Summary Basis of Decision for Akynzeo

 

Clinical Pharmacology

The clinical pharmacology included reports on the human pharmacodynamic and pharmacokinetic studies. Akynzeo contains two medicinal ingredients, netupitant and palonosetron.

Netupitant is a selective antagonist of human substance P/neurokinin-1 (NK1) receptors. Delayed emesis has been associated with the activation of tachykinin family 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.

Palonosetron is a 5-hydroxytryptamine type 3 (5-HT₃) receptor antagonist with a strong binding affinity for this receptor and little or no affinity for other receptors. Chemotherapeutic substances 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.

Netupitant is a substrate and a moderate inhibitor of cytochrome P450 isoenzyme 3A4 (CYP3A4). Studies have shown that when co-administered with ketoconazole (a CYP3A4 inhibitor) approximately 2-fold increases in netupitant exposure were observed. Similarly, co-administration of a CYP3A4 inducer (rifampicin) resulted in a 5- to 6-fold reduction in netupitant exposure. Based on pharmacokinetic interaction studies performed during the development program, administration of the fixed-dose combination with CYP3A4 substrates may result in increased exposure to the substrate. Midazolam, erythromycin, dexamethasone, docetaxel, etoposide, and levonorgestrel were all increased during co-administration with netupitant. Netupitant exposure, on the other hand, was not impacted by co-administration with CYP3A4 substrates. Cancer patients may, however, have marginally higher exposures to docetaxel, cyclophosphamide, and etoposide in the period with Akynzeo co-medication. To mitigate the risk, the Product Monograph includes serious warnings of possible drug interactions that may occur with other medicinal products that are substrates of CYP3A4 liver enzymes, including chemotherapeutic agents that are CYP3A4 substrates.

Limited data exist on the use of Akynzeo in patients with severe hepatic impairment (Grade C, Child-Pugh score >9). Therefore, it is recommended to avoid use of Akynzeo in patients with severe hepatic impairment because of the potential for increased exposure to netupitant.

The pharmacokinetics of palonosetron and netupitant has not been studied in patients with severe or end-stage renal disease requiring hemodialysis and no data on the effectiveness or safety of Akynzeo in these patients are available. Therefore, it is recommended to avoid use of Akynzeo in patients with severe or end-stage renal disease.

Overall, the clinical pharmacological data support the use of Akynzeo for the specified indication. All potential risks identified have been included in the Akynzeo Product Monograph.

For further details, please refer to the Akynzeo Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Efficacy

This New Drug Submission (NDS) was filed to obtain market authorization for Akynzeo (netupitant and palonosetron capsules), a combination product. The primary focus of this NDS was to evaluate the new active substance netupitant, as the efficacy of oral palonosetron capsules in the prevention of acute nausea and vomiting associated with moderate emetogenic chemotherapy has been previously established.

The development program of the Akynzeo combination product was conducted in adult patients. The sponsor's intent was to evaluate the efficacy of Akynzeo for prevention of chemotherapy-induced nausea and vomiting (CINV) in both moderately emetogenic chemotherapy and highly emetogenic chemotherapy, in both the acute and delayed phases. However, in 2011, the American Society of Clinical Oncology revised their clinical practice guideline and reclassified combined anthracycline and cyclophosphamide regimens as highly emetic. As a result, the two key controlled studies (NETU-07-07 and NETU-08-18) included in this submission to support the efficacy of Akynzeo were conducted with chemotherapies now considered to be highly emetogenic. Both controlled studies assessed the superiority of Akynzeo compared to 0.5 mg palonosetron capsules administered alone in chemotherapy naïve patients.

Only palonosetron administered intravenously, however, is currently approved for use with highly emetogenic cancer chemotherapy. The sponsor therefore submitted Study PALO-10-01 to demonstrate the non-inferiority of oral palonosetron 0.5 mg (single oral dose) versus palonosetron 0.25 mg (single intravenous dose) for the prevention of chemotherapy-induced nausea and vomiting in cancer patients receiving highly emetogenic cisplatin-based chemotherapy. The results from Study PALO-10-01 showed support for use of palonosetron oral capsules where the primary efficacy endpoint was Complete Response (CR) in the prevention of nausea and vomiting in cancer patients within 24 hours (acute phase) after the start of highly emetogenic cisplatin-based chemotherapy. As such, palonosetron 0.5 mg oral capsules were considered to be an acceptable comparator for both pivotal studies, NETU-07-07 and NETU-08-18.

