SONATA 5mg capsules medication leaflet

Sonata 5 mg hard capsules

Each capsule contains 5 mg of zaleplon.

Excipient with known effect: Lactose monohydrate 54 mg.

For the full list of excipients, see section 6.1.

Capsule, hard.

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

Sonata is indicated for the treatment of patients with insomnia who have difficulty falling asleep. It isindicated 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 isexperiencing difficulty falling asleep. As administration after food delays the time to maximal plasmaconcentration 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 notto take a second dose within a single night.

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

Sonata is contraindicated in children and adolescents under 18 years of age (see section 4.3).

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

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

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

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Sleep apnoea syndrome

Myasthenia gravis

Severe respiratory insufficiency

Children and adolescents (under 18 years of age)

Complex behaviours such as “sleep-driving” (i.e., driving while not fully awake after ingestion of asedative-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 experiencedpersons. Although behaviours such as sleep-driving may occur with a sedative-hypnotic alone attherapeutic doses, the use of alcohol and other central nervous system (CNS) depressants withsedative-hypnotics appears to increase the risk of such behaviours, as does exceeding the maximumrecommended dose. Due to the risk to the patient and the community, discontinuation of zaleplon isrecommended 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 arenot fully awake after taking a sedative-hypnotic. As with sleep-driving, patients usually do notremember 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 inpatients after taking the first or subsequent doses of sedative-hypnotics, including zaleplon. Somepatients taking sedative-hypnotics have had additional symptoms such as dyspnoea, throat closing, ornausea and vomiting. Some patients have required medical therapy in the emergency department. Ifangioedema involves the tongue, glottis or larynx, airway obstruction may occur and be fatal. Patientswho develop angioedema after treatment with zaleplon should not be rechallenged with the activesubstance.

Insomnia may represent an underlying physical or psychiatric disorder. Insomnia that persists orworsens 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 morningawakening 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 toresult in changes in zaleplon’s plasma concentrations. (See section 4.5).

Concomitant intake with alcohol is not recommended. The sedative effect may be enhanced when theproduct is used in combination with alcohol which may affect the ability to drive or use machines thenext day (see section 4.7).

Tolerance

Some loss of efficacy to the hypnotic effects of short-acting benzodiazepines and benzodiazepine-likeagents 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 patientshaving 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 ofheadaches, muscle pain, extreme anxiety, tension, restlessness, confusion and irritability. In severecases the following symptoms may occur: unreality, depersonalisation, hyperacusis, numbness andtingling of the extremities, hypersensitivity to light, noise and physical contact, hallucinations orepileptic 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 orbenzodiazepine-like agent recur in an enhanced form, may occur on withdrawal of treatment. It maybe accompanied by other reactions including mood changes, anxiety, or sleep disturbances andrestlessness.

The duration of treatment should be as short as possible (see section 4.2), and should not exceed twoweeks. Extension beyond these periods should not take place without clinical re-evaluation of thepatient.

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

Memory and psychomotor impairment

Benzodiazepines and benzodiazepine-like agents may induce anterograde amnesia and psychomotorimpairment. 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 moreafter taking Sonata (see section 4.7).

Psychiatric and “paradoxical” reactions

Reactions like restlessness, agitation, irritability, decreased inhibition, aggressiveness, abnormalthinking, delusion, rages, nightmares, depersonalisation, hallucinations, psychoses, inappropriatebehaviour, extroversion that seems out of character and other behavioural effects are known to occurwhen 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 aremore likely to occur in the elderly. Should this occur, use of this product should be discontinued. Anynew 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 ahistory of alcohol or medicinal product abuse.

Benzodiazepine and benzodiazepine-like agents are not indicated to treat patients with severe hepaticinsufficiency as they may precipitate encephalopathy (see section 4.2). In patients with mild tomoderate hepatic insufficiency, the bioavailability of zaleplon is increased because of reducedclearance, and the dose will therefore need to be modified in these patients.

Sonata is not indicated to treat patients with severe renal impairment as it has not been adequatelystudied in those patients. In patients with mild to moderate renal impairment, the pharmacokineticprofile of zaleplon is not significantly different than that in healthy subjects. Hence, no doseadjustment is required in these patients.

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

Psychosis

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

Depression

Benzodiazepines and benzodiazepine-like agents should not be used alone to treat depression oranxiety associated with depression (suicide may be precipitated in such patients). Also, because of theincreased risk for intentional overdose in patients with depression in general, the quantity of amedicinal product, including zaleplon, prescribed for such patients should be kept to the necessaryminimum.

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

Concomitant intake with alcohol is not recommended. The sedative effect may be enhanced when theproduct is used in combination with alcohol which may affect the ability to drive or use machines thenext day (see section 4.7).

