Oxaliplatin accord

INSTRUCTIONS for medical use of the medicinal product Oxaliplatin Accord (OxaliplatinAccord)

Composition:

Active substance: oxaliplatin;

1 ml of concentrate contains 5 mg of oxaliplatin;

Excipient: water for injections.

Pharmaceutical form. Concentrate for solution for infusion.

Main physicochemical properties: clear, colourless solution in a transparent glass vial. The solution should be practically free from visible mechanical particles when inspected visually.

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

Synergistic cytotoxic effects have been observed in vitro and in vivo when oxaliplatin is combined with 5-fluorouracil (5-FU).

Although the mechanism of action is not fully understood, studies suggest that aqueous derivatives formed during the biotransformation of oxaliplatin interact with DNA by forming intra- and inter-strand cross-links. This disrupts DNA synthesis, leading to cytotoxic and antitumor effects.

The efficacy of oxaliplatin (at a dose of 85 mg/m² every 2 weeks) in combination with 5-fluorouracil/folinic acid (5-FU/FA) in patients with metastatic colorectal cancer has been demonstrated in three clinical trials:

• In the EFCT2962 study, a comparative Phase III first-line therapy trial was conducted, in which 420 patients were randomized into two groups: those receiving 5-FU/FA alone (LV5FU2, N=210) and those receiving the combination of oxaliplatin with 5-FU/FA (FOLFOX4, N=210);
• In the EFCT4584 study, a comparative Phase III trial involving 821 patients previously treated with the combination of irinotecan (CPT-11) and 5-FU/FA and refractory to this regimen, patients were randomized into three groups: 5-FU/FA alone (LV5FU2, N=275), oxaliplatin alone (N=275), and the combination of oxaliplatin with 5-FU/FA (FOLFOX4, N=271);
• In the EFCT2964 study, a Phase II single-arm trial without a control group, patients previously treated and refractory to 5-FU/FA alone received combination therapy with oxaliplatin and 5-FU/FA (FOLFOX4, N=57).

Two randomized clinical trials—EFCT2962 in first-line treatment and EFCT4584 in previously treated patients—demonstrated significantly higher response rates and prolonged progression-free survival (PFS) or time to progression (TTP) compared to monotherapy with 5-FU/FA.

In the EFCT4584 trial, which included previously treated and refractory patients, the difference in median overall survival (OS) between the oxaliplatin plus 5-FU/FA combination group and the control groups did not reach statistical significance.

Table 1

Response rates with the FOLFOX4 regimen compared to the LV5FU2 regimen

* NA – not applicable.

Table 2

Median progression-free survival (PFS)/median time to progression (TTP): FOLFOX4 regimen compared with LV5FU2 regimen

• NA – not applicable.

Table 3

Median overall survival (OS): comparison of FOLFOX4 regimen with LV5FU2 regimen

* NA – not applicable.

Among patients who had disease symptoms at baseline and had previously received anticancer therapy (EF34584), a statistically significant improvement in symptoms was observed more frequently in the group receiving oxaliplatin with 5-FU/FA than in the group receiving 5-FU/FA alone (27.7% vs. 14.6%, p≤0.0033).

In patients who had not received prior treatment (EFC2962), no statistically significant differences between the two groups were observed for any of the quality-of-life parameters.

However, quality-of-life parameters reflecting general health status and presence or absence of pain were generally better in the control group and worse in the group receiving oxaliplatin, due to nausea and vomiting.

In the context of adjuvant therapy assignment during the phase III comparative MOSAIC study (EFC3313), 2246 patients were randomized into treatment groups (899 patients with stage II disease (Duke’s B2) and 1347 patients with stage III disease (Duke’s C)) following complete resection of primary colorectal cancer tumor, to receive either 5-FU/FA (LV5FU2, N=1123 (B2/C)=448/675) or combination therapy with oxaliplatin and 5-FU/FA (FOLFOX4, N=1123 (B2/C)=451/672).

