Akynzeo

Akynzeo information, interactions and side effects, AKYNZEO (300 mg netupitant/0.5 mg palonosetron) is an oral fixed combination product of netupitant, a substance P/neurokinin 1 (NK1) receptor antagonist, and palonosetron hydrochloride, a serotonin-3 (5HT3) receptor antagonist. Both netupitant and palonosetron hydrochloride are anti-nausea and anti-emetic agents.

Netupitant is chemically described: 2-[3,5-bis(trifluoromethyl)phenyl]-N, 2 dimethyl-N-[4-(2methylphenyl)-6-(4-methylpiperazin-1-yl)pyridin-3-yl] propanamide. The empirical formula is C30H32F6N4O, with a molecular weight of 578.61. Netupitant exists as a single isomer and has the following structural formula:

akynzeo

Palonosetron hydrochloride is chemically described: (3aS)-2-[(S)-1-Azabicyclo [2.2.2]oct-3-yl]2,3,3a,4,5,6-hexahydro-1-oxo-1H-benz[de]isoquinoline hydrochloride. The empirical formula is C19H24N2O.HCl, with a molecular weight of 332.87. Palonosetron hydrochloride exists as a single isomer and has the following structural formula:

akynzeo2

Netupitant is white to off-white crystalline powder. It is freely soluble in toluene and acetone, soluble in isopropanol and ethanol, and very slightly soluble in water.

Palonosetron hydrochloride is a white to off-white crystalline powder. It is freely soluble in water, soluble in propylene glycol, and slightly soluble in ethanol and 2-propanol.

Each AKYNZEO (300 mg netupitant/0.5 mg palonosetron) capsule is composed of one white-caramel hard gelatin capsule which contains three tablets each containing 100 mg netupitant and one gelatin capsule containing 0.56 mg palonosetron hydrochloride (equivalent to 0.50 mg palonosetron). The inactive ingredients are microcrystalline cellulose, sucrose fatty acid esters, povidone K-30, croscarmellose sodium, purified water, silicon dioxide, sodium stearyl fumarate, magnesium stearate, mono-and di-glycerides of capryl/capric acid, glycerin, polyglyceryl oleate, butylated hydroxyanisole (BHA), gelatin, sorbitol, titanium dioxide, yellow iron oxide, and red iron oxide. It may contain traces of medium-chain triglycerides, lecithin, and denatured ethanol.

INDICATIONS

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.

DOSAGE AND ADMINISTRATION

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.

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.

HOW SUPPLIED

Dosage Forms And Strengths

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.

Storage And Handling

NDC # 62856-796-01, AKYNZEO (300 mg netupitant/0.5 mg palonosetron). AKYNZEO is supplied as hard gelatin capsules with white body and caramel cap with “HE1” printed on the body, one capsule per blister.

Storage

Store at 20 °C to 25 °C (68 °F to 77 °F); excursions permitted from 15 °C to 30 °C (59 °F to 86 °F).

SIDE EFFECTS

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.

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, 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.

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.

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

 

Adverse Reactions AKYNZEO 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 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.

Table 2: Adverse Reactions Occurring in ≥ 3% of Cancer Patients Receiving AKYNZEO and Anthracyclines and Cyclophosphamide Based Chemotherapy (Cycle 1)

 

Adverse Reactions AKYNZEO 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 > 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.

Table 3: Liver Function Laboratory Abnormalities

 

Laboratory Changes 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
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%)

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.

DRUG INTERACTIONS

Effects Of AKYNZEO On Other Drugs

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 coadministered with AKYNZEO. The inhibitory effect on CYP3A4 can last for multiple days.

Dexamethasone

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.

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.

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. 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.

Effects Of Other Drugs On AKYNZEO

Netupitant, a component of AKYNZEO, is mainly metabolized by CYP3A4.

In vitro metabolism studies have suggested that CYP2D6 and to a lesser extent CYP3A4 and CYP1A2 are involved in the metabolism of palonosetron.

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.

CYP3A4 Inhibitors

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.

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).

PRECAUTIONS

Hypersensitivity

Hypersensitivity reactions, including anaphylaxis, have been reported with or without known hypersensitivity to other 5-HT3 receptor antagonists.

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-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.

Patient Counseling Information

Advise patients to read the FDA-approved patient labeling.

Administration

Advise patients to take AKYNZEO with or without food approximately 1 hour prior to the start of chemotherapy.

Hypersensitivity Reactions

Advise patients that hypersensitivity reactions, including anaphylaxis, have been reported in patients receiving palonosetron. Advise patients to seek immediate medical attention if any signs or symptoms of a hypersensitivity reaction occur while taking AKYNZEO.

Serotonin Syndrome

Advise patients of the possibility of serotonin syndrome especially with concomitant use of AKYNZEO and another serotonergic agent such as medications to treat depression and migraines. Advise patients to seek immediate medical attention if the following symptoms occur: changes in mental status, autonomic instability, neuromuscular symptoms, with or without gastrointestinal symptoms.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Netupitant

Long-term studies in animals to evaluate carcinogenic potential have not been performed with netupitant. Netupitant was not genotoxic in the Ames test, the mouse lymphoma cell mutation test, or the in vivo rat micronucleus test.

