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Indications/Uses
Symptomatic treatment of moderate to severe acute, chronic pain.
Dosage/Direction for Use
Adults and Adolescents (12 years and older): The dose should be individually adjusted according to intensity of pain and response of the patient.
An initial dose of 2 tablets is recommended. Additional doses can be taken at the minimum 6 hours intervals, not exceeding 8 tablets per day.
This drug should under no circumstances be administered for longer than is strictly necessary. If repeated use or long term treatment with this drug is required as a result of the nature and severity of the illness, then careful, regular monitoring should take place, to assess whether continuation of the treatment is necessary.
Pediatrics: The effective and safe use of this drug has not been established in children below the age of 12 years. Treatment is therefore not recommended in this population.
Geriatrics: The usual dosages may be used although it should be noted that in volunteers aged over 75 years the elimination half life of tramadol was increased by 17% following oral administration. In patients over 75 years old, it is recommended that the minimum interval between doses should be not less than 6 hours, due to the presence of tramadol.
Renal insufficiency: Because of the presence of tramadol, the use of CETADOL is not recommended in patients with severe renal insufficiency (creatinine clearance <10 mL/min). In cases of moderate renal insufficiency (creatinine clearance between 10 and 30 mL/min), the dosing should be increased to 12-hourly intervals. As tramadol is removed only very slowly by haemodialysis or by haemofiltration, post dialysis administration to maintain analgesia is not usually required.
Hepatic failure: It is cautiously considered that patients with moderate hepatic failure take this drug at prolonged administration interval.
This drug is contraindicated to patients with moderate hepatic failure.
An initial dose of 2 tablets is recommended. Additional doses can be taken at the minimum 6 hours intervals, not exceeding 8 tablets per day.
This drug should under no circumstances be administered for longer than is strictly necessary. If repeated use or long term treatment with this drug is required as a result of the nature and severity of the illness, then careful, regular monitoring should take place, to assess whether continuation of the treatment is necessary.
Pediatrics: The effective and safe use of this drug has not been established in children below the age of 12 years. Treatment is therefore not recommended in this population.
Geriatrics: The usual dosages may be used although it should be noted that in volunteers aged over 75 years the elimination half life of tramadol was increased by 17% following oral administration. In patients over 75 years old, it is recommended that the minimum interval between doses should be not less than 6 hours, due to the presence of tramadol.
Renal insufficiency: Because of the presence of tramadol, the use of CETADOL is not recommended in patients with severe renal insufficiency (creatinine clearance <10 mL/min). In cases of moderate renal insufficiency (creatinine clearance between 10 and 30 mL/min), the dosing should be increased to 12-hourly intervals. As tramadol is removed only very slowly by haemodialysis or by haemofiltration, post dialysis administration to maintain analgesia is not usually required.
Hepatic failure: It is cautiously considered that patients with moderate hepatic failure take this drug at prolonged administration interval.
This drug is contraindicated to patients with moderate hepatic failure.
Overdosage
In case of overdose, the symptoms may include the signs and symptoms of toxicity of tramadol or paracetamol or of both these active ingredients.
Serious potential consequences of overdosage are respiratory depression, lethargy, coma, seizure, cardiac arrest and death.
Serious potential consequences of overdosage with paracetamol are hepatic centrilobular necrosis, leading to hepatic failure and death. Renal tubular necrosis, hypoglycemia and coagulation defects also may occur. Early symptoms following a potentially hepatotoxic overdose may include: nausea, vomiting, diaphoresis and general malaise. Clinical and laboratory evidence of hepatic toxicity may not be apparent until 48 to 72 hours post ingestion.
In the occurrence of overdose, consultation with a regional poison control center is recommended. In treating an overdose, primary attention should be given to maintaining adequate ventilation along with general supportive treatment. While naloxone will reverse some, but not all, symptoms caused by overdosage with tramadol, the risk of seizures is also increased with naloxone administration. Based on experience with tramadol, hemodialysis is not expected to be helpful in an overdose because it removes less than 7% of the administered dose in a 4-hour dialysis period. In overdose, oral methionine or intravenous N-acetylcysteine (NAC) is taken within 10-12 hours to prevent liver damage.
Serious potential consequences of overdosage are respiratory depression, lethargy, coma, seizure, cardiac arrest and death.
Serious potential consequences of overdosage with paracetamol are hepatic centrilobular necrosis, leading to hepatic failure and death. Renal tubular necrosis, hypoglycemia and coagulation defects also may occur. Early symptoms following a potentially hepatotoxic overdose may include: nausea, vomiting, diaphoresis and general malaise. Clinical and laboratory evidence of hepatic toxicity may not be apparent until 48 to 72 hours post ingestion.
