Reloprim (Tablets) Instructions for Use

Marketing Authorization Holder

Akrikhin Chemical and Pharmaceutical Plant, JSC (Russia)

Contact Information

AKRIKHIN JSC (Russia)

ATC Code

M03BX08 (Cyclobenzaprine)

Active Substance

Cyclobenzaprine (Rec.INN registered by WHO)

Dosage Forms

	Reloprim	Film-coated tablets, 5 mg: 30 pcs.
		Film-coated tablets, 10 mg: 30 pcs.

Dosage Form, Packaging, and Composition

Film-coated tablets from light brown to brown with a pinkish tint, round, biconvex; the core on the cross-section is white or white with a grayish or yellowish tint.

Excipients: microcrystalline cellulose, lactose monohydrate, croscarmellose sodium, colloidal silicon dioxide, calcium stearate, ready-made mixture Opadry 20A250021 RED [hypromellose, hypromellose, titanium dioxide, red iron oxide].

10 pcs. – contour cell packaging (3) – cardboard packs.

Film-coated tablets from light brown to brown with a pinkish tint, round, biconvex; the core on the cross-section is white or white with a grayish or yellowish tint.

Excipients: microcrystalline cellulose, lactose monohydrate, croscarmellose sodium, colloidal silicon dioxide, calcium stearate, ready-made mixture Opadry 20A250021 RED [hypromellose, hypromellose, titanium dioxide, red iron oxide].

10 pcs. – contour cell packaging (3) – cardboard packs.

Clinical-Pharmacological Group

Centrally acting muscle relaxant

Pharmacotherapeutic Group

Centrally-acting muscle relaxant

Pharmacological Action

Cyclobenzaprine eliminates locally originating skeletal muscle spasm without affecting muscle function.

No efficacy of cyclobenzaprine has been identified for muscle spasms resulting from CNS disease. In animal models, Cyclobenzaprine reduces or eliminates skeletal muscle hyperactivity. According to preclinical studies, Cyclobenzaprine does not affect the neuromuscular junction or directly affect skeletal muscles. Such studies indicate that Cyclobenzaprine acts on the CNS primarily at the brainstem level rather than at the spinal cord level, although an additional effect on the latter may contribute to the overall ability of cyclobenzaprine to cause skeletal muscle relaxation.

Experience shows that the result of cyclobenzaprine’s action is a reduction in tonic somatic motor activity due to an effect on both gamma (γ) and alpha (α) motor neurons. Preclinical pharmacological studies have demonstrated similarities between the effects of cyclobenzaprine and structurally related tricyclic antidepressants, including reserpine antagonism, potentiation of norepinephrine action, pronounced peripheral and central anticholinergic effects, and a sedative effect. Cyclobenzaprine leads to an increase (from mild to moderate) in heart rate in animals.

Clinical efficacy and safety

A number of studies have shown the superiority of cyclobenzaprine over placebo in terms of reducing back and neck pain, reducing muscle tenderness, severity of spasm, increasing range of motion, and daily activity.

In the course of 2 randomized double-blind placebo-controlled studies, Cyclobenzaprine showed greater efficacy compared to placebo. A total of 1405 patients with back and neck pain were randomized. Patients took either Cyclobenzaprine at a dose of 2.5, 5, and 10 mg three times a day or placebo for 7 days.

Patients taking Cyclobenzaprine at doses of 5 and 10 mg achieved higher scores on all efficacy endpoints: patient’s global impression of therapy, treatment benefit, and pain reduction. On day 7, a significantly greater number of patients taking Cyclobenzaprine at all studied doses reported pain reduction compared to placebo. The researchers noted good tolerability of cyclobenzaprine. Drowsiness and dry mouth were the most common side effects, were moderate, and were dose-dependent.

Preclinical safety data

Preclinical data obtained from standard studies of pharmacological safety, repeated-dose toxicity, genotoxicity, carcinogenic potential, and reproductive and ontogenetic toxicity did not reveal any particular harm to humans.

