Novantrone

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.

Mitoxantrone is a cancer medication that interferes with cancer cells and slows their growth and spread in the body. Mitoxantrone also affects the immune system.

Mitoxantrone is used to treat prostate cancer and certain types of leukemia.

Mitoxantrone is also used to treat the symptoms of relapsing multiple sclerosis. This medication will not cure multiple sclerosis.

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

Tell your doctor if you are pregnant or plan to become pregnant.

The FDA categorizes medications based on safety for use during pregnancy. Five categories - A, B, C, D, and X, are used to classify the possible risks to an unborn baby when a medication is taken during pregnancy.

This medication falls into category D. Novantrone may harm the unborn baby. If you are using Novantrone, even if you are using birth control, your doctor should give you a pregnancy test before treatment.

Get emergency medical help if you have signs of an allergic reaction: hives; difficult breathing; swelling of your face, lips, tongue, or throat.

Mitoxantrone may cause dangerous effects on your heart. Call your doctor at once if you have chest pain, fast or pounding heartbeats, shortness of breath (even with mild exertion), swelling, or rapid weight gain.

Also call your doctor at once if you have:

• signs of infection such as fever, night sweats, sore throat, easy bruising or bleeding, loss of appetite, weight loss, bone pain, unusual weakness;

• swollen gums, painful mouth sores, pain when swallowing, skin sores, cold or flu symptoms, cough, trouble breathing;

• shortness of breath (even with mild exertion);

• swelling, rapid weight gain;

• pain or burning when you urinate; or

• pain, burning, swelling, redness, bruising, or skin changes where the injection was given.

Common side effects may include:

• nausea, diarrhea, constipation, stomach pain;

• hair loss;

• missed menstrual periods;

• runny or stuffy nose;

• feeling tired; or

• blue-green colored urine or a bluish color of the whites of the eyes for a few days after each dose.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

General

• Consult specialized references for procedures for proper handling and disposal of antineoplastics.1

Acute Myeloid Leukemia

• Appropriate hematologic monitoring required; adjunctive therapies (e.g., anti-infectives, blood and blood products) must be available during the expected period of medullary hypoplasia and severe myelosuppression.1 23 Ensure full hematologic recovery before initiating consolidation therapy and monitor closely.1 23 (See Hematologic Effects under Cautions.)

Administration

Administer by IV infusion.1 Do not administer IM or sub-Q.1 Do not administer by intra-arterial or intrathecal injection.1 (See Neurotoxicity under Cautions.)

Safety of administration by routes other than IV not established.1

IV Administration

For solution and drug compatibility information, see Compatibility under Stability.

Administer diluted solution into tubing of a freely running IV solution of 0.9% sodium chloride injection or 5% dextrose injection, preferably via a Butterfly needle or other suitable device inserted into a large vein.1

When possible, do not use veins over joints or in extremities with compromised venous or lymphatic drainage.1

Avoid extravasation.1 If signs or symptoms of extravasation occur, immediately stop the infusion and restart in another vein.1 (See Local Effects under Cautions.) If sub-Q extravasation occurs or is suspected, elevation of the affected extremity and intermittent application of ice to the site may be useful.1 Because of the progressive nature of extravasation reactions, close observation and surgery consultation recommended.1

Handle cautiously (by trained nonpregnant personnel); use protective equipment (e.g., goggles, gloves, protective gowns).1 Use care to avoid contact of the drug with skin, mucous membranes, and eyes.1 If skin contact occurs, immediately rinse affected areas with copious amounts of warm water; use standard irrigation techniques immediately in the event of eye involvement.1

Must be diluted prior to IV infusion.1 2 3

Dilute dose of mitoxantrone hydrochloride in 0.9% sodium chloride injection or 5% dextrose injection to a final volume of ≥50 mL.1 3 Solutions may be further diluted with 5% dextrose injection, 0.9% sodium chloride injection, or 5% dextrose and 0.9% sodium chloride injection.1

