Sonata 10 mg hard capsules
- 1. Name of the medicinal product
- 2. Qualitative and quantitative composition
- 3. Pharmaceutical form
- 4. Clinical particulars
- 4.1 Therapeutic indications
- 4.2 Posology and method of administration
- 4.3 Contraindications
- 4.4 Special warnings and precautions for use
- 4.5 Interaction with other medicinal products and other forms of interaction
- 4.6 Fertility, pregnancy and lactation
- 4.7 Effects on ability to drive and use machines
- 4.8 Undesirable effects
- 4.9 Overdose
- 5. Pharmacological properties
- 5.1 Pharmacodynamic properties
- 5.2 Pharmacokinetic properties
- 5.3 Preclinical safety data
- 6. Pharmaceutical particulars
- 6.1 List of excipients
- 6.2 Incompatibilities
- 6.3 Shelf life
- 6.4 Special precautions for storage
- 6.5 Nature and contents of container
- 6.6 Special precautions for disposal and other handling
- 7. Marketing authorisation holder
- 8. Marketing authorisation number(s)
- 9. Date of first authorisation/renewal of the authorisation
- 10. Date of revision of the text
- Company information
- More information about this medicine
ElderlyElderly patients may be sensitive to the effects of hypnotics; therefore, 5 mg is the recommended dose of Sonata.
Paediatric patientsSonata is contraindicated in children and adolescents under 18 years of age (see section 4.3).
Hepatic impairmentAs 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.
Renal impairmentNo 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 (see section 4.3.).
ToleranceSome loss of efficacy to the hypnotic effects of short-acting benzodiazepines and benzodiazepine-like agents may develop after repeated use for a few weeks.
DependenceUse 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 anxietyA 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 treatmentThe 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 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 impairmentBenzodiazepines 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 (see section 4.7).
Psychiatric and paradoxical reactionsReactions 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 abuseBenzodiazepine and benzodiazepine-like agents should be used with extreme caution in patients with a history of alcohol or medicinal product abuse.
Hepatic impairmentBenzodiazepine 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 impairmentSonata 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 insufficiencyCaution should be observed when prescribing sedative medicinal products to patients with chronic respiratory insufficiency.
PsychosisBenzodiazepine and benzodiazepine-like agents are not recommended for the primary treatment of psychotic illness.
DepressionBenzodiazepines 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.
|Organ/System (Frequency)||Adverse Reactions|
|Nervous system disordersCommon:Uncommon:||amnesia, paraesthesia, somnolence ataxia/coordination abnormal, dizziness, disturbance in attention, parosmia, speech disorder (dysarthria, slurred speech), hypoaesthesia|
|See also below under Amnesia|
|Eye disordersUncommon:||visual impairment, diplopia|
|Ear and labyrinth disordersUncommon:||hyperacusis|
|Skin and subcutaneous tissue disorders Uncommon: Frequency not known:||photosensitivity reaction angioedema|
|Metabolism and nutrition disordersUncommon:||anorexia|
|General disorders and administration site conditionsUncommon:||asthenia, malaise|
|Immune system disordersVery rare:||anaphylactic/anaphylactoid reactions|
|Hepatobiliary disordersFrequency not known:||hepatotoxicity (mostly described as transaminase increased)|
|Reproductive system and breast disordersCommon:||dysmenorrhea|
|Psychiatric disordersUncommon: Frequency not known:||depersonalisation, hallucinations, depression, confusional state, apathy somnambulism|
|See also below under Depression and Psychiatric and paradoxical reactions|
AmnesiaAnterograde 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).
DepressionPre-existing depression may be unmasked during benzodiazepine or benzodiazepine-like agent use.
Psychiatric and paradoxical reactionsReactions 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.
DependenceUse (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.
Reporting of suspected adverse reactionsReporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.
Symptoms of overdoseOverdose 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.
Therapy of overdoseIn the management of overdose with any medicinal product, it should be borne in mind that multiple agents may have been taken.Treatment of Sonata overdose is largely supportive. Attention to airway patency and supportive management of ventilation and haemodynamics are usually sufficient. In mild cases patients should sleep under control of respiratory and circulatory function. Induced vomiting is not recommended. In severe cases, use of activated charcoal or gastric lavage may be useful when performed soon after ingestion. Further, stabilization of circulatory function and intensive monitoring may be required. The value 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 the management of Sonata overdose. However, there is no clinical experience with the use of flumazenil as an antidote to a Sonata overdose.
AbsorptionZaleplon 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%.
DistributionZaleplon 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 of active substance interaction due to protein binding.
MetabolismZaleplon 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.
ExcretionZaleplon 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 ImpairmentZaleplon 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 ImpairmentThe 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.
Repeated dose toxicityIn line with effects observed with other compounds binding to benzodiazepine receptors, reversible increases in liver and adrenal weights in rats and dogs were only noted upon repeated oral administration of high multiples of the maximum human therapeutic dose. At these doses, a significant reduction in the weight of both prostate and testes was apparent in a three month study in prepubescent dogs.
Reproduction toxicityIn a fertility and reproductive performance study in rats, mortality and decreased fertility were observed in males and females at an oral zaleplon dose of 100 mg/kg/day (equivalent to 49-times the maximum recommended human dose (MRHD) of 20 mg on a mg/m2 basis). Follow-up studies indicated 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 50 mg/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 growth of rats was reduced at the maternally toxic dose of 100 mg/kg/day. The no-effect dose for growth of rat offspring was 10 mg/kg (equivalent to 5-times the MRHD on a mg/m2 basis). No adverse effects on embryofetal development were observed in rabbits.In a pre- and postnatal development study in rats, increased stillbirth and postnatal mortality, and decreased growth and physical development, were observed in the offspring of females treated with doses of ≥7 mg/kg/day that did not elicit maternal toxicity. The no-effect dose for postnatal development was 1 mg/kg/day (equivalent to 0.5-times the MRHD on a mg/m2 basis). In a subsequent cross-fostering study, adverse effects on offspring viability and growth appeared to result from both in utero and lactational exposure to zaleplon.
CarcinogenicityOral 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 Sonata at recommended doses in humans.
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