Oxaliplatin-Ebeve, vial, 50mg

Composition

1 bottle contains:

Active ingredients:

oxaliplatin 50 mg.

Auxiliary substances:

lactose monohydrate.

Pharmacological action

Pharmacodynamics

antitumor drug belonging to a new class of platinum-based compounds, in which a platinum atom forms a complex bond with 1,2-diaminocyclohexane (DAC) and an oxalate group.

Oxaliplatin has antitumor activity in various types of tumors, including colorectal cancer. It is also effective in the treatment of cisplatin-resistant tumors. The effect is manifested regardless of the phase of the cell cycle. When used with 5-fluorouracil, a synergistic cytotoxic effect is observed. The mechanism of the antitumor effect of oxaliplatin is based on cytotoxic action and is not fully understood. Presumably, oxaliplatin forms inter-and inter-stranded bonds with DNA, thereby inhibiting the phases of its replication and transcription.

Pharmacokinetics

In vivo oxaliplatin undergoes active biotransformation and is not detected in plasma by the end of 2 hours after use at a dose of 130 mg / m2, while 15% of the administered platinum is in the blood, and the remaining 85% is rapidly distributed in tissues or excreted by the kidneys.

In vitro biotransformation is the result of nonenzymatic degradation, and there is no evidence that oxaliplatin is metabolized by cytochrome P 450. Oxaliplatin undergoes extensive metabolism, while the drug is not detected in the plasma ultrafiltrate after a 2-hour infusion. Some cytotoxic degradation products of oxaliplatin, including monochloro -, dichloro – and quadro-diaminocyclohexane of platinum, are detected in blood plasma together with inactive conjugates at a later stage of the study.

Platinum binds to plasma albumin and is excreted in the urine within the first 48 hours. By day 5, about 54% of the total dose is detected in the urine and less than 3% in the feces.

Pharmacokinetics in special clinical cases

The effect of impaired renal function on the distribution of oxaliplatin was studied in patients with varying degrees of impaired renal function. Oxaliplatin was administered at a dose of 85 mg / m2 in the control group with normal renal function (creatinine clearance greater than 80 ml / min), in patients with minor (creatinine clearance 50 to 80 ml/min) and moderate renal impairment (creatinine clearance 30 to 49 ml/min); and at a dose of 65 mg/m2 in patients with severe renal insufficiency (creatinine clearance less than 30 ml/min). Oxaliplatin elimination was found to be significantly correlated with creatinine clearance. Renal clearance of platinum was reduced by 30%,65%, and 84% in patients with mild, moderate, and severe renal impairment, respectively, compared to patients with normal renal function.

Indications

• Adjuvant therapy for stage III colorectal cancer (Duke C) after radical resection of the primary tumor in combination with 5-fluorouracil and calcium folinate;
• disseminated colorectal cancer (as monotherapy or combination therapy in combination with 5-fluorouracil/calcium folinate);
• ovarian cancer (as second-line therapy).
• Adjuvant therapy for stage III colorectal cancer (Duke C) after radical resection of the primary tumor in combination with 5-fluorouracil and calcium folinate;
• disseminated colorectal cancer (as monotherapy or combination therapy in combination with 5-fluorouracil/calcium folinate);
• ovarian cancer (as second-line therapy).

Contraindications

• Myelosuppression prior to the first course of therapy at the level of neutrophils less than 2000/µl and/or platelets less than 100,000/µl;
• peripheral sensory neuropathy with functional impairment prior to first course of therapy;
• marked impairment of renal function (QC less than 30 ml/min);
• pregnancy;
• lactation (breastfeeding);
• child;
• hypersensitivity to oxaliplatin, other derivatives of platinum or other componentpart.

With caution: the drug should be prescribed for impaired renal function, rare hereditary forms of lactose intolerance, lactase deficiency or glucose/galactose malabsorption (since the composition contains lactose).

Side effects

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

• very common (≥ 1/10);
• common (≥1/100, < 1/10);
• uncommon (≥1/1000, < 1/100);
• rare (≥1/10000, < 1/1000);
• very rare ( < 1/10000);
• frequency unknown – it was not possible to determine the frequency of occurrence according to available data.

From the hematopoietic system: very often – anemia, leukopenia, neutropenia, thrombocytopenia, lymphopenia; often-febrile neutropenia (including grade 3-4), sepsis on the background of neutropenia; rarely-granulocytopenia, hemolytic anemia, immune thrombocytopenia.

From the nervous system: very often – peripheral sensory neuropathy, sensitivity disorders, headache, asthenia, taste disorders; often-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 are usually relieved between courses, increases depending on the total dose of oxaliplatin. Functional disorders in the form of difficulty performing precise movements are possible consequences of sensory damage. The risk of functional impairment at a total dose of about 850 mg/m2 (10 cycles) is about 10%, reaching 20% in the case of a total dose of 1020 mg/m2 (12 cycles). In most cases, the severity of neurological symptoms decreases or they are completely stopped. In 3% of patients,3 years after the end of treatment, either stable local paresthesias of moderate intensity (2.3%) or paresthesias affecting functional activity (0.5%) were observed.

