Oxaliplatin-Ebeve, 50 mg

How to take, the dosage

Oxaliplatin-Ebeve is administered only in adults as an IV infusion for 2-6 hours.

Hyperhydration is not required when using the drug. If oxaliplatin is used in combination with 5-fluorouracil, the infusion of oxaliplatin should precede the administration of 5-fluorouracil.

Adjuvant therapy for colorectal cancer is 85 mg/m² once every 2 weeks for 12 cycles (6 months).

Treatment of metastatic colorectal cancer – 85 mg/m² once every 2 weeks as monotherapy or in combination with 5-fluorouracil.

Treatment of ovarian cancer – 85 mg/m² once every 2 weeks as monotherapy or in combination with other chemotherapeutic agents.

Repeated infusions of Oxaliplatin-Ebeve are given only when neutrophil counts > 1500/μL and platelet counts > 50000/μL.

Recommendations for dosage adjustment and regimen of oxaliplatin administration

If there are hematologic abnormalities (neutrophil count < 1500/μL and/or platelet count < 50000/μL), the next course is delayed until normal laboratory values are restored.

In case of development of diarrhea of grade 4 toxicity (WHO scale), neutropenia of grade 3-4 (neutrophil count < 1000/μl), thrombocytopenia of grade 3-4 (platelet count < 50000/μl) the dose of Oxaliplatin-Ebeve in subsequent administrations should be reduced from 85 mg/msup>2 to 65 mg/m² for therapy of disseminated colorectal cancer and ovarian cancer; to 75 mg/m² for adjuvant therapy of colorectal cancer, in addition to the usual dose reduction of 5-fluorouracil when they are combined.

Patients who develop acute laryngeopharyngeal dysesthesia during the infusion or within hours of a 2-hour infusion should have their next Oxaliplatin-Ebeve infusion within 6 hours.

If pain (as a sign of neurotoxicity) persists for more than 7 days or if paresthesia without functional impairment persists until the next cycle, the subsequent dose of Oxaliplatin-Ebeve should be decreased from 85 mg/msup>2 to 65 mg/m² (for treatment of metastatic cancer) or to 75 mg/m² (for adjuvant therapy). If paresthesia with functional impairment persists until the next cycle, Oxaliplatin-Ebeve should be withdrawn; if symptoms of neurotoxicity decrease after withdrawal of oxaliplatin, resumption of treatment may be considered.

If stomatitis and/or mucositis of grade 2 or higher toxicity develop, treatment with Oxaliplatin-Ebeve should be suspended until they have resolved or toxicity has been reduced to grade 1.

Patients with impaired renal function

The drug should not be used in patients with significant impairment of renal function. Because of the limited data regarding the safety and tolerability of the drug in patients with moderate renal impairment, the benefit/risk ratio for the patient should be weighed before using the drug. Therapy in this category of patients can be started with the recommended dose, under close monitoring of renal function. No dose adjustment of oxaliplatin is required in mild renal dysfunction.

Patients with impaired hepatic function

There is no need to change the dosing regimen in patients with mild to moderate hepatic impairment. There are no data on the use of oxaliplatin in patients with severe hepatic impairment.

Elderly patients

No dosing adjustment is required when using oxaliplatin in patients over 65 years of age (including when used in combination with 5-fluorouracil).

Regulations for preparation and administration of the solution

Please do not use needles or other equipment containing aluminum when preparing and administering oxaliplatin.

The drug is dissolved in water for injection or in 5% dextrose solution before use, obtaining a solution with a concentration of 5 mg/ml of oxaliplatin (a 50 mg vial takes 10 ml of solvent, a 100 mg vial takes 20 ml of solvent). The drug thus reconstituted is immediately diluted with 250-500 ml of 5% dextrose solution. The concentration of the resulting oxaliplatin solution should be 200 µg/ml to 700 µg/ml; with 700 µg/ml being the highest concentration used in clinical practice at a dose of 85 mg/m².

Only recommended solvents should be used to prepare the drug solution.

The drug should not be used undiluted.

Do not use 0.9% sodium chloride solution or other saline solutions to dissolve or dilute the drug solution (to prepare infusion solution).

The drug should not be mixed in the same container and should not be administered simultaneously in the same infusion system with other drugs (especially with 5-fluorouracil, alkaline solutions, tromethamol and calcium folinate preparations containing tromethamol in their composition).

Oxaliplatin can be administered together with calcium folinate infusions. In this case, the drugs should not be mixed in the same container for infusion. Calcium folinate for infusion should be diluted using 5% dextrose solution, but under no circumstances should solutions containing sodium chloride or alkaline solutions be used.

The drug solution for infusion is recommended to be used immediately after preparation. The reconstituted solution for infusion remains stable for 24 hours at room temperature (not exceeding 25°C).

The prepared drug solution should be clear and contain no undissolved particles. The solution with signs of precipitation shall be destroyed.

If extravasation occurs, the administration of the drug should be stopped immediately.

Interaction

No significant changes in the binding of oxaliplatin to plasma proteins in concomitant use with erythromycin, salicylates, granisetron, paclitaxel and valproic acid were observed.

