FRINDOVYX- cyclophosphamide_injection

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. Cyclophosphamide exposure-response relationships and the time course of pharmacodynamic response have not been fully characterized. Cyclophosphamide is a prodrug. Cyclophosphamide pharmacokinetics are linear over the approved recommended dose range. Distribution The volume of distribution of cyclophosphamide is 30 to 50 L. Cyclophosphamide is approximately 20% protein bound, with no dose dependent changes. Some metabolites are greater than 60% protein bound. Elimination The elimination half-life (t½) of cyclophosphamide ranges from 3 to 12 hours, and the clearance (CL) ranges from 4 to 5. When cyclophosphamide was administered at 4 g/m 2 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 beta-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. Excretion 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. Specific Populations Renal Impairment Following one-hour intravenous infusion, cyclophosphamide AUC increased by 38% in patients with CLcr of 25 to 50 mL/min, by 77% in patients with CLcr of 10 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. Hepatic Impairment Cyclophosphamide 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).

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 1.

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 See full prescribing information for instructions on preparation, handling, and administration. 3 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. 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) FRINDOVYX is a hazardous drug. 1 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. 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. , 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. 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 refrigerated at 2°C to 8°C (36ºF to 46°F) for up to 28 days or at room temperature at 20°C to 25°C (68ºF to 77°F) for up to 7 days. Discard unused portion.

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) Use in Specific Populations (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. 1 To report SUSPECTED ADVERSE REACTIONS, contact Avyxa Pharma, LLC at 1-888-520-0954 or FDA at 1-800-FDA-1088 or www. gov/medwatch. 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: Congenital, Familial and Genetic Ear and Labyrinth: Endocrine: Eye: Gastrointestinal: General Disorders and Administrative Site Conditions: Hematologic: Hepatic: Immune: Infections: Pneumocystis jiroveci Strongyloides Investigations: Metabolism and Nutrition: Musculoskeletal and Connective Tissue Neoplasms: Nervous System: Pregnancy: Psychiatric: Renal and Urinary: Reproductive System: Respiratory: Skin and Subcutaneous Tissue: Tumor lysis syndrome : Vascular:.

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.

Lactation 8. 2 Renal Impairment 8. 3 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) Nonclinical Toxicology (13. 1) [see Data] [see Data] The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. 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. 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. 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 increased gonadotropin but normal testosterone secretion. The safety and effectiveness of FRINDOVYX have been established in pediatric patients and information on this use is discussed throughout the labeling. The alcohol content of FRINDOVYX should be taken into account when given to pediatric patients [see Warnings and Precautions (5. 7) 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. In patients with severe renal impairment, decreased renal excretion may result in increased plasma levels of cyclophosphamide and its metabolites which may increase toxicity [see Clinical Pharmacology (12. 3) Cyclophosphamide and its metabolites are dialyzable although there are probably quantitative differences depending upon the dialysis system. In patients requiring dialysis, consider using a consistent interval between cyclophosphamide administration and dialysis. Patients with severe hepatic impairment have reduced conversion of cyclophosphamide to the active 4-hydroxyl metabolite, potentially reducing efficacy [see Clinical Pharmacology (12. 3) The alcohol content of FRINDOVYX should be taken into account when given to patients with hepatic impairment [see Warnings and Precautions (5.

RECENT MAJOR CHANGES
Dosage and Administration ( 2.2 2.3 Warnings and Precautions, Embryo Fetal Toxicity ( 5.7
DRUG INTERACTIONS
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. 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. Increased cardiotoxicity Anthracyclines Increased pulmonary toxicity Amiodarone Increased nephrotoxicity Amphotericin B Increase in other toxicities: Azathioprine: Increased risk of hepatotoxicity (liver necrosis) 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. 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. , succinylcholine).

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 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.
NONCLINICAL TOXICOLOGY
Cyclophosphamide administered by different routes, including intravenous, subcutaneous or intraperitoneal injection, or in drinking water, caused tumors in both mice and rats. In addition to leukemia and lymphoma, benign and malignant tumors were found at various tissue sites, including urinary bladder, mammary gland, lung, liver, and injection site [see Warnings and Precautions (5.5) Cyclophosphamide was mutagenic and clastogenic in multiple in vitro in vivo Cyclophosphamide is genotoxic in male and female germ cells. Animal data indicate that exposure of oocytes to cyclophosphamide during follicular development may result in a decreased rate of implantations and viable pregnancies, and in an increased risk of malformations. Male mice and rats treated with cyclophosphamide show alterations in male reproductive organs (e.g., decreased weights, atrophy, changes in spermatogenesis), and decreases in reproductive potential (e.g., decreased implantations and increased post-implantation loss) and increases in fetal malformations when mated with untreated females [see Use in Specific Populations (8.3)
REFERENCES
OSHA Hazardous Drugs. OSHA.

Avyxa Pharma, LLC

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