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These highlights do not include all the information needed to use Nymyo safely and effectively. See full prescribing information for Nymyo. Nymyo (norgestimate/ethinyl estradiol tablets) for oral use. Initial U.S. Approval:1989


RECENT MAJOR CHANGES


WARNING: CIGARETTE SMOKING AND SERIOUS CARDIOVASCULAR EVENTS


SPL UNCLASSIFIED SECTION

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 are contraindicated in women who are over 35 years of age and smoke [see Contraindications (4)].


1 INDICATIONS AND USAGE


1.1 Oral Contraceptive

Nymyo Tablets are indicated for use by females of reproductive potential to prevent pregnancy [see Clinical Studies (14)].


2 DOSAGE AND ADMINISTRATION


2.1 How to Start Nymyo

Nymyo is dispensed in 28-tablet blister [see How Supplied/Storage and Handling (16)]. Nymyo may be started using either a Day 1 start or a Sunday start (see Table 1). The plastic compact is pre-set for a Sunday start. Day 1 Start day-label stickers are available. For the first cycle of a Sunday Start regimen, an additional method of contraception should be used until after the first 7 consecutive days of administration.


2.2 How to Take Nymyo

Starting Nymyo after Abortion or Miscarriage

First-trimester

Second-trimester

Starting Nymyo after Childbirth

Compact Blister Dispenser

If the patient starts pill-taking on Sunday, the first active pill should be taken on the first Sunday after the patient's menstrual period begins. Remove the first active pill at the top of the dispenser (Sunday) by pressing the pill through the blister foil.

If the patient will start pill-taking on "Day 1", place a day-label sticker on the compact which starts with the day of the week the patient will take the first pill. Remove the first active pill at the top of the dispenser (Day 1) by pressing the pill through the blister foil.

  • After a first-trimester abortion or miscarriage, Nymyo may be started immediately. An additional method of contraception is not needed if Nymyo is started immediately.
  • If Nymyo is not started within 5 days after termination of the pregnancy, the patient should use additional non-hormonal contraception (such as condoms and spermicide) for the first seven days of her first cycle pack of Nymyo.

2.3 Missed Tablets


2.4 Advice in Case of Gastrointestinal Disturbances

In case of severe vomiting or diarrhea, absorption may not be complete and additional contraceptive measures should be taken. If vomiting or diarrhea occurs within 3 to 4 hours after taking an active tablet, handle this as a missed tablet [see FDA-Approved Patient Labeling].


3 DOSAGE FORMS AND STRENGTHS


SPL UNCLASSIFIED SECTION

Nymyo Tablets are available in blister cards. Each blister card contains 28 tablets in the following order:

  • 21 blue, round, biconvex, coated tablet imprinted "C3" on one side of the tablet and contains 0.250 mg norgestimate and 0.035 mg ethinyl estradiol
  • 7 white, round, biconvex tablets (non-hormonal placebo) imprinted "P" on one side and " N" on the other side contains inert ingredients

4 CONTRAINDICATIONS


SPL UNCLASSIFIED SECTION

Do not prescribe Nymyo 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)]

5 WARNINGS AND PRECAUTIONS


5.1 Thrombotic Disorders and Other Vascular Problems

  • Stop Nymyo if an arterial thrombotic event or venous thromboembolic (VTE) event occurs.
  • Stop Nymyo 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 Nymyo 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 Nymyo 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 COCs and when restarting hormonal contraception after a break of 4 weeks or longer. The risk of thromboembolic disease due to COCs gradually disappears after 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.

5.2 Liver Disease

Impaired Liver Function

Do not use Nymyo 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 Nymyo if jaundice develops.

Liver Tumors

Nymyo 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.


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


5.4 High Blood Pressure

Nymyo 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 Nymyo 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

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 Effects

Carefully monitor prediabetic and diabetic women who take Nymyo. 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

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

Consider discontinuation of Nymyo 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

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 clinical trials of norgestimate and ethinyl estradiol Tablets 0.25mg/0.035mg, the frequency and duration of breakthrough bleeding and/or spotting was assessed in 1,647 patients (21,275 evaluable cycles) and 4,826 patients (35,546 evaluable cycles), respectively. A total of 100 (7.5%) women discontinued norgestimate and ethinyl estradiol Tablets 0.25mg/0.035mg, at least in part, due to bleeding or spotting. Based on data from the clinical trials, 14-34% of women using norgestimate and ethinyl estradiol Tablets 0.25mg/0.035mg experienced unscheduled bleeding per cycle in the first year. The percent of women who experienced breakthrough/unscheduled bleeding tended to decrease over time.

