Expert Opinion on Drug Safety

ISSN: 1474-0338 (Print) 1744-764X (Online) Journal homepage: http://www.tandfonline.com/loi/ieds20

An overview of properties of Amphora (Acidform)

contraceptive vaginal gel

Anita L. Nelson

To cite this article: Anita L. Nelson (2018): An overview of properties of Amphora (Acidform)
contraceptive vaginal gel, Expert Opinion on Drug Safety, DOI: 10.1080/14740338.2018.1515197

To link to this article: https://doi.org/10.1080/14740338.2018.1515197

Accepted author version posted online: 23

Aug 2018.
Published online: 03 Sep 2018.

Submit your article to this journal

Article views: 8

View Crossmark data

Full Terms & Conditions of access and use can be found at

http://www.tandfonline.com/action/journalInformation?journalCode=ieds20
EXPERT OPINION ON DRUG SAFETY
https://doi.org/10.1080/14740338.2018.1515197

REVIEW

An overview of properties of Amphora (Acidform) contraceptive vaginal gel

Anita L. Nelson
Department of Obstetrics and Gynecology, Western University of Health Sciences, Pomona, CA, USA

ABSTRACT ARTICLE HISTORY

Introduction: Although only a minority of contracepting women rely solely on spermicides, they may Received 15 August 2018
soon be the only ongoing female method available without a prescription in the United States. Accepted 20 August 2018
Spermicides are also combined with other methods for additional pregnancy protection and/or lubrica- KEYWORDS
tion. Nonoxynol-9 (N-9), the active ingredient in most spermicides, is cytotoxic and may increase risk of Amphora; Acidform; birth
transmission of HIV and other sexually transmitted infections, especially in high-risk women. Amphora control; vaginal
(previously called Acidform) is a noncytotoxic spermicide composed of a series of generally regarded as contraception; spermicide;
safe compounds, which maintains the acidity of the vagina following coitus to immobilize and kill acid-buffering; microbicide
sperm. Amphora is currently Food and Drug Administration-approved as a vaginal lubricant. Amphora is
currently being tested in a multicenter Phase III contraceptive trial.
Areas covered: This paper describes key properties of Amphora, including its acid-buffering abilities,
viscosity, stability, bioadhesiveness, and tolerability.
Expert opinion: Amphora is a nontoxic spermicide that maintains the pH within the vagina at levels
less than 5.0 for hours, which immobilizes and kills sperm as well as many sexually transmitted
pathogens. If the current clinical trial demonstrates safety, efficacy, and tolerability of Amphora as a
contraceptive, it would represent a viable alternative to N-9. Its potential as a microbicide warrants
further investigation.

1. Overview of the market 2011, unintended pregnancy rates dropped in the US from 51%
to 45% of all pregnancies [1], at a time when utilization of these
Unintended pregnancy continues to be a substantial public and
top tier methods expanded from 6% to 14% of contraceptors [8].
private health problem in both developed as well as developing
However, an even greater reduction in unintended pregnancies
countries around the world. In the United States in 2008–2011,
would be possible if couples who use no method (but do not
45% of women who became pregnant absolutely did not want
want pregnancy) were to use any method at all [8]. Currently
to do so at the time they conceived [1]. Despite the removal of
10% of US couples fall into that category; they account for over
cost barriers to contraceptives in the United States by the
55% of the country’s unintended pregnancies [3]. Reducing their
Affordable Care Act, lower socioeconomic status (SES) women
pregnancy rates from 85% (pregnancy rates with unprotected
are still much more likely than higher SES women to experience
intercourse) to rates (20–29%) associated with typical use of even
unintended pregnancy [1,2]. Currently, it is estimated that 42%
the least effective methods (spermicides) would have a tremen-
of unintended pregnancies (excluding miscarriages) in the US
dous impact. Today in the United States, virtually all forms of
and 49% of those unintended pregnancies worldwide end in
female contraception are available only by prescription; even
abortion [3,4]. In addition, the outcomes of unintended preg-
vaginal barrier methods may soon require clinician visits to
nancies that are continued are poorer than those of intended
obtain access to them. Only one type of emergency contracep-
pregnancies [5]. Of the 55% of US women who became preg-
tion (Plan B One-Step) and vaginal spermicides are available to
nant in 2011 with so-called ‘intended pregnancies,’ many of
women over-the-counter without a prescription. The availability
these women were indifferent or ambivalent about becoming
of a safer female-controlled, self-administered, over-the-counter
pregnant and were not optimally prepared to minimize preg-
method that could be used by a wide range of women could
nancy-related health risks to themselves and to their fetuses.
make a positive contribution to solving the serious health and
Despite the availability of contraception, risk taking rates are
social problems associated with unplanned and unprepared for
very high in most populations. For example, in France, 15% of
pregnancies.
women thought that they could have become pregnant in the
Less than 1% of contracepting women in the United States
last 4 weeks without wanting to do so [6].
rely on spermicides alone. Internationally, estimates from
One approach to reducing the rates of unintended pregnan-
WHO in 2002 were that spermicides are used in Asia by less
cies has been to increase the use of the top tier methods, such as
than 1% of couples, but nearly 17% of women in some Latin
intrauterine devices and implants, which have typical use failure
American countries rely on them [9]. In addition to the women
rates in the first year of use of less than 1% [7]. This approach has
who use spermicides as their only method of birth control,
been credited with some measurable success. Between 2008 and

