DRUGS & SUPPLEMENTS

Ifoxan

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Ifoxan uses


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.

WARNING: MYELOSUPPRESSION, NEUROTOXICITY, and UROTOXICITY

See full prescribing information for complete boxed warning.

  • Myelosuppression can be severe and lead to fatal infections (5.1)
  • CNS toxicities can be severe and result in encephalopathy and death (5.2)
  • Nephrotoxicity can be severe and result in renal failure. Hemorrhagic cystitis can be severe. (5.3)

1 INDICATIONS AND USAGE

Ifoxan is 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.

Ifoxan 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)

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2 DOSAGE AND ADMINISTRATION

Ifoxan 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, Ifoxan 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. Ifoxan should be administered as a slow intravenous infusion lasting a minimum of 30 minutes. Studies of Ifoxan in patients with hepatic or renal impairment have not been conducted .

Injections are prepared for parenteral use by adding Sterile Water for Injection, USP or Bacteriostatic Water for Injection, USP (benzyl alcohol or parabens preserved), to the vial and shaking to dissolve. Before parenteral administration, the substance must be completely dissolved. Use the quantity of diluents shown below to constitute the product:


Dosage Strength


Quantity of Diluent


Final Concentration


1 gram


20 mL


50 mg per mL


3 grams


60 mL


50 mg per mL


Solutions of Ifoxan 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 Injections, 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 (e.g., 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 Ifoxan should be refrigerated and used within 24 hours. Benzyl-alcohol-containing solutions can reduce the stability of Ifoxan.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

Dosage and duration of treatment and/or treatment intervals depend on the scheme of combination therapy, the patient’s general state of health and organ function, and the results of laboratory monitoring. (2)

  • Ifoxan should be administered as a slow intravenous infusion lasting a minimum of 30 minutes at a dose of 1.2 grams per m2 per day for 5 consecutive days. (2)
  • Treatment is repeated every 3 weeks or after recovery from hematologic toxicity. (2)
  • To prevent bladder toxicity, Ifoxan should be given with extensive hydration consisting of at least 2 liters of oral or intravenous fluid per day. (2, 5.3)
  • Mesna should be used to reduce the incidence of hemorrhagic cystitis. (2)
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3 DOSAGE FORMS AND STRENGTHS

1 gram single-dose vial

3 gram single-dose vial

Single dose vials: 1 gram, 3 grams (3)

4 CONTRAINDICATIONS

Ifoxan is contraindicated in patients with:

  • Known hypersensitivity to administration of Ifoxan.
  • Urinary outflow obstruction.
  • Known hypersensitivity to administration of Ifoxan. (4)
  • Urinary outflow obstruction. (4)

5 WARNINGS AND PRECAUTIONS

  • Myelosuppression: Can be severe and lead to fatal infections. Monitor blood counts prior to and at intervals after treatment.
  • Neurotoxicity: Severe and fatal neurotoxicity can occur. Carefully monitor the patient for CNS toxicity and other neurotoxic effects. Discontinue therapy should encephalopathy develop. (5.2)
  • Urotoxicity: Severe nephrotoxicity with renal failure and death can occur. Monitor for nephrotoxicity with serum and urine chemistries. Mesna should be used to reduce hemorrhagic cystitis. (5.3)
  • Cardiotoxicity: Arrhythmias, other ECG changes, and cardiomyopathy can occur and result in death. Use with caution in patients with cardiac risk factors and in patients with preexisting cardiac disease. The risk of cardiotoxicity is dose dependent. (5.4)
  • Pulmonary toxicity: Interstitial pneumonitis, pulmonary fibrosis, and other forms of pulmonary toxicity with fatal outcomes can occur. Monitor for signs and symptoms of pulmonary toxicity and treat as clinically indicated (5.5)
  • Secondary malignancies as late sequelae have occurred. (5.6)
  • Pregnancy: Can cause fetal harm. Women should not become pregnant and men should not father a child during therapy. (5.8)
  • Anaphylactic/anaphylactoid reactions have been reported. (5.10)

5.1 Myelosuppression, Immunosuppression, and Infections

Treatment with Ifoxan 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 Ifoxan 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 Ifoxan include pneumonias, as well as other bacterial, fungal, viral, and parasitic infections. Latent infections can be reactivated. In patients treated with Ifoxan, 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, Ifoxan should not be given to patients with a WBC count below 2000/µL and/or a platelet count below 50,000/µL.

Ifoxan 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.

