WARNINGS
Included as part of the "PRECAUTIONS" Section
PRECAUTIONS
Thromboembolic Disorders And Other Vascular Problems
Stop Nikki if an arterial or venous thrombotic (VTE) event occurs.
Based on presently available information on DRSP-containing COCs with 0.03 mg ethinyl estradiol (that
is, Yasmin), DRSP-containing COCs may be associated with a higher risk of venous thromboembolism
(VTE) than COCs containing the progestin levonorgestrel or some other progestins. Epidemiologic
studies that compared the risk of VTE reported that the risk ranged from no increase to a three-fold
increase. Before initiating use of Nikki in a new COC user or a woman who is switching from a
contraceptive that does not contain DRSP, consider the risks and benefits of a DRSP-containing COC in
light of her risk of a VTE. Known risk factors for VTE include smoking, obesity, and family history of
VTE, in addition to other factors that contraindicate use of COCs [see CONTRAINDICATIONS].
A number of studies have compared the risk of VTE for users of Yasmin (which contains 0.03 mg of
EE and 3 mg of DRSP) to the risk for users of other COCs, including COCs containing levonorgestrel.
Those that were required or sponsored by regulatory agencies are summarized in Table 1.
Table 1: Estimates (Hazard Ratios) of Venous Thromboembolism risk in Current Users of Yasmin Compared to Users of
Oral Contraceptives that Contain Other Progestins
Epidemiologic Study
(Author, Year of Publication)
Population Studied |
Comparator Product
(all are low-dose COCs ; with ≤ 0.04 mg of EE) |
Hazard Ratio (HR)
(95% CI) |
i3 Ingenix
(Seeger 2007)
Initiators, including new users* |
All COCs available in the US during the conduct of the study† |
HR: 0.9
(0.5 to 1.6) |
EURAS (Dinger 2007) Initiators, including new users* |
All COCs available in Europe during the conduct of the study‡ Levonorgestrel/EE |
HR: 0.9 (0.6 to 1.4) HR: 1.0
(0.6 to 1.8) |
“FDA-funded study” (2011)
New users*
All users
(i.e., initiation and continuing
use of study combination hormonal contraception) |
Other COCs available during the course of the study §
Levonorgestrel/0.03 mg EE
Other COCs available during the course of the study§
Levonorgestrel/0.03 mg EE |
HR: 1.8
(1.3 to 2.4)
HR: 1.6
(1.1 to 2.2)
HR: 1.7
(1.4 to 2.1)
HR: 1.5
(1.2 to 1.8) |
* “New users” - no use of combination hormonal contraception for at least the prior 6 months
† Includes low-dose COCs containing the following progestins: norgestimate, norethindrone, levonorgestrel, desogestrel, norgestrel, medroxyprogesterone, or ethynodiol diacetate
‡ Includes low-dose COCs containing the following progestins: levonorgestrel, desogestrel, dienogest, chlormadinone acetate, gestodene, cyproterone acetate, norgestimate, or norethindrone
§ Includes low-dose COCs containing the following progestins: norgestimate, norethindrone, or levonorgestrel |
In addition to these "regulatory studies," other studies of various designs have been conducted. Overall,
there are two prospective cohort studies (see Table 1): the US post-approval safety study Ingenix
[Seeger 2007], the European post-approval safety study EURAS (European Active Surveillance Study)
[Dinger 2007]. An extension of the EURAS study, the Long-Term Active Surveillance Study (LASS),
did not enroll additional subjects, but continued to assess VTE risk. There are three retrospective
cohort studies: one study in the US funded by the FDA (see Table 1), and two from Denmark [Lidegaard
2009, Lidegaard 2011]. There are two case-control studies: the Dutch MEGA study analysis [van
Hylckama Vlieg 2009] and the German case-control study [Dinger 2010]. There are two nested casecontrol
studies that evaluated the risk of non-fatal idiopathic VTE: the PharMetrics study [Jick 2011]
and the GPRD study [Parkin 2011]. The results of all of these studies are presented in Figure 1
Figure 1: VTE Risk with Yasmin Relative to LNG-Containing COCs (adjusted risk#)
 |
Risk ratios displayed on logarithmic scale; risk ratio < 1 indicates a lower risk of VTE for DRSP, > 1
indicates an increased risk of VTE for DRSP.
