Data from FDA (Food and Drug Administration, USA) - Curated by EPG Health - Last updated 12 April 2018

Indication(s)

1 INDICATIONS AND USAGE Climara Pro is an estrogen plus progestin indicated in a woman with a uterus for: •Treatment of Moderate to Severe Vasomotor Symptoms due to Menopause (1.1) •Prevention of Postmenopausal Osteoporosis (1.2) 1.1 Treatment of Moderate to Severe Vasomotor Symptoms due to Menopause 1.2 Prevention of Postmenopausal Osteoporosis Limitation of Use When prescribing solely for the prevention of postmenopausal osteoporosis, therapy should only be considered for women at significant risk of osteoporosis and non-estrogen medication should be carefully considered.

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Advisory information

contraindications
4 CONTRAINDICATIONS Climara Pro is contraindicated in women with any of the following conditions: •Undiagnosed abnormal genital bleeding •Known, suspected, or history of breast cancer •Known or suspected estrogen-dependent neoplasia •Active DVT, PE or a history of these conditions •Active arterial thromboembolic disease (for example, stroke and MI), or a history of these conditions •Known anaphylactic reaction or angioedema with Climara Pro •Known liver impairment or disease •Known protein C, protein S, or antithrombin deficiency, or other known thrombophilic disorders •Known or suspected pregnancy •Undiagnosed abnormal genital bleeding (4) •Known, suspected, or history of breast cancer (4, 5.2) •Known or suspected estrogen-dependent neoplasia (4, 5.2) •Active DVT, PE or a history of these conditions (4, 5.1) •Active arterial thromboembolic disease (for example, stroke and MI), or a history of these conditions (4, 5.1) •Known anaphylactic reaction or angioedema with Climara Pro (4) •Known liver impairment or disease (4, 5.10) •Known protein C, protein S, or antithrombin deficiency, or other known thrombophilic disorders (4) •Known or suspected pregnancy (4, 8.1)
Adverse reactions
6 ADVERSE REACTIONS The following serious adverse reactions are discussed elsewhere in the labeling: •Cardiovascular Disorders [see Boxed Warning, Warnings and Precautions (5.1)] •Malignant Neoplasms [see Boxed Warning, Warnings and Precautions (5.2)] In a prospective, randomized, placebo-controlled, double-blind study, the most common adverse reactions ≥5 percent are: application site reaction, vaginal bleeding, breast pain, upper respiratory infection, back pain, depression, pain, headache and flu syndrome. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact 1-888-84-BAYER (1-888-842-2937) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 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 Study Body System Adverse Reaction Climara Pro 0.045 / 0.015 E2 N N = total number of subjects in a treatment group; n = number of subjects with event. = 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) Cardiovascular System Hypertension 7 (3.3) 9 (4.4) Digestive System 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) Musculoskeletal System Arthralgia 9 (4.2) 10 (4.9) Nervous System Depression 12 (5.7) 7 (3.4) Headache 11 (5.2) 14 (6.9) Respiratory System 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) Urogenital System Urinary Tract Infection 7 (3.3) 8 (3.9) Vaginal Bleeding 78 (36.8) 44 (21.6) Vaginitis 4 (1.9) 6 (2.9) 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 12-week symptom study and in 71 (8.5 percent) of subjects in the 1-year endometrial protection study. 6.2 Postmarketing Experience 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. Genitourinary System Changes in bleeding patterns Gastrointestinal Abdominal distension,* abdominal pain,* nausea Skin Alopecia, night sweats, pruritus,* Rash,* hot flush* Central Nervous System Dizziness, headache, insomnia Miscellaneous Application site reaction,* weight increased, anaphylactic reaction * Combined two or more similar ARs

