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DRUGS & SUPPLEMENTS
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Belustine
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Belustine uses
- Warning: delayed myelosuppression and risk of overdosage
- Indications and usage
- Dosage and administration
- Dosage forms and strengths
- Contraindications
- Warnings and precautions
- Adverse reactions
- Use in specific populations
- Overdosage
- Description
- Clinical pharmacology
- Nonclinical toxicology
- References
- How supplied/storage and handling
- Patient counseling information
WARNING: DELAYED MYELOSUPPRESSION and RISK OF OVERDOSAGE
DELAYED MYELOSUPPRESSION
Belustine causes myelosuppression including fatal myelosuppression. Myelosuppression is delayed, dose-related, and cumulative; occurring 4 to 6 weeks after drug administration and persisting for 1 to 2 weeks. Thrombocytopenia is generally more severe than leukopenia. Cumulative myelosuppression from Belustine is manifested by greater severity and longer duration of cytopenias. Monitor blood counts for at least 6 weeks after each dose. Do not give Belustine more frequently than every 6 weeks .
RISK OF OVERDOSAGE
PRESCRIBE, DISPENSE, AND ADMINISTER ONLY ENOUGH CAPSULES FOR ONE DOSE. Fatal toxicity occurs with overdosage of Belustine. Both physician and pharmacist should emphasize to the patient that only one dose of Belustine is taken every 6 weeks .
WARNING: DELAYED MYELOSUPPRESSION and RISK OF OVERDOSAGE
See full prescribing information for complete boxed warning.
Delayed Myelosuppression
Belustine causes myelosuppression including fatal myelosuppression.
Myelosuppression is delayed, dose-related, and cumulative.
Thrombocytopenia is generally more severe than leukopenia. Monitor blood counts and do not give Belustine more frequently than every 6 weeks. ( 2.2, 2.3, 5.1)
Risk of Overdosage
PRESCRIBE, DISPENSE, AND ADMINISTER ONLY ENOUGH
CAPSULES FOR ONE DOSE. Fatal toxicity occurs with overdosage of Belustine. Both physician and pharmacist should emphasize to patient that only one dose of Belustine is taken every 6 weeks. ( 2.1, 5.2, 10)
1 INDICATIONS AND USAGE
Belustine is an alkylating drug indicated for the treatment of patients with:
- Brain tumors, primary and metastatic, following appropriate surgical and/or radiotherapeutic procedures.
- Hodgkin's lymphoma in combination with other chemotherapies, following disease progression with initial chemotherapy. ( 1)
1.1 Brain Tumors
Belustine is indicated for the treatment of patients with primary and metastatic brain tumors following appropriate surgical and/or radiotherapeutic procedures.
1.2 Hodgkin's Lymphoma
Belustine is indicated as a component of combination chemotherapy for the treatment of patients with Hodgkin's lymphoma whose disease has progressed following initial chemotherapy.
2 DOSAGE AND ADMINISTRATION
- Recommended dose in adult and pediatric patients is 130 mg/m 2 orally every 6 weeks.
- Round dose to nearest 5 mg.
- Give as a single oral dose and do not repeat for at least 6 weeks.
2.1 Important Prescribing and Dispensing Information
PRESCRIBE ONLY ONE DOSE FOR EACH TREATMENT CYCLE. DO NOT DISPENSE ENTIRE CONTAINER. Dispense only a sufficient number of capsules for one dose.
Confirm the total dose prescribed by the physician and the appropriate combination of capsule strengths.
Dispense only the appropriate number of Belustine capsules required for the administration of a single dose.
The prescribed dose may consist of two or more different strengths and colors of capsules.
Instruct patients that Belustine is taken as a single oral dose and will not be repeated for at least 6 weeks. Taking more than the recommended dose causes toxicities, including fatal outcomes .
Belustine is a cytotoxic drug. Follow applicable special handling and disposal procedures. 1
To minimize the risk of dermal exposure, always wear impervious gloves when handling bottles containing Belustine capsules. Do not break Belustine capsules; avoid exposure to broken capsules. If dermal contact occurs, wash areas of skin contact immediately and thoroughly.
