Ifosfamide
Dosage Form: injection
WARNING:
MYELOSUPPRESSION, NEUROTOXICITY, and UROTOXICITY
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WARNING:
MYELOSUPPRESSION, NEUROTOXICITY, AND UROTOXICITY
Myelosuppression can be severe
and lead to fatal infections. Monitor blood counts prior to and at
intervals after each treatment cycle. CNS toxicities can be severe and
result in encephalopathy and death. Monitor for CNS toxicity and discontinue
treatment for encephalopathy. Nephrotoxicity can be severe and result in
renal failure. Hemorrhagic cystitis can be severe and can be reduced by the
prophylactic use of mesna. [see Warnings and
Precautions (5.1 to 5.3) ]
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Indications and Usage for Ifosfamide
Ifosfamide Injection is
indicated for use in combination with certain other approved antineoplastic
agentsfor third-line chemotherapy of germ cell testicular cancer. It should be
used in combination with mesna for prophylaxis of hemorrhagic cystitis.
Ifosfamide Dosage and Administration
Ifosfamide Injection should be
administered intravenously at a dose of 1.2 grams per m2 per day for 5 consecutive
days. Treatment is repeated every 3 weeks or after recovery from hematologic
toxicity.
In order to prevent bladder
toxicity, Ifosfamide injection should be given with extensive hydration
consisting of at least 2 liters of oral or intravenous fluid per day. Mesna
should be used to reduce the incidence of hemorrhagic cystitis. Ifosfamide
injection should be administered as a slow intravenous infusion lasting a
minimum of 30 minutes. Studies of Ifosfamide injection in patients with hepatic
or renal impairment have not been conducted [see
Use in Specifi c Populations (8.6 , 8.7 )].
Preparation
for Intravenous Administration/Stability
Solutions of Ifosfamide
injection may be diluted further to achieve concentrations of 0.6 to 20 mg/mL
in the following fluids:
5% Dextrose Injection
0.9% Sodium Chloride Injection
Lactated Ringer’s Injections
Sterile Water for Injection
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 (e.g., 2.5% Dextrose Injection, 0.45% Sodium Chloride Injection, or
5% Dextrose and 0.9% Sodium Chloride Injection) is also acceptable.
Further diluted solutions of
Ifosfamide injection should be refrigerated and used within 24 hours. Benzyl
alcohol-containing solutions can reduce the stability of Ifosfamide injection.
Parenteral drug products
should be inspected visually for particulate matter and discoloration prior to
administration, whenever solution and container permit.
Dosage Forms and Strengths
1 g/20 mL single-dose vial
3 g/60 mL single-dose vial
Contraindications
Ifosfamide is contraindicated
in patients with:
• Known hypersensitivity to
administration of Ifosfamide.
• Urinary outflow obstruction.
Warnings and Precautions
Myelosuppression,
Immunosuppression, and Infections
Treatment with Ifosfamide may
cause myelosuppression and significant suppression of immune responses, which
can lead to severe infections. Fatal outcomes of Ifosfamide-associated
myelosuppression have been reported. Ifosfamide-induced myelosuppression can
cause leukopenia, neutropenia, thrombocytopenia (associated with a higher risk
of bleeding events), and anemia. The nadir of the leukocyte count tends to be
reached approximately during the second week after administration. When
Ifosfamide is given in combination with other chemotherapeutic/hematotoxic
agents and/or radiation therapy, severe myelosuppression is frequently
observed. The risk of myelosuppression is dose-dependent and is increased with
administration of a single high dose compared with fractionated administration.
The risk of myelosuppression is also increased in patients with reduced renal
function.
Severe immunosuppression has
led to serious, sometimes fatal, infections. Sepsis and septic shock also have
been reported. Infections reported with Ifosfamide include pneumonias, as well
as other bacterial, fungal, viral, and parasitic infections. Latent infections
can be reactivated. In patients treated with Ifosfamide, reactivation has been
reported for various viral infections. Infections must be treated
appropriately. Antimicrobial prophylaxis may be indicated in certain cases of
neutropenia at the discretion of the managing physician. In case of neutropenic
fever, antibiotics and/or antimycotics must be given. 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 after administration. Unless clinically essential, Ifosfamide should
not be given to patients with a WBC count below 2000/μL and/or a platelet count
below 50,000/μL.
Ifosfamide should be given
cautiously, if at all, to patients with presence of an infection, severe
immunosuppression or compromised bone marrow reserve, as indicated by
leukopenia, granulocytopenia, extensive bone marrow metastases, prior radiation
therapy, or prior therapy with other cytotoxic agents.
Central
Nervous System Toxicity, Neurotoxicity
Administration of Ifosfamide
can cause CNS toxicity and other neurotoxic effects. The risk of CNS toxicity
and other neurotoxic effects necessitates careful monitoring of the patient.
Neurologic manifestations consisting of somnolence, confusion, hallucinations,
blurred vision, psychotic behavior, extrapyramidal symptoms, urinary
incontinence, seizures, and in some instances, coma, have been reported
following Ifosfamide therapy. There have also been reports of peripheral
neuropathy associated with Ifosfamide use.
Ifosfamide neurotoxicity may
become manifest within a few hours to a few days after fi rst administration
and in most cases resolves within 48 to 72 hours of Ifosfamide discontinuation.
Symptoms may persist for longer periods of time. Supportive therapy should be
maintained until their complete resolution. Occasionally, recovery has been
incomplete. Fatal outcomes of CNS toxicity have been reported. Recurrence of
CNS toxicity after several uneventful treatment courses has been reported. If
encephalopathy develops, administration of Ifosfamide should be discontinued.
