Oxaliplatin

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT OXALIPLATIN (OXALIPLATIN)

Composition:

active substance: oxaliplatin;

1 ml of concentrate for infusion solution contains 5 mg of oxaliplatin;

10 ml of concentrate for infusion solution contains 50 mg of oxaliplatin;

20 ml of concentrate for infusion solution contains 100 mg of oxaliplatin;

excipient: water for injections.

Pharmaceutical form. Concentrate for solution for infusion.

Main physicochemical properties: clear, colourless solution.

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 single enantiomer (SP-4-2)-[(1R,2R)-cyclohexane-1,2-diamine-kN,kN’] [ethanedioato(2-)-kO1,kO2] platinum. Oxaliplatin exhibits a broad spectrum of cytotoxicity in vitro and antitumor activity in vivo in various tumor models, including human colorectal cancer models. Oxaliplatin also demonstrates in vitro and in vivo activity in various tumor models resistant to cisplatin. Synergistic cytotoxic effects have been observed in vitro and in vivo when oxaliplatin is combined with 5-fluorouracil (5-FU).

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

Clinical efficacy and safety

The efficacy of oxaliplatin (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 and resistant to a combination of irinotecan (CPT-11) and 5-FU/FA was conducted. 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 was conducted in patients previously treated with and resistant to 5-FU/FA alone, who received combination therapy with oxaliplatin and 5-FU/FA (FOLFOX4, N = 57).

Two randomized clinical trials—EFC2962 in first-line therapy patients and EFC4584 in previously treated patients—demonstrated higher response rates and longer progression-free survival (PFS) / time to progression (TTP) compared to monotherapy with 5-FU/FA.

In the EFC4584 trial involving previously treated and resistant patients, median overall survival (OS) did not reach statistical significance between the oxaliplatin plus 5-FU/FA combination and control groups.

Table 1

Therapeutic 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 to LV5FU2 regimen

• NA — not applicable.

Table 3

Median overall survival (OS) of the FOLFOX4 regimen compared to the LV5FU2 regimen

* NA — not applicable.

Among patients who had symptoms of the disease at the beginning of the study and who had previously received anticancer treatment (EFSC4584), significantly positive symptom progression was observed to a greater extent in the group receiving oxaliplatin with 5-FU/FA, compared to the group receiving only 5-FU/FA (27.7% vs. 14.6%, p = 0.0033).

In patients who had not received prior treatment (EFC2962), no statistically significant difference between the two groups was 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, whereas parameters related to nausea and vomiting were worse in the group receiving oxaliplatin.

In the setting of adjuvant therapy during the phase III comparative MOSAIC study (EFC3313), 2246 patients [899 patients with stage II disease (Duke's B2 stage) and 1347 patients with stage III disease (Duke's C stage)] were randomized into groups for complete resection of the primary colorectal cancer tumor followed by treatment with 5-FU/FA (LV5FU2, N = 1123 (B2/C = 448/675)) or treatment with a combination of 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 observed for at least 3 years after completion of treatment).

The study demonstrated a statistically 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 followed for at least 3 years after completion of treatment).

Overall survival (ITT analysis)

At the time of analysis of 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 with 83.8% of patients in the LV5FU2 treatment group. This represented an overall 10% reduction in the risk of death 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 stage B2) (hazard ratio = 1.01) and 80.4% versus 78.1% in the subgroup of patients with stage III disease (Duke's stage C) (hazard ratio — 0.87) for the FOLFOX4 and LV5FU2 treatment regimens, respectively.

Pediatric population

Monotherapy with oxaliplatin was evaluated in children during 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. The 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 compounds has not been defined. The pharmacokinetics of ultrafiltered platinum, representing a mixture of all free, active, and inactive platinum molecules in plasma, after 2-hour infusions 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 pharmacokinetic parameters of platinum in plasma ultrafiltrate following repeated administration of oxaliplatin at 85 mg/m² every 2 weeks or 130 mg/m² every 3 weeks

Mean values of AUC0–48 and Cmax were determined during cycle 3 (85 mg/m²) or cycle 5 (130 mg/m²).

Mean values of AUC, Vss, and clearance were determined during cycle 1. Cmax, AUC, AUC0–48, Vss, and clearance were calculated using non-compartmental analysis. Values of t1/2α, t1/2β, and t1/2γ were determined using compartmental analysis (combined cycles 1–3).

