Oxol

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT OXOL (OXOL)

Composition:

Active ingredient: 1 ml of solution contains oxaliplatin 2 mg;

Excipient: water for injections.

Pharmaceutical form. Solution for injection.

Main physicochemical properties: clear, colorless solution.

Pharmacotherapeutic group. Antineoplastic agents. Platinum compounds. Oxaliplatin. ATC code L01XA03.

Pharmacological Properties

Pharmacodynamics

Oxaliplatin is an antineoplastic agent belonging to a new class of platinum compounds in which the platinum atom forms a complex with 1,2-diaminocyclohexane (DACH) and oxalate.

Oxaliplatin is a single enantiomer: cis-[(1R,2R)-1,2-diaminocyclohexane-N,N'] oxalato(2-)-O,O'] platinum.

Oxaliplatin demonstrates a broad spectrum of both in vitro cytotoxicity and in vivo antitumor activity in various tumor models, including human colorectal cancer models. Oxaliplatin also shows in vitro and in vivo activity against various cell lines resistant to cisplatin.

A synergistic cytotoxic effect has been observed in vitro and in vivo when oxaliplatin is combined with 5-fluorouracil (5-FU).

Studies on the mechanism of action, although not yet fully elucidated, indicate that aqueous derivatives formed during the biotransformation of oxaliplatin interact with DNA by forming intra-strand and inter-strand cross-links. This disrupts DNA synthesis, leading to cytotoxic and antitumor effects.

Pharmacokinetics

Distribution and Metabolism. In vivo, oxaliplatin undergoes rapid biotransformation and is no longer detectable in plasma ultrafiltrate by the end of a 2-hour infusion at a dose of 130 mg/m². At this time, 15% of the administered dose remains in the blood, while the remaining 85% is rapidly distributed into tissues (or excreted in urine). Platinum binds to plasma albumin.

In vitro biotransformation occurs via non-enzymatic degradation. There is no evidence of metabolism of the diaminocyclohexane (DACH) ring by cytochrome P450.

Oxaliplatin undergoes extensive biotransformation and is not detectable in unchanged form in plasma ultrafiltrate by the end of the 2-hour infusion. Later, several cytotoxic metabolites have been detected in systemic circulation, including mono-chloro, di-chloro, and di-aquo derivatives of DACH-platinum, along with some inactive conjugates.

Platinum is primarily excreted in urine within the first 48 hours after administration. By day five, approximately 54% of the total dose is recovered in urine and less than 3% in feces.

Pharmacokinetics in Special Clinical Situations

A significant reduction in clearance from 17.55 ± 2.18 L/h to 9.95 ± 1.91 L/h was observed in patients with renal impairment, along with a statistically significant decrease in volume of distribution from 330 ± 40.9 L to 241 ± 36.1 L. The impact of severe renal impairment on platinum clearance has not been studied.

Clinical characteristics.

Indications. In combination with 5-fluorouracil and folinic acid, oxaliplatin is recommended for:

• adjuvant treatment of stage III colorectal cancer (Duke's stage C) following complete resection of the primary tumor;
• treatment of metastatic colorectal cancer.

Contraindications. The medicinal product should not be used in patients:

• with hypersensitivity to oxaliplatin or to any of the excipients in their medical history;
• during breastfeeding;
• with myelosuppression (neutrophil count < 2×10⁹/L and/or platelet count < 100×10⁹/L) prior to the first treatment cycle;
• with peripheral sensory neuropathy associated with functional impairments prior to the first treatment cycle;
• with severe renal impairment (creatinine clearance < 30 mL/min) (see section "Pharmacological properties. Pharmacodynamics").

Special safety precautions.

Renal function impairment. Patients with mild to moderate renal impairment should be closely monitored for adverse reactions, and the dose should be adjusted according to the level of toxicity (see section "Pharmacological Properties. Pharmacodynamics").

