Akynzeo
(Netupitant And Palonosetron)Dosage & Administration
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Akynzeo Prescribing Information
- AKYNZEO capsules is indicated in combination with dexamethasone in adults for the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of cancer chemotherapy, including, but not limited to, highly emetogenic chemotherapy. AKYNZEO capsules is a combination of palonosetron and netupitant: palonosetron prevents nausea and vomiting during the acute phase and netupitant prevents nausea and vomiting during both the acute and delayed phase after cancer chemotherapy.
- AKYNZEO for injection and AKYNZEO injection are indicated in combination with dexamethasone in adults for the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of highly emetogenic cancer chemotherapy. AKYNZEO for injection is a combination of palonosetron and fosnetupitant, a prodrug of netupitant: palonosetron prevents nausea and vomiting during the acute phase and fosnetupitant prevents nausea and vomiting during both the acute and delayed phase after cancer chemotherapy.
Limitations of Use
AKYNZEO for injection and AKYNZEO injection have not been studied for the prevention of nausea and vomiting associated with anthracycline plus cyclophosphamide chemotherapy.
- AKYNZEO capsules:The recommended dosage is one AKYNZEO capsule administered 1 hour prior to the start of chemotherapy, with or without food. ()
2.1 Recommended DosageThe recommended dosages of AKYNZEO and dexamethasone in adults for the prevention of nausea and vomiting associated with administration of emetogenic chemotherapy are shown in Table 1.
AKYNZEO capsules can be taken with or without food.
Table 1: Antiemetic Treatment Regimen Treatment RegimenDay 1Days 2 to 4Highly Emetogenic Chemotherapy, including Cisplatin-Based ChemotherapyAKYNZEO capsules1 capsule of AKYNZEO
1 hour before chemotherapy
Dexamethasone 8 mg once a day
Dexamethasone 12 mg
30 minutes before chemotherapy
AKYNZEO for injection and AKYNZEO injection1 vial of AKYNZEO
Infuse over 30 minutes starting 30 minutes before chemotherapy
[see Dosage and Administration (2.2)]Dexamethasone 8 mg once a day
Dexamethasone 12 mg
30 minutes before chemotherapy
Anthracyclines and Cyclophosphamide-Based Chemotherapy and Chemotherapy Not Considered Highly EmetogenicAKYNZEO capsules1 capsule of AKYNZEO
1 hour before chemotherapy
None
Dexamethasone 12 mg
30 minutes before chemotherapy
- AKYNZEO injection is supplied either as a Ready-to-Use (with hanger) vial or a To-be-Diluted vial.
2.2 Preparation and Administration of AKYNZEO Injection (Ready-to-Use and To-be-Diluted)AKYNZEO injection is supplied as either a Ready-to-Use (with hanger) vial or a To-be-Diluted vial.
AKYNZEO injection (Ready-to-Use; with hanger)
See Table 2 for preparation instructions of AKYNZEO injection (Ready-to-Use) for intravenous infusion. AKYNZEO injection (Ready-to-Use) does not require dilution prior to administration.Table 2: Preparation and Administration of AKYNZEO Injection (Ready-to-Use) for Intravenous Infusion Step 1 Before administration, inspect the solution for particulate matter and discoloration. Discard the vial if particulates and/or discoloration are observed. Step 2 Using aseptic technique, insert a vented intravenous set through the septum of the vial. Once the stopper is punctured, use immediately. Step 3 To administer, invert and hang the vial utilizing the strap affixed to the bottom of the vial. Step 4 Administer over 30 minutes as an intravenous infusion. At the end of the infusion, flush the infusion line with 0.9% Sodium Chloride Injection, USP or with 5% Dextrose injection, USP to ensure complete drug administration. AKYNZEO injection (Ready-to-Use) contains no antimicrobial preservatives and is intended for single use only.
