Oxaliplatin-vista

INSTRUCTIONS for medical use of the medicinal product OXALIPLATIN-VISTA (OXALIPLATIN-VISTA)

Composition:

active substance: oxaliplatin;

1 ml of concentrate contains 5 mg of oxaliplatin; 1 vial contains 50 mg, 100 mg or 200 mg of oxaliplatin;

excipients: lactose monohydrate, water for injections.

Pharmaceutical form. Concentrate for solution for infusion.

Main physicochemical properties: clear solution ranging from colorless to almost colorless.

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

Pharmacological Properties

Pharmacodynamics

Mechanism of Action

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 an oxalate group. Oxaliplatin is the unique enantiomer (cis-[(1R,2R)-1,2-diaminocyclohexane-N,N'] oxalato(2-)-O,O'] platinum. Oxaliplatin demonstrates a broad spectrum of cytotoxic activity in vitro and antitumor activity in vivo in various tumor models, including models of human colorectal cancer. Oxaliplatin has also shown efficacy in vitro and in vivo in various cell lines resistant to cisplatin. Synergistic cytotoxic effects with 5-fluorouracil (5-FU) have been demonstrated in vitro and in vivo. Studies on the mechanism of action, although not fully elucidated, indicate that hydrated derivatives formed through the biotransformation of oxaliplatin interact with DNA, forming intra- and inter-strand cross-links, leading to disruption of DNA synthesis, which underlies its cytotoxic and antitumor activity.

Clinical Efficacy and Safety

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

• in first-line treatment, in the phase III EFC2962 trial, a two-arm comparative study, 420 patients were randomized between 5-FU/FA alone (LV5FU2, N=210) and the combination of oxaliplatin/5-FU/FA (FOLFOX4, N=210),
• in the phase III EFC4584 trial, a three-arm comparative study, 821 patients refractory to the combination of irinotecan (CPT-11) + 5-FU/FA were randomized between 5-FU/FA alone (LV5FU2, N=275), monotherapy with oxaliplatin (N=275), and the combination of oxaliplatin with 5-FU/FA (FOLFOX4, N=271),
• finally, in the uncontrolled phase II trial EFC2964, patients refractory to 5-FU/FA alone received the combination of oxaliplatin/5-FU/FA (FOLFOX4, N=57).

Both randomized clinical trials, EFC2962 in first-line treatment and EFC4584 in previously treated patients, demonstrated significantly higher response rates and prolonged progression-free survival (PFS)/time to progression (TTP) compared to treatment with 5-FU/FA alone. In the EFC4584 trial conducted in refractory patients who had received prior therapy, the difference in median overall survival (OS) was not statistically significant between the oxaliplatin/5-FU/FA combination and the control arms.

Response rate with FOLFOX4 compared to LV5FU2

NA: Not applicable.

Progression-free survival (PFS) / median time to progression (TTP)

FOLFOX4 versus LV5FU2

NA: Not applicable.

Median overall survival (OS) with FOLFOX4 compared to LV5FU2

NA: Not applicable

In patients who had previously received treatment (EFC4584), initially symptomatic, significant improvement in disease-related symptoms was observed in a higher proportion of patients receiving oxaliplatin/5-FU/FA compared to those receiving 5-FU/FA alone (27.7% vs. 14.6%, p ≤ 0.0033).

In treatment-naïve patients (EFC2962), no statistically significant difference in quality of life was observed between the two treatment groups.

However, quality of life scores were generally better in the control group regarding overall health status and pain, and worse in the oxaliplatin group regarding nausea/vomiting.

In the adjuvant setting, in the phase III comparative clinical study MOSAIC EFC3313, 2246 patients (899 stage II/B2 by Duke and 1347 stage III/C by Duke) were randomized between monotherapy with 5-FU/FA (LV5FU2, N=1123 (stage B2/C=448/675)) and combination therapy with oxaliplatin plus 5-FU/FA (FOLFOX4, N=1123 (stage B2/C=451/672)).

EFC3313 - 3-year disease-free survival (ITT analysis)* in the overall population

*Median follow-up of 44.2 months (all patients were followed for at least 3 years)

The study demonstrated a significant improvement in 3-year disease-free survival with oxaliplatin in combination with 5-FU/FA (FOLFOX4) compared to 5-FU/FA monotherapy (LV5FU2).

