CONTRACEPTION
`
`A PRELIMINARYPHARMACOLOGICALTRIALOPTHEMONTHLY
`INJECTABLECONTRACEPTIVECYCLOPROVERA
`
`K. Fotherby I* , G. Benagiano’, H.K. Toppozada2, A. Abdel-Rahman’,
`F. Navaroli3,
`B. Arce’, R. Ramos-Cordero4, C. Gua14, B-M. Landgren5 and E. Johannisson’
`
`n
`
`1 World Health Organisation, Geneva, Switzerland;
`‘Department
`of Obstetrics and Gynaecology, University of Alexandria, Egypt;
`3 Institute of Endocrinology, Havana, Cuba;
`4 Institute National de la Nutrition, Mexico City, Mexico; and
`5 Karolinska Institute, Stockholm, Sweden
`By the Task Force on Long-Acting Systemic Agents for the Regulation of Fertility,
`World Health Organisation Special Programme of Research
`in Human Reproduction
`
`ABSTRACT
`
`contraceptive
`pilot study of the monthly injectable
`A comparative pharmacological
`in 11 women
`in four centres.
`There were no
`CycloProvera was carried out
`significant differences
`in the results between
`the centres except that the injection-
`bleeding interval appeared
`to be shorter
`in Swedish women than in those in Havana
`and Mexico. Medroxyprogesterone
`acetate was detectable
`in blood for 28 to 62
`days after
`injection of CycloProvera
`and although
`follicular
`activity
`returned
`in
`less than 28 days after injection
`in many of the women, corpus luteum function was
`suppressed for at least seven weeks in all women. Most of the women retained a
`regular menstrual pattern;
`six of 33 cycles were amenorrhoeic.
`There was no
`significant change in any of the biochemical and haematological
`analyses.
`
`Submitted
`Accepted
`
`for publication November 30,198l
`for publication February 4,1982
`
`requests: Dr. K. Fotherby, Royal Postgraduate Medical School, Ducane
`*Reprint
`Road, London, WI2 OHS, England
`
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`
`261
`
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`

`CONTRACEPTION
`
`INTRODUCTION
`
`have undergone pre-
`and gestagens
`oestrogens
`of synthetic
`combinations
`Several
`(1, 2). Only
`two of
`contraceptives
`clinical
`trials as monthly parenteral
`liminary
`these combinations
`have been
`tested more extensively;
`of these
`the first Del-
`adroxate
`(dihydroxyprogesterone
`acetophenide
`150 mg and oestradiol
`oenanthate
`10 mg) is no longer available.
`The second CycloProvera
`(medroxyprogesterone
`(3)
`acetate 25 mg and oestradiol
`cypionate 5 mg) is widely used in some countries
`and reports
`(4, 5, 6, 7, 8) of clinical
`trials of this formulation
`have been published.
`In view of this and the interest
`of the World Health Organisation
`in developing
`a
`monthly
`injectable
`formulation,
`a preliminary
`pharmacological
`trial of CycloProvera
`was undertaken
`to ascertain
`its effect on menstruation,
`on ovarian
`function,
`on a
`number of biochemical
`and haematological
`analyses and on the plasma levels of the
`injected
`steroids.
`No information
`regarding
`the
`latter
`two aspects
`has been
`previously
`reported.
`
`MATERIALS AND METHODS
`
`Clinical material
`in Alexandria,
`for Clinical Research
`Four centres
`(the WHO Collaborating Centres
`Havana and Mexico and the WHO Collaborating Centre on Research and Training
`in
`Human Reproduction,
`Stockholm)
`participated
`in the
`trial;
`each recruited
`three
`subjects. Only healthy
`female volunteers
`aged 21 to 40 years were admitted
`to the
`trial. They were required
`to have had regular menstrual
`cycles of 26 to 32 days in
`to recruitment
`length during
`the 12 months prior
`and
`to have had three
`regular
`menses after discontinuing
`the use of oral contraceptives
`or an IUD. The nature of
`the study and the effects of the drug were explained
`to the subject, her willingness
`and ability
`to abide by the protocol were ascertained
`and her consent
`for inclusion
`A full medical history and physical examination were
`in the trial was obtained.
`then carried out. Women were excluded
`if they had previous history of thrombo-
`embolic disorders,
`recent or severe
`liver disease, suspected breast or other genital
`malignancies,
`if pregnancy was suspected
`or
`if any of
`the
`laboratory
`tests
`described
`in the Results
`section were abnormal. Women who were suitable
`for
`inclusion
`in
`the
`trial were given a diary card on which
`to record episodes of
`menstrual
`bleeding and requested
`to return
`to the clinic within
`four days of the
`onset of the next period of menstruation.
