Lomustine

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# Black Box Warning

# Overview
Lomustine is an antineoplastic agent that is FDA approved for the treatment of brain tumors, Hodgkin's disease. There is a Black Box Warning for this drug as shown here.  Common adverse reactions include leukopenia, myelosuppression, thrombocytopenia,optic atrophy, visual disturbance,nephrotoxicity,Pulmonary toxicity.

# Adult Indications and Dosage

## FDA-Labeled Indications and Dosage (Adult)

# Indications
Gleostine has been shown to be useful as a single agent in addition to other treatment modalities, or in established combination therapy with other approved chemotherapeutic agents in the following:
- Brain tumorsboth primary and metastatic, in patients who have already received appropriate surgical and/or radiotherapeutic procedures.
- Hodgkin's diseasesecondary therapy in combination with other approved drugs in patients who relapse while being treated with primary therapy, or who fail to respond to primary therapy.

# Dosage
- The recommended dose of Gleostine in adult and pediatric patients as a single agent in previously untreated patients is 130 mg/m2 as a single oral dose every 6 weeks . In individuals with compromised bone marrow function, the dose should be reduced to 100 mg/m2 every 6 weeks. When Gleostine is used in combination with other myelosuppressive drugs, the doses should be adjusted accordingly. All doses of Gleostine must be rounded to the nearest 10 mg by the prescriber .
- Doses subsequent to the initial dose should be adjusted according to the hematologic response of the patient to the preceding dose. The following schedule is suggested as a guide to dosage adjustment:
- A repeat course of Gleostine should not be given until circulating blood elements have returned to acceptable levels (platelets above 100,000/mm3; leukocytes above 4000/mm3), and this is usually in 6 weeks. Adequate number of neutrophils should be present on a peripheral blood smear. Blood counts should be monitored weekly and repeat courses should not be given before 6 weeks because the hematologic toxicity is delayed and cumulative.

## Off-Label Use and Dosage (Adult)

### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Lomustine in adult patients.

### NonGuideline-Supported Use
There is limited information regarding Off-Label NonGuideline-Supported Use of Lomustine in adult patients.

# Pediatric Indications and Dosage

## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Lomustine in Pediatric patients.

## Off-Label Use and Dosage (Pediatric)

### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Lomustine in pediatric patients.

### NonGuideline-Supported Use
There is limited information regarding Off-Label NonGuideline-Supported Use of Lomustine in pediatric patients.

# Contraindications
- Gleostine should not be given to individuals who have demonstrated a previous hypersensitivity to it.

# Warnings
- Since the major toxicity is delayed bone marrow suppression, blood counts should be monitored weekly for at least 6 weeks after a dose. At the recommended dosage, courses of Gleostine should not be given more frequently than every 6 weeks.
- The bone marrow toxicity of Gleostine is cumulative and therefore dosage adjustment must be considered on the basis of nadir blood counts from prior dose (see dosage adjustment table under.
- Pulmonary toxicity from Gleostine appears to be dose related.
- Long-term use of nitrosoureas has been reported to be possibly associated with the development of secondary malignancies.
- Liver and renal function tests should be monitored periodically.

# Adverse Reactions

## Clinical Trials Experience
Hematologic Toxicity
- The most frequent and most serious toxicity of Gleostine is delayed myelosuppression. It usually occurs 4 to 6 weeks after drug administration and is dose related. Thrombocytopenia occurs at about 4 weeks post administration and persists for 1 to 2 weeks. Leukopenia occurs at 5 to 6 weeks after a dose of Gleostine and persists for 1 to 2 weeks. Approximately 65% of patients receiving 130 mg/m2 develop white blood counts below 5000 wbc/mm3. Thirty-six percent developed white blood counts below 3000 wbc/mm3. Thrombocytopenia is generally more severe than leukopenia. However, both may be dose-limiting toxicities.
- Gleostine may produce cumulative myelosuppression, manifested by more depressed indices or longer duration of suppression after repeated doses.
- The occurrence of acute leukemia and bone marrow dysplasias have been reported in patients following long-term nitrosourea therapy.
- Anemia also occurs, but is less frequent and less severe than thrombocytopenia or leukopenia.
Pulmonary Toxicity
- Pulmonary toxicity characterized by pulmonary infiltrates and/or fibrosis has been reported rarely with Gleostine. Onset of toxicity has occurred after an interval of 6 months or longer from the start of therapy with cumulative doses of Gleostine usually greater than 1100 mg/m2. There is 1 report of pulmonary toxicity at a cumulative dose of only 600 mg.
- Delayed onset pulmonary fibrosis occurring up to 17 years after treatment has been reported in patients who received related nitrosoureas in childhood and early adolescence (116 years) combined with cranial radiotherapy for intracranial tumors. There appeared to be some late reduction of pulmonary function of all long-term survivors. This form of lung fibrosis may be slowly progressive and has resulted in death in some cases. In this long-term study of carmustine, all those initially treated at less than 5 years of age died of delayed pulmonary fibrosis.
Gastrointestinal Toxicity
- Nausea and vomiting may occur 3 to 6 hours after an oral dose and usually last less than 24 hours. Prior administration of antiemetics is effective in diminishing and sometimes preventing this side effect. Nausea and vomiting can also be reduced if Gleostine is administered to fasting patients.
Hepatotoxicity
A reversible type of hepatic toxicity, manifested by increased transaminase, alkaline phosphatase, and bilirubin levels, has been reported in a small percentage of patients receiving Gleostine.
Nephrotoxicity
- Renal abnormalities consisting of progressive azotemia, decrease in kidney size, and renal failure have been reported in patients who received large cumulative doses after prolonged therapy with Gleostine. Kidney damage has also been reported occasionally in patients receiving lower total doses.
Other Toxicities
- Stomatitis, alopecia, optic atrophy, and visual disturbances, such as blindness, have been reported infrequently.
- Neurological reactions, such as disorientation, lethargy, ataxia, and dysarthria have been noted in some patients receiving Gleostine. However, the relationship to medication in these patients is unclear.

## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Lomustine in the drug label.

# Drug Interactions
There is limited information regarding Lomustine Drug Interactions in the drug label.

# Use in Specific Populations

### Pregnancy
Pregnancy Category (FDA): 
Pregnancy Category D
- Gleostine can cause fetal harm when administered to a pregnant woman. Lomustine is embryotoxic and teratogenic in rats and embryotoxic in rabbits at dose levels equivalent to the human dose. There are no adequate and well controlled studies in pregnant women. If this drug is used during pregnancy, or if the patient becomes pregnant while taking (receiving) this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Lomustine in women who are pregnant.

### Labor and Delivery
There is no FDA guidance on use of Lomustine during labor and delivery.

### Nursing Mothers
- It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Gleostine, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

### Pediatric Use
There is no FDA guidance on the use of Lomustine with respect to pediatric patients.

### Geriatic Use
- No data from 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.

### Gender
There is no FDA guidance on the use of Lomustine with respect to specific gender populations.

### Race
There is no FDA guidance on the use of Lomustine with respect to specific racial populations.

### Renal Impairment
There is no FDA guidance on the use of Lomustine in patients with renal impairment.

### Hepatic Impairment
There is no FDA guidance on the use of Lomustine in patients with hepatic impairment.

### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Lomustine in women of reproductive potentials and males.

### Immunocompromised Patients
There is no FDA guidance one the use of Lomustine in patients who are immunocompromised.

# Administration and Monitoring

### Administration
- Oral

### Monitoring
There is limited information regarding Monitoring of Lomustine in the drug label.

# IV Compatibility
There is limited information regarding IV Compatibility of Lomustine in the drug label.

# Overdosage
- Accidental overdose with lomustine has been reported, including fatal cases. Accidental overdose has been associated with bone marrow suppression, abdominal pain, diarrhea, vomiting, anorexia, lethargy, dizziness, abnormal hepatic function, cough, and shortness of breath.
- No proven antidotes have been established for Gleostine overdosage. In case of overdose, appropriate supportive measures should be taken.

# Pharmacology

## Mechanism of Action
There is limited information regarding Lomustine Mechanism of Action in the drug label.

## Structure
- GleostineTM (lomustine) (CCNU) is one of the nitrosoureas used in the treatment of certain neoplastic diseases. It is 1-(2-chloro-ethyl)-3-cyclohexyl-1-nitrosourea. It is a yellow powder with the empirical formula of C9H16ClN3O2 and a molecular weight of 233.71. Gleostine is soluble in 10% ethanol (0.05 mg per mL) and in absolute alcohol (70 mg per mL). Gleostine is relatively insoluble in water (<0.05 mg per mL).
It is relatively un-ionized at a physiological pH.
Inactive ingredients in Gleostine Capsules are magnesium stearate and mannitol.
The structural formula is:
- Gleostine is available in 10 mg, 40 mg, and 100 mg capsules for oral administration.

## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Lomustine in the drug label.

## Pharmacokinetics
There is limited information regarding Pharmacokinetics of Lomustine in the drug label.

## Nonclinical Toxicology
Carcinogenesis, Mutagenesis, Impairment of Fertility
- Lomustine is carcinogenic in rats and mice, producing a marked increase in tumor incidence in doses approximating those employed clinically. Nitrosourea therapy does have carcinogenic potential in humans. Lomustine also affects fertility in male rats at doses somewhat higher than the human dose.

# Clinical Studies
There is limited information regarding Clinical Studies of Lomustine in the drug label.

# How Supplied
- GleostineTM Capsules are available in individual bottles of 5 capsules each.

## Storage
- Gleostine Capsules are stable for the lot life indicated on package labeling when stored in well-closed containers at 25C (77F); excursions permitted to 15C to 30C (59F to 86F) . Avoid excessive heat (over 40C, 104F).

# Images

## Drug Images

## Package and Label Display Panel

# Patient Counseling Information
Provide patients with the following information and instructions:
- In order to provide the proper dose of Gleostine, the dose may be made up of 2 or more different strengths and colors of capsules. Each strength must be dispensed separately by the pharmacist.
- Gleostine is given as a single oral dose and will not be repeated for at least 6 weeks. Daily use of the recommended dose may lead to toxicities and fatal outcomes.
Patients may experience nausea and vomiting that usually last less than 24 hours. Patients may also experience loss of appetite that may last for several days.
Instruct patients to contact their physician if they develop any of the following reactions: fever, chills, sore throat, unusual bleeding or bruising, shortness of breath, dry cough, swelling of feet or lower legs, mental confusion, or yellowing of eyes and skin.
- Instruct patients to wear impervious (rubber or latex) gloves when handling Gleostine Capsules.

# Precautions with Alcohol
- Alcohol-Lomustine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

# Brand Names
- GLEOSTINE 

# Look-Alike Drug Names
- A  B

# Drug Shortage Status

# Price