**MEMORANDUM** DEPARTMENT OF HEALTH AND HUMAN SERVICES

PUBLIC HEALTH SERVICE

FOOD AND DRUG ADMINISTRATION

CENTER FOR DRUG EVALUATION AND RESEARCH

**DATE:** February 6, 2003

**FROM:** Brian Strongin, R.Ph., M.B.A., Project Manager, *for*

> Robert L. Justice, M.D., M.S., Director
>
> Division of Gastrointestinal and Coagulation Drug Products,
>
> HFD-180

**SUBJECT:** Briefing Document for the March 6, 2003 Meeting of the

Gastrointestinal Drugs Advisory Committee

**MEETING TIME:** 8:30AM -- 5:00PM

**MEETING LOCATION:** Holiday Inn, The Ballroom, 2 Montgomery Village
Avenue, Gaithersburg, MD

**Please find enclosed the following items:**

**Attachment One: Medical Officer's Summary Page 3**

**Attachment Two: Clinical Pharmacology and Page 34**

> **Biopharmaceutics Summary**

The attached package contains background information prepared by the
Food and Drug Administration (FDA) for the panel members of the advisory
committee. The FDA background package often includes initial reviews
and/or preliminary conclusions and recommendations written by individual
FDA reviewers. These conclusions and recommendations do not necessarily
represent the final position of the individual reviewer, nor to they
necessarily represent the final position of the FDA. The FDA will not
issue a final determination on the issues at hand until input from the
advisory committee process has been considered and all reviews have been
finalized.

**ATTACHMENT ONE**

**MEDICAL OFFICER'S SUMMARY**

Memorandum

Date: February 5, 2003

From: Division of Gastrointestinal and Coagulation Drug Products

Gary Della'Zanna D.O. M.Sc. (Medical Officer)

Wen-Jen Chen PhD (Bio-Statistician)

To: Advisory Committee Members

Subject: Background Package for Advisory Committee Meeting on March 6,
2003

Drug Name: EMEND (aprepitant)

#### Subject of Advisory Committee Meeting

> Merck & Co., Inc. submitted a New Drug Application (21-549) on
> September 27, 2002 for aprepitant. Aprepitant (previously known as
> MK-0869 and L-754030) is a New Molecular Entity that is the first in a
> new therapeutic class: NK~1~ -receptor antagonist. The Applicant has
> requested an indication for "the prevention of acute and delayed
> nausea and vomiting associated with initial and repeat courses of
> highly emetogenic chemotherapy". Aprepitant would be the first drug to
> be granted an indication that included the delayed phase of
> chemotherapy-induced nausea and vomiting.
>
> The FDA is requesting the Advisory Committee members to provide us
> views on the following:
>
> [Proposed Indication:]{.underline}
>
> Do the data support the prevention of nausea and vomiting in the
> delayed, acute
>
> and overall phases?

Do the data support the prevention of nausea?

> Did subjects receive "highly emetogenic chemotherapy"?
>
> Do the data support the use of any 5-HT~3~ antagonist as part of the
> aprepitant
>
> regimen?

Do the data support the use of any steroid as part of the aprepitant
regimen?

> Do the data support the Applicant's proposed indication?
>
> [Drug-Drug Interaction]{.underline}:
>
> What concerns does the Committee have regarding drug-drug interactions
> with

other chemotherapeutic agents?

> What concerns does the Committee have in regard to other drug-drug
>
> interactions?

#### Agency's Comments Regarding Study Design and Analysis

#### The Applicant submitted two Phase III trials in support of the proposed indication of prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of high-dose cisplatin either alone or with concomitant chemotherapy. (Study 052 and Study 054). The two Phase III trials were identical in design, except Study 052 contained a protocol amendment to allow for the inclusion of four adolescent patients. The treatment regimens are listed in Table 1. {#the-applicant-submitted-two-phase-iii-trials-in-support-of-the-proposed-indication-of-prevention-of-acute-and-delayed-nausea-and-vomiting-associated-with-initial-and-repeat-courses-of-high-dose-cisplatin-either-alone-or-with-concomitant-chemotherapy.-study-052-and-study-054.-the-two-phase-iii-trials-were-identical-in-design-except-study-052-contained-a-protocol-amendment-to-allow-for-the-inclusion-of-four-adolescent-patients.-the-treatment-regimens-are-listed-in-table-1. .unnumbered}

####  {#section .unnumbered}

Table 1

Treatment Regimens

+-------------+-------------------+-----------------------------------+
| Treatment   | Day 1             | Day 2 to 4                        |
| Regimen     |                   |                                   |
+-------------+-------------------+-----------------------------------+
| MK-0869     | MK-0869 125 mg PO | MK-0869 80 mg PO Daily (Days 2    |
|             |                   | and 3 only)                       |
|             | Dexamethasone 12  |                                   |
|             | mg PO             | Dexamethasone 8 mg PO Daily       |
|             |                   | (morning)                         |
|             | Ondansetron 32 mg |                                   |
|             | IV                | Dexamethasone Placebo PO Daily    |
|             |                   | (evening)                         |
+-------------+-------------------+-----------------------------------+
| Standard    | MK-0869 Placebo   | MK-0869 Placebo PO Daily (Days 2  |
| Therapy     | PO                | and 3 only)                       |
|             |                   |                                   |
|             | Dexamethasone 20  | Dexamethasone 8 mg PO Daily       |
|             | mg PO             | (morning)                         |
|             |                   |                                   |
|             | Ondansetron 32 mg | Dexamethasone 8 mg PO Daily       |
|             | IV                | (evening)                         |
+-------------+-------------------+-----------------------------------+

In adolescent patients 12 and \<18 years of age and 40 kg body weight),
ondansetron was administered in three intravenous doses of 0.15 mg/kg;
the first dose was given 30 minutes prior to cisplatin, and the
subsequent doses were given at 4 and 8 hours after first dosing.

####  A. Efficacy Results {#a.-efficacy-results .unnumbered}

####  {#section-1 .unnumbered}

#### [Primary Endpoint: Complete Response]{.underline} (Overall Phase) {#primary-endpoint-complete-response-overall-phase .unnumbered}

####  {#section-2 .unnumbered}

#### The Agency has verified the Applicant's data and concurs with the results of the major analysis. The primary endpoint for both studies was complete response in the overall phase (0-120 hours post cisplatin administration). Complete response was defined as no emesis and no rescue therapy. The Applicant defined complete response for the acute (0 to 24 hours) and delayed (25 to 120 hours) phases as secondary endpoints. The primary endpoint did not evaluate nausea, however, it is part of the requested treatment indication. {#the-agency-has-verified-the-applicants-data-and-concurs-with-the-results-of-the-major-analysis.-the-primary-endpoint-for-both-studies-was-complete-response-in-the-overall-phase-0-120-hours-post-cisplatin-administration.-complete-response-was-defined-as-no-emesis-and-no-rescue-therapy.-the-applicant-defined-complete-response-for-the-acute-0-to-24-hours-and-delayed-25-to-120-hours-phases-as-secondary-endpoints.-the-primary-endpoint-did-not-evaluate-nausea-however-it-is-part-of-the-requested-treatment-indication. .unnumbered}

> Analysis of the data by the Agency demonstrated the aprepitant regimen
> was statistically superior to standard therapy for the primary
> endpoint of complete response in the overall phase as well as the
> secondary endpoints of complete response for the acute and delayed
> phases. (Table 2) In study 052, 72.7% of the patients in the
> aprepitant group were responders for the primary endpoint compared to
> 52.3% in the standard therapy group (p \< 0.0001). Similar results
> were achieved for study 054 with 62.7% of the patients in the
> aprepitant group were responders for the primary endpoint compared to
> 43.3% in the standard therapy group (p \< 0.0001). The following table
> displays the efficacy results for both pivotal studies.

