Afirmelle

Afirmelle (Levonorgestrel and ethinyl estradiol tablets USP) 0.1 mg/0.02 mg is available in a carton of 6 pouches, each containing 28 tablets:

21 active tablets: White to off-white, round, biconvex, beveled-edge tablets, debossed with “S” on one side and “59” on other side of the tablet.

7 inert tablets: Green, round, mottled, biconvex, beveled-edge uncoated tablets, debossed with “S” on one side and “61” on other side of the tablet.

1 Pouch of 28 tablets - NDC 65862-849-28
Carton of 6 Pouches - NDC 65862-849-92

Store at 20° to 25°C (68° to 77° F) [see USP Controlled Room Temperature].

Manufactured by: Aurobindo Pharma Limited Unit-VII (SEZ) Mahaboob Nagar (Dt)-509302 India. Revised: May 2017

Applies to ethinyl estradiol / levonorgestrel: oral tablet

Applies to ethinyl estradiol / levonorgestrel: oral tablet

Cardiovascular

Cardiovascular side effects of hypertension and edema have been attributed to the estrogen component of this combination product. Significant blood pressure increases generally occurred only in women receiving high-dose estrogen products (50 mcg or more of ethinyl estradiol or equivalent daily). Exogenous estrogens may exert cardioprotective effects due to favorable changes in lipid profiles, however, beneficial effects may be partially or completely offset by alterations in lipid profiles induced by exogenous progestins.[Ref]

Detailed information concerning the effects of oral contraceptive therapy on lipid metabolism is available in the Endocrine paragraph of this side effect monograph.

Early investigations of high dose estrogen combinations (50 mcg or more of ethinyl estradiol or equivalent daily) suggested that women may be at increased risk of cardiovascular complications (myocardial infarction, stroke, and vascular thrombosis, including venous thromboembolism). More recent investigations of low dose estrogen combinations have suggested that oral contraceptive use is not associated with an increased risk of serious cardiovascular complications in healthy non smoking women up to the age of 45. Oral contraceptive use for women aged 35 to 44 who smoke or who have preexisting systemic diseases that may affect the cardiovascular system is not recommended.

Some investigators have suggested that even low dose products may result in adverse lipid metabolism and a woman's cardiovascular risk factors should be assessed before a decision is made to use oral contraceptive combinations.

The frequency of both subarachnoid hemorrhage and thrombotic stroke has been increased in women taking oral contraceptive hormones, however, the risk of these effects with low dose formulations appear to be very small for young women without underlying cardiovascular disease or other risk factors.[Ref]

General

Women taking oral contraceptive combinations have experienced several noncontraceptive health benefits. These benefits have included protection against two malignant neoplasms (endometrial carcinoma and ovarian cancer). In addition, use of oral contraceptive combinations has decreased the frequency of benign breast tumors, the risk of ovarian cysts, the risk of ectopic pregnancy, menstrual irregularity, the incidences of iron deficiency anemia, dysmenorrhea, and pelvic inflammatory disease.

Many of the adverse effects experienced by women on oral contraceptive combination products are related to a relative excess or deficiency of the estrogen and progestin components of these formulations. The following categorizes many of the frequent adverse effects by relative excess or deficiency of these components.

Progestin Excess:

Acne, oily skin
Breast tenderness
Depression
Tiredness, fatigue
Hair loss
Hypertension
Increased appetite
Weight gain
Cholestatic jaundice

Progestin Deficiency:

Late breakthrough bleeding
Amenorrhea
Hypermenorrhea

Estrogen Excess:

Nausea
Headache
Melasma
Hypertension
Breast tenderness
Edema

Estrogen Deficiency:

Early/midcycle breakthrough bleeding
Increased spotting
Hypomenorrhea[Ref]

A number of studies have suggested that use of oral contraceptives decreased the risk of ovarian cancer. Specifically, the risk of epithelial ovarian cancers is decreased by 40%. The protection against ovarian cancer may last for 10 to 15 years after discontinuation of oral contraceptives. After long term use (12 years), the risk of ovarian cancer is decreased by as much as 80%.

