These Highlights Do Not Include All The Information Needed To Use Gleostine Safely And Effectively. See Full Prescribing Information For Gleostine.

Risk Summary

Based on animal data and its mechanism of action, Gleostine can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology ( 12.1)] . There are no available data on Gleostine exposure in pregnant women. Lomustine 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 ²over 6 weeks (0.18 to 0.27 times the single human dose of 130 mg/m ²) based on BSA [see Data]. 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.

Principal Display Panel - Carton Label

NDC58181-3040-5 5 capsules

Gleostine ^®

(lomustine) Capsules

10 mg per capsule

Caution: DO NOT DISPENSE

ENTIRE CONTAINER.

Dispense only enough

capsules for one dose.

Rx Only

NEXTSOURCE

PHARMA

Overdosage with Gleostine has occurred, including fatal cases [see Dosage and Administration ( 2.1), Warnings and Precautions ( 5.2)]. 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 Gleostine overdosage.

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

Gleostine (lomustine) is an alkylating drug for oral administration. The chemical name for lomustine is 1-(2-chloro-ethyl)-3-cyclohexyl-1-nitrosourea and the molecular formula is C ₉H ₁₆ClN ₃O ₂. The molecular weight is 233.71. Lomustine is a yellow powder, which is soluble in 10% ethanol (0.05 mg per mL) and in absolute alcohol (70 mg per mL). Lomustine is insoluble in water (<0.05 mg per mL).

The chemical structure is:

Gleostine is supplied as 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.

Gleostine is indicated for the treatment of patients with primary and metastatic brain tumors following appropriate surgical and/or radiotherapeutic procedures.

Gleostine is available in three strengths, distinguishable by the color of the capsules, in individual bottles of 5 capsules each:

Pediatric use, including dose, is not based on adequate and well-controlled clinical studies.

No data in the clinical studies of Gleostine 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.

Lomustine 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.

Hepatic toxicity, manifested by increased levels of transaminases, alkaline phosphatase, and bilirubin occurs with Gleostine.

Monitor liver function.

Progressive renal failure with a decrease in kidney size occurs with Gleostine.

Monitor renal function.

None.

The following serious adverse reactions are discussed in greater detail in other sections of the labeling:

• Delayed myelosuppression [see Warnings and Precautions ( 5.1)]
• Risks of overdosage [see Warnings and Precautions ( 5.2)]
• Pulmonary toxicity [see Warnings and Precautions ( 5.3)]
• Secondary malignancies [see Warnings and Precautions ( 5.4)]
• Hepatotoxicity [see Warnings and Precautions ( 5.5)]
• Nephrotoxicity [see Warnings and Precautions ( 5.6)]

The following adverse reactions associated with the use of Gleostine 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 establish 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

The recommended dose of Gleostine in adult and pediatric patients is 130 mg/m ²taken as a single oral dose every 6 weeks. Round doses to the nearest 10 mg. Give as a single oral dose and do not repeat for at least 6 weeks. Reduce dose to 100 mg/m ²every 6 weeks in patients with compromised bone marrow function. Also reduce dose accordingly when using with other myelosuppressive drugs.

The pharmacodynamics of lomustine are unknown.

Gleostine is indicated as a component of combination chemotherapy for the treatment of patients with Hodgkin's lymphoma whose disease has progressed following initial chemotherapy.

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 ³or greater and leukocytes recover to 4000/mm ³or greater [see Warnings and Precautions ( 5.1)] .

Modify each dose of Gleostine according to the hematologic response of the preceding dose as described in Table 1:

Fatal toxicity occurs with overdosage of Gleostine. 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 Gleostine is taken every 6 weeks [see Dosage and Administration ( 2.1) and Overdosage ( 10)].

Pulmonary toxicity characterized by pulmonary infiltrates and/or fibrosis occurs with Gleostine. 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 Gleostine usually greater than 1100 mg/m ².

Obtain baseline pulmonary function tests prior to initiating treatment and repeat frequently during treatment. Permanently discontinue Gleostine in patients diagnosed with pulmonary fibrosis.

