Cyclobenzaprine relieves local skeletal muscle spasm without directly interfering with muscle function. Cyclobenzaprine has been shown to be ineffective in muscle spasms associated with central nervous system damage. In animal simulations, cyclobenzaprine reduced or abolished skeletal muscle hyperactivity. Research has shown that cyclobenzaprine does not affect neuromuscular synapses or skeletal muscle directly.
These studies indicate that cyclobenzaprine acts primarily at the level of the brainstem and only a secondary effect occurs at the level of the spinal cord, although the effect on the latter may contribute to the overall relaxing effect of the drug on skeletal muscle. The effect of cyclobenzaprine is to decrease tonic somatic motor activity, affecting both gamma (γ-) and alpha- (α-) motor systems.Pharmacological studies have demonstrated the similarity of the effects of cyclobenzaprine and structurally related tricyclic antidepressants, including an antagonistic effect on reserpine, potentiation of the action of norepinephrine, strong peripheral and central anticholinergic effects, and sedation.
The pharmacokinetic parameters of Miorix®, Cmax, AUC0-168h and AUC0-∞, are dose-dependent and increase in direct proportion to the dose of the drug taken. With a single dose of the drug in doses of 15 and 30 mg, the maximum concentration of cyclobenzaprine in plasma (Tmax) is achieved after 7-8 hours.
A study of the effect of food intake, conducted on healthy adult volunteers (n = 15) using a single dose of Miorix® 30 mg, demonstrated a statistically significant increase in the bioavailability of Miorix® 30 mg with food intake compared to fasting. There was a 35% increase in peak plasma cyclobenzaprine concentration (Cmax) and a 20% increase in exposure (AUC0-168h and AUC0-∞) with food intake. However, no effect was found on the maximum (Tmax) or mean plasma cyclobenzaprine concentration relative to the time profile. The first concentrations of cyclobenzaprine in plasma appear after 1.5 hours both with food intake and on an empty stomach.
In studies of repeated administration of the drug Miorix® 30 mg (for 7 days once a day), a 2.5-fold increase in the level of cyclobenzaprine in blood plasma was revealed in healthy individuals (n = 35).
Metabolism and excretion
Cyclobenzaprine is extensively metabolized and excreted via the kidneys, primarily as glucuronides. Cytochromes P-450 3A4, 1A2, to a lesser extent 2D6, are involved in metabolism through N-dimethylation (one of the oxidative pathways of cyclobenzaprine metabolism). The half-life of cyclobenzaprine is 32 hours (range 8-37 hours); total clearance after taking a single dose of Miorix® 0.7 l / min.
In elderly patients over 65 years of age, there were no significant differences in pharmacokinetic parameters (Cmax or Tmax) compared with younger patients aged 18-45 years, however, the plasma AUC of cyclobenzaprine in elderly people increases by 40% and the half-life of cyclobenzaprine in blood plasma is longer (32 hours for 18-45 years old and up to 50 hours for the elderly). The pharmacokinetic parameters of cyclobenzaprine after taking multiple doses of Miorix® in the elderly have not been evaluated.
The data of studies of pharmacokinetic parameters in patients with mild to moderate severity of hepatic dysfunction (according to the Child Pugh classification) showed an approximately two-fold increase in AUC and Cmax compared to those in a healthy control group. The pharmacokinetics of cyclobenzaprine in patients with severely impaired liver function have not been studied.
Hypersensitivity to any component of this drug. May manifest as an anaphylactic reaction, hives, swelling of the face and / or tongue, or itching. If you suspect a hypersensitivity reaction, stop taking Miorix®
concomitant use of monoamine oxidase inhibitors (MAOs) or use within 14 days of stopping them
acute phase of myocardial infarction, arrhythmias, blockade of the cardiac conduction system, conduction disturbances or congestive heart failure
children under 18 years old
The most common adverse reactions (≥ 3%):
Adverse reactions with a frequency of 1-3%:
confusion of consciousness
Adverse reactions with a frequency of <1%
General symptoms: fainting, malaise, chest pain, swelling.
Cardiovascular system: tachycardia; arrhythmia; vasodilation; palpitations; hypotension; hypertension; myocardial infarction; heart block; stroke.
Digestive system: vomiting; anorexia; diarrhea; gastrointestinal pain; gastritis; thirst; flatulence; swelling of the tongue; impaired liver function and rare reports of hepatitis, jaundice, cholestasis; paralytic intestinal obstruction, discoloration of the tongue; stomatitis; swelling of the parotid glands.
Endocrine system: syndrome of inappropriate antidiuretic hormone secretion.
Hematological and lymphatic disorders: hemorrhagic rash; suppression of bone marrow activity; leukopenia; eosinophilia; thrombocytopenia.
Hypersensitivity: anaphylactic shock; angioedema; itching; swelling of the face; hives; rash.
On the part of the immune system, metabolism and nutrition: increase and decrease in blood sugar, increase or loss of body weight.
Musculoskeletal system disorders: local weakness; myalgia.
Nervous system and mental state: convulsions, ataxia; dizziness; dysarthria; trembling; hypertension; convulsions; muscle twitching; violation of orientation; insomnia; depressed mood; abnormal sensitivity; anxiety; excitation; psychosis, pathological thinking and dreams; hallucinations; emotional excitement; paresthesia; diplopia; serotonin syndrome; neuroleptic malignant syndrome; decrease or increase in libido; atypical gait; rave; aggressive behavior; paranoia; peripheral neuropathy; Bell's palsy; EEG violation; extrapyramidal symptoms.
