HIGHLIGHTS OF PRESCRIBING INFORMATION
`These highlights do not include all the information needed to use
`AKYNZEO® safely and effectively. See full prescribing information for
`AKYNZEO®.
`AKYNZEO® (netupitant and palonosetron) capsules, for oral use
`Initial U.S. Approval: 2014
`AKYNZEO® (fosnetupitant and palonosetron) for injection, for
`intravenous use
`Initial U.S. Approval: 2018
`AKYNZEO® (fosnetupitant and palonosetron) injection, for intravenous
`use
`Initial U.S. Approval: 2018
`---------------------INDICATIONS AND USAGE ------------------------
`• 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. (1)
`• 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. (1)
`Limitations of Use
`o AKYNZEO for injection and AKYNZEO injection have not been
`studied for the prevention of nausea and vomiting associated with
`anthracycline plus cyclophosphamide chemotherapy. (1)
`• AKYNZEO is a combination of palonosetron, a serotonin-3 (5-HT3)
`receptor antagonist, and netupitant or fosnetupitant, substance
`P/neurokinin-1 (NK-1) receptor antagonists: palonosetron prevents
`nausea and vomiting during the acute phase and netupitant/fosnetupitant
`prevents nausea and vomiting during both the acute and delayed phase
`after cancer chemotherapy. (1)
`------------- DOSAGE AND ADMINISTRATION--------------
`Recommended Dosage
`• AKYNZEO capsules: The recommended dosage is one AKYNZEO
`capsule administered 1 hour prior to the start of chemotherapy, with or
`without food. (2.1)
`• AKYNZEO for injection and AKYNZEO injection (Ready-to-Use and To-
`be-Diluted) The recommended dosage is one vial infused intravenously
`over 30 minutes starting 30 minutes before chemotherapy. (2.1)
`Preparation and Administration
`• AKYNZEO injection is supplied either as a Ready-to-Use (with hanger)
`vial or a To-be-Diluted vial. (2.2)
`• AKYNZEO for injection requires dilution prior to administration. (2 3)
`• See full prescribing information for information on preparation,
`administration, and incompatibilities for each product. (2.2, 2.3, 2.4)
`--------------DOSAGE FORMS AND STRENGTHS--------------
`• Capsules: 300 mg netupitant/0.5 mg palonosetron. (3)
`• For Injection: 235 mg fosnetupitant/0.25 mg palonosetron as a lyophilized
`powder in single-dose vial for reconstitution. (3)
`• Injection: 235 mg fosnet upitant/0.25 mg palonosetron (235 mg/0.25 mg
`per 20 mL (11.75 mg/0.0125 mg per mL) solution in single-dose vial. (3)
`o Ready-to
`-Use (with hanger)
`o To-be-Diluted
`---------------------CONTRAINDICATIONS ------------------------
`None. (4)
`-----------------WARNINGS AND PRECAUTIONS------------------
`• 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)
`• 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. (5.2, 7.3)
`------------------------- ADVERSE REACTIONS ----------------------------
`Most common adverse reactions (≥3%) for AKYNZEO capsules are
`headache, asthenia, dyspepsia, fatigue, constipation and erythema (6.1)
`The safety profile of AKYNZEO for injection was generally similar to that
`seen with AKYNZEO capsules (6.1)
`To report SUSPECTED ADVERSE REACTIONS, contact HELSINN at
`1-844-357-4668 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
`---------------------------DRUG INTERACTIONS ----------------------------
`• CYP3A4 Substrates: Inhibition o
` f 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 In
`ducers (e.g., rifampin): Decreased plas ma concentrations of
`netupitant; avoid use. (7.2)
`--------------
`------- USE IN SPECIFIC POPULATIONS ---------------------
`• Pregnancy: May cause fetal harm. (8.1)
`• Hepatic Impairment: Avoid use in patients with severe hepatic
`impairment. (8.6)
`• Renal Im
`pairment: Avoid use in patients with severe renal impairment or
`end-stage renal disease. (8.7)
`
`See 17 for
`PATIENT COUNSELING INFORMATION and FDA-
`approved patient labeling.
` Revised: 2/2023
`______________________________________________________________________________________________________________________________________
`FULL PRESCRIBING INFORMATION: CONTENTS*
`1 INDICATIONS AND USAGE
`2 DOSAGE AND ADMINISTRATION
`2.1 Recommended Dosage
`2.2 Preparation and Administration of AKYNZEO Injection
`(Ready-to-Use and To-be-Diluted)
`2.3 Preparation and Administration of AKYNZEO for Injection
`2.4 Incompatibility of AKYNZEO for Injection and AKYZNEO
`Injection
`3 DOSAGE FORMS AND STRENGTHS
`4 CONTRAINDICATIONS
`5 WARNINGS AND PRECAUTIONS
`5.1 Hypersensitivity
`5.2 Serotonin Syndrome
`6 ADVERSE REACTIONS
`6.1 Clinical Trials Experience
`7 DRUG INTERACTIONS
`7.1 Effects of AKYNZEO on Other Drugs
`7.2 Effects of Other Drugs on AKYNZEO
`7.3 Serotonergic Drugs
`8 USE IN SPECIFIC POPULATIONS
`8.1 Pregnancy
`8.2 Lactation
`8.4 Pediatric Use
`8.5 Geriatric Use
`8.6 Hepatic Impairment
`8.7 Renal Impairment
`10 OVERDOSAGE
`11 DESCRIPTION
`12 CLINICAL PHARMACOLOGY
`12.1 Mechanism of Action
`12.2 Pharmacodynamics
`12.3 Pharmacok
`inetics
`13 NONCLINICAL TOXICOLOGY
`13.1 Carcinogenes
`is, Mutagenesis, Impairment of Fertility
`14 CLINICAL STUDIES
`16 HOW SUPPLIED/STORAGE AND HANDLING
`17 PATIENT COUNSELING INFORMATION
`*Sections or subsections omitted from the full prescribing information are not
`list
`___________________________________________________________________________________________________________
`Reference ID: 5126804
`This label may not be the latest approved by FDA.
