Algesia

Each film-coated tablet contains: Tramadol HCl 37.5 mg, Paracetamol 325 mg.

Pharmacotherapeutic group: Antipyretic/Opioid Analgesic.
Pharmacology: 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 (C_max) 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 (~20%) 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.
Tramadol is cleared from the circulation via renal excretion. The plasma elimination half-lives of racemic tramadol and M1 are approximately five to six, and seven hours, respectively. The plasma elimination half-life of racemic tramadol increased from approximately seven to nine hours upon multiple dosing of tramadol + paracetamol.
Paracetamol has a plasma elimination half-life that ranges from two to three hours in adults, but this may be prolonged in patients with liver disease. It is mainly excreted in the urine in its glucuronide or sulfate form, and less than nine percent is excreted unchanged.
Special Populations: Renal Impairment: Elimination of tramadol and M1 is diminished in patients with renal impairment. In patients with renal failure (creatinine clearance < 5 mL/min), the half-life of tramadol was 11 hours and that of M1 was 17 hours.
Hepatic Impairment: Elimination of tramadol and M1 is diminished in patients with hepatic impairment, the mean half-life of tramadol was 13 hours and the mean half-life of M1 was 19 hours.
Elderly: In the elderly (>75 years old), tramadol's volume of distribution is decreased by 25% and clearance is decreased by 40%. As a result, tramadol's C_max and total exposure are increased by 30% and 50%, respectively. However, the half-life of tramadol is only slightly prolonged by 15%.

For the short-term (five days or less) management of moderate to severe pain.

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 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 10^th 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.

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.

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.