CONTACT Anita L. Nelson anitalnelson@earthlink.net Harbor UCLA Medical Center, 1457 3rd Street, Manhattan Beach, CA 90266, USA
© 2018 Informa UK Limited, trading as Taylor & Francis Group
2 A. L. NELSON
Box 1. Drug Summary.
● Drug name: Amphora (previously called ACIDFORM)
● Phase: Currently in Phase III clinical trial as a single arm, 7-cycle trial in
over 100 US sites.
● Indication: Contraception
● Mechanism of action: Spermicidal by maintaining vaginal pH in acidic range.
● Route of administration: Vaginal
● Chemical structure: (88 mg (1.76%) L-lactic acid; 50 mg (1%) citric acid,
20 mg (0.4%) potassium bitartrate in a 5 mg dose (equivalent to 5 mL)
● Pivotal clinical trial currently underway
Article highlights
● Amphora is a clear, highly viscous, bioadherent noncytotoxic vaginal
spermicide that immobilizes and kills sperm by maintaining the acidic
pH of the vagina in the face of the substantial buffering ability of
semen
● Amphora was approved by the US FDA as a personal lubricant in 2004.
● Amphora is comprised of GRAS (Generally Regarded as Safe by the
FDA) ingredients, including lactic acid.
● Amphora is currently in Phase III clinical trials in a single arm, 7-cycle
trial in over 100 sites in the United States. An earlier comparative trial
showed that Amphora offered contraceptive efficacy that was non-
inferior a commercially available N-9 gel.
● Amphora is a female-controlled method that would be available with-
out prescription and is compatible for use alone or with other pro-
ducts for additional pregnancy protection (e.g. with male condoms,
diaphragms, cervical caps) or for personal lubrication.
● Its potential in reducing selective STD transmission warrants further
study.
others utilize spermicides in conjunction with other contra-
ceptive barriers (diaphragms and cervical caps) or in addition
to external (male) condoms and other methods for additional
pregnancy protection or for lubrication [9].
Vaginal spermicides are available in an array of delivery
systems. There are the immediately active foam and gel sper-
micides. Other formulations, such as suppositories and films,
are more compact and ready for placement, but require
10–15 min in place for activation. Vaginal contraceptive
sponges represent the middle ground. The sponges need to
be moistened to activate the embedded spermicidal foam
prior to placement, but they are immediately active once
they have been placed in the vagina and cover the cervix.
One important challenge posed by many of the current sper-
micide formulations (with the exception of the contraceptive
sponge) is that the spermicide leaks out of the vagina rather
rapidly. Within 2 h, up to 60% of the spermicide from gels or
suppositories can be lost from the vagina [10]. With the vaginal
film, an average of only 49% of total N-9 could be recovered from
the vagina 2 h after placement, even in the absence of coitus; by
4 h the amount let in the vagina was insufficient to immobilize
sperm [11]. For vaginal spermicidal creams, the loss is even greater;
85% is lost in 2 h after placement [12]. For all spermicide except the
sponge, coitus must be completed with 60 min of its placement.
For both suppositories and the film formulations that need
10–15 min to activate, the time frame for sexual pleasure is even
more restrictive. These temporal limitations may detract from
spontaneity and hamper the consistent and correct use of
spermicides.
In the United States, all spermicidal products utilize nonoxynol-
9 (N-9) as their active ingredient. Used as a single agent, N-9
spermicides are quoted as having a first year typical use failure
rate of 28% and a first-year failure rate with correct and consistent
use of 18% [7]. In the most recent Cochran Database Systemic
Review, Grimes et al. reported significant differences in the effects
of different spermicidal products, depending on dose of N-9. The
low dose gel (52.5 mg) was associated with a 22% pregnancy risk at
6 months compared to a 16% risk for the 100 mg N-9 dose and a
14% risk for the 150 mg dose [13]. The gel was generally more liked
by users than film or vaginal suppositories in the largest study they
reviewed [13]. Failure rates have been found to be lower in women
over 35 years of age and higher among nulliparous women [14].
N-9 also raises more important public health concerns, which
has spurred the research to develop replacement compounds.
N-9 is a cytotoxic, nonionic detergent (surfactant) that works by
destroying the sperm’s cell membrane and its tail. Despite in vitro
tests that showed that N-9 demonstrated activity against HIV,
subsequent clinical trials have completely dismissed the poten-
tial for N-9 as a microbicide [9,15]. Instead, clinical studies have
demonstrated that N-9 may increase the risk of HIV infection
either as a gel [16], in a vaginal sponge [17], or a vaginal film,
especially when used frequently by high-risk women [18].
Similarly, in a mouse Herpes Simplex Virus, type 2 (HSV-2) vaginal
transmission model, a single dose of N-9 protected against HSV-2
for a few minutes, but then rapidly increased host susceptibility
to infection. Maximum susceptibility was achieved at 12 h, at
which point susceptibility had increased 20–30-fold, even in the
absence of colposcopically detectable changes [19].
Several important studies have explored the mechanisms by
which N-9 increases susceptibility to HIV and other sexually
transmitted diseases (STDs). On a clinical level, Stafford et al.
demonstrated in 40 volunteers age 18–45 years old that genital
irritation was reported by half the N-9 users and only 25% of
the control gel users. Colposcopically, erythema was seen in
nearly 45% of N-9 users vs 10% of controls. Histologically,
inflammatory changes of patchy infiltrates in the lamina propria
with C8 lymphocytes and macrophages were seen in 3.5 times
more often in N-9 users; protective lactobacillus counts were
also reduced in the majority of N-9 users [20,21]. Similarly,
Hoffman et al. studied 180 HIV-uninfected women and found
total epithelial disruptions without ulcerations in 20% of N-9
users, but in only 3% of placebo users [22]. Tabet found super-
ficial rectal erosions and abnormal or slightly abnormal histolo-
gical changes in rectal biopsies in 89% of subjects who applied
N-9 directly into the rectum [23]. Several investigators have
demonstrated that with N-9, cervicovaginal permeability of
radioactive tagged agents is increased; plasma and urinary
isotope levels were over three times higher following N-9 vagi-
nal use than following placebo gel use [24,25].
At a more cellular level, these physical and functional changes
are explained by an array of mechanisms, including transcrip-
tional upregulation of inflammatory genes for chemokines,
macrophage factors, and interleukin; decreased protein concen-
trations of secretory leukocyte protease inhibitors, and transcrip-
tional upregulation of inflammatory mediators in the

