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`suggested that mifepristone may be partly pooled in the
`enterohepatic cycle [13]. Three metabolites of mifepristone
`have been identified. This compound undergoes deme(cid:173)
`thylation to produce mono-demethylated (RU42633) and
`di-demethylated (RU42848) derivatives as well as hydro(cid:173)
`xylation of the propynyl group to yield hydroxylated meta(cid:173)
`bolite (RU42698). The study showed that metabolism
`of RU486 to RU42633 and RU24698 was rapid but remo(cid:173)
`val of the second methyl group leading to formation of
`RU42848 occurred much more slowly and to much lesser
`extent than removal of the first [5]. Like mifepristone, these
`metabolites are immunologically and biologically active
`and retain anti-progestational and anti-glucocorticoid prop(cid:173)
`erties [5,14]. Elimination of mifepristone and its metabo(cid:173)
`lites from the body is mainly through feces (83%) and urine
`(8.8%) within 6-7 days after administration of a single
`oral dose [12].
`The study in women showed that concentrations of
`mifepristone were 344 ± 195 and 1040 ± 444 pmol/g in
`myometrial and abdominal adipose tissues, respectively,
`at 12-15 h after oral administration of200 mg RU486, while
`its concentration in serum was 921 ± 603 nmoi/l. In these
`women, the non-protein bound fraction of RU486 varied
`from lA to 3.1 % (mean 2.3%). There was a lot of individual
`variation in concentration of RU486 in serum and adipose
`tissues. In these subjects, concentration of combined mono(cid:173)
`and di-demethylated metabolites were approximately lA,
`3.1 and 5.2 times higher in adipose tissues, myometrium
`and serum, respectively, than those of the parent compound
`mifepristone [13]. However, concentration of mifepristone
`in cerebrospinal fluid was relatively low, about 4% of plasma
`concentration, perhaps in consequence of relatively low
`amount of protein in cerebrospinal fluid [12]. The above
`results indicate that the pattern of uptake ofmifepristone and
`its metabolites by adipose and myometrial tissues is similar
`after oral administration of mifepristone.
`
`4. Plasma concentration
`
`4.1. Low dose (1-50 mg)
`
`Daily oral administration of mifepristone for one men(cid:173)
`strual cycle yielded steady plasma RU486 levels that ranged
`from 65 nmol/l with 1 mg per day to 1000 nmolll with
`10 mg per day [15]. However, peak plasma concentrations
`of 0.36 ± 0.1,1.2 ± 0.1 and 6.7 ± 3A /lmolll were reached
`within 0.5-2 h after oral administration of 2, 8 and 25 mg
`mifepristone, respectively [16]. After oral doses, twice a day
`for 4 days in nonnal subjects, plasma concentration of
`mifepristone was found up to day 5, to be steady-state
`ranging from 1-1.5, 1.6-2.6 and 2.2-3.1/lmolll with
`12.5, 25 and 50 mg per dose, respectively [8]. It was also
`demonstrated that daily oral administration of 25 mg mife(cid:173)
`pristone for 14 days produced a steady-state plasma con(cid:173)
`centration of approximately 1 /lmolll [17]. In another study,
`
`steady plasma level of RU486 and its metabolites was found
`to be 2.9 /lmolll after daily ingestion of 50 mg RU486 for 4
`days [6]. No cumulative increase in serum concentration was
`found with prolonged daily administration of low doses of
`mifepristone [6,8,16]. Thus, the findings suggest the possi(cid:173)
`bility of the low-dose mifepristone to be a potential drug for
`various clinical applications.
