Review of the combined contraceptive vaginal ring, NuvaRing

Abstract

The purpose of this review was to test contraceptive efficacy, cycle control, tolerability, and acceptability as found in the non-comparative studies with NuvaRing((R)) by those found in the randomized trials comparing NuvaRing and combined oral contraceptives (COCs). All large non-comparative studies and all relevant randomized controlled trials (RCTs) between NuvaRing and a COC up to and including December 2006 were analyzed. Two large multi-center registration studies, 1 large daily clinical practice study, and 6 RCTs comparing NuvaRing and a COC were identified. The findings in the non-comparative studies were confirmed in the RCTs. Contraceptive efficacy was high showing no significant differences in comparison with the COC; cycle control was good and consistently better than that of the COC; compliance was high and comparable with that of the pill; the incidence of adverse events such as breast tenderness, headache, and nausea was low, but not lower than with the COC despite a halving of the systemic exposure to ethinyl estradiol (EE) with NuvaRing compared with a 30-mug EE-containing COC; the incidence of local and ring-related events was low but higher than with the COC, leading to higher discontinuation rates among NuvaRing users; acceptability was high and comparable between both contraceptives, resulting in a global improvement of sexual function with both methods. After study completion, women using NuvaRing were more likely to continue with their method than women using a COC. The good results with respect to contraceptive efficacy, cycle control, tolerability, and acceptability as achieved with NuvaRing in the large non-comparative registration studies were confirmed in the RCTs comparing NuvaRing with different COCs.

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© 2008 Dove Medical Press Limited. All rights reserved
Therapeutics and Clinical Risk Management 2008:4(2) 441–451 441
REVIEW
Review of the combined contraceptive vaginal
ring, NuvaRing®
Frans JME Roumen
Department of Obstetrics and
Gynecology, Atrium Medical Centre
Parkstad, Heerlen, The Netherlands
Correspondence: Frans JME Roumen
Department of Obstetrics and
Gynecology, Atrium Medical Centre
Parkstad, Post Box 4446, 6401 CX
Heerlen, The Netherlands
Tel +3145 5766513
Fax +31455766625
Email f.roumen@atriummc.nl
Abstract: The purpose of this review was to test contraceptive effi cacy, cycle control,
tolerability, and acceptability as found in the non-comparative studies with NuvaRing® by
those found in the randomized trials comparing NuvaRing and combined oral contraceptives
(COCs). All large non-comparative studies and all relevant randomized controlled trials (RCTs)
between NuvaRing and a COC up to and including December 2006 were analyzed. Two large
multi-center registration studies, 1 large daily clinical practice study, and 6 RCTs compar-
ing NuvaRing and a COC were identifi ed. The fi ndings in the non-comparative studies were
confi rmed in the RCTs. Contraceptive effi cacy was high showing no signifi cant differences in
comparison with the COC; cycle control was good and consistently better than that of the COC;
compliance was high and comparable with that of the pill; the incidence of adverse events such
as breast tenderness, headache, and nausea was low, but not lower than with the COC despite
a halving of the systemic exposure to ethinyl estradiol (EE) with NuvaRing compared with a
30-µg EE-containing COC; the incidence of local and ring-related events was low but higher
than with the COC, leading to higher discontinuation rates among NuvaRing users; acceptability
was high and comparable between both contraceptives, resulting in a global improvement of
sexual function with both methods. After study completion, women using NuvaRing were more
likely to continue with their method than women using a COC. The good results with respect
to contraceptive effi cacy, cycle control, tolerability, and acceptability as achieved with NuvaR-
ing in the large non-comparative registration studies were confi rmed in the RCTs comparing
NuvaRing with different COCs.
Keywords: acceptability, contraceptive effi cacy, cycle control, NuvaRing, tolerability, vaginal
ring
Introduction
The combined contraceptive vaginal ring (CCVR, NuvaRing®, Organon Int., Oss, The
Netherlands) is a new once-a-month method of hormonal contraception. It consists of
a fl exible, soft, transparent, ring measuring 54 mm in diameter and 4 mm thickness
which can easily be inserted by the woman herself into the vagina (see Fig. 1). After
3 weeks of use the woman removes the ring, thereby introducing a ring-free week
during which a withdrawal bleeding normally occurs.
The ring is made of the copolymer evatane, in which the hormones ethinyl estra-
diol (EE, 2.7 mg) and etonogestrel (ENG, 11.7 mg) are equally dispersed. ENG is
3-ketodesogestrel, which is the active metabolite of the progestin desogestrel. Due
to the composition of the ring, it steadily releases 15 µg EE and 120 µg ENG daily
which are then continuously absorbed through the vaginal epithelium. Vaginal admin-
istration of contraceptive hormones with NuvaRing has the advantage of avoiding
gastrointestinal absorption and hepatic fi rst-pass metabolism, but does not produce
elevated uterine concentrations of EE and ENG compared with a COC (Roumen and
Dieben 2006). Compared with a COC containing 150 µg desogestrel and 30 µg EE,

Therapeutics and Clinical Risk Management 2008:4(2)
442
Roumen
systemic exposure to ENG is similar for NuvaRing, whereas
systemic exposure to EE with NuvaRing is approximately
50% of that for the COC (Timmer and Mulders 2000; van
den Heuvel et al 2005). Ovulation suppression, as assessed
by follicular diameter and serum hormone levels, is compa-
rable (Mulders and Dieben 2001) or slightly lower (Duijkers
et al 2004) between NuvaRing and COC use. Ovulations,
however, do not occur (Duijkers et al 2004).
Contraceptive effi cacy, cycle control, tolerability, and
acceptability of NuvaRing have been established in several
large non-comparative multi-center registration studies
(Roumen et al 2001; Dieben et al 2002), and in daily clini-
cal practice (Roumen et al 2006). It is interesting to fi nd out
whether the results of these studies could be confi rmed in
randomized controlled trials (RCTs) comparing NuvaRing
with COCs, as the working mechanism (ovulation inhibition)
and the contraindications for both methods are very similar.