Gleostine is an alkylating drug indicated for the treatment of patients with:

• Brain tumors, primary and metastatic, following appropriate surgical and/or radiotherapeutic procedures. ( 1)
• Hodgkin's lymphoma in combination with other chemotherapies, following disease progression with initial chemotherapy. ( 1)

Lomustine alkylates DNA and RNA. As with other nitrosoureas, it may also inhibit several key enzymatic processes by carbamoylation of amino acids in proteins.

Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Avoid temperatures over 40°C (104°F).

Gleostine 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 Gleostine capsules. Do not break Gleostine capsules; avoid exposure to broken capsules. If dermal contact occurs, wash areas of skin contact immediately and thoroughly.

Based on animal data and its mechanism of action, Gleostine can cause fetal harm when administered to a pregnant woman. Embryo-fetal toxicity and teratogenicity occurred in rats and rabbits receiving lomustine daily during organogenesis at doses approximately two to four times the total human dose of 130 mg/m ²over 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 Gleostine and for 2 weeks after the final dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with Gleostine and for 3.5 months after the final dose [see Use in Specific Populations ( 8.1, 8.3)] .

• Pulmonary toxicity: Pulmonary infiltrates and/or fibrosis occurs with Gleostine. Perform pulmonary function tests prior to treatment and repeat frequently. Permanently discontinue Gleostine in patients diagnosed with pulmonary fibrosis. ( 5.3)
• 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 Gleostine. 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)

Secondary malignancies, including acute leukemia and myelodysplasia, occur with long term use.

• Recommended dose in adult and pediatric patients is 130 mg/m ²orally every 6 weeks. ( 2.1)
• Round dose to nearest 10 mg.
• Give as a single oral dose and do not repeat for at least 6 weeks.

Gleostine capsules are available in three strengths, distinguishable by the color of the capsules:

• 100 mg capsules (green/green)
• 40 mg capsules (white/green)
• 10 mg capsules (white/white)

Gleostine causes myelosuppression that can result in fatal infections and bleeding. Myelosuppression from Gleostine 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 Gleostine is manifested by greater severity and longer duration of cytopenias.

Monitor blood counts for at least 6 weeks after each dose. Do not give Gleostine more frequently than every 6 weeks. Adjust dose based on nadir blood counts from prior dose [see Dosage and Administration ( 2.3)].

Lactation: Do not breastfeed. ( 8.2)

Contraception

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 Gleostine 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 Gleostine 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 [see Warnings and Precautions ( 5.2) and Overdosage ( 10)] .

Gleostine 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 Gleostine capsules. Do not break Gleostine capsules; avoid exposure to broken capsules. If dermal contact occurs, wash areas of skin contact immediately and thoroughly.

DELAYED MYELOSUPPRESSION

Gleostine 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 Gleostine is manifested by greater severity and longer duration of cytopenias. Monitor blood counts for at least 6 weeks after each dose. Do not give Gleostine more frequently than every 6 weeks [see Warnings and Precautions ( 5.1), Dosage and Administration ( 2.2, 2.3)] .

RISK OF OVERDOSAGE

PRESCRIBE, DISPENSE, AND ADMINISTER ONLY ENOUGH CAPSULES FOR ONE DOSE. Fatal toxicity occurs with overdosage of Gleostine. Both physician and pharmacist should emphasize to the patient that only one dose of Gleostine is taken every 6 weeks [see Dosage and Administration ( 2.1), Warnings and Precautions ( 5.2), Overdosage ( 10)] .

Lomustine 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 lomustine 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 ²based on body surface area (BSA), or approximately twice the total clinical dose of lomustine 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 ²based on BSA or approximately equal to the total clinical dose of lomustine over 6 weeks). Gleostine may also result in decreased male fertility. Intraperitoneal injection of lomustine 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 ²based on BSA, or approximately equal to the total clinical dose of lomustine over 6 weeks), and increased resorptions at doses greater than or equal to 2.5 mg/kg/week.