Study NETU-07-07

Study NETU-07-07, was a Phase II, multicentre, randomized, parallel, double-blind, controlled clinical study conducted in 679 patients, which evaluated the efficacy and safety of single oral combinations of netupitant and palonosetron versus a single oral dose of palonosetron in cancer patients receiving the first cycle of a chemotherapy regimen that included cisplatin (median dose = 75 mg/m²). All patients also received a dexamethasone regimen. The efficacy of Akynzeo was assessed in 135 patients who received Akynzeo (300 mg netupitant/0.5 mg palonosetron) and 136 patients who received oral palonosetron 0.5 mg.

The study design included four principal arms which compared three different doses of oral netupitant in combination with 0.5 mg palonosetron to oral palonosetron alone. An additional arm with aprepitant administered with ondansetron was also included for exploratory purposes only. The main goal of the study was to assess whether at least one of the three doses of netupitant concomitantly administered with palonosetron was more effective than palonosetron alone based on the primary efficacy endpoint of Complete Response (CR) during the overall phase (0-120 hours after start of chemotherapy). Complete Response rates in the acute (0-24 hours) and delayed (25-120 hours) phases were secondary efficacy endpoints.

Following the screening visit, eligible patients were randomized (stratified by gender) in a 1:1:1:1:1 ratio to one of the following treatment groups:

• Group 1 - 0.5 mg oral palonosetron on Day 1 (with dexamethasone standard regimen: 20 mg on Day 1 and 8 mg twice a day from Day 2 to Day 4);
• Group 2 - 100 mg oral netupitant and 0.5 mg oral palonosetron on Day 1 (with dexamethasone adjusted regimen: 12 mg on Day 1 and 8 mg daily from Day 2 to Day 4);
• Group 3 - 200 mg oral netupitant and 0.5 mg oral palonosetron on Day 1 (with dexamethasone adjusted regimen: 12 mg on Day 1 and 8 mg daily from Day 2 to Day 4);
• Group 4 - 300 mg oral netupitant and 0.5 mg oral palonosetron on Day 1 (with examethasone adjusted regimen: 12 mg on Day 1 and 8 mg daily from Day 2 to Day 4);
• Group 5 - 125 mg (on Day 1) and 80 mg daily (for the following two days) oral aprepitant and 32 mg intravenous ondansetron (with dexamethasone adjusted regimen: 12 mg on Day 1 and 8 mg daily from Day 2 to Day 4).

Safety assessments conducted during the trial included physical examinations, 12-lead electrocardiograms (ECGs), vital signs, hematology, blood chemistry, and recordings of adverse events.

Results

The results from Study NETU-07-07 demonstrated that all doses of netupitant which were studied (100, 200, and 300 mg), in combination with 0.5 mg palonosetron, were statistically superior to palonosetron administered alone in the primary endpoint (overall phase). The differences versus palonosetron for the individual doses of netupitant ranged from 10.9% (netupitant 100 mg) to 13.2% (netupitant 300 mg). In the acute phase (0 to 24 hours), a statistically significant difference was observed only in the netupitant 300 mg group, while all three netupitant/palonosetron groups were significantly superior to the palonosetron alone group in the delayed phase (25-120 hours).

Study NETU-08-18

Study NETU-08-18, was a Phase III, multicentre, randomized, parallel, double-blind, active controlled, superiority study. In this study, the efficacy and safety of a single oral dose of Akynzeo was compared with a single oral dose of palonosetron 0.5 mg in cancer patients scheduled to receive the first cycle of an anthracycline and cyclophosphamide regimen for the treatment of a solid malignant tumor. At the time of the study, anthracycline-cyclophosphamide-containing chemotherapy regimens were considered to be moderately emetogenic. Recent guidance has updated these regimens to highly emetogenic. All patients received also a single oral dose of dexamethasone.

