MIDAZOLAM ORPHA 15 MG FILM-COATED TABLETS - summary of medicine characteristics

1 NAME OF THE MEDICINAL PRODUCT

Midazolam Orpha 15 mg film-coated tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

One Midazolam Orpha film-coated tablet contains midazolam maleate, equivalent to 15 mg midazolam, as the active ingredient.

Excipient with known effect: Midazolam Orpha contains 72.16 mg lactose/tablet.

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Film-coated tablet.

Blue, 8 × 3.8 mm round tablets with a breaking score on one-side.

The tablet can be divided into equal doses

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

Short-term treatment of insomnia.

Benzodiazepines should only be used if the condition is severe and disabling or in case the patient has extreme distress as a result of the disorder.

Midazolam Orpha is indicated in adults.

4.2 Posology and method of administration

Dosage

Standard dosage: 7.5 to 15 mg

A dosage of 15 mg must not be exceeded.

Special patient groups

In elderly or impaired patients, the recommended dose is 7.5 mg. These patients may be more sensitive to the sedative effect of Midazolam, which may result to a cardiorespiratory depression. Midazolam Orpha should be used with caution in these patient populations and a lower dose should be considered (see section 4.4).

In patients with impaired liver function the recommended dose is 7.5 mg. Midazolam Orpha should be used with great caution in patients with impaired liver function. If necessary, a lower dose should be considered.

In patients with impaired renal function, an accumulation of the main metabolite of midazolam, 1-hydroxymidazolam glucuronide, may occur, resulting in a more manifest and prolonged sedation, which may include clinically relevant respiratory and cardiovascular depression. Midazolam Orpha must be dosed with caution in this patient population. The recommended dose is 7.5 mg and, if necessary, a lower dose should be considered.

A lower dose is recommended for patients with chronic respiratory insufficiency (see section 4.4).

Midazolam Orpha is contraindicated in children (see section 4.3)

Method of administration

The length of treatment should be as short as possible. Usually, the length of treatment varies from several days to a maximum of two weeks. The tapering period should be adjusted to the individual patient. If the dosage is 15 mg/day, this can be reduced to 7,5 mg. If the dosage is 7,5 mg, this can be reduced to 7,5 mg every two days. The treatment should not be suddenly discontinued (see withdrawal in section 4.4)

In certain situations, an extension of the maximum treatment period may be necessary; if this is the case, an extension should only be made if the condition of the patient is re-assessed. Due to the rapid onset of the effect, the drug should be taken immediately before going to sleep and should be swallowed as a whole with liquid. Midazolam Orpha can be taken at any time of the day provided the patient is subsequently assured of at least seven to eight hours of uninterrupted sle­ep.

Treatment should be started with the lowest recommended dose. The maximum dose may not be exceeded on account of the increased possibility of side effects related to the central nervous system, including respiratory and cardiovascular depression.

Dose adjustment due to interactions

There is the possibility of a relevant interaction between Midazolam Orpha and substances that inhibit or induce certain hepatic enzymes. This may lead to dose adjustment (see section 4.5).

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1

Severe respiratory insufficiency

Severe hepatic insufficiency (see section 4.4)

Sleep apnoea syndrome

Children aged below 18 years

Myasthenia gravis

Concomitant therapy with strong CYP3A4 inhibitors such as ketoconazole, itraconazole, voriconazole and HIV protease inhibitors including ‘boosted’ protease inhibitors

4.4 Special warnings and precautions for use

Tolerance

After repeated use for several weeks, the hypnotic effect of short-acting benzodiazepines can become less.

Length of treatment

The length of treatment should be as short as possible (see section 4.2) and may last no longer than two weeks. The tapering period must be adjusted to the individual patient. Treatment should not be continued without a new assessment of the situation.