At the end of the 2-hour infusion, 15% of the administered platinum remains 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 being close to the natural lifespan of erythrocytes and serum albumin. No drug accumulation was observed in the plasma ultrafiltrate when administered either at 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-patient 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 by 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. Subsequently, several cytotoxic metabolites have been detected in systemic circulation, including monochloro-, dichloro-, and diaqua-DACH-platinum derivatives, 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 excreted in urine and less than 3% in feces.

Special patient populations

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, together 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 evaluated.

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 group patients with normal renal function (creatinine clearance [CrCl] >80 mL/min, N=12), and to patients with mild (CrCl 50–80 mL/min, N=13) and moderate (CrCl 30–49 mL/min, N=11) renal impairment, and at a dose of 65 mg/m² to patients with severe renal impairment (CrCl <30 mL/min, N=5). Median exposure to treatment was 9, 4, 6, and 3 cycles, respectively, and pharmacokinetic data from cycle 1 were obtained in 11, 13, 10, and 4 patients, respectively.

An increase in platinum AUC in plasma ultrafiltrate (UF) and a decrease in total and renal clearance 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. 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 platinum clearance 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 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 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 recommended for:

• adjuvant treatment of stage III colorectal cancer (stage C according to the Duke's classification) following 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 < 2x10⁹/L and/or platelet count < 100x10⁹/L) prior to the first treatment cycle;

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

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

Special safety precautions

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

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

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

Neurological symptoms. Neurological toxicity of oxaliplatin should be closely monitored, especially when used in combination with medicinal products known to have specific neurotoxic effects. A neurological examination should be performed before each administration and periodically thereafter.

In patients who develop acute pharyngolaryngeal dysesthesia during or within several hours after the 2-hour infusion (see section "Adverse reactions"), the next dose should be administered no 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 drinks for several hours after drug administration.

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

− if symptoms persist for more than 7 days and are bothersome to the patient, the next dose of oxaliplatin should be reduced by 25%; − if paresthesia without functional impairment persists until the next treatment cycle, the next dose of oxaliplatin should be reduced by 25%; − if paresthesia with functional impairment persists until the next cycle, oxaliplatin treatment should be discontinued; − if these symptoms resolve after discontinuation of oxaliplatin, resumption 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 interfering with functional activity may persist for more than 3 years after completion of adjuvant therapy.

Reversible posterior leukoencephalopathy syndrome (RPLS). Cases of reversible posterior leukoencephalopathy syndrome (RPLS, also known as posterior reversible encephalopathy syndrome (PRES)) have been reported in patients receiving oxaliplatin as part of combination chemotherapy. RPLS is a rare, 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-FU.

Cases of intestinal ischemia, including fatal outcomes, have been reported with oxaliplatin use. In case of intestinal ischemia, oxaliplatin should 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 leukocyte count should be performed before initiation of oxaliplatin therapy and before 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 high 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"). 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, or neutropenia after oxaliplatin and 5-FU administration for appropriate management of these symptoms.

In case of mucositis/stomatitis, with or without neutropenia, the next administration of the drug should be delayed until signs of mucositis/stomatitis resolve to grade I or lower and/or until neutrophil count recovers to >1.5x10⁹/L. When oxaliplatin is combined with 5-FU (with or without folinic acid), dose adjustment of 5-FU is usually recommended due to its toxicity.

In case of grade 4 diarrhea (WHO classification), grade 3–4 neutropenia (neutrophil count <1x10⁹/L), febrile neutropenia (fever of unknown origin without clinically or microbiologically documented infection with absolute neutrophil count <1.0x10⁹/L), single temperature rise >38.3°C or persistent temperature rise >38°C for more than 1 hour, or grade 3–4 thrombocytopenia (platelet count <50x10⁹/L), the dose of oxaliplatin should also be reduced by 25% along with dose reduction of 5-FU.

Pulmonary manifestations. In case of respiratory symptoms of unknown etiology, such as non-productive cough, dyspnea, crackles, or pulmonary infiltrates on chest X-ray, treatment with oxaliplatin should be discontinued until interstitial pneumonitis 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 should be discontinued at the first signs suggestive of microangiopathic hemolytic anemia, such as rapid decrease in hemoglobin level accompanied by thrombocytopenia or elevated levels of bilirubin, creatinine, blood urea, or lactate dehydrogenase (LDH). Renal failure may be irreversible after discontinuation of the drug and may require dialysis.