Risk Summary

Based on animal data and its mechanism of action, Gleostine can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology ( 12.1)] . There are no available data on Gleostine exposure in pregnant women. Lomustine 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 ²over 6 weeks (0.18 to 0.27 times the single human dose of 130 mg/m ²) based on BSA [see Data]. 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.

Principal Display Panel - Carton Label

NDC58181-3040-5 5 capsules

Gleostine ^®

(lomustine) Capsules

10 mg per capsule

Caution: DO NOT DISPENSE

ENTIRE CONTAINER.

Dispense only enough

capsules for one dose.

Rx Only

NEXTSOURCE

PHARMA

Overdosage with Gleostine has occurred, including fatal cases [see Dosage and Administration ( 2.1), Warnings and Precautions ( 5.2)]. 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 Gleostine overdosage.

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

Gleostine (lomustine) is an alkylating drug for oral administration. The chemical name for lomustine is 1-(2-chloro-ethyl)-3-cyclohexyl-1-nitrosourea and the molecular formula is C ₉H ₁₆ClN ₃O ₂. The molecular weight is 233.71. Lomustine is a yellow powder, which is soluble in 10% ethanol (0.05 mg per mL) and in absolute alcohol (70 mg per mL). Lomustine is insoluble in water (<0.05 mg per mL).

The chemical structure is:

Gleostine is supplied as 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.

Gleostine is indicated for the treatment of patients with primary and metastatic brain tumors following appropriate surgical and/or radiotherapeutic procedures.

Gleostine is available in three strengths, distinguishable by the color of the capsules, in individual bottles of 5 capsules each:

Pediatric use, including dose, is not based on adequate and well-controlled clinical studies.

No data in the clinical studies of Gleostine 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.

Lomustine 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.

Hepatic toxicity, manifested by increased levels of transaminases, alkaline phosphatase, and bilirubin occurs with Gleostine.

Monitor liver function.

Progressive renal failure with a decrease in kidney size occurs with Gleostine.

Monitor renal function.

None.

The following serious adverse reactions are discussed in greater detail in other sections of the labeling:

• Delayed myelosuppression [see Warnings and Precautions ( 5.1)]
• Risks of overdosage [see Warnings and Precautions ( 5.2)]
• Pulmonary toxicity [see Warnings and Precautions ( 5.3)]
• Secondary malignancies [see Warnings and Precautions ( 5.4)]
• Hepatotoxicity [see Warnings and Precautions ( 5.5)]
• Nephrotoxicity [see Warnings and Precautions ( 5.6)]

The following adverse reactions associated with the use of Gleostine 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 establish 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

The recommended dose of Gleostine in adult and pediatric patients is 130 mg/m ²taken as a single oral dose every 6 weeks. Round doses to the nearest 10 mg. Give as a single oral dose and do not repeat for at least 6 weeks. Reduce dose to 100 mg/m ²every 6 weeks in patients with compromised bone marrow function. Also reduce dose accordingly when using with other myelosuppressive drugs.

The pharmacodynamics of lomustine are unknown.

Gleostine is indicated as a component of combination chemotherapy for the treatment of patients with Hodgkin's lymphoma whose disease has progressed following initial chemotherapy.

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 ³or greater and leukocytes recover to 4000/mm ³or greater [see Warnings and Precautions ( 5.1)] .

Modify each dose of Gleostine according to the hematologic response of the preceding dose as described in Table 1:

Fatal toxicity occurs with overdosage of Gleostine. 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 Gleostine is taken every 6 weeks [see Dosage and Administration ( 2.1) and Overdosage ( 10)].

Pulmonary toxicity characterized by pulmonary infiltrates and/or fibrosis occurs with Gleostine. 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 Gleostine usually greater than 1100 mg/m ².

Obtain baseline pulmonary function tests prior to initiating treatment and repeat frequently during treatment. Permanently discontinue Gleostine in patients diagnosed with pulmonary fibrosis.

