Heragest Special Precautions

General: Progestins are usually co-administered with estrogens. Some of the information in this section pertaining to combined estrogen-progestin therapy may therefore not apply to progestin-only therapy. Physician discretion is advised.
Estrogen Plus Progestin in Menopausal Hormone Therapy: Endometrial Hyperplasia: Estrogen, as a single systemic agent, is appropriate in women after hysterectomy. Otherwise, addition of micronized progesterone/progestogen is required for endometrial protection.
Estrogens plus progestin therapy should not be used for the prevention of cardiovascular disease or dementia.
Progestogens are not alike with regard to potential adverse metabolic effects, cognitive effects or associated breast cancer risk when combined with systemic estrogen therapy.
Micronized progesterone or dydrogesterone used with estradiol may be associated with a better safety profile than synthetic progestins with regard to breast cancer and cardiovascular risk.
Physical Examinations: Patients should be assessed prior to (and at regular intervals thereafter) taking hormone replacement therapy (HRT). Physical examination (including special attention to the breast and pelvic organs) and a Pap smear should be done. This should be guided by personal and family medical history and by the contraindications and warnings of this product.
Endometrial biopsy should be done when indicated. Baseline tests should include mammography, measurements of blood glucose, calcium, triglycerides, cholesterol, and liver function tests.
The first follow-up examination should be done within 3 to 6 months after initiation of treatment to assess response to treatment. Thereafter, examinations should be made at intervals of at least once a year. Appropriate investigations should be arranged at regular intervals determined by the physician.
Patients are encouraged to practice frequent self-examination of the breasts.
Stroke: The risk of ischemic stroke has been shown to be increased during the first year of treatment with continuous-combined conjugated estrogens (0.625 mg) and medroxyprogesterone acetate (2.5 mg) in postmenopausal women (50 to 79 years old) compared to those receiving placebo. Estrogen plus progestin therapy should be discontinued immediately should a stroke occur or be expected.
Coronary Artery Disease (CAD): Randomized controlled trials have shown no evidence of cardiovascular benefit with the use of continuous-combined conjugated estrogens and medroxyprogesterone acetate. This was demonstrated in the Women's Health Initiative (WHI) and Heart and estrogen/progestin Replacement Study (HERS) which showed a possible increased risk of cardiovascular morbidity in the first year of use with no overall benefit.
High Blood Pressure: Monitor blood pressure in women using HRT. Elevation of blood pressure has been observed in patients using HRT. This elevation in blood pressure should be investigated in previously normotensive or hypertensive patients. In such cases, HRT may have to be discontinued.
Venous Thromboembolism (VTE): A higher relative risk of developing VTE (i.e., deep vein thrombosis or pulmonary embolism) is observed with the use of estrogen or estrogen-progesterone HRT.
Personal history or family history, severe obesity (body mass index, BMI >30 kg/m²), age and smoking are the generally recognized factors for VTE.
Prolonged immobilization, major trauma or major surgery may temporarily increase the risk of VTE. As with all postoperative patients, attention should be given to prophylactic measures to prevent VTE after surgery. HRT should be temporarily stopped 4 to 6 weeks earlier (if possible) in instances where prolonged immobilization is likely to follow elective surgery, particularly abdominal surgery or orthopedic surgery to the lower limbs. Do not restart therapy until the patient is completely mobilized. Also, close supervision is advised in patients with varicose veins.
Progesterone should be discontinued in case VTE is suspected or develops after initiation of therapy.
Fluid Retention: Use progesterone with caution in patients with conditions that might be aggravated by fluid retention (e.g., hypertension, cardiac disease, renal disease, epilepsy, migraine, asthma); in patients with a history of depression, diabetes, mild to moderate hepatic dysfunction, migraine or photosensitivity and in breastfeeding mothers.
Glucose and Lipid Metabolism: A significant percentage of peri- and postmenopausal patients taking progestins has been shown to develop worsening of blood glucose tolerance and lipid metabolism.
Closely observe diabetic patients or those with a predisposition to diabetes to detect any alterations in carbohydrate or lipid metabolism, especially in triglyceride blood levels.
Calcium and Phosphorus Metabolism: The prolonged use of estrogens, with or without progestins, influences calcium and phosphorus metabolism. Patients with metabolic and malignant bone diseases associated with hypercalcemia and patients with renal insufficiency should use estrogens (with or without progestins) with caution.
Familial Hyperlipidemias or Porphyria: Women with familial hyperlipidemias or porphyria need special surveillance. Additional lipid-lowering measures are recommended as appropriate.
Breast Cancer: It is suggested that estrogen plus progestin therapy may cause a mild increase in the risk of breast cancer. Although it is not known whether this also occurs with concurrent progesterone therapy, patients should refer to the prescribing information for the co-prescribed estrogen for information about the risk of breast cancer.
Estrogens with or without progestins is not recommended to be given to women with existing breast cancer or those with a history of the disease. Caution is advised in prescribing estrogens with or without progestins in women with known risk factors associated with the development of breast cancer such as strong family history of breast cancer (first degree relative) or who present a breast condition with an increased risk (abnormal mammograms and/or atypical hyperplasia at breast biopsy). Nulliparity, obesity, early menarche, late age at first full term pregnancy and at menopause should also be evaluated for these are known factors for the development of breast cancer.
