4.1. Therapeutic indications

Xromi is indicated for the prevention of vaso-occlusive complications of Sickle Cell Disease in patients over 9 months of age.

4.2. Posology and method of administration

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 the 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 count1,500/ 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 9 months of age

The safety and efficacy of hydroxycarbamide in children from birth up to 9 months of age have not yet been established.

Method of administration

Xromi is for oral use.

Two dosing syringes (a 3 ml and a 10 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, 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 10 ml syringe, marked from 1 ml to 10 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.

4.3. Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Severe hepatic impairment (Child-Pugh classification C).

Severe renal impairment (CrCl < 30 ml/min).

Toxic ranges of myelosuppression as described in section 4.2.

Breast-feeding (see section 4.6).

Pregnancy (see section 4.6)

Concomitant anti-retroviral medicinal products for HIV disease (see sections 4.4 and 4.5)

4.4. Special warnings and precautions for use

Bone marrow suppression

The complete status of the blood, including bone marrow examination, if indicated, as well as kidney function and liver function should be determined prior to, and repeatedly during, treatment. If bone marrow function is depressed, treatment with hydroxycarbamide should not be initiated.

The full blood cell count with white cell differential, reticulate count, and platelet count should be monitored regularly (see section 4.2).

Hydroxycarbamide may produce bone marrow suppression; leukopenia is generally its first and most common manifestation. Thrombocytopenia and anaemia occur less often and are seldom seen without a preceding leukopenia. Bone marrow depression is more likely in patients who have previously received radiotherapy or cytotoxic cancer chemotherapeutic medicinal products; hydroxycarbamide should be used cautiously in such patients. The recovery from myelosuppression is rapid when hydroxycarbamide therapy is interrupted.

Hydroxycarbamide therapy can then be re-initiated at a lower dose (see section 4.2).

Severe anaemia must be corrected with whole blood replacement before initiating therapy with hydroxycarbamide. If, during treatment, anaemia occurs, correct without interrupting hydroxycarbamide therapy. Erythrocytic abnormalities; megaloblastic erythropoiesis, which is self- limiting, is often seen early in the course of hydroxycarbamide therapy. The morphologic change resembles pernicious anaemia, but is not related to vitamin B12 or folic acid deficiency. The macrocytosis may mask the incidental development of folic acid deficiency; regular determinations of serum folic acid are recommended. Hydroxycarbamide may also delay plasma iron clearance and reduce the rate of iron utilisation by erythrocytes but it does not appear to alter the red blood cell survival time.

Other

Patients who have received irradiation therapy in the past may have an exacerbation of post irradiation erythema when hydroxycarbamide is given.

Renal and hepatic impairment

Hydroxycarbamide should be used with caution in patients with marked renal dysfunction. Hydroxycarbamide may cause hepatotoxicity and liver function tests should be monitored during treatment.

Blood parameters for renal and hepatic impairment should be closely monitored, and hydroxycarbamide should be discontinued if necessary. If appropriate, hydroxycarbamide should be re-started at a lower dose.

HIV patients

Hydroxycarbamide must not be used in combination with anti-retroviral medicinal products for HIV disease and it may cause treatment failure and toxicities (in some cases fatal) in HIV patients (see sections 4.3 and 4.5).

Secondary leukaemia and skin cancer

In patients receiving long-term therapy with hydroxycarbamide for myeloproliferative disorders, such as polycythaemia, secondary leukaemia has been reported. It is unknown whether this leukaemogenic effect is secondary to hydroxycarbamide or associated with the patient's underlying disease. Skin cancer has been reported in patients receiving long-term hydroxycarbamide. Patients should be advised to protect skin from sun exposure. In addition patients should conduct self - inspection of the skin during the treatment and after discontinuation of the therapy with hydroxycarbamide and be screened for secondary malignancies during routine follow-up visits.

Cutaneous vasculitic toxicities

Cutaneous vasculitic toxicities including vasculitic ulcerations and gangrene have occurred in patients with myeloproliferative disorders during therapy with hydroxycarbamide. The risk of vasculitic toxicities is increased in patients who receive prior or concomitant interferon therapy. The digital distribution of these vasculitic ulcerations and progressive clinical behaviour of peripheral vasculitic insufficiency leading to digital infarct or gangrene were distinctly different than the typical skin ulcers generally described with Hydroxycarbamide. Due to potentially severe clinical outcomes for the cutaneous vasculitic ulcers reported in patients with myeloproliferative disease, hydroxycarbamide should be discontinued if cutaneous vasculitic ulcerations develop.

Vaccinations

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 (see section 4.5).

Leg ulcers

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.

