ENDOXAN

Cyclophosphamide is an alkylating drug.

It is an antineoplastic drug chemically related to the nitrogen mustards.

The chemical name for cyclophosphamide is 2-[bis(2-chloroethyl)amino]tetrahydro-2H-1,3,2-oxazaphosphorine 2-oxide monohydrate, and has the following structural formula: Cyclophosphamide has a molecular formula of C 7 H 15 Cl 2 N 2 O 2 P•H 2 O and a molecular weight of 279.1.

Cyclophosphamide is soluble in water, saline, or ethanol.

Cyclophosphamide for

Injection, USP is a sterile white cake available as 500 mg, 1 g and 2 g strength single dose vials. 500 mg vial contains 534.5 mg cyclophosphamide monohydrate equivalent to 500 mg cyclophosphamide and 375 mg mannitol 1 g vial contains 1069 mg cyclophosphamide monohydrate equivalent to 1 g cyclophosphamide and 750 mg mannitol 2 g vial contains 2138 mg cyclophosphamide monohydrate equivalent to 2 g cyclophosphamide and 1500 mg mannitol Cyclophosphamide Monohydrate Structure.

Cyclophosphamide for injection is an alkylating drug indicated for treatment of adults and pediatric patients with: Malignant Diseases: malignant lymphomas: Hodgkin’s disease, lymphocytic lymphoma, mixed-cell type lymphoma, histiocytic lymphoma, Burkitt’s lymphoma; multiple myeloma, leukemias, mycosis fungoides, neuroblastoma, adenocarcinoma of ovary, retinoblastoma, breast carcinoma Minimal Change Nephrotic Syndrome in Pediatric Patients: biopsy proven minimal change nephrotic syndrome patients who failed to adequately respond to or are unable to tolerate adrenocorticosteroid therapy Limitations of Use: The safety and effectiveness for the treatment of nephrotic syndrome in adults or other renal disease has not been established. 1.1 Malignant Diseases Cyclophosphamide for injection is indicated for the treatment of adult and pediatric patients with: malignant lymphomas (Stages III and IV of the Ann Arbor staging system), Hodgkin's disease, lymphocytic lymphoma (nodular or diffuse), mixed-cell type lymphoma, histiocytic lymphoma, Burkitt's lymphoma multiple myeloma leukemias: chronic lymphocytic leukemia, chronic granulocytic leukemia (it is usually ineffective in acute blastic crisis), acute myelogenous and monocytic leukemia, acute lymphoblastic (stem-cell) leukemia (cyclophosphamide given during remission is effective in prolonging its duration) mycosis fungoides (advanced disease) neuroblastoma (disseminated disease) adenocarcinoma of the ovary retinoblastoma carcinoma of the breast Cyclophosphamide, although effective alone in susceptible malignancies, is more frequently used concurrently or sequentially with other antineoplastic drugs. 1.2 Minimal Change Nephrotic Syndrome in Pediatric Patients Cyclophosphamide for injection is indicated for the treatment of biopsy proven minimal change nephrotic syndrome in pediatrics patients who failed to adequately respond to or are unable to tolerate adrenocorticosteroid therapy.

The safety and effectiveness of cyclophosphamide for injection for the treatment of nephrotic syndrome in adults or other renal disease has not been established.

The mechanism of action has not been fully characterized.

However, cross-linking of tumor cell DNA may be involved.

The active alkylating metabolites of cyclophosphamide interfere with the growth of susceptible rapidly proliferating malignant cells 12.2 Pharmacodynamics Cyclophosphamide exposure-response relationships and the time course of pharmacodynamic response have not been fully characterized. 12.3 Pharmacokinetics Cyclophosphamide is a prodrug.

Cyclophosphamide pharmacokinetics are linear over the approved recommended dose range.

The volume of distribution of cyclophosphamide is to 50 L. Cyclophosphamide is approximately 20% protein bound, with no dose dependent changes.

Some metabolites are greater than 60% protein bound.

The elimination half-life (t½) of cyclophosphamide ranges from to 12 hours, and clearance (CL) ranges from to 5.6 L/h.

When cyclophosphamide was administered at 4 g/m 2 (approximately 2 times the approved recommended dosage) over a 90-minute infusion, concentration-time data demonstrate saturable elimination in parallel with first-order renal elimination.

Metabolism Cyclophosphamide is metabolized by cytochrome

P450s including CYP2A6, 2B6, 3A, 2C9, and 2C19.

