Some studies suggest that COC use has been associated with an increase in the risk of cervical cancer or intraepithelial neoplasia. However, there continues to be controversy about the extent to which such findings may be due to differences in sexual behavior and other factors.

5.11 Effect on Binding GlobulinsThe estrogen component of COCs may raise the serum concentrations of thyroxine-binding globulin, sex hormone-binding globulin, and cortisol-binding globulin. The dose of replacement thyroid hormone or cortisol therapy may need to be increased.

5.12 MonitoringA woman who is taking COCs should have a yearly visit with her healthcare provider for a blood pressure check and for other indicated healthcare.

5.13 Hereditary AngioedemaIn women with hereditary angioedema, exogenous estrogens may induce or exacerbate symptoms of angioedema.

5.14 ChloasmaChloasma may occasionally occur, especially in women with a history of chloasma gravidarum. Women with a tendency to chloasma should avoid exposure to the sun or ultraviolet radiation while taking ORTHO TRI-CYCLEN or ORTHO-CYCLEN.
6 ADVERSE REACTIONS

The following serious adverse reactions with the use of COCs are discussed elsewhere in labeling:

Serious cardiovascular events and stroke [see Boxed Warning and Warnings and Precautions (5.1)]
Vascular events [see Warnings and Precautions (5.1)]
Liver disease [see Warnings and Precautions (5.2)]
Adverse reactions commonly reported by COC users are:
Irregular uterine bleeding
Nausea
Breast tenderness
Headache
6.1 Clinical Trial ExperienceBecause clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

ORTHO-CYCLEN

The safety of ORTHO-CYCLEN was eva luated in 1,647 healthy women of child-bearing potential who participated in 3 clinical trials and received at least 1 dose of ORTHO-CYCLEN for contraception. Two trials were randomized active-controlled trials and 1 was an uncontrolled open-label trial. In all 3 trials, subjects were followed for up to 24 cycles.

Common Adverse Reactions (≥ 2% of subjects): The most common adverse reactions reported by at least 2% of the 1,647 women were the following in order of decreasing incidence: headache/migraine (32.9%), abdominal/gastrointestinal pain (7.8%), vaginal infection (8.4%), genital discharge (6.8%), breast issues (including breast pain, discharge, and enlargement) (6.3%), mood disorders (including depression and mood altered) (5.0%), flatulence (3.2%), nervousness (2.9%), and rash (2.6%).

Adverse Reactions Leading to Study Discontinuation: Over the three trials, between 11 to 21% of subjects discontinued the trial due to an adverse reaction. The most common adverse reactions (≥1%) leading to discontinuation were: metrorrhagia (6.9%), nausea/vomiting (5.0%), headache (4.1%), mood disorders (including depression and mood altered) (2.4%), premenstrual syndrome (1.7%), hypertension (1.4%), breast pain (1.4%), nervousness (1.3%), amenorrhea (1.1%), dysmenorrhea (1.1%), weight increased (1.1%), and flatulence (1.1%).

Serious Adverse Reactions: breast cancer (1 subject), mood disor