HYDROXYUREA: 5,966 Adverse Event Reports & Safety Profile

Hydroxyurea Capsules USP are an antineoplastic available for oral use as capsules providing 500 mg hydroxyurea, USP. Inactive ingredients: anhydrous citric acid, benzyl alcohol, black iron oxide, butylparaben, carboxymethylcellulose sodium, D&C red no. 28, D&C yellow no. 10 aluminum lake, dibasic sodium phosphate, edetate calcium disodium, FD&C blue no. 1, FD&C blue no. 1 aluminum lake, FD&C blue no. 2 aluminum lake, FD&C red no. 40, FD&C red no. 40 aluminum lake, gelatin, lactose monohydrate, magnesium stearate, methylparaben, pharmaceutical glaze, propylparaben, propylene glycol, red iron oxide, sodium lauryl sulfate, sodium propionate, and titanium dioxide. Hydroxyurea, USP is a white to off-white crystalline powder. It is hygroscopic and freely soluble in water, but practically insoluble in alcohol. Its structural formula is: CH 4 N 2 O 2 M.W. 76.05 chemical structure

AND USAGE 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 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. ( 1 )

AND ADMINISTRATION 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 )

2.1 Recommended Dosing The recommended SIKLOS dosing is described in Table 1.

Table

1: Dosing Recommendation Based on Blood Count Dosing Regimen Dose Dose Modification Criteria Monitoring Parameters Initial Recommended Dosing Adults: 15 mg/kg Pediatrics: 20 mg/kg once daily based on patient's actual or ideal weight, whichever is less. Monitor the patient's blood count every 2 weeks [see Warnings and Precautions (5.1) ] .

Dosing Adjustment

Based on Blood Counts in an acceptable range Increase dose 5 mg/kg/day every 8 weeks or if a painful crisis occurs. Give until mild myelosuppression (absolute neutrophil count 2,000/uL to 4,000/uL) is achieved, up to a maximum of 35 mg/kg/day. Increase dosing only if blood counts are in an acceptable range. Increase dosing if a painful crisis occurs. Do not increase if myelosuppression occurs.

Blood Counts Acceptable

Range: - neutrophils greater than or equal to 2,000 cells/mm 3 - platelets greater than or equal to 80,000/mm 3 - hemoglobin greater than 5.3 g/dL - reticulocytes greater than or equal to 80,000/mm 3 if the hemoglobin concentration less than 9 g/dL Dosing Adjustment Based on Blood Counts in a toxic range Discontinue treatment. If blood counts are considered toxic, discontinue SIKLOS until hematologic recovery.

Blood Counts Toxic

Range: - neutrophils less than 2,000 cells/mm 3 younger patients with lower baseline counts may safely tolerate absolute neutrophil counts down to 1,250/mm 3 . - platelets less than 80,000/mm 3 - hemoglobin less than 4.5 g/dL - reticulocytes less than 80,000/mm 3 if the hemoglobin concentration less than 9 g/dL Dosing After Hematologic Recovery Reduce dose by 5 mg/kg/day. Reduce the dose from the dose associated with hematologic toxicity. May titrate up or down every 8 weeks in 5 mg/kg/day increments. The patient should be at a stable dose with no hematologic toxicity for 24 weeks. Discontinue the treatment permanently if a patient develops hematologic toxicity twice. 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. Administration: The tablets should be taken once daily, at the same time each day, with a glass of water. For patients who are not able to swallow the tablets, these can be dispersed immediately before use in a small quantity of water in a teaspoon. SIKLOS is a cytotoxic drug. Follow applicable special handling and disposal procedures [see References (15) ].

2.2 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) <span class="opacity-50 text-xs">[see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3) ]</span> . Obtain the creatinine clearance using a 24-hour urine collection.

