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.
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.
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, 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
The following adverse reaction has been identified during post-approval use of EVOXAC (cevimeline hcl) ®. 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 EVENTSLiver and Biliary System Disorders: cholecystitis
Cevimeline is indicated for the treatment of symptoms of dry mouth in patients with Sjögren's Syndrome.
EVOXAC (cevimeline hcl) ® is available as white, hard gelatin capsules containing 30 mg of cevimeline hydrochloride. EVOXAC® capsules (cevimeline hcl) have a white opaque cap and a white opaque body. The capsules are imprinted with "EVOXAC (cevimeline hcl) " on the cap and"30 mg" on the body with a black bar above "30 mg". It is supplied in child resistant bottles of:
100 capsules (NDC 63395-201-13)
Store at 25°C (77°F) excursion permitted to 15°-30°C (59°-86°F)
Norman, OK 73072 Distributed and Marketed by: Daiichi Pharmaceutical Corporation Montvale, NJ 07645
EVOXAC (cevimeline hcl) is a registered trademark of Daiichi Pharmaceutical Co., Ltd.
PRT38A Revised 05/2006 Printed in U.S.A. FDA revision date: 12/13/06
Cardiovascular Disease:
Cevimeline can potentially alter cardiac conduction and/or heart rate. Patients with significant cardiovascular disease may potentially be unable to compensate for transient changes in hemodynamics or rhythm induced by EVOXAC (cevimeline hcl) Ò. EVOXAC (cevimeline hcl) Ò should be used with caution and under close medical supervision in patients with a history of cardiovascular disease evidenced by angina pectoris or myocardial infarction.
Pulmonary Disease:
Cevimeline can potentially increase airway resistance, bronchial smooth muscle tone, and bronchial secretions. Cevimeline should be administered with caution and with close medical supervision to patients with controlled asthma, chronic bronchitis, or chronic obstructive pulmonary disease.
Ocular:
Ophthalmic formulations of muscarinic agonists have been reported to cause visual blurring which may result in decreased visual acuity, especially at night and in patients with central lens changes, and to cause impairment of depth perception. Caution should be advised while driving at night or performing hazardous activities in reduced lighting.
PRECAUTIONSGeneral:
Cevimeline 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.
Cevimeline should be administered with caution to patients with a history of nephrolithiasis or cholelithiasis. Contractions of the gallbladder or biliary smooth muscle could precipitate complications such as cholecystitis, cholangitis and biliary obstruction. An increase in the ureteral smooth muscle tone could theoretically precipitate renal colic or ureteral reflux in patients with nephrolithiasis.
Carcinogenesis, Mutagenesis and Impairment of Fertility:
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 of 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 from14 days prior to mating through day seven of gestation exhibited a statistically significantly smaller number of implantations than did control animals.
Pregnancy
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 EVOXAC (cevimeline hcl) Ò, a decision should be made whether to discontinue nursing or 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:
Although clinical studies of cevimeline included subjects over the age of 65, the numbers were not sufficient to determine whether they respond differently from younger subjects. Special care should be exercised when cevimeline treatment is initiated in an elderly patient, considering the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy in the elderly.
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.
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, 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
The following adverse reaction has been identified during post-approval use of EVOXAC (cevimeline hcl) ®. 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 EVENTSLiver and Biliary System Disorders: cholecystitis
DRUG INTERACTIONSCevimeline should be administered with caution to patients taking beta adrenergic antagonists, because of the possibility of conduction disturbances. Drugs with parasympathomi-metic 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.
