Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2018 Publisher: Bayer plc, 400 South Oak Way, Reading, RG2 6AD
Primolut N should not be used in the presence of any of the conditions listed below. Should any of the conditions appear during the use of Primolut N, the use of the product should be stopped immediately.
Primolut N is contraindicated for concomitant use with the medicinal products containing ombitasvir/paritaprevir/ritonavir and dasabuvir (see section 4.4 and 4.5).
A complete personal and family medical history should be taken for 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 which should be adapted to the individual woman and should include measurement of blood pressure, and if judged appropriate by the clinician, breast, abdominal and pelvic examination including cervical cytology.
Therapy should be discontinued immediately if the following occur:
If any of the conditions/risk factors mentioned below is present or deteriorates while using Primolut N, an individual risk-benefit analysis should be done before Primolut N is started or continued.
It has been concluded from epidemiological surveys that the use of oral oestrogen/progestogen containing ovulation inhibitors is associated by an increased incidence of thromboembolic diseases. Therefore, one should keep the possibility of an increased thromboembolic risk in mind, particularly where there is a history of thromboembolic diseases.
A patient who develops symptoms suggestive of thromboembolic complications should stop treatment immediately. The need for treatment should be reassessed before continuing therapy.
Generally recognised risk factors for venous thromboembolism (VTE) include:
Patients with a history of VTE or known thrombophilic states have an increased risk of VTE. The treatment with steroid hormone may add to this risk. Personal or strong family history of thromboembolism or recurrent spontaneous abortion should be investigated in order to exclude a thromboembolic predisposition. Until a thorough evaluation of thrombophilic factors has been made or anticoagulant treatment initiated, use of progestogens in these patients should be viewed as contraindicated. Where a patient is already taking anticoagulants, the risk and benefits of progestogen therapy should be carefully considered.
The risk of VTE may be temporarily increased with prolonged immobilisation, major trauma or major surgery. As in all post-operative patients, scrupulous attention should be given to prophylactic measures to prevent VTE. Where prolonged immobilisation is likely to follow elective surgery, particularly abdominal or orthopaedic surgery to the lower limbs, consideration should be given to stopping progestogen therapy 4-6 weeks pre-operatively. Treatment should not be restarted until the patient is fully remobilised.
There is no consensus about the possible role of varicose veins and superficial thrombophlebitis in venous thromboembolism.
Women with hypertriglyceridemia, or a family history thereof, may be at increased risk of pancreatitis when using COCs.
Women with hyperlipiaedmia are at increased risk of arterial disease (see section 4.4 “Circulatory disorders”). However, routine screening of women on COCs is not appropriate.
In rare cases, benign liver tumours, and even more rarely, malignant liver tumours have been reported in users of hormonal substances such as the one contained in Primolut N. In isolated cases, these tumours have led to life-threatening intra-abdominal haemorrhages. If severe upper abdominal complaints, liver enlargement or signs of intra-abdominal haemorrhage occur, a liver tumour should be included in the differential diagnosis and, if necessary, the preparation should be withdrawn.
Primolut-N can influence carbohydrate metabolism. Parameters of carbohydrate metabolism should be examined carefully in all diabetics before and regularly during treatment.
Chloasma may occasionally occur, especially in women with a history of chloasma gravidarum. Women with a tendency to chloasma should minimise exposure to the sun or ultraviolet radiation when taking Primolut N.
Patients who have a history of depression should be carefully observed and the drug discontinued if the depression recurs to a serious degree.
Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Any patient who develops an acute impairment of vision, proptosis, diplopia or migraine headache should be carefully evaluated ophthalmologically to exclude papilloedema or retinal lesions before continuing medication.
Progestogens may cause fluid retention. Special care should be taken when prescribing norethisterone in patients with conditions which might be aggravated by this factor:
If menstrual bleeding should fail to follow a course of Primolut N, or if the patient wishes to postpone menstruation in special circumstances, the possibility of pregnancy must be excluded before a further course is given.
