Aurovela 24 Fe Kit
FDA Label NDC 65862-934

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 [see Contraindications (4)].

Aurovela 24 Fe is indicated for use by women to prevent pregnancy [see Clinical Studies (14)].

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

Aurovela 24 Fe is available in a blister pack [see How Supplied/Storage and Handling (16)]. Aurovela 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.

Starting Aurovela 24 Fe after Abortion or Miscarriage

First-trimester

• After a first-trimester abortion or miscarriage, Aurovela 24 Fe may be started immediately. An additional method of contraception is not needed if Aurovela 24 Fe is started immediately.


• If Aurovela 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 Aurovela 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 Aurovela 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 Aurovela 24 Fe [see Contraindications (4), Warnings and Precautions (5.1), and FDA-approved Patient Labeling].



Starting Aurovela 24 Fe after Childbirth



• Do not start until 4 weeks after delivery, due to the increased risk of thromboembolic disease. Start contraceptive therapy with Aurovela 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 Aurovela 24 Fe [see Contraindications (4), Warnings and Precautions (5.1), Use in Specific Populations (8.1 and 8.3)].

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 light yellow to yellow tablet, handle this as a missed tablet [see FDA-Approved Patient Labeling].

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

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

• 24 light yellow to yellow, round, flat-faced, beveled-edge, uncoated (active) tablets debossed with ‘S’ on one side and ‘64’ on other side and each containing 1 mg of norethindrone acetate USP and 20 mcg of ethinyl estradiol USP.


• 4 brown, mottled, round, flat-faced, beveled-edge (non-hormonal placebo) tablets debossed with 'S' on one side and '57' on other side and each containing 75 mg ferrous fumarate USP. The ferrous fumarate tablets do not serve any therapeutic purpose.

Do not prescribe Aurovela 24 Fe 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 [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)]
• Pregnancy, because there is no reason to use COCs during pregnancy [see Warnings and Precautions (5.9) and Use in Specific Populations (8.1)]
• Breast cancer or other estrogen- or progestin-sensitive cancer, now or in the past [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)]

• Stop Aurovela 24 Fe if an arterial thrombotic event or venous thromboembolic (VTE) event occurs.


• Stop Aurovela 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 Aurovela 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 Aurovela 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.

Impaired Liver Function

Do not use Aurovela 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 Aurovela 24 Fe if jaundice develops.

Liver Tumors

Aurovela 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 (greater than 8 years) COC users. However, the risk of liver cancers in COC users is less than one case per million users.

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

Aurovela 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 Aurovela 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.

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.

Carefully monitor prediabetic and diabetic women who are taking Aurovela 24 Fe. 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.

If a woman taking Aurovela 24 Fe develops new headaches that are recurrent, persistent, or severe, evaluate the cause and discontinue Aurovela 24 Fe if indicated.

Consider discontinuation of Aurovela 24 Fe in the case of increased frequency or severity of migraine during COC use (which may be prodromal of a cerebrovascular event).

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.

In a clinical trial of Aurovela 24 Fe, the frequency and duration of unscheduled bleeding and/or spotting was assessed in 743 women (3,823 28-day cycles). A total of 10 subjects (1.3%) discontinued Aurovela 24 Fe, at least in part, due to bleeding or spotting. Based on data from the clinical trial, [24 to 38%] of women using Aurovela 24 Fe experienced unscheduled bleeding per cycle in the six months of the trial. The percent of women who experienced unscheduled bleeding tended to decrease over time.

Amenorrhea and Oligomenorrhea

Women who use Aurovela 24 Fe may experience absence of withdrawal bleeding, even if they are not pregnant. In the clinical trial with Aurovela 24 Fe, 31 to 41% of the women using Aurovela 24 Fe did not have a withdrawal menses in at least one of 6 cycles of use.

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.

Extensive epidemiologic studies have revealed no increased risk of birth defects in women who have used oral contraceptives prior to pregnancy. Studies also do not suggest a teratogenic effect, particularly in so far as cardiac anomalies and limb reduction defects are concerned, when oral contraceptives are taken inadvertently during early pregnancy. Discontinue Aurovela 24 Fe use if pregnancy is confirmed.

Administration of COCs to induce withdrawal bleeding should not be used as a test for pregnancy [see Use in Specific Populations (8.1)].

Carefully observe women with a history of depression and discontinue Aurovela 24 Fe if depression recurs to a serious degree.

Aurovela 24 Fe is contraindicated in women who currently have or have had breast cancer because breast cancer is a hormonally-sensitive [see Contraindications (4)].

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.

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.

A woman who is taking COCs should have a yearly visit with her healthcare provider for a blood pressure check and for other indicated healthcare.

