1 Name of Medicine
Progesterone.
2 Qualitative and Quantitative Composition
Each Cyclogest pessary contains 400 mg progesterone.
For the full list of excipients, see Section 6.1 List of Excipients.
3 Pharmaceutical Form
Pessary.
Off-white, approximately 10 mm x 30 mm, torpedo shaped pessary.
4.1 Therapeutic Indications
Cyclogest is indicated for luteal phase support as part of an Assisted Reproductive Technology (ART) treatment for women.
4.2 Dose and Method of Administration
Dosage.
One 400 mg pessary administered vaginally twice a day (BID) starting at oocyte retrieval. If pregnancy has been confirmed, the administration of progesterone should be continued for 38 days from the start of therapy or up until 12 weeks of pregnancy according to need at the judgement of the treating physician.
Method of administration.
For vaginal insertion.
Patient instructions.
The pessary should be removed from its wrapper and inserted deep into the vagina, by pushing the pessary upwards and backwards while either in a squatting position or lying down. If a recommended twice daily dose is being administered, then a preferable time of dosing is in the morning and at night before retiring.
Missed dose.
A missed dose should be administered as soon as remembered, unless the missed dose is noticed at the day of the next dose. In the latter case, the missed dose should be omitted and the regular dosing regimen continued.4.3 Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in Section 6.1 List of Excipients.
Undiagnosed vaginal bleeding.
Known or suspected progesterone sensitive malignant tumours.
Porphyria.
Known missed abortion or ectopic pregnancy.
Active arterial or venous thromboembolism or severe thrombophlebitis, or a history of these events.
Severe hepatic dysfunction or disease.
4.4 Special Warnings and Precautions for Use
Cyclogest is not indicated in threatened miscarriage. Treatment should be discontinued in the event of a missed miscarriage.
Progesterone should be discontinued if any of the following conditions are suspected:
myocardial infarction;
cerebrovascular disorders;
arterial or venous thromboembolism (venous thromboembolism or pulmonary embolism);
thrombophlebitis;
retinal thrombosis.
Although risk of thromboembolism has been associated with oestrogens a definite causative effect has not been established for progestins. Therefore, in women with generally recognised risk factors for thromboembolic events, such as personal or family history, treatment with progesterone may further increase the risk. In these women, the benefits of progesterone administration need to be weighed against the risks. It should be noted however, that pregnancy itself carries an increased risk of thromboembolic events.
Patients with a history of depression need to be closely observed. Consider discontinuation if symptoms worsen.
Because progesterone may cause some degree of fluid retention, conditions that might be influenced by this factor (e.g. epilepsy, migraine, asthma, cardiac or renal dysfunction) require careful observation.
A decrease in glucose tolerance has been observed in a small number of patients on oestrogen/progestin combination drugs. The mechanism of this decrease is not known. For this reason, diabetic patients should be carefully observed while receiving progestin therapy.
Progesterone is metabolised in the liver and should be used with caution in patients with hepatic dysfunction.
Abrupt discontinuation of progesterone dosing may cause increased anxiety, moodiness and increased sensibility to seizures.
Use in special populations.
There is no experience with use of progesterone in patients with impaired liver or renal function.
Use in the elderly.
No clinical data have been collected in patients over age 65.
Paediatric use.
There is no relevant use of progesterone in the paediatric population.
Effects on laboratory tests.
No data available.4.5 Interactions with Other Medicines and Other Forms of Interactions
Drugs known to induce the hepatic cytochrome-P450-3A4 system (e.g. rifampicin, carbamazepine or phenytoin) may increase the elimination rate and thereby decrease the bioavailability of progesterone.
Ketoconazole and other inhibitors of CY3A4 may increase the bioavailability of progesterone.
The effect of concomitant vaginal products on the exposure of progesterone from Cyclogest 400 mg pessary has not been assessed and is therefore not recommended.
