Zerene - summary of medicine characteristics

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each capsule contains 5 mg of zaleplon.

Excipient: Lactose monohydrate 54 mg.

For a full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Capsule, hard.

Capsules have an opaque white and opaque light brown hard shell with gold b strength “5 mg”.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

Zerene is indicated for the treatment of patients with insomn o have difficulty falling asleep. It is indicated only when the disorder is severe, disabling or subjecting the individual to extreme distress.

4.2 Posology and method of administration

For adults, the recommended dose is 10 m

Zerene 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 Zerene.

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

Elderly

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

Paediatric patients

Zerene is contraindicated in children (see section 4.3).

Hepatic impairment

As clearance is reduced, patients with mild to moderate hepatic impairment should be treated with

Zerene 5 mg. For severe hepatic impairment see section 4.3.

Renal impairment

No dosage adjustment is required in patients with mild to moderate renal insufficiency, because Zerene pharmacokinetics is not altered in such patients. Severe renal impairment is contraindicated (see section 4.3.).

4.3 Contraindications

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)

4.4 Special warnings and precautions for use

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 sedativehypnotics. 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 Zerene with medicinal products known to influence CYP3A4 is expected to result in changes in zaleplon’s plasma concentrations. (See section 4.5)

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 (see section 4.2), 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 li important that patients be aware of the possibility of rebound phenomena, thereby should such symptoms develop when the medicinal product is discontinue

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 Zerene (see section 4.7). .

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 (see section 4.2). 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

Zerene 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.

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

4.5 Interaction with other medicinal products and other forms of interaction

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 (see section 4.7).

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 Zerene.

Co-administration of Zerene 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 Zerene 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 Zerene together with inducers of CYP3A4 such as rifampicin, carbamazepine and phenobarbitone, may result in a reduction of zaleplon’s ef­ficacy.

Zerene 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 Zerene.

4.6 Pregnancy and lactation

Although animal studies have shown no teratogenic or embryotoxic effects, insufficient clinical data are available on Zerene to assess its safety during pregnancy and breastfeeding. Use of Zerene is not recommended during pregnancy. If the medicinal product is prescribed to a woman of child-bearing potential, she should be warned to contact her physician regarding discontinuance of the medicinal product if she intends to become or suspects that she is pregnant.

If for compelling medical reasons, the medicinal product is administered during the late phase of pregnancy, or during labour at high doses, effects on the neonate, such as hypothermia, hypotonia and moderate respiratory depression, can be expected, due to the pharmacological action of the compound.

Infants born to mothers who took benzodiazepine and benzodiazepine-like agents chronically during the latter stages of pregnancy may have developed physical dependence and may be at some risk for developing withdrawal symptoms in the postnatal period.

Because zaleplon is excreted in the breast milk, Zerene should not be administered to breast mothers.

4.7 Effects on ability to drive and use machines

4.8 Undesirable effectsThe most frequent reported adverse drug reactions are dysmenorrhea.a, paraesthesia, somnolence andFrequencies are defined asVery common (>1/10)Common (>1/100 to <1/10)Uncommon (>1/1,000 to <1/100 Rare (>1/10,000 to <1/1,000)Very rare (<1/10,000)

See also below under Depression and Psychiatric and “paradoxical” reactions

Amnesia

Anterograde amnesia may occur using recommended therapeutic dosages, the risk increasing at higher dosages. Amnestic effects may be associated with inappropriate behaviour (see section 4.4).

Depression

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

Psychiatric and “para dox ical” 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.

D epe nd ence

Use (even at therapeutic doses) may lead to the development of physical dependence: discontinuation of therapy may result in withdrawal or rebound phenomena (see section 4.4). Psychic dependence may occur. Abuse of benzodiazepines and benzodiazepine-like active substances has been reported.

4.9 Overdose

There is limited clinical experience with the effects of an acute overdose of Zerene, and overdose levels in humans have not been determined.

As with other benzodiazepines or benzodiazepine-like agents, overdose should not present a threat to life unless combined with other CNS depressants (including alcohol).

