Active ingredients: Tamoxifen
NOLVADEX 10 mg film-coated tablets
NOLVADEX 20 mg film-coated tablets
Why is Nolvadex used? What is it for?
Nolvadex contains tamoxifen, which belongs to a class of medicines called 'antiestrogens'.
Estrogen is a naturally occurring substance in the body known as "sex hormones". Nolvadex works by blocking the effects of estrogen on your body. Nolvadex is indicated:
- in the treatment of breast cancer;
- in men to prevent and treat breast enlargement (gynaecomastia) and breast pain (mastalgia) caused by medicines called antiandrogens used in the treatment of prostate cancer (prostate cancer), a gland that produces seminal fluid.
Talk to your doctor if you don't feel better or if you feel worse.
Contraindications When Nolvadex should not be used
Do not take Nolvadex
- If you are allergic to tamoxifen or any of the other ingredients of this medicine
- If you are pregnant (see "Pregnancy and breastfeeding").
- If you are taking preventive therapy because you have a high risk of developing breast cancer.
- If you have a particular form of breast cancer (ductal carcinoma in situ) and need concomitant blood thinning therapy or if you have ever had a blood clot in a blood vessel (deep vein thrombosis or pulmonary embolism).
Precautions for use What you need to know before taking Nolvadex
Talk to your doctor before taking Nolvadex:
- If you have a low level of white blood cells (leukopenia) or platelets (thrombocytopenia), your doctor will ask you to have periodic blood tests.
- If unusual vaginal bleeding occurs, either during Nolvadex treatment or at any time after it has been stopped. Your doctor will ask you to undergo periodic checks of the genital system, because changes in the uterus (endometrium) can occur, some of which can even be serious and could include cancer.
- If you have ever had a lack of blood supply to the brain (stroke), stroke-like events, diseases due to the formation and detachment of blood clots (thromboembolic) or cancer of the uterus, as these diseases may recur during treatment with Nolvadex (see section Possible side effects).
- If you have a particular form of breast cancer (ductal carcinoma in situ). The decision to initiate tamoxifen therapy should be discussed with your physician, evaluating the potential benefits and risks together.
In the event of hospitalization, please inform the medical staff that you are being treated with Nolvadex.
In breast reconstruction surgery (weeks or years after breast cancer surgery) Nolvadex may increase the risk of blood clots forming in the small vessels of the flap of tissue used to shape the new breast, which they can lead to complications.
For those who carry out sporting activities
The use of the drug without therapeutic necessity constitutes doping and can in any case determine positive anti-doping tests.
Children and adolescents
The use of Nolvadex in children is not recommended as safety and efficacy have not been established
Interactions Which drugs or foods can modify the effect of Nolvadex
Tell your doctor if you are taking, have recently taken or might take any other medicines. In particular, tell your doctor if you are taking:
- paroxetine, fluoxetine (examples of antidepressants);
- bupropion (antidepressant or supportive drug for smoking cessation);
- quinidine (for example used in the treatment of cardiac arrhythmias);
- cinacalcet (for the treatment of parathyroid gland dysfunction);
- cytotoxic drugs (used in cancer treatment) as they can increase the formation of blood clots.
Your doctor will check you for frequent blood tests if you are taking medicines to thin the blood, called coumarol-type anticoagulants (eg warfarin). Tamoxifen can in fact significantly increase the activity of these medicines.
The use of tamoxifen in combination with another breast cancer medicine (aromatase inhibitor) as adjuvant therapy has not shown better efficacy than tamoxifen alone.
In some studies, reduced efficacy of tamoxifen has been reported when administered concomitantly with some SSRI antidepressants (e.g. paroxetine).
Warnings It is important to know that:
Pregnancy
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 Nolvadex if you are pregnant (see section Do not take Nolvadex); avoid becoming pregnant and if you are sexually active using barrier contraceptives (eg condoms or diaphragms) or other non-hormonal methods of contraception during treatment with Nolvadex and in the two months following discontinuation of therapy, as there may be risks for the child.
