Tramadol + paracetamol

Oral
Moderate to severe pain
Adult: Available preparations: Tramadol 37.5 mg and paracetamol 325 mg film-coated tab Tramadol 75 mg and paracetamol 650 mg conventional tab Tramadol 37.5 mg and paracetamol 325 mg effervescent tab As tramadol 37.5 mg and paracetamol 325 mg film-coated tab: 1-2 tab(s) 4-6 hourly as needed. Max: 8 tabs daily. As tramadol 75 mg and paracetamol 650 mg conventional tab: 1 tab 6 hourly as needed. Max: 4 tabs daily. As tramadol 37.5 mg and paracetamol 325 mg effervescent tab: 2 tabs 6 hourly as necessary. Max: 8 tabs daily. Max daily doses are equivalent to tramadol 300 mg and paracetamol 2,600 mg. Use the lowest effective dose for the shortest possible treatment duration. Dose must be adjusted based on the intensity of pain and individual sensitivity. Dosage recommendations may vary among countries and individual product (refer to local detailed product guideline).
Renal impairment:

CrCl (ml/min)	Dosage Recommendation
<10	Not recommended.
10-30	Increase dosing interval to 12 hourly.

Hepatic impairment: Severe: Contraindicated.

Special Populations: Pharmacogenomics: Tramadol Tramadol is metabolised in the liver by CY2D6 isoenzyme to form the active metabolite, O-desmethyltramadol (M1), which has a significantly higher affinity for mc-opioid receptors. CYP2D6 is a highly polymorphic gene that may influence the clinical effect and safety of tramadol. Genetic testing may be considered prior to therapy. According to studies, CYP2D6 ultrarapid metabolisers have 1.1-5.9-fold higher M1 concentrations than normal metabolisers. On the other hand, an approximate 2-4-fold higher nonresponse rate to tramadol was reported among CYP2D6 poor metabolisers than normal metabolisers or intermediate metabolisers. Variations in CYP2D6 polymorphism occur at different frequencies among subpopulations of different ethnic or racial origins. Some individuals may be ultrarapid metabolisers of CYP2D6. The prevalence of CYP2D6 ultrarapid metabolisers varies widely and has been estimated to be 29% in African/Ethiopian, 3.4-6.5% in African American, 1.2-2% in Asian, 3.6-6.5% in Caucasian, 6% in Greek, 1.9% in Hungarian, and 1-2% in Northern European populations; while up to 7% of the Caucasian population has a deficiency or is completely lacking functional CYP2D6 activity. Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline as of December 2020: CYP2D6 ultrarapid metabolisers Patients who have increased formation of O-desmethyltramadol, resulting in a greater risk of toxicity. CPIC recommends avoiding the use of tramadol due to the potential for toxicity. If opioid use is needed, may consider a non-codeine opioid. CYP2D6 intermediate metabolisers Patients who have decreased O-desmethyltramadol formation. CPIC recommends that no dose adjustments needed; however, if there is no response and opioid use is warranted, may consider using a non-codeine opioid. CYP2D6 poor metabolisers Patients who have greatly reduced O-desmethyltramadol formation resulting in diminished therapeutic effect. CPIC recommends avoiding tramadol use due to the possibility of diminished analgesic effect. If opioid use is needed, may consider a non-codeine opioid. The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group (DPWG) Guideline as of November 2018: CYP2D6 ultrarapid metabolisers Patients with increased conversion of tramadol into the active metabolite which may result in a higher risk of potentially life-threatening adverse effects. DPWG recommends choosing an alternative agent that is not metabolised by CYP2D6 (e.g. morphine). If an alternative is not possible, may use 40% of the usual dose and advise the patient to monitor for adverse effects (e.g. drowsiness, confusion, respiratory depression). CYP2D6 intermediate metabolisers Patients with reduced conversion of tramadol into the active metabolite which may result in decreased analgesic effect. DPWG recommends being vigilant for reduced effect. In case of inadequate response, a dose increase may be considered and if there is still no response, an alternative agent that is not metabolised by CYP2D6 (e.g. morphine) may be given. If no alternative agent is selected, advise the patient to report inadequate analgesic effect. CYP2D6 poor metabolisers Patients with reduced conversion of tramadol into the active metabolite which may result in decreased analgesic effect. DPWG recommends being vigilant for reduced effect. In case of inadequate response, a dose increase may be considered and if there is still no response, an alternative agent that is not metabolised by CYP2D6 (e.g. morphine) may be given. If no alternative agent is selected, advise the patient to report inadequate analgesic effect. Additionally, the Annotation of FDA Label for tramadol recommends that CYP2D6 ultrarapid metabolisers must not use tramadol due to the risk of life-threatening respiratory depression even at labelled dosage regimens. Treatment recommendations may vary among local treatment guidelines. Refer to country-specific guidelines.

