4.4       Special warnings and precautions for use

[…]

This medicinal product contains less than 1 mmol sodium (23 mg) per ampoule, i.e essentially ‘sodium free’.

4.5       Interaction with other medicinal products and other forms of interaction

Pharmacokinetic Interactions

Midazolam is metabolised 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 i.v. midazolam, in particular since CYP3A4 also exists in the upper gastro-intestinal tract. This is because for the oral route both systemic clearance and availability will be altered while for the parenteral route only the change in the systemic clearance becomes effective. After a single dose of i.v. midazolam, the consequence on the maximal clinical effect due to CYP3A4 inhibition will be minor while the duration of effect may be prolonged. However, after prolonged dosing of midazolam, both the magnitude and duration of effect will be increased in the presence of CYP3A4 inhibition.

There are no available studies on CYP3A4 modulation on the pharmacokinetics of midazolam after rectal and intramuscular administration.It is expected that these interactions will be less pronounced for the rectal than for the oral route because the gastro-intestinal tract is by-passed whereas after i.m. administration the effects of CYP3A4 modulation should not substantially differ from those seen with i.v. midazolam.

[…]

Drugs that inhibit CYP3A4

Azole antifungals

·           Ketoconazole increased the plasma concentrations of intravenous midazolam by 5-fold while the terminal half-life increased by about 3-fold. If parenteral midazolam is co-administered with the strong CYP3A4 inhibitor ketoconazole, it should be done in an intensive care unit (ICU) or similar setting which ensures close clinical monitoring and appropriate medical management in case of respiratory depression and/or prolonged sedation. Staggered dosing and dosage adjustment should be considered, especially if more than a single i.v. dose of midazolam is administered. The same recommendation may apply also for other azole antifungals (see further), since increased sedative effects of i.v. midazolam, although lesser, are reported.

[…]

Drugs that induce CYP3A4

[…]

4.8       Undesirable effects

The following undesirable effects have been reported (very rarelyfrequency not known, cannot be estimated from the available data) to occur when midazolam is injected:

Immune System Disorders: Generalised hypersensitivity

Frequency categories are as follows:

Very common: ³1/10;             

Common ³1/100 to <1/10;

Uncommon ³1/1,000 to <1/100

Rare (³1/10,000 to <1/1,000)

Very rare (<1/10,000)

Not known (cannot be estimated from the available data)

*Such paradoxical drug reactions (skin reactions, cardiovascular reactions, bronchospasm), anaphylactic shock.

Psychiatric Disorders: Confusional state, euphoric mood, hallucinations.

Paradoxical reactions such as agitation, involuntary movements (including tonic/clonic movements and muscle tremor), hyperactivity, hostility, rage reaction, aggressiveness, paroxysmal excitement and assault, have been reported, particularly among children and the elderly (see section 4.4)

**Anterograde amnesia may still be present at the end of the procedure and in few cases prolonged amnesia has been reported (see section 4.4).

Dependence: Use of midazolam - even in therapeutic doses - may lead to the development of physical dependence. After prolonged i.v. administration, discontinuation, especially abrupt discontinuation of the product, may be accompanied by withdrawal symptoms including withdrawal convulsions (see section 4.4).

Nervous System Disorders: Prolonged sedation, decreased alertness, somnolence, headache, dizziness, ataxia, postoperative sedation, anterograde amnesia, the duration of which is directly related to the administered dose. Anterograde amnesia may still be present at the end of the procedure and in isolated cases prolonged amnesia has been reported.

Convulsions have been reported in premature infants and neonates.

Cardiac Disorders: Severe cardiorespiratory adverse events have occurred. These have included cardiac arrest, hypotension, bradycardia, vasodilating effects. Life-threatening incidents are more likely to occur in adults over 60 years of age and those with pre-existing respiratory insufficiency or impaired cardiac function, particularly when the injection is given too rapidly or when a high dosage is administered (see section 4.4).

Respiratory Disorders: Severe cardiorespiratory adverse events including respiratory depression, apnoea, respiratory arrest, dyspnoea, laryngospasm have been reported. Life-threatening incidents are more likely to occur in adults over 60 years of age and those with pre-existing respiratory insufficiency or impaired cardiac function, particularly when the injection is given too rapidly or when a high dosage is administered (see section 4.4). Hiccup.

Gastrointestinal System Disorders: Nausea, vomiting, constipation, dry mouth.

Skin and Appendages Disorders: Skin rash urticaria, pruritus.

General and Application Site Disorders: Fatigue, erythema and pain on injection site, thrombophlebitis, thrombosis.

Injury, Poisoning and Procedural Complications: An increased risk for falls and fractures has been recorded in elderly benzodiazepine users.

10      DATE OF REVISION OF THE TEXT

 26 March 2010April 2012

Underlined text has been added, text with strike through deleted:

1        NAME OF THE MEDICINAL PRODUCT

Hypnovel Ampoules 10mg/2ml solution for injection