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DRUGS & SUPPLEMENTS
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Hondrea
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Hondrea uses
- Recent major changes
- Indications and usage
- Dosage and administration
- Dosage forms and strengths
- Contraindications
- Warnings and precautions
- Adverse reactions
- Drug interactions
- Use in specific populations
- Overdosage
- 11 description
- Clinical pharmacology
- Nonclinical toxicology
- References
- How supplied/storage and handling
- Patient counseling information
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
Hondrea capsules, USP is indicated for the treatment of:
- Resistant chronic myeloid leukemia.
- Locally advanced squamous cell carcinomas of the head and neck (excluding the lip) in combination with chemoradiation.
Hondrea capsules, USP is an antimetabolite indicated for the treatment of:
- Resistant chronic myeloid leukemia.(1)
- Locally advanced squamous cell carcinomas of the head and neck, (excluding lip) in combination with concurrent chemoradiation.(1)
2 DOSAGE AND ADMINISTRATION
-
Individualize treatment based on tumor type, disease state, response to treatment, patient risk factors, and current clinical practice standards.
-
Renal impairment: Reduce the dose of Hondrea by 50% in patients with creatinine clearance less than 60 mL/min. (2.3, 8.6, 12.3)
2.1 Dosing Information
Hondrea 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.
Hondrea 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 Hondrea accordingly:
- Myelosuppression [see Warnings and Precautions ].
- Cutaneous vasculitis [see Warnings and Precautions (5.4) ]
Monitor blood counts at least once a week during Hondrea therapy. Severe anemia must be corrected before initiating therapy with Hondrea. Consider dose modifications for other toxicities.
2.3 Dose Modifications for Renal Impairment
Reduce the dose of Hondrea 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 Hondrea 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.
3 DOSAGE FORMS AND STRENGTHS
Capsules:
- 500 mg dark green opaque (cap) printed “724” in white ink/ pink opaque (body) printed “par” in black ink.
- Capsules: 500 mg (3)
4 CONTRAINDICATIONS
Hondrea capsules are contraindicated in patients who have demonstrated a previous hypersensitivity to Hondrea or any other component of the formulation.
- In patients who have demonstrated a previous hypersensitivity to Hondrea or any other component of its formulation. (4)
5 WARNINGS AND PRECAUTIONS
- Myelosuppression: Do not give if bone marrow function is markedly depressed. Monitor hematology labs and interrupt, reduce dose as appropriate.
- Malignancies: Advise protection from sun exposure and monitor for secondary malignancies. (5.2)
- Embryo-fetal toxicity: Can cause fetal harm. Advise of potential risk to a fetus and use of effective contraception. (5.3, 8.1, 8.3)
- Vasculitic toxicities: Discontinue Hondrea and initiate treatment if this occurs. (5.4)
- Live Vaccinations: Avoid live vaccine use in a patient taking Hondrea capsules. (5.5)
- Risks with concomitant use of antiretroviral drugs: Pancreatitis, hepatotoxicity, and neuropathy have occurred. Monitor for signs and symptoms in patients with HIV infection using antiretroviral drugs; discontinue Hondrea capsules, and implement treatment. (5.6)
- Radiation recall: Monitor for skin erythema in patients who previously received radiation and manage symptomatically. (5.7)
5.1 Myelosuppression
Hondrea causes severe myelosuppression. Treatment with Hondrea 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 Hondrea cautiously in such patients.
Evaluate hematologic status prior to and during treatment with Hondrea 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
Hondrea is a human carcinogen. In patients receiving long-term Hondrea for myeloproliferative disorders, secondary leukemia has been reported. Skin cancer has also been reported in patients receiving long-term Hondrea. 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. Hondrea 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 Hondrea capsules for at least 6 months after therapy. Advise males of reproductive potential to use effective contraception during and after treatment with Hondrea 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 Hondrea. 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 Hondrea capsules.
5.5 Live Vaccinations
Avoid use of live vaccine in patients taking Hondrea capsules. Concomitant use of Hondrea 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 Hondrea capsules. Vaccination with live vaccines in a patient receiving Hondrea 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 Hondrea 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
Hondrea 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.
6 ADVERSE REACTIONS
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 Hondrea 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 Hondrea and irradiation therapy are similar to those reported with the use of Hondrea 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 Hondrea and irradiation therapy will demonstrate concurrent leukopenia. Platelet depression (<100,000 cells/mm3) has occurred in the presence of marked leukopenia. Hondrea 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.