Cyclophosphamide is activated to form 4-hydroxycyclophosphamide, which is in equilibrium with its ring-open tautomer aldophosphamide. 4-hydroxycyclophosphamide and aldophosphamide can undergo oxidation by aldehyde dehydrogenases to form the inactive metabolites 4-ketocyclophosphamide and carboxyphosphamide, respectively.

Aldophosphamide can undergo β-elimination to form active metabolites phosphoramide mustard and acrolein.

This spontaneous conversion can be catalyzed by albumin and other proteins.

At high doses, the fraction of parent compound cleared by 4-hydroxylation is reduced resulting in non-linear elimination of cyclophosphamide.

Cyclophosphamide appears to induce its own metabolism.

This auto-induction results in an increase in CL, increased formation of active 4-hydroxycyclophosphamide and shortened t½ following multiple doses administered at 12-to 24-hour interval.

Cyclophosphamide and its metabolites are eliminated by hepatic and renal pathways.

Cyclophosphamide is primarily excreted as metabolites.

Ten to 20% is excreted unchanged in the urine.

A small percentage of cyclophosphamide may be eliminated unchanged in bile.

Following one-hour intravenous infusion, cyclophosphamide AUC increased by 38% in patients with CLcr of to 50 mL/min, by 77% in patients with CLcr of to 24 mL/min and by 23% in the hemodialysis group (CLcr of < 10 mL/min) compared to the control group (CLcr≥ 80 mL/min).

Cyclophosphamide is dialyzable.

Dialysis clearance averaged 104 mL/min, which is similar to the metabolic clearance of 95 mL/min for cyclophosphamide.

A mean of 37% of the administered dose of cyclophosphamide was removed during a 4-hour hemodialysis period.

The t½ was 3.3 hours in patients during hemodialysis, a 49% reduction compared to t½ of 6.5 hours in uremic patients.

CL is decreased by 40% (45 ± 8.6 L/kg) and t½ is prolonged by 64% (12.5 ± 1 hours) in patients with hepatic impairment with a mean bilirubin 3.5 mg/dL and mean AST 90 IU/L compared to patients with normal hepatic function (mean bilirubin 0.5 mg/dL, mean AST 10 IU/L).

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

Myelosuppression, Immunosuppression, Bone Marrow Failure, and.

Infections Urinary Tract and Renal Toxicity Cardiotoxicity Pulmonary Toxicity Secondary Malignancies Veno-occlusive Liver Disease Infertility Impaired Wound Healing Hyponatremia Adverse reactions reported most often include neutropenia, febrile neutropenia, fever, alopecia, nausea, vomiting, and diarrhea.

To report SUSPECTED ADVERSE

REACTIONS, contact XGen Pharmaceuticals DJB, Inc.fda.gov/medwatch. 6.1 Clinical Trials and Postmarketing Experience The following adverse reactions associated with the use of cyclophosphamide were identified in clinical studies or postmarketing reports.

Because some of these reactions were 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.

The most common adverse reactions were neutropenia, febrile neutropenia, fever, alopecia, nausea, vomiting, and diarrhea.

Cardiac: cardiac arrest, ventricular fibrillation, ventricular tachycardia, cardiogenic shock, pericardial effusion (progressing to cardiac tamponade), myocardial hemorrhage, myocardial infarction, cardiac failure (including fatal outcomes), cardiomyopathy, myocarditis, pericarditis, carditis, atrial fibrillation, supraventricular arrhythmia, ventricular arrhythmia, bradycardia, tachycardia, palpitations, QT prolongation.

Congenital, Familial and Genetic: intra-uterine death, fetal malformation, fetal growth retardation, fetal toxicity (including myelosuppression, gastroenteritis).

Ear and

Labyrinth: deafness, hearing impaired, tinnitus.

Endocrine: water intoxication.

Eye: visual impairment, conjunctivitis, lacrimation.

Gastrointestinal: gastrointestinal hemorrhage, acute pancreatitis, colitis, enteritis, cecitis, stomatitis, constipation, parotid gland inflammation, nausea, vomiting, diarrhea General.

Disorders and Administrative Site Conditions: multiorgan failure, general physical deterioration, influenza-like illness, injection/infusion site reactions (thrombosis, necrosis, phlebitis, inflammation, pain, swelling, erythema), pyrexia, edema, chest pain, mucosal inflammation, asthenia, pain, chills, fatigue, malaise, headache, febrile neutropenia.

