopathy, cytopenia, increased serum ferritin concentration, hypertriglyceridemia, and abnormal liver function and blood clotting. Typically, symptoms appear within 4 weeks of starting treatment. Patients who develop these signs and symptoms should be evaluated immediately and a diagnosis of HLH should be considered. Treatment with lamotrigine should be discontinued if another cause of symptoms cannot be established.

    Hormonal contraceptives

    Effect of hormonal contraceptives on the pharmacokinetics of lamotrigine

    It has been shown that the combined drug ethinyl estradiol + levonorgestrel (30 μg + 150 μg) approximately doubles the concentration of lagine clearance, which leads to an approximately 2-fold decrease in the concentration of lamotrigine in blood plasma. When it is prescribed, to achieve the maximum therapeutic effect, in most cases, an increase in the maintenance doses of lamotrigine will be required, but not more than 2 times.In women who are no longer taking lamotrigine glucuronidation inducers and taking hormonal contraceptives, the treatment regimen for which includes a week of taking an inactive drug (or a week’s break in taking a contraceptive), a gradual transient increase in the concentration of lamotrigine will be observed during this period of time. The increase in concentration will be more pronounced if the increase in the dose of lamotrigine is carried out several days before taking or during the period of taking an inactive drug.

    Health care providers should be clinically skilled in managing women who begin or stop taking hormonal contraceptives while on lamotrigine treatment, as this will in most cases require a dose adjustment of lamotrigine.

    Other oral contraceptives and hormone replacement therapy have not been studied, but they may have a similar effect on the pharmacokinetic parameters of lamotrigine.

    Effect of lamotrigine on the pharmacokinetics of hormonal contraceptives

    In a study involving 16 healthy volunteers, the combined use of lamotrigine and a combined hormonal contraceptive (containing ethinyl estradiol and levonorgestrel) led to a moderate increase in the clearance of Forgestrel concentration and changes in LH.The effect of these changes on ovulatory activity of the ovaries is unknown. However, the possibility cannot be ruled out that in some women taking lamotrigine and hormonal contraceptives, these changes may cause a decrease in the effectiveness of contraceptives. Therefore, women taking lamotrigine should be instructed to immediately report changes in their menstrual patterns to their doctor. about sudden bleeding.

    Dihydrofolate reductase

    Lamotrigine is a weak inhibitor of dihydrofolate reductase, therefore there is a possibility of the drug’s effect on folate metabolism with its long-term use.However, it has been shown that lamotrigine does not cause significant changes in hemoglobin concentration, average erythrocyte volume and folate concentration in serum or erythrocytes with a duration of use of the drug up to 1 year, and also does not cause significant changes in folate concentration in erythrocytes with a duration of use of the drug up to 5 years.

    Effect of lamotrigine on organic cation carrier 2 (OCT2) substrates

    Lamotrigine is an inhibitor of tubular secretion via organic cation carrier proteins 2 (OCT2).This can lead to an increase in the plasma concentration of some drugs, which are excreted mainly by the kidneys. The combined use of lamotrigine and OCT2 substrates with a narrow therapeutic range, for example, dofetilide, is not recommended.

    Renal failure

    Single administration of lamotrigine to patients with end-stage renal failure did not reveal significant changes in the concentration of lamotrigine in blood plasma.However, the accumulation of the glucuronide metabolite is very likely, therefore, care must be taken when treating patients with renal insufficiency.

    Patients taking other drugs containing lamotrigine

    Do not prescribe Lamolep ® to patients already receiving other drugs containing lamotrigine without consulting a doctor.

    Brugada-like changes on the ECG

    Very rarely, against the background of the use of lamotrigine, the development of brugada-like changes on the ECG was observed, however, a causal relationship with the use of lamotrigine has not been established.Therefore, before using lamotrigine in patients with Brugada syndrome, such treatment should be carefully considered.

    Epilepsy

    Abrupt withdrawal of lamotrigine, like other AEDs, can provoke a relapse of seizures. If the patient’s condition does not require an abrupt cessation of therapy due to a threat to the patient’s safety (for example, when a rash appears), the dose of lamotrigine should be reduced gradually over 2 weeks. There are reports that severe seizures, including status epilepticus, can lead to the development of rhabdomyolysis, multiple organ dysfunctions and disseminated intravascular coagulation, sometimes fatal.Similar cases have been observed with the use of lamotrigine.

    Suicidal risk

    Symptoms of depression and / or bipolar disorder may occur in patients with epilepsy. It has also been shown that patients with epilepsy and bipolar disorder are at high risk of suicide. 25-50% of patients with bipolar disorder have had at least one suicide attempt; such patients may have worsening symptoms of depression and / or develop suicidal ideation and suicidal behavior (suicidality), regardless of the use of drugs for the treatment of bipolar disorder, including lamotrigine.Suicidal thoughts and suicidal behavior have been reported in patients treated with AED for several indications, including epilepsy and bipolar disorder. A meta-analysis of randomized, placebo-controlled trials of AEDs (including lamotrigine) also showed a modest increase in suicidal risk. The mechanism for the development of this risk is unknown, and the available data do not exclude the possibility of an increased risk of suicide with the use of lamotrigine. Therefore, patients should be closely monitored for the occurrence of suicidal thoughts and behavior.Patients (and patient caregivers) should be advised of the need for medical advice if these symptoms occur.

    Bipolar disorder

    Children and adolescents under 18 years of age

    Treatment with antidepressants is associated with an increased risk of suicidal thoughts and behavior in children and adolescents with clinical depression and other mental disorders.

    Clinical deterioration in patients with bipolar disorder

    In patients with bipolar disorder receiving lamotrigine, it is necessary to carefully monitor the symptoms of clinical deterioration (including the appearance of new symptoms) and suicidality, especially at the beginning of treatment and at the time of dose changes.Patients with a history of suicidal thoughts or suicidal behavior, young patients and patients with severe suicidal thinking before starting therapy are at a high risk of suicidal thoughts or suicidal behavior; such patients should be closely monitored during treatment. Patients (and caregivers) should be warned to watch for any worsening patient condition (including new symptoms) and / or suicidal thoughts / behavior or thoughts of self-harm and should seek immediate medical attention if the appearance of such symptoms.Consideration should be given to modifying the treatment regimen, including discontinuing the drug, in patients who experience clinical deterioration (including the onset of new symptoms) and / or the appearance of suicidal thoughts / behavior, especially if these symptoms are severe, with a sudden onset and have not previously been noted …

    Effect on the ability to drive vehicles and mechanisms

    Two studies with healthy volunteers showed that the effect of lamotrigine on fine hand-eye coordination, eye movements and subjective sedation did not differ from the placebo effect.There have been reports of neurological side effects of lamotrigine, such as dizziness and diplopia. Therefore, before getting behind the wheel of a car or operating machinery, patients should evaluate the effect of lamotrigine on their condition.

    Since the effect of all antiepileptic drugs is characterized by individual variability, patients should consult their doctor about the ability to drive a car.

