Tramadol

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

Composition:

Active substance: tramadol;

1 capsule contains tramadol hydrochloride equivalent to 100 % substance 50 mg;

Excipients: lactose monohydrate, magnesium stearate;

gelatin capsule contains the colorant Diamond Black PN (E 151).

Pharmaceutical form. Capsules.

Main physicochemical properties: hard gelatin capsules of cylindrical shape, size № 2. Capsule body and cap – green. The capsule contents – white powder.

Pharmacotherapeutic group. Analgesics. Opioids. 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 suppress respiration over a wide dose range. Gastrointestinal motility is also less inhibited. Effects on the cardiovascular system are generally mild. The activity of tramadol is estimated to be between 1/10 and 1/6 that of morphine.

Pharmacokinetics.

After oral administration, over 90% of tramadol is absorbed in the gastrointestinal tract. Maximum plasma concentration is reached within 4.8 hours. Absolute bioavailability is 68%, independent of concomitant food intake. The difference between absorbed and unchanged available tramadol is likely related to low presystemic metabolism. Presystemic metabolism after oral administration amounts to a maximum of 30%. Tramadol has high tissue affinity (Vd, ß = 203 ± 40 L). Plasma protein binding is 20%.

After a single oral dose of 100 mg tramadol in capsule or tablet form administered to young healthy volunteers, plasma concentrations of the drug were detectable within 15–45 minutes, with mean Cmax values ranging from 280 to 208 µg/L and Tmax from 1.6 to 2 hours.

Tramadol crosses the blood-brain and placental barriers. Approximately 0.1% of the drug and its metabolite O-desmethyl pass into breast milk.

The elimination half-life is 6 hours, independent of the route of administration.

An increase in elimination half-life has been observed in patients aged 75 years and older, with a coefficient of approximately 1.4.

Tramadol and its metabolites are excreted renally (25–35%) in unchanged form. Approximately 7% is removed by hemodialysis.

Clinical characteristics.

Indications.

Treatment of moderate to severe pain.

Contraindications.

• Hypersensitivity to tramadol hydrochloride or to any of the excipients;
• Acute alcohol intoxication, psychotropic drugs, sedatives, analgesics (including opioids);
• Severe renal (creatinine clearance < 10 ml/min) or hepatic impairment;
• During treatment with monoamine oxidase inhibitors (MAOIs) and within 14 days after their discontinuation;
• Epilepsy not controlled by treatment;
• Opioid withdrawal syndrome.

Interaction with other medicinal products and other forms of interaction.

Tramadol capsules must not be used concomitantly with MAO inhibitors. In patients who have 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, including alcohol, may enhance their CNS-depressant effects.

Concomitant use of opioids with sedative medicinal products such as benzodiazepines or related substances increases the risk of sedation, respiratory depression, coma, and death due to additive CNS depressant effects. Therefore, the dose of tramadol and the duration of concomitant use should be reduced.

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 cause clinically significant interactions. Concomitant or prior use of carbamazepine (an enzyme inducer) may reduce the analgesic effect and shorten the duration of action of tramadol.

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

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

When tramadol is used concomitantly with other serotonergic medicinal products, such as selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, MAO inhibitors (see section "Contraindications"), tricyclic antidepressants, and mirtazapine, serotonin syndrome—a potentially life-threatening condition—may occur (see sections "Special precautions for use" and "Adverse reactions").

Theoretically, tramadol may interact with noradrenaline, 5-HT receptors, or lithium through their competitive mechanisms of action, thereby potentiating their antidepressant effects. However, there have been no reports of such interactions.

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

Medicinal products that inhibit CYP3A4, including ketoconazole and erythromycin, may inhibit the metabolism of tramadol (N-demethylation) and probably also that of its active O-demethylated metabolite. The clinical significance of this interaction has not been studied.

In some studies, pre- or postoperative use of ondansetron (a 5-HT3 receptor antagonist antiemetic) has been shown to increase the requirement for tramadol in patients with postoperative pain.