Amenorrhea and Oligomenorrhea

Women who use Nymyo may experience amenorrhea. Some women may experience amenorrhea or oligomenorrhea after discontinuation of COCs, especially when such a condition was pre-existent.

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 COC Use Before or During Early Pregnancy

Extensive epidemiological 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 Nymyo 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)].


5.10 Depression

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


5.11 Carcinoma of the Breast and Cervix

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.

  • Nymyo is contraindicated in women who currently have or have had breast cancer because breast cancer may be hormonally sensitive[see Contraindications (4)] .

5.12 Effect on Binding Globulins

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.


5.13 Monitoring

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.


5.14 Hereditary Angioedema

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


5.15 Chloasma

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 Nymyo.


6 ADVERSE REACTIONS


SPL UNCLASSIFIED SECTION

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

Adverse reactions commonly reported by COC users are:

  • 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)]

6.1 Clinical Trial Experience

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 rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

The safety of norgestimate and ethinyl estradiol 0.25mg/0.035mg tablets was evaluated in 1,647 healthy women of child-bearing potential who participated in 3 clinical trials and received at least 1 dose of norgestimate and ethinyl estradiol 0.25mg/0.035mg tablets for contraception. Two trials were randomized active-controlled trials and 1 was an uncontrolled open-label trial. In all 3 trials, subjects were followed for up to 24 cycles.

Common Adverse Reactions (≥2% of all subjects): The most common adverse reactions reported by at least 2% of the 1,647 women were the following in order of decreasing incidence: headache/migraine (32.9%), abdominal/gastrointestinal pain (7.8%), vaginal infection (8.4%), genital discharge (6.8%), breast issues (including breast pain, discharge,and enlargement) (6.3%), mood disorders (including depression and mood altered) (5.0%), flatulence (3.2%), nervousness (2.9%), and rash (2.6%).

Adverse Reactions Leading to Study Discontinuation: Over the three trials, between 11 to 21% of subjects discontinued the trial due to an adverse reaction. The most common adverse reactions (≥1%) leading to discontinuation were: metrorrhagia (6.9%), nausea/vomiting (5.0%), headache (4.1%), mood disorders (including depression and mood altered) (2.4%), premenstrual syndrome (1.7%), hypertension (1.4%), breast pain (1.4%), nervousness (1.3%), amenorrhea (1.1%), dysmenorrhea (1.1%), weight increased (1.1%), and flatulence (1.1%).

Serious Adverse Reactions: breast cancer (1 subject), mood disorders including depression, irritability, and mood swings (1 subject), myocardial infarction (1 subject), and venous thromboembolic events including pulmonary embolism (1 subject) and deep vein thrombosis (DVT) (1 subject).


6.2 Postmarketing Experience

The following additional adverse drug reactions have been reported from worldwide postmarketing experience with norgestimate/ethinyl estradiol. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Infections and Infestations: Urinary tract infection;

Neoplasms Benign, Malignant and Unspecified (Incl. Cysts and Polyps): Breast cancer, benign breast neoplasm, hepatic adenoma, focal nodular hyperplasia, breast cyst;

Immune System Disorders: Hypersensitivity;

Metabolism and Nutrition Disorders: Dyslipidemia;

Psychiatric Disorders: Anxiety, insomnia;

Nervous System Disorders: Syncope, convulsion, paresthesia, dizziness;

Eye Disorders: Visual impairment, dry eye, contact lens intolerance;

Ear and Labyrinth Disorders: Vertigo;

Cardiac Disorders: Tachycardia, palpitations;

Vascular Events: Deep vein thrombosis, pulmonary embolism, retinal vascular thrombosis, hot flush;

Arterial Events: Arterial thromboembolism, myocardial infarction, cerebrovascular accident;

Respiratory, Thoracic and Mediastinal Disorders: Dyspnea;

Gastrointestinal Disorders: Pancreatitis, abdominal distension, diarrhea, constipation;

Hepatobiliary Disorders: Hepatitis;

Skin and Subcutaneous Tissue Disorders: Angioedema, erythema nodosum, hirsutism, night sweats, hyperhidrosis, photosensitivity reaction, urticaria, pruritus, acne;

Musculoskeletal, Connective Tissue, and Bone Disorders: Muscle spasms, pain in extremity, myalgia, back pain;

Reproductive System and Breast Disorders: Ovarian cyst, suppressed lactation, vulvovaginal dryness;

General Disorders and Administration Site Conditions: Chest pain, asthenic conditions.


