What is altretamine?

Altretamine is a cancer (antineoplastic) medication. Altretamine interferes with the growth of cancer cells and slows their growth and spread in the body.

Altretamine is used to treat cancer of the ovaries.
Altretamine may also be used for purposes other than those listed in this medication guide.

What are the possible side effects of altretamine?

If you experience any of the following serious side effects, seek emergency medical attention or contact your doctor immediately:

• an allergic reaction (shortness of breath; closing of your throat; difficulty breathing; swelling of your lips, face, or tongue; or hives);
• decreased bone marrow function and blood problems (extreme fatigue; easy bruising or bleeding; black, bloody or tarry stools; or fever, chills, or signs of infection);
• pain, tremors, tingling, burning, or prickling in hands or feet;
• mood changes;
• severe drowsiness or loss of consciousness;
• loss of coordination, weakness, dizziness, unsteadiness or falling; or
• severe nausea or vomiting.

Other less serious side effects may be more likely to occur. Talk to your doctor if you experience:

• temporary hair loss;
• itching or rash; or
• mild to moderate nausea or vomiting.

Side effects other than those listed here may also occur. Talk to your doctor about any side effect that seems unusual or that is especially bothersome. You may report side effects.

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

Altretamine should only be administered under the supervision of a qualified healthcare provider experienced in the use of cancer chemotherapeutic agents.

Serious side effects have been reported with the use of altretamine including: allergic reactions (difficulty breathing; closing of the throat; swelling of the lips, tongue, or face; or hives); decreased bone marrow function and blood problems (extreme fatigue; easy bruising or bleeding; black, bloody or tarry stools; fever or chills; or signs of infection such as fever; chills, or sore throat); neurologic problems (mood disorders, altered consciousness, weakness, dizziness, vertigo); and others. Talk to your doctor about the possible side effects from treatment with altretamine.

What should I discuss with my healthcare provider before taking altretamine?

Before taking altretamine, tell your doctor if you have:

• any nervous system (brain and nerves) problems; or
• bone marrow problems.

You may not be able to take altretamine, or you may require a dosage adjustment or special monitoring during treatment if you have any of the conditions listed above.

Altretamine is in the FDA pregnancy category D. This means that altretamine is known to cause birth defects in an unborn baby. Do not take altretamine without first talking to your doctor if you are pregnant or could become pregnant during treatment. Contraceptive measures are recommended during treatment with altretamine.

It is not known whether altretamine passes into breast milk. Do not take altretamine without first talking to your doctor if you are breast feeding a baby.

How should I take altretamine?

Take altretamine exactly as directed by your doctor. If you do not understand these instructions, as your doctor, nurse or pharmacist to explain them to you.

Your doctor will determine the correct amount and frequency of treatment with altretamine depending upon the cancer being treated and other factors. Talk to your doctor if you have any questions or concerns regarding the treatment schedule.

Altretamine is usually taken four times a day, after meals and at bedtime.
Take each oral dose with a large glass of water.

Your doctor will probably want you to have regularly scheduled blood tests and other medical evaluations during treatment with altretamine to monitor progress and side effects.

Store altretamine capsules at room temperature away from heat and moisture. Keep this product out of the reach of children.

What happens if I miss a dose?

Contact your doctor if you miss a dose of altretamine.

What happens if I overdose?

If for any reason an overdose of altretamine is suspected, seek emergency medical attention or contact your healthcare provider immediately.

Symptoms of an altretamine overdose tend to be similar to side effects caused by the medication, although often more severe.

What should I avoid while taking altretamine?

Altretamine can lower the activity of your immune system making you susceptible to infections. Avoid contact with people who have colds, the flu, or other contagious illnesses and do not receive vaccines that contain live strains of a virus (e.g., live oral polio vaccine) during treatment with altretamine. In addition, avoid contact with individuals who have recently been vaccinated with a live vaccine. There is a chance that the virus can be passed on to you.

What other drugs will affect altretamine?

Before taking altretamine, tell your doctor if you are taking a monoamine oxidase inhibitor (MAOI) such as isocarboxazid (Marplan), phenelzine (Nardil), or tranylcypromine (Parnate). You may require a dosage adjustment or special monitoring during treatment if you are taking one of these medicines.

Before taking altretamine, tell your doctor if you are taking cimetidine (Tagamet, Tagamet HB). You may require a dosage adjustment or special monitoring during treatment.

Do not receive "live" vaccines during treatment with altretamine. Administration of a live vaccine may be dangerous during treatment with altretamine.