Hematologic: myelosuppression, bone marrow failure, disseminated intravascular coagulation and hemolytic uremic syndrome (with thrombotic microangiopathy).

Hepatic: veno-occlusive liver disease, cholestatic hepatitis, cytolytic hepatitis, hepatitis, cholestasis; hepatotoxicity with hepatic failure, hepatic encephalopathy, ascites, hepatomegaly, blood bilirubin increased, hepatic function abnormal, hepatic enzymes increased.

Immune: immunosuppression, anaphylactic shock and hypersensitivity reaction.

Infections : The following manifestations have been associated with myelosuppression and immunosuppression caused by cyclophosphamide: increased risk for and severity of pneumonias (including fatal outcomes), other bacterial, fungal, viral, protozoal and, parasitic infections; reactivation of latent infections, (including viral hepatitis, tuberculosis), Pneumocystis jiroveci, herpes zoster, Strongyloides, sepsis and septic shock.

Investigations : blood lactate dehydrogenase increased, C-reactive protein increased.

Metabolism and

Nutrition: hyponatremia, fluid retention, blood glucose increased, blood glucose decreased.

Tissue: rhabdomyolysis, scleroderma, muscle spasms, myalgia, arthralgia.

Neoplasms: acute leukemia, myelodysplastic syndrome, lymphoma, sarcomas, renal cell carcinoma, renal pelvis cancer, bladder cancer, ureteric cancer, thyroid cancer.

System: encephalopathy, convulsion, dizziness, neurotoxicity has been reported and manifested as reversible posterior leukoencephalopathy syndrome, myelopathy, peripheral neuropathy, polyneuropathy, neuralgia, dysesthesia, hypoesthesia, paresthesia, tremor, dysgeusia, hypogeusia, parosmia.

Pregnancy: premature labor.

Psychiatric: confusional state.

Renal and

Urinary: renal failure, renal tubular disorder, renal impairment, nephropathy toxic, hemorrhagic cystitis, bladder necrosis, cystitis ulcerative, bladder contracture, hematuria, nephrogenic diabetes insipidus, atypical urinary bladder epithelial cells.

System: infertility, ovarian failure, ovarian disorder, amenorrhea, oligomenorrhea, testicular atrophy, azoospermia, oligospermia.

Respiratory: pulmonary veno-occlusive disease, acute respiratory distress syndrome, interstitial lung disease as manifested by respiratory failure (including fatal outcomes), obliterative bronchiolitis, organizing pneumonia, alveolitis allergic, pneumonitis, pulmonary hemorrhage; respiratory distress, pulmonary hypertension, pulmonary edema, pleural effusion, bronchospasm, dyspnea, hypoxia, cough, nasal congestion, nasal discomfort, oropharyngeal pain, rhinorrhea.

Tissue: toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme, palmar-plantar erythrodysesthesia syndrome, radiation recall dermatitis, toxic skin eruption, urticaria, dermatitis, blister, pruritus, erythema, nail disorder, facial swelling, hyperhidrosis, alopecia.

Tumor lysis syndrome: like other cytotoxic drugs, cyclophosphamide may induce tumor-lysis syndrome and hyperuricemia in patients with rapidly growing tumors.

Vascular: pulmonary embolism, venous thrombosis, vasculitis, peripheral ischemia, hypertension, hypotension, flushing, hot flush.

No specific antidote for cyclophosphamide is known.

Overdosage should be managed with supportive measures, including appropriate treatment for any concurrent infection, myelosuppression, or cardiac toxicity should it occur.

Serious consequences of overdosage include manifestations of dose dependent toxicities such as myelosuppression, urotoxicity, cardiotoxicity (including cardiac failure), veno-occlusive hepatic disease, and stomatitis.

Patients who received an overdose should be closely monitored for the development of toxicities, and hematologic toxicity in particular.

Cyclophosphamide and its metabolites are dialyzable.

Therefore, rapid hemodialysis is indicated when treating any suicidal or accidental overdose or intoxication.

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

Cyclophosphamide for injection is contraindicated in patients who have a history of severe hypersensitivity reactions to cyclophosphamide, any of its metabolites, or to other components of the product.

Anaphylactic reactions including death have been reported with cyclophosphamide.

Cross-sensitivity with other alkylating agents can occur.

