Zyloprim - Drug Monograph

Introduction

Zyloprim (allopurinol) is a purine analog and xanthine oxidase inhibitor that reduces the production of uric acid. It is a first-line urate-lowering therapy for chronic gout and is widely used for the prevention of tumor lysis syndrome and recurrent calcium oxalate kidney stones in patients with hyperuricosuria. Because it is inexpensive, generally well tolerated, and supported by decades of clinical experience, allopurinol remains a cornerstone of long-term hyperuricemia management.

Drug Class and Overview

• Class: Xanthine oxidase inhibitor (uricosuric-sparing urate-lowering agent).
• Related agents: Febuxostat (a non-purine selective xanthine oxidase inhibitor), pegloticase (recombinant uricase), and probenecid/sulfinpyrazone (uricosurics).
• Distinguishing features: Allopurinol is the prototypical and most widely used xanthine oxidase inhibitor; it is administered orally, requires renal dose adjustment, and is associated with rare but serious cutaneous hypersensitivity reactions, particularly in carriers of the HLA-B*5801 allele.

Mechanism of Action

Allopurinol and its active metabolite oxypurinol (alloxanthine) inhibit xanthine oxidase (and, to a lesser extent, xanthine dehydrogenase), the enzyme that catalyzes the final two steps of purine catabolism: the conversion of hypoxanthine to xanthine and of xanthine to uric acid. By blocking uric acid formation, allopurinol lowers serum and urinary urate concentrations, allowing dissolution of monosodium urate crystal deposits and preventing new crystal formation. Oxypurinol binds tightly to the reduced molybdenum center of xanthine oxidase, producing prolonged enzyme inhibition despite allopurinol's short plasma half-life.

Indications

• Management of chronic hyperuricemia in patients with gout, including those with tophaceous disease or urate nephropathy.
• Prevention of recurrent calcium oxalate kidney stones in patients with hyperuricosuria.
• Prophylaxis and treatment of hyperuricemia associated with chemotherapy for hematologic malignancies (tumor lysis syndrome).
• Adjunctive therapy in patients receiving cytotoxic chemotherapy who are at risk for uric acid nephropathy.
• Off-label/established uses: Lesch-Nyhan syndrome (uricosuric adjunct), certain cases of recurrent uric acid nephrolithiasis, and prevention of cisplatin-associated nephrotoxicity (less well established).

Dosage and Administration

Adults (oral):

• Gout/hyperuricemia: Start 100 mg once daily; increase by 100 mg every 2–4 weeks based on serum urate target (typically <6 mg/dL). Usual maintenance: 200–600 mg/day; maximum 800 mg/day. Doses >300 mg/day are usually divided.
• Tumor lysis syndrome prophylaxis: 200–400 mg/m²/day (often capped at 600–800 mg/day) starting 2–3 days before chemotherapy and continuing for 3–7 days after, with vigorous hydration.
• Renal impairment (adults): Reduce dose; a common practical scheme is ≤100 mg/day for CrCl <10 mL/min, 100 mg/day for CrCl 10–20 mL/min, and 200 mg/day for CrCl 20–40 mL/min (per FDA labeling and standard references). Titrate cautiously.
• Hepatic impairment: No fixed adjustment; use with caution and monitor.

Special populations:

• Pediatric: 10 mg/kg/day (max 400 mg/day) divided every 6–8 hours for tumor lysis syndrome; safety and efficacy for other pediatric indications are less well established.
• Geriatric: Use the lowest effective dose; renal function should guide dosing.
• Pregnancy/Lactation: Pregnancy Category C (US FDA labeling); use only if clearly needed. Allopurinol is excreted in breast milk; caution is advised.

Pharmacokinetics

• Absorption: Rapidly absorbed orally; bioavailability ~50–60% (reduced by food but not clinically meaningful).
• Distribution: Widely distributed; crosses into breast milk; not appreciably protein bound.
• Metabolism: Converted by aldehyde oxidase and xanthine oxidase to the active metabolite oxypurinol. Not significantly metabolized by CYP450 enzymes.
• Elimination: Allopurinol half-life ~1–2 hours; oxypurinol half-life ~18–30 hours (longer in renal impairment). Both are renally excreted; oxypurinol undergoes tubular reabsorption.
• Onset/duration: Urate-lowering effect is delayed (1–2 weeks) because existing urate pools must be mobilized.

Contraindications

• Known hypersensitivity to allopurinol or any component of the formulation.
• A history of severe cutaneous reaction (e.g., Stevens-Johnson syndrome, toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms [DRESS]) to allopurinol is an absolute contraindication to rechallenge.

Warnings and Precautions

• Severe cutaneous adverse reactions (SCARs): Allopurinol can cause Stevens-Johnson syndrome, toxic epidermal necrolysis, and DRESS, particularly within the first weeks of therapy. Risk is markedly increased in carriers of the HLA-B*5801 allele (notably Han Chinese, Thai, and Korean populations); guidelines recommend genotype screening in these groups before initiation.
• Hepatotoxicity: Transaminase elevations and rare hepatic failure have been reported; baseline and periodic liver function testing is prudent.
• Bone marrow suppression: Leukopenia, thrombocytopenia, and aplastic anemia have been reported, especially in patients with renal impairment or concurrent cytotoxic therapy.
• Gout flares on initiation: Urate-lowering therapy can precipitate acute gout flares during the first months; prophylactic colchicine or NSAIDs are commonly used.
• Renal impairment: Increases risk of toxicity; dose reduction is required.
• Cardiovascular caution: Some post-marketing data have raised questions about cardiovascular risk with xanthine oxidase inhibitors; current guidelines consider allopurinol acceptable, with febuxostat reserved for specific scenarios.