`The time required to reach the peak plasma concentration
`after single oral dose of 50 mg or less ranges from 0.5 to 2 h
`[5,6,18]. The maximum plasma concentration of mifepris(cid:173)
`tone was found to be 1.9 ± 0.8 and 1.7 ± OA /lmol in non(cid:173)
`pregnant and pregnant women, respectively, after oral dose
`of 50 mg RU486. This difference was not statistically sig(cid:173)
`nificant [5]. The peak plasma concentration of two active
`metabolites along with the parent compound was also
`reached approximately to 3.5-4.0 /lmolll in both pregnant
`and non-pregnant women after oral administration of 25 or
`50 mg mifepristone [6]. With 50 mg oral dose, peak plasma
`level of RU486 was 2.2 ± 1.0 /lmol/l in both Chinese and
`non-Chinese women, indicating there was no ethnic varia(cid:173)
`tion regarding bioavailability of mifepristone [18]. However,
`high individual variations in plasma concentration virtually
`rendered similar dose response effect with 25 or 50 mg dose
`of mifepristone. Overall, these findings have shown no
`significant difference in the plasma concentrations or phar(cid:173)
`macokinetic parameters of mifepristone and its metabolites
`between non-pregnant and pregnant women [5].
`
`4.2. Medium dose (100-200 mg)
`
`Following repeated oral administration of 100 and 200 mg
`RU486 daily for 4 days, maximum plasma levels reached to
`4.5 and SA /lmol/l, respectively, in both pregnant and non(cid:173)
`pregnant women. The increase in plasma levels was not
`directly proportional to the increase in the dose [6]. In a
`similar dose schedule with 100 mg, the steady plasma level
`of mifepristone ranged from 2.3 ± 0.5 to 2.5 ± OA /lmol/l
`[8]. The discrepancies in the values were probably due to use
`of different assay system for measurement.
`After a single oral dose, the peak plasma concentrations
`were 3.8 ± 1.4 and 3.8 ± 0.9 /lmol/l for 100 and 200 mg
`RU486, respectively, within 1-2 h after ingestion, in non(cid:173)
`pregnant women; whereas, the value for 100 mg dose was
`relatively low (3.0 ± 0.9 /lmolll) in pregnant women [5].
`The peak plasma binding equivalent of RU486 measured by
`radioreceptor assay was 9.3 /lmolll after 200 mg oral dose in
`pregnant women [10]. This value was comparable to the
`findings of another study in which peak plasma concentra(cid:173)
`tion of mifepristone was 4.6 /lmol/l within 1 h after oral
`administration of 100 mg single dose in nonnal subjects
`[14]. These values have shown that differences in plasma
`concentration of mifepristone after 100 and 200 mg dose is
`not significant.
`The above findings have shown that dose-response effects
`of 25, 50 and 200 mg mifepristone are widely studied and
`are found to be equally effective as 600 mg recommended
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`J 15
`
`dose. However, a standard reduced dose of mifepristone for a
`particular clinical application is yet to be determined.
`
`5. AUe, half-life and clearance rate
`
`4.3. High dose (400-600 mg)
`
`The peak plasma concentrations of mifepristone were
`4.8 ± 1.3 and 5.3 ± 1.3 !lmolll in non-pregnant women
`and 4.0 ± 0.8 and 4.4 ± 0.8 !lmol/l in pregnant women after
`oral administration of 400 and 600 mg RU486, respectively
`[5). Following oral dose of 100-800 mg mifepristone in
`women, peak plasma concentration reached 4.6-5.8 !lmol/l
`within I h and after distribution phase, this was not sig(cid:173)
`nificantly affected by the dose but remained in the same
`range throughout 48 h [9). In another study, peak plasma
`equivalent of RU486 were 10.65 and 12.30 ~lmolll in preg(cid:173)
`nant women after intake of 400 and 600 mg dose, respec(cid:173)
`tively [10). This showed plasma levels did not increase
`proportionately with the high doses given. However, sig(cid:173)
`nificant differences were found in peak plasma values
`(P < 0.05) between 200 and 400 mg doses [10,19).
