Ifoxan with Mesna

Ifosfamide:

• Warning: myelosuppression, neurotoxicity, and urotoxicity
• Indications and usage
• Dosage and administration
• Dosage forms and strengths
• Contraindications
• Warnings and precautions
• Adverse reactions
• Drug interactions
• Use in specific populations
• Overdosage
• Description
• Ifoxan with Mesna (Ifosfamide) reviews

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 with Mesna (Ifosfamide) 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 with Mesna (Ifosfamide) 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)

2 DOSAGE AND ADMINISTRATION

Ifoxan with Mesna (Ifosfamide) 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 with Mesna (Ifosfamide) 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 with Mesna (Ifosfamide) should be administered as a slow intravenous infusion lasting a minimum of 30 minutes. Studies of Ifoxan with Mesna (Ifosfamide) 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:

Solutions of Ifoxan with Mesna (Ifosfamide) may be diluted further to achieve concentrations of 0.6 to 20 mg/mL in the following fluids:

5% Dextrose Injection, USP

0.9% Sodium Chloride Injection, USP

Lactated Ringer’s 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 with Mesna (Ifosfamide) should be refrigerated and used within 24 hours. Benzyl-alcohol-containing solutions can reduce the stability of Ifoxan with Mesna (Ifosfamide).

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 with Mesna (Ifosfamide) 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 with Mesna (Ifosfamide) 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)

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 with Mesna (Ifosfamide) is contraindicated in patients with:

• Known hypersensitivity to administration of Ifoxan with Mesna (Ifosfamide).
• Urinary outflow obstruction.

• Known hypersensitivity to administration of Ifoxan with Mesna (Ifosfamide). (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 with Mesna (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 Ifoxan with Mesna (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 Ifoxan with Mesna (Ifosfamide) include pneumonias, as well as other bacterial, fungal, viral, and parasitic infections. Latent infections can be reactivated. In patients treated with Ifoxan with Mesna (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, Ifoxan with Mesna (Ifosfamide) should not be given to patients with a WBC count below 2000/µL and/or a platelet count below 50,000/µL.

Ifoxan with Mesna (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.

5.2 Central Nervous System Toxicity, Neurotoxicity

Administration of Ifoxan with Mesna 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 with Mesna (Ifosfamide) therapy. There have also been reports of peripheral neuropathy associated with Ifoxan with Mesna (Ifosfamide) use.

Ifoxan with Mesna (Ifosfamide) 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 with Mesna (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 Ifoxan with Mesna (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.

5.3 Renal and Urothelial Toxicity and Effects

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

Disorders of renal function, (glomerular and tubular) following Ifoxan with Mesna (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 Ifoxan with Mesna (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 Ifoxan with Mesna (Ifosfamide) treatment.

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

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

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

5.4 Cardiotoxicity

Manifestations of cardiotoxicity reported with Ifoxan with Mesna 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 with Mesna (Ifosfamide) 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 with Mesna (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.

5.6 Secondary Malignancies

Treatment with Ifoxan with Mesna 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 with Mesna (Ifosfamide) or regimens with Ifoxan with Mesna (Ifosfamide) 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 with Mesna (Ifosfamide).

5.8 Pregnancy

Ifoxan with Mesna 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 with Mesna (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 Ifoxan with Mesna (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.

5.9 Effects on Fertility

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

5.10 Anaphylactic/Anaphylactoid Reactions and Cross-sensitivity

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

Cross-sensitivity between oxazaphosphorine cytotoxic agents has been reported.

5.11 Impairment of Wound Healing

Ifoxan with Mesna (Ifosfamide) may interfere with normal wound healing.

5.12 Nursing

Ifoxan with Mesna (Ifosfamide) is excreted in breast milk. Women must not breastfeed during treatment with Ifoxan with Mesna (Ifosfamide).

6 ADVERSE REACTIONS

In clinical trials of Ifoxan with Mesna 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 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 with Mesna (Ifosfamide) as monotherapy with a total dose of 4 to 12 g/m² per course.

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 with Mesna (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 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

7 DRUG INTERACTIONS

Ifoxan with Mesna is a substrate for both CYP3A4 and CYP2B6.

• CYP3A4 Inducers: monitor for increased toxicity when used in combination with CYP3A4 inducers. (7.1)
• CYP3A4 Inhibitors: use in combination with CYP3A4 inhibitors could decrease the effectiveness of Ifoxan with Mesna (Ifosfamide). (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 with Mesna (Ifosfamide) to its active alkylating metabolites. CYP3A4 inducers may increase the formation of the neurotoxic/nephrotoxic Ifoxan with Mesna (Ifosfamide) metabolite, chloroacetaldehyde. Closely monitor patients taking Ifoxan with Mesna (Ifosfamide) 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 with Mesna (Ifosfamide) to its active alkylating metabolites, perhaps decreasing the effectiveness of Ifoxan with Mesna (Ifosfamide) 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 with Mesna (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 Ifoxan with Mesna (Ifosfamide) 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 with Mesna (Ifosfamide) was administered on day 11 of gestation. Embryo-lethal effects were observed in rats following the administration of 54 mg/m² doses of Ifoxan with Mesna (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. Ifoxan with Mesna (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 Ifoxan with Mesna (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.

