After completing this continuing education article, the pharmacist should be able to:
Commonly used methods of reversible contraception include oral contraceptives (OCs), long-acting injectable or implantable progestins, condoms, spermicides, withdrawal, the diaphragm, periodic abstinence, and the intrauterine device (IUD). These methods differ in their relative effectiveness, safety, and patient acceptability.
OCs have been available for almost 4 decades. During this time, changes in contraceptive use in general and OCs in particular have occurred. Knowledge and attitudes about OCs may not always reflect trends in use. Contraceptive use data from 1965 to 1995 show that OCs continue to be the most popular form of reversible birth control, chosen consistently by more than one quarter of women contraceptors. According to estimates by the National Center for Health Statistics, 10.4 million women in the United States used OCs in 1995.1 As a method of contraception, use of birth control pills is second only to female sterilization. In 1995 more women between the ages of 15 and 44 relied on tubal ligation to prevent pregnancy than OCs.1 More women would probably use the pill if they had more accurate information regarding the higher failure rates with barrier methods (especially the condom), if misperceptions about OC safety were put to rest, and if greater awareness of the noncontraceptive health benefits of OCs could be achieved.
Birth control pills have been marketed since 1960; however, today’s OCs contain lower doses of hormones. Despite the lower hormone content, currently available OCs are as effective in preventing pregnancy as the original ones but are considered much safer. However, since their introduction in 1960 in the United States, research identifying the benefits and risks of OCs has yielded mixed results. This has affected utilization. Because the potential long-term effects of hormone therapy continue to be a subject of controversy and intense investigation, many patients and health care professionals remain skeptical and choose alternative therapy when OCs may be more beneficial. Additionally, women’s lack of knowledge about, and discomfort with, short-term adverse effects, such as breakthrough bleeding and gastrointestinal (GI) upset contribute to compliance and utilization problems. About one million unwanted pregnancies each year in the United States are as a result of improper adherence to OC regimens.2 Increased education of women and their health care providers has the potential to positively affect future contraceptive use.
In addition to oral administration, newer delivery systems for hormonal contraception have been developed. Nonoral routes offer the advantage of avoiding the first pass through the liver, thereby allowing lower doses of hormone and reducing the metabolic adverse effects. These delivery systems produce constant serum hormone concentrations and simplify compliance. The steroids used in these systems, most commonly progestins, are useful for long-term contraception when injected or implanted into the skin. This method of hormonal contraception may be an alternative for patients with whom compliance is an issue or for those who may benefit from progestin-only contraception. Well-educated pharmacists have an opportunity to help ensure the proper use of hormonal contraception.
Comprehension of mechanisms involved in the hormonal regulation of the normal menstrual cycle is essential to understanding contraception in women. Contraception generally implies the prevention of pregnancy following sexual intercourse by inhibiting viable sperm from coming into contact with a mature ovum (ie, acting as barriers or preventing ovulation) or by preventing a fertilized ovum from successfully implanting in the endometrium (ie, creating an unfavorable uterine environment).
The normal menstrual cycle consists of three distinct phases, follicular, ovulation, and luteal (Figure).3 These are associated with hormonal changes that facilitate follicle development in the ovary, follicle release, and implantation, respectively.4,5 The average menstrual cycle lasts 28 days.
The follicular phase, which begins at menstruation and continues for approximately 14 days, is regulated by estrogen. Low estrogen levels at the beginning of this phase initiate the release of follicle-stimulating hormone releasing factor (FSH-RF) and luteinizing hormone-releasing factor (LH-RF) from the hypothalamus. Stimulation of those factors triggers the release of gonadotropins from the anterior pituitary gland, including an FSH that stimulates follicle development within the ovary, and an LH that initiates estrogen secretion from the new follicles. The process generates higher levels of estrogen, stimulating endometrial growth, while creating a negative feedback loop in which rising estrogen levels inhibit further FSH release, thus causing the majority of follicles to atrophy. However, one dominant follicle continues to develop and release estrogen.4,5
The ovulatory phase is brief. High levels of estradiol, which is the principal estrogen produced by the ovary and the most potent endogenous estrogen, during a 50-hour period trigger an LH surge, which ultimately stimulates follicle release and formation of the corpus luteum. The LH surge occurs approximately midcycle (day 14) in a normal 28-day cycle.4,5
The luteal phase follows the ovulatory phase, and for most women lasts 13 to 15 days. During this phase, the corpus luteum produces both progesterone and
estradiol, but progesterone dominates. The estradiol enables the development of progesterone receptors. Progesterone causes the transformation of the endometrium to a secretory type in preparation for implantation. If implantation does not occur by days 23 to 25 of the cycle, the corpus luteum regresses, resulting in declining levels of estrogen and progesterone. Because these low hormone levels cannot maintain the uterine lining, sloughing off of the endometrial lining (menstruation)
results.4,5 Declining hormone levels initiate the beginning of a new cycle.
OCs prevent follicle development and ovulation by capitalizing on feedback loops that regulate the normal menstrual cycle. Providing exogenous estrogen inhibits the release of FSH-RF and LH-RF and thereby prevents follicle development. Estrogens also inhibit ovum implantation. The progestin component of combination OCs promotes cervical mucus thickening, thus impeding the transport of sperm through the cervical canal.5
The first OC released in the United States contained both estrogen and progestin, given in fixed doses for 21 days, followed by 7 hormone-free days, thereby mimicking the time frame of the average menstrual cycle in which levels of both endogenous estrogen and progesterone decline.6 These initial formulations contained daily doses of 50 to 100 mcg of estrogen and 1 to 10 mg of progestin. Since the recognition in 1963 of serious thromboembolic adverse effects related to OC use, formulations have been modified. Currently available products contain 50 mcg of estrogen or less (the majority with 35 mcg or less) and 1 mg of progestin or less. In some cases, the hormone components have been modified. Synthetic progestins have been formulated to minimize the androgenic adverse effects attributed to the progestin component of earlier products.
The currently available OCs contain either a combination of a synthetic estrogen and a synthetic progestin or a progestin alone (Table 1).7 The current formulations include monophasic-, biphasic-, and triphasic-dosing cycles. The monophasic products provide a fixed dose of estrogen and progestin throughout the cycle. During the past decade, combination multiphasic (biphasic and triphasic) formulations have further lowered the total monthly hormonal dose, but no significant clinical advantage to this decrease has been observed.8,9 Biphasic and triphasic formulations are designed to mimic physiologic fluctuations in estrogen and progestin levels. Biphasic preparations deliver a fixed dose of estrogen and two different dosages of progestin. Triphasic preparations contain varying dosages of both estrogens and progestins with three distinct dosing phases. The progestin-only “minipills” (28 days of active hormone/ cycle), which were introduced in 1960, are still available. Containing even lower doses of progestin than found in combination OCs and lacking the contribution of estrogen, minipills tend to be less effective than combination OCs with “typical use” and are generally reserved for women who must avoid estrogen. Typical use takes into account the user’s ability to follow directions correctly and consistently and accounts for some degree of OC failure (“typical use failure” or “user failure”).5 Failure inherent in the proper use of the contraceptive alone is considered a “method failure” or “perfect use failure.”5
Table 1. Types of Oral Contraceptives
|Category||Estrogen Content (mcg)||Progestin Content (mg)|
|Low-dose||20-50 (daily for 21 days)||0.15–1.5 (daily for 21 days)|
|Low-dose (shortened hormone-free period)||20 (days 1–21);
10 (days 24–28)
|0.15 (daily for 21 days)|
|Biphasic||35-50||0.5–1.0 (only on days 7–14 per cycle)|
|Triphasic||35-50||0.5–1.0 (only on days 7-14 per cycle)|
|Source: Adapted from reference 7.|
Prior to the 1998 introduction of a low-dose combination OC in which the placebo period was shortened to 2 days,10 all combination formulations had maintained a 7-day hormone-free interval, either by supplying placebo pills or by not including pills during the last 7 days of the cycle.
Components. Two synthetic estrogens commonly used in OCs in the United States, ethinyl estradiol (EE) and mestranol, differ only by the presence of a methyl group attached to mestranol at the C-3 site. Mestranol, which must be converted by the liver to EE before it is pharmacologically active, is estimated to be 50% less potent than EE.5 Progestins currently used in OCs include ethynodiol diacetate, desogestrel, gestodene (not available in the United States), norgestimate, norethindrone, norethindrone acetate, norethynodrel, norgestrel, and its active isomer levonorgestrel. Progestins vary in their progestational activity and differ with respect to inherent estrogenic, antiestrogenic, and androgenic effects.11 Estrogenic and antiestrogenic properties are secondary to the extent of progestin’s metabolism to estrogenic substances, whereas androgenic activity is determined by structural similarity of the progestin to testosterone (receptor binding and activity) and the ability to affect free testosterone concentrations through the impact on sex hormone–binding globulin, a major carrier protein for testosterone.5
Third-generation OCs contain newer progestins (eg, norgestimate, desogestrel, and gestodene). These progestins are potent progestational agents that appear to have no estrogenic effects and are less androgenic when compared with levonorgestrel on a weight basis. Unfortunately, clinical trials comparing the differences between OCs are few, and the sample sizes have been small. As a result, actual relevance of these touted improvements in progestational selectivity and lower androgenic activity remains unknown.12
Health care professionals and patients may be unaware of some of the other numerous uses of OCs beyond pregnancy prevention. The following benefits are recognized by the FDA and are included in the prescribing information of these products.7 Pharmacists should become familiar with these potential uses of OCs to be able to counsel patients on their utility in various situations.
Cycle Control. Although not typically considered a physical health risk, erratic menstrual cycles may be associated with psychological consequences, unwanted pregnancies, and inconveniences related to daily activities. For women with erratic cycles, OCs may improve control and predictability of cycle frequency and duration. Women suffering from prolonged bleeding, more than 7 days, or excessive blood loss (hypermenorrhea or menorrhagia) may obtain relief from OCs.13
Menstrual Migraine. Although not uniformly defined in the literature, a menstrual migraine can be described as a severe headache that begins about 2 days prior to menses initiation and lasts until the end of menses. The reported incidence of menstrual migraine ranges from 4 to 73%, with the true incidence unknown.14 Some women experience symptom relief while taking OCs and have headache recurrences during the hormone-free interval. Some studies have shown results in symptom relief for some women and worsening of headaches in others.14 Continued administration should be based on patient-specific response.
Dysmenorrhea. Dysmenorrhea is defined as painful menstruation. Affecting as many as half of all menstruating women,5,7 this condition varies in severity from mild uterine cramping to severe cramping accompanied by nausea and vomiting. Symptom presence has been linked to abnormal uterine prostaglandin production and release. Progestin-mediated reduction of endometrial lining has been found to provide symptom relief. Nonsteroidal anti-inflammatory drugs and combination OCs that contain a high progesterone-to-estrogen ratio are treatments of choice for this disorder.13
Premenstrual Dysphoric Disorder. The constellation of symptoms that appear during the latter half of the menstrual cycle and remit at some point during menses is referred to as premenstrual dysphoric disorder.5 One or more of the following symptoms are associated with this disorder: bloating, dysmenorrhea, depression, fatigue, mood lability, irritability, thirst, appetite changes, breast tenderness, edema, headache, constipation, diarrhea, and acne. Similar to dysmenorrhea, these symptoms can be a minor nuisance or can substantially impact the patient’s quality of life.
