Composition: Each FLEXAREN 5 F.Ctd. Tab. Contains Cyclobenzaprine Hydrochloride 5 mg.

Each FLEXAREN 10 F.Ctd. Tab. Contains Cyclobenzaprine Hydrochloride 10 mg.

Excipients: Lactose, starch, magnesium stearate.

CLINICAL PHARMACOLOGY:

Cyclobenzaprine Hydrochloride relieves skeletal muscle spasm of local origin without interfering with muscle function. It is ineffective in muscle spasm due to central nervous system disease.

Pharmacokinetics

Estimates mean oral bioavailability of cyclobenzaprine range from 33% to 55%. Cyclobenzaprine is subject to enterohepatic circulation. It is highly bound to plasma proteins. Drug accumulates when dosed three times a day, reaching steady-state within 3-4 days at plasma concentrations about four-fold higher than after a single dose.

Cyclobenzaprine is extensively metabolized, and is excreted primarily as glucuronides via the kidney. Cyclobenzaprine is eliminated slowly, with an effective half-life of 18 hours.

INDICATIONS:

Cyclobenzaprine is 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, limitation of motion, and restriction in activities of daily living.

Cyclobenzaprine 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.

Cyclobenzaprine has not been found effective in the treatment of spasticity associated with cerebral or spinal cord disease, or in children with cerebral palsy.

CONTRAINDICATIONS:

• Hypersensitivity to any component of this product.
• Concomitant use of monoamine oxidase (MAO) inhibitors or within 14 days after their discontinuation. Hyperpyretic crisis seizures and deaths have occurred in patients receiving cyclobenzaprine (or structurally similar tricyclic antidepressants) concomitantly with MAO inhibitor drugs.
• Acute recovery phase of myocardial infarction, and patients with arrhythmias, heart-block or conduction disturbances, or congestive heart failure.

WARNINGS:

• Serotonin Syndrome: The development of a potentially life-threatening serotonin syndrome has been reported with cyclobenzaprine hydrochloride when used in combination with other drugs, such as selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), and tramadol, bupropion, meperidine, verapamil, or (MAO) inhibitors. Serotonin syndrome symptoms may include mental status changes (e.g: confusion, agitation), autonomic instability (e.g: tachycardia), neuromuscular abnormalities (e.g., tremor), and/or gastrointestinal symptoms. Treatment with cyclobenzaprine hydrochloride and any concomitant serotonergic agents should be discontinued immediately if this reaction occurs and supportive symptomatic treatment should be initiated. If concomitant treatment with cyclobenzaprine hydrochloride and other serotonergic drugs is clinically warranted, careful observation is advised, particularly during treatment initiation or dose increases.
• Cyclobenzaprine is closely related to the tricyclic antidepressants, e.g., amitriptyline and imipramine. In short term studies for indications other than muscle spasm associated with acute musculoskeletal conditions, and usually at doses somewhat greater than those recommended for skeletal muscle spasm, some of the more serious central nervous system reactions with the tricyclic antidepressants have occurred. Tricyclic antidepressants have been reported to produce arrhythmias, sinus tachycardia, prolongation of the conduction time leading to myocardial infarction and stroke.

PRECAUTIONS:

• Because of its atropine-like action, Cyclobenzaprine 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. These patients are generally more susceptible to drugs with potentially sedating effects, including cyclobenzaprine. Cyclobenzaprine 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 Cyclobenzaprine in subjects with moderate to severe impairment is not recommended.

Information for Patients:

Cyclobenzaprine, 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 vehicle.

In the elderly, the frequency and severity of adverse events associated with the use of cyclobenzaprine, with or without concomitant medications, is increased.

DRUG ABUSE AND DEPENDENCE

Pharmacologic similarities among the tricyclic drugs require that certain withdrawal symptoms be considered when cyclobenzaprine is 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.

Pregnancy:

Pregnancy Category B: There are no adequate and well-controlled studies in pregnant women; therefore, 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 is administered to a nursing woman.

Pediatric Use:

Safety and effectiveness of Cyclobenzaprine 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.  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, cyclobenzaprine should be used only if clearly needed. In such patients effects should be initiated with a 5 mg dose and titrated slowly upward.

DRUG INTERACTIONS:

• Cyclobenzaprine may have life-threatening interactions with MAO inhibitors.
• Cyclobenzaprine may enhance the effects of alcohol, barbiturates, and other CNS depressants.
• Tricyclic antidepressants may block the antihypertensive action of guanethidine and similarly acting compounds, and it may enhance the seizure risk in patients taking tramadol.

ADVERSE REACTIONS:

The adverse reactions reported most frequently were: drowsiness, dry mouth and dizziness.

Adverse reactions which were reported in 1% to 3% of the patients were: fatigue/tiredness, asthenia, nausea, constipation, dyspepsia, unpleasant taste, blurred vision, headache, nervousness, and confusion.

OVERDOSAGE:

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. Changes in the electrocardiogram, particularly in QRS axis or width, are clinically significant indicators of cyclobenzaprine toxicity.

As management of overdose is complex and changing, it is recommended that the physician contact a poison control center for current information on treatment. In order to protect against the potentially critical manifestations, an ECG should be obtained immediately and cardiac monitoring should be initiated, the patient’s airway should be protected, intravenous line should be established and gastric decontamination should be initiated. If signs of toxicity occur at any time during this period, extended monitoring is required.

DOSAGE & ADMINISTRATION:

For most patients, the recommended dose of cyclobenzaprine is 5 mg three times a day. Based on individual patient response, the dose may be increased to 10 mg three times a day. Use of cyclobenzaprine for periods longer than 2 or 3 weeks is not recommended. Less frequent dosing should be considered for hepatically impaired or elderly patients.

STORAGE:

Store at a dry place, at temperature below 25^°c. Protect from light.

HOW SUPPLIED:

FLEXAREN 5: A carton box containing 10 F.Ctd. Tab.

A carton box containing 30 F.Ctd. Tab.

FLEXAREN 10: A carton box containing 10 F.Ctd. Tab.

A carton box containing 30 F.Ctd. Tab.