8.3 Nursing Mothers

Ifoxan with Mesna (Ifosfamide) is excreted in breast milk. Because of the potential for serious adverse events and the tumorigenicity shown for Ifoxan with Mesna (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 Ifoxan with Mesna (Ifosfamide).

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 Mesna (Ifosfamide) with age. No significant changes in total plasma clearance or renal or non-renal clearance with age were reported.

Ifoxan with Mesna (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.

8.6 Use in Patients with Renal Impairment

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

8.7 Use in Patients with Hepatic Impairment

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

10 OVERDOSAGE

No specific antidote for Ifoxan with Mesna (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.

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 with Mesna (Ifosfamide) as well as Ifoxan with Mesna (Ifosfamide) metabolites are dialyzable.

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

11 DESCRIPTION

Ifoxan with Mesna (Ifosfamide) (ifosfamide for injection, USP) single-dose vials for constitution and administration by intravenous infusion each contain 1 gram or 3 grams of sterile Ifoxan with Mesna (Ifosfamide). Ifoxan with Mesna (Ifosfamide) is a chemotherapeutic agent chemically related to the nitrogen mustards and a synthetic analog of cyclophosphamide. Ifoxan with Mesna (Ifosfamide) is 3-(2-chloroethyl)-2-[(2-chloroethyl)amino]tetrahydro-2H-1,3,2-oxazaphosphorine 2-oxide. The molecular formula is C₇H₁₅Cl₂N₂O₂P and its molecular weight is 261.1. Ifoxan with Mesna (Ifosfamide) 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 with Mesna (Ifosfamide) alone.

Its structural formula is:

Ifoxan with Mesna (Ifosfamide) Container Label

NDC 0338-3991-01

Ifoxan with Mesna (Ifosfamide)

Ifoxan with Mesna (Ifosfamide) FOR INJECTION, USP

Rx only

1 g

SINGLE-DOSE VIAL

This vial contains 1g Ifoxan with Mesna (Ifosfamide).

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 with Mesna (Ifosfamide) Carton Label

1 vial

NDC 0338-3991-01

Ifoxan with Mesna (Ifosfamide)

(ifosfamide for injection, USP)

Single-Dose Vial

FOR IV USE

Rx only

1 g

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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 with Mesna (Ifosfamide). 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 with Mesna (Ifosfamide)

Ifoxan with Mesna (Ifosfamide) FOR INJECTION, USP

Rx only

3 g

SINGLE-DOSE VIAL

This vial contains 3g Ifoxan with Mesna (Ifosfamide).

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 with Mesna (Ifosfamide)

(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 with Mesna (Ifosfamide).

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

Mesna:

• Indications and usage
• Dosage and administration
• Dosage forms and strengths
• Contraindications
• Warnings and precautions
• Adverse reactions
• Drug interactions
• Use in specific populations
• Overdosage
• Description
• Clinical pharmacology
• Nonclinical toxicology
• Clinical studies
• How supplied/storage and handling
• Patient counseling information
• Ifoxan with Mesna (Mesna) reviews

1 INDICATIONS AND USAGE

Ifoxan with Mesna (Mesna) is indicated as a prophylactic agent in reducing the incidence of ifosfamide-induced hemorrhagic cystitis.

Limitation of Use:

Ifoxan with Mesna (Mesna) is not indicated to reduce the risk of hematuria due to other pathological conditions such as thrombocytopenia.

Ifoxan with Mesna (Mesna) is a cytoprotective agent indicated as a prophylactic agent in reducing the incidence of ifosfamide-induced hemorrhagic cystitis. (1)

Limitation of Use:

Ifoxan with Mesna (Mesna) is not indicated to reduce the risk of hematuria due to other pathological conditions such as thrombocytopenia. (1)

2 DOSAGE AND ADMINISTRATION

Ifoxan with Mesna may be given on a fractionated dosing schedule of three bolus intravenous injections or a single bolus injection followed by two oral administrations of Ifoxan with Mesna (Mesna) Tablets as outlined below. The dosing schedule should be repeated on each day that ifosfamide is administered. When the dosage of ifosfamide is adjusted, the ratio of Ifoxan with Mesna (Mesna) to ifosfamide should be maintained. (2)

Maintain sufficient urinary output, as required for ifosfamide treatment, and monitor urine for the presence of hematuria. (2.3)

2.1 Intravenous Dosing

Ifoxan with Mesna (Mesna) may be given on a fractionated dosing schedule of three bolus intravenous injections as outlined below.

Ifoxan with Mesna (Mesna) injection is given as intravenous bolus injections in a dosage equal to 20% of the ifosfamide dosage weight by weight (w/w) at the time of ifosfamide administration and 4 and 8 hours after each dose of ifosfamide. The total daily dose of Ifoxan with Mesna (Mesna) is 60% of the ifosfamide dose. The recommended dosing schedule is outlined below in Table 1.

2.2 Intravenous and Oral Dosing

Ifoxan with Mesna may be given on a fractionated dosing schedule of a single bolus injection followed by two oral administrations of Ifoxan with Mesna (Mesna) tablets as outlined below.

Ifoxan with Mesna (Mesna) injection is given as intravenous bolus injections in a dosage equal to 20% of the ifosfamide dosage (w/w) at the time of ifosfamide administration. Ifoxan with Mesna (Mesna) tablets are given orally in a dosage equal to 40% of the ifosfamide dose 2 and 6 hours after each dose of ifosfamide. The total daily dose of Ifoxan with Mesna (Mesna) is 100% of the ifosfamide dose. The recommended dosing schedule is outlined in Table 2.

The efficacy and safety of this ratio of intravenous and oral Ifoxan with Mesna (Mesna) has not been established as being effective for daily doses of ifosfamide higher than 2 g/m².

Patients who vomit within two hours of taking oral Ifoxan with Mesna (Mesna) should repeat the dose or receive intravenous Ifoxan with Mesna (Mesna).

2.3 Monitoring for Hematuria

Maintain adequate hydration and sufficient urinary output, as required for ifosfamide treatment, and monitor urine for the presence of hematuria. If severe hematuria develops when Ifoxan with Mesna (Mesna) is given according to the recommended dosage schedule, dosage reductions or discontinuation of ifosfamide therapy may be required.

2.4 Preparation for Intravenous Administration and Stability

Preparation

Determine the volume of Ifoxan with Mesna (Mesna) injection for the intended dose.

Dilute the volume of Ifoxan with Mesna (Mesna) injection for the dose in any of the following fluids to obtain a final concentration of 20 mg/mL:

• 5% Dextrose Injection, USP
• 5% Dextrose and 0.2% Sodium Chloride Injection, USP
• 5% Dextrose and 0.33% Sodium Chloride Injection, USP
• 5% Dextrose and 0.45% Sodium Chloride Injection, USP
• 0.9% Sodium Chloride Injection, USP
• Lactated Ringer’s Injection, USP

Stability

The Ifoxan with Mesna (Mesna) injection multidose vials may be stored and used for up to 8 days after initial puncture.

Store diluted solutions at 25°C (77°F). Use diluted solutions within 24 hours.

Do not mix Ifoxan with Mesna (Mesna) injection with epirubicin, cyclophosphamide, cisplatin, carboplatin, and nitrogen mustard.

The benzyl alcohol contained in Ifoxan with Mesna (Mesna) injection vials can reduce the stability of ifosfamide. Ifosfamide and Ifoxan with Mesna (Mesna) may be mixed in the same bag provided the final concentration of ifosfamide does not exceed 50 mg/mL. Higher concentrations of ifosfamide may not be compatible with Ifoxan with Mesna (Mesna) and may reduce the stability of ifosfamide.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Any solutions which are discolored, hazy, or contain visible particulate matter should not be used.

3 DOSAGE FORMS AND STRENGTHS

• Ifoxan with Mesna (Mesna) injection: 1 g Multidose Vial, 100 mg/mL
• Ifoxan with Mesna (Mesna) tablets: 400 mg film-coated tablets with functional score

• Injection: 1g (100 mg/mL) Multidose vials (3)
• Tablets: 400 mg with functional score (3)

4 CONTRAINDICATIONS

Ifoxan with Mesna (Mesna) is contraindicated in patients known to be hypersensitive to Ifoxan with Mesna (Mesna) or to any of the excipients.

• Known hypersensitivity to Ifoxan with Mesna (Mesna) or to any of the excipients, including benzyl alcohol. (4)

5 WARNINGS AND PRECAUTIONS

• Hypersensitivity reactions: Anaphylactic reactions have been reported. Less severe hypersensitivity reactions may also occur. Monitor patients. If a reaction occurs, discontinue Ifoxan with Mesna and provide supportive care. (5.1)
• Dermatologic toxicity: Skin rash with eosinophilia and systemic symptoms, Stevens-Johnson syndrome, and toxic epidermal necrolysis have occurred. Skin rash, urticaria, and angioedema have also been seen. Monitor patients. If a reaction occurs, discontinue Ifoxan with Mesna (Mesna) and provide supportive care. (5.2)
• Benzyl alcohol toxicity: The preservative benzyl alcohol has been associated with serious adverse reactions and death in neonates and premature infants. Avoid use in neonates, premature, and low-birth weight infants. (5.3)
• Laboratory test alterations: False positive tests for urinary ketones and interference with enzymatic CPK activity tests have been seen. (5.4)

5.1 Hypersensitivity Reactions

Ifoxan with Mesna (Mesna) may cause systemic hypersensitivity reactions, including anaphylaxis. These reactions may include fever, cardiovascular symptoms (hypotension, tachycardia), acute renal impairment, hypoxia, respiratory distress, urticaria, angioedema, laboratory signs of disseminated intravascular coagulation, hematological abnormalities, increased liver enzymes, nausea, vomiting, arthralgia, and myalgia. These reactions may occur with the first exposure or after several months of exposure. Monitor for signs or symptoms. Discontinue Ifoxan with Mesna (Mesna) and provide supportive care.

5.2 Dermatologic Toxicity

Drug rash with eosinophilia and systemic symptoms and bullous and ulcerative skin and mucosal reactions, consistent with Stevens-Johnson syndrome or toxic epidermal necrolysis have occurred. Ifoxan with Mesna may cause skin and mucosal reactions characterized by urticaria, rash, erythema, pruritus, burning sensation, angioedema, periorbital edema, flushing and stomatitis. These reactions may occur with the first exposure or after several months of exposure. Discontinue Ifoxan with Mesna (Mesna) and provide supportive care.

