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 BRAND NAMES
 MECHANISM OF ACTION
Paracetamol/Codeine combines the analgesic effects of a centrally acting analgesic, codeine, with a peripherally acting analgesic, Paracetamol (acetaminophen).
- Paracetamol/Codeine combination is indicated for the relief of mild to moderately severe pain
- Tablets containing Paracetamol 300-500mg and codeine 30 mg: 1-2 tablets , 1-3 times a day with an interval of at least 4 hours.
- Codeine-containing products are contraindicated for postoperative pain management in children who have undergone tonsillectomy and/or adenoidectomy.
- Hypersensitivity to codeine or acetaminophen.
- Pre-existing respiratory depression
 WARNINGS AND PRECAUTIONS
- Paracetamol (Acetaminophen) has been associated with cases of acute liver failure, at times resulting in liver transplant and death. Most of the cases of liver injury are associated with the use of Paracetamol at doses that exceed 4000 mg/day. The risk of acute liver failure is higher in individuals with underlying liver disease and in individuals who drink alcohol while taking Paracetamol.
- Death Related to Ultra-Rapid Metabolism of Codeine to Morphine:
Ultra-Rapid metabolizers due to the CYP2D6 gene duplication may experience exaggerated and even potentially dangerous opioidergic effects; respiratory depression and death have occurred in children who received codeine in the postoperative period following tonsillectomy and/or adenoidectomy and had evidence of being ultra-rapid metabolizers of codeine. Deaths have also occurred in nursing infants who were exposed to high levels of morphine in breast milk because their mothers were ultra-rapid metabolizers of codeine.
The prevalence of this CYP2D6 phenotype varies widely and has been estimated at 0.5 to 1% in Chinese and Japanese, 0.5 to 1% in Hispanics, 1 to 10% in Caucasians, 3% in African Americans, and 16 to 28% in North Africans, Ethiopians, and Arabs. These individuals convert codeine into its active metabolite, morphine, more rapidly and completely than other people. This rapid conversion results in higher than expected serum morphine levels. Even at labeled dosage regimens, individuals who are ultra-rapid metabolizers may have life-threatening or fatal respiratory depression or experience signs of overdose (such as extreme sleepiness, confusion, or shallow breathing)
- Hypersensitivity reactions to paracetamol: There have been post-marketing reports of hypersensitivity and anaphylaxis associated with the use of Paracetamol. Clinical signs included swelling of the face, mouth, and throat, respiratory distress, urticaria, rash, pruritus, and vomiting. In case a hypersensitivity reaction occurs, the drug should be discontinued.
- Head Injuries: In the presence of head injury or other intracranial lesions, the respiratory-depressant effects of codeine may be markedly enhanced, as well as their capacity for elevating cerebrospinal fluid pressure. Codeine also produce other CNS-depressant effects, such as drowsiness, that may further obscure the clinical course of the patients with head injuries.
- Abuse Potential: Codeine is potentially abusable. Consequently, its extended use is not recommended
- Codeine may impair the mental and/or physical abilities required for the performance of potentially hazardous tasks such as driving a car or operating machinery. Avoid such tasks while taking it.
- Alcohol and other CNS depressants may produce an additive CNS depression. Avoid drinking alcohol or taking other CNS depressants.
 PREGNANCY AND LACTATION
- Pregnancy Category C (US). There are no adequate and well-controlled studies in pregnant women. This combination should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Dependence has been reported in newborns whose mothers took opiates regularly during pregnancy. Withdrawal signs include irritability, excessive crying, tremors, hyperreflexia, fever, vomiting, and diarrhea. These signs usually appear during the first few days of life.
- Nursing mothers:
- Paracetamol is excreted in breast milk in small amounts, but the significance of its effect on nursing infants is not known. Because of the potential for serious adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.
- Codeine is secreted into human milk. In women with normal codeine metabolism (normal CYP2D6 activity), the amount of codeine secreted into human milk is low and dose-dependent. Despite the common use of codeine products to manage postpartum pain, reports of adverse events in infants are rare.
However, some women are ultra-rapid metabolizers of codeine. These women achieve higher-than-expected serum levels of codeine’s active metabolite, morphine, leading to higher-thanexpected levels of morphine in breast milk and potentially dangerously high serum morphine levels in their breastfed infants. Therefore, maternal use of codeine can potentially lead to serious adverse reactions, including death, in nursing infants. If a codeine-containing product is selected, the lowest dose should be prescribed for the shortest period of time to achieve the desired clinical effect. Mothers using codeine should be informed about when to seek immediate medical care and how to identify the signs and symptoms of neonatal toxicity, such as drowsiness or sedation, difficulty breastfeeding, breathing difficulties, and decreased tone, in their baby.
 SIDE EFFECTS
The most frequently observed adverse reactions include drowsiness, lightheadedness, dizziness, sedation, shortness of breath, nausea and vomiting.
Other adverse reactions include allergic reactions, euphoria, dysphoria, constipation, abdominal pain, pruritus, rash, thrombocytopenia, and agranulocytosis.
At higher doses, codeine has most of the disadvantages of morphine including respiratory depression.