Tramadol hydrochloride

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT TRAMADOL HYDROCHLORIDE (TRAMADOLI HYDROCHLORID)

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 N02AX02.

Pharmacological Properties.

Pharmacodynamics.

Tramadol is a centrally-acting opioid analgesic. It has a mixed mechanism of action. It is a non-selective pure agonist of opioid µ-, δ-, and ĸ-receptors, with the highest affinity for µ-receptors. Other mechanisms contributing to the analgesic effect of tramadol include inhibition of neuronal norepinephrine reuptake and enhancement of serotonergic response.

Tramadol also exerts antitussive effects. Unlike morphine, analgesic doses of tramadol do not significantly suppress respiration across a wide dose range. Gastrointestinal motility is also less inhibited. Effects on the cardiovascular system are generally mild. The potency of tramadol is estimated to be between 1/10 and 1/6 that of morphine.

Pharmacokinetics.

Absorption after intramuscular administration is 100%. Time to reach maximum plasma concentration after intramuscular injection is 45 minutes. Absolute bioavailability is approximately 70%. Plasma protein binding is about 20%. Tramadol crosses the blood-brain and placental barriers. 0.1% of the drug passes into breast milk. It is metabolized in the liver. Elimination half-life is 6 hours. Tramadol and its metabolites are excreted by the kidneys (25–35%) in unchanged form. Approximately 7% is removed by hemodialysis.

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 of monoamine oxidase inhibitors (MAOIs) (see section "Contraindications") and for 2 weeks after their discontinuation; uncontrolled epilepsy; drug withdrawal syndrome.

Interaction with other medicinal products and other forms of interaction.

Concomitant therapeutic use of tramadol and serotonergic medicinal products, such as selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), monoamine oxidase inhibitors (MAOIs) (see section "Contraindications"), tricyclic antidepressants, and mirtazapine, may lead to serotonin syndrome, a potentially life-threatening condition (see sections "Special precautions for use" and "Adverse reactions").

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

Concomitant use of tramadol and medicinal products that depress the central nervous system (CNS), including alcohol, may enhance their CNS-depressant effects.

Concomitant use of tramadol with gabapentinoids (gabapentin and pregabalin) may result in 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 may cause seizures and increase the risk of seizures when used concomitantly with selective serotonin reuptake inhibitors, tricyclic antidepressants, neuroleptics, and other medicinal products that lower the seizure threshold.

There have been isolated reports of serotonin syndrome occurring with combined use of tramadol and other serotonergic medicinal products, such as SSRIs or MAO inhibitors. Signs of serotonin syndrome may include confusion, agitation, hyperthermia, excessive sweating, ataxia, myoclonus, and diarrhea. Discontinuation of serotonergic agents usually leads to rapid improvement. Treatment depends on the nature and severity of symptoms.

Tramadol should be used with caution in combination with coumarin derivatives (e.g., warfarin), as there have been reports of increased INR (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 concentrations of tramadol and reduces concentrations 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 serotonin 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 when cholestyramine is used.

Special precautions for use

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

Tramadol should be administered with particular caution to patients sensitive to opioids.

The drug should be prescribed cautiously 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.

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 lower the seizure threshold, tramadol may increase the risk of epileptic seizures. Tramadol hydrochloride injection solution should be used in patients with epilepsy or those predisposed to epileptic seizures only under life-threatening conditions.

Opioid tolerance and opioid-related disorders (abuse and dependence)

Repeated use of opioids, including tramadol hydrochloride, may lead to the development of tolerance, physical and psychological dependence, and opioid-related disorders (ORD). Repeated administration of tramadol hydrochloride may result in opioid-related disorders (ORD). The risk of developing ORD increases with higher doses and longer duration of opioid treatment. Misuse or intentional inappropriate use of tramadol hydrochloride may lead to overdose and/or death. The risk of developing ORD 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).

Before initiating and during treatment with tramadol hydrochloride, the treatment goals and a plan for discontinuation should be discussed with the patient (see section "Dosage and administration"). Patients should also be informed about the risks and signs of ORD and 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 monitoring concomitant use of opioids and psychoactive medicinal products (e.g., benzodiazepines). If signs and symptoms of ORD occur, consultation with an addiction specialist should be considered.

When a patient no longer requires tramadol therapy, gradual dose reduction is advisable to prevent withdrawal symptoms.

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

CYP2D6 metabolism

Tramadol is metabolized by the liver enzyme CYP2D6. If a patient has a deficiency or complete absence of this enzyme, adequate analgesic effect may not be achieved. Estimates suggest that up to 7% of individuals of Caucasian ethnicity may have this deficiency. However, if a patient is an ultra-rapid metabolizer, there is a risk of developing opioid toxicity side effects even at normal doses.

General symptoms of opioid toxicity include confusion, drowsiness, shallow breathing, pinpoint pupils, nausea, vomiting, constipation, and loss of appetite. In severe cases, this may include circulatory and respiratory depression, which can be life-threatening and, in very rare cases, fatal. Estimates of the prevalence of ultra-rapid metabolizers in various populations are given below:

Sleep-related breathing disorders.

Opioids can cause sleep-related breathing disorders, including central sleep apnea (CSA) and sleep-related hypoxemia. Opioid use increases the risk of developing CSA in a dose-dependent manner. 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 severe abdominal pain, nausea and vomiting, hypotension, profound fatigue, decreased appetite, and weight loss.

Serotonin syndrome.