`After a single oral dose, plasma concentration of RU486
`at 1 and 24 h increased in proportion to log dose. The ratio of
`the 1 :24 h concentration for the doses of RU486 decreased
`with increase in doses (25 mg, 5.8; 100 mg, 3.5; 200 mg,
`2.9; 400 mg, 2.6; 600 mg, 2.4) suggesting that the rate of
`metabolism decreased with increase in dose. This discre(cid:173)
`pancy arose because the time for elimination (Tel) increased
`three- to four-fold with dose. This change resulted from
`changes in volume of distribution (Vd) and clearance (CI)
`which detennine Tel. The increase of Vd with dose suggests
`that mifepristone binds weakly to plasma glycoprotein and
`that this binding is of limited capacity. Clearance appeared
`to reach limiting value at doses above 200 mg and this was
`probably the major factor in determining the elevated
`plasma levels of mifepristone over a long duration [5,17).
`The pharmacokinetic parameters also suggest retention of
`mifepristone in tissues from which the drug is slowly
`released [5,13,18). Elimination from the body is mainly
`through feces and urine [12).
`The plasma concentration of mono-demethylated metabo(cid:173)
`lite (RU42633) reached peak levels that were similar to those
`of parent compound, RU486 but the peak was attained more
`slowly. The peak plasma levels of di-demethylated and hydro(cid:173)
`xylated metabolites were only about 25% of those of RU486
`and mono-demethylated metabolite and occurred much later
`[5). Mifepristone and its metabolites maintained high plasma
`levels up to 48 h for low dose and 72 h for medium or high
`dose of RU486 [5,14,18,20). No significant difference was
`found in plasma concentrations of mifepristone and its meta(cid:173)
`bolites between pregnant and non-pregnant women [5,6).
`The finding that increasing dose of mifepristone from 200
`to 600 mg produces little increase in its plasma concentra(cid:173)
`tions for up to 72 h suggests that clinically, the lower dose is
`as effective as the higher dose and little, if anything, may
`probably be gained by giving multiple doses of mifepristone
`instead of a single dose [5).
`
`After rapid absorption, there was also rapid distribution
`of mifepristone with the mean !X-half life 1.4 h, fitting the
`equation for a two-compartment open model [18). The
`mean apparent volume of distribution was also reported
`to be 1.47 ± 0.25 I/kg [7). Significant difference was found
`between area under curve (AUC) for 200 and 600 mg doses
`(P < 0.01) or 400 and 600 mg doses (P < 0.05) in pregnant
`women [10,19). Values for AUC were consistently higher
`in the non pregnant than in the pregnant women for
`similar doses, whereas, the reverse was the case for clear(cid:173)
`ance values. However, the differences were not statistically
`significant. Difference between mean AUC values for 25
`and 600 mg doses was about lO-fold [5). Elimination
`of mifepristone was rather slow. The elimination or
`~-half-life ranged from 20 to 30 h in most of the subjects
`[6,8,9,16,18,21). However, it was approximately 45-55 or
`80-90 h in some subjects [7,10,16,17). The metabolic clear(cid:173)
`ance rate was also low ranging from 1.04 to 3.0 IIh [7,18).
`The serum transport protein, !Xl-acid glycoprotein (oro so(cid:173)
`mucoid) regulates the serum kinetics of mifepristone. The
`steroid does not bind to sex-honnone-binding globulin
`or cortisol-binding globulin [2). The binding to !Xl-acid
`glycoprotein limits the tissue availability of mifepristone
`explaining the low metabolic clearance rate and low volume
`of distribution. Thus, similar serum concentrations follow(cid:173)
`ing ingestion of single doses exceeding 100 mg could also be
`explained by saturation of binding capacity of serum !X l-acid
`glycoprotein [21).
