CAMILA

ADVERSE REACTIONS Menstrual irregularity is the most frequently reported side effect. Frequent and irregular bleeding are common, while long duration of bleeding episodes and amenorrhea are less likely. Headache, breast tenderness, nausea, and dizziness are increased among progestin-only oral contraceptive users in some studies. Androgenic side effects such as acne, hirsutism, and weight gain occur rarely.

CONTRAINDICATIONS Progestin-only oral contraceptives (POPs) should not be used by women who currently have the following conditions: Known or suspected pregnancy Known or suspected carcinoma of the breast Undiagnosed abnormal genital bleeding Hypersensitivity to any component of this product Benign or malignant liver tumors Acute liver disease

DESCRIPTION Each light pink Camila® tablet provides a continuous oral contraceptive regimen of 0.35 mg norethindrone, USP daily, and has the following inactive ingredients: corn starch, FD&C red no. 40 aluminum lake, lactose monohydrate, magnesium stearate, povidone and sodium starch glycolate. The chemical name for norethindrone is 17-Hydroxy-19-nor-17α-pregn-4-en-20-yn-3-one. The structural formula follows: C 20 H 26 O 2 M.W. 298.42 Therapeutic class = oral contraceptive. Meets USP Dissolution Test 2. Chemical Structure

DOSAGE AND ADMINISTRATION To achieve maximum contraceptive effectiveness, Camila must be taken exactly as directed. One tablet is taken every day, at the same time. Administration is continuous, with no interruption between pill packs. See PATIENT LABELING for detailed instructions.

INDICATIONS AND USAGE 1. Indications Progestin-only oral contraceptives are indicated for the prevention of pregnancy. 2. Efficacy If used perfectly, the first-year failure rate for progestin-only oral contraceptives is 0.5%. However, the typical failure rate is estimated to be closer to 5%, due to late or omitted pills. The following table lists the pregnancy rates for users of all major methods of contraception. Table 2: Percentage of Women Experiencing an Unintended Pregnancy During the First Year of Typical Use and the First Year of Perfect Use of Contraception and the Percentage Continuing Use at the End of the First Year. United States. % of Women Experiencing an Unintended Pregnancy within the First Year of Use % of Women Continuing Use at One Year Method (1) Typical Use Among typical couples who initiate use of a method (not necessarily for the first time), the percentage who experience an accidental pregnancy during the first year if they do not stop use for any reason. (2) Perfect Use Among couples who initiate use of a method (not necessarily for the first time), and who use it perfectly (both consistently and correctly), the percentage who experience an accidental pregnancy during the first year if they do not stop use for any other reason. (3) (4) Emergency Contraceptive Pills: Treatment initiated within 72 hours after unprotected intercourse reduces the risk of pregnancy by at least 75%. The treatment schedule is one dose within 72 hours after unprotected intercourse, and a second dose 12 hours after the first dose. The Food and Drug Administration has declared the following brands of oral contraceptives to be safe and effective for emergency contraception: Ovral (1 dose is 2 white pills), Alesse (1 dose is 5 pink pills), Nordette or Levlen (1 dose is 4 yellow pills). Lactational Amenorrhea Method: LAM is a highly effective, temporary method of contraception. However, to maintain effective protection against pregnancy, another method of contraception must be used as soon as menstruation resumes, the frequency or duration of breastfeeds is reduced, bottle feeds are introduced, or the baby reaches 6 months of age. Source: Trussell, J, Contraceptive Efficacy. In: Hatcher RA, Trussell J, Stewart F, Cates W, Stewart GK, Kowal D, Guest F, Contraceptive Technology: Seventeenth Revised Edition. New York NY: Irvington Publishers, 1998. 3 Among couples attempting to avoid pregnancy, the percentage who continue to use a method for one year. Chance The percentage of women becoming pregnant noted in columns (2) and (3) are based on data from populations where contraception is not used and from women who cease using contraception in order to become pregnant. Among such populations, about 89% become pregnant within one year. This estimate was lowered slightly (to 85%) to represent the percentage that would become pregnant within one year among women now relying on reversible methods of contraception if they abandoned contraception altogether. 85 85 Spermicides Foams, creams, gels, vaginal suppositories, and vaginal film. 26 6 40 Periodic Abstinence Calendar Ovulation Method Sympto-Thermal Cervical mucus (ovulation) method supplemented by calendar in the pre-ovulatory and basal body temperature in the post-ovulatory phases. Post-Ovulation 25 9 3 2 1 63 Cap With spermicidal cream or jelly. Parous Women 40 26 42 Nulliparous Women 20 9 56 Sponge Parous Women 40 20 42 Nulliparous Women 20 9 56 Diaphragm 20 6 56 Withdrawal 19 4 Condom Without spermicides. Female (Reality) 21 5 56 Male 14 3 61 Pill 5 71 Progestin-only 0.5 Combined 0.1 IUDs Progesterone T 2 1.5 81 Copper T380A 0.8 0.6 78 LNg 20 0.1 0.1 81 Depo-Provera 0.3 0.3 70 Levonorgestrel Implants (Norplant) 0.05 0.05 88 Female Sterilization 0.5 0.5 100 Male Sterilization 0.15 0.10 100

