Altretamine

Altretamine comes as a capsule to take by mouth. It is usually taken four times a day (a dose after each meal and a dose at bedtime) for 14 or 21 days in a row. This cycle may be repeated once every 4 weeks depending on your response to the medication. Take altretamine at around the same time every day. Follow the directions on your prescription label carefully, and ask your doctor or pharmacist to explain any part you do not understand. Take altretamine exactly as directed. Do not take more or less of it or take it more often than prescribed by your doctor.

Your doctor may adjust your dose of altretamine depending on your response to treatment and any side effects that you experience. Talk to your doctor about how you are feeling during your treatment. Do not stop taking altretamine without talking to your doctor.

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.

HEXALEN (altretamine) ® (altretamine) capsules is indicated for use as a single agent in the palliative treatment of patients with persistent or recurrent ovarian cancer following first-line therapy with a cisplatin and/or alkylating agent-based combination.

Gastrointestinal

With continuous high-dose daily HEXALEN® (altretamine) capsules, nausea and vomiting of gradual onset occur frequently. Although in most instances these symptoms are controllable with anti-emetics, at times the severity requires HEXALEN® (altretamine) capsules dose reduction or, rarely, discontinuation of HEXALEN® (altretamine) capsules therapy. In some instances, a tolerance of these symptoms develops after several weeks of therapy. The incidence and severity of nausea and vomiting are reduced with moderate-dose administration of HEXALEN® (altretamine) capsules. In 2 clinical studies of single-agent HEXALEN® (altretamine) capsules utilizing a moderate, intermittent dose and schedule, only 1 patient (1%) discontinued HEXALEN® (altretamine) capsules due to severe nausea and vomiting.

Neurotoxicity

Peripheral neuropathy and central nervous system symptoms (mood disorders, disorders of consciousness, ataxia, dizziness, vertigo) have been reported. They are more likely to occur in patients receiving continuous high-dose daily HEXALEN (altretamine) ® (altretamine) capsules than moderate-dose HEXALEN® (altretamine) capsules administered on an intermittent schedule. Neurologic toxicity has been reported to be reversible when therapy is discontinued. Data from a randomized trial of HEXALEN® (altretamine) capsules and cisplatin plus or minus pyridoxine in ovarian cancer indicated that pyridoxine significantly reduced neurotoxicity; however, it adversely affected response duration suggesting that pyridoxine should not be administered with HEXALEN® (altretamine) capsules and/or cisplatin (1).

Hematologic

HEXALEN® (altretamine) capsules causes mild to moderate dose-related myelosuppression. Leukopenia below 3000 WBC/mm³occurred in <15% of patients on a variety of intermittent or continuous dose regimens. Less than 1% had leukopenia below 1000 WBC/mm³. Thrombocytopenia below 50,000 platelets/mm³was seen in <10% of patients. When given in doses of 8-12 mg/kg/day over a 21 day course, nadirs of leukocyte and platelet counts were reached by 3-4 weeks, and normal counts were regained by 6 weeks. With continuous administration at doses of 6-8 mg/kg/day, nadirs are reached in 6-8 weeks (median).

Data in the following table are based on the experience of 76 patients with ovarian cancer previously treated with a cisplatin-based combination regimen who received single-agent HEXALEN® (altretamine) capsules. In one study, HEXALEN® (altretamine) capsules, 260 mg/m²/day, was administered for 14 days of a 28 day cycle. In another study, HEXALEN® (altretamine) capsules, 6-8 mg/kg/day, was administered for 21 days of a 28 day cycle.

ADVERSE EXPERIENCES IN 76 PREVIOUSLY TREATED OVARIAN CANCER PATIENTS RECEIVING SINGLE-AGENT HEXALEN® (altretamine) CAPSULES

Additional adverse reaction information is available from 13 single-agent altretamine studies (total of 1014 patients) conducted under the auspices of the National Cancer Institute. The treated patients had a variety of tumors and many were heavily pretreated with other chemotherapies; most of these trials utilized high, continuous daily doses of altretamine (612 mg/kg/day). In general, adverse reaction experiences were similar in the two trials described above. Additional toxicities, not reported in the above table, included hepatic toxicity, skin rash, pruritus and alopecia, each occurring in <1% of patients.

No case of acute overdosage in humans has been described. The oral LD50 dose in rats was 1050 mg/kg and 437 mg/kg in mice.

You should not use altretamine if you have severe nerve problems or severe bone marrow suppression.

Altretamine can lower blood cells that help your body fight infections and help your blood to clot. Your blood will need to be tested often.

Altretamine can affect your nervous system. Call your doctor at once if you have severe dizziness, fainting, seizure, or severe numbness, tingling, or cold feeling in your hands or feet.

altretamine often causes nausea and vomiting. However, it is very important that you continue to receive the medicine even if you begin to feel ill. Taking altretamine after meals will lessen stomach upset. Ask your health care professional for other ways to lessen these effects.

Dosing

The dose of altretamine 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 altretamine. 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

Call your doctor or pharmacist for instructions.

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.

• It is used to treat ovarian cancer.
• It may be given to you for other reasons. Talk with the doctor.

Use altretamine as ordered by your doctor. Read all information given to you. Follow all instructions closely.

• Take after meals and at bedtime.

What do I do if I miss a dose?

• Call your doctor to find out what to do.

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:

• 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.
• Very upset stomach or throwing up.
• Feeling very tired or weak.
• A burning, numbness, or tingling feeling that is not normal.
• Change in balance.
• Mood changes.
• Dizziness.
• Trouble walking.

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 at room temperature.
• Store in a dry place. Do not store in a bathroom.
• 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: Altretamine is associated with a high emetic potential; antiemetics are recommended to prevent nausea and vomiting (Roila 2010)

Ovarian cancer (persistent or recurrent): Oral: 260 mg/m2/day in 4 divided doses for 14 or 21 days of a 28-day cycle

Refer to adult dosing.

>10%

Anemia (33%)

Nausea/vomiting (33%)

Peripheral sensory neuropathy (31%)

Thrombocytopenia (31%)

1-10%

Alk phos increased (9%)

Leukopenia (5%)

Anorexia (1%)

Seizures (1%)

<1%

Alopecia

Rash

Depression

Dizziness

Hepatotoxicity

Vertigo

Mechanism of Action

Unclear, reactive intermediates covalently bind to microsomal proteins & DNA, possibly causing DNA damage

Metabolism required for cytotoxicity

Pharmacokinetics

Absorption: Well absorbed

Distribution: Highly concentrated in liver, kidney & small intestine

Protein Bound: Plasma proteins

Peak Plasma Time: 0.5-3 hr

Half-life: 7 hr

Metabolism: Liver; rapid & extensive demethylation to active metabolites

Excretion: Urine (90%; <1% as unchanged drug)

Data not available