Drug Safety-related Labeling Changes (SrLC)

Additions underlined

LO/OVRAL-28 is contraindicated in females who are known to have the following conditions to women who are known to have or develop the following conditions:

…

• Current diagnosis of, or history of, breast cancer, which may be hormone-sensitive [see Warnings and Precautions (5.10)]

…

The following subsections created to follow the PLR requirements, please refer to label for complete information.

5.1       Thrombotic Disorders and Other Vascular Problems

5.2       Liver Diseas

5.3       Risk of Liver Enzyme Elevations with Concomitant Hepatitis C Treatment

5.4       High Blood Pressure

5.5       Gallbladder Disease

5.6       Carbohydrate and Lipid Metabolic Effect

5.7       Headache

5.8       Bleeding Irregularities and Amenorrhea

5.9       Depression

5.10     Malignant Neoplasms

Additions underlined

Breast Cancer

Lo/Ovral-28 is contraindicated in women who currently have or have had breast cancer because breast cancer may be hormonally sensitive [see Contraindications (4)].

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. [see Postmarketing Experience (6.2)].

…

5.11     Effect on Binding Globulins

5.12     Hereditary Angioedema

5.13     Chloasma

6.1 Clinical Trials Experience

Newly added subsection, please refer to label for complete information.

6.2 Postmarketing Experience

Newly added subsection

Five studies that compared breast cancer risk between ever-users (current or past use) of COCs and never-users of COCs reported no association between ever use of COCs and breast cancer risk, with effect estimates ranging from 0.90 - 1.12 (Figure 1).

Three studies compared breast cancer risk between current or recent COC users (<6 months since last use) and never users of COCs (Figure 1). One of these studies reported no association between breast cancer risk and COC use. The other two studies found an increased relative risk of 1.19 - 1.33 with current or recent use. Both of these studies found an increased risk of breast cancer with current use of longer duration, with relative risks ranging from 1.03 with less than one year of COC use to approximately 1.4 with more than 8-10 years of COC use.

Figure 1:         Relevant Studies of Risk of Breast Cancer with Combined Oral Contraceptives

Please refer to label to view Figure 1.

…

The following subsections created to follow the PLR requirements, please refer to label for complete information.

7.1       Effects of Other Drugs on Combined Oral Contraceptives

7.2       Concomitant use with HCV combination therapy – Liver enzyme elevation

7.3       Effects of Combined Oral Contraceptives on Other Drugs

7.4       Interactions with Laboratory Tests

New subsection created

The pharmacokinetics of LO/OVRAL-28 has not been studied in women with renal impairment.

8.1 Pregnancy

PLLR conversion

Risk Summary

There is little or no increased risk of birth defects in the children of females who inadvertently use COCs during early pregnancy. Animal data, along with epidemiologic studies, do not show an increased risk of birth defects with use of COCs prior to pregnancy or during early pregnancy.

Discontinue LoOvral use if pregnancy is confirmed.

Do not administer COCs to induce withdrawal bleeding as a test for pregnancy. Do not use COCs during pregnancy to treat threatened or habitual abortion.

Animal Data

Several studies were conducted in rodents and rabbits to evaluate the potential reproductive toxicity of Norgestrel in combination with Ethinyl Estradiol (Norgestrel/EE) during pregnancy or lactation at doses approximately up to 25-fold over the clinical dose.

In rats administered Norgestrel/EE from Day 8-21 of gestation, there were no maternal adverse effects and no effects on embryofetal development or reproductive potential of the offspring. In rabbits, Norgestrel/EE administered from

Day 8-18 of gestation showed a decrease in maternal body weight gain and litter size. There was no indication of teratogenicity in either rats or rabbits.

Administration of Norgestrel/EE in mice and rats to suppress fertility was followed by a recovery of reproductive function and fertility. In lactating female rats administered Norgestrel/EE at doses up to 25-fold the clinical dose from delivery to 21 days post-delivery or weaning, there were no adverse maternal effects, no effect on the lactation process, and no effect on offspring growth.

8.2 Lactation

PLLR conversion

Risk Summary

Contraceptive hormones and/or metabolites are present in human milk in small amounts. The effects of Lo/Ovral-28 on the breastfed child is unknown. COCs can reduce milk production in lactating women. Advise the nursing mother to use a non-COC contraception, when possible, until she has weaned her child. This is less likely to occur once breastfeeding is well-established; however, it can occur at any time in some women. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Lo/Ovral-28 and any potential adverse effects on the breast-fed child from Lo-Ovral-28 or from the underlying maternal condition.

8.6 Hepatic Impairment

New subsection created

The pharmacokinetics of LO/OVRAL-28 has not been studied in subjects with hepatic impairment. However, steroid hormones may be poorly metabolized in patients with hepatic impairment. 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 [see Contraindications (4) and Warnings and Precautions (5.2)].)].

8.9 Body Mass Index

New subsection created

The safety and efficacy of LO/OVRAL-28 in women with a body mass index (BMI) > 35 kg/m2 has not been evaluated

[see Clinical Studies (14)].

Additions underlined

…

Do birth control pills cause cancer?

It is not known if hormonal birth control pills causes breast cancer. Some studies, but not all, suggest that there could be a slight increase in the risk of breast cancer among current users with longer duration of use.

If you have breast cancer now, or have had it in the past, do not use hormonal birth control because some breast cancers are sensitive to hormones.

…

PLR conversion

(Additions and/or revisions are underlined)

Combination oral contraceptives should not be used in women with any of the following conditions:

Are receiving Hepatitis C drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir, due to the potential for ALT elevations.

(Additions and/or revisions are underlined)

5. 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 Lo/Ovral-28 prior to starting therapy with the combination drug regimen ombitasvir/paritaprevir/ritonavir, with or without dasabuvir. Lo/Ovral-28 can be restarted approximately 2 weeks following completion of treatment with the combination drug regimen.

(Additions and/or revisions are underlined)

Concomitant use with HCV combination therapy – Liver enzyme elevation:

Do not co-administer Lo/Ovral-28 with HCV drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir, due to potential for ALT elevations.

(Additions and/or revisions are underlined)

DETAILED PATIENT LABELING

WHO SHOULD NOT TAKE ORAL CONTRACEPTIVES

Some women should not take the pill. You should not take the pill if you have any of the following conditions:

• Take any Hepatitis C drug combination containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir. This may increase levels of the liver enzyme “alanine aminotransferase” (ALT) in the blood.