    Overdose

    Symptoms

    When doses exceeded 10-20 times the maximum therapeutic dose, fatal cases have been reported.Overdose manifested symptoms including nystagmus, ataxia, impaired consciousness, epileptic seizure, and coma. In case of an overdose in patients, an expansion of the QRS interval (prolongation of the time of intraventricular conduction) is also observed.

    Treatment

    Recommended hospitalization and maintenance therapy in accordance with the clinical picture.

    Drug interactions

    Uridine-5′-diphospho- (UDP) -glucuronyltransferases (UGT) have been found to be enzymes responsible for the metabolism of lamotrigine.Therefore, drugs that are inducers or inhibitors of glucuronidation can affect the apparent clearance of lamotrigine. Strong or moderate inducers of the cytochrome P450 3A4 isoenzyme (CYP3A4), which are also known to be inducers of UGT, can also increase the metabolism of lamotrigine. There is no evidence that lamotrigine causes clinically significant induction or inhibition of cytochrome P450 isoenzymes. Lamotrigine can induce its own metabolism, but this effect is moderate and it is unlikely that it has clinically significant consequences.

    Drugs that have been shown to have a clinically significant effect on lamotrigine concentration are listed in Table 6. In addition, this table lists drugs that have been shown to have little or no effect on lamotrigine concentration. generally. Usually, one should not expect that the combined use of such drugs will lead to any clinical consequences. However, attention should be paid to patients with epilepsy, especially sensitive to fluctuations in the concentration of lamotrigine.

    Atazanavir / ritonavir, carbamazepine, lopinavir / ritonavir, primidone, rifampicin, phenytoin, phenobarbital, ethinyl estradiol / levonorgestrel combination drug Aripiprazole, bupropion, gabapentinos, paracetamide, olamparidamide, lacropion, gabapentinos, paracetamide, olymparine pregabalin, topiramate, felbamate

    For dosage instructions, seein the section “Dosing regimen”; for women taking hormonal contraceptives, also see the subsection “Hormonal contraceptives” in the “Special instructions” section.

    Interaction with PEP

    Valproic acid, which inhibits the glucuronization of lamotrigine, reduces the metabolism of lamotrigine and lengthens its average T 1/2 by almost 2 times. Certain AEDs (such as phenytoin, carbamazepine, phenobarbital, and primidone) that induce cytochrome P450 isoenzymes also induce UGT and thus accelerate the metabolism of lamotrigine.It was reported about the development of adverse events from the central nervous system, including dizziness, ataxia, diplopia, blurred vision and nausea in patients who started taking carbamazepine while on lamotrigine therapy. These adverse events usually resolved after lowering the carbamazepine dose. A similar effect was observed in a study of the use of lamotrigine and oxcarbazepine in healthy adult volunteers, but the effect of dose reductions has not been studied. In a study with healthy adult volunteers, lamotrigine 200 mg and oxcarbazepine 1200 mg did not alter lamotrigine metabolism, and lamotrigine did not alter oxcarbazepine metabolism.

    In a study involving healthy volunteers, the combined use of felbamate (1200 mg 2 times / day) and lamotrigine (100 mg 2 times / day for 10 days) did not lead to clinically significant changes in the pharmacokinetics of lamotrigine.

    Based on a retrospective analysis of the drug level in the blood plasma in patients taking lamotrigine with and without gabapentin, it was revealed that gabapentin does not lead to a change in the apparent clearance of lamotrigine.

    Potential drug interactions between levetiracetam and lamotrigine were investigated by assessing the serum concentrations of both drugs in placebo-controlled clinical trials.These data indicate that lamotrigine does not affect the pharmacokinetics of levetiracetam, and levetiracetam does not affect the pharmacokinetics of lamotrigine.

    The combined use of pregabalin (200 mg 3 times / day) had no effect on plasma C ss of lamotrigine. There is no pharmacokinetic interaction between lamotrigine and pregabalin.

    The use of topiramate did not lead to a change in the concentration of lamotrigine in the blood plasma. Taking lamotrigine increased the concentration of topiramate by 15%.

    In a study of patients with epilepsy, the combined use of zonisamide (200-400 mg / day) with lamotrigine (150-500 mg / day) for 35 days did not significantly affect the pharmacokinetics of lamotrigine.

    The simultaneous use of lacosamide (200, 400 or 600 mg / day) did not affect the plasma concentration of lamotrigine in placebo-controlled clinical trials involving patients with partial seizures.

    In a pooled analysis of data from three placebo-controlled clinical trials that examined the adjunctive use of perampanel in patients with partial seizures and primary generalized tonic-clonic seizures, the highest dose of perampanel studied (12 mg / day) resulted in an increase in lamotrigine clearance less than on 10%.

    Although changes in plasma concentrations of other AEDs have previously been reported, controlled studies have not shown that lamotrigine affects plasma concentrations of concomitant AEDs. In vitro studies have shown that lamotrigine does not displace other AEDs from protein binding sites.

    Interaction with other psychotropic drugs

    The pharmacokinetics of lithium when taking anhydrous lithium gluconate (2 g 2 times / day for 6 days) in 20 healthy volunteers did not change with the combined use of lamotrigine at a dose of 100 mg / day …

    Repeated oral administration of bupropion did not have a statistically significant effect on the pharmacokinetics of a single dose of lamotrigine in 12 participants and caused only a slight increase in the AUC of lamotrigine glucuronide.

    In a study involving healthy adult volunteers, olanzapine at a dose of 15 mg reduced the AUC and Cmax max of lamotrigine by an average of 24% and 20%, respectively. Lamotrigine at a dose of 200 mg did not affect the pharmacokinetics of olanzapine.

    Multiple oral administration of lamotrigine (400 mg / day) did not have a clinically significant effect on the pharmacokinetics of risperidone after taking a single dose of 2 mg in 14 healthy adult volunteers.

    At the same time, drowsiness was noted:

    • in 12 out of 14 volunteers with the combined use of risperidone at a dose of 2 mg and lamotrigine;
    • in 1 in 20 volunteers with risperidone alone;
    • in no volunteer with lamotrigine alone.

    In a study involving 18 adult patients with bipolar I disorder who received lamotrigine according to the established regimen (at least 100 mg / day), the dose of aripiprazole was increased from 10 mg / day to a final value of 30 mg / day for 7 the daytime period and then continued treatment with the drug taking 1 time / day for another 7 days.There was an average decrease of about 10% in C max and lamotrigine AUC.

    In in vitro inhibition experiments, it was shown that when co-incubated, amitriptyline, bupropion, clonazepam, fluoxetine, haloperidol or lorazepam had a minimal effect on the formation of the main metabolite of lamotrigine-2-N-glucuronide. Data on the study of the metabolism of bufuralol by liver microsomal enzymes isolated from humans led to the conclusion that lamotrigine does not reduce the clearance of drugs metabolized mainly by CYP2D6 isoenzymes.In vitro studies also suggest that clozapine, phenelzine, risperidone, sertraline, or trazodone are unlikely to affect lamotrigine clearance.