7 DRUG INTERACTIONS


SPL UNCLASSIFIED SECTION

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

No drug-drug interaction studies were conducted with Nymyo.


7.1 Effects of Other Drugs on Combined Oral Contraceptives

Substances decreasing the plasma concentrations 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 hormonal contraceptives include phenytoin, barbiturates, carbamazepine, bosentan, felbamate, griseofulvin, oxcarbazepine, rifampicin, topiramate, rifabutin, rufinamide, aprepitant, and products containing St. John's wort. Interactions between hormonal contraceptives 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.

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 20-25%. 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 andnon-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 (decrease [e.g., boceprevir and telaprevir]) or with non-nucleoside reverse transcriptase inhibitors (decrease [e.g., nevirapine] or increase [e.g., etravirine]).


7.2 Effects of Combined Oral Contraceptives on Other Drugs

● 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, temazepam and lamotrigine. 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.


7.3 Interactions with Laboratory Tests

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


7.4 Concomitant Use with HCV Combination Therapy – Liver Enzyme Elevation

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


8 USE IN SPECIFIC POPULATIONS


8.1 Pregnancy

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.


8.3 Nursing Mothers

Advise the nursing mother to use other forms of contraception, 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.


8.4 Pediatric Use

Safety and efficacy of norgestimate and ethinyl estradiol tablets have been established in women of reproductive age. Efficacy is expected to be the same for post- pubertal adolescents under the age of 18 and for users 18 years and older. Use of this product before menarche is not indicated.


8.5 Geriatric Use

Nymyo has not been studied in postmenopausal women and are not indicated in this population.


8.6 Hepatic Impairment

The pharmacokinetics of Nymyo has not been studied in subjects with hepatic impairment. However, steroid hormones may be poorly metabolized in patients with hepatic impairment. Acute or chronic disturbances of liver function may necessitate the discontinuation of COC use until markers of liver function return to normal and COC causation has been excluded. [See Contraindications (4) and Warnings and Precautions (5.2)].


8.7 Renal Impairment

The pharmacokinetics of Nymyo has not been studied in women with renal impairment.


10 OVERDOSAGE

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


11 DESCRIPTION

Nymyo is a combination oral contraceptive containing the progestational compound norgestimate and the estrogenic compound ethinyl estradiol. Norgestimate is designated as (18,19-Dinor-17-pregn-4-en-20-yn-3-one,17-(acetyloxy)-13-ethyl-, oxime,(17α)(+)-) and ethinyl estradiol is designated as (19-nor-17α-pregna,1,3,5(10)-trien-20-yne-3,17-diol).

  • Each active blue tablet contains 0.250 mg of norgestimate and 0.035 mg of ethinyl estradiol. Inactive ingredients include: FD&C Blue No. 2 Aluminium Lake, FD&C Blue No. 1 Aluminum lake, FD&C Red No. 40 Aluminum Lake, D&C Yellow No. 10 Aluminum Lake, titanium dioxide, polyvinyl alcohol, talc, macrogol/PEG 3350 NF, lecithin, lactose monohydrate, magnesium stearate and pregelatinized corn starch.
  • Each white placebo tablet containing only inert ingredients, as follows: titanium dioxide, polydextrose, hypromellose, triacetin, macrogol/polyethylene glycol, lactose monohydrate, magnesium stearate and pregelatinized corn starch.

12 CLINICAL PHARMACOLOGY


12.1 Mechanism of Action

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.


12.2 Pharmacodynamics

No specific pharmacodynamic studies were conducted with Nymyo.


12.3 Pharmacokinetics

Absorption

Norgestimate (NGM) and EE are rapidly absorbed following oral administration. NGM is rapidly and completely metabolized by first pass (intestinal and/or hepatic) mechanisms to norelgestromin (NGMN) and norgestrel (NG), which are the major active metabolites of norgestimate.

