Active ingredients: Paclitaxel
Abraxane 5 mg / ml powder for suspension for infusion
Why is Abraxane used? What is it for?
What is Abraxane
Abraxane contains paclitaxel bound to albumin, a human protein, as the active ingredient in tiny particles known as nanoparticles. Paclitaxel belongs to a group of medicines called taxanes, which are used in cancer therapy.
- Paclitaxel is the part of the medicine that affects the tumor, it works by stopping the division of the tumor cells, which then die.
- Albumin is the part of the medicine that helps paclitaxel dissolve in the blood and travel through blood vessel walls to the tumor. This means that no other chemicals are needed which can cause side effects, which can be life threatening. Some side effects are much less common with Abraxane.
What Abraxane is for
Abraxane is used to treat the following types of cancer:
Breast cancer
- Breast cancer that has spread to other parts of the body (this is called "metastatic" breast cancer).
- Abraxane is used in metastatic breast cancer when at least one 'other therapy has been tried but has not worked and if the patient is not suitable for treatments containing a group of medicines called' anthracyclines'.
- People with metastatic breast cancer who received Abraxane, in cases where another therapy was unsuccessful, were more likely to see a reduction in tumor size and lived longer than people who took an alternative therapy.
Cancer of the pancreas
- Abraxane is used together with a medicine called gemcitabine for metastatic cancer of the pancreas. People with metastatic pancreatic cancer (pancreatic cancer that has spread to other parts of the body) treated with Abraxane and gemcitabine in a clinical study lived longer than people who received gemcitabine alone.
Lung cancer
- Abraxane is used together with a medicine called carboplatin to treat the most common lung cancer called 'non-small cell lung cancer'.
- Abraxane is used in non-small cell lung cancer when surgery or radiation therapy is not suitable for treating the disease.
Contraindications When Abraxane should not be used
Do not use Abraxane
- if you are allergic to paclitaxel or any of the other ingredients of this medicine (listed in section 6);
- if you are breastfeeding;
- if you have a low white blood cell count (white blood cells, initial neutrophil count <1,500 cells / mm3 - information on this will be provided by your doctor).
Precautions for use What you need to know before you take Abraxane
Talk to your doctor or nurse before using Abraxane
- if kidney function is reduced;
- if you have severe liver problems;
- if you have heart problems.
Consult your doctor or nurse if you have any of these conditions while taking Abraxane; your doctor may decide to stop treatment or reduce the dose:
- if you have abnormal bruising, bleeding, or signs of infection, such as a sore throat or fever;
- if you feel numbness, tingling, stinging, sensitivity to touch or muscle weakness;
- if you have breathing problems, such as shortness of breath or a dry cough.
Children and adolescents
This medicine has not been studied in children and adolescents because breast cancer, pancreatic cancer and lung cancer do not occur in these age groups.
Interactions Which drugs or foods may change the effect of Abraxane
Tell your doctor if you are taking or have recently taken any other medicines, including those obtained without a prescription and herbal medicines. This is because Abraxane can affect the way some other medicines work, and some other medicines can affect the way Abraxan works
Take care and consult your doctor when taking Abraxane together with any of the following:
- medicines to treat infections (ie antibiotics, such as erythromycin, rifampicin, etc .; ask your doctor, nurse or pharmacist if you are not sure whether the medicine you are taking is an antibiotic), including medicines for the treatment fungal infections (e.g. ketoconazole)
- medicines used to stabilize mood, sometimes also called antidepressants (eg fluoxetine)
- medicines used to treat seizures (epilepsy) (e.g. carbamazepine, phenytoin)
- medicines used to lower blood lipid levels (e.g. gemfibrozil)
- medicines used for heartburn or stomach ulcers (e.g. cimetidine)
- medicines used to treat HIV and AIDS (eg ritonavir, saquinavir, indinavir, nelfinavir, efavirenz, nevirapine)
Warnings It is important to know that:
Pregnancy, breastfeeding and fertility
Paclitaxel can cause serious congenital (birth) abnormalities and therefore should not be used in pregnancy.
Women of childbearing potential must use effective contraceptive methods during Abraxane therapy and for 1 month after discontinuation of therapy.
Do not breast-feed while being treated with Abraxane, as it is not known whether the active substance paclitaxel passes into breast milk.
Male patients are advised not to father children during therapy and for six months after therapy has been discontinued, and to inquire about semen storage prior to treatment, due to the possibility that Abraxane therapy may produce permanent infertility.
Ask your doctor for advice before taking this medicine.
Driving and using machines
Some people may feel tired or dizzy after being given Abraxane. If this happens, don't drive vehicles or use any tools or machines.
If other medicines are prescribed as part of your therapy, consult your doctor about the possibility of driving and using machines.
Abraxane contains sodium
Each ml of Abraxane contains approximately 4.2 mg of sodium. If you are on a low sodium diet you should take this into account.
Dosage and method of use How to use Abraxane: Dosage
Abraxane will be administered into a vein by intravenous perfusion by a doctor or nurse. The amount administered depends on the body surface and the results of the blood tests. The usual dose for breast cancer is 260 mg / m2 of body surface area, given over 30 minutes. The usual dose for advanced pancreatic cancer is 125 mg / m2 of body surface area, given over a period of 30 minutes. 30 minutes. The usual dose for non-small cell lung cancer is 100 mg / m2 of body surface area, given over 30 minutes.
How often is Abraxane given?
For the treatment of metastatic breast cancer, Abraxane is usually given once every three weeks (on day 1 of a 21-day cycle).
For the treatment of advanced pancreatic cancer, Abraxane is given on days 1, 8, and 15 of each 28-day treatment cycle, with gemcitabine given soon after Abraxane.
For the treatment of non-small cell lung cancer, Abraxane is given once weekly (i.e. on days 1, 8, and 15 of a 21-day cycle) with carboplatin given once every three weeks (i.e. only on day 1 of each 21-day cycle), immediately following the administration of the Abraxane dose.
If you have any further questions on the use of this medicine, ask your doctor or nurse.
Side Effects What are the side effects of Abraxane
Like all medicines, this medicine can cause side effects, although not everybody gets them.