Due to the potential for
additive effects, drugs acting on the CNS (such as antiemetics, sedatives,
narcotics, or antihistamines) must be used with particular caution or, if
necessary, be discontinued in case of Ifosfamide-induced encephalopathy.
Manifestations of CNS toxicity
may impair a patient’s ability to operate an automobile or other heavy
machinery.
Renal and
Urothelial Toxicity and Effects
Ifosfamide is both nephrotoxic
and urotoxic. Glomerular and tubular kidney function must be evaluated before
commencement of therapy as well as during and after treatment. Monitor urinary
sediment regularly for the presence of erythrocytes and other signs of
uro/nephrotoxicity. Monitor serum and urine chemistries, including phosphorus
and potassium regularly. Administer appropriate replacement therapy as
indicated. Renal parenchymal and tubular necrosis have been reported in
patients treated with Ifosfamide. Acute tubular necrosis, acute renal failure,
and chronic renal failure secondary to Ifosfamide therapy have been reported,
and fatal outcome from nephrotoxicity has been documented.
Disorders of renal function,
(glomerular and tubular) following Ifosfamide administration are very common.
Manifestations include a decrease in glomerular filtration rate, increased
serum creatinine, proteinuria, enzymuria, cylindruria, aminoaciduria,
phosphaturia, and glycosuria as well as tubular acidosis. Fanconi syndrome,
renal rickets, and growth retardation in children as well as osteomalacia in
adults also have been reported. Development of a syndrome resembling SIADH
(syndrome of inappropriate antidiuretic hormone secretion) has been reported
with Ifosfamide.
Tubular damage may become
apparent during therapy, months or even years after cessation of treatment.
Glomerular or tubular dysfunction may resolve with time, remain stable, or
progress over a period of months or years, even after completion of Ifosfamide
treatment.
The risk and expected benefits
of Ifosfamide therapy should be carefully weighed when considering the use of
Ifosfamide in patients with preexisting renal impairment or reduced nephron
reserve.
Urotoxic side effects,
especially hemorrhagic cystitis, have been very commonly associated with the
use of Ifosfamide. These urotoxic effects can be reduced by prophylactic use of
mesna.
Hemorrhagic cystitis requiring
blood transfusion has been reported with Ifosfamide. The risk of hemorrhagic
cystitis is dose-dependent and increased with administration of single high
doses compared to fractionated administration. Hemorrhagic cystitis after a
single dose of Ifosfamide has been reported. Past or concomitant radiation of
the bladder or busulfan treatment may increase the risk for hemorrhagic
cystitis.
Before starting treatment, it
is necessary to exclude or correct any urinary tract obstructions [see Contraindications(4)].
During or immediately after
administration, adequate amounts of fluid should be ingested or infused to
force dieresis in order to reduce the risk of urinary tract toxicity. Obtain a
urinalysis prior to each dose of Ifosfamide. 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
Ifosfamide should be given with vigorous oral or parenteral hydration.
Ifosfamide should be used with
caution, if at all, in patients with active urinary tract infections.
Cardiotoxicity
Manifestations of
cardiotoxicity reported with Ifosfamide treatment include:
- Supraventricular or
ventricular arrhythmias, including atrial/supraventricular tachycardia, atrial
fibrillation, pulseless ventricular tachycardia
- Decreased QRS voltage and
ST-segment or T-wave changes
- Toxic cardiomyopathy leading
to heart failure with congestion and hypotension
- Pericardial effusion,
fibrinous pericarditis, and epicardial fibrosis
Fatal outcome of
Ifosfamide-associated cardiotoxicity has been reported.
The risk of developing
cardiotoxic effects is dose-dependent. It is increased in patients with prior
or concomitant treatment with other cardiotoxic agents or radiation of the
cardiac region and, possibly, renal impairment.
Particular caution should be
exercised when Ifosfamide is used in patients with risk factors for
cardiotoxicity and in patients with preexisting cardiac disease.
Pulmonary
Toxicity
Interstitial pneumonitis,
pulmonary fibrosis, and other forms of pulmonary toxicity have been reported
with Ifosfamide treatment. Pulmonary toxicity leading to respiratory failure as
well as fatal outcome has also been reported. Monitor for signs and symptoms of
pulmonary toxicity and treat as clinically indicated.
Secondary
Malignancies
Treatment with Ifosfamide
involves the risk of secondary tumors and their precursors as late sequelae.
The risk of myelodysplastic alterations, some progressing to acute leukemias,
is increased. Other malignancies reported after use of Ifosfamide or regimens
with Ifosfamide include lymphoma, thyroid cancer, and sarcomas.
The secondary malignancy may
develop several years after chemotherapy has been discontinued.
Veno-occlusive
Liver Disease
Veno-occlusive liver disease
has been reported with chemotherapy that included Ifosfamide.
Pregnancy
Ifosfamide can cause fetal
harm when administered to a pregnant woman. Fetal growth retardation and
neonatal anemia have been reported following exposure to Ifosfamide-containing
chemotherapy regimens during pregnancy. Ifosfamide is genotoxic and mutagenic
in male and female germ cells. Embryotoxic and teratogenic effects have been
observed in mice, rats and rabbits at doses 0.05 to 0.075 times the human dose.
Women should not become
pregnant and men should not father a child during therapy with Ifosfamide.
Further, men should not father a child for up to 6 months after the end of
therapy. If this drug is used during pregnancy, or if the patient becomes
pregnant while taking this drug or after treatment, the patient should be
apprised of the potential hazard to a fetus [see Use in
Specific Populations (8.1) ].
Effects on
Fertility
Ifosfamide interferes with
oogenesis and spermatogenesis. Amenorrhea, azoospermia, and sterility in both
sexes have been reported. Development of sterility appears to depend on the
dose of Ifosfamide, duration of therapy, and state of gonadal function at the
time of treatment. Sterility may be irreversible in some patients.
