dienogest 2 MG / estradiol valerate 2 MG Oral Tablet
Generic Name: ESTRADIOL VALERATE AND ESTRADIOL VALERATE/DIENOGEST
Brand Name: Natazia
DRUG INTERACTIONS
7 Consult the labeling of all concurrently-used drugs to obtain further information about interactions with hormonal contraceptives or the potential for enzyme alterations .
Drugs or herbal products that induce certain enzymes (for example, CYP3A4) may decrease the effectiveness of COCs or increase breakthrough bleeding.
Counsel patients to use a back-up or alternative method of contraception when enzyme inducers are used with COCs.
( 7.1 ) 7.1 Effects of Other Drugs on Combined Oral Contraceptives Substances diminishing the efficacy of COCs: Dienogest is a substrate of CYP3A4.
Women who take medications that are strong CYP3A4 inducers should not choose Natazia as their oral contraceptive while using these inducers and for at least 28 days after discontinuation of these inducers due to the possibility of increased breakthrough bleeding and/or decreased contraceptive efficacy.
Drugs or herbal products that induce certain enzymes, including CYP3A4, may decrease 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, rifampin, topiramate and products containing St.
John’s wort.
Interactions between oral 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.
Multiple dose co-administration of the strong CYP3A4 inducer rifampin with estradiol valerate/dienogest tablets in healthy postmenopausal women led to a decrease in dienogest and estradiol systemic exposure at steady state.
[See Clinical Pharmacology (12.3).] Substances Increasing the Systemic Exposure of COCs (enzyme inhibitors): Concomitant administration of moderate or strong CYP3A4 inhibitors like azole antifungals (for example, ketoconazole, itraconazole, voriconazole, fluconazole), verapamil, macrolides (for example, clarithromycin, erythromycin), diltiazem, and grapefruit increase the serum concentrations of both estradiol and dienogest.
In a multiple dose study investigating the effect of CYP3A4 inhibitors (ketoconazole and erythromycin) on Natazia, steady state estradiol and dienogest exposures were increased when co-administered with ketoconazole or erythromycin [see Clinical Pharmacology 12.3] .
Human Immunodeficiency Virus (HIV)/Hepatitis C Virus (HCV) Protease Inhibitors and Non-Nucleoside Reverse Transcriptase Inhibitors : Significant changes (increase and decrease) in plasma concentrations of estrogen and progestin have been noted in some cases of co-administration of HIV/HCV protease inhibitors or with non-nucleoside reverse transcriptase inhibitors.
Antibiotics : There have been reports of pregnancy while taking hormonal contraceptives and antibiotics, but clinical pharmacokinetic studies have not shown consistent effects of antibiotics on plasma concentrations of synthetic steroids.
7.2 Effects of Combined Oral Contraceptives on Other Drugs COCs containing ethinyl estradiol may inhibit the metabolism of other compounds.
COCs have been shown to significantly decrease plasma concentrations of lamotrigine, likely due to induction of lamotrigine glucuronidation.
This may reduce seizure control; therefore, dosage adjustments of lamotrigine may be necessary.
Consult the labeling of the concurrently-used drug to obtain further information about interactions with COCs or the potential for enzyme alterations.
[See Clinical Pharmacology ( 12.3 ).] In vitro studies with human CYP enzymes did not indicate an inhibitory potential of dienogest at clinically relevant concentrations.
Women on thyroid hormone replacement therapy may need increased doses of thyroid hormone because serum concentrations of thyroid-binding globulin increase with use of COCs.
7.3 Interference 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 [see Warnings and Precautions ( 5.11 ) and Drug Interactions ( 7.2 )].
OVERDOSAGE
10 There have been no reports of serious ill effects from overdose, including ingestion by children.
Overdosage may cause withdrawal bleeding in females and nausea.
DESCRIPTION
11 Natazia (estradiol valerate and estradiol valerate/dienogest) tablets provide an oral contraceptive regimen consisting of 26 active film-coated tablets that contain the active ingredients specified for each tablet below, followed by two inert film-coated tablets: • 2 dark yellow tablets each containing 3 mg estradiol valerate • 5 medium red tablets each containing 2 mg estradiol valerate and 2 mg dienogest • 17 light yellow tablets each containing 2 mg estradiol valerate and 3 mg dienogest • 2 dark red tablets each containing 1 mg estradiol valerate • 2 white tablets (inert) Natazia also contains the excipients lactose monohydrate, maize starch, maize starch pre-gelatinized, povidone 25, magnesium stearate, hypromellose, macrogol 6000, talc, titanium dioxide, and ferric oxide pigment, yellow, or ferric oxide pigment, red.
