Iclevia Drug Information
Generic name: LEVONORGESTREL AND ETHINYL ESTRADIOL
Uses of Iclevia
Iclevia TM (levonorgestrel and ethinyl estradiol tablets) is indicated for use by females of reproductive potential to prevent pregnancy. Iclevia is a combination of levonorgestrel, a progestin, and ethinyl estradiol, an estrogen, indicated for use by females of reproductive potential to prevent pregnancy.
Dosage & Administration of Iclevia
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| On the day when the new pack of the previous COC would have been started | |
| On the day when the next application would have been scheduled. | |
| On the day when the next insertion would have been scheduled. | |
| On the day when the next injection would have been scheduled. | |
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| On the day of removal. |
Side Effects of Iclevia
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 levonorgestrel and ethinyl estradiol tablets 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 levonorgestrel and ethinyl estradiol tablets (345.14 woman-years of exposure) . 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 levonorgestrel and ethinyl estradiol tablets 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.
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 2). Three studies compared breast cancer risk between current or recent COC users (<6 months since last use) and never users of COCs (Figure 2). 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 2: 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. 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 Figure 2
Warnings & Cautions for Iclevia
Thromboembolic Disorders and Other Vascular Conditions Stop Iclevia if an arterial or
venous thrombotic/thromboembolic event occurs. Stop Iclevia if there is unexplained loss of vision, proptosis, diplopia, papilledema, or retinal vascular lesions. Evaluate for retinal vein thrombosis immediately.
Discontinue Iclevia during prolonged immobilization. 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 thromboembolism. Start Iclevia no earlier than 4 weeks after delivery in females who are not breastfeeding.
The risk of postpartum thromboembolism decreases after the third postpartum week, whereas the likelihood of ovulation increases after the third postpartum week. Before starting Iclevia evaluate any past medical history or family history of thrombotic or thromboembolic disorders and consider whether the history suggests an inherited or acquired hypercoagulopathy. Iclevia is contraindicated in females with a high risk of arterial or venous thrombotic/thromboembolic diseases . Arterial Events COCs increase the risk of cardiovascular events and cerebrovascular events, such as myocardial infarction and stroke.
The risk is greater among older women (> 35 years of age), smokers, and females with hypertension, dyslipidemia, diabetes, or obesity. Iclevia is contraindicated in women over 35 years of age who smoke. Cigarette smoking increases the risk of serious cardiovascular events from COC use.
This risk increases with age, particularly in women over 35 years of age, and with the number of cigarettes smoked. Venous Events Use of COCs increases the risk of venous thromboembolic events (VTEs), such as deep vein thrombosis and pulmonary embolism. Risk factors for VTEs include smoking, obesity, and family history of VTE, in addition to other factors that contraindicate use of COCs . While the increased risk of VTE associated with use of COCs is well-established, the rates of VTE are even greater during pregnancy, and especially during the postpartum period (see Figure 1). The rate of VTE in females using COCs has been estimated to be 3 to 9 cases per 10,000 woman years.
The risk of VTE is highest during the first year of use of a COC and when restarting hormonal contraception after a break of four weeks or longer. The risk of thromboembolic disease due to COCs gradually disappears after COC use is discontinued. Figure 1 shows the risk of developing a VTE for females who are not pregnant and do not use oral contraceptives, for females who use oral contraceptives, for pregnant females and for females in the postpartum period.
To put the risk of developing a VTE into perspective: If 10,000 females who are not pregnant and do not use oral contraceptives are followed for one year, between 1 and 5 of these females will develop a VTE. Use of levonorgestrel and ethinyl estradiol tablets 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 levonorgestrel and ethinyl estradiol tablets. Figure 1
Liver Disease Elevated Liver Enzymes Iclevia is contraindicated in females with acute
viral hepatitis or severe (decompensated) cirrhosis of the liver . Acute liver test abnormalities may necessitate the discontinuation of Iclevia until the liver tests return to normal and Iclevia causation has been excluded. Discontinue Iclevia if jaundice develops. Liver Tumors Iclevia is contraindicated in females with benign and malignant liver tumors . COCs increase the risk of hepatic adenomas.
