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Indications/Uses
For the short-term (five days or less) management of moderate to severe pain.
Dosage/Direction for Use
Tramadol + paracetamol can be administered with or without food and is for oral use only. Tablets should be swallowed, with a sufficient quantity of liquid.
The dose should be individually adjusted according to the intensity of pain and response of the patient.
Adults and children over 16 years old: Orally, one to two tablets every four to six hours, as needed for pain relief, or, as prescribed by a physician.
Maximum: Eight tablets per day.
Elderly patients: In patients over 75 years old, it is recommended that the minimum interval between doses should not be less than six hours.
Renal impairment (creatinine clearance < 30 mL/min): It is recommended that the dosing interval of tramadol + paracetamol should be prolonged, and the dose should not exceed 75 mg of tramadol and 650 mg of paracetamol (two tablets) every 12 hours. As tramadol is removed only very slowly by hemodialysis or by hemofiltration, post-dialysis administration to maintain analgesia is not usually required.
Hepatic impairment: In patients with moderate hepatic impairment, prolongation of the dosage interval should be carefully considered.
The dose should be individually adjusted according to the intensity of pain and response of the patient.
Adults and children over 16 years old: Orally, one to two tablets every four to six hours, as needed for pain relief, or, as prescribed by a physician.
Maximum: Eight tablets per day.
Elderly patients: In patients over 75 years old, it is recommended that the minimum interval between doses should not be less than six hours.
Renal impairment (creatinine clearance < 30 mL/min): It is recommended that the dosing interval of tramadol + paracetamol should be prolonged, and the dose should not exceed 75 mg of tramadol and 650 mg of paracetamol (two tablets) every 12 hours. As tramadol is removed only very slowly by hemodialysis or by hemofiltration, post-dialysis administration to maintain analgesia is not usually required.
Hepatic impairment: In patients with moderate hepatic impairment, prolongation of the dosage interval should be carefully considered.
Overdosage
The clinical presentation of overdose may include the signs and symptoms of tramadol toxicity, paracetamol toxicity, or both.
Tramadol overdosage and management: Potential serious consequences of tramadol overdosage include respiratory depression, somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, constricted pupils, pulmonary edema (in some cases), bradycardia, hypotension, partial or complete airway obstruction, atypical snoring, seizures, cardiac arrest, and death. Death may occur within one hour of overdosage.
Deaths due to overdose with abuse and misuse of tramadol have been reported. Moreover, the risk of fatal overdose is further increased when tramadol is abused concomitantly with CNS depressants such as alcohol or opioids.
Primary attention should be given in re-establishing a patent and protected airway and maintaining adequate assisted or controlled ventilation, if needed. General supportive treatment (including oxygen and vasopressors) may also be employed in the management of circulatory shocks and pulmonary edema, as indicated. Naloxone may reverse some, but not all symptoms caused by tramadol overdosage. Serious arrhythmias or cardiac arrest will require advanced life-supporting measures.
Opioid antagonists (e.g., naloxone) should only be administered for the management of clinically significant respiratory or circulatory depression due to tramadol overdose. Although the administration of naloxone will only reverse some (but not all) symptoms caused by tramadol overdosage, it also increases the risk of seizure, for which intravenous diazepam may be given. In individuals who are physically dependent on opioids, the administration of an opioid antagonist should be started with care and by titration with smaller than usual doses of the antagonist to prevent the occurrence of acute withdrawal symptoms.
Since the duration of opioid reversal is expected to be less than the duration of action of tramadol, the patient should be carefully monitored until respiration normalizes.
Gastrointestinal decontamination with activated charcoal or by gastric lavage may also be performed within one to two hours of oral tramadol intoxication to remove any unabsorbed drug. Once the airway is protected, activated charcoal may be administered via nasogastric tube in patients who are not fully conscious or have impaired gag reflex. Gastrointestinal decontamination at a later time may only be useful in cases of overdosage with unusually large quantities.
Hemodialysis is not expected to be helpful for tramadol overdose because it only removes less than seven percent of the administered dose in a four-hour dialysis period.
Paracetamol overdosage and management: Overdosage of paracetamol usually involves four phases with the following signs and symptoms: Anorexia, nausea, vomiting, malaise, and diaphoresis; Right upper abdominal pain or tenderness, liver enlargement which may be characterized by abdominal discomfort of "feeling full", elevated bilirubin and liver enzyme concentrations, prolongation of prothrombin time, and occasionally oliguria; Anorexia, nausea, vomiting, and malaise recur and signs of liver (e.g., jaundice) and possibly kidney failure and cardiomyopathy may develop; Recovery or progression to fatal complete liver failure.
Potentially fatal hepatic necrosis is the most serious adverse effect. Renal tubular necrosis, hypoglycemic coma, thrombocytopenia, metabolic acidosis, and encephalopathy may also occur and may lead to coma and death. Although paracetamol does not normally produce methemoglobinemia or hemolysis even after overdosage or in patients with G6PD deficiency, there have been isolated reports of these complications. Clinical and laboratory evidence of hepatic toxicity may not be apparent 48 to 72 hours post-ingestion.
