PILOCARPINE: 1,782 Adverse Event Reports & Safety Profile

Pilocarpine hydrochloride ophthalmic solution, USP is a cholinergic agonist prepared as a sterile topical ophthalmic solution. The active ingredient is represented by the chemical structure: Established Name: pilocarpine hydrochloride, USP Chemical Name: 2(3 H )-furanone, 3-ethyldihydro-4-[(1-methyl-1 H -imidazol-5-yl)-methyl]-monohydrochloride, (3S- cis ).

Molecular

Formula: C 11 H 16 N 2 O 2

• HCl Molecular Weight:

244.72 Pilocarpine hydrochloride, USP is a white or almost white, crystalline powder or colorless crystals hygroscopic. It is very soluble in water, freely soluble in alcohol, slightly soluble in chloroform and insoluble in ether. Each mL of pilocarpine hydrochloride ophthalmic solution, USP contains: Active: pilocarpine hydrochloride, USP 1% (10 mg/mL), 2% (20 mg/mL), or 4% (40 mg/mL). Preservative: benzalkonium chloride 0.01%. Inactives: 0.5% hypromellose 2910; boric acid; sodium citrate; sodium chloride (present in 1% product only); hydrochloric acid and/or sodium hydroxide (to adjust pH); water for injection. Pilocarpine hydrochloride ophthalmic solution, USP has a pH of 3.5 to 5.5 and an osmolality of 270 to 350 mOsm/kg (1% product), 290 to 350 mOsm/kg (2% product) and 500 to 600 mOsm/kg (4% product). ab

AND USAGE Pilocarpine hydrochloride ophthalmic solution is indicated for the: Pilocarpine hydrochloride ophthalmic solution is a muscarinic cholinergic agonist indicated for:

• The reduction of elevated intraocular pressure (IOP) in patients with open-angle glaucoma or ocular hypertension. ( 1.1 )
• The management of acute angle-closure glaucoma. ( 1.2 )
• The prevention of postoperative elevated IOP associated with laser surgery. ( 1.3 )
• The induction of miosis. ( 1.4 )

1.1 Reduction of Elevated Intraocular Pressure (IOP) in Patients With Open-Angle Glaucoma or Ocular Hypertension .

1.2 Management of Acute Angle-Closure Glaucoma .

1.3 Prevention of Postoperative Elevated IOP Associated With Laser Surgery .

1.4 Induction of Miosis .

AND ADMINISTRATION Instill one drop in the eye(s) up to four times daily (2).

2.1 Reduction of Elevated Intraocular Pressure (IOP) in Patients with Open-Angle Glaucoma or Ocular Hypertension One drop of pilocarpine hydrochloride ophthalmic solution 1%, 2% or 4% should be applied topically in the eye(s) up to four times daily. Pilocarpine-naïve patients should be started on the 1% concentration as higher concentrations are often not tolerated initially. The frequency of instillation and concentration of pilocarpine hydrochloride ophthalmic solution are determined by the severity of the elevated intraocular pressure and miotic response of the patient. To limit systemic exposure to pilocarpine, patients may be instructed to perform punctal occlusion for 2 minutes after instillation of pilocarpine hydrochloride ophthalmic solution.

2.2 Management of Acute Angle-Closure Glaucoma Prior to pilocarpine hydrochloride ophthalmic solution use, treatment with secretory suppressants and hyperosmotic agents may be needed to lower IOP below 50 mmHg and relieve iris ischemia. For initial management of acute angle-closure glaucoma, one drop of pilocarpine hydrochloride ophthalmic solution 1% or 2% may be applied topically in the eye(s) up to three times over a 30-minute period. If laser iridoplasty or iridomy is used to break the attack, one drop of pilocarpine hydrochloride ophthalmic solution 4% should be administered prior to the procedure. Following laser iridoplasty, one drop of pilocarpine hydrochloride ophthalmic solution 1% should be administered four times daily until an iridotomy can be performed.

2.3 Prevention of Postoperative Elevated IOP Associated with Laser Surgery One drop of pilocarpine hydrochloride ophthalmic solution 1%, 2% or 4% (or two drops administered five minutes apart) should be applied topically in the eye(s) 15 to 60 minutes prior to surgery.

2.4 Induction of Miosis One drop of pilocarpine hydrochloride ophthalmic solution 1%, 2% or 4% (or two drops administered five minutes apart) should be applied topically in the eye(s).

2.5 Use with Other Topical Ophthalmic Medications Pilocarpine hydrochloride ophthalmic solution may be used in combination with beta-blockers, carbonic anhydrase inhibitors, sympathomimetics or hyperosmotic agents. If more than one topical ophthalmic drug is being used, the drugs should be administered at least five (5) minutes apart.

2.6 Use in Pediatric Patients In children under 2 years of age, one drop of pilocarpine hydrochloride ophthalmic solution 1% should be applied topically in the eye(s) three times daily.

Children

2 years of age and over should be dosed as for adults. For the induction of miosis prior to goniotomy or trabeculotomy in children, one drop of pilocarpine hydrochloride ophthalmic solution 1% or 2% should be applied topically in the eye 15 to 60 minutes prior to surgery.

