ADVERSE REACTIONS SECTION.

ADVERSE REACTIONS. Head Neck Cancer Patients. In controlled studies, 217 patients received pilocarpine, of whom 68% were men and 32% were women. Race distribution was 91% Caucasian, 8% Black, and 1% of other origin. Mean age was approximately 58 years. The majority of patients were between 50 and 64 years (51%), 33% were 65 years and older and 16% were younger than 50 years of age. The most frequent adverse experiences associated with pilocarpine hydrochloride tablets were consequence of the expected pharmacologic effects of pilocarpine.Adverse EventPilocarpine HydrochloridePlacebo10 mg t.i.d.(30 mg/day)N=1215 mg t.i.d.(15 mg/day)N=141(t.i.d.)N=152Sweating68%29%9%Nausea1564Rhinitis1457Diarrhea745Chills153< 1Flushing1383UrinaryFrequency1297Dizziness1254Asthenia1263In addition, the following adverse events (>= 3% incidence) were reported at dosages of 15 mg/day to 30 mg/day in the controlled clinical trials:Adverse EventPilocarpine HydrochloridePlacebo5 mg to 10 mg t.i.d.(15 mg/day to 30 mg/day)N=212(t.i.d.)N=152Headache11%8%Dyspepsia75Lacrimation68Edema54Abdominal Pain44Amblyopia42Vomiting41Pharyngitis38Hypertension31The following events were reported with treated head and neck cancer patients at incidences of 1% to 2% at dosages of 7.5 mg/day to 30 mg/day: abnormal vision, conjunctivitis, dysphagia, epistaxis, myalgias, pruritus, rash, sinusitis, tachycardia, taste perversion, tremor, voice alteration.The following events were reported rarely in treated head and neck cancer patients (< 1%): Causal relation is unknown.Body as whole: body odor, hypothermia, mucous membrane abnormalityCardiovascular: bradycardia, ECG abnormality, palpitations, syncopeDigestive: anorexia, increased appetite, esophagitis, gastrointestinal disorder, tongue disorderHematologic: leukopenia, lymphadenopathyNervous: anxiety, confusion, depression, abnormal dreams, hyperkinesia, hypesthesia, nervousness, paresthesias, speech disorder, twitchingRespiratory: increased sputum, stridor, yawningSkin: seborrheaSpecial senses: deafness, eye pain, glaucomaUrogenital: dysuria, metrorrhagia, urinary impairment In long-term treatment were two patients with underlying cardiovascular disease of whom one experienced myocardial infarct and another an episode of syncope. The association with drug is uncertain.. Sjogrens syndrome Patients. In controlled studies, 376 patients received pilocarpine, of whom 5% were men and 95% were women. Race distribution was 84% Caucasian, 9% Oriental, 3% Black, and 4% of other origin. Mean age was 55 years. The majority of patients were between 40 and 69 years (70%), 16% were 70 years and older and 14% were younger than 40 years of age. Of these patients, 161/629 (89/376 receiving pilocarpine) were over the age of 65 years. The adverse events reported by those over 65 years and those 65 years and younger were comparable except for notable trends for urinary frequency, diarrhea, and dizziness. The incidences of urinary frequency and diarrhea in the elderly were about double those in the non-elderly. The incidence of dizziness was about three times as high in the elderly as in the non-elderly. These adverse experiences were not considered to be serious. In the placebo-controlled studies, the most common adverse events related to drug use were sweating, urinary frequency, chills, and vasodilatation (flushing). The most commonly reported reason for patient discontinuation of treatment was sweating. Expected pharmacologic effects of pilocarpine include the following adverse experiences associated with pilocarpine hydrochloride tablets:Adverse EventPilocarpine hydrochloridePlacebo5 mg q.i.d.(20 mg/day)N=255(q.i.d.)N=253Sweating40%7%Urinary Frequency104Nausea99Flushing92Rhinitis78Diarrhea67Chills42Increased Salivation30Asthenia22In addition, the following adverse events (>= 3% incidence) were reported at dosages of 20 mg/day in the controlled clinical trials:Adverse EventPilocarpine hydrochloridePlacebo5 mg q.i.d.(20 mg/day)N=255(q.i.d.)N=253Headache13%19%Flu Syndrome99Dyspepsia77Dizziness67Pain42Sinusitis45Abdominal Pain34Vomiting31Pharyngitis25Rash23Infection26The following events were reported in Sjogrens patients at incidences of 1% to 2% at dosing of 20 mg/day: accidental injury, allergic reaction, back pain, blurred vision, constipation, increased cough, edema, epistaxis, face edema, fever, flatulence, glossitis, lab test abnormalities, including chemistry, hematology, and urinalysis, myalgia, palpitation, pruritus, somnolence, stomatitis, tachycardia, tinnitus, urinary incontinence, urinary tract infection, and vaginitis.The following events were reported rarely in treated Sjogrens patients (< 1%) at dosing of 10 mg/day to 30 mg/day: Causal relation is unknown.Body as whole: chest pain, cyst, death, moniliasis, neck pain, neck rigidity, photosensitivity reactionCardiovascular: angina pectoris, arrhythmia, ECG abnormality, hypotension, hypertension, intracranial hemorrhage, migraine, myocardial infarctionDigestive: anorexia, bilirubinemia, cholelithiasis, colitis, dry mouth, eructation, gastritis, gastroenteritis, gastrointestinal disorder, gingivitis, hepatitis, abnormal liver function tests, melena, nausea vomiting, pancreatitis, parotid gland enlargement, salivary gland enlargement, sputum increased, taste loss, tongue disorder, tooth disorderHematologic: hematuria, lymphadenopathy, abnormal platelets, thrombocythemia, thrombocytopenia, thrombosis, abnormal WBCMetabolic and Nutritional: peripheral edema, hypoglycemiaMusculoskeletal: arthralgia, arthritis, bone disorder, spontaneous bone fracture, pathological fracture, myasthenia, tendon disorder, tenosynovitisNervous: aphasia, confusion, depression, abnormal dreams, emotional lability, hyperkinesia, hypesthesia, insomnia, leg cramps, nervousness, paresthesias, abnormal thinking, tremorRespiratory: bronchitis, dyspnea, hiccup, laryngismus, laryngitis, pneumonia, viral infection, voice alterationSkin: alopecia, contact dermatitis, dry skin, eczema, erythema nodosum, exfoliative dermatitis, herpes simplex, skin ulcer, vesiculobullous rashSpecial Senses: cataract, conjunctivitis, dry eyes, ear disorder, ear pain, eye disorder, eye hemorrhage, glaucoma, lacrimation disorder, retinal disorder, taste perversion, abnormal visionUrogenital: breast pain, dysuria, mastitis, menorrhagia, metrorrhagia, ovarian disorder, pyuria, salpingitis, urethral pain, urinary urgency, vaginal hemorrhage, vaginal moniliasisThe following adverse experiences have been reported rarely with ocular pilocarpine: A-V block, agitation, ciliary congestion, confusion, delusion, depression, dermatitis, middle ear disturbance, eyelid twitching, malignant glaucoma, iris cysts, macular hole, shock, and visual hallucination.To report SUSPECTED ADVERSE REACTIONS, contact Amneal Pharmaceuticals at 1-877-835-5472 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