5.2 Central Nervous System Toxicity, Neurotoxicity

Administration of Ifoxan 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 Ifoxan therapy. There have also been reports of peripheral neuropathy associated with Ifoxan use.

Ifoxan neurotoxicity may become manifest within a few hours to a few days after first administration and in most cases resolves within 48 to 72 hours of Ifoxan 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 Ifoxan should be discontinued.

Due to the potential for additive effects, drugs acting on the CNS 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.

5.3 Renal and Urothelial Toxicity and Effects

Ifoxan 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 Ifoxan. Acute tubular necrosis, acute renal failure, and chronic renal failure secondary to Ifoxan therapy have been reported, and fatal outcome from nephrotoxicity has been documented.

Disorders of renal function, (glomerular and tubular) following Ifoxan 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 Ifoxan.

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 Ifoxan treatment.

The risk and expected benefits of Ifoxan therapy should be carefully weighed when considering the use of Ifoxan 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 Ifoxan. These urotoxic effects can be reduced by prophylactic use of mesna.

Hemorrhagic cystitis requiring blood transfusion has been reported with Ifoxan. 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 Ifoxan 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 Ifoxan. 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 Ifoxan should be given with vigorous oral or parenteral hydration.

Ifoxan should be used with caution, if at all, in patients with active urinary tract infections.

5.4 Cardiotoxicity

Manifestations of cardiotoxicity reported with Ifoxan 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 Ifoxan is used in patients with risk factors for cardiotoxicity and in patients with preexisting cardiac disease.

5.5 Pulmonary Toxicity

Interstitial pneumonitis, pulmonary fibrosis, and other forms of pulmonary toxicity have been reported with Ifoxan 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.

5.6 Secondary Malignancies

Treatment with Ifoxan 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 Ifoxan or regimens with Ifoxan include lymphoma, thyroid cancer, and sarcomas.

The secondary malignancy may develop several years after chemotherapy has been discontinued.

5.7 Veno-occlusive Liver Disease

Veno-occlusive liver disease has been reported with chemotherapy that included Ifoxan.

5.8 Pregnancy

Ifoxan 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. Ifoxan 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 Ifoxan. 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.

5.9 Effects on Fertility

Ifoxan 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 Ifoxan, 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 Ifoxan. The risk of permanent chemotherapy-induced amenorrhea increases with age. Pediatric patients treated with Ifoxan 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 Ifoxan may develop oligospermia or azoospermia. Pediatric patients treated with Ifoxan 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 Ifoxan have subsequently fathered children.

5.10 Anaphylactic/Anaphylactoid Reactions and Cross-sensitivity

Anaphylactic/anaphylactoid reactions have been reported in association with Ifoxan.

Cross-sensitivity between oxazaphosphorine cytotoxic agents has been reported.

5.11 Impairment of Wound Healing

Ifoxan may interfere with normal wound healing.

5.12 Nursing

Ifoxan is excreted in breast milk. Women must not breastfeed during treatment with Ifoxan.

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6 ADVERSE REACTIONS

In clinical trials of Ifoxan monotherapy, the most common adverse reactions were alopecia, nausea/vomiting, leukopenia, anemia, CNS toxicity, hematuria, and infection. (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact Baxter Healthcare at phone: 1 866 888 2472 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 Ifoxan as monotherapy with a total dose of 4 to 12 g/m2 per course.


System Organ Class (SOC)


Adverse Reaction


Percentage (Ratio)


INFECTIONS AND INFESTATIONS


Infection


9.9%

(112/1128)


BLOOD AND LYMPHATIC SYSTEM DISORDERS


LeukopeniaThe following adverse reaction terms have been reported for leukopenia: neutropenia, granulocytopenia, lymphopenia, and pancytopenia. For neutropenic fever, see below. (any)


--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.


Leukopenia

<1 x 103/µL


43.5%

(267/614)


ThrombocytopeniaThrombocytopenia may also be complicated by bleeding. Bleeding with fatal outcome has been reported. (any)


--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.


Thrombocytopenia, 

50 x 103/µL


4.8%

(35/729)


AnemiaIncludes cases reported as anemia and decrease in hemoglobin/hematocrit.


37.9%

(202/533)


METABOLISM AND NUTRITION DISORDERS


Anorexia


1.1%

(15/1317)


NERVOUS SYSTEM DISORDERS


Central nervous system toxicityEncephalopathy with coma and death has been reported. , 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 deficiency, 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.