WARNINGS Cigarette smoking greatly increases the possibility of suffering heart attacks and strokes. Women who use oral contraceptives are strongly advised not to smoke. Camila does not contain estrogen and, therefore, this insert does not discuss the serious health risks that have been associated with the estrogen component of combined oral contraceptives. The health care provider is referred to the prescribing information of combined oral contraceptives for a discussion of those risks, including, but not limited to, an increased risk of serious cardiovascular disease in women who smoke, carcinoma of the breast and reproductive organs, hepatic neoplasia, and changes in carbohydrate and lipid metabolism. The relationship between progestin-only oral contraceptives and these risks have not been established and there are no studies definitely linking progestin-only pill (POP) use to an increased risk of heart attack or stroke. The physician should remain alert to the earliest manifestation of symptoms of any serious disease and discontinue oral contraceptive therapy when appropriate. 1. Ectopic Pregnancy The incidence of ectopic pregnancies for progestin-only oral contraceptive users is 5 per 1000 woman-years. Up to 10% of pregnancies reported in clinical studies of progestin-only oral contraceptive users are extrauterine. Although symptoms of ectopic pregnancy should be watched for, a history of ectopic pregnancy need not be considered a contraindication to use of this contraceptive method. Health providers should be alert to the possibility of an ectopic pregnancy in women who become pregnant or complain of lower abdominal pain while on progestin-only oral contraceptives. 2. Delayed Follicular Atresia/Ovarian Cysts If follicular development occurs, atresia of the follicle is sometimes delayed, and the follicle may continue to grow beyond the size it would attain in a normal cycle. Generally these enlarged follicles disappear spontaneously. Often they are asymptomatic; in some cases they are associated with mild abdominal pain. Rarely they may twist or rupture, requiring surgical intervention. 3. Irregular Genital Bleeding Irregular menstrual patterns are common among women using progestin-only oral contraceptives. If genital bleeding is suggestive of infection, malignancy or other abnormal conditions, such nonpharmacologic causes should be ruled out. If prolonged amenorrhea occurs, the possibility of pregnancy should be evaluated. 4. Carcinoma of the Breast and Reproductive Organs Some epidemiologic studies of oral contraceptive users have reported an increased relative risk of developing breast cancer, particularly at a younger age and apparently related to duration of use. These studies have predominantly involved combined oral contraceptives and there is insufficient data to determine whether the use of POPs similarly increase the risk. Women with breast cancer should not use oral contraceptives because the role of female hormone in breast cancer has not been fully determined. Some studies suggest that oral contraceptive use has been associated with an increase in the risk of cervical intraepithelial neoplasia in some populations of women. However, there continues to be controversy about the extent to which such findings may be due to differences in sexual behavior and other factors. There is insufficient data to determine whether the use of POPs increases the risk of developing cervical intraepithelial neoplasia. 5. Hepatic Neoplasia Benign hepatic adenomas are associated with combined oral contraceptive use, although the incidence of benign tumors is rare in the United States. Rupture of benign, hepatic adenomas may cause death through intraabdominal hemorrhage. Studies from Britain and the U.S. have shown an increased risk of developing hepatocellular carcinoma in combined oral contraceptive users. However, these cancers are rare. There is insufficient data to determine whether POPs increase the risk of developing hepatic neoplasia.