Up to and including December 2006, the results of 6 such
trials have been published in 10 peer-reviewed articles. The
results of the non-comparative studies will be compared with
those of these RCTs, and reviewed here.
Contraceptive effi cacy
Contraceptive effi cacy with NuvaRing was examined in two
1-year, open-label, non-comparative studies conducted in 52
Western European centers and in 48 centers in the US and
Canada, involving nearly 1200 women each (Roumen et al
2001; Dieben et al 2002). Throughout the study period, less
unwanted pregnancies occurred in Western Europe (n = 6)
than in North America (n = 15). The Pearl indices for the
intent-to-treat (ITT) populations were 0.65 in the European
study, and 1.75 in the American study (Table 1). The method-
related Pearl indices were lower: 0.40 (95% CI 0.08–1.16),
and 1.27 (95% CI 0.51–2.62), respectively. Pooling the
pregnancies of both studies together resulted in a Pearl index
of 1.18 (95% CI 0.73–1.80). The overall cumulative preg-
nancy rate of in-treatment pregnancy, derived from life table
analysis, was 1.18% (95% CI 0.68–1.69), and comparable
Figure 1 The combined contraceptive vaginal ring (NuvaRing®).

Therapeutics and Clinical Risk Management 2008:4(2) 443
NuvaRing
with the Pearl index. The pooled method-related Pearl index
was 0.77 (95% CI 0.37–1.40).
Occurrence of pregnancy was also determined in a
Phase III, open-label, group-comparative, multi-center trial
conducted in 9 European and 2 South American countries
(Oddsson et al 2005a). In this study, 1030 women were ran-
domized to 13 cycles of treatment with NuvaRing (n = 512) or
a 150 levonorgestrel (LNG)/30EE COC (n = 518) and com-
prised the ITT population. The per protocol (PP) population
comprised 899 subjects (NuvaRing = 440; COC = 459). A
total of 10 pregnancies occurred during treatment in the ITT
population (NuvaRing = 5; COC = 5). Of these, 3 subjects
in the NuvaRing group and 2 subjects in the COC group had
no protocol violations or only minor protocol violations that
occurred after the estimated date of conception, reducing the
number of PP in-treatment pregnancies to 5 (NuvaRing = 3;
COC = 2), with no signifi cant difference between PP treat-
ment groups. The Pearl indices for the ITT populations were
1.23 and 1.19 per 100 women-years for the ring and COC
groups, respectively (Table 1). No signifi cant difference
was found between the two treatment groups. The estimated
cumulative probabilities of in-treatment ITT pregnancy after
cycle 13 were 1.20% (95% CI 0.14–2.26%) for the ring group
and 1.07% (95% CI 0.13–2.00%) for the COC group. For
the PP population, the estimated probabilities were 0.71%
(95% CI 0.00–1.52%) and 0.43% (95% CI 0.00–1.01%) for
the ring and COC groups, respectively. The results show
therefore that contraceptive effi cacy was comparable for
NuvaRing and this COC.
These results were confirmed in another open-
label, group-comparative, multi-center trial conducted in
10 countries in Europe (Ahrendt et al 2006). In this study,
983 women were randomly treated with NuvaRing (n = 499)
or a COC containing 3 mg drospirenone and 30 µg EE
(DRSP/30EE) (n = 484) for 13 cycles (ITT population).
There were 5 pregnancies during the study, 1 in the NuvaR-
ing group and 4 in the COC group. Two pregnancies in
the COC group were associated with protocol violations.
Pearl indices for the ITT population were 0.25 and 0.99
per 100 women-years for the NuvaRing and COC groups,
respectively (Table 1). These results were not signifi cantly
different (p = 0.37).
Cycle control
Bleeding patterns were evaluated in the two 1-year, open-
label, non-comparative studies conducted in 52 Western
European centers and in 48 centers in the US and Canada
(Roumen et al 2001; Dieben et al 2002). Combining the data
of the PP populations of both studies resulted in a withdrawal
bleeding in 98.5% of women (95% CI 97.7%–99.0%); early
withdrawal bleeding (starting before the ring-free week) in
6.1% of women (95% CI 5.1%–8.4%); and late withdrawal
bleeding (persisting after the ring-free week) in 23.9% of
women (95% CI 20.5%–26.5%). In most women, early or
late withdrawal bleeding was restricted to spotting only. The
incidence of irregular bleeding was very low, with an average
of 5.5% per cycle over cycles 1–13, and slightly declining
during the study. Irregular bleeding was less frequent in the
European study (4.4% of women per cycle) than in the North
American study (7.0% of women per cycle). In the majority
of cycles, the irregular bleeding was restricted to spotting
only. Cycles with an “intended bleeding pattern”, defi ned as
a cycle with a withdrawal bleeding in the ring-free week, no
early withdrawal bleeding or continued withdrawal bleeding,
and no irregular bleeding, can be calculated to be 63.0% in
the combined data.
Bleeding patterns were also examined in an observational
study among 854 women in The Netherlands who started
with NuvaRing (Roumen et al 2006). In the subgroup of
participants who had previously used a COC (86.8%), the
percentage of women who reported irregular blood loss dur-
ing the fi rst three NuvaRing cycles decreased from 32% to
16% (p  0.0001) (spotting from 20% to 9%, and bleeding
from 12% to 7%). In total, after 3 cycles, 42% of the ring
users reported a decrease in blood loss during the ring-free
week compared with the pill-free week following the end of
a cycle of COC use, whereas 12% of the ring users reported
an increase. In 39% of the cases, after 3 cycles of ring use
the blood loss was reported to be of shorter duration.
Table 1 Contraceptive effi cacy with NuvaRing in 2 non-comparative
studies, and in 2 randomized controlled trials comparing NuvaRing
with 2 different COCs: 150LNG/30EE and DRSP/30EE (ITT popu-
lation)
Study Method (number
of participants)
Pearl
index
95% CI
Roumen et al 2001 NuvaRing (n = 1145) 0.65 0.24–1.41
Dieben et al 2002 NuvaRing (n = 1177) 1.75 0.98–2.89
Oddsson et al 2005a NuvaRing (n = 512)
150LNG/30EE COC
(n = 518)
1.23
1.19
0.40–2.86
0.39–2.79
Ahrendt et al 2006 NuvaRing (n = 499) 0.25 0.01–1.36
DRSP/30EE COC
(n = 484)
0.99 0.27–2.53
Abbreviations: CI, confi dence interval; COCs, combined oral contraceptives;
DRSP, drospirenone; EE, ethinyl estradiol; ITT, intent-to-treat; LNG, levonorgestrel.