Cases of disseminated intravascular coagulation (DIC), including fatal cases, have been observed during oxaliplatin treatment. In case of DIC, oxaliplatin should be discontinued and appropriate treatment initiated (see section "Adverse reactions"). Particular attention should be paid to patients with conditions predisposing to DIC, such as infections or sepsis.

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. Special monitoring is indicated in patients with a history of QT interval 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 attention is recommended when oxaliplatin is used concomitantly with medicinal products associated with rhabdomyolysis (see sections "Interaction with other medicinal products and other types of interactions" and "Adverse reactions").

Gastrointestinal ulcers / bleeding and 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 ulceration, 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.

Pregnancy. For use during pregnancy, see section "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 the drug (see section "Pharmacokinetics"), it is recommended as a precautionary measure to continue contraception 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 in men and women

Men should be advised to preserve sperm before treatment, as oxaliplatin may cause infertility, which may be irreversible (see section "Special precautions").

Other warnings. In case of intraperitoneal administration of oxaliplatin (a route not recommended in the product instructions), peritoneal bleeding may occur.

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 5-fluorouracil, no changes in the pharmacological effect of 5-fluorouracil were observed.

In in vitro studies, no significant displacement of oxaliplatin bound to plasma proteins by the following medicinal products was observed: 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"). Caution is also recommended when oxaliplatin is used concomitantly with medicinal products that may be associated with rhabdomyolysis.

Special precautions for use

Use during pregnancy or breastfeeding

Pregnancy. There are currently no data on the safety of oxaliplatin use for the treatment of pregnant women. Reproductive toxicity has been observed in animal studies.

Therefore, oxaliplatin is not recommended for use in pregnant women or in women of childbearing potential who are not using contraception.

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

Patients must use appropriate contraceptive methods during treatment. Such contraception should be continued after completion of therapy: in women – for 15 months, in men – for 12 months.

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

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

Breastfeeding. It is not known whether oxaliplatin is excreted in human milk. Breastfeeding is contraindicated during oxaliplatin therapy.

Effect on the ability to drive or operate machinery

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

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

Method of Administration and Dosage

The medicinal product is intended only for treatment of adults.

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

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

Dosage adjustments should be made according to individual tolerance to the medicinal product (see section "Special Warnings and Precautions for Use").

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

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 usually administered in combination with continuous infusion of 5-FU.

For a treatment regimen repeated every two 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 Warnings and Precautions for Use").

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 required for elderly patients.

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

Method of Administration

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

Oxaliplatin is administered as an intravenous infusion. Administration of the medicinal product 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.

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

If hematoma develops at the injection site, administration of the medicinal product must be stopped immediately.

Instructions for Use and Disposal. Preparation of oxaliplatin solutions requires adherence to precautionary measures, as with other potentially toxic substances.

Handling this cytotoxic substance 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 and, above all, protection of 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 work surface covers, 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 substances.

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

In case of contact of oxaliplatin concentrate, reconstituted solution, or infusion solution with the skin, the affected area should be immediately and thoroughly rinsed with water.

In case of contact of oxaliplatin concentrate, reconstituted solution, or infusion solution 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 (Disodium Folinic Acid or Calcium Folinic Acid)

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-shaped 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 in 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 administration.

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

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

Visual inspection of the concentrate for infusion solution should be performed before administration. Only clear solutions without particles should be used.

The vial is intended for single use only. Any unused solution must be discarded.

Dilution prior to Infusion. Withdraw the required amount of concentrate from the vial and dilute in 250–500 ml of 5 % glucose solution to obtain 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 6 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 user. Storage should 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 solutions without mechanical inclusions should be used.

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

Compatibility of 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-fluorouracil, oxaliplatin infusion should precede 5-fluorouracil administration.

Disposal

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

Children

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

Overdose

There is no known antidote for oxaliplatin. In case of overdose, 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 combined therapy with oxaliplatin and 5-fluorouracil/folinic acid (5-FU/FA), the most frequently observed adverse events were gastrointestinal disorders (diarrhea, nausea, vomiting, and mucositis), hematological disorders (neutropenia, thrombocytopenia), and neurological syndromes (acute and cumulative sensory peripheral neuropathy). These adverse reactions were more frequent and more severe when oxaliplatin was combined with 5-FU/FA compared to 5-FU/FA monotherapy.

The adverse reactions listed in Table 7 were observed during clinical trials and post-marketing use.

The frequency of adverse reactions is defined according to 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

* For details, see section "Description of selected adverse reactions" below.