OVERDOSAGE There have been no reports of serious ill effects from overdosage, including ingestion by children.

4. Drug Interactions Change in contraceptive effectiveness associated with coadministration of other products: a. Anti-infective Agents and Anticonvulsants Contraceptive effectiveness may be reduced when hormonal contraceptives are coadministered with antibiotics, anticonvulsants, and other drugs that increase the metabolism of contraceptive steroids. This could result in unintended pregnancy or breakthrough bleeding. Examples include rifampin, barbiturates, phenylbutazone, phenytoin, carbamazepine, felbamate, oxcarbazepine, topiramate, and griseofulvin. b. Anti-HIV Protease Inhibitors Several of the anti-HIV protease inhibitors have been studied with coadministration of oral contraceptives; significant changes (increase and decrease) in the plasma levels of the estrogen and progestin have been noted in some cases. The safety and efficacy of OC products may be affected with the coadministration of anti-HIV protease inhibitors. Health care providers should refer to the label of the individual anti-HIV protease inhibitors for further drug-drug interaction information. c. Herbal Products Herbal products containing St. John's Wort (hypericum perforatum) may induce hepatic enzymes (cytochrome P450) and p-glycoprotein transporter and may reduce the effectiveness of contraceptive steroids. This may also result in breakthrough bleeding.

5. Interactions With Laboratory Tests The following endocrine tests may be affected by progestin-only oral contraceptive use: Sex hormone-binding globulin (SHBG) concentrations may be decreased. Thyroxine concentrations may be decreased, due to a decrease in thyroid binding globulin (TBG).

CLINICAL PHARMACOLOGY 1. Mode of Action Camila progestin-only oral contraceptives prevent conception by suppressing ovulation in approximately half of users, thickening the cervical mucus to inhibit sperm penetration, lowering the mid-cycle LH and FSH peaks, slowing the movement of the ovum through the fallopian tubes, and altering the endometrium. 2. Pharmacokinetics Absorption Norethindrone is rapidly absorbed with maximum plasma concentrations occurring within 1 to 2 hours after Camila administration (see Table 1 ). Norethindrone appears to be completely absorbed following oral administration; however, it is subject to first pass metabolism resulting in an absolute bioavailability of approximately 65%. Figure 1: Mean ± SD Norethindrone Plasma Concentrations Following Camila Administration. Peak plasma concentrations occur approximately 1 hour after administration (mean T max 1.2 hours). The mean (SD) C max was 4816.8 (1532.6) pg/mL and generally occurred within 1 hour (mean) of tablet administration, ranging from 0.5 to 2 hours. The mean (SD) C avg was 885 (250) pg/mL, however, the mean concentration at 24 hrs was 130 (47) pg/mL. Table 1 provides summary statistics of the pharmacokinetic parameters associated with single dose Camila administration. Table 1: Mean ± SD Pharmacokinetic Parameters Following Single Dose Administration of Camila in 12 Healthy Female Subjects Under Fasting Conditions Pharmacokinetic Parameter Norethindrone 0.35 mg T max (hr) 1.2 ± 0.05 C max (pg/mL) 4817 ± 1533 AUC (0-48) (pg∙h/mL) 21233 ± 6002 t 1/2 (h) 7.7 ± 0.5 The food effect on the rate and extent of norethindrone absorption after Camila administration has not been evaluated. Figure 1 Distribution Following oral administration, norethindrone is 36% bound to sex hormone-binding globulin (SHBG) and 61% bound to albumin. Volume of distribution of norethindrone is approximately 4 L/kg. Metabolism Norethindrone undergoes extensive biotransformation, primarily via reduction, followed by sulfate and glucuronide conjugation; less than 5% of a norethindrone dose is excreted unchanged; greater than 50% and 20 to 40% of a dose is excreted in urine and feces, respectively. The majority of metabolites in the circulation are sulfate, with glucuronides accounting for most of the urinary metabolites. Excretion Plasma clearance rate for norethindrone has been estimated to be approximately 600 L/day. Norethindrone is excreted in both urine and feces, primarily as metabolites. The mean terminal elimination half-life of norethindrone following single dose administration of Camila is approximately 8 hours.