In interaction with aluminum a precipitate formation and decreased activity of oxaliplatin are possible.

On a single IV infusion of oxaliplatin at a dose of 85 mg/m2, immediately before administration of 5-fluorouracil, no changes in serum concentrations of 5-fluorouracil were observed.

Pharmaceutical interactions

The drug is pharmaceutically incompatible with alkaline solutions and solutions containing chloride.

Do not mix with alkaline drugs or solutions, especially fluorouracil and calcium folinate preparations containing trometamol as an excipient, and with other active substances in the form of trometamol salts.

Special Instructions

Oxaliplatin-Ebeve should only be used under the supervision of an oncologist experienced in the use of antitumor drugs.

Peripheral blood cells and renal and hepatic function parameters should be monitored regularly (once a week) and before each administration of the drug.

Ahead of each cycle of therapy with Oxaliplatin-Ebeve a neurological examination should be performed to detect signs of neurotoxicity. Patients should be informed about the possibility of persistence of symptoms of peripheral sensory neuropathy after the end of treatment. Localized moderate paresthesias with functional impairment may persist up to 3 years after discontinuation of the drug on adjuvant therapy regimen.

The reversible posterior leukoencephalopathy syndrome (RLS) has been reported in patients receiving oxaliplatin in combination with other chemotherapy drugs. SZOL is a rare, reversible, rapidly developing neurological complication. The main clinical manifestations of SZOL are headache, dizziness, nausea, vomiting, epileptic seizures, behavioral disorders, impaired consciousness (from drowsiness to coma) and visual disturbances in the form of hemianopsia, scotoma, cortical blindness. Since SLE is a potentially life-threatening neurological syndrome and can be complicated by the development of massive brain infarction if not treated in time, its early diagnosis is particularly important, determining the correct treatment of patients. Diagnosis of SLE is based on imaging of the brain by CT or MRI.

If respiratory symptoms occur (dry cough, dyspnea, rales, or pulmonary infiltrates detected on radiologic examination), treatment with Oxaliplatin-Ebeve should be suspended until interstitial pneumonitis is excluded.

In order to prevent and treat gastrointestinal symptoms such as nausea and vomiting, antiemetics are indicated. Symptoms such as dehydration, paralytic ileus, bowel obstruction, hypokalemia, metabolic acidosis and renal failure may be due to severe diarrhea or vomiting, especially when Oxaliplatin-Ebeve is used in combination with 5-fluorouracil.

Patients should be appropriately informed of the risk of diarrhea/vomiting, mucositis/stomatitis and neutropenia when using oxaliplatin and 5-fluorouracil, and should contact their physician if these adverse effects occur for appropriate therapy adjustments.

If liver dysfunction or portal hypertension is detected that is not associated with the presence of liver metastases, drug-induced hepatic vascular dysfunction, specifically the development of hepatic vein obliterating endophlebitis, may occur in very rare cases.

Patients with a history of allergic reactions to other platinum compounds should be monitored for the presence of allergic symptoms.

In case of an anaphylactic-like reaction to Oxaliplatin-Ebeve, the infusion should be stopped immediately and appropriate symptomatic treatment administered. Further use of Oxaliplatin-Ebeve in case of allergic reactions is contraindicated. In case of extravasation the infusion should be stopped immediately and local symptomatic treatment should be started. The remaining dose of the drug should be administered in another vein.

Women and men should use reliable contraceptive methods during treatment and for 6 months after therapy with Oxaliplatin-Ebeve. Because oxaliplatin has a genotoxic effect that may be irreversible, men who wish to have children are advised to consider sperm preservation before starting treatment.

When using Oxaliplatin-Ebeve, all the usual instructions for the use of cytotoxic drugs must be followed. If the drug comes into contact with the skin, immediately rinse the skin thoroughly with soap and water or sodium bicarbonate solution; if it gets into the eyes, pull back the eyelids and rinse the eye (eyes) with plenty of water for 15 minutes.

The remains of the drug and all instruments and materials that have been used to prepare the Oxaliplatin-Ebeve IV infusion solution must be disposed of in accordance with standard hospital procedures for the disposal of cytotoxic waste, subject to current hazardous waste disposal regulations.

The effect of Oxaliplatin-Ebeve on the ability to drive vehicles and other mechanisms requiring high concentration

There have been no studies of the effect of Oxaliplatin-Ebeve on the ability to drive and operate machinery.

Mannered side effects such as dizziness, nausea, vomiting, transient vision loss, other neurologic symptoms may in varying degrees affect the ability to engage in potentially hazardous activities requiring increased concentration and rapid psychomotor reaction.

Contraindications

• Myelosuppression before the first course of therapy with neutrophil levels less than 2,000/μL and/or platelets less than 100,000/μL;
• peripheral sensory neuropathy with functional impairment before the first course of therapy;
• Peripheral neuropathy with functional impairment before the first course of therapySevere renal dysfunction (CKR less than 30 ml/min);
• pregnancy;
• lactation period (breastfeeding);
childhood;
• high sensitivity to oxaliplatin, other platinum derivatives or other components of the drug.