It may be useful to inform the patient at the beginning that treatment will be of limited duration, and to explain precisely how the dosage will be gradually reduced. It is also important to call the patient’s attention to the possibility that „withdrawal“ phenomena may occur. This should be done to limit the anxiety about the occurrence of such symptoms to a minimum during the tapering off period.

Because Midazolam Orpha is a benzodiazepine with short duration, there are indications that withdrawal symptoms can occur within the dosage interval, especially if the dose is high.

Withdrawal

Withdrawal symptoms may express in the form of headache, muscle pain, extreme anxiety, tension, restlessness, confusion, and irritability. In severe cases, the following symptoms can occur: derealisation, depersonalisation, hyperacusis, numbness and tingling in the extremities, hypersensitivity to light, noise and physical contact, hallucinations or epileptic seizures. Because the risk of withdrawal symptoms is greater after sudden discontinuation of treatment, it is recommended to reduce the dose gradually (see section 4.2).

Withdrawal insomnia

When therapy with Midazolam Orpha is discontinued, insomnia can occur, possibly more often than before the start of treatment (‘withdrawal insomnia’). Withdrawal insomnia is a temporary syndrome and can be accompanied by other reactions including mood changes, anxiety and restlessness. The risk of withdrawal symptoms is greater after sudden discontinuation of treatment. It is therefore recommended to gradually reduce the dosage (see section 4.2).

Amnesia

Midazolam Orpha can cause anterograde amnesia, which usually occurs within the first hour after taking the product. In order to reduce this risk, patients should make sure that they are able to get seven to eight hours of uninterrupted sleep (see section 4.8).

Sequelae

Provided that the oral dose of Midazolam Orpha is not more than 15 mg per day and the patient is assured of at least seven to eight hours’ undisturbed sleep, no sequelae were observed after oral use of Midazolam Orpha tablets by standard patients. This was confirmed by clinical observation using sensitive pharmacological methods.

Psychiatric and ‘paradoxical’ reactions

It is known that reactions such as restlessness, agitation, irritability, aggression, delusions, anger, nightmares, hallucinations, psychoses, inappropriate behaviour and other behavioural disorders may occur with the use of benzodiazepines. If this is the case, use of the medicine should be discontinued. These kinds of effects occur most often in the elderly.

Specific patient groups

For both elderly and/or impaired patients with chronic respiratory or cardiovascular insufficiencies the recommended dose is 7.5 mg. These patients may be more sensitive to the clinical side effects of Midazolam Orpha, such as cardiorespiratory depression.

Therefore, Midazolam Orpha should be given with caution to this patient population and, if necessary, a low dose must be considered (see section 4.2).

Benzodiazepines are not indicated for the treatment of patients with severe hepatic insufficiency since benzodiazepines can further the development of encephalopathy.

Dosage instructions for patients with impaired hepatic and / or renal function are given in section 4.2.

Benzodiazepines are not recommended for the primary treatment of psychoses.

Benzodiazepines should not be used as the sole treatment of depressions or anxiety that is associated with depression (such patients may have suicidal tendencies).

Concomitant use of alcohol / CNS depressants

The concomitant use of midazolam with alcohol or/and CNS depressants should be avoided. Such concomitant use has the potential to increase the clinical effects of midazolam possibly including severe sedation or clinically relevant respiratory and/or cardiovascular depression (see section 4.5).

Medical history of alcohol or drug abuse

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

Co-medication with drugs that alter CYP3A4 activity

Midazolam pharmacokinetics is altered in patients receiving concomitantly compounds that inhibit or induce CYP3A4. Consequently the clinical and adverse effects may be increased or decreased respectively. The concomitant use with moderate CYP3A4 inhibitors or strong CYP3A4 inducers should be avoided (see section 4.5).

Dependence

The use of Midazolam Orpha may lead to physical and psychological dependence. The risk of dependence rises as the dose and duration of the treatment increase; the risk is also greater for patients with alcohol and/or drug abuse in their medical history.

Lactose intolerance

Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.

