Data from FDA - Curated by EPG Health - Last updated 01 September 2017

Indication(s)

1. INDICATIONS AND USAGE Simpesse TM (levonorgestrel and ethinyl estradiol tablets USP and ethinyl estradiol tablets USP) is indicated for use by women to prevent pregnancy. Simpesse is an estrogen/progestin COC indicated for use by women to prevent pregnancy. (1)

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Advisory information

contraindications
4. CONTRAINDICATIONS Do not prescribe Simpesse to women who are known to have the following: 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 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 inherited or acquired hypercoagulopathies [see Warnings and Precautions (5.1)]. - Have uncontrolled hypertension [see Warnings and Precautions (5.5)]. - Have diabetes with vascular disease [see Warnings and Precautions (5.7)]. - Have headaches with focal neurological symptoms or have migraine headaches with or without aura if over age 35 [see Warnings and Precautions (5.8)]. Undiagnosed abnormal genital bleeding [see Warnings and Precautions (5.9)]. Breast cancer or other estrogen- or progestin-sensitive cancer, now or in the past [see Warnings and Precautions (5.2)]. Liver tumors, benign or malignant, or liver disease [see Warnings and Precautions (5.3) and Use in Specific Populations (8.6)]. Pregnancy, because there is no reason to use COCs during pregnancy [see Warnings and Precautions (5.10) and Use in Specific Populations (8.1)]. 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 (5.4)]. A high risk of arterial or venous thrombotic diseases (4) Undiagnosed abnormal genital bleeding (4) Breast cancer or other estrogen- or progestin-sensitive cancer (4) Liver tumors or liver disease (4) Pregnancy (4) Co-administration with Hepatitis C drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir (4)
Adverse reactions
6. ADVERSE REACTIONS The following serious adverse reactions with the use of COCs are discussed elsewhere in the labeling: Serious cardiovascular events and smoking [see Boxed Warning and Warnings and Precautions (5.1)] Vascular events [see Warnings and Precautions (5.1)] Liver disease [see Warnings and Precautions (5.3)] Adverse reactions commonly reported by COC users are: Irregular uterine bleeding Nausea Breast tenderness Headache The most common adverse reactions (≥5%) in clinical trials for Simpesse are irregular and/or heavy uterine bleeding, weight gain, and acne. (6) To report SUSPECTED ADVERSE REACTIONS, contact Aurobindo Pharma USA, Inc. at 1-866-850-2876 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 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 clinical trial that evaluated the safety and efficacy of Simpesse was a 12-month, randomized, multicenter, open-label study, which enrolled women aged 18 to 40, of whom 1,006 took at least one dose of Simpesse. Adverse Reactions Leading to Study Discontinuation: 16.3% of the women discontinued from the clinical trial due to an adverse reaction; the most common adverse reactions (≥ 1% of women) leading to discontinuation were irregular and/or heavy uterine bleeding (5.9%), weight gain (2.4%), mood changes (1.5%), and acne (1%). Common Treatment-Emergent Adverse Reactions (≥ 5% of women): irregular and/or heavy uterine bleeding (17%), weight gain (5%), acne (5%). Serious Adverse Reactions: migraine, cholecystitis, cholelithiasis, pancreatitis, abdominal pain, and major depressive disorder. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of Simpesse. Because these reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency of 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 disorders: hypersensitivity reaction 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 Respiratory, thoracic and mediastinal disorders: pulmonary embolism, pulmonary thrombosis Skin and subcutaneous tissue disorders: alopecia Vascular disorders: thrombosis

Usage information

Dosing and administration
2. DOSAGE AND ADMINISTRATION Take one tablet by mouth at the same time every day. The dosage of Simpesse is one white tablet containing levonorgestrel and ethinyl estradiol daily for 84 consecutive days, followed by one light blue ethinyl estradiol tablet for 7 days. To achieve maximum contraceptive effectiveness, Simpesse must be taken exactly as directed and at intervals not exceeding 24 hours. Instruct the patient to begin taking Simpesse on the first Sunday after the onset of menstruation. If menstruation begins on a Sunday, the first white tablet is taken that day. One white tablet should be taken daily for 84 consecutive days, followed by one light blue tablet for 7 consecutive days. A non-hormonal back-up method of contraception (such as condoms or spermicide) should be used until a white tablet has been taken daily for 7 consecutive days. A scheduled period should occur during the 7 days that the light blue tablets are taken. Begin the next and all subsequent 91-day cycles without interruption on the same day of the week (Sunday) on which the patient began her first dose of Simpesse, following the same schedule: 84 days taking a white tablet followed by 7 days taking a light blue tablet. If the patient does not immediately start her next pill pack, she should protect herself from pregnancy by using a non-hormonal back-up method of contraception until she has taken a white tablet daily for 7 consecutive days. If unscheduled spotting or bleeding occurs, instruct the patient to continue on the same regimen. If the bleeding is persistent or prolonged, advise the patient to consult her healthcare provider. For patient instructions regarding missed pills, see FDA-Approved Patient Labeling . For postpartum women who are not breastfeeding, start Simpesse no earlier than four to six weeks postpartum due to increased risk of thromboembolism. If the patient starts on Simpesse postpartum and has not yet had a period, evaluate for possible pregnancy, and instruct her to use an additional method of contraception until she has taken a white tablet for 7 consecutive days. Take one tablet daily by mouth at the same time every day for 91 days. (2)
Use in special populations
8. USE IN SPECIFIC POPULATIONS Nursing Mothers: Not recommended for nursing mothers; can decrease milk production. (8.3) 8.1. Pregnancy There is little or no increased risk of birth defects in women who inadvertently use COCs during early pregnancy. Epidemiologic studies and meta-analyses have not found an increased risk of genital or non-genital birth defects (including cardiac anomalies and limb-reduction defects) following exposure to low dose COCs prior to conception or during early pregnancy. The administration of COCs to induce withdrawal bleeding should not be used as a test for pregnancy. COCs should not be used during pregnancy to treat threatened or habitual abortion. Women who do not breastfeed may start COCs no earlier than four to six weeks postpartum. 8.3. Nursing Mothers When possible, advise the nursing mother to use other forms of contraception until she has weaned her child. Estrogen-containing COCs can reduce milk production in breastfeeding mothers. This is less likely to occur once breastfeeding is well established; however, it can occur at any time in some women. Small amounts of oral contraceptive steroids and/or metabolites are present in breast milk. 8.4. Pediatric Use Safety and efficacy of Simpesse have been established in women of reproductive age. Safety and efficacy are expected to be the same for postpubertal adolescents under the age of 18 as for users 18 years and older. Use of Simpesse before menarche is not indicated. 8.5. Geriatric Use Simpesse has not been studied in women who have reached menopause and is not indicated in this population. 8.6. Hepatic Impairment No studies have been conducted to evaluate the effect of hepatic disease on the disposition of Simpesse. However, steroid hormones may be poorly metabolized in patients with impaired liver function. Acute or chronic disturbances of liver function may necessitate the discontinuation of COC use until markers of liver function return to normal. [See Contraindications (4) and Warnings and Precautions (5.3)]. 8.7. Renal Impairment No studies have been conducted to evaluate the effect of renal disease on the disposition of Simpesse.
Pregnancy and lactation
8.3. Nursing Mothers When possible, advise the nursing mother to use other forms of contraception until she has weaned her child. Estrogen-containing COCs can reduce milk production in breastfeeding mothers. This is less likely to occur once breastfeeding is well established; however, it can occur at any time in some women. Small amounts of oral contraceptive steroids and/or metabolites are present in breast milk.