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

*Median follow-up of 44.2 months (all patients were observed for at least 3 years)

Overall survival (ITT analysis):

At the time of analysis for 3-year disease-free survival, the primary endpoint of the MOSAIC study, 85.1% of patients were still alive in the FOLFOX4 group versus 83.8% in the LV5FU2 group. This corresponds to an overall 10% reduction in mortality risk in favor of FOLFOX4, without reaching statistical significance (hazard ratio = 0.90).

The figures were 92.2% versus 92.4% in the stage II (Dukes B2) subgroup (hazard ratio = 1.01) and 80.4% versus 78.1% in the stage III (Dukes C) subgroup (hazard ratio = 0.87), respectively, for FOLFOX4 and LV5-FU2.

Paediatric population.

Oxaliplatin administered as monotherapy was evaluated in children in two phase I studies (69 patients) and two phase II studies (166 patients). Overall, 235 children (aged from 7 months to 22 years) with solid tumors were treated. Efficacy of oxaliplatin monotherapy has not been established in the treatment group. Enrollment for these two phase II studies was discontinued due to lack of tumor response.

Pharmacokinetics

The pharmacokinetics of individual active metabolites has not been characterized. The pharmacokinetics of ultrafilterable platinum, i.e., the mixture of all forms of non-conjugated active and inactive platinum in plasma after 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, are presented in Table 6.

Table 6

Summary of pharmacokinetic parameter results for platinum in plasma ultrafiltrate after repeated administration of oxaliplatin at a dose of 85 mg/m² every 2 weeks or 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 remains in the 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 being close to the natural lifespan of erythrocytes and serum albumin. The mean terminal elimination half-life in blood and blood cells was also assessed in these two studies (85 mg/m² every 2 weeks or 130 mg/m² every 3 weeks), amounting to 771 hours and 589–1296 hours, respectively. No accumulation of platinum in ultrafiltered plasma was observed after administration of 85 mg/m² every 2 weeks or 130 mg/m² every 3 weeks, and steady state was achieved by cycle 1 in this compartment; inter- and intra-individual 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 detected in unchanged form in plasma ultrafiltrate at the end of the 2-hour infusion. Later, individual cytotoxic metabolites were detected in systemic circulation, including mono-chloro-, di-chloro-, and di-aquo derivatives of DACH-platinum, along with some inactive conjugates.

Elimination

Platinum is primarily excreted in 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.

Special patient populations

Renal impairment.

In patients with renal impairment, a statistically significant reduction in clearance was observed, decreasing from 17.6 ± 2.18 to 9.95 ± 1.91 L/hour, along with a statistically significant reduction in volume of distribution from 330 ± 40.9 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 the pharmacokinetics of oxaliplatin 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). The median exposure to oxaliplatin 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 (UF) 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.

Oxaliplatin elimination is strongly correlated with creatinine clearance. The total clearance of platinum in UF 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 UF 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 UF 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 UF 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 data raise concerns regarding patients with severe renal impairment and should be carefully considered when prescribing oxaliplatin to patients with renal impairment (see sections "Contraindications", "Special precautions", and "Dosage and administration").

Clinical Characteristics

Indications

In combination with fluorouracil and folinic acid, oxaliplatin is indicated 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 is contraindicated in patients:

− with hypersensitivity to oxaliplatin;

− during breastfeeding;

− with myelosuppression (neutrophil count < 2x10⁹/L and/or platelet count < 100x10⁹/L) prior to the start of the first treatment cycle;

− with peripheral sensory neuropathy associated with functional impairments prior to the start of the first treatment cycle;

− with severe renal impairment (creatinine clearance < 30 mL/min) (see section "Pharmacological Properties. Pharmacodynamics").

Interaction with other medicinal products and other forms of interaction

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 oxaliplatin bound to plasma proteins by medicinal products such as erythromycin, salicylates, granisetron, paclitaxel, and sodium valproate.

Caution is recommended and careful monitoring of the QT interval is required when oxaliplatin is used concomitantly with other medicinal products known to prolong the QT interval (see section "Special Warnings and 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 Warnings and 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 adjustments should be made according to the level of toxicity (see section "Pharmacological properties. Pharmacodynamics").

Hypersensitivity reactions.

Particular caution and close monitoring are required in patients with a history of allergic reactions to other platinum-containing medicinal products. In case of anaphylactic reactions during oxaliplatin infusion, administration of oxaliplatin 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 oxaliplatin extravasation, the infusion must 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 exhibiting specific neurotoxicity. A neurological examination should be performed before each administration and periodically thereafter.

