Akynzeo

Name: Akynzeo

Akynzeo Interactions

Follow your doctor's instructions about any restrictions on food, beverages, or activity.

Other drugs may interact with netupitant and palonosetron, including prescription and over-the-counter medicines, vitamins, and herbal products. Tell each of your health care providers about all medicines you use now and any medicine you start or stop using.

What special precautions should I follow?

Before taking netupitant and palonosetron,

  • tell your doctor and pharmacist if you are allergic to netupitant and palonosetron, alosetron (Lotronex), dolasetron (Anzemet), granisetron (Sancuso), ondansetron (Zofran, Zuplenz), any other medications, or any of the ingredients in netupitant and palonosetron capsules. Ask your pharmacist for a list of the ingredients.
  • tell your doctor and pharmacist what prescription and nonprescription medications, vitamins, nutritional supplements, and herbal products you are taking. Be sure to mention any of the following: benzodiazepines including alprazolam (Xanax), midazolam, and triazolam (Halcion); certain chemotherapy medications such as cyclophosphamide (Cytoxan), docetaxel (Docefrez, Taxotere), etoposide, ifosfamide (Ifex), imatinib (Gleevec), irinotecan (Camptosar), paclitaxel (Taxol), vinblastine, vincristine, and vinorelbine (Navelbine); dexamethasone; erythromycin (E.E.S., Ery-tab, others); fentanyl (Abstral, Actiq, Duragesic, Fentora, Lazanda, Onsolis, Subsys); ketoconazole (Nizoral); lithium (Lithobid); medications to treat migraines such as almotriptan (Axert), eletriptan (Relpax), frovatriptan (Frova), naratriptan (Amerge), rizatriptan (Maxalt), sumatriptan (Imitrex), and zolmitriptan (Zomig); methylene blue; mirtazapine (Remeron); monoamine oxidase (MAO) inhibitors including isocarboxazid (Marplan), linezolid (Zyvox), phenelzine (Nardil), selegiline (Eldepryl, Emsam, Zelapar), and tranylcypromine (Parnate); phenobarbital; rifampin (Rifadin, Rimactane, in Rifater, in Rifamate); selective serotonin reuptake inhibitors (SSRIs) such as citalopram (Celexa), escitalopram (Lexapro), fluoxetine (Prozac, Sarafem, in Symbyax), fluvoxamine (Luvox), paroxetine (Brisdelle, Paxil, Pexeva), and sertraline (Zoloft); and tramadol (Conzip, Ultram, in Ultracet). Your doctor may need to change the doses of your medications or monitor you carefully for side effects.
  • tell your doctor if you have or have ever had liver or kidney disease.
  • tell your doctor if you are pregnant, plan to become pregnant, or are breast-feeding. If you become pregnant while taking netupitant and palonosetron, call your doctor.

What should I do if I forget a dose?

Netupitant and palonosetron should only be taken before chemotherapy as instructed by your doctor. It should not be taken on a regularly scheduled basis.

Akynzeo and Lactation

Tell your doctor if you are breastfeeding or plan to breastfeed.

It is not known if Akynzeo crosses into human milk. Because many medications can cross into human milk and because of the possibility for serious adverse reactions in nursing infants with use of this medication, a choice should be made whether to stop nursing or stop the use of this medication. Your doctor and you will decide if the benefits outweigh the risk of using Akynzeo.

Akynzeo Overdose

If you take too much Akynzeo, call your healthcare provider or local Poison Control Center or seek emergency medical attention right away.

If Akynzeo is administered by a healthcare provider in a medical setting, it is unlikely that an overdose will occur. However, if overdose is suspected, seek emergency medical attention.

Other Requirements

  • Store Akynzeo at room temperature.
  • Keep this and all medications out of the reach of children.

What happens if I miss a dose?

Take the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not take extra medicine to make up the missed dose.

