Prescribing
Siklos®

Dosing

Siklos® is available in scored 100 mg (2x 50 mg) 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.

Siklos® tablets offer more tailored 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 

Siklos® 100 mg - Box and pills

Siklos® 1,000 mg - Box and pills

 

The Siklos® Advantage: Body Weight adjusted dosing

Prescribing Siklos®

siklos dosing graph

  • Tailored weight-adjusted dosing in 50mg increments without the need for compounding
  • As the patient grows, Siklos® allows for flexible dosing based on body weight, blood count, and clinical response.
  • Follows throughout the patient’s treatment journey and various stages of growth
  • Dissolvable in water for oral administration
  • Siklos® is contraindicated in patients who have demonstrated a previous hypersensitivity to hydroxyurea or any other component of its formulation.

 

Start Early, Stay the Course, and Switch to Siklos®

  • Start Early:

    In pediatric patients 2 years of age and older with sickle cell anemia with recurrent moderate to severe painful crises, starting Siklos® can help reduce the frequencies of these crises and reduce the need for blood transfusions.

  • Stay the Course:

    Siklos® 100 mg scored and 1,000 mg scored tablets provide tailored weight-adjusted dosing in 50 mg increments without the need for compounding.

  • Switch your Growing Pediatric Patients to Siklos®:

    If patients are 2 years of age or older and already on hydroxyurea, Siklos® can accompany your patients along their treatment journeys by providing a safe and effective dissolvable dosing regimen to help prevent long term complications.

  • The most common adverse reactions to Siklos® (> 10%) include infections and myelosuppression.

 

Switch Growing Patients to Siklos®

Switch to Siklos® Considerations

  • Convenience
    • No refrigeration required
    • No compounding necessary
    • Longer shelf life versus compounded formulations
      • 3 years unopened and 3 months if tablet is broken
    • Dissolvable in minimal volume – 5mL of water on a spoon
    • Siklos® tablets should be taken once daily, at the same time each day, with a glass of water
  • Administration
    • Available in 100 mg and 1,000 mg - scored tablets
    • Tailored weight-based dosing
  • Medicaid and Commercial Insurance Coverage

 

  • Siklos® is a cytotoxic drug. Follow applicable special handling and disposal procedures.

 


Dosage Adjustment

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

  • Starting dose is 20 mg per kg per day.
  • 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.

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 every two weeks 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. Hydroxyurea was embryotoxic and teratogenic in rats and rabbits at doses 0.8 times and 0.3 times, respectively, the maximum recommended human daily dose on a mg/m2 basis. 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. 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 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

View and print Dissolving Instructions

See how a Siklos® tablet dissolves in water


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.
  • Because Siklos® tablets are scored, advise patients on how to take Siklos® properly.
  • 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.
  4. Siklos® (hydroxyurea) tablets, for oral use [Prescribing Information]. Addmedica, May 2019.

Indication and important safety information

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.

DOSAGE AND ADMINISTRATION

SIKLOS dosing is based on patient’s actual or ideal weight, whichever is less. Specific parameters (blood counts) must be monitored every 2 weeks throughout treatment with SIKLOS and dosing must be adjusted accordingly.

Dosing recommendation based on blood count:

  • Initial recommended dose is 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.
  • Dosing adjustments can be made if blood counts are in an acceptable range.
    • Increase dose 5 mg/kg/day every 8 weeks or if a painful crisis occurs, until a maximum tolerated dose of 35 mg/kg/day is reached.
  • If blood counts are considered toxic, discontinue SIKLOS until hematologic recovery.
  • Reduce the dose of SIKLOS by 50% in patients with renal impairment (creatinine clearance of less than 60mL/min.). Monitor the hematologic parameters closely in these patients.

SIKLOS is available in 100 mg and 1,000 mg tablets. The 100 mg tablets have 1 score line and can be split into 2 parts (each 50 mg). The 1,000 mg tablets have 3 score lines and can be split into 4 parts (each 250 mg).

The tablets should be taken once daily, at the same time each day, 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.

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.

Evaluate hematologic status prior to and every two weeks 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 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. 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. Monitor for signs and symptoms in patients with HIV infection using antiretroviral drugs. Discontinue SIKLOS and implement treatment.

Risks with Concomitant Use of Live Virus Vaccine
Avoid use of live virus vaccine in patients taking SIKLOS as it 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.

ADVERSE REACTIONS

The most common adverse reactions to SIKLOS (>10%) include 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.

USE IN SPECIFIC POPULATIONS

  • Pregnancy: SIKLOS can cause fetal harm. Advise pregnant women of the potential risk to a fetus.
  • Lactation: 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: Reduce dosage and closely monitor the hematologic parameters when SIKLOS is administered to patients with renal impairment – creatinine clearance of less than 60mL/min.
  • Hepatic Impairment: Monitor hematologic parameters more frequently 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 at hcp.SIKLOSusa.com.

Indication and important safety information

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: MYELOSUPPRESION 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.

Indication and important safety information

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: MYELOSUPPRESION 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.