Alkeran

• Keep all medicines out of the reach and sight of children.
• Melphalan tablets should be stored in a refrigerator at 2°C to 8°C and kept dry.

Hematologic

The most common side effect is bone marrow suppression leading to leukopenia, thrombocytopenia, and anemia. Although bone marrow suppression frequently occurs, it is usually reversible if melphalan is withdrawn early enough. However, irreversible bone marrow failure has been reported.

Gastrointestinal

Nausea, vomiting, diarrhea, and oral ulceration occur. Hepatic disorders ranging from abnormal liver function tests to clinical manifestations such as hepatitis and jaundice have been reported.

Miscellaneous

Other reported adverse reactions include: pulmonary fibrosis (including fatal outcomes) and interstitial pneumonitis, skin hypersensitivity, maculopapular rashes, vasculitis, alopecia, and hemolytic anemia. Allergic reactions, including urticaria, edema, skin rashes, and rare anaphylaxis, have occurred after multiple courses of treatment. Cardiac arrest has also been reported rarely in association with such reports.

Alkeran is a prescription medication used to treat multiple myeloma (a type of cancer of the bone marrow). It may also be used to treat a certain type of ovarian cancer (cancer that begins in the female reproductive organs where eggs are formed). Alkeran belongs to a group of drugs called alkylating agents. It works by stopping or slowing the growth of cancer cells in your body.

This medication comes in tablet form and is usually take once a day, with or without food.

This medication is available in an injectable form to be given directly into a vein (IV) by a healthcare professional.

Common side effects nausea, vomiting, diarrhea, and mouth ulcers.

Serious side effects have been reported with Alkeran including the following:

• lowered blood counts. This is medically known as bone marrow suppression. Your doctor may monitor for bone marrow suppression, as it can lead to thrombocytopenia, anemia, and leukopenia
  • thrombocytopenia. This is a condition in which your blood has a lower than normal number of blood cell fragments called platelets. Tell your healthcare provider right away if you have the following signs and symptoms of thrombocytopenia:
    • mild to serious bleeding
    • purple, brown, and red bruises (purpura)
    • small red or purple dots on your skin (petechiae)
    • prolonged bleeding, even from minor cuts
    • bleeding or oozing from the mouth or nose, especially nosebleeds or bleeding from brushing your teeth
    • abnormal vaginal bleeding (especially heavy menstrual flow)
    • blood in the urine or stool or bleeding from the rectum. Blood in the stool can appear as red blood or as a dark, tarry color. Taking iron supplements also can cause dark, tarry stools.
    • headaches and other neurological symptoms. These problems are very rare, but you should discuss them with your doctor.
  • anemia. This is a condition in which your blood has a lower than normal number of red blood cells. Tell your healthcare provider right away if you have the following signs and symptoms of anemia:
    • shortness of breath
    • dizziness
    • headache
    • coldness in the hands and feet
    • pale skin
    • chest pain
  • neutropenia. This is when there is an abnormally low number of white blood cells. These cells, which are called neutrophils, help the body fight infection. Those who develop neutropenia are more likely to have fevers and infections.
• serious skin reactions such as rash or skin tissue death
• inflammation of the blood vessels
• hair loss
• severe allergic reaction. Tell your healthcare provider about any signs or symptoms of hypersensitivity, which include the following:
  • chest pain
  • swelling of the face, eyes, lips, tongue, arms, or legs
  • difficulty breathing or swallowing
  • rash
• pulmonary fibrosis. This is a condition in which the tissue deep in your lungs becomes scarred over time. This tissue gets thick and stiff. That makes it hard for you to catch your breath, and your blood may not get enough oxygen.
• interstitial pneumonitis. This is when the lungs are inflamed and become scarred. The inflammation and scarring make it hard to get enough oxygen.

Do not take Alkeran if you are allergic to Alkeran, to any of its ingredients, or if you have experienced resistance to this medication.

Medications can interact with certain foods. In some cases, this may be harmful and your doctor may advise you to avoid certain foods. In the case of Alkeran, there are no specific foods that you must exclude from your diet when receiving this medication.

