Tramaceta (Capsules) Instructions for Use

Marketing Authorization Holder

S.C. Rompharm Company S.R.L. (Romania)

ATC Code

N02AJ13 (Tramadol and Paracetamol)

Active Substances

Paracetamol (Rec.INN registered by WHO)

Tramadol (Rec.INN registered by WHO)

Dosage Form

Tramaceta

Capsules 37.5 mg+325 mg: 15 or 30 pcs.

Dosage Form, Packaging, and Composition

Film-coated tablets light yellow in color, oblong, biconvex, with the engraving “T5” on one side and the “Grünenthal” company logo on the other; the cross-section is almost white.

Excipients: microcrystalline cellulose, pregelatinized starch, sodium starch glycolate, corn starch, purified water, magnesium stearate.

Shell composition Opadry light yellow YS-1-6382-G (hypromellose, titanium dioxide, polyethylene glycol 400 (macrogol), yellow iron oxide dye, polysorbate), carnauba wax.

10 pcs. – blisters (1) – cardboard packs.
10 pcs. – blisters (2) – cardboard packs.
10 pcs. – blisters (3) – cardboard packs.
10 pcs. – blisters (5) – cardboard packs.

Clinical-Pharmacological Group

Combined drug with analgesic action

Pharmacotherapeutic Group

Analgesic agent (analgesic agent with mixed mechanism of action + non-narcotic analgesic agent)

Pharmacological Action

Tramaceta is a combined medicinal product containing Tramadol and Paracetamol.

Tramadol is a synthetic opioid analgesic, has an analgesic effect, and is an opioid receptor agonist. It has a central action and an action on the spinal cord (inhibits the conduction of pain impulses), and enhances the effect of sedatives. It activates opioid receptors (mu-, delta-, kappa-) on the pre- and postsynaptic membranes of afferent fibers of the nociceptive system in the brain and gastrointestinal tract.

Tramadol is a selective agonist of mu-opioid receptors and also inhibits the neuronal reuptake of norepinephrine and enhances the release of serotonin. The severity of the analgesic effect is 6-10 times weaker than that of morphine.

Paracetamol has analgesic and antipyretic effects. It blocks cyclooxygenase in the CNS, affecting the centers of pain and thermoregulation. It does not cause irritation of the gastric and intestinal mucosa, does not affect water-salt metabolism, as it does not affect the synthesis of prostaglandins in peripheral tissues.

Pharmacokinetics

When taken orally, the drug is rapidly and almost completely absorbed from the gastrointestinal tract. The absorption of tramadol occurs more slowly than that of paracetamol. The bioavailability of tramadol is 75%, increasing to 90% with repeated use. The T_max of paracetamol is 1 hour and does not change when used concomitantly with tramadol.

The protein binding of tramadol and paracetamol is about 20%. The volume of distribution is 0.9 l/kg.

Tramadol is metabolized in the liver by N- and O-demethylation followed by conjugation with glucuronic acid. Eleven metabolites have been identified, of which mono-O-desmethyltramadol is pharmacologically active. Paracetamol is metabolized primarily in the liver.

The T_1/2 of tramadol is 4.7-5.1 hours, and of paracetamol is 2-3 hours. Tramadol (about 30%) and its metabolites (about 60%) are excreted primarily by the kidneys. Paracetamol and its conjugates are excreted by the kidneys. In renal insufficiency, the T_1/2 of tramadol and paracetamol increases.

Indications

• Symptomatic treatment of pain syndrome (moderate and severe intensity of various etiologies, including inflammatory, traumatic, vascular origin);
• Pain relief during painful diagnostic or therapeutic procedures.

ICD codes

Dosage Regimen

Orally, regardless of meals, swallow whole (do not break or chew), with liquid.

The dosage regimen and duration of treatment are selected individually depending on the severity of the pain syndrome. For adults and children over 14 years of age, the recommended initial single dose is 1-2 capsules with an interval between doses of at least 6 hours. The maximum daily dose is 8 capsules (300 mg of tramadol and 2600 mg of paracetamol).

In elderly patients (aged 75 years and older), usual doses may be used. However, due to the possibility of delayed excretion, the interval between doses of the drug may be increased. In patients with renal insufficiency (creatinine clearance 10-30 ml/min), the interval between doses should be at least 12 hours. Since Tramadol is excreted very slowly during hemodialysis or hemofiltration, administration of the drug after a dialysis session to maintain the analgesic effect is not required.

In moderate hepatic impairment, the interval between doses of the drug should be increased.

Adverse Reactions

In more than 10% of patients prescribed the combination of tramadol and paracetamol, nausea, dizziness, and drowsiness are observed.