Compatibility
AKYNZEO injection (Ready-to-Use) is compatible with intravenous dexamethasone sodium phosphate which can be infused simultaneously. Do not add dexamethasone sodium phosphate to the AKYNZEO injection (Ready-to-Use) vial.Stability and Storage
Use immediately once the stopper is punctured.AKYNZEO Injection (To-be-Diluted)
See Table 3 for preparation instructions of AKYNZEO injection (To-be-Diluted) for intravenous infusion with dilution.Table 3: Preparation and Administration of AKYNZEO Injection (To-be-Diluted) for Intravenous Infusion Step 1 Before administration, inspect the solution for particulate matter and discoloration. Discard the vial if particulates and/or discoloration are observed. Step 2 Aseptically prepare an infusion vial or bag filled with 30 mL of 5% Dextrose injection, USP or 0.9% Sodium Chloride injection, USP. Step 3 Aseptically withdraw the entire volume of solution from the AKYNZEO vial (20 mL) and transfer it into the infusion vial or bag containing 30 mL of 5% Dextrose injection, USP or 0.9% Sodium Chloride injection, USP to yield a total volume of 50 mL. Step 4 Gently invert the vial or bag until complete dissolution. Step 5 Before administration, inspect the final diluted solution for particulate matter and discoloration. Discard the vial or bag if particulates and/or discoloration are observed. Step 6 Administer over 30 minutes as an intravenous infusion. At the end of the infusion, flush the infusion line with the same carrier solution to ensure complete drug administration. AKYNZEO injection (To-be-Diluted) contains no antimicrobial preservatives and is intended for single use only.
CompatibilityAKYNZEO injection (To-be-Diluted) is compatible with intravenous dexamethasone sodium phosphate which can be added to the infusion bag containing AKYNZEO solution or infused simultaneously.
Stability and StorageThe total time from dilution to the start of the infusion, with or without intravenous dexamethasone sodium phosphate, should not exceed 24 hours.
Store the final diluted solution at room temperature, 20ºC to 25ºC (68Fº to 77ºF).
- AKYNZEO for injection requires dilution prior to administration. ()
2.3 Preparation and Administration of AKYNZEO for InjectionSee Table 4 for preparation instructions of AKYZNEO for injection. AKYNZEO for injection requires dilution prior to administration.
Table 4: Preparation and Administration of AKYNZEO for Injection Step 1 Aseptically inject 20 mL 5% Dextrose injection, USP or 0.9% Sodium Chloride injection, USP into the vial. Ensure the solvent is added to the vial along the vial wall and not jetted in order to prevent foaming. Swirl the vial gently. Step 2 Aseptically prepare an infusion vial or bag filled with 30 mL of 5% Dextrose injection, USP or 0.9% Sodium Chloride injection, USP. Step 3 Aseptically withdraw the entire volume of solution from the AKYNZEO vial and transfer it into the infusion vial or bag containing 30 mL of 5% Dextrose injection, USP or 0.9% Sodium Chloride injection, USP to yield a total volume of 50 mL. Step 4 Gently invert the vial or bag until complete dissolution. Step 5 Before administration, inspect the final diluted solution for particulate matter and discoloration. Discard the vial or bag if particulates and/or discoloration are observed. Step 6 Administer over 30 minutes as an intravenous infusion. At the end of the infusion, flush the infusion line with the same carrier solution to ensure complete drug administration. AKYNZEO for injection contains no antimicrobial preservatives, is intended for single use only.
CompatibilityAKYNZEO for injection is compatible with intravenous dexamethasone sodium phosphate which can be added to the infusion bag containing AKYNZEO solution or infused simultaneously.
Stability and StorageThe total time from reconstitution to the start of the infusion, with or without intravenous dexamethasone sodium phosphate, should not exceed 24 hours.
Store the reconstituted solution and the final diluted solution at room temperature, 20ºC to 25ºC (68ºF to 77ºF).
- See full prescribing information for information on preparation, administration, and incompatibilities for each product. (2.2, 2.3, )
2.4 Incompatibility of AKYNZEO for Injection and AKYZNEO InjectionAKYNZEO for injection, AKYNZEO injection (Ready-to-Use) and AKYNZEO injection (To-be-Diluted) are incompatible with any solution containing divalent cations (e.g., calcium, magnesium), including Lactated Ringer’s injection and Hartmann's Solution.
