The following Structured Product Label (SPL) was submitted to the FDA by Lupin Pharmaceuticals, Inc. for the product Blisovi 24 Fe (NDC 68180-864). This document serves as the official prescribing information, containing essential scientific data and clinical materials required for healthcare providers and patients.
This specific version of the label includes detailed information regarding warning: cigarette smoking and serious cardiovascular events, 1 indications and usage, 2.1 how to start blisovi 24 fe, 2.2 how to take blisovi 24 fe, 2.3 missed tablets, 2.4 advice in case of gastrointestinal disturbances, 3 dosage forms and strengths, 4 contraindications, and other regulatory disclosures. Use the navigation below to review specific sections of the FDA submission.
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)].
Blisovi™ 24 Fe is indicated for use by women to prevent pregnancy [see CLINICAL STUDIES (14)].
The efficacy of Blisovi 24 Fe in women with a body mass index (BMI) of > 35 kg/m2 has not been evaluated.
Blisovi 24 Fe is dispensed in a blister card [see HOW SUPPLIED/STORAGE AND HANDLING (16)]. Blisovi 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 COCs in women not currently using hormonal contraception (Day 1 Start or Sunday Start) | Day 1 Start: ● Take first white active tablet without regard to meals on the first day of menses. |
| Important: Consider the possibility of ovulation and conception prior to initiation of this product. | ● Take subsequent active tablets once daily at the same time each day for a total of 21 days. |
| Tablet Color: ● Blisovi 24 Fe active tablets are white (Day 1 to Day 24). | ● Take one brown inactive tablet daily for 7 days and at the same time of day that active tablets were taken. |
| ● Blisovi 24 Fe inactive tablets are brown (Day 25 to Day 28). | ● Begin each subsequent pack on the same day of the week as the first cycle pack (i.e., on the day after taking the last inactive tablet). |
| Sunday Start: For each 28-day course, take in the following order: | |
| ● Take the white active tablet without regard to meals on the first Sunday after the onset of menses. Due to the potential risk of becoming pregnant, use additional non- hormonal contraception (such as condoms and spermicide) for the first 7 days of the patient’s first cycle pack of Blisovi 24 Fe. | |
| ● Take subsequent active tablets once daily at the same time each day for a total of 24 days. | |
| ● Take one brown tablet (ferrous fumarate) daily for the following 4 days and at the same time of day that active tablets were taken. A scheduled period should occur during the 4 days that the brown tablets are taken. | |
| ● Begin each subsequent pack on the same day of the week as the first cycle pack (i.e., on the Sunday after taking the last inactive tablet) and additional non-hormonal contraceptive is not needed. | |
| Switching to Blisovi 24 Fe from another oral contraceptive | Start on the same day that a new pack of the previous oral contraceptive would have started. |
| Switching from another contraceptive method to Blisovi 24 Fe | Start Blisovi 24 Fe: |
| ● Transdermal patch | ● On the day when next application would have been scheduled. |
| ● Vaginal ring | ● On the day when next insertion would have been scheduled |
| ● Injection | ● On the day when next injection would have been scheduled |
| ● Intrauterine contraceptive | ● On the day of removal |
| ● If the IUD is not removed on first day of the patient’s menstrual cycle, additional non-hormonal contraceptive (such as condoms and spermicide) is needed for the first seven days of the first cycle pack. | |
| ● Implant | ● On the day of removal |
| Complete instructions on proper tablet usage are located in the FDA-approved patient labeling. | |
Starting Blisovi 24 Fe after Abortion or Miscarriage
First-trimester:
Second-trimester:
Starting Blisovi 24 Fe after Childbirth
| ● If one active tablet is missed in Weeks 1, 2 or 3 | Take the tablet as soon as possible. Take the next pill at the regular time, and continue taking one tablet a day until the pack is finished. Back-up contraception is not needed |
| ● If two consecutive active tablets are missed in Week 1 or Week 2 | Take the two missed tablets as soon as possible and the next two active tablets the next day. Continue taking one tablet a day until the pack is finished. Additional non-hormonal contraception (such as condoms and spermicide) must be used as back-up if the patient has sex within 7 days after missing tablets. |
| ● If two consecutive active tablets are missed in Week 3 or Week 4 or three or more consecutive active tablets are missed at any time | Day 1 Start: Throw out the rest of the pack and start a new pack that same day. Sunday Start: Continue taking one tablet a day until Sunday, then throw out the rest of the pack and start a new pack that same day. Additional non-hormonal contraception (such as condoms and spermicide) must be used as back-up if the patient has sex within 7 days after missing 3 tablets. |
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 white tablet, handle this as a missed tablet [see FDA-APPROVED PATIENT LABELING].
Blisovi 24 Fe (norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets) is available in blister.
Each blister (28 tablets) contains in the following order:
Do not prescribe Blisovi 24 Fe to women who are known to have the following conditions:
■ Women over age 35 with any migraine headaches [see WARNINGS AND PRECAUTIONS (5.7)]
Impaired Liver Function
Do not use Blisovi 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 Blisovi 24 Fe if jaundice develops.
