Data from FDA - Curated by EPG Health - Last updated 12 June 2018

Indication(s)

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

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Advisory information

contraindications
4 CONTRAINDICATIONS SIKLOS is contraindicated in: -Patients who have demonstrated a previous hypersensitivity to hydroxyurea or any other component of its formulation [see Adverse Reactions (6)]. Patients who have demonstrated a previous hypersensitivity to hydroxyurea or any other component of its formulation.
Adverse reactions
6 ADVERSE REACTIONS Myelosuppression [see Warnings and Precautions (5.1)] Malignancies [see Warnings and Precautions (5.2)] Embryo-fetal toxicity [see Boxed Warning and Warnings and Precautions (5.3)] Vasculitic toxicities (including Leg Ulcers) [see Warnings and Precautions (5.4)] Risks with concomitant use of antiretroviral drugs [see Warnings and Precautions (5.5)] Risk with concomitant use of live virus vaccine [see Warnings and Precautions (5.6)] Macrocytosis [see Warnings and Precautions (5.7)] Most common adverse reactions to SIKLOS (incidence > 10%) include infections and neutropenia. To report SUSPECTED ADVERSE REACTIONS, contact the marketer Medunik at 1 844-884-5520 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 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 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 32.6 % of the 405 pediatric patients with sickle cell disease in ESCORT-HU. The most frequent serious adverse reactions were infections (17.8 %), and blood and lymphatic system disorders (9.1 %). This included serious neutropenia (3.2%), thrombocytopenia (3.0%) and anemia (3.0%). Other reported serious adverse reactions were gastrointestinal disorders (3.2 %), fever (2.5 %) and nervous system disorders (4.0 %), including headache (2.7%). Table 2: Most frequent (greater than or equal to 2.0%) adverse reactions reported in pediatric patients enrolled in ESCORT-HU Global Safety Set (N=405) Total Intensity Mild Moderate Severe n % n % n % n % n: number of patients with an adverse reaction At least one adverse reaction 261 64.4 Infections 161 39.8 120 29.6 88 21.7 18 4.4 Other Infections 92 22.7 66 16.3 32 7.9 3 0.7 Bacterial 65 16.0 24 5.9 37 9.1 10 2.5 Viral 40 9.9 23 5.7 14 3.5 3 0.7 Parvovirus B19 15 3.7 7 1.7 5 1.2 2 0.5 Blood and lymphatic system disorders 85 21.0 51 12.6 59 14.6 14 3.5 Neutropenia 51 12.6 26 6.4 31 7.7 4 1.0 Thrombocytopenia 30 7.4 16 4.0 15 3.7 2 0.5 Anemia 17 4.2 4 1.0 8 2.0 7 1.7 Gastrointestinal disorders 53 13.1 29 7.2 30 7.4 4 1.0 Other Gastrointestinal Disorders 30 7.4 13 3.2 15 3.7 2 0.5 Constipation 10 2.5 5 1.2 5 1.2 0 0 Nausea 10 2.5 4 1.0 4 1.0 2 0.5 Metabolic and nutrition disorders 44 10.9 24 5.9 21 5.2 1 0.2 Deficiency of vitamin D 25 6.2 19 4.7 7 1.7 1 0.2 Other Metabolic and nutrition disorders 8 2.0 3 0.7 4 1.0 1 0.2 Weight gain 8 2.0 1 0.2 7 1.7 0 0 Nervous system disorders 45 11.1 19 4.7 19 4.7 8 2.0 Headache 30 7.4 15 3.7 7 1.7 4 1.0 Other Nervous system disorders 11 2.7 2 0.5 4 1.0 4 1.0 General disorders 41 10.1 22 5.4 17 4.2 4 1.0 Fever 31 7.7 20 4.9 12 3.0 2 0.5 Skin and subcutaneous tissue disorders 38 9.4 29 7.2 14 3.5 1 0.2 Skin reactions 15 3.7 8 2.0 7 1.7 1 0.2 Other Skin and subcutaneous tissue disorders 13 3.2 8 2.0 5 1.2 0 0 Other Not SCD-related reactions 23 5.7 16 4.0 3 0.7 1 0.2 Other Not SCD-related reactions 23 5.7 16 4.0 3 0.7 1 0.2 Respiratory thoracic and mediastinal disorders 11 2.7 6 1.5 3 0.7 2 0.5 Renal and urinary disorders 8 2.0 2 0.5 4 1.0 0 0 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. Infections and infestations: Parvovirus B19 infection Blood and lymphatic system disorders: bone marrow depression including neutropenia (<2.0 × 109/l), reticulocytopenia (<80 × 109/l), macrocytosis, thrombocytopenia (<80 × 109/l), anemia (hemoglobin <4.5g/dl) Nervous system disorders: headache, dizziness Gastrointestinal disorders: nausea, gastrointestinal disturbances, 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, alopecia, leg ulcers, cutaneous dryness Reproductive system and breast disorders: oligospermia, azoospermia, amenorrhea General disorders: fever Investigations: weight gain

