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Journal of Bioequivalence & Bioavailability
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ISSN: 0975-0851 y

Research Article

Single Dose Bioequivalence Study of Two Rivaroxaban Tablet Formulations,

Administered Orally after Being Crushed and Suspended in Apple Puree
Simona Nicoleta Duna1*, Adrian Ghita1, Adelina Ciuciuleaca2, Irene Manzanera3, David Puibert3, Simona
Rizea-Savu4
1
3S-Pharmacological Consultation & Research SRL, Bucharest, Romania; 2Pharma Serv International SRL, Bucharest, Romania; 3Ferrer
Internacional S.A. (Ferrer Grupo), Barcelona, Spain; 43S-Pharmacological Consultation & Research GmbH, Harpstedt, Germany

ABSTRACT
The bioavailability of an active substance might be altered when a solid oral dosage form (SODF) is crushed or
disintegrated and mixed with fluids or food in order to assist swallowing. In consequence, the current European
Medicines Agency (EMA) practice is to request comparative bioavailability testing for bridging safety and efficacy
data from a formulation administered whole to the same product administered crushed. Specific criteria for waiving
in vivo testing of crushed products are available only for BCS Class I and Class III drugs. Since rivaroxaban is a Class
II drug which can be administered crushed and mixed with fluids, any generic formulation has to be tested against
the originator in this setting. Therefore, an open label, randomized, single dose, two-period, two-sequence, crossover
bioequivalence study with administration of rivaroxaban 10 mg crushed tablets suspended in apple puree was
conducted in 24 fasting healthy volunteers. Both rivaroxaban treatments were well tolerated by the study subjects. A
standardized, dose efficient and fully reproducible protocol for grinding, mixing and administering investigational
medicinal products was developed and applied. Assessment of bioequivalence was based on plasma concentrations
of parent rivaroxaban, quantified using a validated HPLC/MS/MS method. The 90% confidence intervals for
Cmax and AUC0-t least square mean T/R ratios were within the bioequivalence acceptance range of 80% to 125%.
Results from the present study reinforced the bioequivalence conclusion reached for the same test and reference
products following administration of whole tablets in fasting state. No notable changes in bioavailability occurred
when rivaroxaban tablets were crushed, immediately dispensed in 70 mL apple puree and quantitatively (entire dose
recovered) administered to fasting volunteers.
Keywords: Rivaroxaban; Crushed tablets; Crushed versus whole; Comparative bioavailability; Generic; Bioequivalence

INTRODUCTION bridging safety and efficacy data from the formulation administered
whole to the crushed product [2]. For innovative products, the
Rivaroxaban is a highly selective direct factor Xa inhibitor which bioavailability comparison must be carried between the SODF
exerts its antithrombotic effect by interrupting the intrinsic and taken whole versus the same dosage form crushed and mixed with
extrinsic pathway of the blood coagulation cascade, thus inhibiting the fluid/food to be included in the SmPC recommendations for
thrombin formation and development of thrombi [1]. For patients administration. For generics, bioequivalence to the originator must
who are unable to swallow whole tablets, the originator rivaroxaban be shown for the SODF administered whole and also for at least
(Xarelto of Bayer AG, Germany) provides the option of crushing one of the crushed-mix alternatives available in the SmPC of the
the tablets and mixing them with water or apple puree immediately originator. This requirement stems from the observation that a
prior to their oral administration. Since the bioavailability of an test product that is shown to be bioequivalent when administered
active substance may be altered if a solid oral dosage form (SODF) as a whole tablet in fasted state may exhibit significantly different
is crushed or disintegrated and mixed with fluids or food in order bioavailability compared to the reference product when both are
to assist swallowing, the current European Medicines Agency administered crushed/disintegrated and dispersed in food [2]. The
(EMA) practice is to request comparative bioavailability testing for likelihood of a formulation-specific change in bioavailability at

