cyclobenzaprine hydrochloride 2.8 MG Sublingual Tablet

INDICATIONS AND USAGE Cyclobenzaprine hydrochloride extended-release capsules are indicated as an adjunct to rest and physical therapy for relief of muscle spasm associated with acute, painful musculoskeletal conditions. Improvement is manifested by relief of muscle spasm and its associated signs and symptoms, namely, pain, tenderness, and limitation of motion. Limitations of Use: • Cyclobenzaprine hydrochloride extended-release capsules should be used only for short periods (up to two or three weeks) because adequate evidence of effectiveness for more prolonged use is not available and because muscle spasm associated with acute, painful musculoskeletal conditions is generally of short duration and specific therapy for longer periods is seldom warranted. • Cyclobenzaprine hydrochloride extended-release capsules have not been found effective in the treatment of spasticity associated with cerebral or spinal cord disease or in children with cerebral palsy. Cyclobenzaprine hydrochloride extended-release capsules are a muscle relaxant indicated as an adjunct to rest and physical therapy for relief of muscle spasm associated with acute, painful musculoskeletal conditions. Improvement is manifested by relief of muscle spasm and its associated signs and symptoms, namely, pain, tenderness, and limitation of motion. ( 1 ) Limitations of Use: • Cyclobenzaprine hydrochloride extended-release capsules should be used only for short periods (up to 2 or 3 weeks) because adequate evidence of effectiveness for more prolonged use is not available and because muscle spasm associated with acute, painful musculoskeletal conditions is generally of short duration and specific therapy for longer periods is seldom warranted. ( 1 ) • Cyclobenzaprine hydrochloride extended-release capsules have not been found effective in the treatment of spasticity associated with cerebral or spinal cord disease or in children with cerebral palsy. ( 1 )

DOSAGE AND ADMINISTRATION Recommended dosage of TONMYA is 5.6 mg administered sublingually once daily at bedtime ( 2.1 ): Starting dose: Days 1 to 14, administer 2.8 mg (1 sublingual tablet) once daily at bedtime. Target dose: Days 15 and thereafter, administer 5.6 mg (2 sublingual tablets) once daily at bedtime. Maximum recommended dosage: 5.6 mg once daily. Ensure mouth is moist with sips of water before sublingual administration ( 2.4 , 5.6 , 6.1 ) Do not swallow whole, cut, crush, or chew ( 2.4 ) Geriatric patients: Recommended dosage is 2.8 mg administered sublingually once daily at bedtime ( 2.2 , 8.5 ) Hepatic impairment (HI): Recommended dosage in patients with mild HI is 2.8 mg administered sublingually once daily at bedtime. Use not recommended in patients with moderate HI or severe HI ( 2.3 , 8.6 ). See important administration instructions in the Full Prescribing Information ( 2.4 , 2.5 , 2.6 ). 2.1 Recommended Dosage The recommended dosage of TONMYA is 5.6 mg administered sublingually once daily at bedtime: Starting dose: Days 1 to 14, administer 2.8 mg (1 sublingual tablet) once daily at bedtime. Target dose: Days 15 and thereafter, administer 5.6 mg (2 sublingual tablets) once daily at bedtime. Maximum recommended dosage: 5.6 mg once daily. 2.2 Recommended Dosage in Geriatric Patients The recommended TONMYA dosage―and the maximum recommended dosage―in geriatric patients is 2.8 mg administered sublingually once daily at bedtime [see Use in Specific Populations (8.5) ]. 2.3 Recommended Dosage in Patients with Hepatic Impairment The recommended TONMYA dosage―and the maximum recommended dosage―in patients with mild hepatic impairment is 2.8 mg administered sublingually once daily at bedtime . TONMYA is not recommended in patients with moderate or severe hepatic impairment [see Use in Specific Populations (8.6) ]. 