1. Clinical Overview
Amifostine is an organic thiophosphate prodrug and cytoprotective agent. It is a selective cytoprotectant for normal tissues against the toxicities of chemotherapy and radiation therapy, without compromising the anti-tumor efficacy. It is dephosphorylated by alkaline phosphatase to its active metabolite, WR-1065, which acts as a free radical scavenger and promotes cellular repair. In the Indian context, it is primarily used in oncology settings to reduce the incidence of cisplatin-induced nephrotoxicity and radiation-induced xerostomia.
| Onset | Duration | Bioavailability |
|---|---|---|
| Within minutes of intravenous infusion. | Cytoprotective effects are time-dependent and correspond to the pharmacokinetics of the active metabolite, with a protective window of several hours post-administration. | Approximately 100% following intravenous administration (the only approved route). Oral bioavailability is negligible. |
2. Mechanism of Action
Amifostine is a prodrug that is selectively taken up and activated in normal tissues due to higher capillary alkaline phosphatase activity, higher pH, and better vascularization compared to tumor tissues. It is dephosphorylated to the active free thiol metabolite, WR-1065. WR-1065 acts through two primary mechanisms: 1) Scavenging of free radicals generated by chemotherapy agents (e.g., cisplatin) or radiation therapy. 2) Donating a hydrogen atom to repair damaged DNA molecules in normal cells. This selective protection spares normal tissues (kidney, salivary glands, bone marrow) while tumor tissues, which typically have a more acidic and hypoxic environment with lower alkaline phosphatase activity, receive less protection.
3. Indications & Uses
- To reduce the incidence of moderate to severe xerostomia in patients undergoing post-operative radiation treatment for head and neck cancer, where the radiation port includes a substantial portion of the parotid glands.
- To reduce the cumulative renal toxicity associated with repeated administration of cisplatin in patients with advanced ovarian cancer or non-small cell lung cancer.
4. Dosage & Administration
Adult Dosage: For reduction of cisplatin nephrotoxicity: 910 mg/m² administered as a 15-minute IV infusion, starting 30 minutes before cisplatin-based chemotherapy. For reduction of radiation-induced xerostomia: 200 mg/m² administered as a 3-minute IV infusion, starting 30 minutes before standard fraction radiation therapy.
Administration: Reconstitute the 500mg vial with 9.7 mL of sterile 0.9% Sodium Chloride Injection to yield a concentration of 50 mg/mL. Further dilute in 0.9% Sodium Chloride to a total volume as per protocol (usually 50 mL). Administer as a controlled IV infusion over exactly 15 minutes (for 910 mg/m² dose) or 3 minutes (for 200 mg/m² dose). Patient must be in a supine position. Blood pressure must be monitored every 5 minutes during infusion and as needed after. IV hydration with normal saline may be given before and after infusion. Antiemetic premedication (e.g., dexamethasone 20 mg IV + a 5-HT3 antagonist) is mandatory 30-60 minutes before amifostine.
5. Side Effects
Common side effects may include:
- Transient hypotension (requiring interruption of infusion in ~30% of patients).
- Nausea and vomiting (frequent, severe without premedication).
- Flushing or feeling of warmth.
- Chills or dizziness.
- Sneezing, hiccups.
- Mild somnolence.
6. Drug Interactions
| Drug | Effect | Severity |
|---|---|---|
| Antihypertensive medications (e.g., ACE inhibitors, ARBs, Beta-blockers, Diuretics) | Potentiates hypotensive effect of Amifostine. Risk of severe hypotension. | Major |
| Cisplatin | Amifostine is used to protect against cisplatin's nephrotoxicity. Administer Amifostine 30 min BEFORE cisplatin. | Major (timing critical) |
| Chemotherapy agents (Cyclophosphamide, etc.) | Timing is critical to avoid interference with anti-tumor efficacy. Administer Amifostine before chemotherapy. | Moderate |
| Other drugs causing hypotension or bradycardia | Additive hypotensive effects. | Major |
7. Patient Counselling
- DO inform your doctor about all medications, especially blood pressure pills.
- DO lie down during the infusion and get up slowly afterwards.
- DO report any feeling of dizziness, nausea, or flushing immediately.
- DONT drive yourself home after the infusion.
- DONT skip the anti-sickness medicines given before the infusion.
8. Toxicology & Storage
Overdose: Exaggeration of known side effects: Severe, prolonged hypotension, nausea, vomiting, dizziness, loss of consciousness, and potentially seizures or apnea.
Storage: Store unopened vials at 20°C to 25°C (68°F to 77°F). Excursions permitted between 15°C to 30°C (59°F to 86°F). Protect from light. Reconstituted solution (50 mg/mL) is stable for up to 5 hours at room temperature (25°C) or up to 24 hours under refrigeration (2°C to 8°C). After further dilution in 0.9% NaCl, use within 5 hours at room temperature. Do not freeze.