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Public Assessment Report
Scientific discussion
RISENDROS 35 mg Tablet
Risedronate
CZ/H/0135/01/MR
Applicant: Zentiva, a.s., Prague, Czech Republic
This module reflects the scientific discussion for the approval of Risendros 35mg Tablet.
The procedures were finalised at 09-07-2007.
QUALITY ASPECTS
Introduction
Risendros 35 is presented in the form of film coated tablets containing 35 mg of the active
substance risedronate sodium. The excipients are cellulose microcrystalline, crospovidone,
magnesium stearate, hypromellose 2910/5, talc, macrogol 6000, titanium dioxide, ferric oxide
red and ferric oxide yellow.
The packaging for marketing of the tablets is Al/Al blister, consisting of hard and soft
(OPA/Al/PVC) aluminium foils. The blisters are packed in printed paper folding boxes, each
box contains a package leaflet.
Active Substance
Risedronate sodium is white to yellowish powder, it is freely soluble in water, slightly
soluble in methanol and in acetonitril. It shows polymorphism. A semicrystalline form is
produced by manufacturer of the drug substance.
There is no pharmacopoieal monograph for the drug substance. An in-house specification has
been proposed. An appropriate specification for risedronate sodium has been proposed.
Appropriate discussion has been presented on inorganic and organic impurities including
residual solvents. Analytical methods have been described and validated when noncompendial in accordance with ICH requirements.
Certificates of analysis have been provided for three production scale batches. Results comply
with the proposed specification and confirm the consistency of the process.
Primary bag made from polyethylene low density foil (LDPE) is inserted into polyethylene
bag coated with aluminium layer containing desiccant. The certificates of analysis have been
provided and they are satisfactory. The bags are stated to be manufactured from food grade
polymer beads complying with Commission Directive 2002/72/EC.
The degradation of the drug substance under the stress factors was investigated. Risedronate
sodium was found to be resistant against elevated temperature, light and alkaline agent,
significant decomposition occurs in the presence of oxidation and acidic agent.
Appropriate stability studies according to ICH guidelines have been carried out.
The stability data are acceptable, the drug substance remains well within specification for all
characteristics, throughout the study period for which data have been provided, and under all
conditions. No obvious trends in the results are apparent. The proposed re-test period of 1
year is acceptable in the stated container.
Medicinal Product
Pharmaceutical Development
The development of medicinal product has been sufficiently described; the essential similarity
with brand leader Actonel, Aventis product has been documented. The impurity profiles and
dissolution profiles were compared with the batches of Actonel 35.
Manufacturing of the product
The manufacturing process is stated to be standard. The manufacture and in-process controls
are fully described in the dossier. All physical and chemical properties which are critical for
quality of the product were monitored. The control tests (in-process controls) during
manufacture of the tablets are conducted; they are described with satisfactory acceptance
limits. Results of process validation on pilot scale batches have been submitted. Satisfactory
process validation scheme including sampling plan has been provided. It may be concluded
that the manufacturing process has been shown to be reliable and capable of consistently
producing a product that complies with pre-established quality and specifications.
Product specification
Satisfactory control tests are applied at the time of release and during shelf life. Release and
shelf life limits for the assay of risedronate sodium are in line with batch and stability data.
Limits for related substances are in line with ICH guidelines and stability data. Analytical
methods have been satisfactorily described and validated in accordance with regulatory
requirements.
Satisfactory batch analysis data have been provided for pilot scale batches manufactured in
both manufacturing sites.
Stability of the product
Stability trials were performed on the drug product according to the stability protocols and
ICH guidelines. The stability data show no evidence of chemical or physical degradation and
no change in dissolution. Based on the data, shelf life of 2 years without any special storage
conditions is proposed.
Discussion on chemical and pharmaceutical aspects
Information on development, manufacture and control of the drug substance and drug product
has been presented in a satisfactory manner. The results of tests carried out indicate
satisfactory consistency and uniformity of important product quality characteristics, and these
in turn lead to the conclusion that the product should have a satisfactory and uniform
performance in the clinic.
CLINICAL ASPECTS
This mutual recognition application concerns a generic version of Risedronate sodium. In this
Assessment Report, the name Risendros 35 mg is used.
