Noristerat^® 200mg, solution for intramuscular injection.

1ml Noristerat contains 200mg norethisterone enantate in oily solution.

For a list of excipients see Section 6.1.

Solution for Injection

Noristerat is a depot contraceptive. It is intended for short-term use when a high level of efficacy independent of possible errors by the patient is required. It has been licensed for short-term use by women whose partners undergo vasectomy, until the vasectomy is effective, and women immunised against rubella, to prevent pregnancy during the period of activity of the virus.

Use after delivery or abortion: Noristerat can generally be used immediately after delivery or abortion (but see following 'Use during lactation').

Use during lactation: Noristerat has not been reported to inhibit milk production, which is an advantage when the mother wishes to breast-feed. However, traces of the hormone appear in 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.

200 mg Noristerat intramuscularly provides contraception for eight weeks. The first injection should be given within the first five days of a menstrual cycle (the first day of menstruation counting as day 1), unless it is given so soon after delivery or abortion that no possibility of pregnancy exists. Provided the injection is carried out according to these instructions, no additional contraceptive cover is required. The injection may be repeated once, after eight weeks. Noristerat must always be injected deep into the gluteal muscles, care being taken that no liquid runs back from the injection site, which could result in loss of efficacy. The viscosity of the liquid at low temperatures is high, necessitating considerable pressure of injection. Therefore it is suggested that the ampoule be immersed in warm water before injection. A needle of at least medium bore should be used, and care taken to ensure that the needle is securely attached to the syringe.

- Pregnancy.

- Acute and severe chronic liver disease.

- History, during pregnancy, of idiopathic jaundice or general pruritus or of herpes gestationis

- History of deterioration of otosclerosis during pregnancy.

- Dubin-Johnson and Rotor syndromes.

- Sickle-cell anaemia.

- Severe diabetes with vascular changes.

Previous or existing liver tumours.

- Pathologically increased blood pressure.

- Twelve weeks before planned operations and during immobilisation (eg: after accidents.)

- Current thromboembolic disease.

- Disturbances of lipid metabolism.

- Existing or treated breast or endometrial cancer.

- Hypersensitivity to any of the components of Noristerat.

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.

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, during treatment, migrainous headaches occur for the first time or recurrent unusually severe headaches develop, if sudden perceptual disorders occur, if first signs of thrombophlebitis or thromboembolic disease are noted, or if a feeling of pain and tightness in the chest, a significant rise in blood pressure, recurrence of earlier depression or pathological changes of liver function and hormone levels are experienced.

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

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.

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.

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 occurred during the use of Noristerat.

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.

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.

Precautions: Examination of the pelvic organs, breasts and blood pressure should precede the prescribing of Noristerat. Before starting treatment, pregnancy must be excluded.

Women with a history of severe depressive states, porphyria, disturbed liver function or any disease that is prone to worsen during pregnancy should be carefully observed during medication.

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.

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.

Some drugs may accelerate the metabolism of Noristerat. Drugs suspected of having this capacity, which may reduce the efficacy of the preparation, include barbiturates, carbamazepine, phenytoin, phenylbutazone, griseofulvin and rifampicin. Reduced substance levels have been observed during the simultaneous use of certain antibiotics (e.g. ampicillin), possibly due to changes in the intestinal flora. The requirement for oral antidiabetics or insulin can change as a result of the effect on glucose tolerance.

Noristerat is contraindicated in pregnancy.

Noristerat has not been reported to inhibit milk production, which is an advantage when the mother wishes to breast feed. However, traces of the hormone appear in 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.

Subjective symptoms reported consist mainly of bloating, breast discomfort, headaches, dizziness, depressive moods and transient nausea. Marked increases of weight are rare.

Injection site reactions, local skin reactions, various skin disorders and hypersensitivity reactions may occur.

The patient should be informed before starting Noristerat that her menstrual pattern is likely to alter. Menstrual changes in the form of spotting, breakthrough bleeding and delayed menstruation are relatively frequent, and generally do not require treatment. With persistent bleeding however, it may be expedient to administer progestogen/ oestrogen tablets e.g. combined oral contraceptives, for 10 days to create a withdrawal bleed 1-4 days later.

Acute toxicity studies indicated that even in the case of inadvertent administration of a multiple of the contraceptive dose, no acute toxicity risk is to be expected.

Noristerat is a depot contraceptive. The mode of action, following injection, is initially inhibition of ovulation.