Drugs other than those listed here may also interact with altretamine. Talk to your doctor and pharmacist before taking any other prescription or over-the-counter medicines, including herbal products, during treatment with altretamine.

DESCRIPTION

Altretamine capsules, is a synthetic cytotoxic antineoplastic s-triazine derivative. Altretamine capsules contain 50 mg of altretamine for oral administration. Inert ingredients include lactose, anhydrous and calcium stearate. Altretamine, known chemically as N,N,N',N',N",N"-hexamethyl-1,3,5-triazine-2,4,6-triamine, has the following structural formula:

Its empirical formula is C9H18N6 with a molecular weight of 210.28. Altretamine is a white crystalline powder, melting at 172 ± 1°C. Altretamine is practically insoluble in water but is increasingly soluble at pH 3 and below.

CLINICAL PHARMACOLOGY

The precise mechanism by which Altretamine capsules exerts its cytotoxic effect is unknown, although a number of theoretical possibilities have been studied. Structurally, Altretamine capsules resembles the alkylating agent triethylenemelamine, yet in vitro tests for alkylating activity of Altretamine capsules and its metabolites have been negative. Altretamine capsules has been demonstrated to be efficacious for certain ovarian tumors resistant to classical alkylating agents. Metabolism of altretamine is a requirement for cytotoxicity. Synthetic monohydroxymethylmelamines, and products of altretamine metabolism, in vitro and in vivo, can form covalent adducts with tissue macromolecules including DNA, but the relevance of these reactions to antitumor activity is unknown.

Altretamine capsules is well-absorbed following oral administration in humans, but undergoes rapid and extensive demethylation in the liver, producing variation in altretamine plasma levels. The principal metabolites are pentamethylmelamine and tetramethylmelamine.

Pharmacokinetic studies were performed in a limited number of patients and should be considered preliminary. After oral administration of Altretamine capsules to 11 patients with advanced ovarian cancer in doses of 120-300 mg/m2, peak plasma levels (as measured by gas-chromatographic assay) were reached between 0.5 and 3 hours, varying from 0.2 to 20.8 mg/l. Half-life of the ß-phase of elimination ranged from 4.7 to 10.2 hours. Altretamine and metabolites show binding to plasma proteins. The free fractions of altretamine, pentamethylmelamine and tetramethylmelamine are 6%, 25% and 50%, respectively.

Following oral administration of 14C-ring-labeled altretamine (4 mg/kg), urinary recovery of radioactivity was 61% at 24 hours and 90% at 72 hours. Human urinary metabolites were N-demethylated homologues of altretamine with <1% unmetabolized altretamine excreted at 24 hours.

After intraperitoneal administration of 14C-ring-labeled altretamine to mice, tissue distribution was rapid in all organs, reaching a maximum at 30 minutes. The excretory organs (liver and kidney) and the small intestine showed high concentrations of radioactivity, whereas relatively low concentrations were found in other organs, including the brain.

There have been no formal pharmacokinetic studies in patients with compromised hepatic and/or renal function, though Altretamine capsules has been administered both concurrently and following nephrotoxic drugs such as cisplatin.

Altretamine capsules has been administered in 4 divided doses, with meals and at bedtime, though there is no pharmacokinetic data on this schedule nor information from formal interaction studies about the effect of food on its bioavailability or pharmacokinetics.

In two studies in patients with persistent or recurrent ovarian cancer following first-line treatment with cisplatin and/or alkylating agent-based combinations, Altretamine capsules was administered as a single agent for 14 or 21 days of a 28 day cycle. In the 51 patients with measurable or evaluable disease, there were 6 clinical complete responses, 1 pathologic complete response, and 2 partial responses for an overall response rate of 18%. The duration of these responses ranged from 2 months in a patient with a palpable pelvic mass to 36 months in a patient who achieved a pathologic complete response. In some patients, tumor regression was associated with improvement in symptoms and performance status.

INDICATIONS and USAGE

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.

CONTRAINDICATIONS

Altretamine capsules is contraindicated in patients who have shown hypersensitivity to it. Altretamine capsules should not be employed in patients with preexisting severe bone marrow depression or severe neurologic toxicity. Altretamine capsules has been administered safely, however, to patients heavily pretreated with cisplatin and/or alkylating agents, including patients with preexisting cisplatin neuropathies. Careful monitoring of neurologic function in these patients is essential.

