Hydroxyurea

Hydroxyurea is a prescription drug sold under the brand name Hydrea.

It's used to treat psoriasis, chronic myelogenous leukemia (a cancer of the white blood cells), ovarian cancer, melanoma (a form of skin cancer), and certain head and neck cancers.

The medicine also helps people with sickle cell anemia (an inherited blood disorder) by reducing the frequency of painful sickle cell crisis episodes and the need for blood transfusions.

Additionally, hydroxyurea is sometimes used to treat polycythemia vera (a disorder of the bone marrow) by reducing the red blood cell mass.

Hydroxyurea belongs to a class of drugs called antimetabolites. It works by slowing or stopping the growth of cancer cells in the body, and by helping to prevent the formation of abnormal red blood cells.

The Food and Drug Administration (FDA) approved hydroxyurea in 1967. It's marketed by Bristol-Myers Squibb Company.

Hydroxyurea Warnings

Hydroxyurea contains a black-box warning because it can cause a severe drop in the number of blood cells in your bone marrow. This can increase your risk of a serious infection or bleeding.

Tell your doctor right away if you experience any of the following symptoms while taking hydroxyurea:

• Fever, sore throat, cough, congestion, or other signs of infection
• Unusual bruising or bleeding
• Vomit that's bloody or looks like coffee grounds
• Bloody or black, tarry stools

Try to avoid contact with people who have infections or colds while taking this drug.

Don't receive any vaccinations while taking hydroxyurea without first talking to your doctor.

Hydroxyurea also contains a black-box warning because the medicine may increase your chance of developing other cancers.

Some people have reported skin cancer or secondary leukemia after taking hydroxyurea.

Call your healthcare provider right away if you notice any of the following symptoms:

• Change in the appearance of a mole
• A new growth on the skin
• Any unusual skin changes

Before taking hydroxyurea, tell your doctor if you have, or have had:

• Severe bone marrow depression
• Low white blood cell counts
• Low blood platelet levels
• Severe anemia or another blood disorder
• HIV/AIDS
• Kidney disease
• Liver disease
• Allergies to medicines

Also, let your healthcare provider know if you've ever been treated with chemotherapy or radiation.

Tell your doctor you take hydroxyurea before having any type of surgery, including a dental procedure.

Hydroxyurea may interfere with certain medical tests. Tell all health professionals who treat you that you're taking this medicine.

Elderly people may be more sensitive to certain side effects of hydroxyurea. Talk to your doctor if this is a concern.

The safety and effectiveness of hydroxyurea in children haven't been confirmed. Don't give this medicine to a child unless a doctor tells you otherwise.

People who aren't taking hydroxyurea shouldn't come in contact with the medicine. Caregivers should wear disposable gloves when handling this drug.

Your doctor will want to perform important tests to monitor your body's response to hydroxyurea. Keep all appointments with your doctor and laboratory.

Pregnancy and Hydroxyurea

Hydroxyurea can harm an unborn baby. Don't become pregnant while taking this medicine.

Both men and women should use an effective form of birth control while taking hydroxyurea.

The drug may also affect a woman's ability to become pregnant and a man's ability to father a child. Talk to your doctor if this is a concern.

Since hydroxyurea can be absorbed through the skin and lungs, pregnant women, and those who may become pregnant, shouldn't handle the drug or breathe in the dust from the capsules.

Hydroxyurea is passed into breast milk. Don't breastfeed while taking this medicine.

Hydroxyurea can weaken your immune system. Your blood will need to be tested often, and your cancer treatments may be delayed.

Using hydroxyurea may increase your risk of developing other types of cancer, such as leukemia or skin cancer. Wear protective clothing and use sunscreen when you are outdoors.

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

Overdose symptoms may include drowsiness, mouth sores, and swelling with pain and purple discoloration in your hands and feet.

Usual Adult Dose for Chronic Myelogenous Leukemia:

NOTE: Different products have different approved indications. Consult the manufacturer product information for approved indications.

15 mg/kg/day orally

Comments:
-Therapy should be individualized based on tumor type, disease state, response to treatment, patient risk factors, and current clinical practice standards.
-All dosages should be based on patient actual or ideal weight, whichever is less.
-Prophylactic administration of folic acid is recommended.
-Blood counts should be monitored at least once a week during therapy.
-Severe anemia should be corrected before initiating therapy.

Uses:
-Resistant chronic myeloid leukemia (CML)
-Locally advanced squamous cell carcinomas of the head and neck, (excluding lip) in combination with concurrent chemoradiation

Usual Adult Dose for Head and Neck Cancer:

NOTE: Different products have different approved indications. Consult the manufacturer product information for approved indications.