1. Mode of Action Camila progestin-only oral contraceptives prevent conception by suppressing ovulation in approximately half of users, thickening the cervical mucus to inhibit sperm penetration, lowering the mid-cycle LH and FSH peaks, slowing the movement of the ovum through the fallopian tubes, and altering the endometrium.

2. Pharmacokinetics Absorption Norethindrone is rapidly absorbed with maximum plasma concentrations occurring within 1 to 2 hours after Camila administration (see Table 1 ). Norethindrone appears to be completely absorbed following oral administration; however, it is subject to first pass metabolism resulting in an absolute bioavailability of approximately 65%. Figure 1: Mean ± SD Norethindrone Plasma Concentrations Following Camila Administration. Peak plasma concentrations occur approximately 1 hour after administration (mean T max 1.2 hours). The mean (SD) C max was 4816.8 (1532.6) pg/mL and generally occurred within 1 hour (mean) of tablet administration, ranging from 0.5 to 2 hours. The mean (SD) C avg was 885 (250) pg/mL, however, the mean concentration at 24 hrs was 130 (47) pg/mL. Table 1 provides summary statistics of the pharmacokinetic parameters associated with single dose Camila administration. Table 1: Mean ± SD Pharmacokinetic Parameters Following Single Dose Administration of Camila in 12 Healthy Female Subjects Under Fasting Conditions Pharmacokinetic Parameter Norethindrone 0.35 mg T max (hr) 1.2 ± 0.05 C max (pg/mL) 4817 ± 1533 AUC (0-48) (pg∙h/mL) 21233 ± 6002 t 1/2 (h) 7.7 ± 0.5 The food effect on the rate and extent of norethindrone absorption after Camila administration has not been evaluated. Figure 1 Distribution Following oral administration, norethindrone is 36% bound to sex hormone-binding globulin (SHBG) and 61% bound to albumin. Volume of distribution of norethindrone is approximately 4 L/kg. Metabolism Norethindrone undergoes extensive biotransformation, primarily via reduction, followed by sulfate and glucuronide conjugation; less than 5% of a norethindrone dose is excreted unchanged; greater than 50% and 20 to 40% of a dose is excreted in urine and feces, respectively. The majority of metabolites in the circulation are sulfate, with glucuronides accounting for most of the urinary metabolites. Excretion Plasma clearance rate for norethindrone has been estimated to be approximately 600 L/day. Norethindrone is excreted in both urine and feces, primarily as metabolites. The mean terminal elimination half-life of norethindrone following single dose administration of Camila is approximately 8 hours.

20180529

2

CAMILA NORETHINDRONE NORETHINDRONE NORETHINDRONE STARCH, CORN FD&C RED NO. 40 LACTOSE MONOHYDRATE MAGNESIUM STEARATE POVIDONE K90 SODIUM STARCH GLYCOLATE TYPE A POTATO Light Pink m;884

6. Carcinogenesis See WARNINGS section.

ANDA076177

CAMILA

NORETHINDRONE

51862-884

HUMAN PRESCRIPTION DRUG

ORAL

PRINCIPAL DISPLAY PANEL - 0.35 mg Tablet Blister Pack Carton NDC 51862- 884 -03 Camila ® Norethindrone Tablets USP 0.35 mg Rx only 3 Blister Cards, 28 Tablets Each mayne pharma PRINCIPAL DISPLAY PANEL - 0.35 mg Tablet Blister Pack Carton

Rx Only Rev 02/2018 Patients should be counseled that oral contraceptives do not protect against transmission of HIV (AIDS) and other sexually transmitted diseases (STDs) such as Chlamydia, genital herpes, genital warts, gonorrhea, hepatitis B, and syphilis.

