DROXIA™ (hydroxyurea capsules, USP) is available for oral use as capsules providing 200 mg, 300 mg and 400 mg hydroxyurea. Inactive ingredients: citric acid, gelatin, lactose, magnesium stearate, sodium phosphate, titanium dioxide and capsule colorants: FD&C Blue #1 and FD&C Green #3 (200 mg capsules); D&C Red #28, D&C Red #33 and FD&C Blue #1 (300 mg capsules); D&C Red #28, D&C Red #33 and D&C Yellow #10 (400 mg capsules).

Hydroxyurea is an essentially tasteless, white crystalline powder. Its structural formula is:

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 RBCs, decreasing neutrophils, increasing the water content of RBCs, increasing deformability of sickled cells, and altering the adhesion of RBCs to endothelium.

:

Absorption --Hydroxyurea is readily absorbed after oral administration. Peak plasma levels are reached in 1 to 4 hours after an oral dose. With increasing doses, disproportionately greater mean peak plasma concentrations and AUCs are observed.

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

Distribution --Hydroxyurea distributes rapidly and widely in the body with an estimated volume of distribution approximating total body water.

Plasma to ascites fluid ratios range from 2:1 to 7.5:1. Hydroxyurea concentrates in leukocytes and erythrocytes.

Metabolism --Up to 50% of an oral dose undergoes conversion through metabolic pathways that are not fully characterized. In one minor pathway, hydroxyurea may be degraded by urease found in intestinal bacteria. Acetohydroxamic acid was found in the serum of three leukemic patients receiving hydroxyurea and may be formed from hydroxylamine resulting from action of urease on hydroxyurea.

Excretion --Excretion of hydroxyurea in humans is a nonlinear process occurring through two pathways. One is saturable, probably hepatic metabolism; the other is first-order renal excretion. In adults with SCA, mean cumulative urinary hydroxyurea excretion was 62% of the administered dose at 8-hours.

Special Populations:

Geriatric, Gender, Race --No information is available regarding pharmacokinetic differences due to age, gender or race.

Pediatric --No pharmacokinetic data are available in pediatric patients treated with hydroxyurea for SCA.

Renal Insufficiency --There are no data that support specific guidance for dosage adjustment in patients with renal impairment. As renal excretion is a pathway of elimination, consideration should be given to decreasing the dosage of hydroxyurea in patients with renal impairment. Close monitoring of hematologic parameters is advised in these patients.

Hepatic Insufficiency --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.

Drug Interactions --There are no data on concomitant use of hydroxyurea with other drugs in humans.

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) ¹ .

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.

No deaths were attributed to treatment with hydroxyurea, and none of the patients developed neoplastic disorders during the study. Treatment was permanently stopped for medical reasons in 14 hydroxyurea-treated (2 patients with myelotoxicity) and 6 placebo-treated patients. (See ADVERSE REACTIONS section.)

Fetal Hemoglobin:   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.

DROXIA (hydroxyurea capsules, USP) is indicated to reduce the frequency of painful crises and to reduce the need for blood transfusions in adult patients with sickle cell anemia with recurrent moderate to severe painful crises (generally at least 3 during the preceding 12 months).

CONTRAINDICATIONS

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

DROXIA is a cytotoxic and myelosuppressive agent. DROXIA should not be given if bone marrow function is markedly depressed, as indicated by neutrophils below 2000 cells/mm ³ ; a platelet count below 80,000/mm ³ ; a hemoglobin level below 4.5 g/dL; or reticulocytes below 80,000/mm ³ when the hemoglobin concentration is below 9 g/dL. Neutropenia is generally the first and most common manifestation of hematologic suppression. (See DOSAGE AND ADMINISTRATION section.) Thrombocytopenia and anemia occur less often, and are seldom seen without a preceding leukopenia. Recovery from myelosuppression is usually rapid when therapy is interrupted. DROXIA causes macrocytosis, which may mask the incidental development of folic acid deficiency. Prophylactic administration of folic acid is recommended.

Hydroxyurea should be used with caution in patients with renal dysfunction. (See DOSAGE AND ADMINISTRATION section.)

Carcinogenesis and Mutagenesis:   (See Boxed WARNING  section.) Hydroxyurea is genotoxic in a wide range of test systems and is thus presumed to be a human carcinogen. In patients receiving long-term hydroxyurea for myeloproliferative disorders, such as polycythemia vera and thrombocythemia, secondary leukemia has been reported. It is unknown whether this leukemogenic effect is secondary to hydroxyurea or is associated with the patients' underlying disease. Skin cancer has also been reported in patients receiving long-term hydroxyurea.

