FDA

Quartette

Approved 28 Mar 2013OralTablet

Indications

RIVELSA ® is indicated for use by females of reproductive age to prevent pregnancy. RIVELSA is a combination of levonorgestrel, a progestin, and ethinyl estradiol, an estrogen, indicated for use by females of reproductive potential to prevent pregnancy. ( 1 )

Contraindications

RIVELSA 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 females who are known to: Smoke, if over age 35 [see Boxed Warning and Warnings and Precautions ( 5.1 )]. Have current or history of deep vein thrombosis or pulmonary embolism [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 or hypertension with vascular disease [see Warnings and Precautions ( 5.5 )].

Have diabetes mellitus and are over age 35, diabetes mellitus with hypertension or with vascular disease or other end-organ damage, or diabetes mellitus of > 20 years duration [see Warnings and Precautions ( 5.7 )]. Have headaches with focal neurological symptoms, migraine headaches with aura, or over age 35 with any migraine headaches [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 )] .

Liver tumors, acute viral hepatitis, or severe (decompensated) cirrhosis [see Warnings and Precautions ( 5.2 ) and Use in Specific Populations ( 8.6 )]. Undiagnosed abnormal uterine bleeding [see Warnings and Precautions ( 5.9 )]. 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 uterine bleeding ( 4 ) Breast cancer ( 4 ) Liver tumors or liver disease ( 4 ) Co-administration with Hepatitis C drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir ( 4 )

Warnings and precautions

Vascular risks: Stop if a thrombotic or thromboembolic event occurs. Stop at least 4 weeks before and through 2 weeks after major surgery. Start no earlier than 4 weeks after delivery, in women who are not breastfeeding. Consider cardiovascular risk factors before initiating in all females, particularly those over 35 years. ( 5.1 , 5.5 ) Liver disease: Discontinue if jaundice occurs. ( 5.2 ) Hypertension: If used in females with well-controlled hypertension, monitor blood pressure and stop use if blood pressure rises significantly.

At a glance

Brand name: Quartette
Active substance: ethinyl estradiol
Route: Oral
Dosage form: Tablet
Applicant: Teva Branded Pharm
Status: Prescription
FDA approval: 28 Mar 2013
Application: NDA204061-001

Contraindications

Warnings and precautions

Interactions

The sections below provide information on substances for which data on drug interactions with COCs are available. There is little information available about the clinical effect of most drug interactions that may affect COCs. However, based on the known pharmacokinetic effects of these drugs, clinical strategies to minimize any potential adverse effect on contraceptive effectiveness or safety are suggested. Consult the approved product labeling of all concurrently used drugs to obtain further information about interactions with COCs or the potential for metabolic enzyme or transporter system alterations.

No drug-drug interaction studies were conducted with RIVELSA. Enzyme inducers (e.g., CYP3A4): May decrease the effectiveness of RIVELSA or increase breakthrough bleeding. Counsel patients to use a backup or alternative method of contraception when enzyme inducers are used with RIVELSA. ( 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: Table 3 includes substances that demonstrated an important drug interaction with RIVELSA. Table 3: Significant Drug Interactions Involving Substances That Affect COCs Metabolic Enzyme Inducers Clinical effect Concomitant use of COCs with metabolic enzyme inducers may decrease the plasma concentrations of the estrogen and/or progestin component of COCs.

Decreased exposure of the estrogen and/or progestin component of COCs may potentially diminish the effectiveness of COCs and may lead to contraceptive failure or an increase in breakthrough bleeding. Prevention or management Counsel females to use an alternative method of contraception or a backup method when enzyme inducers are used with COCs. Continue backup contraception for 28 days after discontinuing the enzyme inducer to maintain contraceptive reliability.

Examples Aprepitant, barbiturates, bosentan, carbamazepine, efavirenz, felbamate, griseofulvin, oxcarbazepine, phenytoin, rifampin, rifabutin, rufinamide, topiramate, products containing St. John’s wort a , and certain protease inhibitors (see separate section on protease inhibitors below). Colesevelam Clinical effect Concomitant use of COCs with colesevelam significantly decreases systemic exposure of ethinyl estradiol.

Decreased exposure of the estrogen component of COCs may potentially reduce contraceptive efficacy or result in an increase in breakthrough bleeding, depending on the strength of ethinyl estradiol in the COC. Prevention or management Administer 4 or more hours apart to attenuate this drug interaction. a Induction potency of St. John’s wort may vary widely based on preparation. Substances increasing the systemic exposure of COCs: Co-administration of atorvastatin or rosuvastatin and COCs containing ethinyl estradiol increase systemic exposure of ethinyl estradiol by approximately 20 to 25 percent.

Ascorbic acid and acetaminophen may increase systemic exposure of ethinyl estradiol, possibly by inhibition of conjugation. CYP3A4 inhibitors such as itraconazole, voriconazole, fluconazole, grapefruit juice, or ketoconazole may increase systemic exposure of the estrogen and/or progestin component of COCs. Human immunodeficiency virus (HIV)/hepatitis C virus (HCV) protease inhibitors and non-nucleoside reverse transcriptase inhibitors: Significant decreases in systemic exposure of the estrogen and/or progestin have been noted when COCs are co-administered with some HIV protease inhibitors (e.g., nelfinavir, ritonavir, darunavir/ritonavir, (fos)amprenavir/ritonavir, lopinavir/ritonavir, and tipranavir/ritonavir), some HCV protease inhibitors (e.g., boceprevir and telaprevir), and some non-nucleoside reverse transcriptase inhibitors (e.g., nevirapine).