Daily oral administration of netupitant in rats at doses up to 30 mg/kg (1.9 times the human AUC in male rats and 3.7 times the human AUC in female rats at the recommended human dose) had no effects on fertility or reproductive performance.

Palonosetron

In a 104-week carcinogenicity study in CD-1 mice, animals were treated with oral doses of palonosetron at 10, 30, and 60 mg/kg/day. Treatment with palonosetron was not tumorigenic. The highest tested dose produced a systemic exposure to palonosetron (plasma AUC) of about 90 to 173 times the human exposure (AUC=49.7 ng•h/mL) at the recommended oral dose of 0.5 mg. In a 104-week carcinogenicity study in Sprague-Dawley rats, male and female rats were treated with oral doses of 15, 30, and 60 mg/kg/day and 15, 45, and 90 mg/kg/day, respectively. The highest doses produced a systemic exposure to palonosetron (plasma AUC) of 82 and 185 times the human exposure at the recommended dose. Treatment with palonosetron produced increased incidences of adrenal benign pheochromocytoma and combined benign and malignant pheochromocytoma, increased incidences of pancreatic Islet cell adenoma and combined adenoma and carcinoma and pituitary adenoma in male rats. In female rats, it produced hepatocellular adenoma and carcinoma and increased the incidences of thyroid C-cell adenoma and combined adenoma and carcinoma.

Palonosetron was not genotoxic in the Ames test, the Chinese hamster ovarian cell (CHO/HGPRT) forward mutation test, the ex vivo hepatocyte unscheduled DNA synthesis (UDS) test, or the mouse micronucleus test. It was, however, positive for clastogenic effects in the Chinese hamster ovarian (CHO) cell chromosomal aberration test. Palonosetron at oral doses up to 60 mg/kg/day (about 921 times the recommended human oral dose based on body surface area) was found to have no effect on fertility and reproductive performance of male and female rats.

Use In Specific Populations

Pregnancy

Pregnancy Category C

Risk Summary

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.

Animal Data

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.

Nursing Mothers

It is not known whether AKYNZEO is present in human milk. Because many drugs are present in human milk and because of the potential for tumorigenicity shown for palonosetron in the rat carcinogenicity study, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

Safety and effectiveness in patients below the age of 18 years have not been established.

Geriatric Use

Of the 1169 adult cancer patients treated with AKYNZEO in clinical studies, 18% were aged 65 and over, while 2% were aged 75 years and over. The nature and frequency of adverse reactions were similar in elderly and younger patients. Exploratory analyses of the impact of age on efficacy were performed in the two trials that compared AKYNZEO to palonosetron [see Clinical Studies]. In Study 1 in patients treated with cisplatin chemotherapy, among the patients less than age 65 years, 115 were treated with AKYNZEO and 116 were treated with palonosetron alone. Among the patients 65 years or older, 20 were treated with AKYNZEO and 20 were treated with palonosetron alone. The difference in Complete Response (CR) rates between AKYNZEO and palonosetron alone was similar between the two age groups in both the acute and delayed phases. In Study 2 in patients treated with anthracyclines plus cyclophosphamide chemotherapy, among the patients less than age 65 years, 608 were treated with AKYNZEO and 602 were treated with palonosetron alone. Among the patients 65 years or older, 116 were treated with AKYNZEO and 123 were treated with palonosetron alone. The difference in CR rates between AKYNZEO and palonosetron alone (4% in < 65 years and 2% in > 65 years) was similar between the two age groups in the acute phase. In the delayed phase, the difference in CR rates between AKYNZEO and palonosetron alone (9% in < 65 years and 1% in ≥ 65 years) was numerically higher in patients < 65 years. This difference between age groups in the delayed phase of Study 2 may be explained, in part, by higher CR in the delayed phase associated with palonosetron alone in the older age group (81%) relative to the younger patients treated with palonosetron alone (67%).

In general, use caution when dosing elderly patients as they have a greater frequency of decreased hepatic, renal or cardiac function and concomitant disease or other drug therapy.

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 > 9)/ Avoid use of AKYNZEO in patients with severe hepatic impairment.

Renal Impairment

No dosage adjustment for AKYNZEO is necessary in patients with mild to moderate renal impairment. The pharmacokinetics and safety of netupitant has not been studied in patients with severe renal impairment, although severe renal impairment did not substantially affect pharmacokinetics of palonosetron. The pharmacokinetics for netupitant and palonosetron was 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.

OVERDOSE

No specific information is available on the treatment of overdosage with AKYNZEO. In the event of overdose, AKYNZEO should be discontinued and general supportive treatment and monitoring should be provided. Because of the antiemetic activity of AKYNZEO, drug-induced emesis may not be effective. Dialysis studies have not been performed; due to the large volume of distribution, dialysis is unlikely to be an effective treatment for AKYNZEO overdose.

A total of 33 adult cancer patients were administered oral palonosetron at a dose of 90 μg/kg (equivalent to 6 mg fixed dose), as part of a dose ranging study. This is approximately 12 times the recommended oral dose of 0.5 mg palonosetron. This dose group had a similar incidence of adverse events compared to the other dose groups and no dose response effects were observed. The highest dose of netupitant administered to 1169 cancer patients was 300 mg. The highest dose of netupitant administered to 49 healthy subjects was 600 mg. A similar incidence of adverse events was observed when compared to lower doses of netupitant in the respective populations of cancer patients and healthy subjects.

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