**Guidance for Industry**

**Labeling for Combined Oral Contraceptives**

***DRAFT GUIDANCE***

**This guidance document is being distributed for comment purposes
only.**

Comments and suggestions regarding this draft document should be
submitted within 60 days of publication of the *Federal Register* notice
announcing the availability of the draft guidance. Submit comments to
the Division of Dockets Management (HFA-305), Food and Drug
Administration, 5630 Fishers Lane, room 1061, Rockville, MD 20852. All
comments should be identified with the docket number listed in the
notice of availability that publishes in the *Federal Register*.

For questions on the content of the draft document contact Margaret
Kober, 301-827-4243.

**U.S. Department of Health and Human Services**

**Food and Drug Administration**

**Center for Drug Evaluation and Research (CDER)**

**March 2004**

**Labeling**

**Revision 1**

**Guidance for Industry**

**Labeling for Combined Oral Contraceptives**

Additional copies are available from:

*Office of Training and Communication*

*Division of Drug Information (HFD-240)*

*Center for Drug Evaluation and Research (CDER)*

*Food and Drug Administration*

*5600 Fishers Lane*

*Rockville, MD 20857*

*(Tel) 301-827-4570*

*http://www.fda.gov/cder/guidance/index.htm*

**U.S. Department of Health and Human Services**

**Food and Drug Administration**

**Center for Drug Evaluation and Research (CDER)**

**March 2004**

**Labeling**

**Revision 1**

**Table of Contents**

# I. Introduction [1](#i.-introduction) {#i.-introduction-1 .TOC-1}

# II. Labeling for Package INsert [2](#ii.-labeling-for-package-insert) {#ii.-labeling-for-package-insert-2 .TOC-1}

# PROPRIETARY NAME (Established Name) [2](#proprietary-name-established-name) {#proprietary-name-established-name-2 .TOC-1}

# DESCRIPTION [2](#description) {#description-2 .TOC-1}

# CLINICAL PHARMACOLOGY [2](#clinical-pharmacology) {#clinical-pharmacology-2 .TOC-1}

# INDICATIONS AND USAGE [3](#indications-and-usage) {#indications-and-usage-3 .TOC-1}

# CONTRAINDICATIONS [4](#contraindications) {#contraindications-4 .TOC-1}

# WARNINGS [4](#warnings) {#warnings-4 .TOC-1}

# PRECAUTIONS [8](#precautions) {#precautions-8 .TOC-1}

# ADVERSE EXPERIENCES [10](#adverse-experiences) {#adverse-experiences-10 .TOC-1}

# Possible HEALTH BENEFITS [11](#possible-health-benefits) {#possible-health-benefits-11 .TOC-1}

# OVERDOSAGE [11](#overdosage) {#overdosage-11 .TOC-1}

# DOSAGE AND ADMINISTRATION [11](#dosage-and-administration) {#dosage-and-administration-11 .TOC-1}

# HOW SUPPLIED [12](#how-supplied) {#how-supplied-12 .TOC-1}

# STORAGE [12](#storage) {#storage-12 .TOC-1}

# REFERENCES [12](#references) {#references-12 .TOC-1}

# III. PATIENT LABELING [13](#iii.-patient-labeling) {#iii.-patient-labeling-13 .TOC-1}

# WHAT IS (OC NAME)? [13](#what-is-oc-name) {#what-is-oc-name-13 .TOC-1}

# HOW WELL DOES (OC NAME) WORK? [13](#how-well-does-oc-name-work) {#how-well-does-oc-name-work-13 .TOC-1}

# HOW DO I TAKE (OC NAME)? [14](#how-do-i-take-oc-name) {#how-do-i-take-oc-name-14 .TOC-1}

# WHAT SHOULD I DO IF I MISS ANY PILLS? [15](#what-should-i-do-if-i-miss-any-birth-control-pills) {#what-should-i-do-if-i-miss-any-pills-15 .TOC-1}

# WHO SHOULD NOT TAKE (OC NAME)? [16](#who-should-not-take-oc-name) {#who-should-not-take-oc-name-16 .TOC-1}

# WHAT ELSE SHOULD I KNOW ABOUT TAKING (OC NAME)? [16](#what-else-should-i-know-about-taking-oc-name) {#what-else-should-i-know-about-taking-oc-name-16 .TOC-1}

# WHAT ARE COMMON SIDE EFFECTS OF BIRTH CONTROL PILLS? [17](#what-are-common-side-effects-of-birth-control-pills) {#what-are-common-side-effects-of-birth-control-pills-17 .TOC-1}

# WHAT ARE THE MOST SERIOUS RISKS OF TAKING BIRTH CONTROL PILLS? [18](#what-are-the-most-serious-risks-of-taking-birth-control-pills) {#what-are-the-most-serious-risks-of-taking-birth-control-pills-18 .TOC-1}

# DO BIRTH CONTROL PILLS CAUSE CANCER? [19](#do-birth-control-pills-cause-cancer) {#do-birth-control-pills-cause-cancer-19 .TOC-1}

# What if I want to become pregnant? [19](#what-if-i-want-to-become-pregnant) {#what-if-i-want-to-become-pregnant-19 .TOC-1}

# ARE THERE OTHER BENEFITS OF THE BIRTH CONTROL PILL? [19](#are-there-other-benefits-of-the-birth-control-pill) {#are-there-other-benefits-of-the-birth-control-pill-19 .TOC-1}

#  {#section .TOC-1}

**Guidance for Industry**[^1]

**Labeling for Combined Oral Contraceptives**

This draft guidance, when finalized, will represent FDA\'s current
thinking on this topic. It does not create or confer any rights for or
on any person and does not operate to bind FDA or the public. You can
use an alternative approach if it satisfies the requirements of the
applicable statutes and regulations. If you want to discuss an
alternative approach, contact the FDA staff responsible for implementing
this guidance. If you cannot identify the appropriate FDA staff, call
the appropriate number listed on the title page of this guidance.

# I. Introduction

This guidance describes the recommended labeling for health care
providers and patient instructions for use for new drug applications
(NDAs) and abbreviated new drug applications (ANDAs) for combined oral
contraceptives (OCs) that contain estrogen and progestin. A draft
guidance on this topic was issued for comment in June 2000. Many
comments were received on the 2000 draft guidance and, as a result, many
changes have been made to the guidance. Because of the many changes, we
are making the guidance available again in draft to allow for additional
public review and input. The references listed at the end of this
guidance do not go in the labeling.