Correspondence to: Simona Nicoleta Duna, Research Project Manager, 3S-Pharmacological Consultation & Research SRL, Romania, Tel: +40 758 109
202; E-mail: [Link]@[Link]
Received: January 29, 2019, Accepted: February 18, 2019, Published: February 25, 2019
Citation: Duna SN, Ghita A, Ciuciuleaca A, Manzanera I, Puibert D, Savu SR (2019) Single Dose Bioequivalence Study of Two Rivaroxaban
Tablet Formulations, Administered Orally after Being Crushed and Suspended in Apple Puree. J Bioequiv Availab 11:388. doi: 10.35248/0975-
0851.19.11.388
Copyright: © 2019 Duna SN, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which
permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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crushing is considered low enough to waive bioequivalence testing with a washout period of 10 days between crossover doses. Both
in crushed state only if the following conditions are simultaneously study products were orally administered crushed and mixed with
met: bioequivalence of uncrushed products is demonstrated, the 70 mL apple puree, after at least 10 hours of overnight fasting (see
active ingredient is highly soluble and stable in the pH-range of Investigational Products and Administration Method). Except for
the gastrointestinal tract according to BCS-based biowaiver criteria 130 mL of rinsing still bottled water administered after intake
(drugs included in Class I or III); surface active excipients do not of the rivaroxaban-puree suspension, drinking of water or other
differ qualitatively nor quantitatively between test and reference fluids was restricted from one hour prior to dosing until one
and no specific formulation characteristics or manufacturing hour post dosing. For the analytical determination of rivaroxaban
technologies differ; disintegration time is comparable between test plasma levels, venous blood samples of 5 mL were drawn in
and reference; dissolution profiles are similar between test and tubes containing K3EDTA as anticoagulant before study drug
reference product at pH 1.2, 4.5 and 6.8. Being a BCS Class II administration and at 0.167, 0.50, 0.75, 1.00, 1.50, 2.00, 2.50,
drug [3], rivaroxaban did not fulfil the waiver criteria for crushed 3.00, 3.50, 4.00, 4.50, 5.00, 5.50, 6.00, 7.00, 8.00, 10.00, 12.00,
bioequivalence testing. Therefore, after successful demonstration 16.00, 24.00, 36.00, 48.00 and 72.00 hours post dose in each study
of bioequivalence between the test product (Rivaroxaban 10 period. The primary pharmacokinetic parameters considered for
mg film-coated tablets of Ferrer Internacional S.A., Spain) and bioequivalence assessment were AUC0-t and Cmax.
Xarelto® 10 mg film coated tablets in a single-dose pivotal study The study was conducted following unconditional approval from
with administration of whole tablets in fasting state, a second study the National Ethics Committee, the Ethics Committee of the
with crushed tablets was also performed. The latter was an open Clinical Hospital of the Ministry of Health of the Republic of
label, two-period, two-sequence, two-way crossover, randomized, Moldova and the Medicine Agency. Clinical investigations were
single dose bioequivalence study with crushed rivaroxaban tablets, conducted according to the Declaration of Helsinki principles and
conducted in healthy volunteers under fasting conditions. One Good Clinical Practice.
of the biggest challenges faced during pre-trial preparations was
the development of a standardized procedure for crushing the Investigational products and administration methods
tablets, mixing the disintegrated particles with apple puree and
The Reference product, Xarelto® 10 mg film coated tablets (Bayer
administering the resulting suspension without product loss, cross- Schering Pharma AG, Germany) was sourced from the German
contamination or risk of bias due to an uneven size of crushed market. The Test product, Rivaroxaban 10 mg film-coated tablets,
particles. The first step of this process involved the testing of 15 was manufactured by Ferrer Internacional S.A. (Ferrer Grupo) in a
different tablet crushing or grinding devices commonly used in GMP production facility located in Spain.
clinical practice (ranging from hand-held lever or rotating crushers
made of plastic or metal, mortar and pestle, bench top manually In each study period either one crushed film-coated tablet of test
operated vertical or horizontal pressing devices, and electric pill or one crushed film-coated tablet of reference, suspended in 70 mL
grinders). The criteria for evaluation of suitability were: likelihood apple puree, was administered to each subject. Dose preparation
of variability stemming from multiple repetitions of the procedure and administration: Preparation of the apple puree - crushed tablet
(devices that require application of force by a human operator suspension was done for each subject within 5 minutes prior to
yield good results in terms of particle size for the first subjects, dosing. A new 100 mL apple puree pouch was unsealed for each
but performance is likely to decrease over time due to tiredness), subject and a volume of 70 mL puree at room temperature was
recoverability of the grinded product, availability of single use precisely measured in a 100 mL tall Berzelius beaker. A new
glass beaker was used for each subject. After a thorough check of
accessories, and homogeneity of crushed particles in terms of
individual labeling, identity and integrity of each tablet, it was placed
size. The best results were obtained with one of the automated
in a single use grinding cup and covered with a single use round
professional pill grinders, which was subsequently used in the
foil. Then the whole ensemble was inserted in the professional
study according to very detailed instructions for standardization of
pill grinder and submitted to a full automated grinding cycle. The
dose preparation and administration (see Materials and Methods).
grinded rivaroxaban was transferred to the tall Berzelius beaker
MATERIALS AND METHODS containing 70 mL apple puree and mixed vigorously for precisely
30 seconds. The labeled administration beaker, the utensil used for
Study design and participants mixing, the individual packaging of the tablet used for preparation,
the cup and the discus used for grinding were all placed in a single
An open label, randomized, single dose, two-period, two-sequence, use tray and handed over to the administration team. The team
crossover bioequivalence study with administration of crushed supervising the administration was comprised of two physicians
tablets suspended in apple puree was conducted in 24 fasting healthy (the Clinical Investigator and Study Monitor). Before handing
male and female volunteers. All subjects were adults (18 years or the glass beaker to the subject for self-administration, the beaker
older) with a body mass index within 18.5 to 30.0 kg/m2, who did and secondary package labeling were checked once more against
not suffer from rare hereditary problems of glucose intolerance, the the randomization table and subject bracelet and tag. Once the
Lapp lactase deficiency, glucose-galactose malabsorption or gluten subjects were handed the rivaroxaban in apple puree suspension
intolerance. All subjects gave their written informed consent and told that they could start to eat, full intake was achieved
before they underwent any study-related procedures and were within 1 minute. After full intake of the rivaroxaban-apple puree
free to withdraw from the trial at any time. The study medication suspension, the administration beaker and teaspoon as well as the
administration consisted of one single 10 mg rivaroxaban film- grinding cup and disk were rinsed with 65 mL of water which was
coated tablet (test or reference formulation) in each study period, drank by the subject; then, the procedure was repeated once more