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 Pilocarpine HCl Placebo 5 mg q.i.d. (q.i.d.) (20 mg/day) N=255 N=253 Headache 13% 19% Flu Syndrome 9 9 Dyspepsia 7 7 Dizziness 6 7 Pain 4 2 Sinusitis 4 5 Abdominal Pain 3 4 Vomiting 3 1 Pharyngitis 2 5 Rash 2 3 Infection 2 6 The following events were reported in Sjogren's 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 Sjogren's patients (<1%) at dosing of 10-30 mg/day: Causal relation is unknown. Body as a whole: chest pain, cyst, death, moniliasis, neck pain, neck rigidity, photosensitivity reaction Cardiovascular: angina pectoris, arrhythmia, ECG abnormality, hypotension, hypertension, intracranial hemorrhage, migraine, myocardial infarction Digestive: 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 disorder Hematologic: hematuria, lymphadenopathy, abnormal platelets, thrombocythemia, thrombocytopenia, thrombosis, abnormal WBC Metabolic and Nutritional: peripheral edema, hypoglycemia Musculoskeletal: arthralgia, arthritis, bone disorder, spontaneous bone fracture, pathological fracture, myasthenia, tendon disorder, tenosynovitis Nervous: aphasia, confusion, depression, abnormal dreams, emotional lability, hyperkinesia, hypesthesia, insomnia, leg cramps, nervousness, paresthesias, abnormal thinking, tremor Respiratory: bronchitis, dyspnea, hiccup, laryngismus, laryngitis, pneumonia, viral infection, voice alteration Skin: alopecia, contact dermatitis, dry skin, eczema, erythema nodosum, exfoliative dermatitis, herpes simplex, skin ulcer, vesiculobullous rash Special Senses: cataract, conjunctivitis, dry eyes, ear disorder, ear pain, eye disorder, eye hemorrhage, glaucoma, lacrimation disorder, retinal disorder, taste perversion, abnormal vision Urogenital: breast pain, dysuria, mastitis, menorrhagia, metrorrhagia, ovarian disorder, pyuria, salpingitis, urethral pain, urinary urgency, vaginal hemorrhage, vaginal moniliasis The 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 Concordia Pharmaceuticals at 1-877-370-1142 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch MANAGMENT 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.

AND PRECAUTIONS Blurred Vision : Patients should be advised not to drive or operate machinery if vision is not clear (e.g., blurred vision). Exercise caution in night driving and other hazardous activities in poor illumination. ( 5.1 ) Risk of Retinal Detachment : Rare cases of retinal detachment and retinal tear have been reported with miotics, including pilocarpine hydrochloride ophthalmic solution. Individuals with pre-existing retinal disease are at increased risk. Therefore, examination of the retina is advised in all patients prior to initiation of therapy. Patients should be advised to seek immediate medical care with sudden onset of flashing lights, floaters or vision loss. ( 5.2 ) Iritis : Caution is advised in patients with iritis. ( 5.3 )

5.1 Blurred Vision Miotics, including pilocarpine hydrochloride ophthalmic solution, may cause accommodative spasm. Patients should be advised not to drive or operate machinery if vision is not clear (e.g., blurred vision). In addition, patients may experience temporary dim or dark vision with miotics, including pilocarpine hydrochloride ophthalmic solution. Patients should be advised to exercise caution in night driving and other hazardous activities in poor illumination.

5.2 Risk of Retinal Detachment Rare cases of retinal detachment and retinal tear have been reported with miotics, including pilocarpine hydrochloride ophthalmic solution. Individuals with pre-existing retinal disease are at increased risk. Therefore, examination of the retina is advised in all patients prior to the initiation of therapy. Patients should be advised to seek immediate medical care with sudden onset of flashing lights, floaters or vision loss.

5.3 Iritis Pilocarpine hydrochloride ophthalmic solution is not recommended to be used when iritis is present because adhesions (synechiae) may form between the iris and the lens.

5.4 Use with Contact Lenses Contact lens wearers should be advised to remove their lenses prior to the instillation of pilocarpine hydrochloride ophthalmic solution and to wait 10 minutes after dosing before reinserting their contact lenses.

5.5 Potential for Eye Injury or Contamination To prevent eye injury or contamination, care should be taken to avoid touching the dispensing bottle to the eye or to any other surface.

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 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 Impairment 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 to 2 2 to 3 > 3 Albumin (g per 100 mL) 3 to 5 2.8 to 3.5 <

2.8 Prothrombin Time (sec. Prolonged) 1 to 4 4 to 6 &gt; 6 For Primary Biliary Cirrhosis:-Bilirubin (mg per 100 mL) 1 to 4 4 to 10 &gt; 10 *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 to 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 to 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 a patient sweats excessively while taking pilocarpine hydrochloride and cannot drink enough liquid, the patient should consult a 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 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. 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 a systemic exposure approximately 50 times larger than the maximum systemic exposure observed clinically). In rats, a dosage of 18 mg/kg/day, which yielded a systemic exposure approximately 100 times larger than the maximum systemic exposure observed clinically, resulted in a statistically significant increase in the incidence of benign pheochromocytomas in both males and females, and a statistically significant increase in the incidence of hepatocellular adenomas in female rats. The tumorigenicity observed in rats was observed only at a 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 a series of studies that included: 1) bacterial assays ( Salmonella and E. coli ) for reverse gene mutations; 2) an in vitro chromosome aberration assay in a Chinese hamster ovary cell line; 3) an in vivo chromosome aberration assay (micronucleus test) in mice; and 4) a primary DNA damage assay (unscheduled DNA synthesis) in rat hepatocyte primary cultures. Oral administration of pilocarpine to male and female rats at a dosage of 18 mg/kg/day, which yielded a 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 a dosage of 3 mg/kg/day (approximately 3 times the maximum recommended human dose when compared on the basis of body surface area (mg/m 2 ) 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 a child only if the potential benefit justifies potential impairment of fertility. 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.

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 5 women had higher C max’s and AUC’s than the men (see Pharmacokinetics section). Sjogren’s 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).

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.