Respiratory system: shortness of breath.
Skin: sweating; photosensitivity; alopecia.
Sense organs: loss of gustatory sensitivity; noise in ears.
Urogenital system: frequent urination and / or urinary retention; impaired urination; stretching of the urinary tract; impotence; testicular swelling; gynecomastia; breast augmentation; galactorrhea.
Based on its structural similarity to tricyclic antidepressants, Miorix® may have life-threatening interactions with MAO inhibitors and may enhance the effects of alcohol, barbiturates and other CNS depressants. May increase the risk of seizures in patients taking tramadol, may also block the antihypertensive effect of guanethidine and similarly acting compounds.
There have been cases of serotonin syndrome during the combined use of cyclobenzaprine and other drugs, such as selective serotonin reuptake inhibitors, selective serotonin and norepinephrine reuptake inhibitors, tricyclic antidepressants, tramadol, bupropion, trimeperidine, MA inhibitors, or verapamil inhibitors.
Symptoms: The most common effects associated with cyclobenzaprine overdose are drowsiness and tachycardia. Less common manifestations include tremors, agitation, coma, ataxia, hypertension, slurred speech, confusion, dizziness, nausea, vomiting, and hallucinations. Rare but potentially important manifestations of overdose are cardiac arrest, chest pain, cardiac arrhythmias, severe hypotension, seizures, and neuroleptic malignant syndrome. Changes in the electrocardiogram, in particular the QRS complex, are clinically significant indicators of cyclobenzaprine toxicity.
Removal from the gastrointestinal tract
All patients with suspected overdose with Miorix® need to have a gastric lavage with a large volume of water followed by the intake of activated carbon. If consciousness is impaired, then the airways must be protected before gastric lavage and induction of vomiting is contraindicated.
The cardiovascular system
A maximum QRS duration of 0.10 seconds may be the best indicator of the severity of an overdose. For patients with arrhythmias and / or widened QRS, alkaline solutions with a pH of 7.45-7.55 (sodium bicarbonate) should be injected intravenously and hyperventilated. pH above 7.60 or pCO2 below 20 mm Hg are undesirable. Arrhythmias that do not respond to sodium bicarbonate / hyperventilation treatment may be sensitive to lidocaine, bretilium, or phenytoin. Antiarrhythmics such as quinidine, disopyramide, and procainamide (types 1A and 1C) are usually contraindicated.
In patients with a suppressed central nervous system, early intubation is recommended because of the possibility of a sharp deterioration in the condition. Convulsions should be controlled with benzodiazepines or, if ineffective, other anticonvulsants (eg, phenobarbital, phenytoin). Physostigmine is not recommended except for treatment of life-threatening symptoms that have not responded to other treatments, and only after detailed consultation with a poison control center.
Mental health follow-up
Because overdose is often a deliberate occurrence, patients may try to commit suicide by other means during the recovery phase. As a consequence, a referral to a psychiatrist may be required.
Treatment of children
The principles of overdose treatment in children and adults are the same. The physician is strongly advised to contact the local poison control center for specific pediatric treatment.
Miorix® is not effective in treating spasticity associated with cerebral brain diseases.
There have been cases of potentially life-threatening serotonin syndrome when cyclobenzaprine is used in combination with other drugs, such as selective serotonin reuptake inhibitors (SSRIs), selective serotonin norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCA), bupropionmadol, trimeperidine, verapamil, or MAO inhibitors. Symptoms of serotonin syndrome may include changes in mental status (eg: confusion, agitation, hallucinations), instability of the autonomic nervous system (eg: diaphoresis, tachycardia, instability of blood pressure, hyperthermia), neuromuscular abnormalities (eg: tremor, ataxia, hyperreflexia) clonic seizures, muscle stiffness) and / or gastrointestinal symptoms (eg: nausea, vomiting, diarrhea). With the development of the above reactions, treatment with Miorix® and any concomitant serotonergic drugs should be stopped immediately and symptomatic treatment should be initiated. If concomitant treatment with Miorix® and other serotonergic drugs is clinically justified, careful observation is recommended, especially during the initiation of treatment or an increase in the dose of the drug. Similar effects to tricyclic antidepressants
Cyclobenzaprine is structurally related to tricyclic antidepressants such as amitriptyline and imipramine. There have been reports that tricyclic antidepressants cause arrhythmias, sinus tachycardia, and increased pulse conduction time, leading to myocardial infarction and stroke. Miorix® may enhance the effects of alcohol, barbiturates and other central nervous system depressants.
With the development of clinically significant symptoms on the central nervous system, discontinuation of treatment with Miorix® should be considered.
Special patient groups
Due to a 40% increase in plasma cyclobenzaprine levels, and a 56% increase in the half-life in elderly patients, compared with younger patients, the use of Miorix® in the elderly is not recommended.
Use in patients with impaired liver function
Due to a twofold increase in plasma levels of cyclobenzaprine and due to the limited possibility of changing doses of the drug, the use of Miorix® in patients with mild, moderate or severe liver dysfunction is not recommended.
Due to the presence of an atropine-like effect, Miorix® 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.
Pregnancy and lactation
Pregnancy - Category B: There are no adequate and well-controlled studies of the drug in pregnant women. In this regard, use during pregnancy is possible only when the benefits of using the drug outweigh the potential risk to the fetus and newborn.
It is not known whether this drug is excreted in human milk. Since cyclobenzaprine is closely related to tricyclic antidepressants, some of which are known to be excreted in human milk, caution should be exercised when taking the drug in lactating women.