If you are premenopausal, your doctor will carefully check you before starting treatment to rule out the possibility of an ongoing pregnancy.
Feeding time
The use of Nolvadex while breastfeeding is not recommended, as it is not known whether it passes into breast milk. Your doctor will consider whether to discontinue breastfeeding or Nolvadex therapy.
Driving and using machines
Do not drive or use machines if you notice that your abilities are impaired. Nolvadex can cause fatigue.
Nolvadex contains lactose
If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicinal product.
Dose, Method and Time of Administration How to use Nolvadex: Posology
Always take this medicine exactly as your doctor or pharmacist has told you. If in doubt, consult your doctor or pharmacist.
The recommended dose in the treatment of breast cancer is 20 to 40 mg in one or two daily doses.
The recommended dose in the prevention and treatment of breast enlargement and pain caused by antiandrogen medicines used in the treatment of prostate cancer is 20 mg once daily.
You should follow your doctor's instructions regarding how and how often you take the tablets. The tablets should be taken whole with a little water, preferably always at the same time.
Overdose What to do if you have taken too much Nolvadex
If you take more Nolvadex than you should
In case of accidental ingestion / intake of an excessive dose of Nolvadex, notify your doctor immediately or go to the nearest hospital.
If you forget to take Nolvadex
In case you forget to take a dose, it should be taken as soon as possible. Do not take a double dose to make up for a forgotten tablet.
If you stop taking Nolvadex
If you have any further questions on the use of this medicine, ask your doctor or pharmacist. Tamoxifen treatment should not be stopped, even if your health improves, unless your doctor tells you to.
Side Effects What are the side effects of Nolvadex
Like all medicines, this medicine can cause side effects, although not everybody gets them.
Experience with the use of Nolvadex in women is extensive. Although much narrower in men, the overall adverse effect profile appears similar, with the exception of events limited to female sex.
Stop taking tamoxifen and see your doctor immediately if you develop any of the following symptoms:
- difficulty in breathing;
- swelling of the face, lips, tongue and / or throat which may cause difficulty in swallowing;
- swelling of the hands, feet or ankles;
- urticaria.
Tell your doctor immediately if you experience any of the following symptoms:
- numbness of the face or weakness of the arms or legs and changes in speech or vision which could indicate a lack of blood supply to the brain (stroke)
- chest pain or shortness of breath (dyspnoea) which could be symptoms of a blood clot in the pulmonary artery (pulmonary embolism)
- belly pain or abnormal vaginal bleeding which could indicate possible cancer of the uterus
- cough and shortness of breath which could be symptoms of inflammation of the lungs (interstitial pneumonia) characterized by fever, cough, shortness of breath, increased white blood cells, a type of blood cell (neutrophilia).