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.
CYP2D6 and CYP3A4 inhibitors reduce the metabolic clearance and increase the plasma concentrations of tramadol, which can prolong its therapeutic effects and/or increase the risk for serious adverse events such as seizures and serotonin syndrome. CYP2D6 and CYP3A4 inhibitors also decrease the plasma M1 concentrations, which may result to reduced efficacy and in manifestations of opioid withdrawal signs and symptoms in patients who developed physical dependence to tramadol.
The concomitant use of tramadol with CYP450 2D6 or 3A4 inhibitors, or the discontinuation of a CYP450 3A4 inducer, may increase tramadol plasma concentrations, which could increase or prolong adverse reactions; increase the risk for serious adverse events (e.g., seizures and serotonin syndrome); and may cause potentially life-threatening respiratory depression.
The discontinuation of concomitantly used CYP450 2D6 or 3A4 inhibitors may decrease tramadol plasma levels and increase M1 plasma levels, which could consequently increase or prolong adverse reactions associated with opioid toxicity and may cause potentially life-threatening respiratory depression.
Monitor patients receiving tramadol and any CYP2D6 or 3A4 inhibitor for the risk of serious adverse events (e.g., seizures and serotonin syndrome), and signs and symptoms that may indicate opioid toxicity and opioid withdrawal.
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).
The risk of acute liver failure is higher in patients who are taking paracetamol and alcohol, and patients with underlying liver disease.
Patients should be informed to look for paracetamol on package labels and not to take more than one paracetamol-containing product. Patients should be instructed to seek medical attention immediately upon ingestion of more than four grams of paracetamol per day, even if they feel well.
Concomitant Use with Benzodiazepines or Other CNS Depressants: The concurrent use of opioids with CNS depressants (e.g., benzodiazepines, non-benzodiazepine sedative/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol) can lead to profound sedation, respiratory depression, coma, and death. Because of these risks, concomitant prescribing of these drugs should be reserved for patients for whom alternative treatment options are inadequate. (See Interactions.)
The lowest effective dosages and minimum duration of concomitant use should be prescribed if benzodiazepines or other CNS depressant are to be concurrently used with opioid analgesics. In patients already administered with an opioid analgesic, a dose of the benzodiazepine or other CNS depressants lower than indicated in the absence of an opioid should be prescribed initially and subsequently titrate according to clinical response. If an opioid analgesic is to be prescribed in a patient already taking a benzodiazepine or other CNS depressant, a lower initial dose of the opioid analgesic should be prescribed, and titrate according to clinical response. Monitor patients closely for signs and symptoms of respiratory depression and sedation.
Patients and caregivers should be informed about the risks of respiratory depression and sedation when tramadol is concomitantly used with CNS depressants. Patients should be screened for risk of substance use disorders and should be informed of the risk of overdose and death associated with the use of additional CNS depressants. (See Effects on Ability to Drive and Use machine as follows.)
Serotonin Syndrome: Cases of serotonin syndrome, a potentially life-threatening condition, may occur with the use of tramadol within the recommended dose, particularly with concomitant use of serotonergic drugs; drugs that impair the metabolism of serotonin; and drugs that impair the metabolism of tramadol. (See Interactions.)
Serotonin syndrome symptoms may include the following: mental status changes (e.g., agitation, hallucinations, coma); autonomic instability (e.g., hyperthermia, labile blood pressure, tachycardia); neuromuscular aberrations (e.g., hyperreflexia, incoordination, rigidity); and gastrointestinal symptoms (e.g., diarrhea, nausea, vomiting). These symptoms may occur within several hours to a few days of concomitant administration of these drugs, but may occur at a later time. If serotonin syndrome is suspected, use of tramadol should be discontinued and supportive symptomatic treatment should be performed, depending on the nature and severity of symptoms.
Patients should be informed that opioids, when concomitantly administered with serotonergic drugs, could result to a rare but potentially life-threatening condition. Patients should be warned of the symptoms of serotonin syndrome, and to seek medical attention immediately if these symptoms occur. Instruct patient to notify their healthcare provider if they are currently taking, or planning to take serotonergic drugs.
