Siklos Drug Information

® is indicated to reduce the frequency of painful crises and to reduce the need for blood transfusions in adult and pediatric patients, 2 years of age and older, with sickle cell anemia with recurrent moderate to severe painful crises SIKLOS is an antimetabolite, indicated to reduce the frequency of painful crises and to reduce the need for blood transfusions in adult and pediatric patients, 2 years of age and older, with sickle cell anemia with recurrent moderate to severe painful crises.

Clinical Trial Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of SIKLOS has been assessed in 405 pediatric patients with sickle cell disease from 2-18 years of age and 1077 adults in the European Sickle Cell Disease prospective Cohort study ESCORT-HU. The most frequently reported adverse reactions in ESCORT-HU were infections and myelosuppression, with mild to moderate neutropenia as the most common manifestation. Other adverse reactions include skin and subcutaneous disorders (skin depigmentation/melanonychia, skin rash, alopecia), gastrointestinal disorders, vitamin D deficiency and headache.

At least one serious adverse reaction was reported in 33% of the 405 pediatric patients and 32% of the 1077 adults with sickle cell disease in ESCORT-HU. The most frequent serious adverse reactions were infections (18%), and blood and lymphatic system disorders (9%) in children, including serious neutropenia (3.2%), thrombocytopenia (3%) and anemia (3%). Other reported serious adverse reactions were gastrointestinal disorders (3.2 %), fever (2.5 %) and nervous system disorders (4%), including headache (2.7%). Among adults, the most frequent serious adverse reactions were infections (12.9%), respiratory, thoracic and mediastinal disorders (5.8%), blood and lymphatic disorders (4.8%), nervous system disorders (3.6%), and general disorders and administration site disorders (3.1%). Table 2: Most frequent (greater than or equal to 2%) adverse reactions reported in pediatric patients enrolled in ESCORT-HU Global Safety Set (N=405) Total Severity Mild Moderate Severe n % n % n % n % n: number of patients with an adverse reaction At least one adverse reaction 261 64 Infections 161 40 120 30 88 22 18

Other Infections 92 23 66 16 32 8 3 0.7 Bacterial 65

16 24 6 37 9 10

Viral 40 10 23 6 14 3.5 3 0.7 Parvovirus B19 15

4 7 1.7 5 1.2 2

Neutropenia 51 13 26 6 31 8 4 1 Thrombocytopenia 30 7

16 4 15 3.7 2

Anemia 17 4.2 4 1 8 2 7 1.7 Gastrointestinal disorders 53

13 29 7 30 7 4 1 Other Gastrointestinal Disorders 30 7 13 3.2 15 3.7 2

Constipation 10 2.5 5 1.2 5 1.2 0 0 Nausea 10 2.5

4 1 4 1 2

Metabolic and nutrition disorders 44 11 24 6 21 5 1 0.2

Deficiency of vitamin D 25 6 19 4.7 7 1.7 1

Weight gain 8 2 1 0.2 7 1.7 0 0 Nervous system

disorders 45 11 19 4.7 19 4.7 8 2 Headache 30 7 15 3.7 7 1.7 4 1 Other Nervous system disorders 11 2.7 2 0.5 4 1 4 1 General disorders 41 10 22 5 17 4.2 4 1 Fever 31 8 20 4.9 12 3 2

Skin reactions 15 4 8 2 7 1.7 1 0.2 Other Skin

and subcutaneous tissue disorders 13 3.2 8 2 5 1.2 0 0 Other Not SCD-related reactions 23 6 16 4 3 0.7 1

Other Not

SCD-related reactions 23 6 16 4 3 0.7 1

Renal and urinary disorders 8 2 2 0.5 4 1 0 0

Table 3: Most frequent (greater than or equal to 3%) adverse reactions reported in adult patients enrolled in ESCORT-HU Global adult safety set (N=1077) Total Severity Mild Moderate Severe n % n % n % n % At least one adverse reaction 897 84 586 54 617 57 345 32 Infections 465 43 171 16 240 22 101 9 Viral infection 47 4.4 17 1.6 21 1.9 5