Female Patients
Amenorrhea has been reported
in patients treated with Ifosfamide. The risk of permanent chemotherapy-induced
amenorrhea increases with age. Pediatric patients treated with Ifosfamide
during prepubescence subsequently may not conceive and those who retain ovarian
function after completing treatment are at increased risk of developing
premature menopause.
Male Patients
Men treated with Ifosfamide
may develop oligospermia or azoospermia. Pediatric patients treated with
Ifosfamide during prepubescence might not develop secondary sexual characteristics
normally, but may have oligospermia or azoospermia. Azoospermia may be
reversible in some patients, though the reversibility may not occur for several
years after cessation of therapy. Sexual function and libido are generally
unimpaired in these patients. Some degree of testicular atrophy may occur.
Patients treated with Ifosfamide have subsequently fathered children.
Anaphylactic/Anaphylactoid
Reactions and Cross-sensitivity
Anaphylactic/anaphylactoid
reactions have been reported in association with Ifosfamide. Cross-sensitivity
between oxazaphosphorine cytotoxic agents has been reported.
Impairment of
Wound Healing
Ifosfamide may interfere with
normal wound healing.
Nursing
Ifosfamide is excreted in
breast milk. Women must not breastfeed during treatment with Ifosfamide [see Use in
Specific Populations (8.3) ].
Adverse Reactions
Adverse
Reactions from Clinical Trials
Because clinical trials are
conducted from widely varying conditions, adverse reaction rates observed in
the clinical trials of a drug cannot be directly compared to rates in the
clinical trials of another drug and may not reflect the rates observed in
clinical practice. The adverse reactions and frequencies below are based on 30
publications describing clinical experience with fractionated administration of
Ifosfamide as monotherapy with a total dose of 4 to 12 g/m2 per course.
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System Organ Class (SOC)
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Adverse Reaction
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Percentage (Ratio)
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INFECTIONS
AND INFESTATIONS
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Infection
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9.9%
(112/1128)
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BLOOD AND
LYMPHATIC SYSTEM DISORDERS
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Leukopenia1 (any)
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--1a
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Leukopenia
<1 x 103/µL
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43.5%
(267/614)
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Thrombocytopenia2 (any)
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--2a
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Thrombocytopenia
50 x 103/µL
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4.8%
(35/729)
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Anemia3
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37.9%
(202/533)
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METABOLISM
AND NUTRITION DISORDERS
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Anorexia
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1.1%
(15/1317)
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NERVOUS
SYSTEM DISORDERS
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Central
nervous system toxicity4,5
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15.4%
(154/1001)
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Peripheral
neuropathy
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0.4%
(5/1317)
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CARDIAC
DISORDERS
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Cardiotoxicity6
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0.5%
(7/1317)
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VASCULAR
DISORDERS
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Hypotention7
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0.3%
(4/1317)
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GASTROINTESTINAL
DISORDERS
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Nausea/Vomiting
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46.8%
(443/964)
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Diarrhea
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0.7%
(9/1317)
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Stomatitis
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0.3%
(4/1317)
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HEPATOBILIARY
DISORDERS
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Hepatotoxicity8
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1.8%
(22/1190)
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SKIN AND
SUBCUTANEOUS TISSUES DISORDERS
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Alopecia
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89.6%
(540/603)
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Dermatitis
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0.08%
(1/1317)
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Papular
rash
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0.08%
(1/1317)
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RENAL AND
URINARY DISORDERS
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Hemorrhagic
cystitis
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--9
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Hematuria
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- without
mesna
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44.1%
(282/640)
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- with
mesna
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21.3%
(33/155)
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Macrohematuria
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- without
mesna
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11.1%
(66/594)
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- with
mesna
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5.2%
(5/97)
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Renal
dysfunction10
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--
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Renal
structural damage
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--
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GENERAL
DISORDERS AND ADMINISTRATIVE SITE CONDITIONS
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Phlebitis11
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2.8%
(37/1317)
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Neutropenic
fever12
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1%
(13/1317)
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Fatigue
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0.3%
(4/1317)
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Malaise
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Unable to calculate
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1 The following adverse reaction terms have been reported
for leukopenia: neutropenia, granulocytopenia, lymphopenia, and pancytopenia.
For neutropenic fever, see below.
1a The frequency category of leukopenia is based on the
frequency of leukopenia <3 x 103/μL [42.5% (150/353) not shown in table] and <1 x 103/μL; a relevant percentage
ratio cannot be calculated for the pooled data and thus the conservative
frequency category of “Very common” was included in the table.
2 Thrombocytopenia may also be complicated by bleeding.
Bleeding with fatal outcome has been reported.
2a Frequency of thrombocytopenia is based on the frequency of
thrombocytopenia <100 x 103/μL [12.2% (24/196) not shown in table] and
<50 x 103/μL; a relevant percentage ratio cannot be calculated from the
pooled data and thus the conservative frequency of “Very common” was included
in the table.
3 Includes cases reported as anemia and decrease in
hemoglobin/hematocrit.
4 Encephalopathy with coma and death has been reported.
5 Central nervous system toxicity was reported to be
manifested by the following signs and symptoms: Abnormal behavior, Affect
lability Aggression, Agitation, Anxiety, Aphasia, Asthenia, Ataxia, Cerebellar
syndrome, Cerebral function defi ciency, Cognitive disorder, Coma, Confusional
state, Convulsions, Cranial nerve dysfunction, Depressed state of
consciousness, Depression, Disorientation, Dizziness, Electroencephalogram
abnormal, Encephalopathy, Flat affect. Hallucinations, Headache, Ideation,
Lethargy, Memory impairment, Mood change, Motor dysfunction, Muscle spasms,
Myoclonus, Progressive loss of brainstem reflexes, Psychotic reaction,
Restlessness, Somnolence, Tremor, Urinary incontinence.
