on 5.2). Therefore, the risk of metabolic interactions caused by an effect on an individual isoform is limited. Caution should be used in patients receiving concomitant treatment with other medicinal products that are either inhibitors or inducers of these enzymes, particularly if the concomitant medicinal product is known to inhibit or induce several of the enzymes involved in loxapine metabolism. Such medicinal products may modify efficacy and safety of ADASUVE in an irregular manner. Concomitant use of CYP1A2 inhibitors (e.g. fluvoxamine, ciprofloxacin, enoxacin, propranolol and refecoxib) should be avoided, if possible.
Adrenaline
Co-administration of loxapine and adrenaline may cause worsening of hypotension (see section 4.4).
4.6 Fertility, pregnancy and lactation
Pregnancy
New-born infants exposed repeatedly to antipsychotics during the third trimester of pregnancy are at risk of adverse reactions including extrapyramidal and/or withdrawal symptoms that may vary in severity and duration following delivery. There have been reports of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, or feeding disorder. Consequently, monitoring of new-borns should be considered. ADASUVE should be used during pregnancy only if the potential benefit justifies the potential risk to the foetus.
Breast-feeding
The extent of the excretion of loxapine or its metabolites in human milk is not known. However, loxapine and its metabolites have been shown to be transported into the milk of lactating dogs. Patients should be advised not to breast feed for a period of 48 hours after receiving loxapine and discard the milk produced in the meantime.
Fertility
No loxapine specific human data on fertility are available. It is known that in humans, long-term treatment with antipsychotics may lead to loss of libido and amenorrhoea. In female rats, reproductive effects have been observed (see section 5.3).
4.7 Effects on ability to drive and use machines
ADASUVE has major influence on the ability to drive and use machines. Because of the potential for sedation/somnolence, fatigue, or dizziness, patients should not operate hazardous machines, including motor vehicles, until they are reasonably certain that loxapine has not affected them adversely (see section 4.8).
4.8 Undesirable effects
Summary of the safety profile
Assessment of adverse reactions from clinical study data is based on two Phase 3 and one Phase 2A short-term (24-hour) placebo-controlled clinical trials enrolling 524 adult patients with agitation associated with schizophrenia (including 27 patients with schizoaffective disorder) or bipolar disorder, treated with ADASUVE 4.5 mg (265 patients) or ADASUVE 9.1 mg (259 patients).
In studies in agitated patients, bronchospasm was reported as an uncommon, but serious adverse reaction, while in subjects with active airways disease, bronchospasm was commonly reported and often required treatment with a short-acting beta-agonist bronchodilator. The most commonly reported adverse reactions during treatment with ADASUVE were dysgeusia, sedation/somnolence and dizziness (dizziness was more common after placebo treatment than loxapine treatment).
Tabulated list of adverse reactions
The adverse reactions listed below are categorized using the following convention: Very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to &l |