Liver Tumors
Blisovi 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 (>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 Blisovi 24 Fe prior to starting therapy with the combination drug regimen ombitasvir/paritaprevir/ritonavir, with or without dasabuvir [see CONTRAINDICATIONS (4)]. Blisovi 24 Fe can be restarted approximately 2 weeks following completion of treatment with the Hepatitis C combination drug regimen.
Blisovi 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 Blisovi 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 Blisovi 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 Blisovi 24 Fe develops new headaches that are recurrent, persistent, or severe, evaluate the cause and discontinue Blisovi 24 Fe if indicated.
Consider discontinuation of Blisovi 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 Blisovi 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 Blisovi 24 Fe, at least in part, due to bleeding or spotting. Based on data from the clinical trial, [24 to 38%] of women using Blisovi 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 Blisovi 24 Fe may experience absence of withdrawal bleeding, even if they are not pregnant. In the clinical trial with Blisovi 24 Fe, 31 to 41% of the women using Blisovi 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 Blisovi 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 Blisovi 24 Fe if depression recurs to a serious degree.
Blisovi 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 Blisovi 24 Fe.
The following serious adverse reactions with the use of COCs are discussed elsewhere in the labeling:
Adverse reactions commonly reported by COC users are:
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 Blisovi 24 Fe was evaluated in 743 subjects who participated in an open-label, randomized, active-controlled, multicenter clinical trial of Blisovi 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 ≤ 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 (≥ 2% of all subjects)
The most common adverse reactions reported by at least 2% of the 743 women using Blisovi 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 Blisovi 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 Blisovi 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/ritnoavir, 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 Blisovi 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 Blisovi 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.
Blisovi 24 Fe has not been studied in postmenopausal women and is not indicated in this population.
The pharmacokinetics of Blisovi 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 Blisovi 24 Fe has not been studied in women with renal impairment.
The safety and efficacy of Blisovi 24 Fe in women with a body mass index (BMI) > 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.
Blisovi 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.
The chemical name of ethinyl estradiol is 19-nor-17α-pregna-1,3,5(10)-trien-20-yne-3,17-diol. The empirical formula of ethinyl estradiol is C20H24O2 and the structural formula is
The chemical name of norethindrone acetate is 17-hydroxy-19-nor-17α-pregn-4-en-20-yn-3-one acetate. The empirical formula of norethindrone acetate is C22H28O3 and the structural formula is:
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 Blisovi 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 Blisovi 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 Blisovi 24 Fe tablets in 17 healthy female volunteers are provided in Figures 1 and 2, and Table 3.
Following multiple-dose administration of Blisovi 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 Blisovi 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 Blisovi 24 Fe Tablets to Healthy Female Volunteers Under Fasting Condition (n = 17)
Figure 2. Mean Plasma Ethinyl Estradiol Concentration-Time Profiles Following Single- and Multiple-Dose Oral Administration of Blisovi 24 Fe Tablets to Healthy Female Volunteers Under Fasting Condition (n = 17)
| Regimen | Analyte | Arithmetic Mean The harmonic mean (0.693/mean apparent elimination rate constant) is reported for t½, and the median (range) is reported for tmax. (%CV) by Pharmacokinetic Parameter | |||||
| Cmax (pg/mL) | tmax (hr) | AUC(0 to 24) (pg/mL●h) | Cmin (pg/mL) | t1/2(hr) | Cavg (pg/mL) | ||
| NE | 8420 (31) | 1.0 (0.7 to 4.0) | 33390 (40) | -- | -- | -- | |
| Day 1 (Single Dose) | EE | 64.5 (27) | 1.3 (0.7 to 4.0) | 465.4 (26) | -- | -- | -- |
SHBG | -- | -- | -- | 57.5 (37) The SHBG concentration reported here is the pre-dose concentration. | -- | -- | |
| NE | 16400 (26) | 1.3 (0.7 to 4.0) | 88160 (30) | 880 (51) | 8.4 | 3670 (30) | |
| Day 24 (Multiple Dose) | EE | 81.9 (24) | 1.7 (1.0 to 2.0) | 701.3 (28) | 11.4 (43) | 14.5 | 29.2 (28) |
SHBG | -- | -- | -- | 144 (24) | -- | -- | |
Cmax = Maximum plasma concentration
tmax = Time of Cmax
Cmin = minimum plasma concentration at steady-state
AUC(0 to 24) = Area under plasma concentration versus time curve from 0 to 24 hours
t½ = Apparent first-order terminal elimination half-life
Cavg = Average plasma concentration = AUC(0 to 24)/24
% CV = Coefficient of Variation (%)
SHBG = Sex Hormone Binding Globulin (nmol/L)
Food Effect
A single-dose administration of Blisovi 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 (>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 Blisovi 24 Fe tablets are approximately 8 hours and 14 hours, respectively.
In an active-controlled clinical trial, 743 women 18 to 45 years of age were studied to assess the efficacy of Blisovi 24 Fe, for up to six 28-day cycles. The racial demographic of women randomized to Blisovi 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 Blisovi 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 Blisovi 24 Fe was 1.82 (95% confidence interval 0.59 to 4.25).
