An increased risk of the following serious adverse reactions has been associated with the use of oral contraceptives (see WARNINGS).

•  Thrombophlebitis
•  Arterial thromboembolism
•  Pulmonary embolism
•  Myocardial infarction
•  Cerebral hemorrhage
•  Cerebral thrombosis
•  Hypertension
•  Gallbladder disease
•  Hepatic adenomas or benign liver tumors

There is evidence of an association between the following conditions and the use of oral contraceptives:

•  Mesenteric thrombosis
•  Retinal thrombosis

The following adverse reactions have been reported in patients receiving oral contraceptives and are believed to be drug-related:

•  Nausea
•  Vomiting
•  Gastrointestinal symptoms (such as abdominal cramps and bloating)
•  Breakthrough bleeding
•  Spotting
•  Change in menstrual flow
•  Amenorrhea
•  Temporary infertility after discontinuation of treatment
•  Edema
•  Melasma which may persist
•  Breast changes: tenderness, enlargement, secretion
•  Change in weight or appetite (increase or decrease)
•  Change in cervical ectropion and secretion
•  Possible diminution in lactation when given immediately postpartum
•  Cholestatic jaundice
•  Migraine
•  Rash (allergic)
•  Mood changes, including depression
•  Reduced tolerance to carbohydrates
•  Vaginitis, including candidiasis
•  Change in corneal curvature (steepening)
•  lntolerance to contact lenses
•  Decrease in serum folate levels
•  Exacerbation of systemic lupus erythematosus
•  Exacerbation of porphyria
•  Exacerbation of chorea
•  Aggravation of varicose veins
•  Anaphylactic/anaphylactoid reactions, including urticaria, angioedema, and severe reactions with respiratory and circulatory symptoms

The following adverse reactions have been reported in users of oral contraceptives and a causal association has been neither confirmed nor refuted:

•  Acne
•  Budd-Chiari syndrome
•  Cataracts
•  Changes in libido
•  Colitis
•  Cystitis-like syndrome
•  Dizziness
•  Dysmenorrhea
•  Erythema multiforme
•  Erythema nodosum
•  Headache
•  Hemolytic uremic syndrome
•  Hemorrhagic eruption
•  Hirsutism
•  Impaired renal function
•  Loss of scalp hair
•  Nervousness
•  Optic neuritis, which may lead to partial or complete loss of vision
•  Pancreatitis
•  Premenstrual syndrome

The most frequent (> 1%) treatment-emergent adverse events, listed in descending order, reported with the use of YAZ in the contraception clinical trials, which may or not be drug related, included: upper respiratory infection, headache, breast pain, vaginal moniliasis, leukorrhea, diarrhea, nausea, vomiting, vaginitis, abdominal pain, flu syndrome, dysmenorrhea, moniliasis, allergic reaction, urinary tract infection, accidental injury, cystitis, tooth disorder, sore throat, infection, fever, surgery, sinusitis, back pain, emotional liability, migraine, suspicious Papanicolaou smear, dyspepsia, rhinitis, acne, gastroenteritis, bronchitis, pharyngitis, skin disorder, inter-menstrual bleeding, decreased libido, weight gain, pain, depression, increased cough, dizziness, menstrual disorder, pain in extremity, pelvic pain, and asthenia.

The most frequent (> 1%) treatment-emergent adverse events, listed in descending order, reported with the use of YAZ in the PMDD clinical trials, which may or not be drug related, included: intermenstrual bleeding, headache, nausea, breast pain, upper respiratory infection, asthenia, abdominal pain, decreased libido, emotional lability, suspicious Papanicolaou smear, nervousness, menorrhagia, pain in extremity, depression, menstrual disorder, migraine, sinusitis, weight gain, vaginal moniliasis, vaginitis, hyperlipidemia, back pain, diarrhea, increased appetite, enlarged abdomen, accidental injury, acne, dysmenorrhea, and urinary tract infection.

The most frequent (> 1%) treatment-emergent adverse events, listed in descending order, reported with the use of YAZ in the acne clinical trials, which may or not be drug related, included: upper respiratory infection, metrorrhagia, headache, suspicious Papanicolaou smear, nausea, sinusitis, vaginal moniliasis, flu syndrome, menorrhagia, depression, emotional lability, abdominal pain, gastroenteritis, urinary tract infection, tooth disorder, infection, vomiting, pharyngitis, breast pain, dysmenorrhea, menstrual disorder, accidental injury, asthenia, sore throat, weight gain, arthralgia, bronchitis, rhinitis, amenorrhea, and urine abnormality.

Effects of Other Drugs on Combined Hormonal Contraceptives Rifampin: Metabolism of ethinyl estradiol and some progestins (e.g., norethindrone) is increased by rifampin. A reduction in contraceptive effectiveness and an increase in menstrual irregularities have been associated with concomitant use of rifampin.