Cyclophosphamide for injection is contraindicated in patients with urinary outflow obstruction.

Hypersensitivity to cyclophosphamide

Urinary outflow obstruction.

During or immediately after cyclophosphamide for injection administration, administer adequate amounts of fluid to reduce the risk of urinary tract toxicity.

Adult and Pediatric Patients Intravenous: Initial course for patients with no hematologic deficiency: 40 mg per kg to 50 mg per kg in divided doses over to 5 days.

Other regimens include 10 mg per kg to 15 mg per kg given every to 10 days or 3 mg per kg to 5 mg per kg twice weekly.

Oral: 1 mg per kg per day to 5 mg per kg per day for both initial and maintenance dosing.

Minimal Change Nephrotic Syndrome in Pediatric Patients Oral: 2 mg per kg daily for to 12 weeks (maximum cumulative dose 168 mg per kg).

Treatment beyond 90 days increases the probability of sterility in males. 2.1 Important Administration Instructions During or immediately after the administration of cyclophosphamide for injection, adequate amounts of fluid should be ingested or infused to force diuresis in order to reduce the risk of urinary tract toxicity.

Therefore, cyclophosphamide for injection should be administered in the morning. 2.2 Recommended Dosage for Malignant Diseases Adults and Pediatric Patients Intravenous Use When used as the only oncolytic drug therapy, the recommended dosage for the initial course of cyclophosphamide for injection for patients with no hematologic deficiency is 40 mg per kg to 50 mg per kg given intravenously in divided doses over a period of to 5 days.

Other intravenous regimens include 10 mg per kg to 15 mg per kg given every to 10 days or 3 mg per kg to 5 mg per kg twice weekly.

The recommended dosage for oral cyclophosphamide is 1 mg per kg per day to 5 mg per kg per day for both initial and maintenance dosing.

Adjust the dosage of cyclophosphamide for injection based on the specific regimen administered, response to treatment, myelosuppression or other adverse reactions, and patient risk factors. 2.3 Recommended Dosage for Minimal Change Nephrotic Syndrome in Pediatric Patients The recommended dosage is 2 mg per kg orally once daily for to 12 weeks (maximum cumulative dose 168 mg per kg) is recommended.

Treatment beyond 90 days increases the probability of sterility in males. 2.4 Preparation, Handling and Administration Cyclophosphamide for injection is a hazardous drug.

Follow applicable special handling and disposal procedures.

Caution should be exercised when handling and preparing cyclophosphamide for injection.

To minimize the risk of dermal exposure, always wear gloves when handling vials containing cyclophosphamide for injection.

Cyclophosphamide for Injection Intravenous Administration

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

Do not use cyclophosphamide vials if there are signs of melting.

Melted cyclophosphamide is a clear or yellowish viscous liquid usually found as a connected phase or in droplets in the affected vials.

Cyclophosphamide for injection does not contain any antimicrobial preservative and thus care must be taken to assure the sterility of prepared solutions.

Use aseptic technique.

Reconstitute cyclophosphamide for injection with 0.9% Sodium Chloride Injection, USP only, using the volumes listed below in Table 1.

Shake the vial vigorously to dissolve the drug completely.

Do not use Sterile Water for

Injection, USP because it results in a hypotonic solution and should not be injected directly.

Discard unused solution.

Table 1: Reconstitution for Direct Intravenous Injection Strength Volume of 0.9% Sodium Chloride Injection, USP Cyclophosphamide Concentration 500 mg 25 mL 20 mg per mL 1 g 50 mL 2 g 100 mL For Intravenous Infusion Reconstitution of Cyclophosphamide for Injection: Reconstitute cyclophosphamide for injection using 0.9% Sodium Chloride Injection, USP or Sterile Water for Injection, USP with the volume of diluent listed below in Table 2.

Add the diluent to the vial and shake the vial vigorously to dissolve the drug completely.

Table 2: Reconstitution in preparation for Intravenous Infusion Strength Volume of Diluent Cyclophosphamide Concentration 500 mg 25 mL 20 mg per mL 1 g 50 mL 2 g 100 mL Dilution of Reconstituted Cyclophosphamide for Injection: Further dilute the reconstituted cyclophosphamide for injection solution to a minimum concentration of 2 mg per mL with any of the following diluents: 0.45% Sodium Chloride Injection, USP 5% Dextrose Injection, USP 5% Dextrose and 0.9% Sodium Chloride Injection, USP To reduce the likelihood of adverse reactions that appear to be administration rate-dependent (e.g., facial swelling, headache, nasal congestion, scalp burning), cyclophosphamide should be injected or infused very slowly.