Carcinogenesis,Mutagenesis, Impairment of Fertility. Lifetime oral carcinogenicity studies were conducted in CD-1 mice and Sprague-Dawley rats. Pilocarpine did not induce tumors in mice at any dosage studied (up to 30 mg/kg/day, which yielded systemic exposure approximately 50 times larger than the maximum systemic exposure observed clinically). In rats, dosage of 18 mg/kg/day, which yielded systemic exposure approximately 100 times larger than the maximum systemic exposure observed clinically, resulted in statistically significant increase in the incidence of benign pheochromocytomas in both males and females, and statistically significant increase in the incidence of hepatocellular adenomas in female rats. The tumorigenicity observed in rats was observed only at large multiple of the maximum labeled clinical dose, and may not be relevant to clinical use.No evidence that pilocarpine has the potential to cause genetic toxicity was obtained in series of studies that included: 1) bacterial assays (Salmonella and E. coli) for reverse gene mutations; 2) an in vitro chromosome aberration assay in Chinese hamster ovary cell line; 3) an in vivo chromosome aberration assay (micronucleus test) in mice; and 4) primary DNA damage assay (unscheduled DNA synthesis) in rat hepatocyte primary cultures.Oral administration of pilocarpine to male and female rats at dosage of 18 mg/kg/day, which yielded systemic exposure approximately 100 times larger than the maximum systemic exposure observed clinically, resulted in impaired reproductive function, including reduced fertility, decreased sperm motility, and morphologic evidence of abnormal sperm. It is unclear whether the reduction in fertility was due to effects on male animals, female animals, or both males and females. In dogs, exposure to pilocarpine at dosage of mg/kg/day (approximately times the maximum recommended human dose when compared on the basis of body surface area (mg/m2) estimates) for six months resulted in evidence of impaired spermatogenesis. The data obtained in these studies suggest that pilocarpine may impair the fertility of male and female humans. Pilocarpine hydrochloride tablets should be administered to individuals who are attempting to conceive child only if the potential benefit justifies potential impairment of fertility.

