What are the medication considerations for a patient who is a poor metabolizer of CYP2C9 (cytochrome P450 2C9)?

CYP2C9 Poor Metabolizer: Medication Management

**For patients identified as CYP2C9 poor metabolizers (genotypes *2/*2, *3/*3, or 2/3), initiate CYP2C9 substrate medications at 50% of the standard starting dose and consider alternative therapies for drugs with narrow therapeutic indices. 1

Critical High-Risk Medications Requiring Dose Adjustment

Warfarin (Highest Priority)

• Reduce initial warfarin dose by 25-50% in CYP2C9 poor metabolizers to prevent severe and life-threatening bleeding episodes 1
• CYP2C9 metabolizes the S-enantiomer of warfarin, which is 5 times more potent than the R-enantiomer 1
• Poor metabolizers have significantly increased bleeding risk with standard dosing 2
• Monitor INR closely during initiation and with any medication changes 1

Phenytoin

• **Reduce phenytoin maintenance doses by 31-52% in homozygous poor metabolizers (*2/*2, *3/*3, 2/3) 1
• Reduce doses by 23-38% in heterozygous patients (*1/*2, *1/*3) 1
• Severe toxicity has been reported in poor metabolizers receiving standard doses 2
• Monitor phenytoin levels more frequently during dose titration 1

Celecoxib (FDA-Mandated Adjustment)

• FDA labeling mandates starting with half the lowest recommended dose in known or suspected CYP2C9 poor metabolizers 3
• Standard dosing: 200 mg daily for osteoarthritis; reduce to 100 mg daily in poor metabolizers 3
• For pediatric JRA patients who are CYP2C9 poor metabolizers, consider alternative therapies entirely rather than dose reduction 3

Siponimod (Contraindicated in Specific Genotypes)

• *Siponimod is contraindicated in CYP2C93/3 poor metabolizers* per FDA labeling 1
• Dose adjustments for other genotypes: 1 mg/day for *1/*3 or *2/*3; 2 mg/day for *1/*1, *1/*2, *2/*2 1
• Note that CYP2C9*5, *6, *8, and *11 alleles (common in African ancestry populations) are not included in current drug labeling but confer decreased function 1

Additional CYP2C9 Substrates Requiring Caution

NSAIDs

• Diclofenac, ibuprofen, naproxen, and other NSAIDs are metabolized by CYP2C9 4, 5, 6
• Poor metabolizers may experience increased drug exposure and toxicity 4, 5
• Start at lower doses and monitor for adverse effects including gastrointestinal bleeding 4

Oral Hypoglycemics

• Tolbutamide and glyburide are CYP2C9 substrates 4, 5, 6
• Poor metabolizers may have prolonged hypoglycemic effects 4, 5
• Monitor blood glucose more frequently during initiation 4

Antihypertensives

• Losartan requires CYP2C9 for conversion to its active metabolite 4, 5, 6
• Poor metabolizers may have reduced therapeutic efficacy 4
• Consider alternative ARBs not dependent on CYP2C9 metabolism 4

Drug-Drug Interactions: Compounding Risk

CYP2C9 poor metabolizers are at exponentially higher risk when exposed to CYP2C9 inhibitors 1

Strong CYP2C9 Inhibitors to Avoid or Use with Extreme Caution:

• Sulfamethoxazole/trimethoprim: Doubles bleeding risk with warfarin; reduce warfarin dose by 25% prophylactically 1
• Metronidazole: Reduce warfarin dose by 33% prophylactically 1
• Fluconazole: Strong CYP2C9 inhibitor; avoid with narrow therapeutic index CYP2C9 substrates 1
• Amiodarone: Inhibits CYP2C9 moderately; reduce warfarin dose by 50% and digoxin by 30-50% 1
• Fluvoxamine and fluoxetine: Inhibit both CYP2C9 and CYP3A4; prefer sertraline or citalopram/escitalopram as alternatives 1

Moderate CYP2C9 Inhibitors:

• Voriconazole, ciprofloxacin (via CYP1A2 affecting R-warfarin), phenylbutazone, sulfinpyrazone 1, 4

Clinical Monitoring Algorithm

1. Confirm CYP2C9 genotype before initiating narrow therapeutic index drugs (warfarin, phenytoin) 1
2. **For poor metabolizers (*2/*2, *3/*3, *2/*3)**:
   • Start all CYP2C9 substrates at 50% standard dose 1, 3
   • Increase monitoring frequency by 2-fold during titration 1
   • Screen medication list for CYP2C9 inhibitors before each new prescription 1
3. **For intermediate metabolizers (*1/*2, *1/*3)**:
   • Reduce doses by 25-38% for narrow therapeutic index drugs 1
   • Standard monitoring may be adequate for wider therapeutic index drugs 1

Common Pitfalls to Avoid

• Do not assume absence of drug interactions means safety: Drug-drug interactions can convert intermediate metabolizers into phenotypic poor metabolizers 1
• African ancestry patients: Test for CYP2C9*5, *6, *8, *11 alleles, which are not detected by standard panels but confer decreased function 1
• Acetaminophen with warfarin: Even in normal metabolizers, acetaminophen >9.1 g/week increases INR; risk is magnified in poor metabolizers 1
• Alcohol: Inhibits hepatic enzymes and impairs warfarin clearance; counsel poor metabolizers to limit alcohol to <60 g/day 1

Frequency of CYP2C9 Poor Metabolizers

• Caucasians: ~1% are poor metabolizers (*2/*2, *3/*3, *2/*3) 1, 2
• Intermediate metabolizers (*1/*2, *1/*3): ~8% of Caucasians 1
• Asian populations: Lower frequency of poor metabolizers 2
• African populations: Higher frequency of *5, *6, *8, *11 alleles not captured by standard testing 1