In the occurrence of overdose, consultation with a regional poison control center is recommended. In treating an overdose, primary attention should be given to maintaining adequate ventilation along with general supportive treatment. While naloxone will reverse some, but not all, symptoms caused by overdosage with tramadol, the risk of seizures is also increased with naloxone administration. Based on experience with tramadol, hemodialysis is not expected to be helpful in an overdose because it removes less than 7% of the administered dose in a 4-hour dialysis period. In overdose, oral methionine or intravenous N-acetylcysteine (NAC) is taken within 10-12 hours to prevent liver damage.
Administration
May be taken with or without food.
Contraindications
Hypersensitivity to tramadol, paracetamol or to any of the excipients of the medicinal product.
Acute intoxication with alcohol, hypnotic drugs, centrally-acting analgesics, opioids or psychotropic drugs.
Severe respiratory depression (Light respiratory depression may occur).
Due to head injury or encephalopathy, patients with the risk of consciousness disturbance.
Patients who are receiving monoamine oxidase inhibitors or within two weeks of their withdrawal.
Peptic ulcer or severe blood disorder.
Severe liver disease, renal disorder or severe renal failure.
Patients with aspirin asthma (induction of asthmatic attack caused by NSAIDs) or history thereof.
Epilepsy not controlled by treatment.
Acute intoxication with alcohol, hypnotic drugs, centrally-acting analgesics, opioids or psychotropic drugs.
Severe respiratory depression (Light respiratory depression may occur).
Due to head injury or encephalopathy, patients with the risk of consciousness disturbance.
Patients who are receiving monoamine oxidase inhibitors or within two weeks of their withdrawal.
Peptic ulcer or severe blood disorder.
Severe liver disease, renal disorder or severe renal failure.
Patients with aspirin asthma (induction of asthmatic attack caused by NSAIDs) or history thereof.
Epilepsy not controlled by treatment.
Warnings
Convulsions have been reported in patients receiving tramadol at the recommended dose levels. The risk may be increased when doses of tramadol exceed the recommended upper dose limit. Concomitant use of tramadol increases the seizure risk in patients taking: Selective serotonin re-uptake inhibitors (SSRIs and anorectic agent); tricyclic antidepressants (TCAs) and other tricyclic compounds (eg. cyclobenzaprine, promethazine); other opioid.
Administration of tramadol may enhance the seizure risk in patients taking: MAO (Monoamine Oxidase) inhibitor; neuroleptic; other drugs that reduce the seizure threshold.
Risk of convulsions may also increase in patients with epilepsy, those with a history of seizures, or in patients with a recognized risk for seizure (such as head trauma, metabolic disorders, alcohol and drug withdrawal, CNS infections).
Serious anaphylactoid reactions have been reported in patients receiving therapy with tramadol.
When excessive tramadol is administered with anesthetic medications or alcohol, respiratory depression may result. Respiratory depression should be treated as an overdose. If naloxone is to be administered, use cautiously because it may precipitate seizures.
This drug should be used with caution and in reduced dosages when administered to patients receiving CNS depressants. Tramadol increases the risk of CNS and respiratory depression in these patients.
This drug should be used with caution in patients with increased intracranial pressure or head injury. The respiratory depressant effects of opioids include carbon dioxide retention and secondary elevation of cerebrospinal fluid pressure and may be markedly exaggerated in these patients.
If person with consumption more than 3 cups of alcohol beverage every day take this drug or other analgesics, consult physician or pharmacist. If the person takes this drug, liver damage may occur.
Tramadol may induce psychic and physical dependence of the morphine-type (μ-opioid).
This drug should be used with caution in the following patient: Concurrent use with morphine or repeated administration.
Patients who receives CNS depressants such as opioid, anesthetic, hypnotic, phenothiazine, tranquilizer and sedatives.
Patients with biliary tract disorders.
Patients with hepatic disease.
Patients with renal disease.
Patients with alcohol.
Patients with hypersensitivity to opioid.
Patients with epilepsy or possibility of seizure.
In a state of shock, in an altered state of consciousness for unknown reasons.
Administration of tramadol may enhance the seizure risk in patients taking: MAO (Monoamine Oxidase) inhibitor; neuroleptic; other drugs that reduce the seizure threshold.
Risk of convulsions may also increase in patients with epilepsy, those with a history of seizures, or in patients with a recognized risk for seizure (such as head trauma, metabolic disorders, alcohol and drug withdrawal, CNS infections).
Serious anaphylactoid reactions have been reported in patients receiving therapy with tramadol.
When excessive tramadol is administered with anesthetic medications or alcohol, respiratory depression may result. Respiratory depression should be treated as an overdose. If naloxone is to be administered, use cautiously because it may precipitate seizures.
This drug should be used with caution and in reduced dosages when administered to patients receiving CNS depressants. Tramadol increases the risk of CNS and respiratory depression in these patients.
This drug should be used with caution in patients with increased intracranial pressure or head injury. The respiratory depressant effects of opioids include carbon dioxide retention and secondary elevation of cerebrospinal fluid pressure and may be markedly exaggerated in these patients.
