Jan 10, 99 This "lost" technical information is now available at http://www.rxlist.com/cgi/generic/cemp.htm

Extracts from the web site of American Home Products, manufacturers of Premarin, Premphase and Prempro. This site has extremely comprehensive information about these drugs. The extracts below are meant to help physicians prescribe them correctly. 

Precautions
(note: While this was taken from the Prempro page, identical material appears for Premphase. (UK -Premique  Cyclical, Australia Provelle 14) - The Premarin page is not so forthcoming but reads more like the ads for Premarin) 

GENERAL 
Based on experience with estrogens and/or progestins: 

1. Cardiovascular risk. A causal relationship between estrogen replacement therapy and reduction of cardiovascular disease in postmenopausal women has not been proven. Furthermore, the effect of added progestins on this putative benefit is not yet known. 

In recent years many published studies have suggested that there may be a cause-effect relationship between postmenopausal oral estrogen replacement therapy without added progestins and a decrease in cardiovascular disease in women. Although most of the observational studies which assessed this statistical association have reported a 20% to 50% reduction in coronary heart disease risk and associated mortality in estrogen takers, the following should be considered when interpreting these reports. 

Because only one of these studies was randomized and it was too small to yield statistically significant results, all relevant studies were subject to selection bias. Thus, the apparently reduced risk of coronary artery disease cannot be attributed with certainty to estrogen replacement therapy. It may instead have been caused by life-style and medical characteristics of the women studied with the result that healthier women were selected for estrogen therapy. In general, treated women were of higher socioeconomic and educational status, more slender, more physically active, more likely to have undergone surgical menopause, and less likely to have diabetes than the untreated women. Although some studies attempted to control for these selection factors, it is common for properly designed randomized trials to fail to confirm benefits suggested by less rigorous study designs. Thus, ongoing and future large-scale randomized trials may fail to confirm this apparent benefit. 

Current medical practice often includes the use of concomitant progestin therapy in women with intact uteri. While the effects of added progestins on the risk of ischemic heart disease are not known, medroxyprogesterone acetate at the dose in PREMPRO attenuates much of the favorable effect of conjugated estrogens on HDL levels, although it maintains the favorable effect of conjugated estrogens on LDL levels (see Clinical Pharmacology). 

While the effects of added progestins on the risk of breast cancer are also unknown, available epidemiologic evidence suggests that progestins do not reduce, and may enhance, the moderately increased breast cancer risk that has been reported with prolonged estrogen replacement therapy (see Warnings). 

The safety data regarding PREMPRO were obtained primarily from clinical trials and epidemiologic studies of postmenopausal Caucasian women, who were at generally low risk for cardiovascular disease and higher than average risk for osteoporosis. The safety profile of PREMPRO derived from these study populations cannot necessarily be extrapolated to other populations of diverse racial and/or demographic composition. When considering prescribing PREMPRO, physicians are advised to weigh the potential benefits and risks of therapy as applicable to each individual patient.

(See Warnings regarding induction of neoplasia, adverse effects on the fetus, increased incidence of gallbladder disease, elevated blood pressure, thromboembolic disorders, cardiovascular disease, visual abnormalities, and hypercalcemia and Precautions for cardiovascular disease.) 

The following adverse reactions have been reported with estrogen and/or progestin therapy: 

Genitourinary system. Changes in vaginal bleeding pattern and abnormal withdrawal bleeding or flow, breakthrough bleeding, spotting, change in amount of cervical secretion, premenstrual-like syndrome, cystitis-like syndrome, increase in size of uterine leiomyomata, vaginal candidiasis, amenorrhea, changes in cervical erosion. 

Breasts. Tenderness, enlargement, galactorrhea. 

Gastrointestinal. Nausea, cholestatic jaundice, changes in appetite, vomiting, abdominal cramps, bloating, increased incidence of gallbladder disease, pancreatitis. 

Skin. Chloasma or melasma that may persist when drug is discontinued, erythema multiforme, erythema nodosum, hemorrhagic eruption, loss of scalp hair, hirsutism, itching, urticaria, pruritus, generalized rash, rash (allergic) with and without pruritus, acne. 

Cardiovascular. In susceptible individuals, change in blood pressure, thrombophlebitis, pulmonary embolism, cerebral thrombosis and embolism. 

CNS. Headache, dizziness, mental depression, nervousness, migraine, chorea, insomnia, somnolence. 

Eyes. Neuro-ocular lesions, e.g., retinal thrombosis and optic neuritis. Steepening of corneal curvature, intolerance of contact lenses. 

Miscellaneous. Increase or decrease in weight, edema, changes in libido, fatigue, backache, reduced carbohydrate tolerance, aggravation of porphyria, pyrexia, anaphylactoid reactions, anaphylaxis. 

For a demonstration of cautions when reading a study abstract about the effect of continuous progestin on breast tissue see http://www.oxford.net/~tishy/breastconthrt.html

The following might be of interest to women taking or considering continuous hormone "therapy." Seems there might be a little matter of increased endometrial cancer in such patients. I don't think this study is referenced in W/A's ads for these drugs. It should raise some red flags in women counting on these combination drugs to eliminate the carcinogenic properties of estrogen. 8 cases of endometrial cancer in women taking these drugs which were only approved 2-3 years ago is a highly significant number. Caveat emptor.