OCs are among the pharmacologic options that have been evaluated for the management of this condition; however, their use in this setting remains controversial. Women with a history of premenstrual dysphoric disorder experienced a significant decrease in breast pain and bloating with the use of a triphasic OC product in one clinical trial.5 Other reports have shown that symptoms may worsen. Shortening the hormone-free interval may also lead to a reduction in some premenstrual dysphoric disorder symptoms.5
Anemia. A 45% decrease in the incidence of iron-deficiency anemia in OC users compared with nonusers is believed to be the result of OC users experiencing decreased menstrual flow. Menstrual blood flow is decreased by 60% or more with the use of OCs. Anemic women, as well as those frequently experiencing hypermenorrhea or menorrhagia, may benefit from this effect.13
Endometrial Cancer Protection. Progestin-induced reduction in endometrial hyperplasia has been linked to a lower incidence of endometrial cancer in OC users. Clinical trials have found a risk reduction of as much as 50% in women who used OCs for at least 12 months. The beneficial effect is believed to persist for at least 15 years after OC use ceases.9,11
Ovarian Cancer Protection. OC use has been associated with a reduction in the risk of developing ovarian cancer. This protective effect becomes evident as early as 3 to 6 months after therapy initiation. Women who use these agents for up to 4 years are 30% less likely to develop ovarian cancer. An 80% risk reduction has been found in women using OCs for more than 10 years.9,11
Benign Breast Disease. Benign breast disease, fibrocystic and fibroadenomatous, most commonly .manifests as fibrocystic changes and fibroadenomas. The incidence of fibrocystic changes, which are the most frequent findings, varies by age, ranging from 10% in women younger than 21 years of age to 70% in perimenopausal women (up to 10 years before menopause onset). Fibroadenomas most commonly occur in women younger than 25 years of age.15 The incidence of benign breast disease is decreased by 50 to 75% in women who take OCs compared with nonusers.
Pelvic Inflammatory Disease. Women without a history of pelvic inflammatory disease (PID) who take OCs for at least 1 year have been found to have half the risk of developing PID as nonusers. The progesterone-induced thickening of the cervical mucus may help prevent bacteria from entering the uterus and fallopian tubes. The reduction in menstrual blood flow may also contribute to lower PID incidence, because blood can serve as a culture medium for bacterial growth. However, some reports of increased infections caused by chlamydia trachomatis have been linked to contraceptive use. Therefore, the role of OCs in this patient population remains controversial.16
Acne. The development of acne is influenced by the increases in sebum production caused by testosterone and by the degree of skin oiliness. Progesterone has been linked to worsening acne symptoms. Formulations of OCs with low-dose progestins that are less androgenic, such as desogestrel, norgestimate, and norethynodrel, are not commonly associated with acne flares and may improve acne symptoms.2,7,17 The FDA has approved OrthoTricyclen, a combination of EE and norgestimate, for the treatment of acne in postmenarchal women older than age 15.
When used properly, OCs are highly effective and extremely safe. However, a complete medical history and physical examination should be obtained before a patient is started on an OC, and the risks and contraindications to OC use must be carefully considered (Table 2). This gives pharmacists an excellent opportunity to discuss OC use with their patients.
The following are absolute contraindications to the use of OCs:
• Thrombophlebitis, thromboembolic disorders, cerebral vascular disease, coronary occlusion, or a past history of these conditions, or conditions predisposing to these problems.
• Markedly impaired liver function.
• Known or suspected breast cancer.
• Undiagnosed abnormal vaginal bleeding.
• Known or suspected pregnancy.
• Smokers older than age 35.
There are also relative contraindications to OCs that require clinical judgment and informed consent before starting on the pill. Certain patient-specific characteristics and concomitant disease states increase the patient’s risk for adverse effects relating to OC use (Table 2). Pharmacists should take these into consideration when deciding whether a patient should consider OCs as her method of birth control and whether a patient’s OC is causing an adverse effect or worsening a disease.
Table 2. Risks and Contraindications to OC Use
Adolescence. Concerns about possible adverse effects of OC use in adolescence on growth and maturation of the hypothalamic-pituitary-ovarian axis have not been substantiated. OCs can be taken by healthy, menstruating adolescents without any special assessment, regardless of age, character of menstrual cycles, or age at menarche.
Generally, OCs are an acceptable form of birth control for nonsmoking women up to the age of menopause, with women older than 40 using the lowest dose estrogen products.11 OCs containing estrogen are absolutely contraindicated in smokers older than age 35, and relatively contraindicated in younger women who are heavy smokers (15 or more cigarettes per day). One possible exception may be a 20-mcg estrogen formulation. This extremely low-dose OC does not appear to have an impact on clotting factors and platelet activation, even in smokers.5 Progestin-only pills are generally acceptable for women in whom estrogen is contraindicated.
Adverse effects from OCs may lead to early discontinuation and noncompliance in many patients. Such effects may be related to either the estrogen or the progestin component
(Table 3). When the adverse effect is attributable to the estrogen component, it is most often dose-related. Those attributable to the progestin component are most often associated with the type of progestin because some progestins are more androgenic than others. The most common adverse effects associated with estrogen-progestin combination products include spotting, breakthrough bleeding, GI upset, breast
tenderness, weight gain, and headache. Some patients also experience acne flares or unwanted hair growth. More serious adverse effects include thrombophlebitis, venous thrombosis, myocardial infarction (MI), and exacerbation of
Menstrual cycle irregularities, such as spotting, breakthrough bleeding, and amenorrhea (absence of menstrual bleeding), may occur with OC use. These seem to be more frequent with progestin-only and reduced-estrogen products. Breakthrough bleeding is more common during the first month of OC use, with incidence rates dropping by the third month.6 When this effect occurs during the first half of the cycle, it is related to insufficient estrogen levels. Occurrence during the second half of the cycle is related to decreased progesterone levels. Pharmacists can advise on regimen manipulation, which may allow for control and prevention of breakthrough bleeding. Patients should also be informed about changes in menstrual flow, and that this effect most commonly occurs at therapy onset and is transient in nature, usually resolving in three to four cycles. Caution should be used when evaluating patients with menstrual flow complaints, because nonhormonal (eg, pregnancy, infection, or malignancy) causes of menstrual disturbances should be considered in the absence of symptom resolution.
Table 3. Adverse Effects of Hormonal Contraceptives
|Adverse Effect||Causative Component||Comments|
|Bleeding irregularities||Low estrogen days 1-14; low progesterone days 15-21||May need increased estrogen;expected during first 3-6 cycles|
|Gastrointestinal upset||Estrogen||Use lowest dose of estrogen; expected during first 3-6 cycles|
|Breast tenderness||Estrogen||May need reduction in estrogen dose; expected during first 3-6 cycles|
|Acne||Progestin||Use agent with progestin that has low androgenic potential|
|Headache||Estrogen||Evaluate to determine if related to withdrawal|
|Weight gain||Estrogen and progestin||Weight may or may not change|
|Hypertension||Estrogen and progestin||Use low-progestin/low-estrogen product|
|Thromboembolic event||Estrogen||Particularly associated with older products; cigarette smoking increases risk|
|Source: Adopted from references 2,5,7 and 17.|
Migraine headaches, as noted earlier, may be worsened in some patients by the use of OCs. Because this effect is thought to be caused by estrogen, selecting products with a low estrogen component may decrease the occurrence of headaches. In patients who develop a headache during the placebo portion of therapy (hormone-free), the possibility of hormone withdrawal syndrome should be considered.14 Shortening or eliminating the hormone-free period by extending the duration of active medication has been shown to reduce the onset of migraines associated with hormone withdrawal in some patients.5 Reducing the placebo period has proved to delay symptom onset, and the extended period of hormone treatment is generally well tolerated. Clinicians may recommend taking the active pills for three cycles before taking the inactive pills (sometimes called “tricycling”) or taking an OC formulation with a shortened hormone-free interval (Mircette) for patients who suffer from the physiologic effects of hormone withdrawal. If headaches continue, pharmacists should advise their patients to be evaluated for a nonhormonal cause.
Nausea and vomiting have been reported to occur in 10 to 30% of women at the initiation of
therapy.17 Complaints of cramping and bloating have also been reported. Pharmacists should explain to their patients that symptoms should resolve with continued use. These effects are most likely related to the estrogen component, because products containing low estrogen doses cause less GI
upset.2 Patients can take their daily dose with food or at bedtime to improve tolerability of the OC. Rarely is the nausea severe enough to necessitate giving an antinausea agent with the pill for the first few weeks. Alternatively, the pill can be inserted intravaginally initially. The absorption may not be as reliable, so a backup method is advised. However, the nausea is avoided, and the patient can adjust to the hormone dose before switching to oral administration.
Breast tenderness, enlargement, and discharge, which are caused by estrogen, sometimes occur with OC use and may be responsible for a 34% rate of early discontinuation of therapy.2 Although these adverse effects should lessen as therapy continues, patients are recommended to see a clinician if they experience breast discharge. Patients with ongoing symptoms may benefit from changing to a product with a lower dose of estrogen or a progestin-only product. Pharmacists may also inform patients that reducing dietary intake of products containing methylxanthines (eg, coffee or chocolate) may also lessen the discomfort.2,6 If any of these adverse effects continue, the pharmacist should advise the patient to be evaluated by a clinician.
Fluctuations in weight have occurred during the use of OCs; estrogen-induced fat deposits and estrogen- or progestin-induced fluid retention are contributing factors. Approximately equal numbers of OC users gain or lose weight. The effect in the majority of cases is minimal (eg, half a kilogram by the third cycle), but the weight change can contribute to patient nonadherence.
Acne flares may occur in some women using products containing the progestin norgestrel because it is strongly androgenic. Formulations containing progestins with a high androgenic effect, such as norethindrone, may worsen acne severity and would not be a good choice for a patient with acne. Pharmacists can recommend products with less androgenic properties if acne flares occur with one type of OC.
Elevated blood pressure, which is associated with race, family history, obesity, diet, smoking, increasing age, and prolonged OC use, may occur anytime during OC
therapy.6 Clinically significant increases in blood pressure are rare with low-dose OCs. If an OC-related increase in blood pressure occurs, discontinuing the OC usually results in return to pretreatment blood pressure values within 3 to 6
months.5 Patients older than age 35 with underlying cardiovascular risk factors (eg, smoking, diabetes, or hyperlipidemia) are at an increased risk of developing clinically significant hypertension and should be regularly monitored.
In contrast to estrogens, progestins impair glucose tolerance, with the degree of impairment depending on both the type and dose of the OC.6 The impairment is most marked with both nandrolone derivatives, and least with medroxyprogesterone acetate. The formulations containing low doses of progestins do not significantly alter insulin, glucose, or glucagon release after a glucose load in healthy women or in those with a history of gestational diabetes. The new progestins (eg, desogestrel and norgestimate) are believed to have little, if any, effect on carbohydrate metabolism.6 In addition, most women whose glucose metabolism becomes abnormal after they begin taking a combination OC have normal glucose levels after 6 months of use.6 Use of an OC is not absolutely contraindicated in women with diabetes and poses much less of a health risk in these women than pregnancy.
Lipid metabolism is adversely affected by synthetic progestins. High-density lipoprotein (HDL) is decreased, and low-density lipoprotein (LDL) is increased. Estrogens tend to have more beneficial effects by increasing removal of LDL from the circulation and increasing HDL as increases in apoliprotein a1. Estrogens may also alter the composition of very low-density lipoprotein and increase triglycerides.5,6 Most low-dose combination OCs, with the possible exception of monophasic levonorgestrel (0.150 mg), do not significantly impact HDL, LDL, triglycerides, or total cholesterol.5 Although the lipid effects of OCs can theoretically influence cardiovascular risk, the mechanism of the increased incidence of both venous and arterial cardiovascular disease in OC users, including MI, is believed to be secondary to thromboembolic and thrombotic changes, not atherosclerosis.6 Research has found that combination OCs are safe in women who do not have preexisting disease of the circulatory system.6,16 However, pharmacists should advise patients with dyslipidemias to have their lipoprotein profiles monitored monthly by their health care provider for a few visits to ensure no adverse impact.