If person with consumption more than 3 cups of alcohol beverage every day take this drug or other analgesics, consult physician or pharmacist. If the person takes this drug, liver damage may occur.
Tramadol may induce psychic and physical dependence of the morphine-type (μ-opioid).
This drug should be used with caution in the following patient: Concurrent use with morphine or repeated administration.
Patients who receives CNS depressants such as opioid, anesthetic, hypnotic, phenothiazine, tranquilizer and sedatives.
Patients with biliary tract disorders.
Patients with hepatic disease.
Patients with renal disease.
Patients with alcohol.
Patients with hypersensitivity to opioid.
Patients with epilepsy or possibility of seizure.
In a state of shock, in an altered state of consciousness for unknown reasons.
Special Precautions
General caution: Patients should be advised not to exceed the recommended dose and not to use any other paracetamol (including over the counter) or tramadol hydrochloride containing products concurrently.
Although Tramadol Hydrochloride develops low onset of the drug dependence, but duration of therapy should be controlled because the possibility of drug dependency in long term use cannot be completely excluded. Drug-dependent patients or patients with the possibility of drug abuse should be carefully observed and it should be taken during short term. Tramadol is not suitable as a substitute in opioid-dependent patients. Although it is an opioid agonist, tramadol cannot suppress morphine withdrawal symptoms. Concomitant use of opioid agonists-antagonists (nalbuphine, buprenorphine, pentazocine) is not recommended.
If tramadol hydrochloride is discontinued abruptly, withdrawal symptoms such as anxiety, sweating, insomnia, spasticity, pain, nausea, tremor, diarrhea, upper respiratory syndrome, piloerection, excitation, nervousness, hyperkinesias or GI disorder may occur. Panic attacks, severe anxiety, hallucination, paresthesias, tinnitus or very rare abnormal CNS reaction have been reported. Clinical experience suggests that withdrawal symptoms may be relieved by tapering the medication.
In patients who took tramadol, allergic reaction such as urticaria, rash, bronchial convulsion, toxic epidermal necrolysis and Steven Johnson's syndrome, including anaphylactoid reaction have been reported. In patients with a history of anaphylactoid to codeine or other opioids, the risk may increase.
Caution should be exercised when this drug is used to patients who take CNS depressant such as alcohol, opioid, anesthetic, hypnotic, phenothiazine, tranquilizer and sedative antidepressant, sedative antihistamines, neuroleptic, centrally acting antihypertensive drug, thalidomide or baclofen, and dosage reduction should be considered. When tramadol is administered to those patients, the risks of CNS and respiratory depression may increase.
Convulsions have been reported in tramadol-treated patients susceptible to seizures or taking other medications that lower the seizure threshold, especially selective serotonin re-uptake inhibitors, tricyclic antidepressants, antipsychotics, centrally acting analgesics or local anaesthesia. Epileptic patients controlled by a treatment or patients susceptible to seizures should be treated with this drug only if there are compelling circumstances.
If patients with chronic alcoholism take excessive paracetamol, liver toxicity may occur. This drug is not recommended to patients with liver disease.
In patients with hepatic insufficiency, pharmacokinetic and drug intolerance of this drug have not been studied. Tramadol and paracetamol are mainly metabolized in liver. In patients with severe hepatic disease, this drug is not recommended.
There is no clinical trials of compound of tramadol and paracetamol to renal insufficiency. Based on tramadol use, degree or rate in excretion of M1, active metabolite of tramadol may be reduced in patients with renal sufficiency. In cases of moderate renal insufficiency (creatinine clearance below 30 mL/min), the dosing should not exceed 2 tablets at 12-hourly intervals.
In long term use, duration of therapy should be controlled or therapy is temporarily discontinued because the possibility of drug dependency cannot be completely excluded.
As medically appropriate, periodic evaluation of prothrombin time should be performed when this drug and warfarin like compounds are administered concurrently due to reports of increased INR.
In one study, use of tramadol during general anaesthesia with enflurane and nitrous oxide was reported to enhance intra-operative recall. Until further information is available, use of tramadol during light planes of anaesthesia should be avoided.
Others: Tramadol showed tolerance in animal study. Therefore, caution is exercised in continuous use or dose increase.
There are no animal or laboratory studies on the combination product (tramadol and paracetamol) to evaluate carcinogenesis, mutagenesis or impairment of fertility.
A slight but statistically significant increase in two common murine tumors, pulmonary and hepatic, was observed in a mouse carcinogenicity study, particularly in aged mice. Mice were dosed orally up to 30 mg/kg (90 mg/m2 or 0.5 times the maximum daily human tramadol dosage of 185 mg/m2) for approximately two years, although the study was not done with the Maximum Tolerated Dose. This finding is not believed to suggest risk in humans. No such finding occurred in rat carcinogenicity study (dosing orally up to 60 mg/kg, 180 mg/m2, or 1 time the maximum daily human tramadol dosage).
