Active ingredients: Sorafenib
Nexavar 200 mg film-coated tablets
Why is Nexavar used? What is it for?
Nexavar is used for the treatment of hepatocarcinoma.
Nexavar is also used to treat kidney cancer (advanced renal cell carcinoma) when it is in an advanced stage and when standard therapy has not helped to stop it or is considered unsuitable.
Nexavar is used to treat thyroid cancer (differentiated thyroid cancer).
Nexavar is a so-called multi-kinase inhibitor. It works by slowing the growth rate of cancer cells and blocking the blood supply that allows cancer cells to grow.
Contraindications When Nexavar should not be used
Do not take Nexavar
- if you are allergic to sorafenib or any of the other ingredients of this medicine (listed in section 6).
Precautions for use What you need to know before taking Nexavar
Talk to your doctor or pharmacist before taking Nexavar.
Take special care with Nexavar especially
- If skin problems occur. Nexavar can cause rashes and skin reactions, especially on the hands and feet. These effects can usually be treated by the doctor. If not, your doctor can suspend the treatment or stop it completely.
- If you have high blood pressure. Nexavar can cause an increase in blood pressure; your doctor will check your blood pressure regularly and may prescribe medicines to treat high blood pressure.
- If you have bleeding problems or if you are taking warfarin or phenprocomone. Treatment with Nexavar can lead to an increased risk of bleeding. If you are taking warfarin or phenprocomone, medicines that thin the blood to prevent clots, there may be an increased risk of bleeding.
- If you have chest pains or heart problems. Your doctor may decide to stop treatment or stop it completely.
- If you have a heart disorder, such as an 'electrical signal disturbance called' QT prolongation '.
- If you are about to have or have just had surgery. Nexavar can affect wound healing. If you are about to have surgery, your treatment with Nexavar will probably be stopped. Your doctor will then decide when to take it back.
- If you are being treated with irinotecan or docetaxel, which are also medicines for cancer, Nexavar can increase the effects and especially the side effects of these medicines.
- If you are taking neomycin or other antibiotics. The effectiveness of Nexavar may be decreased - If you have severe liver failure. You may have exacerbated side effects when taking this medicine.
- If you have reduced kidney function. Your doctor will monitor your water and electrolyte balance.
- Fertility. Nexavar can reduce fertility in both men and women. If this applies to you, talk to your doctor.
- Gastrointestinal perforation may occur during treatment (see section 4: Possible side effects). In this case the doctor will stop the treatment.
- If you have thyroid cancer, your doctor will check the levels of calcium and thyroid hormone in your blood.
Tell your doctor if any of these apply to you. You may need treatment for these problems, or your doctor may change the dose of Nexavar, or stop treatment altogether (see also section 4: Possible side effects).
Children and adolescents
Nexavar has not yet been studied in children and adolescents.
Interactions Which drugs or foods may change the effect of Nexavar
Some medicines can affect Nexavar or be affected by it. Tell your doctor or pharmacist if you are taking, have recently taken or might take any of the medicines on this list or any other medicines, including those obtained without a prescription:
- Rifampicin, neomycin or other medicines used to treat infections (antibiotics)
- Hypericum perforatum, also known as "St. John's wort, a herbal treatment for depression
- Phenytoin, carbamazepine or phenobarbital, treatments for epilepsy and other diseases
- Dexamethasone, a corticosteroid used for various diseases
- Warfarin or phenprocomone, anticoagulants used to prevent blood clots
- Doxorubicin, capecitabine, docetaxel, paclitaxel and irinotecan, used in the treatment of cancer.
- Digoxin, used in the treatment of mild or moderate heart failure
Warnings It is important to know that:
Pregnancy and breastfeeding
Avoid becoming pregnant while being treated with Nexavar. If you are of childbearing age, you must use effective contraception during treatment with Nexavar. If you become pregnant while being treated with Nexavar, tell your doctor immediately who will decide whether the treatment should be continued or stopped.
You should not breastfeed your baby while being treated with Nexavar, as this medicine can interfere with your baby's growth and development.
Driving and using machines
There is no reason to believe that Nexavar will affect the ability to drive or use machines.
Dose, Method and Time of Administration How to use Nexavar: Posology
The recommended dose of Nexavar for adults is two 200 mg tablets twice a day.
These correspond to a daily dose of 800 mg, or four tablets per day. Take Nexavar tablets with a glass of water, between meals or with low to medium fat foods. Do not take this medicine with very fatty foods, as these may reduce their effectiveness. If you are planning to eat very fatty foods, take the tablets at least 1 hour before or 2 hours after lunch. Always take this medicine exactly as your doctor has told you. If you are unsure, consult your doctor or pharmacist.
It is important to take this medicine at about the same time each day to keep the concentration in the blood constant.
This medicine is usually taken as long as clinical benefits are noted, and there are no intolerable side effects.
Overdose What to do if you have taken too much Nexavar
If you take more Nexavar than you should
Tell your doctor immediately if you, or anyone else, have taken more than the prescribed dose. Taking too much Nexavar makes side effects more likely or more serious, especially diarrhea and skin reactions. Your doctor may tell you to stop taking this medicine.
If you forget to take Nexavar
If you have forgotten to take a dose, take it as soon as you remember. If your next dose is just short of time, forget the missed dose and proceed with your freq
Side Effects What are the side effects of Nexavar
Like all medicines, this medicine can cause side effects, although not everybody gets them. This medicine can also alter the results of some blood tests.
