Jolessa (Page 3 of 8)

5.3 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 JOLESSA prior to starting therapy with the combination drug regimen ombitasvir/paritaprevir/ritonavir, with or without dasabuvir [see Contraindications (4)]. JOLESSA can be restarted approximately 2 weeks following completion of treatment with the Hepatitis C combination drug regimen.

5.4 High Blood Pressure

JOLESSA 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 JOLESSA 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.

5.5 Gallbladder Disease

Studies suggest a small increased relative risk of developing gallbladder disease among COC users. Use of COCs may 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 JOLESSA. COCs may decrease glucose tolerance.

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.

5.7 Headache

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

Consider discontinuation of JOLESSA 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 and Amenorrhea

Bleeding and/or spotting that occurs at any time while taking the first 84 tablets of each extended-cycle regimen is considered “unscheduled” bleeding/spotting. Bleeding that occurs during the time a woman takes the seven white inert tablets 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 JOLESSA, 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 JOLESSA, advise the woman to weigh the convenience of fewer scheduled menses (4 per year instead of 13 per year) against the inconvenience of increased unscheduled bleeding and/or spotting.

The clinical trial of the efficacy of JOLESSA (91-day cycles) in preventing pregnancy also assessed scheduled and unscheduled bleeding. The participants in the study were composed primarily of women who had used oral contraceptives previously as opposed to new users. Women with a history of breakthrough bleeding/spotting ≥ 10 consecutive days on oral contraceptives were excluded from the study. More JOLESSA subjects, compared to subjects on the comparator 28-day cycle regimen, discontinued prematurely for unacceptable bleeding (7.7% [JOLESSA] vs. 1.8% [28-day cycle regimen]).

Unscheduled bleeding and unscheduled spotting decreased over successive 91-day cycles. Table 3 below presents the number of days with unscheduled bleeding and/or spotting for each respective 91-day cycle.

Table 3: Number of Unscheduled Bleeding and/or Spotting Days per 91-day Cycle

Cycle (N)	Days of Unscheduled Bleeding and/or Spotting per 84-Day Interval				Median Days Per Subject-Month
	Mean	Q1	Median	Q3
1 (446)	15.1	3.0	12	23.0	3.0
2 (368)	11.6	2.0	6	17.5	1.5
3 (309)	10.6	1.0	6	15.0	1.5
4 (282)	8.8	1.0	4	14.0	1.0

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

Table 4 shows the percentages of women with ≥ 7 days and ≥ 20 days of unscheduled spotting and/or bleeding in the JOLESSA and the 28-day cycle treatment groups.

Table 4: Percentage of Subjects with Unscheduled Bleeding and/or Spotting

Days of unscheduled bleeding and/or spotting	Percentage of Subjects a
JOLESSA	Cycle 1 (N=385)	Cycle 4 (N=261)
≥ 7 days	65%	42%
≥ 20 days	35%	15%
28-day regimen	Cycles 1-4 (N=194)	Cycles 10-13 (N=158)
≥ 7 days	38%	39%
≥ 20 days	6%	4%

^a Based on spotting and/or bleeding on days 1-84 of a 91 day cycle in the JOLESSA subjects and days 1-21 of a 28 day cycle over 4 cycles in the 28-day dosing regimen.

Total days of bleeding and/or spotting (scheduled plus unscheduled) were similar over one year of treatment for JOLESSA subjects and subjects on the 28-day cycle regimen.

Amenorrhea and Oligomenorrhea

Women who are not pregnant and use JOLESSA may experience amenorrhea. Based on data from the clinical trial, amenorrhea occurred in approximately 0.8% of women during Cycle 1, 1.2% of women during Cycle 2, 3.7% of women during Cycle 3, and 3.4% of women during Cycle 4. Because women using JOLESSA will likely have scheduled bleeding only 4 times per year, rule out pregnancy at the time of any missed menstrual period.

Some women may experience amenorrhea or oligomenorrhea after stopping COCs, especially when such a condition was pre-existent.