Pharmacokinetics

Absorption

The average bioavailability of cyclobenzaprine after oral administration ranges from 33% to 55%. The maximum concentration (C_max) of cyclobenzaprine in blood plasma after oral administration is 5-35 ng/ml 4 hours after administration, and the drug dose (5, 10, or 20 mg) has little effect on C_max.

Distribution

Cyclobenzaprine has a high degree of binding to plasma proteins.

Cyclobenzaprine is characterized by a large volume of distribution and undergoes enterohepatic circulation.

Metabolism

Cyclobenzaprine undergoes a “first-pass” effect through the liver after absorption in the intestine and is metabolized to a significant extent. Cytochrome P450 isoenzymes – P2A, 2D6, and to a lesser extent 3A4, are involved in metabolism via N-demethylation, which is one of the oxidative pathways of cyclobenzaprine metabolism.

Excretion

About 10-20% of the drug is excreted by the kidneys as glucuronides. After oral administration, renal excretion is greater than after intravenous and intramuscular administration. Only a small amount of unchanged cyclobenzaprine is detected in the urine.

Cyclobenzaprine is eliminated rather slowly, the effective half-life is 18 hours (range from 8 to 37 hours; n=18); plasma clearance is 0.7 L/min.

Despite the long effective half-life, the duration of pharmacological action is 4-6 hours, but in some patients it can last significantly longer. At a cyclobenzaprine dose of 10 mg or more, the effective therapeutic concentration is achieved significantly faster than at a dose of 5 mg.

When taken three times a day, the drug accumulates, reaching a steady state within 3-4 days, with a plasma concentration approximately four times the concentration after a single dose.

Linearity (non-linearity)

Cyclobenzaprine exhibits linear pharmacokinetics in the dose range from 2.5 mg to 10 mg.

Special patient groups

Elderly patients. A study was conducted to investigate the pharmacokinetics of cyclobenzaprine in 12 elderly male and female volunteers aged 65-79 years. All volunteers took Cyclobenzaprine at a dose of 5 mg orally in tablet form three times a day for 7 days. The last dose was taken on the 8th day. The results were compared with the results of young volunteers. The steady-state concentration of cyclobenzaprine in elderly volunteers after taking cyclobenzaprine at a dose of 5 mg three times a day was 2 times higher than in young volunteers.

Patients with impaired liver function. A pharmacokinetic study involved 16 male and female volunteers aged 41-67 years with moderate hepatic insufficiency associated with alcoholism and assessed by Child-Pugh score from 5 to 8 points. All volunteers took Cyclobenzaprine at a dose of 5 mg orally in tablet form three times a day for 7 days. One last dose was taken on the 8th day. The steady-state concentration of cyclobenzaprine in volunteers with moderate hepatic insufficiency after taking cyclobenzaprine at a dose of 5 mg three times a day was 2 times higher compared to healthy young volunteers. T_1/2 in this group averaged 46.2 hours (compared to T_1/2=18 hours in healthy young volunteers).

Children. No data available.

Indications

Treatment of painful pathologically increased tone and spasm of striated muscles in adults over 18 years of age with the following conditions

• Dorsopathy;
• Dorsalgia;
• Cervicalgia;
• Lumbalgia;
• Thoracalgia;
• Sciatica.

ICD codes

Dosage Regimen

Adults (18 years – 64 years) are prescribed 5 mg every 8 hours; if necessary, the dose can be increased to 7.5-10 mg every 8 hours.

Special patient groups

Elderly patients (over 65 years). Elderly patients should start taking the drug at a dose of 5 mg with a gradual increase in dose. If necessary, the possibility of reducing the frequency of drug administration should be considered.

Patients with impaired renal function

The use of cyclobenzaprine drugs in patients with impaired renal function has not been studied.

Patients with impaired liver function

The drug should be used with caution in patients with mild liver dysfunction, starting with a dose of 5 mg per day with a gradual increase in dose. If necessary, the possibility of reducing the frequency of drug administration should be considered.

Due to insufficient data on the efficacy and safety of cyclobenzaprine use in patients with more severe liver dysfunction, the use of the drug in patients with moderate and severe liver dysfunction is not recommended.

