NORISTERAT Solution for injection Ref.[50750] Active ingredients: Norethisterone

Medical Examination

Assessment of women prior to starting Noristerat (and at regular intervals thereafter) should include a personal and family medical history of each woman. Physical examination should be guided by this and by the contraindications (section 4.3) and warnings (section 4.4) for this product. The frequency and nature of these assessments should be based upon relevant guidelines and should be adapted to the individual woman, but should include measurement of blood pressure and, if judged appropriate by the clinician, breast, abdominal and pelvic examination including cervical cytology.

Before starting treatment, pregnancy must be excluded.

Women should be advised that progestogen-only contraceptives do not protect against HIV infections (AIDS) and other sexually transmitted diseases.

Gynaecological considerations

Noristerat should not be used in patients with abnormal uterine bleeding until a definite diagnosis has been established and the possibility of genital tract malignancy eliminated. Undiagnosed vaginal bleeding that is suspicious for underlying conditions should be investigated prior to first injection and endometrial pathology should be excluded if it occurs in women over 40 after prolonged amenorrhoea.

If there is a history of ectopic pregnancy or one fallopian tube is missing, the use of Noristerat should be decided on only after carefully weighing the benefits against the risks.

If obscure lower abdominal complaints occur together with an irregular cycle pattern (above all amenorrhoea followed by persistent irregular bleeding), an extrauterine pregnancy must be considered.

The patient should be informed before starting Noristerat that her menstrual pattern is likely to alter during the entire exposure period. Menstrual changes in the form of spotting, breakthrough bleeding and delayed menstruation are relatively frequent, and generally do not require treatment.

Amenorrhoea: if, when the second injection is due, bleeding has not occurred in the preceding eight weeks the second injection should not be given until pregnancy has been ruled out.

Partial metabolization of norethisterone to ethinylestradiol

Norethisterone is partly metabolised to ethinylestradiol (EE) after intramuscular administration in humans. This conversion results in a systemic EE exposure corresponding to an oral equivalent dose of about 4 µg EE per day, on average, over 8 weeks. Mean oral equivalent doses per day are about 10 μg EE during the first 2 weeks after Noristerat administration and decline to about 5 μg EE in the 3rd week and about 2 μg EE from the 5th week onwards. Therefore, systemic estrogen effects cannot be excluded (see section 5.2). Post-marketing experience with Noristerat indicates that the safety profile of Noristerat does not resemble that of combined hormonal contraceptives.

Circulatory disorders

There is a general opinion, based on statistical evidence, that users of hormonal contraceptives experience, more often than non-users, venous thromboembolism, arterial thrombosis, including cerebral and myocardial infarction, and subarachnoid haemorrhage. Full recovery from such disorders does not always occur, and it should be realised that in a few cases they are fatal.

The relative risk of arterial thrombosis (e.g. stroke and myocardial infarction) appears to increase further when heavy smoking, increasing age and the use of hormonal contraceptives coincide.

Although there have been so far no observations of thromboembolic disease during the use of Noristerat, as a precaution it is recommended that this preparation should not be used where there is a history of thromboembolic processes.

No further injection should be given if symptoms of an arterial or venous thrombotic event occur during treatment, e.g.

• new onset or exacerbation of migraine-type headaches,
• sudden disturbances of vision or hearing perceptual disorders occur,
• significant rise in blood pressure,
• first signs of thrombosis or blood clots.

Liver Function

Porphyria and existing impairment of liver function might theoretically be exacerbated by Noristerat.

In rare cases benign, and in even rarer cases malignant, liver tumours leading in isolated cases to life-threatening intra-abdominal haemorrhage, have been observed after the use of hormonal substances such as the one contained in Noristerat. If severe upper abdominal complaints, liver enlargement or signs of intra-abdominal haemorrhage occur, a liver tumour should be considered in the differential diagnosis.

Women with a history of disturbed liver function or any disease that is prone to worsen during pregnancy such as idiopathic jaundice or severe pruritus of pregnancy should be carefully observed during medication.

Recurrence of cholestatic jaundice which occurred first during pregnancy or previous use of sex steroids necessitates the discontinuation of Noristerat.

Other conditions

A reduction of glucose tolerance has been observed in some women using progestogens. Consequently, diabetics and women with a tendency to diabetes should be carefully supervised during the use of Noristerat. In the case of diabetes, it may be necessary to reassess the required doses of antidiabetics or insulin.

In rare cases coughing, dyspnoea and circulatory irregularities may occur during or immediately after the injection. Experience has shown that these reactions can be avoided by injecting Noristerat very slowly.