`
`6. Mechanism of action
`
`Progesterone receptor (PR) contains well defined func(cid:173)
`tional domains: the N-terminal transcription domain, the
`central DNA binding domain, the hinge region and the C(cid:173)
`terminal honnone binding domain. The DNA binding
`domain of PR contains invariant cysteine repeats that form
`two "zinc finger" structure with four cysteines in each finger
`for binding to DNA [22). The nature of the crystal structure
`of progesterone-bound ligand-binding domain of the human
`PR explains the receptors selective affinity for progesterone
`and establishes a common mode of recognition of 3-oxy
`steroids by the cognate receptors. Although the overall fold
`of PR is similar to that found in related receptors, the PR has
`a quite different mode of dimerization. A hormone-induced
`stabilization of the C-terminal secondary structure of the
`ligand-binding domain of PR accounts for stereo-chemical
`properties of this distinctive dimer, and explains the recep(cid:173)
`tor's characteristic pattern of ligand-dependent protease
`resistance and its loss of regression and also indicates
`how anti-progestin, RU486 works as contraceptive [23).
`The binding of both progesterone and mifepristone pro(cid:173)
`duces conformational changes in the form ofPR that permits
`it to bind to DNA [24). The activation ofPR by progesterone
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`
`or mifepristone is accommodated by a loss of associated heat
`shock proteins and dimerization. Human PR has two iso(cid:173)
`forms (A and B) that form in solution homo andlor hetero(cid:173)
`dimers as intermediate step in the transcription activation
`process. The activated receptor dimers (A:A, B:B or A:B)
`bind to progesterone response elements in the promoter
`region of progesterone genes. The extent of binding is
`proportional to the extent of dimerization [25,26]. In the
`case of progesterone, this binding increases the transcription
`of these genes, producing progesterone effects. In contrast, a
`receptor climer complex that has been activated by mife(cid:173)
`pristone also binds to progesterone response elements, but
`an inhibitory function in the C-terminal region of hormone
`binding domain renders this DNA-bound receptor transcrip(cid:173)
`tion inactive. This is the basis of the progesterone antag(cid:173)
`onistic action of mifepristone underlying its abortifacient
`and contraceptive actions [4]. The study also suggests that
`RU486 bound A-receptor homodimers are functionally
`silent, whereas, RU486-bound B-receptor homodimers
`can activate transcription but RU486 bound A:B heterodi(cid:173)
`mers act to dominantly suppress transcriptional activation
`and it is this activity that is typically seen in progesterone
`responsive cells [12].
`
`7. Binding affinity
`
`The relative binding affinity of mifepristone for human
`uterine PR in vitro was higher (100%) than that of proges(cid:173)
`terone (43%), mono-demethylated (21 %), hydroxylated
`(15%) and di-demethylated (9%) metabolites. Thus, the
`pool of certain metabolites of RU486 may contribute to a
`significant extent to the anti-progesterone (23-30%) and
`even greater extent to the anti-glucocorticoid (47-61 %)
`effects of RU486 [14].
`In fact, all receptors that bind mifepristone have a glycine
`at the corresponding position in hormone binding domain.
`Substitution of this glycine by cysteine in human PR abro(cid:173)
`gated binding of mifepristone but not that of an agonist. It is
`suggested that the hormone binding domain of human PR
`may at least or in part correspond to the so-called "llP(cid:173)
`pocket" of the receptor and glycine722 is at a critical position
`in the 11 p-pocket. The glycine at 722 position is a critical
`amino acid without side chain, for binding of bulky aliphatic
`and aromatic IIp-substitutes, because the maturation of
`glycine722 to cysteine results in 40,000-fold lower affinity
`for mifepristone [27].
`
`8. Clinical applications
`
`8.1. Abortifacient potentiality
`
`Use of 600 mg mifepristone for termination of pregnancy
`up to 7 weeks of gestation was approved by the French
`authority [28]. In a multi centre clinical study, women
`
`(n = 1018) with gestation up to 9 weeks were given
`600 mg oral mifepristone followed 48 h later by 1 mg
`vaginal gemeprost for termination of pregnancy. There
`was 94.8% complete abortion and 5.2% required surgical
`evacuation. No significant relationship was found between
`outcome and age of gestation or the day mifepristone was
`given. Seven women were given blood transfusion. Narcotic
`analgesia was administered after gemeprost treatment to
`38.1 % nullipara and 10.7% of multipara. The findings
`suggested that mifepristone and prostaglandin combination
`was an effective and acceptable alternative (not replace(cid:173)
`ment) to surgical method for termination of early pregnancy
`[29]. However, a need to explore the efficacy of reduced
`doses was felt by investigators to be an important issue.
