Cevimeline

Cevimeline was associated with a reduction in the mean number of implantations when given to pregnant Sprague-Dawley rats from 14 days prior to mating through day seven of gestation at a dosage of 45 mg/kg/day (approximately 5 times the maximum recommended dose for a 60 kg human when compared on the basis of body surface area estimates). This effect may have been secondary to maternal toxicity. There are no adequate and well-controlled studies in pregnant women. Cevimeline should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

It is not known whether this drug is secreted in human milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from cevimeline, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

Lifetime carcinogenicity studies were conducted in CD-1 mice and F-344 rats. A statistically significant increase in the incidence of adenocarcinomas of the uterus was observed in female rats that received cevimeline at a dosage of 100 mg/kg/day (approximately 8 times the maximum human exposure based on comparison of AUC data). No other significant differences in tumor incidence were observed in either mice or rats.

Cevimeline exhibited no evidence of mutagenicity or clastogenicity in a battery of assays that included an Ames test, an in vitro chromosomal aberration study in mammalian cells, a mouse lymphoma study in L5178Y cells, or a micronucleus assay conducted in vivo in ICR mice.

Cevimeline did not adversely affect the reproductive performance or fertility of male Sprague-Dawley rats when administered for 63 days prior to mating and throughout the period of mating at dosages up to 45 mg/kg/day (approximately 5 times the maximum recommended dose for a 60 kg human following normalization of the data on the basis of body surface area estimates). Females that were treated with cevimeline at dosages up to 45 mg/kg/day from 14 days prior to mating through day seven of gestation exhibited a statistically significantly smaller number of implantations than did control animals.

Cevimeline was administered to 1777 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:

^* n Is the total number of patients exposed to the dose at any time during the study.

In addition, the following adverse events (≥3% incidence) were reported in the Sjögren’s clinical trials:

^* n is the total number of patients exposed to the dose at any time during the study.

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.