    Interaction with hormonal contraceptives

    Effect of hormonal contraceptives on the pharmacokinetics of lamotrigine

    In a study involving 16 female volunteers, it was noted that taking combined oral contraceptives containing 30 mcdionestrae and one tablet of ethinyl mcg caused an approximately twofold increase in the clearance of lamotrigine (after oral administration), which led to a decrease in the AUC and C max of lamotrigine by an average of 52% and 39%, respectively.During the week without taking the drug (i.e., with a weekly break in taking the contraceptive), a gradual increase in the concentration of lamotrigine in the blood serum was observed, while the concentration of lamotrigine, measured at the end of this week before the introduction of the next dose, was on average about 2 times higher than during the joint admission period.

    Effect of lamotrigine on the pharmacokinetics of hormonal contraceptives

    In a study involving 16 female volunteers, it was shown that during the period of equilibrium concentrations, lamotrigine at a dose of 300 mg did not affect the pharmacokinetics of ethinyl estradiol, a component of a combined oral contraceptive.There was a moderate increase in the clearance of the component of the oral contraceptive – levonorgestrel (after oral administration), which led to a decrease in AUC and C max levonorgestrel on average by 19% and 12%, respectively. Measurements of serum follicle-stimulating hormone (FSH), luteinizing hormone (LH), and estradiol during this study revealed a slight decrease in ovarian suppression in some women, although serum progesterone measurements in none of the 16 women showed hormonal confirmation of ovulation.The effect of a moderate increase in levonorgestrel clearance and changes in serum FSH and LH levels on ovarian ovulation activity has not been established. The effect of other doses of lamotrigine (other than 300 mg / day) has not been studied and studies with other hormonal drugs have not been conducted.

    Interaction with other drugs

    In a study involving 10 male volunteers, rifampicin increased the clearance of lamotrigine and decreased its T 1/2 due to the induction of liver enzymes responsible for glucuronidation.Patients concomitantly taking rifampicin should be advised of a lamotrigine dosing regimen with concomitant glucuronidation inducers.

    In a study with healthy volunteers, lopinavir and ritonavir showed a decrease of about 50% in the plasma concentration of lamotrigine, possibly due to the induction of glucuronidation. Patients concurrently taking lopinavir and ritonavir should be advised of a lamotrigine dosing regimen with concomitant glucuronidation inducers.

    In a study involving healthy adult volunteers, taking atazanavir and / or ritonavir (300 mg / 100 mg) resulted in a decrease in AUC and Cmax values ​​ max of lamotrigine in blood plasma (in a single dose of 100 mg) by an average of 32% and 6 % respectively.

    In a study involving healthy adult volunteers, paracetamol at a dose of 1 g (4 times / day) reduced the AUC and C min of lamotrigine in blood plasma by an average of 20% and 25%, respectively.

    The results of in vitro studies evaluating the effect of lamotrigine on cationic carriers of organic substrates showed that lamotrigine, and not its metabolite 2 (N) -glucuronide, is an inhibitor of cationic carriers of organic substrates at potentially clinically significant concentrations.These data show that lamotrigine is an inhibitor of organic substrate cationic transporters with an IC 50 of 53.8 μM.

    Impact on laboratory parameters

    Lamotrigine has been reported to interfere with some rapid urinalysis tests for illegal drugs, which can lead to false positive results, in particular when detecting phencyclidine. A more specific alternative chemical method should be used to confirm a positive result.

    Storage conditions of the drug Lamolep

    ®

    The drug should be stored out of the reach of children at a temperature not exceeding 30 ° C.

    Shelf life of the drug Lamolep

    ®

    The shelf life is 5 years. Do not use after the expiration date printed on the package.

    Terms of sale

    The drug is available with a prescription.

    Contacts for inquiries

    Organization accepting claims from consumers
    Moscow representative office of Gedeon Richter OJSC
    119049 Moscow, 4th Dobryninsky per., 8
    Tel .: +7 (495) 363-39-50
    E-mail: [email protected]

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    instructions for use, dosage, composition, analogs, side effects / Pillintrip

    Combinazioni controindicato

    Con farmaci em grado di allungare L’inter vallo QT e causare tachicardia parossistica, compresa La tachicardia ventricolare polimorfica pericolosa per la vita del tipo de pirueta-flicker : con-i mezzi Di classe IA (chinidina, disopiramide) E Class and III (Amiodarone, sotalolo, dofetilide, ibutilide), Con bepridil, cisaprida, metadone, sultopride, thioridazine eritromicina (s / i), spiramycin (s / i) , mizolastine, vincamine (s / s), halofantrine, sumfantrine, sparfloxacin, gatifloxacin, moxifloxacin, moxifloxacin, moxifloxacin, pentamidine.

    Con agonisti dopaminergici (cabergolina, quinagolide) when not usati pr trattare La maladie Di Parkinson – antagonismo reciproco degli effetti degli agonisti del recettore della dopamina e dei neuroletici. Apartments Gli agonisti della dopamina, which can causare about amplificare ue simptomenti psicotici. Amisulpride può aumentar i sintomini della maladie Di Parkinson (vedere “istruzioni weapons specialists, but”),

    Con levodopa (vei “controlindicazioni”) – antagonism of reciproco degli effetti Di levodopa e neuroleptici.

    Combinazioni não recomendado

    Con farmaci che aumentano il Risco di tachicardia ventricolare polimorfica pericolosa per la vita del tipo “pirueta” “ (” torsade de pointes “) – pharmaceuticals che causano diltiazem, clonidine, guanfacine, digitali preparation, donepezil, rivastigmine, tacrine, ambenonia cloruro, galantamine, pyridostigmine bromuro, neostigmine bromuro) , GCS, tetracosactide) – quando li si utilizza, è necessario riparinare la perdita di potassio e mantenere ONU agosto março junho normale di potassio nel sangue.

    Con time neuroletici (aloperidolo, pimozide, pipothiazine, sertindole, clorpromazina, sevomepromazine, sultopride, sulpiride, tiapride, veraliprid, droperidolo), antidepressivi, litio, farmici, particolhythti antifolisca aumentare ventricolare Di “piroetta” type “ (” torsade de pointes “):

    Con l’Alco-amisulpride aumenta gli effetti centrali Dell’Alco. L’Alco aumenta l’effetto sedativo dei neuroleptici,

    amantadine, apomorphine, bromocriptina, entacapone, lisuride, pergolide, piribedil, pramipexolo, ropinirole, selegiline) (lead “controindicazioni” e “istruzioni specialist”) – antagonismo reciproco degli effetti dela dei dei neuroletici.Apartments Gli agonisti della dopamina, which can causare about amplificare ue simptomenti psicotici. Amisulpride può pegiorare I sintomini della maladie Di Parkinson.