Mutagenic toxicity: Tramadol was not mutagenic in the following assays: Ames Salmonella microsomal activation test, CHO/HPRT mammalian cell assay, mouse lymphoma assay (in the absence of metabolic activation), dominant lethal mutation tests in mice, chromosome aberration test in Chinese hamsters, and bone marrow micronucleus tests in mice and Chinese hamsters. Weekly mutagenic results occurred in the presence of metabolic activation in the mouse lymphoma assay and micronucleus test in rats. Overall, the weight of evidence from these tests indicates that tramadol does not pose a genetoxic risk to humans.
Fertility: No effects on fertility were observed for tramadol at oral dose levels up to 50 mg/kg (350 mg/m2) in male rats and 75 mg/kg (450 mg/m2) in female rats. These dosages are 1.6 and 2.4 times the maximum daily human tramadol dosage of 185 mg/m2.
Effects on ability to drive and use machines: Tramadol may cause drowsiness or dizziness, which may be enhanced by alcohol or other CNS depressants. The patient using this drug should be cautioned accordingly.
Use in Children & Elderly: The effective and safe use of this drug have not been established in children below the age of 12 years.
In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function; of concomitant disease and multiple drug therapy.
Although Tramadol Hydrochloride develops low onset of the drug dependence, but duration of therapy should be controlled because the possibility of drug dependency in long term use cannot be completely excluded. Drug-dependent patients or patients with the possibility of drug abuse should be carefully observed and it should be taken during short term. Tramadol is not suitable as a substitute in opioid-dependent patients. Although it is an opioid agonist, tramadol cannot suppress morphine withdrawal symptoms. Concomitant use of opioid agonists-antagonists (nalbuphine, buprenorphine, pentazocine) is not recommended.
If tramadol hydrochloride is discontinued abruptly, withdrawal symptoms such as anxiety, sweating, insomnia, spasticity, pain, nausea, tremor, diarrhea, upper respiratory syndrome, piloerection, excitation, nervousness, hyperkinesias or GI disorder may occur. Panic attacks, severe anxiety, hallucination, paresthesias, tinnitus or very rare abnormal CNS reaction have been reported. Clinical experience suggests that withdrawal symptoms may be relieved by tapering the medication.
In patients who took tramadol, allergic reaction such as urticaria, rash, bronchial convulsion, toxic epidermal necrolysis and Steven Johnson's syndrome, including anaphylactoid reaction have been reported. In patients with a history of anaphylactoid to codeine or other opioids, the risk may increase.
Caution should be exercised when this drug is used to patients who take CNS depressant such as alcohol, opioid, anesthetic, hypnotic, phenothiazine, tranquilizer and sedative antidepressant, sedative antihistamines, neuroleptic, centrally acting antihypertensive drug, thalidomide or baclofen, and dosage reduction should be considered. When tramadol is administered to those patients, the risks of CNS and respiratory depression may increase.
Convulsions have been reported in tramadol-treated patients susceptible to seizures or taking other medications that lower the seizure threshold, especially selective serotonin re-uptake inhibitors, tricyclic antidepressants, antipsychotics, centrally acting analgesics or local anaesthesia. Epileptic patients controlled by a treatment or patients susceptible to seizures should be treated with this drug only if there are compelling circumstances.
If patients with chronic alcoholism take excessive paracetamol, liver toxicity may occur. This drug is not recommended to patients with liver disease.
In patients with hepatic insufficiency, pharmacokinetic and drug intolerance of this drug have not been studied. Tramadol and paracetamol are mainly metabolized in liver. In patients with severe hepatic disease, this drug is not recommended.
There is no clinical trials of compound of tramadol and paracetamol to renal insufficiency. Based on tramadol use, degree or rate in excretion of M1, active metabolite of tramadol may be reduced in patients with renal sufficiency. In cases of moderate renal insufficiency (creatinine clearance below 30 mL/min), the dosing should not exceed 2 tablets at 12-hourly intervals.
In long term use, duration of therapy should be controlled or therapy is temporarily discontinued because the possibility of drug dependency cannot be completely excluded.
As medically appropriate, periodic evaluation of prothrombin time should be performed when this drug and warfarin like compounds are administered concurrently due to reports of increased INR.
In one study, use of tramadol during general anaesthesia with enflurane and nitrous oxide was reported to enhance intra-operative recall. Until further information is available, use of tramadol during light planes of anaesthesia should be avoided.
Others: Tramadol showed tolerance in animal study. Therefore, caution is exercised in continuous use or dose increase.
There are no animal or laboratory studies on the combination product (tramadol and paracetamol) to evaluate carcinogenesis, mutagenesis or impairment of fertility.
