Hydroxycarbamide

Hydroxycarbamide (hydroxyurea) is an antineoplastic medicine that inhibits DNA synthesis by blocking ribonucleotide reductase. The effect is most marked in rapidly proliferating cells, which underlies its cytoreductive use in myeloproliferative disorders and leukaemia. In sickle cell disease the benefit comes mainly from a rise in foetal haemoglobin (HbF) and a fall in neutrophil counts.

Mechanism of Action

• Ribonucleotide reductase inhibition: causes an immediate inhibition of DNA synthesis without interfering with RNA or protein synthesis. The SmPC notes that not all of its mechanisms are fully understood.
• Foetal haemoglobin: in sickle cell disease, more HbF interferes with polymerisation of sickle haemoglobin (HbS), impeding sickling of red cells and so reducing vaso-occlusion and haemolysis. HbF also prolongs red-cell survival, raises total haemoglobin and reduces anaemia. Nitric oxide generation, thought to stimulate cyclic GMP and HbF production, has also been described.
• Other effects in sickle cell disease: fewer neutrophils, more water in red cells, more deformable sickled cells and altered adhesion of red cells to the endothelium. The fall in neutrophils correlated most strongly with the reduction in crisis rate.
• With radiotherapy: laboratory studies suggest that hydroxycarbamide kills normally radio-resistant S-phase cells, holds other cells in G1 where they are most sensitive to radiation, and hinders repair of radiation-damaged cells. The Hydrea SmPC asks prescribers to bear this radiosensitising effect in mind.

Pharmacokinetics

• Absorption: rapid after oral dosing; oral bioavailability is almost complete (assessed outside sickle cell syndrome). In sickle cell disease, 20 mg/kg gives peak levels of about 30 mg/L after 0.75 hours in children and 1.2 hours in adults, with 24-hour exposure of 124 mg·h/L in children and adolescents and 135 mg·h/L in adults.
• Distribution: spreads rapidly through the body, enters the cerebrospinal fluid, peritoneal fluid and ascites, and concentrates in leucocytes and erythrocytes. The volume of distribution approximates total body water (0.57 L/kg at steady state in sickle cell disease). Protein binding is unknown.
• Metabolism: the pathways are not fully characterised; urea is one metabolite. In vitro it is not metabolised by human liver cytochrome P450 enzymes and is not a P-glycoprotein substrate, so interactions with their substrates are not expected.
• Elimination: about 60% of the dose appears in urine at steady state in adults with sickle cell disease; total clearance is 9.89 L/h in adults and 7.25 L/h in children. The half-life in sickle cell disease is about 6–7 hours, longer than in other indications.
• Special populations: renal excretion is a main pathway, so the dose is reduced in renal impairment (see Administration and Dosage).

Hydrea 500 mg hard capsules (nationally authorised; wording of the Spanish SmPC)

• Myeloproliferative syndromes: myeloid splenomegaly/myelofibrosis (idiopathic myelofibrosis); essential thrombocythaemia; and polycythaemia vera when phlebotomy alone does not control the disease.
• Chronic myeloid leukaemia and related syndromes: in the pretreatment phase, when a rapid fall in leukocytosis is needed, and as palliative treatment in resistant cases or in patients who cannot tolerate other therapeutic alternatives.
• With radiotherapy: local treatment of carcinoma of the cervix, and local treatment of primary squamous cell (epidermoid) carcinoma of the head and neck, excluding the lip.

Siklos film-coated tablets (central authorisation)

• Prevention of recurrent painful vaso-occlusive crises, including acute chest syndrome, in adults, adolescents and children older than 2 years with symptomatic sickle cell syndrome.

Xromi oral solution (central authorisation)

• Prevention of vaso-occlusive complications of sickle cell disease in patients over 9 months of age.

Hydrea capsules

• Hypersensitivity to hydroxycarbamide or to any excipient.
• Bone marrow depression: leucopenia (below 2,500 leucocytes/mm³), thrombocytopenia (below 100,000 platelets/mm³) or severe anaemia.
• A history of, or current, skin ulcers and/or vasculitic ulcers associated with hydroxycarbamide or interferon alfa.
• Pregnancy and breastfeeding (section 4.3 of the Spanish SmPC; its section 4.6 words the advice differently, see Special Instructions).

