IFEX AND MESNEX
-
ifosfamide and mesna
IFEX
-
ifosfamide injection, powder, for solution
E.R. Squibb & Sons, L.L.C.
----------
IFEX®
(ifosfamide for injection)
WARNING
IFEX should be administered under the supervision of a qualified
physician experienced in the use of cancer chemotherapeutic agents. Urotoxic
side effects, especially hemorrhagic cystitis, as well as CNS toxicities such
as confusion and coma have been associated with the use of IFEX. When they
occur, they may require cessation of IFEX therapy. Severe myelosuppression
has been reported. (See ADVERSE REACTIONS section.)
DESCRIPTION
IFEX® (ifosfamide for injection) single-dose
vials for constitution and administration by intravenous infusion each contain
1 gram or 3 grams of sterile ifosfamide. Ifosfamide is a chemotherapeutic
agent chemically related to the nitrogen mustards and a synthetic analog of
cyclophosphamide. Ifosfamide is 3-(2-chloroethyl)-2-[(2-chloroethyl)amino]tetrahydro-2H-1,3,2-oxazaphosphorine
2-oxide. The molecular formula is C7H15Cl2N2O2P and its molecular weight is 261.1. Its structural formula
is:
Ifosfamide is a white crystalline powder that is soluble in water.
CLINICAL PHARMACOLOGY
Ifosfamide has been shown to require metabolic activation by microsomal
liver enzymes to produce biologically active metabolites. Activation occurs
by hydroxylation at the ring carbon atom 4 to form the unstable intermediate
4-hydroxyifosfamide. This metabolite rapidly degrades to the stable urinary
metabolite 4-ketoifosfamide. Opening of the ring results in formation of the
stable urinary metabolite, 4-carboxyifosfamide. These urinary metabolites
have not been found to be cytotoxic. N, N-bis (2-chloroethyl)-phosphoric
acid diamide (ifosphoramide) and acrolein are also found. Enzymatic oxidation
of the chloroethyl side chains and subsequent dealkylation produces the major
urinary metabolites, dechloroethyl ifosfamide and dechloroethyl cyclophosphamide.
The alkylated metabolites of ifosfamide have been shown to interact with DNA.
In vitro incubation of DNA with activated ifosfamide
has produced phosphotriesters. The treatment of intact cell nuclei may also
result in the formation of DNA-DNA cross-links. DNA repair most likely occurs
in G-1 and G-2 stage cells.
Pharmacokinetics
Ifosfamide exhibits dose-dependent pharmacokinetics in humans.
At single doses of 3.8-5.0 g/m2,
the plasma concentrations decay biphasically and the mean terminal elimination
half-life is about 15 hours. At doses of 1.6-2.4 g/m2/day,
the plasma decay is monoexponential and the terminal elimination half-life
is about 7 hours. Ifosfamide is extensively metabolized in humans and the
metabolic pathways appear to be saturated at high doses.
After administration of doses of 5 g/m2 of 14C-labeled
ifosfamide, from 70% to 86% of the dosed radioactivity was recovered in the
urine, with about 61% of the dose excreted as parent compound. At doses of
1.6-2.4 g/m2 only 12% to 18% of the dose was excreted
in the urine as unchanged drug within 72 hours.
Two different dechloroethylated derivatives of ifosfamide, 4-carboxyifosfamide,
thiodiacetic acid and cysteine conjugates of chloroacetic acid have been identified
as the major urinary metabolites of ifosfamide in humans and only small amounts
of 4-hydroxyifosfamide and acrolein are present. Small quantities (nmole/mL)
of ifosfamide mustard and 4-hydroxyifosfamide are detectable in human plasma.
Metabolism of ifosfamide is required for the generation of the biologically
active species and while metabolism is extensive, it is also quite variable
among patients.
In a study at Indiana University, 50 fully evaluable patients with
germ cell testicular cancer were treated with IFEX in combination with cisplatin
and either vinblastine or etoposide after failing (47 of 50 patients) at least
two prior chemotherapy regimens consisting of cisplatin/vinblastine/bleomycin,
(PVB), cisplatin/vinblastine/actinomycin D/bleomycin/cyclophosphamide, (VAB6),
or the combination of cisplatin and etoposide. Patients were selected for
remaining cisplatin sensitivity because they had previously responded to a
cisplatin containing regimen and had not progressed while on the cisplatin
containing regimen or within 3 weeks of stopping it. Patients served as their
own control based on the premise that long term complete responses could not
be achieved by retreatment with a regimen to which they had previously responded
and subsequently relapsed.