Emergency measures include: Immediate hospitalization.
A serum paracetamol assay to be obtained as soon as possible, but no sooner than four hours following oral ingestion.
Administer the antidote N-acetylcysteine (NAC) as early as possible by intravenous (IV) or oral route. In overdoses of oral paracetamol, NAC is administered, if possible, before the 10th hour after ingestion of paracetamol. However, NAC may give some degree of protection from liver toxicity even after this time. As a guide to treatment of acute ingestion, the acetaminophen level can be plotted against time since oral ingestion on a nomogram (Rumack-Matthew). The lower toxic line on the nomogram is equivalent to 150 mcg/mL at four hours and 37.5 mcg/mL at 12 hours. If serum level is above the lower line, administer the entire course of NAC treatment. Withhold NAC therapy if the paracetamol level is below the lower line.
Symptomatic treatment.
Hepatic tests must be carried out at the beginning of treatment and repeated every 24 hours. In most cases, hepatic transaminases return to normal in one to two weeks with full restitution of the liver function. However, liver transplantation may be necessary in very severe cases.
Tramadol overdosage and management: Potential serious consequences of tramadol overdosage include respiratory depression, somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, constricted pupils, pulmonary edema (in some cases), bradycardia, hypotension, partial or complete airway obstruction, atypical snoring, seizures, cardiac arrest, and death. Death may occur within one hour of overdosage.
Deaths due to overdose with abuse and misuse of tramadol have been reported. Moreover, the risk of fatal overdose is further increased when tramadol is abused concomitantly with CNS depressants such as alcohol or opioids.
Primary attention should be given in re-establishing a patent and protected airway and maintaining adequate assisted or controlled ventilation, if needed. General supportive treatment (including oxygen and vasopressors) may also be employed in the management of circulatory shocks and pulmonary edema, as indicated. Naloxone may reverse some, but not all symptoms caused by tramadol overdosage. Serious arrhythmias or cardiac arrest will require advanced life-supporting measures.
Opioid antagonists (e.g., naloxone) should only be administered for the management of clinically significant respiratory or circulatory depression due to tramadol overdose. Although the administration of naloxone will only reverse some (but not all) symptoms caused by tramadol overdosage, it also increases the risk of seizure, for which intravenous diazepam may be given. In individuals who are physically dependent on opioids, the administration of an opioid antagonist should be started with care and by titration with smaller than usual doses of the antagonist to prevent the occurrence of acute withdrawal symptoms.
Since the duration of opioid reversal is expected to be less than the duration of action of tramadol, the patient should be carefully monitored until respiration normalizes.
Gastrointestinal decontamination with activated charcoal or by gastric lavage may also be performed within one to two hours of oral tramadol intoxication to remove any unabsorbed drug. Once the airway is protected, activated charcoal may be administered via nasogastric tube in patients who are not fully conscious or have impaired gag reflex. Gastrointestinal decontamination at a later time may only be useful in cases of overdosage with unusually large quantities.
Hemodialysis is not expected to be helpful for tramadol overdose because it only removes less than seven percent of the administered dose in a four-hour dialysis period.
Paracetamol overdosage and management: Overdosage of paracetamol usually involves four phases with the following signs and symptoms: Anorexia, nausea, vomiting, malaise, and diaphoresis; Right upper abdominal pain or tenderness, liver enlargement which may be characterized by abdominal discomfort of "feeling full", elevated bilirubin and liver enzyme concentrations, prolongation of prothrombin time, and occasionally oliguria; Anorexia, nausea, vomiting, and malaise recur and signs of liver (e.g., jaundice) and possibly kidney failure and cardiomyopathy may develop; Recovery or progression to fatal complete liver failure.
Potentially fatal hepatic necrosis is the most serious adverse effect. Renal tubular necrosis, hypoglycemic coma, thrombocytopenia, metabolic acidosis, and encephalopathy may also occur and may lead to coma and death. Although paracetamol does not normally produce methemoglobinemia or hemolysis even after overdosage or in patients with G6PD deficiency, there have been isolated reports of these complications. Clinical and laboratory evidence of hepatic toxicity may not be apparent 48 to 72 hours post-ingestion.
Emergency measures include: Immediate hospitalization.
A serum paracetamol assay to be obtained as soon as possible, but no sooner than four hours following oral ingestion.
Administer the antidote N-acetylcysteine (NAC) as early as possible by intravenous (IV) or oral route. In overdoses of oral paracetamol, NAC is administered, if possible, before the 10th hour after ingestion of paracetamol. However, NAC may give some degree of protection from liver toxicity even after this time. As a guide to treatment of acute ingestion, the acetaminophen level can be plotted against time since oral ingestion on a nomogram (Rumack-Matthew). The lower toxic line on the nomogram is equivalent to 150 mcg/mL at four hours and 37.5 mcg/mL at 12 hours. If serum level is above the lower line, administer the entire course of NAC treatment. Withhold NAC therapy if the paracetamol level is below the lower line.