Table 4

EFC3313: 3-year disease-free survival (ITT analysis)* for the overall patient population

* Median follow-up after completion of treatment was 44.2 months (all patients were followed for at least 3 years after completion of treatment).

The study demonstrated a significant overall benefit in 3-year disease-free survival with the combination therapy of oxaliplatin and 5-FU/FA (FOLFOX4) compared to 5-FU/FA (LV5FU2) therapy.

Table 5

EFC3313: 3-year disease-free survival (ITT analysis)* by disease stage

* The median follow-up after completion of treatment was 44.2 months (all patients were observed for at least 3 years after completion of treatment).

Overall survival (ITT analysis). At the time of analysis for 3-year disease-free survival, which was the primary endpoint of the MOSAIC study, 85.1% of patients remained alive in the FOLFOX4 treatment group compared to 83.8% of patients in the LV5FU2 treatment group. This represents an overall 10% reduction in mortality risk in favor of FOLFOX4, which did not reach statistical significance (hazard ratio − 0.90).

Numerical values were 92.2% versus 92.4% in the subgroup of patients with stage II disease (Duke’s B2 classification) (hazard ratio = 1.01) and 80.4% versus 78.1% in the subgroup of patients with stage III disease (Duke’s C classification) (hazard ratio – 0.87) for the FOLFOX4 and LV5FU2 treatment regimens, respectively.

Monotherapy with oxaliplatin was evaluated in children in the course of two phase I studies (69 patients) and two phase II studies (166 patients). A total of 235 children (aged from 7 months to 22 years) with solid tumors received treatment. Efficacy of oxaliplatin monotherapy in treated children was not established. Enrollment in both phase II studies was discontinued due to lack of tumor response.

Pharmacokinetics.

The pharmacokinetics of individual active metabolites has not been defined. The pharmacokinetics of ultrafiltered platinum, i.e., the mixture of all forms of non-conjugated active and inactive platinum in blood plasma, following a 2-hour infusion of oxaliplatin at a dose of 130 mg/m² every 3 weeks for 1–5 cycles and oxaliplatin at a dose of 85 mg/m² every 2 weeks for 1–3 cycles, is presented in Table 6.

Table 6

Summary of results from the assessment of pharmacokinetic parameters of platinum in plasma ultrafiltrate after repeated administration of oxaliplatin at a dose of 85 mg/m² every 2 weeks or at a dose of 130 mg/m² every 3 weeks

The mean AUC0-48 and Cmax values were determined during cycle 3 (85 mg/m²) or cycle 5 (130 mg/m²).

The mean values of AUC, Vss, and clearance were determined during cycle 1.

Cmax, AUC, AUC0-48, Vss, and CL values were determined by non-compartmental analysis.

t1/2α, t1/2β, and t1/2γ were determined by compartmental analysis (combined cycles 1–3).

At the end of the 2-hour infusion, 15% of the administered platinum is present in systemic circulation, while the remaining 85% is rapidly distributed into tissues or excreted in urine.

Irreversible binding to erythrocytes and plasma proteins results in elimination half-lives of these matrices approaching the natural lifespans of erythrocytes and serum albumin. The mean terminal elimination half-life from blood and blood cells was also estimated in these two studies (85 mg/m² every 2 weeks or 130 mg/m² every 3 weeks), amounting to 771 hours and 589 to 1296 hours, respectively. No accumulation of oxaliplatin was observed in plasma ultrafiltrate following administration of either 85 mg/m² every 2 weeks or 130 mg/m² every 3 weeks; steady state in this matrix was achieved during the first treatment cycle. Inter- and intra-patient variability was generally low.

In vitro biotransformation results from non-enzymatic degradation, and no evidence of metabolism of the diaminocyclohexane (DACH) ring via cytochrome P450 has been observed.

Oxaliplatin undergoes extensive biotransformation and is not detectable in unchanged form in plasma ultrafiltrate at the end of the 2-hour infusion. Later, individual cytotoxic metabolites were detected in systemic circulation, including monochloro-, dichloro-, and diaqua-DACH-platinum derivatives, along with some inactive conjugates.

