Clinical
Experience

Siklos® Clinical Trial Experience1

Pediatric Patients with Sickle Cell Disease

The FDA approved Siklos® based on safety and efficacy data from a European prospective open-label, single-arm study, ESCORT-HU, of 405 pediatric patients (safety set) aged 2-18 years, with sickle cell disease, of whom 141 (efficacy set) had not been previously treated with hydroxyurea prior to enrollment.2

After 12 months of Siklos® treatment, hemoglobin F (Hb F) significantly increased and the percentage of patients with at least one vaso-occlusive episode, one episode of acute chest syndrome, one hospitalization due to SCD or one blood transfusion decreased.

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, and alopecia), gastrointestinal disorders, vitamin D deficiency and headache.

At least one serious adverse reaction was reported in 33 % of the 405 pediatric patients with sickle cell disease in ESCORT-HU. The most frequent serious adverse reactions were infections (18 %) and blood and lymphatic system disorders (9 %). This included 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%).

Most frequent (greater than or equal to 2.0%) adverse reactions reported in pediatric patients enrolled in ESCORT-HU 1

Global Safety Set (N=405)TotalIntensity
MildModerateSevere
 n%n%n%n%
At least one adverse reaction 261 64            
Infections 161 40 120 30 88 22 18 4.4
Other infections 92 23 66 16 32 8 3 0.7
Bacterial 65 16 24 6 37 9 10 2.5
Viral 40 10 23 6 14 3.5 3 0.7
Parvovirus B19 15 4 7 1.7 5 1.2 2 0.5
Blood and lymphatic system disorders 85 21 51 13 59 15 14 3.5
Neutropenia 51 13 26 6 31 8 4 1
Thrombocytopenia 30 7 16 4 15 3.7 2 0.5
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 0.5
Constipation 10 2.5 5 1.2 5 1.2 0 0
Nausea 10 2.5 4 1 4 1 2 0.5
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 0.2
Other metabolic and nutrition disorders 8 2 3 0.7 4 1 1 0.2
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 0.5
Skin and subcutaneous tissue disorders 38 9 29 7 14 3.5 1 0.2
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 0.2
Other not SCD-related reactions 23 6 16 4 3 0.7 1 0.2
Respiratory thoracic and mediastinal disorders 11 3 6 1.5 3 0.7 2 0.5
Renal and urinary disorders 8 2 2 0.5 4 1 0 0
n: number of patients with an adverse reaction

Adult Patients with Sickle Cell Disease

In ESCORT-HU 1077 adult patients were included of which 436 patients were naïve to HU treatment. There were 370 evaluable patients who had at least 12 months follow-up (Median [range] 41 months [29, 54]. Median (range) hemoglobin F percentages were 5.2% (0.2, 30.9) at baseline and 14.2% (0.5, 41.5) at least 6 months (the value closest to 6 months collected between 5 and 14 months) after initiation of SIKLOS treatment, with a median (range) change of 8% (-8.0, 33.3) in 181 patients. Among adult patients previously not treated with hydroxyurea prior to enrollment and analyzable for efficacy (N=370), the incidence and number of vaso-occlusive events, hospitalizations, acute chest syndrome and blood transfusions in the 12 month period before treatment and after initiation of treatment decreased after 12 months of SIKLOS treatment.

Comparison of SCD Events in the First Year of Treatment with SIKLOS with SCD Events in the 12 Months Prior to Enrollment – ESCORT HU Trial (N=370) in Adult Patients

SCD eventsAdult Patients previously not treated with hydroxyurea with at least 12 months follow-up data available for clinical efficacy (N=369)
In the 12 months prior to enrolmentAfter 12 months of Siklos® treatmentChange
Number of patients with at least one vaso-occlusive episode (in 367 evaluable patients)
No 133 (36.2%) 226 (61.6%)  
Yes 234 (63.8%) 141 (38.4%)  
Number of vasoocclusive episodes over 12 months (in 343 evaluable patients)
Median (range) 1.0 (0.0, 20.0) 0.0 (0.0, 30.0) 0.0 (-20.0, 24.0)
Number of patients with at least one episode of acute chest syndrome (in 365 evaluable patients)
No 273 (74.8%) 338 (92.6%)  
Yes 92 (25.2%) 27 (7.4%)  
Number of episodes of acute chest syndrome over 12 months (in 364 evaluable patients)
Median (range) 1.0 (0.0, 5.0) 0.0 (0.0, 3.0) 0.0 (-5.0 ; 2.0)
Number of patients with at least one hospitalization related to SCD (in 366 evaluable patients)
No 152 (41.5%) 252 (68.9%)  
Yes 214 (58.5%) 114 (31.1%)  
Number of hospitalizations related to SCD over 12 months (in 360 evaluable patients)
Median (range) 1 (0.0, 15.0) 0 (0.0, 10.0) 0 (-15.0, 8.0)
Number of days of hospitalizations related to SCD over 12 months (in 313 evaluable patients)
Median (range) 2 (0.0, 90.0) 0 (0.0, 77.0) 0 (-90.0, 57.0)
Number of patients with at least one blood transfusion (in 365 evaluable patients)
No 207 (56.7%) 296 (81.1%)  
Yes 158 (43.3%) 69 (18.9%)  

References

  1. Siklos® (hydroxyurea) tablets, for oral use [Prescribing Information]. Addmedica, December 2021.
  2. https://clinicaltrials.gov/ct2/show/NCT02516579

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 adult and 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 initial dose in adults or in children, have experienced severe or life-threatening myelosuppression. During body weight change 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. Leukemia secondary to long-term hydroxyurea has also been reported in patients with sickle cell disease. Leukemia has also been reported in patients with sickle cell disease and no prior history of treatment with hydroxyurea.

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.

Interference with Continuous Glucose Monitoring (CGM) Systems is possible, rendering falsely elevated sensor glucose results from certain 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.

Hemolytic Anemia
Cases of hemolytic anemia in patients treated with hydroxyurea for myeloproliferative disease have been reported. Monitor blood counts throughout treatment. If hemolysis persists, discontinue SIKLOS.

ADVERSE REACTIONS

The most common adverse reactions to SIKLOS (incidence >10%) include infections and neutropenia in children and infections and headache and dry skin in adults.

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. In patients with sickle cell anemia, neutropenia was reported in isolated cases of hydroxyurea overdose (1.43 – 8.57 times the maximum recommended dose). Treat overdose with gastric lavage, symptom treatment and control of bone marrow function. Monitor blood counts weekly until recovery.

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

INDICATION

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.

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

INDICATION

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.

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.