CLINICAL PHARMACOLOGY SECTION.

CLINICAL PHARMACOLOGY. Pharmacodynamics. Pilocarpine is cholinergic parasympathomimetic agent exerting 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 single-dose it causes miosis, spasm of accommodation, and may cause transitory rise in intraocular pressure followed by 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 muscarinic agonist is vasodepression, but administration of pilocarpine may produce hypertension after brief episode of hypotension. Bradycardia and tachycardia have both been reported with use of pilocarpine.In study of 12 healthy male volunteers there was dose-related increase in unstimulated salivary flow following single mg 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 peak effect at hour with duration of to hours (see Pharmacokinetics section).Head Neck Cancer Patients: In 12 week randomized, double-blind, placebo-controlled study in 207 patients (placebo, N=65; 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 mg (63%) and 10 mg (90%) tablet, respectively, were seen 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 to 0.414 and -0.070 to 1.002 mL/min for the mg 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.Sjogrens Syndrome Patients: In two 12 week randomized, double-blind, placebo-controlled studies in 629 patients (placebo, N=253; 2.5 mg, N=121; mg, N=255; mg to 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 mg to 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 multiple-dose pharmacokinetic study in male volunteers following days of mg or 10 mg of oral pilocarpine hydrochloride tablets given at a.m., noontime, and p.m., the mean elimination half-life was 0.76 hours for the 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 mg and 10 mg doses following the last 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 high fat meal by 12 healthy male volunteers, there was decrease in the rate of absorption of pilocarpine from pilocarpine hydrochloride tablets. Mean Tmaxs were 1.47 and 0.87 hours, and mean Cmaxs 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 concentration range of 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 single mg dose resulted in 30% decrease in total plasma clearance and 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 to 40.8 mL/min) compared to the pharmacokinetics previously observed in normal volunteers.. CLINICALSTUDIES. Head Neck Cancer Patients. 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 range of 19 to 77; the racial distribution was Caucasian 95%, Black 4%, and other 1%. In this population, statistically significant improvement in mouth dryness occurred in the mg and 10 mg pilocarpine hydrochloride tablet treated patients compared to placebo treated patients. The mg 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 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 day of pilocarpine hydrochloride tablets for weeks followed by adjustment to mg three times day and 10 mg three times day. Lowering of the dose was necessary because of adverse events in of 67 patients treated with mg of pilocarpine hydrochloride tablets and in of 66 patients treated with 10 mg of pilocarpine hydrochloride tablets. After weeks of treatment, 2.5 mg of pilocarpine hydrochloride tablets three times day was comparable to placebo in relieving dryness. In patients treated with 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 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%).. Sjogrens syndrome Patients. Two separate studies were conducted in patients with primary or secondary Sjogrens Syndrome. In both studies, the majority of patients best fit the European criteria for having primary Sjogrens Syndrome. [Criteria for the Classification of Sjogrens Syndrome (Vitali C, Bombardieri S, Moutsopoulos HM, et al: Preliminary criteria for the classification of Sjogrens Syndrome. Arthritis Rheum 1993; 36:340-347.)]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 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 mg four times day (20 mg/day) for weeks. At weeks, the patients dosage was increased from mg pilocarpine hydrochloride tablets q.i.d. to 7.5 mg q.i.d. The data collected during the first weeks of the trial were evaluated for safety and efficacy, and the data of the second weeks of the trial were used to provide additional evidence of safety.After weeks of treatment, statistically significant global improvement of dry mouth was observed compared to placebo. Global improvement is defined as score of 55 mm or more on 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 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 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, mg pilocarpine hydrochloride tablets, and placebo. All treatments were administered on four times day regimen.After 12 weeks of treatment, statistically significant global improvement of dry mouth was observed at dose of mg compared with placebo. The 2.5 mg (10 mg/day) group was not significantly different than placebo. However, subgroup of patients with rheumatoid arthritis tended to improve in global assessments at both the 2.5 mg q.i.d. (9 patients) and mg q.i.d. (16 patients) dose (10 mg/day to 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 weeks and 12 weeks of pilocarpine hydrochloride tablets use.

