What is triazolam. How many people use triazolam. Can you become addicted to triazolam. What are the side effects of triazolam abuse.

Understanding Triazolam (Halcion)

Triazolam, marketed under the brand name Halcion, is a hypnotic medication primarily used to treat acute insomnia and other temporary sleep disorders. As a member of the benzodiazepine class of drugs, triazolam acts as a central nervous system depressant, helping users fall asleep faster and sleep more soundly. However, its potency and short half-life of 1.5 to 5.5 hours also make it prone to abuse and addiction.

The Prevalence of Triazolam Use

Benzodiazepine medications like triazolam are widely used across the United States to address issues like anxiety, sleep problems, and even dental procedures. In 1991, a New York Times article reported that more than 7 million Americans were taking Halcion as a sleep aid. Today, that number has skyrocketed to over 47 million people, highlighting the growing problem of prescription sedative abuse.

According to the Substance Abuse and Mental Health Services Administration, the reasons for triazolam abuse can vary, including a desire to relax, relieve tension, experiment, or simply to “feel good or get high.” Tragically, benzodiazepines like triazolam had more fatalities in 2015 than cocaine, with approximately 9,000 deaths, the majority of which involved an opioid.

The Risks of Triazolam Addiction

Can you become addicted to triazolam? The answer is a resounding yes. Prolonged use of this medication can lead to both physical and psychological dependence. As the brain becomes accustomed to the mood-altering effects of triazolam, it begins to crave the drug, leading users to constantly increase their dosage and develop a tolerance.

The Food and Drug Administration has warned that with “nightly use for more than a few weeks,” users may experience “some loss of effectiveness or adaptation to the sleep-inducing effects” of triazolam, as well as a degree of dependence that develops. This can manifest in painful withdrawal symptoms when the drug is stopped or its use is reduced.

The Side Effects of Triazolam Abuse

The physical addiction and dependence associated with triazolam can result in a range of unpleasant side effects and withdrawal symptoms. These may include drowsiness, dizziness, headaches, nausea, vomiting, anxiety, depression, seizures, and even hallucinations.

Particularly concerning is the phenomenon of “rebound insomnia,” where users experience continued or intensified sleeplessness after stopping triazolam, essentially a reversal of the medication’s intended effects.

The Dangers of Long-Term Triazolam Use

Triazolam is intended as a short-term solution for acute insomnia and other temporary sleep disorders. Its potency and rapid onset of action make it effective in the short term, but also highly prone to abuse and addiction. Prolonged use can lead to physical and psychological dependence, as well as a host of unpleasant and potentially dangerous side effects and withdrawal symptoms.

It is crucial that triazolam, like other benzodiazepines, be used only under the guidance of a medical professional and for the shortest duration possible. Exceeding the recommended dosage or continuing use beyond the initial treatment period can have serious consequences for one’s health and well-being.

Seeking Help for Triazolam Addiction

If you or a loved one is struggling with triazolam abuse or addiction, it is essential to seek professional help. Abruptly stopping the medication can lead to life-threatening withdrawal symptoms, so it is crucial to undergo a medically supervised detox and rehabilitation process.

Comprehensive treatment options, including behavioral therapy, support groups, and medication-assisted treatment, can help individuals overcome the physical and psychological aspects of triazolam addiction and regain control of their lives. Don’t hesitate to reach out for help – your health and well-being are worth it.

Conclusion

Triazolam, while a legitimate medical treatment for acute insomnia and sleep disorders, is a highly potent and potentially addictive medication. Its widespread use and abuse, as well as the serious risks associated with prolonged use, make it a concerning public health issue. Understanding the dangers of triazolam addiction and seeking professional help when needed are crucial steps in addressing this growing problem.

Triazolam (Halcion) Abuse and Addiction

Triazolam is a hypnotic agent and generic version of Halcion, which is most commonly used to treat insomnia. As you continue using Triazolam, you may rapidly build up a tolerance and more of the medication will be needed to achieve what would normally require a small or regular dose. As you develop a tolerance to benzodiazepines, you’re at a greater risk of becoming physically and mentally addicted to them.

What Is Triazolam?

Triazolam is similar to other benzodiazepines in that it’s a sedative classified as a central nervous system depressant. Triazolam is the most frequently used benzodiazepines for treating acute insomnia and other non-permanent sleep disorders. This is mostly due to its relatively short half-life of 1.5 to 5.5 hours.

Triazolam isn’t used to treat chronic anxiety, epilepsy or other mental disorders. Halcion has also been prescribed in dentist offices to help people sleep while enduring the agony of a toothache. Halcion has also been used to help a person sleep during long flights.

We can’t function without sleep and things like toothaches, back pain and acute insomnia can happen at any time. Medications like Triazolam have a legitimate medical purpose and when used with caution they can be safe—but only when used with the guidance of a medical professional.

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Remember that Halcion is only a temporary solution. It is too potent and too risky a medication to take for long periods of time. Nonetheless, people still abuse it for the mild calming euphoria, sedation and sense of well-being.

How Many People Use Triazolam?

Benzodiazepines are a problem just about anywhere you go in the United States. From Maryland, down to Texas and over to to California, people of all ages and walks of life continue to abuse prescription sedatives such as triazolam. Reasons for abuse can vary between any of the following reasons from Substance Abuse and Mental Health Services Administration:

• to relax or relieve tension
• to help with sleep
• to help with feelings or emotions
• to experiment or to see what the drug was like
• to feel good or get high
• to increase or decrease the effect of some other drug
• because the respondent was “hooked” or needed to have it

In a New York Times article from 1991, there were more than seven million Americans taking Halcion as a sleep aid. Today there are more than 47 million people taking Halcion and it’s rapidly becoming a dangerous abuse of prescription medications.

Benzodiazepines had more fatalities in 2015 than cocaine, with approximately 9,000 deaths in the United States. According to research by National Institute on Drug Abuse, nearly all of those deaths involved an opioid.

Can I Become Addicted To Triazolam?

Yes, addiction and dependence are likely with prolonged use of triazolam. Which is why they’re only prescribed for acute symptoms. So what happens when you continue using them? As with any benzodiazepine tranquilizer, you build up a tolerance—triazolam can have a rapid rate of tolerance in comparison to long-term benzodiazepines.

As your brain becomes accustomed to having a mood altering chemical around, it sends messages to your body via neurotransmitters and tells you that you need more of it. When your body craves more Halcion, you’re constantly increasing your dosage; thus building up a tolerance and becoming physically and mentally addicted.

Triazolam tolerance and dependence are further broken down by the Food and Drug Administration, “some loss of effectiveness or adaptation to the sleep inducing effects of these medications may develop after nightly use for more than a few weeks and there may be a degree of dependence that develops. For the benzodiazepine sleeping pills that are eliminated quickly from the body, a relative deficiency of the drug may occur at some point in the interval between each night’s use. ”

Are There Side-Effects From Triazolam Abuse?

Physical addiction and dependence of Triazolam can consequently end in withdrawals when the medication runs out or use is ceased. It’s not uncommon for Triazolam to have painful side-effects either. These can include:

Side-Effects

• drowsiness
• dizziness
• lightheadedness
• headache
• problems with coordination
• nervousness
• tingling of the skin
• nausea
• vomiting

Withdrawal Symptoms

• nausea
• seizures
• anxiety
• depression
• confusion
• insomnia
• delusions
• intense cravings
• irritability
• muscle pain
• rebound insomnia
• sweating
• fever
• chills
• nausea
• hallucinations
• vomiting
• nausea
• hallucinations
• vomiting

Rebound insomnia happens when a person stops taking triazolam and it results in continued or intensified sleeplessness. Rebound is essentially a reversal of the medication that leads to the very problems that were originally being treated. A major issue with a lot of benzodiazepines is that if they aren’t tapered off of, they can result in a drug rebound including intense anxiety, seizures, sleeplessness and panic attacks.

The symptoms of Halcion withdrawal and side-effects can be comfortably managed in a controlled environment. It can actually be dangerous trying to administer an at home detoxification for benzodiazepines, especially if you’ve been taking them for a long period of time—12 or more weeks.

A medical detox can help you wean off of benzodiazepines by starting with a safe amount (which is monitored by professionals) and decreasing it over time. During the detox stage, the physical complications of addiction are dealt with.

The next step is taking care of the psychological addiction. During this phase of addiction treatment, behavioral therapies have been proven to be some of the most beneficial treatment programs.

There Is A Treatment Program Right For You

If you’re tired of needing medications to function, but afraid of what will happen when you stop, contact Vertava Health Texas to map out a safe plan to quit. Our addiction specialists know their way around benzodiazepines and can help you find freedom from addiction. Call us today to start recovery.

When Can a Normal Dose Be an Overdose? Who Is at Risk?

For most drugs, irrespective of their indications or mechanisms of actions, there is a recommended dose for adults and often multiple age- or weight-based recommended doses for children in the US Food and Drug Administration (FDA)–approved labeling, as seen in the package insert. For triazolam (Halcion) the usual recommended adult dose is 0.25 mg. Some drugs also have a recommended dose for elderly, medically compromised, or debilitated patients. For triazolam, this FDA-recommended dose is 0.125 mg. Many drugs also have an FDA maximum recommended dose (MRD) above which either there is insufficient data on safety and efficacy or else there is sufficient data to suggest that administering or prescribing above that limit markedly increases the risk of serious side effects such as overdose toxicity. For triazolam, the FDA’s MRD is 0.5 mg. In fact, in the package insert, the FDA warns, “A dose of 0.5 mg should be used only for exceptional patients who do not respond adequately to a trial of a lower dose because the risk of several adverse reactions increases with the size of the dose administered. A dose of 0.5 mg should not be exceeded. In geriatric and/or debilitated patients the recommended dosage range is 0.125 mg to 0.25 mg. Therapy should be initiated at 0.125 mg in these groups, and the 0.25 mg dose should be used only for exceptional patients who do not respond to a trial of the lower dose. A dose of 0.25 mg should not be exceeded in these patients.” Although it is true that triazolam is indicated only for short-term insomnia, it is no more or less safe when used off label for procedural sedation at the recommended doses. Depending on the potential severity of the possible toxicity for a selected patient, one could consider giving more than the MRD if needed. However, if subsequent overdose toxicity occurs and causes significant harm, the practitioner may not have sufficient scientific evidence to demonstrate that the decision to use that higher dose was safe, justified, and within the standard of care.