Very common:
may affect more than 1 in 10 people
- diarrhea
- malaise (nausea)
- feeling weak or tired (fatigue)
- pain (including pain in the mouth, abdomen, headache, bone pain, cancer pain)
- hair loss (alopecia)
- redness or pain in the palms or soles of the feet (hand-foot skin reaction)
- itching or rash
- He retched
- bleeding (including haemorrhage in the brain, intestinal wall and respiratory tract)
- high blood pressure, or increased blood pressure (hypertension)
- infections
- loss of appetite (anorexia)
- constipation
- joint pain (arthralgia)
- fever
- weight loss
- dryness of the skin
Common:
may affect up to 1 in 10 people
- flu-like illness
- indigestion (dyspepsia)
- difficulty swallowing (dysphagia)
- inflammation or dryness of the mouth, pain in the tongue (stomatitis and inflammation of the mucous membrane)
- low levels of calcium in the blood (hypocalcemia)
- low levels of potassium in the blood (hypokalaemia)
- muscle pain (myalgia)
- sensitivity disorders in the fingers and toes, including tingling and numbness (peripheral sensory neuropathy)
- depression
- erection problems (impotence)
- voice changes (dysphonia)
- acne
- inflamed, dry or flaking skin (dermatitis, skin peeling)
- heart failure
- heart attack (myocardial infarction) or chest pain
- tinnitus (ringing in the ears)
- kidney failure
- high levels of protein in the urine (proteinuria)
- general weakness or loss of strength (asthenia)
- reduced number of white blood cells (leukopenia and neutropenia)
- reduced number of red blood cells (anemia)
- low number of platelets in the blood (thrombocytopenia)
- inflammation of the hair follicles (folliculitis)
- reduced thyroid activity (hypothyroidism)
- low levels of sodium in the blood (hyponatremia)
- changes in the sense of taste (dysgeusia)
- redness of the face and often other areas of the skin (flushing)
- runny nose (runny nose)
- heartburn (gastroesophageal reflux disease)
- skin cancer (keratoacanthoma / squamous cell skin cancer)
- thickening of the outer layer of the skin (hyperkeratosis)
- sudden involuntary contraction of a muscle (muscle spasms)
Uncommon:
may affect up to 1 in 100 people
- stomach inflammation (gastritis)
- stomach (abdomen) pain due to pancreatitis, inflammation of the gallbladder and / or bile ducts
- yellowing of the skin or eyes (jaundice) caused by high levels of bile pigments (hyperbilirubinaemia)
- allergic-type reactions (including skin reactions and hives)
- dehydration
- breast enlargement (gynecomastia)
- difficulty in breathing (lung disease)
- eczema
- excessive thyroid activity (hyperthyroidism)
- multiple skin rashes (erythema multiforme)
- high blood pressure
- gastrointestinal perforation
- reversible edema in the back of the brain which may be associated with headache, altered consciousness, seizures and visual symptoms including loss of vision (posterior reversible leukoencephalopathy)
- sudden, severe allergic reaction (anaphylactic reaction)
Rare:
may affect up to 1 in 1,000 people
- allergic reaction with swelling of the skin (e.g. face, tongue) which may cause difficulty in breathing and swallowing (angioedema)
- abnormal heart rhythm (QT prolongation)
- Inflammation of the liver, which can lead to nausea, vomiting, abdominal pain and jaundice (drug-induced hepatitis)
- a "sunburn-like rash on skin previously exposed to radiation therapy and may be severe (actinic-like dermatitis)
- severe reactions of the skin and / or mucous membranes which may include painful blisters and fever, with detachment of large areas of skin (Stevens-Johnson syndrome and toxic epidermal necrolysis)
- abnormal muscle injury which can lead to kidney problems (rhabdomyolysis)
- kidney damage causing large amounts of protein to be lost in the urine (nephrotic syndrome)
- inflammation of the blood vessels in the skin which may manifest as a rash (leukocytoclastic vasculitis)
Not known:
frequency cannot be estimated from the available data
- impaired brain function which may be associated with e.g. sleepiness, behavioral changes, or confusion (encephalopathy)
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 listed in Appendix V. By reporting side effects you can help provide more information on the safety of this medicine.
Expiry and Retention
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 carton after EXP and on each blister after EXP. The expiry date refers to the last day of that month.
Do not store this medicine above 25 ° C.
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 Nexavar contains
- The active ingredient is sorafenib. Each film-coated tablet contains 200 mg of sorafenib (as tosylate).
- The other ingredients are: Tablet core: croscarmellose sodium, microcrystalline cellulose, hypromellose, sodium lauryl sulfate and magnesium stearate. Tablet coating: hypromellose, macrogol, titanium dioxide (E 171) and red iron oxide (E 172)
What Nexavar looks like and contents of the pack
Nexavar 200 mg film-coated tablets are red and round, with the Bayer cross on one side and "200" on the other side. They are presented in cartons of 112 tablets, containing four clear calendar blisters of 28 tablets each.
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
NEXAVAR 200 MG
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each film-coated tablet contains 200 mg of sorafenib (as tosylate).
For the full list of excipients, see section 6.1.
03.0 PHARMACEUTICAL FORM
Film-coated tablet (tablet).
Red, round, biconvex, film-coated tablets marked with a Bayer cross on one side and "200" on the other.
04.0 CLINICAL INFORMATION
04.1 Therapeutic indications
Hepatocarcinoma
Nexavar is indicated for the treatment of hepatocarcinoma (see section 5.1).
Renal cell carcinoma
Nexavar is indicated for the treatment of patients with advanced renal cell carcinoma who have failed prior interferon alpha or interleukin-2 therapy, or who are considered ineligible for such therapy.
Differentiated thyroid cancer
Nexavar is indicated for the treatment of patients with locally advanced or metastatic, progressive, radioiodine refractory differentiated thyroid cancer (papillary / follicular / Hürthle cell).
04.2 Posology and method of administration
Treatment with Nexavar should be under the supervision of a physician experienced in the use of anticancer therapies.
Dosage
The recommended dose of Nexavar for adults is 400 mg of sorafenib (two 200 mg tablets) twice daily (equivalent to a total daily dose of 800 mg).
Treatment should continue as long as clinical benefit is observed, or until unacceptable toxicities appear.
Adjustment of the dosage
Management of suspected adverse drug reactions may require temporary interruption or dose reduction of sorafenib therapy.
When a dose reduction is required during the treatment of hepatocellular carcinoma (hepatocellular carcinoma, HCC) and renal cell carcinoma (renal cell carcinoma, RCC), the dose of Nexavar should be reduced to two 200 mg sorafenib tablets once daily (see section 4.4).
When a dose reduction is required during the treatment of differentiated thyroid cancer (differentiated thyroid carcinoma, DTC), the dose of Nexavar should be reduced to 600 mg sorafenib per day in divided doses (two 200 mg tablets and one 200 mg tablet twelve hours apart).
