VIORELE (Page 5 of 11)

4. Liver function

If jaundice develops in any woman receiving such drugs, the medication should be discontinued. Steroid hormones may be poorly metabolized in patients with impaired liver function.

5. Fluid retention

Oral contraceptives may cause some degree of fluid retention. They should be prescribed with caution, and only with careful monitoring, in patients with conditions which might be aggravated by fluid retention.

6. Contact lenses

Contact lens wearers who develop visual changes or changes in lens tolerance should be assessed by an ophthalmologist.

7. Drug interactions

Reduced efficacy and increased incidence of breakthrough bleeding and menstrual irregularities have been associated with concomitant use of rifampin. A similar association, though less marked, has been suggested with barbiturates, phenylbutazone, phenytoin sodium, carbamazepine and possibly with griseofulvin, ampicillin, and tetracyclines (72).

Combined hormonal contraceptives have been shown to significantly decrease plasma concentrations of lamotrigine when co-administered, likely due to induction of lamotrigine glucuronidation. This may reduce seizure control; therefore, dosage adjustments of lamotrigine may be necessary.

Concomitant Use with Hepatitis C Virus (HCV) Combination Therapy — Liver Enzyme Elevation

Co-administration of VIORELE^® with HCV drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir is contraindicated, due to potential for ALT elevations (see WARNINGS, RISK OF LIVER ENZYME ELEVATIONS WITH CONCOMITANT HEPATITIS C TREATMENT). Co-administration of VIORELE^® and glecaprevir/pibrentasvir is not recommended due to potential for ALT elevations.

Consult the labeling of the concurrently-used drug to obtain further information about interactions with hormonal contraceptives or the potential for enzyme alterations.

8. Interactions with laboratory tests

Certain endocrine and liver function tests and blood components may be affected by oral contraceptives:

a.

Increased prothrombin and factors VII, VIII, IX and X; decreased antithrombin 3; increased norepinephrine-induced platelet aggregability.

b.

Increased thyroid binding globulin (TBG) leading to increased circulating total thyroid hormone, as measured by protein-bound iodine (PBI), T4 by column or by radioimmunoassay. Free T3 resin uptake is decreased, reflecting the elevated TBG; free T4 concentration is unaltered.

c.

Other binding proteins may be elevated in serum.

d.

Sex hormone-binding globulins are increased and result in elevated levels of total circulating sex steroids; however, free or biologically active levels either decrease or remain unchanged.

e.

High-density lipoprotein cholesterol (HDL-C) and triglycerides may be increased, while low-density lipoprotein cholesterol (LDL-C) and total cholesterol (Total-C) may be decreased or unchanged.

f.

Glucose tolerance may be decreased.

g.

Serum folate levels may be depressed by oral contraceptive therapy. This may be of clinical significance if a woman becomes pregnant shortly after discontinuing oral contraceptives.

9. Carcinogenesis

See WARNINGS section.

10. Pregnancy

Discontinue VIORELE if pregnancy occurs because there is no reason to use COCs in pregnancy. See WARNINGSsection.

11. Lactation

Small amounts of oral contraceptive steroids have been identified in human milk, and a few adverse effects on the child have been reported, including jaundice and breast enlargement. In addition, oral contraceptives given in the postpartum period may interfere with lactation by decreasing the quantity and quality of breast milk. If possible, the nursing mother should be advised not to use oral contraceptives but to use other forms of contraception until she has completely weaned her child.

12. Pediatric use

Safety and efficacy of VIORELE^® has been established in women of reproductive age. Safety and efficacy are expected to be the same for post-pubertal adolescents under the age of 16 and for users 16 years and older. Use of this product before menarche is not indicated.

PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (PATIENT PACKAGE INSERT BRIEF SUMMARY and DETAILED PATIENT PACKAGE INSERT).

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Counsel patients that cigarette smoking increases the risk of serious cardiovascular events from COC use, and that women who are over 35 years old and smoke should not use COCs (see BOXED WARNING and CONTRAINDICATIONS).

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Counsel patients that the increased risk of venous thromboembolism compared to nonusers of CHCs is greatest after initially starting a CHC or restarting (following a 4-week or greater interruption in intake) the same or a different CHC (see WARNINGS).

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Counsel patients that this product does not protect against HIV-infection (AIDS) and other sexually transmitted infections.

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Counsel patients to take one tablet daily by mouth at the same time every day. Instruct patients what to do in the event pills are missed (see DOSAGE AND ADMINISTRATION).

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Counsel patients to use a back-up or alternative method of contraception when enzyme inducers are used with COCs (see PRECAUTIONS).

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Counsel patients who are breastfeeding or who desire to breastfeed that COCs may reduce breast milk production. This is less likely to occur if breastfeeding is well established (see PRECAUTIONS).

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Counsel any patient who starts VIORELE postpartum, and who has not yet had a period, to use an additional method of contraception until she has taken a light-orange tablet for 7 consecutive days (see DOSAGE AND ADMINISTRATION).

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Counsel patients that amenorrhea may occur. Pregnancy should be considered in the event of amenorrhea, and should be ruled out if amenorrhea is associated with symptoms of pregnancy, such as morning sickness or unusual breast tenderness (see WARNINGS).

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Counsel patients with a history of depression that depression may reoccur. Women should contact their healthcare provider if depression occurs (see WARNINGS).

ADVERSE REACTIONS

An increased risk of the following serious adverse reactions has been associated with the use of oral contraceptives (see WARNINGS section):

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Thrombophlebitis and venous thrombosis with or without embolism

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Arterial thromboembolism

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Pulmonary embolism

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Myocardial infarction

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Cerebral hemorrhage

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Cerebral thrombosis

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Hypertension

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Gallbladder disease

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Hepatic adenomas or benign liver tumors

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 — 1.12 (Figure 2) (64 to 68).

Three studies compared breast cancer risk between current or recent COC users (<6 months since last use) and never users of COCs (Figure 2) (64, 67, 69). 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 2: 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.

There is evidence of an association between the following conditions and the use of oral contraceptives:

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Mesenteric thrombosis

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Retinal thrombosis

The following adverse reactions have been reported in patients receiving oral contraceptives and are believed to be drug-related:

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Nausea

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Vomiting

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Gastrointestinal symptoms (such as abdominal cramps and bloating)

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Breakthrough bleeding

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Spotting

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Change in menstrual flow

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Amenorrhea

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Temporary infertility after discontinuation of treatment

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Edema

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Melasma which may persist

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Breast changes: tenderness, enlargement, secretion

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Change in weight (increase or decrease)

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Change in cervical erosion and secretion

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Diminution in lactation when given immediately postpartum

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Cholestatic jaundice

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Migraine

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Rash (allergic)

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Mental depression

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Reduced tolerance to carbohydrates

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Vaginal candidiasis

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Change in corneal curvature (steepening)

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Intolerance to contact lenses

The following adverse reactions have been reported in users of oral contraceptives and the association has been neither confirmed nor refuted:

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Pre-menstrual syndrome

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Cataracts

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Changes in appetite

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Cystitis-like syndrome

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Headache

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Nervousness

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Dizziness

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Hirsutism

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Loss of scalp hair

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Erythema multiforme

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Erythema nodosum

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Hemorrhagic eruption

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Vaginitis

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Porphyria

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Impaired renal function

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Hemolytic uremic syndrome

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Acne

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Changes in libido

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Colitis

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Budd-Chiari Syndrome