5.3 Benzyl Alcohol Toxicity

Benzyl alcohol, a preservative in Ifoxan with Mesna (Mesna), has been associated with serious adverse reactions and death (including gasping syndrome) in neonates, premature, and low-birth weight infants. The minimum amount of benzyl alcohol at which toxicity may occur is not known. Consider the combined daily metabolic load of benzyl alcohol from all sources when prescribing Ifoxan with Mesna (Mesna) (10.4 mg benzyl alcohol per mL). Neonates, premature, and low-birth weight infants, as well as patients receiving high dosages, may be more likely to develop toxicity. Monitor patients for signs or symptoms of toxicity. Avoid use in neonates, premature, and low-birth weight infants..

5.4 Laboratory Test Interferences

False-Positive Urine Tests for Ketone Bodies

A false positive test for urinary ketones may arise in patients treated with Ifoxan with Mesna when using nitroprusside sodium-based urine tests (including dipstick tests). The addition of glacial acetic acid can be used to differentiate between a false positive result (cherry-red color that fades) and a true positive result (red-violet color that intensifies).

False-Negative Tests for Enzymatic CPK Activity

Ifoxan with Mesna (Mesna) may interfere with enzymatic creatinine phosphokinase (CPK) activity tests that use a thiol compound (e.g., N-acetylcysteine) for CPK reactiviation. This may result in a falsely low CPK level.

False-Positive Tests for Ascorbic Acid

Ifoxan with Mesna (Mesna) may cause false-positive reactions in Tillman’s reagent-based urine screening tests for ascorbic acid.

5.5 Use in Patients with a History of Adverse Reactions to Thiol Compounds

Ifoxan with Mesna (Mesna) is a thiol compound, i.e., a sulfhydryl (SH) group-containing organic compound. Hypersensitivity reactions to Ifoxan with Mesna (Mesna) and to amifostine, another thiol compound, have been reported. It is not clear whether patients who experienced an adverse reaction to a thiol compound are at increased risk for a hypersensitivity reaction to Ifoxan with Mesna (Mesna).

6 ADVERSE REACTIONS

The following are discussed in more detail in other sections of the labeling.

• Hypersensitivity Reactions
• Dermatological Toxicity
• Benzyl Alcohol Toxicity
• Laboratory Test Interferences
• Use in Patients with a History of Adverse Reactions to Thiol Compounds.

The most common adverse reactions (> 10%) when Ifoxan with Mesna (Mesna) is given with ifosfamide are nausea, vomiting, constipation, leukopenia, fatigue, fever, anorexia, thrombocytopenia, anemia, granulocytopenia, diarrhea, asthenia, abdominal pain, headache, alopecia, and somnolence. (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact Baxter Healthcare at 1-866-888-2472, or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch

6.1 Clinical Trials Experience

Because clinical trials are conducted under 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 practice.

Ifoxan with Mesna (Mesna) adverse reaction data are available from four Phase 1 studies in which single intravenous doses of 600-1200 mg Ifoxan with Mesna (Mesna) Injection without concurrent chemotherapy were administered to a total of 53 healthy volunteers and single oral doses of 600-2400 mg of Ifoxan with Mesna (Mesna) Tablets were administered to a total of 82 healthy volunteers. The most frequently reported side effects (observed in two or more healthy volunteers) for healthy volunteers receiving single doses of Ifoxan with Mesna (Mesna) Injection alone were headache, injection site reactions, flushing, dizziness, nausea, vomiting, somnolence, diarrhea, anorexia, fever, pharyngitis, hyperesthesia, influenza-like symptoms, and coughing. In two Phase 1 multiple-dose studies where healthy volunteers received Ifoxan with Mesna (Mesna) Tablets alone or intravenous Ifoxan with Mesna (Mesna) followed by repeated doses of Ifoxan with Mesna (Mesna) Tablets, flatulence and rhinitis were reported. In addition, constipation was reported by healthy volunteers who had received repeated doses of intravenous Ifoxan with Mesna (Mesna).

Additional adverse reactions in healthy volunteers receiving Ifoxan with Mesna (Mesna) alone included injection site reactions, abdominal pain/colic, epigastric pain/burning, mucosal irritation, lightheadedness, back pain, arthralgia, myalgia, conjunctivitis, nasal congestion, rigors, paresthesia, photophobia, fatigue, lymphadenopathy, extremity pain, malaise, chest pain, dysuria, pleuritic pain, dry mouth, dyspnea, and hyperhidrosis. In healthy volunteers, Ifoxan with Mesna (Mesna) was commonly associated with a rapid (within 24 hours) decrease in lymphocyte count, which was generally reversible within one week of administration.

Because Ifoxan with Mesna (Mesna) is used in combination with ifosfamide or ifosfamide-containing chemotherapy regimens, it is difficult to distinguish the adverse reactions which may be due to Ifoxan with Mesna (Mesna) from those caused by the concomitantly administered cytotoxic agents.

Adverse reactions reasonably associated with Ifoxan with Mesna (Mesna) administered intravenously and orally in four controlled studies in which patients received ifosfamide or ifosfamide-containing regimens are presented in Table 3.

6.2 Postmarketing Experience

The following adverse reactions have been reported in the postmarketing experience of patients receiving Ifoxan with Mesna (Mesna) in combination with ifosfamide or similar drugs, making it difficult to distinguish the adverse reactions which may be due to Ifoxan with Mesna (Mesna) from those caused by the concomitantly administered cytotoxic agents. Because these reactions are reported from a population of unknown size, precise estimates of frequency cannot be made.

