Summary Of Exposure |
A) USES: Amifostine is indicated for protection against nephrotoxicity due to repeated cisplatin administration in patients with advanced ovarian cancer. It is also used to reduce the incidence of moderate to severe xerostomia in patients with head and neck cancer undergoing post-operative radiation treatment.
B) PHARMACOLOGY: Amifostine, an organic thiophosphate cytoprotective agent, is a prodrug that requires dephosphorylation in the tissues by alkaline phosphatase to an active thiol metabolite. This metabolite detoxifies the reactive metabolites of cisplatin and scavenges reactive oxygen species produced by radiation exposure or cisplatin.
C) EPIDEMIOLOGY: Exposure may occur.
D) WITH THERAPEUTIC USE
1) COMMON: Nausea, vomiting, and hypotension are the most commonly reported adverse effects with amifostine therapy.
2) INFREQUENT: Adverse effects reported less frequently include hypocalcemia, skin rashes (ie, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, exfoliative dermatitis), and acute allergic reactions, including anaphylaxis.
3) RARE: Dysrhythmias (ie, tachycardia, bradycardia, atrial fibrillation/flutter, supraventricular tachycardia), chest pain, myocardial infarction, syncope, cardiac arrest, seizures, respiratory insufficiency (ie, dyspnea, apnea, hypoxia, respiratory arrest), renal failure and loss of consciousness have been reported rarely in association with hypotension. Transient hypertension has also been rarely reported with amifostine therapy.
E) WITH POISONING/EXPOSURE
1) During clinical trials, the maximum single doses administered in adult and pediatric patients were 1300 mg/m(2) and 2700 mg/m(2), respectively. At these doses, anxiety and reversible urinary retention were reported. Hypotension is a dose-limiting toxicity and is likely to occur following overdose.
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Vital Signs |
3.3.1) SUMMARY
A) WITH THERAPEUTIC USE 1) Hypotension and fever have been reported with amifostine use.
3.3.3) TEMPERATURE
A) WITH THERAPEUTIC USE 1) FEVER has been observed during or after administration of amifostine during clinical trials (Prod Info amifostine intravenous injection lyophilized powder for solution, 2014).
3.3.4) BLOOD PRESSURE
A) WITH THERAPEUTIC USE 1) HYPOTENSION is a common occurrence with amifostine therapy (Prod Info amifostine intravenous injection lyophilized powder for solution, 2014).
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Cardiovascular |
3.5.2) CLINICAL EFFECTS
A) HYPOTENSIVE EPISODE 1) WITH THERAPEUTIC USE a) Transient hypotension (all grades) was reported in 61% of women with ovarian cancer who received amifostine 910 mg/m(2) prior to chemotherapy (n=122) in a randomized, phase 3 study; grade 3 or higher hypotension (that required interruption of infusion) occurred in 8% of patients. The mean time of hypotension onset was 14 minutes into the 15-minute IV infusion, and the mean duration was 6 minutes. The blood pressure (BP) usually returned to normal within 5 to 15 minutes. Discontinuation of amifostine infusion was required in less than 3% of patients (Prod Info amifostine intravenous injection lyophilized powder for solution, 2014).
b) Transient hypotension has been reported in 18 of 25 patients during a clinical trial of stage IV non-small cell lung cancer patients (Schuchter, 1996).
c) A dose-limiting adverse effect of IV amifostine is hypotension, usually manifested as a decrease in systolic BP of 20 mmHg or greater for at least 5 minutes (Glover et al, 1989; Glover et al, 1988). Hypotension was reported in 1% to 17% of treatment courses in cancer patients who received doses of 740 mg/m(2) infused over 15 minutes (Glover et al, 1989; Glover et al, 1988; Glover et al, 1987; Glover et al, 1986; Glover et al, 1986a; Turrisi et al, 1986), and in 4% to 27% of courses in patients who received 910 mg/m(2) infused over 15 minutes (Glover et al, 1989; Glover et al, 1988). Significantly higher incidences are observed with doses of 1100 and 1300 mg/m(2) (Glover et al, 1989).
d) Amifostine infusion rates of longer than 15 minutes have been associated with a higher incidence of hypotension in some studies (Glover et al, 1988; Turrisi et al, 1986).
