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The following serious adverse reactions are discussed elsewhere in the labeling:
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
From clinical trials with different dose formulations of Angeliq containing E2 dose ranging from 0.5 mg to 1.0 mg combined with DRSP dose ranging from 0.25 mg to 3 mg:
- The most common adverse reactions were gastrointestinal and abdominal pain, female genital bleeding, breast pain and headache. The frequencies of common adverse reactions, in general, were higher for the Angeliq dose formulation containing E2 1 mg compared to Angeliq containing E2 0.5 mg.
- The most common adverse reactions leading to drug discontinuation in controlled clinical trials were abdominal pain, headache, postmenopausal bleeding, breast tenderness, and weight increased.
In a placebo-controlled trial evaluating Angeliq 0.25 mg DRSP/0.5 mg E2, 183 postmenopausal women received at least one dose of DRSP 0.25 mg/0.5 mg E2 and 180 received placebo. Study subjects were treated for 3 cycles of 28 days each for a total of 12 weeks of treatment. The median age was 53 years (range: 40-77 years) and over 50% of subjects had a hysterectomy, 68% were Caucasian and 24% were Black. Table 1 summarizes adverse reactions reported in at least 2% of subjects receiving Angeliq 0.25 mg DRS/0.5 mg E2 and at a higher incidence than subjects receiving placebo.
Table 1: Adverse Reactions that Occurred at a
Frequency of ≥ 2% with Angeliq 0.25 mg DRSP/0.5 mg E2 and at a higher
incidence than placebo
|Adverse Reaction||Angeliq (0.25 mg DRSP/0.5 mg E2)
|Gastrointestinal and abdominal pains*||11 (6.0)||5 (2.8)|
|Headache||11 (6.0)||9 (5.0)|
|Vulvovaginal fungal infections||10 (5.5)||1 (0.6)|
|Breast pain**||6 (3.3)||1 (0.6)|
|Nausea||6 (3.3)||2 (1.1)|
|Diarrhea||4 (2.2)||1 (0.6)|
|Peripheral Edema||4 (2.2)||2 (1.1)|
|*Gastrointestinal and abdominal
pain includes: abdominal pain (overall, lower, and upper), abdominal
discomfort, abdominal tenderness
**Breast pain includes: breast pain, breast tenderness, nipple pain
Pooled Data Of Clinical Trials With Different Dose Formulations Of Angeliq
Data from 13 clinical trials in postmenopausal subjects treated with different dose formulations of Angeliq containing 1 mg E2 (1 mg E2 + 0.5 mg – 3.0 mg DRSP; N=2842) were pooled to provide an overall estimate of adverse reactions. Similarly, data from 2 clinical trials with Angeliq containing 0.5 mg E2 (0.5 mg E2 + DRSP 0.25 mg – 0.5 mg; N=853) were pooled for the same purpose. Table 2 shows adverse reactions reported in at least 1% of subjects treated with Angeliq.
Table 2: Adverse Reactions
that Occurred at a Frequency of ≥ 1% in Clinical Trials
|Adverse Reaction||Angeliq containing 1 mg E2
N = 2842
|Angeliq containing 0.5 mg E2
|Breast pain or discomfort||508 (17.9)||53 (6.2)|
|Female genital tract bleeding||397 (14.0)||21 (2.5)|
|Gastrointestinal and abdominal pain||186 (6.5)||31 (3.6)|
|Cervical polyp||34 (1.2)||3 (0.4)|
|Emotional lability||35 (1.2)||11 (1.3)|
|Migraine||28 (1.0)||5 (0.6)|
Adverse Reactions in clinical studies were coded using the MedDRA dictionary (version 13.0). Different MedDRA terms representing the same medical phenomenon have been grouped together as single adverse reactions to avoid diluting or obscuring the true effect.
The following additional adverse reactions have been reported during post approval use of Angeliq. Because these reactions are reported voluntarily from a population of uncertain size, reliably estimating their frequency or establishing a causal relationship to drug exposure is not always possible.
Immune System Disorders: Hypersensitivity reactions, including rash, pruritis, and urticaria
Reproductive system and breast disorders: Breast cancer
Vascular disorders: venous and arterial thromboembolic events (peripheral deep venous occlusion, thrombosis and embolism/pulmonary vascular occlusion, thrombosis, embolism and infarction/myocardial infarction/cerebral infarction and stroke not specified as hemorrhagic)
Read the Angeliq (drospirenone and estradiol) Side Effects Center for a complete guide to possible side effects
No formal drug-drug interaction studies have been conducted for Angeliq.
