Summary Basis of Decision for Emend ™

3.3.1 Pharmacodynamics and Pharmacokinetics

A total of 3 pharmacodynamic (PD) studies and 27 human pharmacokinetic (PK) studies of aprepitant and/or its prodrug were carried out. None of the PD studies tested the final market composition capsules, and of the 27 PK studies, only 16 tested the final market composition capsules. The pertinent findings in the PD and PK studies may be summarized as follows:

• Commercial formulation aprepitant has good bioavailability (60-65%) with low average food effect (1.2-fold increase).
• At the proposed oral dose (plasma level >75 ng/mL at both 80 and 125 mg), NK₁ receptor occupancy is >90%.
• The observed t_1/2 (11-11.5 hours) supports single daily dosing.
• Metabolism is primarily via hepatic P450 system (CYP3A4).
• Dose adjustments are not necessary in elderly patients, or based on gender, mild to moderate hepatic impairment, or severe renal impairment.
• An approximate 50% downward dose adjustment of dexamethasone is required when co-administered with aprepitant.
• No adjustment of ondansetron or granisetron dose is required when co-administered with aprepitant.
• A decrease in INR following discontinuation of aprepitant may occur in patients on warfarin.
• Co-administration of aprepitant may decrease the efficacy of oral contraceptives.
• No dose adjustment of diltiazam is required when aprepitant (125/80/80 mg) is co-administered.
• Aprepitant does not affect the PK of P-glycoprotein pump substrates such as digoxin.
• A downward dose adjustment in midazolam may be required when aprepitant is co-administered.
• The combination of aprepitant and strong inhibitors of CYP3A4, e.g. rifampin, should be avoided.
• Generally low toxicity was observed over the dose range of aprepitant formulations employed in PK studies.

In response to the NON, regarding potential drug-drug interactions, the sponsor provided a study demonstrating that there is no clinically-relevant interaction between aprepitant and the 5-HT3 antagonist, dolasetron. The sponsor also submitted drug interaction studies on two chemotherapy agents, docetaxel and vinorelbine, both substrates for CYP3A4, which ruled out the potential for interactions. A study was requested on etoposide but was not provided; appropriate labelling to cover this risk is included in the Product Monograph.

3.3.2 Clinical Efficacy

In the original submission, the sponsor had conducted six Phase II trials; four were identified as non-pivotal. Only one Phase II non-pivotal study (P040Cl) and two Phase III pivotal studies (P052 and P054) tested the final market composition capsule, combined with intravenous (IV) ondansetron and IV/oral dexamethasone, in patients receiving highly emetogenic chemotherapy. An additional study, P071, was conducted in patients receiving moderately emetogenic chemotherapy including cyclophosphamide and possibly doxorubicin or epirubicin.

In studies P052 and P054, 544 patients received high-dose cisplatin. Approximately 95% of the patients received a concomitant chemotherapeutic agent (etoposide, fluorouracil, gemcitabine, vinorelbine, paclitaxel, cyclophosphamide, doxorubicin, docitaxel). In both studies, a statistically significantly higher proportion of patients receiving the aprepitant regimen had a complete response (no emetic episodes and no use of rescue therapy) compared with patients receiving standard therapy. The aprepitant group received aprepitant 125 mg on Day 1 and 80 mg daily on Days 2 and 3, in combination with ondansetron 32 mg IV and dexamethasone 12 mg on Day 1 and dexamethasone 8 mg once daily on Days 2 through 4. The standard therapy consisted of a placebo combined with ondansetron 32 mg IV and dexamethasone 20 mg on Day 1 and dexamethasone 8 mg orally twice daily on Days 2 through 4.

In both studies, the estimated time to first emesis after initiation of cisplatin treatment was longer with the aprepitant regimen and the incidence of first emesis was also reduced in this group. The impact of nausea and vomiting on daily activities was evaluated with the FLIE (Functional Living Index Emesis) questionnaire and in each of the two studies, a higher proportion of patients receiving the aprepitant regimen reported minimal or no impact of nausea and vomiting on daily life (74% vs. 64%). The efficacy of aprepitant was maintained for up to six cycles of chemotherapy.

In study P071 for moderately emetogenic chemotherapy (MEC), 438 patients (99% women with breast cancer) received aprepitant with a chemotherapy regimen including cyclophosphamide and possibly doxorubicin or epirubicin. Some patients also received fluorouracil, methotrexate, docetaxel or paclitaxel. The total number of participants was 866. As in the two previously described studies, aprepitant combined with ondansetron and dexamethasone was compared with a placebo administered with ondansetron and dexamethasone. For moderately emetogenic chemotherapy, a slightly statistically significant higher proportion of patients receiving the aprepitant regimen (51%) had a complete response (no emetic episodes and no use of rescue therapy) in comparison with patients receiving standard therapy (42%). The difference between treatment groups was primarily driven by the no emesis endpoint.

Both pivotal Phase III studies employed IV ondansetron, and all but one Phase II study used IV 5-HT₃ antagonists. In the Phase II study that combined Emend™ with oral ondansetron, the effectiveness of the combination regimen could not be demonstrated. Since the most common route of administration of 5-HT₃ antagonists in cancer clinics across Canada is oral, efficacy relative to the standard of practice for Canadians failed to be demonstrated.

In the refiled submission, the sponsor presented new information regarding the efficacy concerns. Study P071 data was updated as a Phase III study where patients were administered ondansetron orally at a dose of 8 mg twice daily and 12 mg oral dexamethasone once daily on Day 1. A new study, P801, was a post-marketing study evaluating the safety and efficacy of aprepitant in patients receiving highly emetogenic chemotherapy (HEC), specifically high-dose (>70 mg/m²) cisplatin-based chemotherapy. Ondansetron use was extended to Day 4 in the standard arm. The study enrolled 489 patients.

