Iclevia

Iclevia (levonorgestrel and ethinyl estradiol tablets USP) are available in Extended-Cycle Wallets, each containing a 13-week supply of tablets in the following order:

• 84 white tablets, each containing 0.15 mg of levonorgestrel and 0.03 mg ethinyl estradiol; round, biconvex, beveled-edge tablets debossed with “S” on one side and “27” on other side.
• 7 green inert tablets; round, mottled, biconvex, beveled-edge uncoated tablets, debossed with “S” on one side and “61” on other side of the tablet.

Do not prescribe Iclevia to women who are known to have the following conditions:

• A high risk of arterial or venous thrombotic diseases. Examples include women who are known to: 
  • Smoke, if over age 35 [see Boxed Warning and Warnings and Precautions (5.1)].
  • Have deep vein thrombosis or pulmonary embolism, now or in the past [see Warnings and Precautions (5.1)].
  • Have inherited or acquired hypercoagulopathies [see Warnings and Precautions (5.1)].
  • Have cerebrovascular disease [see Warnings and Precautions (5.1)].
  • Have coronary artery disease [see Warnings and Precautions (5.1)].
  • Have thrombogenic valvular or thrombogenic rhythm diseases of the heart (for example, subacute bacterial endocarditis with valvular disease, or atrial fibrillation) [see Warnings and Precautions (5.1)].
  • Have uncontrolled hypertension [see Warnings and Precautions (5.4)].
  • Have diabetes mellitus with vascular disease [see Warnings and Precautions (5.6)].
  • Have headaches with focal neurological symptoms or migraine headaches with aura [see Warnings and Precautions (5.7)].
    • Women over age 35 with any migraine headaches [see Warnings and Precautions (5.7)].
    •  Liver tumors, benign or malignant, or liver disease [see Warnings and Precautions (5.2) and Use in Specific Populations (8.6)].
    •  Undiagnosed abnormal uterine bleeding [see Warnings and Precautions (5.8)].
    •  Pregnancy, because there is no reason to use COCs during pregnancy [see Warnings and Precautions (5.9) and Use in Specific Populations (8.1)].
    •  Breast cancer or other estrogen- or progestin-sensitive cancer, now or in the past [see Warnings and Precautions (5.11)].
    •  Use of Hepatitis C drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir, due to the potential for ALT elevations [see Warnings and Precautions (5.3)].

Thrombotic Disorders and Other Vascular Problems

• Stop Iclevia if an arterial thrombotic event or venous thromboembolic (VTE) event occurs.
• Stop Iclevia if there is unexplained loss of vision, proptosis, diplopia, papilledema, or retinal vascular lesions. Evaluate for retinal vein thrombosis immediately.
• If feasible, stop Iclevia at least 4 weeks before and through 2 weeks after major surgery or other surgeries known to have an elevated risk of VTE as well as during and following prolonged immobilization.
• Start Iclevia no earlier than 4 weeks after delivery, in women who are not breastfeeding. The risk of postpartum VTE decreases after the third postpartum week, whereas the risk of ovulation increases after the third postpartum week.
• The use of COCs increases the risk of VTE. However, pregnancy increases the risk of VTE as much or more than the use of COCs. The risk of VTE in women using COCs is 3 to 9 cases per 10,000 woman - years. The risk of VTE is highest during the first year of use of COCs and when restarting hormonal contraception after a break of 4 weeks or longer. The risk of thromboembolic disease due to COCs gradually disappears after use is discontinued.
• Use of Iclevia provides women with more hormonal exposure on a yearly basis than conventional monthly COCs containing the same strength synthetic estrogens and progestins (an additional 9 weeks of exposure per year). In the clinical trial, one case of pulmonary embolism was reported. Postmarketing adverse reactions of VTE have been reported in women who used Iclevia.
• Use of COCs also increases the risk of arterial thromboses such as strokes and myocardial infarctions, especially in women with other risk factors for these events. Stroke has been reported in women associated with the use of Iclevia. COCs have been shown to increase both the relative and attributable risks of cerebrovascular events (thrombotic and hemorrhagic strokes). This risk increases with age, particularly in women over 35 years of age who smoke.
• Use COCs with caution in women with cardiovascular disease risk factors.