4.6 Fertility, Pregnancy and Lactation
Effects on fertility.
See Section 4.1 Therapeutic Indications. 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 could impair fertility until the cessation of treatment.
(Category A)
Cyclogest 400 mg pessary is only indicated during the first trimester of pregnancy for use as part of an assisted reproduction (ART) treatment (see Section 4.1 Therapeutic Indications for full details). Progesterone crosses the placenta. There is limited and inconclusive data on the risk of congenital anomalies, including genital abnormalities in male or female infants, following intrauterine exposure during pregnancy. The rates of congenital anomalies, spontaneous abortion and ectopic pregnancies observed during the clinical trial were comparable with the event rate described in the general population although the total exposure is too low to allow conclusions to be drawn.
Detectable amounts of progesterone have been identified in the milk of mothers. Therefore Cyclogest 400 mg pessary should not be used during lactation.4.7 Effects on Ability to Drive and Use Machines
Progesterone may cause dizziness. Therefore, caution is advised in drivers and users of machines.
4.8 Adverse Effects (Undesirable Effects)
Adverse reactions in patients undergoing luteal support as a part of ART treatment is presented in Table 1 displaying the adverse reactions by system organ classes (SOC) and frequencies:
As with other vaginal preparations, some leakage of the pessary base may occur.
Clinical trials.
Adverse effects reported from a Phase III clinical trial (Cyclogest Study: ACT-CYC-300-2013-01) comparing Cyclogest with Crinone 8% gel (90 mg) (see Section 5.1 Pharmacodynamic Properties, Clinical trials) the frequencies of patients reporting AEs were comparable for both treatments (Cyclogest: 43.6% and Crinone: 44.6%) are tabulated in Table 2.
Reporting suspected adverse effects.
Reporting suspected adverse reactions after registration 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 at www.tga.gov.au/reporting-problems.4.9 Overdose
There is a wide margin of safety with progesterone pessaries, but overdosing may produce euphoria or dysmenorrhoea.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).
5 Pharmacological Properties
5.1 Pharmacodynamic Properties
Mechanism of action.
Progesterone is a naturally occurring steroid that is secreted by the ovary, placenta, and adrenal gland. In the presence of adequate oestrogen, progesterone transforms a proliferative endometrium into a secretory endometrium. Progesterone is necessary to increase endometrial receptivity for implantation of an embryo. Once an embryo is implanted, progesterone acts to maintain the pregnancy.
Clinical trials.
A multi-centre, multi-national, open-label, randomised, parallel group, non-inferiority phase III trial in premenopausal women (Cyclogest study: ACT-CYC-300-2013-01 (2014)) was performed to compare Cyclogest 400 mg pessary twice daily (BID) to Crinone 8% gel (90 mg) once daily (QD).
The primary endpoint of the study was the clinical pregnancy rate (foetal heart movement measured by transvaginal ultrasonography (TVUS)) achieved after 38 days of Luteal Phase Support (LPS) in patients undergoing ART.
812 patients were enrolled and 769 patients were randomised to receive either Cyclogest 400 mg pessary BID (n=385) or Crinone 8% vaginal progesterone gel (90 mg) QD (n=384), both for a period of 10 weeks. Subjects ranged in age from 18 to 40 years. The study drug was initiated on the day after oocyte retrieval.
In the Full Analysis Set (FAS), the pregnancy rate on Day 38 was 38.3% for Cyclogest and 39.9% for Crinone (Table 3). The Cyclogest-Crinone pregnancy rate difference was -1.6% with a 97.5% CI lower bound of -8.6%.
In the Per Protocol (PP) set, the pregnancy rate on Day 38 was 38.1% for Cyclogest and 40.4% for Crinone (Table 3). The Cyclogest-Crinone pregnancy rate difference was -2.4% with a 97.5% CI lower bound of -9.5%.