Symptomatic treatment.
Hepatic tests must be carried out at the beginning of treatment and repeated every 24 hours. In most cases, hepatic transaminases return to normal in one to two weeks with full restitution of the liver function. However, liver transplantation may be necessary in very severe cases.
Administration
May be taken with or without food.
Contraindications
Hypersensitivity to tramadol, paracetamol, or to any component in the product.
Acute intoxication with alcohol, hypnotics, narcotics, centrally acting analgesics, opioids or psychotropic drugs.
Patients on monoamine oxidase inhibitor (MAOI) therapy or if patients have taken such medications within the last 14 days before treatment with tramadol. (See Interactions.)
Severe hepatic or renal impairment.
Severely impaired kidney function (creatinine clearance < 10 mL/min).
Severe respiratory impairment (e.g., acute or severe bronchial asthma, bronchial asthma, chronic obstructive airway, or status asthmaticus) in an unmonitored setting or in the absence of resuscitative equipment.
Acute alcoholism, delirium tremens, and convulsive disorders.
Suspected or known mechanical gastrointestinal (GI) obstruction, (e.g., bowel obstruction or strictures); any conditions affecting bowel transit (e.g., ileus of any type); or in patients with suspected surgical abdomen (e.g., acute appendicitis or pancreatitis).
Significant acute respiratory depression, elevated carbon dioxide levels in the blood, and cor pulmonale.
Patients suffering from uncontrolled epilepsy or epilepsy not adequately controlled by treatment.
Severe central nervous system (CNS) depression, increased cerebrospinal or intracranial pressure, and head injury.
Children who are younger than 12 years old and to patients younger than 18 years old who have tonsillectomy and/or adenoidectomy.
Acute intoxication with alcohol, hypnotics, narcotics, centrally acting analgesics, opioids or psychotropic drugs.
Patients on monoamine oxidase inhibitor (MAOI) therapy or if patients have taken such medications within the last 14 days before treatment with tramadol. (See Interactions.)
Severe hepatic or renal impairment.
Severely impaired kidney function (creatinine clearance < 10 mL/min).
Severe respiratory impairment (e.g., acute or severe bronchial asthma, bronchial asthma, chronic obstructive airway, or status asthmaticus) in an unmonitored setting or in the absence of resuscitative equipment.
Acute alcoholism, delirium tremens, and convulsive disorders.
Suspected or known mechanical gastrointestinal (GI) obstruction, (e.g., bowel obstruction or strictures); any conditions affecting bowel transit (e.g., ileus of any type); or in patients with suspected surgical abdomen (e.g., acute appendicitis or pancreatitis).
Significant acute respiratory depression, elevated carbon dioxide levels in the blood, and cor pulmonale.
Patients suffering from uncontrolled epilepsy or epilepsy not adequately controlled by treatment.
Severe central nervous system (CNS) depression, increased cerebrospinal or intracranial pressure, and head injury.
Children who are younger than 12 years old and to patients younger than 18 years old who have tonsillectomy and/or adenoidectomy.
Warnings
Addiction, Abuse, and Misuse: The use of tramadol HCl exposes patients and other users to the risks of opioid addiction, abuse, and misuse, which can lead to overdose and death. The patient's risk should be assessed prior to prescribing tramadol, and the development of related behaviors and conditions should be monitored regularly. (See Precautions.)
Life-Threatening Respiratory Depression: Serious, life-threatening, or fatal respiratory depression may occur with the use of tramadol. Close monitoring for respiratory depression should be performed, especially during initiation of tramadol and following a dose increase. (See Precautions.)
Accidental Ingestion: Accidental ingestion of even one tramadol dose, particularly by children, can result in respiratory depression and death. Patients should be instructed that medicines containing tramadol should be securely stored. Unused tramadol-containing medicines should also be disposed accordingly.
Neonatal Opioid Withdrawal Syndrome: Prolonged use of tramadol during pregnancy may lead to opioid withdrawal in the neonate. Neonatal opioid may be fatal if not immediately recognized and treated. It also requires management according to protocols developed by neonatology experts. Signs of neonatal opioid withdrawal syndrome should be observed in newborns and should be managed accordingly. If the prolonged use of opioid is necessary during pregnancy, the patient should be advised of the risk of neonatal opioid withdrawal syndrome and guarantee that the appropriate treatment will be available.
Interactions with Drugs Affecting Cytochrome P450 Isoenzymes: The concomitant use or discontinuation of cytochrome (CYP) P450 3A4 inducers, 3A4 inhibitors, or 2D6 inhibitors with tramadol produces complex effects. Therefore, careful considered on the effects of the concomitant use of these agents on tramadol (a weak serotonin and norepinephrine reuptake inhibitor and µ-opioid agonist) and M1 (which is more potent than tramadol in µ-opioid receptor binding) is required. (See Precautions.)
