CYCLOPHOSPHAMIDE

1 INDICATIONS AND USAGE

INDICATIONS & USAGE SECTION

2 DOSAGE AND ADMINISTRATION

DOSAGE & ADMINISTRATION SECTION

During or immediately after the administration, adequate amounts of fluid should be ingested or infused to force diuresis in order to reduce the risk of urinary tract toxicity. Therefore, cyclophosphamide should be administered in the morning.

3 DOSAGE FORMS AND STRENGTHS

DOSAGE FORMS & STRENGTHS SECTION

Cyclophosphamide for Injection, USP is a sterile white powder available in • 500 mg • 1 g • 2 g

4 CONTRAINDICATIONS

CONTRAINDICATIONS SECTION

• Hypersensitivity Cyclophosphamide is contraindicated in patients who have a history of severe hypersensitivity reactions to it, any of its metabolites, or to other components of the product. Anaphylactic reactions including death have been reported with cyclophosphamide. Possible cross-sensitivity with other alkylating agents can occur. • Urinary Outflow Obstruction Cyclophosphamide is contraindicated in patients with urinary outflow obstruction [see Warnings and Precautions (5.2) ].

5 WARNINGS AND PRECAUTIONS

WARNINGS AND PRECAUTIONS SECTION

6 ADVERSE REACTIONS

ADVERSE REACTIONS SECTION

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) ] • Embryo-Fetal Toxicity [see Warnings and Precautions (5.7) ] • Reproductive System Toxicity [see Warnings and Precautions (5.8) and Use in Specific Populations ( 8.4 and 8.6 )] • Impaired Wound Healing [see Warnings and Precautions (5.9) ] • Hyponatremia [see Warnings and Precautions (5.10) ]

7 DRUG INTERACTIONS

DRUG INTERACTIONS SECTION

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

USE IN SPECIFIC POPULATIONS SECTION

10 OVERDOSAGE

OVERDOSAGE SECTION

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.

11 DESCRIPTION

DESCRIPTION SECTION

Cyclophosphamide 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 is a white crystalline powder with the molecular formula 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 powder available as 500 mg, 1 g, and 2 g strength vials. • 500 mg vial contains 534.5 mg cyclophosphamide monohydrate equivalent to 500 mg cyclophosphamide • 1 g vial contains 1069.0 mg cyclophosphamide monohydrate equivalent to 1 g cyclophosphamide • 2 g vial contains 2138.0 mg cyclophosphamide monohydrate equivalent to 2 g cyclophosphamide

12 CLINICAL PHARMACOLOGY

CLINICAL PHARMACOLOGY SECTION

13 NONCLINICAL TOXICOLOGY

NONCLINICAL TOXICOLOGY SECTION

15 REFERENCES

REFERENCES SECTION

1. OSHA Hazardous Drugs. OSHA . http://www.osha.gov/SLTC/hazardousdrugs/index.html.

16 HOW SUPPLIED/STORAGE AND HANDLING

HOW SUPPLIED SECTION

Cyclophosphamide for Injection, USP is a sterile white powder containing cyclophosphamide and is supplied in vials for single dose use. Cyclophosphamide for Injection, USP NDC 10019-943-01 500 mg vial, carton of 1 NDC 10019-944-01 1 g vial, carton of 1 NDC 10019-945-01 2 g 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, [see Dosage and Administration (2.3) ]. Cyclophosphamide is an antineoplastic product. Follow special handling and disposal procedures. 1

17 PATIENT COUNSELING INFORMATION

INFORMATION FOR PATIENTS SECTION

Advise the patient of the following: • Inform patients of the possibility of myelosuppression, immunosuppression, and infections. Explain the need for routine blood cell counts. Instruct patients to monitor their temperature frequently and immediately report any occurrence of fever [see Warnings and Precautions (5.1)]. • Advise the patient to report urinary symptoms (patients should report if their urine has turned a pink or red color) and the need for increasing fluid intake and frequent voiding [see Warnings and Precautions (5.2) ] . • Advise patients to contact a healthcare professional immediately for any of the following: new onset or worsening shortness of breath, cough, swelling of the ankles/legs, palpitations, weight gain of more than 5 pounds in 24 hours, dizziness or loss of consciousness [see Warnings and Precautions (5.3) ]. • Warn patients of the possibility of developing non-infectious pneumonitis. Advise patients to report promptly any new or worsening respiratory symptoms [see Warnings and Precautions (5.4) ]. • Advise female patients of reproductive potential to use highly effective contraception during treatment and for up to 1 year after completion of therapy. There is a potential for harm to a fetus if a patient becomes pregnant during this period. Patients should immediately contact their healthcare provider if they become pregnant or if pregnancy is suspected during this period [see Warnings and Precautions (5.7) and Use in Specific Populations (8.1) ]. • Advise male patients who are sexually active with a female partner who is or may become pregnant to use condoms during treatment and for up to 4 months after completion of therapy. There is a potential for harm to a fetus if a patient fathers a child during this period. Patients should immediately contact their healthcare provider if their female partner becomes pregnant or if pregnancy is suspected during this period [see Warnings and Precautions (5.7) and Use in Specific Populations (8.1) ]. • Advise nursing mothers treated with cyclophosphamide to discontinue nursing or discontinue cyclophosphamide, taking into account the importance of the drug to the mother [see Use in Specific Populations (8.3)] . • Explain to patients that side effects such as nausea, vomiting, stomatitis, impaired wound healing, amenorrhea, premature menopause, sterility and hair loss may be associated with cyclophosphamide administration. Other undesirable effects (including, e.g., dizziness, blurred vision, visual impairment) could affect the ability to drive or use machines [see Adverse Reactions ( 6.1 and 6.2 )].

