Akynzeo

Follow all directions on your prescription label. Do not use this medicine in larger or smaller amounts or for longer than recommended.

Netupitant and palonosetron is usually taken 1 hour before the start of chemotherapy. Follow your doctor's instructions.

You may take netupitant and palonosetron with or without food.

This medicine is given ahead of time and will not treat nausea or vomiting you already have.

Store at room temperature away from moisture and heat.

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

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.

Keep this medication in the container it came in, tightly closed, and out of reach of children. Store it at room temperature and away from light, excess heat and moisture (not in the bathroom). Throw away any medication that is outdated or no longer needed. Talk to your pharmacist about the proper disposal of your medication.

It is important to keep all medication out of sight and reach of children as many containers (such as weekly pill minders and those for eye drops, creams, patches, and inhalers) are not child-resistant and young children can open them easily. To protect young children from poisoning, always lock safety caps and immediately place the medication in a safe location – one that is up and away and out of their sight and reach. http://www.upandaway.org

Medications can interact with certain foods. In some cases, this may be harmful and your doctor may advise you to avoid certain foods. In the case of Akynzeo, there are no specific foods that you must exclude from your diet when receiving this medication.

Before taking Akynzeo, tell your doctor about all of your medical conditions. Especially tell your doctor if you:

• are allergic to Akynzeo or to any of its ingredients
• have or have had liver disease
• have or have had kidney disease
• are pregnant or breastfeeding

Tell your doctor about all the medicines you take including prescription and non-prescription medicines, vitamins, and herbal supplements.

Take Akynzeo exactly as prescribed.

Akynzeo is available in capsule form and is taken 1 hour before the start of chemotherapy. It can be taken with or without food.

Netupitant and palonosetron is a combination medicine used in adults to prevent nausea and vomiting caused by medicine to treat cancer (chemotherapy).

Netupitant and palonosetron helps prevent nausea and vomiting that occurs both during your chemotherapy treatment, or that occurs later on (delayed nausea and vomiting).

Netupitant and palonosetron is not for preventing nausea or vomiting caused by factors other than chemotherapy.

Netupitant and palonosetron may also be used for purposes not listed in this medication guide.

Netupitant and palonosetron combination is used to prevent nausea and vomiting that is caused by cancer medicines (chemotherapy). Palonosetron and netupitant work by blocking the signals to the brain that cause nausea and vomiting.

This medicine is available only with your doctor's prescription.

In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For this medicine, the following should be considered:

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to this medicine or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.

Pediatric

Appropriate studies have not been performed on the relationship of age to the effects of netupitant and palonosetron combination in the pediatric population. Safety and efficacy have not been established.

Geriatric

Appropriate studies performed to date have not demonstrated geriatric-specific problems that would limit the usefulness of netupitant and palonosetron combination in the elderly. However, elderly patients are more likely to have kidney, liver, or heart problems, which may require caution in patients receiving netupitant and palonosetron combination.

Pregnancy

Breast Feeding

There are no adequate studies in women for determining infant risk when using this medication during breastfeeding. Weigh the potential benefits against the potential risks before taking this medication while breastfeeding.

Interactions with Medicines

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are taking this medicine, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using this medicine with any of the following medicines is not recommended. Your doctor may decide not to treat you with this medication or change some of the other medicines you take.