The empirical formula of estradiol valerate is C 23 H 32 O 3 and the chemical structure is: Estradiol Valerate The chemical name of estradiol valerate is Estra-1,3,5(10)-triene-3,17-diol(17ß)-,17-pentanoate.
The empirical formula of dienogest is C 20 H 25 NO 2 and the chemical structure is: Dienogest The chemical name of dienogest is (17α)-17-Hydroxy-3-oxo-19-norpregna-4,9-diene-21-nitrile.
Chemical Strcuture EV Dienogest Chemical Structure
CLINICAL STUDIES
14 14.1 Oral Contraceptive Clinical Trials The study conducted in North America (U.S.
and Canada) was a multicenter, open-label, single-arm, unintended pregnancy study.
There were 490 healthy subjects between 18 and 35 years of age (mean age: 25.1 years) who were treated for up to 28 cycles of 28 days each.
The racial demographic of enrolled women was: Caucasian (76%), Hispanic (13%), African-American (7%), Asian (3%), and Other (1%).
The weight range for treated women was 40 to 100 kg (mean weight: 62.5 kg) and the BMI range was 14 to 30 kg/m 2 (mean BMI: 23.3 kg/m 2 ).
Of treated women, 15% discontinued the study treatment due to an adverse event, 13% were lost to follow up, 10% withdrew their consent, 8% discontinued due to other reason, 1% discontinued due to protocol deviation, and 1% discontinued due to pregnancy.
The study conducted in Europe (Germany, Austria and Spain) was a multicenter, open-label, single-arm contraceptive reliability study.
There were 1,377 healthy subjects between 18 and 50 years of age (mean age: 30.3 years) who were treated for 20 cycles of 28 days each.
The racial demographic of enrolled women was predominantly Caucasian (99.2%).
The weight range for treated women was 38 to 98 kg (mean weight: 63.8 kg) and the BMI range was 15 to 31.8 kg/m 2 (mean BMI: 22.8 kg/m 2 ).
Of treated women, 10% discontinued the study treatment due to an adverse event, 5% discontinued due to other reason, 2% were lost to follow up, 2% discontinued due to protocol deviation, 2% withdrew their consent, and 1% discontinued due to pregnancy.
The Pearl Index (PI) was the primary efficacy endpoint used to assess contraceptive reliability and was assessed in each of the two studies, assuming all subjects were at risk of pregnancy in all medication cycles unless back-up contraception was documented.
The PI is based on pregnancies that occurred after the onset of treatment and within 7 days after the last pill intake.
Cycles in which conception did not occur, but which included the use of back-up contraception, were not included in the calculation of the PI.
The PI also includes patients who did not take the drug correctly.
The estimated PI for the North American study is 1.64 and the estimated PI for the European study is 1.04.
The Kaplan-Meier method was also used to calculate the contraceptive failure rate.
The summary of the Pearl Indexes and cumulative contraceptive failure rates are provided in Table 2: Table 2 Summary of the Pearl Indexes and the Cumulative Contraceptive Failure Rates Study Age Group Relative Treatment Exposure Cycles Total treatment exposure time without back-up contraception Number of Pregnancies within 13 Cycles and 7 Days after Last Treatment Pearl Index Upper Limit of 95% CI Contraceptive Failure Rate at the End of First Year North America 18–35 3,969 5 1.64 3.82 0.016 Europe 18–35 11,275 9 1.04 1.97 0.010 14.2 Heavy Menstrual Bleeding Clinical Trials The efficacy and safety of Natazia were evaluated in two multi-regional, multicenter, double-blind, randomized, placebo-controlled clinical trials.
Study 308960 was performed in the United States and Canada and Study 308961 was performed in Australia and 9 European countries.
The studies were identical in design.
The studies enrolled women, 18 years of age or older, with a diagnosis of dysfunctional uterine bleeding characterized as heavy, prolonged and/or frequent bleeding without organic pathology.
Heavy menstrual bleeding (HMB) was defined as menstrual blood loss of 80 mL or more in at least 2 bleeding episodes.