2.4 Administration Instructions TONMYA is only for sublingual use. Administer after brushing teeth and finishing other oral care and ensure a moist mouth/sublingual area by drinking a few sips of water prior to administration. Place the sublingual tablet(s) under the tongue until dissolved. Do not swallow whole, cut, crush, or chew. Avoid eating or drinking for at least 15 minutes after the sublingual tablet(s) has/have completely dissolved at bedtime and preferably avoid any hot, cold, or acidic beverages until the morning. Avoid talking for at least 5 minutes after administration. 2.5 Recommendations Regarding Missed Dose(s) If you missed a TONMYA bedtime dose, take TONMYA the next evening. Do not take a missed dose during the day. 2.6 Pregnancy Testing Prior to Administration Pregnancy testing is recommended in females of reproductive potential prior to initiating treatment with TONMYA [see Warnings and Precautions (5.1) , and Use in Specific Populations (8.1 , 8.3) ]

WARNINGS AND PRECAUTIONS Embryofetal Toxicity : Based on animal data, TONMYA may cause neural tube defects when used two weeks prior to conception and through the first trimester of pregnancy. Advise females of reproductive potential of the potential risk and to use effective contraception during treatment and for two weeks after the final dose. ( 5.1 , 8.1 , 8.3 ) Serotonin Syndrome: Potentially life-threatening serotonin syndrome has been reported with cyclobenzaprine when used in combination with other drugs. Immediately discontinue concomitant treatment with TONMYA and a serotonergic agent if serotonin syndrome symptoms occur and initiate supportive symptomatic treatment. If concomitant treatment with TONMYA and other serotonergic drugs is clinically warranted, careful observation is advised, particularly during treatment initiation or dosage increases. ( 5.2 ) Tricyclic Antidepressant-like Adverse Reactions: TCAs have been reported to produce arrhythmias, sinus tachycardia, prolongation of the conduction time leading to myocardial infarction and stroke. TCAs lower the seizure threshold, and are associated with serious CNS reactions. If clinically significant CNS symptoms develop, consider discontinuation of TONMYA. ( 5.3 ) Atropine-like Adverse Reactions: Use with caution in patients with a history of urinary retention, angle-closure glaucoma, increased intraocular pressure and in patients taking anticholinergic medications. ( 5.4 ) CNS Depression and Risk of Operating a Motor Vehicle or Hazardous Machinery: TONMYA monotherapy may cause CNS depression. Advise patients not to operate a motor vehicle or other dangerous machinery until they are reasonably certain that TONMYA therapy will not adversely affect their ability to engage in such activities. ( 5.5 ) Oral Mucosal Adverse Reactions : In clinical studies, oral mucosal adverse reactions occurred more frequently in TONMYA-treated patients compared to placebo-treated patients. Advise patients to moisten the mouth with sips of water before administration of TONMYA to reduce the risk of oral sensory changes (hypoesthesia). Consider discontinuation of TONMYA if severe reactions occur. ( 5.6 ) 5.1 Embryofetal Toxicity Based on data from animal reproduction studies, TONMYA may cause an increased risk of neural tube defects when administered to a pregnant female two weeks prior to conception and during the first trimester of pregnancy. Neural tube defects (splayed vertebral arches and spina bifida occulta) were observed in a rabbit embryofetal development study at the highest maternal dose tested, in the absence of maternal toxicity. Because neural tube development occurs early in pregnancy, often before pregnancy is recognized, advise females of reproductive potential of the potential risk to the fetus and avoid use of TONMYA two weeks prior to conception and through the first trimester of pregnancy. Perform a pregnancy test prior to initiation of treatment with TONMYA to exclude use of TONMYA during the first trimester of pregnancy. Advise females of reproductive potential to use effective contraception during TONMYA treatment and for two weeks after the final dose [see Use in Specific Populations (8.1 , 8.3) ]. 