• Apomorphine

Using this medicine with any of the following medicines is usually not recommended, but may be required in some cases. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Alfentanil
• Alfuzosin
• Almotriptan
• Alprazolam
• Amineptine
• Amitriptyline
• Amitriptylinoxide
• Amlodipine
• Amoxapine
• Amphetamine
• Aripiprazole
• Atazanavir
• Atorvastatin
• Avanafil
• Axitinib
• Bedaquiline
• Benzphetamine
• Bromocriptine
• Brompheniramine
• Buprenorphine
• Buspirone
• Butorphanol
• Cabozantinib
• Carbamazepine
• Chlorpheniramine
• Cilostazol
• Cisapride
• Citalopram
• Clarithromycin
• Clomipramine
• Cobicistat
• Cocaine
• Codeine
• Colchicine
• Crizotinib
• Cyclobenzaprine
• Cyclosporine
• Dabrafenib
• Daclatasvir
• Desipramine
• Desvenlafaxine
• Dextroamphetamine
• Dextromethorphan
• Diazepam
• Dibenzepin
• Dihydrocodeine
• Dihydroergotamine
• Diltiazem
• Docetaxel
• Dolutegravir
• Domperidone
• Doxepin
• Duloxetine
• Efavirenz
• Elbasvir
• Eletriptan
• Enzalutamide
• Ergotamine
• Erythromycin
• Escitalopram
• Estradiol
• Eszopiclone
• Fentanyl
• Fluoxetine
• Fluvoxamine
• Fosphenytoin
• Frovatriptan
• Furazolidone
• Grazoprevir
• Guanfacine
• Haloperidol
• Hydrocodone
• Hydrocortisone
• Hydromorphone
• Hydroxytryptophan
• Imatinib
• Imipramine
• Iproniazid
• Irinotecan
• Irinotecan Liposome
• Isocarboxazid
• Itraconazole
• Ixazomib
• Lapatinib
• Lercanidipine
• Levomilnacipran
• Levorphanol
• Linezolid
• Lisdexamfetamine
• Lithium
• Lofepramine
• Lopinavir
• Lorcaserin
• Melitracen
• Meperidine
• Methadone
• Methamphetamine
• Methylene Blue
• Milnacipran
• Mirtazapine
• Mitotane
• Moclobemide
• Morphine
• Morphine Sulfate Liposome
• Nalbuphine
• Naloxegol
• Naratriptan
• Nateglinide
• Nefazodone
• Nelfinavir
• Nialamide
• Nifedipine
• Nilotinib
• Nisoldipine
• Nortriptyline
• Olaparib
• Omeprazole
• Ondansetron
• Opipramol
• Oxcarbazepine
• Oxycodone
• Oxymorphone
• Paclitaxel
• Paritaprevir
• Paroxetine
• Pentazocine
• Perampanel
• Phenelzine
• Phenytoin
• Pimozide
• Piperaquine
• Primidone
• Procarbazine
• Progesterone
• Protriptyline
• Quinidine
• Ranolazine
• Rasagiline
• Reboxetine
• Remifentanil
• Rifabutin
• Rifampin
• Rifapentine
• Rilpivirine
• Rivaroxaban
• Rizatriptan
• Rolapitant
• Salmeterol
• Saquinavir
• Selegiline
• Sertraline
• Sibutramine
• Simeprevir
• Sonidegib
• St John's Wort
• Sufentanil
• Sumatriptan
• Sunitinib
• Suvorexant
• Tacrolimus
• Tamoxifen
• Tapentadol
• Telithromycin
• Tianeptine
• Ticagrelor
• Trabectedin
• Tramadol
• Tranylcypromine
• Trazodone
• Trimipramine
• Tryptophan
• Velpatasvir
• Venlafaxine
• Verapamil
• Vilazodone
• Vincristine
• Vorapaxar
• Vortioxetine
• Zaleplon
• Ziprasidone
• Zolmitriptan
• Zolpidem

Using this medicine with any of the following medicines may cause an increased risk of certain side effects, but using both drugs may be the best treatment for you. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Dexamethasone

Interactions with Food/Tobacco/Alcohol

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. Discuss with your healthcare professional the use of your medicine with food, alcohol, or tobacco.

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.

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. A single dose of netupitant 300 mg (or Akynzeo containing 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 dose of netupitant increased the systemic exposure of concomitant dexamethasone by more than 2-fold on Days 2 and 4. Administer a reduced dose of dexamethasone with Akynzeo [see Dosage and Administration (2), 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.

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.

Effects of Other Drugs on Akynzeo

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.  

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 (12.3)].

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 [see Clinical Pharmacology (12.3)].

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) [see Warnings and Precautions (5.2)].

Mechanism of Action

Netupitant is a selective antagonist of human substance P/neurokinin 1 (NK1) receptors.

Palonosetron is a 5-HT3 receptor antagonist with a strong binding affinity for this receptor and little or no affinity for other receptors. Cancer chemotherapy may be associated with a high incidence of nausea and vomiting, particularly when certain agents, such as cisplatin, are used. 5-HT3 receptors are located on the nerve terminals of the vagus in the periphery and centrally in the chemoreceptor trigger zone of the area postrema. Chemotherapeutic agents produce nausea and vomiting by stimulating the release of serotonin from the enterochromaffin cells of the small intestine. Serotonin then activates 5-HT3 receptors located on vagal afferents to initiate the vomiting reflex. The development of acute emesis is known to depend on serotonin and its 5-HT3 receptors have been demonstrated to selectively stimulate the emetic response.

Delayed emesis has been largely associated with the activation of tachykinin family neurokinin 1 (NK1) receptors (broadly distributed in the central and peripheral nervous systems) by substance P. As shown in in vitro and in vivo studies, netupitant inhibits substance P mediated responses.

