FDA

Blisovi 24 Fe

Approved 28 Oct 2015OralTablet

Indications

Blisovi ™ 24 Fe is indicated for use by women to prevent pregnancy [see CLINICAL STUDIES ( 14 )]. The efficacy of Blisovi 24 Fe in women with a body mass index (BMI) of > 35 kg/m 2 has not been evaluated. Blisovi 24 Fe is a combination of norethindrone acetate, a progestin, and ethinyl estradiol, an estrogen, indicated for use by women to prevent pregnancy. (1) The efficacy of Blisovi 24 Fe in women with a body mass index (BMI) of >35 kg/m 2 has not been evaluated.

( 1 , 8.8 )

Contraindications

Blisovi 24 Fe 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 have 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 )] Undiagnosed abnormal uterine bleeding [see WARNINGS AND PRECAUTIONS ( 5.8 )] Current diagnosis of, or history of, breast cancer, which may be hormone sensitive [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 )] A high risk of arterial or venous thrombotic diseases ( 4 ) Liver tumors or liver disease ( 4 ) Undiagnosed abnormal uterine bleeding ( 4 ) Breast cancer ( 4 ) Co-administration with Hepatitis C drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir ( 4 )

Warnings and precautions

Thrombotic Disorders and Other Vascular Problems: Stop Blisovi 24 Fe if a thrombotic event occurs. Stop at least 4 weeks before through 2 weeks after major surgery. Start no earlier than 4 weeks after delivery, in women who are not breastfeeding. ( 5.1 ) Liver disease: Discontinue Blisovi 24 Fe if jaundice occurs. ( 5.2 ) High blood pressure: If used in women with well-controlled hypertension, monitor blood pressure and stop Blisovi 24 Fe if blood pressure rises significantly.

At a glance

Brand name: Blisovi 24 Fe
Active substance: ethinyl estradiol
Route: Oral
Dosage form: Tablet
Applicant: Lupin
Status: Prescription
FDA approval: 28 Oct 2015
Application: ANDA091398-001

Indications

( 1 , 8.8 )

Contraindications

Warnings and precautions

Interactions

Consult the labeling of concurrently used drugs to obtain further information about interactions with oral 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 method or alternative method of contraception when enzyme inducers are used with COCs.

( 7.1 )

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 oral contraceptives including phenytoin, barbiturates, carbamazepine, bosentan, felbamate, griseofulvin, oxcarbazepine, rifampicin, topiramate, rifabutin, rufinamide, aprepitant, and products containing St.

John's wort. Interactions between COCs 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. 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/ritnoavir, and tipranavir/ritonavir] or increase [e.g., indinavir and atazanavir/ritonavir])/HCV protease inhibitors or with non-nucleoside reverse transcriptase 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, and temazepam. 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 HCV Combination

Therapy – Liver Enzyme Elevation Co-administration of Blisovi 24 Fe with HCV drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir is contraindicated due to potential for ALT elevations [see WARNINGS AND PRECAUTIONS ( 5.3 )] . Co-administration of Blisovi 24 Fe and glecaprevir/pibrentasvir is not recommended 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%) were: headache, vaginal candidiasis, nausea, menstrual cramps, breast tenderness, mood changes, bacterial vaginitis, acne, and weight gain.

( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Lupin Pharmaceuticals, Inc. at 1-800-399-2561 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 practice. The safety of Blisovi 24 Fe was evaluated in 743 subjects who participated in an open-label, randomized, active-controlled, multicenter clinical trial of Blisovi 24 Fe for contraception.

This trial examined healthy, non-pregnant volunteers aged 18 to 45 years, who were sexually active and had a body mass index of ≤ 35 kg/m 2 . Subjects were followed for up to six 28-day cycles providing a total of 3,823 treatment-cycles of exposure. Common Adverse Reactions (≥ 2% of all subjects) The most common adverse reactions reported by at least 2% of the 743 women using Blisovi 24 Fe were the following, in order of decreasing incidence: headache (6.3%), vaginal candidiasis (6.1%), nausea (4.6%), menstrual cramps (4.4%), breast tenderness (3.4%), mood changes (including mood swings (2.2%) and depression (1.1%), bacterial vaginitis (3.1%), acne (2.7%), and weight gain (2.0%).