Ten of 50 fully evaluable patients were still alive 2 to 5 years
after treatment. Four of the 10 long term survivors were rendered free of
cancer by surgical resection after treatment with the ifosfamide regimen;
median survival for the entire group of 50 fully evaluable patients was 53
weeks.
INDICATION AND USAGE
IFEX, used in combination with certain other approved antineoplastic
agents, is indicated for third line chemotherapy of germ cell testicular cancer.
It should ordinarily be used in combination with a prophylactic agent for
hemorrhagic cystitis, such as mesna.
CONTRAINDICATIONS
Continued use of IFEX is contraindicated in patients with severely
depressed bone marrow function (see WARNINGS and PRECAUTIONS sections). IFEX is also contraindicated
in patients who have demonstrated a previous hypersensitivity to it.
WARNINGS
Urinary System
Urotoxic side effects, especially hemorrhagic cystitis, have been
frequently associated with the use of IFEX. It is recommended that a urinalysis
should be obtained prior to each dose of IFEX. If microscopic hematuria (greater
than 10 RBCs per high power field), is present, then subsequent administration
should be withheld until complete resolution.
Further administration of IFEX should be given with vigorous oral
or parenteral hydration.
Hematopoietic System
When IFEX is given in combination with other chemotherapeutic agents,
severe myelosuppression is frequently observed. Close hematologic monitoring
is recommended. White blood cell (WBC) count, platelet count and hemoglobin
should be obtained prior to each administration and at appropriate intervals.
Unless clinically essential, IFEX should not be given to patients with a WBC
count below 2000/µL and/or a platelet count below 50,000/µL.
Central Nervous System
Neurologic manifestations consisting of somnolence, confusion,
hallucinations and in some instances, coma, have been reported following IFEX
therapy. The occurrence of these symptoms requires discontinuing IFEX therapy.
The symptoms have usually been reversible and supportive therapy should be
maintained until their complete resolution.
Pregnancy
Animal studies indicate that the drug is capable of causing gene
mutations and chromosomal damage in vivo. Embryotoxic and
teratogenic effects have been observed in mice, rats and rabbits at doses
0.05 to 0.075 times the human dose. Ifosfamide can cause fetal damage when
administered to a pregnant woman. If IFEX is used during pregnancy, or if
the patient becomes pregnant while taking this drug, the patient should be
apprised of the potential hazard to the fetus.
PRECAUTIONS
General
IFEX should be given cautiously to patients with impaired renal
function as well as to those with compromised bone marrow reserve, as indicated
by: leukopenia, granulocytopenia, extensive bone marrow metastases, prior
radiation therapy, or prior therapy with other cytotoxic agents.
Laboratory Tests
During treatment, the patient’s hematologic profile (particularly
neutrophils and platelets) should be monitored regularly to determine the
degree of hematopoietic suppression. Urine should also be examined regularly
for red cells which may precede hemorrhagic cystitis.
Drug Interactions
The physician should be alert for possible combined drug actions,
desirable or undesirable, involving ifosfamide even though ifosfamide has
been used successfully concurrently with other drugs, including other cytotoxic
drugs.
Wound Healing
Ifosfamide may interfere with normal wound healing.
Pregnancy
Pregnancy “Category D.” (See WARNINGS section.)
Nursing Mothers
Ifosfamide is excreted in breast milk. Because of the potential
for serious adverse events and the tumorigenicity shown for ifosfamide in
animal studies, a decision should be made whether to discontinue nursing or
to discontinue the drug, taking into account the importance of the drug to
the mother.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Ifosfamide has been shown to be carcinogenic in rats, with female
rats showing a significant incidence of leiomyosarcomas and mammary fibroadenomas.
The mutagenic potential of ifosfamide has been documented in bacterial
systems in vitro and mammalian cells in vivo. In
vivo, ifosfamide has induced mutagenic effects in mice and Drosophila
melanogaster germ cells, and has induced a significant increase in
dominant lethal mutations in male mice as well as recessive sex-linked lethal
mutations in Drosophila.