# II. Labeling for Package INsert

We recommend the following labeling be used for combined oral
contraceptives:

# PROPRIETARY NAME (Established Name)

*Supplied by manufacturer*

**WARNING: CIGARETTE SMOKING**

Combined oral contraceptives (OCs) are not recommended for women who are
over 35 years old and smoke. Cigarette smoking increases the risk of
serious cardiovascular side effects from OC use. The risk increases with
age and with the number of cigarettes smoked.

**This product does not protect against infection from HIV (the virus
that causes AIDS) or other sexually transmitted diseases.**

# DESCRIPTION

*Supplied by* *manufacturer*

# CLINICAL PHARMACOLOGY

**Mode of action**

OCs lower the risk of becoming pregnant primarily by suppressing
ovulation. Other possible mechanisms may include cervical mucus changes
that inhibit sperm penetration and endometrial changes that reduce the
likelihood of implantation.

*Receptor binding studies can be summarized briefly here if clinically
relevant.*

**Pharmacokinetics**

*Supplied by manufacturer, to include the following subsections:*

-   *Absorption*

-   *Distribution*

-   *Metabolism*

-   *Excretion*

-   *Special Populations*

-   *Renal and Hepatic Impairment*

-   *Drug-drug Interactions (include mechanism for drug interaction for
    specific product, refer to PRECAUTIONS for class-labeling for OC
    products.)*

# INDICATIONS AND USAGE

*(Name of OC)* is indicated for use by women to lower the risk of
becoming pregnant.

*Other approved indications appear here.*

*Pregnancy rates from clinical trials should be placed here.*

In clinical trials of (*insert name of OC here*), about (*insert whole
number here*) out of 100 women became pregnant during the first year of
use. The effectiveness of any OC depends on correct and consistent use,
and factors that affect ability to conceive, including age and frequency
of intercourse.

The following table shows estimates of the number of women who become
pregnant during the first year of use, based mainly on clinical trial
data, for various birth control methods.

+------------------------------------+---------------------------------+
| Approximate Percentage of Women    |                                 |
| Who Become Pregnant During the     |                                 |
| First Year of Use of a Birth       |                                 |
| Control Method^\*^                 |                                 |
+------------------------------------+---------------------------------+
| Method                             | Pregnancies per 100 women per   |
|                                    | year                            |
+------------------------------------+---------------------------------+
| estrogen/progestin injection       | Fewer than 1                    |
|                                    |                                 |
| levonorgestrel implants            |                                 |
|                                    |                                 |
| levonorgestrel IUD and copper IUD  |                                 |
|                                    |                                 |
| medroxyprogesterone acetate        |                                 |
| injection                          |                                 |
|                                    |                                 |
| sterilization                      |                                 |
+------------------------------------+---------------------------------+
| estrogen/progestin contraceptive   | 1                               |
| products:                          |                                 |
|                                    |                                 |
| -   pills                          |                                 |
|                                    |                                 |
| -   skin patch                     |                                 |
|                                    |                                 |
| -   vaginal ring                   |                                 |
+------------------------------------+---------------------------------+
| progestin-only pills               | 2                               |
+------------------------------------+---------------------------------+
| condom (male)                      | 15                              |
|                                    |                                 |
| diaphragm                          |                                 |
+------------------------------------+---------------------------------+
| spermicides                        | 25 or more                      |
+------------------------------------+---------------------------------+

^\*^ The estimates for drugs, condoms, diaphragms, and IUDs are derived
from clinical trial data reviewed by the Food and Drug Administration.
The estimates for sterilization and spermicides come from the medical
literature.

**Clinical Studies**

*This section can contain a brief description of the extent of the Phase
III program, such as the number of patients, the number of patients less
than 35 years old, the number of treatment months. This section can also
be used when there is an efficacy or safety issue specific to the
product that is not addressed in class labeling. The location of this
section may vary, depending on content.*

# CONTRAINDICATIONS

OCs should not be used by women who have the following conditions:

-   Breast cancer or other hormone-sensitive cancer, now or in the past

-   Liver tumors, now or in the past, or liver disease

-   Undiagnosed abnormal genital bleeding

-   Any condition predisposing to thrombotic diseases

-   Thrombophlebitis or pulmonary embolism, now or in the past

-   Cerebrovascular disease

-   Coronary artery disease

-   Thrombogenic valvular or thrombogenic rhythm diseases of the heart

-   Congenital hypercoagulopathies

-   Diabetes with vascular disease

-   Uncontrolled hypertension

-   Migraines with focal neurologic symptoms

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-   Smoking and over age 35

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-   Pregnancy

-   Allergy to any components of this drug product

# WARNINGS

The use of OCs with estrogen and progestin increases the risk of serious
conditions, including myocardial infarction, thromboembolism, stroke,
hepatic neoplasia, and gallbladder disease. However, the risk of serious
morbidity or mortality is small in healthy women without underlying risk
factors. When considering OCs for a woman with underlying risk factors,
the risks of pregnancy and the feasibility of other birth control
methods must also be considered.

Minimizing exposure to estrogen and progestin reduces the risk of
thrombotic events. For any particular estrogen/progestin combination,
the recommended dosage regimen is that which contains the least amount
of estrogen and progestin that is compatible with a low pregnancy rate
and the medical needs of the individual patient.

**1. Vascular Risks**

a.  Mortality

For nonsmokers, the risk of cardiovascular death from OC use is less
than the risk of death from pregnancy. However, for smokers over age 35,
the risk of cardiovascular death from OC use is greater than the risk of
death from pregnancy for women over age 35.[^2]

b.  Thromboembolism

    Observational studies suggest an increased risk of superficial
    thrombophlebitis, deep vein thrombosis, and pulmonary embolism in OC
    users compared to non-OC
    users.[^3]^,^[^4]^,^[^5]^,^[^6]^,^[^7]^,^[^8]^,^[^9]^,^[^10]^,^[^11]
    The risk of thromboembolic disease associated with OCs is not
    related to length of use and disappears after use of the drug
    product is stopped.Error: Reference source not found

    A 2- to 4-fold increase in relative risk of postoperative
    thromboembolic complications has been reported with the use of
    OCs.Error: Reference source not found The relative risk of venous
    thrombosis in women who have predisposing conditions is twice that
    of women without such medical conditions.[^12] If feasible, OCs
    should be stopped at least 4 weeks before through 2 weeks after
    elective surgery of a type associated with an increase in risk of
    thromboembolism and during prolonged immobilization.[^13]^,^[^14]

    OCs should be started no earlier than 3 to 4 weeks after delivery in
    women who elect not to breast-feed. The increased risk of
    thromboembolism in the postpartum period appears to decrease after
    the third postpartum week, whereas the risk of ovulation increases
    after the third postpartum week. [^15]^,^[^16]

    OCs are associated with retinal vein thrombosis in case reports. OCs
    should be discontinued if there is unexplained partial or complete
    loss of vision; onset of proptosis or diplopia, papilledema, or
    retinal vascular lesions. Symptoms of retinal vein thrombosis should
    be evaluated immediately.[^17]^,^[^18]^,^[^19]

    OC use may also increase the risk of thrombosis in women with
    valvular heart conditions[^20] or arrhythmias that predispose to
    thrombosis, such as atrial fibrillation.