Therapeutics and Clinical Risk Management 2008:4(2)
444
Roumen
Data on cycle control with NuvaRing versus the
150LNG/30EE COC were obtained in the randomized,
comparative, multicenter, Phase III study conducted in 11
countries (Oddsson et al 2005a, b). In the ITT analysis,
the incidence of breakthrough bleeding and spotting over
cycles 2–13, the primary effi cacy parameter, was lower
with NuvaRing (range 2.0%–6.4%) than the COC (range
3.5%–12.6%), and for cycles 2 and 9 the lower incidence
with NuvaRing was confi rmed as statistically signifi cant
(p  0.003). As shown in Table 2, the incidence of
intended bleeding pattern was signifi cantly higher over
all cycles with NuvaRing (58.8%–72.8%) than with the
COC (43.4%–57.9%) (p  0.005). This was mainly due
to a lower incidence of continued withdrawal bleeding for
the NuvaRing group (21.7%–27.3%) than the COC group
(33.8%–39.0%) in cycles 1–13 and this was statistically
signifi cant for all cycles (p  0.02). Continued withdrawal
bleeding with spotting days occurred less frequently in
the NuvaRing group (16.2%–23.2%) in cycles 1–13 and
was statistically signifi cant for cycles 1, 3–7, 9, 10, and 12
(p  0.05) compared with the COC group (25.6%–30.7%).
There was no signifi cant difference in the incidence of
early withdrawal bleeding or spotting between both treat-
ment groups.
Cycle control was also studied in the women participat-
ing in the European open-label, group-comparative, multi-
center trial of Ahrendt et al (2006). A signifi cantly higher
incidence of intended bleeding in the NuvaRing group
(55.2%–68.5%) compared with the DRSP/30EE COC group
(35.6%–56.6%) was found for each of the ITT cycles 1–12
(p  0.01). Breakthrough bleeding or spotting during cycles
2–13 ranged from 3.6% to 6.2% in the NuvaRing group and
from 4.7% to 10.4% in the COC group. The incidence of
breakthrough bleeding/spotting was lower with NuvaRing
than with the COC for all cycles except cycles 11 and 12,
but this did not achieve statistical signifi cance. However,
signifi cantly fewer breakthrough spotting episodes were
observed in the NuvaRing group during cycles 1, 3, 4, 6, and
10 (p  0.05), whereas signifi cantly more early withdrawal
bleedings were observed in the NuvaRing group compared
with the COC group during cycles 1, 5, 8, and 12 (p  0.05).
Between-group differences for continued withdrawal bleed-
ing were statistically signifi cant in each of cycles 1−12 in
favor of NuvaRing (p  0.0001). In both groups, early and
continued withdrawal bleeding consisted mainly of spotting
days during the ring/pill period. The incidence of cycles
(1−13) without withdrawal bleeding ranged from 0.2% to
3.2% for NuvaRing users and from 0.5% to 1.7% for COC
users, with no statistically signifi cant differences between
the groups in any cycle.
Bleeding patterns were also studied using the Quick Start
approach, which means that the contraceptive method is
initiated immediately, at the time of the clinic visit, regard-
less of menstrual cycle day (Westhoff et al 2005). In an
open-label, one-center, controlled trial, 201 women were
randomly assigned to NuvaRing (ITT = 78) or a triphasic
COC containing norgestimate (0.18 mg during the fi rst week;
0.215 mg during the second week; 0.25 mg during the third
week) and 25 µg EE (NOR/25EE) (ITT = 78). Using the
standardized defi nitions of the clinically important WHO
menstrual indices, which exclude any menstrual events in
progress at the beginning and end of the reference period,
the NuvaRing users experienced significantly fewer
bleeding-spotting days (14.5 versus 19.2 days, respectively,
p  0.001) during the 84-day reference period (three 28-day
cycles). Ethnicity, weight, body mass index, and smoking
were not associated with the number of bleeding-spotting
days. In the COC group, however, there was a weak asso-
ciation between nulliparity and bleeding-spotting days,
particularly for older nulliparous participants. No signifi cant
differences in bleeding patterns were found based on analysis
of cycle week at study enrolment. The difference in bleed-
ing-spotting days was largely attributable to a difference in
bleeding, with NuvaRing users experiencing fewer bleeding-
only days (9.1 versus 11.9 days, respectively). The number
of bleeding-spotting episodes was also signifi cantly lower
(2.4 versus 3.0, respectively) in NuvaRing users, and their
bleeding-spotting-free intervals were signifi cantly longer
Table 2 The incidence of intended bleeding pattern – defi ned as
cycles with a withdrawal bleeding, no early or continued withdrawal
bleeding, and no irregular bleeding – during NuvaRing and COC
use in 1 large non-comparative study and 2 large randomized
controlled trials
Study Method (number
of participants)
Cycles with
an intended
bleeding pat-
tern (%)
p value
Dieben et al 2002 NuvaRing (n = 2322) 63.0
Oddsson et al
2005b (13 cycles)
NuvaRing (n = 512)
150LNG/30EE
COC (n = 518)
58.8–72.8
43.4–57.9
0.005
for all cycles
Milsom et al 2006
(13 cycles)
NuvaRing (n = 499)
DRSP/30EE
COC (n = 484)
55.2–68.5
35.6–56.6
0.01
for all cycles
Abbreviations: COCs, combined oral contraceptives; DRSP, drospirenone; EE,
ethinyl estradiol.