2.2 Recommended Dose
The recommended dose of Belustine in adult and pediatric patients is 130 mg/m 2 taken as a single oral dose every 6 weeks. Round doses to the nearest 5 mg. Give as a single oral dose and do not repeat for at least 6 weeks. Reduce dose to 100 mg/m 2 every 6 weeks in patients with compromised bone marrow function. Also reduce dose accordingly when using with other myelosuppressive drugs.
2.3 Dose Modifications
Perform weekly complete blood counts and withhold each subsequent dose for more than 6 weeks if needed until platelet counts recover to 100,000/mm 3 or greater and leukocytes recover to 4000/mm 3or greater .
Modify each dose of Belustine according to the hematologic response of the preceding dose as described in Table 1:
| Nadir After | r Prior Dose | Dose Adjustment |
| Leukocytes (/mm 3 ) | Platelets (/mm 3 ) | |
| ≥ 4000 | ≥ 100,000 | None |
| 3000 – 3999 | 75,000 – 99,999 | None |
| 2000 – 2999 | 25,000 – 74,999 | Reduce dose by 30% |
| < 2000 | < 25,000 | Reduce dose by 50% |
3 DOSAGE FORMS AND STRENGTHS
Belustine capsules are available in four strengths, distinguishable by the color of the capsules:
- 100 mg capsules (green/green)
- 40 mg capsules (white/green)
- 10 mg capsules (white/white)
- 5 mg capsules (yellow/yellow)
Capsules: 5mg, 10 mg, 40 mg, and 100 mg ( 3)
4 CONTRAINDICATIONS
None.
5 WARNINGS AND PRECAUTIONS
- Pulmonary toxicity: Pulmonary infiltrates and/or fibrosis occurs with Belustine. Perform pulmonary function tests prior to treatment and repeat frequently. Permanently discontinue Belustine in patients diagnosed with pulmonary fibrosis.
- Secondary malignancies: Acute leukemia and myelodysplasia can occur with long-term use. ( 5.4)
- Hepatotoxicity: Increased levels of transaminases, alkaline phosphatase and bilirubin can occur with Belustine. Monitor liver function. ( 5.5)
- Nephrotoxicity: Can cause renal failure. Monitor renal function. ( 5.6)
- Embryo-fetal toxicity: Can cause fetal harm. Advise males and females of reproductive potential of the potential risk to a fetus and to use effective contraception. ( 5.7, 8.1, 8.3)
5.1 Delayed Myelosuppression
Belustine causes myelosuppression that can result in fatal infections and bleeding. Myelosuppression from Belustine is delayed, dose-related, and cumulative. It usually occurs 4 to 6 weeks after drug administration and persists for 1 to 2 weeks. Thrombocytopenia is generally more severe than leukopenia. Cumulative myelosuppression from Belustine is manifested by greater severity and longer duration of cytopenias.
Monitor blood counts for at least 6 weeks after each dose. Do not give Belustine more frequently than every 6 weeks. Adjust dose based on nadir blood counts from prior dose .
5.2 Risk of Overdosage
Fatal toxicity occurs with overdosage of Belustine. Dispensing or administering more than one dose can lead to fatal toxicity.
Prescribe only one dose at a time. Dispense only enough capsules for one dose. Both physician and pharmacist should emphasize to the patient that only one dose of Belustine is taken every 6 weeks .
5.3 Pulmonary Toxicity
Pulmonary toxicity characterized by pulmonary infiltrates and/or fibrosis occurs with Belustine. Patients with a baseline below 70% of the predicted Forced Vital Capacity (FVC) or Carbon Monoxide Diffusing Capacity
(DL CO) are at increased risk. The onset of pulmonary toxicity occurs after an interval of 6 months or longer from the start of therapy, with cumulative doses of Belustine usually greater than 1100 mg/m 2.
Obtain baseline pulmonary function tests prior to initiating treatment and repeat frequently during treatment. Permanently discontinue Belustine in patients diagnosed with pulmonary fibrosis.
5.4 Secondary Malignancies
Secondary malignancies, including acute leukemia and myelodysplasia, occur with long term use.