In regard to thromboembolic events, estrogens play a dose-related role in the development of venous thrombosis and consequent pulmonary embolism (PE), especially in women who smoke or have other underlying conditions that are either inherited (eg, deficiencies in antithrombin III, protein C, protein S, or factor V Leiden mutation) or acquired (eg, immobility, trauma, surgery, and certain malignancies), which predispose them to coagulation abnormalities.5,18 Studies of newer products have not been conducted. Early studies reported the incidence of venous thromboembolism (VTE) to be as much as 12 times greater in OC users than in nonusers.18 These data have been confirmed for the older products; however, the risk is much less (less than threefold increase in relative risk) than originally thought. The absolute risk is low, 15 cases/ 100,000 woman-years.18 Increased risk of VTE and PE appears to be limited to current users, with the disappearance of the risk within 3 months after stopping the OC. The 20-mcg EE formulations do not appear to have an effect on clotting parameters, even in smokers; however, whether these products lower the risk of thrombotic events has not been studied.
OCs are currently contraindicated in any woman at risk for VTE or with a history of deep venous thrombosis. Women who develop thrombotic complications while taking a low-dose OC should be evaluated for an underlying coagulation disorder. Some experts support the use of OCs in women with coagulation disorders who have been properly anticoagulated, citing the potential advantages of lowering the risk of fetal exposure to warfarin, bleeding corpus luteum cysts, and excessive blood loss during menses.5
Both thrombotic and hemorrhagic strokes have been associated with OC use. However, early studies used higher dose products and did not take into account independent factors for vascular disease (eg, smoking, hypertension, and advancing age). More recent data evaluating the low-dose OCs currently being used found the risk for stroke to be extremely low in healthy young women.6,18 These results suggest that the effect of smoking in women younger than age 35 is minimal in the absence of hypertension, and that hypertension appears to be the major risk factor for stroke. Cerebrovascular accidents (CVAs) are often preceded by persistent headaches, those occurring for weeks or months, or temporary hemiparesis. Pharmacists should educate patients on the warning signs of CVAs, such as slurring of speech, unilateral numbness, weakness, or tingling, to decrease their risk.
MI occurs primarily in OC users who are older than age 35 and who have additional risk factors for cardiovascular disease (eg, smoking, diabetes, hypertension, or obesity).6,9 These risk factors, particularly smoking, appear to act synergistically with OCs to increase the risk of cardiovascular disease.9 Since 1989, when the FDA lifted its restrictions on OC use in healthy nonsmoking women older than age 40, OCs containing 30 mcg of estrogen or less have been used more frequently in healthy, nonsmoking women up to the age of menopause without evidence of significantly increased risk of cardiovascular events.5,9 However, a black-box warning has been issued for the entire class of OCs, indicating that cigarette smoking increases the risk of cardiovascular effects associated with OC use.
The possibility of increased cancer risk with OCs may influence a woman’s choice of therapy and affect compliance. Numerous epidemiologic studies have been performed on the incidence of breast, endometrial, ovarian, and cervical cancer in women using OCs. Although conflicting reports exist, overall the literature suggests that the use of OCs is not associated with an increased risk of developing breast cancer, regardless of age and parity of first use.6,9,16,18 The Cancer and Steroid Hormone study17 showed no latent effect on the risk of breast cancer for at least 10 years following long-term use. Other studies have shown an increased relative risk of developing breast cancer, particularly at a younger age and apparently related to the duration of use. These studies have predominantly involved combination OCs, and there is insufficient data to determine whether the use of progestin-only contraceptives similarly increases the risk.
Women with breast cancer should not use OCs because the role of female hormones in breast cancer has not been fully determined. Most studies have not shown such a risk, and methodologies of earlier studies have been questioned. One study suggests that OC use prior to the first full-term pregnancy was associated with a significant relative risk of breast cancer, especially when OC use began before age 25.5,6 The Centers for Disease Control and Prevention has identified a small subset of premenopausal-associated breast cancers, but there is no proof of cause and effect; thus, no association with the postmenopausal variety exists.9 Other studies have demonstrated no increased risk of breast cancer in OC users with prior benign breast disease. Close clinical surveillance of all women taking OCs is essential; as with all women, OC users should be reexamined at least once a year. In all cases of undiagnosed persistent or recurrent abnormal vaginal bleeding, malignancy should be ruled out. Pharmacists should encourage women who have a strong family history of breast cancer or who have breast nodules, fibrocystic disease of the breast, cervical dysplasia, or abnormal mammograms to be monitored more closely.
Some studies suggest that OC use is associated with an increase in the risk of cervical intraepithelial neoplasia in some populations of women.9,16 However, insufficient data exist to determine whether the use of progestin-only OCs increases the risk of developing cervical intraepithelial neoplasia. Controversy continues about the extent to which such findings may be the result of differences in sexual behavior and other factors. Other epidemiologic studies have suggested an increased risk of cervical dysplasia and carcinoma.9 Despite many studies on the relationship between OC use and breast and cervical cancers, a cause-and-effect relationship has not been established.
Women who have previously used OCs may take longer to return to their baseline fertility than women who have used barrier contraception
methods.11 However, the percentage of women who conceive after stopping OCs is the same as for barrier-method users. Traditionally, women are counseled to allow for two to three normal menstrual periods before becoming pregnant to permit the establishment of menses and ovulation. However, clinical trials have shown that infants conceived in the first month after an OC was discontinued had no greater chance of being born with a birth defect than those born in the general
Any method of hormonal contraception is acceptable to begin immediately after first- or second-trimester termination of pregnancy (spontaneous or induced). Following third-trimester childbirth, ovulation does not usually occur again for 3 weeks, even in nonbreastfeeding women. The risk of maternal thromboembolic disease is increased for approximately the same period. Ideally, estrogen-containing contraceptives are withheld until the third week after delivery, but progestin-only methods can be initiated immediately.
Because the hormones in OCs are excreted into breast milk, breastfeeding is generally regarded as a relative contraindication to OC use. This was based on early findings using OCs with higher doses of hormones and probably does not apply to current products. Another concern is that estrogens inhibit the action of prolactin in breast tissue receptors, resulting in decreased milk production and protein
content.11 Although this is not a particular problem when used in well-nourished breastfeeding women, many practitioners recommend progestin-only contraceptives because progestins do not diminish the amount of breast milk, and they provide highly effective contraception in breastfeeding
Drug interactions sometimes limit the effectiveness of OCs, resulting in interference with GI absorption, increased intestinal motility by alteration of gut bacteriologic flora, and alterations in the metabolism, excretion, or binding of the OC (Table 4).17,19,20 Pharmacists should proactively screen for possible drug interactions whenever medications are added or removed from a patient’s therapeutic regimen.
High doses of estrogens can cause almost immediate shedding of the endometrium and prevent implantation of the fertilized ovum.21 The FDA has declared that OCs in one-time high doses are safe and effective as “emergency contraception” to prevent pregnancy after unprotected intercourse (eg, condom breakage, diaphragm dislodging, or sexual assault).5 Specifically, a dose of one of the following six brands can be taken within 72 hours of unprotected intercourse, with a follow-up dose 12 hours after the first: Ovral (two tablets/dose), Nordette, Lo/Ovral, Triphasil, Levlen, or Tri-Levlen (four tablets/ dose).17 The efficacy of this regimen declines if started more than 72 hours after intercourse, and treatment is ineffective by day 7 following intercourse, when implantation usually occurs.
New products have been developed specifically for this indication. The Preven emergency contraceptive kit contains four tablets, each containing 50 mcg of EE, 0.25 mg of levonorgestrel, and a pregnancy test that can be used to verify an existing pregnancy resulting from intercourse that occurred earlier in the current menstrual cycle or the previous cycle. If a positive pregnancy result is obtained, the pharmacist should advise the patient not to take the pills in the kit. The recently approved emergency contraceptive pill, Plan B, contains two 0.75-mg tablets of levonorgestrel and appears to be more effective and better tolerated than estrogen-progestin combinations. (It is associated with less nausea and vomiting.)
As with the use of OCs, pharmacists should counsel patients to take the initial one (Plan B) or two (Preven) pills as soon as possible but within 72 hours of unprotected intercourse. This is followed by the second dose of one (Plan B) or two (Preven) pills 12 hours later. Emergency contraception can be used at any time during the menstrual cycle. Patients should be informed that if they vomit within 1 hour of taking either dose of the medication, they should contact their health care professional to discuss whether to repeat that dose or take an antinausea medication. Emergency contraceptive pills are not indicated for ongoing pregnancy protection and should not be used as a woman’s routine form of contraception.17 The patient should also be advised to have a pregnancy test if she does not get her menses within 3 weeks after taking the emergency contraception.
Newer formulations of hormonal contraception, such as long-acting injectables and implants, offer select patients an option for hormonal contraception. Pharmacists should be knowledgeable about these products and be able to counsel patients on their use and adverse effects.
The most commonly used steroids for injectable or implantable contraception are progestins. Sustained progestin exposure blocks the LH surge, thus preventing ovulation. Should ovulation occur, progestins reduce ovum motility in the fallopian tubes. If fertilization occurs, progestins thin the endometrium, reducing the chance of implantation. Progestins also thicken the cervical mucus, producing a barrier for sperm penetration. However, FSH is not intensely suppressed by progestin-only contraception; therefore, follicular growth and estrogen concentrations, although lower than normal at times, are maintained.
Women likely to benefit from injectable or implantable progestin-only methods are those who are breastfeeding; those who have contraindications or intolerance to estrogens (eg, patients with systemic lupus erythematosus [SLE], sickle-cell hemoglobinopathies, a history of estrogen-related headache, or hypertension); or those who smoke and are older than age 35.8,9,11 Women who report premenstrual weight gain, nausea, or acne may also benefit from these methods.8,11
Pregnancy failure rates with long-acting progestin contraception are comparable to female sterilization.8 If pregnancy does occur while the patient is using one of the progestin-only methods, the risk of the pregnancy being ectopic is increased. These methods of contraception do not offer protection from sexually transmitted diseases (STDs), but the thickened cervical mucus may help prohibit entry of bacteria into the upper pelvic region, thus preventing PID.
Injectable. One type of injectable contraception is depomedroxyprogesterone acetate (Depo-Provera Contraception Injection [DMPA]). Medroxyprogesterone is a C21-17 acetoxy-progestogen that is similar in structure to naturally occurring progesterone. DMPA, 150 mg administered by a deep intramuscular (IM) injection in the gluteal or deltoid muscle within 5 days after the onset of menstrual bleeding, inhibits ovulation for more than 3 months. Although DMPA, 150 mg IM, may inhibit ovulation for as many as 14 weeks, the dose should be repeated every 12 weeks to ensure continuous contraception.17 The manufacturer recommends excluding pregnancy in women more than 1 week late for repeat injection. No apparent weight restrictions apply in women using DMPA. Pharmacists should be aware that there are two strengths of DMPA available, 100- and 400-mg/mL suspensions. The 400-mg/mL concentrated form has inconsistent bioavailability, may be less effective, and is more painful than the less concentrated formulation. It is not approved for contraception.17,22
DMPA can be used in lactating women, and it may increase the length of time a woman can breastfeed. Although DMPA is safe postpartum and no adverse effects have occurred in infants exposed to DMPA through breast milk, the manufacturer recommends initiating DMPA at 6 weeks postpartum in women who are breastfeeding. DMPA is also safe in women with sickle-cell disease and may reduce the propensity of red blood cell sickling. DMPA does not alter blood pressure or increase the frequency of seizures.
Noncontraceptive benefits observed in women using DMPA include reducing the risk of anemia —users of DMPA experience less menstrual blood loss—and decreasing the incidence of menstrual cramps and pain at ovulation. The incidence of candida vulvovaginitis, ectopic pregnancy, PID, and endometrial and ovarian cancer is decreased in women using DMPA for contraception compared with women using no contraception.
