Progesterone Sustained Release Tablets 200 mg/300 mg
Each film coated sustained release tablet contains:
Progesterone IP (as Nanonized)………………………………. 200 mg/ 300 mg
Excipients q.s.
Colour: Titanium Dioxide IP.
Film coated tablet 200 mg/ 300 mg
For the treatment of secondary amenorrhea associated with normal estrogen level in women.
GestaPink tablet should be taken in the evening before going to bed. The usual dosage is 200–300 mg daily, administered at bedtime, preferably before meals.
Cardiovascular Disorders and Probable Dementia
Oestrogens plus progestin therapy should not be used for the prevention of cardiovascular disease or dementia. The Women's Health Initiative (WHI) oestrogen plus progestin substudy reported increased risks of deep vein thrombosis, pulmonary embolism, stroke and myocardial infarction in postmenopausal women (50 to 79 years of age) during 5.6 years of treatment with daily oral conjugated oestrogens (CE) [0.625 mg] combined with medroxyprogesterone acetate (MPA) [2.5 mg], relative to placebo. The WHI Memory Study (WHIMS) oestrogen plus progestin ancillary study of the WHI reported an increased risk of developing probable dementia in postmenopausal women 65 years of age or older during 4 years of treatment with daily CE (0.625 mg) combined with MPA (2.5 mg), relative to placebo. It is unknown whether this finding applies to younger postmenopausal women.
Breast Cancer
The WHI oestrogen plus progestin substudy also demonstrated an increased risk of invasive breast cancer. In the absence of comparable data, these risks should be assumed to be similar for other doses of CE and MPA, and other combinations and dosage forms of oestrogens and progestins. Progestins with oestrogens should be prescribed at the lowest effective doses and for the shortest duration consistent with treatment goals and risks for the individual woman.
1. Cardiovascular disorders
An increased risk of pulmonary embolism, deep vein thrombosis (DVT), stroke, and myocardial infarction has been reported with oestrogen plus progestin therapy. Should any of these occur or be suspected, oestrogen with progestin therapy should be discontinued immediately. Risk factors for arterial vascular disease (for example, hypertension, diabetes mellitus, tobacco use, hypercholesterolemia, and obesity) and/or venous thromboembolism (for example, personal history or family history of venous thromboembolism [VTE], obesity, and systemic lupus erythematosus) should be managed appropriately.
a. Stroke
In the Women's Health Initiative (WHI) oestrogen plus progestin substudy, a statistically significant increased risk of stroke was reported in women 50 to 79 years of age receiving daily CE (0.625 mg) plus MPA (2.5 mg) compared to women in the same age group receiving placebo (33 versus 25 per 10,000 women-years). The increase in risk was demonstrated after the first year and persisted. Should a stroke occur or be suspected, oestrogen plus progestin therapy should be discontinued immediately.
b. Coronary Heart Disease
In the WHI oestrogen plus progestin substudy, there was a statistically non significant increased risk of coronary heart disease (CHD) events (defined as nonfatal myocardial infarction [MI], silent MI, or CHD death) reported in women receiving daily CE (0.625 mg) plus MPA (2.5 mg) compared to women receiving placebo (41 versus 34 per 10,000 women-years). An increase in relative risk was demonstrated in year 1 and a trend toward decreasing relative risk was reported in years 2 through 5. In postmenopausal women with documented heart disease (n = 2,763, average age 66.7 years), in a controlled clinical trial of secondary prevention of cardiovascular disease (Heart and Oestrogen/Progestin Replacement Study [HERS]), treatment with daily CE (0.625 mg) plus MPA (2.5 mg) demonstrated no cardiovascular benefit. During an average follow-up of 4.1 years, treatment with CE plus MPA did not reduce the overall rate of CHD events in postmenopausal women with established coronary heart disease. There were more CHD events in the CE plus MPA-treated group than in the placebo group in year 1, but not during the subsequent years. Two thousand, three hundred and twenty-one (2,321) women from the original HERS trial agreed to participate in an open-label extension of HERS, HERS II. Average follow-up in HERS II was an additional 2.7 years, for a total of 6.8 years overall. Rates of CHD events were comparable among women in the CE plus MPA group and the placebo group in HERS, HERS II, and overall.
c. Venous Thromboembolism
In the WHI oestrogen plus progestin substudy, a statistically significant 2-fold greater rate of VTE (DVT and pulmonary embolism [PE]) was reported in women receiving daily CE (0.625 mg) plus MPA (2.5 mg) compared to women receiving placebo (35 versus 17 per 10,000 women-years). Statistically significant increases in risk for both DVT (26 versus 13 per 10,000 women years) and PE (18 versus 8 per 10,000 women-years) were also demonstrated. The increase in VTE risk was demonstrated during the first year and persisted. Should a VTE occur or be suspected, oestrogen plus progestin therapy should be discontinued immediately. If feasible, oestrogens with progestins should be discontinued at least 4 to 6 weeks before surgery of the type associated with an increased risk of thromboembolism, or during periods of prolonged immobilization.
