Tramadol-zn

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

Composition:

Active substance: tramadol;

1 capsule contains tramadol hydrochloride 50 mg;

Excipients: lactose monohydrate; light magnesium carbonate; calcium stearate;

Hard gelatin capsule No. 1 and No. 2 contain: gelatin, titanium dioxide (E 171), indigotine (E 132), erythrosine (E 127).

Pharmaceutical form. Capsules.

Main physicochemical properties: hard gelatin capsules No. 1 or No. 2 with a white opaque body and a red opaque cap. The contents of the capsules – white powder.

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

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 tramadol's analgesic effect include inhibition of norepinephrine reuptake in neurons and enhancement of serotonergic response.

Tramadol also exerts antitussive effects. Unlike morphine, analgesic doses of tramadol over a wide range do not suppress respiration. 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.

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%. Plasma protein binding is 20%. Tramadol penetrates 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 renally (25–35%) in unchanged form. Approximately 7% is removed by hemodialysis.

An increased elimination half-life has been observed in patients aged 75 years and older.

Inhibition of one or both of the CYP3A4 and CYP2D6 isoenzymes involved in tramadol biotransformation may affect plasma concentrations of tramadol or its active metabolite.

Clinical characteristics.

Indications.

Treatment of moderate to severe pain.

Contraindications.

• Hypersensitivity to tramadol hydrochloride or to any of the excipients;
• Acute alcohol intoxication, psychotropic, sedative, analgesic (including opioid) agents;
• Severe renal impairment (creatinine clearance < 10 mL/min) or severe hepatic insufficiency;
• During treatment with monoamine oxidase inhibitors (MAOIs) and within 14 days after their discontinuation;
• Epilepsy not controlled by treatment;
• Not indicated for the treatment of opioid dependence;
• Drug withdrawal syndrome.

Interaction with other medicinal products and other forms of interactions.

Tramadol-ZN capsules must not be used concomitantly with MAO inhibitors. Life-threatening reactions affecting the central nervous, respiratory, and cardiovascular systems have been observed in patients receiving MAOIs within 14 days prior to administration of the opioid meperidine. A similar interaction with MAOIs cannot be excluded when tramadol is used.

Concomitant use of Tramadol-ZN capsules and medicinal products that depress the central nervous system (CNS), including alcohol, may enhance their effect on the CNS.

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

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

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.

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

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), severe bleeding, and hemorrhage in some patients.

Medicinal products that inhibit CYP3A4, including ketoconazole and erythromycin, may inhibit the metabolism of tramadol (N-demethylation) and of 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 by 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-ZN, capsules, should be used with caution in cases of opioid dependence, head injury, shock, impaired consciousness of unknown origin, respiratory dysfunction, or increased intracranial pressure.

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

The drug should be administered cautiously in cases of respiratory depression, concomitant use of CNS depressants, or when 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-ZN, capsules, should be used in patients with epilepsy or predisposition to seizures only when 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 types of interactions", "Adverse reactions", and "Overdose").

If concomitant treatment with other serotonergic medicinal products is clinically justified, close monitoring of the patient is recommended, especially during initiation of therapy and 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. Withdrawal of serotonergic medicinal products usually leads to rapid improvement.

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 estimated prevalence of ultra-rapid metabolizers in various populations is 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 led to life-threatening adverse reactions. Extreme caution must be exercised when administering tramadol to children for postoperative pain relief, and careful monitoring for symptoms 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 major surgeries. These factors may exacerbate symptoms of opioid toxicity.

Sleep-related breathing disorders

Opioids may cause sleep-related breathing disorders, including central sleep apnea (CSA) and sleep-associated hypoxemia. Opioid use increases the risk of 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 replacement therapy with glucocorticoids. 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.

When a patient no longer requires therapy with tramadol, it is advisable to gradually reduce the dose to prevent the onset of withdrawal symptoms.

Tolerance and opioid use disorders (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 (particularly alcohol), in tobacco users, and in patients with other psychiatric disorders (e.g., severe depression, anxiety, and personality disorders).

Prior to initiating and during treatment with tramadol, the treatment goals and a plan for discontinuation should be discussed with the patient (see section "Dosage and administration"). 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 addictive behavior (e.g., early requests for additional doses). This includes monitoring concomitant use of opioids and psychoactive medications (e.g., benzodiazepines). If a patient develops signs and symptoms of OUD, consultation with an addiction specialist should be considered.

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-ZN.

Tramadol-ZN capsules contain lactose. If a patient has been diagnosed with intolerance to certain sugars, consultation with a physician is recommended before taking this medication.

