Lomustine - Uses, Dosage, Side Effects, Interaction - Rxharun

Lomustine – Uses, Dosage, Side Effects, Interaction

Mechanism of Action

Lomustine is a highly lipophilic nitrosourea compound that undergoes hydrolysis in vivo to form reactive metabolites. These metabolites cause alkylation and cross-linking of DNA (at the O6 position of guanine-containing bases) and RNA, thus inducing cytotoxicity. Other biologic effects include inhibition of DNA synthesis and some cell cycle phase specificity. Nitrosoureas generally lack cross-resistance with other alkylating agents. As lomustine is a nitrosourea, it may also inhibit several key processes such as carbamoylation and modification of cellular proteins. Although lomustine is believed to act by alkylation, the mechanism of action has not been completely elucidated, and other effects such as carbamoylation and modification of cellular proteins may be involved. The overall result is thought to be the inhibition of both DNA and RNA synthesis.

Lomustine is an alkylating agent of the nitrosourea type. Lomustine and its metabolites interfere with the function of DNA and RNA. It is cell cycle–phase nonspecific. Cancers form when some cells within the body multiply uncontrollably and abnormally. These cells then spread and destroy nearby tissues. Lomustine acts by slowing this process down. It kills cancer cells by damaging the DNA (the genetic material inside the cells) and stops them from dividing.

Indications

  • For the treatment of primary and metastatic brain tumors as a component of combination chemotherapy in addition to appropriate surgical and/or radiotherapeutic procedures. Also used in combination with other agents as secondary therapy for the treatment of refractory or relapsed Hodgkin’s disease.
  • Lomustine is an alkylating agent used as a part of chemotherapeutic regimens for the treatment of primary and metastatic brain tumors as well as refractory or relapsed Hodgkin’s disease in addition to surgical and/or radiotherapeutic treatments.
  • Lomustine is an orally administered alkylating agent used alone and in combination with other antineoplastic agents in the treatment of several malignancies including Hodgkin’s disease, lymphoma, and brain cancer.
  • 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.
  • Antineoplastic agent. The compound has had limited use since the early 1970s in the treatment of Hodgkin’s disease and various solid tumors. These include primary and metastatic brain tumors, colorectal tumors, and certain pulmonary malignancies. It is usually used in conjunction with other antineoplastic drugs.
  • Although lomustine is labeled for use in combination with other agents as secondary therapy for the treatment of refractory or relapsed Hodgkin’s disease, combination regimens containing other agents currently are preferred for this cancer.
  • Metastatic Brain Tumors
  • Primary Brain Neoplasm
  • Refractory Hodgkin Lymphoma

Use in Cancer

Lomustine is approved to be used alone or with other drugs to treat:

Lomustine is also being studied in the treatment of other types of cancer.

Contraindications

  • decreased function of bone marrow
  • decreased blood platelets
  • low levels of white blood cells
  • bleeding
  • a condition where there is a formation of fibrous tissue in the lung called pulmonary fibrosis
  • x-ray results showing lung tissue changes
  • decreased kidney function
  • the high amount of bilirubin in the blood
  • abnormal liver function tests
  • pregnancy
  • a patient who is producing milk and breastfeeding

Dosage

Strengths: 10 mg; 40 mg; 100 mg; triphasic; 5 mg

Brain/Intracranial Tumor

As a single agent in previously untreated patients:

  • 130 mg/m2 orally as a single dose every 6 weeks

As a single agent in patients with compromised bone marrow function:

  • 100 mg/m2 orally as a single dose every 6 weeks
  • The dose should be adjusted accordingly when this drug is used in combination with other myelosuppressive drugs.
  • All doses of this drug should be rounded to the nearest 10 mg by the prescriber.
  • Only a single dose of this drug should be dispensed.

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 tumors; 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.