15.4%

(154/1001)


Peripheral neuropathy


0.4%

(5/1317)


CARDIAC DISORDERS


CardiotoxicityCardiotoxicity was reported as congestive heart failure, tachycardia, pulmonary edema. Fatal outcome has been reported.


0.5%

(7/1317)


VASCULAR DISORDERS


HypotentionHypotension leading to shock and fatal outcome has been reported.


0.3%

(4/1317)


GASTROINTESTINAL DISORDERS


Nausea/Vomiting


46.8%

(443/964)


Diarrhea


0.7%

(9/1317)


Stomatitis


0.3%

(4/1317)


HEPATOBILIARY DISORDERS


HepatotoxicityHepatotoxicity 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.


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


--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).


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 dysfunctionRenal 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.


--


Renal structural damage


--


GENERAL DISORDERS AND ADMINISTRATIVE SITE CONDITIONS


PhlebitisIncludes cases reported as phlebitis and irritation of the venous walls.


2.8%

(37/1317)


Neutropenic feverFrequency of neutropenic fever: Includes cases reported as granulocytopenic fever.


1.0%

(13/1317)


Fatigue


0.3%

(4/1317)


Malaise


Unable to calculate

6.2 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 Ifoxan: 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 fibrillation*, 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 fibrillation, Atrial flutter, 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 fibrosis*, 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, inflammation, pain, erythema, tenderness, pruritus; Chest pain, Edema, Mucosal inflammation, Pain, Pyrexia, Chills

* Including fatal outcomes

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7 DRUG INTERACTIONS

Ifoxan is a substrate for both CYP3A4 and CYP2B6.

  • CYP3A4 Inducers: monitor for increased toxicity when used in combination with CYP3A4 inducers.
  • CYP3A4 Inhibitors: use in combination with CYP3A4 inhibitors could decrease the effectiveness of Ifoxan. (7.2)

7.1 Inducers of CYP3A4

CYP3A4 inducers (e.g., carbamazepine, phenytoin, fosphenytoin, phenobarbital, rifampin, St. John Wort) may increase the metabolism of Ifoxan to its active alkylating metabolites. CYP3A4 inducers may increase the formation of the neurotoxic/nephrotoxic Ifoxan metabolite, chloroacetaldehyde. Closely monitor patients taking Ifoxan with CYP3A4 inducers for toxicities and consider dose adjustment.

7.2 Inhibitors of CYP3A4

CYP3A4 inhibitors (e.g., ketoconazole, fluconazole, itraconazole, sorafenib, aprepitant, fosaprepitant, grapefruit, grapefruit juice) may decrease the metabolism of Ifoxan to its active alkylating metabolites, perhaps decreasing the effectiveness of Ifoxan treatment.

8 USE IN SPECIFIC POPULATIONS

  • Pregnancy: fetal growth retardation and neonatal anemia.
  • Geriatric use: dose selection should be cautious. (8.5)
  • Patients with renal impairment: monitor for toxicity and consider dose reduction as needed ( 8.6)

8.1 Pregnancy

Pregnancy Category D.

.

Ifoxan 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 Ifoxan is capable of causing gene mutations and chromosomal damage in vivo. In pregnant mice, resorptions increased and anomalies were present at day 19 after a 30 mg/m2 dose of Ifoxan was administered on day 11 of gestation. Embryo-lethal effects were observed in rats following the administration of 54 mg/m2 doses of Ifoxan 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. Ifoxan 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 Ifoxan. 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.

8.3 Nursing Mothers

Ifoxan is excreted in breast milk. Because of the potential for serious adverse events and the tumorigenicity shown for Ifoxan 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 Ifoxan.

8.4 Pediatric Use

Safety and effectiveness have not been established in pediatric patients.

8.5 Geriatric Use

In general, dose selection for an elderly patient should be cautious, reflecting 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. This apparent increase in half-life appeared to be related to increases in volume of distribution of Ifoxan with age. No significant changes in total plasma clearance or renal or non-renal clearance with age were reported.

Ifoxan 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.

8.6 Use in Patients with Renal Impairment

No formal studies were conducted in patients with renal impairment. Ifoxan 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. Ifoxan and its metabolites are dialyzable.

8.7 Use in Patients with Hepatic Impairment

No formal studies were conducted in patients with hepatic impairment. Ifoxan is extensively metabolized in the liver and forms both efficacious and toxic metabolites. Ifoxan should be given cautiously to patients with impaired hepatic function.

10 OVERDOSAGE

No specific antidote for Ifoxan 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.