endometrium [26]. Recruitment of HIV-susceptible lymphocytes
has also been reported [20].
Regardless of the actual mechanisms involved, the clinical
consequences are clear. Over a decade ago, the Food and
Drug Administration (FDA) published a Final Rule in the
Federal Register stating that use of spermicide containing
N-9 can irritate the vagina and rectum and may increase the
risk of getting the AIDS virus (HIV) from an infected partner
[27]. The US MEC 2016 similarly recognizes this potential risk
and rates the use of N-9 spermicides as Category 4 for women
who are at high risk for HIV infection because ‘repeated and
high-dose use of the spermicide nonoxynol-9 was associated
with increased risk for genital lesions, which might increase
the risk for HIV infection.’ It also rates N-9 spermicide use as
Category 3 for women who are HIV-infected, are not well or
not receiving antiretroviral (ARV) therapy because ‘these con-
ditions are associated with increased risk for adverse health
events as a result of pregnancy’[28].
The search for a replacement for N-9 for contraception
started two decades ago. The ideal replacement compound
would not only meet the needs for a female-controlled method
to prevent unwanted pregnancy (contraception), but would
also provide protection against sexually transmitted infections
(STIs) (microbicide) as a multipurpose technology [29].
Benzalkonium chloride (C12Bzk) has been available in some
contraceptive sponges and (in Canada) as a vaginal suppository,
but has also been tested as a vaginal gel [30], and as a vaginal
capsule [31]. With a vaginal pessary (diaphragm), this gel is as
effective as N-9 as a contraceptive, but it still has been found to
have surfactant properties that could adversely affect vaginal
epithelial. C31G (SAVVY®) was another surfactant that was
thought to disrupt the outer membrane of HIV as well as
sperm. When it was tested in a comparative randomized trial
with N-9, it was as effective as N-9 as a contraceptive, but it
lacked the ability to reduce HIV transmission [32,33].
Other mechanisms of action have been tested for vaginal
contraception. There has been particular interest in identifying
target ion channels in sperm that could be manipulated to kill
or inactivate the sperm after ejaculation [34]. Investigation of
several other cationic surfactants such as benzalkonium bro-
mide, pyridinium bromide, and dodecyl trimethylammonium
bromide, has suggested they may also act by increasing cal-
cium signaling and promoting higher calcium flux [35]. Adjudin
is another agent that has been found to inhibit sperm capacita-
tion in part by impeding chloride ion transport in the sperm
[36]. Other Catsper calcium channel or soluble sodium–hydro-
gen exchanges, and soluble adenylyl cyclase are all excellent
targets which excellent targets which would have great poten-
tial as vaginal spermicides, but inhibitors for them have not yet
been identified [37]. Natural products with unspecified mechan-
isms of action have been tested in earlier stage studies.
Oleanolic acid 3-beta-D-glucuronide at 50 mcg 1 mL doses
are 100% spermicidal [38] and extracts from Achyranthes aspera
and Stephania hernandifolia immobilize sperm in 20 s [39].
However, most research in developing new spermicidal com-
pounds has focused on products that maintain the acidity of the
vaginal pH in its natural range from 3.5 to 4.5. That range
normally is achieved in vivo by the release of hydrogen peroxide
EXPERT OPINION ON DRUG SAFETY 3
and lactic acid from resident lactobacilli. At that pH, sperm are
immobilized. Immobilization is more rapid at lower pH levels; at a
pH of 4.0, sperm are completely immobilized within 30 s, but at a
pH of 5.0, immobilization takes 5 min [40]. Similarly, the rate at
which sperm are killed is linearly proportional to pH. At pH of 4.0,
all sperm are dead within 10 min, but at a pH of 4.5, it takes
15 min to kill them all [40]. Low vaginal pH also provides a
measure of protection against STIs. HIV is inactivated at low pH
as are Neisseria Gonorrhoeae, Herpes Simplex Virus, Chlamydia
trachomatous and Haemophilus ducreyi; the growth of many
organisms associated with bacterial vaginosis (BV) is virtually
halted at low pH levels [41]. To protect the sperm, semen has a
pH of 7.2–8.0 and has good buffering properties. The ejaculate
typically raises the pH of the vagina above six for several hours,
which permits the sperm to remain intact and mobile and HIV
and other STI organisms to survive [42].
Only a few spermicidal compounds that utilize this buffer-
ing approach have reached Phase III clinical trials. Most have
no generic names since they are composed of several different
compounds. BufferGel was one of the earlier agents designed
to maintain the low vaginal pH. In lay terms, it is composed of
vegetable oil, sodium bicarbonate, magnesium oxide, silicon
dioxide, vitamin E supplement, vitamin B12 supplement, ribo-
flavin, supplement, D-calcium pantothenate, niacinamide, vita-
min B6, ascorbic acid, and mixed tocopherols (preservative).
BufferGel was administered with a diaphragm. Clinical trials
demonstrated that it offered contraceptive protection similar
to an existing N-9 comparator gel (Conceptrol) when used
with a diaphragm [43], but did not protect against HIV infec-
tion or other STDs with or without a diaphragm [44–46].
This article will focus on another compound in this class –
Amphora™ (Evofem Inc, San Diego, USA, previously known as
Instead Healthcare LLC), which was originally known as
ACIDFORM. Amphora is acid-buffering vaginal spermicide with
unique with bioadhesive and viscosity-retaining properties. This
product is administered in a 5 g dose intravaginally prior to
intercourse; no activation time is needed. ACIDFORM/Amphora
was initially developed by the Topical Prevention of Conception
and Disease Program at the Rush-Presbyterian-St. Lukes Medical
Center, Chicago, IL, USA to achieve three main objectives [42].
● To maintain the acidic pH of the vagina after the semen
has be deposited.
● To be bioadhesive to maintain its presence in the vagina
for longer periods of time than prior comparators and to
cover the surface of the vaginal and cervical epithelia.
● To maintain thick viscosity that is only minimally diluted
by ejaculate or vaginal fluids.
Worldwide license for Amphora/Acidform was granted to
Evofem, Inc. in 2002. Amphora was originally approved by
the FDA and marketed as a personal lubricant starting in
2004 (Instead Intimate Lubricant).
Because Amphora is not absorbed systemically, the studies of
pharmacokinetics, pharmacodynamics, pharmacogenetics, gen-
otoxicity, and drug–drug interactions with Amphora have not
been performed for this product as a whole. However, all the
