Cyclobenzaprine hydrochloride

Pharmacological properties

cyclobenzaprine eliminates skeletal muscle spasm of local origin without affecting muscle function. the effectiveness of cyclobenzaprine has not been identified for muscle cramps resulting from a central nervous system disease. in animal models, cyclobenzaprine reduces or eliminates skeletal muscle hyperactivity. according to preclinical studies, cyclobenzaprine does not affect the neuromuscular synapse or directly on skeletal muscle. such studies show that cyclobenzaprine acts primarily on the central nervous system at the level of the brain stem, and not at the level of the spinal cord, although an additional effect on the latter may contribute to the overall ability of cyclobenzaprine to cause relaxation of skeletal muscles. experience shows that the result of the action of cyclobenzaprine is a decrease in tonic somatic motor activity due to the influence of both gamma (γ) and alpha (α) motor neurons. preclinical pharmacological studies have shown similarities between the effects of cyclobenzaprine and structurally related tricyclic antidepressants, including antagonism to reserpine, potentiation of the effects of norepinephrine, pronounced peripheral and central anticholinergic effects, as well as a sedative effect. cyclobenzaprine leads to an increase (from mild to moderate) heart rate in animals.

Pharmacokinetics Absorption. After applying a single dose of Myorix 15 mg or 30 mg by healthy volunteers (n = 15), indicators C_maxAUC_0–168hAUC_0–∞ increased approximately in proportion to the dose of 15 to 30 mg. Time to reach C_max plasma cyclobenzaprine (Tmax) is 7–8 hours for both doses of the drug.

A study of the effects of food intake, conducted with healthy volunteers (n = 15) using a single dose of Myorix 30 mg, showed a statistically significant increase in the bioavailability of Myorix 30 mg when taken with food compared with fasting. An increase in C was noted_max 35% plasma cyclobenzaprine and increased exposure (AUC_0–168hAUC_0–∞) 20% in the presence of food. However, no effect on the indicator T_max or the level of dependence of the average concentration of cyclobenzaprine in blood plasma on time. Cyclobenzaprine is first detected in blood plasma after 1.5 hours both when taken with food and on an empty stomach.

In a study using several doses of Myorix 30 mg once a day for 7 days in the group of healthy volunteers (n = 35), a 2.5-fold steady increase in the level of plasma cyclobenzaprine was observed.

Metabolism and excretion. Cyclobenzaprine is extensively metabolized and excreted from the body by the kidneys, primarily in the form of glucuronides. Cytochromes P450 3A4, 1A2 and to a lesser extent 2D6 mediate N-demethylation, one of the oxidative pathways of cyclobenzaprine metabolism. T_½ cyclobenzaprine is 32 hours (range 8–37 hours, n = 18); plasma clearance - 0.7 l / min after applying a single dose of Myorix.

Elderly patients. In patients over the age of 65 years, AUC in plasma plasma cyclobenzaprine increased by 40%, and the half-life of plasma cyclobenzaprine prolonged up to 50 hours after taking a single dose of the drug compared with patients aged 18–45 years (32 hours), although not notable differences were found between indicators C_max and Tmax. The pharmacokinetic properties of cyclobenzaprine after administration of several doses of Myorix in elderly patients have not been evaluated.

Patients with liver failure. In pharmacokinetic studies of immediate-release cyclobenzaprine in 16 patients with hepatic insufficiency (15 - mild, 1 - moderate on the Child-Pugh scale), both AUC and C_max were approximately 2 times higher than the values ​​in the control group of healthy volunteers. The pharmacokinetics of cyclobenzaprine in individuals with severe hepatic insufficiency is unknown.

Indications

Elimination of muscle spasm, accompanied by acute pain from the musculoskeletal system, in addition to the regime of limited physical activity and physiotherapy exercises. the improvement is manifested by the elimination of muscle cramps and related signs and symptoms, namely pain, increased sensitivity and limitation of movement.

Application

The recommended dose is 15 mg (1 capsule of Myorix 15 mg) 1 time per day. some patients require a dose increase of up to 30 mg once a day (1 capsule of Myorix 30 mg or 2 capsules of Myorix 15 mg).