`
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`CONTRACEPTION
`
`administered
`Preparation
`suspension containing 25 mg medroxy-
`CycloProvera
`(1 ml aqueous microcrystalline
`progesterone acetate and 5 mg oestradiol cypionate, Upjohn, Kalamazoo, USA) was
`given by deep intragluteal
`injection between days 1 and 5 of the menstrual cycle
`with the subsequent
`two injections being given at 28-day intervals.
`
`Table 1. Details of women enrolled in the trial (Values shown are ranges)
`
`Centre
`
`Alexandria
`Havana
`Mexico City
`Stockholm
`
`Age (y)
`
`36 - 39
`24- 32
`28 - 38
`31- 39
`
`Height (cm)
`
`Body weight (kg)
`
`155 - 168
`152 - 174
`158 - 164
`158 - 170
`
`62 - 76
`73 - 76
`69 - 76
`57 - 78
`
`Design of investigation
`of drug, during three
`for one cycle prior to administration
`Subjects were studied
`months when the drug was injected and for a further
`two months after
`treatment.
`Blood samples were
`taken weekly
`throughout
`the
`trial
`for
`the estimation
`of
`oestradiol and progesterone by radioimmunoassay.
`In samples collected during the
`three
`treatment months,
`the concentration
`of medroxyprogesterone
`acetate was
`also measured by radioimmunoassay
`(9). Between days 20 and 23 of the control
`cycle and
`thereafter
`at monthly
`intervals,
`blood samples were
`taken
`for bio-
`chemical and haematological
`analyses. Between days 20 and 23 of the control
`cycle and of the third
`injection month, an endometrial
`biopsy was taken and a
`glucose tolerance
`test carried out. Blood pressure and body weight were recorded
`at each weekly visit.
`
`RESULTS
`
`for the
`The mean ages, heights and body weights at the beginning of the trial
`groups of subjects are shown in Table I. Two subjects gained more than 3 kg during
`the trial and one subject
`lost more than 3 kg. There was no significant
`change in
`blood pressure in any subject during the trial.
`
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`CONTRACEPTION
`
`function
`on ovarian
`Effect of CycloProvera
`in the subjects studied in Alexandria,
`cycles were ovulatory
`The control pretreatment
`as shown by the increases
`in blood levels of both oestradiol
`Mexico and Stockholm
`and progesterone.
`During
`the
`treatment
`period
`serum oestradiol
`levels were
`elevated during
`the first
`few days after
`injection because of the injected oestradiol
`cypionate
`(Figure 1). Ovulation was suppressed during
`the
`treatment
`period as
`shown by the low levels of progesterone;
`in no subject did the plasma progesterone
`However
`in some
`concentration
`exceed 3 ng/ml during
`the
`treatment
`period.
`subjects
`there was evidence
`from
`the rise
`in blood oestradiol
`levels
`to values
`in
`excess of 150 pg/ml for the occurrence
`of follicular
`activity
`towards
`the end of the
`injection
`interval
`(Table
`II). This was particularly
`noticeable
`in subject Sl who
`showed increased oestradiol
`levels 22 and 26 days after
`the first
`injection
`(293 and
`736 pg/ml,
`respectively),
`24 days after
`the second
`(469 pg/ml) and 21, 24 and 27
`days after
`the third (335-693 pg/ml) and in subject S3 who showed an increase
`to
`195 pg/ml on day 25 of the first
`injection period and to 242 pg/ml and 246 pg/ml at
`the end of the second and third
`injection
`periods,
`respectively.
`The oestradiol
`levels of subject M2 21 days after
`the second injection
`and of subject A2 at the end
`of the first injection period were above 200 pg/ml.
`
`four weeks of the
`in three subjects within
`returned
`activity
`follicular
`Although
`third injection
`and in all within 50 days, plasma progesterone
`levels suggested
`that
`luteal activity was not present until more than seven weeks after
`the last injection
`(Table II).