2. Malignant neoplasms
a. Breast Cancer
The WHI substudy of daily CE (0.625 mg)-alone provided information about breast cancer in oestrogen-alone users. In the WHI oestrogen-alone substudy, after an average of follow-up of 7.1 years, daily CE-alone was not associated with an increased risk of invasive breast cancer [relative risk (RR) 0.80] compared to placebo. In this sub study, prior use of oestrogen-alone or oestrogen plus progestin therapy was reported by 26 percent of the women. The relative risk of invasive breast cancer was 1.24, and the absolute risk was 41 versus 33 cases per 10,000 women-years, for CE plus MPA compared with placebo. Among women who reported prior use of hormone therapy, the relative risk of invasive breast cancer was 1.86, and the absolute risk was 46 versus 25 cases per 10,000 women-years, for oestrogen plus progestin compared with placebo. Among women who reported no prior use of hormone therapy, the relative risk of invasive breast cancer was 1.09, and the absolute risk was 40 versus 36 cases per 10,000 women-years for CE plus MPA compared with placebo. In the substudy, invasive breast cancers were larger, were more likely to be node positive, and were diagnosed at a more advanced stage in the CE (0.625 mg) plus MPA (2.5 mg) group compared with the placebo group. Metastatic disease was rare, with no apparent difference between the two groups. Other prognostic factors such as histologic subtype, grade and hormone receptor status did not differ between the groups. Consistent with the WHI clinical trials, observational studies have also reported an increased risk of breast cancer for oestrogen plus progestin therapy, and a smaller increased risk for oestrogen-alone therapy, after several years of use. One large meta-analysis of prospective cohort studies reported increased risks that were dependent upon duration of use and could last up to >10 years after discontinuation of oestrogen plus progestin therapy and oestrogen-alone therapy. Extension of the WHI trials also demonstrated increased breast cancer risk associated with oestrogen plus progestin therapy. Observational studies also suggest that the risk of breast cancer was greater, and became apparent earlier, with oestrogen plus progestin therapy as compared to oestrogen alone therapy. However, these studies have not generally found significant variation in the risk of breast cancer among different oestrogen plus progestin combinations, doses, or routes of administration. The use of oestrogen plus progestin has been reported to result in an increase in abnormal mammograms requiring further evaluation. All women should receive yearly breast examinations by a healthcare provider and perform monthly breast self-examinations. In addition, mammography examinations should be scheduled based on patient age, risk factors, and prior mammogram results.
b. Endometrial Cancer
An increased risk of endometrial cancer has been reported with the use of unopposed oestrogen therapy in a woman with a uterus. The reported endometrial cancer risk among unopposed oestrogen users is about 2 to 12 times greater than in non users, and appears dependent on duration of treatment and on oestrogen dose. Most studies show no significant increased risk associated with the use of oestrogens for less than 1 year. The greatest risk appears associated with prolonged use, with increased risks of 15-to 24-fold for 5 to 10 years or more and this risk has been shown to persist for at least 8 to 15 years after oestrogen therapy is discontinued. Clinical surveillance of all women using oestrogen plus progestin therapy is important. Adequate diagnostic measures, including directed or random endometrial sampling when indicated, should be undertaken to rule out malignancy in all cases of undiagnosed persistent or recurring abnormal genital bleeding. There is no evidence that the use of natural oestrogens results in a different endometrial risk profile than synthetic oestrogens of equivalent oestrogen dose. Adding a progestin to oestrogen therapy in postmenopausal women has been shown to reduce the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer.
c. Ovarian Cancer
The WHI oestrogen plus progestin substudy reported a statistically non significant increased risk of ovarian cancer. After an average follow-up of 5.6 years, the relative risk for ovarian cancer for CE plus MPA versus placebo was 1.58 (95 percent nCI, 0.77 – 3.24). The absolute risk for CE plus MPA versus placebo was 4 versus 3 cases per 10,000 women-years. In some epidemiologic studies, the use of oestrogen plus progestin and oestrogen-only products, in particular for 5 or more years, has been associated with an increased risk of ovarian cancer. However, the duration of exposure associated with increased risk is not consistent across all epidemiologic studies and some report no association.
3. Probable dementia
In the oestrogen plus progestin Women's Health Initiative Memory Study (WHIMS), an ancillary study of WHI, a population of 4,532 postmenopausal women 65 to 79 years of age was randomized to daily CE (0.625 mg) plus MPA (2.5 mg) or placebo. In the WHIMS oestrogen plus progestin ancillary study, after an average follow up of 4 years, 40 women in the CE plus MPA group and 21 women in the placebo group were diagnosed with probable dementia. The relative risk of probable dementia for oestrogen plus progestin versus placebo was 2.05 (95 percent CI, 1.21-3.48). The absolute risk of probable dementia for CE plus MPA versus placebo was 45 versus 22 cases per 10,000 women-years. It is unknown whether these findings apply to younger postmenopausal women.