Risedronate is a pyrindinyl-bisphosphonate that inhibits osteoclast bone resorption and
modulates bone metabolism. Absorption of risedronate after an oral dose is relatively rapid
and occurs throughout the gastrointestinal tract. Peak plasma concentrations are observed 0.5
to 2 hours after drug administration. The fraction that is absorbed after a single oral dose is
independent of the dose over the studied range (2.5 to 60 mg). Mean oral bioavailability is
0.63% for a tablet and it is bioequivalent to a solution. There is no evidence that risedronate is
systematically metabolized. The observed plasma terminal half-life for risedronate ranges
between 1 and 5 hours after oral administration of a 35 mg dose. The approved indications are
treatment of post-menopausal osteoporosis with the aim to reduce the risk of vertebral
fractures and treatment of established post-menopausal osteoporosis with the aim to reduce
the risk of hip fracture.
The originator product is Actonel (35 mg, film-coated tablet) by Aventis Pharma s.r.o.,
Prague, Czech Republic, authorised in the Czech Republic since 2003. The first authorization
was granted on 7.10.1999 in Sweden.
This is an abridged application. The applicant claims essential similarity, under Article 10.2(b)
of Directive 2001/83/EC, to Actonel, 35 mg, film coated tablets, Aventis Pharma s.r.o.,
Prague, the Czech Republic, authorised in the Czech Republic since 2003 (MANo 87/090/03C, marketing authorisation holder Aventis Pharma, Prague, the Czech Republic).
The application contains an adequate review of published clinical data. One bioequivalence
study has been conducted. Essential similarity has been sufficiently proven by the
bioequivalence study that complies with current requirements and by comparison of
dissolution and impurity profiles.
Quality of the product risendros 35 mg, and Actonel, 35 mg, film coated tablets and GMP
standards of manufacture have been sufficiently demonstrated.
The SPC of product Risendros, 35 mg, film coated tablets, corresponds to the SPC of
reference product.
To support the application, the applicant has submitted as report one bioequivalence study.
The primary objective of this study was to compare pharmacokinetics of new generic
risedronate formulation – Risendros 35 mg – and original product Actonel 35 mg in healthy
subjects.
This was a two-centre, randomized, single-dose, open-label, two-way crossover,
bioequivalence study to compare rate and extend of absorption of a test and a reference
risedronate, under fasting conditions.
After a supervised overnight fast of at least 10 hours, subjects were dosed on the morning of
January 7 and January 14 – with a washout of 7 days. Single oral dose (1 x 35 mg) was
administrated in each period with 240 ml of water. A controlled meal was served not less than
4 hours post-dose, fluids were not permitted for 2 hours before and after dosing.
A total of 18 blood samples (7 ml for each sampling time) were taken per period: pre-dose
and 0.167, 0.333, 0.50, 0.75, 1.00, 1.25, 1.50, 1.75, 2.00, 2.50, 3.00, 4.00, 5.00, 6.00, 8.00,
10.00, and 12.00 hours post-dose. The study was conducted in compliance with Protocol and
Good Clinical Practice Rules (GCP).
Subjects planned for this study were healthy males or females aged between 18 and 55 years;
light smokers or non-smokers; with body mass indices from 19 to 30 kg/m2. The sample size
was based on data from previous studies (with respect to intra-subject variability about 45%
and 50 % for AUC and Cmax respectively, ratio within 0.95 and 1.05, and 80% power study).
100 volunteers (55 females and 45 males) were dosed and enrolled in the study. 98 of them
completed the study and were included in the pharmacokinetic analysis. Mean age of studied
population was 34 years (range from 19 to 55), mean BMI reached 24.6 (range 19.4 – 29.7).
85 subjects were Caucasian, 10 American Hispanic, 3 Black and 2 were Asian. The majority
(88) was non-smokers, 12 volunteers smoked maximally 9 cigarettes per day.
The Bioanalytical Division of SFBC Anapharm analyzed risedronic acid in plasma samples
using a LC MS MS method. Quantification limit was 199.50 pg/ml and the sample analysis
range lied between 199.50 and 15960.00 pg/ml. The precision (between run coefficient of
variation of lower limit of quantification) was 5.26 % and the accuracy (between run %
nominal of LLOQ) reached 102.52 %.
Analysis of variance was carried out on untransformed data of T1/2 el and Kel, and on lntransformed data of AUC0-t, AUC0-inf, and Cmax at the α-level of 5%. Wilcoxon’s test was
performed on Tmax.
90% geometric confidence interval of the ratio (T/R) of least-square means from the ANOVA
of the ln-transformed AUC0-t, AUC0-inf, and Cmax should lie within 80 % to 125 % and 75 % to
133 %, respectively.
Based on the presented bioequivalence study Risendros 35 mg is considered bioequivalent
with Actonel 35 mg. Based on the review of data on quality, safety and efficacy the
application for Risendros 35mg, por.tbl.flm., in the treatment of post.menopausal osteoporosis
is approved.