Netupitant, palonosetron, and fosnetupitant
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From MedlinePlus, U.S. National Library of Medicine
Serotonin-3 Receptor Antagonist, Substance P/Neurokinin-1 Receptor Antagonist
Dosing in kidney impairment
Renal Impairment No 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 [see Clinical Pharmacology ] .
Dosing in liver impairment
Hepatic Impairment No 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 ] .
Preparation and administration
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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. [See table below.] 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. [See table below.] AKYNZEO injection (To-be-Diluted) contains no antimicrobial preservatives and is intended for single use only.
Compatibility AKYNZEO 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 Storage The 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).
Preparation and Administration of AKYNZEO for Injection See Table 4 for preparation instructions of AKYZNEO for injection. AKYNZEO for injection requires dilution prior to administration. [See table below.] AKYNZEO for injection contains no antimicrobial preservatives, is intended for single use only. Compatibility AKYNZEO 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 Storage The 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).
Incompatibility of AKYNZEO for Injection and AKYZNEO Injection AKYNZEO 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.
| 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. |
| 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. |
| 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. |
Drug interactions
Check netupitant, palonosetron, and fosnetupitant against a medication listLabel text (8 paragraphs)
7 DRUG INTERACTIONS CYP3A4 Substrates: inhibition of CYP3A4 by netupitant can result in increased plasma concentrations of the concomitant drug for 6 days after single dosage administration of AKYNZEO; avoid concomitant CYP3A4 substrates for one week, if feasible. If not avoidable, consider dose reduction of the CYP3A4 substrate ( 7.1 ) CYP3A4 Inducers (e.g., rifampin): decreased plasma concentrations of netupitant; avoid use ( 7.2 )
7.1 Effects of AKYNZEO on Other Drugs Interaction with CYP3A4 Substrates Netupitant is a moderate inhibitor of CYP3A4. AKYNZEO should be used with caution in patients receiving concomitant medications that are primarily metabolized through CYP3A4. A single oral dose of netupitant 300 mg significantly inhibits CYP3A4 for 6 days. Avoid concomitant use of drugs that are CYP3A4 substrates for one week, if feasible. If not avoidable, consider dose reduction of CYP3A4 substrates. Dexamethasone A single oral dose of netupitant 300 mg or a single fosnetupitant infusion of 235 mg increased the systemic exposure of concomitant dexamethasone more than 2-fold on Days 2 and 4.
Administer a reduced dose of dexamethasone with AKYNZEO [see Dosage and Administration ( 2.1 ), Clinical Pharmacology ( 12.3 )] . Midazolam When administered with netupitant, the systemic exposure to midazolam was significantly increased. Consider the potential effects of increased plasma concentrations of midazolam or other benzodiazepines metabolized via CYP3A4 (alprazolam, triazolam) when administering these drugs with AKYNZEO [see Clinical Pharmacology ( 12.3 )] . Chemotherapeutic Agents The systemic exposure of chemotherapy agents metabolized by CYP3A4 can increase when administered with AKYNZEO.
Chemotherapy agents that are known to be metabolized by CYP3A4 include docetaxel, paclitaxel, etoposide, irinotecan, cyclophosphamide, ifosfamide, imatinib, vinorelbine, vinblastine, and vincristine [see Clinical Pharmacology ( 12.3 )] . Caution and monitoring for chemotherapeutic related adverse reactions are advised in patients receiving chemotherapy agents metabolized primarily by CYP3A4. Oral Contraceptives There is no clinically significant effect of AKYNZEO on the efficacy of oral contraceptives containing levonorgestrel and ethinyl estradiol [see Clinical Pharmacology ( 12.3 )] .
Warfarin Although it was predicted that co-administration of intravenous AKYNZEO with warfarin would not substantially increase the systemic exposure to S-warfarin (CYP2C9 substrate), the active enantiomer, the effects of AKYNZEO for injection and AKYNZEO capsules on INR and prothrombin time have not been studied. Monitor INR and adjust the dosage of warfarin, as needed with concomitant use of AKYNZEO, to maintain the target INR range.
7.2 Effects of Other Drugs on AKYNZEO Netupitant is mainly metabolized by CYP3A4. Palonosetron is mainly metabolized by CYP2D6 and to a lesser extent by CYP3A4 and CYP1A2. CYP3A4 Inducers Avoid concomitant use of AKYNZEO in patients who are chronically using a strong CYP3A4 inducer such as rifampin. A strong CYP3A inducer can decrease the efficacy of AKYNZEO by substantially reducing plasma concentrations of the netupitant component [see Clinical Pharmacology ( 12.3 )] . CYP3A4 Inhibitors Concomitant use of AKYNZEO with a strong CYP3A4 inhibitor (e.g., ketoconazole) can increase the systemic exposure to the netupitant component of AKYNZEO.
However, no dosage adjustment is necessary for single dose administration of AKYNZEO [see Clinical Pharmacology ( 12.3 )] .
7.3 Serotonergic Drugs Serotonin syndrome (including altered mental status, autonomic instability, and neuromuscular symptoms) has been described following the concomitant use of 5-HT 3 receptor antagonists and other serotonergic drugs, including selective serotonin reuptake inhibitors (SSRIs) and serotonin and noradrenaline reuptake inhibitors (SNRIs). If symptoms occur, discontinue AKYNZEO and initiate supportive treatment [see Warnings and Precautions ( 5.2 )].
Contraindications
None. None ( 4 )
Pregnancy and lactation
Pregnancy
8.1 Pregnancy Risk Summary Limited 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…
For breastfeeding, also see LactMed (National Library of Medicine), which summarizes milk levels and infant effects.
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