Platinum is excreted predominantly via urine within the first 48 hours after administration. By day 5, approximately 54% of the total dose is recovered in urine and less than 3% in feces.

Renal impairment. In patients with renal impairment, a statistically significant decrease in clearance was observed, from 17.6 ± 2.18 L/h to 9.95 ± 1.91 L/h, along with a statistically significant reduction 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 adequately assessed.

The effect of renal impairment on oxaliplatin distribution was studied in patients with varying degrees of renal dysfunction. Oxaliplatin was administered at a dose of 85 mg/m² to control patients with normal renal function (CLcr >80 mL/min, N=12), and to patients with mild (CLcr 50–80 mL/min, N=13) and moderate (CLcr 30–49 mL/min, N=11) renal impairment, and at a dose of 65 mg/m² to patients with severe renal impairment (CLcr <30 mL/min, N=5). Median exposure to the drug was 9, 4, 6, and 3 cycles, respectively, and pharmacokinetic data during cycle 1 were obtained from 11, 13, 10, and 4 patients, respectively.

An increase in AUC of platinum in plasma ultrafiltrate (PUF) and a decrease in total and renal clearance (CL) and Vss were observed with increasing severity of renal impairment, particularly in the small group of patients with severe renal impairment: the point estimate (90% CI) of the calculated geometric mean ratio relative to normal renal function for AUC was 1.36 (1.08; 1.71), 2.34 (1.82; 3.01), and 4.81 (3.49; 6.64) in patients with mild, moderate, and severe renal impairment, respectively.

Excretion of oxaliplatin correlates strongly with creatinine clearance. Total clearance of platinum in PUF was 0.74 (0.59; 0.92), 0.43 (0.33; 0.55), and 0.21 (0.15; 0.29), and Vss was 0.52 (0.41; 0.65), 0.73 (0.59; 0.91), and 0.27 (0.20; 0.36) in patients with mild, moderate, and severe renal impairment, respectively. Thus, total systemic clearance of platinum in PUF decreased by 26% in mild, 57% in moderate, and 79% in severe renal impairment compared to patients with normal renal function.

Renal clearance of platinum in PUF decreased by 30% in mild, 65% in moderate, and 84% in severe renal impairment compared to patients with normal renal function.

An increase in the beta-phase elimination half-life of platinum in PUF was observed with increasing severity of renal impairment, particularly in the group of patients with severe renal impairment. Although the number of patients with severe renal dysfunction was small, these findings raise concerns regarding patients with severe renal impairment and must be taken into account when prescribing oxaliplatin to patients with renal impairment (see sections "Contraindications", "Special warnings and precautions for use", and "Dosage and administration").

Clinical characteristics.

Indications.

In combination with fluorouracil and folinic acid, oxaliplatin is recommended for:

• adjuvant treatment of stage III colorectal cancer (stage C according to Duke’s classification) after complete resection of the primary tumor;
• treatment of metastatic colorectal cancer.

Contraindications.

The drug is contraindicated in patients:

• with hypersensitivity to oxaliplatin;
• 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 impairment prior to the first treatment cycle;
• with severe renal impairment (creatinine clearance <30 mL/min) (see section «Pharmacological properties»).

Interaction with other medicinal products and other types of interactions.

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

In vitro studies showed no significant displacement of protein-bound oxaliplatin 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 known to prolong the QT interval (see section «Special precautions for use»). Caution is also recommended when oxaliplatin is used concomitantly with other medicinal products that may be associated with the risk of rhabdomyolysis (see section «Special precautions for use»).

Patients receiving oxaliplatin should avoid vaccination with live or live attenuated vaccines (see section «Special precautions for use»).

Special precautions for use.

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

Hypersensitivity reactions. Particular caution and close monitoring are required in patients with a history of allergy to other platinum-containing drugs. In case of anaphylactic reactions during drug infusion, the infusion must be stopped immediately 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, the 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 have specific neurotoxic effects. Neurological examination should be performed before each administration and periodically thereafter.