Against the background of oxaliplatin treatment, acute sensorineural manifestations were noted, which usually occurred within a few hours after use of the drug and were most often provoked by exposure to cold. They were characterized by transient paresthesia, dysesthesia or hypesthesia, rarely (1-2%) – acute laryngopharyngeal dysesthesia syndrome. The latter was manifested by a subjective feeling of dysphagia and shortness of breath without objective signs of respiratory distress syndrome (cyanosis or hypoxia), or laryngeal spasm, or bronchospasm (without stridor or wheezing). There were also symptoms such as jaw muscle spasms, tongue dysesthesia, dysarthria, and chest pressure. Usually, these symptoms were quickly relieved both without the use of medication, and with the introduction of antihistamines and bronchodilators. Increasing the duration of the infusion during subsequent cycles of oxaliplatin therapy reduces the frequency of this syndrome.

From the sensory organs: often-conjunctivitis, visual disturbances; infrequently-ototoxicity; rarely-transient decrease in visual acuity, loss of visual fields, hearing loss, neuritis of the auditory nerve, neuritis of the ocular nerve, deafness.

From the respiratory system: very often – cough, shortness of breath; often – rhinitis, upper respiratory tract infections, chest pain; rarely – pulmonary fibrosis, intestinal lung diseases, sometimes with the development of a fatal outcome.

From the digestive system: very often – nausea, vomiting, diarrhea, stomatitis, mucositis, abdominal pain, constipation, loss of appetite, increased levels of alkaline phosphatase, liver enzymes, bilirubin, LDH; often – dyspepsia, hiccups, gastro-esophageal reflux, bleeding from the gastrointestinal tract (including from the rectum); infrequently – intestinal obstruction, paralytic ileus; rarely – colitis, including cases of pseudomembranous colitis, pancreatitis; very rarely – obliterating endophlebitis of the hepatic veins, including hepatic purpura, nodular regenerative hyperplasia, perisinusoidal fibrosis, which can clinically manifest as signs of portal hypertension and/or an increase in the activity of “hepatic” transaminases.

From the urinary system: often-hematuria, dysuria, changes in the frequency of urination, increased creatinine concentration in blood plasma; very rarely-hemolytic-uremic syndrome, acute tubular necrosis, acute interstitial nephritis, acute renal failure.

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

From the musculoskeletal system: very often – back pain; often-arthralgia, bone pain.

From the side of metabolism: very often – anorexia, hyperglycemia, hypokalemia, hyponatremia; often-dehydration; infrequently-metabolic acidosis.

From the cardiovascular system: often-pain behind the sternum, deep vein thrombophlebitis, pulmonary embolism, bleeding, increased blood pressure, “flushes” 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 occur. Allergic reactions such as skin rash (especially urticaria), conjunctivitis or rhinitis were frequently reported.

Local reactions: with extravasation of the drug-pain and inflammatory reactions at the injection site.

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

Interaction

No significant changes in the binding of oxaliplatin to plasma proteins were observed when co-administered with erythromycin, salicylates, granisetron, paclitaxel, and valproic acid.

When interacting with aluminum, it is possible to form a precipitate and reduce the activity of oxaliplatin.

With a single intravenous use of oxaliplatin at a dose of 85 mg / m2, immediately before the use of 5-fluorouracil, no changes in serum concentrations of 5-fluorouracil were observed.

Pharmaceutical interaction

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

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

How to take, course of use and dosage

Oxaliplatin-Ebeve is prescribed only for adults as an intravenous infusion for 2-6 hours.

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

Adjuvant therapy for colorectal cancer-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 drugs.

Repeated use of Oxaliplatin-Ebeve is performed only when the number of neutrophils > 1500/µl and platelets > > 50000/µl.

Recommendations for adjusting the dose and mode of use of oxaliplatin

With hematological disorders (neutrophil count < 1500 / µl and / or platelets

With the development of diarrhea of 4 degrees of toxicity (according to the WHO scale), neutropenia of 3-4 degrees (neutrophil count < 1000/µl), thrombocytopenia of 3-4 degrees (platelet count

Patients who develop acute laryngopharyngeal dysesthesia during the infusion or within a few hours after the 2-hour infusion, the next Oxaliplatin-Ebeve infusion should be administered within 6 hours.

If there is pain (as a sign of neurotoxicity) lasting more than 7 days or if paresthesia without functional disorders persists until the next cycle, the subsequent dose of Oxaliplatin-Ebeve should be reduced from 85 mg/m2 to 65 mg/m2 (in the treatment of metastatic cancer) or to 75 mg / m2 (in adjuvant therapy). If paresthesia with functional disorders persists until the next cycle, Oxaliplatin-Ebeve should be discontinued; if the severity of neurotoxicity symptoms decreases after oxaliplatin is discontinued, you can consider resuming treatment.

With the development of stomatitis and / or mucositis of the 2nd or higher degree of toxicity, treatment with Oxaliplatin-Ebeve should be suspended until they stop or reduce the manifestations of toxicity to the 1st degree.