    The presence of factor V Leiden mutation and other hereditary or
    acquired coagulation disorders increases the risk of thromboembolic
    disease.[^21]

    *For desogestrel containing products: Several epidemiologic studies
    indicate that OCs containing desogestrel are associated with a
    higher risk of venous thromboembolism than OCs containing other
    progestins. In general, these studies indicate an approximate 2-fold
    increased risk, which corresponds to an additional 1 to 2 cases of
    venous thromboembolism per 10,000 women-years of use. However, data
    from other studies have not shown this 2-fold increase in risk.*

c.  Myocardial infarction

    An increased risk of myocardial infarction is attributed to OC use.
    This risk is mainly in women with underlying risk factors for
    coronary artery disease such as smoking, hypertension,
    hypercholesterolemia, morbid obesity, and diabetes. The relative
    risk of heart attack for current OC users compared to nonusers is
    estimated to be two to
    six.[^22]^,^[^23]^,^[^24]^,^[^25]^,^[^26]^,^[^27]^,^[^28] The risk
    is very low under the age of 30.

    Smoking in combination with OC use contributes substantially to the
    incidence of myocardial infarctions in women in their mid-30s or
    older, with smoking accounting for the majority of excess cases. In
    one study, the relative risk of myocardial infarction in heavy
    smokers who use OCs was 39, compared to 4.9 for nonsmokers who use
    OCs, and 1.0 for nonsmokers who do not use OCs.[^29] Estimates of
    the annual mortality rate from cardiovascular disease in OC users
    over age 35 show a five-fold higher risk for smokers compared to
    nonsmokers.[^30]

    OCs must be used with caution in women with cardiovascular disease
    risk factors. OCs may further increase the effects of well-known
    risk factors, such as hypertension, diabetes, hyperlipidemias, age,
    and obesity. [^31]

d.  Cerebrovascular diseases

    In observational studies, OCs appear to increase the risk of
    strokes, although, in general, the risk is greatest among
    hypertensive women over age 35 who also smoke. [^32]^,^[^33]^,^[^34]

    The relative risk of thrombotic strokes has been shown to range from
    3 for normotensive users to 14 for users with severe
    hypertension.[^35] The relative risk of hemorrhagic stroke is
    reported to be 1.2 for nonsmokers who used OCs, 2.6 for smokers who
    did not use OCs, 7.6 for smokers who used OCs, 1.8 for normotensive
    users, and 25.7 for users with severe hypertension.Error: Reference
    source not found

e.  Dose-related risk of vascular disease from OCs

    A positive association has been observed between the amount of
    estrogen and progestin in OCs and the risk of vascular
    disease.[^36]^,^[^37]^,^[^38] A decline in serum high-density
    lipoproteins (HDL) is seen with many progestational
    agents.[^39]^,^[^40]^,^[^41]

**2. Carcinoma of the Breast and Cervix**

Women who currently have or have had breast cancer should not use oral
contraceptives because breast cancer may be hormonally sensitive.

There is substantial evidence that OCs do not increase the incidence of
breast cancer.[^42]^,^[^43] Although some past studies have suggested
that OCs might increase the incidence of breast cancer, more recent and
thorough studies have not confirmed such findings.

Some studies suggest that OCs are associated with an increase in the
risk of cervical cancer or intraepithelial
neoplasia.[^44]^,^[^45]^,^[^46]^,^[^47] However, there is controversy
about the extent to which these findings are due to differences in
sexual behavior and other factors.

**3. Liver Disease**

Benign hepatic adenomas are associated with OC use. Indirect
calculations have estimated the attributable risk to be 3.3
cases/100,000 for OC users.[^48] Rupture of benign, hepatic adenomas may
cause death through intra-abdominal hemorrhage.[^49]^,^[^50]

Studies from Britain have shown an increased risk of developing
hepatocellular carcinoma in long-term (more than 8 years) OC
users.[^51]^,^[^52]^,^[^53]^,^[^54] However, the attributable risk (the
excess incidence) of liver cancers in OC users is less than one per
million users.

OC-related cholestasis has been described in women with a history of
pregnancy-related cholestasis. Women with a history of OC-related
cholestasis may have the condition recur with subsequent OC use.[^55]

OCs should be discontinued if jaundice develops. Steroid hormones may be
poorly metabolized in patients with impaired liver function.

**4. Gallbladder Disease**

Studies have shown that the increased relative risk of developing
gallbladder disease among OC users may be
minimal.[^56]^,^[^57]^,^[^58]^,^[^59]^,^[^60]^,^[^61]^,^[^62]

**5. Carbohydrate and Lipid Metabolic Effects**

OCs may decrease glucose tolerance in a dose-related
fashion.[^63]^,^[^64] Therefore, prediabetic and diabetic women should
be carefully monitored while taking OCs. However, in nondiabetic women,
OCs appear to have no effect on fasting blood glucose.[^65]

A small proportion of women will have adverse lipid changes while on
OCs. Alternative contraception should be considered in women with
uncontrolled dyslipidemias.[^66] Elevations of plasma triglycerides may
lead to pancreatitis and other complications.

**6. High Blood Pressure**

Women with uncontrolled hypertension or hypertension with vascular
disease should not use OCs.[^67]^,^[^68]^,^[^69] An increase in blood
pressure has been reported in women taking OCs,[^70] and this increase
is more likely in older OC users[^71] and with extended duration of use.
Data from the Royal College of General Practitioners[^72] and subsequent
randomized trials have shown that the incidence of hypertension
increases with increasing progestational activity and concentrations of
progestins. If OCs are prescribed for women with well-controlled
hypertension, close blood pressure monitoring is recommended and OCs
should be discontinued if blood pressure rises significantly.

**7. Headache**

The onset or exacerbation of migraine or development of headache with a
new pattern that is recurrent, persistent, or severe requires
discontinuation of OCs and evaluation of the cause.

**8. Vaginal Bleeding Problems**

Breakthrough bleeding and spotting are sometimes seen in patients on
OCs, especially during the first 3 months of use. If bleeding persists,
nonhormonal causes such as pregnancy or malignancy should be considered.
If pathology and pregnancy are excluded, time or a change to another
formulation may solve the problem.

