Lomustine

Trade Names:CeeNU- Capsules 10 mg- Capsules 40 mg- Capsules 100 mg

Pharmacology

Its mechanism of action involves the inhibition of both DNA and RNA synthesis through DNA alkylation. Lomustine has been shown to affect a number of cellular processes including RNA, protein synthesis, and the processing of ribosomal and nucleoplasmic messenger RNA; DNA base component structure; the rate of DNA synthesis and DNA polymerase activity. It is cell cycle nonspecific.

Pharmacokinetics

Absorption

Bioavailability is 100%.

Distribution

Vd is 3.25 L/kg. High lipid solubility; crosses blood-brain barrier readily. Levels of radioactivity in the CSF are at least 50% of those in plasma.

Metabolism

Readily degraded, apparently in the liver, to several cytotoxic metabolites.

Elimination

Plasma t _½ of the metabolites is about 16 h to 2 days. The average terminal t _½ is 22 min. Cl is 56 mL/min/kg. 60% to 70% of the total dose is excreted in the urine in 96 h and 6% is expired as CO ₂ .

Indications and Usage

Brain tumors, Hodgkin disease.

Contraindications

Standard considerations.

Dosage and Administration

PO 100 to 130 mg/m ² administered as a single dose every 6 wk. Do not administer repeat doses of lomustine until leukocyte and platelet counts have recovered to acceptable levels (usually 4,000/mm ³ and 100,000/mm ³ , respectively). Reduce lomustine dose if administered with other myelosuppressive drugs. Give 100 mg/m ² to patients with compromised bone marrow function. Some clinicians advocate dosage reductions of 25% when platelet nadirs are 50,000 to 74,999/mm ³ , 50% when platelet nadirs are 25,000 to 49,999/mm ³ , and 75% when platelet nadirs are less than 25,000/mm ³ .

PO 75 to 150 mg/m ² administered as a single dose every 6 wk. Do not administer repeat doses of lomustine until leukocyte and platelet counts have recovered to acceptable levels (usually 4,000/mm ³ and 100,000/mm ³ , respectively). Follow dosage adjustment guidelines recommended for adults.

PO Give 100% of the prior dose if the leukocytes are greater than 3,000 cells/mm ³ and the platelets are greater than 75,000 cells/mm ³ . Give 70% of the prior dose if the leukocytes are 2,000 to 2,999 cells/mm ³ and the platelets are 25,000 to 74,999 cells/mm ³ . Give 50% of the prior dose if the leukocytes are less than 2,000 cells/mm ³ and the platelets less than 25,000 cells/mm.

General Advice

• Administer orally. Take lomustine on an empty stomach to reduce nausea.
• Nausea and vomiting may occur 3 to 6 h after an oral dose and usually last less than 24 h. Antiemetics prior to dosing may diminish and sometimes prevent these effects. Also may be reduced by administration to fasting patients.

Storage/Stability

Store in well-closed containers at room temperature. Avoid excessive heat (greater than 104°F).

Drug Interactions

Lomustine is soluble in alcohol. Some sources recommend avoidance of alcohol on days that lomustine is administered to avoid possible effects on the absorption of lomustine, although there is no documentation of an interaction.

Laboratory Test Interactions

None well documented.

Adverse Reactions

CNS

Disorientation; lethargy; ataxia; slurred speech.

GI

Very high potential for nausea and vomiting with doses at least 60 mg/m ² , moderate to high potential for nausea and vomiting with doses less than 60 mg/m ² ; anorexia; transient elevation of LFTs.

Hematologic

Bone marrow suppression, nadir at 4 to 6 wk.

Renal

Renal failure associated with large cumulative dose.

Miscellaneous

Acute leukemia and myelodysplastic disorders have occurred after long-term nitrosourea therapy.

Precautions

Pregnancy

Category D .

Lactation

Undetermined.

Children

See Route/Dosage.

Fertility

There have been reports of persistent testicular damage causing infertility.

Hepatic toxicity

A reversible type of hepatic toxicity manifested by increased transaminase, alkaline phosphatase, and bilirubin levels has occurred in a small percentage of patients.

Renal toxicity

Decreased kidney size, progressive azotemia, and renal failure have occurred in patients who received large cumulative doses after prolonged therapy.

Pulmonary toxicity

Pulmonary toxicity characterized by pulmonary infiltrates or fibrosis occurs rarely and appears to be dose-related. Onset of toxicity has occurred after an interval of at least 6 mo from start of therapy with cumulative doses usually greater than 1100 mg/m ² .

Secondary malignancies

Long-term use of nitrosoureas may be associated with development of secondary malignancies.

Patient Information

• Notify health care provider if fever, chills, sore throat, unusual bleeding or bruising, shortness of breath, dry cough, swelling of feet or lower legs, yellowing of eyes and skin, confusion, sores on the mouth or lips, or unusual tiredness occurs.
• Medication may cause loss of appetite; nausea; vomiting; hair loss; skin rash or itching (infrequent); notify health care provider if these reactions become pronounced.
• Take on an empty stomach to reduce nausea.
• Avoid alcohol for short periods after taking a dose of lomustine.
• Contraceptive measures are recommended during therapy.

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