FDA filings in the form of structured product labels are documents that include all published material associated whith this product. Product label information includes data like indications and usage generic names, contraindications, active ingredients, strength dosage, routes of administration, appearance, usage, warnings, inactive ingredients, etc.
Warning: Cigarette Smoking And Serious Cardiovascular Events
Cigarette smoking increases the risk of serious cardiovascular events from combination oral contraceptive (COC) use. This risk increases with age, particularly in women over 35 years of age, and with the number of cigarettes smoked. For this reason, COCs are contraindicated in women who are over 35 years of age and smoke [see Contraindications (4)].
1 Indications And Usage
Iclevia (levonorgestrel and ethinyl estradiol tablets) is indicated for use by females of reproductive potential to prevent pregnancy.
2.1 How To Start Iclevia
Iclevia is dispensed in an Extended-Cycle Wallet [see How Supplied/Storage and Handling (16)]. Iclevia should be started on a Sunday (see Table 1). For the first cycle of a Sunday Start regimen, an additional method of contraception should be used until after the first 7 consecutive days of administration.
Instruct patients to take Iclevia once a day by mouth at the same time every day for 91 days. To achieve maximum contraceptive effectiveness, Iclevia should be taken exactly as directed and at intervals not exceeding 24 hours. For patient instructions regarding missed pills, see FDA-approved patient labeling.
2.2 How To Take Iclevia
Table 1: Instructions for Administration of Iclevia
|Starting COCs in women not currently using hormonal contraception (Sunday Start)|
Consider the possibility of ovulation and conception prior to initiation of this product.
- Iclevia active tablets are white (Day 1 to Day 84).
- Iclevia inactive tablets are green (Day 85 to Day 91).
For each 91 - day course, take in the following order:
- Take the first white tablet (0.15 mg of levonorgestrel and 0.03 mg ethinyl estradiol) on the first Sunday after the onset of menstruation. If menstruation begins on a Sunday, take the tablet on that day. Due to the potential risk of becoming pregnant, use additional non-hormonal contraception (such as condoms or spermicide) for the first 7 days of treatment.
- Take subsequent white tablets once daily at the same time each day for a total of 84 days.
- Take one green tablet (inert) daily for the following 7 days and at the same time of day that active tablets were taken. A scheduled period should occur during the 7 days that the green tablets are taken.
- Begin the next and all subsequent 91-day courses of Iclevia without interruption on the same day of the week (i.e., Sunday) on which the patient began her first dose. Follow the same schedule as the initial 91-day course: a white tablet once a day for 84 days, and a green tablet once a day for 7 days. If the patient does not immediately start her next pill pack, instruct her to protect herself from pregnancy by using a non-hormonal back-up method of contraception until she has taken a white tablet daily for 7 consecutive days.
|Switching to Iclevia from another oral contraceptive||Start on the same day that a new pack of the previous oral contraceptive would have started.|
|Switching from another contraceptive method to Iclevia|| Start Iclevia:|
• Transdermal patch
- On the day when the next application would have been scheduled.
• Vaginal ring
- On the day when the next insertion would have been scheduled.
- On the day when the next injection would have been scheduled.
• Intrauterine contraceptive (IUD)
- On the day of removal.
- If the IUD is not removed on first day of the patient’s menstrual cycle, additional non- hormonal contraception (such as condoms or spermicide) is needed for the first seven days of the first 91-day course.
| • Implant|
| Complete instructions to facilitate patient counseling on proper tablet usage are located in the FDA-approved patient labeling.|
Starting Iclevia after Abortion or Miscarriage
2.3 Missed Tablets
Table 2: Instructions for Missed Iclevia Tablets
- If one active tablet (white) is missed in Days 1 through 84
Take the tablet as soon as possible. Take the next tablet at the regular time and continue taking one tablet a day until the 91 - day course is finished.
- If two consecutive active tablets (white) are missed in Days 1 through 84
Take 2 tablets on the day remembered and 2 tablets the next day. Then continue taking one tablet a day until the 91 - day course is finished. Additional non-hormonal contraception (such as condoms or spermicide) should be used as back-up if the patient has sex within 7 days after missing 2 tablets.