Bacterial infection 45 4.2 9 0.8 27 2.5 5 0.5 Bronchitis 41

3.8 10 0.9 19 1.8 3

Influenza 40 3.7 8 0.7 15 1.4 5 0.5 Urinary tract infection

40 3.7 19 1.8 11 1.0 1

Nasopharyngitis 40 3.7 21 1.9 13 1.2 1 0.1 Nervous system disorders

313 29 131 12 125 12 54 5 Headache 211 20 84 8 74 7 27

Dizziness 100 9 43 4.0 32 3.0 9 0.8 General disorders and

administration site conditions 300 28 111 10 113 10 24

Asthenia 100 9 30 2.8 18 1.7 10 0.9 Pyrexia 91 8

27 2.5 39 3.6 4

Fatigue 51 4.7 22 2.0 17 1.6 2 0.2 Edema peripheral 33

3.1 9 0.8 13 1.2 2

Dry skin 128 12 67 6.2 36 3.3 5 0.5 Skin ulcer

80 7 19 1.8 44 4.1 11

Alopecia 49 4.5 31 2.9 13 1.2 5 0.5 Gastrointestinal disorders 267

25 116 11 110 10 25

Nausea 69 6 28 2.6 26 2.4 3 0.3 Abdominal pain upper

52 4.8 15 1.4 22 2.0 5

Diarrhea 37 3.4 10 0.9 13 1.2 Respiratory, thoracic and mediastinal disorders

256 24 70 7 103 10 48

Cough 59 5.5 23 2.1 21 1.9 3 0.3 Lung disorder 51

4.7 4 0.4 28 2.6 16

Dyspnea 44 4.1 12 1.1 14 1.3 4 0.4 Blood and lymphatic

system disorders 250 23 74 7 121 11.2 61 6 Anemia 103 10 11 1.0 51 4.7 37

Thrombocytopenia 70 7 29 2.7 30 2.8 13 1.2 Neutropenia 50 4.6

24 2.2 18 1.7 7

Arthralgia 95 9 26 2.4 31 2.9 7 0.6 Back pain 48

4.5 11 1.0 18 1.7 6

Pain in extremity 33 3.1 14 1.3 10 0.9 Investigations 198 18

40 3.7 47 4.4 10

Weight increased 43 4.0 15 1.4 22 2.0 4 0.4 6.2 Postmarketing

Experience The following adverse reactions have been identified during post-approval use of SIKLOS. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Blood and lymphatic system disorders : macrocytosis, hemolytic anemia in patients who are treated with hydroxyurea for myeloproliferative disorders. Gastrointestinal disorders: vomiting, gastrointestinal ulcer, severe hypomagnesemia Hepatobiliary disorders: elevation of hepatic enzymes Skin and subcutaneous tissue disorders: skin reactions (oral, ungula and cutaneous pigmentation), oral mucositis, rash, melanonychia, Reproductive system and breast disorders : oligospermia, azoospermia, amenorrhea

Increased Toxicity with

Concomitant Use of Antiretroviral Drugs Pancreatitis Pancreatitis (including fatal cases) have occurred in patients with HIV infection during therapy with hydroxyurea and didanosine, with or without stavudine. Hydroxyurea is not indicated for the treatment of HIV infection; however, if patients with HIV infection are treated with hydroxyurea, and in particular, in combination with didanosine and/or stavudine, monitor closely for signs and symptoms of pancreatitis. Permanently discontinue therapy with hydroxyurea in patients who develop signs and symptoms of pancreatitis.

Hepatotoxicity Hepatotoxicity and hepatic failure resulting in death have been reported during postmarketing surveillance in patients with HIV infection treated with hydroxyurea and other antiretroviral drugs. Fatal hepatic events were reported most often in patients treated with the combination of hydroxyurea, didanosine, and stavudine. Avoid this combination.

Peripheral Neuropathy Peripheral neuropathy, which was severe in some cases, has been reported in patients with HIV infection receiving hydroxyurea in combination with antiretroviral drugs, including didanosine, with or without stavudine.

Concomitant Use of Live Virus Vaccine

Concomitant use of SIKLOS with a live virus vaccine may potentiate the replication of the vaccine virus and/or may increase the adverse reactions of the vaccine virus, because normal defense mechanisms may be suppressed by SIKLOS therapy. Vaccination with a live vaccine in a patient taking SIKLOS may result in severe infections. Generally, the patient's antibody response to vaccines may be decreased.

Treatment with SIKLOS and concomitant immunization with live virus vaccines should only be performed if benefits clearly outweigh potential risks. Consider consultation with a specialist.

Test Interference Interference with Uric Acid, Urea, or Lactic Acid Assays Studies

have shown that there is an analytical interference of SIKLOS with the enzymes (urease, uricase, and lactate dehydrogenase) used in the determination of urea, uric acid, and lactic acid, rendering falsely elevated results of these in patients treated with SIKLOS. Interference with Continuous Glucose Monitoring Systems Hydroxyurea may falsely elevate sensor glucose results from certain continuous glucose monitoring (CGM) systems and may lead to hypoglycemia if sensor glucose results are relied upon to dose insulin. If a patient using a CGM is to be prescribed hydroxyurea, consult with the CGM prescriber about alternative glucose monitoring methods.