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. Ifoxan as well as Ifoxan metabolites are dialyzable.

Cystitis prophylaxis with mesna may be helpful in preventing or limiting urotoxic effects with overdose.

11 DESCRIPTION

Ifoxan (ifosfamide for injection, USP) single-dose vials for constitution and administration by intravenous infusion each contain 1 gram or 3 grams of sterile Ifoxan. Ifoxan is a chemotherapeutic agent chemically related to the nitrogen mustards and a synthetic analog of cyclophosphamide. Ifoxan 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. Ifoxan is a white crystalline powder soluble in water. There are no excipients in the formulation. Each vial contains 1 gram or 3 grams of sterile Ifoxan alone.

Its structural formula is:

Ifoxan Container Label

NDC 0338-3991-01

Ifoxan

Ifoxan FOR INJECTION, USP

Rx only

1 g

SINGLE-DOSE VIAL

This vial contains 1g Ifoxan.

Add 20 mL Sterile Water for

Injection, USP, or Sterile

Bacteriostatic Water for Injection,

USP, (benzyl alcohol or parabens

preserved), shaking to dissolve,

for a reconstituted concentration

of 50 mg per mL.

Store at controlled room

temperature 20° C to 25° C

(68° F to 77° F)

Protect from temperatures

above 30° C (86° F).

FOR IV USE

READ ACCOMPANYING

PACKAGE INSERT for detailed

indications, dosage, and

precautions.

Manufactured by:

Baxter Healthcare Corporation

Deerfield, IL 60015 USA

USA 5561 0780 C 85

Bar Code

N(01)1 03 0338 3991 01 7

Lot:/Exp.:

Ifoxan Carton Label

1 vial

NDC 0338-3991-01

Ifoxan

(ifosfamide for injection, USP)

Single-Dose Vial

FOR IV USE

Rx only

1 g

Baxter Logo

Manufactured by

Baxter Healthcare Corporation

Deerfield, IL 60015 USA

See bottom panel for lot

number and expiration date.

Bar Code

N3 0338399101 0

This vial contains 1 g Ifoxan. Add

20 mL Sterile Water for Injection, USP,

or Sterile Bacteriostatic Water for

Injection, USP, (benzyl alcohol or

parabens preserved), shaking to

dissolve, for a reconstituted

concentration of 50 mg per mL.

READ ACCOMPANYING PACKAGE

INSERT for detailed indications,

dosage, and precautions.

Store at controlled room

temperature 20° C to 25° C

(68° F to 77° F). Protect from

temperatures above 30° C (86° F).

Constituted solutions should be

refrigerated and used within 24 hours.

Manufactured by:

Baxter Healthcare Corporation

Deerfield, IL 60015 USA

Made in Germany

NDC 0338-3993-01

Ifoxan

Ifoxan FOR INJECTION, USP

Rx only

3 g

SINGLE-DOSE VIAL

This vial contains 3g Ifoxan.

Add 60 mL Sterile Water for

Injection, USP, or Sterile

Bacteriostatic Water for Injection,

USP, (benzyl alcohol or parabens

preserved), shaking to dissolve,

for a reconstituted concentration

of 50 mg per mL.

Store at controlled room

temperature 20° C to 25° C

(68° F to 77° F)

Protect from temperatures

above 30° C (86° F).

FOR IV USE

READ ACCOMPANYING

PACKAGE INSERT for detailed

indications, dosage, and

precautions.

Manufactured by:

Baxter Healthcare Corporation

Deerfield, IL 60015 USA

USA 5561 0790 C 86

Bar Code

N(01)1 03 0338 3993 01 1

Lot:/Exp.:

JMXXX

MM.JJJJ

1 vial

NDC 0338-3993-01

Ifoxan

(ifosfamide for injection, USP)

Single-Dose Vial

FOR IV USE

Rx only

3 g

Baxter Logo

Manufactured by

Baxter Healthcare Corporation

Deerfield, IL 60015 USA

See bottom panel for lot

number and expiration date.

Bar Code

N3 0338399301 4

This vial contains 3 g Ifoxan.

Add 60 mL Sterile Water for Injection, USP,

or Sterile Bacteriostatic Water for

Injection, USP, (benzyl alcohol or

parabens preserved), shaking to

dissolve, for a reconstituted

concentration of 50 mg per mL.

READ ACCOMPANYING PACKAGE

INSERT for detailed indications,

dosage, and precautions.