We are all aware of the bell-shaped curve of biological variability, where the response to a dose of a drug can produce only a small effect in some people, a usual effect in most people, and an exaggerated effect in others. Thus, neither the recommended dose nor the MRD is absolutely safe for everyone. The dentist must understand this point and take into consideration all the patient variables that might make the MRD, or even the recommended dose, unsafe. So who are these susceptible patients? Smaller females and children certainly can have exaggerated drug effects from a usual dose. Those with unknown genetic factors that slow drug biotransformation or have altered drug receptors may fit into this category. Patients who have other drugs in their system that are known or sometimes unknown to the dentist can have additive effects. A large number of medically compromised, debilitated, and elderly patients can also exhibit drug toxicity from even small doses.

The unfortunate patient who happens to be supersusceptible to even the usual recommended dose may develop overdose toxicity even though that dose when given to the vast majority of patients would be fine. For example, a normal dose of a drug with sedative properties given to a morbidly obese patient with severe obstructive sleep apnea (OSA) or to a severely debilitated patient can produce unconsciousness, loss of airway, and even apnea during a procedure. Interestingly, drugs with intermediate or long duration of clinical activity can also pose an additional problem once the patient is dismissed for home. This is especially a concern for patients with severe OSA, of whom some have a normal body habitus and many others are morbidly obese. These patients have numerous apneic periods in their sleep due to pharyngeal soft tissue relaxation resulting in airway obstruction that causes their oxygen saturation to drop to life-threatening levels in conjunction with elevated levels of carbon dioxide. These abnormalities then trigger a primitive arousal mechanism that briefly awakens the patient and causes him or her to open the obstructed airway, which allows several breaths to be taken, often just before irreversible brain damage from hypoxic ischemia would otherwise start to occur. With these several breaths, oxygen levels then rise, carbon dioxide levels fall, and the patient again falls asleep, obstructs again, and the cycle repeats itself throughout the night. Any interference with this primitive arousal system by central nervous system depressant drugs such as sedatives, anxiolytics, opioids, and alcohol can be lethal because the obstruction would not be relieved if the patient does not awaken, and ventilation would soon be blocked until the patient dies. Additionally, the continuing elevation of carbon dioxide levels during this prolonged obstructed period also contributes to deeper levels of unconsciousness, because these high levels can have general anesthetic properties.

Residual effects from the drugs still present from the procedural sedation and possibly augmented by opioids prescribed for pain relief can block the arousal mechanism in those with OSA so that the patient does not awaken, does not open the airway, and does not breathe, and soon death ensues. Although the patient might appear to be only slightly affected by these drugs while awake, once he or she goes to sleep, the insidious depressant effects of the residual drugs combined with OSA can result in a disaster. The drug blood levels of the deceased when measured at autopsy might indicate that the patient was in a subtherapeutic range, but that dose nevertheless was just enough to produce an overdose for that highly susceptible patient.

For the normal-sized dental patient, the maximum recommended dose for lidocaine with 1 : 100,000 epinephrine is 7 mg/kg. A 50-kg healthy teenager therefore could be expected to safely tolerate a dose of 350 mg of the lidocaine, which is the equivalent of almost 10 cartridges of the 2% concentration. However, if a patient previously weighed 120 kg but now has metastatic cancer with significant liver involvement, is severely jaundiced, and now weighs 50 kg, the same 350-mg dose that was safe for the 50-kg teenager is not equally safe for this 50-kg cancer patient needing a full-mouth extraction. Although there are no specific guidelines on how to calculate a safe reduced dosage for severely compromised patients, the dentist is expected to use due caution and perhaps give no more than half of the MRD to avoid a toxic local anesthetic overdose in this patient with reduced serum protein binding capacity and hepatic dysfunction. Thus under this circumstance of severe medical debilitation, an overdose of local anesthetic can occur even within the normal dose range.

When triazolam was originally developed, the FDA approved marketing of a 0.5 mg tablet, but because of postmarketing reports of significant side effects at that dose, the 0.5 mg tablet was eliminated in favor of the lower dosage forms currently available. Similarly, the FDA recently has decreased the MRD for zolpidem (Ambien), a drug for insomnia that is similar to triazolam, although it is in a slightly different class. The FDA has now indicated that the 10-mg dose recommendation should be decreased to 5 mg in women, and the prescriber should consider also dropping the recommended dose to 5 mg in men. In light of recent enteral sedation deaths in dental offices in North Carolina, Hawaii, and earlier in Missouri where overdoses in susceptible patients appear to have occurred, the FDA could issue a black box warning not to administer more than its current MRD for all types of oral drugs used for procedural sedation, especially in patients who suffer from OSA or are otherwise debilitated or elderly.

The bottom line is that elderly, debilitated, and medically compromised patients, including those with diagnosed as well as undiagnosed severe OSA, are at increased risk for dying during procedural sedation and afterwards at home during sleep when sedatives and opioids can still exert their depressant effects on the central nervous system. To help screen for undiagnosed OSA, the dentist should use the STOP-BANG scoring system questionnaire:

• Snoring—loud enough to be heard through closed doors?

• Tired—often feel tired, fatigued, or sleepy during daytime?

• Observed—has anyone observed you stop breathing during sleep?

• Pressure—do you have or are you being treated for high blood pressure?

• BMI—more than 35 kg/m² according to BMI [body mass index] chart?

• Age—over 50?

• Neck—circumference greater than 40 cm?

• Gender—male?

For those with OSA already diagnosed in a sleep study laboratory, its severity is typically graded by the Apnea-Hypopnea Index (AHI) that combines the number of apneic episodes lasting at least 10 seconds and hypopneas per hour of sleep while simultaneously a recording of the lowest pulse oximeter reading is made. The AHI values for the severity of the OSA range from mild (5–15/h) through moderate (15–30/h) and severe (>30/h).

Not all patients are suitable for office sedation at any dose, and a cookbook sedation formula for everyone is likewise a disaster waiting to happen when given to highly susceptible patients. Once a thorough past medical history and an evaluation have been completed by the dentist, augmented when indicated by additional information supplied by the patient’s medical team, an appropriate individualized sedation plan may be devised, with safety being the primary objective rather than attaining ideal clinical efficacy where the patient does not move during the dental procedure. A normal dose can definitely be an overdose in highly susceptible people. “Safety first” must be our motto.

Halcion (triazolam) dosing, indications, interactions, adverse effects, and more

Triazolam: MedlinePlus Drug Information

Triazolam may increase the risk of serious or life-threatening breathing problems, sedation, or coma if used along with certain medications. Tell your doctor if you are taking or plan to take certain opiate medications for cough such as codeine (in Triacin-C, in Tuzistra XR) or hydrocodone (in Anexsia, in Norco, in Zyfrel) or for pain such as codeine (in Fiorinal), fentanyl (Actiq, Duragesic, Subsys, others), hydromorphone (Dilaudid, Exalgo), meperidine (Demerol), methadone (Dolophine, Methadose), morphine (Astramorph, Duramorph PF, Kadian), oxycodone (in Oxycet, in Percocet, in Roxicet, others), and tramadol (Conzip, Ultram, in Ultracet). Your doctor may need to change the dosages of your medications and will monitor you carefully. If you take triazolam with any of these medications and you develop any of the following symptoms, call your doctor immediately or seek emergency medical care immediately: unusual dizziness, lightheadedness, extreme sleepiness, slowed or difficult breathing, or unresponsiveness. Be sure that your caregiver or family members know which symptoms may be serious so they can call the doctor or emergency medical care if you are unable to seek treatment on your own.

Triazolam may be habit forming. Do not take a larger dose, take it more often, or for a longer time than your doctor tells you to. Tell your doctor if you have ever drunk large amounts of alcohol, if you use or have ever used street drugs, or have overused prescription medications. Do not drink alcohol or use street drugs during your treatment. Drinking alcohol or using street drugs during your treatment with triazolam also increases the risk that you will experience these serious, life-threatening side effects. Also tell your doctor if you have or have ever had depression or another mental illness.

Triazolam may cause a physical dependence (a condition in which unpleasant physical symptoms occur if a medication is suddenly stopped or taken in smaller doses), especially if you take it for several days to several weeks. Do not stop taking this medication or take fewer doses without talking to your doctor. Stopping triazolam suddenly can worsen your condition and cause withdrawal symptoms that may last for several weeks to more than 12 months. Your doctor probably will decrease your triazolam dose gradually. Call your doctor or get emergency medical treatment if you experience any of the following symptoms: unusual movements; ringing in your ears; anxiety; memory problems; difficulty concentrating; sleep problems; seizures; shaking; muscle twitching; changes in mental health; depression; burning or prickling feeling in hands, arms, legs or feet; seeing or hearing things that others do not see or hear; thoughts of harming or killing yourself or others; overexcitement; or losing touch with reality.

Triazolam – an overview | ScienceDirect Topics

Psychological

Triazolam alone (0.25 or 0.50 mg/70 kg) dexamfetamine sulfate alone (20 or 30 mg/70 kg), and triazolam + dexamfetamine sulfate in all dose combinations have been compared in a crossover, double-blind, staggered-dosage, placebo-controlled study in 18 healthy adults across nine sessions [16]. Relative to the sedative measures, the effects of triazolam on memory were generally less extensively reversed by dexamfetamine. The memory measures ranged in degree of reversal: the greatest degree reversal was observed for reaction time on the n-back working memory task, and the least for accuracy on the Sternberg working memory task; most of the measures showed an overall pattern of partial reversal. Benzodiazepines have specific effects on memory that are not merely a by-product of sedative effects, and the degree to which the sedative effects contribute to the amnestic effects varies as a function of the particular memory process being assessed.

The effect of triazolam on muscarinic acetylcholine receptor binding has been investigated in living brain slices by the use of a positron-based imaging technique [17]. Stimulation of GABA/benzodiazepine binding sites lowered the affinity of the muscarinic acetylcholine cholinergic receptor for its ligand, which may underlie benzodiazepine-induced amnesia, a serious clinical adverse effect of benzodiazepines.

