XROMI Oral solution Ref.[28014] Active ingredients: Hydroxycarbamide

Hydroxycarbamide treatment should be supervised by a physician or other healthcare professionals experienced in the management of patients with Sickle Cell Disease.

Posology

The posology should be based on the patient’s body weight (kg). The usual starting dose of hydroxycarbamide is 15 mg/kg/day and usual maintenance dose is between 20-25 mg/kg/day. The maximum dose is 35 mg/kg/day. Full blood cell count with white cell differential and reticulocyte count should be monitored once a month for the first 2 months following treatment initiation.

A target absolute neutrophil count 1,500–4,000/μL should be aimed for, whilst maintaining platelet count >80,000/μL. If neutropenia or thrombocytopenia occurs, hydroxycarbamide dosing should be temporarily withheld and full blood cell count with white cell differential should be monitored weekly. When blood counts have recovered, hydroxycarbamide should be reinstated at a dose 5 mg/kg/day lower than the dose given before onset of cytopenias.

If dose escalation is warranted based on clinical and laboratory findings, the following steps should be taken:

• Dose to be increased by 5 mg/kg/day increments every 8 weeks
• Increases in dose to be continued until mild myelosuppression (absolute neutrophil count 1,500/μL to 4,000/μL) is achieved, up to a maximum of 35 mg/kg/day.
• Full blood cell count with white cell differential and reticulocyte count to be monitored at least every 4 weeks when adjusting dosage.

Once a maximum tolerated dose is established, laboratory safety monitoring should include full blood cell count with white cell differential, reticulocyte count, and platelet count every 2-3 months.

Red blood cell (RBC), mean cell volume (MCV), and foetal haemoglobin (HbF) levels should be monitored for evidence of consistent or progressive laboratory response. However, a lack of increase in MCV, HbF, or both, is not an indication to discontinue therapy if the patient responds clinically (e.g. decreased incidence of pain or hospitalisation).

A clinical response to treatment with hydroxycarbamide may take 3-6 months and therefore, a 6-month trial on the maximum tolerated dose is required prior to considering discontinuation due to treatment failure (whether due to lack of adherence or failure to respond to therapy).

Special populations

Elderly

Elderly patients may be more sensitive to the myelosuppressive effects of hydroxycarbamide, and may require a lower dosage regimen.

Renal impairment

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 (see section 4.4). Hydroxycarbamide must not be administered to patients with severe renal impairment (CrCl <30 ml/min) (see sections 4.3, 4.4, and 5.2).

Hepatic impairment

There are no data that support specific dose adjustments in patients with hepatic impairment. Close monitoring of blood parameters is advised in these patients. Due to safety considerations, hydroxycarbamide is contraindicated in patients with severe hepatic impairment (see sections 4.3 and 4.4).

Children less than 2 years of age

The safety and efficacy of hydroxycarbamide in children from birth up to 2 years have not yet been established. No data are available.

Method of administration

Xromi is for oral use.

Two dosing syringes (a red syringe graduated to 3 ml and a white syringe graduated to 12 ml) are provided for accurate measurement of the prescribed dose of the oral solution. It is recommended that the healthcare professional advises the patient or carer which syringe to use to ensure that the correct volume is administered.

The smaller 3 ml syringe (red), marked from 0.5 ml to 3 ml, is for measuring doses of less than or equal to 3 ml. This syringe should be recommended for doses less than or equal to 3 ml (each graduation of 0.1 ml contains 10 mg of hydroxycarbamide). The larger 12 ml syringe (white), marked 1 ml to 12 ml, is for measuring doses of more than 3 ml. This syringe should be recommended for doses greater than 3 ml (each graduation of 0.25 ml contains 25 mg of hydroxycarbamide).

In adults without swallowing difficulties, solid oral formulations may be more appropriate and convenient.

Xromi may be taken with or after meals at any time of the day but patients should standardise the method of administration and time of day.

To assist accurate and consistent dose delivery to the stomach water should be taken after each dose of Xromi.

Symptoms

Acute mucocutaneous toxicity has been reported in patients receiving hydroxycarbamide at a dosage several times greater than that recommended. Soreness, violet erythema, oedema on palms and foot soles followed by scaling of hands and feet, intense generalised hyperpigmentation of skin, and severe acute stomatitis were observed.

In patients with sickle cell disease, severe bone marrow depression was reported in isolated cases of hydroxycarbamide overdose between 2 and 10 times the prescribed dose (up to 8.57 times of the maximum recommended dose of 35 mg/kg/day). It is recommended that blood counts are monitored for several weeks after overdose since recovery may be delayed.

Treatment

Immediate treatment consists of gastric lavage, followed by supportive therapy for the cardiorespiratory systems if required. Patients should be monitored for vital signs, blood and urine chemistry, renal and hepatic function and full blood counts for at least 3 weeks. Longer periods of monitoring may be required. If necessary, blood should be transfused.

2 years.

After first opening: 12 weeks.

Store in a refrigerator (2°C–8°C).

Amber type III glass bottle with tamper evident child-resistant closure (HDPE with expanded polyethylene liner) containing 150 ml of oral solution.

Each pack contains one bottle, an HDPE bottle adaptor and 2 polyethylene dosing syringes (a red syringe graduated to 3 ml and a white syringe graduated to 12 ml).

Safe handling

Anyone handling hydroxycarbamide should wash their hands before and after administering a dose. To decrease the risk of exposure, parents and care givers should wear disposable gloves when handling hydroxycarbamide. To minimise air bubbles, the bottle should not be shaken prior to dosing.

Hydroxycarbamide contact with skin or mucous membrane must be avoided. If hydroxycarbamide comes into contact with skin or mucosa, it should be washed immediately and thoroughly with soap and water. Spillages must be wiped immediately.

Women who are pregnant, planning to be or breast-feeding should not handle hydroxycarbamide.

Parents/care givers and patients should be advised to keep hydroxycarbamide out of the sight and reach of children. Accidental ingestion can be lethal for children.

Keep the bottle tightly closed to protect the integrity of the product and minimise the risk of accidental spillage.

Syringes should be rinsed and washed with cold or warm water and dried completely before the next use. Store syringes in a hygienic place with the medicine.

Disposal

Hydroxycarbamide is cytotoxic. Any unused product or waste material should be disposed of in accordance with local requirements.