Pilocarpine Hydrochloride

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.

DOSAGE AND ADMINISTRATION Regardless of the indication, the starting dose in patients with moderate hepatic impairment should be 5 mg twice daily, followed by adjustment based on therapeutic response and tolerability. Patients with mild hepatic insufficiency do not require dosage reductions. The use of pilocarpine in patients with severe hepatic insufficiency is not recommended. If needed, refer to the Hepatic Insufficiency subsection of the Precautions section of this label for definitions of mild, moderate and severe hepatic impairment. Head & Neck Cancer Patients The recommended initial dose of pilocarpine hydrochloride tablets is 5 mg taken three times a day. Dosage should be titrated according to therapeutic response and tolerability. The usual dosage range is up to 15 mg per day to 30 mg per day (Not to exceed 10 mg per dose). Although early improvement may be realized, at least 12 weeks of uninterrupted therapy with pilocarpine hydrochloride tablets may be necessary to assess whether a beneficial response will be achieved. The incidence of the most common adverse events increases with dose. The lowest dose that is tolerated and effective should be used for maintenance. Sjogren’s syndrome Patients The recommended dose of pilocarpine hydrochloride tablets is one tablet (5 mg) taken four times a day. Efficacy was established by 6 weeks of use.

CONTRAINDICATIONS Pilocarpine hydrochloride tablets, USP 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.

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 a consequence of the expected pharmacologic effects of pilocarpine. Adverse Event Pilocarpine HCl Placebo 10 mg t.i.d. 5 mg t.i.d. (t.i.d.) (30 mg/day) (15 mg/day) N=121 N=141 N=152 Sweating 68% 29% 9% Nausea 15 6 4 Rhinitis 14 5 7 Diarrhea 7 4 5 Chills 15 3 <1 Flushing 13 8 3 Urinary Frequency 12 9 7 Dizziness 12 5 4 Asthenia 12 6 3 In addition, the following adverse events (≥3% incidence) were reported at dosages of 15-30 mg/day in the controlled clinical trials: Adverse Event Pilocarpine HCl Placebo 5-10 mg t.i.d. (t.i.d.) (15-30 mg/day) N=212 N=152 Headache 11% 8% Dyspepsia 7 5 Lacrimation 6 8 Edema 5 4 Abdominal Pain 4 4 Amblyopia 4 2 Vomiting 4 1 Pharyngitis 3 8 Hypertension 3 1 The following events were reported with treated head and neck cancer patients at incidences of 1% to 2% at dosages of 7.5 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 a whole: body odor, hypothermia, mucous membrane abnormality Cardiovascular: bradycardia, ECG abnormality, palpitations, syncope Digestive: anorexia, increased appetite, esophagitis, gastrointestinal disorder, tongue disorder Hematologic: leukopenia, lymphadenopathy Nervous: anxiety, confusion, depression, abnormal dreams, hyperkinesia, hypesthesia, nervousness, paresthesias, speech disorder, twitching Respiratory: increased sputum, stridor, yawning Skin: seborrhea Special senses: deafness, eye pain, glaucoma Urogenital: dysuria, metrorrhagia, urinary impairment In long-term treatment were two patients with underlying cardiovascular disease of whom one experienced a myocardial infarct and another an episode of syncope. The association with drug is uncertain. Sjogren's 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 of 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 2 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 Event Pilocarpine HCl Placebo 5 mg q.i.d. (q.i.d.) (20 mg/day) N=255 N=253 Sweating 40% 7% Urinary Frequency 10 4 Nausea 9 9 Flushing 9 2 Rhinitis 7 8 Diarrhea 6 7 Chills 4 2 Increased Salivation 3 0 Asthenia 2 2 In addition, the following adverse events (≥3% incidence) were reported at dosages of 20 mg/day in the controlled clinical trials: Adverse Event P …

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 Sjogren's efficacy studies: acetylsalicylic acid, artificial tears, calcium, conjugated estrogens, hydroxychloroquine sulfate, ibuprofen, levothyroxine sodium, medroxyprogesterone acetate, methotrexate, multivitamins, naproxen, omeprazole, paracetamol, and prednisone.

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(3 H )-Furanone, 3-ethyldihydro-4-[(1-methyl-1 H -imidazol-5-yl)methyl]monohydrochloride, has a molecular weight of 244.72. 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. Chemical Structure

Management of Overdose: Fatal overdosage with pilocarpine has been reported in the scientific literature at doses presumed to be greater than 100 mg in two hospitalized patients. 100 mg of pilocarpine is considered potentially fatal. 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. Epinephrine (0.3 mg to 1.0 mg, subcutaneously or intramuscularly) may also be of value in the presence of severe cardiovascular depression or bronchoconstriction. It is not known if pilocarpine is dialyzable. To report SUSPECTED ADVERSE REACTIONS contact AvKARE at 1-855-361-3993; email drugsafety@avkare.com; or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

HOW SUPPLIED Pilocarpine Hydrochloride Tablets, USP 5 mg are off white to white colour, biconvex round shaped film-coated tablet debossed with “PIL” on one side and “5” on the other side. Each tablet contains 5 mg pilocarpine hydrochloride USP. They are supplied as follows: Bottles of 100 NDC 59651-224-01 Pilocarpine Hydrochloride Tablets, USP 7.5 mg are light blue to blue colour, biconvex round shaped film-coated tablet debossed with “PIL” on one side and “7.5” on the other side. Each tablet contains 7.5 mg pilocarpine hydrochloride USP. They are supplied as follows: Bottles of 100 NDC 59651-225-01 Store at 20 o to 25 o C (68 o to 77 o F) [see USP Controlled Room Temperature]. Distributed by: Aurobindo Pharma USA, Inc. 279 Princeton-Hightstown Road East Windsor, NJ 08520 Manufactured by: Aurobindo Pharma Limited Hyderabad-500 038, India Revised: 09/2019