5.2 Serotonin Syndrome The development of a potentially life-threatening serotonin syndrome has been reported with cyclobenzaprine when used in combination with other drugs, such as selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), tramadol, bupropion, meperidine, verapamil, or MAO inhibitors. The concomitant use of TONMYA with MAO inhibitors is contraindicated [see Contraindications (4) ] . Serotonin syndrome symptoms may include mental status changes (e.g., confusion, agitation, hallucinations), autonomic instability (e.g., diaphoresis, tachycardia, labile blood pressure, hyperthermia), neuromuscular abnormalities (e.g., tremor, ataxia, hyperreflexia, clonus, muscle rigidity), and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Treatment with TONMYA and any concomitant serotonergic agents should be discontinued immediately if serotonin syndrome symptoms occur and supportive symptomatic treatment should be initiated. If concomitant treatment with TONMYA and other serotonergic drugs is clinically warranted, careful observation is advised, particularly during treatment initiation or dosage increases. 5.3 Tricyclic Antidepressant-like Adverse Reactions Cyclobenzaprine is structurally related to tricyclic antidepressants (TCAs). TCAs have been reported to produce arrhythmias, sinus tachycardia, prolongation of the conduction time leading to myocardial infarction and stroke [see Contraindications (4) ] . Some of the more TCA-associated serious central nervous system (CNS) reactions have occurred in short-term studies of oral cyclobenzaprine. If clinically significant CNS symptoms develop, consider discontinuation of TONMYA. Caution should be used when TCAs are given to patients with a history of seizure disorder, because TCAs may lower the seizure threshold. Patients with a history of seizures should be monitored during TCA use to identify recurrence of seizures or increase in frequency of seizures. 5.4 Atropine-like Adverse Reactions Because of its atropine-like action, TONMYA should be used with caution in patients with a history of urinary retention, angle-closure glaucoma, increased intraocular pressure, and in patients taking anticholinergic drugs. 5.5 CNS Depression and Risk of Operating a Motor Vehicle or Hazardous Machinery TONMYA monotherapy may cause CNS depression and concomitant use of TONMYA with alcohol, barbiturates, or other CNS depressants may increase the risk of CNS depression [see Drug Interactions (7) ]. Symptoms of CNS depression include somnolence. Advise patients not to operate a motor vehicle or dangerous machinery until they are reasonably certain that TONMYA therapy will not adversely affect their ability to engage in such activities. 5.6 Oral Mucosal Adverse Reactions Oral mucosal adverse reactions, including sensory changes (e.g., numbness, tingling), discomfort, pain, irritation, inflammation, and lesions, occurred more frequently in patients treated with TONMYA compared to placebo (43% vs. 8%) [see Adverse Reactions (6.1) ]. Reactions typically occurred within minutes of administration and most resolved within 60 minutes. Five patients experienced severe oral mucosal adverse reactions, including sensory changes (paresthesia, hypoesthesia), inflammation (glossitis), oral pain, and dry mouth . Most severe oral mucosal adverse reactions resolved within days after TONMYA was discontinued and no treatment was required. Advise patients to moisten the mouth with sips of water before administration of TONMYA to reduce the risk of oral sensory changes (hypoesthesia). Advise patients to report severe oral mucosal adverse reactions to their healthcare provider. Consider discontinuation of TONMYA if severe reactions occur.