Diluted solutions contain no preservatives; prepare immediately before use.1

Administer diluted solution slowly over ≥3 minutes;1 2 3 infusions are typically administered over 15–30 minutes.3 15

In patients with prostate cancer or multiple sclerosis, infuse dose over approximately 5–15 minutes.1

Dosage

Available as mitoxantrone hydrochloride; dosage expressed in terms of mitoxantrone.1

Adults

12 mg/m2 daily on days 1–3 in combination with cytarabine 100 mg/m2 daily (as a continuous IV infusion over 24 hours) on days 1–7.1 8 10 11

If antileukemic response to the first induction course is incomplete, a second induction course consisting of 2 days of mitoxantrone (12 mg/m2 daily) and 5 days of cytarabine (100 mg/m2 daily) may be given.1 8 10 11

If severe or life-threatening nonhematologic toxicity is observed during the initial induction course, withhold second induction course until toxicity resolves.1

12 mg/m2 daily on days 1 and 2 in combination with cytarabine 100 mg/m2 daily (as a continuous IV infusion over 24 hours) on days 1–5.1 8 10 Administer initial consolidation course approximately 6 weeks after the final induction course; administer the second consolidation course generally 4 weeks after the initial course.1 8

12–14 mg/m2 once every 21 days; give as an adjunct to corticosteroid therapy (e.g., prednisone 5 mg orally twice daily, hydrocortisone 40 mg orally daily).1 14 Some clinicians recommend discontinuance of mitoxantrone (and continuation of corticosteroid therapy alone) in patients who are still responding after a cumulative mitoxantrone dose of 140 mg/m2 due to risk of cardiac toxicity.14

12 mg/m2 once every 3 months.1

Prescribing Limits

Adults

Maximum cumulative lifetime dose: 140 mg/m2.1

Special Populations

Hepatic Impairment

Decreased clearance; dosage adjustment may be required, however, no specific dosage adjustment recommendations.1 (See Hepatic Impairment under Cautions.)

Renal Impairment

Dosage reduction not required.15 16

• Importance of providing patients who have multiple sclerosis with a copy of the manufacturer’s patient information prior to initiation of therapy and before each dose of the drug.1

• Importance of recognizing and reporting adverse effects of mitoxantrone, including myelosuppressive effects (and related precautions), CHF symptoms, and injection site pain.1

• Risk of irreversible myocardial toxicity and secondary leukemia.1

• Importance of women informing clinicians immediately if they are or plan to become pregnant or plan to breast-feed; necessity for clinicians to advise women to avoid pregnancy during therapy and advise pregnant women of risk to the fetus.1

• Importance of patients informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as concomitant illnesses.1

• Possible blue-green appearance of urine for 24 hours after administration; the white part of the eyes also may appear blue.1

• Importance of informing patients of other important precautionary information.1 (See Cautions.)

Mitoxantrone injection is used alone or together with other medicines to treat advanced prostate cancer and acute nonlymphocytic leukemia (ANLL). It belongs to the group of medicines known as antineoplastics or cancer medicines. Mitoxantrone is also used to treat some forms of multiple sclerosis (MS). This medicine will not cure MS, but it may extend the time between relapses.

Mitoxantrone interferes with the growth of cancer cells, which are eventually destroyed. Since the growth of normal body cells may also be affected by mitoxantrone, other unwanted effects will also occur. Some of these may be serious and must be reported to your doctor. Other effects, like hair loss, may not be serious but may cause concern. Some unwanted effects may not occur for months or years after the medicine is used.

Before you begin treatment with mitoxantrone, you and your doctor should talk about the good this medicine will do as well as the risks of using it.

This medicine is to be administered only by or under the immediate supervision of your doctor.

