Hexalen

What preparations of altretamine are available?

Capsules of 50 mg.

How should I keep altretamine stored?

Capsules should be stored at room temperature, 15 C to 30 C (59 F to 86 F).

White blood cell counts and platelet counts may drop with altretamine treatment, increasing the risk of infection and bleeding, respectively.

Before taking altretamine, tell your doctor or pharmacist if you are allergic to it; or if you have any other allergies. This product may contain inactive ingredients, which can cause allergic reactions or other problems. Talk to your pharmacist for more details.Before using this medication, tell your doctor or pharmacist your medical history, especially of: kidney disease, liver disease, brain/nerve disorders, blood/bone marrow disorders (e.g., low levels of platelets/white blood cells/red blood cells).Do not have immunizations/vaccinations without the consent of your doctor, and avoid contact with people who have recently received oral polio vaccine or flu vaccine inhaled through the nose.To lower your risk of getting cut, bruised, or injured, use caution with sharp objects like razors and nail cutters, and avoid activities such as contact sports.Wash your hands well to prevent the spread of infections.This drug may make you dizzy. Do not drive, use machinery, or do any activity that requires alertness until you are sure you can perform such activities safely. Limit alcoholic beverages.This medication is not recommended for use during pregnancy. It may harm an unborn baby. Therefore, it is important to prevent pregnancy while taking this medication. Consult your doctor for more details and to discuss the use of reliable forms of birth control (e.g., condoms, birth control pills) while taking this medication. If you become pregnant or think you may be pregnant, tell your doctor immediately.It is not known whether this drug passes into breast milk. Because of the possible risk to the infant, breast-feeding while using this drug is not recommended. Consult your doctor before breast-feeding.

See BOXED WARNINGS.

Concurrent administration of HEXALEN® (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 HEXALEN® (altretamine) capsules and MAO inhibitors.

HEXALEN® (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 HEXALEN® (altretamine) capsules adjusted as clinically indicated (see DOSAGE AND ADMINISTRATION).

Pregnancy: Category D

HEXALEN® (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. HEXALEN® (altretamine) capsules may cause fetal damage when administered to a pregnant woman. If HEXALEN® (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.

• Store this medication at room temperature (between 59° to 86°F).
• Keep this and all medications out of the reach of children.

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

Altretamine is used to ease the symptoms of ovarian cancer. This medication will not treat the cancer itself.

Altretamine is usually given after other cancer medicines have been tried without success.

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

Altretamine is usually taken 4 times per day. Follow all directions on your prescription label. Do not take this medicine in larger or smaller amounts or for longer than recommended.

Altretamine is given in a 28-day treatment cycle, and you may only need to take the medicine during the first 2 or 3 weeks of each cycle. Your doctor will determine how long to treat you with altretamine.

Take altretamine after meals and at bedtime, unless your doctor tells you otherwise.

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. Your cancer treatments may be delayed based on the results of these tests.

Your nerve and muscle function may also need to be checked.

Store at room temperature away from moisture and heat.

Tell your doctor about all medicines you use, and those you start or stop using during your treatment with altretamine, especially:

• vitamin B6 (pyridoxine).

This list is not complete. Other drugs may interact with altretamine, including prescription and over-the-counter medicines, vitamins, and herbal products. Not all possible interactions are listed in this medication guide.

Contraindications

• Known hypersensitivity to altretamine.1

• Preexisting severe bone marrow depression.1 (See Hematologic Effects under Cautions.)

• Preexisting severe neurologic toxicity.1 (See Nervous System Effects under Cautions.)

Warnings/Precautions

Warnings

Nervous System Effects

Risk of dose-related neurotoxicity, manifested as peripheral neuropathy and CNS manifestations (e.g., mood disorders, disorders of consciousness, ataxia, dizziness, vertigo).1 Neurotoxicity may be reversible upon discontinuance of the drug.1 8

Perform neurologic examinations prior to the initiation of each course and regularly during therapy.1 If manifestations of neurotoxicity occur, discontinue therapy; dosage modification may be required.1 (See Dosage Modification for Toxicity under Dosage and Administration.)

Careful monitoring of neurologic function required during therapy in patients who have received previous treatment with cisplatin and/or alkylating agents, particularly in patients with preexisting cisplatin-induced neuropathies.1

Hematologic Effects

Risk of mild to moderate dose-related myelosuppression, including leukopenia, anemia, and thrombocytopenia.1 Perform peripheral blood cell counts at least monthly, prior to the initiation of each course of therapy, and as clinically indicated;1 dosage modification may be required.1 (See Dosage Modification for Toxicity under Dosage and Administration.)