Patients who develop acute laryngopharyngeal dysesthesia during or within several hours after the 2-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 to avoid cold exposure and refrain from consuming cold or 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 treatment 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 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, reversible neurological disorder that develops rapidly and may be associated with seizures, 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, manifested 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 impairment, particularly when oxaliplatin is used in combination with 5-FU.

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

If hematological toxicity occurs (neutrophil count <1.5×10⁹/L or platelet count <50×10⁹/L), the next treatment cycle should be delayed until acceptable hematological parameters are restored. A complete blood count with differential should be performed before starting oxaliplatin therapy and prior to each subsequent cycle. Myelosuppressive effects of the drug may be additive to those of concomitantly administered chemotherapeutic agents. Patients with severe and persistent myelosuppression are at increased risk of infectious diseases. Cases of sepsis, neutropenic sepsis, and septic shock, including fatal outcomes, 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 to seek immediate medical attention if diarrhea/vomiting, mucositis/stomatitis, or neutropenia occur after administration of oxaliplatin and 5-FU, to ensure appropriate management of these symptoms.

If mucositis/stomatitis develops, with or without neutropenia, the next administration should be delayed until signs of mucositis/stomatitis decrease to grade I or lower and/or until neutrophil count exceeds 1.5×10⁹/L. When oxaliplatin is used in combination with 5-FU (with or without folic acid), dose adjustments of 5-FU are usually recommended due to its toxicity.

In case of WHO grade 4 diarrhea, grade 3–4 neutropenia (neutrophil count <1×10⁹/L), febrile neutropenia (fever of unknown origin without clinically or microbiologically documented infection with absolute neutrophil count (ANC) <1.0×10⁹/L), single temperature elevation >38.3 °C or sustained temperature elevation >38 °C for more than 1 hour, or grade 3–4 thrombocytopenia (platelet count <50×10⁹/L), the dose of oxaliplatin should also be reduced by 25% along with dose reduction of 5-fluorouracil.

Respiratory disorders. In case of respiratory symptoms of unknown etiology, such as non-productive cough, dyspnea, wheezing, or pulmonary infiltrates on X-ray, treatment with oxaliplatin should be discontinued until interstitial pneumonia or pulmonary fibrosis is ruled out by additional lung investigations (see section "Adverse reactions").

Blood disorders. Hemolytic uremic syndrome (HUS) is a life-threatening adverse reaction (frequency not known). Oxaliplatin Accord 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 LDH. Renal failure may be irreversible after discontinuation of the drug and may require dialysis.

Cases of disseminated intravascular coagulation (DIC), including fatal outcomes, have been reported with oxaliplatin treatment. In case of DIC, oxaliplatin should be discontinued and appropriate treatment initiated (see section "Adverse reactions"). Patients with conditions associated with DIC development, such as infections or sepsis, require particularly close monitoring.

QT interval prolongation. Prolongation of the QT interval may increase 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. Particular monitoring is indicated in patients with a history of QT prolongation or predisposition to QT prolongation, patients taking medicinal products known to prolong the QT interval, and patients with electrolyte imbalances such as hypokalemia, hypocalcemia, or hypomagnesemia.

Rhabdomyolysis. Cases of rhabdomyolysis, including fatal outcomes, have been reported in patients receiving oxaliplatin. In case of muscle pain and swelling combined with weakness, fever, or darkening of urine, oxaliplatin should be discontinued. In case of confirmed rhabdomyolysis, appropriate treatment should be initiated. Particular close monitoring is required 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 ulcers/bleeding and gastrointestinal ulcer perforation. Oxaliplatin treatment may lead to gastrointestinal ulceration and potential complications such as gastrointestinal bleeding and perforation, which may be fatal. In case of gastrointestinal ulcer development, oxaliplatin should 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 vascular disorders of the liver induced by the drug should be considered.

