Chlorambucil

Chlorambucil may cause side effects. Tell your doctor if any of these symptoms are severe or do not go away:

• nausea
• vomiting
• sores in the mouth and throat
• tiredness
• missed menstrual periods (in girls and women)

Some side effects can be serious. If you experience any of these symptoms, call your doctor immediately:

• skin rash
• unusual bruising or bleeding
• black, tarry stools
• red urine
• cough
• sore throat
• congestion
• fever
• difficulty breathing
• seizures
• yellowing of the skin or eyes
• pain in the upper right part of the stomach
• dark colored urine
• frequent urination
• unusual lumps or masses

Chlorambucil may cause other side effects. Call your doctor if you have any unusual problems while taking this medication.

If you experience a serious side effect, you or your doctor may send a report to the Food and Drug Administration's (FDA) MedWatch Adverse Event Reporting program online (http://www.fda.gov/Safety/MedWatch) or by phone (1-800-332-1088).

In case of overdose, call your local poison control center at 1-800-222-1222. If the victim has collapsed or is not breathing, call local emergency services at 911.

LEUKERAN (chlorambucil) is indicated in the treatment of chronic lymphatic (lymphocytic) leukemia, malignant lymphomas including lymphosarcoma, giant follicular lymphoma, and Hodgkin's disease. It is not curative in any of these disorders but may produce clinically useful palliation.

Chlorambucil is a prescription medication used to treat chronic lymphocytic leukemia (CLL; a type of cancer of the white blood cells). Chlorambucil is also approved for the treatment of certain lymphomas.

This medication may be prescribed for other uses. Ask your doctor or pharmacist for more information.

The recommended dosage is usually 4 mg to 10 mg taken once daily for 3 to 6 weeks. For some people, chlorambucil is taken intermittently, as a single dose once every 2 weeks, or as a single dose once a month. The dose is individualized based on weight, the type of cancer being treated, response to the medication, and other medical conditions.

Your doctor may recommend a lower dosage if you have kidney or liver disease or if, during treatment, your blood counts drop too low.

Hematologic

The most common side effect is bone marrow suppression, anemia, leukopenia, neutropenia, thrombocytopenia, or pancytopenia. Although bone marrow suppression frequently occurs, it is usually reversible if the chlorambucil is withdrawn early enough. However, irreversible bone marrow failure has been reported.

Gastrointestinal

Gastrointestinal disturbances such as nausea and vomiting, diarrhea, and oral ulceration occur infrequently.

CNS4

Tremors, muscular twitching, myoclonia, confusion, agitation, ataxia, flaccid paresis, and hallucinations have been reported as rare adverse experiences to chlorambucil which resolve upon discontinuation of drug. Rare, focal and/or generalized seizures have been reported to occur in both children and adults at both therapeutic daily doses and pulse-dosing regimens, and in acute overdose (see PRECAUTIONS: General).

Dermatologic

Allergic reactions such as urticaria and angioneurotic edema have been reported following initial or subsequent dosing. Skin hypersensitivity (including rare reports of skin rash progressing to erythema multiforme, toxic epidermal necrolysis, and Stevens-Johnson syndrome) has been reported (see WARNINGS).

Miscellaneous

Other reported adverse reactions include: pulmonary fibrosis, hepatotoxicity and jaundice, drug fever, peripheral neuropathy, interstitial pneumonia, sterile cystitis, infertility, leukemia, and secondary malignancies (see WARNINGS).

Read the entire FDA prescribing information for Leukeran (Chlorambucil)

Chlorambucil is a cancer medicine that interferes with the growth and spread of cancer cells in the body.

Chlorambucil is used to treat several types of cancer, including Hodgkin's disease and certain types of leukemia or lymphoma.

Chlorambucil may also be used for purposes not listed in this medication guide.

You should not use chlorambucil if you are allergic to it, or if you have received chlorambucil in the past without successful treatment of your condition.

To make sure chlorambucil is safe for you, tell your doctor if you have:

• kidney disease;

• liver disease;

• a history of seizures;

• a history of head injury or brain tumor; or

• if you have received radiation or chemotherapy within the past 4 weeks.

Taking chlorambucil may increase your risk of developing other types of cancer. Talk to your doctor about your specific risk.

Do not use chlorambucil if you are pregnant. It could harm the unborn baby. Use effective birth control to prevent pregnancy during treatment. Tell your doctor if you miss a menstrual period.

Chlorambucil may affect fertility (your ability to have children), whether you are a man or a woman.

It is not known whether chlorambucil passes into breast milk or if it could harm a nursing baby. You should not breast-feed while using this medicine.

Take the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not take extra medicine to make up the missed dose.

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

In the U.S.

