Benzodiazepine related drugs - ATC Code N05CF03

Zaleplon

Each capsule contains 5 mg of zaleplon. Excipient: Lactose monohydrate 54 mg.

Capsule, hard. Capsules have an opaque white and opaque light brown hard shell with gold band, “W” and the strength “5 mg”.

Treatment of patients with insomnia who have difficulty falling asleep. It is indicated only when the disorder is severe, disabling or subjecting the individual to extreme distress.

For adults, the recommended dose is 10 mg.

Treatment should be as short as possible with a maximum duration of two weeks.

Sonata can be taken immediately before going to bed or after the patient has gone to bed and is experiencing difficulty falling asleep. As administration after food delays the time to maximal plasma concentration by approximately 2 hours no food should be eaten with or shortly before intake of Sonata.

The total daily dose of Sonata should not exceed 10 mg in any patient. Patients should be advised not to take a second dose within a single night.

Hepatic impairment

As clearance is reduced, patients with mild to moderate hepatic impairment should be treated with Sonata 5 mg.

Renal impairment

No dosage adjustment is required in patients with mild to moderate renal insufficiency, because Sonata pharmacokinetics is not altered in such patients. Severe renal impairment is contraindicated

Sonata is contraindicated in children.

Elderly patients may be sensitive to the effects of hypnotics; therefore, 5 mg is the recommended dose of Sonata.

Hypersensitivity to the active substance or to any of the excipients

Severe hepatic impairment

Severe renal impairment

Sleep apnoea syndrome

Myasthenia gravis

Severe respiratory insufficiency

Children (under 18 years of age)

Complex behaviours such as “sleep-driving” (i.e., driving while not fully awake after ingestion of a sedative-hypnotic, with amnesia for the event) have been reported in patients taking sedative-hypnotics. These events can occur in sedative-hypnotic-naive as well as in sedative-hypnotic experienced persons. Although behaviours such as sleep-driving may occur with a sedative-hypnotic alone at therapeutic doses, the use of alcohol and other central nervous system (CNS) depressants with sedative-hypnotics appears to increase the risk of such behaviours, as does exceeding the maximum recommended dose. Due to the risk to the patient and the community, discontinuation of zaleplon is recommended for patients who report a “sleep-driving” episode. Other complex behaviours (e.g., preparing and eating food, making phone calls, or having sex) have been reported in patients who are not fully awake after taking a sedative-hypnotic. As with sleep-driving, patients usually do not remember these events.

Severe anaphylactic/anaphylactoid reactions have been reported with the use of sedative-hypnotics, including zaleplon. Cases of angioedema involving the tongue, glottis or larynx have been reported in patients after taking the first or subsequent doses of sedative-hypnotics, including zaleplon. Some patients taking sedative-hypnotics have had additional symptoms such as dyspnoea, throat closing, or nausea and vomiting. Some patients have required medical therapy in the emergency department. If angioedema involves the tongue, glottis or larynx, airway obstruction may occur and be fatal. Patients who develop angioedema after treatment with zaleplon should not be rechallenged with the active substance.

Insomnia may represent an underlying physical or psychiatric disorder. Insomnia that persists or worsens after a short course of zaleplon treatment may indicate a need to re-evaluate the patient.

Due to zaleplon's short plasma half-life, alternative therapy should be considered if early morning awakening is experienced. Patients should be advised not to take a second dose within a single night.

Co-administration of Sonata with medicinal products known to influence CYP3A4 is expected to result in changes in zaleplon's plasma concentrations.

Tolerance

Some loss of efficacy to the hypnotic effects of short-acting benzodiazepines and benzodiazepine-like agents may develop after repeated use for a few weeks.

Dependence

Use of benzodiazepines and benzodiazepine-like agents may lead to physical and psychic dependence. The risk of dependence increases with dose and duration of treatment and is greater with patients having a history of alcohol and medicinal product abuse. Once physical dependence has developed, abrupt termination of treatment will be accompanied by withdrawal symptoms. These may consist of headaches, muscle pain, extreme anxiety, tension, restlessness, confusion and irritability. In severe cases the following symptoms may occur: unreality, depersonalisation, hyperacusis, numbness and tingling of the extremities, hypersensitivity to light, noise and physical contact, hallucinations or epileptic seizures. There have been post-marketing reports of dependence associated with zaleplon, predominantly in combination with other psychotropic agents.

Rebound insomnia and anxiety

A transient syndrome whereby the symptoms that led to the treatment with a benzodiazepine or benzodiazepine-like agent recur in an enhanced form, may occur on withdrawal of treatment. It may be accompanied by other reactions including mood changes, anxiety, or sleep disturbances and restlessness.

Duration of treatment

The duration of treatment should be as short as possible, and should not exceed two weeks. Extension beyond these periods should not take place without clinical re-evaluation of the patient.

It may be useful to inform the patient when treatment is started that it will be of limited duration. It is important that patients be aware of the possibility of rebound phenomena, thereby minimising anxiety should such symptoms develop when the medicinal product is discontinued.

Memory and psychomotor impairment

Benzodiazepines and benzodiazepine-like agents may induce anterograde amnesia and psychomotor impairment. These occur most often up to several hours after ingesting the product. To reduce the risk, patients should not undertake activities requiring psychomotor co-ordination until 4 hours or more after taking Sonata.

