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:

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.

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.

Interactions

Cimetidine should be avoided while being treated with this medicine. Inquire with your doctor or pharmacist about other heartburn/upset stomach medications.

Overdose

Missed Dose

Storage

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

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 I_Kr, 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 I_Na,_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.

References: 1. 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
• Infections

• Ask your doctor if you are not sure about the medicines you take. Tell your doctor about all prescription and non-prescription medicines, vitamins, dietary supplements, and any natural or herbal remedies. Tikosyn and other medicines may affect each other, causing serious side effects. If you take Tikosyn with certain medicines, you will be more likely to have a different type of abnormal heartbeat.

Know the medicines you take. Keep a list of your medicines and show it to your doctor and pharmacist when you get a new medicine.

How should I take Tikosyn ?

• Take Tikosyn exactly as your doctor tells you.
• Do not change your Tikosyn dose unless your doctor tells you to.
• Your doctor will do tests before you start and while you take Tikosyn .
• Do not stop taking Tikosyn until your doctor tells you to stop. If you miss a dose, just take the next dose at your regular time. Do not take 2 doses of Tikosyn at the same time.
• Tikosyn can be taken with or without food.
• If you take too much Tikosyn , call your doctor or go to the nearest hospital emergency room right away. Take your Tikosyn capsules with you to show to the doctor.

What are the possible side effects of Tikosyn ?

• Headache
• Chest pain
• dizziness

• Call your doctor right away if you have signs of electrolyte imbalance:

• Severe diarrhea
• Unusual sweating
• Vomiting
• Not hungry (loss of appetite)
• Increased thirst (drinking more than normal)

• 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).
• Keep Tikosyn away from moisture and humidity.
• Keep Tikosyn in a tightly closed container.
• Keep Tikosyn and all medicines out of the reach of children.

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)

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.

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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: 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:

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:

Dosage for patients with impaired renal function.

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.