Buccolam

/ Neopharm Cure

Infants, toddlers, children and adolescents:
3 to 6 months hospital setting: 2.5mg
> 6 months to < 1 year: 2.5mg
1 year to < 5 years: 5 mg
5 years to < 10 years: 7.5 mg
10 years to < 18 years: 10 mg
Carers should only administer a single dose of midazolam. If the seizure has not stopped within 10 minutes after administration of midazolam, emergency medical assistance must be sought and the empty syringe given to the healthcare professional to provide information on the dose received by the patient. A second or repeat dose when seizures re-occur after an initial response should not be given without prior medical advice.
Paediatric population: The safety and efficacy of midazolam in children aged 0 to 3 months has not been established. No data are available.
Renal impairment: No dose adjustment is required, however, this product should be used with caution in patients with chronic renal failure as elimination of midazolam may be delayed and the effects prolonged.
Hepatic impairment: Hepatic impairment reduces the clearance of midazolam with a subsequent increase in terminal half-life. Therefore, the clinical effects may be stronger and prolonged, hence careful monitoring of the clinical effects and vital signs is recommended following administration of midazolam in patients with hepatic impairment. This product is contraindicated in patients with severe hepatic impairment.
Method of administration: This product is for oromucosal use. The full amount of solution should be inserted slowly into the space between the gum and the cheek. Laryngo-tracheal insertion should be avoided to prevent accidental aspiration of the solution. If necessary (for larger volumes and/or smaller patients), approximately half the dose should be given slowly into one side of the mouth, then the other half given slowly into the other side.

Treatment of prolonged, acute, convulsive seizures in infants, toddlers, children and adolescents (from 3 months to < 18 years). It 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.

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

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 this product 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: 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.

Published clinical studies show that oromucosal midazolam was administered to approx 443 children 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.
Common adverse reactions: Sedation, somnolence, depressed levels of consciousness, Respiratory depression, Nausea and vomiting.
For full details see prescribing information.

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. Dopaminergic agents: Midazolam may cause inhibition of levodopa.
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.
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.
Medicinal products s 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.
Azole antifungals: Ketoconazole increased the plasma concentrations of intravenous midazolam by 5-fold while the terminal half-life increased by about 3-fold. Voriconazole increased the exposure of intravenous midazolam by 3-fold whereas its elimination half-life increased by about 3-fold. Fluconazole and itraconazole both increased the plasma concentrations of intravenous midazolam by 2 to 3-fold associated with an increase in terminal half-life by 2.4-fold for itraconazole and 1.5-fold for fluconazole.Posaconazole increased the plasma concentrations of intravenous midazolam by about 2-fold.
Macrolide antibiotics: Erythromycin resulted in an increase in the plasma concentrations of intravenous midazolam by about 1.6 to 2 –fold associated with an increase of the terminal half-life of midazolam by 1.5 to 1.8-fold. Clarithromycin increased the plasma concentrations of intravenous midazolam by up to 2.5-fold associated with an increase in terminal half-life by 1.5 to 2-fold.
HIV Protease inhibitors: Saquinavir and other HIV protease inhibitors: Co-administration with protease inhibitors may cause a large increase in the concentration of midazolam. Upon co-administration with ritonavir-boosted lopinavir, the plasma concentrations of intravenous midazolam increased by 5.4-fold, associated with a similar increase in terminal half-life.
Calcium-channel blockers: Diltiazem: A single dose of diltiazem increased the plasma concentrations of intravenous midazolam by about 25% and the terminal half-life was prolonged by 43%.
Various medicinal products: Atorvastatin showed a 1.4-fold increase in plasma concentrations of intravenous midazolam compared to control group.
Medicinal products that induce CYP3A4: Rifampicin (7 days of 600 mg once daily) decreased the plasma concentrations of intravenous midazolam by about 60%. The terminal half-life decreased by about 50-60%.
Herb and food: St John’s Wort decreased plasma concentrations of midazolam by about 20-40% associated with a decrease in terminal half life of about 15-17%. Depending on the specific St John’s Wort extract, the CYP3A4-inducing effect may vary. Grapefruit juice: reduces the clearance of midazolam and potentiates its action.
Pharmacodynamic Drug-Drug Interactions (DDI): The co-administration of midazolam with other sedative/hypnotic agents and CNS depressants, including alcohol, is likely to result in enhanced sedation and respiratory depression. Examples include opiate derivatives (used as analgesics, antitussives or substitutive treatments), antipsychotics, other benzodiazepines used as anxiolytics or hypnotics, barbiturates, propofol, ketamine, etomidate; sedative antidepressants, non-recent H1-antihistamines and centrally acting antihypertensive medicinal products. Alcohol, including alcohol-containing medicinal products may markedly enhance the sedative effect of midazolam. Alcohol intake should be strongly avoided in case of midazolam administration. Midazolam decreases the minimum alveolar concentration (MAC) of inhalation anaesthetics. The effect of CYP3A4 inhibitors may be larger in infants since part of the oromucosal dose is probably swallowed and absorbed in the gastro-intestinal tract.
For full details see prescribing information

Pregnancy: 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.
Lactation: Midazolam passes in low quantities (0.6%) into breast milk. As a result it may not be necessary to stop breast feeding following a single dose of midazolam.
For full details see prescribing information.

Symptoms: Midazolam overdose can present a threat to life if the patient has pre-existing respiratory or cardiac insufficiency, or when combined with other CNS depressants (including alcohol).
Overdose of benzodiazepines 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.
Management: 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 midazolam, 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 absorption. Special attention should be paid to respiratory and cardiovascular functions in intensive care.
Flumazenil may be useful as an antidote.

Precautions to be taken before handling or administering the product: No needle, intravenous tubing or any other device for parenteral administration should be attached to the oral syringe. This product is not for intravenous use. The oral syringe cap should be removed before use to avoid risk of choking.
Effects on ability to drive and use machines: Midazolam has a major influence on the ability to drive and use machines. Sedation, amnesia, impaired attention and impaired muscular function may adversely affect the ability to drive, ride a bicycle or use machines. After receiving midazolam, the patient should be warned not to drive a vehicle or operate a machine until completely recovered.
Storage: Store below 30°C. Do not refrigerate or freeze.