Usage information

Dosing and administration
2 DOSAGE AND ADMINISTRATION Initial dose: 20 mg/kg once daily. Monitor blood counts every two weeks. (2.1) The dose may be increased by 5 mg/kg/day every 8 weeks, or sooner if a severe painful crisis occurs, until a maximum tolerated dose or 35 mg/kg/day is reached if blood counts are in an acceptable range. (2.1) Discontinue SIKLOS until hematologic recovery if blood counts are considered toxic. Resume treatment after reducing the dose by 5 mg/kg/day from the dose associated with hematological toxicity. (2.1) Renal impairment: Reduce the dose of SIKLOS by 50% in patients with creatinine clearance less than 60 mL/min. (2.2, 8.6, 12.3) 2.1 Recommended Dosing The recommended SIKLOS dosing is described in Table 1. Table 1: Dosing Recommendation Based on Blood Count Dosing Regimen Dose Dose Modification Criteria Monitoring Parameters Initial Recommended Dosing 20 mg/kg once daily based on patient's actual or ideal weight, whichever is less. Monitor the patient's blood count every 2 weeks [see Warnings and Precautions (5.1)]. Dosing Adjustment Based on Blood Counts in an acceptable range Increase dose 5 mg/kg/day every 8 weeks or if a painful crisis occurs. Give until mild myelosuppression (absolute neutrophil count 2,000/uL to 4,000/uL) is achieved, up to a maximum of 35 mg/kg/day. Increase dosing only if blood counts are in an acceptable range. Increase dosing if a painful crisis occurs. Do not increase if myelosuppression occurs. Blood Counts Acceptable Range: - neutrophils greater than or equal to 2,000 cells/mm3 - platelets greater than or equal to 80,000/mm3 - hemoglobin greater than 5.3 g/dL - reticulocytes greater than or equal to 80,000/mm3 if the hemoglobin concentration less than 9 g/dL Dosing Adjustment Based on Blood Counts in a toxic range Discontinue treatment. If blood counts are considered toxic, discontinue SIKLOS until hematologic recovery. Blood Counts Toxic Range: - neutrophils less than 2,000 cells/mm3 younger patients with lower baseline counts may safely tolerate absolute neutrophil counts down to 1,250/mm3. - platelets less than 80,000/mm3 - hemoglobin less than 4.5 g/dL - reticulocytes less than 80,000/mm3 if the hemoglobin concentration less than 9 g/dL Dosing After Hematologic Recovery Reduce dose by 5 mg/kg/day. Reduce the dose from the dose associated with hematologic toxicity. May titrate up or down every 8 weeks in 5 mg/kg/day increments. The patient should be at a stable dose with no hematologic toxicity for 24 weeks. Discontinue the treatment permanently if a patient develops hematologic toxicity twice. Siklos is available in 100 mg and 1,000 mg tablets. The 1,000 mg tablets have 3 score lines and can be split into 4 parts (each 250 mg). Therefore, the two strengths can be used to deliver doses of 1,000 mg, 750 mg, 500 mg, 250 mg, 100 mg, and combinations thereof. Calculate the rounded doses to the nearest 50 mg or 100 mg strength based on clinical judgment. Do not split the SIKLOS 100 mg tablets into smaller parts. Patients must be able to follow directions regarding drug administration and their monitoring and care. Fetal hemoglobin (HbF) levels may be used to evaluate the efficacy of SIKLOS in clinical use. Obtain HbF levels every three to four months. Monitor for an increase in HbF of at least two-fold over the baseline value. Administration: The tablet should be taken once daily, with a glass of water. For patients who are not able to swallow the tablets, these can be dispersed immediately before use in a small quantity of water in a teaspoon. SIKLOS is a cytotoxic drug. Follow applicable special handling and disposal procedures [see References (15)]. 2.2 Dose Modifications for Renal Impairment Reduce the dose of SIKLOS by 50% in patients with creatinine clearance of less than 60 mL/min or with end-stage renal disease (ESRD) [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)]. Obtain the creatinine clearance using a 24-hour urine collection. Creatinine Clearance (mL/min) Recommended SIKLOS Initial Dose (mg/kg daily) Greater than or equal to 60 20 Less than 60 or ESRDOn dialysis days, administer SIKLOS to patients with ESRD following hemodialysis 10 Monitor the hematologic parameters closely in these patients.
Use in special populations
8 USE IN SPECIFIC POPULATIONS Lactation: Advise women to stop breastfeeding while taking SIKLOS. 8.1 Pregnancy Risk Summary SIKLOS can cause fetal harm based on findings from animal studies and the drug's mechanism of action [see Clinical Pharmacology (12.1)]. 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/m² 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/m2 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/m2 basis) in rats and at 30 mg/kg/day (about 0.3 times the maximum recommended human daily dose on a mg/m2 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/m2 basis) to rats caused growth retardation and impaired learning ability. 8.2 Lactation Risk Summary It is not known whether SIKLOS is excreted in human milk, the effects of SIKLOS on the breastfed child, or the effects of SIKLOS on milk production. Because of the potential for serious adverse reactions in a breastfed child from SIKLOS, including carcinogenicity, advise patients not to breastfeed during treatment with SIKLOS. 8.3 Females and Males of Reproductive Potential Pregnancy Testing SIKLOS can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)]. Verify the pregnancy status of females of reproductive potential prior to initiating SIKLOS therapy. Contraception Females Advise females of reproductive potential to use effective contraception during and after treatment with SIKLOS for at least 6 months after therapy. Advise females to immediately report pregnancy. Males SIKLOS may damage spermatozoa and testicular tissue, resulting in possible genetic abnormalities. Males with female sexual partners of reproductive potential should use effective contraception during and after treatment with SIKLOS for at least 6 months after therapy [see Nonclinical Toxicology (13.1)]. Infertility Males Based on findings in animals and humans, male fertility may be compromised by treatment with SIKLOS. Azoospermia or oligospermia, sometimes reversible, has been observed in men. Before the start of therapy, inform male patients about the possibility of sperm conservation [see Adverse Reactions (6) and Nonclinical Toxicology (13.1)]. 8.4 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) [see Clinical Studies (14)]. 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. 8.6 Renal Impairment The exposure to SIKLOS is higher in patients with creatinine clearance of less than 60 mL/min. Reduce dosage and closely monitor the hematologic parameters when SIKLOS is to be administered to these patients [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3)]. 8.7 Hepatic impairment Close monitoring of hematologic parameters is advised in patients with hepatic impairment receiving SIKLOS.

