Oxaliplatin amaksa

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT Oxaliplatin Amaxa Oxaliplatin Amaxa

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. Other antineoplastic agents, platinum compounds.

ATC code L01XA03.

Pharmacological Properties.

Pharmacodynamics.

Oxaliplatin Amaksa is an antineoplastic medicinal product belonging to a new class of platinum-based compounds containing a platinum atom complexed with 1,2-diaminocyclohexane (DACH) and an oxalate group.

Oxaliplatin Amaksa is a single enantiomer designated as (SP-4-2)-[(1R,2R)-cyclohexane-1,2-diamine-kN,kN′] [ethanedioate(2−)-kO1,kO2] platinum.

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

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

Although the mechanism of action of oxaliplatin has not been fully elucidated, studies indicate that aqueous derivatives formed during the biotransformation of oxaliplatin interact with DNA, forming both interstrand and intrastrand cross-links, thereby disrupting DNA synthesis. This disruption underlies the cytotoxic and antitumor effects.

Efficacy of oxaliplatin (85 mg/m² every 2 weeks) in combination with 5-FU/leucovorin (LV) has been reported in three clinical trials in patients with metastatic colorectal cancer:

• In the phase III, two-arm, first-line treatment study EFC2962, 420 patients were randomly assigned either to receive 5-FU/LV alone (LV5FU2, N=210) or combination therapy with oxaliplatin plus 5-FU/LV (FOLFOX4, N=210).
• In the phase III, three-arm comparative study EFC4584 involving previously treated patients, 821 patients with resistance to prior combination therapy with irinotecan (CPT-11) plus 5-FU/LV were randomly assigned to receive either 5-FU/LV alone (LV5FU2, N=275), oxaliplatin monotherapy (N=275), or combination therapy with oxaliplatin plus 5-FU/LV (FOLFOX4, N=271).
• The phase II, single-arm, non-comparative study EFC2964 included patients with resistance to prior 5-FU/LV therapy who received combination treatment with oxaliplatin and 5-FU/LV (FOLFOX4, N=57).

Two randomized clinical trials—EFC2962 in first-line treatment patients and EFC4584 in previously treated patients—demonstrated significantly higher response rates and longer progression-free survival (PFS)/time to progression (TTP) compared to patients receiving 5-FU/LV alone. In the EFC4584 trial, which included previously treated and treatment-refractory patients, the difference in median overall survival (OS) between the oxaliplatin plus 5-FU/LV treatment group and the 5-FU/LV alone group did not reach statistical significance.

Table 1

Clinical efficacy of the FOLFOX4 regimen compared to the LV5FU2 regimen

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

NA* – not applicable.

Table 2

Median PFS/median OS: FOLFOX4 regimen compared with LV5FU2 regimen

Median PFS/TTSP months (95 % CI) independent radiological review (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 (TTSP) (resistant 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 (resistant to 5-FU/FA)	NA*	5.1 (3.1–5.7)	NA*

NA* – not applicable.

Table 3

Median overall survival (OS): FOLFOX4 regimen compared with LV5FU2 regimen

Median PFS, months (95% CI) (ITT analysis)	LV5FU2	FOLFOX4	Monotherapy with oxaliplatin
First-line therapy EFC2962	14.7 (13.0–18.2)	16.2 (14.7–18.2)	NA*
	Log-rank test P = 0.12
Previously treated patients EFC4584 (refractory to CPT-11 + 5-FU/FA)	8.8 (7.3–9.3)	9.9 (9.1–10.5)	8.1 (7.2–8.7)
	Log-rank test P = 0.09
Previously treated patients EFC2964 (refractory to 5-FU/FA)	NA*	10.8 (9.3–12.8)	NA*

NA* – not applicable.

Among patients who had received prior treatment (EFC4584) and had symptoms at the start of treatment, the majority experienced a significant improvement in disease-related symptoms after treatment with oxaliplatin and 5-FU/FA, compared with patients who received treatment with 5-FU/FA alone (27.7% vs. 14.6%, p = 0.0033).

