Active ingredients: Sunitinib
SUTENT 12.5 mg hard capsules
SUTENT 25 mg hard capsules
SUTENT 37.5 mg hard capsules
SUTENT 50 mg hard capsules
Indications Why is Sutent used? What is it for?
Sutent contains the active substance sunitinib, which is a protein kinase inhibitor. It is used to treat cancer by preventing the activity of a specific group of proteins that are known to be involved in the growth and spread of cancer cells.
Sutent will only be prescribed to you by a doctor who has experience in the use of cancer medicines.
Sutent is used to treat adults with the following types of cancer:
- Gastrointestinal stromal cancer (GIST), a type of cancer of the stomach and intestines, in cases where imatinib (another anticancer medicine) no longer works or can no longer be taken.
- Metastatic kidney cancer (MRCC), a type of kidney cancer that has spread to other parts of the body.
- Pancreatic neuroendocrine tumors (pNETs) (cancers of the hormone-producing cells of the pancreas) that are progressing or unresectable
. If you are not sure how Sutent works or why this medicine has been prescribed for you, ask your doctor.
Contraindications When Sutent should not be used
Do not take Sutent:
- If you are allergic to sunitinib or any of the other ingredients of this medicine (listed in section 6).
Precautions for use What you need to know before taking Sutent
Tell your doctor before taking Sutent:
- If you have high blood pressure. Sutent can cause your blood pressure to rise. Your doctor may check your blood pressure while you are taking Sutent and will need to take medicines to lower your blood pressure if necessary.
- If you have or have had blood disorders, bleeding problems or bruises. Treatment with Sutent may carry an increased risk of bleeding, changes in the number of certain blood cells whose deficiency leads to anemia or affects the ability of the blood to clot. The risk of bleeding may be higher if you are taking warfarin or acenocoumarol, medicines that thin the blood to prevent blood clots. Tell your doctor if you experience any bleeding while taking Sutent.
- If you have heart problems. Sutent can cause heart problems. Tell your doctor if you feel very tired, have shortness of breath or have swollen feet and ankles.
- If you experience abnormal heart rhythm changes. Sutent can cause changes in the heart rhythm. While you are being treated with Sutent, your doctor may have an electrocardiogram done to assess the extent of these changes. Tell your doctor if you feel dizzy, faint or have abnormal heartbeats while taking Sutent.
- If you have recently had problems due to the formation of blood clots in the veins and / or arteries (types of blood vessels), including stroke, heart attack, embolism or thrombosis. Contact your doctor immediately if you experience symptoms such as chest tightness or pain, pain in the arms, back, neck or jaw, shortness of breath, numbness or weakness on one side of the body, shaky walking, pain during treatment with Sutent. headache or dizziness.
- If you have thyroid problems. Sutent can cause thyroid problems. Tell your doctor if you get tired more easily while you are taking Sutent, you generally feel colder than other people or your voice drops. Thyroid function should be checked before taking Sutent and regularly while you are taking the medicine. If the thyroid does not produce enough thyroid hormone, it may be necessary to take a replacement thyroid hormone.
- If you have or have had problems with your pancreas or gallbladder. Tell your doctor if you get any of the following signs and symptoms: pain in the stomach (upper abdomen), nausea, vomiting and fever. These could be caused by inflammation of the pancreas or gallbladder.
- If you have or have ever had liver problems. Tell your doctor if you experience any of the following signs and symptoms of liver problems during treatment with Sutent: itching, yellowing of the skin or eyes, dark urine and pain or discomfort in the upper right area of the stomach. Your doctor should perform tests. to check liver function before and during treatment with Sutent, and as clinically appropriate.
- If you have or have had kidney problems. The doctor will monitor the function of the kidneys.
- If you are about to have surgery or have had an operation recently. Sutent can affect how your wounds heal. Generally if you are about to have an operation you will need to stop using Sutent. Your doctor will decide when to start Sutent treatment again.
- It is advisable to have a dental check-up before starting treatment with Sutent.
- if you have or have had pain in the mouth, teeth and / or jaw, swelling or sores in the mouth, numbness or a feeling of heaviness in the jaw, or loosening of teeth, tell your doctor and dentist immediately.
- if you are undergoing invasive dental treatment or dental surgery, tell your doctor that you are being treated with Sutent, particularly if you are also taking intravenous bisphosphonates or have taken them previously. Bisphosphonates are medicines used to prevent bone complications that may have been prescribed for another medical problem.
- If you have or have ever had skin and subcutaneous tissue disorders. 'Gangrenous pyoderma' (painful ulceration of the skin) or 'necrotizing fasciitis' (a rapidly spreading' skin / soft tissue infection which can be fatal) may occur during treatment with this medicine. This is usually reversible afterwards. discontinuation of treatment. Serious skin reactions (Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme) have been reported with the use of sunitinib, initially appearing on the trunk as reddish target-shaped spots or circular patches, often with blisters in the center. The reaction can progress to widespread blistering or peeling of the skin, and can be fatal. If you develop a rash or any of these skin symptoms, see a doctor immediately.
- If you have or have had seizures. Tell your doctor as soon as possible if you have high blood pressure, headache, loss of vision.
- If you have diabetes. Blood sugar levels should be checked regularly in diabetic patients to see if the dosage of diabetes medications needs to be changed in order to minimize the risk of low blood sugar.
Children and adolescents
Sutent is not indicated for patients under 18 years of age. Sutent has not been studied in children and adolescents.
Interactions Which drugs or foods can modify the effect of Sutent
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines, including those bought without a prescription and those without a prescription.
Some medicines can change the levels of Sutent in the body. You should tell your doctor if you are taking medicines that contain the following active substances:
- ketoconazole, itraconazole - used to treat fungal infections
- erythromycin, clarithromycin, rifampicin - used to treat infections
- ritonavir - used to treat AIDS
- dexamethasone - a corticosteroid used for several conditions
- phenytoin, carbamazepine, phenobarbital - used to treat epilepsy and other neurological conditions
- herbal preparations containing St. John's wort (Hypericum perforatum) - used to treat depression and anxiety
Sutent with food and drink
Intake of grapefruit juice should be avoided during treatment with Sutent.
Warnings It is important to know that:
Pregnancy and breastfeeding
If you are pregnant or suspect that you are pregnant, please tell your doctor.
Sutent should not be used during pregnancy unless strictly necessary. Your doctor will discuss with you the possible risks of Sutent treatment during pregnancy.
If pregnancy is possible, you must use a reliable method of contraception while being treated with Sutent.
If you are breast-feeding, please tell your doctor. You must not breastfeed while being treated with Sutent.
Driving and using machines
If you feel dizzy or unusually tired, take special care when driving or using machines.
Dose, Method and Time of Administration How to use Sutent: Posology
Always take this medicine exactly as your doctor has told you.
If in doubt, consult your doctor. Your doctor will prescribe the right dose for you, based on the type of cancer you need to treat. If you are being treated for GIST or MRCC, the usual dose is 50 mg once daily to be taken for 28 days (4 weeks), followed by 14 days (2 weeks) of rest (without medication), in cycles of 6 weeks. If you are being treated for pNET the usual dose is 37.5 mg once a day, without a rest period. Your doctor will work out the dose you need and when to stop Sutent treatment. Sutent can be taken with or without food.
Overdose What to do if you have taken too much Sutent
If you take more Sutent than you should
If you have accidentally taken too many capsules, talk to your doctor right away. Medical attention may be required
If you forget to take Sutent
Do not take a double dose to make up for a forgotten dose.
Side Effects What are the side effects of Sutent
Like all medicines, this medicine can cause side effects, although not everybody gets them.
Contact your doctor immediately if you experience any of these serious side effects (see also What you need to know before you take Sutent):
Heart problems. Tell your doctor if you feel very tired, have shortness of breath or have swollen feet and ankles. These could be symptoms of heart problems such as heart failure and heart muscle problems (cardiomyopathy).
Lung or breathing problems. Tell your doctor if you experience cough, chest pain, sudden onset of shortness of breath or coughing up blood. These could be symptoms of a pulmonary embolism that occurs when blood clots travel to the lungs.
Kidney problems. Tell your doctor if you experience an "altered frequency or absence to urinate, which could be symptoms of" kidney failure.
Bleeding. Tell your doctor immediately if you experience any of the following symptoms or a serious bleeding problem while taking Sutent: swollen, painful stomach (abdomen); vomiting with blood; dark, sticky stools; headache or changes in mental status, coughing up blood or sputum with blood from the lungs or airways.
Destruction of the tumor causing bowel perforation. Tell your doctor if you have severe bowel pain, fever, nausea, vomiting, blood in stools or changes in bowel habits.
Other side effects that may occur with Sutent are:
Very common side effects (may affect more than 1 in 10 people)
- Reduction in the number of platelets, red blood cells and / or white blood cells (e.g. neutrophils).
- Shortness of breath
- High blood pressure.
- Excessive tiredness, loss of strength.
- Swelling caused by fluid under the skin and around the eyes, deep allergic rash.
- Mouth pain / irritation, soreness / inflammation / dry mouth, taste disturbances, stomach upset, nausea, vomiting, diarrhea, constipation, abdominal pain / swelling, loss / reduction of appetite.
- Reduced activity of the thyroid gland (hypothyroidism).
- Dizziness
- Headache.
- Nose bleeding.
- Back pain, joint pain.
- Pain in the arms and legs.
- Yellowing of the skin / discolouration of the skin, excessive pigmentation of the skin, discolouration of the hair, rash on the palms and soles of the feet, rash, dry skin.
