Oxaliplatin fares

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

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, colorless solution.

Pharmacotherapeutic group. Antineoplastic agents. Platinum compounds. Oxaliplatin.

ATC Code L01XA03.

Pharmacological Properties.

Pharmacodynamics.

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

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

Oxaliplatin 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 activity in vitro and in vivo against various cell lines resistant to cisplatin.

When combined with 5-fluorouracil (5-FU), synergistic cytotoxic effects have been observed both in vitro and in vivo.

Studies on the mechanism of action, although not yet fully elucidated, indicate that aqueous derivatives formed as a result of oxaliplatin biotransformation 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 (85 mg/m² every 2 weeks) in combination with 5-fluorouracil (5-FU) and leucovorin (LV) in patients with metastatic colorectal cancer has been demonstrated in three clinical trials:

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

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

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

Table 1

Response rates with the FOLFOX4 regimen compared to the LV5FU2 regimen

Frequency of occurrence of therapeutic response % (CI = 95%) Independent radiological assessment All patients enrolled in the study (ITT analysis)	LV5FU2	FOLFOX4	Monotherapy with oxaliplatin
First-line therapy EFC2962	22 (16–27)	49 (42−56)	NA*
Response was assessed every 8 weeks	Criterion P = 0.0001
Patients previously treated with anticancer therapy EFC4584 (resistant to CPT-11 + 5-FU/FA)	0.7 (0.0–2.7)	11.1 (7.6–15.5)	1.1 (0.2–3.2)
Response was assessed every 6 weeks	Criterion P < 0.0001
Patients previously treated with anticancer therapy EFC2964 (resistant to 5-FU/FA) Response was assessed every 12 weeks	NA*	23 (13–36)	NA*

• NA – not applicable.

Table 2

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

Median PFS/TTD (months) (CI = 95%) Independent radiological review Intent-to-treat (ITT) analysis	LV5FU2	FOLFOX4	Monotherapy with oxaliplatin
First-line therapy EFC2962 (PFS)	6.0 (5.5–6.5)	8.2 (7.2–8.8)	NA*
	Log-rank test p = 0.0003
Patients previously treated with anticancer therapy EFC4584 (TTP) (refractory to CPT-11 + 5-FU/FA)	2.6 (1.8–2.9)	5.3 (4.7–6.1)	2.1 (1.6–2.7)
	Log-rank test p < 0.0001
Patients previously treated with anticancer therapy EFC2964 (refractory to 5-FU/FA)	NA*	5.1 (3.1–5.7)	NA*

• NA – not applicable.

Table 3

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

Median PFS, months (95% CI) Analysis of data from all patients included in the studies (ITT analysis)	LV5FU2	FOLFOX4	Oxaliplatin monotherapy
First-line therapy EFC2962	14.7 (13.0–18.2)	16.2 (14.7–18.2)	NA*
	Log-rank test p = 0.12
Patients previously treated with anticancer therapy EFC4584 (CPT-11 + 5-FU/FA refractory)	8.8 (7.3–9.3)	9.9 (9.1–10.5)	8.1 (7.2–8.7)
	Log-rank test p = 0.09
Patients previously treated with anticancer therapy EFC2964	NA*	10.8 (9.3–12.8)	NA*

* NA – not applicable.

Among patients who had disease symptoms at baseline and who had previously received anticancer therapy (EF4584), a statistically significant improvement in symptoms was observed to a greater extent 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 adjuvant setting, 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 therapy (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

Therapeutic group	LV5FU2	FOLFOX4
Percentage of patients with 3-year disease-free survival (CI = 95%)	73.3 (70.6–75.9)	78.7 (76.2–81.1)
Hazard ratio (CI = 95%)	0.76 (0.64–0.89)
Stratified log-rank test	P = 0.0008

*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 combined oxaliplatin and 5-FU/FA (FOLFOX4) therapy compared to 5-FU/FA (LV5FU2) therapy.