• Leukeran

Available Dosage Forms:

• Tablet

Therapeutic Class: Antineoplastic Agent

Pharmacologic Class: Alkylating Agent

Chemical Class: Nitrogen Mustard

In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For chlorambucil, the following should be considered:

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to chlorambucil or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.

Pediatric

Appropriate studies have not been performed on the relationship of age to the effects of chlorambucil in the pediatric population. Safety and efficacy have not been established.

Geriatric

Appropriate studies performed to date have not demonstrated geriatric-specific problems that would limit the usefulness of chlorambucil in the elderly. However, elderly patients are more likely to have kidney, liver, or heart problems, which may require caution and an adjustment in the dose for patients receiving this chlorambucil.

Pregnancy

Breast Feeding

There are no adequate studies in women for determining infant risk when using this medication during breastfeeding. Weigh the potential benefits against the potential risks before taking this medication while breastfeeding.

Interactions with Medicines

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are taking chlorambucil, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using chlorambucil with any of the following medicines is not recommended. Your doctor may decide not to treat you with this medication or change some of the other medicines you take.

• Measles Virus Vaccine, Live
• Mumps Virus Vaccine, Live
• Rotavirus Vaccine, Live
• Rubella Virus Vaccine, Live
• Varicella Virus Vaccine

Using chlorambucil with any of the following medicines is usually not recommended, but may be required in some cases. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Adenovirus Vaccine
• Bacillus of Calmette and Guerin Vaccine, Live
• Bupropion
• Cholera Vaccine, Live
• Donepezil
• Influenza Virus Vaccine, Live
• Poliovirus Vaccine, Live
• Smallpox Vaccine
• Typhoid Vaccine
• Yellow Fever Vaccine

Interactions with Food/Tobacco/Alcohol

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. Discuss with your healthcare professional the use of your medicine with food, alcohol, or tobacco.

Other Medical Problems

The presence of other medical problems may affect the use of chlorambucil. Make sure you tell your doctor if you have any other medical problems, especially:

• Bone marrow depression or
• Head injury or
• Seizures, history of—Use with caution. May make these conditions worse.

• Gout or
• Kidney stones, history of—Chlorambucil may increase levels of uric acid in the body, which can cause gout or kidney stones.

• Infection—May decrease your body's ability to fight infection.

• Kidney disease (e.g., nephrotic syndrome)—Use with caution. May increase risk for seizures.

• Liver disease—Use with caution. The effects may be increased because of slower removal of the medicine from the body.

It is very important that your doctor check your progress at regular visits to make sure chlorambucil is working properly. Blood tests will be needed to check for unwanted effects.

Using chlorambucil while you are pregnant can harm your unborn baby. Use an effective form of birth control to keep from getting pregnant. If you think you have become pregnant while using chlorambucil, tell your doctor right away.

If you plan to have children, talk with your doctor before using chlorambucil. Some men and women using chlorambucil have become infertile (unable to have children).

Serious skin reactions can occur with chlorambucil. Stop using chlorambucil and check with your doctor right away if you have blistering, peeling, or loosening of the skin; red skin lesions; severe acne or skin rash; sores or ulcers on the skin; or fever or chills while you are using chlorambucil.

While you are being treated with chlorambucil, and after you stop treatment with it, do not have any immunizations (vaccinations) without your doctor's approval. Chlorambucil may lower your body's resistance and there is a chance you might get the infection the immunization is meant to prevent. In addition, other persons living in your household should not take oral polio vaccine since there is a chance they could pass the polio virus on to you. Also, avoid persons who have taken oral polio vaccine within the last several months. Do not get close to them, and do not stay in the same room with them for very long. If you cannot take these precautions, you should consider wearing a protective face mask that covers the nose and mouth.

Chlorambucil can temporarily lower the number of white blood cells in your blood, increasing the chance of getting an infection. It can also lower the number of platelets, which are necessary for proper blood clotting. If this occurs, there are certain precautions you can take, especially when your blood count is low, to reduce the risk of infection or bleeding:

• If you can, avoid people with infections. Check with your doctor immediately if you think you are getting an infection or if you get a fever or chills, cough or hoarseness, lower back or side pain, or painful or difficult urination.
• Check with your doctor immediately if you notice any unusual bleeding or bruising; black, tarry stools; blood in the urine or stools; or pinpoint red spots on your skin.
• Be careful when using a regular toothbrush, dental floss, or toothpick. Your medical doctor, dentist, or nurse may recommend other ways to clean your teeth and gums. Check with your medical doctor before having any dental work done.
• Do not touch your eyes or the inside of your nose unless you have just washed your hands and have not touched anything else in the meantime.
• Be careful not to cut yourself when you are using sharp objects such as a safety razor or fingernail or toenail cutters.
• Avoid contact sports or other situations where bruising or injury could occur.

Check with your doctor right away if you have the following symptoms while taking chlorambucil: skin rash, fever, cough that won't go away, irregular monthly period, nausea or vomiting, seizures, unusual lumps, or yellow eyes or skin.

