Hydroxyurea

1. Hydroxyurea Sahar Habibollah 18/09/08

2. Contents • Chemical formula • Mechanism of Action • Pharmacokinetics • Indications • Contraindications • Side effects • Therapeutic considerations

3. Hydroxyurea Cytotoxic drug- Antimetabollite Hydroxycarbamide

4. White crystalline powder • Chemical formula Monohydroxyl-substituted urea (hydroxycarbamate)

5. Pharmacokinetics • Method of administration – Oral(500mg capsule) • Readily absorbed • Peak plasma levels reached in 1 - 4 hours

6. Half life 3-4 hours Peak in 1 - 4 hours 60% metabolism unknown Intestinal bacteria Urease Acetohydroxamic Acid

7. Mechanism of Action Hydroxyurea causes an immediate inhibition of DNA synthesis by acting as a ribonucleotide reductase inhibitor

8. Cell cycle

9. A protein complex that converts ribonucleotidediphosphates (NDPs) – ADP, CDP to 2'-deoxyribonucleotidediphosphates (dNDPs) – dADP, dCDP It is crucial for DNA synthesis. dNDPs NDPs NADPH

10. Cell cycle

11. Mechanism of action • Increases Fetal Hemoglobin levels Hydroxyurea increases Nitric Oxide levels, causing rise in cGMP, and the activation of synthesis of fetal hemoglobin

13. Indications • Chronic myeloid leukaemia • Myeloproliferative diseases • Polycythemia vera • Essential thrombocytosis • Moderate to severe psoriasis • Advanced cervical cancer with radiotherapy

14. Hemoglobinopathies • Sickle cell disease • β-Thalassemia Intermedia • BTM controversial

15. Reduces the frequency of crises ; need for blood transfusions; May increase survival And elevates Hb levels Charache S, Terrin ML, Moore RD, et al. Effects of hydroxyurea on the frequency of painful crises in sickle cell anemia. N Engl J Med. 1995;332: 1317-1322. Evidence for efficacy of hydroxyurea in children with sickle cell disease is encouraging but is not as strong as in adults. The beneficial effects of hydroxyurea do not become manifest for several months, and its use must be carefully monitored. The long-term safety of hydroxyurea in patients with sickle cell anemia is uncertain.

16. Candidates for this treatment have frequent painful crises (6 or more per year), severe unremitting chronic pain that cannot be controlled by conservative measures, acute chest syndrome, and a history of stroke or a high risk for stroke.

17. Randomized trial showed that after 2 years of HU, the Hb level was higher in hydroxyurea recipients (difference, 6 g/L) as was fetal hemoglobin levels (absolute difference, 3.2%) The median number of painful crises was 44% lower. Zeng YT, Huang SZ, Ren ZR, et al. Hydroxyurea therapy in β-thalassaemia intermedia: improvement in haematological parameters due to enhanced β-globin synthesis. Br J Haematol. 1995; 90:557-563. HK J Paediatr (new series) 2006;11:20-21 Hydroxyurea Treatment in Beta-Thalassaemia Intermedia

18. Concluded that HU can eliminate transfusional needs in children with beta thalassemia major BLOOD, 15 AUGUST 2003 VOLUME 102, NUMBER 4 Reported a 12-year-old Iranian patient with homozygous β0 thalassemia who is transfusion-independent for the last 7 years since being treated with hydroxyurea (HU) and recombinant erythropoietin (rEPO)* Journal of Pediatric Hematology/Oncology, Vol. 24, No. 9, December 2002 Olivieri NF. Reactivation of fetal hemoglobin in patients with β-thalassemia. Semin Hematol. 1996;33:24-42. Arruda VR, Lima CSP, Saad STO, Costa FF. Successful use of hydroxyurea in β-thalassemia major. N Engl J Med. 1997;336:964.

19. Dosage • 20-30 mg/kg daily* • 80 mg/kg every third day

20. Nov 2006 Hydroxyurea

21. Side Effects • Drowsiness • Nausea * and vomiting • Diarrhea, constipation • Mucositis, stomatitis • Anorexia • Myelosuppression * • Alopecia • Skin reactions * (rash, darkening, peeling, cancer)

22. Precautions • Renal Insufficiency • Hepatic Insufficiency - There are no data that support specific guidance for dosage adjustment in patients with hepatic impairment. • Pediatric -No pharmacokinetic data are available in pediatric patients treated with Hydroxyurea • Hydroxyurea itself carries a leukemia risk, but large studies have shown that the risk is either absent or very small • Fertility concern - women less affected but can cause premature menopause • Drug Interactions -There are no data on concomitant use of Hydroxyurea with other drugs in humans

23. Further precautions • Co-administration with didanosine has caused fatal and nonfatal pancreatitis; hepatic failure • Coadministration with other myelosuppressive agents may increase toxicity

24. CRM Guidelines on handling cytotoxic drugs • Wear protective eyewear, clothing, gloves • Pregnant staff should not handle the drug • Care in disposal of waste material

25. Contra-indications • Bone marrow depression* • Pregnancy category D • Breastfeeding • Previous hypersensitivity

26. Before starting Hydroxyurea • Is it indicated? • Inform patients of drug hazards • Baseline investigations • Pregnancy test and contraception advice

27. Follow Up • FBC • Urea & electrolytes • Liver enzymes (ALT; AST) • Renal function

28. References • DOHMS Formulary 2007 • BNF September 2006 • www.drugs.com • www.cancer.gov • www.sickle.bwh.harvard.edu • www.ncbi.nlm.nih.gov • www.medscape.com

29. Thank You for your attention Any Questions?