Pilocarpine Hydrochloride: Package Insert and Label Information

PILOCARPINE HYDROCHLORIDE- pilocarpine hydrochloride tablet, film coated
Lannett Company, Inc.

DESCRIPTION:

Pilocarpine hydrochloride tablets, USP contain pilocarpine hydrochloride, a cholinergic agonist for oral use. Pilocarpine hydrochloride, USP is a hygroscopic, odorless, bitter tasting white crystal or powder, which is soluble in water and alcohol and virtually insoluble in most non-polar solvents. Pilocarpine hydrochloride, USP with a chemical name of (3S-cis)-2(3H)-Furanone, 3-ethyldihydro-4-[(1-methyl-1H -imidazol-5-yl)methyl]monohydrochloride, has a molecular weight of 244.72.

Chemical Structure
(click image for full-size original)

Each 5 mg Pilocarpine Hydrochloride Tablet, USP for oral administration contains 5 mg of pilocarpine hydrochloride. Inactive ingredients in the tablet are microcrystalline cellulose and stearic acid, the tablet’s film coating is: polyvinyl alcohol, titanium dioxide, polyethylene glycol, and talc.

Each 7.5 mg Pilocarpine Hydrochloride Tablet, USP for oral administration contains 7.5 mg of pilocarpine hydrochloride. Inactive ingredients in the tablet are microcrystalline cellulose and stearic acid, the tablet’s film coating is: FD&C Blue #2/Indigo Carmine aluminum lake, polyvinyl alcohol, titanium dioxide, polyethylene glycol, and talc.

CLINICAL 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 pilocarpine hydrochloride tablets. This effect of pilocarpine on salivary flow was time-related with an onset at 20 minutes and a peak effect at 1 hour with a duration of 3 to 5 hours (See Pharmacokinetics section).

Head & 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 −0.690 to 0.728 and −0.380 to 1.689) of whole saliva flow for the 5 mg (63%) and 10 mg (90%) tablet, respectively, were seen 1 hour after the first dose of pilocarpine hydrochloride tablets. Increases in unstimulated parotid flow were seen following the first dose (means 0.025 and 0.046 mL/min, ranges 0 to 0.414 and −0.070 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 pilocarpine hydrochloride tablets to stimulate saliva production was assessed. In these trials using varying doses of pilocarpine hydrochloride tablets (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 first dose of pilocarpine hydrochloride tablets and was maintained throughout the duration (12 weeks) of the trials in an approximate dose response fashion (See Clinical Studies section).

Pharmacokinetics:

In a multiple-dose pharmacokinetic study in male volunteers following 2 days of 5 or 10 mg of oral pilocarpine hydrochloride tablets given at 8 a.m., noontime, and 6 p.m., the mean elimination half-life was 0.76 hours for the 5 mg dose and 1.35 hours for the 10 mg dose. Tmax values were 1.25 hours and 0.85 hours. Cmax values were 15 ng/mL and 41 ng/mL. The AUC trapezoidal values were 33 h(ng/mL) and 108 h(ng/mL), respectively, for the 5 and 10 mg doses following the last 6 hour dose.

Pharmacokinetics in elderly male volunteers (N = 11) were comparable to those in younger men. In five healthy elderly female volunteers, the mean Cmax 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 pilocarpine hydrochloride 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, 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 to 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.

Clinical Studies:

Head & 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 to 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 5 and 10 mg pilocarpine hydrochloride tablet treated patients compared to placebo treated patients. The 5 and 10 mg treated patients could not be distinguished. (See Pharmacodynamics section for flow study details.)

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 to 80; the racial distribution was Caucasian 88%, Black 10%, and other 2%. The effects of placebo were compared to 2.5 mg three times a day of pilocarpine hydrochloride tablets for 4 weeks followed by adjustment to 5 mg three times a day and 10 mg three times a day. Lowering of the dose was necessary because of adverse events in 3 of 67 patients treated with 5 mg of pilocarpine hydrochloride tablets and in 7 of 66 patients treated with 10 mg of pilocarpine hydrochloride tablets. After 4 weeks of treatment, 2.5 mg of pilocarpine hydrochloride tablets three times a day was comparable to placebo in relieving dryness. In patients treated with 5 mg and 10 mg of pilocarpine hydrochloride tablets, 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 two 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 t.i.d. ≤1%; 10 mg t.i.d. =12%).

Sjogren’s Syndrome Patients:

Two 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. [“Criteria for the Classification of Sjogren’s Syndrome” (Vitali C, Bombardieri S, Moutsopoulos HM, et al: Preliminary criteria for the classification of Sjogren’s syndrome. Arthritis Rheum 36:340-347, 1993.)]

A twelve 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 to 85 years. The racial distribution was as follows: Caucasian 91%, Black 6%, and other 3%.