components of Amphora are organic molecules whose safety
4 A. L. NELSON
has been established. All occur naturally in animals and/or are
found in food – either naturally or as a food additive. In lieu of the
usual sections describing those features, this article will focus on
the elements that are relevant to a product that is active locally
within the vagina – its mechanisms of action, ability to immobi-
lize and kill sperm, its ability to maintain high concentrations
over time, and its safety and tolerability.
2. Description of Amphora
Amphora is a whitish/colorless dense gel that is uniform in
consistency [41]. It contains three active ingredients which are
all acidic compounds, whose chemical names are:
● L-lactic acid: 2-Hydroxypropanoic acid
● Citric acid: 2-Hydroxypropane-1,2,3-tricarboxylic acid
● Potassium bitartrate: Potassium; (2R, 3R)-2,3,4-trihydroxy-
4-oxobutanoate.
In addition, Amphora contains the following inactive ingredients:
benzoic acid (preservative), alginic acid and xanthan gum (poly-
mer thickeners), glycerin(a humectant), sodium hydroxide, and
water [47]. All these ingredients except one are generally regarded
as safe by the FDA; the one exception is currently used in the
market as a vaginal formulation [42]. All of these ingredients are
water soluble and acid stable; none is cytotoxic. Amphora gel has
a pH of 3.55 [46]. It maintains its viscosity when it is mixed with
semen. These features make Amphora’s use compatible with
other barrier contraceptives, such as external (male) condoms
made of latex, polyurethane or polyisoprene, internal (female)
condoms, diaphragms and cervical caps. Amphora is also compa-
tible with other commonly used vaginal medications.
Amphora is in Phase III contraceptive trials, now packaged in a
5 g prefilled vaginal applicator (a capped plastic tube), which
itself is wrapped in an individual heat-sealed overwrap. The filled
applicators should be stored at room temperature 68–77°F (20–
25°C), but it can tolerate storage at 40°C for up to 6 months. At
ambient temperature, the compound is stable for at least 2 years.
The pH of the product is consistent throughout the tube.
Samples obtained from different sections of the tube were tested
for their pH and their buffering capacities after being stored for 6
and 24 months and found to be equivalent and unchanged [42].
3. Contraceptive properties of Amphora
3.1. General acid-buffering activity
Amphora has strong acid-buffering abilities [42]. Starting with
a baseline pH of 3.5–3.55, it is more acidic than any other
currently available vaginal compound. Amphora has been
tested against the only other product (acetic acid and oxyqui-
noline sulfate in a buffered vaginal jelly [AciJel]) that was
marketed at the time in the US as a vaginal acid-buffering
agent. Aci-Jel was used only to treat ‘nonspecific vaginitis,’ not
to prevent pregnancy [42]. The object of the experiment was
to compare the volume of dilution that would be needed to
be added to a fixed volume of each product to raise its pH to
5.0 (the upper limit of pH needed for spermicidal activity). One
gram of each gel was first diluted to 10 mL with 0.9% NaCl
(normal saline 1:10 w/v). The pH of normal saline is 5.5 slightly
more alkalotic than the pH of the healthy vagina. Since both
compounds were equally diluted, the pH of the dilatant itself
would not alter the outcome being studied – the relative
buffing capacities of the two compounds. Sodium hydroxide
(1.0 N) was added to each diluted specimen in 20 µl incre-
ments. Thirty seconds after every addition, the pH was mea-
sured with a standard electrode. Amphora had four-time
greater acid-buffering capacity than Aci-Jel [42]. It was calcu-
lated that 0.320 microequilalents (meg) NaOH was required to
raise the pH of 1 g Amphora to 5.0 from its initial pH of 3.57.
On the other hand, Aci-Jel had a higher baseline pH (4.07), and
required only 0.076 meg NaOH to raise the pH of 1 g of it to
5.0. The pKa values for Amphora were lower (3.7, 4.0, and 4.7)
than those of Aci-Jel (4.4 and 5.5) [42].
3.2. Acid-buffering with semen
Amphora has been found to have strong acid-buffering capacity
when tested with the more relevant challenge – ejaculate. The
buffering activity of Amphora and Aci-Jel was calculated by mea-
suring the pH of the undiluted gels after a direct addition of whole
human semen was made in varying (W/W) proportions [42].
Amphora again maintained acidity significantly better than did
Aci-Jel. When one part of Amphora was mixed with two parts of
semen, the pH of the mixture was still below 4.5, but with Aci-Jel,
two parts of semen raised its pH to 6.0. To raise the pH of Amphora
to 5.0 required 3.4 parts semen. No sperm had any forward motility
when the vaginal pH was below 5.0. The minimum percentage of
gel in semen needed to raise the pH of Amphora to 5.0 was 22.9%.
The typical volume of ejaculate is 2–5 cc. According to these
measures, a volume as small as 0.46–1.2 cc of the product would
maintain the pH of the vagina in the lethal range for sperm; the
volume used this product is 5 cc. This larger volume for its distribu-
tion throughout the vaginal cavity. This 3.4 parts semen to one part
Amphora is significantly better than the results of studies of the
only other acid-buffering contraceptive compound BufferGel.
BufferGel was able to buffer only a volume of semen equivalent
to its volume. When mixed with three parts semen, the pH rose to
5.3–5.7 a range where only partial immobilization of sperm could
be expected [40,48]. Finally, Amphora was diluted with saline to
test five different concentrations from 200 to 25 Amphora/mL. The
dilute Amphora solutions were added 5:1 (V:V) to semen. The
percent of motile sperm were measured 30 s later. Two hundred
cells were observed in each sample to establish that percentage.
No motile sperm were noted at the 1:2 ratio, but at 1:4, 33% of the
sperm were motile [42].
Another important feature of any spermicide that relies on
buffering the vaginal pH is the persistence of the low pH. In
vitro studies show that about one third of sperm which are
initially immobilized by a low pH are able to regain motility
when the pH is raised to 5.54 so prolonged action is needed
for cidal activity to be complete [42]. In vitro, Amphora immo-
bilizes sperm for at least 8 h. In vivo, similar impacts are seen
[49]. In a study of product tolerability with Amphora, the pH of
vagina was measured at several sites (posterior fornix, lateral
vaginal wall, and cervix) 2 h after application; that pH was
maintained below five at all sites [50]. Once the pH of the
ejaculate has been completely buffered, the natural pH of the
vagina would be restored. However, there is nothing in the