B) SYNCOPE 1) WITH THERAPEUTIC USE a) Syncope has been rarely reported with amifostine use (Prod Info amifostine intravenous injection lyophilized powder for solution, 2014).
C) CONDUCTION DISORDER OF THE HEART 1) WITH THERAPEUTIC USE a) Dysrhythmias, such as atrial fibrillation or flutter and supraventricular tachycardia, have been reported with amifostine use. These dysrhythmias were sometimes associated with hypotension or allergic reactions Other cardiac effects that have been reported in association with hypotension include tachycardia, bradycardia, extrasystoles, chest pain, myocardial ischemia, myocardial infarction, and cardiac arrest (Prod Info amifostine intravenous injection lyophilized powder for solution, 2014).
D) HYPERTENSIVE DISORDER 1) WITH THERAPEUTIC USE a) Transient hypertension and exacerbation of preexisting hypertension have been observed after amifostine administration (Prod Info amifostine intravenous injection lyophilized powder for solution, 2014).
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Respiratory |
3.6.2) CLINICAL EFFECTS
A) SNEEZING 1) WITH THERAPEUTIC USE a) Sneezing has been reported during or after an amifostine infusion (Prod Info amifostine intravenous injection lyophilized powder for solution, 2014).
b) Episodic sneezing has been a relatively frequent adverse effect of amifostine infusion, occurring in 25% to 35% of courses with either 740 or 910 mg/m(2) over 15 minutes (Glover et al, 1988; Glover et al, 1987; Glover et al, 1986).
B) HICCOUGHS 1) WITH THERAPEUTIC USE a) Hiccups have been reported during or after an amifostine infusion (Prod Info amifostine intravenous injection lyophilized powder for solution, 2014).
C) RESPIRATORY INSUFFICIENCY 1) WITH THERAPEUTIC USE a) Dyspnea, apnea, hypoxia, and, in rare instances, respiratory arrest have been reported with amifostine use in association with the development of hypotension (Prod Info amifostine intravenous injection lyophilized powder for solution, 2014).
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Neurologic |
3.7.2) CLINICAL EFFECTS
A) DIZZINESS 1) WITH THERAPEUTIC USE a) Dizziness has been reported with amifostine administration (Prod Info amifostine intravenous injection lyophilized powder for solution, 2014).
B) DROWSY 1) WITH THERAPEUTIC USE a) Somnolence has been reported with amifostine use (Prod Info amifostine intravenous injection lyophilized powder for solution, 2014).
b) With 15-minute infusions of amifostine in cancer patients, mild drowsiness has occurred in 1% to 6% of courses with 740 mg/m(2) and 1% to 10% with 910 mg/m(2) (Glover et al, 1986a; Glover et al, 1988; Turrisi et al, 1986).
c) Drowsiness is usually short-lived, subsiding within 30 minutes following the infusion (Glover et al, 1986a).
d) The incidence of drowsiness appears to be higher with prolonged infusion rates of amifostine (longer than 15 minutes) (Turrisi et al, 1986).
C) SEIZURE 1) WITH THERAPEUTIC USE a) Seizures, associated with hypotension, have been rarely reported with amifostine use (Prod Info amifostine intravenous injection lyophilized powder for solution, 2014).
D) LOSS OF CONSCIOUSNESS 1) WITH THERAPEUTIC USE a) Reversible, short-term loss of consciousness associated with hypotension has been reported with amifostine use (Prod Info amifostine intravenous injection lyophilized powder for solution, 2014).
E) ANXIETY 1) WITH POISONING/EXPOSURE a) During clinical trials, the maximum single doses administered in adult and pediatric patients were 1300 mg/m(2) and 2700 mg/m(2), respectively. At these doses, anxiety and reversible urinary retention were reported (Prod Info amifostine intravenous injection lyophilized powder for solution, 2014).