4. Vision abnormalities
Retinal vascular thrombosis has been reported in patients receiving oestrogen. Discontinue oestrogen plus progestin therapy pending examination if there is sudden partial or complete loss of vision, or if there is a sudden onset of proptosis, diplopia or migraine. If examination reveals papilledema or retinal vascular lesions, oestrogen plus progestin therapy should be permanently discontinued.
A. General
1. Addition of a progestin when a woman has not had a hysterectomy
Studies of the addition of a progestin for 10 or more days of a cycle of oestrogen administration, or daily with oestrogen in a continuous regimen, have reported a lowered incidence of endometrial hyperplasia than would be induced by oestrogen treatment alone. Endometrial hyperplasia may be a precursor to endometrial cancer.
2. Fluid Retention
Progesterone may cause some degree of fluid retention. Women with conditions that might be influenced by this factor, such as cardiac or renal dysfunction, warrant careful observation.
Combination with other medicinal products may decrease progesterone metabolism which may alter its effect.
Prolonged concurrent use (over three months) of barbiturates, carbamazepine, hydantoins, anti-epileptics (phynytoin), phenylbutazone, spironolactone, griseofulvin or rifampicin with Progesterone can result in clinically relevant interactions. Probably these compounds decrease the effectiveness of Progesterone by increasing the hepatic metabolism.
Some antibiotics (ampicillins, tetracyclines): changes in the intestinal flora leading to a change in the steroid enterohepatic cycle.
As these interactions may vary between people, the clinical results are not necessarily predictable.
Although data are limited, it is considered possible that activated charcoal and griseofulvin may decrease the effectiveness of Progesterone.
Progesterone may possibly increase the therapeutic, pharmacologic, or toxicologic effects of cyclosporin, theophyllines and troleandomycin.
Progesterone may interfere with the effects of bromocriptine. Progestogens may impair glucose tolerance and, because of this, increase requirements for insulin or other antidiabetic agents in diabetic patients.
The bioavailability of progesterone may be reduced by smoking and increased by alcohol abuse.
The metabolism of progesterone by human liver microsomes was inhibited by ketoconazole (IC50 <0.1 μM). Ketoconazole is a known inhibitor of cytochrome P450 3A4. These data therefore suggest that ketoconazole may increase the bioavailability of progesterone. The clinical relevance of the in vitro findings is unknown.
Pregnancy
Progesterone tablet should not be used during pregnancy.
Lactation
There are insufficient data on the use of progesterone during lactation to assess potential harm. Progesterone passes into the breast milk. It should therefore be avoided in women whilst they are breast-feeding.
Patients with Renal Impairment
No formal studies have evaluated the effect of renal disease on the disposition of progesterone. Since progesterone metabolites are eliminated mainly by the kidneys, progesterone capsules should be used with caution and only with careful monitoring in patients with renal dysfunction.
Patients with Hepatic Impairment
No formal studies have evaluated the effect of hepatic disease on the disposition of progesterone. However, since progesterone is metabolized by the liver, use in patients with severe liver dysfunction or disease is contraindicated. If treatment with progesterone is indicated in patients with mild to moderate hepatic dysfunction, these patients should be monitored carefully.
Progesterone may cause drowsiness or dizziness in a minority of patients. Therefore, caution should be taken when driving or using machines.
| System Organ Class | Common (≥1/100 to <1/10) | Uncommon (≥1/1,000 to <1/100) | Rare (≥1/10,000 to <1/1,000) | Very rare (<1/10,000) |
|---|---|---|---|---|
| Reproductive system and breast disorders | Altered periods, amenorrhoea, intercurrent bleeding | Mastodynia | — | — |
| Nervous system disorders | Headache | Drowsiness, dizziness | — | Depression |
| Gastrointestinal disorders | — | Vomiting, diarrhoea, constipation | Nausea | — |
| Hepatobiliary disorders | — | Cholestatic jaundice | — | — |
| Immune system disorders | — | — | — | Urticaria |
| Skin and subcutaneous tissue disorders | — | Pruritus, acne | — | Chloasma |
Drowsiness, somnolence and/or fleeting dizzy sensations are seen particularly with concomitant hypoestrogenism. These effects disappear immediately without compromising the benefit of treatment when doses are reduced or higher estrogen levels are restored. If the treatment sequence is started too early in the month, particularly before the 15th day of the cycle, the cycle may be shortened or intercurrent bleeding may occur.