Siklos tablets

• Hypersensitivity to hydroxycarbamide or to any excipient.
• Severe hepatic impairment (Child-Pugh class C) and severe renal impairment (creatinine clearance below 30 mL/min).
• Toxic ranges of myelosuppression as defined in section 4.2 (see Administration and Dosage).
• Breastfeeding.

Xromi oral solution

• The same as Siklos and, in addition, pregnancy and concomitant antiretroviral medicinal products for HIV disease.

Bone marrow suppression is the main dose-limiting toxicity of hydroxycarbamide, with neutropenia usually appearing first. Frequencies differ between the myeloproliferative product and the sickle cell products, so each SmPC is summarised separately.

Hydrea (myeloproliferative disorders)

Very common (≥1/10): bone marrow depression, leucopenia, thrombocytopenia, anaemia and reduced CD4 lymphocytes; anorexia; pancreatitis, stomatitis, nausea, vomiting, diarrhoea and constipation; maculopapular rash, facial and peripheral erythema, skin ulceration and dermatomyositis; raised blood creatinine, urea and uric acid; azoospermia and oligospermia; fever, chills, malaise and asthenia.

Common (≥1/100 to <1/10): somnolence and peripheral neuropathy; hepatotoxicity, raised liver enzymes, cholestasis and hepatitis.

Uncommon (≥1/1,000 to <1/100): skin cancer; vasculitic ulcerations.

Rare (≥1/10,000 to <1/1,000): gangrene; tumour lysis syndrome; hallucinations and disorientation; headache, dizziness and convulsions; acute pulmonary reactions (diffuse infiltrates or fibrosis, with dyspnoea); dysuria.

Very rare (<1/10,000): alopecia.

Not known: haemolytic anaemia; interstitial lung disease, pneumonitis, alveolitis (including allergic alveolitis) and cough; skin and nail hyperpigmentation, erythema, skin and nail atrophy, scaling, violaceous papules and cutaneous lupus erythematosus; systemic lupus erythematosus; drug-induced fever.

Alopecia and most of the skin and nail changes appeared after several years of long-term daily maintenance treatment. Gangrene and vasculitic ulcerations were reported more often in patients who had received interferon. In HIV-infected patients given hydroxycarbamide with antiretroviral medicines, especially didanosine plus stavudine, fatal and non-fatal pancreatitis, hepatotoxicity and severe peripheral neuropathy occurred. Drug-induced fever above 39 °C, sometimes with gastrointestinal, pulmonary, musculoskeletal, hepatobiliary, skin or cardiovascular symptoms and needing hospital admission, usually began within 6 weeks, settled after stopping and returned within 24 hours of re-exposure. With radiotherapy the SmPC gives a separate table of similar reactions, several at higher frequencies (skin cancer, hallucinations, convulsions and pulmonary fibrosis are common; alopecia, skin atrophy, mucositis and gastric pain are very common); mucositis and gastric pain from radiotherapy may be increased.

Siklos (sickle cell syndrome)

Very common (≥1/10): bone marrow depression (neutropenia below 1.5 × 10⁹/L, reticulocytopenia below 80 × 10⁹/L) and macrocytosis; oligospermia and azoospermia.

Common (≥1/100 to <1/10): thrombocytopenia (below 80 × 10⁹/L); anaemia (haemoglobin below 4.5 g/dL); headache; skin reactions (oral, nail and skin pigmentation) and oral mucositis.

Uncommon (≥1/1,000 to <1/100): dizziness; nausea; rash, melanonychia and alopecia.

Rare (≥1/10,000 to <1/1,000): raised liver enzymes; leg ulcers.

Very rare (<1/10,000): systemic and cutaneous lupus erythematosus.

Not known: leukaemia and, in elderly patients, skin cancer; limbal stem cell deficiency; bleeding; gastrointestinal disturbances, vomiting, gastrointestinal ulcer and severe hypomagnesaemia; dry skin; amenorrhoea; fever; weight gain.

Xromi (sickle cell disease)

Very common (≥1/10): bone marrow depression (neutropenia below 1,500/μL, reticulocytopenia below 80,000/μL) and macrocytosis; oligospermia and azoospermia.

Common (≥1/100 to <1/10): thrombocytopenia (below 80,000/μL); anaemia (haemoglobin below 4.5 g/dL); headache and dizziness; nausea and constipation; skin ulcer, oral, nail and skin hyperpigmentation, dry skin and alopecia.

Uncommon (≥1/1,000 to <1/100): stomatitis, diarrhoea and vomiting; raised liver enzymes and hepatotoxicity; rash.

