CENTER FOR DRUG EVALUATION AND RESEARCH

APPLICATION NUMBER:

207968Orig1s000

CLINICAL PHARMACOLOGY AND BIOPHARMACEUTICS REVIEW(S)

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Clinical Pharmacology Review

NDA (SDN) 207968 Submission Date: July 21, 2016

\\CDSESUB1\evsprod\NDA207968\0000 PDUFA Date: May 21, 2017 Brand Name: Jadenu® Sprinkle granules Generic Name: Deferasirox Formulation/Strength: 90 mg, 180 mg, 360 mg Applicant: Novartis Submission Type: Original Proposed Dosing Regimens:

Transfusion iron overload, 14 mg/kg Non-transfusion dependent thalassemia, 7 mg/kg Adjust dose according to liver iron concentration (LIC) and serum ferritin.

Proposed Indications Treatment of chronic iron overload due to blood transfusions in patients 2 years of age and older. Treatment of chronic iron overload in patients 10 years of age and older with non-transfusion-dependent thalassemia syndromes (NTDT) and with a liver iron (Fe) concentration (LIC) of at least 5 mg Fe per gram of dry weight (Fe/g dw) and a serum ferritin > 300 mcg/L

OCP Review Team: Sriram Subramaniam, Ph.D., and Stacy Shord, Pharm.D. OCP Division: Division of Clinical Pharmacology V OND Division: Division of Hematology Products (DHP) 1 EXECUTIVE SUMMARY ............................................................................................................. 2

Recommendations ............................................................................................................................ 2 1.1 Post-Marketing Requirements and Commitments ........................................................................... 3 1.2

2 SUMMARY OF CLINICAL PHARMACOLOGY ASSESSMENT .............................................. 3 Pharmacology and Clinical Pharmacokinetics ................................................................................. 3 2.1 Dosing and Therapeutic Individualization ....................................................................................... 3 2.2

2.2.1 General dosing ............................................................................................................. 3 Outstanding Issues ........................................................................................................................... 3 2.3 Summary of Labeling Recommendations ........................................................................................ 3 2.4

3 COMPREHENSIVE CLINICAL PHARMACOLOGY REVIEW ................................................. 4 Overview of the Product and Regulatory Background .................................................................... 4 3.1 General Pharmacology and Pharmacokinetic Characteristics .......................................................... 5 3.2 Clinical Pharmacology Review Questions ....................................................................................... 5 3.3

3.3.1 What is the relative bioavailability of Jadenu Sprinkle granules compared to Exjade tablets? ......................................................................................................................... 5

3.3.2 Do the exposure-response relationships for safety support the proposed doses? ......... 6 3.3.3 What is the effect of food on the bioavailability of the deferasirox following

administration of Jadenu Sprinkle granules? What are the dosing recommendations

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regarding the administration of the Jadenu Sprinkle granules in relation to meals or meal types?................................................................................................................... 8

Is the bioanalytical method to assess deferasirox concentrations reliable? ...................................... 9 3.4 Did OSIS inspection of clinical and bioanalytical sites find the study data reliable for Agency 3.5

review?............................................................................................................................................. 9

TABLES AND FIGURES Table 1: Approved Dosing Regimen for Exjade tablets and Jadenu tablets ........................................................................ 4 Table 2. Overview of clinical pharmacology studies and additional analyses to support the Granule NDA ...................... 5 Table 3: Geometric mean ratios, 90% confidence intervals, and geometric means of deferasirox PK of Jadenu Sprinkle granules and Exjade tablets for oral suspension. ................................................................................................................. 6 Table 4: Effect of food on deferasirox exposure following administration of Jadenu Sprinkle granules ............................ 9 Figure 1: Time-concentration profiles of Jadenu Sprinkle granules (1080 mg) and Exjade tablets (1500 mg). ................. 6 Figure 2: Cmax distribution in healthy subjects for Exjade tablets, Jadenu tablets, and Jadenu Sprinkle granules .............. 7 Figure 3: Steady-state C2h with Jadenu tablets versus Cmax with the Jadenu Sprinkle granules .......................................... 8 1 EXECUTIVE SUMMARY Deferasirox is an iron chelator. Jadenu Sprinkle granules is a new formulation of deferasirox for the treatment of chronic iron overload in patients ≥ 2 years old due to blood transfusions, and in patients ≥10 years of age with NTDT and with a LIC ≥ 5 mg iron (Fe) per gram of liver dry weight (dw) and a serum ferritin > 300 µg/L. Currently, the following deferasirox formulations are approved for the same indications: • Exjade (NDA 021882) tablets for oral suspension: 125 mg, 250 mg and 500 mg on November 2, 2005;

and • Jadenu (NDA 206910) tablets for oral use: 90 mg, 180 mg, and 360 mg, on March 30, 2015.