Table 2

###### Efficacy Summary

+-----------------------+----------------------+---+-----------------------+
|                       | Aprepitant Regimen   |   | Standard Therapy      |
|                       |                      |   |                       |
|                       | n/m (%)              |   | n/m (%)               |
+-----------------------+----------------------+---+-----------------------+
| **Complete Response** |                      |   |                       |
| (no emetic episodes   |                      |   |                       |
| and no rescue         |                      |   |                       |
| therapy)              |                      |   |                       |
+-----------------------+----------------------+---+-----------------------+
| Study 052             |                      |   |                       |
+-----------------------+----------------------+---+-----------------------+
| Overall Phase         | 189/260 (72.7)\*\*   |   | 136/260 (52.3)        |
|                       | (p \< 0.0001)        |   |                       |
+-----------------------+----------------------+---+-----------------------+
| Acute Phase           | 231/259 (89.2)\*\*   |   | 203/260 (78.1)        |
|                       | (p = 0.0009)         |   |                       |
+-----------------------+----------------------+---+-----------------------+
| Delayed Phase         | 196 / 260 (75.4)\*\* |   | 145/260 (55.8)        |
|                       | (p \< 0.0001)        |   |                       |
+-----------------------+----------------------+---+-----------------------+
| Study 054             |                      |   |                       |
+-----------------------+----------------------+---+-----------------------+
| Overall Phase         | 163 / 260 (62.7)\*\* |   | 114/263 (43.3)        |
|                       | (p \< 0.0001)        |   |                       |
+-----------------------+----------------------+---+-----------------------+
| Acute Phase           | 216 / 261 (82.8)\*\* |   | 180/263 (68.4)        |
|                       | (p = 0.0001)         |   |                       |
+-----------------------+----------------------+---+-----------------------+
| Delayed Phase         | 176 / 260 (67.7)\*\* |   | 123/263 (46.8)        |
|                       | (p \< 0.0001)        |   |                       |
+-----------------------+----------------------+---+-----------------------+
| **No Nausea**         |                      |   |                       |
| (maximum nausea       |                      |   |                       |
| VAS\<5 )              |                      |   |                       |
+-----------------------+----------------------+---+-----------------------+
| Study 052             |                      |   |                       |
+-----------------------+----------------------+---+-----------------------+
| Overall Phase         | 122 /257 (47.5) (p = |   | 115 / 260 (44.2)      |
|                       | 0.48)                |   |                       |
+-----------------------+----------------------+---+-----------------------+
| Acute Phase           | 185/256 (72.3) (p =  |   | 179/ 259 (69.1)       |
|                       | 0.48)                |   |                       |
+-----------------------+----------------------+---+-----------------------+
| Delayed Phase         | 132/259 (51.0) (p =  |   | 124 / 260 (47.7)      |
|                       | 0.46)                |   |                       |
+-----------------------+----------------------+---+-----------------------+
| Study 054             |                      |   |                       |
+-----------------------+----------------------+---+-----------------------+
| Overall Phase         | 127 / 260 (48.8)\*   |   | 102 / 263 (38.8)      |
|                       | (p = 0.021)          |   |                       |
+-----------------------+----------------------+---+-----------------------+
| Acute Phase           | 176 / 260 (67.7) (p  |   | 174 / 263 (66.2)      |
|                       | = 0.71)              |   |                       |
+-----------------------+----------------------+---+-----------------------+
| Delayed Phase         | 137 / 260 (52.7)\*\* |   | 105 / 263 (39.9)      |
|                       | (p = 0.003)          |   |                       |
+-----------------------+----------------------+---+-----------------------+
| **No Significant      |                      |   |                       |
| Nausea** (maximum     |                      |   |                       |
| nausea VAS\<25 )      |                      |   |                       |
+-----------------------+----------------------+---+-----------------------+
| Study 052             |                      |   |                       |
+-----------------------+----------------------+---+-----------------------+
| Overall Phase         | 188 / 257 (73.2) (p  | 1 |                       |
|                       | = 0.09)              | 7 |                       |
|                       |                      | 1 |                       |
|                       |                      | / |                       |
|                       |                      | 2 |                       |
|                       |                      | 5 |                       |
|                       |                      | 9 |                       |
|                       |                      | ( |                       |
|                       |                      | 6 |                       |
|                       |                      | 6 |                       |
|                       |                      | . |                       |
|                       |                      | 0 |                       |
|                       |                      | ) |                       |
+-----------------------+----------------------+---+-----------------------+
| Acute Phase           | 232 /256 (91.0) (p = | 2 |                       |
|                       | 0.16)                | 2 |                       |
|                       |                      | 4 |                       |
|                       |                      | / |                       |
|                       |                      | 2 |                       |
|                       |                      | 5 |                       |
|                       |                      | 9 |                       |
|                       |                      | ( |                       |
|                       |                      | 8 |                       |
|                       |                      | 6 |                       |
|                       |                      | . |                       |
|                       |                      | 5 |                       |
|                       |                      | ) |                       |
+-----------------------+----------------------+---+-----------------------+
| Delayed Phase         | 195 / 259 (75.3) (p  | 1 |                       |
|                       | = 0.09)              | 7 |                       |
|                       |                      | 8 |                       |
|                       |                      | / |                       |
|                       |                      | 2 |                       |
|                       |                      | 6 |                       |
|                       |                      | 0 |                       |
|                       |                      | ( |                       |
|                       |                      | 6 |                       |
|                       |                      | 8 |                       |
|                       |                      | . |                       |
|                       |                      | 5 |                       |
|                       |                      | ) |                       |
+-----------------------+----------------------+---+-----------------------+
| Study 054             |                      |   |                       |
+-----------------------+----------------------+---+-----------------------+
| Overall Phase         | 185 / 260 (71.2) (p  | 1 |                       |
|                       | = 0.08)              | 6 |                       |
|                       |                      | 8 |                       |
|                       |                      | / |                       |
|                       |                      | 2 |                       |
|                       |                      | 6 |                       |
|                       |                      | 3 |                       |
|                       |                      | ( |                       |
|                       |                      | 6 |                       |
|                       |                      | 3 |                       |
|                       |                      | . |                       |
|                       |                      | 9 |                       |
|                       |                      | ) |                       |
+-----------------------+----------------------+---+-----------------------+
| Acute Phase           | 235 / 260 (90.4)\*   | 2 |                       |
|                       | (p = 0.011)          | 1 |                       |
|                       |                      | 8 |                       |
|                       |                      | / |                       |
|                       |                      | 2 |                       |
|                       |                      | 6 |                       |
|                       |                      | 3 |                       |
|                       |                      | ( |                       |
|                       |                      | 8 |                       |
|                       |                      | 2 |                       |
|                       |                      | . |                       |
|                       |                      | 3 |                       |
|                       |                      | ) |                       |
+-----------------------+----------------------+---+-----------------------+
| Delayed Phase         | 189 / 260 (72.7) (p  | 1 |                       |
|                       | = 0.07)              | 7 |                       |
|                       |                      | 2 |                       |
|                       |                      | / |                       |
|                       |                      | 2 |                       |
|                       |                      | 6 |                       |
|                       |                      | 3 |                       |
|                       |                      | ( |                       |
|                       |                      | 6 |                       |
|                       |                      | 5 |                       |
|                       |                      | . |                       |
|                       |                      | 4 |                       |
|                       |                      | ) |                       |
+-----------------------+----------------------+---+-----------------------+

\*\* p\<0.01 when compared with Standard Therapy; \* p\<0.05 when
compared with Standard Therapy

n/m = Number of patients with desired response/number of patients
included in time point.