Hepatotoxicity: Paracetamol is associated with cases of acute liver failure, at times leading to liver transplant and death. Majority of these cases involved the use of more than one paracetamol-containing product and with the use of paracetamol at doses exceeding four grams per day. The excessive intake of paracetamol may be intentional (to inflict self-harm) or unintentional (to attain more pain relief or unknowingly taking other products containing paracetamol). (See Precautions.)
Risks from Concomitant Use with Benzodiazepines or Other Central Nervous System (CNS) Depressants: The concurrent use of opioids with CNS depressants (e.g., benzodiazepines, alcohol) can result in respiratory depression, coma, and death. (See Precautions.) The concomitant prescribing of tramadol with benzodiazepines or other CNS depressants should be reserved for use in patients for whom alternative treatment options are inadequate. Treatment should be limited to the minimum effective dosages and durations. Monitor patients for signs and symptoms of respiratory depression and sedation.
Life-Threatening Respiratory Depression: Serious, life-threatening, or fatal respiratory depression may occur with the use of tramadol. Close monitoring for respiratory depression should be performed, especially during initiation of tramadol and following a dose increase. (See Precautions.)
Accidental Ingestion: Accidental ingestion of even one tramadol dose, particularly by children, can result in respiratory depression and death. Patients should be instructed that medicines containing tramadol should be securely stored. Unused tramadol-containing medicines should also be disposed accordingly.
Neonatal Opioid Withdrawal Syndrome: Prolonged use of tramadol during pregnancy may lead to opioid withdrawal in the neonate. Neonatal opioid may be fatal if not immediately recognized and treated. It also requires management according to protocols developed by neonatology experts. Signs of neonatal opioid withdrawal syndrome should be observed in newborns and should be managed accordingly. If the prolonged use of opioid is necessary during pregnancy, the patient should be advised of the risk of neonatal opioid withdrawal syndrome and guarantee that the appropriate treatment will be available.
Interactions with Drugs Affecting Cytochrome P450 Isoenzymes: The concomitant use or discontinuation of cytochrome (CYP) P450 3A4 inducers, 3A4 inhibitors, or 2D6 inhibitors with tramadol produces complex effects. Therefore, careful considered on the effects of the concomitant use of these agents on tramadol (a weak serotonin and norepinephrine reuptake inhibitor and µ-opioid agonist) and M1 (which is more potent than tramadol in µ-opioid receptor binding) is required. (See Precautions.)
Hepatotoxicity: Paracetamol is associated with cases of acute liver failure, at times leading to liver transplant and death. Majority of these cases involved the use of more than one paracetamol-containing product and with the use of paracetamol at doses exceeding four grams per day. The excessive intake of paracetamol may be intentional (to inflict self-harm) or unintentional (to attain more pain relief or unknowingly taking other products containing paracetamol). (See Precautions.)
Risks from Concomitant Use with Benzodiazepines or Other Central Nervous System (CNS) Depressants: The concurrent use of opioids with CNS depressants (e.g., benzodiazepines, alcohol) can result in respiratory depression, coma, and death. (See Precautions.) The concomitant prescribing of tramadol with benzodiazepines or other CNS depressants should be reserved for use in patients for whom alternative treatment options are inadequate. Treatment should be limited to the minimum effective dosages and durations. Monitor patients for signs and symptoms of respiratory depression and sedation.
Special Precautions
Addiction, Abuse, and Misuse: As an opioid analgesic, the use of tramadol HCl is associated with the risks of opioid addiction, abuse, and misuse, which can lead to overdose and death. Addiction may occur even if tramadol is appropriately prescribed at recommended dosages and if it is abused or misused.
The patient's risk should be assessed prior to prescribing tramadol, and the development of related behaviors and conditions should be monitored regularly. Patients with a personal or family history of substance abuse (such as drug or alcohol abuse or addiction) or mental illness (e.g., major depression) have an increased risk for addiction. However, these potential risks should not interfere with the proper pain management on any patient. Though tramadol may be prescribed in high-risk patients, it may require intensive counseling about the risks and proper use of tramadol, together with intensive monitoring for signs of addiction, abuse, and misuse.
Strategies to reduce the risk of addiction (e.g., prescribing the drug in the smallest appropriate dose; advising the patient on the proper disposal of the unused drug) should be considered when prescribing or dispensing tramadol.
Life-Threatening Respiratory Depression: Serious, life-threatening respiratory depression may occur with the use of tramadol. If not immediately diagnosed and treated, respiratory depression may lead to respiratory arrest and death. The sedating effects of opioids can be exacerbated by the carbon dioxide retention from opioid-induced respiratory depression. Management of respiratory depression (which may include close observation, supportive measures, and use of opioid antagonists) should be performed, depending on the clinical status of the patient. Patients with impending respiratory depression should be immediately brought to an emergency room with facilities for respiratory/ventilatory support.