Conventional long-term studies to evaluate the carcinogenic potential of DROXIA have not been performed. However, intraperitoneal administration of 125-250 mg/kg hydroxyurea (about 0.6-1.2 times the maximum recommended human oral daily dose on a mg/m ² basis) 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 vitro to 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.

Pregnancy:   DROXIA can cause fetal harm when administered to a pregnant woman. Hydroxyurea is embryotoxic and causes fetal malformations (partially ossified cranial bones, absence of eye sockets, hydrocephaly, bipartite sternebrae, missing lumbar vertebrae) at 180 mg/kg/day (about 0.8 times the maximum recommended human daily dose on a mg/m ² basis) in rats and at 30 mg/kg/day (about 0.3 times the maximum recommended human daily dose on a mg/m ² basis) in rabbits. Embryotoxicity was characterized by decreased fetal viability, reduced live litter sizes, and developmental delays. Hydroxyurea crosses the placenta. Single doses of >/= 375 mg/kg (about 1.7 times the maximum recommended human daily dose on a mg/m ² basis) to rats caused growth retardation and impaired learning ability. There are no adequate and well-controlled studies in pregnant women. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential harm to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant.

PRECAUTIONS

Therapy with DROXIA requires close supervision. Some patients treated at the recommended initial dose of 15 mg/kg/day have experienced severe or life-threatening myelosuppression, requiring interruption of treatment and dose reduction. The hematologic status of the patient, as well as kidney and liver function should be determined prior to, and repeatedly during treatment. Treatment should be interrupted if neutrophil levels fall to < 2000/mm ³ ; platelets fall to < 80,000/mm ³ ; hemoglobin declines to less than 4.5 g/dL; or if reticulocytes fall below 80,000/mm ² when the hemoglobin concentration is below 9 g/dL. Following recovery, treatment may be resumed at lower doses (see DOSAGE AND ADMINISTRATION section).

Patients must be able to follow directions regarding drug administration and their monitoring and care.

Carcinogenesis, Mutagenesis, and Impairment of Fertility:   See and Boxed WARNING sections for Carcinogenesis and Mutagenesis information.

Impairment of Fertility --Hydroxyurea administered to male rats at 60 mg/kg/day (about 0.3 times the maximum recommended human daily dose on a mg/m ² basis) produced testicular atrophy, decreased spermatogenesis, and significantly reduced their ability to impregnate females.

Pregnancy    Pregnancy "Category D". (See section.)

Nursing Mothers:   Hydroxyurea is excreted in human milk. Because of the potential for serious adverse reactions with hydroxyurea, a decision should be made either to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

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

Drug Interactions:   Prospective studies on the potential for hydroxyurea to interact with other drugs have not been performed.

Information for Patients:   (See Patient Information at end of labeling.) Patients should be reminded that this medication must be handled with care. People who are not taking DROXIA (hydroxyurea capsules, USP) should not be exposed to it. If the powder from the capsule is spilled, it should be wiped up immediately with a damp disposable towel and discarded in a closed container, such as a plastic bag. The medication should be kept away from children and pets.

The necessity of monitoring blood counts every two weeks, throughout the duration of therapy, should be emphasized. For additional information, see the accompanying Patient Information leaflet.

ADVERSE REACTIONS

Sickle Cell Anemia:    In patients treated for sickle cell anemia in the Multicenter Study of Hydroxyurea in Sickle Cell Anemia ¹ , the most common adverse reactions were hematologic, with neutropenia, and low reticulocyte and platelet levels necessitating temporary cessation in almost all patients. Hematologic recovery usually occurred in two weeks.

Non-hematologic events that possibly were associated with treatment include hair loss, skin rash, fever, gastrointestinal disturbances, weight gain, bleeding and parvovirus B-19 infection; however, these non-hematologic events occurred with similar frequencies in the hydroxyurea and placebo treatment groups. Melanonychia has also been reported in patients receiving DROXIA for SCA.

