These Highlights Do Not Include All The Information Needed To Use Siklos Safely And Effectively. See Full Prescribing Information For Siklos.

Myelosuppression:SIKLOS may cause severe myelosuppression. Monitor blood counts at baseline and throughout treatment. Interrupt treatment and reduce dose as necessary [see Warnings and Precautions (5.1)] .

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 tablets must be stored in the bottle and must be used within three months.

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.

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

SIKLOS (hydroxyurea) is an antimetabolite that is available for oral use as functionally scored 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:

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.

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.

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 1000 mg tablets is supplied in a carton.

SIKLOS is supplied in the following strengths:

• 100 mg off-white, capsule-shaped, film-coated, functionally scored tablet with scoring on both sides which can be divided into two equal parts, each part is debossed with "H" 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, each part is debossed with "T" on one side.

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.

SIKLOS is contraindicated in:

• Patients who have demonstrated a previous hypersensitivity to hydroxyurea or any other component of its formulation [see Adverse Reactions (6)].

The following clinically significant adverse reactions are described elsewhere in the labeling:

• Myelosuppression [see Warnings and Precautions (5.1)]
• Malignancies [see Warnings and Precautions (5.2)]
• Vasculitic toxicities (including Leg Ulcers) [see Warnings and Precautions (5.4)]
• Risks with concomitant use of antiretroviral drugs [see Warnings and Precautions (5.5)]
• Risk with concomitant use of live virus vaccine [see Warnings and Precautions (5.6)]
• Macrocytosis [see Warnings and Precautions (5.7)]
• Hemolytic Anemia [see Warnings and Precautions (5.9)]

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 15 mg/kg/day in adults or 20 mg/kg/day in children, 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 [see Dosage and Administration (2.1)] .

Cases of hemolytic anemia in patients treated with hydroxyurea for myeloproliferative diseases have been reported [see Adverse Reactions (6.1)] . Patients who develop acute jaundice or hematuria in the presence of persistent or worsening of anemia should have laboratory tests evaluated for hemolysis (e.g., measurement of serum lactate dehydrogenase, haptoglobin, reticulocyte, unconjugated bilirubin levels, urinalysis, and direct and indirect antiglobulin [Coombs] tests). In the setting of confirmed diagnosis of hemolytic anemia not related to the disease and in the absence of other causes, discontinue SIKLOS.

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)] .

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 100 mg tablethas one separation line (score line) and can be broken at this score line to provide smaller doses. Each 100 mg tablet can be divided into 2 equal parts (each part is 50 mg).

SIKLOS 1,000 mg tablethas 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).

SIKLOS tablet breaking instructions

You will need the following supplies to break a SIKLOS tablet:

• SIKLOS tablets
• A damp disposable paper towel
• A tablet cutter
• Disposable gloves

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 tablets
  • Note:If you need to break your tablets, use the SIKLOS Tablet Breaking Instructions aboveto get your prescribed dose beforeyou begin the steps below.
• A teaspoon
• Water to dissolve tablets

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.

Revised 11/2023

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

Mean peak plasma concentrations and AUCs increase more than proportionally with increase of dose. There is no drug accumulation upon once daily dosing of hydroxyurea.

Interference with Uric Acid, Urea, or Lactic Acid Assays is possible, rendering falsely elevated results of these in patients treated with hydroxyurea [see Drug Interactions (7.3)].

Hydroxyurea may falsely elevate sensor glucose results from certain continuous glucose monitoring (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.

The recommended SIKLOS dosing is described in Table 1.

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). Therefore, the two strengths can be used to deliver doses of 1,000 mg, 750 mg, 500 mg, 250 mg, 100 mg, 50 mg and combinations thereof. Calculate the rounded doses to the nearest 50 mg or 100 mg strength based on clinical judgment.

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.

Monitor hematologic parameters more frequently in patients with hepatic impairment receiving SIKLOS.

SIKLOS ^®is 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

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.

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 pregnant women of the potential risk to a fetus [see Use in Specific Populations (8.1)] .

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 [see Use in Specific Populations (8.1, 8.3)] .