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

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 Aurovela 24 Fe.

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

• Serious cardiovascular events and stroke [see Boxed Warning and Warnings and Precautions (5.1)]
• Vascular events [see Warnings and Precautions (5.1)]
• Liver disease [see Warnings and Precautions (5.2)]



Adverse reactions commonly reported by COC users are:



• Irregular uterine bleeding
• Nausea
• Breast tenderness
• Headache

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 Aurovela 24 Fe was evaluated in 743 subjects who participated in an open-label, randomized, active-controlled, multicenter clinical trial of Aurovela 24 Fe for contraception. This trial examined healthy, non-pregnant volunteers aged 18 to 45 years, who were sexually active and had a body mass index of less than or equal to 35 kg/m². Subjects were followed for up to six 28-day cycles providing a total of 3,823 treatment-cycles of exposure.

Common Adverse Reactions (greater than or equal to 2% of all subjects): The most common adverse reactions reported by at least 2% of the 743 women using Aurovela 24 Fe were the following, in order of decreasing incidence: headache (6.3%), vaginal candidiasis (6.1%), nausea (4.6%), menstrual cramps (4.4%), breast tenderness (3.4%), mood changes (including mood swings (2.2%) and depression (1.1%), bacterial vaginitis (3.1%), acne (2.7%), and weight gain (2.0%).

Adverse Reactions Leading to Study Discontinuation: Among the 743 women using Aurovela 24 Fe, 46 women (6.2%) withdrew because of an adverse event. Adverse events occurring in 3 or more subjects leading to discontinuation of treatment were, in decreasing order: abnormal bleeding (0.9%), nausea (0.8%), mood changes (0.8%), menstrual cramps (0.4%), increased blood pressure (0.4%), and irregular bleeding (0.4%).

The following adverse reactions have been identified during post approval use of Aurovela 24 Fe. 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.

Cardiovascular: chest pain, palpitations, tachycardia, angina pectoris, myocardial infarction.

Endocrine disorders: hypothyroidism, hyperthyroidism.

Eye disorders: blurred vision, visual impairment, transient blindness, corneal thinning, change in corneal curvature (steepening).

GI disorders: nausea, vomiting, abdominal pain, constipation, pancreatitis.

Hepatobiliary disorders: cholelithiasis, cholecystitis, hepatic adenoma, hemangioma of liver.

Immune system disorders: anaphylactic reactions, including urticaria, angioedema, and

severe reactions with respiratory and circulatory symptoms.

Infections: vaginal infection.

Metabolism and nutrition disorders: change in weight or appetite (increase or decrease).

hypoglycemia, diabetes mellitus, anemia.

Musculoskeletal and connective tissue disorders: myalgia.

Skin and subcutaneous disorders: alopecia, rash (generalized and allergic), pruritus, skin

discoloration, night sweats, swelling face or lips, hirsutism, skin burning sensation, erythema

multiforme, erythema nodosum, hemorrhagic eruption.

Nervous system disorders: headache, dizziness, migraine, hyperesthesia, paraesthesia, hypoaesthesia, somnolence, loss of consciousness, sensory disturbance.

Psychiatric disorders: mood swings, depression, insomnia, anxiety, suicidal ideation, panic attack, changes in libido, bipolar disorder, dissociation, homicidal ideation.

Renal and urinary disorders: pollakiuria, dysuria, cystitis-like syndrome.

Reproductive system and breast disorders: breast changes (tenderness, pain, enlargement, and secretion), premenstrual syndrome, ovarian cyst, pelvic pain, ovarian cyst ruptured, pelvic fluid collection.

Vascular disorders: hot flush, thrombosis/embolism (coronary artery, pulmonary, cerebral, deep vein), migraine, transient ischemic attack, ischemic stroke.

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

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 method of contraception or a back-up method when enzyme inducers are used with COCs, and to continue back-up contraception for 28 days after discontinuing the enzyme inducer to ensure contraceptive reliability.

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. 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] or increase [e.g., etravirine]).

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. 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 [see Warnings and Precautions (5.12)].

Do not co-administer Aurovela 24 Fe with HCV drug combinations containing ombitasvir/ paritaprevir/ritonavir, with or without dasabuvir, due to potential for ALT elevations [see Warnings and Precautions (5.3)].

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

There is little or no increased risk of birth defects in women who inadvertently use COCs during early pregnancy. Epidemiologic studies and meta-analyses have not found an increased risk of genital or non-genital birth defects (including cardiac anomalies and limb reduction defects) following exposure to low dose COCs prior to conception or during early pregnancy.

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.

Women who do not breastfeed should not start COCs earlier than 4 weeks postpartum.

