Drug Safety-related Labeling Changes (SrLC)

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LO/OVRAL FE (NDA-018206)

(ETHINYL ESTRADIOL; LEVONORGESTREL; FERROUS FUMARATE)

Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)

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10/18/2017 (SUPPL-20)

Approved Drug Label (PDF)

Boxed Warning

(Additions and/or revisions are underlined)

WARNING: CIGARETTE SMOKING AND SERIOUS CARDIOVASCULAR EVENTS

Cigarette smoking increases the risk of serious cardiovascular events from combination oral contraceptive (COC) use. This risk increases with age, particularly in women over 35 years of age, and with the number of cigarettes smoked. For this reason, COCs should not be used by women who are over 35 years of age and smoke.

4 Contraindications

(Additions and/or revisions are underlined)

Do not prescribe LO/OVRAL-28 to women who are known to have the following conditions:

  • A high risk of arterial or venous thrombotic diseases. Examples include women who are known to:

    • Smoke, if over age 35

    • Have deep vein thrombosis or pulmonary embolism, now or in the past

    • Have inherited or acquired hypercoagulopathies

    • Have cerebrovascular disease

    • Have coronary artery disease

    • Have thrombogenic valvular or thrombogenic rhythm diseases of the heart (for example, subacute bacterial endocarditis with valvular disease, or atrial fibrillation)

    • Have uncontrolled hypertension

    • Have diabetes mellitus with vascular disease

    • Have headaches with focal neurological symptoms or have migraine headaches with aura

      • Women over age 35 with any migraine headaches

  • Liver tumors, benign or malignant, or liver disease

  • Undiagnosed abnormal uterine bleeding

  • Pregnancy, because there is no reason to use COCs during pregnancy

  • Breast cancer or other estrogen- or progestin-sensitive cancer, now or in the past

5 Warnings and Precautions

5.1 Thrombotic Disorders and Other Vascular Problems

(Subsection title has been revised; Additions and/or revisions are underlined)

  • Stop LO/OVRAL-28 if an arterial thrombotic event or venous thromboembolic (VTE) event occurs.

  • Stop LO/OVRAL-28 if there is unexplained loss of vision, proptosis, diplopia, papilledema. Evaluate for retinal vein thrombosis immediately.

  • If feasible, stop LO/OVRAL-28 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 and following prolonged immobilization.

  • Start LO/OVRAL-28 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 that result in 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.

5.10 Carcinoma of the Breast and Cervix

(Subsection title has been revised; Additions and/or revisions are underlined)

  • LO/OVRAL-28 is contraindicated in women who currently have or have had breast cancer because breast cancer is hormonally-sensitive.

  • There is substantial evidence that COCs do not increase the incidence of breast cancer. Although some past studies have suggested that COCs might increase the incidence of breast cancer, more recent studies have not confirmed such findings.

  • 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 may be due to differences in sexual behavior and other factors.

5.11 Effect on Binding Globulins

(Newly added subsection)

The estrogen component of COCs 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.

5.12 Hereditary Angioedema

(Newly added subsection)

In women with hereditary angioedema, exogenous estrogens may induce or exacerbate symptoms of angioedema.

5.13 Chloasma

(Newly added subsection)

Chloasma may occasionally occur, especially in women with a history of chloasma gravidarum. Women with a tendency to chloasma should avoid exposure to the sun or ultraviolet radiation while taking LO/OVRAL-28.

5.2 Liver Disease

(Subsection title has been revised; Additions and/or revisions are underlined)

Impaired Liver Function

Do not use LO/OVRAL-28 in women with liver disease, such as acute viral hepatitis or severe (decompensated) cirrhosis of liver. 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 LO/OVRAL-28 if jaundice develops.

Liver Tumors

LO/OVRAL-28 is contraindicated in women with benign and malignant liver tumors. 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.

5.4 High Blood Pressure

(Subsection title has been revised; Additions and/or revisions are underlined)

LO/OVRAL-28 is contraindicated in women with uncontrolled hypertension or hypertension with vascular disease. For women with well-controlled hypertension, monitor blood pressure and stop LO/OVRAL-28 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

(Additions and/or revisions are underlined)

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.

