Altretamine

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product

Capsule, Oral:

Hexalen: 50 mg [DSC]

Pharmacology

Mechanism of Action

Altretamine structurally resembles alkylating agents, although has demonstrated activity in tumors resistant to classic alkylating agents. Cytotoxic effect not fully characterized, however it is likely that after activation, metabolites form crosslinks with DNA and RNA and inhibit DNA and RNA synthesis (Perry 2012). Altretamine has demonstrated more activity in platinum-sensitive ovarian cancers than platinum-resistant disease (Alberts 2004).

Pharmacokinetics/Pharmacodynamics

Absorption

Well absorbed

Distribution

Distributed into tissues high in lipid content and into tumor tissue (Damia 1995)

Metabolism

Hepatic; rapid and extensive demethylation to active metabolites (pentamethylmelamine and tetramethylmelamine)

Excretion

Urine (90% [at 72 hours], <1% as unchanged drug)

Time to Peak

Plasma: 0.5 to 3 hours

Half-Life Elimination

4.7 to 10.2 hours

Use: Labeled Indications

Ovarian cancer (persistent or recurrent): Palliative treatment (single agent) of persistent or recurrent ovarian cancer after first-line treatment with a cisplatin and/or alkylating agent-based combination.

Contraindications

Hypersensitivity to altretamine or any component of the formulation; preexisting severe bone marrow suppression or severe neurologic toxicity

Dosage and Administration

Dosing: Adult

Note: Hexalen has been discontinued in the United States for more than 1 year.

Note: Altretamine is associated with a high emetic potential; antiemetics are recommended to prevent nausea and vomiting (Hesketh 2017; Roila 2016)

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

Dosing: Geriatric

Refer to adult dosing.

Dosing: Adjustment for Toxicity

Temporarily withhold for 14 days or longer, and resume dose at 200 mg/m²/day for any of the following:

Platelet count <75,000/mm³

White blood cell count <2000/mm³ or granulocyte count <1000/mm³

Progressive neurotoxicity

Gastrointestinal intolerance not responsive to antiemetic regimens

Discontinue if neurotoxicity does not stabilize at 200 mg/m²/day.

Dosing: Obesity

ASCO Guidelines for appropriate chemotherapy dosing in obese adults with cancer: Utilize patient’s actual body weight (full weight) for calculation of body surface area- or weight-based dosing, particularly when the intent of therapy is curative; manage regimen-related toxicities in the same manner as for nonobese patients; if a dose reduction is utilized due to toxicity, consider resumption of full weight-based dosing with subsequent cycles, especially if cause of toxicity (eg, hepatic or renal impairment) is resolved (Griggs 2012).

Administration

Altretamine is associated with a high emetic potential; antiemetics are recommended to prevent nausea and vomiting (Dupuis 2011; Hesketh 2017; Roila 2016)

Administer total daily dose orally as 4 divided doses after meals and at bedtime.

Storage

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

Drug Interactions

Baricitinib: Immunosuppressants may enhance the immunosuppressive effect of Baricitinib. Management: Use of baricitinib in combination with potent immunosuppressants such as azathioprine or cyclosporine is not recommended. Concurrent use with antirheumatic doses of methotrexate or nonbiologic disease modifying antirheumatic drugs (DMARDs) is permitted. Consider therapy modification

BCG (Intravesical): Immunosuppressants may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

BCG (Intravesical): Myelosuppressive Agents may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

Chloramphenicol (Ophthalmic): May enhance the adverse/toxic effect of Myelosuppressive Agents. Monitor therapy

Cladribine: May enhance the immunosuppressive effect of Immunosuppressants. Avoid combination

Cladribine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Avoid combination

CloZAPine: Myelosuppressive Agents may enhance the adverse/toxic effect of CloZAPine. Specifically, the risk for neutropenia may be increased. Monitor therapy

Coccidioides immitis Skin Test: Immunosuppressants may diminish the diagnostic effect of Coccidioides immitis Skin Test. Monitor therapy

Deferiprone: Myelosuppressive Agents may enhance the neutropenic effect of Deferiprone. Management: Avoid the concomitant use of deferiprone and myelosuppressive agents whenever possible. If this combination cannot be avoided, monitor the absolute neutrophil count more closely. Consider therapy modification

Denosumab: May enhance the adverse/toxic effect of Immunosuppressants. Specifically, the risk for serious infections may be increased. Monitor therapy

Dipyrone: May enhance the adverse/toxic effect of Myelosuppressive Agents. Specifically, the risk for agranulocytosis and pancytopenia may be increased Avoid combination