A total of 1,450 patients were treated in the NETU-08-18 study. Patients were randomized to receive either Akynzeo (300 mg netupitant/0.5 mg palonosetron) fixed-dose combination with oral dexamethasone 12 mg or oral palonosetron 0.50 mg alone with oral dexamethasone 20 mg. After completion of cycle 1, patients had the option to participate in a multiple-cycle extension, receiving the same treatment as assigned in cycle 1. There was no pre-specified limit of the number of repeat consecutive cycles for any patient.

During cycle 1, patients participated in the study for a maximum of 37 days (including a screening period up to 14 days, one day of treatment, and a follow-up visit or a telephone call of 21 ± 2 days after Day 1). In the multiple-cycle extension, patients participated for a maximum of 30 days in every repeat cycle (including a 7 day screening period, one day of treatment, and a follow-up visit or a telephone call 21 ± 2 day after Day 1.

The primary efficacy endpoint was the Complete Response rate in the delayed phase, 25-120 hours after the start of the first cycle of chemotherapy administration.

Results

The results from Study NETU-08-18 demonstrated that the percentage of patients with Complete Response rate over the delayed phase (25-120) hours after the start of administration in cycle 1 was 7.4% higher in the Akynzeo treatment group compared to the palonosetron treatment group (76.9% versus [vs.] 69.5%). Superiority of Akynzeo compared to palonosetron alone was demonstrated using a two-sided Cochran/Mantel-Haesnszel (CMH) test with age class and region as strata. In the acute phase, the percentage of patients with Complete Response rate was 3.4% higher in the Akynzeo treatment group than in the palonosetron group. In the overall phase, the percentage of patients with Complete Response rate was 7.7% higher in the Akynzeo treatment group compared to the palonosetron group (74.3% vs. 66.6%) and showed statistical superiority.

During all cycles the Complete Response rates in the delayed, acute and overall phases were higher in the Akynzeo group compared to palonosetron alone.

Overall Analysis of Efficacy

Oral administration of Akynzeo in combination with dexamethasone has been shown to prevent acute and delayed nausea and vomiting associated with highly emetogenic cancer chemotherapy in two separate pivotal studies, NETU-07-07 and NETU-08-18.

Results of the pivotal studies showed a statistical superiority in terms of acute, overall and delayed emesis of netupitant plus palonosetron over palonosetron alone in cancer patients receiving a cisplatin regimen or a combination of anthracyclines plus cyclophosphamide regimen.

The efficacy of the palonosetron component of Akynzeo in the prevention of acute nausea and vomiting associated with moderate emetogenic chemotherapy has already been established; there is uncertainty, however, in terms of establishing a clear benefit of the inclusion of netupitant (a neurokinin-1 receptor antagonist) in the prevention of delayed nausea with moderate emetogenic chemotherapy, particularly those in the middle to lower end of the emetogenicity scale. In accordance with a number of Canadian practice guidelines, the indication for the prevention of acute nausea and vomiting associated with moderately emetogenic cancer therapy was limited to cancer patients whose nausea and vomiting were previously uncontrolled with the use of a 5-hydroxytryptamine type 3 (5-HT₃) receptor antagonist (including palonosetron) alone. Besides the demonstrated efficacy advantage of Akynzeo compared to the use of a 5-HT₃ receptor antagonist alone, decreasing the number of individual dose units to be taken by the patient may simplify therapy and thereby improve overall patient compliance. As a result, the benefit-harm-uncertainty profile of Akynzeo is considered acceptable with respect to efficacy.

Indication

The New Drug Submission for Akynzeo was filed by the sponsor with the following indication:

• Akynzeo (netupitant/palonosetron) is a combination product indicated for once-per-cycle treatment in adult patients for prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of highly and moderately emetogenic cancer chemotherapy.