The drug is taken daily at about the same time.

The use of the drug Myorix for more than 2-3 weeks is not recommended.

Elderly patients (65 years and older). Clinical studies of the use of the drug Myorix in this category of patients are not enough. The use of the drug Myorix in elderly patients is not recommended.

Patients with liver failure. The use of the drug Myorix is ​​not recommended for patients with mild, moderate or severe degree of liver failure (see SPECIAL INSTRUCTIONS).

Contraindications

Hypersensitivity reactions to the components of the drug, including anaphylactic reactions, urticaria, swelling of the face and / or tongue, itching. in case of suspicion of the development of hypersensitivity reactions, the use of the drug Myorix should be discontinued.

Simultaneous use with MAO inhibitors or within 14 days after their withdrawal. In patients taking cyclobenzaprine (or structurally similar tricyclic antidepressants) concurrently with MAO inhibitors, hyperpyretic crisis, convulsions, and death were observed.

During the recovery phase after acute myocardial infarction and in the presence of cardiac arrhythmias and conduction disorders, including blockade, or congestive heart failure.

Hyperthyroidism

Side effects

The most common adverse reactions in clinical studies of the drug Myorix. the most common adverse reactions that have been reported with a frequency of ≥3% are dry mouth, dizziness, fatigue, constipation, nausea, dyspepsia, and drowsiness.

Additional adverse reactions that have been reported in clinical studies and in post-marketing use. The following are adverse reactions that have been reported in clinical trials or in the post-marketing use of prolonged-release cyclobenzaprine, immediate-release cyclobenzaprine or tricyclic drugs. Since some of these reactions received voluntary reports from a population of uncertain numbers, it is not always possible to reliably estimate their frequency or establish a causal relationship with the effect of the use of the drug on their occurrence.

In the immediate-release post-registration monitoring program for cyclobenzaprine, frequent adverse reactions are drowsiness, dry mouth and dizziness, and adverse reactions that occurred in 1-3% of patients include fatigue / fatigue, asthenia, nausea, constipation, dyspepsia, bad taste, blurred vision headache, nervousness and confusion.

Adverse reactions that have been reported during post-marketing use of sustained release cyclobenzaprine or immediate release cyclobenzaprine, in clinical trials of immediate release cyclobenzaprine (with a frequency of 1%), or during post-marketing use of other tricyclic drugs are presented below.

Common disorders: fainting, malaise, chest pain, swelling.

From the cardiovascular system: tachycardia, arrhythmia, vasodilation, palpitations, arterial hypotension, hypertension, myocardial infarction, cardiac conduction blockade, stroke.

From the digestive system: vomiting, anorexia, diarrhea, abdominal pain, gastritis, thirst, flatulence, swelling of the tongue, impaired liver function and rare cases of hepatitis, jaundice and cholestasis, paralytic intestinal obstruction, discoloration of the tongue, stomatitis, edema of the parotid salivary gland .

From the endocrine system: syndrome of inadequate secretion of ADH.

On the part of the blood and lymphatic system: purpura, inhibition of bone marrow function, leukopenia, eosinophilia, thrombocytopenia.

Hypersensitivity reactions: anaphylactic shock, angioedema, itching, swelling of the face, urticaria, rash.

Metabolic, nutritional and immune disorders: increase or decrease in blood glucose, increase or decrease in body weight.

From the musculoskeletal system and connective tissue: local muscle weakness, myalgia.

From the side of the nervous system and psyche: seizures, ataxia, vertigo, dysarthria, tremor, hypertension, cramps, muscle twitching, disorientation, insomnia, depressed mood, unusual sensations, anxiety, agitation, psychosis, abnormal thoughts and dreams, hallucinations, excitements, paresthesia, diplopia, serotonin syndrome, malignant antipsychotic syndrome, decreased or increased libido, gait disturbance, delirium, aggressive behavior, paranoia, peripheral neuropathy, Bell paralysis, changes in EEG, extrapyramidal symptoms.

From the respiratory system: shortness of breath.

From the skin and subcutaneous tissues: increased sweating, photosensitivity, alopecia.