Jadenu Sprinkle granules were developed to improve palatability and patient adherence.

The current review includes evaluation of relative bioavailability (RBA) of the Jadenu Sprinle granules compared to the Exjade tablets, and the effect of food on the BA of the Jadenu Sprinkle granules.

The following key questions were addressed in this review. • What is the RBA of Jadenu Sprinkle granules compared to Exjade tablets? • What is the effect of food on BA of the deferasirox following administration of Jadenu Sprinkle

granules? • Is the proposed dose and dosing regimen of Jadenu Sprinkle granules supported by the RBA study, the

food effect study and the exposure-response (E-R) relationship for safety?

Recommendations 1.1This NDA is approvable from a clinical pharmacology perspective, provided that the Applicant and the Agency come to an agreement regarding the labeling language, and the Office of Study Integrity and Surveillance (OSIS) inspection finds the clinical conduct of the RBA study acceptable. The Office of Clinical Pharmacology recommends approval of this NDA. Key review issues with specific recommendations and comments are summarized below:

• The recommended initial dose is 14 mg/kg/day with an increase up to 28 mg/kg based on serum ferritin for patients with transfusional overload, and 7 mg/kg with an increase up to 14 mg/kg in patients with NTDT and baseline LIC > 15 mg (initial therapy) or > 7 mg (after 6 months of therapy) Fe per gram of liver dw. The initial and maximum doses are supported by the RBA study and E-R analysis for safety.

• Jadenu Sprinkle granules is recommended to be taken on an empty stomach or light meal, and administered orally by sprinkling the contents on soft food immediately prior to use. This recommendation is supported by the food effect study.

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(b) (4)

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Post-Marketing Requirements and Commitments 1.2There are no post-marketing requirements or commitments.

2 SUMMARY OF CLINICAL PHARMACOLOGY ASSESSMENT Pharmacology and Clinical Pharmacokinetics 2.1

The pharmacokinetics (PK) of deferasirox was previously described in the clinical pharmacology review of Exjade tablets for oral suspension in the original NDA 021882 (DARRTS ID 3836843).

The following is a summary of the PK of Jadenu Sprinkle granules (also refer to Section 3.2). • The BA (based on dose-adjusted AUC) of deferasirox following administration of Jadenu Spring

granules was 52% higher than that of Exjade tablets.

• The mean AUCinf following a single 1080 mg dose of Jadenu Sprinkle granules was similar to that of a 1500 mg dose of Exjade tablets under fasting condition; however, the mean Cmax following a dose of Jadenu Sprinkle granules was 34% higher as compared to Exjade tablets. The difference is not clinically meaningful based on E-R analysis for safety. Similarly, the mean Cmax was higher following the same dose of Jadenu tablets and it was concluded that the differences in exposure were not clinically meaningful.

• The mean AUCinf and Cmax of deferasirox with a soft meal (e.g., yogurt and apple sauce) or low-fat meal (~450 calories with fat content ~30% of total calories), were similar to those under fasting conditions. Also, the increase in mean AUCinf with a high-fat meal (~1000 calories with fat content > 50% of total calories) was within 1.2-fold with no changes in mean Cmax compared to that under fasting conditions.

Dosing and Therapeutic Individualization 2.22.2.1 General dosing

The Applicant proposes an initial dose of 14 mg/kg/day and an increase in steps of 3.5 mg/kg or 7 mg/kg up to maximum dose of 28 mg/kg based on serum ferritin for patients with transfusional overload, and an initial dose of 7 mg/kg with an increase up to a maximum dose of 14 mg/kg based on LIC values for patients with NTDT. These proposed doses are the same doses listed in the approved labeling for Jadenu tablets, and 30% lower compared to doses listed in the approved labeling for Exjade tablets (refer to Section 3.1). The doses for the Jadenu products are different compared to that of Exjade tablets based on differences in relative bioavailability at the same dose. Jadenu Sprinkle granules is recommended to be taken on an empty stomach or with a light meal, and administered by sprinkling the contents on soft food.

The proposed dosing regimens for Jadenu Sprinkle granules are supported by the RBA study, the E-R analysis for safety, and the food effect study (refer to Section 3.3).

Outstanding Issues 2.3There are no outstanding issues at this time.