Hypersensitivity reactions. Special careful monitoring is required for patients with a history of allergy to other platinum-containing drugs. In case of anaphylactic reactions during infusion, administration of the drug must be immediately discontinued and appropriate symptomatic treatment initiated. Re-administration of oxaliplatin to such patients is contraindicated. Cases of cross-reactions with all platinum compounds, sometimes resulting in fatal outcomes, have been reported.

In case of drug extravasation, infusion should be immediately stopped and standard local symptomatic treatment initiated.

Neurological symptoms. Neurological toxicity of oxaliplatin should be carefully monitored, especially when used in combination with medicinal products known to cause specific neurological toxicity. A neurological examination of the patient should be performed before each administration and periodically thereafter.

Patients who develop acute pharyngolaryngeal dysesthesia during or within several hours after completion of the two-hour infusion (see section "Adverse Reactions") should receive the next dose no sooner than 6 hours after the previous one. To prevent such dysesthesia, patients should be informed about the necessity to avoid cold exposure and swallowing cold/fresh food and/or drinks for several hours after drug administration.

Peripheral neuropathy. If neurological symptoms (paresthesia, dysesthesia) occur, dose adjustment of oxaliplatin should be based on the duration and severity of these symptoms:

• if symptoms persist for more than 7 days and are bothersome to the patient, the next dose of oxaliplatin should be reduced by 25%;
• if paresthesia without functional impairment persists until the next treatment cycle, the next dose of oxaliplatin should be reduced by 25%;
• if paresthesia with functional impairment persists until the next cycle, oxaliplatin treatment should be discontinued;
• if these symptoms resolve after discontinuation of oxaliplatin, re-initiation of treatment may be considered.

Patients should be informed that symptoms of sensory peripheral neuropathy may persist after treatment discontinuation. Mild localized paresthesia or paresthesia that may interfere with functional activity can persist for more than 3 years after completion of adjuvant therapy.

Reversible posterior leukoencephalopathy syndrome (RPLS). Cases of reversible posterior leukoencephalopathy syndrome (RPLS, also known as posterior reversible encephalopathy syndrome — PRES) have been reported in patients receiving oxaliplatin as part of combination chemotherapy. RPLS is a rare, rapidly developing reversible neurological disorder that may present with seizures, arterial hypertension, headache, confusion, blindness, and other visual and neurological disturbances (see section "Adverse Reactions"). Diagnosis of RPLS is confirmed by brain imaging techniques, preferably MRI (magnetic resonance imaging).

Nausea, vomiting, diarrhea, dehydration, and hematological changes. Gastrointestinal toxicity of oxaliplatin, manifesting as nausea and vomiting, requires the use of antiemetic agents for prophylactic and/or therapeutic purposes (see section "Adverse Reactions").

Severe diarrhea and/or vomiting may lead to dehydration, paralytic ileus, intestinal obstruction, hypokalemia, metabolic acidosis, and renal dysfunction, especially when oxaliplatin is used in combination with 5-fluorouracil.

Cases of intestinal ischemia, including fatal cases, have been reported with the use of oxaliplatin. In case of intestinal ischemia, oxaliplatin must be discontinued and appropriate treatment initiated (see section "Adverse Reactions").

In case of hematological toxicity (neutrophil count <1.5×10⁹/L or platelet count <50×10⁹/L), the start of the next treatment cycle should be delayed until acceptable hematological parameters are restored. Complete blood count with differential leukocyte count should be performed before initiation of oxaliplatin therapy and prior to each subsequent cycle. Myelosuppressive effects of the drug may be enhanced by concomitantly administered chemotherapeutic agents. Patients with severe and persistent myelosuppression are at high risk of infectious complications. Cases of sepsis, neutropenic sepsis, and septic shock, including fatal cases, have been observed in patients receiving oxaliplatin (see section "Adverse Reactions"). Oxaliplatin should be discontinued in case of any of these events.