Effect of Drospirenone on Other Drugs
The potential effect of DRSP on CYP2C19 activity was investigated in a clinical pharmacokinetic study using omeprazole as a marker substrate. No significant effect of DRSP on the systemic clearance of the CYP3A4 product omeprazole sulfone was found. These results demonstrated that DRSP did not inhibit CYP2C19 and CYP3A4 in vivo. Two further clinical drug-drug interaction studies using simvastatin and midazolam as marker substrates for CYP3A4, respectively, were performed and the results of these studies demonstrated that pharmacokinetics of the CYP3A4 substrates were not influenced by steady-state DRSP concentrations.
Co-administration of DRSP and drugs that may increase serum potassium: There is a potential for an increase in serum potassium in women taking DRSP with other drugs that may affect electrolytes, such as ACE inhibitors, angiotensin receptor blockers, or NSAIDs, more pronounced in diabetic women [see WARNINGS AND PRECAUTIONS, and CLINICAL PHARMACOLOGY].
Electrolytes were studied in postmenopausal women with hypertension and/or diabetes mellitus requiring an ACE inhibitor or angiotensin receptor blocker. After 28 days of exposure to 1 mg E2 and 3 mg DRSP (n=112) or placebo (n=118). The mean change from baseline in serum potassium was 0.11 mEq/L for the E2/DRSP group and 0.08 mEq/L for the placebo group. None of the subjects with serum potassium concentrations ≥ 5.5 mEq/L had cardiovascular adverse events.
A drug-drug interaction study of DRSP 3 mg/E2 1 mg versus placebo was performed in mildly hypertensive postmenopausal women taking enalapril maleate 10 mg twice daily. Potassium concentrations were obtained every other day for a total of 2 weeks in all subjects. Mean serum potassium concentrations in the DRSP/E2 treatment group relative to baseline were 0.22 mEq/L higher than those in the placebo group. 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).
Of note, occasional or chronic use of NSAID medication was not restricted in any of the Angeliq clinical trials.
Effect of Other Drugs on Estrogens and Progestins
In vitro and in vivo studies have shown that estrogens and progestins are metabolized partially by cytochrome P450 3A4 (CYP3A4). Therefore, inducers or inhibitors of CYP3A4 may affect estrogen and progestin drug metabolism. In a clinical drug-drug interaction study conducted in premenopausal women, once daily co-administration of DRSP 3 mg/E2 1.5 mg containing tablets with strong CYP3A4 inhibitor, ketoconazole 200 mg twice daily for 10 days resulted in a moderate increase of exposure and a mild increase of peak concentration for DRSP. The E2 exposure and peak concentration were unaffected by ketoconazole, although the exposure and peak concentration of estrone (E1) increased. Although no clinically relevant effects on any safety or laboratory parameters including serum potassium were observed, this study only assessed subjects for 10 days. The clinical impact for a woman taking a DRSP-containing combination hormone and chronic use of a CYP3A4/5 inhibitor is unknown.
Substances Decreasing The Exposure And Possibly Diminishing The Efficacy Of Estrogens And Progestins (Enzyme Inducers)
Inducers of CYP3A4 such as St. John's wort (Hypericum perforatum), phenobarbital, carbamazepine, and rifampin may reduce plasma concentrations of estrogens and progestins, possibly resulting in a decrease in therapeutic effects and/or changes in the uterine bleeding profile.
Substances Increasing The Exposure Of Estrogens And Progestins (Enzyme Inhibitors)
Concomitant administration of moderate or strong CYP3A4 inhibitors such as azole antifungals (for example, ketoconazole, itraconazole, voriconazole, fluconazole), verapamil, macrolides (for example, clarithromycin, erythromycin), diltiazem, and grapefruit juice did increase the plasma concentrations of the estrogen or the progestin or both [see WARNINGS AND PRECAUTIONS and CLINICAL PHARMACOLOGY].
HIV/HCV Protease Inhibitors And Non-Nucleoside Reverse Transcriptase Inhibitors
Significant changes (increase or decrease) in the plasma concentrations of estrogen and progestin have been noted in some cases of co-administration with HIV/HCV protease inhibitors or with non-nucleoside reverse transcriptase inhibitors.
Interaction With Alcohol
Acute alcohol ingestion during use of hormone therapy may lead to elevations of circulating E2 concentrations.
Read the Angeliq Drug Interactions Center for a complete guide to possible interactions
Last reviewed on RxList: 7/13/2015
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