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-ZN capsules should not be used during pregnancy.

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 newborns.

Breastfeeding

Approximately 0.1% of the dose of tramadol taken by the mother is excreted in breast milk. In the immediate postpartum period, with an oral daily dose of up to 400 mg for the mother, the average amount of tramadol ingested by the infant via breast milk is 3% of the maternal dose adjusted for body weight; therefore, Tramadol-ZN capsules are not recommended during this period, or breastfeeding should be discontinued. Usually, after a single dose of tramadol, interruption of breastfeeding is not necessary.

Ability to affect reaction speed when driving or operating machinery

Tramadol-ZN may cause drowsiness and dizziness, which may impair the ability to drive or operate machinery. Therefore, such activities should be avoided during treatment with this medication.

Method of Administration and Dosage

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

For adults and children aged 14 years and older, the recommended dose is 1–2 capsules (50–100 mg) taken 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), another single dose (50–100 mg) may be administered.

In cases of severe pain, a higher initial dose of Tramadol-ZN (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 needed for additional analgesia, if necessary. The daily dose should not exceed the commonly used dose.

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

Elderly patients.

For elderly patients (up to 75 years of age) without clinically significant hepatic or renal impairment, dose adjustment is usually 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 individual needs.

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

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

Treatment goals and discontinuation.

Before initiating tramadol therapy, a treatment strategy, including duration and 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 discontinuation, and, if necessary, adjust the dosage. When a patient no longer requires tramadol therapy, a gradual dose reduction is recommended to prevent withdrawal symptoms. In the absence of adequate pain control, the possibility of hyperalgesia, development of tolerance, or progression of the underlying disease should be considered (see section "Special precautions").

Treatment duration.

Tramadol-ZN should not be used for longer than recommended. If prolonged analgesia with tramadol is required due to 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 with other opioid analgesics: miosis, vomiting, collapse, coma, seizures, and respiratory depression. Serotonin syndrome has also been reported.

Treatment. Symptomatic therapy, maintenance of airway patency, monitoring of vital functions, prevention of hypothermia, and intravenous administration of naloxone. In case of seizures, intravenous diazepam should be administered.

In cases of overdose with oral formulations, gastric lavage and administration of activated charcoal are recommended within 2 hours after tramadol intake. Gastrointestinal decontamination may be beneficial only after ingestion of very high doses, even at later time points.

A small amount of tramadol is removed by hemodialysis or hemofiltration (these methods are ineffective in treating Tramadol-ZN overdose).

Side effects.

The most common adverse reactions were: nausea, dizziness, headache.

Cardiovascular system: tachycardia, orthostatic hypotension, cardiovascular collapse, palpitations. These adverse effects may occur particularly after intravenous administration of tramadol and in debilitated patients. Arterial hypertension, bradycardia.

Nervous system: 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.

If recommended doses are significantly exceeded, and also when other central nervous system 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.

Psychiatric disorders: hallucinations, sleep disturbances and nightmares, convulsions, anxiety.

Eye disorders: blurred vision, mydriasis.

Gastrointestinal system: nausea, vomiting urges, vomiting, constipation, diarrhea, dryness of mucous membranes, belching, irritation of gastric and intestinal mucosa.

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

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

Musculoskeletal system: muscle weakness.

Hepatobiliary system: in individual cases, elevation of liver enzymes has been observed.

Urinary system: difficulty in urination and urinary retention, dysuria.

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

Withdrawal syndrome may occur, as with other opioids. These symptoms include agitation, anxiety, nervousness, sleep disturbances, hyperkinesia, tremor, and gastrointestinal disorders. Other symptoms observed rarely after tramadol discontinuation include pain episodes, severe anxiety, hallucinations, paresthesia, tinnitus, and unusual central nervous system symptoms (confusion, mania, depersonalization, disturbances in perception of surroundings, paranoia).

After tramadol administration, various adverse effects may occur (depending on patient characteristics and duration of treatment), including mood changes (euphoria, dysphoria), changes in activity (decrease or increase), changes in cognitive functions and perception (e.g., decision-making processes, perception disorders (including hyperacusis)). Dependence may develop.

Drug dependence.

Repeated use of tramadol, 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").

Shelf life.

2 years.

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, 2, or 3 blisters per box.

Prescription status.

Prescription only.

Manufacturer.

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

Manufacturer's address and location of business activity.

Ukraine, 61002, Kharkiv region, Kharkiv city, Kulikovska Street, 41.