Limited data are available on the compatibility of AKYNZEO for injection, AKYNZEO injection (Ready-to-Use), and AKYNZEO injection (To-be-Diluted) with other intravenous substances, additives, or other medications with the exception of intravenous dexamethasone sodium phosphate
[see Dosage and Administration (2.2,2.3)]and they should not be added to the AKYNZEO solution or infused simultaneously. If the same intravenous line is used for sequential infusion of several different drugs, flush the line before and after infusion of AKYNZEO solution with 0.9% Sodium Chloride Injection, USP.
- Capsules: 300 mg netupitant/0.5 mg palonosetron in a hard gelatin capsule with white body and caramel cap with “HE1” printed on the body.
- For Injection: 235 mg fosnetupitant/0.25 mg palonosetron white to off-white lyophilized powder in single-dose vial for reconstitution.
- Injection: 235 mg fosnetupitant/0.25 mg palonosetron per 20 mL (11.75 mg/0.0125 mg per mL) as a clear solution in single-dose vial.
- Ready-to-Use (with hanger)
- To-be-Diluted
- Pregnancy:May cause fetal harm ().
8.1 PregnancyRisk SummaryLimited available data with AKYNZEO use in pregnant women are insufficient to inform a drug- associated risk of adverse developmental outcomes. In animal reproduction studies with netupitant, no effects on embryo-fetal development were observed following daily oral administration in pregnant rats during the period of organogenesis at doses up to 3.7 times the human AUC (area under the plasma concentration-time curve) at the recommended single dose to be given with each cycle of chemotherapy. However, a dose-dependent increase in adverse effects on embryo-fetal development was observed following daily oral administration of netupitant in pregnant rabbits during the period of organogenesis with doses at least 0.2 times the human AUC at the recommended single dose to be given with each cycle of chemotherapy. Daily oral administration of netupitant in rats up to 3.7 times the human AUC at the recommended dose during organogenesis through lactation produced no adverse effects in the offspring (see Data).
In animal reproduction studies with fosnetupitant, delayed ossification of pubis occurred after intravenous administration in rats during the period of organogenesis at a dose 3 times the human AUC for netupitant at the recommended single dose to be given with each cycle of chemotherapy. In pregnant rabbits, an increase in resorptions was observed with daily intravenous administration of fosnetupitant during the period of organogenesis at doses up to 9 times the human AUC for fosnetupitant and 0.4 times the human AUC for netupitant at the recommended single dose to be given with each cycle of chemotherapy. Daily intravenous
administration of fosnetupitant (3 times the human AUC for netupitant at the recommended single dose to be given with each cycle of chemotherapy) in rats during organogenesis through lactation produced lower bodyweight in offspring at birth through maturation, and delayed physical development (see Data).In animal reproduction studies with palonosetron, no effects on embryo-fetal development were observed following oral administration during the period of organogenesis at doses up to 921 and 1841 times the recommended oral dose in rats and rabbits, respectively (see Data).
Based on animal data from netupitant studies, advise pregnant women of the potential risk to a fetus.The estimated background risk of major birth defects and miscarriage for the indicated populations are unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.
DataAnimal DataNetupitantDaily oral administration of up to 30 mg/kg netupitant in rats (3.7 times the human AUC at the recommended single dose to be given with each cycle of chemotherapy) during the period of organogenesis produced no effects on embryo-fetal development. However, an increased incidence of external and skeletal abnormalities in rabbit fetuses was observed following daily oral administration of netupitant in rabbits at 10 mg/kg/day and higher (0.2 times the human AUC at the recommended single dose to be given with each cycle of chemotherapy) during the period of organogenesis. These abnormalities included positional abnormalities in the limbs and paws, and fused sternebrae. Reduction in fetal rabbit weight occurred at 30 mg/kg/day. Maternal toxicity in rabbits (i.e., loss of bodyweight during the treatment period) was also observed at 30 mg/kg/day. Daily oral administration of up to 30 mg/kg netupitant (3.7 times the human AUC at the recommended dose) in rats during organogenesis through lactation produced no adverse effects in the offspring.
