PRECAUTIONS General Because of its atropine-like action, Fexmid should be used with caution in patients with a history of urinary retention, angle-closure glaucoma, increased intraocular pressure, and in patients taking anticholinergic medication. Impaired Hepatic Function The plasma concentration of cyclobenzaprine is increased in patients with hepatic impairment (see CLINICAL PHARMACOLOGY, Pharmacokinetics , Hepatic Impairment ). These patients are generally more susceptible to drugs with potentially sedating effects, including cyclobenzaprine. Cyclobenzaprine HCl should be used with caution in subjects with mild hepatic impairment starting with a 5 mg dose and titrating slowly upward. Due to the lack of data in subjects with more severe hepatic insufficiency, the use of Fexmid in subjects with moderate to severe impairment is not recommended. Information for Patients Fexmid, especially when used with alcohol or other CNS depressants, may impair mental and/or physical abilities required for performance of hazardous tasks, such as operating machinery or driving a motor vehicle. In the elderly, the frequency and severity of adverse events associated with the use of cyclobenzaprine, with or without concomitant medications, is increased. In elderly patients, cyclobenzaprine HCl should be initiated with a 5 mg dose and titrated slowly upward. Patients should be cautioned about the risk of serotonin syndrome with the concomitant use of Cyclobenzaprine Hydrochloride and other drugs, such as SSRIs, SNRIs, TCAs, tramadol, bupropion, meperidine, verapamil, or MAO inhibitors. Patients should be advised of the signs and symptoms of serotonin syndrome, and be instructed to seek medical care immediately if they experience these symptoms (see WARNINGS , and see PRECAUTIONS , Drug Interactions ). Drug Interactions Fexmid may have life-threatening interactions with MAO inhibitors (see CONTRAINDICATIONS ). Postmarketing cases of serotonin syndrome have been reported during combined use of Cyclobenzaprine Hydrochloride and other drugs, such as SSRIs, SNRIs, TCAs, tramadol, bupropion, meperidine, verapamil, or MAO inhibitors. If concomitant treatment with Fexmid and other serotonergic drugs is clinically warranted, careful observation is advised, particularly during treatment initiation or dose increases (see WARNINGS ). Fexmid may enhance the effects of alcohol, barbiturates, and other CNS depressants. Tricyclic antidepressants may block the antihypertensive action of guanethidine and similarly acting compounds. Tricyclic antidepressants may enhance the seizure risk in patients taking tramadol.† †ULTRAM® (tramadol HCl tablets, PriCara, Division of Ortho-McNeil-Janssen Pharmaceuticals, Inc.) †ULTRACET® (tramadol HCl and acetaminophen tablets, PriCara, Division of Ortho-McNeil-Janssen Pharmaceuticals, Inc.) Carcinogenesis, Mutagenesis, Impairment of Fertility In rats treated with cyclobenzaprine HCl for up to 67 weeks at doses of approximately 5 to 40 times the maximum recommended human dose, pale, sometimes enlarged, livers were noted and there was a dose-related hepatocyte vacuolation with lipidosis. In the higher dose groups this microscopic change was seen after 26 weeks and even earlier in rats which died prior to 26 weeks; at lower doses, the change was not seen until after 26 weeks. Cyclobenzaprine did not affect the onset, incidence or distribution of neoplasia in an 81-week study in the mouse or in a 105-week study in the rat. At oral doses of up to 10 times the human dose, cyclobenzaprine did not adversely affect the reproductive performance or fertility of male or female rats. Cyclobenzaprine did not demonstrate mutagenic activity in the male mouse at dose levels of up to 20 times the human dose. Pregnancy Pregnancy Category B Reproduction studies have been performed in rats, mice and rabbits at doses up to 20 times the human dose, and have revealed no evidence of impaired fertility or harm to the fetus due to cyclobenzaprine HCl. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Nursing Mothers It is not known whether this drug is excreted in human milk. Because cyclobenzaprine is closely related to the tricyclic antidepressants, some of which are known to be excreted in human milk, caution should be exercised when cyclobenzaprine HCl is administered to a nursing woman. Pediatric Use Safety and effectiveness of Fexmid in pediatric patients below 15 years of age have not been established. Use in the Elderly The plasma concentration of cyclobenzaprine is increased in the elderly (see CLINICAL PHARMACOLOGY, Pharmacokinetics , Elderly ). The elderly may also be more at risk for CNS adverse events such as hallucinations and confusion, cardiac events resulting in falls or other sequelae, drug-drug and drug-disease interactions. For these reasons, in the elderly, Fexmid should be used only if clearly needed. In such patients cyclobenzaprine HCl should be initiated with a 5 mg dose and titrated slowly upward.