5.6 Carbohydrate and Lipid Metabolic Effect

(Additions and/or revisions are underlined)

Carefully monitor prediabetic and diabetic women who are taking LO/OVRAL-28. COCs may decrease glucose tolerance.

Consider alternative contraception for women with uncontrolled dyslipidemias. A small proportion of women will have adverse lipid changes while on COCs.

Women with hypertriglyceridemia, or a family history thereof, may be at an increased risk of pancreatitis when using COCs.

5.7 Headache

(Additions and/or revisions are underlined)

If a woman taking LO/OVRAL-28 develops new headaches that are recurrent, persistent, or severe, evaluate the cause and discontinue LO/OVRAL-28 if indicated.

Consider discontinuation of LO/OVRAL-28 in the case of increased frequency or severity of migraine during COC use (which may be prodromal of a cerebrovascular event).

5.8 Bleeding Irregularities and Amenorrhea

(Subsection title has been revised; Additions and/or revisions are underlined)

Unscheduled Bleeding and Spotting

Unscheduled (breakthrough or intracyclic) bleeding and spotting sometimes occur in patients on COCs, especially during the first three months of use. If bleeding persists or occurs after previously regular cycles, check for causes such as pregnancy or malignancy. If pathology and pregnancy are excluded, bleeding irregularities may resolve over time or with a change to a different contraceptive product.

The frequency and duration of unscheduled bleeding and/or spotting was assessed in 1,343 subjects across nine studies. Unscheduled bleeding and spotting occurred in 15% of women in the first cycle on treatment, 9% in Cycle 3, 5% in Cycle 6, 5% in Cycle 9 and 5% in Cycle 12. In 1287 subjects, LO/OVRAL-28 was discontinued in 1% of subjects due to breakthrough bleeding and 1% of subjects discontinued due to spotting.

Amenorrhea and Oligomenorrhea

Women who use LO/OVRAL-28 may experience amenorrhea, absence of withdrawal bleeding, even if they are not pregnant. In the clinical trials with LO/OVRAL-28, amenorrhea was reported in 3% of subjects in the first cycle, 2% in Cycle 3, 2% in Cycle 6, 1% in Cycle 9 and 2% in Cycle 12. Amenorrhea was the reason for study discontinuation in < 1% of subjects.

Some women may experience amenorrhea or oligomenorrhea after discontinuation of COCs, especially when such a condition was preexistent.

If scheduled (withdrawal) bleeding does not occur, consider the possibility of pregnancy. If the patient has not adhered to the prescribed dosing schedule (missed one or more active tablets or started taking them on a day later than she should have), consider the possibility of pregnancy at the time of the first missed period and take appropriate diagnostic measures. If the patient has adhered to the prescribed regimen and misses two consecutive periods, rule out pregnancy.

5.9 Depression

(Subsection title has been revised; Additions and/or revisions are underlined)

Carefully observe women with a history of depression and discontinue LO/OVRAL-28 if depression recurs to a serious degree.

8.7 Renal Impairment

(Newly added subsection)

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

6 Adverse Reactions

(Additions and/or revisions are underlined)

The following serious adverse reactions with the use of COCs are discussed elsewhere in the labeling:

  • Serious cardiovascular events and stroke

  • Vascular events

  • Liver disease

The following adverse reactions are commonly reported by COC users. Because these reactions are voluntarily reported by from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure:

  • Irregular uterine bleeding

  • Nausea

  • Breast tenderness

  • Headache

6.1 Clinical Trial Experience

(Newly added subsection title; Additions and/or revisions are underlined)

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to the rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The safety of LO/OVRAL-28 was evaluated in nine clinical investigations with a cumulative total of 1,343 subjects aged 15 to 40 and followed for a total of 11,085 cycles (852 women years of study). The subjects were recruited from a wide geographical distribution in the United States and including all socio-economic groups. The ethnic distribution of study volunteers was: 69% white; 28% black; 1.0% Asian; and 2% other backgrounds. 28% nulligravidas and 72% gravidas.

Common Adverse Reactions (Greater than or equal to 2% of all subjects): The most common adverse reactions were headache (6%), nausea (5%), acne (4%), vaginal infection (4%), vaginal discharge (4%), dysmenorrhea (4%) breast discomfort (3%), depression (3%), increased appetite (3%), gastrointestinal symptoms (3%), nervousness (3%), backache (2%), change in menstrual flow (2%), chloasma/melasma (2%), exacerbation of varicose veins (2%).