Serotonin syndrome, a potentially life-threatening condition, has been reported in patients receiving tramadol in combination with other serotonergic medicinal products, as well as with tramadol alone (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 warranted, careful patient monitoring is recommended, particularly at the initiation of therapy and during dose escalation.

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

Postoperative use in children.

Published literature has reported rare but life-threatening adverse reactions following postoperative use of tramadol in children after tonsillectomy and/or adenoidectomy for obstructive sleep apnea. Extreme caution must be exercised when administering tramadol to children for postoperative pain relief. Administration should be accompanied by careful monitoring for symptoms of opioid toxicity, including respiratory depression.

Children with respiratory function disorders.

Tramadol is not recommended for use in children who may have impaired respiratory function, including neuromuscular disorders, severe cardiac or respiratory diseases, upper respiratory tract infections or lung infections, multiple traumas, or major surgical procedures. These factors may exacerbate symptoms of opioid toxicity.

Alcohol must not be consumed during treatment with Tramadol hydrochloride.

Tramadol hydrochloride injection solution contains less than 1 mmol (23 mg/dose) of sodium, i.e., essentially "sodium-free".

Use during pregnancy or breastfeeding.

Pregnancy.

Animal studies have shown that very high doses of tramadol affect organ development, bone growth, and neonatal mortality. No teratogenic effects were observed. Tramadol crosses the placental barrier. Data on the safety of tramadol use during pregnancy are lacking; therefore, Tramadol hydrochloride should not be used in pregnant women.

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

Breastfeeding.

Approximately 0.1% of the maternal dose of tramadol is excreted in breast milk. In the early postpartum period, when the mother receives a daily dose of tramadol (up to 400 mg), the amount of tramadol received by the infant through breastfeeding averages approximately 3% of the maternal dose. For this reason, tramadol should not be used during lactation; otherwise, breastfeeding should be discontinued during tramadol treatment. Usually, there is no need to discontinue breastfeeding after a single dose of the drug.

Ability to affect reaction speed when driving or operating machinery.

During treatment, patients should refrain from driving or operating other potentially hazardous machinery or activities requiring increased attention and rapid psychomotor reaction times.

Method of administration and dosage.

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

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 lasts 4–8 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. For pain relief, 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.

For 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 selected. Daily dose –
4–8 mg/kg body weight. Maximum daily dose of tramadol – 8 mg/kg body weight or 400 mg of tramadol.

Tramadol hydrochloride, injection solution, should be diluted with water for injections.

The concentrations achieved by dilution 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 Tramadol Hydrochloride 50 mg solution for injection (equivalent to 2 ampoules) with 4 mL of water for injection. 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). Dispose of any remaining solution.

Treatment goals and discontinuation

Before initiating treatment with tramadol hydrochloride, the treatment strategy—including duration and treatment goals—should be agreed upon with the patient according to the pain management protocol. During therapy, the physician should maintain regular contact with the patient to assess the need for continuing treatment, consider the possibility of discontinuation, and adjust doses as necessary. When the patient no longer requires tramadol hydrochloride therapy, gradual dose reduction is recommended to prevent withdrawal symptoms. If pain is not adequately controlled, consider the possibility of hyperalgesia, development of tolerance, or progression of the underlying disease (see section "Special precautions").

Elderly patients

Elderly patients (up to 75 years of age) without clinically significant hepatic or renal impairment generally do not require dose adjustment.

Hepatic and renal impairment/dialysis

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

Note: Only the recommended low doses of the drug should be used. When treating chronic pain, tramadol hydrochloride should be administered according to a fixed schedule.

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

Duration of treatment

Do not use tramadol hydrochloride 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 applied. Ensure airway patency (aspiration possible), 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, intravenous diazepam should be administered.

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.

Side effects

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

Psychiatric disorders: hallucinations, convulsions, sleep disorders, 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 (usually decreased, sometimes increased), changes in cognitive functions and perception (e.g., decision-making process, perceptual disturbances). Dependence may develop.

Nervous system disorders: dizziness, headache, clouding of consciousness, change 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 doses of tramadol or when used concomitantly with medicinal products that lower the seizure threshold.

Eye disorders: blurred vision, mydriasis.

Cardiac and vascular 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, thoracic and mediastinal disorders: dyspnea. There have been reports of asthma development; however, a causal relationship has not been established. Hiccups.

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

Hepatobiliary disorders: increased liver enzyme levels, which occurred temporally during 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 (difficulty in urination, dysuria, and urinary retention).

General disorders: fatigue, allergic reactions (dystonia, bronchospasm, angioedema, 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 agitation, anxiety, nervousness, sleep disturbances, hyperkinesia, tremor, and gastrointestinal disturbances. Other symptoms observed rarely after tramadol discontinuation include pain attacks, severe anxiety, hallucinations, paresthesia, tinnitus, and unusual CNS symptoms (confusion, mania, depersonalization, disturbances in perception of surroundings, paranoia).

Drug dependence

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

Reporting suspected adverse reactions

Reporting suspected adverse reactions after medicine registration is highly important. It allows continuous monitoring of the benefit-risk balance of the medicine. Healthcare professionals, pharmacists, patients, and their legal representatives should report all cases of suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life. 4 years.

Do not use the medicinal product after the expiry date stated on the packaging.

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

Keep out of reach and sight of children.

Packaging. 2 ml in an ampoule; 10 ampoules per pack. 2 ml in an ampoule; 5 ampoules per blister; 2 blisters per pack.

Prescription status. Prescription only.

Manufacturer. JSC "Farmak".

Manufacturer's address and place of business.

74 Kyrylivska Street, Kyiv, 04080, Ukraine