Patients should be informed that in case of diarrhea/vomiting, mucositis/stomatitis, or neutropenia occurring after administration of oxaliplatin and 5-fluorouracil, they should immediately contact their physician for appropriate management of these symptoms.

In case of mucositis/stomatitis, with or without neutropenia, the next administration of oxaliplatin should be postponed until signs of mucositis/stomatitis subside to Grade I or lower and/or until neutrophil count exceeds 1.5×10⁹/L. When oxaliplatin is combined with 5-fluorouracil (with or without folinic acid), dose adjustments of 5-fluorouracil are usually recommended due to its toxicity.

In cases of WHO Grade IV diarrhea, Grade III–IV neutropenia (neutrophil count <1×10⁹/L), febrile neutropenia (fever of unknown origin without clinically or microbiologically confirmed infection and absolute neutrophil count <1.0×10⁹/L), single temperature elevation >38.3°C or persistent temperature elevation >38°C for more than 1 hour, or Grade III–IV thrombocytopenia (platelet count <50×10⁹/L), the dose of oxaliplatin should be reduced by 25% along with dose reduction of 5-fluorouracil.

Pulmonary manifestations. In case of respiratory symptoms of unknown etiology such as non-productive cough, dyspnea, crackles, or pulmonary infiltrates on chest X-ray, oxaliplatin treatment should be discontinued until interstitial pneumonitis is ruled out by additional pulmonary investigations (see section "Adverse Reactions").

Blood disorders. Hemolytic-uremic syndrome (HUS) is a life-threatening adverse reaction (frequency not known). Oxaliplatin should be discontinued at the first signs suggestive of microangiopathic hemolytic anemia, such as rapid decrease in hemoglobin level accompanied by thrombocytopenia or increased levels of bilirubin, creatinine, blood urea, or lactate dehydrogenase (LDH). Renal failure may become irreversible after drug discontinuation and may require dialysis.

Cases of disseminated intravascular coagulation (DIC), including fatal cases, have been reported with oxaliplatin treatment. In case of DIC, oxaliplatin must be discontinued and appropriate treatment initiated (see section "Adverse Reactions"). Patients with conditions predisposing to DIC, such as infections, sepsis, etc., require special careful monitoring.

QT interval prolongation. Prolongation of the QT interval increases the risk of ventricular arrhythmias, including polymorphic ventricular tachycardia (torsade de pointes), which may be fatal (see section "Adverse Reactions"). Careful periodic monitoring of the QT interval before and after oxaliplatin administration is required. Special monitoring is indicated for patients with a history of QT prolongation or predisposition to QT prolongation, patients taking medicinal products capable of prolonging the QT interval, and patients with electrolyte imbalances such as hypokalemia, hypocalcemia, or hypomagnesemia.

Rhabdomyolysis. Cases of rhabdomyolysis, including fatal cases, have been reported in patients receiving oxaliplatin. Oxaliplatin must be discontinued in case of muscle pain and swelling combined with weakness, fever, or darkening of urine. Appropriate treatment should be initiated if rhabdomyolysis is confirmed. Special careful monitoring is recommended when oxaliplatin is used concomitantly with medicinal products associated with rhabdomyolysis (see sections "Interaction with Other Medicinal Products and Other Forms of Interaction" and "Adverse Reactions").

Gastrointestinal ulceration / bleeding and gastrointestinal ulcer perforation. Oxaliplatin treatment may lead to gastrointestinal ulceration and complications such as gastrointestinal bleeding and perforation, which may be fatal. In case of gastrointestinal ulceration, oxaliplatin must be discontinued and appropriate treatment initiated (see section "Adverse Reactions").

Hepatic manifestations. In case of liver function abnormalities in laboratory tests, splenomegaly, or portal hypertension not caused by liver metastases, the possibility of rare drug-induced vascular disorders in the liver should be considered.

Pregnancy. For use during pregnancy, see section "Use During Pregnancy or Breastfeeding".