Advise the nursing mother to use another contraceptive method, when possible, until she has weaned her child. COCs can reduce milk production in breastfeeding mothers. This is less likely to occur once breastfeeding is well-established; however, it can occur at any time in some women. Small amounts of oral contraceptive steroids and/or metabolites are present in breast milk.

Safety and efficacy of Aurovela 24 Fe 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 product before menarche is not indicated.

Aurovela 24 Fe has not been studied in postmenopausal women and is not indicated in this population.

The pharmacokinetics of Aurovela 24 Fe 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)].

The pharmacokinetics of Aurovela 24 Fe has not been studied in women with renal impairment.

The safety and efficacy of Aurovela 24 Fe in women with a body mass index (BMI) greater than 35 kg/m² has not been evaluated [see Clinical Studies (14)].

There have been no reports of serious ill effects from overdose of oral contraceptives, including ingestion by children. Overdosage may cause withdrawal bleeding in females and nausea.

Aurovela 24 Fe is a combination oral contraceptive for oral administration consisting of active tablets containing norethindrone acetate, a progestin, and ethinyl estradiol, an estrogen, and placebo tablets containing ferrous fumarate, which serve no therapeutic purpose.

• Each active light yellow to yellow tablet contains 1 mg norethindrone acetate USP and  20 mcg ethinyl estradiol USP. Inactive ingredients include compressible sugar, croscarmellose sodium, D & C Yellow No. 10 Aluminum Lake, lactose monohydrate, magnesium stearate, microcrystalline cellulose, povidone and vitamin E.


• Each placebo brown tablet contains 75 mg ferrous fumarate, croscarmellose sodium, lactose monohydrate, magnesium stearate, microcrystalline cellulose, Nat spearmint FL SD #11475, povidone and sucralose. The ferrous fumarate tablets do not serve any therapeutic purpose. Ferrous fumarate tablets are not USP for dissolution and assay.



The chemical name of ethinyl estradiol is 19-nor-17α-pregna-1,3,5(10)-trien-20-yne-3,17-diol. The molecular formula of ethinyl estradiol is C₂₀H₂₄O₂ and the structural formula is:





Structure-1 (Norethindroneethinyl Str1)

 



The chemical name of norethindrone acetate is 17-hydroxy-19-nor-17α-pregn-4-en-20-yn-3-one acetate. The molecular formula of norethindrone acetate is C₂₂H₂₈O₃ and the structural formula is:





Structure-2 (Norethindroneethinyl Str2)

 




 

 

USP Dissolution Test Pending.

COCs lower the risk of becoming pregnant primarily by suppressing ovulation. Other possible mechanisms may include cervical mucus changes that inhibit sperm penetration and endometrial changes that reduce the likelihood of implantation.

No specific pharmacodynamic studies were conducted with Aurovela 24 Fe.

Absorption

Norethindrone acetate appears to be completely and rapidly deacetylated to norethindrone after oral administration, because the disposition of norethindrone acetate is indistinguishable from that of orally administered norethindrone. Norethindrone acetate and ethinyl estradiol are rapidly absorbed from Aurovela 24 Fe tablets, with maximum plasma concentrations of norethindrone and ethinyl estradiol occurring 1 to 4 hours postdose. Both are subject to first-pass metabolism after oral dosing, resulting in an absolute bioavailability of approximately 64% for norethindrone and 43% for ethinyl estradiol.

The plasma norethindrone and ethinyl estradiol pharmacokinetics following single- and multiple-dose administrations of Aurovela 24 Fe tablets in 17 healthy female volunteers are provided in Figures 1 and 2, and Table 3.

Following multiple-dose administration of Aurovela 24 Fe tablets, mean maximum concentrations of norethindrone and ethinyl estradiol were increased by 95% and 27%, respectively, as compared to single-dose administration. Mean norethindrone and ethinyl estradiol exposures (AUC values) were increased by 164% and 51% respectively, as compared to single-dose administration of Aurovela 24 Fe tablets.

Steady-state with respect to norethindrone was reached by Day 17 and steady-state with respect to ethinyl estradiol was reached by Day 13.

Mean SHBG concentrations were increased by 150% from baseline (57.5 nmol/L) to    144 nmol/L at steady-state.

