Blisovi 24 Fe Drug Information

Blisovi ™ 24 Fe is indicated for use by women to prevent pregnancy. 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.

The efficacy of Blisovi 24 Fe in women with a body mass index (BMI) of >35 kg/m 2 has not been evaluated.

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 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%).

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 - 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

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 or increase )/HCV protease inhibitors or with non-nucleoside reverse transcriptase inhibitors (decrease or increase ).

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, 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.

Concomitant 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 . Co-administration of Blisovi 24 Fe and glecaprevir/pibrentasvir is not recommended due to potential for ALT elevations.

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.

Pregnancy Risk Summary There is no use for contraception in pregnancy; therefore, Blisovi 24 Fe should be discontinued during pregnancy. Epidemiologic studies and meta-analyses have not found an increased risk of genital or nongenital birth defects (including cardiac anomalies and limb-reduction defects) following exposure to CHCs 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.

Data Human Data Epidemiologic studies and meta-analyses have not found an increased risk of genital or nongenital birth defects (including cardiac anomalies and limb-reduction defects) following exposure to CHCs before conception or during early pregnancy.

Pediatric Use Safety and efficacy of Blisovi 24 Fe have been established in women of reproductive age. Efficacy is expected to be the same in postpubertal adolescents under the age of 18 years as for users 18 years and older. Use of this product before menarche is not indicated.

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 Have deep vein thrombosis or pulmonary embolism, now or in the past Have inherited or acquired hypercoagulopathies 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 uncontrolled hypertension Have diabetes mellitus with vascular disease Have headaches with focal neurological symptoms or have migraine headaches with aura ■ Women over age 35 with any migraine headaches Liver tumors, benign or malignant, or liver disease Undiagnosed abnormal uterine bleeding Current diagnosis of, or history of, breast cancer, which may be hormone sensitive 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 Undiagnosed abnormal uterine bleeding Breast cancer Co-administration with Hepatitis C drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir

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.