Table 5

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

Stage of disease	Stage II (Duke’s B2)		Stage III (Duke’s C)
Treatment group	LV5FU2	FOLFOX4	LV5FU2	FOLFOX4
Percentage of patients with 3-year disease-free survival (CI = 95%)	84.3 (80.9–87.7)	87.4 (84.3–90.5)	65.8 (62.2–69.5)	72.8 (69.4–76.2)
Hazard ratio (CI = 95%)	0.79 (0.57–1.09)		0.75 (0.62–0.90)
Log-rank test	P=0.151		P=0.002

*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 of the 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% 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).

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

Monotherapy with oxaliplatin was evaluated in children during 2 phase I studies (69 patients) and 2 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 metabolites has not been defined. The pharmacokinetics of ultrafilterable platinum, i.e., the mixture of all forms of non-conjugated active and inactive platinum in blood 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 is presented in Table 6.

Table 6

Summary 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

Dose	Cmax	AUC0-48	AUC	t1/2α	t1/2β	t1/2Y	Vss	Clearance
	μg/mL	μg·h/mL	μg·h/mL	hours	hours	hours	liters	L/h
85 mg/m² (mean standard deviation)	0.814 0.193	4.19 0.647	4.68 1.40	0.43 0.35	16.8 5.74	391 406	440 199	17.4 6.35
130 mg/m² (mean standard deviation)	1.21 0.10	8.20 2.40	11.9 4.60	0.28 0.06	16.3 2.90	273 19.0	582 261	10.1 3.07

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 using non-compartmental analysis.

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 lifespans 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, with steady-state conditions achieved in this matrix during the first treatment cycle. Pharmacokinetic parameters generally show little inter- and intra-patient variability.

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, various cytotoxic metabolites are detected in systemic circulation, including mono-chloro, di-chloro, and di-aquo derivatives of DACH-platinum, along with some inactive conjugates.

Platinum is primarily excreted in urine within the first 48 hours after administration. By day 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/hour 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 evaluated.

The effect of renal impairment on oxaliplatin disposition 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 treatment 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.

Oxaliplatin elimination correlates significantly 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 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 5-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 < 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.

Oxaliplatin should be administered only in specialized oncology departments and under the supervision of an experienced oncologist.

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

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

In case of extravasation of the drug, 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 for specific neurotoxicity. A neurological examination should be performed before each administration and periodically thereafter.

Patients who develop acute laryngopharyngeal dysesthesia during or within several hours after a 2-hour infusion (see section "Adverse reactions") should receive the next dose no sooner than 6 hours after the previous infusion. To prevent such dysesthesia, patients should be advised to avoid cold exposure and swallowing 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 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 sensory peripheral neuropathy symptoms 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 PRES — posterior reversible encephalopathy syndrome) have been reported in patients receiving oxaliplatin as part of combination chemotherapy. RPLS is a rare, rapidly developing, reversible neurological disorder that may present with seizures, arterial hypertension, headache, confusion, blindness, and other visual and neurological disturbances (see section "Adverse reactions"). Diagnosis of RPLS is confirmed by brain imaging techniques, preferably MRI (magnetic resonance imaging).

Nausea, vomiting, diarrhea, dehydration, and hematological changes. Gastrointestinal toxicity of oxaliplatin, 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 should be performed before initiation of oxaliplatin therapy and prior to each subsequent cycle. Myelosuppressive effects of the drug may be additive to those of concurrently 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"). Oxaliplatin should be discontinued in case of any of these events.

Patients should be informed that they must seek immediate medical attention if diarrhea/vomiting, mucositis/stomatitis, or neutropenia develop after administration of oxaliplatin and 5-FU, to receive appropriate treatment.