Fertility. Genotoxic effects of oxaliplatin have been observed in preclinical studies. Men are advised to use effective contraception throughout the entire period of oxaliplatin treatment and for 6 months after treatment discontinuation, and to consult about the possibility of sperm cryopreservation before starting therapy, as oxaliplatin may cause irreversible infertility. Women should avoid pregnancy during treatment and use a reliable method of contraception (see section "Use During Pregnancy or Breastfeeding").

Other precautions. Peritoneal hemorrhage may occur if oxaliplatin is administered by intraperitoneal route (which is not the route recommended in the product instructions).

Interaction with Other Medicinal Products and Other Forms of Interaction.

In patients who received a single dose of oxaliplatin 85 mg/m² immediately before 5-fluorouracil, no changes in the pharmacological effect of 5-fluorouracil were observed.

In vitro studies showed no significant displacement of oxaliplatin bound to plasma proteins by the following medicinal products: erythromycin, salicylates, granisetron, paclitaxel, and sodium valproate.

Caution is required and careful monitoring of the QT interval is necessary when oxaliplatin is used concomitantly with other medicinal products capable of prolonging the QT interval (see section "Special Precautions"). Caution is also recommended when oxaliplatin is used concomitantly with other medicinal products associated with rhabdomyolysis (see section "Special Precautions").

Special precautions for use.

Use during pregnancy or breastfeeding.

Pregnancy. There is currently no information available regarding the safety of oxaliplatin use for treatment in pregnant women. Reproductive toxicity has been observed in animal studies.

Therefore, oxaliplatin is not recommended during pregnancy and in women of childbearing potential who are not using contraception.

The decision to administer oxaliplatin to a pregnant woman may be considered only after clearly informing the patient about the potential risks to the fetus and obtaining her informed consent.

Patients must use appropriate contraceptive measures during treatment. Such precautions should continue after completion of treatment: for 4 months in women and for 6 months in men.

Fertility. Oxaliplatin may have a negative effect on fertility. Due to the potential genotoxic effects of oxaliplatin, appropriate contraceptive methods should be used during treatment and for 4 months after treatment in women and 6 months in men.

Breastfeeding. Excretion of oxaliplatin into breast milk has not been studied. Breastfeeding is contraindicated during oxaliplatin treatment.

Ability to influence reaction speed when driving or operating machinery.
The effect of the drug on the ability to drive or operate machinery has not been studied. However, since oxaliplatin administration may increase the risk of dizziness, nausea, vomiting, and other neurological symptoms affecting gait and balance, treatment may have a minor or moderate influence on the ability to drive or operate machinery.

Impairments in vision, including temporary loss of vision (which resolves after discontinuation of therapy), may also affect patients' ability to drive or operate machinery. Therefore, patients should be warned about the possible impact of these effects on their ability to drive or operate machinery.

Method of Administration and Dosage.

The medicinal product is intended only for treatment of adults.

The recommended dose of oxaliplatin for adjuvant therapy is 85 mg/m² administered intravenously, repeated every two weeks for 12 cycles (6 months).

The recommended dose of oxaliplatin for the treatment of metastatic colorectal cancer is 85 mg/m² administered intravenously, repeated every two weeks until disease progression or until signs of unacceptable toxicity occur.

The dose should be adjusted according to individual patient tolerability (see section "Special Precautions").

Oxaliplatin should always be administered before fluoropyrimidines, for example prior to 5-fluorouracil administration.

Oxaliplatin should be administered as a 2–6 hour intravenous infusion, diluted in 250–500 mL of 5 % glucose solution to achieve a concentration between 0.2 mg/mL and 0.7 mg/mL; 0.7 mg/mL corresponds to the highest concentration used clinically with an oxaliplatin dose of 85 mg/m².

Oxaliplatin is preferably administered in combination with continuous infusion of 5-fluorouracil.