Combination with other CNS-acting compounds should be taken into account. Enhancement of thecentral 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. Concomitant use of zaleplon with these drugs may increasethe risk of next day drowsiness, including impaired driving ability (see section 4.7).

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

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

Diphenhydramine is reported to be a weak inhibitor of aldehyde oxidase in rat liver, but its inhibitoryeffects in human liver are not known. There is no pharmacokinetic interaction between zaleplon anddiphenhydramine following the administration of a single dose (10 mg and 50 mg, respectively) ofeach drug. However, because both of these compounds have CNS effects, an additivepharmacodynamic effect is possible.

Cimetidine, a non-specific moderate inhibitor of several hepatic enzymes including both aldehydeoxidase and CYP3A4, produced an 85% increase in plasma concentrations of zaleplon because itinhibited both the primary (aldehyde oxidase) and secondary (CYP3A4) enzymes responsible forzaleplon’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 CYP3A4inhibitor, produced a 34% increase in zaleplon’s plasma concentrations. A routine dosage adjustmentof Sonata is not considered necessary, but patients should be advised that the sedative effects might beenhanced.

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

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

Although animal studies have shown no teratogenic or embryotoxic effects, insufficient clinical dataare available on Sonata to assess its safety during pregnancy and breastfeeding. Use of Sonata is notrecommended during pregnancy. If the medicinal product is prescribed to a woman of child-bearingpotential, she should be warned to contact her physician regarding discontinuance of the medicinalproduct 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 ofpregnancy, or during labour at high doses, effects on the neonate, such as hypothermia, hypotonia andmoderate 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 duringthe latter stages of pregnancy may have developed physical dependence and may be at some risk fordeveloping withdrawal symptoms in the postnatal period.

Because zaleplon is excreted in the breast milk, Sonata should not be administered to breast-feedingmothers.

Sonata has major influence on the ability to drive and use machines.

Sedation, amnesia, impaired concentration and impaired muscular function may adversely affect theability to drive or to use machines the next day. If insufficient sleep duration occurs, the likelihood ofimpaired alertness may be increased. Furthermore, the co-administration of zaleplon with alcohol andother CNS depressants increases this risk (see section 4.5). Caution is recommended for patientsperforming skilled tasks. Patients should be advised not to drive or operate machinery until it isestablished that their performance is not impaired.

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

Frequencies are defined as

Very 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)not known (cannot be estimated from the available data)

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

Organ/System Adverse Reactions(Frequency)

Common: amnesia, paraesthesia, somnolence

Uncommon: ataxia/coordination abnormal, dizziness,disturbance in attention, parosmia, speechdisorder (dysarthria, slurred speech),hypoaesthesia

See also below under Amnesia

Uncommon: visual impairment, diplopia

Ear and labyrinth disorders

Uncommon: hyperacusis

Uncommon: nausea

Uncommon: photosensitivity reaction

Frequency not known: angioedema

Uncommon: anorexia

Uncommon: asthenia, malaise

Very rare: anaphylactic/anaphylactoid reactions

Frequency not known: hepatotoxicity (mostly described astransaminase increased)

Common: dysmenorrhea

Uncommon: depersonalisation, hallucinations, depression,confusional state, apathy

Frequency not known: somnambulism

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

Anterograde amnesia may occur using recommended therapeutic dosages, the risk increasing at higherdosages. 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 “paradoxical” reactions

Reactions like restlessness, agitation, irritability, decreased inhibition, aggressiveness, abnormalthinking, delusions, rages, nightmares, depersonalisation, hallucinations, psychoses, inappropriatebehaviour, extroversion that seems out of character, and other adverse behavioural reactions areknown to occur when using benzodiazepines or benzodiazepine-like agents. Such reactions are morelikely to occur in the elderly.

Dependence

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

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

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

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

Symptoms of overdose

Overdose of benzodiazepine or benzodiazepine-like agents is usually manifested by degrees of centralnervous system depression ranging from drowsiness to coma. In mild cases, symptoms includedrowsiness, 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.

Therapy of overdose

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

Treatment of Sonata overdose is largely supportive. Attention to airway patency and supportivemanagement of ventilation and haemodynamics are usually sufficient. In mild cases patients shouldsleep under control of respiratory and circulatory function. Induced vomiting is not recommended. Insevere cases, use of activated charcoal or gastric lavage may be useful when performed soon afteringestion. Further, stabilization of circulatory function and intensive monitoring may be required. Thevalue of forced dialysis or haemodialysis in the treatment of over dosage has not been determined.

Animal studies suggest that flumazenil is an antagonist to zaleplon and should be considered in themanagement of Sonata overdose. However, there is no clinical experience with the use of flumazenilas an antidote to a Sonata overdose.