Ten healthy men participated in a randomized, double-blind, crossover study involving placebo and triazolam 0.125 mg [18]. Resting electroencephalography and event-related potentials under an oddball paradigm were recorded before drug administration, and at 1, 2, 4, 6, and 8 hours after. P300 waveforms were analysed by peak amplitudes. Triazolam can cause cognitive dysfunction without general sedation or apparent sleepiness, and this effect appeared up to 6 hours after administration of a low dose of triazolam.

The subjective and behavioral effects of triazolam were investigated in 20 healthy women, who took oral triazolam 0.25 mg or placebo at the follicular, periovulatory, and luteal phases of their menstrual cycle in a within-subject design [19]. After triazolam most of them reported the expected increases in fatigue and decreases in arousal and psychomotor performance. Neither plasma concentrations of triazolam nor mood and performance differed across the three phases. This study shows that the effects of triazolam are highly stable across the menstrual cycle.

The potential effects of triazolam on cognitive performance have been studied in a double-blind, placebo-controlled comparison of the acute effects of triazolam and alcohol in 20 social drinkers [20]. Triazolam was more likely to impair several objective measures of cognitive performance, such as episodic memory and divided attention, and it also slowed performance across several cognitive measures. Triazolam alone impaired other measures of metacognition, such as error detection on a choice reaction time task.

How Long Does Halcion Stay In Your System?

In answering the “What is cocaine?” question, it’s important to consider what this drug looks like. Many illicit substances have a light, powdery appearance like that of cocaine, making it harder to identify cocaine in a lineup of other drugs. When asked, “What does cocaine look like?” experts might emphasize the distinct white color and smooth texture, not unlike a powder laundry detergent.

Due to its consistency, dealers tend to sell cocaine in small, tightly wound plastic baggies or twisted-up plastic wrap. Cocaine is one of the most expensive drugs on the market, so cocaine addiction is also very expensive. Due to its high cost, the average person who uses it likely holds only small amounts at a time. When sold on the street, cocaine tends to come in grams or ounces. Larger stocks of the drug are sold in heavyweight plastic bags or dense, rectangular units of plastic wrap. These are referred to as “bricks.” You may find cocaine in a solid, chalk-like form as well, which can be easily broken down into the eventual powder. The powder is usually then formed into thin lines or “bumps” to be snorted up the nose.

Because of the high demand for the drug and its nondescript appearance, dealers tend to mix it with similar light powders to take advantage of buyers. These powders may include:

• Baking soda
• Flour
• Cornstarch
• Sugar
• Laundry detergents
• Boric acid
• Laxatives
• Local anesthetics
• Amphetamines
• Silicon
• Talcum powder

Street cocaine may contain certain additives that actually speed up or intensify the high. But in general, dealers add cheap substances to extend their supply and maximize their profit. Impure cocaine can appear off-white, pinkish or brownish depending on the other contained ingredients. A 2015 London study revealed that a typical ounce of cocaine sold on the street was only 22–25 percent pure. This percentage can drop even lower as it moves down the line through different transactions. Many people who are paying $100 for a gram of “cocaine” may only be receiving 1–3 percent actual of pure cocaine, if not less.

Crack cocaine (freebase cocaine), the base form of the drug, takes on a more crystalline or rock-like consistency. It varies in color from white to yellow to a pale rose. This substance has an ever-growing reputation as a hyper-potent and addictive drug that is dangerously affordable and available. Someone who gets hooked may find themselves turning to crack as an inexpensive way to feed their cocaine addiction, which can greatly exacerbate their health risks and the severity of their dependence.

Triazolam – Uses, Side Effects, Interactions

How does this medication work? What will it do for me?

Triazolam belongs to the class of medications called benzodiazepines. It is used for the short-term (usually no more than 7 to 10 days) relief of sleep disturbances. It can be helpful for people who have difficulty falling asleep. Triazolam is not recommended for early morning awakenings.

This medication may be available under multiple brand names and/or in several different forms. Any specific brand name of this medication may not be available in all of the forms or approved for all of the conditions discussed here. As well, some forms of this medication may not be used for all of the conditions discussed here.

Your doctor may have suggested this medication for conditions other than those listed in these drug information articles. If you have not discussed this with your doctor or are not sure why you are taking this medication, speak to your doctor. Do not stop taking this medication without consulting your doctor.

Do not give this medication to anyone else, even if they have the same symptoms as you do. It can be harmful for people to take this medication if their doctor has not prescribed it.

What form(s) does this medication come in?

0.25 mg
Each pale blue, oval, flat-faced, bevelled-edged, scored tablet, identified “APO” over “0.25”, contains 0.25 mg of triazolam. Nonmedicinal ingredients: croscarmellose sodium, FD&C Blue No. 2 Aluminum Lake, lactose monohydrate, magnesium stearate, and microcrystalline cellulose.

How should I use this medication?

The recommended dose of triazolam ranges from 0.125 mg to 0.25 mg taken before bedtime. The starting dose is usually 0.125 mg taken immediately before bedtime. The lowest effective dose of the medication should be used. Your doctor may increase the dose if necessary.

This medication should not normally be used for more than 7 to 10 consecutive days as triazolam is habit-forming. If used for more than a few weeks, this medication may lose some of its effectiveness (meaning the dose needs to be increased to have the same effect) and may also cause some dependence.

Many things can affect the dose of a medication that a person needs, such as body weight, other medical conditions, and other medications. If your doctor has recommended a dose different from the ones listed here, do not change the way that you are taking the medication without consulting your doctor.

It is important to take this medication exactly as prescribed by your doctor. If you miss a dose, take it as soon as possible and continue with your regular schedule. If it is several hours later and taking the medication will interfere with your next day’s activities, skip the missed dose and continue with your regular dosing schedule. Do not take more medication than prescribed.

Store this medication at room temperature, protect it from light and moisture, and keep it out of the reach of children.

Do not dispose of medications in wastewater (e.g. down the sink or in the toilet) or in household garbage. Ask your pharmacist how to dispose of medications that are no longer needed or have expired.

Who should NOT take this medication?

Do not take this medication if you:

• are allergic to triazolam or any ingredients of this medication
• are pregnant
• have a history of substance or alcohol abuse
• have myasthenia gravis
• have severe breathing difficulties
• have sleep apnea
• have uncorrected narrow-angle glaucoma

What side effects are possible with this medication?

Many medications can cause side effects. A side effect is an unwanted response to a medication when it is taken in normal doses. Side effects can be mild or severe, temporary or permanent.

The side effects listed below are not experienced by everyone who takes this medication. If you are concerned about side effects, discuss the risks and benefits of this medication with your doctor.

The following side effects have been reported by at least 1% of people taking this medication. Many of these side effects can be managed, and some may go away on their own over time.

Contact your doctor if you experience these side effects and they are severe or bothersome. Your pharmacist may be able to advise you on managing side effects.

• clumsiness or unsteadiness
• dizziness or lightheadedness
• drowsiness
• false sense of well-being
• nausea or vomiting
• unusual tiredness or weakness

Although most of the side effects listed below don’t happen very often, they could lead to serious problems if you do not seek medical attention.

Check with your doctor as soon as possible if any of the following side effects occur:

• behavioural changes, including:
• aggressiveness
• agitation
• angry outbursts
• anxiety
• bizarre behaviour
• decreased inhibition
• confusion
• depression (e.g., poor concentration, changes in weight, changes in sleep, decreased interest in activities, thoughts of suicide)
• hallucinations (hearing or seeing things that aren’t there)
• lack of memory (of events taking place after the medication was taken)
• muscle weakness
• trouble sleeping

Stop taking the medication and seek immediate medical attention if any of the following occur:

• signs of a serious allergic reaction (e.g., abdominal cramps, difficulty breathing, nausea and vomiting, or swelling of the face and throat)

Some people may experience side effects other than those listed. Check with your doctor if you notice any symptom that worries you while you are taking this medication.

Are there any other precautions or warnings for this medication?

Before you begin using a medication, be sure to inform your doctor of any medical conditions or allergies you may have, any medications you are taking, whether you are pregnant or breast-feeding, and any other significant facts about your health. These factors may affect how you should use this medication.

Addiction potential: Triazolam is habit-forming. Withdrawal symptoms similar to those occurring with other benzodiazepines (as well as with alcohol) have been observed after stopping triazolam suddenly when it has been taken regularly over a period of time (more than 2 weeks). These symptoms include:

• abdominal cramps
• agitation
• confusion
• diarrhea
• extreme anxiety
• headache
• irritability
• memory impairment
• muscle pain
• nervousness
• restlessness
• sleep problems
• tension
• tremors
• vomiting

Alcohol and other medications that cause drowsiness: People taking this medication should not combine it with alcohol and avoid combining it with other medications, such as narcotic pain relievers, that cause drowsiness. Doing so can cause additional drowsiness and reduced breathing as well as other side effects, which can be dangerous and potentially fatal. 

Behaviour changes: Using triazolam can cause an increase in daytime anxiety or restlessness. There have also been reports of aggressive behaviour or hostility, anxiousness, disorientation or decreased memory.

As with other medications to help with sleep problems, these effects are more likely to happen to seniors. If you experience any of these effects or notice them in a family member who is taking this medication contact your doctor as soon as possible.

Breathing problems: Triazolam, like many other sedative medications can suppress breathing. If you have asthma, other lung disease, or sleep apnea, discuss with your doctor how this medication may affect your medical condition, how your medical condition may affect the dosing and effectiveness of this medication, and whether any special monitoring is needed.

Confusion: This medication may affect mental efficiency (e.g., concentration, attention, and vigilance). The risk of confusion is greater for seniors and for those with brain injury.

Depression or psychosis: Triazolam is not recommended for use by people with depression or psychosis. Abnormal thinking and psychotic behavioural changes have been reported (e.g., aggressiveness). Particular caution is warranted for patients with a history of violent behaviour. If you have a history of mental illness, discuss with your doctor how this medication may affect your medical condition, how your medical condition may affect the dosing and effectiveness of this medication, and whether any special monitoring is needed.

Drowsiness/reduced alertness: Avoid performing hazardous activities requiring complete mental alertness, such as driving or operating machinery, until the effects of triazolam wear off. Using alcohol or other drugs that cause drowsiness or sedation is also not recommended.