Pharmacodynamics

NK1 Receptor Occupancy

The receptor occupancy for the CINV dosing regimen of netupitant was measured in a human Positron Emission Tomography (PET) study. Netupitant was shown to cross the blood brain barrier with a NK1 receptor occupancy of 92.5%, 86.5%, 85.0%, 78.0%, and 76.0% in striatum at 6, 24, 48, 72, and 96 hours, respectively, after administration of 300 mg netupitant.

Cardiac Electrophysiology

Co-administration of single dose netupitant 600 mg and palonosetron 1.5 mg had no significant effects on the QTc interval.

Pharmacokinetics

After single dose administration of Akynzeo in healthy subjects, the peak plasma concentrations for netupitant and palonosetron were reached in about 5 hours.

 1 median (min-max)

When administered under fed condition, the systemic exposure to netupitant and palonosetron was similar to those obtained under fasting condition.

In cancer patients who received a single dose of Akynzeo 1 hour prior to chemotherapy (docetaxel, etoposide, or cyclophosphamide), the Cmax and AUC of netupitant and its metabolites were similar to those in healthy subjects. The mean Cmax and AUC of palonosetron in cancer patients were similar to those in healthy subjects.

No significant changes in pharmacokinetics of netupitant and palonosetron were observed when 450 mg oral netupitant and 0.75 mg oral palonosetron were co-administered.

Netupitant

Absorption

Upon oral administration of a single dose of netupitant, netupitant started to be measurable in plasma between 15 minutes and 3 hours after dosing. Plasma concentrations reached Cmax in approximately 5 hours. There was a greater than dose-proportional increase in the systemic exposure with the dose increase from 10 mg to 300 mg and a dose-proportional increase in systemic exposure with a dose increase from 300 mg to 450 mg.

Distribution

In cancer patients netupitant disposition was characterized by a large apparent volume of distribution (Vz/F: 1982 ± 906 L) (mean ± SD). Human plasma protein binding of netupitant is greater than 99.5% at drug concentrations ranging from 10-1300 ng/mL and protein binding of its major metabolites (M1, M2 and M3) is greater than 97% at drug concentrations ranging from 100 to 2000 ng/mL.

Metabolism

Once absorbed, netupitant is extensively metabolized to form three major metabolites: desmethyl derivative, M1; N-oxide derivative, M2; and OH-methyl derivative, M3. Metabolism is mediated primarily by CYP3A4 and to a lesser extent by CYP2C9 and CYP2D6. Metabolites M1, M2 and M3 were shown to bind to the substance P/neurokinin 1 (NK1) receptor.

Mean Cmax was approximately 11%, 47% and 16% of netupitant for metabolites M1, M2 and M3, respectively. Mean AUC for metabolites M1, M2 and M3 was 29%, 14% and 33% of netupitant, respectively. The median tmax for metabolite M2 was 5 hours and was about 17-32 hours for metabolites M1 and M3. 

Elimination

Netupitant is eliminated from the body in a multi-exponential fashion, with an apparent elimination half-life in cancer patients of 80 ± 29 hours (mean ± SD) and with an estimated systemic clearance of 20.3 ± 9.2 L/h (mean ± SD) after a single oral dose of Akynzeo.

After a single oral administration of [14C]-­netupitant, approximately half the administered radioactivity was recovered from urine and feces within 120 hours of dosing. The total of 3.95% and 70.7% of the radioactive dose was recovered in the urine and feces collected over 336 hours, respectively, and the mean fraction of an oral dose of netupitant excreted unchanged in urine is less than 1% suggesting renal clearance is not a significant elimination route for the netupitant-related entities. About 86.5% and 4.7% of administered radioactivity was estimated to be excreted via the feces and urine in 30 days post-dose

Palonosetron

Absorption

Following oral administration, palonosetron is well absorbed with its absolute bioavailability reaching 97%. After single oral doses using buffered solution mean maximum palonosetron concentrations (Cmax) and area under the concentration-time curve (AUC0-∞) were dose proportional over the dose range of 3.0 to 80 µg/kg in healthy subjects.

Distribution

Palonosetron has a volume of distribution of approximately 8.3 ± 2.5 L/kg. Approximately 62% of palonosetron is bound to plasma proteins.

