Active ingredients: Oxaliplatin
OXALIPLATINO MYLAN GENERICS 5 mg / ml powder for solution for infusion
Why is Oxaliplatin used? What is it for?
The active ingredient of OXALIPLATINO MYLAN GENERICS is oxaliplatin.
OXALIPLATINO MYLAN GENERICS is used to treat colon cancer (treatment of stage III colon cancer after complete resection of the primary tumor, treatment of metastatic colorectal cancer). OXALIPLATINO MYLAN GENERICS is used in combination with other anticancer medicines called 5-fluorouracil and folinic acid.
Before it can be injected into a vein, OXALIPLATINO MYLAN GENERICS must be dissolved and prepared in solution. OXALIPLATINO MYLAN GENERICS is an anticancer drug and contains platinum.
Contraindications When Oxaliplatin should not be used
Do not use OXALIPLATINO MYLAN GENERICS
- if you are allergic to oxaliplatin or any of the other ingredients of this medicine, such as lactose monohydrate;
- if you are breast-feeding;
- if you already have too low a blood cell count;
- if you have ever had tingling and numbness in your fingers and / or toes and have had difficulty performing delicate tasks, such as fastening buttons;
- if you have severe kidney problems.
Precautions for use What you need to know before taking Oxaliplatin
Talk to your doctor or pharmacist before using OXALIPLATINO MYLAN GENERICS:
- If you have ever had allergic reactions to platinum-containing medicines such as carboplatin or cisplatin in the past. Allergic reactions may occur during the oxaliplatin infusion.
- If you have moderate kidney problems.
- If you have any kind of liver problems.
Interactions Which drugs or foods can modify the effect of Oxaliplatin
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines.
Warnings It is important to know that:
Pregnancy, breastfeeding and fertility
Pregnancy
You should not use oxaliplatin during pregnancy unless specifically directed by your doctor.
You must not become pregnant while being treated with oxaliplatin and you must use an effective method of contraception.
If you become pregnant during therapy, you must inform your doctor immediately. During therapy and for a period of 4 months after its cessation for women, it is necessary to use effective contraceptive methods.
Feeding time
You should not breast-feed while taking oxaliplatin.
Ask your doctor or pharmacist for advice before taking any medicine.
Fertility
Oxaliplatin can have a negative effect on the ability to conceive, which could be irreversible. Therefore, male patients are recommended not to conceive a child during and up to 6 months after treatment and to consider storing sperm prior to initiation of therapy.
Driving and using machines
Oxaliplatin therapy may cause an increased risk of dizziness, nausea and vomiting and other nervous symptoms affecting gait (difficulty walking and movement) and balance (ability to stand upright or the onset of dizziness). if this happens, you should not drive or use machines. If you have vision problems while taking Oxaliplatin Mylan Generics, do not drive, use heavy machinery, or start hazardous activities
Dose, Method and Time of Administration How to use Oxaliplatin: Posology
OXALIPLATINO MYLAN GENERICS is reserved for adult patients.
Dosage
The dose of oxaliplatin is based on the size of your body surface. It is obtained by calculating his height and weight.
The recommended dose for adult patients, including the elderly, is 85 mg / m2 body surface area. The dose you receive will also depend on the results of your blood tests and whether you have previously had side effects caused by oxaliplatin.
Posology and method of administration
OXALIPLATINO MYLAN GENERICS will be prescribed to you by a specialized oncologist. It will be taken over by a specialist doctor who will have decided on the dose you need of oxaliplatin. This medicine is given as a slow injection into one of the veins (an 'intravenous infusion) over a period of 2 to 6 hours.
This medicine will be given to you at the same time as folinic acid and before the 5-fluorouracil infusion. Frequency of administration This is determined by your doctor. Please note that the infusions should be repeated once every two weeks.
Duration of treatment
It is determined by the doctor.
In case of treatment after complete tumor resection, the treatment will last for up to 6 months.
Overdose What to do if you have taken an overdose of Oxaliplatin
As this medicine is given in a hospital setting, it is unlikely that you will be given too little or too much; however, if this worries you, talk to your doctor or pharmacist.
In case of overdose, it could have an increase in side effects. Your doctor can give you appropriate therapy for these side effects.
If you have any further questions about your treatment, ask your doctor, pharmacist or nurse.
Side Effects What are the side effects of Oxaliplatin
Like all medicines, this medicine can cause side effects, although not everybody gets them. If you experience any side effects it is important that you tell your doctor before the next course of treatment.
Tell your doctor immediately if you notice any of the following side effects:
- Bruising, bleeding, and abnormal signs of infection, such as a sore throat or a high temperature
- Persistent or severe diarrhea or vomiting;
- Stomatitis / mucositis (pain in the lips or mouth ulcers);
- Unexplained respiratory symptoms, such as non-productive cough, difficulty breathing, or crackles
- Symptoms of an allergic reaction with sudden signs such as rash, itching or hives on the skin, swelling of the face, lips, tongue or other parts of the body, wheezing, wheezing or breathing problems, and may feel like you are going to pass out (symptoms of shock anaphylactic);
- Inflammation of the pancreas with severe pain in the upper abdomen, often with nausea and vomiting.
