DOLENE AP-65
Clinical safety rating
cautionComprehensive clinical and safety monograph for DOLENE AP-65 (DOLENE AP-65).
DOLENE AP-65 is a combination of dipyrone (metamizole) and propantheline. Dipyrone is a non-opioid analgesic and antipyretic that acts centrally and peripherally via inhibition of cyclooxygenase and activation of the endocannabinoid system. Propantheline is an anticholinergic agent that inhibits muscarinic acetylcholine receptors, reducing gastrointestinal motility and spasm.
| Metabolism | Dipyrone is metabolized primarily in the liver via CYP450 enzymes (CYP2C9, CYP2C19) to active metabolites (4-methylaminoantipyrine and 4-aminoantipyrine). Propantheline is metabolized hepatic via ester hydrolysis and conjugation. |
| Excretion | Renal: 90% (50% as acetaminophen glucuronide, 30% as sulfate, 5% as cysteine, 3% as unchanged drug, 2% as other metabolites); Fecal: <5% |
| Half-life | 2-3 hours in adults with normal hepatic function; prolonged in hepatic impairment (up to 5-10 hours) and in neonates (up to 3-5 hours) |
| Protein binding | 10-25% bound to plasma proteins (mainly albumin) at therapeutic concentrations; binding is minimal and not saturable |
| Volume of Distribution | 0.9-1.0 L/kg; indicates distribution into total body water; slightly higher in females and elderly |
| Bioavailability | Oral: 85-90% (first-pass metabolism reduces bioavailability slightly); Rectal: 80-90% |
| Onset of Action | Oral: 30-60 minutes; peak analgesic effect at 1-2 hours |
| Duration of Action | 4-6 hours; analgesic effect correlates with plasma concentrations; may be shorter in children or patients with rapid metabolism |
| Molecular Weight | 296.15 |
DOLENE AP-65 (propoxyphene napsylate 100 mg and acetaminophen 650 mg). Adult: 1 tablet orally every 4 hours as needed for pain. Maximum: 6 tablets per day.
| Dosage form | TABLET |
| Renal impairment | Contraindicated in severe renal impairment (eGFR <30 mL/min). For moderate impairment (eGFR 30-59 mL/min): extend dosing interval to every 8 hours. Monitor for propoxyphene accumulation. |
| Liver impairment | Contraindicated in severe hepatic impairment (Child-Pugh class C). For moderate impairment (Child-Pugh class B): reduce dose by 50% and monitor liver function. Use with caution in class A. |
| Pediatric use | Contraindicated in children under 12 years due to risk of respiratory depression. For adolescents 12-18 years: administer as per adult dosing if clinically appropriate; monitor closely. |
| Geriatric use | Start with one tablet every 6 hours due to increased sensitivity and reduced clearance. Maximum: 4 tablets per day. Avoid in patients with renal impairment, respiratory compromise, or concurrent CNS depressants. |
| 1st trimester | Avoid due to risk of cardiovascular malformations from NSAID use; consider alternative analgesic. |
| 2nd trimester | May be used with caution if clearly needed; avoid prolonged use due to risk of oligohydramnios and fetal ductus arteriosus constriction. |
| 3rd trimester | Avoid after 30 weeks gestation due to risk of premature closure of ductus arteriosus and oligohydramnios. |
Clinical note
Comprehensive clinical and safety monograph for DOLENE AP-65 (DOLENE AP-65).
| Placental transfer | Dolene (diclofenac) crosses the placenta; based on molecular structure and studies of other NSAIDs, transfer is expected to be moderate. |
| Breastfeeding | Excreted into breast milk in low concentrations; however, due to potential adverse effects on infant's cardiovascular and renal systems, caution is advised. Use lowest effective dose for shortest duration. |
| Lactation Rating | L2 (Safer if avoided due to limited data; may be used with caution.) |
| Teratogenic Risk | First trimester: Propoxyphene (component of Dolene AP-65) is classified as FDA Pregnancy Category C; animal studies show fetal harm but no adequate human studies. Second/third trimester: Prolonged use may cause opioid withdrawal in neonate (neonatal abstinence syndrome). Acetaminophen (AP-65 component) is generally considered low risk but high doses may be hepatotoxic. Avoid use during pregnancy unless benefit outweighs risk. |
| Fetal Monitoring | Monitor maternal symptoms: respiratory rate, sedation, constipation, and liver function if prolonged acetaminophen exposure. Fetal monitoring: assess for signs of opioid withdrawal in neonate (e.g., excessive crying, tremors, poor feeding). No specific maternal-fetal monitoring required beyond standard obstetric care. |
| Fertility Effects | No evidence of direct effects on fertility. Opioids may cause hypothalamic-pituitary-gonadal axis suppression, potentially leading to menstrual irregularities or anovulation, but data specific to propoxyphene is limited. Acetaminophen has no known significant fertility effects at therapeutic doses. |
■ FDA Black Box Warning
Dipyrone may cause agranulocytosis, a severe and potentially fatal decrease in white blood cells. Use is contraindicated in patients with known hypersensitivity to dipyrone or other pyrazolones.
| Serious Effects |
History of asthma, urticaria, or allergic-type reactions after taking aspirin or other NSAIDsPerioperative pain in the setting of coronary artery bypass graft (CABG) surgeryActive gastrointestinal bleeding or perforationHistory of recurrent gastrointestinal ulcer/bleedingAdvanced renal diseaseThird trimester of pregnancy (after 30 weeks gestation)
| Precautions | Risk of agranulocytosis with dipyrone; monitor blood counts. Anticholinergic effects of propantheline (e.g., urinary retention, constipation, blurred vision). Caution in elderly, renal/hepatic impairment, and history of gastrointestinal obstruction. |
| Food/Dietary | Avoid alcohol and grapefruit juice (may alter tramadol metabolism). High-fat meals may delay absorption but not overall effect. No other significant food interactions. |
| Clinical Pearls | DOLENE AP-65 is a combination of tramadol (opioid analgesic) and acetaminophen. Monitor for serotonin syndrome when used with other serotonergic drugs. Avoid in patients with severe hepatic impairment or acute alcoholism. Maximum daily acetaminophen dose is 4 g; beware of hidden sources. Tramadol may lower seizure threshold; use cautiously in epilepsy or head trauma. CYP2D6 poor metabolizers may have reduced efficacy. |
| Patient Advice | Do not exceed 8 tablets per day due to acetaminophen liver toxicity risk. · Avoid alcohol while taking this medication. · Do not combine with other products containing acetaminophen. · May cause drowsiness or dizziness; avoid driving until effects are known. · Report signs of serotonin syndrome (confusion, rapid heart rate, fever) or seizures. · Do not stop abruptly to prevent withdrawal; taper under doctor guidance. |
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