AKYNZEO- netupitant and palonosetron capsule
AKYNZEO is indicated 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 is an oral fixed 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.
Highly Emetogenic Chemotherapy, including Cisplatin Based Chemotherapy
The recommended dosage in adults is one capsule of AKYNZEO administered approximately 1 hour prior to the start of chemotherapy with dexamethasone 12 mg administered orally 30 minutes prior to chemotherapy on day 1 and 8 mg orally once daily on days 2 to 4 [see Clinical Studies (14),Table 5].
Anthracyclines and Cyclophosphamide Based Chemotherapy and Chemotherapy Not Considered Highly Emetogenic
The recommended dosage in adults is one capsule of AKYNZEO approximately 1 hour prior to the start of chemotherapy with dexamethasone 12 mg administered orally 30 minutes prior to chemotherapy on day 1. Administration of dexamethasone on days 2 to 4 is not necessary [see Clinical Studies (14), Table 7].
AKYNZEO can be taken with or without food.
AKYNZEO (300 mg netupitant/0.5 mg palonosetron) capsules are hard gelatin capsules with white body and caramel cap with “HE1” printed on the body.
Hypersensitivity reactions, including anaphylaxis, have been reported with or without known hypersensitivity to other 5-HT3 receptor antagonists.
The development of serotonin syndrome has been reported with 5-HT3 receptor antagonists. Most reports have been associated with concomitant use of serotonergic drugs (e.g., selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), monoamine oxidase inhibitors, mirtazapine, fentanyl, lithium, tramadol, and intravenous methylene blue). Some of the reported cases were fatal. Serotonin syndrome occurring with overdose of another 5-HT3 receptor antagonist alone has also been reported. The majority of reports of serotonin syndrome related to 5-HT3 receptor antagonist use occurred in a post-anesthesia care unit or an infusion center.
Symptoms associated with serotonin syndrome may include the following combination of signs and symptoms: mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, and hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, and incoordination), seizures, with or without gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Patients should be monitored for the emergence of serotonin syndrome, especially with concomitant use of AKYNZEO and other serotonergic drugs. If symptoms of serotonin syndrome occur, discontinue AKYNZEO and initiate supportive treatment. Patients should be informed of the increased risk of serotonin syndrome, especially if AKYNZEO is used concomitantly with other serotonergic drugs [see Drug Interactions ( 7 ), Patient Counseling Information ( 17 )].
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
The overall safety of AKYNZEO was evaluated in 1538 cancer patients and healthy volunteers in clinical trials. The data described below reflect exposure to AKYNZEO in 1169 cancer patients, receiving at least one cycle of cancer chemotherapy in 3 active-controlled trials [ see Clinical Studies (14) ] , including 782 exposed to AKYNZEO for at least 4 cycles and 321 exposed for at least 6 cycles, up to a maximum of 12 cycles of chemotherapy. The median age was 55, 79% were female, 83% were White, 13% were Asian, and 4% were Hispanic. All patients received a single oral dose of AKYNZEO 1 hour prior to the start of each chemotherapy cycle. In all studies, dexamethasone was co-administered with AKYNZEO [see Clinical Studies (14), Table 5 and Table 7].
Cisplatin Based Highly Emetogenic Chemotherapy
In a single-cycle study of patients receiving cisplatin-based highly emetogenic chemotherapy, 136 patients were treated with AKYNZEO. Table 1 shows adverse reactions defined as adverse events reported at an incidence of at least 3% and for which the AKYNZEO rate exceeded palonosetron alone.
|Adverse Reactions||AKYNZEO netupitant 300 mg/ palonosetron 0.5 mg (N=136)||Palonosetron 0.5 mg (N=136)|
Anthracyclines and Cyclophosphamide Based Chemotherapy
In a study of patients receiving anthracycline and cyclophosphamide based chemotherapy, 725 patients were treated with AKYNZEO during Cycle 1, and 635 of these patients continued for up to 8 cycles in a multiple-cycle extension. Table 2 shows adverse reactions defined as adverse events reported at an incidence of at least 3% and for which the AKYNZEO rate exceeded palonosetron alone during Cycle 1. The adverse reaction profile in subsequent cycles was similar to that observed in Cycle 1.
AKYNZEO netupitant 300 mg/ palonosetron 0.5 mg (N=725)
Palonosetron 0.5 mg (N=725)
In addition to the adverse reactions shown above, there were reports of concomitant elevations of transaminases > 3 x ULN and total bilirubin in both arms of the two trials that compared AKYNZEO to oral palonosetron, and the frequency of these elevations was comparable between treatment groups. See Table 3.
