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Quartette

WARNINGS

Included as part of the “PRECAUTIONS” Section

PRECAUTIONS

Thromboembolic Disorders And Other Vascular Problems

Stop Quartette if an arterial or deep venous thrombotic event (VTE) occurs. Stop Quartette if there is unexplained loss of vision, proptosis, diplopia, papilledema, or retinal vascular lesions. Evaluate for retinal vein thrombosis immediately.

If feasible, stop Quartette at least 4 weeks before and through 2 weeks after major surgery or other surgeries known to have an elevated risk of VTE.

Start Quartette 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 per 10,000 woman-years. The risk of VTE is highest during the first year of use of a COC. 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 COCs gradually disappears after COC use is discontinued.

Use of Quartette provides women with more hormonal exposure on a yearly basis than conventional monthly oral contraceptives containing the same strength synthetic estrogens and progestins (an additional 9 and 13 weeks of exposure to progestin and estrogen, respectively, per year). In the clinical trial, three cases of deep vein thrombosis were reported.

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), and hypertensive women who also smoke. COCs also increase the risk for stroke in women with other underlying risk factors.

Use COCs with caution in women with cardiovascular disease risk factors.

Liver Disease

Impaired Liver Function

Do not use Quartette in women with acute viral hepatitis or severe (decompensated) cirrhosis of the liver [see CONTRAINDICATIONS]. Acute 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 Quartette if jaundice develops.

Liver Tumors

Quartette is contraindicated in women with benign and malignant liver tumors [see CONTRAINDICATIONS]. 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.

High Blood Pressure

Quartette is contraindicated in women with uncontrolled hypertension or hypertension with vascular disease [see CONTRAINDICATIONS]. For women with well-controlled hypertension, monitor blood pressure and stop Quartette 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 and with extended duration of use. The incidence of hypertension increases with increasing concentration of progestin.

Risk Of Liver Enzyme Elevations With Concomitant Hepatitis C Treatment

During clinical trials with the Hepatitis C combination drug regimen that contains obmitasvir/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 Quartette prior to starting therapy with the combination drug regimen ombitasvir/paritaprevir/ritonavir, with or without dasabuvir [see CONTRAINDICATIONS]. Quartette can be restarted approximately 2 weeks following completion of treatment with the Hepatitis C combination drug regimen.

Gallbladder Disease

Studies suggest a small increased relative risk of developing gallbladder disease among COC users. Use of COCs may also 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.

Carbohydrate And Lipid Metabolic Effects

Carefully monitor prediabetic and diabetic women who are taking Quartette. COCs may decrease glucose tolerance 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 COCs.

Women with hypertriglyceridemia, or a family history thereof, may be at an increased risk of pancreatitis when using COCs.

Headache

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

Consider discontinuation of Quartette in the case of increased frequency or severity of migraine during COC use (which may be prodromal of a cerebrovascular event) [see CONTRAINDICATIONS].

Bleeding Irregularities

Bleeding and/or spotting that occurs at any time while taking the first 84 tablets (light pink, pink and purple) of each extended-cycle regimen is considered “unscheduled” bleeding/spotting. Bleeding that occurs during the time a woman takes the seven tablets (yellow) containing 10 mcg of ethinyl estradiol is considered “scheduled” bleeding.

Unscheduled And Scheduled Bleeding And Spotting

Unscheduled (breakthrough) bleeding and spotting sometimes occur in patients on COCs, especially during the first 3 months of use. If unscheduled bleeding persists or occurs after previously regular cycles on Quartette, 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.

Before prescribing Quartette, consider the occurrence of fewer scheduled menses (4 per year instead of 13 per year) against the occurrence of increased unscheduled bleeding and/or spotting. A 12-month open-label study of the efficacy of Quartette in preventing pregnancy assessed scheduled and unscheduled bleeding [see Clinical Studies] in 3,597 women who completed 34,087 28-day cycles of exposure. A total of 178 (4.9%) of the women discontinued Quartette, at least in part, due to bleeding or spotting.

Scheduled (withdrawal) bleeding and/or spotting remained fairly stable over time, with an average of 3 to 4 days of bleeding and/or spotting per each 91-day cycle.

Unscheduled bleeding and unscheduled spotting decreased over successive 91-day cycles. Table 1 below presents the number of days with unscheduled bleeding, spotting, and unscheduled bleeding and/or spotting in Treatment Cycles 1 to 4.