In study P071, although Emend™ was combined with oral ondansetron, the patients were treated with MEC, specifically cyclophosphamide and an anthracycline. These agents may induce nausea and vomiting by a different mechanism than that by cisplatin-based chemotherapy, thus it is not possible to extrapolate the efficacy results to highly emetic chemotherapy. In patients being administered MEC, the results show that aprepitant significantly decreased the risk of vomiting. There was positive, though not statistically significant, effect of aprepitant on the occurrence of nausea and the need to use rescue medication when MEC was being administered. The benefits of aprepitant were documented with the same degree of efficacy through several cycles of MEC (four cycles) given to more than 300 patients. This consistency of efficacy of aprepitant through several treatment cycles supports administration of this drug for as long as MEC is required. The limitations of this study are that only two men were included in the study population, therefore any recommendation for the use of aprepitant in the context of MEC should be limited to women.

In study P801, although the patient population was administered highly emetogenic chemotherapy, the study did not support the claim for efficacy since the Emend arm was not combined with oral ondansetron. The main objective of the sponsor in this study was to compare "triple therapy" with standard therapy that incorporated a longer use of 5-HT₃ antagonists, which is sometimes employed by physicians in an attempt to reduce delayed nausea and vomiting.

The updated submission dossier for Emend™ alone did not include sufficient information to overturn Health Canada's position on the efficacy issue. However, a review of the international guidelines and positive reviews by other regulatory jurisdictions provided adequate support to alleviate most of Health Canada's concerns regarding efficacy. The guidelines examined were those of the following associations: the Multinational Association of Supportive Care in Cancer, the National Comprehensive Cancer Network, the American Society of Clinical Oncology, Cancer Care Ontario, the BC Cancer Agency, and Cancer Care Nova Scotia. Although Health Canada maintains its position that efficacy should be proven in adequate and well-controlled clinical trials, it is willing to accept in this case the overwhelming support for Emend™ in the prevention of CINV due to HEC by the international oncology research community.

In summary, although Health Canada requests proof of effectiveness and safety in the Canadian context, in the case of Emend™, it accepts the general scientific consensus that aprepitant is likely efficacious with an oral ondansetron dose. The Product Monograph has included a statement regarding the presence of only limited efficacy data for Emend™.

3.3.3 Clinical Safety

Aprepitant is a selective antagonist of NK₁ receptors which modulate, via substance P, the neuroimmune system. Thus, aprepitant may have an immunosuppressive effect on patients. Emend™'s potential for drug interactions also may increase this risk of immunosuppression. However, no immunotoxicity studies were performed, likely because Emend™ is only administered for short term use.

In the combined results of the two pivotal studies submitted in the original application, P052 and P054, slightly more serious infectious events (3.7%) were reported in the aprepitant arm compared to the control arm (2.4%). However, a more notable increase in infectious events was identified in the aprepitant arm in patients administered chemotherapy agents metabolized by CYP3A4, specifically etoposide (18% vs. 9% in controls) and vinorelbine (18% vs. 12%). Further, there were reports of respiratory insufficiency (4.9% vs. 0%) in the subset of patients taking vinorelbine. In response to this finding, the sponsor carried out study P101 and demonstrated no clinically relevant interaction between aprepitant and vinorelbine. The sponsor did not perform an interaction study with etoposide, claiming that the chance of an interaction with etoposide is unlikely. The sponsor examined the subgroups of patients who were co-administered vinorelbine or etoposide in P801 and concluded that there was no increase in infections, including respiratory insufficiency, in these subgroups. Unfortunately, this data could not be verified as the sponsor did not submit a full report. A request was made for the data, but the sponsor was unable to provide further information.

The available data for P801 was examined and an increased incidence of infection adverse events on the aprepitant arm compared to the control arm was noted (13.7% vs. 7.0%). A drug-related assessment concluded that the frequency of infections on the aprepitant arm was 0.8% compared to 0% on the control arm. The frequency of serious infections was similar in both arms and there were no fatalities due to infections.

No increase in infections was seen in the aprepitant arm in study P071 for MEC. This may have been due to the limited use of concomitant administration of dexamethasone; one day in the MEC regimen compared to four days in the highly emetogenic chemotherapy regimen (corticosteroids also have an immunosuppressive effect).

Since global market introduction in March 2003, only 11 reports of infection have been collected by post-marketing surveillance and reviewed in Periodic Safety Update Reports (PSURs). Nausea and vomiting were among the most frequently reported adverse drug reactions, demonstrating that the use of Emend™ may not be effective in all patients.

In summary, a small increase in infections may be associated with the use of Emend™, due to the antagonism of the NK₁ receptors on the immune system. Immunosuppression possibly exacerbated by the concomitant use of CYP3A4-metabolized chemotherapy agents (specifically vinorelbine and etoposide), as seen in studies P052 and P054, was not observed in study P801, but the data could not be verified. No increase in infections was seen in study P071 for MEC, and infections were reported very infrequently in the previous 6 PSURs over the last 3 years. Interpretation of this data is difficult since many cancer patients are on multiple medications which have immunosuppressive potential. At this time, Emend™ is indicated for short-term use only, and the increase in incidence of infections observed has been minimal. The role of aprepitant in immune suppression should be further investigated if Emend™ is ever to be indicated for long-term use. Continued surveillance of post-marketing infections is also recommended.