Cardiovascular: Hypertension

Gastrointestinal: Dysgeusia

Hepatobiliary: Hepatitis

Nervous System: Convulsion

Respiratory: Hemoptysis

7 DRUG INTERACTIONS

No clinical drug interaction studies have been conducted with Ifoxan with Mesna (Mesna).

8 USE IN SPECIFIC POPULATIONS

• Pregnancy: Use only if clearly needed.
• Nursing mothers: Women should not breastfeed during therapy. (8.3)
• Geriatric use: Dose selection should be cautious. (8.5)

8.1 Pregnancy

Pregnancy Category B.

Risk Summary

There are no studies of Ifoxan with Mesna in pregnant women. Reproduction studies performed in rats and rabbits at oral doses approximately 10 times the maximum recommended total daily intravenous-oral-oral human dose on a body surface area basis (1000 mg/kg in rabbits and 2000 mg/kg in rats) revealed no evidence of harm to the fetus due to Ifoxan with Mesna (Mesna). The incidence of malformations in human pregnancies has not been established for Ifoxan with Mesna (Mesna). All pregnancies, regardless of drug exposure, have a background rate of 2 to 4% for major malformations and 15 to 20% for pregnancy loss. Because animal reproductive studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

8.3 Nursing Mothers

It is not known whether Ifoxan with Mesna (Mesna) or dimesna is excreted in human milk. Benzyl alcohol present in maternal serum is likely to cross into human milk and may be orally absorbed by a nursing infant. Because many drugs are excreted in human milk and because of the potential for adverse reactions in nursing infants from Ifoxan with Mesna (Mesna), a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

8.4 Pediatric Use

Safety and effectiveness of Ifoxan with Mesna in pediatric patients have not been established. Ifoxan with Mesna (Mesna) contains benzyl alcohol (10.4 mg benzyl alcohol per mL) which has been associated with serious adverse reactions and death in pediatric patients. The "gasping syndrome," (characterized by central nervous system depression, metabolic acidosis and gasping respirations) has been associated with benzyl alcohol dosages >99 mg/kg/day in neonates, premature, and low-birth weight infants. Additional symptoms may include gradual neurological deterioration, seizures, intracranial hemorrhage, hematologic abnormalities, skin breakdown, hepatic and renal failure, hypotension, bradycardia, and cardiovascular collapse. The minimum amount of benzyl alcohol at which toxicity may occur is not known. Neonates, premature, and low-birth weight infants, as well as patients receiving high dosages, may be more likely to develop toxicity. Practitioners administering this and other medications containing benzyl alcohol should consider the combined daily metabolic load of benzyl alcohol from all sources.

8.5 Geriatric Use

Clinical studies of Ifoxan with Mesna (Mesna) did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. 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. The ratio of ifosfamide to Ifoxan with Mesna (Mesna) should remain unchanged.

8.6 Use in Patients with Renal Impairment

No clinical studies were conducted to evaluate the effect of renal impairment on the pharmacokinetics of Ifoxan with Mesna.

8.7 Use in Patients with Hepatic Impairment

No clinical studies were conducted to evaluate the effect of hepatic impairment on the pharmacokinetics of Ifoxan with Mesna (Mesna).

10 OVERDOSAGE

There is no known antidote for Ifoxan with Mesna (Mesna).

In a clinical trial, 11 patients received intravenous Ifoxan with Mesna (Mesna) 10 mg/kg to 66 mg/kg per day for 3 to 5 days. Patients also received ifosfamide or cyclophosphamide. Adverse reactions included nausea, vomiting, diarrhea and fever. An increased rate of these adverse reactions has also been found in oxazaphosphorine-treated patients receiving ≥80 mg Ifoxan with Mesna (Mesna) per kg per day intravenously compared with patients receiving lower doses or hydration treatment only.

Postmarketing, administration of 4.5 g to 6.9 g of Ifoxan with Mesna (Mesna) resulted in hypersensitivity reactions including mild hypotension, shortness of breath, asthma exacerbation, rash, and flushing.

11 DESCRIPTION

Ifoxan with Mesna (Mesna) is a detoxifying agent to inhibit the hemorrhagic cystitis induced by ifosfamide. The active ingredient, Ifoxan with Mesna (Mesna), is a synthetic sulfhydryl compound designated as sodium-2-mercaptoethane sulfonate with a molecular formula of C₂H₅NaO₃S₂ and a molecular weight of 164.18. Its structural formula is as follows:

HS–CH₂–CH₂SO₃–Na⁺

Ifoxan with Mesna (Mesna) (mesna) injection is a sterile, nonpyrogenic, aqueous solution of clear and colorless appearance in clear glass multidose vials for intravenous administration. Ifoxan with Mesna (Mesna) injection contains 100 mg/mL Ifoxan with Mesna (Mesna), 0.25 mg/mL edetate disodium and sodium hydroxide for pH adjustment. Ifoxan with Mesna (Mesna) Injection multidose vials also contain 10.4 mg/mL of benzyl alcohol as a preservative. The solution has a pH range of 7.5-8.5.