`
`II. Return of ovarian
`Table
`receiving CycloProvera
`in women
`activity
`show earliest
`time
`in days after
`third
`injection
`for occurrence
`of
`activity,
`assessed
`by a plasma oestradiol
`150 pg/ml,
`and of
`luteal
`3 ng/ml)
`assessed by a plasma progesterone
`level
`
`(Figures
`follicular
`activity,
`
`Subject
`
`Follicular
`activity
`Luteal
`activity
`
`Al
`
`33
`
`-
`
`A2
`
`Hl
`
`H2
`
`H3
`
`Ml
`
`M2 M3
`
`Sl
`
`S2
`
`S3
`
`33
`
`_
`
`_
`
`28
`
`50
`
`78
`
`40
`
`82
`
`-
`
`48
`
`21
`
`63
`
`49
`
`79
`
`28
`
`55
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`CONTRACEPTION
`
`0 +
`
`/*
`l e
`
`00
`
`:
`0
`
`i
`.a
`
`l
`
`I
`7
`
`l
`
`;*
`.i@,;! it
`
`.
`
`l
`
`I
`14
`Days after
`injection
`
`l
`
`:
`
`.g
`
`0:
`l *
`
`:
`
`::
`
`28
`
`l
`
`l
`
`l
`
`:!
`
`I
`21
`
`:’
`
`5
`-0 2 t; 400-
`i%
`2
`2200-t
`
`l
`
`0
`
`l
`
`8
`
`0
`
`Figure 1. Serum e&radio1 concentrations at various times after
`injection of CycloProvera.
`
`Figure 2. Serum medroxyprogesterone acetate concentrations at
`various times after injection of CycloProvera on Day 0.
`
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`CONTRACEPTION
`
`acetate
`Serum levels of medroxyprogesterone
`are shown in
`Serum levels of MPA at various
`times after
`injection of CycloProvera
`Figure 2. As expected
`the concentrations
`were highest within
`the first 10 days of
`injection
`and then decreased
`slowly,
`the decrease
`being significantly
`correlated
`with
`time
`(P < 0.05, correlation
`coefficient
`= 0.63). There was, however, a wide
`variation between
`subjects and in 7 women,
`levels never exceeded 1000 pg/ml even
`during
`the first seven days after
`injection.
`Although
`in some subjects
`low values
`had been
`reached
`by
`the end of
`the
`injection
`interval,
`in others
`significant
`amounts,
`up to 1000 pg/ml, were still circulating
`at
`this
`time.
`The regression
`equation
`for the best straight
`line fitted
`to the plot of the logarithms of the serum
`levels of MPA (Y) against
`time after
`injection
`(X) was calculated
`to be Y = -0.03X +
`3.09. After
`the third injection
`the time required
`for serum MPA levels
`to become
`undetectable
`(i.e. < 100 pg/ml) varied from 28 to 62 days.
`
`on menstruation
`Effect of CycloProvera
`The menstrual
`bleeding pattern
`of each subject during
`matically
`in Figure 3 and the information
`is summarised
`except S2, Ml and
`the Egyptian women maintained
`pattern during the treatment
`period.
`
`is shown diagra-
`the trial
`in Table III. All subjects
`a fairly
`regular menstrual
`
`interval between
`The time
`injection-bleeding
`interval)
`
`and the onset of bleeding
`injection of CycloProvera
`for each subject
`is also shown in Table III.
`
`(the
`
`in this interval between women but for any one subject
`There was a wide variation
`the interval
`remained
`fairly constant.
`The mean (+SD) injection-bleeding
`interval
`for the 27 periods studied was 21.1 + 4.9 days. The injection-bleeding
`interval
`in
`the Swedish women was statistically
`significantly
`less (PC 0.01) than
`that of the
`Cuban
`and Mexican women.
`Six episodes of amenorrhoea,
`i.e. no bleeding
`occurring
`before
`the
`time of the next
`injection, were recorded
`in the 33 cycles
`studied and amenorrhoea was particularly
`prevalent
`in the Egyptian women.
`
`on endometrium
`Effect of CycloProvera
`During
`the control cycle, biopsies
`taken between days 20 and 22 from the Swedish
`women showed a mid-secretory
`pattern.
`The biopsy from subject Sl taken 27 days
`after
`the third injection
`showed an endometrium
`in the resting phase and that of S3
`taken 22 days after
`injection
`showed a proliferative
`endometrium.
