BUCCOLAM 7.5mg oral solution medication leaflet

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 6.1.

Oromucosal solution

Clear colourless solutionpH 2.9 to 3.7

Treatment of prolonged, acute, convulsive seizures in infants, toddlers, children and adolescents (from3 months to < 18 years).

BUCCOLAM must only be used by parents/carers where the patient has been diagnosed to haveepilepsy.

For infants between 3-6 months of age treatment should be in a hospital setting where monitoring ispossible and resuscitation equipment is available. See section 4.2.

Standard doses are indicated below:

Age range Dose Label colour3 to 6 months hospital 2.5 mg Yellowsetting> 6 months to < 1 year 2.5 mg Yellow1 year to < 5 years 5 mg Blue5 years to < 10 years 7.5 mg Purple10 years to < 18 years 10 mg Orange

Carers should only administer a single dose of midazolam. If the seizure has not stopped within 10minutes after administration of midazolam, emergency medical assistance must be sought and theempty syringe given to the healthcare professional to provide information on the dose received by thepatient.

A second or repeat dose when seizures re-occur after an initial response should not be given withoutprior medical advice (see section 5.2).

No dose adjustment is required, however, BUCCOLAM should be used with caution in patients withchronic renal failure as elimination of midazolam may be delayed and the effects prolonged. (seesection 4.4)

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 theclinical effects and vital signs is recommended following administration of midazolam in patients withhepatic impairment (see section 4.4).

BUCCOLAM is contraindicated in patients with severe hepatic impairment (see section 4.3).

The safety and efficacy of midazolam in children aged 0 to 3 months has not been established. No dataare available.

BUCCOLAM is for oromucosal use. The full amount of solution should be inserted slowly into thespace between the gum and the cheek. Laryngo-tracheal insertion should be avoided to preventaccidental 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 halfgiven slowly into the other side.

For detailed instructions on how to administer the medicinal product, see section 6.6.

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

BUCCOLAM is not for intravenous use.

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

Hypersensitivity to the active substance, benzodiazepines or to any of the excipients listed in section6.1

Myasthenia gravis

Severe respiratory insufficiency

Sleep apnoea syndrome

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

Given the higher metabolite to parent drug ratio in younger children, a delayed respiratory depressionas 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 underthe supervision of a health care professional where resuscitation equipment is available and whererespiratory 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 orcardiac function. Midazolam may accumulate in patients with chronic renal failure or impaired hepaticfunction whilst in patients with impaired cardiac function it may cause decreased clearance ofmidazolam.

Debilitated patients are more prone to the central nervous system (CNS) effects of benzodiazepinesand, 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.

This medicine contains less than 1 mmol sodium (23 mg) per oral syringe, that is to say essentially‘sodium-free’.

Midazolam is metabolized by CYP3A4. Inhibitors and inducers of CYP3A4 have the potential torespectively increase and decrease the plasma concentrations and, subsequently, the effects ofmidazolam thus requiring dose adjustments accordingly. Pharmacokinetic interactions with CYP3A4inhibitors or inducers are more pronounced for oral as compared to oromucosal or parenteralmidazolam as CYP3A4 enzymes are also present in the upper gastro-intestinal tract. After oromucosaladministration, only systemic clearance will be affected. After a single dose of oromucosalmidazolam, the consequence on the maximal clinical effect due to CYP3A4 inhibition will be minorwhile the duration of effect may be prolonged. Hence, a careful monitoring of the clinical effects andvital signs is recommended during the use of midazolam with a CYP3A4 inhibitor even after a singledose.

Fentanyl may reduce midazolam clearance.

Co-administration with midazolam may cause enhanced sedation or respiratory or cardiovasculardepression. Midazolam may interact with other hepatically metabolised medicinal products, e.g.phenytoin, causing potentiation.

Diltiazem and verapamil have been shown to reduce the clearance of midazolam and otherbenzodiazepines and may potentiate their actions.

Cimetidine, ranitidine and omeprazole have been shown to reduce the clearance of midazolam andother benzodiazepines and may potentiate their actions.

Metabolism of midazolam and other benzodiazepines is accelerated by xanthines.

Midazolam may cause inhibition of levodopa.

E.g. baclofen. Midazolam may cause potentiation of muscle relaxants, with increased CNS depressanteffects.

Co-administration with midazolam may cause enhanced sedation or respiratory and cardiovasculardepression.

Medicinal product interactions following oromucosal administration of midazolam are likely to besimilar to those observed after intravenous midazolam rather than oral administration.

Grapefruit juice reduces the clearance of midazolam and potentiates its action.