Psychiatric and “paradoxical” reactions

Reactions like restlessness, agitation, irritability, decreased inhibition, aggressiveness, abnormal thinking, delusion, rages, nightmares, depersonalisation, hallucinations, psychoses, inappropriate behaviour, extroversion that seems out of character and other behavioural effects are known to occur when using benzodiazepines or benzodiazepine-like agents. They may be active substance-induced, spontaneous in origin, or a result of an underlying psychiatric or physical disorder. These reactions are more likely to occur in the elderly. Should this occur, use of this product should be discontinued. Any new behavioural sign or symptom requires careful and immediate evaluation.

Specific patient groups

Alcohol and medicinal product abuse

Benzodiazepine and benzodiazepine-like agents should be used with extreme caution in patients with a history of alcohol or medicinal product abuse.

Hepatic impairment

Benzodiazepine and benzodiazepine-like agents are not indicated to treat patients with severe hepatic insufficiency as they may precipitate encephalopathy. In patients with mild to moderate hepatic insufficiency, the bioavailability of zaleplon is increased because of reduced clearance, and the dose will therefore need to be modified in these patients.

Renal impairment

Sonata is not indicated to treat patients with severe renal impairment as it has not been adequately studied in those patients. In patients with mild to moderate renal impairment, the pharmacokinetic profile of zaleplon is not significantly different than that in healthy subjects. Hence, no dose adjustment is required in these patients.

Respiratory insufficiency

Caution should be observed when prescribing sedative medicinal products to patients with chronic respiratory insufficiency.

Psychosis

Benzodiazepine and benzodiazepine-like agents are not recommended for the primary treatment of psychotic illness.

Depression

Benzodiazepines and benzodiazepine-like agents should not be used alone to treat depression or anxiety associated with depression (suicide may be precipitated in such patients). Also, because of the increased risk for intentional overdose in patients with depression in general, the quantity of a medicinal product, including zaleplon, prescribed for such patients should be kept to the necessary minimum.

Sonata contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Concomitant intake with alcohol is not recommended. The sedative effect may be enhanced when the product is used in combination with alcohol. This affects the ability to drive or use machines.

Combination with other CNS-acting compounds should be taken into account. Enhancement of the central sedation may occur in cases of concomitant use with antipsychotics (neuroleptics), hypnotics, anxiolytics/sedatives, antidepressant agents, narcotic analgesics, anti-epileptic medicinal products, anaesthetics, and sedative antihistamines.

Coadministration of a single zaleplon 10 mg dose and venlafaxine (extended release) 75 mg or 150 mg daily did not produce any interaction on memory (immediate and delayed word recall) or psychomotor performance (digit symbol substitution test). Additionally, there was no pharmacokinetic interaction between zaleplon and venlafaxine (extended release).

In the case of narcotic analgesics enhancement of the euphoria may occur leading to an increase in physiological dependence.

Cimetidine, a non-specific moderate inhibitor of several hepatic enzymes including both aldehyde oxidase and CYP3A4, produced an 85% increase in plasma concentrations of zaleplon because it inhibited both the primary (aldehyde oxidase) and secondary (CYP3A4) enzymes responsible for zaleplon's metabolism. Therefore, caution is advisable in co-administering cimetidine and Sonata.

Co-administration of Sonata with a single 800 mg dose of erythromycin, a strong, selective CYP3A4 inhibitor, produced a 34% increase in zaleplon's plasma concentrations. A routine dosage adjustment of Sonata is not considered necessary, but patients should be advised that the sedative effects might be enhanced.

In contrast, rifampicin, a strong inducer of several hepatic enzymes, including CYP3A4 resulted in a four fold reduction in zaleplon plasma concentration. Co-administration of Sonata together with inducers of CYP3A4 such as rifampicin, carbamazepine and phenobarbitone, may result in a reduction of zaleplon's efficacy.

Sonata did not affect the pharmacokinetic and pharmacodynamic profiles of digoxin and warfarin, two compounds with a narrow therapeutic index. In addition, ibuprofen, as an example of compounds that alter renal excretion, showed no interaction with Sonata.

The most frequent reported adverse drug reactions are amnesia, paraesthesia, somnolence and dysmenorrhea.

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Amnesia

Anterograde amnesia may occur using recommended therapeutic dosages, the risk increasing at higher dosages. Amnestic effects may be associated with inappropriate behaviour.

Depression

Pre-existing depression may be unmasked during benzodiazepine or benzodiazepine-like agent use.

Psychiatric and “paradoxical” reactions

Reactions like restlessness, agitation, irritability, decreased inhibition, aggressiveness, abnormal thinking, delusions, rages, nightmares, depersonalisation, hallucinations, psychoses, inappropriate behaviour, extroversion that seems out of character, and other adverse behavioural reactions are known to occur when using benzodiazepines or benzodiazepine-like agents. Such reactions are more likely to occur in the elderly.

Dependence

Use (even at therapeutic doses) may lead to the development of physical dependence: discontinuation of therapy may result in withdrawal or rebound phenomena. Psychic dependence may occur. Abuse of benzodiazepines and benzodiazepine-like active substances has been reported.

Meda Pharmaceuticals

(POM)

14 February 2012