During treatment with tamoxifen, as with any other drug, side effects may occur, according to the following frequency, such as:
Very common (may affect more than 1 in 10 patients)
- nausea
- fluid retention which causes swelling
- vaginal bleeding
- vaginal discharge
- rash
- hot flashes
- fatigue
Common (may affect up to 1 in 10 patients)
- decrease in the number of red blood cells (anemia)
- opacification of the lens, the lens of the eye used to focus images (cataract)
- disease of the retina, the innermost membrane of the eye (retinopathy)
- allergic reactions
- high levels of fat in the blood (triglycerides)
- leg cramps
- muscle pain (myalgia)
- benign growths in the uterus (uterine fibroids)
- sudden onset of weakness, paralysis of the arms or legs, sudden difficulty speaking, walking, difficulty holding things or difficulty thinking which may be due to reduced blood supply to the brain (e.g. stroke)
- headache
- dizziness
- sensory disturbances (including numbness and altered taste)
- itching of the external genitalia
- changes in the endometrium, the lining of the uterus (including hyperplasia and polyps)
- hair and hair loss (alopecia)
- He retched
- diarrhea
- constipation
- changes in liver enzyme levels
- fatty (steatotic) liver
- formation and detachment of blood clots in blood vessels (including deep vein thrombosis, microvascular thrombosis and pulmonary embolism)
Uncommon (may affect up to 1 in 100 patients)
- decrease in the number of platelets (thrombocytopenia)
- decreased number of white blood cells (leukopenia)
- visual disturbances
- inflammation of the pancreas, a gland in the body (pancreatitis)
- increased calcium in the blood (hypercalcaemia), in patients with tumors spread to the bone
- cancer of the endometrium, the lining of the womb (endometrial cancer)
- inflammation of the lungs (interstitial pneumonia) characterized by fever, cough, shortness of breath, increased white blood cells
- severe liver disease (cirrhosis)
Rare (may affect up to 1 in 1,000 patients)
- decrease in the number of a type of white blood cell (neutropenia)
- severe decrease in the number of white blood cells (agranulocytosis)
- changes in the transparent membrane that covers the eye (cornea)
- disease of the optic nerve, the nerve that transmits images from the eye to the brain (optic neuropathy)
- uterus cancer
- growths (polyps) of the vagina
- worsening of a tumor (tumor recurrence)
- endometriosis (when cells that are usually found only in the lining of the uterus are present in other parts of the body, usually in other systems near the uterus)
- swelling of ovarian cysts
- severe inflammation of the optic nerve, the nerve that transmits images from the eye to the brain (optic neuritis)
- inflammation of the liver (hepatitis)
- stagnation of bile (cholestasis)
- liver abnormalities
- liver damage (hepatocellular)
- death of liver cells (liver necrosis)
- allergic reaction characterized by swelling of the face, lips and throat (angioedema)
- severe allergic reaction with blistering and pustules (Stevens-Johnson syndrome)
- inflammation of blood vessels with formation of lumps and patches of the skin (skin vasculitis)
- immune system disease characterized by the formation of lumps under the skin (bullous pemphigoid)
- allergic reaction characterized by spots on the skin (erythema multiforme)
Very rare (may affect up to 1 in 10,000 patients)
- immune system disease affecting the skin with the formation of erythema, lesions, hair loss (cutaneous lupus erythematosus)
- disease caused by the accumulation in the blood of certain liver proteins, porphyrins, which leads to the formation of blisters, lesions that turn into scabs and cysts on the skin (porphyria cutanea tarda)
Other side effects reported in the literature are: dizziness, depression, confusion and fatigue.
The results of a large 5-year study involving approximately 13,000 women at high risk for breast cancer showed an increased incidence of the following adverse reactions in women treated with tamoxifen compared to those not treated: uterine cancer (endometrial adenocarcinoma and uterine sarcoma), pulmonary embolism, deep vein thrombosis, stroke, cataract formation and cataract surgery. Some of the cases of uterine malignant tumors, stroke and pulmonary embolism were fatal.
Uterine fibroids, endometriosis and other endometrial changes including hyperplasia and polyps have been reported.
Interstitial pneumonia can occur and can have the same symptoms as pneumonia, such as wheezing and coughing.
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 the safety of this medicine.
Expiry and Retention
Do not store above 30 ° C.
Store in the original package to protect the medicine from light.
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.
What Nolvadex contains
Nolvadex 10 mg film-coated tablets
- The active ingredient is tamoxifen citrate equal to 10 mg tamoxifen.
- The other ingredients are lactose monohydrate (see section Nolvadex contains lactose), maize starch, gelatin, croscarmellose sodium, magnesium stearate, hypromellose, macrogol 300, titanium dioxide
Nolvadex 20 mg film-coated tablets
- The active ingredient is tamoxifen citrate equal to 20 mg tamoxifen.
- The other ingredients are lactose monohydrate (see section 2. Nolvadex contains lactose), maize starch, gelatin, croscarmellose sodium, magnesium stearate, hypromellose, macrogol 300, titanium dioxide
What Nolvadex looks like and contents of the pack
Nolvadex comes as white film-coated tablets.