Creatinine

Clearance (mL/min) Recommended SIKLOS Initial Dose (mg/kg daily)

Pediatrics Adults

Greater than or equal to 60 20 15 Less than 60 or ESRD On dialysis days, administer SIKLOS to patients with ESRD following hemodialysis 10

7.5 Monitor the hematologic parameters closely in these patients.

SIKLOS is contraindicated in: Patients who have demonstrated a previous hypersensitivity to hydroxyurea or any other component of its formulation [see Adverse Reactions (6) ]. Patients who have demonstrated a previous hypersensitivity to hydroxyurea or any other component of its formulation. ( 4 )

REACTIONS 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) ] Most common adverse reactions to SIKLOS (incidence > 10%) include infections and neutropenia in children and infections and headache and dry skin in adults. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact the marketer Medunik at 1 844-884-5520 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

6.1 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 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%).

Table

2: Most frequent (greater than or equal to 2%) adverse reactions reported in pediatric patients enrolled in ESCORT-HU Global Safety Set (N=405)

Total Severity Mild Moderate

Severe n % n % n % n % n: number of patients with an adverse reaction 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 Table 3: Most frequent (greater than or equal to 3%) adverse reactions reported in adult patients enrolled in ESCORT-HU Global adult safety set (N=1077)

Total Severity Mild Moderate

Severe n % n % n % n % At least one adverse reaction 897 84 586 54 617 57 345 32 Infections 465 43 171 16 240 22 101 9 Viral infection 47 4.4 17 1.6 21 1.9 5

0.5 Bacterial infection 45 4.2 9 0.8 27 2.5 5

0.5 Bronchitis 41 3.8 10 0.9 19 1.8 3

0.3 Influenza 40 3.7 8 0.7 15 1.4 5

0.5 Urinary tract infection 40 3.7 19 1.8 11 1.0 1

0.1 Nasopharyngitis 40 3.7 21 1.9 13 1.2 1

0.1 Nervous system disorders 313 29 131 12 125 12 54 5 Headache 211 20 84 8 74 7 27

2.5 Dizziness 100 9 43 4.0 32 3.0 9

0.8 General disorders and administration site conditions 300 28 111 10 113 10 24

2.2 Asthenia 100 9 30 2.8 18 1.7 10

0.9 Pyrexia 91 8 27 2.5 39 3.6 4

0.4 Fatigue 51 4.7 22 2.0 17 1.6 2

0.2 Edema peripheral 33 3.1 9 0.8 13 1.2 2

0.2 Skin and subcutaneous tissue disorders 297 28 160 15 123 11 23

2.1 Dry skin 128 12 67 6.2 36 3.3 5

0.5 Skin ulcer 80 7 19 1.8 44 4.1 11

1.0 Alopecia 49 4.5 31 2.9 13 1.2 5

0.5 Gastrointestinal disorders 267 25 116 11 110 10 25

2.3 Nausea 69 6 28 2.6 26 2.4 3

0.3 Abdominal pain upper 52 4.8 15 1.4 22 2.0 5

0.5 Diarrhea 37 3.4 10 0.9 13

1.2 Respiratory, thoracic and mediastinal disorders 256 24 70 7 103 10 48

4.5 Cough 59 5.5 23 2.1 21 1.9 3

0.3 Lung disorder 51 4.7 4 0.4 28 2.6 16

1.5 Dyspnea 44 4.1 12 1.1 14 1.3 4

0.4 Blood and lymphatic system disorders 250 23 74 7 121 11.2 61 6 Anemia 103 10 11 1.0 51 4.7 37

3.4 Thrombocytopenia 70 7 29 2.7 30 2.8 13

1.2 Neutropenia 50 4.6 24 2.2 18 1.7 7

0.6 Musculoskeletal and connective tissue disorders 247 23 93 9 101 9 25

2.3 Arthralgia 95 9 26 2.4 31 2.9 7

0.6 Back pain 48 4.5 11 1.0 18 1.7 6

0.6 Pain in extremity 33 3.1 14 1.3 10

0.9 Investigations 198 18 40 3.7 47 4.4 10

0.9 Weight increased 43 4.0 15 1.4 22 2.0 4 0.4

6.2 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. 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

