4.1. Therapeutic indications

• 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.

4.2. Posology and method of administration

Posology

• For head and neck cancer patients:

The recommended initial dose for adults is 1 tablet of 5 mg three times daily. The maximal therapeutic effect is normally obtained after 4 to 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 to 3 months of therapy.

• For Sjögren's syndrome patients:

The recommended dose for adults is one tablet of 5 mg four times daily. 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 to 3 months.

Special Populations

Use in the elderly:

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

Paediatric population:

The safety and efficacy of this medicinal product in the paediatric population 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 the safety and tolerability, the dosage may gradually be increased to the normal daily dosage schedule of 5 mg three times a day.

Use in patients with impaired renal function:

Insufficient information is available to determine the importance of renal excretion of pilocarpine and its metabolites so as to recommend dosage adjustments for patients with renal insufficiency (see Section 4.4 and Section 5.2).

Method of administration

• For head and neck cancer patients:

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.

• For Sjögren's syndrome patients:

Tablets should be taken with a glass of water at mealtimes and bedtime.

4.3. Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

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.

4.4. Special warnings and precautions for use

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

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.

- Caution should be exercised when administering Salagen in patients with renal insufficiency.

- 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.

4.5. Interaction with other medicinal products and other forms of interaction

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.

In in vitro studies pilocarpine has been found to be an inhibitor of CYP2A6. In vivo inhibition and therefore an interaction with CYP2A6 substrates (e.g. irbesartan, coumarin) cannot be ruled out (see section 5.2).

4.6. Fertility, pregnancy and lactation

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. Studies in animals have shown reproductive toxicity (see section 5.3).

Salagen is not recommended during pregnancy and in women of child bearing potential not using contraception.

Breastfeeding:

Animal studies have shown excretion of pilocarpine in 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 mice, rats and dogs have shown adverse effects on spermatogenesis. A study in rats has also indicated a possible impairment of female fertility (see section 5.3). The safety margin for the effects on fertility is unknown.

Based on the results of available studies in animals (see section 5.3) as a precautionary meaure, Salagen tablets should be administered to individual human males who are attempting to father a child, only, if the expected benefit justifies potential impairment of fertility.

4.7. Effects on ability to drive and use machines

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

Pilocarpine has 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.

4.8. Undesirable effects

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.

Reporting of suspected adverse reactions

Reporting 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.

4.9. Overdose

Overdose may lead to a 'cholinergic crisis' characterised by both muscarinic and nicotinic effects.

Signs of overdose due to muscarinic effects may include abdominal cramps, diarrhoea, nausea and vomiting, involuntary defecation and urination, sweating, salivation, increased bronchial secretions, miosis, bradycardia and hypotension.

Nicotinic effects may include involuntary twitching, fasciculations and generalised weakness.

Parenteral atropine may be used as an antidote to the muscarinic effects. Supportive treatment should be given as required; artificial respiration should be instituted if respiratory depression is severe.