Cevimeline Hydrochloride

INDICATIONS AND USAGE Cevimeline hydrochloride capsules are indicated for the treatment of symptoms of dry mouth in patients with Sjögren’s Syndrome.

DOSAGE AND ADMINISTRATION The recommended dose of cevimeline hydrochloride capsules is 30 mg taken three times a day. There is insufficient safety information to support doses greater than 30 mg tid. There is also insufficient evidence for additional efficacy of cevimeline hydrochloride at doses greater than 30 mg tid.

ADVERSE REACTIONS Cevimeline was administered to 1,777 patients during clinical trials worldwide, including Sjögren’s patients and patients with other conditions. In placebo-controlled Sjögren’s studies in the U.S., 320 patients received cevimeline doses ranging from 15 mg tid to 60 mg tid, of whom 93% were women and 7% were men. Demographic distribution was 90% Caucasian, 5% Hispanic, 3% Black and 2% of other origin. In these studies, 14.6% of patients discontinued treatment with cevimeline due to adverse events. The following adverse events associated with muscarinic agonism were observed in the clinical trials of cevimeline in Sjögren’s syndrome patients: Adverse Event Cevimeline 30 mg (tid) n n is the total number of patients exposed to the dose at any time during the study. = 533 Placebo (tid) n = 164 Excessive Sweating 18.7% 2.4% Nausea 13.8% 7.9% Rhinitis 11.2% 5.4% Diarrhea 10.3% 10.3% Excessive Salivation 2.2% 0.6% Urinary Frequency 0.9% 1.8% Asthenia 0.5% 0.0% Flushing 0.3% 0.6% Polyuria 0.1% 0.6% In addition, the following adverse events (≥ 3% incidence) were reported in the Sjögren’s clinical trials: Adverse Event Cevimeline 30 mg (tid) n n is the total number of patients exposed to the dose at any time during the study. = 533 Placebo (tid) n = 164 Headache 14.4% 20.1% Sinusitis 12.3% 10.9% Upper Respiratory Tract Infection 11.4% 9.1% Dyspepsia 7.8% 8.5% Abdominal Pain 7.6% 6.7% Urinary Tract Infection 6.1% 3.0% Coughing 6.1% 3.0% Pharyngitis 5.2% 5.4% Vomiting 4.6% 2.4% Injury 4.5% 2.4% Back Pain 4.5% 4.2% Rash 4.3% 6.0% Conjunctivitis 4.3% 3.6% Dizziness 4.1% 7.3% Bronchitis 4.1% 1.2% Arthralgia 3.7% 1.8% Surgical Intervention 3.3% 3.0% Fatigue 3.3% 1.2% Pain 3.3% 3.0% Skeletal Pain 2.8% 1.8% Insomnia 2.4% 1.2% Hot Flushes 2.4% 0.0% Rigors 1.3% 1.2% Anxiety 1.3% 1.2% The following events were reported in Sjögren's patients at incidences of < 3% and ≥ 1%: constipation, tremor, abnormal vision, hypertonia, peripheral edema, chest pain, myalgia, fever, anorexia, eye pain, earache, dry mouth, vertigo, salivary gland pain, pruritus, influenza-like symptoms, eye infection, post-operative pain, vaginitis, skin disorder, depression, hiccup, hyporeflexia, infection, fungal infection, sialoadenitis, otitis media, erythematous rash, pneumonia, edema, salivary gland enlargement, allergy, gastroesophageal reflux, eye abnormality, migraine, tooth disorder, epistaxis, flatulence, toothache, ulcerative stomatitis, anemia, hypoesthesia, cystitis, leg cramps, abscess, eructation, moniliasis, palpitation, increased amylase, xerophthalmia, allergic reaction. The following events were reported rarely in treated Sjögren's patients (< 1%): Causal relation is unknown: Body as a Whole Disorders : aggravated allergy, precordial chest pain, abnormal crying, hematoma, leg pain, edema, periorbital edema, activated pain trauma, pallor, changed sensation temperature, weight decrease, weight increase, choking, mouth edema, syncope, malaise, face edema, substernal chest pain Cardiovascular Disorders : abnormal ECG, heart disorder, heart murmur, aggravated hypertension, hypotension, arrhythmia, extrasystoles, t wave inversion, tachycardia, supraventricular tachycardia, angina pectoris, myocardial infarction, pericarditis, pulmonary embolism, peripheral ischemia, superficial phlebitis, purpura, deep thrombophlebitis, vascular disorder, vasculitis, hypertension Digestive Disorders : appendicitis, increased appetite, ulcerative colitis, diverticulitis, duodenitis, dysphagia, enterocolitis, gastric ulcer, gastritis, gastroenteritis, gastrointestinal hemorrhage, gingivitis, glossitis, rectum hemorrhage, hemorrhoids, ileus, irritable bowel syndrome, melena, mucositis, esophageal stricture, esophagitis, oral hemorrhage, peptic ulcer, periodontal destruction, rectal disorder, stomatitis, tenesmus, tongue discoloration, tongue disorder, geographic tongue, tongue ulceration, dental caries Endocrine Disorders : increased glucocorticoids, goiter, hypothyroidism Hematologic Disorders : thrombocytopenic purpura, thrombocythemia, thrombocytopenia, hypochromic anemia, eosinophilia, granulocytopenia, leucopenia, leukocytosis, cervical lymphadenopathy, lymphadenopathy Liver and Biliary System Disorders : cholelithiasis, increased gamma-glutamyl transferase, increased hepatic enzymes, abnormal hepatic function, viral hepatitis, increased