Buccolam 2.5mg, 5mg, 7.5mg and 10 mg Oromucosal Solution: Indications, Dosage, Precautions, Adverse Effects
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Buccolam 2.5mg, 5mg, 7.5mg and 10 mg Oromucosal Solution - Product Information

Manufacture: Shire Pharmaceuticals
Country: United States
Condition: Epilepsy
Class: Psychotherapeutic agents
Form: Liquid solution
Ingredients: midazolam, sodium chloride, water for injection, hydrochloric acid and sodium hydroxide (for pH adjustment)

Name of the Medicinal Product

BUCCOLAM 2.5 mg oromucosal solution

BUCCOLAM 5 mg oromucosal solution

BUCCOLAM 7.5 mg oromucosal solution

BUCCOLAM 10 mg oromucosal solution

Qualitative and Quantitative Composition

Each pre filled oral syringe contains 2.5 mg midazolam (as hydrochloride) in 0.5 ml solution

Each pre filled oral syringe contains 5 mg midazolam (as hydrochloride) in 1 ml solution

Each pre filled oral syringe contains 7.5 mg midazolam (as hydrochloride) in 1.5 ml solution

Each pre filled oral syringe contains 10 mg midazolam (as hydrochloride) in 2 ml solution

For the full list of excipients, see section List of Excipients

Pharmaceutical Form

Oromucosal solution

Clear colourless solution

pH 2.9 to 3.7

Clinical Particulars

Therapeutic Indications

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

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 Posology and Method of Administration

Posology and Method of Administration

Posology

Standard doses are indicated below:

Infants, toddlers, children and adolescents:

Age range Dose Label colour
3 to 6 months hospital setting 2.5 mg Yellow
> 6 months to < 1 year 2.5 mg Yellow
1 year to < 5 years 5 mg Blue
5 years to <10 years 7.5 mg Purple
10 years to < 18 years 10 mg Orange

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 (see section Pharmacokinetic Properties)

Special populations

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, BUCCOLAM should be used with caution in patients with chronic renal failure as elimination of midazolam may be delayed and the effects prolonged. (see section Special Warnings and Precautions for Use)

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 (see section Special Warnings and Precautions for Use).

BUCCOLAM is contraindicated in patients with severe hepatic impairment (see section Contraindications).

Method of administration

BUCCOLAM 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.

For detailed instructions on how to administer the medicinal product, see section Nature and Contents of Container

Precautions to be taken before handling or administering the medicinal product

No needle, intravenous tubing or any other device for parenteral administration should be attached to the oral syringe.

BUCCOLAM is not for intravenous use.

The oral syringe cap should be removed before use to avoid risk of choking.

Contraindications

Hypersensitivity to the active substance, benzodiazepines or to any of the excipients listed in section List of Excipients

Myasthenia gravis

Severe respiratory insufficiency

Sleep apnoea syndrome

Severe hepatic impairment

Special Warnings and Precautions for Use

Midazolam should be used with caution in patients with chronic respiratory insufficiency because midazolam may further depress respiration.

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.

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.

Debilitated patients are more prone to the central nervous system (CNS) effects of benzodiazepines and, therefore, lower doses may be required.

Midazolam should be avoided in patients with a medical history of alcohol or drug abuse.

Midazolam may cause anterograde amnesia.

Interaction With Other Medicinal Products and Other Forms of Interaction

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 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 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

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.

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 (see section Special Warnings and Precautions for Use).

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.

Fertility, Pregnancy and Lactation

Pregnancy

Insufficient data are available on midazolam to assess its safety during pregnancy. Animal studies do not indicate a teratogenic effect, but foetotoxicity was observed 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 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.

Fertility

Animal studies did not show an impairment of fertility (see section Preclinical Safety Data).

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.

Undesirable Effects

Published clinical studies show that oromucosal midazolam was administered to approx 443 children with seizures.

Most studies did not indicate numbers of adverse reactions but stated that no severe events had been reported or there was no difference from the active comparator, rectal or intravenous diazepam. 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 benzodiazepine use. One episode of pruritus was possibly attributed to the use of buccal midazolam.

The table below lists the adverse reactions reported to occur when oromucosal midazolam was administered to children in clinical studies.