The pre-determined non-inferiority margin was -9% based on a reference pregnancy rate of 30% and a one-sided significance level of 2.5%. For the primary efficacy outcome measure using unadjusted data, the results were consistent with the criteria for non-inferiority for the FAS dataset, but not for the PP dataset. After a post hoc adjustment of the non-inferiority margin to -10% based on an observed reference pregnancy rate of 40%, the results of both sets were consistent with the post hoc non-inferiority criteria.
In fact, both analyses (FAS and PP set) showed similar results in this trial i.e. a difference in the clinical pregnancy rates of about -2% points (Cyclogest minus Crinone) associated with lower limits of the 95% confidence interval around -9%. Thus, non-inferiority of Cyclogest in comparison to Crinone can be concluded.
5.2 Pharmacokinetic Properties
Absorption.
Vaginal administration of Cyclogest 400 mg every 12 h in healthy women has been shown effective in rapidly achieving and maintaining serum progesterone concentrations at physiological levels appropriate to the midluteal phase of the ovarian cycle and early pregnancy. The mean Cmax after 10 days of multiple dosing was 18.4 nanogram/mL and Ctrough was 10.5 nanogram/mL.
Distribution.
Progesterone is approximately 96% to 99% bound to serum proteins, primarily to serum albumin and corticosteroid binding globulin.
Metabolism.
Progesterone is metabolized primarily by the liver largely to pregnanediols and pregnanolones.
Pregnanediols and pregnanolones are conjugated in the liver to glucuronide and sulfate metabolites. Progesterone metabolites that are excreted in the bile may be deconjugated and may be further metabolized in the gut via reduction, dehydroxylation, and epimerization.
Excretion.
Progesterone undergoes renal and biliary elimination.
5.3 Preclinical Safety Data
Genotoxicity.
Progesterone did not induce chromosomal aberrations or sister chromatid exchanges in cultured human cells nor old chromosomal aberration or DNA strand breaks end in rodent cells. Progesterone did not induce dominant lethal mutation in mice or chromosomal aberrations in the bone marrow rats in vivo although in vivo studies for chromosome damage have yield positive results in mice at oral doses of 1000 mg/kg and 2000 mg/kg. Weak clastogenic activity was from progesterone in the rat hepatocyte micronucleus test after treatment with high oral dose (100 mg/kg). Studies on transformation of rodent cells in vitro were inconclusive. Variable results were obtained with progesterone in the mouse lymphoma tk assay. In assays for induction of DNA repair, progesterone produces variable results rats hepatocytes and negative results in human hepatocytes progesterone was not beta genic to bacteria.
Carcinogenicity.
Animal studies showed that progesterone was able to induce and/ or promote the formation of mammary, uterine, ovarian, endometrial, cervical and vagina tumours. When implanted into female mice, progesterone produces mammary carcinomas, ovarian granulosa cell tumours and endometrial stromal sarcomas. In dogs, long-term intramuscular injections produced nodular hyperplasia and benign and malignant memory tumours. Subcutaneous or intramuscular injections of progesterone decreased the latency period and increased the incidence of mammary tumours in rats previously treated with chemical carcinogen. The clinical relevance of these findings remains unclear.6 Pharmaceutical Particulars
6.1 List of Excipients
Hard fat.
6.2 Incompatibilities
Incompatibilities were either not assessed or not identified as part of the registration of this medicine.
6.3 Shelf Life
In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry can be found on the packaging.
6.4 Special Precautions for Storage
Store below 25°C.
6.5 Nature and Contents of Container
PVC/PE strip packs.
Pack sizes.
15 pessaries.
6.6 Special Precautions for Disposal
In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.
6.7 Physicochemical Properties
Pharmacotherapeutic group: Sex hormones and modulators of the genital system; Progestogens; Pregnen-(4) derivatives.
ATC code: G03DA04.
Chemical structure.
CAS number.
57-83-0.7 Medicine Schedule (Poisons Standard)
Prescription Only Medicine.
Summary Table of Changes
