Cevimeline HCL

Cevimeline is cis-2'-methylspiro {1-azabicyclo [2.2.2] octane-3, 5' -[1,3] oxathiolane} hydro-chloride, hydrate (2:1). Its empirical formula is C10H17NOS•HCl•½ H2O, and its structural formula is:

Cevimeline has a molecular weight of 244.79. It is a white to off white crystalline powder with a melting point range of 201 to 203°C. It is freely soluble in alcohol and chloroform, very soluble in water, and virtually insoluble in ether. The pH of a 1% solution ranges from 4.6 to 5.6. Inactive ingredients include lactose monohydrate, hydroxypropyl cellulose, and magnesium stearate.

Cevimeline is indicated for the treatment of symptoms of dry mouth in patients with Sjögren's Syndrome.

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:

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

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, supraventric-ular 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, duod-enitis, 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 amino-transferase)

Metabolic and Nutritional Disorders: dehydration, diabetes mellitus, hypercalcemia, hyper-cholesterolemia, hyperglycemia, hyperlipemia, hypertriglyceridemia, hyperuricemia, hypoglycemia, hypokalemia, hyponatremia, thirst

Musculoskeletal Disorders: arthritis, aggravated arthritis, arthropathy, femoral head avas-cular 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, lichen-oid dermatitis, eczema, furunculosis, hyperkeratosis, lichen planus, nail discoloration, nail disorder, onychia, onychomycosis, paronychia, photosensitivity reaction, rosacea, sclero-derma, 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, hyper-kalemia, hyperproteinemia, increased lactic dehydrogenase (LDH), increased alkaline phos-phatase, 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

POST-MARKETING ADVERSE EVENTS

Liver and Biliary System Disorders: cholecystitis

Patients should be informed that cevimeline may cause visual disturbances, especially at night, that could impair their ability to drive safely.

If a patient sweats excessively while taking cevimeline, dehydration may develop. The patient should drink extra water and consult a health care provider.

Do not take this medication if you are allergic to cevimeline, or if you have untreated or uncontrolled asthma, glaucoma, or an eye condition called iritis or uveitis.

Before taking cevimeline, tell your doctor if you have heart disease, heart rhythm disorder, angina (chest pain), or a history of heart attack, high blood pressure (hypertension), asthma or other breathing disorder, or a history of kidney or gall stones.

Cevimeline can cause side effects that may impair your vision, especially at night. Be careful if you drive or do anything that requires you to be able to see clearly.

Avoid becoming overheated or dehydrated during exercise and in hot weather. Cevimeline may cause excessive sweating and you may get dehydrated more easily while taking this medication. Follow your doctor's instructions about the type and amount of liquids you should drink.

Your pharmacist can provide more information about cevimeline.

Remember, keep this and all other medicines out of the reach of children, never share your medicines with others, and use this medication only for the indication prescribed.

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