If further dose reduction is required, Nexavar can be reduced to 400 mg sorafenib per day in divided doses (two 200 mg tablets twelve hours apart) and, if necessary, further reduced to one 200 mg tablet once once daily After improvement of non-haematological adverse reactions, the dose of Nexavar can be increased.
Pediatric population
The safety and efficacy of Nexavar in older children and adolescents
Elderly population
For the elderly population (patients over 65 years of age) no dosage adjustment is necessary.
Renal impairment
No dosage adjustment is necessary for patients with mild, moderate or severe renal impairment. No data are available for patients on dialysis (see section 5.2).
Monitoring of water and electrolyte balance is advisable in patients at risk of renal insufficiency.
Hepatic impairment
No dosage adjustment is required for patients with Child Pugh A or B (mild to moderate) hepatic impairment. No data are available on patients with severe Child Pugh C hepatic impairment (see sections 4.4 and 5.2).
Method of administration
For oral use
Sorafenib should be administered between meals or with a low or moderate fat meal. If the patient intends to have a high fat meal, sorafenib tablets should be taken at least one hour before or two hours after the meal. The tablets should be swallowed with a glass of water.
04.3 Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
04.4 Special warnings and appropriate precautions for use
Dermatological toxicity
Hand-foot skin reaction (palmar-plantar erythrodysaesthesia) e rash represent the most common adverse reactions to sorafenib. Rash and hand-foot skin reaction are usually Grade 1 and 2, according to i Common Toxicity Criteria (CTC), and generally appear during the first six weeks of sorafenib treatment. Management of dermatological toxicity may include topical therapies to relieve symptoms, temporary interruption of treatment and / or a change in the dosage of sorafenib, or in severe or persistent cases, definitive interruption of its administration (see section 4.8).
Hypertension
A higher incidence of arterial hypertension was observed in patients treated with sorafenib. In these patients, hypertension was usually mild to moderate, occurred in the early stages of treatment, and responded to standard antihypertensive therapy. Blood pressure should be monitored regularly and treated as necessary according to current medical practice. In the event of severe or persistent hypertension, or a hypertensive crisis, despite initiation of antihypertensive therapy, it is recommended to consider permanently discontinuing sorafenib administration (see section 4.8).
Hemorrhage
The risk of bleeding may increase following administration of sorafenib. If a bleeding episode requires medical intervention, it is recommended to consider permanently discontinuing sorafenib administration (see section 4.8).
Cardiac ischemia and / or heart attack
In a double-blind, randomized, placebo-controlled study (study 1, see section 5.1) the incidence of treatment-onset cardiac infarction or ischaemia was higher in the sorafenib group (4.9%) than in the treatment group. placebo (0.4%). In study 3 (see section 5.1) the incidence of treatment-onset cardiac infarction or ischaemia was 2.7% in sorafenib-treated patients and 1.3% in patients treated with placebo. Patients with unstable coronary artery disease or with recent myocardial infarction were excluded from these studies. The need for temporary or permanent discontinuation of sorafenib treatment should be considered in patients who develop cardiac ischaemia and / or infarction (see section 4.8).
QT interval prolongation
Sorafenib has been shown to prolong the QT / QTc interval (see section 5.1), which may lead to an increased risk of ventricular arrhythmia. Use sorafenib with caution in patients who have or may develop QTc prolongation, such as patients with a Congenital Long QT Syndrome, those treated with a high cumulative dose of anthracyclines, patients taking certain antiarrhythmic drugs or other drugs that can lead to QT prolongation, and those with electrolyte disturbances, for example hypokalaemia, hypocalcaemia or hypomagnesaemia When sorafenib is used in these patients, periodic electrocardiography and electrolyte (magnesium, potassium and calcium) measurements should be performed during the treatment period.
Gastrointestinal perforation
Gastrointestinal perforation is an uncommon event and has been reported in less than 1% of patients taking sorafenib. In some cases, there was no association with obvious intra-abdominal tumor. In the event of gastrointestinal perforation, administration of sorafenib should be discontinued (see section 4.8).
Hepatic impairment
No data are available in patients with severe hepatic impairment (Child Pugh C). In such patients, exposure may be increased as sorafenib is eliminated primarily via the liver (see sections 4.2 and 5.2).
Concomitant administration of warfarin
Infrequent bleeding episodes or an increase in the INR (International Normalized
Ratio) have been reported in some patients taking warfarin during sorafenib therapy. Patients on warfarin or phenprocoumon therapy should be monitored regularly for changes in prothrombin time, INR or clinically relevant bleeding episodes (see sections 4.5 and 4.8).
Complications in wound healing
No formal studies on the effect of sorafenib on wound healing have been conducted. Temporary suspension of sorafenib treatment is recommended for precautionary reasons in patients undergoing major surgery. Clinical experience regarding when to resume. therapy after major surgery is limited. Therefore, the decision to resume sorafenib therapy following major surgery should be based on a clinical assessment of adequate wound healing.
Elderly population
Cases of renal failure have been reported. Therefore, monitoring of renal function should be considered.
Interaction between drugs
Caution is advised when administering sorafenib with substances that are metabolised and / or eliminated predominantly via the UGT1A1 (e.g. irinotecan) or UGT1A9 metabolic pathways (see section 4.5).
Caution is recommended in case of concomitant administration of sorafenib and docetaxel (see section 4.5).
The combination with neomycin or with other antibiotics capable of causing serious ecological disturbances in the gastrointestinal microflora may lead to a decrease in the bioavailability of sorafenib (see section 4.5). The risk of a decrease in plasma concentration of sorafenib should be evaluated before starting. a course of treatment with antibiotics.
Higher mortality was observed in patients with squamous cell lung cancer treated with sorafenib in combination with platinum-based chemotherapy.
In two randomized clinical trials, which studied patients with non-small cell lung cancer (Non-Small Cell Lung Cancer, NSCLC), the overall survival hazard ratio (HR) in a subgroup of patients with squamous cell lung cancer was 1.81 (95% CI 1.19, 2.74) in patients treated with sorafenib in addition to paclitaxel / carboplatin therapy and 1.22 (95% CI 0.82; 1.80) in patients treated with sorafenib in addition to gemcitabine / cisplatin therapy. No predominant cause of death was observed, but an increased incidence of respiratory failure, haemorrhages and infections was observed in patients treated with sorafenib in addition to platinum-based therapy.