Therapeutics and Clinical Risk Management 2008:4(2) 445
NuvaRing
(21.2 versus 19.0 days, respectively). Fifteen percent of
NuvaRing users experienced prolonged bleeding (at least 1
bleeding-spotting episode lasting 10 or more days), compared
with 31% of pill users (p = 0.04). At the end of the study, the
women answered exit questions about their perceptions of
bleeding during the 84-day reference period compared with
their bleeding at times when they were not using hormonal
contraception. A signifi cantly greater proportion of women
using NuvaRing perceived a decrease in duration of bleed-
ing than those on the COC (p  0.01). Similarly, NuvaRing
users were less likely to report an increase in fl ow, although
this difference did not reach statistical signifi cance. NuvaR-
ing users were more likely to report no change or a “good”
change in their bleeding, whereas COC users were more
likely to report a “bad” change (p  0.01). Hence, alongside
conventional method initiation, the Quick Start approach also
gave women using NuvaRing better bleeding patterns than
those using the COC.
An open-label, single-center, cross-over study was
carried out in which women were randomly assigned to
either NuvaRing (ITT = 33) or a COC containing 100 µg
levonorgestrel and 20 µg EE (100LNG/20EE) (ITT = 31)
for 3 consecutive 28-day cycles, directly followed by three
cycles of the alternative study drug (Veres et al 2004).
During NuvaRing use, there were fewer total bleeding
days, and the number of inter-menstrual bleeding days
averaged 0.2 days compared with 1.4 days with COC use
(p  0.001).
A prospective study during 1 year was carried out in
280 women who were randomized to either NuvaRing
(n = 94), or a COC containing 100 µg levonorgestrel and
20 µg EE (100LNG/20EE) (n = 94), or a COC containing
60 µg gestodene and 15 µg EE (60 gestodene [GES]/15EE)
(n = 92) (Sabatini and Cagiano 2006). The incidence of
irregular bleeding was signifi cantly lower in the NuvaRing
group as compared with both COC groups in all cycles
(p  0.05).
Bleeding patterns in extended ring regimens were exam-
ined in a 1-year open-label, comparative study in 10 European
centers and 10 centers in the US (Miller et al 2005). The
women were randomly assigned to 1 of 4 regimens: monthly
(28-day cycle), every other month (49-day cycle), every third
month (91-day cycle), or continuous (264-day cycle). The
mean percentages of bleeding and/or spotting days were
17.6% (28-day), 15.5% (49-day), 20.9% (91-day), and 24.4%
(364-day). Discontinuation rates for unacceptable bleeding
were higher for the 91-day and 364-day cycles compared
with the 28-day cycle.
Tolerability
Compliance
In the non-comparative studies, compliance with the pre-
scribed NuvaRing regimen was higher in Europe (90.8%)
than in North America (79.9%) (Roumen et al 2001; Dieben
et al 2002). The fi rst experience in daily clinical practice in
The Netherlands revealed a compliance of 88% (Roumen
et al 2006). In this study, 3% of women inserted the ring
too early or too late, and 3.4% removed it too early or too
late. Another 3.2% had intentionally not complied with the
prescribed regimen in order to regulate their cycle, whereas
0.9% reported loss of the ring. In the fi rst cycle, 2.1% of
women left the ring outside the vagina for longer than the
advised 3 h, and 1.8% of women did this during the second
and third cycles.
In most randomized studies, compliance with the pre-
scribed regimen was high and comparable between the
NuvaRing groups and the COC groups (87.4% versus 86.6%
(Oddsson et al 2005a), and 89.2% versus 85.5% (Ahrendt
et al 2006), of ITT cycles, respectively).
Blood pressure
In the non-comparative studies, no clinically relevant changes
from baseline were observed in blood pressure (Roumen et al
2001; Dieben et al 2002). In most randomized studies, blood
pressure did not change signifi cantly from baseline in either
NuvaRing or COC users (Veres et al 2004; O’Connell et al
2005; Oddsson et al 2005a; Ahrendt et al 2006; Roumen and
Dieben 2006; Sabatini and Cagiano 2006). In 1 study, 4 sub-
jects in the NuvaRing group (0.8%) and 8 in the COC group
(1.5%) experienced hypertension (Oddsson et al 2005a).
Body weight
In the non-comparative European study, mean body weight
increased by 0.43 ± 3.35 kg over the 13 cycles of treatment
(Roumen et al 2001). A decrease in body weight from screen-
ing to the last visit of 7% was reported for 8% of the women
while an increase in body weight of 7% was reported for
10% of women. The combined data of the non-comparative
European and American studies showed a mean body weight
increase by 0.84 ± 3.81 kg over the 13 cycles of treatment
(Dieben et al 2002). In most randomized studies no marked
changes in body weight were seen between comparator
groups (O’Connell et al 2005; Roumen and Dieben 2006;
Sabatini and Cagiano 2006).
In the study of Oddsson et al (2005a), fewer NuvaRing
users had an increase of 7% in body weight from base-
line than COC (150LNG/30EE) users (8.4% versus 9.8%,

Therapeutics and Clinical Risk Management 2008:4(2)
446
Roumen
respectively), and more women had a decrease of 7%
(6.8% versus 5.0%, respectively). However, no signifi cant
differences between groups in body weight were found at
study end.
In the study of Milsom et al (2006) which compared
NuvaRing with DRSP/30EE, effects on body weight and
body composition were relatively small and similar with both
contraceptives over 1 year. For the NuvaRing ITT group, the
estimated mean body weight change from baseline to the
last assessment was 0.37 kg (two-sided 95% CI 0.10–0.64).
For the COC ITT group, the estimated mean bodyweight
change from baseline was –0.03 kg (2-sided 95% CI –0.29
to 0.23). In both cases, the upper limit of the 2-sided 95%
CI was below the pre-specifi ed 1.5 kg, and therefore it was
concluded that weight neutrality of both NuvaRing and the
COC was demonstrated. Individual data were not given.