Interactions

7 DRUG INTERACTIONS 7.1 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. 7.2 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. 7.3 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.

More information

Category Value
Authorisation number NDA208843
Agency product number X6Q56QN5QC
Orphan designation No
Product NDC 71770-100,71770-120
Date Last Revised 08-02-2018
Type HUMAN PRESCRIPTION DRUG
Storage and handling 16.2 Storage Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C and 30°C (59°F and 86°F) [see USP Controlled Room Temperature]. Keep tightly closed. Broken 1,000 mg tablets must be stored in the bottle and must be used within three months.
Marketing authorisation holder Medunik
Warnings WARNING: MYELOSUPPRESSION and MALIGNANCIES WARNING: MYELOSUPPRESSION and MALIGNANCIES See full prescribing information for complete boxed warning. Myelosuppression : SIKLOS may cause severe myelosuppression. Do not give if bone marrow function is markedly depressed. Monitor blood counts at baseline and throughout treatment. Interrupt treatment and reduce dose as necessary. (5.1) Malignancies : Hydroxyurea is carcinogenic. Advise sun protection and monitor patients for malignancies. (5.2) Myelosuppression: SIKLOS may cause severe myelosuppression. Monitor blood counts at baseline and throughout treatment. Interrupt treatment and reduce dose as necessary [see Warnings and Precautions (5.1)] . Malignancies: Hydroxyurea is carcinogenic. Advise sun protection and monitor patients for malignancies [see Warnings and Precautions (5.2)] .