healthy vaginal environment that would tend to raise the pH
and revive the sperm.
More importantly, is the persistence of the buffering capa-
city it allows flexibility in the timing of application.
Intercourse does not have to immediately follow vaginal
placement of this product. In a Phase I blinded, randomized,
crossover clinical trial with 30 women comparing Amphora to
an N-9 product, vaginal and cervical mucus samples were
obtained within 2 h following midcycle coitus. Coitus fol-
lowed either immediately after administration of Amphora
or was delayed 8–10 h after application. The mean number of
progressively motile sperm seen in cervical mucus when
coitus occurred midcycle within 30 min of Amphora applica-
tion was 0.19. Even when intercourse was delayed for 10 h
following application, the mean number of progressively
motile sperm was only 0.75. All subjects had ≤5 progressive
motile sperm in midcycle cervical mucus. No woman had any
progressively motile sperm in the vaginal pool when coitus
occurred within 30 min, and only one woman in 19 had any
motile sperm in her vaginal pool when coitus was delayed for
8–10 h after application; that subject had 1–5 such sperm per
high field [49].
3.3. Bioadhesion
Under real life conditions, many variables affect the loss/leak-
age of vaginal drugs from the vagina, including the strength
of the compound’s epithelial adhesion, the amount and char-
acteristic of vaginal secretions, coital activity, gravity, and
smooth muscle contractions. In vitro simulation models have
been used to compare the bioadhesive properties of Amphora
to the other marketed vaginal gels including Aci-Jel, 2 N-9
contraceptives (including Advantage 24), K-Y jelly (a proprie-
tary water soluble vaginal lubricant) and Replens (a vaginal
moisturizer containing polycarbophil, mineral oil, hydroge-
nated palm oil, glyceride, glycerin, carbomer homopolymer
type 5, sodium hydroxide, and sorbic acid). Simulated models
were made of either sheep vaginal mucosa or cellophane
membranes hydrated with simulated vaginal fluid (SVF) or of
sheep vaginal mucosa. To simulate vaginal dilution, each of
the gels (0.5 g) was mixed with 0.25 mL SVF and then placed
between the test membranes (12 cm2 area). The membranes
were initially kept in contact with the gel for 5 min. One set of
membranes was mounted horizontally; the other was
mounted vertically. The strength needed to separate the two
membranes was used to represent the bioadhesive strength.
The strength needed to separate the vertically mounted mem-
branes represented the shear stress. The strength needed to
move one membrane in a parallel direction relative to the
other represented the tensile strength. Amphora had excellent
bioadhesive properties in both systems. It demonstrated at
least twice the bioadhesive strength of the only marketed
vaginal contraceptive formulation that claims bioadhesive
properties – Advantages [42]. In vivo, Amphora has been
shown to form a layer visible colposcopically over some or
most of the vaginal and cervical surfaces for at least 12 h [49].
Furthermore, it was so adhesive that it could not be removed
by rinsing with saline or diluted acetic acid [49].
EXPERT OPINION ON DRUG SAFETY 5
3.4. Viscosity for sperm immobilization and product
stability
The viscosity of Amphora measured in vitro tests of each of
the same comparators with dilution with deionized water
added to the gel to achieve a 20% solution/suspension. The
combination was stirred for 30 min. Viscosity was measured
at a standard temperature with a viscometer under standard
conditions. Amphora had viscosity 21–271 times greater
than the viscosity of the other vaginal gels listed about
that were used in the tests of bioadhesion [42]. The spermi-
cidal properties of Amphora had to be assessed in this
experiment with dilution since the thick, viscous mixture
that formed when Amphora was mixed with semen trapped
the sperm made it difficult to distinguish between immotile
and dead sperm.
4. Product tolerability
For products to which each member of the couple would be
exposed, tolerability must be studied for each of the partners.
4.1. Female tolerability
Vaginal tolerance of Amphora was initially studied in three
groups of six women, each randomized to receive the study
drug with 0%, 2.5%, and 5% of N-9 [51]. The impacts of daily
dosing for days during the follicular phase were assessed by
reported symptoms, pelvic exam and colposcopy done 1 and
7 days after initial exposure. Amphora alone (0% N-9) was
associated with only one episode vaginal erythema at
3 days, whereas, with the addition of N-9, many more lesions
were observed [51]. However, when Amphora was compared
in another study to a water-based lubricant (K-Y jelly) with
multiple doses over longer time, the results were different.
When the products were applied twice daily for 14 days, sig-
nificantly more women (61%) in the Amphora group reported
at least one symptom of genital irritation compared to K-Y
jelly users (29%) (odds ratio 2.62 [95% CI 1.30–5.31] [47].
In another multi-dose, longer exposure, comparative study
in which 36 abstinent women applied either Amphora or
hydroxyethyl cellulose (HEC) placebo gel twice daily for 14
consecutive days, product tolerability was measured by history
and physical examination. Overall 65% of women using
Amphora reported at least one local adverse event compared
to 11% of those who used the placebo [47]. The most com-
mon adverse events were vulvovaginal itching and burning,
which generally occurred as each gel was applied. Each of
those symptoms usually lasted for less than 30 min. No
increase were observed in cytokines or chemokines with either
agent, but concentration of lactoferrin and interleukin-1 recep-
tor antagonist were lower in Amphora users [47].
Safety and tolerability of Amphora in women was also
studied when the product was used with a diaphragm. In a
short-term trial with 81 low-risk, abstinent women, Amphora
and two comparator gels – KY jelly and BufferGel – were used
with a diaphragm for 6–10 h nightly for 14 nights. No signifi-
cant difference were seen in complaints among the groups.
Colposcopically detected changes were more frequently
6 A. L. NELSON
reported in the Amphora group. Overall, 28% of subjects had
such findings at baseline and 53% during follow-up, but many
may have resulted from diaphragm placement or removal [52].
Vaginal lavages performed on study days 8 and 16 showed
that inflammatory markers were not increased by daily over-
night use of Amphora with a diaphragm [53].
A 6-month, Phase II trial compared Amphora to KY jelly used
with a diaphragm in 120 HIV-uninfected women in South Africa.
The rates for pelvic events were very similar between the two
groups: 338.3 vs 247.1 per 100 women-years with a rate ratio of
1.37 [95% CI (0.89–2.11)]. The most common vaginal symptoms
were discharge (27%) and itching (28.6%) in the Amphora
group. At month 2, 33.9% and 28.6% of women had abnormal
vaginal and cervical findings (usually erythema) [50].
4.2. Male tolerability testing
Male tolerance of Amphora gel was studied in a 7-day rando-
mized, double masked, single center Phase I study using KY
Jelly as the comparator product [54]. The 36 participants were
instructed to apply 2 mL of the study product to their penis at
bedtime each night and to wash each product off 6–10 h after
application, but 30% of the time the product was left on for
too long. Overall, 8.3% of Amphora users reported adverse
events (tingling and dryness), and 41.7% of KY Jelly users
reported genital symptoms. All adverse events were rated as
mild intensity. Circumcision did not impact on the incidence of
symptoms or physical findings, which were observed in 8.3%
of each group (1 mm ulceration, small vesicles, and an area of
erythema on the glans of three different subjects). Amphora
users liked the comfort and ease of use best while gel con-
sistency was liked the least. Many also disliked the prolonged
drying time. About 70% of all gel users (K-Y or Amphora) said
they did not think they would be able to tell if their partner
used a gel. 91% of Amphora users said they would not object
to their partner using that gel in the future [54].
5. Phase III clinical trials of contraceptive efficacy
A multicenter, open-labeled, randomized, noninferiority
6-month (seven cycle) study compared the contraceptive effi-
cacy and safety of Amphora to Conceptrol vaginal gel (N-9,
4%) (ClinicalTrials.gov NCT01306331) [55]. It was conducted in
49 sites in the United States and 13 sites in Russia. Subjects
were healthy, sexually active women aged 18–45 years. In
total, 1665 women were randomized to Amphora and 1659
to the N-9 product (Conceptrol). Study results are not posted
on the ClinicalTrials website and have not been published. The
results have been presented by poster at an ACOG national
meeting [55]. The Kaplan–Meier 6-month cumulative preg-
nancy percentage with Amphora was 10.5% [95% CI (8.6–
11.9)]. Among those 1153 women who reported using the
product correctly and consistently, the pregnancy percentage
at 6 months was 4.1% [95% CI (8.6–12.3)]. For N-9, the corre-
sponding numbers were very similar: 10.0% [95% CI (8.1–11.9)]
and 4.2% [95% CI (2.8–5.6)]. Over half the women (53.5%)
discontinued the study before 6 months – 52.7% in Amphora
group and 54.3% in the N-9 group. Adverse events leading to
discontinuation were very infrequent; fewer than 2% of
women in either group left the study early due to adverse
events.
The FDA was apparently reluctant to accept the data from
this first Phase III clinical trial and has instructed the sponsor to
conduct another Phase III clinical trial, which is currently recruit-
ing subjects. This study (ClinicalTrials.gov NCT03243305) is an
open label, single label, Phase III trial ongoing in around 100
sites in the United States. Entitled ‘AMPOWER: A single-arm,
Phase III, open label, multicenter study in 1,350 women aged
18–35 years of the contraceptive efficacy and safety of
AMPHORA® contraceptive gel.’ Subjects will be followed
through cycles 0–7 with cycles 1–7 being on treatment. The
primary study outcome is contraceptive efficacy (number of
patients who do not become pregnant as assessed by the
Kaplan–Meier statistical method). Other outcomes will be safety
and tolerability as measured by incidence of treatment-emer-
gent adverse events and by female sexual function (as assessed
by female sexual subjectivity Inventory Standardized tool).
Subjects must have 21–35 days cycles, be sexually active, not
at high-risk of STIs and willing to use this vaginal spermicide as
their only contraceptive method.
6. Microbicidal potential of Amphora
Although the focus of this article is on contraceptive applications,
Amphora is also known to support vaginal defense system and
may provide protection against a variety of infections and vaginal
microbial imbalances by enhancing its acidity. Amphora does not
alter the vaginal microbiota. In a randomized, controlled study
which compared the impact of Amphora vs HEC given twice daily
for 14 days, Amphora did not change the numbers of women with
detectable Lactobacilli crispate or Lactobacilli jesenia [47].
Theoretically, since the L-lactic acid isomer is more potent
in inactivating HIV than other vaginal acids, the fact that
Amphora 100 mg of L-lactic acid suggests that it may poten-
tially provide some viricidal activity [40]. Several animal model
studies have investigated the ability of Amphora to prevent
STI. In an in vitro mouse model, Amphora was more active
against Neisseria gonorrhoeae than other microbicides
(BufferGel®, polystyrene sulfonate, CarraGuara®, PRO 2000®,
cellulose acetate phthalate and Ushercell®) [56] Amphora-
treated mice had only a 6% rate of gonococcal transmission
compared to untreated control mice who experienced an 87%
transmission rate [56]. Using a similar mouse model, only 19%
of mice pretreated with Amphora became infected with chla-
mydia compared to 88% of untreated mice [40,54]. Amphora
has been found to be effective against trichomoniasis [42].
The data about HSV-2 transmission are less clear. In the
mouse model, exactly the same results were noted; only 19%
of Amphora-treated animals acquired HSV-2 compared to 88% of
those treated with a placebo gel [57]. In this model, Amphora
provided protection even when mice were challenged with HSV
in seminal fluid [57]. The authors point out that pretreatment of
HSV-2 with pH 3.5–4.5 induced proteolysis of the HSV-2, which
disrupted that particle and reduced particle binding and inva-
sion. However, preclinical studies in women have not been able
to confirm anti-HSV activity [47]. When used by women, there
was no significant increase in anti-HSV activity seen in the