For a treatment regimen repeated every two weeks, a dosing schedule involving bolus administration of 5-fluorouracil followed by continuous infusion of 5-fluorouracil is recommended.

Special Patient Populations.

Renal impairment. Oxaliplatin is contraindicated in patients with severe renal impairment (see sections "Contraindications" and "Pharmacological Properties. Pharmacodynamics").

For patients with mild to moderate renal impairment, the recommended dose of oxaliplatin is 85 mg/m² (see sections "Special Precautions" and "Pharmacological Properties. Pharmacodynamics").

Hepatic impairment. In a phase I study involving patients with varying degrees of hepatic impairment, the frequency and severity of hepatobiliary disorders were related to disease progression and pre-existing liver function abnormalities.

No specific dose adjustments were made in clinical trials for patients with impaired liver function.

Elderly patients. No increase in oxaliplatin toxicity has been observed when administered as monotherapy or in combination with 5-fluorouracil in patients over 65 years of age. Therefore, no special dose adjustment is necessary for elderly patients.

Children. There are no established indications for the use of oxaliplatin in children. The efficacy of oxaliplatin as monotherapy in children with solid tumors has not been established (see section "Pharmacological Properties").

Method of Administration.

Oxaliplatin must be diluted prior to administration. Only the recommended diluent – 5 % glucose solution – should be used for reconstitution and preparation of the infusion solution.

Oxaliplatin should be administered as an intravenous infusion. Administration of the medicinal product does not require hyperhydration.

Oxaliplatin diluted in 250–500 mL of 5 % glucose solution to achieve a concentration of at least 0.2 mg/mL should be administered via central or peripheral vein over 2–6 hours.

Infusion of oxaliplatin should always precede infusion of 5-fluorouracil.

If extravasation occurs at the injection site, administration of the drug should be immediately discontinued.

Instructions for Use and Disposal. Precautions must be taken when preparing oxaliplatin solutions, as with other potentially toxic substances.

Handling this cytotoxic agent requires healthcare personnel to take all necessary precautions to ensure worker and environmental safety.

Preparation of injectable solutions of cytotoxic agents should be performed by experienced personnel familiar with the handling procedures for such medicinal products, under conditions ensuring protection of the environment and, above all, of the personnel handling these agents. A designated area for preparation must be available. Smoking, eating, or drinking is prohibited in this area.

Personnel must be provided with appropriate materials for handling the medicinal product, including medical gowns with long sleeves, protective masks, head covers, protective goggles, sterile disposable gloves, protective coverings for work surfaces, and containers and bags for waste collection.

Particular caution is required when handling patient excreta and vomitus.

Pregnant women should be advised to avoid handling cytotoxic agents.

Any damaged packaging should be handled with these precautions and considered contaminated waste. Contaminated waste must be incinerated in rigid, sealed containers with appropriate labeling (see subsection "Disposal" below).

If the reconstituted oxaliplatin solution, reconstituted solution, or infusion solution comes into contact with the skin, the affected area should be immediately and thoroughly washed with water.

If the reconstituted oxaliplatin solution, reconstituted solution, or infusion solution comes into contact with mucous membranes, the affected area should be immediately and thoroughly washed with water.

Special Warnings for Administration.

• Never administer the medicinal product in undiluted form.
• Use only the recommended diluents.

Administration with Folinic Acid (Sodium Folinate or Calcium Folinate).

Intravenous infusion of oxaliplatin 85 mg/m² in 250–500 mL of 5 % glucose solution is administered simultaneously with intravenous infusion of folinic acid in 5 % glucose solution. The infusion lasts from 2 to 6 hours and is delivered via a Y-type infusion system with a side arm located immediately before the infusion site.

These two medicinal products must not be mixed in the same infusion bag. Folinic acid must not contain trometamol as an excipient. It should be diluted only with 5 % glucose solution and must never be diluted with alkaline solutions, sodium chloride, or chloride-containing solutions.

