Ivadal^® (Tablets) Instructions for Use

Marketing Authorization Holder

Sanofi-Aventis France (France)

Manufactured By

Sanofi Winthrop Industrie (France)

ATC Code

N05CF02 (Zolpidem)

Active Substance

Zolpidem (Rec.INN registered by WHO)

Dosage Form

Ivadal®

Film-coated tablets, 10 mg: 7 or 20 pcs.

Dosage Form, Packaging, and Composition

Film-coated tablets white or almost white, oblong, with a break line and the engraving “SN 10” on one side.

Excipients: lactose monohydrate, microcrystalline cellulose, hypromellose, sodium carboxymethyl starch (type A), magnesium stearate.

Shell composition: hypromellose, titanium dioxide (E171), macrogol 400.

7 pcs. – blisters (1) – cardboard packs.
10 pcs. – blisters (2) – cardboard packs.
20 pcs. – blisters (1) – cardboard packs.

Clinical-Pharmacological Group

Hypnotic drug

Pharmacotherapeutic Group

Hypnotic agent

Pharmacological Action

A hypnotic drug from the group of imidazopyridines, which are close in pharmacological activity to benzodiazepines. It has effects qualitatively similar to those of other drugs in this group: muscle relaxant, anxiolytic, sedative, hypnotic, anticonvulsant, amnesic. The development of these effects is associated with a specific agonistic effect on central ω-receptors (type I and II benzodiazepine receptors), which belong to the macromolecular GABA-receptor complexes, causing the opening of neuronal anion channels for chlorine.

Zolpidem selectively interacts with central type I benzodiazepine receptors (ω-1 receptor subtype). Therefore, the sedative effect of the drug is observed at lower doses than the doses required for the development of muscle relaxant, anticonvulsant and anxiolytic effects.

In humans, Zolpidem shortens the sleep onset period and reduces the number of awakenings, increases the total duration and improves the quality of sleep. These effects are associated with the characteristic EEG profile of the drug, which differs from that of benzodiazepines. Zolpidem prolongs stage II sleep and deep sleep (stages III and IV). In recommended doses, Zolpidem does not affect the total duration of paradoxical (rapid eye movement) sleep.

Pharmacokinetics

Absorption

After oral administration, C_max in plasma is noted after 0.5-3 hours. Bioavailability is about 70%.

In the therapeutic dose range, the pharmacokinetics of zolpidem are linear.

Distribution

Plasma protein binding is 92%. V_d is 0.54±0.02 L/kg.

Metabolism and excretion

Zolpidem is metabolized in the liver and excreted in the urine (about 60%) and feces (about 40%) as inactive metabolites. It does not induce liver microsomal enzymes.

T_1/2 is about 2.4 hours (0.7-3.5 hours).

Pharmacokinetics in special clinical cases

In elderly patients, the clearance of zolpidem in plasma may decrease, while T_1/2 increases slightly (on average 3 hours), C_max increases by 50%, V_d decreases to 0.34±0.05 L/kg.

In patients with renal failure (regardless of receiving hemodialysis procedures), a moderate decrease in zolpidem clearance is observed; other pharmacokinetic parameters do not change. Zolpidem is not removed by hemodialysis.

In patients with impaired liver function, the bioavailability of zolpidem increases, clearance decreases somewhat, and T_1/2 increases to 10 hours.

Indications

• Treatment of transient and situational insomnia in adults, including difficulty falling asleep, nocturnal and early awakenings.

ICD codes

Dosage Regimen

The drug is intended for oral administration.

Treatment should always be started with the minimum effective dose, and the maximum dose should never be exceeded.

The recommended dose for adults is 10 mg/day. The drug should be taken immediately before going to bed or already in bed.

For elderly or debilitated patients, in patients with impaired liver function the initial dose is 5 mg. The dose can be increased to 10 mg only in case of insufficient clinical effect and good tolerability of the drug.

The maximum daily dose is 10 mg.

The duration of treatment should be minimal: from several days to 4 weeks, including the dose reduction period. Extension of treatment beyond the maximum allowable periods is carried out with special caution after a repeated clinical assessment of the patient’s condition.

The recommended duration of the drug in case of transient insomnia (for example, during travel) is 2-5 days, for situational insomnia (for example, caused by a traumatic situation) – for 2-3 weeks.

In case of a very short period of treatment, gradual withdrawal of the drug is not required.

In case of long-term use, to reduce the possibility of developing rebound insomnia, zolpidem withdrawal should be carried out gradually: first – reducing the daily dose and only then – complete withdrawal of the drug.

