United States - English - NLM (National Library of Medicine)
MICROGESTIN 1.5/30 - norethindrone acetate/ethinyl estradiol
Mayne Pharma Inc.
(Norethindrone Acetate and Ethinyl Estradiol Tablets, USP)
Patients should be counseled that this product does not protect against HIV infection (AIDS) and
other sexually transmitted diseases.
Cigarette smoking increases the risk of serious cardiovascular side effects from oral
contraceptive use. This risk increases with age and with heavy smoking (15 or more cigarettes
per day) and is quite marked in women over 35 years of age. Women who use oral contraceptives
should be strongly advised not to smoke.
Microgestin 1.5/30 is a progestogen-estrogen combination.
Microgestin 1.5/30 provides a continuous dosage regimen consisting of 21 yellow oral contraceptive
Each yellow tablet contains norethindrone acetate (17 alpha-ethinyl-19-nortestosterone acetate), 1.5 mg;
ethinyl estradiol (17 alpha-ethinyl-1,3,5(10)-estratriene-3, 17 beta-diol), 30mcg. Also contains polyvinyl
alcohol, titanium dioxide, talc, macrogol/polyethylglycol 3350 NF, lecithin (soya), iron oxide yellow,
FD&C Blue No.2 Aluminum Lake, D&C Yellow No.10 Aluminum Lake, FD&C Yellow No.6
Aluminum Lake, lactose, magnesium stearate and pregelatinized corn starch.
The structural formulas are as follows:
Combination oral contraceptives act by suppression of gonadotropins. Although the primary mechanism
of this action is inhibition of ovulation, other alterations include changes in the cervical mucus (which
increase the difficulty of sperm entry into the uterus) and the endometrium (which reduce the likelihood
The pharmacokinetics of Microgestin 1.5/30 has not been characterized; however, the following
pharmacokinetic information regarding norethindrone acetate and ethinyl estradiol is taken from the
Norethindrone acetate appears to be completely and rapidly deacetylated to norethindrone after oral
administration, since the disposition of norethindrone acetate is indistinguishable from that of orally
administered norethindrone (1). Norethindrone acetate and ethinyl estradiol are subject to first-pass
metabolism after oral dosing, resulting in an absolute bioavailability of approximately 64% for
norethindrone and 43% for ethinyl estradiol (1 to 3).
Volume of distribution of norethindrone and ethinyl estradiol ranges from 2 to 4 L/kg (1 to 3). Plasma
protein binding of both steroids is extensive (greater than 95%); norethindrone binds to both albumin and
sex hormone binding globulin, whereas ethinyl estradiol binds only to albumin (4).
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 (5). A small amount of norethindrone acetate is
metabolically converted to ethinyl estradiol. 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 (6).
Norethindrone and ethinyl estradiol are excreted in both urine and feces, primarily as metabolites (5,6).
Plasma clearance values for norethindrone and ethinyl estradiol are similar (approximately 0.4 L/hr/kg)
(1 to 3).
The effect of race on the disposition of Microgestin 1.5/30 has not been evaluated.
The effect of renal disease on the disposition of Microgestin 1.5/30 has not been evaluated. In
premenopausal women with chronic renal failure undergoing peritoneal dialysis who received multiple
doses of an oral contraceptive containing ethinyl estradiol and norethindrone, plasma ethinyl estradiol
concentrations were higher and norethindrone concentrations were unchanged compared to
concentrations in premenopausal women with normal renal function.
The effect of hepatic disease on the disposition of Microgestin 1.5/30 has not been evaluated.
However, ethinyl estradiol and norethindrone may be poorly metabolized in patients with impaired liver
Numerous drug-drug interactions have been reported for oral contraceptives. A summary of these is
found under PRECAUTIONS, Drug Interactions.
INDICATIONS AND USAGE
Microgestin 1.5/30 is indicated for the prevention of pregnancy in women who elect to use oral
contraceptives as a method of contraception.
Oral contraceptives are highly effective. Table 1 lists the typical accidental pregnancy rates for users
of combination oral contraceptives and other methods of contraception. The efficacy of these
contraceptive methods, except sterilization, depends upon the reliability with which they are used.
Correct and consistent use of methods can result in lower failure rates.