Other:   Adverse events associated with the use of hydroxyurea in the treatment of neoplastic diseases, in addition to hematologic effects include: gastrointestinal symptoms (stomatitis, anorexia, nausea, vomiting, diarrhea, and constipation), and dermatological reactions such as maculopapular rash, skin ulceration, dermatomyositis-like skin changes, peripheral erythema and facial erythema. Hyperpigmentation, atrophy of skin and nails, scaling and violet papules have been observed in some patients after several years of long-term daily maintenance therapy with hydroxyurea. Skin cancer has been reported. Dysuria and alopecia occur very rarely. Large doses may produce moderate drowsiness. Neurological disturbances have occurred extremely rarely and were limited to headache, dizziness, disorientation, hallucinations, and convulsions. Hydroxyurea occasionally may cause temporary impairment of renal tubular function accompanied by elevations in serum uric acid, BUN, and creatinine levels. Abnormal BSP retention has been reported. Fever, chills, malaise, edema, asthenia, and elevation of hepatic enzymes have also been reported.

The association of hydroxyurea with the development of acute pulmonary reactions consisting of diffuse pulmonary infiltrates, fever and dyspnea has been rarely reported. Pulmonary fibrosis also has been reported rarely.

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.

DOSAGE AND ADMINISTRATION

Dosage should be based on the patient's actual or ideal weight, whichever is less. The initial dose of DROXIA is 15 mg/kg/day as a single dose. The patient's blood count must be monitored every two weeks. (See section.)

If blood counts are in an acceptable range* , the dose may be increased by 5 mg/kg/day every 12 weeks until a maximum tolerated dose (the highest dose that does not produce toxic blood counts over 24 consecutive weeks), or 35 mg/kg/day, is reached.

If blood counts are between the acceptable range * and toxic ** , the dose is not increased.

If blood counts are considered toxic ** , DROXIA should be discontinued until hematologic recovery. Treatment may then be resumed after reducing the dose by 2.5 mg/kg/day from the dose associated with hematologic toxicity. DROXIA may then be titrated up or down, every 12 weeks in 2.5 mg/kg/day increments, until the patient is at a stable dose that does not result in hematologic toxicity for 24 weeks. Any dosage on which a patient develops hematologic toxicity twice should not be tried again.

     *acceptable range =

neutrophils >/= 2500 cells/mm ³ ,
platelets >/= 95,000/mm ³ ,
hemoglobin > 5.3 g/dL and
reticulocytes >/= 95,000/mm ³ if the hemoglobin concentration < 9 g/dL.

     **toxic =

neutrophils < 2000 cells/mm ³ ,
platelets < 80,000/mm ³ ,
hemoglobin < 4.5 g/dL and
reticulocytes < 80,000/mm ³ if the hemoglobin concentration < 9 g/dL.

Renal Insufficiency:   There are no data that support specific guidance for dosage adjustment in patients with renal impairment. As renal excretion is a pathway of elimination, consideration should be given to decreasing the dosage of DROXIA in patients with renal impairment. Close monitoring of hematologic parameters is advised in these patients.

Hepatic Insufficiency:   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.

Procedures for proper handling and disposal of cytotoxic drugs should be considered. Several guidelines on this subject have been published. ^2-8 There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.

HOW SUPPLIED

DROXIA™ (hydroxyurea capsules, USP).

200 mg capsules packaged in HDPE bottles of 60 with a plastic safety screw cap. ( NDC 0003-6335-17). The cap and body are opaque blue-green. The capsule is marked in black ink on both the cap and body with DROXIA and 6335 .

300 mg capsules packaged in HDPE bottles of 60 with a plastic safety screw cap. ( NDC 0003-6336-17). The cap and body are opaque purple. The capsule is marked in black ink on both the cap and body with DROXIA and 6336 .

400 mg capsules packaged in HDPE bottles of 60 with a plastic safety screw cap. ( NDC 0003-6337-17). The cap and body are opaque reddish-orange. The capsule is marked in black ink on both the cap and body with DROXIA and 6337 .

Storage   Store at 25° C (77° F); excursions permitted to 15-30° C (59-86° F). Keep tightly closed.