Alkeran should be administered under the supervision of a qualified physician experienced in the use of cancer chemotherapeutic agents. Severe bone marrow suppression with resulting infection or bleeding may occur. Controlled trials comparing intravenous (IV) to oral Alkeran have shown more myelosuppression with the IV formulation. Hypersensitivity reactions, including anaphylaxis, have occurred in approximately 2% of patients who received the IV formulation. Alkeran is leukemogenic in humans. Alkeran produces chromosomal aberrations in vitro and in vivo and, therefore, should be considered potentially mutagenic in humans.

General

• Adjust dosage carefully according to clinical and hematologic response, based on weekly blood counts, and tolerance of the patient to obtain optimum therapeutic results with minimum adverse effects.a b

• Consult specialized references for procedures for proper handling and disposal of antineoplastics.106 b c

Administration

Administer orally or by IV infusion.b c

Has been administered by regional isolation perfusion† (e.g., for melanoma†)144 145 146 148 149 and intraperitoneally† (e.g., for advanced ovarian cancer).101

Usually administered orally;113 123 124 125 126 127 b however, can also be administered IV in the palliative treatment of multiple myeloma106 114 115 116 117 118 120 in patients in whom oral therapy is not feasible.106 118 120 c

Oral Administration

Administer orally on an empty stomach.108

Administer continuously (as single daily doses) or intermittently (e.g., daily for 7 days every 4–6 weeks).a b

IV Administration

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

Administer IV only by individuals experienced in the administration of the drug.a c

Administer diluted solution slowly into a freely running IV infusion via an injection port or into a central venous line.c

Avoid extravasation; do not administer by direct injection into a peripheral vein.c (See Local Effects under Cautions.)

Handle cautiously (e.g., use protective gloves);c avoid exposure during handling and preparation of IV solution.c If skin or mucosal contact occurs, immediately wash skin or mucosa with soap and water and flush with water.c

Reconstitute vial containing 50 mg of melphalan by rapidly adding 10 mL of the diluent provided by the manufacturer with a 20-gauge or larger needle to provide a solution containing 5 mg/mL.106 118 119 c

Shake vigorously until a clear solution is obtained.106 118 119 c Must be diluted (immediately after reconstitution) prior to IV infusion.a

Immediately dilute reconstituted solution with 0.9% sodium chloride injection to a concentration not >0.45 mg/mL.106 118 119 c

Administer by IV infusion over >15 minutes.106 119 120 c Administration should be completed within 60 minutes of reconstitution.106 119 c

Dosage

Available as melphalan and melphalan hydrochloride; dosage expressed in terms of melphalan.106 b c

Consult published protocols for the dosage of melphalan and other chemotherapeutic agents and the method and sequence of administration.a

Consider dosage adjustments based on the blood cell nadir and blood counts taken on the day of therapy.106 113 119 Generally, maintain leukocyte count between 3000–3500/mm3.b

Therapeutic response may occur gradually over several months.b 3–12 months of repeated courses or continuous therapy may be required to evaluate drug response and obtain maximum benefit from the drug.a b

Adults

Usual initial and maintenance dosage regimen: 6 mg daily for 2–3 weeks.a b Withhold therapy until leukocyte and platelet counts increase (i.e., up to 4 weeks) and then initiate maintenance therapy of 2 mg daily.a b Adjust dosage, as required, to maintain a degree of bone marrow depression.a b

Alternatively, 10 mg daily for 7–10 days.113 Withhold therapy until platelet and leukocyte counts exceed 100,000/mm3 and 4000/mm3, respectively, and then initiate maintenance therapy of 2 mg daily.113 Adjust dosage, as required, to between 1–3 mg daily, depending on hematologic response.113

Alternatively, 0.15 mg/kg daily for 7 days.a b Withhold therapy until platelet and leukocyte counts increase (i.e., 2–6 weeks), and then initiate maintenance therapy of ≤0.05 mg/kg daily.b Adjust dosage, as required, depending on hematologic response.b

Alternatively, 0.25 mg/kg daily for 4 days or 0.2 mg/kg daily for 5 days, with prednisone; administer at 4–6 week-intervals, if granulocyte and platelet counts are normal.b

Usual dosage: 16 mg/m2 at 2-week intervals for 4 doses.106 118 119 120 After satisfactory recovery from toxicity, initiate maintenance therapy of 16 mg/m2 at 4-week intervals.106 118 119 120

Usual dosage: 0.2 mg/kg daily for 5 successive days; administer at intervals of 4–5 weeks.113 b

Special Populations

Hepatic Impairment

No specific dosage recommendations at this time.b c

Renal Impairment

In patients with moderate to severe renal impairment, consider reducing initial dosage; however, no specific dosage recommendations at this time.b

In patients with renal impairment (BUN ≥30 mg/dL), reduce dosage by 50%. 106 118 120 c

Geriatric Patients

Select dosage with caution because of age-related decreases in hepatic, renal, and/or cardiac function and potential for concomitant disease and drug therapy.b c

In the U.S.

