Chemical formula: CH₄N₂O₂ Molecular mass: 76.055 g/mol PubChem compound: 3657
Hydroxycarbamide interacts in the following cases:
Concomitant use of hydroxycarbamide with a live virus vaccine may potentiate the replication of the vaccine virus and/or may increase some of the adverse reactions of the vaccine virus because normal defence mechanisms may be suppressed by hydroxycarbamide. Vaccination with a live vaccine in a patient taking hydroxycarbamide may result in severe infection. The patient’s antibody response to vaccines may be decreased. The use of live vaccines should be avoided during treatment and for at least six months after treatment has finished and individual specialist advice sought.
Since renal excretion is a pathway of elimination, consideration should be given to decreasing the dosage of hydroxycarbamide in renally impaired patients. In patients with a creatinine clearance (CrCl) ≤60 ml/min the initial hydroxycarbamide dose should be decreased by 50%. Close monitoring of blood parameters is advised in these patients.
Reduce the dose of hydroxycarbamide by 50% in patients with measured creatinine clearance of less than 60 mL/min.
| Creatinine Clearance (mL/min) | Recommended hydroxycarbamide Initial Dose (mg/kg once daily) |
|---|---|
| ≥60 | 15 |
| <60 | 7.5 |
Close monitoring of hematologic parameters is advised in these patients.
Reduce the dose of hydroxycarbamide by 50% in patients with measured creatinine clearance of less than 60 mL/min or with end-stage renal disease (ESRD).
| Creatinine Clearance (mL/min) | Recommended hydroxycarbamide Initial Dose (mg/kg once daily) |
|---|---|
| <60 or ESRD* | 7.5 |
* On dialysis days, administer hydroxycarbamide to patients following hemodialysis.
Close monitoring of hematologic parameters is advised in these patients.
There are no data that support specific dose adjustments in patients with hepatic impairment. Close monitoring of blood parameters is advised in these patients.
Fertility in males might be affected by treatment. Very common reversible oligo- and azoospermia have been observed in man, although these disorders are also associated with the underlying disease. Impaired fertility has been observed in male rats.
Male patients should be informed by their healthcare professionals about the possibility of sperm conservation (cryopreservation) before the start of therapy.
Patients who have received irradiation therapy in the past may have an exacerbation of post irradiation erythema when hydroxycarbamide is given.
In patients with leg ulcers, hydroxycarbamide should be used with caution. Leg ulcers are a common complication of Sickle Cell Disease, but have also been reported in patients treated with hydroxycarbamide.
Studies in animals have shown reproductive toxicity. Patients on hydroxycarbamide should be made aware of the risks to the foetus.
There is limited amount of data from the use of hydroxycarbamide in pregnant women.
Hydroxycarbamide can cause foetal harm when administered to a pregnant woman. Therefore it must not be administered to patients who are pregnant.
Patients on hydroxycarbamide wishing to conceive should stop treatment 3 to 6 months before pregnancy if possible.
The patient should be instructed to immediately contact a doctor in case of suspected pregnancy.
Hydroxycarbamide is excreted in human breast milk. Because of the potential for serious adverse reactions in breast-feeding infants, breast-feeding must be discontinued while taking hydroxycarbamide.
Medicinal products which affect DNA synthesis, such as hydroxycarbamide, may be potent mutagenic active substances. This possibility should be carefully considered before administering this medicinal product to male or female patients who may contemplate conception.
Both male and female patients should be advised to use contraceptive measures before, during and after treatment with hydroxycarbamide. The recommended duration of contraception in male and female patients following the end of treatment with hydroxycarbamide, should be 3 and 6 months, respectively.
Fertility in males might be affected by treatment. Very common reversible oligo- and azoospermia have been observed in man, although these disorders are also associated with the underlying disease. Impaired fertility has been observed in male rats.
Male patients should be informed by their healthcare professionals about the possibility of sperm conservation (cryopreservation) before the start of therapy.
Hydroxycarbamide has minor influence on the ability to drive and use machines. Patients should be advised not to drive or operate machines, if dizziness is experienced while taking hydroxycarbamide.
The safety profile of hydroxycarbamide in sickle cell disease was established from clinical studies and confirmed with long-term cohort studies including up to 1935 adults and children of more than 9 months of age.
Bone-marrow suppression is the major toxic effect of hydroxycarbamide and is dose related. At lower doses, mild, transient and reversible cytopenias are commonly reported in Sickle Cell Disease patients which is expected based on the pharmacology of hydroxycarbamide.
Hydroxycarbamide affects spermatogenesis, and hence oligospermia and azoospermia are very commonly reported.
Other commonly reported adverse effects also include nausea, constipation, headache, and dizziness. Adverse reactions affecting the skin and subcutaneous tissue such as darkening of the skin nail beds, dry skin, skin ulcers, and alopecia tend to occur following several years of long-term daily maintenance therapy. Rarely leg ulcers and very rarely systemic lupus erythematosus have been reported.