Very common side effects may affect more than 1 in 10 people:
- Hair loss (most cases of hair loss occurred less than one month after starting Abraxane treatment. When it occurs, hair loss is pronounced (over 50%) in most patients )
- Rash
- Abnormal decrease in the number of certain types of white blood cells (neutrophils, lymphocytes or leukocytes) in the blood
- Deficiency of erythrocytes (red blood cells)
- Reduction in the number of platelets in the blood
- Effects on peripheral nerves (pain, numbness, tingling or loss of sensation)
- Pain in one or more joints
- Muscular pain
- Nausea, diarrhea, constipation, mouth irritation, loss of appetite
- He retched
- Weakness and fatigue, fever
- Dehydration, taste changes, weight loss
- Low levels of potassium in the blood
- Depression, sleep disturbances
- Headache
- Chills
- Difficulty in breathing
- Dizziness
- Swelling of the mucous membranes and soft tissues
- Increase in liver function values
- Pain in the extremities
- Cough
- Abdominal pain
- nose bleeding
Common side effects may affect up to 1 in 10 people:
- Itching, dry skin, nail changes
- Infection, fever with a reduction in the number of a type of white blood cell (neutrophil) in the blood, flushing, oral thrush, severe infection of the blood which may be caused by a reduction in white blood cells
- Reduction in the number of all types of blood cells
- Chest pain or sore throat
- Indigestion, abdominal problems
- Stuffed nose
- Back pain, bone pain
- Reduced muscle coordination or difficulty reading, increased or decreased tearing, loss of eyelashes
- Changes in heart rate or rhythm, heart failure
- Decrease or increase in blood pressure
- Redness or swelling at the needle insertion site
- Anxiety
- Infection in the lungs
- Urinary tract infection
- Bowel obstruction, large intestine inflammation, bile duct inflammation
- Acute renal failure
- Increased bilirubin in the blood
- Cough with blood
- Dry mouth, difficulty in swallowing
- Muscle weakness
- Blurred vision
Uncommon side effects may affect up to 1 in 100 people:
- Weight gain, blood lactate dehydrogenase (an enzyme) increased, kidney function decreased, blood sugar increased, blood phosphorus increased
- Decreased or lack of reflexes, involuntary movements, neuralgia, fainting, dizziness on standing up, tremor, facial nerve paralysis
- Eye irritation, eye pain, eye redness, eye itching, double vision, decreased visual acuity or vision of flashing lights, blurred vision due to swelling of the retina (cystoid macular edema)
- Ear pain, ringing in the ears
- Cough with mucus, shortness of breath when walking or climbing stairs, runny or dry nose, decreased breathing sounds, water in the lungs, hoarseness, blood clot in the lung, dry throat
- Flatulence (intestinal gas), stomach cramps, pain in the gums, rectal bleeding
- Painful urination, frequent urination, blood in the urine, urinary incontinence
- Nail pain, painful nail sensitivity, nail loss, hives, skin pain, photosensitive reaction, pigmentation disorder, increased sweating, night sweats, white patches on the skin, skin lesions, facial swelling
- Decreased blood phosphorus, fluid retention, low blood albumin, increased thirst, decreased blood calcium, decreased blood sugar, decreased blood sodium
- Pain and congestion of the nose, skin infections, catheter infection
- Bruise
- Pain where the tumor is located, tumor necrosis
- Decreased blood pressure when standing, cold extremities (hands and feet)
- Difficulty walking, swelling
- Allergic reaction
- Decreased liver function, enlarged liver
- Chest pain ? Restlessness
- Small bleeding in the skin due to blood clots?
- A disease involving the destruction of red blood cells and acute kidney failure
Rare side effects may affect up to 1 in 1,000 people:
- Skin reaction to another agent or lung inflammation following radiation
- Formation of blood clots
- Very slow pulse, heart attack
- Leakage of the medicine from the vein
- A disturbance of the electrical conduction system of the heart (atrioventricular block)
Very rare side effects may affect up to 1 in 10,000 people:
Severe inflammation / rash of the skin and mucous membranes (Stevens-Johnson syndrome, toxic epidermal necrolysis) Reporting of side effects If you get any side effects, talk to your doctor or nurse. This includes any possible side effects not listed in this leaflet. 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 vial after EXP. The expiry date refers to the last day of that month.
Closed vials: Keep the vial in the outer carton to protect from light.
After the first reconstitution, the suspension should be used immediately. If not used immediately, the suspension can be stored in the refrigerator (2 ° C - 8 ° C) for up to 8 hours in the vial kept in the outer carton which protects the medicine from light.
The reconstituted suspension in intravenous perfusion can be stored for up to 8 hours at a temperature not exceeding 25 ° C.
Your doctor or pharmacist is responsible for the proper disposal of unused Abraxane.
What Abraxane contains
The active ingredient is paclitaxel.
Each vial contains 100 mg or 250 mg of paclitaxel bound to albumin formulated in nanoparticles
After reconstitution, each ml of suspension contains 5 mg of paclitaxel bound to albumin formulated in nanoparticles.
The other component is human albumin (containing sodium, sodium caprylate and N-acetyl DL tryptophanate).
What Abraxane looks like and contents of the pack
Abraxane is a white to yellow powder for suspension for infusion. Abraxane is available in glass vials containing 100 mg or 250 mg of albumin-bound paclitaxel formulated in nanoparticles.
Each pack contains 1 vial.
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
ABRAXANE 5 MG / ML POWDER FOR SUSPENSION FOR INFUSION
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each vial contains 100 mg of paclitaxel bound to albumin formulated in nanoparticles.
Each vial contains 250 mg of paclitaxel bound to albumin formulated in nanoparticles.
After reconstitution, each ml of suspension contains 5 mg of paclitaxel bound to albumin formulated in nanoparticles.
Excipients with known effects
Each ml of concentrate contains 0.183 mmol of sodium, equivalent to 4.2 mg of sodium.
For the full list of excipients, see section 6.1.
03.0 PHARMACEUTICAL FORM
Powder for suspension for infusion.
The reconstituted suspension has a pH of 6-7.5 and an osmolality value of 300-360 mOsm / kg.
The powder is white to yellow in color.
04.0 CLINICAL INFORMATION
04.1 Therapeutic indications
Abraxane monotherapy is indicated for the treatment of metastatic breast cancer in adult patients who have failed first-line treatment for metastatic disease and for whom standard anthracycline-containing therapy is not indicated (see section 4.4).
Abraxane in combination with gemcitabine is indicated for the first-line treatment of adult patients with metastatic adenocarcinoma of the pancreas.
Abraxane in combination with carboplatin is indicated for the first-line treatment of non-small cell lung cancer in adult patients not candidates for potentially curative surgery and / or radiotherapy.
04.2 Posology and method of administration
Abraxane should only be administered under the supervision of a qualified oncologist in wards specialized in the administration of cytotoxic agents. It should not be replaced with other paclitaxel formulations.
Dosage
Breast cancer
The recommended dose of Abraxane is 260 mg / m2 to be administered intravenously over 30 minutes every 3 weeks.
Dose adjustment during breast cancer treatment
In patients who present with severe neutropenia (neutrophil count 3 for one week or more) or severe sensory neuropathy during Abraxane therapy, the dose should be reduced to 220 mg / m2 in subsequent courses. If severe neutropenia or sensory neuropathy recurs, the dose should be further reduced to 180 mg / m2. Abraxane should not be administered until the neutrophil count returns to above 1,500 cells / mm3. For Grade 3 sensory neuropathy, withhold treatment until return to Grade 1 or 2, and then reduce the dose for all subsequent courses.
Pancreatic adenocarcinoma
The recommended dose of Abraxane in combination with gemcitabine is 125 mg / m2, to be administered intravenously over 30 minutes on days 1, 8 and 15 of each 28-day cycle. The recommended concomitant dose of gemcitabine is 1,000 mg / m2, to be administered intravenously over 30 minutes immediately after completing the Abraxane administration on days 1, 8 and 15 of each 28-day cycle.
Dose adjustment during treatment of pancreatic adenocarcinoma
Table 1: Dose level reductions for patients with pancreatic adenocarcinoma
Table 2: Dose modifications for neutropenia and / or thrombocytopenia at the start of a cycle or during a cycle for patients with pancreatic adenocarcinoma
Abbreviations: ANC = absolute neutrophil count (ANC = Absolute Neutrophil Count); WBC = leukocytes (WBC = White Blood Cell)
Table 3: Dose modifications for other adverse drug reactions in patients with pancreatic adenocarcinoma
a See Table 1 for dose level reductions
Non-small cell lung cancer:
The recommended dose of Abraxane is 100 mg / m2, to be administered by intravenous infusion over 30 minutes on days 1, 8 and 15 of each 21-day cycle. The recommended carboplatin dose is AUC = 6 mg · min / ml, to be administered only on day 1 of each 21 day cycle, starting as soon as Abraxane is finished.
