Hydroxycarbamide

Detailed information

EMA’s scientific discussion Siklos

Scientific discussion for Siklos (hydroxycarbamide) from 10/08/2007.

"The environmental risk assessment (ERA) has been calculated, and the PEC value is less than 0.01ug/l. Siklos is unlikely to represent a risk for the environment following its prescribed usage. No phase II environmental effect analysis has been submitted for this marketing authorization." No data have been presented.

Comment

Hydroxycarbamide has only undergone a phase I study in accordance with regulatory requirements for environmental risk assessments (Guideline on the environmental risk assessment of medicinal products for human use, EMEA/CHMP/SWP/4447/00 Rev. 1- Corr.) A phase I study includes data on bioaccumulation and an estimation of the environmental concentration of hydroxycarbamide (PEC_{Surface water}). If the specified threshold values are not exceeded, the company is not required to conduct a Phase II study, which includes data on toxicity, persistence, and risk assessment based on PEC/PNEC.

Assessment report Xromi 2024

Assessment report for Xromi (hydroxicarbamide), type II variation, 22 February 2024, EMA/153487/2024.

No new non-clinical data were submitted apart from the required Environmental Risk Assessment (ERA), which was considered acceptable by CHMP. Following initial approval of Xromi 100 mg/ml oral solution, the applicant was requested to perform an OECD 309 study within 18 months and a full Phase II ERA including an OECD 308 study within 3 years.

Subsequent submissions included OECD 309, OECD 301B, and OECD 308 studies. The OECD 301B study showed that hydroxycarbamide is not readily biodegradable (2.7 % degradation in 28 days), while OECD 308 demonstrated high ultimate biodegradation (67–76.6 %). However, since the substance failed the OECD 301 criteria, CHMP concluded that a full Phase II ERA could not be waived. Additionally, 11 % of the substance remained in sediment, triggering the need for further sediment toxicity testing.

An updated PEC calculation using refined prevalence data (Fpen = 0.0003) and a maximum daily dose of 2100 mg resulted in a PEC_SURFACEWATER of 0.315 µg/L, exceeding the 0.01 µg/L threshold. Consequently, the applicant committed to completing the full Phase II ERA and submitting results by Q4 2026.

Although hydroxycarbamide is not considered PBT or vPvB and is rapidly degraded in the environment, further assessment is required under current guidelines.

Assessment report Xromi 2019

Assessment report for Xromi 2019, 26 April 2019, EMA/CHMP/170631/2019.

Hazard

Persistence: No data.

Bioaccumulation: Log K_ow = -1.27.

Toxicity: No data.

Risk

The applicant suggested that the PEC_SURFACEWATER for Hydroxycarbamide Nova Laboratories 100 mg/ml oral solution is below the action limit of 0.01 µg/L and that the substance is not PBT, as log K_ow is below 4.5.

However, CHMP requested clarification on the DOSEai calculation, which must be based on the maximum recommended dose for adults (35 mg/kg/day), not children, since the product is indicated for both age groups.

The Fpen value, initially based on use in children aged 2–9, was also not accepted. CHMP stated it should reflect the EU prevalence of sickle cell disease (1.5 in 10,000).

Based on revised calculations, the PEC_SURFACEWATER exceeds 0.01 µg/L, and a Phase II environmental risk assessment is therefore required.

The applicant should conduct an OECD 309 test on biodegradability and submit the results within 18 months. In addition, a full Phase II study, including an OECD 308 test, should be conducted with results to be submitted within 3 years following the approval of Xromi 100 mg/ml oral solution.