Implant. The progestin subdermal levonorgestrel implant (Norplant), developed by the Population Council, was the first progestin subdermal implant approved for use in the United States in 1990. Levonorgestrel implants are a set of six flexible, closed capsules made of Silastic (dimethylsiloxane/ methylvinylsiloxane copolymer), each containing 36 mg of the progestin levonorgestrel in an insertion kit to facilitate implantation. The capsules are sealed with Silastic adhesive (polydimethylsiloxane) and sterilized.
The initial dose is about 85 mcg/day, followed by a decline to about 50 mcg/day by 9 months, and to about 35 mcg/day by 18 months, with a further decline thereafter to about 30 mcg/day. It is a synthetic and biologically active progestin that exhibits no significant estrogenic activity and is highly progestational. Diffusion of levonorgestrel through the wall of each capsule provides a continuous low dose of progestin. Resulting blood levels are substantially below those generally observed among users of combination OCs containing the progestins norgestrel or levonorgestrel. Because of the range of variability in blood levels and variation in individual response, blood levels alone are not predictive of the risk of pregnancy in an individual woman.
The implant system is a long-term (as many as 5 years), reversible contraceptive system. Because the cumulative pregnancy rate in all groups of women significantly increases during the sixth year, the implant should be replaced after 5 years. Even with the softer capsules currently available in the United States, failure rates may be unacceptable during the fourth and fifth years of use in women weighing more than 154 lb. Replacement after 3 years in heavier women helps ensure effectiveness.8
A new system can be inserted immediately after removal of the old system. Removal often becomes complicated as a result of poor insertion technique, broken capsules, or impedance by fibrous tissue. A “U” technique of drug removal using a 4-mm incision located parallel to the third and fourth implant appears to be an improvement over the manufacturer-recommended technique, especially for personnel who are not highly experienced in this procedure.5 A levonorgestrel, two-rod, 150-mg implant system providing 3 years of contraception (Norplant II) may prove easier to insert and remove than the older system. Other progestin implants, some of which are biodegradable, are under development.5
Noncontraceptive benefits are similar to those of DMPA, and the same patient types would benefit from the use of this implant.
The most frequent adverse effects from DMPA are menstrual irregularities, including irregular, unpredictable spotting or, more rarely, continuous heavy bleeding. In some cases, bleeding may be severe enough to cause a significant drop in hemoglobin. Women who cannot tolerate prolonged bleeding may benefit from a short course of oral estrogen (eg, 7 days of 2 mg of estradiol or 1.25 mg of conjugated estrogen). The incidence of irregular bleeding decreases from 30% in the first year to 10% thereafter.8 After 12 months of therapy, 57% of women report amenorrhea, with the incidence increasing to 68% after 2 years.17
Because estrogen concentrations may be lower than normal in women using DMPA, changes in bone mineral density may occur. The rate of bone loss is greatest in the early years of use and then subsequently approaches the normal rate of age-related loss. The clinical significance of this bone loss is unknown.22
Pharmacists should inform patients using DMPA about the earliest manifestations of thrombotic disorders:
• Thrombophlebitis (severe pains, tenderness, swelling, warmth, or palpable cord in leg)
• Pulmonary embolism (coughing up blood)
• Cerebrovascular disorders (slurring of speech, unilateral numbness, weakness, or tingling)
• Retinal thrombosis (loss of vision, diplopia, or papilledema)
If a patient experiences or suspects any of those symptoms or if there is a sudden onset of proptosis, migraine, or retinal vascular lesions, DMPA should not be readministered.
Patients should be prepared that there is a tendency to gain weight while on medroxyprogesterone therapy. From an initial average body weight of 136 lb, women who completed 1 year of therapy gained an average of 5.4 lb; women who completed 2 years of therapy gained an average of 8.1 lb; those who completed 4 years gained an average of 13.8 lb; and those who completed 6 years gained an average of 16.5 lb. Two percent of women withdrew from a large-scale clinical trial because of excessive weight gain.17,22 It may take 6 to 8 months after the last injection for the weight gain to resolve.
Minor elevations in serum total triglycerides and decreases in serum HDL cholesterol, particularly HDL-2, have been noted after DMPA exposure. LDL cholesterol and total cholesterol concentrations have increased in some studies, with no change reported in others. Carbohydrate metabolism and coagulation factors are not affected. The clinical significance of these minor alterations in metabolism is unknown.
Although used in developing countries for decades, DMPA was not approved as a contraceptive in the United States until 1992 because of a concern about a possible increased incidence of breast cancer.8 Long-term, case-controlled surveillance of users found slight or no increased overall risk of breast cancer and no overall increased risk of ovarian, liver, or cervical cancer. A prolonged, protective effect of reducing the risk of endometrial cancer in the population of users was observed. An increased relative risk of 2.19 of breast cancer has been associated with the use of medroxyprogesterone in women whose first exposure to the drug was within the previous 4 years and who were younger than age 35. However, the overall relative risk for ever-users was only 1.2.17 A statistically insignificant increase in relative risk estimates of invasive squamous cell cervical cancer has been associated with the use of medroxyprogesterone in women who first used the product before age 35.
Several reports suggest an association between intrauterine exposure to progestational drugs in the first trimester of pregnancy and genital abnormalities in male and female fetuses. The risk of hypospadias (5 to 8 per 1,000 male births in the general population) may be approximately doubled with exposure to these drugs. Insufficient data exist to quantify the risk to exposed female fetuses. However, some of those drugs induce mild virilization of the external genitalia of the female fetus and are associated with hypospadias in the male fetus; thus, it is prudent to avoid the use of such drugs during the first trimester of pregnancy. To ensure that medroxyprogesterone is not administered inadvertently to a pregnant woman, it is important that the first injection be given only during the first 5 days after the onset of a normal menstrual period, within 5 days postpartum if the woman is not breastfeeding, and at the sixth week postpartum if she is.
Pharmacists should inform patients that return of fertility may be delayed after discontinuation of DMPA as a result of its prolonged contraceptive effect. It is expected that 68% of women who do become pregnant may conceive within 12 months, 83% may conceive within 15 months, and 93% may conceive within 18 months from the last injection.17,22 The median time to conception for those who do conceive is 10 months following the last injection, with a range of 4 to 31 months. This is unrelated to the duration of use.
Similar to other progestin-only methods, the most common adverse effect of the subdermal progestin implant is irregular menstrual bleeding, which occurs in approximately 60 to 70% of women using the implant during the first year after insertion. As with DMPA, prolonged bleeding can be treated with a short course of estrogen (eg, 2 mg of estradiol or 1.25 mg of conjugated estrogen for 7 to 10 days).5,17 Spotting and bleeding decrease in amount and duration with time. By the fifth year of use, regular bleeding cycles may resume in more than 60% of users. Regular cycle bleeding while using the implant indicates return of ovulation and a higher risk of method failure. Pharmacists can educate patients to watch for regular bleeding and be prepared to seek alternative methods of contraception.
Miscellaneous adverse effects that have been reported include headache, nervousness, nausea, dizziness, adnexal enlargement, dermatitis, acne, change of appetite, mastalgia, weight gain, hirsutism, hypertrichosis, and scalp hair loss. Overdosage can result if more than six capsules are in situ. Thus, all implanted capsules should be removed before inserting a new set. Overdosage may cause fluid retention, with its associated effects and uterine bleeding irregularities.
Progestin subdermal implants are contraindicated in patients with active thrombophlebitis or thromboembolic disorders, undiagnosed abnormal genital bleeding, known or suspected pregnancy, acute liver disease, benign or malignant liver tumors, or known or suspected carcinoma of the breast.22 Patients who develop active thrombophlebitis or thromboembolic disease should have the capsules removed.
Although bleeding irregularities have occurred in clinical trials, proportionately more women had increases rather than decreases in hemoglobin concentrations, a difference that was highly statistically significant. This finding generally indicates that reduced menstrual blood loss is associated with the use of the implants. In rare instances, blood loss did result in hemoglobin values consistent with anemia.
Delayed follicular atresia may occur in some patients.17,22 If follicular development occurs, atresia of the follicle is sometimes delayed, and the follicle may continue to grow beyond the size it would attain in a normal cycle. These enlarged follicles cannot be distinguished clinically from ovarian cysts. In the majority of women, enlarged follicles will spontaneously disappear and should not require surgery. Rarely, they may twist or rupture, sometimes causing abdominal pain; surgical intervention may be required.
Ectopic pregnancies have occurred among levonorgestrel implant users, although clinical studies have shown no increase in the rate of ectopic pregnancies per year among users as compared with those who used no method or used IUDs. The incidence among users was 1.3 per 1,000 woman-years, a rate significantly below the rate that has been estimated for noncontraceptive users in the United States (2.7 to 3 per 1,000 woman-years). The risk of ectopic pregnancy may increase with the duration of use and, possibly, with increased weight of the user. Patients who present with lower abdominal pain should be referred for evaluation to rule out ectopic pregnancy.
Although it is believed that the occurrence of retinal thrombosis associated with the use of OCs is related to the estrogen component of OCs, implant users should be instructed to have their progestin capsules removed if there is unexplained partial or complete loss of vision, onset of proptosis, diplopia, papilledema, or retinal vascular lesions. Patients should be encouraged to undertake appropriate diagnostic and therapeutic measures immediately.
Although an altered glucose tolerance characterized by decreased insulin sensitivity following glucose loading has been found in some users of combination and progestin-only OCs, the effect of the levonorgestrel implants on carbohydrate metabolism appears to be minimal. In a study in which pretreatment serum glucose levels were compared with levels after 1 and 2 years of use, no statistically significant differences in mean serum glucose levels were evident 2 hours after glucose loading. The clinical significance of these findings is unknown, but clinicians should carefully observe diabetic and prediabetic patients when they are using the implant.
Women using the implants who are being treated for hyperlipidemias should also be monitored closely. Some progestins may elevate LDL levels and render the control of hyperlipidemias more difficult. Although lipoprotein levels were altered in several clinical studies with the levonorgestrel implants, the long-term clinical effects of these changes have not been determined. A decrease in total cholesterol levels has occurred in all lipoprotein studies and reached statistical significance in several. Both increases and decreases in HDL levels have been reported in clinical trials. LDL and triglyceride levels also decreased from pretreatment values.
Infection at the implant site has been uncommon (0.7%). Attention to aseptic technique and proper insertion and removal of the capsules reduces the possibility of infection. If infection occurs, clinicians should institute suitable treatment. If infection persists, the capsules should be removed. Expulsion of capsules is uncommon, occurring more frequently when placement of the capsules is extremely shallow, too close to the incision, or when infection is present. Replacement of an expelled capsule must be accomplished using a new sterile capsule. If infection is present, patients should be treated and cured before replacement. Contraceptive efficacy may be inadequate with less than six capsules. Pharmacists should advise women that the capsules can be removed by a clinician at any time for any reason. The removal should be done on such request or at the end of 5 years of usage by personnel instructed in the removal technique.
Aminoglutethimide may significantly depress the serum concentrations of medroxyprogesterone, and the efficacy of levonorgestrel may be reduced by carbamazepine and phenytoin. Pharmacists should warn users of the possibility of decreased efficacy with the use of these or any related drugs.
Before a hormonal contraceptive is prescribed, several questions must be answered. Are there any contraindications to the use of hormonal contraception? Does this form of contraception fit the patient’s lifestyle, and will the patient be compliant? Is cost a factor for the patient? The advantages and disadvantages of all available forms of contraception should then be discussed with the patient to ensure that an informed choice is made.
Some areas that pharmacists should discuss with patients include that minipills and injectable/implantable progestin-only products tend to be less effective than combination OCs with typical use and are associated with irregular and unpredictable menstrual bleeding and an increased frequency of functional ovarian cysts. Before starting these methods, patients should know that irregular menstrual cycles indicate that ovulation has been inhibited. This effect is one of the most frequent reasons for discontinuation of these methods.
Most clinicians routinely prescribe a combination OC that contains less than 50 mcg of EE. This strategy is based on evidence that most serious adverse effects of combination OCs (eg, thromboembolic stroke or MI) result from excessive estrogen content.
