Contraindications
Do not take Duphaston if you:

• are hypersensitive(allergic) to the active substance or to any of the excipients.
• have a known or suspected progestogen dependent neoplasm.
• have undiagnosed vaginal bleeding.
• are using this medicine to prevent endometrial hyperplasia (abnormal growth of the lining of the uterus), specifically if you are also taking oestrogens: See contraindications for use of oestrogens in combination with progestagens, such as dydrogesterone.

Medical examination / follow-up

• Your doctor will take a full medical history (including family history) before starting you on hormone replacement therapy (HRT) or when its use is to be resumed after an interruption. Your doctor will also perform a complete physical examination (including gynaecological (pelvic) and breast examination) as guided by your history and by the contraindications and warnings described in this leaflet. During the treatment period it is highly recommended to have regular check-ups, the frequency and nature of which will be determined by your doctor according to your personal situation. Any changes in your breast must be reported to your doctor immediately. Your doctor can explain to you what types of changes are particularly important to report.
• In accordance with the current guidelines for healthy women it is important to have regular breast examinations, including mammography, performed. These should be scheduled according to your personal medical needs.

Endometrial hyperplasia (abnormal growth of the inner lining of uterus)

• Long-term use of oestrogens without the addition of a progestagen increases the chance of endometrial hyperplasia and endometrial carcinoma (cancer) in women with an intact uterus. This risk may largely be prevented by combining the oestrogen therapy for atleast 12 days per cycle with a progestagen, such as dydrogesterone, the active ingredient in Duphaston.

Mammary cancer

• A randomised placebo-controlled study, the Women’s Health Initiative Study (WHI) and epidemiological studies, including the Million Women Study (MWS) have shown that in women who have taken oestrogen, oestrogen-progestagen combinations or tibolone as hormone replacement therapy for a number of years there is a relative increased risk of breast cancer. For all HRT this increased risk occurs within a couple of years of use and increases as the treatment period continues. The risk returns to pretreatment leven within a couple of years (a maximum of five) after the treatment is discontinued.
  The MWS showed that the relative risk of breast cancer in women who were treated with conjugated equine oestrogens (CEE) or oestradiol (E2) was higher when a progestagen was added. This risk was independent of the dosage schedule used (sequential or continuous administration of progestagen) and the type of progestagen.

Venous thromboembolism

• Hormone replacement therapy is associated with a higher relative risk for the occurence of a venous thromboembolism (VTE), that is deep vein thrombosis or pulmonary embolism. One randomised controlled study and epidemiological studies report a two to three times higher risk of VTE among users of HRT compared with women who do not use HRT. The chance of VTE is greater during the first year of HRT treatment than thereafter.
• General risk factors for the occurence of VTE are:
  • A positive personal history;
  • A positive family history;
  • Serious obesity (Body Mass Index greater that 30 kg/m2);
  • Systemic lupus erythematotus (SLE)

There is no consensus regarding the possible role of varicosis in VTE.

• If you have a previous history of repeated VTE or have thrombophilia (a blood disorder in which there is an increased tendency to form blood clots), you are at an increased risk of VTE. Hormone replacement could increase this risk even further. If you have a previous personal or clear family history of VTE or have suffered repeated spontaneous abortions, your doctor must carry out an investigation to ensure you do not have a thrombophilic predisposition. Until a thorough evaluation of the thrombophilic factors have been carried out or anticoagulant therapy has been started, the use of HRT is contraindicated. If you are already being treated with anticoagulant therapy, your doctor must carefully assess the advantages and disadvantages of HRT treatment before starting you on it.
• The chance of VTE may be increased temporarily from long-term immobilisation, serious trauma or major surgical operation. If you are a postoperative patient, your doctors will do all that is necessary to help prevent the occurrence of a VTE after your surgery. If you are to undergo an elective surgery (in particular abdominal or orthopaedic surgery of the lower limbs), after which long-term immobilisation is anticipated, your doctor will likely stop your HRT four to six weeks before the operation. Your doctor can restart your HRT when you are fully mobile again.
• If a VTE develops after starting the therapy, you must stop taking Duphaston (your doctor will discontinue the prescription). Also, contact your doctor immediately if any potentially thromboembolic symptoms occur (for example: painful swelling of a leg, sudden pain in the chest, shortness of breath).

Coronary heart disease

• Randomised controlled studies have not provided any evidence of a favourable effect of continuous combined conjugated oestrogens and medroxyprogesterone acetate on the risk of coronary heart disease (i.e.: no positive influence on the risk of coronary heart disease seen during HRT). Two large clinical studies (WHI and HERS (Heart and Oestrogen/progestin Replacement Study)) showed a possible increased risk of cardiovascular morbidity during the first year of use and no indications of an overall favourable effect.

Cerebrovascular accident (CVA)

• In one large randomised clinical trial (WHI study) in healthy women, as a secondary outcome, an increased risk of ischemic CVA was reported during treatment with continuous combined conjugated oestrogens with medroxyprogesterone acetate.