    Combinazioni da consider

    Con agenti depressivi del sistema nervoso central-derivina della morfina (analgesici, antitosse), barbiturici, benzodiazepínicos, ansiolitici não benz amodiazepin, anti-depressive ), H-blockanti 1 – recettori Dell’istamina con effetto sedativo, farmacio antipertensivi Di azione central (clonidina), neurolettici, baclofeno, talidomide, pisotifen – aumento nerunciato Dell’effetto inibitorio sul sistem.Hidden rizione della concentrazione, che crea un pericolo maggiore per i conducenti Di trasporto e le persone che lavoro con le macchine,

    Con agenti ipotensivi, inclusi beta-blockanti (bisoprololo, carvedilolo, metoprololo) – Il Risco di ipotensione arterios ipotensione ortostatica (effetto additivo). Per i beta-blocquanti, vedere “Interazioni, combinazioni non recommandate”.

    BISEPTOL instruction UA ​​/ 9311/01/01 (5326) MEDANA PHARMA Aktsionerne Partnership

    Ingredients:

    Active ingredients: sulfamethoxazole / trimethoprim;

    5 ml of suspension contains 200 mg of sulfamethoxazole, 40 mg of trimethoprim;

    Excipients : polyethylene glycol (macrogol) hydroxystearate, sodium carmellose, aluminum magnesium silicate, citric acid, sodium phosphate dodecahydrate, methyl parahydroxybenzoate (E 218), propyl parahydroxybenzoate (E 216), sodium maltitol (aromatic substances of sodium, aromatic substances, aromatic substances) , propylene glycol), propylene glycol, purified water.

    Dosage form. Oral suspension.

    Basic physical and chemical properties: suspension of white or light cream color with a strawberry smell.

    Pharmacological group. Antimicrobial agents for systemic use; a combination of sulfonamides and trimethoprim and its derivatives. ATX code J01E E01.

    Pharmacological properties.

    Pharmacodynamics.

    The in vitro antibacterial effect of cotrimoxazole extends to both gram-positive and gram-negative pathogens, including the microorganisms listed below, although sensitivity may vary by geographic area.

    Pathogens of course are sensitive (MIC (minimum inhibitory concentration) 90 ≤ 2 mg / l [trimethoprim]; ≤ 38 mg / l [sulfamethoxazole]).

    Koki: Moraxella catarrhalis.

    Gram-negative rods: Haemophilus Parainfluenzae , Citrobacter Freundii , others Citrobacter spp. , Klebsiella Oxytoca , others Klebsiella spp. , Enterobacter cloacae, Enterobacter aerogenes, Hafnia alvei, Serratia Marcescens , Serratia liquefaciens, others Serratia spp., Yersinia enterocolitica, others Yersinia spp. , Vibrio cholerae.

    Various gram-negative rods: Edwardsiella tarda, Alcaligenes faecalis, Burkholderia pseudomallei.

    Based on clinical experience, such pathogens are also considered susceptible: Brucella, Listeria monocytogenes, Nocardia asteroides, Pneumocystis jiroveci (P. carinii), Cyclospora cayetanensis.

    Partially sensitive pathogens (IPC 90 = 4 mg / l [trimethoprim]; = 76 mg / l [sulfamethoxazole])

    Koki: Staphylococcus aureus (methicillinchutlivi and methicillin), Staphylococcusspp. (coagulase negative), Streptococcus pneumoniae (penicillin sensitive, penicillin resistant).

    Gram-negative bacilli: Haemophilus influenzae (β-lactamase-positive, β-lactamase-negative), Haemophilus Ducreyi , E. coli, Klebsiella Pneumoniae , Morganis , Proteganella 159415 Proteganella 159415 Proteganella , Providencia Rettgeri , others Providencia spp., Salmonella Typhi , Salmonella Enteritidis , Stenotrophomonas maltophilia (formerly Xanthomonas maltophilia).

    Various gram-negative bacilli: Acinetobacter Lwoffii , Acinetobacter anitratus (especially baumanii), Aeromonas Hydrophila .

    Resistant pathogens (MIC 90 ≥ 8 mg / L [trimethoprim]; ≥ 152 mg / L [sulfamethoxazole])

    Burkholderia (Pseudomonas) cepacia, Pseudomonas Aeruginosa , Mycoplasma spp., Mycobacterium Tuberculosis , Shigella spp. , Treponema Pallidum , Neisseria Gonorrhoeae , Bacteroides, other exclusively anaerobic pathogens.

    When using Biseptol on an empirical basis, it is necessary to take into account the local prevalence of cotrimoxazole resistance among the bacteria causing the infection for which the treatment is being carried out.

    For infections caused by moderately susceptible pathogens, susceptibility tests should be performed to exclude resistance.

    Cotrimoxazole susceptibility can be determined using standard methods such as the disc method or the dilution method recommended by the Clinical and Laboratory Standards Institute (ICLS). ICLS recommends using the following sensitivity criteria:

    Disc method, inhibition zone diameter (mm) Dilution method, ** MIC (mg / ml) TM + CMC
    Sensitive > 16 <2 + <38
    Partially sensitive 11-15 4 + 76
    Persistent <10 > 8 +> 152

    Disc: 1.25 mcg trimethoprim and 23.75 mcg sulfamethoxazole.

    ** Trimethoprim (TM) and sulfamethoxazole (SMS) in a ratio of 1 to 19.

    Development of resistance, cross-resistance.

    Resistance to cotrimoxazole during treatment develops only in rare cases. Cross-resistance exists between all sulfonamides; cross-resistance to chemically unrelated antibiotics does not develop as a result of acquisition of resistance to cotrimoxazole.

    Synergism, antagonism.

    There is a pronounced synergy between sulfamethoxazole and trimethoprim. In most cases, this synergism manifests itself even in the presence of resistance to one of the two components of the drug.

    Pharmacokinetics.

    In terms of clinically significant pharmacokinetic properties, trimethoprim and sulfamethoxazole are largely similar.

    Suction.

    After taking trimethoprim and sulfamethoxazole, these drugs are rapidly and almost completely absorbed (bioavailability 80-100%) in the upper digestive tract.After a single dose of 160 mg trimethoprim + 800 mg sulfamethoxazole, the maximum plasma concentration of 1.5-3 mg / l for trimethoprim and 40-80 mg / l for sulfamethoxazole is achieved within 1-4 hours. If the administration is repeated every 12 hours, then the equilibrium plasma concentration of sulfamethoxazole and trimethoprim in most cases is 50-100% higher than after a single dose. Plasma level is dose-proportional. The effect of food on the kinetics of the active substances of Biseptol has not been studied.When the trimethoprim suspension is taken after a meal, absorption is less than when taken on an empty stomach, although the rate of absorption will not change with normal food.

    Distribution.

    The volume of distribution of trimethoprim and sulfamethoxazole is approximately 1.2-1.5 l / kg and 0.15-0.36 l / kg, respectively.

    At the above concentrations, 42-46% of trimethoprim and 66% of sulfamethoxazole bind to plasma proteins.

    Studies in animals and in humans have shown that trimoxazole penetrates well into tissues.A significant amount of trimethoprim and a small amount of sulfamethoxazole pass from the circulation to the interstitial fluid and other extravascular body fluids. The concentration of trimethoprim and sulfamethoxazole may be elevated in inflamed tissues.

