Akynzeo

SIDE EFFECTS

The following clinically significant adverse reactions are found elsewhere in the labeling:

• Hypersensitivity Reactions [see WARNINGS AND PRECAUTIONS]
• Serotonin Syndrome [see WARNINGS AND PRECAUTIONS]

Clinical Trials Experience

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.

AKYNZEO Capsules

The overall safety of AKYNZEO capsules was evaluated in 1538 cancer patients and healthy subjects 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], 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, Table 15 and Table 17].

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 4: Adverse Reactions Occurring in ≥3% of Cancer Patients Receiving AKYNZEO Capsules and Cisplatin Based Highly Emetogenic Chemotherapy (Cycle 1) shows adverse reactions reported at an incidence of at least 3% and for which the AKYNZEO rate exceeded palonosetron alone.

Table 4: Adverse Reactions Occurring in ≥3% of Cancer Patients Receiving AKYNZEO Capsules and Cisplatin Based Highly Emetogenic Chemotherapy (Cycle 1)

Adverse Reactions	AKYNZEO Capsules netupitant 300 mg/ palonosetron 0.5 mg (N=136)	Palonosetron 0.5 mg (N=136)
Dyspepsia	4%	2%
Fatigue	4%	2%
Constipation	3%	1%
Erythema	3%	2%

Anthracyclines And Cyclophosphamide Based Chemotherapy

In a study of patients receiving anthracycline and cyclophosphamide based chemotherapy, 725 patients were treated with AKYNZEO capsules during Cycle 1, and 635 of these patients continued for up to 8 cycles in a multiple-cycle extension. Table 5 shows adverse reactions reported at an incidence of at least 3% and for which the AKYNZEO capsules rate exceeded palonosetron alone during Cycle 1. The adverse reaction profile in subsequent cycles was similar to that observed in Cycle 1.

Table 5: Adverse Reactions Occurring in ≥3% of Cancer Patients Receiving AKYNZEO Capsules and Anthracyclines and Cyclophosphamide Based Chemotherapy (Cycle 1)

Adverse Reactions	AKYNZEO Capsules netupitant 300 mg/palonosetron 0.5 mg (N=725)	Palonosetron 0.5 mg (N=725)
Headache	9%	7%
Asthenia	8%	7%
Fatigue	7%	5%

In addition to the adverse reactions shown above, there were reports of concomitant elevations of transaminases greater than 3 times the upper limit of normal and total bilirubin in both arms of the two trials that compared AKYNZEO capsules to oral palonosetron, and the frequency of these elevations was comparable between treatment groups. See Table 6.

Table 6: Liver Function Laboratory Abnormalities

Laboratory Changes	AKYNZEO Capsules 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	3 (0.3%)	5 (0.6%)
AST > 10 x ULN and/or ALT > 10 x ULN with Total Bilirubin > ULN	-	2 (0.2%)
AST > 3 x ULN and/or ALT > 3 x ULN with Total Bilirubin ≥ 2 x ULN	1 (0.1%)	1 (0.1%)
ULN = upper limit of normal

In a multi-cycle safety study of 412 patients, the safety profile of AKYNZEO capsules (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 greater than 3 times the upper limit of normal 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 (greater than or equal to 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 greater than 10 times the upper limit of normal.

AKYNZEO For Injection

The safety of AKYNZEO for injection was evaluated in 203 patients in an active-controlled multi-cycle (median 4 cycles, range of 1-4 cycles) safety clinical study in patients receiving HEC regimens, not including anthracycline plus cyclophosphamide, (e.g., cisplatin, cyclophosphamide, carmustine, dacarbazine and mechlorethamine) compared to 201 patients receiving AKYNZEO capsules (NCT02517021). The median age was 60 years, 46% were female, 99.5 % were White, 0.3% were Asian, and 0.3% were Hispanic. All patients received a single dose of AKYNZEO for injection 30 minutes prior to the start of each chemotherapy cycle; dexamethasone was co-administered with AKYNZEO. The safety profile of AKYNZEO for injection was generally similar to that seen with AKYNZEO capsules.

DRUG INTERACTIONS

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, CLINICAL PHARMACOLOGY].

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].

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]. 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].

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.

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].

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].

Serotonergic Drugs

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). If symptoms occur, discontinue AKYNZEO and initiate supportive treatment [see WARNINGS AND PRECAUTIONS].

Read the entire FDA prescribing information for Akynzeo (Netupitant and Palonosetron Capsules)