6 Cardiotoxicity was reported as congestive heart failure,
tachycardia, pulmonary edema. Fatal outcome has been reported.
7 Hypotension leading to shock and fatal outcome has been
reported.
8 Hepatotoxicity was reported as increases in liver enzymes,
i.e., serum alanine aminotransferase, serum aspartate aminotransferase,
alkaline phosphatase, gamma-glutamyltransferase and lactate dehydrogenase,
increased bilirubin, jaundice, hepatorenal syndrome.
9 Frequency of hemorrhagic cystitis is estimated based on
the frequency of hematuria. Reported symptoms of hemorrhagic cystitis included
dysuria and pollakiuria. See also Post-marketing
Adverse Reactions (6.2).
10 Renal dysfunction was reported to be manifested as: Renal
failure (including acute renal failure, irreversible renal failure; fatal
outcomes have been reported), Serum creatinine increased, BUN increased,
Creatinine clearance decreased, Metabolic acidosis, Anuria, Oliguria,
Glycosuria, Hyponatremia, Uremia, Creatinine clearance increased. Renal
structural damage was reported to be manifested as: Acute tubular necrosis,
renal parenchymal damage, Enzymuria, Cylindruria, Proteinuria.
11 Includes cases reported as phlebitis and irritation of the
venous walls.
12 Frequency of neutropenic fever: Includes cases reported as
granulocytopenic fever.
Postmarketing
Experience
The following adverse
reactions have been reported in the post-marketing experience, listed by MedDRA
System Organ Class (SOC), then by Preferred Term in order of severity, where
feasible. Because these reactions are reported voluntarily from a population of
uncertain size, it is not always possible to reliably estimate their frequency
or establish a causal relationship to drug exposure.
INFECTIONS AND INFESTATIONS:
The following manifestations
have been associated with myelosuppression and immunosuppression caused by
Ifosfamide: increased risk for and severity of infections†, pneumonias†, sepsis
and septic shock (including fatal outcomes), as well as reactivation of latent
infections, including viral hepatitis†, Pneumocystis
jiroveci†, herpes zoster, Strongyloides,
progressive multifocal leukoencephalopathy†, and other viral and fungal
infections.
† Severe immunosuppression has
led to serious, sometimes fatal, infections.
NEOPLASMS, BENIGN AND
MALIGNANT AND UNSPECIFIED (INCL. CYSTS AND POLYPS):
As treatment-related secondary
malignancy*, Acute leukemia* (Acute myeloid leukemia)*, Acute promyelocytic
leukemia*, Acute lymphocytic leukemia*, Myelodysplastic syndrome, Lymphoma
(Non-Hodgkin’s lymphoma), Sarcomas*, Renal cell carcinoma, Thyroid cancer
BLOOD AND LYMPHATIC SYSTEM
DISORDERS:
Hematotoxicity*,
Myelosuppression manifested as Bone marrow failure, Agranulocytosis; Febrile
bone marrow aplasia; Disseminated intravascular coagulation, Hemolytic uremic
syndrome, Hemolytic anemia, Neonatal anemia, Methemoglobinemia
IMMUNE SYSTEM DISORDERS:
Angioedema*, Anaphylactic
reaction, Immunosuppression, Urticaria, Hypersensitivity reaction
ENDOCRINE DISORDERS:
Syndrome of inappropriate
antidiuretic hormone secretion (SIADH)
METABOLISM AND NUTRITION
DISORDERS:
Tumor lysis syndrome,
Metabolic acidosis, Hypokalemia, Hypocalcemia, Hypophosphatemia, Hyperglycemia,
Polydipsia
PSYCHIATRIC DISORDERS:
Panic attack, Catatonia,
Mania, Paranoia, Delusion, Delirium, Bradyphrenia, Mutism, Mental status
change, Echolalia, Logorrhea, Perseveration, Amnesia
NERVOUS SYSTEM DISORDERS:
Convulsion*, Status
epilepticus (convulsive and nonconvulsive), reversible posterior
leukoencephalopathy syndrome, Leukoencephalopathy, Extrapyramidal disorder,
Asterixis, Movement disorder, Polyneuropathy, Dysesthesia, Hypothesia,
Paresthesia, Neuralgia, Gait disturbance, Fecal incontinence, Dysarthria
EYE DISORDERS:
Visual impairment, Vision
blurred, Conjunctivitis, Eye irritation
EAR AND LABYRINTH DISORDERS:
Deafness, Hypoacusis, Vertigo,
Tinnitus
CARDIAC DISORDERS:
Cardiotoxicity*, Cardiac
arrest*, Ventricular fi brillation*, Ventricular tachycardia*, Cardiogenic
shock*, Myocardial infarction*, Cardiac failure*, Bundle branch block left,
Bundle branch block right, Pericardial effusion, Myocardial hemorrhage, Angina
pectoris, Left ventricular failure, Cardiomyopathy*, Congestive cardiomyopathy,
Myocarditis*, Arrhythmia*, Pericarditis, Atrial fi brillation, Atrial fl utter,
Bradycardia, Supraventricular extrasystoles, Premature atrial contractions,
Ventricular extrasystoles, Myocardial depression, Palpitations, Ejection
fraction decreased*, Electrocardiogram ST-segment abnormal, Electrocardiogram
T-wave inversion, Electrocardiogram QRS complex abnormal
VASCULAR DISORDERS:
Pulmonary embolism, Deep vein
thrombosis, Capillary leak syndrome, Vasculitis, Hypertension, Flushing, Blood
pressure decreased
RESPIRATORY, THORACIC, AND
MEDIASTINAL DISORDERS:
Respiratory failure*, Acute
respiratory distress syndrome*, Pulmonary hypertension*, Interstitial lung