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Gastrointestinal |
3.8.2) CLINICAL EFFECTS
A) NAUSEA AND VOMITING 1) WITH THERAPEUTIC USE a) Nausea and vomiting (all grades) was reported in 96% of women with ovarian cancer who received amifostine 910 mg/m(2) prior to chemotherapy (n=122) in a randomized, phase 3 study; grade 3 or higher nausea and vomiting was reported in 30% of women. Severe nausea or vomiting on day 1 of cyclophosphamide-cisplatin chemotherapy was 19% in patients who received amifostine compared with 10% in patients who did not receive amifostine (Prod Info amifostine intravenous injection lyophilized powder for solution, 2014; Schuchter, 1996; Spencer & Goa, 1995).
b) Nausea and vomiting are common, dose-related adverse effects of amifostine. The incidence of these complications has ranged from 19% to 58% with doses of 740 mg/m(2) or greater infused over 15 minutes (Glover et al, 1988; Turrisi et al, 1986; Glover et al, 1986; Glover et al, 1986a).
c) With doses of 910 mg/m(2) over 15 minutes, nausea and vomiting has occurred in 72% to 89% of courses (Glover et al, 1988).
d) There is evidence that infusion times of longer than 15 minutes are associated with higher incidences of nausea and vomiting, particularly in women (Turrisi et al, 1986).
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Genitourinary |
3.10.2) CLINICAL EFFECTS
A) RETENTION OF URINE 1) WITH POISONING/EXPOSURE a) During clinical trials, the maximum single doses administered in adult and pediatric patients were 1300 mg/m(2) and 2700 mg/m(2), respectively. At these doses, anxiety and reversible urinary retention were reported (Prod Info amifostine intravenous injection lyophilized powder for solution, 2014).
B) RENAL FAILURE SYNDROME 1) WITH THERAPEUTIC USE a) Renal failure, associated with hypotension, has been rarely reported with amifostine use (Prod Info amifostine intravenous injection lyophilized powder for solution, 2014).
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Dermatologic |
3.14.2) CLINICAL EFFECTS
A) ERUPTION 1) WITH THERAPEUTIC USE a) Serious, sometimes fatal skin reactions, including erythema multiforme, exfoliative dermatitis, toxic epidermal necrolysis, have occurred with amifostine. These serious reactions were reported to have a higher incidence in patients receiving amifostine as a radioprotectant than as a chemoprotectant. Serious cutaneous reactions may develop weeks after initiation of amifostine therapy (Prod Info amifostine intravenous injection lyophilized powder for solution, 2014).
B) STEVENS-JOHNSON SYNDROME 1) WITH THERAPEUTIC USE a) Stevens-Johnson syndrome has been reported with amifostine, and has occurred at a higher incidence in patients receiving amifostine as a radioprotectant, developing weeks after initiation of amifostine therapy, and may be fatal (Prod Info amifostine intravenous injection lyophilized powder for solution, 2014).
b) Stevens-Johnson syndrome (SJS; less than 10% body surface involvement) and Stevens-Johnson syndrome/toxic epidermal necrolysis overlap (SJS/TEN; cutaneous detachment between 10% and 30%) developed in 2 patients after 4 weeks of amifostine administration prior to radiotherapy treatments. A 66-year-old woman received IV amifostine 250 mg/m(2) prior to postoperative radiotherapy treatments for cancer of the tongue. Concomitant medications included metoclopramide, benzydamine, and sucralfate from the beginning of radiotherapy. A rash developed on the extremities at the end of the 4th week of radiotherapy and all medications except amifostine were discontinued. Three days later, the patient had generalized erythema over the whole body, bullous and targetoid cutaneous lesions, and oral and genital mucosal ulcerations. Amifostine was discontinued, a diagnosis of SJS/TEN was made, and the patient recovered after a 27-day hospitalization, during which she received prednisone, topical skin care, fluconazole (for oral candidiasis), and plasma (for low serum protein and albumin). A 60-year-old woman received IV amifostine 200 mg/m(2) prior to radiotherapy treatments for cervical lymph node metastasis from an unknown primary tumor. Metoclopramide and benzydamine were also started at the beginning of radiotherapy treatments. At the end of the fourth week of treatment, she developed malaise, nausea, vomiting, fever, large blisters, and detachments on the upper trunk and shoulders, erythematous macular lesions on the extremities, and oral mucosal involvement. A diagnosis of SJS was made, the patient was hospitalized and treated with prednisone, and was discharged, fully recovered, 2 weeks later (Atahan et al, 2000).
