Frindovyx

1 INDICATIONS AND USAGE Malignant Diseases FRINDOVYX 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. FRINDOVYX 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 ( 1 )

2 DOSAGE AND ADMINISTRATION During or immediately after FRINDOVYX administration, administer adequate amounts of fluid to reduce the risk of urinary tract toxicity ( 2.1 ). Malignant Diseases: Adult and Pediatric Patients ( 2.2 ) Intravenous: Initial course for patients with no hematologic deficiency: 40 mg/kg to 50 mg/ kg in divided doses over 2 to 5 days. Other regimens include 10 mg/kg to 15 mg/kg given every 7 to 10 days or 3 mg/kg to 5 mg/kg twice weekly. ( 2.2 ) See full prescribing information for instructions on preparation, handling, and administration. ( 2.3 ) 2.1 Important Administration Instructions During or immediately after the administration of FRINDOVYX, adequate amounts of fluid should be ingested or infused to force diuresis in order to reduce the risk of urinary tract toxicity. Therefore, FRINDOVYX should be administered in the morning. 2.2 Recommended Dosage for Malignant Diseases Adults and Pediatric Patients Intravenous When used as the only oncolytic drug therapy, the recommended dosage for the initial course of FRINDOVYX for patients with no hematologic deficiency is 40 mg/kg to 50 mg/kg given intravenously in divided doses over a period of 2 to 5 days. Other intravenous regimens include 10 mg/kg to 15 mg/kg given every 7 to 10 days or 3 mg/kg to 5 mg/kg twice weekly. Adjust the dosage of FRINDOVYX based on the specific regimen administered, response to treatment, myelosuppression or other adverse reactions, and patient risk factors [see Warnings and Precautions (5) ] . 2.3 Preparation, Handling and Administration FRINDOVYX is a hazardous drug. Follow applicable special handling and disposal procedures 1 . Caution should be exercised when handling and preparing FRINDOVYX. To minimize the risk of dermal exposure, always wear gloves when handling vials containing FRINDOVYX. FRINDOVYX 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 particulate matter. Cyclophosphamide does not contain any antimicrobial preservative and thus care must be taken to assure the sterility of prepared solutions. Use aseptic technique. For Direct Intravenous Injection Withdraw the prescribed dose of FRINDOVYX from the vial with a syringe and dilute with 0.9% Sodium Chloride Injection, USP to a concentration of 20 mg/mL of cyclophosphamide. For Intravenous Infusion Withdraw the prescribed dose of FRINDOVYX from the vial with a syringe and dilute FRINDOVYX to a concentration of 2 mg/mL with any of the following diluents: 0.9% Sodium Chloride Injection, USP 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 Diluted Cyclophosphamide Solution: If not used immediately, for microbiological integrity, cyclophosphamide solutions should be stored as described in Table 1. Table 1: Storage of Cyclophosphamide Solutions Diluent Storage Room Temperature Refrigerated Diluted Solution (20 mg/mL) for Direct Intravenous Injection 0.9% Sodium Chloride Injection, USP up to 24 hours up to 6 days Diluted Solutions (2 mg/mL) for Intravenous Infusion 0.9% Sodium Chloride Injection, USP up to 24 hours up to 6 days 0.45% Sodium Chloride Injection, USP up to 24 hours up to 6 days 5% Dextrose Injection, USP up to 24 hours up to 36 hours 5% Dextrose and 0.9% Sodium Chloride Injection, USP up to 24 hours up to 36 hours Storage of Undiluted Cyclophosphamide Solution (Multiple-Dose Vial): After first use, store partially used multiple-dose vial in the original carton refr …

3 DOSAGE FORMS AND STRENGTHS FRINDOVYX: Clear, colorless to yellow sterile solution of cyclophosphamide in multiple-dose vial in the following three strengths. 500 mg/mL 1 g/2 mL (500 mg/mL) 2 g/4 mL (500 mg/mL) Injection: 500 mg/mL, 1 g/2 mL (500 mg/mL), and 2 g/4mL (500 mg/mL) in multiple-dose vial ( 3 )

4 CONTRAINDICATIONS Hypersensitivity FRINDOVYX 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. Urinary Outflow Obstruction FRINDOVYX is contraindicated 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) ] Alcohol Content [see Warnings and Precautions (5.7) ] Infertility [see Warnings and Precautions (5.9) and Use in Specific Populations (8.3 and 8.4) ] Impaired Wound Healing [see Warnings and Precautions (5.10)] Hyponatremia [see Warnings and Precautions (5.11) ] Adverse reactions reported most often include neutropenia, febrile neutropenia, fever, alopecia, nausea, vomiting, and diarrhea. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact AVYXA Pharma, LLC at 1-888-520-0954 or FDA at 1-800-FDA-1088 or www.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 glucos …

