Simpesse Drug Information

Thromboembolic Disorders and Other Vascular Conditions Stop Lo Simpesse if an arterial

or deep venous thrombotic/thromboembolic event occurs. Stop Lo Simpesse if there is unexplained loss of vision, proptosis, diplopia, papilledema, or retinal vascular lesions and evaluate for retinal vein thrombosis immediately. Discontinue Lo Simpesse during prolonged immobilization.

If feasible, stop Lo Simpesse at least 4 weeks before and through 2 weeks after major surgery, or other surgeries known to have an elevated risk of thromboembolism. Start Lo Simpesse no earlier than 4 weeks after delivery, in females who are not breastfeeding. The risk of postpartum thromboembolism decreases after the third postpartum week, whereas the risk of ovulation increases after the third postpartum week.

Before starting Lo Simpesse evaluate any past medical history or family history of thrombotic or thromboembolic disorders and consider whether the history suggests an inherited or acquired hypercoagulopathy. Lo Simpesse is contraindicated in females with a high risk of arterial or venous/thromboembolic diseases . Arterial Events COCs increase the risk of cardiovascular events and cerebrovascular events, such as myocardial infarction and stroke. The risk is greater among older women (>35 years of age), smokers, and females with hypertension, dyslipidemia, diabetes, or obesity.

Lo Simpesse is contraindicated in women over 35 years of age who smoke . Cigarette smoking increases the risk of serious cardiovascular events from COC use. This risk increases with age, particularly in women over 35 years of age, and with the number of cigarettes smoked. Venous Events Use of COCs increases the risk of venous thromboembolic events (VTEs), such as deep vein thrombosis and pulmonary embolism.

Risk factors for VTEs include smoking, obesity, and family history of VTE, in addition to other factors that contraindicate use of COCs . While the increased risk of VTE associated with use of COCs is well-established, the rates of VTE are even greater during pregnancy, and especially during the postpartum period (see Figure 1). The rate of VTE in females using COCs has been estimated to be 3 to 9 cases per 10,000 woman years. The risk of VTE is highest during the first year of use of a COC and when restarting hormonal contraception after a break of four weeks or longer. The risk of thromboembolic disease due to COCs gradually disappears after COC use is discontinued.

Figure 1 shows the risk of developing a VTE for females who are not pregnant and do not use oral contraceptives, for females who use oral contraceptives, and for females in the postpartum period. To put the risk of developing a VTE into perspective: If 10,000 females who are not pregnant and do not use oral contraceptives are followed for one year, between 1 and 5 of these females will develop a VTE. Use of Lo Simpesse provides females with more hormonal exposure on a yearly basis than conventional monthly oral contraceptives containing the same strength synthetic estrogens and progestins (an additional 9 and 13 weeks of exposure to progestin and estrogen, respectively, per year). Figure 1

Liver Disease Elevated Liver Enzymes Lo Simpesse is contraindicated in females with

acute viral hepatitis or severe (decompensated) cirrhosis of the liver . Acute liver test abnormalities may necessitate the discontinuation of Lo Simpesse until the liver tests return to normal and Lo Simpesse causation has been excluded. Discontinue Lo Simpesse if jaundice develops. Liver Tumors Lo Simpesse is contraindicated in females with benign or malignant liver tumors . COCs increase the risk of hepatic adenomas.

An estimate of the attributable risk is 3.3 cases/100,000 COC users. Rupture of hepatic adenomas may cause death from abdominal hemorrhage. Studies have shown an increased risk of developing hepatocellular carcinoma in long-term (> 8 years) COC users.

The attributable risk of liver cancers in COC users is less than one case per million users.

Hypertension Lo Simpesse is contraindicated in females with uncontrolled hypertension or hypertension

with vascular disease . For all females, including those with wellcontrolled hypertension, monitor blood pressure at routine visits and stop Lo Simpesse if blood pressure rises significantly. An increase in blood pressure has been reported in females taking COCs, and this increase is more likely in older women and with extended duration of use. The effect of COCs on blood pressure may vary according to the progestin in the COC.

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 Lo Simpesse prior to starting therapy with the combination drug regimen ombitasvir/paritaprevir/ritonavir, with or without dasabuvir, . Lo Simpesse can be restarted approximately 2 weeks following completion of treatment with the Hepatitis C combination drug regimen.

Age-related Considerations

The risk for cardiovascular disease and prevalence of risk factors for cardiovascular disease increases with age. Certain conditions, such as smoking and migraine headache without aura, that do not contraindicate COC use in younger females, are contraindications to use in women over 35 years of age . Consider the presence of underlying risk factors that may increase the risk of cardiovascular disease or VTE, particularly before initiating a COC for women over 35 years, such as: Hypertension Diabetes Dyslipidemia Obesity

Gallbladder Disease Studies suggest a small increased relative risk of developing gallbladder

disease among COC users. Use of COCs, including Lo Simpesse, may also worsen existing gallbladder disease. A past history of COC-related cholestasis predicts an increased risk with subsequent COC use.

Females with a history of pregnancy-related cholestasis may be at an increased risk for COC-related cholestasis.

Adverse Carbohydrate and Lipid Metabolic Effects Hyperglycemia Lo Simpesse is contraindicated in

diabetic women over age 35, or females who have diabetes with hypertension, nephropathy, retinopathy, neuropathy, other vascular disease, or females with diabetes of > 20 years duration . Lo Simpesse may decrease glucose tolerance. Carefully monitor prediabetic and diabetic females who are taking COCs. Dyslipidemia Consider alternative contraception for females with uncontrolled dyslipidemias.