Many symptoms occurring in the first cycle of OC use (eg, breakthrough bleeding and adverse effects related to estrogen excess) improve spontaneously by the second or third cycle of use as the body adjusts to the altered hormonal level. Initial OC use should be reevaluated during the first 3 to 6 months of therapy to determine if the patient is experiencing any adverse effects and if she wishes to continue with that method. Such evaluations give pharmacists a wonderful opportunity to discuss therapy with patients, provide education, and offer alternatives if adverse effects are intolerable.
If a patient complains of symptoms related to OC use, the pharmacist should determine if the symptoms indicate the presence or potential development of a serious illness. Nearly all OC-induced adverse effects parallel the symptoms and physiologic changes of pregnancy (hormone excess) or perimenopausal period (hormone deficiency). In some cases, symptoms relating to the hormonal imbalance may benefit from adjustments in the specific combination of estrogen and progestin because progestins can contribute to estrogenic and antiestrogenic activity. Pharmacists are in a good position to recognize adverse effects and suggest adjustments to the regimens.
The cost of the medication should also be a consideration when selecting hormonal contraception. The pharmacist should determine if a patient has any insurance or a drug benefit plan that will cover hormonal contraceptives. Many insurance companies do not cover birth control, because it is does not fall within the definition of “disease prevention.” The pharmacist has an opportunity in these situations to suggest a less expensive therapeutic equivalent (ie, generic) product.
When an innovator’s patent has expired, generic manufacturers can compete for a position in the marketplace. Because of this competition and lower development costs, such drugs usually sell for less than the originally marketed product. The therapeutic equivalent product may be 10 to 30%, and up to 50%, less in cost.
Although the cost benefit of prescribing a therapeutic equivalent OC is apparent, discussion continues about what therapeutically equivalent or bioequivalent means with regard to efficacy. Patients or prescribers may express concern about the interchangeability of certain products they view as having a narrow therapeutic index, and some remain unsure that a bioequivalent OC is as effective as the originally marketed product.
Pharmacists can help ensure proper understanding of bioequivalence with regard to interchangeability, and how such products are approved and regulated, thus assuring the quality of the product, ie, that it is safe and effective. It is important that this concept is understood by providers as well as patients, because there are occasions when prescribing a therapeutic equivalent product enables the patient to afford and therefore receive the particular therapy.
Simply stated, a drug is determined bioequivalent if its pharmacokinetic parameters are comparable to those of the original drug (eg, it is absorbed by the body to an extent similar to the original). A product is deemed a therapeutic equivalent when it is both pharmaceutically equivalent and bioequivalent.
To receive FDA approval for such a product, an abbreviated new drug application (ANDA) process is undertaken in which the manufacturer must show that the product in the ANDA is the same as the originally marketed drug, in terms of active ingredient, dosage form, strength, and route of administration, and that it is bioequivalent. Additionally, the manufacturer must comply with the same FDA standards developed for the original product, including manufacturing practices, identity, strength, quality, and purity.23
The USP DI, Approved Drug Products and Legal Requirements, Volume III defines the range of bioequivalence in a therapeutic equivalent product to be not less than 20% and not more than 25% observed mean difference from the original.24
Because of the ANDA process, the FDA does not recommend that any additional tests be performed when a patient is switched to a therapeutic equivalent. However, to further assure the safety of such switches, the FDA regularly assesses the quality of products in the marketplace and thoroughly researches reports on alleged drug product inequivalence. It has also performed postmarketing testing on some occasions comparing the therapeutic equivalent and the originally marketed products.25 To date, there is no compelling evidence of therapeutic failures for ANDA-reviewed and FDA-approved generic products.25
Pharmacists will also want to be prepared to explain the coding on some therapeutic equivalent products (eg, AA, B, or AB). Drug products designated with the first letter “A” are those that the FDA considers to be therapeutically equivalent products for which there are no known or suspected bioequivalence problems. These are designated AA, AN, AO, AP, or AT, depending on the dosage form (eg, N = solutions and powders for aerosolization, O = injectable oil solutions). Drug products that the FDA considers not to be therapeutically equivalent products are given the first letter “B” rating. These drug products have actual or potential bioequivalent problems that have not been resolved; often the problem is associated with specific dosage forms rather than with the active ingredients. Products designated AB had actual or potential bioequivalence problems that have been resolved with adequate in vivo or in vitro evidence supporting bioequivalence. Multisource drug products listed under the same heading—identical active ingredients(s), dosage form, and route(s) of administration—and having the same strength generally will be coded AB if a study is submitted demonstrating bioequivalence.23 Currently all the bioequivalent hormonal contraceptives on the market today are AB rated.
In the OC category, there are several therapeutic equivalent options on the market. Many simply are identified by their generic name; a few have come on the market with their own “brand names.” Table 5 lists several bioequivalent OCs currently on the market. Pharmacists should be aware of the OC options and should be prepared to talk with patients and prescribers regarding the safety of switching from an originally marketed product to a therapeutic equivalent, if the situation warrants.
Many women who take OCs are poorly informed about the proper use of these medications. Thus, patients should be instructed to carefully read the package inserts, which are required for all estrogen products. That material should be supplemented with a one-on-one discussion with the patient to explain how the OC works, how to recognize both common and more serious adverse effects, and how to manage them. Also, benefits and risks should be discussed in terms patients can understand, such as informing them that OCs provide no physical barrier to the transmission of STDs, including human immunodeficiency virus (HIV). Pharmacists should make patients aware that OCs may cause spotting or breakthrough bleeding during the first few months of therapy, and if the bleeding occurs in more than one cycle or lasts more than a few days, they should notify their prescriber.
Detailed instructions on when to start taking the medication should be provided. Patients should be informed that to achieve maximum contraceptive effectiveness, the OC must be taken exactly as directed at intervals not exceeding 24 hours and preferably at the same time each day, including throughout all bleeding episodes. Pharmacists can suggest taking the tablets regularly with a meal or at bedtime. They can also reiterate that efficacy depends on strict adherence to the dosage schedule and that missing a pill can cause spotting or light bleeding. They should also be counseled about using an additional method of birth control until after the first week of administration in the initial cycle or for the entire cycle if vomiting or diarrhea occurs.
Patients taking combination OCs should be informed that if the instructions recommend starting the regimen on Sunday, that they take the first tablet on the first Sunday after menstruation begins. If menstruation begins on Sunday, the patient should take the first tablet on that day. Regarding the 21-day regimen, if the patient is going to start on day 1, she must count the first day of menstrual bleeding as day 1, then take one tablet daily for 21 days. Patients need to understand that with this regimen no tablets are taken for 7 days, whether bleeding has stopped or not. Following those 7 days, a new course of 21 days of pills is started. Withdrawal flow will normally occur more than 3 days after the last tablet is taken. Pharmacists can inform patients to follow the schedule whether flow occurs as expected or whether spotting or breakthrough bleeding occurs during the cycle.
Pharmacists can explain to patients on a 28-day regimen that to eliminate the need to count the days between cycles, some products contain seven inert or iron-containing tablets to permit continuous daily dosage during the entire 28-day cycle and that those seven tablets are taken on the last 7 days of the cycle.
Minipills are always begun on the first day of menses and must be taken every day at approximately the same time to maintain contraceptive efficacy. Patients taking the biphasic or triphasic OCs should follow instructions on the dispensers or packs. These are clearly marked, usually indicating when to start the regimen and in what order to take the pills (usually marked with arrows), along with the appropriate week numbers. If there are any questions, detailed instructions are provided in the specific package insert. One tablet is taken each day; as the color of the tablet changes, the strength of the tablet also changes (ie, the estrogen/ progestin ratio varies).
If a patient forgets to take one or more progestin-only OC tablets, the pharmacist should suggest the following:
If she misses:
• One tablet. She should take it as soon as remembered, or take two tablets the next day. Alternatively, she could take one tablet, discard the other missed tablet, continue as scheduled, and use another form of contraception until menses.
• Two consecutive tablets. She should take two tablets as soon as remembered with the next pill at the usual time, or take two tablets daily for the next 2 days, then resume the regular schedule.
• Two active pills in a row in the third week and the patient is a Sunday starter. She should take one pill every day until Sunday. On Sunday, the rest of the pack should be discarded, and a new pack of pills started that same day.
• Two active pills in a row in the third week and the patient is a day 1 starter. She should discard the rest of the pill pack and start a new pack that same day. Menses may not occur this month, but this is expected. However, if menses do not occur 2 months in a row, the physician or clinic should be contacted because of the possibility of pregnancy.
• Three consecutive tablets. If the patient is a Sunday starter, she should keep taking one pill every day until Sunday. On Sunday, the rest of the pack should be discarded and a new pack of pills started that same day.
Patients should be made aware that if they miss one day’s pill and take it with the regularly scheduled pill, they may be nauseous on that day. Because the possibility of ovulation occurring increases with each successive day that scheduled tablets are missed, patients must be informed that any time one or more active tablets are missed, they should use a backup method, such as a condom or spermicide, every time they have sexual intercourse for the balance of the cycle or until tablets have been taken for 7 consecutive days.
The pharmacist should explain to the patient the procedure for switching from one type of OC to another. If the patient is switching from combination OCs to progestin-only OCs, she should take the first progestin-only pill the day after the last active combined pill has been taken. She should be informed not to take any of the seven inactive pills from the combination OC pack and that many women have irregular periods after switching to progestin-only pills and that this is normal and to be expected. If the patient is switching from progestin-only pills to combination OCs, she should take the first active combined pill on the first day of menses, even if the progestin-only pill pack is not finished. If the patient is switching to another brand of progestin-only pills, she can start the new brand any time.
Pharmacists are in a unique position to counsel patients on the use of hormonal contraceptives. Both verbal and written instruction concerning the chosen method should be given to the patient. Follow-up appointments can increase compliance, provide the patient with time to ask questions, and provide opportunities to address other health maintenance issues (eg, self-breast exam, Pap smears, or STD risk). The follow-ups also can facilitate blood pressure monitoring, which is recommended at least once per year for all OC users. When an OC is started or stopped in a diabetic patient, glucose should be monitored for deterioration of the condition. Patients should be monitored for adverse effects (eg, breakthrough bleeding). Women using an implantable product should be monitored for menstrual cycle disturbances, weight gain, local inflammation or infection at the injection site, breast tenderness, headaches, and hair loss. Women using DMPA should be asked at 3-month follow-up visits about any problems (eg, menstrual cycle disturbances) or concerns (eg, STD risks) they may have. DMPA users should also have their weight and blood pressure checked and receive annual exams (eg, physical, Pap smear, or mammogram). Choosing a contraceptive method most suited to the patient’s needs will significantly reduce the chance of unintended pregnancy.
Hormonal methods of contraception, as mentioned in Part I, are the most effective means of contraception except for abstinence or sterilization. However, some women seeking contraception cannot tolerate the adverse effects of these methods or they may have a concomitant condition that is a contraindication for the use of hormonal contraceptives. In addition, some women fear that use of particular hormonal contraceptives may increase their risk of developing breast cancer. These women seek an alternative method of contraception. Nonhormonal contraceptives and coitus interruptus (withdrawal) are such options.
Nonhormonal contraceptive methods include IUDs, vaginal barriers (diaphragm, cervical cap, contraceptive sponge, or male and female condoms), and spermicides. Each of these methods is less reliable in preventing pregnancy than hormonal methods even if they are used in a “perfect manner,” but they have fewer adverse effects. Perfect manner of use means that the device is used properly and used every time that intercourse occurs. Because they lack experience with a method, couples using any nonhormonal contraceptive for the first time may be more likely to have the method fail. However, lack of commitment to using the method every time that intercourse occurs, whether a couple are experienced users or not, often leads to contraceptive failure. “Typical use” of contraceptives frequently means that the method is not used every time, but it could mean improper use as well. Typical use leads to higher rates of unintended pregnancies.