The diagnosis of HMB was documented through the collection of used sanitary protection (pads and tampons) to quantify blood loss assessed by the alkaline hematin method.
Overall, about 85% of the subjects qualified for the study because they had heavy menstrual bleeding symptoms.
A total of 421 women with a mean age of 38.2 and a mean BMI of 25.5 were randomized to the two clinical studies, for a total of 269 women in the Natazia group and 152 women in the placebo group, and treated for seven 28-day cycles.
Approximately 81% were Caucasian, 13% were Black, and 6% were Hispanic or Asian or Other.
The primary efficacy variable was the proportion of subjects who were completely relieved of symptoms, which was defined by the number of subjects with the absence of any dysfunctional bleeding symptom and who met up to 8 strictly defined criteria for success during the 90-day efficacy assessment phase.
In Study 308960, the proportion of the intent-to-treat subjects with complete symptom relief was 29.2% in the Natazia group compared to 2.9% in the placebo group.
In Study 308961, the proportion of the intent-to-treat subjects with complete symptom relief was 29.5% in the Natazia group compared to 1.2% in the placebo group.
In both studies, Natazia was effective in treating the symptoms of HMB in the subset of women who entered the study with symptoms specific to HMB.
Among patients with HMB, menstrual blood loss (MBL) was statistically significantly reduced in the group treated with Natazia compared with placebo (p<0.0001 for both studies).
Evaluating data based on 28-day cycles, the median menstrual blood volume at Cycle 7 was reduced from the baseline median by 90% in one trial and 87% in the other.
For women treated with placebo, the median menstrual blood volume at Cycle 7 was reduced from the baseline median by 14% and 32% in the two trials, respectively.
Figures 1 and 2 display the MBL volume by cycle and by study.
Figure 1 Median Menstrual Blood Loss Volume by Cycle (Study 308960) Figure 2 Median Menstrual Blood Loss Volume by Cycle (Study 308961) Figure 1 Figure 2
HOW SUPPLIED
16 /STORAGE AND HANDLING 16.1 How Supplied Natazia (estradiol valerate and estradiol valerate/dienogest) tablets are available in packages of three blister packs (NDC 50419-409-03).
The active and inert film-coated tablets are rounded with biconvex faces, one side is embossed with a regular hexagon shape with the letters DD or DJ or DH or DN or DT.
Each blister pack (28 film-coated tablets) contains in the following order: • 2 round biconvex dark yellow film-coated tablets with embossed “DD” in a regular hexagon on one side each containing 3 mg estradiol valerate • 5 round biconvex medium red film-coated tablets with embossed “DJ” in a regular hexagon on one side each containing 2 mg estradiol valerate and 2 mg dienogest • 17 round biconvex light yellow film-coated tablets with embossed “DH” in a regular hexagon on one side each containing 2 mg estradiol valerate and 3 mg dienogest • 2 round biconvex dark red film-coated tablets with embossed “DN” in a regular hexagon on one side each containing 1 mg estradiol valerate • 2 white round biconvex white film-coated tablets with embossed “DT” in a regular hexagon on one side (inert) 16.2 Storage Store at 25º C (77º F); excursions permitted to 15–30 o C (59–86 o F) [see USP Controlled Room Temperature] .
GERIATRIC USE
8.5 Geriatric Use Natazia has not been studied in postmenopausal women and is not indicated in this population.
DOSAGE FORMS AND STRENGTHS
3 Natazia (estradiol valerate and estradiol valerate/dienogest) tablets are available in blister packs.
Each blister pack contains 28 round, biconvex, film-coated tablets in the following order: • 2 dark yellow tablets, with an embossed “DD” in a regular hexagon on one side, each containing 3 mg estradiol valerate • 5 medium red tablets, with an embossed “DJ” in a regular hexagon on one side, each containing 2 mg estradiol valerate and 2 mg dienogest • 17 light yellow tablets, with an embossed “DH” in a regular hexagon on one side, each containing 2 mg estradiol valerate and 3 mg dienogest • 2 dark red tablets, with an embossed “DN” in a regular hexagon on one side, each containing 1 mg estradiol valerate • 2 white tablets (inert), with an embossed “DT” in a regular hexagon on one side Natazia consists of 28 film-coated, unscored tablets in the following order ( 3 ): • 2 dark yellow tablets each containing 3 mg estradiol valerate • 5 medium red tablets each containing 2 mg estradiol valerate and 2 mg dienogest • 17 light yellow tablets each containing 2 mg estradiol valerate and 3 mg dienogest • 2 dark red tablets each containing 1 mg estradiol valerate • 2 white tablets (inert)
MECHANISM OF ACTION
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.