Figure 1. Mean Plasma Norethindrone Concentration-Time Profiles Following Single- and Multiple-Dose Oral Administration of Aurovela 24 Fe Tablets to Healthy Female Volunteers Under Fasting Condition (n = 17)

Figure-1 (Norethindroneethinyl Fig1)

Figure 2. Mean Plasma Ethinyl Estradiol Concentration-Time Profiles Following Single- and Multiple-Dose Oral Administration of Aurovela 24 Fe Tablets to Healthy Female Volunteers Under Fasting Condition (n = 17)

Figure-2 (Norethindroneethinyl Fig2)

Table 3. Summary of Norethindrone (NE) and Ethinyl Estradiol (EE) Pharmacokinetics Following Single- and Multiple-Dose Oral Administration of Aurovela 24 Fe Tablets to Healthy Female Volunteers Under Fasting Condition (n = 17)

C_max = Maximum plasma concentration

t_max = Time of C_max

C_min = minimum plasma concentration at steady-state

AUC₍₀₋₂₄₎ = Area under plasma concentration versus time curve from 0 to 24 hours

t_½ = Apparent first-order terminal elimination half-life

C_avg = Average plasma concentration = AUC_(0–24)/24

% CV = Coefficient of Variation (%)

SHBG = Sex Hormone Binding Globulin (nmol/L)

^a The harmonic mean (0.693/mean apparent elimination rate constant) is reported for t_½, and the median (range) is reported for t_max.

^b The SHBG concentration reported here is the pre-dose concentration.

Food Effect

A single-dose administration of Aurovela 24 Fe tablet with food decreased the maximum concentration of norethindrone by 11% and increased the extent of absorption by 27% and decreased the maximum concentration of ethinyl estradiol by 30% but not the extent of absorption.

Distribution

Volume of distribution of norethindrone and ethinyl estradiol ranges from 2 to 4 L/kg. Plasma protein binding of both steroids is extensive (greater than 95%); norethindrone binds to both albumin and SHBG, whereas ethinyl estradiol binds only to albumin. Although ethinyl estradiol does not bind to SHBG, it induces SHBG synthesis.

Metabolism

Norethindrone undergoes extensive biotransformation, primarily via reduction, followed by sulfate and glucuronide conjugation. The majority of metabolites in the circulation are sulfates, with glucuronides accounting for most of the urinary metabolites.

Ethinyl estradiol is also extensively metabolized, both by oxidation and by conjugation with sulfate and glucuronide. Sulfates are the major circulating conjugates of ethinyl estradiol and glucuronides predominate in urine. The primary oxidative metabolite is 2-hydroxy ethinyl estradiol, formed by the CYP3A4 isoform of cytochrome P450. Part of the first-pass metabolism of ethinyl estradiol is believed to occur in gastrointestinal mucosa. Ethinyl estradiol may undergo enterohepatic circulation.

Excretion

Norethindrone and ethinyl estradiol are excreted in both urine and feces, primarily as metabolites. Plasma clearance values for norethindrone and ethinyl estradiol are similar (approximately 0.4 L/hr/kg). Steady-state elimination half-lives of norethindrone and ethinyl estradiol following administration of Aurovela 24 Fe tablets are approximately 8 hours and 14 hours, respectively.

[See Warnings and Precautions (5.2, 5.11) and Use in Specific Populations (8.1).]

In an active-controlled clinical trial, 743 women 18 to 45 years of age were studied to assess the efficacy of Aurovela 24 Fe, for up to six 28-day cycles. The racial demographic of women randomized to Aurovela 24 Fe was: 69.5% Caucasian, 15.5% African-American, 10.4% Hispanic, 2.3% Asian and 2.3% Native American/Other. Women with body mass index (BMI) greater than 35 mg/m² were excluded from the study. The weight range for those women treated was 90 to 260 pounds, with a mean weight of 147 pounds. Among the women in the study randomized to Aurovela 24 Fe, 38.9% had not used hormonal contraception immediately prior to enrolling in this study.

A total of 583 women completed 6 cycles of treatment. There were a total of 5 on-treatment pregnancies among women aged 18 to 45 years in 3,565 treatment cycles during which no back-up contraception was used. The Pearl Index for Aurovela 24 Fe was 1.82 (95% confidence interval 0.59 to 4.25).

Aurovela^TM 24 Fe is available in blister packs containing 28 tablets. The Blister Packs are packed in pouches (NDC 65862-934-87) and the pouches are packaged in cartons:

Carton of 1 Pouch                   NDC 65862-934-87

Carton of 5 Pouches               NDC 65862-934-58

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

• 24 light yellow to yellow, round, flat-faced, beveled-edge, uncoated (active) tablets debossed with ‘S’ on one side and ‘64’ on other side and each containing 1 mg of norethindrone acetate USP and 20 mcg of ethinyl estradiol USP.



• 4 brown, mottled, round, flat-faced, beveled-edge (non-hormonal placebo) tablets debossed with ‘S’ on one side and ‘57’ on other side and each containing 75 mg ferrous fumarate USP. The ferrous fumarate tablets do not serve any therapeutic purpose.

• Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature].
• Protect from light.

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 [see Boxed Warning].


• 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 [see Warnings and Precautions (5.1)].


• Aurovela 24 Fe does not protect against HIV infection (AIDS) and other sexually transmitted diseases.


• Aurovela 24 Fe is not to be used during pregnancy; if pregnancy occurs during use of Aurovela 24 Fe instruct the patient to stop further use [see Warnings and Precautions (5.9)].


• Take one tablet daily by mouth at the same time every day. Instruct patients what to do in the event pills are missed [see Dosage and Administration (2.2)].


• Use a back-up or alternative method of contraception when enzyme inducers are used with Aurovela 24 Fe [see Drug Interactions (7.1)].


• COCs may reduce breast milk production; this is less likely to occur if breastfeeding is well established [see Use in Specific Populations (8.3)].


• Women who start COCs postpartum, and who has not yet had a period, must use an additional method of contraception until she has taken a light yellow to yellow tablet for 7 consecutive days [see Dosage and Administration (2.2)].


• Amenorrhea may occur. Consider pregnancy in the event of amenorrhea at the time of the first missed period. Rule out pregnancy in the event of amenorrhea in two or more consecutive cycles [see Warnings and Precautions (5.8)].

 

PATIENT INFORMATION

Aurovela^TM 24 Fe

(aw-roh-vee-luh)

(norethindrone acetate and ethinyl estradiol tablets USP

and ferrous fumarate tablets)

What is the most important information I should know about Aurovela 24 Fe?

Do not use Aurovela 24 Fe if you smoke cigarettes and are over 35 years old. Smoking increases your risk of serious cardiovascular side effects from hormonal birth control pills, including death from heart attack, blood clots or stroke. This risk increases with age and the number of cigarettes you smoke.




What is Aurovela 24 Fe?




Aurovela 24 Fe is a birth control pill (hormonal contraceptive) used by women to prevent pregnancy.




How does Aurovela 24 Fe work for contraception?




Your chance of getting pregnant depends on how well you follow the directions for taking your birth control pills. The better you follow the directions, the less chance you have of getting pregnant.




Based on the results from the clinical study, about 1 to 4 out of 100 women may get pregnant during the first year they use Aurovela 24 Fe.




The following chart shows the chance of getting pregnant for women who use different methods of birth control. Each box on the chart contains a list of birth control methods that are similar in effectiveness. The most effective methods are at the top of the chart. The box on the bottom of the chart shows the chance of getting pregnant for women who do not use birth control and are trying to get pregnant.




Figure (Norethindroneethinyl Fig3)

Who should not take Aurovela 24 Fe?




Do not take Aurovela 24 Fe if you:



• smoke and are over 35 years of age
• had blood clots in your arms, legs, lungs, or eyes
• had a problem with your blood that makes it clot more than normal
• have certain heart valve problems or irregular heart beat that increases your risk of having blood clots
• had a stroke
• had a heart attack
• have high blood pressure that cannot be controlled by medicine
• have diabetes with kidney, eye, nerve, or blood vessel damage


• have certain kinds of severe migraine headaches with aura, numbness, weakness or changes in vision, or any migraine headaches if you are over 35 years of age
• have liver problems, including liver tumors
• have any unexplained vaginal bleeding
• are pregnant
• had breast cancer or any cancer that is sensitive to female hormones
• 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. 



If any of these conditions happen while you are taking Aurovela 24 Fe, stop taking Aurovela 24 Fe right away and talk to your healthcare provider. Use non-hormonal contraception (such as condoms and spermicide) when you stop taking Aurovela 24 Fe.




What should I tell my healthcare provider before taking Aurovela 24 Fe?

Tell your healthcare provider if you:



• are pregnant or think you may be pregnant


• are depressed now or have been depressed in the past


• had yellowing of your skin or eyes (jaundice) caused by pregnancy (cholestasis of pregnancy)


• are breastfeeding or plan to breastfeed. Aurovela 24 Fe may decrease the amount of breast milk you make. A small amount of the hormones in Aurovela 24 Fe may pass into your breast milk. Talk to your healthcare provider about the best birth control method for you while breastfeeding.  



Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins and herbal supplements.




Aurovela 24 Fe may affect the way other medicines work, and other medicines may affect how well Aurovela 24 Fe works.




Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist when you get a new medicine.




How should I take Aurovela 24 Fe?

Read the Instructions for Use at the end of this Patient Information.

What are the possible serious side effects of Aurovela 24 Fe?



