Usage
Altretamine is an antineoplastic agent, specifically classified as an alkylating agent, primarily used in the palliative treatment of persistent or recurrent ovarian cancer after failure of first-line therapy with a cisplatin and/or alkylating agent-based combination. It is also sometimes employed to treat other types of cancers. Altretamine impedes cancer cell growth, ultimately leading to their destruction. This is achieved through the activation of metabolites which bind to and damage DNA, thus interfering with cell replication.
Alternate Names
Generic Name: Altretamine
Brand Name: Hexalen
Other Names: HMM (Hexamethylmelamine)
How It Works
Pharmacodynamics: Altretamine is an alkylating agent, which means it damages DNA by adding alkyl groups to it, hindering the ability of cancer cells to replicate. This DNA damage can lead to cell death.
Pharmacokinetics:
- Absorption: Altretamine is administered orally and is well-absorbed from the gastrointestinal tract. Taking it with food can help reduce gastrointestinal side effects, although food’s impact on bioavailability hasn’t been extensively studied.
- Metabolism: The drug undergoes rapid and extensive hepatic metabolism through N-demethylation by CYP enzymes in the liver. It’s these metabolites that are believed to be the active antineoplastic agents.
- Elimination: The precise elimination pathways haven’t been fully elucidated, but it is thought to be primarily eliminated via hepatic metabolism and subsequent excretion.
Mode of Action: Altretamine’s cytotoxic effect arises from its metabolites, formed through oxidative N-demethylation in the liver. These metabolites bind to DNA, causing damage and inhibiting replication. The exact mechanism of DNA binding isn’t entirely characterized, but it is a crucial aspect of its antineoplastic activity. No specific receptor binding, enzyme inhibition, or neurotransmitter modulation is known to be directly involved in altretamine’s anti-cancer action.
Dosage
Standard Dosage
Adults:
The standard dose of altretamine is 260 mg/m²/day, administered orally in four divided doses. It is typically given after meals and at bedtime for 14 or 21 consecutive days within a 28-day cycle. This cycle can be repeated up to 12 times.
Children:
The safety and efficacy of altretamine have not been established in pediatric patients.
Special Cases:
- Elderly Patients: While no specific dosage adjustments are indicated for the elderly, careful monitoring for adverse effects is crucial due to potential age-related decline in organ function.
- Patients with Renal Impairment: No specific dosage adjustments are described for patients with renal impairment. However, cautious use is recommended.
- Patients with Hepatic Dysfunction: No specific dosage adjustments are outlined for patients with hepatic dysfunction. Given that hepatic metabolism is essential for the activation of the drug, careful observation is warranted.
- Patients with Comorbid Conditions: Use with caution in patients with preexisting neurologic or hematologic conditions.
Clinical Use Cases
Altretamine’s clinical use is mainly restricted to ovarian cancer. It isn’t typically utilized in settings such as intubation, surgical procedures, mechanical ventilation, ICU use, or emergency situations.
Dosage Adjustments
Dose reduction to 200 mg/m²/day is required if the patient develops:
- Gastrointestinal intolerance unresponsive to symptomatic treatment
- White blood cell count < 2000/mm³ or granulocyte count < 1000/mm³
- Platelet count < 75,000/mm³
- Progressive neurotoxicity
Treatment should be temporarily discontinued (for 14 days or longer) before restarting at the reduced dose. If neurologic symptoms persist despite dose reduction, altretamine should be discontinued indefinitely.
Side Effects
Common Side Effects:
Nausea, vomiting, loss of appetite, peripheral neuropathy (numbness, tingling, pain in hands and feet), fatigue, dizziness, anemia, thrombocytopenia, leukopenia, rash, itching, hair loss, elevated liver enzymes.
Rare but Serious Side Effects:
Severe neurotoxicity (mood disorders, confusion, seizures, ataxia), severe myelosuppression (dangerously low blood cell counts), hepatotoxicity, allergic reactions.
Long-Term Effects:
Peripheral neuropathy can persist even after discontinuation of treatment.
Adverse Drug Reactions (ADR):
Severe orthostatic hypotension with concomitant MAOIs, especially in patients over 60.