Other side effects
Very common (may affect more than 1 in 10 people):
- A nerve disorder that can cause weakness, tingling or numbness in the fingers and toes, around the mouth or throat, which may sometimes occur in association with cramps. This is often triggered by exposure to cold, such as opening a refrigerator or holding a cold drink. He may also have difficulty performing delicate tasks, such as buttoning clothes. Although in most cases these symptoms disappear completely, there is a possibility that they will persist after the end of the treatment;
- Some people have experienced a tingling and shocking sensation running down their arms or trunk when they bend their neck;
- Sometimes oxaliplatin can cause an unpleasant sensation in the throat, particularly when swallowing, and give the sensation of dyspnea. This sensation, if it occurs, usually occurs during the infusion or within hours of it, and can be triggered by the infusion. "exposure to cold. Although it is unpleasant, it does not last long and passes without the need for any treatment. Because of this side effect, your doctor may decide to change your therapy;
- Signs of infection such as a sore throat and a high temperature
- This medicine causes a temporary reduction in the number of blood cells.A reduction in the number of white blood cells, which makes infections more likely a reduction in the number of platelets, which increases the risk of bleeding or contusion; a reduction in the number of red blood cells, which can make the skin pale and cause weakness or breathlessness. Your doctor will carry out blood tests to check that the number of blood cells is sufficient before starting therapy and before each course of the same;
- Loss or lack of appetite
- Excessive levels of glucose (sugar) in the blood, which can cause severe thirst, dry mouth or the need to urinate more often
- Low blood levels of potassium, which can cause abnormal heart rhythms
- High blood levels of sodium due to the loss of water from the body, which can cause thirst, lethargy, weakness, irritability, muscle problems and swelling in different parts of the body (hypernatremia);
- Taste disturbances;
- Headache
- Epistaxis (nosebleeds);
- Dyspnea;
- Cough;
- Nausea (feeling unwell), vomiting (being unwell) usually before treatment your doctor will advise you of a medicine that can prevent them, which you can continue to take even after treatment;
- Diarrhea - if you have persistent or severe diarrhea or vomiting contact your doctor immediately;
- Pain in the mouth or lips, mouth ulcers;
- Stomach pain, constipation;
- Skin problems;
- Hair loss
- Back pain
- Tiredness, unusual loss of strength / weakness, body pain;
- Pain or redness near or at the injection site during the infusion, which can lead to necrosis (death of living cells and tissues) in case of extravasation (blood drainage);
- Fever associated with possible involuntary movements of the hands or other limbs;
- Blood tests showing changes in liver function
- Blood tests showing an increase in lactate dehydrogenase enzyme;
- Weight gain.
Common (may affect up to 1 in 10 people):
- Rhinorrhea;
- Chest infections
- Severe infections caused by a reduction in the number of white blood cells, which can cause fever (febrile neutropenia) or high fever with chills, headache, confusion, rapid breathing (neutropenic sepsis);
- Anaphylactic shock or severe allergic reaction (bronchospasm, edema);
- Loss of body fluids (dehydration);
- Depression;
- Difficulty falling asleep (insomnia)
- Dizziness
- Swelling of the nerves afferent to the muscles;
- Stiff neck, intolerance / aversion to bright light and headache;
- Conjunctivitis, visual problems;
- Abnormal bleeding
- Blood clots, usually in the leg, causing pain, swelling, or redness
- Lung blood clots, causing chest pain and wheezing
- Redness;
- High blood pressure (hypertension)
- Hiccups;
- Indigestion and heartburn;
- Hemorrhage of the lower gastrointestinal tract and the gastrointestinal tract;
- Skin peeling, red rash, rash, increased sweating and nail disease;
- Joint and bone pain;
- Blood in the urine
- Pain when urinating or a change in the frequency of urination
- Blood tests showing changes in kidney function
- Weight loss.
Uncommon (may affect up to 1 in 100 people):
- Condition with abnormal blood tests showing increased acidity due to kidney problems (metabolic acidosis);
- Feeling anxious or nervous
- Hearing problems
- Obstruction or impairment of the intestine;
- Nerve symptoms such as involuntary muscle twitching, tightness in the chest and throat, or symptoms that affect gait (walking and movement difficulties) and balance (ability to stand upright or dizziness from standing);
- Symptoms that show changes in the function of the nerves of the skull (eye and vision disturbances, speech and voice disturbances, persistent pain in the face).
Rare (may affect up to 1 in 1,000 people):
- Reduction in the number of platelets (lack of platelets in the blood with bruises and abnormal bleeding, with the body being allergic to oxaliplatin);
- Abnormal reduction of red blood cells (anemia due to excessive depletion of red blood cells);
- Indistinct language;
- Visual problems such as reduced acuity / sharpness of perception or visual field, transient loss of vision, reversible following discontinuation of therapy;
- Inflammation of the optic nerve;
- Deafness (impaired hearing);
- Unexplained respiratory symptoms, difficulty in breathing, scarring of the lungs causing dyspnoea, sometimes fatal;
- Scarring and thickening of the lungs with dyspnoea (pulmonary fibrosis)
- Inflammation of the colon causing abdominal pain or diarrhea.
- Reversible neurological problems such as seizures, hypertension, headache, confusion and visual disturbances including blindness (Posterior Reversible Leukoencephalopathy syndrome).
The following side effects occur very rarely (may affect up to 1 in 10,000 people):
- Liver disease, which will be monitored by the doctor;
- Changes in kidney function, acute kidney disorders
- Reduction or absence of urine production (symptoms of acute renal failure).
There have been a few reported cases of convulsion (uncontrolled shaking of the body), and extreme tiredness with a decrease in the number of red blood cells (microangiopathic haemolytic anemia), abnormal bruising (with low platelet count), decreased or no urine production (insufficiency acute kidney disease), signs of infection (symptoms of haemolytic uremic syndrome (HUS), which can be fatal.
Reporting of side effects
If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the website: https://www.aifa.gov. it / content / reports-adverse-reactions
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.
Unopened vials do not require any special storage conditions.
Do not use this medicine after the expiry date which is stated on the carton or vial. The expiry date refers to the last day of that month.
When the infusion is finished, the medicine will be carefully disposed of by your doctor or nurse.
What OXALIPLATINO MYLAN GENERICS contains
- The active ingredient is: oxaliplatin.
- The other component is: lactose monohydrate.
Description of the appearance of OXALIPLATINO MYLAN GENERICS and contents of the pack:
This medicine comes as a powder for solution for infusion.
50 mg vials: Each 30 ml vial contains 50 mg of oxaliplatin for reconstitution in 10 ml of solvent.