Male and female condoms have the ability to protect the user from sexually transmitted infections (STIs) or STDs that are transmitted with bodily fluids, such as HIV, chlamydia, and gonorrhea, something that hormonal contraceptives cannot do. Infections that are transmitted with skin-to-skin contact may still be transmitted however, if they are present in areas not covered by the condom. Diaphragms, cervical caps, and spermicides may reduce the incidence of STIs, but they do not prevent transmission of STIs.26 Whether the contraceptive sponge, which contains a spermicide, prevents transmission of STIs has not been proven.
The advantages and disadvantages associated with each of the nonhormonal contraceptive methods will be described. However, it is usually the sexual behavior characteristics of the potential user that determine which contraceptive method is the most appropriate recommendation. Because condoms, cervical sponges, and spermicides are nonprescription products, pharmacists have an excellent opportunity to exercise their role as both advisor and educator for individuals seeking contraceptive recommendations.
If a woman chooses to use an IUD, a diaphragm, or a cervical cap for contraception, she must first see a clinician because these devices require a prescription. An IUD is a device that is inserted into the uterus by a clinician. After an IUD is properly inserted, it remains in place until a decision is made to remove it, which again requires a visit to a clinician. No further action by the user is necessary for the IUD to exert its contraceptive effect. This makes it a good choice as a contraceptive method for a woman who is likely to be noncompliant with other contraceptive methods, provided that she has no conditions that are contraindications for IUD usage.
Occasionally, the uterus may expel the device spontaneously, most often within the first 3 months after its insertion. Expulsion rates of 2 to 10% are reported for the first year of use.27,28 Expulsion is more likely to occur in nulliparous women, making the recommendation of an IUD more appropriate for parous women. IUDs have a filament or string that extends through the cervix into the vagina, which can be felt by the woman to check its placement. Women are advised to check the IUD about once per month to make sure it is still in place. If abdominal cramping or unusual bleeding occur, the user should immediately check to be sure the IUD has not been expelled.27,28
Currently, two IUD devices are available in the United States, Alza Corporation’s Progestasert and Ortho Pharmaceutical
Corporation’s Paragard Cu (copper) T 380A. Progestasert is a “T”-shaped device composed of an ethylene vinyl acetate polymer containing 38 mg of progesterone, which is released at the rate of 65
mcg/day.27,28 It must be replaced on a yearly schedule to maintain its contraceptive effectiveness as a result of the depletion of progesterone that occurs. The Cu T 380A is made of polyethylene with fine copper wire wound around it and does not need replacement for 10 years. The LNg 20-IUD by Leiras, also “T” shaped, which currently is not available in the United States, contains levonorgestrel that is released at a rate of 20 mcg daily and may be used for 5 years before replacement is
Each of the approved devices contains a small amount of barium sulfate, a radiopaque substance, which permits visualization of the device by X-ray examination in case it is displaced. The frame of the “T” of the LNg 20-IUD is radiopaque itself.
The exact mechanism by which IUDs prevent fertilization is not completely understood. There is evidence that sperm migration from the vagina to the fallopian tubes is impaired and the release of macrophages and phagocytic leukocytes triggered by an inflammatory response to the presence of the IUD are cytotoxic to sperm and ova.29-32 Spinnato33 reported that copper IUDs exert both a prefertilization (spermicidal) and a postfertilization (prevention of fertilized ovum implantation) action.
Despite the fact that IUDs are the most effective nonhormonal contraceptives, they are among the least popular methods of contraception in the United States, with less than 1% of women practicing birth control using them.34,35 The reported pregnancy rates during the first year of use for the Cu T 380A and Progestasert are 0.6 and 1.5%, respectively, when used in a perfect manner (checking the string as directed to detect for expulsion). Comparable rates for perfect use of hormonal contraceptive methods range from 0.05 to 0.5% pregnancies within the first year. When no contraceptive measure is used, about 85% of sexually active, fertile women will become pregnant.36
Although the number of women using IUDs is low, there is a high degree of satisfaction among users. IUDs have the highest rate, about 80%, for continuing use at the end of 1 year compared with OCs (71%), male condoms (61%), female condoms (56%), spermicides (40%), diaphragms (56%), cervical caps (56% in nulliparous women), and cervical sponges (56% in nulliparous women).31
IUDs are more widely accepted in other countries. Their lack of popularity in the United States may be as a result of issues that surrounded the use of the Dalkon Shield, an IUD that was widely used during the 1960s and 1970s. As reports of serious adverse effects in Dalkon Shield users increased, the overall use of all IUDs decreased dramatically. Because of the publicity surrounding the litigation in settling the Dalkon Shield cases, most pharmaceutical manufacturers stopped producing IUDs in the
Controversy continues about whether the reported increased risk for PID was because of the use of IUDs or other risk factors. Improper diagnoses of PID, improper selection of women who were at high risk for PID, and the methodology used in estimating relative risk of PID have been cited as factors contributing to the reports of increased PID cases.34-36 Recent analyses of earlier studies on PID risk found the actual risk to be much lower than those initial reports.34,35,37
The Dalkon Shield was larger than other IUDs and had multiple filaments rather than a monofilament, which extended through the cervix into the vagina. This may have caused a greater inflammatory response and facilitated the entry of bacteria into the uterus, thereby increasing the risk of PID for Dalkon Shield users. Farley et al37 investigated the risk of PID associated with IUDs of various designs and concluded that the greatest risk for PID was immediately after insertion, within 20 days, and was a result of the insertion process itself and not related to the filament strings or the IUD device. After 21 days, the rate of PID was the same for women with or without an IUD.
Because PID appeared to be related to the introduction of bacteria during the insertion process, the value of using an antibiotic for prophylaxis of PID was examined. Neither azithromycin nor doxycline demonstrated any significant effect in reducing PID, thus, the value of prophylaxis remains questionable at this time.38,39
An IUD is most appropriately recommended for a multiparous woman with a low risk for PID who is in a monogamous relationship with a partner who does not have an STI. IUDs may be safely used by women who are breastfeeding and are usually inserted immediately postpartum in women wishing to use birth control after pregnancy.27,28 IUDs are poor recommendations for younger, nulliparous women, especially adolescents,40 as those patients have higher expulsion rates for IUDs and are more likely to experience dysmenorrhea and heavy uterine bleeding.
Disadvantages associated with the use of a copper IUD include an increase in dysmenorrhea, irregular spotting, and heavy uterine bleeding that may be severe enough to cause anemia or cause women to terminate use of the IUD. Because of the tendency to increase bleeding, women relying solely on IUDs may increase their risk of HIV infection.27 Conversely, women who are infected with HIV increase the chance of transmission to their partner unless condoms are used.41 The progesterone- and levonorgestrel-releasing IUDs decrease menstrual flow and reduce the intensity of dysmenorrhea.28
There is a risk of less than 0.1% that the uterus may be perforated by inserting an IUD.28 IUDs are associated with an increased risk of ectopic pregnancies, with the risk being about 10 times greater for Progestasert than for the Cu T 380A.28 IUDs should not be recommended for women with a history of ectopic pregnancy. There is an increased risk of spontaneous abortion if a woman with an IUD in place becomes pregnant. Thus, the IUD should be removed as soon as possible.
The estimated cost for IUDs is about $300, which is due mostly to the insertion process, but costs after that are negligible.
Barrier contraceptives vary greatly in their effectiveness and depend on whether there is perfect or typical use of the method. These contraceptives can be classified into three categories of use. First, a diaphragm or cervical cap requires a prescription and must be fitted by a clinician; the cervical sponge or condom (male or female) is available without a prescription.
A second classification depends on the ability of the barrier method (ie, condoms) to prevent transmission of STIs, including HIV, and those that only reduce the risk of STIs (diaphragms, cervical caps, and the contraceptive sponge). Diaphragms, cervical caps, and the contraceptive sponge require the use of a spermicide for proper use as contraceptives. Nonoxynol 9 is the spermicide most frequently used, and it has demonstrated its effectiveness in reducing the risk of gonorrhea, chlamydia, genital herpes, and PID.42,43
The last classification describes who exerts control over the contraceptive method. Women initiate the use of all barrier contraceptives except for male condoms.
Diaphragms were used in Asia and Europe for contraception during the last half of the 19th century and were introduced in the United States during the first part of the 20th century. The cervical cap was developed during the first part of the 20th century but was not widely used in the United States until the FDA approved the Prentif Cap in 1988.44,45 Both devices require exact measurements so that the entire cervix is covered for effective contraceptive protection. Some women may not be able to use these devices for anatomic reasons; others may not use them because they cannot properly insert the device or because of an allergic response to the spermicide or the composition of the device.
A diaphragm is a dome-shaped rubber cup with a flexible rim that is available in several styles. The cup comes in a variety of diameters measuring from 50 to 95 mm.44,45 Before the diaphragm is inserted, the dome is filled with spermicide, and spermicide is placed around the dome rim. The rim is compressed together, inserted into the vagina, and placed over the cervix. If coitus does not occur within 6 hours, additional spermicide should be inserted into the vagina with an applicator without removing the diaphragm. After coitus, the diaphragm should remain in place for at least 6 hours. Additional spermicide should be placed in the vagina without removing the diaphragm before any subsequent act of intercourse. The diaphragm may remain in place for up to 24 hours before it should be removed.
The cervical cap is smaller than a diaphragm and is available in diameters from 22 to 31 mm.44,45 The Prentif Cap is a deep, soft, rubber cup. Its rim has a groove that provides a firmer fit over the cervix than does the diaphragm. The cup should be filled to one third of its volume with spermicide and inserted prior to coitus. It may remain in place for up to 48 hours, and no additional spermicide is needed regardless of the frequency of intercourse. Keeping either a diaphragm or cervical cap in place for a period of time longer than recommended increases the risk of toxic shock syndrome.44,45
The FDA approved the Today Sponge in 1983. It is a polyurethane, pillow-shaped device that is 5.5 cm in diameter with a dimple on one side containing 1 gram of nonoxynol 9.44,45 The sponge must be moistened before it is inserted. Two tablespoons of water are added to the sponge, which is squeezed once and then inserted, so that the dimpled side covers the cervix. It retains its effectiveness for 24 hours without the need for additional spermicide.
The original manufacturer of the Today Sponge, Whitehall-Robins Healthcare, discontinued the product in 1995 after the FDA found problems relating to good manufacturing practice regulations. The company decided to discontinue manufacturing the device based on financial reasons not because of any product safety or efficacy problems. Allendale Pharmaceuticals entered into an agreement with American Home Products in 1999 and began producing the sponge using the name Today Contraceptive Sponge.
Even when used in a perfect manner, the diaphragm, cervical cap, and cervical sponge have the greatest rate of failure when compared with other methods of contraception, except for spermicides. Pregnancy rates during the first year based on perfect use for the diaphragm, cervical cap, and sponge are 6, 9 (nulliparous women), and 9% (nulliparous women), respectively.36 The failure rate of the cap (under conditions of perfect use) by parous women was 26%, and 20% for the sponge. (The reported rate of failure use for the diaphragm did not make any distinction between parous and nulliparous women.) Typical use of these methods yields failure rates that were about double those for perfect use.36
To properly use barrier methods, similar processes must be undertaken. The user’s hands should be washed thoroughly before insertion and removal of the device, or at any time that placement of the device is checked. Each device requires proper storage before use and must be handled carefully so that no cuts or tears occur in the device. This is especially true for the sponge because during its moistening a fingernail could easily pierce the polyurethane covering. Diaphragms and caps should be carefully washed with mild soap and warm water after each use. The sponge can only be used once and then must be discarded. All devices must remain in place for at least 6 hours after intercourse.