CLINICAL STUDIES SECTION.

CLINICALSTUDIES. Head Neck Cancer Patients. 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 range of 19 to 77; the racial distribution was Caucasian 95%, Black 4%, and other 1%. In this population, statistically significant improvement in mouth dryness occurred in the mg and 10 mg pilocarpine hydrochloride tablet treated patients compared to placebo treated patients. The mg 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 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 day of pilocarpine hydrochloride tablets for weeks followed by adjustment to mg three times day and 10 mg three times day. Lowering of the dose was necessary because of adverse events in of 67 patients treated with mg of pilocarpine hydrochloride tablets and in of 66 patients treated with 10 mg of pilocarpine hydrochloride tablets. After weeks of treatment, 2.5 mg of pilocarpine hydrochloride tablets three times day was comparable to placebo in relieving dryness. In patients treated with 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 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%).. Sjogrens syndrome Patients. Two separate studies were conducted in patients with primary or secondary Sjogrens Syndrome. In both studies, the majority of patients best fit the European criteria for having primary Sjogrens Syndrome. [Criteria for the Classification of Sjogrens Syndrome (Vitali C, Bombardieri S, Moutsopoulos HM, et al: Preliminary criteria for the classification of Sjogrens Syndrome. Arthritis Rheum 1993; 36:340-347.)]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 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 mg four times day (20 mg/day) for weeks. At weeks, the patients dosage was increased from mg pilocarpine hydrochloride tablets q.i.d. to 7.5 mg q.i.d. The data collected during the first weeks of the trial were evaluated for safety and efficacy, and the data of the second weeks of the trial were used to provide additional evidence of safety.After weeks of treatment, statistically significant global improvement of dry mouth was observed compared to placebo. Global improvement is defined as score of 55 mm or more on 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 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 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, mg pilocarpine hydrochloride tablets, and placebo. All treatments were administered on four times day regimen.After 12 weeks of treatment, statistically significant global improvement of dry mouth was observed at dose of mg compared with placebo. The 2.5 mg (10 mg/day) group was not significantly different than placebo. However, subgroup of patients with rheumatoid arthritis tended to improve in global assessments at both the 2.5 mg q.i.d. (9 patients) and mg q.i.d. (16 patients) dose (10 mg/day to 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 weeks and 12 weeks of pilocarpine hydrochloride tablets use.

GENERAL PRECAUTIONS SECTION.

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 mg twice daily, followed by adjustment based on therapeutic response and tolerability. Patients with mild hepatic insufficiency (Child-Pugh score of to 6) do not require dosage reductions. To date, pharmacokinetic studies in subjects with severe hepatic impairment (Child-Pugh score of 10 to 15) have not been carried out. The use of pilocarpine in these patients is not recommended.Child-Pugh Scoring System for Hepatic ImpairmentClinical and Biochemical MeasurementsPoints Scored for Increasing Abnormality123Encephalopathy (grade)None1 and 23 and 4AscitesAbsentSlightModerateBilirubin (mg per 100 mL)1 to 22 to 3> 3Albumin (g per 100 mL)3 to 52.8 to 3.5< 2.8Prothrombin Time (sec. Prolonged)1 to 44 to 6> For Primary Biliary Cirrhosis:-Bilirubin (mg per 100 mL)1 to 44 to 10> 10According to grading of Trey C, Burns D, and Saunders S. Treatment of hepatic coma by exchange blood transfusion. Engl Med. 1966; 274:473-481.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.