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 or nurse immediately if any of the following side effects occur:

• Black, tarry stools
• bladder pain
• bloody or cloudy urine
• cough or shortness of breath
• difficult, burning, or painful urination
• dizziness
• fainting
• fast, slow, or irregular heartbeat
• frequent urge to urinate
• lower back or side pain
• pale skin
• stomach pain
• swelling or inflammation of the mouth
• troubled breathing with exertion
• ulcers, sores, or white spots in the mouth
• unusual bleeding or bruising
• unusual tiredness or weakness

• Blood in the urine or stools
• decrease in urination
• fever or chills
• pinpoint red spots on the skin
• seizures
• sore, red eyes
• swelling of the feet and lower legs
• yellow eyes or skin

• Blue skin at the place of injection
• pain or redness at the place of injection
• skin rash

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:

• Absent, missed, or irregular menstrual periods
• back pain
• body aches or pains
• congestion
• constipation
• diarrhea
• dryness or soreness of the throat
• hair loss
• headache
• longer or heavier menstrual periods
• nausea or vomiting
• oral bleeding
• pain or tenderness around the eyes and cheekbones
• runny nose
• sneezing
• stopping of menstrual bleeding
• stuffy nose
• tender, swollen glands in the neck
• thinning of the hair

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.

Novantrone® (mitoxantrone for injection concentrate) should be administered under the supervision of a physician experienced in the use of cytotoxic chemotherapy agents.

Novantrone® should be given slowly into a freely flowing intravenous infusion.  It must never be given subcutaneously, intramuscularly, or intra-arterially.  Severe local tissue damage may occur if there is extravasation during administration.  (See ADVERSE REACTIONS, General,Cutaneous and DOSAGE AND ADMINISTRATION, Preparation and Administration Precautions).

NOT FOR INTRATHECAL USE.  Severe injury with permanent sequelae can result from intrathecal administration.  (See WARNINGS, General)

Except for the treatment of acute nonlymphocytic leukemia, Novantrone® therapy generally should not be given to patients with baseline neutrophil counts of less than 1,500 cells/mm3.  In order to monitor the occurrence of bone marrow suppression, primarily neutropenia, which may be severe and result in infection, it is recommended that frequent peripheral blood cell counts be performed on all patients receiving Novantrone®.

Cardiotoxicity:

Congestive heart failure (CHF), potentially fatal, may occur either during therapy with Novantrone® or months to years after termination of therapy.  Cardiotoxicity risk increases with cumulative Novantrone dose and may occur whether or not cardiac risk factors are present.  Presence or history of cardiovascular disease, radiotherapy to the mediastinal/pericardial area, previous therapy with other anthracyclines or anthracenediones, or use of other cardiotoxic drugs may increase this risk.  In cancer patients, the risk of symptomatic CHF was estimated to be 2.6% for patients receiving up to a cumulative dose of 140 mg/m2.  To mitigate the cardiotoxicity risk with Novantrone, prescribers should consider the following:

All Patients:

– All patients should be assessed for cardiac signs and symptoms by history, physical examination, and ECG prior to start of Novantrone® therapy.

– All patients should have baseline quantitative evaluation of left ventricular ejection fraction (LVEF) using appropriate methodology (ex. Echocardiogram, multi-gated radionuclide angiography (MUGA), MRI, etc.).

Multiple Sclerosis Patients:

– MS patients with a baseline LVEF below the lower limit of normal should not be treated with Novantrone®.

– MS patients should be assessed for cardiac signs and symptoms by history, physical examination and ECG prior to each dose.

– MS patients should undergo quantitative reevaluation of LVEF prior to each dose using the same methodology that was used to assess baseline LVEF.  Additional doses of Novantrone® should not be administered to multiple sclerosis patients who have experienced either a drop in LVEF to below the lower limit of normal or a clinically significant reduction in LVEF during Novantrone® therapy.

– MS patients should not receive a cumulative Novantrone dose greater than 140 mg/m2.