100 mg vials: Each 50 ml vial contains 100 mg of oxaliplatin for reconstitution in 20 ml of solvent.
One ml of the reconstituted solution contains 5 mg of oxaliplatin.
Vials of 50 mg or 100 mg of powder. 1, 2, 3, 5, 10 or 50 vials per pack.
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
OXALIPLATIN MYLAN GENERICS 5 MG / ML
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION
50 mg vial: Each 30 ml vial contains 50 mg of oxaliplatin for reconstitution in 10 ml of solvent.
100 mg vial: Each 50 ml vial contains 100 mg of oxaliplatin for reconstitution in 20 ml of solvent.
One ml of the reconstituted solution contains 5 mg of oxaliplatin.
For the full list of excipients, see section 6.1.
03.0 PHARMACEUTICAL FORM
Powder for solution for infusion.
White freeze-dried powder.
04.0 CLINICAL INFORMATION
04.1 Therapeutic indications
Oxaliplatin, in combination with 5-fluorouracil (5 FU) and folinic acid (FA), is indicated in the following conditions:
• Adjuvant therapy of stage III (Duke's C) colon cancer after complete resection of the primary tumor;
• metastatic colorectal cancer therapy.
04.2 Posology and method of administration
The preparation of injectable solutions of cytotoxic agents must be carried out by specialized personnel with in-depth knowledge of the medicines in use, in conditions that guarantee the integrity of the medicine, the protection of the environment and in particular the protection of the personnel handling the medicines, in accordance with hospital directives. This preparation requires a "specially reserved area. In this area it is forbidden to smoke and consume food or drinks (see paragraph 6.6).
Dosage
ONLY FOR ADULT PATIENTS
The recommended dose of oxaliplatin in adjuvant therapy is 85 mg / m2 intravenously with repeated administration every two weeks for 12 cycles (6 months).
The recommended dose of oxaliplatin in the treatment of metastatic colorectal cancer is 85 mg / m2 intravenously with repeated administration every 2 weeks.
The dose administered should be adapted to its tolerability (section 4.4).
Oxaliplatin should always be administered before fluoropyrimidines - eg 5-fluorouracil (5 FU).
Oxaliplatin is administered as an intravenous infusion lasting 2-6 hours in 250-500 ml of 5% glucose solution (50 mg / ml) in order to obtain a concentration between 0.2 mg / ml and 0.70 mg / ml; 0.70 mg / ml is the maximum concentration in clinical practice for an 85 mg / m2 oxaliplatin dose.
Oxaliplatin was mainly used in combination with 5-fluorouracil (5 FU) by continuous infusion. For the two-week regimen, regimens of 5-fluorouracil (5 FU) were used which combined bolus and continuous infusion.
Special populations :
- Impaired renal function:
Oxaliplatin has not been studied in patients with severe renal impairment (see section 4.3).
In patients with moderate renal impairment, therapy can be initiated at the normal recommended dose (see section 4.4). Patients with mild renal dysfunction do not need dose adjustment.
- Hepatic insufficiency:
In a phase I study that included patients with varying degrees of hepatic impairment, the frequency and severity of hepatobiliary disorders appeared to be related to progressive disease and tests showing impaired liver function at baseline.
During clinical development, no specific dose adjustments were made for patients with abnormal liver function test results.
- Elderly patients:
When oxaliplatin was used alone or in combination with 5-fluorouracil (5 FU) in patients over 65 years of age, no serious increase in toxicity was observed. Consequently, no specific adaptation is required in the elderly patient. of the dose.
- Pediatric population
There are no relevant indications for the use of oxaliplatin in children. The efficacy of oxaliplatin as a single agent in pediatric populations with solid tumors has not been established (see section 5.1).
Method of administration
Oxaliplatin is administered by intravenous infusion.
Administration of oxaliplatin does not require hyperhydration.
Oxaliplatin, diluted in 250 - 500 ml of 5% glucose solution (50 mg / ml), in order to provide a concentration of not less than 0.2 mg / ml, must be infused via a central or peripheral venous route in a 2 to 6 hours. The oxaliplatin infusion should always precede the administration of 5-fluorouracil (5 FU).
In case of extravasation, administration must be stopped immediately.
Instructions for Use:
Oxaliplatin must be reconstituted and further diluted before use. To reconstitute and then dilute the lyophilized product, only a diluent based on 5% glucose solution (50 mg / ml) should be used (see section 6.6).
04.3 Contraindications
Oxaliplatin is contraindicated in patients who
- have a "hypersensitivity to" oxaliplatin or its excipient lactose monohydrate.
- are breastfeeding.
- have myelosuppression prior to the beginning of the first cycle, as evidenced in basal conditions by neutrophils
- suffer from peripheral sensory neuropathy with functional incapacity prior to the first cycle.
- have severely impaired renal function (creatinine clearance less than 30 ml / min).
04.4 Special warnings and appropriate precautions for use
Oxaliplatin should only be reserved for specialized medical oncology wards and should be administered under the supervision of a qualified medical oncologist.
Since safety data in patients with moderately impaired renal function are limited, its administration should be subject to a careful risk / benefit assessment for the individual patient.
In these cases, renal function should be monitored closely and the dose adjusted for toxicity.
Patients with a history of allergic manifestations to other platinum-containing products should be carefully monitored. In the case of anaphylactic reactions, perfusion should be stopped immediately and appropriate symptomatic treatment initiated. Re-administration of oxaliplatin to such patients is contraindicated. Cross reactions, sometimes fatal, have been reported with all platinum compounds.
In the event of oxaliplatin extravasation, the infusion should be stopped immediately and the usual local symptomatic treatment initiated.
The neurotoxicity of oxaliplatin should be carefully monitored, particularly in the case of combination with other drugs presenting specific neurological toxicity. A neurological examination should be performed before each administration and periodically thereafter.
