Combipatch (Estradiol / Norethindrone Acetate Transdermal) - Drug Interactions, Contraindications, Overdosage, etc

DRUG INTERACTIONS

Adhesion

Averaging across six clinical trials lasting three months to one year, of 1,287 patients treated, CombiPatch transdermal systems completely adhered to the skin nearly 90% of the time over the 3- to 4-day wear period. Less than 2% of the patients required reapplication or replacement of systems due to lifting or detachment. Only two patients (0.2%) discontinued therapy during clinical trials due to adhesion failure.

Clinical Studies

Effects on Vasomotor Symptoms

In two clinical trials designed to assess the degree of relief of moderate to severe vasomotor symptoms in postmenopausal women (n=332), CombiPatch was administered for three 28-day cycles in Continuous Combined or Continuous Sequential treatment regimens versus placebo. In the Continuous Combined regimen, CombiPatch was applied throughout the three cycles, replacing the system twice weekly. In the Continuous Sequential regimen, an estradiol-only transdermal system (Vivelle^® 0.05 mg) was applied twice weekly during the first 14 days of a 28-day cycle; CombiPatch was applied for the remaining 14 days of the cycle and replaced twice weekly, as well. The mean number of hot flushes at baseline were 10 to 11 per day and 11 to 12 per day in the Continuous Combined and Continuous Sequential regimen trials, respectively. The mean number and intensity of daily hot flushes (intent-to-treat population) was significantly reduced from baseline to endpoint with either the Continuous Combined or Continuous Sequential administration of CombiPatch at all doses as compared to placebo (intent-to-treat population). (See tables below.)

Adjusted Mean Change in the Number of Hot Flushes and Daily Intensity of Hot Flushes per Day in CombiPatch^® Continuous Combined Transdermal Therapy

	CombiPatch ® Continuous Combined		Placebo
Adjusted Mean Change from Baseline 1	0.05/0.14 mg per day2 n=57	0.05/0.25 mg per day2 n=52	n=51
Number of Hot Flushes3	-9.35	-8.95	-6.2
Daily Intensity of Hot Flushes3,4	-4.65,6	-5.05	-2.87

¹      Means were adjusted for imbalance among treatment groups and investigators (least squares mean from ANOVA).

²      Represents the milligrams of estradiol/norethindrone acetate delivered daily by each system.

³      Population represents those patients who had baseline and endpoint observations.

⁴      The intensity of hot flushes was evaluated on a scale of 0 to 9 (none = 0, mild = 1-3, moderate = 
4-6, severe = 7-9).

⁵      P value versus placebo = <0.001.

⁶      Total number of patients with available data is 56.

⁷      Total number of patients with available data is 50.

Adjusted Mean Change in the Number of Hot Flushes and Daily Intensity of Hot Flushes per Day in CombiPatch^® Continuous Sequential Transdermal Therapy

	CombiPatch ® Continuous Sequential		Placebo
Adjusted Mean Change from Baseline 1	0.05/0.14 mg per day2 n=54	0.05/0.25 mg per day2 n=59	n=53
Number of Hot Flushes3	-9.35	-9.55	-5.5
Daily Intensity of Hot Flushes3,4	-4.45	-4.55	-2.1

¹      Means were adjusted for imbalance among treatment groups and investigators (least squares 
mean from ANOVA).

²      Represents the milligrams of estradiol/norethindrone acetate delivered daily by each system.

³      Population represents those patients who had baseline and endpoint observations.

⁴      The intensity of hot flushes was evaluated on a scale of 0 to 9 (none = 0, mild = 1-3, moderate = 
4-6, severe = 7-9).

     ⁵      P value versus placebo = <0.001.

Effects on the   Edometrium

The use of unopposed estrogen therapy has been associated with an increased risk of endometrial hyperplasia, a possible precursor of endometrial adenocarcinoma. Progestins counter the estrogenic effects by decreasing the number of nuclear estradiol receptors and suppressing epithelial DNA synthesis in endometrial tissue.

      Clinical studies indicate that the addition of a progestin to an estrogen regimen at least 12 days per cycle reduces the incidence of endometrial hyperplasia and the potential risk of adenocarcinoma in women with intact uteri. The addition of a progestin to an estrogen regimen has not been shown to interfere with the efficacy of estrogen therapy for its approved indications.