INDICATIONS AND USAGE
1 • Natazia is an estrogen/progestin COC indicated for use by women to prevent pregnancy.
( 1 ) • Treatment of heavy menstrual bleeding in women without organic pathology who choose to use an oral contraceptive as their method of contraception.
( 1.2 ) • The efficacy of Natazia in women with a body mass index (BMI) of >30 kg/m 2 has not been evaluated.
( 1 , 8.8 ) 1.1 Oral Contraception Natazia ® is indicated for use by women to prevent pregnancy.
The efficacy of Natazia in women with a body mass index (BMI) of > 30 kg/m 2 has not been evaluated.
1.2 Heavy Menstrual Bleeding Natazia is also indicated for the treatment of heavy menstrual bleeding in women without organic pathology who choose to use an oral contraceptive as their method of contraception [see Clinical Studies ( 14.2 )].
PEDIATRIC USE
8.4 Pediatric Use Safety and efficacy of Natazia have been established in women of reproductive age.
Efficacy is expected to be the same for postpubertal adolescents under the age of 18 and for users 18 years and older.
Use of this product before menarche is not indicated.
PREGNANCY
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.
The administration of COCs to induce withdrawal bleeding should not be used as a test for pregnancy.
COCs should not be used during pregnancy to treat threatened or habitual abortion.
Women who do not breastfeed may start COCs no earlier than four weeks postpartum.
NUSRING MOTHERS
8.3 Nursing Mothers When possible, advise the nursing mother to use other forms of contraception until she has weaned her child.
Estrogen-containing 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.
BOXED WARNING
WARNING: CIGARETTE SMOKING AND SERIOUS CARDIOVASCULAR EVENTS Cigarette smoking increases the risk of serious cardiovascular events from combination oral contraceptives (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 ).] WARNING: CIGARETTE SMOKING AND SERIOUS CARDIOVASCULAR EVENTS See full prescribing information for complete boxed warning.
• Women over 35 years old who smoke should not use Natazia.
( 4 ) • Cigarette smoking increases the risk of serious cardiovascular events from combination oral contraceptive (COC) use.
( 4 )
WARNING AND CAUTIONS
5 WARNINGS AND PRECAUTIONS • Vascular risks : Stop Natazia if a thrombotic event occurs.
Stop Natazia at least 4 weeks before and through 2 weeks after major surgery.
Start Natazia no earlier than 4 weeks after delivery, in women who are not breastfeeding.
( 5.1 ) • Liver disease : Discontinue Natazia if jaundice occurs.
( 5.3 ) • High blood pressure : Do not prescribe Natazia for women with uncontrolled hypertension or hypertension with vascular disease.
( 5.4 ) • Carbohydrate and lipid metabolic effects : Monitor prediabetic and diabetic women taking Natazia.
Consider an alternate contraceptive method for women with uncontrolled dyslipidemia.
( 5.6 ) • Headache : Evaluate significant change in headaches and discontinue Natazia if indicated.
( 5.7 ) • Uterine bleeding : Evaluate irregular bleeding or amenorrhea.
( 5.8 ) • CYP3A4 induction : Women taking strong CYP3A4 inducers (for example, carbamazepine, phenytoin, rifampicin, and St.
John’s wort) should not choose Natazia as their oral contraceptive due to the possibility of decreased contraceptive efficacy.
( 5.13 , 7.1 ) 5.1 Thromboembolic Disorders and Other Vascular Problems Stop Natazia if an arterial or venous thrombotic event (VTE) occurs.
The use of COCs increases the risk of venous thromboembolism.
However, pregnancy increases the risk of venous thromboembolism as much or more than the use of COCs.
The risk of VTE in women using COCs has been estimated to be 3 to 9 per 10,000 woman-years.
The risk of VTE is highest during the first year of use.
Data from a large, prospective cohort safety study of various COCs suggest that this increased risk, as compared to that in non-COC users, is greatest during the first 6 months of COC use.
Data from this safety study indicate that the greatest risk of VTE is present after initially starting a COC or restarting (following a 4 week or greater pill-free interval) the same or a different COC.