Ifoxan with Mesna (Mesna) (mesna) tablets are white, oblong, scored biconvex film-coated tablets with the imprint M4. They contain 400 mg Ifoxan with Mesna (Mesna). The excipients are calcium phosphate, cornstarch, hydroxypropylmethylcellulose, lactose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, povidone, simethicone, and titanium dioxide.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Ifoxan with Mesna reacts chemically with the urotoxic ifosfamide metabolites, acrolein and 4-hydroxy-ifosfamide, resulting in their detoxification. The first step in the detoxification process is the binding of Ifoxan with Mesna (Mesna) to 4-hydroxy-ifosfamide forming a non-urotoxic 4-sulfoethylthioifosfamide. Ifoxan with Mesna (Mesna) also binds to the double bonds of acrolein and to other urotoxic metabolites and inhibits their effects on the bladder.

12.3 Pharmacokinetics

Absorption

Following oral administration, peak plasma concentrations were reached within 1.5 to 4 hours and 3 to 7 hours for free Ifoxan with Mesna (Mesna) and total Ifoxan with Mesna (Mesna) (mesna plus dimesna and mixed disulfides), respectively. Oral bioavailability averaged 58% (range 45 to 71%) for free Ifoxan with Mesna (Mesna) and 89% (range 74 to 104%) for total Ifoxan with Mesna (Mesna) based on plasma AUC data from 8 healthy volunteers who received 1200 mg oral or intravenous doses.

Food does not affect the urinary availability of orally administered Ifoxan with Mesna (Mesna).

Distribution

Mean apparent volume of distribution (V_d) for Ifoxan with Mesna (Mesna) is 0.652 ± 0.242 L/kg after intravenous administration which suggests distribution to total body water (plasma, extracellular fluid, and intracellular water).

Metabolism

Analogous to the physiological cysteine-cystine system, Ifoxan with Mesna (Mesna) is rapidly oxidized to its major metabolite, Ifoxan with Mesna (Mesna) disulfide (dimesna). Plasma concentrations of Ifoxan with Mesna (Mesna) exceed those of dimesna after oral or intravenous administration.

Excretion

Following intravenous administration of a single 800 mg dose, approximately 32% and 33% of the administered dose was eliminated in the urine in 24 hours as Ifoxan with Mesna (Mesna) and dimesna, respectively. Mean plasma elimination half-lives of Ifoxan with Mesna (Mesna) and dimesna are 0.36 hours and 1.17 hours, respectively. Ifoxan with Mesna (Mesna) has a plasma clearance of 1.23 L/h/kg.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

No long-term studies in animals have been performed to evaluate the carcinogenic potential of Ifoxan with Mesna (Mesna).

Ifoxan with Mesna (Mesna) was not genotoxic in the in vitro Ames bacterial mutagenicity assay, the in vitro mammalian lymphocyte chromosomal aberration assay or the in vivo mouse micronucleus assay.

No studies on male or female fertility were conducted. No signs of male or female reproductive organ toxicity were seen in 6-month oral rat studies (≤ 2000 mg/kg/day) or 29-week oral dog studies (520 mg/kg/day) at doses approximately 10-fold higher than the maximum recommended human dose on a body surface area basis.

14 CLINICAL STUDIES

14.1 Intravenous Ifoxan with Mesna

Hemorrhagic cystitis produced by ifosfamide is dose dependent (Table 4). At a dose of 1.2 g/m² ifosfamide administered daily for 5 days, 16 to 26% of the patients who received conventional uroprophylaxis (high fluid intake, alkalinization of the urine, and the administration of diuretics) developed hematuria (>50 RBC per hpf or macrohematuria) (Studies 1, 2, and 3). In contrast, none of the patients who received Ifoxan with Mesna (Mesna) injection together with this dose of ifosfamide developed hematuria (Studies 3 and 4). In two randomized studies, (Studies 5 and 6), higher doses of ifosfamide, from 2 g/m² to 4 g/m² administered for 3 to 5 days, produced hematuria in 31 to 100% of the patients. When Ifoxan with Mesna (Mesna) was administered together with these doses of ifosfamide, the incidence of hematuria was less than 7%.

14.2 Oral Ifoxan with Mesna

Clinical studies comparing recommended intravenous and oral Ifoxan with Mesna (Mesna) dosing regimens demonstrated incidences of grade 3 to 4 hematuria of <5%. Study 7 was an open label, randomized, two-way crossover study comparing three intravenous doses with an initial intravenous dose followed by two oral doses of Ifoxan with Mesna (Mesna) in patients with cancer treated with ifosfamide at a dose of 1.2 g/m² to 2.0 g/m² for 3 to 5 days. Study 8 was a randomized, multicenter study in cancer patients receiving ifosfamide at 2.0 g/m² for 5 days. In both studies, development of grade 3 or 4 hematuria was the primary efficacy endpoint. The percent of patients developing hematuria in each of these studies is presented in Table 5.