Pregnancy Risk Summary SIKLOS can cause fetal harm based on findings from animal studies and the drug's mechanism of action . There are no studies with the use of SIKLOS in pregnant women, and limited available data on SIKLOS use during pregnancy are insufficient to inform drug-associated risks. Drugs which affect DNA synthesis, such as hydroxyurea, may be potential mutagenic agents. In animal reproduction studies, administration of hydroxyurea to pregnant rats and rabbits during organogenesis produced embryotoxic and teratogenic effects at doses 0.8 times and 0.3 times, respectively, the maximum recommended human daily dose on a mg/m 2 basis.

In rats and rabbits, fetal malformations were observed with partially ossified cranial bones, absence of eye sockets, hydrocephaly, bipartite sternebrae, and missing lumbar vertebrae. Embryotoxicity was characterized by decreased fetal viability, reduced live litter sizes, and developmental delays (see Data ). Advise pregnant women of the potential risk to a fetus (see Clinical Considerations ). Background risk of major birth defects and miscarriage for the indicated population are unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2%–4% and 15%–20%, respectively. Clinical Considerations Fetal/Neonatal adverse reactions Although the data on a limited number of exposed pregnancies indicate no adverse effects on pregnancy or on the health of the fetus/newborn, patients on SIKLOS should be made aware of the potential risks to the fetus. Based on the limited amount of available information, in case of an exposure to SIKLOS of pregnant female patients or pregnant partners of male patients, treated by SIKLOS, a careful follow-up with adequate clinical, biological and ultrasonographic examinations should be considered.

Data Human Data According to a retrospective analysis of a cohort of 123 adult patients treated with hydroxyurea, twenty-three pregnancies have been reported from 15 women treated with hydroxyurea and partners of 3 men not using barrier contraception treated with hydroxyurea. Most (61%) had no adverse developmental outcomes. In the other cases with known evolution, pregnancy had been interrupted either voluntarily or upon medical advice.

In retrospective cohorts of 352 children and adolescents with sickle cell disease older than 2 years treated with hydroxyurea for a period of up to 12 years, 3 pregnancies under hydroxyurea were reported with no adverse developmental outcomes. From post-marketing data of SIKLOS, 3 pregnancies have been reported while the father was treated with SIKLOS and 16 pregnancies have been reported in 15 females treated with SIKLOS. Among the 13 cases with known evolution, 5 pregnancies had no adverse developmental outcomes, 4 led to premature birth, and 4 were early terminated. Animal Data Hydroxyurea has been demonstrated to be a potent teratogen in a wide variety of animal models, including mice, hamsters, cats, miniature swine, dogs, and monkeys at doses within 1-fold of the human dose given on a mg/m 2 basis.

Hydroxyurea is embryotoxic and causes fetal malformations (partially ossified cranial bones, absence of eye sockets, hydrocephaly, bipartite sternebrae, missing lumbar vertebrae) at 180 mg/kg/day (about 0.8 times the maximum recommended human daily dose on a mg/m 2 basis) in rats and at 30 mg/kg/day (about 0.3 times the maximum recommended human daily dose on a mg/m 2 basis) in rabbits. Embryotoxicity was characterized by decreased fetal viability, reduced live litter sizes, and developmental delays. Hydroxyurea crosses the placenta.

Single doses of ≥375 mg/kg (about 1.7 times the maximum recommended human daily dose on a mg/m 2 basis) to rats caused growth retardation and impaired learning ability.

Pediatric Use The safety and effectiveness of SIKLOS have been established in pediatric patients aged 2-18 years with sickle cell anemia with recurrent moderate to severe painful crises. Use of SIKLOS in these age groups is supported by evidence from a non-interventional cohort study, the European Sickle Cell Disease prospective Cohort study, ESCORT-HU, in which 405 pediatric patients ages 2 to <18 were enrolled. Among the 405 pediatric patients treated with SIKLOS, 274 were children (2-11) and 108 were adolescents (12-16) . Continuous follow-up of the growth of treated children is recommended.

Pediatric patients aged 2-16 years had a higher risk of neutropenia than patients more than 16 years old. The safety and effectiveness of SIKLOS have not been established in pediatric patients less than 2 years of age.

is contraindicated in: Patients who have demonstrated a previous hypersensitivity to hydroxyurea or any other component of its formulation. Patients who have demonstrated a previous hypersensitivity to hydroxyurea or any other component of its formulation.

Acute mucocutaneous toxicity has been reported in patients receiving hydroxyurea at doses several times above the therapeutic dose. Soreness, violet erythema, oedema on palms and soles followed by scaling of hand and feet, severe generalized hyperpigmentation of the skin and stomatitis have been observed. In patients with sickle cell anemia, neutropenia was reported in isolated cases of hydroxyurea overdose (1.43 times and 8.57 times of the maximum recommended dose of 35 mg/kg b.w./day). Monitor blood counts weekly until recovery.

Treatment of overdose consists of gastric lavage, followed by symptomatic treatment and control of bone marrow function.