Pharmacotherapeutic Group: Benzodiazepine related drugs, ATC Code N05CF03

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

Zaleplon’s pharmacokinetic profile shows rapid absorption and elimination (see section 5.2). Incombination with its subtype selective receptor-binding characteristics, with high selectivity and lowaffinity for the benzodiazepine type I receptor, these properties are responsible for the overallcharacteristics of Sonata.

Sonata’s efficacy has been demonstrated in both sleep laboratory studies using objectivepolysomnography (PSG) measures of sleep and in outpatient studies using patient questionnaires toassess 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 Sonata10 mg. In elderly patients, sleep latency was often significantly decreased with Sonata 5 mg and wasconsistently decreased with Sonata 10 mg compared with placebo in 2-week studies. This decreasedsleep 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 Sonata.

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

Zaleplon is rapidly and almost completely absorbed after oral administration, and peak concentrationsare 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 approximately30%.

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

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

Zaleplon plasma concentrations increased linearly with dose, and zaleplon showed no signs ofaccumulation following administration of up to 30 mg/day. The elimination half-life of zaleplon isapproximately 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 itsglucuronide metabolite, an additional 9% is recovered as 5-oxo-desethylzaleplon and its glucuronidemetabolite. The remainder of the urinary recovery consists of minor metabolites. The majority of thefaecal 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 anddecompensated cirrhotic patients, respectively, leading to marked increases in mean Cmax and AUC (upto 4-fold and 7-fold in compensated and decompensated patients, respectively) relative to healthysubjects. The dose of zaleplon should be reduced in patients with mild to moderate hepaticimpairment, 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 clearance40 to 89 ml/min) and moderate (20 to 39 ml/min) renal impairment, and in patients on dialysis. Inpatients 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 wassimilar among all groups. Therefore, no dose adjustment is necessary in patients with mild to moderaterenal impairment. Zaleplon has not been adequately studied in patients with severe renal impairment.

In line with effects observed with other compounds binding to benzodiazepine receptors, reversibleincreases in liver and adrenal weights in rats and dogs were only noted upon repeated oraladministration of high multiples of the maximum human therapeutic dose. At these doses, a significantreduction in the weight of both prostate and testes was apparent in a three month study in prepubescentdogs.

Reproduction toxicity

In a fertility and reproductive performance study in rats, mortality and decreased fertility wereobserved in males and females at an oral zaleplon dose of 100 mg/kg/day (equivalent to 49-times themaximum recommended human dose (MRHD) of 20 mg on a mg/m2 basis). Follow-up studiesindicated that impaired fertility was due to an effect on the female.

In embryofetal development studies, oral administration of zaleplon up to 100 mg/kg/day and 50mg/kg/day to pregnant rats and rabbits, respectively, produced no evidence of teratogenicity(equivalent to 49- (rat) and 48-(rabbit) times the MRHD on a mg/m2 basis). Pre-and postnatal growthof rats was reduced at the maternally toxic dose of 100 mg/kg/day. The no-effect dose for growth ofrat offspring was 10 mg/kg (equivalent to 5-times the MRHD on a mg/m2 basis). No adverse effects onembryofetal development were observed in rabbits.

In a pre- and postnatal development study in rats, increased stillbirth and postnatal mortality, anddecreased growth and physical development, were observed in the offspring of females treated withdoses of ≥7 mg/kg/day that did not elicit maternal toxicity. The no-effect dose for postnataldevelopment was 1 mg/kg/day (equivalent to 0.5-times the MRHD on a mg/m2 basis). In a subsequentcross-fostering study, adverse effects on offspring viability and growth appeared to result from both inutero and lactational exposure to zaleplon.

Oral administration of zaleplon to rats for 104 consecutive weeks at dosage levels up to 20 mg/kg/daydid not result in compound-related tumorigenicity. Oral administration of zaleplon to mice for 65 or104 consecutive weeks at high dosage levels (≥100 mg/kg/day) elicited a statistically significantincrease in benign but not in malignant liver tumors. The increased incidence of benign liver tumors inmice was likely an adaptive event.

Overall, the results of the preclinical studies do not suggest any significant safety hazard for use of

Sonata at recommended doses in humans.

Capsule core

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

Capsule shellgelatin,titanium dioxide (E171),red iron oxide (E172),yellow iron oxide (E172),black iron oxide (E172),sodium lauryl sulphate,

Printing inks on the shell contain the following (gold ink SB-3002):shellac,ammonium hydroxide,yellow iron oxide (E172).

Not applicable.

3 years.

This medicinal product does not require any special temperature storage conditions.

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

No special requirements.

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

Meda AB

Pipers väg 2A

S-170 09 Solna

Sweden

EU/1/99/102/001-003

Date of first authorisation: 12 March 1999

Date of latest renewal: 12 March 2009

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu/.