Liver Disease

Impaired Liver Function

Do not use Iclevia in women with liver disease, such as acute viral hepatitis or severe (decompensated) cirrhosis of the liver [see Contraindications (4)]. Acute or chronic disturbances of liver function may necessitate the discontinuation of COC use until markers of liver function return to normal and COC causation has been excluded. Discontinue Iclevia if jaundice develops.

Liver Tumors

Iclevia is contraindicated in women with benign and malignant liver tumors [see Contraindications (4)]. Hepatic adenomas are associated with COC use. An estimate of the attributable risk is 3.3 cases/100,000 COC users. Rupture of hepatic adenomas may cause death through intra-abdominal hemorrhage.

Studies have shown an increased risk of developing hepatocellular carcinoma in long-term (> 8 years) COC users. However, the attributable risk of liver cancers in COC users is less than one case per million users.

Risk of Liver Enzyme Elevations with Concomitant Hepatitis C Treatment

During clinical trials with the Hepatitis C combination drug regimen that contains obmitasvir/paritaprevir/ritonavir, with or without dasabuvir, ALT elevations greater than 5 times the upper limit of normal (ULN), including some cases greater than 20 times the ULN, were significantly more frequent in women using ethinyl estradiol-containing medications, such as COCs. Discontinue Iclevia prior to starting therapy with the combination drug regimen ombitasvir/paritaprevir/ritonavir, with or without dasabuvir [see Contraindications (4)]. Iclevia can be restarted approximately 2 weeks following completion of treatment with the Hepatitis C combination drug regimen.

High Blood Pressure

Iclevia is contraindicated in women with uncontrolled hypertension or hypertension with vascular disease [see Contraindications (4)]. For women with well-controlled hypertension, monitor blood pressure and stop Iclevia if blood pressure rises significantly.

An increase in blood pressure has been reported in women taking COCs, and this increase is more likely in older women and with extended duration of use. The incidence of hypertension increases with increasing concentration of progestin.

Gallbladder Disease

Studies suggest a small increased relative risk of developing gallbladder disease among COC users. Use of COCs may worsen existing gallbladder disease.

A past history of COC-related cholestasis predicts an increased risk with subsequent COC use. Women with a history of pregnancy-related cholestasis may be at an increased risk for COC-related cholestasis.

Carbohydrate and Lipid Metabolic Effects

Carefully monitor prediabetic and diabetic women who are taking Iclevia. COCs may decrease glucose tolerance.

Consider alternative contraception for women with uncontrolled dyslipidemia. A small proportion of women will have adverse lipid changes while on COCs.

Women with hypertriglyceridemia, or a family history thereof, may be at an increased risk of pancreatitis when using COCs.

Headache

If a woman taking Iclevia develops new headaches that are recurrent, persistent, or severe, evaluate the cause and discontinue Iclevia if indicated.

Consider discontinuation of Iclevia in the case of increased frequency or severity of migraine during COC use (which may be prodromal of a cerebrovascular event) [see Contraindications (4)].

Bleeding Irregularities and Amenorrhea

Bleeding and/or spotting that occurs at any time while taking the first 84 tablets of each extended-cycle regimen is considered “unscheduled” bleeding/spotting. Bleeding that occurs during the time a woman takes the seven green inert tablets is considered “scheduled” bleeding.

Unscheduled and Scheduled Bleeding and Spotting

Unscheduled (breakthrough) bleeding and spotting sometimes occur in patients on COCs, especially during the first 3 months of use. If unscheduled bleeding persists or occurs after previously regular cycles on Iclevia, check for causes such as pregnancy or malignancy. If pathology and pregnancy are excluded, bleeding irregularities may resolve over time or with a change to a different COC.

Before prescribing Iclevia, advise the woman to weigh the convenience of fewer scheduled menses (4 per year instead of 13 per year) against the inconvenience of increased unscheduled bleeding and/or spotting.