Metabolism

Palonosetron is eliminated by multiple routes with approximately 50% metabolized to form two primary metabolites: N-oxide-palonosetron and 6-S-­hydroxy-palonosetron. These metabolites each have less than 1% of the 5-HT3 receptor antagonist activity of palonosetron. In vitro metabolism studies have suggested that CYP2D6 and to a lesser extent CYP3A4 and CYP1A2 are involved in the metabolism of palonosetron.  However, clinical pharmacokinetic parameters are not significantly different between poor and extensive metabolizers of CYP2D6 substrates.

Elimination

Following administration of a single oral 0.75 mg dose of [14C]-­palonosetron to six healthy subjects, 85% to 93% of the total radioactivity was excreted in urine, and 5% to 8% was eliminated in feces. The amount of unchanged palonosetron excreted in the urine represented approximately 40% of the administered dose. In cancer patients, t½ was 48 ± 19 hours. After a single-dose of approximately 0.75 mg intravenous palonosetron, the total body clearance of palonosetron in healthy subjects was 160 ± 35 mL/h/kg (mean ± SD) and renal clearance was 66.5 ± 18.2 mL/h/kg.

Specific Populations

Gender

In a pooled analysis, the Cmax for netupitant was 35% higher in females than in males while the AUC was similar between males and females. In female subjects, the mean AUC for palonosetron was 35% higher and the mean Cmax was 26% higher than in male subjects.

Geriatrics

In cancer patients receiving Akynzeo, population PK analysis indicated that age (within the range of 29 to 75 years old) did not influence the pharmacokinetics of netupitant or palonosetron. In healthy elderly subjects (>65 years old)  the mean AUC0-∞ and Cmax was 25% and 36% higher, respectively, for netupitant, and 37% and 10% higher, respectively, for palonosetron compared to those in healthy younger adults (22-45 years old).  

Hepatic Impairment

The effects of hepatic impairment on the PK of netupitant and palonosetron were studied following administration of a single oral dose of Akynzeo to patients with mild (Child-Pugh score 5 to 6), moderate (Child-Pugh score 7 to 9), or severe (Child-Pugh score >9) hepatic impairment.

In patients with mild or moderate hepatic impairment, the mean AUC0-∞ of netupitant was 67% and 86% higher, respectively, than in healthy subjects and the mean Cmax for netupitant was about 40% and 41% higher, respectively, than in healthy subjects.

In patients with mild or moderate hepatic impairment, the mean AUC0-∞ of palonosetron was 33% and 62% higher, respectively, than in healthy subjects and the mean Cmax for palonosetron was about 14% higher and unchanged, respectively, than in healthy subjects.

The pharmacokinetics of netupitant and palonosetron was available from only two patients with severe hepatic impairment. As such the data are too limited to draw a conclusion. 

Renal Impairment

In a population PK analysis, mild and moderate renal impairment did not significantly affect the pharmacokinetics of netupitant in cancer patients. Netupitant has not been studied in patients with severe renal impairment.

Mild to moderate renal impairment does not significantly affect palonosetron pharmacokinetic parameters. In a study with intravenous palonosetron, total systemic exposure to palonosetron increased by approximately 28% in patients with severe renal impairment relative to healthy subjects.

The pharmacokinetics of either palonosetron or netupitant has not been studied in subjects with end-stage renal disease.

Drug Interactions:In vitro studies have shown that netupitant and its metabolite M1 are inhibitors of CYP3A4. An in vivo study has confirmed that netupitant is a moderate inhibitor of CYP3A4.

Based on the in vitro studies, netupitant and its metabolites’ are unlikely to have in vivo drug-drug interaction via inhibition of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, and CYP2D6 at the clinical dose of 300 mg.

Netupitant and its metabolites, M1, M2 and M3, are not inducers of CYP1A2, CYP2B6, CYP2C9, CYP2C19 and CYP3A4.

Based on in vitro studies, netupitant is an inhibitor of P-gp and BCRP transporters. In addition, netupitant is not a substrate for P-gp, metabolite M2 is a substrate for P-gp. In vitro studies indicate that netupitant and its three major metabolites are unlikely to have in vivo drug-drug interactions with human efflux transporters BSEP, MRP2, and human uptake transporters OATP1B1, OATP1B3, OAT1, OAT3, OCT1, and OCT2 at the clinical dose of 300 mg.

In vitro studies, palonosetron does not inhibit CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2D6, CYP2E1 and CYP3A4/5 or induce CYP1A2, CYP2D6 or CYP3A4/5. CYP2C19 was not investigated.

