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5.11 Malignant Neoplasms
Breast Cancer
Levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets are contraindicated in females who currently have or have had breast cancer because breast cancer may be hormonally sensitive [see Contraindications (4)].
Epidemiology studies have not found a consistent association between use of combined oral contraceptives (COCs) and breast cancer risk. Studies do not show an association between ever (current or past) use of COCs and risk of breast cancer. However, some studies report a small increase in the risk of breast cancer among current or recent users (<6 months since last use) and current users with longer duration of COC use [see Postmarketing Experience (6.2)].
Cervical Cancer
Some studies suggest that COCs are associated with an increase in the risk of cervical cancer or intraepithelial neoplasia. However, there is controversy about the extent to which these findings are due to differences in sexual behavior and other factors.
5.12 Effect on Binding Globulins
The estrogen component of levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets 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.
5.13 Hereditary Angioedema
In females with hereditary angioedema, exogenous estrogens, including levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets, may induce or exacerbate symptoms of hereditary angioedema.
5.14 Chloasma
Chloasma may occur with levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets use, especially in women with a history of chloasma gravidarum. Advise women with a history of chloasma to avoid exposure to the sun or ultraviolet radiation while using levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets.
6 ADVERSE REACTIONS
The following serious adverse reactions with the use of COCs are discussed elsewhere in the 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)]
6.1 Clinical Trial Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to the rates in the clinical trials of another drug and may not reflect the rates observed in practice.
The clinical trial that evaluated the safety and efficacy of levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets was a 12-month, randomized, multicenter, open-label study, which enrolled women aged 18 to 40, of whom 1,006 took at least one dose of levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets.
Adverse Reactions Leading to Study Discontinuation: 16.3% of the women discontinued from the clinical trial due to an adverse reaction; the most common adverse reactions (≥ 1% of women) leading to discontinuation were irregular and/or heavy uterine bleeding (5.9%), weight gain (2.4%), mood changes (1.5%), and acne (1%).
Common Treatment-Emergent Adverse Reactions (≥ 5% of women): irregular and/or heavy uterine bleeding (17%), weight gain (5%), acne (5%).
Serious Adverse Reactions: migraine, cholecystitis, cholelithiasis, pancreatitis, abdominal pain, and major depressive disorder.
6.2 Postmarketing Experience
Five studies that compared breast cancer risk between ever-users (current or past use) of COCs and never-users of COCs reported no association between ever use of COCs and breast cancer risk, with effect estimates ranging from 0.90 to 1.12 (Figure 3).
Three studies compared breast cancer risk between current or recent COC users (<6 months since last use) and never users of COCs (Figure 3). One of these studies reported no association between breast cancer risk and COC use. The other two studies found an increased relative risk of 1.19 to 1.33 with current or recent use. Both of these studies found an increased risk of breast cancer with current use of longer duration, with relative risks ranging from 1.03 with less than one year of COC use to approximately 1.4 with more than 8 to 10 years of COC use.
Figure 3: Relevant Studies of Risk of Breast Cancer with Combined Oral Contraceptives
RR = relative risk; OR = odds ratio; HR = hazard ratio. “ever COC” are females with current or past COC use; “never COC use” are females that never used COCs.
The following adverse reactions have been identified during post-approval use of levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets. Because these reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency of establish a causal relationship to drug exposure.
Gastrointestinal disorders: abdominal distension, vomiting
General disorders and administration site conditions: chest pain, fatigue, malaise, edema peripheral, pain
Immune system disorders: hypersensitivity reaction
Investigations: blood pressure increased
Musculoskeletal and connective tissue disorders: muscle spasms, pain in extremity
Nervous system disorders: dizziness, loss of consciousness
Psychiatric disorders: insomnia
Reproductive and breast disorders: dysmenorrhea
Respiratory, thoracic and mediastinal disorders: pulmonary embolism, pulmonary thrombosis
Skin and subcutaneous tissue disorders: alopecia
Vascular disorders: thrombosis
7 DRUG INTERACTIONS
The sections below provide information on substances for which data on drug interactions with COCs are available. There is little information available about the clinical effect of most drug interactions that may affect COCs. However, based on the known pharmacokinetic effects of these drugs, clinical strategies to minimize any potential adverse effect on contraceptive effectiveness or safety are suggested.
Consult the approved product labeling of all concurrently used drugs to obtain further information about interactions with COCs or the potential for metabolic enzyme or transporter system alterations.
No drug-drug interaction studies were conducted with levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets.
7.1 Effects of Other Drugs on Combined Oral Contraceptives
Substances Decreasing the Plasma Concentrations of COCs and Potentially Diminishing the Efficacy of COCs:
Table 4 includes substances that demonstrated an important drug interaction with levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets.
Table 4: Significant Drug Interactions Involving Substances That Affect COCs
Metabolic Enzyme Inducers | |
Clinical effect |
|
Prevention or management |
|
Examples | Aprepitant, barbiturates, bosentan, carbamazepine, efavirenz, felbamate, griseofulvin, oxcarbazepine, phenytoin, rifampin, rifabutin, rufinamide, topiramate, products containing St. John’s worta , and certain protease inhibitors (see separate section on protease inhibitors below). |
Colesevelam | |
Clinical effect |
|
Prevention or management | Administer 4 or more hours apart to attenuate this drug interaction. |
a Induction potency of St. John’s wort may vary widely based on preparation.
Substances increasing the systemic exposure of COCs:
Co-administration of atorvastatin or rosuvastatin and COCs containing ethinyl estradiol increase systemic exposure of ethinyl estradiol by approximately 20 to 25 percent. Ascorbic acid and acetaminophen may increase systemic exposure of ethinyl estradiol, possibly by inhibition of conjugation. CYP3A inhibitors such as itraconazole, voriconazole, fluconazole, grapefruit juice, or ketoconazole may increase systemic exposure of the estrogen and/or progestin component of COCs.
Human immunodeficiency virus (HIV)/hepatitis C virus (HCV) protease inhibitors and non-nucleoside reverse transcriptase inhibitors:
Significant decreases in systemic exposure of the estrogen and/or progestin have been noted when COCs are co-administered with some HIV protease inhibitors (e.g., nelfinavir, ritonavir, darunavir/ritonavir, (fos)amprenavir/ritonavir, lopinavir/ritonavir, and tipranavir/ritonavir), some HCV protease inhibitors (e.g., boceprevir and telaprevir), and some non-nucleoside reverse transcriptase inhibitors (e.g., nevirapine).
In contrast, significant increases in systemic exposure of the estrogen and/or progestin have been noted when COCs are co-administered with certain other HIV protease inhibitors (e.g., indinavir and atazanavir/ritonavir) and with other non-nucleoside reverse transcriptase inhibitors (e.g., etravirine).
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