Cevimeline Hydrochloride

Description

DESCRIPTION Cevimeline is cis-2’-methylspiro {1-azabicyclo [2.2.2] octane-3, 5’ -[1,3] oxathiolane} hydrochloride, hydrate (2:1). Its empirical formula is C 10 H 17 NOS.HCl.1/2 H 2 O, 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, low substituted hydroxypropyl cellulose, hydroxypropyl cellulose, and magnesium stearate. Components of the capsule shell include gelatin, sodium lauryl sulfate, titanium dioxide and water. In addition to the ingredients listed above, imprinting black ink contains black iron oxide, butyl alcohol, isopropyl alcohol, propylene glycol, potassium hydroxide, shellac, strong ammonia solution, dehydrated alcohol and purified water. cevimeline-structure.jpg

What Is Cevimeline Hydrochloride Used For?

INDICATIONS & USAGE Cevimeline is indicated for the treatment of symptoms of dry mouth in patients with Sjögren’s Syndrome.

Dosage and Administration

DOSAGE & ADMINISTRATION The recommended dose of cevimeline hydrochloride 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.

Side Effects (Adverse Reactions)

ADVERSE REACTIONS 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: Adverse Event Cevimeline 30 mg (tid) n*=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% *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: Adverse Event Cevimeline 30 mg (tid) n*=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% *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, influenzalike 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...

Drug Interactions

DRUG INTERACTIONS Cevimeline 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 cevimeline can be expected to have additive effects. Cevimeline might interfere with desirable antimuscarinic effects of drugs used concomitantly. Drugs which inhibit CYP2D6 and CYP3A3/4 also inhibit the metabolism of cevimeline. Cevimeline should be used with caution in individuals known or suspected to be deficient in CYP2D6 activity, based on previous experience, as they may be at a higher risk of adverse events. In an in vitro study, cytochrome P450 isozymes 1A2, 2A6, 2C9, 2C19, 2D6, 2E1, and 3A4 were not inhibited by exposure to cevimeline.

Contraindications

CONTRAINDICATIONS Cevimeline is contraindicated in patients with uncontrolled asthma, known hypersensitivity to cevimeline, and when miosis is undesirable, e.g., in acute iritis and in narrow-angle (angle-closure) glaucoma.

Pregnancy and Breastfeeding

PREGNANCY Teratogenic Effects Pregnancy Category C. 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.

NURSING MOTHERS 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 hydrochloride, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

Overdosage

MANAGEMENT OF OVERDOSE Management of the signs and symptoms of acute overdosage should be handled in a manner consistent with that indicated for other muscarinic agonists: general supportive measures should be instituted. If medically indicated, atropine, an anti-cholinergic agent, may be of value as an antidote for emergency use in patients who have had an overdose of cevimeline. If medically indicated, epinephrine may also be of value in the presence of severe cardiovascular depression or bronchoconstriction. It is not known if cevimeline is dialyzable.

How Supplied

HOW SUPPLIED Cevimeline hydrochloride is available as white, hard gelatin capsules containing 30 mg of cevimeline hydrochloride. Cevimeline hydrochloride capsules have a white opaque cap and a white opaque body. White opaque Cap and body, Size 3 hard gelatin capsule, imprinted with "L 80" on cap and "30 mg" on body with black ink, filled with white to off white powder. It is supplied in child resistant bottles of: 100 capsules (NDC 33342-216-11) Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [See USP Controlled Room Temperature]. Rx Only Manufactured for: Macleods Pharma USA, Inc. Princeton, NJ 08540 Manufactured by: Macleods Pharmaceuticals Ltd. INDIA Revised: April 2025