In pregnant mice, resorptions increased and anomalies were present
at day 19 after 30 mg/m2 dose of ifosfamide was
administered on day 11 of gestation. Embryolethal effects were observed in
rats following the administration of 54 mg/m2 doses
of ifosfamide from the 6th through the 15th day of gestation and embryotoxic
effects were apparent after dams received 18 mg/m2 doses
over the same dosing period. Ifosfamide is embryotoxic to rabbits receiving
88 mg/m2/day doses from the 6th
through the 18th day after mating. The number of anomalies was also significantly
increased over the control group.
Pediatric Use
Safety and effectiveness in pediatric patients have not been established.
ADVERSE REACTIONS
In patients receiving IFEX as a single agent, the dose-limiting
toxicities are myelosuppression and urotoxicity. Dose fractionation, vigorous
hydration, and a protector such as mesna can significantly reduce the incidence
of hematuria, especially gross hematuria, associated with hemorrhagic cystitis.
At a dose of 1.2 g/m2 daily for 5 consecutive days,
leukopenia, when it occurs, is usually mild to moderate. Other significant
side effects include alopecia, nausea, vomiting, and central nervous system
toxicities.
| Adverse Reaction | *Incidence
(%) |
| *Based upon 2,070 patients from
the published literature in 30 single agent studies. |
| Alopecia | 83 |
| Nausea-Vomiting | 58 |
| Hematuria | 46 |
| Gross Hematuria | 12 |
| CNS Toxicity | 12 |
| Infection | 8 |
| Renal Impairment | 6 |
| Liver Dysfunction | 3 |
| Phlebitis | 2 |
| Fever | 1 |
| Allergic Reaction | <1 |
| Anorexia | <1 |
| Cardiotoxicity | <1 |
| Coagulopathy | <1 |
| Constipation | <1 |
| Dermatitis | <1 |
| Diarrhea | <1 |
| Fatigue | <1 |
| Hypertension | <1 |
| Hypotension | <1 |
| Malaise | <1 |
| Polyneuropathy | <1 |
| Pulmonary Symptoms | <1 |
| Salivation | <1 |
| Stomatitis | <1 |
Hematologic Toxicity
Myelosuppression was dose related and dose limiting. It consisted
mainly of leukopenia and, to a lesser extent, thrombocytopenia. A WBC count<3000/µL is expected in 50% of the patients treated with IFEX single agent
at doses of 1.2 g/m2 per day for 5 consecutive
days. At this dose level, thrombocytopenia (platelets <100,000/µL) occurred
in about 20% of the patients. At higher dosages, leukopenia was almost universal,
and at total dosages of 10-12 g/m2/cycle, one half
of the patients had a WBC count below 1000/µL and 8% of patients had platelet
counts less than 50,000/µL. Myelosuppression was usually reversible and treatment
can be given every 3 to 4 weeks. When IFEX is used in combination with other
myelosuppressive agents, adjustments in dosing may be necessary. Patients
who experience severe myelosuppression are potentially at increased risk for
infection. Anemia has been reported as part of postmarketing surveillance.
Digestive System
Nausea and vomiting occurred in 58% of the patients who received
IFEX. They were usually controlled by standard antiemetic therapy. Other gastrointestinal
side effects include anorexia, diarrhea, and in some cases, constipation.
Urinary System
Urotoxicity consisted of hemorrhagic cystitis, dysuria, urinary
frequency and other symptoms of bladder irritation. Hematuria occurred in
6% to 92% of patients treated with IFEX. The incidence and severity of hematuria
can be significantly reduced by using vigorous hydration, a fractionated dose
schedule and a protector such as mesna. At daily doses of 1.2 g/m2 for
5 consecutive days without a protector, microscopic hematuria is expected
in about one half of the patients and gross hematuria in about 8% of patients.
Renal toxicity occurred in 6% of the patients treated with ifosfamide
as a single agent. Clinical signs, such as elevation in BUN or serum creatinine
or decrease in creatinine clearance, were usually transient. They were most
likely to be related to tubular damage. One episode of renal tubular acidosis
which progressed into chronic renal failure was reported. Proteinuria and
acidosis also occurred in rare instances. Metabolic acidosis was reported
in 31% of patients in one study when IFEX was administered at doses of 2.0
to 2.5 g/m2/day for 4 days. Renal tubular acidosis,
Fanconi syndrome, renal rickets, and acute renal failure have been reported.
