Droxia

The following adverse reactions are described in detail in other labeling sections:

• Myelosuppression [see WARNINGS AND PRECAUTIONS]
• Malignancies [see WARNINGS AND PRECAUTIONS]
• Embryo-fetal toxicity [see BOXED WARNING and WARNINGS AND PRECAUTIONS]
• Vasculitic toxicities [see WARNINGS AND PRECAUTIONS]
• Risks with concomitant use of antiretroviral drugs [see WARNINGS AND PRECAUTIONS]
• Macrocytosis [see WARNINGS AND PRECAUTIONS]

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.

Clinical Trial Experience

In 299 patients treated for sickle cell anemia in the Multicenter Study of Hydroxyurea in Sickle Cell Anemia, 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.

Other adverse reactions include hair loss, macrocytosis, bleeding, and melanonychia.

Postmarketing Experience

The following adverse reactions have been identified during postapproval use of hydroxyurea in the treatment of neoplastic diseases. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency.

• 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, dermatomyositis-like
• skin changes, peripheral and facial erythema, 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

Medications can interact with certain foods. In some cases, this may be harmful and your doctor may advise you to avoid certain foods. In the case of Droxia, there are no specific foods that you must exclude from your diet when receiving this medication.

 

You should not use hydroxyurea if you are allergic to it.

To make sure hydroxyurea is safe for you, tell your doctor if you have:

• bone marrow suppression or anemia (low red blood cells);

• low levels of platelets in your blood;

• a history of skin cancer;

• high levels of uric acid in your blood;

• HIV or AIDS;

• kidney disease (or if you are on dialysis);

• liver disease;

• a pancreas disorder; or

• if you are receiving chemotherapy or radiation.

Using hydroxyurea may increase your risk of developing other types cancer or leukemia. Talk with your doctor about your specific risk.

This medicine can harm an unborn baby or cause birth defects. Do not use if you are pregnant.

Both men and women taking this medicine should use birth control to prevent pregnancy. Hydroxyurea use by either parent may cause birth defects. After the last dose of hydroxyurea, a man must use birth control for much longer than a woman.

• For women: Use effective birth control to prevent pregnancy while you are using this medicine and for at least 6 months after your treatment ends.

• For men: Use birth control to prevent pregnancy while using hydroxyurea and for at least 1 year after your treatment ends.

This medication can also affect fertility (your ability to have children), whether you are a man or a woman.

Hydroxyurea can pass into breast milk and may harm a nursing baby. You should not breast-feed while you are taking hydroxyurea.

Older adults may be more likely to have side effects from this medicine.

Using hydroxyurea may increase your risk of developing skin cancer. Avoid exposure to sunlight or tanning beds. Wear protective clothing and use sunscreen (SPF 30 or higher) when you are outdoors.

Do not receive a "live" vaccine while using hydroxyurea, or you could develop a serious infection. Live vaccines include measles, mumps, rubella (MMR), polio, rotavirus, typhoid, yellow fever, varicella (chickenpox), zoster (shingles), and nasal flu (influenza) vaccine.

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

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

This medicine can pass into body fluids (urine, feces, vomit). Caregivers should wear rubber gloves while cleaning up a patient's body fluids, handling contaminated trash or laundry or changing diapers. Wash hands before and after removing gloves. Wash soiled clothing and linens separately from other laundry.

Get emergency medical help if you have signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat.

Call your doctor at once if you have:

• skin numbness or purple discoloration, skin ulcers or open sores;

• painful or difficult urination;

• numbness, tingling, or burning pain in your hands or feet;

• signs of a weak immune system--fever, chills, body aches, flu symptoms, sores in your mouth and throat, pale skin, feeling light-headed or short of breath, easy bruising or bleeding;

• pancreas problems--severe pain in your upper stomach spreading to your back, nausea and vomiting, fast heart rate; or

• liver problems--nausea, upper stomach pain, itching, tired feeling, loss of appetite, dark urine, clay-colored stools, jaundice (yellowing of the skin or eyes).

Common side effects may include:

• bleeding;

• loss of appetite, upset stomach, constipation, diarrhea, vomiting;

• skin peeling or itching, mild rash;

• hair loss, darkening of your nails;

• headache, dizziness; or

• swelling in your hands or feet.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

This section provides information on the proper use of a number of products that contain hydroxyurea. It may not be specific to Droxia. Please read with care.

Use this medicine exactly as directed by your doctor. Do not use more of it, do not use it more often, and do not use it for a longer time than your doctor ordered.

This medicine comes with a patient information insert. Read and follow the instructions carefully. Ask your doctor if you have any questions.

Your doctor may want you to take folic acid with this medicine.