`In a similar study with 1182 women, pregnant for 1-4
`weeks, the rate of complete abortion was 93.8, 94.1 and
`94.3% with a single dose of 200, 400 and 600 mg mifepris(cid:173)
`tone followed 48 h later by vaginal pessary of 1 mg geme(cid:173)
`prost, respectively, with overall 3.7% incomplete and 0.3%
`missed abortion. About 50% of those who had incomplete
`abortion underwent emergency uterine curettage usually for
`hemostatic purpose, besides blood transfusion to three
`women. The number of reported complaints such as bleed(cid:173)
`ing patterns, changes in blood pressure and hemoglobin
`concentration were similar with the three treatment doses.
`Thus, for termination of early pregnancy, a single dose of
`200 mg mifepristone was reported to be as effective as the
`recommended dose of 600 mg when used in combination
`with a vaginal pessary of 1 mg gemeprost [30]. This clinical
`finding also correlates well with plasma mifepristone levels
`up to 72 h after a single oral dose.
`In a WHO sponsored study, treatment with 25 mg mife(cid:173)
`pristone five times at 12 h intervals to women (n = 192)
`pregnant for ::;49 days, or 600 mg as a single dose (n = 193)
`followed by 1 mg gemeprost 60 h after start of mifepristone
`showed complete abortion rate of 92.7%. Frequency of
`complaints such as bleeding patterns and changes in hemo(cid:173)
`globin, p-hCG, estradiol and progesterone levels were simi(cid:173)
`lar in both groups. However, levels of cortisol at 12 and 36 h
`and prolactin at 12 h after administration of mifepristone
`were significantly higher in 600 mg dose group [31]. The
`findings suggest that a lower dose of mifepristone may
`suffice for termination of early pregnancy.
`In another multicentre trial in China, treatment with initial
`dose of 50 mg RU486 followed by 25 mg every 12 h up to a
`total dose of 150 mg plus a single oral dose of 600 J-tg
`misoprostol in the morning of the third day was given to
`women of group I (n = 301) pregnant for ::;49 days. The
`group II women (n = 155) received the same dose of
`mifepristone plus 1 mg vaginal suppository of PG05
`inserted on the third day and group III (n = 149) was given
`a single dose of 200 mg RU486 plus 600 J-tg misoprostol as
`in group 1. No significant difference was found in the rate of
`complete, incomplete abortion and treatment failure among
`group I (94.4, 3 and 1.7%), group II (97.3, 2 and 0.7%) and
`group III (94.6, 2.7 and 2%), respectively. Lower abdominal
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`
`pain was the main complaint reported by 82% of women
`after PG05 administration. Incidence of diarrhea in PG05
`group II (38.7%) was significantly higher than that in group I
`(21.6%) and group III (20.1 %) (P < 0.001) and so was
`vomiting [32]. The clinical findings confirm abortifacient
`potentiality of repeated doses of 25 or 50 mg or single dose
`of 200 mg mifepristone as well as conform with kinetic and
`metabolic outcome of low and medium dose of mifepristone.
`Even a single oral dose of 50 mg mifepristone plus 0.5 mg
`gemeprost yielded 82% complete abortion [33].
`The medical abortion with mifepristone plus prostaglan(cid:173)
`din analogue had more side effects such as cramping,
`nausea, vomiting, and particularly bleeding, than surgical
`abortion but very few serious side effects [34,35]. The
`average blood loss due to medical abortion with RU486
`plus prostaglandin was found to be 136.8 ml but this did not
`adversely affect the hemoglobin level in volunteers. They
`described it as a heavy period [36].
