Salagen® 5 mg film-coated tablets

Each film coated tablet contains 5 mg of pilocarpine hydrochloride.

For a full list of excipients, see section 6.1.

Film-coated tablet

Salagen film-coated tablets are white, round biconvex tablets, marked “SAL” on one side and “5 mg” on the other side.

• Alleviation of symptoms of salivary gland hypofunction in patients with severe xerostomia following irradiation for head and neck cancer.

• Treatment of symptoms of dry mouth and dry eyes in patients with Sjögren's syndrome.

•For head and neck cancer patients:

The recommended initial dose for adults is 1 tablet of 5 mg three times daily. Tablets should be taken with a glass of water during or directly after meals. The last tablet should always be taken in conjunction with the evening meal. The maximal therapeutic effect is normally obtained after 4–8 weeks of therapy. For patients who have not responded sufficiently after 4 weeks and who tolerate the dose of 5 mg three times daily, doses of up to a maximum of 30 mg daily may be considered. However, higher daily doses are probably accompanied by an increase in drug-related adverse effects. Therapy should be discontinued if no improvement in xerostomia is noted after 2–3 months of therapy.

•For Sjögren's syndrome patients:

The recommended dose for adults is one tablet of 5 mg four times daily. Tablets should be taken with a glass of water at mealtimes and bedtime. For patients who have not responded sufficiently to a dosage of 5 mg four times daily and who tolerate this dosage, increasing the dose up to a maximum of 30 mg daily, divided over the day, may be considered. Therapy should be discontinued if no improvement in the symptoms of dry mouth and dry eyes is noted after 2 - 3 months.

Use in the elderly:

There is no evidence to suggest that dosage should be different in the elderly.

Use in children:

The safety and efficacy of this medicinal product in children have not been established.

Use in patients with impaired hepatic function:

Patients with moderate and severe cirrhosis should start treatment on a reduced daily dosage schedule. Depending on safety and tolerability, the dosage may gradually be increased to the normal daily dosage schedule of 5 mg three times a day.

Hypersensitivity to the active substance or to any of the excipients.

Salagen is contraindicated in patients with clinically significant, uncontrolled cardiorenal disease, uncontrolled asthma and other chronic disease at risk for cholinergic agonists.

Salagen is contraindicated in cases where miosis is undesirable, such as in acute iritis.

Pilocarpine has been reported to increase airway resistance in asthmatic patients. Also, patients with significant cardiovascular disease may be unable to compensate for transient changes in haemodynamics or heart rhythm induced by pilocarpine. Therefore, Salagen should be administered to patients with controlled asthma or significant cardiovascular disease only if the benefits are believed to outweigh the risks, and under close medical supervision.

Salagen should be used with caution in patients with the following illnesses/pathologies:

• chronic bronchitis and/or chronic obstructive pulmonary disease. These patients have hyperactive airways and may experience adverse effects due to increased bronchial smooth muscle tone and increased bronchial secretions.

• known or suspected cholelithiasis or biliary tract disease. Contractions of the gallbladder or biliary smooth muscle could precipitate complications including cholecystitis, cholangitis and biliary obstruction.

• peptic ulceration, due to the risk of increased acid secretion.

• underlying cognitive or psychiatric disturbances. Cholinergic agonists, like pilocarpine hydrochloride, may have dose-related central nervous system effects.

• renal insufficiency. Insufficient information is available to determine the importance of renal excretion of pilocarpine and its metabolites in relation to metabolic inactivation so as to recommend dosage adjustments for these patients. Pilocarpine may increase ureteral smooth muscle tone and could theoretically precipitate renal colic (or “ureteral reflux”), particularly in patients with nephrolithiasis.

Salagen should be administered with caution in patients with narrow-angle glaucoma.

Caution should be exercised in patients who are known or expected to sweat excessively and who cannot drink enough liquids, since dehydration could develop.

Salagen should be administered with caution to patients taking beta adrenergic antagonists because of the possibility of conduction disturbances.

Concurrent administration of Salagen and drugs with parasympathomimetic effects is expected to result in additive pharmacologic effects.

Pilocarpine might antagonise the anticholinergic effects of other drugs used concomitantly (e.g. atropine, inhaled ipratropium).

While no formal drug interaction studies have been performed, the following concomitant drugs were used in at least 10% of patients in either or both Sjögren's efficacy studies: acetylsalicylic acid, artificial tears, calcium, conjugated estrogens, hydroxychloroquine sulfate, ibuprofen, levothyroxine sodium, medroxyprogesterone acetate, methotrexate, multivitamins, naproxen, omeprazole, paracetamol, and prednisone. There were no reports of drug toxicities during either efficacy study.