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

Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness:

System Organ Class Frequency: Adverse Drug Reaction
Nervous system disorders Common:

Sedation, somnolence, depressed levels of consciousness
Respiratory depression
Gastrointestinal disorders Common:

Nausea and vomiting
Skin and subcutaneous tissue disorders Uncommon:

Pruritus, rash and urticaria

The following adverse reactions have been reported to occur (very rarely) when midazolam is injected in children and or adults, which may be of relevance to oromucosal administration:

System Organ Class Frequency: Adverse Drug Reaction ­All occur very rarely
Psychiatric disorders aggression, agitation, anger, confusional state, euphoric mood, hallucination, hostility, movement disorder, physical assault.
Nervous system disorders anterograde amnesia, ataxia, dizziness, headache, seizure, paradoxical reactions.
Cardiac disorders bradycardia, cardiac arrest, hypotension, vasodilatation
Respiratory, thoracic and mediastinal disorders apnoea, dyspnoea, laryngospasm, respiratory arrest,
Gastrointestinal disorders constipation, dry mouth
General disorders and administration site conditions fatigue, hiccups

Description of selected adverse reactions

An increased risk for falls and fractures has been recorded in elderly benzodiazepine users.

Life threatening incidents are more likely to occur in those with pre existing respiratory insufficiency or impaired cardiac function, particularly when a high dosage is administered (see section Special Warnings and Precautions for Use).

Reporting of suspected adverse reactions

Reporting 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:

United Kingdom

Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard

Ireland

HPRA Pharmacovigilance

Earlsfort Terrace

IRL Dublin 2

Tel: +353 1 6764971

Fax: +353 1 6762517

Website: www.hpra.ie

e mail: medsafety@hpra.ie

Overdose

Midazolam overdose should not present a threat to life unless the patient has pre existing respiratory or cardiac insufficiency, or when 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 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.

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.

Flumazenil may be useful as an antidote

Pharmacological Properties

Pharmacodynamic Properties

Pharmacotherapeutic group: ATC code: N05CD08

Midazolam is a derivative of the imidazobenzodiazepine group. The free base is a lipophilic substance with low solubility in water. The basic nitrogen in position 2 of the imidazobenzodiazepine ring system enables midazolam to form the hydrochloride salt with acids. These produce a stable solution suitable for oromucosal administration.

The pharmacological action of midazolam is characterized by short duration because of rapid metabolic transformation. Midazolam has an anticonvulsant effect. It also exerts a sedative and sleep inducing effect of pronounced intensity, and an anxiolytic and a muscle relaxant effect.

In 4 rectal diazepam controlled studies and one study versus intravenous diazepam, in a total of 688 children, cessation of visible signs of seizures within 10 minutes was observed in 65% to 78% of children receiving oromucosal midazolam. Additionally, in 2 of the studies, cessation of visible signs of seizures within 10 minutes without recurrence within 1 hour after administration was observed in 56% to 70% of children. The frequency and severity of adverse drug reactions reported for Oromucosal midazolam during published clinical trials were similar to the adverse drug reactions reported in the comparative group using rectal diazepam.

The European Medicines Agency has waived the obligation to submit the results of studies with BUCCOLAM in the subset of the paediatric population < 3months old, on the grounds that the specific medicinal product does not represent a significant therapeutic benefit over existing treatments for these paediatric patients. The treatment of infants between 3 6 months of age should be provided only under the supervision of a health care professional in a hospital setting where resuscitation equipment is available. See section Posology and Method of Administration

Pharmacokinetic Properties

Simulated pharmacokinetic parameters for the recommended posology in children aged 3 months to less than 18 years, based on a population pharmacokinetic study are provided in tabulated format below:

Dose Age Parameter Mean SD
2.5 mg 3 m < 1 yr AUC0-inf (ng.h/ml)
Cmax (ng/ml)
168
104
98
46
5 mg 1 yr < 5 yrs AUC0-inf (ng.h/ml)
Cmax (ng/ml)
242
148
116
62
7.5 mg 5 yrs <10 yrs AUC0-inf (ng.h/ml)
Cmax (ng/ml)
254
140
136
60
10 mg 10 yrs < 18 yrs AUC0-inf (ng.h/ml)
Cmax (ng/ml)
189
87
96
44

Absorption after oromucosal administration

After oromucosal administration midazolam is absorbed rapidly. Maximum plasma concentration is reached within 30 minutes in children. The absolute bioavailability of oromucosal midazolam is about 75% in adults. The bioavailability of oromucosal midazolam has been estimated at 87% in children with severe malaria and convulsions.

Distribution

Midazolam is highly lipophilic and distributes extensively. The steady state volume of distribution following oromucosal administration is estimated to be 5.3 l/kg.

Approximately 96 98% of midazolam is bound to plasma proteins. The major fraction of plasma protein binding is due to albumin. There is a slow and insignificant passage of midazolam into the cerebrospinal fluid. In humans, midazolam has been shown to cross the placenta slowly and to enter foetal circulation. Small quantities of midazolam are found in human milk.