After oral administration, norethisterone is partly metabolised to ethinylestradiol resulting in an equivalent dose of about 4-6 micrograms ethinylestradiol per 1 milligram of orally administered norethisterone or norethisterone acetate (see section 5.2)
Due to the partial conversion of norethisterone to ethinylestradiol, administration of Primolut N is expected to result in similar pharmacological effects as seen with COCs. Therefore, the following general warnings associated with the use of COCs should also be considered:
Venous thromboembolic events (VTE):
Epidemiological studies have shown that the incidence of venous thromboembolism (VTE) in users of oral contraceptives with low oestrogen content (<50 µg ethinylestradiol) ranges from about 20 to 40 cases per 100,000 women-years, but this risk estimate varies according to the progestogen. This compares with 5 to 10 cases per 100,000 women-years for non-users. The use of any combined oral contraceptive carries an increased risk of VTE compared with no use. This increased risk is less than the risk of VTE associated with pregnancy, which is estimated as 60 cases per 100,000 pregnancies. The excess risk of VTE is highest during the first year a woman initially starts using a COC or when she restarts COC use after a pill-free interval of at least a month.
VTE may be life-threatening or may have a fatal outcome (in 1-2% of the cases).
VTE manifesting as deep venous thrombosis and/or pulmonary embolism, may occur during the use of all COCs.
Extremely rarely, thrombosis has been reported to occur in other blood vessels, e.g. hepatic, mesenteric, renal, cerebral or retinal veins and arteries, in COC users.
Common signs/symptoms of VTE include:
Arterial thromboembolic related conditions:
The use of a combined oral contraceptive may also increase the risk of conditions such as stroke and myocardial infarction which are secondary to arterial thromboembolic events.
Common signs/symptoms associated with arterial thromboembolism include:
Risk Factors for Thromboembolic Events:
Other factors affecting circulatory events:
Other medical conditions which have been associated with adverse circulatory events include:
Biochemical factors that may be indicative of hereditary or acquired predisposition for venous or arterial thrombosis include:
When considering risk/benefit, the physician should take into account that adequate treatment of a condition may reduce the associated risk of thrombosis and that the risk associated with pregnancy is higher than that associated with COC use (<0.05 mg ethinylestradiol).
Cervical Cancer:
The most important risk factor for cervical cancer is persistent HPV infection. Some epidemiological studies have indicated that long-term use of COCs may further contribute to this increased risk but there continues to be controversy about the extent to which this finding is attributable to confounding effects, e.g., cervical screening and sexual behaviour including use of barrier contraceptives.
Breast Cancer:
A meta-analysis from 54 epidemiological studies reported that there is a slightly increased relative risk (RR = 1.24) of having breast cancer diagnosed in women who are currently using COCs. The excess risk gradually disappears during the course of the 10 years after cessation of COC use. Because breast cancer is rare in women under 40 years of age, the excess number of breast cancer diagnoses in current and recent COC users is small in relation to the overall risk of breast cancer. These studies do not provide evidence for causation. The observed pattern of increased risk may be due to an earlier diagnosis of breast cancer in COC users, the biological effects of COCs or a combination of both. The breast cancers diagnosed in ever-users tend to be less advanced clinically than the cancers diagnosed in never-users.
Malignancies may be life-threatening or may have a fatal outcome.
Blood pressure:
Although small increases in blood pressure have been reported in many women taking COCs, clinically relevant increases are rare. However, if a sustained clinically significant hypertension develops during the use of a COC then it is prudent for the physician to withdraw the COC and treat the hypertension. Where considered appropriate, COC use may be resumed if normotensive values can be achieved with antihypertensive therapy.
Conditions which deteriorate in pregnancy or during previous COC use:
The following conditions have been reported to occur or deteriorate with both pregnancy and COC use, but the evidence of an association with COC use is inconclusive:
In women with hereditary angioedema exogenous estrogens may induce or exacerbate symptoms of angioedema.
Acute or chronic disturbances of liver function may necessitate the discontinuation of COC use until markers of liver function return to normal. Recurrence of cholestatic jaundice which occurred first during pregnancy or previous use of sex steroids necessitates the discontinuation of COCs.
Crohn’s disease and ulcerative colitis have been associated with COC use.
During clinical trials with patients treated for hepatitis C virus infections (HCV) with the medicinal products containing ombitasvir/paritaprevir/ritonavir and dasabuvir with or without ribavirin, transaminase (ALT) elevations higher than 5 times the upper limit of normal (ULN) occurred significantly more frequent in women using ethinylestradiol-containing medications such as combined hormonal contraceptives (CHCs). As norethisterone is partly metabolized into ethinylestradiol, this warning applies to women using norethisterone (see sections 4.3 and 4.5).
Note: the prescribing information of concomitant medications should be consulted to identify interactions.
Interactions can occur with drugs that induce microsomal enzymes, which can result in increased clearance of sex hormones and which may lead to changes in the uterine bleeding profile and/or reduction of the therapeutic effect.
Enzyme induction can already be observed after a few days of treatment. Maximal enzyme induction is generally seen within a few weeks. After the cessation of drug therapy enzyme induction may be sustained for about 4 weeks.
Substances increasing the clearance of sex hormones (diminished efficacy by enzyme-induction), e.g.: Phenytoin, barbiturates, bosentan, primidone, carbamazepine, rifampicin and HIV medication ritonavir, nevirapine and efavirenz, and possibly also oxcarbazepine, topiramate, felbamate, griseofulvin and products containing St. John’s wort (Hypericum perforatum).
Substances with variable effects on the clearance of sex hormones, e.g.: When co-administered with sex hormones, many HIV/HCV protease inhibitors and non-nucleoside reverse transcriptase inhibitors can increase or decrease plasma concentrations of estrogen or progestin. These changes may be clinically relevant in some cases.
Substances decreasing the clearance of sex hormones (enzyme inhibitors): The clinical relevance of potential interactions with enzyme inhibitors remains unknown.
Strong and moderate CYP3A4 inhibitors such as azole antifungals (e.g. itraconazole, voriconazole, fluconazole), verapamil, macrolides (e.g. clarithromycin, erythromycin), diltiazem and grapefruit juice can increase plasma concentrations of the estrogen or the progestin or both.
Etoricoxib doses of 60 to 120 mg/day have been shown to increase plasma concentrations of ethinylestradiol 1.4 to 1.6-fold, respectively when taken concomitantly with a combined hormonal medicinal product containing 0.035 mg ethinylestradiol.
Progestogens may interfere with the metabolism of other drugs. Accordingly, plasma and tissue concentrations may either increase (e.g. ciclosporin) or decrease (e.g. lamotrigine).
Clinical data suggest that ethinylestradiol inhibits the clearance of CYP1A2 substrates, leading to a weak (e.g. theophylline) or moderate (e.g. tizanidine) increase in plasma concentration.
Concomitant use with the medicinal products containing ombitasvir/paritaprevir/ritonavir and dasabuvir, with or without ribavirin may increase the risk of ALT elevations (see sections 4.3 and 4.4). Primolut N can be restarted 2 weeks following completion of treatment with this combination drug regimen.
The use of progestogens may influence the results of certain laboratory tests (e.g. tests for hepatic function, thyroid function and coagulation).
The administration of Primolut N during pregnancy is contraindicated.
Primolut N can pass into breast milk and therefore should be avoided during lactation.
None known.
Undesirable effects are more common during the first months after start of intake of Primolut preparations, and subside with duration of treatment. The frequencies are based on reporting rates from postmarketing experience and literature.
Very common (≥1/10)
Common (≥1/100 to <1/10)
Uncommon (≥1/1,000 to <1/100)
Rare (≥1/10,000 to <1/1000)
Very rare (<1/10,000)
Frequency (not known)
Rare: Hypersensitivity reactions
Common: Headache
Uncommon: Migraine
Νot known: Dizziness
Νot known: Depression aggravated
η3. Eye disorders
Very rare: Visual disturbances
Very rare: Dyspnoea
Common: Nausea
Νot known: Abdominal pain
Νot known: Cholestasis, Jaundice
Rare: Urticaria, Rash
Very common: Uterine/Vaginal bleeding including Spotting*, Hypomenorrhoea*
Common: Amenorrhoea*
Common: Oedema
* in the indication Endometriosis
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.
Not known.
© All content on this website, including data entry, data processing, decision support tools, "RxReasoner" logo and graphics, is the intellectual property of RxReasoner and is protected by copyright laws. Unauthorized reproduction or distribution of any part of this content without explicit written permission from RxReasoner is strictly prohibited. Any third-party content used on this site is acknowledged and utilized under fair use principles.