Administration with 5-Fluorouracil.

Oxaliplatin should always be administered before fluoropyrimidines, for example prior to 5-fluorouracil administration.

After oxaliplatin infusion, the infusion line must be flushed before administering 5-fluorouracil.

For additional information regarding medicinal products that can be combined with oxaliplatin, refer to the general product characteristics provided by the respective manufacturer.

Infusion Solution. Perform visual inspection before administration. Only clear, particle-free solutions should be used.

The medicinal product is intended for single use only. Any unused solution must be destroyed.

Dilution Prior to Infusion. Withdraw the required amount from the vial and dilute in 250–500 mL of 5 % glucose solution to achieve an oxaliplatin concentration between 0.2 mg/mL and 0.7 mg/mL. Physical and chemical stability of oxaliplatin has been demonstrated at concentrations from 0.2 mg/mL to 2 mg/mL.

Administer as an intravenous infusion.

After dilution with 5 % glucose solution, physicochemical stability of the solution is maintained for 48 hours at 2–8 °C or 24 hours at 25 °C.

However, from a microbiological standpoint, the prepared solution should be used immediately.

If the solution is not administered immediately after preparation, responsibility for storage conditions and duration rests solely with the healthcare professional administering it. The storage period must not exceed 24 hours at 2–8 °C, provided dilution was performed under aseptic conditions in controlled and standardized environments.

Infusion solution should be used immediately.

The medicinal product is intended for single use only. Any unused solution must be destroyed.

Perform visual inspection of the solution before administration. Only clear, particle-free solutions should be used.

Do not use chloride-containing solutions or sodium chloride solution for dilution.

Compatibility of the oxaliplatin infusion solution has been tested with standard PVC infusion sets.

Infusion. Administration of oxaliplatin does not require prehydration. Oxaliplatin diluted in 250–500 mL of 5 % glucose solution to achieve a concentration of at least 0.2 mg/mL should be administered via peripheral or central vein over 2–6 hours. When oxaliplatin is used in combination with 5-fluorouracil, oxaliplatin infusion must precede 5-fluorouracil administration.

Disposal. Residual medicinal product and all materials used for reconstitution and administration of oxaliplatin must be destroyed according to standard procedures for disposal of cytotoxic waste, in accordance with applicable regulations for toxic waste disposal.

Children. The medicinal product is intended for use in adults only. There are no established indications for the use of oxaliplatin in children. The efficacy of oxaliplatin as monotherapy in children with solid tumors has not been established (see section "Pharmacological Properties").

Overdose.

There is no known antidote for oxaliplatin. In case of overdose, an increase in the severity of adverse effects may be expected. Hematological monitoring should be performed, along with symptomatic treatment of other signs of intoxication.

Adverse reactions

During combination therapy with oxaliplatin and 5-fluorouracil/folinic acid (5-FU/FA), gastrointestinal adverse effects (diarrhea, nausea, vomiting, and mucositis), hematological disorders (neutropenia, thrombocytopenia), and neurological syndromes (acute and dose-dependent sensory peripheral neuropathy) were most frequently observed. These adverse effects were generally more frequent and more severe with the combination of oxaliplatin and 5-FU/FA than with 5-FU/FA therapy alone.

The adverse effects listed in Table 1 were observed during clinical trials and reported from post-marketing experience.

The frequency of adverse effects listed in Table 7 was determined using the following criteria: very common (> 1/10), common (>1/100, <1/10), uncommon (> 1/1,000, <1/100), rare (> 1/10,000, <1/1,000), very rare (> 1/10,000), unknown (cannot be estimated based on available data).

Table 1

* See details below.

** See section "Special safety precautions".

*** Microangiopathic hemolytic anemia associated with hemolytic-uremic syndrome (HUS), or hemolytic anemia with positive Coombs test (see section "Special safety precautions").

• Septic neutropenia, including fatal cases, is frequently observed.