Data on the safety and efficacy of cyclobenzaprine use in children and adolescents under 18 years of age are not available.

Method of administration – orally.

If the patient forgot to take Reloprim

In case of a missed dose, the patient should take the prescribed dose as soon as they remember. If it is time for the next dose, then the drug should be taken without doubling the dose and return to the usual dosing schedule.

The duration of administration is determined by the doctor. The patient should not stop taking the drug on their own without a doctor’s prescription.

Adverse Reactions

The most typical (frequency ≥ 3% when taking cyclobenzaprine 5 mg) adverse reactions recorded during clinical studies of cyclobenzaprine at doses of 5 and 10 mg were drowsiness, dry mouth, fatigue, headache.

Adverse reactions recorded in 1-3% of patients: abdominal pain, gastroesophageal reflux, constipation, diarrhea, nausea, dizziness, irritability, impaired mental performance, anxiety, upper respiratory tract infection and pharyngitis.

The frequency of adverse reactions is dose-dependent. The frequency of drowsiness during the use of cyclobenzaprine at a dose of 5 mg three times a day was significantly reduced compared to taking cyclobenzaprine at a dose of 10 mg three times a day. The frequency of adverse reactions in the post-registration study of cyclobenzaprine use was significantly lower than the frequency of adverse reactions recorded in the clinical trials.

Adverse reactions are listed below by system organ class and frequency of occurrence. Frequency of occurrence is defined as: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1000 to <1/100); rare (≥1/10000 to <1/1000); very rare (<1/10000) and unknown (cannot be estimated from the available data).

Frequency of adverse reactions identified in clinical studies of immediate-release cyclobenzaprine and from literature data

Reporting of suspected adverse reactions

It is important to report suspected adverse reactions after drug registration to ensure continuous monitoring of the benefit-risk ratio of the drug. Healthcare professionals are encouraged to report any suspected adverse drug reactions through the national adverse reaction reporting systems of the member states of the Eurasian Economic Union.

Contraindications

• Hypersensitivity to cyclobenzaprine or to any of the excipients;
• Concomitant use with MAO inhibitors or within 14 days after their discontinuation;
• In children and adolescents under 18 years of age (due to lack of data);
• Recovery period after acute myocardial infarction;
• Cardiac arrhythmias and conduction disorders, including heart block;
• Congestive heart failure;
• Hyperthyroidism.

Use in Pregnancy and Lactation

Pregnancy

Adequate and well-controlled studies of cyclobenzaprine in pregnant women have not been conducted. Use during pregnancy is possible only in cases where the intended benefit to the mother outweighs the potential risk to the fetus.

Lactation

There are no data on the excretion of the drug into breast milk. Since Cyclobenzaprine is structurally similar to tricyclic antidepressants, many of which are known to be excreted in breast milk, if it is necessary to use the drug during lactation, the issue of discontinuing breastfeeding should be decided.

Fertility

When administered at doses up to 10 times the recommended human dose, Cyclobenzaprine did not have a negative effect on the fertility and reproductive potential of male and female rats.

Use in Hepatic Impairment

The concentration of cyclobenzaprine in patients with impaired liver function increases. These patients are usually more sensitive to drugs with potential sedative effects, including Cyclobenzaprine. Cyclobenzaprine should be used with caution in patients with mild liver dysfunction. Patients with mild liver dysfunction should be prescribed the drug at an initial dose of 5 mg with a gradual increase in dose. Due to insufficient data on use in patients with more severe liver dysfunction, the use of the drug in patients with moderate to severe liver dysfunction is not recommended.

Use in Renal Impairment

In case of impaired liver function, dose adjustment may be required.

Pediatric Use

Contraindicated for use in children and adolescents under 18 years of age.

Geriatric Use

In elderly patients, there may be an increased risk of adverse reactions from the central nervous system, such as hallucinations and confusion, and adverse reactions from the cardiovascular system, which can lead to fainting and other consequences, as well as the risk of drug interactions and the effect of the drug on concomitant diseases. In this regard, Cyclobenzaprine should be used in elderly patients only in case of urgent need. Elderly patients should be prescribed the drug at an initial dose of 5 mg with a gradual increase in dose. If necessary, the possibility of reducing the frequency of drug administration should be considered.

