Prescribing
Siklos®

Dosing

Siklos® is available in 100 mg film-coated tablets and 1,000 mg triple-scored (4 x 250 mg) tablets to allow dose adjustment based on patient body weight and clinical response.

Where both strengths of Siklos® (100 mg and 1,000 mg) are prescribed simultaneously, make sure that the patient and/or the parents or caregivers understand the prescription in order to avoid confusion.

Do not split 100 mg tablets.

Siklos® 1,000 mg triple-scored tablets allow dose adjustments in increments as small as 50 mg* to help optimize dosing.

  • Children with sickle cell disease are at increased risk of infection and recurrent painful episodes during childhood, which may lead to severe organ failure. Recurrences of painful episodes or evidence of organ dysfunction are clearly associated with poor prognosis and early mortality.1 
  • The importance of optimal dosing of hydroxyurea in sickle cell anemia patients based on patient body weight and biological and clinical response has been well established.2, 3 

*Beginning at a 200 mg dose.

Box 100

Important: Siklos® 100 mg tablets must NOT be split into smaller parts.

comp 100mg 100 mg

With Siklos® 100 mg tablets, dose adjustments can be made in 100 mg increments:

Graph1

Possible daily doses with Siklos® 100 mg film-coated tablets:

Chart1

 

 

 

Siklos® 1,000 mg triple-scored tablets allow further customization by permitting dose adjustments in increments as small as 50 mg (beginning at a 200 mg dose).

Box 1000

Important: Siklos® 100 mg tablets must NOT be split into smaller parts.

comp 1000mg

Graph2

*Beginning at a 200 mg dose.

 

By combining Siklos® 100 mg film-coated tablets and 1,000 mg triple-scored tablets, you can prescribe any of the following daily doses:

Chart2

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Handling and Breaking Instructions

These are the precise dosages required, based on patient age and body weight:

Graph5

Siklos® 1,000 mg triple-scored tablets allow you to achieve a dosage closer to the required dosage:

Graph4

 


Dosage Adjustment

Daily dose should be adjusted based on patient body weight and clinical response.

  • Starting dose is 15 mg per kg per day.
  • The usual maintenance dose is between 15 and 30 mg/kg/day.
  • In some exceptional cases, a maximum dose of 35 mg/kg/day may be justified and administered under close monitoring of blood counts.

Dosing Recommendation Based on Blood Count:

Dosing RegimenDoseDose Modification CriteriaMonitoring 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.

Please see Warnings and Precautions in Section 5 of PI

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 is 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.

 
Dose Modifications for Renal Impairment Reduce dose by 50% in patients with creatinine clearance of less than 60 mL/min or with end-stage renal disease (ESRD). Obtain creatinine clearance using a 24-hour urine collection.

Creatinine Clearance
(mL/min) greater than or equal to 60: recommended initial dose: 20 mg/kg daily.

Creatinine Clearance
(mL/min) less than 60 or ERSD (On dialysis days, administer Siklos® to patients with ESRD following hemodialysis).

Monitor the hematologic parameters closely in these patients: 10 mg/kg daily.

Please see Dose Modifications for Renal Impairment in Section 2.2 of PI.

Do not split the Siklos® 100 mg tablets into smaller parts.

Patients and/or caregivers must be able to follow directions regarding drug administration and patient 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.


Contraindications

Siklos® is contraindicated in patients who have demonstrated a previous hypersensitivity to hydroxyurea or any other component of its formulation.


Warnings and Precautions

  • Myelosuppression:

    Hydroxyurea causes severe myelosuppression. Do not initiate treatment with hydroxyurea in patients if bone marrow function is markedly depressed. Bone marrow suppression may occur, and leukopenia is generally its first and most common manifestation. Thrombocytopenia and anemia occur less often, and are seldom seen without a preceding leukopenia.

    Some patients, treated at the recommended initial dose of 20 mg/kg/day, have experienced severe or life-threatening myelosuppression. Due to the change in body weight requiring modification of daily dose, pediatric patients have an increased risk of myelosuppression at the time of dose adjustment.

    Evaluate hematologic status prior to and during treatment with Siklos®. Provide supportive care and modify dose or discontinue Siklos® as needed. Recovery from myelosuppression is usually observed within 15 days when therapy is interrupted. Resume therapy after interruption at a lower dose.

  • Malignancies:

    Hydroxyurea is a human carcinogen. In patients receiving long-term hydroxyurea for myeloproliferative disorders (a condition for which Siklos® is not approved), secondary leukemia has been reported. Skin cancer has also been reported in patients receiving long-term hydroxyurea. Advise protection from sun exposure and monitor for the development of secondary malignancies.