With caution: The drug should be used in patients with renal impairment, rare hereditary forms of lactose intolerance, lactase deficiency, or impaired glucose/galactose absorption (because it contains lactose).

Side effects

According to the WHO, adverse reactions are classified according to their frequency of development as follows:

• very frequently (≥1/10);
• frequently (≥1/100, < 1/10);<
• frequently (≥1/1000, < 1/100);
• infrequently (≥1/10000, < 1/1000);
• very rarely ( < 1/10000);
• frequency unknown – it was not possible to determine the frequency of occurrence from the available data.

In the hematopoietic system: very often – anemia, leukopenia, neutropenia, thrombocytopenia, lymphopenia; often – febrile neutropenia (including degree 3-4), sepsis with neutropenia; rarely – granulocytopenia, hemolytic anemia, immune thrombocytopenia.

Nervous system disorders: very frequently – peripheral sensory neuropathy, sensory disorders, headache, asthenia, taste disorders; frequently – dizziness, meningism, depression, insomnia; infrequently – increased nervousness; rarely – dysarthria, posterior reversible leukoencephalopathy syndrome.

Neurotoxicity is a dose-limiting factor. Often the symptoms of sensory neuropathy are provoked by cold. The duration of these symptoms, which usually subside between courses, increases with the total dose of oxaliplatin. Functional impairment in the form of difficulty performing precise movements is a possible consequence of sensory damage. The risk of functional impairment at a total dose of about 850 mg/m² (10 cycles) is about 10%, reaching 20% for a total dose of 1020 mg/m² (12 cycles). In most cases, the severity of neurological symptoms decreases or they completely disappear. In 3% of patients 3 years after the end of treatment there were either persistent local paresthesias of moderate intensity (2.3%) or paresthesias affecting functional activity (0.5%).

In the background of oxaliplatin treatment, acute neurosensory manifestations were observed, which usually occurred within a few hours after the drug administration and were most often provoked by exposure to cold. They were characterized by transient paresthesia, dysesthesia or hypoesthesia, rarely (1-2%) – acute laryngeopharyngeal dysesthesia syndrome. The latter was manifested by a subjective feeling of dysphagia and dyspnea without objective signs of respiratory distress syndrome (cyanosis or hypoxia), or laryngeal spasm, or bronchospasm (without stridor or wheezing). There were also phenomena such as jaw muscle spasm, tongue dysesthesia, dysarthria and a feeling of pressure in the chest. Usually these symptoms quickly subsided both without drug therapy and with the administration of antihistamines and bronchodilators. Increasing the duration of infusion in subsequent cycles of oxaliplatin therapy can reduce the frequency of this syndrome.

Senses: common – conjunctivitis, visual disturbances; infrequent – ototoxicity; rare – transient decrease in visual acuity, loss of visual fields, decreased hearing, auditory nerve neuritis, optic neuritis, deafness.

Respiratory system: very often – cough, dyspnea; often – rhinitis, upper respiratory tract infections, pain in the chest; rarely – pulmonary fibrosis, intestinal lung disease, sometimes with development of fatal outcome.

Digestive system disorders: very common – nausea, vomiting, diarrhea, stomatitis, mucositis, abdominal pain, constipation, loss of appetite, increased ALP level, liver enzymes activity, bilirubin, LDH; common – dyspepsia, hiccups, gastro-esophageal reflux, GI bleeding (including rectal bleeding); infrequent – intestinal obstruction, paraletic ileus; rare – colitis, including cases of pseudomembranous colitis, pancreatitis; very rare – hepatic vein obliterating endophlebitis, including hepatic purpura, nodular regenerative hyperplasia, perisinusoidal fibrosis, which clinically may manifest as signs of portal hypertension and/or increased activity of “liver” transaminases.

Urinary system disorders: often – hematuria, dysuria, change of frequency of urination, increased concentration of creatinine in plasma; very rarely – hemolytic-uremic syndrome, acute tubular necrosis, acute interstitial nephritis, acute renal failure.

Skin and subcutaneous tissues: very common – alopecia, skin rashes; common – skin peeling of the palms and feet, erythematous rashes, increased sweating, changes in the nails.

Muscular system disorders: very often – back pain; often – arthralgia, bone pain.

Mechanical system disorders: very common – anorexia, hyperglycemia, hypokalemia, hyponatremia; common – dehydration; infrequent – metabolic acidosis.

Cardiovascular system disorders: frequently – pain in the sternum, deep vein thrombophlebitis, pulmonary embolism, bleeding, high blood pressure, “rushes” of blood to the face.

Allergic reactions: rarely (when used as monotherapy) or often (in combination with 5-fluorouracil +/- calcium folinate) bronchospasm, angioedema, hypotension and anaphylactic shock may be observed. Allergic manifestations such as skin rash (especially urticaria), conjunctivitis or rhinitis have often been reported.

Local reactions: in case of extravasation of the drug – pain and inflammatory reactions at the site of injection.

Others: very often – increased body temperature, increased fatigue, weight gain, asthenia.

Overdose

Symptoms: myelosuppression, neurotoxicity, diarrhea, nausea, vomiting.

Treatment: hematologic control and symptomatic therapy. An antidote to oxaliplatin is not known.