Cyclophosphamide

1 INDICATIONS AND USAGE Cyclophosphamide capsules, USP is an alkylating drug indicated for treatment of: 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 ( 1.1 ) Minimal Change Nephrotic Syndrome in Pediatric Patients: biopsy proven minimal change nephrotic syndrome in pediatric patients who failed to adequately respond to or are unable to tolerate adrenocorticosteroid therapy ( 1.2 ) 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 capsules,USP are indicated for the treatment of: 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 capsules, USP 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 capsules, USP is indicated for the treatment of biopsy proven minimal change nephrotic syndrome in pediatric patients who failed to adequately respond to or are unable to tolerate adrenocorticosteroid therapy. Limitations of Use: The safety and effectiveness of cyclophosphamide capsules, USP for the treatment of nephrotic syndrome in adults or other renal disease has not been established.

2 DOSAGE AND ADMINISTRATION During or immediately after the administration, administer adequate amounts of fluid to reduce the risk of urinary tract toxicity ( 2.1 ). Malignant Diseases: Adult and Pediatric Patients ( 2.2 ) • Oral: Usually 1 mg per kg per day to 5 mg per kg orally once daily for both initial and maintenance dosing. Minimal Change Nephrotic Syndrome in Pediatric Patients ( 2.3 ) • Recommended oral dose: 2 mg per kg once daily for 8 to 12 weeks (maximum cumulative dose 168 mg per kg). Treatment beyond 90 days increases the probability of sterility in males. 2.1 Hydration and Important Administration Instructions During or immediately after the administration of Cyclophosphamide Capsules, adequate amounts of fluid should be ingested or infused to force diuresis in order to reduce the risk of urinary tract toxicity. Therefore, Cyclophosphamide Capsules should be taken in the morning. Cyclophosphamide Capsules should be swallowed whole. The capsules should not be opened, chewed, or crushed. Cyclophosphamide Capsules is a cytotoxic drug. Follow applicable special handling and disposal procedures. 1 Exposure to broken capsules should be avoided. If contact with broken capsules occurs, wash hands immediately and thoroughly. 2.2 Recommended Dosage for Malignant Diseases Adults and Pediatric Patients The recommended dosage of Cyclophosphamide Capsules is in the range of 1 mg per kg to 5 mg per kg orally once daily for both initial and maintenance dosing. Other regimens of intravenous and oral cyclophosphamide have been reported. Dosages should be adjusted based on evidence of antitumor activity, myelosuppression, or other severe adverse reactions [see Warnings and Precautions ( 5 )]. When cyclophosphamide is included in combined cytotoxic regimens, it may be necessary to reduce the dose of cyclophosphamide, as well as that of the other drugs. 2.3 Recommended Dosage for Minimal Change Nephrotic Syndrome in Pediatric Patients The recommended dosage of Cyclophosphamide Capsules is 2 mg per kg orally once daily for 8 to 12 weeks (maximum cumulative dose 168 mg per kg). Treatment beyond 90 days increases the probability of sterility in males [see Use in Specific Populations ( 8.4 )].

3 DOSAGE FORMS AND STRENGTHS Capsules: • 25 mg capsule for oral administration contains 25 mg of cyclophosphamide USP. It is a blue opaque cap / blue opaque body size ‘3’ hard gelatin capsule shells radially imprinted with “A” on cap and “346” on body in black ink filled with white to off-white powder. • 50 mg capsule for oral administration contains 50 mg of cyclophosphamide USP. It is a blue opaque cap / blue opaque body size ‘1’ hard gelatin capsule shells radially imprinted with “A” on cap and “347” on body in black ink filled with white to off-white powder. Capsules: 25 mg and 50 mg (3)

4 CONTRAINDICATIONS Cyclophosphamide Capsules are contraindicated in patients with: • 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. • In patients with urinary outflow obstruction [see Warnings and Precautions ( 5.2 )]. • Hypersensitivity to cyclophosphamide ( 4 ) • Urinary outflow obstruction ( 4 )