cervicovaginal lavage. The authors point out that the vaginal pH
(4.5) after 2 h is not low enough to inactivate HSV which requires
a pH of 3.5. Also, immune mediators typically associated with
anti-HSV activity were found in lower concentrations following
Amphora administration than at baseline [47].
Lactobacillus plays a pivotal role in maintaining the health
(acidity) of the vagina; its loss is noted in BV. The lactic acid in
Amphora may be helpful in suppression of the bacteria asso-
ciated with BV [40]. Keller et al. found that concentration of
one of those bacteria (Gardnerella vaginales) tended to decline
following twice daily application of Amphora for 14 days [47],
but Amphora is not as an effective treatment as metronidazole
for acute episodes of BV [58].
Amphora may reduce STI risk indirectly when used with
external (male) condoms by reducing condom failure [59] and
by increasing condom use by making condom use more com-
fortable to use with added lubrication.
7. Conclusions
Amphora appears to be an attractive alternative to N-9 as the
active ingredient in vaginal spermicidal gels if the ongoing
Phase III clinical trial supports earlier findings of noninferiority
in efficacy with existing N-9 products. At a minimum having
Amphora available will expand the numbers of women who
are eligible to use a female-controlled, rapidly reversible, con-
traceptive that is available without a prescription. Amphora
works by maintaining the vaginal pH in an acidic range (<5.0),
which immobilizes and kills sperm. It is extremely adhesive to
vaginal walls and the cervix, which reduces leakage and helps
maintain its activity for hours. These properties also enable
early placement up to 8–10 h in advance of coitus and helps
ensure persistent sperm immobilization. Amphora was reason-
ably well tolerated even with prolonged frequent exposure.
Few women discontinued use due to adverse events in the
earlier Phase III clinical trial. The vast majority of men in
tolerability testing said that they did not believe they would
be able to detect if their partners were using the product.
Already approved as a personal lubricant, Amphora can be
used as a single contraceptive agent with relatively high fail-
ure rates (but better than no method) or in conjunction with
latex or synthetic external (male) condoms or other internal
(female) barrier methods to increase their efficacy. And it can
be used with any other method to increase pleasure if vaginal
dryness is a problem. Amphora has demonstrated interesting
potential as a microbicide, which deserves further study.
8. Expert opinion
Amphora has many appealing features as a spermicide; it is
noncytotoxic, viscous, adherent, and reasonably well tolerated.
If the current Phase III clinical trial demonstrates that Amphora
contraceptive gel has failure rates in the range traditionally
seen with N-9 containing spermicides and has tolerability and
safety findings that have been reported in earlier studies, it
may well replace N-9 contraceptive gels, creams, and foams if
those compounds are further associated with HIV transmission
or if authorities revoke its approval. Clearly the ongoing Phase
III clinical trial will need to provide detailed answers about the
EXPERT OPINION ON DRUG SAFETY 7
efficacy of the product, potential side effects (especially geni-
tal irritation), and tolerability in widespread generalized usage.
Its viscosity may be an advantage for spermicide activity, but
may prove problematic when the product ultimately leaves
the vagina. There are other important clinical questions that
need to be answered – will the product work as well in
women with higher vaginal pHs, such as those who have BV?
At a minimum, Amphora could permit the continued avail-
ability of spermicides should N-9 be removed from the market.
Professional hesitancy to recommend spermicides due to con-
cerns of HIV vulnerability should be assuaged. This will enable
more high-risk women safe access to this female-controlled
method. However, given its relatively high rate of contracep-
tive failure, clinicians will not recommend it enthusiastically as
a single method except to women reluctant or unable to use
other methods. Amphora may play a greater role as a personal
lubricant in conjunction with other methods if it is popularized
as a contraceptive. The biggest unanswered question, how-
ever, is Amphora’s role as a microbicide. Will it help fill the
need for multipurpose preventative technology? [29] If
Amphora is shown in anticipated human trials to have signifi-
cant microbicidal activity, there may be a marked increase in
enthusiasm to recommend it for STD risk reduction, when
couples are not interested in using external (male) or internal
(female) condoms. Many women apparently feel stigmatized
and do not ask for PREP. Disguising their request for a micro-
bicide as a request for contraception may prove to be more
acceptable socially.
The facts that Amphora is female-controlled and is avail-
able over-the-counter without prescription will hopefully
appeal to more women who do not currently use any method
of birth control. This may help reduce unintended pregnancy
rates, especially if these women have been reluctant to use
available hormonal or ‘invasive’ contraceptive methods.
However, given Amphora’s relatively high failure rates, even
with correct and consistent use, research should continue to
discover other approaches to immobilize, inactivate, or
destroy sperm so that other products may be developed to
help women control their own fertility.
Funding
This paper was not funded.
Declaration of interest
ALN declares that she has received payments for research from Agile,
ContraMed/Sebela, Estetra SPRL, Evofem Inc, FHI (MonaLisa), Mathra
Phram, and Merck and honoraria for participation on advisory boards or
speaker bureaus for Agile, Allergan, AMG Pharma, Bayer, ContraMed/
Sebela, Merck and Pharmanest. ALN has received grant funding as princi-
pal investigator at one of the sites currently conducting a Phase III trial of
the safety and efficacy of Amphora.
Reviewer disclosures
Peer reviewers on this manuscript have no relevant financial or other
relationships to disclose.
8 A. L. NELSON
References
Papers of special note have been highlighted as either of interest (•) or of
considerable interest (••) to readers.
1. Finer LB, Zolna MR. Declines in unintended pregnancy in the
United States, 2008–2011. N Engl J Med. 2016;374(9):843–852.
2. Iseyemi A, Zhao Q, McNicholas C, et al. Socioeconomic status as a
risk factor for unintended pregnancy in the contraceptive CHOICE
project. Obstet Gynecol. 2017;130(3):609–615.
3. State facts about unintended pregnancy. Guttmacher Institute.
2016 Sept [cited 2018 Jun 18]. Available from: https://www.guttma
cher.org/fact-sheet/state-facts-about-unintended-pregnancy
4. Global, regional, and subregional trends in unintended pregnancy
and its outcomes from 1990–2014: estimates from a Bayesian
Hierarchical Model. Guttmacher Institute; 2018 March [cited 2018