In the Quick Start trial, the women were weighed upon
enrolment and at exit after three cycles (NuvaRing = 82;
COC = 79) (O’Connell et al 2005; Westhoff et al 2005). Par-
ticipants gained an average of 2.8 lb over 3 months (95% CI
1.9–3.6 lb; p  0.001). Weight change ranged from an 11-lb
weight loss to a 20-lb weight gain (SD = 5.5). Subjects under-
went an average increase in their BMI of 0.6 kg/m2, ranging
from a decrease of 1.8 kg/m2 to an increase of 3.2 kg/m2
(SD = 0.9). These gains were similar between NuvaRing and
COC groups (NuvaRing = 2.5 lb, COC = 3.1 lb (p = 0.49);
NuvaRing = 0.53 kg/m2, COC = 0.58 kg/m2 (p = 0.76)),
regardless of weight class, baseline weight, baseline BMI or
the season of study enrolment or exit. Therefore, a small, but
clinically unimportant weight gain was demonstrated with
both contraceptives. Again, individual data were not given.
Premenstrual syndrome
and dysmenorrhea
The fi rst experience in daily clinical practice in The Nether-
lands showed that during the fi rst three months of NuvaRing
use, in comparison with the preceding contraceptive method,
the percentage of women with complaints of dysmenorrhoea
decreased from 42% to 26% (p  0.0001), and of those with
complaints of PMS from 45% to 29% (Roumen et al 2006).
After 1 year of treatment, moderate or severe PMS or dys-
menorrhea decreased in both the NuvaRing and COC groups
(DRSP/30EE) with no apparent differences between the
treatments (Milsom et al 2006). The proportion of subjects
reporting moderate or severe PMS symptoms decreased
from 12.6% to 4.5% in the NuvaRing group and from
14.7% to 4.7% in the COC group (screening versus cycle
13). The proportion of subjects reporting moderate or severe
dysmenorrhea also decreased at study end compared with
screening (decreasing from 17.4% to 5.9% in the NuvaRing
group and from 19% to 6.4% in the COC group).
Negative mood impact (irritability and depression),
however, was experienced less by NuvaRing users (4.2%)
than by COC (100LNG/20EE and 60GES/15EE) users (8.5%
and 8.6%, respectively) (p  0.05) (Sabatini and Cagiano
2006).
Adverse events
In the combined data of the non-comparative European and
American studies, 65.5% of women reported at least one
adverse event, of which 37.5% were considered by the inves-
tigator as at least possibly related to NuvaRing use (Dieben
et al 2002). The most frequently reported adverse events
were headache, vaginitis, and leukorrhea. The incidence of
breast tenderness and nausea was low. Vaginal discomfort
was reported by 2.4% of women, and device-related events
by 4.4%. As shown in Table 3, there were no major differ-
ences in the incidence of these events between the European
and North American studies (Roumen et al 2001; Dieben
et al 2002).
The proportion of subjects reporting adverse events was
comparable in the NuvaRing group and the COC (150LNG/
30EE) group (57.6% and 54.3%, respectively) (Oddsson et al
2005a). Similar percentages of adverse events considered by
the investigator to be at least possibly related to study treat-
ment were also observed when the ring was compared with
150LNG/30EE or DRSP/30EE (NuvaRing: 28.9% (Oddsson
et al 2005a), and 29.1% (Ahrendt et al 2006) versus COC:
22.1% (Oddsson et al 2005a), and 23.5% (Ahrendt et al
2006). The incidence of estrogen-related adverse events such
as breast tenderness, headache, and nausea were comparable
between treatment groups (Table 3) (Oddsson et al 2005a;
Ahrendt et al 2006; Sabatini and Cagiano 2006). The main
differences in at least “possibly” treatment-related adverse
events between both groups were the higher incidences of
local events such as leukorrhea, vaginal discomfort, vaginitis,
and ring-related events (comprising foreign body sensation,
coital problems and expulsions) in the NuvaRing groups than
in the COC groups.
In the combined data of the non-comparative European
and American studies, 15.1% of women discontinued because
of adverse events (Roumen et al 2001; Dieben et al 2002).
The most frequently reported adverse events that resulted
in withdrawal were device-related problems (2.5%), head-
ache (1.3%), emotional lability (1.2%), weight increase
(1.0%), bleeding irregularities (0.8%), vaginitis (0.7%), and

Therapeutics and Clinical Risk Management 2008:4(2) 447
NuvaRing
leukorrhea (0.6%). Ring-related problems were also the most
important reason for premature discontinuation (3.9% of
women) in the Netherlands’ study (Roumen et al 2006).
In most randomized studies, discontinuation due to
adverse events was higher in the NuvaRing groups than in
the COC groups (NuvaRing: 11.3% (Oddsson et al 2005a),
and 12.2% (Ahrendt et al 2006), versus COC: 8.7% (Oddsson
et al 2005a), and 9.9% (Ahrendt et al 2006), respectively),
due to the additional ring-related events. In another study,
however, the discontinuation rate was lower in NuvaRing
users (11.7%) than in COC (100LNG/20EE and 60GES/
15EE) users (22.3% and 30.4%, respectively) (Sabatini and
Cagiano 2006).
In the “genital symptoms” study, Veres et al reported that
the ring never slipped (ring descent with bearing down) in 46
(71.9%) NuvaRing users, while 6 (9.4%) users reported ring
slippage at least once a week or more (Veres et al 2004). Ring
slippage was not associated with an increase in vaginal wet-
ness scores or any examination or laboratory fi nding. In this
study, 72% of men never or rarely felt the ring during coitus,
92% reported no change in sensation during intercourse, and
87% did not feel the ring move during intercourse. Of the
24 men who reported 10 or more coital events with ring use,
4 (16%) reported that the ring would sometimes come out
during coitus and 2 of these men thought that it interrupted
sexual activity.
In the study by Guida et al (2005), 89% of women and
68% of partners never felt NuvaRing during sexual inter-
course (10% of women and 24% of partners felt it occasion-
ally, and 1% of women and 8% of partners always felt it).