Peak serum concentrations of NGMN and EE are generally reached by 2 hours after administration of norgestimate and ethinyl estradiol tablets. Accumulation following multiple dosing of the 250 mcg NGM / 35 mcg EE dose is approximately 2-fold for NGMN and EE compared with single dose administration. The pharmacokinetics of NGMN is dose-proportional following NGM doses of 180 mcg to 250 mcg. Steady-state concentration of EE is achieved by Day 7 of each dosing cycle. Steady-state concentrations of NGMN and NG are achieved by Day 21. Non-linear accumulation (approximately 8 fold) of NG is observed as a result of high-affinity binding to SHBG, which limits its biological activity (Table 3).

Food Effect

The effect of food on the pharmacokinetics of Nymyo has not been studied.

Distribution

NGMN and NG are highly bound (>97%) to serum proteins. NGMN is bound to albumin and not to SHBG, while NG is bound primarily to SHBG. EE is extensively bound (>97%) to serum albumin and induces an increase in the serum concentrations of SHBG.

Metabolism

NGM is extensively metabolized by first-pass mechanisms in the gastrointestinal tract and/or liver. NGM's primary active metabolite is NGMN. Subsequent hepatic metabolism of NGMN occurs and metabolites include NG, which is also active, and various hydroxylated and conjugated metabolites. Although NGMN and its metabolites inhibit a variety of P450 enzymes in human liver microsomes, under the recommended dosing regimen, the in vivo concentrations of NGMN and its metabolites, even at the peak serum levels, are relatively low compared to the inhibitory constant (Ki). EE is also metabolized to various hydroxylated products and their glucuronide and sulfate conjugates.

Excretion

The metabolites of NGMN and EE are eliminated by renal and fecal pathways. Following administration of 14C-norgestimate, 47% (45-49%) and 37% (16-49%) of the administered radioactivity was eliminated in the urine and feces, respectively. Unchanged NGM was not detected in the urine. In addition to 17-deacetyl norgestimate, a number of metabolites of NGM have been identified in human urine following administration of radiolabeled NGM. These include 18, 19-Dinor-17-pregn-4-en-20-yn-3-one,17-hydroxy-13-ethyl,(17α)-(-);18,19-Dinor-5β-17-pregnan-20-yn,3α,17β-dihydroxy-13-ethyl,(17α), various hydroxylated metabolites and conjugates of these metabolites.


13 NONCLINICAL TOXICOLOGY


13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

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


14 CLINICAL STUDIES


14.1 Contraception

In three US clinical trials with norgestimate and ethinyl estradiol 0.25mg/0.035mg, 1,651 women aged 18 to 38 years were studied for up to 24 cycles, proving a total of 24,272 cycles of exposure. The racial demographic was about 73-86% Caucasian, 8-13% African-American, 6-14% Hispanic with the remainder Asian or Other (≤1%). There were no exclusions on the basis of weight; the weight range for women treated was 82-303 lbs, with a mean weight of about 135 lbs. The pregnancy rate was approximately 1 pregnancy per 100 women-years.


16 HOW SUPPLIED/STORAGE AND HANDLING


16.1 How Supplied

Nymyo Tablets are available in a compact blister card (NDC 51862-645-01) containing 28 tablets in the following order: 21 blue, biconvex, round, coated tablets with "C3" debossed on one side containing 0.250 mg norgestimate and 0.035 mg ethinyl estradiol, and 7 white, biconvex, round, coated tablets with "P" debossed on one side and the "N" debossed on the other side containing inert ingredients.

Nymyo Tablets are available in the following packaging configurations:

Carton of 1 blister card NDC 51862-645-02

Carton of 3 blister cards NDC 51862-645-03

Carton of 6 blister cards NDC 51862-645-06


16.2 Storage Conditions

  • Store at 20° to 25°C (68° to 77°F), [see USP Controlled Room Temperature].
  • Protect from light.
  • Keep out of the reach of children.

17 PATIENT COUNSELING INFORMATION

See FDA-approved Patient Labeling (Patient Information and Instructions for Use).

Counsel patients about the following information:

Distributed by: Mayne Pharma

                         Greenville, NC 27834

  • 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)] .
  • Nymyo does not protect against HIV infection (AIDS) and other sexually transmitted infections.
  • Nymyo is not to be used during pregnancy; if pregnancy occurs during use of Nymyo 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 tablets are missed[see Dosage and Administration (2.2)] .
  • Use a back-up or alternative method of contraception when enzyme inducers are used with Nymyo[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 have not yet had a period, should use an additional method of contraception until they have taken an active 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)].

