Tramadol-m

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT TRAMADOL-M (TRAMADOL-M)

Composition:

active substance: tramadol;

1 ml of solution contains: tramadol hydrochloride 50 mg;

excipients: sodium acetate trihydrate, water for injections.

Pharmaceutical form. Injection solution.

Main physico-chemical properties: clear, colorless liquid.

Pharmacotherapeutic group. Analgesics. Opioids. Tramadol. ATC code N02AX02.

Pharmacological Properties

Pharmacodynamics. Central-acting analgesic. Non-selective agonist of opioid µ-, δ-, and ĸ-receptors in the CNS, with the highest affinity for µ-receptors. Inhibits the activity of the nociceptive system and activates the antinociceptive system. Promotes opening of potassium and calcium channels, causing membrane hyperpolarization and inhibition of nerve impulse conduction. Stimulates the adrenergic system by inhibiting neuronal reuptake of norepinephrine. Enhances serotonin release. Exerts sedative and antitussive effects. At therapeutic doses, it hardly suppresses respiration and does not impair cardiovascular function.

After parenteral administration, the analgesic effect develops within 5–10 minutes and lasts for 3–5 hours.

Pharmacokinetics. After intramuscular administration, tramadol is rapidly and completely absorbed into the bloodstream, with a bioavailability of approximately 100%. Maximum blood concentration is reached within 45 minutes after injection. Plasma protein binding is 20%. Tramadol distributes well into tissues; the volume of distribution after intravenous administration is 203 L. It penetrates histohematogenous barriers (blood-brain barrier, placental barrier) and is excreted into breast milk. Metabolism occurs in the liver via demethylation and conjugation, producing one active metabolite (O-demethyltramadol) and ten inactive metabolites. The elimination half-life of tramadol is 6 hours; for O-demethyltramadol, it is approximately 8 hours. Excretion occurs primarily via the kidneys (90%) and the intestine (about 10%), both in unchanged form and as metabolites.

In elderly patients (up to 75 years of age) and in patients with impaired liver or kidney function (creatinine clearance less than 80 mL/min), elimination is slowed. Drug accumulation may occur. Therefore, for this patient group, a reduced dosage and extended dosing intervals are recommended.

Clinical characteristics.

Indications.

Treatment of moderate to severe pain.

Contraindications.

Hypersensitivity to tramadol or to any of the excipients. Acute alcohol intoxication; acute poisoning with sedatives, analgesics, opioids, or psychotropic agents; severe hepatic/renal impairment (creatinine clearance less than 10 ml/min); concurrent use of MAO inhibitors (and within 2 weeks after their discontinuation); uncontrolled epilepsy; opioid withdrawal syndrome.

Interaction with other medicinal products and other types of interactions.

Tramadol-M must not be used together with MAO inhibitors. In patients who had received MAO inhibitors within 14 days prior to administration of the opioid meperidine, life-threatening reactions affecting the CNS, respiratory and cardiovascular systems were observed. A similar interaction with MAO inhibitors cannot be excluded when tramadol is used.

Concomitant use of tramadol and medicinal products that depress the CNS, including alcohol, may enhance their effect on the CNS.

Concomitant use of tramadol with gabapentinoids (gabapentin and pregabalin) may lead to respiratory depression, hypotension, profound sedation, coma, or death.

Pharmacokinetic studies have shown that concomitant or prior use of cimetidine (an enzyme inhibitor) is unlikely to result in clinically significant interaction. Concomitant or prior use of carbamazepine (an enzyme inducer) may reduce the analgesic effect and shorten the duration of action of the drug.

Combination of mixed agonists/antagonists (e.g., buprenorphine, nalbuphine, pentazocine) with tramadol is not recommended, as such combination may (theoretically) reduce the analgesic effect of a pure agonist.

Tramadol-M may cause seizures and increase the risk of seizures when used concomitantly with selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants, neuroleptics, and other medicinal products that lower the seizure threshold.

When tramadol is used in combination with other serotonergic medicinal products, such as selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), or MAO inhibitors, tricyclic antidepressants, and mirtazapine, a potentially life-threatening serotonin syndrome may occur (see sections "Special precautions" and "Adverse reactions").

Tramadol should be used with caution together with coumarin derivatives (e.g., warfarin), as there have been reports of increased INR with severe bleeding and hemorrhages in some patients.