- Cough.
- Fever.
- Difficulty falling asleep.
Common side effects (may affect 1 to 10 in 100 people)
- Clot formation in the blood vessels.
- Insufficient blood supply to the heart muscle, due to obstruction or constriction of the coronary arteries.
- Chest pain.
- Reduced amount of blood pumped by the heart.
- Fluid retention also around the lungs.
- Infections.
- Reduced blood sugar level. If you experience signs and symptoms of low blood sugar: Tell your doctor as soon as possible if you experience fatigue, palpitations, sweating, hunger and loss of consciousness.
- Loss of protein in the urine, which sometimes leads to swelling.
- Flu syndrome.
- Abnormal blood tests, including liver and pancreatic enzyme levels.
- High levels of uric acid in the blood.
- Hemorrhoids, rectal pain, gum bleeding, difficulty in swallowing or inability to swallow.
- Burning or painful sensation in the tongue, inflammation of the lining of the digestive tract, excess gas in the stomach or intestines.
- Weight loss.
- Musculoskeletal pain (pain in muscles and bones), muscle weakness, muscle fatigue, muscle pain, muscle spasms.
- Nasal dryness, nasal congestion.
- Excessive tearing.
- Changes in skin sensitivity, dry skin, itching, peeling and inflammation of the skin, blistering, acne, nail discoloration, hair loss.
- Abnormal sensations in the extremities.
- Excessive reduction / increase in sensitivity, especially to touch.
- Burning in the stomach.
- Dehydration.
- Facial redness.
- Change in the color of the urine.
- Depression.
- Chills.
Uncommon side effects (may affect 1 to 10 in 1,000 people)
- Soft tissue infections, including in the anogenital region, potentially life-threatening. Contact your doctor immediately if you experience symptoms of infection around a skin wound, including fever, pain, redness, swelling, or drainage of pus or blood.
- Stroke.
- Heart attack caused by an interrupted or reduced blood supply to the heart.
- Changes in the electrical activity of the heart or altered heart rhythm.
- Fluid around the heart (pericardial effusion).
- Hepatic insufficiency.
- Pain in the stomach (abdomen) caused by "inflammation of the pancreas.
- Destruction of the tumor causing perforation of the intestine.
- Inflammation (swelling and redness) of the gallbladder with or without associated stones.
- Abnormal communication channel between two body cavities or with the skin.
- Pain in the mouth, teeth and / or jaw, swelling or irritation in the mouth, numbness or a feeling of heaviness in the jaw, or loosening of teeth. These could be the signs and symptoms of a jaw / jaw bone injury (osteonecrosis). Tell your doctor and dentist immediately if you get any of these signs and symptoms.
- Excessive production of thyroid hormones resulting in increased metabolism. Problems with wound healing after surgery.
- Increase in a muscle enzyme in the blood (creatine phosphokinase).
- Inappropriate and excessive reaction to allergens.
Rare side effects (may affect 1 to 10 in 10,000 people)
- Severe reactions of the skin and / or mucous membranes (Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme).
- Tumor Lysis Syndrome (TLS) - TLS encompasses a set of metabolic complications that can occur during cancer treatment. They are caused by the breakdown products of affected cancer cells and can include: nausea, shortness of breath, irregular heartbeat, muscle cramps, convulsion, cloudy urine and fatigue associated with abnormal laboratory test results (high levels of potassium, uric acid and phosphoric acid and low blood calcium levels) which can lead to changes in kidney function and acute kidney failure.
- Abnormal breakdown of muscles which can cause kidney problems (rhabdomyolysis).
- Impaired brain function which can lead to a variety of symptoms, such as headache, confusion, seizures and loss of vision (posterior reversible leukoencephalopathy syndrome).
- Painful ulceration of the skin (gangrenous pyoderma).
- Inflammation of the liver (hepatitis).
- Inflammation of the thyroid gland.
Reporting of side effects
If you get any side effects, talk to your doctor. 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 and on the label after "EXP". The expiry date refers to the last day of the month.
- This medicinal product does not require any special storage conditions.
- Do not use this medicine if you notice that the pack is damaged or shows signs of tampering.
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 Sutent contains
Sutent 12.5 mg hard capsules
The active ingredient is sunitinib. Each capsule contains sunitinib malate equivalent to 12.5 mg of sunitinib.
The other ingredients are:
- Capsule contents: mannitol (E421), croscarmellose sodium, povidone (K-25) and magnesium stearate.
- Capsule shell: gelatin, red iron oxide (E172) and titanium dioxide (E171).
- Ink: shellac, propylene glycol, sodium hydroxide, povidone and titanium dioxide (E171).
Sutent 25 mg hard capsules
The active ingredient is sunitinib. Each capsule contains sunitinib malate equivalent to 25 mg of sunitinib.
The other ingredients are:
- Capsule contents: mannitol (E421), croscarmellose sodium, povidone (K-25) and magnesium stearate.
- Capsule shell: gelatin, titanium dioxide (E171), yellow iron oxide (E172), red iron oxide (E172), black iron oxide (E172).
- Ink: shellac, propylene glycol, sodium hydroxide, povidone and titanium dioxide (E171)
Sutent 37.5 mg hard capsules
The active ingredient is sunitinib. Each capsule contains sunitinib malate equivalent to 37.5 mg of sunitinib.
The other ingredients are:
- Capsule contents: mannitol (E421), croscarmellose sodium, povidone (K-25) and magnesium stearate.
- Capsule shell: gelatin, titanium dioxide (E171), yellow iron oxide (E172).
- Ink: shellac, propylene glycol, potassium hydroxide, black iron oxide (E172).
Sutent 50 mg hard capsules
The active ingredient is sunitinib. Each capsule contains sunitinib malate equivalent to 50 mg of sunitinib.
The other ingredients are:
- Capsule contents: mannitol (E421), croscarmellose sodium, povidone (K-25) and magnesium stearate.
- Capsule shell: gelatin, titanium dioxide (E171), yellow iron oxide (E172), red iron oxide (E172) and black iron oxide (E172).
- Ink: shellac, propylene glycol, sodium hydroxide, povidone and titanium dioxide (E171).
Description of what Sutent looks like and contents of the pack
Sutent 12.5 mg is available as hard gelatin capsules with an orange cap and body, with "Pfizer" in white ink on the cap and "STN 12.5 mg" on the body, containing colored granules. yellow-orange.
Sutent 25 mg is available as hard gelatin capsules with a caramel cap and orange body, with "Pfizer" in white ink on the cap and "STN 25 mg" on the body, containing colored granules. yellow-orange.
Sutent 37.5 mg is available as hard gelatin capsules with a yellow cap and body, with "Pfizer" in black ink on the cap and "STN 37.5 mg" on the body, containing colored granules. yellow-orange.
Sutent 50 mg is available as hard gelatin capsules with a caramel-colored cap and body, with "Pfizer" in white ink on the cap and "STN 50 mg" on the body, containing yellow-orange granules. . It is available in bottles of 30 capsules and perforated unit dose blisters containing 28 x 1 capsules.
Not all pack sizes may be marketed.
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
SUTENT 12.5 MG HARD CAPSULES
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each capsule contains sunitinib malate, corresponding to 12.5 mg of sunitinib.
For the full list of excipients, see section 6.1.
03.0 PHARMACEUTICAL FORM
Hard capsule.
Gelatin capsules with orange cap and body, marked with white ink "Pfizer" on the cap, "STN 12.5 mg" on the body and containing yellow-orange granules.
04.0 CLINICAL INFORMATION
04.1 Therapeutic indications
Stromal tumor of the gastrointestinal tract (GIST)
SUTENT is indicated for the treatment of unresectable and / or metastatic gastrointestinal stromal cancer (GIST) in adults after failure of imatinib treatment due to resistance or intolerance.
Metastatic renal cell carcinoma (MRCC)
SUTENT is indicated for the treatment of advanced / metastatic renal cell carcinoma (MRCC) in adults.
Pancreatic neuroendocrine tumors (pNET)
SUTENT is indicated for the treatment of well-differentiated, unresectable or metastatic pancreatic neuroendocrine tumors (pNETs) in progressing disease in adults.
Experience with SUTENT as a first-line drug is limited (see section 5.1).
04.2 Posology and method of administration
Sunitinib therapy should be initiated by a physician experienced in the administration of anticancer agents.
Dosage
For GIST and MRCC the recommended dose of SUTENT is 50 mg to be taken orally once a day, for 4 consecutive weeks, followed by 2 weeks of rest (schedule 4/2) in order to carry out a full course of 6 weeks.
For pNET, the recommended dose of SUTENT is 37.5 mg to be taken orally once daily, without a scheduled rest period.
Dose adjustment
Safety and tolerability
For GIST and MRCC, dose modifications in 12.5 mg increments can be made based on individual patient safety and tolerability. The daily dose should not exceed 75 mg nor should it be reduced below 25 mg.
For pNET, posology adjustments in 12.5 mg increments can be made based on individual patient safety and tolerability. The maximum dose administered in the phase 3 pNET study was 50 mg per day.
It may be necessary to suspend the intake of some doses based on the safety and tolerability of the individual patient.
CYP3A4 inhibitors / inducers
Co-administration of sunitinib with potent CYP3A4 inducers, such as rifampicin, should be avoided (see sections 4.4. And 4.5). If this is not possible, the dose of sunitinib may need to be increased in 12.5 mg increments (up to 87.5 mg / day for GIST and MRCC or 62.5 mg / day for pNET) based on careful monitoring of tolerability.