Nolvadex 10 mg film-coated tablets are available in blisters of 30 tablets
Nolvadex 20 mg film-coated tablets are available in blisters of 20 tablets
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.
01.0 NAME OF THE MEDICINAL PRODUCT
NOLVADEX 10 - 20 MG
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION
Nolvadex 10 mg film-coated tablets
One film-coated tablet contains:
Active ingredient: tamoxifen citrate (equal to tamoxifen) 10 mg.
Excipients: lactose 117 mg.
Nolvadex 20 mg film-coated tablets
One film-coated tablet contains:
Active ingredient: tamoxifen citrate (equal to tamoxifen) 20 mg.
Excipients: lactose 234 mg.
For the full list of excipients see 6.1.
03.0 PHARMACEUTICAL FORM
White film-coated tablets.
04.0 CLINICAL INFORMATION
04.1 Therapeutic indications
Nolvadex is indicated for the treatment of breast cancer.
In men Nolvadex is indicated in the prophylaxis and treatment of gynecomastia and mastalgia caused by antiandrogens in the monotherapy treatment of prostate cancer.
04.2 Posology and method of administration
Adult and elderly patients
Breast cancer: 20 to 40 mg in one or two daily administrations.
Prophylaxis and treatment of gynecomastia and mastalgia caused by antiandrogens in the monotherapy treatment of prostate cancer: 20 mg once daily.
Children
The use of Nolvadex in children is not recommended as safety and efficacy have not been established (see sections 5.1 and 5.2).
04.3 Contraindications
- Hypersensitivity to the active substance or to any of the excipients.
- Nolvadex must not be administered if you are pregnant (see also section 4.6).
- Preventive therapy in patients at high risk of breast cancer.
- Ductal carcinoma in situ in women who require concomitant anticoagulation therapy or who have a history of deep vein thrombosis or pulmonary embolism.
04.4 Special warnings and appropriate precautions for use
Nolvadex should be used with caution in patients with persistent leukopenia or thrombocytopenia. Periodic checks of the blood count, including platelets, are advisable.
Stopping of menstrual flow may occur in pre-menopausal patients, which does not affect the antitumor activity of the drug.
An "increased incidence of endometrial changes including hyperplasia, polyps, carcinoma and sarcomas of the body of the uterus (mostly mixed Mullerian malignancies)" has been reported during treatment with Nolvadex. The incidence and picture of these changes suggest a basic mechanism related to the estrogenic properties of Nolvadex. It is therefore advisable that patients undergoing therapy are subjected to adequate checks of the genital system, in particular of the endometrium.
Patients being treated with tamoxifen should be instructed to notify their physician immediately if they experience any of the following symptoms: numbness of the face or weakness of the arms or legs and problems with speech or vision which could indicate a stroke. The same is true for chest pain or dyspnoea which could be symptoms of pulmonary embolism or if you have abdominal pain or abnormal vaginal bleeding which could indicate possible cancer of the uterus. Also for cough and wheezing which could be symptoms of a interstitial pneumonia patients should be instructed to notify their physician. Patients should be asked if they have had a previous history of stroke, stroke-like events, thromboembolic events or cancer of the uterus.
Second primary tumors at sites other than the endometrium and the contralateral breast have been reported in clinical trials with tamoxifen in breast cancer; no causal relationship has been established and the clinical significance of these findings is unclear.
In an uncontrolled study of 28 girls aged 2 to 10 years with McCune Albrigth syndrome (MAS), treated with 20 mg once daily for up to 12 months, the mean volume uterus increased after 6 months of treatment and doubled at the end of the one-year study. This observation is consistent with the pharmacodynamic properties of tamoxifen, but a causal relationship has not been established (see section 5.1).