Jun 18]. Available from: https://www.guttmacher.org/article/2018/
03/unintended-pregnancy-and-its-outcomes-global-regional-and-
subregional-trends-1990
5. Cleland K, Peipert JF, Westhoff C, et al. Family planning as a cost-
saving preventive health service. N Engl J Med. 2011;364(18):e37.
6. Moreau C, Bohet A. Frequency and correlates of unintended preg-
nancy risk perceptions. Contraception. 2016;94(2):152–159.
7. Hatcher RA, Trussell J, Nelson AL, et al. Contraceptive Technology
20th edition: Chapter 3, Choosing a contraceptive: Efficacy, safety,
and personal considerations: p. 50. New York (NY); Ardent Media;
2011.
8. Kavanaugh ML, Jerman J. Contraceptive method use in the United
States: trends and characteristics between 2008, 2012 and 2014.
Contraception. 2017;97(1):14–21.
9. WHO. Nonoxynol-9 ineffective in preventing HIV infection; 2002
[cited 2018 Jun 18]. Available from: http://www.who.int/mediacen
tre/news/notes/release55/en/
• This was a very important pivotal pronouncement which
encouraged the search for a replacement spermicidal product.
10. Brown J, Hooper G, Kenyon CJ, et al. Spreading and retention of
vaginal formulations in post-menopausal women as assessed by
gamma scintigraphy. Pharm Res. 1997;14(8):1073–1078.
11. Mauck CK, Allen S, Baker JM, et al. An evaluation of the amount of
nonoxynol-9 remaining in the vagina up to 4 h after insertion of a
vaginal contraceptive film (VCF) containing 70 mg nonoxynol-9.
Contraception. 1997;56(2):103–110.
12. Witter FR, Barditch-Crovo P, Rocco L, et al. Duration of vaginal
retention and potential duration of antiviral activity for five non-
oxynol-9 containing intravaginal contraceptives. Int J Gynaecol
Obstet. 1999;65(2):165–170.
13. Grimes DA, Lopez LM, Raymond EG, et al. Spermicide used alone for
contraception. Cochrane Database Syst Rev. 2013;12:CD005218.pub4.
14. Schreiber CA, Ratcliffe SJ, Sammel MD, et al. A self-assessment
efficacy tool for spermicide contraceptive users. Am J Obstet
Gynecol. 2016;214(2):264.e1–264.e7.
15. Wilkinson D, Ramjee G, Tholandi M, et al. Nonoxynol-9 for prevent-
ing vaginal acquisition of HIV infection by women from men.
Cochrane Database Syst Rev. 2002;4:CD003936.
16. Van Damme L, Chandeying V, Ramjee G, et al. Safety of multiple
daily applications of COL-1492, a nonoxynol-9 vaginal gel, among
female sex workers. COL-1492 phase II study group. AIDS. 2000;14
(1):85–88.
17. Kreiss J, Ngugi E, Holmes K, et al. Efficacy of nonoxynol 9 contra-
ceptive sponge use in preventing heterosexual acquisition of HIV in
Nairobi prostitutes. JAMA. 1992;268(4):477–482.
18. Roddy RE, Zekeng L, Ryan KA, et al. A controlled trial of nonoxynol
9 film to reduce male-to-female transmission of sexually trans-
mitted diseases. N Engl J Med. 1998;339(8):504–510.
19. Cone RA, Hoen T, Wong X, et al. Vaginal microbicides: detecting
toxicities in vivo that paradoxically increase pathogen transmission.
BMC Infect Dis. 2006;6:90.
20. Fields S, Song B, Rasoul B, et al. New candidate biomarkers in the
female genital tract to evaluate microbicide toxicity. PLoS One.
2014;9(10):e110980.
21. Stafford MK, Ward H, Flanagan A, et al. Safety study of nonoxynol-9
as a vaginal microbicide: evidence of adverse effects. J Acquir
Immune Defic Syndr Hum Retrovirol. 1998;17(4):327–331.
22. Hoffman IF, Taha TE, Padian NS, et al. Nonoxynol-9 100 mg gel:
multi-site safety study from sub-Saharan Africa. AIDS. 2004;18
(16):2191–2195.
23. Tabet SR, Surawicz C, Horton S, et al. Safety and toxicity of non-
oxynol-9 gel as a rectal microbicide. Sex Transm Dis. 1999;26
(10):564–571.
24. Fuchs EJ, Grohskopf LA, Lee LA, et al. Quantitative assessment of
altered rectal mucosal permeability due to rectally applied nonox-
ynol-9, biopsy, and simulated intercourse. J Infect Dis. 2013 May
1;207(9):1389–1396.
25. Coleman JS, Fuchs E, Aung WS, et al. Feasibility of radiolabeled
small molecule permeability as a quantitative measure of micro-
bicide candidate toxicity. Contraception. 2016 Apr;93(4):331–336.
26. Smith-McCune K, Chen JC, Greenblatt RM, et al. Unexpected inflam-
matory effects of intravaginal gels (universal placebo gel and
Nonoxynol-9) on the upper female reproductive tract: a rando-
mized crossover study. PLoS One. 2015;10(7):e0129769.
27. Department of Health and Human Services. FDA final rule. Over-the
counter vaginal contraceptive and spermicide drug products con-
taining Nonoxynol 0; required labeling. [cited 2018 Jun 10].
Available from: ww.fda.gov/OHRMS/DOCKETS/98fr/80n-0280-
nfr0003.pdf
28. U.S. Medical Eligibility Criteria for Contraceptive Use. 2016 [cited
2018 Jun 18]. Available from: https://www.cdc.gov/mmwr/
volumes/65/rr/pdfs/rr6503.pdf
•• This document and the WHO Medical Eligibility Criteria docu-
ment have revolutionized contraceptive practice by providing
evidence based expert guidelines that freed clinicians from
product labeling warnings.
29. Stone A. Multipurpose prevention technologies for reproductive
and sexual health. Reprod Health Matters. 2014;22(44):213–217.
• An early optimistic description of the possible potential of
Amphora as an example of progress made in the field of multi-
purpose prevention technologies.
30. Li W, Huang Z, Wu Y, et al. Effectiveness of an optimized benzalk-
onium chloride gel as vaginal contraceptive: a randomized controlled
trial among Chinese women. Contraception. 2013;87(6):756–765.
31. Aubeny E, Colau JC, Nandeuil A. Local spermicidal contraception: a
comparative study of the acceptability and safety of a new phar-
maceutical formulation of benzalkonium chloride, the vaginal cap-
sule, with a reference formulation, the pessary. Eur J Contracept
Reprod Health Care. 2000;5(1):61–67.
32. Burke AE, Barnhart K, Jensen JT, et al. Contraceptive efficacy,
acceptability, and safety of C31G and nonoxynol-9 spermicidal
gels: a randomized controlled trial. Obstet Gynecol. 2010;116
(6):1265–1273.
33. Feldblum PJ, Adeiga A, Bakare R, et al. SAVVY vaginal gel (C31G) for
prevention of HIV infection: a randomized controlled trial in
Nigeria. PLoS One. 2008;3(1):e1474.
34. Lishko PV. Contraception: search for an ideal unisex mechanism by
targeting ion channels. Trends Biochem Sci. 2016;41(10):816–818.
35. Baptista M, Publicover SJ, Ramalho-Santos J. In vitro effects of
cationic compounds on functional human sperm parameters.
Fertil Steril. 2013;99(3):705–712.
36. Li K, Ni Y, He Y, et al. Inhibition of sperm capacitation and fertilizing
capacity by adjudin is mediated by chloride and its channels in
humans. Hum Reprod. 2013;28(1):47–59.
37. Cooper TG, Yeung CH. Pharmacological approaches to male contra-
ception. In: Chapter 30 in andrology: male reproductive health and
dysfunction. 2nd ed. Berlin: Springer; 2010. p. 589–598.
38. Das N, Chandran P, Chakraborty S. Potent spermicidal effect of
oleanolic acid 3-beta-D-glucuronide, an active principle isolated
from the plant Sesbania Sesban Merrill. Contraception. 2011;83
(2):167–175.
39. Paul D, De D, Ali KM, et al. Comparative study on the spermicidal
activity of organic solvent fractions from hydroethanolic extracts of