disease* as manifested by Pulmonary fi brosis*, Alveolitis allergic,
Interstitial pneumonitis, Pneumonitis*, Pulmonary edema*, Pleural effusion,
Bronchospasm, Dyspnea, Hypoxia, Cough
GASTROINTESTINAL DISORDERS:
Cecitis, Colitis,
Enterocolitis, Pancreatitis, Ileus, Gastrointestinal hemorrhage, Mucosal
ulceration, Constipation, Abdominal pain, Salivary hypersecretion
HEPATOBILIARY DISORDERS:
Hepatic failure*, Hepatitis
fulminant*, Veno-occlusive liver disease, Portal vein thrombosis, Cytolytic
hepatitis, Cholestasis
SKIN AND SUBCUTANEOUS TISSUE
DISORDERS:
Toxic epidermal necrolysis,
Stevens-Johnson syndrome, Palmar-plantar erythrodysesthesia syndrome, Radiation
recall dermatitis, Skin necrosis, Facial swelling, Petechiae, Macular rash,
Rash, Pruritus, Erythema, Skin hyperpigmentation, Hyperhidrosis, nail disorder
MUSCULOSKELETAL AND CONNECTIVE
TISSUE DISORDER:
Rhabdomyolysis, Osteomalacia,
Rickets, Growth retardation, Myalgia, Arthralgia, Pain in extremity, Muscle
twitching
RENAL AND URINARY DISORDERS:
Fanconi syndrome,
Tubulointerstitial nephritis, Nephrogenic diabetes insipidus, Phosphaturia,
Aminoaciduria, Polyuria, Enuresis, Feeling of residual urine Fatal outcomes
from acute and chronic renal failure have been documented.
REPRODUCTIVE SYSTEM AND BREAST
DISORDERS:
Infertility, Ovarian failure,
Premature menopause, Amenorrhea, Ovarian disorder, Ovulation disorder, Azoospermia,
Oligospermia, Impairment of spermatogenesis, Blood estrogen decreased, Blood
gonadotrophin increased
CONGENITAL, FAMILIAL AND
GENETIC DISORDERS:
Fetal growth retardation
GENERAL DISORDERS AND
ADMINISTRATIVE SITE CONDITIONS:
Multi-organ failure*, General
physical deterioration, Injection/Infusion site reactions including swelling,
infl ammation, pain, erythema, tenderness, pruritus; Chest pain, Edema, Mucosal
infl ammation, Pain, Pyrexia, Chills
* Including fatal outcomes
Drug Interactions
Ifosfamide is a substrate for
both CYP3A4 and CYP2B6.
Inducers of
CYP3A4
CYP3A4 inducers (e.g.,
carbamazepine, phenytoin, fosphenytoin, phenobarbital, rifampin, St. John Wort)
may increase the metabolism of Ifosfamide to its active alkylating metabolites.
CYP3A4 inducers may increase the formation of the neurotoxic/nephrotoxic
Ifosfamide metabolite, chloroacetaldehyde. Closely monitor patients taking
Ifosfamide with CYP3A4 inducers for toxicities and consider dose adjustment.
Inhibitors of
CYP3A4
CYP3A4 inhibitors (e.g.,
ketoconazole, fluconazole, itraconazole, sorafenib, aprepitant, fosaprepitant,
grapefruit, grapefruit juice) may decrease the metabolism of Ifosfamide to its
active alkylating metabolites, perhaps decreasing the effectiveness of
Ifosfamide treatment.
USE IN SPECIFIC POPULATIONS
Pregnancy
Pregnancy Category D [see Warnings
and Precautions (5.8) ].
Ifosfamide can cause fetal
harm when administered to a pregnant woman. Fetal growth retardation and
neonatal anemia have been reported following exposure to Ifosfamide-containing
chemotherapy regimens during pregnancy.
Animal studies indicate that
Ifosfamide is capable of causing gene mutations and chromosomal damage invivo. In pregnant mice, resorptions increased and
anomalies were present at day 19 after a 30 mg/m2 dose of Ifosfamide was
administered on day 11 of gestation. Embryo-lethal 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.
Women should not become
pregnant and men should not father a child during therapy with Ifosfamide.
Further, men should not father a child for up to 6 months after the end of
therapy. If this drug is used during pregnancy, or if the patient becomes
pregnant while taking this drug or after treatment, the patient should be
apprised of the potential hazard to a fetus.
Labor and
Delivery
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. Women must not breastfeed
during treatment with Ifosfamide.
Pediatric Use
Safety and effectiveness have
not been established in pediatric patients.
Geriatric Use
In general, dose selection for
an elderly patient should be cautious, refl ecting the greater frequency of
decreased hepatic, renal, or cardiac function, and of concomitant disease or
other drug therapy.
A study of patients 40 to 71
years of age indicated that elimination half-life appears to increase with
advancing age [see Pharmacokinetics
(12.3) ]. This apparent increase in half-life appeared to be related to
increases in volume of distribution of Ifosfamide with age. No signifi cant
changes in total plasma clearance or renal or non-renal clearance with age were
reported.
Ifosfamide and its metabolites
are known to be substantially excreted by the kidney, and the risk of toxic
reactions to this drug may be greater in patients with impaired renal function.
Because elderly patients are more likely to have decreased renal function, care
should be taken in dose selection, and it may be useful to monitor renal
function.