Among previously untreated patients (EFC2962), no statistically significant differences between the two treatment groups were observed for any quality-of-life parameter. However, quality-of-life scores for general health status and pain were generally better in the control group, whereas scores for nausea and vomiting were worse in the oxaliplatin treatment group. In the comparative Phase III MOSAIC trial (EFC3313), 2246 patients (899 at Duke's stage II/B2 and 1347 at Duke's stage III/C) undergoing adjuvant therapy were randomly assigned after complete resection of primary colorectal cancer either to treatment with 5-FU/FA alone (LV5FU2, N = 1123 (B2/C = 448/675)) or to combination treatment with oxaliplatin and 5-FU/FA (FOLFOX4, N = 1123 (B2/C) = 451/672).

Table 4

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

Treatment 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 was 44.2 months (all patients were followed for at least 3 years after completion of treatment).

The study demonstrated a statistically significant overall benefit in 3-year disease-free survival for the oxaliplatin plus 5-FU/FA (FOLFOX4) treatment group compared to the 5-FU/FA (LV5FU2) group.

Table 5

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

Stage of disease	Stage II (Dukes B2)		Stage III (Dukes 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 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 for 3-year disease-free survival, which was the primary endpoint of the MOSAIC study, 85.1% of patients remained alive in the FOLFOX4 treatment group versus 83.8% in the LV5FU2 treatment group. This represented an overall 10% reduction in the risk of death in favor of the FOLFOX4 group, which did not reach statistical significance (hazard ratio = 0.90). The respective figures were 92.2% versus 92.4% in the subgroup with stage II (Dukes B2) disease (hazard ratio = 1.01) and 80.4% versus 78.1% in the subgroup with stage III (Dukes C) disease (hazard ratio = 0.87) for FOLFOX4 and LV5FU2, respectively.

Monotherapy with oxaliplatin was evaluated in the pediatric population in two phase I studies (69 patients) and two phase II studies (166 patients). Overall, 235 pediatric patients (aged from 7 months to 22 years) with solid tumors received treatment. The efficacy of oxaliplatin monotherapy in pediatric treatment groups has not been established. Enrollment in both phase II studies was discontinued due to lack of tumor response.

Pharmacokinetics.

The pharmacokinetics of individual active compounds was not studied. The pharmacokinetics of ultrafilterable platinum, representing a mixture of all free, active, and inactive platinum molecules, after a two-hour infusion of oxaliplatin at a dose of 130 mg/m² every 3 weeks (1 to 5 cycles) and oxaliplatin at a dose of 85 mg/m² every 2 weeks (1 to 3 cycles) is presented in Table 6.

Table 6

Pharmacokinetic parameters of platinum measured in plasma ultrafiltrate after multiple administrations of oxaliplatin at a dose of 85 mg/m² every 2 weeks or 130 mg/m² every 3 weeks

Dose	Cmax (μg/mL)	AUC0-48 (μg·h/mL)	AUC (μg·h/mL)	t1/2α (h)	t1/2β (h)	t1/2γ (h)	Vss (L)	Clearance (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

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

Mean values of AUC, Vss, and clearance (CL) 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 values were determined using compartmental analysis (pooled cycles 1–3).

At the end of the two-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 in these compartments close to the natural lifespan of erythrocytes and serum albumin. After administration of 85 mg/m² every 2 weeks or 130 mg/m² every 3 weeks, no accumulation was observed in plasma ultrafiltrate, and steady-state levels were achieved by cycle 1. Both intra-subject and inter-subject variability are generally low.

In vitro biotransformation is considered to result from non-enzymatic degradation, and there is no evidence of cytochrome P450-mediated metabolism of the diaminocyclohexane (DACH) ring.

Oxaliplatin undergoes extensive biotransformation in patients; at the end of the two-hour infusion, the unchanged drug was not detected in plasma ultrafiltrate. Subsequently, several cytotoxic biotransformation products were identified in systemic circulation, including mono-, di-chloro-, and diaqua-DACH-platinum derivatives, along with a number of inactive conjugates.

Platinum is primarily excreted in urine, with most elimination occurring within the first 48 hours after administration. By day 5, approximately 54% of the total dose is excreted in urine and <3% in feces.

In patients with renal impairment, clearance significantly decreased from 17.6 ± 2.18 L/h to 9.95 ± 1.91 L/h, along with a statistically significant reduction in volume of distribution from 330 ± 40.9 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 group 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 number of treatment cycles was 9, 4, 6, and 3, respectively. Pharmacokinetic data from cycle 1 were available for 11, 13, 10, and 4 patients, respectively.

An increase in plasma ultrafiltrate (PUF) platinum AUC, AUC/dose ratio, and a decrease in total CL and Vss were observed as the degree of renal impairment increased, 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/dose 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 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 was reduced 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 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 Warnings and Precautions”, and “Dosage and Administration”).