The clinical trial of the efficacy of Iclevia (91-day cycles) in preventing pregnancy also assessed scheduled and unscheduled bleeding. The participants in the study were composed primarily of women who had used oral contraceptives previously as opposed to new users. Women with a history of breakthrough bleeding/spotting ≥ 10 consecutive days on oral contraceptives were excluded from the study. More Iclevia subjects, compared to subjects on the comparator 28-day cycle regimen, discontinued prematurely for unacceptable bleeding (7.7% [Iclevia] vs. 1.8% [28-day cycle regimen]).

Unscheduled bleeding and unscheduled spotting decreased over successive 91-day cycles. Table 3 below presents the number of days with unscheduled bleeding and/or spotting for each respective 91-day cycle.

Table 4 shows the percentages of women with ≥ 7 days and ≥ 20 days of unscheduled spotting and/or bleeding in the Iclevia and the 28-day cycle treatment groups.

Total days of bleeding and/or spotting (scheduled plus unscheduled) were similar over one year of treatment for Iclevia subjects and subjects on the 28-day cycle regimen.

Amenorrhea and Oligomenorrhea

Women who are not pregnant and use Iclevia may experience amenorrhea. Based on data from the clinical trial, amenorrhea occurred in approximately 0.8% of women during Cycle 1, 1.2% of women during Cycle 2, 3.7% of women during Cycle 3, and 3.4% of women during Cycle 4. Because women using Iclevia will likely have scheduled bleeding only 4 times per year, rule out pregnancy at the time of any missed menstrual period.

Some women may experience amenorrhea or oligomenorrhea after stopping COCs, especially when such a condition was pre-existent.

COC Use Before or During Early Pregnancy

Extensive epidemiological studies have revealed no increased risk of birth defects in women who have used oral contraceptives prior to pregnancy. Studies also do not suggest a teratogenic effect, particularly in so far as cardiac anomalies and limb-reduction defects are concerned, when oral contraceptives are taken inadvertently during early pregnancy. Discontinue Iclevia use if pregnancy is confirmed.

Administration of oral contraceptives to induce withdrawal bleeding should not be used as a test for pregnancy [see Use in Specific Populations (8.1)].

Depression

Depression associated with the use of Iclevia has been reported. Carefully observe women with a history of depression and discontinue Iclevia if severe depression recurs.

Carcinoma of the Breast and Cervix

• Iclevia is contraindicated in women who currently have or have had breast cancer because breast cancer may be hormonally sensitive [see Contraindications (4)].

There is substantial evidence that COCs do not increase the incidence of breast cancer. Although some past studies have suggested that COCs might increase the incidence of breast cancer, more recent studies have not confirmed such findings.

• 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.

Effect on Binding Globulins

The 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.

Monitoring

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

Hereditary Angioedema

In women with hereditary angioedema, exogenous estrogens may induce or exacerbate symptoms of angioedema.

Chloasma

Chloasma may occasionally occur, especially in women with a history of chloasma gravidarum. Women with a tendency to develop chloasma should avoid prolonged exposure to the sun or ultraviolet radiation while taking Iclevia.

Consult the labeling of concurrently used drugs to obtain further information about interactions with hormonal contraceptives or the potential for enzyme alterations.

Effects of Other Drugs on Combined Oral Contraceptives

Substances decreasing the plasma concentrations of COCs and potentially diminishing the efficacy of COCs:

Drugs or herbal products that induce certain enzymes, including cytochrome P450 3A4 (CYP3A4), may decrease the plasma concentrations of COCs and potentially diminish the effectiveness of COCs or increase breakthrough bleeding. Some drugs or herbal products that may decrease the effectiveness of hormonal contraceptives include phenytoin, barbiturates, carbamazepine, bosentan, felbamate, griseofulvin, oxcarbazepine, rifampicin, topiramate, rifabutin, rufinamide, aprepitant, and products containing St. John’s wort. Interactions between oral contraceptives and other drugs may lead to breakthrough bleeding and/or contraceptive failure. Counsel women to use an alternative method of contraception or a back-up method when enzyme inducers are used with COCs, and to continue back-up contraception for 28 days after discontinuing the enzyme inducer to ensure contraceptive reliability.