Dexamethasone

Co-administration of a single dose of netupitant (300 mg) with a dexamethasone regimen (20 mg on Day 1, followed by 8 mg twice daily from Day 2 to Day 4) significantly increased exposure to dexamethasone. When netupitant was co-administered on Day 1, the mean AUC of dexamethasone was increased by 1.7-fold on Day 1 and up to 2.4-fold on Day 2 and Day 4. [see Drug Interactions (7.1)]

The duration of CYP3A4 inhibition by single dose Akynzeo (300 mg netupitant/0.5 mg palonosetron) was assessed using dexamethasone as a CYP3A4 probe substrate. Co-administration of a single dose of Akynzeo on Day 1 with a dexamethasone regimen (12 mg on Day 1 followed by 8 mg on Days 2, 3, 4, 6, 8 and 10) increased mean AUC of dexamethasone by 1.6-fold on Day 1, 2.4-fold on Day 4, 1.5-fold on Day 6, and 1.2-fold on Day 8 [see Drug Interactions (7.1)].

Chemotherapeutic Agents (docetaxel, etoposide, cyclophosphamide)

Systemic exposure to intravenously administered chemotherapeutic agents that are metabolized by CYP3A4 was higher when Akynzeo was co-administered than when palonosetron alone was co-administered in cancer patients. [see Drug Interactions (7.1)]

With co-administration of Akynzeo the mean Cmax and AUC of docetaxel were 49% and 35% higher, respectively, and mean Cmax and AUC of etoposide were increased by 10% and 28%, respectively, compared to when co-administered with palonosetron alone.

Mean Cmax and AUC for cyclophosphamide after co-administration with Akynzeo was 27% and 20% higher compared to when co-administered with palonosetron alone.

The mean AUC of palonosetron was about 65% higher when Akynzeo was co-administered with docetaxel than with etoposide or cyclophosphamide, while the mean AUC of netupitant was similar among groups that received docetaxel, etoposide, or cyclophosphamide.

Midazolam

When co-administered with netupitant 300 mg the mean Cmax and AUC of midazolam after single dose oral administration of 7.5 mg midazolam was 36% and 126% higher, respectively. [see Drug Interactions (7.1)]

Erythromycin

When 500 mg erythromycin was co-administered with netupitant 300 mg, the systemic exposure of erythromycin was highly variable and the mean Cmax and AUC of erythromycin were increased by 92% and 56%, respectively.

Oral Contraceptives

Single dose Akynzeo, when given with a single oral dose of 60 μg ethinyl estradiol and 300 μg levonorgestrel, increased the AUC of levonorgestrel by 46%. Akynzeo had no significant effect on the AUC of ethinyl estradiol. [see Drug Interactions (7.1)]

Digoxin

Co-administration of netupitant 450 mg did not significantly affect the systemic exposure and urinary excretion of digoxin, a substrate of P-glycoprotein, at steady-state. Concurrent administration of Akynzeo with digoxin is not expected to affect the systemic exposure to digoxin.

Effects of other drugs on Akynzeo

Rifampicin

Single dose Akynzeo was administered with rifampicin, a strong CYP3A4 inducer, following once daily administration of 600 mg rifampicin for 17 days. Pharmacokinetics of netupitant and palonosetron were compared to that after administration of Akynzeo alone. Co-administration of rifampicin decreased the mean Cmax and AUC0-∞ of netupitant by 62% and 82%, respectively, compared to those after Akynzeo alone. Co-administration of rifampicin decreased the mean Cmax and AUC for palonosetron by 15% and 19%, respectively. [see Drug Interactions (7.1)]

Ketoconazole

Single dose Akynzeo was administered with ketoconazole, a strong CYP3A4 inhibitor, following once daily administration of 400 mg ketoconazole for 12 days. Pharmacokinetics of netupitant and palonosetron were compared to that after administration of Akynzeo alone. Co-administration with ketoconazole increased mean Cmax and AUC of netupitant by 25% and 140%, respectively, compared to those after administration of Akynzeo alone. The mean AUC and Cmax of palonosetron were 10% and 15% higher, respectively, when co-administered with ketoconazole. [see Drug Interactions (7.1)]

Akynzeo contains a combination of netupitant and palonosetron. Netupitant and palonosetron are used in adults to prevent nausea and vomiting caused by medicine to treat cancer (chemotherapy).

Akynzeo helps prevent nausea and vomiting that occurs both during your chemotherapy treatment, or that occurs later on (delayed nausea and vomiting).

Akynzeo is not for preventing nausea or vomiting caused by factors other than chemotherapy.

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.