BENZAFLEX® (cyclobenzaprine hydrochloride) 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, and limitation of motion.

Limitations of Use:

 

BENZAFLEX 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.

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

For oral administration.

For most patients, the recommended dose of BENZAFLEXis 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 BENZAFLEXfor periods longer than two or three weeks is not recommended.

 It is recommended that doses be taken at approximately the same time each day.

 Use of BENZAFLEX for periods longer than two or three weeks is not recommended.

 

Use in hepatic impairment

 

As a result of two-fold higher cyclobenzaprine plasma levels in subjects with mild hepatic impairment, as compared to healthy subjects, following administration of immediate-release cyclobenzaprine and because there is limited dosing flexibility with BENZAFLEX, use of BENZAFLEX is not recommended in patients with mild, moderate or severe hepatic impairment.

 

Pediatric Use

 

Safety and effectiveness of BENZAFLEX has not been studied in pediatric patients.

 

Use in the Elderly

 

As a result of a 40% increase in cyclobenzaprine plasma levels and a 56% increase in plasma half-life following administration of BENZAFLEX in elderly subjects as compared to young adults, use of BENZAFLEX is not recommended in the elderly.

 

Hypersensitivity to any component of this product. These adverse reactions may manifest as an anaphylactic reaction, urticaria, facial and/or tongue swelling or pruritus. Discontinue BENZAFLEX if a hypersensitivity reaction is suspected. 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. During the acute recovery phase of myocardial infarction, and in patients with arrhythmias, heart block or conduction disturbances, or congestive heart failure. Hyperthyroidism.

 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 BENZAFLEX with MAO inhibitors is contraindicated [see 4.3 Contraindications]. 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 BENZAFLEX and any concomitant serotonergic agents should be discontinued immediately if the above reactions occur and symptomatic treatment should be initiated. If concomitant treatment with BENZAFLEX and other serotonergic drugs is clinically warranted, careful observation is advised, particularly during treatment initiation or dose increases.

 

Tricyclic Antidepressant-like Effects

Cyclobenzaprine is structurally related to the tricyclic antidepressants, e.g., amitriptyline and imipramine. Tricyclic antidepressants have been reported to produce arrhythmias, sinus tachycardia, prolongation of the conduction time leading to myocardial infarction and stroke. BENZAFLEX may enhance the effects of alcohol, barbiturates, and other CNS depressants.

Some of the more serious central nervous system (CNS) reactions noted with the tricyclic antidepressants have occurred in short-term studies of cyclobenzaprine for indications other than muscle spasm associated with acute musculoskeletal conditions, and usually at doses somewhat greater than those recommended for skeletal muscle spasm. If clinically significant CNS symptoms develop, consider discontinuation of BENZAFLEX.

 

Use in the Elderly

As a result of a 40% increase in cyclobenzaprine plasma levels and a 56% increase in plasma half-life following administration of BENZAFLEX in elderly subjects as compared to young adults, use of BENZAFLEX is not recommended in the elderly.

 

Use in Patients with Hepatic Impairment

As a result of two-fold higher cyclobenzaprine plasma levels in subjects with mild hepatic impairment, as compared to healthy subjects, following administration of immediate-release cyclobenzaprine and because there is limited dosing flexibility with BENZAFLEX, use of BENZAFLEX is not recommended in patients with mild, moderate or severe hepatic impairment.

 

Atropine-like Action

Because of its atropine-like action, BENZAFLEX 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.

Based on its structural similarity to tricyclic antidepressants, BENZAFLEX may have life- threatening interactions with MAO inhibitors [see 4.3 Contraindications], 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 4.4 Special warnings and precautions for use]

1.1  Pregnancy

Pregnancy Category B:

There are no adequate and well-controlled studies of BENZAFLEX in pregnant women. Because animal reproduction studies are not always predictive of human response, BENZAFLEX should be used during pregnancy only if clearly needed.

No treatment-related effects on embryofetal development were observed in mice and rabbits at approximately 3 and 15 times the maximum recommended human dose (MRHD), respectively (on a mg/m2 basis at maternal doses of 20 mg/kg/day in both mice and rabbits).

 

Nonteratogenic Effects

Cyclobenzaprine has been shown to adversely affect pup postnatal development when dams were treated with the drug during pregnancy and lactation periods in rats. This study found that cyclobenzaprine decreased pup body weight and survival at approximately ≥3 times the MRHD (on a mg/m2 basis at maternal doses of 10 and 20 mg/kg/day in rats).