Amenorrhea is sometimes seen in women who are using OCs. Pregnancy
should be ruled out in the event of amenorrhea.

*A description of vaginal bleeding patterns from the controlled clinical
trials that supported drug approval should be placed here if relevant.*

# PRECAUTIONS

**1. General**

Women who are using oral contraceptives should have an annual history
and physical examination, including special reference to blood pressure,
breasts, abdomen and pelvic organs, as well as cervical cytology and
relevant laboratory tests.

**2. Information for Patients**

See patient labeling.

**3**. **Hypocalcemia**

Estrogens should be used with caution in individuals with severe
hypocalcemia because this condition may be aggravated.

**4. Drug Interactions**

Changes in contraceptive effectiveness associated with co-administration
of other products:

a\. Anti-infective agents and anticonvulsants

Contraceptive effectiveness may be reduced when hormonal contraceptives
are co-administered with antibiotics, anticonvulsants, and other drugs
that increase the metabolism of contraceptive steroids.[^73] This could
result in unintended pregnancy or breakthrough bleeding. Some examples
include rifampin, barbiturates, phenylbutazone, phenytoin,
carbamezepine, felbamate, oxcarbazepine, topiramate, and griseofulvin.

b\. Anti-HIV protease inhibitors

Several of the anti-HIV protease inhibitors have been studied with
co-administration of oral combination hormonal contraceptives;
significant changes (increase and decrease) in the plasma levels of the
estrogen and progestin have been noted in some cases. The safety and
efficacy of OC products may be affected with co-administration of
anti-HIV protease inhibitors. Health care providers should refer to the
label of the individual anti-HIV protease inhibitors for further
drug-drug interaction information.

c\. Herbal products

Herbal products containing St. John's Wort (hypericum perforatum) may
induce hepatic enzymes (cytochrome P450) and p-glycoprotein transporter
and may reduce the effectiveness of contraceptive steroids. This may
also result in breakthrough bleeding.

**Increase in plasma levels of estradiol associated with co-administered
drugs:**

Co-administration of atorvastatin and certain OCs containing ethinyl
estradiol increase AUC values for ethinyl estradiol by approximately
20%. Ascorbic acid and acetaminophen may increase plasma ethinyl
estradiol levels, possibly by inhibition of conjugation. CYP 3A4
inhibitors such as itraconazole or ketoconazole may increase plasma
hormone levels.

**Changes in plasma levels of co-administered drugs:**

Combination hormonal contraceptives containing some synthetic estrogens
(e.g., ethinyl estradiol) may inhibit the metabolism of other compounds.
Increased plasma concentrations of cyclosporin, prednisolone, and
theophylline have been reported with concomitant administration of OCs.
Decreased plasma concentrations of acetaminophen and increased clearance
of temazepam, salicylic acid, morphine and clofibric acid, due to
induction of conjugation have been noted when these drugs were
administered with OCs.

**5. Interactions with Laboratory Tests**

Certain endocrine and liver function tests and blood components may be
affected by OCs:

a.  Increased prothrombin and factors VII, VIII, IX, and X; decreased
    antithrombin 3; increased norepinephrine-induced platelet
    aggregability.

b.  Increased thyroid binding globulin (TBG) leading to increased
    circulating total thyroid hormone, as measured by protein-bound
    iodine (PBI), T4 by column or by radioimmunoassay. Free T3 resin
    uptake is decreased, reflecting the elevated TBG, free T4
    concentration is unaltered. Patients dependent on thyroid hormone
    replacement therapy who are also receiving estrogens may require
    increased doses of their thyroid replacement therapy.

c.  Other binding proteins may be elevated in serum.

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d.  Sex hormone binding globulins are increased and result in elevated
    levels of total circulating sex steroids; however, free or
    biologically active levels either decrease or remain unchanged.

e.  Triglycerides may be increased and levels of various other lipids
    and lipoproteins may be affected.

f.  Glucose tolerance may be decreased.

**6. Carcinogenesis, Mutagenesis, Impairment of Fertility**

See CONTRAINDICATIONS and WARNINGS (subsection 2. Carcinoma of the
Breast and Cervix**)**. *If the OC contains a new progestin or estrogen,
data on animal carcinogenicity, mutagenicity, and return to fertility
should be placed here.*

**7. Pregnancy**

There appears to be little or no increased risk of birth defects in
women who have used OCs inadvertently during early
pregnancy.[^74]^,^[^75] *However, if any component of the drug product
is associated with birth defects, add a statement about the types of
defects, estimated frequency, the associated doses, and the gestational
age of exposure, if known.*

*If the OC contains a new progestin or estrogen, a statement that
summarizes what is known about pregnancy risk should be placed here,
followed by a summary of the animal/human data.*

**8. Nursing Mothers**

Small amounts of OC steroids have been identified in the milk of nursing
mothers. In addition, OCs given in the postpartum period may interfere
with lactation by decreasing the quantity and quality of breast milk. If
possible, the nursing mother should be advised to use other forms of
contraception until she has weaned her child.

**9. Pediatric Use**

Safety and efficacy are expected to be the same for postpubertal
adolescents and adult women. OCs are not indicated before menarche.

**10. Geriatric Use**

OCs have not been studied in postmenopausal women and are not indicated
in this population.

# ADVERSE EXPERIENCES

The most serious adverse reactions associated with the use of OCs are in
the WARNINGS and PRECAUTIONS sections.

Other side effects commonly reported by OC users are:

-   Nausea

-   Breast tenderness

-   Headaches

The following adverse reactions may occur less frequently:

-   Acne

-   Decreased libido

-   Dizziness

-   Fluid retention

-   Increased cervical ectopia

-   Melasma

-   Mood changes and depression

-   Ocular effects, including decreased tolerability to contact lenses

-   Vaginal candidiasis

-   Vomiting and other gastrointestinal symptoms (e.g., bloating)

-   Weight changes

It is not always clear whether these side effects are caused by OCs and,
if so, whether the estrogen and/or the progestin is responsible. These
side effects are most common in the first 1 to 3 pill cycles.

*Manufacturers should add additional details regarding adverse
experiences and cycle control unique to the product.*

# Possible HEALTH BENEFITS

Possible benefits associated with OC use beyond lowering of risk of
becoming pregnant include the following effects on menses:

-   More regular

-   Less blood loss

-   Less dysmenorrhea

# OVERDOSAGE

There have been no reports of serious ill effects from overdose,
including ingestion by children. Overdose may cause nausea and
withdrawal bleeding.

