CeeNU® (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. CeeNU is soluble in 10% ethanol (0.05 mg per mL) and in absolute alcohol (70 mg per mL). CeeNU is relatively insoluble in water ( < 0.05 mg per mL).

It is relatively unionized at a physiological pH.

Inactive ingredients in CeeNU Capsules are magnesium stearate and mannitol.

The structural formula is:

CeeNU is available in 10 mg, 40 mg and 100 mg capsules for oral administration.

Last updated on RxList: 6/10/2009

CeeNU 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 tumors—both primary and metastatic, in patients who have already received appropriate surgical and/or radiotherapeutic procedures.

Hodgkin's Disease—secondary 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.

The recommended dose of CeeNU 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 CeeNU is used in combination with other myelosuppressive drugs, the doses should be adjusted accordingly.

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:

Nadir After Prior Dose		Percentage of Prior Dose to be Given
Leukocytes	Platelets
> 4000	> 100,000	100%
3000–3999	75,000–99,999	100%
2000–2999	25,000–74,999	70%
< 2000	< 25,000	50%

A repeat course of CeeNU 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.

The dose pack of CeeNU® (lomustine) Capsules, NDC 0015-3034-10, contains:

2—100 mg capsules (Green/Green)
2—40 mg capsules (White/Green)
2—10 mg capsules (White/White)

Stability

CeeNU Capsules are stable for the lot life indicated on package labeling when stored in well-closed containers at 25° C (77° F); excursions permitted to 15° C–30° C (59° F–86° F) [see USP Controlled Room Temperature]. Avoid excessive heat (over 40° C, 104° F).

Directions to the Pharmacist

The dose pack contains a total of 300 mg and will provide enough medication for titration of a single dose. The total dose prescribed by the physician can be obtained (to within 10 mg) by determining the appropriate combination of the enclosed capsule strengths.

The appropriate number of capsules of each size should be placed in a single vial to which the patient information label (gummed label provided) explaining the differences in the appearance of the capsules is affixed. Each color-coded capsule is imprinted with the dose in milligrams.

Caution should be exercised when handling CeeNU Capsules. Procedures for proper handling and disposal of anticancer drugs should be utilized. Several guidelines on this subject have been published.^1-4 To minimize the risk of dermal exposure, always wear impervious gloves when handling bottles containing CeeNU Capsules. CeeNU Capsules should not be broken. Personnel should avoid exposure to broken capsules. If contact occurs, wash immediately and thoroughly. More information is available in the references listed below.

A patient information sticker, to be placed on dispensing container, is enclosed.

Also available: Individual bottles of 20 capsules each.

NDC 0015-3032-20—100 mg capsules (Green/Green)
NDC 0015-3031-20—40 mg capsules (White/Green)
NDC 0015-3030-20—10 mg capsules (White/White)

REFERENCES

1. NIOSH Alert: Preventing occupational exposures to antineoplastic and other hazardous drugs in healthcare settings. 2004. U.S. Department of Health and Human Services, Public Health Service, Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health, DHHS (NIOSH) Publication No. 2004-165.

2. OSHA Technical Manual, TED 1-0.15A, Section VI: Chapter 2. Controlling Occupational Exposure to Hazardous Drugs. OSHA, 1999. http://www.osha.gov/dts/osta/otm/otm_vi/otm_vi_2.html

3. American Society of Health-System Pharmacists. ASHP guidelines on handling hazardous drugs. Am J Health-Syst Pharm. 2006; 63:1172-1193.

4. Polovich M, White JM, Kelleher LO, eds. 2005. Chemotherapy and biotherapy guidelines and recommendations for practice (2nd. ed.) Pittsburgh, PA: Oncology Nursing Society.

Bristol-Myers Squibb Company, Princeton, NJ 08543 USA. Made in Italy. Revised February 2009

Last updated on RxList: 6/11/2009

Hematologic Toxicity

The most frequent and most serious toxicity of CeeNU is delayed myelosuppression. It usually occurs 4 to 6 weeks after drug administration and is dose related. Thrombocytopenia occurs at about 4 weeks postadministration and persists for 1 to 2 weeks. Leukopenia occurs at 5 to 6 weeks after a dose of CeeNU 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.