SPL UNCLASSIFIED SECTION

SPL UNCLASSIFIED SECTION

Manufactured by: Baxter Healthcare Corporation Deerfield, IL 60015 USA Product Made in Germany PREMIERProRx® For Product Inquiry 1 800 ANA DRUG (1-800-262-3784) Baxter is a trademark of Baxter International Inc. PREMIERProRx® is a trademark of Premier Healthcare Alliance, L.P., used under license. HA-30-01-686 Revised March 2017

PACKAGE/LABEL PRINCIPAL DISPLAY PANEL

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL

Container Label NDC 10019-943-25 C yclophosphamide for Injection, USP 500 mg/vial CYTOTOXIC AGENT FOR SINGLE DOSE USE STERILE, NON-PYROGENIC FOR PARENTERAL USE Baxter Logo Manufactured by Baxter Healthcare Corporation Deerfield, IL 60015 USA PREMIER Pro Rx Logo Made in Germany LOT/EXP: Each vial contains 500 mg cyclophosphamide. For IV Infusion Use: Add 25 mL Sterile Water for Injection, USP, and shake vigorously to dissolve the drug. For Direct Injection Use: Add 25 mL 0.9% Sodium Chloride Injection, USP, and shake vigorously to dissolve the drug. See insert for indications and dosage schedule. Store vial at or below 25°C (77°F) [see USP Controlled Room Temperature]. Bar Code (01)00310019943251 USA HA-65-01-637 C922 Carton Label NDC 10019-943-01 C yclophosphamide for Injection, USP 500 mg/vial Rx only MUST BE DILUTED FOR IV INFUSION OR DIRECT INJECTION USE 1 Single Dose Vial Baxter Logo Manufactured by Baxter Healthcare Corporation Deerfield, IL 60015 USA PREMIER Pro RxLogo Made in Germany C yclophosphamide for Injection, USP 500 mg/vial Barcode HA-80-02-322 USA Each vial contains 500 mg cyclophosphamide. For IV Infusion Use: Add 25 mL Sterile Water for Injection, USP, and shake vigorously to dissolve the drug. For Direct Injection Use: Add 25 mL 0.9% Sodium Chloride Injection, USP, and shake vigorously to dissolve the drug. Store vial at or below 25°C (77°F) [ see USP Controlled Room Temperature ]. DOSAGE: See accompanying literature for directions for use. Should not be prescribed without thorough knowledge of dose, indications and toxicity as contained in accompanying literature. CYTOTOXIC AGENT FOR SINGLE DOSE USE STERILE, NON-PYROGENIC FOR PARENTERAL USE C 609 NDC 10019-943-01 C yclophosphamide for Injection, USP 500 mg/vial Rx only MUST BE DILUTED FOR IV INFUSION OR DIRECT INJECTION USE 1 Single Dose Vial Baxter Logo Manufactured by Baxter Healthcare Corporation Deerfield, IL 60015 USA PremierProRx is a trademark of Premier Healthcare Alliance, L.P., used under license. Made in Germany LOT/EXP: 2638B5159 Barcode NDC 10019-943-01 C yclophosphamide for Injection, USP 500 mg/vial Rx only MUST BE DILUTED FOR IV INFUSION OR DIRECT INJECTION USE 1 Single Dose Vial Baxter Logo Manufactured by Baxter Healthcare Corporation Deerfield, IL 60015 USA PremierProRx is a trademark of Premier Healthcare Alliance, L.P., used under license. Made in Germany Container Label NDC 10019-944-50 C yclophosphamide for Injection, USP 1 gram/vial CYTOTOXIC AGENT FOR SINGLE DOSE USE STERILE, NON-PYROGENIC FOR PARENTERAL USE Rx only Baxter Logo Manufactured by Baxter Healthcare Corporation Deerfield, IL 60015 USA PREMIER Pro Rx Logo Made in Germany LOT/EXP: Each vial contains 1 gram cyclophosphamide. For IV Infusion Use: Add 50 mL Sterile Water for Injection, USP, and shake vigorously to dissolve the drug. For Direct Injection Use: Add 50 mL 0.9% Sodium Chloride Injection, USP, and shake vigorously to dissolve the drug. See insert for indications and dosage schedule. Store vial at or below 25°C (77°F) [see USP Controlled Room Temperature]. Bar Code (01)00310019944500 USA HA-65-01-638 C 923 Carton Label NDC 10019-944-01 C yclophosphamide for Injection, USP 1 gram/vial Rx only MUST BE DILUTED FOR IV INFUSION OR DIRECT INJECTION USE 1 Single Dose Vial Baxter Logo Manufactured by Baxter Healthcare Corporation