####   {#section-3 .unnumbered}

> With regard to the definitions for the acute and delayed phases, the
> Applicant's terminology is consistent with medical literature. This is
> the first time the Agency will be granting an indication for the
> delayed phase and would like the committee's opinion.
>
> The Applicant pre-specified multiple secondary and exploratory
> endpoints (including emesis, nausea, and significant nausea) in the
> protocol. When analyses were performed for the nausea endpoints
> independently (i.e. no nausea, and no significant nausea), only in
> Study 054 did some of the results reach statistical significance. The
> significant results for the nausea endpoints failed to be replicated
> in Study 052. (Table 2) Furthermore, since several secondary and
> exploratory endpoints were analyzed, the nominally significant results
> can not be taken quite at face value due to multiple comparisons.
>
> Therefore, the statistical significance of the no nausea endpoints is
> not persuasive when evaluated independently.
>
> The Agency acknowledges that the results of the nausea endpoints may
> have been effected by the use of antiemetic "rescue" therapy. A higher
> proportion of patients in the standard therapy group than aprepitant
> group utilized rescue therapy. (27.6% vs 18.0% respectively)
>
> The Agency seeks guidance on whether the data supports the proposed
> indication; specifically, regarding the delayed phase and the
> prevention of nausea and vomiting.

####  Highly Emetogenic Chemotherapy

> The Applicant proposes the aprepitant regimen will prevent
> chemotherapy induced nausea and vomiting associated with highly
> emetogenic chemotherapy. The Applicant has studied safety and efficacy
> only with highly emetogenic doses of cisplatin with or without other
> concomitant chemotherapy. The safety and efficacy of the aprepitant
> regimen with of other chemotherapeutic agents at highly emetogenic
> doses have not been evaluated.
>
> The Phase III protocols defined a highly emetogenic dose of cisplatin
> as ≥70 mg/m^2^. However, approximately 20% of the patients received
> less than the protocol dose and were included in efficacy analysis.
> The Applicant states all patients received a highly emetogenic dose of
> cisplatin (\>50 mg/m^2^) and submitted the Hesketh Classification in
> support of this dose.
>
> The Applicant reportedly modeled the primary endpoint on the protocol
> used in the approval of ondansetron. However, when ondansetron was
> approved, the highly emetogenic cisplatin dose was 100 and 120
> mg/m^2^. The cisplatin dose range of 50-80 mg/m^2^ is described as a
> moderate emetogenic dose in label. The defined dose of highly
> emetogenic cisplatin has varied since the approval of ondansetron. The
> Kytril label describes a highly emetogenic cisplatin dose as 80
> mg/m^2^ and the Anzemet label describes a highly emetogenic cisplatin
> dose as 70 mg/m^2^ in one study and 80 mg/m^2^ in another.
>
> The number of patients who received less than 70 mg/m^2^ cisplatin
> were balanced between treatment groups and should not affect the
> primary endpoint analysis. However, the Agency is interested in the
> Committee's opinion on whether
>
> 50-70 mg/m^2^ of cisplatin is highly emetogenic.

#### Safety 

**A. [5-HT~3~ Antagonists: ]{.underline}**

> The aprepitant regimen, as defined by the proposed label, states that
> a corticosteroid and a 5-HT~3~ antagonists be used in the treatment.
> The Applicant has provided exposure data only for ondansetron and
> granisetron. During the phase II trials 332 patients were treated with
> a regimen that included the combination of aprepitant with
> granisetron, and 520 patients received aprepitant with ondansetron.
> During the Phase III trials only odansetron was utilized in the
> protocol. A total of 549 patients received aprepitant in combination
> with intravenous ondansetron.
>
> The NDA submission included pharmacokinetic data for intravenous
> ondansetron and oral granisetron. In these drug interaction studies,
> aprepitant did not have clinically important effects on the
> pharmacokinetics of the specific drug formulations studied. The Agency
> does not have drug interaction studies for the oral formulation of
> ondansetron or the intravenous formulation of granisetron. The Agency
> has no exposure safety data on the use of aprepitant with dolasetron.
>
> Because of first pass metabolism, one cannot extrapolate PK results
> from intravenous studies to oral formulations. The CYP3A4 inhibitory
> effect of aprepitant is not as pronounced when CYP3A4 substrates are
> administered intravenously. For example, when the same dose of
> aprepitant (125 mg) was administered prior to IV methylprednisolone
> compared to oral dexamethasone (both CYP3A4 substrates), aprepitant
> increased the AUC of methylprednisolone 1.3-fold, and the AUC of
> dexamethasone 2.3-fold increase. Since the Applicant studied the
> "worse case" situation with granisetron (oral formulation), additional
> PK information is not needed for granisetron. However, there are no PK
> studies for the oral formulation of odansetron and one needs to
> consider that the oral formulations may be utilized as rescue therapy.
> This may result in higher plasma concentrations of odansetron.
>
> Within the class of 5-HT~3~ antagonists, there are differences in
> metabolic pathways. Both ondansetron and granisetron are predominately
> metabolized by CYP3A4. Dolasetron, however, is metabolized by carbonyl
> reductase to hydrodolasetron. CYP2D6 is primarily responsible for the
> subsequent hydroxylation of hydrodolasetron and both CYP3A4 and flavin
> monooxygenase are responsible for the N-oxidation of hydrodolasetron.
> Furthermore, dolasetron is the only drug in the class to have QTc and
> cardiac warnings in its label.
>
> Since there is no exposure data on the use of aprepitant with
> dolasetron and it has a different metabolic pathway, the Agency seeks
> advice as to whether the regimen proposed in the label should specify
> only the 5-HT~3~ antagonists that have been studied. The Agency would
> like the committee's opinion on whether or not additional PK studies
> are required on the oral formulation of ondansetron.

