Nabumetone

Usage

Nabumetone is prescribed for the relief of signs and symptoms of osteoarthritis and rheumatoid arthritis. It is pharmacologically classified as a Nonsteroidal Anti-inflammatory Drug (NSAID). Specifically, it’s a non-acidic NSAID prodrug. Nabumetone itself has minimal direct effects; its active metabolite, 6-methoxy-2-naphthylacetic acid (6-MNA), inhibits cyclooxygenase (COX-1 and COX-2) enzymes, reducing prostaglandin synthesis and thereby diminishing inflammation and pain.

Alternate Names

While “nabumetone” is the generic name, it’s marketed under various brand names such as Relafen®, Relafen DS®, and others internationally.

How It Works

Pharmacodynamics: Nabumetone is a prodrug; after oral administration, it undergoes rapid hepatic metabolism to 6-MNA. 6-MNA exerts its anti-inflammatory, analgesic, and antipyretic effects by inhibiting COX-1 and COX-2 enzymes, thus suppressing prostaglandin synthesis. This action reduces inflammation and pain at the peripheral sites of injury or inflammation.

Pharmacokinetics:

• Absorption: Nabumetone is well-absorbed from the gastrointestinal tract. Food may slightly delay absorption but does not affect overall bioavailability.
• Metabolism: Extensively metabolized in the liver, primarily via oxidation by CYP1A2 and CYP2C9, to 6-MNA, its active metabolite.
• Elimination: 6-MNA is primarily eliminated via renal excretion (approximately 80%), and a small portion undergoes biliary excretion. The elimination half-life of 6-MNA is approximately 24 hours in young adults, and may be prolonged in elderly patients (around 30 hours).

Dosage

Standard Dosage

Adults:

Initial dose: 1000 mg orally once a day, preferably at bedtime. Maintenance dose: 1500 mg to 2000 mg orally per day, as a single daily dose or in two divided doses (every 12 hours). Maximum dose: 2000 mg/day.

Children:

Nabumetone is generally not recommended for pediatric patients under 18 years of age. Limited research suggests 30 mg/kg/day (up to a maximum of 2000 mg/day) may be used in juvenile rheumatoid arthritis, but this is not a standard approved indication.

Special Cases:

• Elderly Patients: Start with the lowest effective dose (e.g., 1000 mg/day) and titrate cautiously. Close monitoring for adverse events is crucial due to increased risk in elderly individuals.
• Patients with Renal Impairment:
  • Mild renal impairment (CrCl ≥ 50 mL/min): No dosage adjustment is typically needed.
  • Moderate renal impairment (CrCl 30-49 mL/min): Initial dose: 750 mg/day; maximum dose: 1500 mg/day.
  • Severe renal impairment (CrCl < 30 mL/min): Initial dose: 500 mg/day; maximum dose: 1000 mg/day.
• Patients with Hepatic Dysfunction: Start with the lowest effective dose and titrate cautiously. Close monitoring is recommended. In severe hepatic impairment or active liver disease, nabumetone is contraindicated.
• Patients with Comorbid Conditions: Exercise caution in patients with heart disease, hypertension, history of GI bleeding, or other relevant conditions. Individualized dosage adjustments may be required.

Clinical Use Cases

Nabumetone is not typically indicated for intubation, surgical procedures, mechanical ventilation, ICU use, or emergency situations. Its primary indication is for managing chronic pain and inflammation associated with osteoarthritis and rheumatoid arthritis. Other NSAIDs or analgesics may be more appropriate for acute pain management in these settings.

Dosage Adjustments

Dosage adjustments are necessary for patients with renal or hepatic impairment as outlined above. Consider lower initial doses and cautious titration in elderly patients. In patients with certain comorbid conditions (e.g., cardiovascular disease, diabetes), careful monitoring and potential dosage adjustments are necessary. Genetic polymorphisms affecting drug metabolism are not routinely tested for, but may influence individual responses and necessitate tailored dosing.

Side Effects

Common Side Effects:

Diarrhea, indigestion/heartburn, abdominal pain, constipation, dizziness, edema (swelling), flatulence, headache, nausea, positive stool guaiac, skin itching, rash, tinnitus, dry mouth, fatigue.

Rare but Serious Side Effects:

Myocardial infarction (heart attack), stroke, heart failure, gastrointestinal bleeding or perforation, hepatotoxicity, serious skin reactions (e.g., Stevens-Johnson Syndrome), anaphylaxis, renal impairment.

Long-Term Effects:

Chronic use of nabumetone can contribute to gastrointestinal issues, including ulcers and bleeding, cardiovascular complications, and renal dysfunction.

Adverse Drug Reactions (ADR):

Clinically significant ADRs include GI bleeding, acute renal failure, severe allergic reactions, Stevens-Johnson Syndrome, hepatotoxicity, myocardial infarction, and stroke. These require immediate medical intervention.

Contraindications

• Absolute: Aspirin allergy or hypersensitivity to other NSAIDs; severe renal impairment; perioperative pain in the setting of coronary artery bypass graft (CABG) surgery; severe hepatic impairment or active liver disease; pregnancy (third trimester).
• Relative: History of peptic ulcer disease; gastrointestinal bleeding; stomatitis; systemic lupus erythematosus; ulcerative colitis; congestive heart failure; hypertension; asthma; fluid retention; coagulopathies; pregnancy (first and second trimesters); breastfeeding.