Hodgkin’s Disease

As a single agent in previously untreated patients:

  • 130 mg/m2 orally as a single dose every 6 weeks

As a single agent in patients with compromised bone marrow function:

  • 100 mg/m2 orally as a single dose every 6 weeks
  • The dose should be adjusted accordingly when this drug is used in combination with other myelosuppressive drugs.
  • All doses of this drug should be rounded to the nearest 10 mg by the prescriber.
  • Only a single dose of this drug should be dispensed.

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 tumors; 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.

Pediatric Dose

Brain/Intracranial Tumor

As a single agent in previously untreated patients:

  • 130 mg/m2 orally as a single dose every 6 weeks

As a single agent in patients with compromised bone marrow function:

  • 100 mg/m2 orally as a single dose every 6 weeks
  • The dose should be adjusted accordingly when this drug is used in combination with other myelosuppressive drugs.
  • All doses of this drug should be rounded to the nearest 10 mg by the prescriber.
  • Only a single dose of this drug should be dispensed.

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 tumors; 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.

Hodgkin’s Disease

As a single agent in previously untreated patients:

  • 130 mg/m2 orally as a single dose every 6 weeks

As a single agent in patients with compromised bone marrow function:

  • 100 mg/m2 orally as a single dose every 6 weeks
  • The dose should be adjusted accordingly when this drug is used in combination with other myelosuppressive drugs.
  • All doses of this drug should be rounded to the nearest 10 mg by the prescriber.
  • Only a single dose of this drug should be dispensed.

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 tumors; 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.

Dose Adjustments

Doses subsequent to the initial dose should be adjusted according to the hematologic response of the patient to the preceding dose:
NADIR AFTER PRIOR DOSE:

  • 4000/mm3 or greater leukocytes; 100,000/mm3 or greater platelets: 100% of prior dose to be given
  • 3000 to 3999/mm3 leukocytes; 75,000 to 99,999/mm3 platelets: 100% of prior dose to be given
  • 2000 to 2999/mm3 leukocytes; 25,000 to 74,999/mm3 platelets: 70% of prior dose to be given
  • Less than 2000/mm3 leukocytes; less than 25,000/mm3 platelets: 50% of prior dose to be given
  • A repeat course should not be given until circulating blood elements have returned to acceptable levels (leukocytes above 4000/mm3; platelets above 100,000/mm3).
  • Repeat courses should not be given before 6 weeks because the hematologic toxicity is delayed and cumulative.
  • An adequate number of neutrophils should be present on a peripheral blood smear; blood counts should be monitored weekly.

Administration Advice:

  • Administering of this drug on an empty stomach may reduce the incidence of nausea and vomiting.
  • Rubber or latex gloves should be worn when handling containers and capsules of this drug.
  • Areas that come into contact with broken capsules should be washed immediately and thoroughly with soap and water.
  • Handling and disposal of this drug should be performed in a manner consistent with safe procedures for cytotoxic agents.
  • In order to provide the proper dose of this drug, the prescribed dose may be made up of 2 or more different strengths and colors of capsules; only the appropriate number of drug capsules required for a single dose should be dispensed and different capsule strengths should be dispensed separately.
  • Cross-resistance with other nitrosoureas is usual (cross-resistance between this drug and carmustine has occurred), but cross-resistance with conventional alkylating agents is unusual.
  • Overdosage: 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; treat overdosage immediately with gastric lavage and appropriate supportive measures.

Side Effects

The Most Common

  • nausea
  • vomiting
  • loss of appetite
  • sores in the mouth and throat
  • unusual tiredness or weakness
  • pale skin
  • fainting
  • hair loss
  • unsteady walk
  • slurred speech
  • difficulty breathing
  • shortness of breath
  • dry cough
  • chest pain
  • wheezing
  • decreased urination;
  • swelling of the face, arms, hands, feet, ankles, or lower legs.
  • yellowing or eyes and skin
  • confusion
  • sudden change or loss of vision