Dose adjustment during non-small cell lung cancer treatment:
Abraxane should not be administered on day 1 of the cycle until the absolute neutrophil count (ANC) is ≥ 1500 cells / mm3 and the platelet count is ≥ 100,000 cells / mm3. For each subsequent weekly dose of Abraxane, patients must have an ANC ≥ 500 cells / mm3 and a platelet count> 50,000 cells / mm3; otherwise, the dose must be suspended until these values are recovered. When values return to these levels, resume dosing the following week according to the criteria shown in Table 4. Reduce the next dose only if the criteria in Table 4 are met.
Table 4: Dose reductions for haematological toxicities in patients with non-small cell lung cancer
1 On day 1 of the 21-day cycle reduce the dose of Abraxane and carboplatin at the same time. On days 8 or 15 of the 21-day cycle, reduce the dose of Abraxane; reduce the carboplatin dose on the next cycle.
2 For up to 7 days after the scheduled dose of day 1 of the next cycle
For Grade 2 or 3 skin toxicity, Grade 3 diarrhea, or Grade 3 mucositis, discontinue treatment until toxicity improves to ≤ Grade 1, then resume treatment according to the guidelines in Table 5. For Grade peripheral neuropathy ≥ 3, withhold treatment until condition returns to ≤ Grade 1. Treatment can be resumed at the next lower dose level in subsequent cycles according to the guidelines in Table 5. For any other Grade 3 non-haematological toxicity or 4, discontinue treatment until toxicity improves to ≤ grade 2, then resume treatment as reported in Table 5.
Table 5: Dose reductions for non-haematological toxicities in patients with non-small cell lung cancer
1 On day 1 of the 21-day cycle reduce the dose of Abraxane and carboplatin at the same time. On days 8 or 15 of the 21-day cycle, reduce the dose of Abraxane; reduce the carboplatin dose on the next cycle.
Special populations
Patients with hepatic insufficiency
For patients with mild hepatic impairment (total bilirubin> 1 to ≤ 1.5 x ULN and aspartate aminotransferase [AST] ≤ 10 x ULN) no dose adjustment is required, regardless of indication. Doses are the same as expected. for patients with normal liver function.
For patients with metastatic breast cancer and for patients with non-small cell lung cancer with moderate to severe hepatic impairment (total bilirubin> 1.5 to ≤ 5 x ULN and AST ≤ 10 x ULN), a 20% dose reduction is recommended. The reduced dose may be increased to the dose intended for patients with normal hepatic function, if the patient tolerates the treatment for at least two cycles (see sections 4.4 and 5.2).
For patients with metastatic adenocarcinoma of the pancreas with moderate to severe hepatic impairment, there are insufficient data to allow dosing recommendations (see sections 4.4 and 5.2).
For patients with total bilirubin> 5 x ULN or AST> 10 x ULN, there are insufficient data to allow dosing recommendations, regardless of indication (see sections 4.4 and 5.2).
Patients with renal insufficiency
For patients with mild to moderate renal impairment (estimated creatinine clearance ≥ 30 to estimated creatinine clearance
Elderly patients
For patients 65 years of age and older, no further dose reductions are recommended beyond those for all patients.
Of the 229 patients treated with Abraxane monotherapy for breast cancer in a randomized study, 13% were at least 65 years of age and peripheral edema in patients ≥ 65 years of age.
Of the 421 pancreatic adenocarcinoma patients treated with Abraxane in combination with gemcitabine in a randomized study, 41% were 65 years of age or older and 10% were 75 years of age or older. In patients 75 years of age and older treated with Abraxane and gemcitabine, there was an increased incidence of serious adverse reactions and adverse reactions leading to treatment discontinuation (see section 4.4). Patients with pancreatic adenocarcinoma of age 75 or older should be carefully evaluated before considering treatment (see section 4.4).
Of the 514 patients with non-small cell lung cancer treated with Abraxane in combination with carboplatin in the randomized study, 31% were 65 years of age or older and 3.5% were 75 years of age or older. years. Events of myelosuppression, peripheral neuropathy and arthralgia were more frequent in patients 65 years of age and older than in patients less than 65 years of age. Experience with the use of Abraxane / carboplatin in patients 75 years of age and older is limited.
Pharmacokinetic / pharmacodynamic modeling, using data from 125 patients with advanced solid tumors, indicate that patients ≥ 65 years of age may be more prone to developing neutropenia during the first course of treatment.
Pediatric population
The safety and efficacy of Abraxane in children and adolescents aged 0-17 years have not been established. There is no indication for a specific use of Abraxane in the pediatric population in the indication of metastatic breast cancer, pancreatic adenocarcinoma or non-small cell lung cancer.
Method of administration
Administer the reconstituted suspension of Abraxane intravenously using an infusion set equipped with a 15 micron filter. After administration, it is recommended to flush the infusion line with sodium chloride 9 mg / ml (0.9%) solution for injection to ensure administration of the full dose.
For instructions on reconstitution of the medicinal product before administration, see section 6.6.
04.3 Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
Breastfeeding (see section 4.6).
Patients with an initial neutrophil count value 3.
04.4 Special warnings and appropriate precautions for use
Abraxane is an albumin nanoparticle-bound paclitaxel formulation, which may have substantially different pharmacological properties than other paclitaxel formulations (see sections 5.1 and 5.2). It should not be substituted for other paclitaxel formulations.
Hypersensitivity
Rare cases of serious hypersensitivity reactions have been reported, including very rare events of fatal anaphylactic reactions. If a hypersensitivity reaction occurs, the medicinal product should be discontinued immediately, symptomatic therapy initiated and the patient no longer undergoing treatment with paclitaxel.
Hematology
Bone marrow suppression (mainly neutropenia) is common following Abraxane therapy. Neutropenia is dose related and is a form of dose limiting toxicity. Frequent monitoring of blood counts should be performed during Abraxane therapy. The patient should not be re-submitted to subsequent courses of Abraxane until neutrophils return to levels of> 1,500 cells / mm3 and platelets to levels of> 100,000 cells / mm3 (see section 4.2).
Neuropathy
Sensory neuropathy is common following Abraxane therapy, although the development of severe symptoms is less common. Grade 1 or 2 sensory neuropathy generally requires no dose reduction. When Abraxane is used on its own, if Grade 3 sensory neuropathy develops, therapy should be suspended until the condition returns to Grade 1 or 2, and it is recommended thereafter to reduce the dose for all subsequent courses of Abraxane (see paragraph 4.2). For the combined use of Abraxane and gemcitabine, if Grade 3 or greater peripheral neuropathy develops, discontinue Abraxane; continue gemcitabine treatment at the same dose. Resume Abraxane at a reduced dose when peripheral neuropathy falls to Grade 0 or 1 ( see section 4.2). For the combined use of Abraxane and carboplatin, in the presence of Grade 3 or greater peripheral neuropathy, treatment should be withheld until improvement to Grade 0 or 1, and thereafter the dose of Abraxane and carboplatin should be reduced for all subsequent cycles (see section 4.2).
Sepsis
Sepsis was observed at a 5% incidence in patients with or without neutropenia treated with Abraxane in combination with gemcitabine.Complications due to pre-existing pancreatic cancer, in particular biliary obstruction or the presence of biliary stent, have been identified as important factors involved. If a patient has a fever (regardless of the neutrophil count), start treatment with broad-spectrum antibiotics. For febrile neutropenia, withhold Abraxane and gemcitabine until fever subsides and ANC ≥ 1,500 cells / mm3, then resume treatment at reduced dose levels (see section 4.2).