Pregnancy:

The safety of this medicinal product for use in human pregnancy has not been established. There are no known human data for the effects of pilocarpine on foetal survival and development. However, pre- and post-natal studies in rats have shown some toxicity (see section 5.3).

Salagen should not be given to a pregnant woman unless the risks and benefit of the treatment have been carefully evaluated by the physician.

Nursing mothers:

Animal studies have shown excretion of pilocarpine in breast milk at concentrations similar to those seen in plasma. It is not known whether pilocarpine is secreted in human milk. A decision must be made whether to discontinue breast-feeding or to discontinue from Salagen therapy.

Fertility:

The effects of pilocarpine on male and female fertility are not known. Studies in rats have shown adverse effects on spermatogenesis and a possible impairment of female fertility (see section 5.3).

Ocular formulations of pilocarpine have been reported to cause impairment of depth perception and visual blurring. The latter may result in decreased visual acuity, especially at night and in patients with central lens changes. If this occurs, patients should be advised not to drive at night or perform hazardous activities in reduced lighting.

Patients who experience dizziness during Salagen treatment should be advised not to drive or operate machinery.

Most of the adverse experiences observed during Salagen treatment were a consequence of exaggerated parasympathetic stimulation. These adverse experiences were dose-dependent and usually mild and self-limited. However, severe adverse experiences might occasionally occur and therefore careful monitoring of the patient is recommended.

In controlled clinical trials the following adverse reactions were observed:

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Very common ( 1/10); common ( 1/100, < 1/10); uncommon ( 1/1,000, < 1/100); rare ( 1/10,000, < 1/1,000); very rare ( < 1/10,000), not known (cannot be estimated from the available data).

Nervous system disorders

Very common: headache

Common: dizziness

Eye disorders

Common: lacrimation; blurred vision; abnormal vision; conjunctivitis; eye pain

Cardiac disorders

Common: flushing (vasodilatation); hypertension; palpitations

Respiratory, thoracic and mediastinal disorders

Common: rhinitis

Gastrointestinal disorders

Common: dyspepsia; diarrhoea; abdominal pain; nausea, vomiting; constipation, increased salivation

Uncommon: flatulence

Skin and subcutaneous tissue disorders

Very common: sweating

Common: allergic reactions, including rash; pruritus

Renal and urinary disorders

Very common: increased urinary frequency

Uncommon: urinary urgency

General disorders and administration site conditions

Very common: flu syndrome

Common: asthenia; chills

There is no indication of a difference between older and younger patients receiving Salagen as regards reporting adverse experiences, except for dizziness, which was reported significantly more often by patients aged over 65 years.

The following adverse effects, which are due to the intrinsic pharmacological properties of pilocarpine, have been published in the medical literature: respiratory distress, gastro-intestinal spasm, atrioventricular block, tachycardia, bradycardia, cardiac arrhythmia, hypotension, shock, tremors, and mental status changes including memory loss, hallucinations, lability of affect, confusion, agitation.

Overdosage should be treated with atropine titration (0.5 mg to 1.0 mg given subcutaneously or intravenously) and supportive measures to maintain respiration and circulation. Adrenaline (0.3 mg to 1.0 mg, subcutaneously or intramuscularly) may also be of value in the presence of severe cardiovascular depression or bronchoconstrictor responses. It is not known if pilocarpine is dialysable. There is no safety information for doses greater than 10 mg three times daily.

Pharmacotherapeutic group: Parasympathominetic, ATC code: N07A X01.

Pilocarpine is a cholinergic parasympathomimetic agent exerting a broad spectrum of pharmacologic effects with predominant muscarinic action. Pilocarpine, in appropriate dosage, can increase secretion by exocrine glands such as the sweat, salivary, lacrimal, gastric, pancreatic and intestinal glands and the mucous cells of the respiratory tract.

Dose-related smooth muscle stimulation of the intestinal tract may cause increased tone, increased motility, spasm and tenesmus. Bronchial smooth muscle tone may increase. The tone and motility of urinary tract, gallbladder and biliary duct smooth muscle may be enhanced.

Pilocarpine may have paradoxical effects on the cardiovascular system. The expected effect of a muscarinic agonist is vasodepression, but administration of pilocarpine may produce hypertension after a brief episode of hypotension. Bradycardia and tachycardia have both been reported with use of pilocarpine.

In a study in healthy male volunteers an increase in salivary flow following single 5 and 10 mg doses of Salagen was noted 20 minutes after administration, and lasted for 3 to 5 hours with a peak at 1 hour.

•For head and neck cancer patients:

In two 12-week randomised, double-blind placebo-controlled clinical studies in patients with xerostomia resulting from irradiation to the head and neck for cancer, Salagen treatment reduced dryness of the mouth; in one of these studies this did not occur until after 12 weeks of treatment. Also, Salagen treatment increased salivary flow. The greatest improvement in dryness was noted in patients with no measurable salivary flow at baseline.