** See section "Special precautions".

*** Microangiopathic hemolytic anemia associated with HUS or positive Coombs' test hemolytic anemia, see section "Special precautions".

• Sepsis-associated neutropenia is frequently observed, including cases with fatal outcome.

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

+++ 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 administered via peripheral vein infusion (see section "Special safety precautions").

Description of selected adverse reactions

Disorders of the blood and lymphatic system

Table 8

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

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

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

Infections and parasitic diseases.

Table 9

Incidence in patients (%)

Post-marketing experience (frequency unknown): septic shock, including fatal outcomes.

Immune system disorders

Table 10

Frequency of allergic reactions in patients (%), by severity degree

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

Nervous system disorders

Neurological toxicity of oxaliplatin is dose-dependent. It mainly manifests as sensory peripheral neuropathies characterized by paresthesia and/or dysesthesia of the extremities, with or without spasms, often triggered by cold. These symptoms occur 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 "Dosage and Administration"), 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 positive progression or complete resolution at the time of treatment discontinuation.

Six months after discontinuation 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 occur within several hours after drug administration, often triggered by exposure to cold. They are characterized by transient paresthesia, dysesthesia, and hypoesthesia. This acute pharyngolaryngeal dysesthesia syndrome, estimated to occur in 1–2% of cases, is characterized by subjective sensations of dysphagia or dyspnea/choking without objective signs of respiratory distress syndrome (not accompanied by cyanosis or hypoxia), laryngospasm, or bronchospasm (without stridor or wheezing).

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

Other observed symptoms include: jaw spasms, muscle spasms, involuntary muscle contractions, myoclonus, coordination disorders, gait disturbances, ataxia, balance disorders, throat or chest tightness, depression, discomfort, and pain. Additionally, cranial nerve involvement may occur, presenting as ptosis, diplopia, aphonia, dysphonia, hoarseness sometimes referred to as aphasia, 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 occurred during oxaliplatin treatment. Isolated cases of optic neuritis have also been reported.

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

Cardiac disorders

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

Respiratory, thoracic and mediastinal disorders

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

Gastrointestinal disorders

Table 11

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-fluorouracil.

Adverse reactions observed in the post-marketing period (frequency unknown): intestinal ischaemia, including fatal cases (see section "Special precautions"), oesophagitis. Gastrointestinal ulcers and perforations, which may be fatal (see section "Special precautions").

Hepatobiliary disorders

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

Disorders of the musculoskeletal system and connective tissue

Adverse reactions observed in the post-marketing period (frequency unknown): rhabdomyolysis, including fatal cases (see section "Special precautions").

Renal and urinary disorders

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

Skin and subcutaneous tissue disorders

Adverse reactions observed in the post-marketing period (frequency unknown): leukocytoclastic vasculitis.

Reporting of suspected adverse reactions after marketing authorization of a medicinal product is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare and pharmacy 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: https://aisf.dec.gov.ua.

Shelf life. 2 years.

After dilution in 5% glucose solution, the chemical and physical stability of the ready-to-use solution is maintained for 24 hours at 2–8 °C and for 6 hours at 20–25 °C.

From a microbiological point of view, 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 normally not exceed 24 hours at 2–8 °C, unless dilution has been carried out under controlled and validated aseptic conditions.

Storage conditions

Store at a temperature not exceeding 25 °C.

Keep in the original packaging in a place protected from light.

Do not freeze.

Keep out of reach of children.

Incompatibilities

The diluted preparation must 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, trometamol, and medicinal products containing folic acid and trometamol 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 administration system.

Do not use injectable products containing aluminium.

Packaging. 10 ml (50 mg) or 20 ml (100 mg) in a vial; 1 vial per cardboard box.

Prescription status

By prescription only.

Manufacturer

Qilu Pharmaceutical (Hainan) Co., Ltd.

Qilu Pharmaceutical (Hainan) Co., Ltd.

Manufacturer's address

No. 273-A, Nanhai Avenue, National High-Tech Zone, Haikou, Hainan 570314, China

No.273-A, Nanhai Avenue, National High-Tech Zone, Haikou, Hainan 570314, China

Marketing Authorization Holder

M.BIOTECH LIMITED

M.BIOTECH LIMITED

Address of Marketing Authorization Holder

Gladstone House, 77-79 High Street, Egham TW20 9HY, Surrey, United Kingdom

Gladstone House, 77-79 High Street, Egham TW20 9HY, Surrey, United Kingdom