In the management of overdose with any medicinal product, it should be borne in mind that multiple agents may have been taken.

Following overdose with oral benzodiazepine or benzodiazepine-like agents, vomiting should be induced (within one hour) if the patient is conscious or gastric lavage undertaken with the airway protected if the patient is unconscious. If there is no advantage in emptying the stomach, activated charcoal should be given to reduce the absorption. Special attention should be paid to respiratory or cardiovascular functions in intensive care.

Overdose of benzodiazepine or benzodiazepine-like agents is usually manifested by degrees of central nervous system depression ranging from drowsiness to coma. In mild cases, symptoms include drowsiness, mental confusion, and lethargy, in more serious cases, symptoms may include ataxia, hypotonia, hypotension, respiratory depression, rarely coma and very rarely death.

Chromaturia (blue-green urine discolouration) has been reported with zaleplon overdose.

Flumazenil may be useful as an antidote. Animal studies suggest that flumazenil is an antagonist to zaleplon and should be considered in the management of Zerene overdose. However, there is no clinical experience with the use of flumazenil as an antidote to a Zerene overdose.

5. PHARMACOLOGICAL PROPERTIES5.1 Pharmacodynamic properties

Pharmacotherapeutic Group: Benzodiazepine related d

Zaleplon is a pyrazolopyrimidine hypnotic that is structurally different from benzodiazepines and other hypnotics. Zaleplon binds selectively to the benzodiazepine type I receptor.

Zaleplon’s phar­macokinetic profile shows rapid absorption and elimination (see section 5.2). In combination with its subtype selective receptor-binding characteristics, with high selectivity and low affinity for the benzodiazepine type I receptor, these properties are responsible for the overall characteristics of Zerene.

Zerene’s efficacy has been demonstrated in both sleep laboratory studies using objective polysomnography (PSG) measures of sleep and in outpatient studies using patient questionnaires to assess sleep. In these studies, patients were diagnosed with primary (psychophysio­logical) insomnia.

Sleep latency in outpatient studies was decreased for up to 4 weeks in non-elderly patients with Zerene 10 mg. In elderly patients, sleep latency was often significantly decreased with Zerene 5 mg and was consistently decreased with Zerene 10 mg compared with placebo in 2-week studies. This decreased sleep latency was significantly different from that observed with placebo. Results from the 2– and 4-week studies showed that no pharmacological tolerance developed with any dose of Zerene.

In Zerene studies using objective PSG measures, Zerene 10 mg was superior to placebo in decreasing sleep latency and increasing sleep duration during the first half of the night. Zerene has been shown to preserve sleep stages in controlled studies that measured the percentage of sleep time spent in each sleep stage.

5.2 Pharmacokinetic properties

Absorption

Zaleplon is rapidly and almost completely absorbed after oral administration, and peak concentrations are reached in approximately 1 hour. At least 71% of the orally-administered dose is absorbed.

Zaleplon undergoes presystemic metabolism, resulting in an absolute bioavailability of approximately 30%.

Distribution

Zaleplon is lipophilic with a volume of distribution of about 1.4±0.3 l/kg following intravenous administration. The in vitro plasma protein binding is approximately 60%, suggesting little risk o active substance interaction due to protein binding.

Metabolism                                 W

Zaleplon is primarily metabolised by aldehyde oxidase to form 5-oxo-zaleplon. Additionally, zaleplon is metabolised by CYP3A4 to form desethylzaleplon which is further metabolised by aldehyde oxidase to form 5-oxo-desethylzaleplon. The oxidative metabolites are further metabolised by conjugation via glucuronidation. All of zaleplon’s me­tabolites are inactive in both animal behavioural models and in vitro activity assays.

Zaleplon plasma concentrations increased linearly with dose, and zaleplon showed no signs of accumulation following administration of up to 30 mg/day. The elimination half-life of zaleplon is approximately 1 hour.