16 HOW SUPPLIED/STORAGE AND HANDLING

Ifoxan with Mesna (Mesna) (mesna) injection 100 mg/mL

• NDC 0338-1305-01
  

  1 g Multidose Vial, Box of 1 vial of 10 mL

• NDC 0338-1305-03
  

  1 g Multidose Vial, Box of 10 vials of 10 mL

Store at 20°C to 25°C (68°F to 77°F), excursions permitted to 15°C to 30°C (59°F to 86°F)

Ifoxan with Mesna (Mesna) (mesna) tablets

• NDC 67108-3565-9
  

  400 mg scored tablets packaged in box of 10 tablets

Store at 20°C to 25°C (68°F to 77°F), excursions permitted to 15°C to 30°C (59°F to 86°F)

17 PATIENT COUNSELING INFORMATION

• Advise the patient to discontinue Ifoxan with Mesna (Mesna) and seek immediate medical attention if any signs or symptoms of a hypersensitivity reaction, including systemic anaphylactic reactions occur.
• Advise the patient to take Ifoxan with Mesna (Mesna) at the exact time and in the exact amount as prescribed. Advise the patient to contact their healthcare provider if they vomit within 2 hours of taking oral Ifoxan with Mesna (Mesna), or if they miss a dose of oral Ifoxan with Mesna (Mesna).
• Ifoxan with Mesna (Mesna) does not prevent hemorrhagic cystitis in all patients nor does it prevent or alleviate any of the other adverse reactions or toxicities associated with ifosfamide. Advise the patient to report to their healthcare provider if his/her urine has turned a pink or red color.
• Advise the patient to drink 1 to 2 liters of fluid each day during Ifoxan with Mesna (Mesna) therapy.
• Advise the patient that Stevens-Johnson syndrome, toxic epidermal necrolysis, and drug rash with eosinophilia and systemic symptoms and bullous and ulcerative skin and mucosal reactions have occurred with Ifoxan with Mesna (Mesna). Advise the patient to report to their healthcare provider if signs and symptoms of these syndromes occur.

Baxter Logo

Ifoxan with Mesna (Mesna) (mesna) injection manufactured by:

Ifoxan with Mesna (Mesna) (mesna) tablets manufactured for:

Baxter Healthcare Corporation

Deerfield, IL 60015 USA

For Product Inquiry 1800 ANA DRUG (1-800-262-3784)

Made in Germany

Baxter, Ifoxan with Mesna (Mesna), and IFEX are trademarks of Baxter International Inc.

Material No. HA-30-01-447

Patient Information

Ifoxan with Mesna (Mesna) (MES-nex)

(mesna)

tablets

Ifoxan with Mesna (Mesna) (MES-nex)

(mesna)

injection

What is the most important information I should know about Ifoxan with Mesna (Mesna)?

Ifoxan with Mesna (Mesna) can cause serious allergic reactions and skin reactions. These side effects can happen the first time you are treated with Ifoxan with Mesna (Mesna), or after several months of treatment with Ifoxan with Mesna (Mesna). Stop treatment with Ifoxan with Mesna (Mesna) and call your doctor or go to the nearest hospital emergency room right away if you develop any of the symptoms listed below:

• fever
• swelling of your face, lips, mouth, or tongue
• trouble breathing or wheezing
• itching
• burning
• skin rash or hives
• skin redness or swelling
• skin blisters or peeling
• feel lightheaded or faint
• feel like your heart is racing
• nausea or vomiting
• joint or muscle aches
• mouth sores

See “What are the possible side effects of Ifoxan with Mesna (Mesna)?” for more information about side effects.

What is Ifoxan with Mesna (Mesna)?

Ifoxan with Mesna (Mesna) is a prescription medicine used to reduce the risk of inflammation and bleeding of the bladder (hemorrhagic cystitis) in people who receive ifosfamide (a medicine used to treat cancer).

Ifoxan with Mesna (Mesna) is not for use to reduce the risk of blood in the urine (hematuria) due to other medical conditions.

It is not known if Ifoxan with Mesna (Mesna) is safe and effective in children.

Who should not receive Ifoxan with Mesna (Mesna)?

Do not take Ifoxan with Mesna (Mesna) if you are allergic to Ifoxan with Mesna (Mesna) or any of the ingredients in Ifoxan with Mesna (Mesna). See the end of this leaflet for a complete list of ingredients in Ifoxan with Mesna (Mesna).

What should I tell my doctor before receiving Ifoxan with Mesna (Mesna)?

Before you receive Ifoxan with Mesna (Mesna), tell your doctor if you:

• have any other medical conditions
• are pregnant or plan to become pregnant. It is not known if Ifoxan with Mesna (Mesna) will harm your unborn baby.
• are breastfeeding or plan to breastfeed. It is not known if Ifoxan with Mesna (Mesna) passes into your breast milk. You and your doctor should decide if you will receive Ifoxan with Mesna (Mesna) or breastfeed. You should not do both.

Tell your doctor about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.

How will I receive Ifoxan with Mesna (Mesna)?

• Ifoxan with Mesna (Mesna) is given on the same day that you receive ifosfamide.
• Ifoxan with Mesna (Mesna) can be given by an intravenous (IV) infusion into a vein or tablets taken by mouth.
• You will receive Ifoxan with Mesna (Mesna) in one of two ways:
  • Ifoxan with Mesna (Mesna) intravenous (IV) infusion into a vein at the time you receive ifosfamide and 4 and 8 hours after you receive ifosfamide.
  • Ifoxan with Mesna (Mesna) intravenous (IV) infusion into a vein at the time you receive ifosfamide and Ifoxan with Mesna (Mesna) tablets taken by mouth 2 and 6 hours after you receive ifosfamide.
• Take Ifoxan with Mesna (Mesna) tablets at the exact times and the exact dose your doctor tells you to take it.
• You may need to take half of a Ifoxan with Mesna (Mesna) tablet for your complete dose. Each tablet has a groove in the middle that will make it easier to break the tablet in half.
• During treatment with Ifoxan with Mesna (Mesna),you should drink 4 to 8 cups of liquid (1 to 2 liters) each day, whether you receive Ifoxan with Mesna (Mesna) by intravenous infusion or take Ifoxan with Mesna (Mesna) tablets by mouth.
• Tell your doctor if you:
  • vomit within 2 hours of taking Ifoxan with Mesna (Mesna) tablets by mouth
  • miss a dose of Ifoxan with Mesna (Mesna) tablets
  • have pink or red colored urine

What are the possible side effects of Ifoxan with Mesna (Mesna)?