Poor metabolisers for CYP2D6 have been reported in the literature to have reduced plasma levels of endoxifen, one of the most important active metabolites of tamoxifen (see section 5.2). Concomitant administration of drugs that inhibit CYP2D6 may lead to a reduction in the concentration of the active metabolite endoxifen. Therefore, administration of potent CYP2D6 inhibitors (e.g. paroxetine, fluoxetine, quinidine, cinacalcet or buproprone) should whenever possible be avoided during tamoxifen treatment (see sections 4.5 and 5.2).
The decision to initiate tamoxifen therapy in patients with ductal carcinoma in situ should be discussed with the patients, evaluating the potential benefits and risks with them.
Important information about some of the ingredients
The medicine contains lactose; Patients with rare hereditary problems of galactose intolerance, lactase deficiency or glucose / galactose malabsorption should not take this medicine.
The administration of Nolvadex is not recommended during lactation.
04.5 Interactions with other medicinal products and other forms of interaction
The use of tamoxifen in patients undergoing therapy with dicumarolic anticoagulants can significantly increase the anticoagulant activity; in this case it is advisable to closely monitor the coagulation indices.
When Nolvadex is administered in combination with cytotoxic drugs, an increased risk of thromboembolic episodes may occur (see also section 4.8).
The use of tamoxifen in combination with an aromatase inhibitor as adjuvant therapy has not shown better efficacy than tamoxifen alone.
The known and major pathway of tamoxifen metabolism in humans is demethylation, catalysed by CYP3A4 enzymes. It has been reported in the literature that the pharmacokinetic interaction with the CYP3A4 inducing agent rifampicin results in a reduction in plasma levels of tamoxifen. The clinical relevance of this interaction is unknown.
Pharmacokinetic interactions with CYP2D6 inhibitors have been reported in the literature, resulting in a 65 - 75% reduction in plasma levels of an active metabolite of tamoxifen, 4-hydroxy-N-desmethyltamoxifen (endoxifen). In some studies, reduced efficacy of tamoxifen has been reported when administered concomitantly with some SSRI antidepressants (e.g. paroxetine). Whenever possible, concomitant administration of potent CYP2D6 inhibitors (eg paroxetine, fluoxetine, quinidine, cinacalcet or bupropion) should be avoided (see sections 4.4 and 5.2), as a reduction in the efficacy of tamoxifen cannot be excluded.
04.6 Pregnancy and lactation
Pregnancy: Nolvadex is contraindicated in pregnancy.
Although no causal relationship with the drug has been established, few cases of miscarriages, congenital anomalies and fetal deaths have been reported in patients.
who had taken Nolvadex.
In reproductive toxicity studies in rats, rabbits and monkeys, tamoxifen did not show teratogenic potential. In experimental models of rodent fetal reproductive tract development, tamoxifen has been associated with modifications similar to those caused by estradiol, ethinyl estradiol, clomiphene and diethylstilbestrol (DES). Although the clinical relevance of these changes is unknown, some of these, especially vaginal adenosis, are similar to those seen in young women who, in intrauterine life, had been exposed to DES and who present a risk of 1: 1000 to develop clear cell carcinoma of the vagina or cervix.
Only a small number of patients were exposed to tamoxifen during pregnancy. Such exposure has not been reported to cause subsequent vaginal adenosis or clear cell carcinoma of the vagina or cervix in young women who had undergone exposure to tamoxifen in intrauterine life.
Patients should be advised of the need to avoid pregnancy during treatment with Nolvadex and, if sexually active, they should use barrier contraceptives or other non-hormonal methods of contraception.
Pre-menopausal patients, before starting treatment, must undergo careful checks to exclude the possibility of an ongoing pregnancy.
Patients should be informed of the potential risks to the fetus if pregnancy occurs during treatment with Nolvadex or in the two months following discontinuation of therapy.
Breastfeeding: the use of Nolvadex during lactation is not recommended, as it is not known whether it is excreted in breast milk. The decision to discontinue breastfeeding or Nolvadex therapy should be weighed on the basis of treatment needs.
04.7 Effects on ability to drive and use machines
There is no known interference with the ability to drive and use machines.