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.
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 ombitasvir/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 levonorgestrel and ethinyl estradiol tablets. Discontinue levonorgestrel and ethinyl estradiol tablets prior to starting therapy with the combination drug regimen ombitasvir/paritaprevir/ritonavir, with or without dasabuvir . Levonorgestrel and ethinyl estradiol tablets can be restarted approximately 2 weeks following completion of treatment with the Hepatitis C combination drug regimen.
Hypertension Iclevia is contraindicated in females with uncontrolled hypertension or hypertension with
vascular disease. For all women, including those with well-controlled hypertension, monitor blood pressure at routine visits and stop Iclevia if blood pressure rises significantly. An increase in blood pressure has been reported in females taking COCs, and this increase is more likely in older women and with extended duration of use.
The effect of COCs on blood pressure may vary according to the progestin in the COC.
Age-related Considerations
The risk for cardiovascular disease and prevalence of risk factors for cardiovascular disease increase with age. Certain conditions, such as smoking and migraine headache without aura, that do not contraindicate COC use in younger females, are contraindications to use in women over 35 years of age. Consider the presence of underlying risk factors that may increase the risk of cardiovascular disease or VTE, particularly before initiating Iclevia for women over 35 years, such as: Hypertension Diabetes Dyslipidemia Obesity
Gallbladder Disease Studies suggest a small increased relative risk of developing gallbladder
disease among COC users. Use of COCs, including Iclevia, may worsen existing gallbladder disease. A past history of COC-related cholestasis predicts an increased risk with subsequent COC use.
Females with a history of pregnancy-related cholestasis may be at an increased risk for COC-related cholestasis.
Adverse Carbohydrate and Lipid Metabolic Effects Hyperglycemia Iclevia is contraindicated in diabetic
women over age 35, or females who have diabetes with hypertension, nephropathy, retinopathy, neuropathy, other vascular disease or females with diabetes of >20 years of duration. Iclevia may decrease glucose tolerance. Carefully monitor prediabetic and diabetic females who are using Iclevia.
Dyslipidemia Consider alternative contraception for females with uncontrolled dyslipidemia. Iclevia may cause adverse lipid changes. Females with hypertriglyceridemia, or a family history thereof, may have an increase in serum triglyceride concentrations when using Iclevia, which may increase the risk of pancreatitis.
Headache Iclevia is contraindicated in females who have headaches with focal neurological
symptoms or have migraine headaches with aura, and in women over age 35 years who have migraine headaches with or without aura . If a female taking Iclevia develops new headaches that are recurrent, persistent, or severe, evaluate the cause and discontinue Iclevia if indicated. Consider discontinuation of Iclevia if there is an increased frequency or severity of migraine during COC use (which may be prodromal of a cerebrovascular event).
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 Bleeding and Spotting Females using Iclevia may experience unscheduled (breakthrough or intracyclic) bleeding and spotting especially during the first 3 months of use.
Bleeding irregularities may resolve over time or by changing to a different contraceptive product. If unscheduled bleeding persists or occurs after previously regular cycles, evaluate for causes such as pregnancy or malignancy. Before prescribing Iclevia, advise the woman to weigh the occurrence of fewer scheduled menses (4 per year instead of 13 per year) against the occurrence of increased unscheduled bleeding and/or spotting.
The clinical trial of the efficacy of levonorgestrel and ethinyl estradiol tablets (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 levonorgestrel and ethinyl estradiol tablets subjects, compared to subjects on the comparator 28-day cycle regimen, discontinued prematurely for unacceptable bleeding (7.7% vs. 1.8% ). 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 Cycl e (N) Day s of Unscheduled Bleeding and/or Spotting per 84- Day Interval Median Days Per Subject-Month Mean Q1 Median Q3 1 15.1 3.0 12 23.0 3.0 2 11.6 2.0 6 17.5 1.5 3 10.6 1.0 6 15.0 1.5 4 8.8 1.0 4 14.0
Table 4 shows the percentages of women with ≥7 days and ≥20
days of unscheduled spotting and/or bleeding in the levonorgestrel and ethinyl estradiol tablets 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 Subjects a a Based on spotting and/or bleeding on days 1 to 84 of a 91 day cycle in the levonorgestrel and ethinyl estradiol tablets subjects and days 1 to 21 of a 28 day cycle over 4 cycles in the 28-day dosing regimen. L evonorgestrel and ethinyl estradiol tablets 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 levonorgestrel and ethinyl estradiol tablets subjects and subjects on the 28-day cycle regimen.