More common

  • Bleeding gums
  • chest pain
  • shortness of breath
  • sore throat
  • sores, ulcers, or white spots on the lips or in the mouth
  • unusual bleeding or bruising
  • unusual tiredness or weakness
  • Awkwardness
  • black, tarry stools
  • blood in the urine or stools
  • confusion
  • cough or hoarseness
  • decrease in urination
  • fever or chills
  • lower back or side pain
  • painful or difficult urination
  • pale skin
  • pinpoint red spots on the skin
  • slurred speech
  • swelling of the feet or lower legs
  • troubled breathing with exertion
  • unusual bleeding or bruising
  • unusual tiredness or weakness

Rare

  • Abdominal or stomach pain or tenderness
  • bone pain
  • change in frequency of urination or amount of urine
  • clay colored stools
  • dark urine
  • decreased appetite
  • dizziness
  • drowsiness
  • dry mouth
  • headache
  • increased blood pressure
  • increased thirst
  • itching
  • loss of appetite
  • nausea or vomiting
  • skin rash
  • weight gain
  • yellow eyes or skin
  • Darkening of the skin
  • diarrhea
  • Blurred vision
  • changes in patterns and rhythms of speech
  • confusion about identity, place, and time
  • decreased vision
  • eye pain
  • hair loss or thinning of the hair
  • shakiness and unsteady walk
  • swelling or inflammation of the mouth
  • trouble with speaking
  • unsteadiness, trembling, or other problems with muscle control or coordination
  • unusual drowsiness, dullness, tiredness, weakness, or feeling of sluggishness

Drug Interaction

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Pregnancy and Lactation

AU TGA pregnancy category: D
US FDA pregnancy category: D

Pregnancy

Based on animal data and its mechanism of action, Gleostine can cause fetal harm when administered to a pregnant woman. 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/m2 over 6 weeks (0.18 to 0.27 times the single human dose of 130 mg/m2
) 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.

Lactation

There is no information on the presence of lomustine 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 Gleostine.

Why is this medication prescribed?

Lomustine is used to treat certain types of brain tumors. Lomustine is also used with other medications to treat Hodgkin’s lymphoma (Hodgkin’s disease) that has not improved or that has worsened after treatment with other medications. Lomustine is in a class of medications called alkylating agents. It works by slowing or stopping the growth of cancer cells in your body.

How should this medicine be used?

Lomustine comes as a capsule to take by mouth. It is usually taken once every 6 weeks on an empty stomach. Your full dose may contain two or more different types and colors of capsules. You will receive only enough capsules for one dose. Take all of the capsules given to you in the prescription bottle at the same time. Follow the directions on your prescription label carefully, and ask your doctor or pharmacist to explain any part you do not understand. Take lomustine exactly as directed. Do not take more or less of it or take it more often than prescribed by your doctor.

You should wear rubber or latex gloves when you handle the capsules so that your skin does not come into contact with the capsules. If the capsule contents touch your skin, wash the area well with soap and water right away. Swallow the capsules whole; do not split, chew, or crush them. Ask your pharmacist or doctor for a copy of the manufacturer’s information for the patient.

What special precautions should I follow?

Before taking lomustine,

  • tell your doctor and pharmacist if you are allergic to lomustine, any other medications, or any of the ingredients in lomustine capsules. Ask your pharmacist for a list of the ingredients.
  • tell your doctor and pharmacist what other prescription and nonprescription medications, vitamins, nutritional supplements, and herbal products you are taking or plan to take.
  • you should know that lomustine may decrease fertility in men and women. However, you should not assume that you or your partner cannot become pregnant. Tell your doctor if you are pregnant or plan to become pregnant. If you are female, you should use birth control to prevent pregnancy during your treatment with lomustine and for at least 2 weeks after your final dose. If you are male, you and your female partner should use birth control during your treatment with lomustine and continue for 4 months after your final dose. If you or your partner become pregnant while taking lomustine, call your doctor. Lomustine may harm the fetus.
  • tell your doctor if you are breastfeeding or plan to breastfeed. You should not breastfeed while taking lomustine and for 2 weeks after your final dose.

References

Consumer Information – TrustArc The Leader in Privacy Management SoftwareLooking online for info on your child's health? Here are some tipsJanja Kristan - Chief Administrative Officer - AACI | LinkedIn
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