AKYNZEO (netupitant-palonosetron)

AKYNZEO ® (netupitant and palonosetron)

Usual Diluents

Standard Dilutions   [Amt of drug] [Infusion vol] [Infusion rate]

Preparation 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 reconstituted 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 till 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.

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.

Storage
The total time from reconstitution to the start of the infusion should not exceed 3 hours. Store the reconstituted solution and the final diluted solution at room temperature.

WARNINGS 

DESCRIPTION OF AKYNZEO   

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.

AKYNZEO (235 mg fosnetupitant/0.25 mg palonosetron) for injection is a combination product of fosnetupitant, a prodrug of netupitant, which is a substance P/neurokinin 1 (NK-1) receptor antagonist, and palonosetron hydrochloride, a serotonin-3 (5-HT3) receptor antagonist.

Fosnetupitant chloride hydrochloride is chemically described as 2-(3,5-bis-trifluoromethylphenyl)-N-methyl-N-[6-(4-methyl-4-O-methylene-phosphatepiperazinium-1-yl)-4-o-tolyl-pyridin-3-yl]-isobutyramide chloride hydrochloride. The empirical formula is C31H36F6N4O5P•Cl•HCl, with a molecular weight of 761.53.

Fosnetupitant chloride hydrochloride is white to off-white to yellowish solid or powder. Its solubility is pH dependent: at acidic pH (pH 2), its solubility is 1.4 mg/mL; at basic pH (pH 10), its solubility is 11.5 mg/mL.

AKYNZEO for injection is available for intravenous infusion, and is supplied as a sterile lyophilized powder in a single-dose vial. Each vial contains 235 mg of fosnetupitant (equivalent to 260 mg fosnetupitant chloride hydrochloride) and 0.25 mg of palonosetron (equivalent to 0.28 mg of palonosetron hydrochloride). The inactive ingredients are edetate disodium (6.4 mg), mannitol (760 mg), sodium hydroxide and/or hydrochloric acid (for pH adjustment).

CLINICAL PHARMACOLOGY OF AKYNZEO  

Netupitant is a selective antagonist of human substance P/neurokinin 1 (NK-1) 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 (NK-1) 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.

INDICATIONS AND USAGE 

Limitations of Use
AKYNZEO for injection has not been studied for the prevention of nausea and vomiting associated with anthracycline plus cyclophosphamide chemotherapy.

CONTRAINDICATIONS

None.

PRECAUTIONS

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-HT3 receptor antagonists.
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-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 ( 7.3)].

ADVERSE REACTIONS OF AKYNZEO  

See PACKAGE INSERT for PATIENT COUNSELING INFORMATION and Medication Guide. Drug information

DOSAGE AND ADMINISTRATION OF AKYNZEO  

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.

2.2 Preparation and Administration of AKYNZEO Intravenous Solution

Preparation

AKYNZEO for injection contains no antimicrobial preservatives and is intended for single use only.

Preparation 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 reconstituted 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 till 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

Administration

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.

Storage

The total time from reconstitution to the start of the infusion should not exceed 3 hours. Store the reconstituted solution and the final diluted solution at room temperature.

2.3 Incompatibility of AKYNZEO for Injection

AKYNZEO for injection is 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 with other intravenous substances, additives or other medications, 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.

HOW AKYNZEO IS SUPPLIED 

For Injection: 235 mg fosnetupitant/0.25 mg palonosetron white to off-white lyophilized powder in single-dose vial for reconstitution.

Storage and Stability

AKYNZEO (235 mg fosnetupitant/0.25 mg palonosetron) for injection: sterile, white to off-white lyophilized powder in single-dose vial for reconstitution.

NDC # 69639-102-01: pack of one vial

Storage
AKYNZEO for injection should be stored in carton, protected from light at 2° to 8°C (35.6 F to 46.4°F).