A slight but statistically significant increase in two common murine tumors, pulmonary and hepatic, was observed in a mouse carcinogenicity study, particularly in aged mice. Mice were dosed orally up to 30 mg/kg (90 mg/m2 or 0.5 times the maximum daily human tramadol dosage of 185 mg/m2) for approximately two years, although the study was not done with the Maximum Tolerated Dose. This finding is not believed to suggest risk in humans. No such finding occurred in rat carcinogenicity study (dosing orally up to 60 mg/kg, 180 mg/m2, or 1 time the maximum daily human tramadol dosage).
Mutagenic toxicity: Tramadol was not mutagenic in the following assays: Ames Salmonella microsomal activation test, CHO/HPRT mammalian cell assay, mouse lymphoma assay (in the absence of metabolic activation), dominant lethal mutation tests in mice, chromosome aberration test in Chinese hamsters, and bone marrow micronucleus tests in mice and Chinese hamsters. Weekly mutagenic results occurred in the presence of metabolic activation in the mouse lymphoma assay and micronucleus test in rats. Overall, the weight of evidence from these tests indicates that tramadol does not pose a genetoxic risk to humans.
Fertility: No effects on fertility were observed for tramadol at oral dose levels up to 50 mg/kg (350 mg/m2) in male rats and 75 mg/kg (450 mg/m2) in female rats. These dosages are 1.6 and 2.4 times the maximum daily human tramadol dosage of 185 mg/m2.
Effects on ability to drive and use machines: Tramadol may cause drowsiness or dizziness, which may be enhanced by alcohol or other CNS depressants. The patient using this drug should be cautioned accordingly.
Use in Children & Elderly: The effective and safe use of this drug have not been established in children below the age of 12 years.
In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function; of concomitant disease and multiple drug therapy.
Use In Pregnancy & Lactation
There are no adequate and well-controlled studies in pregnant women and safety for fetus has not established. This drug should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Tramadol and its metabolite are excreted in human milk. Therefore, this drug is not recommended to nursing mother.
Tramadol and its metabolite are excreted in human milk. Therefore, this drug is not recommended to nursing mother.
Adverse Reactions
Hypersensitivity: In the occurrence of hypersensitivity such as shock, therapy should be discontinued.
Body as a whole: Anergia, fatigue, flushing, occasional chest pain, spasticity, syncope, withdrawal symptom.
Circulatory: Occasional hypertension, exacerbation of hypertension, hypotension, arrhythmia, palpitation, and tachycardia.
CNS and peripheral nervous system: Dizziness, headaches, tremor, occasional hyperkinesis, convulsion, hypertension, migraine, exacerbation of migraine, contraction of involuntary muscle, sensory anomaly, stupor, and vertigo may occur.
GI system: Bellyache, constipation, diarrhea, dyspepsia, flatulence, dry mouth, nausea, vomiting and occasional dysphagia, melena and tongue edema may occur.
Psychiatric disorder: Anorexia, anxiety, confusion, insomnia, nervousness, drowsiness, amnesia, depersonalization, depression, drug abuse and dependence, mood change, hallucinations, impotence, nightmares and abnormal thought may occur.
Blood: Occasional anemia may occur.
Respiratory: Occasional respiratory distress syndrome may occur.
Urinary: Proteinuria, dysuria, oliguria and urine retention may occur.
Skin: Pruritus, rash, sweating and urticaria may occur.
Others: Hepatic dysfunction, weight loss, tinnitus, abnormal vision and chilling may occur.
Although not observed during clinical trials of tramadol/paracetamol, the occurrence of the following undesirable effects has been reported in the clinical trial and post marketing study related to the administration of tramadol or paracetamol: Tramadol Hydrochloride: Vasodilation, orthostatic hypotension, bradycardia, collapse, myocardial ischemia, pulmonary edema, respiratory symptoms (Dyspnea, bronchospasm, wheeze, angioneurotic edema), allergic reactions (including anaphylaxis and urticaria, Steven-Johnsons syndrome/TENS), change in appetite, motor weakness, respiratory depression, cognitive function disorder, difficulty concentrating, depression, suicidal tendency, hepatitis, liver failure, GI bleeding and various psychic side-effects including change in mood, change in activity, and changes in cognitive and sensorial capacity can be individualized. Reported laboratory abnormalities included elevated creatinine and liver function tests. Post-marketing surveillance of tramadol has revealed rare alterations of warfarin effect, including elevation of prothrombin times. Serotonin syndrome (whose symptoms may include mental status change, hyperreflexia, fever, shivering, tremor, agitation, diaphoresis, seizures, coma, tachycardia, confusion, kinesioneurosis, muscle cramp, diarrhea) has been reported with tramadol when used concomitantly with other serotonergic agents such as SSRIs and MAOIs.
Worsening of asthma has been reported though a causal relationship has not been established. Symptoms of withdrawal reactions, similar to those occurring during opiate withdrawal may occur.