• Alkeran

Available Dosage Forms:

• Tablet

Therapeutic Class: Antineoplastic Agent

Pharmacologic Class: Alkylating Agent

Chemical Class: Nitrogen Mustard

Take melphalan only as directed by your doctor. Do not take more or less of it, do not take it more often, and do not take it for a longer time than your doctor ordered. The exact amount of medicine you need has been carefully worked out. Taking too much may increase the chance of side effects, while taking too little may not improve your condition.

Melphalan is sometimes given together with certain other medicines. If you are using a combination of medicines, it is important that you receive each one at the proper time. If you are taking some of these medicines by mouth, ask your health care professional to help you plan a way to remember to take your medicine at the right times.

While you are using melphalan, your doctor may want you to drink extra fluids so that you will pass more urine. This will help prevent kidney problems and keep your kidneys working well.

This medicine may cause nausea, vomiting, and loss of appetite. However, it is very important that you continue to receive the medicine, even if you begin to feel ill. Ask your health care professional for ways to lessen these effects.

If you vomit shortly after taking a dose of melphalan, check with your doctor. You will be told whether to take the dose again or to wait until the next scheduled dose.

Dosing

The dose of this medicine will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of this medicine. If your dose is different, do not change it unless your doctor tells you to do so.

The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.

Missed Dose

If you miss a dose of this medicine, skip the missed dose and go back to your regular dosing schedule. Do not double doses.

Storage

Store the medicine in a closed container at room temperature, away from heat, moisture, and direct light. Keep from freezing.

Keep out of the reach of children.

Do not keep outdated medicine or medicine no longer needed.

Ask your healthcare professional how you should dispose of any medicine you do not use.

It is very important that your doctor check your progress at regular visits to make sure that this medicine is working properly and to check for unwanted effects.

While you are being treated with melphalan, and after you stop treatment with it, do not have any immunizations (vaccinations) without your doctor's approval. Melphalan 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 or should not have taken oral polio vaccine within the last several months since there is a chance they could pass the polio virus on to you. Also, avoid other persons who have taken oral polio vaccine. 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.

Melphalan can lower the number of white blood cells in your blood temporarily, 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 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.

The following information on adverse reactions is based on data from both oral and IV administration of melphalan as a single agent, using several different dose schedules for treatment of a wide variety of malignancies.

Hematologic

The most common side effect is bone marrow suppression leading to leukopenia, thrombocytopenia, and anemia. White blood cell count and platelet count nadirs usually occur 2 to 3 weeks after treatment, with recovery in 4 to 5 weeks after treatment. Irreversible bone marrow failure has been reported.

Gastrointestinal

Gastrointestinal disturbances such as nausea and vomiting, diarrhea, and oral ulceration occur infrequently. Hepatic disorders ranging from abnormal liver function tests to clinical manifestations such as hepatitis and jaundice have been reported. Hepatic veno-occlusive disease has been reported.

Hypersensitivity

Acute hypersensitivity reactions including anaphylaxis were reported in 2.4% of 425 patients receiving Alkeran for Injection for myeloma (see WARNINGS). These reactions were characterized by urticaria, pruritus, edema, skin rashes, and in some patients, tachycardia, bronchospasm, dyspnea, and hypotension. These patients appeared to respond to antihistamine and corticosteroid therapy. If a hypersensitivity reaction occurs, IV or oral melphalan should not be readministered since hypersensitivity reactions have also been reported with oral melphalan. Cardiac arrest has also been reported rarely in association with such reports.

Miscellaneous

Other reported adverse reactions include skin hypersensitivity, skin ulceration at injection site, skin necrosis rarely requiring skin grafting, maculopapular rashes, vasculitis, alopecia, hemolytic anemia, allergic reaction, pulmonary fibrosis (including fatal outcomes), and interstitial pneumonitis. Temporary significant elevation of the blood urea has been seen in the early stages of therapy in patients with renal damage. Subjective and transient sensation of warmth and/or tingling.