• Like pregnancy, Aurovela 24 Fe may cause serious side effects, including blood clots in your lungs, heart attack, or a stroke that may lead to death. Some other examples of serious blood clots include blood clots in the legs or eyes.



Serious blood clots can happen especially if you smoke, are obese, or are older than 35 years of age. Serious blood clots are more likely to happen when you:



• first start taking birth control pills


• restart the same or different birth control pills after not using them for a month or more



Call your healthcare provider or go to a hospital emergency room right away if you have:

• leg pain that will not go away
•  sudden severe shortness of breath
• sudden change in vision or blindness
• chest pain
• a sudden, severe headache unlike your usual headaches
• weakness or numbness in your arm or leg
• trouble speaking



Other serious side effects include:

• liver problems, including:


• rare liver tumors
• jaundice (cholestasis), especially if you previously had cholestasis of pregnancy. Call your healthcare provider if you have yellowing of your skin or eyes.


• high blood pressure. You should see your healthcare provider for a yearly check of your blood pressure.
• gallbladder problems
• changes in the sugar and fat (cholesterol and triglycerides) levels in your blood
• new or worsening headaches including migraine headaches
• depression
• possible cancer in your breast and cervix
• swelling of your skin especially around your mouth, eyes, and in your throat (angioedema). Call your healthcare provider if you have a swollen face, lips, mouth tongue or throat, which may lead to difficulty swallowing or breathing. Your chance of having angioedema is higher is you have a history of angioedema.
• dark patches of skin around your forehead, nose, cheeks and around your mouth, especially during pregnancy (chloasma). Women who tend to get chloasma should avoid spending a long time in sunlight, tanning booths, and under sun lamps while taking Aurovela 24 Fe. Use sunscreen if you have to be in the sunlight.



What are the most common side effects of Aurovela 24 Fe?



• headache
• vaginal infections
• nausea
• menstrual cramps
• breast tenderness
• mood changes
• acne
• weight gain



These are not all the possible side effects of Aurovela 24 Fe. For more information, ask your healthcare provider or pharmacist.




You may report side effects to the FDA at 1-800-FDA-1088.

What else should I know about taking Aurovela 24 Fe?



• If you are scheduled for any lab tests, tell your healthcare provider you are taking Aurovela 24 Fe. Certain blood tests may be affected by Aurovela 24 Fe.
• Aurovela 24 Fe does not protect against HIV infection (AIDS) and other sexually transmitted infections.

How should I store Aurovela 24 Fe?



• Store Aurovela 24 Fe at room temperature between 20° to 25°C (68° to 77°F).
• Store away from light.
• Keep Aurovela 24 Fe and all medicines out of the reach of children.



General information about the safe and effective use of Aurovela 24 Fe.

Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use Aurovela 24 Fe for a condition for which it was not prescribed. Do not give Aurovela 24 Fe to other people.




This Patient Information summarizes the most important information about Aurovela 24 Fe. You can ask your pharmacist or healthcare provider for information about Aurovela 24 Fe that is written for health professionals.




For more information, call Aurobindo Pharma USA, Inc. at 1-866-850-2876.

Do birth control pills cause cancer?




Birth control pills do not seem to cause breast cancer. However, if you have breast cancer now, or have had it in the past, do not use birth control pills because some breast cancers are sensitive to hormones.




Women who use birth control pills may have a slightly higher chance of getting cervical cancer. However, this may be due to other reasons such as having more sexual partners.

What if I want to become pregnant?




You may stop taking the pill whenever you wish. Consider a visit with your healthcare provider for a pre-pregnancy checkup before you stop taking the pill.




What should I know about my period when taking Aurovela 24 Fe?




Your periods may be lighter and shorter than usual. Some women may miss a period. Irregular vaginal bleeding or spotting may happen while you are taking Aurovela 24 Fe, especially during the first few months of use. This usually is not a serious problem. It is important to continue taking your pills on a regular schedule to prevent a pregnancy.




What are the ingredients in Aurovela 24 Fe?

Active ingredients:

Light yellow to yellow pills: norethindrone acetate and ethinyl estradiol

Inactive ingredients:

Light yellow to yellow pills: compressible sugar, croscarmellose sodium, D & C Yellow No. 10 Aluminum Lake, lactose monohydrate, magnesium stearate, microcrystalline cellulose, povidone and vitamin E.




Brown pills:  ferrous fumarate, croscarmellose sodium, lactose monohydrate, magnesium stearate, microcrystalline cellulose, Nat spearmint FL SD #11475, povidone and sucralose.




INSTRUCTIONS FOR USE




Aurovela 24 Fe

(aw-roh-vee-luh)

(norethindrone acetate and ethinyl estradiol tablets USP

and ferrous fumarate tablets)

Important Information about taking Aurovela 24 Fe

• Take 1 pill every day at the same time. Take the pills in the order directed on your blister pack.


