Instructions for use Miorix prolonged-release capsules, hard, 30 mg, blister No. 14
Composition
active ingredient: cyclobenzaprine hydrochloride;
1 capsule contains 30 mg of cyclobenzaprine hydrochloride;
excipients: spherical sugar, opadry clear YS-1-7006, ethyl cellulose, diethyl phthalate;
capsule shell 30 mg: red iron oxide (E 172), yellow iron oxide (E 172), titanium dioxide (E 171), gelatin, blue ink TekPrintTM SB-6018.
Dosage form
The extended-release capsules are hard.
Main physicochemical properties: opaque, hard gelatin capsules with a dark blue body and the inscription “1002-30” and a red cap with the inscription “EUR”. The contents of the capsules are spherical granules from white to yellow.
Pharmacotherapeutic group
Muscle relaxants. Other centrally acting muscle relaxants.
ATX code M03B X08.
Pharmacological properties
Pharmacodynamics
Cyclobenzaprine relieves skeletal muscle spasm of local origin without affecting muscle function. Cyclobenzaprine has not been shown to be effective in muscle spasms resulting from central nervous system (CNS) disease. In animal models, cyclobenzaprine reduces or eliminates skeletal muscle hyperactivity. Preclinical studies suggest that cyclobenzaprine does not affect the neuromuscular junction or skeletal muscle directly. Such studies suggest that cyclobenzaprine acts on the central nervous system primarily at the level of the brainstem rather than the spinal cord, although additional effects on the spinal cord may contribute to cyclobenzaprine's overall ability to cause skeletal muscle relaxation. Experience suggests that the effect of cyclobenzaprine is to reduce tonic somatic motor activity due to effects on both gamma (γ) and alpha (α) motor neurons. Pharmacological preclinical studies have demonstrated similarities between the effects of cyclobenzaprine and structurally related tricyclic antidepressants, including antagonism to reserpine, potentiation of norepinephrine, strong peripheral and central anticholinergic effects, and sedation. Cyclobenzaprine causes a mild to moderate increase in heart rate in animals.
Pharmacokinetics
Absorption: After a single dose of Miorix® 15 mg or 30 mg in healthy volunteers (n = 15), Cmax, AUC0-168h, and AUC0-∞ increased approximately dose-proportionally from 15 to 30 mg. The time to reach maximum plasma cyclobenzaprine concentration (Tmax) was 7 to 8 hours for both doses.
A food effect study conducted in healthy volunteers (n = 15) using a single dose of Miorix® 30 mg demonstrated a statistically significant increase in the bioavailability of Miorix® 30 mg when administered with food compared to fasting. There was a 35% increase in peak plasma cyclobenzaprine concentration (Cmax) and a 20% increase in exposure (AUC0-168h, AUC0-∞) in the presence of food. However, there was no effect on Tmax or the mean plasma concentration-time profile of cyclobenzaprine. Cyclobenzaprine first appears in plasma after 1.5 hours in both fed and fasting conditions.
In a study using multiple doses of Miorix® 30 mg once daily for 7 days in a group of healthy volunteers (n = 35), a 2.5-fold sustained increase in plasma cyclobenzaprine levels was observed.
Metabolism and Elimination: Cyclobenzaprine is extensively metabolized and excreted by the kidneys, primarily as glucuronides. Cytochromes P450 3A4, 1A2, and to a lesser extent 2D6 mediate N-demethylation, one of the oxidative pathways of cyclobenzaprine metabolism. The elimination half-life of cyclobenzaprine is 32 hours (range 8-37 hours, n = 18); plasma clearance is 0.7 L/min after a single dose of Miorix®.
Special patient groups.
Elderly patients. In patients over 65 years of age, the plasma AUC of cyclobenzaprine was increased by 40% and the plasma half-life of cyclobenzaprine was prolonged to 50 hours after a single dose compared to patients 18 to 45 years of age (32 hours), although no significant differences in Cmax and Tmax were observed. The pharmacokinetics of cyclobenzaprine following multiple doses of Miorix® have not been evaluated in elderly patients.
Patients with Hepatic Impairment: In a pharmacokinetic study of immediate-release cyclobenzaprine in 16 subjects with hepatic impairment (15 mild, 1 moderate on the Child-Pugh scale), both AUC and Cmax were approximately two-fold higher than those observed in healthy control subjects. The pharmacokinetics of cyclobenzaprine in subjects with severe hepatic impairment are unknown.