Use in
Patients with Renal Impairment
No formal studies were
conducted in patients with renal impairment. Ifosfamide and its metabolites are
known to be excreted by the kidneys and may accumulate in plasma with decreased
renal function. Patients with renal impairment should be closely monitored for
toxicity and dose reduction may be considered. Ifosfamide and its metabolites
are dialyzable.
Use in
Patients with Hepatic Impairment
No formal studies were
conducted in patients with hepatic impairment. Ifosfamide is extensively metabolized
in the liver and forms both efficacious and toxic metabolites. Ifosfamide
should be given cautiously to patients with impaired hepatic function.
Overdosage
No specific antidote for
Ifosfamide is known.
Patients who receive an
overdose should be closely monitored for the development of toxicities. Serious
consequences of overdosage include manifestations of dose-dependent toxicities
such as CNS toxicity, nephrotoxicity, myelosuppression, and mucositis [see Warnings
and Precautions (5)].
Management of overdosage would
include general supportive measures to sustain the patient through any period
of toxicity that might occur, including appropriate state-of-the-art treatment
for any concurrent infection, myelosuppression, or other toxicity. Ifosfamide
as well as Ifosfamide metabolites are dialyzable.
Cystitis prophylaxis with
mesna may be helpful in preventing or limiting urotoxic effects with overdose.
Ifosfamide Description
Ifosfamide injection is
presented in sterile, single-dose vials for administration by intravenous
infusion. Each mL contains Ifosfamide, 50 mg, monobasic sodium phosphate
monohydrate, 1.035 mg, dibasic sodium phosphate, 3.55 mg and water for
injection, q.s.. Ifosfamide is a chemotherapeutic agent chemically related to
the nitrogen mustards and a synthetic analog cyclophosphamide. Ifosfamide is
3-(2-ChloroethyI)-2-[(2-chloroethyl) amino]tetrahydro-2H-1,3,2-
oxazaphosphorine 2-oxide.
Its structural formula is:
C7H15Cl2N2O2P
M. W. = 261.09
Ifosfamide is a white
crystalline powder that is soluble in water.
Ifosfamide - Clinical Pharmacology
Mechanism of
Action
Ifosfamide is a prodrug that
requires metabolic activation by hepatic cytochrome P450 isoenzymes to exert
its cytotoxic activity. Activation occurs by hydroxylation at the ring carbon
atom forming the unstable intermediate 4-hydroxyIfosfamide and its ring-opened
aldo tautomer, which decomposes to yield the cytotoxic and urotoxic compound
acrolein and an alkylating isophosphoramide mustard as well as multiple other
nontoxic products. The exact mechanism of action of Ifosfamide has not been
determined, but its cytotoxic action is primarily through DNA crosslinks caused
by alkylation by the isophosphoramide mustard at guanine N-7 positions. The
formation of inter- and intra-strand cross-links in the DNA results in cell
death.
Pharmacokinetics
concentrations decay
biphasically and the mean terminal elimination half-life is about 15 hours. At
doses of 1.6 to 2.4 g/m2/day, the plasma decay is monoexponential and the terminal
elimination half-life is about 7 hours.
Ifosfamide exhibits
time-dependent pharmacokinetics in humans. Following intravenous administration
of 1.5 g/m2 over 0.5 hour once daily for 5 days to 15 patients with
neoplastic disease, a decrease in the median elimination half-life from 7.2
hours on Day 1 to 4.6 hours on Day 5 occurred with a concomitant increase in
the median clearance from 66 mL/min on Day 1 to 115 mL/min on Day 5. There was
no significant change in the volume of distribution on Day 5 compared with Day
1.
Distribution
Ifosfamide volume of
distribution (Vd) approximates the total body water volume, suggesting that
distribution takes place with minimal tissue binding. Following intravenous
administration of 1.5 g/m2over 0.5 hour once daily for 5 days to 15 patients with
neoplastic disease, the median Vd of Ifosfamide was 0.64 L/kg on Day 1 and 0.72
L/kg on Day 5. Ifosfamide shows little plasma protein binding. Ifosfamide and
its active metabolites are extensively bound by red blood cells. Ifosfamide is
not a substrate for P-glycoprotein.
Metabolism
Ifosfamide is extensively
metabolized in humans through two metabolic pathways: ring oxidation
(“activation”) to form the active metabolite, 4-hydroxy-Ifosfamide and
side-chain oxidation to form the inactive metabolites,
3-dechloro-ethylIfosfamide or 2-dechloroethylIfosfamide with liberation of the
toxic metabolite, chloroacetaldehyde.
Small quantities (nmol/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.
Excretion
After administration of doses
of 5 g/m2 of 14C-labeled Ifosfamide, from 70% to 86% of the dosed
radioactivity was recovered in urine as metabolites, with about 61% of the dose
excreted as parent compound. At doses of 1.6 to 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 identifi ed as the
major urinary metabolites of Ifosfamide in humans and only small amounts of
4-hydroxyIfosfamide and acrolein are present.
Pediatrics
Population PK analysis was
performed on plasma data from 32 pediatric patients various malignant diseases
aged between 1 and 18 years. Patients received a total of 45 courses of
Ifosfamide at doses of 1.2, 2 and 3 g/m2 given intravenously over 1 or 3 hours on 1, 2, or 3 days.
The mean ± standard error population estimates for the initial clearance and
volume of distribution of Ifosfamide were 2.4±0.33 L/h/m2 and 21±1.6 L/m2with an interindividual
variability of 43% and 32%, respectively.
Effect
of Age
A study of 20 patients between
40 to 71 years of age receiving 1.5 g/m2 of Ifosfamide daily for 3 or 5 days indicated that
elimination half-life appears to increase with age. The elimination half-life
increase appeared to be related to the increase in Ifosfamide volume of
distribution with age. No significant changes in total plasma clearance or
renal clearance with age were reported.