Cervical caps should be replaced every year and diaphragms every 1 to 3 years. Any significant weight change, about 20 to 30 lb, may alter the fit of the diaphragm, requiring the woman to visit her clinician to assure that it still fits properly. Diaphragms and caps cost about $30 to $40, and an additional charge is incurred for each clinician visit, which increases the total cost to several hundred dollars. Additionally, a spermicide is required whenever these devices are used. The cost of a sponge is about $2.
Advantages of these barrier devices include female control of the method, reduced risk of STIs and PID, and protection that lasts for at least 24 hours (48 hours for the cap). These methods are most appropriately recommended for women who are in a monogamous, long-term relationship with a partner who does not have an STI, especially HIV. These methods are not suitable contraceptives for women with HIV unless a condom is used.41,46
Common disadvantages include difficulty in placement of the device over the cervix, possible displacement of the device during coitus, difficulty in removal of the device, possible irritation from either the device or spermicide, and increased risk of toxic shock syndrome. Women should be informed of the symptoms associated with the syndrome. These include acute fever, fatigue, weakness, faintness, dizziness, muscle aches and pains, and the appearance of a rash. None of these methods should be used during menses. Table 6 compares important advantages and disadvantages of these devices.
Both male and female condoms are more effective contraceptives than the other barrier methods, but they are less effective than IUDs or hormonal methods. Male condoms have a pregnancy rate of 3% during the first year under conditions of perfect use, and the female condom has a pregnancy rate of 5%. Pregnancy rates increase to 12 and 21%, respectively, for male and female condoms under conditions of typical use (not used every time).36 Only condoms made of latex or polyurethane prevent transmission of STIs, including HIV.
The first male condoms used were made of fine linen; animal bladders (cecum of sheep, lambs, or goats) and vulcanized rubber condoms were developed later.46 Today, lamb cecum (skins or natural condoms), latex (rubbers), and polyurethane (plastics) are used for manufacturing condoms. Polyurethane condoms (Durex Avanti and Trojan Supra) and lamb cecum condoms (Kling-Tite Naturalamb) are suitable alternatives if an individual has a latex allergy.
Although lamb cecum condoms are effective as contraceptives, they provide no protection against STIs because they have pores too large to prevent transmission of bacteria and viruses. Latex condoms have demonstrated that they are effective in preventing transmission of Neisseria gonorrhea, Treponema pallidum, Chlamydia trachomatis, hepatitis B virus, HIV, herpes simplex virus (HSV), human papillovirus, and cytomegalovirus in actual use and in laboratory testing.47 Polyurethane has similar effectiveness in laboratory tests, but its effectiveness must be confirmed in human clinical trials.48,49
Most male condoms have a width of 2.05 inches and a length of 7.2 inches. Trojan-Enz Large, Trojan Magnum, Kimono, Kimono PLUS, and Kimono Microthin condoms measure 2.13 inches wide and 8.0 inches long. Because slippage of condoms during coitus is a major cause of contraceptive failure, larger-sized condoms should only be used when they are actually needed. Holding the condom at the base of a still erect penis at the conclusion of intercourse reduces the risk of condom slippage during withdrawal from the vagina.
There are more than 100 different male condoms on the market, providing users with many options, including plain or reservoir tip, lubricated or nonlubricated, spermicide or nonspermicide lubricant, flavored or unflavored, scented or unscented, varying thickness, multiple colors, and plain, ribbed, or studded. Breakage or tearing of the condom during use obviously lessens its effectiveness for prevention of both conception and disease. Reservoir-tipped, lubricated condoms are less likely to break or tear. If a condom is to be used during oral or anal sex, condoms with greater thickness may afford greater protection, or two condoms should be used instead of one.46 Table 7 lists the characteristics of several condoms.
Condoms should be unrolled onto an erect penis before there is any genital contact. If a condom without a reservoir tip is used, about 1/2 inch of empty space should be left at the tip of the condom. The tip should be pressed together to remove any air, and then the condom can be rolled onto the penis. Failure to do this may result in rupture of the condom during ejaculation. Uncircumcised men should pull back the foreskin before putting on a condom.
Silicone and nonoxynol 9 are the most frequently used lubricants for condoms. The efficacy of condoms with or without spermicidal lubricants in preventing pregnancy has yet to be demonstrated in clinical trials.46 The quantity of spermicide present on the condom is much less than that used in spermicidal contraceptives. If additional lubricant is needed when a latex condom is used, only a water-soluble agent is suitable. Any over-the-counter (OTC) vaginal lubricant (K-Y Jelly, Astroglide, Condom-Mate, or Lubrin) or any OTC spermicide listed in Table 8 may be used. Oil-based lubricants, such as petrolatum (Vaseline), mineral oil, baby oil, or vaginal preparations, such as Femstat, Vagisil, or Monistat, may cause deterioration of the latex, thereby increasing the risk of rupture.46 If a condom does rupture, a spermicide should be inserted into the vagina immediately. Washing the external genital area with mild soap and water may reduce the risk of transmission of any STI.46
Polyurethane condoms are not adversely affected by oil-based lubricants.50 However, condom users may not be aware of the composition of the condom they have chosen, and so it may be best for pharmacists to recommend only water-based lubricants to all condom purchasers.
Care must be taken not to tear or puncture the condom while opening the package or placing the condom on the penis. If a tear or break in the condom occurs, it must be discarded, and a new condom selected. Improper storage in excessive heat and exposure to light may lead to accelerated deterioration of condoms. Any condom that is discolored, brittle, or sticky should be discarded and not used.
Although there is concern about the physical failure of male condoms, slippage because of improper use is the most frequent cause of contraceptive failure. The reported rates for latex condoms slipping during vaginal intercourse are between 3.4 and 13.1%, but only 0.6 to 5.4% of the time did the condom fall off. Slippage is more likely to occur during anal sex.51 Frezieres52,53 reported that slippage and breakage were higher for polyurethane condoms than for latex condoms.
Before packaging, manufacturers test each condom for pinhole leaks using an electrical method; defective condoms are destroyed. The FDA requires that a random sample of condoms passing the pinhole test from each manufactured lot be subjected to leak testing. Condoms are filled with 300 mL of water, and if more than 4 per 1,000 condoms leak, the lot is unacceptable.54
Consumer Reports tested condom integrity in June 1999 and compared the results with a similar test they performed in 1995.55 They concluded that the quality control of condoms was greatly improved. In 1995, 7 of 37 different brands of condoms failed an air inflation test developed by Consumer Reports; only 2 of 30 failed in 1999.
Male condoms have proved to be popular, convenient, inexpensive, and effective contraceptives that provide excellent protection against STIs. Publicity about the rate of transmission of HIV among heterosexuals and educational efforts by governmental agencies and other organizations have resulted in an increase in male condom usage among all women of reproductive age from 13% in 1988 to 19% in 1995.46 The rate of use among adolescent women between 15 and 19 years of age was about 30%.
Recent surveys of both men and women engaging in high-risk sexual practices revealed that many do not use condoms. Many reasons are given for not using condoms, including lack of spontaneity, decrease in sensation, lack of trust in a partner, and embarrassment. However, sexually active individuals should be reminded that the man or the woman can purchase condoms, and that they are available in many retail outlets and frequently available in vending machines. In addition, many school districts and planned parent organizations provide condoms free or at reduced cost for those who have financial problems.
The manufacturer of LifeStyle condoms has an advertising campaign aimed at the pleasure that can be derived from putting on a condom as part of foreplay, thus making it a “part of” and not a “break in” sexual activity. Ribbed and studded condoms are reported to enhance coital pleasure. Colored and scented condoms may provide added sensuality for some couples. Most condom manufacturers have web sites on which each product is described and often a free sample is available for trial use.
Reality, a polyurethane condom for women, has a flexible ring at each end. The device is 7.8 cm wide, 17 cm long, and closed at one end. The rim around the closed end is inserted vaginally, and the rim at the open end extends outside the vagina, providing protection to the labia.44 It may be inserted up to 8 hours before intercourse. The condom is lubricated but additional lubricant may be used if needed. Because it is polyurethane, the lubricant may be either water or oil soluble.
The rate of pregnancy during the first year is 5% for perfect use of the female condom, and 21% for typical use.36 It costs about $1.50, which is about two to three times more than most male condoms.
The fact that it is a loose sheath and protrudes from the vagina may be objectionable to some users. Because it may be inserted well before sexual activity commences, it may be acceptable to those couples who find use of a male condom an inconvenience or interruption. Male and female condoms should not be used simultaneously; excess friction during coitus may cause one or both of the condoms to be dislodged.
Spermicides are chemical compounds that kill sperm. They have a physical barrier effect, but their primary mode of action, as a result of their nonionic surfactant properties, is to disrupt the lipid portion of spermatozoa. The FDA approved the use of menfegol, nonoxynol 9, and octoxynol 9 as spermicidal agents.56 The majority of products available contain nonoxynol 9, and there are no products containing menfegol available at this time.
Spermicidal suppositories, films, or tablets must be inserted vaginally at least 15 minutes before intercourse to permit release of the spermicide from the dosage form used. Foams, creams, and jellies can be used just before intercourse. All spermicides must be applied near the cervix to be optimally effective and require reapplication after about an hour, except Advantage 24.57 This product may be inserted up to 24 hours before intercourse because of its adhesive properties. Additional spermicide must be used for subsequent coital acts regardless of the spermicide used. Some women who have anatomical anomalies may not be able to use spermicides. If a woman wishes to use a douche, she should wait until at least 6 hours after intercourse.56
Some spermicidal jellies and creams may be used alone; others are only intended for use with diaphragms or cervical caps. VCF (Vaginal Contraceptive Film), a contraceptive film containing nonoxynol 9, is the most recent form of a spermicide available. It may be used alone or with a diaphragm or male condom. The film should be inserted 15 minutes before intercourse and placed on or near the cervix when used alone. If the film is used with a diaphragm, it is placed in the dome.58
Products vary in the concentration of spermicide present because of the differences in their formulation. Therefore, choice of product should not depend on the labeled concentration of spermicide but on the formulation preference of the user. The FDA has requested all manufacturers of spermicidal contraceptives to submit data on the clinical effectiveness of each formulation for review.59
Although laboratory tests demonstrated that nonoxynol 9 has the ability to kill organisms causing some STIs (genital herpes, gonorrhea, syphilis, trichomoniasis, and HIV), there is no conclusive evidence for this effect in randomized controlled
trials.60-63 Spermicides have been shown to alter vaginal pH and vaginal flora and to cause irritation of vaginal mucosa. These changes could enhance transmission of HIV and favor colonization of bacteria and
candida.64-66 Fihn et al67 showed that the use of spermicide with diaphragms increased the incidence of urinary tract infections.
Spermicides and other barrier methods of contraception have been shown to reduce the risk of cervical cancer in sexually active women.68 Although some early reports linked spermicides to possible adverse fetal outcomes, more recent studies have shown them to be safe.69
The efficacy of a spermicide when used in a perfect manner is about the same as that for perfect use of a diaphragm and female condom. The cost per use varies, depending on the formulation used as well as whether individual prefilled applicators or multidose containers are purchased.