CeeNU 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 CeeNU. Onset of toxicity has occurred after an interval of 6 months or longer from the start of therapy with cumulative doses of CeeNU usually greater than 1100 mg/m². There is one 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 (1–16 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 CeeNU 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 CeeNU.

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 CeeNU. 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 CeeNU. However, the relationship to medication in these patients is unclear.

No information provided.

Last updated on RxList: 6/10/2009

Since the major toxicity is delayed bone marrow suppression, blood counts should be monitored weekly for at least 6 weeks after a dose (see ADVERSE REACTIONS). At the recommended dosage, courses of CeeNU should not be given more frequently than every 6 weeks.

The bone marrow toxicity of CeeNU is cumulative and therefore dosage adjustment must be considered on the basis of nadir blood counts from prior dose (see dosage adjustment table under DOSAGE AND ADMINISTRATION).

Pulmonary toxicity from CeeNU appears to be dose related (see ADVERSE REACTIONS).

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 (see ADVERSE REACTIONS).

Pregnancy Category D

CeeNU can cause fetal harm when administered to a pregnant woman. CeeNU 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.

General

In all instances where the use of CeeNU is considered for chemotherapy, the physician must evaluate the need and usefulness of the drug against the risks of toxic effects or adverse reactions. Most such adverse reactions are reversible if detected early. When such effects or reactions do occur, the drug should be reduced in dosage or discontinued and appropriate corrective measures should be taken according to the clinical judgment of the physician. Reinstitution of CeeNU therapy should be carried out with caution, and with adequate consideration of the further need for the drug and alertness as to possible recurrence of toxicity.

Laboratory Tests

Due to delayed bone marrow suppression, blood counts should be monitored weekly for at least 6 weeks after a dose.

Baseline pulmonary function studies should be conducted along with frequent pulmonary function tests during treatment. Patients with a baseline below 70% of the predicted Forced Vital Capacity (FVC) or Carbon Monoxide Diffusing Capacity (DL_CO) are particularly at risk.

Since CeeNU may cause liver dysfunction, it is recommended that liver function tests be monitored periodically.

Renal function tests should also be monitored periodically.

Carcinogenesis, Mutagenesis, Impairment of Fertility

CeeNU 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 (see ADVERSE REACTIONS). CeeNU also affects fertility in male rats at doses somewhat higher than the human dose.

Pregnancy

Pregnancy “Category D.” (See WARNINGS.)

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 CeeNU, 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

See ADVERSE REACTIONS: Pulmonary Toxicity, and DOSAGE AND ADMINISTRATION.

Geriatric Use

No data from clinical studies of CeeNU 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.

Last updated on RxList: 6/10/2009

No proven antidotes have been established for CeeNU overdosage.

CeeNU should not be given to individuals who have demonstrated a previous hypersensitivity to it.

Last updated on RxList: 6/10/2009

Although it is generally agreed that CeeNU alkylates DNA and RNA, it is not cross resistant with other alkylators. As with other nitrosoureas, it may also inhibit several key enzymatic processes by carbamoylation of amino acids in proteins.

CeeNU may be given orally. Following oral administration of radioactive CeeNU at doses ranging from 30 mg/m² to 100 mg/m², about half of the radioactivity given was excreted in the urine in the form of degradation products within 24 hours.

The serum half-life of the metabolites ranges from 16 hours to 2 days. Tissue levels are comparable to plasma levels at 15 minutes after intravenous administration.

Because of the high lipid solubility and the relative lack of ionization at physiological pH, CeeNU crosses the blood-brain barrier quite effectively. Levels of radioactivity in the CSF are 50% or greater than those measured concurrently in plasma.

