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Amifostine for Injection | AMIFOSTINE

04:55 EDT 27th August 2014 | BioPortfolio

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Amifostine for injection is an organic thiophosphate cytoprotective agent known chemically as 2-[(3-aminopropyl) amino] ethanethiol dihydrogen phosphate (ester) and has the following structural formula:

Amifostine is a white crystalline powder, which is freely soluble in water. Its molecular formula is CHNOPS and it has a molecular weight of 214.22. Amifostine for Injection is the trihydrate form of amifostine and is supplied as a sterile powder requiring reconstitution for intravenous infusion. Each single-use 10 mL vial contains 500 mg of amifostine on the anhydrous basis.

Clinical pharmacokinetic studies show that Amifostine is rapidly cleared from the plasma with a distribution half-life of <1 minute and an elimination half-life of approximately 8 minutes. Less than 10% of Amifostine remains in the plasma 6 minutes after drug administration. Amifostine is rapidly metabolized to an active free thiol metabolite. A disulfide metabolite is produced subsequently and is less active than the free thiol. After a 10-second bolus dose of 150 mg/m of Amifostine, renal excretion of the parent drug and its two metabolites was low during the hour following drug administration, averaging 0.69%, 2.64% and 2.22% of the administered dose for the parent, thiol and disulfide, respectively. Measurable levels of the free thiol metabolite have been found in bone marrow cells 5 to 8 minutes after intravenous infusion of Amifostine. Pretreatment with dexamethasone or metoclopramide has no effect on Amifostine pharmacokinetics.

Chemotherapy for Ovarian Cancer.

A randomized controlled trial compared six cycles of cyclophosphamide 1000 mg/m, and cisplatin 100 mg/m with or without Amifostine pretreatment at 910 mg/m, in two successive cohorts of 121 patients with advanced ovarian cancer. In both cohorts, after multiple cycles of chemotherapy, pretreatment withAmifostine significantly reduced the cumulative renal toxicity associated with cisplatin as assessed by the proportion of patients who had ≥ 40% decrease in creatinine clearance from pretreatment values, protracted elevations in serum creatinine (>1.5 mg/dL), or severe hypomagnesemia. Subgroup analyses suggested that the effect of Amifostine was present in patients who had received nephrotoxic antibiotics, or who had preexisting diabetes or hypertension (and thus may have been at increased risk for significant nephrotoxicity), as well as in patients who lacked these risks. Selected analyses of the effects of Amifostine in reducing the cumulative renal toxicity of cisplatin in the randomized ovarian cancer study are provided in TABLES 1 and 2, below.

In the randomized ovarian cancer study, Amifostine had no detectable effect on the antitumor efficacy of cisplatin-cyclophosphamide chemotherapy. Objective response rates (including pathologically confirmed complete remission rates), time to progression, and survival duration were all similar in the Amifostine and control study groups. The table below summarizes the principal efficacy findings of the randomized ovarian cancer study.

TABLE 1 Proportion of Patients with ≥40% Reduction in Calculated Creatinine ClearanceCreatinine clearance values were calculated using the Cockcroft-Gault formula, Nephron 1976; 16:31-41.
  Amifostine+CP CP p-value
(2-sided)
All Patients 16/122 (13%) 36/120 (30%) 0.001
First Cohort 10/63 20/58 0.018
Second Cohort 6/59 16/62 0.026
TABLE 2 NCI Toxicity Grades of Serum Magnesium Levels for Each Patient's Last Cycle of Therapy
NCI-CTC Grade:
(mEq/L)
  0    
>1.4
     1      
≤1.4 to >1.1
      2       
≤1.1 to >0.8
      3       
≤0.8 to >0.5
   4   
≤0.5
p-value Based on 2-sided Mantel-Haenszel Chi-Square statistic.
All Patients
   Amifostine+CP
   CP
92
73
13
18
3
7
0
5
0
1
0.001
First Cohort
   Amifostine+CP
   CP
49
35
10
8
3
6
0
3
0
1
 0.017
Second Cohort
   Amifostine+CP
   CP
43
38
3
10
0
1
0
2
0
0
0.012
TABLE 3 Comparison of Principal Efficacy Findings
      Amifostine +CP CP
Complete pathologic tumor response rate 21.3% 15.8%
Time to progression (months)
  Median (± 95% CI)  
15.8   (13.2, 25.1)  18.1  (12.5, 20.4)
  Mean (± Std error) 19.8   (±1.04) 19.1   (±1.58)
  Hazard ratio
   (95% Confidence Interval)
 .98 (.64, 1.4)
Survival (months)
  Median (± 95% CI) 
31.3  (28.3, 38.2) 31.8  (26.3, 39.8)
  Mean (± Std error) 33.7   (±2.03)  34.3  (±2.04)
  Hazard ratio
   (95% Confidence Interval)
 .97 (.69, 1.32)
TABLE 4 Incidence of Common Adverse Events in Patients Receiving Amifostine
  Phase III Ovarian Cancer
Trial (WR-1)
910 mg/m2 _____________________________
Per Patient           Per Infusion
Nausea/Vomiting
  ≥Grade 3
  All Grades
36/122 (30%)
117/122 (96%)
53/592 (9%)
520/592 (88%)
Hypotension
  ≥Grade 3According to protocol-defined criteria. WR-1: requiring interruption of infusion; WR-38: drop of >20mm Hg.
  All Grades
10/122 (8%)
75/122 (61%)
159/592 (27%)
Guideline for Interrupting Amifostine for injection Infusion Due to Decrease in Systolic Blood Pressure
Baseline Systolic Blood Pressure (mm Hg)
<100 100 to 119 120 to 139 140 to 179 ≥180
Decrease in systolic blood pressure during infusion of Amifostine for injection (mm Hg) 20 25 30 40 50