Adverse Reactions

Side effects, especially from the CNS, are dose-dependent and depend on the individual patient’s response. They are more often observed in elderly patients, their severity should theoretically be less when taking the drug immediately before going to bed or already in bed.

Definition of the frequency of side effects: very common (≥10%; common (≥1%, <10%), uncommon (≥ 0.1%, <1%), rare (from 0.01% to 0.1%), very rare (<0.01%), including isolated cases; unknown – based on available data, the frequency cannot be determined.

From the nervous system: common – drowsiness, feeling of intoxication, headache, dizziness, increased insomnia, anterograde amnesia (may be observed even when using the drug in therapeutic doses, with the risk of its development increasing in proportion to the dose) sometimes in combination with behavioral disorders, hallucinations, agitation, nightmares; uncommon – confusion, irritability; unknown – impaired consciousness, dysphoria, aggressiveness, visual and auditory hallucinations, excitability, behavioral abnormalities, sleepwalking (somnambulism), dependence, which may develop even when using the drug in therapeutic doses (after discontinuation of treatment, withdrawal syndrome or rebound insomnia may develop), decreased libido, gait disturbance, ataxia, falls (mainly in elderly patients and when the prescribed recommendations for administration are not followed), tolerance to the drug (decrease in sedative and hypnotic effects when used for several weeks).

Most side effects from the psyche are paroxysmal reactions.

From the organ of vision: uncommon – diplopia.

From the digestive system: common – diarrhea, nausea, vomiting, abdominal pain; unknown – increased activity of liver enzymes.

From the musculoskeletal system: unknown – muscle weakness.

Dermatological reactions: unknown – rash, itching, hyperhidrosis (excessive sweating).

Allergic reactions: unknown – urticaria, angioedema.

Other: common – feeling of fatigue.

Contraindications

• Acute and/or severe respiratory failure;
• Sleep apnea syndrome;
• Severe acute or chronic liver failure (risk of encephalopathy);
• Childhood and adolescence under 18 years of age (lack of clinical data);
• First trimester of pregnancy;
• Congenital galactosemia, glucose or galactose malabsorption syndrome, lactase deficiency;
• Hypersensitivity to the components of the drug.

With caution should be used in severe pseudoparalytic myasthenia (asthenic bulbar palsy), impaired liver function, chronic alcoholism, drug addiction and other types of addiction (increased risk of developing dependence on zolpidem).

Use in Pregnancy and Lactation

Ivadal^® is contraindicated for use in the first trimester of pregnancy.

Due to insufficient data on the use of Ivadal^® in pregnant women, it is not recommended to prescribe the drug in the second and third trimesters of pregnancy.

Women of childbearing age receiving the drug should be warned about the need to consult a doctor in case of planned or occurred pregnancy.

If it is necessary to prescribe the drug in the second and third trimesters of pregnancy, the expected benefit of therapy for the mother and the potential risk to the fetus and newborn should be carefully assessed.

When taking zolpidem in high doses in the second and third trimesters of pregnancy, a decrease in mobility and a change in heart rate in the fetus are possible.

In case of taking benzodiazepines at the end of pregnancy or during childbirth (even in low doses), active substances may enter the fetus’s body and the newborn may develop hypothermia, transient respiratory depression or apnea, axial hypotension, arterial hypotension, as well as sucking disorders. Based on this, as well as the known pharmacodynamic effects of zolpidem, the possibility of such phenomena when taking it at the end of pregnancy or during childbirth cannot be excluded. In addition, children born to mothers who have long taken sedative/hypnotic drugs at the end of pregnancy may develop physical dependence, and there is a risk of developing withdrawal syndrome in the postnatal period, which is manifested primarily by increased excitability and tremor of the newborn, occurring some time after birth. The time of onset of such phenomena depends on the rate of elimination of the sedative/hypnotic from the mother’s body.

Small amounts of zolpidem are excreted in human breast milk. Therefore, it is not recommended to take Zolpidem during breastfeeding.

In experimental studies on animals, no teratogenic effect of the drug was detected.

Use in Hepatic Impairment

Contraindicated in severe acute or chronic liver failure (risk of encephalopathy).

With caution should be used in case of impaired liver function.

Pediatric Use

Contraindication: children and adolescents under 18 years of age (lack of clinical data).

Geriatric Use

For elderly or debilitated patients the initial dose is 5 mg. The dose can be increased to 10 mg only in case of insufficient clinical effect and good tolerability of the drug.