PHARMACODYNAMICS SECTION.

Pharmacodynamics. Pilocarpine is cholinergic parasympathomimetic agent exerting 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 single-dose it causes miosis, spasm of accommodation, and may cause transitory rise in intraocular pressure followed by 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 muscarinic agonist is vasodepression, but administration of pilocarpine may produce hypertension after brief episode of hypotension. Bradycardia and tachycardia have both been reported with use of pilocarpine.In study of 12 healthy male volunteers there was dose-related increase in unstimulated salivary flow following single mg 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 peak effect at hour with duration of to hours (see Pharmacokinetics section).Head Neck Cancer Patients: In 12 week randomized, double-blind, placebo-controlled study in 207 patients (placebo, N=65; 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 mg (63%) and 10 mg (90%) tablet, respectively, were seen 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 to 0.414 and -0.070 to 1.002 mL/min for the mg 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.Sjogrens Syndrome Patients: In two 12 week randomized, double-blind, placebo-controlled studies in 629 patients (placebo, N=253; 2.5 mg, N=121; mg, N=255; mg to 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 mg to 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 SECTION.

Pharmacokinetics. In multiple-dose pharmacokinetic study in male volunteers following days of mg or 10 mg of oral pilocarpine hydrochloride tablets given at a.m., noontime, and p.m., the mean elimination half-life was 0.76 hours for the 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 mg and 10 mg doses following the last 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 high fat meal by 12 healthy male volunteers, there was decrease in the rate of absorption of pilocarpine from pilocarpine hydrochloride tablets. Mean Tmaxs were 1.47 and 0.87 hours, and mean Cmaxs 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 concentration range of 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 single mg dose resulted in 30% decrease in total plasma clearance and 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 to 40.8 mL/min) compared to the pharmacokinetics previously observed in normal volunteers.

PRECAUTIONS SECTION.