In patients who have experienced acute pharyngolaryngeal dysesthesia (see section 4.8) during or in the hours following the 2-hour infusion, subsequent administration of oxaliplatin should be given over 6 hours.
In case of neurological symptoms (paraesthesia, dysesthesia), the dose of oxaliplatin should be adjusted according to the duration and severity of these symptoms, with the following recommendations:
- in case the symptoms last more than seven days and are painful, the following dose of oxaliplatin should be reduced from 85 to 65 mg / m2 (in the metastatic) or 75 mg / m2 (in the adjuvant).
- If paraesthesia, without functional disturbance, persists until the start of the next cycle, the following dose of oxaliplatin should be reduced from 85 to 65 mg / m2 (in the metastatic) or 75 mg / m2 (in the adjuvant).
- In the event that paraesthesia with functional disturbance persists until the beginning of the following cycle, the treatment should be stopped.
- In the event that symptoms improve after stopping the treatment, it can be considered as a resumption.
Patients should be adequately informed of the risk of persistence of symptoms of peripheral sensory neuropathy after termination of therapy. Moderate localized paraesthesia or paraesthesia that may interfere with functional activities may persist for up to 3 years after termination of adjuvant therapy.
Gastrointestinal toxicity, manifested in the form of nausea and vomiting, justifies a prophylactic and / or therapeutic antiemetic treatment (see section 4.8).
Severe diarrhea / vomiting can cause dehydration, paralytic ileus, intestinal obstruction, hypokalaemia, metabolic acidosis and impaired renal function, particularly when oxaliplatin and 5-fluorouracil (5 FU) are co-administered. Pancreatitis has been reported in isolated cases.
In case of presentation of haematological toxicity (platelet neutrophils blood count with leukocyte formula before starting treatment and before each new cycle.
Patients should be adequately informed about the risk of diarrhea / vomiting, mucositis / stomatitis and neutropenia after administration of oxaliplatin and 5-fluorouracil (5 FU) so that they can urgently contact their treating physician for appropriate treatment. treatment.
In case of onset of mucositis / stomatitis with or without neutropenia, the following cycle should be delayed until mucositis / stomatitis is grade 1 or lower and / or until the neutrophil count is 1.5x109 / l .
For oxaliplatin administered in combination with 5-fluorouracil (5 FU) (with or without folinic acid (FA)), the usual dose adjustment should be made in relation to the toxicity of 5-fluorouracil (5 FU).
In case of onset of grade 4 diarrhea (WHO), grade 3-4 neutropenia (neutrophils, grade 3-4 thrombocytopenia (platelets 2 (in the metastatic) or 75 mg / m2 (in the adjuvant), in addition to the necessary reduction in dose of 5-fluorouracil (5 FU).
In case of unexplained respiratory symptoms, such as non-productive cough, dyspnoea, crackles or radiological pulmonary infiltrates, oxaliplatin treatment should be discontinued until further pulmonary investigations rule out interstitial lung disease or pulmonary fibrosis (see section 4.8).
In case of liver function tests with abnormal results or portal hypertension not clearly resulting from liver metastases, the possibility of very rare cases of drug-induced hepatic vascular disorder should be considered.
For use in pregnant women, see section 4.6.
Genotoxic effects were observed in preclinical studies with oxaliplatin. Therefore, the male patient on oxaliplatin therapy should be warned not to conceive during therapy and up to 6 months after the therapy ends, and to inquire about the possibility of sperm storage before therapy, because oxaliplatin may have a negative effect on the ability to conceive which could be irreversible.
During oxaliplatin therapy, the woman must not become pregnant and must use an effective method of contraception (see section 4.6).
04.5 Interactions with other medicinal products and other forms of interaction
No change in the level of exposure to 5-fluorouracil (5 FU) was observed in patients who received a single dose of 85 mg / m2 of oxaliplatin immediately prior to administration of 5-fluorouracil (5 FU).
In vitro no significant displacement of oxaliplatin protein binding was observed with the following drugs: erythromycin, salicylates, granisetron, paclitaxel and sodium valproate.
04.6 Pregnancy and lactation
No information is available so far on the safe use of oxaliplatin in pregnancy. Reproductive toxicity has been observed in animal studies. Therefore, the use of oxaliplatin is not recommended during pregnancy and in women of childbearing potential who do not use contraceptive measures. .
The use of oxaliplatin should only be considered after the patient has been adequately informed of the risk to the fetus and with the patient's consent.
Patients should use appropriate contraceptive methods during and after therapy is stopped for a period of 4 months for the woman and 6 months for the man.
Excretion into breast milk has not been studied. Oxaliplatin is contraindicated during lactation.
Oxaliplatin may have a negative effect on the ability to conceive (see section 4.4).
04.7 Effects on ability to drive and use machines
No studies on the effects of the drug on the ability to drive and use machines have been performed. However, oxaliplatin therapy causes an increased risk of dizziness, nausea and vomiting, and other neurological symptoms that affect gait and balance. and this may have a mild to moderate influence on the ability to drive and use machines.
Changes in vision, in particular transient loss of vision (reversible after discontinuation of therapy), may affect patients' ability to drive and use machines. Therefore, patients should be warned of the potential effects of these events on the ability to drive or use machines.
04.8 Undesirable effects
The most frequent adverse events of oxaliplatin in combination with 5-fluorouracil / folinic acid (5 FU / FA) were gastrointestinal (diarrhea, nausea, vomiting and mucositis), haematological (neutropenia, thrombocytopenia) and neurological (acute peripheral sensory neuropathy). and by repeated doses). Overall, these adverse events were more frequent and severe with oxaliplatin in combination with 5 FU / FA than with 5 FU / FA alone.
The frequencies shown in the table below result from clinical trials in both metastatic and adjuvant treatment (416 and 1108 patients were included in the oxaliplatin + 5 FU / FA treatment groups, respectively) and post-marketing experience.
The frequencies shown in the table below were defined using the following conversion: very common (≥1 / 10), common (≥1 / 100,
Further details are provided after the table.
