Afirmelle Drug Information

To achieve maximum contraceptive effectiveness, Afirmelle TM (levonorgestrel and ethinyl estradiol tablets) must be taken exactly as directed and at intervals not exceeding 24 hours. The dosage of Afirmelle is one white tablet daily for 21 consecutive days, followed by one green inert tablet daily for 7 consecutive days, according to prescribed schedule. It is recommended that Afirmelle tablets be taken at the same time each day.

The blister pack should be kept in the pouch supplied to avoid possible fading of the pills. If the pills fade, patients should continue to take them as directed. During The First Cycle of Use The possibility of ovulation and conception prior to initiation of medication should be considered.

The patient should be instructed to begin taking Afirmelle on either the first Sunday after the onset of menstruation (Sunday Start) or on Day 1 of menstruation (Day 1 Start). Sunday Start The patient is instructed to begin taking Afirmelle on the first Sunday after the onset of menstruation. If menstruation begins on a Sunday, the first tablet (white) is taken that day. One white tablet should be taken daily for 21 consecutive days, followed by one green inert tablet daily for 7 consecutive days.

Withdrawal bleeding should 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, contraceptive reliance should not be placed on Afirmelle until a white tablet has been taken daily for 7 consecutive days, and a nonhormonal back-up method of birth control should be used during those 7 days. Day 1 Start During the first cycle of medication, the patient is instructed to begin taking Afirmelle during the first 24 hours of her period (day one of her menstrual cycle). One white tablet should be taken daily for 21 consecutive days, followed by one green inert tablet daily for 7 consecutive days.

Withdrawal bleeding should usually occur within 3 days following discontinuation of white tablets and may not have finished before the next pack is started. If medication is begun on day one of the menstrual cycle, no back-up contraception is necessary. If Afirmelle tablets are started later than day one of the first menstrual cycle or postpartum, contraceptive reliance should not be placed on Afirmelle tablets until after the first 7 consecutive days of administration, and a nonhormonal back-up method of birth control should be used during those 7 days.

After the First Cycle of Use The patient begins her next and all subsequent courses of tablets on the day after taking her last green tablet. She should follow the same dosing schedule: 21 days on white tablets followed by 7 days on green tablets. If in any cycle the patient starts tablets later than the proper day, she should protect herself against pregnancy by using a nonhormonal 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, she should wait 7 days after her last tablet before she starts Afirmelle. She will probably experience withdrawal bleeding during that week. She should be sure that no more than 7 days pass after her previous 21-day regimen.

When the patient is switching from a 28-day regimen of tablets, she should start her first pack of Afirmelle 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 Afirmelle the next day.

If switching from an implant or injection, the patient should start Afirmelle on the day of implant removal or, if using an injection, the day the next injection would be due. In switching from a progestin-only pill, injection, or implant, the patient should be advised to use a nonhormonal back-up method of birth control for the first 7 days of tablet-taking. If Spotting or Breakthrough Bleeding Occurs If spotting or breakthrough bleeding occur, the patient is instructed to continue on the same regimen.

This type of bleeding is usually transient and without significance; however, if the bleeding is persistent or prolonged, the patient is advised to consult her physician. Risk of Pregnancy if Tablets are Missed While there is little likelihood of ovulation occurring if only one or two white tablets are missed, the possibility of ovulation increases with each successive day that scheduled white tablets are missed. Although the occurrence of pregnancy is unlikely if Afirmelle is taken according to directions, if withdrawal bleeding does not occur, the possibility of pregnancy must be considered.

If the patient has not adhered to the prescribed schedule (missed one or more tablets or started taking them on a day later than she should have), the probability of pregnancy should be considered at the time of the first missed period and appropriate diagnostic measures taken. If the patient has adhered to the prescribed regimen and misses two consecutive periods, pregnancy should be ruled out. The risk of pregnancy increases with each active (white) tablet missed.