Oral contraceptives should not be used in women who currently have the following conditions:
Thrombophlebitis or thromboembolic disorders
A past history of deep vein thrombophlebitis or thromboembolic disorders
Cerebral vascular or coronary artery disease
Known or suspected carcinoma of the breast
Carcinoma of the endometrium or other known or suspected estrogen-dependent neoplasia
Undiagnosed abnormal genital bleeding
Cholestatic jaundice of pregnancy or jaundice with prior pill use
Hepatic adenomas or carcinomas
Known or suspected pregnancy
Are receiving Hepatitis C drug combinations containing ombitasvir/paritaprevir/ritonavir, with or
without dasabuvir, due to the potential for ALT elevations (see Warnings, RISK OF LIVER ENZYME
ELEVATIONS WITH CONCOMITANT HEPATITIS C TREATMENT).
The use of oral contraceptives is associated with increased risks of several serious conditions
including myocardial infarction, thromboembolism, stroke, hepatic neoplasia, and gallbladder disease,
although the risk of serious morbidity or mortality is very small in healthy women without underlying
risk factors. The risk of morbidity and mortality increases significantly in the presence of other
underlying risk factors such as hypertension, hyperlipidemias, obesity, and diabetes.
Practitioners prescribing oral contraceptives should be familiar with the following information relating
to these risks.
The information contained in this package insert is principally based on studies carried out in patients
who used oral contraceptives with higher formulations of estrogens and progestogens than those in
common use today. The effect of long-term use of the oral contraceptives with lower formulations of
both estrogens and progestogens remains to be determined.
Throughout this labeling, epidemiological studies reported are of two types: retrospective or case
control studies and prospective or cohort studies. Case control studies provide a measure of the
relative risk of a disease, namely, a ratio of the incidence of a disease among oral contraceptive users
to that among nonusers. The relative risk does not provide information on the actual clinical occurrence
of a disease.
Cohort studies provide a measure of attributable risk, which is the difference in the incidence of
disease between oral contraceptive users and nonusers. The attributable risk does provide information
about the actual occurrence of a disease in the population (adapted from References 8 and 9 with the
author's permission). For further information, the reader is referred to a text on epidemiological
1. Thromboembolic Disorders and Other Vascular Problems
a. Myocardial Infarction
An increased risk of myocardial infarction has been attributed to oral contraceptive use. This risk is
primarily in smokers or women with other underlying risk factors for coronary artery disease such as
hypertension, hypercholesterolemia, morbid obesity, and diabetes. The relative risk of heart attack for
current oral contraceptive users has been estimated to be two to six (10 to 16). The risk is very low
under the age of 30.
Smoking in combination with oral contraceptive use has been shown to contribute substantially to the
incidence of myocardial infarctions in women in their mid-thirties or older with smoking accounting for
the majority of excess cases (17). Mortality rates associated with circulatory disease have been shown
to increase substantially in smokers over the age of 35 and non-smokers over the age of 40 (Table II)
among women who use oral contraceptives.
Oral contraceptives may compound the effects of well-known risk factors, such as hypertension,
diabetes, hyperlipidemias, age and obesity (19). In particular, some progestogens are known to decrease
HDL cholesterol and cause glucose intolerance, while estrogens may create a state of hyperinsulinism
(20 to 24). Oral contraceptives have been shown to increase blood pressure among users (see section
10 in WARNINGS). Similar effects on risk factors have been associated with an increased risk of heart
disease. Oral contraceptives must be used with caution in women with cardiovascular disease risk
An increased risk of thromboembolic and thrombotic disease associated with the use of oral
contraceptives is well established. Case control studies have found the relative risk of users compared
to non-users to be 3 for the first episode of superficial venous thrombosis, 4 to 11 for deep vein
thrombosis or pulmonary embolism, and 1.5 to 6 for women with predisposing conditions for venous
thromboembolic disease (9,10,25 to 30). Cohort studies have shown the relative risk to be somewhat
lower, about 3 for new cases and about 4.5 for new cases requiring hospitalization (31). The risk of
thromboembolic disease due to oral contraceptives is not related to length of use and disappears after
pill use is stopped (8).
A two- to four-fold increase in relative risk of postoperative thromboembolic complications has been
reported with the use of oral contraceptives (15,32). The relative risk of venous thrombosis in women
reported with the use of oral contraceptives (15,32). The relative risk of venous thrombosis in women
who have predisposing conditions is twice that of women without such medical conditions (15,32). If
feasible, oral contraceptives should be discontinued at least four weeks prior to and for two weeks
after elective surgery of a type associated with an increase in risk of thromboembolism and during and
following prolonged immobilization. Since the immediate postpartum period is also associated with an
increased risk of thromboembolism, oral contraceptives should be started no earlier than four to six
weeks after delivery in women who elect not to breastfeed.
c. Cerebrovascular Diseases
Oral contraceptives 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), hypertensive women who also smoke. Hypertension was found to be a risk
factor for both users and nonusers, for both types of strokes, while smoking interacted to increase the
risk for hemorrhagic strokes (33 to 35).
