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Hydrox

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Hydrox uses


RECENT MAJOR CHANGES

Indications and Usage, melanoma (1) Removed 7/2015

Indications and Usage, carcinoma of the ovary (1) Removed 7/2015

Dosage and Administration (2) 7/2015

Warnings and Precautions, Embryo-Fetal Toxicity (5.3) 3/2016

Warnings and Precautions, Live Vaccinations (5.5) 3/2016

1 INDICATIONS AND USAGE

Hydrox capsules, USP is indicated for the treatment of:


Hydrox capsules, USP is an antimetabolite indicated for the treatment of:

2 DOSAGE AND ADMINISTRATION

2.1 Dosing Information

Hydrox is used alone or in conjunction with other antitumor agents or radiation therapy to treat neoplastic diseases. Individualize treatment based on tumor type, disease state, response to treatment, patient risk factors, and current clinical practice standards.

Base all dosage on the patient’s actual or ideal weight, whichever is less.

Hydrox is a cytotoxic drug. Follow applicable special handling and disposal procedures [see REFERENCES (15) ].

Prophylactic administration of folic acid is recommended [see Warnings and Precautions (5.7) ].

2.2 Dose Modifications for Toxicity

Monitor for the following and reduce the dose or discontinue Hydrox accordingly:


Monitor blood counts at least once a week during Hydrox therapy. Severe anemia must be corrected before initiating therapy with Hydrox. Consider dose modifications for other toxicities.

2.3 Dose Modifications for Renal Impairment

Reduce the dose of Hydrox capsules by 50% in patients with measured creatinine clearance of less than 60 mL/min or with end-stage renal disease (ESRD) [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3) ].


Creatinine Clearance

(mL/min)


Recommended Hydrox

Capsules Initial Dose

(mg/kg daily)

≥60 15
<60 or ESRD* 7.5
*On dialysis days, administer hyroxyurea capsules to patients following hemodialysis.

Close monitoring of hematologic parameters is advised in these patients.

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3 DOSAGE FORMS AND STRENGTHS

Capsules:

4 CONTRAINDICATIONS

Hydrox capsules are contraindicated in patients who have demonstrated a previous hypersensitivity to Hydrox or any other component of the formulation.

5 WARNINGS AND PRECAUTIONS

5.1 Myelosuppression

Hydrox causes severe myelosuppression. Treatment with Hydrox 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. Bone marrow depression is more likely in patients who have previously received radiotherapy or cytotoxic cancer chemotherapeutic agents; use Hydrox cautiously in such patients.

Evaluate hematologic status prior to and during treatment with Hydrox capsules. Provide supportive care and modify dose or discontinue hydroxyurea as needed. Recovery from myelosuppression is usually rapid when therapy is interrupted.

5.2 Malignancies

Hydrox is a human carcinogen. In patients receiving long-term Hydrox for myeloproliferative disorders, secondary leukemia has been reported. Skin cancer has also been reported in patients receiving long-term Hydrox. Advise protection from sun exposure and monitor for the development of secondary malignancies.

5.3 Embryo-Fetal Toxicity

Based on the mechanism of action and findings in animals, hydroxyurea can cause fetal harm when administered to a pregnant woman. Hydrox 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 [see Use in Specific Populations ].

Advise females of reproductive potential to use effective contraception during and after treatment with Hydrox capsules for at least 6 months after therapy. Advise males of reproductive potential to use effective contraception during and after treatment with Hydrox capsules for at least 1 year after therapy [see Use in Specific Populations (8.1, 8.3 ) ].

5.4 Vasculitic Toxicities

Cutaneous vasculitic toxicities, including vasculitic ulcerations and gangrene, have occurred in patients with myeloproliferative disorders during therapy with Hydrox. 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 Hydrox capsules.

5.5 Live Vaccinations

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

5.6 Risks with Concomitant Use of Antiretroviral Drugs

Pancreatitis, hepatotoxicity, and peripheral neuropathy have occurred when Hydrox was administered concomitantly with antiretroviral drugs, including didanosine and stavudine [see Drug Interactions ].

5.7 Radiation Recall

Patients who have received irradiation therapy in the past may have an exacerbation of postirradiation erythema. Monitor for skin erythema in patients who previously received radiation and manage symptomatically.

5.8 Macrocytosis

Hydrox capsules 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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6 ADVERSE REACTIONS

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


Postmarketing Experience

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

Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency.


Adverse reactions observed with combined Hydrox and irradiation therapy are similar to those reported with the use of Hydrox 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 Hydrox and irradiation therapy will demonstrate concurrent leukopenia. Platelet depression (<100,000 cells/mm3) has occurred in the presence of marked leukopenia. Hydrox capsules may potentiate some adverse reactions usually seen with irradiation alone, such as gastric distress and mucositis.