    Trimethoprim and sulfamethoxazole were found in the fetal placenta, umbilical cord blood, amniotic fluid and fetal tissues (liver, lungs), which confirms the penetration of these substances through the placental barrier. As a rule, the concentration of trimethoprim is close in value to the concentration in the mother’s circulation, while the level of sulfamethoxazole in the fetus is lower.

    Both substances pass into breast milk. The concentration in breast milk is close in value (trimethoprim) or lower (sulfamethoxazole) compared to the concentration of the drug in the mother’s blood plasma.

    Metabolism.

    About 50-70% of the dose of trimethoprim and 10-30% of sulfamethoxazole are excreted in the urine unchanged. The main metabolites of trimethoprim are 1- and 3-oxides and 3′- and 4′-hydroxy derivatives; some of the metabolites are active. Sulfamethoxazole is metabolized in the liver mainly by N4-acetylation and to a lesser extent by glucuronidation; its metabolites are inactive.

    Conclusion.

    With normal renal function, the half-life of both components is very close in value (an average of 10 hours for trimethoprim and 11 hours for sulfamethoxazole).

    The total clearance is about 100 ml / min for trimethoprim and 20 ml / min for sulfamethoxazole.

    The half-life of trimethoprim in children is approximately equal to half the half-life in adults, while there are no corresponding significant differences for sulfamethoxazole.

    Both substances and their metabolites are excreted mainly by the kidneys, both by glomerular filtration and by tubular secretion. The concentration of trimethoprim and sulfamethoxazole in urine is approximately 100 and 5 times higher than the corresponding concentration in blood plasma.

    The level of renal clearance is 20-80 ml / min for trimethoprim and 1-5 ml / min for sulfamethoxazole.

    Both substances are found in small quantities in feces.

    Pharmacokinetics in special patient groups.

    In elderly patients, as well as in patients with impaired renal function, the half-life of both components of the drug is increased, which necessitates an appropriate dose adjustment.

    Despite the fact that the kinetics, especially trimethoprim, in patients with impaired liver function will not undergo significant changes, caution is shown when using Biseptol in high doses in severely impaired liver function. Determination of the drug level in the blood and dose adjustment are necessary when using hemodialysis.

    Clinical characteristics.

    Indications.

    Infections caused by microorganisms susceptible to cotrimoxazole:

    • infections of the upper and lower respiratory tract and ear infections: exacerbation of chronic bronchitis, bronchiectasis, pneumonia (including pneumonia caused by Pneumocystis Jiroveci ), sinusitis, otitis media;
    • infections of the genitourinary system: acute and chronic cystitis, pyelonephritis, urethritis, prostatitis
    • infections of the digestive tract, including typhoid and paratyphoid fever (including treatment of chronic carriers) and cholera (in addition to fluid and electrolyte recovery)
    • other bacterial infections caused by susceptible microorganisms: acute brucellosis, nocardiosis, actinomycetoma (with the exception of those caused by real fungi), American blastomycosis (Paracoccidioides Brasiliensis ).

    For osteomyelitis – as a last-line drug (for example, if vancomycin is contraindicated), if the sensitivity of multidrug-resistant pathogens to cotrimoxazole has been proven.

    Official guidelines for the appropriate use of antibiotics should be followed, especially those for use to prevent an increase in antibiotic resistance.

    Contraindications.

    • Hypersensitivity to active ingredients, to sulfonamides or trimethoprim, or to any of the excipients.
    • Severe parenchymal liver disease.
    • Severe renal impairment (creatinine clearance <15 ml / min), if it is not possible to periodically determine the concentration of trimethoprim and sulfamethoxazole in blood plasma.
    • Megaloblastic anemia due to folate deficiency.
    • Immune thrombocytopenia caused by trimethoprim and / or sulfonamides.
    • Hematological disorders.
    • Combination with dofetilide.
    • Deficiency of glucose-6-phosphate dehydrogenase.
    • Should not be used in children under 2 months of age.
    • Porphyria.
    • Last trimester of pregnancy and lactation.

    Interaction with other drugs and other types of interactions .

    An increase in the level of digoxin in the blood can develop with simultaneous treatment with cotrimoxazole, especially in elderly patients.

    Trimoxazole can inhibit hepatic metabolism of phenytoin.After the use of co-trimoxazole at usual clinical doses, an increase in the half-life of phenytoin was observed by 39% and a decrease in the metabolic clearance rate by 27%. With the simultaneous administration of these drugs, the likelihood of an undesirable increase in the effect of phenytoin should be taken into account. Careful monitoring of such patients is necessary, the level of phenytoin in blood plasma should be monitored.

    The effectiveness of tricyclic antidepressants may decrease with the simultaneous use of cotrimoxazole.

    Sulfonamides, including sulfamethoxazole, can displace methotrexate from the points of binding to blood plasma proteins and impair the renal transport of methotrexate, thus increasing the concentration of free methotrexate and enhancing its effect.

    Trimoxazole may affect the need for oral antidiabetic agents.

    Like other antibiotics, Biseptolum can reduce the effectiveness of oral contraceptives. Therefore, patients should be advised to take additional contraceptive measures during treatment with Biseptol.

    With the simultaneous administration of indomethacin and cotrimoxazole, the level of sulfamethoxazole in the blood may increase.

    In elderly patients who were simultaneously taking some diuretics, mainly of the thiazide series, there was an increased incidence of thrombocytopenia with purpura.

    It has been reported that trimoxazole can prolong prothrombin time in patients taking the anticulant warfarin (sulfamethoxazole can displace warfarin from the plasma albumin compound).This interaction should be taken into account when using Biseptol in patients already taking anticoagulants. In such cases, it is necessary to regularly monitor the prothrombin time and control the blood clotting time in patients.

    Patients treated with trimoxazole and cyclosporine after kidney transplantation showed a reversible deterioration in renal function, as measured by an increase in serum creatinine levels. This interaction is believed to be due to trimethoprim.

    Cases of pancytopenia have been reported in patients taking a combination of trimethoprim and methotrexate (see.Section “Features of application”). Trimethoprim has a low affinity for human dihydrofolate reductase, while it is able to increase the side effects of methotrexate, which leads to unwanted hematological interactions with methotrexate, in particular in the presence of other risk factors, such as old age, hypoalbuminemia, impaired renal function and a decrease in bone marrow reserve. These unwanted side reactions can occur, for example, with the use of high doses of methotrexate.

    These patients should be given folic acid or calcium folinate to counteract the effect on hematopoiesis (emergency treatment).

    Some reports indicate that patients taking pyrimethamine drugs for the prevention of malaria in doses exceeding 25 mg pyrimethamine per week, while taking cotrimoxazole, may develop megaloblastic anemia.

    Cases of toxic delirium have been reported after concomitant administration of Biseptol and amantadine.