`
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`and length of injection-
`
`of CycloProvera
`
`injection
`
`the first
`
`of the 84 days after
`
`amenorrhoea)
`analysis
`
`(A denotes
`
`intervals
`
`pattern
`
`III. Bleeding
`
`bleeding
`Table
`
`15
`
`A
`
`15
`
`23
`
`20
`
`A
`
`24
`
`30
`
`24
`
`A
`
`A
`
`14
`
`A
`
`17
`
`24
`
`24
`
`26
`
`17
`
`20
`
`20
`
`A
`
`13
`
`17
`
`57
`
`22
`
`21
`
`23
`
`47
`
`23
`
`28
`
`27
`
`83
`
`63
`
`of longest
`
`Duration
`
`idays)
`
`interval
`
`bleedinnfree
`
`36
`
`5
`
`15
`
`27
`
`18
`
`10
`
`25
`
`12
`
`10
`
`3
`
`13
`
`s3
`
`s2
`
`Sl
`
`M3
`
`M2
`
`Ml
`
`H3
`
`H2
`
`Hl
`
`A2
`
`Al
`
`bleeding
`enisodes of
`Number of
`
`bleeding occuked
`which snottinn
`Number of days on
`
`or
`
`Subject
`
`W
`3
`
`t;:
`
`c
`E
`
`5
`
`15
`
`20
`
`16
`
`22
`
`25
`
`20
`
`21
`
`25
`
`20
`
`25
`
`34
`
`3rd
`
`(days)
`
`2nd
`
`1st
`
`interval
`
`Injection-bleeding
`
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`CONTRACEPTION
`
`in Mexico, M2 and M3 showed secretory endometria during the
`Of the women
`control cycle whereas Ml showed an endometrium in the early proliferative
`phase.
`Biopsies
`from all
`three
`subjects during
`the
`third
`treatment
`cycle showed an
`endometrium with secondary changes due to exogenous gestagen
`treatment,
`a lax
`stroma with pseudo-decidual
`changes and
`tubular glands without
`secretory
`or
`mitotic activity.
`
`Effect of CycloProvera on biochemical and haematological measurements
`A number of biochemical
`and haematological
`analyses were carried out on blood
`samples
`taken monthly
`from women
`in the
`trial.
`Analyses of thyroxine,
`tri-
`iodothyronine
`resin uptake, prolactin,
`total protein, ablumin, globulin, urea, cre-
`atinine, bilirubin, cholesterol,
`triglycerides,
`aspartate
`transaminase,
`alanine
`trans-
`aminase
`and alkaline
`phosphatase
`and of urinary 17-hydroxycorticosteroids
`or
`cortisol were carried out in all centres except prolactin and urinary steroids were
`in Alexandria and thyroid function tests were not done in Havana. A
`not analysed
`number of haematological measurements
`including haemoglobin, white cell count,
`PCV, MCV, MCHC, prothrombin
`time, partial
`thromboplastin
`time, platelet
`count,
`Factor VII and Factor VBl were performed
`in all centres except Havana. Analyses
`of variance showed that there were no significant
`changes produced as a result of
`the injection of CycloProvera.
`
`Al
`HI
`H2
`xH3
`.z Sl g
`; 52
`s3
`Ml
`M2
`M3-
`I
`-42
`
`I
`I
`-
`I
`I
`
`I
`
`n
`
`I
`I
`
`I
`
`I
`
`n
`I
`
`n
`
`-m
`
`I
`I
`I
`
`I
`im
`n
`I
`
`I
`
`I
`
`I
`
`I
`
`I
`I
`
`I
`
`I
`
`I
`
`I
`-28
`
`I
`-14
`
`I
`0
`
`I
`14
`
`n
`I
`I
`I
`I
`I
`I
`I
`I
`1
`28 42 56 70 84 98 112 126 140
`Days
`
`in women during the six
`(solid blocks)
`Figure 3. Episodes of bleeding
`weeks prior to the first
`injection
`of CycloProvera on Day 0 and dw
`injections
`of GycloProvera were
`third
`second ma
`next
`twenty weeks.
`administered on days 28 and 56,respectively.
`
`the
`
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`CONTRACEPTION
`
`including estimations of insulin and growth hormone, were
`tests,
`tolerance
`Glucose
`performed
`in Havana, Mexico and Stockholm during
`the control cycle and during
`the third
`injection
`cycle. There were no significant
`differences between
`the two
`test periods.
`
`DISCUSSION
`
`trials of CycloProvera have been reported. Coutinho and de Souza (4)
`Five clinical
`studied 104 women for 623 cycles, 100 women were studied for 1108 cycles by Lotvin
`et al. (51, 60 women for 583 cycles by Azcona
`(61, 40 women for 510 cycles by
`--
`Rustrian et aL (7) and ill women for 2356 cycles by Koetsawang eJ 81. (8). All
`--
`reported
`that
`the preparation was acceptable with negligible
`side-effects
`and no
`pregnancies were reported. The high degree of effectiveness
`is in agreement with
`our finding
`that ovulation was inhibited during the 28-day injection
`interval.
