Low-Ogestrel Norgestrel and Ethinyl Estradiol Kit — NDC 51862-564-06 (Billing 51862-0564-06)

WARNINGS 1. Thromboembolic Disorders and Other Vascular Problems Stop Low-Ogestrel if an arterial thrombotic event or venous thromboembolic (VTE) event occurs. Stop Low-Ogestrel if there is unexplained loss of vision, proptosis, diplopia, papilledema, or retinal vascular lesions.

Evaluate for retinal vein thrombosis immediately. If feasible, stop Low-Ogestrel 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 Low-Ogestrel 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 COCs also increases the risk of arterial thromboses such as strokes and myocardial infarctions, especially in women with other risk factors for these events. 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. 2. Liver Disease Impaired Liver Function Do not use Low-Ogestrel in women with liver disease, such as acute viral hepatitis or severe (decompensated) cirrhosis of the liver [see Contraindications ] .

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 Low-Ogestrel if jaundice develops. Liver Tumors Low-Ogestrel is contraindicated in women with benign and malignant liver tumors [see Contraindications ] .

Hepatic adenomas are associated with COC use. An estimate of the attributable risk is 3.3 cases/100,000 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 risk of liver cancers in COC users approaches 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 COCs.

Discontinue Low-Ogestrel prior to starting therapy with the combination drug regimen ombitasvir/paritaprevir/ritonavir, with or without dasabuvir [see Contraindications ]. Low-Ogestrel can be restarted approximately 2 weeks following completion of treatment with the combination drug regimen. 3.

High Blood Pressure Low-Ogestrel is contraindicated in women with uncontrolled hypertension or hypertension with vascular disease [see Contraindications ] . For women with well-controlled hypertension, monitor blood pressure and stop Low-Ogestrel 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 with extended duration of use.

The incidence of hypertension increases with increasing quantities of progestin. 4. Gallbladder Disease Studies suggest a small increased relative risk of developing gallbladder disease among COC users.… [Excerpted — this section continues on DailyMed.]

ADVERSE REACTIONS An increased risk of the following serious adverse reactions (see Warnings section for additional information) has been associated with the use of oral contraceptives: Serious cardiovascular events and stroke [see Boxed Warning ] Vascular events Liver disease Adverse reactions commonly reported by COC users are: Irregular uterine bleeding Nausea Breast tenderness Headache Clinical Trials 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 rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

The safety of Low-Ogestrel was evaluated in 1,343 healthy women of child-bearing potential who participated in 9 clinical trials and received at least one dose of Low-Ogestrel for contraception. Subjects were exposed for a total of 11,085 cycles, with 429 women completing one year of exposure. Subjects ranged in age from 15-40 years.

Demographics were 69% Caucasian, 28% Black, and 3% other. Common Adverse Reactions (≥ 2% of women): Weight increase (11%) Cervical erosion (9%) Weight decrease (6%) Acne (4%) Dysmenorrhea (4%) Vaginal discharge (4%) Abdominal pain, cramps, and bloating (3%) Appetite increase (3%) Depression (3%) Nervousness (3%) Chloasma/melasma (2%) Fatigue (2%) Varicose veins, aggravation of (2%) A total of 8% of subjects discontinued the trials prematurely due to an adverse reaction, most commonly due to unscheduled bleeding, spotting, headache (including migraine), nausea, acne, changes in menstrual flow, weight increase, nervousness, high blood pressure, and depression.

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: Risk of Breast Cancer with Combined Oral Contraceptive Use 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 additional adverse drug reactions have been reported from worldwide postmarketing experience with Low-Ogestrel. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Arterial Events: Arterial thromboembolism, Myocardial infarction, Cerebral hemorrhage Eye Disorder: Optic neuritis, which may lead to partial or complete loss of vision, Intolerance to contact lenses, Change (steepening) in corneal curvature Gastrointestinal Disorders: Colitis, Nausea, Pancreatitis Hepatobiliary Disorders: Gallbladder disease, Cholestatic jaundice, Budd-Chiari syndrome Immune System Disorders: Anaphylactic/anaphylactoid reactions, including urticaria, angioedema, and severe reactions with respiratory and circulatory symptoms Metabolism and Nutrition Disorders: Carbohydrate and lipid effects, Porphyria, exacerbation of Porphyria Neoplasms, Benign, Malignant, and Unspecified: Carcinoma of the reproductive organs and breasts , Hepatic neoplasia (including hepatic adenomas or benign liver tumors) Psychiatric Disorders: Mood changes Reproductive System and Breast Disorders: Temporary inferti… [Excerpted — this section continues on DailyMed.]

4. Drug Interactions Consult the labeling of all concurrently-used drugs to obtain further information about interactions with hormonal contraceptives or the potential for enzyme alterations . Concomitant Use with HCV Combination Therapy – Liver Enzyme Elevation Do not co-administer Low-Ogestrel with HCV drug combinations containing ombitasvir/ paritaprevir/ritonavir, with or without dasabuvir, due to potential for ALT elevations (see Warnings, Risk of liver enzyme elevations with concomitant hepatitis c treatment ).

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 hormonal 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 EE increase AUC values for EE by approximately 20-25%.

Ascorbic acid and acetaminophen may increase plasma EE concentrations, possibly by inhibition of conjugation. Concomitant administration of CYP3A4 inhibitors such as itraconazole, 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 the estrogen and/or progestin have been noted when COCs are co-administered with some 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]).

Effects of Combined Oral Contraceptives on Other Drugs COCs containing EE may inhibit the metabolism of other drugs (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 the 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 serum concentration of thyroid-binding globulin increases with use of COCs.

PRECAUTIONS 1. 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.

2. Hereditary Angioedema In females with hereditary angioedema, exogenous estrogens may induce or exacerbate symptoms of angioedema. 3.

Chloasma Chloasma may occasionally occur, especially in women with a history of chloasma gravidarum. Women with a tendency to chloasma should avoid exposure to the sun or ultraviolet radiation while taking Low-Ogestrel. 4.

Drug Interactions Consult the labeling of all concurrently-used drugs to obtain further information about interactions with hormonal contraceptives or the potential for enzyme alterations . Concomitant Use with HCV Combination Therapy – Liver Enzyme Elevation Do not co-administer Low-Ogestrel with HCV drug combinations containing ombitasvir/ paritaprevir/ritonavir, with or without dasabuvir, due to potential for ALT elevations (see Warnings, Risk of liver enzyme elevations with concomitant hepatitis c treatment ). 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 hormonal 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 EE increase AUC values for EE by approximately 20-25%. Ascorbic acid and acetaminophen may increase plasma EE concentrations, possibly by inhibition of conjugation. Concomitant administration of CYP3A4 inhibitors such as itraconazole, 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 the estrogen and/or progestin have been noted when COCs are co-administered with some 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]).

Effects of Combined Oral Contraceptives on Other Drugs COCs containing EE may inhibit the metabolism of other drugs (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 the plasma concentration of lamotrigine has been shown, likely du… [Excerpted — this section continues on DailyMed.]