Interactions

7. DRUG INTERACTIONS No drug-drug interaction studies were conducted with Simpesse. Drugs or herbal products that induce certain enzymes, including 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 Changes in Contraceptive Effectiveness Associated with Co-Administration of Other Products If a woman on hormonal contraceptives takes a drug or herbal product that induces enzymes, including CYP3A4, that metabolize contraceptive hormones, counsel her to use additional contraception or a different method of contraception. Drugs or herbal products that induce such enzymes may decrease the plasma concentrations of contraceptive hormones, and may decrease the effectiveness of hormonal contraceptives or increase breakthrough bleeding. Some drugs or herbal products that may decrease the effectiveness of hormonal contraceptives include: barbiturates bosentan carbamazepine felbamate griseofulvin oxcarbazepine phenytoin rifampin St. John’s wort topiramate HIV protease inhibitors and non-nucleoside reverse transcriptase inhibitors: Significant changes (increase or decrease) in the plasma levels of the estrogen and progestin have been noted in some cases of co-administration of HIV protease inhibitors or with non-nucleoside reverse transcriptase inhibitors. Antibiotics: There have been reports of pregnancy while taking hormonal contraceptives and antibiotics, but clinical pharmacokinetic studies have not shown consistent effects of antibiotics on plasma concentrations of synthetic steroids. Consult the labeling of all concurrently-used drugs to obtain further information about interactions with hormonal contraceptives or the potential for enzyme alterations. 7.2 Increase in Plasma Levels of Estradiol Associated with Co-Administered Drugs Co-administration of atorvastatin and certain COCs containing ethinyl estradiol increase AUC values for ethinyl estradiol by approximately 20%. Ascorbic acid and acetaminophen may increase plasma ethinyl estradiol levels, possibly by inhibition of conjugation. CYP3A4 inhibitors such as itraconazole or ketoconazole may increase plasma hormone levels. 7.3 Concomitant Use with Hepatitis C Vaccine (HCV) Combination Therapy – Liver Enzyme Elevation Do not co-administer Simpesse with HCV drug combinations containing ombitasvir /paritaprevir/ritonavir, with or without dasabuvir, due to potential for ALT elevations [see Warnings and Precautions (5.4)]. 7.4 Changes in Plasma Levels of Co-Administered Drugs COCs containing some synthetic estrogens (e.g., ethinyl estradiol) may inhibit the metabolism of other compounds. COCs have been shown to significantly decrease plasma concentrations of lamotrigine likely due to induction of lamotrigine glucuronidation. This may reduce seizure control; therefore, dosage adjustments of lamotrigine may be necessary. Consult the labeling of the concurrently-used drug to obtain further information about interactions with COCs or the potential for enzyme alterations.

More information

Category Value
Authorisation number ANDA206851
Orphan designation No
Product NDC 65862-864
Date Last Revised 16-08-2017
Type HUMAN PRESCRIPTION DRUG
Marketing authorisation holder Aurobindo Pharma Limited
Warnings WARNING: CIGARETTE SMOKING AND SERIOUS CARDIOVASCULAR EVENTS Cigarette smoking increases the risk of serious cardiovascular events from combination oral contraceptives (COC) use. This risk increases with age, particularly in women over 35 years of age, and with the number of cigarettes smoked. For this reason, COCs should not be used by women who are over 35 years of age and smoke. [See Contraindications (4) .] WARNING: CIGARETTE SMOKING AND SERIOUS CARDIOVASCULAR EVENTS See full prescribing information for complete boxed warning. Women who are over 35 years old and smoke should not use Simpesse. Cigarette smoking increases the risk of serious cardiovascular events from combination oral contraceptive (COC) use.