Clinical characteristics.

Indications.

Oxaliplatin Amaksa is indicated in combination with 5-fluorouracil (5-FU) and folinic acid (FA):

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

Contraindications.

Oxaliplatin is contraindicated in patients:

• with hypersensitivity to oxaliplatin or to any of the excipients of the medicinal product;
• during breastfeeding;
• with myelosuppression prior to the first cycle of treatment, defined by baseline neutrophil count <2×10⁹/L and/or platelet count <100×10⁹/L;
• with pre-existing peripheral sensory neuropathy associated with functional impairment prior to the first treatment cycle;
• with severe renal impairment (creatinine clearance less than 30 mL/min) (see section "Pharmacological properties" (subsection "Pharmacokinetics")).

Special precautions.

The use of oxaliplatin should be restricted to medical centers specialized in cytotoxic chemotherapy and must be administered only under the supervision of an experienced oncologist.

Renal impairment

Patients with mild to moderate renal impairment should be closely monitored for adverse reactions, and dose adjustments should be made according to toxicity (see section "Pharmacological properties" (subsection "Pharmacokinetics")).

Hypersensitivity reactions

Patients with a history of allergic reactions to other platinum-containing agents should be closely monitored. In case of anaphylactic reactions, infusion must be stopped immediately and appropriate symptomatic treatment initiated. Re-administration of oxaliplatin to such patients is contraindicated. Cross-reactivity, sometimes fatal, has been reported with other platinum compounds.

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

Neurological symptoms

Neurological toxicity of oxaliplatin should be carefully monitored, especially when the drug is used in combination with other medicinal products known to have neurotoxic potential. Neurological examinations should be performed before each administration and periodically thereafter.

For patients who develop acute laryngopharyngeal dysesthesia during or within several hours after the 2-hour infusion (see section "Adverse reactions"), the next oxaliplatin infusion should be administered over 6 hours. To prevent dysesthesia, patients should be informed to avoid exposure to cold and to refrain from ingesting cold food and/or drinks for several hours after drug administration.

Peripheral neuropathy

If neurological symptoms (paresthesia, dysesthesia) occur, the following dose modifications of oxaliplatin are recommended based on the duration and severity of symptoms:

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

Patients should be informed about the possibility of persistent peripheral sensory neuropathy symptoms after completion of treatment. Mild to moderate paresthesias or paresthesias affecting functional activity may persist for more than 3 years after discontinuation 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 in combination chemotherapy. RPLS is a rare, reversible, rapidly evolving neurological disorder that may include seizures, hypertension, headache, confusion, blindness, and other visual and neurological disturbances (see section "Adverse reactions"). Diagnosis of RPLS is confirmed by brain imaging, preferably MRI (magnetic resonance imaging).

Nausea, vomiting, diarrhea, dehydration, and hematological changes

Gastrointestinal toxicity, manifesting as nausea and vomiting, requires prophylactic and/or therapeutic antiemetic treatment (see section "Adverse reactions").

Acute diarrhea/vomiting may lead to dehydration, paralytic ileus, intestinal obstruction, hypokalemia, metabolic acidosis, and renal impairment, especially when oxaliplatin is combined with 5-FU.

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

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

Patients should be adequately informed about the risk of developing diarrhea/vomiting, mucositis/stomatitis, and neutropenia after oxaliplatin and 5-FU administration, so they can promptly contact their physician if necessary for appropriate management.

If mucositis/stomatitis occurs with or without neutropenia, subsequent treatment should be delayed until recovery to grade 1 severity or less and/or until neutrophil count is ≥1.5×10⁹/L.

Dose adjustments for oxaliplatin in combination with 5-FU (with or without FA) are required based on toxicity related to 5-FU.

In case of grade 4 diarrhea (WHO classification), grade 3–4 neutropenia (neutrophils <1.0×10⁹/L), febrile neutropenia (fever of unknown origin without clinically or microbiologically confirmed infection when absolute neutrophil count <1.0×10⁹/L, single temperature elevation >38.3°C or sustained temperature >38°C for more than 1 hour), or grade 3–4 thrombocytopenia (platelets <50×10⁹/L), the dose of oxaliplatin should be reduced from 85 to 65 mg/m² (for metastatic treatment) or to 75 mg/m² (for adjuvant treatment), in addition to necessary dose reduction of 5-FU.

