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Dienogest

This draft guidance from the FDA outlines their recommendations for bioequivalence studies to assess generic versions of dienogest; estradiol valerate tablets. It recommends three studies be conducted: two single-dose, two-way crossover studies in healthy postmenopausal women under fasting and fed conditions using a 3 mg/2 mg tablet, and one such study using a 3 mg estradiol valerate tablet under fasting conditions. It provides details on the analytes and samples needed and states bioequivalence should be based on dienogest and adjusted total estrone levels. Waivers for alternative strengths are also recommended if proportional and dissolution testing results are acceptable.

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Ana Belga
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87 views

Dienogest

This draft guidance from the FDA outlines their recommendations for bioequivalence studies to assess generic versions of dienogest; estradiol valerate tablets. It recommends three studies be conducted: two single-dose, two-way crossover studies in healthy postmenopausal women under fasting and fed conditions using a 3 mg/2 mg tablet, and one such study using a 3 mg estradiol valerate tablet under fasting conditions. It provides details on the analytes and samples needed and states bioequivalence should be based on dienogest and adjusted total estrone levels. Waivers for alternative strengths are also recommended if proportional and dissolution testing results are acceptable.

Uploaded by

Ana Belga
Copyright
© © All Rights Reserved
We take content rights seriously. If you suspect this is your content, claim it here.
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Download as PDF, TXT or read online on Scribd
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Contains Nonbinding Recommendations

Draft Guidance on Dienogest; Estradiol Valerate

This draft guidance, once finalized, will represent the Food and Drug Administration's (FDA's)
current thinking on this topic. It does not create or confer any rights for or on any person and does
not operate to bind FDA or the public. You can use an alternative approach if the approach satisfies
the requirements of the applicable statutes and regulations. If you want to discuss an alternative
approach, contact the Office of Generic Drugs.

Active ingredient: Dienogest;Estradiol Valerate

Form/Route: Tablets/Oral

Recommended studies: 3 studies

1. Type of study: Fasting


Design: Single-dose, two-way crossover in-vivo
Strength: 3 mg/ 2 mg tablet of dienogest and estradiol valerate
Subjects: Healthy postmenopausal women
Additional Comments:
______________________________________________________________________________

2. Type of study: Fed


Design: Single-dose, two-way crossover in-vivo
Strength: 3 mg/ 2 mg tablet of dienogest and estradiol valerate
Subjects: Healthy postmenopausal women
Additional Comments:
______________________________________________________________________________

3. Type of study: Fasting


Design: Single-dose, two-way crossover in-vivo
Strength: 3 mg tablet of estradiol valerate
Subjects: Healthy postmenopausal women
Additional Comments:
______________________________________________________________________________

Analytes to measure (in appropriate biological fluid): Dienogest, estradiol, unconjugated


estrone, total estrone in plasma for combination tablets. Estradiol, unconjugated estrone, total
estrone for the single component tablet.

Please provide baseline correction for endogenous estradiol, unconjugated estrone and total
estrone in the analysis. Please measure baseline estradiol, unconjugated estrone and total estrone
levels at -1, -0.5 and 0 hours. The mean of the pre-dose levels should be used for the baseline
adjustment of the post-dose levels. Any negative values obtained from baseline correction should
be designated as zero (0) and any subject with baseline-adjusted pre-dose concentrations (at time
0 hour) greater than 5% of their Cmax should be excluded from the bioequivalence statistical
analysis and the 90% confidence interval based on the remaining subjects.

Recommended Dec 2010


Bioequivalence based on (90% CI): Dienogest and baseline-adjusted total estrone

Statistical analysis should be performed on data both with and without baseline
adjustment. Bioequivalence acceptance criteria will be based on baseline-adjusted results
only.

Waiver request of in-vivo testing: Dienogest; Estradiol valerate Tablets, 2 mg/2 mg


based on (i) acceptable bioequivalence studies on the 3 mg/2 mg strength, (ii) the
formulations are proportionally similar, and (iii) acceptable in vitro dissolution testing of
both strengths.

Estradiol Valerate Tablets, 1 mg based on (i) acceptable bioequivalence studies on the 3


mg strength, (ii) the formulations are proportionally similar, and (iii) acceptable in vitro
dissolution testing of both strengths.

Dissolution test method and sampling times:

Please note that a Dissolution Methods Database is available to the public at the OGD
website at http://www.accessdata.fda.gov/scripts/cder/dissolution/. Please find the
dissolution information for this product at this website. Please conduct comparative
dissolution testing on 12 dosage units each of all strengths of the test and reference
products. Specifications will be determined upon review of the application.

Recommended Dec 2010

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