`In the comparative study of blood loss or side effects,
`between surgical and medical abortion with 600 mg RU486
`plus 400 Ilg misoprostol, an oral regimen in women
`(n = 1373) pregnant for ::;56 days in China, Cuba and India,
`the medical group perceived their bleeding to be heavier
`than did the surgical group. However, their perception did
`not prevent them from having higher satisfaction levels [37].
`The medical group experienced more side effects than the
`surgical group. Disparity between these two groups was
`more pronounced for bleeding and pain but reports of well(cid:173)
`being and satisfaction were similar in both groups [38]. In
`the similar study in the US women (n = 269), pregnant for
`::;63 days, the median time delay for therapeutic curettage
`was significantly longer in the medical group, 35 versus 8
`days. They also experienced significantly longer bleeding.
`No significant change in hemoglobin occurred in either
`group. However, the medical group reported significantly
`greater pain and nausea or vomiting [39].
`In the US multicentre trial (n = 2015), pregnancies were
`terminated in 92, 83 and 77% women, pregnant for ::;49, 50-
`56 and 57-63 days, respectively, with 600 mg mifepristone
`and 400 Ilg misoprostol (p < 0.001). This occurred within
`4 h in 49% women and within 24 h in 75% women after
`administration of misoprostol. The failure rate increased
`with increasing duration of pregnancy, I % in ::;49 days
`group to 9% in 57-63 group (P < 0.001). Abdominal pain,
`nausea, vomiting, diarrhea and vaginal bleeding also
`increased with advancing gestational age [40]. However,
`no difference in efficacy or side effects was found during the
`treatment with 600 mg mifepristone and 1 mg gemeprost,
`whether latter was administered 24 or 48 h after mifepris(cid:173)
`tone intake, suggesting that the treatment period could be
`reduced from conventional 48 to 24 h [41].
`Women received 200 mg mifepristone orally followed
`36-48 h later by 800 Ilg misoprostol vaginally for termina(cid:173)
`tion of pregnancy up to 63 days (n = 2000). The rates of
`complete, incomplete and missed abortion were 97.5, 1.4
`and 0.4%, respectively. This regimen appeared effective in
`
`term of high complete abortion rate and low continuing
`pregnancy rate (0.6%) and was also less costly as the dose of
`mifepristone was lower and misoprostol was less expensive,
`easy for transport and storage [42]. With the same treatment
`regimen, 80% of women (n = 933), pregnant for 8 weeks
`bled within 4 hand 98% within 24 h of using misoprostol.
`The success rate was 97%. Side effects were acceptable to
`85% and 94% women found procedure acceptable. The
`findings suggested that low-dose mifepristone plus vaginal
`misoprostol was highly effective as an abortifacient [43].
`In the WHO sponsored trial, 1589 women, pregnant for
`::;35 days received a single dose of 200 or 600 mg mife(cid:173)
`pristone followed 48 h by 400 Ilg oral misoprostol. The
`complete abortion rates were 89.3 and 88.1% for lower
`and higher doses, respectively. This finding suggests that
`the same outcome can be achieved by reducing the dose of
`mifepristone from 600 to 200 mg [44].
`In a multicentre trial, 200 mg mifepristone followed by
`800 Ilg vaginal misoprostol was received by 827 women,
`pregnant for ::;56 days, and 308 women, pregnant for 57-63
`days, for termination of pregnancy. Complete medical abor(cid:173)
`tion occurred in 97% of women in the former group and 96%
`in the latter group. However, side effects were less in the
`fOlmer group [45].
`The results of mifepristone-misoprostol clinical trials have
`shown that the dose of mifepristone can be reduced from 600
`to 200 mg when followed by vaginal misoprostol without loss
`of efficacy. In fact, vaginal misoprostol extends efficacy to 56
`days' LMP and associated with less nausea and vomiting
`[46,47]. The studies have also shown that efficacy decreases
`with increasing gestational age (P < 0.001), and difference
`by regimens are not statistically significant, except at gesta(cid:173)
`tional age 257 days [48].
