Buccolam · 4.4 Special warnings and precautions for use · 1

HOS-095976 · has-adverse-reaction-information · PDF-Seite 8

Summary of the safety profile Published clinical studies show that oromucosal midazolam was administered to approximately 443 children and 224 adults with seizures. Respiratory depression occurs at a rate of up to 5%, although this is a known complication of convulsive seizures as well as being related to midazolam use. One episode of pruritus was possibly attributed to the use of buccal midazolam. Tabulated list of adverse reactions The table below lists the adverse reactions reported to occur when oromucosal midazolam was administered in clinical studies and postmarketing experience. The frequency of adverse reactions is classified as follows: Common: ≥ 1/100 to < 1/10 Uncommon: ≥ 1/1,000 to < 1/100 Very rare: < 1/10,000 Not known: cannot be estimated from the available data Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness: System Organ Class Frequency: Adverse Drug Reaction Psychiatric disorders Very rare: Aggression**, agitation**, anger**, confusional state**, euphoric mood**, hallucination**, hostility**, movement disorder**, physical assault** Nervous system disorders Common: Sedation, somnolence, depressed levels of consciousness Respiratory depression Very rare: Anterograde amnesia**, ataxia**, dizziness**, headache**, seizure**, paradoxical reactions** Cardiac disorders Very rare: Bradycardia**, cardiac arrest**, hypotension**, vasodilatation** Respiratory, thoracic and Very rare: mediastinal disorders Apnoea**, dyspnea**, laryngospasm**, respiratory arrest** Gastrointestinal disorders Common: Nausea and vomiting Very rare: Constipation**, dry mouth** Skin and subcutaneous tissue Uncommon: disorders Pruritus, rash and urticarial Not known: Angioedema*

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HOS-095972 · has-contraindication-information · PDF-Seite 4

Hypersensitivity to the active substance, benzodiazepines or to any of the excipients listed in section 6.1 Myasthenia gravis Severe respiratory insufficiency Sleep apnoea syndrome Severe hepatic impairment

HOS-095971 · has-indication-information · PDF-Seite 2

Treatment of prolonged, acute, convulsive seizures in infants from 3 months to adults. BUCCOLAM must only be used by parents/carers where the patient has been diagnosed to have epilepsy. For infants between 3-6 months of age treatment should be in a hospital setting where monitoring is possible and resuscitation equipment is available. See section 4.2. 2

HOS-095974 · has-interaction-information · PDF-Seite 5

Midazolam is metabolized by CYP3A4. Inhibitors and inducers of CYP3A4 have the potential to respectively increase and decrease the plasma concentrations and, subsequently, the effects of midazolam thus requiring dose adjustments accordingly. Pharmacokinetic interactions with CYP3A4 inhibitors or inducers are more pronounced for oral as compared to oromucosal or parenteral midazolam as CYP3A4 enzymes are also present in the upper gastro-intestinal tract. After oromucosal administration, only systemic clearance will be affected. After a single dose of oromucosal midazolam, the consequence on the maximal clinical effect due to CYP3A4 inhibition will be minor while the duration of effect may be prolonged. Hence, a careful monitoring of the clinical effects and vital signs is recommended during the use of midazolam with a CYP3A4 inhibitor even after a single dose. Anaesthetics and narcotic analgesics Fentanyl may reduce midazolam clearance. Antiepileptics Co-administration with midazolam may cause enhanced sedation or respiratory or cardiovascular depression. Midazolam may interact with other hepatically metabolised medicinal products, e.g. phenytoin, causing potentiation. Calcium-channel blockers Diltiazem and verapamil have been shown to reduce the clearance of midazolam and other benzodiazepines and may potentiate their actions. Ulcer-healing medicinal products Cimetidine, ranitidine and omeprazole have been shown to reduce the clearance of midazolam and other benzodiazepines and may potentiate their actions. Xanthines Metabolism of midazolam and other benzodiazepines is accelerated by xanthines. Dopaminergic medicinal products Midazolam may cause inhibition of levodopa. 5 Muscle relaxants E.g. baclofen. Midazolam may cause potentiation of muscle relaxants, with increased CNS depressant effects. Nabilone Co-administration with midazolam may cause enhanced sedation or respiratory and cardiovascular depression. Medicinal products that inhibit CYP3A4 Medicinal product interactions following oromucosal administration of midazolam are likely to be similar to those observed after intravenous midazolam rather than oral administration. Food Grapefruit juice reduces the clearance of midazolam and potentiates its action. Azole antifungals Ketoconazole increased the plasma concentrations of intravenous midazolam by 5-fold while the terminal half-life increased by about 3-fold. Voriconazole incr

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HOS-095975 · has-pregnancy-information · PDF-Seite 7

Pregnancy There are no or limited amount of data from the use of midazolam in pregnant women. Animal studies do not indicate a teratogenic effect with respect to reproductive toxicity, but foetotoxicity has been observed in humans as with other benzodiazepines. No data on exposed pregnancies are available for the first two trimesters of pregnancy. The administration of high doses of midazolam in the last trimester of pregnancy or during labour has been reported to produce maternal or foetal adverse reactions (risk of aspiration of fluids and stomach contents during labour in the mother, irregularities in the foetal heart rate, hypotonia, poor suckling, hypothermia and respiratory depression in the new-born infant). Midazolam may be used during pregnancy if clearly necessary. The risk for new-born infants should be taken into account in the event of administration of midazolam in the third trimester of pregnancy. Breast-feeding Midazolam is excreted in low quantities (0.6%) in human milk. As a result it may not be necessary to stop breast feeding following a single dose of midazolam. Fertility 7 Animal studies did not show an impairment of fertility (see section 5.3).

HOS-095973 · has-warning-information · PDF-Seite 4

Special caution should be exercised when administering midazolam to high-risk patients: • adults over 60 years of age • chronically ill or debilitated patients, e.g. • patients with chronic respiratory insufficiency • patients with chronic renal failure, impaired hepatic function or with impaired cardiac function • paediatric patients with cardiovascular instability. These high-risk patients may require lower dosages. Respiratory insufficiency Midazolam should be used with caution in patients with chronic respiratory insufficiency because midazolam may further depress respiration. Paediatric patients aged 3 to 6 months Given the higher metabolite to parent drug ratio in younger children, a delayed respiratory depression as a result of high active metabolite concentrations in the 3-6 months age group cannot be excluded. Therefore, the use of BUCCOLAM in the 3-6 month age group should be limited for use only under the supervision of a health care professional where resuscitation equipment is available and where respiratory function can be monitored and equipment for respiratory assistance, if needed, is available. Altered elimination of midazolam Midazolam should be used with caution in patients with chronic renal failure, impaired hepatic or cardiac function. Midazolam may accumulate in patients with chronic renal failure or impaired hepatic function whilst in patients with impaired cardiac function it may cause decreased clearance of midazolam. Concomitant use with other benzodiazepines 4 Debilitated patients are more prone to the central nervous system (CNS) effects of benzodiazepines and, therefore, lower doses may be required. Medical history of alcohol or drug abuse Midazolam should be avoided in patients with a medical history of alcohol or drug abuse. Amnesia Midazolam may cause anterograde amnesia. Excipients Sodium This medicine contains less than 1 mmol sodium (23 mg) per oral syringe, that is to say essentially ‘sodium-free’.