Hydroxyurea Tablets, for Oral Use

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.

Dosage Forms And Strengths

Film-coated tablets:

• 100 mg tablets: off-white round, film-coated tablet embossed 100 on one side.
• 1,000 mg tablets: off-white, capsule-shaped, film-coated, functionally triple-scored tablet with scoring on both sides which can be divided into four equal parts embossed with “T” on one side.

Storage And Handling

SIKLOS (hydroxyurea) film-coated tablet is supplied in high density polyethylene (HDPE) bottle with polypropylene child-resistant cap with a desiccant unit containing 30 (SIKLOS 1,000 mg) or 60 (SIKLOS 100 mg) film coated tablets. Each bottle containing SIKLOS 100 mg tablets or SIKLOS 1,000 mg tablets is supplied in a carton.

SIKLOS is supplied in the following strengths:

• 100 mg off-white round, film-coated tablet, embossed with 100 on one side.
• 1,000 mg off-white, capsule-shaped, film-coated, functionally triple-scored tablet with scoring on both sides which can be divided into four equal parts embossed with “T” on one side.

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.

SIKLOS is a cytotoxic drug. Follow applicable special handling and disposal procedures [see REFERENCES].

To decrease the risk of contact, advise caregivers to wear disposable gloves when handling SIKLOS or bottles containing SIKLOS. Wash hands with soap and water before and after contact with the bottle or tablets when handling SIKLOS. Avoid exposure to crushed tablets. If contact with crushed tablets occurs on the skin, wash affected area immediately and thoroughly with soap and water. If contact with crushed tablets occurs on the eye(s), the affected area should be flushed thoroughly with water or isotonic eyewash designated for that purpose for at least 15 minutes.

Powder spilled from the broken tablet should be wiped up with a damp disposable towel which must be thrown away in a closed container such as a plastic bag to avoid ingestion of powder by other people. The spill areas should then be cleaned using a detergent solution followed by clean water.

REFERENCES

OSHA Hazardous Drugs. OSHA.http://www.osha.gov/SLTC/hazardousdrugs/index.html.

Manufactured by: Addmedica, France. Revised: Dec 2017

• Myelosuppression [see WARNINGS AND PRECAUTIONS]
• Malignancies [see WARNINGS AND PRECAUTIONS]
• Embryo-fetal toxicity [see BOX WARNING and WARNINGS AND PRECAUTIONS]
• Vasculitic toxicities (including Leg Ulcers) [see WARNINGS AND PRECAUTIONS]
• Risks with concomitant use of antiretroviral drugs [see WARNINGS AND PRECAUTIONS]
• Risk with concomitant use of live virus vaccine [see WARNINGS AND PRECAUTIONS]
• Macrocytosis [see WARNINGS AND PRECAUTIONS]

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

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 x 109/l), reticulocytopenia (<80 x 109/l), macrocytosis, thrombocytopenia (<80 x 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

Mechanism Of Action

The precise mechanism by which hydroxyurea produces its cytotoxic and cytoreductive effects is not known. However, various studies support the hypothesis that hydroxyurea causes an immediate inhibition of DNA synthesis by acting as a ribonucleotide reductase inhibitor, without interfering with the synthesis of ribonucleic acid or of protein.

The mechanisms by which SIKLOS produces its beneficial effects in patients with sickle cell Anemia (SCA) are uncertain. Known pharmacologic effects of SIKLOS that may contribute to its beneficial effects include increasing hemoglobin F levels in red blood cells (RBCs), decreasing neutrophils, increasing the water content of RBCs, increasing deformability of sickled cells, and altering the adhesion of RBCs to endothelium.

Pharmacodynamics

The correlation between hydroxyurea concentrations, reduction of crisis rate, and increase in HbF, is not known.

Pharmacokinetics

Following oral administration, hydroxyurea reaches peak plasma concentrations in 1 to 4 hours. Mean peak plasma concentrations and AUCs increase more than proportionally with increase of dose.

Effect of Food

There are no data on the effect of food on the absorption of hydroxyurea.

Hydroxyurea distributes throughout the body with a volume of distribution approximating total body water. Hydroxyurea concentrates in leukocytes and erythrocytes.

Metabolism

Up to 60% of an oral dose undergoes conversion through saturable hepatic metabolism and a minor pathway of degradation by urease found in intestinal bacteria.

Excretion

The percentage of the dose excreted in urine was approximately 40% in pediatric patients with sickle cell anemia.