++ Very common allergic/allergic-type reactions, mostly occurring during infusion and sometimes resulting in death. Frequent allergic reactions include skin rash (particularly urticaria), conjunctivitis, and rhinitis. Anaphylactic reactions including bronchospasm, angioedema, arterial hypotension, chest pain, and anaphylactic shock or anaphylactoid reactions have been reported. Hypersensitivity reactions of delayed type, occurring several hours or even days after infusion, have also been reported.

+++ Fever and chills (shivering) are very commonly observed, either of infectious origin (with or without febrile neutropenia) or possibly of immunological origin.

++++ Injection site reactions have been observed, including localized pain, redness, swelling, and thrombosis. Extravasation may also cause local pain and inflammation, which can be severe and lead to complications, including necrosis, especially with intravenous infusion of oxaliplatin into a peripheral vein (see section "Special safety precautions").

Disorders of the blood and lymphatic system.

Table 2

Incidence of adverse reactions in patients (%), by grade

Rare (>1/10,000, <1/1,000): disseminated intravascular coagulation (DIC), including fatal cases (see section "Special precautions").

Adverse reactions observed during the post-marketing period (frequency unknown): hemolytic uremic syndrome; autoimmune pancytopenia; pancytopenia; secondary leukemia.

Infectious and parasitic diseases.

Frequency of adverse reactions in patients (%), by grades

Table 3

Adverse reactions observed in the post-marketing period (frequency unknown): septic shock, including fatal cases.

Immune system disorders.

Table 4

Adverse reactions observed during the post-marketing period (with unknown frequency): delayed-type hypersensitivity reactions.

Nervous system disorders. Neurological toxicity of oxaliplatin is dose-dependent. It primarily manifests as sensory peripheral neuropathies characterized by dysesthesia and/or paresthesia of the extremities, with or without associated muscle spasms, often triggered by cold. These symptoms occur in approximately 95% of patients receiving treatment. The duration of these symptoms, which usually regress between treatment cycles, increases with the number of treatment cycles administered.

Depending on the duration of symptoms such as pain and/or functional impairment (see section "Dosage and Administration"), dose adjustments or even discontinuation of treatment may be necessary. Functional impairment, such as difficulty performing fine motor tasks, may result from sensory dysfunction. The risk of developing persistent symptoms with a cumulative dose of approximately 850 mg/m² (i.e., 10 cycles) is about 10%, and with a cumulative dose of 1020 mg/m² (i.e., 12 cycles) – approximately 20%.

In most cases, neurological symptoms show positive progression or complete resolution at the time of treatment discontinuation.

Six months after completion of adjuvant therapy for colorectal cancer, 87% of patients had no symptoms or only mild symptoms. After 3 years or more, approximately 3% of patients experienced either persistent localized moderate paresthesia (2.3%) or paresthesia interfering with functional activity (0.5%).

Acute neurosensory disturbances have been reported. These symptoms occur within several hours after drug administration, often triggered by exposure to cold. They are characterized by transient paresthesia, dysesthesia, and hypoesthesia. This acute pharyngolaryngeal dysesthesia syndrome, estimated to occur in 1–2% of patients, is characterized by subjective sensations of dysphagia or dyspnea / throat tightness, without objective signs of respiratory distress syndrome (no cyanosis or hypoxia), laryngospasm, or bronchospasm (without stridor or wheezing).

Although antihistamines and bronchodilators have been administered in such cases, these symptoms resolve rapidly even without treatment. Prolonging the infusion duration in subsequent cycles reduces the frequency of this syndrome (see section "Dosage and Administration").