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bringing the total volume of room-temperature rinsing still bottle were used for sample processing. Eight-point calibration curves
water drank by each subject to 130 mL. All the transparent single were prepared in appropriate matrix (pooled human plasma
use labware used for preparation and dosing was clean after the deriving from blank blood samples collected on K3EDTA from
second rinsing cycle, thus confirming that the full medication dose healthy volunteers were spiked with internal standard, processed
was successfully administered to each subject (Figure 1). and diluted according to the same protocol previously described for
study samples). The concentration range of the calibration curve
Handling and bioanalysis of study samples was 1.0 - 800.0 ng/mL (lower limit and respectively upper limit
of quantification for the analytical method). Spiked QC samples
For the quantification of rivaroxaban, venous blood samples of
were prepared at the following concentrations: 3.0, 64.0, 160.0,
approximately 5 mL were collected in labelled tubes containing
K3EDTA as anticoagulant. After collection, the blood samples were 320.0 and 640.0 ng/mL. Calibration curves and QC samples were
centrifuged under refrigeration (10 minutes at 1500 (± 5) g and a analyzed during each analytical sequence. Analyses were carried
nominal temperature of 4°C). Plasma was separated, divided into out on a MPX-2 multiplexing HPLC system (Applied Biosystems-
duplicate aliquots and, within 60 minutes from collection, frozen for Sciex, Canada) comprised of an autosampler (HTS PAL of CTC
storage at –20°C nominal until shipped to the analytical laboratory. Analytics, Switzerland) with 2 injection valves that permitted
Plasma samples (first aliquot) were sent from the clinical site to the injection into 2 separate HPLC columns, each of them connected
analytical facility in a thermo-insulated box containing an adequate to a high pressure gradient system (Schimadzu Prominence of
amount of dry ice. During transport, an electronic logger was used Shimadzu, Japan). A selector valve was connected to the exit of each
for monitoring plasma samples temperature. Once received at the column, permitting to alternatively introduce the mobile phase in
analytical laboratory, the samples were stored at –20°C or colder the LC-MS source. The software MPX-2 controlled all functions
until submitted to analysis. Before analysis, plasma samples were of the multiplexing, keeping a clear audit-trail of the operations,
thawed, mixed for 3 minutes and centrifuged for 3 minutes at sample by sample. A triple quadrupole MS/MS mass spectrometer
4000 rpm and 20ºC nominal. Aliquots of samples were spiked model API 6500 (Applied Biosystems-Sciex, Canada) equipped
with internal standard ([13C6]-rivaroxaban), diluted, vortexed and with atmospheric pressure electrospray ionization interface (Turbo-
centrifuged. Supernatants were diluted with ammonium acetate in Spray ion Drive) was used. Each analytical sequence, composed of
water + 0.1% formic acid solution, mixed and centrifuged again. calibration curve, quality controls and study samples, was injected
Finally, the samples have been transferred to the autosampler, in a single column, to avoid the risk of differences in quantitation
awaiting [Link] analytical and internal standard used for between the 2 columns, and 2 sequences were run in parallel. To
HPLC-MS/MS determinations were rivaroxaban and respectively minimize idle time between injections only the periods of peaks
[13C6]-rivaroxaban (both purchased from AlsaChim, France). elution of each sample were acquired, and samples were injected
Commercially available reagents of analytical/HPLC grade purity overlapping the initial part of the chromatograms as well as the