Co-administration of sunitinib with potent CYP3A4 inhibitors, such as ketoconazole, should be avoided (see sections 4.4 and 4.5). If this is not possible, the dose of sunitinib may need to be reduced to a minimum dose of 37.5 mg per day for GIST and MRCC or 25 mg per day for pNET, based on careful monitoring of tolerability.
The choice of an alternative concomitant medicinal product with no or minimal potential to induce or inhibit CYP3A4 should be considered.
Special populations
Pediatric population
The safety and efficacy of sunitinib in patients below 18 years of age have not been established.
No data are available.
There is no indication for a specific use of sunitinib in children from birth to 6 years of age in the treatment of unresectable and / or metastatic GIST following failure of imatinib treatment due to resistance or intolerance. There is no indication for a specific use of sunitinib in the pediatric population in the treatment of MRCC and in the treatment of well-differentiated, unresectable or metastatic pNETs in disease progression.
The use of sunitinib in the pediatric population is not recommended.
Elderly patients (≥ 65 years old)
Approximately one third of the patients enrolled in clinical trials who received sunitinib were aged 65 years or older. No significant differences in safety and efficacy were observed between younger and older subjects.
Hepatic impairment
No initial dosage adjustment is required when sunitinib is administered to patients with mild or moderate hepatic impairment (Child-Pugh stage A and B). The use of sunitinib in subjects with severe hepatic impairment (Child-Pugh stage C) has not been studied, therefore its use in patients with hepatic impairment is not recommended (see section 5.2).
Renal impairment
No initial dose adjustment is required when sunitinib is administered to patients with renal impairment (moderate to severe) or end stage renal disease (ESRD) undergoing hemodialysis. Subsequent dose adjustments should be made based on the safety and tolerability of the individual patient (see section 5.2).
Method of administration
SUTENT is for oral administration. It can be taken with or without food.
If a dose is not taken, an additional dose should not be given. The patient should take the usual prescribed dose the next day.
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
Co-administration with strong CYP3A4 inducers should be avoided as it may reduce the plasma concentration of sunitinib (see sections 4.2 and 4.5).
Co-administration with potent CYP3A4 inhibitors should be avoided as it may increase the plasma concentration of sunitinib (see sections 4.2 and 4.5).
Skin and tissue disorders
Discolouration of the skin, which may be due to the color of the active substance (yellow), is a very common adverse reaction occurring in approximately 30% of patients. Patients should be advised that during treatment with sunitinib they may discoloration of the hair or skin may also occur.Other possible dermatological effects may include dryness, thickening or cracking of the skin, blisters or an occasional rash on the palms or soles of the feet.
The above reactions were not cumulative, were generally reversible and usually did not lead to discontinuation of treatment. Cases of gangrenous pyoderma, generally reversible after discontinuation of the drug, have been reported. Serious skin reactions have been reported, including cases of erythema multiforme (EM) and cases attributable to Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (NET), some of them fatal. With signs or symptoms of SJS, NET, or EM (eg skin rash often with blistering or mucosal lesions) treatment with sunitinib should be discontinued. If the diagnosis of SJS or NET is confirmed, treatment should not be resumed. In some cases of suspected EM, after resolution of the reaction patients have reintroduction of sunitinib therapy at lower doses tolerated; some of these patients also received concomitant treatment with corticosteroids or antiseptics tamines.
Hemorrhage and bleeding caused by tumors
Haemorrhagic events, some with fatal outcome, including gastrointestinal, respiratory, urinary and cerebral haemorrhages have been reported from post-marketing experience.
Bleeding episodes occurred in 18% of patients treated with sunitinib compared to 17% of patients in the placebo group in a GIST phase 3 study. Patients with MRCC on sunitinib never previously treated with sunitinib reported events bleeding in 39% of cases compared to 11% of patients treated with IFN-α. Seventeen (4.5%) patients on sunitinib compared with 5 (1.7%) patients on IFN-α experienced Grade 3 or higher bleeding episodes. Twenty-six percent of patients receiving sunitinib for cytokine-refractory MRCC reported bleeding episodes. Bleeding events, excluding epistaxis, occurred in 21.7% of patients treated with sunitinib compared with 9.85% of patients in the placebo group in the Phase 3 pNET study. Routine evaluation of this event should include a complete blood count and a physical examination.
Epistaxis was the most common adverse haemorrhagic reaction, having been reported in approximately half of patients with solid tumors who reported bleeding events. Some of these epistaxis episodes were serious but very rarely fatal.
Tumor haemorrhage events, sometimes associated with tumor necrosis, have been reported; some of these bleeding events were fatal.
In clinical trials, "tumor haemorrhage occurred in approximately 2% of patients with GIST. These events can occur suddenly and, in the case of lung cancers, may present in the form of" severe and potentially fatal "hemoptysis or pulmonary haemorrhage. . Cases of pulmonary haemorrhage, some with fatal outcome, have been observed in clinical trials and have also been reported post-marketing in patients treated with sunitinib for MRCC, GIST and lung cancer. SUTENT is not approved for use in patients with lung cancer.
Patients on concomitant treatment with anticoagulants (eg warfarin, acenocoumarol) may be periodically monitored by a complete blood count (platelet), coagulation factors (PT / INR) and a physical examination.
Gastrointestinal disorders
Diarrhea, nausea / vomiting, abdominal pain, dyspepsia and stomatitis / oral pain were the most frequently reported gastrointestinal adverse reactions; Cases of esophagitis have also been reported (see section 4.8).
Supportive care for gastrointestinal adverse reactions requiring treatment may include medicinal products with anti-emetic, antidiarrheal, or antacid properties.
Serious, sometimes fatal, gastrointestinal complications, including gastrointestinal perforation, have occurred in patients with intra-abdominal malignancy treated with sunitinib. In the phase 3 GIST study, fatal gastrointestinal bleeding occurred in 0.98% of patients treated with placebo.
Hypertension
Hypertension was a very common adverse reaction reported in clinical trials. The dose of sunitinib was reduced or its administration temporarily suspended in approximately 2.7% of the patients in whom hypertension occurred. In none of these patients sunitinib was permanently discontinued. Severe hypertension (> 200 mmHg systolic or 110 mmHg diastolic) occurred in 4.7% of patients with solid tumors. In MRCC and previously treated patients, cases of hypertension were reported in 33, 9% of patients on sunitinib compared with 3.6% of patients on IFN-α. Episodes of severe hypertension occurred in 12% of previously untreated patients in the sunitinib group and in less than 1% of those of the IFN-α group. In the Phase 3 pNET study, hypertension was reported in 26.5% of patients taking sunitinib compared with 4.9% of patients in the placebo group. Episodes of severe hypertension occurred in patients with pNET in 10%. of patients treated with sunitinib and 3% of those treated with placebo. Patients should be screened for hypertension and monitored appropriately. Temporary suspension of treatment is recommended in patients with severe uncontrolled hypertension with drug treatment. Treatment can resume when hypertension is adequately controlled.
Hematological disorders
An absolute reduction in Grade 3 and 4 neutrophil counts was observed in 10% and 1.7% of patients enrolled in the phase 3 GIST study, respectively, and in 16% and 1.6% of patients included in the study. MRCC in phase 3 and in 13% and 2.4% of patients included in the phase 3 pNET study. A reduction in Grade 3 and 4 platelet counts was reported in 3.7% and 0.4% of patients, respectively. patients enrolled in the phase 3 GIST study, in 8.2% and 1.1% of patients included in the phase 3 MRCC study and in 3.7% and 1.2% of patients included in the phase 3 study on pNETs.
The above events were not cumulative, were generally reversible and usually did not lead to discontinuation of treatment. None of these events in the phase 3 studies were fatal, but rare haematological events have been reported in the post-marketing phase of the product. fatal, including haemorrhage associated with thrombocytopenia and neutropenic infections.
Anemia has been observed to occur in both early and late stages of sunitinib treatment; Grades 3 and 4 have been reported.
Complete blood counts should be performed at the start of each treatment cycle in patients receiving sunitinib.
Cardiac pathologies
Cardiovascular events, some of them fatal, including heart failure, cardiomyopathy, myocardial ischaemia and myocardial infarction, have been reported in patients treated with sunitinib. These data indicate that sunitinib increases the risk of cardiomyopathy. No specific additional risk factors for sunitinib-induced cardiomyopathy other than the specific effect of the drug have been identified in treated patients. Sunitinib should be used with caution in patients at risk for these events or who have a history of such events. .
In clinical studies, decreases in left ventricular ejection fraction (LVEF) ≥ 20% and below the lower limit of normal occurred in approximately 2% of sunitinib-treated GIST patients, in 4% of MRCC patients refractory to cytokines treated with sunitinib and in 2% of placebo-treated GIST patients. These decreases in LVEF do not appear to be progressive and often improved with continued treatment. In the study conducted in patients with MRCC and never previously treated, 27% of patients treated with sunitinib and 15% of those treated with IFN-α had an LVEF value below the lower limit of normal. To two patients (
In patients with GIST, episodes of "heart failure", "congestive heart failure" or "left ventricular failure" were reported in 1.2% of patients treated with sunitinib and in 1% of patients treated with placebo. In the pivotal study In phase 3 on GIST (n = 312), treatment-related fatal cardiac reactions occurred in 1% of patients in both study arms (sunitinib and placebo arm). In a Phase 2 study of cytokine-refractory MRCC patients, 0.9% of patients reported treatment-related fatal myocardial infarction and in a Phase 3 study of previously treated MRCC patients, 0.6 % of patients in the IFN-α arm and 0% of patients in the sunitinib arm reported fatal cardiac events. In the Phase 3 pNET study, one patient (1%) taking sunitinib had treatment-related fatal heart failure. A possible correlation between tyrosine kinase receptor (RTK) inhibition and cardiac function is unclear.
