Cyclobenzaprine Hydrochloride (Page 2 of 6)

6.2 Postmarketing Experience

The following adverse reactions have been reported in clinical studies or postmarketing experience with cyclobenzaprine hydrochloride extended-release capsules, cyclobenzaprine IR, or tricyclic drugs. Because some of these 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.

In a postmarketing surveillance program of cyclobenzaprine IR, the adverse reactions reported most frequently were drowsiness, dry mouth, and dizziness and adverse reactions reported in 1% to 3% of the patients were: fatigue/tiredness, asthenia, nausea, constipation, dyspepsia, unpleasant taste, blurred vision, headache, nervousness, and confusion.

The following adverse reactions have been reported in postmarketing experience (cyclobenzaprine hydrochloride extended-release capsules or cyclobenzaprine IR), in clinical studies of cyclobenzaprine IR (incidence <1%), or in postmarketing experience with other tricyclic drugs:

Body as a Whole: Syncope; malaise; chest pain; edema.

Cardiovascular: Tachycardia; arrhythmia; vasodilatation; palpitation; hypotension; hypertension; myocardial infarction; heart block; stroke.

Digestive: Vomiting; anorexia; diarrhea; gastrointestinal pain; gastritis; thirst; flatulence; edema of the tongue; abnormal liver function and rare reports of hepatitis, jaundice, and cholestasis; paralytic ileus, tongue discoloration; stomatitis; parotid swelling.

Endocrine: Inappropriate ADH syndrome.

Hematologic and Lymphatic: Purpura; bone marrow depression; leukopenia; eosinophilia; thrombocytopenia.

Hypersensitivity: Anaphylaxis; angioedema; pruritus; facial edema; urticaria; rash.

Metabolic, Nutritional, and Immune: Elevation and lowering of blood sugar levels; weight gain or loss.

Musculoskeletal: Local weakness; myalgia.

Nervous System and Psychiatric: Seizures, ataxia; vertigo; dysarthria; tremors; hypertonia; convulsions; muscle twitching; disorientation; insomnia; depressed mood; abnormal sensations; anxiety; agitation; psychosis, abnormal thinking and dreaming; hallucinations; excitement; paresthesia; diplopia; serotonin syndrome; neuroleptic malignant syndrome; decreased or increased libido; abnormal gait; delusions; aggressive behavior; paranoia; peripheral neuropathy; Bell’s palsy; alteration in EEG patterns; extrapyramidal symptoms.

Respiratory: Dyspnea.

Skin: Sweating; photosensitization; alopecia.

Special Senses: Ageusia; tinnitus.

Urogenital: Urinary frequency and/or retention; impaired urination; dilatation of urinary tract; impotence; testicular swelling; gynecomastia; breast enlargement; galactorrhea.

7 DRUG INTERACTIONS

Based on its structural similarity to tricyclic antidepressants, cyclobenzaprine hydrochloride extended-release capsules may have life-threatening interactions with MAO inhibitors [see Contraindications (4)] , may enhance the effects of alcohol, barbiturates, and other CNS depressants, may enhance the seizure risk in patients taking tramadol, or may block the antihypertensive action of guanethidine and similarly acting compounds.

Postmarketing cases of serotonin syndrome have been reported during combined use of cyclobenzaprine and other drugs, such as SSRIs, SNRIs, TCAs, tramadol, bupropion, meperidine, verapamil, or MAO inhibitors [see Warnings and Precautions (5.1)].

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

Available data from case reports with cyclobenzaprine hydrochloride extended-release capsules use in pregnancy have not identified a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. In rats, decreased pup body weight and survival was noted at cyclobenzaprine doses ≥10 mg/kg/day (approximately ≥3 times the maximum recommended human dose (MRHD) of 30 mg/day), when administered orally during pregnancy and lactation (see Data).

The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the US general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Data

Animal Data

No adverse embryofetal effects were reported following oral administration of cyclobenzaprine during organogenesis to mice and rabbits at maternal doses up to 20 mg/kg/day (approximately 3 and 15 times the MRHD, respectively, on a mg/m² basis). Maternal toxicity characterized by decreased body weight gain was observed only in mice at the highest tested dose of 20 mg/kg/day.

Decreased pup body weight and survival were reported in a prenatal and postnatal study where pregnant rats were treated orally with cyclobenzaprine during pregnancy and lactation with maternal doses of 10 and 20 mg/kg/day (approximately 3 and 6 times the MRHD on a mg/m² basis). Maternal toxicity, characterized by a decreased body weight gain, was observed only at the highest tested dose of 20 mg/kg/day.

8.2 Lactation

Risk Summary

There are no data on the presence of cyclobenzaprine in either human or animal milk, the effects on a breastfed infant, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for cyclobenzaprine hydrochloride extended-release capsules and any potential adverse effects on the breastfed child from cyclobenzaprine hydrochloride extended-release capsules or from the underlying maternal condition.

8.4 Pediatric Use

Safety and effectiveness of cyclobenzaprine hydrochloride extended-release capsules have not been studied in pediatric patients.

8.5 Geriatric Use

Clinical studies of cyclobenzaprine hydrochloride extended-release capsules did not include sufficient numbers of patients aged 65 and over to determine the safety and efficacy of cyclobenzaprine hydrochloride extended-release capsules in the elderly population. The plasma concentration and half-life of cyclobenzaprine are substantially increased in the elderly when compared to the general patient population. Accordingly, use of cyclobenzaprine hydrochloride extended-release capsules is not recommended in the elderly [see Warnings and Precautions (5.3) and Clinical Pharmacology (12.3)].

8.6 Hepatic Impairment

The use of cyclobenzaprine hydrochloride extended-release capsules is not recommended in patients with mild, moderate, or severe hepatic impairment [ see Warnings and Precautions (5.4) and Clinical Pharmacology (12.3)].

9 DRUG ABUSE AND DEPENDENCE

9.3 Dependence

Pharmacologic similarities among the tricyclic drugs require that certain withdrawal symptoms be considered when cyclobenzaprine hydrochloride extended-release capsules are administered, even though they have not been reported to occur with this drug. Abrupt cessation of treatment after prolonged administration rarely may produce nausea, headache, and malaise. These are not indicative of addiction.

10 OVERDOSAGE

10.1 Manifestations

Although rare, deaths may occur from overdosage with cyclobenzaprine hydrochloride extended-release capsules. Multiple drug ingestion (including alcohol) is common in deliberate cyclobenzaprine overdose. As management of overdose is complex and changing, it is recommended that the physician contact a poison control center for current information on treatment. Signs and symptoms of toxicity may develop rapidly after cyclobenzaprine overdose; therefore, hospital monitoring is required as soon as possible.

The most common effects associated with cyclobenzaprine overdose are drowsiness and tachycardia. Less frequent manifestations include tremor, agitation, coma, ataxia, hypertension, slurred speech, confusion, dizziness, nausea, vomiting, and hallucinations. Rare but potentially critical manifestations of overdose are cardiac arrest, chest pain, cardiac dysrhythmias, severe hypotension, seizures, and neuroleptic malignant syndrome. Changes in the electrocardiogram, particularly in QRS axis or width, are clinically significant indicators of cyclobenzaprine toxicity. Other potential effects of overdosage include any of the symptoms listed under Adverse Reactions (6).