Paracetamol: Allergic reactions (primarily skin rash) or reports of hypersensitivity secondary to paracetamol are rare generally controlled by discontinuation of the drug and, when necessary, symptoms treatment. There have been reports of blood dyscrasias including thrombocytopenia and agranulocytosis, but there were not necessarily casually related to paracetamol. There have been several reports that suggest that paracetamol may produce hypoprothrombinemia when administered with warfarin-like compounds. In other studies, prothrombin time did not change.
Inform the doctor or pharmacist if any side effects occur.
Body as a whole: Anergia, fatigue, flushing, occasional chest pain, spasticity, syncope, withdrawal symptom.
Circulatory: Occasional hypertension, exacerbation of hypertension, hypotension, arrhythmia, palpitation, and tachycardia.
CNS and peripheral nervous system: Dizziness, headaches, tremor, occasional hyperkinesis, convulsion, hypertension, migraine, exacerbation of migraine, contraction of involuntary muscle, sensory anomaly, stupor, and vertigo may occur.
GI system: Bellyache, constipation, diarrhea, dyspepsia, flatulence, dry mouth, nausea, vomiting and occasional dysphagia, melena and tongue edema may occur.
Psychiatric disorder: Anorexia, anxiety, confusion, insomnia, nervousness, drowsiness, amnesia, depersonalization, depression, drug abuse and dependence, mood change, hallucinations, impotence, nightmares and abnormal thought may occur.
Blood: Occasional anemia may occur.
Respiratory: Occasional respiratory distress syndrome may occur.
Urinary: Proteinuria, dysuria, oliguria and urine retention may occur.
Skin: Pruritus, rash, sweating and urticaria may occur.
Others: Hepatic dysfunction, weight loss, tinnitus, abnormal vision and chilling may occur.
Although not observed during clinical trials of tramadol/paracetamol, the occurrence of the following undesirable effects has been reported in the clinical trial and post marketing study related to the administration of tramadol or paracetamol: Tramadol Hydrochloride: Vasodilation, orthostatic hypotension, bradycardia, collapse, myocardial ischemia, pulmonary edema, respiratory symptoms (Dyspnea, bronchospasm, wheeze, angioneurotic edema), allergic reactions (including anaphylaxis and urticaria, Steven-Johnsons syndrome/TENS), change in appetite, motor weakness, respiratory depression, cognitive function disorder, difficulty concentrating, depression, suicidal tendency, hepatitis, liver failure, GI bleeding and various psychic side-effects including change in mood, change in activity, and changes in cognitive and sensorial capacity can be individualized. Reported laboratory abnormalities included elevated creatinine and liver function tests. Post-marketing surveillance of tramadol has revealed rare alterations of warfarin effect, including elevation of prothrombin times. Serotonin syndrome (whose symptoms may include mental status change, hyperreflexia, fever, shivering, tremor, agitation, diaphoresis, seizures, coma, tachycardia, confusion, kinesioneurosis, muscle cramp, diarrhea) has been reported with tramadol when used concomitantly with other serotonergic agents such as SSRIs and MAOIs.
Worsening of asthma has been reported though a causal relationship has not been established. Symptoms of withdrawal reactions, similar to those occurring during opiate withdrawal may occur.
Paracetamol: Allergic reactions (primarily skin rash) or reports of hypersensitivity secondary to paracetamol are rare generally controlled by discontinuation of the drug and, when necessary, symptoms treatment. There have been reports of blood dyscrasias including thrombocytopenia and agranulocytosis, but there were not necessarily casually related to paracetamol. There have been several reports that suggest that paracetamol may produce hypoprothrombinemia when administered with warfarin-like compounds. In other studies, prothrombin time did not change.
Inform the doctor or pharmacist if any side effects occur.
Drug Interactions
When this drug is used to patients who take selective serotonin re-uptake inhibitors (SSRIs), tricyclic antidepressants (TCAs) and other tricyclic compounds (eg, promethazine) or other opioid, the risk of seizure may be increased. Tramadol may enhance the seizure risk in patients taking MAO inhibitor reducing the threshold of seizure, neuroleptic or other drugs. Caution should be exercised when this drug is administered to the patients who are receiving MAO inhibitor. In animal test, concurrent use of tramadol and MAO inhibitor enhanced the number of death. Concurrent use of tramadol with MAO inhibitor or selective serotonin re-uptake inhibitors may increase adverse reaction such as seizure or serotonin syndrome.
Patients taking carbamazepine may have a significantly reduced analgesic effect of tramadol. Because carbamazepine increases tramadol metabolism and because of the seizure risk associated with tramadol, concomitant administration of this drug and carbamazepine is not recommended.
Tramadol is metabolized to M1 by CYP2D6. Quinidine is a selective inhibitor of that isoenzyme; so that concomitant administration of quinidine and tramadol results in increased concentrations of tramadol and reduced concentrations of M1. The clinical consequences of these findings are unknown. In vitro drug interaction studies in human liver microsomes indicate that tramadol has no effect on quinidine metabolism, and concomitant administration with inhibitors of CYP2D6 such as fluoxetine, paroxetine, and amitriptyline could result in some inhibition of the metabolism of tramadol.
