Blisovi 24 Fe: Package Insert and Label Information

BLISOVI 24 FE — norethindrone acetate and ethinyl estradiol
Lupin Pharmaceuticals, Inc.

1 INDICATIONS AND USAGE

Blisovi^™ 24 Fe is indicated for use by women to prevent pregnancy [see CLINICAL STUDIES (14)].

The efficacy of Blisovi 24 Fe in women with a body mass index (BMI) of > 35 kg/m² has not been evaluated.

2 DOSAGE AND ADMINISTRATION

2.1 How to Start Blisovi 24 Fe

Blisovi 24 Fe is dispensed in a blister card [see HOW SUPPLIED/STORAGE AND HANDLING (16)]. Blisovi 24 Fe may be started using either a Day 1 start or a Sunday start (see Table 1). For the first cycle of a Sunday Start regimen, an additional method of contraception must be used until after the first 7 consecutive days of administration.

2.2 How to Take Blisovi 24 Fe

Table 1: Instructions for Administration of Blisovi 24 Fe

Starting COCs in women not currently using hormonal contraception (Day 1 Start or Sunday Start)	Day 1 Start: ● Take first white active tablet without regard to meals on the first day of menses.
Important: Consider the possibility of ovulation and conception prior to initiation of this product.	● Take subsequent active tablets once daily at the same time each day for a total of 24 days.
Tablet Color: ● Blisovi 24 Fe active tablets are white (Day 1 to Day 24).	● Take one brown inactive tablet daily for 4 days and at the same time of day that active tablets were taken.
● Blisovi 24 Fe inactive tablets are brown (Day 25 to Day 28).	● Begin each subsequent pack on the same day of the week as the first cycle pack (i.e., on the day after taking the last inactive tablet).
	Sunday Start: For each 28-day course, take in the following order:
	● Take the white active tablet without regard to meals on the first Sunday after the onset of menses. Due to the potential risk of becoming pregnant, use additional non- hormonal contraception (such as condoms and spermicide) for the first 7 days of the patient’s first cycle pack of Blisovi 24 Fe.
	● Take subsequent active tablets once daily at the same time each day for a total of 24 days.
	● Take one brown tablet (ferrous fumarate) daily for the following 4 days and at the same time of day that active tablets were taken. A scheduled period should occur during the 4 days that the brown tablets are taken.
	● Begin each subsequent pack on the same day of the week as the first cycle pack (i.e., on the Sunday after taking the last inactive tablet) and additional non-hormonal contraceptive is not needed.
Switching to Blisovi 24 Fe from another oral contraceptive	Start on the same day that a new pack of the previous oral contraceptive would have started.
S w itching from another contraceptive method to Blisovi 24 Fe	Start Blisovi 24 Fe:
● Transdermal patch	● On the day when next application would have been scheduled.
● Vaginal ring	● On the day when next insertion would have been scheduled
● Injection	● On the day when next injection would have been scheduled
● Intrauterine contraceptive	● On the day of removal
	● If the IUD is not removed on first day of the patient’s menstrual cycle, additional non-hormonal contraceptive (such as condoms and spermicide) is needed for the first seven days of the first cycle pack.
● Implant	● On the day of removal

Starting Blisovi 24 Fe after Abortion or Miscarriage

First-trimester:

• After a first-trimester abortion or miscarriage, Blisovi 24 Fe may be started immediately. An additional method of contraception is not needed if Blisovi 24 Fe is started immediately.
• If Blisovi 24 Fe is not started within 5 days after termination of the pregnancy, the patient must use additional non-hormonal contraception (such as condoms and spermicide) for the first 7 days of her first 28-day course of Blisovi 24 Fe.

Second-trimester:

• Do not start until 4 weeks after a second-trimester abortion or miscarriage, due to the increased risk of thromboembolic disease. Start Blisovi 24 Fe following the instructions in Table 1 for Sunday start. Use additional non-hormonal contraception (such as condoms and spermicide) for the first 7 days of the patient’s first 28-day course of Blisovi 24 Fe [see CONTRAINDICATIONS (4) and WARNINGS AND PRECAUTIONS (5.1).

Starting Blisovi 24 Fe after Childbirth

• Do not start until 4 weeks after delivery, due to the increased risk of thromboembolic disease. Start contraceptive therapy with Blisovi 24 Fe following the instructions in Table 1 for women not currently using hormonal contraception.
• If the woman has not yet had a period postpartum, consider the possibility of ovulation and conception occurring prior to use of Blisovi 24 Fe [see CONTRAINDICATIONS (4), WARNINGS AND PRECAUTIONS (5.1), USE IN SPECIFIC POPULATIONS (8.1 and 8.2].

2.3 Missed Tablets

Table 2: Instructions for Missed Blisovi 24 Fe Tablets

● If one active tablet is missed in Weeks 1, 2 or 3	Take the tablet as soon as possible. Take the next pill at the regular time and continue taking one tablet a day until the pack is finished. Back-up contraception is not needed
● If two consecutive active tablets are missed in Week 1 or Week 2	Take the two missed tablets as soon as possible and the next two active tablets the next day. Continue taking one tablet a day until the pack is finished. Additional non-hormonal contraception (such as condoms and spermicide) must be used as back-up if the patient has sex within 7 days after missing tablets.
● If two consecutive active tablets are missed in Week 3 or Week 4 or three or more consecutive active tablets are missed at any time	Day 1 Start: Throw out the rest of the pack and start a new pack that same day.Sunday Start: Continue taking one tablet a day until Sunday, then throw out the rest of the pack and start a new pack that same day. Additional non-hormonal contraception (such as condoms and spermicide) must be used as back-up if the patient has sex within 7 days after missing 3 tablets.