Echinacea: May diminish the therapeutic effect of Immunosuppressants. Consider therapy modification

Fingolimod: Immunosuppressants may enhance the immunosuppressive effect of Fingolimod. Management: Avoid the concomitant use of fingolimod and other immunosuppressants when possible. If combined, monitor patients closely for additive immunosuppressant effects (eg, infections). Consider therapy modification

Leflunomide: Immunosuppressants may enhance the adverse/toxic effect of Leflunomide. Specifically, the risk for hematologic toxicity such as pancytopenia, agranulocytosis, and/or thrombocytopenia may be increased. Management: Consider not using a leflunomide loading dose in patients receiving other immunosuppressants. Patients receiving both leflunomide and another immunosuppressant should be monitored for bone marrow suppression at least monthly. Consider therapy modification

Lenograstim: Antineoplastic Agents may diminish the therapeutic effect of Lenograstim. Management: Avoid the use of lenograstim 24 hours before until 24 hours after the completion of myelosuppressive cytotoxic chemotherapy. Consider therapy modification

Lipegfilgrastim: Antineoplastic Agents may diminish the therapeutic effect of Lipegfilgrastim. Management: Avoid concomitant use of lipegfilgrastim and myelosuppressive cytotoxic chemotherapy. Lipegfilgrastim should be administered at least 24 hours after the completion of myelosuppressive cytotoxic chemotherapy. Consider therapy modification

Mesalamine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Monitor therapy

Monoamine Oxidase Inhibitors (Antidepressant): Altretamine may enhance the orthostatic hypotensive effect of Monoamine Oxidase Inhibitors (Antidepressant). Monitor therapy

Multivitamins/Fluoride (with ADE): May diminish the therapeutic effect of Altretamine. Specifically, vitamin B6 (pyridoxine) supplementation may diminish the response to altretamin/cisplatin treatment. Management: In spite of its beneficial effects on altretamine-associated neurotoxicity, the potential reduction in response duration may warrant consideration of not using multivitamins containing pyridoxine (vitamin B6) with an altretamine/cisplatin regimen. Consider therapy modification

Multivitamins/Minerals (with ADEK, Folate, Iron): May diminish the therapeutic effect of Altretamine. Management: Consider avoiding use of multivitamins that contain vitamin B6 in combination with altretamine. Consider therapy modification

Multivitamins/Minerals (with AE, No Iron): May diminish the therapeutic effect of Altretamine. Management: Consider avoiding use of multivitamins that contain vitamin B6 in combination with altretamine. Consider therapy modification

Natalizumab: Immunosuppressants may enhance the adverse/toxic effect of Natalizumab. Specifically, the risk of concurrent infection may be increased. Avoid combination

Nivolumab: Immunosuppressants may diminish the therapeutic effect of Nivolumab. Consider therapy modification

Ocrelizumab: May enhance the immunosuppressive effect of Immunosuppressants. Monitor therapy

Palifermin: May enhance the adverse/toxic effect of Antineoplastic Agents. Specifically, the duration and severity of oral mucositis may be increased. Management: Do not administer palifermin within 24 hours before, during infusion of, or within 24 hours after administration of myelotoxic chemotherapy. Consider therapy modification

Pidotimod: Immunosuppressants may diminish the therapeutic effect of Pidotimod. Monitor therapy

Pimecrolimus: May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

Promazine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Monitor therapy

Pyridoxine: May diminish the therapeutic effect of Altretamine. Specifically when altretamine is used in combination with Cisplatin the response duration may be diminished. Consider therapy modification

Roflumilast: May enhance the immunosuppressive effect of Immunosuppressants. Consider therapy modification

Siponimod: Immunosuppressants may enhance the immunosuppressive effect of Siponimod. Monitor therapy

Sipuleucel-T: Immunosuppressants may diminish the therapeutic effect of Sipuleucel-T. Management: Evaluate patients to see if it is medically appropriate to reduce or discontinue therapy with immunosuppressants prior to initiating sipuleucel-T therapy. Consider therapy modification

Smallpox and Monkeypox Vaccine (Live): Immunosuppressants may diminish the therapeutic effect of Smallpox and Monkeypox Vaccine (Live). Monitor therapy

Tacrolimus (Topical): May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

Tertomotide: Immunosuppressants may diminish the therapeutic effect of Tertomotide. Monitor therapy

Tofacitinib: Immunosuppressants may enhance the immunosuppressive effect of Tofacitinib. Management: Concurrent use with antirheumatic doses of methotrexate or nonbiologic disease modifying antirheumatic drugs (DMARDs) is permitted, and this warning seems particularly focused on more potent immunosuppressants. Consider therapy modification

