"The U.S. Food and Drug Administration today approved Osphena (ospemifene) to treat women experiencing moderate to severe dyspareunia (pain during sexual intercourse), a symptom of vulvar and vaginal atrophy due to menopause.
The following serious adverse reactions are discussed elsewhere in the labeling:
- Cardiovascular Disorders [see BOXED WARNING, WARNINGS AND PRECAUTIONS]
- Malignant Neoplasms [see BOXED WARNING, WARNINGS AND PRECAUTIONS]
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.
The data described below is from a one-year, prospective, multicenter, double blind, double dummy, randomized, controlled trial investigating the effect of three different dosage combinations of E2/LNG versus E2 alone on the development of endometrial hyperplasia. All women were postmenopausal, had a serum estradiol level of less than 20 pg/mL, and the sample included both symptomatic and asymptomatic women. The data below includes all adverse reactions reported at a frequency of > 3% in the E2/LNG 0.045 / 0.015 group (the approved dosage for Climara Pro, N=212) and the E2 alone group (N=204).
Table 1: All Treatment Emergent Reactions Regardless
of Relationship Reported at a Frequency of > 3% with Climara Pro in the
1-year Endometrial Hyperplasia Studya)
|Body System Adverse Reaction||Climara Pro 0.045 / 0.015
Na = 212
N = 204
|Body as a Whole|
|Abdominal pain||9 (4.2)||11 (5.4)|
|Accidental injury||7 (3.3)||6 (2.9)|
|Back pain||13 (6.1)||12 (5.9)|
|Flu syndrome||10 (4.7)||13 (6.4)|
|Infection||7 (3.3)||10 (4.9)|
|Pain||11 (5.2)||13 (6.4)|
|Hypertension||7 (3.3)||9 (4.4)|
|Flatulence||8 (3.8)||11 (5.4)|
|Metabolic and Nutritional|
|Edema||8 (3.8)||5 (2.5)|
|Weight gain||6 (2.8)||10 (4.9)|
|Arthralgia||9 (4.2)||10 (4.9)|
|Depression||12 (5.7)||7 (3.4)|
|Headache||11 (5.2)||14 (6.9)|
|Bronchitis||9 (4.2)||7 (3.4)|
|Sinusitis||8 (3.8)||12 (5.9)|
|Upper respiratory infection||28 (13.2)||26 (12.7)|
|Skin and Appendages|
|Application site reaction||86 (40.6)||69 (33.8)|
|Breast pain||40 (18.9)||20 (9.8)|
|Rash||5 (2.4)||10 (4.9)|
|Urinary Tract Infection||7 (3.3)||8 (3.9)|
|Vaginal Bleeding||78 (36.8)||44 (21.6)|
|Vaginitis||4 (1.9)||6 (2.9)|
|aN = total number of subjects in a treatment group; n = number of subjects with event.|
Irritation potential of Climara Pro was assessed in a 3-week irritation study. The study compared the irritation of a Climara Pro placebo patch (22 cm²) to a placebo (25 cm²). Visual assessments of irritation were made on Day 7 of each wear period, approximately 30 minutes after patch removal using a 7-point scale (0 = no evidence of irritation; 1 = minimal erythema, barely perceptible; 2 = definite erythema, readily visible, or minimal edema, or minimal papular response; 3–7 = erythema and papules, edema, vesicles, strong extensive reaction).
The mean irritation scores were 0.13 (week 1), 0.12 (week 2), and 0.06 (week 3) for the Climara Pro placebo. The mean scores for the Climara placebo were 0.2 (week 1), 0.26 (week 2), 0.12 (week 3). There were no irritation scores greater than 2 at any timepoint in any subject.
In controlled clinical trials, withdrawals due to application site reactions occurred in 6 (2.1 percent) of subjects in the 12week symptom study and in 71 (8.5 percent) of subjects in the 1-year endometrial protection study.
The following adverse reactions have been identified during post-approval use of the Climara Pro transdermal system. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Changes in bleeding patterns
Abdominal distension,* abdominal pain,* nausea
Central Nervous System
Dizziness, headache, insomnia
Application site reaction,* weight increased, anaphylactic reaction
* Combined two or more similar ARs
Read the Climara Pro (estradiol, levonorgestrel transdermal) Side Effects Center for a complete guide to possible side effects
In vitroand in vivo studies have shown that estrogens are metabolized partially by cytochrome P450 3A4 (CYP3A4). Therefore, inducers or inhibitors of CYP3A4 may affect estrogen drug metabolism. Inducers of CYP3A4 such as St. John's wort (Hypericum perforatum) preparations, phenobarbital, carbamazepine, and rifampin may reduce plasma concentrations of estrogens, possibly resulting in a decrease in therapeutic effects and/or changes in the uterine bleeding profile. Inhibitors of CYP3A4 such as erythromycin, clarithromycin, ketoconazole, itraconazole, ritonavir and grapefruit juice may increase plasma concentrations of estrogens and may result in side effects.
Hydroxylation of levonorgestrel is a conversion step, which is mediated by cytochrome P450 enzymes. Based on in-vitro and in-vivo studies, it can be assumed that CYP3A, CYP2E and CYP2C are involved in the metabolism of levonorgestrel. Likewise, inducers or inhibitors of these enzymes may either, respectively, decrease the therapeutic effects or result in side effects.This monograph has been modified to include the generic and brand name in many instances.
Last reviewed on RxList: 11/6/2013
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