Pneumonia
Pneumonia occurred in 1% of patients when Abraxane was used alone and in 4% of patients when Abraxane was used in combination with gemcitabine. Monitor all patients closely for signs and symptoms of pneumonia. Once ruled out. an "infectious etiology and diagnosis of pneumonia established, permanently discontinue treatment with Abraxane and gemcitabine and immediately initiate" appropriate therapy and supportive measures (see section 4.2).
Hepatic insufficiency
Since the toxicity of paclitaxel may be increased in hepatic insufficiency, caution is required when administering Abraxane to patients with hepatic insufficiency. Patients with hepatic insufficiency may present an increased risk of toxicity, especially following myelosuppression; these patients should be carefully monitored, as they can develop forms of profound myelosuppression.
Abraxane is not recommended in patients with total bilirubin> 5 x ULN or AST> 10 x ULN). Furthermore, Abraxane is not recommended in patients with metastatic adenocarcinoma of the pancreas with moderate to severe hepatic insufficiency (total bilirubin> 1.5 x ULN and AST ≤ 10 x ULN) (see section 5.2).
Cardiotoxicity
Rare reports of congestive heart failure and left ventricular dysfunction have been observed among subjects treated with Abraxane. Most of the subjects had previously been exposed to cardiotoxic drugs, such as anthracyclines, or had previous heart disease. Therefore, patients treated with Abraxane will need to be carefully monitored for the onset of cardiac events.
CNS metastasis
The efficacy and safety of Abraxane in patients with central nervous system (CNS) metastases have not been established. CNS metastases are generally not well controlled by systemic chemotherapy.
Gastrointestinal symptoms
In case of nausea, vomiting and diarrhea following the administration of Abraxane, patients may be treated with commonly used antiemetics and constipating agents.
Patients aged 75 years or older
For patients 75 years of age and older, no benefit has been shown for treatment with Abraxane in combination with gemcitabine, compared to gemcitabine alone. In very elderly patients (≥75 years) treated with Abraxane and gemcitabine, there was an increased incidence of serious adverse reactions and adverse reactions leading to treatment discontinuation, including haematological toxicity, peripheral neuropathy, decreased appetite and dehydration In patients with pancreatic adenocarcinoma 75 years of age and older, carefully evaluate the ability to tolerate Abraxane in combination with gemcitabine, taking into account in particular the performance status, co-morbidities and increased risk of infections (see sections 4.2 and 4.8).
Other
Although available data are limited, no clear benefit in terms of prolonged overall survival has been demonstrated in patients with pancreatic adenocarcinoma who have normal CA 19-9 levels prior to initiation of treatment with Abraxane and gemcitabine (see section 5.1).
Erlotinib must not be administered in combination with Abraxane plus gemcitabine (see section 4.5).
Excipients
In reconstituted form, each ml of Abraxane concentrate contains 0.183 mmol of sodium, equivalent to 4.2 mg of sodium. Patients on a low sodium diet should take this into account.
04.5 Interactions with other medicinal products and other forms of interaction
The metabolism of paclitaxel is catalysed in part by cytochrome P450 isoenzymes CYP2C8 and CYP3A4 (see section 5.2). Therefore, in the absence of a pharmacokinetic drug-drug interaction study, caution should be exercised when administering paclitaxel concomitantly with medicinal products known to have inhibitory properties (eg, ketoconazole and other imidazole-derived antifungals, erythromycin, fluoxetine , gemfibrozil, cimetidine, ritonavir, saquinavir, indinavir and nelfinavir) or induction (rifampicin, carbamazepine, phenytoin, efavirenz, nevirapine) of the isoenzyme CYP2C8 or CYP3A4.
Paclitaxel and gemcitabine do not have a common metabolic pathway. Paclitaxel clearance is mainly determined by CYP2C8 and CYP3A4 mediated metabolism, followed by biliary excretion, while gemcitabine is inactivated by cytidine deaminase, followed by urinary excretion. Pharmacokinetic interactions between Abraxane and gemcitabine have not been evaluated in humans.
A pharmacokinetic study was conducted with Abraxane and carboplatin in patients with non-small cell lung cancer. There were no clinically relevant pharmacokinetic interactions between Abraxane and carboplatin.
Abraxane is indicated as monotherapy for breast cancer, in combination with gemcitabine for pancreatic adenocarcinoma or in combination with carboplatin for non-small cell lung cancer (see section 4.1). Abraxane should not be used concomitantly with other agents. anticancer.
04.6 Pregnancy and lactation
Contraception in men and women
Women of childbearing potential should use effective contraceptive methods during Abraxane therapy and for up to one month after stopping therapy. For male patients receiving Abraxane therapy, it is advised not to father children during therapy and for six months after its discontinuation.
Pregnancy
There are very limited data from the use of paclitaxel in pregnant women. Paclitaxel is thought to cause serious birth defects when administered during pregnancy. Animal studies have shown reproductive toxicity (see section 5.3). Abraxane It must not be used during pregnancy and in women of childbearing potential who are not using effective methods of contraception, unless the clinical condition of the mother requires treatment with paclitaxel.
Feeding time
It is not known whether paclitaxel is excreted in human milk. Given the possibility of serious side effects that could occur in infants, Abraxane is contraindicated during breastfeeding. Breast milk feeding should therefore be suspended for the duration of therapy.
Fertility
Abraxane was found to cause infertility in male rats (see section 5.3). Male patients are advised to inquire about semen storage prior to treatment as Abraxane therapy may cause permanent infertility.
04.7 Effects on ability to drive and use machines
Abraxane has mild or moderate effects on the ability to drive or use machines. Abraxane can cause adverse reactions such as tiredness (very frequent) and dizziness (frequent) which may affect the ability to drive and use machines. Patients should be advised that in the event of tiredness or dizziness, they should refrain from driving and using machines.
04.8 Undesirable effects
Summary of the safety profile
The most common clinically relevant adverse reactions associated with the use of Abraxane were neutropenia, peripheral neuropathy, arthralgia / myalgia and gastrointestinal disorders.
The frequency of adverse reactions associated with Abraxane administration is listed in Table 6 (Abraxane as monotherapy), Table 7 (Abraxane in combination with gemcitabine) and Table 9 (Abraxane in combination with carboplatin).
Frequencies are defined as follows: very common (≥1 / 10), common (≥1 / 100,
Breast cancer (Abraxane given alone)
Table of adverse reactions Table 6 lists adverse reactions associated with Abraxane administration and experienced by patients included in studies where Abraxane was administered as monotherapy for each dose and indication (N = 789).
Table 6: Adverse reactions reported with Abraxane monotherapy in clinical trials for each dose
MedDRA = Medical Dictionary for Regulatory Activities
SMQ = Standardized MedDra Query (standardized MedDRA queries, group of several MedDRA preferred terms to render a medical concept).
1 The frequency of hypersensitivity reactions is calculated based on a strongly related case in a population of 789 patients.
2 As reported in the post marketing monitoring of Abraxane.
3 The frequency of pneumonia is calculated by combining data from 1310 patients in clinical studies treated with Abraxane monotherapy for breast cancer and other indications using the MedDRA SMQ Interstitial lung disease. See section 4.4.
Description of selected adverse reactions
The most common and clinically relevant adverse reactions in 229 patients with metastatic breast cancer treated with 260 mg / m2 Abraxane once every three weeks in the pivotal phase III clinical study are listed below.