Ketoconazole increased the plasma concentrations of intravenous midazolam by 5-fold while theterminal 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 2to 3-fold associated with an increase in terminal half-life by 2.4-fold for itraconazole and 1.5-fold forfluconazole.

Posaconazole increased the plasma concentrations of intravenous midazolam by about 2-fold.

Erythromycin resulted in an increase in the plasma concentrations of intravenous midazolam by about1.6 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-foldassociated with an increase in terminal half-life by 1.5 to 2-fold.

Co-administration with protease inhibitors (e.g. Saquinavir and other HIV protease inhibitors) maycause 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.

A single dose of diltiazem increased the plasma concentrations of intravenous midazolam by about25% and the terminal half-life was prolonged by 43%.

Atorvastatin showed a 1.4-fold increase in plasma concentrations of intravenous midazolam comparedto control group.

Rifampicin7 days of 600 mg once daily decreased the plasma concentrations of intravenous midazolam by about60%. The terminal half-life decreased by about 50-60%.

St John’s Wort decreased plasma concentrations of midazolam by about 20-40% associated with adecrease in terminal half life of about 15-17%. Depending on the specific St John's Wort extract, the

CYP3A4-inducing effect may vary.

The co-administration of midazolam with other sedative/hypnotic medicinal products and CNSdepressants, 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 actingantihypertensive medicinal products.

Alcohol (including alcohol-containing medicinal products may markedly enhance the sedative effectof midazolam. Alcohol intake should be strongly avoided in case of midazolam administration (seesection 4.4).

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 isprobably swallowed and absorbed in the gastro-intestinal tract.

There are no or limited amount of data from the use of midazolam in pregnant women. Animal studiesdo not indicate a teratogenic effect with respect to reproductive toxicity, but foetotoxicity has beenobserved in humans as with other benzodiazepines. No data on exposed pregnancies are available forthe first two trimesters of pregnancy.

The administration of high doses of midazolam in the last trimester of pregnancy or during labour hasbeen reported to produce maternal or foetal adverse reactions (risk of aspiration of fluids and stomachcontents 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 shouldbe taken into account in the event of administration of midazolam in the third trimester of pregnancy.

Midazolam is excreted in low quantities (0.6%) in human milk. As a result it may not be necessary tostop breast feeding following a single dose of midazolam.

Animal studies did not show an impairment of fertility (see section 5.3).

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 abilityto drive, ride a bicycle or use machines. After receiving midazolam, the patient should be warned notto drive a vehicle or operate a machine until completely recovered.

Published clinical studies show that oromucosal midazolam was administered to approx 443 childrenwith seizures. Respiratory depression occurs at a rate of up to 5%, although this is a knowncomplication of convulsive seizures as well as being related to midazolam use. One episode of prurituswas possibly attributed to the use of buccal midazolam.

The table below lists the adverse reactions reported to occur when oromucosal midazolam wasadministered to children 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**, movementdisorder**, physical assault**

Nervous system disorders Common:

Sedation, somnolence, depressed levels of consciousness

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*

General disorders and Very rare:administration site conditions Fatigue**, hiccups**

**These adverse reactions have been reported to occur when midazolam is injected in children and/oradults, which may be of relevance to oromucosal administration.

* ADR identified from postmarketing experience

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 insufficiencyor impaired cardiac function, particularly when a high dosage is administered (see section 4.4).

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.

Midazolam overdose can present a threat to life if the patient has pre-existing respiratory or cardiacinsufficiency, or when combined with other CNS depressants (including alcohol).

Overdose of benzodiazepines is usually manifested by degrees of central nervous system depressionranging from drowsiness to coma. In mild cases, symptoms include drowsiness, mental confusion andlethargy, in more serious cases, symptoms may include ataxia, hypotonia, hypotension, respiratorydepression, rarely coma and very rarely death.

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

Following overdose with oral midazolam, vomiting should be induced (within one hour) if the patientis conscious or gastric lavage undertaken with the airway protected if the patient is unconscious. Ifthere is no advantage in emptying the stomach, activated charcoal should be given to reduceabsorption. Special attention should be paid to respiratory and cardiovascular functions in intensivecare.

Flumazenil may be useful as an antidote.

Pharmacotherapeutic group: Psycholeptics, benzodiazepine derivatives ATC code: N05CD08.

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

The pharmacological action of midazolam is characterized by short duration because of rapidmetabolic 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 688children, cessation of visible signs of seizures within 10 minutes was observed in 65% to 78% ofchildren receiving oromucosal midazolam. Additionally, in 2 of the studies, cessation of visible signsof seizures within 10 minutes without recurrence within 1 hour after administration was observed in56% 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 reactionsreported 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 thespecific medicinal product does not represent a significant therapeutic benefit over existing treatmentsfor these paediatric patients.