**B.** **[Drug-Drug Interactions]{.underline} (General)**

> Aprepitant is a substrate and a moderate inhibitor of CYP3A4 and may
> affect the pharmacokinetics of drugs that are metabolized by CYP3A4.
> In addition, administration of aprepitant for 28 days has shown
> aprepitant is also an inducer of CYP3A4. Aprepitant was also shown to
> be an inducer of CYP2C9. This was characterized by a drug interaction
> study with S-warfarin, whose metabolism is mediated almost exclusively
> by CYP2C9. Consequently, aprepitant might also affect the
> pharmacokinetics of drugs that are CYP2C9 substrates. Please refer to
> Clinical Pharmacology and Biopharmaceutics section for a detailed
> review.
>
> During the Phase IIb studies a drug-drug interaction was identified
> between aprepitant and dexamethasone that resulted in a 2-fold
> increase in plasma concentrations of dexamethasone. This finding
> resulted in the adjustment of dexamethasone in the aprepitant group in
> the Phase III protocols. During these Phase IIb studies the incidences
> of febrile neutropenia and serious infections were higher in the
> aprepitant groups than the standard therapy group. The Applicant
> attributes these adverse events to the increased exposure to
> dexamethasone. The adverse events reported during the Phase II trials
> are presented in Table 3.
>
> ![](media/image1.png){width="3.995833333333333in"
> height="4.758333333333334in"}
>
> Table 3
>
> Table 3 (cont)
>
> ![](media/image2.png){width="5.993055555555555in"
> height="7.121527777777778in"}

Although a patient may have had 2 or more clinical adverse experiences,
the patient is counted only once in a

category. The same patient may appear in different categories.

CINV = Chemotherapy-induced nausea and vomiting.

(Ref Table E-37 ISS.pdf)

> Based on the Phase II data, several adverse experiences were
> identified as being of special interest: fever, febrile neutropenia,
> infections, leukopenia, neutropenia, anemia, thrombocytopenia,
> hypertension, hyperglycemia, hypokalemia, and dehydration.
>
> The Agency has concerns regarding the potential for aprepitant to
> alter the pharmacokinetics of therapeutic agents via CYP3A4
> interaction. There are no PK data available regarding the drug-drug
> interaction of the aprepitant regimen on chemotherapeutic agents
> metabolized by CYP3A4. Therefore, the focus of the remainder of this
> review will be on the safety data from the Phase III Studies in regard
> to concomitant chemotherapeutic agents.

**C.** **[Drug-Drug Interactions]{.underline} (Chemotherapy)**

> The most common concomitant chemotherapeutic agents used during the
> Phase III trials were cyclophosphamide, etoposide, fluorouracil,
> gemcitabine, paclitaxel, and vinorelbine tartrate (Table 4). The
> Applicant performed additional safety analyses for these concomitant
> chemotherapeutic agents. Limited safety data is available for the
> remaining chemotherapeutic agents.

Table 4

![](media/image3.png){width="5.185416666666667in"
height="6.384722222222222in"}

> (Ref Table E-60 ISS.pdf)

#### [Drug-Drug Interactions]{.underline} (Chemotherapy CYP3A4 substrates)

> The Applicant identified the following chemotherapies as CYP3A4
> substrates: etoposide, vinca alkaloids (vinblastine, vincristine, and
> vinorelbine tartrate),
>
> Taxanes (docetaxel and paclitaxel), irinotecan, and ifosfamide. The
> adverse events for patients who received cisplatin in combination with
> a concomitant chemotherapy metabolized by CYP3A4 are listed in the
> table below. (Table 5)

###### Table 5

![](media/image4.png){width="5.999305555555556in"
height="7.39375in"}(Ref Table E-113 ISS.pdf)

> Table 5 (cont)
>
> ![](media/image5.png)

(Ref Table E-113 ISS.pdf)

Table 5 (cont)

![](media/image6.png){width="5.996527777777778in"
height="6.055555555555555in"}

\* The same patient may appear more than once in different categories.

(Ref Table E-113 ISS.pdf)

Two hundred sixty-six patients in the aprepitant group and 251 patients
in the standard therapy group received, in addition to cisplatin, a
concomitant chemotherapy metabolized by CYP3A4. Overall, the incidence
of serious adverse experiences in this subpopulation was slightly higher
in the aprepitant group than the standard therapy group (15.0% Vs 13.5%
respectively).

There were more infection related serious adverse events reported in the
aprepitant group. In the aprepitant group, septic shock was reported in
3 patients, sepsis in one patient and upper respiratory infection in the
1 patient. In the corresponding standard therapy group there were no
reports of these serious adverse events.

A higher incidence of hematologic serious adverse events was also seen
in this subpopulation. Neutropenia was reported as a serious adverse
event in 8 of the 266 patients receiving the aprepitant regimen,
compared to 2 of the 251 patients in the corresponding standard therapy
group. The incidence of anemia, febrile neutropenia and thrombocytopenia
were generally similar between treatment groups with a difference
between treatment groups less then 1 %.

**E. [Drug-Drug Interactions]{.underline} (Most Common Chemotherapy)**

> The applicant performed additional safety analysis for the most common
> concomitant chemotherapy (both CYP3A4 and non- CYP3A4) utilized during
> the Phase III trials. These results are discussed below.
>
> As previously stated, several adverse experiences (serious and
> non-serious) were identified as being of special interest: fever,
> febrile neutropenia, infections, leukopenia, neutropenia, anemia,
> thrombocytopenia, hypertension, hyperglycemia, hypokalemia, and
> dehydration. In order to focus on the Agency's concerns, the incidence
> of these as serious adverse events will be discussed.
>
> [Etoposide]{.underline} (CYP3A4 substrate)
>
> One hundred ninety seven patients received etoposide in combination
> with cisplatin (106 patients in the aprepitant group and 91 patients
> in the standard therapy group). The following table displays the
> serious adverse events by body system for patients who received
> etoposide in combination with cisplatin.
>
> ![](media/image7.png){width="4.750694444444444in" height="5.5in"}Table
> 6
>
> (Ref Table E-127 ISS.pdf)
>
> Table 6 (cont)
>
> ![](media/image8.png){width="4.214583333333334in" height="4.25in"}
> (Ref Table E-127 ISS.pdf)
>
> Overall, the incidence of serious adverse experiences in this
> subpopulation was similar between treatment groups. Serious adverse
> experiences were reported in 16 out of 106 aprepitant patients (15.1%)
> and 14 out of 91 patients (15.4%) receiving standard therapy. Analysis
> of serious adverse events by body system, however, demonstrates three
> times as many hematologic serious adverse events occurred in the
> aprepitant group. Nine out of 106 patients (8.5%) in the aprepitant
> group compared to 3 out of 91 patients (3.3%) in the standard therapy
> group developed a serious hematologic adverse event. Neutropenia was
> reported as a serious adverse event in 4 of the 106 patients receiving
> the aprepitant regimen in combination with etoposide and cisplatin,
> compared to none in the corresponding standard therapy group. Febrile
> neutropenia was described as a serious adverse event in twice as many
> patients in the aprepitant group. This was reported in 4 of the 106
> patients in the aprepitant group compared to 2 cases in the standard
> therapy group.
>
> Infection was reported as an adverse event (serious and non-serious)
> in more than twice as many patients in the aprepitant group. It was
> reported in19 patients (17.9%) in the aprepitant group compared to 8
> patients (8.8%) in the standard therapy group. Although the incidence
> of fever, septic shock and upper respiratory infection as serious
> adverse events were small, they were only reported in the aprepitant
> group.
>
> On analyzing the data, there was a notable difference in the incidence
> of serious hematologic and serious infection related adverse events
> for patients receiving concomitant etoposide.