Adverse Reactions Leading to Study Discontinuation: A total of 103 subjects (8%) dropped out of the trials due to adverse reactions, including unscheduled bleeding (breakthrough bleeding 1%; spotting 1%), and the following each in < 1%, headache including migraine, amenorrhea, nausea, acne, change in menstrual flow, nervousness, increase in weight, depression, and high blood pressure.

6.2 Postmarketing Experience

(Newly added subsection title; Additions and/or revisions are underlined)

The following adverse reactions have been identified during post approval use of LO/OVRAL-28. Because these reactions are reported voluntarily from a population of uncertain size, it is difficult to reliably estimate their frequency or evaluate a causal relationship to drug exposure.

Arterial events: myocardial infarction, arterial thromboembolism, and cerebral hemorrhage.

Eye disorders: retinal vein thrombosis, change in corneal curvature (steepening).

GI disorders: nausea, pancreatitis.

Hepatobiliary disorders: gallbladder disease and cholestatic jaundice.

Immune system disorders: anaphylactic/anaphylactoid reactions, including urticaria, angioedema, and severe reactions with respiratory and circulatory symptoms.

Metabolism and nutrition disorders: change in weight or appetite (increase or decrease), carbohydrate and lipid effects.

Neoplasms, Benign, Malignant, and Unspecified: Carincoma of the reproductive organs and breasts, Hepatic neoplasia (including hepatic adenomas, or benign liver tumors).

Skin and subcutaneous disorders:, hirsutism, erythema multiforme, erythema nodosum, hemorrhagic eruption, and melasma/chloasma, which may persist

Nervous system disorders: headache, migraine.

Psychiatric disorders: mood swings.

Reproductive system and breast disorders: breast changes (tenderness, pain, enlargement, and secretion), premenstrual syndrome.

Vascular disorders: venous thrombosis, pulmonary embolism, cerebral thrombosis, mesenteric thrombosis, and retinal vascular thrombosis.

7 Drug Interactions

(Additions and/or revisions are underlined)

Consult the labeling of concurrently used drugs to obtain further information about interactions with hormonal contraceptives or the potential for enzyme alterations.

7.1 Effects of Other Drugs on Combined Oral Contraceptives

(Additions and/or revisions are underlined)

Substances decreasing the plasma concentrations of COCs and potentially diminishing the efficacy of COCs:

Drugs or herbal products that induce certain enzymes, including cytochrome P450 3A4 (CYP3A4), may decrease the plasma concentrations of COCs and potentially diminish the effectiveness of COCs or increase breakthrough bleeding. Some drugs or herbal products that may decrease the effectiveness of oral contraceptives including phenytoin, barbiturates, carbamazepine, bosentan, felbamate, griseofulvin, oxcarbazepine, rifampicin, topiramate, rifabutin, rufinamide, aprepitant, and products containing St. John’s wort. Interactions between COCs and other drugs may lead to breakthrough bleeding and/or contraceptive failure. Counsel women to use an alternative non-hormonal method of contraception or a back-up method when enzyme inducers are used with COCs, and to continue back-up non-hormonal contraception for 28 days after discontinuing the enzyme inducer to ensure contraceptive reliability.

Colesevelam: Colesevelam, a bile acid sequestrant, given together with a COC, has been shown to significantly decrease the AUC of EE. The drug interaction between the contraceptive and colesevelam was decreased when the two drug products were given 4 hours apart.


Substances increasing the plasma concentrations of COCs:

Co-administration of atorvastatin or rosuvastatin and certain COCs containing ethinyl estradiol (EE) increase AUC values for EE by approximately 20 to 25%. Ascorbic acid and acetaminophen may increase plasma EE concentrations, possibly by inhibition of conjugation. Concomitant administration of CYP3A4 inhibitors such as itraconazole, voriconazole, fluconazole, grapefruit juice, or ketoconazole may increase plasma hormone concentrations.