Patients who have reported cardiac events within 12 months prior to sunitinib administration, such as myocardial infarction (including severe / unstable angina), coronary / peripheral bypass surgery, symptomatic CHF, cerebrovascular event or transient ischemic attack or pulmonary embolism, are were excluded from clinical trials with sunitinib. It is not known whether patients with such concomitant conditions may be at increased risk of developing drug-related left ventricular dysfunction.
Close monitoring for clinical signs and symptoms of congestive heart failure should be undertaken, particularly in patients with cardiac risk factors and / or with a history of coronary artery disease.
Doctors are advised to weigh this risk against the potential benefits of the drug. These patients should be closely monitored for clinical signs and symptoms of congestive heart failure during treatment with sunitinib. Baseline and periodic left ventricular ejection fraction assessments should also be considered when the patient is being treated with sunitinib. In patients with no cardiac risk factors, an assessment of the ventricular ejection fraction at baseline should still be considered.
In the presence of clinical manifestations of CHF, discontinuation of sunitinib treatment is recommended. Sunitinib administration should be interrupted and / or the dose reduced in patients with no clinical evidence of congestive heart failure but with a decrease in ejection fraction between 20% and 50% from baseline.
Prolongation of the QT interval
Data from preclinical studies (in vitro And in vivo), conducted at doses higher than those recommended in humans, indicate that sunitinib may inhibit cardiac repolarization processes (eg QT interval prolongation).
Increases in the QTc interval to more than 500 msec occurred at a rate of 0.5%, and changes from baseline of more than 60 msec occurred in 1.1% of 450 patients with solid tumors; both of these parameters are recognized as potentially significant variations. At concentrations corresponding to approximately twice therapeutic concentrations, sunitinib was found to prolong the QTcF interval (corrected according to Frederica's formula).
QT interval prolongation was studied in a study involving 24 patients, aged 20-87 years, with advanced malignancies. The results of this study demonstrated that sunitinib had an effect on the QTc interval ( defined as placebo-adjusted mean change> 10 msec, with an upper limit of 90% CI> 15 msec) at therapeutic concentration (day 3) using the 24-hour baseline correction method, and at concentrations above to therapeutic ones (day 9) using both correction methods at baseline. No patient reported a QTc value> 500 msec. Although an effect on the QTcF interval was observed on day 3 24 hours after dosing (i.e. with the expected therapeutic plasma concentration after the recommended starting dose of 50 mg) with the 24-hour baseline correction method , the clinical significance of this finding is unclear.
Using comprehensive serial ECG assessments corresponding to therapeutic exposures or exposures above therapeutic, none of the patients in the evaluable or ITT populations was observed to have a prolongation of the "severe" QTc interval (therefore equal to or greater than
Grade 3 of CTCAE version 3.0).
At therapeutic plasma concentrations, the mean maximum change in QTcF interval (corrected by Frederica's formula) from baseline was 9.6 msec (90% CI 15.1 msec). At therapeutic concentrations corresponding to approximately twice the therapeutic concentrations, the maximum change in QTcF interval from baseline was 15.4 msec (90% CI 22.4 msec).
Moxifloxacin (400 mg) used as a positive control exhibited a mean maximum change in QTcF interval from baseline of 5.6 msec. No subject reported an effect on QTc interval greater than Grade 2 (CTCAE version 3.0).
QT interval prolongation may cause an increased risk of ventricular arrhythmias, including Torsade de Pointes. Torsade de Pointes has been observed in
Sunitinib should be used with caution in patients with a history of QT interval prolongation, in patients treated with antiarrhythmics, or with medicinal products that can prolong the QT interval, or in patients with pre-existing relevant heart disease, bradycardia or abnormalities. electrolytic. Co-administration of sunitinib with potent CYP3A4 inhibitors should be limited due to the possible increase in sunitinib plasma concentrations (see sections 4.2 and 4.5).
Venous thromboembolic events
Treatment-related venous thromboembolic events were observed in approximately 1.0% of patients with solid tumors treated with sunitinib in clinical studies, including the GIST and MRCC studies.
In a phase 3 GIST study, seven patients (3%) receiving sunitinib and no patients in the placebo group experienced venous thromboembolic events; five of the seven patients had grade 3 deep vein thrombosis (DVT) and two had grade 1 or 2 deep vein thrombosis. Four of these seven patients being treated for GIST discontinued after observation of DVT.
Thirteen patients (3%) treated with sunitinib in the MRCC phase 3 study and never previously treated and four patients (2%) of the two cytokine-refractory MRCC studies reported venous thromboembolic events. Nine of these patients had venous thromboembolic events. one "pulmonary embolism, one with Grade 2 and eight with Grade 4. Eight of these patients had DVT, one with Grade 1, two with Grade 2, four with Grade 3 and one with Grade 4." In a patient with pulmonary embolism in the MRCC study, refractory to cytokines, the dose was stopped.
Of the previously untreated MRCC patients on IFN-α, six (2%) reported venous thromboembolic events, one patient (pulmonary embolism, all grade 4.
Venous thromboembolic events were reported for 1 (1.2%) patient in the sunitinib arm and 5 (6.1%) patients in the placebo arm in the phase 3 pNET study. Two of these placebo-treated subjects reported DVT, one Grade 2 and one Grade 3.
No cases with a fatal outcome were observed in the pivotal studies of GIST, MRCC and pNET. Cases with fatal outcomes have been observed in the post-marketing setting of the product (see respiratory events and section 4.8).
Arterial thromboembolic events
Cases of arterial thromboembolic events (ATEs), sometimes fatal, have been reported in patients treated with sunitinib. The most frequent events included cerebrovascular accident, transient ischemic attack, and cerebral ischemia. Risk factors associated with arterial thromboembolic events, in addition to pre-existing malignancy and age 65 years or older, included hypertension, diabetes mellitus, and previous thromboembolic event.
Respiratory events
Patients who had 'pulmonary embolism within the previous 12 months were excluded from clinical trials with sunitinib.
In patients receiving sunitinib in the pivotal phase 3 studies, pulmonary events (dyspnoea, pleural effusion, pulmonary embolism, or pulmonary edema) were observed in approximately 17.8% of patients with GIST, in approximately 26.7% of those with MRCC and in 12% of patients with pNET.
Approximately 22.2% of patients with solid tumors, including GIST and MRCC, treated with sunitinib in clinical studies reported pulmonary events.
Cases of pulmonary embolism were observed in approximately 3.1% of patients with GIST and approximately 1.2% of patients with MRCC treated with sunitinib in phase 3 studies (see section 4.4. - Venous thromboembolic events). No cases of pulmonary embolism were observed in pNET patients treated with sunitinib in the Phase 3 study. Rare cases with fatal outcome have been observed in the post-marketing setting (see section 4.8).
Thyroid dysfunction
It is recommended that evaluation of thyroid function by measuring the baseline laboratory values in all patients. Patients with pre-existing hypothyroidism or hyperthyroidism should be treated according to standard clinical practice prior to initiation of sunitinib treatment. During treatment with sunitinib, a routine check of thyroid function should be performed every 3 months. Additionally, all patients should be closely monitored during treatment for possible signs and symptoms of thyroid dysfunction and patients who develop any signs and / or symptoms indicative of thyroid dysfunction should undergo laboratory testing of thyroid function as clinically expected. Patients who develop thyroid dysfunction should be treated according to standard clinical practice.
Hypothyroidism has been reported to occur at the start or end of sunitinib treatment.
Hypothyroidism was reported as an adverse reaction in 7 patients (4%) receiving sunitinib in the two MRCC studies conducted in cytokine refractory patients; in 61 patients (16%) receiving sunitinib and in three patients (
Additionally, elevations in TSH were reported in 4 patients (2%) treated for cytokine-refractory MRCC. Overall, 7% of the MRCC population reported clinical or laboratory evidence of treatment-related hypothyroidism. Acquired hypothyroidism was observed in 6.2% of patients in the GIST study taking sunitinib compared with 1% in the placebo group. In the Phase 3 pNET study, hypothyroidism was reported in 6 patients (7.2%) receiving sunitinib and in one patient (1.2%) receiving placebo.
Thyroid function was prospectively monitored in two studies in breast cancer patients; SUTENT is not approved for the treatment of breast cancer. In one study, hypothyroidism was reported in 15 subjects (13.6%) treated with sunitinib and in 3 subjects (2.9%) treated with standard therapy. Increased blood TSH was reported in 1 subject. (0.9%) treated with sunitinib and in no subjects treated with standard therapy. Hyperthyroidism was not reported in any of the subjects treated with sunitinib and was reported in 1 subject (1.0%) who received standard therapy. In the other study, hypothyroidism was reported in a total of 31 subjects (13%) treated with sunitinib and 2 subjects (0.8%) treated with capecitabine. Increased blood TSH was reported in 12 subjects (5.0%) treated with sunitinib and in no subjects treated with capecitabine . Hyperthyroidism was reported in 4 subjects (1.7%) treated with sunitinib and in no subjects treated with capecitabine. Decreased blood TSH was reported in 3 subjects (1.3%) treated with sunitinib and in no subjects. treated with capecitabine. T4 increase was reported in 2 subjects (0.8%) treated with sunitinib and in 1 subject (0.4%) treated with capecitabine. The increase in T3 was reported in 1 subject (0.8%) treated with sunitinib and in no subject treated with capecitabine. All thyroid-related events reported were Grade 1-2.