Indication
Elimination of muscle spasm, accompanied by acute pain sensations from the musculoskeletal system, as a supplement to a regimen of limited physical activity and therapeutic exercise. Improvement is manifested by the elimination of muscle spasms and associated signs and symptoms, namely: pain, increased sensitivity and restriction of movement.
Contraindication
Hypersensitivity reactions to any component of the drug, including anaphylactic reactions, urticaria, swelling of the face and/or tongue, itching. If hypersensitivity reactions are suspected, the use of Miorix® should be discontinued. Concomitant use with monoamine oxidase inhibitors (MAOIs) or within 14 days of their withdrawal. Hyperpyretic crises, convulsions and death have been observed in patients receiving cyclobenzaprine (or structurally similar tricyclic antidepressants) concomitantly with MAOIs. During the recovery phase after acute myocardial infarction and in the presence of cardiac rhythm and conduction disorders, including blocks, or congestive heart failure. Hyperthyroidism.
Interaction with other medicinal products and other types of interactions
Due to its structural similarity to tricyclic antidepressants, the drug Miorix® may interact with MAO inhibitors (see Contraindications), may potentiate the effects of alcohol, barbiturates, and other CNS depressants, may increase the risk of seizures in patients taking tramadol, or may block the antihypertensive effects of guanethidine and similar compounds.
In the post-marketing period, cases of serotonin syndrome have been reported with the combined use of cyclobenzaprine with other drugs, such as selective serotonin reuptake inhibitors (SSRIs), selective serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), tramadol, bupropion, meperidine, verapamil, or MAO inhibitors.
Application features
Application restrictions.
Myorix® should only be used for a short period of time (up to
2-3 weeks), because there is insufficient evidence of efficacy for longer periods and because muscle spasm associated with acute musculoskeletal pain is usually short-lived and specific therapy for a longer period is rarely justified. Miorix® has not been shown to be effective in the treatment of muscle spasticity associated with brain or spinal cord disease or cerebral palsy.
Serotonin syndrome. The development of potentially life-threatening serotonin syndrome has been reported when cyclobenzaprine is used in combination with other drugs such as SSRIs, SNRIs, TCAs, tramadol, bupropion, meperidine, verapamil or MAO inhibitors. The simultaneous use of Miorix® with MAO inhibitors is contraindicated (see section "Contraindications"). Symptoms of serotonin syndrome may include mental status changes (e.g., confusion, agitation, hallucinations), autonomic disturbances (e.g., increased sweating, tachycardia, lability of blood pressure, hyperthermia), neuromuscular disturbances (e.g., tremor, ataxia, hyperreflexia, clonus, muscle rigidity) and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). If the above reactions occur, Miorix® and any concomitant serotonergic agents should be discontinued immediately and symptomatic treatment initiated. If concomitant treatment with Miorix® and other serotonergic agents is clinically warranted, close monitoring of the patient is recommended, especially at the start of treatment or when the dose is increased.
Effects similar to those seen with tricyclic antidepressants. Cyclobenzaprine is structurally similar to tricyclic antidepressants, such as amitriptyline and imipramine. Cases of arrhythmia, sinus tachycardia, and prolongation of conduction time leading to myocardial infarction and stroke have been reported with tricyclic antidepressants (see Contraindications). Miorix® may potentiate the effects of alcohol, barbiturates, and other CNS depressants.
Some of the more serious CNS reactions seen with tricyclic antidepressants have been observed in short-term studies with cyclobenzaprine in indications other than muscle spasm associated with acute musculoskeletal disorders, and mostly at doses somewhat higher than those recommended for the relief of skeletal muscle spasm. If clinically significant CNS symptoms occur, Miorix® should be discontinued.
Elderly patients. The use of Miorix® in elderly patients is not recommended due to a 40% increase in cyclobenzaprine plasma levels and a 56% increase in plasma half-life compared to younger patients.
Atropine-like action. Due to the presence of atropine-like action, Miorix® should be used with caution in patients with a history of urinary retention, angle-closure glaucoma, increased intraocular pressure, and patients taking anticholinergic drugs.
Dependence. The pharmacological similarity of tricyclics makes it possible to experience certain withdrawal symptoms after the use of Miorix®, even if these are not reported. Abrupt withdrawal after prolonged use may sometimes cause nausea, headache, and malaise. These symptoms do not indicate the development of dependence.
Ability to influence reaction speed when driving vehicles or other mechanisms
Use with caution in patients driving or operating machinery until it is established that treatment does not adversely affect the ability to engage in such activities.