Increased Risk of Seizures: Seizures have been reported in patients receiving tramadol even within the recommended dosage range. Seizure risk is increased in patients administered with tramadol doses above the recommended range. Seizures can also occur after the first dose. Concomitant use of tramadol increases seizure risk in patients taking: Selective serotonin reuptake inhibitor (SSRI) and serotonin-norepinephrine reuptake inhibitor (SNRI) antidepressants or anorectics; Tricyclic antidepressants (TCAs), and other tricyclic compounds (e.g., cyclobenzaprine, promethazine, etc.); Monoamine oxidase inhibitors (MAOIs); Antipsychotics or neuroleptics (e.g., haloperidol, droperidol, thioridazine); Other drugs that reduce seizure threshold; Other opioids (see Interactions).
Tramadol may also increase the risk of convulsions in patients with epilepsy; those with a history of seizures; or in patients with a recognized risk for seizure (e.g., head trauma, metabolic disorders, alcohol and drug withdrawal, CNS infections). Administration of naloxone for tramadol overdose may increase the risk of seizure. Patients with epilepsy or those susceptible to seizures should be treated only if there are compelling situations.
Increased Risk of Suicide: Do not prescribe tramadol to patients who are suicidal or prone to addiction. (See Drug Abuse and Dependence as follows). Prescribe tramadol with caution in patients who: Have a history of misuse and/or are currently taking CNS-active drugs (e.g., tranquilizers, antidepressant drugs, excessive alcohol) (See Interactions).
Are suffering from emotional disturbance or depression.
The cautious prescribing of tramadol is essential for the safe use of this drug. The use of non-narcotic analgesics for patients who are depressed or suicidal should be considered. Patients should be informed not to exceed the recommended dose and to limit their alcohol intake.
Adrenal Insufficiency: Cases of adrenal insufficiency have been reported with the use of opioids, more often after greater than one month of use. Adrenal insufficiency may be manifested by non-specific symptoms and signs including nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. If adrenal insufficiency is suspected, the diagnosis should be confirmed immediately with appropriate diagnostic testing. If adrenal insufficiency is diagnosed, the patient should be administered with physiologic replacement doses of corticosteroids. The patient may be weaned off from opioids to allow the recovery of adrenal function. Corticosteroid therapy should be continued until adrenal function recovers. Other opioids may be tried, since some cases reported that adrenal insufficiency did not recur with the use of different opioids.
Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic or Debilitated Patients: Tramadol should be administered cautiously in patients at risk for respiratory depression. The administration of tramadol at recommended dosages in patients with significant chronic obstructive pulmonary disease or cor pulmonale; and those with a substantially reduced respiratory reserve; hypoxia; hypercapnia; or pre-existing respiratory depression, poses a risk of decreased respiratory drive, including apnea. Patients who may have altered pharmacokinetics (elderly, cachectic, or debilitated patients) are also more likely to experience life-threatening respiratory depression. Consider alternative, non-opioid analgesics for these patients. Moreover, the concomitant administration of tramadol with other drugs that depress respiration must be avoided. Close monitoring for respiratory depression should be performed, especially during treatment initiation and following dosage increases. (See Interactions.)
Severe Hypotension: The use of tramadol in ambulatory patients may cause severe hypotension including orthostatic hypotension and syncope. The risk of severe hypotension is increased in patients with compromised ability to maintain blood pressure due to reduced blood volume or concomitant administration of certain CNS depressant drugs (See Interactions).
Patients should be monitored for signs of hypotension after initiating or titrating the dosage of tramadol. The use of tramadol in patients with circulatory shock should be avoided, since tramadol may cause vasodilation that can further decrease the cardiac output in these patients.