In patients who develop acute laryngopharyngeal dysesthesia during or within several hours after the 2-hour infusion (see section "Adverse reactions"), the next oxaliplatin dose should not be administered earlier than 6 hours after the previous infusion. To prevent such dysesthesia, patients should be informed about the necessity to avoid cold exposure and swallowing fresh/cold food and/or beverages for several hours after oxaliplatin administration.

Peripheral neuropathy.

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

• if symptoms last longer than 7 days and cause discomfort, the oxaliplatin dose for the next cycle should be reduced from 85 to 65 mg/m² (metastatic treatment) or to 75 mg/m² (adjuvant treatment);
• if paresthesia without functional impairment persists until the next cycle, the oxaliplatin dose should be reduced from 85 to 65 mg/m² (metastatic treatment) or to 75 mg/m² (adjuvant treatment);
• if paresthesia with functional impairment persists until the next cycle, oxaliplatin treatment should be discontinued;
• if these symptoms resolve after discontinuation of oxaliplatin treatment, re-initiation of therapy may be considered.

Patients should be informed that symptoms of sensory peripheral neuropathy may persist after treatment discontinuation. Mild localized paresthesia or paresthesia interfering with functional activity may be observed 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, reversible neurological disorder that develops rapidly and 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 magnetic resonance imaging (MRI).

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 function impairment, especially when oxaliplatin is used in combination with 5-fluorouracil.

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

In case of hematological toxicity (neutrophil count < 1.5x10⁹/L or platelet count < 50x10⁹/L), the next treatment cycle should be delayed until acceptable hematological parameters are restored. Complete blood count with differential should be performed before initiation of oxaliplatin therapy and prior to each subsequent cycle. Myelosuppressive effects of oxaliplatin may be additive to those of concurrently 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 outcomes, have been reported in patients receiving oxaliplatin (see section "Adverse reactions"). In case of any of these events, oxaliplatin should be discontinued. Patients should be informed to seek immediate medical attention in case of diarrhea/vomiting, mucositis/stomatitis, and neutropenia following oxaliplatin and 5-fluorouracil administration for appropriate management.

In case of mucositis/stomatitis, with or without neutropenia, the next oxaliplatin dose should be delayed until mucositis/stomatitis symptoms resolve to Grade 1 or lower and/or until neutrophil count exceeds 1.5x10⁹/L. When oxaliplatin is combined with 5-FU (with or without leucovorin), dose adjustments of 5-FU are generally recommended due to its toxicity. The occurrence of Grade 4 diarrhea, Grade 3 or 4 neutropenia (neutrophils < 1 x 10⁹/L), febrile neutropenia (fever of unknown origin without clinically or microbiologically confirmed infection, with neutrophil count < 1 x 10⁹/L, isolated temperature > 38.3 °C or temperature ≥ 38 °C persisting for more than 1 hour), or Grade 3 or 4 thrombocytopenia (platelets < 50 x 10⁹/L) will require, in addition to 5-fluorouracil (5-FU) dose adaptation, reduction of oxaliplatin dose from 85 to 65 mg/m² (metastatic treatment) or to 75 mg/m² (adjuvant treatment).

Pulmonary manifestations.

In case of respiratory symptoms of unclear etiology, such as non-productive cough, dyspnea, crackles, or pulmonary infiltrates on chest X-ray, oxaliplatin treatment should be discontinued until interstitial pneumonitis or pulmonary fibrosis 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 LDH. Renal failure may be irreversible after oxaliplatin discontinuation and may require dialysis.

Cases of disseminated intravascular coagulation (DIC), including fatal outcomes, have been observed 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 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 must be discontinued. Appropriate treatment should be initiated upon confirmation of rhabdomyolysis diagnosis. Particular close 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 / gastrointestinal bleeding and 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 ulceration, oxaliplatin must be discontinued and appropriate treatment initiated (see section "Adverse reactions").

Immunosuppressive effect/increased susceptibility to infections.

Administration of live or live-attenuated vaccines to patients with immunosuppression due to chemotherapy may result in severe or fatal infections. Patients receiving oxaliplatin should avoid live vaccination. Inactivated or killed vaccines may be administered; however, the immune response to these vaccines may be reduced.

Hepatic manifestations.