- If three or more consecutive active tablets (white) are missed in Days 1 through 84
Do not take the missed tablets. Continue taking one tablet a day until the 91 - day course is finished. Additional non-hormonal contraception (such as condoms or spermicide) must be used as back-up if the patient has sex within 7 days after missing 3 tablets.
2.4 Advice In Case Of Gastrointestinal Disturbances
In case of severe vomiting or diarrhea, absorption may not be complete and additional contraceptive measures should be taken. If vomiting or diarrhea occurs within 3 to 4 hours after taking a white tablet, handle this as a missed tablet [see FDA-approved patient labeling].
3 Dosage Forms And Strengths
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:
5.1 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.
5.2 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.
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.
5.3 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.
5.4 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.
5.5 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.
5.6 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.
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)].
5.8 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 3: Number of Unscheduled Bleeding and/or Spotting Days per 91-day Cycle
|Q1=Quartile 1: 25% of women had ≤ this number of days of unscheduled bleeding/spotting |
Median: 50% of women had ≤ this number of days of unscheduled bleeding/spotting
Q3=Quartile 3: 75% of women had ≤ this number of days of unscheduled bleeding/spotting
| Cycle (N)|| Days of Unscheduled Bleeding and/or Spotting per |
|Median Days Per Subject- Month|
| Mean||Q1|| Median||Q3|
| 1 (446)|| 15.1|| 3.0|| 12|| 23.0|| 3.0|
| 2 (368)|| 11.6|| 2.0|| 6|| 17.5|| 1.5|
| 3 (309)|| 10.6|| 1.0|| 6|| 15.0|| 1.5|
| 4 (282)|| 8.8|| 1.0|| 4|| 14.0|| 1.0|
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.
Table 4: Percentage of Subjects with Unscheduled Bleeding and/or Spotting
|Days of unscheduled bleeding and/or spotting||Percentage of Subjectsa|
|a Based on spotting and/or bleeding on days 1 to 84 of a 91 day cycle in the Iclevia subjects and days 1 to 21 of a 28 day cycle over 4 cycles in the 28-day dosing regimen.|
| Iclevia||Cycle 1 (N=385)||Cycle 4 (N=261)|
| ≥ 7 days||65%||42%|
| ≥ 20 days||35%||15%|
| 28-day regimen||Cycles 1 to 4 (N=194)||Cycles 10 to 13 (N=158)|
| ≥ 7 days||38%||39%|
| ≥ 20 days||6%||4%|
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.
5.9 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 associated with the use of Iclevia has been reported. Carefully observe women with a history of depression and discontinue Iclevia if severe depression recurs.
5.11 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.
5.12 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.
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.
5.14 Hereditary Angioedema
In women with hereditary angioedema, exogenous estrogens may induce or exacerbate symptoms of angioedema.
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.
6 Adverse Reactions
The following serious adverse reactions with the use of COCs are discussed elsewhere in the labeling:
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 clinical practice.
The clinical trial that evaluated the safety and efficacy of Iclevia was a 12-month, randomized, multicenter, open-label study, which enrolled women aged 18 to 40, of whom 456 took at least one dose of Iclevia (345.14 woman-years of exposure) [see Clinical Studies (14)].
Adverse Reactions Leading to Study Discontinuation: 14.9% of the women discontinued from the clinical trial due to an adverse reaction; the most common adverse reactions (≥ 1% of women) leading to discontinuation in the Iclevia group were menorrhagia (5.7%), mood swings (1.9%), weight/appetite increase (1.5%), and acne (1.3%).
Common Adverse Reactions (≥ 2% of women): headache (20.6%), menorrhagia (11.6%), nausea (7.5%), dysmenorrhea (5.7%), acne (4.6%), migraine (4.4%), breast tenderness (3.5%), weight increased (3.1%), and depression (2.1%).
Serious Adverse Reactions: pulmonary embolus, cholecystitis.
6.2 Postmarketing Experience
The following adverse reactions have been identified during post-approval use of Iclevia. Because these reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency or 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 disorder: hypersensitivity reactions, including itching, rash, and angioedema
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
Skin and subcutaneous tissue disorders: alopecia
Vascular disorders: thrombosis, pulmonary embolism, pulmonary thrombosis
7 Drug Interactions
Consult the labeling of concurrently used drugs to obtain further information about interactions with hormonal contraceptives or the potential for enzyme alterations.
7.1 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]).