Consumer Information Use and Disclaimer

  • If your symptoms or health problems do not get better or if they become worse, call your doctor.
  • Do not share your drugs with others and do not take anyone else's drugs.
  • Keep a list of all your drugs (prescription, natural products, vitamins, OTC) with you. Give this list to your doctor.
  • Talk with the doctor before starting any new drug, including prescription or OTC, natural products, or vitamins.
  • Some drugs may have another patient information leaflet. Check with your pharmacist. If you have any questions about Akynzeo, please talk with your doctor, nurse, pharmacist, or other health care provider.
  • If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about Akynzeo. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using Akynzeo.

Review Date: October 4, 2017

Contraindications

None.

Warnings and 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 [see Drug Interactions (7), Patient Counseling Information (17)].

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 [see Nonclinical Toxicology (13.1)], 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 (14)]. 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. [see Overdosage (10), Clinical Pharmacology (12.3)].

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 [see Clinical Pharmacology (12.3)].

Akynzeo Description

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 (5-HT3) 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-(2-methylphenyl)-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:

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:

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, polyglyeryl dioleate, 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.

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.

Before taking this medicine

You should not use Akynzeo if you are allergic to netupitant or palonosetron.

To make sure Akynzeo is safe for you, tell your doctor if you have:

  • liver disease;

  • kidney disease; or

  • if you have ever had an allergic reaction to a medicine for nausea or vomiting, such as dolasetron (Anzemet) or ondansetron (Zofran).

FDA pregnancy category C. It is not known whether Akynzeo will harm an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant while using this medicine.

It is not known whether netupitant and palonosetron passes into breast milk or if it could harm a nursing baby. You should not breast-feed while using this medicine.

Akynzeo is not approved for use by anyone younger than 18 years old.

What other drugs will affect Akynzeo?

Other drugs may interact with netupitant and palonosetron, including prescription and over-the-counter medicines, vitamins, and herbal products. Tell each of your health care providers about all medicines you use now and any medicine you start or stop using.

For Healthcare Professionals

Applies to netupitant / palonosetron: oral capsule

Dermatologic

Common (1% to 10%): Erythema[Ref]

Gastrointestinal

Common (1% to 10%): Dyspepsia, constipation[Ref]

Hepatic

AST greater than 3 times the upper limit of normal (ULN) and/or ALT greater than 3 x ULN with total bilirubin greater than ULN occurred in up to 0.3% of patients, and AST greater than 3 x ULN and/or ALT greater than 3 x ULN with total bilirubin greater than or equal to 2 x ULN occurred in up to 0.1% of patients.[Ref]

Uncommon (0.1% to 1%): Elevated AST, elevated ALT, elevated total bilirubin[Ref]

Nervous system

Common (1% to 10%): Headache[Ref]

Other

Common (1% to 10%): Fatigue, asthenia[Ref]

Some side effects of Akynzeo may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.

Uses for Akynzeo

Cancer Chemotherapy-induced Nausea and Vomiting

Used in fixed combination for 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 2 3 26 Should be used in combination with dexamethasone.1

Palonosetron prevents nausea and vomiting during the acute phase after chemotherapy; netupitant prevents nausea and vomiting during both the acute and delayed phase after chemotherapy.1

For prevention of nausea and vomiting associated with highly emetogenic chemotherapy regimens (including an anthracycline plus cyclophosphamide), ASCO recommends a 3-drug antiemetic regimen consisting of an NK1 receptor antagonist (e.g., either oral aprepitant or IV fosaprepitant), a 5-HT3 receptor antagonist (e.g., dolasetron, granisetron, ondansetron, palonosetron), and dexamethasone.28 33 ASCO states that fixed-combination netupitant and palonosetron plus dexamethasone is an additional treatment option.33