Although serious, life-threatening, or fatal respiratory depression can occur at any time with the use of tramadol, the risk is greatest during the initiation of tramadol therapy or following a dose increase. Thus, close monitoring for respiratory depression should be performed, especially within the first 24 to 72 hours of treatment initiation and following dosage increases.
Proper dosing and titration of tramadol are necessary to reduce the risk of respiratory depression. Overestimation of the tramadol dosage when converting patients from another opioid can lead to a fatal overdose with the first dose.
Interactions with Drugs Affecting Cytochrome P450 Isoenzymes: The concomitant use or discontinuation of cytochrome (CYP) P450 3A4 inducers, 3A4 inhibitors, or 2D6 inhibitors with tramadol produces complex effects. Therefore, careful consideration on the effects of the concomitant use of these agents on tramadol (a weak serotonin and norepinephrine reuptake inhibitor and µ-opioid agonist) and M1 (which is more potent than tramadol in µ-opioid receptor binding) is required.
The patient's risk should be assessed prior to prescribing tramadol, and the development of related behaviors and conditions should be monitored regularly. Patients with a personal or family history of substance abuse (such as drug or alcohol abuse or addiction) or mental illness (e.g., major depression) have an increased risk for addiction. However, these potential risks should not interfere with the proper pain management on any patient. Though tramadol may be prescribed in high-risk patients, it may require intensive counseling about the risks and proper use of tramadol, together with intensive monitoring for signs of addiction, abuse, and misuse.
Strategies to reduce the risk of addiction (e.g., prescribing the drug in the smallest appropriate dose; advising the patient on the proper disposal of the unused drug) should be considered when prescribing or dispensing tramadol.
Life-Threatening Respiratory Depression: Serious, life-threatening respiratory depression may occur with the use of tramadol. If not immediately diagnosed and treated, respiratory depression may lead to respiratory arrest and death. The sedating effects of opioids can be exacerbated by the carbon dioxide retention from opioid-induced respiratory depression. Management of respiratory depression (which may include close observation, supportive measures, and use of opioid antagonists) should be performed, depending on the clinical status of the patient. Patients with impending respiratory depression should be immediately brought to an emergency room with facilities for respiratory/ventilatory support.
Although serious, life-threatening, or fatal respiratory depression can occur at any time with the use of tramadol, the risk is greatest during the initiation of tramadol therapy or following a dose increase. Thus, close monitoring for respiratory depression should be performed, especially within the first 24 to 72 hours of treatment initiation and following dosage increases.
Proper dosing and titration of tramadol are necessary to reduce the risk of respiratory depression. Overestimation of the tramadol dosage when converting patients from another opioid can lead to a fatal overdose with the first dose.
Interactions with Drugs Affecting Cytochrome P450 Isoenzymes: The concomitant use or discontinuation of cytochrome (CYP) P450 3A4 inducers, 3A4 inhibitors, or 2D6 inhibitors with tramadol produces complex effects. Therefore, careful consideration on the effects of the concomitant use of these agents on tramadol (a weak serotonin and norepinephrine reuptake inhibitor and µ-opioid agonist) and M1 (which is more potent than tramadol in µ-opioid receptor binding) is required.
Use In Pregnancy & Lactation
Pregnancy: Pregnancy Category C.
Epidemiological studies in human pregnancy did not demonstrate detrimental effects of paracetamol used in the recommended dosages. However, tramadol crosses the placenta. Since there are no adequate and well-controlled studies in pregnant women, tramadol + paracetamol should not be used in pregnant women, unless the potential benefits outweigh the possible risks to the fetus. Neonatal seizures, neonatal withdrawal syndrome, fetal death, and still birth have been reported in post-marketing surveillance. Signs of neonatal opioid withdrawal syndrome should be observed in newborns and should be managed accordingly.
Labor and Delivery: The safe use of tramadol + paracetamol during pregnancy has not been established. Tramadol should not be used in pregnant women prior to or during labor when other analgesics are more appropriate unless the potential benefits outweigh the potential risks. The use of tramadol may affect the duration of labor due to its inhibitory actions on uterine contractions or facilitatory actions on cervical dilation.
Chronic use during pregnancy may lead to neonatal withdrawal symptoms (See Precautions). If tramadol will be used during labor, it may cause respiratory depression in the newborn. An opioid antagonist (e.g., naloxone) should be available to reverse the opioid-induced respiratory depression in the neonate. Monitor newborns exposed to tramadol during labor for signs of excess sedation and respiratory depression.
Tramadol has also been shown to cross the placenta. The effect of tramadol, if any, on the later growth, development and functional maturation of the child is unknown.
Lactation: The use of tramadol as an obstetric preoperative medication or for post-delivery analgesia in breastfeeding mothers is not recommended.
