Altretamine

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# Black Box Warning

# Overview
Altretamine is an alkylating agent that is FDA approved for the treatment of patients with persistent or recurrent ovarian cancer following first-line therapy with a cisplatin and/or alkylating agent-based combination.. There is a Black Box Warning for this drug as shown here.  Common adverse reactions include nausea, vomiting ,Peripheral neuropathy and central nervous system symptoms (mood disorders, disorders of consciousness, ataxia, dizziness, vertigo) and mild to moderate dose-related myelosuppression.

# Adult Indications and Dosage

## FDA-Labeled Indications and Dosage (Adult)
- 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.
- Altretamine is administered orally. Doses are calculated on the basis of body surface area.
- Altretamine 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 bioavailability or pharmacokinetics has not been evaluated.
- Altretamine should be temporarily discontinued (for 14 days or longer) and subsequently restarted at 200 mg/m2/day for any of the following situations:
- Gastrointestinal intolerance unresponsive to symptomatic measures;
- White blood count <2000/mm3 or granulocyte count <1000/mm3;
- Platelet count <75,000/mm3;
- Progressive neurotoxicity.
- If neurologic symptoms fail to stabilize on the reduced dose schedule, Altretamine 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.

## Off-Label Use and Dosage (Adult)

### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Altretamine in adult patients.

### NonGuideline-Supported Use
- Altretamine 260 milligrams (mg)/square meter/day (maximum daily dose 400 mg) in 4 divided doses after meals and at bedtime for 14 consecutive days of each 28-day cycle for 6 cycles
- Small cell lung cancer vary between 60 to 400 milligrams/square meter/day given for 5 to 21 days 

# Pediatric Indications and Dosage

## FDA-Labeled Indications and Dosage (Pediatric)
The safety and effectiveness of Altretamine in children have not been established.

## Off-Label Use and Dosage (Pediatric)

### Guideline-Supported Use
The safety and effectiveness of Altretamine in children have not been established.

### NonGuideline-Supported Use
The safety and effectiveness of Altretamine in children have not been established.

# Contraindications
- Altretamine is contraindicated in patients who have shown hypersensitivity to it.
- Altretamine should not be employed in patients with preexisting severe bone marrow depression or severe neurologic toxicity.
- Altretamine 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 and antidepressants of the monoamine oxidase inhibitor(MAO) 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 and MAO inhibitors.
- Altretamine 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 adjusted as clinically indicated

### Precautions
- Neurologic examination should be performed regularly

# Adverse Reactions

## Clinical Trials Experience
- With continuous high-dose daily Altretamine, 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 dose reduction or, rarely, discontinuation of Altretamine 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. In 2 clinical studies of single-agent Altretamine utilizing a moderate, intermittent dose and schedule, only 1 patient (1%) discontinued Altretamine 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 capsules than moderate-dose Altretamine administered on an intermittent schedule. Neurologic toxicity has been reported to be reversible when therapy is discontinued. Data from a randomized trial of Altretamine 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 and/or cisplatin.
- Altretamine 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. In one study, Altretamine, 260 mg/m2/day, was administered for 14 days of a 28 day cycle. In another study, Altretamine, 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.

## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Altretamine in the drug label.

# Drug Interactions
- Concurrent administration of Altretamine 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 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 and/or cisplatin .

# Use in Specific Populations

### Pregnancy
Pregnancy Category (FDA): D
- Altretamine has been shown to be embryotoxic and teratogenic in rats and rabbits when given at doses 2 and 10 times the human dose. Altretamine may cause fetal damage when administered to a pregnant woman. If Altretamine 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.
Pregnancy Category (AUS): 
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Altretamine in women who are pregnant.

### Labor and Delivery
There is no FDA guidance on use of Altretamine during labor and delivery.

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

### Pediatric Use
The safety and effectiveness of Altretamine in children have not been established.

### Geriatic Use
There is no FDA guidance on the use of Altretamine with respect to geriatric patients.

### Gender
There is no FDA guidance on the use of Altretamine with respect to specific gender populations.

### Race
There is no FDA guidance on the use of Altretamine with respect to specific racial populations.

### Renal Impairment
- There have been no formal pharmacokinetic studies in patients with compromised renal function, though Altretamine has been administered both concurrently and following nephrotoxic drugs such as cisplatin.

### Hepatic Impairment
- There have been no formal pharmacokinetic studies in patients with compromised hepatic function, though Altretamine has been administered both concurrently and following nephrotoxic drugs such as cisplatin.

### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Altretamine in women of reproductive potentials and males.

### Immunocompromised Patients
There is no FDA guidance one the use of Altretamine in patients who are immunocompromised.

# Administration and Monitoring

### Administration
- Oral

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

# IV Compatibility
There is limited information regarding IV Compatibility of Altretamine in the drug label.

# 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.

# Pharmacology

## Mechanism of Action
- The precise mechanism by which Altretamine exerts its cytotoxic effect is unknown, although a number of theoretical possibilities have been studied. Structurally, Altretamine resembles the alkylating agent triethylenemelamine, yet in vitro tests for alkylating activity of Altretamine and its metabolites have been negative. Altretamine 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.

## Structure
- Altretamine, is a synthetic cytotoxic antineoplastic s-triazine derivative. Altretamine 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 1C. Altretamine is practically insoluble in water but is increasingly soluble at pH 3 and below.

## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Altretamine in the drug label.

## Pharmacokinetics
- Altretamine 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 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 -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 Ndemethylated 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 has been administered both concurrently and following nephrotoxic drugs such as cisplatin.
- Altretamine 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 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.

## Nonclinical Toxicology
- The carcinogenic potential of Altretamine has not been studied in animals, but drugs with similar mechanisms of action have been shown to be carcinogenic. Altretamine was weakly mutagenic when tested in strain TA100 of Salmonella typhimurium. Altretamine 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 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 at 450 mg/m2/day for 10 days had decreased spermatogenesis, atrophy of testes, seminal vesicles and ventral prostate.

# Clinical Studies
There is limited information regarding Clinical Studies of Altretamine in the drug label.

# How Supplied
- HEXALEN (altretamine) capsules is available in 50 mg clear, hard gelatin capsules imprinted with the following inscription:
- USB 001.
- Bottles of 100 capsules
- (NDC 58063-001-70)

## Storage
- Store up to 25oC (77oF); excursions permitted to 15 to 30C (59 to 86F).

# Images

## Drug Images

## Package and Label Display Panel

# Patient Counseling Information
There is limited information regarding Patient Counseling Information of Altretamine in the drug label.

# Precautions with Alcohol
- Alcohol-Altretamine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

# Brand Names
- Hexalen 

# Look-Alike Drug Names
There is limited information regarding Altretamine Look-Alike Drug Names in the drug label.

# Drug Shortage Status

# Price