Drug Interactions

Nabumetone can interact with numerous medications.

• Anticoagulants (e.g., warfarin): Increased risk of bleeding.
• Antihypertensives (e.g., ACE inhibitors, beta-blockers, diuretics): Reduced antihypertensive effect.
• Aspirin and other NSAIDs: Increased risk of GI adverse events.
• Corticosteroids: Increased risk of GI ulceration and bleeding.
• Lithium: Increased lithium levels.
• Methotrexate: Increased methotrexate toxicity.
• Selective Serotonin Reuptake Inhibitors (SSRIs): Increased risk of GI bleeding.
• CYP450 interactions: Nabumetone is metabolized by CYP1A2 and CYP2C9. Inhibitors of these enzymes (e.g., fluconazole, ciprofloxacin) can increase nabumetone levels, while inducers (e.g., rifampin, smoking) can decrease levels.

It’s also important to be aware of potential interactions with OTC drugs, supplements (e.g., herbal remedies), alcohol, and certain foods (e.g., grapefruit juice). Always review a patient’s full medication list and assess for potential interactions before prescribing nabumetone.

Pregnancy and Breastfeeding

• Pregnancy: Nabumetone is contraindicated during the third trimester due to the risk of premature closure of the ductus arteriosus and potential complications during delivery. Use during the first and second trimesters should be carefully considered and only if the potential benefit outweighs the potential risk to the fetus.
• Breastfeeding: It is unknown if nabumetone is excreted in breast milk. Due to potential adverse effects in nursing infants, it is generally recommended to avoid nabumetone during breastfeeding. If use is deemed essential, an alternative safer option or discontinuation of breastfeeding may be considered.

Drug Profile Summary

• Mechanism of Action: NSAID prodrug; active metabolite 6-MNA inhibits COX-1 and COX-2, reducing prostaglandin synthesis.
• Side Effects: Common: GI upset, dizziness, headache. Serious: GI bleeding, cardiovascular events, renal impairment.
• Contraindications: Aspirin or NSAID allergy, severe renal/hepatic impairment, CABG surgery, third-trimester pregnancy.
• Drug Interactions: Anticoagulants, antihypertensives, other NSAIDs, corticosteroids, methotrexate.
• Pregnancy & Breastfeeding: Contraindicated in third trimester. Avoid during breastfeeding if possible.
• Dosage: Adults: 1000-2000 mg/day. Adjust for renal impairment. Not recommended for children.
• Monitoring Parameters: Blood pressure, renal function, signs of GI bleeding, liver function tests.

Popular Combinations

Nabumetone is generally not used in combination with other NSAIDs due to the increased risk of adverse effects. It can be used cautiously with gastroprotective agents (e.g., proton pump inhibitors) to reduce the risk of GI ulceration.

Precautions

• General Precautions: Evaluate for allergies, renal/hepatic function, cardiovascular risk factors before initiating therapy.
• Specific Populations: See section on dosage adjustments for elderly, renal/hepatic impairment, and pregnancy/breastfeeding.
• Lifestyle Considerations: Advise patients to limit alcohol intake as it can increase the risk of GI bleeding. Smoking can interact with nabumetone metabolism.

FAQs (Frequently Asked Questions)

Q1: What is the recommended dosage for Nabumetone?

A: The standard adult initial dose is 1000 mg once daily, preferably at bedtime. The maintenance dose ranges from 1500 to 2000 mg/day, taken as a single dose or divided twice daily. Adjust dosage for renal impairment and in the elderly. Not recommended for children under 18 years of age.

Q2: How does nabumetone compare to other NSAIDs like ibuprofen?

A: Nabumetone is generally considered to have a lower risk of GI side effects than some other NSAIDs. However, the cardiovascular risks are similar across most NSAIDs. Ibuprofen is available over-the-counter, while nabumetone requires a prescription.

Q3: What are the most serious side effects of nabumetone?

A: The most serious potential side effects include gastrointestinal bleeding, ulceration or perforation, myocardial infarction, stroke, heart failure, hepatotoxicity, and severe allergic reactions.

Q4: Can nabumetone be taken during pregnancy?

A: Nabumetone is contraindicated during the third trimester. Use in the first and second trimesters should be carefully evaluated and avoided if possible.

Q5: What should I advise patients regarding alcohol consumption while taking nabumetone?

A: Advise patients to limit alcohol intake, as it can increase the risk of gastrointestinal bleeding.

Q6: How should nabumetone be administered?

A: Nabumetone tablets should be swallowed whole, preferably with food or after a meal. Do not crush or chew the tablets.

Q7: Does nabumetone interact with any other medications?

A: Yes, nabumetone can interact with many medications, including anticoagulants, antihypertensives, other NSAIDs, corticosteroids, and methotrexate. A full medication review is necessary to assess potential interactions.

Q8: Are there any contraindications to using nabumetone?

A: Yes, contraindications include known hypersensitivity to nabumetone or other NSAIDs, severe renal or hepatic impairment, CABG surgery, and the third trimester of pregnancy.

Q9: How long does it take for nabumetone to start working?

A: Nabumetone’s onset of action can be slower compared to some other NSAIDs, sometimes taking several days to a week to experience full benefit for arthritic conditions.

Q10: What should I monitor in patients taking nabumetone?

A: Monitor blood pressure, renal function (especially in those with pre-existing renal disease), and look for signs of gastrointestinal bleeding. Periodic liver function tests may also be advisable.