In a large study, the relative risk of thrombotic strokes has been shown to range from 3 for
normotensive users to 14 for users with severe hypertension (36). The relative risk of hemorrhagic
stroke is reported to be 1.2 for non-smokers who used oral contraceptives, 2.6 for smokers who did not
use oral contraceptives, 7.6 for smokers who used oral contraceptives, 1.8 for normotensive users, and
25.7 for users with severe hypertension (36). The attributable risk is also greater in older women (9).
d. Dose-Related Risk of Vascular Disease from Oral Contraceptives
A positive association has been observed between the amount of estrogen and progestogen in oral
contraceptives and the risk of vascular disease (37 to 39). A decline in serum high-density lipoproteins
(HDL) has been reported with many progestational agents (20 to 22). A decline in serum high-density
lipoproteins has been associated with an increased incidence of ischemic heart disease. Because
estrogens increase HDL cholesterol, the net effect of an oral contraceptive depends on a balance
achieved between doses of estrogen and progestin and the nature of the progestin used in the
contraceptives. The amount and activity of both hormones should be considered in the choice of an oral
Minimizing exposure to estrogen and progestogen is in keeping with good principles of therapeutics.
For any particular oral contraceptive, the dosage regimen prescribed should be one which contains the
least amount of estrogen and progestogen that is compatible with the needs of the individual patient.
New acceptors of oral contraceptive agents should be started on preparations containing the lowest
dose of estrogen which produces satisfactory results for the patient.
e. Persistence of Risk of Vascular Disease
There are two studies which have shown persistence of risk of vascular disease for ever-users of oral
contraceptives. In a study in the United States, the risk of developing myocardial infarction after
discontinuing oral contraceptives persists for at least 9 years for women 40 to 49 years who had used
oral contraceptives for 5 or more years, but this increased risk was not demonstrated in other age
groups (14). In another study in Great Britain, the risk of developing cerebrovascular disease persisted
for at least 6 years after discontinuation of oral contraceptives, although excess risk was very small
(40). However, both studies were performed with oral contraceptive formulations containing 50 mcg or
higher of estrogens.
2. Estimates of Mortality from Contraceptive Use
One study gathered data from a variety of sources which have estimated the mortality rate associated
with different methods of contraception at different ages (Table III). These estimates include the
combined risk of death associated with contraceptive methods plus the risk attributable to pregnancy in
the event of method failure. Each method of contraception has its specific benefits and risks. The study
concluded that with the exception of oral contraceptive users 35 and older who smoke and 40 and older
who do not smoke, mortality associated with all methods of birth control is low and below that
associated with childbirth. The observation of a possible increase in risk of mortality with age for oral
contraceptive users is based on data gathered in the 1970's but not reported until 1983 (41). However,
current clinical practice involves the use of lower estrogen dose formulations combined with careful
restriction of oral contraceptive use to women who do not have the various risk factors listed in this
Because of these changes in practice and, also, because of some limited new data which suggest that
the risk of cardiovascular disease with the use of oral contraceptives may now be less than previously
observed (Porter JB, Hunter J, Jick H, et al. Oral contraceptives and nonfatal vascular disease. Obstet
Gynecol 1985;66:1–4; and Porter JB, Hershel J, Walker AM. Mortality among oral contraceptive users.
Obstet Gynecol 1987;70:29–32), the Fertility and Maternal Health Drugs Advisory Committee was
asked to review the topic in 1989. The Committee concluded that although cardiovascular disease risks
may be increased with oral contraceptive use after age 40 in healthy non-smoking women (even with the
newer low-dose formulations), there are greater potential health risks associated with pregnancy in
older women and with the alternative surgical and medical procedures which may be necessary if such
women do not have access to effective and acceptable means of contraception.
Therefore, the Committee recommended that the benefits of oral contraceptive use by healthy non-
smoking women over age 40 may outweigh the possible risks. Of course, older women, as all women
who take oral contraceptives, should take the lowest possible dose formulation that is effective.
3. Carcinoma of the Reproductive Organs
Numerous epidemiological studies have been performed on the incidence of breast, endometrial,
ovarian, and cervical cancer in women using oral contraceptives. Most of the studies on breast cancer
and oral contraceptive use report that the use of oral contraceptives is not associated with an increase in
the risk of developing breast cancer (42,44,89). Some studies have reported an increased risk of
developing breast cancer in certain subgroups of oral contraceptive users, but the findings reported in
these studies are not consistent (43,45 to 49,85 to 88).