Low levels of tramadol have been detected in breastmilk. Moreover, paracetamol is excreted in human breastmilk in clinically insignificant amounts. Instruct nursing mothers to monitor infants for unusually increased sleepiness, limpness, or breathing difficulties; and to seek medical care immediately. Withdrawal symptoms may occur in breastfed infants when tramadol maternal administration is stopped, or when breast-feeding is stopped.
Epidemiological studies in human pregnancy did not demonstrate detrimental effects of paracetamol used in the recommended dosages. However, tramadol crosses the placenta. Since there are no adequate and well-controlled studies in pregnant women, tramadol + paracetamol should not be used in pregnant women, unless the potential benefits outweigh the possible risks to the fetus. Neonatal seizures, neonatal withdrawal syndrome, fetal death, and still birth have been reported in post-marketing surveillance. Signs of neonatal opioid withdrawal syndrome should be observed in newborns and should be managed accordingly.
Labor and Delivery: The safe use of tramadol + paracetamol during pregnancy has not been established. Tramadol should not be used in pregnant women prior to or during labor when other analgesics are more appropriate unless the potential benefits outweigh the potential risks. The use of tramadol may affect the duration of labor due to its inhibitory actions on uterine contractions or facilitatory actions on cervical dilation.
Chronic use during pregnancy may lead to neonatal withdrawal symptoms (See Precautions). If tramadol will be used during labor, it may cause respiratory depression in the newborn. An opioid antagonist (e.g., naloxone) should be available to reverse the opioid-induced respiratory depression in the neonate. Monitor newborns exposed to tramadol during labor for signs of excess sedation and respiratory depression.
Tramadol has also been shown to cross the placenta. The effect of tramadol, if any, on the later growth, development and functional maturation of the child is unknown.
Lactation: The use of tramadol as an obstetric preoperative medication or for post-delivery analgesia in breastfeeding mothers is not recommended.
Low levels of tramadol have been detected in breastmilk. Moreover, paracetamol is excreted in human breastmilk in clinically insignificant amounts. Instruct nursing mothers to monitor infants for unusually increased sleepiness, limpness, or breathing difficulties; and to seek medical care immediately. Withdrawal symptoms may occur in breastfed infants when tramadol maternal administration is stopped, or when breast-feeding is stopped.
Adverse Reactions
Tramadol + Paracetamol: The most frequently reported adverse effects are abdominal pain, anorexia, constipation, diarrhea, dizziness, dry mouth, dyspepsia, fatigue, flatulence, headache, hot flushes, hypertension, hypoesthesia, increased sweating, influenza-like symptoms, insomnia, nausea, nervousness, prostatic disorder, pruritus, rash, somnolence, trembling, and vomiting.
Blood and lymphatic system disorders: Agranulocytosis, anemia, granulocytopenia, leukocytosis, thrombocytopenic purpura.
Immune system disorders: Acute generalized exanthematous pustulosis, allergic reactions, anaphylaxis, bronchospasm, Stevens-Johnson Syndrome, toxic epidermal necrolysis, urticaria.
Metabolism and nutrition disorders: Hypoglycemia, hyponatremia.
Psychiatric disorders: Abnormal thinking, anxiety, cognitive dysfunction, confusion, depression, drug abuse, drug dependence, emotional lability, euphoria, hallucinations, mental status changes, mood changes, nervousness, panic attacks, paroniria, sleep disorders, stupor, suicidal tendency.
Nervous disorder: Abnormal dreams, agitation, amnesia, ataxia, coma, convulsions, difficulty concentrating, dyskinesia, dystonia, hyperreflexia, involuntary muscle contractions, migraine, paresthesia, seizure, syncope, tremor, vertigo. Eye disorders: Abnormal vision, blurred vision.
Ear and Labyrinth disorders: Tinnitus.
Cardiac disorders: Arrhythmia, chest pain, dependent edema, myocardial ischemia, palpitation, pulmonary edema, tachycardia.
Vascular disorders: Aggravated hypertension, cardiovascular collapse, hypertension, hypotension, orthostatic hypotension, syncope, vasodilation.
Respiratory, thoracic and mediastinal disorders: Dyspnea.
Gastrointestinal disorders: Abdominal pain, dysphagia, gastrointestinal bleeding, melena, tongue edema.
Hepatobiliary disorders: Hepatitis, hepatotoxicity, liver failure.
Skin and subcutaneous tissue disorders: Dermatitis, erythematous rash, urticaria.
Musculoskeletal and connective tissue disorders: Arthralgia, hypertonia, rigors, shivers.
Renal and urinary disorders: Albuminuria, dysuria, micturition disorders, urinary retention, oliguria.
Reproductive system and breast disorders: Impotence, prostatic disorder.
General disorders and administration site conditions: Asthenia, fever, diaphoresis, withdrawal syndrome.
Blood and lymphatic system disorders: Agranulocytosis, anemia, granulocytopenia, leukocytosis, thrombocytopenic purpura.