Author :   Comerci JT Jr; Fields AL; Runowicz CD; Goldberg GL 
Address:  Department of Obstetrics and Gynecology, Albert Einstein College of Medicine and Montefiore Medical Center, Bronx, New York 10461, USA.
Source 
    Gynecol Oncol, 1997 Mar, 64:3, 425-30 
Abstract 
  Hormone replacement therapy (HRT) provides relief of menopausal symptoms, reverses atrophic urogenital changes, prevents osteoporosis, and produces favorable lipoprotein effects. Continuous combined HRT using 2.5 mg of medroxyprogesterone was designed to increase patient compliance by eliminating withdrawal bleeding while at the same time retaining the beneficial effects of HRT. There are limited long-term data, however, regarding the safety of continuous combined HRT. Of concern are reports of endometrial carcinoma arising in women receiving continuous HRT with low-dose progestin. Eight cases of women who developed endometrial carcinoma while on this regimen are presented. The possible increased risk of endometrial cancer associated with this regimen may be related to inadequate progestin dose, prior use of unopposed estrogen, poor patient compliance, use of less effective progestins, less efficient reversal of hyperplasia, and the use of progestin continuously. 

Terri

Of course your doctor tells you she'd take it if she were you. What else can she say? " I wouldn't touch it, but I think you should." Always take that little anecdote with a huge teaspoon of salt. 
Terri 

        Let alone HRT which is even less efficacious than post castration ERT, and  is showing that it cancels out any putative estrogen heart benefit in the first place.  Plus the estradiol patch delivery is showing no heart benefits at all. 

        The only things we seem to know about HRT in the intact woman is that the estrogen part causes uterine dysplasias and an increase in uterine cancers and that the addition of a progestin on top of the cancer causing estrogen may help to prevent these drug induced uterine cancers, so maybe you won't have to have a hysterectomy to cure the estrogen induced uterine cancers.

        The only thing we know about Prempro is that it is a totally unnatural combination of drugs of limited usefulness in the first place, with no credible testing history whatsoever in this unnatural combination, let alone in each of its separate elements. 

        Add to that the studies that are showing 40-60% placebo effect for hot flash reduction and that hot flashes are episodic in the first place and you have various forms of menopause drug "treatment" of highly questionable efficacy. 

        The only consistent findings seem to be the subjective reports on post surgical relief when using these drugs post castration. Nothing else checks out.  Although, I will side with the reports of increased BCA after long-term use of estrogens. This will be clearer one way or the other after the WHI study results start coming in 2005. 

Joan 

Cornifying the endometrium? I've never heard this word before. What exactly does it mean? Did your doctor explain? It sounds like a perfectly awful thing to do to living tissue. And how does the medical profession KNOW that doing this to endometrial tissue doesn't result in some kind of cellular change that may itself be a precursor to a malignancy? Prempro was so godawful for me that I flushed the pills six weeks after I started taking them and spent more than a year trying to recover from taking them at all. Unholy alliance sounds just about right to me. Yuck. 
Terri 

There is also a question as to whether the lack of cyclic bleeding protects the uterus as thoroughly as the cyclic regimen does.  Well, it doesn't sound like wonderful stuff to me -- but, then, there's a woman  who sings in my church choir who swears by it. One size doesn't fit all -- for  sure. 
lblanch000 

 Want to know if anyone who takes Prempro has a period.   Found out I was not taking them incorrectly...which is supposed to be all the time..no stopping...   was on Premarin & Provera, over- doing the Premarin..   Been having headaches too.   What's going to happen? 
 Thanks, 

        Hi, unfortunately the very "unnatural" Prempro combination was  concocted to benefit the doctors and not the patient so no one really  knows how it will affect women.  Right now is being tested on the  patients who are taking it. Reactions to it have been all over the place  when reported to this group from okay to total disaster. 

        You will be the one to tell us what is going to happen and in this  way we can collect our own data on it. If you have any adverse reactions  to it please report them to the FDA: 1-800-FDA-1088 at Medwatch. 

        Read the product insert very carefully that accompanied this drug or ask for a new copy from your pharmacist and go over it in detail with  your doctor. However the product insert does -not- discuss any findings about taking this combination of drugs everyday, but rather reports only  the findings on each of the individual drug components: estrogen and  provera. This unusual combined from is the mystery element. 

        Drug reports have a euphemism called "post marketing results"  where they finally tell what the drug does after it is put on the market  so the patients themselves have been the experimental models. This is the  case with Prempro, we will all learn as you women who are willing to take  it start reporting what happens to you. 

        There are no legitimate long term studies on any of these drugs so it is all hit and miss experimental. The individual drugs have been -used- a long time on women, but they are only now just starting adequate testing of them and the results will not be in until the year 2005. I am not sure  if the Prempro combination is even included in this WHI study. We have some very sharp researchers here on this newsgroup though who can bring us  up to date on this question. 

        Meanwhile keep in touch and tell us what you experience and please notify the FDA if this drug does not do what it  claimed. In that way you can help lots of women. And by telling what is  good about this drug over time for you, you will also be helping a lot of  women who also want to experiment with it. 
 

        FDA MedWatch: 1-800-FDA-1088  (USA - toll free telephone call) 

        Anyone out there who knows if Prempro was included in the WHI  study? Thanks.   asd

[Apparently Prempro is the only HRT to be used]]