`The
`lack of prolonged suppression of ovarian
`function
`is in agreement with the findings
`regarding
`return of fertility
`in women who have been using CycloProvera
`(8).
`
`There are no previous reports of metabolic studies in women receiving CycloProvera.
`The present study shows that no significant
`changes occurred during three months’
`use in a number of biochemical
`and haematological measurements.
`As would
`be expected, changes do occur in the endometrium with the normal cyclic changes
`being
`inhibited;
`similar observations
`have been made
`in other studies
`(4, 5, 7,
`8).
`
`trial, a detailed
`in the present
`In view of the small number of women studied
`analysis of the bleeding pattern was not carried out. Only three subjects
`(H3,
`M3 and S3) appeared
`to have an increased number of days of bleeding. Of the
`33 cycles studied, 18 were within
`the range of 25-35 days duration. Whereas
`the Cuban and Mexican women
`tended
`to maintain
`a normal cycle
`length,
`those
`of the Swedish women tended to be reduced. Other studies have shown a majority
`of cycles
`to be ‘normal’ in length (4, 5, 6, 7). Although
`the total number of cycles
`analysed
`in studies with CycloProvera
`is small,
`they suggest
`that menstrual
`cycle
`lengths
`show less
`irregularity
`in women using CycloProvera
`than
`in those using
`DepoProvera.
`In a large-scale
`trial using the latter
`formulation,
`70.6% of women
`
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`CONTRACEPTION
`
`of amenorrhoea
`(10). The incidence
`cycle
`even one normal
`did not experience
`periods compared
`to be 5.9% (4) and 7.2% (8) of treatment
`has been
`reported
`to 18% (6 out of 33 periods studied)
`in the present
`trial. Of women using DepoProvera,
`35% had total amenorrhoea
`at the end of the first year (10).
`
`to be due
`has been assumed
`of CycloProvera
`The high degree of effectiveness
`the present
`study
`is the first
`to demonstrate
`to inhibition
`of ovulation,
`although
`acitivity may occur
`towards
`the end of some
`this
`inhibition.
`Although
`follicular
`injection
`intervals
`and returned
`in all subjects within 50 days of the last
`injection,
`no evidence of luteal activity was obtained until at least seven weeks after
`the
`last injection. This inhibition of luteal activity
`is undoubtedly due to the persistence
`of MPA in the circulation;
`in the present
`study MPA was detectable
`for 28 to
`This period
`is similar
`to that
`(29 to 55 days)
`62 days after
`the third
`injection.
`found after
`the
`injection
`of 25 mg DepoProvera
`(11). For many women serum
`levels of MPA at the end of the injection period were above 400 pg/ml and ranged
`from 0 to 520 pg MPA/ml compared
`to values of 902 to 1238 pg/ml found previously
`(12). Much higher values
`(1400 to 3500 pg/ml) have been
`reported
`(8) and
`the
`difference
`is most probably due to differences
`in the specificity
`of the antisera
`Thus,
`the present
`findings
`support
`the previous
`used in the radioimmunoassays.
`suggestion
`(12) that
`the dose of MPA in the formulation
`could be reduced.
`Serum
`levels of oestradiol
`resulting
`from
`the administered
`oestradiol
`cypionate
`(Figure
`1) were highest during
`the first 4 days after
`injection
`and then decreased
`reaching
`levels by about day 14. These
`findings are
`in agreement with
`the results
`basal
`of a more detailed pharmacokinetic
`investigation
`of oestradiol
`cypionate
`(13).
`
`between women
`study to assess possible differences
`this preliminary
`In conclusion,
`supports
`the findings of previous clinical
`trials carried out mainly
`in
`in four centres
`Central
`and South America
`showing
`that CycloProvera
`is an effective
`and
`acceptable method of fertility
`control and further suggests
`that on short-term
`use
`The pharmacokinetic
`studies
`show
`that
`there
`are no metabolic
`disturbances.
`ovulation
`is regularly
`inhibitied,
`that even after only three
`injections
`corpus 1UteUm
`function
`does not return until at least seven weeks after
`the third
`injection
`and
`that MPA is detectable
`in blood for much longer
`than the 28-day
`injection
`interval
`in a large proportion
`of women.