The rate of absorption may be increased by metoclopramide or domperidone and decreased by cholestyramine.

Special precautions for use.

Tramadol should be used with caution in opioid dependence, traumatic brain injury, shock, impaired consciousness of unknown origin, respiratory center and breathing function disorders, increased intracranial pressure, and predisposition to seizures.

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

Concomitant use of tramadol and sedative medicinal products such as benzodiazepines or related substances may result in sedation, respiratory depression, coma, and death. Due to these risks, concomitant administration of these medicinal products to the patient is possible only when no alternative treatment options exist. If a decision has been made to co-prescribe tramadol with sedative medicinal products, the lowest effective dose of tramadol should be used, and the duration of concomitant sedative use should be as short as possible.

Close monitoring for signs and symptoms of respiratory depression and sedation is required in such patients. Therefore, it is strongly recommended to inform patients and caregivers about these symptoms.

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. Rare cases of respiratory depression have been reported with tramadol use at therapeutic doses.

Seizures have been reported in patients receiving tramadol at the recommended dosage. The risk increases when the dose exceeds the recommended maximum daily dose (400 mg). Concomitant use of medicinal products that lower the seizure threshold increases the risk of epileptic seizures with tramadol. Tramadol should be prescribed to patients with epilepsy or those predisposed to seizures only for vital indications.

Serotonin syndrome

Serotonin syndrome, a potentially life-threatening condition, has been reported in patients receiving tramadol in combination with other serotonergic medicinal products or tramadol alone (see sections "Interaction with other medicinal products and other forms of interaction," "Side effects," and "Overdose").

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

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

Sleep-related breathing disorders

Opioids may cause sleep-related breathing disorders, including central sleep apnea (CSA) and sleep-related hypoxemia. Opioid use increases the risk of CSA in a dose-dependent manner. For patients with CSA, a reduction in the total opioid dose should be considered.

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.

Metabolism via CYP2D6

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. Up to 7% of the Caucasian population may have this deficiency. However, if a patient is an ultra-rapid metabolizer, there is a risk of developing opioid toxicity-related adverse 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, circulatory and respiratory depression may occur, which can be life-threatening and very rarely fatal. The prevalence estimates of ultra-rapid metabolizers in various populations are presented below:

Postoperative use in children

Scientific publications have reported that tramadol used in children after tonsillectomy and/or adenoidectomy for obstructive sleep apnea has rarely caused life-threatening adverse reactions. Extreme caution must be exercised when using tramadol in children for postoperative pain relief, and careful monitoring for signs of opioid toxicity, including respiratory depression, is required.

Children with impaired respiratory function

Tramadol is not recommended for use in children who may have impaired respiratory function, including those with neuromuscular disorders, severe cardiac or respiratory diseases, upper respiratory tract infections or lung infections, multiple injuries, or after major surgery. These factors may increase the risk of opioid toxicity symptoms.

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

Tolerance and opioid use disorders (abuse and dependence)

Tolerance, physical and psychological dependence, and opioid use disorders (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 result in 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 use disorders), in current tobacco users, or in patients with existing psychiatric disorders (e.g., severe depression, anxiety, and personality disorders).

Prior to initiating and during therapy with tramadol, 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 OUD before and during treatment. Patients should be advised to contact their physician if such signs occur.

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 medications (e.g., benzodiazepines). Patients exhibiting signs and symptoms of OUD should be considered for referral to a specialist in addiction medicine.

When a patient no longer requires tramadol therapy, gradual dose reduction may be appropriate 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.

Alcohol must not be consumed during treatment with tramadol.

The medicinal product contains lactose; therefore, it should not be used in patients with rare hereditary forms of galactose intolerance, lactase deficiency, or glucose-galactose malabsorption syndrome.

The dye diamond black PN may cause allergic reactions.

Use during pregnancy or breastfeeding

Pregnancy

Animal studies have shown that very high doses of tramadol affect organ development, bone growth, and may be lethal to newborns. Tramadol crosses the placental barrier. Data on the safety of tramadol use during pregnancy are lacking; therefore, tramadol should not be used during pregnancy.