Other drugs known to inhibit CYP3A4, such as ketoconazole and erythromycin, might inhibit the metabolism of tramadol (N-demethylation) probably also the metabolism of the active O-demethylated metabolite. The clinical importance of such an interaction has not been studied.
The speed of absorption of paracetamol may be increased by metoclopramide or domperidone and absorption reduced by cholestyramine.
Patients taking carbamazepine may have a significantly reduced analgesic effect of tramadol. Because carbamazepine increases tramadol metabolism and because of the seizure risk associated with tramadol, concomitant administration of this drug and carbamazepine is not recommended.
Tramadol is metabolized to M1 by CYP2D6. Quinidine is a selective inhibitor of that isoenzyme; so that concomitant administration of quinidine and tramadol results in increased concentrations of tramadol and reduced concentrations of M1. The clinical consequences of these findings are unknown. In vitro drug interaction studies in human liver microsomes indicate that tramadol has no effect on quinidine metabolism, and concomitant administration with inhibitors of CYP2D6 such as fluoxetine, paroxetine, and amitriptyline could result in some inhibition of the metabolism of tramadol.
Other drugs known to inhibit CYP3A4, such as ketoconazole and erythromycin, might inhibit the metabolism of tramadol (N-demethylation) probably also the metabolism of the active O-demethylated metabolite. The clinical importance of such an interaction has not been studied.
The speed of absorption of paracetamol may be increased by metoclopramide or domperidone and absorption reduced by cholestyramine.
Storage
Store at temperatures not exceeding 30°C.
Action
Pharmacology: Pharmacodynamics: Analgesics: Tramadol is an opioid analgesic that acts on the central nervous system. Tramadol is a pure non selective agonists 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 reuptake of noradrenaline and enhancement of serotonin release. Tramadol has an antitussive effect. Unlike morphine, a broad range of analgesic doses of tramadol has no respiratory depressant effect. Similarly, the gastro-intestinal motility is not modified. The cardiovascular effects are generally slight. The potency of tramadol is considered to be one-tenth to one-sixth that of morphine. The precise mechanism of the analgesic properties of paracetamol is unknown and may involve central and peripheral effects.
This drug is positioned as a step II analgesic in the WHO pain ladder and should be utilized accordingly by the physician.
Pharmacokinetics: Tramadol is administered in racemic form and the [-] and [+] forms of tramadol and its metabolite M1, are detected in the blood. Although tramadol is rapidly absorbed after administration, its absorption is slower (and its half-life longer) than that of paracetamol.
After a single oral administration of tramadol/paracetamol (37.5 mg/325 mg) tablet, peak plasma concentrations of 64.3/55.5 mg/mL [(+)-tramadol/(-)-tramadol] and 4.2 μg/mL (paracetamol) are reached after 1.8 h [(+)-tramadol/(-)-tramadol] and 0.9 h (paracetamol) respectively. The mean elimination half-lives t1/2 are 5.1/4.7 h [(+)-tramadol/(-)-tramadol] and 2.5 h (paracetamol). During pharmacokinetic studies in healthy volunteers after single and repeated oral administration of this drug, no clinically significant change was observed in the kinetic parameters of each active ingredient compared to the parameters of the active ingredients used alone.
Absorption: Racemic tramadol is rapidly and almost completely absorbed after oral administration. The mean absolute bioavailability of a single 100 mg dose is approximately 75%. After repeated administration, the bioavailability is increased and reaches approximately 90%. After administration of this drug, the oral absorption of paracetamol is rapid and nearly complete and takes place mainly in the small intestine. Peak plasma concentrations of paracetamol are reached in one hour and are not modified by concomitant administration of tramadol. The oral administration of this drug with food has no significant effect on the peak plasma concentration or extent of absorption of either tramadol or paracetamol so that this drug can be taken independently of meal times.
Distribution: Tramadol has a high tissue affinity (Vδβ=203±40 L). It has plasma protein binding of about 20%. Paracetamol appears to be widely distributed throughout most body tissues except fat. Its apparent volume of distribution is about 0.9 L/kg. A relatively small portion (-20%) of paracetamol is bound to plasma proteins.
Metabolism: Tramadol is extensively metabolized after oral administration. About 30% of the dose is excreted in urine as unchanged drug, whereas 60% of the dose is excreted as metabolites. Tramadol is metabolized through O-demethylation (catalyzed by the enzyme CYP2D6) to the metabolite M1, and through N-demethylation (catalyzed by CYP3A4) to the metabolite M2. M1 is further metabolized through N-demethylation and by conjugation with glucuronic acid. The plasma elimination half-life of M1 is 7 hours. The metabolite M1 has analgesic properties and is more potent than the parent drug. The plasma concentrations of M1 are several-fold lower than those of tramadol and the contribution to the clinical effect is unlikely to change on multiple dosing. Paracetamol is principally metabolized in the liver through two major hepatic routes: glucuronidation and sulphation. The latter route can be rapidly saturated at doses above the therapeutic doses. A small fraction (less than 4%) is metabolized by cytochrome P450 to an active intermediate (the N-acetyl benzoquinoneimine) which, under normal conditions of use, is rapidly detoxified by reduced glutathione and excreted in urine after conjugation to cysteine and mercapturic acid. However, during massive overdose, the quantity of this metabolite is increased.