Close clinical monitoring of serum and urine chemistries including phosphorus,
potassium, alkaline phosphatase and other appropriate laboratory studies is
recommended. Appropriate replacement therapy should be administered as indicated.
Central Nervous System
CNS side effects were observed in 12% of patients treated with
IFEX. Those most commonly seen were somnolence, confusion, depressive psychosis,
and hallucinations. Other less frequent symptoms include dizziness, disorientation,
and cranial nerve dysfunction. Seizures and coma with death were occasionally
reported. The incidence of CNS toxicity may be higher in patients with altered
renal function.
Other
Alopecia occurred in approximately 83% of the patients treated
with IFEX as a single agent. In combination, this incidence may be as high
as 100%, depending on the other agents included in the chemotherapy regimen.
Increases in liver enzymes and/or bilirubin were noted in 3% of the patients.
Other less frequent side effects included phlebitis, pulmonary symptoms, fever
of unknown origin, allergic reactions, stomatitis, cardiotoxicity, and polyneuropathy.
OVERDOSAGE
No specific antidote for IFEX is known. Management of overdosage
would include general supportive measures to sustain the patient through any
period of toxicity that might occur.
DOSAGE AND ADMINISTRATION
IFEX should be administered intravenously at a dose of 1.2 g/m2 per
day for 5 consecutive days. Treatment is repeated every 3 weeks or after recovery
from hematologic toxicity (Platelets ≥100,000/µL, WBC ≥4,000/µL). In order
to prevent bladder toxicity, IFEX should be given with extensive hydration
consisting of at least 2 liters of oral or intravenous fluid per day. A protector,
such as mesna, should also be used to prevent hemorrhagic cystitis. IFEX should
be administered as a slow intravenous infusion lasting a minimum of 30 minutes.
Although IFEX has been administered to a small number of patients with compromised
hepatic and/or renal function, studies to establish optimal dose schedules
of IFEX in such patients have not been conducted.
Preparation for Intravenous Administration/Stability
Injections are prepared for parenteral use by adding Sterile
Water for Injection, USP, or Sterile Bacteriostatic Water
for Injection, USP (benzyl alcohol or parabens preserved), to the
vial and shaking to dissolve. Use the quantity of diluent shown below to constitute
the product:
| Dosage Strength | Quantity of Diluent | Final Concentration |
| 1 gram | 20 mL | 50 mg/mL |
| 3 grams | 60 mL | 50 mg/mL |
Solutions of ifosfamide may be diluted further to achieve concentrations
of 0.6 to 20 mg/mL in the following fluids:
5%
Dextrose Injection, USP
0.9%
Sodium Chloride Injection, USP
Lactated
Ringer’s Injection, USP
Sterile
Water for Injection, USP
Because essentially identical stability results were obtained for
Sterile Water admixtures as for the other admixtures (5% Dextrose Injection,
0.9% Sodium Chloride Injection, and Lactated Ringer’s Injection), the use
of large volume parenteral glass bottles, Viaflex bags or PAB™ bags
that contain intermediate concentrations or mixtures of excipients (eg, 2.5%
Dextrose Injection, 0.45% Sodium Chloride Injection, or 5% Dextrose and 0.9%
Sodium Chloride Injection) is also acceptable.
Constituted or constituted and further diluted solutions of IFEX
should be refrigerated and used within 24 hours.
Parenteral drug products should be inspected visually for particulate
matter and discoloration prior to administration.
HOW SUPPLIED
IFEX® (ifosfamide for injection) is
available in combination packages with the uroprotective agent Mesnex® (mesna)
injection or as single-dose vials as follows:
IFEX (ifosfamide for injection)/Mesnex (mesna) injection.
| NDC 0015-3556-26 | 5 × 1-gram Single-Dose Vial of
Ifex/3 × 1-gram Multidose Vial of Mesnex |
| NDC 0015-3554-27 | 10 × 1-gram Single-Dose
Vial of Ifex/10 × 1-gram Multidose Vial of Mesnex |
| NDC 0015-3564-15 | 2 × 3-gram Single-Dose Vial of
Ifex/6 × 1-gram Multidose Vial of Mesnex |
IFEX (ifosfamide for injection).
| NDC 0015-0556-05 | 1-gram Single-Dose
Vial |
| NDC 0015-0557-41 | 3-gram Single-Dose
Vial |
Store at controlled room temperature 20° C to 25°
C (68° F to 77° F).