– MS patients should undergo yearly quantitative LVEF evaluation after stopping Novantrone to monitor for late occurring cardiotoxicity.

Secondary Leukemia:

Novantrone® therapy in patients with MS and in patients with cancer increases the risk of developing secondary acute myeloid leukemia.

For additional information, see WARNINGS and DOSAGE AND ADMINISTRATION.

Novantrone® (mitoxantrone for injection concentrate) is a sterile aqueous solution containing mitoxantrone hydrochloride at a concentration equivalent to 2 mg mitoxantrone free base per mL supplied in vials for multidose use as follows:

NDC 44087-1520-1         - 20 mg/10 mL/multidose vial (2 mg/mL)

Novantrone® (mitoxantrone for injection concentrate) should be stored between 15°-25°C (59°-77°F).  DO NOT FREEZE.

Issue Date:  June 2010

Manufactured for: EMD Serono, Inc. Rockland, MA 02370 USA

Marketed by:                                                                   Marketed by:
(OSI)TM oncology                                                           EMD Serono, Inc.
For oncology                                                                   For multiple sclerosis

PATIENT INFORMATION

Novantrone®

(noe-VAN-trone)

mitoXANTRONE

for injection concentrate

For Treating Multiple Sclerosis

Read this information carefully before you start taking Novantrone for multiple sclerosis (MS).  This information does not take the place of talking with your doctor.  Your doctor can tell you more about Novantrone and answer any questions you have about this treatment.  Novantrone is used for other conditions besides MS.  This leaflet has information about using Novantrone specifically for MS.

What is the most important information I should know about Novantrone?

• Novantrone can reduce relapses and disability for patients with worsening forms of MS.

• Novantrone may damage your heart at any time during therapy or months to years after therapy ends.  Heart damage caused by Novantrone can be serious and may cause death.  Your doctor will perform certain tests to see that your heart is working normally before you start to take Novantrone.  Your doctor will repeat these heart tests before you receive each additional dose and every year after stopping Novantrone.  Your doctor will also perform these tests if you have any symptoms of heart problems.  Because the risk to your heart may depend on the total amount of Novantrone given, your doctor will limit the number of doses you get.  Most patients will reach this limit after about 8 to 12 doses given over 2 to 3 years.  After you have reached your limit, you should not receive any additional Novantrone.  You and your doctor should both keep track of how much Novantrone you get.  (See the sections “What diagnostic tests will be performed?” and “What are the possible side effects of Novantrone?”)
• MS and cancer patients treated with Novantrone have an increased risk of developing leukemia.  Your doctor should perform blood tests before, during and every year after stopping treatment.
• Novantrone can increase your chance of getting an infection.  If you begin to have any signs of infection, such as fever, chills, sore throat, cough, pain with urinating, or urinating more often, call your doctor right away.  If you have such an infection, it can usually be treated by taking antibiotics.

What is Novantrone?

Novantrone is a medicine to treat MS patients with secondary (chronic) progressive, progressive relapsing, or worsening relapsing-remitting MS.  It is not for treating primary progressive MS.  Patients treated with Novantrone may have fewer relapses and keep their mobility longer.

Who should not take Novantrone?

Women who are pregnant, are trying to become pregnant, or are breastfeeding should not take Novantrone because it may harm the baby.  You should use birth control while taking Novantrone to avoid becoming pregnant.  Your doctor should also give you a pregnancy test before each dose, and you should know the results of this test before you get each dose of Novantrone.  If you plan on getting pregnant, talk with your doctor about stopping the Novantrone treatments.  If you do become pregnant, contact your doctor right away.

You should not take Novantrone if your doctor finds you have a low number of white blood cells (leukocytes).

You should not take Novantrone if your doctor finds your heart’s ability to pump blood is decreased.

If you are allergic to Novantrone, you should not take it.  The active ingredient is mitoxantrone.  Ask your doctor about the inactive ingredients.