An increase in abnormal mammograms has been observed with the use of progestin plus estrogen therapy. Further evaluation is required to confirm these results. All women should receive yearly breast examinations (by a healthcare provider) and perform monthly breast self-examinations. Mammography examinations should be scheduled based on patient age, risk factors and prior mammogram results.
The degree of association between breast cancer and menopause hormone therapy (MHT) remains controversial. Most long-term studies reflect the use of one specific combination of oral estrogen and progestogen and suggest a possible increased risk with increasing duration. Three studies suggest that micronized progesterone or dydrogesterone could be associated with a lower risk than synthetic progestogen. A large European observational study suggested that micronized progesterone or dydrogesterone used in association with oral or percutaneous estradiol may be associated with a better risk profile for breast cancer than synthetic progestogens. A case-control study from France also showed a lower level of risk with progesterone than synthetic progestogens.
The increased risk of breast cancer is primarily associated with the addition of a synthetic progestogen to estrogen therapy (conjugated estrogen and medroxyprogesterone acetate continuous combined therapy) and related to the duration of use. The risk may be lower with micronized progesterone or dydrogesterone than with a synthetic progestogen. The risk of breast cancer attributable to MHT is small and the risk decreases progressively after treatment is stopped.
Endometrial Cancer: When estrogens are administered alone or for prolonged periods, the risk of endometrial hyperplasia and carcinoma is increased.
Progestins may cause breakthrough bleeding and spotting bleeding during the first months of treatment. If these symptoms are still present after 6 months of treatment, if it starts beyond that time or if it continues after treatment has been discontinued, advise patients to report to their doctor and be referred for gynecological investigation.
In such cases, diagnostic measures (e.g., endometrial biopsy or curettage) must be undertaken to rule out the possibility of uterine malignancy and treatment should be re-evaluated in these patients. The addition of progesterone to estrogen-only HRT for 10 or more days per cycle greatly reduces this risk in non-hysterectomized women.
Ovarian Cancer: Some epidemiological studies have shown that long-term use (at least 5 years or more) of estrogen plus progestin and estrogen-only HRT products has been associated with an increased risk of ovarian cancer. However, it is uncertain whether long-term use of combined HRT confers a different risk than estrogen-only products.
Cerebrovascular Insufficiency: Discontinue therapy if patient experiences visual disturbances, classical migraine, transient aphasia, paralysis, or loss of consciousness during therapy.
Patients with a previous history of classical migraine and who develop a recurrence or worsening of migraine symptoms should be re-evaluated.
Dementia: Although some evidence exist from the WHI trial of increased risk of probable dementia in women who start using continuous combined conjugated estrogen and medroxyprogesterone acetate after 65 years old, it is not known whether these findings apply to younger postmenopausal women or other HRT products.
Pre-existing Mental Depression: Use progesterone with caution in patients with pre-existing mental depression. Progesterone should be discontinued if depression recurs to a serious degree during therapy.
Visual Effects: Retinal vascular thrombosis has occurred in patients receiving estrogen. Estrogen plus progesterone therapy should be withheld if unexplained, sudden or gradual, partial or complete loss of vision, proptosis or diplopia, papilledema, retinal vascular lesions, or migraine occurs. Appropriate and therapeutic measures should be instituted in these patients. Discontinue permanently if examination reveals papilledema or retinal vascular lesions.
Hepatic Impairment: The effect of hepatic impairment on the pharmacokinetics of progesterone has not been studied. However, since sexual hormones are metabolized in the liver, progesterone should be used with caution in these patients.
Liver function tests should be done regularly in patients who are suspected of having hepatic disease.
Renal Impairment: The effect of renal impairment on the pharmacokinetics of progesterone has not been studied.
Effects on the Ability to Drive and Use Machines: Progesterone use may result in transient and occasional somnolence or dizziness/drowsiness which usually occurs 1 to 4 hours after ingestion. This condition may be aggravated when progesterone is administered with food. Patients should be warned that visual symptoms may make activities such as driving or operating machinery more hazardous than usual under conditions of variable lighting. Taking the capsules at bedtime should reduce these effects during the day.
Carcinogenicity, Mutagenesis, Impairment of Fertility: Progesterone, when implanted into female mice, produced mammary carcinomas, ovarian granulosa cell tumors and endometrial stromal carcinomas. Long-term intramuscular (IM) injections in dogs produced nodular hyperplasia and benign and malignant mammary tumors. Rats that were given subcutaneous (SC) or IM injections of progesterone and were previously treated with chemical carcinogen had a lower latency period and an increased incidence of mammary tumors. Progesterone has not been tested for carcinogenicity in animals by the oral route of administration.
In vitro studies, progesterone did not show evidence of genotoxicity for point mutations or for chromosomal damage. In in vivo studies, however, chromosomal damage was present in mice at oral doses of 1000 mg/kg and 2000 mg/kg. Inhibition of ovulation has been shown in a number of species when progesterone is administered exogenously. Impaired fertility is expected when progesterone is given at high doses and for an extended duration until treatment is stopped.
Use in Children: Progesterone is not intended for use in children. No clinical studies in pediatric population have been conducted.
Use in the Elderly: In the WHI estrogen plus progestin substudy, there was a higher relative risk of nonfatal stroke and invasive breast cancer in women >65 years old. There was an increased risk of developing probable dementia in WHIMS estrogen plus progestin ancillary study in women aged 65 to 79 years. However, no sufficient numbers of geriatric women are involved in clinical studies to determine if there is a difference in the response of women over 65 years from the younger subjects to progesterone.