Pathology specific warnings
Differentiated Thyroid Carcinoma (DTC)
Prior to initiating treatment, physicians are recommended to carefully evaluate individual patient prognosis based on maximum lesion size (see section 5.1), disease-related symptoms (see section 5.1) and rate of progression.
Management of suspected adverse drug reactions may necessitate a "temporary interruption or dose reduction of sorafenib therapy. In study 5 (see section 5.1), 37% of subjects temporarily discontinued therapy and 35% reduced the dose as early as cycle 1 of sorafenib treatment.
Dose reduction was only partially effective in alleviating adverse reactions. Repeated benefit and risk assessments are therefore recommended, taking into account antitumor activity and tolerability.
Hemorrhage in the DTC
Because of the potential risk of haemorrhage, tracheal, bronchial and esophageal infiltration must be treated with local therapy before sorafenib is administered to patients with DTC.
Hypocalcemia in the DTC
When using sorafenib in patients with DTC, close monitoring of blood calcium levels is recommended. In clinical trials, hypocalcaemia was more frequent and more severe in patients with DTC, particularly in those with a history of hypoparathyroidism, compared to patients with renal cell carcinoma or hepatocarcinoma. Grade 3 and 4 hypocalcaemia occurred. manifested in 6.8% and 3.4% of sorafenib-treated patients with DTC (see section 4.8). Severe hypocalcaemia should be corrected to prevent complications such as QT interval prolongation or torsades de pointes (see QT interval prolongation section).
Suppression of TSH in the DTC
In study 5 (see section 5.1), increases in TSH levels greater than 0.5 mU / L were observed in patients treated with sorafenib. Close monitoring of TSH levels is recommended when using sorafenib in patients with DTC.
Renal cell carcinoma
High-risk patients, as defined by the MSKCC prognostic group (Memorial Sloan Kettering Cancer Center), were not included in the phase III clinical study in renal cell carcinoma (see study 1 in section 5.1) and the benefit-risk ratio in these patients has not been established.
04.5 Interactions with other medicinal products and other forms of interaction
Inducers of metabolic enzymes
Administration of rifampicin for 5 days prior to administration of a single dose of sorafenib resulted in a mean reduction of sorafenib AUC of 37%. Other inducers of CYP3A4 and / or glucuronidation (eg. hypericum perforatum also known as "St. John's wort", phenytoin, carbamazepine, phenobarbital and dexamethasone) can increase the metabolism of sorafenib and thereby reduce its concentration.
CYP3A4 inhibitors
Ketoconazole, a potent CYP3A4 inhibitor, administered once daily for 7 days to healthy male volunteers did not alter the mean AUC of a single 50 mg dose of sorafenib. These data suggest that the clinical pharmacokinetic interactions of sorafenib with CYP3A4 inhibitors are unlikely.
CYP2B6, CYP2C8 and CYP2C9 substrates
In vitro sorafenib inhibits CYP2B6, CYP2C8 and CYP2C9 with nearly equal potency. However, in clinical pharmacokinetic studies, co-administration of sorafenib 400 mg twice daily with cyclophosphamide, a CYP2B6 substrate, or paclitaxel, a CYP2C8 substrate, did not result in clinically significant inhibition. These data suggest that sorafenib , at the recommended dose of 400 mg twice daily, may not be an inhibitor in vivo CYP2B6 or CYP2C8.
Furthermore, concomitant treatment with sorafenib and warfarin, a substrate of CYP2C9, did not lead to changes in the mean PT-INR compared to placebo. Therefore, also the risk of an "inhibition in vivo clinically relevant CYP2C9 by sorafenib can be considered low. However, patients taking warfarin or phenprocoumon should have their INR monitored regularly (see section 4.4).
CYP3A4, CYP2D6 and CYP2C19 substrates
Concomitant administration of sorafenib and midazolam, dextromethorphan or omeprazole, which are substrates for the cytochromes CYP3A4, CYP2D6 and CYP2C19, respectively, did not alter the exposure to these agents. This indicates that sorafenib is neither an inhibitor nor an inducer of these isoenzymes. Therefore, clinical pharmacokinetic interactions of sorafenib with substrates of these enzymes are unlikely.
UGT1A1 and UGT1A9 substrates
In vitro, sorafenib inhibited glucuronidation by UGT1A1 and UGT1A9. The clinical relevance of this finding is unknown (see below and section 4.4).
Education in vitro on the induction of enzymes of the CYP system
CYP1A2 and CYP3A4 activities were not altered after exposure of human hepatocyte cultures to sorafenib, thus indicating that sorafenib is unlikely to be an inducer of CYP1A2 and CYP3A4.
Substrates for P-gp
In vitro, sorafenib has been shown to inhibit the transport protein p-glycoprotein (P-gp). In case of concomitant treatment with sorafenib, an increase in the plasma concentration of substrates for P-gp, such as digoxin, cannot be excluded.
Association with other antineoplastic agents
In clinical studies, sorafenib was administered with a number of other antineoplastic agents at their commonly used posology, including gemcitabine, cisplatin, oxaliplatin, paclitaxel, carboplatin, capecitabine, doxorubicin, irinotecan, docetaxel and cyclophosphamide. Sorafenib had no clinically relevant effect on the pharmacokinetics of gemcitabine, cisplatin, carboplatin, oxaliplatin or cyclophosphamide.
Paclitaxel / carboplatin
• Administration of paclitaxel (225 mg / m2) and carboplatin (AUC = 6) with sorafenib (≤ 400 mg twice daily), with a 3-day interruption of sorafenib administration (the previous two days and the day of administration of paclitaxel / carboplatin), had no significant effect on the pharmacokinetics of paclitaxel.
• Concomitant administration of paclitaxel (225 mg / m2, once every 3 weeks) and carboplatin (AUC = 6) with sorafenib (400 mg twice daily, without interruption of sorafenib dosing) resulted in a 47% increase in sorafenib exposure, a 29% increase in paclitaxel exposure and a 50% increase in 6-OH paclitaxel exposure. The pharmacokinetics of carboplatin were not affected.
These data indicate that no dosage adjustment is required when paclitaxel and carboplatin are co-administered with sorafenib with a 3-day interruption of sorafenib administration (the two days prior to and the day of paclitaxel / carboplatin administration). Note the clinical relevance of the increased exposure to sorafenib and paclitaxel soon after co-administration of sorafenib without dosing interruption.