* See in detail in the section below
** See section 4.4.
+ Very frequent: allergies / allergic reactions, which occur more often during perfusion, sometimes fatal (frequent allergic reactions such as rash, especially urticaria, conjunctivitis, rhinitis.
++ Frequent anaphylactic reactions, including bronchospasm, angioedema, low blood pressure and anaphylactic shock.
Cross reactions, sometimes fatal, with all platinum salts have been reported.
+++ Very common: fever, chills (tremors), caused by infection (with or without febrile neutropenia) or isolated fever possibly due to an immunological mechanism.
++++ Local tenderness, redness, swelling and thrombosis have been reported among the administration site reactions. Extravasation can also cause local pain and inflammation, even severe, which can lead to complications such as necrosis, particularly when oxaliplatin is infused via the peripheral vein (see section 4.4).
Hepatobiliary disorders
Very rare (≤1 / 10,000):
Hepatic sinusoidal obstruction syndrome, also known as occlusive venopathy of the liver, or pathological manifestations related to this liver disorder, including hepatic peliosis, nodular regenerative hyperplasia and perisinusoidal fibrosis. Their clinical manifestations may be portal hypertension and / or elevated transaminases.
Very rare (≤1 / 10,000):
Pancreatitis.
Renal and urinary disorders
Very rare (≤1 / 10,000):
Acute tubular necrosis, acute interstitial nephritis and acute renal failure.
Hematological toxicity :
Incidence by patient (%), by grade
Post-marketing experience with unknown frequency:
Hemolytic uremic syndrome
Digestive toxicity:
Incidence by patient (%), by grade
Prophylaxis and / or treatment with potent antiemetic drugs are indicated.
Severe diarrhea / vomiting can cause dehydration, paralytic ileus, intestinal obstruction, hypokalaemia, metabolic acidosis and renal failure, particularly when oxaliplatin and 5-fluorouracil (5 FU) are co-administered (see section 4.4).
Nervous system
The toxicity limiting oxaliplatin administration is neurological. It is a peripheral sensory neuropathy characterized by dysesthesia and / or paraesthesia of the extremities accompanied or not by cramps, often triggered by the cold. These symptoms occur in 95% of treated patients. The duration of these symptoms, which usually subside between courses, increases with the number of treatment courses.
The onset of pain and / or a functional disturbance provide indications, depending on the duration of symptoms, to adjust the dose or even to discontinue treatment (see section 4.4).
This functional disorder includes difficulty in performing fine movements and is a possible consequence of sensory impairment. The risk of persistent symptoms for a total dose of 850 mg / m2 (10 cycles) is approximately 10%, and for a dose total of 1020 mg / m2 (12 cycles) is about 20%.
In most cases, neurological symptoms improve or disappear completely with discontinuation of treatment. In adjuvant colon cancer treatment, 87% of patients reported mild to no symptoms 6 months after discontinuation of treatment. over a period of up to 3 years of follow-up, approximately 3% of patients had either persistent localized paraesthesia of moderate intensity (2.3%) or paraesthesia capable of interfering with functional activities (0.5%).
Acute sensorineural manifestations have been reported (see section 5.3). These reactions begin within hours of administration and often occur with exposure to cold. They usually manifest as transient paraesthesia, dysesthesia and hypoesthesia. Acute pharyngolaryngeal dysesthesia syndrome occurs in 1% and 2% of patients. by subjective sensations of dysphagia or dyspnoea / choking sensation, with no objective evidence of respiratory distress (absence of cyanosis or hypoxia) or of laryngospasm or bronchospasm (absence of stridor or wheezing). Although antihistamines and bronchodilators have been administered in these cases, the symptoms are rapidly reversible even without treatment. Prolonging the infusion helps reduce the incidence of this syndrome (see section 4.4).
Other symptoms have occasionally been observed, including jaw spasm / muscle spasm / involuntary muscle contractions / muscle tension / myoclonus, coordination abnormalities / gait abnormalities / ataxia / balance disturbances, tightness / compression / malaise / chest or chest pain. throat.
In addition, cranial nerve dysfunctions are possible in association with or even as isolated events in the form of ptosis, diplopia, aphonia / dysphonia / hoarseness, sometimes described as vocal cord paralysis, sensation of lingual abnormality or dysarthria, sometimes described as aphasia, trigeminal neuralgia / face pain / eye pain, visual acuity decreased, visual field disturbances.
Other neurological symptoms such as dysarthria, loss of deep tendon reflex and Lhermitte's sign have also been reported during oxaliplatin therapy. Isolated cases of optic neuritis have been reported.
Post-marketing experience with unknown frequency:
Convulsions and Reversible Posterior Leukoencephalopathy Syndrome (SLPR).
Allergic reactions :
Incidence by patient (%), by grade
04.9 Overdose
There is no known antidote to oxaliplatin. Exacerbation of adverse events can be expected in the event of overdose. Monitoring of haematological parameters should be initiated and symptomatic therapy administered.
05.0 PHARMACOLOGICAL PROPERTIES
05.1 Pharmacodynamic properties
Pharmacotherapeutic group: other antineoplastic drugs, platinum compounds.
ATC code: L01XA 03.
Oxaliplatin is an antineoplastic active ingredient belonging to a new class of platinum-based compounds in which the platinum atom forms a complex with 1,2-diaminocyclohexane ("DACH") and an oxalate group.
Oxaliplatin is a unique enantiomer, (SP-4-2) - [(1R, 2R) -Cyclohexane-1,2-diamine-kN, kN "] [ethanediumate (2 -) - kO1, kO2] [platinum ].
Oxaliplatin exhibits a broad spectrum of both cytotoxicity in vitro that of antitumor activity in vivo in several tumor model systems, including human colorectal cancer models.
Oxaliplatin also demonstrates both activity in vitro that in vivo in various models resistant to cisplatin.