Special Precautions

In all cases, before prescribing a hypnotic, the cause of sleep disorders should be established and the underlying causes should be corrected (including medication). The persistence of insomnia for 7-14 days of treatment indicates the presence of primary mental disorders and/or disorders of the nervous system. Therefore, to identify these disorders, it is necessary to regularly re-evaluate the patient’s condition.

Hypnotics, such as Zolpidem, are not recommended as the main treatment for mental illness.

The use of zolpidem in patients with symptoms of depression, like other drugs with sedative/hypnotic effects, requires special caution. Such patients should be treated for depression and benzodiazepines and drugs with similar effects should not be prescribed as monotherapy because these drugs can mask the symptoms of depression, which may continue to develop against their background with the persistence or intensification of suicidal tendencies.

Since the cause of insomnia may be depression, in case of persistent insomnia, the patient’s mental state should be re-evaluated to identify possible depression.

Sedative/hypnotic drugs, such as Zolpidem, can cause anterograde amnesia. This condition is most often observed several hours after taking the drug, and therefore, to reduce the risk of its development, patients should have conditions for uninterrupted 7-8 hours of sleep.

Mental and paradoxical reactions: as is known with the use of sedative/hypnotics, including zolpidem, the following may occur: increased insomnia, nightmares, agitation, nervousness, delirium, hallucinations, confusion and oneirism, psychotic symptoms, disinhibition with impulsivity, euphoria, excitability, anterograde amnesia, increased suggestibility, aggressiveness. This syndrome may be accompanied by the following behavioral disorders that are potentially dangerous for the patient or others: behavior unusual for the patient, self-aggression or aggression towards other persons who are trying to prevent the patient’s dangerous actions; automatic behavior with subsequent amnesia. If these effects occur, zolpidem should be discontinued. The likelihood of these effects is higher in elderly patients.

Sleepwalking and related complex behavior: In some individuals, benzodiazepines and related drugs can cause a syndrome of combined disorders of consciousness, behavior and memory of varying severity. In patients receiving Zolpidem, sleepwalking and other related complex behavior have been observed: driving a car in a half-asleep state, preparing and eating food, making phone calls, having sexual intercourse with incomplete awakening with amnesia of these actions. The use of alcohol and other drugs with a depressant effect on the central nervous system together with zolpidem, as well as taking zolpidem in doses exceeding the recommended dose, apparently increases the risk of such behavior. If the patient reports an episode(s) of such behavior, Ivadal^® should be discontinued.

After a course of treatment for several weeks with sedative/hypnotic drugs similar to zolpidem, some reduction in their sedative and hypnotic effects is possible.

The use of benzodiazepines and drugs with similar effects, especially prolonged use, can lead to the formation of physical and/or mental dependence. The risk of dependence increases with increasing drug dose and duration of treatment, it is also higher in patients with a history of alcohol or other drug and non-drug substance abuse. Such patients, when receiving hypnotics, should be under especially careful supervision.

However, dependence can also occur when using the drug in therapeutic doses and/or in patients without individual risk factors.

When using Ivadal^® in therapeutic doses, the state of dependence on the drug is extremely rare.

In case of drug dependence, when it is discontinued, a withdrawal syndrome may develop, the common symptoms of which are: insomnia, headache and myalgia, dysphoria, anxiety, muscle tension and irritability. Less commonly (in more severe cases of withdrawal syndrome), agitation or even episodes of confusion, derealization, depersonalization, numbness and paresthesia of the extremities, excessive sensitivity to light, noise, physical contact, hallucinations and convulsions are observed.

Withdrawal syndrome may be observed for several days after discontinuation of treatment. When taking zolpidem (like other short-acting benzodiazepines), withdrawal symptoms may occur in the interval between two doses, especially at high doses.

Regardless of the indications for use, the combination of zolpidem with benzodiazepines increases the risk of developing dependence.

There are reports of cases of drug abuse.

Rebound insomnia is a transient syndrome upon discontinuation of treatment with hypnotics in the form of a return of insomnia in an enhanced form. It may be combined with other reactions, including mood changes, anxiety and dysphoria. It is important that the patient is warned about the possibility of the rebound phenomenon, which will reduce anxiety about the occurrence of such symptoms when discontinuing the drug.

Risk of accumulation: Benzodiazepines and related compounds remain in the body for approximately five half-lives. In elderly patients or in patients with impaired liver function, a significant increase in T_1/2 is possible, which can lead to the accumulation of the drug when it is taken repeatedly. Based on the pharmacokinetic features of zolpidem, no accumulation of the drug is expected in renal failure.