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

Dose Age Parameter Mean SD2.5 mg 3 m < 1 yr AUC0-inf (ng.h/ml) 168 98

Cmax (ng/ml) 104 465 mg 1 yr < 5 yrs AUC0-inf (ng.h/ml) 242 116

Cmax (ng/ml) 148 627.5 mg 5 yrs <10 yrs AUC0-inf (ng.h/ml) 254 136

Cmax (ng/ml) 140 6010 mg 10 yrs < 18 AUC0-inf (ng.h/ml) 189 96yrs Cmax (ng/ml) 87 44

After oromucosal administration midazolam is absorbed rapidly. Maximum plasma concentration isreached within 30 minutes in children. The absolute bioavailability of oromucosal midazolam is about75% in adults. The bioavailability of oromucosal midazolam has been estimated at 87% in childrenwith severe malaria and convulsions.

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

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

Midazolam is almost entirely eliminated by biotransformation. The fraction of the dose extracted bythe liver has been estimated to be 30-60%. Midazolam is hydroxylated by the cytochrome P4503A4isozyme and the major urinary and plasma metabolite is alpha-hydroxy-midazolam. Followingoromucosal administration in children the area under the curve ratio for alpha-hydroxy midazolam tomidazolam is 0.46.

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

Plasma clearance of midazolam in children following oromucosal administration is 30 ml/kg/min. Theinitial and terminal elimination half-lives are 27 and 204 minutes, respectively. Midazolam is excretedmainly 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.

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

The elimination half-life in cirrhotic patients may be longer and the clearance lower as compared tothose in healthy volunteers (see section 4.4).

The elimination half-life in patients with chronic renal failure is similar to that in healthyvolunteers.

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

Cardiac insufficiency

The elimination half-life is longer in patients with congestive heart failure compared with that inhealthy subjects (see section 4.4).

Simulated exposure data show that the overall AUC approximately doubles when a second dose isadministered at 10, 30 and 60 minutes following the first dose. A second dose at 10 minutes results ina significant increase in mean Cmax of between 1.7 to 1.9 fold. At 30 and 60 minutes, significantelimination of midazolam has already occurred and therefore the increase in mean Cmax is lesspronounced; 1.3 to 1.6 and 1.2 to 1.5 fold respectively. (see section 4.2).

Clinical studies have included patients from Japanese and non-Japanese groups, and no differences inthe pharmacokinetic profile have been identified on exposure to Buccolam.

No dose adjustment is warranted.

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

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

Sodium chloride

Water for injections

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

Sodium hydroxide (for pH adjustment)

Not applicable

BUCCOLAM 2.5 mg oromucosal solution18 months

BUCCOLAM 5 mg, 7.5 mg, 10 mg oromucosal solution2 years

Keep the oral syringe in the protective plastic tube.

Do not refrigerate or freeze.

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 Syringe Age range Label coloursolution volume2.5 mg 0.5 ml 1 ml 3 months to < 1 year Yellow5 mg 1 ml 3 ml 1 year to < 5 years Blue7.5 mg 1.5 ml 3 ml 5 years to < 10 years Purple10 mg 2 ml 3 ml 10 years to < 18 years Orange

BUCCOLAM is available in two pack sizes:

- Cartons containing 2 pre-filled syringes.

- Cartons containing 4 pre-filled syringes.

Not all pack sizes may be marketed.

BUCCOLAM is not for intravenous use.

Step 1

Hold the plastic tube and pull the cap off.

Take the syringe out of the tube.

Step 2

Pull the red cap off the tip of the syringe anddispose of it safely.

Step 3

Using the finger and thumb gently pinch andpull back the child’s cheek. Put the tip of thesyringe into the back of the space betweenthe inside of the cheek and the lower gum.

Step 4

Slowly press the syringe plunger until theplunger stops.

The full amount of solution should beinserted slowly into the space between thegum and the cheek (buccal cavity).

If necessary (for larger volumes and/orsmaller patients), approximately half thedose should be given slowly into one side ofthe mouth, then the other half given slowlyinto the other side.

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

Laboratorios Lesvi, S.L.

Avda. Barcelona 6908970 Sant Joan Despí - Barcelona

Spain

EU/1/11/709/001

EU/1/11/709/005

EU/1/11/709/002

EU/1/11/709/006

EU/1/11/709/003

EU/1/11/709/007

EU/1/11/709/004

EU/1/11/709/008

Date of first authorisation: 05 September 2011

Date of latest renewal: 26 May 2016