Both in vitro that in vivo a synergistic cytotoxic action in association with 5-fluorouracil (5 FU).
Studies on the mechanism of action of oxaliplatin, even if it has not been fully elucidated, show that the hydrated derivatives obtained from the biotransformation of oxaliplatin interact with DNA to form both intra- and inter-chain cross-links leading to a " interruption of DNA synthesis with consequent cytotoxic and antitumor effect.
In patients with metastatic colorectal cancer, the efficacy of oxaliplatin (85 mg / m2 repeated every two weeks) in combination with 5-fluorouracil / folinic acid (5-FU / FA) is reported in three clinical studies:
- In first-line treatment, Phase III, two-group study EFC2962 randomized 420 patients to either 5-FU / FA alone (LV5FU2, N = 210) or oxaliplatin in combination with 5 FU / FA (FOLFOX4, N = 210);
- In pretreated patients, the three-group comparison study EFC4584 phase III randomized 821 patients refractory to the combination of irinotecan (CPT-11) + 5 FU / FA to the only 5 FU / FA group (LV5FU2, N = 275), with oxaliplatin alone (N = 275), or with oxaliplatin in combination with 5 FU / FA (FOLFOX4, N = 271);
- Finally, the uncontrolled phase II EFC2964 study included patients refractory to 5 FU / FA only, who were treated with oxaliplatin in combination with 5 FU / FA (FOLFOX4, N = 57).
The two randomized clinical trials, EFC2962 in first-line treatment and EFC4584 in pretreated patients, demonstrated a significantly higher response rate and greater progression-free survival (PFS) / time to progression (TTP) compared to treatment with only 5 FU / AF.
In study EFC4584, performed in refractory pretreated patients, the difference in median overall survival (OS) between the combination with oxaliplatin and 5 FU / FA did not reach statistical significance.
Response index in FOLFOX4 compared to LV5FU2
* NA: not applicable
Median progression-free survival (PFS) / Median time to progression (TTP)
FOLFOX4 compared to LV5FU2
* NA: not applicable
Median overall survival (OS) in FOLFOX4 compared with LV5FU2
* NA: not applicable
In pretreated patients (EFC4584), symptomatic at baseline, a higher percentage of those treated with oxaliplatin combined with 5 FU / FA had significant improvement in disease-related symptoms compared to those treated with 5 FU / FA alone. (27.7% vs 14.6% p = 0.0033).
In non-pretreated patients (EFC2962), there was no statistically significant difference between the two treatment groups for any of the quality of life aspects. However, quality of life scores were generally better in the control group for measures of overall health and pain and worse in the oxaliplatin group for nausea and vomiting.
In the adjuvant, the MOSAÏC phase III comparative study (EFC3313) randomized 2246 patients (899 stage II / Duke B2 and 1347 stage III / Duke C), after complete resection of primary colon cancer, with only 5 FU / AF (LV5FU2, N = 1123 (B2 / C = 448/675) or with oxaliplatin in association with 5 FU / AF (FOLFOX4, N = 1123 (B2 / C) = 451/672).
EFC3313 3-year disease-free survival (ITT analysis) * for the general population.
* median follow-up 44.2 months (all patients followed for at least 3 years)
The study demonstrated a significant overall advantage in 3-year disease-free survival for oxaliplatin in combination with 5 FU / FA (FOLFOX4) compared to only 5 FU / FA (LV5FU2).
EFC3313 3-year disease-free survival (ITT analysis) * by stage of disease
* median follow-up 44.2 months (all patients followed for at least 3 years)
Total survival (ITT analysis):
At the time of the 3-year disease-free survival analysis, which was the primary endpoint of the MOSAIC study, 85.1% of patients were still alive in the FOLFOX4 group compared to 83.8% in the LV5FU2 group. This translates into a general reduction in mortality risk of 10% in favor of the FOLFOX4 group, although not reaching statistical significance (hazard ratio = 0.90).
Values were 92.2% versus 92.4% in the stage II subpopulation (Duke B2) (hazard ratio = 1.01) and 80.4% versus 78.1% in the stage III subpopulation (Duke C ) (hazard ratio = 0.87), for FOLFOX4 and LV5FU2 respectively.
Oxaliplatin as a single agent has been evaluated in the pediatric population in 2 Phase I studies (69 patients) and 2 Phase II studies (90 patients). A total of 159 pediatric patients (7 months-22 years of age) with solid tumors were treated. The efficacy of oxaliplatin as a single agent in the treated pediatric population has not been established. Patient enrollment in both phase II studies was discontinued due to lack of tumor response.
05.2 "Pharmacokinetic properties
The pharmacokinetic properties of the individual active compounds have not been determined. The pharmacokinetic properties of ultrafilterable platinum, which represents a combination of all unbound active and inactive platinum species, after a two-hour infusion of oxaliplatin at 130 mg / m2 every three weeks for 1/5 cycles and oxaliplatin at 85 mg / m2 every two weeks for 1/3 cycles are shown below:
Summary of estimates of the pharmacokinetic parameters of platinum in ultrafiltrate following multiple doses of oxaliplatin at 85 mg / m2 every two weeks or at 130 mg / m2 every three weeks
Mean AUC0-48 and Cmax values were determined at cycle 3 (85 mg / m2) or cycle 5 (130 mg / m2).
The mean values of AUC, Vss, CL and CLR0-48 were determined in cycle 1.
Values of Cend, Cmax, AUC, AUC0-48, Vss and CL were determined by non-compartmental analysis.
Values of t½α, t½β and t½γ were determined by compartmental analysis (cycles 1-3 combined).
At the end of a 2-hour infusion, 15% of the administered platinum is present in the systemic circulation, while the remaining 85% is rapidly distributed in the tissues or is eliminated in the urine. environment a half-life close to the natural turnover time of erythrocytes and serum albumin. No accumulation in plasma ultrafiltrate was observed after doses of 85 mg / m2 every two weeks or 130 mg / m2 every three weeks, and steady state was reached at the first cycle in this matrix. Inter- and intra-individual variability is generally low.