[Fluorouracil]{.underline}

One hundred ninety three patients (100 patients in the aprepitant group
and 93 patients in the standard therapy group) received fluorouracil in
combination with cisplatin. The following table displays the serious
adverse events by body system for patients who received fluorouracil in
combination with cisplatin.

Table 7

![](media/image9.png){width="4.3625in" height="5.3284722222222225in"}

(Ref Table E-129 ISS.pdf)

Table 7 (cont)

![](media/image10.png){width="3.823611111111111in"
height="5.163194444444445in"}

(Ref Table E-129 ISS.pdf)

The incidence of serious adverse experiences was smaller in the
aprepitant group than the standard therapy group (14.0% vs 22.6%
respectively). Serious hematologic adverse events occurred less
frequently in the aprepitant group as well.

The incidence of neutropenia was similar in both treatment groups. It
was reported as a serious adverse event in 2 of the 100 patients in the
aprepitant group who received fluorouracil in combination with
cisplatin, compared to 3 patients receiving standard therapy. The
incidence of febrile neutropenia was also smaller in the aprepitant
group. It was reported as a serious adverse event in 1 of the 100
patients in the aprepitant group compared to 3 in the standard therapy
group.

> The incidences of fever, sepsis and septic shock as a serious adverse
> event were small and similar between treatment groups. Overall, the
> incidence of infection was similar between treatment groups.
>
> On analyzing the data, there was little difference seen in the safety
> profile of fluorouracil between treatment groups.

[Gemcitabine]{.underline}

> A total of 190 patients were treated with gemcitabine in combination
> with cisplatin: 89 in the aprepitant group and 101 in the standard
> therapy group. Sixteen out of 89 patients (18.0%) in the aprepitant
> group had a serious adverse experience compared with 14 out of 101
> patients (13.9%) in the standard therapy group. The following table
> displays the serious adverse events by body system for patients who
> received gemcitabine in combination with cisplatin.

Table 8

![](media/image11.png){width="3.3243055555555556in"
height="6.361111111111111in"}

(Ref Table E-131 ISS.pdf)

> Overall, the incidence of serious adverse experiences in this
> subpopulation was similar between treatment groups. Neutropenia was
> reported as a serious adverse event in 1 patient from each group.
> Although the incidences of febrile neutropenia and thrombocytopenia as
> serious adverse events were small, they were only reported in the
> aprepitant group.

On analyzing the data, there was little difference seen in the safety
profile of gemcitabine between treatment groups.

[Vinorelbine tartrate]{.underline} (CYP3A4 substrate)

A total of 158 patients were treated with vinorelbine tartrate in
combination with cisplatin: 82 in the aprepitant group and 76 in the
standard therapy group. Thirteen out of 82 patients (15.9%) in the
aprepitant group had serious adverse experiences compared to 8 out of 76
patients (10.5%) in the standard therapy group. The following table
displays the serious adverse events by body system for patients who
received vinorelbine tartrate in combination with cisplatin.

![](media/image12.png){width="4.179861111111111in"
height="3.6631944444444446in"}

Table 9

> (Ref Table E-133 ISS.pdf)
>
> Table 9 (cont)
>
> ![](media/image13.png){width="4.070138888888889in"
> height="3.2631944444444443in"} (Ref Table E-133 ISS.pdf)

The incidence of serious adverse experiences were higher in the
aprepitant group than the standard therapy group (15.9% VS 10.5%
respectively).

> The incidences of serious hematologic adverse events were similar in
> both treatment groups. Neutropenia was reported as a serious adverse
> event in 2 patients in the aprepitant group compared to 1 in the
> standard therapy group.
>
> Febrile neutropenia and thrombocytopenia were not reported as a
> serious adverse event in either group.
>
> Infection was reported in 15 out of 82 patients (18.3%) and 9 out of
> 76 patients (11.8%) in the aprepitant and standard therapy groups,
> respectively. Of these adverse experiences of infections, 6 were
> described as serious: 4 (4.9%) in the aprepitant group and 2 (2.6%) in
> the standard therapy group.
>
> The incidence of fever as serious adverse event was smaller in the
> aprepitant group than the standard therapy group. Only one patient
> (1.3%) in the standard therapy group reported a serious adverse
> experience of fever.
>
> Review of the data demonstrated a notable difference in the incidence
> of serious adverse events involving the respiratory system. Six of 82
> patients (7.3%) in the aprepitant group compared to 1 out of 76
> patients (1.3%) in the standard therapy group experienced a serious
> adverse event involving the respiratory system.
>
> None of the patient receiving standard therapy reported respiratory
> insufficiency, whereas 4 patients in the aprepitant group developed a
> fatal respiratory insufficiency. These 4 patients (ANs 5097, 5109,
> 5114, and 6088) were randomized at the same study site (Site 018 in
> Protocol 054). The Applicant conducted an audit. The investigator
> reported that the cases of respiratory insufficiency represented
> progression of underlying malignant disease (lung cancer) and did not
> consider the events to be drug related. Analyzing the data suggests
> that these deaths were not related to the patient developing either
> pneumonia or pleural effusions.
>
> In addition to these four fatalities, 3 additional deaths (7) occurred
> in the aprepitant group. There were 2 fatalities in the corresponding
> standard therapy group.
>
> Analysis of the data does not suggest that the aprepitant regimen
> increased the hematologic toxicity of vinorelbine tartrate. However,
> twice as many patients in the aprepitant regime developed a serious
> infection. There were 3 reported cases of sepsis or septic shock as
> serious adverse events in the aprepitant group compared to no cases in
> the standard therapy.
>
> The Agency noted that the aprepitant regimen may have increased the
> pulmonary toxicity of vinorelbine tartrate, since all the fatal cases
> of respiratory insufficiency occurred in the aprepitant group. Given
> that no formal drug-drug interaction PK study was completed for
> vinorelbine tartrate (CYP3A4 substrate), the Agency seeks the opinion
> of the Committee whether PK studies should be performed.

[Paclitaxel]{.underline} (CYP3A4 substrate)

A total of 110 patients were treated with Paclitaxel in combination with
cisplatin: 52 in the aprepitant group and 58 in the standard therapy
group. Seven out of 52 patients (13.5%) in the aprepitant group had
serious adverse experiences compared to 6 out of 58 patients (10.3%) in
the standard therapy group. The following table displays the serious
adverse events by body system for patients who received Paclitaxel in
combination with cisplatin.

Table 10

![](media/image14.png){width="4.746527777777778in" height="4.3875in"}

(Ref Table E-135 ISS.pdf)

> The incidences of serious hematologic adverse events were small and
> similar in both treatment groups. The only serious hematologic adverse
> event reported was febrile neutropenia, which occurred in one patient
> from each group.
>
> Incidences of prespecified adverse experiences were generally similar
> between treatment groups. Six out of 52 patients (11.5%) in the
> aprepitant group compared to 7 of the 58 patients (12.1%) receiving
> standard therapy reported infection as an adverse event.
>
> On analyzing the data, there was little difference seen in the safety
> profile of paclitaxel between treatment groups.