`These
`findings
`suggest
`that
`the dose of the
`contraceptive
`steroids
`in the formulation
`could be reduced without
`any 1OSS Of
`efficacy.
`The results
`are encouraging
`enough
`to suggest
`that
`further
`large-scale
`
`270
`
`MARCH 1982 VOL. 25 NO. 3
`
`AMN1087
`Amneal Pharmaceuticals LLC v. Alkermes Pharma Ireland Limited
`IPR2018-00943
`
`

`

`CONTRACEPTION
`
`The maintenance
`trials of CycloProvera be initiated.
`clinical and pharmacological
`of regular menstruation
`in most women using CycloProvera
`in contrast with the
`marked disturbances
`observed
`in women using longer acting injectable preparations
`(10,14) is a distinct advantage of a monthly injectable
`formulation.
`
`REFERENCES
`
`Population Reports,
`
`25 mg coma regulador de la fertilidad.
`
`Revista
`
`In: Regulation of Human
`systemic contraceptives.
`1. Benagiano, G. Long-acting
`Fertility.
`E. Diczfalusy, editor. Scriptor, Copenhagen, 1977, pp 323-360.
`2. Toppozada, M. The clinical use of monthly
`injectable
`contraceptive
`prepara-
`tions. Obstet. Gynaecol. Survey 32:335-347 (1977).
`3. Rinehart, W. and Winter, J.
`Injectables
`and implants.
`Series K, No. l(l975).
`injections
`control by monthly
`4. Coutinho, E.M. and De Souza, J.C. Contraception
`J. Reprod.
`of medroxyprogesterone
`suspension and a long-acting
`oestrogen.
`Fert. 15:209-214 (1968).
`con
`5. Lotvin, B.R., Moreno, J.A.R., Arista, R.B. and Ansorena, R.G. Experiencia
`Ciclo-Provera
`anticonceptivo mensual parenteral.
`Prensa Med. Mex. 39:48-50
`(1974).
`6. Azcona, S.C. Ciclo-Provera
`Medicina 54:300-304 (1974).
`Estudio clinic0 de medroxy-
`J.A.
`7. Rustrian, A., Luyando, H. and Huerta,
`progesterona
`y cipionata
`de estradiol
`en
`inyeccion mensual
`corn0 anticon-
`ceptivo. Revista Medicina 54:378-380 (1974).
`8. Koetsawang, S., Srisupandit, S., Kiriwat, 0. and Koetsawang, A. The monthly
`injectable
`contraceptive:
`A two-year clinical
`trial.
`Int. 3. Gynaecol. Obstet.
`16:61-64 (1978).
`9. Shrimanker, K., Saxena, B.N. and Fotherby, K. A radioimmunoassay
`medroxyprogesterone
`acetate.
`J. Steroid Biochem. 9:359-363 (1978).
`10. World Health Organisation. Multinational
`comparative
`clinical evaluation,
`Bleeding patterns and side effects. Contraception
`17:395-406 (1978).
`11. Fotherby, K., Koetsawanp, S. and Mathrubutham, M. Pharmacokinetic
`different doses of DepoProvera. Contraception
`22:527-536 (1980).
`12. Koetsawang, S., Shrimanker, K. and Fotherby, K. Rlood levels of medroxy-
`progesterone
`acetate after multiple
`injections of DepoProvera or CycloProvera.
`Contraception
`20:1-4 (1979).
`
`for serum
`
`2.
`
`study of
`
`MARCH 1982 VOL. 25 NO. 3
`
`271
`
`AMN1087
`Amneal Pharmaceuticals LLC v. Alkermes Pharma Ireland Limited
`IPR2018-00943
`
`

`

`CONTRACEPTION
`
`13. Oriowo, M.A., Landgren, B.M., Stenstrom, B. and Diczfalusy, E. A comparison
`Contraception
`of the pharmacokinetic
`properties
`of three e&radio1 esters.
`21:415-424 (1980).
`14. Howard, G., Blair, M., Fotherby, K., Howell, R., Elder, M.G. and Bye, P.
`Clinical
`experience with intramuscular
`norethisterone
`oenanthate
`as a contra-
`ceptive.
`J. Obstet. Gynaecol.
`1:53-58 (1980).
`
`272
`
`MARCH 1982 VOL. 25 NO. 3
`
`AMN1087
`Amneal Pharmaceuticals LLC v. Alkermes Pharma Ireland Limited
`IPR2018-00943
`
`