Lo Simpesse may cause adverse lipid changes. Females with hypertriglyceridemia, or a family history thereof, may have an increase in serum triglyceride concentrations when using Lo Simpesse, which may increase the risk of pancreatitis.

Headache Lo Simpesse is contraindicated in females who have headaches with focal

neurological symptoms or have migraine headaches with aura, and in women over 35 years of age who have migraine headaches with or without aura . If a woman taking Lo Simpesse develops new headaches that are recurrent, persistent, or severe, evaluate the cause and discontinue Lo Simpesse if indicated. Consider discontinuation of Lo Simpesse if there is an increased frequency or severity of migraine during COC use (which may be prodromal of a cerebrovascular event).

Bleeding Irregularities and Amenorrhea Unscheduled Bleeding and Spotting Females using Lo Simpesse

may experience unscheduled (breakthrough or intracyclic) bleeding and spotting, especially during the first 3 months of use. Bleeding irregularities may resolve over time or by changing to a different contraceptive product. If bleeding persists or occurs after previously regular cycles, evaluate for causes such as pregnancy or malignancy.

When prescribing Lo Simpesse, the occurrence of fewer planned menses (4 per year instead of 13 per year) should be weighed against the occurrence of increased unscheduled bleeding and/or spotting. The clinical trial that evaluated the efficacy of Lo Simpesse also assessed unscheduled bleeding. The participants in this 12-month clinical trial (N=2,185) completed the equivalent of over 20,000 28-day cycles of exposure and were composed primarily of women who had used OCs previously (89%), as opposed to new users (11%). A total of 209 subjects (9.6%) discontinued Lo Simpesse, at least in part, due to bleeding and/or spotting.

Scheduled (withdrawal) bleeding and/or spotting remained fairly constant over time, with an average of 2 to 3 days of bleeding and/or spotting per each 91-day cycle. Unscheduled bleeding and unscheduled spotting decreased over successive 91-day cycles. Table 2 below presents the number of days with unscheduled bleeding in treatment cycles 1 and 4. Table 3 presents the number of days with unscheduled spotting in treatment cycles 1 and 4. Table 2: Total Number of Days with Unscheduled Bleeding Q1=Quartile 1: 25% of women had this number of days of unscheduled bleeding Median: 50% of women had ≤ this number of days of unscheduled bleeding Q3=Quartile 3: 75% of women had ≤ this number of days of unscheduled bleeding 91-Day Treatment Cycle Days per 84-Day Interval Days per 28-Day Interval Q1 Median Q3 Mean Mean 1st 0 5 11 7.5 2.5 4th 0 0 5 3.5

Table 3: Total Number of Days with Unscheduled Spotting Q1=Quartile 1: 25%

of women had ≤ this number of days of unscheduled spotting Median: 50% of women had ≤ this number of days of unscheduled spotting Q3=Quartile 3: 75% of women had ≤ this number of days of unscheduled spotting 91-Day Treatment Cycle Days per 84-Day Interval Days per 28-Day Interval Q1 Median Q3 Mean Mean 1st 3 10 19 14 4.7 4th 0 3 10 6.5

Figure 2 shows the percentage of Lo Simpesse subjects participating 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 2: Percent of Women Taking Lo Simpesse who Reported Unscheduled Bleeding and/or Spotting (Based on Daily Diaries) If unscheduled spotting or bleeding occurs, instruct the patient to continue on the same regimen. If the bleeding is persistent or prolonged, advise the patient to consult her healthcare provider.

Amenorrhea and Oligomenorrhea Females who use Lo Simpesse may experience absence of scheduled (withdrawal) bleeding, even if they are not pregnant. If scheduled bleeding does not occur, consider the possibility of pregnancy. After discontinuation of Lo Simpesse, amenorrhea or oligomenorrhea may occur, especially if these conditions were pre-existent.

Figure 2 5.10 Depression Carefully observe females with a history of depression and discontinue Lo Simpesse if depression recurs to a serious degree. Data on the association of COCs with the onset of depression or exacerbation of existing depression are limited. 5.11 Malignant Neoplasms Breast Cancer Lo Simpesse is contraindicated in females who currently have or have had breast cancer because breast cancer may be hormonally sensitive. Epidemiology studies have not found a consistent association between use of combined oral contraceptives (COCs) and breast cancer risk.

Studies do not show an association between ever (current or past) use of COCs and risk of breast cancer. However, some studies report a small increase in the risk of breast cancer among current or recent users (<6 months since last use) and current users with longer duration of COC use . Cervical Cancer 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 are due to differences in sexual behavior and other factors. 5.12 Effect on Binding Globulins The estrogen component of Lo Simpesse may raise the serum concentrations of thyroxine binding globulin, sex hormone-binding globulin, and cortisol-binding globulin.

The dose of replacement thyroid hormone or cortisol therapy may need to be increased. 5.13 Hereditary Angioedema In females with hereditary angioedema, exogenous estrogens, including Lo Simpesse, may induce or exacerbate symptoms of hereditary angioedema. 5.14 Chloasma Chloasma may occur with Lo Simpesse use, especially in females with a history of chloasma gravidarum. Advise females with a history of chloasma to avoid exposure to the sun or ultraviolet radiation while using Lo Simpesse.