Cyclophosphamide

A total of 93 patients were treated with cyclophosphamide in combination
with cisplatin: 50 in the aprepitant group and 43 in the standard
therapy group. Three out of 50 patients (6.0%) in the aprepitant group
had serious adverse experiences compared to 3 out of 43 patients (7.0%)
in the standard therapy group. The following table displays the serious
adverse events by body system for patients who received cyclophosphamide
in combination with cisplatin.

Table 11

![](media/image15.png){width="4.106944444444444in"
height="3.5902777777777777in"}

(Ref Table E-137 ISS.pdf)

> Overall, the incidences of serious and non-serious adverse experiences
> were similar between treatment groups. However, serious and
> non-serious hematologic adverse events were more common in the
> aprepitant group. Four patients in the aprepitant group compared to 1
> patient receiving standard therapy reported a hematologic adverse
> event. The only serious hematologic adverse events in this population
> were reported in the aprepitant group (2 patients, 4.0%).

Incidences of prespecified adverse experiences were similar between
treatment groups. Eleven of the 50 patients (22.0%) in the aprepitant
group compared to 12 of the 43 patients (27.9%) in the standard therapy
group reported an adverse experience. The most frequently reported
prespecified adverse experience was infection.

Four out of 50 patients (8.0%) in the aprepitant group compared to 8 of
the 43 patients (18.6%) in the standard therapy group experienced an
adverse experience of infection. None of these infections were reported
as serious adverse experiences.

> On analyzing the data, the number of patients with hematologic adverse
> events are small, but the possibility of a small signal can not ruled
> out. Over all, there was little difference seen in the safety profile
> of cyclophosphamide between treatment groups.

[Doxorubicin]{.underline}

Eighty-one patients were treated with doxorubicin in combination with
cisplatin: 38 in the aprepitant group and 43 in the standard therapy
group. The following table displays the serious adverse events by body
system for patients who received doxorubicin in combination with
cisplatin.

> Table 12

![](media/image16.png){width="3.8402777777777777in"
height="3.379861111111111in"}

(Ref Table E-139 ISS.pdf)

> Out of these 81 patients, 14 out of 38 patients (36.8%) in the
> aprepitant group and 15 out of 43 patients (34.9%) in the standard
> therapy group had one or more prespecified adverse experiences.
>
> The incidences of infection were similar between treatment groups. Six
> out of 38 patients (15.8%) in the aprepitant group compared to 7 of
> the 43 patients (16.3%) in the standard therapy group. Similarly, the
> incidence of neutropenia was higher in the standard therapy group.
> Neutropenia was reported as an adverse event in 1 of the 38 patients
> in the aprepitant group (2.6%) compared to 6 of the 43 patients
> (14.0%) receiving standard therapy. The incidence of hematologic
> serious adverse events were only reported in the standard therapy
> group (2 patients, 4.7%). Overall, the incidence of serious adverse
> experiences was less in the aprepitant group than in the standard
> therapy group. Only 1 of 38 patients (2.6%) in the aprepitant group
> had serious adverse experiences compared to 5 out of 43 patients
> (7.0%) in the standard therapy group.
>
> The number of patients included in this analysis was small. However,
> on analyzing the data, there was little difference seen in the safety
> profile of doxorubicin between treatment groups.

####### 

####### Docetaxel (CYP3A4 substrate)

A total of 24 patients were treated with docetaxel in combination with
cisplatin: 11 in the aprepitant group and 13 in the standard therapy
group. The following table displays the serious adverse events by body
system for patients who received docetaxel in combination with
cisplatin.

Table 13

![](media/image17.png){width="4.053472222222222in"
height="3.4166666666666665in"}

(Ref Table E-141 ISS.pdf)

> Three of the 11 patients (27.3%) in the aprepitant group and 5 out of
> the 13 patients (38.5%) in the standard therapy group reported a
> serious adverse experience.
>
> The incidences of hematologic serious adverse events were balanced
> between treatment groups. Two patients from each group experienced a
> serious hematologic adverse event.

The numbers of patients in this sub-population were too small to permit
a meaningful analysis. Overall, the data does not suggest that the
aprepitant regimen in combination with cisplatin adversely affected the
safety profile of docetaxel.

######### Summary 

> The incidences of prespecified adverse experiences in the subgroup of
> patients who, in addition to cisplatin, received concomitant
> chemotherapy metabolized by CYP3A4, were generally similar in the 2
> treatment groups (30.1% and 28.3% in the aprepitant and standard
> therapy group, respectively). However, the incidence of infections was
> higher in the aprepitant group (15.4%) compared with the standard
> therapy group (10.0%).
>
> Overall, analysis of adverse events of individual chemotherapeutic
> agents did not identify a definite signal. There were small
> differences in the incidence of infection and hematologic adverse
> events that may represent a signal. The number of patients studied was
> too small to draw any definite conclusions. A possible concern
> identified during the review is the increased pulmonary adverse events
> associated with concomitant use of the aprepitant regimen and
> vinorelbine tartrate.

**ATTACHMENT TWO**

**CLINICAL PHARMACOLOGY AND BIOPHARMACEUTICS**

**SUMMARY**

Clinical Pharmacology and Biopharmaceutics

**1.1. Formulation:** The development program for aprepitant utilized
several different formulations of this drug including three tablet
formulations of aprepitant and an intravenous (IV) formulation of a
prodrug of aprepitant (L-758298) that were used in early clinical
studies. However the tablet formulations have low oral bioavailability
due to poor solubility of the drug. Subsequently, a nanoparticle capsule
formulation with enhanced bioavailability was developed for marketing
purposes. This nanoparticle capsule formulation was used in late Phase
IIb and all Phase III clinical studies. Critical drug interaction
studies were also conducted with this final formulation.

**1.2. Pharmacokinetics:**

###### **1.2.1. Absorption**

The absolute bioavailability of aprepitant from the nanoparticle capsule
formulation of 125 mg and 80 mg doses is 59% and 67%, respectively.
Plasma concentrations of aprepitant reach peak levels at 4 hours. The
pharmacokinetics are slightly nonlinear with approximately 25% higher
AUC at the 125 mg dose compared to the 80 mg dose. The pharmacokinetics
of aprepitant administered as a 3- or 5-day regimen (125 mg on Day 1 and
80 mg/day on subsequent days) show that plasma concentrations of
aprepitant are similar (for 3 --Day) or slightly higher (for 5-Day) on
the last day of dosing compared to Day 1. Following multiple dosing of
fixed doses (125 mg or 375 mg) over 28 days, the plasma concentrations
of aprepitant accumulate over the first 7 days and then decline from Day
7 to Day 28. The later decline in plasma concentrations may be due to
auto induction of cytochrome P450 3A4 enzyme by aprepitant.

##### 

##### **Food effect**

The capsule formulation did not have a significant food effect.

**1.2.2. Distribution**

Following intravenous administration, aprepitant had a mean apparent
volume of distribution of 66 L. It is more than 95% bound to plasma
proteins in healthy subjects.