SIKLOS is a cytotoxic drug. Follow applicable special handling and disposal procedures [see References (15)] .

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.

• Embryo-Fetal toxicity: Can cause fetal harm. Advise of potential risk to a fetus and use of effective contraception. ( 5.3, 8.1, 8.3)
• Cutaneous vasculitic toxicities (incl. leg ulcers): Institute treatment and discontinue SIKLOS and/or reduce dose if this occurs. ( 5.4)
• Risks with concomitant use of antiretroviral drugs: Pancreatitis, hepatotoxicity, and neuropathy have occurred. Monitor for signs and symptoms patients with HIV infection using antiretroviral drugs; discontinue SIKLOS, and implement treatment. ( 5.5)
• Concomitant use with live virus vaccine: increased risk of severe infections. ( 5.6)
• Hemolytic Anemia: Monitor blood counts throughout treatment. If hemolysis persists, discontinue SIKLOS. ( 5.9)

Initial dose: 15 mg/kg in adults and 20 mg/kg in children once daily. Monitor blood counts every two weeks. ( 2.1)

• The dose may be increased by 5 mg/kg/day every 8 weeks, or sooner if a severe painful crisis occurs, until a maximum tolerated dose or 35 mg/kg/day is reached if blood counts are in an acceptable range. ( 2.1)
• Discontinue SIKLOS until hematologic recovery if blood counts are considered toxic. Resume treatment after reducing the dose by 5 mg/kg/day from the dose associated with hematological toxicity. ( 2.1)
• Renal impairment: Reduce the dose of SIKLOS by 50% in patients with creatinine clearance less than 60 mL/min. ( 2.2, 8.6, 12.3)

Tablets: functionally scored 100 mg and functionally triple-scored 1,000 mg tablet ( 3)

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.

• Blood and lymphatic system disorders: macrocytosis, hemolytic anemia in patients who are treated with hydroxyurea for myeloproliferative disorders.
• Gastrointestinal disorders: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,
• Reproductive system and breast disorders: oligospermia, azoospermia, amenorrhea

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 and 1077 adults 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 33% of the 405 pediatric patients and 32% of the 1077 adults with sickle cell disease in ESCORT-HU. The most frequent serious adverse reactions were infections (18%), and blood and lymphatic system disorders (9%) in children, including 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%). Among adults, the most frequent serious adverse reactions were infections (12.9%), respiratory, thoracic and mediastinal disorders (5.8%), blood and lymphatic disorders (4.8%), nervous system disorders (3.6%), and general disorders and administration site disorders (3.1%).

Lactation: Advise women to stop breastfeeding while taking SIKLOS. ( 8.2)

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 [see Use in Specific Populations (8.3)] .
• 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)] .
• Advise patients to notify their healthcare provider if they are using a continuous glucose monitoring system while taking SIKLOS [see Warnings and Precautions (5.8)].
• Advise patients of the risk of hemolytic anemia. Advise patients that they will have blood tests to evaluate for this if they develop persistent anemia not related to sickle cell anemia [see Warnings and Precautions (5.9)] .
• Because SIKLOS tablets are scored, advise patients on how to take SIKLOS properly.

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. 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.

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. ( 5.1)
• Malignancies: Hydroxyurea is carcinogenic. Advise sun protection and monitor patients for malignancies. ( 5.2)

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.

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).

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 [see Drug Interactions (7.2)]. Patient's antibody response to vaccines may be decreased. Consider consultation with a specialist.

Siklos ^®

100 mg

(hydroxyurea)

100 mg per tablet

60 tablets

NDC 71770-105-60

Store at 20°C to 25°C (68°F to 77°F)

Wear disposable gloves when handling Siklos ^®or bottles containing Siklos ^®

ATTENTION PHARMACIST:

Each patient is required to

receive the enclosed

Medication Guide

RX Only.

theravia

NDC 71770-105-60

Siklos ^®100 mg

(hydroxyurea)

tablets

100 mg per tablet

ATTENTION

PHARMACIST:

Each patient is

required to receive

the enclosed

Medication Guide

60 tablets

theravia

NDC 71770-120-30

Siklos ^®1,000 mg

(hydroxyurea) tablets

1,000 mg per tablet

ATTENTION PHARMACIST:

Each patient is required

to receive the enclosed

Medication Guide

30 tablets

RX Only.

