Cyclobenzaprine HCL Tablets

CLINICAL PHARMACOLOGY

id: 7e013db2-3c08-40ff-80f3-833b2faf7dbe
displayName: CLINICAL PHARMACOLOGY SECTION
FDA Article Code: 34090-1

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. PharmacokineticsEstimates 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. (See PRECAUTIONS, Use in the Elderly and PRECAUTIONS, Impaired Hepatic
Function
.) ElderlyIn 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 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 HCl in the elderly
should be initiated with a 5 mg dose and titrated slowly upward. Hepatic ImpairmentIn 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 HCl 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 HCl in subjects with moderate
to severe impairment is not recommended. No significant effect on plasma levels or bioavailability of cyclobenzaprine
HCl or aspirin was noted when single or multiple doses of the two drugs were
administered concomitantly. Concomitant administration of cyclobenzaprine HCl
and naproxen or diflunisal was well tolerated with no reported unexpected
adverse effects. However combination therapy of cyclobenzaprine HCl 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 HCl enhances the clinical effect of
aspirin or other analgesics, or whether analgesics enhance the clinical effect
of cyclobenzaprine HCl in acute musculoskeletal conditions. Clinical StudiesEight double-blind controlled clinical studies were performed in
642 patients comparing cyclobenzaprine HCl 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 HCl 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 HCl were comparable to those observed in patients
treated with diazepam, dry mouth was observed more frequently in patients
treated with cyclobenzaprine HCl 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 HCl 5 mg was demonstrated in two seven-day,
double-blind, controlled clinical trials enrolling 1405 patients. One study
compared cyclobenzaprine HCl 5 and 10 mg t.i.d. to placebo; and a second study
compared cyclobenzaprine HCl 5 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 HCl 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 HCl 10 mg
(all endpoints). Physician-assessed secondary endpoints also showed that
cyclobenzaprine HCl 5 mg was associated with a greater reduction in palpable
muscle spasm than placebo. Analysis of the data from controlled studies shows that cyclobenzaprine HCl
produces clinical improvement whether or not sedation occurs. _________________________________ **VALIUM® (diazepam, Roche) Surveillance ProgramA post-marketing surveillance program was carried out in 7607
patients with acute musculoskeletal disorders, and included 297 patients treated
with cyclobenzaprine HCl 10 mg for 30 days or longer. The overall effectiveness
of cyclobenzaprine HCl was similar to that observed in the double-blind
controlled studies; the overall incidence of adverse effects was less (see ADVERSE REACTIONS ).

INDICATIONS AND USAGE

id: 81782781-b247-40b9-829a-5a469889dc6c
displayName: INDICATIONS & USAGE SECTION
FDA Article Code: 34067-9

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

CONTRAINDICATIONS

id: 9c44c545-dfde-4a0b-8be6-422655bf19e5
displayName: CONTRAINDICATIONS SECTION
FDA Article Code: 34070-3

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. Hyperthyroidism.

WARNINGS

id: 4a1b3fdf-d84a-484d-b372-5ed29b595d7a
displayName: WARNINGS SECTION
FDA Article Code: 34071-1

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
noted with the tricyclic antidepressants have occurred (see WARNINGS , below, and ADVERSE REACTIONS ). Tricyclic antidepressants have been reported to produce arrhythmias, sinus
tachycardia, prolongation of the conduction time leading to myocardial
infarction and stroke. Cyclobenzaprine HCl may enhance the effects of alcohol, barbiturates, and
other CNS depressants.

PRECAUTIONS

id: 88342715-d9c3-4b1a-be05-824a875ecb3d
displayName: PRECAUTIONS SECTION
FDA Article Code: 42232-9

GeneralBecause of its atropine-like action, cyclobenzaprine HCl 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 FunctionThe plasma concentration of cyclobenzaprine is increased in
patients with hepatic impairment (see CLINICAL PHARMACOLOGY, Pharmacokinetics
,

Hepatic
Impairment ). These patients are generally more susceptible to drugs with potentially
sedating effects, including cyclobenzaprine. Cyclobenzaprine HCl 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 HCl in subjects with
moderate to severe impairment is not recommended.

Information for Patients

id: dfe25d3d-570a-4b59-9f7b-127b04d7c9af
displayName: INFORMATION FOR PATIENTS SECTION
FDA Article Code: 34076-0

Cyclobenzaprine HCl, 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 a motor vehicle. In the
elderly, the frequency and severity of adverse events associated with the use of
cyclobenzaprine, with or without concomitant medications, is increased. In
elderly patients, cyclobenzaprine HCl should be initiated with a 5 mg dose and
titrated slowly upward.

