DROXIA (hydroxyurea) capsules

DROXIA (hydroxyurea) capsules

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DROXIA (hydroxyurea) capsules

DROXIA (hydroxyurea capsules, USP) is available for oral use as capsules containing 200 mg, 300 mg, and 400 mg hydroxyurea. Inactive ingredients include citric acid, gelatin, lactose, magnesium stearate, sodium phosphate, titanium dioxide, and capsule colorants: FD&C Blue No. 1 and FD&C Green No. 3 (200 mg capsules); D&C Red No. 28, D&C Red No. 33, and FD&C Blue No. 1 (300 mg capsules); D&C Red No. 28, D&C Red No. 33, and D&C Yellow No. 10 (400 mg capsules).

Hydroxyurea is a white to off-white crystalline powder. It is hygroscopic and freely soluble in water, but practically insoluble in alcohol. The empirical formula is CH4N2O2 and it has a molecular weight of 76.05.

Indications and usage

DROXIA is indicated to reduce the frequency of painful crises and to reduce the need for blood transfusions in patients with sickle cell anemia with recurrent moderate to severe painful crises.

Swallow DROXIA capsules whole. Do NOT open, break, or chew capsules because DROXIA is a cytotoxic drug. 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 DROXIA 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.

DROXIA causes macrocytosis, which may mask the incidental development of folic acid deficiency. Prophylactic administration of folic acid is recommended.

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 DROXIA produces its beneficial effects in patients with sickle cell anemia (SCA) are uncertain. Known pharmacologic effects of DROXIA 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.

Pharmacokinetics

Absorption: Following oral administration of DROXIA, hydroxyurea reaches peak plasma concentrations in 1 to 4 hours. Mean peak plasma concentrations and AUCs increase more than proportionally with increase of dose. There are no data on the effect of food on the absorption of hydroxyurea.

Distribution: 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: In patients with sickle cell anemia, the mean cumulative urinary recovery of hydroxyurea was about 40% of the administered dose.

Dose Modifications for Renal Impairment

Reduce the dose of DROXIA by 50% in patients with creatinine clearance of less than 60 mL/min or with end-stage renal disease (ESRD)

Dosage forms and strengths

Capsules:

  • 200 mg opaque blue-green capsules, imprinted with black ink “DROXIA” and “6335”.
  • 300 mg opaque purple capsules, imprinted with black ink “DROXIA” and “6336”.
  • 400 mg opaque reddish-orange capsules, imprinted with black ink “DROXIA” and “6337”.

Contraindications

DROXIA is contraindicated in patients who have demonstrated a previous hypersensitivity to hydroxyurea or any other component of its formulation.

Warnings and precautions

Myelosuppression: Hydroxyurea causes severe myelosuppression. 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.

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.

Embryo-Fetal Toxicity: Based on the mechanism of action and findings in animals, DROXIA 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.

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 DROXIA.

Live Vaccinations: Avoid use of live vaccine in patients taking DROXIA. Concomitant use of DROXIA 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 DROXIA. Vaccination with live vaccines in a patient receiving DROXIA may result in severe infection. Patient’s antibody response to vaccines may be decreased. Consider consultation with a specialist.

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.

Macrocytosis: DROXIA 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.

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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. Safety and effectiveness have not been established for the use of DROXIA in the treatment of myeloproliferative neoplasms and the use is not approved by the FDA. Monitor patients developing pyrexia, cough, dyspnea, or other respiratory symptoms frequently, investigate and treat promptly. Discontinue DROXIA and manage with corticosteroids.