Women with a history of severe depressive states should be carefully observed during medication. No further injection should be given, if during treatment, recurrence of earlier depression is experienced.

Depressed mood and depression are well-known undesirable effects of hormonal contraceptive use (see section 4.8). Depression can be serious and is a well-known risk factor for suicidal behaviour and suicide. Women should be advised to contact their physician in case of mood changes and depressive symptoms, including shortly after initiating the treatment.

Effect on blood chemistry: No influence of Noristerat on basal plasma cortisol, the ACTH test or the metyrapone test has been observed. In the acute dexamethasone suppression test, however, a higher plasma cortisol value than expected was found in 4 out of 10 women, although there were no clinical indications of disturbed adrenocortical function. A shortening of the recalcification time and of the thromboplastin time (Quick’s test) were observed in studies of the blood coagulation system.

Information about excipients

This medicine contains 333.8 mg benzyl benzoate in each 1 ml ampoule.

Benzyl benzoate may increase jaundice in newborn babies (up to 4 weeks old).

Note: The prescribing information of concomitant medications should be consulted to identify potential interactions.

There are no data on progestogen-only injectables drug interactions.

Effects of other medicinal products on Noristerat

Direct clinical evidence for reduced effectiveness of Noristerat has not been obtained. However, theoretical interactions based on findings with combined oral contraceptives include the following, which have been shown to have clinically important interactions:

Anticonvulsants: phenytoin, barbiturates, primidone, carbamazepine, phenylbutazone, oxcarbazepine, topiramate, felbamate.

Antifungal agents: griseofulvin.

Certain antibiotics: rifampicin and ampicillin (possibly due to changes in the intestinal flora).

Herbal remedies: products containing St John’s wort (Hypericum perforatum).

Antiviral agents: HIV/HCV protease inhibitors and non-nucleoside reverse transcriptase inhibitors can have variable effects on the plasma concentrations of sex hormones.

Substances decreasing the clearance of sex hormones (enzyme inhibitors)

Strong and moderate CYP3A4 inhibitors such as azole antifungals (e.g. fluconazole, itraconazole, ketoconazole, voriconazole) and macrolides (e.g. erythromycin) can increase plasma concentrations of the progestin.

Effects of Noristerat on other medicinal products

Hormonal contraceptives may affect the metabolism of certain other drugs. Accordingly, plasma and tissue concentrations may be affected (e.g. increased ciclosporin plasma concentrations).

The requirement for oral antidiabetics or insulin can change as a result of the effect on glucose tolerance.

Other forms of interaction

Laboratory tests

The use of contraceptive steroids may influence the results of certain laboratory tests.

Pharmacodynamic interactions

Co-administration of ethinylestradiol-containing medicinal products with direct-acting antiviral (DAA) medicinal products containing ombitasvir, paritaprevir, or dasabuvir, and combinations of these has been shown to be associated with increases in ALT levels to greater than 20 times the upper limit of normal in healthy female subjects and HCV infected women. Since norethisterone is partly metabolised to ethinylestradiol after intramuscular Noristerat administration in humans (see section 5.2) such an interaction cannot be excluded.

Pregnancy

Noristerat is contraindicated in pregnancy.

Like all nortestosterone derivatives used for contraception, Noristerat has slight androgenic activity, and a virilising effect on the external genitalia of a female foetus exposed to Noristerat after the first month of pregnancy cannot be totally ruled out on theoretical grounds. However, no such virilisation has been observed after the few pregnancies that have been reported during the use of Noristerat.

Lactation

There appear to be no adverse effects on infant growth or development when using Noristerat after six weeks postpartum. Noristerat does not appear to affect the quantity or quality of breast milk, however, minute amounts of the active substance are excreted with the milk and although considered harmless to a healthy neonate, might theoretically, like other steroids, impair the degradation of bilirubin, especially during the first week of life. If the mother has received Noristerat, breast-feeding should therefore be withheld from neonates with severe or persistent jaundice requiring medical treatment.

None known.

Undesirable effects that have been reported in users of Noristerat (based on post-marketing data) are:

Administration-related events

Experience has shown that the short-lasting reactions (urge to cough, paroxysmal cough, respiratory distress, dyspnoea and circulatory irregularities) may occur in isolated cases during or immediately after the injection of oily solutions if the solution is injected too rapidly (see Section 4.4).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation 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 the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

In the absence of compatibility studies, this medicinal product should not be mixed with other medicinal products.