PRODUCT PHOTO(S):

REFERENCES

1. Charache, S, et al: Hydroxyurea and Sickle Cell Anemia: Clinical Utility of a Myelosuppressive "Switching" Agent. Medicine 1996; 75:300-326.
2. Recommendations for the Safe Handling of Parenteral Antineoplastic Drugs. NIH Publications. No. 83-2621. For sale by the Superintendent of Documents, US Government Printing Office, Washington, DC 20402.
3. AMA Council Report: Guidelines for Handling Parenteral Antineoplastics. JAMA 1985; 253(11):1590-1592.
4. National Study Commission on Cytotoxic Exposure-Recommendations for Handling Cytotoxic Agents. Available from Louis P. Jeffrey, ScD, Chairman, National Study Commission on Cytotoxic Exposure, Massachusetts College of Pharmacy and Allied Health Sciences, 179 Longwood Avenue, Boston, MA 02115.
5. Clinical Oncological Society of Australia: Guidelines and Recommendations for Safe Handling of Antineoplastic Agents. Med J Australia 1983; 1:426-428.
6. Jones RB, et al: Safe Handling of Chemotherapeutic Agents: A Report from the Mount Sinai Medical Center, CA--A Cancer Journal for Clinicians . 1983; (Sept./Oct.)258-263.
7. American Society of Hospital Pharmacists Technical Assistance Bulletin on Handling Cytotoxic and Hazardous Drugs. Am J Hosp Pharm 1990; 47:1033-1049.
8. Controlling Occupational Exposure to Hazardous Drugs. (OSHA Work--Practice Guidelines). Am J Health--Syst Pharm 1996; 53:1669-1685.

Patient Information About
DROXIA ™ Capsules
(generic name = hydroxyurea)

WHAT IS DROXIA?

DROXIA is a prescription medicine that is used to reduce the frequency of painful crises and reduce the need for blood transfusions in adults with sickle cell anemia. How DROXIA works is not certain but it may work by reducing the number of white blood cells and/or increasing red blood cells that carry fetal hemoglobin (HbF). Fetal hemoglobin may prevent sickling.

WHAT IS SICKLE CELL ANEMIA?

Sickle cell anemia is an inherited disorder of the red blood cells. Red blood cells carry oxygen to all parts of the body by using a protein called hemoglobin. Normal red blood cells contain only normal hemoglobin and are shaped like indented disks. These cells are very flexible and move easily through small blood vessels.

In sickle cell anemia, the red blood cells contain sickle hemoglobin, which causes them to change to a rigid, spiked shape (sickle shape) after oxygen is released. Sickled cells get stuck and form plugs in small blood vessels. These plugs restrict blood flow, causing damage to surrounding tissues resulting in a painful crisis.

Because there are blood vessels in all parts of the body, painful crises can occur anywhere in your body. In addition, sickle cells are trapped and destroyed in the liver and spleen. This results in a shortage of red blood cells (anemia).

WILL DROXIA CURE MY SICKLE CELL ANEMIA?

No. However, DROXIA may help you better control your sickle cell anemia, but it is important to follow your doctor' instructions carefully.

In a study of adults taking recommended doses, daily treatment with DROXIA resulted in fewer painful crises, fewer patients with "acute chest syndrome" (a pneumonia-like condition that leads to difficulty in breathing) and less need for blood transfusions.

WHO SHOULD NOT TAKE DROXIA CAPSULES?

Do not take DROXIA capsules if you are allergic to any of the ingredients. Besides the active ingredient hydroxyurea, DROXIA capsules contain the following inactive ingredients: citric acid, gelatin, lactose, magnesium stearate, sodium phosphate, titanium dioxide and capsule colorants. Tell your doctor if you think you have ever had an allergic reaction.

If you get pregnant, DROXIA (hydroxyurea capsules, USP) may harm or cause death to your unborn child. You should not become pregnant while taking DROXIA. Make sure you use a contraceptive method. Tell your doctor if you become pregnant or plan to become pregnant while taking DROXIA.

HOW DO I TAKE DROXIA CAPSULES?

Always follow your doctor' instructions carefully when taking DROXIA capsules or any prescription medication. The usual dose of DROXIA may range from as few as one to several capsules per day. DROXIA is usually taken once a day. You should try to take it at the same time each day. Your doctor will determine the proper starting dose of DROXIA for you based on your weight and blood count. The dose will then be increased slowly to your maximum tolerated dose (maximum dose that does NOT produce severely low blood counts). Your doctor should measure your blood counts every two weeks after you begin treatment with DROXIA. Depending on the results, your dosage may be adjusted or the drug may be stopped for a while.

DROXIA is a medication that must be handled with care. People who are not taking DROXIA should not be exposed to it. If the powder from the capsule is spilled, it should be wiped up immediately with a damp disposable towel and discarded in a closed container, such as a plastic bag.

