Novartis Pharmaceuticals UK Ltd

5.3     Preclinical safety data

Genotoxicity and carcinogenicity:

Pilocarpine did not indicate a genotoxic potential in a series of in vitro  and  in vivo genotoxicity studies.  In lifetime oral carcinogenicity studies in rodents Pilocarpine did not cause an increase in tumour incidence in mice, but was associated with an increased incidence in benign pheochromocytomas in rats at >15 times the exposure at the maximum recommended human dose and therefore not considered relevant to clinical use.  Preclinical data revealed no special hazard for humans based on conventional studies of genotoxicity and carcinogenic potential.

Fertility

Animal studies have shown adverse effects on the male reproductive tract following chronic exposures to pilocarpine. Impaired spermatogenesis was observed in rats and dogs following 28-day and 6-month oral exposures respectively. Histopathological changes were also observed in the testes and bulbourethral glands of mice given pilocarpine for 2 years.

The safety margin for the effects in humans is unknown. However, body surface area [mg/m²] comparisons suggest that the lowest dose associated with impaired fertility, (3 mg/kg/day in the dog), is approximately 3 times the maximum recommended human dose, therefore a risk to humans cannot be ruled out. A study in rats has also indicated a possible impairment of female fertility (see section 4.6).

Reproductive toxicity:

Studies in pregnant rats showed treatment-related reductions in the mean fetal body weight and increases in the incidence of skeletal variations [at approximately 26 times the maximum recommended dose for a 50 kg human (based on comparisons of body surface area [mg/m²]. These effects occurred at doses that were maternally toxic. There was no evidence of a teratogenic effect in the animal studies.  Treatment related increases in the incidence of stillbirths with decreased neonatal survival and reduced mean body weight of pups were observed in pre- and postnatal studies. A safety margin for these effects cannot be calculated. However, body surface area [mg/m2] comparisons suggest that the effect occurred at approximately 5 times the maximum recommended dose for a 50 kg human. The clinical relevance of these findings is unknown (see section 4.6).

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.

4.6       Fertility, pPregnancy 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. However, pre- and post-natal sStudies in rats animals have shown some reproductive 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 physicianSalagen is not recommended during pregnancy and in women of child bearing potential not using contraception.

Nursing mothersBreastfeeding:

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 mice, rats and dogs have shown adverse effects on spermatogenesis. A study in rats has also indicated and 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.

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.

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.

·         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– 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. 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 –to 3 months.

Special Populations

Use in the elderly:

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

Use in childrenPaediatric population:

The safety and efficacy of this medicinal product in childrenthe 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).

-   Caution should be exercised when administering Salagen in patients with 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

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).

Absorption

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 T½ 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 male volunteers, respectively.

Distribution

Pilocarpine is extensively distributed with an apparent volume of distribution of 2.1 L/kg. Data from animal studies indicates that pilocarpine is distributed into breast milk at concentrations similar to plasma. Preclinical data also suggests that pilocarpine can cross the blood brain barrier at high dose.  Pilocarpine does not bind to plasma proteins.

Metabolism

Pilocarpine is primarily metabolized by CYP2A6 and has demonstrated a capacity to inhibit CYP2A6 in vitro.  Serum esterases are also involved in the biotransformation of pilocarpine to pilocarpic acid.

Elimination

Approximately 35% of dose is eliminated as 3-hydroxypilocarpine in urine and 20% of dose is excreted unchanged in the urine. Mean elimination half-lives for pilocarpine is 0.76 and 1.35 hours after repeated oral doses of 5 and 10 mg of pilocarpine hydrochloride, respectively.

Elderly

PharmacokineticsPilocarpine AUC values in elderly male volunteers were comparable to those in younger subjectsmales. In a small number of healthy elderly female volunteers the mean C_max and AUC werewas approximately twice that of elderly and young male volunteers due to smallerreduced volumes of distribution. However, the observed difference in pharmacokinetics was not reflected in the incidence of adverse events between young and elderly female patients. No dosage adjustment is required in elderly subjects.

Renal impairment

A pharmacokinetic study of pilocarpine in patients with mild and moderately impaired renal function showed that there was no significant difference in clearance and exposure compared with subjects with normal renal function.

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.

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

Ocular formulations of Ppilocarpine have 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.

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

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

Film-coated tablet

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

Film coating:

Opadry White, YS-1OY-70037300, containing hypromellose, macrogol 4000, 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.

• "film coated" added after Salagen and "for oral use" deleted.

• Minor changes to the wording: Use in children: "Safety" changed to "The safety", "effectiveness" changed to "efficacy", "drug" changed to "medicinal product"
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• "Hypersensitivity to the active substance or any of the excipients" moved from within the last paragraph to start of the section.

• Nursing mothers: "Animal studies have shown excretion of pilocarpine in breast milk at concentrations similar to those seen in plasma" added
• Nursing mothers: Last sentance reworded from "Salagen should not be prescribed to a woman during lactation unless the risks for the baby of continuing breast feeding has been carefully evaluated by the physician" changed to "A decision must be made whether to discontinue breast-feeding or to discontinue Salagen therapy."

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