Immunosuppressive effect/increased susceptibility to infections: Administration of live or attenuated vaccines to patients whose immune system is compromised by chemotherapy, including oxaliplatin, may lead to serious or fatal infections. Live vaccines should not be administered during oxaliplatin therapy. Inactivated or killed vaccines may be administered, but the immune response to such vaccines may be diminished.

Contraception in men and women of reproductive age. Due to the potential genotoxic effects of oxaliplatin, patients should use appropriate contraceptive methods during and after oxaliplatin therapy. Considering the long elimination period of the drug (see section "Pharmacokinetics"), as a precautionary measure, contraception should be continued for 15 months after discontinuation of treatment in women of reproductive age and for 12 months after discontinuation of treatment in men (see section "Use during pregnancy or breastfeeding").

Fertility. Men should be advised to consider sperm preservation before starting treatment, as oxaliplatin may cause irreversible infertility (see section "Use during pregnancy or breastfeeding").

Other warnings. Peritoneal hemorrhage may occur if oxaliplatin is administered intraperitoneally (a route not recommended in the product instructions).

Use during pregnancy or breastfeeding.

Contraception in men and women of reproductive age. Due to the potential genotoxic effect of oxaliplatin, patients should use appropriate contraceptive methods during and after oxaliplatin therapy. Considering the long elimination period of the drug (see section "Pharmacokinetics"), as a precautionary measure, contraception should be continued for 15 months after discontinuation of treatment in women of reproductive age and for 12 months after discontinuation of treatment in men.

Pregnancy. There are no data on the safety of oxaliplatin use in pregnant women. Reproductive toxicity has been observed in animal studies. Therefore, oxaliplatin is not recommended for use in pregnant women and in women of reproductive age who are not using contraception.

The use of oxaliplatin in pregnant women may be considered only after clear patient counseling regarding the risk to the fetus and obtaining informed consent.

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

Fertility. Oxaliplatin may negatively affect fertility. Patients planning pregnancy after oxaliplatin treatment should seek genetic counseling. Men should be advised to consider sperm preservation before starting treatment, as oxaliplatin may cause irreversible infertility.

Ability to affect reaction speed when driving or operating machinery.

The effect of oxaliplatin on the ability to drive has not been studied. However, since oxaliplatin administration increases the risk of dizziness, nausea, vomiting, and other neurological symptoms affecting gait and balance, treatment may have a minor or moderate effect on driving ability.

Visual disturbances, including transient loss of vision (which resolves after discontinuation of therapy), may affect patients' ability to drive vehicles or operate machinery. Therefore, patients should be warned about the potential impact of these symptoms on their ability to drive or operate machinery.

Dosage and Administration

The medication is intended only for the treatment of adult patients

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 2 weeks until disease progression or until signs of intolerable toxicity appear.

Dosage should be adjusted according to individual tolerance to the drug (see section "Special Instructions").

Oxaliplatin should always be administered before fluoropyrimidines, for example before 5-fluorouracil

Oxaliplatin is administered as a 2–6-hour intravenous infusion, diluted in 250–500 mL of 5% glucose solution (50 mg/mL) to achieve a concentration between 0.2 and 0.7 mg/mL; 0.7 mg/mL corresponds to the highest concentration used in clinical practice with an oxaliplatin dose of 85 mg/m².

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

For a treatment regimen repeated every 2 weeks, bolus administration combined with continuous infusion of 5-fluorouracil is recommended.

Special Patient Categories

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

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

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

No specific dose adjustments were made for patients with hepatic impairment during clinical trials.

Elderly patients. No increased toxicity of oxaliplatin was observed when administered as monotherapy or in combination with 5-fluorouracil in patients aged 65 years and older. 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").

Administration Method

Oxaliplatin must be diluted before administration. Only the recommended diluent—5% glucose solution—should be used to reconstitute the concentrate for infusion solution.

Oxaliplatin is administered as an intravenous infusion. Administration of the drug does not require hyperhydration.