Capecitabine
Concomitant administration of capecitabine (750-1050 mg / m2 twice daily, days 1-14 every 21 days) and sorafenib (200 or 400 mg twice daily without dosing interruption) did not result in significant changes in exposure. to sorafenib, but a 15-50% increase in capecitabine exposure and a 0-52% increase in 5-FU exposure. The clinical relevance of these small, modest increases in exposure to 5-FU is unknown. capecitabine and 5-FU when co-administered with sorafenib.
Doxorubicin / Irinotecan
Concomitant treatment with sorafenib resulted in a 21% increase in the AUC of doxorubicin. When administered with irinotecan, whose metabolite SN-38 is subsequently metabolised via the UGT1A1 pathway, there was a 67-120% increase in "AUC of SN-38 and 26 - 42% in AUC of irinotecan." The clinical relevance of these data is unknown (see section 4.4).
Docetaxel
Docetaxel (a dose of 75 or 100 mg / m2 every 21 days) administered concomitantly with sorafenib (200 mg or 400 mg twice daily on days 2 to 19 of a 21-day course of therapy, with an interruption of 3 days corresponding to docetaxel administration) resulted in an increase in docetaxel AUC and Cmax of 36 - 80% and 16 - 32%, respectively. Caution is recommended when co-administered with sorafenib and docetaxel (see section 4.4 ).
Association with other agents
Neomycin
The combination with neomycin, a non-systemic antimicrobial agent used to eradicate the gastrointestinal flora, interferes with the enterohepatic recirculation of sorafenib (see section 5.2, Biotransformation and Metabolism), resulting in decreased exposure to sorafenib. In healthy volunteers treated with neomycin for 5 days, the mean sorafenib exposure decreased by 54%. The effects of other antibiotics have not been studied but will most likely depend on their ability to interfere with microorganisms with glucuronidase activity.
04.6 Pregnancy and lactation
Pregnancy
There are no data on the use of sorafenib in pregnant women.Animal studies have shown reproductive toxicity, including malformations (see section 5.3). Sorafenib and its metabolites have been shown to cross the placenta in rats, and sorafenib is expected to cause harmful effects on the fetus. Sorafenib should not be used during pregnancy unless clearly necessary and only after a "careful consideration of the needs of the mother and the risk to the fetus."
Women of childbearing potential should use effective contraception during treatment.
Feeding time
It is unknown whether sorafenib is excreted in human milk. In animals, sorafenib and / or its metabolites are excreted in milk. Since sorafenib may impair the growth and development of the newborn (see section 5.3), women should discontinue breastfeeding during treatment with sorafenib.
Fertility
Animal studies show that sorafenib may impair male and female fertility (see section 5.3).
04.7 Effects on ability to drive and use machines
No studies on the ability to drive or use machines have been performed. There is no reason to believe that sorafenib affects the ability to drive or use machines.
04.8 Undesirable effects
The most important serious adverse reactions were myocardial ischaemia and infarction, gastrointestinal perforation, drug hepatitis, haemorrhage and hypertension or hypertensive crisis.
The most common adverse reactions were diarrhea, asthenia, alopecia, infection, hand-foot skin reaction (corresponding in MedDRA to "palmar-plantar erythrodysaesthesia syndrome") and rash.
Adverse reactions reported in various clinical trials or post-marketing use are listed in table 1, sorted by MedDRA and frequency. Frequencies are defined as follows: very common (≥1 / 10 ), common (≥1 / 100,
Within each frequency class, undesirable effects are presented in descending order of severity.
Table 1: Overall adverse reactions reported in patients in different clinical studies or in post-marketing use.
* Adverse reactions can be life-threatening or fatal. These events are either uncommon or less frequent than uncommon.
** Hand-foot skin reaction corresponds to palmar-plantar erythrodysaesthesia syndrome in MedDRA
Learn more about some adverse reactions
Congestive heart failure
In a company-sponsored clinical study, congestive heart failure was reported as an adverse event in 1.9% of patients treated with sorafenib (N = 2276). In study 11213 (RCC) adverse events consistent with congestive heart failure were reported in 1.7% of sorafenib-treated patients and 0.7% of placebo-treated patients. In study 100554 (HCC) such events were reported in 0.99% of sorafenib-treated patients and 1.1% of placebo-treated patients.
Additional information for special populations
In clinical studies, certain adverse drug reactions, such as hand-foot skin reaction, diarrhea, alopecia, weight loss, hypertension, hypocalcaemia and keratoacanthoma / squamous cell skin carcinoma, occurred with a considerably higher frequency in patients with differentiated thyroid cancer compared to patients included in the renal or hepatocellular cell carcinoma studies.
Changes in laboratory tests in patients with HCC (study 3) and RCC (study 1)
An increase in lipase and amylase has been reported very commonly. A Grade 3 or 4 increase in lipase Common Toxicity CriteriaAdvers Events (CTCAE) occurred in 11% and 9% of patients in the sorafenib group in Study 1 (RCC) and Study 3 (HCC), respectively, versus 7% and 9% of patients in the Sorafenib group. treated with placebo. A CTCAE Grade 3 or 4 amylase elevation occurred in 1% and 2% of patients in the sorafenib group in study 1 and study 3, respectively, versus 3% of patients in both. placebo groups. Clinical pancreatitis was reported in 2 of 451 patients treated with sorafenib (CTCAE Grade 4) in Study 1, in 1 of 297 patients treated with sorafenib (CTCAE Grade 2) in Study 3 and in 1 of 451 patients (CTCAE Grade 2) treated with placebo in study 1.
Hypophosphataemia is a very common laboratory finding, and was observed in 45% and 35% of sorafenib-treated patients in study 1 and study 3, respectively, versus 12% and 11% of placebo-treated patients, respectively. . CTCAE Grade 3 hypophosphataemia (1 - 2 mg / dL) occurred in study 1 in 13% of sorafenib-treated patients and in 3% of placebo-treated patients, while in study 3 it occurred in 11% of patients treated with sorafenib and in 2% of patients treated with placebo No cases of CTCAE Grade 4 hypophosphataemia have been reported (etiology of hypophosphataemia associated with sorafenib is unknown.