In case of mucositis/stomatitis, with or without neutropenia, the next administration of the drug should be delayed until symptoms of mucositis/stomatitis decrease to grade I or lower and/or until neutrophil count exceeds 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 WHO grade 4 diarrhea, grade 3–4 neutropenia (neutrophil count <1x10⁹/L), febrile neutropenia (body temperature elevation of unknown origin without clinically or microbiologically documented infection when absolute neutrophil count is <1.0x10⁹/L), single temperature elevation >38.3°C or persistent temperature elevation >38°C for more than 1 hour, or grade 3–4 thrombocytopenia (platelet count <50x10⁹/L), the dose of oxaliplatin should be reduced by 25% in addition to 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, oxaliplatin treatment should be discontinued until interstitial pneumonitis or pulmonary fibrosis is ruled out by further 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 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 cases, have been reported during oxaliplatin treatment. In case of DIC, oxaliplatin should be discontinued and appropriate treatment initiated (see section "Adverse reactions"). Particular vigilance is required in 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 cases, have been reported in patients receiving oxaliplatin. In case of muscle pain and swelling combined with weakness, elevated body temperature, or darkening of urine, oxaliplatin should be discontinued. Appropriate treatment should be initiated upon confirmed diagnosis of rhabdomyolysis. Particular vigilance is recommended when oxaliplatin is co-administered with medicinal products associated with rhabdomyolysis (see sections "Interaction with other medicinal products and other forms of interaction" and "Adverse reactions").

Gastrointestinal ulceration/bleeding and gastrointestinal ulcer perforation. Oxaliplatin treatment may lead to gastrointestinal ulceration and 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 or portal hypertension not caused by liver metastases, the possibility of rare drug-induced hepatic vascular disorders should be considered.

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

Fertility. Genotoxic effects of oxaliplatin have been observed in preclinical studies. Men are advised to use reliable contraception throughout the entire period of oxaliplatin treatment and for 6 months after treatment discontinuation, and to consider sperm cryopreservation prior to treatment initiation, as oxaliplatin may cause irreversible infertility. Women should avoid pregnancy during treatment and use a reliable contraceptive method (see section "Use during pregnancy or breastfeeding").

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

Interaction with other medicinal products and other forms of interaction.

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

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

Caution is required when oxaliplatin is used concomitantly with other medicinal products known to prolong the QT interval, and careful monitoring of the QT interval is necessary (see section "Special precautions for use"). Caution is also recommended when oxaliplatin is used concomitantly with other medicinal products that may be associated with rhabdomyolysis (see section "Special precautions for use").

Special precautions for use.

Use during pregnancy or breastfeeding.

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

Therefore, oxaliplatin is not recommended for administration to pregnant women or 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 risk to the fetus and obtaining her consent.

Patients should use appropriate contraceptive methods during treatment. Such methods should be continued after completion of treatment: in women – for 4 months, in men – for 6 months.

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

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

Ability to affect reaction speed when driving or operating machinery.

The effect on the ability to drive vehicles or operate machinery has not been studied. However, since administration of oxaliplatin 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 loss of vision (which resolves after discontinuation of therapy), may also affect a patient's ability to drive vehicles or operate machinery. Therefore, patients should be warned about the possible impact of these effects on their ability to drive vehicles or operate machinery.

Dosage and Administration

The medicinal product is intended for use in adults only.

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 occur.

Dosage should be adjusted according to individual tolerability (see section "Special Warnings and Precautions for Use").

Oxaliplatin must always be administered before fluoropyrimidines, for example prior to 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 generally administered in combination with continuous infusion of 5-FU.

For a two-weekly treatment regimen, bolus administration combined with continuous infusion of 5-FU is recommended.

Special Patient Categories

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

No specific dose adjustments were performed in clinical trials for patients with hepatic impairment.

Elderly Patients. No increased toxicity of oxaliplatin 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.

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

Administration Method.

Oxaliplatin must be diluted prior to administration. Only the recommended diluent – 5% glucose solution – should be used for reconstitution of 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 not less than 0.2 mg/mL is administered via central or peripheral vein over 2–6 hours.

Oxaliplatin infusion should always precede 5-FU infusion.

If extravasation occurs at the injection site, administration must be stopped immediately.

Instructions for Handling and Disposal. Precautions must be observed during the preparation of 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 experienced personnel familiar with the handling of such medicinal products, under conditions ensuring environmental protection and, above all, protection of the personnel handling these agents. A specifically designated area must be available for preparation procedures. Eating, drinking, and smoking are strictly prohibited in the designated area.

Personnel must be provided with appropriate materials for handling the medicinal product, including medical gowns with long sleeves, protective masks, head coverings, 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 agents.