15 mg/kg/day orally

Comments:
-Therapy should be individualized based on tumor type, disease state, response to treatment, patient risk factors, and current clinical practice standards.
-All dosages should be based on patient actual or ideal weight, whichever is less.
-Prophylactic administration of folic acid is recommended.
-Blood counts should be monitored at least once a week during therapy.
-Severe anemia should be corrected before initiating therapy.

Uses:
-Resistant chronic myeloid leukemia (CML)
-Locally advanced squamous cell carcinomas of the head and neck, (excluding lip) in combination with concurrent chemoradiation

Usual Adult Dose for Sickle Cell Anemia:

NOTE: Different products have different approved indications. Consult the manufacturer product information for approved indications.

Initial dose: 15 mg/kg orally per day; increase 5 mg/kg/day every 12 weeks
Maximum dose: 35 mg/kg/day

Dosing based on blood counts:
-Counts in acceptable range: Increase dose 5 mg/kg/day every 12 weeks to a maximum dose of 35 mg/kg/day (maximal dose is the highest dose that does not produce toxic blood counts over 24 consecutive weeks); increase dosing only if blood counts are in acceptable range; do not increase if myelosuppression occurs
-Counts between acceptable and toxic range: Do not increase dose; if in toxic range, discontinue therapy until hematologic recovery
-Dosing after hematologic recovery: Reduce dose by 2.5 mg/kg/day. Reduce the dose from the dose associated with hematologic toxicity. May titrate up or down every 12 weeks in 2.5 mg/kg/day increments. The patient should be at a stable dose with no hematologic toxicity for 24 weeks. Discontinue treatment permanently if patient develops hematologic toxicity twice.

-BLOOD COUNTS IN THE ACCEPTABLE RANGE:
Neutrophils greater than or equal to 2500 cells/mm3
Platelets greater than or equal to 95,000/mm3
Hemoglobin greater than 5.3 g/dL
Reticulocytes greater than or equal to 95,000/mm3 if the hemoglobin concentration is less than 9 g/dL
-BLOOD COUNTS IN THE TOXIC RANGE:
Neutrophils less than 2000 cells/mm3
Platelets less than 80,000/mm3
Hemoglobin less than 4.5 g/dL
Reticulocytes less than 80,000/mm3 if the hemoglobin concentration is less than 9 g/dL

Comments:
-Dosage is based on the actual or ideal patient weight, whichever is less.
-The patient blood count should be monitored every 2 weeks.
-Fetal hemoglobin (HbF) levels may be used to evaluate the efficacy of therapy in clinical use. Obtain HbF levels every 3 to 4 months. Monitor for an increase in HbF of at least 2-fold over the baseline value.
-Prophylactic administration of folic acid is recommended.

Use: 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.

Chronic Myelogenous Leukemia

Treatment of resistant chronic myelogenous leukemia (CML).166 177 212

Used as an alternative agent for the palliative treatment of chronic-phase CML in patients who cannot undergo allogeneic bone marrow or stem cell transplantation;166 167 212 superior to busulfan for the palliative treatment of CML.212 213

Used as an alternative agent for the palliative treatment of the accelerated phase of CML.166 212

Used to reduce WBC count prior to bone marrow transplantation or initiation of interferon alfa therapy.212

Sickle Cell Anemia

Palliative treatment of sickle cell anemia generally in patients with recurrent moderate to severe painful crises occurring on at least 3 occasions during the preceding 12 months (designated an orphan drug by FDA for this use).106 107 111 113 114 116 117 118 122 123 124 125 151 155 156 157 158 178 179

Therapy is prophylactic; the drug has no role in the treatment of a crisis in progress.117

Polycythemia Vera

Management of polycythemia vera† including use as an adjunct to intermittent phlebotomy.136 143 144 145 146 152 164 171 174 176

Cervical Cancer

Has been used for treatment of cervical cancer†;206 207 208 however, other agents are considered more effective.203 204 205 209

Head and Neck Cancer

Has been used in combination with radiation therapy for local control of primary squamous cell (epidermoid) carcinoma of the head and neck, excluding the lip.177

Melanoma

Has been used for treatment of melanoma;177 however, other agents are preferred.166

Ovarian Cancer

Has been used for treatment of recurrent, metastatic, or inoperable ovarian cancer;177 however, other agents are preferred.166

Specific Drugs

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

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

• Myelosuppression [see Warnings and Precautions (5.1)]
• Malignancies [see Warnings and Precautions (5.2)]
• Embryo-fetal toxicity [see Warnings and Precautions (5.3)]
• Vasculitic toxicities [see Warnings and Precautions (5.4)]
• Risks with concomitant use of antiretroviral drugs [see Warnings and Precautions (5.6)]
• Radiation recall [see Warnings and Precautions (5.7)]
• Macrocytosis [see Warnings and Precautions (5.8)]

Postmarketing Experience

The following adverse reactions have been identified during postapproval use of Hydroxyurea capsules.