Store at controlled room

temperature 20° C to 25° C

(68° F to 77° F). Protect from

temperatures above 30° C (86° F).

Constituted solutions should be

refrigerated and used within 24 hours.

Manufactured by:

Baxter Healthcare Corporation

Deerfield, IL 60015 USA

Made in Germany

Ifoxan pharmaceutical active ingredients containing related brand and generic drugs:

infoActive ingredient is the part of the drug or medicine which is biologically active. This portion of the drug is responsible for the main action of the drug which is intended to cure or reduce the symptom or disease. The other portions of the drug which are inactive are called excipients; there role is to act as vehicle or binder. In contrast to active ingredient, the inactive ingredient's role is not significant in the cure or treatment of the disease. There can be one or more active ingredients in a drug.


Ifoxan available forms, composition, doses:

infoForm of the medicine is the form in which the medicine is marketed in the market, for example, a medicine X can be in the form of capsule or the form of chewable tablet or the form of tablet. Sometimes same medicine can be available as injection form. Each medicine cannot be in all forms but can be marketed in 1, 2, or 3 forms which the pharmaceutical company decided based on various background research results.
Composition is the list of ingredients which combinedly form a medicine. Both active ingredients and inactive ingredients form the composition. The active ingredient gives the desired therapeutic effect whereas the inactive ingredient helps in making the medicine stable.
Doses are various strengths of the medicine like 10mg, 20mg, 30mg and so on. Each medicine comes in various doses which is decided by the manufacturer, that is, pharmaceutical company. The dose is decided on the severity of the symptom or disease.


Ifoxan destination | category:

infoDestination is defined as the organism to which the drug or medicine is targeted. For most of the drugs what we discuss, human is the drug destination.
Drug category can be defined as major classification of the drug. For example, an antihistaminic or an antipyretic or anti anginal or pain killer, anti-inflammatory or so.


Ifoxan Anatomical Therapeutic Chemical codes:

infoA medicine is classified depending on the organ or system it acts [Anatomical], based on what result it gives on what disease, symptom [Therapeutical], based on chemical composition [Chemical]. It is called as ATC code. The code is based on Active ingredients of the medicine. A medicine can have different codes as sometimes it acts on different organs for different indications. Same way, different brands with same active ingredients and same indications can have same ATC code.


Ifoxan pharmaceutical companies:

infoPharmaceutical companies are drug manufacturing companies that help in complete development of the drug from the background research to formation, clinical trials, release of the drug into the market and marketing of the drug.
Researchers are the persons who are responsible for the scientific research and is responsible for all the background clinical trials that resulted in the development of the drug.


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References

  1. Dailymed."IFEX (IFOSFAMIDE) INJECTION, POWDER, FOR SOLUTION [BAXTER HEALTHCARE CORPORATION]". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
  2. Dailymed."IFOSFAMIDE: DailyMed provides trustworthy information about marketed drugs in the United States. DailyMed is the official provider of FDA label information (package inserts).". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
  3. "ifosfamide". https://pubchem.ncbi.nlm.nih.gov/co... (accessed August 28, 2018).

Frequently asked Questions

Can i drive or operate heavy machine after consuming Ifoxan?

Depending on the reaction of the Ifoxan after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Ifoxan not safe to drive or operate heavy machine after consumption. Meaning that, do not drive or operate heavy duty machines after taking the capsule if the capsule has a strange reaction on your body like dizziness, drowsiness. As prescribed by a pharmacist, it is dangerous to take alcohol while taking medicines as it exposed patients to drowsiness and health risk. Please take note of such effect most especially when taking Primosa capsule. It's advisable to consult your doctor on time for a proper recommendation and medical consultations.

Is Ifoxan addictive or habit forming?

Medicines are not designed with the mind of creating an addiction or abuse on the health of the users. Addictive Medicine is categorically called Controlled substances by the government. For instance, Schedule H or X in India and schedule II-V in the US are controlled substances.

Please consult the medicine instruction manual on how to use and ensure it is not a controlled substance.In conclusion, self medication is a killer to your health. Consult your doctor for a proper prescription, recommendation, and guidiance.

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Review

sDrugs.com conducted a study on Ifoxan, and the result of the survey is set out below. It is noteworthy that the product of the survey is based on the perception and impressions of the visitors of the website as well as the views of Ifoxan consumers. We, as a result of this, advice that you do not base your therapeutic or medical decisions on this result, but rather consult your certified medical experts for their recommendations.

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The information was verified by Dr. Arunabha Ray, MD Pharmacology

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