# 

# DOSAGE AND ADMINISTRATION

To achieve maximum contraceptive effectiveness, OCs must be taken as
directed. One tablet is taken at about the same time every day. Single
missed pills should be taken as soon as remembered. For detailed
instructions, see the patient labeling that is printed below.

OCs may be started 3 to 4 weeks postpartum in women who do not breast
feed. When OCs are used during the postpartum period, the increased risk
of thromboembolic disease associated with the postpartum period must be
considered.Error: Reference source not found The possibility of
ovulation and conception before starting OCs should also be
considered.Error: Reference source not found

# HOW SUPPLIED

*Manufacturer to provide information on available dosage forms, potency,
color, and packaging.*

*Manufacturer to include statement such as \"Keep out of reach of
children.\"*

## 

# STORAGE

*Manufacturer to provide information on pill storage.*

# REFERENCES 

*Supplied upon request.*

# III. PATIENT LABELING 

**Guide for Using (*OC name*)**

**WARNING TO WOMEN WHO SMOKE**

Do not use *(OC name)* if you smoke cigarettes and are over 35 years
old. Smoking increases your risk of serious side effects from birth
control pills, including death from heart attack, blood clots, or
stroke. The risk increases with age and the number of cigarettes you
smoke.

**Birth control pills help to lower the chances of becoming pregnant.
They do not protect against HIV infection (AIDS) and other sexually
transmitted diseases.**

## 

# WHAT IS (OC NAME)?

*(OC name)* is a birth control pill. It contains two hormones, an
estrogen called *(name of estrogen)*, and a progestin called *(name of
progestin).*

# HOW WELL DOES (OC NAME) WORK?

Your chance of getting pregnant depends on how well you follow the
directions for taking your birth control pills. The more carefully you
follow the directions, the less chance you have of getting pregnant.

In clinical studies, about (*insert whole number here)* out of 100 women
got pregnant during the first year that they used (*insert OC name
here).*

The following table shows how the birth control pill compares with some
other methods of birth control. The numbers are estimates of the number
of women out of 100 women who become pregnant in 1 year of use.[^76]

![](media/image1.wmf)

# HOW DO I TAKE (OC NAME)?

*Consider the instructions given to women during clinical trials when
crafting the text for this section. To minimize errors, all OC
instructions should be similar, but some differences are inevitable
because of the diversity of OCs.*

*To improve clarity, place the instructions for only one brand and
regimen in the patient label for a given birth control pill. For
example, package only 21-day pill instructions with 21-day pills, and
only 28-day pill instructions with 28-day pills.*

*Insert illustration of pill pack, direction in which pills are taken,
and other labeling that might make the directions clearer, such as which
pills are active and which are inactive.*

*The sample answers below apply to an imaginary birth control pill named
Brand X, a 28-day pack with 21 active pills. In the Brand X clinical
trials, women were told to start the first pack on day 1 of their
menstrual periods. Brand X instructions do not include Sunday Start
instructions because Sunday Start was not studied in the clinical
trials.*

If you have regular periods, take the [first pill]{.underline} of the
[first pack]{.underline} on the [first day]{.underline} of your period.
If you are not having regular periods, talk with your health care
provider about when to start your birth control pill.

[Take one pill about the same time every day]{.underline}. Taking a pill
every day must become a habit.

When you finish a pill pack, start the next pack on the following day so
you are always taking one pill a day, whether or not you are having your
period. You are more likely to get pregnant if you start the next pack
late or miss any pills.

Look at the picture of your pill pack. There are 21 active *(insert
color here)* pills that contain hormones and 7 inactive *(insert color
here)* pills that do not contain hormones. You are most likely to have
your period during the time you are taking the inactive pills.

# WHAT SHOULD I DO IF I MISS ANY birth control PILLS?

*As noted in the preceding question, consider the instructions given to
women during clinical trials when crafting the text for this section.
The sample answers for Brand X follow.*

Use a backup birth control method such as condoms or spermicide for 7
days after you miss any of the active *(insert color here)* pills.

If you miss 1 active *(insert color here)* pill take it as soon as you
remember. Take the next pill at your regular time. You may take 2 pills
in 1 day.

If you miss 2 active *(insert color here)* pills in a row in week 1 or
week 2 of your pack, take 2 pills as soon as you remember and 2 pills
the next day. Then take 1 pill a day until you finish the pack.

If you miss 2 active *(insert color here)* pills in a row in week 3 of
your pack, throw out the rest of the pack and start a new pack that same
day. You may not have your period this month. However, if you miss 2
periods in a row, call your health care provider to check for pregnancy.

If you miss 3 or more active *(insert color here)* pills in a row during
the first 3 weeks, throw out the rest of the pack and start a new pack
that same day. Call your health care provider for further advice.

If you forget any of the *(insert color here)* inactive pills, throw
away the pills you missed and continue to take one pill a day. You do
not need a backup method.

#  

# WHO SHOULD NOT TAKE (OC NAME)?

Birth control pills are safe for most women. However, taking birth
control pills can cause serious health problems, especially for women
with certain conditions. Do not take *(name of OC)* if you have:

-   Ever had breast cancer or any cancer that is sensitive to hormones

-   Liver disease, including liver tumors

-   Unexplained bleeding from your vagina

-   Ever had blood clots in your arms, legs, or lungs

-   Ever had a stroke

-   Ever had a heart attack or chest pains

-   Certain heart valve problems or heart rhythm abnormalities that can
    cause blood clots to form in the heart

-   An inherited problem with your blood that makes it clot more than
    normal

-   High blood pressure that medicine can\'t control

-   Diabetes with kidney, eye, or blood vessel damage

-   Severe migraine headaches

Also, do not take birth control pills if you:

-   Smoke and are over 35 years old

-   Are pregnant

-   Are allergic to anything in *(OC)*

*If applicable, the following statement is inserted here: The risks for
serious blood clots may be greater with desogestrel-containing pills
such as (name of OC) than with certain other birth control pills.*

Birth control pills may not be a good choice for you if you have ever
had jaundice (yellowing of the skin or eyes) caused by pregnancy, also
called cholestasis of pregnancy.

## 

# WHAT ELSE SHOULD I KNOW ABOUT TAKING (OC NAME)?

[Do not skip]{.underline} any pills, even if you do not have sex often.