    There is evidence that trimethoprim can interact with dofetilide by inhibiting the renal transport system. With the simultaneous administration of trimethoprim at a dose of 160 mg in combination with sulfamethoxazole at a dose of 800 mg 2 times a day and dofetilide at a dose of 500 μg 2 times a day for 4 days, an increase in the area under the concentration-time curve (AUC) of dofetilide was observed by 103 % and maximum plasma concentration (Cmax) by 93%. Dofetilide can cause serious ventricular arrhythmias associated with prolongation of the QT interval, including bidirectional ventricular tachycardia (pirouette-type), which directly depends on the plasma concentration of dofetilide.The simultaneous administration of dofetilide and trimethoprim is contraindicated.

    Caution should be exercised if the patient is taking other drugs that may cause hyperkalemia.

    Also, the simultaneous use of trimethoprim / sulfamethoxazole (cotrimoxazole) and spironolactone can lead to clinically significant hyperkalemia.

    Concomitant use with cotrimoxazole can increase the systemic exposure of drugs that are metabolized mainly by CYP2C8, in particular paclitaxel, amiodarone, dapsone, repaglinide, rosiglitazone and pioglitazone.

    Paclitaxel and amiodarone have a narrow therapeutic index. If the patient is receiving paclitaxel or amiodarone, an alternative antibiotic should be considered.

    Both dapsone and trimoxazole can cause methemoglobinuria. Patients receiving dapsone in combination with cotrimoxazole should be monitored for methemoglobinuria. Alternative treatments should be prescribed whenever possible.

    Influence on laboratory parameters.

    Biseptol, namely trimethoprim, included in its composition, can affect the results of determining the concentration of methotrexate in blood serum, carried out by the method of competitive binding to proteins using bacterial dihydrofolate reductase as a ligand.However, when determining methotrexate by radioimmunoassay, interference does not occur.

    Biseptol can change the reaction of determination of creatinine using alkaline picrate according to the Jaffe method (increases the level of creatinine by about 10%). Functional disorders of the tubular secretion of creatinine can give a false decrease in the level of creatinine clearance.

    Prescribing cotrimoxazole at a dose of 160 mg of trimethoprim and 800 mg of sulfamethoxazole causes an increase in lamivudine exposure by 40% (for trimethoprim).Lamivudine does not affect the pharmacokinetics of trimethoprim and sulfamethoxazole.

    Application features .

    Biseptol should be used with caution in patients with a history of allergies or bronchial asthma.

    Depending on the dose and duration of treatment, there may be an increase in the risk of severe adverse reactions in elderly patients, patients with complicated conditions such as impaired liver and / or kidney function, as well as in patients who are simultaneously taking other drugs.Although rare, fatalities have been reported due to adverse reactions, namely persistent pathological changes in the cellular composition of the blood (dyscrasia), Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell’s syndrome) and fulminant liver necrosis.

    After the use of sulfamethoxazole, manifestations of life-threatening reactions (Stevens-Johnson syndrome and toxic epidermal necrolysis (TEN)) were observed. The patient should be informed about the signs and symptoms of skin lesions and the need for careful monitoring of this reaction.The greatest risk of developing skin changes associated with Stevens-Johnson syndrome and toxic epidermal necrolysis occurs during the first weeks of treatment.

    If skin symptoms of Stevens-Johnson syndrome or toxic epidermal necrolysis (eg, skin blistering or enanthema) appear, sulfamethoxazole should be discontinued.

    The best treatment results for Stevens-Johnson syndrome and toxic epidermal necrolysis are achieved with early diagnosis and immediate discontinuation of the suspected product.Early diagnosis is associated with a better prognosis.

    If a patient is diagnosed with Stevens-Johnson syndrome or toxic epidermal necrolysis, sulfamethoxazole should not be taken again.

    Rare cases of life-threatening complications associated with the use of sulfonamides are described, including Stevens-Johnson syndrome, TEN, acute liver necrosis, agranulocytosis, megaloblastic anemia and other bone marrow lesions, as well as hypersensitivity from the respiratory tract.

    Except in exceptional cases, Biseptol should not be prescribed to patients with severe persistent changes in the cellular composition of the blood. From time to time, the drug was prescribed to patients who were receiving cytotoxic agents for the treatment of leukemia, and there were no signs of any side effects from the bone marrow or peripheral blood.

    Given the likelihood of hemolysis, Biseptol should not be prescribed to patients with certain hemoglobinopathies (Hb-Zurich, Hb-Cologne), unless absolutely necessary and only in minimal doses.

    Treatment should be stopped immediately at the first appearance of skin rashes or any other serious adverse reactions.

    To minimize the risk of adverse reactions, the duration of treatment with Biseptol should be as short as possible, in particular in elderly patients. In case of impaired renal function, the dose should be adjusted in accordance with the dosage instructions set out in the section “Dosage and Administration”.

    Adverse reactions such as rash, fever, leukopenia, elevated serum aminotransferase levels, hypokalemia, and hyponatremia are more common in AIDS patients who have received trimoxazole to treat Pneumocystis Jiroveci infection.

    Severe persistent diarrhea during or after treatment may indicate pseudomembranous colitis and requires urgent treatment. In such cases, it is necessary to stop taking Biseptol and start appropriate diagnostic and therapeutic measures (for example, vancomycin 250 mg 4 times a day by mouth). Antiperistaltic drugs are contraindicated in such cases.

    If Biseptol is taken for a long period of time (more than 14 days), a regular complete blood count is necessary.Consideration should be given to prescribing folic acid during treatment, however, the possible effect on antibacterial efficacy should be considered.

    In rare cases, usually in emaciated patients, crystals in the urine were observed with the use of sulfonamides.

    During long-term treatment, it is necessary to monitor the function of the kidneys and urinary system, especially in patients with impaired renal function.

    To prevent the development of crystalluria during treatment, you should ensure adequate fluid intake and urine output.

    The presence of crystals in fresh urine was rare, but was observed in the cooled urine of patients during the treatment period. In patients with hypoalbuminuria, the risk of crystal formation may be increased.

    Since Biseptol, like other antibiotics, can reduce the effect of oral contraceptives, patients should be advised to take additional contraceptive measures while treating with Biseptol.

    Long-term treatment with Biseptol can lead to overgrowth of insensitive microorganisms and fungi.In case of superinfection, appropriate treatment should be started immediately.

    Caution is required when treating patients with porphyria or thyroid dysfunction.

    In elderly patients or patients with impaired renal function, changes in the blood may be observed, indicating a deficiency of folic acid. They disappear after folic acid administration.

    Caution is needed when treating patients with additional risk factors for folate deficiency, such as treatment with phenytoin or other folate antagonists and malnutrition.

    Cases of pancytopenia have been reported in patients taking a combination of trimethoprim and methotrexate (see Section “Interaction with other medicinal products and other forms of interaction”).

    Trimethoprim has been found to have side effects on phenylalanine metabolism. However, this does not apply to PKU patients who are on an appropriate diet.

    Persons with “slow acetylation” have an increased risk of idiosyncratic reactions to sulfonamides.