INFORMATION FOR THE PATIENT See PATIENT LABELING for detailed information. Counseling Issues The following points should be discussed with prospective users before prescribing progestin-only oral contraceptives: The necessity of taking pills at the same time every day, including throughout all bleeding episodes. The need to use a backup method such as condoms and spermicides for the next 48 hours whenever a progestin-only oral contraceptive is taken 3 or more hours late. The potential side effects of progestin-only oral contraceptives, particularly menstrual irregularities. The need to inform the clinician of prolonged episodes of bleeding, amenorrhea or severe abdominal pain. The importance of using a barrier method in addition to progestin-only oral contraceptives if a woman is at risk of contracting or transmitting STDs/HIV.

INSTRUCTIONS TO PATIENTS How to Use the Camila Tablets Blister Card 1. The first time you use these pills, take your first pill on the first day of your menstrual period. Pick the Days of the Week Sticker that starts the first day of your period. When you have picked the right sticker, throw away the others and place the sticker on the blister card over the pre-printed days of the week and make sure it lines up with the pills. 2. Your blister package consists of three parts, the foil pouch, wallet, and a blister card containing 28 individually sealed pills. Note that the pills are arranged in four numbered rows of 7 pills, with the preprinted days of the week printed above them. All 28 pills are "active" birth control pills. Refer to the sample of the blister card below: 3. To remove a pill, push down on the pill with your thumb and forefinger so that the pill releases through the back of the blister card. Each day, take one pill. Always go from left to right along the row. Each new row will begin on the same day of the week. 4. Take one pill every day for 28 days, whether bleeding or not, until you have taken all the pills. It is important that you take your pill at the same time every day. 5. After you have taken all 28 pills, begin taking your pills again the next day. Be sure that the calendar day on your new package corresponds with the actual day. All brand names listed are the registered trademarks of their respective owners and are not trademarks of Mayne Pharma. Manufactured for: Mayne Pharma Greenville, NC 27834 Manufactured by: Piramal Healthcare UK Limited Whalton Road Morpeth, NE61 3 YA Rev. 02/2018 20716134 Image

8. Nursing Mothers Small amounts of progestin pass into the breast milk, resulting in steroid levels in infant plasma of 1 to 6% of the levels of maternal plasma. 6 However, isolated post-market cases of decreased milk production have been reported in POPs. Very rarely, adverse effects in the infant/child have been reported, including jaundice.

12. Pediatric Use Safety and efficacy of Camila have been established in women of reproductive age. Safety and efficacy are expected to be the same for postpubertal adolescents under the age of 16 and for users 16 years and older. Use of this product before menarche is not indicated.

7. Pregnancy Many studies have found no effects on fetal development associated with long-term use of contraceptive doses of oral progestins. The few studies of infant growth and development that have been conducted have not demonstrated significant adverse effects. It is nonetheless prudent to rule out suspected pregnancy before initiating any hormonal contraceptive use.

HOW SUPPLIED Camila ® (norethindrone tablets USP, 0.35 mg) are packaged in cartons of 3 blister cards (NDC 51862-884-03) each containing 28 tablets. Each light pink, round, flat-faced, beveled-edge, unscored tablet is debossed with m on one side and 884 on the other side. KEEP THIS AND ALL MEDICATIONS OUT OF THE REACH OF CHILDREN. STORAGE Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature].

STORAGE Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature].

1. General Patients should be counseled that oral contraceptives do not protect against transmission of HIV (AIDS) and other sexually transmitted diseases (STDs) such as Chlamydia, genital herpes, genital warts, gonorrhea, hepatitis B, and syphilis.