Ifoxan with Mesna (Mesna) may cause serious side effects, including:

See “What is the most important information I should know about Ifoxan with Mesna (Mesna)?”

• Ifoxan with Mesna (Mesna) that is given by intravenous infusion contains the preservative benzyl alcohol. Benzyl alcohol has been shown to cause serious side effects and death in newborn, premature, and low-birth weight babies. Ifoxan with Mesna (Mesna) tablets do not contain benzyl alcohol.

The most common side effects of Ifoxan with Mesna (Mesna) when given with ifosfamide include:

• nausea
• vomiting
• constipation
• decreased white blood cell count
• tiredness
• fever
• decreased appetite
• decreased platelet count
• decreased red blood cell count
• diarrhea
• weakness
• stomach (abdomen) pain
• headache
• hair loss
• sleepiness

Tell your doctor if you have any side effect that bothers you or that does not go away.

These are not all the possible side effects of Ifoxan with Mesna (Mesna). For more information, ask your doctor or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store Ifoxan with Mesna (Mesna) tablets?

• Store Ifoxan with Mesna (Mesna) tablets at room temperature between 68°F to 77°F (20°C to 25°C).

Keep Ifoxan with Mesna (Mesna) and all medicines out of the reach of children.

General information about the safe and effective use of Ifoxan with Mesna (Mesna)

Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use Ifoxan with Mesna (Mesna) for a condition for which it was not prescribed. Do not give Ifoxan with Mesna (Mesna) to other people, even if they have the same symptoms that you have. It may harm them. If you would like more information, talk with your doctor. You can ask your pharmacist or doctor for information about Ifoxan with Mesna (Mesna) that is written for health professionals.

For more information, call 1-800-262-3784.

What are the ingredients in Ifoxan with Mesna (Mesna)?

Active ingredient: Ifoxan with Mesna (Mesna)

Inactive ingredients:

Ifoxan with Mesna (Mesna) injection: edetate disodium, sodium hydroxide, and benzyl alcohol as a preservative.

Ifoxan with Mesna (Mesna) tablets: calcium phosphate, cornstarch, hydroxypropylmethylcellulose, lactose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, povidone, simethicone, and titanium dioxide.

This Patient Information has been approved by the U.S. Food and Drug Administration.

Manufactured by:

Baxter Healthcare Corporation

Deerfield, IL 60015 USA

Baxter and Ifoxan with Mesna (Mesna) are trademarks of Baxter International Inc.

Revised: January 2015

Container Label 400 mg Tablets

List 3565-9

Rx only

400 mg

Mesnex®

(mesna) Tablets

Baxter Healthcare

Corporation

460-656-00

Lot-number/Expires:

JMXXX MM.JJJJ

Carton Label 400 mg Tablets

10 400 mg Tablets

NDC 67108-3565-9

400 mg

Ifoxan with Mesna (Mesna)

(mesna) Tablets

10 400 mg Tablets

NDC 67108-3565-9

400 mg

Ifoxan with Mesna (Mesna)

(mesna) Tablets

Rx only

Each tablet contains 400 mg Ifoxan with Mesna (Mesna).

Store at 20°-25°C (68°-77°F), excursions permitted to 15°-30°C (59°-86°F)

.

For ORAL ADMINISTRATION

Dosage: See package insert for directions for use. Should not be prescribed without thorough

knowledge of dose, indications, and toxicology as contained in accompanying literature.

Manufactured for:

Baxter Logo

Baxter Healthcare Corporation

Deerfield, IL 60015 USA

10 400 mg Tablets

NDC 67108-3565-9

400 mg

Ifoxan with Mesna (Mesna)

(mesna) Tablets

10 400 mg Tablets

NDC 67108-3565-9

400 mg

Ifoxan with Mesna (Mesna)

(mesna) Tablets

Rx only

Each tablet contains 400 mg Ifoxan with Mesna (Mesna).

Store at 20°-25°C (68°-77°F), excursions permitted to 15°-30°C (59°-86°F)

.

For ORAL ADMINISTRATION

Dosage: See package insert for directions for use. Should not be prescribed without thorough

knowledge of dose, indications, and toxicology as contained in accompanying literature.

Manufactured for:

Baxter Logo

Baxter Healthcare Corporation

Deerfield, IL 60015 USA

460-657-00

Bar Code

N3 6710835659 1

70010157-

1714/943

10 400 mg Tablets

NDC 67108-3565-9

400 mg

Ifoxan with Mesna (Mesna)

(mesna) Tablets

C

943

HA-80-01-785

USA

Lot Number/Expires:

2640B4050

JMXXXA MM.JJJJ

Bar Code