Transcript Hydroxyurea - Thalassemia Dubai

Hydroxyurea
Sahar Habibollah
18/09/08
Contents
Chemical formula
 Mechanism of Action
 Pharmacokinetics
 Indications
 Contraindications
 Side effects
 Therapeutic considerations

Hydroxyurea
Hydroxycarbamide
Cytotoxic drugAntimetabollite
White crystalline powder
 Chemical formula

Monohydroxyl-substituted urea
(hydroxycarbamate)
Pharmacokinetics
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Method of administration – Oral(500mg capsule)
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Readily absorbed
Peak plasma levels reached in 1 - 4 hours
Half life 3-4 hours
Peak in 1 - 4 hours
60% metabolism unknown
Intestinal bacteria Urease
Acetohydroxamic Acid
Mechanism of Action
Hydroxyurea causes an immediate
inhibition of DNA synthesis by
acting as a ribonucleotide
reductase inhibitor
Cell cycle
A protein complex that converts
ribonucleotide diphosphates (NDPs) – ADP,
CDP to 2'-deoxyribonucleotide diphosphates
(dNDPs) – dADP, dCDP
It is crucial for DNA synthesis.
dNDPs
NDPs
NADPH
Cell cycle
Mechanism of action

Increases Fetal Hemoglobin levels
Hydroxyurea increases Nitric Oxide levels, causing rise in
cGMP, and the activation of synthesis of fetal
hemoglobin
Indications
Chronic myeloid leukaemia
 Myeloproliferative diseases

– Polycythemia vera
– Essential thrombocytosis
Moderate to severe psoriasis
 Advanced cervical cancer with radiotherapy

Hemoglobinopathies
Sickle
cell disease
β-Thalassemia Intermedia
BTM controversial
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.
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.

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
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.
Dosage
20-30 mg/kg daily*
 80 mg/kg every third day

80
70
60
50
40
30
20
10
0
64.6
68.4
66.3
65.5
64.5
67.3
Hb
MCV
12
8
8.9
20
0
/6
/
/1
1
/2
0
07
/0
7
/0
2
/0
6
/1
2
13
Nov 2006 Hydroxyurea
9.1
7.6
11
7.8
/0
6
/1
1
14
/1
0
/0
6
7.4
22
7.6
19
Value
Hb and MCV Trend
Side Effects
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Drowsiness
Nausea * and vomiting
Diarrhea, constipation
Mucositis, stomatitis
Anorexia
Myelosuppression *
Alopecia
Skin reactions * (rash, darkening, peeling,
cancer)
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
Further precautions
Co-administration with didanosine has
caused fatal and nonfatal pancreatitis;
hepatic failure
 Coadministration with other
myelosuppressive agents may increase
toxicity

CRM Guidelines on handling
cytotoxic drugs
Wear protective eyewear, clothing, gloves
 Pregnant staff should not handle the drug
 Care in disposal of waste material

Contra-indications
Bone marrow depression*
 Pregnancy category D
 Breastfeeding
 Previous hypersensitivity

Before starting Hydroxyurea
Is it indicated?
 Inform patients of drug hazards
 Baseline investigations
 Pregnancy test and contraception advice

Follow Up
FBC
 Urea & electrolytes
 Liver enzymes (ALT; AST)
 Renal function

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

Thank You for your
attention
Any Questions?