CTCAE grade 3 or 4 laboratory abnormalities, including lymphopenia and neutropenia, were observed in ≥ 5% of patients treated with sorafenib.
Hypocalcaemia was observed in 12% and 26.5% of sorafenib-treated patients compared with 7.5% and 14.8% of patients in the placebo group in study 1 and study 3, respectively. cases of hypocalcaemia were mild (CTCAE grade 1 and 2). A CTCAE grade 3 hypocalcaemia (6.0 - 7.0 mg / dL) occurred in 1.1% and 1.8% of patients treated with sorafenib and in 0.2% and 1.1% of patients in the placebo group, and a CTCAE grade 4 hypocalcaemia (
In studies 1 and 3, a reduction in potassium was observed in 5.4% and 9.5% of patients treated with sorafenib, respectively, compared with 0.7% and 5.9% of patients who received placebo. Most cases of hypokalaemia were mild (CTCAE grade 1). In these studies, CTCAE grade 3 hypokalaemia occurred in 1.1% and 0.4% of sorafenib-treated patients and 0.2% and 0.7% of patients in the placebo group. cases of CTCAE grade 4 hypokalaemia.
Changes in laboratory tests in patients with DTC (study 5)
Hypocalcaemia was observed in 35.7% of sorafenib-treated patients compared with 11.0% of patients in the placebo group. Most cases of hypocalcemia were mild in severity. CTCAE grade 3 hypocalcaemia occurred in 6.8% of sorafenib-treated patients and 1.9% of patients in the placebo group, while CTCAE grade 4 hypocalcaemia occurred in 3.4% of patients. patients treated with sorafenib and in 1.0% of patients in the placebo group.
Other clinically relevant laboratory changes observed in study 5 are shown in Table 2.
Table 2: Treatment-emergent laboratory abnormalities reported in DTC patients (study 5) in the double-blind phase
* Common Terminology Criteria for Adverse Events (CTCAE), version 3.0
** The etiology of sorafenib associated hypophosphataemia is unknown.
Reporting of suspected adverse reactions
The reporting of suspected adverse reactions that occur after authorization of the medicinal product is important, as it allows continuous monitoring of the benefit / risk ratio of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Italian Medicines Agency, website: www.agenziafarmaco.gov.it/it/responsabili.
04.9 Overdose
There are no specific treatments in case of sorafenib overdose. The highest dose of sorafenib studied clinically is 800 mg twice daily. Adverse events observed following this dosage were mainly diarrhea and dermatological reactions. If overdose is suspected, sorafenib should be discontinued and, if necessary, supportive therapy initiated.
05.0 PHARMACOLOGICAL PROPERTIES
05.1 Pharmacodynamic properties
Pharmacotherapeutic group: antineoplastic agents, protein kinase inhibitors.
ATC code: L01XE05.
Sorafenib is a kinase inhibitor that has demonstrated both anti-proliferative and anti-angiogenic properties in vitro and in vivo.
Mechanism of action and pharmacodynamic effects
Sorafenib is a kinase inhibitor that inhibits the proliferation of cancer cells in vitro. Sorafenib inhibits the growth of a broad spectrum of human tumors transplanted into athymic mice, also resulting in a reduction in tumor angiogenesis. Sorafenib inhibits the activity of targets present in the tumor cell (CRAF, BRAF, V600E BRAF, c-KIT and FLT- 3) and in the blood vessels of the tumor (CRAF, VEGFR-2, VEGFR-3 and PDGFR-ß). RAF kinases are serine / threonine kinases, while c-KIT, FLT-3, VEGFR-2, VEGFR-3 and PDGFR-ß are receptor tyrosine kinases.
Clinical efficacy
The safety and clinical efficacy of sorafenib have been studied in patients with hepatocellular carcinoma (hepatocellular carcinoma, HCC), in patients with advanced renal cell carcinoma (renal cell carcinoma, RCC) and in patients with differentiated thyroid cancer (differentiated thyroid carcinoma, DTC).
Hepatocarcinoma
Study 3 (study 100554) was a multicentre, randomized, double-blind, placebo-controlled, international Phase III clinical study in 602 patients with hepatocellular cancer. Baseline demographics and disease characteristics were comparable between the sorafenib and placebo groups with respect to the Estern Cooperative Oncology Group (ECOG) classification (grade 0: 54% versus 54%; grade 1: 38% versus 39%; grade 2: 8% versus 7%), to the TNM classification (stage I:
The study was closed after a planned interim Overall Survival (OS) analysis exceeded the predefined efficacy limit. This OS analysis showed a statistically significant increase in OS for sorafenib-treated patients compared to placebo-treated patients (HR: 0.69, p = 0.00058, see table 3).
In this study data in patients with Child Pugh B hepatic impairment are limited, and only one Child Pugh C patient was included.
Table 3: Efficacy Results from Study 3 (Study 100554) in Hepatocarcinoma
CI = Confidence interval, HR = Hazard ratio (sorafenib over placebo)
* statistically significant as the p-value was below the default O "cutoff limit, set at 0.0077
** independent radiological review
A second Phase III, international, multicenter, randomized, double-blind, placebo-controlled study (Study 4, 11849) evaluated the clinical benefit of sorafenib in 226 patients with advanced liver cancer. This study, conducted in China, Korea and Taiwan, confirmed the results of Study 3 with respect to the favorable benefit-risk profile of sorafenib (HR (OS): 0.68, p = 0.01414).
In the predefined stratification factors (ECOG classification, presence or absence of macroscopic vascular invasion and / or extrahepatic spread of the tumor) of Studies 3 and 4, the HR was consistently in favor of sorafenib over placebo. Exploratory subgroup analyzes suggested a less pronounced treatment effect in patients with distant metastases already at baseline.
Renal cell carcinoma
The tolerability and efficacy of sorafenib in the treatment of advanced renal cell carcinoma (RCC) were studied in two clinical studies:
Study 1 (study 11213) was a multicentre, randomized, double-blind, placebo-controlled Phase III clinical study conducted in 903 patients. Only patients with clear cell renal tumors and with low and medium risk factor according to MSKCC were enrolled. The endpointprimary were overall survival (OS, overall survival) and progression-free survival (PFS, Progression Free Survival).