Last updated on RxList: 6/10/2009

Patients receiving CeeNU should be given the following information and instructions by the physician:

1. Patients should be told that CeeNU is an anticancer drug and belongs to the group of medicines known as alkylating agents.
2. In order to provide the proper dose of CeeNU, patients should be aware that there may be two or more different types and colors of capsules in the container dispensed by the pharmacist.
3. Patients should be told that CeeNU is given as a single oral dose and will not be repeated for at least 6 weeks.
4. Patients should be told that nausea and vomiting usually last less than 24 hours, although loss of appetite may last for several days.
5. If any of the following reactions occur, notify the physician: 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.
6. Patients should be told to wear gloves when handling CeeNU Capsules.

Last updated on RxList: 6/10/2009

IMPORTANT NOTE: This is a summary and does not contain all possible information about this product. For complete information about this product or your specific health needs, ask your health care professional. Always seek the advice of your health care professional if you have any questions about this product or your medical condition. This information is not intended as individual medical advice and does not substitute for the knowledge and judgment of your health care professional. This information does not contain any assurances that this product is safe, effective, or appropriate for you.

LOMUSTINE - ORAL

(low-MUSS-teen)

COMMON BRAND NAME(S): Ceenu

WARNING: Lomustine may cause serious blood disorders (decreased bone marrow function leading to low number of white blood cells/platelets and anemia). It can lower your body's ability to fight an infection and increase your risk of bleeding. These side effects usually occur 4-6 weeks after your dose. Higher doses and more doses increase the chance of these side effects.

Seek immediate medical attention if you develop symptoms of infection (fever, chills, persistent sore throat) or unusually easy bruising/ bleeding. (See also Side Effects section.)

Your doctor will monitor you and perform blood tests weekly for at least 6 weeks after each dose. Your dose and any further treatment will be based on your blood tests. You will have to wait at least 6 weeks between doses.

USES: This medication is used to treat various types of cancer. Lomustine belongs to a class of drugs known as alkylating agents. It works by slowing or stopping the growth of cancer cells.

HOW TO USE: Take this medication by mouth as a single dose as directed by your doctor. (See also Warning section.) Your dose may consist of 2 or more different strengths/colors of capsules. Taking this medication on an empty stomach with a full glass of water may decrease nausea and vomiting. Unless your doctor instructs you otherwise, drink plenty of fluids to avoid a serious loss of body water (dehydration).

The dosage is based on your medical condition, other treatments (e.g., radiation, chemotherapy), body size, and response to therapy (e.g., side effects such as low white blood cell count).

Do not increase your dose or take this medication more often than prescribed. Your condition will not improve any faster, and the risk of serious side effects may be increased.

Since this drug can be absorbed through the skin and lungs, women who are pregnant or who may become pregnant should not handle this medication or breathe the dust from the capsules.

SIDE EFFECTS: Nausea, vomiting, loss of appetite, diarrhea, and mouth/lip sores may occur. Nausea and vomiting usually last for less than 24 hours, though loss of appetite can last for several days. Nausea and vomiting can be quite severe. In some cases, your doctor may prescribe medication to prevent/treat nausea and vomiting. Changes in diet such as eating several small meals or limiting activity may help decrease some of these effects. If these effects persist or worsen, notify your doctor or pharmacist promptly.

Temporary hair loss may occur. Normal hair growth should return after treatment has ended.

Remember that your doctor has prescribed this medication because he or she has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects. (See also Warning section.)

Tell your doctor immediately if any of these unlikely but serious side effects occur: confusion, swelling of lower legs/feet, vision changes.

Tell your doctor immediately if any of these rare but very serious side effects occur: coughing up blood, persistent nausea/vomiting, stomach/abdominal pain, black tarry stools, unusual tiredness, change in the amount of urine, dark or pink urine, yellow eyes/skin.

A severe (sometimes fatal) lung problem (pulmonary fibrosis) has occurred in patients using this drug. This condition can occur months to years after you start taking this medication. Tell your doctor immediately if you experience any of these serious side effects: cough, chest pain, difficult/painful breathing.