In case of abnormal liver function tests, splenomegaly, or portal hypertension not clearly attributable to liver metastases, very rare cases of drug-induced hepatic vascular disorders should be considered.

Contraception in men and women of reproductive potential.

Due to the potential genotoxic effects of oxaliplatin during and after treatment, appropriate contraceptive measures should be taken.

Considering the long elimination period of oxaliplatin (see section "Pharmacokinetics"), it is recommended as a precautionary measure to continue contraception for 15 months after treatment discontinuation in women of reproductive potential and for 12 months after treatment discontinuation in men (see section "Use during pregnancy or breastfeeding").

Fertility in men and women.

Men should be informed about sperm preservation prior to treatment initiation, as oxaliplatin may cause infertility, which may be irreversible (see section "Special precautions for use").

Other warnings.

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

Use during pregnancy or breastfeeding

Contraception in men and women of reproductive potential.

Due to the potential genotoxic effects of oxaliplatin during and after treatment, appropriate contraceptive measures should be taken.

Considering the long elimination period of oxaliplatin (see section "Pharmacokinetics"), it is recommended as a precautionary measure to continue contraception for 15 months after treatment discontinuation in women of reproductive potential and for 12 months after treatment discontinuation in men.

Pregnancy.

There are no data on the safety of oxaliplatin use for the treatment of pregnant women. Reproductive toxicity was observed in animal studies. Therefore, oxaliplatin is not recommended for use in pregnant women or women of reproductive potential not using contraception. The decision to administer oxaliplatin during pregnancy may be considered only after clear patient counseling regarding the risk to the fetus and obtaining her consent.

Breastfeeding.

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

Fertility in men and women.

Oxaliplatin may cause infertility. Men should be informed about sperm preservation prior to treatment initiation, as oxaliplatin may cause infertility, which may be irreversible (see section "Special precautions for use").

Patients who plan pregnancy after oxaliplatin treatment are advised to seek genetic counseling.

Ability to affect reaction speed when driving or operating machinery

The effect 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 impact on the ability to drive.

Visual disturbances, including temporary vision loss (resolving after treatment discontinuation), may affect patients' ability to drive vehicles and operate machinery. Therefore, patients should be warned about the potential impact of these manifestations on their ability to drive vehicles and operate machinery.

Method of Administration and Dosage

The medicinal product is intended only for the 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 intolerable toxicity appear.

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

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 at an oxaliplatin dose of 85 mg/m².

Oxaliplatin is preferably administered in combination with continuous infusion of 5-FU. For a treatment regimen repeated every 2 weeks, bolus administration combined with continuous infusion of 5-FU is recommended.

Special Patient Populations

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

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

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 the progression of the disease and pre-existing liver function abnormalities.

During clinical trials, no specific dose adjustment was performed for patients with hepatic impairment.

Elderly patients. No increase in oxaliplatin toxicity was observed when administered as monotherapy or in combination with 5-FU in patients aged 65 years and older. Therefore, no special dose adjustment is required for elderly patients. Children. There are no established indications for the use of oxaliplatin in children. The efficacy of oxaliplatin monotherapy in children with solid tumors has not been established (see section "Pharmacodynamic Properties").

Method of Administration

Oxaliplatin must be diluted prior to 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 oxaliplatin 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 should be administered via central or peripheral vein over 2–6 hours.

Oxaliplatin infusion must always precede 5-FU infusion. If a hematoma develops at the injection site, administration of oxaliplatin should be stopped immediately. Instructions for Use and Disposal. Precautions must be observed when preparing oxaliplatin solutions, as with other potentially toxic substances.

Handling this cytotoxic agent requires healthcare personnel to follow all precautionary measures 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, particularly for personnel handling these agents. A specially designated area must be available for preparation procedures. Smoking, eating, or drinking is prohibited in this designated area.

Personnel must be provided with appropriate materials for handling the medicinal product, including medical gowns with long sleeves, protective masks, head covers, protective eyewear, 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 must be handled with these precautionary measures and considered contaminated waste. Contaminated waste must be incinerated in solid, 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 medicinal product 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 delivered 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 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.

Instructions for Use with 5-Fluorouracil

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

After administration of oxaliplatin, the infusion system should be flushed before administering 5-FU.

For additional information on medicinal products that can be combined with oxaliplatin, refer to the Summary of Product Characteristics of the respective manufacturer.

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

The medicinal product in the vial is intended for single use only. Any unused solution must be discarded.