Carcinogenesis, Mutagenesis, Impairment of Fertility

id: 401a95b3-92a4-4ce4-9d02-61cd45a56d97
displayName: CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION
FDA Article Code: 34083-6

In rats treated with cyclobenzaprine HCl for up to 67 weeks at
doses of approximately 5 to 40 times the maximum recommended human dose, pale,
sometimes enlarged, livers were noted and there was a dose-related hepatocyte
vacuolation with lipidosis. In the higher dose groups this microscopic change
was seen after 26 weeks and even earlier in rats which died prior to 26 weeks;
at lower doses, the change was not seen until after 26 weeks. Cyclobenzaprine did not affect the onset, incidence or distribution of
neoplasia in an 81-week study in the mouse or in a 105-week study in the
rat. At oral doses of up to 10 times the human dose, cyclobenzaprine did not
adversely affect the reproductive performance or fertility of male or female
rats. Cyclobenzaprine did not demonstrate mutagenic activity in the male mouse
at dose levels of up to 20 times the human dose.

Pregnancy

id: 7bd83b2a-5af8-4b41-becb-fe1c0177fd75
displayName: PREGNANCY SECTION
FDA Article Code: 42228-7

Pregnancy Category B Reproduction studies have been performed in rats, mice and rabbits at doses
up to 20 times the human dose, and have revealed no evidence of impaired
fertility or harm to the fetus due to cyclobenzaprine HCl. There are, however,
no adequate and well-controlled studies in pregnant women. Because animal
reproduction studies are not always predictive of human response, this drug
should be used during pregnancy only if clearly needed.

Nursing Mothers

id: 50e7236c-850a-4ad3-91f5-171eef2d9d8c
displayName: NURSING MOTHERS SECTION
FDA Article Code: 34080-2

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 HCl is administered to a nursing woman.

Pediatric Use

id: 7116403c-70a4-4989-a81e-84367063f34a
displayName: PEDIATRIC USE SECTION
FDA Article Code: 34081-0

Safety and effectiveness of cyclobenzaprine HCl in pediatric patients below 15
years of age have not been established.

Use in the Elderly

id: e66bb99a-489a-44e2-8145-0d4be048dcca
displayName: GERIATRIC USE SECTION
FDA Article Code: 34082-8

The plasma concentration of cyclobenzaprine is increased in the elderly
(see CLINICAL PHARMACOLOGY,
Pharmacokinetics
,
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 cyclobenzaprine HCl should be initiated with a
5 mg dose and titrated slowly upward.

ADVERSE REACTIONS

id: c02c6f13-c8ae-4eed-9f27-550b43e7aaeb
displayName: ADVERSE REACTIONS SECTION
FDA Article Code: 34084-4

Incidence of most common adverse reactions in the 2
double-blind^‡, placebo-controlled 5 mg studies (incidence
of > 3% on cyclobenzaprine HCl 5 mg):

	Cyclobenzaprine HCl T ablets	Cyclobenzaprine HCl Tablets	Placebo
	5 mg	10 mg
	N=464	N=249	N=469
Drowsiness	29%	38%	10%
Dry Mouth	21%	32%	7%
Fatigue	6%	6%	3%
Headache	5%	5%	8%

Adverse reactions which were reported in 1% to 3% of the patients were:
abdominal pain, acid regurgitation, constipation, diarrhea, dizziness, nausea,
irritability, mental acuity decreased, nervousness, upper respiratory infection,
and pharyngitis. The following list of adverse reactions is based on the experience in 473
patients treated with cyclobenzaprine HCl 10 mg in additional controlled
clinical studies, 7607 patients in the post-marketing surveillance program, and
reports received since the drug was marketed. The overall incidence of adverse
reactions among patients in the surveillance program was less than the incidence
in the controlled clinical studies. The adverse reactions reported most frequently with cyclobenzaprine HCl were
drowsiness, dry mouth and dizziness. The incidence of these common adverse
reactions was lower in the surveillance program than in the controlled clinical
studies:

	Clinical Studies with	Surveillance Program with
	Cyclobenzaprine HCl Tablets 10 mg	Cyclobenzaprine HCl Tablets 10 mg
Drowsiness	39%	16%
Dry mouth	27%	7%
Dizziness	11%	3%