    In patients at risk of hyperkalemia and hyponatremia, careful monitoring of plasma potassium and sodium is warranted. The simultaneous use of drugs that cause hyperkalemia and spironolactone can lead to severe hyperkalemia.

    Should be avoided in patients at risk or suspected of developing porphyria. The use of trimethoprim and sulfamethoxazole has been associated with exacerbation of porphyria.

    Since liquid maltitol is a part of excipients, patients with rare hereditary fructose intolerance should not take this drug.Maltitol liquid may have a mild laxative effect.

    The medicinal product contains methyl parahydroxybenzoate and propyl parahydroxybenzoate, therefore it can cause allergic reactions (possibly delayed).

    The medicinal product contains polyethylene glycol (macrogol) hydroxystearate, therefore it can cause headache, irritation of the gastrointestinal tract and diarrhea.

    5 ml of this medicine contains 38 mg of sodium. Caution should be exercised when using in patients on a controlled sodium diet.

    Application during pregnancy or lactation .

    Pregnancy.

    Trimethoprim and sulfamethoxazole cross the placental barrier; their safety in pregnant women has not been established.

    Trimethoprim is a folic acid antagonist, and high doses of cotrimoxazole have been associated with malformations in animal studies. Control clinical studies have revealed a possible relationship between the use of folic acid antagonists and congenital malformations in humans, therefore it is not recommended to prescribe the drug during pregnancy, especially in the first trimester, unless the expected benefit to the mother outweighs the risk to the fetus.If the drug is prescribed during pregnancy, folic acid should be considered.

    Use in the third trimester of pregnancy is contraindicated (see “Contraindications”).

    Sulfamethoxazole competes with bilirubin for binding with blood plasma albumin, as a result of which a significant amount of the drug penetrates the placental barrier and remains in the blood of the newborn for several days. As a result, the development and exacerbation of hyperbilirubinemia and associated nuclear jaundice is possible if the drug was used by the mother several days before delivery.This theoretical risk is of particular importance in neonates at increased risk of hyperbilirubinemia, that is, in premature infants or in wild game with glucose-6phosphate dehydrogenase deficiency.

    Breastfeeding.

    Since trimethoprim and sulfamethoxazole pass into breast milk, breastfeeding while taking Biseptol is not recommended. If the use of the drug is necessary, breastfeeding should be discontinued.

    The ability to influence the reaction rate when driving motor transport or other mechanisms.

    Biseptol usually does not directly affect the ability to drive vehicles or work with other mechanisms. However, there is a possibility of side effects from the nervous system and psyche, which can affect this ability, in some cases – to a large extent (see Section “Adverse Reactions”).

    Method of administration and dosage.

    Biseptol should be taken every 12 hours. Biseptol is best used after meals with a sufficient amount of liquid.In acute infections, Biseptol is prescribed for a period of at least 5 days.

    The drug is administered orally.

    Shake well before use until a homogeneous suspension is obtained.

    5 ml of suspension contains 200 mg of sulfamethoxazole and 40 mg of trimethoprim.

    A graduated measure is attached to the bottle.

    Children and adolescents

    2-5 months – 2.5 ml (morning and evening) with an interval of 12 hours;

    6 months – 5 years – 5 ml twice a day with an interval of 12 hours;

    6-12 years old – 10 ml twice a day with an interval of 12 hours;

    12 years – 20 ml twice a day with an interval of 12 hours.

    The dosage regimen corresponds approximately to a daily dose of 6 mg of trimethoprim and 30 mg of sulfamethoxazole per 1 kg of body weight. For severe infections, the dose can be increased by 50%.

    Adults

    Take 20 ml of suspension every 12 hours.

    The minimum dose for adults and adolescents over 12 years of age, as well as for long-term treatment (longer than 14 days) – 10 ml of suspension every 12 hours.

    In especially difficult cases of infection – 30 ml of suspension every 12 hours.

    Dosing in special cases.

    Pneumocystis jiroveci pneumonia.

    The recommended dose is up to 20 mg of trimethoprim and up to 100 mg of sulfamethoxazole per 1 kg of body weight per day, divided into equal doses for administration every 6 hours for 14 days.

    The maximum dose depending on the patient’s body weight is determined according to the table:

    Body weight, kg Doses for taking every 6 hours
    8 5 ml
    16 10ml
    24 15 ml
    32 20 ml
    40 25 ml
    48 30 ml
    64 40 ml
    80 50 ml

    For the prevention of pneumonia caused by Pneumocystis jiroveci, adults should be prescribed 800 mg sulfamethoxazole and 160 mg trimethoprim.Children are recommended a dose of trimethoprim 150 mg / m 2 / day and sulfamethoxazole 750 mg / m 2 / day, which is used at 2 levels of intake for 3 consecutive days.

    The total daily dose should not exceed 320 mg of trimethoprim and 1600 mg of sulfamethoxazole. In this case, you can adhere to the following recommendations:

    Body surface area, m 2

    Doses for taking every 12 hours

    0.26

    2.5 ml

    0.53

    5 ml

    1.06

    10 ml

    Dosage for patients with impaired renal function.

    Creatinine clearance

    Recommended dosage regimen

    > 30 ml / min

    15-30 ml / min

    <15 ml / min

    Usual dose

    Half of the usual dose

    It is not recommended to use Biseptol

    Patients on hemodialysis.

    If Biseptol is indicated for patients on hemodialysis, it should be taken the first time in a standard dose, then half or a third of the standard dose every 24-48 hours. It is necessary to monitor the concentration of the drug in the blood serum and adjust the dose accordingly.

    Children.

    The drug can be used in children from 2 months.

    Biseptol should not be prescribed to premature babies, as well as newborns during the first 2 months of life, given the increased risk of kernicterus (bilirubin encephalopathy).

    Overdose.

    Symptoms of acute overdose : nausea, vomiting, diarrhea, colic, headache, vertigo, dizziness, drowsiness, loss of consciousness, confusion, fever, intellectual and visual disturbances, jaundice, changes in blood composition, in severe cases – crystalluria, hematuria and anuria.

    Symptoms of chronic overdose: oppression of hematopoiesis (thrombocytopenia, leukopenia, megaloblastic anemia), as well as other pathological changes in the blood picture due to folic acid deficiency.

    Treatment (depending on symptoms): gastric lavage, taking medications that induce vomiting, increased renal excretion by forced diuresis (alkalinization of urine promotes the elimination of sulfamethoxazole), hemodialysis (peritoneal dialysis is ineffective). It is necessary to monitor the blood picture and the level of electrolytes. With pronounced pathological changes in the blood picture or jaundice, specific treatment is prescribed. To eliminate the effect of trimethoprim on hematopoiesis, calcium folinate can be prescribed at a dose of 3-6 mg for 5-7 days.

    Adverse reactions.

    The main side effects are skin reactions and mild gastrointestinal disturbances, observed during treatment in about 5% of cases.

    Infections and parasitic diseases: fungal infections, namely candidiasis.