The effects of placebo were compared with those of pilocarpine hydrochloride tablets 5 mg four times a day (20 mg/day) for 6 weeks. At 6 weeks, the patients’ dosage was increased from 5 mg pilocarpine hydrochloride tablets q.i.d. to 7.5 mg q.i.d. 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 or more 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 such as 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 to 84. The racial distribution was Caucasian 80%, Oriental 14%, Black 2%, and 4% of other origin. The treatment groups were 2.5 mg pilocarpine tablets, 5 mg pilocarpine hydrochloride tablets, and placebo. All treatments were administered on a four 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 (10mg/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 q.i.d. (9 patients) and 5 mg q.i.d. (16 patients) dose (10-20 mg/day). The clinical significance of this finding is unknown.

Patients’ assessments of specific dry mouth symptoms such as 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 pilocarpine hydrochloride tablets use.

INDICATIONS AND USAGE:

Pilocarpine hydrochloride tablets, USP are indicated for 1) the treatment of symptoms of dry mouth from salivary gland hypofunction caused by radiotherapy for cancer of the head and neck; and 2) the treatment of symptoms of dry mouth in patients with Sjogren’s syndrome.

CONTRAINDICATIONS:

Pilocarpine hydrochloride tablets are contraindicated in patients with uncontrolled asthma, known hypersensitivity to pilocarpine, and when miosis is undesirable, e.g., in acute iritis and in narrow-angle (angle closure) glaucoma.

WARNINGS:

Cardiovascular Disease:

Patients with significant cardiovascular disease may be unable to compensate for transient changes in hemodynamics or rhythm induced by pilocarpine. Pulmonary edema has been reported as a complication of pilocarpine toxicity from high ocular doses given for acute angle-closure glaucoma. Pilocarpine should be administered with caution in and under close medical supervision of patients with significant cardiovascular disease.

Ocular:

Ocular formulations of pilocarpine have been reported to cause visual blurring which may result in decreased visual acuity, especially at night and in patients with central lens changes, and to cause impairment of depth perception. Caution should be advised while driving at night or performing hazardous activities in reduced lighting.

Pulmonary Disease:

Pilocarpine has been reported to increase airway resistance, bronchial smooth muscle tone, and bronchial secretions. Pilocarpine hydrochloride should be administered with caution to and under close medical supervision in patients with controlled asthma, chronic bronchitis, or chronic obstructive pulmonary disease requiring pharmacotherapy.

PRECAUTIONS:

General:

Pilocarpine toxicity is characterized by an exaggeration of its parasympathomimetic effects. These may include: headache, visual disturbance, lacrimation, sweating, respiratory distress, gastrointestinal spasm, nausea, vomiting, diarrhea, atrioventricular block, tachycardia, bradycardia, hypotension, hypertension, shock, mental confusion, cardiac arrhythmia, and tremors.

The dose-related cardiovascular pharmacologic effects of pilocarpine include hypotension, hypertension, bradycardia, and tachycardia.

Pilocarpine should be administered with caution to patients with 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.

Pilocarpine may increase ureteral smooth muscle tone and could theoretically precipitate renal colic (or “ureteral reflux”), particularly in patients with nephrolithiasis.

Cholinergic agonists may have dose-related central nervous system effects. This should be considered when treating patients with underlying cognitive or psychiatric disturbances.

Hepatic Insufficiency:

Based on decreased plasma clearance observed in patients with moderate hepatic impairment, the starting dose in these patients should be 5 mg twice daily, followed by adjustment based on therapeutic response and tolerability. Patients with mild hepatic insufficiency (Child-Pugh score of 5-6) do not require dosage reductions. To date, pharmacokinetic studies in subjects with severe hepatic impairment (Child-Pugh score of 10-15) have not been carried out. The use of pilocarpine in these patients is not recommended.

Child-Pugh scoring system for Hepatic Impairment

*
According to grading of Trey C, Burns D, and Saunders S. Treatment of hepatic coma by exchange blood transfusion. N Engl J Med. 1966; 274:473-481.
Clinical and Biochemical
Measurements
Points Scored for
Increasing Abnormality
1 2 3
Encephalopathy (grade)* None 1 and 2 3 and 4
Ascites Absent Slight Moderate
Bilirubin (mg. Per 100 ml.) 1-2 2-3 >3
Albumin (g. per 100 ml.) 3-5 2.8-3.5 <2.8
Prothrombin time (sec. Prolonged) 1-4 4-6 >6
For primary biliary cirrhosis:-
Bilirubin (mg. Per 100 ml.)
1-4 4-10 >10

Reference: Pugh, RNH, Murray-Lyon, IM, Dawson, JL Pietroni, MC, Williams, R. Transection of the Oesophagus for Bleeding Oesophageal Varices, Brit. J. Surg. 1973;60:646-9.

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