AND PRECAUTIONS 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) Hemolytic anemia: Monitor blood counts throughout treatment. If hemolysis persists, discontinue Hydroxyurea. (5.2) Malignancies: Advise protection from sun exposure and monitor for secondary malignancies. ( 5.3) Embryo-Fetal toxicity: Can cause fetal harm. Advise of potential risk to a fetus and use of effective contraception. ( 5.4 , 8.1 , 8.3 ) Vasculitic toxicities: Discontinue hydroxyurea and initiate treatment if this occurs. (5.5)

Live

Vaccinations: Avoid live vaccine use in a patient taking hydroxyurea capsules. (5.6) Risks with concomitant use of antiretroviral drugs: Pancreatitis, hepatotoxicity, and neuropathy have occurred. Monitor for signs and symptoms in patients with HIV infection using antiretroviral drugs; discontinue hydroxyurea capsules and implement treatment. (5.7) Radiation recall: Monitor for skin erythema in patients who previously received radiation and manage symptomatically. (5.8)

5.1 Myelosuppression s ion Hydroxyurea causes severe myelosuppression. Treatment with hydroxyurea should not be initiated 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. Bone marrow depression is more likely in patients who have previously received radiotherapy or cytotoxic cancer chemotherapeutic agents; use hydroxyurea cautiously in such patients. Evaluate hematologic status prior to and during treatment with hydroxyurea capsules. Provide supportive care and modify dose or discontinue hydroxyurea as needed. Recovery from myelosuppression is usually rapid when therapy is interrupted.

5.2 Hemolytic Anemia Cases of hemolytic anemia in patients treated with hydroxyurea for myeloproliferative diseases have been reported <span class="opacity-50 text-xs">[see Adverse Reactions (6.1) ]</span>. 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 and in the absence of other causes, discontinue hydroxyurea.

5.3 Malignancies Hydroxyurea is a human carcinogen. In patients receiving long-term hydroxyurea for myeloproliferative disorders, secondary leukemia has been reported. Skin cancer has also been reported in patients receiving long-term hydroxyurea. Advise protection from sun exposure and monitor for the development of secondary malignancies.

5.4 Embryo-Fetal Toxicity Based on the mechanism of action and findings in animals, hydroxyurea 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/m 2 basis. Advise pregnant women of the potential risk to a fetus <span class="opacity-50 text-xs">[see Use in Specific Populations (8.1) ]</span>. Advise females of reproductive potential to use effective contraception during and after treatment with hydroxyurea capsules for at least 6 months after therapy. Advise males of reproductive potential to use effective contraception during and after treatment with hydroxyurea capsules for at least 1 year after therapy <span class="opacity-50 text-xs">[see Use in Specific Populations (8.1 , 8.3) ]</span>.

5.5 Vasculitic Toxicities 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. If cutaneous vasculitic ulcers occur, institute treatment and discontinue hydroxyurea capsules.

5.6 Live Vaccinations Avoid use of live vaccine in patients taking hydroxyurea capsules. Concomitant use of hydroxyurea capsules with a live virus vaccine may potentiate the replication of the virus and/or may increase the adverse reaction of the vaccine because normal defense mechanisms may be suppressed by hydroxyurea capsules. Vaccination with live vaccines in a patient receiving hydroxyurea capsules may result in severe infection. Patient’s antibody response to vaccines may be decreased. Consider consultation with a specialist.

5.7 Risks with Concomitant Use of Antiretroviral Drugs Pancreatitis, hepatotoxicity, and peripheral neuropathy have occurred when hydroxyurea was administered concomitantly with antiretroviral drugs, including didanosine and stavudine <span class="opacity-50 text-xs">[see Drug Interactions (7.1) ]</span>.

5.8 Radiation Recall Patients who have received irradiation therapy in the past may have an exacerbation of post-irradiation erythema. Monitor for skin erythema in patients who previously received radiation and manage symptomatically.