Psychiatric disorders

• Common (from ≥ 1/100 to < 1/10): confusion, mood changes, anxiety, nervousness, euphoria, sleep disorders;
• Uncommon (from ≥ 1/1000 to < 1/100): depression, hallucinations, nightmares, amnesia;
• Rare (from ≥ 1/10000 to < 1/1000): drug dependence;
• Very rare (<1/10000): abuse.

Nervous system disorders

• Very common ( ≥ 1/10): drowsiness, dizziness;
• Common (from ≥ 1/100 to < 1/10): headache, tremor;
• Uncommon (from ≥ 1/1000 to < 1/100): involuntary muscle contractions, paresthesia;
• Rare (from ≥ 1/10000 to < 1/1000): convulsions, ataxia.

Eye disorders

• Rare (from ≥1/10000 to < 1/1000): "blurred" vision.

Ear and labyrinth disorders

• Uncommon (from ≥ 1/1000 to < 1/100): tinnitus.

Cardiac disorders

• Uncommon (from ≥ 1/1000 to < 1/100): arrhythmia, tachycardia, palpitations, increased blood pressure, "hot flashes".

Respiratory, thoracic and mediastinal disorders

• Uncommon (from ≥ 1/1000 to < 1/100): dyspnea.

Gastrointestinal disorders

• Very common ( ≥ 1/10): nausea;
• Common (from ≥ 1/100 to < 1/10): vomiting, constipation, dry mouth, diarrhea, abdominal pain, dyspepsia, flatulence;
• Uncommon (from ≥ 1/1000 to < 1/100): dysphagia, melena.

Skin and subcutaneous tissue disorders

• Common (from ≥ 1/100 to < 1/10): sweating, skin itching;
• Uncommon (from ≥ 1/1000 to < 1/100): skin reactions (e.g., rash, urticaria).

Renal and urinary disorders

• Uncommon (from ≥ 1/1000 to < 1/100): urination disorders (dysuria and urinary retention), albuminuria.

General disorders and administration site conditions

• Uncommon (from ≥ 1/1 000 to < 1/100): chills, chest pain.

Investigations

• Uncommon (from ≥ 1/1000 to < 1/100): increased plasma transaminase activity.

Other sweating, weakness, increased fatigue, menstrual cycle disorders.

Adverse effects that were not encountered in clinical studies, but whose connection with the use of tramadol or paracetamol cannot be excluded.

Tramadol hydrochloride

• Orthostatic hypotension, bradycardia, collapse;
• Post-marketing use of tramadol has revealed rare cases of changes in the effectiveness of warfarin, including increased prothrombin time;
• Rare (from ≥ 1/10000 to < 1/1000): allergic reactions with symptoms of respiratory distress (e.g., dyspnea, bronchospasm, wheezing, angioedema) and anaphylactic shock;
• Rare (from ≥ 1/10000 to < 1/1000): changes in appetite, muscle weakness, respiratory depression;

After taking tramadol, mental disorders of varying severity and nature may be observed (depending on the personality type and duration of treatment), including mood changes (usually euphoria, sometimes dysphoria), changes in activity (usually increased fatigue, less often increased physical activity), impaired cognitive functions and perception (e.g., decision-making process, perception disorders).

Cases of exacerbation of bronchial asthma have been reported, but a causal relationship with the use of the drug has not been established.

Signs of withdrawal syndrome similar to the opioid withdrawal syndrome. They may manifest as restlessness, anxiety, nervousness, insomnia, hyperkinesia, tremor, and gastrointestinal disorders. Other symptoms that have been observed very rarely with abrupt discontinuation of tramadol treatment include: panic attacks, severe anxiety, hallucinations, paresthesia, tinnitus. Unforeseen, previously undescribed CNS symptoms are possible.

Paracetamol side effects are rare, hypersensitivity reactions to the drug are possible, including skin rash; hematopoietic disorders, including thrombocytopenia and agranulocytosis, however, a causal relationship with the use of paracetamol has not been established;

There is evidence that simultaneous use of paracetamol with indirect anticoagulants (e.g., warfarin) may lead to hypoprothrombinemia; in other observations, prothrombin time did not change.

Contraindications

• Hypersensitivity to the active substances or auxiliary components of the drug;
• Conditions accompanied by respiratory depression or severe depression of the central nervous system (including acute intoxication with alcohol or drugs, hypnotics, narcotic analgesics and psychotropic drugs);
• Concomitant use of MAO inhibitors (and within 2 weeks after their discontinuation);
• Severe hepatic and/or renal failure (creatinine clearance less than 10 ml/min);
• Epilepsy not controlled by therapy;
• Withdrawal syndrome from narcotic drugs;
• Children under 14 years of age;
• Pregnancy, lactation period.