      CombiPatch was effective in reducing the incidence of estrogen-induced endometrial hyperplasia after one year of therapy in two Phase II clinical trials. Nine hundred fifty-five (955) postmenopausal women (with intact uteri) were treated with (i) a continuous regimen of CombiPatch alone (Continuous Combined regimen), (ii) a sequential regimen with an estradiol-only (Vivelle 0.05 mg) transdermal system followed by a CombiPatch transdermal system (Continuous Sequential regimen), or (iii) continuous regimen with an estradiol-only transdermal system (Vivelle 0.05 mg). The incidence of endometrial hyperplasia (primary endpoint) was significantly less after one year of therapy with either CombiPatch regimen than with the estradiol-only transdermal system. The tables below summarize these results (intent-to-treat populations).

Incidence of Endometrial Hyperplasia in a Continuous Combined CombiPatch^® Regimen

	CombiPatch ® Continuous Combined		Vivelle ® Continuous
	0.05/0.14 mg per day1	0.05/0.25 mg per day1	0.05 mg per day
No. of Patients       with Biopsies 2	123	98	103
No. (%) of Patients       with Hyperplasia	1 (<1%)3	1 (1%)3,4	39 (38%)5

     ¹      Represents milligrams of estradiol/NETA delivered daily by each system.

     ²      Biopsy after 12 cycles of treatment or hyperplasia before cycle 12.

     ³      Comparison of continuous combined regimen versus estradiol-only patch was significant (p value
<0.001).

     ⁴      This patient had hyperplasia at baseline.

     ⁵      One of 39 patients had hyperplasia in an endometrial polyp.

Incidence of Endometrial Hyperplasia in a Continuous Sequential CombiPatch^® Regimen

	CombiPatch ® Continuous Sequential		Vivelle ® Continuous
	0.05/0.14 mg per day1	0.05/0.25 mg per day1	0.05 mg per day
No. of Patients       with Biopsies 2	117	114	115
No. (%) of Patients       with Hyperplasia	1 (<1%)3,4	1 (<1%)3,5	23 (20%)

     ¹      Represents milligrams of estradiol/NETA delivered daily by each system.

     ²      Biopsy after 12 cycles of treatment or hyperplasia before cycle 12.

     ³      Comparison of continuous sequential regimen versus estradiol-only patch was significant (p value
<0.001).

     ⁴      This patient had hyperplasia at baseline.

     ⁵      This patient had hyperplasia in an endometrial polyp.

Effects on Uterine Bleeding or Spotting

With the Continuous Combined regimen, of the women treated with CombiPatch and who completed the one-year study, the incidence of cumulative amenorrhea (the absence of bleeding or spotting during a 28-day cycle and sustained to the end of the study) increased over time. The incidence of amenorrhea from cycle 10 through 12 was 53% and 39% for the CombiPatch 0.05/0.14 mg per day and CombiPatch 0.05/0.25 mg per day treatment groups, respectively. Women who experienced bleeding, usually characterized it as light (intensity of 1.3 on a scale of 1 to 4) with a duration of four and six days for the CombiPatch 0.05/0.14 mg per day and CombiPatch 0.05/0.25 mg per day treatment groups, respectively.

Incidence of Cumulative Amenorrhea* in CombiPatch® Continuous Combined Transdermal Therapy by Cycle over a One-Year Period (Intent-to-Treat Population)

*Cumulative amenorrhea is defined as the absence of bleeding for the duration of a 28-day cycle and sustained to the end of the study.

OVERDOSAGE

Overdosage may cause nausea, and withdrawal bleeding may occur in females. Serious ill effects have not been reported following acute ingestion of large doses of estrogen/progestin-containing oral contraceptives by young children. In the event of a possible overdosage, the system should be removed immediately and medical attention sought.

CONTRAINDICATIONS

CombiPatch should not be used in women under any of the following conditions: 

• Undiagnosed abnormal genital bleeding.
  
• Known, suspected, or history of cancer of the breast.
  
• Known or suspected estrogen-dependent neoplasia.
  
• Active deep vein thrombosis, pulmonary embolism or history of these conditions.
  
• Active or recent (e.g., within the past year) arterial thromboembolic disease (e.g., stroke, myocardial infarction).
  
• Liver dysfunction or disease.
  
• CombiPatch should not be used in patients with known hypersensitivity to its ingredients.
  
• Known or suspected pregnancy. There is no indication for CombiPatch in pregnancy. There appears to be little or no increased risk of birth defects in children born to women who have used estrogens and progestins from oral contraceptives inadvertently during early pregnancy (see PRECAUTIONS).