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 between 0.2 and 0.7 mg/mL. Physical and chemical stability of oxaliplatin has been demonstrated at concentrations between 0.2 and 2 mg/mL.

Administer as 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 lies solely with the healthcare professional administering the solution. 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. Visual inspection of the solution should be performed before administration. Only clear, particle-free solutions should be used.

Solutions containing chlorides or sodium chloride solution must never be used 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 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. Any unused oxaliplatin and all materials used for reconstitution and administration must be destroyed according to standard procedures for disposal of cytotoxic waste, taking into account current regulations on 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 monotherapy in children with solid tumors has not been established (see section "Pharmacological Properties").

Overdose

Symptoms. In case of overdose, an increased severity of adverse reactions may be expected. Treatment. There is no known antidote for oxaliplatin. Hematological monitoring should be performed along with symptomatic treatment of other manifestations of intoxication.

Adverse Reactions

During combination therapy with oxaliplatin and 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 with the combination of oxaliplatin and 5-FU/FA than with 5-FU/FA therapy alone.

The adverse reactions listed in Table 7 were observed during clinical studies and reported from post-marketing experience.

The frequency of adverse reactions listed in Table 7 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), unknown (cannot be estimated based on available data).

Table 7

* See detailed information in the section provided below.

** See section "Special safety precautions".

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

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

++ Very common allergic/allergic reactions, occurring predominantly during infusion and sometimes resulting in death. Common 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. Hypersensitivity reactions of delayed type have also been reported, occurring several hours or even days after infusion.

+++ Very commonly observed increase in body temperature, chills (shivering), 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 when oxaliplatin is administered intravenously via a peripheral vein (see section "Special safety precautions").

Disorders of the blood and lymphatic system

Table 8

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"). 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 9

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

Immune system disorders

Table 10

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 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 impaired sensory function. 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 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 had either persistent localized moderate paresthesia (2.3%) or paresthesia that may interfere with functional activity (0.5%). Acute neurosensory disturbances have been reported. These symptoms begin within several hours after oxaliplatin infusion and are often triggered by exposure to cold. They are characterized by transient paresthesia, dysesthesia, and hyposthesia. 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 (not associated with 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, depression, discomfort, and pain. Additionally, cranial nerve involvement 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, 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 during the post-marketing period (with unknown frequency): seizures, ischemic and hemorrhagic cerebrovascular events, falls.

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 fatal (see section "Special precautions"), acute coronary syndrome, including myocardial infarction, coronary arteriospasm, 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 11

Frequency of adverse reactions in patients (%), by severity 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, especially when oxaliplatin is used in combination with 5-fluorouracil. Adverse reactions observed in the post-marketing period (frequency unknown): intestinal ischemia, including fatal cases (see section "Special Warnings and Precautions for Use"), esophagitis.

Gastrointestinal ulcers and perforations, which may be fatal (see section "Special Warnings and Precautions for Use").

Hepatobiliary disorders. Very rare (≤ 1/10,000): 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 elevated transaminase levels.

Disorders of the musculoskeletal and connective tissue. Adverse reactions observed in the post-marketing period (frequency unknown): rhabdomyolysis, including fatal cases (see section "Special Warnings and Precautions for Use").

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 in the post-marketing period (frequency unknown): leukocytoclastic vasculitis. Reporting of suspected adverse reactions

Reporting of adverse reactions after medicinal product registration is of great importance. It allows ongoing 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 through the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life. 2 years.

After dilution in 5% glucose, chemical and physical stability has been demonstrated for 24 hours at a temperature of 2 °C to 8 °C and for 6 hours at 25 °C.

From a microbiological standpoint, the infusion preparation should be used immediately. If not used immediately, the user is responsible for the duration and conditions of storage, which generally should not exceed 24 hours at a temperature of 2 °C to 8 °C, provided that dilution was performed under controlled and validated aseptic conditions.

Storage conditions

Store in the original packaging to protect from light at a temperature not exceeding 25 °C. Keep out of reach of children.

Incompatibilities

The diluted medicinal product should never be mixed 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 agents 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

10 ml (50 mg), 20 ml (100 mg), or 40 ml (200 mg) in a vial, 1 vial per cardboard pack.

Prescription category. Prescription only.

Manufacturer

Pharmahem B.V.

Manufacturer's address and place of business

Svensweg 5, Haarlem, 2031 GA, the Netherlands.