Hydroxyurea capsules

Some medicines are not suitable for people with certain conditions, and sometimes a medicine may only be used if extra care is taken. For these reasons, before you start taking hydroxyurea it is important that your physician knows:

• If you are pregnant or breast-feeding.
• If you have any problems with the way your liver or kidneys work.
• If you have had irradiation therapy in the past.
• If you have any leg ulcers.
• If you are taking any other medicines. This includes any medicines you are taking which are available to buy without a prescription, as well as herbal and complementary medicines.
• If you have ever had an allergic reaction to a medicine.

• You must try to keep your regular appointments with your physician or hospital. This is so your physician can check on your progress. You will need to have regular blood tests and check-ups during your treatment with hydroxyurea. The blood tests are important as a way of monitoring your treatment, and also to check that your kidneys and liver are working properly.
• Your physician may also prescribe a vitamin tablet called folic acid. Taking this vitamin can help reduce the severity of some side-effects associated with hydroxyurea.
• It is important that you do not get pregnant while you are taking hydroxyurea. Make sure you have discussed with your physician which types of contraception are suitable for you and your partner. Many anti-cancer treatments are associated with reduced fertility (particularly in men), so you may also want to ask your physician for family planning advice if you would like to have children.
• While you are taking hydroxyurea and for six months after you have stopped the treatment, do not have any immunisations (vaccinations) without talking to your specialist physician first. Hydroxyurea lowers your body's resistance and there is a risk that you will get an infection from some vaccines.
• Rarely, people who take hydroxyurea over a long period of time can develop skin cancer. You can reduce the risk of this by protecting your skin from the sun by wearing suitable clothing and using a sunscreen with a high sun protection factor (SPF) of at least 15.

Medicines like hydroxyurea which can be used to treat cancer can have a number of side-effects, some of which you might not experience until several days or weeks after starting the medicine. They can lower the number of white cells in your blood, which increases the risk of you getting an infection. While you are taking hydroxyurea you should take precautions to reduce the risk of getting an infection - you can do this by avoiding being with people who you know have an infection. If you think you are getting a sore throat or if you have a high temperature (fever), please let your physician know as soon as possible so that you can get some treatment straightaway.

Your physician will discuss with you the possibility of unwanted side-effects from your treatment. The table below contains some of the most common side-effects associated with hydroxyurea, although not everyone experiences these. You will find a full list in the manufacturer's information leaflet supplied with your treatment. Please let your physician know if you experience any of the following:

If you experience any other symptoms which you think may be due to this medicine, speak with your physician or pharmacist.

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. Its structural formula is:

Dosage Forms And Strengths

• 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.”

Storage And Handling

DROXIA® (hydroxyurea capsules, USP) is supplied in HDPE bottles with a plastic safety screw cap. Each bottle contains 60 capsules. DROXIA is supplied in the following strengths:

200 mg opaque blue-green capsules, marked in black ink with “DROXIA” and “6335” (NDC 0003- 6335-17).
300 mg opaque purple capsules, marked in black ink with “DROXIA” and “6336” (NDC 0003-6336- 17).
400 mg opaque reddish-orange capsules, marked in black ink with “DROXIA” and “6337” (NDC 0003- 6337-17).

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.

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

To decrease the risk of contact, advise caregivers to wear disposable gloves when handling 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.

REFERENCES

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

Manufactured for: Bristol-Myers Squibb Company, Princeton, New Jersey 08543 USA. Revised: March 2016

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

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.

Hydroxyurea distributes throughout the body with a volume of distribution approximating total body water.

Hydroxyurea concentrates in leukocytes and erythrocytes.

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.

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

Specific Populations

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

Clinical Studies

The efficacy of hydroxyurea in sickle cell anemia was assessed in a large clinical study (Multicenter Study of Hydroxyurea in Sickle Cell Anemia) (see Table 2).

The study was a randomized, double-blind, placebo-controlled trial that evaluated 299 adult patients ( ≥ 18 years) with moderate to severe disease ( ≥ 3 painful crises yearly). The trial was stopped by the Data Safety Monitoring Committee, after accrual was completed but before the scheduled 24 months of follow-up was completed in all patients, based on observations of fewer painful crises among patients receiving hydroxyurea.

Compared to placebo treatment, treatment with hydroxyurea resulted in a significant decrease in the yearly rate of painful crises, the yearly rate of painful crises requiring hospitalization, the incidence of chest syndrome, the number of patients transfused, and units of blood transfused. Hydroxyurea treatment significantly increased the median time to both first and second painful crises.

Although patients with 3 or more painful crises during the preceding 12 months were eligible for the study, most of the benefit in crisis reduction was seen in the patients with 6 or more painful crises during the preceding 12 months.

Table 2: Results from the Multicenter Study of Hydroxyurea in Sickle Cell Anemia

In patients with SCA treated with hydroxyurea, fetal hemoglobin (HbF) increases 4 to 12 weeks after initiation of treatment. In general, average HbF levels correlate with dose and plasma level with possible plateauing at higher dosages.

A clear relation between reduction in crisis frequency and increased HbF or F-cell levels has not been demonstrated. The dose-related cytoreductive effects of hydroxyurea, particularly on neutrophils, was the factor most strongly correlated with reduced crisis frequency.

Do not handle hydroxyurea pills or the medicine bottle without skin protection (disposable gloves).

Avoid being near people who are sick or have infections. Tell your doctor at once if you develop signs of infection.

Your pharmacist can provide more information about hydroxyurea.

Remember, keep this and all other medicines out of the reach of children, never share your medicines with others, and use this medication only for the indication prescribed.

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