Use during pregnancy or breastfeeding
Pregnancy
Available data from case reports of cyclobenzaprine use during pregnancy do not identify a drug-associated risk of serious birth defects, miscarriage, or adverse maternal or fetal outcomes.
In rats, reduced pup body weight and survival were observed at doses of ≥10 mg/kg/day of cyclobenzaprine (equivalent to approximately ≥3 times the maximum recommended human daily dose (MRHD) of 30 mg/day) when administered orally during pregnancy and lactation.
The estimated risk of major birth defects and miscarriage for this population is unknown. All pregnancies have a background risk of birth defects, miscarriage, or other adverse outcomes.
Animal research data
There were no reports of adverse embryofetal effects following oral administration of cyclobenzaprine to mice and rabbits during organogenesis at doses of 20 mg/kg/day (3 and 15 times the maximum recommended human daily dose (MRHD) on a mg/m2 basis, respectively). Maternal toxicity, characterized by decreased body weight, was observed only in mice at the highest dose tested, 20 mg/kg/day.
Decreased body weight and pup survival were reported in a prenatal and postnatal study when pregnant rats were treated with cyclobenzaprine orally during pregnancy and lactation at doses of 10 and 20 mg/kg/day (3 and 6 times the maximum recommended human daily dose (MRHD) on a mg/m2 basis, respectively). Maternal toxicity, characterized by decreased body weight, was observed only at the highest dose tested, 20 mg/kg/day.
Breast-feeding
There are no data on the presence of cyclobenzaprine in human or animal milk, the effects on the breastfed infant, or the effects on the mother's milk secretion. The benefit of breastfeeding to the health and development of the infant and the mother's clinical need for cyclobenzaprine should be taken into account, as well as any potential adverse effects in the breastfed infant from cyclobenzaprine or from the underlying maternal condition.
Method of administration and doses
The recommended dose for adults is 15 mg (1 capsule of Miorix® 15 mg) once daily. Some patients may require an increase in dose to 30 mg once daily (1 capsule of Miorix® 30 mg or 2 capsules of Miorix® 15 mg).
The drug is taken every day at approximately the same time.
The use of Miorix® for more than 2-3 weeks is not recommended.
Elderly patients (65 years and older). Clinical studies of the use of Miorix® in this category of patients are insufficient. The use of Miorix® in elderly patients is not recommended.
Patients with hepatic impairment: The use of Miorix® is not recommended in patients with mild, moderate or severe hepatic impairment (see section 4.4).
Children
There are no clinical data on the efficacy and safety of the drug for the treatment of children, therefore Miorix® is not recommended for use in pediatric practice.
Overdose
Symptoms.
In rare cases, overdose can be fatal. Taking multiple drugs (including alcohol) at the same time is common in intentional cyclobenzaprine overdose.
Because approaches to treating overdose are complex and subject to change, it is recommended that the physician consult with a toxicologist for up-to-date information on therapy.
The most common symptoms of cyclobenzaprine overdose are drowsiness and tachycardia. Less common symptoms include tremor, agitation, coma, ataxia, hypertension, slurred speech, confusion, dizziness, nausea, vomiting, and hallucinations. Rare but potentially serious symptoms of overdose include cardiac arrest, chest pain, cardiac arrhythmia, severe hypotension, seizures, and neuroleptic malignant syndrome. ECG abnormalities, particularly changes in QRS complex height or width, are clinically significant indicators of cyclobenzaprine overdose. Other potential effects of overdose include any of the symptoms listed in the Adverse Reactions section.
Intentional overdose with cyclobenzaprine is often associated with its use in combination with several drugs, as well as with alcohol. Symptoms of poisoning may develop rapidly after an overdose of cyclobenzaprine, so monitoring of the patient's condition in a hospital setting is necessary as soon as possible. Overdose of the drug Miorix® can rarely lead to death.
Treatment.
General. To prevent the rare but potentially critical events described above, an ECG should be obtained and cardiac monitoring should be initiated immediately. The patient's airway should be secured, intravenous access should be established, and gastric decontamination should be initiated. Observation for signs of CNS or respiratory depression, hypotension, cardiac arrhythmias and/or cardiac conduction block, and seizures should also be performed. If signs of toxicity occur at any time during this period, extended observation should be considered. Monitoring of blood levels should not interfere with patient management. Dialysis is likely to be ineffective due to the low plasma concentrations of the drug.
Gastrointestinal decontamination. Gastrointestinal decontamination should be performed in all patients suspected of having overdosed with Miorix®. This should include gastric lavage with large volumes of fluid followed by administration of activated charcoal. If consciousness is impaired, the airway should be maintained prior to gastric lavage; induction of vomiting is contraindicated.