Drug Interactions

• Azathioprine / 6-mercaptopurine: Allopurinol inhibits xanthine oxidase-mediated metabolism of these agents, increasing their toxicity (myelosuppression). Reduce azathioprine/6-MP dose to ~25–33% of usual when given with allopurinol.
• Warfarin: Possible potentiation of anticoagulant effect; monitor INR.
• Diuretics (especially thiazides): May increase serum urate and reduce allopurinol efficacy; renal function may also decline.
• Amoxicillin / ampicillin: Increased risk of rash.
• ACE inhibitors / ARBs: Concomitant use may increase hypersensitivity risk; monitor renal function and for rash.
• Cyclophosphamide, doxorubicin, bleomycin: Possible increased toxicity; monitor closely.
• Didanosine: Increased didanosine exposure; avoid combination if possible.

Adverse Effects

• Common: Rash (maculopapular), pruritus, gastrointestinal upset (nausea, vomiting, diarrhea), elevated liver enzymes.
• Serious/rare: Stevens-Johnson syndrome, toxic epidermal necrolysis, DRESS, severe hepatotoxicity, bone marrow suppression, interstitial nephritis, vasculitis.
• Frequency note: Most cutaneous reactions occur within the first 2–3 months of therapy; immediate discontinuation is required for any new rash.

Monitoring Parameters

• Serum uric acid: Target <6 mg/dL (or <5 mg/dL in tophaceous disease) every 2–5 weeks during titration.
• Renal function: Serum creatinine and/or estimated GFR at baseline and periodically.
• Liver function tests: Baseline and as clinically indicated.
• Complete blood count: Baseline and during therapy, especially in renal impairment or with concomitant myelosuppressive drugs.
• Clinical: Surveillance for rash, gout flares, and signs of hypersensitivity.

Patient Education

• Take exactly as prescribed; do not stop during a gout flare unless directed.
• Drink adequate fluids (≥2 L/day) to help prevent kidney stones.
• Report any new rash, fever, mouth or eye sores, swelling, or unusual bruising immediately; these may signal a serious reaction.
• Avoid sudden changes in diet or alcohol intake without discussing with your clinician.
• If also taking azathioprine or 6-mercaptopurine, remind your prescriber; doses of those medications must be adjusted.
• Use prophylactic anti-inflammatory therapy (e.g., colchicine) as directed during the first months to reduce flare risk.

Clinical Pearls

1. "Start low, go slow": Begin at 100 mg/day and titrate every 2–4 weeks to reach the serum urate target—this reduces flare risk and improves tolerability.
2. Screen for HLA-B*5801 in high-risk populations (Han Chinese, Thai, Korean) before initiation to mitigate SCAR risk.
3. Allopurinol is contraindicated with full-dose azathioprine/6-MP; reduce those agents to ~25–33% of usual or avoid.
4. A rising serum creatinine or new rash in a patient on allopurinol should prompt immediate evaluation—renal impairment amplifies oxypurinol accumulation and hypersensitivity risk.
5. Prophylactic colchicine or an NSAID for 3–6 months during initiation reduces early gout flares and improves adherence.
6. Allopurinol lowers urate production but does not treat acute gout attacks; it is a long-term disease-modifying therapy.

References

1. U.S. Food and Drug Administration. Zyloprim (allopurinol) prescribing information. Prometheus Laboratories / Casper Pharma.
2. FitzGerald JD, Dalbeth N, Mikuls T, et al. 2020 American College of Rheumatology Guideline for the Management of Gout. Arthritis Care & Research. 2020;72(6):744–760.
3. Goodman & Gilman's The Pharmacological Basis of Therapeutics, 14th edition. McGraw-Hill.
4. Lexicomp Online, Allopurinol monograph. Wolters Kluwer Clinical Drug Information.
5. Coiffer B, Altman A, Pui CH, et al. Guidelines for the management of pediatric and adult tumor lysis syndrome. Journal of Clinical Oncology. 2008;26(16):2767–2778.
6. World Health Organization. WHO Model List of Essential Medicines, 23rd edition. 2023.
7. KDIGO Clinical Practice Guideline for Acute Kidney Injury. Kidney International Supplements. 2012;2(1).
8. Hershfield MS, Callaghan JT, Tassaneeyakul W, et al. Allopurinol hypersensitivity: HLA-B*5801 and beyond. Clinical Pharmacology & Therapeutics. 2012;91(4):571–576.
9. American Society of Health-System Pharmacists. ASHP Guidelines on the Prevention and Treatment of Tumor Lysis Syndrome. American Journal of Health-System Pharmacy.
10. UpToDate. Allopurinol: Drug information. Wolters Kluwer.