In vitro, biotransformation is considered to result from non-enzymatic degradation and there is no evidence of cytochrome P450 mediated metabolism of the diaminocyclohexane ring (DACH).
In patients, oxaliplatin undergoes extensive biotransformation, and at the end of a 2-hour infusion no intact active substance was detected in the plasma ultrafiltrate. Several cytotoxic biotransformation products have been identified in the systemic circulation, including monochlor, dichloro and the diaquo DACH platinum species together, in successive moments, with a certain number of inactive conjugates.
Platinum is eliminated predominantly in the urine, with maximum clearance within 48 hours after administration.
On the fifth day, approximately 54% of the total dose is eliminated in the urine and less than 3% in the faeces.
A significant decrease in clearance from 17.6 ± 2.18 L / h to 9.95 ± 1.91 L / h was observed in subjects with renal impairment associated with a statistically significant decrease in volume of distribution from 330 ± 40. , 9 to 241 ± 36.1 l. The effect of severe renal impairment on platinum clearance has not been investigated.
05.3 Preclinical safety data
Target organs identified in preclinical species (mice, rats, dogs and / or monkeys) in single-dose and repeat-dose studies included bone marrow, gastrointestinal tract, kidneys, testes, nervous system and heart. The target organ toxicities observed in animals are consistent with those caused by other platinum-based medicinal products and DNA-damaging cytotoxic drugs used in anti-cancer treatment in humans, except for effects on the heart. Effects on the heart have been observed. only in the dog and included electrophysiological disturbances with lethal ventricular fibrillation. Cardiotoxicity is considered specific to the dog, not only because it was observed only in the dog, but also because doses similar to those producing lethal cardiotoxicity in the dog (150 mg / m2 ) have been well tolerated in humans.
Preclinical studies in rat sensory neurons suggest that acute sensorineural symptoms related to oxaliplatin may involve an "interaction with voltage-gated Na + channels.
In mammalian test systems, oxaliplatin was mutagenic and clastogenic and produced embryofoetal toxicity in rats. Oxaliplatin is considered a probable carcinogen, although carcinogenicity studies have not been conducted.
06.0 PHARMACEUTICAL INFORMATION
06.1 Excipients
Lactose monohydrate.
06.2 Incompatibility
The diluted drug must not be mixed with other drugs in the same infusion bag or line. In accordance with the instructions for use described in section 6.6, oxaliplatin can be administered simultaneously with folinic acid (FA) using a Y-line.
- DO NOT mix with alkaline drugs or alkaline solutions, especially preparations of 5-fluorouracil (5 FU) or folinic acid (AF) containing trometamol as an excipient and other active ingredients containing trometamol salts. Alkaline drugs or alkaline solutions will have an adverse effect on the stability of oxaliplatin (see section 6.6).
- DO NOT reconstitute or dilute oxaliplatin with saline or other solutions containing chlorides (including calcium chloride, potassium chloride or sodium chloride).
- DO NOT mix with other drugs in the same infusion bag or line (see section 6.6 for instructions on simultaneous administration with folinic acid (FA)).
- DO NOT use injection materials containing aluminum.
06.3 Period of validity
3 years.
Reconstituted solution in the original vial:
for microbiological and chemical reasons, the reconstituted solution must be diluted immediately.
Solution for infusion:
after dilution of the reconstituted solution in 5% glucose solution (50 mg / ml), under the current conditions of use, the chemical-physical stability has been demonstrated for 48 hours at a temperature between 2 ° C and 8 ° C.
For microbiological reasons, the infusion solution should be used immediately.
If not used immediately, in-use storage times and conditions under current conditions of use are the responsibility of the user and would normally not be longer than 24 hours at 2 ° C to 8 ° C, unless dilution took place under controlled and validated aseptic conditions.
06.4 Special precautions for storage
This medicinal product does not require any special storage conditions.
For storage conditions of the reconstituted and diluted drug, see section 6.3
06.5 Nature of the immediate packaging and contents of the package
30 ml vial (type I neutral glass) of oxaliplatin powder (50 mg) with bromobutyl rubber stopper and cap (flip-off).
50 ml vial (type I neutral glass) of oxaliplatin powder (100 mg) with bromobutyl rubber stopper and cap (flip-off).
Pack sizes: 1, 2, 3, 5, 10 or 50 vials per carton.
Not all pack sizes may be marketed.
06.6 Instructions for use and handling
As with other potentially toxic compounds, care should be taken in handling and preparing oxaliplatin solutions.
Handling instructions
The handling of this cytotoxic drug by medical or paramedical personnel requires every precaution to ensure the protection of the person carrying out the manipulation and of the environment in which he works.
The preparation of injectable solutions of cytotoxic agents must be carried out by specialized personnel with in-depth knowledge of the medicinal products in use, in conditions that guarantee the integrity of the medicinal product, the protection of the environment and in particular the protection of the personnel handling the products. medicines, in accordance with hospital policies. This preparation requires a specially reserved area. In this area it is forbidden to smoke and consume food or drinks.
Personnel must have appropriate material for handling, in particular long-sleeved gowns, protective masks, headgear, protective goggles, sterile disposable gloves, protective mats for the work area, containers and collection bags for waste .
Excrement and vomit must be handled with care.
Pregnant women should be advised to avoid handling cytotoxic drugs.
Any broken container should be treated with the same precautions and considered as contaminated waste. Contaminated waste must be incinerated in rigid containers prepared for use. See also the chapter "Disposal".
In case of accidental skin contact with unreconstituted oxaliplatin lyophilisate, reconstituted solution or infusion solution, immediately and thoroughly rinse the skin with water.
In case of accidental contact of the mucous membranes with the unreconstituted oxaliplatin lyophilisate, the reconstituted solution or the infusion solution, immediately and thoroughly rinse the part with water.