For additional patient instructions regarding missed tablets, see the WHAT TO DO IF YOU MISS PILLS section in the DETAILED PATIENT LABELING below. Use after Pregnancy, Abortion or Miscarriage Afirmelle may be initiated 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). The patient should be advised to use a nonhormonal back-up method for the first 7 days of tablet taking. Afirmelle may be initiated immediately after a first trimester abortion or miscarriage.

If the patient starts Afirmelle immediately, back-up contraception is not needed.

An increased risk of the following serious adverse reactions (see WARNINGS section for additional information) has been associated with the use of oral contraceptives: Thromboembolic and thrombotic disorders and other vascular problems (including thrombophlebitis and venous thrombosis with or without pulmonary embolism, mesenteric thrombosis, arterial thromboembolism, myocardial infarction, cerebral hemorrhage, cerebral thrombosis), carcinoma of the reproductive organs and breasts, hepatic neoplasia (including hepatic adenomas or benign liver tumors), ocular lesions (including retinal vascular thrombosis), gallbladder disease, carbohydrate and lipid effects, elevated blood pressure, and headache including migraine. The following adverse reactions have been reported in patients receiving oral contraceptives and are believed to be drug related (alphabetically listed): Acne Amenorrhea Anaphylactic/anaphylactoid reactions, including urticaria, angioedema, and severe reactions with respiratory and circulatory symptoms. Breast changes: tenderness, pain, enlargement, secretion Budd-Chiari syndrome Cervical erosion and secretion, change in Cholestatic jaundice Chorea, exacerbation of Colitis Contact lenses, intolerance to Corneal curvature (steepening), change in Dizziness Edema/fluid retention Erythema multiforme Erythema nodosum Gastrointestinal symptoms (such as abdominal pain, cramps, and bloating) Hirsutism Infertility after discontinuation of treatment, temporary Lactation, diminution in, when given immediately postpartum Libido, change in Melasma/chloasma which may persist Menstrual flow, change in Mood changes, including depression Nausea Nervousness Pancreatitis Porphyria, exacerbation of Rash (allergic) Scalp hair, loss of Serum folate levels, decrease in Spotting Systemic lupus erythematosus, exacerbation of Unscheduled bleeding Vaginitis, including candidiasis Varicose veins, aggravation of Vomiting Weight or appetite (increase or decrease), change in The following adverse reactions have been reported in users of oral contraceptives: Cataracts Cystitis-like syndrome Dysmenorrhea Hemolytic uremic syndrome Hemorrhagic eruption Optic neuritis, which may lead to partial or complete loss of vision Premenstrual syndrome Renal function, impaired Post Marketing 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 to 1.12 (Figure III). Three studies compared breast cancer risk between current or recent COC users (<6 months since last use) and never users of COCs (Figure III). 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 to 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 to 10 years of COC use. Figure III: 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.

Figure III: Risk of Breast Cancer with Combined Oral Contraceptive Use

9. Drug Interactions Changes in Contraceptive Effectiveness Associated with Coadministration of Other Products: Contraceptive effectiveness may be reduced when hormonal contraceptives are coadministered with antibiotics, anticonvulsants, and other drugs that increase the metabolism of contraceptive steroids. This could result in unintended pregnancy or breakthrough bleeding. Examples include rifampin, rifabutin, barbiturates, primidone, phenylbutazone, phenytoin, dexamethasone, carbamazepine, felbamate, oxcarbazepine, topiramate, griseofulvin, and modafinil.

In such cases a back-up nonhormonal method of birth control should be considered. Several cases of contraceptive failure and breakthrough bleeding have been reported in the literature with concomitant administration of antibiotics such as ampicillin and other penicillins, and tetracyclines. However, clinical pharmacology studies investigating drug interactions between combined oral contraceptives and these antibiotics have reported inconsistent results.

Several of the anti-HIV protease inhibitors have been studied with co-administration of oral combination hormonal contraceptives; significant changes (increase and decrease) in the plasma levels of the estrogen and progestin have been noted in some cases. The safety and efficacy of oral contraceptive products may be affected with coadministration of anti-HIV protease inhibitors. Healthcare providers should refer to the label of the individual anti-HIV protease inhibitors for further drug-drug interaction information.