Rare (≥1/10,000 to <1/1,000): leg ulcers.

Very rare (<1/10,000): systemic and cutaneous lupus erythematosus.

Not known: leukaemia and, in elderly patients, skin cancers; weight gain and vitamin D deficiency; limbal stem cell deficiency; bleeding; gastrointestinal disturbances, gastrointestinal ulcer and severe hypomagnesaemia; amenorrhoea; fever.

In sickle cell disease the blood count usually recovers within two weeks of stopping treatment. Skin changes tend to appear after several years of daily maintenance therapy. Leukaemia and skin cancer are serious risks of long-term use, although their frequency is not known.

Specific interaction studies have not been performed with hydroxycarbamide.

• Antiretroviral medicines for HIV: potentially fatal pancreatitis and hepatotoxicity and severe peripheral neuropathy have been reported, particularly with didanosine plus stavudine; with didanosine, stavudine and indinavir the median fall in CD4 cells was about 100/mm³. The Hydrea SmPC advises avoiding the combination with didanosine and stavudine, and Xromi is contraindicated with antiretrovirals for HIV.
• Other myelosuppressive medicines and radiotherapy: increase bone marrow depression, gastrointestinal disturbance and mucositis, and may aggravate radiation erythema. The dose may need adjusting.
• Interferon alfa: skin ulcers, vasculitic ulcers and gangrene may appear or worsen when hydroxycarbamide is given with or after it.
• Live vaccines: may raise replication and adverse effects of the vaccine virus and cause severe or fatal infection, and antibody responses to vaccines may be reduced. Avoid them; the Siklos SmPC allows them only if the benefit clearly outweighs the risk.
• Cytarabine: in vitro, hydroxycarbamide markedly increased its activity. Whether this causes synergistic clinical toxicity, or needs a cytarabine dose change, has not been established.
• Uricosuric medicines: hydroxycarbamide can raise serum uric acid, so their dose may need adjusting.
• Glucose sensors and laboratory tests: some continuous glucose monitoring sensors may read falsely high, risking hypoglycaemia if insulin is dosed from sensor values; urea, uric acid and lactic acid assays may also be falsely raised.
• Fluids: drink plenty of fluids to keep urine flow and kidney function up.

Hydroxycarbamide is taken by mouth and dosed by body weight; for Hydrea the lower of the actual and ideal weight is used. Siklos must be started by a physician experienced in managing sickle cell syndrome, and Xromi treatment is supervised by a physician or other healthcare professional experienced in sickle cell disease. Doses below follow each SmPC.

Hydrea Capsules

• Myelofibrosis: 5–15 mg/kg per 24 hours.
• Essential thrombocythaemia: initial 25–50 mg/kg per 24 hours, then maintenance 10–20 mg/kg per 24 hours, adjusted to control blood counts. Continue while platelet and/or white cell counts stay controlled and there is no resistance or intolerance.
• Polycythaemia vera: initial 15–20 mg/kg per 24 hours, then maintenance 10 mg/kg per 24 hours; most patients need an average of 500–1,000 mg daily. Full blood counts every 6–8 weeks are recommended.
• Chronic myeloid leukaemia: initial 30–60 mg/kg per 24 hours, then maintenance 15–30 mg/kg per 24 hours.
• With radiotherapy (cervical, or head and neck carcinoma): 80 mg/kg as a single dose every third day, started at least 7 days before radiotherapy, continued during it and indefinitely afterwards. This intermittent schedule has the advantage of lower toxicity. Radiotherapy is given at the maximum dose appropriate for the patient, and the radiation dose does not normally need adjusting.
• Duration and stopping: six weeks is the trial period for judging antineoplastic effect; continue indefinitely if there is a significant clinical response. Interrupt if leucocytes fall below 2,500/mm³ or platelets below 100,000/mm³; repeat counts after three days and restart once they are normal. Other myelosuppressive medicines may require a dose adjustment, and caution is advised after recent extensive radiotherapy or chemotherapy.
• Method: swallow the capsule; if that is not possible, the contents can be dispersed in a glass of water and taken at once (some insoluble excipients float on the surface). Handling precautions are in section 6.6 of the SmPC.
• Special populations: elderly patients may be more sensitive and may need a lower dose. In renal impairment the dose should be reduced, with close blood monitoring, because elimination is mainly renal. For hepatic impairment no specific adjustment is supported, but blood parameters are monitored closely. Safety and efficacy in children have not been established.

