Section 4.2
· 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).
Section 4.4
As present until...........
- 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
As present until end
Section 4.5
The following has been added as last paragraph.
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).
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 Tmax after the final dose was approximately 1 hour, the elimination T½ was approximately 1 hour, and the mean Cmax’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 Cmax 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 Tmax’s were 1.47 and 0.87 hours and mean Cmax’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 Cmax 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.
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