Camrese: Package Insert and Label Information

CAMRESE- levonorgestrel / ethinyl estradiol and ethinyl estradiol
Teva Pharmaceuticals USA, Inc.

1 INDICATIONS AND USAGE

CAMRESE^® is indicated for use by females of reproductive potential to prevent pregnancy.

2 DOSAGE AND ADMINISTRATION

2.1 How to Start and Take CAMRESE

Begin CAMRESE on the first Sunday after the onset of menstruation. If menstruation begins on a Sunday, take the first light blue-green tablet that day.

For each 91-day course, take in the following order:

1. Start the first light blue-green tablet on the first Sunday after onset of menstruation. Then take one light blue-green tablet daily for 84 consecutive days. Use a non-hormonal back-up method of contraception (such as condoms and spermicide) until a light blue-green tablet has been taken daily for 7 consecutive days.

2. Then take one yellow tablet for 7 consecutive days. Bleeding should occur during the 7 days that the yellow tablets are taken.

Begin the next and all subsequent 91-day cycles without interruption on the same day of the week (Sunday) on which the patient began her first dose of CAMRESE, following the same schedule: 84 days taking a light blue-green tablet followed by 7 days taking a yellow tablet. If the patient does not immediately start her next pill pack, instruct her to protect herself from pregnancy by using a non-hormonal back-up method of contraception until she has taken a light blue-green tablet daily for 7 consecutive days.

Switching to CAMRESE from another oral hormonal contraceptive or from another contraceptive method (transdermal patch, vaginal ring, injection, intrauterine contraceptive, implant)

Start on the Sunday after the patient’s next period starts. Use additional non-hormonal contraceptive (such as condoms and spermicide) until the patient has taken a light blue-green tablet for 7 consecutive days.

Starting CAMRESE after Abortion or Miscarriage

First-trimester

CAMRESE may be started on the Sunday after an abortion or miscarriage. The patient must use additional non-hormonal contraception (such as condoms and spermicide) until the patient has taken a light blue-green tablet for 7 consecutive days.

Second-trimester

Do not start until 4 weeks after a second-trimester abortion or miscarriage, due to the increased risk of thromboembolic disease. Start contraceptive therapy with CAMRESE following the instructions for women not currently using hormonal contraception. Use additional non-hormonal contraception (such as condoms and spermicide) until the patient has taken a light blue-green tablet for 7 consecutive days [see Contraindications (4) and Warnings and Precautions (5.1)].

Starting CAMRESE after Childbirth

Do not start until 4 weeks after delivery, due to the increased risk of thromboembolic disease. Start contraceptive therapy with CAMRESE following the instructions for women not currently using hormonal contraception. Use additional non-hormonal contraception (such as condoms and spermicide) until the patient has taken a light blue-green tablet for 7 consecutive days [see Contraindications (4) and Warnings and Precautions (5.1)].

If the woman has not yet had a period postpartum, consider the possibility of ovulation and conception occurring prior to use of CAMRESE [see Warnings and Precautions (5.1), Use in Specific Populations (8.1)].

2.2 Dosing CAMRESE

Take one tablet by mouth at the same time every day. The dosage of CAMRESE is one light blue-green tablet daily for 84 consecutive days, followed by one yellow tablet daily for 7 days. To achieve maximum contraceptive effectiveness, CAMRESE must be taken exactly as directed, in the order directed, and at intervals not exceeding 24 hours. The failure rate may increase when pills are missed or taken incorrectly.

2.3 Missed Doses

Table 1. Instructions for Missed CAMRESE Tablets

If one light blue-green tablet is missed	Take the missed tablet as soon as possible. Take the next tablet at the regular time. Continue taking one tablet a day until the pack is finished. A back-up birth control method is not required if the patient has sex.
If two light blue-green tablet in a row are missed	Take the two missed tablets as soon as possible, and the next two tablets the next day. Continue taking one tablet a day until the pack is finished. Use additional nonhormonal contraception (such as condoms and spermicide) until tablets have been taken for 7 days after missing tablets.
If three or more light blue-green pills in a row are missed	Throw away the missed pills. Continue taking one tablet every day as indicated on the pack until the pack is finished. Bleeding may occur during the week following the missed tablets. Use additional nonhormonal contraception (such as condoms and spermicide) until tablets have been taken for 7 days after missing tablets.
If any of the seven yellow tablets are missed	Throw away the missed tablets. Continue taking the remaining tablets until the pack is finished. A backup birth control method is not needed.