Any damaged packaging must be handled according to 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 must 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 must 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 administered via a Y-type infusion system with a side arm 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 must 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 must always be administered before fluoropyrimidines, for example prior to 5-FU administration.

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

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

Prior to administration, a visual inspection of the concentrate for infusion solution must be performed. Only clear solutions free from particles should be used.

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

Dilution Prior to Infusion. The required amount of concentrate for infusion solution should be 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.

The solution is administered as an intravenous infusion.

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

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

If the solution is not administered immediately after preparation, the 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 the dilution was performed under aseptic conditions in controlled and standardized settings.

The infusion solution should be used immediately. A visual inspection must be performed prior to administration. Only clear, particle-free solutions should be used.

Chloride-containing solutions or sodium chloride solution must never be used for dilution.

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

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

Disposal. Any unused medicinal product and all materials used for reconstitution and administration of oxaliplatin must be destroyed in accordance with standard procedures for disposal of cytotoxic waste, taking into account applicable regulations for the destruction of toxic waste.

Paediatric Population

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 tumours has not been established (see section "Pharmacological Properties").

Overdose

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

Adverse reactions

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

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

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

Table 7

System Organ Classes	Adverse reactions by frequency
	Very common	Common	Uncommon	Rare
Laboratory investigations	elevation of liver enzymes, elevation of alkaline phosphatase in blood, elevation of bilirubin in blood, elevation of LDH in blood, weight gain (in adjuvant therapy)	elevation of creatinine, weight loss (in treatment of metastatic cancer)
Injury, poisoning and procedural complications		Falls
Blood and lymphatic system disorders*	anemia, neutropenia, thrombocytopenia, leukopenia, lymphopenia	febrile neutropenia		immune-mediated thrombocytopenia, hemolytic anemia
Nervous system disorders*	peripheral sensory neuropathy, sensory disturbances, taste disturbances, headache	dizziness, motor nerve neuritis, meningism		dysarthria, reversible posterior leukoencephalopathy syndrome (PRES) (see section "Special precautions")
Eye disorders		conjunctivitis, visual disturbances		transient decrease in visual acuity, visual field disturbances, optic neuritis; transient loss of vision, which resolves after discontinuation of therapy
Ear and labyrinth disorders			ototoxicity	deafness
Respiratory, thoracic and mediastinal disorders	dyspnea, cough, nosebleeds	hiccups, pulmonary artery embolism		acute interstitial lung disease, sometimes fatal; pulmonary fibrosis**
Gastrointestinal disorders*	nausea, diarrhea, vomiting, stomatitis/mucositis, abdominal pain, constipation	dyspepsia, gastroesophageal reflux, gastrointestinal hemorrhage, rectal hemorrhage	intestinal paresis, intestinal obstruction	colitis, including diarrhea caused by Clostridium difficile, diarrhea, pancreatitis
Renal and urinary system disorders		hematuria, dysuria, urination frequency disturbances
Skin and subcutaneous tissue disorders	skin disorders, alopecia	skin peeling (e.g., palmar-plantar syndrome), erythematous rash, rash, hyperhidrosis, nail disorders
Musculoskeletal and connective tissue disorders	back pain	arthralgia, bone pain
Metabolism and nutrition disorders	anorexia, hyperglycemia, hypokalemia, hypernatremia	dehydration, hypocalcemia	metabolic acidosis
Infections and infestations*	infections	rhinitis, upper respiratory tract infections, neutropenic sepsis	sepsis+
Vascular disorders		bleeding, hyperemia, deep vein thrombophlebitis, arterial hypertension, thromboembolism
General disorders and administration site conditions	fatigue, fever+++, asthenia, pain, injection site reaction++++
Immune system disorders*	allergy/ allergic reaction++
Psychiatric disorders		depression, insomnia	anxiety

* See detailed information in the section provided below.

**See section "Special precautions".

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

++ Very common allergic/allergic reactions, occurring predominantly during infusion and sometimes resulting in death. Common allergic reactions include skin rashes (particularly urticaria), conjunctivitis, and rhinitis. Anaphylactic reactions, including bronchospasm, angioneurotic edema, 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.