7.2 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)].
7.3 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)].
7.4 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.
There is little or no increased risk of birth defects in women who inadvertently use COCs during early pregnancy. Epidemiologic studies and meta-analyses have not found an increased risk of genital or non-genital birth defects (including cardiac anomalies and limb-reduction defects) following exposure to low dose COCs prior to conception or during early pregnancy.
Do not administer COCs to induce withdrawal bleeding as a test for pregnancy. Do not use COCs during pregnancy to treat threatened or habitual abortion.
8.3 Nursing Mothers
Advise the nursing mother to use other forms of contraception, when possible, until she has weaned her child. COCs can reduce milk production in breastfeeding mothers. This is less likely to occur once breastfeeding is well established; however, it can occur at any time in some women. Small amounts of oral contraceptive steroids and/or metabolites are present in breast milk.
8.4 Pediatric Use
Safety and efficacy of Iclevia have been established in women of reproductive age. Efficacy is expected to be the same for postpubertal adolescents under the age of 18 as for users 18 years and older. Use of Iclevia before menarche is not indicated.
8.5 Geriatric Use
Iclevia has not been studied in postmenopausal women and is not indicated in this population.
8.6 Hepatic Impairment
The pharmacokinetics of Iclevia have not been studied in subjects with hepatic impairment. However, steroid hormones may be poorly metabolized in patients with hepatic impairment. 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 [see Contraindications (4) and Warnings and Precautions (5.2)].
8.7 Renal Impairment
The pharmacokinetics of Iclevia have not been studied in women with renal impairment.
There have been no reports of serious ill effects from overdose of oral contraceptives, including ingestion by children. Overdosage may cause withdrawal bleeding in females and nausea.
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)-.
12.1 Mechanism Of Action
COCs 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.
No specific pharmacodynamic studies were conducted with Iclevia.
No specific investigation of the absolute bioavailability of Iclevia in humans has been conducted. However, literature indicates that levonorgestrel is rapidly and completely absorbed after oral administration (bioavailability nearly 100%) and is not subject to first-pass metabolism. EE is rapidly and almost completely absorbed from the gastrointestinal tract but, due to first-pass metabolism in gut mucosa and liver, the bioavailability of EE is approximately 43%.
Following continuous dosing with once-daily administration of Iclevia tablets, plasma concentrations of levonorgestrel and EE reached steady-state within 7 days. The mean plasma pharmacokinetic parameters for Iclevia under fasting conditions in normal healthy women following once-daily administration of one levonorgestrel/EE combination tablet for 10 days are summarized in Table 5.
Table 5: Mean±SD Pharmacokinetic Parameters Under Fasting Conditions in Healthy Women Following 10 Days Administration of One Tablet of Iclevia (n=44)
|Analyte||AUC0-24|| Cmax|| C min|| Cavga|| Tmax|
|a Cavg = AUC0-24/24|
| Levonorgestrel||54.6 ± 16.5|
|5.0 ± 1.5 ng/mL||1.6 ± 0.5|
|2.3 ± 0.7|
|1.4 ± 0.7 hours|
|Ethinyl estradiol ||935.5 ± 346.9 pg*hr/mL||106.1 ± 41.2 pg/mL ||18.5 ± 9.4 pg/mL||38.9 ± 14.4 pg/mL ||1.6 ± 0.6 hours |
The effect of food on the rate and the extent of levonorgestrel and EE absorption following oral administration of Iclevia has not been evaluated.
The apparent volume of distribution of levonorgestrel and EE are reported to be approximately 1.8 L/kg and 4.3 L/kg, respectively. Levonorgestrel is about 97.5 to 99% protein-bound, principally to sex hormone binding globulin (SHBG) and, to a lesser extent, serum albumin. EE is about 95 to 97% bound to serum albumin. EE does not bind to SHBG, but induces SHBG synthesis, which leads to decreased levonorgestrel clearance. Following repeated daily dosing of levonorgestrel/EE oral contraceptives, levonorgestrel plasma concentrations accumulate more than predicted based on single-dose pharmacokinetics, due in part, to increased SHBG levels that are induced by EE, and a possible reduction in hepatic metabolic capacity.