If you [miss a period]{.underline}, you could be pregnant. However, some
women miss periods or have light periods on birth control pills, even
when they are not pregnant. Contact your health care provider for advice
if you:

-   Think you are pregnant

-   Miss 1 period and have not taken your birth control pills according
    to directions

-   Miss 2 periods

Birth control pills should not be taken during pregnancy. However, birth
control pills [taken by accident during pregnancy]{.underline} do not
seem to cause birth defects. *If the OC contains a new progestin or
estrogen, note that fact and summarize what is known about pregnancy
risk here. If any component of the drug product is associated with birth
defects, add a statement about the types of defects, estimated
frequency, the associated doses, and the gestational age of exposure, if
known.*

You should consider another birth control method if you are
breast-feeding because birth control pills may decrease the amount and
quality of your milk. A small amount of the pill\'s hormones are passed
on to your baby in your milk.

If you need [laboratory tests]{.underline}, tell your health care
provider that you are taking birth control pills. Birth control pills
may affect some blood tests.

Tell your health care provider about all [medicines and herbal
products]{.underline} that you take. Some medicines and herbal products
may make birth control pills less effective. Some examples are rifampin,
medicines used for epilepsy (such as barbiturates, topiramate,
carbamazepine, and phenytoin), phenylbutazone, certain medicines used to
treat HIV or AIDS, certain antibiotics, and the herbal product St.
John\'s Wort. Consider using another birth control method when you take
medicines that may make birth control pills less effective.

If you have [vomiting or diarrhea]{.underline}, your birth control pills
may not work as well. Use another birth control method, like condoms,
until you check with your health care provider.

# WHAT ARE COMMON SIDE EFFECTS OF BIRTH CONTROL PILLS?

The most common side effects of birth control pills are:

-   Nausea

-   Breast tenderness

-   Headache

-   Bleeding between menstrual periods

    These side effects are usually mild and may disappear with time.

    Less common side effects are:

-   Bloating or fluid retention.

-   Darkening of the skin, especially on the face. This problem may be
    related to the darkening of the skin that sometimes happens during
    pregnancy.

-   High blood sugar, especially in women who already have diabetes.

-   High triglycerides (high fat levels in the blood).

-   Depression, especially if you have had depression in the past. Call
    your health care provider immediately if you have any thoughts of
    harming yourself.

-   Weight changes.

This is not a complete list of possible side effects. Talk to your
health care provider if you develop any side effects that concern you.

No serious problems have been reported from a birth control pill
overdose, even when accidentally taken by children.

# WHAT ARE THE MOST SERIOUS RISKS OF TAKING BIRTH CONTROL PILLS?

Like pregnancy, birth control pills increase the risk of serious blood
clots. It is possible to die from a problem caused by a blood clot, such
as a heart attack or a stroke. Some examples of serious blood clots are
blood clots in the:

-   Legs (thrombophlebitis)

-   Lungs (pulmonary embolus)

-   Eyes (blindness)

-   Heart (heart attack)

-   Brain (stroke)

    A few women who take birth control pills may get:

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-   Rare cancerous or noncancerous liver tumors

-   Gallbladder problems

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-   High blood pressure

    **Call your health care provider right away if you have:**

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-   Persistent pain in the calf (lower leg)

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-   Sudden shortness of breath

-   Sudden blindness, partial or complete

-   Severe pain in your chest

-   Sudden, severe headache

-   Weakness or numbness in an arm or leg, or trouble speaking

-   Yellowing of the skin or eyeballs

# DO BIRTH CONTROL PILLS CAUSE CANCER?

Birth control pills do [not]{.underline} seem to cause breast cancer.
However, if you have breast cancer now, or have had it in the past, do
not use birth control pills because some breast cancers are sensitive to
hormones.

Women who use birth control pills may have a slightly higher chance of
getting cervical cancer. However, this may be due to other reasons such
as having more sexual partners.

# What if I want to become pregnant?

Consider a visit with your health care provider for a pre-pregnancy
checkup before you stop taking the pill. Your health care provider may
advise you to wait for your first regular period before you try to
become pregnant. A daily dose of the vitamin called folic acid is
recommended for all women who are planning a pregnancy.

# ARE THERE OTHER BENEFITS OF THE BIRTH CONTROL PILL?

Yes. Your menstrual periods may become:

-   More regular

-   Lighter

-   Less painful

**General Advice about *(OC name)***

Your health care provider prescribed *(OC name)* for you. Please do not
share *(OC name)* with anyone else. Keep *(OC name)* out of the reach of
children.

Birth control pills are sometimes prescribed for reasons other than
those listed in your Guide. If you have concerns or questions, ask your
health care provider. You may also ask your health care provider for a
more detailed label written for medical professionals.

*List the name and place of business of the manufacturer, packer, or
distributor of OC here.*

*Write the date of the most recent revision of the Guide here.*

[^1]: This guidance was developed by the Division of Reproductive and
    Urologic Drug Products in the Center for Drug Evaluation and
    Research (CDER), Food and Drug Administration (FDA).

[^2]: Schwingl PJ, Ory HW, and Visness CM. Estimates of the risk of
    cardiovascular death attributable to low-dose oral contraceptives in
    the United States. Am J Obstet Gynecol 1999; 180:241-249

[^3]: Stadel BV. Oral contraceptives and cardiovascular disease. (Pt.1).
    N Engl J Med 1981; 305:612-618

[^4]: Stadel BV. Oral contraceptives and cardiovascular disease. (Pt.2).
    N Engl J Med 1981; 305:672-677

[^5]: Inman WH, Vessey MP. Investigation of death from pulmonary,
    coronary, and cerebral thrombosis and embolism in women of
    child-bearing age. Br Med J 1968; 2(5599):193-199

[^6]: Maguire MG, Tonascia J, Sartwell PE, Stolley PD, Tockman MS.
    Increased risk of thrombosis due to oral contraceptives: a further
    report. Am J Epidemiol 1979; 110(2):188-195

[^7]: Petitti DB, Wingerd J, Pellegrin F, Ramacharan S. Risk of vascular
    disease in women: smoking, oral contraceptives, noncontraceptive
    estrogens, and other factors. JAMA 1979; 242:1150-1154

[^8]: Vessey MP, Doll R, Investigation of relation between use of oral
    contraceptives and thromboembolic disease. Br Med J 1968;
    2(5599):199-205

[^9]: Vessey MP, Doll R. Investigation of relation between use of oral
    contraceptives and thromboembolic disease. A further report. Br Med
    J 1969; 2(658):651-657

[^10]: Porter JB, Hunter JR, Danielson DA, Jick H, Stergachis A. Oral
    contraceptives and non-fatal vascular disease-recent experience.
    Obstet Gynecol 1982; 59(3):299-302

[^11]: Vessey M, Doll R, Peto R, Johnson B, Wiggins P. A long-term
    follow-up study of women using different methods of contraception:
    an interim report. J Biosocial Sci 1976; 8:375-427

