FDA

Introvale

Approved 27 Sept 2010OralTablet

Indications

Introvale ® (levonorgestrel and ethinyl estradiol tablets) is indicated for use by females of reproductive potential to prevent pregnancy. Introvale is an estrogen/progestin COC indicated for use by women to prevent pregnancy. ( 1 )

Contraindications

Introvale 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 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 ) ]. Current diagnosis of, or history of, breast cancer, which may be hormone-sensitive [see Warnings and Precautions ( 5.11 )]. Use of Hepatitis C drug combination containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir, due to the potential for ALT elevations [ see Warnings and Precautions ( 5.3 ) ] A high risk of arterial or venous thrombotic diseases ( 4 ) Liver tumors or liver disease ( 4 ) Undiagnosed abnormal uterine bleeding ( 4 ) Pregnancy ( 4 ) Breast cancer or other estrogen- or progestin-sensitive cancer ( 4 ) Use of Hepatitis C drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir, due to the potential for ALT elevations ( 4 )

Warnings and precautions

At a glance

Brand name: Introvale
Active substance: ethinyl estradiol
Route: Oral
Dosage form: Tablet
Applicant: Xiromed
Status: Prescription
FDA approval: 27 Sept 2010
Application: ANDA079064-001

Contraindications

Interactions

Consult the labeling of concurrently used drugs to obtain further information about interactions with hormonal contraceptives or the potential for enzyme alterations. Drugs or herbal products that induce certain enzymes (for example CYP3A4) may decrease the effectiveness of COCs or increase breakthrough bleeding. Counsel patients to use a back-up or alternative method of contraception when enzyme inducers are used with COCs.

( 7.1 )

7.1Effects 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]).

7.2Effects 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 )].

7.3Concomitant Use with Hepatitis C Vaccine (HCV) Combination

Therapy - Liver Enzyme Elevation Do not administer Introvale with HCV drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir, due to potential for ALT elevations.

7.4Interactions 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.

Adverse reactions

The following serious adverse reactions with the use of COCs are discussed elsewhere in the labeling:

Serious cardiovascular events and stroke [see Boxed Warning and Warnings and Precautions ( 5.1 )]
Vascular events [see Warnings and Precautions ( 5.1 )]
Liver disease [see Warnings and Precautions ( 5.2 )] Adverse reactions commonly reported by COC users are:
Irregular uterine bleeding
Nausea
Breast tenderness
Headache The most common adverse reactions (≥2%) reported during clinical trials were headache, menorrhagia, nausea, dysmenorrhea, acne, migraine, breast tenderness, weight increased, and depression. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Xiromed, LLC at 1-844-XIROMED (1-844-947-6633) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1Clinical 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 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 (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 levonorgestrel and ethinyl estradiol 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.

6.2Postmarketing 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 - 1.12 (Figure A). Three studies compared breast cancer risk between current or recent COC users (<6 months since last use) and never users of COCs (Figure A). 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 - 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 8-10 years of COC use. Figure A: 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. 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 image description

Introvale

Indications

Contraindications

Warnings and precautions

At a glance

Two medicines in one question?

Introvale

Indications

Contraindications

Warnings and precautions

At a glance

Two medicines in one question?

5.1Thrombotic Disorders and Other Vascular Problems

5.2Liver Disease Impaired Liver Function Do

5.3Risk of Liver Enzyme Elevations with Concomitant Hepatitis C Treatment

5.4High Blood Pressure Levonorgestrel

5.5Gallbladder Disease

5.6Carbohydrate and Lipid Metabolic Effects

5.7Headache If

5.8Bleeding Irregularities and Amenorrhea

Interactions

7.1Effects of Other Drugs on Combined Oral Contraceptives

7.2Effects of Combined Oral Contraceptives on Other Drugs

7.3Concomitant Use with Hepatitis C Vaccine (HCV) Combination

7.4Interactions with Laboratory Tests

Pregnancy and breastfeeding

8.1Pregnancy

Adverse reactions

6.1Clinical Trial Experience

6.2Postmarketing Experience

Composition

Official product information