Pilocarpine Hydrochloride

INDICATIONS AND USAGE Pilocarpine hydrochloride tablets are indicated for: The treatment of symptoms of dry mouth from salivary gland hypofunction caused by radiotherapy for cancer of the head and neck. 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.

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.

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.

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.

Pregnancy: Teratogenic Effects 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/m 2 ) 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/m 2 ) 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/m 2 ) 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, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

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 Hydrochloride Placebo 10 mg three times a day (30 mg/day) 5 mg three times a day (15 mg/day) (three times a day) Sweating N = 121/68% N = 141/29% N= 152/9% 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 mg/day to 30 mg/day in the controlled clinical trials: Adverse Event Pilocarpine Hydrochloride Placebo 5 mg to 10 mg three times a day (15 mg/day to 30 mg/day) (three times a day) Headache N = 212/11% N = 152/8% 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 mg/day to 30 mg/day: abnormal vision, conjunctivitis, dysphagia, epistaxis, myalgias, pruritus, rash, sinusitis, tachycardia, taste perversion, tremor, and 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 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 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 hydrochloride Placebo 5 mg four times a day (20 mg/day) (four times a day) N=253 Sweating N = 255/40% N = 253/7% Urinary Frequency 10 4 Nausea 9 9 Flushing 9 2 Rhinitis 7 8 Diarrhea 6 7 Chills 4 2 Increased Salivation 3 0 …