Cases of hyperthyroidism, some followed by hypothyroidism, and cases of thyroiditis have been reported uncommonly in clinical trials and in the product marketing phase.
Pancreatitis
Increases in serum lipase and amylase activity have been observed in patients with several solid tumors receiving sunitinib. The increases in serum lipase activity were transient and generally not associated with signs and symptoms of pancreatitis in subjects with solid tumors of various types.
Pancreatitis was observed uncommonly (
Cases of serious pancreatic events, some with fatal outcome, have been reported.
If symptoms of pancreatitis occur, sunitinib treatment should be discontinued and patients should be provided with adequate supportive care. No treatment-related pancreatitis events were reported in the Phase 3 pNET study.
Hepatotoxicity
Hepatotoxicity has been observed in patients treated with sunitinib. Cases of hepatic failure, sometimes with fatal outcome, have been observed in liver function (alanine transaminase [ALT], aspartate transaminase [AST], bilirubin levels). signs or symptoms of liver failure, sunitinib treatment should be discontinued and patients should be provided with appropriate supportive medical care.
Hepatobiliary disorders
Treatment with sunitinib may be associated with cholecystitis, including alithiasic cholecystitis and enphthematous cholecystitis. In pivotal clinical studies, the incidence of cholecystitis was 0.5%.
Cases of post-marketing cholecystitis have been reported.
Renal function
Cases of renal impairment, renal failure and / or acute renal failure, in some cases with fatal outcome, have been reported.
Risk factors associated with renal impairment / failure in patients receiving sunitinib included, in addition to pre-existing renal cell carcinoma: advanced age, diabetes mellitus, pre-existing renal impairment, heart failure, hypertension, sepsis, dehydration / hypovolaemia and rhabdomyolysis.
The safety of continuing sunitinib treatment in patients with moderate to severe proteinuria has not been systematically evaluated.
Cases of proteinuria and rare cases of nephrotic syndrome have been reported. Baseline urinalysis is recommended and patients should be monitored for possible development or worsening of proteinuria.
Sunitinib treatment should be discontinued in patients with nephrotic syndrome.
Fistulas
If fistula formation occurs, sunitinib treatment should be discontinued. There is limited information available on prolonged sunitinib treatment in patients presenting with fistulas.
Impairment of the wound healing process
Cases of impaired wound healing have been reported during sunitinib therapy. No formal clinical studies have been conducted on the effect of sunitinib on wound healing. For precautionary reasons it is recommended that sunitinib therapy be temporarily interrupted in patients undergoing major surgery. Clinical experience regarding the timing required to restart. therapy after major surgery is limited. Therefore, the decision to resume sunitinib therapy following major surgery must be based on the clinical judgment of recovery from surgery.
Osteonecrosis of the mandible / maxilla
Cases of osteonecrosis of the jaw have been reported in patients treated with SUTENT. In the majority of reported cases, patients had received prior or concomitant treatment with intravenous bisphosphonates, with which osteonecrosis of the jaw is an identified risk. Therefore caution should be exercised when SUTENT and intravenous bisphosphonates are administered concomitantly or in combination. sequential way.
Invasive dental interventions have also been identified as a risk factor. A dental examination and appropriate preventive dental care should be considered prior to treatment with SUTENT. If possible, invasive dental interventions should be avoided in patients who have previously taken or are taking intravenous bisphosphonates (see section 4.8).
Hypersensitivity / angioedema
If edema due to a hypersensitivity reaction occurs, treatment with sunitinib should be discontinued and standard medical treatment given.
Disorders of the nervous system
Taste disturbances
Dysgeusia was reported in approximately 28% of patients receiving sunitinib during clinical trials.
Convulsions
In clinical trials with sunitinib and post-marketing, cases of seizures have been observed in subjects with or without radiological evidence of brain metastases. In addition, there have been a limited number of reports (headache, decreased alertness, impaired mental function and loss of vision, including cortical blindness, should be controlled with medical treatment including hypertension control. It is recommended temporary suspension of sunitinib; after resolution of the event, treatment may be resumed at the discretion of the treating physician.
Tumor Lysis Syndrome (TLS)
Cases of tumor lysis syndrome (TLS), some with fatal outcome, have been rarely observed in clinical studies and have been reported post-marketing in patients treated with sunitinib. Risk factors for TLS include high tumor burden, pre-existing chronic renal failure, oliguria, dehydration, hypotension, and acidic urine. These patients should be carefully monitored and treated as clinically indicated; for these patients Prophylactic hydration should be considered.
Infections
Cases of serious infections, with or without neutropenia, including some cases with fatal outcome, have been reported.
The infections most commonly seen with sunitinib treatment are infections typical of the cancer patient, such as respiratory, urinary tract, skin, and sepsis.
Rare, sometimes fatal, cases of necrotizing fasciitis, including that of the perineum, have been reported. Sunitinib therapy should be discontinued in patients who develop necrotizing fasciitis and appropriate treatment initiated promptly.
Hypoglycemia
There have been reports of decreased blood glucose during treatment with sunitinib, some of them clinically symptomatic and requiring hospitalization due to loss of consciousness. In the event of symptomatic hypoglycaemia, sunitinib treatment should be temporarily interrupted. Blood glucose levels should be checked regularly in diabetic patients to assess whether the dosage of diabetes medications needs to be adjusted to minimize the risk of hypoglycemia.
04.5 Interactions with other medicinal products and other forms of interaction
Interaction studies have only been performed in adults.
Medicines that can to increase plasma concentrations of sunitinib
In healthy volunteers, co-administration of a single dose of sunitinib with ketoconazole, a strong CYP3A4 inhibitor, resulted in an increase in the combined [sunitinib + primary metabolite] Cmax and AUC0-∞ by 49% and 51%, respectively. .
Administration of sunitinib with strong CYP3A4 inhibitors (e.g. ritonavir , itraconazole, erythromycin, clarithromycin, grapefruit juice) may increase sunitinib concentrations.
Combination with CYP3A4 inhibitors should therefore be avoided or an alternative medicinal product with no or minimal potential to inhibit CYP3A4 should be considered.
If this is not possible, the dose of SUTENT may need to be reduced to a minimum of 37.5 mg / day for GIST and MRCC or 25 mg / day for pNET, based on careful monitoring of tolerability (see section 4.2).
Medicines that can reduce plasma concentrations of sunitinib
In healthy volunteers, co-administration of a single dose of sunitinib and CYP3A4 inducer rifampicin resulted in a reduction of combined [sunitinib + primary metabolite] Cmax and AUC0-∞ by 23% and 46%, respectively.
Administration of sunitinib with strong CYP3A4 inducers (eg, dexamethasone, phenytoin, carbamazepine, rifampicin, phenobarbital or herbal preparations containing St John's wort /Hypericum perforatum) can reduce sunitinib concentrations. The association with inducers of CYP3A4 should therefore be avoided or an alternative medicinal product with no or minimal potential to induce CYP3A4 should be considered. If this is not possible, the dose of SUTENT can be increased in increments of 12. , 5 mg (up to 87.5 mg / day for GIST and MRCC or 62.5 mg / day for pNET) based on careful monitoring of tolerability (see section 4.2).
04.6 Pregnancy and lactation
Pregnancy
No studies have been conducted in pregnant women receiving sunitinib. Animal studies have shown reproductive toxicity, including fetal malformations (see section 5.3).
SUTENT should not be used during pregnancy or in women not using effective contraception, unless the potential benefits justify the potential risk to the fetus. If SUTENT is used during pregnancy, or if the patient becomes pregnant during treatment with SUTENT, the patient should be informed of the potential risks to the fetus.
Women of childbearing potential should be advised to use effective contraception and to avoid pregnancy when being treated with SUTENT.
Feeding time
Sunitinib and / or its metabolites are excreted in rat milk. It is unknown whether sunitinib or its major active metabolite are excreted in human milk.Since the active substances are generally excreted in breast milk and considering the possible serious adverse reactions in nursing infants, women should not breastfeed during treatment with SUTENT.
Fertility
Preclinical data suggest that male and female fertility may be impaired by treatment with sunitinib (see section 5.3).
04.7 Effects on ability to drive and use machines
No studies on the effects on the ability to drive and use machines have been performed. Patients should be informed of the possible occurrence of dizziness during treatment with sunitinib.
04.8 Undesirable effects
Summary of the safety profile
The most serious sunitinib treatment-related adverse reactions, some fatal, are renal failure, heart failure, pulmonary embolism, gastrointestinal perforation, and haemorrhages (e.g. respiratory, gastrointestinal, tumor-related, urinary, and brain haemorrhages).
The most common adverse reactions of any grade (reported by patients in pivotal clinical trials for RCC, GIST and pNET) included decreased appetite, taste disturbances, hypertension, fatigue, gastrointestinal disturbances (eg, diarrhea, nausea, stomatitis, dyspepsia and vomiting), discolouration of the skin and palmar-plantar erythrodysaesthesia syndrome. These symptoms may lessen with continued treatment. Hypothyroidism can arise during treatment. Haematological disorders (eg neutropenia, thrombocytopenia and anemia) were among the most common adverse drug reactions.
Fatal adverse events other than those listed in section 4.4. or in section 4.8 and considered possibly related to sunitinib include multiple organ failure, disseminated intravascular coagulation, peritoneal haemorrhage, adrenal insufficiency, pneumothorax, shock and sudden death.