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

Adverse reactions

  • Myelosuppression
  • Malignancies
  • Vasculitic toxicities
  • Risks with concomitant use of antiretroviral drugs
  • Macrocytosis
  • Pulmonary Toxicity

Side effects

  • Reproductive System and Breast disorders: azoospermia, and oligospermia
  • Gastrointestinal disorders: stomatitis, nausea, vomiting, diarrhea, and constipation
  • Metabolism and Nutrition disorders: anorexia
  • Skin and subcutaneous tissue disorders: maculopapular rash, skin ulceration, cutaneous lupus erythematosus, dermatomyositis-like skin changes, peripheral and facial erythema, hyperpigmentation, nail hyperpigmentation, atrophy of skin and nails, scaling, violet papules, and alopecia
  • Renal and urinary disorders: dysuria, elevations in serum uric acid, blood urea nitrogen (BUN), and creatinine levels.
  • Nervous system disorders: headache, dizziness, drowsiness, disorientation, hallucinations, and convulsions
  • General disorders: fever, chills, malaise, edema, and asthenia
  • Hepatobiliary disorders: elevation of hepatic enzymes, cholestasis, and hepatitis
  • Respiratory disorders: diffuse pulmonary infiltrates, dyspnea, and pulmonary fibrosis, interstitial lung disease, pneumonitis, alveolitis, allergic alveolitis and cough
  • Immune disorders: systemic lupus erythematosus
  • Hypersensitivity: Drug-induced fever (pyrexia) (>39°C, >102°F) requiring hospitalization has been reported concurrently with gastrointestinal, pulmonary, musculoskeletal, hepatobiliary, dermatological or cardiovascular manifestations. Onset typically occurred within 6 weeks of initiation and resolved upon discontinuation of hydroxyurea. Upon re-administration fever reoccurred typically within 24 hours.
Use in specific populations

Pregnancy: DROXIA can cause fetal harm based on findings from animal studies and the drug’s mechanism of action. Advise women of the potential risk to a fetus and to avoid becoming pregnant while being treated with DROXIA.

Lactation: Hydroxyurea is excreted in human milk. Because of the potential for serious adverse reactions in a breastfed infant from hydroxyurea, including carcinogenicity, discontinue breastfeeding during treatment with DROXIA.

Pregnancy Testing: Verify the pregnancy status of females of reproductive potential prior to initiating DROXIA therapy.

Contraception: Females; DROXIA can cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential to use effective contraception during and after treatment with DROXIA for at least 6 months after therapy. Advise females to immediately report pregnancy.

Contraception: Males; DROXIA may damage spermatozoa and testicular tissue, resulting in possible genetic abnormalities. Males with female sexual partners of reproductive potential should use effective contraception during and after treatment with DROXIA for at least 1 year after therapy.

Pediatric Use: Safety and effectiveness in pediatric patients have not been established.

Geriatric Use: Clinical studies of DROXIA did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.

Renal Impairment: The exposure to hydroxyurea is higher in patients with creatinine clearance of less than 60 mL/min. Reduce dosage and closely monitor the hematologic parameters when DROXIA is to be administered to these patients.

Hepatic Impairment: There are no data that support specific guidance for dosage adjustment in patients with hepatic impairment. Close monitoring of hematologic parameters is advised in these patients.

Overdosage

Acute mucocutaneous toxicity has been reported in patients receiving hydroxyurea at dosages several times the therapeutic dose. Soreness, violet erythema, edema on palms and soles followed by scaling of hands and feet, severe generalized hyperpigmentation of the skin, and stomatitis have been observed.

Storage

Store at 25°C (77°F); excursions permitted to 15°C-30°C (59°F-86°F) [see USP Controlled Room Temperature]. Keep tightly closed.

Handling and Disposal

DROXIA is a cytotoxic drug. Follow applicable special handling and disposal procedures.

To decrease the risk of contact, advise caregivers to wear disposable gloves when handling DROXIA or bottles containing DROXIA. Wash hands with soap and water before and after contact with the bottle or capsules when handling DROXIA. Do not open DROXIA capsules. Avoid exposure to crushed or opened capsules. If contact with crushed or opened capsules occurs on the skin, wash affected area immediately and thoroughly with soap and water. If contact with crushed or opened capsules 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. If the powder from the capsule is spilled, immediately wipe it up with a damp disposable towel and discard in a closed container, such as a plastic bag; as should the empty capsules. The spill areas should then be cleaned three times using a detergent solution followed by clean water. Keep the medication away from children and pets. Contact your doctor for instructions on how to dispose of outdated capsules.

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