Ifosfamide
Generic: IFOSFAMIDE
Basic Information
Manufacturer
Hikma Pharmaceuticals USA Inc.
Product Type
HUMAN PRESCRIPTION DRUG
Route of Administration
INTRAVENOUS
FDA Set ID
c90ab05f-8fe5-437e-a1c0-8b11ef63291e
Indications & Usage
1 INDICATIONS AND USAGE 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 Injection is an alkylating drug indicated for use in combination with certain other approved antineoplastic agents for third-line chemotherapy of germ cell testicular cancer.
It should be used in combination with mesna for prophylaxis of hemorrhagic cystitis.
(1)
It should be used in combination with mesna for prophylaxis of hemorrhagic cystitis.
Ifosfamide Injection is an alkylating drug indicated for use in combination with certain other approved antineoplastic agents for third-line chemotherapy of germ cell testicular cancer.
It should be used in combination with mesna for prophylaxis of hemorrhagic cystitis.
(1)
Adverse Reactions
6 ADVERSE REACTIONS In clinical trials of ifosfamide monotherapy, the most common (≥ 10%) adverse reactions were alopecia, nausea/vomiting, leukopenia, anemia, CNS toxicity, hematuria, and infection.
(6.1) To report SUSPECTED ADVERSE REACTIONS, contact Hikma Pharmaceuticals USA Inc.
at 1-877-845-0689, or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
6.1 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/m 2 per course.
System Organ Class (SOC) Adverse Reaction Percentage (Ratio) INFECTIONS AND INFESTATIONS Infection 9.9% (112/1128) BLOOD AND LYMPHATIC SYSTEM DISORDERS Leukopenia 1 (any) Leukopenia <1 x 10 3 /µL 43.5% (267/614) Thrombocytopenia 2 (any) Thrombocytopenia 50 x 10 3 /µL 4.8% (35/729) Anemia 3 37.9% (202/533) METABOLISM AND NUTRITION DISORDERS Anorexia 1.1% (15/1317) NERVOUS SYSTEM DISORDERS Central nervous system toxicity 4,5 15.4% (154/1001) Peripheral neuropathy 0.4% (5/1317) CARDIAC DISORDERS Cardiotoxicity 6 0.5% (7/1317) VASCULAR DISORDERS Hypotention 7 0.3% (4/1317) GASTROINTESTINAL DISORDERS Nausea/Vomiting 46.8% (443/964) Diarrhea 0.7% (9/1317) Stomatitis 0.3% (4/1317) HEPATOBILIARY DISORDERS Hepatotoxicity 8 1.8% (22/1190) SKIN AND SUBCUTANEOUS TISSUES DISORDERS Alopecia 89.6% (540/603) Dermatitis 0.08% (1/1317) Papular rash 0.08% (1/1317) RENAL AND URINARY DISORDERS Hemorrhagic cystitis 9 Hematuria - without mesna 44.1% (282/640) - with mesna 21.3% (33/155) Macrohematuria - without mesna 11.1% (66/594) - with mesna 5.2% (5/97) Renal dysfunction 10 -- Renal structural damage -- GENERAL DISORDERS AND ADMINISTRATIVE SITE CONDITIONS Phlebitis 11 2.8% (37/1317) Neutropenic fever 12 1% (13/1317) Fatigue 0.3% (4/1317) Malaise Unable to calculate 1 The following adverse reaction terms have been reported for leukopenia: neutropenia, granulocytopenia, lymphopenia, and pancytopenia.
For neutropenic fever, see below.
2 Thrombocytopenia may also be complicated by bleeding.
Bleeding with fatal outcome has been reported.
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 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 Includes cases reported as granulocytopenic fever.
6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of Ifosfamide injection.
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 Ifosfamide has been reintroduced after neurotoxicity.
While some patients did not experience neurotoxicity, others had recurrent, including fatal, events.
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
6.1 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/m 2 per course.
System Organ Class (SOC) Adverse Reaction Percentage (Ratio) INFECTIONS AND INFESTATIONS Infection 9.9% (112/1128) BLOOD AND LYMPHATIC SYSTEM DISORDERS Leukopenia 1 (any) Leukopenia <1 x 10 3 /µL 43.5% (267/614) Thrombocytopenia 2 (any) Thrombocytopenia 50 x 10 3 /µL 4.8% (35/729) Anemia 3 37.9% (202/533) METABOLISM AND NUTRITION DISORDERS Anorexia 1.1% (15/1317) NERVOUS SYSTEM DISORDERS Central nervous system toxicity 4,5 15.4% (154/1001) Peripheral neuropathy 0.4% (5/1317) CARDIAC DISORDERS Cardiotoxicity 6 0.5% (7/1317) VASCULAR DISORDERS Hypotention 7 0.3% (4/1317) GASTROINTESTINAL DISORDERS Nausea/Vomiting 46.8% (443/964) Diarrhea 0.7% (9/1317) Stomatitis 0.3% (4/1317) HEPATOBILIARY DISORDERS Hepatotoxicity 8 1.8% (22/1190) SKIN AND SUBCUTANEOUS TISSUES DISORDERS Alopecia 89.6% (540/603) Dermatitis 0.08% (1/1317) Papular rash 0.08% (1/1317) RENAL AND URINARY DISORDERS Hemorrhagic cystitis 9 Hematuria - without mesna 44.1% (282/640) - with mesna 21.3% (33/155) Macrohematuria - without mesna 11.1% (66/594) - with mesna 5.2% (5/97) Renal dysfunction 10 -- Renal structural damage -- GENERAL DISORDERS AND ADMINISTRATIVE SITE CONDITIONS Phlebitis 11 2.8% (37/1317) Neutropenic fever 12 1% (13/1317) Fatigue 0.3% (4/1317) Malaise Unable to calculate 1 The following adverse reaction terms have been reported for leukopenia: neutropenia, granulocytopenia, lymphopenia, and pancytopenia.
