Drug Information for Prempro (Physicians Total Care, Inc.): 14 CLINICAL STUDIES

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  • 14.1 Effects on Vasomotor Symptoms

    In the first year of the Health and Osteoporosis, Progestin and Estrogen (HOPE) Study, a total of 2,805 postmenopausal women (average age 53.3 ± 4.9 years) were randomly assigned to one of eight treatment groups of either placebo or conjugated estrogens, with or without medroxyprogesterone acetate. Efficacy for vasomotor symptoms was assessed during the first 12 weeks of treatment in a subset of symptomatic women (n = 241) who had at least seven moderate to severe hot flushes daily, or at least 50 moderate to severe hot flushes during the week before randomization. With PREMPRO 0.625 mg/2.5 mg, 0.45 mg/1.5 mg, and 0.3 mg/1.5 mg, the relief of both the frequency and severity of moderate-to-severe vasomotor symptoms was shown to be statistically improved compared to placebo at weeks 4 and 12. Table 5 shows the adjusted mean number of hot flushes in the PREMPRO 0.625 mg/2.5 mg, 0.45 mg/1.5 mg, 0.3 mg/1.5 mg, and placebo groups during the initial 12-week period.

    TABLE 5: SUMMARY TABULATION OF THE NUMBER OF HOT FLUSHES PER DAY – MEAN VALUES AND COMPARISONS BETWEEN THE ACTIVE TREATMENT GROUPS AND THE PLACEBO GROUP – PATIENTS WITH AT LEAST 7 MODERATE TO SEVERE FLUSHES PER DAY OR AT LEAST 50 PER WEEK AT BASELINE, LAST OBSERVATION CARRIED FORWARD (LOCF)
    Treatment (a)(No. of Patients)----------------No. of Hot Flushes/Day-----------------
    Time Period(week)BaselineMean ± SD ObservedMean ± SD MeanChange ± SDp-Valuesvs. Placebo (b)
    0.625 mg/2.5 mg(N = 34)
    411.98 ± 3.54 3.19 ± 3.74-8.78 ± 4.72less than 0.001
    1211.98 ± 3.54 1.16 ± 2.22-10.82 ± 4.61less than 0.001
    0.45 mg/1.5 mg(n = 29)
    412.61 ± 4.293.64 ± 3.61-8.98 ± 4.74less than 0.001
    1212.61 ± 4.291.69 ± 3.36-10.92 ± 4.63less than 0.001
    0.3 mg/1.5 mg(n = 33)
    411.30 ± 3.133.70 ± 3.29-7.60 ± 4.71less than 0.001
    1211.30 ± 3.131.31 ± 2.82-10.00 ± 4.60less than 0.001
    Placebo(n = 28)
    411.69 ± 3.877.89 ± 5.28-3.80 ± 4.71--
    1211.69 ± 3.875.71 ± 5.22-5.98 ± 4.60--
    (a) Identified by dosage (mg) of Premarin/MPA or placebo.(b) There were no statistically significant differences between the 0.625 mg/2.5 mg, 0.45 mg/1.5 mg, and 0.3 mg/1.5 mg groups at any time period.14.2 Effects on Vulvar and Vaginal Atrophy

    Results of vaginal maturation indexes at cycles 6 and 13 showed that the differences from placebo were statistically significant (p less than 0.001) for all treatment groups.

    14.3 Effects on the Endometrium

    In a 1-year clinical trial of 1,376 women (average age 54 ± 4.6 years) randomized to PREMPRO 0.625 mg/2.5 mg (n = 340), PREMPRO 0.625 mg/5 mg (n = 338), PREMPHASE 0.625 mg/5 mg (n = 351), or Premarin 0.625 mg alone (n = 347), results of evaluable biopsies at 12 months (n = 279, 274, 277, and 283, respectively) showed a reduced risk of endometrial hyperplasia in the two PREMPRO treatment groups (less than 1 percent) and in the PREMPHASE treatment group (less than 1 percent; 1 percent when focal hyperplasia was included) compared to the Premarin group (8 percent; 20 percent when focal hyperplasia was included), see Table 6.