To ensure safe and effective use of the product, Health Canada approved the following indication:

• Akynzeo (netupitant/palonosetron) in combination with dexamethasone, is indicated for once-per-cycle treatment in adult patients for:

   

  • Prevention of acute and delayed nausea and vomiting associated with highly emetogenic cancer chemotherapy
  • Prevention of acute nausea and vomiting associated with moderately emetogenic cancer therapy that is uncontrolled by a 5-HT₃ receptor antagonist alone

For more information, refer to the Akynzeo Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Safety

The Akynzeo (netupitant/palonosetron) clinical program comprised safety data from 28 studies that were performed with oral netupitant alone or in combination with palonosetron, or with palonosetron alone. The safety population is derived primarily from the Phase II and III studies which included over 3,000 cancer patients. A description of the key Phase II and III studies has been presented in the Clinical Efficacy section.

Based on the clinical safety programme, the combination of 300 mg netupitant and 0.5 mg palonosetron was shown to be safe and well tolerated, in both single and multiple cycle studies. Treatment-emergent adverse events, serious adverse events, deaths, and discontinuation due to adverse events were reported in similar frequencies across the netupitant and palonosetron combination groups and palonosetron alone groups.

The nature and frequency of adverse events in general was consistent with the disease under study or associated cytotoxic therapies, and there was no increase in adverse events observed after multiple cycles. The most common adverse events reported with Akynzeo were headache (3.6%), constipation (3.0%), and fatigue (1.2%). None of these events were serious. The frequency of headache, constipation, and fatigue were similar (2.9%, 2.5%, and 0.7%, respectively) in patients receiving oral palonosetron 0.5 mg alone.

As palonosetron may increase large bowel transit time, patients with a history of constipation or signs of subacute intestinal obstruction should be monitored closely following administration. Cases of severe constipation and complications due to constipation were observed in the clinical studies.

There have been reports of serotonin syndrome with the use of 5-HT₃ antagonists either alone or in combination with other serotonergic medicinal products (including selective serotonin reuptake inhibitors and serotonin noradrenaline reuptake inhibitors). Appropriate observation of patients for serotonin syndrome-like symptoms is advised.

An electrocardiogram study was conducted in adult male and female healthy volunteers with oral netupitant 200 or 600 mg administered in combination with oral palonosetron 0.5 or 1.5 mg, respectively. The study demonstrated small corrected QTcF interval (using the Frederick correction) averaging up to 4.39 ms (90% confidence interval [CI] 2.47, 6.31) at 14 hours after administration of 200 mg netupitant/0.5 mg palonosetron treatment and 5.8 ms (90% CI 3.98, 7.62) at 16 hours after the administration of 600 mg netupitant/1.5 mg palonosetron.

The magnitude of the QT prolongation observed in healthy volunteers might translate into more profound effects in vulnerable patients. Patients with underlying cardiac conditions (e.g., heart failure) or similar condition along with frequent vomiting and diarrhea who then receive other drugs susceptible to increase QT interval, could be at risk in decreasing their repolarisation reserve. Caution should be exercised in concomitant use with medicinal products that increase the QT interval or in patients who have or are likely to develop prolongation of the QT interval. These conditions include patients with a personal or family history of QT prolongation, electrolyte abnormalities, congestive heart failure, bradyarrhythmia, conduction disturbances and in patients taking antiarrhythmic medicinal products or other medicinal products that lead to QT prolongation or electrolyte abnormalities. In addition, prior to administration, hypokalemia, hypocalcemia and hypomagnesemia should be corrected, if required.

Akynzeo should also be used with caution in patients receiving concomitant orally administered active substances that are metabolised primarily through CYP3A4 and with a narrow therapeutic range, such as cyclosporine, tacrolimus, sirolimus, everolimus, alfentanil, diergotamine, ergotamine, fentanyl, and quinidine.

Use of Akynzeo is contraindicated during pregnancy and women of childbearing potential must use effective contraception during and up to one month after treatment with Akynzeo.

Overall Analysis of Safety

Overall, Akynzeo was well-tolerated. Many adverse reactions reported are likely to be associated with either the underlying condition or associated cytotoxic therapies. Similarly, serious adverse events and deaths reflect the patient population and concurrent treatment. The known pharmacokinetic interaction of netupitant with CYP3A4, which might be associated with an increase in the exposure to chemotherapy agents metabolized via this pathway, is adequately addressed in Akynzeo Product Monograph.

For more information, refer to the Akynzeo Product Monograph, approved by Health Canada and available through the Drug Product Database.