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.
The risk of thromboembolic disease due to oral contraceptives gradually disappears after COC use is discontinued.
If feasible, stop Natazia at least 4 weeks before and through 2 weeks after major surgery or other surgeries known to have an elevated risk of thromboembolism.
Start Natazia no earlier than 4 weeks after delivery, in women who are not breastfeeding.
The risk of postpartum thromboembolism decreases after the third postpartum week, whereas the risk of ovulation increases after the third postpartum week.
COCs have been shown to increase both the relative and attributable risks of cerebrovascular events (thrombotic and hemorrhagic strokes), although, in general, the risk is greatest among older (>35 years of age), hypertensive women who also smoke.
COCs also increase the risk for stroke in women with other underlying risk factors.
Oral contraceptives must be used with caution in women with cardiovascular disease risk factors.
Stop Natazia if there is unexplained loss of vision, proptosis, diplopia, papilledema, or retinal vascular lesions.
Evaluate for retinal vein thrombosis immediately.
[See Adverse Reactions ( 6 ).] 5.2 Carcinoma of the Breasts and Reproductive Organs Women who currently have or have had breast cancer should not use Natazia because breast cancer is a hormonally-sensitive tumor.
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.
Endometrial biopsies performed in a subset of subjects in a Phase 3 Natazia clinical trial did not reveal any unexpected or concerning findings for subjects taking COCs.
[See Adverse Reactions ( 6.1 ).] 5.3 Liver Disease Discontinue Natazia if jaundice develops.
Steroid hormones may be poorly metabolized in patients with impaired liver function.
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.
Hepatic adenomas are associated with COC use.
An estimate of the attributable risk is 3.3 cases/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 attributable risk of liver cancers in COC users is less than one case per million users.
Oral contraceptive-related cholestasis may occur in women with a history of pregnancy-related cholestasis.
Women with a history of COC-related cholestasis may have the condition recur with subsequent COC use.
5.4 High Blood Pressure For women with well-controlled hypertension, monitor blood pressure and stop Natazia if blood pressure rises significantly.
Women with uncontrolled hypertension or hypertension with vascular disease should not use COCs.
An increase in blood pressure has been reported in women taking COCs, and this increase is more likely in older women and with extended duration of use.
The incidence of hypertension increases with increasing concentration of progestin.
5.5 Gallbladder Disease Studies suggest a small increased relative risk of developing gallbladder disease among COC users.
5.6 Carbohydrate and Lipid Metabolic Effects Carefully monitor prediabetic and diabetic women who are taking Natazia.
COCs may decrease glucose tolerance in a dose-related fashion.
Consider alternative contraception for women with uncontrolled dyslipidemia.
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 Natazia develops new headaches that are recurrent, persistent, or severe, evaluate the cause and discontinue Natazia if indicated.
An increase in frequency or severity of migraine during COC use (which may be prodromal of a cerebrovascular event) may be a reason for immediate discontinuation of the COC.
5.8 Bleeding Irregularities Breakthrough 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 COC.
Women who are not pregnant and use Natazia, may experience amenorrhea.
Based on patient diaries, amenorrhea occurs in approximately 16% of cycles in women using Natazia.
Pregnancy should be ruled out in the event of amenorrhea occurring in two or more consecutive cycles.
Some women may encounter amenorrhea or oligomenorrhea after stopping COCs, especially when such a condition was pre-existent.
Based on patient diaries from three clinical trials evaluating the safety and efficacy of Natazia for contraception, 10-23% of women experienced intracyclic bleeding per cycle.
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 taken inadvertently during early pregnancy.
Oral contraceptive use should be discontinued if pregnancy is confirmed.
The administration of oral contraceptives to induce withdrawal bleeding should not be used as a test for pregnancy [see Use in Specific Populations ( 8.1 )] .
5.10 Depression Women with a history of depression should be carefully observed and Natazia discontinued if depression recurs to a serious degree .
5.11 Interference with Laboratory Tests The use of COCs may change the results of some laboratory tests, such as coagulation factors, lipids, glucose tolerance, and binding proteins.
Women on thyroid hormone replacement therapy may need increased doses of thyroid hormone because serum concentrations of thyroid-binding globulin increase with use of COCs [see Clinical Pharmacology ( 12.3 )] .
5.12 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.