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 mg twice daily, followed by adjustment based on therapeutic response and tolerability. Patients with mild hepatic insufficiency (Child-Pugh score of to 6) do not require dosage reductions. To date, pharmacokinetic studies in subjects with severe hepatic impairment (Child-Pugh score of 10 to 15) have not been carried out. The use of pilocarpine in these patients is not recommended.Child-Pugh Scoring System for Hepatic ImpairmentClinical and Biochemical MeasurementsPoints Scored for Increasing Abnormality123Encephalopathy (grade)None1 and 23 and 4AscitesAbsentSlightModerateBilirubin (mg per 100 mL)1 to 22 to 3> 3Albumin (g per 100 mL)3 to 52.8 to 3.5< 2.8Prothrombin Time (sec. Prolonged)1 to 44 to 6> For Primary Biliary Cirrhosis:-Bilirubin (mg per 100 mL)1 to 44 to 10> 10According to grading of Trey C, Burns D, and Saunders S. Treatment of hepatic coma by exchange blood transfusion. Engl Med. 1966; 274:473-481.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.. Information for Patients. Patients should be informed that pilocarpine may cause visual disturbances, especially at night, that could impair their ability to drive safely.If patient sweats excessively while taking pilocarpine hydrochloride and cannot drink enough liquid, the patient should consult physician. Dehydration may develop.. Drug Interactions. Pilocarpine should be administered with caution to patients taking beta-adrenergic antagonists because of the possibility of conduction disturbances. Drugs with parasympathomimetic effects administered concurrently with pilocarpine would be expected to result in additive pharmacologic effects. Pilocarpine might antagonize the anticholinergic effects of drugs used concomitantly. These effects should be considered when anticholinergic properties may be contributing to the therapeutic effect of concomitant medication (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 Sjogrens efficacy studies: acetylsalicylic acid, artificial tears, calcium, conjugated estrogens, hydroxychloroquine sulfate, ibuprofen, levothyroxine sodium, medroxyprogesterone acetate, methotrexate, multivitamins, naproxen, omeprazole, paracetamol, and prednisone.. Carcinogenesis,Mutagenesis, Impairment of Fertility. Lifetime oral carcinogenicity studies were conducted in CD-1 mice and Sprague-Dawley rats. Pilocarpine did not induce tumors in mice at any dosage studied (up to 30 mg/kg/day, which yielded systemic exposure approximately 50 times larger than the maximum systemic exposure observed clinically). In rats, dosage of 18 mg/kg/day, which yielded systemic exposure approximately 100 times larger than the maximum systemic exposure observed clinically, resulted in statistically significant increase in the incidence of benign pheochromocytomas in both males and females, and statistically significant increase in the incidence of hepatocellular adenomas in female rats. The tumorigenicity observed in rats was observed only at large multiple of the maximum labeled clinical dose, and may not be relevant to clinical use.No evidence that pilocarpine has the potential to cause genetic toxicity was obtained in series of studies that included: 1) bacterial assays (Salmonella and E. coli) for reverse gene mutations; 2) an in vitro chromosome aberration assay in Chinese hamster ovary cell line; 3) an in vivo chromosome aberration assay (micronucleus test) in mice; and 4) primary DNA damage assay (unscheduled DNA synthesis) in rat hepatocyte primary cultures.Oral administration of pilocarpine to male and female rats at dosage of 18 mg/kg/day, which yielded systemic exposure approximately 100 times larger than the maximum systemic exposure observed clinically, resulted in impaired reproductive function, including reduced fertility, decreased sperm motility, and morphologic evidence of abnormal sperm. It is unclear whether the reduction in fertility was due to effects on male animals, female animals, or both males and females. In dogs, exposure to pilocarpine at dosage of mg/kg/day (approximately times the maximum recommended human dose when compared on the basis of body surface area (mg/m2) estimates) for six months resulted in evidence of impaired spermatogenesis. The data obtained in these studies suggest that pilocarpine may impair the fertility of male and female humans. Pilocarpine hydrochloride tablets should be administered to individuals who are attempting to conceive child only if the potential benefit justifies potential impairment of fertility.. Pregnancy: Teratogenic Effects. Pregnancy Category C: Pilocarpine was associated with reduction in the mean fetal body weight and an increase in the incidence of skeletal variations when given to pregnant rats at dosage of 90 mg/kg/day (approximately 26 times the maximum recommended dose for 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 dosage of 36 mg/kg/day (approximately 10 times the maximum recommended dose for 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 times the maximum recommended dose for 50 kg human when compared on the basis of body surface area (mg/m2) estimates) and above. There are no adequate and well-controlled studies in pregnant women. Pilocarpine hydrochloride tablets should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.. Nursing Mothers. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from pilocarpine hydrochloride tablets, decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.. Pediatric Use. Safety and effectiveness in pediatric patients have not been established.. Geriatric Use. Head and Neck Cancer Patients: In the placebo-controlled clinical trials (see Clinical Studies section) the mean age of patients was approximately 58 years (range 19 to 80). Of these patients, 97/369 (61/217 receiving pilocarpine) were over the age of 65 years. In the healthy volunteer studies, 15/150 subjects were over the age of 65 years. In both study populations, the adverse events reported by those over 65 years and those 65 years and younger were comparable. Of the 15 elderly volunteers (5 women, 10 men), the women had higher Cmaxs and AUCs than the men (see Pharmacokinetics section).Sjogrens Syndrome Patients: In the placebo-controlled clinical trials (see Clinical Studies section), the mean age of patients was approximately 55 years (range 21 to 85). The adverse events reported by those over 65 years and those 65 years and younger were comparable except for notable trends for urinary frequency, diarrhea, and dizziness (see ADVERSE REACTIONS section).

SPL UNCLASSIFIED SECTION.

Head Neck Cancer Patients. 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 range of 19 to 77; the racial distribution was Caucasian 95%, Black 4%, and other 1%. In this population, statistically significant improvement in mouth dryness occurred in the mg and 10 mg pilocarpine hydrochloride tablet treated patients compared to placebo treated patients. The mg 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 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 day of pilocarpine hydrochloride tablets for weeks followed by adjustment to mg three times day and 10 mg three times day. Lowering of the dose was necessary because of adverse events in of 67 patients treated with mg of pilocarpine hydrochloride tablets and in of 66 patients treated with 10 mg of pilocarpine hydrochloride tablets. After weeks of treatment, 2.5 mg of pilocarpine hydrochloride tablets three times day was comparable to placebo in relieving dryness. In patients treated with 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 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%).