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)

WARNING: MYELOSUPPRESSION AND

MALIGNANCIES

Handle tablets with care.

Do not use or dispense before reading directions

and warnings in accompanying product

information.

Wear disposable gloves when handling Siklos ^®or

bottles containing Siklos ^®

Dosage and Use:See prescribing information.

Distributed by Medunik USA

Princeton, NJ, USA 08540

theravia

Pancreatitis, hepatotoxicity, and peripheral neuropathy have occurred when hydroxyurea was administered concomitantly with antiretroviral drugs, including didanosine and stavudine [see Drug Interactions (7.1)] .

NDC 71770-120-30

Siklos ^®1,000 mg

(hydroxyurea)

tablets

1,000 mg per tablet

ATTENTION

PHARMACIST:

Each patient is

required to receive

the enclosed

Medication Guide

30 tablets

theravia

Conventional long-term studies to evaluate the carcinogenic potential of hydroxyurea have not been performed. However, hydroxyurea is presumed to be a transspecies carcinogen. Intraperitoneal administration of 125 to 250 mg/kg hydroxyurea (about 0.6-1.2 times the maximum recommended human oral daily dose on a mg/m ²basis) thrice weekly for 6 months to female rats increased the incidence of mammary tumors in rats surviving to 18 months compared to control. Hydroxyurea is mutagenic in vitroto bacteria, fungi, protozoa, and mammalian cells. Hydroxyurea is clastogenic in vitro(hamster cells, human lymphoblasts) and in vivo(SCE assay in rodents, mouse micronucleus assay). Hydroxyurea causes the transformation of rodent embryo cells to a tumorigenic phenotype [see Warnings and Precautions (5.2, 5.3)].

Hydroxyurea administered to male rats at 60 mg/kg /day (about 0.3 times the maximum recommended human daily dose on a mg/m ²basis) produced testicular atrophy, decreased spermatogenesis and significantly reduced their ability to impregnate females [see Use in Specific Populations (8.3)].

Myelosuppression:SIKLOS may cause severe myelosuppression. Monitor blood counts at baseline and throughout treatment. Interrupt treatment and reduce dose as necessary [see Warnings and Precautions (5.1)] .

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 tablets must be stored in the bottle and must be used within three months.

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.

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

SIKLOS (hydroxyurea) is an antimetabolite that is available for oral use as functionally scored 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:

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.

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.

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 1000 mg tablets is supplied in a carton.

SIKLOS is supplied in the following strengths:

• 100 mg off-white, capsule-shaped, film-coated, functionally scored tablet with scoring on both sides which can be divided into two equal parts, each part is debossed with "H" 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, each part is debossed with "T" on one side.

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.

SIKLOS is contraindicated in:

• Patients who have demonstrated a previous hypersensitivity to hydroxyurea or any other component of its formulation [see Adverse Reactions (6)].

The following clinically significant adverse reactions are described elsewhere in the labeling:

• Myelosuppression [see Warnings and Precautions (5.1)]
• Malignancies [see Warnings and Precautions (5.2)]
• Vasculitic toxicities (including Leg Ulcers) [see Warnings and Precautions (5.4)]
• Risks with concomitant use of antiretroviral drugs [see Warnings and Precautions (5.5)]
• Risk with concomitant use of live virus vaccine [see Warnings and Precautions (5.6)]
• Macrocytosis [see Warnings and Precautions (5.7)]
• Hemolytic Anemia [see Warnings and Precautions (5.9)]

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 15 mg/kg/day in adults or 20 mg/kg/day in children, 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 [see Dosage and Administration (2.1)] .

Cases of hemolytic anemia in patients treated with hydroxyurea for myeloproliferative diseases have been reported [see Adverse Reactions (6.1)] . Patients who develop acute jaundice or hematuria in the presence of persistent or worsening of anemia should have laboratory tests evaluated for hemolysis (e.g., measurement of serum lactate dehydrogenase, haptoglobin, reticulocyte, unconjugated bilirubin levels, urinalysis, and direct and indirect antiglobulin [Coombs] tests). In the setting of confirmed diagnosis of hemolytic anemia not related to the disease and in the absence of other causes, discontinue SIKLOS.