From the sensory organs: ageusia, tinnitus.

From the side of the kidneys and urinary tract: increase and / or decrease in the frequency of urination, impaired urination, dilatation of the urinary tract, impotence, testicular edema, gynecomastia, breast enlargement, galactorrhea.

special instructions

Limitation of use. Myorix should be used only for a short period (up to 2-3 weeks), since there is no sufficient evidence of effectiveness when using the drug for a longer time, and therefore muscle spasm associated with acute pain from the musculoskeletal system, mainly short-term, and specific therapy over a long period is rarely justified.

The effectiveness of the use of the drug Myorix for the treatment of muscle spasticity associated with diseases of the brain or spinal cord, or with cerebral palsy has not been identified.

Serotonin syndrome. The development of a potentially life-threatening serotonin syndrome has been reported with cyclobenzaprine in combination with other drugs, such as selective serotonin reuptake inhibitors, selective serotonin and noradrenaline reuptake inhibitors, tricyclic antidepressants, tramadol, bupropion, meperidine, verapamil or. The simultaneous use of the drug Myorix with MAO inhibitors is contraindicated (see CONTRAINDICATIONS). Symptoms of the serotonin syndrome may include changes in the mental state (for example, confusion, agitation, hallucinations), disorders of the autonomic nervous system (such as increased sweating, tachycardia, blood pressure lability, hyperthermia), neuromuscular disorders (in particular tremor, ataxia, hyperreflexia , clonus, muscle stiffness) and / or gastrointestinal symptoms (e.g. nausea, vomiting, diarrhea). If the above reactions develop, it is necessary to immediately stop taking Myorix and any concomitant serotonergic agents and begin symptomatic treatment.If simultaneous treatment with Myorix and other serotonergic drugs is clinically justified, careful monitoring of the patients condition is recommended, especially at the beginning of treatment or with an increase in dose.

Effects similar to those associated with tricyclic antidepressants. Cyclobenzaprine is structurally similar to tricyclic antidepressants, such as amitriptyline and imipramine. In the case of the use of tricyclic antidepressants, cases of arrhythmia, sinus tachycardia, an increase in the time of excitation in the heart, leading to the development of myocardial infarction and stroke, have been reported (see CONTRAINDICATIONS). The drug Myorix can enhance the effect of alcohol, barbiturates and other drugs that depress the central nervous system.

Some of the more serious reactions from the central nervous system that were observed with tricyclic antidepressants were noted in short-term studies using cyclobenzaprine for other indications, except for muscle spasm associated with acute disorders of the musculoskeletal system, and mainly in doses, of several higher than those recommended for eliminating skeletal muscle spasm. If clinically significant symptoms of the central nervous system occur, the use of the drug Myorix should be discontinued.

Elderly patients. The use of the drug Myorix in elderly patients is not recommended due to an increase in the level of cyclobenzaprine in blood plasma by 40% and an increase in T_½ 56% compared with the corresponding indicators in young patients.

Patients with liver failure. The use of the drug Myorix is ​​not recommended for patients with mild, moderate or severe liver failure due to a 2-fold increase in the level of plasma cyclobenzaprine in patients with mild hepatic impairment compared with healthy volunteers after the use of cyclobenzaprine in the form of immediate release and due to limitations in the dosage range of the drug.

Atropine-like action. Due to the presence of an atropine-like effect, Myorix should be used with caution in patients with a history of urinary retention, angle-closure glaucoma, increased intraocular pressure, and patients taking anticholinergics.

Dependence. The pharmacological similarity of tricyclic drugs causes the occurrence of certain withdrawal symptoms after using the Myorix drug, even if they are not reported. Sudden withdrawal of the drug after prolonged use can sometimes cause nausea, headache and malaise. These symptoms do not indicate the development of addiction.

Use during pregnancy and lactation. Pregnancy. Adequate and well-controlled studies of the drug Myorix involving pregnant women have not been conducted. Myorix can be used during pregnancy only if absolutely necessary.

Lactation. There is no data on the excretion of the drug in breast milk. Since cyclobenzaprine is close to tricyclic antidepressants, many of which are known to be excreted in breast milk, Myorix should be used with caution during breastfeeding.