Increased Intracranial Pressure or Head Trauma: Tramadol should be used with caution in patients with increased intracranial pressure, head trauma or tumor, shock, or a reduced level of consciousness of uncertain origin. The respiratory depressant effects of opiate agonists, which include carbon dioxide retention and secondary elevation of cerebrospinal fluid pressure, may be markedly exaggerated in these patients. Also, pupillary changes (i.e., miosis) and other adverse events (e.g., confusion, vomiting) caused by tramadol may obscure the existence, extent or course of intracranial pathology. Tramadol should only be used with extreme caution and only if it is deemed necessary.
Patients should be monitored for signs of sedation and respiratory depression, especially during the initiation of tramadol therapy. Moreover, clinicians should maintain a high index of suspicion for adverse reactions when evaluating altered mental status in these patients administered with tramadol.
Serious Skin Reactions: Rarely, the use of paracetamol may cause serious (and sometimes fatal) skin reactions such as acute generalized exanthematous pustulosis (AGEP), Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN). Inform patients about the signs of these serious skin reactions, and that the use of this drug should be discontinued at the first appearance of signs of hypersensitivity (e.g., rash, urticaria, pruritus).
Anaphylaxis and Other Hypersensitivity Reactions: Serious fatal anaphylactic reactions have been rarely reported in patients receiving tramadol. These events often occur after the first dose. Other allergic reactions, such as pruritus, hives, bronchospasm, angioedema, TEN, and SJS, were also reported.
Symptoms of hypersensitivity and anaphylactic reactions to paracetamol (e.g., swelling of the face, mouth, and throat, respiratory distress, urticaria, rash, pruritus, vomiting, rare life-threatening anaphylaxis requiring emergency medical attention) were reported in postmarketing studies. Patients should be instructed to discontinue the use of tramadol + paracetamol and seek medical care once these symptoms occurred. Tramadol + paracetamol should not be prescribed in patients with paracetamol allergy.
Patients with a higher risk for these anaphylactic reactions (e.g., patients with history of anaphylactoid reactions to codeine and other opioids) should not receive tramadol + paracetamol. If anaphylaxis or other hypersensitivity reactions occur, the administration of tramadol + paracetamol should be stopped immediately and discontinued permanently. Do not rechallenge with any tramadol-containing formulation. Patients should be advised to seek immediate medical attention if any symptom of a hypersensitivity reaction occurred.
Hyponatremia: Hyponatremia has been rarely reported with the use of tramadol, usually in patients with predisposing risk factors [old age and/or using concomitant medications that may cause hyponatremia (e.g., antidepressants, benzodiazepines, diuretics)]. Some reports have demonstrated that hyponatremia resulted from the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Hyponatremia can be resolved with discontinuation of tramadol + paracetamol and by appropriate treatment (e.g., fluid restriction). Patients with predisposing should be monitored for signs and symptoms of hyponatremia during tramadol + paracetamol therapy.
Gastrointestinal Conditions: Morphine-like opioids, including tramadol, have been demonstrated to decrease bowel motility. Tramadol may complicate the clinical assessment of patients with acute abdominal conditions. It may cause spasm of the sphincter of Oddi, while opioids may increase serum amylase levels. Patients with biliary tract disease, including acute pancreatitis, should be monitored for worsening of symptoms.
Concomitant Conditions in Adolescents: The use of tramadol in adolescents between 12 and 18 years old who are obese, or have conditions such as obstructive sleep apnea or severe lung disease is not recommended, due to the increased risk of serious breathing problems.
Breastfeeding: Breastfeeding is not recommended during tramadol therapy due to the risk of serious adverse reactions, including difficulty in breastfeeding, excessive sleepiness and serious breathing problems that may lead to death of the breastfed infant. (See Use in Pregnancy & Lactation.)
Withdrawal: The use of mixed agonist/antagonist analgesics or partial agonists must be avoided in patients receiving a full opioid agonist analgesic, including tramadol. Do not abruptly discontinue tramadol in patient who developed physical dependence.
Concomitant Diseases/Conditions: Paracetamol should be administered with caution in patients with the following conditions: Alcoholism, excessive alcohol intake (three or more alcoholic drinks every day) Glucose-6-phosphate dehydrogenase (G6PD) deficiency (may lead to hemolytic anemia; Anorexia, bulimia or cachexia; chronic malnutrition (low reserves of hepatic glutathione); Severe hypovolemia (e.g., due to dehydration or blood loss); Severe renal impairment (creatinine clearance ≤ 30 mL/min); Dehydration.