*Comparator "Other COCs", including LNG- containing COCs
† LASS is an extension of the EURAS study
#Some adjustment factors are indicated by superscript letters: a) Current heavy smoking, b)
hypertension, c) obesity, d) family history, e) age, f) BMI, g) duration of use, h) VTE history, i) period
of inclusion, j) calendar year, k) education, l) length of use, m) parity, n) chronic disease, o) concomitant
medication, p) smoking, q) duration of exposure, r) site
|
(References: Ingenix [Seeger 20071]1, EURAS (European Active Surveillance Study) [Dinger 2007]2,
LASS (Long-Term Active Surveillance Study) [Dinger, unpublished document on file], FDA-funded
study [Sidney 2011]3, Danish [Lidegaard 2009]4, Danish reanalysis [ Lidegaard 2011]5, MEGA study
[van Hylckama Vlieg 2009]6, German Case-Control study [Dinger 2010]7, PharMetrics [Jick 2011]8,
GPRD study [Parkin 2011]9 )
Although the absolute VTE rates are increased for users of hormonal contraceptives compared to nonusers,
the rates during pregnancy are even greater, especially during the post-partum period (see Figure
2). 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.
The risk of thromboembolic disease due to oral contraceptives gradually disappears after COC use is
discontinued.
Figure 2 shows the risk of developing a VTE for women who are not pregnant and do not use oral
contraceptives, for women who use oral contraceptives, for pregnant women, and for women in the
postpartum period. To put the risk of developing a VTE into perspective: If 10,000 women who are not
pregnant and do not use oral contraceptives are followed for one year, between 1 and 5 of these women
will develop a VTE.
Figure 2: Likelihood of Developing a VTE
If feasible, stop Nikki at least 4 weeks before and through 2 weeks after major surgery or other
surgeries known to have an elevated risk of thromboembolism.
Start Nikki 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.
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), 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 Nikki if there is unexplained loss of vision, proptosis, diplopia, papilledema, or retinal vascular
lesions. Evaluate for retinal vein thrombosis immediately. [see ADVERSE REACTIONS]
Hyperkalemia
Nikki contains 3 mg of the progestin DRSP which has anti-mineralocorticoid activity, including the
potential for hyperkalemia in high-risk patients, comparable to a 25 mg dose of spironolactone. Nikki is
contraindicated in patients with conditions that predispose to hyperkalemia (that is, renal impairment,
hepatic impairment and adrenal insufficiency). Women receiving daily, long-term treatment for chronic
conditions or diseases with medications that may increase serum potassium concentration should have
their serum potassium concentration checked during the first treatment cycle. Medications that may
increase serum potassium concentration include ACE inhibitors, angiotensin-II receptor antagonists,
potassium-sparing diuretics, potassium supplementation, heparin, aldosterone antagonists, and NSAIDS.
Consider monitoring serum potassium concentration in high-risk patients who take a strong CYP3A4
inhibitor long-term and concomitantly. Strong CYP3A4 inhibitors include azole antifungals (e.g.
ketoconazole, itraconazole, voriconazole), HIV/HCV protease inhibitors (e.g., indinavir, boceprevir),
and clarithromycin [see CLINICAL PHARMACOLOGY].
Carcinoma Of The Breasts And Reproductive Organs
Women who currently have or have had breast cancer should not use Nikki 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.
Liver Disease
Discontinue Nikki 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.
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
Nikki prior to starting therapy with the combination drug regimen ombitasvir/paritaprevir/ritonavir, with
or without dasabuvir [see CONTRAINDICATIONS]. Nikki can be restarted approximately 2
weeks following completion of treatment with the Hepatitis C combination drug regimen.
High Blood Pressure
For women with well-controlled hypertension, monitor blood pressure and stop Nikki 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.
Gallbladder Disease
Studies suggest a small increased relative risk of developing gallbladder disease among COC users.
Carbohydrate And Lipid Metabolic Effects
Carefully monitor prediabetic and diabetic women who are taking Nikki. COCs may decrease glucose
intolerance in a dose-related fashion.