Patients with impaired renal function

Do not use the drug in patients with severe renal impairment. Due to limited data on 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 careful monitoring of renal function. In patients with mild renal impairment, no dose adjustment of oxaliplatin is required.

Patients with impaired liver function

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

Elderly patients

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

Rules for preparation and use of the solution

When preparing and administering oxaliplatin, do not use needles or other equipment containing aluminum.

Before use, the drug is dissolved in water for injection or in a 5% dextrose solution, obtaining a solution with a concentration of 5 mg / ml of oxaliplatin (10 ml of solvent is introduced into a 50 mg bottle,20 ml of solvent is introduced into a 100 mg bottle). The drug recovered in this way is immediately diluted with 250-500 ml of a 5% dextrose solution. The concentration of the resulting oxaliplatin solution should be from 200 mcg / ml to 700 mcg / ml, with 700 mcg / ml being the highest concentration used in clinical practice at a dose of 85 mg / m2.

To prepare a solution of the drug, only the recommended solvents should be used.

Do not use the drug undiluted.

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

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

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

The solution of the drug for infusions is recommended to be used immediately after preparation. The reconstituted infusion solution remains stable for 24 hours at room temperature (no higher than 25°C).

The prepared solution of the drug should be transparent and should not contain undissolved particles. The solution with signs of precipitation must be destroyed.

In case of extravasation, the drug should be discontinued immediately.

Overdose

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

Treatment: hematological control and symptomatic therapy. The antidote to oxaliplatin is not known.

Special instructions

Oxaliplatin-Ebeve should only be used under the supervision of an oncologist who has experience with anticancer drugs.

Regularly (once a week), as well as before each use of the drug, it is necessary to monitor the formed elements of peripheral blood and indicators of kidney and liver function.

Before starting 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 maintaining symptoms of peripheral sensory neuropathy after the end of treatment. Localized moderate paresthesias with functional disorders may persist for up to 3 years after the end of the drug use according to the adjuvant therapy scheme.

Reverse posterior leukoencephalopathy (NWOL) syndrome 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 NWOL are headache, dizziness, nausea, vomiting, epileptic seizures, behavioral disorders, disorders of consciousness (from drowsiness to coma) and visual disturbances in the form of hemianopsia, scotoma, cortical blindness. Since SPD is a potentially life-threatening neurological syndrome and, if not treated promptly, can be complicated by the development of a massive cerebral infarction, its early diagnosis is especially important to determine the correct treatment of patients. Diagnosis of SPD is based on brain imaging using computer or magnetic resonance imaging.

If respiratory symptoms appear (dry cough, dyspnoea, wheezing, or detection of pulmonary infiltrates during X-ray examination), treatment with Oxaliplatin-Ebev should be suspended until the presence of interstitial pneumonitis is excluded.

For the prevention and treatment of gastrointestinal symptoms such as nausea and vomiting, the use of antiemetic drugs is indicated. Symptoms such as dehydration, paralytic ileus, intestinal 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 properly informed about the risk of developing diarrhea/vomiting, mucositis/stomatitis and neutropenia when using oxaliplatin and 5-fluorouracil, as well as the need to contact their doctor if these undesirable effects occur for appropriate correction of therapy.

If liver dysfunction is detected or portal hypertension occurs, which is not associated with the presence of liver metastases, in very rare cases, drug-induced disorders of the liver vascular bed may occur, namely, the development of obliterating endophlebitis of the hepatic veins.

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

In the event of an anaphylactic reaction to Oxaliplatin-Ebeve, the infusion should be stopped immediately and appropriate symptomatic treatment should be prescribed. 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 initiated. The remaining dose of the drug should be injected into another vein.

Women and men should use reliable methods of contraception during treatment and for 6 months after the end of Oxaliplatin-Ebeve therapy. Since oxaliplatin has a genotoxic effect that can be irreversible, men who want to have children are advised to consider preserving sperm 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 wash the skin thoroughly with soap and water or sodium bicarbonate solution; in case of contact with the eyes-pull back the eyelids and wash the eye (s) with plenty of water for 15 minutes.

Drug residues and all tools and materials that were used to prepare the solution for intravenous infusion of Oxaliplatin-Ebeve should be disposed of in accordance with the standard hospital procedure for the disposal of cytotoxic substance waste, taking into account the current regulations for the disposal of hazardous waste.

Influence on the ability to drive vehicles and other mechanisms that require increased concentration of attention

No studies have been conducted on the effect of Oxaliplatin-Ebeve on the ability to drive a car or work with mechanisms.

Side effects such as dizziness, nausea, vomiting, transient vision loss, and other neurological symptoms may affect the ability to engage in potentially dangerous activities that require increased concentration and speed of psychomotor reactions to varying degrees.

Form of production

Lyophilizate for infusion solution preparation

Storage conditions

At a temperature not exceeding 25 °C

Shelf life

3 years

Active ingredient

Oxaliplatin

Conditions of release from pharmacies

By prescription

Dosage form

solution for infusions

Purpose

For adults as directed by your doctor

Indications

Cancer