The open-label, randomized, cross-over study of Veres
et al (2004) was specifi cally designed to investigate genital
symptoms, signs, examination, and laboratory fi ndings with
NuvaRing use compared with 100LNG/20EE. At baseline,
15% of women had yeast on culture; during NuvaRing use,
18.8% of women were positive for yeast by culture com-
pared with 22.5% of women during COC use (p = 0.12). At
baseline, 83.8% of women were positive for any Lactobacil-
lus by culture, and at subsequent visits this percentage was
similar and not different by method (p = 0.28). However, the
concentration of Lactobacillus colony-forming units positive
for hydrogen peroxide (H2O2) production increased during
Table 3 Percentage of women reporting adverse events with NuvaRing and a COC in two non-comparative studies and three
randomized controlled trials
Adverse event Method NuvaRing (n = 2322)
(Europe3 -America4)
NuvaRing (n = 512) vs
150LNG/30EE COC
(n = 518)5
NuvaRing
(n = 499) vs
DRSP/30 EE COC
(n = 484)6
NuvaRing
(n = 94) vs
100LNG/20EE
COC (n = 94)7
NuvaRing
(n = 94)
vs 60GES/
15EE COC
(n = 92) 7
Breast tenderness NuvaRing 2.6 (1.9–3.3) 3.1 3.2 4.2 4.2
COC 1.3 4.7 6.3 6.5
Headache NuvaRing 5.8 (6.6–5.0) 7.2 6.8 6.3 6.3
COC 5.8 7.6 9.5 9.7
Nausea NuvaRing 3.2 (2.8–3.6) 2.7 0.8 2.1 2.1
COC 4.0 3.7 7.4 5.4
Leukorrhea NuvaRing 4.8 (5.3–4.2) 3.5 3.2 - -
COC 0.2 1.0 - -
Vaginal discomfort NuvaRing 2.4 (2.2–2.6) - 1.4 - -
COC - 0.0 - -
Vaginitis NuvaRing 5.6 (5.0–6.2) 3.9 4.6 - -
COC 1.0 2.1 - -
Ring-related events1NuvaRing 4.4 (3.8–5.0) 4.7 6.6 - -
COC 0.0 0.42--
1Ring-related adverse events comprise foreign body sensation, coital problems, and expulsions.
2dyspareunia.
3Roumen et al 2001.
4Dieben et al 2002.
5Oddsson et al 2005a.
6Ahrendt et al 2006.
7Sabatini and Cagiano 2006.
Abbreviations: COCs, combined oral contraceptives; DRSP, drospirenone; EE, ethinyl estradiol; GES, gestodene; LNG, levonorgestrel.

Therapeutics and Clinical Risk Management 2008:4(2)
448
Roumen
NuvaRing use (2.67-fold difference, 95% CI 1.49–4.78;
p  0.001) and increased over baseline values, possibly due
to some sort of preferential delivery of EE to the vaginal tissue
and suggesting improvement of the vaginal fl ora. All other
examination and laboratory fi ndings were not signifi cantly
different, including Nugent Gram stain score, vaginal white
blood cell count, vaginal pH values and discharge weight.
Most subjects reported few genital symptoms with either
method, but 63% of subjects reported vaginal wetness during
NuvaRing use compared with 43% during COC use. Most
vaginal symptoms were scored as mild, and a severe score
was very rare and sporadic. Vaginal wetness had the highest
symptom score among NuvaRing users, but the scores were
still quite low considering they represent 3-cycle averages
of 28-day totals. There was a non-signifi cant trend over the
entire study of decreased reporting of symptoms, with on
average 20% fewer total symptoms reported after cross-over
(p = 0.28), perhaps refl ecting improved method tolerance over
time for both methods. However, both the ring-fi rst and
pill-fi rst subjects reported on average more vaginal wetness
during NuvaRing use than during COC use (2.74-fold dif-
ference, 95% CI 1.80–4.18; p  0.001). There was also a
carry-over effect for total symptoms, with ring-fi rst subjects
reporting more symptoms with subsequent pill use than pill-
fi rst-subjects (p = 0.045). Women who reported more vaginal
wetness did not differ on laboratory fi ndings from women who
did not report this symptom, except for increased cervical
ectopy at baseline, to predict the occurrence of this symptom
and the fi nding of leukorrhea on examination (p = 0.03).
These fi ndings were confi rmed in another study (Sabatini
and Cagiano 2006), in which after three cycles vaginal dry-
ness was reported by less NuvaRing users (2.1%) than by
COC (100LNG/20EE and 60GES/15EE) users (12.7% and
30.4%, respectively) (p  0.005).
Serious adverse events
In most studies, no serious adverse events were reported
(Roumen et al 2001; Dieben et al 2002; Veres et al 2004;
O’Connell et al 2005; Roumen and Dieben 2006). One case
of a cerebral venous sinus thrombosis was reported in the
Netherlands’ study (Roumen et al 2006), and 3 cases (0,2%)
of deep vein thrombosis, possibly related to study medication,
were reported in the NuvaRing groups (Miller et al 2005;
Oddsson et al 2005a; Ahrendt et al 2006).
Acceptability
In the combined data of the non-comparative European
and North-American studies, the proportion of women
who reported at least occasionally feeling the ring during
intercourse was 18% and higher in the discontinuers (23%)
than the completers (15%) (Roumen et al 2001; Dieben et al
2002). The percentage of partners feeling the ring during
intercourse was 32% (discontinuers 37%, completers 29%).
Most partners, however, in both the completers (83%) and
the discontinuers (83%) groups did not object to women
using the ring. From all participating women, 85% were
satisfi ed or very satisfi ed with the ring at last assessment,
and 90% of respondents (97% in completers and 75% in
discontinuers) indicated that they would recommend the ring
to others. There were no major differences between Europe
and North-America.
Compared to the preceding method of contraception, the
percentage of (very) satisfi ed users increased from 34% to
72% during NuvaRing use in The Netherlands, whereas the
percentage of (very) dissatisfi ed users decreased from 44% to
16% (Roumen et al 2006). Of the study population, 82% of
women and 67% of their partners never or rarely felt the ring
during intercourse. For the women who completed all 3 cycles,
these percentages were 85% and 68%, respectively, and for
the group of women who discontinued, these percentages were
65% and 62%, respectively. In couples who felt the ring during
intercourse, 56% of women and 38% of their partners found
it unpleasant. From the 82.6% of women who completed the
3-month study period, 80% continued with NuvaRing use. The
most frequently reported reasons for satisfaction (more than
one answer possible) were once-a month administration (54%),
low hormonal dose (31%), and ease of use (27%). The most
frequently reported reasons for dissatisfaction were general
adverse events (16%), local adverse events like expulsion
(8%), and/or inconvenience during intercourse (7%).