Other observed symptoms include jaw spasms, muscle spasms, involuntary muscle contractions, myoclonus, coordination disturbances, gait disturbances, ataxia, balance disorders, throat or chest tightness, depression, discomfort, and pain. Additionally, cranial nerve damage may occur either simultaneously or separately, presenting as eyelid ptosis, diplopia, aphonia, dysphonia, hoarseness (sometimes referred to as vocal cord paralysis), tongue dysesthesia, or dysarthria (sometimes referred to as aphasia), trigeminal neuralgia, facial or ocular pain, decreased visual acuity, or visual field disturbances.

Other neurological symptoms such as dysarthria, loss of deep tendon reflexes, and Lhermitte's sign have been observed during oxaliplatin treatment. Isolated cases of optic neuritis have also been reported.

Adverse reactions observed during the post-marketing period (with unknown frequency): seizures, ischemic and hemorrhagic cerebrovascular events. Falls are common.

Cardiac disorders. Adverse reactions observed during the post-marketing period (with unknown frequency): QT interval prolongation, which may lead to ventricular arrhythmias, including polymorphic ventricular tachycardia (torsade de pointes), potentially resulting in fatal outcomes (see section "Dosage and Administration"). Frequency unknown: acute coronary syndrome, including myocardial infarction, coronary artery spasm, and angina in patients receiving oxaliplatin in combination with 5-FU or bevacizumab.

Respiratory, thoracic and mediastinal disorders. Adverse reactions observed during the post-marketing period (with unknown frequency): laryngospasm; pneumonia and bronchopneumonia, including fatal cases.

Gastrointestinal disorders.

Table 5

Frequency of adverse reactions in patients (%), by grade

Treatment or prophylactic administration of potent antiemetic agents is indicated.

Severe diarrhea/vomiting may lead to dehydration, paralytic ileus, intestinal obstruction, hypokalemia, metabolic acidosis, and renal failure, particularly when oxaliplatin is used in combination with 5-fluorouracil.

Adverse reactions observed during the post-marketing period (frequency unknown): intestinal ischemia, including fatal cases (see section "Special precautions"), esophagitis.

Gastrointestinal ulcers and perforations, which may be fatal (see section "Special precautions").

Hepatobiliary disorders. Very rare (≤1/10,000): sinusoidal obstruction syndrome, also known as veno-occlusive liver disease, or related pathological changes including peliosis hepatis, nodular regenerative hyperplasia, and perisinusoidal fibrosis. Clinical manifestations may include portal hypertension and/or elevated transaminase levels.

Disorders of the musculoskeletal system and connective tissue. Adverse reactions observed during the post-marketing period (frequency unknown): rhabdomyolysis, including fatal cases (see section "Special precautions").

Renal and urinary disorders. Very rare (≤1/10,000): acute tubular necrosis, acute interstitial nephritis, and acute renal failure.

Skin and subcutaneous tissue disorders. Adverse reactions observed during the post-marketing period (frequency unknown): leukocytoclastic vasculitis.

Shelf life. 2 years.

Storage conditions.

Store at a temperature not exceeding 25 °C, protected from light and out of reach of children. Do not freeze.

Incompatibilities.

Do not mix the diluted preparation with other medicinal products in the same vial or infusion system unless specified in the instructions for medical use.

Do not administer simultaneously with alkaline medicinal products or solutions (especially 5-fluorouracil, alkaline solutions, tromethamine, and medicinal products containing folic acid and tromethamine as excipients).

Alkaline solutions and preparations negatively affect the stability of oxaliplatin.

Do not dilute with saline solutions containing chlorides (including Ca, K, and Na chlorides).

Do not mix with other medicinal products in the same infusion vial or intravenous administration system.

Do not use injectable preparations containing aluminum.

Packaging.

25 ml or 50 ml of solution in a vial. 1 vial per cardboard box.

Prescription category. Prescription only.

For hospital use only by oncology specialists.

Manufacturer.

Venus Remedies Limited.

Manufacturer's address and place of business.

Hill Top Industrial Estate, Jharmajri, ERIP Phase-I (Ext.), Battoli Kalan, Baddi, Solan District, Himachal Pradesh 173205, India.