Towards the end of the injection interval, the action is mainly local on the cervical mucus and endometrium. These latter effects prevent ascension of sperm into the uterine cavity and impede nidation.

Norethisterone enantate was completely absorbed after intramuscular injection. The ester was quickly and eventually completely hydrolyzed to its pharmacologically active compound norethisterone once it was released from the depot.

Maximum levels of norethisterone were measured about 3-20 days after i.m. administration. They amounted on average to 13.4 ± 5.4 ng/ml and 12.2 ± 2.7 ng/ml about 7 days (median) after i.m. administration of 200 mg norethisterone enantate in 2 ml and 1 ml oily solution, respectively.

Plasma levels of norethisterone declined in two disposition phases with half-lives of 4-5 days and 15-20 days, respectively, which were due to a biphasical release of norethisterone enantate from the depot.

Norethisterone enantate is metabolized completely. Norethisterone enantate is split mainly in the liver by enzymatic hydrolysis into norethisterone and heptanoic acid.

While the fatty acid is metabolized by means of (β-oxidation, norethisterone is transformed mainly through the reduction of the C₄ -C₅ double bond and the C₃ keto group. The majority of metabolites found in urine were present as conjugates, mainly as sulfates, which are expected to be inactive. Qualitative transformation of norethisterone to ethinyloestradiol in vivo has been reported, but the contribution of this metabolic pathway to the pharmacological action of norethisterone is still unknown.

Up to 85% of the norethisterone enantate dose were excreted within 30 days in urine (40%) and faeces (60%). No unchanged norethisterone enantate was recovered in urine or faeces. In urine and faeces, similar excretion half-lives of 6 - 9 days were estimated for radioactive labelled substances during the observation period of 30 days and - in a further study - an excretion half-life of 20 - 30 days was measured in urine between day 30 and 80 after i.m. administration of 200 mg ³H-norethisteteroneenantate. Based on animal studies, retention of the drug in the body is not to be expected.

In plasma of women, 96% of norethisterone are bound to proteins. The respective percentages bound to SHBG and albumin are approximately 35% and 61% as long as SHBG levels are within the normal range.

Due to the half-life of the terminal disposition phase from plasma (about 2.5 weeks) and the initial dose regimen (one injection every 2 months), a slight accumulation of the drug will be expected after multiple administrations. A steady state will already be reached after the second administration.

Transfer of norethisterone into mother's milk was negligible. During the first week after i.m. injection of 200 mg norethisterone enantate, a daily intake of norethisterone with mother's milk in the range of 0.5 μg to 2.4 μg was calculated from norethisterone concentrates in the milk, assuming that the infant ingests 600 ml milk daily.

Although there is no direct investigation on bioavailability of norethisterone after i.m. administration of norethisterone enantate reported, complete availability can be estimated by comparison of norethisterone AUC values determined in different studies after i.v. injection of norethisterone and after i.m. injection of norethisteroneenantate.

Besides the studies with the active ingredient norethisterone enantate, data recorded for norethisterone and norethisterone acetate were also taken into consideration for the toxicological evaluation of the risk from use of Noristerat.

In animal studies on systemic tolerance with repeated administration (including studies for evaluation of a tumorigenic activity), no systemic intolerance reactions were observed which would raise objections to the use of the preparation in dosages required for contraception.

On principle, however, it should be kept in mind that sex steroids might stimulate the growth of hormone-dependent tissues and tumours.

In reproduction toxicological studies no indication of a teratogenic potential was noted. This is in accordance with reports on clinical experience after accidental administration of Noristerat during pregnancy or on the rare cases of pregnancies occurring during use of Noristerat, where no indication of a teratogenic potential was noted.

Local tolerance was assessed in the course of systemic tolerance studies and indicated only a mild irritant potential of the drug substance. The good local tolerance has been confirmed by long-term clinical experience.

Experimental investigations into possible sensitising effects of norethisterone enantate have not been carried out.

In vitro studies for evaluation of genotoxicity did not indicate that norethisterone or its esters possess a mutagenic potential.

Castor oil for injection

Benzyl benzoate

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

5 years.

Store below 25°C.

Protect from light.

Carton containing one 1ml glass ampoule.

Keep out of the reach of children.

Bayer plc

Bayer House

Strawberry Hill

Newbury

Berkshire RG14 1JA

PL 00010/0548

23 February 2009

11 April 2012