 

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 BENZAFLEX is administered to a nursing woman.

You should not drink alcohol until you know how BENZAFLEX affects you. Taking BENZAFLEX with alcohol or other medicines that depress your central nervous system can slow your thinking and physical response times.

 

Do not drive, operate machinery, or do other dangerous activities until you know how BENZAFLEX affects you.

Most Common Adverse Reactions in the BENZAFLEX Clinical Trials

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

The data described below reflect exposure to BENZAFLEX in 253 patients in 2 clinical trials. BENZAFLEX was studied in two double-blind, parallel-group, placebocontrolled, active- controlled trials of identical design. The study population was composed of patients with muscle spasms associated with acute painful musculoskeletal conditions. Patients received 15 mg or 30 mg of BENZAFLEX taken orally once daily, cyclobenzaprine immediate-release (IR) 10 mg three times a day, or placebo for 14 days.

Incidence of most common adverse reactions in the 2 double-blind3, placebo-controlled 5 mg studies (incidence of > 3% on Benzaflex5 mg):

	Benzaflex 5 mg N=464	Benzaflex10 mg N=249	Placebo N=469
Drowsiness	29%	38%	10%
Dry Mouth	21%	32%	7%
Fatigue	6%	6%	3%
Headache	5%	5%	8%

 

Additional Adverse Reactions from Clinical Studies and Postmarketing Experience

The following adverse reactions have been reported in clinical studies or postmarketing experience with BENZAFLEX, 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 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.

 

To report any side effect(s): The National Pharmacovigilance and Drug Safety Centre (NPC) o Fax: +966-11-205-7662 o Call NPC at +966-11-2038222, Exts: 2317-2356-2353-2354-2334-2340. o  Toll free phone: 8002490000 o  E-mail: npc.drug@sfda.gov.sa o  Website: www.sfda.gov.sa/npc     UAE PV address Pharmacovigilance & Medical Device section P.O.Box: 1853 Tel: 80011111  Email : pv@moh.gov.ae Drug Department Ministry of Health & Prevention Dubai

Although rare, deaths may occur from overdosage with BENZAFLEX. 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.

 

Manifestations

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.

 

Management

 

General

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 rare but potentially critical manifestations described above, obtain an ECG and immediately initiate cardiac monitoring. Protect the patient’s airway, establish an intravenous line, and initiate gastric decontamination. Observation with cardiac monitoring and observation for signs of CNS or respiratory depression, hypotension, cardiac dysrhythmias and/or conduction blocks, and seizures is necessary. If signs of toxicity occur at any time during this period, extended monitoring is required. Monitoring of plasma drug levels should not guide management of the patient. Dialysis is probably of no value because of low plasma concentrations of the drug.

 

Gastrointestinal Decontamination

All patients suspected of an overdose with BENZAFLEX should receive gastrointestinal decontamination. This should include large volume gastric lavage followed by activated charcoal. If consciousness is impaired, the airway should be secured prior to lavage and emesis is contraindicated.

 

Cardiovascular

A maximal limb-lead QRS duration of 0.10 seconds may be the best indication of the severity of the overdose. Serum alkalinization, to a pH of 7.45 to 7.55, using intravenous sodium bicarbonate and hyperventilation (as needed), should be instituted for patients with dysrhythmias and/or QRS widening. A pH >7.60 or a pCO2 <20 mmHg is undesirable. Dysrhythmias unresponsive to sodium bicarbonate therapy/hyperventilation may respond to lidocaine, bretylium, or phenytoin. Type 1A and 1C antiarrhythmics are generally contraindicated (e.g., quinidine, disopyramide, and procainamide).

 

CNS

In patients with CNS depression, early intubation is advised because of the potential for abrupt deterioration. Seizures should be controlled with benzodiazepines or, if these are ineffective, other anticonvulsants (e.g., phenobarbital, phenytoin). Physostigmine is not recommended

except to treat life-threatening symptoms that have been unresponsive to other therapies, and then only in close consultation with a poison control center.

 

Psychiatric Follow-Up

Since overdosage is often deliberate, patients may attempt suicide by other means during the recovery phase. Psychiatric referral may be appropriate.