  • Embryo-Fetal Toxicity:

    Based on the mechanism of action and findings in animals, Siklos® can cause fetal harm when administered to a pregnant woman. Advise women of the potential risk to the fetus.

    Advise females of reproductive potential to use effective contraception during and after treatment with Siklos® for at least 6 months after therapy. Advise males of reproductive potential to use effective contraception during and after treatment with Siklos® for at least 6 months after therapy.

  • Vasculitic Toxicities (Including Leg Ulcers):

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

    Avoid use of Siklos® in patients with wounds on the legs (leg ulcers).

  • Risks with Concomitant Use of Antiretroviral Drugs:

    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. Pancreatitis, hepatotoxicity, and neuropathy have occurred when hydroxyurea was administered concomitantly with antiretroviral drugs, including didanosine and stavudine. 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.

  • Risks with Concomitant Use of Live Virus Vaccine:

    Avoid use of live virus vaccine in patients taking Siklos®. Concomitant use of hydroxyurea with a live virus vaccine may potentiate the replication of the vaccine virus and/or may increase the adverse reactions of the vaccine virus and result in severe infections. Patient’s antibody response to vaccines may be decreased. Consider consultation with a specialist.

  • Macrocytosis

    Siklos® may cause macrocytosis, which is self-limiting, and is often seen early in the course of treatment.
    The morphologic change resembles pernicious anemia, but is not related to vitamin B12 or folic acid deficiency. This may mask the diagnosis of pernicious anemia. Prophylactic administration of folic acid is recommended.

  • Test Interference

    Interference with uric acid, urea, or lactic acid assays is possible, rendering falsely elevated results of these in patients treated with hydroxyurea.


Administration

Siklos® should be taken once daily, at the same time every day, with a glass of water. For patients who are not able to swallow the tablets whole, they can be dispersed immediately before use in a small quantity of water in a teaspoon.

Siklos® is a cytotoxic drug.

Siklos® tablets must be handled with care.

View and print
Handling and Breaking Instructions
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Dissolving Instructions

Please see Dose Modifications for Renal Impairment in Section 2.2 of PI.


Patient Counseling Information

Advise patient or caregiver to read the FDA-approved patient labeling: Instructions for Use and Medication Guide.

  • There is a risk of myelosuppression. Emphasize the importance of monitoring blood counts every two weeks throughout the duration of therapy to patients taking Siklos®. Please read Warnings and Precautions in Section 5 of PI. Advise patients to report signs and symptoms of infection or bleeding immediately to their HCP or, in case of emergency, to call 911.
  • Advise patients that there is a risk of cutaneous vasculitic toxicities and secondary malignancies including leukemia. Advise use of sun protection. Please read Warnings and Precautions in Section 5 of PI.
  • Advise females of reproductive potential of the potential risk to a fetus should they become pregnant while taking Siklos®. Advise patients to inform their healthcare provider of a known or suspected pregnancy. Advise females and males of reproductive potential to use contraception during and after treatment with Siklos® for at least 6 months after therapy.
  • Advise females to discontinue breastfeeding during treatment with Siklos®. See Section 8.2 of PI.
  • Advise male patients of potential risk to fertility.
  • Advise patients with HIV infection to contact their physician for signs and symptoms of pancreatitis, hepatic events and peripheral neuropathy. See Section 7.1 of PI.
  • Where both strengths of Siklos® (100 mg and 1,000 mg) are prescribed simultaneously, make sure that the patient and/or the parents or caregivers understand the prescription in order to avoid confusion.

References

  1. Ferster, A. et al. Hydroxyurea for treatment of severe sickle cell anemia: a pediatric clinical trial. Blood 88, 1960-1964 (1996).
  2. Ware et al. Hematology Am Soc Hematol Educ Program. 2015;2015:436-432.
  3. Strouse et al. Pediatr Blood Cancer. 2012 August ; 59(2): 365–371.

Indication and important safety information

INDICATION

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.

IMPORTANT SAFETY INFORMATION

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.
  • Malignancies: Hydroxyurea is carcinogenic. Advise sun protection and monitor patients for malignancies.

CONTRAINDICATIONS

Siklos® is contraindicated in patients who have demonstrated a previous hypersensitivity to hydroxyurea or any other component of its formulation.

WARNINGS AND PRECAUTIONS

Myelosuppression
Hydroxyurea causes severe myelosuppression. Do not initiate treatment with hydroxyurea in patients if bone marrow function is markedly depressed. Bone marrow suppression may occur, and leukopenia is generally its first and most common manifestation. Thrombocytopenia and anemia occur less often, and are seldom seen without a preceding leukopenia.