04.8 Undesirable effects
Experience with the use of Nolvadex in women is extensive. Although much narrower in humans, the overall adverse event profile appears similar, with the exception of events limited to females.
In long-term treatment, reported side effects are less frequent or less severe than those seen with androgens and estrogens used to treat the same condition.
Some side effects are attributable to the anti-estrogenic action of the drug: hot flashes, vaginal bleeding, vaginal discharge and vulvar itching.
In some pre-menopausal patients Nolvadex suppresses menstrual flow.
Other general side effects include gastrointestinal intolerance, dizziness, skin rash and, in some cases, fluid retention and alopecia.
When these side effects are severe it is possible to control them by simply reducing the dosage without affecting the response to treatment. It is necessary to consult the specialist to evaluate the advisability of continuing or suspending the treatment or of any changes thereto.
Skin rash (including rare reports of erythema multiforme, Steven-Johnson syndrome, cutaneous vasculitis and bullous pemphigoid) and commonly hypersensitivity reactions, including angioedema, have been reported.
In the early stages of therapy, hypercalcaemia has occasionally developed in patients with bone lesions.
At the beginning of Nolvadex therapy, episodes of symptomatological flare may occur. These manifestations are transient and often associated with a good response to therapy.
Cases of visual disturbances have been reported, including rare cases of corneal changes and common cases of cataracts and retinopathy.
Cases of optic neuropathy and optic neuritis have been reported in patients receiving tamoxifen and blindness has occurred in a limited number of cases.
Uterine fibroids, endometriosis and other endometrial changes including hyperplasia and polyps have been reported.
In patients treated with Nolvadex, thrombocytopenia has been observed, generally limited to values such as 80,000 - 90,000 mm3, but sometimes even lower.
Leukopenia sometimes associated with anemia and / or thrombocytopenia has been reported during Nolvadex therapy. Neutropenia, sometimes severe, has been rarely reported and cases of agranulocytosis have been reported rarely.
There is evidence of cerebrovascular ischemic events commonly occurring during Nolvadex therapy. Serious thromboembolic episodes which occur commonly during Nolvadex therapy have been reported. Since the incidence of such events is increased in patients with malignant diseases, a causal relationship with tamoxifen has not been established.
Leg cramps and myalgia have been commonly reported in patients receiving Nolvadex.
Cases of interstitial pneumonia have occasionally been reported.
Nolvadex has been associated with changes in liver enzyme levels and a picture of more severe liver abnormalities, in some cases fatal, including fatty liver, cholestasis and hepatitis, liver failure, cirrhosis and hepatocellular damage (including hepatic necrosis).
An increase in the volume of ovarian cysts has been observed rarely in patients treated with Nolvadex. Vaginal polyps have rarely been observed in women receiving Nolvadex.
Commonly, an increase in serum triglyceride levels may be associated with the use of tamoxifen, in some cases with pancreatitis.
Other side effects reported in the literature are: dizziness, headache, depression, confusion, fatigue.
An uncommon incidence of endometrial cancer and rare cases of sarcomas of the body of the uterus (mostly mixed Mullerian malignancies) have been reported in association with Nolvadex treatment.
Cutaneous lupus erythematosus has been observed very rarely in patients treated with Nolvadex.
Porphyria cutanea tarda has been observed very rarely in patients treated with Nolvadex.
Results from the NSABP P-1 clinical trial, a large 5-year study involving approximately 13,000 women at high risk for breast cancer who took tamoxifen or placebo, showed an increase in women treated with tamoxifen. the incidence of the following adverse reactions compared to the control group:
- cancer of the uterus: endometrial adenocarcinoma (incidence rate per 1000 years / woman equal to 2.20 in the group of women treated versus 0.71 in the control group), uterine sarcoma, including mixed Mullerian-type sarcoma (rate of incidence per 1000 years / woman equal to 0.17 in the group of treated women versus 0.00 in the control group);
- stroke (incidence rate per 1000 years / woman equal to 1.43 in the group of treated women versus 1.00 in the control group); pulmonary embolism (incidence rate per 1000 woman-years equal to 0.75 in the group of treated women versus 0.25 in the control group).