Medicinal products that inhibit CYP3A4, including ketoconazole and erythromycin, may inhibit the metabolism of tramadol (N-demethylation) and its active O-demethylated metabolite. The clinical significance of this interaction has not been studied. Quinidine increases plasma concentration of tramadol and decreases concentration of the M1 metabolite due to competitive inhibition of the CYP2D6 isoenzyme.

In a limited number of studies, pre- or postoperative use of selective 5-HT3 receptor antagonists (ondansetron) has been shown to increase tramadol requirements in patients with postoperative pain.

The rate of absorption may be increased when metoclopramide or domperidone are used, and decreased by cholestyramine.

Special precautions for use.

Tramadol-M should be used with caution in opioid dependence, head injury, shock, impaired consciousness of unknown origin, respiratory dysfunction, and increased intracranial pressure.

Tramadol should be used with particular caution in patients sensitive to opioids.

The drug should be prescribed with caution in patients with respiratory depression or when used concomitantly with central nervous system (CNS) depressants, or if the maximum recommended daily dose is significantly exceeded, as respiratory depression may occur.

Sleep-related breathing disorders

Opioids may cause sleep-related breathing disorders, including central sleep apnea (CSA) and sleep-related hypoxemia. The use of opioids increases the risk of CSA in a dose-dependent manner. In patients with CSA, consideration should be given to reducing the total opioid dose.

Adrenal insufficiency

Opioid analgesics may occasionally cause reversible adrenal insufficiency, which requires monitoring and glucocorticoid replacement therapy. Symptoms of acute or chronic adrenal insufficiency may include, for example, severe abdominal pain, nausea and vomiting, low blood pressure, profound fatigue, decreased appetite, and weight loss.

Seizures have been reported in patients receiving tramadol at recommended doses. The risk may increase when doses exceed the recommended maximum daily dose (400 mg). When used concomitantly with medicinal products that lower the seizure threshold, tramadol may increase the risk of epileptic seizures. Tramadol-M injection solution should be used in patients with epilepsy or those predisposed to seizures only under life-threatening conditions.

Serotonin syndrome

Cases of serotonin syndrome, a potentially life-threatening condition, have been reported in patients receiving tramadol in combination with other serotonergic medicinal products or without such combination (see sections "Interaction with other medicinal products and other forms of interaction", "Adverse reactions", and "Overdose").

If concomitant treatment with other serotonergic medicinal products is clinically justified, careful monitoring of the patient is recommended, particularly during initiation of therapy and dose escalation.

Symptoms of serotonin syndrome may include mental status changes, autonomic instability, neuromuscular disturbances, and/or gastrointestinal symptoms.

In case of suspected serotonin syndrome, dose reduction or discontinuation of therapy should be considered depending on the severity of symptoms. Discontinuation of serotonergic medicinal products usually leads to rapid improvement.

Tolerance and opioid use disorder (OUD) (abuse and dependence)

Tolerance, physical and psychological dependence, as well as OUD, may develop after repeated use of opioids such as tramadol. Repeated use of tramadol may lead to OUD. Higher doses and longer duration of opioid treatment may increase the risk of developing OUD. Misuse or intentional inappropriate use of tramadol may lead to overdose and/or death. The risk of developing OUD is increased in patients with a personal or family history (parents or siblings) of substance use disorders (including alcohol-related disorders), in current tobacco users, or in patients with other existing psychiatric disorders (e.g., severe depression, anxiety, and personality disorders).

Prior to initiating and during tramadol treatment, the treatment goals and a plan for discontinuation should be discussed with the patient (see section "Method of administration and dosage"). Before and during treatment, patients should also be informed about the risks and signs of OUD. Patients should be advised to contact their physician if such signs appear.

Patients should be monitored for signs of addictive behavior (e.g., early requests for additional doses). This includes checking for concomitant use of opioids and psychoactive medicinal products (e.g., benzodiazepines). Patients showing signs and symptoms of OUD should be considered for consultation with an addiction specialist.

Tramadol is not suitable for substitution therapy in opioid-dependent patients. Despite being an opioid agonist, it cannot suppress morphine withdrawal symptoms.

Alcohol should not be consumed during treatment with this medicinal product.

Tramadol-M injection solution contains less than 1 mmol (23 mg/dose) of sodium, i.e., it is almost sodium-free.