Summary of Labeling Recommendations 2.4The Office of Clinical Pharmacology recommends the following labeling concepts in the final package insert:

• In Section 2.3, o Included instructions to take Jadenu Sprinkle granules on an empty stomach or with a light meal.

Although there was no significant effect of a low-fat or high-fat meal on deferasirox PK of Jadenu Sprinkle granules, the above dosing instructions are recommended to be consistent with the dosing recommendation for Jadenu tablets and to avoid confusion.

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Table 2. Overview of clinical pharmacology studies and additional analyses to support the Granule NDA

Studies F2104, F2105 & F2106 used 400 mg strength granules

General Pharmacology and Pharmacokinetic Characteristics 3.2The mechanism of action and PK of deferasirox was previously described in the clinical pharmacology review in the original NDA 021882 (DARRTS ID 3836843).

The following is a summary of the clinical PK of Jadenu Sprinkle granules:

• The exposure appears dose proportional between doses of 400 mg and 1200 mg.

• The BA (based on dose adjusted AUC) of Jadenu Sprinkle granules was 52% greater than that of Exjade tablets.

• The mean AUCinf of deferasirox following a 1080 mg dose of Jadenu Sprinkle granules was similar to that of Exjade tablets following a 1500 mg dose under fasting conditions. The Cmax following the Jadenu Sprinkle granules was 34% higher compared to that of Exjade tablets. The difference is not clinically meaningful based on E-R analysis for safety following administration of deferasirox tablets (Exjade tablets or Jadenu tablets).

• With a soft meal (e.g., yogurt and apple sauce) or a low-fat meal (~450 calories with fat content ~30% of total calories), the mean AUCinf and Cmax were similar to those under fasting conditions. With a high-fat meal (~1000 calories with fat content > 50% of total calories), the mean AUCinf increased by 1.2 fold with no changes in Cmax compared to those under fasting conditions.

Clinical Pharmacology Review Questions 3.33.3.1 What is the relative bioavailability of Jadenu Sprinkle granules compared to Exjade tablets?

The BA (based on dose-adjusted AUC) of deferasirox following administration of Jadenu Sprinkle granules was 52% greater compared to that of Exjade tablets for oral suspension. The mean AUCinf of Jadenu Sprinkle granules at a dose of 1080 mg was equivalent to that of Exjade tablets at a dose of 1500 mg under fasting conditions.

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Figure 3: Steady-state C2h with Jadenu tablets versus Cmax with the Jadenu Sprinkle granules

Source: Applicant’s Biopharmaceutics Summary, Figure 3.10 3.3.3 What is the effect of food on the bioavailability of the deferasirox following administration of

Jadenu Sprinkle granules? What are the dosing recommendations regarding the administration of the Jadenu Sprinkle granules in relation to meals or meal types?

The food-effect study (see Table 4) support taking Jadenu Sprinkle granules on an empty stomach or with a light meal, as deferasirox exposure (AUCinf and Cmax) with a low-fat (~450 calories with fat content ~30% of total calories) were similar to that under fasting conditions. Although, the food-effect study supports taking Jadenu Sprinkle granules with low-fat meal, and indicates no clinically meaningful effect of a high-fat meal on deferasirox PK of Jadenu Sprinkle granules, a light meal is recommended to maintain consistency with administration of Jandeu tablet formulation with food and to avoid confusion.

Administering Jadenu Sprinkle granules by sprinkling the contents on soft food immediately prior to use is supported by the food effect study as the deferasirox exposures with soft foods (yoghurt or apple sauce) were similar to that under fasting conditions.

The effect of food on Jadenu Sprinkle granules was evaluated in Study F2106: a single dose (1200 mg: 400 mg x 3), two-arm, three-way crossover study in healthy subjects (n=24 per arm). Arm 1 included fasted (A), with yogurt (B), and with apple sauce (C) treatments. Arm 2 included fasted (A), low-fat meal (D), and high-fat meal (E) treatments. The results show that deferasirox exposures with soft foods or a low-fat meal were within the bioequivalence limits compared to those under fasting conditions. Further, the increase in mean AUCinf and AUC0-t were within ~1.2 fold (90% CI outside the upper bioequivalence limit) with a high fat meal, with no changes in Cmax.

Reference ID: 4083952

---------------------------------------------------------------------------------------------------------This is a representation of an electronic record that was signedelectronically and this page is the manifestation of the electronicsignature.---------------------------------------------------------------------------------------------------------/s/----------------------------------------------------

SRIRAM SUBRAMANIAM04/13/2017

STACY S SHORD04/13/2017I concur.

Reference ID: 4083952