 

Pediatric Management

The principles of management of child and adult overdosage are similar. It is strongly recommended that the physician contact the local poison control center for specific pediatric treatment.

ATC Code: M03BX08

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 (γ) and alpha (α) 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.

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 3-4 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, 12.8-46.1 ng/mL), and area under the concentration-time (AUC) curve over an 8-hour dosing interval was 177 ng.hr/mL (range, 80-319 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 8-37 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.

 

Elderly

 

In a pharmacokinetic study in elderly individuals (≥65yrs old), mean (n=10) steady-state cyclobenzaprine AUC values were approximately 1.7-fold (171.0 ng.hr/mL, range 96.1-255.3) higher than those seen in a group of eighteen younger adults (101.4 ng.hr/mL, range 36.1- 182.9) from another study. Elderly male subjects had the highest observed mean increase, approximately 2.4-fold (198.3 ng.hr/mL, range 155.6-255.3 versus 83.2 ng.hr/mL, range 41.1- 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 96.1-196.3 versus 115.9 ng.hr/mL, range 36.1-182.9 for younger females).

 

In light of these findings, therapy with Benzaflexin 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 Cmax were approximately double the values seen in the healthy control group. Based on the findings, Benzaflexshould 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 Benzaflexin subjects with moderate to severe impairment is not recommended.

 

No significant effect on plasma levels or bioavailability of Benzaflexor aspirin was noted when single or multiple doses of the two drugs were administered concomitantly. Concomitant administration of Benzaflexand naproxen or diflunisal was well tolerated with no reported unexpected adverse effects. However, combination therapy of Benzaflexwith 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 Benzaflexenhances the clinical effect of aspirin or other analgesics, or whether analgesics enhance the clinical effect of Benzaflexin acute musculoskeletal conditions.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term studies were conducted in CD-1 mice and Sprague-Dawley rats with cyclobenzaprine to evaluate its carcinogenic potential. In an 81-week carcinogenicity study, metastatic hemangiosarcoma was seen in 3 of 21 male mice at 10 mg/kg/day (2 times the MRHD on a mg/m2 basis). In a 105-week carcinogenicity study, malignant astrocytoma was seen in 3 of 50 male rats at 10 mg/kg/day (3 times the MRHD on a mg/m2 basis). There were no tumor findings in female mice or rats.

Cyclobenzaprine HCl was not mutagenic or clastogenic in the following assays: an in vitro Ames bacterial mutation assay, in vitro Chinese hamster ovary (CHO) cell chromosomal aberration test, and in vivo mouse bone marrow micronucleus assay.

Cyclobenzaprine HCl had no effects on fertility and reproductive performance in male or female rats at oral doses up to 20 mg/kg/day (6 times the MRHD on a mg/m2 basis).

 

Animal Toxicology and/or Pharmacology

In a 67-week study with rats that received cyclobenzaprine at oral doses of 10, 20 or 40 mg/kg/day (3 to 15 times the MRHD on mg/m2 basis), there were findings in the liver consisting of midzonal vacuolation with lipidosis for males and midzonal and centrilobular hepatocytic enlargement for females. In addition, there were findings of centrilobular coagulative necrosis. In the higher dose groups, these microscopic changes were seen after 26 weeks and even earlier in rats that died prior to

26 weeks; at lower doses, these changes were not seen until after 26 weeks.

In a 26-week study with Cynomolgus monkeys that received cyclobenzaprine at oral of doses of 2.5, 5, 10, or 20 mg/kg/day, one monkey at 20 mg/kg/day (15 times the MRHD on mg/m2 basis) was euthanized in week 17. Morbidity for this animal was attributed to findings of chronic pancreatitis, cholecystitis, cholangitis, and focal liver necrosis.

Lactose Monohydrate

Starch 1500

Croscarmellose Sodium Type A

Colloidal Silicon Dioxide

Magnesium Stearate

Hydroxypropyl Methylcellulose

Titanium Dioxide Pharma Grade

Purified Talc

Polyethylene Glycol MW 6000

Iron Oxide Yellow

Purified Water

Not applicable.

36 months (3 years).

This medicinal product does not require any special storage conditions.

Do not store above 30°C

 Transparent Thermoformed PVC/PE/PVDC reel with hard tempered aluminum foil lid.

Each pack contains 30 Film-Coated Tablets in 3 blister strips.

No special requirements.