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)] .

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 100 mg tablethas one separation line (score line) and can be broken at this score line to provide smaller doses. Each 100 mg tablet can be divided into 2 equal parts (each part is 50 mg).

SIKLOS 1,000 mg tablethas 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).

SIKLOS tablet breaking instructions

You will need the following supplies to break a SIKLOS tablet:

• SIKLOS tablets
• A damp disposable paper towel
• A tablet cutter
• Disposable gloves

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 tablets
  • Note:If you need to break your tablets, use the SIKLOS Tablet Breaking Instructions aboveto get your prescribed dose beforeyou begin the steps below.
• A teaspoon
• Water to dissolve tablets

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.

Revised 11/2023

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

Mean peak plasma concentrations and AUCs increase more than proportionally with increase of dose. There is no drug accumulation upon once daily dosing of hydroxyurea.

Interference with Uric Acid, Urea, or Lactic Acid Assays is possible, rendering falsely elevated results of these in patients treated with hydroxyurea [see Drug Interactions (7.3)].

Hydroxyurea may falsely elevate sensor glucose results from certain continuous glucose monitoring (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.

The recommended SIKLOS dosing is described in Table 1.

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). Therefore, the two strengths can be used to deliver doses of 1,000 mg, 750 mg, 500 mg, 250 mg, 100 mg, 50 mg and combinations thereof. Calculate the rounded doses to the nearest 50 mg or 100 mg strength based on clinical judgment.

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.

Monitor hematologic parameters more frequently in patients with hepatic impairment receiving SIKLOS.

SIKLOS ^®is 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

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.

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 pregnant women of the potential risk to a fetus [see Use in Specific Populations (8.1)] .

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 [see Use in Specific Populations (8.1, 8.3)] .

SIKLOS is a cytotoxic drug. Follow applicable special handling and disposal procedures [see References (15)] .

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.

• Embryo-Fetal toxicity: Can cause fetal harm. Advise of potential risk to a fetus and use of effective contraception. ( 5.3, 8.1, 8.3)
• Cutaneous vasculitic toxicities (incl. leg ulcers): Institute treatment and discontinue SIKLOS and/or reduce dose if this occurs. ( 5.4)
• Risks with concomitant use of antiretroviral drugs: Pancreatitis, hepatotoxicity, and neuropathy have occurred. Monitor for signs and symptoms patients with HIV infection using antiretroviral drugs; discontinue SIKLOS, and implement treatment. ( 5.5)
• Concomitant use with live virus vaccine: increased risk of severe infections. ( 5.6)
• Hemolytic Anemia: Monitor blood counts throughout treatment. If hemolysis persists, discontinue SIKLOS. ( 5.9)

Initial dose: 15 mg/kg in adults and 20 mg/kg in children once daily. Monitor blood counts every two weeks. ( 2.1)

• The dose may be increased by 5 mg/kg/day every 8 weeks, or sooner if a severe painful crisis occurs, until a maximum tolerated dose or 35 mg/kg/day is reached if blood counts are in an acceptable range. ( 2.1)
• Discontinue SIKLOS until hematologic recovery if blood counts are considered toxic. Resume treatment after reducing the dose by 5 mg/kg/day from the dose associated with hematological toxicity. ( 2.1)
• Renal impairment: Reduce the dose of SIKLOS by 50% in patients with creatinine clearance less than 60 mL/min. ( 2.2, 8.6, 12.3)

Tablets: functionally scored 100 mg and functionally triple-scored 1,000 mg tablet ( 3)

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.

• Blood and lymphatic system disorders: macrocytosis, hemolytic anemia in patients who are treated with hydroxyurea for myeloproliferative disorders.
• Gastrointestinal disorders: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,
• Reproductive system and breast disorders: oligospermia, azoospermia, amenorrhea

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 and 1077 adults 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 33% of the 405 pediatric patients and 32% of the 1077 adults with sickle cell disease in ESCORT-HU. The most frequent serious adverse reactions were infections (18%), and blood and lymphatic system disorders (9%) in children, including 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%). Among adults, the most frequent serious adverse reactions were infections (12.9%), respiratory, thoracic and mediastinal disorders (5.8%), blood and lymphatic disorders (4.8%), nervous system disorders (3.6%), and general disorders and administration site disorders (3.1%).