Some studies suggest that oral contraceptive use has been associated with an increase in the risk of
cervical intraepithelial neoplasia in some populations of women (51 to 54). However, there continues to
be controversy about the extent to which such findings may be due to differences in sexual behavior and
In spite of many studies of the relationship between oral contraceptive use and breast and cervical
cancers, a cause and effect relationship has not been established.
4. Hepatic Neoplasia
Benign hepatic adenomas are associated with oral contraceptive use, although the incidence of benign
tumors is rare in the United States. Indirect calculations have estimated the attributable risk to be in the
range of 3.3 cases/100,000 for users, a risk that increases after four or more years of use (55). Rupture
of rare, benign, hepatic adenomas may cause death through intra-abdominal hemorrhage (56 to 57).
Studies from Britain have shown an increased risk of developing hepatocellular carcinoma (58 to 60) in
long-term (greater than 8 years) oral contraceptive users. However, these cancers are extremely rare in
the U.S., and the attributable risk (the excess incidence) of liver cancers in oral contraceptive users
approaches less than one per million users.
5. Risk of Liver Enzyme Elevations with Concomitant Hepatitis C Treatment
During clinical trials with the Hepatitis C combination drug regimen that contains
ombitasvir/paritaprevir/ritonavir, with or without dasabuvir, ALT elevations greater than 5 times the
upper limit of normal (ULN), including some cases greater than 20 times the ULN, were significantly
more frequent in women using ethinyl estradiol-containing medications such as COCs. Discontinue
Microgestin 1.5/30 prior to starting therapy with the combination drug regimen
ombitasvir/paritaprevir/ritonavir, with or without dasabuvir [see Contraindications (4)]. Microgestin
1.5/30 can be restarted approximately 2 weeks following completion of treatment with the combination
6. Ocular Lesions
There have been clinical case reports of retinal thrombosis associated with the use of oral
contraceptives. Oral contraceptives should be discontinued if there is unexplained partial or complete
loss of vision; onset of proptosis or diplopia; papilledema; or retinal vascular lesions. Appropriate
diagnostic and therapeutic measures should be undertaken immediately.
7. Oral Contraceptive Use Before and During Early Pregnancy
Extensive epidemiological studies have revealed no increased risk of birth defects in women who have
used oral contraceptives prior to pregnancy (61 to 63). Studies also do not suggest a teratogenic effect,
particularly insofar as cardiac anomalies and limb reduction defects are concerned (61,62,64,65) when
taken inadvertently during early pregnancy.
The administration of oral contraceptives to induce withdrawal bleeding should not be used as a test for
pregnancy. Oral contraceptives should not be used during pregnancy to treat threatened or habitual
It is recommended that for any patient who has missed two consecutive periods, pregnancy should be
ruled out before continuing oral contraceptive use. If the patient has not adhered to the prescribed
schedule, the possibility of pregnancy should be considered at the time of the first missed period. Oral
contraceptive use should be discontinued if pregnancy is confirmed.
8. Gallbladder Disease
Earlier studies have reported an increased lifetime relative risk of gallbladder surgery in users of oral
contraceptives and estrogens (66,67). More recent studies, however, have shown that the relative risk
of developing gallbladder disease among oral contraceptive users may be minimal (68 to 70). The
recent findings of minimal risk may be related to the use of oral contraceptive formulations containing
lower hormonal doses of estrogens and progestogens.
9. Carbohydrate and Lipid Metabolic Effects
Oral contraceptives have shown to cause glucose intolerance in a significant percentage of users (23).
Oral contraceptives containing greater than 75 mcg of estrogens cause hyperinsulinism, while lower
doses of estrogen cause less glucose intolerance (71). Progestogens increase insulin secretion and
create insulin resistance, this effect varying with different progestational agents (23,72). However, in
the non-diabetic woman, oral contraceptives appear to have no effect on fasting blood glucose (73).
Because of these demonstrated effects, prediabetic and diabetic women should be carefully observed
while taking oral contraceptives.
A small proportion of women will have persistent hypertriglyceridemia while on the pill. As discussed
earlier (see WARNINGS1a. and 1d.), changes in serum triglycerides and lipoprotein levels have been
reported in oral contraceptive users.
10. Elevated Blood Pressure
An increase in blood pressure has been reported in women taking oral contraceptives (74) and this
increase is more likely in older oral contraceptive users (75) and with continued use (74). Data from the
Royal College of General Practitioners (18) and subsequent randomized trials have shown that the
incidence of hypertension increases with increasing concentrations of progestogens.