5.5 Hepatotoxicity
Hepatic toxicity, manifested by increased levels of transaminases, alkaline phosphatase, and bilirubin occurs with Belustine.
Monitor liver function.
5.6 Nephrotoxicity
Progressive renal failure with a decrease in kidney size occurs with Belustine.
Monitor renal function.
5.7 Embryo-Fetal Toxicity
Based on animal data and its mechanism of action, Belustine can cause fetal harm when administered to a pregnant woman. Embryo-fetal toxicity and teratogenicity occurred in rats and rabbits receiving Belustine daily during organogenesis at doses approximately two to four times the total human dose of 130 mg/m 2 over 6 weeks (0.18 to 0.27 times the single human dose of 130 mg/m 2) based on body surface area (BSA). Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with Belustine and for 2 weeks after the final dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with Belustine and for 3.5 months after the final dose .
6 ADVERSE REACTIONS
The following serious adverse reactions are discussed in greater detail in other sections of the labeling:
- Delayed myelosuppression
- Risks of overdosage
- Pulmonary toxicity
- Secondary malignancies
- Hepatotoxicity
- Nephrotoxicity
The following adverse reactions associated with the use of Belustine were identified in clinical trials or postmarketing reports. Because these reactions were reported from a population of uncertain size, it is not possible to estimate their frequency, reliability, or establishment a causal relationship to drug exposure.
Gastrointestinal disorders: nausea, vomiting, and stomatitis
Ocular disorders: optic atrophy, visual disturbances, and blindness
Neurologic disorders: disorientation, lethargy, ataxia, and dysarthria
Other: alopecia
Common adverse reactions include delayed myelosupression, nausea, vomiting, stomatitis, and alopecia. ( 6)
To report SUSPECTED ADVERSE REACTIONS, contact NextSource Biotechnology at 855- 672-2468 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .
8 USE IN SPECIFIC POPULATIONS
Lactation: Do not breastfeed.
8.1 Pregnancy
Risk Summary
Based on animal data and its mechanism of action, Belustine can cause fetal harm when administered to a pregnant woman . There are no available data on Belustine exposure in pregnant women. Belustine was teratogenic in rats and embryotoxic in rabbits at total dose levels approximately two to four times the total human dose of 130 mg/m 2 over 6 weeks (0.18 to 0.27 times the single human dose of 130 mg/m 2) based on BSA . Advise pregnant women of the potential risk to a fetus.
In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.
Data
Animal Data
Belustine was administered by intraperitoneal injection daily to pregnant rats during the period of organogenesis at dose levels of 0, 2, 4, 6, and 8 mg/kg. Resorption rates and post-implantation loss occurred at doses greater than or equal to 4 mg/kg (approximately 0.18 times the clinical dose of 130 mg/m 2 based on BSA or approximately twice the total clinical dose of Belustine over 6 weeks). Malformations (omphalocele, ectepia cordis, scoliosis, syndactyly, hydrocephalus, microphthalmia, anophthalmia, anomalies of aortic arch, dextrocardia, malpositioning of the ovaries and testes, sternoschisis, and shortened/misshapen bone of the fore or hind limbs) and decreased fetal body weight occurred at all dose levels. In pregnant rabbits treated with Belustine at 3 mg/kg (approximately 0.27 times the 130 mg/m 2 clinical dose based on BSA or approximately four times the total clinical dose of Belustine over 6 weeks) during organogenesis, there were increases in abortions and decreases in surviving pup weight that persisted postnatally.
8.2 Lactation
Risk Summary
There is no information on the presence of Belustine or its metabolites in human milk, its effects on the breastfed infant, or its effects on milk production. Because of the potential for serious adverse reactions in breastfed infants from Belustine, advise women not to breastfeed during treatment with Belustine and for 2 weeks after the final dose.
8.3 Females and Males of Reproductive Potential
Contraception
Females
Based on animal data and its mechanism of action, Belustine can cause fetal harm . Advise females of reproductive potential to use effective contraception during treatment and for 2 weeks after the final dose.
Males
Based on Gleostine's mechanism of action, advise males with female partners of reproductive potential to use effective contraception during treatment with Belustine and for 3.5 months after the final dose .