Adverse Reactions Leading to Study Discontinuation Among the 743 women using Blisovi 24 Fe, 46 women (6.2%) withdrew because of an adverse event. Adverse events occurring in 3 or more subjects leading to discontinuation of treatment were, in decreasing order: abnormal bleeding (0.9%), nausea (0.8%), mood changes (0.8%), menstrual cramps (0.4%), increased blood pressure (0.4%), and irregular bleeding (0.4%).

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 1). Three studies compared breast cancer risk between current or recent COC users (<6 months since last use) and never users of COCs (Figure 1). 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 1: 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 Blisovi 24 Fe. Because these reactions are reported voluntarily from a population of uncertain size, it is difficult to reliably estimate their frequency or evaluate a causal relationship to drug exposure. Cardiovascular Chest pain, palpitations, tachycardia, angina pectoris, myocardial infarction. Endocrine Disorders Hypothyroidism, hyperthyroidism.

Eye Disorders Blurred vision, visual impairment, transient blindness, corneal thinning, change in corneal curvature (steepening). GI Disorders Nausea, vomiting, abdominal pain, constipation, pancreatitis. Hepatobiliary Disorders Cholelithiasis, cholecystitis, hepatic adenoma, hemangioma of liver. Immune System Disorders Anaphylactic reactions, including urticaria, angioedema, and severe reactions with respiratory and circulatory symptoms.

Infections Vaginal infection. Metabolism and Nutrition Disorders Change in weight or appetite (increase or decrease). hypoglycemia, diabetes mellitus, anemia. Musculoskeletal and Connective Tissue Disorders Myalgia. Skin and Subcutaneous Disorders Alopecia, rash (generalized and allergic), pruritus, skin discoloration, night sweats, swelling face or lips, hirsutism, skin burning sensation, erythema multiforme, erythema nodosum, hemorrhagic eruption.

Nervous System Disorders Headache, dizziness, migraine, hyperesthesia, paraesthesia, hypoaesthesia, somnolence, loss of consciousness, sensory disturbance. Psychiatric Disorders Mood swings, depression, insomnia, anxiety, suicidal ideation, panic attack, changes in libido, bipolar disorder, dissociation, homicidal ideation. Renal and Urinary Disorders Pollakiuria, dysuria, cystitis-like syndrome. Reproductive System and Breast Disorders Breast changes (tenderness, pain, enlargement, and secretion), premenstrual syndrome, ovarian cyst, pelvic pain, ovarian cyst ruptured, pelvic fluid collection.

Vascular Disorders Hot flush, thrombosis/embolism (coronary artery, pulmonary, cerebral, deep vein), migraine, transient ischemic attack, ischemic stroke. 1

Blisovi 24 Fe

Indications

Contraindications

Warnings and precautions

At a glance

Two medicines in one question?

Blisovi 24 Fe

Indications

Contraindications

Warnings and precautions

At a glance

Two medicines in one question?

5.1Thrombotic Disorders and Other Vascular Problems Stop Blisovi 24

5.2Liver Disease Impaired Liver Function Do

5.3Risk of Liver Enzyme Elevations with Concomitant Hepatitis C Treatment

5.4High Blood Pressure Blisovi 24

5.5Gallbladder Disease

5.6Carbohydrate and Lipid Metabolic Effects

5.7Headache If

5.8Bleeding Irregularities and Amenorrhea Unscheduled Bleeding and Spotting Unscheduled (breakthrough

5.9COC Use Before or During Early Pregnancy

Interactions

7.2Effects of Combined Oral Contraceptives on Other Drugs

7.3Concomitant Use with HCV Combination

7.4Interactions with Laboratory Tests

Pregnancy and breastfeeding

8.1Pregnancy Risk Summary

Adverse reactions

6.1Clinical Trial Experience

6.2Postmarketing Experience

Composition

Official product information