Oxaliplatin diluted in 250–500 mL of 5% glucose solution (50 mg/mL) to achieve a concentration of at least 0.2 mg/mL is administered into a central or peripheral vein over 2–6 hours.

Infusion of oxaliplatin must always precede infusion of 5-FU.

If hematoma develops at the injection site, administration must be immediately discontinued.

Instructions for Use and Disposal. As with other potentially toxic substances, precautions must be observed when preparing oxaliplatin solutions. Handling this cytotoxic substance requires healthcare personnel to follow all safety precautions to ensure protection of the worker and the surrounding environment.

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

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

Particular caution is required when handling patient excreta and vomitus.

Pregnant women should be warned to avoid working with cytotoxic substances.

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

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

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

Special Precautions for Administration

• Never administer the drug in undiluted form.
• Use only the recommended diluent.

Instructions for Use 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 administered via a Y-type infusion system with a side port immediately before the infusion site.

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

Instructions for Use with 5-FU

Oxaliplatin should always be administered before fluoropyrimidines, for example before 5-FU administration.

After oxaliplatin infusion, the infusion system must be flushed before 5-FU is administered.

For additional information on drugs that can be combined with oxaliplatin, refer to the instructions for medical use provided by the respective manufacturer.

Visual inspection of the concentrate for infusion solution must be performed before administration. Only clear, particle-free solutions should be used.

The medication in the vial is intended for single use only. Any unused solution must be destroyed.

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

The solution is administered as an intravenous infusion.

After dilution with 5% glucose solution, the physical and chemical 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 compliance with 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 settings.

The infusion solution should be used immediately. Visual inspection must be performed before administration. Only clear, particle-free solutions should be used.

Never use chloride-containing solutions or sodium chloride solution for dilution.

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

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 into a peripheral or central vein over 2–6 hours. When oxaliplatin is used in combination with 5-FU, the oxaliplatin infusion must precede 5-FU administration.

Disposal. Any unused medication and all materials used for dissolving and administering oxaliplatin must be destroyed according to standard procedures for disposal of cytotoxic waste, taking into account current regulations regarding the destruction of toxic waste.

Children

The medication 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, increased 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), the most commonly observed adverse reactions were gastrointestinal (diarrhea, nausea, vomiting, and mucositis), hematological disorders (neutropenia, thrombocytopenia), and neurological syndromes (acute and dose-dependent sensory peripheral neuropathy). These adverse reactions generally occurred more frequently and were more severe when oxaliplatin was combined with 5-FU/FA than with 5-FU/FA therapy alone.

The adverse reactions listed below were observed during clinical trials and reported from post-marketing experience.

The frequency of the adverse effects listed below was determined using the following criteria: very common (>1/10), common (>1/100, <1/10), uncommon (>1/1000, <1/100), rare (>1/10,000, <1/1000), very rare (<1/10,000), frequency not known (cannot be estimated from available data).

Laboratory tests: very common – increased levels of liver enzymes, increased alkaline phosphatase (ALP) in blood, increased bilirubin levels in blood, increased LDH levels in blood, weight gain (during adjuvant therapy); common – increased creatinine levels, weight loss (during treatment of metastatic cancer).

Blood and lymphatic system disorders*: very common – anemia, neutropenia, thrombocytopenia, leukopenia, lymphopenia; common – febrile neutropenia; rare – immune-mediated allergic thrombocytopenia, hemolytic anemia***.

Nervous system disorders*: very common – peripheral sensory neuropathy, sensory disturbances, taste alterations, headache; common – dizziness, motor nerve neuritis, meningeal irritation; rare – dysarthria, reversible posterior leukoencephalopathy syndrome (RPLS) (see section "Special precautions"); frequency not known – convulsions, ischemic or hemorrhagic cerebrovascular events.

Eye disorders: common – conjunctivitis, visual disturbances; rare – transient decrease in visual acuity, visual field defects, optic neuritis; transient vision loss, which resolves after discontinuation of therapy.