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, tumor lysis syndrome
• 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

Adverse reactions observed with combined Hydroxyurea and irradiation therapy are similar to those reported with the use of Hydroxyurea or radiation treatment alone. These effects primarily include bone marrow depression (anemia and leukopenia), gastric irritation, and mucositis. Almost all patients receiving an adequate course of combined Hydroxyurea and irradiation therapy will demonstrate concurrent leukopenia. Platelet depression (<100,000 cells/mm3) has occurred in the presence of marked leukopenia. Hydroxyurea capsules may potentiate some adverse reactions usually seen with irradiation alone, such as gastric distress and mucositis.

12.1 Mechanism of Action

The precise mechanism by which Hydroxyurea produces its antineoplastic effects cannot, at present, be described.  However, the reports of various studies in tissue culture in rats and humans lend support to 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. This hypothesis explains why, under certain conditions, Hydroxyurea may induce teratogenic effects.

Three mechanisms of action have been postulated for the increased effectiveness of concomitant use of Hydroxyurea therapy with irradiation on squamous cell (epidermoid) carcinomas of the head and neck. In vitro studies utilizing Chinese hamster cells suggest that Hydroxyurea (1) is lethal to normally radioresistant S-stage cells, and (2) holds other cells of the cell cycle in the G1 or pre-DNA synthesis stage where they are most susceptible to the effects of irradiation. The third mechanism of action has been theorized on the basis of in vitro studies of HeLa cells. It appears that Hydroxyurea, by inhibition of DNA synthesis, hinders the normal repair process of cells damaged but not killed by irradiation, thereby decreasing their survival rate; RNA and protein synthesis have shown no alteration.

12.3 Pharmacokinetics

Absorption

Following oral administration of Hydroxyurea capsules, 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.

Specific Populations

Renal Impairment

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 to 80 mL/min), moderate (CrCl =30 to <50 mL/min), or severe (<30 mL/min) renal impairment received a single oral dose of 15 mg/kg Hydroxyurea.  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 Hydroxyurea capsules when it is administered to patients with creatinine clearance of <60 mL/min or with ESRD following hemodialysis [see Dosage and Administration (2.3) and Use in Specific Populations (8.6)].

There is a risk of myelosuppression. Monitoring blood counts weekly throughout the duration of therapy should be emphasized to patients taking Hydroxyurea capsules [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 [see Warnings and Precautions (5.2, 5.4)].

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 Hydroxyurea capsules [see Warnings and Precautions (5.3) and Use in Specific Populations (8.1,8.3)].

Advise patients to inform their healthcare provider if they have received or are planning to receive vaccinations while taking Hydroxyurea capsules as this may result in a severe infection [see Warnings and Precautions (5.5)].

Advise females to discontinue breastfeeding during treatment with Hydroxyurea capsules [see Use in Specific Populations (8.3)].

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)].

Postirradiation erythema can occur in patients who have received previous irradiation therapy [see Warnings and Precautions (5.7)].

Manufactured by:

Par Pharmaceutical

Chestnut Ridge, NY 10977

For more information, go to www.parpharm.com or call 1-800-828-9393.

Revised 05/2016

Antimetabolite which selectively inhibits ribonucleoside diphosphate reductase, preventing the conversion of ribonucleotides to deoxyribonucleotides, halting the cell cycle at the G1/S phase and therefore has radiation sensitizing activity by maintaining cells in the G1 phase and interfering with DNA repair. In sickle cell anemia, hydroxyurea increases red blood cell (RBC) hemoglobin F levels, RBC water content, deformability of sickled cells, and alters adhesion of RBCs to endothelium.

Absorption

Readily absorbed (≥80%); relatively rapid (Rodriguez 1998)

Distribution

Distributes widely into tissues (including into the brain); estimated volume of distribution approximates total body water (Gwilt 1998); concentrates in leukocytes and erythrocytes

Vd: Children: ~12 L (range: 2.5 to 52) (Ware 2011); Adults: ~20 L/m2 (Rodriguez 1998)

Metabolism

Up to 60% via hepatic metabolism and urease found in intestinal bacteria

Excretion

Urine (sickle cell anemia: ~40% of administered dose)

Clearance: Children: ~7 L/hour (range: 1.6 to 22) (Ware 2011); Adults: ~7.5 L/hour (Rodriguez 1998)

Because renal excretion is a pathway of elimination for hydroxyurea, consider dosage reduction in patients with renal impairment. Mean AUC was 64% higher in patients with CrCl <60 mL/minute than in patients with healthy renal function.