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

Breastfeeding

Approximately 0.1% of the dose received by a breastfeeding woman passes into breast milk. In the early postpartum period, when a nursing 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. Therefore, tramadol is not recommended during lactation—otherwise, breastfeeding should be discontinued during tramadol treatment. Usually, breastfeeding need not be interrupted after a single dose of tramadol.

Reproductive function

During the post-marketing period, no effects of tramadol on reproductive function have been observed. Animal studies also did not show any effect of tramadol on fertility.

Ability to affect reaction speed when driving or operating machinery

Tramadol may cause drowsiness and dizziness, even when taken as directed. These effects may be enhanced by alcohol and other medicinal products affecting the CNS (depressants or psychotropic substances), potentially impairing cognitive function and thereby affecting a patient's ability to drive or operate machinery. Therefore, such activities should be avoided during treatment with this medicinal product.

Method of Administration and Dosage.

The dosage and duration of treatment are determined individually by a physician, depending on the intensity of pain.

Adults and children aged 14 years and older should take 1–2 capsules (50–100 mg) orally every 4–6 hours.

Maximum daily dose – 8 capsules (400 mg).

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

In cases of severe pain, a higher initial dose of Tramadol (100 mg) may be required.

Depending on the intensity of pain, the duration of action ranges from 4 to 8 hours. During the early postoperative period, higher doses may be needed for additional analgesia, if necessary. The daily dose should not exceed the dose usually administered.

For pain relief, the lowest effective dose should generally be prescribed. The daily dose of tramadol (400 mg) should not be exceeded, except in the presence of specific clinical circumstances (e.g. cancer pain or severe postoperative pain).

Treatment goals and discontinuation

Prior to initiating therapy with Tramadol, the physician should discuss with the patient the treatment strategy, including its duration and goals, in accordance with 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, if necessary, adjust the dosage. When the patient no longer requires tramadol therapy, a gradual dose reduction is recommended to prevent withdrawal symptoms. If adequate pain control is not achieved, consider the possibility of hyperalgesia, development of tolerance, or progression of the underlying disease (see section "Special Instructions").

Elderly patients. Dose adjustment is generally not required in elderly patients (up to 75 years of age) who do not have clinically significant hepatic or renal impairment. In elderly patients aged 75 years and older, elimination may be prolonged. Therefore, if necessary, the dosing interval should be extended according to the patient's clinical condition.

Hepatic and renal impairment / dialysis. In patients with mild to moderate hepatic and/or renal dysfunction, tramadol elimination is slowed. In such patients, the dosing interval should be extended as needed.

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

Capsules should be swallowed whole with sufficient fluid, independent of food intake.

Duration of treatment. Do not use Tramadol 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 treatment breaks) to determine the need for continued therapy.

Children.

The drug is contraindicated in children under 14 years of age.

Overdose.

Symptoms of overdose are similar to those observed after overdose of other opioid analgesics: pinpoint pupils, vomiting, cardiovascular collapse, sedation, impaired consciousness up to coma, seizures, and respiratory depression, which may lead to respiratory arrest. Serotonin syndrome has also been reported.

Treatment. General supportive measures should be implemented. Ensure airway patency (aspiration possible), support respiration and circulation. The antidote for respiratory depression is naloxone. Animal studies have shown that naloxone does not affect seizures. In case of seizures, diazepam should be administered intravenously.

In cases of overdose with oral formulations, gastric lavage and administration of activated charcoal are recommended within 2 hours after tramadol ingestion. Gastrointestinal decontamination at later stages may be beneficial only after ingestion of very high doses or prolonged-release formulations.

Only a small amount of tramadol is removed by hemodialysis or hemofiltration; therefore, the use of these methods alone is not considered appropriate for treatment of Tramadol overdose.

Side effects

The most commonly observed side effects were nausea and dizziness, occurring in more than 10% of patients.