[^12]: Royal College of General Practitioners: Oral Contraceptives,
    venous thrombosis, and varicose veins. J Royal Coll Gen Pract 1978;
    28:393-399

[^13]: Guillebaud, J. Surgery and the pill. Br Med J 1985; 29:498-499

[^14]: Robinson GE, Burren T, Mackie IJ, Bounds W, Walshek, et al.
    Changes in haemostasis after stopping the combined contraceptive
    pill: implications for major surgery. Br Med J 1991;302: 269-271

[^15]: Dahlman T, Hellgren M, Blombach M. Changes in blood coagulation
    and fibrinolysis in the normal puerperium. Gynecol Obstet Invest
    1985; 20:37-44

[^16]: Gray RH, Campbell OM, Zacur HA, Labbok MH, MacRae SL. Postpartum
    return of ovarian activity in nonbreastfeeding women monitored by
    urinary assays. J Clin Endocrin Metabol 1987; 64(4):645-650

[^17]: Jaais F, Habib, ZA. Unilateral superior ophthalmic vein
    thrombosis in a user of oral contraceptives. Med J Malaysia 1994;
    49:416-418

[^18]: Leong KC, Tan PL. Central retinal vein thrombosis in a woman on
    contraceptive pills. Singapore Med J 1974; 15:156-157

[^19]: Varga M. Recent experience on the ophthalmologic complications of
    oral contraceptives. Ann Ophthalmol 1976; 8:925-934

[^20]: WHO Collaborative Study of Cardiovascular Disease and Steroid
    Hormone Contraception. Acute myocardial infarction and combined oral
    contraceptives: results of an international multicentre case-control
    study. Lancet 1997; 349:1202-1209

[^21]: Vandenbroucke JP, Koster T, Briet E, Teitsma PH, Bertina RM,
    Rosendaal FR. Increased risk of venous thrombosis in
    oral-contraceptive users who are carriers of factor V Leiden
    mutation. Lancet 1994; 334:1453-1457

[^22]: Adam SA, Thorogood M. Oral contraception and myocardial
    infarction revisited: the effects of new preparations and
    prescribing patterns. Br J Obstet Gynaecol 1981; 88:838-845

[^23]: Mann Jl, Inman WH. Oral contraceptives and death from myocardial
    infarction. Br Med J 1975; 2(5965):245-248

[^24]: Mann JI, Vessey MP, Thorogood M, Doll R. Myocardial infarction in
    young women with special reference to oral contraceptive practice.
    Br Med J 1975; 2(5959):241-245

[^25]: Royal College of General Practitioners\' Oral Contraception
    Study. Further analyses of mortality in oral contraceptive users.
    Lancet 1981; 1:541-546.

[^26]: Slone D, Shapiro S, Kaufman DW, Rosenberg L, Miettinene OS,
    Stolley PD. Risk of myocardial infarction in relation to current and
    discontinued use of oral contraceptives. N Engl J Med 1981;
    305:420-424

[^27]: Vessey MP. Female hormones and vascular disease-an
    epidemiological overview. Br J Fam Plann 1980; 6(Supplement):1-12

[^28]: Russell-Briefel RG, Ezzati TM, Fulwood R, Perlman JA, Murphy RS.
    Cardiovascular risk status and oral contraceptive use, United States
    1976-80. Prevent Med 1986; 15:352-362

[^29]: Goldbaum GM, Kendrick JS, Hogelin GC, Gentry EM. The relative
    impact of smoking and oral contraceptive use on women in the United
    States. JAMA 1987; 258:1339-1342

[^30]: Schwingl, PJ, Ory HW, Visness CM. Estimates of the risk of
    cardiovascular death attributable to low-dose oral contraceptives in
    the United States. Am J Obstet Gynecol 1999; 180:241-249

[^31]: Knopp RH. Arteriosclerosis risk: the roles of oral contraceptives
    and postmenopausal estrogens. J Reprod Med 1986; 31(9)
    (Supplement):913-921

[^32]: Collaborative Group for the Study of Stroke in Young Women. Oral
    contraception and increased risk of cerebral ischemia or thrombosis.
    N Engl J Med 1973; 288:871-878

[^33]: Petitti DB, Wingerd J. Use of oral contraceptives, cigarette
    smoking, and risk of subarachnoid hemorrhage. Lancet 1978; 2:234-236

[^34]: Inman WH. Oral contraceptives and fatal subarachnoid hemorrhage.
    Br Med J 1979; 2(6203):1468-1470

[^35]: Collaborative Group for the Study of Stroke in Young Women. Oral
    Contraceptives and stroke in young women: associated risk factors.
    JAMA 1975; 231:718-722

[^36]: Inman WH, Vessey MP, Westerholm B, Engelund A. Thromboembolic
    disease and the steroidal content of oral contraceptives. A report
    to the Committee on Safety of Drugs. Br Med J 1970; 2:203-209

[^37]: Meade TW, Greenberg G, Thompson SG. Progestogens and
    cardiovascular reactions associated with oral contraceptives and a
    comparison of the safety of 50- and 35-microgram oestrogen
    preparations. Br Med J 1980; 280(6224):1157-1161

[^38]: Kay CR. Progestogens and arterial disease\--evidence from the
    Royal College of General Practitioners\' Study. Am J Obstet Gynecol
    1982; 142:762-765

[^39]: Krauss RM, Roy S, Mishell DR, Casagrande J, Pike MC. Effects of
    two low-dose oral contraceptives on serum lipids and lipoproteins:
    differential changes in high-density lipoprotein subclasses. Am J
    Obstet 1983; 145:446-452

[^40]: Wahl P, Walden C, Knopp R, Hoover J, Wallace R, et al. Effect of
    estrogen/progestin potency on lipid/lipoprotein cholesterol. N Engl
    J Med 1983; 308:862-867

[^41]: Wynn V, Niththyananthan R. The effect of progestin in combined
    oral contraceptives on serum lipids with special reference to
    high-density lipoproteins. Am J Obstet Gynecol 1982;142:766-771

[^42]: Collaborative Group on Hormonal Factors in Breast Cancer. Breast
    cancer and hormonal contraceptives: collaborative reanalysis of
    individual data on 53,297 women with breast cancer and 100,239 women
    without breast cancer from 54 epidemiological studies. Lancet 1996;
    347:1713-1727

[^43]: Marchbanks PA, McDonald JA, Wilson HG, Folger SG, Madel MG, et
    al. Oral contraceptives and the risk of breast cancer. N Engl J Med
    2002; 346:2025-2032