Protect from temperatures above 30° C (86° F).
Procedures for proper handling and disposal of anticancer drugs
should be considered. Skin reactions associated with accidental exposure to
IFEX may occur. The use of gloves is recommended. If IFEX solution contacts
the skin or mucosa, immediately wash the skin thoroughly with soap and water
or rinse the mucosa with copious amounts of water. Several guidelines on this
subject have been published.1-7 There is no general
agreement that all of the procedures recommended in the guidelines are necessary
or appropriate.
References
- Recommendations for the Safe Handling of Parenteral Antineoplastic
Drugs. NIH Publication No. 83-2621. For sale by the Superintendent of Documents,
U.S. Government Printing Office, Washington, DC 20402.
- AMA Council Report. Guidelines for Handling Parenteral Antineoplastics.
JAMA 1985; 253 (11):1590-1592.
- National Study Commission on Cytotoxic Exposure-Recommendations
for Handling Cytotoxic Agents. Available from Louis P. Jeffrey, Sc.D., Chairman,
National Study Commission on Cytotoxic Exposure, Massachusetts College of
Pharmacy and Allied Health Sciences, 179 Longwood Avenue, Boston, Massachusetts
02115.
- Clinical Oncological Society of Australia: Guidelines and Recommendations
for Safe Handling of Antineoplastic Agents. Med J Australia 1983;1:426-428.
- Jones, RB, et al: Safe Handling of Chemotherapeutic
Agents: A Report from the Mount Sinai Medical Center, CA-A Cancer Journal
for Clinicians 1983; (Sept./Oct.) 258-263.
- American Society of Hospital Pharmacists Technical Assistance Bulletin
on Handling Cytotoxic and Hazardous Drugs. Am J Hosp Pharm 1990;47:1033-1049.
- Controlling Occupational Exposure to Hazardous Drugs. (OSHA WORK-PRACTICE
GUIDELINES). Am J Health-Syst Pharm 1996; 53:1669-1685.
Manufactured by:
Baxter Healthcare
Corporation
Deerfield, IL 60015 USA
Distributed by:
Bristol-Myers Squibb Company
Princeton,
New Jersey 08543 USA
Made in Germany
1029940A5
USA 5663-7004 C
470
Rev Jul 2007
-----------------------------------------
REPRESENTATIVE PACKAGING
Not Applicable - No Longer Marketed
IFEX AND MESNEX
ifosfamide and mesna
kit |
|
|
|
|
|
|
| Part 1 of 2 |
IFEX
ifosfamide
injection, powder, for solution |
|
|
|
|
|
|
|
|
|
|
|
|
|
| Part 2 of 2 |
MESNEX
mesna
injection, solution |
|
|
|
|
|
|
|
|
|
|
|
|
|
IFEX AND MESNEX
ifosfamide and mesna
kit |
|
|
|
|
|
|
| Part 1 of 2 |
IFEX
ifosfamide
injection, powder, for solution |
|
|
|
|
|
|
|
|
|
|
|
|
|
| Part 2 of 2 |
MESNEX
mesna
injection, solution |
|
|
|
|
|
|
|
|
|
|
|
|
|
IFEX AND MESNEX
ifosfamide and mesna
kit |
|
|
|
|
|
|
| Part 1 of 2 |
IFEX
ifosfamide
injection, powder, for solution |
|
|
|
|
|
|
|
|
|
|
|
|
|
| Part 2 of 2 |
MESNEX
mesna
injection, solution |
|
|
|
|
|
|
|
|
|
|
|
|
|
IFEX
ifosfamide
injection, powder, for solution |
|
|
|
|
|
|
|
|
|
|
IFEX
ifosfamide
injection, powder, for solution |
|
|
|
|
|
|
|
|
|
|
Revised: 02/2008E.R. Squibb & Sons, L.L.C.