Excretion

Zaleplon is excreted in the form of inactive metabolites, mainly in the urine (71%) and faeces (17%). Fifty-seven percent (57%) of the dose is recovered in urine in the form of 5-oxo-zaleplon and its glucuronide metabolite, an additional 9% is recovered as 5-oxo-desethylzaleplon and its glucuronide metabolite. The remainder of the urinary recovery consists of minor metabolites. The majority of the faecal recovery consists of 5-oxo-zaleplon.

Hepatic Impairment

Zaleplon is metabolised primarily by the liver and undergoes significant presystemic metabolism. Consequently, the oral clearance of zaleplon was reduced by 70% and 87% in compensated and decompensated cirrhotic patients, respectively, leading to marked increases in mean Cmax and AUC (up to 4-fold and 7-fold in compensated and decompensated patients, respectively) relative to healthy subjects. The dose of zaleplon should be reduced in patients with mild to moderate hepatic impairment, and zaleplon is not recommended for use in patients with severe hepatic impairment.

Renal Impairment

The single dose pharmacokinetics of zaleplon were studied in patients with mild (creatinine clearance 40 to 89 ml/min) and moderate (20 to 39 ml/min) renal impairment, and in patients on dialysis. In patients with moderate impairment and those on dialysis there was a reduction of approximately 23% in peak plasma concentration compared to healthy volunteers. The extent of exposure to zaleplon was similar among all groups. Therefore, no dose adjustment is necessary in patients with mild to moderate renal impairment. Zaleplon has not been adequately studied in patients with severe renal impairment.

5.3 Preclinical safety data

Repeated oral administration of zaleplon to rats and dogs elicited increases in liver and adrenal weights; however, these increases occurred at high multiples of the maximum therapeutic dose, were reversible, were not associated with degenerative microscopic changes in liver or adrenal glands, and were consistent with effects in animals with other compounds that bind to benzodiazepine receptors. In a three month study in prepubescent dogs there was significant reduction in the weight of both prostate and testes at high multiples of the maximum therapeutic dose. Oral administration of zaleplon to rats for 104 consecutive weeks at dosage levels up to 20 mg/kg/day did not result in compound-related tumorigenicity. Oral administration of zaleplon to mice for 65 or 104 consecutive weeks at high dosage levels (>100 mg/kg/day) elicited a statistically significant increase in benign but not in malignant liver tumors. The increased incidence of benign liver tumors in mice was likely an adaptive event.

Overall, the results of the preclinical studies do not suggest any significant safety hazard for use of Zerene at recommended doses in humans.

6. PHARMACEUTICAL PARTICULARS6.1 List of excipients

Capsule core Microcrystalline cellulose, pregelatinised starch, silicon dioxide, sodium lauryl sulphate, magnesium stearate, lactose monohydrate, indigo carmine (E132), titanium dioxide (E171).

Capsule shell gelatin, titanium dioxide (E171), red iron oxide (E172), yellow iron oxide (E172), black iron oxide (E172), sodium lauryl sulphate, silicon dioxide.

Printing inks on the shell contain the following (gold ink S-13050): shellac, lecithin, simethicone, yellow iron oxide (E1

6.2 Incompatibilities6.3Not appli

3 years.

6.4 Special precautions for storage

Do not store above 30°C.

6.5 Nature and contents of container

PVC / PVDC aluminium blister packages of 7, 10, 14 capsules in perforated unit-dose blisters. Not all pack sizes may be marketed.

6.6 Special precautions for disposal and handling

No special requirements.

Zerene has been designed so that if the contents of the capsule are dissolved in a liquid, the liquid will change colour and become cloudy.

7. MARKETING AUTHORISATION HOLDER

Meda AB

Pipers vag 2A

S-170 09 Solna

Sweden

8. MARKETING AUTHORISATION NUMBERS

EU/1/99/099/001–003

9. DATE OF FIRST AUTHORISATION/RENEWAL OF AUTHORISATION

Date of first authorisation: 12 March 1999

Date of latest renewal: 12 March 2009