7 DRUG INTERACTIONS 7.1 Effect of Other Drugs on Cyclophosphamide Exposure Protease Inhibitors Concomitant use of protease inhibitors may increase the concentration of cytotoxic metabolites and may enhance the toxicities of cyclophosphamide, including higher incidence of infections, neutropenia, and mucositis. Monitor for increased toxicities in patients receiving protease inhibitors. 7.2 Drugs that Potentiate Cyclophosphamide Toxicities Drugs or agents with similar toxicities to FRINDOVYX and can potentiate these effects are listed in Table 2. Table 2: Drugs that Potentiate Cyclophosphamide Toxicities Toxicity Drugs Increased hematotoxicity and/or immunosuppression ● 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 ● Anthracyclines ● Cytarabine ● Pentostatin ● Radiation therapy of the cardiac region ● Trastuzumab Increased pulmonary toxicity ● Amiodarone ● G-CSF, GM-CSF (granulocyte colony-stimulating factor, granulocyte macrophage colony-stimulating factor) Increased nephrotoxicity ● 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 ● Radiation treatment: Increased risk of hemorrhagic cystitis may result from a combined effect of cyclophosphamide and past or concomitant radiation treatment. 7.3 Effect of Cyclophosphamide on Other Drugs Metronidazole Acute encephalopathy has been reported in a patient receiving cyclophosphamide and metronidazole. Monitor for neurologic toxicities in patients receiving metronidazole. Tamoxifen Concomitant use of tamoxifen and a cyclophosphamide-containing chemotherapy regimen may increase the risk of thromboembolic complications. Monitor for signs and symptoms of thromboembolic events in patients receiving tamoxifen. Coumarins Both increased and decreased warfarin effect have been reported in patients receiving warfarin and cyclophosphamide. Monitor anticoagulant activity closely in patients receiving warfarin or other coumarins. Cyclosporine Concomitant administration of cyclophosphamide may decrease serum concentrations of cyclosporine. This interaction may result in an increased incidence of graft-versus-host disease. Monitor for signs and symptoms of graft-versus-host disease in patients receiving cyclosporine. Depolarizing Muscle Relaxants If a patient has been treated with cyclophosphamide within 10 days of general anesthesia, alert the anesthesiologist. Cyclophosphamide causes a marked and persistent inhibition of cholinesterase activity. Prolonged apnea may occur with concurrent depolarizing muscle relaxants (e.g., succinylcholine).

8 USE IN SPECIFIC POPULATIONS Lactation : Advise not to breastfeed. ( 8.2 ) Renal Impairment : Monitor for toxicity in patients with moderate and severe renal impairment. ( 8.6 , 12.3 ) 8.1 Pregnancy Risk Summary Based on its mechanism of action and published reports of effects in pregnant patients or animals, FRINDOVYX 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 a 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 of miscarriage is 15% - 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, advise lactating women not to breastfeed during treatment with FRINDOVYX and for 1 week after the last dose. 8.3 Females and Males of Reproductive Potential FRINDOVYX can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1) ] . Pregnancy Testing Verify the pregnancy status of females of reproductive potential prior to the initiation of FRINDOVYX [see Use in Specific Populations (8.1) ] . Contraception Females Advise females of reproductive potential to use effective contraception during treatment with FRINDOVYX and for up to 1 year after completion of therapy. 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 FRINDOVYX and for 4 months after completion of therapy [see 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 during any of their maturation phases. The exact duration of follicular development in humans is not known, but may be longer than 12 months [see Nonclinical Toxicology (13.1) ] . Males Men treated with cyclophosphamide may develop oligospermia or azoospermia which are normally associated with increa …

12.1 Mechanism of Action 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.

11 DESCRIPTION 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 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. The pK a of cyclophosphamide is 5.7. FRINDOVYX is a clear, colorless to yellow sterile solution available as 500 mg/mL, 1 g/2 mL, and 2 g/4 mL in multiple dose vial for dilution prior to intravenous administration. 500 mg/mL vial contains 534.5 mg cyclophosphamide monohydrate, equivalent to 500 mg cyclophosphamide and 500 mg dehydrated alcohol (equivalent to 63% v/v). 1 g/2 mL vial contains 1069.0 mg cyclophosphamide monohydrate equivalent to 1 g cyclophosphamide and 1000 mg dehydrated alcohol (equivalent to 63% v/v). 2 g/4 mL vial contains 2138.0 mg cyclophosphamide monohydrate, equivalent to 2 g cyclophosphamide and 2000 mg dehydrated alcohol (equivalent to 63% v/v). 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 [see Clinical Pharmacology (12.3) ] . Cystitis prophylaxis with mesna may be helpful in preventing or limiting urotoxic effects with cyclophosphamide overdose.

16 HOW SUPPLIED/STORAGE AND HANDLING FRINDOVYX TM is a ready-to-dilute clear, colorless to yellow sterile solution containing cyclophosphamide and is supplied in multiple-dose vial. FRINDOVYX TM Injection NDC Number Strength Vial Presentation 83831-119-01 500 mg/mL Multiple-dose vial, carton of 1 83831-120-02 1 g/2 mL Multiple-dose vial, carton of 1 83831-121-04 2 g/4 mL Multiple-dose vial, carton of 1 Store vials refrigerated at 2°C to 8°C (36°F to 46°F). Store diluted solutions of cyclophosphamide according to Table 1 [see Dosage and Administration (2.3) ]. Cyclophosphamide is a hazardous product. Follow special handling and disposal procedures. 1