NETUPITANT Drug Interactions: What You Need to Know

INTERACTIONS CYP3A4 Substrates: inhibition of 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 Inducers (e.g., rifampin): decreased plasma concentrations of netupitant; avoid use ( 7.2 )

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 <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.1 ), Clinical Pharmacology ( 12.3 )]</span> .

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 Pharmacology ( 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.

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 <span class="opacity-50 text-xs">[see Clinical Pharmacology ( 12.3 )]</span> . 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 <span class="opacity-50 text-xs">[see Clinical Pharmacology ( 12.3 )]</span> .

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 <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.2 )]</span>.

None. None ( 4 )

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-HT 3 receptor antagonists. ( 5.1 ) Serotonin syndrome has been reported with 5-HT 3 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 )

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-HT 3 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-HT 3 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 <span class="opacity-50 text-xs">[see Drug Interactions ( 7.3 )]</span> .