`The vaginal misoprostol, 800 Ilg is found to be more
`effective than oral misoprostol, 400 Ilg for uterine evacua(cid:173)
`tion of early pregnancy failure [49]. The regular uterine
`contraction developed slowly in all women treated vaginally,
`irrespective of the dose of misoprostol. However, this was
`not the case after oral treatment. Only 20 and 50% of women
`treated orally with 200 and 400 Ilg of misoprostol, respec(cid:173)
`tively, developed such an effect [50].
`A significant difference in the pharmacokinetics of mis(cid:173)
`oprostol administered by vaginal and oral routes was
`observed. The mean AUC of misoprostol was much higher
`when administered through the vaginal than oral route. This
`discrepancy may explain the difference observed in clinical
`efficacy [51]. The long lasting and continuously increasing
`uterine contractility after vaginal administration may be
`explained, only in part by the direct effect and the longer
`period of elevated plasma level of misoprostol [50].
`No significant difference was observed in serum levels of
`mifepristone or its metabolites and concentration of serum
`binding protein, IXracid glycoprotein, between responders
`and non-responders. This suggested that failure to abort in
`response to mifepristone therapy was not associated with
`altered pharmacokinetics or metabolism of mifepristone
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`
`[52]. Approximately 1 % of women do not respond to the
`antagonistic action of mifepristone but respond normally to
`progesterone [53]. In these cases, a maturation at position
`722 in the PR might be responsible for the failure of
`mifepristone to induce abortion [27].
`
`8.2. Emergency contraception
`
`Emergency contraception (EC) means prevention of preg(cid:173)
`nancy after unprotected sexual intercourse. This is also
`called post-coital contraception (PCC). High doses of estro(cid:173)
`gen or progestogen or a combination of both may be used as
`PCC within 72 h after unprotected intercourse. Use of
`mifepristone as EC has also shown promising effect.
`In another study with women and adolescents who had
`unprotected sexual intercourse and requested EC, one group
`(n = 398) received 0.1 mg ethinyl estradiol and 1 mg nor(cid:173)
`gestrel, each given twice 12 h apart (Yuzpe method) and the
`other group (n = 402) was given 600 mg mifepristone. None
`of the subjects treated with mifepristone became pregnant as
`compared with four of those who received the combination
`regimen. The number of pregnancy in each group was
`significantly lower than the number expected according to
`calculation based on the day of the cycle during which
`intercourse had taken place (P < 0.001). The volunteers
`treated with mifepristone showed less nausea (40%), vomit(cid:173)
`ing (3%) on the day of treatment as well as lower rate of
`other side effects than those treated with the combination
`therapy, but the mifepristone group had delay in onset of
`next menstrual cycle (42%). Thus, mifepristone has been
`proven to be a highly effective post-coital contraceptive
`agent which if used widely, could help reduce the unplanned
`and unwanted pregnancies [54].
`In a comparative study to evaluate effectiveness and
`acceptability (n = 616), the raw pregnancy rate for Yuzpe
`method, danazol (600 mg) and RU486 (600 mg) were 2.6,
`4.6 and 0.0%, respectively. Overall, the rates differed sig(cid:173)
`nificantly (P = 0.011). Side effects were more common and
`more severe in the Yuzpe group (70%) than in either danazol
`group (30%) or the RU486 group (37%). The study sug(cid:173)
`gested that RU486 was effective in reducing the expected
`pregnancy rates, the Yuzpe method also had clinical effect
`but danazol had little or no effect [55].
`Recent clinical studies showed that a single dose of
`600 mg RU486 within 72 h of a single act of unprotected
`sexual intercourse could be used successfully for post-coital
`contraception. This treatment was found to be highly effec(cid:173)
`tive and to have a more favorable side effect profile in
`comparison with estrogen-progestogen regimen [56,57].