Ear and labyrinth disorders: uncommon – ototoxicity; rare – deafness.

Respiratory, thoracic and mediastinal disorders: very common – dyspnea, cough, epistaxis; common – hiccups, pulmonary embolism; rare – acute interstitial lung disease (sometimes fatal), pulmonary fibrosis**.

Gastrointestinal disorders*: very common – nausea, diarrhea, vomiting, stomatitis/mucositis, abdominal pain, constipation; common – dyspepsia, gastroesophageal reflux, gastrointestinal hemorrhage; rectal bleeding; uncommon – intestinal paresis, intestinal obstruction; rare – colitis, including diarrhea caused by Clostridium difficile; diarrhea; pancreatitis.

Renal and urinary disorders: common – hematuria, dysuria, urinary frequency disorders.

Hepatobiliary disorders: very common – increased liver enzymes, increased bilirubin levels in blood; rare – hepatic sinusoidal obstruction syndrome (also known as veno-occlusive liver disease); frequency not known – focal nodular hyperplasia.

Skin and subcutaneous tissue disorders: very common – skin disorders, alopecia; uncommon – skin desquamation (e.g., palmar-plantar erythrodyplasia), erythematous rash, rash, hyperhidrosis, nail disorders.

Musculoskeletal and connective tissue disorders: very common – back pain; common – arthralgia, bone pain.

Metabolism and nutrition disorders: very common – anorexia, hyperglycemia, hypokalemia, hypernatremia; common – dehydration, hypocalcemia; uncommon – metabolic acidosis.

Infections and infestations*: very common – infections; common – rhinitis, upper respiratory tract infections, neutropenic sepsis; uncommon – sepsis+; frequency not known – septic shock, including fatal cases.

Cardiac disorders: frequency not known – acute coronary syndrome, including myocardial infarction, coronary artery spasm, and angina in patients receiving oxaliplatin in combination with 5-FU or bevacizumab.

Vascular disorders: common – hemorrhage, hyperemia, deep vein thrombophlebitis, arterial hypertension, thromboembolism.

General disorders and administration site conditions: very common – fatigue, fever+++, asthenia, pain, injection site reaction++++.

Immune system disorders*: very common – allergy/allergic reaction++.

Psychiatric disorders: common – depression, insomnia; uncommon – restlessness.

Injury, poisoning and procedural complications: common – falls.

* See detailed information in the section below.

** See section "Special precautions".

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

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

++ Very common allergic/allergic reactions, mostly occurring during infusion and sometimes resulting in death. Common allergic reactions include skin rashes (particularly urticaria), conjunctivitis, and rhinitis. Anaphylactic reactions, including bronchospasm, angioedema, hypotension, chest pain, anaphylactic shock, or anaphylactoid reactions, have been reported. Delayed-type hypersensitivity reactions 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, erythema, swelling, and thrombosis. Extravasation may also cause local pain and inflammation, which can be severe and lead to complications, including necrosis, especially when oxaliplatin is infused into a peripheral vein (see section "Special safety measures").

Blood and lymphatic system disorders.

Table 7

Frequency of adverse reactions in patients (%) by grade

Rare (>1/10000, <1/1000): disseminated intravascular coagulation (DIC syndrome), including fatal cases (see section "Special precautions for use").

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 8

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

Immune system disorders.

Table 9

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

Nervous system disorders. Neurological toxicity of oxaliplatin is dose-dependent. It mainly manifests as sensory peripheral neuropathy characterized by paresthesia and/or dysesthesia of the extremities, with or without seizures, often triggered by cold. These symptoms are observed in approximately 95% of patients undergoing 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 "Special precautions"), dose adjustment or even discontinuation of treatment may be required. Functional impairment, such as difficulty in performing fine motor tasks, may result from sensory dysfunction. The risk of developing persistent symptoms at a cumulative dose of approximately 850 mg/m² (i.e., 10 cycles) is about 10%, and at a cumulative dose of 1020 mg/m² (i.e., 12 cycles) is about 20%.