A very serious allergic reaction to this drug is rare. However, seek immediate medical attention if you notice any symptoms of a serious allergic reaction, including: rash, itching, swelling, severe dizziness, trouble breathing.

This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.

Contact your doctor for medical advice about side effects. The following numbers do not provide medical advice, but in the US you may report side effects to the Food and Drug Administration (FDA) at 1-800-FDA-1088. In Canada, you may call Health Canada at 1-866-234-2345.

PRECAUTIONS: Before taking lomustine, tell your doctor or pharmacist if you are allergic to it; or if you have any other allergies.

This medication should not be used if you have certain medical conditions. Before using this medicine, consult your doctor or pharmacist if you have: current infection.

Before using this medication, tell your doctor or pharmacist your medical history, especially of: blood disorder (e.g., anemia, clotting problem), kidney disease, liver disease, lung disease.

Do not have immunizations/vaccinations without the consent of your doctor, and avoid contact with people who have recently received oral polio vaccine or flu vaccine inhaled through the nose. To prevent the spread of infections, wash your hands well, and avoid touching your eyes or the inside of your nose without first washing your hands.

To lower your risk of getting cut, bruised, or injured, use caution with sharp objects like razors and nail cutters, and avoid activities such as contact sports.

Limit alcoholic beverages as drinking alcohol may increase your chances of bleeding in your stomach or intestines.

During pregnancy, lomustine should be used only when clearly needed. It may harm an unborn baby. If you become pregnant or think you may be pregnant, inform your doctor immediately. Women of childbearing age should use 2 forms of birth control while using this medication. Discuss the use of birth control, the risks and benefits of this medication, and any other concerns about using this medication with your doctor.

It is not known whether this drug passes into breast milk. Because of the possible risk to the infant, breast-feeding while using this drug is not recommended. Consult your doctor before breast-feeding.

DRUG INTERACTIONS: Your doctor or pharmacist may already be aware of any possible drug interactions and may be monitoring you for them. Do not start, stop, or change the dosage of any medicine before checking with your doctor or pharmacist first.

This drug should not be used with the following medications because very serious interactions may occur: nalidixic acid, live vaccines.

If you are currently using either of the medications listed above, or have received or plan to receive any vaccines, tell your doctor or pharmacist before starting lomustine.

Before using this medication, tell your doctor or pharmacist of all prescription and nonprescription/herbal products you may use, especially of: 'blood thinners" (e.g., heparin, warfarin), other drugs that can affect the immune system (e.g., chemotherapy, cyclosporine).

This document does not contain all possible interactions. Therefore, before using this product, tell your doctor or pharmacist of all the products you use. Keep a list of all your medications with you, and share the list with your doctor and pharmacist.

OVERDOSE: If overdose is suspected, contact your local poison control center or emergency room immediately. US residents should call the US National Poison Hotline at 1-800-222-1222. Canada residents should call a provincial poison control center.

NOTES: Do not share this medication with others.

Laboratory and/or medical tests (e.g., complete blood count, kidney/liver/lung tests) should be performed periodically to monitor your progress or check for side effects. Consult your doctor for more details.

MISSED DOSE: It is important that you take lomustine as scheduled by your doctor. If you miss a dose, contact your doctor immediately to obtain a new dosing schedule.

STORAGE: Store in a tightly closed container at room temperature below 104 degrees F (40 degrees C) away from moisture and sunlight. Do not store in the bathroom. Keep all medicines away from children and pets.

Do not flush medications down the toilet or pour them into a drain unless instructed to do so. Properly discard this product when it is expired or no longer needed. Consult your pharmacist or local waste disposal company for more details about how to safely discard your product.

MEDICAL ALERT: Your condition can cause complications in a medical emergency. For information about enrolling in MedicAlert, call 1-800-854-1166 (USA) or 1-800-668-1507 (Canada).

Information last revised July 2008 Copyright(c) 2008 First DataBank, Inc.