Nonclinical Toxicology
Carcinogenesis,
Mutagenesis, Impairment of Fertility
Ifosfamide has been shown to
be carcinogenic in rats when administered by intraperitoneal injection at 6
mg/kg (37 mg/m2, or about 3% of the daily human dose on a mg/m2 basis) 3 times a week
for 52 weeks. Female rats had a signifi cantly higher incidence of uterine
leiomyosarcomas and mammary fibroadenomas than vehicle controls.
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.
Ifosfamide was administered to
male and female beagle dogs at doses of 1 or 4.64 mg/kg/day (20 or 93 mg/m2) orally 6 days a week for 26
weeks. Male dogs at 4.64 mg/kg (about 7.7% of the daily clinical dose on a mg/m2 basis) had testicular
atrophy with degeneration of the seminiferous tubular epithelium. In a second
study, male and female rats were given 0, 25, 50, or 100 mg/kg (0, 150, 300, or
600 mg/m2) Ifosfamide intraperitoneally once every 3 weeks for 6 months.
Decreased spermatogenesis was observed in most male rats given 100 mg/kg (about
half the daily clinical dose on a mg/m2 basis).
Clinical Studies
Patients with refractory
testicular cancer (n=59) received a combination of Ifosfamide, cisplatin, and
either etoposide (VePesid®) or vinblastine (VIP) as third-line therapy or
later. The selection of etoposide or vinblastine (“V” in the VIP regimen) was
guided by the therapeutic effect achieved with prior regimens. The contribution
of Ifosfamide to the VIP combination was determined in patients treated with
cisplatin-etoposide prior to Ifosfamide-cisplatin-etoposide or those who
received cisplatin-vinblastine prior to Ifosfamide-cisplatin-vinblastine.
A total of 59 patients
received a third-line salvage regimen which consisted of Ifosfamide 1.2 g/m2/day intravenously on days 1
to 5, cisplatin 20 mg/m2/day intravenously on days 1 to 5, and either etoposide
75 mg/m2/day intravenously on days 1 to 5 or vinblastine 0.22 mg/kg
intravenously on day 1. Efficacy results with the VIP regimen were compared to
data pooled from six single agent phase II trials conducted between August 1980
and October 1985 including a total of 90 patients of whom 65 were eligible as
controls of this study. Twenty-three patients in the VIP regimen became free of
disease with VIP alone or VIP plus surgery, whereas a single patient in the
historical control group achieved complete response. The median survival time
exceeded two years in the VIP group versus less than one year in the control
group.
Performance status ≥ 80,
embryonal carcinoma and minimal disease were favorable prognostic factors for
survival. In all prognostic categories, the difference between VIP and
historical controls remained highly significant.
|
|
Number. (%) of Patients
|
p-value
|
|
VIP
|
Control
|
|
Total
Patients
|
59 (100)
|
65 (100)
|
|
|
Disease-free
|
23 (39)
|
1 (2)
|
< 0.001
|
|
Chemotherapy
alone
|
15 (25)
|
1 (2)
|
< 0.001
|
|
Chemotherapy
plus surgery
|
8 (14)
|
0
|
|
|
Overall
Response
|
32 (54)
|
2 (3)
|
< 0.001
|
|
Time to
progression (weeks)
|
|
|
|
|
Median
|
19
|
4
|
< 0.001a
|
|
Range
|
1 to 205+
|
1 to 29
|
|
|
Disease-free
interval (weeks)
|
|
|
|
|
Median
|
114
|
29
|
|
|
Range
|
13 to 205+
|
--
|
|
|
Survival
(weeks)
|
|
|
|
|
Median
|
53
|
10
|
< 0.001a
|
|
Range
|
1 to 205+
|
1 to 123+
|
|
a: Gehan-Breslow and Mantel-Cox
tests
In a study, 50 fully evaluable
patients with germ cell testicular cancer were treated with Ifosfamide 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.
REFERENCES
1. NIOSH Alert: Preventing
occupational exposures to antineoplastic and other hazardous drugs in healthcare
settings. 2004. U.S. Department of Health and Human Services, Public Health
Service, Centers for Disease Control and Prevention, National Institute for
Occupational Safety and Health, DHHS (NIOSH) Publication No. 2004-165.
2. OSHA Technical Manual, TED
1-0.15A, Section VI: Chapter 2. Controlling occupational exposure to hazardous
drugs. OSHA, 1999. http://www.osha.gov/dts/osta/otm/otm_vi/otm_vi_2.html
3. American Society of
Health-System Pharmacists. ASHP guidelines on handling hazardous drugs. Am JHealth-Syst Pharm. 2006; 63:1172-1193.
4. Polovich M, White JM,
Kelleher LO, (eds.) 2005. Chemotherapy and biotherapy guidelines and
recommendations for practice. (2nd ed.) Pittsburgh, PA: Oncology Nursing
Society.
How Supplied/Storage and Handling
Ifosfamide Injection is
available in single-dose vials as follows:
NDC 0143-9531-01 – 1 g/20 mL Single Dose Vial of Ifosfamide;
individually-boxed.
NDC 0143-9530-01 – 3 g/60 mL Single Dose Vial of Ifosfamide;
individually-boxed.
Store in a refrigerator 2°C to
8°C (36°F to 46°F). See USP.
Exercise caution when handling
Ifosfamide. The handling and preparation of Ifosfamide should always be in
accordance with current guidelines on safe handling of cytotoxic agents.
Several guidelines on this subject have been published.1-4 Skin reactions
associated with accidental exposure to Ifosfamide may occur. To minimize the
risk of dermal exposure, always wear impervious gloves when handling vials and
solutions containing Ifosfamide. If Ifosfamide solution contacts the skin or
mucosa, immediately wash the skin thoroughly with soap and water or rinse the
mucosa with copious amounts of water.