Hydroxyurea should be handled with care. People who are not taking this medicine should avoid touching it. To decrease your chance of touching the medicine:

• Wear disposable gloves when handling the bottle or capsules.
• Wash your hands with soap and water before and after contact with the bottle or capsules.
• Do not open the capsules. Avoid exposure to crushed or opened capsules.
• If you touch an opened or crushed capsule, wash your skin right away with soap and water.
• If powder from the capsule gets into your eyes, rinse them with water or an isotonic eyewash for 15 minutes.
• If powder from the capsule is spilled, wipe it up right away with a damp disposable towel. Place the towel and the empty capsule in a closed container, such as a plastic bag.
• The area where the powder spilled should be cleaned 3 times using a detergent solution followed by clean water.

Dosing

The dose of this medicine will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of this medicine. If your dose is different, do not change it unless your doctor tells you to do so.

The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.

• For oral dosage form (capsules):
  • For cancer of the head and neck:
    • Adults—Dose is based on body weight and must be determined by your doctor. The dose is 15 milligrams (mg) per kilogram (kg) of body weight per day, taken as a single dose. Your doctor may adjust your dose as needed.
    • Children—Use and dose must be determined by your doctor.
  • For chronic myelocytic leukemia (CML):
    • Adults—Dose is based on body weight and must be determined by your doctor. The dose is 15 milligrams (mg) per kilogram (kg) of body weight per day, taken as a single dose. Your doctor may adjust your dose as needed.
    • Children—Use and dose must be determined by your doctor.
  • For sickle cell anemia:
    • Adults—Dose is based on body weight and must be determined by your doctor. At first, the dose is 15 milligrams (mg) per kilogram (kg) of body weight per day, taken as a single dose. Your doctor may adjust your dose as needed. However, the dose is usually not more than 35 mg per kg of body weight per day.
    • Children—Use and dose must be determined by your doctor.

Missed Dose

If you miss a dose of this medicine, take it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not double doses.

Storage

Store the medicine in a closed container at room temperature, away from heat, moisture, and direct light. Keep from freezing.

Keep out of the reach of children.

Do not keep outdated medicine or medicine no longer needed.

Ask your healthcare professional how you should dispose of any medicine you do not use.

• If you have an allergy to hydroxyurea or any other part of Droxia (hydroxyurea capsules 200 mg, 300 mg, 400 mg).
• If you are allergic to any drugs like this one, any other drugs, foods, or other substances. Tell your doctor about the allergy and what signs you had, like rash; hives; itching; shortness of breath; wheezing; cough; swelling of face, lips, tongue, or throat; or any other signs.
• If you have any of these health problems: Anemia (other than sickle cell anemia) or bone marrow disease.
• If you have a low platelet count or a low white blood cell count.
• If you are taking any of these drugs: Didanosine or stavudine.
• If you are breast-feeding. Do not breast-feed while you take this medicine.

This is not a list of all drugs or health problems that interact with Droxia.

Tell your doctor and pharmacist about all of your drugs (prescription or OTC, natural products, vitamins) and health problems. You must check to make sure that it is safe for you to take this medicine with all of your drugs and health problems. Do not start, stop, or change the dose of any drug without checking with your doctor.

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:

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

Event	Hydroxyurea (N=152)	Placebo (N=147)	Percent Change Versus Placebo	P-value
*   A painful crisis was defined in the study as acute sickling-related pain that resulted in a visit to a medical facility, that lasted more than 4 hours, and that required treatment with a parenteral narcotic or NSAID. Chest syndrome, priapism, and hepatic sequestration were also included in this definition.
Median yearly rate of painful crises*	2.5	4.6	−46	=0.001
Median yearly rate of painful crises requiring hospitalization	1.0	2.5	−60	=0.0027
Median time to first painful crisis (months)	2.76	1.35	+104	=0.014
Median time to second painful crisis (months)	6.58	4.13	+59	=0.0024
Incidence of chest syndrome (# episodes)	56	101	−45	=0.003
Number of patients transfused	55	79	−30	=0.002
Number of units of blood transfused	423	670	−37	=0.003

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.

Advise the patient to read the FDA-approved patient labeling (Patient Information).

• There is a risk of myelosuppression. Monitoring blood counts every two weeks throughout the duration of therapy should be emphasized to patients taking Droxia [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 and skin cancers. Advise use of sun protection [see Warnings and Precautions (5.2, 5.4)]. • Advise patients to inform their healthcare provider if they have received or are planning to receive vaccinations while taking Droxia as this may result in a severe infection [see Warnings and Precautions (5.5)]. • Advise females of reproductive potential of the potential risk to a fetus and 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 Droxia [see Warnings and Precautions (5.3) and Use in Specific Populations (8.1, 8.3)]. • Advise females to discontinue breastfeeding during treatment with Droxia [see Use in Specific Populations (8.2)]. • Patients with HIV infection should contact their physician for signs and symptoms of pancreatitis, hepatic events, and peripheral neuropathy [see Warnings and Precautions (5.6)].

