OZALIN Oral solution Ref.[7755] Active ingredients: Midazolam

Midazolam should be administered only by healthcare professionals in a setting fully equipped for the monitoring and support of respiratory and cardiovascular function and by persons specifically trained in the recognition and management of expected adverse events including respiratory and cardiac resuscitation. Severe cardiorespiratory adverse events have been reported. These have included respiratory depression, apnoea, respiratory arrest and/or cardiac arrest. Such life-threatening incidents are more likely to occur when given a high dosage.

Administration to high risk patients

Midazolam should be used with caution in patients with chronic respiratory failure because it can exacerbate respiratory depression.

Midazolam should be used with caution in patients with mild or moderate hepatic impairment, heart failure or chronic renal failure. Midazolam or its metabolite may accumulate in patients with chronic renal failure or with liver failure, and the clearance of midazolam may be decreased in patients with heart failure.

Oral midazolam should be used with caution in patients in poor general health as they are more sensitive to the effects of benzodiazepines on the central nervous system.

Modification of midazolam elimination

Oral midazolam should be used with caution in patients treated with medicinal products known to inhibit or induce CYP3A4 (see Section 4.5).

Concomitant use of alcohol/central nervous system depressants

Combined use of midazolam and alcohol and/or central nervous system depressants should be avoided. Such a combination is likely to increase the clinical effects of midazolam, which may cause deep sedation or clinically significant respiratory depression (see Section 4.5).

History of alcoholism or drug addiction

Like other benzodiazepines, midazolam should be avoided in patients with a history of alcoholism or drug addiction.

Amnesia

Midazolam causes anterograde amnesia.

Conditions for discharge

Patients who have received midazolam should be accompanied by an adult upon discharge and leave the treatment room only after receiving authorisation from the doctor.

Excipients

At the recommended single dose of 0.25 mg/kg (with a maximum single dose of 20 mg), the amount of γ-cyclodextrin is 10 mg/kg (with a maximum single dose of 800 mg). This amount of γ-cyclodextrin is below the permitted daily exposure (200 mg/kg/day, and 20 mg/kg/day for children younger than 2 years old). Therefore, even if OZALIN would be inadvertently used with 0.5 mg/kg dose, the amount of γ-cyclodextrin would not exceed the permitted daily exposure.

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

This medicine contains small amounts of ethanol (alcohol), less than 100 mg per ampoule.

Pharmacokinetic drug interactions

Because midazolam is metabolised primarily by CYP3A4 enzyme, CYP3A4 inhibitors and inducers may, respectively, increase or decrease plasma concentrations and hence the clinical effects of midazolam may be increased or reduced and its duration of action prolonged or shortened. Careful monitoring of clinical effects and patient’s vital signs is therefore recommended after administering midazolam with a CYP3A4 inhibitor, even after a single dose.

In the case of CYP3A4 inhibition or irreversible inhibition, the effect on the pharmacokinetics of midazolam may persist for several days to several weeks after administration of the CYP3A4 modulator (clarithromycin, erythromycin, HIV protease inhibitors, verapamil, diltiazem, atorvastatin, aprepitant, for example).

During co-administration with ethinylestradiol and norgestrel used as an oral contraceptive, exposure to midazolam is not significantly altered.

CYP3A4 inhibitors

• Azole antifungals: ketoconazole, itraconazole, voriconazole, fluconazole, posaconazole.
• HIV protease inhibitors: saquinavir and other protease inhibitors, including combinations containing ritonavir.
• Macrolide antibiotics: clarithromycin, erythromycin, telithromycin, roxithromycin; roxithromycin increases the terminal half-life of midazolam administered orally in tablet form by 30%.
• Calcium-channel blockers: diltiazem, verapamil; verapamil and diltiazem multiply the plasma concentrations of oral midazolam by 3 and 4 respectively and increase its terminal half-life by 41% and 49% respectively.
• Substance P antagonists: aprepitant; aprepitant causes a dose-dependent increase in the plasma concentrations of oral midazolam, the plasma concentration is multiplied by 3.3 after 80 mg/day of aprepitant and its terminal half-life by about 2.
• H₂-antagonists: cimetidine, ranitidine.
• Selective serotonin reuptake inhibitors: fluvoxamine.
• Anticholinergic drugs: propiverine.
• Other drugs (atorvastatin, nefazodone, aprepitant, ivacaftor).
• Plant products: grapefruit juice, Echinacea purpurea, turmeric rhizome.

CYP3A4 inducers

• Rifamycin antibiotics: rifampicin; rifampicin reduces the plasma concentration of oral midazolam by 96% in healthy subjects with an almost total disappearance of midazolam’s psychomotor effects.
• Antiepileptic drugs: carbamazepine, phenytoin; repeated administration of carbamazepine or phenytoin reduces the plasma concentration of oral midazolam by as much as 90% and decreases the terminal half-life by 60%.
• Reverse-transcriptase inhibitors: efavirenz; the ratio of α-hydroxymidazolam (metabolite generated by CYP3A4) is increased by a factor of five compared to midazolam, confirming the induction effect of efavirenz on CYP3A4.
• St. John’s wort (Hypericum perforatum).

Midazolam is not known to alter the pharmacokinetics of other medicinal products.

Pharmacodynamic drug interactions

Concomitant administration of midazolam with other sedative/hypnotic agents and central nervous system depressants is likely to increase sedation and respiratory depression.

Such sedative/hypnotic agents include alcohol (including medicinal products containing alcohol), opiates/opioids (when used as analgesics, antitussives or substitutive treatments), antipsychotics, other benzodiazepines used as anxiolytics or hypnotics, barbiturates, propofol, ketamine, etomidate, sedative antidepressants, antihistamines, antiepileptics and centrally acting antihypertensives. Midazolam decreases the minimum alveolar concentration (MAC) of inhalation anaesthetics.

The combined effect of alcohol and midazolam should be strictly avoided, and alcohol consumption should be strictly avoided when administering midazolam (see Section 4.4 and Section 4.9).

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, during labour or when used as an induction agent of anaesthesia for caesarean section has been reported to produce maternal or foetal adverse effects (inhalation risk in mother, irregularities in the fetal heart rate, hypotonia, poor sucking, hypothermia and respiratory depression in the neonate). Moreover, infants born from mothers who received benzodiazepines chronically during the latter stage of pregnancy may have developed physical dependence and may be at some risk of developing withdrawal symptoms in the postnatal period.

Consequently, midazolam may be used during pregnancy if clearly necessary but it is preferable to avoid using it for caesarean section.

The risk for neonates should be taken into account in case of administration of midazolam for any surgery near the term.

Breastfeeding

Midazolam passes in low quantities into breast milk. Nursing mothers should be advised to discontinue breast-feeding for 24 hours following administration of midazolam.

Fertility

Animal studies have not shown a decrease in fertility (see Section 5.3).

OZALIN has a major influence on the ability to drive and use machines.

Sedation, anterograde amnesia, impaired attention and impaired muscular function can momentarily affect the ability to drive vehicles or use machines. Before administering OZALIN, the patient must be warned not to drive or use a machine until fully recovered. The doctor must decide when these activities may be resumed. It is recommended for the patient to be accompanied by an adult when returning home after discharge.

During the administration of midazolam the following adverse reactions have been reported at an unknown frequency, which cannot be estimated from the available data:

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 the national reporting system: HPRA Pharmacovigilance, Website: www.hpra.ie

In the absence of compatibility studies, this medicinal product should not be mixed with other medicinal products.