Women seeking effective contraception without the use of systemic hormonal agents have many choices, but not all nonhormonal contraceptives are suitable for all women. Pharmacists must ask questions in a sensitive manner about sexual behavior without causing undo uneasiness or embarrassment. It is only after discerning the commitment a woman has to avoiding pregnancy and the likelihood of adherence to a contraceptive method that a pharmacist can make a suitable recommendation. The following summary of the advantages and disadvantages of the nonhormonal methods discussed can serve as a guide.
|The IUD is the most effective nonhormonal method for women without contraindications for its use. However, it is not usually recommended for younger, nulliparous women, who represent a large segment of the population using contraceptives. Once inserted into the uterus by a clinician, no further action is required for an IUD to be effective, but the woman must check periodically to be sure it remains in place.|
|Male condoms are the most effective, least costly, nonprescription contraceptives, but they are male-controlled devices and
require joint agreement for use. The female condom is somewhat less effective than a male condom, and its general acceptance is low. |
| Diaphragms used with a spermicide or spermicides used alone have about the same contraceptive effectiveness. The cervical sponge and cervical cap are the least effective of the nonhormonal contraceptives, and for parous women they have the highest failure rate, 20 and 26%, respectively. |
|Only latex condoms are approved for the prevention of STIs, including HIV, but polyurethane condoms and spermicides reduce the risk of STIs.|
The best contraceptive method is the one that meets the satisfaction of the woman and her partner and is used every time. If maximum protection against pregnancy and an STI is desired, the use of a male condom and any of the other nonhormonal methods, except for the female condom, should be used. Patients should be advised that there may be failure of nonhormonal devices, for example, slippage or tearing of condoms, cervical caps, diaphragms, or
contraceptive sponges. Women should ask their clinicians for prescriptions for emergency contraception pills to be prepared for such
1. Centers for Disease Control and Prevention. NCHS FASTATS: Available at www.cdc.gov/nchcwww/fastats/usecon.htm.
2. Lawrence H. How early-cycle side effects discourage pill use. Contemp OB/Gyn 1997;42:45-70.
3. Reproduction. In: Vander AJ, Sherman JH, Luciano DS, eds. Human Physiology: The Mechanisms of Body Function. New York: McGraw-Hill Book Company; 1975:443.
4. Fauser BCJM, VanHeusden AM. Manipulation of human ovarian function: Physiological concepts and clinical consequences. Endocr Rev 1997;18:71-106.
5. Bucci KK, Carson DS. Contraception. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM, eds. Pharmacotherapy: A pathophysiologic approach. Stanford: Appleton and Lange; 1999:1327-41.
6. Baird DT, Glasier AF. Drug therapy: Hormonal contraception. N Engl J Med 1993;328:1543-49.
7. Ruggerio RJ. Contraception. In: Young LY, Koda-Kimble MA, eds. Applied therapeutics: The clinical use of drugs. Vancouver: Applied Therapeutics, Inc; 1997:43-1-43-19.
8. Choice of contraceptives. Med Lett Drug Ther 1995;37:9-12.
9. Hormonal contraception. ACOG Technical Bull 1994;198:1-11.
10. Organon Incorporated. Mircette: Organon, Incorporated, 1998.
11. Mishell DR. Contraception. N Engl J Med 1989;320:777-85.
12. Kaplan B. Desogestrel, norgestimate, and gestodene: The newer progestins. Ann Pharmacother 1995;29:736-42.
13. Nelson AL. Menstrual Problems and Common Gynecologic Concerns. In: Hatcher RA, Trussell J, Stewart F, et al, eds. Contraceptive Technology. New York: Ardent Media, Inc; 1998:95-140.
14. MacGregor EA. Menstruation, sex hormones, and migraine. Neurologic Clinics 1997;15:125-41.
15. Drukker BH. The diagnosis and management of breast disease. In: Sciarra JJ, ed. Gynecology and Obstetrics. Vol. 1. Philadelphia: Lippincott-Raven; 1998; 26:1-9.
16. Hannaford PC, Webb AMC. Evidence-guided prescribing of combined oral contraceptives: Consensus Statement. Contraception 1996;54:125-9.
17. Oral Contraceptives. In: Hebel SK, Olin BR, eds. Drug Facts and Comparisons. St. Louis, MO: Wolters Kluwer Company, CliniSphere. Version 2.0;1999.
18. Lewis MA. The epidemiology of oral contraceptive use: A critical review of the studies on oral contraceptives and the health of young women. Am J Obstet Gynecol 1998;179:1086-97.
19. Tatro DS. Oral contraceptive drug interactions. Pharmacist’s Letter 1997.
20. Tatro DS, ed. Drug Interaction Facts. St. Louis, MO: Wolters Kluwer Company; 1999.
21. Ovral as a “morning-after” contraceptive. Med Lett Drug Ther 1989;31:93-4.
22. Depo-Provera Contraception Injection package information. Kalamazoo, MI, Upjohn, December 1992.
23. Molzon JA. The Generic Drug Approval Process. J Pharm Law 1995;5:275-284.
24. USP DI, Approved Drug Products and Legal Requirements, Vol. III, 1999.
25. Nightingale S. Letter, Department of Health and Human Services, 1998.
26. d’Oro LC, Parazzini F, Naldi L, et al. Barrier methods of contraception, spermicides, and sexually transmitted diseases: A review. Genitourin Med 1995;71(3):410-7.
27. Johnson CA. Intrauterine Devices. In: Johnson CA, Johnson BE, Murray JL, Apgar BS, eds. Women’s Health Care Handbook. Philadelphia: Hanley & Belfus, Inc; 1996:172-5.
28. Stewart GK. Intrauterine devices. In: Hatcher RA, Stewart F, Trussel J, et al, eds. Contraceptive Technology. 17th ed. New York: Irvington Publishers, Inc; 1998;511-43.
29. Alvarez F, Brache V, Fernandez E, et al. New insights on the mode of action of intrauterine devices in women. Fertil Steril 1988;97:768-73.
30. Ortiz ME, Croxatto HB, Bardin CW. Mechanisms of action of intrauterine devices. Obstet Gynecol Surv 1996; 51(suppl):S42-S51.
31. Sagiroglu N. Phagocytosis of spermatozoa in the uterine cavity of women using intrauterine devices. Int J Fert 1971;16:1-14.
32. Hagenfeldt K. Intrauterine contraception with the copper-T device: Effect on trace elements in the endometrium, cervical mucus and plasma. Contraception 1972;6:37-54.
33. Spinnato JA II. Mechanism of action of intrauterine contraceptive devices and its relation to informed consent. Am J Obstet Gynecol 1997;176(3):503-6.
34. Dardano KL, Burkman RT. The intrauterine contraceptive device: An often-forgotten and maligned method of contraception. Am J Obstet Gynecol 1999;181:1-5.
35. Mishell RD Jr, Sulak PJ. The IUD: Dispelling the myths and assessing the potential. Dialogues in Contraception 1997;5:1-4.
36. Trussell J, Kowal D. The essentials of contraception: Effectiveness, safety & personal considerations. In: Hatcher RA, Stewart F, Trussel J, et al, eds. Contraceptive Technology. 17th ed. New York: Irvington Publishers, Inc; 1998:211-47.
37. Farley TMM, Rosenberg MJ, Rowe PJ, et al. Intrauterine devices and pelvic inflammatory disease: An international perspective. Lancet 1992;339:785-8.
38. Sinei SKA, Schulz KF, Lamptey PR, et al. Preventing IUD-related pelvic infection: The efficacy of prophylactic doxycycline at insertion. Br J Obstet Gynaecol 1990;97(5):412-9.
39. Walsh T, Grimes D, Friezes R, et al. Randomised controlled trial of prophylactic antibiotics before insertion of intrauterine devices. IUD Study Group. Lancet 1998;351:1005-8.
40. Rieder J, Coupey SM. The use of nonhormonal methods of contraception in adolescents. Ped Clin North Amer 1999;46(4):671-94.
41. Korn AP, Abercrombie PD. Gynecology and family planning care for the woman infected with HIV. Obstet Gynecol Clinics 1997;24(4):856-72.
42. Rosenberg MJ, Davidson AJ, Chen JH, et al. Barrier contraceptives and sexually transmitted diseases in women: A comparison of female dependent methods and condoms. Am J Public Health 1992;82:669-74.
43. Rosenberg MJ, Gollub EL. Methods that women can use that may prevent sexually transmitted disease, including HIV (Commentary). Am J Public Health 1992;82:1473-8.
44. Stewart F. Vaginal Barriers. The diaphragm, contraceptive sponge, cervical cap, and female condom. In: Hatcher RA, Stewart F, Trussel J, et al, eds. Contraceptive Technology. 17th ed. New York: Irvington Publishers, Inc; 1998;371-404.
45. Johnson CA. Vaginal barrier contraceptive methods. In: Johnson CA, Johnson BE, Murray JL, Apgar BS, eds. Women’s Health Care Handbook. Philadelphia: Hanley & Belfus, Inc; 1996:161-7.
46. Warner DL, Hatcher RA. Male condoms. In: Hatcher RA, Stewart F, Trussel J, et al, eds. Contraceptive Technology. 17th ed. New York: Irvington Publishers, Inc; 1998;325-55.
47. Centers for Disease Control and Prevention: Condom prevention of sexually transmitted diseases. Morb Mortal Wkly Rep 1988;37:133-7.
48. Nelson A, Bernstein GS, Frezieres R, et al. Study of the efficacy, acceptability and safety of non-latex (polyurethane) male condom: Revised final report (N01-HD-1-3109). Bethesda, MD: National Institute of Child Health and Human Development, September 15, 1997.
49. Nelson A, Frezieres R, Walsh T, et al. Controlled randomized evaluation of a commercially available polyurethane and latex condom (Avanti versus Ramses Sensitol): Final report (N01-HD-1-3109). Bethesda, MD: National Institute of Child Health and Human Development, November 6, 1996.
50. Grimes DA. Future barrier methods. The Contraception Report 1997;8:9-13.
51. Rosenberg MJ. Latex condom breakage and slippage in a controlled trial. Contraception 1997;56(1):17-21.
52. Frezieres RG. Breakage and acceptability of a polyurethane condom: A randomized, controlled study. Fam Plan Perspect 1998;30(2):73-8.
53. Frezieres RG. Evaluation of the efficacy of a polyurethane condom: Results from a randomized, controlled clinical study. Fam Plan Perspect 1999;31(2):81-7.
54. FDA develops latex condom permeability test method. The Gray Sheet 1990; 16(52):22.
55. Condoms get better. Consumer Reports 1999;64(6):46-9.
56. Fed Reg 1980;45:82014-49.
57. OTC spermicides with low noxoxynol-9 doses may be the safest choice. The Tan Sheet 1997;5(11):4.
58. Apothecus: <www.Apothecus.com/film.htm>
59. Fed Reg 1995;60:6892-6903.
60. Elias CJ, Coggin C. Female-controlled methods to prevent sexual transmission of HIV. AIDS 1996;10(suppl 3):S43-S51.
61. Louv WC, Austin WJ, Stango S, Cheeks J. A clinical trial of nonoxynol-9 for preventing gonoccal and chlamydial infections. J Infect Dis 1988;158:518-23.
62. Cook RL, Rosenberg MJ. Do spermicides containing nonoxynol-9 prevent sexually transmitted infections? A meta-analysis. Sex Transm Dis 1998;25:144-50.
63. Roddy RE, Zenkeng L, Ryan A, et al. A controlled trial of nonoxynol 9 film to reduce male-to-female transmission of sexually transmitted diseases. N Engl J Med 1998;339:504-10.
64. Niruthisard S, Roddy RE, Chutivongse S. The effects of frequent nonoxynol-9 use on the vaginal and cervical mucosa. Sex Transm Dis 1991;18:176-9.
65. Hooten TM, Fennel O, Clark AM, et al. Nonoxynol 9 differential antibacterial activity and enhancement of bacterial to vaginal epithelial cells. J Infect Dis 1991;164:1216-19.
66. Sobel JD, Faro S, Rex WF, et al. Vulvovaginal candidiasis: Epidemiologic, diagnostic, and therapeutic considerations. Am J Obstet Gynecol 1998;178(2):203-11.
67. Fihn SD, Latham RH, Roberts P, et al. Association between diaphragm use and urinary tract infection. JAMA 1985;254:240-5.
68. Hildesheim A, Brinton LA, Malin K, et al. Barrier and spermicidal contraceptive methods and risk of invasive cervical cancer. Epidemiology 1990;1:266-72.
69. Einarson TR, Koren G, Mattice D, Schechter-Tsafriri O. Maternal spermicide use and adverse reproductive outcome: A meta-analysis. Am J Obstet Gynecol 1990;162:655-60.