Complex sleep-related behaviours such as “sleep-driving” (i.e., driving while not fully awake after ingestion of a sedative-hypnotic, with no memory of the event) have been reported by patients who have taken triazolam. The use of alcohol or other medications that cause drowsiness seems to increase the risk of this happening.

Glaucoma: This medication may cause the symptoms of glaucoma (increased pressure in the eye) to worsen. If you have glaucoma, discuss with your doctor how this medication may affect your medical condition, how your medical condition may affect the dosing and effectiveness of this medication, and whether any special monitoring is needed. Report any changes in vision to your doctor as soon as possible while you are taking this medication.

Kidney function: If you have reduced kidney function or kidney disease, discuss with your doctor how this medication may affect your medical condition, how your medical condition may affect the dosing and effectiveness of this medication, and whether any special monitoring is needed.

Liver function: Liver disease or reduced liver function may cause this medication to build up in the body, causing side effects. If you have liver problems, discuss with your doctor how this medication may affect your medical condition, how your medical condition may affect the dosing and effectiveness of this medication, and whether any special monitoring is needed.

Pregnancy: This medication should not be used during pregnancy. If you become pregnant while taking this medication, contact your doctor.

Breast-feeding: It is not known if triazolam passes into breast milk. If you are a breast-feeding mother and are taking this medication it may affect your baby. Talk to your doctor about whether you should continue breast-feeding.

Children: The safety and effectiveness of triazolam for children below the age of 18 have not been established.

Seniors: The sedative effects of triazolam may affect seniors more than others. Extra caution is needed, for example, when getting up during the night.

What other drugs could interact with this medication?

There may be an interaction between triazolam and any of the following:

• alcohol
• amiodarone
• antihistamines (e.g., cetirizine, doxylamine, diphenhydramine, hydroxyzine, loratadine)
• antipsychotics (e.g., chlorpromazine, clozapine, haloperidol, olanzapine, quetiapine, risperidone)
• apalutamide
• azelastine
• “azole” antifungals (e.g., ketoconazole, fluconazole, miconazole, voriconazole)
• barbiturates (e.g., phenobarbital, secobarbital)
• other benzodiazepines (e.g., alprazolam, diazepam, lorazepam)
• bicalutamide
• bosentan
• brimonidine
• buprenorphine
• buspirone
• calcium channel blockers (e.g., amlodipine, diltiazem, nifedipine, verapamil)
• cannabis
• chloral hydrate
• ciprofloxacin
• cobicistat
• conivaptan
• crizotinib
• cyclosporine
• dabrafenib
• deferasirox
• dexamethasone
• dronedarone
• enzalutamide
• everolimus
• general anesthetics (medications used to put people to sleep before surgery)
• grapefruit juice
• HIV non-nucleoside reverse transcriptase inhibitors (NNRTIs; e.g., efavirenz, etravirine, nevirapine)
• HIV protease inhibitors (e.g., atazanavir, indinavir, ritonavir, saquinavir)
• imatinib
• lomitapide
• macrolide antibiotics (e.g., erythromycin, clarithromycin)
• methadone
• mirtazapine
• mifepristone
• mitotane
• modafinil
• muscle relaxants (e.g., baclofen, cyclobenzaprine, methocarbamol, orphenadrine)
• nabilone
• narcotics (e.g., codeine, fentanyl, morphine, hydromorphone)
• olopatadine
• pramipexole
• quinidine
• rifabutin
• rifampin
• ropinirole
• St. John’s wort
• sarilumab
• seizure medications (e.g., carbamazepine, clobazam, levetiracetam, phenobarbital, phenytoin, primidone, topiramate, valproic acid, zonisamide)
• siltuximab
• selective serotonin reuptake inhibitors (SSRIs; e.g., citalopram, duloxetine, fluoxetine, paroxetine, sertraline)
• suvorexant
• tapentadol
• thalidomide
• theophyllines (e.g., aminophylline, oxtriphylline, theophylline)
• tocilizumab
• tolcapone
• tramadol
• tricyclic antidepressants (e.g., clomipramine, desipramine, imipramine)
• valerian
• zolpidem
• zopiclone

If you are taking any of these medications, speak with your doctor or pharmacist. Depending on your specific circumstances, your doctor may want you to:

• stop taking one of the medications,
• change one of the medications to another,
• change how you are taking one or both of the medications, or
• leave everything as is.

An interaction between two medications does not always mean that you must stop taking one of them. Speak to your doctor about how any drug interactions are being managed or should be managed.

Medications other than those listed above may interact with this medication. Tell your doctor or prescriber about all prescription, over-the-counter (non-prescription), and herbal medications you are taking. Also tell them about any supplements you take. Since caffeine, alcohol, the nicotine from cigarettes, or street drugs can affect the action of many medications, you should let your prescriber know if you use them.

All material copyright MediResource Inc. 1996 – 2021. Terms and conditions of use. The contents herein are for informational purposes only. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a medical condition. Source: www.medbroadcast.com/drug/getdrug/Triazolam

TRIAZOLAM, triazolam – instructions for use of the drug, reviews, description, price

Description of the active component

Pharmacological action

A hypnotic from the group of benzodiazepine derivatives. It also has sedative, anxiolytic, central muscle-relaxing and anticonvulsant properties. The main effects are due to the stimulation of benzodiazepine receptors in the brain, the excitation of which increases the sensitivity of GABA receptors to the mediator.As a result, GABA-ergic transmission is enhanced: chlorine channels are activated, hyperpolarization of neuronal membranes increases, and neuronal activity decreases. Triazolam shortens the period of falling asleep, reduces the number of nighttime awakenings, and increases the overall duration of sleep. It has relatively little effect on the structure of sleep, including the duration of the REM sleep phase. It is characterized by a short duration of action – the half-life is 1.5-5.5 hours. In this regard, the aftereffects are less pronounced in the morning and afternoon after taking the drug at night.

Readings

Sleep disorders – insomnia (short-term treatment – up to 2 weeks).

Dosing regimen

Average therapeutic dose – 125-250 mcg at night. For elderly patients, a dose of 250 mcg is used only if necessary.

Side effects

From the side of the central nervous system: drowsiness, dizziness, a state of stupidity, difficulty concentrating, memory impairment, depression, impaired coordination of movements, ataxia, increased excitability, aggressiveness, hallucinations.

Contraindications

Myasthenia gravis, liver and kidney disease with severe impairment of their functions, I trimester of pregnancy, hypersensitivity to benzodiazepines.

Pregnancy and lactation

Triazolam is contraindicated for use in the first trimester of pregnancy.

Application for violations of liver function

Contraindicated in liver diseases with severe impairment of their functions.

Application for impaired renal function

Contraindicated in kidney disease with severe impairment of their functions.

Special instructions

With long-term use of triazolam, drug dependence may develop.

During the period of treatment with triazolam, the use of alcoholic beverages is prohibited.

Influence on the ability to drive vehicles and use mechanisms

During the period of treatment, one should refrain from engaging in potentially hazardous activities that require increased attention and speed of psychomotor reactions (driving vehicles or working with mechanisms).

Drug interactions

With simultaneous use with anticonvulsants, the possibility of reducing the effectiveness of triazolam is expected.

Concomitant use of caffeine reduces the effectiveness of triazolam.

With simultaneous oral administration with fluconazole, itraconazole, ketoconazole, an increase in the concentration of triazolam in blood plasma, an increase in sedation and amnesia, and a prolongation of the hypnotic effect are observed.

With the simultaneous administration of isoniazid, the excretion of triazolam from the body decreases and its effects may increase.

With simultaneous use with nefazodone, the concentration of triazolam in the blood plasma increases and its inhibitory effect on the central nervous system increases.

With simultaneous use with omeprazole, cases of gait disturbance were observed, which is due to an increase in the effect of triazolam.

When used simultaneously with rifampicin, the C _max and the AUC of triazolam decrease and its effectiveness decreases.

When used simultaneously with erythromycin, clarithromycin, roxithromycin, josamycin, the effects of triazolam are enhanced due to a decrease in its excretion from the body and an increase in plasma concentration.This, apparently, is due to inhibition of the metabolism of triazolam in the liver and / or in the intestinal wall under the influence of antibiotics from the macrolide group.

When used simultaneously with ethanol, the inhibitory effect on the central nervous system is enhanced.

“Agricultural Biology”: 5-2019 Shcherbakova

doi: 10.15389 / agrobiology.2019.5.875rus

UDC 632.952: 632.95.025.8

This work was supported by the Russian Science Foundation (project No. 18-16-00084).

DEVELOPMENT OF RESISTANCE TO FUNGICIDES
IN PHYTOPATOGENIC FUNGI AND THEIR CHEMOSENSITIZATION
AS A WAY TO INCREASE PROTECTIVE EFFICIENCY
TRIAZOLES AND STROBILURINS (review)

L.A. SHCHERBAKOVA

The chemical method is still the most effective way to protect the harvest of economically significant crops and ensure its quality. In world agriculture, at least 150 fungicidal compounds with various mechanisms of action are now used, and the number of products developed on their basis and registered is several times greater. Triazoles and strobilurins are among those fungicides, the use of which in the 1980s-1990s provided a breakthrough in the fight against pathogens of the most harmful diseases (D.Fernández-Ortuño et al., 2008). However, for reliable protection of plants from fungi and oomycetes infecting them, multiple treatments with fungicides are often required, repeated during each new growing season, which worsens the ecological situation and increases the risk of developing resistance of these phytopathogens to fungicides. Resistance is the most difficult to overcome consequence of fungicidal treatments (J.A. Lucas et al., 2015), which in many cases makes them ineffective and economically unjustified (K.J. Brent et al. 2007; R.P. Oliver, 2014). Attempts to combat resistant forms of phytopathogenic fungi and oomycetes by increasing the dosage of fungicides and the frequency of treatments are futile, since they cause the spread of more and more resistant populations of these pathogens. The dominant tendencies in modern agriculture aimed at its ecologization are considered to be a reduction in the dosage of fungicides without reducing the effectiveness of their protective action and overcoming the resistance of phytopathogens.At the same time, rejection of modern fungicides from the group of high and medium risk of resistance, including strobilurins and triazoles, does not seem to be successful from a practical point of view, since they provide highly effective control of a wide range of diseases and have a number of other advantages (A.V. Filippov et al., 2016). One of the strategies contributing to overcoming many of the above contradictions could be chemosensitization of phytopathogens, that is, increasing their sensitivity to fungicides.Chemosensitization can be achieved by combining a commercial fungicide with a non-fungicidal or slightly fungitoxic natural compound (B.C. Campbell et al., 2012; V.G. Dzhavakhiya et al., 2012). In this case, concentrations are used that are insufficient to suppress the pathogen when separately treated with agents, but when they are used together, a synergistic fungicidal effect is achieved, including significantly higher than that at dosages of the fungicide to which resistant strains are insensitive.Chemosensitizing substances attack biochemical and structural targets different from those targeted by the action of fungicides, and therefore do not contribute to the selection of resistant forms. In this review, the promise of chemosensitization as an antiresistant strategy for enhancing the protective effect of fungicides is demonstrated by the example of several economically significant phytopathogenic fungi, the sensitivity of which to strobilurins and triazoles can be increased many times when they are used together with plant and microorganism metabolites or with their analogs.In addition, the problem of the development of resistance of phytopathogenic fungi and the methods that prevent its spread are briefly discussed, information on the types and main mechanisms of resistance, in particular those responsible for resistance to triazoles and strobilurins, is provided, and information on the mechanisms of action of some chemosensitizers is provided.

