Cevimeline

Keep this medication in the container it came in, tightly closed, and out of reach of children. Store it at room temperature and away from excess heat and moisture (not in the bathroom).

Unneeded medications should be disposed of in special ways to ensure that pets, children, and other people cannot consume them. However, you should not flush this medication down the toilet. Instead, the best way to dispose of your medication is through a medicine take-back program. Talk to your pharmacist or contact your local garbage/recycling department to learn about take-back programs in your community. See the FDA's Safe Disposal of Medicines website (http://goo.gl/c4Rm4p) for more information if you do not have access to a take-back program.

It is important to keep all medication out of sight and reach of children as many containers (such as weekly pill minders and those for eye drops, creams, patches, and inhalers) are not child-resistant and young children can open them easily. To protect young children from poisoning, always lock safety caps and immediately place the medication in a safe location – one that is up and away and out of their sight and reach. http://www.upandaway.org

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat.

Stop taking cevimeline and call your doctor at once if you have any of these serious side effects:

• shortness of breath, wheezing, or tightness in your chest;
• chest pain, uneven heart rate;
• attacks of severe stomach pain on the right side, extending up to your shoulder (sometimes worse after meals);
• nausea and vomiting, bloating, fever, chills, and jaundice (yellowing of the skin or eyes);
• swelling in your hands or feet;
• eye pain or drainage;
• fever, ear ache, flu symptoms; or
• white patches or sores inside your mouth or on your lips.

Less serious side effects may include:

• blurred vision, dry eyes;
• excessive sweating or salivating, drooling;
• runny or stuffy nose;
• nausea, diarrhea, constipation, loss of appetite;
• dry mouth;
• muscle pain;
• vaginal itching or discharge;

This is not a complete list of side effects and others may occur. Tell your doctor about any unusual or bothersome side effect. You may report side effects to FDA at 1-800-FDA-1088.

Common side effects include:

• excessive sweating
• nausea
• runny nose
• diarrhea

This is not a complete list of cevimeline side effects. Ask your doctor or pharmacist for more information.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

You should not take this medicine if you have uncontrolled asthma, glaucoma, or an eye condition called iritis or uveitis.

Usual Adult Dose for Sjogren's Syndrome:

30 mg orally three times a day

Comments:
-There is insufficient safety information and insufficient evidence for additional efficacy to support doses greater than 30 mg three times a day.

Use: Treatment of symptoms of dry mouth in patients with Sjögren's Syndrome.

Cevimeline is used to treat the symptoms of dry mouth often experienced by patients with Sjogren's syndrome. It works by causing certain mouth glands to produce more saliva.

cevimeline is available only with your doctor's prescription.

Cevimeline is cis-2’-methylspiro {1-azabicyclo [2.2.2] octane-3, 5’ -[1,3] oxathiolane} hydrochloride, hydrate (2:1). Its empirical formula is C10H17NOS.HCl.1/2 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.

Empty capsule shell consists of Titanium Dioxide and Gelatin. Ink used in the imprint is Black SW-9049 which contains Shellac, Dehydrated alcohol, Isopropyl Alcohol, Butyl Alcohol, Propylene Glycol, Purified Water, Strong Ammonia Solution, Potassium Hydroxide, and Black Iron Oxide.

General:
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.

Information for Patients:
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.

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.

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 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.

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 Cevimeline Hydrochloride capsules, 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.

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.

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.

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Capsule, Oral, as hydrochloride:

Evoxac: 30 mg

Generic: 30 mg

• Cholinergic Agonist

Data not available

Data not available

Animal studies have revealed evidence of a reduction in the mean number of implantations. There are no controlled data in human pregnancy. US FDA pregnancy category C: Animal reproduction studies have shown an adverse effect on the fetus and there are no adequate and well-controlled studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks.

This drug should be used during pregnancy only if the benefit outweighs the risk. US FDA pregnancy category: C

A decision should be made to discontinue breastfeeding or discontinue the drug, taking into account the importance of the drug to the mother. Excreted into human milk: Unknown Excreted into animal milk: Data not available Comments: The effects in the nursing infant are unknown. .