AKYNZEO netupitant 300 mg/ palonosetron 0.5 mg N=861
Palonosetron 0.5 mg N=861
AST > 3 x ULN and/or ALT > 3 x ULN with Total Bilirubin > ULN
AST > 10 x ULN and/or ALT > 10 x ULN with Total Bilirubin > ULN
AST > 3 x ULN and/or ALT > 3 x ULN with Total Bilirubin ≥ 2 x ULN
In a multi-cycle safety study of 412 patients, the safety profile of AKYNZEO (n = 308) was comparable to aprepitant and palonosetron (n = 104) in patients undergoing initial and repeat cycles (median 5 cycles, range of 1-14 cycles) of chemotherapy, including carboplatin, cisplatin, oxaliplatin, and doxorubicin regimens. There were no reports of concomitant elevations of transaminases > 3 x ULN and total bilirubin in this study in either arm.
In a randomized, clinical non-inferiority study, that compared oral palonosetron 0.5 mg to intravenous palonosetron 0.25 mg in cancer patients scheduled to receive highly emetogenic cisplatin (>70 mg/m2) based chemotherapy, there were two patients (0.5%; 2/369) in the intravenous palonosetron arm who had concomitant elevations of transaminases and total bilirubin. Neither experienced transaminase elevations of > 10 x ULN.
Interaction with CYP3A4 Substrates
Netupitant, a component of AKYNZEO, is a moderate inhibitor of CYP3A4.
AKYNZEO should be used with caution in patients receiving concomitant medications that are primarily metabolized through CYP3A4. The plasma concentrations of CYP3A4 substrates can increase when co-administered with AKYNZEO. The inhibitory effect on CYP3A4 can last for multiple days.
A two-fold increase in the systemic exposure of dexamethasone was observed 4 days after single dose of netupitant. The duration of the effect was not studied beyond 4 days. Administer a reduced dose of dexamethasone with AKYNZEO [see Dosage and Administration ( 2 ), Clinical Pharmacology (12.3)].
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.
Interaction with 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.
Interaction with oral contraceptives
Clinically significant effect of AKYNZEO on the efficacy of oral contraceptives containing levonorgestrel and ethinyl estradiol is unlikely.
Netupitant, a component of AKYNZEO, is mainly metabolized by CYP3A4 [see Clinical Pharmacology (12.3)].
In vitro metabolism studies have suggested that CYP2D6 and to a lesser extent CYP3A4 and CYP1A2 are involved in the metabolism of palonosetron.
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)].
Concomitant use of AKYNZEO with a strong CYP3A4 inhibitor (e.g., ketoconazole) can significantly 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)].
Serotonin syndrome (including altered mental status, autonomic instability, and neuromuscular symptoms) has been described following the concomitant use of 5-HT3 receptor antagonists and other serotonergic drugs, including selective serotonin reuptake inhibitors (SSRIs) and serotonin and noradrenaline reuptake inhibitors (SNRIs) [see Warnings and Precautions (5.2)].
Pregnancy Category C
Adequate and well-controlled studies with AKYNZEO have not been conducted in pregnant women. In animal reproduction studies, no effects on embryo-fetal development were observed following daily administration of netupitant 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 human 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 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 human dose to be given with each cycle of chemotherapy. Daily administration of netupitant in rats up to 3.7 times the human AUC at the recommended human dose during organogenesis through lactation produced no adverse effects in the offspring. 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 human oral dose in rats and rabbits, respectively. AKYNZEO should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Daily administration of up to 30 mg/kg netupitant in rats (3.7 times the human AUC at the recommended single human 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 administration of netupitant in rabbits at 10 mg/kg/day and higher (0.2 times the human AUC at the recommended single human 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 administration of up to 30 mg/kg netupitant (3.7 times the human AUC at the recommended human dose) in rats during organogenesis through lactation produced no adverse effects in the offspring.
In 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 human oral dose based on body surface area) or pregnant rabbits given oral doses up to 60 mg/kg/day (1841 times the recommended human oral dose based on body surface area) during the period of organogenesis.
DrugInserts.com provides trustworthy package insert and label information about marketed drugs as submitted by manufacturers to the US Food and Drug Administration. Package information is not reviewed or updated separately by DrugInserts.com. Every individual package label entry contains a unique identifier which can be used to secure further details directly from the US National Institutes of Health and/or the FDA.