Specific Populations

The effect of renal impairment on the pharmacokinetics of hydroxyurea was assessed in adult patients with sickle cell anemia and renal impairment. Patients with normal renal function (creatinine clearance [CrCl] >80 mL/min), mild (CrCl 50-80 mL/min), moderate (CrCl =30-<50 mL/min), or severe (<30 mL/min) renal impairment received a single oral dose of 15 mg/kg hydroxyurea. Creatinine clearance values were obtained using 24-hour urine collections. Patients with ESRD received two doses of 15 mg/kg separated by 7 days; the first was given following a 4-hour hemodialysis session, the second prior to hemodialysis. The exposure to hydroxyurea (mean AUC) in patients with CrCl <60 mL/min and those with ESRD was 64% higher than in patients with normal renal function (CrCl >60 mL/min). Reduce the dose of SIKLOS when it is administered to patients with creatinine clearance of <60 mL/min or with ESRD following hemodialysis [see DOSAGE AND ADMINISTRATION and Use In Specific Populations].

There are no data that support specific guidance for dose adjustment in patients with hepatic impairment.

The pharmacokinetics of hydroxyurea is similar between children (4 to 17 years) and adults.

Clinical Studies

The efficacy of SIKLOS was assessed in the European Sickle Cell Disease Cohort study (ESCORT HU) [NCT02516579]. This is an open-label single-arm study of 405 pediatric patients with sickle cell disease from 2-18 years of age, of which 141 had not been previously treated with hydroxyurea prior to enrollment. Evaluable patients had at least 12 months follow-up (median [range] 23 months [12,80]). Median (range) hemoglobin F percentages were 5.6% (1.3, 15.0) at baseline and 12.8% (2.1, 37.2) at least 6 months (the value closest to 6 months collected between 5 and 14 months) after initiation of SIKLOS treatment, with median (range) change of 5.9% (-2.2, 34.7) in 47 patients. Median (range) hemoglobin levels were 8.2 g/dL (3.7, 14.2) at baseline, 8.8 g/dL (0.7, 13.1) at 6 months (the value closest to 6 months collected between 5 and 7 months), and 8.9 g/dL (5.5, 13.2) at 12 months (the value closest to 12 months collected between 10 and 14 months) after initiation of SIKLOS treatment. The median (range) change was 0.5 g/dL (-4.6, 6.1) in 63 patients at 6 months (the post-baseline value closest to 6 months collected between 5 and 7 months) and 0.7 g/dL (-6.4, 6.0) in 83 patients at 12 months (the post-baseline value closest to 12 months collected between 10 and 14 months) after initiation of SIKLOS treatment.

Among pediatric patients not previously treated with hydroxyurea prior to enrollment and analyzable for efficacy (N=141), 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 after 12 months of SIKLOS treatment (Table 2).

Table 2: 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=141)

SIKLOS
(See – k – los)
(hydroxyurea) Tablets

What is the most important information I should know about SIKLOS?

SIKLOS can cause serious side effects including:

• Low blood cell counts are common with SIKLOS, including low red blood cells, white blood cells, and platelets, and can be severe and life-threatening. If your white blood cell count becomes very low, you are at increased risk for infection. Your healthcare provider will check your blood cell counts before and during treatment with SIKLOS. Your healthcare provider may change your dose or tell you to stop taking SIKLOS if you have low blood cell counts. Tell your healthcare provider right away if you get any of the following symptoms:
  • fever or chills
  • shortness of breath
  • body aches
  • unusual headache
  • feeling very tired
  • bleeding or unexplained bruising
• Cancer. Some people have developed cancer, such as leukemia and skin cancer, after taking SIKLOS for a long time. Your healthcare provider will check you for cancer. You should protect your skin from the sun using sunblock, hats, and sun-protective clothing.
• SIKLOS can harm your unborn baby.
  For females taking SIKLOS who can become pregnant:
  • You should talk with your healthcare provider about the risks of SIKLOS to your unborn baby.
  • You should use effective birth control during treatment with SIKLOS and for at least 6 months after treatment with SIKLOS.
  • Your healthcare provider will perform a pregnancy test before you start treatment with SIKLOS. Tell your healthcare provider right away if you become pregnant or think you may be pregnant.
  • For males taking SIKLOS: SIKLOS can affect your sperm. If you have a female sexual partner who can become pregnant, you should use effective birth control during treatment with SIKLOS and for at least 6 months after treatment.

SIKLOS may cause fertility problems in males. Talk to your healthcare provider if this is a concern for you.

See “What are the possible side effects of SIKLOS?” for more information about side effects.