Human immunodeficiency virus (HIV)/Hepatitis C virus (HCV) protease inhibitors and non-nucleoside reverse transcriptase inhibitors:

Significant changes (increase or decrease) in the plasma concentrations of estrogen and/or progestin have been noted in some cases of co-administration with HIV protease inhibitors (decrease [e.g., nelfinavir, ritonavir, darunavir/ritonavir, (fos)amprenavir/ritonavir, lopinavir/ritonavir, and tipranavir/ritonavir] or increase [e.g., indinavir and atazanavir/ritonavir])/HCV protease inhibitors or with non-nucleoside reverse transcriptase inhibitors (decrease [e.g., nevirapine and efavirenz] or increase [e.g., etravirine]). These changes may be clinically relevant in some cases.

7.3 Effects of Combined Oral Contraceptives on Other Drugs

(Additions and/or revisions are underlined)

COCs containing EE may inhibit the metabolism of other compounds (e.g., cyclosporine, prednisolone, theophylline, tizanidine, and voriconazole) and increase their plasma concentrations. COCs have been shown to decrease plasma concentrations of acetaminophen, clofibric acid, morphine, salicylic acid, and temazepam. A significant decrease in plasma concentration of lamotrigine has been shown, likely due to induction of lamotrigine glucuronidation. This may reduce seizure control; therefore, dosage adjustments of lamotrigine may be necessary.

Women on thyroid hormone replacement therapy may need increased doses of thyroid hormone because the serum concentration of thyroid-binding globulin increases with use of COCs.

7.4 Interactions with Laboratory Tests

(Additions and/or revisions are underlined)

The use of contraceptive steroids may influence the results of certain laboratory tests, such as coagulation factors, lipids, glucose tolerance, and binding proteins.

8 Use in Specific Populations

8.1 Pregnancy

(Pregnancy and Lactation Labeling Rule (PLLR) Conversion; additions and/or revisions are underlined)

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

(Pregnancy and Lactation Labeling Rule (PLLR) Conversion; additions and/or revisions are underlined)

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.

8.4 Pediatric Use

(Additions and/or revisions are underlined)

Safety and efficacy of LO/OVRAL-28 have been established in women of reproductive age. Efficacy is expected to be the same in postpubertal adolescents under the age of 18 years as for users 18 years and older. Use of this LO/OVRAL- 28 before menarche is not indicated.

8.5 Geriatric Use

(Additions and/or revisions are underlined)

LO/OVRAL-28 has not been studied in postmenopausal women and is not indicated in this population.

8.6 Hepatic Impairment

(Newly added subsection)

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.

8.8 Body Mass Index

(Newly added subsection)

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

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

17 PATIENT COUNSELING INFORMATION

(Newly added subsection)

See FDA-approved Patient Labeling (Patient Information and Instructions for Use). Counsel patients about the following information:

  • Cigarette smoking increases the risk of serious cardiovascular events from COC use, and that women who are over 35 years old and smoke should not use COCs.

  • Increased risk of VTE compared to non-users of COCs is greatest after initially starting a COC or restarting (following a 4-week or greater pill-free interval) the same or a different COC.

  • LO/OVRAL-28 does not protect against HIV infection (AIDS) and other sexually transmitted diseases.

  • LO/OVRAL-28 is not to be used during pregnancy; if pregnancy occurs during use of LO/OVRAL-28 instruct the patient to stop further use.

  • Take one tablet daily by mouth at the same time every day. Instruct patients what to do in the event pills are missed.

  • Use a back-up or alternative method of contraception when enzyme inducers are used with LO/OVRAL-28.

  • COCs may reduce breast milk production; this is less likely to occur if breastfeeding is well established.

  • Women who start COCs postpartum, and who have not yet had a period, should use an additional method of contraception until she has taken a white tablet for 7 consecutive days.

  • Amenorrhea may occur. Consider pregnancy in the event of amenorrhea at the time of the first missed period. Rule out pregnancy if amenorrhea persists beyond two consecutive cycles.

PATIENT INFORMATION

(Extensive changes; please refer to label)

Other

(Physician Labeling Rule (PLR) Conversion; please refer to label)

08/09/2017 (SUPPL-21)

Approved Drug Label (PDF)

4 Contraindications

(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.

5 Warnings and Precautions

WARNINGS

(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.

7 Drug Interactions

(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.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

Patient Information

(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.

Questions related to the drug data in these files should be directed to the Center for Drug Evaluation and Research, Division of Drug Information
druginfo@fda.hhs.gov.

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