4.5 Interaction with other medicinal products and other forms of interaction

Pharmacokinetic interactions (see sections 4.3 and 4.4)

The cytochrome P450 (CYP3A4) iso-enzyme plays a predominant role in the metabolism of midazolam. Inhibitors and inducers of CYP3A4 can significantly increase or decrease midazolam plasma concentrations. Strong CYP3A4 inhibitors may increase plasma exposure of midazolam 5 to 10-fold or more.

Thus, in case of simultaneous administration with a CYP3A inhibitor the clinical effects of midazolam, when used orally, can be stronger and last longer. On the opposite: the effects of midazolam can be weaker and last shorter in case of simultaneous administration with a CYP3A inducer. In case of induction and irreversible inhibition (‘mechanism-based’ inhibition) of CYP3A, the effect of the pharmacokinetics of midazolam can continue for a few days to a few weeks after administering the CYP3A modulator. A few examples of mechanism-based inhibitors are: clarithromycin, erythromycin, HIV protease inhibitors, verapamil, diltiazem (see section 4.3).

Important note: The list of inhibitors and inducers given below cannot be considered complete. Therefore, the prescriber must always consult the product information for the concomitant medicinal product to verify that it is not a strong or moderate CYP3A4 inhibitor or a strong CYP3A4 inducer.

Classification of CYP3A inhibitors

CYP3A inhibitors can be classified in accordance with their inhibiting effect and the importance of the clinical changes in case of simultaneous oral use of midazolam.

Strong inhibitors: midazolam,exposure (AUC) increases>5-fold. The following medicines fall in this category: ketaconazole, itraconazole, voriconazole, posaconazole, HIV protease inhibitors including ‘boosted’ protease inhibitors, clarithromycin, telithromycin, boceprevir, nefazodone and grapefruit juice. The combined use of orally administered midazolam with strong CYP3A inhibitors is contraindicated (see section 4.3).

Moderate inhibitors: midazolamAUC increases >2-fold to <5-fold. The following medicines and other agents are seen as moderate inhibitors: fluconazole, , erythromycin, diltiazem, verapamil, , aprepitant, dronedarone, crizotinib, casopitant, imatinib, cyclosporine, ciprofloxacine, cimetidine and lomitapide.

The combined use of orally administered midazolam with moderate CYP3A inhibitors should be avoided (see section 4.4).

Weak inhibitors: midazolam, AUC increases 1,25 to < 2-fold. The following medicines and herbs belong to this category: roxithromycin, ranitidine, fluvoxamine, bicalutamide, propiverine, tabmoreline, Purple coneflower and Goldenseal.

Simultaneous administration of midazolam with weak CYP3A inhibitors mostly does not lead to a significant change in midazolam’s cli­nical effect.

Medicines that induce CYP3A

Concomitant administration of strong CYP3A4 inducers with oral midazolam should be avoided (see section 4.4). As due to lack of effect, the midazolam dose may be largely increased, which may lead to toxic concentrations if treatment with the strong inducer is discontinued. Known strong CYP3A4 inducers are St John’s wort (Hypericum perforatum), rifampicin, carbamazepine and phenytoin.

Patients receiving a combination of midazolam with mild or moderate CYP3A inducers may require a higher dose of midazolam. However, a dosage of 15 mg midazolam must not be exceeded.

In case of simultaneous administration with ethinyl estradiol/nor­gestrel (‘mechanismbased’ inhibitors), which are used as contraception, the exposure to midazolam is not changed significantly.

Pharmacodynamic interactions

Simultaneous use of midazolam and other sedatives/hypnotics probably results in an increase in sedative/hypnotic effects. Examples of these are alcohol, opiates/opioids (when they are used as analgesics, antitussives or substitution treatment) antipsychotics, other benzodiazepines used as anxiolytics or hypnotics, barbiturates, propofol, ketamine, etomidate, sedative antidepressants, antihistamines and centrally acting antihypertensives. Midazolam reduces the minimum alveolar concentration (MAC) of inhalation anesthetics. In case of narcotic analgesics potentiating of euphoria can occur and this can lead to increased psychological dependency.