Immune system disorders: Acute generalized exanthematous pustulosis, allergic reactions, anaphylaxis, bronchospasm, Stevens-Johnson Syndrome, toxic epidermal necrolysis, urticaria.
Metabolism and nutrition disorders: Hypoglycemia, hyponatremia.
Psychiatric disorders: Abnormal thinking, anxiety, cognitive dysfunction, confusion, depression, drug abuse, drug dependence, emotional lability, euphoria, hallucinations, mental status changes, mood changes, nervousness, panic attacks, paroniria, sleep disorders, stupor, suicidal tendency.
Nervous disorder: Abnormal dreams, agitation, amnesia, ataxia, coma, convulsions, difficulty concentrating, dyskinesia, dystonia, hyperreflexia, involuntary muscle contractions, migraine, paresthesia, seizure, syncope, tremor, vertigo. Eye disorders: Abnormal vision, blurred vision.
Ear and Labyrinth disorders: Tinnitus.
Cardiac disorders: Arrhythmia, chest pain, dependent edema, myocardial ischemia, palpitation, pulmonary edema, tachycardia.
Vascular disorders: Aggravated hypertension, cardiovascular collapse, hypertension, hypotension, orthostatic hypotension, syncope, vasodilation.
Respiratory, thoracic and mediastinal disorders: Dyspnea.
Gastrointestinal disorders: Abdominal pain, dysphagia, gastrointestinal bleeding, melena, tongue edema.
Hepatobiliary disorders: Hepatitis, hepatotoxicity, liver failure.
Skin and subcutaneous tissue disorders: Dermatitis, erythematous rash, urticaria.
Musculoskeletal and connective tissue disorders: Arthralgia, hypertonia, rigors, shivers.
Renal and urinary disorders: Albuminuria, dysuria, micturition disorders, urinary retention, oliguria.
Reproductive system and breast disorders: Impotence, prostatic disorder.
General disorders and administration site conditions: Asthenia, fever, diaphoresis, withdrawal syndrome.
Drug Interactions
May alter effect of warfarin. Tramadol: Additive effects w/ other opioids (eg, fentanyl, pethidine) or illicit drugs causing CNS depression (eg, γ-hydroxybutyrate, flunitrazepam). Decreased analgesic effect & risk of tramadol-associated seizures w/ carbamazepine. Decreased plasma conc w/ CYP3A4 inducers eg, rifampicin, St. John's wort. Reduced metabolic clearance w/ CYP2D6 inhibitors (eg, amitriptyline, fluoxetine, paroxetine) &/or CYP3A4 inhibitors (eg, ketoconazole, erythromycin). Increased plasma conc w/ quinidine. Increased risk of serious adverse events including seizures & serotonin syndrome w/ serotonergic drugs (MAOIs, SSRIs, SNRIs, triptans, lithium). Paracetamol: Increased risk of hepatotoxicity w/ anticonvulsants eg, phenytoin, barbiturates, carbamazepine. Possible increased risk of hepatotoxicity w/ INH & severe hypothermia w/ phenothiazines. Additive effects w/ ethanol.
Storage
Store at temperatures not exceeding 30°C.
Action
Pharmacodynamics: Tramadol is a synthetic opioid analgesic that acts on the central nervous system. It is a pure non-selective agonist of the µ, δ, and κ opioid receptors with a higher affinity for the µ receptors. Other mechanisms which contribute to its analgesic effect are inhibition of neuronal uptake of noradrenaline and enhancement of serotonin release.
Paracetamol exhibits analgesic and antipyretic activity by inhibiting prostaglandin synthesis. It produces analgesia by elevating the pain threshold and antipyresis through its action on the hypothalamic heat regulating center. In therapeutic doses, the analgesic and antipyretic action of paracetamol is comparable to that of aspirin. Paracetamol does not adversely affect platelet function and hemostasis.
The combination of tramadol + paracetamol exhibits a synergistic effect. Controlled studies demonstrated that the combination provided analgesia comparable to ibuprofen and superior to that provided by monotherapy of either ingredient or placebo. Onset of pain relief occurred in about 17 minutes (vs. 15 minutes for paracetamol alone and 30 minutes for tramadol alone or placebo), while duration of pain relief was about five hours (vs. two hours with tramadol alone and three hours with paracetamol alone).
Pharmacokinetics: After a single oral dose of tramadol 37.5 mg + paracetamol 325 mg combination tablet, peak plasma concentrations (Cmax) of both tramadol enantiomers were 64.3 ng/mL [(+)-tramadol] and 55.5 ng/mL [(-)-tramadol]. These concentrations were achieved after 1.8 hours. Peak plasma concentration of paracetamol achieved after 0.9 hour was 4.2 mcg/mL. The mean elimination half-lives (t1/2) of both tramadol enantiomers were 5.1 hours [(+)-tramadol] and 4.7 hours [(-)-tramadol] and 2.5 hours for paracetamol.