Adverse reactions are classified by frequency of occurrence as follows: very common (> 1/10), common (> 1/100 and < 1/10), uncommon (> 1/1000 and < 1/100), rare (> 1/10000 and < 1/1000), very rare (< 1/10000), frequency not known (cannot be estimated from available data).

Blood and lymphatic system disorders: pathological blood changes have been observed during tramadol treatment, but a direct causal relationship has not been confirmed.

Immune system disorders: rare – hypersensitivity/allergic reactions (e.g., dyspnea, bronchospasm, wheezing, angioedema) and anaphylactic reactions.

Psychiatric disorders: rare – sleep disturbances, delirium, anxiety, confusion, nightmares, hallucinations. Psychiatric adverse reactions following tramadol administration may vary in nature and intensity (depending on individual patient characteristics and duration of treatment). These include mood changes (usually euphoria, sometimes dysphoria), changes in activity (usually decreased, sometimes increased), and changes in cognitive functions and perception (e.g., decision-making processes, perceptual disturbances, including hyperacusis). Prolonged use of tramadol may lead to dependence.

Withdrawal symptoms. Symptoms after discontinuation are similar to those occurring upon withdrawal of other opioids. These symptoms include agitation, anxiety, nervousness, insomnia, hyperkinesia, tremor, and gastrointestinal disturbances. Other symptoms have been observed rarely after tramadol discontinuation, including panic attacks, severe anxiety, hallucinations, paresthesia, tinnitus, and unusual central nervous system symptoms (confusion, delirium, depersonalization, derealization, paranoia).

Nervous system disorders: very common – dizziness; common – headache, somnolence; rare – paresthesia, tremor, involuntary muscle twitching, coordination disturbances, syncope, speech disorders, epileptiform seizures. Epileptiform seizures occur mainly after administration of high doses of tramadol or when used concomitantly with medicinal products that lower the seizure threshold or themselves cause central-origin seizures (e.g., antidepressants or antipsychotics); frequency not known – serotonin syndrome.

Eye disorders: rare – miosis, blurred vision, mydriasis.

Cardiac disorders: uncommon – tachycardia, palpitations (these adverse effects may occur particularly after intravenous administration and in physically weakened patients); rare – bradycardia.

Vascular disorders: uncommon – postural hypotension or cardiovascular collapse (these adverse effects may occur particularly after intravenous administration and in physically weakened patients).

Respiratory, thoracic and mediastinal disorders: rare – respiratory depression, dyspnea. Worsening of asthma has been reported, but a causal relationship has not been established. When recommended doses are significantly exceeded, and especially when other centrally acting depressants are used concomitantly, respiratory depression may occur; frequency not known – hiccups.

Gastrointestinal disorders: very common – nausea; common – vomiting, constipation, dry mouth; uncommon – diarrhea, gastrointestinal discomfort (feeling of heaviness in the stomach, flatulence), belching; frequency not known – urge to vomit.

Skin and subcutaneous tissue disorders: common – increased sweating; uncommon – skin reactions (including rash, urticaria, pruritus); frequency not known – erythema.

Musculoskeletal and connective tissue disorders: rare – motor weakness.

Hepatobiliary disorders: in several isolated cases, elevated liver enzymes have been observed temporally associated with tramadol therapy.

Renal and urinary disorders: rare – urinary disorders and urinary retention, dysuria.

Metabolism and nutrition disorders: rare – appetite changes; frequency not known – hypoglycemia.

General disorders: common – fatigue; frequency not known – taste disturbances, weakness, lethargy, reduced reaction speed, menstrual cycle disturbances.

Investigations: rare – increased blood pressure.

Drug dependence

Repeated use of Tramadol may lead to drug dependence, even when taken 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").

Reporting of suspected adverse reactions

Reporting of adverse reactions after medicinal product registration is highly important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy through 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 of children.

Packaging. 10 capsules in a blister. 1 or 3 blisters per carton.

Prescription status. Prescription only.

Manufacturer. JSC "Farmak".

Manufacturer's address.

74 Kyrylivska Street, Kyiv, 04080, Ukraine.