Carcinogenicity

Hydroxycarbamide is unequivocally genotoxic in a wide range of test systems. Hydroxycarbamide is presumed to be a transspecies carcinogen (see section 5.3).

Interference with Continuous Glucose Monitoring systems

If a patient using a CGM is to be prescribed hydroxycarbamide, consult with the CGM prescriber about appropriate glucose monitoring methods (see section 4.5).

Safe handling of the solution

Parents and care givers should avoid hydroxycarbamide contact with skin or mucous membrane. If the solution comes into contact with skin or mucosa, it should be washed immediately and thoroughly with soap and water (see section 6.6).

Excipients

This medicinal product contains methyl parahydroxybenzoate (E218) which may cause allergic reactions (possibly delayed).

4.5. Interaction with other medicinal products and other forms of interaction

The myelosuppressive activity may be potentiated by previous or concomitant radiotherapy or cytotoxic therapy.

Concurrent use of hydroxycarbamide and other myelosuppressive medicinal products or radiation therapy may increase bone marrow depression, gastro - intestinal disturbances or mucositis. An erythema caused by radiation therapy may be aggravated by hydroxycarbamide.

Patients must not be treated with hydroxycarbamide and anti-retroviral medicinal products concurrently (see sections 4.3 and 4.4).

Fatal and non-fatal pancreatitis has occurred in HIV-infected patients during therapy with hydroxycarbamide and didanosine, with or without stavudine.

Hepatotoxicity and hepatic failure resulting in death were reported during post-marketing surveillance in HIV-infected patients treated with hydroxycarbamide and other antiretroviral medicinal products. Fatal hepatic events were reported most often in patients treated with the combination of hydroxycarbamide, didanosine, and stavudine.

Peripheral neuropathy, which was severe in some cases, has been reported in HIV-infected patients receiving hydroxycarbamide in combination with anti-retroviral medicinal products, including didanosine, with or without stavudine (see section 4.4).

Patients treated with hydroxycarbamide in combination with didanosine, stavudine, and indinavir showed a median decline in CD4 cells of approximately 100/ mm3.

Studies have shown that there is an analytical interference of hydroxycarbamide with the enzymes (urease, uricase, and lactic dehydrogenase) used in the determination of urea, uric acid, and lactic acid, rendering falsely elevated results of these in patients treated with hydroxycarbamide.

Vaccinations

There is an increased risk of severe or fatal infections with the concomitant use of live vaccines. Live vaccines are not recommended in immunosuppressed patients.

Concomitant use of hydroxycarbamide with a live virus vaccine may potentiate the replication of the vaccine virus and/or may increase the adverse reaction of the vaccine virus, because normal defence mechanisms may be suppressed by hydroxycarbamide therapy. Vaccination with a live vaccine in a patient taking hydroxycarbamide may result in severe infections. Generally, the patient's antibody response to vaccines may be decreased. Treatment with hydroxycarbamide and concomitant immunisation with live virus vaccines should only be performed if benefits clearly outweigh potential risks (see section 4.4).

Cutaneous vasculitic toxicities, including vasculitic ulcerations and gangrene, have occurred in patients with myeloproliferative disorders during therapy with hydroxycarbamide. These vasculitic toxicities were reported most often in patients with a history of, or currently receiving, interferon therapy (see section 4.4).

Interference with Continuous Glucose Monitoring systems

Hydroxycarbamide may falsely elevate sensor glucose results from certain continuous glucose monitoring (CGM) systems. This may lead to missed hypoglycaemic episodes and can also cause hypoglycaemia if sensor glucose results are relied upon to dose insulin.

If a patient using a CGM is to be prescribed hydroxycarbamide, consult with the CGM prescriber about appropriate glucose monitoring methods.

4.6. Fertility, pregnancy and lactation

Women of childbearing potential/Contraception in males and females

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.

Pregnancy

Studies in animals have shown reproductive toxicity (see section 5.3). 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.

Breast-feeding

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.

Fertility

Fertility in males might be affected by treatment. Very common reversible oligo- and azoo-spermia have been observed in man, although these disorders are also associated with the underlying disease. Impaired fertility has been observed in male rats (see section 5.3).

Male patients should be informed by their healthcare professionals about the possibility of sperm conservation (cryopreservation) before the start of therapy.

4.7. Effects on ability to drive and use machines

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.

4.8. Undesirable effects

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.

Summary of the safety profile

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.

Tabulated list of adverse reactions

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).

Table 1: 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 deficiency

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

Description of selected adverse reactions

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 (see section 4.2).

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 (see section 5.3). These disorders are also associated with the underlying disease.

Paediatric population

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 Xromi 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.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

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.