Hypersensitivity to tramadol or paracetamol. Significant respiratory depression, acute or severe bronchial asthma (in unmonitored setting or lack of resuscitative equipment), known or suspected gastrointestinal obstruction, including paralytic ileus; uncontrolled epilepsy. Acute intoxication with centrally-acting analgesics, opioids, hypnotics, psychotropic drugs, or alcohol. CYP2D6 ultrarapid and poor metabolisers. Severe hepatic impairment. Children <12 years; post-operative use in children <18 years who have undergone tonsillectomy and/or adenoidectomy; adolescents between 12-18 years who have other risk factors (e.g. obesity, obstructive sleep apnoea) that may increase their sensitivity to respiratory depression. Concomitant use or within 2 weeks after MAOI therapy.

Patient with hypovolaemia, CV disease (including acute MI); history of seizures or risk factors for seizures (e.g. CNS infection, metabolic disorders, malignancy, alcohol/drug withdrawal), delirium tremens, head injury, intracranial lesions, elevated intracranial pressure, toxic psychosis, emotional disturbance including depression, history of drug abuse or acute alcoholism; acute abdominal conditions, adrenal insufficiency (e.g. Addison disease); biliary tract dysfunction, acute pancreatitis; prostatic hyperplasia, urinary stricture, significant COPD or cor pulmonale, substantially decreased respiratory reserve, hypoxia, hypercapnia, pre-existing respiratory depression; G6PD deficiency; thyroid dysfunction. Not recommended in patients with severe respiratory insufficiency. Avoid use in patients with circulatory shock, impaired consciousness or coma, moderate to severe sleep-disordered breathing and suicidal patients. Cachectic, debilitated or morbidly obese patients. Avoid abrupt withdrawal. Renal and mild to moderate hepatic impairment. Elderly. Pregnancy and lactation. Patient Counselling This drug may cause dizziness and drowsiness, if affected, do not drive or operate machinery. Monitoring Parameters Monitor pain relief, blood pressure, heart rate, respiratory and mental status; bowel function. Observe for signs of tolerance, misuse, abuse, addiction, or suicidal ideation. Closely monitor for signs and symptoms of respiratory depression (particularly during initiation or dose increases), serotonin syndrome, sedation, hypotension, and hyponatraemia (in at-risk patients).

Significant: CNS depression, severe hypotension (including orthostatic hypotension and syncope), seizures, sleep-related breathing disorders (e.g. central sleep apnoea, sleep-related hypoxaemia); reversible adrenal insufficiency, spasm of sphincter of Oddi, decreased bowel motility particularly in post-operative patients; drug tolerance, misuse, abuse, or addiction; withdrawal symptoms. Rarely, hyponatraemia. Gastrointestinal disorders: Nausea, vomiting, constipation, dry mouth, diarrhoea, abdominal pain, dyspepsia, flatulence. Metabolism and nutrition disorders: Anorexia. Nervous system disorders: Dizziness, somnolence, headache, trembling. Psychiatric disorders: Confusional state, altered mood, anxiety, nervousness, euphoric mood, sleep disorders, insomnia. Skin and subcutaneous tissue disorders: Hyperhidrosis, pruritus.
Potentially Fatal: Acute liver failure, respiratory depression, serotonin syndrome; neonatal withdrawal syndrome (long-term use during pregnancy). Rarely, serious anaphylactoid reactions and serious skin reactions (e.g. Stevens-Johnson syndrome, toxic epidermal necrolysis, acute generalised exanthematous pustulosis).

Symptoms: Tramadol: Miosis, CV collapse, consciousness disorders including convulsions, coma, respiratory depression leading to respiratory arrest. Paracetamol: Pallor, nausea, vomiting, abdominal pain, anorexia, abnormalities of glucose metabolism, metabolic acidosis; liver damage may be apparent after 12-48 hours of ingestion which may progress to encephalopathy in severe cases, acute renal failure with acute tubular necrosis, cardiac arrhythmia, and pancreatitis. Management: Supportive treatment. Perform gastric lavage to empty the stomach. Giving oral methionine or IV N-acetylcysteine may be beneficial for up to at least 48 hours after ingestion (most effective if given within 8 hours). May administer naloxone to reverse respiratory depression and diazepam for seizures. Maintain respiratory and circulatory functions.