Deerfield, IL 60015 USA PREMIER Pro Rx Logo Made in Germany Cyclophosphamide for Injection, USP 1 gram/vial Barcode HA-80-02-323 USA Each vial contains 1 g cyclophosphamide. For IV Infusion Use: Add 50 mL Sterile Water for Injection, USP, and shake vigorously to dissolve the drug. For Direct Injection Use: Add 50 mL 0.9% Sodium Chloride Injection, USP, and shake vigorously to dissolve the drug. Store vial at or below 25°C (77°F) [ see USP Controlled Room Temperature ]. DOSAGE: See accompanying literature for directions for use. Should not be prescribed without thorough knowledge of dose, indications and toxicity as contained in accompanying literature. CYTOTOXIC AGENT FOR SINGLE DOSE USE STERILE, NON-PYROGENIC FOR PARENTERAL USE C 610 NDC 10019-944-01 C yclophosphamide for Injection, USP 1 gram/vial Rx only MUST BE DILUTED FOR IV INFUSION OR DIRECT INJECTION USE 1 Single Dose Vial Baxter Logo Manufactured by Baxter Healthcare Corporation Deerfield, IL 60015 USA PremierProRx is a trademark of Premier Healthcare Alliance, L.P., used under license. Made in Germany LOT/EXP: 2638B5160 Barcode NDC 10019-944-01 C yclophosphamide for Injection, USP 1 gram/vial Rx only MUST BE DILUTED FOR IV INFUSION OR DIRECT INJECTION USE 1 Single Dose Vial Baxter Logo Manufactured by Baxter Healthcare Corporation Deerfield, IL 60015 USA PremierProRx is a trademark of Premier Healthcare Alliance, L.P., used under license. Made in Germany Container Label NDC 10019-945-10 C yclophosphamide for Injection, USP 2 gram/vial CYTOTOXIC AGENT FOR SINGLE DOSE USE STERILE, NON-PYROGENIC FOR PARENTERAL USE Rx only Baxter Logo Manufactured by Baxter Healthcare Corporation Deerfield, IL 60015 USA PREMIER Pro Rx Logo Made in Germany LOT/EXP: Each vial contains 2 g cyclophosphamide. For IV Infusion Use: Add 100 mL Sterile Water for Injection, USP, and shake vigorously to dissolve the drug. For Direct Injection Use: Add 100 mL 0.9% Sodium Chloride Injection, USP, and shake vigorously to dissolve the drug. See insert for indications and dosage schedule. Store vial at or below 25°C (77°F) [see USP Controlled Room Temperature]. Bar Code (01)00310019945101 USA HA-65-01-639 C924 Carton Label NDC 10019-945-01 C yclophosphamide for Injection, USP 2 gram/vial Rx only MUST BE DILUTED FOR IV INFUSION OR DIRECT INJECTION USE 1 Single Dose Vial Baxter Logo Manufactured by Baxter Healthcare Corporation Deerfield, IL 60015 USA PREMIER Pro Rx Logo Made in Germany C yclophosphamide for Injection, USP 2 gram/vial Barcode HA-80-02-324 USA Each vial contains 2 g cyclophosphamide. For IV Infusion Use: Add 100 mL Sterile Water for Injection, USP, and shake vigorously to dissolve the drug. For Direct Injection Use: Add 100 mL 0.9% Sodium Chloride Injection, USP, and shake vigorously to dissolve the drug. Store vial at or below 25°C (77°F) [ see USP Controlled Room Temperature ]. DOSAGE: See accompanying literature for directions for use. Should not be prescribed without thorough knowledge of dose, indications and toxicity as contained in accompanying literature. CYTOTOXIC AGENT FOR SINGLE DOSE USE STERILE, NON-PYROGENIC FOR PARENTERAL USE C 611 NDC 10019-945-01 C yclophosphamide for Injection, USP 2 gram/vial Rx only MUST BE DILUTED FOR IV INFUSION OR DIRECT INJECTION USE 1 Single Dose Vial Baxter Logo Manufactured by Baxter Healthcare Corporation Deerfield, IL 60015 USA PremierProRx is a trademark of Premier Healthcare Alliance, L.P., used under license. Made in Germany LOT/EXP: 2638B5161 Barcode NDC 10019-945-01 C yclophosphamide for Injection, USP 2 gram/vial Rx only MUST BE DILUTED FOR IV INFUSION OR DIRECT INJECTION USE 1 Single Dose Vial Baxter Logo Manufactured by Baxter Healthcare Corporation Deerfield, IL 60015 USA PremierProRx is a trademark of Premier Healthcare Alliance, L.P., used under license. Made in Germany