Table of adverse reactions
Adverse reactions reported by patients with GIST, MRCC and pNET in a pooled dataset of 7115 patients are listed below and categorized by system organ class, frequency and severity (NCI-CTCAE). Post-marketing adverse reactions identified in clinical studies are also reported. Within each frequency class, undesirable effects are reported in order of decreasing severity.
Frequencies are defined as follows: very common (≥1 / 10), common (≥1 / 100a
Table 1 - Adverse reactions reported in clinical studies
The following terms have been grouped:
a Nasopharyngitis and oral herpes
b Bronchitis, lower respiratory tract infection, pneumonia and respiratory tract infection
c Abscess, limb abscess, anal abscess, gum abscess, liver abscess, pancreatic abscess, perineal abscess, perirectal abscess, rectal abscess, subcutaneous abscess and dental abscess
d Esophageal candidiasis and oral candidiasis
and Cellulitis and skin infection
f Sepsis and septic shock
g Abdominal abscess, abdominal sepsis, diverticulitis and osteomyelitis
h Reduced appetite and anorexia
i Dysgeusia, ageusia and taste alteration
j Acute coronary syndrome, angina pectoris, unstable angina, coronary artery occlusion, myocardial ischaemia
k Reduction / anomaly of the ejection fraction
l Acute myocardial infarction, myocardial infarction, silent myocardial infarction
m Oropharyngeal and pharyngolaryngeal pain
n Stomatitis and aphthous stomatitis
o Abdominal pain, lower and upper abdominal pain
p Gastrointestinal and intestinal perforation
q Cholecystitis and alithic cholecystitis
r Yellow skin, skin discolouration and pigmentation disorders
s Psoriasiform dermatitis, exfoliative rash, rash, erythematous rash, follicular rash, generalized rash, macular rash, maculo-papular rash, papular rash and pruritic rash
t Skin reaction and skin pathology
u Nail pathology and nail discolouration
v Fatigue and asthenia
w Facial edema, edema and peripheral edema
x Amylase and increased amylase
* Includes fatal events
Description of adverse reactions identified
Infections and infestations: Cases of serious infections (with or without neutropenia), including cases with fatal outcome, have been reported. Cases of necrotizing fasciitis, sometimes fatal, which could also affect the perineum area have been reported (see also section 4.4).
Disorders of the blood and lymphatic system: Cases of thrombotic microangiopathy have been reported. In these cases, temporary suspension of SUTENT is recommended; after the resolution of these events, treatment can be restarted at the discretion of the treating physician.
Immune system disorders: Hypersensitivity reactions, including angioedema, have been reported.
Nervous system disorders: Few cases, some fatal, of subjects presenting with seizures and radiological evidence of reversible posterior leukoencephalopathy syndrome (RPLS) have been reported (see also section 4.4).
Metabolism and nutrition disorders: A higher incidence of hypoglycemic events has been reported in patients with pNET compared to patients with MRCC and GIST. However, many of the adverse events observed in clinical trials were not considered to be related to study treatment.
Hepatobiliary disorders: Hepatic dysfunction has been reported and may include liver function test abnormalities, hepatitis or liver failure.
Skin and subcutaneous tissue disorders: Cases of gangrenous pyoderma, generally reversible after discontinuation of treatment, have been reported (see also section 4.4).
Musculoskeletal and connective tissue disorders: Cases of myopathy and / or rhabdomyolysis, some associated with acute renal failure, have been reported. Patients presenting with signs or symptoms of muscle toxicity should be treated in accordance with standard medical practice.
Cases of fistula formation, sometimes associated with tumor necrosis and regression, in some cases with fatal outcome, have been reported.
Cases of osteonecrosis of the jaw have been reported in patients treated with SUTENT, many of which occurred in patients who had recognized risk factors for osteonecrosis of the jaw, particularly exposure to intravenous bisphosphonates and / or history of dental disease requiring invasive dental interventions (see also section 4.4).
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. in "Annex V.
04.9 Overdose
There is no specific antidote to overdose with sunitinib and the treatment of overdose should include general supportive measures. If indicated, elimination of the unabsorbed active substance can be accomplished by emesis or gastric lavage. They have been reported. cases of overdose; in some of these cases the adverse reactions that occurred were consistent with the known safety profile of sunitinib.
05.0 PHARMACOLOGICAL PROPERTIES
05.1 Pharmacodynamic properties
Pharmacotherapeutic group: antineoplastic agents, protein kinase inhibitors.
ATC code: LO1XE04.
Mechanism of action
Sunitinib inhibits multiple tyrosine kinase (RTK) receptors that are involved in tumor growth, tumor neoangiogenesis and cancer metastatic progression. Sunitinib has been identified as an inhibitor of platelet-derived growth factor receptors (PDGFRα and PDGFRβ), vascular endothelial growth factor receptors (VEGFR1, VEGFR2 and VEGFR3), stem cell factor receptor (KIT), FLT3 tyrosine kinase receptor (Fms-like tyrosine kinase 3), the CSF-1R receptor (colony stimulating factor receptor (CSF-1R)) and the glial-derived neutrophic factor receptor (RET). The main metabolite shows a potency comparable to that of sunitinib in biochemical and cellular tests.
Clinical efficacy and safety
The safety and clinical efficacy of sunitinib have been studied in the treatment of patients with GIST resistant to imatinib (ie, those patients who had progressed disease during or after treatment with imatinib) or intolerant to imatinib (ie, those who had significant toxicity during treatment with imatinib which prevented the continuation of treatment), in the treatment of patients with MRCC and in the treatment of patients with inoperable pNET.
Efficacy is based on time to tumor progression and increase in survival in patients with GIST, progression-free survival and objective response rate in previously untreated MRCC and MRCC patients refractory to therapy with MRCC, respectively. cytokines, and on progression-free survival for patients with pNET.
Stromal tumors of the gastrointestinal tract (GIST)
An initial open-label escalating study was conducted in patients with GIST after imatinib failure (median maximum daily dose 800 mg) due to resistance or intolerance. 97 patients with different dosages and dosing regimens were enrolled; 55 patients were treated with SUTENT 50 mg according to the recommended 4-week drug and two-week drug withdrawal schedule (schedule 4/2).
In this study, the median Time To Progression TTP was 34.0 weeks (95% CI = 22.0-46.0 weeks).
A randomized, double-blind, placebo-controlled Phase 3 study of sunitinib was conducted in patients with GIST who were intolerant or had disease progression during or after treatment with imatinib (median maximum daily dose 800 mg). In this study, 312 patients (2: 1) were randomized to be treated with 50 mg sunitinib or placebo, orally once daily according to the 4/2 schedule until disease progression or withdrawal from the study for a " other reason (207 patients received sunitinib and 105 placebo).
The study's primary efficacy endpoint was TTP, defined as the time from randomization to first documentation of objective tumor progression. At the time of the pre-specified interim analysis, the median TTP with sunitinib was 28.9 weeks (95% CI = 21.3-34.1 weeks) when assessed by the investigator, and 27.3 weeks (95% CI = 16.0-32.1 weeks) when assessed by the Independent Review Committee and was statistically superior to the 5.1-week TTP obtained with placebo (95% CI = 4.4-10.1 weeks, p
Independent Review Committee. The difference in overall survival was statistically in favor of sunitinib [hazard ratio: 0.491 95% (CI 0.290-0.831)]; the risk of death was 2 times higher in patients in the placebo arm than in those in the sunitinib arm.
Following the interim efficacy and safety analysis, on the recommendation of the independent DSMB, the study was blinded and patients in the placebo arm were offered to switch to open-label sunitinib treatment.
A total of 255 patients were treated with sunitinib in the open-label treatment phase of the study, including 99 patients initially treated with placebo.
The analysis of the primary and secondary endpoints in the open-label phase of the study reconfirmed the results obtained at the time of the interim analysis, as shown in the table below.
Table 2 - Summary of Efficacy Endpoints (ITT population)
Median overall survival (OS) in the ITT population was 72.7 weeks and 64.9 weeks (HR 0.876, 95% CI 0.679 - 1.129, p = 0.306) in the sunitinib treatment arm and the placebo arm, respectively. In this analysis, the placebo arm included those patients randomized to placebo and subsequently switched to open-label sunitinib treatment.
Metastatic renal cell carcinoma (MRCC) in previously untreated patients
A randomized, multicenter, international Phase 3 study was conducted to evaluate the efficacy and safety of sunitinib compared to interferon IFN-α in previously untreated MRCC patients. Seven hundred and fifty patients were randomized 1: 1 to the treatment arms; received sunitinib treatment in repeated 6-week cycles. Each cycle consists of 4 weeks with 50 mg per day orally followed by 2 weeks without taking the drug (schedule 4/2), or with IFN-α administered orally subcutaneous at a dose of 3 million units (MU) the first week, 6 MU the second week and from the third week onwards at a dose of 9 MU according to a treatment of 3 non-consecutive days each week.
The mean duration of treatment was 11.1 months (range: 0.4 - 46.1) for sunitinib treatment and 4.1 months (range 0.1 - 45.6) for IFN- α treatment. . Treatment-related serious adverse events (TRSAEs) were reported in 23.7% of patients receiving sunitinib and 6.9% of patients receiving IFN-α. However, the discontinuation rates due to adverse events were 20% for sunitinib and 23% for IFN-α. Discontinuations of treatment occurred in 202 patients (54%) in the sunitinib group and 141 patients (39%) in the IFN-α group.