FosnetupitantDaily intravenous administration of 39 mg/kg/day fosnetupitant in rats (3 times the human AUC for netupitant at the recommended single dose to be given with each cycle of chemotherapy) during the period of organogenesis produced delayed ossification of pubis. No effects on embryo-fetal development were observed with daily administration of up to 13 mg/kg fosnetupitant in rats (2 times the human AUC for netupitant at the recommended single dose to be given with each cycle of chemotherapy). Due to the limited systemic exposure to fosnetupitant in pregnant rats, it is not possible to provide an AUC-based comparison of fosnetupitant exposure in rats and humans. An increase in resorptions was observed with daily intravenous administration of fosnetupitant at 6 mg/kg/day and higher in rabbits (9 times the human AUC for fosnetupitant and 0.4 times the human AUC for netupitant at the recommended single dose to be given with each cycle of chemotherapy) during the period of organogenesis. No effects were observed in rabbits at 3 mg/kg/day (5.4 times the human AUC for fosnetupitant and 0.4 times the human AUC for netupitant at the recommended single dose to be given with each cycle of chemotherapy). Daily intravenous administration of 39 mg/kg fosnetupitant in rats (3 times the AUC for netupitant at the recommended single dose to be given with each cycle of chemotherapy) during organogenesis through lactation produced lower bodyweight in offspring at birth through maturation, and delayed physical development (pinna detachment, eye opening, and preputial separation). These effects were associated with maternal toxicity (reduced weight gain and food consumption). No effects occurred in offspring or dams at 13 mg/kg/day (2 times the human AUC for netupitant at the recommended single dose to be given with each cycle of chemotherapy).
PalonosetronIn animal reproduction studies with palonosetron, no effects on embryo-fetal development were observed in pregnant rats given oral doses up to 60 mg/kg/day (921 times the recommended oral dose based on body surface area) or pregnant rabbits given oral doses up to 60 mg/kg/day (1841 times the recommended oral dose based on body surface area) during the period of organogenesis.
- Hepatic Impairment:Avoid use in patients with severe hepatic impairment ()
8.6 Hepatic ImpairmentNo dosage adjustment for AKYNZEO is necessary for patients with mild to moderate hepatic impairment (Child-Pugh score 5 to 8). Limited data are available with AKYNZEO in patients with severe hepatic impairment (Child-Pugh score greater than 9). Avoid use of AKYNZEO in patients with severe hepatic impairment[see Overdosage ,Clinical Pharmacology]. - Renal Impairment:Avoid use in patients with severe renal impairment or end-stage renal disease ()
8.7 Renal ImpairmentNo dosage adjustment for AKYNZEO is necessary in patients with mild to moderate renal impairment (creatinine clearance of 30 to 60 mL/min). The pharmacokinetics and safety of netupitant have not been studied in patients with severe renal impairment. Severe renal impairment (creatinine clearance < 30 mL/min) did not substantially affect pharmacokinetics of palonosetron. The pharmacokinetics for netupitant and palonosetron were not studied in patients with end-stage renal disease requiring hemodialysis. Avoid use of AKYNZEO in patients with severe renal impairment or end-stage renal disease[seeClinical Pharmacology].
None.
- Hypersensitivity reactions, including anaphylaxis, have been reported in patients receiving palonosetron, one of the components of AKYNZEO, with or without known hypersensitivity to other 5-HT3 receptor antagonists. ()
5.1 HypersensitivityHypersensitivity reactions, including anaphylaxis, have been reported in patients treated with palonosetron, one of the components of AKYNZEO, with or without known hypersensitivity to other 5-HT3receptor antagonists.
- Serotonin syndrome has been reported with 5-HT3 receptor antagonists alone but particularly with concomitant use of serotonergic drugs. If such symptoms occur, discontinue AKYNZEO and initiate supportive treatment. If concomitant use of AKYNZEO with other serotonergic drugs is clinically warranted, patients should be made aware of a potential increased risk for serotonin syndrome.