SPL PATIENT PACKAGE INSERT SECTION

Patient Information

Nymyo [NIH-me-oh]

(norgestimate and ethinyl estradiol) Tablets

What is the most important information I should know about Nymyo?

Do not use Nymyo 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 Nymyo?

Nymyo is a birth control pill (oral contraceptive) used by women to prevent pregnancy.

How does Nymyo 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 of clinical studies, about 1 out of 100 women may get pregnant during the first year they use Nymyo.

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 Nymyo? Do not take Nymyo if you:

If any of these conditions happen while you are taking Nymyo, stop taking Nymyo right away and talk to your healthcare provider. Use non-hormonal contraception when you stop taking Nymyo.

What should I tell my healthcare provider before taking Nymyo? 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.

Nymyo may affect the way other medicines work, and other medicines may affect how well Nymyo 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 Nymyo?

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

What are the possible serious side effects of Nymyo?

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 Nymyo?

These are not all the possible side effects of Nymyo. 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 Nymyo?

How should I store Nymyo?

General information about the safe and effective use of Nymyo.

Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use Nymyo for a condition for which it was not prescribed. Do not give Nymyo to other people, even if they have the same symptoms that you have.

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

For more information, call Mayne Pharma at 1-844-825-8500.

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 Nymyo?

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 Nymyo, 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 Nymyo?

Active ingredients:Each blue pill contains norgestimate and ethinyl estradiol.

Inactive ingredients:

Blue pills: FD&C Blue No. 2 Aluminium Lake, FD&C Blue No. 1 Aluminum lake, FD&C Red No. 40 Aluminum Lake, D&C Yellow No. 10 Aluminum Lake, titanium dioxide, polyvinyl alcohol, talc, macrogol/PEG 3350 NF, lecithin, lactose monohydrate, magnesium stearate and pregelatinized corn starch

White pills: titanium dioxide, polydextrose, hypromellose, triacetin, macrogol/polyethylene glycol, lactose monohydrate, magnesium stearate and pregelatinized corn starch.

  • 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
  • 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.
  • have any unexplained vaginal bleeding
  • are pregnant
  • had breast cancer or any cancer that is sensitive to female hormones

SPL UNCLASSIFIED SECTION

Instructions For Use

Nymyo [NIH-me-oh]

(norgestimate and ethinyl estradiol) Tablets

Important Information about taking Nymyo

Before you start taking Nymyo:

When should I start taking Nymyo?

If you start taking Nymyo and you have not used a hormonal birth control method before:

If you start taking Nymyo and you are switching from another birth control pill:

If you start taking Nymyo and previously used a vaginal ring or transdermal patch:

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

If you start taking Nymyo 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 Nymyo?" above.

Nymyo is available as a blister card placed within a white compact with the days of the week imprinted on the white compact preset for a Sunday start. The Nymyo blister card has 21 blue "active" pills (with hormones) to take for 3 weeks. This is followed by 1 week of 7 white "reminder" pills (without hormones). The Nymyo blister card and the imprinted days of the week on the compact is shown in the picture below.

On the above blister card find where on the card to start taking pills, in what order to take the pills and the week numbers. Day 1 stickers are also provided.

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. Refer to Day 1 Start instructions below.

1. Pick the day label sticker that starts with the first day of your period.

2. Place this day label sticker over the area on the plastic compact which already has the days of the week (starting with Sunday) imprinted and press firmly. See the picture below as an example.

What should I do if I miss any Nymyo pills?

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

If you miss 2 pills in Week 1 or Week 2 of your pack, follow these steps:

If you miss 2 pills in a row in Week 3, or you miss 3 or more pills in a row during Weeks 1, 2, or 3 of the pack, follow these steps:

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

Distributed by: Mayne Pharma

                         Greenville, NC 27834

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

Revised: Aug 2020                                                                                                                                                             I0144 Rev.A

  • Take 1 pill every day at the same time. Take the pills in the order directed on your pill dispenser.
  • 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 Nymyo, talk to your healthcare provider. When you first start taking Nymyo, 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 Nymyo. 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 Nymyo 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 Nymyo 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 Nymyo.
  • If you have vomiting or diarrhea within 3-4 hours of taking your pill, take another pill of the same color from your extra pill dispenser. If you do not have an extra pill dispenser, take the next pill in your pill dispenser. Continue taking all your remaining pills in order. Start the first pill of your next pill dispenser the day after finishing your current pill dispenser. 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 Nymyo 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.