Siklos · 4.6 Fertility, pregnancy and lactation · 1

HOS-094352 · has-adverse-reaction-information · PDF-Seite 6

Summary of the safety profile The safety profile of hydroxycarbamide in sickle cell syndrome was established from clinical trials and confirmed with long-term cohort studies including up to 1 903 adults and children of more than 2 years of age. The most frequently reported adverse reaction is myelosuppression with neutropenia as the most common manifestation. Bone marrow depression is the dose-limiting toxic effect of hydroxycarbamide. When the maximum tolerated dose is not reached, transient myelotoxicity usually occurs in less than 10% of patients, while under the maximum tolerated dose more than 50% can experience reversible bone marrow suppression. These adverse reactions are expected based on the pharmacology of hydroxycarbamide. Gradual dose titration may help diminish these effects (see section 4.2). The clinical data obtained in patients with sickle cell syndrome have not shown evidence of adverse reactions of hydroxycarbamide on hepatic and renal function. Tabulated list of adverse reactions The adverse reactions are listed below by system organ class and absolute frequency. Frequencies are defined as 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), not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness: Neoplasms, benign, malignant and unspecified: Not known: Leukaemia and in elderly patients, skin cancers Blood and lymphatic system disorders: Very common: Bone marrow depression1 including neutropenia (< 1.5 x 109/L), reticulocytopenia (< 80 x 109/L), macrocytosis2 Common: Thrombocytopenia (< 80 x 109/L), anaemia (haemoglobin < 4.5 g/dL)3 Nervous system disorders: Common: Headache Uncommon: Dizziness Eye disorders: Not known: Limbal stem cell deficiency Vascular disorders: Not known: Bleeding Gastrointestinal disorders: Uncommon: Nausea Not known: Gastrointestinal disturbances, vomiting, gastrointestinal ulcer, severe hypomagnesaemia Hepatobiliary disorders: Rare: Elevated liver enzymes

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HOS-094348 · has-contraindication-information · PDF-Seite 3

Hypersensitivity to the active substance or to any of the excipients. Severe hepatic impairment (Child-Pugh classification C). 3 Severe renal impairment (creatinine clearance < 30 mL/min). Toxic ranges of myelosuppression as described in section 4.2. Breast-feeding (see section 4.6).

HOS-094347 · has-indication-information · PDF-Seite 2

Siklos is indicated for the prevention of recurrent painful vaso-occlusive crises including acute chest syndrome in adults, adolescents and children older than 2 years suffering from symptomatic sickle cell syndrome (see section 5.1).

HOS-094350 · has-interaction-information · PDF-Seite 5

Specific interaction studies have not been performed with hydroxycarbamide. Potentially fatal pancreatitis and hepatotoxicity, and severe peripheral neuropathy have been reported in HIV-infected patients who received hydroxycarbamide in combination with first generation antiretroviral medicinal products, particularly didanosine plus stavudine. Patients treated with hydroxycarbamide in combination with didanosine, stavudine, and indinavir showed a median decline in CD4 cells of approximately 100/mm3. 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. 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 Siklos and concomitant immunisation with live virus vaccines should only be performed if benefits clearly outweigh potential risks. Interference with Continuous Glucose Monitoring systems Hydroxycarbamide may falsely elevate sensor glucose results from certain continuous glucose monitoring (CGM) systems and may lead to hypoglycaemia if sensor glucose results are relied upon to dose insulin.

HOS-094351 · has-pregnancy-information · PDF-Seite 5

Women of childbearing potential/Contraception in males and females Women of childbearing age receiving hydroxycarbamide should be advised to avoid becoming pregnant, and to inform the treating physician immediately should this occur. An effective method of contraception is strongly recommended in women of childbearing potential. Male and female patients on hydroxycarbamide wishing to conceive should stop treatment 3 to 6 months before pregnancy if possible. The evaluation of the risk-benefit ratio should be made on an individual basis taking into consideration the respective risk of hydroxycarbamide therapy against the switch to a blood transfusion programme. 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. Siklos is not recommended during pregnancy. The patient should be instructed to immediately contact a doctor in case of suspected pregnancy. Breast-feeding Hydroxycarbamide is excreted in human milk. Because of the potential for serious adverse reactions in infants, breastfeeding must be discontinued while taking Siklos. Fertility 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 was observed in male rats (see section 5.3). 5

HOS-094349 · has-warning-information · PDF-Seite 4

Bone marrow depression Treatment with Siklos requires close clinical monitoring. The haematological status of the patient, as well as renal and hepatic functions should be determined prior to, and repeatedly during treatment. During treatment with Siklos, blood counts must be monitored once a month at treatment initiation (i.e. for the first two months) and if the daily dose of hydroxycarbamide is up to 35 mg/kg b.w. Patients who are stable on lower doses should be monitored every 2 months. Treatment with Siklos should be discontinued if bone marrow function is markedly depressed. Neutropenia is generally the first and most common manifestation of haematological suppression. Thrombocytopenia and anaemia occur less frequently, and are rarely seen without preceding neutropenia. Recovery from myelosuppression is usually rapid when therapy is discontinued. Siklos therapy can then be re-initiated at a lower dose (see section 4.2). Renal and hepatic impairment Siklos should be used with caution in patients with mild to moderate renal impairment (see section 4.2). Since there are limited data in patients with mild to moderate liver impairment, Siklos should be used with caution (see section 4.2). Leg ulcers and cutaneous vasculitis toxicities In patients with leg ulcers, Siklos should be used with caution. Leg ulcers are a common complication of sickle cell syndrome, but have also been reported in patients treated with hydroxycarbamide. 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. Due to potentially severe clinical outcomes for the cutaneous vasculitic ulcers reported in patients with myeloproliferative disease, hydroxycarbamide should be discontinued and/or its dose reduced if cutaneous vasculitic ulcerations develop. Rarely, ulcers are caused by leukocytoclastic vasculitis. Limbal stem cell deficiency Cases of limbal stem cell deficiency have been reported during treatment with hydroxycarbamide. In some cases, limbal stem cell deficiency improved after treatment discontinuation. Patients presenting with relevant signs and symptoms (reduced/impaired vision, photophobia, redness, and pain) should be referred to an ophthalmologist. If limbal stem cell deficiency is confirmed, discontinuation of the treat

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