CONTRAINDICATIONS Hypersensitivity to cyclobenzaprine or any inactive ingredient in TONMYA. Hypersensitivity reactions may manifest as an anaphylactic reaction, urticaria, facial and/or tongue swelling, or pruritus. Discontinue TONMYA if a hypersensitivity reaction is suspected. Concomitant use of monoamine oxidase (MAO) inhibitors or within 14 days after discontinuation of a MAO inhibitor. Hyperpyretic crisis seizures and deaths have occurred in patients who received cyclobenzaprine (or structurally similar tricyclic antidepressants) concomitantly with MAO inhibitors drugs. During the acute recovery phase of myocardial infarction, and in patients with arrhythmias, heart block or conduction disturbances, or congestive heart failure. Hyperthyroidism. Hypersensitivity to cyclobenzaprine or any inactive ingredient in TONMYA ( 4 ) Concomitant use of monoamine oxidase (MAO) inhibitors or within 14 days after their discontinuation ( 4 ) During acute recovery phase of myocardial infarction and in patients with arrhythmias, heart block or conduction disturbances, or congestive heart failure ( 4 ) Hyperthyroidism ( 4 )

CLINICAL PHARMACOLOGY Cyclobenzaprine HCl relieves skeletal muscle spasm of local origin without interfering with muscle function. It is ineffective in muscle spasm due to central nervous system disease. Cyclobenzaprine reduced or abolished skeletal muscle hyperactivity in several animal models. Animal studies indicate that cyclobenzaprine does not act at the neuromuscular junction or directly on skeletal muscle. Such studies show that cyclobenzaprine acts primarily within the central nervous system at brain stem as opposed to spinal cord levels, although its action on the latter may contribute to its overall skeletal muscle relaxant activity. Evidence suggests that the net effect of cyclobenzaprine is a reduction of tonic somatic motor activity, influencing both gamma (g) and alpha (μ) motor systems. Pharmacological studies in animals showed a similarity between the effects of cyclobenzaprine and the structurally related tricyclic antidepressants, including reserpine antagonism, norepinephrine potentiation, potent peripheral and central anticholinergic effects, and sedation. Cyclobenzaprine caused slight to moderate increase in heart rate in animals. Surveillance Program A postmarketing surveillance program was carried out in 7607 patients with acute musculoskeletal disorders, and included 297 patients treated with cyclobenzaprine hydrochloride tablets 10 mg for 30 days or longer. The overall effectiveness of cyclobenzaprine hydrochloride was similar to that observed in the double-blind controlled studies; the overall incidence of adverse effects was less (see ADVERSE REACTIONS ). Pharmacokinetics Estimates of mean oral bioavailability of cyclobenzaprine range from 33% to 55%. Cyclobenzaprine exhibits linear pharmacokinetics over the dose range 2.5 mg to 10 mg, and is subject to enterohepatic circulation. It is highly bound to plasma proteins. Drug accumulates when dosed three times a day, reaching steady-state within 3 to 4 days at plasma concentrations about four-fold higher than after a single dose. At steady state in healthy subjects receiving 10 mg t.i.d. (n = 18), peak plasma concentration was 25.9 ng/mL (range, 12.8 to 46.1 ng/mL), and area under the concentration-time (AUC) curve over an 8-hour dosing interval was 177 ng.hr/mL (range, 80 to 319 ng.hr/mL). Cyclobenzaprine is extensively metabolized, and is excreted primarily as glucuronides via the kidney. Cytochromes P-450 3A4, 1A2, and, to a lesser extent, 2D6, mediate N-demethylation, one of the oxidative pathways for cyclobenzaprine. Cyclobenzaprine is eliminated quite slowly, with an effective half-life of 18 hours (range 8 to 37 hours; n = 18); plasma clearance is 0.7 L/min. The plasma concentration of cyclobenzaprine is generally higher in the elderly and in patients with hepatic impairment. (See PRECAUTIONS , and PRECAUTIONS, Impaired Hepatic Function .) Elderly In a pharmacokinetic study in elderly individuals (≥ 65yrs old), mean (n = 10) steady-state cyclobenzaprine AUC values were approximately 1.7 fold (171 ng.hr/mL, range 96.1 to 255.3) higher than those seen in a group of eighteen younger adults (101.4 ng.hr/mL, range 36.1 to 182.9) from another study. Elderly male subjects had the highest observed mean increase, approximately 2.4 fold (198.3 ng.hr/mL, range 155.6 to 255.3 versus 83.2 ng.hr/mL, range 41.1 to 142.5 for younger males) while levels in elderly