Safyral (Page 3 of 10)

5.2 Hyperkalemia

Safyral contains 3 mg of the progestin DRSP, which has anti-mineralocorticoid activity, including the potential for hyperkalemia in high-risk patients, comparable to a 25 mg dose of spironolactone. Safyral is contraindicated in patients with conditions that predispose to hyperkalemia (that is, renal impairment, hepatic impairment, and adrenal insufficiency). Women receiving daily, long-term treatment for chronic conditions or diseases with medications that may increase serum potassium concentration should have their serum potassium concentration checked during the first treatment cycle. Medications that may increase serum potassium concentration include ACE inhibitors, angiotensin–II receptor antagonists, potassium-sparing diuretics, potassium supplementation, heparin, aldosterone antagonists, and NSAIDs. Consider monitoring serum potassium concentration in high-risk patients who take a strong CYP3A4 inhibitor long-term and concomitantly. Strong CYP3A4 inhibitors include azole antifungals (e.g. ketoconazole, itraconazole, voriconazole), HIV/HCV protease inhibitors (e.g., indinavir, boceprevir), and clarithromycin [see Clinical Pharmacology (12.3)].

5.3 Carcinoma of the Breasts and Reproductive Organs

Women who currently have or have had breast cancer should not use Safyral because breast cancer is a hormonally-sensitive tumor.

There is substantial evidence that COCs do not increase the incidence of breast cancer. Although some past studies have suggested that COCs might increase the incidence of breast cancer, more recent studies have not confirmed such findings.

Some studies suggest that COCs are associated with an increase in the risk of cervical cancer or intraepithelial neoplasia. However, there is controversy about the extent to which these findings may be due to differences in sexual behavior and other factors.

5.4 Liver Disease

Discontinue Safyral if jaundice develops. 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 and COC causation has been excluded.

Hepatic adenomas are associated with COC use. An estimate of the attributable risk is 3.3 cases/100,000 COC users. Rupture of hepatic adenomas may cause death through intra-abdominal hemorrhage.

Studies have shown an increased risk of developing hepatocellular carcinoma in long-term (> 8 years) COC users. However, the attributable risk of liver cancers in COC users is less than one case per million users.

Oral contraceptive-related cholestasis may occur in women with a history of pregnancy-related cholestasis. Women with a history of COC-related cholestasis may have the condition recur with subsequent COC use.

5.5 Risk of Liver Enzyme Elevations with Concomitant Hepatitis C Treatment

During clinical trials with the Hepatitis C combination drug regimen that contains ombitasvir/paritaprevir/ritonavir, with or without dasabuvir, ALT elevations greater than 5 times the upper limit of normal (ULN), including some cases greater than 20 times the ULN, were significantly more frequent in women using ethinyl estradiol-containing medications, such as COCs. Discontinue Safyral prior to starting therapy with the combination drug regimen ombitasvir/paritaprevir/ritonavir, with or without dasabuvir [see Contraindications (4)]. Safyral can be restarted approximately 2 weeks following completion of treatment with the Hepatitis C combination drug regimen.

5.6 High Blood Pressure

For women with well-controlled hypertension, monitor blood pressure and stop Safyral if blood pressure rises significantly. Women with uncontrolled hypertension or hypertension with vascular disease should not use COCs.

An increase in blood pressure has been reported in women taking COCs, and this increase is more likely in older women and with extended duration of use. The incidence of hypertension increases with increasing concentration of progestin.

5.7 Gallbladder Disease

Studies suggest a small increased relative risk of developing gallbladder disease among COC users.

5.8 Carbohydrate and Lipid Metabolic Effects

Carefully monitor prediabetic and diabetic women who are taking Safyral. COCs may decrease glucose tolerance in a dose-related fashion.

Consider alternative contraception for women with uncontrolled dyslipidemia. A small proportion of women will have adverse lipid changes while on COCs.

Women with hypertriglyceridemia, or a family history thereof, may be at an increased risk of pancreatitis when using COCs.

5.9 Headache

If a woman taking Safyral develops new headaches that are recurrent, persistent, or severe, evaluate the cause and discontinue Safyral if indicated.

An increase in frequency or severity of migraine during COC use (which may be prodromal of a cerebrovascular event) may be a reason for immediate discontinuation of the COC.

5.10 Bleeding Irregularities

Unscheduled (breakthrough or intracyclic) bleeding and spotting sometimes occur in patients on COCs, especially during the first three months of use. If bleeding persists or occurs after previously regular cycles, check for causes such as pregnancy or malignancy. If pathology and pregnancy are excluded, bleeding irregularities may resolve over time or with a change to a different COC.

Data from ten Yasmin contraceptive efficacy clinical trials (N=2,467) show that the percent of women who took Yasmin and experienced unscheduled bleeding decreased over time from 12% at cycle 2 to 6% (cycle 13). A total of 25 subjects out of 3,009 in the Yasmin and Safyral trials (<1%) discontinued due to bleeding complaints. These are described as metrorrhagia, vaginal hemorrhage, menorrhagia, abnormal withdrawal bleeding, and menometrorrhagia.

The average duration of scheduled bleeding episodes in the majority of subjects (86%–88%) was 4–7 days. Women who use Safyral may experience absence of withdrawal bleeding, even if they are not pregnant. Based on subject diaries from Yasmin contraceptive efficacy trials, during cycles 2–13, 1–11% of women per cycle experienced no withdrawal bleeding. Some women may encounter post-pill amenorrhea or oligomenorrhea, especially when such a condition was pre-existent.

If withdrawal bleeding does not occur, consider the possibility of pregnancy. If the patient has not adhered to the prescribed dosing schedule (missed one or more active tablets or started taking them on a day later than she should have), consider the possibility 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.

5.11 COC Use Before or During Early Pregnancy

Extensive epidemiological studies have revealed no increased risk of birth defects in women who have used oral contraceptives prior to pregnancy. Studies also do not suggest a teratogenic effect when COCs are taken inadvertently during early pregnancy, particularly in so far as cardiac anomalies and limb-reduction defects are concerned. Discontinue Safyral if pregnancy is confirmed and initiate a prenatal vitamin containing folate supplementation.

The administration of oral contraceptives to induce withdrawal bleeding should not be used as a test for pregnancy [see Use in Specific Populations (8.1)].

5.12 Depression

Women with a history of depression should be carefully observed and Safyral discontinued if depression recurs to a serious degree.

5.13 Interference with Laboratory Tests

The use of COCs may change the results of some laboratory tests, such as coagulation factors, lipids, glucose tolerance, and binding proteins. Women on thyroid hormone replacement therapy may need increased doses of thyroid hormone because serum concentrations of thyroid-binding globulin increase with use of COCs [see Drug Interactions (7.2)].

DRSP causes an increase in plasma renin activity and plasma aldosterone induced by its mild anti-mineralocorticoid activity.

Folates may mask vitamin B12 deficiency.

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