With caution

• Traumatic brain injury, intracranial hypertension;
• Tendency to convulsive syndrome (in patients with epilepsy controlled therapeutically, the drug can be used only for vital indications);
• Shock, confusion of unknown etiology, impaired respiratory function;
• Concomitant use of psychotropic and other centrally acting analgesics, local anesthetics;
• Use before general anesthesia;
• Diseases of the biliary tract; benign hyperbilirubinemia, viral hepatitis, glucose-6-phosphate dehydrogenase deficiency;
• Alcoholic liver disease, alcoholism, drug addiction;
• Moderate hepatic and renal (creatinine clearance less than 10-30 ml/min) insufficiency;
• Against the background of abdominal pain of unclear genesis (“acute abdomen”);
• Old age (over 75 years).

Use in Pregnancy and Lactation

There are no reliable results of clinical studies during pregnancy and breastfeeding, therefore, the use of the drug Tramaceta during this period is contraindicated.

Use in Hepatic Impairment

In moderate hepatic impairment, the interval between doses of the drug should be increased.

Use in Renal Impairment

In patients with renal insufficiency (creatinine clearance 10-30 ml/min), the interval between doses should be at least 12 hours. Since Tramadol is excreted very slowly during hemodialysis or hemofiltration, administration of the drug after a dialysis session to maintain the analgesic effect is not required.

Pediatric Use

Contraindicated in children under 14 years of age.

Geriatric Use

In elderly patients (aged 75 years and older), usual doses may be used. However, due to the possibility of delayed excretion, the interval between doses of the drug may be increased.

Special Precautions

For adults and children over 14 years of age, the maximum daily dose of Tramaceta is 8 capsules. To avoid accidental overdose, patients should be informed not to exceed the recommended dose or simultaneously take other drugs containing Paracetamol (including over-the-counter ones) or tramadol hydrochloride without consulting a doctor.

Tramaceta is contraindicated in severe renal failure (creatinine clearance <10 ml/min).

Tramaceta is contraindicated in patients with severe hepatic impairment.

The risk of paracetamol overdose is higher in patients with alcoholic fatty liver disease.

In moderate hepatic impairment, the interval between doses of the drug should be increased.

It is not recommended to prescribe Tramaceta for severe respiratory failure.

Tramadol is not used as a means for treating withdrawal syndrome in patients dependent on opioids.

Tramadol hydrochloride is an opioid receptor agonist, but it cannot relieve morphine withdrawal syndrome.

The development of a convulsive syndrome is possible when prescribing tramadol hydrochloride to patients prone to seizures or taking other drugs that lower the seizure threshold (for example, selective serotonin reuptake inhibitors, tricyclic antidepressants, antipsychotics, centrally acting analgesics or local anesthetics). In patients with epilepsy controlled by medication or patients prone to convulsive syndrome, Tramaceta can be used only for vital indications. The occurrence of a convulsive syndrome is possible in patients taking tramadol hydrochloride at the recommended therapeutic dose. The risk increases significantly when exceeding the maximum allowable doses of the drug.

Concomitant use with opioid agonist-antagonists (nalbuphine, buprenorphine, pentazocine) is not recommended.

Effect on ability to drive vehicles and operate machinery

During treatment with Tramaceta, one should refrain from driving vehicles and engaging in potentially hazardous activities that require increased concentration and speed of psychomotor reactions.

Overdose

Symptoms of Tramaceta overdose may include symptoms of overdose of either tramadol, paracetamol, or both substances.

Symptoms of tramadol overdose

• In case of tramadol overdose, symptoms observed with overdose of other opioid analgesics are possible, for example: miosis, vomiting, collapse, impaired consciousness up to coma, convulsions and respiratory depression up to apnea.

Symptoms of paracetamol overdose

• Overdose is more common in children. Symptoms of paracetamol overdose in the first 24 hours are pallor, nausea, vomiting, anorexia and abdominal pain. Liver damage may occur 12-48 hours after paracetamol overdose. Impaired glucose metabolism and metabolic acidosis may be noted. In case of significant overdose, liver failure may progress to encephalopathy, coma and death. Acute renal failure with acute tubular necrosis may develop even in the absence of severe liver damage. Cardiac arrhythmias and pancreatitis are possible.

In adults, liver damage is possible after oral intake of 7.5-10 g or more of paracetamol. It has been established that an excessive amount of a toxic metabolite (which, when paracetamol is used in recommended doses, is neutralized by glutathione) irreversibly binds to liver tissue.