Table 1: Number of Unscheduled Bleeding, Spotting and Bleeding and/or Spotting Days per 91-day Cycle




















Cycle (N) Days of Unscheduled Bleeding per 84-Day Interval Median Days Per Subject-Month
Mean Q1 Median Q3
1 (3330) 7.2 0 4 10 1.0
2 (2820) 3.3 0 0 4 0.0
3 (2433) 2.5 0 0 3 0.0
4 (2213) 2.2 0 0 2 0.0
Cycle (N) Days of Unscheduled Bleeding per 84-Day Interval Median Days Per Subject-Month
Mean Q1 Median Q3
1 (3330) 10.7 2 7 15 1.8
2 (2820) 6.7 0 3 9 0.8
3 (2433) 5.2 0 2 6 0.5
4 (2213) 4.4 0 1 5 0.3
Cycle (N) Days of Unscheduled Bleeding per 84-Day Interval Median Days Per Subject-Month
Mean Q1 Median Q3
1 (3330) 17.9 5 14 27 3.5
2 (2820) 10.0 1 5 14 1.3
3 (2433) 7.7 0 3 10 0.8
4 (2213) 6.6 0 3 8 0.8
Q1=Quartile 1: 25% of women had ≤ this number of days of unscheduled bleeding/spotting

Median: 50% of women had ≤ this number of days of unscheduled bleeding/spotting

Q3=Quartile 3: 75% of women had ≤ this number of days of unscheduled bleeding/spotting

Figure 1 shows the percent of Quartette subjects in the primary clinical trial with ≥7 days or ≥20 days of unscheduled bleeding and/or spotting, or just unscheduled bleeding, during each 91-day treatment cycle.

Figure 1: Percent of Women Taking Quartette Who Reported Unscheduled Bleeding and/or Spotting
Amenorrhea and Oligomenorrhea


Amenorrhea And Oligomenorrhea

Women who are not pregnant and use Quartette may experience amenorrhea. Based on data from the clinical trial, amenorrhea occurred in approximately 1.9% of women during Cycle 1, 7.7% during Cycle 2, 10.7% during Cycle 3, and 10.1% during Cycle 4 using Quartette. Rule out pregnancy in the event of amenorrhea. Some women may experience amenorrhea or oligomenorrhea after stopping COCs, especially when such a condition was pre-existent.

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. Discontinue Quartette 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].

Depression

Carefully observe women with a history of depression and discontinue Quartette if depression recurs to a serious degree. Six cases of suicidality (suicide attempts and suicidal behavior) were reported in the clinical trial; several of these cases occurred in women with a psychiatric history.

Carcinoma Of The Breast And Cervix

Quartette is contraindicated in women who currently have or have had breast cancer because breast cancer may be hormonally sensitive [see CONTRAINDICATIONS].

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 are due to differences in sexual behavior and other factors.

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.

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 health care.

Hereditary Angioedema

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

Chloasma

Chloasma may occur with COC use, especially in women with a history of chloasma gravidarum. Advise women who tend to develop chloasma to avoid exposure to the sun or ultraviolet radiation while taking Quartette.

Patient Counseling Information

See FDA-approved patient labeling (PATIENT INFORMATION). Counsel patients on the following information:

  • 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.
  • 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.
  • Quartette does not protect against HIV-infection (AIDS) and other sexually transmitted infections.
  • The Warnings and Precautions associated with COCs.
  • Quartette is not to be used during pregnancy; if pregnancy occurs during use of Quartette, instruct the patient to stop further intake.
  • 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 of FDA-Approved Patient Labeling.
  • Use a back-up or alternative method of contraception when enzyme inducers are used with COCs.
  • COCs may reduce breast milk production. This is less likely to occur if breastfeeding is well established.
  • Women who start COCs postpartum, and who have not yet had a period, should use an additional method of contraception until they have taken a light pink tablet for 7 consecutive days.
  • Amenorrhea may occur. Consider pregnancy in the event of amenorrhea, and rule out pregnancy if amenorrhea is associated with symptoms of pregnancy, such as morning sickness or unusual breast tenderness.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

[See WARNINGS AND PRECAUTIONS
and Use In Specific Populations].

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 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.

Nursing Mothers

When possible, advise the nursing mother to use other forms of contraception 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.

Pediatric Use

Safety and efficacy of Quartette have been established in women of reproductive age. Efficacy is expected to be the same for postpubertal adolescents under the age of 18 as for users 18 years and older. Use of Quartette before menarche is not indicated.

Geriatric Use

Quartette has not been studied in women who have reached menopause and is not indicated in this population.

Hepatic Impairment

No studies have been conducted to evaluate the effect of hepatic impairment on the disposition of Quartette. 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 and WARNINGS AND PRECAUTIONS]

Renal Impairment

No studies have been conducted to evaluate the effect of renal impairment on the disposition of Quartette.

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