Patient Counseling Information
Inform patients of the risks
associated with the use of Ifosfamide as well as the plan for regular blood monitoring
during therapy.
Specifically inform patients
of the following:
• Treatment with Ifosfamide
may cause myelosuppression which can be severe and lead to fatal outcome.
Significant suppression of immune responses can also occur which can lead to
severe infections. Latent infections can be reactivated. Patients should report
fever or other symptoms of an infection.
• The risk of bleeding and
anemia.
• The risk of CNS toxicity and
other neurotoxic effects with fatal outcome.
• The risk of bladder and kidney
toxicity. Patients should be aware of the need to increase fl uid intake and
frequent voiding to prevent accumulation in the bladder.
• The risk of cardiotoxicity
and fatal outcome. Patients should report preexisting cardiac disease.
• The risk of pulmonary
toxicity leading to respiratory failure with fatal outcome.
• The risk of secondary
malignancies due to therapy.
• The risk of veno-occlusive
liver disease.
• The potential hazard to a
fetus if a patient becomes pregnant or fathers a child during therapy and for
up to 6 months after therapy. Effective methods of contraception should be used
during therapy and for up to 6 months after therapy.
• The potential for serious
adverse reactions and tumorigenicity when children are breastfed during
therapy.
• The risk of amenorrhea,
premature menopause, and sterility.
• The risk of alopecia, wound
healing, and other serious skin and subcutaneous tissue disorders.
• Therapy may cause
gastrointestinal disorders and alcohol may increase nausea and vomiting.
• The risk of stomatitis and
the importance of proper oral hygiene.
• The risk of eye disorders
such as visual impairment, blurred vision, and eye irritation.
• The risk of ear and
labyrinth disorders such as deafness, vertigo, and tinnitus.
Manufactured
by:
THYMOORGAN PHARMAZIE GmbH,
Schiffgraben 23, 38690 Goslar,
Germany
Distributed by:
West-Ward
Pharmaceuticals
Eatontown, NJ 07724 USA
Revised September 2015
127.207.010/00
PACKAGE/LABEL PRINCIPAL DISPLAY PANEL
NDC 0143-9531-01
Rx only
Ifosfamide INJECTION
1 g/20 mL
(50 mg/mL)
FOR INTRAVENOUS USE
Cytotoxic Agent
Vial label for Ifosfamide Injection 1 g/20 mL
PACKAGE/LABEL PRINCIPAL DISPLAY PANEL
NDC 0143-9530-01
Rx only
Ifosfamide INJECTION
3 g/60 mL
(50 mg/mL)
FOR INTRAVENOUS USE
Cytotoxic Agent
Vial label for Ifosfamide Injection 60 mL
|
Ifosfamide Ifosfamide injection
|
|
Product
Information
|
|
Product Type
|
HUMAN
PRESCRIPTION DRUG LABEL
|
Item Code
(Source)
|
NDC:0143-9531
|
|
Route of
Administration
|
INTRAVENOUS
|
DEA Schedule
|
|
|
|
Active
Ingredient/Active Moiety
|
|
Ingredient
Name
|
Basis of
Strength
|
Strength
|
|
Ifosfamide (Ifosfamide)
|
Ifosfamide
|
50 mg
in 1 mL
|
|
|
Inactive
Ingredients
|
|
Ingredient
Name
|
Strength
|
|
SODIUM PHOSPHATE, MONOBASIC, MONOHYDRATE
|
1.035 mg
in 1 mL
|
|
SODIUM PHOSPHATE, DIBASIC
|
3.55 mg
in 1 mL
|
|
WATER
|
|
|
|
|
|
Packaging
|
|
#
|
Item Code
|
Package
Description
|
|
|
1
|
NDC:0143-9531-01
|
1 VIAL in 1 BOX
|
|
|
1
|
|
20 mL in 1 VIAL
|
|
|
|
|
|
Marketing Information
|
|
Marketing
Category
|
Application
Number or Monograph Citation
|
Marketing
Start Date
|
Marketing
End Date
|
|
ANDA
|
ANDA076619
|
06/10/2017
|
|
|
|
Ifosfamide Ifosfamide injection
|
|
Product
Information
|
|
Product Type
|
HUMAN
PRESCRIPTION DRUG LABEL
|
Item Code
(Source)
|
NDC:0143-9530
|
|
Route of
Administration
|
INTRAVENOUS
|
DEA Schedule
|
|
|
|
Active
Ingredient/Active Moiety
|
|
Ingredient
Name
|
Basis of
Strength
|
Strength
|
|
Ifosfamide (Ifosfamide)
|
Ifosfamide
|
50 mg
in 1 mL
|
|
|
Inactive
Ingredients
|
|
Ingredient
Name
|
Strength
|
|
SODIUM PHOSPHATE, MONOBASIC, MONOHYDRATE
|
1.035 mg
in 1 mL
|
|
SODIUM PHOSPHATE, DIBASIC
|
3.55 mg
in 1 mL
|
|
WATER
|
|
|
|
|
|
Packaging
|
|
#
|
Item Code
|
Package
Description
|
|
|
1
|
NDC:0143-9530-01
|
1 VIAL in 1 BOX
|
|
|
1
|
|
60 mL in 1 VIAL
|
|
|
|
|
|
Marketing Information
|
|
Marketing
Category
|
Application
Number or Monograph Citation
|
Marketing
Start Date
|
Marketing
End Date
|
|
ANDA
|
ANDA076619
|
06/10/2017
|
|
|
|
Labeler - West-Ward Pharmaceuticals Corp (001230762)
|
Revised:
11/2017
West-Ward
Pharmaceuticals Corp