+++ Fever and chills (shivering) are very common, either of infectious origin (with or without febrile neutropenia) or possibly 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, particularly when oxaliplatin is administered intravenously via a peripheral vein (see section "Special precautions").

Blood and lymphatic system disorders.

Table 8

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

Oxaliplatin in combination with 5-FU/FA 85 mg/m2 every 2 weeks	Treatment of metastases			Adjuvant therapy
	All grades	Grade 3	Grade 4	All grades	Grade 3	Grade 4
Anemia	82.2	3	< 1	75.6	0.7	0.1
Neutropenia	71.4	28	14	78.9	28.8	12.3
Thrombocytopenia	71.6	4	< 1	77.4	1.5	0.2
Febrile neutropenia	5	3.6	1.4	0.7	0.7	0

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

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

Infectious and parasitic diseases.

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

Table 9

Oxaliplatin in combination with 5-FU/FA 85 mg/m2 every 2 weeks	Treatment of metastases All grades	Adjuvant therapy All grades
Sepsis (including neutropenic sepsis)	1.5	1.7

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

Immune system disorders.

Table 10

Oxaliplatin in combination with 5-FU/FA 85 mg/m2 every 2 weeks	Treatment of metastases			Adjuvant therapy
	All grades	Grade 3	Grade 4	All grades	Grade 3	Grade 4
Allergic reactions/allergic events	9.1	1	< 1	10.3	2.3	0.6

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 mainly manifests as sensory peripheral neuropathies characterized by paresthesia and/or dysesthesia of the extremities, with or without associated muscle spasms, often triggered by cold. These symptoms are observed in approximately 95% of patients receiving treatment. The duration of these symptoms, which usually regress between treatment cycles, increases with the number of treatment cycles administered.

Depending on the duration of symptoms such as pain and/or functional impairment (see section "Dosage and Administration"), dose 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 positive progression or complete resolution at the time of treatment discontinuation.

Six months after completion of adjuvant therapy for colorectal cancer, 87% of patients had no symptoms or only mild symptoms. After three 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 drug administration and are 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/throat tightness 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 "Dosage and Administration").

Other observed symptoms include: jaw spasms, muscle spasms, involuntary muscle contractions, myoclonus, coordination disturbances, gait disturbances, ataxia, balance disorders, throat or chest tightness, lethargy, discomfort, and pain. Additionally, cranial nerve involvement may occur either simultaneously or separately, presenting as 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 resulting in fatal outcomes (see section "Dosage and Administration"), acute coronary syndrome including myocardial infarction, coronary arteriospasm, and angina pectoris 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 cases with fatal outcome.

Gastrointestinal disorders.

Table 11

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

Oxaliplatin in combination with 5-FU/FA 85 mg/m² every 2 weeks	Treatment of metastases			Adjuvant therapy
	All grades	Grade 3	Grade 4	All grades	Grade 3	Grade 4
Nausea	69.9	8	< 1	73.7	4.8	0.3
Diarrhea	60.8	9	2	56.3	8.3	2.5
Vomiting	49	6	1	47.2	5.3	0.5
Mucositis/stomatitis	39.9	4	< 1	42.1	2.8	0.1

Treatment or prophylactic administration of potent antiemetic agents is indicated.

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

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

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

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

Musculoskeletal and connective tissue disorders. 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.

Shelf life. 3 years.

Storage conditions.

Store in the original packaging to protect from light, in a place inaccessible to children. Do not freeze.

Incompatibilities.

Never mix the diluted preparation with other medicinal products in the same vial or infusion system unless specified in the instructions for medical use.

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

Alkaline solutions and preparations negatively affect the stability of oxaliplatin.

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

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

Do not use injectable preparations containing aluminum.

Packaging.

10 ml, 20 ml, or 40 ml of concentrate in a vial, 1 vial per carton.

Prescription category. Prescription only.

For use only in hospital settings by oncology specialists.

Manufacturer.

Timoorgan Pharma GmbH.

Manufacturer's address and place of business.

Schiffgraben 23, Goslar, Lower Saxony, 38690, Germany.