Special Precautions

Limitations of Use

Cyclobenzaprine should be used only for a short period (up to 2-3 weeks) because there is insufficient evidence of efficacy for longer use, and because pathological tone and spasm of skeletal muscles in musculoskeletal diseases are mostly short-term, and specific long-term therapy is rarely justified.

No efficacy has been identified for the use of cyclobenzaprine in the treatment of muscle spasm associated with diseases of the brain or spinal cord, or with cerebral palsy.

Serotonin Syndrome

The development of a potentially life-threatening serotonin syndrome has been reported with the use of cyclobenzaprine in combination with the following drugs: selective serotonin reuptake inhibitors, serotonin and norepinephrine reuptake inhibitors, tricyclic antidepressants, tramadol, bupropion, meperidine, verapamil, or MAO inhibitors.

Concomitant use of cyclobenzaprine with MAO inhibitors is contraindicated (see section “Contraindications”). Symptoms of serotonin syndrome may include mental status changes (e.g., confusion, agitation, hallucinations), autonomic nervous system disorders (such as increased sweating, tachycardia, blood pressure lability, hyperthermia), neuromuscular disorders (particularly tremor, ataxia, hyperreflexia, clonus, muscle rigidity) and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). If the above reactions develop, it is necessary to immediately discontinue the drug and any concomitant serotonergic substances and initiate symptomatic treatment. If concomitant treatment with cyclobenzaprine and other serotonergic drugs is clinically justified, careful monitoring of the patient’s condition is recommended, especially at the start of treatment or when increasing the dose.

Effects Similar to Those of Tricyclic Antidepressants

Cyclobenzaprine is structurally similar to tricyclic antidepressants, for example, amitriptyline and imipramine. Cases of arrhythmia, sinus tachycardia, and prolonged cardiac conduction time have been reported with the use of tricyclic antidepressants, which may lead to myocardial infarction and stroke (see section “Contraindications”).

Reloprim may enhance the effect of alcohol, barbiturates, and other drugs that depress the CNS.

Some of the more serious CNS reactions accompanying the use of tricyclic antidepressants were noted in short-term studies with the use of cyclobenzaprine for indications other than pathological tone and spasm of skeletal muscles in musculoskeletal diseases, and mainly at doses exceeding the recommended ones. If clinically significant CNS symptoms occur, the use of the drug should be discontinued.

Elderly Patients

The plasma concentration of cyclobenzaprine in elderly patients is increased (see section “Pharmacokinetics”). Also, elderly patients may have an increased risk of CNS adverse reactions such as hallucinations and confusion, and cardiovascular adverse reactions that may lead to fainting and other consequences, as well as the risk of drug interactions and the effect of the drug on concomitant diseases. In this regard, Cyclobenzaprine should be used in elderly patients only in case of acute necessity. Elderly patients should be prescribed the drug at an initial dose of 5 mg with a gradual dose increase. If necessary, the possibility of reducing the frequency of drug administration should be considered.

Patients with Hepatic Impairment

The concentration of cyclobenzaprine in patients with impaired liver function is increased (see section “Pharmacokinetics”). These patients are usually more sensitive to drugs with potential sedative effects, including Cyclobenzaprine. Cyclobenzaprine should be used with caution in patients with mild hepatic impairment. Patients with mild hepatic impairment should be prescribed the drug at an initial dose of 5 mg with a gradual dose increase. Due to insufficient data on use in patients with more severe hepatic impairment, the use of the drug in patients with moderate to severe hepatic impairment is not recommended.

Atropine-like Action

Due to the 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 drugs.

Dependence

Sudden withdrawal of the drug after long-term use may in rare cases cause nausea, headache, and malaise. These symptoms do not indicate the development of dependence.

Children

Cyclobenzaprine should not be used in pediatric practice because clinical data on the efficacy and safety of the drug in children under 18 years of age are lacking.

Excipients

The drug contains lactose monohydrate. Patients with rare hereditary galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption should not take this drug.