If you accidentally take an overdose of DROXIA capsules, seek medical attention immediately. Contact your doctor, local poison control center, or emergency room.

WHAT IF I MISS A DOSE OF DROXIA CAPSULES?

Try not to miss your dose of DROXIA, but if you do, take it as soon as possible. If it is almost time for your next dose, skip the missed dose and resume your regular dosing schedule. Do not take two doses during the same day . If you miss more than one dose, call your doctor for instructions.

WHAT SHOULD I AVOID WHILE TAKING DROXIA CAPSULES?

Some other medications can increase your risk of experiencing serious side effects from DROXIA. While you are taking DROXIA capsules, you should inform your doctor of all prescription and over-the-counter medicines that you are taking.

In nursing mothers, DROXIA is present in breast milk. Because of the potential for side effects in the newborn, you should discontinue nursing your baby while taking DROXIA.

WHAT ARE THE POSSIBLE SIDE EFFECTS OF DROXIA CAPSULES?

As with other medicines, DROXIA may cause unwanted effects, although it is not always possible to tell whether such effects are caused by DROXIA, another medication you may be taking, or your sickle cell anemia. Any side effects or unusual symptoms that you experience should be reported to your doctor, particularly if they persist or are troublesome.

The most serious side effects of DROXIA involve the blood, and may include severely low white blood cell counts (leukopenia, neutropenia), which can decrease your resistance to infections; severely low red blood cell counts (anemia); or severely low platelet counts (thrombocytopenia), which can cause bleeding. Almost all patients who received DROXIA in clinical studies needed to have their medication stopped for a time to allow their low blood counts to return to acceptable levels.

The side effects reported most often by adults with sickle cell anemia participating in studies of DROXIA included hair loss, skin rash, fever, stomach and/or bowel disturbances, weight gain, bleeding, virus infection, and discolored nails (melanonychia), but these were equally common in people getting a placebo (sugar pill).

Skin cancer and leukemia, which can be fatal, have been reported in patients receiving long-term hydroxyurea for conditions other than sickle cell anemia. In laboratory tests DROXIA causes changes in chromosomes and DNA (genetic material) that strongly suggest it can cause cancer in people, especially if it is taken for a long time.

ARE REGULAR BLOOD COUNTS NECESSARY WHILE TAKING DROXIA CAPSULES?

Yes. Your doctor should measure your blood counts every two weeks while you are taking DROXIA. Your DROXIA dose will require adjustment based on these regular blood counts. Serious problems can occur if the DROXIA dose is not adjusted on time.

WHAT ELSE SHOULD I KNOW ABOUT DROXIA CAPSULES?

If you have kidney or liver disease, close monitoring of your blood count, kidney and liver function will be required.

Because it may not be possible to detect a deficiency of folic acid in patients taking DROXIA, your doctor may prescribe a folic acid supplement for you.

WHAT ELSE SHOULD I DO TO CONTROL MY SICKLE CELL CRISES?

Because painful crises can be brought on by factors such as infection, dehydration, worsening anemia, emotional stress, extreme temperature exposure, or ingestion of substances such as alcohol or other recreational drugs, you should be aware of the following general guidelines that will help keep you pain-free:

• Seek immediate medical attention when a fever develops or signs of infection appear.
• Avoid smoking and drinking more than 1-2 alcoholic beverages a day.
• Drink 8 to 10 glasses of water or other fluid each day.
• Avoid any types of physical exertion that seem to bring on painful crises or other discomfort.
• Avoid extreme temperature changes and dress appropriately in hot and cold weather.

This medicine was prescribed for your particular condition. Do not use DROXIA Capsules for another condition or give it to others. Keep DROXIA Capsules and all medicines out of the reach of children. Discard DROXIA Capsules when they are outdated or no longer needed by flushing the contents of your bottle down the toilet.

The summary does not include everything there is to know about DROXIA Capsules. Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. If you have questions or concerns, or want more information about DROXIA Capsules, your physician and pharmacist have the complete prescribing information upon which this leaflet is based. You may want to read it and discuss it with your doctor. Remember, no written summary can replace careful discussion with your doctor.

This Patient Information leaflet has been approved by the U.S. Food and Drug Administration.

BRISTOL LABORATORIES

ONCOLOGY PRODUCTS

A Bristol-Myers Squibb Company

Princeton, NJ 08543

U.S.A.

Made in Italy

U4-B001-7-99             1053547

                       Issued: April 1999