Salagen Mechanism of Action

Pharmacology: Pharmacodynamics: 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 the exocrine glands. The sweat, salivary, lacrimal, gastric, pancreatic and intestinal glands, and the mucous cells of the respiratory tract may be stimulated. When applied topically to the eye as a single dose, it causes miosis, spasm of accommodation and may cause a transitory rise in intraocular pressure followed by a more persistent fall. 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 of 12 healthy male volunteers there was a dose-related increase in unstimulated salivary flow following single 5- and 10-mg oral doses of Salagen. This effect of pilocarpine on salivary flow was time-related with an onset at 20 min and a peak effect at 1 hr with a duration of 3-5 hrs (see Pharmacokinetics as follows).
Head and Neck Cancer Patients: In a 12-week randomized, double-blind, placebo-controlled study in 207 patients (placebo, N=65; 5 mg, N=73; 10 mg, N=69), increases from baseline (means 0.072 and 0.112 mL/min, ranges -0.69 to 0.728 and -0.38 to 1.689) of whole saliva flow for the 5-mg (63%) and 10-mg (90%) tablet, respectively, were seen 1 hr after the 1st dose of Salagen. Increases in unstimulated parotid flow were seen following the 1st dose (means 0.025 and 0.046 mL/min, ranges 0-0.414 and -0.07 to 1.002 mL/min for the 5- and 10-mg dose, respectively). In this study, no correlation existed between the amount of increase in salivary flow and the degree of symptomatic relief.
Sjogren's Syndrome Patients: In two 12-week randomized, double-blind, placebo-controlled studies in 629 patients (placebo, n=253; 2.5 mg, n=121; 5 mg, n=255; 5-7.5 mg, n=114), the ability of Salagen to stimulate saliva production was assessed. In these trials using varying doses of Salagen (2.5-7.5 mg), the rate of saliva production was plotted against time. An area under the curve (AUC) representing the total amount of saliva produced during the observation interval was calculated. Relative to placebo, an increase in the amount of saliva being produced was observed following the 1st dose of Salagen and was maintained throughout the duration (12 weeks) of the trials in an approximate dose-response fashion (see Clinical Studies as follows).
Clinical Studies: Head and Neck Cancer Patients: A 12-week randomized, double-blind, placebo-controlled study in 207 patients (142 men, 65 women) was conducted in patients whose mean age was 58.5 years with a range of 19-77; the racial distribution was Caucasian 95%, Black  4% and other 1%. In this population, a statistically significant improvement in mouth dryness occurred in the Salagen 5- and 10-mg treated patients compared to placebo-treated patients. The 5-mg and 10-mg treated patients could not be distinguished.
Another 12-week, double-blind, randomized, placebo-controlled study was conducted in 162 patients whose mean age was 57.8 years with a range of 27-80; the racial distribution was Caucasian 88%, Black 10% and other 2%. The effects of placebo were compared to 2.5 mg 3 times a day of Salagen for 4 weeks followed by adjustment to 5 mg 3 times a day and 10 mg 3 times a day. Lowering of the dose was necessary because of adverse events in 3 of 67 patients treated with Salagen 5 mg and in 7 of 66 patients treated with Salagen 10 mg. After 4 weeks of treatment, Salagen 2.5 mg 3 times a day was comparable to placebo in relieving dryness. In patients treated with Salagen 5 mg and 10 mg, 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 global assessment of their dry mouth, speaking without liquids and a reduced need for supplemental oral comfort agents.
In the 2 placebo-controlled clinical trials, the most common adverse events related to drug and increasing in rate as dose increases, were sweating, nausea, rhinitis, diarrhea, chills, flushing, urinary frequency, dizziness and asthenia. The most common adverse experience causing withdrawal from treatment was sweating (5 mg 3 times daily <1%; 10 mg 3 times daily=12%).
Sjogren's Syndrome Patients: Two (2) separate studies were conducted in patients with primary or secondary Sjogren's syndrome. In both studies, the majority of patients best fit the European criteria for having primary Sjogren's syndrome.
A 12-week, randomized, double-blind, parallel-group, placebo-controlled study was conducted in 256 patients (14 men, 242 women) whose mean age was 57 years with a range of 24-85 years. The racial distribution was as follows: Caucasian 91%, Black 6% and other 3%.
The effects of placebo were compared with those of Salagen 5 mg 4 times a day (20 mg/day) for 6 weeks. At 6 weeks, the patients’ dosage was increased from Salagen 5 mg 4 times daily to 7.5 mg 4 times daily. The data collected during the first 6 weeks of the trial were evaluated for safety and efficacy, and the data of the second 6 weeks of the trial were used to provide additional evidence of safety.