In the comparison with DRSP/30EE, both NuvaRing
and COC were found to be highly acceptable (Ahrendt et al
2006). The majority of women were satisfi ed with NuvaRing
(59% very satisfi ed, 25% satisfi ed) and the COC (54% very
satisfi ed, 33% satisfi ed) and would recommend the method
to others (87% NuvaRing, 92% COC).
In the comparison with 100LNG/20EE, average levels of
satisfaction reported at exit visit were 4.3 ± 0.9 for NuvaRing
use and 3.6 ± 1.0 for COC use (p  0.001), based on a scale
of 1 to 5, where 1 = dissatisfi ed and 5 = best method (Veres
et al 2004). At study completion, 50% of all women planned
to continue using the ring, compared with 28% of women
who planned to continue using the COC (6% chose another
method and 16% chose no contraception). Ninety-three per-
cent of partners said that they would defi nitely or possibly
recommend NuvaRing to other couples.

Therapeutics and Clinical Risk Management 2008:4(2) 449
NuvaRing
User satisfaction and method continuation were also
assessed in the previously described group of women with a
Quick Start approach (O’Connell et al 2005; Westhoff et al
2005; Schafer et al 2006). At 3 months, 174 subjects (87%)
had follow-up interviews (Schafer et al 2006). Signifi cantly
more NuvaRing users than COC users were very satisfi ed
with their method (61% versus 34%; p = 0.003), and chose
to continue their method (79% versus 59%; p  0.001). Both
the higher user satisfaction and the continuation of NuvaRing
for birth control were not associated with prior use of vaginal
contraceptives or products, masturbation, discomfort with
intercourse or other behaviors that involve genital touching
such as waxing and shaving pubic hair or having tattoos
and/or body piercings. Neither demographic characteristics
nor vaginal experiences identifi ed successful ring users.
In an open-label, randomized, single center study, the
infl uence of intravaginal and oral hormonal contraception
on the sexual life of women and their partners was evaluated
(Guida et al 2005). Healthy women with a permanent partner
and an active sexual life were randomly assigned to NuvaR-
ing (ITT = 26) or a COC containing 150 µg desogestrel and
20 µg EE (ITT = 25) for 6 consecutive 28-day cycles. A
control group was also included, consisting of 25 women not
using hormonal contraception. Sexual activity of the women
and their partners was assessed by the Interviewer Ratings
of Sexual Function (IRSF) questionnaire, at the start of the
study and after cycles 3 and 6. Compared with women not
using hormonal contraception, women in both the NuvaR-
ing and the COC groups reported a global improvement of
sexual function after 3 months, which was sustained until the
6-month assessment. Compared with the group not using hor-
monal contraception, in both contraceptive groups, signifi cant
improvements were observed for anxiousness (p  0.001),
sexual pleasure (p  0.001), frequency and intensity of
orgasm (p  0.001), satisfaction (p  0.001), sexual interest
(p  0.01), and complicity (p  0.01). Only women using
NuvaRing reported a signifi cant increase in sexual fantasy
compared with the women using the COC or no hormonal
contraception (p  0.001). A signifi cant increase in the fre-
quency of sexual intercourse was seen in both contraceptive
groups at cycle 3 (p  0.001) and at cycle 6 (p  0.001) in
comparison with baseline, and with women not using hor-
monal contraception at cycle 3 (p  0.001) and at cycle 6
(p  0.001). After 3 cycles, a signifi cant reduction in anxiety
and an increase in pleasure and satisfaction, frequency and
intensity of orgasm were reported for partners of women
in both the NuvaRing and the COC groups. A signifi cant
increase in sexual interest, complicity, and sexual fantasy was
observed only in partners of women using NuvaRing. As for
the women, the improvement of sexual function in the male
partners of both contraceptive groups showed substantial
consistency after 6 months.
The improved sexuality among NuvaRing users was
confi rmed in another study, in which after 12 cycles an
increase of sexual desire and sexual satisfaction was reported
by more NuvaRing users (75.5%, and 77.6%, respectively)
than by COC (100LNG/20EE) users (26.5%, and 46.8%,
respectively) (p  0.005), and COC (60GES/15EE) users
(30.4%, and 22.8%, respectively) (p  0.005) (Sabatini and
Cagiano 2006).
Discussion
In this review, contraceptive effi cacy, cycle control, toler-
ability, and acceptability of NuvaRing as established in
several large non-comparative multi-center registration
studies (Roumen et al 2001; Dieben et al 2002), and in daily
clinical practice (Roumen et al 2006), were compared with
those of RCTs comparing NuvaRing with COCs (Veres et al
2004; Guida et al 2005; O’Connell et al 2005; Oddsson et al
2005a, b; Westhoff et al 2005; Ahrendt et al 2006; Milsom
et al 2006; Sabatini and Cagiani 2006; Schafer et al 2006).
The reason for this testing was that results of registration
studies may be biased by the willingness of the participants
and the fact, that these studies were funded by, undertaken
by, analyzed by and the results written up by staff of the
company which manufactures the CCVR. Although the latter
is also true for most of the RCTs, these studies represent the
highest possible level of evidence.
The good contraceptive effi cacy during the fi rst year
of NuvaRing use in the non-comparative studies (Roumen
et al 2001; Dieben et al 2002) was confi rmed in the RCTs,
in which contraceptive effi cacy was comparable between
NuvaRing and the COC (Oddsson et al 2005a; Ahrendt et al
2006). This fi nding is not surprising, as ovarian suppression
was shown to be adequate with both methods (Mulders and
Dieben 2001; Duijkers et al 2004). This result should be
interpreted with caution, of course, as it is not predictive of
the long-term contraceptive results.