2.4 Advice in Case of Gastrointestinal Disturbances

In case of severe vomiting or diarrhea, absorption may not be complete and additional contraceptive measures must be taken. If vomiting or diarrhea occurs within 3 to 4 hours after taking a white tablet, handle this as a missed tablet [see DOSAGE AND ADMINISTRATION (2.3)].

3 DOSAGE FORMS AND STRENGTHS

Blisovi 24 Fe (norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets) is available in blister packs.

Each blister pack (28 tablets) contains in the following order:

• 24 white to off-white, round, flat face beveled edged (active) tablets debossed with “LU” on one side and “N21” on the other side and each containing 1 mg norethindrone acetate and 20 mcg ethinyl estradiol.
• 4 brown mottled, round, flat face beveled edge (non-hormonal placebo) tablets debossed with “LU” on one side and “M22” on the other side and each containing 75 mg ferrous fumarate. The ferrous fumarate tablets do not serve any therapeutic purpose.

4 CONTRAINDICATIONS

Blisovi 24 Fe is contraindicated in females who are known to have or develop the following conditions:

• A high risk of arterial or venous thrombotic diseases. Examples include women who are known to:
  • Smoke, if over age 35 [see BOXED WARNING and WARNINGS AND PRECAUTIONS (5.1)]
  • Have deep vein thrombosis or pulmonary embolism, now or in the past [see WARNINGS AND PRECAUTIONS (5.1)]
  • Have inherited or acquired hypercoagulopathies [see WARNINGS AND PRECAUTIONS (5.1)]
  • Have cerebrovascular disease [see WARNINGS AND PRECAUTIONS (5.1)]
  • Have coronary artery disease [see WARNINGS AND PRECAUTIONS (5.1)]
  • Have thrombogenic valvular or thrombogenic rhythm diseases of the heart (for example, subacute bacterial endocarditis with valvular disease, or atrial fibrillation) [see WARNINGS AND PRECAUTIONS (5.1)]
  • Have uncontrolled hypertension [see WARNINGS AND PRECAUTIONS (5.4)]
  • Have diabetes mellitus with vascular disease [see WARNINGS AND PRECAUTIONS (5.6)]
  • Have headaches with focal neurological symptoms or have migraine headaches with aura [see WARNINGS AND PRECAUTIONS (5.7)]

■ Women over age 35 with any migraine headaches [see WARNINGS AND PRECAUTIONS (5.7)]

• Liver tumors, benign or malignant, or liver disease [see WARNINGS AND PRECAUTIONS (5.2)]
• Undiagnosed abnormal uterine bleeding [see WARNINGS AND PRECAUTIONS (5.8)]
• Current diagnosis of, or history of, breast cancer, which may be hormone sensitive [see WARNINGS AND PRECAUTIONS (5.11)]
• Use of Hepatitis C drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir, due to the potential for ALT elevations [see WARNINGS AND PRECAUTIONS (5.3)]

5 WARNINGS AND PRECAUTIONS

5.1 Thrombotic Disorders and Other Vascular Problems

• Stop Blisovi 24 Fe if an arterial thrombotic event or venous thromboembolic (VTE) event occurs.
• Stop Blisovi 24 Fe if there is unexplained loss of vision, proptosis, diplopia, papilledema, or retinal vascular lesions. Evaluate for retinal vein thrombosis immediately [see ADVERSE REACTIONS (6.2)].
• If feasible, stop Blisovi 24 Fe at least 4 weeks before and through 2 weeks after major surgery or other surgeries known to have an elevated risk of VTE as well as during the following prolonged immobilization.
• Start Blisovi 24 Fe no earlier than 4 weeks after delivery, in women who are not breastfeeding. The risk of postpartum VTE decreases after the third postpartum week, whereas the risk of ovulation increases after the third postpartum week.
• The use of COCs increases the risk of VTE. However, pregnancy increases the risk of VTE as much or more than the use of COCs. The risk of VTE in women using COCs is 3 to 9 cases per 10,000 woman-years. The risk of VTE is highest during the first year of use of a COCs and when restarting oral contraception after a break of 4 weeks or longer. The risk of thromboembolic disease due to COCs gradually disappears after COC use is discontinued.
• Use of COCs also increases the risk of arterial thromboses such as strokes and myocardial infarctions, especially in women with other risk factors for these events. COCs have been shown to increase both the relative and attributable risks of cerebrovascular events (thrombotic and hemorrhagic strokes). This risk increases with age, particularly in women over 35 years of age who smoke.
• Use COCs with caution in women with cardiovascular disease risk factors.

5.2 Liver Disease

Impaired Liver Function

Do not use Blisovi 24 Fe in women with liver disease, such as acute viral hepatitis or severe (decompensated) cirrhosis of liver [see CONTRAINDICATIONS (4)]. 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. Discontinue Blisovi 24 Fe if jaundice develops.

Liver Tumors

Blisovi 24 Fe 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 per 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 risk of liver cancers in COC users is less than one case per million users.

5.3 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 Blisovi 24 Fe prior to starting therapy with the combination drug regimen ombitasvir/paritaprevir/ritonavir, with or without dasabuvir [see CONTRAINDICATIONS (4)]. Blisovi 24 Fe can be restarted approximately 2 weeks following completion of treatment with the Hepatitis C combination drug regimen.

5.4 High Blood Pressure

Blisovi 24 Fe 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 Blisovi 24 Fe 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 with extended duration of use. The incidence of hypertension increases with increasing concentrations 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.