Pulmonary disorders

In case of unexplained respiratory symptoms such as dry cough, dyspnea, crackles, or radiological pulmonary infiltrates, oxaliplatin should be discontinued until further investigations rule out interstitial pneumonitis and pulmonary fibrosis (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 decline in hemoglobin levels accompanied by thrombocytopenia, increased serum bilirubin, creatinine, blood urea nitrogen, or lactate dehydrogenase (LDH). Renal impairment may be irreversible after discontinuation of the drug and may require dialysis.

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

QT interval prolongation

Prolongation of the QT interval may increase the risk of ventricular arrhythmias, including polymorphic ventricular tachycardia (Torsade de Pointes), which may be fatal (see section "Adverse reactions"). Careful periodic monitoring of the QT interval before and after oxaliplatin administration is required. Special monitoring is indicated in patients with a history of QT prolongation or predisposition to QT prolongation, patients taking medicinal products known to prolong the QT interval, and patients with electrolyte imbalances such as hypokalemia, hypocalcemia, or hypomagnesemia. In case of QT interval prolongation, oxaliplatin treatment should be discontinued (see sections "Interaction with other medicinal products and other forms of interaction" and "Adverse reactions").

Rhabdomyolysis

Cases of rhabdomyolysis, including fatal cases, have been reported in patients receiving oxaliplatin. In case of muscle pain and swelling associated with weakness, fever, or dark urine, oxaliplatin treatment must be discontinued. If rhabdomyolysis is confirmed, appropriate treatment should be initiated. Particular caution and close monitoring are required when oxaliplatin is used concomitantly with medicinal products associated with rhabdomyolysis (see sections "Interaction with other medicinal products and other forms of interaction" and "Adverse reactions").

Gastrointestinal ulcers/bleeding ulcers and gastrointestinal perforations

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

Hepatic disorders

In case of liver function abnormalities or portal hypertension not attributable to liver metastases, the possibility of rare drug-induced vascular liver disorders should be considered.

Pregnancy

For use in pregnant women, see section "Use during pregnancy or breastfeeding".

Reproductive function

Genotoxic effects have been observed in preclinical studies with oxaliplatin. Therefore, male patients undergoing treatment with oxaliplatin are advised to use reliable contraception during treatment and for 6 months after treatment, and to seek consultation regarding sperm cryopreservation prior to treatment initiation, as oxaliplatin may cause irreversible infertility.

Female patients should use effective contraception during treatment with oxaliplatin (see section "Use during pregnancy or breastfeeding").

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

Interaction with other medicinal products and other forms of interaction.

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

In vitro studies showed no significant displacement of oxaliplatin from plasma protein binding when interacting with the following medicinal products: erythromycin, salicylates, granisetron, paclitaxel, and sodium valproate.

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

Special precautions for use.

Use during pregnancy or breastfeeding.

Pregnancy. There is currently no available information on the safety of oxaliplatin use in pregnant women. Reproductive toxicity has been observed in animal experimental studies. Therefore, Oxaliplatin Amaksa is not recommended for use in pregnant women or in women of childbearing potential who are not using effective contraception.

Oxaliplatin use may be considered only after careful assessment of the potential risk to the fetus and with patient consent.

Women and men undergoing treatment, as well as for 4 months after treatment discontinuation in women and 6 months in men, should use effective contraceptive measures.

Breastfeeding. It has not been studied whether oxaliplatin is excreted in human breast milk. Breastfeeding is contraindicated during oxaliplatin therapy.

Reproductive function. Oxaliplatin may have a negative impact on fertility. Due to the potential genotoxic effect of oxaliplatin, appropriate contraception should be used during treatment with this medicinal product and for at least 4 months (in women) or 6 months (in men) after completion of treatment.

Ability to affect reaction speed when driving vehicles or operating machinery.

Studies on the influence of oxaliplatin on the ability to drive vehicles or operate machinery have not been conducted. However, oxaliplatin treatment, which may increase the risk of dizziness, nausea, vomiting, and other neurological symptoms affecting gait and balance, could have a minor to moderate effect on the ability to drive or operate machinery.

Visual abnormalities, including transient loss of vision (reversible after therapy discontinuation), may also affect the ability to drive vehicles or operate machinery. Therefore, patients should be advised about the potential impact of these effects on their ability to drive or operate machinery.