Keywords: chemosensitization, resistance to fungicides, phytopathogenic fungi, triazoles, strobilurins, anti-stress metabolic pathways, overcoming resistance.

FUNGICIDE RESISTANCE OF PLANT PATHOGENIC FUNGI AND THEIR CHEMOSENSITIZATION AS A TOOL TO INCREASE ANTI-DISEASE EFFECTS OF TRIAZOLES AND STROBILURINES (review)

L.A. Shcherbakova

The chemical method for plant protection is still the most reliable way to provide the high yield of economically significant crops and ensure its quality. In the world agriculture, at least 150 different fungicidal compounds with different mechanisms of action are now used, and the number of products developed and registered on their basis is much more.Triazoles and strobilurins belong to fungicides, which have expanded the opportunities to control causative agents of the most damaging diseases (D. Fernández-Ortuño et al., 2008). Nevertheless, multiple applications of fungicides during each new growing season are often required to achieve an effective control of fungal and oomycete pathogens. Such extensive applications of fungicides exacerbate negative impact on environment, and promote developing the resistance by these pathogens, representing the most disturbing consequence of fungicidal treatments (J.A. Lucas et al., 2015) that makes them relatively short-lived and eventually uneconomical (K.J. Brent et al., 2007; R.P. Oliver, 2014). Attempts to combat resistant forms of plant pathogenic fungi and oomycetes by increasing the dosage of fungicides and treatment numbers are futile, as they cause accumulation of more and more resistant strains in fungal populations. Therefore, control of these pathogens by minimal effective dosages of fungicides, without any decrease in the fungicidal efficacy, and search for ways to overcome the plant pathogen resistance to fungicides are dominant trends in plant protection for current sustainable agriculture.At the same time, the rejection of modern fungicides with high and medium risk of the resistance, including strobilurins and triazoles, does not seem to be practically rational, since they provide a highly effective control of a wide range of diseases and have several other advantages (AV Filippov et al., 2016). Chemosensitization of plant pathogens by natural compounds to increase efficacy of fungicidal treatments is an approach to solving the aforementioned problems. Chemosensitization can be accomplished by combining a commercial fungicide with a certain non- or marginally fungicidal substance at concentrations where, alone, neither compounds would be effective, while after their co-application a synergistic fungicidal effect is achieved, sometimes at a level significantly exceeding that of the fungicide dosages to which resistant strains are insensitive (B.C. Campbell et al., 2012; V.G. Dzhavakhiya et al., 2012). Since biochemical and structural targets of chemosensitizing substances differ from those targeted by fungicides, chemosensitization do not contribute to the selection of resistant pathogenic form, and reduces the toxic impact on the environment by lowering effective dosage levels of toxic fungicides. In this review, the promise of chemosensitization as an antiresistant strategy to improve efficacy of the protective fungicide effect is exemplified by experiments with several economically significant phytopathogenic fungi, which sensitivity to strobilurins and triazoles was demonstrated to enhance significantly by co-application of these fungicides with secondary plant or microbial metabolites and their synthetic analogues.In addition, the problem of the development of resistance in plant pathogenic fungi and the methods for its management are briefly described, information on the types and main mechanisms of resistance, in particular, those responsible for resistance to triazoles and strobilurins as well as data on the mechanisms of action of some chemosensitizers are presented.

Keywords: chemosensitization, plant pathogenic fungi, resistance to fungicides, triazoles, strobilurins, fungicide stress-responsive metabolic pathways, resistance overcoming.

Arpimed

Symptoms : cases of drug overdose were observed, accompanied by hallucinations and paranoid behavior.

Treatment – symptomatic (supportive measures and gastric lavage).

fluconazole is excreted mainly in the urine, therefore forced diuresis can accelerate the excretion of the drug.

A hemodialysis session lasting 3 hours reduces the plasma level of fluconazole by about 50%.

Interaction with other medicinal products and other forms of interaction

Simultaneous use of the following drugs with fluconazole is contraindicated:

Cisapride: cases of cardiovascular complications of the torsade de pointes type have been reported in patients who simultaneously used fluconazole and cisapride.A controlled clinical trial has shown that co-administration of 200 mg of fluconazole once a day and 20 mg of cisapride four times a day leads to a significant increase in plasma levels of cisapride and a prolongation of the QTc interval. Concomitant use of cisapride is contraindicated in patients receiving fluconazole.

Terfenadine: in patients receiving azole antifungal drugs in combination with terfenadine, studies of this interaction were conducted due to the occurrence of serious cardiac arrhythmias due to prolongation of the secondary QT interval.One study using a 200 mg daily dose of fluconazole showed no prolongation of the QT interval. Another study of 400 mg and 800 mg daily doses of fluconazole showed that fluconazole taken at doses of 400 mg daily or more, when taken simultaneously, significantly increased plasma levels of terfenadine. The combined use of fluconazole 400 mg or more with terfenadine is contraindicated. The process should be carefully monitored while concomitant administration of fluconazole in doses lower than 400 mg per day with terfenadine.

Astemizole: Simultaneous use of fluconazole with astemizole may decrease the clearance of astemizole. As a result, an increase in the concentration of astemizole in blood plasma can lead to QT prolongation and rare cases of arrhythmias of the type torsade de pointes . The combined use of fluconazole and astemizole is contraindicated.

Pimozide: Although not studied in vitro and in vivo, the simultaneous use of fluconazole with pimozide can lead to inhibition of the metabolism of pimozide.Elevated plasma concentrations of pimozide can lead to prolongation of the QT interval and, in rare cases, to the development of arrhythmias of the type torsade de pointes . The co-administration of fluconazole and pimozide is contraindicated.

Quinidine: Being unstudied in vitro and in vivo, the simultaneous use of fluconazole with quinidine can lead to inhibition of the metabolism of the latter. Quinidine use is associated with QT prolongation and rare manifestations of arrhythmias such as torsades de pointes . Concomitant administration of fluconazole and quinidine is contraindicated.

Erythromycin: The simultaneous use of fluconazole and erythromycin increases the risk of cardiotoxicity (prolongation of the QT interval, arrhythmias like torsade de pointes ) and sudden cardiac death. Concomitant use of fluconazole and erythromycin is contraindicated.

The simultaneous use of the following medicinal products is inadmissible:

Halofantrine Fluconazole may increase plasma halofantrine concentration due to its inhibitory effect on CYP3A4.The simultaneous use of fluconazole and halofantrine increases the risk of cardiotoxicity (prolongation of the QT interval, arrhythmias of the type torsade de pointes ) and sudden death of cardiac origin. This combination should be avoided.

Concomitant use of the following medicines leads to precautions and dose adjustments:

Effect of other drugs on fluconazole

Rifampicin: The simultaneous use of fluconazole and rifampicin leads to a 25% decrease in AUC (area under the concentration-time curve) and a 20% decrease in the half-life of fluconazole.In patients receiving concomitant rifampicin therapy, an increase in the dose of fluconazole is necessary.

Effect of fluconazole on other medicinal products

Fluconazole is a potent inhibitor of the cytochrome P450 isoenzyme (CYP) 2C9 and a moderate inhibitor of the CYP3A4 enzyme. In addition to the interactions indicated below, there is a risk of increased plasma concentrations of other compounds metabolized by CYP2C9 and CYP3A4 enzymes when used concomitantly with Fluconazole.Therefore, caution should be exercised when using these combinations, and careful monitoring is necessary for patients. The enzyme-inhibiting effect of fluconazole persists for 4-5 days after stopping treatment with fluconazole due to the long half-life.

Alfentanil: with simultaneous therapy with fluconazole, there is a decrease in clearance and volume of distribution, as well as an increase in T½ (half-life) of alfentanil. A possible mechanism of action is inhibition of the CYP3A4 enzyme by fluconazole.Alfentanil dose adjustment may be required.

Amphotericin B : The simultaneous use of fluconazole and amphotericin B in infected mice with normal and weakened immunity showed the following results: a small additional antifungal effect in systemic infections caused by C . albicans , no interaction for intracranial infection with Cryptococcus neoformans , antagonism of the two drugs for systemic infection with A . fumigatus . Clinically significant results from this study are unknown.

Anticoagulants: Fluconazole increases prothrombin time (12%) when used simultaneously with warfarin. In a post-marketing study, as with other azole antifungal drugs, episodes of bleeding (hematomas, nosebleeds, gastrointestinal bleeding, hematuria and melena) were reported associated with an increase in prothrombin time in patients receiving fluconazole concurrently with warfarin.Careful monitoring of prothrombin time is required in patients taking coumarin anticoagulants. Dose adjustment of warfarin may be required.

Benzodiazepines (short-acting): when used simultaneously with midazolam, fluconazole leads to a significant increase in midazolam concentration and psychomotor effects. This effect on midazolam is more pronounced after oral administration of fluconazole than after intravenous administration. If patients receiving fluconazole require concomitant benzodiazepine therapy, a dose reduction of benzodiazepines is necessary, and patients should be closely monitored.