Women with a history of hypertension or hypertension-related diseases or renal disease (76) should be
encouraged to use another method of contraception. If women elect to use oral contraceptives, they
should be monitored closely, and if significant elevation of blood pressure occurs, oral contraceptives
should be discontinued. For most women, elevated blood pressure will return to normal after stopping
oral contraceptives (75), and there is no difference in the occurrence of hypertension among ever and
never users (74,76,77).
The onset or exacerbation of migraine or development of headache with a new pattern which is
recurrent, persistent, or severe requires discontinuation of oral contraceptives and evaluation of the
12. Bleeding Irregularities
Breakthrough bleeding and spotting are sometimes encountered in patients on oral contraceptives,
especially during the first three months of use. Non-hormonal causes should be considered, and
adequate diagnostic measures taken to rule out malignancy or pregnancy in the event of breakthrough
bleeding, as in the case of any abnormal vaginal bleeding. If pathology has been excluded, time or a
change to another formulation may solve the problem. In the event of amenorrhea, pregnancy should be
Some women may encounter post-pill amenorrhea or oligomenorrhea, especially when such a condition
1. Patients should be counseled that this product does not protect against HIV infection (AIDS)
and other sexually transmitted diseases.
2. Physical Examination and Follow-Up
It is good medical practice for all women to have annual history and physical examinations, including
women using oral contraceptives. The physical examination, however, may be deferred until after
initiation of oral contraceptives if requested by the woman and judged appropriate by the clinician. The
physical examination should include special reference to blood pressure, breasts, abdomen and pelvic
organs, including cervical cytology, and relevant laboratory tests. In case of undiagnosed, persistent or
recurrent abnormal vaginal bleeding, appropriate measures should be conducted to rule out malignancy.
Women with a strong family history of breast cancer or who have breast nodules should be monitored
with particular care.
3. Lipid Disorders
Women who are being treated for hyperlipidemia should be followed closely if they elect to use oral
contraceptives. Some progestogens may elevate LDL levels and may render the control of
hyperlipidemias more difficult.
4. Liver Function
If jaundice develops in any woman receiving such drugs, the medication should be discontinued. Steroid
hormones may be poorly metabolized in patients with impaired liver function.
5. Fluid Retention
Oral contraceptives may cause some degree of fluid retention. They should be prescribed with caution,
and only with careful monitoring, in patients with conditions which might be aggravated by fluid
6. Emotional Disorders
Women with a history of depression should be carefully observed and the drug discontinued if
depression recurs to a serious degree.
7. Contact Lenses
Contact lens wearers who develop visual changes or changes in lens tolerance should be assessed by
8. Drug Interactions
Effects of Other Drugs on Oral Contraceptives (78)
Rifampin: Metabolism of both norethindrone and ethinyl estradiol is increased by rifampin. A reduction
in contraceptive effectiveness and increased incidence of breakthrough bleeding and menstrual
irregularities have been associated with concomitant use of rifampin.
Anticonvulsants: Anticonvulsants such as phenobarbital, phenytoin, and carbamazepine, have been
shown to increase the metabolism of ethinyl estradiol and/or norethindrone, which could result in a
reduction in contraceptive effectiveness.
Troglitazone: Administration of troglitazone with an oral contraceptive containing ethinyl estradiol and
norethindrone reduced the plasma concentrations of both by approximately 30%, which could result in a
reduction of contraceptive effectiveness.
Antibiotics: Pregnancy while taking oral contraceptives has been reported when the oral contraceptives
were administered with antimicrobials such as ampicillin, tetracycline, and griseofulvin. However,
clinical pharmacokinetic studies have not demonstrated any consistent effect of antibiotics (other than
rifampin) on plasma concentrations of synthetic steroids.
Atorvastatin: Coadministration of atorvastatin and an oral contraceptive increased AUC values for
norethindrone and ethinyl estradiol by approximately 30% and 20%, respectively.
Concomitant Use with HCV Combination Therapy – Liver Enzyme Elevation Do not co-administer
[DRUG] with HCV drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without
dasabuvir, due to potential for ALT elevations (see Warnings, RISK OF LIVER ENZYME
ELEVATIONS WITHCONCOMITANT HEPATITIS C TREATMENT)
Others: Ascorbic acid and acetaminophen may increase plasma ethinyl estradiol concentrations,
possibly by inhibition of conjugation. A reduction in contraceptive effectiveness and increased
incidence of breakthrough bleeding has been suggested with phenylbutazone.
Effects of Oral Contraceptives on Other Drugs