After 6 weeks of treatment, statistically significant global improvement of dry mouth was observed compared to placebo. “Global improvement” is defined as a score of ≥55 mm on a 100 mm visual analogue scale in response to the question, “Please rate your present condition of dry mouth (xerostomia) compared with your condition at the start of this study. Consider the changes to your dry mouth and other symptoms related to your dry mouth that have occurred since you have taken this medication.” Patients’ assessments of specific dry mouth symptoms eg, severity of dry mouth, mouth discomfort, ability to speak without water, ability to sleep without drinking water, ability to swallow food without drinking and a decreased use of saliva substitutes were found to be consistent with the significant global improvement described.
Another 12-week randomized, double-blind, parallel-group, placebo-controlled study was conducted in 373 patients (16 men, 357 women) whose mean age was 55 years with a range of 21-84. The racial distribution was Caucasian 80%, Oriental 14%, Black 2% and 4% of other origin. The treatment groups were pilocarpine 2.5 mg tablets, Salagen 5 mg and placebo. All treatments were administered on a 4 times a day regimen.
After 12 weeks of treatment, statistically significant global improvement of dry mouth was observed at a dose of 5 mg compared with placebo. The 2.5 mg (10 mg/day) group was not significantly different than placebo. However, a subgroup of patients with rheumatoid arthritis tended to improve in global assessments at both the 2.5 mg 4 times daily (9 patients) and 5 mg 4 times daily (16 patients) dose (10-20 mg/day). The clinical significance of this finding is unknown.
Patients’ assessments of specific dry mouth symptoms eg, severity of dry mouth, mouth discomfort, ability to sleep without drinking water and decreased use of saliva substitutes were also found to be consistent with the significant global improvement described when measured after 6 weeks and 12 weeks of Salagen use.
Pharmacokinetics: In a multiple-dose pharmacokinetic study in male volunteers following  2 days of 5 or 10 mg of oral pilocarpine HCl tablets given at 8 am, noontime and 6 pm, the mean elimination half-life was 0.76 hr for the 5-mg dose and 1.35 hrs for the 10-mg dose. T_max values were 1.25 hrs and 0.85 hr. C_max values were 15 ng/mL and 41 ng/mL. The AUC trapezoidal values were 33 hr (ng/mL) and 108 hr (ng/mL), respectively, for the 5-mg and 10-mg doses following the last 6-hr dose.
Pharmacokinetics in elderly male volunteers (N=11) were comparable to those in younger men. In 5 healthy elderly female volunteers, the mean C_max and AUC were approximately twice that of elderly males and young normal male volunteers.
When taken with a high-fat meal by 12 healthy male volunteers, there was a decrease in the rate of absorption of pilocarpine from Salagen. Mean T_max were 1.47 and 0.87 hrs and mean C_max were 51.8 and 59.2 ng/mL for fed and fasted, respectively.
Limited information is available about the metabolism and elimination of pilocarpine in humans. Inactivation of pilocarpine is thought to occur at neuronal synapses and probably in plasma. Pilocarpine and its minimally active or inactive degradation products, including pilocarpic acid, are excreted in the urine. Pilocarpine does not bind to human or rat plasma proteins over a concentration range of 5-25,000 ng/mL. The effect of pilocarpine on plasma protein-binding of other drugs has not been evaluated.
In patients with mild to moderate hepatic impairment (n=12), administration of a single 5-mg dose resulted in a 30% decrease in total plasma clearance and a doubling of exposure (as measured by AUC). Peak plasma levels were also increased by about 30% and half-life was increased to 2.1 hrs.
There were no significant differences in the pharmacokinetics of oral pilocarpine in volunteer subjects (N=8) with renal insufficiency (mean creatinine clearances 25.4 mL/min; range 9.8-40.8 mL/min) compared to the pharmacokinetics previously observed in normal volunteers.
Pilocarpine was associated with a reduction in the mean fetal body weight and an increase in the incidence of skeletal variations when given to pregnant rats at a dosage of 90 mg/kg/day [approximately 26 times the maximum recommended dose for a 50 kg human when compared on the basis of body surface area (mg/m²) estimates]. These effects may have been secondary to maternal toxicity. In another study, oral administration of pilocarpine to female rats during gestation and lactation at a dosage of 36 mg/kg/day [approximately 10 times the maximum recommended dose for a 50 kg human when compared on the basis of body surface area (mg/m²) estimates] resulted in an increased incidence of stillbirths; decreased neonatal survival and reduced mean body weight of pups were observed at dosages of 18 mg/kg/day [approximately 5 times the maximum recommended dose for a 50 kg human when compared on the basis of body surface area (mg/m²) estimates] and above.