Method of Administration and Dosage

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 (BSA), administered intravenously every 2 weeks for 12 cycles of therapy (6 months).

The recommended dose of oxaliplatin for the treatment of metastatic colorectal cancer is 85 mg/m² BSA administered intravenously every 2 weeks until disease progression or until signs of intolerable toxicity develop.

Dosage should be adjusted according to individual tolerance (see section "Special Precautions").

Oxaliplatin should always be administered before fluoropyrimidines, e.g., prior to 5-FU administration.

Oxaliplatin Amaksa is administered as an intravenous infusion over 2–6 hours, diluted in 250–500 mL of 5% glucose solution 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 two-weekly repeating treatment regimen, a dosing schedule involving bolus administration of 5-FU followed by continuous infusion of 5-FU is recommended.

Special Patient Populations

Patients with Renal Impairment

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

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

Patients with 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 underlying disease and baseline impaired liver function tests.

During clinical trials, no separate dose adjustment was performed for patients with abnormal liver function tests.

Elderly Patients

When oxaliplatin was used as monotherapy or in combination with 5-FU in patients aged 65 years and older, no increase in the frequency of severe toxicity was observed. Therefore, no special dose adjustment is required for elderly patients.

Children

There is no appropriate indication for the use of oxaliplatin in children. Efficacy of oxaliplatin monotherapy in pediatric solid tumor populations has not been established (see section "Pharmacological Properties" (subsection "Pharmacodynamics")).

Method of Administration

Oxaliplatin Amaksa is administered as an intravenous infusion.

Administration of oxaliplatin does not require hyperhydration.

Oxaliplatin, diluted in 250–500 mL of 5% glucose solution to achieve a concentration of at least 0.2 mg/mL, should be infused via a central venous catheter or a peripheral vein over 2–6 hours. Infusion of oxaliplatin must always precede administration of 5-FU.

In case of extravasation, administration must be stopped immediately.

Instructions for Use

Oxaliplatin Amaksa must be diluted before administration. Only 5% glucose solution should be used for dilution of the concentrate for infusion solution.

As with other potentially toxic compounds, caution should be exercised when handling and preparing oxaliplatin solutions.

Instructions for Administration and Disposal

Medical personnel handling this cytotoxic agent must take all necessary precautions to ensure protection of personnel and the environment.

Preparation of cytotoxic injectable solutions should be performed by trained specialized staff under conditions ensuring product integrity and protection of the environment, particularly protection of personnel handling the medicinal product, in accordance with hospital internal procedures. A designated preparation area is required. Smoking, eating, and drinking are prohibited in this area. Personnel must be provided with appropriate protective equipment, including long-sleeved gowns, protective masks, head covers, protective eyewear, sterile disposable gloves, protective work surface covers, waste containers, and disposal bags. Excreta and vomitus of patients should be handled with care. Pregnant women should be advised to avoid handling cytotoxic agents. Any damaged container should be handled with the same safety precautions as contaminated materials. Contaminated waste should be incinerated in appropriately labeled rigid containers; see the "Disposal" section below.

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

Special Warnings for Administration

• DO NOT use injection equipment containing aluminum.
• DO NOT administer the medicinal product in undiluted form.
• Only 5% glucose solution for infusion should be used as diluent. DO NOT dilute with sodium chloride solutions or chloride-containing solutions.
• DO NOT mix with other medicinal products in the same infusion bag or administer simultaneously through the same infusion system.
• DO NOT mix with alkaline medicinal products or solutions, including 5-FU, folinic acid preparations containing tromethamine as an excipient, or tromethamine salts of other medicinal products. Alkaline medicinal products or solutions adversely affect the stability of oxaliplatin.

Instructions for Use with Folinic Acid (as calcium folinate or disodium folinate)

Intravenous infusion of oxaliplatin 85 mg/m² in 250–500 mL of 5% glucose solution should be administered simultaneously with intravenous infusion of folinic acid in 5% glucose solution over 2–6 hours, using a Y-type infusion system with a side port immediately before the infusion site. These two agents must not be mixed in the same infusion bag. Folinic acid must not contain tromethamine as an excipient and should be diluted only with isotonic 5% glucose solution. Alkaline solutions, sodium chloride, or chloride-containing solutions must never be used.

Instructions for Use with 5-FU

Oxaliplatin Amaksa should always be administered before fluoropyrimidines, i.e., 5-FU.

