FAYOSIM (Page 2 of 5)

5.2 Liver Disease

Impaired Liver Function

Do not use Fayosim in women with acute viral hepatitis or severe (decompensated) cirrhosis of the liver [see CONTRAINDICATIONS (4)].Acute 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. Discontinue Fayosim if jaundice develops.

Liver Tumors

Fayosim is contraindicated in women with benign and malignant liver tumors [see CONTRAINDICATIONS (4)]. 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.

5.3 High Blood Pressure

Fayosim is contraindicated in women with uncontrolled hypertension or hypertension with vascular disease [see CONTRAINDICATIONS (4)]. For women with well-controlled hypertension, monitor blood pressure and stop Fayosim if blood pressure rises significantly.

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.

5.4 Risk of Liver Enzyme Elevations with Concomitant Hepatitis C Treatment

​ During clinical trials with the Hepatitis C combination drug regimen that contains obmitasvir/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 Fayosim prior to starting therapy with the combination drug regimen ombitasvir/paritaprevir/ritonavir, with or without dasabuvir [see CONTRAINDICATIONS (4)]. Fayosim can be restarted approximately 2 weeks following completion of treatment with the Hepatitis C combination drug regimen.

5.5 Gallbladder Disease

Studies suggest a small increased relative risk of developing gallbladder disease among COC users. Use of COCs may also worsen existing gallbladder disease.

A past history of COC-related cholestasis predicts an increased risk with subsequent COC use. Women with a history of pregnancy-related cholestasis may be at an increased risk for COC-related cholestasis.

5.6 Carbohydrate and Lipid Metabolic Effects

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

Consider alternative contraception for women with uncontrolled dyslipidemias. 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.

5.7 Headache

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

Consider discontinuation of Fayosim in the case of increased frequency or severity of migraine during COC use (which may be prodromal of a cerebrovascular event) [see CONTRAINDICATIONS ( 4)].

5.8 Bleeding Irregularities

Bleeding and/or spotting that occurs at any time while taking the first 84 tablets (pink, white and light blue) of each extended-cycle regimen is considered “unscheduled” bleeding/spotting. Bleeding that occurs during the time a woman takes the seven tablets (mustard) containing 10 mcg of ethinyl estradiol is considered “scheduled” bleeding.

Unscheduled and Scheduled Bleeding and Spotting

Unscheduled (breakthrough) bleeding and spotting sometimes occur in patients on COCs, especially during the first 3 months of use. If unscheduled bleeding persists or occurs after previously regular cycles on Fayosim, 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.

Before prescribing Fayosim, consider the occurrence of fewer scheduled menses (4 per year instead of 13 per year) against the occurrence of increased unscheduled bleeding and/or spotting. A 12- month open-label study of the efficacy of Fayosim in preventing pregnancy assessed scheduled and unscheduled bleeding [see CLINICAL STUDIES (14)] in 3,597 women who completed 34,087 28-day cycles of exposure. A total of 178 (4.9%) of the women discontinued Fayosim, at least in part, due to bleeding or spotting.

Scheduled (withdrawal) bleeding and/or spotting remained fairly stable over time, with an average of 3 to 4 days of bleeding and/or spotting per each 91-day cycle.

Unscheduled bleeding and unscheduled spotting decreased over successive 91-day cycles. Table 1 below presents the number of days with unscheduled bleeding, spotting, and unscheduled bleeding and/or spotting in Treatment Cycles 1 to 4.

Table 1 Number of Unscheduled Bleeding, Spotting and Bleeding and/or Spotting Days per 91-day Cycle

Q1 = Quartile 1: 25% of women had ≤ this number of days of unscheduled bleeding/spotting
Median: 50% of women had ≤ this number of days of unscheduled bleeding/spotting
Q3 = Quartile 3: 75% of women had ≤ this number of days of unscheduled bleeding/spotting
Cycle ( N )	Days of Unscheduled Bleeding per 84 – Day Interval				Median Days Per Subject – Month
	Mean	Q1	Median	Q3
1(3330)	7.2	0	4	10	1.0
2(2820)	3.3	0	0	4	0.0
3(2433)	2.5	0	0	3	0.0
4(2213)	2.2	0	0	2	0.0
Cycle ( N )	Days of Unscheduled Spotting per 84 – Day Interval				Median Days Per Subject – Month
	Mean	Q1	Median	Q3
1(3330)	10.7	2	7	15	1.8
2(2820)	6.7	0	3	9	0.8
3(2433)	5.2	0	2	6	0.5
4(2213)	4.4	0	1	5	0.3
Cycle ( N )	Days of Unscheduled Bleeding and / or Spotting per 84 – Day Interval				Median Days Per Subject – Month
	Mean	Q1	Median	Q3
1(3330)	17.9	5	14	27	3.5
2(2820)	10.0	1	5	14	1.3
3(2433)	7.7	0	3	10	0.8
4(2213)	6.6	0	3	8	0.8

Figure 1 shows the percent of Fayosim subjects in the primary clinical trial with ≥ 7 days or ≥ 20 days of unscheduled bleeding and/or spotting, or just unscheduled bleeding, during each 91-day treatment cycle.

Figure 1: Percent of Women Taking Fayosim Who Reported Unscheduled Bleeding and/or Spotting

Amenorrhea and Oligomenorrhea

Women who are not pregnant and use Fayosim may experience amenorrhea. Based on data from the clinical trial, amenorrhea occurred in approximately 1.9% of women during Cycle 1, 7.7% during Cycle 2, 10.7% during Cycle 3, and 10.1% during Cycle 4 using Fayosim. Rule out pregnancy in the event of amenorrhea. Some women may experience amenorrhea or oligomenorrhea after stopping COCs, especially when such a condition was pre-existent.