Children. Clinical data on the effectiveness and safety of the drug in children are not available, therefore Myorix is ​​not recommended for use in pediatric practice.

The ability to influence the reaction rate when driving vehicles or other mechanisms. The possible development of adverse reactions should be taken into account (see ADVERSE EFFECTS).

Interactions

Due to its structural similarity to tricyclic antidepressants, the myorix drug can cause life-threatening interactions with MAO inhibitors (seecontraindications), enhance the effect of alcohol, barbiturates and other drugs that inhibit central nervous system, increase the risk of convulsive seizures in patients using tramadol, or block the antihypertensive effect of guanethidine and similarly acting compounds.

In the post-marketing period of drug use, cases of serotonin syndrome were reported with combined use of cyclobenzaprine with other drugs, such as selective serotonin reuptake inhibitors, selective serotonin and norepinephrine reuptake inhibitors, tricyclic antidepressants, tramadol, bupropion, meperidine or meperidine meperidine.

Overdose

Symptoms the most common symptoms of an overdose of cyclobenzaprine are drowsiness and tachycardia. less frequent manifestations include tremor, agitation, coma, ataxia, ag, slurred speech, confusion, dizziness, nausea, vomiting, and hallucinations. rare but potentially critical manifestations of an overdose include heart failure, chest pain, arrhythmia, severe arterial hypotension, convulsions, and malignant antipsychotic 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 an overdose include any of the symptoms listed in the side effects section.

With a deliberate overdose of cyclobenzaprine, its use in combination with several drugs, as well as with alcohol, is frequent. After an overdose of cyclobenzaprine, symptoms of poisoning can develop quickly, so monitoring the patients condition in a hospital is necessary as soon as possible. An overdose of Myorix can rarely be fatal.

Treatment. The general. To prevent the occurrence of the rare, but potentially critical manifestations described above, it is necessary to conduct an ECG and immediately begin monitoring cardiac activity. It should also protect the patients airways, provide iv access and begin decontamination of the stomach. Monitoring is also necessary to detect signs of central nervous system depression or breathing, hypotension, cardiac arrhythmias and / or blockade of cardiac conduction, seizures. If at any time during this period signs of poisoning occur, extended surveillance will be required. Monitoring blood drug levels should not affect patient management. Dialysis is probably ineffective due to the low concentration of the drug in blood plasma.

Decontamination of the digestive tract. All patients who suspect an overdose of Myorix should have a GI decontamination. It should include washing the stomach with large volumes of fluid, followed by the use of activated carbon. If the consciousness is confused, it is necessary to ensure the patency of the airways before washing the stomach, inducing vomiting is contraindicated.

The cardiovascular system. Maximum QRS duration in standard leads of 0.10 s may be the best indicator of overdose severity. Alkalization of blood serum to a pH of 7.45–7.55 by iv administration of sodium bicarbonate and hyperventilation (if necessary) should be carried out in patients with arrhythmia and / or expansion of the QRS complex. PH 7.60 or pCO₂ 20 mmHg Art. undesirable. Arrhythmias that do not respond to sodium bicarbonate therapy / hyperventilation may respond to treatment with lidocaine, bretilium, or phenytoin. Class 1A and 1C antiarrhythmic drugs (e.g. quinidine, disopyramide, and procainamide) are usually contraindicated.

CNS. Patients with central nervous system depression are recommended for early intubation due to the possibility of a sharp deterioration.Seizures should be controlled with benzodiazepines or, if the latter are ineffective, with other anticonvulsants (e.g. phenobarbital, phenytoin). Physostigmine is not recommended, except for the treatment of life-threatening symptoms and are unresponsive to other methods of treatment, and only with inpatient treatment.

Psychiatric observation. Because overdose is often deliberate, patients may repeat suicide attempts with other means during the recovery phase. For such patients, a psychiatrist consultation may be appropriate.

Treatment of overdose in children. The principles of overdose in children and adults are similar.

Storage conditions

At a temperature not exceeding 25 ° C.

UA / MRX / 1018/0026