PHENYLBUTAZONE
Clinical safety rating: caution
Comprehensive clinical and safety monograph for PHENYLBUTAZONE (PHENYLBUTAZONE).
Phenylbutazone is a nonsteroidal anti-inflammatory drug (NSAID) that inhibits cyclooxygenase (COX) enzymes, reducing prostaglandin synthesis, thereby causing anti-inflammatory, analgesic, and antipyretic effects. It also inhibits leukocyte migration and lysosomal enzyme release.
| Metabolism | Hepatic metabolism via CYP2C9 and CYP3A4; major metabolite is oxyphenbutazone; minor pathways include hydroxylation and glucuronidation. |
| Excretion | Primarily hepatic metabolism; renal excretion of metabolites (<1% unchanged). Biliary/fecal excretion accounts for ~20% of total elimination. |
| Half-life | Terminal elimination half-life is 50–65 hours, but exhibits dose-dependent kinetics; can extend to 72–100 hours with repeated dosing or in elderly. |
| Protein binding | 98–99% bound, primarily to albumin. |
| Volume of Distribution | 0.05–0.1 L/kg, indicating limited extravascular distribution; increased in hypoalbuminemia. |
| Bioavailability | Oral: 100% absorbed, though systemic availability may be reduced by first-pass metabolism (bioavailability ~90%). Intramuscular: near 100%. |
| Onset of Action | Oral: 30–60 minutes for analgesic effect; 2–4 days for full anti-inflammatory effect. Intramuscular: 20–30 minutes for analgesic effect. |
| Duration of Action | Analgesic duration: 4–6 hours. Anti-inflammatory duration persists up to 24 hours due to long half-life, but accumulation leads to prolonged effects. |
| Molecular Weight | 308.37 |
Oral: 100-200 mg three times daily with food; maximum 600 mg/day. For acute gout: initial 400 mg followed by 200 mg every 4-6 hours for 1-2 days, then reduce.
| Dosage form | TABLET |
| Renal impairment | GFR 10-50: use 50% of normal dose. GFR <10: contraindicated due to accumulation of active metabolite oxyphenbutazone. |
| Liver impairment | Child-Pugh A: no adjustment. Child-Pugh B: reduce dose by 50%. Child-Pugh C: contraindicated due to risk of hepatotoxicity. |
| Pediatric use | Not recommended in children under 14 years due to risk of Reye-like syndrome and hypersensitivity; safety and efficacy not established. |
| Geriatric use | Initiate at lowest effective dose (100 mg once or twice daily); monitor closely for fluid retention, GI bleeding, and renal impairment; avoid long-term use. |
| 1st trimester | Phenylbutazone is contraindicated in the first trimester due to risk of teratogenicity (e.g., cardiovascular malformations) and potential for premature closure of the ductus arteriosus. |
| 2nd trimester | Use is not recommended in the second trimester due to risks of fetal nephrotoxicity and oligohydramnios. |
| 3rd trimester | Contraindicated in the third trimester due to risk of premature closure of the ductus arteriosus, fetal renal impairment, and inhibition of labor. |
Clinical note
Comprehensive clinical and safety monograph for PHENYLBUTAZONE (PHENYLBUTAZONE).
| Placental transfer | Phenylbutazone readily crosses the human placenta, with fetal serum concentrations reaching approximately 50-60% of maternal levels. |
| Breastfeeding | Phenylbutazone is excreted into breast milk in low amounts, but due to its long half-life and potential for serious adverse effects (e.g., bone marrow suppression, hepatotoxicity), breastfeeding is generally contraindicated. Alternative agents with a better safety profile should be considered. |
■ FDA Black Box Warning
WARNING: Aplastic anemia, agranulocytosis, and other blood dyscrasias have been associated with phenylbutazone. Use only when other NSAIDs have failed due to serious adverse effects. Monitor blood counts regularly. Risk is dose-related and increased with prolonged use.
| Serious Effects |
History of hypersensitivity to phenylbutazone or other NSAIDsActive peptic ulcer disease or gastrointestinal bleedingSevere hepatic impairment (Child-Pugh class C)Severe renal impairment (creatinine clearance <30 mL/min)Blood dyscrasias (e.g., aplastic anemia, agranulocytosis)Third trimester of pregnancyBreastfeedingConcomitant use of other NSAIDs or anticoagulants
| Precautions | Risk of bone marrow suppression (aplastic anemia, agranulocytosis); gastrointestinal ulceration and bleeding; renal toxicity (especially in elderly, dehydrated, or those with pre-existing renal impairment); hepatic dysfunction; hypersensitivity reactions; sodium and water retention; increased cardiovascular risk; use lowest effective dose for shortest duration. |
| Food/Dietary | Avoid taking with alcohol as it may increase the risk of gastrointestinal bleeding and hepatotoxicity. Grapefruit juice may increase drug levels and toxicity; avoid concurrent consumption. High-fat meals can delay but do not significantly reduce absorption; take with food or milk to minimize gastrointestinal irritation. Maintain adequate hydration unless contraindicated due to fluid retention concerns. |
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| Lactation Rating | L5 |
| Teratogenic Risk | First trimester: Increased risk of cardiovascular malformations and neural tube defects due to inhibition of prostaglandin synthesis. Second and third trimesters: Risk of premature closure of ductus arteriosus, oligohydramnios, and neonatal renal impairment. Avoid in all trimesters unless absolutely necessary. |
| Fetal Monitoring | Monitor maternal renal function, hepatic function, and complete blood count regularly. Fetal ultrasound for ductal patency and amniotic fluid volume if used in later pregnancy. Monitor for signs of bleeding in the neonate at delivery. |
| Fertility Effects | May impair female fertility by inhibiting ovulation and luteal phase function due to anti-prostaglandin effects. Reversible upon discontinuation. Limited data on male fertility. |
| Clinical Pearls | Phenylbutazone is a nonsteroidal anti-inflammatory drug (NSAID) with potent anti-inflammatory, antipyretic, and analgesic effects, but its use is severely limited due to high risk of serious adverse effects including agranulocytosis, aplastic anemia, and hepatotoxicity. It is reserved for short-term treatment of severe conditions such as ankylosing spondylitis, acute gouty arthritis, and acute exacerbations of rheumatoid arthritis when other therapies are ineffective or contraindicated. Due to its long half-life (50-100 hours), dosing should be carefully adjusted, and complete blood counts (CBC) and liver function tests must be monitored regularly. It inhibits prostaglandin synthesis and can cause sodium and water retention, exacerbating hypertension and heart failure. Avoid concomitant use with other NSAIDs, anticoagulants, or methotrexate due to increased bleeding risk and toxicity. |
| Patient Advice | Take this medication exactly as prescribed; do not exceed the recommended dose or duration of therapy due to risk of serious side effects. · Report any signs of infection (fever, sore throat, mouth ulcers), unusual bleeding or bruising, skin rash, or jaundice immediately. · Avoid alcohol and aspirin-containing products while taking this drug. · This medication may cause dizziness or drowsiness; avoid driving or operating heavy machinery until you know how it affects you. · Use effective contraception if you are of childbearing age; this drug may be harmful to an unborn baby and should not be used in late pregnancy. · Do not take this drug with other NSAIDs (e.g., ibuprofen, naproxen) or corticosteroids without consulting your doctor. |