Boxed Warnings
Estrogens and progestogens should not be used for the prevention of cardiovascular disease or dementia.
The Women's Health Initiative (WHI) study reported increased risks of myocardial infarction, stroke, invasive breast cancer, pulmonary emboli, and deep vein thrombosis in postmenopausal women (50 to 79 years of age) during 5 years of treatment with conjugated estrogens (0.625 mg) combined with medroxyprogesterone acetate (2.5 mg) relative to placebo (see Section 5.1 Pharmacodynamic Properties, Clinical trials; Section 4.4 Special Warnings and Precautions for Use).
The WHI study reported increased risks of stroke and deep vein thrombosis in postmenopausal women (50 to 79 years of age) during 6.8 years of treatment with conjugated estrogens (0.625 mg) relative to placebo (see Section 5.1 Pharmacodynamic Properties, Clinical trials; Section 4.4 Special Warnings and Precautions for Use).
The Women's Health Initiative Memory Study (WHIMS), a sub-study of WHI, reported increased risk of developing probable dementia in postmenopausal women 65 years of age or older during 4 to 5.2 years of treatment with conjugated estrogens, with or without medroxyprogesterone acetate, relative to placebo. It is unknown whether this finding applies to younger postmenopausal women (see Section 5.1 Pharmacodynamic Properties, Clinical trials; Section 4.4 Special Warnings and Precautions for Use).
Other doses of conjugated estrogens and medroxyprogesterone acetate, and other combinations and dosage forms of estrogens and progestogens were not studied in the WHI clinical trials and, in the absence of comparable data, these risks should be assumed to be similar. Because of these risks, estrogens with or without progestogens should be prescribed at the lowest effective doses and for the shortest duration consistent with treatment goals and risks for the individual woman.
1 Name of Medicine
Estradiol (as hemihydrate) and progesterone.
2 Qualitative and Quantitative Composition
Each soft capsule contains 1 mg of estradiol (as hemihydrate) and 100 mg of progesterone.
For the full list of excipients, see Section 6.1 List of Excipients.
3 Pharmaceutical Form
Soft capsule.
Bijuva 1/100 soft capsules are oval and opaque, light pink on one side and dark pink on the other side with the marking "1C1" printed in white ink.
Capsules are oval and approximately 5.2 - 6 mm in size.
4 Clinical Particulars
4.9 Overdose
There is little experience with overdose in human clinical trials. Both estradiol and progestogen are substances with low toxicity. Symptoms such as nausea, vomiting, breast tenderness, dizziness, abdominal pain, drowsiness/fatigue, and withdrawal bleeding could occur in cases of overdosing. It is unlikely that any specific or symptomatic treatment will be necessary.
Treatment of overdose should consist of general supportive measures.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).
5 Pharmacological Properties
5.3 Preclinical Safety Data
Genotoxicity. No genotoxicity studies have been conducted with combination of estradiol (hemihydrate)/progesterone.
There is limited evidence available in the literature suggesting that estradiol may be weakly genotoxic. No evidence could be found for an increase in the rate of gene mutation in bacterial or mammalian cells, but there was some evidence for the induction of chromosomal aberrations and aneuploidy and an increased incidence of sister chromatid exchanges (indicative of DNA damage) in mammalian cells. None of these effects were induced by estradiol in human lymphocyte cultures. Importantly, there was no evidence of clastogenicity in rodent bone marrow micronucleus assays.
Progesterone did not induce chromosomal aberrations or sister chromatid exchanges in cultured human cells nor chromosomal aberrations or DNA strand breaks in rodent cells. Progesterone did not induce dominant lethal mutations in mice or chromosomal aberrations in the bone marrow of rats in vivo although in vivo studies for chromosome damage have yielded positive results in mice at oral doses of 1000 mg/kg and 2000 mg/kg. Weak clastogenic activity was found for progesterone in the rat hepatocyte micronucleus test after treatment with a high oral dose (100 mg/kg). Studies on transformation of rodent cells in vitro were inconclusive. Variable results were obtained in the mouse lymphoma tk assay. Progesterone was not mutagenic to bacteria.
Carcinogenicity. No carcinogenicity studies have been conducted with combination of estradiol (hemihydrate)/progesterone.
Long-term, continuous administration of natural and synthetic estrogens in laboratory animal species increases the frequency of carcinomas of the breast, uterus, cervix, vagina, testis, and liver. Carcinogenicity by estradiol may involve gene mutation induced by reactive metabolites or the activation of estrogen receptor-mediated signalling pathways that sustain the growth and survival of preneoplastic and malignant cells.
Progesterone has not been tested for carcinogenicity in animals by the oral route of administration. Progesterone has been shown to induce/promote the formation of ovarian, uterine, mammary, and genital tract tumours in animals. The clinical relevance of these findings is unknown. Literature data provides no indication of potential carcinogenicity in humans.
When implanted into female mice, progesterone produced mammary carcinomas, ovarian granulosa cell tumours and endometrial stromal sarcomas. In dogs, long-term intramuscular injections produced nodular hyperplasia and benign and malignant mammary tumours.
Subcutaneous or intramuscular injections of progesterone decreased the latency period and increased the incidence of mammary tumours in rats previously treated with a chemical carcinogen.
6 Pharmaceutical Particulars
6.7 Physicochemical Properties
Chemical structure. Estradiol hemihydrate.
https://stagingapi.mims.com/au/public/v2/images/fullchemgif/CSESTHEM.gif Chemical name: estra-1,3,5(10)-triene-3,17β-diol (as hemihydrate). Estradiol has 5 chiral centres.
Molecular formula: C18H24O2.
Molecular weight: 281.39.
CAS number. Estradiol hemihydrate: 35380-71-3.
Progesterone.
https://stagingapi.mims.com/au/public/v2/images/fullchemgif/CSPROGES.gif Chemical name: pregn-4-ene-3,20-dione.
Molecular formula: C21H30O2.
Molecular weight: 314.5.
CAS number. Progesterone: 57-83-0.
7 Medicine Schedule (Poisons Standard)
Schedule 4 - Prescription Only Medicine.
Summary Table of Changes
https://stagingapi.mims.com/au/public/v2/images/fulltablegif/BIJUVAST.gif
