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hydroxyurea; hydroxycarbamide (Hydrea, Droxia)

Indications: 1) sickle cell anemia a) increases hemoglobin F b) reduces frequency of acute chest syndrome, painful crises, hospitalizations, & blood transfusions [9] c) underutilized [9] 2) polycythemia vera 3) essential thrombocytosis 4) psoriasis 5) AIDS 6) malignant neoplasms a) melanoma b) granulocytic leukemia (CML) c) ovarian carcinomas d) trophoblastic neoplasm e) squamous cell carcinoma of the head & neck -> used in association with radiation therapy Contraindications: 1) severe anemia 2) WBC < 2500/mm3 3) platelets < 100,000/mm3 4) pregnancy - stop at least 3 months prior to conception [5] Dosage: 1) solid tumor: 80 mg/kg PO as single dose or every 3rd day 2) CML: 30-30 mg/kg daily 3) sickle cell & polycythemia: 500 mg PO QD - 15-20 mg/kg daily, increase PRN Capsules: 500 mg. Pharmacokinetics: 1) well abosorbed orally 2) 50% metabolized by liver to inactive metabolites 3) 50% eliminated in the urine unchanged 4) 1/2life 2-4 hours Adverse effects: 1) common (> 10%) a) drowsiness b) myelosuppression - dose-limiting toxicity - onset 4-5 days (WBC), RBC & platelets 7 days - nadir 10 days - recovery 21 days, faster for WBC c) gastrointestinal - nausea/vomiting - diarrhea/constipation - mucositis - ulceration of GI tract - stomatitis 2) less common (1-10%) - skin changes: hyperpigmentation, erythema of hands & face, maculopapular rash, dry skin - dermatomyositis-like eruption [5] - alopecia - increased creatinine & BUN - abnormal LFTs - carcinogenic potential - cutaneous squamous cell carcinoma [5] 3) uncommon (< 1%) - neurotoxicity, renal tubular impairment, hyperuricemia, dizziness, disorientation, hallucination, seizures, headache, dysuria 4) other - vasculitis, resulting in ulcerations & gangrene [4] - decreased sperm count - macrocytosis & macrocytic anemia [5] Drug interactions: 1) 5-fluorouracil 2) interferon therapy may increase risk of vasculitis [4] Test interactions: increases serum K+ Mechanism of action: 1) antimetabolite 2) inhibits the incorporation of thymidine into DNA 3) directly damages DNA 4) S-phase inhibitor 5) urease inhibitor 6) induces fetal hemoglobin synthesis 7) inhibits ribonucleotide reductase Mechanism of drug resistance: -> alteration in target enzyme ribonucleotide reductase

Related

ribonucleotide reductase

General

antimetabolite enzyme inhibitor thrombocytosis agent

Properties

INHIBITS: ribonucleotide reductase MISC-INFO: elimination route KIDNEY LIVER 1/2life 2-4 HOURS

Database Correlations

PUBCHEM cid=3657

References

  1. Kaiser Permanente Northern California Regional Drug Formulary, 1998
  2. Drug Information & Medication Formulary, Veterans Affairs, Central California Health Care System, 1st ed., Ravnan et al eds, 1998
  3. Harrison's Principles of Internal Medicine, 14th ed. Fauci et al (eds), McGraw-Hill Inc. NY, 1998, pg 529, 533
  4. FDA Medwatch http://www.fda.gov/medwatch/safety/2006/safety06.htm#Hydrea
  5. Medical Knowledge Self Assessment Program (MKSAP) 16, 17. American College of Physicians, Philadelphia 2012, 2015
  6. Burns ER, Reed LJ, Wenz B. Volumetric erythrocyte macrocytosis induced by hydroxyurea. Am J Clin Pathol. 1986 Mar;85(3):337-41. PMID: 3790210
  7. Platt OS. Hydroxyurea for the treatment of sickle cell anemia. N Engl J Med. 2008 Mar 27;358(13):1362-9. PMID: 18367739
  8. Voskaridou E, Christoulas D, Bilalis A et al The effect of prolonged administration of hydroxyurea on morbidity and mortality in adult patients with sickle cell syndromes: results of a 17-year, single-center trial (LaSHS). Blood. 2010 Mar 25;115(12):2354-63. PMID: 19903897
  9. Stettler N et al. Proportion of adults with sickle cell anemia and pain crises receiving hydroxyurea. JAMA 2015 Apr 28; 313:1671 PMID: 25919532
  10. Nevitt SJ et al Hydroxyurea (hydroxycarbamide) for sickle cell disease. Cochrane Database Syst Rev 2017 Apr 20; 4:CD002202 PMID: 28426137 PMCID: PMC6478259 Free PMC article