Fluconazole increases the AUC of triazolam (single dose) by approximately 50%, C _max by 20-32% and t½ by 25-50%, due to inhibition of the metabolism of triazolam. Dose adjustment of triazolam may be required.

Carbamazepine: Fluconazole inhibits the metabolism of carbamazepine and increases the concentration of the latter in serum by 30%. There is a risk of developing carbamazepine toxicity. Dose adjustment of carbamazepine may be required depending on concentration / effect measurements.

Calcium channel blockers: Some calcium channel antagonists (nifedipine, isradipine, amlodipine, verapamil and felodipine) are metabolized by the CYP3A4 enzyme. Fluconazole can significantly increase the systemic exposure to calcium channel antagonists. Frequent monitoring for side effects of drugs is recommended.

Fluconazole increases the sensitivity to the systemic effects of calcium channel blockers. Continuous monitoring of the development of side effects is recommended.

Celecoxib: during concomitant therapy with fluconazole (200 mg per day) and celecoxib (200 mg per day), C _max and AUC of celecoxib increased by 68% and 134%, respectively. It may take half the dose of celecoxib in combination with fluconazole.

Cyclophosphamide: Combination therapy of cyclophosphamide and fluconazole results in an increase in serum bilirubin and creatinine levels. The combination may be used before there is a risk of increased serum bilirubin and creatinine levels.

Fentanyl: Fluconazole significantly delays the elimination of fentanyl. Elevated concentrations of fentanyl can lead to respiratory failure.

Inhibitors of hydroxymethylglutaryl coenzyme A -reductase (HMG-Co A -reductase): increases the risk of myopathy and acute necrosis of skeletal muscles) ( when prescribing fluconazole simultaneously with HMG-CoA reductase inhibitors, which are metabolized through CYP3A4, such as atorvastatin and simvastatin, or through CYP2C9, such as fluvastatin.If concomitant therapy is necessary, the patient should be monitored for the appearance of symptoms of myopathy and rhabdomyolysis, and the level of creatine kinase should also be monitored. HMG-CoA reductase inhibitors should be discontinued if there is a significant increase in creatine kinase levels, or if myopathy / rhabdomyolysis is diagnosed or suspected.

Immunosuppressants (eg cyclosporine, everolimus, sirolimus and tacrolimus):

Cyclosporine: Fluconazole significantly increases the concentration and AUC of cyclosporine.This combination can be used by reducing the dose of cyclosporine depending on its concentration.

Everolimus: Although not studied in vivo or in vitro, fluconazole may increase serum concentrations of everolimus through inhibition of CYP3A4.

Sirolimus: Fluconazole increases the plasma concentration of sirolimus, presumably by inhibiting the metabolism of sirolimus by CYP3A4 and P-glycoprotein.This combination can be used to adjust the dose of sirolimus based on effect / concentration measurements.

Tacrolimus: Fluconazole can increase serum concentrations of oral tacrolimus up to 5-fold by inhibiting intestinal tacrolimus metabolism by CYP3A4. No significant pharmacokinetic changes were found with intravenous tacrolimus. Increased tacrolimus levels have been associated with nephrotoxicity.The dosage of oral tacrolimus should be reduced depending on the concentration of the drug.

Losartan: Fluconazole inhibits the conversion of losartan to its active metabolite (E-31 74), which is responsible for much of the angiotensin II receptor antagonism that occurs during losartan treatment. Patients should constantly monitor their blood pressure.

Methadone: Fluconazole may increase serum methadone concentrations.Dose adjustment of methadone may be required.

Non-steroidal anti-inflammatory drugs (NSAIDs): C _max and AUC of flurbiprofen increase by 23% and 81%, respectively, when administered simultaneously with fluconazole compared with flurbiprofen monotherapy. Similarly, C _max and AUC of the pharmacologically active isomer [S – (+) – ibuprofen] were increased by 15% and 82%, respectively, when fluconazole was administered concomitantly with the racemic ibuprofen mixture (400 mg) compared with the latter alone.

Fluconazole may increase the systemic effects of other NSAIDs that are metabolized by CYP2C9 (eg, naproxen, lornoxicam, meloxicam, diclofenac). Frequent monitoring of side effects and toxicity associated with NSAIDs is recommended. Dose adjustment of NSAIDs may be required.

Phenytoin: Fluconazole inhibits the hepatic metabolism of phenytoin. When taken concomitantly, serum phenytoin levels should be monitored to avoid phenytoin toxicity.

Prednisone: Patients on long-term treatment with fluconazole and prednisone should be monitored for the development of adrenal cortex insufficiency after discontinuation of Fluconazole.

Rifabutin: Concomitant use with fluconazole results in an increase in serum rifabutin levels of up to 80%. Cases of uveitis have been reported in patients who were simultaneously prescribed fluconazole and rifabutin. Careful monitoring of the condition of patients receiving rifabutin and fluconazole at the same time is required.

Saquinavir: Fluconazole increases the AUC of saquinavir by about 50%, C _max by about 55% and reduces the clearance of saquinavir by about 50% by inhibiting the hepatic metabolism of saquinavir by CYP3A4 and inhibition of P-glycoprotein. Dose adjustment of saquinavir may be required.

Sulfonylurea: Fluconazole lengthens the serum half-life with concomitant oral sulfonylureas (eg chlorpropamide, glibenclamide, glipizide, tolbutamide).Frequent monitoring of blood glucose and a corresponding reduction in the dose of sulfonylurea is recommended.

Theophylline: taking Fluconazole 200 mg for 14 days leads to a decrease in the average rate of theophylline clearance by 18%. It is necessary to carefully monitor patients taking fluconazole and theophylline in high doses, or patients with an increased risk of theophylline toxicity, in order to detect early symptoms of theophylline overdose; when they appear, therapy should be modified accordingly.

Vinca alkaloids: Fluconazole may increase plasma levels of vinca alkaloids (eg vincristine and vinblastine) and lead to neurotoxicity due to its inhibitory effect on CYP3A4.

Vitamin A: This combination can be used, but patients should be monitored for CNS-related side effects.

Voriconazole (inhibitor CYP 2 C 9, CYP 2 C 19 and CYP 3 A 4): concomitant oral voriconazole (400 mg every 12 hours on day 1, then 200 mg every 12 hours for 2.5 days) and oral fluconazole (400 mg on day 1, then 200 mg every 24 hours for 4 days) increased the concentration and AUC of voriconazole by an average of 57% (90% C1: 20%, 107%) and 79% (90 % CI: 40%, 128%), respectively.Concomitant administration of voriconazole and fluconazole at any dose is not recommended.

Zidovudine: Fluconazole increases C _max and AUC of zidovudine by 84% and 74%, respectively, due to an approximately 45% decrease in oral zidovudine clearance. The half-life of zidovudine is prolonged by approximately 128% after combination therapy with fluconazole. Patients receiving this combination should be monitored to identify adverse reactions associated with taking zidovudine.Zidovudine dose reduction may be required.

Azithromycin: No significant pharmacokinetic interaction was found between fluconazole and azithromycin.

Oral contraceptives: there was no significant effect of the dose of fluconazole 50 mg on the level of these hormones, while with a daily dose of 200 mg, the AUC (area under the concentration-time curve) of ethinyl estradiol and levonorgestrel were increased by 40% and 24%, respectively.Thus, repeated use of Fluconazole in such doses is unlikely to affect the effectiveness of combined oral contraceptives.

Storage conditions

Keep out of the reach of children, protected from moisture and light at a temperature of 15 ° C to 25 ° C.

Shelf life

Shelf life – 3 years.

Vacation conditions

Available by prescription.

Form of issue and packaging

10 capsules (1 blister of 10 capsules) together with a leaflet in a cardboard box.

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

Special warnings and precautions

WARNINGS

Risks from concomitant use with opioids

Concomitant use of benzodiazepines, including HALCION
and opioids can cause profound sedation, respiratory depression, coma, and
death. Because of these risks, reserve the concomitant prescription of these medications
for use in patients for whom alternative treatment options are insufficient.

Observational studies have demonstrated this concomitant
the use of opioid analgesics and benzodiazepines increases the risk of drug-related
mortality compared to opioid use alone. If a decision is made to appoint
HALF concurrently with opioids, appoint the lowest effective dose and
minimum duration of concomitant use, and closely monitor patients for signs and
symptoms of respiratory depression and sedation.Patients are already receiving
opioid analgesic, give a lower starting dose of HALCION than indicated
in the absence of opioids and titrate based on clinical response. If the opioid
starts in a patient already taking HALCION, a lower initial
opioid dose and titrate based on clinical response.

Counseling both patients and carers about the risks
respiratory depression and sedation when using HALCION with opioids. Advise
patients should not drive or operate heavy equipment prior to exposure
concomitant administration with an opioid have been identified.

Persistent or quenching insomnia

Because sleep disorders can be a presentation
manifestation of physical and / or mental disorder, symptomatic treatment
insomnia should only be started after careful evaluation of the patient.
Failure to translate insomnia after 7-10 days of treatment may
indicate the presence of a primary psychiatric and / or medical illness, which should
to be appreciated. Worsening of insomnia or new thinking or
behavioral disorders may be due to unrecognized psychiatric or
physical disorder.Such results appeared during the course of treatment.
with sedative-hypnotic drugs. Because some of the important adverse effects
sedative-hypnotics appear to be dose related (see PRECAUTIONS and DOSAGE
AND ADMINISTRATION ), it is important to use the smallest possible effective
dose, especially in the elderly.

“Driving in a dream” and other complex behaviors

Complicated behaviors such as “driving in a dream”
(T.i.e. driving when not fully awake after taking a sedative-hypnotic drug
with amnesia for the event) have been reported. These events can take place in
sedative-hypnotic-on-ve, as well as in sedative-hypnotic people.
Although behaviors such as driving while sleeping can only occur with sedative sleeping pills
in therapeutic doses – alcohol and other CNS depressants
sedatives-hypnotics appear to increase the risk of these behaviors, as does
the use of sedative-hypnotic drugs in doses exceeding the maximum recommended dose.Because of
to the risk to the patient and the community, discontinuation
sedative-hypnotic drugs should be carefully considered for patients who report
Driving in a dream episode.