Disorders of the blood and lymphatic system
The most frequent form of haematological toxicity was found to be neutropenia (reported in 79% of patients), which was rapidly reversible and related to the dose; leukopenia was found in 71% of patients. Grade 4 neutropenia occurred in 9% of patients treated with Abraxane. Febrile neutropenia occurred in four patients. Forms of anemia (Hb
Nervous system disorders
In general, the frequency and severity of neurotoxicity in Abraxane-treated patients was related to dose. Peripheral neuropathy (mainly grade 1 or 2 sensory neuropathy) was experienced in 68% of patients treated with Abraxane, of which 10% were grade 3; there were no cases of grade 4 sensory neuropathy.
Gastrointestinal disorders
29% of patients reported nausea and 25% reported diarrhea.
Skin and subcutaneous tissue disorders
Alopecia has been observed in> 80% of patients treated with Abraxane. Most cases of alopecia have occurred within one month of starting treatment with Abraxane. Pronounced hair loss of ≥ 50% is expected in the majority of patients with alopecia.
Musculoskeletal and connective tissue disorders
Arthralgia occurred in 32% of patients treated with Abraxane, severe in 6% of cases. 24% of patients treated with Abraxane had myalgia, which was severe in 7% of cases. Symptoms, usually transient, typically appeared three days after Abraxane was given and resolved within one week.
General disorders and administration site conditions
Asthenia / fatigue was reported in 40% of patients.
Pancreatic adenocarcinoma (Abraxane given in combination with gemcitabine)
Table of adverse reactions
Adverse reactions were evaluated in 421 patients treated with Abraxane in combination with gemcitabine and in 402 patients treated with gemcitabine monotherapy receiving systemic first-line treatment for metastatic adenocarcinoma of the pancreas in a randomized, controlled, phase III study. open. Table 7 lists the adverse reactions evaluated in patients with pancreatic adenocarcinoma treated with Abraxane in combination with gemcitabine.
Table 7: Adverse reactions reported with Abraxane in combination with gemcitabine (N = 421)
MedDRA = Medical Dictionary for Regulatory Activities; SMQ = Standardized MedDra Query (standardized MedDRA queries, group of several MedDRA preferred terms to render a medical concept).
1 assessed by SMQ (broad scope).
2 assessed by SMQ interstitial lung disease (broad scope).
In this randomized, controlled, open-label phase III study, adverse reactions resulting in death within 30 days of the last dose of study drug were reported in 4% of patients treated with Abraxane in combination with gemcitabine and in 4% of patients treated with Abraxane in combination with gemcitabine. % of patients treated with gemcitabine alone.
Description of selected adverse reactions
The most common and important incidences of adverse reactions in 421 patients with metastatic adenocarcinoma of the pancreas, treated with 125 mg / m2 of Abraxane in combination with gemcitabine, at a dose of 1,000 mg / m2 administered on days 1, 8 and 15 of each 28-day cycle in the phase III clinical trial.
Disorders of the blood and lymphatic system
Table 8 reports the frequency and severity of laboratory-detected haematological abnormalities for patients treated with Abraxane in combination with gemcitabine or with gemcitabine alone.
Table 8: Hematological abnormalities detected in the laboratory in the pancreatic adenocarcinoma study
a405 patients evaluated in the Abraxane / gemcitabine group
b388 patients evaluated in the gemcitabine group
c404 patients evaluated in the Abraxane / gemcitabine group
Peripheral neuropathy
For patients treated with Abraxane in combination with gemcitabine, the median time to first appearance of Grade 3 peripheral neuropathy was 140 days. The median time to improvement of at least 1 grade was 21 days, and the median time to improvement in grade 3 to grade 0 or 1 peripheral neuropathy was 29 days. Of the patients who discontinued due to peripheral neuropathy, 44% (31/70 patients) were able to restart Abraxane at a reduced dose. None of the patients treated with Abraxane in combination with gemcitabine had grade 4 peripheral neuropathy.
Sepsis
Sepsis was observed at a "5% incidence in patients with or without neutropenia treated with Abraxane in combination with gemcitabine while conducting a clinical study in pancreatic adenocarcinoma. Complications due to pre-existing pancreatic cancer, particularly biliary obstruction. or presence of biliary stent, have been identified as important factors involved. If a patient has fever (regardless of neutrophil count), start treatment with broad spectrum antibiotics. In case of febrile neutropenia, stop Abraxane and gemcitabine until the fever and at ANC ≥ 1,500 cells / mm3, then resume treatment at reduced dose levels (see section 4.2).
Pneumonia
Pneumonia was observed at a 4% incidence with the use of Abraxane in combination with gemcitabine. Of the 17 cases of pneumonia reported in patients treated with Abraxane in combination with gemcitabine, 2 were fatal. Monitor patients closely for signs and symptoms of pneumonia. Once an infectious etiology has been ruled out and a diagnosis of pneumonia is established, treatment with Abraxane and gemcitabine is permanently discontinued and appropriate therapy and supportive measures initiated immediately (see section 4.2).
Non-small cell lung cancer (Abraxane given in combination with carboplatin)
Table of adverse reactions
Adverse reactions associated with administration of Abraxane in combination with carboplatin are listed in Table 9.
Table 9: Adverse reactions reported with Abraxane in combination with carboplatin (N = 514)
MedDRA = Medical Dictionary for Regulatory Activities: SMQ = Standardized MedDra Query
1 Based on laboratory assessments: highest degree of myelosuppression (treated population)
2 assessed by SMQ neuropathy (broad scope)
3 assessed by SMQ interstitial lung disease (broad scope)
For patients with non-small cell lung cancer treated with Abraxane and carboplatin, the median time to first appearance of treatment-related grade 3 peripheral neuropathy was 121 days, while the median time to improvement in treatment-related peripheral neuropathy grade 3 to grade 1 was 38 days. None of the patients treated with Abraxane and carboplatin experienced grade 4 peripheral neuropathy.
Anemia and thrombocytopenia were reported more commonly in the Abraxane arm than in the Taxol arm (54% vs 28% and 45% vs 27%, respectively).
Patient-reported taxane-associated toxicity was assessed by the 4 subgroups of the Functional Assessment of Cancer Therapy (FACT) -Taxanes questionnaire. Using repeated measures analysis, 3 of the 4 subgroups (peripheral neuropathy, hand / foot pain and hearing) favored Abraxane and carboplatin (p ≤ 0.002). For the other subgroup (edema), there were no differences between treatment arms.
Post marketing experience
Cases of cranial nerve palsy, vocal cord paresis, and - rarely - severe hypersensitivity reactions have been reported during post marketing monitoring of Abraxane.
During treatment with Abraxane, there have been rare reports of decreased visual acuity due to cystoid macular edema. Abraxane should be discontinued upon diagnosis of cystoid macular edema.
Cases of palmar-plantar erythrodysaesthesia have been reported in patients previously treated with capecitabine as part of the continuous monitoring of Abraxane. As these events have been reported voluntarily in clinical practice, an accurate assessment of the frequency and not a causal correlation with the use of the drug was therefore ascertained.
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.
04.9 Overdose
There is no known antidote for paclitaxel overdose. In the event of an overdose, the patient should be carefully monitored. Therapy should be targeted at the main expected toxicities, in particular: bone marrow suppression, mucositis and peripheral neuropathy.