Tramadol is well absorbed with mean absolute bioavailability of approximately 75% after a single oral 100 mg dose. Peak concentrations of tramadol and the M1 metabolite (major metabolite) occur after two and three hours, respectively.
Paracetamol is rapidly and completely absorbed in the small intestine. Peak plasma concentrations are achieved in one hour and are not modified by concomitant administration of tramadol.
The oral administration of tramadol + paracetamol with food has no significant effect on the peak plasma concentration or extent of absorption of either tramadol or paracetamol.
Tramadol has high tissue affinity with a volume of distribution of 2.6 and 2.9 L/kg in male and female subjects, respectively, after intravenous administration. Its affinity for plasma proteins is approximately 20% and saturation occurs at doses beyond the therapeutic range.
Paracetamol is evenly distributed throughout most body fluids, but not in fatty tissue. Volume of distribution is approximately 0.9 L/kg. A relatively small portion (Yulex20%) of paracetamol is bound to plasma proteins.
Tramadol and its metabolites undergo extensive hepatic metabolism via the cytochrome P (CYP) 2D6 and CYP3A4 pathways and conjugation of the parent drug and its metabolites. Most of the drug is excreted in the urine as metabolites (approximately 60%) and the remaining drug fraction is excreted in its unchanged form.
Paracetamol metabolism follows first-order kinetics, and primary metabolic pathways involve conjugation with glucuronide and sulfate; and oxidation via the CYP450 mixed-function oxidase pathway. In adults, most of the drug fraction is transformed into the inactive glucuronide salt, and the remainder is conjugated with sulfate.
Paracetamol exhibits analgesic and antipyretic activity by inhibiting prostaglandin synthesis. It produces analgesia by elevating the pain threshold and antipyresis through its action on the hypothalamic heat regulating center. In therapeutic doses, the analgesic and antipyretic action of paracetamol is comparable to that of aspirin. Paracetamol does not adversely affect platelet function and hemostasis.
The combination of tramadol + paracetamol exhibits a synergistic effect. Controlled studies demonstrated that the combination provided analgesia comparable to ibuprofen and superior to that provided by monotherapy of either ingredient or placebo. Onset of pain relief occurred in about 17 minutes (vs. 15 minutes for paracetamol alone and 30 minutes for tramadol alone or placebo), while duration of pain relief was about five hours (vs. two hours with tramadol alone and three hours with paracetamol alone).
Pharmacokinetics: After a single oral dose of tramadol 37.5 mg + paracetamol 325 mg combination tablet, peak plasma concentrations (Cmax) of both tramadol enantiomers were 64.3 ng/mL [(+)-tramadol] and 55.5 ng/mL [(-)-tramadol]. These concentrations were achieved after 1.8 hours. Peak plasma concentration of paracetamol achieved after 0.9 hour was 4.2 mcg/mL. The mean elimination half-lives (t1/2) of both tramadol enantiomers were 5.1 hours [(+)-tramadol] and 4.7 hours [(-)-tramadol] and 2.5 hours for paracetamol.
Tramadol is well absorbed with mean absolute bioavailability of approximately 75% after a single oral 100 mg dose. Peak concentrations of tramadol and the M1 metabolite (major metabolite) occur after two and three hours, respectively.
Paracetamol is rapidly and completely absorbed in the small intestine. Peak plasma concentrations are achieved in one hour and are not modified by concomitant administration of tramadol.
The oral administration of tramadol + paracetamol with food has no significant effect on the peak plasma concentration or extent of absorption of either tramadol or paracetamol.
Tramadol has high tissue affinity with a volume of distribution of 2.6 and 2.9 L/kg in male and female subjects, respectively, after intravenous administration. Its affinity for plasma proteins is approximately 20% and saturation occurs at doses beyond the therapeutic range.
Paracetamol is evenly distributed throughout most body fluids, but not in fatty tissue. Volume of distribution is approximately 0.9 L/kg. A relatively small portion (Yulex20%) of paracetamol is bound to plasma proteins.
Tramadol and its metabolites undergo extensive hepatic metabolism via the cytochrome P (CYP) 2D6 and CYP3A4 pathways and conjugation of the parent drug and its metabolites. Most of the drug is excreted in the urine as metabolites (approximately 60%) and the remaining drug fraction is excreted in its unchanged form.
Paracetamol metabolism follows first-order kinetics, and primary metabolic pathways involve conjugation with glucuronide and sulfate; and oxidation via the CYP450 mixed-function oxidase pathway. In adults, most of the drug fraction is transformed into the inactive glucuronide salt, and the remainder is conjugated with sulfate.
MedsGo Class
Analgesics (Opioid)
Features
Dosage
37.5mg / 325mg
Ingredients
- Paracetamol
- Tramadol
Packaging
Tablet 1's
Generic Name
Tramadol Hydrochloride / Paracetamol
Registration Number
DR-XY34809
Classification
Prescription Drug (RX)
Product Questions
Questions