Following absorption, levonorgestrel is conjugated at the 17β-OH position to form sulfate and to a lesser extent, glucuronide conjugates in plasma. Significant amounts of conjugated and unconjugated 3α,5β-tetrahydrolevonorgestrel are also present in plasma, along with much smaller amounts of 3α,5α-tetrahydrolevonorgestrel and 16β-hydroxylevonorgestrel. Levonorgestrel and its phase I metabolites are excreted primarily as glucuronide conjugates. Metabolic clearance rates may differ among individuals by several-fold, and this may account in part for the wide variation observed in levonorgestrel concentrations among users.
First-pass metabolism of EE involves formation of EE-3-sulfate in the gut wall, followed by 2-hydroxylation of a portion of the remaining untransformed EE by hepatic cytochrome P-450 3A4 (CYP3A4). Levels of CYP3A4 vary widely among individuals and can explain the variation in rates of EE hydroxylation. Hydroxylation at the 4-, 6-, and 16-positions may also occur, although to a much lesser extent than 2-hydroxylation. The various hydroxylated metabolites are subject to further methylation and/or conjugation.
About 45% of levonorgestrel and its metabolites are excreted in the urine and about 32% are excreted in feces, mostly as glucuronide conjugates. The terminal elimination half-life for levonorgestrel after a single dose of Iclevia was about 30 hours.
EE is excreted in the urine and feces as glucuronide and sulfate conjugates, and it undergoes enterohepatic recirculation. The terminal elimination half-life of EE after a single dose of Iclevia was found to be about 15 hours.
14 Clinical Studies
In a 12-month, multicenter, randomized, open-label clinical trial, 456 women aged 18 to 40 were studied to assess the safety and efficacy of Iclevia, completing 809 91-day cycles of exposure. The racial demographic of those enrolled was: Caucasian (77%), African-American (11%), Hispanic (7%), Asian (2%), and Other (3%).
There were no exclusions for body mass index (BMI) or weight. The weight range of those women treated was 84 to 304 pounds, with a mean weight of 157 pounds and a median weight of 147 pounds. Among the women in the trial, 63% were current or recent hormonal contraceptive users, 29% were prior users (who had used hormonal contraceptives in the past but not in the 6 months prior to enrollment), and 8% were new starts.
The pregnancy rate (Pearl Index [PI]) in the 397 women aged 18 to 35 years was 1.98 pregnancies per 100 women-years of use (95% CI: 0.54 to 5.03), based on 4 pregnancies that occurred after the onset of treatment and within 14 days after the last combination pill. Cycles in which conception did not occur, but which included the use of back-up contraception, were not included in the calculation of the PI.
16.1 How Supplied
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:
16.2 Storage Conditions
- Store at 20° to 25°C (68° to 77° F) [see USP Controlled Room Temperature].
- Protect from light.
17 Patient Counseling Information
See FDA-approved patient labeling (Patient Information and Instructions for Use).
Counsel patients on the following information:
- Cigarette smoking increases the risk of serious cardiovascular events from COC use, and that women who are over 35 years old and smoke should not use COCs [see Boxed Warning].
- Increased risk of VTE compared to non-users of COCs is greatest after initially starting a COC or restarting (following a 4-week or greater pill-free interval) the same or a different COC [see Warnings and Precautions (5.1)].
- Iclevia does not protect against HIV-infection (AIDS) and other sexually transmitted infections.
- Iclevia is not to be used during pregnancy; if pregnancy occurs during use of Iclevia, instruct the patient to stop further use [see Warnings and Precautions (5.9)].
- Take one tablet daily by mouth at the same time every day. Instruct patients what to do in the event tablets are missed [see Dosage and Administration (2.3)].
- Use a back-up or alternative method of contraception when enzyme inducers are used with Iclevia [see Drug Interactions (7.1)].
- COCs may reduce breast milk production; this is less likely to occur if breastfeeding is well established [see Use in Specific Populations (8.3)].
- Women who start on COCs postpartum, and who have not yet had a period, should use an additional method of contraception until they have taken a white tablet for 7 consecutive days [see Dosage and Administration (2.2)].
- Amenorrhea may occur. 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 [see Warnings and Precautions (5.8)].
Aurobindo Pharma USA, Inc.