Most common adverse reactions (≥30%) are hematological, gastrointestinal symptoms, and anorexia. (6)

To report SUSPECTED ADVERSE REACTIONS, contact Par Pharmaceutical at 1-800-828-9393 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

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7 DRUG INTERACTIONS

7.1 Increased Toxicity with Concomitant Use of Antiretroviral Drugs

Pancreatitis

In patients with HIV infection during therapy with Hydrox and didanosine, with or without stavudine, fatal and nonfatal pancreatitis have occurred. Hydrox is not indicated for the treatment of HIV infection; however, if patients with HIV infection are treated with Hydrox, and in particular, in combination with didanosine and/or stavudine, close monitoring for signs and symptoms of pancreatitis is recommended. Permanently discontinue therapy with Hydrox in patients who develop signs and symptoms of pancreatitis.

Hepatotoxicity

Hepatotoxicity and hepatic failure resulting in death have been reported during postmarketing surveillance in patients with HIV infection treated with Hydrox and other antiretroviral drugs. Fatal hepatic events were reported most often in patients treated with the combination of Hydrox, didanosine, and stavudine. Avoid this combination.

Peripheral Neuropathy

Peripheral neuropathy, which was severe in some cases, has been reported in patients with HIV infection receiving Hydrox in combination with antiretroviral drugs, including didanosine, with or without stavudine.

7.2 Test Interference

Interference with Uric Acid, Urea, or Lactic Acid Assays

Studies have shown that there is an analytical interference of Hydrox with the enzymes (urease, uricase, and lactate dehydrogenase) used in the determination of urea, uric acid, and lactic acid, rendering falsely elevated results of these in patients treated with Hydrox.

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8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

Hydrox capsules can cause fetal harm based on findings from animal studies and the drug’s mechanism of action [see Clinical Pharmacology (12.1) ]. There are no data with Hydrox capsules use in pregnant women to inform a drug-associated risk. In animal reproduction studies, administration of Hydrox to pregnant rats and rabbits during organogenesis produced embryotoxic and teratogenic effects at doses 0.8 times and 0.3 times, respectively, the maximum recommended human daily dose on a mg/m2 basis (see Data). Advise women of the potential risk to a fetus and to avoid becoming pregnant while being treated with Hydrox capsules.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Data

Animal Data

Hydrox has been demonstrated to be a potent teratogen in a wide variety of animal models, including mice, hamsters, cats, miniature swine, dogs, and monkeys at doses within 1-fold of the human dose given on a mg/m2 basis. Hydrox 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/m2 basis) in rats and at 30 mg/kg/day (about 0.3 times the maximum recommended human daily dose on a mg/m2 basis) in rabbits. Embryotoxicity was characterized by decreased fetal viability, reduced live litter sizes, and developmental delays. Hydrox crosses the placenta. Single doses of ≥375 mg/kg (about 1.7 times the maximum recommended human daily dose on a mg/m2 basis) to rats caused growth retardation and impaired learning ability.

8.2 Lactation

Risk Summary

Hydrox is excreted in human milk. Because of the potential for serious adverse reactions in a breastfed infant from Hydrox, including carcinogenicity, discontinue breastfeeding during treatment with Hydrox capsules.

8.3 Females and Males of Reproductive Potential

Pregnancy Testing

Verify the pregnancy status of females of reproductive potential prior to initiating Hydrox capsules therapy.

Contraception

Females

Hydrox capsules can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations ]. Advise females of reproductive potential to use effective contraception during and after treatment with Hydrox capsules for at least 6 months after therapy. Advise females to immediately report pregnancy.

Males

Hydrox capsules 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 Hydrox capsules for at least 1 year after therapy [see Nonclinical Toxicology (13.1) ].

Infertility

Males

Based on findings in animals and humans, male fertility may be compromised by treatment with Hydrox capsules. Azoospermia or oligospermia, sometimes reversible, has been observed in men. Inform male patients about the possibility of sperm conservation before the start of therapy [see Adverse Reactions (6) and Nonclinical Toxicology (13.1)].

8.4 Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

8.5 Geriatric Use

Elderly patients may be more sensitive to the effects of Hydrox, and may require a lower dose regimen. Hydrox is excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function [see Dosage and Administration ].

​ 8.6 Renal Impairment

The exposure to Hydrox is higher in patients with creatinine clearance of less than 60 mL/min or in patients with end-stage renal desease (ESRD). Reduce dosage and closely monitor the hematologic parameters when Hydrox capsules is to be administered to these patients [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3) ].

8.7 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.

10 OVERDOSAGE

Acute mucocutaneous toxicity has been reported in patients receiving Hydrox 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 also been observed.

​11 DESCRIPTION

Hydrox Capsules, USP are an antineoplastic agent available for oral use as capsules containing 500 mg Hydrox. Inactive ingredients include colloidal silicon dioxide, colorants (D&C Yellow No. 10, FD&C Blue No. 1 and FD&C Red No. 40), gelatin, magnesium stearate and titanium dioxide. Imprinting ink constituents: D&C Yellow No. 10 Aluminum Lake, FD&C Blue No. 1 Aluminum Lake, FD&C Blue No. 2 Aluminum Lake, FD&C Red No. 40 Aluminum Lake, pharmaceutical glaze, pharmaceutical shellac, propylene glycol, polyvinylpyrrolidone, sodium hydroxide, synthetic black iron oxide and titanium dioxide.