Usage information

Dosing and administration
2 DOSAGE AND ADMINISTRATION Use of estrogen-alone, or in combination with a progestin, should be with the lowest effective dose and for the shortest duration consistent with treatment goals and risks for the individual women. Postmenopausal women should be re-evaluated periodically as clinically appropriate to determine if treatment is still necessary. One Climara Pro transdermal system is available for use. Initiation of Therapy Women not currently using continuous estrogen-alone therapy or estrogen plus progestin therapy may start therapy with Climara Pro at any time. However, women currently using continuous estrogen-alone therapy or estrogen plus progestin therapy should complete the current cycle of therapy before initiating Climara Pro therapy. Women often experience withdrawal bleeding at the completion of the cycle. The first day of this bleeding would be an appropriate time to begin Climara Pro therapy. •Apply Climara Pro once-weekly to the lower abdomen (2.3) 2.1 Treatment of Moderate to Severe Vasomotor Symptoms due to Menopause Climara Pro 0.045 mg per day/0.015 mg per day applied to the skin once weekly. Therapy should be started at the lowest effective dose and the shortest duration consistent with the treatment goals. Attempts to discontinue the medication should be made at 3 to 6 month intervals. 2.2 Prevention of Postmenopausal Osteoporosis Climara Pro 0.045 mg per day/0.015 mg per day applied to the skin once weekly. 2.3 Application of the Transdermal System Site Selection •The adhesive side of Climara Pro should be placed on a smooth (fold free), clean, dry area of the skin on the lower abdomen or the upper quadrant of the buttock. •Climara Pro should not be applied to or near the breasts. •The area selected should not be oily (which can impair adherence of the system), damaged, or irritated. •The waistline should be avoided, since tight clothing may rub Climara Pro off or modify drug delivery. •Application to areas where sitting would dislodge Climara Pro should also be avoided. •The sites of application must be rotated, with an interval of at least 1-week allowed between applications to the same site. Application •Climara Pro should be applied immediately after opening the pouch and removing the protective lining. •Climara Pro should be pressed firmly in place with the fingers for at least 10 seconds, making sure there is good contact, especially around the edges. •If the system lifts, apply pressure to maintain adhesion. •In the event that a system should fall off, the same system may be reapplied to another area of the lower abdomen. If the system cannot be reapplied, a new system may be applied, in which case, the original treatment schedule should be continued. •Only one system should be worn at any one time during 7-day dosing interval. •Once in place, the transdermal system should not be exposed to the sun for prolonged periods of time. •Swimming, bathing, or using a sauna while using Climara Pro has not been studied, and these activities may decrease the adhesion of the system and the delivery of the estrogen and progestin. 2.4 Removal of the Transdermal System •Removal of Climara Pro should be done carefully and slowly to avoid irritation of the skin. •Should any adhesive remain on the skin after removal of the system, allow the area to dry for 15 minutes. •Then gently rubbing the area with an oil-based cream or lotion should remove the adhesive residue. •Used patches still contain some active hormones. Each patch should be carefully folded in half so that it sticks to itself before throwing it away
Use in special populations
8 USE IN SPECIFIC POPULATIONS •Nursing Mothers: Estrogen administration to nursing women has been shown to decrease the quantity and quality of breast milk (8.3) •Geriatric Use: An increased risk of probable dementia in women over 65 years of age was reported in the WHIMS ancillary studies of the WHI (5.3, 8.5, 14.6) 8.1 Pregnancy Climara Pro should not be used during pregnancy [see Contraindications (4)]. There appears to be little or no increased risk of birth defects in children born to women who have used estrogens and progestins as oral contraceptives inadvertently during early pregnancy. 8.3 Nursing Mothers Climara Pro should not be used during lactation. Estrogen administration to nursing women has been shown to decrease the quantity and quality of the breast milk. Detectable amounts of estrogens and progestins have been identified in the milk of women receiving estrogen therapy. Caution should be exercised when the Climara Pro transdermal system is administered to a nursing woman. 8.4 Pediatric Use Climara Pro is not indicated in children. Clinical studies have not been conducted in the pediatric populations. 8.5 Geriatric Use There have not been sufficient numbers of geriatric women involved in studies utilizing Climara Pro to determine whether those over 65 years of age differ from younger subjects in their response to Climara Pro. The Women’s Health Initiative Studies In the WHI estrogen plus progestin substudy (daily CE [0.625 mg] plus MPA [2.5 mg] versus placebo), there was a higher relative risk of nonfatal stroke and invasive breast cancer in women greater than 65 years of age [see Clinical Studies (14.5)]. In the WHI estrogen-alone substudy (daily CE [0.625 mg]-alone versus placebo), there was a higher relative risk of stroke in women greater than 65 years of age [see Clinical Studies (14.5)] The Women’s Health Initiative Memory Study In the WHIMS ancillary studies of postmenopausal women 65 to 79 years of age, there was an increased risk of developing probable dementia in women receiving estrogen plus progestin or estrogen-alone when compared to placebo [see Warnings and Precautions (5.3), and Clinical Studies (14.6)]. Since both ancillary studies were conducted in women 65 to 79 years of age, it is unknown whether these findings apply to younger postmenopausal women8 (see Warnings and Precautions (5.3), and Clinical Studies (14.6)]. 8.6 Renal Impairment In postmenopausal women with end stage renal disease (ESRD) receiving maintenance hemodialysis, total estradiol serum levels are higher than in normal subjects at baseline and following oral doses of estradiol. Therefore, conventional transdermal estradiol doses used in individuals with normal renal function may be excessive for postmenopausal women with ESRD receiving maintenance hemodialysis. 8.7 Hepatic Impairment Estrogens may be poorly metabolized in patients with impaired liver function and should be administered with caution.
Pregnancy and lactation
8.3 Nursing Mothers Climara Pro should not be used during lactation. Estrogen administration to nursing women has been shown to decrease the quantity and quality of the breast milk. Detectable amounts of estrogens and progestins have been identified in the milk of women receiving estrogen therapy. Caution should be exercised when the Climara Pro transdermal system is administered to a nursing woman.

Interactions

7 DRUG INTERACTIONS •Inducers and/or inhibitors of CYP3A4 may affect estrogen drug metabolism (7.1) •Hydroxylation of levonorgestrel may interact with inhibitors of CYP3A, CYP2E and CYP2C and decrease the therapeutic effects (7.1) 7.1 Metabolic Interactions In vitro and 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.