Figure 1: Representative snapshots of the preparation and rinsing processes

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final equilibration, when data acquisition was not needed, with the RESULTS AND DISCUSSION
recording of peaks from the sample running in parallel.
Pharmacokinetic results
Reversed phase analytical columns Ascentis Express C18, 10 cm*
2.1 mm, 2.7 μm silica packing (Supelco, Germany) were used, This study aimed to compare the relative bioavailability of one
heated at 40ºC nominal. The sample extracts were injected on the generic rivaroxaban film-coated tablet formulation versus the
column eluted at 0.4 mL/min. Separations were carried out in marketed reference product Xarelto®, administered after being
isocratic conditions. The injection volume was 50 μL. Quantitative crushed and mixed with 70 mL apple puree. Since the SmPC
of the reference product did not offer any specific information
data were acquired in positive ions mode using a multiple reaction
regarding the volume of fluid in which one crushed tablet should
monitoring method (MRM). The MRM transitions considered be dispersed, the administration conditions were selected in
were 436.032/ 145.000 for rivaroxaban and 442.021/ 145.000 for accordance to publicly available data from the bioequivalence study
[13C6]-rivaroxaban. The analytical method was fully validated as per of Xarelto®-crushed versus Xarelto®-whole which was conducted by
the latest EMA and FDA requirements [4,5] before the start of the originator company (crushed products suspended in a precisely
analysis of the study plasma samples. The method was verified for measured 70 mL volume of apple puree) [6]. The preparation,
linearity, quantification limits, assay specificity, between-run and administration and rinsing protocols developed in-house ensured
within-run precision and accuracy, analyte recovery, and stability in the homogeneity of crushed particles and reduced to a minimum
the risks of cross-contamination and product loss.
stock solution and biological matrix under processing conditions
during the entire period of storage. The analytical protocol was A total of 24 healthy male and female volunteers were enrolled
prepared prior to the start of bioanalysis. Analytical work was in the study. All subjects were Caucasian with the mean age of
performed blindly (without access to the randomization list) and 30.38 years (range 18-49 years) and mean BMI of 24.10 kg/m2
(range 18.7- 29.8 kg/m2). After the first study period, two subjects
according to Good Laboratory Practices (GLP). The bioassay
exercised their right to withdraw from the study (for personal
reproducibility was assessed through incurred samples reanalysis. reasons, unrelated to the study medication). The Per Protocol
Pharmacokinetic and statistical analysis Safety Population was comprised of all 24 subjects enrolled and
treated with at least one dose of study medication (drop-outs after
Non-compartmental PK analysis was performed using SAS® Period I included). The Per Protocol PK Population was comprised
statistical software, version 9.4 (SAS Institute Inc., USA).Maximum of the 22 subjects who completed both study periods and provided
plasma concentration (Cmax) and time to reach maximum plasma fully evaluable pharmacokinetic profiles. The mean rivaroxaban
concentration-time curves after test and reference are shown in
concentration (Tmax) were obtained directly from the plasma values
Figure 2 while mean pharmacokinetic parameters are summarized
(observed, not calculated). The linear trapezoidal rule was used to
in Table 1.
calculate the area under the concentration-time curve from time
zero to the last quantifiable concentration (AUC0–t). The apparent The mean rivaroxaban pharmacokinetic curves were remarkably