Other complex behaviors (e.g., cooking and eating
phone calls or sex) have been reported from patients who do not
fully awake after taking a sedative-hypnotic. As with driving in a dream, patients
I usually don’t remember these events.

Severe anaphylactic and anaphylactoid reactions

Rare cases of angioedema involving the tongue, glottis, or
larynx has been reported in patients after taking the first or subsequent
doses of sedative-hypnotics, including HALCION.Some patients had additional
symptoms such as shortness of breath, closing of the throat, or nausea and vomiting, which suggest
anaphylaxis. Some patients need medical treatment in an emergency
Department. If angioedema affects the tongue, glottis, or larynx, airway
obstruction can occur and be fatal. Patients who develop angioedema after
treatment with HALCION should not be re-associated with the drug.

Manifestations of the central nervous system

Increase in day alarm reported
HALF after only 10 days of continuous use.In some patients, this may be
manifestation of interdose withdrawal (see CLINICAL PHARMACOLOGY ). If
increased daytime anxiety occurs during treatment, discontinuation of treatment
may be appropriate.

A variety of abnormal changes in thinking and behavior have
this has been reported to be due to the use of benzodiazepine hypnotics
including galcium. Some of these changes may be characterized by a decrease in
inhibition, such as aggressiveness and extraversion, which seem excessive, similar to
this is seen with alcohol and other CNS depressants (eg, sedative / hypnotics).Other types of behavioral changes have also been reported, such as strange
behavior, agitation, hallucinations, depersonalization. Mostly depressed
patients, exacerbation of depression, including suicidal ideation, have been reported
in combination with the use of benzodiazepines.

It is rarely possible to determine with certainty whether a particular
An example of the abnormal behavior listed above is drug-induced spontaneous in
the origin or result of the underlying mental or physical disorder.However, the appearance of any new behavioral or symptom of anxiety
requires careful and immediate evaluation.

Due to its depressive effects of the central nervous system, patients receive
triazolam should be cautioned against engaging in hazardous occupations
requiring full mental activity, such as operating a car or driving
automobile. For the same reason, patients should be warned about
simultaneous intake of alcohol and other depressive drugs of the central nervous system during
treatment with HALCION tablets.

Like some, but not all benzodiazepines, anterograde
amnesia of varying severity and paradoxical reactions have been reported
after therapeutic doses of HALCION. Data from multiple sources suggests this
Anterograd amnesia may occur more frequently with HALCION than with other benzodiazepines
hypnotics.

Interaction of triazolam with drugs that inhibit metabolism
Via Cytochrome P450 3A

The initial step in the metabolism of triazolam is hydroxylation
catalyzed by cytochrome P450 3A (CYP 3A).Drugs that suppress this metabolism
the pathway can have a profound effect on the clearance of triazolam. Hence,
triazolam should be avoided in patients receiving very potent CYP inhibitors
3A. With drugs that inhibit CYP 3A to a lesser, but still significant extent
triazolam should only be used with caution and with appropriate
reduction in dosage. For some drugs, interactions with triazolam have been
quantitatively with clinical data; interactions are predicted for other drugs
in vitro data and / or experience of using similar preparations in the same pharmacological preparation
Class.

The following are examples of drugs known to inhibit metabolism
triazolam and / or related benzodiazepines, presumably by inhibiting
CYP 3A.

Potent CYP 3A inhibitors

Potent CYP 3A inhibitors that should not be used
concurrently with triazolam include ketoconazole, itraconazole, nefazodone and
several HIV protease inhibitors including ritonavir, indinavir, nelfinavir, saquinavir
and lopinavir. Although evidence of the effects of the azole-type antifungal agent
no agents other than ketoconazole and itraconazole in triazolam metabolism
available, they should be considered potent inhibitors of CYP 3A and their
coadministration with triazolam is not recommended (see CONTRAINDICATIONS ).

The drugs have been demonstrated to be CYP 3A inhibitors based on
clinical trials involving triazolam (with caution and dose
reduction is recommended when coadministered with triazolam)

Macrolide antibiotic

Joint administration of erythromycin increased the maximum
plasma triazolam concentration by 46%, clearance decrease by 53%, and
increase in half-life by 35%; caution and consideration of the appropriate triazolam
dose reduction is recommended.This caution should be exercised during
co-administration with clarithromycin and other macrolide antibiotics.

Cimetidine

Coadministration of cimetidine increased the maximum
the concentration of triazolam in plasma by 51%, a decrease in clearance by 55% and
increase in half-life by 68%; caution and consideration of the appropriate triazolam
dose reduction is recommended.

Other drugs possibly affecting the metabolism of triazolam

Other drugs possibly affecting the metabolism of triazolam
inhibition of CYP 3A is discussed in the PRECAUTIONS section (see
DRUG INTERACTIONS ).

PRECAUTIONS

General

Recommended for elderly and / or debilitated patients
that treatment with HALCION tablets should be started at 0.125 mg in order to reduce
the possibility of developing excessive sedation, dizziness, or poor coordination.

Several side effects have been reported with the use of
Half appears to be dose related. These include drowsiness, dizziness
dizziness and amnesia.

Relationship between dose and what may be greater
severe behavioral phenomena are less certain.In particular, some evidence
based on spontaneous marketing reports suggests that confusion, strange or
abnormal behavior, agitation, and hallucinations may also be dose related, but
this evidence is inconclusive. According to good medical practice, this is
recommended starting therapy at the lowest effective dose (see
DOSAGE AND ADMINISTRATION ).

Traveler amnesia cases were
reported by individuals who have taken HALCION to induce sleep while traveling
for example during an airplane flight.In some of these cases, there is not enough time
was allowed for a period of sleep before waking up and before
activity. In addition, concomitant alcohol use may have been a factor in some
cases.

Use caution if HALCION is prescribed
patients with signs or symptoms of depression that may be exacerbated
hypnotic drugs. Suicidal tendencies may be present in these patients and
protective measures may be required. Intentional overdosing is more common
these patients and the smallest amount of medication that is possible should be
available to the patient at any time.

Usual precautions should be observed in patients with
impaired kidney or liver function, chronic pulmonary failure, and sleep
apnea. In patients with impaired respiratory function, respiratory depression
and apnea has been reported infrequently.

Information for patients

Text a Drug Guide for Patients Included
at the end of this box. To ensure the safe and effective use of HALCION,
the information and instructions provided in this Medication Guide should be
discussed with patients.

Risks from concomitant use with opioids

Counseling both patients and carers about the risks
potentially fatal respiratory depression and sedation when using HALCION
opioids and do not use such drugs at the same time unless controlled
health care provider. Advise patients not to drive or operate heavy equipment
until the effects of concomitant use with an opioid are determined.

“Driving in a dream” and other complex behaviors

There have been reports of people getting out of bed
after taking a sedative-hypnotic and driving their cars, not fully awake,
often without memory of the event.If the patient experiences such an episode, it is
you should tell your doctor immediately, as
Dream driving can be dangerous. This behavior is more likely
occur when sedative-hypnotic drugs are taken with alcohol or other central nervous
systemic depressants (see WARNINGS ). Other complex behaviors (eg.,
cooking and eating food, calling or having sex)
reported in patients who are not fully awake after taking a sedative sleeping pill.As with dream driving, patients usually do not remember these events.

Laboratory tests

Laboratory tests are usually not required otherwise
healthy patients.

Carcinogenesis, mutagenesis, impaired fertility

No evidence of carcinogenic potential was observed
mice during a 24-month study with HALCION at doses 4,000 times human
dose.

Pregnancy

Teratogenic effects

Pregnancy Category X

(See CONTRAINDICATIONS ).

Non-teratogenic effects

It should be borne in mind that the child was born of a mother
who is on benzodiazepines may be at some risk of withdrawal symptoms
the drug, in the postnatal period. Neonatal lethargy has also been reported
in a child born to a mother who has received benzodiazepines.

Nursing mothers

No human studies conducted; However, research
in rats, HALCION and its metabolites are indicated to be excreted in milk.Therefore, the administration of HALCION to nursing mothers is not recommended.

Pediatric use

Safety and efficacy of HALCION in humans is lower
18 years have not been identified.

Geriatric use

Elderly people are particularly susceptible to dose
associated side effects of HALCION. They show higher plasma levels of triazolam
concentrations due to decreased drug clearance compared to younger subjects
at the same dose. To minimize the possibility of squatting,
the lowest effective dose should be used (see CLINICAL PHARMACOLOGY , WARNINGS ,
PRECAUTIONS and DOSAGE AND ADMINISTRATION ).

Tolerance / Withdrawal Phenomenon

Some loss of efficiency or sleep adaptation
the inducing effects of these drugs may develop after overnight use for more
than a few weeks, and a degree of dependence may develop. For
benzodiazepine hypnotics, which are rapidly excreted from the body, and
a relative deficiency of the drug may occur at some point in the interval between them
use of every night. This can result in (1) increased wakefulness during the last
a third of the night and (2) the appearance of increased signs of daytime
anxiety or nervousness.These two events were recorded, in particular for
HALCION.

With a. there may be more serious ‘leaving’ effects
the benzodiazepine hypnotic is discontinued. Such effects may occur after
stopping the use of these drugs after using only for a week or two, but there may be more
general and more severe after longer periods of continuous use. One type
the phenomenon of abstinence is the occurrence of the so-called “rebound insomnia”.
That is, in the first few nights after stopping the drug, insomnia
actually worse than before the sleeping pill was given.Another conclusion
events after sudden stopping of benzodiazepine hypnotics range from
mild discomfort with severe withdrawal symptoms, which may include
abdominal and muscle cramps, vomiting, sweating, tremors, and rarely
convulsions.

Publications in mass media

Pharmaceutical action. Antiviral drug – HIV protease inhibitor. Unlike nucleoside analogs, it acts directly on the target enzyme of the virus and does not need metabolic activation.It is active in nanomolar concentrations, has a high antiviral therapeutic index (over 1000). Has an additional synergistic effect on HIV-1 in double and triple combinations with various reverse transcriptase inhibitors (including zidovudine, zalcitabine, didanosine), without increasing cytotoxicity. There is no cross-resistance between saquinavir and reverse transcriptase inhibitors. Zidovudine-resistant HIV-1 isolates are completely susceptible to saquinavir.