Among the less frequent adverse reactions, there was no appreciable
difference in incidence in controlled clinical studies or in the surveillance
program. 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. The following adverse reactions have been reported in post-marketing
experience or with an incidence of less than 1% of patients in clinical trials
with the 10 mg tablet: Body as a Whole: Syncope; malaise. Cardiovascular: Tachycardia; arrhythmia;
vasodilatation; palpitation; hypotension. Digestive: Vomiting; anorexia; diarrhea;
gastrointestinal pain; gastritis; thirst; flatulence; edema of the tongue;
abnormal liver function and rare reports of hepatitis, jaundice and
cholestasis. Hypersensitivity: Anaphylaxis; angioedema;
pruritis; facial edema; urticaria; rash. Musculoskeletal: Local weakness. 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. Skin: Sweating. Special Senses: Ageusia; tinnitus. Urogenital: Urinary frequency and/or
retention. ________________________ ^‡Note: Cyclobenzaprine HCl Tablets 10 mg data are from
one clinical trial. Cyclobenzaprine HCl Tablets 5 mg and placebo data are from
two studies. Causal Relationship Unknown Other reactions, reported rarely for cyclobenzaprine HCl under circumstances
where a causal relationship could not be established or reported for other
tricyclic drugs, are listed to serve as alerting information to physicians: Body as a Whole: Chest pain; edema. Cardiovascular: Hypertension; myocardial
infarction; heart block; stroke. Digestive: Paralytic ileus; tongue discoloration;
stomatitis; parotid swelling. Endocrine: Inappropriate ADH syndrome. Hematic and Lymphatic: Purpura; bone marrow
depression; leukopenia; eosinophilia; thrombocytopenia. Metabolic, Nutritional and Immune: Elevation and
lowering of blood sugar levels; weight gain or loss. Musculoskeletal: Myalgia. Nervous System and Psychiatric: Decreased or
increased libido; abnormal gait; delusions; aggressive behavior; paranoia;
peripheral neuropathy; Bell’s palsy; alteration in EEG patterns; extrapyramidal
symptoms. Respiratory: Dyspnea. Skin: Photosensitization; alopecia. Urogenital: Impaired urination; dilatation of
urinary tract; impotence; testicular swelling; gynecomastia; breast enlargement;
galactorrhea.

DRUG ABUSE AND DEPENDENCE

id: 91938448-6193-4629-8381-2d1a70c42cee
displayName: DRUG ABUSE AND DEPENDENCE SECTION
FDA Article Code: 42227-9

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

OVERDOSAGE

id: cf072482-c6e2-42d3-8ba1-7488ea740756
displayName: OVERDOSAGE SECTION
FDA Article Code: 34088-5

Although rare, deaths may occur from overdosage with
cyclobenzaprine HCl. 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 acute oral LD₅₀ of cyclobenzaprine HCl is approximately 338 and 425 mg/kg in
mice and rats, respectively. 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 cyclobenzaprine HCl 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 less than 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 overdosages are similar. It
is strongly recommended that the physician contact the local poison control
center for specific pediatric treatment.

DOSAGE AND ADMINISTRATION

id: f618023d-346b-4777-8ec5-1aa2cca70281
displayName: DOSAGE & ADMINISTRATION SECTION
FDA Article Code: 34068-7

For most patients, the recommended dose of cyclobenzaprine HCl is
5 mg three times a day. Based on individual patient response, the dose may be
increased to either 7.5 mg or 10 mg three times a day. Use of cyclobenzaprine
HCl for periods longer than two or three weeks is not recommended. (See INDICATIONS AND USAGE
.) Less frequent dosing should be considered for hepatically impaired or elderly
patients (see PRECAUTIONS, Impaired
Hepatic Function , and Use in
the Elderly ).

HOW SUPPLIED

id: aa60374a-1441-4f30-8d70-bd5f5c6cd58b
displayName: HOW SUPPLIED SECTION
FDA Article Code: 34069-5

Cyclobenzaprine Hydrochloride Tablets USP, 10 mg are round, white,
film-coated tablets imprinted DAN and 5658 supplied in bottles of 100, 500 and 1000. Dispense in a well-closed container with child-resistant closure. Store at 20°-25°C (68°-77°F). [See USP controlled
room temperature.] Watson Laboratories, Inc.

Corona, CA 92880
USA Rev: April 2005