Tramadol-zn

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT TRAMADOL-ZN (TRAMADOL-ZN)

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 physicochemical properties: clear, colorless liquid.

Pharmacotherapeutic group. Analgesics. Opioids. Tramadol. ATC code N02A X02.

Pharmacological Properties.

Pharmacodynamics. Central-acting analgesic. Non-selective agonist of opioid µ-, δ-, and ĸ-receptors in the central nervous system (CNS), with the highest affinity for µ-receptors. Suppresses the activity of the nociceptive system and activates the antinociceptive system. Promotes the 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 blood, with bioavailability of approximately 100%. Maximum blood concentration is reached within 45 minutes after injection. Plasma protein binding is 20%. Tramadol is well distributed in tissues; the volume of distribution after intravenous administration is 203 L. It penetrates through histohematologic barriers (blood-brain barrier, placental barrier) and into breast milk. Metabolized in the liver via demethylation and conjugation, forming 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. Excreted predominantly by the kidneys (90%) and the intestine (about 10%) 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 these patient groups, a reduced dose and increased dosing interval 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 insufficiency (creatinine clearance less than 10 ml/min); concomitant use with monoamine oxidase inhibitors (MAOIs) and within 2 weeks after their discontinuation; epilepsy not controlled by treatment; narcotic withdrawal syndrome.

Interaction with other medicinal products and other forms of interactions.

The medicinal product must not be used concomitantly 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 using tramadol.

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

Concomitant use of tramadol with gabapentinoids (gabapentin and pregabalin) may cause 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.

The medicinal product 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 concomitantly with other serotonergic medicinal products, such as selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), or monoamine oxidase inhibitors (MAOIs), tricyclic antidepressants, and mirtazapine, serotonin syndrome, potentially life-threatening, may occur (see sections "Special precautions for use" and "Adverse reactions").

The medicinal product should be used with caution in combination with coumarin derivatives (e.g., warfarin), as there have been reports of increased international normalized ratio (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 small number of studies, pre- or postoperative use of selective 5HT3-receptor antagonists (ondansetron) has been shown to increase the need for tramadol in patients with postoperative pain.

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

Special precautions for use.

The medicinal product should be used with caution in opioid dependence, head injury, shock, impaired consciousness of unknown origin, and respiratory dysfunction.

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

The drug should be prescribed with caution in patients with respiratory depression or when used concomitantly with 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-associated hypoxemia. Opioid use in a dose-dependent manner increases the risk of CSA. For 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, severe fatigue, decreased appetite, and weight loss.

Seizures have been reported in patients receiving tramadol at the recommended dosage. The risk may increase when doses exceed the recommended maximum daily dose (400 mg). When used concomitantly with medicinal products that reduce the seizure threshold, tramadol may increase the risk of epileptic seizures. The medicinal product should be used in patients with epilepsy or a predisposition to seizures only if strictly indicated.

Serotonin syndrome

Cases of serotonin syndrome, a potentially life-threatening condition, have been reported in patients receiving tramadol alone or in combination with other serotonergic medicinal products (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 at the beginning of treatment and during dose escalation.

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

If serotonin syndrome is suspected, consideration should be given to reducing the dose or discontinuing therapy 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, and 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 (in parents or siblings) of substance use disorders (including alcohol), in tobacco users, and in patients with other psychiatric disorders (e.g., severe depression, anxiety, and personality disorders).

Prior to initiating and during tramadol treatment, the goals of therapy and a plan for discontinuation should be discussed with the patient (see section "Method of administration and dosage"). Before starting 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 drug-seeking behavior (e.g., early requests for additional doses). This includes monitoring concomitant use of opioids and psychoactive medicinal products (e.g., benzodiazepines). Patients showing signs and symptoms of OUD should be considered for referral to a specialist in addiction medicine.

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

Alcohol consumption should be avoided during treatment with this medicinal product.

The 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 medicinal product 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 neonatal withdrawal syndrome.