2400 Route 130 North
Dayton, NJ 08810
Aurobindo Pharma Limited
Mahaboob Nagar (Dt)-509302
Issued: September 2017
[eye kle' vee ah]
(levonorgestrel and ethinyl estradiol tablets USP)
What is the most important information I should know about Iclevia?
Do not use Iclevia if you smoke cigarettes and are over 35 years old. Smoking increases your risk of serious cardiovascular side effects from hormonal birth control pills, including death from heart attack, blood clots or stroke. This risk increases with age and the number of cigarettes you smoke.
What is Iclevia?
Iclevia is a birth control pill (oral contraceptive) used by women to prevent pregnancy.
How does Iclevia work for contraception?
Your chance of getting pregnant depends on how well you follow the directions for taking your birth control pills. The better you follow the directions, the less chance you have of getting pregnant.
Based on the results of clinical studies, about 1 to 5 out of 100 women may get pregnant during the first year they use Iclevia.
The following chart shows the chance of getting pregnant for women who use different methods of birth control. Each box on the chart contains a list of birth control methods that are similar in effectiveness. The most effective methods are at the top of the chart. The box on the bottom of the chart shows the chance of getting pregnant for women who do not use birth control and are trying to get pregnant.
Who should not take Iclevia?
Do not take Iclevia if you:
- smoke and are over 35 years of age
- had blood clots in your arms, legs, lungs, or eyes
- had a problem with your blood that makes it clot more than normal
- have certain heart valve problems or irregular heart beat
- had a stroke
- had a heart attack
- have high blood pressure that cannot be controlled by medicine
- have diabetes with kidney, eye, nerve, or blood vessel damage
- have certain kinds of severe migraine headaches with aura, numbness, weakness or changes in vision, or any migraine headaches if you are over 35 years of age
- have liver problems, including liver tumors
- take any Hepatitis C drug combination containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir. This may increase levels of the liver enzyme “alanine aminotransferase” (ALT) in the blood.
- have any unexplained vaginal bleeding
- are pregnant
- had breast cancer or any cancer that is sensitive to female hormones
If any of these conditions happen while you are taking Iclevia, stop taking Iclevia right away and talk to your healthcare provider. Use non-hormonal contraception when you stop taking Iclevia.
What should I tell my healthcare provider before taking Iclevia?
Tell your healthcare provider if you:
- are pregnant or think you may be pregnant
- are depressed now or have been depressed in the past
- had yellowing of your skin or eyes (jaundice) caused by pregnancy (cholestasis of pregnancy)
- are breastfeeding or plan to breastfeed. Iclevia may decrease the amount of breast milk you make. A small amount of the hormones in Iclevia may pass into your breast milk. Talk to your healthcare provider about the best birth control method for you while breastfeeding.
Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins and herbal supplements.
Iclevia may affect the way other medicines work, and other medicines may affect how well Iclevia works.
Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist when you get a new medicine.
How should I take Iclevia?
Read the Instructions for Use at the end of this Patient Information.
What are the possible serious side effects of Iclevia?
- Like pregnancy, Iclevia may cause serious side effects, including blood clots in your lungs, heart attack, or a stroke that may lead to death. Some other examples of serious blood clots include blood clots in the legs or eyes.
Serious blood clots can happen especially if you smoke, are obese, or are older than 35 years of age. Serious blood clots are more likely to happen when you:
- first start taking birth control pills
- restart the same or different birth control pills after not using them for a month or more
Call your healthcare provider or go to a hospital emergency room right away if you have:
- leg pain that will not go away
- sudden severe shortness of breath
- sudden change in vision or blindness
- chest pain
- a sudden, severe headache unlike your usual headaches
- weakness or numbness in your arm or leg
- trouble speaking
Other serious side effects include:
- liver problems, including:
- rare liver tumors
- jaundice (cholestasis), especially if you previously had cholestasis of pregnancy. Call your healthcare provider if you have yellowing of your skin or eyes.
- high blood pressure. You should see your healthcare provider for a yearly check of your blood pressure.
- gallbladder problems
- changes in the sugar and fat (cholesterol and triglycerides) levels in your blood
- new or worsening headaches including migraine headaches
- irregular or unusual vaginal bleeding and spotting between your menstrual periods, especially during the first 3 months of taking Iclevia.