`Even administration of 25 mg mifepristone twice 12 h apart
`(n = 100) or a single dose of 25 mg to women (n
`99)
`within 72 h after unprotected sexual intercourse showed 100
`or 83% contraceptive efficacy, respectively. The overall
`menstrual disturbance and other side effects were low
`[58]. This suggests that both 25 and 50 mg mifepristone
`regimens are also effective for EC. These clinical findings
`
`also conform with the outcome of the pharmacokinetic and
`metabolic studies of mifepristone.
`In the WHO multicentre trial, a dose of 600, 50 and 10 mg
`mifepristone was given
`to
`three groups of women
`(n = 1717) who requested EC within 120 h of unprotected
`intercourse. The failure rates were 1.3, 1.1 and 1.2% in 600,
`50 and 10 mg group, respectively. The treatment delay did
`not appear to influence the effectiveness. Not major side
`effects occurred except a delay in onset of the next menstrual
`cycle significantly (P < 0.001) related to the dose of mife(cid:173)
`pristone. The lowering of the dose of mifepristone to 60-fold
`did not decrease its effectiveness. This finding suggested that
`the dose of mifepristone may be reduced from 600 to 10 mg
`without altering its efficacy as EC [59].
`There is a risk of congenital malformations, especially of
`the limbs after unsuccessful use of EC. Patients should be
`informed about this risk in an ongoing pregnancy.
`Occasional use of EC to prevent unwanted pregnancies
`may reduce the number of therapeutic abortions. However,
`the frequency and extent of side effects of EC do not allow
`for repeated post-coital use after every act of unprotected
`intercourse. Obviously, development of an effective and safe
`EC requires further basic and clinical research [56].
`
`8.3. Contraceptive potentiality
`
`The possible contraceptive use of mifepristone has been
`evaluated in both clinical and experimental studies [60-62]
`Administration of mifepristone during the follicular phase
`has an inhibitory effect on follicular development and
`ovulation, whereas, endometrial development and function
`is affected if administered during the luteal phase of the
`menstrual cycle [63]. Thus, mifepristone administered
`immediately following ovulation is highly effective in pre(cid:173)
`venting implantation, most likely due to an effect on endo(cid:173)
`metrial receptivity. It seems that endometrium is more
`sensitive to mifepristone than is the ovulatory process
`[63]. Administration of 25 mg mifepristone once a week
`interfered with normal follicular development and function
`but inhibition of ovulation was not consistent in women [64].
`However, weekly dose of 2.5-5 mg and daily dose of 0.5-
`1 mg mifepristone did not inhibit ovulation but significant
`inhibitory effects on endometrial development and function
`were demonstrated [60,61,65,66].
`Twenty-one women were treated with once-a-month,
`200 mg mifepristone on day 2 of LH surge over 157
`ovulatory cycles for testing contraceptive efficacy. One
`pregnancy occurred. Women did not complain about any
`side effects apart from slight bleeding for 2-3 days starting a
`few days after the day of treatment in 35% of the cycles [67].
`A low dose of mifepristone which does not inhibit ovula(cid:173)
`tion reduced fertility significantly by affecting endometrial
`development and function [66]. Anti-nidatory effect ofluteal
`phase administration of RU486 is said to be associated with
`changes in endometrial prostaglandins during the implanta(cid:173)
`tion window in primates [62]. These show that there is a
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`Teva Pharmaceuticals USA, Inc. v. Corcept Therapeutics, Inc.
`PGR2019-00048
`Corcept Ex. 2050, Page 6
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`N.N. SarkarlEllropeall Journal of Obstetrics & Gynecology and Reproductive Biology 101 (2002) 113-120
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`119
`
`strong probability for use of mifepristone as a low-dose
`(luteal phase) oral contraceptive.
`Recent clinical studies have shown that once-a-month
`treatment with mifepristone in the early luteal phase is an
`effective contraceptive method and that the endometrium is
`more susceptible to mifepristone than are the hypothalamic
`and pituitary regions.
`Therefore, it may be possible to develop a new contra(cid:173)
`ceptive method based on low daily or once weekly doses of
`mifepristone that does not influence ovarian function [57].
`Mifep