2.4 Advice in Case of Gastrointestinal Disturbances

In case of prolonged vomiting or diarrhea, absorption may not be complete and additional contraceptive measures should be taken.

3 DOSAGE FORMS AND STRENGTHS

CAMRESE tablets (levonorgestrel/ethinyl estradiol tablets and ethinyl estradiol tablets) are available in Extended-Cycle Tablet Dispensers, each containing a 13-week supply of tablets: 84 light blue-green tablets, each containing 0.15 mg of levonorgestrel and 0.03 mg ethinyl estradiol, and 7 yellow tablets each containing 0.01 mg of ethinyl estradiol. The light blue-green tablets are round, film-coated, biconvex, unscored tablets debossed with stylized b on one side and 555 on the other side. The yellow tablets are round, biconvex, film-coated, unscored tablets debossed with stylized b on one side and 556 on the other side.

4 CONTRAINDICATIONS

CAMRESE 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 females who are known to:
  • Smoke, if over age 35 [see Boxed Warning and Warnings and Precautions (5.1)].
  • Have current or history of deep vein thrombosis or pulmonary embolism [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 inherited or acquired hypercoagulopathies [see Warnings and Precautions (5.1)].
  • Have uncontrolled hypertension or hypertension with vascular disease [see Warnings and Precautions (5.3)].
  • Have diabetes mellitus and are over age 35, diabetes mellitus with hypertension or with vascular disease or other end-organ damage, or diabetes mellitus of > 20 years duration [see Warnings and Precautions (5.7)].
  • Have headaches with focal neurological symptoms, migraine headaches with aura, or over age 35 with any migraine headaches [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)].
• Liver tumors, acute viral hepatitis, or severe (decompensated) cirrhosis [see Warnings and Precautions (5.2) and Use in Specific Populations (8.6)].
  
• Undiagnosed abnormal uterine bleeding [see Warnings and Precautions (5.9)].
• ​ 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 (5.4)].

5 WARNINGS AND PRECAUTIONS

5.1 Thromboembolic Disorders and Other Vascular Conditions

• Stop CAMRESE if an arterial or deep venous thrombotic/thrombembolic event occurs.
• Stop CAMRESE if there is unexplained loss of vision, proptosis, diplopia, papilledema, or retinal vascular lesions and evaluate for retinal vein thrombosis immediately.
• Discontinue CAMRESE during prolonged immobilization. If feasible, stop CAMRESE at least 4 weeks before and through 2 weeks after major surgery, or other surgeries known to have an elevated risk of thromboembolism.
• Start CAMRESE no earlier than 4 weeks after delivery, in women 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 CAMRESE evaluate any past medical history or family history of thrombotic or thromboembolic disorders and consider whether the history suggests an inherited or acquired hypercoagulopathy. CAMRESE is contraindicated in women with a high risk of arterial or venous/thromboembolic diseases [see Contraindications (4)].

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.

CAMRESE is contraindicated in women over 35 years of age who smoke [see Contraindications (4)]. 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 CHCs [see Contraindications (4)]. 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 women who are not pregnant and do not use oral contraceptives, for women who use oral contraceptives, and for women in the postpartum period. To put the risk of developing a VTE into perspective: If 10,000 women who are not pregnant and do not use oral contraceptives are followed for one year, between 1 and 5 of these women will develop a VTE.

Use of CAMRESE provides women 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).

5.2 Liver Disease

Elevated Liver Enzymes

CAMRESE is contraindicated in women with acute viral hepatitis or severe (decompensated) cirrhosis of the liver [see Contraindications (4)]. Acute liver test abnormalities may necessitate the discontinuation of CAMRESE until the liver tests return to normal and CAMRESE causation has been excluded. Discontinue CAMRESE if jaundice develops.

Liver Tumors

CAMRESE is contraindicated in women with benign or malignant liver tumors [see Contraindications (4)]. 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.

5.3 Hypertension

CAMRESE is contraindicated in women with uncontrolled hypertension or hypertension with vascular disease [see Contraindications (4)]. For all women, including those with well-controlled hypertension, monitor blood pressure at routine visits and stop CAMRESE 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 effect of COCs on blood pressure may vary according to the progestin in the COC.

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

5.5 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 [see Contraindications (4) and Warnings and Precautions (5.1)]. 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