For neutropenic fever, see below.
2 Thrombocytopenia may also be complicated by bleeding.
Bleeding with fatal outcome has been reported.
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 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 Includes cases reported as granulocytopenic fever.
6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of Ifosfamide injection.
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 Ifosfamide has been reintroduced after neurotoxicity.
While some patients did not experience neurotoxicity, others had recurrent, including fatal, events.
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
(6.1) To report SUSPECTED ADVERSE REACTIONS, contact Hikma Pharmaceuticals USA Inc.
at 1-877-845-0689, or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
6.1 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/m 2 per course.
System Organ Class (SOC) Adverse Reaction Percentage (Ratio) INFECTIONS AND INFESTATIONS Infection 9.9% (112/1128) BLOOD AND LYMPHATIC SYSTEM DISORDERS Leukopenia 1 (any) Leukopenia <1 x 10 3 /µL 43.5% (267/614) Thrombocytopenia 2 (any) Thrombocytopenia 50 x 10 3 /µL 4.8% (35/729) Anemia 3 37.9% (202/533) METABOLISM AND NUTRITION DISORDERS Anorexia 1.1% (15/1317) NERVOUS SYSTEM DISORDERS Central nervous system toxicity 4,5 15.4% (154/1001) Peripheral neuropathy 0.4% (5/1317) CARDIAC DISORDERS Cardiotoxicity 6 0.5% (7/1317) VASCULAR DISORDERS Hypotention 7 0.3% (4/1317) GASTROINTESTINAL DISORDERS Nausea/Vomiting 46.8% (443/964) Diarrhea 0.7% (9/1317) Stomatitis 0.3% (4/1317) HEPATOBILIARY DISORDERS Hepatotoxicity 8 1.8% (22/1190) SKIN AND SUBCUTANEOUS TISSUES DISORDERS Alopecia 89.6% (540/603) Dermatitis 0.08% (1/1317) Papular rash 0.08% (1/1317) RENAL AND URINARY DISORDERS Hemorrhagic cystitis 9 Hematuria - without mesna 44.1% (282/640) - with mesna 21.3% (33/155) Macrohematuria - without mesna 11.1% (66/594) - with mesna 5.2% (5/97) Renal dysfunction 10 -- Renal structural damage -- GENERAL DISORDERS AND ADMINISTRATIVE SITE CONDITIONS Phlebitis 11 2.8% (37/1317) Neutropenic fever 12 1% (13/1317) Fatigue 0.3% (4/1317) Malaise Unable to calculate 1 The following adverse reaction terms have been reported for leukopenia: neutropenia, granulocytopenia, lymphopenia, and pancytopenia.
For neutropenic fever, see below.
2 Thrombocytopenia may also be complicated by bleeding.
Bleeding with fatal outcome has been reported.
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 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 Includes cases reported as granulocytopenic fever.
6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of Ifosfamide injection.
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 Ifosfamide has been reintroduced after neurotoxicity.
While some patients did not experience neurotoxicity, others had recurrent, including fatal, events.
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
6.1 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/m 2 per course.
System Organ Class (SOC) Adverse Reaction Percentage (Ratio) INFECTIONS AND INFESTATIONS Infection 9.9% (112/1128) BLOOD AND LYMPHATIC SYSTEM DISORDERS Leukopenia 1 (any) Leukopenia <1 x 10 3 /µL 43.5% (267/614) Thrombocytopenia 2 (any) Thrombocytopenia 50 x 10 3 /µL 4.8% (35/729) Anemia 3 37.9% (202/533) METABOLISM AND NUTRITION DISORDERS Anorexia 1.1% (15/1317) NERVOUS SYSTEM DISORDERS Central nervous system toxicity 4,5 15.4% (154/1001) Peripheral neuropathy 0.4% (5/1317) CARDIAC DISORDERS Cardiotoxicity 6 0.5% (7/1317) VASCULAR DISORDERS Hypotention 7 0.3% (4/1317) GASTROINTESTINAL DISORDERS Nausea/Vomiting 46.8% (443/964) Diarrhea 0.7% (9/1317) Stomatitis 0.3% (4/1317) HEPATOBILIARY DISORDERS Hepatotoxicity 8 1.8% (22/1190) SKIN AND SUBCUTANEOUS TISSUES DISORDERS Alopecia 89.6% (540/603) Dermatitis 0.08% (1/1317) Papular rash 0.08% (1/1317) RENAL AND URINARY DISORDERS Hemorrhagic cystitis 9 Hematuria - without mesna 44.1% (282/640) - with mesna 21.3% (33/155) Macrohematuria - without mesna 11.1% (66/594) - with mesna 5.2% (5/97) Renal dysfunction 10 -- Renal structural damage -- GENERAL DISORDERS AND ADMINISTRATIVE SITE CONDITIONS Phlebitis 11 2.8% (37/1317) Neutropenic fever 12 1% (13/1317) Fatigue 0.3% (4/1317) Malaise Unable to calculate 1 The following adverse reaction terms have been reported for leukopenia: neutropenia, granulocytopenia, lymphopenia, and pancytopenia.
For neutropenic fever, see below.
2 Thrombocytopenia may also be complicated by bleeding.
Bleeding with fatal outcome has been reported.
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 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 Includes cases reported as granulocytopenic fever.
6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of Ifosfamide injection.
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 Ifosfamide has been reintroduced after neurotoxicity.
While some patients did not experience neurotoxicity, others had recurrent, including fatal, events.
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