More information

Category Value
Authorisation number NDA021258
Agency product number 4TI98Z838E
Orphan designation No
Product NDC 50419-491
Date Last Revised 01-11-2017
Type HUMAN PRESCRIPTION DRUG
RXCUI 402250
Marketing authorisation holder Bayer HealthCare Pharmaceuticals Inc.
Warnings WARNING: CARDIOVASCULAR DISORDERS, BREAST CANCER, ENDOMETRIAL CANCER AND PROBABLE DEMENTIA Estrogen Plus Progestin Therapy Cardiovascular Disorders and Probable Dementia Estrogen plus progestin therapy should not be used for the prevention of cardiovascular disease or dementia [see Warnings and Precautions (5.1, 5.3), and Clinical Studies (14.5, 14.6)]. The Women's Health Initiative (WHI) estrogen plus progestin substudy reported an increased risk of deep vein thrombosis (DVT), pulmonary embolism (PE), stroke and myocardial infarction (MI) in postmenopausal women (50 to 79 years of age) during 5.6 years of treatment with daily oral conjugated estrogens (CE) [0.625 mg] combined with medroxyprogesterone acetate (MPA) [2.5 mg], relative to placebo [see Warnings and Precautions (5.1), and Clinical Studies (14.5)]. The WHI Memory Study (WHIMS) estrogen plus progestin ancillary study of WHI reported an increased risk of developing probable dementia in postmenopausal women 65 years of age or older during 4 years of treatment with daily CE (0.625 mg) combined with MPA (2.5 mg), relative to placebo. It is unknown whether this finding applies to younger postmenopausal women [see Warnings and Precautions (5.3), Use in Specific Populations (8.5), and Clinical Studies (14.6)]. Breast Cancer The WHI estrogen plus progestin substudy demonstrated an increased risk of invasive breast cancer [see Warnings and Precautions (5.2), and Clinical Studies (14.5)]. In the absence of comparable data, these risks should be assumed to be similar for other doses of CE and MPA and other combinations and dosage forms of estrogens and progestins. Estrogens with or without progestins should be prescribed at the lowest effective doses and for the shortest duration consistent with treatment goals and risks for the individual woman. Estrogen-Alone Therapy Endometrial Cancer There is an increased risk of endometrial cancer in a woman with a uterus who uses unopposed estrogens. Adding a progestin to estrogen therapy has been shown to reduce the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer. Adequate diagnostic measures, including directed or random endometrial sampling when indicated, should be undertaken to rule out malignancy in postmenopausal women with undiagnosed persistent or recurring abnormal genital bleeding [see Warnings and Precautions (5.2)]. Cardiovascular Disorders and Probable Dementia Estrogen-alone therapy should not be used for the prevention of cardiovascular disease or dementia [see Warnings and Precautions (5.1, 5.3), and Clinical Studies (14.5, 14.6)]. The WHI estrogen-alone substudy reported increased risks of stroke and DVT in postmenopausal women (50 to 79 years of age) during 7.1 years of treatment with daily oral CE (0.625 mg)-alone, relative to placebo [see Warnings and Precautions (5.1), and Clinical Studies (14.5)]. The WHIMS estrogen-alone ancillary study of WHI reported an increased risk of developing probable dementia in postmenopausal women 65 years of age or older during 5.2 years of treatment with daily CE (0.625 mg)-alone, relative to placebo. It is unknown whether this finding applies to younger postmenopausal women [see Warnings and Precautions (5.3), Use in Specific Populations (8.5), and Clinical Studies (14.6)]. In the absence of comparable data, these risks should be assumed to be similar for other doses of CE and other forms of estrogens. Estrogens with or without progestins should be prescribed at the lowest effective doses and for the shortest duration consistent with treatment goals and risks for the individual woman. WARNING: CARDIOVASCULAR DISORDERS, BREAST CANCER, ENDOMETRIAL CANCER AND PROBABLE DEMENTIA See full prescribing information for complete boxed warning. Estrogen Plus Progestin Therapy • Estrogen plus progestin therapy should not be used for the prevention of cardiovascular disease or dementia (5.1, 5.3) • The Women’s Health Initiative (WHI) estrogen plus progestin substudy reported increased risks of stroke, deep vein thrombosis (DVT), pulmonary embolism (PE), and myocardial infarction (MI) (5.1) • The WHI estrogen plus progestin substudy reported increased risks of invasive breast cancer (5.2) • The WHI Memory Study (WHIMS) estrogen plus progestin ancillary study of WHI reported an increased risk of probable dementia in postmenopausal women 65 years of age and older (5.3) Estrogen-Alone Therapy • There is an increased risk of endometrial cancer in a woman with a uterus who uses unopposed estrogens (5.2) • Estrogen-alone therapy should not be used for the prevention of cardiovascular disease or dementia (5.1, 5.3) • The WHI estrogen-alone substudy reported increased risks of stroke and DVT (5.1) The WHIMS estrogen-alone ancillary study of WHI reported an increased risk of probable dementia in postmenopausal women 65 years of age and older (5.3)