5.9 Macrocytosis Hydroxyurea capsules 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 B 12 or folic acid deficiency. This may mask the diagnosis of pernicious anemia. Prophylactic administration of folic acid is recommended.

5.10 Pulmonary Toxicity Interstitial lung disease including pulmonary fibrosis, lung infiltration, pneumonitis, and alveolitis/allergic alveolitis (including fatal cases) have been reported in patients treated for myeloproliferative neoplasm. Monitor patients developing pyrexia, cough, dyspnea, or other respiratory symptoms frequently, investigate and treat promptly. Discontinue hydroxyurea and manage with corticosteroids [ see Adverse Reactions (6.1) ].

5.11 Laboratory Test Interference Interference with Uric Acid, Urea, or Lactic Acid Assays is possible, rendering falsely elevated results of these in patients treated with hydroxyurea <span class="opacity-50 text-xs">[see Drug Interactions (7.2) ]</span>. 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 <span class="opacity-50 text-xs">[see Drug Interactions (7.2) ]</span>.

5.1 Myelosuppression s ion Hydroxyurea causes severe myelosuppression. Treatment with hydroxyurea should not be initiated 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. Bone marrow depression is more likely in patients who have previously received radiotherapy or cytotoxic cancer chemotherapeutic agents; use hydroxyurea cautiously in such patients. Evaluate hematologic status prior to and during treatment with hydroxyurea capsules. Provide supportive care and modify dose or discontinue hydroxyurea as needed. Recovery from myelosuppression is usually rapid when therapy is interrupted.

5.2 Hemolytic Anemia Cases of hemolytic anemia in patients treated with hydroxyurea for myeloproliferative diseases have been reported <span class="opacity-50 text-xs">[see Adverse Reactions (6.1) ]</span>. 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 and in the absence of other causes, discontinue hydroxyurea.

5.3 Malignancies Hydroxyurea is a human carcinogen. In patients receiving long-term hydroxyurea for myeloproliferative disorders, secondary leukemia has been reported. Skin cancer has also been reported in patients receiving long-term hydroxyurea. Advise protection from sun exposure and monitor for the development of secondary malignancies.

5.4 Embryo-Fetal Toxicity Based on the mechanism of action and findings in animals, hydroxyurea 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/m 2 basis. Advise pregnant women of the potential risk to a fetus <span class="opacity-50 text-xs">[see Use in Specific Populations (8.1) ]</span>. Advise females of reproductive potential to use effective contraception during and after treatment with hydroxyurea capsules for at least 6 months after therapy. Advise males of reproductive potential to use effective contraception during and after treatment with hydroxyurea capsules for at least 1 year after therapy <span class="opacity-50 text-xs">[see Use in Specific Populations (8.1 , 8.3) ]</span>.

5.5 Vasculitic Toxicities 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. If cutaneous vasculitic ulcers occur, institute treatment and discontinue hydroxyurea capsules.

5.6 Live Vaccinations Avoid use of live vaccine in patients taking hydroxyurea capsules. Concomitant use of hydroxyurea capsules with a live virus vaccine may potentiate the replication of the virus and/or may increase the adverse reaction of the vaccine because normal defense mechanisms may be suppressed by hydroxyurea capsules. Vaccination with live vaccines in a patient receiving hydroxyurea capsules may result in severe infection. Patient’s antibody response to vaccines may be decreased. Consider consultation with a specialist.

5.7 Risks with Concomitant Use of Antiretroviral Drugs Pancreatitis, hepatotoxicity, and peripheral neuropathy have occurred when hydroxyurea was administered concomitantly with antiretroviral drugs, including didanosine and stavudine <span class="opacity-50 text-xs">[see Drug Interactions (7.1) ]</span>.

5.8 Radiation Recall Patients who have received irradiation therapy in the past may have an exacerbation of post-irradiation erythema. Monitor for skin erythema in patients who previously received radiation and manage symptomatically.

5.9 Macrocytosis Hydroxyurea capsules 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 B 12 or folic acid deficiency. This may mask the diagnosis of pernicious anemia. Prophylactic administration of folic acid is recommended.