WARNINGS

Concurrent administration of Altretamine capsules and antidepressants of the monoamine oxidase (MAO) inhibitor class may cause severe orthostatic hypotension. Four patients, all over 60 years of age, were reported to have experienced symptomatic hypotension after 4 to 7 days of concomitant therapy with Altretamine capsules and MAO inhibitors.

Altretamine capsules causes mild to moderate myelosuppression and neurotoxicity. Blood counts and a neurologic examination should be performed prior to the initiation of each course of therapy and the dose of Altretamine capsules adjusted as clinically indicated.

Altretamine capsules has been shown to be embryotoxic and teratogenic in rats and rabbits when given at doses 2 and 10 times the human dose. Altretamine capsules may cause fetal damage when administered to a pregnant woman. If Altretamine capsules is used during pregnancy, or if the patient becomes pregnant while taking the drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant.

PRECAUTIONS

Neurologic examination should be performed regularly.

Peripheral blood counts should be monitored at least monthly, prior to the initiation of each course of Altretamine capsules, and as clinically indicated.

Concurrent administration of Altretamine capsules and antidepressants of the MAO inhibitor class may cause severe orthostatic hypotension. Cimetidine, an inhibitor of microsomal drug metabolism, increased altretamine's half-life and toxicity in a rat model.

Data from a randomized trial of 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 Altretamine capsules and/or cisplatin (1).

The carcinogenic potential of Altretamine capsules has not been studied in animals, but drugs with similar mechanisms of action have been shown to be carcinogenic. Altretamine capsules was weakly mutagenic when tested in strain TA100 of Salmonella typhimurium. Altretamine capsules administered to female rats 14 days prior to breeding through the gestation period had no adverse effect on fertility, but decreased post-natal survival at 120 mg/m2/day and was embryocidal at 240 mg/m2/day. Administration of 120 mg/m2/day Altretamine capsules to male rats for 60 days prior to mating resulted in testicular atrophy, reduced fertility and a possible dominant lethal mutagenic effect. Male rats treated with Altretamine capsules at 450 mg/m2/day for 10 days had decreased spermatogenesis, atrophy of testes, seminal vesicles and ventral prostate.

Pregnancy Category D:

It is not known whether altretamine is excreted in human milk. Because there is a possibility of toxicity in nursing infants secondary to Altretamine capsules treatment of the mother, it is recommended that breast feeding be discontinued if the mother is treated with Altretamine capsules.

The safety and effectiveness of Altretamine capsules in children have not been established.

ADVERSE REACTIONS

With continuous high-dose daily 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 Altretamine capsules dose reduction or, rarely, discontinuation of 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 Altretamine capsules. In 2 clinical studies of single-agent Altretamine capsules utilizing a moderate, intermittent dose and schedule, only 1 patient (1%) discontinued Altretamine capsules due to severe nausea and vomiting.

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 Altretamine (altretamine) capsules than moderate-dose 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 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 Altretamine capsules and/or cisplatin (1).

Altretamine capsules causes mild to moderate dose-related myelosuppression. Leukopenia below 3000 WBC/mm3 occurred 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/mm3 was 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 Altretamine capsules. In one study, Altretamine capsules, 260 mg/m2/day, was administered for 14 days of a 28 day cycle. In another study, Altretamine capsules, 6-8 mg/kg/day, was administered for 21 days of a 28 day cycle.

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.

OVERDOSAGE

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.

DOSAGE AND ADMINISTRATION

Altretamine capsules is administered orally. Doses are calculated on the basis of body surface area.

Altretamine capsules may be administered either for 14 or 21 consecutive days in a 28 day cycle at a dose of 260 mg/m2/day. The total daily dose should be given as 4 divided oral doses after meals and at bedtime. There is no pharmacokinetic information supporting this dosing regimen and the effect of food on Altretamine capsules bioavailability or pharmacokinetics has not been evaluated.

Altretamine capsules should be temporarily discontinued (for 14 days or longer) and subsequently restarted at 200 mg/m2/day for any of the following situations:
  1) Gastrointestinal intolerance unresponsive to symptomatic measures;
  2) White blood count <2000/mm3 or granulocyte count <1000/mm3;
  3) Platelet count <75,000/mm3;
  4) Progressive neurotoxicity.

If neurologic symptoms fail to stabilize on the reduced dose schedule, Altretamine capsules should be discontinued indefinitely.

Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published (2-9). There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.

HOW SUPPLIED

Altretamine (altretamine) capsules is available in 50 mg clear, hard gelatin capsules imprinted with the following inscription:
USB 001.

Bottles of 100 capsules
(NDC 0000-000-00)

Store up to 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F).