Your doctor needs to know the following information about you to help decide if Novantrone is right for you.  Tell your doctor if you have now or had in the past:

• heart disease
• treatment with Novantrone
• cancer chemotherapy treatment
• radiation treatment to the chest area
• blood-clotting problems
• anemia or low red blood cell counts
• low white blood cell counts
• unusual or unexpected bleeding
• infections
• liver disease or problems
• any known allergies or sensitivities

Also tell your doctor if you take other medicines, including nonprescription medicines and nutritional supplements.

How do I take Novantrone?

Novantrone is given through a needle placed in a vein in your arm.  The dose takes about 5 to 15 minutes to deliver.  Novantrone treatment is usually given once every 3 months for about 2 to 3 years (8 to 12 doses).  However, this may differ for different patients.

What diagnostic tests will be performed?

You will need to have regular testing of your heart and blood to help avoid serious side effects.

Before each dose of Novantrone, your doctor will take blood samples to check your blood counts and liver function.  Your doctor may also take a blood sample if you begin to have signs of an infection.  If you are a woman who is capable of becoming pregnant, even if you are using birth control, you must have a pregnancy test before each Novantrone dose, and you should know the results before you receive each Novantrone dose.

To measure possible changes to the heart, you should have regular electrocardiograms (ECGs) and you should have regular testing of your heart’s ability to pump blood.  Measuring your heart’s ability to pump blood requires taking pictures of your heart using a simple, painless test such as an echocardiogram.  Your heart should be tested before each dose of Novantrone, or if you show signs of heart problems.

You and your doctor should carefully track the total amount of Novantrone you get.  Your doctor may stop Novantrone if your tests show that your heart’s ability to pump blood has decreased.  If you change doctors, make sure your new doctor knows how much Novantrone you have taken.

What should I avoid while taking Novantrone?

• Women should not become pregnant or breastfeed while taking Novantrone because it may harm the baby.  Talk with your doctor about effective birth control.  Tell your doctor if you become pregnant.
• Talk with your doctor about any medicines you currently take and any medicines you plan to start or stop taking.  These include prescription and non-prescription medicines and nutritional supplements.  Some medicines may affect how Novantrone works.

What are the possible side effects of Novantrone?

Most side effects of Novantrone are not severe and can normally be treated by your doctor.  The most common side effects of Novantrone in patients with MS are nausea, hair thinning, loss of menstrual periods, bladder infections, and mouth sores.  The nausea is usually mild and generally lasts for less than 24 hours.  A small number of patients treated with Novantrone develop heart problems during treatment or after treatment has stopped.  Tell your doctor if you have trouble breathing, swelling of your legs or ankles, or uneven or fast heartbeat.  These problems generally happen in people who get a total lifetime dose of more than 12 doses (usually more than 140 mg/m2) of Novantrone, but can also occur at lower lifetime doses.

Novantrone may cause your white blood cell count to go down, which increases your chance of getting an infection.  This risk is greatest within one month after each dose.  In addition, Novantrone may cause your platelet count to go down, which increases your chance of bleeding.  Call your doctor right away if you begin to have fever, chills, sore throat, cough, pain with urination, urination more often, or if you notice any unusual bleeding or bruising.

Novantrone is dark blue in color, so it may turn your urine a blue-green color for a few days after each dose.  The white part of your eyes may also have a slight blue color.

Other side effects may occur.  Be sure to tell your doctor about any side effects whether or not they are listed here.

General advice about prescription medicines

Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet.  If you have any concerns about Novantrone, ask your doctor.  Your doctor can give you information about Novantrone that was written for health care professionals.  For more information, call MS LifeLines toll free at 1-877-447-3243.

Manufactured for:

EMD Serono, Inc.