Pharmacokinetics. Absorption – 30%, bioavailability – 4% (“first pass” effect through the liver). Food intake increases TCmax from 2.4 to 3.8 h and significantly increases its value (from 3 to 35.5 ng / ml). This effect of food continues for 2 hours after eating.
Well distributed in tissues. The average volume of distribution in an equilibrium state after intravenous administration of 12 mg is 700 liters.
Communication with plasma proteins – 98%, does not depend on the concentration of the drug (15-700 ng / ml).
Undergoes significant hepatic metabolism.Metabolism to mono- and dihydroxylated derivatives is mediated through the CYP3A4, CYP3A5 and CYP3A7 system, while hepatic metabolism is more than 90% carried out by the specific isoenzyme CYP3A4. It is an inhibitor of the isoenzyme CYP3A4, CYP3A5 and CYP3A7.
System clearance – 80 l / h. After intravenous infusion of 6, 36 and 72 mg for 3 hours, the systemic clearance remains constant. Cumulates with repeated administration of 25-600 mg 3 times a day. In the equilibrium state, the AUC increases by 150% compared with that after a single dose.
Excreted through the intestines – 96%, within 48 hours.

Indications. AIDS: as part of combination therapy with zalcitabine and / or zidovudine for the treatment of adult patients with severe HIV infection with a CD4 cell count of no more than 300 / μl; monotherapy of patients with intolerance to nucleoside analogs.

Contraindications. Hypersensitivity, concomitant use of terfenadine, astemizole, cisapride, liver failure.
Carefully.Children’s age (up to 13 years old – invirase, up to 16 years old – fortovaz), old age (over 60 years old), pregnancy, lactation period, chronic renal failure.

Dosing. Invirase. Orally, 600 mg 3 times a day (no later than 2 hours after meals), in combination with 0.75 mg of zidovudine and / or 200 mg of zidovudine (total daily dose of saquinavir – 1.8 g, zalcitabine – 2.2 g and / or zidovudine – 0.6 G).
Fortovaz. Inside, when used in combination with nucleoside analogs – 1200 mg 3 times a day.If combination therapy includes other protease inhibitors, dose reduction may be required.

Side effects . Diarrhea, abdominal pain, nausea, rash, itching, ossalgia, myalgia, headache, peripheral neuropathy, confusion, ataxia, weakness, dizziness, numbness of the extremities, ulceration of the oral mucosa, pharyngitis, asthenia, hemolytic anemia, malignant erythema (Stevens-Johnson syndrome), epileptic seizures, dermatitis, increased activity of “hepatic” transaminases, thrombophlebitis, hepatitis, jaundice.
When combined with zalcitabine (optional): paresthesia, insomnia, vomiting, stomatitis, impaired appetite.
With zidovudine: “flushing” of blood to the face, changes in pigmentation, confusion, intestinal hypermotility, dry mouth, euphoria, insomnia, irritability, fecal discoloration, glossitis, laryngitis, urinary retention, decreased appetite, xerophthalmia, neutropenia, myeloid leukemia (via 2 months after stopping treatment).
With zalcitabine and zidovudine: increased sweating, confusion, visual impairment, decreased intelligence, euphoria, dyspepsia, constipation, belching, glossitis, pharyngitis, shortness of breath, fever, exhaustion, change in taste, pancreatitis, depression; hepatomegaly, steatosis and lactic acidosis of unknown origin; increased CPK activity, hypoglycemia, increased activity of “hepatic” transaminases, hyper- and hypocalcemia, hypophosphatemia, hyperbilirubinemia, hypokalemia, hyper- and hyponatremia, anemia, thrombocytopenia.

Interaction. Simultaneous use of anxiolytic drugs metabolized by CYP3A4 (midazolam, triazolam) should be avoided due to the possibility of a prolonged sedative effect.
Plasma concentrations of other drugs that are a substrate for CYP3A4 (nifedipine, verapamil, diltiazem, clindamycin, dapsone, quinidine, ergot derivatives, cyclosporine, fentanyl, alfentanil, alprazolam, triazolam, disapyramide, simvacvastatin) may also rise.
Inhibitors of the CYP3A4 isoenzyme (including ketoconazole, fluconazole, itraconazole, miconazole) increase the concentration of saquinavir without affecting T1 / 2 and the rate of absorption.
Inductors of “liver” enzymes (including rifampicin, rifabutin, phenytoin, carbamazepine, nevirapine, phenobarbital, dexamethasone) reduce the plasma concentration of saquinavir, reducing its effectiveness.
When used simultaneously with indinavir, nelfinavir, ritonavir, clarithromycin, terfenadine, the AUC and Cmax of saquinavir and all of the above drugs increase.

Special instructions . In patients with mild to moderate hepatic or renal impairment, the use of saquinavir is not accompanied by laboratory signs of deterioration of its function. Does not cure HIV infection, patients may develop AIDS-associated diseases, incl. opportunistic infections. Patients should also be informed that they may experience toxic effects of simultaneously prescribed drugs such as zalcitabine and zidovudine. Patients with hemophilia types A and B have a high risk of increased bleeding and the formation of spontaneous hematomas.In patients receiving protease inhibitors, cases of newly diagnosed diabetes mellitus, hyperglycemia or decompensation of existing diabetes have been described.

NEW TRIAZOLE ANTIFUNGAL DRUGS

was the rate of endoscopically confirmed clinical response at the end of the

therapy period. Efficacy was evaluated in 153 of 160 enrolled

patients.In 146 (95.4%) patients, clinical efficacy was achieved according to

endoscopic data, while each of the

isavuconazole therapy groups was at least as good as (non-inferior) fluconazole therapy. [41]

Safety and tolerability of isavuconazole

Based on the results of clinical studies, as well as on the basis of

separate reports, the safety and tolerability profile of isavuconazole

is regarded as favorable.The largest number of adverse events (AE)

occurred from the gastrointestinal tract, including nausea, vomiting, diarrhea,

, but which very rarely led to discontinuation of the drug. The increase in the

activity of liver enzymes, including ALT, AST and alkaline phosphatase, in frequency

did not exceed the value for other triazoles. Cases of acute liver failure occurred during therapy with isavukonazole

, but the exact relationship with

use of the study drug was not determined.Some patients had

infusion reactions, including respiratory symptoms, shortness of breath,

chills, hypotension. Probably, these manifestations were associated exclusively with the

composition of the i / v form of the drug, which, in particular, became the reason for the introduction in the instruction

for the use of isavuconazole that it was necessary to administer it through

an integrated filter with a pore diameter of 0.2-1 , 2 microns. [8, 42]

In the SECURE study, isavuconazole was better tolerated compared to

with voriconazole.The incidence of AEs during therapy, starting from the first

administration of the drug and up to 28 days after discontinuation, was statistically significantly lower in the

group of isavuconazole compared with voriconazole: 42.4 vs. 60% (p <0.05), as well as

, the number of treatment cancellations due to AE: 14.4 vs. 22.8% (p = 0.05). The differences were

due to a smaller number of events from the following organs and systems:

hepatobiliary (8.9 vs.16.2%, p = 0.016), skin (33.5 vs. 42.5%, p = 0.037) and visual organ

(15.2 vs. 26.6%, p = 0.002). Serious AEs occurred in 52% of patients in the

isavuconazole group and 57.5% in the voriconazole group. [33]

In the VITAL study, AEs during therapy and AEs associated with the use of

of the study drug were observed in 35 (94.6%) and 13 (35%) patients,

, respectively. The most common AE during therapy was vomiting (n = 12; 32.4%).

Diarrhea, nausea and fever were the next most frequent AEs during therapy, each

of which occurred in 10 patients (27%). Serious AEs associated with therapy

with the study drug occurred in 3 patients (8%): ​​1 – graft reaction

contraindications, side effects, dosages, composition – tablets in the drug reference

Triazolam should be administered with caution to patients with impaired liver function.

In order to avoid the possibility of an overdose, dizziness or impaired coordination in elderly and debilitated patients, treatment should be started with a dose of 0.125 mg. In other cases, the recommended dose in adults is 0.25 mg.

Triazolam should be taken with caution in situations where a full night’s sleep and complete elimination of the drug from the tissues are impossible until the moment when patients need full activity, for example, during night flights for less than 7-8 hours, since in such cases episodes of amnesia were observed.

When triazolam is used in recommended doses for short-term treatment, the likelihood of dependence is low. However, as with all benzodiazepines, the risk of dependence increases with dose and duration of treatment, especially in patients with a history of alcoholism and substance abuse.

In patients taking triazolam several times a day, after abrupt withdrawal of the drug, withdrawal symptoms, including seizures, were observed.

Although benzodiazepines do not cause depression, their use may be associated with mental depression, in which there may be suicidal thoughts or actual suicidal attempts.This is rare and unpredictable. Therefore, in patients with symptoms of depressive disorders or suicidal tendencies, triazolam should be used with caution and only in limited doses.

As well as for other benzodiazepines and drugs active against the central nervous system, there are three, possibly overlapping, groups of idiosyncratic symptoms that were occasionally observed when taking triazolam:

• symptoms of amnesia (anterograde amnesia with adequate and inappropriate behavior), symptoms of confusion (disorientation, derealization, depersonalization and / or clouding of consciousness) and a state of agitation (anxiety, increased excitability and irritability).These reactions can be caused by the simultaneous action of other factors, for example, concomitant use of alcohol or other drugs, sleep deprivation, abnormal premorbid state, etc.

There have been reports of patients who did not fully wake up after taking sedatives-hypnotics, including triazolam, develop complex manifestations associated with sleepy behavior, such as “sleepy driving” (i.e., driving in the time when full awakening has not yet come after taking sedatives-hypnotics with amnesia for this event).These and other complex manifestations associated with sleep behavior can occur when taking sedatives-hypnotics, including triazolam, only at therapeutic doses. The use of alcohol and other CNS depressants concurrently with sedative-hypnotics may increase the risk of developing this behavior, as can the use of sedatives-hypnotics in doses exceeding the maximum recommended dose. Due to the risk to the patient and society, patients who experience such manifestations should be strongly advised to stop taking sedatives-hypnotics.