Consider alternative contraception for women with uncontrolled dyslipidemias. A small proportion of
women will have adverse lipid changes while on COC's.
Women with hypertriglyceridemia, or a family history thereof, may be at an increased risk of
pancreatitis when using COCs.
Headache
If a woman taking Nikki develops new headaches that are recurrent, persistent, or severe, evaluate the
cause and discontinue Nikki 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.
Bleeding Irregularities
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 COC.
Based on patient diaries from two contraceptive clinical trials of Nikki, 8 to 25% of women
experienced unscheduled bleeding per 28-day cycle. A total of 12 subjects out of 1,056 (1.1%)
discontinued due to menstrual disorders including intermenstrual bleeding, menorrhagia, and
metrorrhagia.
Women who use Nikki may experience absence of withdrawal bleeding, even if they are not pregnant.
Based on subject diaries from contraception trials for up to 13 cycles, 6 to 10% of women experienced
cycles with no withdrawal bleeding. Some women may encounter post-pill amenorrhea or
oligomenorrhea, especially when such a condition was pre-existent.
If 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.
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.
The administration of oral contraceptives to induce withdrawal bleeding should not be used as a test for
pregnancy [see Use In Specific Populations]
Depression
Women with a history of depression should be carefully observed and Nikki discontinued if depression
recurs to a serious degree.
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 DRUG INTERACTIONS].
DRSP causes an increase in plasma renin activity and plasma aldosterone induced by its mild antimineralocorticoid
activity.
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.
Other Conditions
In women with hereditary angioedema, exogenousestrogens 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.
Patient Counseling Information
Advise the patient to read the FDA-approved patient labeling (PATIENT INFORMATION).
- Counsel patients that cigarette smoking increases the risk of serious cardiovascular events from
COC use, and that woman 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 about the information regarding the risk of VTE with DRSP-containing COCs
compared to COCs that contain levonorgestrel or some other progestins.
- Counsel patients that Nikki does not protect against HIV-infection (AIDS) and other sexually
transmitted diseases.
- Counsel patients on Warnings and Precautions associated with COCs.
- Counsel patients that Nikki contains DRSP. Drospirenone may increase potassium. Patients should be
advised to inform their healthcare provider if they have kidney, liver or adrenal disease because the
use of Nikki in the presence of these conditions could cause serious heart and health problems.
They should also inform their healthcare provider if they are currently on daily, long-term treatment
(NSAIDs, potassium-sparing diuretics, potassium supplementation, ACE inhibitors, angiotensin-II
receptor antagonists, heparin or aldosterone antagonists) for a chronic condition or taking strong
CYP3A4 inhibitors.
- Inform patients that Nikki is not indicated during pregnancy. If pregnancy occurs during treatment
with Nikki, instruct the patient to stop further intake.
- Counsel patients to take one tablet daily by mouth at the same time every day. Instruct patients what to
do in the event pills are missed. See "WHAT to DO if YOU MISS PILLS " section in FDA-Approved
Patient Labeling .
- Counsel patients to use a back-up or alternative method of contraception when enzyme inducers are
used with COCs.
- 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 have not yet had a period, to use an
additional method of contraception until she has taken a pink tablet for 7 consecutive days.
- Counsel patients that amenorrhea may occur. Rule out pregnancy in the event of amenorrhea in two
or more consecutive cycles.
The other brands listed are trademarks of their respective owners and are not trademarks of Lupin
Pharmaceuticals, Inc. The makers of these brands are not affiliated with and do not endorse Lupin
Pharmaceuticals, Inc. or its products.
Nonclinical Toxicology
Carcinogenesis, Mutagenesis, Impairment Of Fertility
In a 24 month oral carcinogenicity study in mice dosed with 10 mg/kg/day DRSP alone or 1 + 0.01, 3 +
0.03 and 10 + 0.1 mg/kg/day of DRSP and EE, 0.1 to 2 times the exposure (AUC of DRSP) of women
taking a contraceptive dose, there was an increase in carcinomas of the harderian gland in the group that
received the high dose of DRSP alone. In a similar study in rats given 10 mg/kg/day DRSP alone or 0.3
+ 0.003, 3 + 0.03 and 10 + 0.1 mg/kg/day DRSP and EE, 0.8 to 10 times the exposure of women taking a
contraceptive dose, there was an increased incidence of benign and total (benign and malignant) adrenal
gland pheochromocytomas in the group receiving the high dose of DRSP. Mutagenesis studies for
DRSP were conducted in vivo and in vitro and no evidence of mutagenic activity was observed.