Some of the cases of uterine malignancies, strokes and pulmonary embolisms have been fatal. An increase in the incidence of deep vein thrombosis, cataract formation, cataract surgery was also found in the same study.
The side effects of Nolvadex are listed in table 1.
Unless otherwise specified, the following frequency categories were calculated based on the number of undesirable effects reported in a Phase III study of 9,366 postmenopausal patients with operable breast cancer treated for 5 years and if unspecified, the frequency within the comparative treatment group or the fact that the researcher considered it related to the study drug was not taken into account.
Table 1 Undesirable effects shown by Nolvadex:
• Myalgia
a This side effect was not reported in subjects treated with tamoxifen (n = 3094) in the above study. However, it has been reported in other studies or drawn from other sources. The frequency was calculated using the upper bound of the 95% confidence interval for the point estimate (based on 3 / X, where X represents the sample total, e.g. 3094). This is calculated as 3/3094 which it is equivalent to the frequency category "rare".
b The event was not observed in other pivotal clinical studies. The frequency was calculated using the upper limit of the 95% confidence interval for the point estimate (based on 3 / X, where X represents the total sample of 13,357 patients in pivotal clinical trials). This is calculated as 3 / 13,357 which equates to the "very rare" frequency category.
04.9 Overdose
Theoretically, an overdose should manifest itself with an "exaltation of the anti-estrogenic side effects.
Studies in experimental animals have shown that a large overdose (100-200 times the recommended daily dose) can cause estrogenic effects.
In the literature, it has been reported that Nolvadex, given at doses several times the standard dose, could be associated with a prolongation of the QT interval of the ECG.
There is no specific antidote for the treatment of overdose cases, which therefore must be symptomatic.
05.0 PHARMACOLOGICAL PROPERTIES
05.1 Pharmacodynamic properties
Pharmacotherapeutic group: hormone antagonists and related substances.
Antiestrogens.
ATC code: L02BA01.
Nolvadex (tamoxifen) is a non-steroidal drug, derivative of triphenylethylene, which exhibits a complex spectrum of anti-estrogenic and estrogenic-like pharmacological effects in different tissues.
In breast cancer patients, at the tumor level, tamoxifen acts primarily as an anti-estrogen by inhibiting the binding of estrogen to the estrogen receptor.
In clinical experience, it is recognized that tamoxifen induces a reduction in blood levels of total cholesterol and low density lipoproteins in the order of 10-20% in postmenopausal women. Additionally, tamoxifen has been reported to induce maintenance of bone mineral density in postmenopausal women.
In clinical trials where Nolvadex (tamoxifen) was used in patients with prostate cancer, as prophylactic therapy, in combination with an antiandrogen, a significant reduction in gynecomastia and mastalgia was observed compared to patients who were treated with the antiandrogen alone. .
Nolvadex has also been shown to be effective in the treatment of gynaecomastia and mastalgia occurring in patients receiving antiandrogens.
In patients whose gynecomastia and mastalgia appeared after Nolvadex was discontinued, reintroduction of treatment was effective.
Nolvadex was administered for up to one year in these studies, with no evidence of any adverse effect on prostate cancer control as assessed by PSA assay. No long-term data are available.
An uncontrolled study was conducted with a heterogeneous group with 28 girls aged 2 to 10 years, affected by McCune Albrigth syndrome (MAS), treated with 20 mg once daily for up to 12 months. . Of the patients who reported vaginal bleeding in the pre-study period, 62% (13 of 21 patients) had no vaginal bleeding for a period of 6 months and 33% (7 of 21) for the duration of the study. The mean uterus volume increased after 6 months of treatment and doubled at the end of the one-year study. This observation is consistent with the pharmacodynamic properties of tamoxifen, but a causal relationship has not been established (see section 4.4). . There are no long-term safety data in children. In particular, the long-term effect of tamoxifen on growth, puberty and development in general has not been studied.