Some patients, treated at the recommended initial dose of 20 mg/kg/day, have experienced severe or life-threatening myelosuppression. Due to the change in body weight requiring modification of daily dose, pediatric patients have an increased risk of myelosuppression at the time of dose adjustment.

Evaluate hematologic status prior to and during treatment with Siklos® Provide supportive care and modify dose or discontinue Siklos® as needed. Recovery from myelosuppression is usually observed within 15 days when therapy is interrupted. Resume therapy after interruption at a lower dose.

Malignancies
Hydroxyurea is a human carcinogen. In patients receiving long-term hydroxyurea for myeloproliferative disorders (a condition for which Siklos® is not approved), secondary leukemia has been reported. Skin cancer has also been reported in patients receiving long-term hydroxyurea. Advise protection from sun exposure and monitor for the development of secondary malignancies.

Embryo-Fetal Toxicity
Based on the mechanism of action and findings in animals, Siklos® can cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to a fetus.

Advise females of reproductive potential to use effective contraception during and after treatment with Siklos® for at least 6 months after therapy. Advise males of reproductive potential to use effective contraception during and after treatment with Siklos® for at least 6 months after.

Vasculitic Toxicities (including Leg Ulcers)
Cutaneous vasculitic toxicities, including vasculitic ulcerations and gangrene, have occurred in patients with myeloproliferative disorders during therapy with hydroxyurea. 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 (a condition for which Siklos® is not approved), treatment with Siklos® should be discontinued and/or its dose reduced if cutaneous vasculitic ulcerations develop. Rarely, ulcers are caused by leukocytoclastic vasculitis.

Avoid use of Siklos® in patients with wounds on the legs (leg ulcers).

Risks with Concomitant Use of Antiretroviral Drugs
Pancreatitis, hepatotoxicity, and peripheral neuropathy have occurred when hydroxyurea was administered concomitantly with antiretroviral drugs, including didanosine and stavudine.

Risks with Concomitant Use of Live Virus Vaccine
Avoid use of live virus vaccine in patients taking Siklos®. Concomitant use of hydroxyurea with a live virus vaccine may potentiate the replication of the vaccine virus and/or may increase the adverse reactions of the vaccine virus and result in severe infection. Patient’s antibody response to vaccines may be decreased. Consider consultation with a specialist.

Macrocytosis
Siklos® may cause macrocytosis, which is self-limiting, and is often seen early in the course of treatment. The morphologic change resembles pernicious anemia, but is not related to vitamin B12 or folic acid deficiency. This may mask the diagnosis of pernicious anemia. Prophylactic administration of folic acid is recommended.

Test Interference
Interference with Uric Acid, Urea, or Lactic Acid Assays is possible, rendering falsely elevated results of these in patients treated with hydroxyurea.

DOSAGE AND ADMINISTRATION

  • Do not split the Siklos® 100 mg tablets into smaller parts.
  • Siklos® is a cytotoxic drug. Ensure patients follow applicable special handling and disposal procedures.
  • Siklos® dosing is based on patient’s actual or ideal weight, whichever is less. Specific parameters (blood counts) must be monitored throughout treatment with Siklos® and dosing must be adjusted accordingly.
  • Monitor the hematologic parameters closely in patients with renal impairments.

ADVERSE REACTIONS

  • The most common adverse reactions to Siklos® (incidence > 10%) include infections and neutropenia. Other adverse reactions include skin and subcutaneous disorders (skin depigmentation/melanonychia, skin rash, alopecia), gastrointestinal disorders, vitamin D deficiency and headache.
  • Clinical Trial Experience: 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.

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%).

USE IN SPECIFIC POPULATIONS

  • Pregnancy: Siklos® can cause fetal harm based on findings from animal studies and the drug’s mechanism of action. Advise pregnant women of the potential risk to a fetus.
  • Lactation: 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®.
  • Females and Males of Reproductive Potential: Advise patients to inform their healthcare provider of a known or suspected pregnancy. Advise females and males of reproductive potential to use contraception during and after treatment with Siklos® for at least 6 months after therapy. Based on findings in animals and humans, male fertility may be compromised by treatment with Siklos®. Prior to therapy, advise male patients about the possibility of sperm conservation.
  • Pediatric Use: 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.
  • 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
  • Hepatic impairment: Close monitoring of hematologic parameters is advised in patients with hepatic impairment receiving Siklos®.

OVERDOSAGE

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.

To report suspected adverse reactions, contact Medunik USA at 1-844-884-5520 or medicalinfo@medunikusa.com.

Please read the Full Prescribing Information, including Boxed Warning.

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