Cardiovascular system. A maximum QRS duration in standard leads of 0.10 seconds may be the best indicator of the severity of overdose. Serum alkalinization to pH 7.45–7.55 with intravenous sodium bicarbonate and hyperventilation (if necessary) should be considered in patients with arrhythmias and/or QRS complex widening. A pH > 7.60 or pCO2 < 20 mm Hg is undesirable. Arrhythmias that do not respond to sodium bicarbonate/hyperventilation therapy may respond to lidocaine, bretylium, or phenytoin. Class 1A and 1C antiarrhythmics (e.g., quinidine, disopyramide, and procainamide) are usually contraindicated.
CNS. Early intubation is recommended for patients with CNS depression because of the potential for rapid deterioration. Seizures should be controlled with benzodiazepines or, if these fail, with other anticonvulsants (e.g., phenobarbital, phenytoin). Physostigmine is not recommended except for life-threatening symptoms that are refractory to other treatments, and only in the setting of inpatient treatment.
Psychiatric follow-up: Because overdose is often intentional, patients may re-attempt suicide by other means during the recovery phase. Psychiatric consultation may be appropriate for such patients.
Treatment of overdose in children. The principles of management of overdose in children and adults are similar. The physician is advised to consult a toxicologist for specialized pediatric treatment.
Adverse reactions
The following adverse reactions have been reported in clinical trials or during post-marketing use of cyclobenzaprine, immediate-release cyclobenzaprine, or tricyclics. Some reactions are reported voluntarily from a population of uncertain size, and it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
In the post-marketing surveillance program for immediate-release cyclobenzaprine, the most common adverse reactions are: drowsiness, dry mouth, and dizziness, and adverse reactions occurring in 1 to 3% of patients are: fatigue/tiredness, asthenia, nausea, constipation, dyspepsia, unpleasant taste, blurred vision, headache, nervousness, and confusion.
The following adverse reactions have been reported during postmarketing use of cyclobenzaprine extended-release or immediate-release cyclobenzaprine, in clinical trials of immediate-release cyclobenzaprine (with an incidence of < 1%), or during postmarketing use of other tricyclics:
General disorders: fainting, malaise, chest pain, edema.
On the part of the digestive system: vomiting, anorexia, diarrhea, abdominal pain, gastritis, thirst, flatulence, swelling of the tongue, liver dysfunction and rare cases of hepatitis, jaundice and cholestasis, paralytic intestinal obstruction, tongue discoloration, stomatitis, swelling of the parotid salivary gland.
On the part of the endocrine system: syndrome of inappropriate secretion of antidiuretic hormone (ADH).
Blood and lymphatic system disorders: purpura, bone marrow depression, leukopenia, eosinophilia, thrombocytopenia.
Hypersensitivity reactions: anaphylactic shock, angioedema, itching, facial swelling, urticaria, rash.
Metabolic, nutritional and immune disorders: increased or decreased blood sugar levels, weight gain or loss.
Musculoskeletal and connective tissue disorders: local muscle weakness, myalgia.
Nervous system and psyche: seizures, ataxia, vertigo, dysarthria, tremor, arterial hypertension, convulsions, muscle twitching, disorientation, insomnia, depressed mood, unusual sensations, anxiety, agitation, psychosis, abnormal thoughts and dreams, hallucinations, agitation, paresthesia, diplopia, serotonin syndrome, neuroleptic malignant syndrome, decreased or increased libido, gait disturbance, delirium, aggressive behavior, paranoia, peripheral neuropathy, Bell's palsy, changes in electroencephalography (EEG), extrapyramidal symptoms.
Respiratory system: shortness of breath.
Skin and subcutaneous tissue disorders: sweating, photosensitivity, alopecia.
From the sensory organs: ageusia, tinnitus.
On the part of the kidneys and urinary tract: increased and/or decreased frequency of urination, urination disorders, dilatation of the urinary tract, impotence, testicular swelling, gynecomastia, breast enlargement, galactorrhea.
Expiration date
4 years.
Storage conditions
Store at a temperature not exceeding 25 ° C. Keep out of the reach of children!
Packaging
14 capsules in a blister; 1 blister in a cardboard box.
Vacation category
According to the recipe.
Producer
Takeda Pharma Sp. z o.o., Poland/ Takeda Pharma Sp. z o. o., Poland.
Location of the manufacturer and its business address
12, Ksiestwa Lowickiego Str., 99-420 Lyszkowice, Poland.