There is also a serious risk of leukaemia and in the elderly, skin cancer, although the frequency is not known.
The list is presented by system organ class, MedDRA preferred term, and frequency using the following frequency categories: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1 000 to <1/100), rare (≥1/10 000 to <1/1 000), very rare (<1/10 000), and not known (cannot be estimated from the available data).
Adverse reactions:
| System organ class | Frequency | Adverse reaction |
|---|---|---|
| Neoplasms benign, malignant and unspecified (including cysts and polyps) | Not known | Leukaemia, skin cancers (in elderly patients) |
| Blood and lymphatic system disorders | Very common | Bone marrow depression including neutropenia (<1,500/μL), reticulocytopenia (<80,000/μL), macrocytosis |
| Common | Thrombocytopenia (<80,000/μL), anaemia (haemoglobin <4.5 g/dl) | |
| Metabolism and nutrition disorders | Not known | Weight gain, vitamin D |
| Nervous system disorders | Common | Headache, dizziness |
| Vascular disorders | Not known | Bleeding |
| Gastrointestinal disorders | Common | Nausea, constipation |
| Uncommon | Stomatitis, diarrhoea, vomiting | |
| Not known | Gastrointestinal disturbances, gastrointestinal ulcer, severe hypomagnesaemia | |
| Hepatobiliary disorders | Uncommon | Elevated liver enzymes, Hepatotoxicity |
| Skin and subcutaneous tissue disorders | Common | Skin ulcer, oral, nail and skin hyperpigmentation, dry skin, alopecia |
| Uncommon | Rash | |
| Rare | Leg ulcers | |
| Very Rare | Systemic and cutaneous lupus erythematosus | |
| Reproductive system and breast disorders | Very common | Oligospermia, azoospermia |
| Not known | Amenorrhea | |
| General disorders and administration site conditions | Not known | Fever |
In the event of bone marrow suppression, haematological recovery usually occurs within two weeks of withdrawal of hydroxycarbamide. Gradual dose titration is recommended to avoid more severe bone marrow suppressions.
The macrocytosis caused by hydroxycarbamide is not vitamin B12 or folic acid dependent. The anaemia commonly observed has mainly been due to an infection with Parvovirus, splenic or hepatic sequestration, renal impairment.
Weight gain observed during treatment with hydroxycarbamide may be an effect of improved general conditions.
Oligospermia and azoospermia caused by hydroxycarbamide are in general reversible, but have to be taken into account when fatherhood is desired. These disorders are also associated with the underlying disease.
Frequency, type and severity of adverse reactions in children are expected to be similar to adults. Data from an observational study (ESCORT-HU) of hydroxycarbamide in a large set of patients (n=1 906) with sickle cell disease showed that patients aged 2 to 10 years were at higher risk for neutropenia and at lower risk for dry skin, alopecia, headache and anaemia. Patients aged 10 to 18 years were at lower risk for dry skin, skin ulcer, alopecia, weight increase and anaemia compared to adults.
Safety data in children under the age of 2 years is limited. The BABY HUG trial, a phase III double-blinded, multi-centre, randomised, controlled study in infants aged 9–18 months, compared fixed moderate dose hydroxycarbamide at 20 mg/kg/day with placebo (Wang et al. 2011). Mild-to-moderate neutropenia (absolute neutrophil count [ANC] 500–1249/μL), occurred more frequently in the hydroxycarbamide group; 107 times in 45 participants versus 34 times in 18 participants in the placebo group. Recurrent or persistent neutropenia resulted in nine long-term dose decreases (to 17·5 mg/kg per day) in the hydroxycarbamide group and five in the placebo group (p=0·20). Infants treated with hydroxycarbamide did not have significant differences from those treated with placebo in rates of severe neutropenia (ANC <500/μL), thrombocytopenia (platelet count <80,000/ μL), anaemia (haemoglobin <7 g/dL), reticulocytopenia (absolute reticulocyte count <80,000/μL), or abnormal tests of liver function (alanine aminotransferase >150 units/L or bilirubin >10 mg/dL).
The safety of hydroxycarbamide has been assessed in 32 children aged 9 months – 18 years with sickle cell anaemia in a single-arm, open-label, prospective, multi-center, pharmacokinetic, safety and efficacy study (HUPK study). The total number of hydroxycarbamide-related adverse events was 28 (8.3%) in 9 (28%) patients. Haematological toxicity dominated with 21 reports (75%) of cytopenias and then skin and subcutaneous disorders (5 reports; 18%). The 9 months to 2 year age group had 19 related events (29.2%), a higher proportion compared to the 2 to 6 year group (5 events; 3.4%) and 6 to 16 year group (4 events; 3.2%). The reported cytopenias were typically isolated, transient and benign.
The long term safety of hydroxycarbamide initiated in children less than 2 years remains to be established.
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