CLOPINE

What it is

CLOPINE is clozapine, available as tablets of 25 mg, 50 mg, 100 mg and 200 mg, and as a 50 mg/mL oral suspension.

Approved indications

— Treatment of people with treatment-resistant schizophrenia, defined as people with schizophrenia who are non-responsive to, or intolerant of other antipsychotic drugs.

Dosing overview

Dosage must be adjusted individually, with the lowest effective dose used for each patient. Initial dosing is 12.5 mg once or twice daily on the first day, followed by one or two doses of 25 mg on the second day, then increased slowly in increments of 25 to 50 mg to achieve a dose level of up to 300 mg/day within two to three weeks. In most patients, antipsychotic efficacy can be expected with 200 to 450 mg/day in divided doses. The recommended maximum dose for most patients is 600 mg/day, although some patients may require larger doses up to a maximum of 900 mg/day. After achieving maximum therapeutic benefit, many patients can be maintained effectively on lower doses, with careful downward titration recommended to 150 to 300 mg/day in divided doses.

Key safety warnings

Severe gastrointestinal adverse reactions have occurred with clozapine, with potential outcomes of hospitalisation, surgery and death. Prior to initiating and during treatment, screen for constipation and manage as per current clinical guidelines. Severe gastrointestinal adverse reactions are primarily due to potent anti-cholinergic effects resulting in gastrointestinal hypomotility, ranging from constipation to paralytic ileus, intestinal impaction, faecal impaction, megacolon, intestinal obstruction, ischaemia, infarction, perforation, ulceration or necrosis, with these reactions resulting in hospitalisation, surgery and death. Cases of myocarditis and cardiomyopathy, some of which have been fatal, and pericarditis have been reported in patients on clozapine. Most reported cases of myocarditis have occurred in the first month of treatment, and patients commencing clozapine treatment require close medical supervision. Clozapine can cause agranulocytosis and neutropenia, and use should be limited to patients with initially normal leucocyte findings in whom regular blood counts can be performed weekly during the first 18 weeks, at least monthly thereafter throughout treatment, and for one month after complete discontinuation. Severe neutropenia occurs in a small percentage of patients taking clozapine and is associated with an increase in the risk of serious and potentially fatal infections. Tachycardia, bradycardia and postural hypotension with or without syncope may occur especially in the initial weeks of treatment, and rarely collapse can be profound and accompanied by respiratory and/or cardiac arrest, which can be fatal. Clozapine lowers the seizure threshold in a dose-dependent manner and may induce myoclonic jerks or generalised seizures.

Contraindications

CLOPINE is contraindicated in patients with a history of drug-induced granulocytopenia or agranulocytosis, bone marrow disorders, inability to undergo regular blood tests, circulatory collapse and/or CNS depression due to any cause, alcoholic and other toxic psychoses, drug intoxication, comatose conditions, severe renal or cardiac disease including myocarditis, severe hepatic disease including active hepatic disease associated with nausea, anorexia or jaundice, progressive hepatic disease, hepatic failure, uncontrolled epilepsy, and paralytic ileus.

PBS listing

CLOPINE 50 mg tablets, 200 mg tablets, and 50 mg/mL oral liquid are listed on the PBS with streamlined restriction, with ex-manufacturer prices of A$55.49 for the 50 mg tablets, A$208.08 for the 200 mg tablets, and A$135.00 for the 100 mL oral liquid.

Regulatory history

CLOPINE was first registered on the ARTG on 4 October 2000, with ARTG registrations for 25 mg and 100 mg tablets in blister pack format. Additional registrations for 50 mg and 200 mg tablets and bottle formats were listed between 2003 and 2008, with an oral liquid suspension registered on 16 May 2008. PBAC recommended CLOPINE in July 2018 for schizophrenia through temporary Section 100 Highly Specialised Drugs Program and Section 100 Community Access listings as an alternative to address current supply shortage of Clopine Suspension.