Lactation: Advise women to stop breastfeeding while taking SIKLOS. ( 8.2)

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 [see Use in Specific Populations (8.3)] .
• 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)] .
• Advise patients to notify their healthcare provider if they are using a continuous glucose monitoring system while taking SIKLOS [see Warnings and Precautions (5.8)].
• Advise patients of the risk of hemolytic anemia. Advise patients that they will have blood tests to evaluate for this if they develop persistent anemia not related to sickle cell anemia [see Warnings and Precautions (5.9)] .
• Because SIKLOS tablets are scored, advise patients on how to take SIKLOS properly.

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. 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.

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. ( 5.1)
• Malignancies: Hydroxyurea is carcinogenic. Advise sun protection and monitor patients for malignancies. ( 5.2)

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.

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).

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 [see Drug Interactions (7.2)]. Patient's antibody response to vaccines may be decreased. Consider consultation with a specialist.

Siklos ^®

100 mg

(hydroxyurea)

100 mg per tablet

60 tablets

NDC 71770-105-60

Store at 20°C to 25°C (68°F to 77°F)

Wear disposable gloves when handling Siklos ^®or bottles containing Siklos ^®

ATTENTION PHARMACIST:

Each patient is required to

receive the enclosed

Medication Guide

RX Only.

theravia

NDC 71770-105-60

Siklos ^®100 mg

(hydroxyurea)

tablets

100 mg per tablet

ATTENTION

PHARMACIST:

Each patient is

required to receive

the enclosed

Medication Guide

60 tablets

theravia

NDC 71770-120-30

Siklos ^®1,000 mg

(hydroxyurea) tablets

1,000 mg per tablet

ATTENTION PHARMACIST:

Each patient is required

to receive the enclosed

Medication Guide

30 tablets

RX Only.

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)

WARNING: MYELOSUPPRESSION AND

MALIGNANCIES

Handle tablets with care.

Do not use or dispense before reading directions

and warnings in accompanying product

information.

Wear disposable gloves when handling Siklos ^®or

bottles containing Siklos ^®

Dosage and Use:See prescribing information.

Distributed by Medunik USA

Princeton, NJ, USA 08540

theravia

Pancreatitis, hepatotoxicity, and peripheral neuropathy have occurred when hydroxyurea was administered concomitantly with antiretroviral drugs, including didanosine and stavudine [see Drug Interactions (7.1)] .

NDC 71770-120-30

Siklos ^®1,000 mg

(hydroxyurea)

tablets

1,000 mg per tablet

ATTENTION

PHARMACIST:

Each patient is

required to receive

the enclosed

Medication Guide

30 tablets

theravia

Conventional long-term studies to evaluate the carcinogenic potential of hydroxyurea have not been performed. However, hydroxyurea is presumed to be a transspecies carcinogen. Intraperitoneal administration of 125 to 250 mg/kg hydroxyurea (about 0.6-1.2 times the maximum recommended human oral daily dose on a mg/m ²basis) thrice weekly for 6 months to female rats increased the incidence of mammary tumors in rats surviving to 18 months compared to control. Hydroxyurea is mutagenic in vitroto bacteria, fungi, protozoa, and mammalian cells. Hydroxyurea is clastogenic in vitro(hamster cells, human lymphoblasts) and in vivo(SCE assay in rodents, mouse micronucleus assay). Hydroxyurea causes the transformation of rodent embryo cells to a tumorigenic phenotype [see Warnings and Precautions (5.2, 5.3)].

Hydroxyurea administered to male rats at 60 mg/kg /day (about 0.3 times the maximum recommended human daily dose on a mg/m ²basis) produced testicular atrophy, decreased spermatogenesis and significantly reduced their ability to impregnate females [see Use in Specific Populations (8.3)].