Use during pregnancy or breastfeeding.

Animal studies have shown that very high doses of tramadol affect organ development, bone growth, and neonatal mortality. Teratogenic effects were not observed. Tramadol crosses the placental barrier. Data on the safety of tramadol use during pregnancy are lacking; therefore, the drug should not be used in pregnant women.

Tramadol administered before or during labor does not affect uterine contractions. It may cause changes in neonatal respiratory rate, usually clinically insignificant. Prolonged use of tramadol during pregnancy may lead to withdrawal syndrome in newborns.

Approximately 0.1% of the dose received by a breastfeeding woman passes into breast milk; therefore, Tramadol-M is not recommended for use during this period. Usually, breastfeeding does not need to be interrupted after a single dose of tramadol.

Ability to affect reaction speed when driving or operating machinery.

During treatment with this medicinal product, patients should refrain from driving or operating other potentially hazardous machinery requiring heightened attention and rapid psychomotor reactions.

Administration and dosage.

Dosage and duration of treatment are determined individually by a physician, depending on the severity of pain.

The drug can be administered intravenously, intramuscularly, or subcutaneously.

Adults and children aged 14 years and older:

If pain relief does not occur within 30–60 minutes after administration of a single 50 mg dose of tramadol, a second 50 mg dose may be administered.

In cases of severe pain, a higher initial dose of tramadol hydrochloride (100 mg) may be required. Depending on the intensity of pain, the duration of effect ranges from 4 to 8 hours. During the early postoperative period, higher doses may be necessary for additional analgesia, if needed.

The daily dose should not exceed the dose usually administered. To relieve pain, the lowest effective dose should generally be used. The daily dose of 400 mg of tramadol should not be exceeded, except under specific clinical circumstances (e.g., cancer pain or severe postoperative pain).

Children aged 1 to 14 years.

Administer 1–2 mg of tramadol hydrochloride per 1 kg of body weight as a single dose. The lowest effective dose of tramadol should be used. The daily dose is 4–8 mg/kg of body weight. The maximum daily dose of tramadol is 8 mg/kg of body weight or 400 mg of tramadol, whichever is lower.

Tramadol-M must be diluted with water for injections.

The following are the concentrations achieved when diluted with water for injections.

Calculation of the total dose of tramadol hydrochloride (mg): body weight (kg) × dose (mg/kg).

Calculation of the volume (ml) of diluted solution for administration: divide the total dose (mg) by the corresponding concentration of the diluted solution (mg/ml):

Example: for a child weighing 45 kg, a dose of 1.5 mg of tramadol hydrochloride per 1 kg of body weight should be administered. This requires 67.5 mg of tramadol hydrochloride. Dilute 2 ml of Tramadol-M (equivalent to 2 ampoules of 1 ml) with 4 ml of water for injections. This results in a concentration of 16.7 mg of tramadol hydrochloride per 1 ml. Then administer 4 ml of the solution (approximately 67 mg of tramadol hydrochloride). Any remaining solution should be discarded.

Elderly patients.

Dose adjustment is generally not required in elderly patients (under 75 years of age) who do not have clinically significant hepatic or renal impairment.

Hepatic and renal impairment/dialysis.

In patients with mild to moderate hepatic and/or renal impairment, tramadol elimination is slowed. In such patients, the dosing interval should be prolonged according to clinical need.

Note. Only the recommended low doses of the drug should be used. When treating chronic pain, Tramadol-M doses should be administered according to the established regimen.

The injection solution should be administered slowly, i.e., 1 ml of Tramadol-M injection solution (equivalent to 50 mg of tramadol hydrochloride) per minute, or diluted in an infusion solution and administered as an infusion.

Treatment goals and discontinuation.

Prior to initiating tramadol therapy, the treatment strategy—including duration and treatment goals—should be discussed and agreed upon with the patient, in accordance with the pain management protocol. During therapy, the physician should maintain regular contact with the patient to assess the need for continued treatment, consider the possibility of discontinuation, and, if necessary, adjust doses. When a patient no longer requires tramadol therapy, gradual dose reduction is recommended to prevent withdrawal symptoms. If adequate pain control is not achieved, the possibility of hyperalgesia, development of tolerance, or progression of the underlying disease should be considered (see section "Special precautions").

Duration of treatment.