When prescribing benzodiazepines and related compounds to elderly patients, caution should be exercised due to the danger of developing sedative and/or muscle relaxant effects, which can lead to falls with serious consequences.

Patients should always be warned about the recommended duration of treatment, which is determined by the type of insomnia.

Use in pediatrics

The safety and efficacy of Ivadal^® in children and adolescents under 18 years of age have not been established.

Effect on the ability to drive vehicles and mechanisms

Patients engaged in driving vehicles and working with mechanisms should be warned about the risk of drowsiness and dizziness during treatment with Ivadal^®, which can be significantly enhanced when the drug is used in combination with other drugs with a sedative effect and/or with alcohol.

If the duration of sleep after taking Ivadal^® was not sufficient, then the risk of impaired psychomotor reactions increases, which may pose an additional danger when driving vehicles and other potentially hazardous activities.

Overdose

Overdose when taking zolpidem alone or zolpidem in combination with other substances that depress the central nervous system (including alcohol) can be life-threatening.

Symptoms are mainly due to depression of the central nervous system: possible impairment of consciousness from mild forms (confusion, lethargy) to severe (up to coma), ataxia, arterial hypotension, respiratory depression dangerous to the patient’s life.

Treatment: if less than 1 hour has passed after taking an excessive dose and the patient is conscious, an attempt should be made to induce vomiting. If it is impossible to induce vomiting or if the patient is unconscious, gastric lavage is recommended. If more than 1 hour has passed after accidental or intentional ingestion of an excessive dose of the drug, the patient should be given activated charcoal orally or administered through a tube (if unconscious) to reduce the absorption of zolpidem. In case of overdose, symptomatic therapy and treatment aimed at maintaining the basic functions of the body, in particular the functions of respiration and the cardiovascular system, are carried out. In case of severe overdose, the issue of administering flumazenil (a benzodiazepine receptor antagonist) should be considered for differential diagnosis and/or treatment, but it should be remembered that suppression of benzodiazepine receptors can cause neurological disorders (convulsions), especially in patients with epilepsy. Zolpidem is not removed by hemodialysis.

Drug Interactions

Not Recommended Combinations

Ethanol potentiates the sedative effect of the drug, which affects the ability to drive vehicles and operate machinery. Simultaneous consumption of alcoholic beverages and medicinal products containing ethyl alcohol with zolpidem should be avoided.

Combinations Requiring Caution During Use

Medicinal products that depress the central nervous system: neuroleptics, barbiturates, other hypnotics, anxiolytics/sedatives, antidepressants with sedative effects, morphine derivatives (opioid analgesics, antitussives), antiepileptic drugs, anesthetics, antihistamines with sedative effects, centrally acting antihypertensive agents, baclofen, thalidomide; pizotifen – when co-administered with zolpidem, an enhancement of the depressant effect on the central nervous system and, accordingly, the risk of respiratory depression is possible, which can be fatal in case of overdose (especially in combination with morphine derivatives, barbiturates), a weakening of psychomotor reactions and a decrease in the ability to drive.

Buprenorphine: increased risk of respiratory depression up to a fatal outcome. The benefit/risk ratio of such a combination requires careful assessment. The patient should be warned about the need to strictly follow the doctor’s recommendations regarding the dosage regimen.

Ketoconazole (a potent CYP3A4 inhibitor): Zolpidem is metabolized by several CYP450 isoenzymes, the main one being CYP3A4, with CYP1A2 also contributing to its metabolism. With simultaneous administration of zolpidem and ketoconazole (200 mg twice daily), the T_1/2 of zolpidem and AUC increase, and clearance decreases, which leads to a slight increase in the sedative effect of zolpidem.

Itraconazole (CYP3A4 inhibitor): a slight, clinically insignificant change in the pharmacokinetics and pharmacodynamics of zolpidem.

Interaction to be Taken into Account

Rifampicin (CYP3A4 inducer): a decrease in the effectiveness of zolpidem associated with a reduction in plasma concentration of zolpidem, due to accelerated metabolism of zolpidem in the liver.

Warfarin, digoxin, ranitidine, or cimetidine: absence of significant pharmacokinetic interaction.

Selective serotonin reuptake inhibitors – fluoxetine and sertraline: no clinically significant pharmacokinetic or pharmacodynamic interaction was detected.

Storage Conditions

The drug should be stored out of the reach of children at a temperature not exceeding 25°C (77°F).

Shelf Life

Shelf life is 4 years.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.