Elimination: Tramadol and its metabolites are eliminated mainly by the kidneys. The half-life of paracetamol is approximately 2 to 3 hours in adults. It is shorter in children and slightly longer in the newborn and in cirrhotic patients. Paracetamol is mainly eliminated by dose-dependent formulation of glucuro- and sulpho-conjugate derivatives. Less than 9% of paracetamol is excreted unchanged in urine. In renal insufficiency, the half-life of both compounds is prolonged.
This drug is positioned as a step II analgesic in the WHO pain ladder and should be utilized accordingly by the physician.
Pharmacokinetics: Tramadol is administered in racemic form and the [-] and [+] forms of tramadol and its metabolite M1, are detected in the blood. Although tramadol is rapidly absorbed after administration, its absorption is slower (and its half-life longer) than that of paracetamol.
After a single oral administration of tramadol/paracetamol (37.5 mg/325 mg) tablet, peak plasma concentrations of 64.3/55.5 mg/mL [(+)-tramadol/(-)-tramadol] and 4.2 μg/mL (paracetamol) are reached after 1.8 h [(+)-tramadol/(-)-tramadol] and 0.9 h (paracetamol) respectively. The mean elimination half-lives t1/2 are 5.1/4.7 h [(+)-tramadol/(-)-tramadol] and 2.5 h (paracetamol). During pharmacokinetic studies in healthy volunteers after single and repeated oral administration of this drug, no clinically significant change was observed in the kinetic parameters of each active ingredient compared to the parameters of the active ingredients used alone.
Absorption: Racemic tramadol is rapidly and almost completely absorbed after oral administration. The mean absolute bioavailability of a single 100 mg dose is approximately 75%. After repeated administration, the bioavailability is increased and reaches approximately 90%. After administration of this drug, the oral absorption of paracetamol is rapid and nearly complete and takes place mainly in the small intestine. Peak plasma concentrations of paracetamol are reached in one hour and are not modified by concomitant administration of tramadol. The oral administration of this drug with food has no significant effect on the peak plasma concentration or extent of absorption of either tramadol or paracetamol so that this drug can be taken independently of meal times.
Distribution: Tramadol has a high tissue affinity (Vδβ=203±40 L). It has plasma protein binding of about 20%. Paracetamol appears to be widely distributed throughout most body tissues except fat. Its apparent volume of distribution is about 0.9 L/kg. A relatively small portion (-20%) of paracetamol is bound to plasma proteins.
Metabolism: Tramadol is extensively metabolized after oral administration. About 30% of the dose is excreted in urine as unchanged drug, whereas 60% of the dose is excreted as metabolites. Tramadol is metabolized through O-demethylation (catalyzed by the enzyme CYP2D6) to the metabolite M1, and through N-demethylation (catalyzed by CYP3A4) to the metabolite M2. M1 is further metabolized through N-demethylation and by conjugation with glucuronic acid. The plasma elimination half-life of M1 is 7 hours. The metabolite M1 has analgesic properties and is more potent than the parent drug. The plasma concentrations of M1 are several-fold lower than those of tramadol and the contribution to the clinical effect is unlikely to change on multiple dosing. Paracetamol is principally metabolized in the liver through two major hepatic routes: glucuronidation and sulphation. The latter route can be rapidly saturated at doses above the therapeutic doses. A small fraction (less than 4%) is metabolized by cytochrome P450 to an active intermediate (the N-acetyl benzoquinoneimine) which, under normal conditions of use, is rapidly detoxified by reduced glutathione and excreted in urine after conjugation to cysteine and mercapturic acid. However, during massive overdose, the quantity of this metabolite is increased.
Elimination: Tramadol and its metabolites are eliminated mainly by the kidneys. The half-life of paracetamol is approximately 2 to 3 hours in adults. It is shorter in children and slightly longer in the newborn and in cirrhotic patients. Paracetamol is mainly eliminated by dose-dependent formulation of glucuro- and sulpho-conjugate derivatives. Less than 9% of paracetamol is excreted unchanged in urine. In renal insufficiency, the half-life of both compounds is prolonged.
MedsGo Class
Analgesics (Opioid)
Features
Dosage
325 mg / 37.5 mg
Ingredients
- Paracetamol
- Tramadol
Packaging
Film-Coated Tablet 1's
Generic Name
Paracetamol / Tramadol Hcl
Registration Number
DRP-5082
Classification
Prescription Drug (RX)
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