In contrast, significant increases in systemic exposure of the estrogen and/or progestin have been noted when COCs are co-administered with certain other HIV protease inhibitors (e.g., indinavir and atazanavir/ritonavir) and with other non-nucleoside reverse transcriptase inhibitors (e.g., etravirine).

7.2Effects of Combined Oral Contraceptives on Other Drugs Table

4 provides significant drug interaction information for drugs co-administered with RIVELSA. Table 4: Significant Drug Interaction Information for Drugs Co-Administered With COCs Lamotrigine Clinical effect Concomitant use of COCs with lamotrigine may significantly decrease systemic exposure of lamotrigine due to induction of lamotrigine glucuronidation. Decreased systemic exposure of lamotrigine may reduce seizure control.

Prevention or management Dose adjustment may be necessary. Consult the approved product labeling for lamotrigine. Thyroid Hormone Replacement Therapy or Corticosteroid Replacement Therapy Clinical effect Concomitant use of COCs with thyroid hormone replacement therapy or corticosteroid replacement therapy may increase systemic exposure of thyroid-binding and cortisol-binding globulin [see Warnings and Precautions ( 5.12 )] .

Prevention or management The dose of replacement thyroid hormone or cortisol therapy may need to be increased. Consult the approved product labeling for the therapy in use [see Warnings and Precautions ( 5.12 )] . Other Drugs Clinical effect Concomitant use of COCs may decrease systemic exposure of acetaminophen, morphine, salicylic acid, and temazepam. Concomitant use with ethinyl estradiol-containing COCs may increase systemic exposure of other drugs (e.g., cyclosporine, prednisolone, theophylline, tizanidine, and voriconazole).

Prevention or management The dosage of drugs that can be affected by this interaction may need to be increased. Consult the approved product labeling for the concomitantly used drug.

7.3Concomitant Use with Hepatitis C Virus (HCV) Combination

Therapy – Liver Enzyme Elevation Do not co-administer RIVELSA with HCV drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir [see Warnings and Precautions ( 5.4 )] , and glecaprevir/pibrentasvir due to potential for ALT elevations .

7.4Effect on Laboratory Tests

The use of COCs may influence the results of certain laboratory tests, such as coagulation factors, lipids, glucose tolerance, and binding proteins.

Our copy of this section ends here. The full text is in the official label at the FDA. Open Drugs@FDA

Adverse reactions

The following serious adverse reactions with the use of COCs are discussed elsewhere in the labeling: Serious cardiovascular events [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 )] The most common adverse reactions (≥2%) in clinical trials for RIVELSA were headaches, heavy/irregular vaginal bleeding, nausea/vomiting, acne, dysmenorrhea, weight increased, mood changes, anxiety/panic attack, breast pain and migraines.

( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Teva Pharmaceuticals at 1-888-483-8279 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 data described below are from a 12-month, US, open-label study, which enrolled women aged 18-40, of whom 3,597 took at least one dose of RIVELSA (2,661 woman-years of exposure) [see Clinical Studies ( 14 )] .

Adverse Reactions Leading to Study Discontinuation : 13.3% 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 heavy/irregular bleeding (5.0%), mood swings/alteration/affect lability (1.4%), headaches/migraines (1.3%), weight increased (1.3%) and acne (1.0%). Common Adverse Reactions (≥2% of women) : headaches (12.2%), heavy/irregular vaginal bleeding (9.7%), nausea/vomiting (8.8%), acne (5.4%), dysmenorrhea (5.4%), weight increased (4.6%), mood changes (depression, depressed mood, crying, major depression, affective disorder, depression suicidal, dysthymic disorder) (2.9%), anxiety/panic attack (2.4%), breast tenderness/pain/discomfort (2.2%), migraine (2.0%).

Serious Adverse Reactions (≥2 women): abortion spontaneous, suicide attempt, cholecystitis/cholelithiasis, deep vein thrombosis, ectopic pregnancy.

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 3). Three studies compared breast cancer risk between current or recent COC users (<6 months since last use) and never users of COCs (Figure 2). 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 3: 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 extended-cycle COCs containing levonorgestrel and ethinyl estradiol. 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. 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 Figure Breast cancer data

Quartette

Indications

Contraindications

Warnings and precautions

At a glance

Two medicines in one question?

Quartette

Indications

Contraindications

Warnings and precautions

At a glance

Two medicines in one question?

5.1Thromboembolic Disorders and Other Vascular Conditions Stop

5.2Liver Disease Elevated Liver Enzymes

5.3Hypertension

5.4Risk of Liver Enzyme Elevations with Concomitant Hepatitis C Treatment

5.5Age-related Considerations

5.6Gallbladder Disease

5.7Adverse Carbohydrate and Lipid Metabolic Effects Hyperglycemia

Interactions

7.2Effects of Combined Oral Contraceptives on Other Drugs Table

7.3Concomitant Use with Hepatitis C Virus (HCV) Combination

7.4Effect on Laboratory Tests

Pregnancy and breastfeeding

8.1Pregnancy Risk Summary

Adverse reactions

6.1Clinical Trial Experience

6.2Postmarketing Experience

Composition

Official product information