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm;1 16 17 embryotoxic and teratogenic effects demonstrated in animals.1 Avoid pregnancy during therapy.1 If used during pregnancy or if patient becomes pregnant, apprise of potential fetal hazard.1

Major Toxicities

GI Effects

Risk of dose-related nausea and vomiting; reported frequently with continuous high-dose therapy.1 If required, administer antiemetic therapy; dose reduction or, rarely, discontinuance of therapy may be required for severe symptoms.1 (See Dosage Modification for Toxicity under Dosage and Administration.) Tolerance to GI symptoms may develop after several weeks of therapy.1

General Precautions

Carcinogenic Effects

Acute myeloid leukemia reported in one patient.20

Studies not performed to evaluate carcinogenic potential; drugs with similar mechanisms of action have been shown to be carcinogenic.1

Specific Populations

Pregnancy

Category D.1 (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Lactation

Not known if distributed into milk.1 Discontinue nursing because of potential risk to nursing infant.1

Pediatric Use

Safety and efficacy not established.1

Geriatric Use

Safety and efficacy in geriatric patients not studied.26

Common Adverse Effects

Nausea, vomiting, peripheral sensory neuropathy, leukopenia, thrombocytopenia, anemia, increased serum alkaline phosphatase, increased serum creatinine/BUN.1

Absorption

Bioavailability

Readily absorbed from GI tract, with peak plasma concentrations attained within 0.5–3 hours.1

Food

Food may delay and decrease extent of absorption.14

Distribution

Extent

Distributed into tissues with a high lipid component (e.g., omentum and subcutaneous tissue).2 3 19

Concentrations in primary tumor similar to plasma concentrations;27 concentrations higher in metastases than in primary tumor.27

Not known if distributed into milk.1

Plasma Protein Binding

Altretamine: 94%.1 19

Pentamethylmelamine and tetramethylmelamine: 75% and 50%, respectively.1 19

Elimination

Metabolism

Rapidly and extensively metabolized in the GI tract and liver;1 19 oxidative N-demethylation occurs to form active hydroxymethyl derivatives, principally pentamethylmelamine and tetramethylmelamine.1 2 3 19

Metabolism and activation also may occur in tumor cells or other extrahepatic sites.2 19

Elimination Route

Excreted in urine, mostly as metabolites.1 2 3 19

Half-life

Biphasic; terminal half-life is about 5–10 hours.1 2 19 23

Special Populations

Effect of hepatic and/or renal impairment on elimination not established.1

Ascites does not appear to alter pharmacokinetics.28

Gastrointestinal

With continuous high-dose daily Hexalen® 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® capsules dose reduction or, rarely, discontinuation of Hexalen® 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® capsules. In 2 clinical studies of single-agent Hexalen® capsules utilizing a moderate, intermittent dose and schedule, only 1 patient (1%) discontinued Hexalen® 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) capsules than moderate-dose Hexalen® 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® 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® capsules and/or cisplatin (1).

Hematologic

Hexalen® 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 Hexalen® capsules. In one study, Hexalen® capsules, 260 mg/m2/day, was administered for 14 days of a 28 day cycle. In another study, Hexalen® 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® CAPSULES

Adverse Experiences	% Patients
Gastrointestinal Nausea and Vomiting     Mild to Moderate     Severe Increased Alkaline Phosphatase	33            32      1 9
Neurologic Peripheral Sensory Neuropathy     Mild     Moderate to Severe Anorexia and Fatigue Seizures	31            22      9 1      1
Hematologic Leukopenia     WBC 2000-2999/mm3     WBC <2000/mm3 Thrombocytopenia     Platelets 75,000-99,000/mm3     Platelets <75,000/mm3 Anemia     Mild     Moderate to Severe	5           4      1 9           6      3 33            20        13
Renal Serum Creatinine 1.6-3.75 mg/dl BUN     25-40 mg%     41-60 mg%     >60 mg%	7      9           5      3      1

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.

Applies to altretamine: oral capsule

Hematologic

Very common (10% or more): Anemia (33%)
Common (1% to 10%): Thrombocytopenia, leukopenia[Ref]

Gastrointestinal

Very common (10% or more): Nausea and vomiting (33%)
Common (1% to 10%): Increased alkaline phosphatase[Ref]

Nervous system

Very common (10% or more): Peripheral sensory neuropathy (31%)
Common (1% to 10%): Seizures
Frequency not reported: CNS symptoms (mood disorders, disorders of consciousness, ataxia, dizziness, vertigo)[Ref]

Renal

Common (1% to 10%): Increased BUN, increased serum creatinine[Ref]

Metabolic

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

Other

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

Hepatic

Frequency not reported: Hepatic toxicity[Ref]

Dermatologic

Frequency not reported: Skin rash, pruritus, alopecia[Ref]

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