Approximately half of the patients had their general condition equal to 0 on the ECOG scale, and half of the patients belonged to the prognostic group with a low score according to the MSKCC classification.
PFS was assessed according to RECIST criteria with a blinded independent radiological review. PFS analysis was performed on 342 events in 769 patients. The median PFS was 167 days in sorafenib-treated patients compared with 84 days in patients who received placebo (HR = 0.44; 95% CI : 0.35 - 0.55; p
An "analysis interim (second analysis interim) for overall survival (overall survival) was conducted on 367 deaths in 903 patients. The nominal alpha value for this analysis was 0.0094. Median survival was 19.3 months in sorafenib-treated patients, compared with 15.9 months in patients randomized to placebo (HR = 0.77; 95% CI: 0.63-0.95; p = 0.015) . At the time of analysis, approximately 200 patients switched from the placebo group to the sorafenib group.
Study 2 was a Phase II study with randomized discontinuation of treatment in patients with metastatic cancer, including RCC. Patients with stable disease and on sorafenib therapy were randomized to placebo or to continuation of sorafenib therapy. PFS in patients with RCC was significantly greater (163 days) for sorafenib-treated patients than that observed in patients who received placebo (41 days) (p = 0.0001, HR = 0.29).
Differentiated thyroid carcinoma (DTC)
Study 5 (study 14295) was an international, multicentre, randomized, double-blind, placebo-controlled phase III study conducted in 417 patients with locally advanced or metastatic radioiodine refractory DTC. Progression-free survival (PFS), as determined by blinded independent radiological assessment based on RECIST criteria, was the primary endpoint of the study. Secondary endpoints included overall survival (OS), tumor response rate, and duration of response After progression, patients could receive open-label sorafenib.
Patients were included in the study if they progressed within 14 months prior to enrollment and if they had a DTC refractory to radioiodine (radioactive iodine, RAI).DTC refractory to RAI was defined as the presence of a non-iodine-enhancing lesion on RAI scintigraphy, or cumulative administration of RAI ≥ 22.2 GBq, or progression after RAI treatment within the previous 16 months. enrollment or after two treatments with RAI performed at a maximum distance of 16 months from each other.
Baseline demographics and patient characteristics were well balanced in the two treatment groups. Metastases were present in the lungs in 86%, in the lymph nodes in 51% and in the bone in 27% of patients. The median cumulative radioiodine activity administered prior to enrollment was approximately 14.8 GBq. Most patients had papillary carcinoma (56.8%), followed by follicular carcinoma (25.4%) and poorly differentiated carcinoma (9.6%).
Median time to PFS was 10.8 months in the sorafenib group, compared with 5.8 months in the placebo group. (HR = 0.587; 95% confidence interval (CI): 0.454, 0.758; p unilateral
The effect of sorafenib on PFS was constant regardless of geographic region, age above or below 60 years, gender, histology, and presence or absence of bone metastases.
In an overall survival analysis conducted 9 months after the cut-off date for the final PFS analysis, there was no statistically significant difference in overall survival between the treatment groups (HR 0.884; CI 95 %: 0.633; 1.236, one-sided p-value of 0.236). Median OS was not achieved in the sorafenib arm, while it was 36.5 months in the placebo arm. One hundred and fifty-seven patients (75%) randomized to placebo and 61 patients (30%) randomized to sorafenib received open label sorafenib.
The median duration of therapy in the double-blind phase was 46 weeks (range 0.3-135) for patients who received sorafenib and 28 weeks (range 1.7-132) for patients who received placebo. .
No complete response was observed (complete response, CR) according to RECIST criteria. The overall response rate (CR + partial response, partial response (PR)), determined by independent radiological evaluation, was higher in the sorafenib group (24 patients, 12.2%) compared to the placebo group (1 patient, 0.5%), p unilateral
A post-group subgroup analysis based on maximal tumor size showed a treatment effect on PFS in favor of sorafenib compared to placebo in patients with maximal tumor lesion size of 1.5 cm or more (HR 0.54 (95% CI: 0.41-0.71)), while a numerically lower effect was recorded in patients with maximum tumor lesion size less than 1.5 cm (HR 0.87 (95% CI: 0.40 -1.89)).
A post-hoc analysis based on thyroid cancer-related symptoms present in baseline conditions showed a treatment effect on PFS in favor of sorafenib over placebo in both symptomatic and asymptomatic patients. HR value for free survival progression was 0.39 (95% CI: 0.21 - 0.72) for patients with symptoms at baseline and 0.60 (95% CI: 0.45 - 0.81) for patients without symptoms in basal conditions.
Prolongation of the QT interval
In a clinical pharmacology study, QT / QTc was measured in 31 patients at baseline (pre-treatment) and after treatment. After a 28-day treatment cycle, at the time of maximum sorafenib concentration, QTcB was prolonged by 4 ± 19 msec and QTcF by 9 ± 18 msec, compared to baseline for the placebo group. No patient showed a QTcB or QTcF value> 500 msec during post-treatment ECG monitoring (see section 4.4).
Pediatric population
The European Medicines Agency has waived the obligation to submit the results of studies in all subsets of the pediatric population for kidney and renal pelvis cancer (excluding nephroblastoma, nephroblastomatosis, clear cell sarcoma, mesoblastic nephroma, renal medullary carcinoma and rhabdoid tumor of the kidney) and carcinoma of the liver and intrahepatic bile duct (excluding hepatoblastoma) and differentiated thyroid carcinoma (see section 4.2 for information on pediatric use).
05.2 "Pharmacokinetic properties
Absorption and distribution
After administration of sorafenib tablets, the mean relative bioavailability is 38 - 49% when compared to an oral solution. Absolute bioavailability is unknown. Following oral administration, sorafenib reaches peak plasma levels in approximately 3 hours. When given with a high fat meal, the absorption of sorafenib is reduced by approximately 30% when compared to administration in the fasted state.
The mean Cmax and AUC increase less than proportionally with doses above 400 mg twice daily. Plasma protein binding of sorafenib in vitro is 99.5%.
Repeated dosing of sorafenib for 7 days resulted in 2.5 to 7 fold accumulation compared to single administration. Steady state of sorafenib is achieved within 7 days, with a ratio of mean peak to trough plasma concentrations of less than 2.
