LOW-OGESTREL

Low-Ogestrel is a combination oral contraceptive containing the progestational compound norgestrel and the estrogenic compound ethinyl estradiol. Norgestrel is designated as (2) (±)-13­ Ethyl-17-hydroxy-18,19-dinor-17α-pregn-4-en-20-yn-3-one and ethinyl estradiol is designated as (19-nor-17α-pregna-1,3,5 (10)-trien-20-yne-3,17-diol). Each white active Low-Ogestrel tablet contains 0.3 mg norgestrel and 0.03 mg ethinyl estradiol and the following inert ingredients: croscarmellose sodium, lactose, magnesium stearate, microcrystalline cellulose, and povidone. Each peach placebo tablet contains only the following inert ingredients: anhydrous lactose, FD&C Yellow No. 6 Lake, lactose monohydrate, magnesium stearate, and microcrystalline cellulose. Each pill pack contains 21 white active tablets and 7 peach inert tablets. Norgestrel C 21 H 28 O 2 M.W. 312.45 Ethinyl Estradiol C 20 H 24 O 2 M.W. 296.40 Chemical Structure Chemical Structure

Low-Ogestrel is indicated for use by females of reproductive potential to prevent pregnancy. In a study of 1,287 women with a total of 11,085 cycles or 852.7 women-years of usage, the pregnancy rate in women age 15-40 years was approximately 1 pregnancy per 100 women-years of use.

To achieve maximum contraceptive effectiveness, Low-Ogestrel (norgestrel and ethinyl estradiol tablets) must be taken exactly as directed and at intervals not exceeding 24 hours. The dosage of Low-Ogestrel is one white tablet daily for 21 consecutive days, followed by one peach inert tablet daily for 7 consecutive days, according to prescribed schedule. It is recommended that Low-Ogestrel tablets be taken by mouth at the same time each day. How to Start Low-Ogestrel Consider the possibility of ovulation and conception prior to initiation of medication. Instruct the patient to begin taking Low-Ogestrel on the first Sunday after the onset of menstruation. If menstruation begins on a Sunday, the first tablet (white) is taken that day. The patient should take one white tablet daily for 21 consecutive days followed by one peach inert tablet daily for 7 consecutive days. Withdrawal bleeding will usually occur within 3 days following discontinuation of white tablets and may not have finished before the next pack is started. During the first cycle, the patient should not rely on Low-Ogestrel for contraception until a white tablet has been taken daily for 7 consecutive days and she should use a non-hormonal back-up method of birth control during those 7 days. After the first cycle of use The patient is to begin her next and all subsequent 28-day courses of tablets on the same day of the week (Sunday) on which she began her first course, following the same schedule: 21 days of white tablets, followed by 7 days of peach inert tablets. If in any cycle the patient starts tablets later than the proper day, instruct her to protect herself against pregnancy by using a non-hormonal back-up method of birth control until she has taken a white tablet daily for 7 consecutive days. Switching from another hormonal method of contraception When the patient is switching from a 21-day regimen of tablets, instruct her to wait 7 days after her last tablet before she starts Low-Ogestrel. She will probably experience withdrawal bleeding during that week. Instruct her not to let more than 7 days pass after her previous 21-day regimen before she starts Low-Ogestrel. When the patient is switching from a 28-day regimen of tablets, instruct her to start her first pack of Low-Ogestrel on the day after her last tablet. She should not wait any days between packs. The patient may switch any day from a progestin-only pill and should begin Low-Ogestrel the next day. If switching from an implant or injection, instruct the patient to start Low-Ogestrel on the day of implant removal or the day the next injection would be due. If switching from a contraceptive vaginal ring or transdermal patch instruct the patient to start Low-Ogestrel on the day they would have inserted the next ring or applied the next patch. If switching from an Intrauterine Device (IUD) or Intrauterine System (IUS), instruct the patient to start Low-Ogestrel on the day of IUD/IUS removal. If the IUD/IUS is not removed on the first day of the patient's menstrual cycle, instruct her to use a non-hormonal back-up method of birth control for the first 7 days of tablet-taking. Use after pregnancy, abortion, or miscarriage Initiate Low-Ogestrel no earlier than day 28 postpartum in the nonlactating mother or after a second-trimester abortion due to the increased risk for thromboembolism (see Contraindications , Warnings and Precautions concerning thromboembolic disease). Advise the patient to use a non-hormonal back-up method for the first 7 days of tablet-taking. Low-Ogestrel may be initiated immediately after a first-trimester abortion or miscarriage. If the patient starts Low-Ogestrel immediately, back-up contraception is not needed. If spotting or breakthrough bleeding occurs If spotting or breakthrough bleeding occurs, instruct the patient to continue on the same regimen. This type of bleeding is usually transient and without significance; however, advise the patient to consult her healthcare provider if the bleeding is persistent or prolonged. Missed Tablets The possibility of ovulation and pregnancy increases with each successive day that scheduled white tablets are missed. If withdrawal bleeding does not occur, the possibility of pregnancy must be considered. If the patient has not adhered to the prescribed schedule (if she missed one or more tablets or started taking them on a day later than she should have), consider the probability of pregnancy at the time of the first missed period and take appropriate diagnostic measures. If the patient has adhered to the prescribed regimen and misses two consecutive periods, rule out pregnancy. For additional patient instructions regarding missed tablets, see the WHAT TO DO IF YOU MISS PILLS section in FDA-Approved Patient Labeling below. Advice in Case of Gastrointestinal Disturbances In case of severe vomiting or diarrhea, absorption may not be complete and additional contraceptive measures should be taken. If vomiting or diarrhea occurs within 3 to 4 hours after taking an active tablet, handle this as a missed tablet [see FDA-Approved Patient Labeling] .

Low-Ogestrel 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 coagulopathies 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 Headaches with focal neurological symptoms or migraine headaches with aura Women over age 35 with any migraine headaches Liver tumors, benign or malignant, or liver disease Undiagnosed abnormal uterine bleeding Pregnancy, because there is no reason to use COCs during pregnancy Current diagnosis of, or history of, breast cancer, which may be hormone-sensitive Hypersensitivity to any of the components of Low-Ogestrel Women who are receiving Hepatitis C drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir, due to the potential for ALT Elevations (see Warnings, Risk of liver enzyme elevations with concomitant hepatitis c treatment ).

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 infertility after discontinuation of treatment, Changes in libido, Vaginitis, including candidiasis; Breast secretion Skin and Subcutaneous Tissue Disorders: Melasma/chloasma, which may persist; Erythema multiforme, Erythema nodosum, Hemorrhagic eruption, Hirsutism Vascular Events: Venous thrombosis, Pulmonary embolism, Cerebral thrombosis, Mesenteric thrombosis, Retinal vascular thrombosis Figure 1

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.

Store at 20°C to 25°C (68°F to 77°F) [See USP controlled room temperature].