BENZAFLEX XR® (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 XR 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 XR 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 BENZAFLEX XR is 15 mg once daily. Based on
individual patient response, the dose may be increased to 30 mg once daily. Use of
BENZAFLEX XR
for 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 XR 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 XR, use of
BENZAFLEX XR is not recommended in patients with mild, moderate or severe hepatic
impairment.
 

Pediatric Use
Safety and effectiveness of BENZAFLEX XR 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 XR in elderly subjects as compared to
young adults, use of BENZAFLEX XR 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 XR 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 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 XR 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 XR 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 XR 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 XR 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 XR.

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 XR in elderly subjects as compared to
young adults, use of BENZAFLEX XR 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 XR, use of

BENZAFLEX XR is not recommended in patients with mild, moderate or severe hepatic
impairment.

Atropine-like Action
Because of its atropine-like action, BENZAFLEX XR 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 XR may have lifethreatening
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]

Pregnancy
Pregnancy Category B:
There are no adequate and well-controlled studies of BENZAFLEX XR in pregnant women.
Because animal reproduction studies are not always predictive of human response,
BENZAFLEX XR 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 XR is administered to a nursing
woman.

You should not drink alcohol until you know how BENZAFLEX XR affects you. Taking
BENZAFLEX XR 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 XR affects you.

General
The most frequently occurring adverse reactions have included dry mouth, dizziness, fatigue,
constipation, nausea, dyspepsia, and somnolence.

Nervous system
Very common (10% or more): Drowsiness (up to 38%)
Common (1% to 10%): Dizziness, somnolence
Postmarketing reports: Headache, serotonin syndrome, seizures, ataxia, tremors, hypertonia,
convulsions, abnormal sensations, paresthesia, and ageusia
Elderly patients may be particularly susceptible to the sedation and confusion which may
accompany cyclobenzaprine therapy.

Psychiatric
Common (1% to 10%): Irritability, mental acuity decreased, nervousness.
Postmarketing reports: Nervousness, confusion, disorientation, insomnia, depressed mood,
anxiety, agitation, psychosis, abnormal thinking and dreaming, hallucinations, excitement

Hypersensitivity
Postmarketing reports: Anaphylaxis, angioedema, pruritus, facial edema, urticaria, rash.

Gastrointestinal
Very common (10% or more): Dry mouth (up to 32%)
Common (1% to 10%): Constipation, nausea, dyspepsia, abdominal pain, acid regurgitation,
diarrhea
Postmarketing reports: Unpleasant taste, vomiting, anorexia, gastritis, thirst, flatulence, tongue
edema.

Hepatic
Postmarketing reports: Abnormal liver function, hepatitis, jaundice, cholestasis.

Cardiovascular
Postmarketing reports: Syncope, tachycardia, arrhythmia, vasodilation, palpitation,
hypotension.

Other
Common (1% to 10%): Fatigue
Postmarketing reports: Asthenia, malaise, vertigo.

Dermatologic
Postmarketing reports: Sweating.

Genitourinary
Postmarketing reports: Urinary frequency and/or retention.

Musculoskeletal
Postmarketing reports: Local weakness, dysarthria, muscle twitching.

Ocular
Postmarketing reports: Blurred vision, diplopia, tinnitus.

Respiratory
Common (1% to 10%): Upper respiratory infection, pharyngitis.

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

 

Although rare, deaths may occur from overdosage with BENZAFLEX XR. 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 XR 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 BENZAFLEX XRin 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, BENZAFLEX XRshould 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
BENZAFLEX XRin subjects with moderate to severe impairment is not recommended.
No significant effect on plasma levels or bioavailability of BENZAFLEX XRor aspirin was
noted when single or multiple doses of the two drugs were administered concomitantly.
Concomitant administration of BENZAFLEX XRand naproxen or diflunisal was well tolerated
with no reported unexpected adverse effects. However combination therapy of BENZAFLEX
XRwith 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 BENZAFLEX XRenhances the clinical effect of aspirin or other analgesics, or
whether analgesics enhance the clinical effect of BENZAFLEX XRin 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.

Hypromellose,
Isopropyl alcohol,
Methylene chloride,
Colloidal silicon dioxide,
Ethyl cellulose, &
Sugar spheres.

Not applicable.

24 months.

This medicinal product does not require any special storage conditions.
Do not store above 30°C.

PVC/PE/PVDC Clear.

No special disposal.