Minocycline: Minocycline-related changes in estradiol, progesterone, FSH and LH plasma levels, breakthrough bleeding, or contraceptive failure cannot be ruled out. Anticonvulsants: Anticonvulsants such as phenobarbital, phenytoin, and carbamazepine have been shown to increase the metabolism of ethinyl estradiol and/or some progestins, which could result in a reduction of contraceptive effectiveness. Antibiotics: Pregnancy while taking combined hormonal contraceptives has been reported when the combined hormonal contraceptives were administered with antimicrobials such as ampicillin, tetracycline, and griseofulvin. However, clinical pharmacokinetic studies have not demonstrated any consistent effects of antibiotics (other than rifampin—see above) on plasma concentrations of synthetic steroids. See also separate discussion on minocycline (above).

Atorvastatin: Coadministration of atorvastatin and an oral contraceptive increased AUC values for norethindrone and ethinyl estradiol by approximately 30% and 20%, respectively. St. John's Wort: Herbal products containing St. John's Wort (hypericum perforatum) may induce hepatic enzymes (cytochrome P450) and p-glycoprotein transporter and may reduce the effectiveness of oral contraceptives and emergency contraceptive pills. This may also result in breakthrough bleeding. Other: Ascorbic acid and acetaminophen may increase plasma concentrations of some synthetic estrogens, possibly by inhibition of conjugation.

Effects of Drospirenone on Other Drugs

Metabolic Interactions

Metabolism of DRSP and potential effects of DRSP on hepatic cytochrome P450 (CYP) enzymes have been investigated in in vitro and in vivo studies (see Metabolism). In in vitro studies DRSP did not affect turnover of model substrates of CYP1A2 and CYP2D6, but had an inhibitory influence on the turnover of model substrates of CYP1A1, CYP2C9, CYP2C19 and CYP3A4 with CYP2C19 being the most sensitive enzyme. The potential effect of DRSP on CYP2C19 activity was investigated in a clinical pharmacokinetic study using omeprazole as a marker substrate. In the study with 24 postmenopausal women [including 12 women with homozygous (wild type) CYP2C19 genotype and 12 women with heterozygous CYP2C19 genotype] the daily oral administration of 3 mg DRSP for 14 days did not affect the oral clearance of omeprazole (40 mg, single oral dose) and the CYP2C19 product 5-hydroxy omeprazole. Furthermore, no significant effect of DRSP on the systemic clearance of the CYP3A4 product omeprazole sulfone was found. These results demonstrate that DRSP did not inhibit CYP2C19 and CYP3A4 in vivo.

Two additional clinical drug-drug interaction studies using simvastatin and midazolam as marker substrates for CYP3A4 were each performed in 24 healthy postmenopausal women. The results of these studies demonstrated that pharmacokinetics of the CYP3A4 substrates were not influenced by steady state DRSP concentrations achieved after administration of 3 mg DRSP/day.

Interactions with Drugs that Have the Potential to Increase Serum Potassium

There is a potential for an increase in serum potassium in women taking YAZ with other drugs (see BOLDED WARNING). Of note, occasional or chronic use of NSAID medication was not restricted in any of the clinical trials with YAZ.

A drug-drug interaction study of DRSP 3 mg/estradiol (E2) 1 mg versus placebo was performed in 24 mildly hypertensive post-menopausal women taking enalapril maleate 10 mg twice daily. Potassium levels were obtained every other day for a total of 2 weeks in all subjects. Mean serum potassium levels in the DRSP/E2 treatment group relative to baseline were 0.22 mEq/L higher than those in the placebo group. Serum potassium concentrations also were measured at multiple timepoints over 24 hours at baseline and on Day 14. On Day 14, the ratios for serum potassium Cmax and AUC in the DRSP/E2 group to those in the placebo group were 0.955 (90% CI: 0.914, 0.999) and 1.01 (90% CI: 0.944, 1.08), respectively. No patient in either treatment group developed hyperkalemia (serum potassium concentrations >5.5 mEq/L).

Effects of Combined Hormonal Contraceptives on Other Drugs

Combined oral contraceptives containing ethinyl estradiol may inhibit the metabolism of other compounds. Increased plasma concentrations of cyclosporine, prednisolone, and theophylline have been reported with concomitant administration of oral contraceptives. In addition, oral contraceptives may induce the conjugation of other compounds. Decreased plasma concentrations of acetaminophen and increased clearance on temazepam, salicylic acid, morphine, and clofibric acid have been noted when these drugs were administered with oral contraceptives.

Interactions With Laboratory Tests

Certain endocrine- and liver-function tests and blood components may be affected by oral contraceptives:

a. Increased prothrombin and factors VII, VIII, IX and X; decreased antithrombin 3; increased norepinephrine-induced platelet aggregability.

b. Increased thyroid-binding globulin (TBG) leading to increased circulating total thyroid hormone, as measured by protein-bound iodine (PBI), T4 by column or by radioimmunoassay. Free T3 resin uptake is decreased, reflecting the elevated TBG, free T4 concentration is unaltered.

c. Other binding proteins may be elevated in serum.

d. Sex-hormone-binding globulins are increased and result in elevated levels of total circulating sex steroids and corticoids; how-ever, free or biologically active levels remain unchanged.

e. Triglycerides may be increased.

f.Glucose tolerance may be decreased.

g. Serum folate levels may be depressed by oral contraceptive therapy. This may be of clinical significance if a woman becomes pregnant shortly after discontinuing oral contraceptives.

Bookmark this page: