PRIMOLUT NOR - PACKAGE LEAFLET - LEAFLETS

Home / leaflets / 2021

Primolut Nor - Package Leaflet

Indications Contraindications Precautions for use Interactions Warnings Dosage and method of use Overdose Undesirable Effects Shelf life and Storage Composition and pharmaceutical form

Active ingredients: Norethisterone (norethisterone acetate)

Primolut Nor 10 mg tablets

Why is Primolut Nor used? What is it for?

Primolut Nor contains norethisterone acetate, which belongs to the progestogen group, a group of products similar to the natural female hormone progesterone.

This medicine is used to treat:

functional metrorrhagia (loss of blood from the uterus, outside the menstrual periods) and prophylaxis of relapses (ie the recurrence of this disorder after it has been treated with therapy);
primary amenorrhea (total absence of the menstrual cycle) and secondary (cessation of the menstrual cycle);
premenstrual syndrome (symptoms that anticipate the onset of the menstrual cycle);
endometriosis (presence of uterine mucosa in abnormal locations);
polymenorrhea (shorter than normal interval between menstruation).

Contraindications When Primolut Nor should not be used

Do not take Primolut Nor

if you are allergic to norethisterone acetate or any of the other ingredients of this medicine (listed in section 6);
if you are pregnant or if you suspect a pregnancy;
if you are breastfeeding;
if you have suffered from severe liver function impairment and your liver function is still abnormal. Symptoms of liver disease may include, for example, yellowing of the skin and / or itching all over the body.
if you have or have suffered in the past from liver tumors (benign or malignant);
if you have or have suffered in the past from blood clots in a vein or artery (thrombosis), deep vein (deep vein thrombosis), blood vessel in the lung (pulmonary embolism), myocardial infarction or cerebrovascular accident (stroke caused by a blood clot or rupture of a blood vessel in the brain);
if you have a disease that may be a sign of a future heart attack (for example angina pectoris which causes severe pain in the chest and can radiate to the left arm) or a stroke (for example a minor stroke with no residual consequences, a so-called transient ischemic attack);
if you have some form of migraine with so-called focal neurological symptoms such as poor vision, difficulty speaking, weakness or numbness in any part of the body;
if you have severe or multiple risk factors for developing blood clots (arterial venous thrombosis) (see "Warnings and precautions");
if you have diabetes with damage to the blood vessels;
if you have known or suspected sex hormone-dependent cancers (e.g. breast or genital organ cancer).

If any of the above conditions appear for the first time while using Primolut Nor, stop the treatment immediately and consult your doctor.

Precautions for use What you need to know before you take Primolut Nor

Talk to your doctor or pharmacist before taking Primolut Nor.

Before starting or resuming treatment with Primolut Nor, your doctor will give you a thorough general and gynecological examination, including breast, abdomen and Papanicolau smears (Pap smears), and blood pressure checks. In addition, an ongoing pregnancy must be ruled out. As a precaution, the doctor will decide which checks to perform and how often.

The progestin contained in this medicine is partially converted into estrogen. Consequently, the general warnings associated with the use of combined oral contraceptives containing estrogen / progestogen should be further considered for Primolut Nor.

In some situations you need to be especially careful while using Primolut Nor, and your doctor may need to see you regularly. You should consult your doctor before you start using Primolut Nor, if any of the following apply to you or if any of these conditions develop or worsen while using Primolut Nor:

if you smoke;
if you have diabetes;
if you are overweight;
if you have high blood pressure;
if you have heart problems (valve disorders, heart rhythm disorder);
if you have a history of thrombosis / thromboembolism (blood clot);
if you have a family history of thrombosis (thromboembolism in a brother / sister or parent at a relatively young age), heart attack or stroke at a young age;
if you have inflammation of the veins (superficial phlebitis);
if you have varicose veins;
if you have any family history of breast cancer;
if you have a history of chloasma (yellow-brown patches on the skin, especially on the face); if so, avoid too much exposure to the sun or ultraviolet rays;
if you have a history of depression; if the depression recurs in severe form, stop taking Primolut Nor;
if you suffer from migraines;
if you have epilepsy (see "Other medicines and Primolut Nor");
if you have high levels of cholesterol or triglycerides (fatty substances in the blood);
if you have liver or gallbladder disease (jaundice and / or itching due to cholestasis; biliary stone formation);
if you have Crohn's disease or ulcerative colitis (inflammatory bowel disease);
if you suffer from systemic lupus erythematosus (SLE, a disease of the immune system);
if you suffer from haemolytic uremic syndrome (HUS, a disease which causes damage to the kidneys);
if you have sickle cell anemia;
if you have a disease that first appeared during pregnancy or a previous use of sex steroids (for example, hearing loss from otosclerosis, a blood disorder called porphyria, a rash called herpes gravidarum, a nerve disease called chorea by Sydenham);
if you have hereditary angioedema. If you experience symptoms of angioedema such as swelling of the face, tongue and / or pharynx and / or difficulty in swallowing or hives with difficulty in breathing, contact your doctor immediately. Medicines containing estrogen can cause or worsen the symptoms of angioedema.

If any of the above conditions appear for the first time, come back or worsen while using Primolut Nor, contact your doctor.

Primolut Nor and venous and arterial blood clots (thrombosis)

The progestogen contained in this medicinal product is partially converted into estrogen, therefore assimilable to a progestogen / estrogen combination. Consequently, the general warnings associated with the use of combined oral contraceptives apply to Primolut Nor.

The use of Primolut Nor, as with COCs, is associated with an increased risk of venous thromboembolism (VTE) when compared with non-use. This increased risk is however lower than the risk of VTE associated with pregnancy.

VTE can be life-threatening or can be fatal

Venous thromboembolism (VTE) manifesting as deep vein thrombosis and / or pulmonary embolism can occur while using all COCs.

Very rarely, thrombosis of other vascular districts, eg hepatic, mesenteric, cerebral, renal or retinal artery or vein, has been reported in COC users. There is no consensus that the occurrence of these events is associated with the use of combined oral contraceptives.

Symptoms of venous or arterial thrombotic / thromboembolic events or of a cerebrovascular accident may include:

unusual unilateral pain and / or swelling in one leg;
severe and sudden chest pain, regardless of irradiation to the left arm;
sudden difficulty in breathing;
sudden onset of cough;
unusual, severe and prolonged headache;
sudden partial or complete loss of vision;
double vision;
indistinct speech or aphasia;
dizziness;
collapse with or without focal seizures (the seizure begins in a certain part of the brain);
sudden weakness or very marked numbness of one side or part of the body;
motor disturbances;
"acute" abdomen (severe abdominal pathological condition).

The possibility of an increased synergistic risk of thrombosis should be considered in women with a combination of risk factors or who show greater severity of a single risk factor. This increased risk may be greater than a simple cumulative factor risk. In case of a negative benefit / risk assessment, a COC should not be prescribed (see section "Do not take Primolut Nor").

The risk of venous or arterial thrombotic / thromboembolic events or cerebrovascular accidents increases with:

the age;
l "obesity (body mass index over 30 kg / m2);
positive family history (arterial or venous thromboembolism in a brother / sister or parent at a relatively young age);
prolonged immobilization, major surgery, any leg operation or severe trauma;
smoking (the risk increases further for heavy smokers and with increasing age, especially for women over the age of 35;
dyslipoproteinemia (high level of lipids in the blood);
hypertension (high blood pressure);
migraine;
valvulopathy (heart valve disease);
atrial fibrillation (altered heart rhythm).

Tell your doctor if any of the above apply to you.

There is no consensus on the possible role of varicose veins and superficial thrombophlebitis in venous thromboembolism.

Other medical conditions that have been associated with adverse vascular events include:

diabetes mellitus;
systemic lupus erythematosus (disease of the immune system);
haemolytic uremic syndrome (HUS), which causes damage to the kidneys;
chronic inflammatory bowel disease (Crohn's disease or ulcerative colitis);
sickle cell disease (sickle cell anemia).

If there is an increase in the frequency and severity of migraine (which may be prodromal of a cerebrovascular event), you should see your doctor immediately.

If your blood tests have shown that you have resistance to Activated Protein C, hyperhomocysteinemia (excessive homocysteine concentration in the blood), antithrombin III deficiency, protein C deficiency, protein S deficiency or antiphospholipid antibodies (anticardiolipin antibodies, lupus anticoagulant) , may have hereditary or acquired predisposition to venous or arterial thrombosis.

See your doctor as soon as possible if:

notice any changes in your health, especially in the situations described in the sections "Do not take Primolut Nor" and "Warnings and precautions";
you feel a lump in your breast;
use other medicines (see "Other medicines and Primolut Nor");
have unusual vaginal bleeding.

Stop treatment immediately in case of:

first-time onset or exacerbation of migraines or an increase in the frequency of headaches of unusual intensity;
sudden disturbances in vision or hearing or other disturbances in perception;
early symptoms of thrombophlebitis or thromboembolism, eg. unusual pain or swelling in the legs, stabbing pains when breathing, or coughing with no apparent cause;
feeling of pain and tightness in the chest;
surgery and state of immobilization: six weeks before surgery and for the entire duration of a state of immobilization, such as in the case of accidents;
onset of jaundice, hepatitis, generalized itching;
noticeable increase in blood pressure;
pregnancy.

In case of abnormal endocrine and liver function tests, stop treatment and repeat the tests after approximately 2 months.

Primolut Nor and cancer

Breast cancer occurs slightly more often in women using the combined pill, but it is not known whether this is due to the treatment. For example, women on the Pill may be diagnosed with more cancers because they undergo more frequent medical checks. The risk of developing breast cancer gradually decreases after stopping combined hormonal contraception. It is important that you regularly check your breasts and contact your doctor if you feel any lumps.

Rare cases of benign liver tumors and, even more rarely, malignant liver tumors have been observed in women taking hormonal substances. These tumors can cause internal bleeding.

The most important risk factor for cervical cancer is human papillomavirus (HPV) infection. Some studies suggest an increased risk of cervical cancer in long-term contraceptive users, but the extent to which the sexual behavior or other factors such as human papilloma virus increase this risk.

Malignant tumors can be life-threatening or can be fatal.

Contact your doctor immediately if you experience severe pain in your abdomen.

Interactions Which drugs or foods can modify the effect of Primolut Nor

Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines.

Some medicines may decrease the effectiveness of Primolut Nor. These include medicines that increase the metabolism of Primolut Nor, such as:

medicines used to treat epilepsy (primidone, phenytoin, barbiturates, carbamazepine, oxcarbazepine),
medicines used to treat tuberculosis (rifampicin, rifabutin),
antibiotics against fungal infections (griseofulvin),
l "St. John's wort (Hypericum perforatum, used mainly for the treatment of depressive states).

Primolut Nor can interfere with the way some other medicines work, for example medicines containing cyclosporine (mainly used to prevent organ transplant rejection).

Warnings It is important to know that:

Laboratory tests

The use of Primoluto Nor can affect the results of some laboratory tests. Tell your doctor if you need to have a blood or urine test.

Pregnancy and breastfeeding

If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before taking this medicine.

Do not take Primolut Nor if you are pregnant, if you think you may be pregnant, or if you are breast-feeding.

Driving and using machines

Primolut Nor does not affect the ability to drive or use machines.

Primolut Nor contains lactose

If you have been told by your doctor that you have "intolerance to some sugars, contact your doctor before taking this medicinal product.

Dose, Method and Time of Administration How to use Primolut Nor: Posology

How to take Primolut Nor

Always take this medicine exactly as your doctor or pharmacist has told you. If in doubt, consult your doctor or pharmacist.

Dose, method and time of administration

The tablets should be swallowed with some liquid.

The effectiveness of Primolut Nor may be reduced if not all tablets are taken according to the instructions.

Non-hormonal methods (excluding the rhythm method and the basal temperature method) should be used as contraceptive measures. If, during treatment, withdrawal bleeding does not occur at regular intervals of approximately 28 days, the possibility of pregnancy should be considered, despite the adoption of contraceptive measures. In this case, stop the treatment immediately until that this has not been ruled out.

The recommended treatment regimens are:

Functional Metrorrhagia

By taking half a Primolut Nor tablet (= 5 mg) three times a day for 10 days, uterine bleeding not associated with organic lesions is achieved in most cases within 1-3 days; however, Primolut Nor should be taken regularly for the entire 10-day period to ensure the full success of the treatment. Approximately 2-4 days after the end of the treatment, withdrawal bleeding occurs corresponding, in quantity and duration, to a normal menstrual flow .

Slight bleeding while taking the tablets

Occasionally, slight bleeding may occur after the initial bleeding has stopped. Even in these cases, you should not interrupt or stop taking the tablets.

Failure to stop bleeding, heavy breakthrough bleeding

If, despite taking the tablets regularly, the bleeding does not stop, one must think of an organic cause or an extra-genital factor which generally requires other therapeutic measures. "haemorrhage, rather intense haemorrhages reappear while taking the tablets.

Prophylaxis of relapses

To prevent relapses (i.e. the recurrence of this disorder after it has been treated with therapy) in patients with anovulatory cycles Primolut Nor can be administered for prophylactic purposes (1/2 tablet - 5 mg - 1-2 times a day from 16 To the 25th day of the cycle [1st day of the cycle = 1st day of the last menstruation]).

The withdrawal bleeding will appear a few days after taking the last tablet.

Primary and secondary amenorrhea

Hormonal treatment of secondary amenorrhea should only be started after pregnancy has been ruled out.

Sometimes, primary or secondary amenorrhea is caused by a prolactinoma (a benign tumor of the pituitary gland that results in "increased production of the hormone" prolactin), the presence of which must be ruled out by your doctor before starting treatment with Primolut Nor, because it may increase in size.

Before starting treatment with Primolut Nor, your doctor will prescribe you an estrogen (for example for 14 days). You will then take half a tablet of Primolut Nor 10 mg (= 5 mg) 1-2 times a day for 10 days. suspension will appear a few days after taking the last tablet.

If sufficient endogenous estrogen production has been obtained, the doctor will consider whether to discontinue estrogen treatment and to induce "cyclical bleeding by taking half a tablet of Primolut Nor 10 mg twice a day from the 16th to the 25th day of the cycle.

Premenstrual syndrome

Half a tablet of Primolut Nor 10 mg taken 1-3 times a day during the luteal phase of the cycle (ie the second part of the cycle from "ovulation to" the beginning of the next menstruation) can relieve or improve premenstrual symptoms such as headache, mood depressed, water retention and a feeling of tightness in the breasts.

Polymenorrhea

In the case of too frequent menstrual flows, menstruation can be postponed by administering Primolut Nor. However, this method should be limited to patients who are not at risk of becoming pregnant during the course of treatment.

Dose: one half tablet of Primolut Nor 10 mg (= 5 mg) 2-3 times a day for no more than 10-14 days, starting approximately 3 days before the expected date of menstruation. Menstruation will occur 2-3 days after stopping treatment.

Endometriosis

Treatment should begin between the 1st and 5th day of the cycle with half a tablet of Primolut Nor 10 mg (= 5 mg) twice a day, possibly increasing the dose to one tablet a day in the presence of spotting, after which you can return to the initial dosage. Treatment should continue for at least 4-6 months. If you take the medicine without interruption every day, you will normally fail both ovulation and menstruation.

Overdose What to do if you have taken too much Primolut Nor

If you take more Primolut Nor than you should

No cases of overdose have been reported.

If you accidentally take too much Primolut Nor, tell your doctor immediately or go to the nearest hospital.

If you forget to take Promolut Nor

Take only the last forgotten tablet as soon as you remember and then continue taking your tablets at the usual time the next day.

Side Effects What are the side effects of Primolut Nor

Like all medicines, this medicine can cause side effects, although not everybody gets them. Side effects are most common during the first few months of taking Primolut Nor and tend to go away with continued treatment.

Very common side effects (may affect more than 1 in 10 users) Uterine / vaginal bleeding, including small intermenstrual bleeding (spotting) *, hypomenorrhea (decreased menstrual flow) *.
Common side effects (may affect up to 1 in 10 users) Headache, nausea, amenorrhea * (lack of menstruation), generalized swelling (edema).
Uncommon side effects (may affect up to 1 in 100 users) Migraine.
Rare side effects (may affect up to 1 in 1,000 users) Hypersensitivity reactions, hives, rash.
Very rare side effects (may affect up to 1 in 10,000 users) Visual disturbances, dyspnoea (difficulty in breathing).

* in the indication Endometriosis.

Other reported secondary reactions are:

changes in libido,
dizziness,
phenomena of nervous irritation,
hirsutism (excessive hair growth),
changes in liver function tests and haemagglutination tests.

Compliance with the instructions contained in the package leaflet reduces the risk of undesirable effects.

Reporting of side effects

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system at https://www.aifa.gov.it/content/segnalazioni-reazioni-avverse. By reporting side effects you can help provide more information on safety. of this medicine.

Expiry and Retention

This medicine does not require any special storage conditions. Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date which is stated on the package after EXP.

The expiry date refers to the last day of that month.

Do not throw any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. This will help protect the environment.

Composition and pharmaceutical form

What Primolut Nor contains

The active ingredient is: norethisterone acetate. 1 tablet contains 10 mg of norethisterone acetate.
The other ingredients are: lactose monohydrate, corn starch, povidone 25, talc, magnesium stearate.

What Primolut Nor looks like and contents of the pack

30 tablets of 10 mg in blister packs.

Source Package Leaflet: AIFA (Italian Medicines Agency). Content published in January 2016. The information present may not be up-to-date.
To have access to the most up-to-date version, it is advisable to access the AIFA (Italian Medicines Agency) website. Disclaimer and useful information.

Further information on Primolut Nor can be found in the "Summary of Characteristics" tab. 01.0 NAME OF THE MEDICINAL PRODUCT 02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION 03.0 PHARMACEUTICAL FORM 04.0 CLINICAL PARTICULARS 04.1 Therapeutic indications 04.2 Posology and method of administration 04.3 Contraindications 04.4 Special warnings and appropriate precautions for use 04.5 Interactions with other medicinal products and other forms of interaction 04.6 Pregnancy and lactation 04.7 Effects on ability to drive and use machines 04.8 Undesirable effects 04.9 Overdose 05.0 PHARMACOLOGICAL PROPERTIES 05.1 Pharmacodynamic properties 05.2 Pharmacokinetic properties 05.3 Preclinical safety data 06.0 PHARMACEUTICAL PARTICULARS 06.1 Excipients 06.2 Incompatibilities 06.3 Shelf life 06.4 Special precautions for storage 06.5 Nature of the primary packaging and contents of the package 06.6 Instructions for use and handling 07.0 MARKETING AUTHORIZATION HOLDER 08.0 MARKETING AUTHORIZATION NUMBER CIO 09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION 10.0 DATE OF REVISION OF THE TEXT 11.0 FOR RADIO DRUGS, FULL DATA ON INTERNAL RADIATION DOSIMETRY 12.0 FOR RADIO DRUGS, FURTHER DETAILED INSTRUCTIONS ON PREPARATION AND QUALITY CONTROL

01.0 NAME OF THE MEDICINAL PRODUCT

PRIMOLUT NOR 10 MG TABLETS

02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION

One tablet contains:

Active ingredient: norethisterone acetate 10 mg.

Excipients: lactose 62.375 mg

For the full list of excipients, see section 6.1.

03.0 PHARMACEUTICAL FORM

Tablets

04.0 CLINICAL INFORMATION

04.1 Therapeutic indications

Functional bleeding and prophylaxis of relapses.

Primary and secondary amenorrhea.

Premenstrual syndrome.

Endometriosis.

Polymenorrhea.

04.2 Posology and method of administration

The tablets should be swallowed with some liquid.

The effectiveness of Primolut Nor may be reduced if not all tablets are taken according to the instructions. The woman should only take the last missed tablet as soon as she remembers and then continue taking the tablets at the usual time the next day.

If contraceptive protection is required, it is also recommended to use non-hormonal (barrier) methods of contraception.

• Functional Metrorrhagia

By taking half a tablet of Primolut Nor (= 5 mg) three times a day for 10 days, in most cases, the arrest of uterine bleeding not associated with organic lesions is achieved within 1-3 days; however, Primolut Nor should be taken regularly for the entire 10 day period to ensure the full success of the treatment.

Approximately 2-4 days after the end of treatment, a withdrawal bleeding occurs corresponding, in quantity and duration, to a normal menstrual flow.

Slight bleeding while taking the tablets

Occasionally, slight bleeding may occur after the initial bleeding has stopped. Even in these cases, tablet-taking must not be interrupted or discontinued.

Failure to stop bleeding, heavy breakthrough bleeding

If, despite the regular intake of the tablets, the bleeding does not stop, an organic cause or an extra-genital factor must be considered (for example polyps, carcinoma of the cervix or endometrium, myomas, abortion residues, extra-uterine pregnancy, or bleeding disorders), which typically requires other therapeutic measures. The same applies in the case that, after an initial stop of the bleeding, rather intense bleeding occurs again while taking the tablets.

Prophylaxis of relapses

To prevent relapse in patients with anovulatory cycles Primolut Nor can be administered for prophylactic purposes (1/2 tablet - 5 mg - 1-2 times a day from the 16th to the 25th day of the cycle (1st day of the cycle = 1st day of last menstruation)). The withdrawal bleeding will appear a few days after taking the last tablet.

• Primary and secondary amenorrhea

Hormonal treatment of secondary amenorrhea should only be started after excluding pregnancy.

Before starting the treatment of primary or secondary amenorrhea, the presence of a prolactin-secreting pituitary tumor must be ruled out, as it is possible that any macroadenomas exposed to high doses of estrogen for prolonged periods of time may increase in size.

Before starting treatment with Primolut Nor, a pre-treatment of the endometrium with an estrogen must be performed (for example for 14 days). Then you will take half a tablet of Primolut Nor 10 mg (= 5 mg) 1-2 times a day for 10 days. Withdrawal bleeding will appear a few days after taking the last tablet.

In patients in whom sufficient endogenous estrogen production has been obtained, an attempt can be made to suspend estrogen treatment and induce "cyclical bleeding by administering half a tablet of Primolut Nor 10 mg twice a day from the 16th to the 25th day of the day. cycle.

• Premenstrual syndrome

Half a tablet of Primolut Nor 10 mg 1-3 times a day during the luteal phase of the cycle can relieve or improve premenstrual symptoms such as headache, depressed mood, water retention and a feeling of breast tenderness.

• Polymenorrhea

Dosage: one half tablet of Primolut Nor 10 mg (= 5 mg) 2-3 times a day for no more than 10-14 days, starting approximately 3 days before the expected date of menstruation. Menstruation will occur 2-3 days after stopping treatment.

• Endometriosis

Treatment should begin between the 1st and 5th day of the cycle with half a tablet of Primolut Nor 10 mg (= 5 mg) twice a day, possibly increasing the dose to one tablet a day in the presence of spotting, after which it will be possible to return to the initial posology. Treatment should continue for at least 4-6 months. If you take the drug every day without interruption, you will normally miss both ovulation and menstruation. At the end of the hormonal treatment, a withdrawal bleeding will occur.

04.3 Contraindications

Primolut Nor should not be used in the presence of the conditions listed below, which are also derived from information on progestogen-only products and combined oral contraceptives (COCs). The appearance of any of these conditions while using Primolut Nor requires immediate discontinuation of treatment.

• hypersensitivity to the active substance or to any of the excipients listed in section 6.1

• known or presumed pregnancy

• feeding time

• venous or arterial thrombosis / current or previous thromboembolic events (for example deep vein thrombosis, pulmonary embolism, myocardial infarction) or cerebrovascular accidents

• current or previous prodrome of a thrombosis (for example, transient ischemic attack, angina pectoris)

• serious risk factor for venous or arterial thrombosis (see section "Special warnings and precautions for use")

• history of migraine accompanied by focal neurological symptoms

• diabetes mellitus with vascular involvement

• current or previous severe liver disease, until the liver function indices return to normal

• existing or previous liver tumors (benign or malignant)

• Known or suspected sex hormone dependent malignant tumors

04.4 Special warnings and appropriate precautions for use

If any of the conditions / risk factors mentioned below present or worsen, an individual benefit / risk analysis should be performed before starting or continuing treatment with Primolut Nor.

• Circulatory disorders

From the results of the epidemiological studies it was concluded that the use of ovulation inhibitors containing estrogen / progestogens is associated with an increased incidence of thromboembolic diseases. Therefore, the possibility of an increased thromboembolic risk should be taken into account, particularly in the presence of thromboembolic pathologies in the anamnesis.

Generally recognized risk factors for venous thromboembolism (VTE) include a "positive personal or family history (presence of VTE in a sibling or parent at a relatively early age), age, obesity, prolonged immobilization, major or major trauma.

The increased risk of thromboembolism present during the puerperium should be considered.

Treatment should be stopped immediately if symptoms of arterial or venous thrombosis occur or if such conditions are suspected.

• Tumors

Benign liver tumors and, even more rarely, malignant liver tumors have been reported rarely in women taking hormonal substances, such as that contained in Primolut Nor. In isolated cases, these tumors have resulted in life-threatening intra-abdominal haemorrhages.

If a woman taking Primolut Nor presents with severe upper abdominal pain, liver enlargement or signs of intra-abdominal haemorrhage, liver cancer should be considered in the differential diagnosis.

• Other conditions

In diabetic subjects, special attention from the doctor is required.

Occasionally chloasma may appear, particularly in women with a history of chloasma gravidarum. Women with a tendency to chloasma should avoid exposure to the sun or ultraviolet rays while using Primolut Nor.

It is recommended that patients with a history of psychological depression be carefully monitored, stopping the administration of the drug if the depression recurs in a severe form.

• Medical examination

Before initiating or resuming use of Primolut Nor, a complete medical history and physical and gynecological examination should be taken, taking into account the contraindications (see section 4.3) and warnings (see section 4.4), to be repeated periodically during the treatment. The frequency and type of checks must be adapted to the individual patient, but should generally pay particular attention to blood pressure, breast, abdomen and pelvic organs, including cervical cytology.

• Reasons for immediate discontinuation of treatment are:

First-time onset of migraine headaches or increased frequency of headaches of unusual intensity, sudden disturbances in perception (for example, disturbances in vision or hearing), early signs of thrombophlebitis or thromboembolic symptoms (for example, unusual pain or swelling of the legs, excruciating pain in breathing or coughing with no apparent cause), a feeling of pain or tightness in the chest, scheduled surgery (six weeks earlier), immobilization (for example following accidents), onset of jaundice or anittic hepatitis, generalized itching, significant increase in blood pressure, pregnancy.

In case of alterations in the endocrine and hepatic function tests, the treatment should be interrupted and the tests repeated after about 2 months.

• Information on excipients

The medicine contains lactose, therefore patients with rare hereditary problems of galactose intolerance, the Lapp-lactase deficiency, or glucose-galactose malabsorption should not take this medicine.

• Partial metabolization of norethisterone to ethinylestradiol

After oral administration, norethisterone is partially metabolised to ethinylestradiol; 1 milligram of norethisterone corresponds to a dose equivalent to approximately 4-6 mcg of ethinylestradiol (see "Pharmacokinetic properties").

Following the partial transformation of norethisterone to ethinylestradiol, pharmacological effects similar to those observed with COCs are expected from administration of Primolut Nor.Consequently, the following general warnings associated with the use of COCs need to be further considered:

Circulatory disorders

The additional risk of VTE is highest during the first year of use when the woman first uses a COC or when the woman resumes COC use after a pill-free interval of at least one month.

Epidemiological studies have shown that the incidence of venous thromboembolism (VTE) in women using low-dose estrogen COCs (pregnancies.

VTE can be life-threatening or fatal (1-2% of cases).

Venous thromboembolism (VTE) manifesting as deep vein thrombosis and / or pulmonary embolism can occur while using all COCs.

Very rarely, thrombosis of other vascular districts, such as hepatic, mesenteric, cerebral, renal or retinal artery or vein, has been reported in COC users. There is no consensus that the occurrence of these events is associated with the use of COCs.

Symptoms of venous or arterial thrombotic / thromboembolic events or of a cerebrovascular accident may include:

• unusual unilateral pain and / or swelling in one leg

• severe and sudden chest pain, regardless of irradiation to the left arm

• sudden dyspnea

• sudden onset of cough

• unusual, severe and prolonged headache

• sudden partial or complete loss of vision

• diplopia

• indistinct speech or aphasia

• dizziness

• collapse with or without focal seizures

• sudden weakness or very marked numbness of one side or part of the body

• motor disturbances

• "acute" abdomen

The possibility of an increased synergistic risk of thrombosis should be considered in women with a combination of risk factors or who show greater severity of a single risk factor. This increased risk may be greater than a simple cumulative factor risk. In the event of a negative benefit / risk assessment, a COC should not be prescribed (see section "Contraindications").

The risk of venous or arterial thrombotic / thromboembolic events or cerebrovascular accidents increases with:

• the age

• obesity (body mass index over 30 kg / m2)

• positive family history (arterial or venous thromboembolism in a brother / sister or parent at a relatively young age). If a hereditary predisposition is suspected, the woman should consult a specialist for advice before deciding to take any CHC

• Prolonged immobilization, major surgery, any operation on the legs or severe trauma. In these circumstances it is advisable to stop taking the COC (in the case of elective surgery, at least 4 weeks before the operation) and resume it not before they are 2 weeks passed from complete remobilization

• smoking (the risk increases further for heavy smokers and with increasing age, especially for women over the age of 35

• dyslipoproteinemia

• hypertension

• migraine

• valvulopathy

• atrial fibrillation

There is no consensus on the possible role of varicose veins and superficial thrombophlebitis in venous thromboembolism.

Other medical conditions that have been associated with adverse vascular events include diabetes mellitus, systemic lupus erythematosus, haemolytic uremic syndrome, chronic inflammatory bowel disease (Crohn's disease or ulcerative colitis) and sickle cell disease.

An increase in migraine frequency and severity during CHC use (which may be prodromal of a cerebrovascular event) may be a reason for immediate discontinuation of CHC.

Biochemical factors that may be indicative of hereditary or acquired predisposition to venous or arterial thrombosis include Activated Protein C resistance, hyperhomocysteinemia, antithrombin III deficiency, protein C deficiency, protein S deficiency, antiphospholipid antibodies (anticardiolipin antibodies, lupus anticoagulant) .

In considering the risk / benefit ratio, physicians should bear in mind that adequate treatment of a clinical condition may reduce the associated risk of thrombosis, and that the risk associated with pregnancy is higher than that associated with the use of combined oral contraceptives. low dose (

Tumors

The most important risk factor for cervical cancer is human papillomavirus (HPV) infection. An increased risk of cervical cancer in long-term COC users has been reported in some epidemiological studies, but is still controversial. to what extent this finding is attributable to the confounding effects of cervical screening and sexual behavior including the use of barrier contraceptive methods.

A meta-analysis of 54 epidemiological studies found that women currently using CHCs have a slightly higher relative risk (RR = 1.24) of having breast cancer diagnosed. The excess risk gradually disappears over the 10 years following the discontinuation of the COCs. Because breast cancer is rare in women under the age of 40, the extra number of breast cancers diagnosed in women who use or have recently used COCs is small in relation to the overall risk of breast cancer. Such studies provide no evidence of a causal relationship. The observed increased risk may be due to an earlier diagnosis of breast cancer in COC users, the biological effects thereof, or a combination of both. Breast cancer diagnosed in COC users tends to be clinically less advanced than that diagnosed in women who have never used it.

Malignant tumors can be life-threatening or can be fatal.

Other conditions

Although a small rise in blood pressure has been reported in many women taking COCs, a clinically relevant increase is rare.

However, if clinically significant hypertension occurs during the use of a COC, the COC should be discontinued and the hypertension treated. If considered appropriate, COC use may be reintroduced if blood pressure returns to normal with antihypertensive therapy.

The onset or worsening of the conditions listed below has been reported both during pregnancy and while taking COCs; however, there is no conclusive evidence regarding the correlation between these conditions and the use of COCs: jaundice and / or cholestatic pruritus ; gallstone formation, porphyria, systemic lupus erythematosus, hemolytic uremic syndrome, Sydenham's chorea, herpes gestationis, otosclerosis hearing loss.

In women with hereditary angioedema, exogenous estrogens can induce or aggravate the symptoms of angioedema.

Acute or chronic disturbances of liver function may require discontinuation of COC treatment until liver function indices have returned to normal. Return of cholestatic jaundice already occurring in pregnancy or during previous sex steroid treatment requires treatment. "interruption of the COC.

Worsening of conditions such as endogenous depression, epilepsy, Crohn's disease and ulcerative colitis have been reported during COC use.

04.5 Interactions with other medicinal products and other forms of interaction

Drug interactions that result in increased clearance of sex hormones may reduce the therapeutic efficacy of the drug. This type of interaction has been demonstrated for several drugs that induce liver enzymes (including phenytoin, barbiturates, primidone, carbamazepine, rifampicin, oxcarbazepine , Hypericum perforatum and rifabutin) and is also hypothesized for griseofulvin.

Progestogens can interfere with the metabolism of other drugs, affecting their plasma and tissue concentrations (eg cyclosporine).

Note: It is recommended that the physician information of concomitant medications be consulted in order to identify potential interactions.

• Laboratory tests

The use of progestogens may affect the results of certain laboratory tests, including biochemical parameters of liver, thyroid, renal and adrenal function, plasma levels of (transporter) proteins, such as corticosteroid-binding globulin and lipid fractions / lipoprotein, glucose metabolism parameters, and coagulation and fibrinolysis parameters. Changes generally remain within the normal laboratory range.

04.6 Pregnancy and lactation

The use of Primolut Nor during pregnancy is contraindicated.

Primolut Nor must not be used during lactation (see also section 5.2 "Distribution").

04.7 Effects on ability to drive and use machines

No studies on the ability to drive and use machines have been performed.

04.8 Undesirable effects

Side effects are most common during the first months of taking Primolut Nor and tend to disappear as treatment continues. In addition to the undesirable effects listed in section 4.4 "Special warnings and precautions for use", the following side effects have been reported in women using Primolut Nor, although a causal relationship with the medicine cannot always be confirmed.

Adverse reactions according to MedDRA System Organ Class (MedDRA SOC) are presented in the table below. Frequencies are based on data from post-marketing experience and literature.

System and organ classification Very Common ≥1 / 10 Common ≥1 / 100, Uncommon ≥1 / 1000, Rare ≥1 / 10,000, Very rare Disorders of the immune system Hypersensitivity reactions Nervous system disorders Headache Migraine Eye disorders Visual disturbances Respiratory, thoracic and mediastinal disorders Dyspnea Gastrointestinal disorders Nausea Skin and subcutaneous tissue disorders Hives, rash Diseases of the reproductive system and breast Uterine / vaginal haemorrhage, including spotting *, hypomenorrhea * Amenorrhea* General disorders and administration site conditions Edema

* in the indication Endometriosis

The most appropriate MedDRA term was used to describe a particular reaction as well as its synonyms and related conditions.

Other reported secondary reactions are changes in libido, dizziness, nerve irritation phenomena, hirsutism, changes in liver function tests and haemagglutination tests.

Reporting of suspected adverse reactions

Reporting of suspected adverse reactions occurring after authorization of the medicinal product is important as it allows continuous monitoring of the benefit / risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system. "address https://www.aifa.gov.it/content/segnalazioni-reazioni-avverse.

04.9 Overdose

Acute toxicity studies performed with norethisterone acetate do not indicate risks of acute side effects after accidental intake of a dose even many times higher than the therapeutic one.

05.0 PHARMACOLOGICAL PROPERTIES

05.1 Pharmacodynamic properties

Pharmacotherapeutic group: progestogens.

ATC code: G03D.

Norethisterone is a potent progestin. In women pre-treated with estrogen, the complete transformation of the endometrium from the proliferative to the secretory state can be achieved with the oral administration of 100-150 mg of norethisterone per cycle. The progestin effects of norethisterone on the endometrium are the basis of the treatment of functional metrorrhagia, primary and secondary amenorrhea and endometriosis with Primolut Nor.

Inhibition of gonadotropic secretion and suppression of ovulation can be achieved with a daily intake of 0.5 mg norethisterone acetate. The positive effects of Primolut Nor on premenstrual symptoms can be traced back to suppression of ovarian function.

For the stabilizing effects of norethisterone on the endometrium, administration of Primolut Nor can be used to regulate the menstrual cycle.

Like progesterone, norethisterone is thermogenic and alters basal body temperature.

05.2 Pharmacokinetic properties

• Absorption

Norethisterone acetate (NETA), administered orally, is rapidly and completely absorbed over a wide dose range. Already during absorption and the first hepatic passage norethisterone acetate is hydrolyzed to norethisterone, the active ingredient of the drug, and acetic acid. Maximum serum concentrations of norethisterone of about 18 ng / ml (after taking 5 mg of NETA) and 25 ng / ml (after taking 10 mg of NETA) are reached within 2 hours of oral administration of a Primolut Nor tablet. Based on a relative bioavailability study, the drug is completely released from the tablet.

• Distribution

Norethisterone binds to serum albumin and sex hormone binding globulin (SHBG). Only about 3-4% of total serum drug concentrations are present as a free steroid, while about 35% and 61% are bound. respectively to SHBG and albumin. The apparent volume of distribution of norethisterone is 4.4 ± 1.3 L / kg. Following oral administration, the trend of serum drug concentrations over time follows a biphasic model. The two phases are characterized respectively by a half-life of 1-3 hours and approximately 5-13 hours.

Norethisterone passes into breast milk, where it reaches levels approximately 10% of those found in maternal plasma, regardless of the route of administration. Based on an estimate of a maximum concentration in maternal serum of about 16 ng / ml and a "daily intake of 600 ml of milk by the infant, the infant can receive a maximum of about 1 mcg of norethisterone (0.02% maternal dose).

• Metabolism

Norethisterone is mainly metabolised through saturation of the double bond in ring A and reduction of the 3-keto group to hydroxyl group followed by conjugation to form the corresponding sulfates and glucuronides. Some of these metabolites are eliminated rather slowly from the plasma, with half-lives. approximately 67 hours Thus, during long-term treatment with daily norethisterone administration, some of these metabolites accumulate in the plasma.

Norethisterone is partially metabolised to ethinylestradiol following oral administration of norethisterone or norethisterone acetate in humans. This transformation produces an ethinylestradiol dose equivalent to 4-6 mcg per 1 milligram of orally administered norethisterone / norethisterone acetate.

• Elimination

Norethisterone is not excreted unchanged in significant quantities. The compound is excreted predominantly in the form of reduced A-ring metabolites and hydroxylated metabolites and related conjugates (glucuronides and sulphates) in the urine and faeces at a ratio of approximately 7: 3. Most renally excreted metabolites are eliminated within 24 hours with a half-life of approximately 19 hours.

• Steady state conditions

During repeated daily administration of norethisterone, accumulation of the drug is unlikely due to the relatively short half-life of the drug. However, if SHBG-inducing agents such as ethinylestradiol are co-administered, an increase in serum levels may occur. norethisterone due to its binding to SHBG.

05.3 Preclinical safety data

Non-clinical data for norethisterone or its esters reveal no special hazard for humans based on conventional studies of repeated dose toxicity, genotoxicity and carcinogenic potential which are not already included in other sections. However, it should be remembered that sex steroids can stimulate the growth of hormone-dependent tissues and tumors.

Reproductive toxicity studies have highlighted the risk of masculinization in female fetuses if the drug is administered in high doses during the period of formation of the external genitalia.

Since epidemiological studies have shown that this effect also affects men after taking the higher dosages, it must be stated that Primolut Nor can cause signs of virilization in female fetuses if administered during the hormone-sensitive phase of somatic sexual differentiation (this from the 45th pregnancy day onwards).

Apart from this, no teratogenic effects have been identified.