`For current labeling information, please visit https://www.fda.gov/drugsatfda
`
`HELSINN EXHIBIT 2035
`Azurity Pharmaceuticals, Inc. v. Helsinn Healthcare S.A.
`IPR2025-00945
`Page 1 of 35
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`FULL PRESCRIBING INFORMATION
`1 INDICATIONS AND USAGE
`• 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 combina tion 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.
`2 DOSAGE AND ADMINISTRATION
`2.1 Recommended Dosage
`The 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.
`Reference ID: 5126804
`This label may not be the latest approved by FDA.
`For current labeling information, please visit https://www.fda.gov/drugsatfda
`
`Page 2 of 35
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`Table 1: Antiemetic Treatment Regimen
`Treatment
`Regimen Day 1 Days 2 to 4
`Highly Emetogenic Chemotherapy, including Cisplatin-Based Chemotherapy
`AKYNZEO
`capsules
`1 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
`injection
`(Ready-to-Use
`and To-be-
`Diluted)
`1 vial of AKYNZEO
`Infuse over 30 minutes starting 30 minutes
`before chemotherapy [see Dosage and
`Administration (2.2, 2.3)]
`Dexamethasone
`8 mg once a day
`Dexamethasone 12 mg 30 minutes before chemotherapy
`Anthracyclines and Cyclophosphamide-Based Chemotherapy and Chemotherapy Not Considered Highly
`Emetogenic
`AKYNZEO
`capsules
`1 capsule of AKYNZEO 1 hour before chemotherapy
`None
`Dexamethasone 12 mg 30 minutes before chemotherapy
`
`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-D iluted
`vial.
`AKYNZEO injectio n (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 I njection (Ready-to-Use) for I ntravenous
`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.
`
`
`Reference ID: 5126804
`This label may not be the latest approved by FDA.
`For current labeling information, please visit https://www.fda.gov/drugsatfda
`
`Page 3 of 35
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`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 I njection (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.
`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).
`2.3 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.
`
`Reference ID: 5126804
`This label may not be the latest approved by FDA.
`For current labeling information, please visit https://www.fda.gov/drugsatfda
`
`Page 4 of 35
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`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.
`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).
`
`2.4 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.
`
`3 DOSAGE FORMS AND STRENGTHS
`• 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.
`Reference ID: 5126804
`This label may not be the latest approved by FDA.
`For current labeling information, please visit https://www.fda.gov/drugsatfda
`
`Page 5 of 35
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`• 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.
`o Ready-to-Use (with hanger)
`o To-be-Diluted
`
`4 CONTRAINDICATIONS
`None.
`
`5 WARNINGS AND PRECAUTIONS
`5.1 Hypersensitivity
`Hypersensitivity 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-HT
`3 receptor antagonists.
`5.2 Serotonin Syndrome
`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- HT
`3 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 (7.3)].
`
`6 ADVERSE REACTIONS
`The following clinically significant adverse reactions are found elsewhere in the labeling:
`• Hypersensitivity Reactions [see Warnings and Precautions (5.1)]
`• Serotonin Syndrome [see Warnings and Precautions (5.2)]
`Reference ID: 5126804
`This label may not be the latest approved by FDA.
`For current labeling information, please visit https://www.fda.gov/drugsatfda
`
`Page 6 of 35
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`6.1 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 act ive-controlled trials [see
`Clinical Studies (14.1)] , 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 stu dies, dexamethasone was co -administered with AKYNZEO [see Clinical Studies ( 14.1),
`Table 16 and Table 18].
`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 5 shows adverse reactions reported at an incidence
`of at least 3% and for which the AKYNZEO rate exceeded palonosetron alone.
`Table 5: 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 6 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.
`
`Reference ID: 5126804
`This label may not be the latest approved by FDA.
`For current labeling information, please visit https://www.fda.gov/drugsatfda
`
`Page 7 of 35
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`Table 6: 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 7.
`Table 7: 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/m
`2) 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 -
`Reference ID: 5126804
`This label may not be the latest approved by FDA.
`For current labeling information, please visit https://www.fda.gov/drugsatfda
`
`Page 8 of 35
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`administered with AKYNZEO. The safety profile of AKYNZEO for injection was generally
`similar to that seen with AKYNZEO capsules.
`
`7 DRUG INTERACTIONS
`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 Pharmacol ogy (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.
`Reference ID: 5126804
`This label may not be the latest approved by FDA.
`For current labeling information, please visit https://www.fda.gov/drugsatfda
`
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`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 Cl inical
`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)].
`8 USE IN SPECIFIC POPULATIONS
`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
`Reference ID: 5126804
`This label may not be the latest approved by FDA.
`For current labeling information, please visit https://www.fda.gov/drugsatfda
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`Page 10 of 35
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`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.
`Data
`Animal Data
`Netupitant
`Daily 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.
`Fosnetupitant
`Daily 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 o