In most cases, neurological symptoms show improvement or complete resolution by the end of treatment.

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 had either persistent localized moderate paresthesia (2.3%) or paresthesia interfering with functional activity (0.5%).

Acute neurosensory disturbances have been reported. These symptoms begin within several hours after drug administration and are often triggered by cold exposure. They are characterized by transient paresthesia, dysesthesia, and hypoesthesia. This acute pharyngolaryngeal dysesthesia syndrome, estimated to occur in 1–2% of cases, is characterized by subjective sensations of dysphagia or dyspnea/choking without objective signs of respiratory distress syndrome (not accompanied by cyanosis or hypoxia) or 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 "Special precautions").

Other observed symptoms include: jaw spasms, muscle spasms, involuntary muscle contractions, myoclonus, movement coordination disorders, gait disturbances, ataxia, balance disorders, throat or chest tightness, lethargy, discomfort, and pain. Additionally, cranial nerve involvement may occur 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, and 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 in the post-marketing period (with unknown frequency): seizures, ischemic and hemorrhagic cerebrovascular events.

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

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

Gastrointestinal disorders.

Table 10

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

Treatment or prophylactic administration of potent antiemetic agents is indicated.

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

Adverse reactions observed in the post-marketing period (frequency not known): intestinal ischaemia, including fatal cases (see section "Special warnings and precautions for use"), oesophagitis.

Gastrointestinal ulceration and perforation, which may be fatal (see section "Special warnings and precautions for use").

Hepatobiliary disorders. Very rare: sinusoidal obstruction syndrome of the liver, also known as veno-occlusive liver disease, or related pathological conditions including hepatic peliosis, nodular regenerative hyperplasia and perisinusoidal fibrosis. Clinical manifestations may include portal hypertension and/or increased transaminase levels.

Disorders of the musculoskeletal and connective tissue. Adverse reactions observed in the post-marketing period (frequency not known): rhabdomyolysis, including fatal cases (see section "Special warnings and precautions for use").

Renal and urinary disorders. Very rare: acute tubular necrosis, acute interstitial nephritis and acute renal failure.

Skin and subcutaneous tissue disorders. Adverse reactions observed in the post-marketing period (frequency not known): leukocytoclastic vasculitis.

Reporting suspected adverse reactions.

Reporting of suspected adverse reactions after marketing authorization of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at the following link: http://aisf.dec.gov.ua.

Shelf life. 2 years.

Storage conditions.

Store the vial in the original packaging to protect from light. Do not freeze. Keep out of the reach of children.

After dilution in 5% glucose solution, the chemical and physical stability of the ready-to-use solution is maintained for 48 hours at a temperature of 2 to 8 °C and for 24 hours at +25 °C.

From a microbiological standpoint, the product should be used immediately. If not used immediately, storage time and conditions prior to use are the responsibility of the user and should generally not exceed 24 hours at 2–8 °C, unless reconstitution was performed under controlled and validated aseptic conditions.

Incompatibilities.

Never mix the diluted product 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 products 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 infusion system.

Do not use injectable preparations containing aluminium.

Packaging.

10 ml, 20 ml, 40 ml in a vial, 1 vial per pack.

Prescription status. Prescription only.

Manufacturer.

Accord Healthcare Polska Sp. z o.o. Importer's Composition / Accord Healthcare Polska Sp. z o.o. Importer's Warehouse.

Manufacturer's address and place of business.

ul. Lutomierska 50, Pabianice, 95-200, Poland.

Marketing Authorisation Holder. Accord Healthcare Polska Sp. z o.o. / Accord Healthcare Polska Sp. z o.o.

Complaints regarding poor quality of the medicinal product; questions concerning safety of use, improper use or adverse reactions are accepted 24/7 by phone at +380993100335 or by email at: [email protected].

Address of the Marketing Authorisation Holder. 7 Tasmowa St., Warsaw, 02-677, Poland.