    TABLE 6: INCIDENCE OF ENDOMETRIAL HYPERPLASIA AFTER ONE YEAR OF TREATMENT
    ------------------Groups----------------
    PREMPRO0.625 mg/2.5 mgPREMPRO0.625 mg/5 mgPREMPHASE0.625 mg/5 mg Premarin0.625 mg
    Total number of patients340338351347
    Number of patients with evaluable biopsies279274277283
    No. (%) of patients with biopsies:
    • All focal and non-focal hyperplasia2 (less than 1) *0 (0) *3 (1) *57 (20)
    • Excluding focal cystic hyperplasia2 (less than 1) *0 (0) *1 (less than 1) *25 (8)
    * Significant (p less than 0.001) in comparison with Premarin (0.625 mg) alone.

    In the first year of the Health and Osteoporosis, Progestin and Estrogen (HOPE) Study, 2,001 women (average age 53.3 ± 4.9 years), of whom 88 percent were Caucasian, were treated with either Premarin 0.625 mg alone (n = 348), Premarin 0.45 mg alone (n = 338), Premarin 0.3 mg alone (n = 326) or PREMPRO 0.625 mg/2.5 mg (n = 331), PREMPRO 0.45 mg/1.5 mg (n = 331) or PREMPRO 0.3 mg/1.5 mg (n = 327). Results of evaluable endometrial biopsies at 12 months showed a reduced risk of endometrial hyperplasia or cancer in the PREMPRO treatment groups compared with the corresponding Premarin alone treatment groups, except for the PREMPRO 0.3 mg/1.5 mg and Premarin 0.3 mg alone groups, in each of which there was only 1 case, see Table 7.

    No endometrial hyperplasia or cancer was noted in those patients treated with the continuous combined regimens who continued for a second year in the osteoporosis and metabolic substudy of the HOPE study, see Table 8.

    TABLE 7: INCIDENCE OF ENDOMETRIAL HYPERPLASIA/CANCER (a) AFTER ONE YEAR OF TREATMENT (b)
    ----------Groups ----------
    PatientPrempro0.625 mg/2.5 mgPremarin0.625 mgPrempro0.45 mg/1.5 mgPremarin0.45 mgPrempro0.3 mg/1.5 mgPremarin 0.3 mg
    Total number of patients331348331338327326
    Number of patients with evaluablebiopsies278249272279271269
    No. (%) of patients with biopsies:
    • Hyperplasia/cancer (a)(consensus) (c)0 (0) (d)20 (8)1 (less than 1) (a,d)9 (3)1 (less than 1) (e)1 (less than 1) (a)
    (a) All cases of hyperplasia/cancer were endometrial hyperplasia, except for 1 patient in the Premarin 0.3 mg group diagnosed with endometrial cancer based on endometrial biopsy and 1 patient in the Premarin/MPA 0.45 mg/1.5 mg group diagnosed with endometrial cancer based on endometrial biopsy.(b) Two (2) primary pathologists evaluated each endometrial biopsy. Where there was lack of agreement on the presence or absence of hyperplasia/cancer between the two, a third pathologist adjudicated (consensus).(c) For an endometrial biopsy to be counted as consensus endometrial hyperplasia or cancer, at least 2 pathologists had to agree on the diagnosis.(d) Significant (p less than 0.05) in comparison with corresponding dose of Premarin alone.(e) Non-significant in comparison with corresponding dose of Premarin alone.
    TABLE 8: OSTEOPOROSIS AND METABOLIC SUBSTUDY, INCIDENCE OF ENDOMETRIAL HYPERPLASIA/CANCER (a) AFTER TWO YEARS OF TREATMENT (b)
    ----------Groups---------
    Prempro0.625 mg/2.5 mgPremarin0.625 mgPrempro0.45 mg/1.5 mgPremarin0.45 mgPrempro0.3 mg/1.5 mgPremarin 0.3 mg
    Total number of patients756575747973
    Number of patients with evaluablebiopsies625569677563
    No. (%) of patients with biopsies:
    • Hyperplasia/cancer (a) (consensus) (c)0 (0) (d)15 (27)0 (0) (d)10 (15)0 (0) (d)2 (3)
    (a)      All cases of hyperplasia/cancer were endometrial hyperplasia in patients who continued for a second year in the osteoporosis and metabolic substudy of the HOPE study.(b)      Two (2) primary pathologists evaluated each endometrial biopsy. Where there was lack of agreement on the presence or absence of hyperplasia/cancer between the two, a third pathologist adjudicated (consensus).(c)      For an endometrial biopsy to be counted as consensus endometrial hyperplasia or cancer, at least 2 pathologists had to agree on the diagnosis.(d)      Significant (p less than 0.05) in comparison with corresponding dose of Premarin alone.
  • Drug Information Provided by National Library of Medicine (NLM).
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