• Do not skip your pills, even if you do not have sex often. If you miss pills (including starting the pack late), you could get pregnant. The more pills you miss, the more likely you are to get pregnant.


• If you have trouble remembering to take Aurovela 24 Fe, talk to your healthcare provider.


• When you first start taking Aurovela 24 Fe, spotting or light bleeding in between your periods may occur. Contact your healthcare provider if this does not go away after a few months.


• You may feel sick to your stomach (nauseous), especially during the first few months of taking Aurovela 24 Fe. If you feel sick to your stomach, do not stop taking the pill. The problem will usually go away. If your nausea does not go away, call your healthcare provider.
• Missing pills can also cause spotting or light bleeding, even when you take the missed pills later. On the days you take 2 pills to make up for missed pills (see What should I do if I miss any Aurovela 24 Fe pills? below), you could also feel a little sick to your stomach.


• It is not uncommon to miss a period. However, if you miss a period and have not taken Aurovela 24 Fe according to directions, or miss 2 periods in a row, or feel like you may be pregnant, call your healthcare provider. If you have a positive pregnancy test, you should stop taking Aurovela 24 Fe.


• If you have vomiting or diarrhea within 3 to 4 hours of taking a light yellow to yellow active pill, take another light yellow to yellow pill from your extra blister pack. If you do not have an extra blister pack, take the next light yellow to yellow pill in your blister pack. Continue taking all your remaining pills in order. Start the first pill of your next blister pack the day after finishing your current blister pack. This will be 1 day earlier than originally scheduled. Continue on your new schedule.


• If you have vomiting or diarrhea for more than 1 day, your birth control pills may not work as well. Use an additional birth control method, like condoms and a spermicide, until you check with your healthcare provider.


• Stop taking Aurovela 24 Fe at least 4 weeks before you have major surgery and do not restart after the surgery without asking your healthcare provider. Be sure to use other forms of contraception (like condoms and spermicide) during this time period.

Before you start taking Aurovela 24 Fe:



• Decide what time of day you want to take your pill. It is important to take it at the same time every day and in the order as directed on your blister pack.


• Have backup contraception (condoms and spermicide) available and if possible, an extra full pack of pills as needed.



When should I start taking Aurovela 24 Fe?

If you start taking Aurovela 24 Fe and you have not used a hormonal birth control method before:



• There are 2 ways to start taking your birth control pills. You can either start on a Sunday (Sunday Start) or on the first day (Day 1) of your natural menstrual period (Day 1 Start). Your healthcare provider should tell you when to start taking your birth control pill.


• If you use the Sunday Start, use non-hormonal back-up contraception such as condoms and spermicide for the first 7 days that you take Aurovela 24 Fe. You do not need back-up contraception if you use the Day 1 Start.



If you start taking Aurovela 24 Fe and you are switching from another birth control pill:



• Start your new Aurovela 24 Fe pack on the same day that you would start the next pack of your previous birth control method.


• Do not continue taking the pills from your previous birth control pack.



If you start taking Aurovela 24 Fe and previously used a vaginal ring or transdermal patch:



• Start using Aurovela 24 Fe on the day you would have reapplied the next ring or patch.

If you start taking Aurovela 24 Fe and you are switching from a progestin-only method such as an implant or injection:



• Start taking Aurovela 24 Fe on the day of removal of your implant or on the day when you would have had your next injection.



If you start taking Aurovela 24 Fe and you are switching from an intrauterine device or system (IUD or IUS):



• Start taking Aurovela 24 Fe on the day of removal of your IUD or IUS.


• You do not need back-up contraception if your IUD or IUS is removed on the first day (Day 1) of your period. If your IUD or IUS is removed on any other day, use non-hormonal back-up contraception such as condoms and spermicide for the first 7 days that you take Aurovela 24 Fe.



Keep a calendar to track your period:

If this is the first time you are taking birth control pills, read, “When should I start taking Aurovela 24 Fe?” above. Follow these instructions for either a Sunday Start or a Day 1 Start.

Sunday Start:




You will use a Sunday Start if your healthcare provider told you to take your first pill on a Sunday.



• Take pill 1 on the Sunday after your period starts.


• If your period starts on a Sunday, take pill “1” that day and refer to Day 1 Start instructions below.


• Take 1 pill every day in the order on the blister pack at the same time each day for 28 days.


• After taking the last pill on Day 28 from the blister pack, start taking the first pill from a new pack, on the same day of the week as the first pack (Sunday). Take the first pill in the new pack whether or not you are having your period.