Use In Specific Populations
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 nongenital
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.
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.
After oral administration of 3 mg DRSP/0.03 mg EE (Yasmin) tablets, about 0.02% of the DRSP dose
was excreted into the breast milk of postpartum women within 24 hours. This results in a maximal daily
dose of about 0.003 mg DRSP in an infant.
Pediatric Use
Safety and efficacy of Nikki 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.
Geriatric Use
Nikki has not been studied in postmenopausal women and is not indicated in this population.
Patients With Renal Impairment
Nikki is contraindicated in patients with renal impairment [see CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS].
In subjects with creatinine clearance (CLcr) of 50 to 79 mL/min, serum DRSP levels were comparable
to those in a control group with CLcr ≥80 mL/min. In subjects with CLcr of 30 to 49 mL/min, serum
DRSP concentrations were on average 37% higher than those in the control group. In addition, there is a
potential to develop hyperkalemia in subjects with renal impairment whose serum potassium is in the
upper reference range, and who are concomitantly using potassium sparing drugs [see CLINICAL PHARMACOLOGY].
Patients With Hepatic Impairment
Nikki is contraindicated in patients with hepatic disease [see CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS]. The mean exposure to DRSP in women with moderate liver
impairment is approximately three times higher than the exposure in women with normal liver function.
Nikki has not been studied in women with severe hepatic impairment.
Race
No clinically significant difference was observed between the pharmacokinetics of DRSP or EE in
Japanese versus Caucasian women [see CLINICAL PHARMACOLOGY].
REFERENCES
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thromboembolism in women taking ethinylestradiol/drospirenone and other oral contraceptives.
Obstet Gynecol 110, 587-593.
2. Dinger, J.C., Heinemann, L.A., and Kuhl-Habich, D. (2007). The safety of a drospirenone-containing
oral contraceptive: final results from the European Active Surveillance Study on oral contraceptives
based on 142,475 women-years of observation. Contraception 75, 344-354.
3. Combined hormonal contraceptives (CHCs) and the risk of cardiovascular endpoints. Sidney, S.
(primary author) http://www.fda.gov/downloads/Drugs/DrugSafety/UCM277384.pdf, accessed Oct
27, 2011.
4. Lidegaard, O., Lokkegaard, E., Svendsen, A.L., and Agger, C. (2009). Hormonal contraception and
risk of venous thromboembolism: national follow-up study. BMJ 339, b2890.
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venous thromboembolism from use of oral contraceptives containing different progestogens and
oestrogen doses: Danish cohort study, 2001-9. BMJ 343, d6423.
6. van Hylckama Vlieg, A., Helmerhorst, F.M., Vandenbroucke, J.P., Doggen, C.J., and Rosendaal, F.R.
(2009). The venous thrombotic risk of oral contraceptives, effects of oestrogen dose and
progestogen type: results of the MEGA case-control study. BMJ 339, b2921.
7. Dinger, J., Assmann, A., Mohner, S., and Minh, T.D. (2010). Risk of venous thromboembolism and
the use of dienogest- and drospirenone-containing oral contraceptives: results from a German casecontrol
study. J Fam Plann Reprod Health Care 36, 123-129.
8. Jick, S.S., and Hernandez, R.K. (2011). Risk of non-fatal venous thromboembolism in women using
oral contraceptives containing drospirenone compared with women using oral contraceptives
containing levonorgestrel: case-control study using United States claims data. BMJ 342, d2151.
9. Parkin, L., Sharples, K., Hernandez, R.K., and Jick, S.S. (2011). Risk of venous thromboembolism in
users of oral contraceptives containing drospirenone or levonorgestrel: nested case-control study
based on UK General Practice Research Database. BMJ 342, d2139.