Amenorrhea and Oligomenorrhea Females who use levonorgestrel and ethinyl estradiol tablets may experience absence of scheduled (withdrawal) bleeding, even if they are not pregnant. Based on data from the clinical trial of levonorgestrel and ethinyl estradiol tablets, amenorrhea occurred in approximately 0.8% of females during Cycle 1, 1.2% of females during Cycle 2, 3.7% of females during Cycle 3, and 3.4% of females during Cycle 4. Because females using levonorgestrel and ethinyl estradiol tablets will likely have scheduled bleeding only 4 times per year, rule out pregnancy at the time of any missed menstrual period. After discontinuation of levonorgestrel and ethinyl estradiol tablets, amenorrhea or oligomenorrhea may occur, especially if these conditions were pre-existent. 5.10 Depression Carefully observe females with a history of depression and discontinue Iclevia if depression recurs to a serious degree.
Data on the association of COCs with onset of depression or exacerbation of existing depression are limited. 5.11 Malignant Neoplasms Breast Cancer Iclevia is contraindicated in females who currently have or have had breast cancer because breast cancer may be hormonally sensitive. 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 . Cervical Cancer Some studies suggest that COC are associated with an increase in the risk of cervical cancer or intraepithelial neoplasia. However, there is 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 Iclevia 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 Iclevia, may induce or exacerbate symptoms of hereditary angioedema. 5.14 Chloasma Chloasma may occur with Iclevia use, especially in females with a history of chloasma gravidarum.
Advise females with a history of chloasma to avoid exposure to the sun or ultraviolet radiation while taking Iclevia.
Drug Interactions with Iclevia
Effects of Other Drugs on Combined Oral Contraceptives Substances decreasing the plasma
concentrations of COCs and potentially diminishing the efficacy of COCs: Table 5 includes substances that demonstrated an important drug interaction with levonorgestrel and ethinyl estradiol tablets. Table 5: Significant Drug Interactions Involving Substances That Affect COCs a Induction potency of St. John’s wort may vary widely based on preparation.
Metabolic Enzyme Inducers Clinical effect Concomitant use of COCs with metabolic enzyme inducers may decrease the plasma concentrations of the estrogen and/or progestin component of COCs. Decreased exposure of the estrogen and/or progestin component of COCs may potentially diminish the effectiveness of COCs and may lead to contraceptive failure or an increase in breakthrough bleeding. Prevention or management Counsel females to use an alternative method of contraception or a backup method when enzyme inducers are used with COCs.
Continue backup contraception for 28 days after discontinuing the enzyme inducer to maintain contraceptive reliability. Examples Aprepitant, barbiturates, bosentan, carbamazepine, efavirenz, felbamate, griseofulvin, oxcarbazepine, phenytoin, rifampin, rifabutin, rufinamide, topiramate, products containing St. John’s wort a, and certain protease inhibitors (see separate section on protease inhibitors below). Colesevelam Clinical effect Concomitant use of COCs with colesevelam significantly decreases systemic exposure of ethinyl estradiol . Decreased exposure of the estrogen component of COCs may potentially reduce contraceptive efficacy or result in an increase in breakthrough bleeding, depending on the strength of ethinyl estradiol in the COC. Prevention or management Administer 4 or more hours apart to attenuate this drug interaction.
Substances increasing the systemic exposure 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 systemic exposure of EE possibly by inhibition of conjugation. CYP3A4 inhibitors such as itraconazole, voriconazole, fluconazole, grapefruit juice, or ketoconazole may increase systemic exposure of 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] or some HCV protease inhibitors (e.g. boceprevir and telaprevir) and some non-nucleosidase 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).