Reloprim contains less than 1 mmol (23 mg) of sodium per 1 tablet, i.e., it is essentially sodium-free.

Effect on Ability to Drive and Operate Machinery

Due to the risk of adverse reactions such as dizziness, fatigue, and drowsiness, during treatment, patients should refrain from driving vehicles and engaging in other potentially hazardous activities that require increased concentration and speed of psychomotor reactions.

Overdose

Symptoms

The most common symptoms of 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 include cardiac arrest, chest pain, arrhythmia, severe arterial hypotension, seizures, and malignant neuroleptic syndrome. ECG abnormalities, especially changes in the height or width of the QRS complex, are clinically significant indicators of cyclobenzaprine overdose. Other potential consequences of overdose include any of the signs listed in the “Adverse Reactions” section.

In intentional cyclobenzaprine overdose, its use with multiple medications, as well as with alcohol, is often encountered. After cyclobenzaprine overdose, symptoms of poisoning may develop rapidly, so patient monitoring in a hospital setting should be initiated as soon as possible. Cyclobenzaprine overdose can rarely be fatal.

Other potential consequences of overdose include any of the signs listed in the “Adverse Reactions” section.

Treatment

General

To prevent the occurrence of rare but potentially critical manifestations described above, an ECG should be performed and cardiac monitoring should be initiated immediately. The patient’s airway should be secured, intravenous access should be established, and gastric lavage should be initiated. Monitoring for signs of CNS or respiratory depression, hypotension, cardiac arrhythmia and/or cardiac conduction block, and seizures is also necessary. If signs of poisoning appear at any time during this period, longer observation will be required. Treatment tactics should not be based on blood drug concentration. Dialysis is probably ineffective due to the low plasma concentration of the drug.

Gastrointestinal Decontamination

All patients suspected of cyclobenzaprine overdose should undergo gastrointestinal decontamination. It should include gastric lavage with large volumes of fluid followed by the use of activated charcoal. If consciousness is impaired, the airway should be secured before gastric lavage; induction of vomiting is contraindicated.

Cardiovascular System

A maximum QRS duration in standard leads of ≥0.10 s may be the best indicator of overdose severity. Serum alkalinization to a pH level of 7.45-7.55 by intravenous administration of sodium bicarbonate and hyperventilation (if necessary) should be performed in patients with arrhythmia and/or QRS complex widening. A pH >7.60 or pCO₂<20 mmHg is undesirable. Arrhythmias that do not respond to sodium bicarbonate/hyperventilation therapy may respond to treatment with lidocaine, bretylium, or phenytoin. Class 1A and 1C antiarrhythmic drugs (e.g., quinidine, disopyramide, and procainamide) are generally contraindicated.

CNS

Patients with CNS depression are recommended for early intubation due to the possibility of sudden deterioration. Seizures should be controlled with benzodiazepines or, if the latter are ineffective, with other anticonvulsant drugs (e.g., phenobarbital, phenytoin). Physostigmine is not recommended, except for the treatment of life-threatening symptoms that are unresponsive to other treatments, and only under inpatient conditions.

Psychiatric Observation

Since overdose is often intentional, during the recovery phase, patients may repeat suicide attempts using other means. A psychiatric consultation may be appropriate for such patients.

Drug Interactions

Due to its structural similarity to tricyclic antidepressants, cyclobenzaprine may cause life-threatening interactions with MAO inhibitors (see section “Contraindications”), enhance the effects of alcohol, barbiturates, and other CNS depressants, increase the risk of seizures in patients using tramadol, or block the antihypertensive effect of guanethidine and similarly acting compounds.

There are reports of cases of serotonin syndrome developing during concomitant use of cyclobenzaprine and other drugs, such as selective serotonin reuptake inhibitors, serotonin and norepinephrine reuptake inhibitors, tricyclic antidepressants, tramadol, bupropion, meperidine, verapamil, or MAO inhibitors.

Storage Conditions

The drug should be stored out of the reach of children at a temperature not exceeding 25°C (77°F).

Shelf Life

Shelf life is 2 years.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.