Rockland, MA 02370 USA

PI 719603

Issued 9/2009

Applies to mitoxantrone: intravenous solution

Hematologic

Very common (10% or more): Platelets low (up to 33%), leukopenia (up to 19%), white blood cells low (up to 100%)
Common (1% to 10%): Myelosuppression (especially leucopenia)
Uncommon (0.1% to 1%): Thrombocytopenia, anemia
Frequency not reported: Bone marrow depression[Ref]

Oncologic

Frequency not reported: Acute myeloid leukemia (AML), acute myelodysplastic syndrome (AMS)[Ref]

Gastrointestinal

Very common (10% or more): Nausea (up to 76%), stomatitis (up to 19%), diarrhea (up to 16%), gastralgia/stomach burn/epigastric pain (up to 14%), constipation (up to 10%), aphthosis (up to 10%)
Common (1% to 10%): Vomiting
Uncommon (0.1% to 1%): Anorexia, GI bleeding, abdominal pain, altered taste
Frequency not reported: Mucositis, vomiting[Ref]

Cardiovascular

Very common (10% or more): Arrhythmia (up to 18%), ECG abnormal (up to 11%)
Uncommon (0.1% to 1%): Hypotension
Frequency not reported: Acute arrhythmias, transient ECG alterations, reduced left ventricular output, cardiac insufficiency, congestive heart failure (CHF)[Ref]

Local

Uncommon (0.1% to 1%): Phlebitis, erythema, swelling, pain, burning and/or blue discoloration of the skin
Rare (less than 0.1%): Tissue necrosis (following extravasation)[Ref]

Nervous system

Common (1% to 10%): Headache
Uncommon (0.1% to 1%): Somnolence, mild paresthesia[Ref]

Hypersensitivity

Uncommon (0.1% to 1%): Anaphylaxis[Ref]

Dermatologic

Very common (10% or more): Reversible alopecia (up to 61%)
Uncommon (0.1% to 1%): Urticaria, rash, nail pigmentation, onycholysis[Ref]

Renal

Uncommon (0.1% to 1%): Elevated serum creatinine, elevated blood urea nitrogen
Frequency not reported: Renal failure[Ref]

Hepatic

Very common (10% or more): Gamma-glutamyl transpeptidase increased (up to 15%)
Common (1% to 10%): Alanine aminotransferase (ALT or SGPT) increased, aspartate aminotransferase (AST or SGOT) increased, granulocytopenia, anemia
Uncommon (0.1% to 1%): Increased liver enzyme levels, elevated bilirubin levels[Ref]

Other

Very common (10% or more): Asthenia (up to 24%)
Uncommon (0.1% to 1%): Fever, fatigue, weakness[Ref]

Genitourinary

Very common (10% or more): Menstrual disorder (including amenorrhea) (up to 61%), urinary tract infection (up to 32%), abnormal urine (up to 11%)
Common (1% to 10%): Menorrhagia
Frequency not reported: Blue-green coloration of the urine 1 to 2 days after administration[Ref]

Endocrine

Frequency not reported: Amenorrhea[Ref]

Immunologic

Very common (10% or more): Infection (e.g., tonsillitis, enteritis, urinary tract infection, viral infection, endometritis) (up to 85%), cutaneous mycosis (up to 10%)[Ref]

Metabolic

Very common (10% or more): Glucose high (up to 10%), potassium low (up to 10%)
Common (1% to 10%): Back pain
Rare (less than 0.1%): Tumor lysis syndrome (characterized by hyperuricemia, hypercalcemia, hyperphosphatasemia, hypocalcemia)[Ref]

Ocular

Uncommon (0.1% to 1%): Reversible blue coloration of the sclera
Frequency not reported: Lethargy, fatigue, seizures[Ref]

Psychiatric

Frequency not reported: Depression[Ref]

Respiratory

Very common (10% or more): Upper respiratory tract infection (up to 53%), pharyngitis/throat infection (up to 19%), rhinitis (up to 10%)
Common (1% to 10%): Sinusitis
Uncommon (0.1% to 1%): Dyspnea, pneumonitis[Ref]

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