Hydrox 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:

This is the structure

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

The precise mechanism by which Hydrox 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 Hydrox 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, Hydrox may induce teratogenic effects.

Three mechanisms of action have been postulated for the increased effectiveness of concomitant use of Hydrox therapy with irradiation on squamous cell carcinomas of the head and neck. In vitro studies utilizing Chinese hamster cells suggest that Hydrox (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 Hydrox, 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 Hydrox capsules, Hydrox 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 Hydrox.

Distribution

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

Hydrox 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 Hydrox was about 40% of the administered dose.

Specific Populations

Renal Impairment

The effect of renal impairment on the pharmacokinetics of Hydrox 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 Hydrox. 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 Hydrox (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 Hydrox 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) ].

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Conventional long-term studies to evaluate the carcinogenic potential of Hydrox capsules have not been performed. However, intraperitoneal administration of 125 to 250 mg/kg Hydrox (about 0.6 to 1.2 times the maximum recommended human oral daily dose on a mg/m2 basis) thrice weekly for 6 months to female rats increased the incidence of mammary tumors in rats surviving to 18 months compared to control. Hydrox is mutagenic in vitro to bacteria, fungi, protozoa, and mammalian cells. Hydrox is clastogenic in vitro (hamster cells, human lymphoblasts) and in vivo (SCE assay in rodents, mouse micronucleus assay). Hydrox causes the transformation of rodent embryo cells to a tumorigenic phenotype.

Hydrox administered to male rats at 60 mg/kg/day (about 0.3 times the maximum recommended human daily dose on a mg/m2 basis) produced testicular atrophy, decreased spermatogenesis, and significantly reduced their ability to impregnate females.

15 REFERENCES

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

16 HOW SUPPLIED/STORAGE AND HANDLING

16.1 How Supplied

Hydrox capsules, USP 500 mg are dark green opaque printed "724" in white ink/ pink opaque (body) printed "par" in black ink capsules.

They are supplied in bottles of 100 (NDC# 49884-724-01).

Dispense in a tight container as defined in the USP.

16.2 Storage

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

16.3 Handling and Disposal

Hydrox capsules 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 Hydrox capsules or bottles containing Hydrox capsules. Wash hands with soap and water before and after contact with the bottle or capsules when handling Hydrox capsules. Do not open Hydrox 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.

17 PATIENT COUNSELING INFORMATION

There is a risk of myelosuppression. Monitoring blood counts weekly throughout the duration of therapy should be emphasized to patients taking Hydrox 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 Hydrox 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 Hydrox capsules as this may result in a severe infection [see Warnings and Precautions (5.5) ].

Advise females to discontinue breastfeeding during treatment with Hydrox 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

Hydrox pharmaceutical active ingredients containing related brand and generic drugs:


Hydrox available forms, composition, doses:


Hydrox destination | category:


Hydrox Anatomical Therapeutic Chemical codes:


Hydrox pharmaceutical companies:


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References

  1. Dailymed."HYDROXYUREA CAPSULE [PAR PHARMACEUTICAL, INC.]". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
  2. Dailymed."HYDROXYUREA: DailyMed provides trustworthy information about marketed drugs in the United States. DailyMed is the official provider of FDA label information (package inserts).". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
  3. "hydroxyurea". https://pubchem.ncbi.nlm.nih.gov/co... (accessed August 28, 2018).

Frequently asked Questions

Can i drive or operate heavy machine after consuming Hydrox?

Depending on the reaction of the Hydrox after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Hydrox not safe to drive or operate heavy machine after consumption. Meaning that, do not drive or operate heavy duty machines after taking the capsule if the capsule has a strange reaction on your body like dizziness, drowsiness. As prescribed by a pharmacist, it is dangerous to take alcohol while taking medicines as it exposed patients to drowsiness and health risk. Please take note of such effect most especially when taking Primosa capsule. It's advisable to consult your doctor on time for a proper recommendation and medical consultations.

Is Hydrox addictive or habit forming?

Medicines are not designed with the mind of creating an addiction or abuse on the health of the users. Addictive Medicine is categorically called Controlled substances by the government. For instance, Schedule H or X in India and schedule II-V in the US are controlled substances.

Please consult the medicine instruction manual on how to use and ensure it is not a controlled substance.In conclusion, self medication is a killer to your health. Consult your doctor for a proper prescription, recommendation, and guidiance.

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Review

sdrugs.com conducted a study on Hydrox, and the result of the survey is set out below. It is noteworthy that the product of the survey is based on the perception and impressions of the visitors of the website as well as the views of Hydrox consumers. We, as a result of this, advice that you do not base your therapeutic or medical decisions on this result, but rather consult your certified medical experts for their recommendations.

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The information was verified by Dr. Rachana Salvi, MD Pharmacology


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