Drug Abuse and Dependence: Abuse: Tramadol has μ-opioid agonist activity which may be abused and subject to criminal diversion. Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena which is developed after repeated substance use and includes the following: impaired or difficult control over drug use; compulsive use; use for non-medical purposes; persistent use despite harm or risk of harm; craving; a higher priority given to drug usage compared to other activities and obligations, increased tolerance, and in some cases, physical withdrawal. Although relapse is common, drug addiction can be treated by utilizing a multidisciplinary approach.
Abuse and addiction are distinct from physical dependence and tolerance. Healthcare providers should be aware that addiction may not be accompanied by coexisting tolerance and symptoms of physical dependence in all addicts. Furthermore, tramadol abuse may occur even in the absence of true addiction.
Proper assessment of the patient and periodic re-evaluation of therapy are appropriate measures that can help limit the potential abuse of tramadol.
Generally, tolerance and/or withdrawal are more likely to occur the longer a patient is on continuous therapy with tramadol.
Dependence: Chronic therapy with opioids may lead to the development of tolerance and physical dependence. Tolerance is the need for increasing doses to maintain the desired effect (e.g., analgesia in the absence of disease progression or other external factors), and may occur to both the desired and undesired effects of drugs. Tolerance may develop at different rates for various effects.
Physical dependence may result to withdrawal symptoms if tramadol was abruptly discontinued or if the dosage was significantly reduced. Withdrawal may also be precipitated through the administration of opioid antagonists (e.g., naloxone, nalmefene), mixed agonist/antagonist analgesics (pentazocine, butorphanol, nalbuphine), or partial agonists (buprenorphine). Physical dependence may not be manifested to a clinically significant degree until after several days to weeks of continued opioid use.
Do not abruptly discontinue tramadol in patient who developed physical dependence, otherwise, symptoms of withdrawal reactions to tramadol (e.g., agitation, anxiety, nervousness, irritability, insomnia, hyperkinesia, tremor, pyrexia, myalgia, chills, gastrointestinal symptoms, restlessness, rhinorrhea, lacrimation, yawning, mydriasis, perspiration) may occur. Other symptoms, such as panic attacks, severe anxiety, hallucinations, paresthesias, tinnitus and unusual CNS symptoms (i.e., confusion, delusions, depersonalization, derealization, paranoia), are rarely seen. Withdrawal symptoms may be avoided by tapering the dose of the medicine at the time of discontinuation. The use of mixed agonist/antagonist analgesics or partial agonists must be avoided in patients receiving a full opioid agonist analgesic, including tramadol.
Renal and Hepatic Impairment: Impaired renal function results in decreased rate and extent of excretion of tramadol and its active metabolite, M1; while their metabolism is reduced in patients with advanced hepatic cirrhosis. Adjust doses as necessary (see Dosage & Administration). With the prolonged half-life in these conditions, achievement of steady-state is delayed, so it may take several days for elevated plasma concentrations to develop.
Paracetamol may cause acute liver failure (see Precautions).
Effects on Ability to Drive and Use Machine: Tramadol may impair mental or physical abilities required for the performance of potentially hazardous tasks such as driving and operating machinery. Caution patients to avoid these potentially hazardous tasks unless they can tolerate the effects of tramadol and know how they will react to the medication. Patients should also be warned about the combined effects of tramadol with other CNS depressants.
Carcinogenesis, Mutagenesis, Impairment of Fertility: Results of tests and investigations did not show a risk of carcinogenicity, mutagenesis or impairment of fertility for tramadol or paracetamol in man.
Use in the Elderly: Elderly patients (>65 years old) have increased sensitivity to tramadol + paracetamol. Generally, the dosage of tramadol + paracetamol should be titrated cautiously in elderly patients, usually starting therapy at the lower end of the dosing range, considering the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or drug therapy.
Use in Children: Children (< 12 years old): Tramadol + paracetamol is contraindicated in children younger than 12 years old. Its use in children is not recommended since the safety and efficacy of tramadol + paracetamol have not been established.