Dose reductions occurred in 194 patients (52%) treated with sunitinib and 98 patients (27%) treated with IFN-α. Patients were treated until disease progression or study withdrawal. The primary efficacy endpoint was progression-free survival (PFS).
A planned interim analysis showed a statistically significant advantage for SUTENT over IFN-α. In this study, the median PFS for the sunitinib group was 47.3 weeks compared with 22.0 weeks for the IFN-α group; the hazard ratio was 0.415 (95% CI: 0.320-0.539, p-value
Sunitinib treatment was associated with longer survival than IFN-α treatment. Median overall survival was 114.6 weeks for the sunitinib arm (95% CI: 100.1 - 142.9 weeks) and 94.9 weeks for the IFN-α arm (95% CI: 77.7 - 117.0 weeks) with a hazard ratio of 0.821 (95% CI: 0.673-1.001; p = 0.0510 based on the unstratified log-rank test).
Progression-free survival (PFS) and overall survival (OS), observed in the intention to treat (ITT) population and determined by radiological laboratory assessment, are summarized in the following tables:
Summary of efficacy endpoints (ITT population)
Cytokine-refractory metastatic renal cell carcinoma (MRCC)
A phase 2 study was conducted with SUTENT in patients refractory to prior cytokine therapy treated with interleukin-2 or IFN-α. Sixty-three patients received an oral starting dose of 50 mg sunitinib once daily for 4 consecutive weeks followed by a 2-week rest period to complete a full 6-week course (treatment schedule 4 / 2). The primary efficacy endpoint was the objective response rate (Objective
Response Rate (ORR)) according to the RECIST criteria (Response Evaluation Criteria in Solid Tumors).
In this study, the objective response rate was 36.5% (95% CI 24.7% -49.6%) and the median time to progression (TTP) was 37.7 weeks (95% CI 24.0-46.4 weeks).
An open-label, single-arm, multicenter, confirmatory study to evaluate the efficacy and safety of sunitinib was conducted in patients with MRCC refractory to prior cytokine therapy. One hundred and six patients received at least one dose of 50 sunitinib. mg in the framework of the 4/2 scheme.
The primary efficacy endpoint of this study was the rate of ORR. Secondary endpoints included TTP, duration of response (DR), and overall survival (OS).
In this study, the ORR was 35.8% (95% CI 26.8% -47.5%). The DR and median OS had not yet been reached.
Pancreatic neuroendocrine tumors (pNET)
An open-label, multicenter, phase 2 supportive study evaluated the efficacy and safety of sunitinib monotherapy at 50 mg daily doses on a 4/2 schedule [4 weeks of treatment, 2 weeks off] in patients with Inoperable pNET In a cohort of 66 patients with pancreatic islet cell cancer the primary response endpoint was 17%.
A pivotal Phase 3, multicentre, international, randomized, double-blind, placebo-controlled study of sunitinib monotherapy in patients with inoperable pNET was conducted.
Patients who were required to have had documented RECIST-based disease progression within the previous 12 months were randomized (1: 1) to receive 37.5 mg of sunitinib once daily without a scheduled withdrawal period (n = 86) or placebo (n = 85).
The primary endpoint was the assessment of progression-free survival (PFS) in patients taking sunitinib versus those receiving placebo. Other endpoints were OS, ORR rate, PRO-Patient-reported Outcomes. ) and safety.
From the point of view of demographic characteristics, the groups of patients treated with sunitinib and placebo were comparable. In addition, 49% of sunitinib-treated patients and 52% of patients receiving placebo had nonfunctioning tumors and 92% of patients in both arms had liver metastases. The study allowed the use of somatostatin analogues. 66% of patients treated with sunitinib and 72% of patients treated with placebo were previously treated with systemic therapy. In addition, 24% of patients in the sunitinib group and 22 % of patients in the placebo group received somatostatin analogues. A clinically meaningful advantage of sunitinib PFS compared to placebo was observed at investigator assessment. Median PFS was 11.4 months in the sunitinib arm compared to 5, 5 months in the placebo arm [hazard ratio: 0.418 (95% CI 0.263, 0.662), p-value = 0.0001]; similar results were seen when assessments of tumor response, based on the application of RECIST to measurements of the tumor performed by the investigators, were used to determine disease progression as shown in Table 3. A hazard ratio in favor of sunitinib was observed in all subgroups assessed for baseline characteristics, including analysis by number of prior systemic therapies. A total of 29 patients in the sunitinib arm and 24 in the placebo group had received no prior systemic therapies; in these patients there "hazard ratio for PFS it was 0.365 (95% CI 0.156, 0.857), p = 0.0156.
Similarly, among the 57 patients in the sunitinib arm (including 28 with 1 prior systemic therapy and 29 with 2 or more systemic therapies) and 61 patients in the placebo arm (including 25 with 1 prior systemic therapy and 36 with 2 or more therapies systemic) l "hazard ratio for PFS it was 0.456 (95% CI 0.264, 0.787), p = 0.0036.
A sensitivity analysis of PFS was performed when PFS was based on investigator measurements of the tumor and when all subjects, censored for reasons other than study termination, were considered to be PFS events. This analysis provided a conservative estimate of the effect of sunitinib treatment and confirmed the primary analysis, demonstrating a "hazard ratio 0.507 (95% CI 0.350, 0.733), p = 0.000193. The pivotal study in pancreatic NET was terminated prematurely based on the recommendation of an independent Drug Evaluation Committee, and the primary endpoint was based on investigator assessment: both conditions may have affected the estimate of treatment effect.
To rule out bias in investigators' assessment of PFS, an independent, blinded central review of diagnostic imaging was conducted; this review supported investigator assessment, as shown in Table 3.
Table 3 - Efficacy results from the phase 3 pNET study
CI = confidence interval, HR = Hazard ratio, NA = Not applicable, NR = not reached
a 2-sided log-rank non-stratified test
b Fisher "s Exact test
The overall survival figure was not mature when the analysis was conducted. There were 9 deaths in the sunitinib arm and 21 deaths in the placebo arm. A statistically significant difference was observed in the objective response rate of the sunitinib compared to placebo.
In cases of disease progression, patients were informed about the treatment they were receiving and patients taking placebo were offered the option of being enrolled in a different open-label extension study with sunitinib. Due to the early closure of the study, the remaining patients were informed about the treatment they were receiving and were offered access to an open-label extension study with sunitinib. A total of 59 patients in the placebo arm were treated with sunitinib in the study. of extension.
The results of the Questionnaire on the Quality of Life of the European Organization for Research and Treatment of Cancer (EORTC QLQ-C30) showed that the overall health-related quality of life and the five functional domains (physical, role, cognitive , emotional and social) were conserved in patients receiving sunitinib, compared to those receiving placebo, with few symptomatic side effects.
Pediatric population
The European Medicines Agency has deferred the obligation to submit the results of studies with SUTENT in one or more subsets of the pediatric population for the treatment of GISTs (see section 4.2 for information on pediatric use).
The European Medicines Agency has waived the obligation to submit the results of studies with SUTENT in all subsets of the pediatric population for the treatment of renal and renal pelvic carcinomas (with the exclusion of nephroblastoma, nephroblastomatosis, sarcoma clear cell, mesoblastic nephroma, renal medullary carcinoma and rhabdoid tumor of the kidney) (see section 4.2 for information on pediatric use).
The European Medicines Agency has waived the obligation to submit the results of studies with SUTENT in all subsets of the pediatric population for the treatment of gastroenteropancreatic neuroendocrine tumors (with the exclusion of neuroblastoma, neuroganglioblastoma, pheochromocytoma) (see section 4.2 for information on pediatric use).
05.2 "Pharmacokinetic properties
The pharmacokinetics of sunitinib were evaluated in 135 healthy volunteers and in 266 patients with solid tumors. Pharmacokinetics were similar in all solid tumor patient populations tested and in healthy volunteers.
Within the 25-100 mg dose regimens, the area under the curve (AUC) and Cmax increase in a dose-proportional manner. With repeated daily administration, sunitinib accumulates 3-4 fold and the main active metabolite accumulates 7-10 fold. Steady-state concentrations of sunitinib and its major active metabolite are achieved within 10-14 days. By day 14, the combined plasma concentrations of sunitinib and its major active metabolite are 62.9 - 101 ng / mL and represent predicted target concentrations based on pre-clinical data to inhibit receptor phosphorylation in vitro and lead to a reduction in tumor stasis / growth in vivo.
The major active metabolite accounts for 23-37% of total drug exposure. No significant changes in the pharmacokinetics of sunitinib or major active metabolite are observed with repeated once-daily or repeated courses at the dose regimens tested.
Absorption
After oral administration of sunitinib, peak concentrations (Cmax) are generally observed within 6-12 hours (Tmax) of drug intake.
Food has no effect on the bioavailability of sunitinib.
Distribution
The binding of sunitinib and its major active metabolite to human plasma proteins in tests in vitro they were 95% and 90%, respectively, without an "apparent dependence on concentration.
The apparent volume of distribution (Vd) of sunitinib was large - 2,230 l - and indicates tissue distribution.
Metabolic interactions
The calculated Ki values in vitro for all cytochrome (CYP) isoforms examined (CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4 / 5 and CYP4A9 / 11) indicated that it is unlikely that sunitinib and its major active metabolite to a clinically relevant extent the metabolism of other active substances which can be metabolised by these enzymes.
Biotransformation
Sunitinib is metabolised primarily by CYP3A4, the cytochrome P450 isoform, which produces its major active metabolite, desethyl sunitinib, which is further metabolised by the same isoenzyme.