Duration of the infusion also should be appropriate for the volume and type of carrier fluid to be infused.

Storage of Reconstituted and Diluted Cyclophosphamide Solution: If not used immediately, for microbiological integrity, cyclophosphamide solutions should be stored as described in Table 3: Table 3: Storage of Cyclophosphamide Solutions Diluent Storage Room Temperature Refrigerated Reconstituted Solution (Without Further Dilution) 0.9% Sodium Chloride Injection, USP up to 24 hrs Up to 6 days Sterile Water for Injection, USP Do not store; use immediately Diluted Solutions 1 0.45% Sodium Chloride Injection, USP up to 24 hrs up to 6 days 5% Dextrose Injection, USP up to 24 hrs up to 36 hrs 5% Dextrose and 0.9% Sodium Chloride Injection, USP up to 24 hrs up to 36 hrs 1 Storage time is the total time cyclophosphamide is in solution including the time it is reconstituted in 0.9% Sterile Sodium Chloride Injection, USP or Sterile Water for Injection, USP.

Liquid preparations of cyclophosphamide for oral administration may be prepared by dissolving cyclophosphamide for injection in Aromatic Elixir, National Formulary (NF).

Store preparations under refrigeration in glass containers and used within 14 days.

See the prescribing information for cyclophosphamide for oral use for additional dosage information.

Cyclophosphamide for

Injection, USP (lyophilized powder) is a sterile white cake containing cyclophosphamide and mannitol and is supplied in single dose vials.

Injection, USP NDC 39822-0250-1 500 mg per vial, carton of 1 NDC 39822-0255-1 1 g per vial, carton of 1 NDC 39822-0260-1 2 g per vial, carton of 1 Store vials at or below 25°C (77°F).

During transport or storage of cyclophosphamide vials, temperature influences can lead to melting of the active ingredient, cyclophosphamide.

Cyclophosphamide is a hazardous product.

Follow special handling and disposal procedures.

Based on its mechanism of action and published reports of effects in pregnant patients or animals, cyclophosphamide for injection can cause fetal harm when administered to a pregnant woman.

Exposure to cyclophosphamide during pregnancy may cause fetal malformations, miscarriage, fetal growth retardation, and toxic effects in the newborn.

Cyclophosphamide is teratogenic and embryo-fetal toxic in mice, rats, rabbits and monkeys.

Advise pregnant women and females of reproductive potential of the potential risk to the fetus.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown.

In the

U.S. general population, the estimated background risk of major birth defects is 2%-4% and miscarriage is 15%-20% of clinically recognized pregnancies.

Malformations of the skeleton, palate, limbs and eyes as well as miscarriage have been reported after exposure to cyclophosphamide in the first trimester.

Fetal growth retardation and toxic effects manifesting in the newborn, including leukopenia, anemia, pancytopenia, severe bone marrow hypoplasia, and gastroenteritis have been reported after exposure to cyclophosphamide.

Administration of cyclophosphamide to pregnant mice, rats, rabbits and monkeys during the period of organogenesis at doses at or below the dose in patients based on body surface area resulted in various malformations, which included neural tube defects, limb and digit defects and other skeletal anomalies, cleft lip and palate, and reduced skeletal ossification.

The safety and effectiveness of cyclophosphamide have been established in pediatric patients and information on this use is discussed throughout the labeling.

Pre-pubescent females who receive cyclophosphamide generally develop secondary sexual characteristics normally and have regular menses.

Ovarian fibrosis with apparently complete loss of germ cells after prolonged administration of cyclophosphamide in late pre-pubescence has been reported.

Females who received cyclophosphamide who have retained ovarian function after completing treatment are at increased risk of developing premature menopause.

Pre-pubescent males who receive cyclophosphamide develop secondary sexual characteristics normally, but may have oligospermia or azoospermia and increased gonadotropin secretion.

Some degree of testicular atrophy may occur.

Cyclophosphamide-induced azoospermia is reversible in some patients, though the reversibility may not occur for several years after cessation of therapy.

There is insufficient data from clinical studies of cyclophosphamide available for patients 65 years of age and older to determine whether they respond differently than younger patients.

In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac functioning, and of concomitant disease or other drug therapy.