05.0 PHARMACOLOGICAL PROPERTIES
05.1 Pharmacodynamic properties
Pharmacotherapeutic group: antineoplastics, alkaloids from plants and other natural products, taxanes, ATC code: L01CD01
Mechanism of action
Paclitaxel is an antimicrotubular agent that promotes the aggregation of microtubules from tubulin dimers, and stabilizes them, preventing their depolymerization. This stabilization inhibits the normal dynamic reorganization of the microtubule structure, essential for the vital interphase and for cellular mitotic functions. Furthermore, paclitaxel induces the formation of abnormal clumps or "bundles". of microtubules during the cell cycle and of multiple microtubule astrospheres during mitosis.
Abraxane contains human serum albumin-bound paclitaxel nanoparticles approximately 130 nm in size, in which paclitaxel is present in an amorphous, non-crystalline state. With intravenous administration, the nanoparticles rapidly dissociate into albumin-bound paclitaxel complexes. , soluble, about 10 nm in size. Albumin's property of mediating caveolar endothelial transcytosis of plasma constituents is known, and studies in vitro demonstrated that the presence of albumin in Abraxane promotes the transport of paclitaxel through endothelial cells. It is hypothesized that the enhanced caveolar transendothelial transport is mediated by the albumin receptor gp-60, and that increased accumulation of paclitaxel occurs in the tumor area due to the secreted cysteine-rich acidic protein (Secreted protein acidic rich in cysteine, SPARC), an albumin binding protein.
Clinical efficacy and safety
Breast cancer
Data from 106 patients from two single-arm open-label studies and from 454 patients treated in a randomized phase III comparative study are available to support the use of Abraxane for metastatic breast cancer. These data are presented below.
Open single-arm studies
In one study, Abraxane was administered as a 30-minute infusion at a dose of 175 mg / m2 to 43 patients with metastatic breast cancer. In the other, the dose used was 300 mg / m2 as a 30 minute infusion in 63 patients with metastatic breast cancer. The medicine was administered without steroid pretreatment or scheduled support with G-CSF. Cycles were given at intervals. Response rates for total patients were 39.5% (95% CI: 24.9% - 54.2%) and 47.6% (95% CI: 35.3%), respectively. % - 60.0%). Mean time to disease progression was 5.3 months (175 mg / m2; 95% CI: 4.6 - 6.2 months) and 6.1 months (300 mg / m2; 95% CI: 4.2 - 9.8 months).
Randomized comparative study
The multicenter study was performed in patients with metastatic breast cancer, treated every 3 weeks with paclitaxel as the sole agent, or in the form of paclitaxel formulated with solvent at a dose of 175 mg / m2, as a 3 hour infusion with pretreatment for prevent hypersensitivity (N = 225), or in the Abraxane form at a dose of 260 mg / m2 by infusion lasting 30 minutes without pretreatment (N = 229).
Sixty-four percent of patients had deteriorated general conditions (ECOG 1 or 2) upon admission to the study; 79% had visceral metastases and 76% had metastases at more than 3 sites. Fourteen percent of patients were not received prior chemotherapy; 27% had only adjuvant chemotherapy, 40% had only metastatic disease chemotherapy, and 19% had chemotherapy in both disease situations. Fifty-nine percent had been treated with the drug experimental as second-line or higher therapy Seventy-seven percent of patients had previously been exposed to anthracyclines.
Results for overall response rate, time to disease progression, disease-free survival, and overall survival for patients receiving therapy beyond 1a are shown below.
* Data based on Clinical Study Report: CA012-0 Final Appendix March 23, 2005
a Chi-square test
bTest log-rank
In the randomized, controlled clinical trial, 229 Abraxane-treated patients were evaluated for safety. Paclitaxel neurotoxicity was assessed by one grade improvement for patients who experienced grade 3 peripheral neuropathy at any time during the course of therapy. The natural course of peripheral neuropathy on resolution at baseline due to cumulative toxicity of Abraxane after> 6 treatment courses has not been evaluated and remains unknown.
Pancreatic adenocarcinoma
A multi-center, multinational, randomized, open-label study in 861 patients was conducted to compare Abraxane / gemcitabine with gemcitabine alone as first-line treatment in patients with metastatic adenocarcinoma of the pancreas. Abraxane was administered to patients (N = 431) as an intravenous infusion over 30-40 minutes, at a dose of 125 mg / m2, followed by gemcitabine as an intravenous infusion over 30-40 minutes, at a dose of of 1,000 mg / m2, administered on days 1, 8, and 15 of each 28-day cycle. In the comparator treatment arm, gemcitabine monotherapy was administered to patients (N = 430) at the recommended dose and regimen. Treatment was administered until disease progression or development of unacceptable toxicity. Of the 431 pancreatic adenocarcinoma patients randomized to treatment with Abraxane in combination with gemcitabine, the majority (93%) were white, 4% were black, and 2% were Asian.16% had a Karnofsky scale (KPS) score of 100; 42% had a KPS of 90; 35% had a KPS of 80; 7% had a KPS of 70 and high cardiovascular risk, a history of peripheral arterial disease and / or connective tissue disease and / or interstitial lung disease were excluded from the study.
Patients received treatment for a median duration of 3.9 months in the Abraxane / gemcitabine arm and 2.8 months in the gemcitabine arm. 32% of patients in the Abraxane / gemcitabine arm were treated for 6 months or longer compared with 15% of patients in the gemcitabine arm. For the treated population, the median relative dose intensity for gemcitabine was 75% in the Abraxane / gemcitabine arm and 85% in the gemcitabine arm. The median relative dose intensity of Abraxane was 81%. Abraxane / gemcitabine arm, a higher median cumulative dose of gemcitabine (11,400 mg / m2) was administered than the gemcitabine arm (9,000 mg / m2).
The primary efficacy endpoint was overall survival (OS). Key secondary endpoints were progression-free survival (PFS) and overall response rate (ORR), both assessed by independent, central, blinded radiological review. using the RECIST guidelines (version 1.0).
Table 11: Efficacy results from the randomized study in patients with pancreatic adenocarcinoma (intent-to-treat population)
CI = confidence interval, HRA + G / G = hazard ratio of Abraxane + gemcitabine / gemcitabine, pA + G / pG = ratio of Abraxane + gemcitabine / gemcitabine response rates
stratified Cox proportional hazards model
Stratified log rank btest, stratified by geographic region (North America vs. others), KPS (70-80 vs. 90-100) and presence of liver metastases (yes vs. no).
There was a statistically significant improvement in OS for patients treated with Abraxane / gemcitabine compared to gemcitabine alone, with a 1.8 month increase in median OS, an overall 28% reduction in the risk of death, an improvement 59% 1-year survival and a 125% improvement in 2-year survival rates.
Treatment effects on OS were in favor of the Abraxane / gemcitabine arm in most pre-specified subgroups (including gender, KPS, geographic region, primary pancreatic cancer site, stage at diagnosis, presence of liver metastases, presence peritoneal carcinomatosis, previous Whipple procedure, presence of biliary stent at baseline, presence of lung metastases and number of metastatic sites). for survival it was 1.08 (95% CI 0.653, 1.797). For patients with CA 19-9 levels within normal baseline, the HR for survival was 1.07 (95% CI 0.692; 1.661).
There was a statistically significant improvement in PFS for patients treated with Abraxane / gemcitabine compared to gemcitabine alone, with a 1.8-month increase in median PFS.