An increase in side-effects such as sedation and cardio-respiratory depression can occur in case of simultaneous administration with alcohol and/or CNS-depressants. Combined use with alcohol is discouraged (see section 4.4) This has an influence on driving ability and the ability to operate machines (see section 4.9) ‘Overdosing’ for warnings for other CNS-depressants and alcohol.

Medicines that increase alertness or improve the memory, such as the ACE inhibitor physostigmine, undo the hypnotic effects of midazolam. In the same manner the sedative effect of midazolam is partially offset by 250 mg caffeine.

4.6 Fertility, pregnancy and lactation

Pregnancy

There is no or a limited amount of data from the use of midazolam in pregnant women.

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 sucking, hypothermia and respiratory depression in the new-born infant).

Midazolam should not be used during pregnancy unless 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.

Breastfeeding

Midazolam is excreted in breast milk. Breast-feeding is recommended to be discontinued for 24 hours after administration of midazolam.

Fertility

Animal studies did not show an impairment of male or female fertility.

4.7 Effects on ability to drive and use machines

Midazolam Orpha affects the ability to drive and operate machines by the occurrence of sedation, amnesia, impaired concentration and impaired muscular function.

With too little sleep the possibility of impaired alertness is increased (see also section 4.5).

4.8 Undesirable effects

The following undesirable effects are ranked according to system organ class and to their frequency:

Very common (> 1/10)

Common (>1/100 to < 1/10)

Uncommon (>1/1.000 to < 1/100)

Rare (> 1/10.000 to < 1/1.000)

Very rare (< 1/10.000)

not known (cannot be estimated from the available data)

* These paradoxical reactions can occur in case of use of benzodiazepines or medicines similar to benzodiazepines. If this is the case, the use of the medicines should be discontinued. These reactions mostly occur in the elderly (see section 4.4).

* * Anterograde amnesia can occur when administering therapeutic doses and the risk increases in case of higher doses. Amnestic effects can lead to inappropriate behaviour (see section 4.4). Data from different sources suggest that anterograde amnesia is observed more in case of this medicine than in case of other hypnotics. Concluding evidence based on comparative research is lacking.

* ** These side-effects mainly occur at the start of the therapy and mostly disappear after repeated administration.

* *** The risk of falls and fractures is increased in those taking concomitant sedatives (including

alcoholic beverages) and in the elderly.

Dependency

Use of Midazolam Orpha (even in therapeutic doses) can lead to physical dependency: Discontinuation of the therapy can result in withdrawal symptoms or ‘rebound’ effects, including ‘rebound’ insomnia, mood swings, anxiety and restlessness (see section 4.4). Physical dependency can occur.

Abuse of this medicine was reported in patients who are known to abuse combinations of medicines (see section 4.4).

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 Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

4.9 Overdose

Benzodiazepines generally cause drowsiness, ataxia, dysarthria and nystagmus. Overdose from Midazolam Orpha is rarely life-threatening if other drugs have not been taken, but it may lead to areflexia, apnoea, hypotonia, hypotension, cardiorespiratory depression and rare cases of coma. When coma occurs it usually lasts several hours but it may last longer, especially in elderly patients. The respiratory depressant effects of benzodiazepines are more serious in patients with respiratory disorders.

Benzodiazepines increase the effect of drugs that depress the central nervous system, including alcohol.

After an overdose of oral benzodiazepines further absorption should be prevented, e.g. by means of treatment with activated charcoal within two hours. In the event that the patient is already drowsy, treatment with activated charcoal should be avoided. Intubation and activated charcoal administration, all at the same time, is not considered to be meaningful. In case of mixed intoxication, gastric lavage may be considered, but this should not be the standard treatment. Monitoring of vital signs may be necessary.