Acute myeloid leukemia, cytoreduction

Data from a nonrandomized, open-label trial in adults with acute myeloid leukemia (AML) suggest that hydroxyurea may be beneficial for cytoreduction in patients with AML [Grund 1977]. Additional trials may be necessary to further define the role of hydroxyurea in the treatment of this condition.

Based on the European LeukemiaNET panel recommendations, hydroxyurea is effective and recommended for cytoreduction in AML [European LeukemiaNET [Dohner 2010]].

Essential thrombocythemia, high-risk

Data from an open-label, randomized trial in patients with essential thrombocythemia at high risk for vascular events supports the use of hydroxyurea (in combination with low-dose aspirin) for the management of this condition [Harrison 2005].

Head and neck cancer (with concurrent radiation therapy and fluorouracil)

Data from a phase II randomized trial in patients with advanced squamous carcinoma of the head and neck supports the use of hydroxyurea in the treatment of this condition [Garden 2004].

Hypereosinophilic syndrome

Data from a nonrandomized, retrospective study evaluating multiple therapies in patients with hypereosinophilic syndrome supports the use of hydroxyurea in the treatment of patients with this condition [Parillo 1978]. Clinical experience also suggests the utility of hydroxyurea in the treatment of hypereosinophilic syndrome [Klion 2006]. Additional trials may be necessary to further define the role of hydroxyurea in the treatment of this condition.

Meningioma

Data from 2 open-label, nonrandomized trials in patients with recurrent or high risk meningioma or those with an unresectable or residual meningioma suggest that hydroxyurea may be beneficial for the treatment of this condition [Newton 2000], [Rosenthal 2002]. Additional data may be necessary to further define the role of hydroxyurea in this condition.

Polycythemia vera, high-risk

Data from a randomized trial in patients with polycythemia vera supports the use of hydroxyurea in the treatment of patients with this condition [Najean 1997]. Clinical experience also suggests the utility of hydroxyurea in the treatment of patients with polycythemia vera [Finazzi 2007]. Additional trials may be necessary to further define the role of hydroxyurea in the treatment of this condition.

ASCO Guidelines for appropriate chemotherapy dosing in obese adults with cancer (solid tumors): Utilize patient’s actual body weight (full weight) for calculation of body surface area- or weight-based dosing, particularly when the intent of therapy is curative; manage regimen-related toxicities in the same manner as for nonobese patients; if a dose reduction is utilized due to toxicity, consider resumption of full weight-based dosing with subsequent cycles, especially if cause of toxicity (eg, hepatic or renal impairment) is resolved (Griggs 2012). Note: The manufacturer recommends dosing based on ideal or actual body weight, whichever is less.

Administer at the same time each day.

Impervious gloves should be worn when handling bottles containing hydroxyurea or when handling/administering intact capsules (single gloves are recommended for administration of intact capsules). Wash hands with soap and water before and after contact with the bottle or capsules when handling. Avoid exposure to crushed or open capsules. If skin contact with crushed or opened capsules occurs, immediately wash the affected area thoroughly with soap and water. If eye(s) contact with crushed or opened capsules occurs, 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 (along with the empty capsules) in a closed container, such as a plastic bag. The spill areas should then be cleaned 3 times using a detergent solution followed by clean water.

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience alopecia, nausea, vomiting, lack of appetite, constipation, diarrhea, dizziness, headache, or mouth irritation. Have patient report immediately to prescriber signs of infections, signs of bleeding (vomiting blood or vomit that looks like coffee grounds; coughing up blood; blood in the urine; black, red, or tarry stools; bleeding from the gums; abnormal vaginal bleeding; bruises without a reason or that get bigger; or any bleeding that is very bad or that will not stop), seizures, illogical thinking, urinary retention, change in amount of urine passed, pain with urination, mole changes, skin growths, loss of strength and energy, hallucinations, swelling of arms or legs, or skin or nail changes (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.

-Concurrent use of this drug with other myelosuppressive agents may require adjustment of dosages.
-Although no specific dose adjustment guidelines have been suggested, elderly patients may require a lower dose of this drug.

US BOXED WARNINGS:
-MYELOSUPPRESSION: This drug may cause severe myelosuppression. Blood counts should be monitored at baseline and throughout treatment. Treatment should be interrupted and the dose should be reduced as necessary.
MALIGNANCIES: This drug is carcinogenic. Patients should use sun protection and be monitored for malignancies.

Safety and efficacy have not been established in patients younger than 18 years.

Consult WARNINGS section for additional precautions.