Manufactured for:
Bristol-Myers Squibb Company
Princeton, New Jersey 08543 USA


[Print code]

60 CAPSULES
NDC 0003-6337-17
Droxia®
(hydroxyurea capsules, USP)
400 mg per capsule
Rx only
Bristol-Myers Squibb

Droxia  hydroxyurea capsule

Product Information Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:0003-6336 Route of Administration ORAL DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength hydroxyurea (hydroxyurea) hydroxyurea 300 mg

Inactive Ingredients Ingredient Name Strength citric acid monohydrate   gelatin   LACTOSE, UNSPECIFIED FORM   magnesium stearate   sodium phosphate   titanium dioxide   D&C Red No. 28   D&C Red No. 33   FD&C Blue No. 1

Product Characteristics Color PURPLE Score no score Shape CAPSULE Size 19mm Flavor Imprint Code Droxia;6336;Droxia;6336 Contains

Packaging # Item Code Package Description 1 NDC:0003-6336-17 60 CAPSULE in 1 BOTTLE

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date NDA NDA016295 06/01/2009

Droxia  hydroxyurea capsule

Product Information Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:0003-6335 Route of Administration ORAL DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength hydroxyurea (hydroxyurea) hydroxyurea 200 mg

Inactive Ingredients Ingredient Name Strength citric acid monohydrate   gelatin   LACTOSE, UNSPECIFIED FORM   magnesium stearate   sodium phosphate   titanium dioxide   FD&C Blue No. 1   FD&C Green No. 3

Product Characteristics Color TURQUOISE (blue-green) Score no score Shape CAPSULE Size 16mm Flavor Imprint Code Droxia;6335;Droxia;6335 Contains

Packaging # Item Code Package Description 1 NDC:0003-6335-17 60 CAPSULE in 1 BOTTLE

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date NDA NDA016295 06/01/2009

Droxia  hydroxyurea capsule

Product Information Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:0003-6337 Route of Administration ORAL DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength hydroxyurea (hydroxyurea) hydroxyurea 400 mg

Inactive Ingredients Ingredient Name Strength citric acid monohydrate   gelatin   LACTOSE, UNSPECIFIED FORM   magnesium stearate   sodium phosphate   titanium dioxide   D&C Red No. 28   D&C Red No. 33   D&C Yellow No. 10

Product Characteristics Color ORANGE Score no score Shape CAPSULE Size 22mm Flavor Imprint Code Droxia;6337;Droxia;6337 Contains

Packaging # Item Code Package Description 1 NDC:0003-6337-17 60 CAPSULE in 1 BOTTLE

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date NDA NDA016295 06/01/2009

Labeler - E.R. Squibb & Sons, L.L.C. (011550092)

Revised: 06/2017   E.R. Squibb & Sons, L.L.C.

This drug crosses the placenta and has been shown to be embryotoxic in animal studies. It can cause fetal malformations (partially ossified cranial bones, absence of eye sockets, hydrocephaly, bipartite sternebrae, missing lumbar vertebrae). Embryotoxicity was characterized by decreased fetal viability, reduced live litter sizes, and developmental delays. AU TGA pregnancy category D: Drugs which have caused, are suspected to have caused or may be expected to cause, an increased incidence of human fetal malformations or irreversible damage. These drugs may also have adverse pharmacological effects. Accompanying texts should be consulted for further details. US FDA pregnancy category D: There is positive evidence of human fetal risk based on adverse reaction data from investigational or marketing experience or studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks.

Use should be avoided. AU TGA pregnancy category: D US FDA pregnancy category: D Comments: -This drug affects DNA synthesis and may be a potent mutagenic agent. -An effective method of contraception is advised in both male and female patients before and during treatment. -If this drug is used during pregnancy or if a patient becomes pregnant while taking this drug, the patient should be apprised of the potential harm to the fetus.

-Contraindicated (UK) -A decision should be made to discontinue breastfeeding or discontinue the drug, taking into account the importance of the drug to the mother. (AU, US) Excreted into human milk: Yes

Most experts consider breastfeeding contraindicated during maternal antineoplastic drug therapy. It might be possible to breastfeed safely during intermittent therapy with an appropriate period of breastfeeding abstinence. Although only minimal data are available to determine an appropriate period to withhold breastfeeding, the drug terminal half-live of 4.5 hours with normal kidney function suggests that withholding breastfeeding for at least 24 hours may be sufficient. This period may be longer in patients with impaired kidney function. Chemotherapy may adversely affect the normal microbiome and chemical makeup of breastmilk.