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.

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.
Investigations: Abnormal hepatic function, alterations in liver function test values, decreased weight, increased alkaline phosphatase, increased ALT, increased aspartate transaminase (AST), increased coagulation time, increased weight
Tramadol: The most frequently reported adverse effects are dizziness and nausea. Other common effects include abdominal pain, anorexia, anxiety, confusion, constipation, coordination disturbance, dry mouth, euphoria, flatulence, headache, hypertonia, malaise, menopausal symptoms, miosis, nervousness, rash, sleep disorder, somnolence, insomnia, urinary frequency, urinary retention, vasodilation, visual disturbance, and vomiting.
Blood and lymphatic system disorders: Blood dyscrasias.
Infections and infestations: Cellulitis, epididymitis, pneumonia.
Immune system disorders: Allergic reactions, anaphylaxis, angioedema, bronchospasm, Stevens-Johnson syndrome, toxic epidermal necrolysis, urticaria, vesicles.
Endocrine disorders: Androgen deficiency, syndrome of inappropriate antidiuretic hormone secretion.
Metabolism and nutrition disorders: Adrenal insufficiency, changes in appetite, edema, hypoglycemia, hyponatremia.
Psychiatric disorders: Changes in activity (usually suppression, occasionally increase), changes in cognitive capacity and sensorial capacity (e.g., decision behavior, perception disorders), depersonalization, depression, derealization, delusions, difficulty in attention, dysphoria, elation, emotional lability, hallucinations, hyperactivity, hypoactivity, mental status changes, mood changes, nightmares, panic attacks, suicidal tendencies.
Nervous system disorders: Abnormal dreams, abnormal gait, agitation, amnesia, asthenia, cognitive disorder, convulsions, CNS stimulation, coma, delirium, difficulty in concentration, disorientation, dysgeusia, dyskinesia, dystonia, epileptiform convulsions, hyperkinesia, hyperreflexia, involuntary muscle contractions, irritability, migraine, motor weakness, movement disorder, paresthesia, seizure, sedation, serotonin syndrome, spasticity, speech disorders, trembling, tremor, vertigo.
Eye disorders: Blurred vision, cataracts, mydriasis.
Ear and Labyrinth disorders: Deafness, tinnitus.
Cardiac Disorders: Arrhythmia, bradycardia, cardiac arrest, chest pain, myocardial infarction, myocardial ischemia, palpitations, pulmonary edema, tachycardia.
Vascular disorders: Circulatory depression, flushing, hot flushes, hypertension, hypotension, orthostatic dysregulation (tendency to collapse and cardiovascular collapse), orthostatic or postural hypotension, peripheral ischemia, shock, syncope.
Respiratory, thoracic and mediastinal disorders: Apnea, coughing, dyspnea, nasal symptoms, nasopharyngitis, pulmonary embolism, respiratory arrest, respiratory depression, sinusitis, sneezing, upper respiratory tract infection, wheezing, worsening of asthma, yawning.
Gastrointestinal disorders: Appendicitis, bloating, diarrhea, dyspepsia, dysphagia, gastritis, gastroenteritis, gastrointestinal bleeding, gastrointestinal irritation (feeling of pressure in the stomach), pancreatitis, retching, sore throat, stomatitis, toothache.
Hepatobiliary disorders: Cholecystitis, cholelithiasis, hepatitis, liver failure.
Skin and subcutaneous tissue disorders: Dermatitis, piloerection, pruritus, sweating.
Musculoskeletal and connective tissue disorders: Arthralgia, joint stiffness, joint swelling, muscle cramps, muscle injury, muscle spasms, muscle twitching, musculoskeletal pain, myalgia, osteoarthritis aggravated, rigors, shivering.
Renal and urinary disorders: Dysuria, hematuria, micturition disorder, proteinuria, urinary tract infection.
Reproductive system and breast disorders: Amenorrhea, decreased libido, erectile dysfunction, impotence, infertility, menstrual disorder.
General disorders and administration site conditions: Asthenia, clamminess, death, dependence, diaphoresis, fatigue, fever, hyperthermia, influenza-like symptoms, jittery feeling, lethargy, peripheral swelling, pyrexia, withdrawal syndrome.
Investigations: Abnormal electrocardiogram (ECG), decreased hemoglobin, elevated liver enzymes, increased blood creatine phosphokinase, increased blood glucose concentrations, increased creatinine, weight decreased.
Injury, poisoning and procedural complications: Accidental injury, contusions, falls, joint sprain.
Paracetamol: Paracetamol, when taken within the recommended dose and duration of treatment, has low incidence of side effects. The most common side effects are constipation, headache, insomnia, nausea, and vomiting.
Blood and lymphatic system disorders: Agranulocytosis, anemia, blood dyscrasias, jaundice, leukopenia, methemoglobinemia, neutropenia, pancytopenia, thrombocytopenia, thrombocytopenic purpura Infections and infestations: Colds, infections.
Immune system disorders: Acute generalized exanthematous pustulosis, allergic reactions, anaphylactoid reactions, anaphylaxis, angioedema, hypersensitivity reactions, laryngeal edema, periorbital edema, swelling of the face, mouth, or throat, Stevens-Johnson syndrome, toxic epidermal necrolysis, urticaria.
Metabolism and nutrition disorders: Loss of appetite.
Respiratory, thoracic, and mediastinal disorders: Bronchospasm, breathing problems, respiratory distress, severe asthma episode.
Gastrointestinal disorders: Minor stomach and intestinal disturbances, mouth ulcers.
Hepatobiliary disorders: Acute liver failure, hepatic dysfunction, hepatotoxicity.
Skin and subcutaneous tissue disorders: Maculopapular rash, peeling, pruritus, rash.
Renal and urinary disorders: Kidney damage.
General disorders and administration site conditions: Unusual tiredness.
Investigations: Increased alanine transaminase (ALT), sudden weight loss.
Injury, poisoning and procedural complications: Unexplained bruising or bleeding.

See table as follows.

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Store at temperatures not exceeding 30°C.

Analgesics (Opioid)

N02AJ13 - tramadol and paracetamol ; Belongs to the class of opioids in combination with other non-opioid analgesics. Used to relieve pain.

Rx