serum glutamate oxaloacetic transaminase (SGOT) (also called AST-aspartate aminotransferase), increased serum glutamate pyruvate transaminase (SGPT) (also called ALT-alanine aminotransferase) Metabolic and Nutritional Disorders: dehydration, diabetes mellitus, hypercalcemia, hypercholesterolemia, hyperglycemia, hyperlipemia, hypertriglyceridemia, hyperuricemia, hypoglycemia, hypokalemia, hyponatremia, thirst Musculoskeletal Disorders : arthritis, aggravated arthritis, arthropathy, femoral head avascular necrosis, bone disorder, bursitis, costochondritis, plantar fasciitis, muscle weakness, osteomyelitis, osteoporosis, synovitis, tendinitis, tenosynovitis Neoplasms: basal cell carcinoma, squamous carcinoma Nervous Disorders : carpal tunnel syndrome, coma, abnormal coordination, dysesthesia, dyskinesia, dysphonia, aggravated multiple sclerosis, involuntary muscle contractions, neuralgia, neuropathy, paresthesia, speech disorder, agitation, confusion, depersonalization, aggravated depression, abnormal dreaming, emotional lability, manic reaction, paroniria, somnolence, abnormal thinking, hyperkinesia, hallucination Miscellaneous Disorders : fall, food poisoning, heat stroke, joint dislocation, post-operative hemorrhage Resistance Mechanism Disorders: cellulitis, herpes simplex, herpes zoster, bacterial infection, viral infection, genital moniliasis, sepsis Respiratory Disorders : asthma, bronchospasm, chronic obstructive airway disease, dyspnea, hemoptysis, laryngitis, nasal ulcer, pleural effusion, pleurisy, pulmonary congestion, pulmonary fibrosis, respiratory disorder Rheumatologic Disorders : aggravated rheumatoid arthritis, lupus erythematosus rash, lupus erythematosus syndrome Skin and Appendages Disorders : acne, alopecia, burn, dermatitis, contact dermatitis, lichenoid dermatitis, eczema, furunculosis, hyperkeratosis, lichen planus, nail discoloration, nail disorder, onychia, onychomycosis, paronychia, photosensitivity reaction, rosacea, scleroderma, seborrhea, skin discoloration, dry skin, skin exfoliation, skin hypertrophy, skin ulceration, urticaria, verruca, bullous eruption, cold clammy skin Special Senses Disorders: deafness, decreased hearing, motion sickness, parosmia, taste perversion, blepharitis, cataract, corneal opacity, corneal ulceration, diplopia, glaucoma, anterior chamber eye hemorrhage, keratitis, keratoconjunctivitis, mydriasis, myopia, photopsia, retinal deposits, retinal disorder, scleritis, vitreous detachment, tinnitus Urogenital Disorders: epididymitis, prostatic disorder, abnormal sexual function, amenorrhea, female breast neoplasm, malignant female breast neoplasm, female breast pain, positive cervical smear test, dysmenorrhea, endometrial disorder, intermenstrual bleeding, leukorrhea, menorrhagia, menstrual disorder, ovarian cyst, ovarian disorder, genital pruritus, uterine hemorrhage, vaginal hemorrhage, atrophic vaginitis, albuminuria, bladder discomfort, increased blood urea nitrogen, dysuria, hematuria, micturition disorder, nephrosis, nocturia, increased nonprotein nitrogen, pyelonephritis, renal calculus, abnormal renal function, renal pain, strangury, urethral disorder, abnormal urine, urinary incontinence, decreased urine flow, pyuria In one subject with lupus erythematosus receiving concomitant multiple drug therapy, a highly elevated ALT level was noted after the fourth week of cevimeline therapy. In two other subjects receiving cevimeline in the clinical trials, very high AST levels were noted. The significance of these findings is unknown. Additional adverse events (relationship unknown) which occurred in other clinical studies (patient population different from Sjögren's patients) are as follows: cholinergic syndrome, blood pressure fluctuation, cardiomegaly, postural hypotension, aphasia, convulsions, abnormal gait, hyperesthesia, paralysis, abnormal sexual function, enlarged abdomen, change in bowel habits, gum hyperplasia, intestinal obstruction, bundle branch block, increased creatine phosphokinase, electrolyte abnormality, glycosuria, gout, hyperkalemia, hyperproteinemia, increased lactic dehydrogenase (LDH), increased alkaline phosphatase, failure to thrive, abnormal platelets, aggressive reaction, amnesia, apathy, delirium, delusion, dementia, illusion, impotence, neurosis, paranoid reaction, personality disorder, hyperhemoglobinemia, apnea, atelectasis, yawning, oliguria, urinary retention, distended vein, lymphocytosis. The following adverse reaction has been identified during post‑approval use of cevimeline. Because post-marketing adverse reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. POST-MARKETING ADVERSE EVENTS Liver and Biliary System Disorders: cholecystitis To report SUSPECTED ADVERSE REACTIONS, contact Bionpharma Inc. at 1-888-235-BION or 1-888-235-2466 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.