females were increased to a much lesser extent, approximately 1.2 fold (143.8 ng.hr/mL, range 96.1 to 196.3 versus 115.9 ng.hr/mL, range 36.1 to 182.9 for younger females). In light of these findings, therapy with cyclobenzaprine hydrochloride in the elderly should be initiated with a 5 mg dose and titrated slowly upward. Hepatic Impairment In a pharmacokinetic study of sixteen subjects with hepatic impairment (15 mild, 1 moderate per Child-Pugh score), both AUC and C max were approximately double the values seen in the healthy control group. Based on the findings, cyclobenzaprine hydrochloride tablets should be used with caution in subjects with mild hepatic impairment starting with the 5 mg dose and titrating slowly upward. Due to the lack of data in subjects with more severe hepatic insufficiency, the use of cyclobenzaprine hydrochloride tablets in subjects with moderate to severe impairment is not recommended. No significant effect on plasma levels or bioavailability of cyclobenzaprine hydrochloride or aspirin was noted when single or multiple doses of the two drugs were administered concomitantly. Concomitant administration of cyclobenzaprine hydrochloride and naproxen or diflunisal was well tolerated with no reported unexpected adverse effects. However combination therapy of cyclobenzaprine hydrochloride with naproxen was associated with more side effects than therapy with naproxen alone, primarily in the form of drowsiness. No well-controlled studies have been performed to indicate that cyclobenzaprine hydrochloride enhances the clinical effect of aspirin or other analgesics, or whether analgesics enhance the clinical effect of cyclobenzaprine hydrochloride in acute musculoskeletal conditions. Clinical Studies Eight double-blind controlled clinical studies were performed in 642 patients comparing cyclobenzaprine hydrochloride 10 mg, diazepam ** , and placebo. Muscle spasm, local pain and tenderness, limitation of motion, and restriction in activities of daily living were evaluated. In three of these studies there was a significantly greater improvement with cyclobenzaprine hydrochloride than with diazepam, while in the other studies the improvement following both treatments was comparable. Although the frequency and severity of adverse reactions observed in patients treated with cyclobenzaprine hydrochloride were comparable to those observed in patients treated with diazepam, dry mouth was observed more frequently in patients treated with cyclobenzaprine hydrochloride and dizziness more frequently in those treated with diazepam. The incidence of drowsiness, the most frequent adverse reaction, was similar with both drugs. The efficacy of cyclobenzaprine hydrochloride 5 mg was demonstrated in two seven-day, double-blind, controlled clinical trials enrolling 1405 patients. One study compared cyclobenzaprine hydrochloride 5 mg and 10 mg t.i.d. to placebo; and a second study compared cyclobenzaprine hydrochloride 5 mg and 2.5 mg t.i.d. to placebo. Primary endpoints for both trials were determined by patient-generated data and included global impression of change, medication helpfulness, and relief from starting backache. Each endpoint consisted of a score on a 5-point rating scale (from 0 or worst outcome to 4 or best outcome). Secondary endpoints included a physician’s evaluation of the presence and extent of palpable muscle spasm. Comparisons of cyclobenzaprine hydrochloride 5 mg and placebo groups in both trials established the statistically significant superiority of the 5 mg dose for all three primary endpoints at day 8 and, in the study comparing 5 and 10 mg, at day 3 or 4 as well. A similar effect was observed with cyclobenzaprine hydrochloride 10 mg (all endpoints). Physician-assessed secondary endpoints also showed that cyclobenzaprine hydrochloride 5 mg was associated with a greater reduction in palpable muscle spasm than placebo. Analysis of the data from controlled studies shows that cyclobenzaprine hydrochloride produces clinical improvement whether or not sedation occurs. ** VALIUM ® (diazepam, Roche) Surveillance Program A postmarketing surveillance program was carried out in 7607 patients with acute musculoskeletal disorders, and included 297 patients treated with cyclobenzaprine hydrochloride 10 mg for 30 days or longer. The overall effectiveness of cyclobenzaprine hydrochloride was similar to that observed in the double-blind controlled studies; the overall incidence of adverse effects was less (see ADVERSE REACTIONS ).