Nabumet

Approved Indications:

• Osteoarthritis (OA): Indicated for the relief of signs and symptoms such as joint pain, swelling, and stiffness in adults with osteoarthritis.
• Rheumatoid Arthritis (RA): Used in the treatment of adult patients with rheumatoid arthritis to reduce joint inflammation, morning stiffness, and associated pain.

Clinically Accepted Off-Label Uses:

• Acute Musculoskeletal Pain: Occasionally used for short-term relief of non-specific musculoskeletal pain or inflammation when NSAID therapy is appropriate.
• Acute Gouty Arthritis (Flare): May be used off-label for symptom relief during acute gout attacks, although not considered a first-line NSAID in this setting.

General Instructions:

• Administer orally with food or milk to minimize gastrointestinal upset.

Adults:

• Initial Dose: 1000 mg once daily with food.
• Titration: If necessary, the dose may be increased to 1500 mg or 2000 mg daily, given either as a single dose or divided into two doses.
• Maximum Dose: 2000 mg per day.

Elderly:

• Start at the lowest effective dose, typically 1000 mg/day, due to increased risk of adverse effects. Monitor renal and gastrointestinal status closely.

Renal Impairment:

• Mild to Moderate (CrCl 30–50 mL/min): Use cautiously; monitor renal function.
• Severe (CrCl <30 mL/min): Use is not recommended due to accumulation of active metabolite and increased toxicity risk.

Hepatic Impairment:

• Use with caution; although no specific dose adjustment is defined, careful monitoring is advised due to hepatic metabolism of the drug.

Pediatric Use:

• Safety and efficacy in children have not been established; not recommended for pediatric use.

Duration:

• Use the lowest effective dose for the shortest duration consistent with therapeutic goals.

Nabumetone is a non-acidic prodrug that undergoes hepatic metabolism to its active form, 6-methoxy-2-naphthylacetic acid (6-MNA). This active metabolite selectively inhibits cyclooxygenase-2 (COX-2) over cyclooxygenase-1 (COX-1), thereby suppressing the synthesis of prostaglandins involved in pain, inflammation, and fever. By reducing prostaglandin levels at sites of inflammation, nabumetone alleviates inflammatory symptoms with comparatively less gastrointestinal irritation than non-selective NSAIDs.

• Absorption: Nabumetone is rapidly absorbed after oral administration.
• Bioactivation: It is a prodrug converted in the liver to 6-MNA, the active metabolite.
• Onset of Action: Begins within 1 to 2 hours post-dose.
• Time to Peak (6-MNA): Approximately 2.5 to 4 hours.
• Bioavailability: Adequate systemic levels of 6-MNA are achieved; absolute bioavailability of parent drug is not relevant.
• Half-life (6-MNA): Approximately 24 hours, supporting once-daily dosing.
• Distribution: 6-MNA is highly protein-bound (~99%) to plasma albumin.
• Metabolism: Primarily hepatic, via oxidation.
• Excretion: Eliminated mostly via urine (75%) and feces (6%) as metabolites. Unchanged drug is minimally excreted.

• Pregnancy:
• Old FDA Category: C (up to 30 weeks gestation); D (from 30 weeks onward).
• Use Recommendation: Avoid during pregnancy, particularly in the third trimester, due to risk of premature closure of the ductus arteriosus and fetal renal dysfunction.
• Lactation:
• Unknown whether nabumetone or 6-MNA is excreted in human milk.
• Due to potential adverse effects in the infant, either discontinue nursing or avoid the drug.
• Use with caution in breastfeeding mothers; alternatives may be safer.

• Primary Class: Nonsteroidal Anti-inflammatory Drug (NSAID)
• Subclass: Non-acidic, relatively COX-2-selective prodrug NSAID

• Known hypersensitivity to nabumetone or any excipients in the formulation
• History of asthma, urticaria, or allergic-type reactions after taking aspirin or other NSAIDs
• Active gastrointestinal ulcer, bleeding, or perforation
• Severe renal impairment (CrCl <30 mL/min)
• Severe hepatic impairment
• Perioperative pain in the setting of coronary artery bypass graft (CABG) surgery
• Pregnancy during third trimester

• Cardiovascular Events: Increased risk of thrombotic events (e.g., myocardial infarction, stroke). Risk increases with duration and in patients with underlying heart disease.
• Gastrointestinal Effects: Risk of GI ulceration, bleeding, and perforation, especially in the elderly or with prolonged use.
• Renal Toxicity: May reduce renal perfusion; monitor serum creatinine and electrolytes in patients at risk.
• Hepatic Dysfunction: Liver function tests should be monitored periodically.
• Hypertension and Fluid Retention: May exacerbate or cause new-onset hypertension or edema.
• Serious Skin Reactions: Rare but severe reactions (e.g., Stevens-Johnson syndrome, TEN) may occur.
• Hematologic Effects: Rare cases of anemia, leukopenia, or thrombocytopenia reported.
• Elderly Patients: At increased risk for GI bleeding and renal adverse events.

Common Adverse Effects:

• Gastrointestinal: Diarrhea, dyspepsia, nausea, abdominal pain
• Central Nervous System: Dizziness, headache, fatigue
• Dermatologic: Rash, pruritus

Serious or Rare Side Effects:

• Cardiovascular: Hypertension, edema, heart failure, myocardial infarction, stroke
• Renal: Elevated creatinine, renal failure, nephrotic syndrome
• Hepatic: Hepatitis, liver enzyme elevation
• Hematologic: Anemia, leukopenia, thrombocytopenia
• Dermatologic: Stevens-Johnson syndrome, toxic epidermal necrolysis

Onset & Dose Dependence:

• Gastrointestinal and CNS symptoms may occur early; serious adverse effects are often dose- and duration-dependent.

• Warfarin and other anticoagulants: Increased risk of bleeding.
• ACE inhibitors, ARBs: May reduce antihypertensive effect and worsen renal function.
• Diuretics: Reduced diuretic efficacy and increased nephrotoxicity risk.
• Lithium: May increase lithium serum concentration and toxicity.
• Methotrexate: Potential for increased methotrexate toxicity due to reduced clearance.
• Other NSAIDs: Avoid concomitant use due to additive GI and renal toxicity.
• Corticosteroids: Increased risk of GI ulceration and bleeding.
• Alcohol: Increases risk of gastrointestinal bleeding.

• FDA Update (2020): Added warnings regarding NSAID use after 20 weeks’ gestation due to risk of fetal renal dysfunction leading to oligohydramnios.
• Labeling Enhancements: Emphasized cardiovascular and gastrointestinal warnings for all NSAIDs including nabumetone.
• Clinical Recommendations: Use gastroprotective agents (e.g., PPIs) in high-risk patients requiring long-term NSAID use.

• Temperature: Store at 20°C to 25°C (68°F to 77°F); allow temperature excursions between 15°C and 30°C.
• Humidity & Light: Protect from moisture and direct light; keep container tightly closed.
• Handling: No need for reconstitution or refrigeration.
• Formulation: Oral tablets; do not crush or break unless scored.