For moderately emetogenic chemotherapy regimens, ASCO recommends a 2-drug antiemetic regimen preferably consisting of palonosetron and dexamethasone.28 33 If palonosetron is not available, a first-generation 5-HT3 receptor antagonist (preferably granisetron or ondansetron) may be substituted.28 Limited evidence suggests that aprepitant may be added to this regimen; in such cases, use of any 5-HT3 receptor antagonist is appropriate.28

For chemotherapy regimens with a low emetogenic risk, ASCO recommends administration of a single dose of dexamethasone prior to chemotherapy.28

For chemotherapy regimens with minimal emetogenic risk, ASCO states that routine antiemetic administration is not necessary.28

Akynzeo Dosage and Administration

Administration

Oral Administration

Administer fixed-combination capsules containing netupitant and palonosetron hydrochloride (netupitant/palonosetron; Akynzeo) orally approximately one hour before the start of chemotherapy without regard to meals.1

Administer as part of an antiemetic regimen that also includes dexamethasone.1

Dosage

Netupitant/palonosetron hydrochloride is a fixed combination; each capsule contains 300 mg of netupitant and 0.5 mg of palonosetron.1

The palonosetron component is provided as palonosetron hydrochloride; dosage expressed in terms of palonosetron.1

Adults

Cancer Chemotherapy-induced Nausea and Vomiting Highly Emetogenic Chemotherapy, including Cisplatin-based Chemotherapy Oral

Administer one capsule (300 mg of netupitant and 0.5 mg of palonosetron) approximately 1 hour prior to start of chemotherapy in conjunction with dexamethasone 12 mg administered orally 30 minutes prior to chemotherapy on day 1 followed by 8 mg orally once daily on days 2–4 of the treatment regimen.1

Anthracycline- and Cyclophosphamide-based Chemotherapy and Chemotherapy Not Considered Highly Emetogenic Oral

Administer one capsule (300 mg of netupitant and 0.5 mg of palonosetron) approximately 1 hour prior to start of chemotherapy in conjunction with dexamethasone 12 mg administered orally 30 minutes prior to chemotherapy on day 1 only; administration of dexamethasone on days 2–4 not necessary.1

Special Populations

Hepatic Impairment

No dosage adjustments necessary in patients with mild or moderate hepatic impairment (Child-Pugh score 5–9).1

Not adequately studied in patients with severe hepatic impairment (Child-Pugh score >9); avoid use in such patients.1

Renal Impairment

No dosage adjustments necessary in patients with mild to moderate renal impairment.1

Not studied in patients with severe renal impairment or end-stage renal disease; avoid use in such patients.1

Geriatric Patients

Dosage adjustments based on age not needed; however, select dosage with caution because of age-related decreases in hepatic, renal, and/or cardiac function and concomitant diseases and drug therapy.1

Advice to Patients

  • Importance of reading the patient information provided by the manufacturer before beginning therapy and rereading it each time netupitant/palonosetron is taken.1

  • Importance of informing patients to take netupitant/palonosetron with or without food approximately 1 hour before initiation of antineoplastic chemotherapy.1

  • Importance of informing patients that hypersensitivity reactions, including anaphylaxis, have been reported in patients receiving palonosetron.1 Advise patients to seek immediate medical attention if any signs or symptoms of a hypersensitivity reaction occur while receiving netupitant/palonosetron fixed combination.1

  • Importance of informing patients of the possibility of serotonin syndrome, particularly with concomitant use of netupitant/palonosetron and another serotonergic agent (e.g., antidepressants, antimigraine agents).1 Advise patients to seek immediate medical attention should they experience symptoms of serotonin syndrome, such as alterations in mental status, autonomic instability, or neuromuscular symptoms (with or without GI symptoms).1

  • Importance of women informing their clinician if they are or plan to become pregnant or plan to breast-feed.

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.1

  • Importance of informing patients of other precautionary information.1 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Netupitant and Palonosetron Hydrochloride

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Capsules

Netupitant 300 mg and Palonosetron Hydrochloride 0.5 mg

Akynzeo

Eisai

Medical Disclaimer

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