Siklos Tablets

• Dose: start at 15 mg/kg once daily; the usual dose is 15–30 mg/kg per day. While the patient responds clinically or haematologically (for example higher HbF or MCV, lower neutrophil count), keep the dose. If there is no response, increase in steps of 2.5–5 mg/kg per day; 35 mg/kg per day may be justified in exceptional circumstances under close haematological monitoring. If there is no response to 35 mg/kg per day over three to six months, consider stopping permanently.
• Toxic blood counts: stop temporarily if neutrophils fall below 1,500/mm³, platelets below 80,000/mm³ or haemoglobin below 4.5 g/dL, or reticulocytes below 80,000/mm³ when haemoglobin is below 9 g/dL. Recovery usually takes about two weeks; restart at a lower dose and increase again under close monitoring. A dose that caused haematological toxicity should not be tried more than twice.
• How to take: once daily, preferably in the morning before breakfast, with a glass of water or a very small amount of food. The 100 mg tablet can be split into halves and the 1,000 mg tablet into quarters. Patients who cannot swallow tablets can disintegrate them in a little water in a teaspoon just before use; a drop of syrup or some food can mask the bitter taste.
• Special populations: with creatinine clearance up to 60 mL/min, reduce the initial dose by 50% and monitor the blood closely; do not use below 30 mL/min. No specific adjustment is supported in hepatic impairment (close monitoring; contraindicated if severe). For children under 2 years no dose recommendation can be made. The duration of treatment is for the prescribing physician to decide.

Xromi Oral Solution

• Dose: the usual starting dose is 15 mg/kg per day, the usual maintenance dose 20–25 mg/kg per day, and the maximum 35 mg/kg per day.
• Monitoring: full blood count with white cell differential and reticulocyte count monthly for the first 2 months. Aim for an absolute neutrophil count of 1,500–4,000/μL while keeping platelets above 80,000/μL. If neutropenia or thrombocytopenia occurs, withhold the dose, check counts weekly and restart 5 mg/kg per day lower once they recover.
• Dose escalation (when clinically warranted): increase by 5 mg/kg per day every 8 weeks until mild myelosuppression is reached, up to 35 mg/kg per day, checking counts at least every 4 weeks. Once the maximum tolerated dose is found, check counts every 2–3 months.
• Response: a clinical response may take 3–6 months, so a 6-month trial at the maximum tolerated dose is needed before stopping for treatment failure. A lack of rise in MCV or HbF is not by itself a reason to stop if the patient responds clinically.
• Special populations: elderly patients may be more sensitive to myelosuppression and may need a lower dose. For renal and hepatic impairment, children and the dosing device, see the Xromi SmPC.

Bone Marrow Suppression and Blood Monitoring

Treatment needs close clinical monitoring, with blood counts and liver and kidney function checked before and regularly during treatment.

• Hydrea: do not start if bone marrow function is depressed, and correct severe anaemia first. Leucopenia is the main and commonest sign, with thrombocytopenia and anaemia less often; the risk is higher after previous radiotherapy or cytotoxic medicines. Section 4.4 asks for haemoglobin, leucocyte and platelet counts at least once a week. Anaemia can be treated without stopping, and recovery after stopping is rapid.
• Siklos: blood counts monthly for the first two months and while the dose is up to 35 mg/kg per day, then every 2 months in patients stable on lower doses. Neutropenia is usually the first sign; thrombocytopenia and anaemia are rarely seen without it. Stop if bone marrow function is markedly depressed.

Skin Ulcers, Vasculitis and Gangrene

• Hydrea: in myeloproliferative disorders, skin ulcers including vasculitic ulceration and gangrene have occurred, mostly on the feet and legs and more often with arterial or venous disease. They usually appear after more than a year of continuous treatment and affect roughly 9% of patients; gangrene is much less common. If ulcers develop, stop hydroxycarbamide and use another cytoreductive treatment. Interferon alfa raises the risk (ulcers, often on the fingers, may progress to gangrene), and both medicines are stopped if signs progress. Diabetes, hypertension and previous vascular or vasculitic disease are risk factors.
• Siklos: use with caution in patients with leg ulcers, a common complication of sickle cell disease that has also been reported with hydroxycarbamide. Stop or reduce the dose if cutaneous vasculitic ulceration develops.