Infertility
Based on animal findings and its mechanism of action, Belustine may result in reduced fertility in males and females of reproductive potential .
8.4 Pediatric Use
Pediatric use, including dose, is not based on adequate and well-controlled clinical studies.
8.5 Geriatric Use
No data in the clinical studies of Belustine are available for patients 65 years of age and over to determine whether they respond differently than younger patients. Other reported clinical experience has not identified differences in responses between elderly and younger patients. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy.
Belustine and its metabolites are known to be substantially excreted by the kidney, and the risk of toxic 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 renal function should be monitored.
10 OVERDOSAGE
Overdosage with Belustine has occurred, including fatal cases . Overdosage causes severe myelosuppression, as well as abdominal pain, diarrhea, vomiting, anorexia, lethargy, dizziness, abnormal hepatic function, cough, and shortness of breath.
No antidotes exist for Belustine overdosage.
11 DESCRIPTION
Belustine (lomustine) is an alkylating drug for oral administration. The chemical name for Belustine is 1-(2chloro-ethyl)-3-cyclohexyl-1-nitrosourea and the molecular formula is C 9H 16ClN 3O 2. The molecular weight is 233.71. Belustine is a yellow powder, which is soluble in 10% ethanol (0.05 mg per mL) and in absolute alcohol (70 mg per mL). Belustine is insoluble in water (<0.05 mg per mL).
The chemical structure is:
Belustine is supplied as 5 mg, 10 mg, 40 mg, and 100 mg capsules and contains the following inactive ingredients: magnesium stearate NF and mannitol USP. The capsule shells are composed of gelatin and coloring pigments, depending on the strength: titanium dioxide, and/or yellow iron oxide, and/or Indigotine – FD&C Blue2.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Belustine alkylates DNA and RNA. As with other nitrosoureas, it may also inhibit several key enzymatic processes by carbamoylation of amino acids in proteins.
12.2 Pharmacodynamic
The pharmacodynamics of Belustine are unknown.
12.3 Pharmacokinetics
Distribution
Belustine crosses the blood-brain barrier.
Elimination
The serum half-life of Belustine metabolites ranges from 16 hours to 48 hours.
Metabolism
Metabolic pathways involved in the elimination of Belustine have not been characterized.
Excretion
Following oral administration of radioactive Belustine at doses ranging from 30 mg/m 2 to 100 mg/m 2, approximately half of the radioactivity administered was excreted in the urine in the form of degradation products within 24 hours.
Specific Populations
The impact of patient specific (e.g., age, sex, and race) or disease (e.g., renal or hepatic impairment) characteristics on the pharmacokinetics of Belustine is unknown.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Belustine is carcinogenic in rats and mice, producing a marked increase in tumor incidence in doses lower than those employed clinically.
In female rats, daily intraperitoneal treatment with Belustine for 2 weeks prior to mating with untreated males resulted in dose dependent decreases in number of corpora lutea and resorption rates with no live births at a dose of 3 mg/kg (approximately 0.14 times the recommended clinical dose of 130 mg/m 2 based on body surface area (BSA), or approximately twice the total clinical dose of Belustine over 6 weeks) and decreased pup survival during the first 4 postnatal days at doses greater than or equal to 1.5 mg/kg (a daily dose of approximately 0.06 times the recommended clinical dose of 130 mg/m 2 based on BSA or approximately equal to the total clinical dose of Belustine over 6 weeks). Belustine may also result in decreased male fertility. Intraperitoneal injection of Belustine resulted in decreased fertility in male rats mated to untreated females based on decreased implantations and decreased fetal body weight at weekly doses greater than or equal to 5 mg/kg (approximately 0.23 times the single clinical dose of 130 mg/m 2 based on BSA, or approximately equal to the total clinical dose of Belustine over 6 weeks), and increased resorptions at doses greater than or equal to
2.5 mg/kg/week.
15 REFERENCES
OSHA. http://www.osha.gov/SLTC/hazardousdrugs/index.html.
