Novartis Pharmaceuticals UK Ltd

Absorption

Following oral administration, the drug is rapidly and almost completely absorbed from the gastrointestinal tract.  Absorption of pizotifen in man is fast (absorption half life 0.5 to 0.8 hours) and nearly complete.  The mean absolute bioavailablility after oral administration is about 78 [H1] 780%. Maximum blood levels are reached 5 hours after Following a single 1mg2mg [H2] oral administration of pizotifen (parent compound and N-glucuronide-conjugate measured together) 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).

Distribution

Pizotifen is extensively and rapidly distributed throughout the body with the mean Protein binding of pizotifen in human plasma in vitro amounts to 91%. The distribution volume in man is of 833 L and 70 L for pizotifen 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.

BiotransformationMetabolism

Pizotifen is extensively metabolised  in the liver primarily by Gglucuronidation. is the main route of biotransformation and The main metabolite is the N-glucuronide-conjugate and accountings for at least 50% of the plasma exposure. and 60-70% of urinary excreted radioactivity. 

Elimination

About one-third of an orally applied dose is excreted via the biliary route. into the faeces, aA significant proportion of the parent drug, corresponding to about 18% of the appliedadministered dose, is found in the faeces. The remaining fraction of the administered dose  [H3]  (about 55%) is primarily eliminated in the forms of metabolites in the urine.  , representing parent drug, likely produced in the intestine after biliary excretion of the N-glucuronide-conjugate.  Less than 1% of the administered dose of pizotifen is excreted unchanged in the urine through the kidneys. whereas up to 55% is excreted as metabolites. Pizotifen and its major metabolite is eliminated with a half life of approximately 23 hours (total radioactivity). Unchanged pizotifen and the N-glucuronide conjugate is eliminated with a half-life of approximately 23 hours. have, as estimated from the excretion in the urine, a comparable elimination half-life.

Special patient groupspopulation

Renal impairment

No 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.

In patients with kidney insufficiency dosage adjustment may be necessary.

Hepatic impairment

Although 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.

 
Section 5.3

            There are no pre-clinical data of relevance to the prescriber, which are additional to that already included in other sections of the SPC.

Repeat-dose toxicity

Repeat-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 which is over 30-fold greater than the maximum recommended human daily dose(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 toxicity

Pizotifen hydrogen malate was evaluated in multiple reproductive and developmental toxicity studies in mice, rats and rabbits. for its effects on fertility and its embryotoxic, fetotoxic, teratogenic and developmental toxic potential. There were no effects on fertility or teratologic effects noted at all doses up to specific reproductive or developmental effects observed in mice, rats or rabbits up to the highest tested doses of 30 mg/kg/day.   This dose level is greater than 300 times the daily maximum recommended adult human dose of 0.09 mg/kg.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

In vitro and in vivo mutagenicity tests were performed and did not reveal any mutagenic activity of pizotifen hydrogen malate.

Carcinogenicity

A 2-year rat toxicity study did not reveal any gross lesions or masses attributable to pizotifen hydrogen malate administration at dose levels of up to 27 mg/kg which is 300 fold greater than the maximum recommended human daily dose on a mg/kg basis.

Mutagenicity and Carcinogenicity

Pizotifen hydrogen malate was not genotoxic in standard in vitro and in vivo tests. Conventional rodent carcinogenicity studies have not been conducted.

            The following drugs may exhibit drug interactions with pizotifen upon concomitant administration.

Anticipated drug interactions to be considered

Pizotifen 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 agents

            The central effects of sedatives, hypnotics, antihistamines (including certain common cold preparations) and alcohol may be enhanced by SANOMIGRAN.

SANOMIGRAN antagonises the hypotensive effect of adrenergic neurone blockers

            The most common side-effects are appetite stimulating effect, increase in body weight and drowsiness (including somnolence and fatigue).

Adverse reactions are ranked under headings of frequency, the most frequent first, using the following convention: Very common (≥ 1/10); common (≥ 1/100, < 1/10); uncommon
(≥ 1/1000, < 1/100); rare (≥ 1/10,000, < 1/1000); very rare (< 1/10,000), including isolated reports unknown (frequency cannot be estimated from available data).

^*1  These adverse events were reported in patients treated with pizotifen based on post-marketing spontaneous reports.

Withdrawal symptoms

Acute withdrawal reactions have been reported following abrupt cessation of SANOMIGRAN therefore gradual withdrawal is recommended. Withdrawal symptoms include anxiety, tremors, insomnia, nausea and loss of consciousness.

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 may include: depression, tremor, nausea, anxiety, malaise, dizziness, sleep disorder and weight decrease.

4.4       Special Warnings and Precautions

SANOMIGRAN Elixir does not contain sucrose nor tartrazine.  The sweetening agent in SANOMIGRAN Elixir is maltitol liquid at a concentration of 4g in 5ml.  Maltitol liquid contains 45% readily absorbable carbohydrate.  This should be considered if prescribing the drug for diabetic patients.

Hepatic injury has been reported, ranging from transaminase elevations to severe hepatitis.  Pizotifen treatment should be discontinued if there is any clinical evidence of hepatic dysfunction during treatment and until the cause of the liver abnormality is determined.

            Although the anticholinergic activity of SANOMIGRAN is relatively weak, caution is required in the presence of closed angle glaucoma and in patients with a predisposition to urinary retention.  Dosage adjustment may be necessary in patients with kidney insufficiency.

            Pizotifen should be used with caution in patients with a history of epilepsy.

            Withdrawal symptoms like depression, tremor, nausea, anxiety, malaise, dizziness, sleep disorder and weight decrease have been reported following abrupt cessation of pizotifen, therefore gradual withdrawal is recommended.

4.7       Effects on Ability to Drive and use Machinery

            Pizotifen may cause drowsiness, somnolence, and, dizziness and other CNS effects. Therefore, caution should be exercised when driving or using machines.

4.9       Overdose

Symptoms:  drowsiness, dizziness, pyrexia,  hypotension, dryness of the mouth, confusion, excitatory states (in children), ataxia, nausea, vomiting, dyspnoea, cyanosis, tachycardia, convulsions (particularly in children), coma and respiratory paralysis. 

Treatment: Administration of activated charcoal is recommended; in case of very recent uptake, gastric lavage may be considered. Severe hypotension must be corrected (CAVE: adrenaline may produce paradoxical effects).  If necessary, symptomatic treatment should be given including monitoring of the cardiovascular and respiratory systemssymptoms. Excitatory states or convulsions may be treated with short acting benzodiazepines.

•    "Pizotifen should be used with caution in patients with a history of epilepsy" added.

• "Sanomigran antagonises the hypotensive effects of adrenergic neurone blockers" added

• "Pregnancy" and "Lactation" headings added

• Reworded and dizziness and somnolence added.

• Incidence figures added and section divided with subheadings according to area of the body
• The following have also been added: drowsiness (including somnolence), seizures, myalgia, arthralgia, fatigue
• "Acute withdrawal reactions have been reported following abrupt cessationof Sanomigran therefore, gradual withdrawal is recommended. Withdrawal symptoms include anxiety, tremors, insomnia, nausea and loss of consciousness" has been added.

• "Symptoms of overdosage may include" has been changed to "Symptoms:"

• Pharmacotherapeutic group and ATC code added

• Absorption: Info on absolute bioavailability has been added
• Biotransformation: Reworded and percentage figures re. urinary excretion added
• Distribution: Data re. distribution volume added
• Elimination: Additional information re. elimination of an orally applied dose has been added
• Section on special patient groups has been added