The incidence of estrogen-related adverse events such
as breast tenderness, headache, and nausea was low in the
non-comparative registration studies (Roumen et al 2001;
Dieben et al 2002). Although this fi nding could be confi rmed
in the RCTs, the incidence of estrogen-related adverse events
was not signifi cantly lower with NuvaRing compared with
the COC (Oddsson et al 2005a; Ahrendt et al 2006; Sabatini
and Cagiano 2006). This is somewhat disappointing, as the

Therapeutics and Clinical Risk Management 2008:4(2)
450
Roumen
systemic exposure to EE with NuvaRing (releasing 15 µg EE
per day) compared with that for a COC containing 30 µg EE
per pill, is approximately 50% (Timmer and Mulders 2000;
van den Heuvel et al 2005). In the non-comparative studies,
no clinically relevant changes from baseline were observed in
blood pressure and body weight (Roumen et al 2001; Dieben
et al 2002). Also no apparent differences between NuvaRing
and the COC were found in blood pressure changes (Veres
et al 2004; O’Connell et al 2005; Oddsson et al 2005a;
Ahrendt et al 2006; Roumen and Dieben 2006; Sabatini and
Cagiano 2006), body weight changes (Oddsson et al 2005a;
Westhoff et al 2005; Roumen and Dieben 2006; Sabatini and
Cagiano 2006; Schafer et al 2006), or decreasing rates of
PMS and dysmenorrhea complaints (Milsom et al 2006).
An important fi nding in the non-comparative studies was
the good cycle control with NuvaRing (Roumen et al 2001;
Dieben et al 2002; Roumen et al 2006). This was confi rmed
in the RCTs, in which a better cycle control with NuvaRing
than with the COC was a consistent fi nding (Sabatini and
Cagiano 2006). Cycle control is a key factor that affects
contraceptive acceptability, compliance, and convenience,
especially for the vaginal route of administration. The inci-
dence of an intended bleeding pattern, defi ned as a cycle
with only a withdrawal bleeding in the hormone-free week,
was high in the combined data of the large international
registration studies (Roumen et al 2001; Dieben et al 2002).
This high incidence of an intended bleeding pattern with
NuvaRing was confi rmed in the RCTs, and shown to be
signifi cantly higher in most cycles with NuvaRing than with
the COC (Oddsson et al 2005b; Milsom et al 2006). This was
mainly due to a signifi cantly lower incidence of withdrawal
bleeding persisting after the hormone-free week in the
NuvaRing groups compared with the COC. This continued
withdrawal bleeding consisted mainly of spotting days in
both groups. A better bleeding pattern with NuvaRing than
with the COC was also found when the same women used
both methods in a cross-over study (Veres et al 2004). Even
after initiation of the contraceptive method regardless of
menstrual cycle day, the bleeding patterns with NuvaRing
were better than with the COC (Westhoff et al 2005). The
superior cycle control with NuvaRing is remarkable, as the
total daily dose of EE is only half of that of a 30 µg EE COC.
So, other mechanisms must be responsible for this. A local
effect is unlikely, as no elevated concentrations of EE and
ENG were found in the endometrial and myometrial tissues
with NuvaRing compared with a 20 EE µg COC (Roumen
and Dieben 2006). It is most obvious, therefore, that the
considerably lower variation in daily EE serum levels with
NuvaRing compared with the COC is an important causative
factor (van den Heuvel et al 2005).
It is not surprising, that the vaginal route of hormone
administration was associated with higher incidences of
local adverse events such as leukorrhea, vaginal discomfort,
vaginitis, and ring-related events comprising foreign body
sensation, coital problems and expulsions, than the oral route
in both the non-comparative studies and the RCTs (Roumen
et al 2001; Dieben et al 2002; Oddsson et al 2005a; Ahrendt
et al 2006). In one study, increased vaginal wetness during
NuvaRing use was accompanied by an improvement of the
bacterial fl ora in the vagina (Veres et al 2004). In another
study, less vaginal dryness was reported by NuvaRing users
(Sabatini and Cagiano 2006). As could be expected, discon-
tinuation rates due to local and ring-related adverse events
were also higher in the NuvaRing groups than in the COC
groups (Oddsson et al 2005a; Ahrendt et al 2006). The inci-
dences of serious adverse events were low and comparable
in both groups. However, the number of participants in the
studies was too small and the duration of the studies too
short to provide any reliable information on the incidence
of infrequent but serious adverse events like thromboembo-
lism. Unfortunately, the infl uence of the lower EE exposure
with NuvaRing on coagulation factors and lipid metabolism
remains unknown, as no RCTs between NuvaRing and the
COC on these important metabolic parameters have been
published yet. In two different open-label, non-randomized
comparative studies, both NuvaRing and a 150LNG/30EE
COC were associated with minimal effects on hemostatic
variables and on lipid profi le (Magnusdóttir et al 2004;
Tuppurainen et al 2004).
In the non-comparative studies and the RCTs, both
NuvaRing and the COC were found to be highly accept-
able methods of contraception (Roumen et al 2001; Dieben
et al 2002; Ahrendt et al 2006; Roumen et al 2006). Com-
pared with women not using hormonal contraception, both
women using NuvaRing and the COC reported a global
improvement of sexual function (Guida et al). The higher
satisfaction and stronger preference for method continua-
tion of NuvaRing users is remarkable, and its explanation
did not emerge from the studies (Veres et al 2004; Schafer
et al 2006). The most important reason is possibly, that
the once-a-month use of NuvaRing is easy and more con-
venient for many women (Roumen et al 2006), although
NuvaRing compliance was not different from the daily pill
regimen (Dieben et al 2002; Oddsson et al 2005a; Ahrendt
et al 2006). Also, the superior cycle control is a possible
attractive reason for many women. A third argument could

Therapeutics and Clinical Risk Management 2008:4(2) 451
NuvaRing
be, that many women feel that the lower daily EE dose and
the less fl uctuating hormone levels with the CCVR are less
harmful for their general health (Roumen et al 2006). Lastly,
the signifi cant increase in sexual desire, satisfaction and
fantasy of women and partners of women using the CCVR
is a possible contributing factor (Guida et al 2005; Sabatini
and Cagiano 2006).
Disclosures
The author has no confl icts of interest to disclose.
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