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

Ability to influence 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.

Method of administration and dosage.

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

The medicinal product 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 as needed for additional analgesia.

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.

The medicinal product must be diluted with water for injections.

The concentrations achieved when diluted with water for injections are given below.

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

Calculation of the volume (ml) of diluted solution to be administered: 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 the medicinal product (equivalent to 2 ampoules of 1 ml each) with 4 ml of water for injections. This yields 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). Dispose of any remaining solution.

Elderly patients.

For elderly patients (up to 75 years of age) without clinically significant hepatic or renal impairment, dose adjustment is generally not required.

Hepatic and renal impairment/dialysis.

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

Note. Only the recommended low doses of the medicinal product should be used. When treating chronic pain, the medicinal product should be administered according to a fixed schedule.

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

Therapeutic goals and discontinuation.

Prior to initiating tramadol therapy, the treatment strategy—including duration and therapeutic goals—should be discussed and agreed upon with the patient, in accordance with pain management protocols. 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 should be recommended to prevent withdrawal symptoms. In the absence of adequate pain control, the possibility of hyperalgesia, development of tolerance, and progression of the underlying disease should be considered (see section "Special precautions for use").

Treatment duration.

Do not use the medicinal product for 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 monitored regularly and carefully (with possible therapy breaks) to determine the need for continued treatment.

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 implemented. Ensure airway patency (aspiration possible), and provide respiratory and circulatory support as needed. Naloxone is the antidote for respiratory depression. Animal studies have shown that naloxone does not affect seizures; therefore, diazepam should be administered intravenously.

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

Adverse Reactions.

The most common adverse reactions associated with tramadol hydrochloride use are nausea and dizziness.

Psychiatric disorders: hallucinations, seizures, sleep disturbances, anxiety, nightmares. Various adverse effects may occur after tramadol administration (depending on patient characteristics and duration of treatment). These include mood changes (usually euphoria, sometimes dysphoria), changes in activity level (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, clouding of consciousness, changes in appetite, paresthesia, tremor, respiratory depression, epileptiform seizures, involuntary muscle twitching, coordination disturbances, syncope, insomnia, somnolence, speech disorders, serotonin syndrome.

Respiratory depression may occur if recommended doses are significantly exceeded or when other centrally acting depressants are used concomitantly. Epileptiform seizures mainly occur after administration of high tramadol doses or when used concomitantly with drugs that lower the seizure threshold.

Eye disorders: blurred vision, mydriasis.

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

Respiratory system disorders: dyspnea, hiccups. There have been reports of asthma occurrence; however, a causal relationship has not been established.

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

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

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

Musculoskeletal and connective tissue disorders: muscle weakness.

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

General disorders and administration site conditions: fatigue, allergic reactions (dystonia, bronchospasm, angioneurotic edema, hoarseness), anaphylaxis, taste disturbances, weakness, lethargy, decreased reaction speed, menstrual cycle disturbances.

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

Drug dependence.

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

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 pack. 1 or 2 blisters per cardboard box.

Prescription status.

Prescription only.

Manufacturer.

Limited Liability Company "Kharkiv Pharmaceutical Enterprise "Zdorov'ya Narodu".

(for packages: 1 ml or 2 ml in an ampoule. 5 ampoules in a blister. 1 or 2 blisters per cardboard box)

Limited Liability Company "Pharmaceutical Company "Zdorov'ya".

(for packages: 2 ml in an ampoule. 5 ampoules in a blister. 1 or 2 blisters per cardboard box)

Manufacturer's address and location of business activity.

Ukraine, 61002, Kharkiv region, city of Kharkiv, Kulikivska Street, 41.

(Limited Liability Company "Kharkiv Pharmaceutical Enterprise "Zdorov'ya Narodu")

Ukraine, 61013, Kharkiv region, city of Kharkiv, Shevchenka Street, 22.

(Limited Liability Company "Pharmaceutical Company "Zdorov'ya")