The risk of endometrial cancer is decreased by approximately 50%. Protection may last for 15 years after discontinuation and may be greatest for nulliparous women who may be at higher risk for endometrial carcinoma than other women.

The incidence of hospitalization for pelvic inflammatory disease has been approximately 50% lower in women taking oral contraceptives. The reason for the decrease in the frequency (or severity) of pelvic inflammatory disease in women taking oral contraceptives has not been fully elucidated.

Some recent studies have suggested that the decrease in frequency of functional ovarian cysts reported with some older formulations may not occur in women taking newer low dose formulations.

One recent study (The Nurses' Health Study) has suggested that long term use of oral contraceptives is safe and does not adversely affect long term risk for mortality.[Ref]

Gastrointestinal

Nausea, a relatively common gastrointestinal side effect, has occurred in approximately 10% of treated women during the first cycles of therapy. Some early reports suggested an association between oral contraceptive use and gallbladder disease.[Ref]

Cases of oral contraceptive induced esophageal ulceration and geographic tongue have been reported rarely.

More recent studies have suggested that the risk of gallbladder disease is minimal.[Ref]

Oncologic

Oral contraceptive combinations have been studied extensively for oncologic side effects. A number of studies have examined a possible relationship between the use of oral contraceptives and the development of breast cancer. Many of the studies have reported conflicting results. A committee of the World Health Organization evaluated these studies and the risks of breast cancer and concluded that: "Numerous studies have found no overall association between oral contraceptive use and risk of breast cancer." In addition, the same committee also examined a possible relationship between oral contraceptive use and neoplasms of the uterine cervix and concluded that: "There are insufficient data to draw any firm conclusions regarding the effects of combined oral contraceptives on the risk of cervical adenocarcinoma."[Ref]

The World Health Organization committee also noted that some studies "have found a weak association between long-term use of oral contraceptives and breast cancer diagnosed before the age of 36, and perhaps up to the age 45....It is unclear whether this observed association is attributable to bias, the development of new cases of cancer, or accelerated growth of existing cancers."

The World Health Organization committee further concluded that there is no increased risk of breast cancer in women over the age of 45 who have previously taken oral contraceptives. In addition, studies suggest that use of oral contraceptives does not place specific groups of women (like those with a family history of breast cancer) at higher or lower risk, and variations in the hormonal content of oral contraceptives do not influence the risk of breast cancer.

In general, studies evaluating the potential risk of cervical cancer in patients taking oral contraceptives have been complicated by the large number of confounding factors which make investigations into the epidemiology of this neoplasm difficult. Some studies have suggested that women taking oral contraceptives are at increased risk of dysplasia, epidermoid carcinoma, and adenocarcinoma of the cervix. However, other studies have not found such an association.[Ref]

Endocrine

Endocrine effects have included complex alterations in plasma lipid profiles.[Ref]

All progestins which occur in commercially available oral contraceptive combinations have adverse effects on lipid profiles. These progestins exert antiestrogen and androgen effects and decrease HDL (and HDL2) cholesterol levels and increase LDL cholesterol levels. The estrogen component of oral contraceptive combinations exert opposing effects. Consequently, alterations in lipid profiles are related to the relative amount and potency of the specific estrogen and progestin in a given product. (Levonorgestrel exerts potent progestin, antiestrogen, and androgen effects.)[Ref]

Hepatic

The rate of death due to hepatocellular carcinoma in the United States has not changed during the last 25 years (a time during which use of oral contraceptive hormones has increased dramatically).

A committee of the World Health Organization has reported that in developing countries where hepatitis B virus infection and hepatocellular carcinoma are common, "short term use of oral contraceptives does not appear to be associated with an increased risk. Data on the effects of long term use are scarce."