Emergency medical care

• Immediate hospitalization in a specialized department;
• Maintenance of respiratory and circulatory functions;
• Before starting therapy, it is necessary to perform a blood test to determine the concentration of tramadol and paracetamol in the blood plasma and to determine biochemical markers of liver damage;
• Laboratory determination of biochemical markers of liver damage is carried out upon admission of the patient with an overdose and repeated every 24 hours, an increase in the activity of liver enzymes in the blood plasma is observed: aspartate aminotransferase (AST), ALT (ALT), which normalizes within one or two weeks;
• Empty the stomach by inducing vomiting (if the patient is conscious) or perform gastric lavage;
• It is necessary to ensure airway patency and maintain the function of the cardiovascular system, in case of respiratory depression, naloxone is used, in case of convulsions – diazepam. Diazepam should be used with caution as it may increase the risk of respiratory depression;
• Tramadol is poorly removed from the blood serum by hemodialysis or hemofiltration, so hemodialysis or hemofiltration is not an effective method of therapy for tramadol overdose.

If symptoms of paracetamol overdose appear, immediate initiation of therapy is required. Even in the absence of early symptoms of overdose, the patient should be urgently hospitalized for medical care. Gastric lavage is required if within the previous 4 hours an adult or adolescent has taken >7.5 g of paracetamol or a child > 150 mg/kg of paracetamol. Four hours after the overdose, it is necessary to determine the concentration of paracetamol in the blood plasma to assess the likelihood of developing toxic hepatitis (according to the paracetamol nomogram). Prescribing methionine orally or acetylcysteine intravenously is effective within the first 48 hours after an overdose. The administration of acetylcysteine intravenously is most effective within the first 8 hours after an overdose. However, acetylcysteine should be prescribed even 8 hours after an overdose, until the end of therapy. If a massive overdose is suspected, acetylcysteine administration should be started immediately. In addition, general supportive therapy is required.

Regardless of the dose of paracetamol, the antidote for paracetamol (acetylcysteine) should be started orally or intravenously as early as possible. If possible, within the first 8 hours after the overdose.

Drug Interactions

Concomitant use is contraindicated with

• MAO inhibitors (non-selective, A and B-selective), as the development of serotonin syndrome or symptoms similar to the clinical picture of serotonin syndrome is possible: diarrhea, tachycardia, sweating, tremor, confusion, coma. Tramadol can be prescribed no earlier than 2 weeks after discontinuation of MAO inhibitors.

Concomitant use is not recommended with

• Alcohol. Alcohol potentiates the sedative effect of opioid analgesics, impairs concentration, and the ability to drive a car and operate machinery. Consumption of alcoholic beverages and medicinal products containing alcohol should be avoided;
• Carbamazepine and other inducers of liver microsomal enzymes. A decrease in the effectiveness and duration of the analgesic effect is possible due to a decrease in the plasma concentration of tramadol.
• Opioid receptor agonist-antagonists (buprenorphine, nalbuphine, pentazocine). They reduce the analgesic effect by competitively blocking opioid receptors, and there is a risk of developing withdrawal syndrome.

Caution is required with concomitant use with

• Selective serotonin reuptake inhibitors (SSRIs) and triptans. In rare cases, the development of serotonin syndrome is possible in patients receiving Tramadol in combination with other serotonergic drugs. Signs of serotonin syndrome may include confusion, psychomotor agitation, increased body temperature, sweating, ataxia, hyperreflexia, myoclonus, and diarrhea.
• Other opioids (including antitussives and drugs for the treatment of withdrawal syndrome), benzodiazepines and barbiturates. Combination with these drugs increases the risk of respiratory depression, which can be fatal in case of overdose.
• Other drugs that depress the CNS, opioids (including antitussives and drugs for the treatment of withdrawal syndrome), barbiturates, benzodiazepines, anxiolytics, hypnotics, sedative antidepressants, sedative H1-receptor blockers, neuroleptics, centrally acting antihypertensive drugs, thalidomide and baclofen. These drugs may enhance CNS depression.
• With concomitant use of tramadol and indirect anticoagulants (e.g., warfarin), periodic monitoring of prothrombin time in accordance with standard medical practice is necessary, as an increase in the International Normalized Ratio (INR) is possible.
• With ketoconazole, erythromycin and other inhibitors of the CYP3A4 isoenzyme, as a slowdown in the N-demethylation of tramadol and the metabolism of the active O-demethylated metabolite is possible. Clinical study of such interaction has not been conducted.
• Concomitant use of tramadol with drugs that lower the seizure threshold, such as bupropion, antidepressants from the group of selective serotonin reuptake inhibitors, tricyclic antidepressants and neuroleptics, may increase the risk of seizures. The absorption rate of paracetamol may be increased when co-administered with metoclopramide and domperidone, and when cholestyramine is administered, the absorption of paracetamol may be reduced.
• Administration of antiemetics from the group of serotonin 5-HT3 receptor blockers (e.g., ondansetron) in the pre- and postoperative period requires the use of higher doses of tramadol in patients with postoperative pain syndrome.

Storage Conditions

In a dry place, protected from light, at a temperature not exceeding 25°C (77°F). Keep out of reach of children.

Shelf Life

The shelf life is 3 years.

Dispensing Status

By prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.