Flumazenil may be useful as an antidote. It should only be administered under strictly controlled conditions. Caution must be observed with the use of flumazenil in patients with epilepsy who are treated with benzodiazepines, and in patients who use medicines that lower the threshold for convulsions (e.g. tricyclic antidepressants).

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: hypnotics and sedatives (benzodiazepine derivatives),

ATC-code: N05CD08

Midazolam is a benzodiazepine. It has anxiolytic, sedative and hypnotic properties, as well as possible muscle relaxant and anticonvulsant properties.

5.2 Pharmacokinetic properties

Absorption

After oral administration of a dose of 15 mg, a Cmax of 154 ± 51 ng/mL is reached with a Tmax of 0.5 to 1.5 hours. The systemic bioavailability averages 44% after a 15 mg dose. It has a low oral bioavailability due to first-pass hepatic extraction.

Distribution

Midazolam is 96–98% bound to plasma proteins. The volume of distribution ranges from 0.7 to 1.2 L/kg. Midazolam is lipophilic and distributes extensively. It crosses the placenta and is distributed into breast milk.

Biotransformation

Midazolam is metabolised by way of cytochrome P450 (CYP3A4 enzymes). The 2 metabolites are a-hydroxymidazolam and 4-hydroxymidazolam.

There is one active metabolite, a-hydroxymidazolam, which has a T1/2 of 0.8 to 1.0 hours. Both metabolites are rapidly conjugated to glucuronides to form products with low pharmacological activity.

Elimination

The elimination half-life amounts to 2.1 – 3.5 hours.

Pharmacokinetics in special populations

Elderly

The elimination half-life of midazolam in patients older than 60 years can be prolonged up to 4 times.

Patients with hepatic impairment

The pharmacokinetics of midazolam was significantly altered in patients with chronic liver disease, including advanced cirrhosis of the liver. Particularly, as a result of reduced hepatic clearance, half-life was prolonged, and the absolute bioavailability of oral midazolam was significantly increased in patients with cirrhosis compared to the control group.

Patients with renal impairment

Pharmacokinetics of midazolam was not altered in patients with chronic renal failure. But the main midazolam metabolite, 1'-hydroxymidazolam glucuronide, which is excreted through the kidneys, accumulates in patients with severe chronic renal failure. This accumulation causes prolonged sedation. Therefore, oral midazolam should be carefully administered to patients with renal impairment.

Critically ill patients

The elimination half-life in critically ill patients is prolonged up to 6 times.

Patients with cardiac insufficiency

The elimination half-life of midazolam in patients with decompensated cardiac insufficiency is prolonged compared to healthy people.

Obese patients

In obese patients, the volume of distribution of midazolam was increased. Therefore, the average half-life of midazolam is longer in obese patients than in non-obese patients (5.9 hours compared to 2.3 hours). Oral bioavailability of midazolam tablets in obese patients does not differ from those in non-obese patients.

5.3 Preclinical safety data

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

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Core of tablet:

Lactose monohydrate

Microcrystalline cellulose

Pregelatinised starch

Magnesium stearate

Talc

Film coating (Opadry OY-4492 Blue):

Hypromellose

Macrogol 400

Titanium dioxide (E171)

Indigo carmine (E132)

6.2 Incompatibilities

Not applicable

6.3 Shelf life

2 years

6.4 Special precautions for storage

Do not store above 30°C.

6.5 Nature and contents of container

PVC/PVDC Aluminium blister containing 10 film-coated tablets.

Pack sizes: 10 or 30 film-coated tablets in cardboard boxes.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

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

7 MARKETING AUTHORISATION HOLDER

Orpha-Devel Handels und Vertriebs GmbH

Wintergasse 85/1B,

A-3002 Purkersdorf,

Austria

8 MARKETING AUTHORISATION NUMBER(S)

PL 30414/0014

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

15/11/2018