Frindovyx
(Cyclophosphamide)Frindovyx Prescribing Information
Dosage and Administration (
FRINDOVYX is a hazardous drug.Follow applicable special handling and disposal procedures1. Caution should be exercised when handling and preparing FRINDOVYX. To minimize the risk of dermal exposure, always wear gloves when handling vials containing FRINDOVYX.
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.
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.
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.
If not used immediately, for microbiological integrity, cyclophosphamide solutions should be stored as described in Table 1.
| 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 |
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.
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.
During or immediately after FRINDOVYX administration, administer adequate amounts of fluid to reduce the risk of urinary tract toxicity (
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.
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
- 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 Recommended Dosage for Malignant DiseasesAdults and Pediatric PatientsIntravenous
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)]. - See full prescribing information for instructions on preparation, handling, and administration. ()2.2 Recommended Dosage for Malignant DiseasesAdults and Pediatric PatientsIntravenous
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: Clear, colorless or slight 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)
- Lactation: Advise not to breastfeed. ()8.2 LactationRisk 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.
- Renal Impairment: Monitor for toxicity in patients with moderate and severe renal impairment. (,8.6 Renal Impairment
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)]. Monitor patients with severe renal impairment (CLcr =10 mL/min to 24 mL/min) for signs and symptoms of toxicity.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.
)12.3 PharmacokineticsCyclophosphamide is a prodrug. Cyclophosphamide pharmacokinetics are linear over the approved recommended dose range.
DistributionThe 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.
EliminationThe elimination half-life (t½) of cyclophosphamide ranges from 3 to 12 hours, and the clearance (CL) ranges from 4 to 5.6 L/h.
When cyclophosphamide was administered at 4 g/m2(approximately 2 times the approved recommended dosage) over a 90-minutes infusion, concentration-time data demonstrate saturable elimination in parallel with first-order renal elimination.
MetabolismCyclophosphamide 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.
ExcretionCyclophosphamide 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 PopulationsRenal ImpairmentFollowing 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 ImpairmentCyclophosphamide 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).
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.
FRINDOVYX is contraindicated in patients with urinary outflow obstruction
Hemorrhagic cystitis, pyelitis, ureteritis, and hematuria have been reported with cyclophosphamide. Medical and/or surgical supportive treatment may be required to treat protracted cases of severe hemorrhagic cystitis. Discontinue cyclophosphamide therapy in case of severe hemorrhagic cystitis.
Urotoxicity (bladder ulceration, necrosis, fibrosis, contracture and secondary cancer) may require interruption of cyclophosphamide treatment or cystectomy. Urotoxicity can be fatal. Urotoxicity can occur with short-term or long-term use of cyclophosphamide.
Before starting treatment, exclude or correct any urinary tract obstructions