Colesevelam: Colesevelam, a bile acid sequestrant, given together with a COC, has been shown to significantly decrease the AUC of EE. The drug interaction between the contraceptive and colesevelam was decreased when the two drug products were given 4 hours apart.

Substances increasing the plasma concentrations of COCs:

Co-administration of atorvastatin or rosuvastatin and certain COCs containing ethinyl estradiol (EE) increase AUC values for EE by approximately 20 to 25%. Ascorbic acid and acetaminophen may increase plasma EE concentrations, possibly by inhibition of conjugation. CYP3A4 inhibitors such as itraconazole, voriconazole, fluconazole, grapefruit juice, or ketoconazole may increase plasma hormone concentrations.

Human immunodeficiency virus (HIV)/ Hepatitis C virus (HCV) protease inhibitors and non-nucleoside reverse transcriptase inhibitors:

Significant changes (increase or decrease) in the plasma concentrations of estrogen and/or progestin have been noted in some cases of co-administration with HIV protease inhibitors (decrease [e.g., nelfinavir, ritonavir, darunavir/ritonavir, (fos) amprenavir/ritonavir, lopinavir/ritonavir, and tipranavir/ritonavir] or increase [e.g., indinavir and atazanavir/ritonavir])/HCV protease inhibitors (decrease [e.g., nevirapine] or increase [e.g., etravirine]).

Effects of Combined Oral Contraceptives on Other Drugs

COCs containing EE may inhibit the metabolism of other compounds (e.g., cyclosporine, prednisolone, theophylline, tizanidine, and voriconazole) and increase their plasma concentrations.

COCs have been shown to decrease plasma concentrations of acetaminophen, clofibric acid, morphine, salicylic acid, temazepam and lamotrigine. Significant decrease in plasma concentration of lamotrigine has been shown, likely due to induction of lamotrigine glucuronidation. This may reduce seizure control; therefore, dosage adjustments of lamotrigine may be necessary.

Women on thyroid hormone replacement therapy may need increased doses of thyroid hormone because the serum concentration of thyroid-binding globulin increases with use of COCs [see Warnings and Precautions (5.12)].

Concomitant Use with Hepatitis C Vaccine (HCV) Combination Therapy – Liver Enzyme Elevation

Do not co-administer Iclevia with HCV drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir, due to potential for ALT elevations [see Warnings and Precautions (5.3)].

Interactions with Laboratory Tests

The use of contraceptive steroids may influence the results of certain laboratory tests, such as coagulation factors, lipids, glucose tolerance, and binding proteins.

Iclevia (levonorgestrel and ethinyl estradiol tablets USP) is an extended-cycle combination oral contraceptive consisting of 84 white active tablets each containing 0.15 mg of levonorgestrel USP, a synthetic progestin and 0.03 mg of ethinyl estradiol USP, an estrogen, and 7 green inert tablets (without hormones).

The structural formulas for the active components are:

Levonorgestrel is chemically 18,19-Dinorpregn-4-en-20-yn-3-one, 13-ethyl-17-hydroxy-, (17α)-, (-)-.

Ethinyl Estradiol is 19-Norpregna-1,3,5(10)-trien-20-yne-3,17-diol, (17α)-.

• Each white active tablet contains the following inactive ingredients: croscarmellose sodium, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and povidone. 
• Each green inert tablet contains the following inactive ingredients: anhydrous lactose, croscarmellose sodium, FD&C Blue No.2 Aluminum Lake, ferric oxide yellow, magnesium stearate, microcrystalline cellulose, and povidone.

USP dissolution test is pending.

Carcinogenesis, Mutagenesis, Impairment of Fertility

[see Warnings and Precautions (5.2, 5.11) and Use in Specific Populations (8.1)].