Blisovi 24 Fe is available in a blister (NDC 68180-864-71) containing 28 tablets packed in a pouch (NDC 68180-864-71). Such three pouches are packaged in a carton (NDC 68180-864-73).
Each blister (28 tablets) contains in the following order:
See FDA-approved Patient Labeling (Patient Information and Instructions for Use).
Counsel patients about the following information:
Distributed by:
Lupin Pharmaceuticals, Inc.
Baltimore, Maryland 21202
United States
Manufactured by:
Lupin Limited
Pithampur (M.P.) - 454 775
INDIA
Revised: August 2019
PATIENT INFORMATION
Blisovi™ 24 Fe (bli-SO-vee EFF-EE)
(norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets)
What is the most important information I should know about Blisovi 24 Fe?
Do not use Blisovi 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 Blisovi 24 Fe?
Blisovi 24 Fe is a birth control pill (hormonal contraceptive) used by women to prevent pregnancy.
How does Blisovi 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 Blisovi 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.
Who should not take Blisovi 24 Fe?
Do not take Blisovi 24 Fe if you:
If any of these conditions happen while you are taking Blisovi 24 Fe, stop taking Blisovi 24 Fe right away and talk to your healthcare provider. Use non-hormonal contraception (such as condoms and spermicide) when you stop taking Blisovi 24 Fe.
What should I tell my healthcare provider before taking Blisovi 24 Fe?
Tell your healthcare provider if you:
Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins and herbal supplements.
Blisovi 24 Fe may affect the way other medicines work, and other medicines may affect how well Blisovi 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 Blisovi 24 Fe?
Read the Instructions for Use at the end of this Patient Information.
What are the possible serious side effects of Blisovi 24 Fe?
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:
Call your healthcare provider or go to a hospital emergency room right away if you have:
Other serious side effects include:
What are the most common side effects of Blisovi 24 Fe?
These are not all the possible side effects of Blisovi 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 Blisovi 24 Fe?
How should I store Blisovi 24 Fe?
General information about the safe and effective use of Blisovi 24 Fe.
Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use Blisovi 24 Fe for a condition for which it was not prescribed. Do not give Blisovi 24 Fe to other people.
This Patient Information summarizes the most important information about Blisovi 24 Fe. You can ask your pharmacist or healthcare provider for information about Blisovi 24 Fe that is written for health professionals.
For more information, call Lupin Pharmaceuticals, Inc. at 1-800-399-2561 or visit our website at www.lupinpharmaceuticals.com.
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 Blisovi 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 Blisovi 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 Blisovi 24 Fe?
Active ingredients:
White pills: norethindrone acetate and ethinyl estradiol
Inactive ingredients:
Brown pills: ferrous fumarate
INSTRUCTIONS FOR USE
Blisovi™ 24 Fe (bli-SO-vee EFF-EE)
(norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets)
Important Information about taking Blisovi 24 Fe
Before you start taking Blisovi 24 Fe:
When should I start taking Blisovi 24 Fe?
If you start taking Blisovi 24 Fe and you have not used a hormonal birth control method before:
If you start taking Blisovi 24 Fe and you are switching from another birth control pill:
If you start taking Blisovi 24 Fe and previously used a vaginal ring or transdermal patch:
If you start taking Blisovi 24 Fe and you are switching from a progestin-only method such as an implant or injection:
If you start taking Blisovi 24 Fe and you are switching from an intrauterine device or system (IUD or IUS):
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 Blisovi 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.
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.
Instructions for using your blister:
The Blisovi 24 Fe blister has 24 "active" white 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.
Look for:
What if should I do if I miss any Blisovi 24 Fe white pills?
If you miss 1 white pill in Weeks 1, 2, or 3, follow these steps:
If you miss 2 white pills in a row in Week 1 or Week 2 of your pack, follow these steps:
If you miss 2 white pills in a row in Week 3 or Week 4, or you miss 3 or more white pills in a row at any time, follow these steps:
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.
Blisovi™ 24 Fe is a trademark of Lupin Pharmaceuticals, Inc.
Distributed by:
Lupin Pharmaceuticals, Inc.
Baltimore, Maryland 21202
United States
Manufactured by:
Lupin Limited
Pithampur (M.P.) - 454 775
INDIA
This Patient Information and Instructions for Use has been approved by the U.S. Food and Drug Administration.
Revised: August 2019 ID#:255577
Blisovi™ 24 Fe [norethindrone acetate and ethinyl estradiol tablets USP, (1 mg/0.02 mg) and ferrous fumarate tablets, (75 mg)]
Rx only
NDC 68180-864-71
Blister Label: 28 Tablets
Blisovi™ 24 Fe [norethindrone acetate and ethinyl estradiol tablets USP, (1 mg/0.02 mg) and ferrous fumarate tablets, (75 mg)]
Rx only
NDC 68180-864-71
Pouch Label: 1 blister of 28 Tablets
Blisovi™ 24 Fe [norethindrone acetate and ethinyl estradiol tablets USP, (1 mg/0.02 mg) and ferrous fumarate tablets, (75 mg)]
Rx only
NDC 68180-864-73
Carton Label: 3 blisters of 28 Tablets
* Please review the disclaimer below.