Special precautions for administration
- DO NOT use injection materials containing aluminum.
- DO NOT administer the product undiluted.
- Use only 5% glucose solution for infusion (50 mg / ml) as a diluent. DO NOT reconstitute or dilute for infusion with solutions containing sodium chloride or other chlorides.
- DO NOT mix with any other type of medicinal product in the same infusion bag or administer simultaneously in the same infusion line.
- DO NOT mix with alkaline drugs or alkaline solutions, especially preparations of 5-fluorouracil (5 FU) or folinic acid (AF) containing trometamol as an excipient and other active ingredients containing trometamol salts. Medicines or alkaline solutions will have an adverse effect on the stability of oxaliplatin.
Instructions for use with folinic acid (AF) (as calcium folinate or disodium folinate):
Oxaliplatin 85 mg / m2 for intravenous infusion in 250/500 ml of 5% glucose solution (50 mg / ml), is administered simultaneously with the intravenous infusion of folinic acid (FA) in 5% glucose solution. % (50 mg / ml), over a period of 2/6 hours, using a Y-line placed immediately before the infusion site. The two drugs must not be placed together in the same infusion bag. Folinic acid (AF) must not contain trometamol as an excipient and must only be diluted using 5% isotonic glucose solution (50 mg / ml), never alkaline or sodium chloride solutions or solutions containing chlorides.
Instructions for use with 5-fluorouracil (5 FU):
Oxaliplatin should always be administered before fluoropyrimidines - eg 5-fluorouracil (5 FU).
After administration of oxaliplatin, flush the infusion line and then administer 5-fluorouracil (5 FU).
For more information regarding oxaliplatin associated medicines, see the summary of product characteristics for those products.
- USE ONLY the recommended solvents (see below).
- All reconstituted solutions showing traces of precipitate must not be administered and must be destroyed, in compliance with the laws regarding the disposal of hazardous waste (see below).
Reconstitution of the solution
- To reconstitute the solution use water for injections or 5% glucose solution (50 mg / ml).
- For a 50 mg vial: add 10 ml of solvent to obtain an oxaliplatin concentration of 5 mg / ml.
- For a 100 mg vial: add 20 ml of solvent to obtain an oxaliplatin concentration of 5 mg / ml.
For microbiological and chemical reasons, the reconstituted solution must be diluted immediately with 5% glucose solution (50 mg / ml).
Visually examine before use. Use only clear, particle-free solutions.
The medicine is for single use only. All unused solutions should be discarded.
Dilution before intravenous infusion
Withdraw the required amount of reconstituted solution from the vial (s) and then dilute with 250-500 ml of 5% glucose solution (50 mg / ml) to obtain an oxaliplatin concentration of not less than 0.2 mg / ml and between 0.2 mg / ml and 0.7 mg / ml.
Administer by intravenous infusion.
After dilution in 5% glucose solution (50 mg / ml), under the current conditions of use, the chemical-physical stability has been demonstrated for 48 hours at a temperature between 2 ° C and 8 ° C.
For microbiological reasons, the infusion solution should be used immediately.
If not used immediately, in-use storage times and conditions under current conditions of use are the responsibility of the user and would normally not be longer than 24 hours at 2 ° C to 8 ° C, unless dilution took place under controlled and validated aseptic conditions.
Visually examine before use. Use only clear, particle-free solutions.
The medicine is for single use only. All unused infusion solutions must be discarded (see chapter "Disposal" below).
NEVER use sodium chloride solutions or solutions containing chlorides for either reconstitution or dilution.
The compatibility of oxaliplatin solution for infusion has been tested with representative PVC-based administration kits.
Infusion
Administration of oxaliplatin does not require pre-hydration.
Oxaliplatin diluted in 250 - 500 ml of 5% glucose solution (50 mg / ml), in order to provide a concentration of not less than 0.2 mg / ml, must be infused peripherally or centrally over an arc 2 to 6 hours. When oxaliplatin is administered with 5-fluorouracil (5 FU), the oxaliplatin infusion must precede that of 5-fluorouracil (5 FU).
Disposal
Medicinal product residues and any materials used for reconstitution, dilution and administration must be destroyed in accordance with standard hospital cytotoxic waste disposal procedures, in compliance with applicable laws regarding the disposal of hazardous waste.
07.0 MARKETING AUTHORIZATION HOLDER
Mylan S.p.A. - Via Vittor Pisani, 20 - 20124 Milan, Italy
08.0 MARKETING AUTHORIZATION NUMBER
5 mg / ml powder for solution for infusion 1 glass vial of 50 mg AIC no .: 038097010 / M
5 mg / ml powder for solution for infusion 2 glass vial of 50 mg AIC no .: 038097022 / M
5 mg / ml powder for solution for infusion 3 glass vial of 50 mg AIC no .: 038097034 / M
5 mg / ml powder for solution for infusion 5 glass vial of 50 mg AIC no .: 038097046 / M
5 mg / ml powder for solution for infusion 10 glass vial of 50 mg AIC no .: 038097059 / M
5 mg / ml powder for solution for infusion 50 50 mg glass vial AIC no .: 038097061 / M
5 mg / ml powder for solution for infusion 1 glass vial of 100 mg AIC no .: 038097073 / M
5 mg / ml powder for solution for infusion 2 glass vial of 100 mg AIC no .: 038097085 / M
5 mg / ml powder for solution for infusion 3 glass vial of 100 mg AIC no .: 038097097 / M
5 mg / ml powder for solution for infusion 5 glass vial of 100 mg AIC no .: 038097109 / M
5 mg / ml powder for solution for infusion 10 glass vial of 100 mg AIC no .: 038097111 / M
5 mg / ml powder for solution for infusion 50 glass vial of 100 mg AIC no .: 038097123 / M
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION
February 2008
10.0 DATE OF REVISION OF THE TEXT
February 2013