Do not use Tramadol-M longer than recommended. If prolonged analgesia with tramadol is required depending on the nature and severity of the condition, the patient's condition should be regularly and carefully monitored (with possible treatment breaks) to determine the need for continued therapy.

Children.

Do not use in children under 1 year of age.

Overdose.

Symptoms: specific miosis, vomiting, cardiovascular collapse, impaired consciousness up to coma, seizures, and respiratory depression up to respiratory arrest. Serotonin syndrome has also been reported.

Treatment: general supportive measures should be initiated. Ensure airway patency (aspiration possible), and provide respiratory and circulatory support as needed based on symptoms. Naloxone is the antidote for respiratory depression. Animal studies have shown that naloxone does not affect seizures; therefore, intravenous diazepam should be administered.

Tramadol is only minimally removed from blood plasma by hemodialysis or hemofiltration. Therefore, treatment of acute tramadol overdose using hemodialysis or hemofiltration is insufficient to eliminate intoxication.

Side effects.

The most common side effects of tramadol hydrochloride are nausea and dizziness.

Psychiatric disorders: hallucinations, convulsions, sleep disorders, anxiety, nightmares. Various adverse effects may occur after administration of tramadol (depending on patient characteristics and duration of treatment). These reactions include mood changes (usually euphoria, sometimes dysphoria), changes in activity (usually decreased, sometimes increased), changes in cognitive functions and perception (e.g., decision-making processes, perceptual disturbances). Dependence may develop.

Nervous system disorders: dizziness, headache, altered consciousness, change in appetite, paresthesia, tremor, respiratory depression, epileptiform seizures, involuntary muscle twitching, coordination disturbances, syncope, insomnia, somnolence, speech disorders, serotonin syndrome.

If recommended doses are significantly exceeded, or when other centrally acting depressants are used concomitantly, respiratory depression may occur. Epileptiform seizures occur mainly after administration of high doses of tramadol or when used concomitantly with medicinal products that lower the seizure threshold.

Eye disorders: blurred vision, mydriasis.

Cardiovascular system disorders: effects on cardiovascular regulation (rapid heartbeat, tachycardia, bradycardia, arterial hypertension, orthostatic hypotension, or cardiovascular collapse). These adverse effects may be particularly evident during intravenous administration and in debilitated patients.

Respiratory system disorders: dyspnea, hiccup. Cases of asthma have been reported; however, a causal relationship has not been established.

Gastrointestinal disorders: nausea, vomiting, constipation, dry mouth, urge to vomit, gastrointestinal irritation (e.g., feeling of heaviness in the stomach, flatulence), diarrhea.

Hepatobiliary disorders: increased liver enzyme levels temporally associated with tramadol therapy.

Skin disorders: increased sweating, skin reactions (including rash, pruritus, erythema, urticaria).

Musculoskeletal system disorders: motor weakness.

Renal and urinary disorders: urinary disorders (difficulty urinating, dysuria, urinary retention).

General disorders: fatigue, allergic reactions (dystonia, bronchospasm, angioedema, hoarseness), anaphylaxis, taste disturbances, weakness, lethargy, reduced reaction speed, menstrual cycle disturbances.

Withdrawal syndrome similar to that observed with other opioids may occur. These symptoms include agitation, anxiety, nervousness, sleep disturbances, hyperkinesia, tremor, and gastrointestinal disorders. Other symptoms occurring rarely after discontinuation of tramadol include pain attacks, severe anxiety, hallucinations, paresthesia, tinnitus, unusual CNS symptoms (confusion, mania, depersonalization, disturbances in perception of the environment (including hyperacusis), paranoia).

Drug dependence.

Repeated use of tramadol may lead to drug dependence, even at therapeutic doses. The risk of developing drug dependence may vary depending on individual patient risk factors, dosage, and duration of opioid treatment (see section "Special precautions").

Shelf life. 3 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 °C.

Packaging.

1 ml or 2 ml in an ampoule. 5 ampoules in a blister. 1 or 2 blisters in a cardboard box.

Prescription status.

Prescription only.

Manufacturer.

Limited liability company "Kharkiv Pharmaceutical Enterprise "Zdorov'ya Narodu".

Manufacturer's address and location of its operations.

41 Kulikivska Street, Kharkiv, Kharkiv Oblast, 61002, Ukraine.