7 DRUG INTERACTIONS
- Antiretroviral drugs
7.1 Increased Toxicity with Concomitant Use of Antiretroviral Drugs
Pancreatitis
In patients with HIV infection during therapy with Hondrea and didanosine, with or without stavudine, fatal and nonfatal pancreatitis have occurred. Hondrea is not indicated for the treatment of HIV infection; however, if patients with HIV infection are treated with Hondrea, and in particular, in combination with didanosine and/or stavudine, close monitoring for signs and symptoms of pancreatitis is recommended. Permanently discontinue therapy with Hondrea 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 Hondrea and other antiretroviral drugs. Fatal hepatic events were reported most often in patients treated with the combination of Hondrea, 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 Hondrea 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 Hondrea 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 Hondrea.
8 USE IN SPECIFIC POPULATIONS
- Lactation: Hondrea is excreted in human milk. Discontinue breastfeeding during treatment with Hondrea capsules.
- Geriatric Use: Care should be taken in dose selection and may require a lower dose regimen and monitoring of renal function. (8.5)
8.1 Pregnancy
Risk Summary
Hondrea 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 Hondrea capsules use in pregnant women to inform a drug-associated risk. In animal reproduction studies, administration of Hondrea 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 Hondrea 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
Hondrea 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. Hondrea 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. Hondrea 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
Hondrea is excreted in human milk. Because of the potential for serious adverse reactions in a breastfed infant from Hondrea, including carcinogenicity, discontinue breastfeeding during treatment with Hondrea capsules.
8.3 Females and Males of Reproductive Potential
Pregnancy Testing
Verify the pregnancy status of females of reproductive potential prior to initiating Hondrea capsules therapy.
Contraception
Females
Hondrea 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 Hondrea capsules for at least 6 months after therapy. Advise females to immediately report pregnancy.
Males
Hondrea 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 Hondrea 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 Hondrea 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 Hondrea, and may require a lower dose regimen. Hondrea 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 Hondrea 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 Hondrea 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 Hondrea 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
Hondrea Capsules, USP are an antineoplastic agent available for oral use as capsules containing 500 mg Hondrea. 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.
Hondrea 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:
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
The precise mechanism by which Hondrea 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 Hondrea 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, Hondrea may induce teratogenic effects.
Three mechanisms of action have been postulated for the increased effectiveness of concomitant use of Hondrea therapy with irradiation on squamous cell carcinomas of the head and neck. In vitro studies utilizing Chinese hamster cells suggest that Hondrea (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 Hondrea, 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 Hondrea capsules, Hondrea 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 Hondrea.
Distribution
Hondrea distributes throughout the body with a volume of distribution approximating total body water.
Hondrea 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 Hondrea was about 40% of the administered dose.
Specific Populations
Renal Impairment
The effect of renal impairment on the pharmacokinetics of Hondrea 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 Hondrea. 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 Hondrea (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 Hondrea 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 Hondrea capsules have not been performed. However, intraperitoneal administration of 125 to 250 mg/kg Hondrea (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. Hondrea is mutagenic in vitro to bacteria, fungi, protozoa, and mammalian cells. Hondrea is clastogenic in vitro (hamster cells, human lymphoblasts) and in vivo (SCE assay in rodents, mouse micronucleus assay). Hondrea causes the transformation of rodent embryo cells to a tumorigenic phenotype.
Hondrea 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
Hondrea 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
Hondrea 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 Hondrea capsules or bottles containing Hondrea capsules. Wash hands with soap and water before and after contact with the bottle or capsules when handling Hondrea capsules. Do not open Hondrea 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 Hondrea 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 Hondrea 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 Hondrea capsules as this may result in a severe infection [see Warnings and Precautions (5.5) ].
Advise females to discontinue breastfeeding during treatment with Hondrea 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
Hondrea pharmaceutical active ingredients containing related brand and generic drugs:
Hondrea available forms, composition, doses:
Composition is the list of ingredients which combinedly form a medicine. Both active ingredients and inactive ingredients form the composition. The active ingredient gives the desired therapeutic effect whereas the inactive ingredient helps in making the medicine stable.
Doses are various strengths of the medicine like 10mg, 20mg, 30mg and so on. Each medicine comes in various doses which is decided by the manufacturer, that is, pharmaceutical company. The dose is decided on the severity of the symptom or disease.