5.13 Drug Interactions Women who take medications that are strong cytochrome P450 3A4 (CYP3A4) inducers (for example, carbamazepine, phenytoin, rifampicin, and St.
John’s wort) should not choose Natazia as their oral contraceptive while using these inducers and for at least 28 days after discontinuation of these inducers due to the possibility of decreased contraceptive efficacy.
[See Drug Interactions ( 7.1 ) and Clinical Pharmacology ( 12.3 ).] 5.14 Other Conditions 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 COCs.
INFORMATION FOR PATIENTS
17 PATIENT COUNSELING INFORMATION See “FDA-approved patient labeling (Patient Information).” • Counsel patients that 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.
• Counsel patients that the 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.
• Counsel patients that Natazia does not protect against HIV infection (AIDS) and other sexually transmitted diseases.
• Counsel patients on Warnings and Precautions associated with COCs.
• Inform patients that Natazia is not indicated during pregnancy.
If pregnancy occurs during treatment with Natazia, instruct the patient to stop further intake.
• Counsel patients to take one tablet daily by mouth at the same time every day in the exact order noted on the blister.
Instruct patients what to do in the event pills are missed.
See What Should I Do if I Miss any Pills section in FDA-Approved Patient Labeling.
• Counsel women who are taking strong CYP3A4 inducers (for example, carbamazepine, phenytoin, rifampicin, and St.
John’s wort) not to choose Natazia as their oral contraceptive due to the possibility of decreased contraceptive efficacy.
• Counsel patients to use a back-up or alternative method of contraception when weak or moderate enzyme inducers are used with Natazia.
• Counsel patients who are breastfeeding or who desire to breastfeed that COCs may reduce breast milk production.
This is less likely to occur if breastfeeding is well established.
• Counsel any patient who starts COCs postpartum, and who has not yet had a period, to use an additional method of contraception until she has taken Natazia for 9 consecutive days.
• Counsel patients that amenorrhea may occur.
Rule out pregnancy in the event of amenorrhea in two or more consecutive cycles.
DOSAGE AND ADMINISTRATION
2 • Take one tablet daily by mouth at the same time every day.
( 2.1 ) • Tablets must be taken in the order directed on the blister pack.
( 2.1 ) • Do not skip or delay intake by more than 12 hours.
( 2.1 ) 2.1 How to Take Natazia To achieve maximum contraceptive effectiveness, Natazia must be taken exactly as directed.
Take one tablet by mouth at the same time every day.
Tablets must be taken in the order directed on the blister pack.
Tablets should not be skipped or intake delayed by more than 12 hours.
For patient instructions for missed pills, see FDA-Approved Patient Labeling.
2.2 How to Start Natazia Instruct the patient to begin taking Natazia on Day 1 of her menstrual cycle (that is, the first day of her menstrual bleeding).
See FDA-Approved Patient Labeling .
Instruct the patient to use a non-hormonal contraceptive as back-up during the first 9 days.
For postpartum women who do not breastfeed or after a second trimester abortion, start Natazia no earlier than 4 weeks postpartum due to the increased risk of thromboembolism.
If the patient starts on Natazia postpartum and has not yet had a period, evaluate for possible pregnancy, and instruct her to use an additional method of contraception until she has taken Natazia for 9 consecutive days.
The possibility of ovulation and conception prior to initiation of medication should also be considered.
If the patient is switching from a combination hormonal method such as: • Another pill • Vaginal ring • Patch • Instruct her to take the first dark yellow pill on the first day of her withdrawal bleed.
She should not continue taking the pills from her previous birth control pack.
If she does not have a withdrawal bleed, rule out pregnancy before starting Natazia.
• If she previously used a vaginal ring or transdermal patch, she should start using Natazia on the day the ring or patch is removed.
• Instruct the patient to use a non-hormonal back-up method such as a condom or spermicide for the first 9 days.
If the patient is switching from a progestin-only method such as a: • Progestin-only pill • Implant • Intrauterine system • Injection • Instruct her to take the first dark yellow pill on the day she would have taken her next progestin-only pill or on the day of removal of her implant or intrauterine system or on the day when she would have had her next injection.
• Instruct the patient to use a non-hormonal back-up method such as a condom or spermicide for the first 9 days.
2.3 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 3-4 hours after taking a colored tablet, this can be regarded as a missed tablet.