Equilibrium concentrations of sorafenib administered at 400 mg twice daily were determined in patients with DTC, RCC and HCC. The highest mean concentration was observed in patients with DTC (approximately double that observed in patients with RCC and HCC), but the variability was high for all tumor types The cause of this higher concentration in DTC patients is unknown.
Biotransformation and elimination
The elimination half-life of sorafenib is approximately 25 to 48 hours. Sorafenib is metabolised primarily in the liver via CYP3A4-mediated oxidative metabolism and UGT1A9-mediated glucurono-conjugation. Conjugated sorafenib can be released in the gastrointestinal tract by the glucuronidase activity of some bacteria, thus allowing the reabsorption of the unconjugated active ingredient. The combination with neomycin has been observed to interfere with this process, decreasing the mean bioavailability of sorafenib by 54%.
Sorafenib accounts for approximately 70 - 85% of the analytes circulating in steady state plasma. Eight metabolites of sorafenib have been identified, five of which have been found in plasma. The major metabolite of sorafenib circulating in plasma, pyridine N-oxide, exhibits potencyin vitro similar to that of sorafenib. This metabolite accounts for approximately 9 - 16% of the analytes circulating at steady state.
Following oral administration of a 100 mg dose of sorafenib solution, 96% of the dose was recovered within 14 days: 77% in faeces and 19% in urine as glucuronate metabolites. Unchanged sorafenib, which represents 51% of the dose, was recovered in faeces but not urine, indicating that biliary excretion of the unmetabolised active substance may contribute to the elimination of sorafenib.
Pharmacokinetics in particular categories of patients
Analysis of demographic data showed that there is no correlation between pharmacokinetics and age (up to 65 years), sex or body weight.
Pediatric population
No studies have been conducted to verify the pharmacokinetics of sorafenib in pediatric patients.
Race
There are no clinically relevant differences in pharmacokinetics between Caucasian and Asian subjects.
Renal impairment
In four Phase I clinical studies, steady-state sorafenib exposure in patients with mild or moderate renal impairment was similar to that found in patients with normal renal function. In a clinical pharmacology study (400 mg single dose of sorafenib) no relationship was observed between sorafenib exposure and renal function in subjects with normal renal function or mild, moderate or severe renal impairment. No data are available in patients requiring dialysis.
Hepatic impairment
In patients with hepatocellular carcinoma (HCC) and with hepatic impairment assessed as Child-Pugh A or B (mild to moderate), exposure values were comparable and within the range observed in patients without hepatic impairment. The pharmacokinetics of sorafenib in Child-Pugh A and B patients without HCC were similar to that seen in healthy volunteers. There are no data for patients with severe (Child-Pugh C) hepatic impairment. Sorafenib is eliminated primarily via the liver and exposure may be increased in this patient population.
05.3 Preclinical safety data
The preclinical safety profile of sorafenib was evaluated in mice, rats, dogs and rabbits.
Repeated dose toxicity studies have revealed changes in various organs (degeneration and regeneration) at exposures below those of the dosages used in clinical studies (based on a comparison of AUC).
After repeated dosing in young and growing dogs, effects on bones and teeth were observed at exposures below those of the dosages used in clinical studies. These effects consisted of uneven thickening of the growth plate of the femur, medullary hypoplasia in the vicinity of the altered growth plates and changes in the composition of the dentin. Similar effects were not induced in the adult dog.
The standard program of genotoxicity studies was conducted and positive results were obtained as an increase in chromosomal structural aberrations was noted in one assay. in vitro in mammalian cells (Chinese hamster ovaries) for the measurement of clastogenicity in the presence of metabolic activation. Sorafenib was not genotoxic in the Ames test or the micronucleus test in vivo in the mouse. An intermediate of the manufacturing process, which is also present in the final active substance (in vitro on bacterial cells (Ames test). In addition, the batch of sorafenib tested in the standard genotoxic battery included 0.34% PAPE.
Carcinogenicity studies have not been performed with sorafenib.
No specific animal studies have been performed with sorafenib to evaluate the effect on fertility. An adverse effect on male and female fertility is however to be expected, as repeated dose animal studies have shown changes in male and female reproductive organs at exposures below those of the dosages used in clinical trials (based on AUC). The changes typically consisted of signs of degeneration and delayed development of the testes, epididymis, prostate and seminal vesicles in rats. Female rats showed central necrosis of the corpora lutei and blockage of follicular development in the ovaries. Dogs showed tubular degeneration in the ovaries. testes and oligospermia.
Sorafenib has been shown to be embryotoxic and teratogenic when administered to rats and rabbits at exposures below those of the dosages used in clinical studies. Effects observed included a decrease in maternal and fetal body weight, an increase in the number of fetal resorptions, and an increased number of external and visceral malformations.
Environmental risk assessment studies have shown that sorafenib tosylate is potentially persistent, bioaccumulative and toxic to the environment. Information on the environmental risk assessment is available in the European Public Assessment Report (EPAR) for this medicinal product (see section 6.6 ).
06.0 PHARMACEUTICAL INFORMATION
06.1 Excipients
Core of the tablet:
Croscarmellose sodium
Microcrystalline cellulose
Hypromellose
Sodium lauryl sulfate
Magnesium stearate
Tablet coating:
Hypromellose
Macrogol
Titanium dioxide (E 171)
Red iron oxide (E 172)
06.2 Incompatibility
Not relevant.
06.3 Period of validity
3 years.
06.4 Special precautions for storage
Do not store above 25 ° C.
06.5 Nature of the immediate packaging and contents of the package
Carton containing 112 film-coated tablets (4 x 28) in clear blister (PP / Aluminum).
06.6 Instructions for use and handling
This medicinal product may pose a potential risk to the environment. Unused medicinal product and waste derived from this medicinal product must be disposed of in accordance with local regulations.
07.0 MARKETING AUTHORIZATION HOLDER
Bayer Pharma AG
13342 Berlin
Germany
08.0 MARKETING AUTHORIZATION NUMBER
EU / 1/06/342/001
037154010
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION
Date of first authorization: 19 July 2006
Date of most recent renewal: 21st July 2011
10.0 DATE OF REVISION OF THE TEXT
05/2014