A recent Italian case control study of women with hepatocellular carcinoma has suggested that the relative risk of hepatocellular carcinoma is 2.2 for oral contraceptive users compared to women who never used oral contraceptives.

A similar American case control study from 1989 also reported a strong association between oral contraceptive use and hepatocellular carcinoma but concluded that: "If this observed association is causal, the actual number of cases of liver cancer in the United States attributable to oral contraceptive use is small. Therefore, these findings do not have public health importance in the United States and other Western nations."[Ref]

Hepatic side effects have included focal nodular hyperplasia, intrahepatic cholestasis, liver cell adenomas, hepatic granulomas, hepatic hemangiomas and well differentiated hepatocellular carcinomas, which have been reported rarely in association with estrogen therapy and therapy with oral contraceptive combinations.[Ref]

Hematologic

Cases of venous thrombosis, pulmonary embolism (sometimes fatal), and arterial thrombosis have been reported rarely.

Previous thrombotic disease is considered a contraindication to use of oral contraceptive combinations.[Ref]

A hematologic concern has been the risk of thromboembolism associated with exogenous estrogens. Because the dose of exogenous estrogens is low in most commercially available preparations, the risk of thromboembolism is minimal for most women. Risk is greater in women who are over age 35, smoke, and/or with a history of previous thrombotic diseases. The incidence of venous thrombosis in women with inherited clotting defects has been greater and developed sooner (within the first six months to one year of therapy).[Ref]

Genitourinary

A common genitourinary side effect has been breakthrough bleeding and spotting, especially during the first several cycles of oral contraceptive use. Nonhormonal causes of such bleeding should be excluded. In addition, oral contraceptive use may cause conception delay.[Ref]

Some women have experienced oligomenorrhea and amenorrhea following termination or oral contraceptive use.[Ref]

Psychiatric

Psychiatric side effects have included depression and precipitation of panic disorder.[Ref]

Immunologic

Immunologic side effects have included rare cases of oral contraceptive induced systemic lupus erythematosus.[Ref]

Nervous system

Nervous system side effects have been rare. A case of chorea has been reported in association with oral contraceptives.[Ref]

Ocular

Ocular side effects have included rare cases of retinal thrombosis. In addition, the manufacturers of oral contraceptive products report that some patients have developed changes in contact lens tolerance.[Ref]

Respiratory

A case of fatal pulmonary venooclusive disease has been reported.[Ref]

Metabolic

Despite the potentially adverse effects of oral contraceptives on lipid levels and glucose tolerance, some investigators have suggested that young diabetic women without existing vascular disease or severe lipidemias may be candidates for low dose oral contraceptive combinations with appropriate clinical monitoring of patient response and tolerance.[Ref]

Metabolic side effects have resulted in altered carbohydrate metabolism. The suggested effect that oral contraceptive combinations may have on glucose tolerance has been varied. Decreased glucose tolerance has been observed, however, studies with low dose preparations have suggested that decreased glucose tolerance due to oral contraceptive combinations generally has been minimal.[Ref]

Some side effects of Afirmelle may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.

Oral contraceptive combinations have been assigned to pregnancy category X. Although some reports have suggested that oral contraceptive hormones may cause a variety of congenital malformations, recent studies (including a meta-analysis of prospective studies) have suggested that an association between oral contraceptive use and congenital malformations does not exist. Some progestins may cause masculinization of female infants. There is no indication for the use of oral contraceptive combinations during pregnancy. Oral contraceptive combinations are contraindicated for use during pregnancy.

One case report has suggested that oral contraceptive hormones may cause choreoathetosis in infants exposed in utero. A recent case control study has suggested a weak association between use of older high dose contraceptives (particularly those containing 1.0 mg of ethynodiol diacetate) and the occurrence of congenital limb defects. However, the authors concluded that "this weak causal relationship was probable in the past when relatively high doses of contraceptive pills were used. This risk is apparently minimized by the use of new type (e.g., D-norgestrel) and lower dose of contraceptive pills".