- possible cancer in your breast and cervix
- swelling of your skin especially around your mouth, eyes, and in your throat (angioedema). Call your healthcare provider if you have a swollen face, lips, mouth tongue or throat, which may lead to difficulty swallowing or breathing. Your chance of having angioedema is higher is you have a history of angioedema.
- dark patches of skin around your forehead, nose, cheeks and around your mouth, especially during pregnancy (chloasma). Women who tend to get chloasma should avoid spending a long time in sunlight, tanning booths, and under sun lamps while taking Iclevia. Use sunscreen if you have to be in the sunlight.
What are the most common side effects of Iclevia?
- headache (migraine)
- heavier or longer periods, pain with periods
- breast tenderness
- increase in weight
These are not all the possible side effects of Iclevia. For more information, ask your healthcare provider or pharmacist.
You may report side effects to the FDA at 1-800-FDA-1088.
What else should I know about taking Iclevia?
- If you are scheduled for any lab tests, tell your healthcare provider you are taking Iclevia. Certain blood tests may be affected by Iclevia.
- Iclevia does not protect against HIV infection (AIDS) and other sexually transmitted infections.
How should I store Iclevia?
- Store Iclevia at room temperature between 20° to 25°C (68° to 77° F).
- Protect from light.
General information about the safe and effective use of Iclevia.
Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use Iclevia for a condition for which it was not prescribed. Do not give Iclevia to other people, even if they have the same symptoms that you have.
This Patient Information summarizes the most important information about Iclevia. You can ask your pharmacist or healthcare provider for information about Iclevia that is written for health professionals.
For more information, call Aurobindo Pharma USA, Inc. at 1-866-850-2876.
Do birth control pills cause cancer?
Birth control pills do not 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?
You may stop taking the pill whenever you wish. Consider a visit with your healthcare provider for a pre-pregnancy checkup before you stop taking the pill.
What should I know about my period when taking Iclevia?
When you take Iclevia, which has a 91-day extended dosing cycle, you should have 4 scheduled periods a year (bleeding when you are taking the 7 green pills). However, you will probably have more bleeding or spotting between your scheduled periods than if you were using a birth control pill with a 28-day dosing cycle. During the first Iclevia 91-day treatment cycle, about 1 in 3 women may have 20 or more days of unplanned bleeding or spotting. This bleeding or spotting tends to decrease with time. Do not stop taking Iclevia because of this bleeding or spotting. If the spotting continues for more than 7 days in a row or if the bleeding is heavy, call your healthcare provider.
What are the ingredients in Iclevia?
Active ingredients: Each white pill contains levonorgestrel and ethinyl estradiol.
White pills: croscarmellose sodium, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and povidone.
Green pills: anhydrous lactose, croscarmellose sodium, FD &C Blue No.2 Aluminum Lake, ferric oxide yellow, magnesium stearate, microcrystalline cellulose, and povidone.
Instructions For Use
[eye kle' vee ah]
(levonorgestrel and ethinyl estradiol tablets USP)
Important Information about taking Iclevia
Package Label-Principal Display Panel - 0.15 Mg/0.03 Mg (91 Tablets Pouch)
(Levonorgestrel and Ethinyl
Estradiol Tablets USP)
0.15 mg/0.03 mg
Rx only 1 Extended-Cycle Wallet,
Containing 91 Tablets
Contains 1 Extended-Cycle Wallet containing 91 tablets: Eighty-four white
tablets, each containing 0.15 mg levonorgestrel USP with 0.03 mg ethinyl
estradiol USP, and seven green inert tablets.
Package Label-Principal Display Panel - 0.15 Mg/0.03 Mg (91 Tablets Carton)
(Levonorgestrel and Ethinyl
Estradiol Tablets USP)
0.15 mg/0.03 mg
Rx only 3 Extended-Cycle Wallets,
91 Tablets each
THIS PRODUCT (LIKE ALL ORAL CONTRACEPTIVES) IS INTENDED TO PREVENT PREGNANCY. IT DOES NOT PROTECT
AGAINST HIV INFECTION (AIDS) AND OTHER SEXUALLY TRANSMITTED DISEASES.
Contains 3 Extended-Cycle Wallets, each containing 91 tablets: Eighty-four white
tablets, each containing 0.15 mg levonorgestrel USP with 0.03 mg ethinyl estradiol
USP, and seven green inert tablets.
* Please review the disclaimer below.