Contraindications
- Hypersensitivity to altretamine
- Pre-existing severe bone marrow suppression
- Severe neurologic toxicity
Drug Interactions
- MAO Inhibitors: Can cause severe orthostatic hypotension.
- Cimetidine: Can affect the metabolism and clearance of altretamine.
- Pyridoxine (Vitamin B6): Can reduce the therapeutic efficacy of altretamine.
- Live vaccines: Should be avoided due to potential immunosuppression.
- Myelosuppressive agents: Increased risk of myelosuppression when used concurrently.
Many other drug interactions, both major and minor, have been documented with altretamine. A thorough medication review is necessary before initiating treatment.
Pregnancy and Breastfeeding
Altretamine is classified as Pregnancy Category D. It is contraindicated during pregnancy due to the risk of fetal harm. Effective contraception is essential for women of childbearing potential. Breastfeeding is not recommended as it is unknown if altretamine is excreted in breast milk.
Drug Profile Summary
- Mechanism of Action: Alkylating agent; metabolites bind to and damage DNA, inhibiting cell replication.
- Side Effects: Nausea, vomiting, peripheral neuropathy, myelosuppression, hepatotoxicity.
- Contraindications: Hypersensitivity, severe bone marrow suppression, severe neurologic toxicity.
- Drug Interactions: MAOIs, cimetidine, pyridoxine, live vaccines.
- Pregnancy & Breastfeeding: Contraindicated in pregnancy; not recommended during breastfeeding.
- Dosage: 260 mg/m²/day orally in 4 divided doses (after meals and bedtime) for 14 or 21 days of a 28-day cycle; dose reduction may be necessary based on toxicity.
- Monitoring Parameters: Complete blood count (CBC) with differential, liver function tests (LFTs), neurological examination.
Popular Combinations
Altretamine is typically used as a single agent for recurrent ovarian cancer.
Precautions
- Administer under the supervision of a physician experienced in cancer chemotherapy.
- Monitor blood counts regularly before and during treatment.
- Conduct neurological examinations routinely.
- Avoid pregnancy.
- Caution in patients with pre-existing neurologic or hematologic conditions.
- Pre-screening for allergies and organ dysfunction is essential.
FAQs (Frequently Asked Questions)
Q1: What is the recommended dosage for Altretamine?
A: 260 mg/m²/day orally in four divided doses, after meals and at bedtime for 14 or 21 consecutive days of a 28-day cycle. Dose reduction may be needed depending on the patient’s response and tolerance.
Q2: What are the most common side effects of Altretamine?
A: Nausea, vomiting, and peripheral neuropathy (numbness, tingling or pain in hands and feet) are the most frequently reported side effects.
Q3: Is Altretamine safe to use during pregnancy or breastfeeding?
A: No, Altretamine is contraindicated during pregnancy (Category D) and is not recommended during breastfeeding.
Q4: How does Altretamine work against cancer?
A: It’s an alkylating agent. Its metabolites damage cancer cell DNA, preventing replication and leading to cell death.
Q5: What are the contraindications for using Altretamine?
A: Hypersensitivity to the drug, pre-existing severe bone marrow suppression, and severe neurologic toxicity are absolute contraindications.
Q6: Are there any specific monitoring parameters for Altretamine?
A: Yes, regular monitoring of complete blood counts (CBC), liver function tests (LFTs), and neurological examinations is crucial.
Q7: What should be done if a patient experiences neurotoxicity while on Altretamine?
A: Dose reduction, or temporary discontinuation of the drug, is usually necessary. If symptoms persist, altretamine should be permanently discontinued.
Q8: What are the key drug interactions to be aware of with Altretamine?
A: MAO inhibitors, cimetidine, and pyridoxine can interact significantly with altretamine. Concomitant use of MAOIs can lead to severe orthostatic hypotension.
Q9: What is the pharmacological classification of Altretamine?
A: Altretamine is classified as an antineoplastic agent, specifically an alkylating agent.
Q10: Can Altretamine be used in pediatric patients?
A: No, the safety and efficacy of Altretamine have not been established in children.