Herbal products containing St. John’s Wort ( Hypericum perforatum ) may induce hepatic enzymes (cytochrome P 450) and p-glycoprotein transporter and may reduce the effectiveness of contraceptive steroids. This may also result in breakthrough bleeding.

Increase in Plasma Levels Associated with Co-Administered Drugs Co-administration of atorvastatin and certain oral contraceptives containing ethinyl estradiol increases AUC values for ethinyl estradiol by approximately 20%. Ascorbic acid and acetaminophen increase the bioavailability of ethinyl estradiol since these drugs act as competitive inhibitors for sulfation of ethinyl estradiol in the gastrointestinal wall, a known pathway of elimination for ethinyl estradiol. CYP 3A4 inhibitors such as indinavir, itraconazole, ketoconazole, fluconazole, and troleandomycin may increase plasma hormone levels. Troleandomycin may also increase the risk of intrahepatic cholestasis during coadministration with combination oral contraceptives.

Changes in Plasma Levels of Co-Administered Drugs Combination hormonal contraceptives containing some synthetic estrogens (e.g., ethinyl estradiol) may inhibit the metabolism of other compounds. Increased plasma concentrations of cyclosporine, prednisolone and other corticosteroids, and theophylline have been reported with concomitant administration of oral contraceptives. Decreased plasma concentrations of acetaminophen and increased clearance of temazepam, salicylic acid, morphine, and clofibric acid, due to induction of conjugation (particularly glucuronidation), have been noted when these drugs were administered with oral contraceptives.

The prescribing information of concomitant medications should be consulted to identify potential interactions. Concomitant Use with HCV Combination Therapy – Liver Enzyme Elevation Do not co-administer Afirmelle 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 ).

12. Pregnancy Pregnancy Category X. See CONTRAINDICATIONS and WARNINGS sections.

14. Pediatric Use Safety and efficacy of Afirmelle tablets have been established in women of reproductive age. Safety and efficacy are expected to be the same for postpubertal adolescents under the age of 16 and for users 16 years and older. Use of Afirmelle before menarche is not indicated.

Afirmelle is contraindicated in females who are known to have or develop the following conditions: Thrombophlebitis or thromboembolic disorders A history of deep-vein thrombophlebitis or thromboembolic disorders Cerebrovascular or coronary artery disease (current or past history) Valvular heart disease with thrombogenic complications Thrombogenic rhythm disorders Hereditary or acquired thrombophilias Major surgery with prolonged immobilization Diabetes with vascular involvement Headaches with focal neurological symptoms Uncontrolled hypertension Current diagnosis of, or history of, breast cancer, which may be hormone-sensitive Carcinoma of the endometrium or other known or suspected estrogen-dependent neoplasia Undiagnosed abnormal genital bleeding Cholestatic jaundice of pregnancy or jaundice with prior pill use Hepatic adenomas or carcinomas, or active liver disease Known or suspected pregnancy Hypersensitivity to any of the components of Afirmelle 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 ).

Symptoms of oral contraceptive overdosage in adults and children may include nausea, vomiting, and drowsiness/fatigue; withdrawal bleeding may occur in females. There is no specific antidote and further treatment of overdose, if necessary, is directed to the symptoms. NONCONTRACEPTIVE HEALTH BENEFITS The following noncontraceptive health benefits related to the use of oral contraceptives are supported by epidemiological studies which largely utilized oral-contraceptive formulations containing doses exceeding 0.035 mg of ethinyl estradiol or 0.05 mg of mestranol.

Effects on menses: Increased menstrual cycle regularity Decreased blood loss and decreased incidence of iron-deficiency anemia Decreased incidence of dysmenorrhea Effects related to inhibition of ovulation: Decreased incidence of functional ovarian cysts Decreased incidence of ectopic pregnancies Effects from long-term use: Decreased incidence of fibroadenomas and fibrocystic disease of the breast Decreased incidence of acute pelvic inflammatory disease Decreased incidence of endometrial cancer Decreased incidence of ovarian cancer