6 ADVERSE REACTIONS The following adverse reactions are discussed in more detail in other sections of the labeling. • Hypersensitivity [see Contraindications ( 4 )] • Myelosuppression, Immunosuppression, Bone Marrow Failure, and Infections [see Warnings and Precautions ( 5.1 )] • Urinary Tract and Renal Toxicity [see Warnings and Precautions ( 5.2 )] • Cardiotoxicity [see Warnings and Precautions ( 5.3 )] • Pulmonary Toxicity [see Warnings and Precautions ( 5.4 )] • Secondary Malignancies [see Warnings and Precautions ( 5.5 )] • Veno-occlusive Liver Disease [see Warnings and Precautions ( 5.6 )] • Infertility [see Warnings and Precautions ( 5.8 ) and Use in Specific Populations ( 8.3 ) and ( 8.4 )] • Impaired Wound Healing [see Warnings and Precautions ( 5.9 )] • Hyponatremia [see Warnings and Precautions ( 5.10 )] Adverse reactions reported most often include neutropenia, febrile neutropenia, fever, alopecia, nausea, vomiting, and diarrhea. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Hikma Pharmaceuticals USA Inc. at 1-800-962-8364 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Common Adverse Reactions Hematopoietic system Neutropenia occurs in patients treated with cyclophosphamide. The degree of neutropenia is particularly important because it correlates with a reduction in resistance to infections. Fever without documented infection has been reported in neutropenic patients. Gastrointestinal system Nausea and vomiting occur with cyclophosphamide therapy. Anorexia and, less frequently, abdominal discomfort or pain and diarrhea may occur. There are isolated reports of hemorrhagic colitis, oral mucosal ulceration and jaundice occurring during therapy. Skin and its structures Alopecia occurs in patients treated with cyclophosphamide. Skin rash occurs occasionally in patients receiving the drug. Pigmentation of the skin and changes in nails can occur. 6.2 Postmarketing Experience The following adverse reactions have been identified from clinical trials or post-marketing surveillance. Because they are reported from a population from unknown size, precise estimates of frequency cannot be made. 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. General Disorders and Administrative Site Conditions: multiorgan failure, general physical deterioration, influenza-like illness, pyrexia, edema, chest pain, mucosal inflammation, asthenia, pain, chills, fatigue, malaise, headache. 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, vi …

7 DRUG INTERACTIONS Cyclophosphamide is a pro-drug that is activated by cytochrome P450s [see Clinical Pharmacology ( 12.3 )] . An increase of the concentration of cytotoxic metabolites may occur with: • Protease inhibitors: Concomitant use of protease inhibitors may increase the concentration of cytotoxic metabolites. Use of protease inhibitor-based regimens was found to be associated with a higher incidence of infections and neutropenia in patients receiving cyclophosphamide, doxorubicin, and etoposide (CDE) than use of a Non-Nucleoside Reverse Transcriptase Inhibitor-based regimen. Combined or sequential use of cyclophosphamide and other agents with similar toxicities can potentiate toxicities. • Increased hematotoxicity and/or immunosuppression may result from a combined effect of cyclophosphamide and, for example: • ACE inhibitors: ACE inhibitors can cause leukopenia. • Natalizumab • Paclitaxel: Increased hematotoxicity has been reported when cyclophosphamide was administered after paclitaxel infusion. • Thiazide diuretics • Zidovudine • Increased cardiotoxicity may result from a combined effect of cyclophosphamide and, for example: • Anthracyclines • Cytarabine • Pentostatin • Radiation therapy of the cardiac region • Trastuzumab • Increased pulmonary toxicity may result from a combined effect of cyclophosphamide and, for example: • Amiodarone • G-CSF, GM-CSF (granulocyte colony-stimulating factor, granulocyte macrophage colony-stimulating factor): Reports suggest an increased risk of pulmonary toxicity in patients treated with cytotoxic chemotherapy that includes cyclophosphamide and G-CSF or GMCSF. • Increased nephrotoxicity may result from a combined effect of cyclophosphamide and, for example: • Amphotericin B • Indomethacin: Acute water intoxication has been reported with concomitant use of indomethacin • Increase in other toxicities: • Azathioprine: Increased risk of hepatotoxicity (liver necrosis) • Busulfan: Increased incidence of hepatic veno-occlusive disease and mucositis has been reported. • Protease inhibitors: Increased incidence of mucositis • Increased risk of hemorrhagic cystitis may result from a combined effect of cyclophosphamide and past or concomitant radiation treatment. Etanercept: In patients with Wegener’s granulomatosis, the addition of etanercept to standard treatment, including cyclophosphamide, was associated with a higher incidence of non-cutaneous malignant solid tumors. Metronidazole: Acute encephalopathy has been reported in a patient receiving cyclophosphamide and metronidazole. Causal association is unclear. In an animal study, the combination of cyclophosphamide with metronidazole was associated with increased cyclophosphamide toxicity. Tamoxifen: Concomitant use of tamoxifen and chemotherapy may increase the risk of thromboembolic complications. Coumarins: Both increased and decreased warfarin effect have been reported in patients receiving warfarin and cyclophosphamide. Cyclosporine: Lower serum concentrations of cyclosporine have been observed in patients receiving a combination of cyclophosphamide and cyclosporine than in patients receiving only cyclosporine. This interaction may result in an increased incidence of graft-versus-host disease. Depolarizing muscle relaxants: Cyclophosphamide treatment causes a marked and persistent inhibition of cholinesterase activity. Prolonged apnea may occur with concurrent depolarizing muscle relaxants (e.g., succinylcholine). If a patient has been treated with cyclophosphamide within 10 days of general anesthesia, alert the anesthesiologist.