Trastuzumab: May enhance the neutropenic effect of Immunosuppressants. Monitor therapy

Tricyclic Antidepressants: Altretamine may enhance the orthostatic hypotensive effect of Tricyclic Antidepressants. Monitor therapy

Upadacitinib: Immunosuppressants may enhance the immunosuppressive effect of Upadacitinib. Avoid combination

Vaccines (Inactivated): Immunosuppressants may diminish the therapeutic effect of Vaccines (Inactivated). Management: Vaccine efficacy may be reduced. Complete all age-appropriate vaccinations at least 2 weeks prior to starting an immunosuppressant. If vaccinated during immunosuppressant therapy, revaccinate at least 3 months after immunosuppressant discontinuation. Consider therapy modification

Vaccines (Live): Immunosuppressants may enhance the adverse/toxic effect of Vaccines (Live). Immunosuppressants may diminish the therapeutic effect of Vaccines (Live). Management: Avoid use of live organism vaccines with immunosuppressants; live-attenuated vaccines should not be given for at least 3 months after immunosuppressants. Exceptions: Smallpox and Monkeypox Vaccine (Live). Avoid combination

Adverse Reactions

>10%:

Central nervous system: Peripheral sensory neuropathy (31%; mild: 9%; moderate-to-severe: 9%)

Gastrointestinal: Nausea and vomiting (33%; severe 1%)

Hematologic & oncologic: Anemia (33%), leukopenia (5% to 15%, grade 4: <1%)

1% to 10%:

Central nervous system: Fatigue, seizure

Gastrointestinal: Anorexia

Hematologic & oncologic: Thrombocytopenia

Hepatic: Increased serum alkaline phosphatase

Renal: Increased blood urea nitrogen, increased serum creatinine

<1%, postmarketing, and/or case reports: Alopecia, ataxia, depression, dizziness, hepatotoxicity, mood disorder, neurotoxicity, pruritus, skin rash, vertigo

Warnings/Precautions

Concerns related to adverse effects:

• Bone marrow suppression: [US Boxed Warning]: Peripheral blood counts should be monitored at least monthly, prior to each cycle, and as clinically indicated. Mild to moderate dose-related hematological toxicity has been reported; may require dosage modification. With an intermittent dosing schedule, WBC and platelet nadirs occur at 3 to 4 weeks, with recovery by 6 weeks.
• Gastrointestinal toxicity: Altretamine is associated with a high emetic potential; antiemetics are recommended to prevent nausea and vomiting (Dupuis 2011; Hesketh 2017; Roila 2016).
• Neurotoxicity: [US Boxed Warning]: Due to the potential for altretamine-associated neurologic toxicity, neurologic examinations should be done regularly during altretamine treatment. Mild to moderate neurotoxicity, including peripheral neuropathy and CNS symptoms (ataxia, dizziness, vertigo, mood disorders, and disorders of consciousness) have been reported; may require dosage modification. Neurotoxicity is generally reversible upon discontinuation. Peripheral neuropathy and CNS symptoms are more common in patients receiving a continuous high-dose daily schedule (compared to an intermittent schedule). Altretamine has been administered safely in patients with preexisting cisplatin-associated neuropathy; close monitoring is required.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.
• MAO inhibitors: Concurrent use of altretamine and MAO inhibitors may cause severe orthostatic hypotension. Symptomatic orthostatic hypotension has been reported 4 to 7 days after concurrent administration.

Other warnings/precautions:

• Experienced physician: [US Boxed Warning]: Should be administered under the supervision of an experienced cancer chemotherapy physician.

Monitoring Parameters

CBC with differential (prior to treatment initiation, before each cycle, and regularly during treatment), neurologic examination (before each cycle and regularly during treatment). Monitor adherence.

Pregnancy

Pregnancy Considerations

Altretamine may cause fetal harm if administered during pregnancy. Women of childbearing potential should avoid becoming pregnant while on therapy.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)
• Have patient report immediately to prescriber signs of infection, signs of bleeding (vomiting blood or vomit that looks like coffee grounds; coughing up blood; blood in the urine; black, red, or tarry stools; bleeding from the gums; abnormal vaginal bleeding; bruises without a reason or that get bigger; or any severe or persistent bleeding), sore throat, shortness of breath, severe nausea, vomiting, severe loss of strength and energy, burning or numbness feeling, change in balance, mood changes, dizziness, or abnormal gait (HCAHPS).
• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.