Secondary Cancers and Skin Protection

Hydroxycarbamide is genotoxic in a wide range of test systems and is presumed to be a carcinogen. Secondary leukaemia has been reported after long-term use for myeloproliferative disorders (it is unknown whether the medicine or the disease is responsible), and skin cancer has been reported. Patients should protect their skin from the sun, inspect it during and after treatment, and be checked for secondary cancers at follow-up. The Hydrea SmPC advises considering other treatment if skin cancer or epithelial dysplasia is found, with dermatological follow-up continuing afterwards.

Lung, Blood and Other Warnings

• Interstitial lung disease (pulmonary fibrosis, infiltration, pneumonitis, alveolitis) has been reported in patients treated for myeloproliferative neoplasms and can be fatal. Fever, cough, dyspnoea or other respiratory symptoms need prompt investigation; stopping hydroxycarbamide and giving corticosteroids appear to resolve the events.
• Haemolytic anaemia has been reported in myeloproliferative disease. Persistent anaemia should prompt tests for haemolysis, and hydroxycarbamide is stopped if it is confirmed.
• Macrocytosis can mask folic acid or vitamin B12 deficiency. Folic acid levels should be checked regularly with Hydrea, and the Siklos SmPC recommends prophylactic folic acid.
• Fluids: keep up fluid intake and ensure plenty of urine, especially at the start.
• Radiotherapy: earlier radiotherapy can bring on a flare of radiation erythema. Severe gastric symptoms with combined treatment usually respond to interrupting hydroxycarbamide; mucositis is managed with topical anaesthetics and oral analgesics, with temporary interruption if severe and postponement of radiotherapy if extremely severe.
• Limbal stem cell deficiency: patients with reduced vision, photophobia, redness or eye pain should see an ophthalmologist, and stopping should be considered if it is confirmed (Siklos).
• Safe use: patients or carers must be able to follow directions for administration, monitoring and care (Siklos).

Pregnancy, Breastfeeding and Fertility

• Hydrea: hydroxycarbamide can cause foetal harm and is a potent teratogen in animals (malformations in rabbit and mouse offspring at about one-third and twice the maximum human dose). Women of childbearing potential should avoid pregnancy and tell their doctor at once if it occurs; a patient treated during pregnancy must be told of the potential harm to the foetus. It passes into breast milk, and section 4.6 says to choose between stopping Hydrea and stopping breastfeeding, while section 4.3 lists pregnancy and breastfeeding as contraindications, so the SmPC should be consulted. Azoospermia or oligospermia, sometimes reversible, can occur in men, who should be told about sperm preservation. Men should use reliable contraception during treatment and for at least 3 months afterwards, and women of childbearing potential effective contraception during treatment and for at least 6 months afterwards.
• Siklos: not recommended during pregnancy, and effective contraception is strongly recommended in women of childbearing potential. Male and female patients wishing to conceive should, if possible, stop 3 to 6 months beforehand, weighing the risk against a switch to a transfusion programme. Breastfeeding must be stopped. Male fertility may be affected (reversible oligospermia and azoospermia are very common).
• Xromi: contraindicated in pregnancy and during breastfeeding; see its SmPC for contraception and fertility advice.

Excipients

Each Hydrea capsule contains lactose (40.1 mg): patients with hereditary galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take it. Each capsule also contains 11.7 mg of sodium, 0.6% of the maximum daily sodium intake of 2 g recommended by the WHO for adults.

Effect on Driving

Siklos has a minor influence on the ability to drive and use machines; patients who feel dizzy should not drive or operate machines. The Hydrea and Xromi SmPCs give their own statements.

• Hydrea capsules: do not store above 25 °C; keep in the original package.
• Siklos tablets: store below 30 °C. Unused broken tablets go back into the bottle (child-resistant closure, desiccant unit) and are used within three months.
• Xromi oral solution: store in a refrigerator at 2–8 °C. As a refrigerated product it needs cold-chain handling in transport and storage.

• Hydrea capsules: 3 years.
• Siklos tablets: 3 years; unused broken tablets within three months.
• Xromi oral solution: 2 years unopened, and 12 weeks after first opening.

Prescription only (Rx). Siklos is subject to restricted medical prescription (Annex II B) and is started by a physician experienced in managing sickle cell syndrome; Xromi is supervised by a physician or other healthcare professional experienced in sickle cell disease. The capsules, tablets and oral solution are taken at home, so they are supplied to the patient or to the treating clinic on prescription; Xromi oral solution is delivered under cold-chain conditions (2–8 °C).