    On the part of the blood and lymphatic system: leukopenia, granulocytopenia, thrombocytopenia, eosinophilia, agranulocytosis, anemia (megaloblastic, immunohemolytic, aplastic), methemoglobinemia, pancytopenia, neutropenia, polycythemia-6 deficiency, hemolysis-phytogenosisMost often, changes in the blood were detected were mild, asymptomatic and reversible after discontinuation of the drug.

    From the immune system: allergic reactions, namely fever, drug fever, angioedema, urticaria, anaphylactoid reactions and serum sickness, periarteritis nodosa, allergic vasculitis, allergic myocarditis, exfoliative dermatitis erythematosus, systemic reactions.

    Metabolic and Nutritional Disorders: Elevated Serum Potassium – In a significant proportion of patients with pneumonia caused by Pneumocystis Jiroveci , high doses of trimethoprim cause a progressive but reversible increase in serum potassium.In patients with impaired potassium metabolism or renal failure, or in those taking drugs that induce hyperkalemia, trimethoprim can very often lead to hyperkalemia (more than 60% of patients), even when used at recommended doses. In such patients, careful monitoring of potassium levels should be ensured.

    Hyponatremia.

    Hypoglycemia in non-diabetic patients usually develops in the first few days of treatment. Patients with impaired renal function, liver disease or malnutrition and those taking high doses of trimethoprim-sulfamethoxazole are at particular risk.

    From the side of the psyche: hallucinations, depression, apathy, insomnia, increased fatigue, sleep disturbance. Delirium and psychosis, particularly in elderly patients.

    From the nervous system: neuropathy (including peripheral neuritis and paresthesia), uveitis. Aseptic meningitis or meningitis-like symptoms, ataxia, convulsions, vertigo, tinnitus, headache, dizziness.

    Respiratory organs: pneumonitis with eosinophilic infiltration, shortness of breath, cough, shallow breathing, pulmonary infiltrates.Cough, shallow breathing, pulmonary infiltrates can be early indicators of respiratory hypersensitivity, which are very rarely fatal.

    From the digestive tract: nausea (with or without vomiting), anorexia, stomatitis, glossitis, gingivitis, diarrhea, pseudomembranous enterocolitis, acute pancreatitis in seriously ill patients, gastritis, abdominal pain.

    On the part of the digestive system: increased levels of transaminases and bilirubin, hepatitis, cholestasis, jaundice, liver necrosis, syndrome of disappearance of bile ducts, fulminant hepatitis, inflammation of the liver parenchyma.

    Skin: rashes. In most cases, these side effects are mild and quickly disappear after the drug is discontinued.

    As with other drugs containing sulfonamides, very rare side effects are erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell’s syndrome), purpura, Henoch-Henoch purpura, photosensitization. Unknown: Drug rash with eosinophilia and systemic symptoms (DRESS)

    From the musculoskeletal system: arthralgia, myalgia, rhabdomyolysis.

    From the kidneys and urinary tract: impaired renal function and renal failure, oliguria, anuria, interstitial nephritis, increased blood urea nitrogen, increased serum creatinine, crystalluria. Sulfonamides, including Biseptol, can increase diuresis, in particular in patients with edema caused by diseases of the cardiovascular system.

    The drug contains methyl parahydroxybenzoate (E 218) and propyl parahydroxybenzoate (E 216), which can cause allergic reactions (possibly delayed).

    Side effects in HIV-infected patients:

    HIV-infected patients with frequent comorbidities and their treatment usually receive long-term prophylaxis or treatment of pneumonia caused by Pneumocystis Jiroveci using high doses of Biseptol. Apart from a small number of additional side effects, the profile of side effects in these patients is similar to that in the population of patients who are not HIV-infected.However, some side effects are observed more often (in about 65% of patients) and often more severe, which makes it necessary to interrupt the course of treatment with Biseptol in 20-25% of patients.

    In particular, the following adverse reactions were observed in addition or with a higher frequency:

    From the blood and lymphatic system: mainly neutropenia, but also anemia, leukopenia, granulocytopenia and thrombocytopenia, agranulocytosis.

    From the immune system: fever, usually due to skin rashes, allergic reactions such as angioedema, anaphylactoid reactions and serum sickness, hypersensitivity reactions.

    Metabolic and nutritional disorders: hyperkalemia. In such patients, it is necessary to ensure careful monitoring of the level of potassium in the blood serum hyponatremia, hypoglycemia.

    On the part of the psyche: acute psychosis.

    From the nervous system: neuropathy (including peripheral neuritis and paresthesia), hallucinations, uveitis. Aseptic meningitis or meningitis-like symptoms, ataxia, seizures, resting tremors of the type of Parkinson’s disease, sometimes in combination with apathy, cramps of the feet and swinging gait, vertigo, tinnitus.

    Respiratory organs: pneumonitis with eosinophilic infiltration.

    From the digestive tract: anorexia, nausea with or without vomiting, as well as diarrhea, stomatitis, glossitis, pancreatitis.

    From the digestive system: increased levels of liver enzymes / transaminases, cholestatic jaundice, severe hepatitis.

    Skin: maculopapular rash, which quickly disappear after discontinuation of the drug, usually with itching, photosensitivity, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell’s syndrome), Henoch-Genoch purpura.

    From the musculoskeletal system: arthralgia, myalgia, rhabdomyolysis.

    From the kidneys and urinary tract: impaired renal function, azotemia, increased serum creatinine levels, crystalluria, sulfonamides, including Biseptol, can increase diuresis, in particular in patients with edema caused by diseases of the cardiovascular system.

    Adverse Reactions Associated with Pneumocystis jioverci (P.cairnii), which leads to pneumocystis pneumonia (PCP): severe hypersensitivity reactions, skin rashes, fever, neutropenia, thrombocytopenia, increased hepatic transaminases, rhabdomyolysis, hypocalcemia, hyponatremia, hyperkalemia.

    With the use of high doses in PCP therapy, severe hypersensitivity reactions were observed, which required discontinuation of the drug. If signs of bone marrow suppression appear, the patient should be prescribed corrections for calcium folate deficiency (5-10 mg / day).

    Severe hypersensitivity reactions have been observed in PCP patients who were re-prescribed trimethoprim and sulfamethoxazole after a few days’ interval.

    Rhabdomyolysis has been observed in HIV-positive patients taking trimoxazole prophylactically or for the treatment of PCP.

    Expiry date. 3 years.

    Storage conditions .

    Store in original packaging at a temperature not exceeding 25 ° C.Keep out of the reach of children.

    After opening, store the bottle tightly closed for 8 months.

    Do not use after the expiration date.

    Packaging.

    80 ml dark glass vials with a polyethylene cap, screwed.

    1 bottle with a dispenser (measured with divisions) in a cardboard box.

    Vacation category.

    By prescription.

    Manufacturer.

    Medana Pharma Joint Stock Company /

    Medana Pharma Spolka Akcyjna.

    Manufacturer’s location and address of the place of business.

    st. Polish Military Organization 57, 98-200 Sieradz, Poland /

    57, Polskiej Organizacji Wojskowej Str.