Zapralda

Uses

Flexor is used for 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.

Zapralda is also used to associated treatment for these conditions: Muscle Spasms

How Zapralda works

The exact mechanism of action of cyclobenzaprine has not been fully elucidated in humans, and much of the information available regarding its mechanism has been ascertained from early animal studies. There is some evidence that cyclobenzaprine exerts its effects at the supraspinal level, specifically within the locus coeruleus of the brainstem, with little-to-no action at neuromuscular junctions or directly on skeletal musculature. Action on the brainstem is thought to result in diminished activity of efferent alpha and gamma motor neurons, likely mediated by inhibition of coeruleus-spinal or reticulospinal pathways, and ultimately depressed spinal cord interneuron activity.

More recently it has been suggested that inhibition of descending serotonergic pathways in the spinal cord via action on 5-HT2 receptors may contribute to cyclobenzaprine’s observed effects.

Dosage

Zapralda dosage

The usual dose is 5-10 mg three times daily given by mouth. The daily dose should not exceed 60 mg. Treatment for more than 2 or 3 weeks is not recommended.

Dose in elderly: Therapy with Flexor in the elderly should be initiated with a 5 mg dose and titrated slowly upward.

Dose in hepatic impairment: Flexor should be used with caution in subjects with mild hepatic impairment starting with the 5 mg dose and titrating slowly upward. The use of Flexor in subjects with moderate to severe impairment is not recommended.

Pediatric Use: Safety and effectiveness of Zapralda Hydrochloride in pediatric patients below 15 years of age have not been established.

Side Effects

The adverse reactions reported most frequently with Zapralda Hydrochloride are drowsiness, dry mouth and dizziness. The incidence of these common adverse reactions is lower in the surveillance program than in the controlled clinical studies.

Toxicity

The oral LD₅₀ of cyclobenzaprine in mice and rats is 338 mg/kg and 425 mg/kg, respectively. Signs of overdose may develop rapidly after ingestion and commonly include significant drowsiness and tachycardia, with less common manifestations including tremor, agitation, ataxia, GI upset, and other CNS effects such as confusion and hallucinations. Potentially critical manifestations, though rare, include cardiac arrest or dysrhythmias, severe hypotension, seizures, and neuroleptic malignant syndrome.

As the management of cyclobenzaprine overdose is complex and ever-changing, it is recommended that a poison control center be consulted prior to treatment. Typical management involves gastrointestinal decontamination, close cardiac monitoring, and monitoring for signs of CNS or respiratory depression. As cyclobenzaprine exists in relatively low concentrations in plasma, monitoring of drug plasma levels should not guide management and dialysis is likely of no value.

Precaution

Because of its atropine-like action, Zapralda Hydrochloride 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.

Interaction

Plasma concentration may be increased with the use of cimetidine, diltiazem, disulfiram, methylphenidate, ritonavir, and verapamil. Side-effects are increased by adrenaline, amiodarone, general anesthetics, SSRIs, antihistamines, antimuscarinics, antipsychotics, anxiolytics and hypnotics, clozapine, disopyramide, diuretics, flecainide, MAOIs, moclobemide, moxifloxacin, nefopam, nicorandil, noradrenaline, phenothiazine, pimozide, procainamide, propafenone, quinidine, selegiline, sibutramine, sotalol, terfenadine, thioridazine, and tramadol. Effects of adrenergic neurone blockers, clonidine, barbiturates, nitrates, and primidone are reduced while effects of baclofen, opioid analgesics, and thyroid hormones are enhanced with concomitant use of cyclobenzaprine. Carbamazepine and rifampicin may increase metabolism of cyclobenzaprine. Effects may be antagonized by oestrogens. Avoid use with brimonidine, entacapone, artemether with lumefantrine, or sibutramine. CNS effects may be enhanced by other CNS depressants.

Food Interaction

• Avoid alcohol. Zapralda is a central nervous system depressant which may be potentiated by the co-administration of alcohol.

[Moderate] GENERALLY AVOID: Alcohol may potentiate some of the pharmacologic effects of CNS-active agents.

Use in combination may result in additive central nervous system depression and
MANAGEMENT: Patients receiving CNS-active agents should be warned of this interaction and advised to avoid or limit consumption of alcohol.

Ambulatory patients should be counseled to avoid hazardous activities requiring complete mental alertness and motor coordination until they know how these agents affect them, and to notify their physician if they experience excessive or prolonged CNS effects that interfere with their normal activities.

Zapralda Drug Interaction

Major: duloxetine, duloxetine, acetaminophen / hydrocodone, acetaminophen / hydrocodoneModerate: diphenhydramine, diphenhydramine, pregabalin, pregabalin, alprazolam, alprazolam, cetirizine, cetirizineUnknown: omega-3 polyunsaturated fatty acids, omega-3 polyunsaturated fatty acids, cyanocobalamin, cyanocobalamin, ascorbic acid, ascorbic acid, cholecalciferol, cholecalciferol

Zapralda Disease Interaction

Major: cardiovascular diseaseModerate: anticholinergic effects

Volume of Distribution

The volume of distribution of cyclobenzaprine is approximately 146 L. The combination of high plasma clearance despite a relatively long half-life observed with cyclobenzaprine is suggestive of extensive tissue distribution.

Elimination Route

The oral bioavailability of cyclobenzaprine has been estimated to be between 0.33 and 0.55. C_max is between 5-35 ng/mL and is achieved after 4 hours (T_max). AUC over an 8 hour dosing interval was reported to be approximately 177 ng.hr/mL.

Half Life

The effective half-life of cyclobenzaprine in young healthy subjects is approximately 18 hours. These values are extended in the elderly and those with hepatic insufficiency, with a mean effective half-life of 33.4 hours and 46.2 hours in these groups, respectively.

Clearance

The approximate plasma clearance of cyclobenzaprine is 0.7 L/min.

Elimination Route

After administration of a radio-labeled dose of cyclobenzaprine, 38-51% of radioactivity was excreted in the urine while 14-15% was excreted in the feces. Zapralda is highly metabolized, with only approximately 1% of this same radio-labeled dose recovered in the urine as unchanged drug. Metabolites excreted in the urine are likely water-soluble glucuronide conjugates.

Pregnancy & Breastfeeding use

Pregnancy: Pregnancy category B. This drug should be used during pregnancy only if clearly needed.

Lactation: Caution should be exercised when Zapralda Hydrochloride is administered to a nursing mother.

Contraindication

Recent MI, arrhythmias, severe liver disease.

Special Warning

Dose in hepatic impairment: Zapralda should be used with caution in subjects with mild hepatic impairment starting with the 5 mg dose and titrating slowly upward. The use of Zapralda in subjects with moderate to severe impairment is not recommended.

Acute Overdose

Although rare, deaths may occur from over dosage with Zapralda Hydrochloride. Signs and symptoms of toxicity may develop rapidly after Zapralda overdose; therefore, hospital monitoring is required as soon as possible.

Innovators Monograph

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