Effects of Combined Oral Contraceptives on Other Drugs Table 6 provides significant
drug interaction information for drugs co-administered with levonorgestrel and ethinyl estradiol tablets. Table 6: Significant Drug Interaction Information for Drugs Co-Administered With COCs Lamotrigine Clinical effect Concomitant use of COCs with lamotrigine may significantly decrease systemic exposure of lamotrigine due to induction of lamotrigine glucuronidation . Decreased systemic exposure of lamotrigine may reduce seizure control. Prevention or management Dose adjustment may be necessary.
Consult the approved product labeling for lamotrigine. Thyroid Hormone Replacement Therapy or Corticosteroid Replacement Therapy Clinical effect Concomitant use of COCs with thyroid hormone replacement therapy or corticosteroid replacement therapy may increase systemic exposure of thyroid-binding and cortisol-binding globulin . Prevention or management The dose of replacement thyroid hormone or cortisol therapy may need to be increased. Consult the approved product labeling for the therapy in use . Other Drugs Clinical effect Concomitant use of COCs may decrease systemic exposure of acetaminophen, morphine, salicylic acid, and temazepam.
Concomitant use with ethinyl estradiol-containing COCs may increase systemic exposure of other drugs (e.g., cyclosporine, prednisolone, theophylline, tizanidine, and voriconazole). Prevention or management The dosage of drugs that can be affected by this interaction may need to be increased. Consult the approved product labeling for the concomitantly used drug.
Concomitant Use with Hepatitis C Virus (HCV) Combination Therapy-Liver Enzyme Elevation Co-administration
of Iclevia with HCV drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir is contraindicated due to potential for ALT elevations. Co-administration of Iclevia and glecaprevir/pibrentasvir is not recommended due to potential for ALT elevations.
Effect on Laboratory Tests
The use of COCs may influence the results of certain laboratory tests, such as coagulation factors, lipids, glucose tolerance, and binding proteins.
Pregnancy Safety for Iclevia
Pregnancy Risk Summary There is no use for contraception in pregnancy; therefore, Iclevia should be discontinued during 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 COCs before conception or during early pregnancy. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4 percent and 15 to 20 percent, respectively.
Pediatric Use of Iclevia
Pediatric Use Safety and efficacy of levonorgestrel and ethinyl estradiol tablets 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 levonorgestrel and ethinyl estradiol tablets before menarche is not indicated.
Contraindications for Iclevia
Iclevia is contraindicated in females who are known to have or develop the following conditions: A high risk of arterial or venous thrombotic diseases. Examples include females who are known to: Smoke, if over age 35. Have current or history of deep vein thrombosis or pulmonary embolism. Have cerebrovascular disease.
Have coronary artery disease. Have thrombogenic valvular or thrombogenic rhythm diseases of the heart (for example, subacute bacterial endocarditis with valvular disease, or atrial fibrillation). Have inherited or acquired hypercoagulopathies. Have uncontrolled hypertension or hypertension with vascular disease.
Have diabetes mellitus and are over age of 35, diabetes mellitus with hypertension or vascular disease or other end-organ damage, or diabetes mellitus of >20 years duration . Have headaches with focal neurological symptoms, migraine headaches with aura, or over age 35 with any migraine headaches. Current diagnosis of, or history of breast cancer, which may be hormone sensitive. Liver tumors, acute viral hepatitis, or severe (decompensated) cirrhosis.
Undiagnosed abnormal uterine bleeding . Use of Hepatitis C drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir, due to the potential for ALT elevations. A high risk of arterial or venous thrombotic diseases Liver tumors or liver disease, acute viral hepatitis or decompensated cirrhosis Undiagnosed abnormal uterine bleeding Breast cancer Co-administration with Hepatitis C drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir.
Overdosage Information for Iclevia
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.
Clinical Studies of Iclevia
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 levonorgestrel and ethinyl estradiol tablets, 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 ) 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.
Drug information sourced from the FDA. This content is for informational purposes only and does not constitute medical advice. Consult a healthcare professional before making any medication decisions.
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