What is SIKLOS?

SIKLOS is a prescription medicine that is used to reduce the frequency of painful crises and reduce the need for blood transfusions in children, 2 years of age and older, with sickle cell anemia with recurrent moderate to severe painful crises. It is not known if SIKLOS is safe and effective in children less than 2 years of age.

Do not take SIKLOS if you are allergic to hydroxyurea or any of the ingredients in SIKLOS. See the end of this Medication Guide for a list of the ingredients in SIKLOS.

Before taking SIKLOS, tell your healthcare provider about all of your medical conditions, including if you:

• have kidney problems or are receiving hemodialysis
• have liver problems
• have human immunodeficiency virus (HIV) or take HIV medicines. Taking SIKLOS with certain HIV medicines can cause serious reactions and may lead to death.
• have increased levels of uric acid in your blood (hyperuricemia)
• have a history of receiving interferon therapy or are currently receiving interferon therapy
• have leg wounds or ulcers
• plan to receive any vaccinations. You should not receive “live vaccines” during treatment with SIKLOS.
• are pregnant or plan to become pregnant. See “What is the most important information I should know about SIKLOS?”
• are breastfeeding or plan to breastfeed. It is not known if SIKLOS can pass into your breast milk. Do not breastfeed during treatment with SIKLOS.

Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.

How should I take SIKLOS?

Read the Instructions for Use at the end of this Medication Guide for step-by-step instructions on how to prepare a dose of SIKLOS. If you have any questions, talk to your healthcare provider or pharmacist.

• Take SIKLOS exactly as your healthcare provider tells you to take it.
• Take SIKLOS 1 time a day at the same time each day.
• Swallow the tablet with a glass of water.
• SIKLOS is supplied as 100 mg tablets and 1,000 mg tablets. The SIKLOS 1,000 mg tablet has three separation lines (score lines) and can be broken at these score lines to provide smaller doses. Each 1,000 mg tablet can be divided into 4 equal parts (each part is 250 mg).
• Do not break the SIKLOS 100 mg tablets into smaller parts.
• Your healthcare provider will tell you how many tablets or parts of a tablet you should take. If you are not able to swallow SIKLOS tablets, you can dissolve your prescribed dose in a small amount of water in a teaspoon and swallow right away.
• SIKLOS tablets must be handled with care. To decrease the risk of exposure, you or your caregivers should do the following when handling SIKLOS:
  • Wear disposable gloves when handling SIKLOS or bottles containing SIKLOS. Wash your hands with soap and water before and after handling SIKLOS tablets or bottles containing SIKLOS.
  • Avoid contact with crushed tablets. If contact with crushed tablets happens on the skin, wash the skin area right away and thoroughly with soap and water. If contact with crushed tablets happens in the eyes, flush the eyes thoroughly with water or isotonic eyewash used for that purpose for at least 15 minutes.

Powder spilled from the broken tablet should be wiped up with a damp disposable towel which must be thrown away in a closed container such as a plastic bag to avoid ingestion of powder by other people. The spill areas should then be cleaned using a detergent solution followed by clean water.

• If you take too much SIKLOS, call your healthcare provider or go to the nearest hospital emergency room right away.

What are the possible side effects of SIKLOS?

SIKLOS may cause serious side effects, including:

See “What is the most important information I should know about SIKLOS?”

• Skin ulcers, including leg ulcers have happened in people who take SIKLOS. This has happened most often in people who receive interferon therapy or have a history of interferon therapy. Your healthcare provider will decrease your dose or stop treatment with SIKLOS if you develop any skin ulcers.
• Enlarged red blood cells (macrocytosis). Macrocytosis is common in people who take SIKLOS and can make it difficult to detect a decrease of folic acid. Your healthcare provider may prescribe a folic acid supplement for you.

  The most common side effects of SIKLOS include:

  • infections
  • headache
  • fever
  • skin problems including:
    • skin reactions
    • dry skin
    • changes in skin and nail color
  • stomach and intestine (gastrointestinal) problems including:
    • nausea
    • constipation
  • decrease in vitamin D
  • weight gain

These are not all the possible side effects of SIKLOS.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store SIKLOS?

• Store SIKLOS at room temperature between 68°F to 77°F (20°C to 25°C).
• Keep the SIKLOS bottle tightly closed.
• Broken 1,000 mg SIKLOS tablets must be stored in the bottle and must be used within three months.