Non-small cell lung cancer
An open-label, randomized, multicenter study was conducted in 1052 chemotherapy-naive patients with stage IIIb / IV non-small cell lung cancer. The study compared Abraxane in combination with carboplatin versus solvent formulated paclitaxel in combination with carboplatin, as first-line treatment in patients with advanced non-small cell lung cancer. Over 99% of patients had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Patients with pre-existing grade ≥ 2 neuropathy or serious risk factors affecting any of the major organ systems were excluded. . Abraxane was administered to patients (N = 521) as an intravenous infusion over 30 minutes, at a dose of 100 mg / m2, on days 1, 8 and 15 of each 21-day cycle without steroid premedication and without prophylaxis. with granulocyte colony stimulating factor. Immediately following the end of Abraxane administration, carboplatin was administered intravenously at a dose of AUC = 6 mg min / ml on day 1 of each 21 day cycle only. Paclitaxel formulated with solvent was administered to patients (N = 531) at a dose of 200 mg / m2 by intravenous infusion over 3 hours with standard premedication, immediately followed by carboplatin, administered intravenously at a dose of AUC 6 mg · min. / ml. Each drug was administered on day 1 of each 21-day cycle. In both arms, treatment was administered until disease progression or development of unacceptable toxicity. Patients received a median of 6 treatment cycles in both study arms.
The primary efficacy endpoint was the overall response rate, defined as the percentage of patients who achieved a confirmed complete response or objective partial response, based on an independent, central, blinded radiological review according to RECIST criteria. (version 1.0). Patients in the Abraxane / carboplatin arm reported a significantly higher overall response rate than patients in the control arm: 33% vs 25%, p = 0.005 (table 12). There was a significant difference overall response rate in the Abraxane / carboplatin arm, compared to the control arm, in patients with squamous histology non-small cell lung cancer (N = 450, 41% vs 24%, p
Table 12: Overall Response Rate in the Randomized Study in Patients with Non-Small Cell Lung Cancer (Intent-to-Treat Population)
CI = confidence interval; HRA / T = hazard ratio Abraxane + carboplatin / paclitaxel formulated with solvent + carboplatin; pA / pT = ratio of response rates Abraxane + carboplatin / paclitaxel formulated with solvent + carboplatin.
aP value is based on the chi-squared test.
There were no statistically significant differences in progression-free survival (on a blinded radiological assessment) and overall survival between the two treatment arms. A non-inferiority analysis was performed for PFS and OS, with a prespecified non-inferiority margin of 15%. The non-inferiority criterion was met for both PFS and OS, with the upper limit 95% confidence interval for associated hazard ratios less than 1.176 (Table 13).
Table 13: Non-inferiority analysis of progression-free survival and overall survival in the randomized study in patients with non-small cell lung cancer (intent-to-treat population)
CI = confidence interval; HRA / T = hazard ratio Abraxane + carboplatin / paclitaxel formulated with solvent + carboplatin; pA / pT = ratio of response rates Abraxane + carboplatin / paclitaxel formulated with solvent + carboplatin.
a According to EMA's methodological considerations relating to the PFS endpoint, missing observations or the initiation of a new subsequent therapy were not used for censoring.
Pediatric population
The European Medicines Agency has waived the obligation to submit the results of studies with Abraxane in all subsets of the pediatric population in metastatic breast cancer, pancreatic adenocarcinoma and non-small cell lung cancer ( see section 4.2 for information on pediatric use).
05.2 "Pharmacokinetic properties
Clinical studies have enabled the pharmacokinetics of total paclitaxel to be established following Abraxane infusions lasting 30-180 minutes at dose levels of 80 to 375 mg / m2. Paclitaxel exposure (AUC) increases linearly from 2,653 to 16,736 ng.hr/ml with dosages from 80 to 300 mg / m2.
In a study in patients with advanced solid tumors, the pharmacokinetic characteristics of paclitaxel following the intravenous administration of 260 mg / m2 of Abraxane for 30 minutes were compared to those observed after the injection of 175 mg / m2 of paclitaxel in solvent for 3 hours. Based on non-compartmental pharmacokinetic analysis, the plasma clearance of paclitaxel with Abraxane was higher (43%) than that obtained with solvent formulated paclitaxel injection, and the volume of distribution was also higher (53%).
There was no difference in the terminal half-life.
In a repeat-dose study in 12 patients treated with Abraxane administered intravenously at a dose of 260 mg / m2, the intra-individual variability in AUC was 19% (range = 3.21% -27.70%). There was no evidence of accumulation of paclitaxel with multiple treatment courses.
Distribution
Following administration of Abraxane to patients with solid tumors, paclitaxel distributes uniformly in blood cells and plasma, with high plasma protein binding (94%).
The protein binding of paclitaxel following administration of Abraxane was evaluated in patients in a comparison study by ultrafiltration. The free paclitaxel fraction was significantly higher with Abraxane (6.2%) than with solvent-based paclitaxel (2.3%). This resulted in significantly higher exposure to unbound paclitaxel with Abraxane compared to solvent-dissolved paclitaxel, although the total exposure is comparable. This may be due to the fact that paclitaxel is not trapped in the Cremophor EL micelles, as is the case with paclitaxel dissolved in solvent. According to published data, the results of studies in vitro on human serum binding proteins, (with use of paclitaxel at concentrations between 0.1 and 50 mcg / ml), indicate that the presence of cimetidine, ranitidine, dexamethasone or diphenhydramine does not affect the protein binding of paclitaxel.
Based on a population pharmacokinetic analysis, the total volume of distribution is approximately 1,741 L. The relevant magnitude of the volume of distribution indicates extensive extravascular distribution of paclitaxel and / or its link to tissues.
Biotransformation and elimination
According to published data, the results of studies in vitro on microsomes and tissue sections from human liver indicate that paclitaxel is metabolised mainly to 6α-hydroxypaclitaxel plus two minor metabolites, 3 "-p-hydroxypaclitaxel and 6α-3 "-p-dihydroxyaclitaxel. The formation of these hydroxylated metabolites is catalysed by CYP2C8, CYP3A4, and both CYP2C8 and CYP3A4 isoenzymes, respectively.
In patients with metastatic breast cancer, following an infusion of 260 mg / m2 of Abraxane for a duration of 30 minutes, the mean value for cumulative urinary excretion of unchanged active substance represented 4% of the total administered dose, and less than 1% consisted of the metabolites 6α-hydroxypaclitaxel and 3 "-p-hydroxypaclitaxel, indicating a large percentage of non-renal elimination. Paclitaxel is eliminated primarily by hepatic metabolism and biliary excretion.
In the clinical dose range of 80 to 300 mg / m2, the mean plasma clearance of paclitaxel ranges from 13 to 30 l / h / m2, while the mean terminal half-life is between 13 and 27 hours.
Hepatic insufficiency
The effect of hepatic impairment on the population pharmacokinetics of Abraxane was studied in patients with advanced solid tumors. The analysis included patients with normal hepatic function (n = 130) and pre-existing mild (n = 8), moderate (n = 7) or severe (n = 5) hepatic insufficiency (according to the criteria of theOrgan Dysfunction Working Group of the NCI). The results demonstrate that mild hepatic insufficiency (total bilirubin> 1 to ≤ 1.5 x ULN) has no clinically relevant effect on paclitaxel pharmacokinetics. Patients with moderate (total bilirubin> 1.5 to ≤ 3 x ULN) or severe (total bilirubin> 3 to ≤ 5 x ULN) hepatic impairment have a 22% -26% reduction in the maximum elimination rate of paclitaxel and an approximately 20% increase in the mean paclitaxel AUC compared to patients with normal hepatic function. Hepatic impairment has no effect on the mean paclitaxel Cmax. Furthermore, the elimination of paclitaxel shows an inverse correlation with total bilirubin and a direct correlation with serum albumin.