In both studies, some patients noted improvement in the overall condition of xerostomia, speaking without drinking liquids, and mouth comfort, and there was reduced use of concomitant therapy (i.e. artificial saliva) for dry mouth.

•For Sjögren's syndrome patients:

Two separate 12-week randomised, double-blind placebo-controlled clinical studies were conducted in patients diagnosed with primary or secondary Sjögren's syndrome. In both studies, the majority of patients best fit the European criteria for having primary Sjögren's syndrome. The ability of Salagen to stimulate saliva production was assessed. Relative to placebo, an increase in the amount of saliva being produced was observed following the first dose and was maintained throughout the duration of the trials in an approximate dose response fashion.

Compared to placebo a statistically significant global improvement for both dry mouth and dry eyes was observed.

Efficacy of Salagen has not been established in patients with the Sjögren's syndrome during long term treatment (>12 weeks).

In a multiple-dose pharmacokinetic study in volunteers given 5 or 10 mg of pilocarpine hydrochloride three times daily for two days, the T_max after the final dose was approximately 1 hour, the elimination T_½ was approximately 1 hour, and the mean C_max's were 15 ng/ml and 41 ng/ml for the 5 and 10 mg doses, respectively.

Pharmacokinetics in elderly male volunteers were comparable to those in younger subjects. In a small number of healthy elderly female volunteers the mean C_max and AUC were approximately twice that of elderly and young male volunteers due to smaller volumes of distribution. However, the observed difference in pharmacokinetics was not reflected in the incidence of adverse events between young and elderly female patients.

When taken with a high-fat meal by healthy male volunteers, there was a decrease in the rate of absorption of pilocarpine from Salagen tablets. Mean T_max's were 1.47 and 0.87 hours and mean C_max's were 51.8 and 59.2 ng/ml for fed and fasted volunteers, respectively.

In a study in male albino rats, which were administered single subcutaneous injections at doses in the range of the median lethal dose (200–1,000 mg/kg in rat), pilocarpine hydrochloride was found to cross the blood-brain barrier.

There is limited information available concerning the metabolism and elimination of pilocarpine in humans. Inactivation of pilocarpine is thought to occur at neuronal synapses and probably in plasma.

A single-dose pharmacokinetic study in humans showed that an average of 30% of the orally administered dose of 10 mg pilocarpine could be detected in the urine after 12 hours, of which 14% was recovered as pilocarpic acid. No other metabolites were detected in the urine. It is expected that the remaining 70% is excreted via other routes and/or metabolised to unknown metabolites.

An in-vitro study showed that pilocarpine does not bind to plasma proteins.

Genotoxicity and carcinogenicity:

Preclinical data revealed no special hazard for humans based on conventional studies of genotoxicity and carcinogenic potential.

Reproductive toxicity:

Two studies were conducted in rats in which males and females were exposed to pilocarpine before and after mating, dosing in the females continuing to 21 days after parturition. There was evidence that doses of 18 mg/kg/day and above for 28 days to male rats would affect fertility adversely, decrease sperm motility and increase incidence of abnormal sperm. In females at these doses there was evidence of decreased fertility index and prolonged di-oestrus. Offspring survival was decreased.

For these changes to reproductive performance, 3 mg/kg/day was a No Effect dose.

The post-natal development of the surviving F1 generation was not affected by doses of up to 72 mg/kg/day to the dams, and the F2 generation was normal.

There was no evidence of a teratogenic effect at any dose in these studies.

Binder/diluent:

Microcrystalline cellulose

Acidifier/lubricant:

Stearic acid

Film coating:

Opadry White, YS-1-7003, containing hypromellose, macrogol 400, polysorbate 80 and titanium dioxide (E171)

Polish:

Carnauba wax

Branding ink:

Opacode Black, S-1-17823, containing synthetic black iron oxide (E172), shellac, propylene glycol and ammonium hydroxide.

Not applicable

3 years

Do not store above 25°C.

Store in the original package in order to protect from light and moisture.

Salagen is distributed for sale in perforated Al/PVC/PVDC blisters.

Each blister contains 14 or 21 tablets.

A carton contains 1, 2 or 6 of the 14-tablet blisters, or 1 or 4 of the 21-tablet blisters.

Not all pack sizes may be marketed.

No special requirements.

Novartis Pharmaceuticals UK Ltd

Frimley Business Park

Frimley

Surrey GU16 7SR

UK

PL 00101/0630

Date of first authorisation: 1 July 2001

Date of last renewal: 1 July 2006

28 September 2007

POM