Changes in periods, amenorrhoea or intercurrent bleeding have been observed and associated with the use of progesterones in general. Rashes, fluid retention, weight changes, changes in libido, premenstrual symptoms, pyrexia, insomnia, alopecia, hirsutism; rarely jaundice. Venous thromboembolism, i.e. deep leg or pelvic venous thrombosis and pulmonary embolism, is more frequent among hormone replacement therapy users than among non-users.
Reporting of Suspected Adverse Reactions
Reporting suspected adverse reactions after authorization of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via email to: medico@zorvia.com
By reporting side effects, you can help provide more information on the safety of this medicine.
No studies on overdosage have been conducted in humans. In the case of overdosage, progesterone tablet should be discontinued, and the patient should be treated symptomatically. Symptoms of overdosage may include somnolence, dizziness, euphoria or dysmenorrhoea. Treatment is observation and, if necessary, symptomatic and supportive measures should be provided.
Progesterone is a natural progestative agent, the standard hormone of the family of progestative agents. It possesses the set of properties characterizing natural progesterone, namely, antiestrogenic, slightly antiandrogenic, anti-aldosterone, gestagen. Progesterone is capable of inducing dose-dependent secretory changes in the endometrium, such as pseudo-stratification and basal vacuolation of glycogen. In addition, progesterone exerts anti proliferative or anti-mitotic effects on the endometrium, e.g., suppression of nuclear estradiol receptors, suppression of DNA synthesis, and induction of 17β Estradiol and isocitric dehydrogenase activities. In part of the patients (depending on the estrogen-progesterone dose regimen) progesterone treatment does not lead to complete secretory transformation of the endometrium, and often there is no withdrawal bleeding. However, this lack of complete transformation and cyclic bleeding is no cause for concern about endometrial hyperplasia since progesterone fully suppresses mitotic activity in the endometrial glandular cells after 12 days of administration (200 mg or 300 mg daily dose). With regard to metabolic side-effects and safety, progesterone has anti-mineralocorticoid effects upon the urinary sodium excretion. Accordingly, in hypertensive patients a slight reduction in blood pressure has been observed.
Oral administration of progesterone induces an increase in unconjugated pregnandiol and pregnanolone plasma values, two metabolites with possible anaesthetic effects. This probably explains the transient drowsiness or dizziness which may occur in certain patients, especially after ingestion of 200 mg dose or more, while fasting.
Absorption
Progesterone is absorbed by the digestive tract. Plasmatic progesterone levels increase from the first hour, and the highest plasmatic levels are observed 1 to 3 hours after administration. Pharmacokinetic studies carried out with volunteers have shown that after a simultaneous ingestion of two capsules of Progesterone 100, the mean plasmatic progesterone concentration increases from 0.13 ng/ml to 4.25 ng/ml after 1 hour, to 11.75 ng/ml after 2 hours, to 8.37 ng/ml after 4 hours, to 2.00 ng/ml after 6 hours, and to 1.64 ng/ml after 8 hours.
Taking into account the tissue retention time of the hormone, it seemed necessary to divide the dose into two applications, about 12 hours between one another, in order to achieve impregnation through all day. Although there are considerable individual variations, any individual preserves the same pharmacokinetic characteristics for several months, enabling individual adaptation of the dosage.
Metabolism
The main metabolites in the plasma are 20-α-hydroxy-Δ-4α pregnanolone and 5-α-dihydroprogesteron. Urinary elimination is observed in 95% of cases in the form of glycuroconjugate metabolites, mainly 3-α-5-α-pregnandiol. These plasmatic and urinary metabolites are similar to those found during the physiological secretion of the ovarian corpus luteum.
Progesterone has not been tested for carcinogenicity in animals by the oral route of administration. When implanted into female mice, progesterone produced mammary carcinomas, ovarian granulosa cell tumors and endometrial stromal sarcomas. In dogs, long-term intramuscular injections produced nodular hyperplasia and benign and malignant mammary tumors. Subcutaneous or intramuscular injections of progesterone decreased the latency period and increased the incidence of mammary tumors in rats previously treated with a chemical carcinogen. Progesterone did not show evidence of genotoxicity in in vitro studies for point mutations or for chromosomal damage. In vivo studies for chromosome damage have yielded positive results in mice at oral doses of 1000 mg/kg and 2000 mg/kg. Exogenously administered progesterone has been shown to inhibit ovulation in a number of species and it is expected that high doses given for an extended duration would impair fertility until the cessation of treatment.
GestaPink tablet contains nanonized progesterone
Molecular Formula: C21H30O2
Molecular Weight: 314.5 g/mol
Not applicable
Refer on pack
As per carton
Store below 25°C in a dry place, protect from light. Keep out of reach of children. Direction for use: The tablet should be swallowed whole and not to be broken, chewed or crushed.