16 HOW SUPPLIED/STORAGE AND HANDLING
16.1 How Supplied
Belustine is available in four strengths, distinguishable by the color of the capsules, in individual bottles of 5 capsules each:
| Strength | Capsule Description | NDC Code |
| 100 mg | Moss green cap and body, imprinted in black ink, with "CPL" over "3032" on the cap and "100 mg" on the body of the capsule. | 58181-3042-5 |
| 40 mg | White cap and a moss green body, imprinted in black ink, with "CPL" over "3031" on the cap and "40 mg" on the body of the capsule. | 58181-3041-5 |
| 10 mg | White cap and body, imprinted in black ink, with "CPL" over "3030" on the cap and "10 mg" on the body of the capsule | 58181-3040-5 |
| 5 mg | Yellow cap and body, imprinted in black ink, with "CPL" over "3033" on the cap and "5 mg" on the body of the capsule. | 58181-3043-5 |
16.2 Storage and Handling
Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). Avoid temperatures over 40°C (104°F).
Belustine is a cytotoxic drug. Follow applicable special handling and disposal procedures. 1
To minimize the risk of dermal exposure, always wear impervious gloves when handling bottles containing Belustine capsules. Do not break Belustine capsules; avoid exposure to broken capsules. If dermal contact occurs, wash areas of skin contact immediately and thoroughly.
17 PATIENT COUNSELING INFORMATION
Myelosuppression
Advise patients that periodic assessment of their blood counts are required. Advise patients to contact their healthcare provider for new onset of bleeding or fever or symptoms of infection .
Overdosage
Advise patients that toxicity including fatal toxicity occurs with Belustine overdosage .
Advise patients to take Belustine as directed:
- Belustine is taken as a single oral dose that will not be repeated for at least 6 weeks.
- Use of the recommended dose at less than 6 week intervals leads to toxicities including fatal toxicities.
- Each dose may consist of 2 or more different strengths and colors of capsules.
Pulmonary Fibrosis
Advise patients to contact their healthcare provider for new or worsening cough, chest pain, or shortness of breath .
Hepatotoxicity
Inform patients that Belustine can cause hepatotoxicity and that liver function monitoring during treatment is necessary .
Nephrotoxicity
Inform patients that Belustine can cause nephrotoxicity and that renal function and electrolyte monitoring during treatment is necessary .
Embryo-Fetal Toxicity
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 of reproductive potential to use effective contraception during treatment with Belustine and for at least 2 weeks after the final dose .
Advise male patients with female partners of reproductive potential to use condoms during treatment with Belustine and for 4 months after the final dose .
Lactation
Advise women not to breastfeed during treatment with Belustine and for 2 weeks after the final dose .
Infertility
Advise females and males of reproductive potential of the potential for reduced fertility from Belustine .
Manufactured by Corden Pharma Latina S.p. A., Sermoneta (LT), Italy for:
NextSource Biotechnology, LLC Miami, FL 33155 USA
Logo
Principal Display Panel - Carton Label
NDC 58181-3040-5 5 capsules
Belustine ®
(lomustine) Capsules
10 mg per capsule
Caution: DO NOT DISPENSE
ENTIRE CONTAINER.
Dispense only enough
capsules for one dose.
Rx Only
NEXTSOURCE
Biotechnology
Principal Display Panel - Carton Label
NDC 58181-3041-5 5 capsules
Belustine ®
(lomustine) Capsules
40 mg per capsule
Caution: DO NOT DISPENSE
ENTIRE CONTAINER.
Dispense only enough
capsules for one dose.
Rx Only
NEXTSOURCE
Biotechnology
Principal Display Panel - Carton Label
NDC 58181-3042-5 5 capsules
Belustine ®
(lomustine) Capsules
100 mg per capsule
Caution: DO NOT DISPENSE
ENTIRE CONTAINER.
Dispense only enough
capsules for one dose.
Rx Only
NEXTSOURCE
Biotechnology
Principal Display Panel - Carton Label
NDC 58181-3043-5 5 capsules
Belustine ®
(lomustine) Capsules
5 mg per capsule
Caution: DO NOT DISPENSE
ENTIRE CONTAINER.
Dispense only enough
capsules for one dose.
Rx Only
NEXTSOURCE
Biotechnology
Belustine pharmaceutical active ingredients containing related brand and generic drugs:
Belustine 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.