Pharmacokinetic / pharmacodynamic models indicate an absence of correlation between liver function (indicated by baseline albumin or total bilirubin level) and neutropenia, following an adjustment for exposure to Abraxane.
No pharmacokinetic data are available for patients with total bilirubin> 5 x ULN or for patients with metastatic adenocarcinoma of the pancreas (see section 4.2).
Kidney failure
The population pharmacokinetic analysis included patients with normal renal function (n = 65) and pre-existing mild (n = 61), moderate (n = 23) or severe (n = 1) renal impairment (according to the draft guideline of the 2010 FDA). Mild to moderate renal insufficiency (creatinine clearance ≥ 30 to
Elderly patients
The population pharmacokinetic analysis for Abraxane included patients aged 24 to 85 years and demonstrates that age does not significantly affect the maximum elimination rate and systemic exposure (AUC and Cmax) of paclitaxel.
Pharmacokinetic / pharmacodynamic modeling, using data from 125 patients with advanced solid tumors, indicate that patients ≥ 65 years of age may be more prone to developing neutropenia during the first course of treatment. although age does not affect plasma exposure to paclitaxel.
Other intrinsic factors
Population pharmacokinetic analyzes for Abraxane indicate that gender, race (Asian vs White) and type of solid tumors do not have a clinically important effect on systemic exposure (AUC and Cmax) of paclitaxel. In patients weighing 50 kg of paclitaxel. weight The paclitaxel AUC was approximately 25% lower than in patients weighing 75 kg. The clinical relevance of this finding is unknown.
05.3 Preclinical safety data
Studies on the carcinogenic potential of paclitaxel have not been performed. Based on published data, however, paclitaxel at clinical doses is potentially carcinogenic and genotoxic due to its pharmacodynamic mechanism of action. Paclitaxel was found to be both clastogenic and in vitro(chromosomal aberrations in human lymphocytes) that in vivo (micronucleus test in mice). Paclitaxel was genotoxic in vivo (micronucleus test in mice), but no mutagenic properties were found in the Ames test or in the Chinese Hamster Ovary Hypoxanthine-Guanine-Phosphoribosyl-Transferase Gene Mutation Assay (CHO / HGPRT).
Paclitaxel at doses below the therapeutic doses used in humans was related to impaired fertility and fetal toxicity in rats. Animal studies with Abraxane revealed non-reversible toxic effects affecting male reproductive organs at clinically relevant exposure levels.
06.0 PHARMACEUTICAL INFORMATION
06.1 Excipients
Human albumin solution (containing sodium, sodium caprylate and N-acetyl DL tryptophanate).
06.2 Incompatibility
This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.
06.3 Period of validity
Closed vial
3 years
Stability of the reconstituted suspension in the original vial
After the first reconstitution, the suspension should be immediately transferred to an infusion bag. However, the drug was chemically and physically stable in use for 8 hours at 2 ° C - 8 ° C in the original packaging, protected from intense light. Alternative light protection can be provided in a clean room.
Stability of the reconstituted suspension in the infusion bag
After reconstitution, the suspension placed in the infusion bag should be used immediately. The drug was however chemically and physically stable for 8 hours at temperatures not exceeding 25 ° C.
06.4 Special precautions for storage
Closed vials
Keep the vial in the outer carton to protect the medicine from light. Freezing and refrigeration have no adverse effect on the stability of the medicine.This medicinal product does not require any special storage temperatures.
Reconstituted suspension
For storage conditions after reconstitution see section 6.3.
06.5 Nature of the immediate packaging and contents of the package
50 ml vial (type 1 glass) with a stopper (butyl rubber) and with a seal (aluminum) containing 100 mg of paclitaxel bound to albumin formulated in nanoparticles.
100 ml vial (type 1 glass) with a stopper (butyl rubber) and with a seal (aluminum) containing 250 mg of paclitaxel bound to albumin formulated in nanoparticles.
Pack size of one vial.
06.6 Instructions for use and handling
Precautions for preparation and administration
Paclitaxel is a cytotoxic anticancer medicine; as with other potentially toxic compounds, certain precautions should be taken when handling Abraxane. The use of gloves, goggles and protective clothing is recommended. If the suspension comes into contact with the skin, wash the skin immediately and thoroughly with soap and water. If contact occurs with the mucous membranes, they must be rinsed well with plenty of water Abraxane should only be prepared and administered by personnel adequately trained in the handling of cytotoxic agents Abraxane should not be handled by pregnant women.
Given the possibility of extravasation, it is recommended that the site of the infusion be monitored closely for infiltration during drug administration. Limiting the infusion of Abraxane to 30 minutes, as indicated, reduces the likelihood of infusion-related reactions.
Reconstitution and administration of the medicinal product
Abraxane is supplied as a sterile lyophilized powder and must be reconstituted before use. After reconstitution, each ml of suspension contains 5 mg of albumin-bound paclitaxel formulated in nanoparticles.
100 mg vial: Using a sterile syringe, slowly inject 20 ml of sodium chloride 9 mg / ml (0.9%) solution for infusion into a vial of Abraxane for at least 1 minute.
250 mg vial: Using a sterile syringe, slowly inject 50 ml of sodium chloride 9 mg / ml (0.9%) solution for infusion into a vial of Abraxane for at least 1 minute.
The solution should be oriented towards the inner wall of the vial. The solution should not be injected directly onto the powder as this will cause foam to form.
Once you have finished adding the solution, let it sit for at least 5 minutes for the powder to permeate completely. Then, gently and slowly swirl and / or invert the vial, for at least 2 minutes, until all powder is completely resuspended. Avoid foam formation If foam or lumps form, allow the solution to stand for at least 15 minutes until the foam disappears.
The reconstituted suspension should have a milky and homogeneous appearance with no visible precipitate. Deposits may occur in the reconstituted suspension. If precipitates or deposits are visible, gently invert the vial again to ensure complete resuspension before use.
Examine the suspension in the vial for the presence of precipitate. Do not administer the reconstituted suspension if precipitates are observed in the vial.
The exact total volume of the 5 mg / ml suspension needed by the patient should be calculated and the appropriate amount of reconstituted Abraxane should be injected into an empty, sterile, PVC or other material intravenous infusion bag.
The use of medical devices containing silicone lubricating oil (syringes and IV bags) to reconstitute and administer Abraxane may result in the formation of proteinaceous filaments. Administer Abraxane using an infusion set equipped with a 15 micron filter to avoid administration of these filaments. The use of a 15 micron filter removes filaments and does not change the physical or chemical properties of the reconstituted product.
The use of filters with a pore diameter of less than 15 microns can cause the filter to become clogged.
The use of special containers or administration sets not containing (2-ethylhexyl) phthalate (DEHP) is not required for the preparation and administration of Abraxane infusions.
After administration, it is recommended to flush the infusion line with sodium chloride 9 mg / ml (0.9%) solution for injection to ensure administration of the full dose.
Unused medicine and wastes derived from this medicine must be disposed of in accordance with local regulations.
07.0 MARKETING AUTHORIZATION HOLDER
Celgene Europe Limited
1 Longwalk Road
Stockley Park
Uxbridge
UB11 1DB
UK
08.0 MARKETING AUTHORIZATION NUMBER
EU / 1/07/428/001
EU / 1/07/428/002
039399011
039399023
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION
Date of first authorization: 11 January 2008
Date of most recent renewal: 11 January 2013
10.0 DATE OF REVISION OF THE TEXT
D.CCE July 2015
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