• Use non-hormonal back-up contraception such as condoms and spermicide for the first 7 days of the first cycle that you take Aurovela 24 Fe.



Day 1 Start:




You will use a Day 1 Start if your doctor told you to take your first pill (Day 1) on the first day of your period.



• Take 1 pill every day in the order of the blister pack, at the same time each day, for 28 days.


• After taking the last pill on Day 28 from the blister pack, start taking the first pill from a new pack, on the same day of the week as the first pack. Take the first pill in the new pack whether or not you are having your period.



Instructions for using your blister pack:




The Aurovela 24 Fe blister pack has 24 "active" light yellow to yellow pills (with hormones) to be taken for 24 days, followed by 4 "reminder" brown pills (without hormones) to be taken for the next 4 days.



Figure A (Norethindroneethinyl Fig4)

Look for:

• Where on the pack to start taking pills
• In what order to take the pills. Follow the arrows shown in Figure A.
• The week numbers as shown in Figure A.



What if should I do if I miss any Aurovela 24 Fe light yellow to yellow pills?

If you miss 1 light yellow to yellow pill in Weeks 1, 2, or 3, follow these steps:



• Take it as soon as you remember. Take the next pill at your regular time. This means you may take 2 pills in 1 day.


• Then continue taking 1 pill every day until you finish the pack.


• You do not need to use a back-up birth control method if you have sex.



If you miss 2 light yellow to yellow pills in a row in Week 1 or Week 2 of your pack, follow these steps:



• Take the 2 missed pills as soon as possible and the next 2 pills the next day.


• Then continue to take 1 pill every day until you finish the pack.


• Use a non-hormonal birth control method (such as a condom and spermicide) as a back-up if you have sex during the first 7 days after missing your pills.

If you miss 2 light yellow to yellow pills in a row in Week 3 or Week 4, or you miss 3 or more light yellow to yellow pills in a row at any time, follow these steps:



• If you are a Day 1 Starter:


• Throw out the rest of the pill pack and start a new pack that same day.


• If you are a Sunday Starter:


• Keep taking 1 pill every day until Sunday. On Sunday, throw out the rest of the pack and start a new pack of pills that same day.


• You may not have your period this month but this is expected. However, if you miss your period 2 months in a row, call your healthcare provider because you might be pregnant.


• You could become pregnant if you have sex during the first 7 days after you restart your pills. You MUST use a non-hormonal birth control method (such as a condom and spermicide) as a back-up if you have sex during the first 7 days after you restart your pills.



If you miss any of the 4 brown “reminder” pills in Week 4, throw away the pills you missed and keep taking 1 pill each day until the pack is empty. You do not need to use a back-up method of birth control.

If you have any questions or are unsure about the information in this leaflet, call your healthcare provider.




This Patient Information and Instructions for Use has been approved by the U.S. Food and Drug Administration.




Manufactured for:
Aurobindo Pharma USA, Inc.
2400 Route 130 North
Dayton, NJ 08810

Manufactured by:
Aurobindo Pharma Limited
Unit-VII (SEZ)
Mahaboob Nagar (Dt)
509302, India

Revised: 08/2017

NDC 65862-934-87
28 Day Regimen

Aurovela^TM 24 Fe provides
24 days of active therapy

Aurovela^TM 24 Fe
(Norethindrone Acetate and Ethinyl Estradiol
Tablets USP and Ferrous Fumarate Tablets)
1 mg/20 mcg

Each light yellow to yellow tablet contains norethindrone
acetate USP, 1 mg: ethinyl estradiol USP, 20 mcg; each brown
tablet contains ferrous fumarate USP, 75 mg.

Each pouch contains 24 light yellow to yellow tablets and 4
brown tablets.

This product (like all oral contraceptives) is
intended to prevent pregnancy. It does not
protect against HIV infection (AIDS) and other
sexually transmitted diseases.

Rx only                                     This pouch contains 
                                                one blister card  of 28 tablets

AUROBINDO

Package Label-principal Display Panel (1 mg/20 mcg Pouch Label)

NDC 65862-934-58
28 Day Regimen

Aurovela^TM 24 Fe provides
24 days of active therapy

Aurovela^TM 24 Fe
(Norethindrone Acetate and Ethinyl Estradiol
Tablets USP and Ferrous Fumarate Tablets)
1 mg/20 mcg

This product (like all oral contraceptives) is intended to prevent pregnancy. It does not
protect against HIV infection (AIDS) and other sexually transmitted diseases.

                                                This carton contains 5 pouches.
Rx only              Each pouch contains 1 blister card of 28 tablets.

Package Label-principal Display Panel (1 mg/20 mcg Pouch Carton Label)