8 USE IN SPECIFIC POPULATIONS Lactation: Advise not to breastfeed. (8.2) Females and Males of Reproductive Potential: Verify pregnancy status prior to initiation of cyclophosphamide capsules. May impair fertility. (8.3) Renal Impairment: Monitor for toxicity in patients with moderate and severe renal impairment. (8.6, 12.3) See 17 for PATIENT COUNSELING INFORMATION Revised: 02/2026 8.1 Pregnancy Risk Summary Based on its mechanism of action and published reports of effects in pregnant patients or animals, cyclophosphamide capsules can cause fetal harm when administered to a pregnant woman [see CLINICAL PHARMACOLOGY (12.1) and NONCLINICAL TOXICOLOGY (13.1)] . Exposure to cyclophosphamide during pregnancy may cause fetal malformations, miscarriage, fetal growth retardation, and toxic effects in the newborn [see Data] . Cyclophosphamide is teratogenic and embryo-fetal toxic in mice, rats, rabbits and monkeys [see Data] . 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% to 4% and of miscarriage is 15% to 20% of clinically recognized pregnancies. Data Human Data 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. Animal Data 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. 8.2 Lactation Risk Summary Cyclophosphamide is present in breast milk. Neutropenia, thrombocytopenia, low hemoglobin, and diarrhea have been reported in infants breast fed by women treated with cyclophosphamide. Because of the potential for serious adverse reactions in a breastfed child from cyclophosphamide capsules, advise lactating women not to breastfeed during the treatment and for 1 week after the last dose. 8.3 Females and Males of Reproductive Potential Pregnancy Testing Verify the pregnancy status of females of reproductive potential prior to the initiation of cyclophosphamide capsules [see USE IN SPECIFIC POPULATIONS (8.1)] . Contraception Females Cyclophosphamide capsules can cause fetal harm. Advise females of reproductive potential to use effective contraception during treatment with cyclophosphamide capsules for up to 1 year after completion of therapy [ see USE IN SPECIFIC POPULATIONS (8.1) ]. Males Based on findings in genetic toxicity and animal reproduction studies, advise male patients with female partners of reproductive potential to use effective contraception during treatment with cyclophosphamide capsules and for 4 months after completion of therapy [see USE IN SPECIFIC POPULATIONS (8.1) and NONCLINICAL TOXICOLOGY (13.1)] . Infertility Females Amenorrhea, transient or permanent, associated with decreased estrogen and increased gonadotropin secretion develops in a proportion of women treated with cyclophosphamide. Affected patients generally resume regular menses within a few months after cessation of therapy. The risk of premature menopause with cyclophosphamide increases with age. Oligomenorrhea has also been reported in association with cyclophosphamide treatment. Animal data suggest an increased risk of failed pregnancy and malformations may persist after discontinuation of cyclophosphamide as long as oocytes/follicles exist that were exposed to cyclophosphamide durin …

12.1 Mechanism of Action The mechanism of action is thought to involve cross-linking of tumor cell DNA.

11 DESCRIPTION Cyclophosphamide capsules, USP is a synthetic 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 279.10. Cyclophosphamide is soluble in water and alcohol. Each capsule for oral use contains 25 mg or 50 mg cyclophosphamide (monohydrate, USP) and the following inactive ingredients: pregelatinized starch and sodium stearyl fumarate. Each gelatin capsule shell contains FD&C Blue #1, FD&C Red #3, gelatin and titanium dioxide. In addition to the ingredients listed above, each capsule contains black ink. Black ink contains, black iron oxide, isopropyl alcohol, butyl alcohol, propylene glycol, strong ammonia solution, dehydrated alcohol, potassium hydroxide, purified water and shellac. Image

10 OVERDOSAGE 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 [see Warnings and Precautions ( 5.1 , 5.2 , 5.3 , and 5.6 )] . 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.

16 HOW SUPPLIED/STORAGE AND HANDLING Cyclophosphamide Capsules, USP 25 mg, supplied as white to off white blend filled in hard gelatin capsule size 3, cap opaque white imprinted with "Cipla" in black ink and body opaque blue imprinted with "516 25 MG" with black ink NDC 69097-516-07: 100's Bottle with child-resistant closure 50 mg, supplied as white to off white blend filled in hard gelatin capsule size 1, cap opaque white imprinted with "Cipla" in black ink and body opaque blue imprinted with "517 50 MG" with black ink NDC 69097-517-07: 100's Bottle with child-resistant closure Storage This package is child-resistant. Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C and 30°C (59°F and 86°F). [See USP Controlled Room Temperature.] Cyclophosphamide is an antineoplastic product. Follow special handling and disposal procedures. 1