1.2.3. Metabolism

Aprepitant undergoes extensive metabolism, primarily via - CYP3A4
mediated oxidation. Seven metabolites have been identified in human
plasma following oral administration of \[^14^C\]-aprepitant. The
metabolites are not likely to contribute significantly to the efficacy
of aprepitant because these metabolites are either inactive or weakly
active or are present at low levels relative to aprepitant.

1.2.4. Elimination

After IV administration of the prodrug, \[ ^14^C\]-L-758298 in humans,
approximately 45% and 58% of total radioactivity was excreted in feces
and urine respectively as metabolites of aprepitant. The prodrug was
shown to be completely and rapidly converted to aprepitant, *in* *vivo*.
No unchanged aprepitant was detected in urine. Overall, it appears that
aprepitant undergoes extensive metabolism and was primarily eliminated
via excretion of metabolites. Following intravenous administration,
aprepitant had mean plasma clearance of 84 mL/minute, and terminal
half-life of about 13 hours. The half-life was similar after oral
administration.

**1.2.5. Special Populations:**

### [Elderly]{.underline}

Compared to young adults ( 45 years), elderly subjects ( 65 years)
showed small increases of 36% and 24% in AUC and C~max~, respectively.

### [Gender]{.underline}

Compared to men, women had slightly lower (up to 16%) AUC and slightly
higher (up to 27%) C~max~.

### [Race]{.underline}

Slightly higher (20 to 30%) plasma concentrations of aprepitant were
noted in hispanic subjects compared to white or black subjects.

These differences in elderly, gender, and race were concluded as not
clinically significant by the sponsor and no dosage adjustment is
recommended in these groups.

#### *[Renal Insufficiency]{.underline}* {#renal-insufficiency .unnumbered}

Systemic exposure (AUC) of total aprepitant is lower (20 to 40%) in
patients with severe renal insufficiency and end stage renal disease
compared to healthy subjects with normal renal function. Since unbound
drug concentrations of aprepitant are similar in patients with renal
insufficiency compared to healthy subjects with normal renal function,
sponsor concluded that dosage adjustment is not necessary.

### [Hepatic Insufficiency]{.underline}

An increase of up to 20% in AUC was noted in patients with moderate
hepatic impairment compared to age matched control subjects with normal
hepatic function. No dosage adjustment is recommended for patients with
mild and moderate hepatic impairment. Pharmacokinetics of aprepitant in
patients with severe hepatic impairment were not studied.

# 1.3. Drug-Drug Interactions:

Aprepitant is extensively metabolized by CYP3A4. *In vitro* metabolism
studies and *in vivo* pharmacokinetic studies have shown that aprepitant
inhibits CYP450 3A4 on short term dosing (up to 5 days) and induces
CYP3A4 on chronic dosing (over 28 days). Several drug interaction
studies were conducted to investigate 1) The potential of aprepitant to
affect the pharmacokinetics of drugs metabolized by CYP3A4, CYP2C9, or
CYP2D6, 2) The potential of aprepitant to affect P-glycoprotein (P-gp)
mediated transport, 3) The effect of potent CYP3A4 inhibitors and
inducers on the pharmacokinetics of aprepitant. The results of the drug
interactions submitted in the NDA are briefly summarized in the
following table.

## Table. 1. Drug Interactions of aprepitant (AP).

+------------------------------------------+------------+-------------+
| **Drug**                                 | **Mean     | **Mean      |
|                                          | ratio of   | ratio of    |
|                                          | AUC\***    | C~max~\***  |
+------------------------------------------+------------+-------------+
| # Effect on aprepitant                   | 4.8        | 1.5         |
|                                          |            |             |
| Ketoconazole (potent 3A4 inhibitor)      | 2.0        | 2.0         |
|                                          |            |             |
| Diltiazem with 300 mg AP(moderate 3A4    | 1.5        | 1.2         |
| inhibitor)                               |            |             |
|                                          | 0.09       | 0.4         |
| Diltiazem with 100 mg IV L-758298        |            |             |
|                                          | 1.3 (day   |             |
| Rifampin (potent inducer)                | 1)         |             |
|                                          |            |             |
| Dexamethasone (3A4 substrate)            | 0.98 (Day  |             |
|                                          | 5)         |             |
+------------------------------------------+------------+-------------+
| # Effect of aprepitant                   | 2.3 (day   | 1.5 (day 1) |
|                                          | 1)         |             |
| ####### On CYP3A4 substrates             |            | 1.9 (day 5) |
|                                          | 3.3 (day   |             |
| Midazolam                                | 5)         | 1.5         |
|                                          |            |             |
| Diltiazem                                | 1.7        | 1.5         |
|                                          |            |             |
| Dexamethasone                            | 2.2        | 0.64        |
|                                          |            |             |
| Methylprednisolone (oral)                | 2.5        | 0.81        |
|                                          |            |             |
| Methylprednisolone (IV)                  | 1.34       | No effect   |
|                                          |            |             |
| Ethinyl estradiol (with 14 days of AP)   | 0.59       | No effect   |
|                                          |            |             |
| Norethindrone (with 14 days of AP)       | 0.91       | No effect   |
|                                          |            |             |
| Ondansetron (IV)                         | No effect  |             |
|                                          |            |             |
| Granisetron (oral)                       | No effect  |             |
|                                          |            |             |
| ####### Other isozymes                   | 0.89 INR   |             |
|                                          | (day 8)    |             |
| Warfarin (CYP2C9 substrate)              |            |             |
|                                          | 0.75       |             |
| Paroxetine (CYP2D6 substrate)            |            |             |
|                                          | No effect  |             |
| Digoxin (P-gp substrate)                 |            |             |
+------------------------------------------+------------+-------------+

\*Ratio of AUC or Cmax with and without the interacting drug, denotes
increase, denotes decrease.

The following are the main conclusions from the drug interaction
studies:

Conclusions relevant to the short term administration (up to 5 days)-

-   Aprepitant, upon short term administration (for 5 days) is an
    inhibitor of CYP3A4 and results in 2 to 3 fold increase in mean AUC
    of orally coadministered midazolam, a sensitive CYP3A4 substrate. In
    contrast, ketoconazole, a potent inhibitor of CYP 3A4 is known to
    increase the AUC of midazolam by 9 to 16 fold.

-   Aprepitant also increases the AUC of orally administered diltiazem
    and methyl prednisolone (not so highly specific substrates!) by
    about two fold.

-   Concomitant administration of aprepitant increased dexamethasone AUC
    by 2 fold. Therefore, dexamethasone dose in the clinical trials for
    the aprepitant (active) treatment group was approximately half of
    that used in the standard therapy (comparator) group.

-   Coadministration of aprepitant did not significantly affect the
    pharmacokinetics of intravenously administered ondansetron or orally
    administered granisetron. Drug interaction data with dolasetron is
    unavailable. However, dolasetron is known to be metabolized by
    multiple pathways including CYP2D6 and CYP3A4. Blood levels of
    hydrodolasetron (active metabolite of dolasetron) increased 24% when
    dolasetron was coadministered with cimetidine (nonselective
    inhibitor of cytochrome P-450) for 7 days, and decreased 28% with
    coadministration of rifampin (potent inducer of cytochrome P-450)
    for 7 days.