Achyranthes aspera and Stephania hernandifolia in human and rat
sperm. Contraception. 2010;81(4):355–361.
40. Bayer LL, Jensen JT. ACIDFORM: a review of the evidence.
Contraception. 2014;90(1):11–18.
•• The most comprehensive article written on this topic.
41. Amaral E, Perdigao A, Souza MH, et al. Vaginal safety after use of a
bioadhesive, acid-buffering, microbicidal contraceptive gel
(ACIDFORM) and a 2% nonoxynol-9 product. Contraception. 2006;73
(5):542–547.
42. Garg S, Anderson RA, Chany CJ 2nd, et al. Properties of a new acid-
buffering bioadhesive vaginal formulation (ACIDFORM). Contraception.
2001;64(1):67–75.
•• The most detailed study of the spermicidal properties of
Amphora. All other articles rely on these results.
43. Schwartz JL, Weiner DH, Lai JJ, et al. Contraceptive efficacy, safety,
fit, and acceptability of a single-size diaphragm developed with
end-user input. Obstet Gynecol. 2015;125(4):895–903.
44. Abdool Karim SS, Richardson BA, Ramjee G, et al. Safety and effec-
tiveness of BufferGel and 0.5% PRO2000 gel for the prevention of
HIV infection in women. AIDS. 2011;25(7):957–966.
45. Guffey MB, Richardson B, Husnik M, et al. Network (HPTN) 035
Study Team. HPTN 035 phase II/IIb randomised safety and effec-
tiveness study of the vaginal microbicides BufferGel and 0.5% PRO
2000 for the prevention of sexually transmitted infections in
women. Sex Transm Infect. 2014;90(5):363–369.
46. Zeitlin L, Hoen TE, Achilles SL, et al. Tests of Buffergel for contra-
ception and prevention of sexually transmitted diseases in animal
models. Sex Transm Dis. 2001;28(7):417–423.
47. Keller MJ, Carpenter CA, Lo Y, et al. Phase I randomized safety study
of twice daily dosing of acidform vaginal gel: candidate antimicro-
bial contraceptive. PLoS One. 2012;7(10):e46901.
48. Olmsted SS, Dubin NH, Cone RA, et al. The rate at which human
sperm are immobilized and killed by mild acidity. Fertil Steril.
2000;73(4):687–693.
49. Amaral E, Perdigão A, Souza MH, et al. Postcoital testing after the
use of a bio-adhesive acid buffering gel (ACIDFORM) and a 2%
nonoxynol-9 product. Contraception. 2004 Dec;70(6):492–497.
EXPERT OPINION ON DRUG SAFETY 9
50. von Mollendorf CE, Van Damme L, Moyes JA, et al. Results of a
safety and feasibility study of the diaphragm used with ACIDFORM
Gel or K-Y Jelly. Contraception. 2010;81(3):232–239.
51. Amaral E, Faúndes A, Zaneveld L, et al. Study of the vaginal
tolerance to Acidform, an acid-buffering, bioadhesive gel.
Contraception. 1999;60(6):361–366.
52. Williams DL, Newman DR, Ballagh SA, et al. Phase I safety trial of
two vaginal microbicide gels (Acidform or BufferGel) used with a
diaphragm compared to KY jelly used with a diaphragm. Sex
Transm Dis. 2007;34(12):977–984.
53. Anderson DJ, Williams DL, Ballagh SA, et al. Safety analysis of the
diaphragm in combination with lubricant or acidifying microbi-
cide gels: effects on markers of inflammation and innate immu-
nity in cervicovaginal fluid. Am J Reprod Immunol. 2009;61
(2):121–129.
54. Schwartz JL, Poindexter A, Schmitz SW, et al. Male tolerance of
ACIDFORM gel. Contraception. 2005;71(6):443–446.
55. Barnhart K, Dart C, Culwell K. Efficacy, safety, and acceptability of acid-
form (Amphora) and nonoxynol-9 contraceptive vaginal gels [16N].
Poster presentation. ACOG Annual Clinical Meeting. Washington, DC.
2016.
• The only source of information about the outcomes of the first
Phase III clinical trial of this spermicide.
56. Spencer SE, Valentin-Bon IE, Whaley K, et al. Inhibition of
Neisseria gonorrhoeae genital tract infection by leading-candi-
date topical microbicides in a mouse model. J Infect Dis.
2004;189(3):410–419.
57. Tuyama AC, Cheshenko N, Mj C, et al. ACIDFORM inactivates herpes
simplex virus and prevents genital herpes in a mouse model:
optimal candidate for microbicide combinations. J Infect Dis.
2006 Sep 15;194(6):795–803.
58. Simoes JA, Bahamondes LG, Camargo RP, et al. A pilot clinical trial
comparing an acid-buffering formulation (ACIDFORM gel) with
metronidazole gel for the treatment of symptomatic bacterial vagi-
nosis. Br J Clin Pharmacol. 2006;61(2):211–217.
59. Gabbay M, Gibbs A. Does additional lubrication reduce condom
failure? Contraception. 1996;53(3):155–158.