Biotransformation

Midazolam is almost entirely eliminated by biotransformation. The fraction of the dose extracted by the liver has been estimated to be 30 60%. Midazolam is hydroxylated by the cytochrome P4503A4 isozyme and the major urinary and plasma metabolite is alpha hydroxy midazolam. Following oromucosal administration in children the area under the curve ratio for alpha hydroxy midazolam to midazolam is 0.46.

In a population pharmacokinetic study, the metabolite levels are shown to be higher in younger than older paediatric patients and thus likely to be of more importance in children than in adults.

Elimination

Plasma clearance of midazolam in children following oromucosal administration is 30 ml/kg/min. The initial and terminal elimination half lives are 27 and 204 minutes, respectively. Midazolam is excreted mainly by the renal route (60 80% of the injected dose) and recovered as glucuroconjugated alpha hydroxy midazolam. Less than 1% of the dose is recovered in urine as unchanged medicinal product..

Pharmacokinetics in special populations

Obese

The mean half life is greater in obese than in non obese patients (5.9 versus 2.3 hours). This is due to an increase of approximately 50% in the volume of distribution corrected for total body weight. The clearance is not significantly different in obese and non obese patients.

Patients with hepatic impairment

The elimination half life in cirrhotic patients may be longer and the clearance lower as compared to those in healthy volunteers (see section Special Warnings and Precautions for Use).

Patients with renal impairment

The elimination half life in patients with chronic renal failure is similar to that in healthy volunteers.

The elimination half life of midazolam is prolonged up to six times in the critically ill.

Patients with cardiac insufficiency

The elimination half life is longer in patients with congestive heart failure compared with that in healthy subjects (see section Special Warnings and Precautions for Use).

Exposure following a second dose in the same seizure episode

Simulated exposure data show that the overall AUC approximately doubles when a second dose is administered at 10, 30 and 60 minutes following the first dose. A second dose at 10 minutes results in a significant increase in mean Cmax of between 1.7 to 1.9 fold. At 30 and 60 minutes, significant elimination of midazolam has already occurred and therefore the increase in mean Cmax is less pronounced; 1.3 to 1.6 and 1.2 to 1.5 fold respectively. (see section Posology and Method of Administration).

Preclinical Safety Data

In a rat fertility study, animals dosed up to ten times the clinical dose, no adverse effects on fertility were observed.

There are no other preclinical data of relevance to the prescriber which are additional to that already included in other sections of the SmPC.

Pharmaceutical Particulars

List of Excipients

Sodium chloride

Water for injections

Hydrochloric acid (for pH adjustment and conversion of midazolam to the hydrochloride salt)

Sodium hydroxide (for pH adjustment)

Incompatibilities

Not applicable

Shelf Life

18 months

Special Precautions for Storage

Keep the oral syringe in the protective plastic tube.

Do not refrigerate or freeze.

 Nature and Contents of Container

Amber, pre filled needle free oral syringe (polypropylene) with plunger (polypropylene) and end cap (high density polyethylene) packed in a protective, capped plastic tube.

Strength Volume of solution Syringe volume Age range Label colour
2.5 mg 0.5 ml 1 ml 3 months to < 1 year Yellow
5 mg 1 ml 3 ml 1 year to <5 years Blue
7.5 mg 1.5 ml 3 ml 5 years to <10 years Purple
10mg 2 ml 3 ml 10 years to <18 years Orange

BUCCOLAM is available in cartons containing 4 prefilled syringes.

Special Precautions for Disposal and Other Handling

Administration of BUCCOLAM

BUCCOLAM is not for intravenous use.

Step 1

Hold the plastic tube, break the seal at one end and pull the cap off. Take the syringe out of the tube.

Step 2

Pull the red cap off the tip of the syringe and dispose of it safely.

Step 3

Using the finger and thumb gently pinch and pull back the child's cheek. Put the tip of the syringe into the back of the space between the inside of the cheek and the lower gum.

Step 4

Slowly press the syringe plunger until the plunger stops.
The full amount of solution should be inserted slowly into the space between the gum and the cheek (buccal cavity).
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.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

Marketing authorisation holder

Shire Services BVBA

rue Montoyer 47

1000 Brussels

Belgium

Marketing authorisation number(s)

EU/1/11/709/001

EU/1/11/709/002

EU/1/11/709/003

EU/1/11/709/004

Date of first authorisation/renewal of the authorisation

Date of first authorisation: 05 September 2011

Date of revision of the text

11/2015

Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu

Company Contact Details

Shire Pharmaceuticals Limited

http://www.shire.com

Address

Hampshire International Business Park, Chineham, Basingstoke, Hampshire , RG24 8EP


Medical Information Direct Line

0800 055 6614


Customer Care direct line

+44 (0)1256 894 107


Telephone

+44 (0)1256 894 000


Medical Information email

medinfoeuceemea@shire.com