-   Potent CYP3A4 inhibitor, ketoconazole, inhibited the metabolism of
    aprepitant significantly resulting in a 5-fold mean increase in AUC
    of aprepitant, while a moderate CYP3A4 inhibitor, diltiazem resulted
    in about two fold increase. However, since all the three drugs in
    the aprepitant regimen are CYP3A4 substrates, coadministration of
    CYP3A4 inhibitors may result in increased concentrations of these
    drugs.

-   Potent CYP3A4 inducer, rifampin, reduced the plasma concentration of
    coadministered aprepitant by 90%. However, since all the three drugs
    in the aprepitant regimen are CYP3A4 substrates, coadministration of
    CYP3A4 inducers may result in decreased concentrations of these
    drugs.

-   Aprepitant is an inducer of CYP2C9; the ratio of International
    Normalized Ratio (INR) fold- change from baseline decreased by about
    11% on Day 8 following concomitant administration of aprepitant 125
    mg/80 mg three day regimen. The S-warfarin trough plasma
    concentration decreased by up to 34% by Day 8.

-   Aprepitant does not have significant effect on P-gp mediated
    transport as evidenced by no change in the pharmacokinetics of
    coadministered digoxin, a substrate of P-gp transporter.

##### Conclusions relevant to the long term administration (more than 7 days)-

-   On chronic administration, aprepitant is an inducer of CYP3A4 and
    resulted in a 40% reduction in levels of ethinyl estradiol (CYP3A4
    substrate).

-   Concomitant administration of two weeks of aprepitant tablet
    formulation (approximately comparable to 85 to 170 mg of the market
    formulation), resulted in slightly decreased (25%) AUC of paroxetine
    (CYP2D6 substrate). Mechanism for lowering of paroxetine
    concentrations is not understood because CYP2D6 isozyme is not known
    to be inducible enzyme. However, these results indicate the
    aprepitant does not inhibit the metabolism of CYP2D6 substrates.

**1.3.1. Potential of aprepitant to interact with chemotherapeutic
agents that are metabolized by CYP3A4 isozyme:**

The drug interaction study results in the NDA have shown that aprepitant
is an inhibitor of CYP3A4 on short term administration. Aprepitant
administered as 5 day regimen (125 mg on Day 1, 80 mg/day from Day 2 to
5) showed significant inhibition of CYP 3A4, as seen by 2 to 3 fold mean
increase in midazolam (highly specific substrate) AUC. Aprepitant also
resulted in a two fold increase in AUC of dexamethasone and diltiazem,
not so highly specific substrate of CYP3A4. Thus it is possible that
aprepitant (at the doses recommended in Emend) may result in a two to
three fold mean increase in the plasma levels of coadministered drugs
that are primarily metabolized by CYP 3A4.

There are many chemotherapeutic agents for which CYP 3A4 plays an
important role in their metabolism. Increase in chemotherapeutic agent's
plasma concentration due to inhibition of its metabolism by aprepitant
may result in significant toxicity of these agents. Some of the
chemotherapeutic agents that are known or suspected to be metabolized by
CYP3A4 isozyme include: docetaxel, paclitaxel, irinotecan, etopsoide,
vinorelbine, vinblastine, vincristine, ifosfamide, cyclophosphamide, and
imatinib. Unfortunately, adequate information regarding drug--drug
interactions is not available for many of these agents either from
sponsor's studies or published literature. Based on the sponsor's
background package for the AC meeting, there is an ongoing drug
interaction study which investigates the effect of aprepitant on
docetaxel (given intravenously), a chemotherapeutic drug primarily
metabolized by CYP3A4. Preliminary results with five patients suggest no
clinically significant interaction.

One study reported in the literature showed that ketoconazole increased
the exposure to SN-38, the active metabolite of irinotecan by 109% and
the article recommends up to four-fold reduction in dosage. Due to lack
of data from the controlled drug interaction study(ies) between Emend
and chemotherapeutic drugs and lack of sufficient information in the
literature about the effect of CYP3A inhibitors on chemotherapeutic
drugs, it is difficult to recommend any dosage adjustments/appropriate
precaution/warning in the label. However, clinical trial database
consists of patients who were administered some of these chemotherapy
agents metabolized by CYP3A4. For discussion on the safety database in
the Phase III clinical studies, please refer to the clinical review
section.

**1.4. QT analysis in Clinical Pharmacology studies:**

There was no prospectively planned, controlled clinical study to
evaluate the effect of aprepitant on QT interval. A comprehensive
analysis of the effect of aprepitant on QT~c~ interval was performed on
the EKG data collected in several clinical pharmacology studies.

Most of the QT interval readings consisted of automatic readings
measured at either one to two time points (4, or 8 hours) with capsule
formulation or more frequently with tablet or IV formulation (e.g., 0.5,
1, 2, 4, 8, and 24 hours).

Only 4 subjects in each of nanoparticle capsule clinical dose (4 of 86
subjects; 4.7%), nanoparticle capsule higher than clinical dose (4 of 43
subjects, 9.3%) and placebo treatment groups (4 of 43 subjects; 9.3%)
had QT~c~ interval increases from baseline 30 and 60 msec.

QT~c~ interval increases from baseline 30 and 60 msec were slightly
higher (8 subjects, 11.6%) for the early tablet formulation compared to
capsule formulation. For the L-758298 IV treatment, 9 subjects (of 80
subjects; 11.3%) and 1 subject (of 40; 2.5%) on placebo had QT~c~
interval changes 30 and 60 msec.

Only one subject had QTc interval \>500 msec at 24 hours following
administration of 800 mg tablet formulation. This subject also received
a single dose of 1200 mg with no prolongation of QT~c~.

In summary, the sponsor concluded that there were few, if any, outliers
of clinical concern and many of the subjects who are outliers had
subsequent higher doses of L-758298 or oral aprepitant with no changes
in QT~c~.

**1.5. Exposure-Response (PK/PD) information:**

The correlation between plasma concentrations of aprepitant and the
binding to brain NK~1~ receptors (measured by using positron emission
tomography (PET)) was assessed in two clinical pharmacology studies in
healthy young men. Based on the data from the two studies, there is good
correlation between plasma trough concentrations of aprepitant and its
binding to brain NK1 receptors. Based on the correlation, trough
concentrations of 10 ng/ml and 100 ng/ml produce NK~1~ receptor
occupancy of about 50% and 90%, respectively.

In Phase IIb dose ranging studies of CINV, submaximal antiemetic
efficacy was achieved at 40-mg/25 mg regimen, while maximum efficacy was
achieved with 125 mg/80 mg regimen and there was no apparent benefit at
the highest dose regimen of 375 mg/250 mg. Based on the pharmacokinetic
pharmacodynamic (PK/PD) correlation, trough concentrations from 375mg
/250 mg and 125-mg/80-mg regimens are predicted to provide \>95% NK~1~
receptor blockade, while 40 mg/25 mg results in approximately 80 to 89%
receptor occupancy. Based on the Phase IIb dose ranging studies and the
PK/PD relationship, the sponsor concluded that nearly complete (\>95%)
NK~1~ receptor blockade is required to obtain maximum antiemetic
efficacy of aprepitant and NK~1~ receptor blockade of 80 to 90% still
provides significant but less than maximal antiemetic efficacy.