Co-administration of sunitinib and strong CYP3A4 inducers or inhibitors should be avoided because plasma levels of sunitinib may be altered (see sections 4.4 and 4.5).
Elimination
Excretion occurs mainly via faeces (61%) and renal elimination of the unchanged active substance and its metabolites represents 16% of the administered dose. Sunitinib and its major active metabolite were the major compounds identified in plasma, urine and faeces and accounted for 91.5%, 86.4% and 73.8%, respectively, of the radioactivity detected in the pooled samples. Minor metabolites have been identified in urine and faeces, but generally not detected in plasma. Total oral clearance (CL / F) was 34-62 L / h.
After oral administration to healthy volunteers, the elimination half-lives of sunitinib and its major active metabolite desethyl are approximately 40-60 hours and 80-110 hours, respectively.
Special populations
Hepatic impairment: Sunitinib and its major metabolite are primarily metabolised by the liver. Systemic exposures following a single dose of sunitinib were similar in subjects with mild or moderate hepatic impairment (Child-Pugh stages A and B) compared to subjects with normal hepatic function. SUTENT has not been studied in subjects with severe hepatic impairment (Child-Pugh stage C).
Cancer studies excluded patients with ALT or AST> 2.5 x ULN (Upper Limit of Normal) or if these values were> 5.0 x ULN due to liver metastases.
Renal impairment: Population pharmacokinetic analyzes indicated that sunitinib apparent clearance (CL / F) was not affected by creatinine clearance over the range considered (42-347 mL / min). Systemic exposures after one single dose of sunitinib were similar in subjects with severe renal impairment (CLcr80 ml / min). Although sunitinib and its major metabolite were not eliminated by hemodialysis in subjects with ESRD, total systemic exposures were 47% lower for sunitinib and 31% for its main metabolite compared to subjects with normal renal function.
Weight, performance status: Population pharmacokinetic analyzes indicate that no starting dose adjustments are required for weight and Eastern Cooperative Oncology Group (ECOG) performance status.
Gender of belonging: Available data indicate that females may have 30% lower apparent sunitinib clearance (CL / F) than males; this difference, however, does not require starting dose adjustments.
05.3 Preclinical safety data
Repeated dose toxicity studies in rats and monkeys lasting up to 9 months showed that the main target organ effects are in the gastrointestinal tract (emesis and diarrhea in monkeys); the adrenal glands (cortical congestion and / or haemorrhage in rats and monkeys, with necrosis followed by fibrosis in rats); the blood and lymphatic system (hypocellularity of the bone marrow and lymphoid depletion of the thymus, spleen and lymph nodes); the exocrine pancreas (degranulation of acinar cells with single cell necrosis); the salivary glands (acinar hypertrophy); bony joints (thickening of the growth plate); the uterus (atrophy) and ovaries (reduction of follicular development). All results occurred with clinically relevant plasma exposure levels of sunitinib. Other effects observed in the studies included: a prolongation of the QTc interval, reduction left ventricular ejection fraction (LVEF) and testicular tubular atrophy, increased mesangial cells in the kidney, haemorrhage of the gastrointestinal tract and oral mucosa, and hypertrophy of the anterior pituitary cells. endometrium) and bone growth plate (epiphyseal thickening or cartilage dysplasia) are related to the pharmacological action of sunitinib. Most of these events were reversible following discontinuation of treatment for 2-6 weeks.
Genotoxicity
The genotoxic potential of sunitinib was evaluated in vitro and in vivo. Sunitinib did not show mutagenic effects in bacteria using the metabolic activation provided by the rat liver. Sunitinib did not induce structural chromosomal aberrations in human peripheral lymphocytes in vitro. Polyploidy (aberrations in chromosome number) has been observed in human peripheral lymphocytes in vitro, both in the presence and in the absence of metabolic activation. Sunitinib showed no clastogenic potential in the rat bone marrow in vivo. The major active metabolite has not been evaluated for genotoxic potential.
Carcinogenicity
In the 1-month study to find the dose range (0, 10, 25, 75, or 200 mg / kg / day) in which the rasH2 transgenic mice were fed by an oral probe by dosing daily and continuously the dose when administered, at the highest doses (200 mg / kg / day) carcinoma and hyperplasia of Brunner's glands of the duodenum were observed.
A 6-month study was conducted to evaluate carcinogenicity in rasH2 transgenic mice fed with an oral tube by dosing the administered dose daily (0, 8, 25, 75 [reduced to 50] mg / kg / day). At doses ≥25 mg / kg / day administered for 1 or 6 months (≥7.3 times the AUC seen in patients receiving the recommended daily dose [RDD]), gastroduodenal carcinomas, an increased background incidence were observed. haemangiosarcoma and / or hyperplasia of the gastric mucosa.
In a 2-year study to evaluate carcinogenicity in rats (0, 0.33, 1 or 3 mg / kg / day) when sunitinib was administered in 28-day cycles followed by 7-day non-dosing periods, an increase was found the incidence of pheochromocytoma and medullary hyperplasia of the adrenal gland in male rats that had received a dose of 3 mg / kg / day for more than 1 year (≥ 7.8 times the AUC in patients receiving RDD). Brunner's gland carcinoma occurred in the duodenum at doses ≥ 1 mg / kg / day in females, at doses of 3 mg / kg / day in males and mucosal cell hyperplasia was evident in the stomach glands at equal doses. at 3 mg / kg / day in males; these events occurred at doses of 0.9, 7.8 and 7.8 times the AUC observed in patients receiving RDD, respectively. The relevance of these neoplastic findings observed in mouse (rasH2 transgenic) and rat carcinogenicity studies to humans treated with sunitinib is uncertain.
Reproductive and developmental toxicity
No effects on male or female fertility were observed in reproductive toxicity studies. However, repeated dose toxicity studies conducted in rats and monkeys have shown effects on female fertility in the form of follicular atresia, degeneration of the corpus luteum, endometrial changes in the uterus and reduction of the weight of the uterus and ovaries to levels of clinically relevant systemic exposure. Effects on male rat fertility were observed in the form of tubular atrophy in the testes, reduced spermatozoa in the epididymis and colloidal depletion in the prostate and seminal vesicles at plasma exposure levels 25 times the human systemic exposure.
In rats, embryo-fetal mortality resulted in significant reductions in the number of live fetuses, increased number of resorptions, increased post-implantation losses and total offspring losses in 8 of 28 pregnant females at plasma exposure levels of 5.5 times the systemic exposure in humans. In rabbits, reductions in the weight of the pregnant uterus and the number of live fetuses were caused by the increase in fetal resorptions, post-implantation losses and total offspring losses in 4 of 6 pregnant females at 3-fold plasma exposure levels. systemic exposure in humans. Treatment with sunitinib in rats during organogenesis resulted in developmental effects at doses ≥ 5 mg / kg / day, consisting of an increased incidence of fetal skeletal malformations, mainly characterized by delayed ossification of the thoracic / lumbar vertebrae and occurring occur at plasma exposure levels 5.5 times the human systemic exposure. In rabbits, developmental effects consisted of an increased incidence of cleft lip at plasma exposure levels approximately equal to those observed in the clinic, and cleft lip and cleft palate at plasma exposure levels 2.7 times the systemic exposure. in man.
The effects of sunitinib (0.3; 1.0; 3.0 mg / kg / day) on pre- and postnatal development were evaluated in a study in pregnant female rats. Maternal body weight gain during gestation and lactation was reduced at doses> 1 mg / kg / day, but no maternal reproductive toxicity was observed up to doses of 3 mg / kg / day (estimated exposure> 2 , 3 times the AUC seen in patients receiving RDD). Reduced offspring body weights were observed at doses of 3 mg / kg / day in the pre- and post-weaning periods. No developmental toxicity was observed at doses of 1 mg / kg / day (exposure approximately ≥0.9 times the AUC seen in patients receiving RDD).
06.0 PHARMACEUTICAL INFORMATION
06.1 Excipients
Capsule contents
Mannitol (E421)
Croscarmellose sodium
Povidone (K-25)
Magnesium stearate
Capsule shell
Jelly
Red iron oxide (E172)
Titanium dioxide (E171)
Ink
Shellac
Propylene glycol
Sodium hydroxide
Povidone
Titanium dioxide (E171)
06.2 Incompatibility
Not relevant.
06.3 Period of validity
3 years.
06.4 Special precautions for storage
This medicinal product does not require any special storage conditions.
06.5 Nature of the immediate packaging and contents of the package
High-density polyethylene (HDPE) bottles, with a polypropylene closure, containing 30 hard capsules.
Transparent poly (chlorotrifluoroethylene) / PVC blisters with perforated unit doses and with aluminum foil with heat seal lacquer containing 28 x 1 hard capsules.
Not all pack sizes may be marketed.
06.6 Instructions for use and handling
No special instructions.
07.0 MARKETING AUTHORIZATION HOLDER
Pfizer Ltd
Ramsgate Road
Sandwich, Kent CT13 9NJ
UK
08.0 MARKETING AUTHORIZATION NUMBER
EU / 1/06/347/001
037192022
EU / 1/06/347/004
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION
Date of first authorization: 19 July 2006
Date of most recent renewal: 09 January 2012
10.0 DATE OF REVISION OF THE TEXT
11.0 FOR RADIO DRUGS, COMPLETE DATA ON THE INTERNAL RADIATION DOSIMETRY
12.0 FOR RADIO DRUGS, FURTHER DETAILED INSTRUCTIONS ON EXEMPORARY PREPARATION AND QUALITY CONTROL