The polymorphic form of CYP2D6 may be associated with the variability of the clinical response to tamoxifen.The slow metabolizer state may be associated with a reduced response. The effects of these observations in the treatment of CYP2D6 poor metabolisers have not yet been fully elucidated (see sections 4.4, 4.5 and 5.2).
CYP2D6 genotype
Available clinical data suggest that patients homozygous for non-functional CYP2D6 alleles may show reduced efficacy of breast cancer treatment with tamoxifen. The available studies have mainly been performed in postmenopausal women (see sections 4.4 and 5.2).
05.2 Pharmacokinetic properties
Nolvadex is rapidly absorbed after oral administration. The maximum serum concentration is reached between 4 and 7 hours. Steady state concentrations (approximately 300 ng / ml) are reached after 4 weeks at 40 mg / day.
The drug demonstrates a high bond to plasma albumin (> 99%). It is metabolized by hydroxylation, demethylation and conjugation giving rise to numerous metabolites that have a pharmacological profile similar to that of the drug.
unchanged and contributing to the therapeutic effect.
Tamoxifen is metabolised, predominantly by CYP3A4, to N-desmethyltamoxifene; the latter is further metabolised by CYP2D6 to the active metabolite endoxifen. In patients with CYP2D6 deficiency, concentrations of endoxifen are approximately 75% lower than those in patients with normal CYP2D6 activity. circulating endoxifen levels also occur with the administration of potent CYP2D6 inhibitors.
The excretion of tamoxifen occurs mainly via the faecal route and an elimination half-life has been calculated equal to about 7 days for the unchanged drug while for the N-desmethyltamoxifen, the main metabolite in circulation, it was equal to 14 days.
In a study of 2 to 10 year old girls with McCune Albrigth syndrome (MAS) treated with 20 mg of tamoxifen once a day for up to 12 months, compared to adults, an age-dependent reduction in clearance and an increase in exposure (AUC) with values up to 50% higher in younger patients.
05.3 Preclinical safety data
Tamoxifen was not mutagenic in a series of in vitro and in vivo mutagenicity tests. Tamoxifen was genotoxic in in vitro and in vivo rodent genotoxicity tests. Tumors of the gonads in mice and liver tumors in rats have been reported in long-term studies with tamoxifen; The clinical relevance of these observations has not been established. Additional information regarding your prescription is given in section 4.6.
06.0 PHARMACEUTICAL INFORMATION
06.1 Excipients
Lactose monohydrate, corn starch, gelatin, croscarmellose sodium, magnesium stearate, hypromellose, macrogol 300, titanium dioxide.
06.2 Incompatibility
Not relevant.
06.3 Period of validity
In intact packaging: 5 years.
06.4 Special precautions for storage
Store away from light and at a temperature not exceeding + 30 ° C.
06.5 Nature of the immediate packaging and contents of the package
Oriented nylon - aluminum - PVC / aluminum blister
Nolvadex 10 mg film-coated tablets: 30 tablets.
Nolvadex 20 mg film-coated tablets: 20 tablets.
06.6 Instructions for use and handling
No special instructions.
07.0 MARKETING AUTHORIZATION HOLDER
AstraZeneca S.p.A.
Volta Palace
Via F. Sforza
Basiglio (MI)
08.0 MARKETING AUTHORIZATION NUMBER
Nolvadex 10 mg film-coated tablets: AIC 023362039
Nolvadex 20 mg film-coated tablets: AIC 023362041
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION
Nolvadex 10 mg film-coated tablets: AIC date: August 1976 / Renewal date: June 2005 / December 2009
Nolvadex 20 mg film-coated tablets: AIC date: October 1985 / Renewal date: June 2005 / December 2009
10.0 DATE OF REVISION OF THE TEXT
February 2013
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