PRECAUTIONS 1. General Patients should be counseled that oral contraceptives do not protect against transmission of HIV (AIDS) and other sexually transmitted diseases (STDs) such as Chlamydia, genital herpes, genital warts, gonorrhea, hepatitis B, and syphilis. 2. Physical Examination and Follow-up It is considered good medical practice for sexually active women using oral contraceptives to have annual history and physical examinations. The physical examination may be deferred until after initiation of oral contraceptives if requested by the woman and judged appropriate by the clinician. 3. Carbohydrate and Lipid Metabolism Some users may experience slight deterioration in glucose tolerance, with increases in plasma insulin, but women with diabetes mellitus who use progestin-only oral contraceptives do not generally experience changes in their insulin requirements. Nonetheless, prediabetic and diabetic women in particular should be carefully monitored while taking POPs. Lipid metabolism is occasionally affected in that HDL, HDL2, and apolipoprotein A-I and A-II may be decreased; hepatic lipase may be increased. There is no effect on total cholesterol, HDL3, LDL, or VLDL. 4. Drug Interactions Change in contraceptive effectiveness associated with coadministration of other products: a. Anti-infective Agents and Anticonvulsants Contraceptive effectiveness may be reduced when hormonal contraceptives are coadministered with antibiotics, anticonvulsants, and other drugs that increase the metabolism of contraceptive steroids. This could result in unintended pregnancy or breakthrough bleeding. Examples include rifampin, barbiturates, phenylbutazone, phenytoin, carbamazepine, felbamate, oxcarbazepine, topiramate, and griseofulvin. b. Anti-HIV Protease Inhibitors Several of the anti-HIV protease inhibitors have been studied with coadministration of oral contraceptives; significant changes (increase and decrease) in the plasma levels of the estrogen and progestin have been noted in some cases. The safety and efficacy of OC products may be affected with the coadministration of anti-HIV protease inhibitors. Health care providers should refer to the label of the individual anti-HIV protease inhibitors for further drug-drug interaction information. c. Herbal Products Herbal products containing St. John's Wort (hypericum perforatum) may induce hepatic enzymes (cytochrome P450) and p-glycoprotein transporter and may reduce the effectiveness of contraceptive steroids. This may also result in breakthrough bleeding. 5. Interactions With Laboratory Tests The following endocrine tests may be affected by progestin-only oral contraceptive use: Sex hormone-binding globulin (SHBG) concentrations may be decreased. Thyroxine concentrations may be decreased, due to a decrease in thyroid binding globulin (TBG). 6. Carcinogenesis See WARNINGS section. 7. Pregnancy Many studies have found no effects on fetal development associated with long-term use of contraceptive doses of oral progestins. The few studies of infant growth and development that have been conducted have not demonstrated significant adverse effects. It is nonetheless prudent to rule out suspected pregnancy before initiating any hormonal contraceptive use. 8. Nursing Mothers Small amounts of progestin pass into the breast milk, resulting in steroid levels in infant plasma of 1 to 6% of the levels of maternal plasma. 6 However, isolated post-market cases of decreased milk production have been reported in POPs. Very rarely, adverse effects in the infant/child have been reported, including jaundice. 9. Fertility Following Discontinuation The limited available data indicate a rapid return of normal ovulation and fertility following discontinuation of progestin-only oral contraceptives. 10. Headache/Migraine If you have a headache or a worsening migraine headache with a new pattern that is recurrent, persistent, or severe, this requires discontinuation of oral contraceptives and evaluation of the cause. 11. Gastrointestinal Diarrhea and/or vomiting may reduce hormone absorption resulting in decreased serum concentrations. 12. Pediatric Use Safety and efficacy of Camila have been established in women of reproductive age. Safety and efficacy are expected to be the same for postpubertal adolescents under the age of 16 and for users 16 years and older. Use of this product before menarche is not indicated.