similar, to the point where scaling of the plots was needed (data
elimination rate constant (Kel) was estimated by regression of
display truncated at 48 hours) in order to develop graphs in which
the terminal ln-linear portion of the plasma concentration–time
the reader can distinguish between the two almost superimposable
profile; apparent terminal half-life (t½) was calculated as the profiles. The analysis of variance (ANOVA) did not show any
quotient of ln (2) and Kel. Area under the curve to infinity (AUC0–∞) statistically significant difference between the test and the reference
was estimated as the sum of AUC0–t and the extrapolated area given formulations with respect to the fixed effects of period, sequence
by the quotient of the last quantifiable plasma concentration and and treatment on the pharmacokinetic parameters analyzed (Cmax,
Kel. ANOVA was performed on ln-transformed Cmax, AUC0-t and AUC0-t and AUC0-∞). The subject within sequence fixed effect
AUC0–∞ using the General Linear Models (GLM) procedure fitted was statistically significant (p<0.05) for all three pharmacokinetic
in SAS® software (version 9.4) using the method of least squares. parameters analyzed. It is worth noting that this effect is almost
The confidence interval for the ratio of the population means was always statistically significant as it only indicates that the enrolled
subjects have different physiological characteristics [7], heterogeneity
calculated considering a classic (shortest) 90% confidence interval.
being key when a test group is intended to be representative
The bioequivalence acceptance range was set to 80.00-125.00%
for the general population. Identical median Tmax values were
for rivaroxaban. The effect of sequence, period, subject within obtained for the two treatments (Table 1) and the statistical test
sequence and treatment on rivaroxaban Cmax, AUC0-t and AUC0–∞ (Wilcoxon Signed-Rank) applied to untransformed individual
has been separately evaluated on ln-transformed data. The intra- data further demonstrated that there is no statistically significant
subject variability (ISCV) of Cmax, AUC0-t and AUC0–∞ was also difference between treatments with respect to time needed to
separately determined. The bioequivalence comparison has been reach maximum plasmatic concentration. The point estimates of
carried out on the primary pharmacokinetic parameters Cmax and rivaroxaban pharmacokinetic. ln-transformed parameters and the
AUC0-t, while the data presented for AUC0–∞ can be regarded as 90% confidence intervals for the ratios of the population means,
supporting evidence. Tmax data have been compared using the along with the intra-subject CVs registered are shown in Table 2.
non-parametric Wilcoxon Signed-Rank Test. The test was applied The statistical evaluation of pharmacokinetic data presented herein
to untransformed data. The limit of statistical significance was shows that the two rivaroxaban formulations are bioequivalent as
considered p<0.05. the test-reference ratios for the geometric means (%) of the primary

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Figure 2: Rivaroxaban mean pharmacokinetic curves after test and reference (linear-linear and ln-linear display)

Table 1: Mean Pharmacokinetic Parameters for rivaroxaban 10 mg crushed and mixed with 70 mL apple puree (N=22).
PK parameter Data presented Test (T) Reference (R)
Cmax (ng/mL) Mean (±SD) 158.357 (29.752) 160.454 (42.644)
AUC0-t (ng*h/mL) Mean (±SD) 1077.053 (280.839) 1102.087 (315.683)
AUC0-∞ (ng*h/mL) Mean (±SD) 1100.902 (279.597) 1124.025 (317.889)
Tmax (h) Median (Range) 2.0 (0.5 – 3.0) 2.0 (0.5 – 5.0)
Kel (1/h) Mean (±SD) 0.103 (0.037) 0.106 (0.052)
t½ (h) Mean (±SD) 7.904 (4.014) 7.927 (3.262)

