Siklos

Recommended Dosing

The recommended Siklos dosing is described in Table 1.

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)].

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.

Monitor the hematologic parameters closely in these patients.

Film-coated tablets:

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.

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.

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)].

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.

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)].

Hepatic impairment

Close monitoring of hematologic parameters is advised in patients with hepatic impairment receiving Siklos.

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.

Siklos (hydroxyurea) is an antimetabolite that is available for oral use as 100 mg film-coated tablet and functionally triple-scored 1,000 mg film-coated tablet containing 100 and 1,000 mg of hydroxyurea, respectively. Inactive ingredients include silicified microcrystalline cellulose, sodium stearyl fumarate, and film-coating agent amino methacrylate copolymer.

Hydroxyurea is a white crystalline powder. It has a molecular weight of 76.05. Its structural formula is:

Advise the 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 [see Warnings and Precautions (5.1)]. Advise patients to report signs and symptoms of infection or bleeding immediately.
• Advise patients that there is a risk of cutaneous vasculitic toxicities and secondary malignancies including leukemia. Advise use of sun protection [see Warnings and Precautions (5.1)].
• 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 [see Warnings and Precautions (5.3) and Use in Specific Populations (8.1,8.3)].
• Advise females to discontinue breastfeeding during treatment with Siklos [see Use in Specific Populations (8.2)].
• 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 Warnings and Precautions (5.5)].
• Because Siklos 1,000 mg tablets are scored, advise patients on how to take Siklos properly.

Distributed by:
Medunik USA, Inc, Bryn Mawr, (Pennsylvania).

Manufactured by: Addmedica, France.

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Siklos is a trademark of Addmedica.

INSTRUCTIONS FOR USE
Siklos (See – k – los)
(hydroxyurea)
tablets

Read this Instructions for Use before you start taking Siklos and each time you get a refill. There may be new information. This Instructions for Use does not take the place of talking to your healthcare provider about your medical condition or treatment. You and your healthcare provider should talk about Siklos when you start taking it and at regular checkups.

Storing your Siklos tablets:

• Store Siklos at room temperature between 68°F to 77°F (20°C to 25°C).
• Keep the Siklos bottle tightly closed.

Keep Siklos and all medicines out of the reach of children.

Distributed by: MEDUNIK USA.
This Instructions for Use has been approved by the U.S. Food and Drug Administration.
Issued: 12/2017

Special form to illustrate daily dose and how to handle tablets

• If you have an allergy to hydroxyurea or any other part of this medicine (Siklos).
• If you are allergic to any drugs like this one, any other drugs, foods, or other substances. Tell your doctor about the allergy and what signs you had, like rash; hives; itching; shortness of breath; wheezing; cough; swelling of face, lips, tongue, or throat; or any other signs.
• If you have any of these health problems: Anemia (other than sickle cell anemia); bone marrow problems like low platelet count, low red blood cell count, or low white blood cell count; or wounds on the legs (leg ulcers).
• If you are taking any of these drugs: Didanosine or stavudine.
• If you are breast-feeding. Do not breast-feed while you take this medicine (Siklos).

This is not a list of all drugs or health problems that interact with this medicine (Siklos).

Tell your doctor and pharmacist about all of your drugs (prescription or OTC, natural products, vitamins) and health problems. You must check to make sure that it is safe for you to take this medicine (Siklos) with all of your drugs and health problems. Do not start, stop, or change the dose of any drug without checking with your doctor.

• Store at room temperature.
• Keep lid tightly closed.
• Store in a dry place. Do not store in a bathroom.
• If using the 1000 mg tablets and you have split them, store the smaller parts in the bottle. Use the smaller parts within 3 months.
• You must handle and throw away this medicine (Siklos) the right way. If powder from a broken tablet is spilled, wipe it up with a damp paper towel. Throw away the towel in a closed holder, such as a plastic bag. Wash your hands fully.
• Keep all drugs in a safe place. Keep all drugs out of the reach of children and pets.
• Throw away unused or expired drugs. Do not flush down a toilet or pour down a drain unless you are told to do so. Check with your pharmacist if you have questions about the best way to throw out drugs. There may be drug take-back programs in your area.

Both men and women using Siklos should use birth control to prevent pregnancy. The use of Siklos by either parent may cause birth defects.

Using Siklos may increase your risk of developing other types of cancer, such as leukemia or skin cancer. Wear protective clothing and use sunscreen when you are outdoors.

Siklos can weaken your immune system. Call your doctor at once if you have a fever, chills, body aches, extreme tiredness, shortness of breath, bruising, or unusual bleeding.

You should not use Siklos if you are allergic to it.

Tell your doctor if you have ever had:

• kidney disease (or if you are on dialysis);

• liver disease;

• a wound or ulcer on your leg;

• HIV or AIDS (especially if you take antiviral medicine);

• high levels of uric acid in your blood; or

• treatment with an interferon, chemotherapy, or radiation.

Using Siklos may increase your risk of developing other types cancer or leukemia. Talk with your doctor about your specific risk.

Siklos can harm an unborn baby. Both men and women using this medicine should use birth control to prevent pregnancy. The use of this medicine by either parent may cause birth defects.

• If you are a woman, keep using birth control for at least 6 months after your last dose of Siklos.

• If you are a man, keep using birth control for at least 1 year after your last dose (6 months if you took Siklos).

• Tell your doctor right away if a pregnancy occurs while either the mother or the father is using this medicine.

This medicine may affect fertility (ability to have children) in men. However, it is important to use birth control because Siklos may harm the baby if a pregnancy does occur.

You should not breast-feed while you are taking Siklos.