C) FLUSHING 1) WITH THERAPEUTIC USE a) Flushing or a feeling of warmth has been reported with amifostine injections (Prod Info amifostine intravenous injection lyophilized powder for solution, 2014).
b) A warm or flushed feeling occurring near the end of amifostine infusion has been reported in 27% to 40% of cancer patients (or courses) treated with 740 to 910 mg/m(2) over 15 minutes. The incidence has been similar with each dose (Glover et al, 1989; Glover et al, 1987; Glover et al, 1986; Glover et al, 1986a).
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Immunologic |
3.19.2) CLINICAL EFFECTS
A) ACUTE ALLERGIC REACTION 1) WITH THERAPEUTIC USE a) Allergic reactions, characterized by hypotension, fever, chills/rigor, dyspnea, hypoxia, chest tightness, cutaneous eruptions, pruritus, urticaria and laryngeal edema, have occurred during or after amifostine administration (Prod Info amifostine intravenous injection lyophilized powder for solution, 2014).
B) ANAPHYLACTOID REACTION 1) WITH THERAPEUTIC USE a) Anaphylactic reactions have occurred after amifostine administration (Prod Info amifostine intravenous injection lyophilized powder for solution, 2014).
b) CASE REPORT: A 51-year-old man with dermatomyositis and stage IV nasopharyngeal cancer receiving concurrent chemoradiotherapy experienced a severe anaphylactoid reaction to subQ amifostine. The patient was diagnosed with dermatomyositis following a 5-month period of symptoms, including myopathy and a photosensitive rash on the face, neck, and dorsum of the fingers. Subsequent evaluation produced a diagnosis of nasopharyngeal cancer and treatment was commenced with cisplatin and fluorouracil. Amifostine was administered subQ 30 minutes prior to radiotherapy at a dose of 200 mg/m(2) or 325 mg daily. Prednisone was administered for the dermatomyositis with mild improvement in symptoms. The patient experienced rigors, a fever of 40 degree C, and hypotension (blood pressure, 80/60 mmHg) following the eighth fraction of radiotherapy. An erythematous rash on the trunk and thighs was apparent following antibiotic therapy and radiotherapy. A drug reaction rash was suspected. Changing antibiotic therapy improved the condition. However, hypotension, fever, and rash reappeared after a subsequent radiotherapy. The patient deteriorated and required an intensive care transfer due to unresponsive hypotension, neck and facial swelling, and increasing shortness of breath associated with fluid overload. The patient's blood pressure stabilized following 2 days of adrenaline infusion and the rash improved over a 4-day period. The patient resumed radiotherapy without amifostine after 1 week (Vardy et al, 2002).
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Reproductive |
3.20.1) SUMMARY
A) Amifostine is classified as FDA pregnancy category C. Amifostine has been shown to be embryotoxic in rabbits.
3.20.3) EFFECTS IN PREGNANCY
A) PREGNANCY CATEGORY 1) Amifostine is rated FDA Pregnancy Category C (Prod Info amifostine intravenous injection, 2013).
2) Amifostine should only be used during pregnancy if the potential benefit justifies the potential risk to fetus (Prod Info amifostine intravenous injection, 2013).
B) ANIMAL STUDIES 1) RABBITS: Embryotoxicity was reported in rabbits administered 50 mg/kg doses (approximately 60% of the recommended dose in humans, based on body surface area) (Prod Info amifostine intravenous injection, 2013).
3.20.4) EFFECTS DURING BREAST-FEEDING
A) BREAST MILK 1) It is not known if amifostine is excreted into human breast milk. It is recommended that breast feeding be discontinued if the mother is treated with amifostine (Prod Info amifostine intravenous injection, 2013).
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Carcinogenicity |
3.21.4) ANIMAL STUDIES
A) LACK OF INFORMATION 1) No long-term animal studies have been performed to evaluate the carcinogenic potential of amifostine in humans.
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Genotoxicity |
A) Animal studies reported amifostine was negative for the Ames and mouse micronucleus testing. The free thiol metabolite was positive in the Ames test with S9 microsomal fraction in the TA1535 Salmonella Typhimurium strain and at the TK locus in a mouse L5178Y cell assay. The metabolite was negative in the mouse micronucleus test and negative for clastogenicity in human lymphocytes (Prod Info Ethyol(R), amifostine, 2000).
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