Tramadol: May increase the risk of convulsions with SSRIs, serotonin-norepinephrine reuptake inhibitors (SNRIs), TCAs and other seizure threshold lowering-drugs (e.g. bupropion, mirtazapine). Decreased serum concentrations with CYP3A4 inducers (e.g. rifampicin, carbamazepine, phenytoin). CYP2D6 inhibitors (e.g. quinidine, fluoxetine) may increase plasma levels of tramadol and decrease plasma concentrations of M1 (active metabolite). CYP3A4 inhibitors (e.g. erythromycin, ketoconazole, ritonavir) may elevate tramadol plasma levels and result in increased amount of metabolism by CYP2D6 isoenzyme and higher M1 levels. Mixed opioid agonist/antagonists (e.g. nalbuphine, pentazocine) may reduce the analgesic effect or precipitate withdrawal symptoms of tramadol. May result in serotonin syndrome with serotonergic agents (e.g. triptans, SSRIs, SNRIs, TCAs). May lead to increased INR when used with warfarin. Paracetamol: Increased risk of hepatotoxicity when given with other potentially hepatotoxic agents. Decreased absorption with colestyramine. May decrease the serum concentrations with rifampicin and some anticonvulsants (e.g. phenytoin, phenobarbital, carbamazepine, primidone). Enhances the anticoagulant effect of warfarin. Increased absorption with metoclopramide. May increase the serum concentration with probenecid.
Potentially Fatal: Tramadol: Increased risk of serotonin syndrome when used concurrently or within 2 weeks of MAOIs. May lead to profound sedation, respiratory depression and coma with benzodiazepines and other CNS depressants.

Tramadol: Increased sedative effect with alcohol. May increase risk of serotonin syndrome with St. John's wort.

Tramadol: May cause false-positive result with urine detection of phencyclidine. Paracetamol: May result in false-positive urinary 5-hydroxyindoleacetic acid.

Tramadol is a centrally acting opioid analgesic that binds to mc-opiate receptors in the CNS, leading to inhibited ascending pain pathways and altered pain perception and response. It also inhibits the reuptake of norepinephrine and enhances the release of serotonin. Paracetamol is a para-aminophenol derivative with analgesic, antipyretic and weak anti-inflammatory activity. The exact mechanism of its analgesic action is still unknown, but it is believed to be by activating the descending serotonergic inhibitory pathways in the CNS. Synonym: Paracetamol: acetaminophen.
Onset: Paracetamol: <1 hour. Tramadol: Within 1 hour.
Duration: Paracetamol: 4-6 hours (analgesia).
Absorption: Tramadol: Readily absorbed. Bioavailability: Approx 70-75%. Time to peak plasma concentration: Approx 2 hours (tramadol); approx 3 hours (active metabolite). Paracetamol: Readily absorbed from the gastrointestinal tract, mainly in the small intestine. Time to peak plasma concentration: Approx 10-60 minutes.
Distribution: Tramadol: Widely distributed in the body. Crosses the placenta; enters breast milk (small amounts). Plasma protein binding: Approx 20%. Paracetamol: Widely distributed to body tissues, except fat. Crosses the placenta and enters breast milk. Volume of distribution: Approx 1 L/kg. Plasma protein binding: 10-25%.
Metabolism: Tramadol: Extensively metabolised in the liver via N- and O-demethylation by CYP3A4 and CYP2D6 isoenzymes and by glucuronidation and sulfation; O-desmethyltramadol (M1) is the active metabolite formed by CYP2D6. Paracetamol: Metabolised primarily in the liver via glucuronidation and sulfation to glucuronide and sulfate conjugates.
Excretion: Tramadol: Via urine (approx 30% as unchanged drug, 60% as metabolites). Elimination half-life: Approx 6 hours (tramadol); approx 7.4 ± 1.4 hours (active metabolite). Paracetamol: Via urine (<5% as unchanged drug; 60-80% as glucuronide metabolites; 20-30% as sulfate metabolites; approx 8% as cysteine and mercapturic acid metabolite). Elimination half-life: Approx 2-3 hours.

Oral: Conventional/film-coated tab: Store below 30°C. Effervescent tab: Store below 30°C. Protect from moisture.

Analgesics (Non-Opioid) & Antipyretics / Analgesics (Opioid)

N02BE01 - paracetamol ; Belongs to the class of anilide preparations. Used to relieve pain and fever.
N02AX02 - tramadol ; Belongs to the class of other opioids. Used to relieve pain.