Table 2: Rivaroxaban point estimates, 90% CIs and ISCV for Cmax, AUC0-t, AUC0-∞ (N=22).
PK parameter T/R Ratio (%) 90% Confidence Interval Intra-subject CV (%)
Cmax 100.05 92.24 - 108.53 15.73
AUC0-t 98.16 89.77 - 107.34 17.32
AUC0-∞ 98.47 90.28 - 107.40 16.81

Figure 3: Rivaroxaban mean pharmacokinetic curves after test and reference administered crushed or whole, including a summary
data table on PK parameters. Note: While individual data markers were removed for a better view of the four overlaid curves, it is
important to note that the sampling time points were identical among studies.

parameters (Cmax and AUC0-t) and their corresponding two-sided half-life and total extent of absorption. None of the subjects had
90% CIs were contained within the predefined regulatory limits measurable (above the 1.0 ng/mL LLOQ of the analytical method)
of 80.00% to 125.00% [8]. Results from the statistical analysis levels of rivaroxaban at the second period pre-dose time point,
of the additional pharmacokinetic parameter AUC0–∞ further confirming that the washout of 10 days was adequate for total
sustain the conclusion of equivalence between the two products. elimination of the drug between subsequent administrations.
All individual extrapolated areas were well below the commonly Results from this study are consistent with those obtained for the
accepted threshold of 20% (maximum observed being slightly below same formulations in a single dose study in which the tablets were
6% for both formulations), thus demonstrating that the sampling administered whole, in fasting state (Figure 3). No notable changes
schedule allowed for a proper evaluation of terminal elimination in bioavailability occurred when rivaroxaban tablets were crushed,

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immediately dispensed in 70 mL apple puree and quantitatively of Ferrer Internacional S.A. as test) are bioequivalent as the test-
(entire dose recovered) administered to fasting volunteers. Results reference ratios for the geometric means (%) of Cmax and AUC0-t
from the present study reinforced the bioequivalence conclusion and their corresponding two-sided 90% CIs were contained within
reached following administration of the test and reference whole the predefined regulatory limits of 80% to 125%. Presented in
tablets. conjunction with data from a previous study in which the same
test and reference were administered as whole tablets in fasting
Peak rivaroxaban plasma levels were reached 30 minutes earlier
state, these results suggest that no notable changes in bioavailability
and a mild increase was seen in mean Cmax (5% for reference,
occurr when rivaroxaban tablets are crushed, immediately
8% for test) when comparing between administration of crushed
dispensed in 70 mL apple puree and quantitatively (entire dose
versus whole tablets. When administered in crushed state, the
recovered) administered to fasting volunteers. Both rivaroxaban
higher rate of exposure was most likely owed to the fact that
treatments, administered in single dose to healthy volunteers, were
disintegration was already achieved by the time the micronized
well tolerated.
rivaroxaban formulations [3] reached the absorption site (the
primary absorption site is the stomach, absorption being gradually ACKNOWLEDGMENT
reduced should drug release occur into the proximal small intestine
or more distally into the small intestine or colon [9]). At the same The study was sponsored by Ferrer Internacional S.A. (Ferrer
time, total exposure (AUC0-t) was approximately 12% lower when Grupo), Barcelona, Spain as manufacturer of the test product.
comparing between administration of crushed versus whole tablets, The clinical, analytical, pharmacokinetic and statistical parts of
due to the slower elimination observed in the whole tablets study the study were carried out by 3S Pharmacological Consultation
(most likely because starting with the 10 mg dose the elimination & Research GmbH, Harpstedt, Germany through its affiliates
of rivaroxaban becomes absorption rate limited [3], mean terminal (3S-Pharmacological Consultation & Res. SRL and Pharma Serv
half-life being 3 hours longer in the whole tablets study where International SRL, both located in Bucharest, Romania).
absorption was slower).
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