Gleostine is an alkylating drug indicated for the treatment of patients with:

• Brain tumors, primary and metastatic, following appropriate surgical and/or radiotherapeutic procedures. ( 1)
• Hodgkin's lymphoma in combination with other chemotherapies, following disease progression with initial chemotherapy. ( 1)

Lomustine alkylates DNA and RNA. As with other nitrosoureas, it may also inhibit several key enzymatic processes by carbamoylation of amino acids in proteins.

Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Avoid temperatures over 40°C (104°F).

Gleostine 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 Gleostine capsules. Do not break Gleostine capsules; avoid exposure to broken capsules. If dermal contact occurs, wash areas of skin contact immediately and thoroughly.

Based on animal data and its mechanism of action, Gleostine can cause fetal harm when administered to a pregnant woman. Embryo-fetal toxicity and teratogenicity occurred in rats and rabbits receiving lomustine daily during organogenesis at doses approximately two to four times the total human dose of 130 mg/m ²over 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 Gleostine and for 2 weeks after the final dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with Gleostine and for 3.5 months after the final dose [see Use in Specific Populations ( 8.1, 8.3)] .

• Pulmonary toxicity: Pulmonary infiltrates and/or fibrosis occurs with Gleostine. Perform pulmonary function tests prior to treatment and repeat frequently. Permanently discontinue Gleostine in patients diagnosed with pulmonary fibrosis. ( 5.3)
• 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 Gleostine. 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)

Secondary malignancies, including acute leukemia and myelodysplasia, occur with long term use.

• Recommended dose in adult and pediatric patients is 130 mg/m ²orally every 6 weeks. ( 2.1)
• Round dose to nearest 10 mg.
• Give as a single oral dose and do not repeat for at least 6 weeks.

Gleostine capsules are available in three strengths, distinguishable by the color of the capsules:

• 100 mg capsules (green/green)
• 40 mg capsules (white/green)
• 10 mg capsules (white/white)

Gleostine causes myelosuppression that can result in fatal infections and bleeding. Myelosuppression from Gleostine 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 Gleostine is manifested by greater severity and longer duration of cytopenias.

Monitor blood counts for at least 6 weeks after each dose. Do not give Gleostine more frequently than every 6 weeks. Adjust dose based on nadir blood counts from prior dose [see Dosage and Administration ( 2.3)].

Lactation: Do not breastfeed. ( 8.2)

Contraception

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 Gleostine 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 Gleostine 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 [see Warnings and Precautions ( 5.2) and Overdosage ( 10)] .

Gleostine 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 Gleostine capsules. Do not break Gleostine capsules; avoid exposure to broken capsules. If dermal contact occurs, wash areas of skin contact immediately and thoroughly.

DELAYED MYELOSUPPRESSION

Gleostine 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 Gleostine is manifested by greater severity and longer duration of cytopenias. Monitor blood counts for at least 6 weeks after each dose. Do not give Gleostine more frequently than every 6 weeks [see Warnings and Precautions ( 5.1), Dosage and Administration ( 2.2, 2.3)] .

RISK OF OVERDOSAGE

PRESCRIBE, DISPENSE, AND ADMINISTER ONLY ENOUGH CAPSULES FOR ONE DOSE. Fatal toxicity occurs with overdosage of Gleostine. Both physician and pharmacist should emphasize to the patient that only one dose of Gleostine is taken every 6 weeks [see Dosage and Administration ( 2.1), Warnings and Precautions ( 5.2), Overdosage ( 10)] .

Lomustine 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 lomustine 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 ²based on body surface area (BSA), or approximately twice the total clinical dose of lomustine 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 ²based on BSA or approximately equal to the total clinical dose of lomustine over 6 weeks). Gleostine may also result in decreased male fertility. Intraperitoneal injection of lomustine 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 ²based on BSA, or approximately equal to the total clinical dose of lomustine over 6 weeks), and increased resorptions at doses greater than or equal to 2.5 mg/kg/week.