- pizotifen malate
POM: Prescription only medicine
This information is intended for use by health professionals
Adults:Usually 1.5mg daily, at night or in 3 divided doses. Dosage should be adjusted according to need, up to a maximum of 4.5mg daily. Up to 3mg can be given as a single dose.
Children (aged 2 years and over only):Use of 1.5mg tablet is not recommended for children. The appropriate paediatric doses may be given using the 0.5mg tablets.
Elderly:As for adults. Clinical work with this product has not shown elderly patients to require different dosages form younger patients
Renal and hepatic impairmentCaution is required in patients with renal or hepatic impairment and dosage adjustment may be necessary (see section 5.2). Method of administration: oral
Anticipated drug interactions to be consideredPizotifen is extensively metabolized in the liver, primarily by N-glucuronidation. Increased plasma concentration of pizotifen upon concomitant administration of drugs which exclusively undergo glucuronidation can not be excluded.
Central nervous system agentsThe central effects of sedatives, hypnotics, antihistamines (including certain common cold preparations) and alcohol may be enhanced by pizotifen.Pizotifen antagonises the hypotensive effect of adrenergic neurone blockers.
PregnancyAs clinical data with pizotifen are very limited, it should only be administered under compelling circumstances. Use in nursing mothers is not recommended.
LactationAlthough the concentrations of Pizotifen measured in the milk of treated mothers are not likely to affect the infant, its use in nursing mothers is not recommended.
Immune system disorders:Rare: Hypersensitivity reactions, face oedema,
Skin and Subcutaneous tissues disordersRare: urticaria, rash
Metabolism and nutrition disorders:Very common: Appetite stimulating effect and increase in body weight
Psychiatric disorders:Rare: Depression, CNS stimulation (e.g. aggression, agitation), hallucination, insomnia and anxiety
Nervous system disorders:Common: Drowsiness (including somnolence), dizziness Rare: Paraesthesia Very rare: Seizures
Gastrointestinal disorders:Common: Nausea, dry mouth Uncommon: Constipation
Hepatobillary disordersUnknown: Hepatic enzyme increased, jaundice, hepatitis
Musculoskeletal and connective tissue disorders:Rare: Myalgia, arthralgia Unknown: Muscle cramps
General disorders and administration site conditions:Common: Fatigue
Withdrawal symptomsAcute withdrawal reactions have been reported following abrupt cessation of Pizotifen, therefore, gradual withdrawal is recommended (See section 4.4 Special warnings and precautions for use.). Withdrawal symptoms include Depression, Malaise, dizziness, sleep disorder weight decrease, anxiety, tremors, insomnia, nausea, and loss of consciousness.
Reporting of suspected adverse reactionsReporting 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 yellow card scheme at www.mhra.gov.uk/yellowcard
AbsorptionFollowing oral administration, the drug is rapidly and almost completely absorbed from the gastrointestinal tract. The mean absolute bioavailablility after oral administration is about 78%. Following a single 1mg oral administration of pizotifen the mean maximum plasma concentration (Cmax) of pizotifen and its metabolite measured together were about 5 ng/mL (Tmax: 5.5 hr). Following repeated administration of 1mg three times a day for six days, the mean maximum plasma concentration at steady state was observed at 4 hr post dose (Cmax,ss: 14 ng/mL) and the mean trough plasma concentration was about 11 ng/mL (Cmin,ss).
DistributionPizotifen is extensively and rapidly distributed throughout the body with the mean distribution volume of 833 L and 70 L for the parent drug and its metabolite N-glucuronide, respectively. Approximately, 91% of the drug is bound to plasma proteins. The distribution and elimination kinetics have generally been described as a bi-exponential decay function using two-compartment model.
MetabolismPizotifen is extensively metabolised in the liver primarily by glucuronidation. The main metabolite is the N-glucuronide-conjugate and accounts for at least 50% of the plasma exposure.
EliminationAbout one-third of an orally applied dose is excreted via the biliary route. A significant proportion of the parent drug, corresponding to about 18% of the administered dose, is found in the faeces. The remaining fraction of the administered dose (about 55%) is primarily eliminated in the forms of metabolites in the urine. Less than 1% of the administered dose of pizotifen is excreted unchanged through the kidneys. Pizotifen and its major metabolite the N-glucuronide conjugate is eliminated with a half-life of approximately 23 hours.
Renal impairmentNo specific pharmacokinetic studies were conducted in patients with renal impairment. Although pizotifen is primarily eliminated in the form of metabolites in the urine, the possibility of accumulation of inactive metabolites subsequently leading to the accumulation of the parent drug can not be ruled out. Caution is required in patients with renal impairment and dosage adjustment may be necessary.
Hepatic impairmentAlthough no specific pharmacokinetic studies were conducted in patients with hepatic impairment, pizotifen is extensively metabolized in liver and primarily eliminated in the form of glucuronides in the urine. Caution is required in patients with hepatic impairment and dosage adjustment may be necessary.
Repeat-dose toxicityRepeat-dose toxicity studies were performed in rats and dogs of up to 2 years duration. Target organs, based on histopathological findings, were liver, kidney and possibly thyroid in rats and liver, thyroid and spleen in dogs. The no-observed-effect level (NOEL) in both rats and dogs was 3 mg/kg (corresponding to 18 mg/m2 in rats and to 60 mg/m2 in dogs) which is, respectively, 5- and 18-times the maximum recommended human daily dose of 3.33 mg/m2 based on body surface area comparisons.
Reproductive toxicityPizotifen hydrogen malate was evaluated in reproductive and developmental toxicity studies in mice, rats and rabbits. There were no effects on fertility or teratologic effects noted at all doses up to 30 mg/kg/day. At 10 and 30 mg/kg/day in mice there was a small decrease in fetal body weight in the presence of increased maternal mortality and in rats at the highest dose there was evidence of fetotoxicity.
Mutagenicity and CarcinogenicityPizotifen hydrogen malate was not genotoxic in standard in vitro and in vivo tests. Conventional rodent carcinogenicity studies have not been conducted.
Tablet coreLactose monohydrate Cellulose microcrystallineMaize starch, Povidone K30Magnesium stearateSilicon dioxide
Tablet coatingHypromelloseMacrogol 6000Talc Titanium dioxide (E171).