Make sure your doctor knows if you have had any other cancer treatments or radiation therapy within the past 4 weeks.

Cancer medicines can cause diarrhea, nausea, or vomiting in most people, sometimes even after receiving medicines to prevent it. Ask your doctor or nurse about other ways to control these side effects.

Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur:

• Black, tarry stools
• bleeding gums
• blood in the urine or stools
• chest pain
• cough or hoarseness, accompanied by fever or chills
• fever or chills
• lower back or side pain, accompanied by fever or chills
• painful or difficult urination, accompanied by fever or chills
• pinpoint red spots on the skin
• shortness of breath
• sores, ulcers, or white spots on the lips or in the mouth
• swollen glands
• troubled breathing with exertion
• unusual bleeding or bruising
• unusual tiredness or weakness

• Itching
• joint pain
• large, swollen hives
• skin rash
• swelling of the feet or lower legs

• Blistering, peeling, or loosening of the skin
• diarrhea
• muscle pain
• muscle twitching
• red skin lesions, often with a purple center
• red, irritated eyes
• seizures
• shakiness and unsteady walk
• shakiness in the legs, arms, hands, or feet
• sore throat
• sudden jerky movements of the body
• unsteadiness, trembling, or other problems with muscle control or coordination

• Abdominal or stomach pain or tenderness
• bone pain
• clay colored stools
• dark urine
• decreased appetite
• difficult breathing
• headache
• large, hive-like swelling on the face, eyelids, lips, tongue, throat, hands, legs, feet, or sex organs
• loss of appetite
• trouble getting pregnant
• troubled or quick, shallow breathing
• yellow eyes or skin

Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

• Changes in menstrual period
• nausea and vomiting

• Anxiety
• confusion
• dry mouth
• hyperventilation
• irregular heartbeats
• irritability
• no muscle tone or movement
• restlessness
• seeing, hearing, or feeling things that are not there
• trouble sleeping

• Hives or welts

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

For all patients taking chlorambucil:

• Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.
• Signs of infection like fever, chills, very bad sore throat, ear or sinus pain, cough, more sputum or change in color of sputum, pain with passing urine, mouth sores, or wound that will not heal.
• Signs of bleeding like throwing up blood or throw up that looks like coffee grounds; coughing up blood; blood in the urine; black, red, or tarry stools; bleeding from the gums; vaginal bleeding that is not normal; bruises without a reason or that get bigger; or any bleeding that is very bad or that you cannot stop.
• Signs of liver problems like dark urine, feeling tired, not hungry, upset stomach or stomach pain, light-colored stools, throwing up, or yellow skin or eyes.
• Feeling very tired or weak.
• A burning, numbness, or tingling feeling that is not normal.
• Change in balance.
• Hallucinations (seeing or hearing things that are not there).
• Seizures.
• Shortness of breath.
• Feeling confused.
• Shakiness.
• Twitching.
• Feeling agitated.
• Upset stomach or throwing up.
• A skin lump or growth.
• A very bad skin reaction (Stevens-Johnson syndrome/toxic epidermal necrolysis) may happen. It can cause very bad health problems that may not go away, and sometimes death. Get medical help right away if you have signs like red, swollen, blistered, or peeling skin (with or without fever); red or irritated eyes; or sores in your mouth, throat, nose, or eyes.

Women:

• For women, no period.

If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

• Store in a refrigerator. Do not freeze.
• Keep all drugs in a safe place. Keep all drugs out of the reach of children and pets.
• Check with your pharmacist about how to throw out unused drugs.

Note: Reduce initial dose if full-dose radiation or myelotoxic drugs have been administered within the last month. With bone marrow lymphocytic infiltration involvement (in CLL, Hodgkin lymphoma, or NHL), the maximum dose is 0.1 mg/kg/day. While short treatment courses are preferred, if maintenance therapy is required, the maximum dose is 0.1 mg/kg/day.

Chronic lymphocytic leukemia (CLL): Oral: 0.1 mg/kg/day for 3 to 6 weeks or 0.4 mg/kg pulsed doses administered intermittently, biweekly, or monthly (increased by 0.1 mg/kg/dose until response/toxicity observed)

CLL (off-label dosing): 0.4 mg/kg day 1 every 2 weeks; if tolerated may increase by 0.1 mg/kg with each treatment course to a maximum dose of 0.8 mg/kg and maximum of 24 cycles (Eichhorst 2009) or 30 mg/m2 day 1 every 2 weeks (in combination with prednisone) (Raphael 1991) or 40 mg/m2 day 1 every 4 weeks until disease progression or complete remission or response plateau for up to a maximum of 12 cycles (Rai 2000)

CLL in previously untreated patients (off-label combinations): Oral:

In combination with obinutuzumab: 0.5 mg/kg on days 1 and 15 every 28 days for 6 cycles (Goede 2014)

In combination with ofatumumab: 10 mg/m2 once daily for 7 days (days 1 to 7) every 28 days for a minimum of 3 cycles and up to 12 cycles or best response (clinical response that did not improve after 3 additional cycles); if necessary, reduce dose to 7.5 mg/m2/day and then to 5 mg/m2/day for hematologic toxicity (Hillmen 2015)

Hodgkin lymphoma: Oral: 0.2 mg/kg/day for 3 to 6 weeks

Non-Hodgkin lymphomas (NHL): Oral: 0.1 mg/kg/day for 3 to 6 weeks

Waldenström macroglobulinemia (off-label use): Oral: 0.1 mg/kg/day (continuously) for at least 6 months or 0.3 mg/kg/day for 7 days every 6 weeks for at least 6 months (Kyle 2000)

Store in refrigerator at 2°C to 8°C (36°F to 46°F).

Consult your pharmacist.

Applies to chlorambucil: oral tablet

Along with its needed effects, chlorambucil may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur while taking chlorambucil:

• Black, tarry stools
• bleeding gums
• blood in the urine or stools
• chest pain
• cough or hoarseness, accompanied by fever or chills
• fever or chills
• lower back or side pain, accompanied by fever or chills
• painful or difficult urination, accompanied by fever or chills
• pinpoint red spots on the skin
• shortness of breath
• sores, ulcers, or white spots on the lips or in the mouth
• swollen glands
• troubled breathing with exertion
• unusual bleeding or bruising
• unusual tiredness or weakness

• Itching
• joint pain
• large, swollen hives
• skin rash
• swelling of the feet or lower legs

• Blistering, peeling, or loosening of the skin
• diarrhea
• muscle pain
• muscle twitching
• red skin lesions, often with a purple center
• red, irritated eyes
• seizures
• shakiness and unsteady walk
• shakiness in the legs, arms, hands, or feet
• sore throat
• sudden jerky movements of the body
• unsteadiness, trembling, or other problems with muscle control or coordination

• Abdominal or stomach pain or tenderness
• bone pain
• clay colored stools
• dark urine
• decreased appetite
• difficult breathing
• headache
• large, hive-like swelling on the face, eyelids, lips, tongue, throat, hands, legs, feet, or sex organs
• loss of appetite
• trouble getting pregnant
• troubled or quick, shallow breathing
• yellow eyes or skin

Some side effects of chlorambucil may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

• Changes in menstrual period
• nausea and vomiting

• Anxiety
• confusion
• dry mouth
• hyperventilation
• irregular heartbeats
• irritability
• no muscle tone or movement
• restlessness
• seeing, hearing, or feeling things that are not there
• trouble sleeping

• Hives or welts

Applies to chlorambucil: compounding powder, oral tablet

Hematologic

Bone marrow suppression has been reported to usually be reversible if chlorambucil is withdrawn early enough. However, irreversible bone marrow failure has been reported.[Ref]

Hematologic side effects including bone marrow suppression have been the most commonly reported with the use of chlorambucil. Anemia, leukopenia, neutropenia, thrombocytopenia, and pancytopenia have also been reported.[Ref]

Nervous system

Most nervous system effects have been reported to resolve upon discontinuation of the drug.

The manufacturer has noted that children with nephrotic syndrome and patients receiving high pulse doses of chlorambucil may have an increased risk of seizures.[Ref]

Nervous system side effects including coma, tremors, muscular twitching, confusion, agitation, ataxia, flaccid paresis, hallucinations, and focal and/or generalized seizures have been reported rarely. Peripheral neuropathy has also been reported.[Ref]

Dermatologic

Dermatologic side effects have included skin hypersensitivity with rare reports of skin rash progressing to erythema multiforme, toxic epidermal necrolysis, and Stevens-Johnson syndrome.[Ref]

Gastrointestinal

Gastrointestinal side effects including nausea, vomiting, diarrhea, and oral ulceration have been reported infrequently. Jaundice has also been reported.[Ref]

Respiratory

Respiratory side effects including pulmonary fibrosis and interstitial pneumonia have been reported.[Ref]

Hepatic

Hepatic side effects including hepatotoxicity have been reported. A case of chlorambucil-induced acute hepatic failure has been reported in a patient with membranous nephropathy.[Ref]

Genitourinary

Genitourinary side effects including sterile cystitis and infertility have been reported.[Ref]

Oncologic

Oncologic side effects including leukemia and secondary malignancies have been reported.[Ref]

General

General side effects including drug fever have been reported.[Ref]

Ocular

Ocular side effects including one case of visual failure and optic atrophy have been reported.[Ref]

Psychiatric

Psychiatric side effects including lethargy and stupor have been reported.[Ref]

Some side effects of chlorambucil may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.