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

General information about the safe and effective use of SIKLOS

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use SIKLOS for a condition for which it was not prescribed. Do not give SIKLOS to other people, even if they have the same symptoms you have. It may harm them. You can ask your healthcare provider or pharmacist for information about SIKLOS that is written for health professionals.

What are the ingredients of SIKLOS?

Active ingredient: hydroxyurea

Inactive ingredients: silicified microcrystalline cellulose, sodium stearyl fumarate, and film-coating agent amino methacrylate copolymer.

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.

Important Information:

• Wash your hands with soap and water before and after handling SIKLOS tablets or bottles containing SIKLOS.
• Wear disposable gloves when handling SIKLOS tablets or bottles containing SIKLOS.
• Take SIKLOS 1 time a day at the same time each day.
• Powder spilled from a broken tablet should be wiped up right away with a damp disposable paper towel and thrown away in a closed container, such as a plastic bag to avoid harm to other people. The spill area should then be cleaned using a detergent solution followed by clean water.
• When the tablet is broken, avoid touching the broken surfaces.
• If contact with crushed tablets happens on the skin, wash the skin area right away and thoroughly with soap and water.
• If contact with crushed tablets happens in the eyes, flush the eyes thoroughly with water or isotonic eyewash used for that purpose for at least 15 minutes.

SIKLOS is supplied in 2 different strengths:

SIKLOS 1,000 mg tablet has three separation lines (score lines) and can be broken at these score lines to provide smaller doses. Each 1,000 mg tablet can be divided into 4 equal parts (each part is 250 mg).

Do not break the SIKLOS 100 mg into smaller tablets.

SIKLOS 1,000 mg Tablet Breaking Instructions:

You will need the following supplies to break a SIKLOS 1,000 mg tablet:

• SIKLOS 1,000 mg tablets
• A damp disposable paper towel
• A tablet cutter
• Disposable gloves

Step 1: Place a damp disposable paper towel on a flat surface where the tablets will be broken.

Step 2: Wash and dry your hands before handling SIKLOS tablets or bottles containing the tablets.

Step 3: Check your prescribed dose. You may need more than 1 tablet to get your prescribed dose.

Step 4: Put on disposable gloves.

Step 5: Remove the SIKLOS 1,000 mg tablet out of the bottle needed to get your dose.

Step 6: Use your index fingers and thumbs to hold each end of the SIKLOS 1,000 mg tablet.

Step 7: While holding the ends of the SIKLOS 1,000 mg tablet, push down on the tablet to break the tablet on the score line to get your prescribed dose.

SIKLOS 1,000 mg tablets can be broken as:

• 1/4 of a tablet for a dose of 250 mg of SIKLOS:
• 1/2 of a tablet for a dose of 500 mg of SIKLOS:
• 3/4 of a tablet for a dose of 750 mg of SIKLOS:
• a whole tablet for a dose of 1,000 mg of SIKLOS (no breaking needed):

Note: You may need to use a tablet cutter to get the smaller tablets (1/4 of a tablet).

Step 8: Take your prescribed dose by swallowing it with a glass of water.

Important: If you have difficulty swallowing SIKLOS tablets, please stop here and follow the instructions below, “For people who cannot swallow SIKLOS tablets”.

Step 9: Throw away the damp disposable paper towel in the trash. Pull off disposable gloves and throw away in the trash.

Wash and dry your hands.

Step 10: Store any unused broken tablet in the bottle and put the bottle back in the box. Broken tablets must be used within three months.

For people who cannot swallow SIKLOS tablets

You will need the following supplies to prepare and take your dose by dissolving the tablet:

• Your bottle of SIKLOS 1,000 mg tablets or SIKLOS 100 mg tablets
  • Note: If you have been prescribed SIKLOS 1,000 mg and need to break your tablets, use the SIKLOS 1,000 mg Tablet Breaking Instructions above to get your prescribed dose before you begin the steps below.
• A teaspoon
• Water to dissolve tablets

Step 1: Get your prescribed dose of SIKLOS tablets. Put your prescribed dose of SIKLOS tablets onto the teaspoon.

SIKLOS 100 mg tablet

SIKLOS 1,000 mg tablet (broken)

Step 2: Add a small amount of water to the teaspoon. The tablet dissolves within about 1 minute.

SIKLOS 100 mg tablet

SIKLOS 1,000 mg tablet (broken)

Step 3: Swallow the mixture right away.

Step 4: After you take your prescribed dose of SIKLOS tablets, drink a glass of water. When you are finished drinking a glass of water, continue to Step 9 and Step 10 above.

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.

This Instructions for Use has been approved by the U.S. Food and Drug Administration.