5.10 Pulmonary Toxicity Interstitial lung disease including pulmonary fibrosis, lung infiltration, pneumonitis, and alveolitis/allergic alveolitis (including fatal cases) have been reported in patients treated for myeloproliferative neoplasm. Monitor patients developing pyrexia, cough, dyspnea, or other respiratory symptoms frequently, investigate and treat promptly. Discontinue hydroxyurea and manage with corticosteroids [ see Adverse Reactions (6.1) ].

5.11 Laboratory Test Interference Interference with Uric Acid, Urea, or Lactic Acid Assays is possible, rendering falsely elevated results of these in patients treated with hydroxyurea <span class="opacity-50 text-xs">[see Drug Interactions (7.2) ]</span>. 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 <span class="opacity-50 text-xs">[see Drug Interactions (7.2) ]</span>.

INTERACTIONS Antiretroviral drugs (7.1)

Laboratory Test

Interference. (7.2)

7.1 Increased Toxicity with Concomitant Use of Antiretroviral Drugs Pancreatitis In patients with HIV infection during therapy with hydroxyurea and didanosine, with or without stavudine, fatal and nonfatal pancreatitis have occurred. Hydroxyurea is not indicated for the treatment of HIV infection; however, if patients with HIV infection are treated with hydroxyurea, and in particular, in combination with didanosine and/or stavudine, close monitoring for signs and symptoms of pancreatitis is recommended. Permanently discontinue therapy with hydroxyurea in patients who develop signs and symptoms of pancreatitis.

Hepatotoxicity

Hepatotoxicity and hepatic failure resulting in death have been reported during postmarketing surveillance in patients with HIV infection treated with hydroxyurea and other antiretroviral drugs. Fatal hepatic events were reported most often in patients treated with the combination of hydroxyurea, didanosine, and stavudine. Avoid this combination.

Peripheral Neuropathy

Peripheral neuropathy, which was severe in some cases, has been reported in patients with HIV infection receiving hydroxyurea in combination with antiretroviral drugs, including didanosine, with or without stavudine.

7.2 Laboratory Test Interference Interference with Uric Acid, Urea, or Lactic Acid Assays Studies have shown that there is an analytical interference of hydroxyurea with the enzymes (urease, uricase, and lactate dehydrogenase) used in the determination of urea, uric acid, and lactic acid, rendering falsely elevated results of these in patients treated with hydroxyurea. Interference with Continuous Glucose Monitoring Systems 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.

7.1 Increased Toxicity with Concomitant Use of Antiretroviral Drugs Pancreatitis In patients with HIV infection during therapy with hydroxyurea and didanosine, with or without stavudine, fatal and nonfatal pancreatitis have occurred. Hydroxyurea is not indicated for the treatment of HIV infection; however, if patients with HIV infection are treated with hydroxyurea, and in particular, in combination with didanosine and/or stavudine, close monitoring for signs and symptoms of pancreatitis is recommended. Permanently discontinue therapy with hydroxyurea in patients who develop signs and symptoms of pancreatitis.

Hepatotoxicity

Hepatotoxicity and hepatic failure resulting in death have been reported during postmarketing surveillance in patients with HIV infection treated with hydroxyurea and other antiretroviral drugs. Fatal hepatic events were reported most often in patients treated with the combination of hydroxyurea, didanosine, and stavudine. Avoid this combination.

Peripheral Neuropathy

Peripheral neuropathy, which was severe in some cases, has been reported in patients with HIV infection receiving hydroxyurea in combination with antiretroviral drugs, including didanosine, with or without stavudine.

7.2 Laboratory Test Interference Interference with Uric Acid, Urea, or Lactic Acid Assays Studies have shown that there is an analytical interference of hydroxyurea with the enzymes (urease, uricase, and lactate dehydrogenase) used in the determination of urea, uric acid, and lactic acid, rendering falsely elevated results of these in patients treated with hydroxyurea. Interference with Continuous Glucose Monitoring Systems 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.