Amifostine for Injection USP is supplied as a sterile powder in 10 mL single-use vials (NDC 47335-581-40). Each single-use vial contains 500 mg of amifostine on the anhydrous basis. The vials are available packaged as follows:

1 pack - 1 vial per carton (NDC 47335-581-40).

3 pack - 3 vials per carton (NDC 47335-581-42).

Store the powder dosage form at Controlled Room Temperature 20°-25°C (68°-77°F) [See USP].

Distributed by: Caraco Pharmaceutical Laboratories, Ltd. 1150 Elijah McCoy Drive, Detroit, MI 48202 Manufactured by: Sun Pharmaceutical Ind. Ltd. Halol-Baroda Highway,Halol-389 350, Gujarat, India. ISS. 01/2011PJPI0327

NDC 47335-581-40Amifostine for Injection USP500 mg/vialSterileSingle use vialsFor Intravenous UseRx only

NDC 47335-581-40Amifostine for Injection USP500 mg/vialSterileSingle use vialsFor Intravenous Use1 VialRx onlySun Pharmaceutical Industries Ltd.

NDC 47335-581-42Amifostine for Injection USP500 mg/vialSterileSingle use vialsFor Intravenous Use3 VialsRx onlySun Pharmaceutical Industries Ltd.

Manufacturer

Sun Pharma Global FZE

Active Ingredients

Source

Clinical Trials [49 Associated Clinical Trials listed on BioPortfolio]

Determination of Amifostine Levels During Radiation Therapy

Currently, there are no published methods for easily determining the level of amifostine in the blood or saliva. A method has been developed within the Department of Radiation Oncology by ...

Subcutaneous Amifostine Safety Study

Amifostine is a radioprotective drug which is approved by the US FDA for administration prior to each radiation treatment using the intravenous route. The study evaluated the safety of am...

Amifostine in Treating Patients With Myelodysplastic Syndrome

RATIONALE: Amifostine may improve blood counts in patients with myelodysplastic syndrome. PURPOSE: Phase II trial to study the effectiveness of amifostine in treating patients with myelod...

Amifostine in Treating Patients With Advanced Myelodysplastic Syndrome

RATIONALE: Amifostine may be effective in helping blood counts return to normal in treating patients with myelodysplastic syndrome. PURPOSE: Phase II trial to study the effectiveness of a...

Combination Chemotherapy Plus Amifostine in Treating Patients With Advanced Cancer

RATIONALE: Drugs used in chemotherapy use different ways to stop tumors from dividing so they stop growing or die. Chemoprotective drugs, such as amifostine, may protect normal cells from ...

PubMed Articles [10 Associated PubMed Articles listed on BioPortfolio]

Cancer Incidence in C3H Mice Protected from Lethal Total-Body Radiation after Amifostine.

Amifostine is a potent antioxidant that protects against ionizing radiation effects. In this study, we evaluated the effect of Amifostine administered before total-body irradiation (TBI), at a drug do...

Evaluation of a method for measuring the radioprotective metabolite WR-1065 in plasma using chemical derivatization combined with UHPLC-MS/MS.

Hypotension is the dose-limiting side effect of the radio-protective drug Amifostine and results from relaxation of the vascular smooth muscle, which is directly mediated by the active metabolite, WR-...

Protective effects of amifostine, curcumin, and melatonin against cisplatin-induced acute kidney injury.

Despite the enormous advances made in the field of oncology, no solution to the side effect of nephrotoxicity caused by cisplatin used as an antineoplastic agent for approximately 40 years has yet be...

Final outcomes of escalated melphalan 280 mg/m with amifostine cytoprotection followed autologous hematopoietic stem cell transplantation for multiple myeloma: high CR and VGPR rates do not translate into improved survival.

The most common preparative regimen for autologous transplantation (ASCT) in myeloma (MM) consists of melphalan 200 mg/m (MEL 200). Higher doses of melphalan 220-260 mg/m, although relatively well...

Radio-protective dosimetry of Pangasius sutchi as a biomarker, against gamma radiation dosages perceived by genotoxic assays.

Exposure to ionizing radiation is harmful to any living organism. It may cause varying levels of genetic mutation or ultimately death. Synthetic compounds have been used to counteract the hazardous ef...

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