[^44]: Vessey MP, Lawless M, McPherson K, Yeates D. Neoplasia of the
    cervix uteri and contraception: a possible adverse effect of the
    pill. Lancet 1983; 2:930

[^45]: Brinton LA, Huggins GR, Lehman HF, Malli K, Savitz DA, et al.
    Long-term use of oral contraceptives and risk of invasive cervical
    cancer. Int J Cancer 1986; 38:339-344

[^46]: WHO Collaborative Study of Neoplasia and Steroid Contraceptives.
    Invasive cervical cancer and combined oral contraceptives. Br Med J
    1985; 290:961-965

[^47]: Moreno V, Bosch FX, Munoz N, Meijer CJLM, Shah KV, et al. Effect
    of oral contraceptives on risk of cervical cancer in women with
    human papillomavirus infections: the IARC multicentric case-control
    study. Lancet 2002; 359:1085-1092

[^48]: Rooks JB, Ory HW, Ishak KG, Strauss LT, Greenspan JR, et al.
    Epidemiology of hepatocellular adenoma: the role of oral
    contraceptive use. JAMA 1979; 242:644-648

[^49]: Bein NN, Goldsmith HS. Recurrent massive hemorrhage from benign
    hepatic tumors secondary to oral contraceptives. Br J Surg 1977;
    64:433-435

[^50]: Klatskin G. Hepatic tumors: possible relationship to use of oral
    contraceptives. Gastroenterology 1977; 73:386-394

[^51]: Henderson BE, Preston-Martin S, Edmondson HA, Peters RL, Pike MC.
    Hepatocellular carcinoma and oral contraceptives. Br J Cancer 1983;
    48:437-440

[^52]: Neuberger J, Forman D, Doll R, Williams R. Oral contraceptives
    and hepatocellular carcinoma. Br Med J 1986; 292:1355-1357

[^53]: Forman D, Vincent TJ, Doll R, Cancer of the liver and oral
    contraceptives. Br Med J 1986; 292:1357-1361

[^54]: Palmer JR, Rosenberg L, Kaufman DW, Warshauer ME, Stolley P, et
    al. Oral contraceptive use and liver cancer. Am J Epidemiol 1989;
    130:878-882

[^55]: Lindberg MC. Hepatobiliary complications of oral contraceptives.
    J of Gen Intern Med 1992; 7:199-209

[^56]: Thijs C, Knipschild P. Oral contraceptives and the risk of
    gallbladder disease: a meta-analysis. Am J Public Health 1993;
    83:1113-1120

[^57]: Vessey M, Painter R. Oral contraceptive use and benign
    gallbladder disease; revisited. Contracept Rep 1994; 50:167-73

[^58]: Grodstein F, Colditz GA, Hunter DJ, Manson JE, Willett WC, et al.
    A prospective study of symptomatic gallstones in women: relation
    with oral contraceptives and other risk factors. Obstet Gynecol
    1994; 84:207-214

[^59]: Boston Collaborative Drug Surveillance Program. Oral
    contraceptives and venous thromboembolic disease, surgically
    confirmed gallbladder disease, and breast tumors. Lancet 1973;
    1:1399-1404

[^60]: Layde PM, Vessey MP, Yeates D. Risk of gallbladder disease: a
    cohort study of young women attending family planning clinics. J
    Epidemiol Community Health 1982; 36:274-278

[^61]: Rome Group for Epidemiology and Prevention of Cholelithiasis
    (GREPCO): Prevalence of gallstone disease in an Italian adult female
    population. Am J Epidemiol 1984; 119:796-805

[^62]: Storm BL, Tamragouri RT, Morse ML, Lazar EL, West SL, et al. Oral
    contraceptives and other risk factors for gallbladder disease. Clin
    Pharmacol Ther 1986; 39:335-341

[^63]: Wynn V, Godsland I. Effects of oral contraceptives on
    carbohydrate metabolism. J Reprod Med 1986;
    31(9)(Supplement):892-897

[^64]: Wynn V, Adams PW, Godsland IF, Melrose J, Niththyananthan R, et
    al. Comparison of effects of different combined oral contraceptive
    formulations on carbohydrate and lipid metabolism. Lancet 1979;
    1:1045-1049

[^65]: Perlman JA, Roussell-Briefel RG, Ezzati TM, Lieberknecht G. Oral
    glucose tolerance and the potency of oral contraceptive
    progestogens. J Chronic Dis 1985; 38:857-864

[^66]: Knopp RH, LaRosa JC, Burkman RT Jr. Contraception and
    dyslipidemia. Am J Obstet Gynecol 1993;168:1994-2005

[^67]: Improving access to quality care in family planning: Medical
    eligibility criteria for contraceptive use. Second Edition. Geneva:
    WHO, Family and Reproductive Health, 2000

[^68]: Laragh AJ. Oral contraceptives\--induced hypertension\--nine
    years later. Am J Obstet Gynecol 1976; 126:141-147

[^69]: Ramcharan S, Peritz E, Pellegrin FA, Williams WT. Incidence of
    hypertension in the Walnut Creek Contraceptive Drug Study cohort. In
    Pharmacology of steroid contraceptive drugs. Garattini S, Berendes
    HW. Eds. New York, Raven Press, 1977; pp. 277-288, (Monographs of
    the Mario Negri Institute for Pharmacological Research Milan)

[^70]: Royal College of General Practitioners\' Oral Contraception
    Study. Effect on hypertension and benign breast disease of
    progestogen component in combined oral contraceptives. Lancet 1977;
    1:624

[^71]: Fisch IR, Frank J. Oral contraceptives and blood pressure. JAMA
    1977; 237:2499-2503

[^72]: Layde PM, Beral V. Further analyses of mortality in oral
    contraceptive users; Royal College of General Practitioners\' Oral
    Contraception Study (Table 5). Lancet 1981; 1:541-546

[^73]: Stockley I. Interactions with oral contraceptives. J Pharm 1976;
    216:140-143

[^74]: Briggs GG, Freeman RK, Yaffe SJ. Oral Contraceptives. In Drugs in
    pregnancy and lactation: a reference guide to fetal and neonatal
    risk. Fifth Edition. Maryland: Williams & Wilkins,1998, pp. 805-807

[^75]: Reprotox®. Oral Contraceptives. From summary updated based on a
    complete literature search in February, 2001.
    http://www.tomescps.com/DATA/RX/RX1162.HTM

[^76]: The estimates for drugs and devices come from clinical trial data
    reviewed by the Food and Drug Administration. The IUDs include the
    levonorgestrel IUD and the copper IUD. The estimates for
    sterilization and spermicides come from the medical literature.