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

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

Concentrate for Infusion Solution

The product should be visually inspected before administration. Only clear solutions without visible particles should be used.

The medicinal product is for single use only. Any unused concentrate must be disposed of.

Dilution Prior to Infusion

The required volume of concentrate should be withdrawn from the vial(s) and diluted in 250–500 mL of 5% glucose solution to achieve an oxaliplatin concentration between 0.2 and 0.7 mg/mL. Physical and chemical stability of oxaliplatin has been demonstrated at concentrations between 0.2 and 2 mg/mL.

Administer by intravenous infusion.

After dilution in 5% glucose solution, chemical and physical stability is maintained for 24 hours at 2–8°C and for 6 hours at temperatures not exceeding 25°C.

From a microbiological standpoint, this infusion preparation should be used immediately. If not used immediately, the user is responsible for the duration and conditions of storage during use. If dilution was not performed under controlled and validated aseptic conditions, the storage period should not exceed 24 hours at 2–8°C.

The product should be visually inspected before use. Only clear solutions without visible particles should be used.

The medicinal product is for single use only. Any unused infusion solution must be disposed of.

NEVER use sodium chloride or chloride-containing solutions for dilution.

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

Infusion

Administration of oxaliplatin does not require prehydration.

Oxaliplatin Amaksa, diluted in 250–500 mL of 5% glucose solution to achieve a concentration of at least 0.2 mg/mL, should be administered via a peripheral or central vein over 2–6 hours. When oxaliplatin is used in combination with 5-FU, the oxaliplatin infusion must precede 5-FU administration.

Disposal

Any unused medicinal product and all materials used for dissolving and administering oxaliplatin must be destroyed in accordance with standard procedures for disposal of cytotoxic waste, in compliance with current regulations.

Children

The medicinal product is intended for use in adults only.

Overdose

There is no known antidote for oxaliplatin. In case of overdose, adverse reactions may be exacerbated. Hematological monitoring should be initiated along with symptomatic treatment.

Adverse reactions

The most commonly observed adverse reactions during treatment with oxaliplatin in combination with 5-FU/FA were gastrointestinal disorders (diarrhea, nausea, vomiting, and mucositis), hematological abnormalities (neutropenia, thrombocytopenia), and neurological side effects (acute and cumulative peripheral sensory neuropathy). Overall, these adverse reactions occurred more frequently and were more severe with the combination of oxaliplatin and 5-FU/FA compared to 5-FU/FA alone.

The frequencies of adverse reactions listed in Table 7 are derived from clinical trials of metastatic and adjuvant therapy (involving 416 and 1108 patients, respectively, in the oxaliplatin + 5-FU/FA treatment groups) and from post-marketing experience.

The adverse reactions are categorized in the table according to the following frequency categories:

Very common (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1000, <1/100), rare (≥1/10,000, <1/1000), very rare (<1/10,000), frequency not known (cannot be estimated from the available data).

Table 7

MedDRA System Organ Classes	Very common	Common	Uncommon	Rare	Frequency not known
Laboratory investigations	Elevated liver enzymes Elevated alkaline phosphatase in blood Elevated blood bilirubin Elevated blood lactate dehydrogenase Increased body weight (adjuvant therapy)	Elevated blood creatinine Decreased body weight (anti-metastatic therapy)
Blood and lymphatic system disorders*	Anemia Neutropenia Thrombocytopenia Leukopenia Lymphopenia	Febrile neutropenia+		Immunoallergic thrombocytopenia Hemolytic anemia
Nervous system disorders*	Peripheral sensory neuropathy Sensory disturbances Dysgeusia Headache	Dizziness Motor nerve neuritis Meningism		Dysarthria Reversible posterior leukoencephalopathy syndrome (RPLS or PRES)**
Eye disorders		Conjunctivitis Visual disturbance		Transient decrease in visual acuity Visual field defect Optic neuritis Transient vision loss (reversible after discontinuation of therapy)
Ear and labyrinth disorders			Ototoxicity	Deafness
Respiratory, thoracic and mediastinal disorders	Dyspnea Cough Nasal hemorrhage	Hiccups Pulmonary artery embolism		Acute interstitial lung disease, sometimes fatal Lung fibrosis**
Gastrointestinal disorders*	Nausea Diarrhea Vomiting Stomatitis/mucositis Abdominal pain Constipation	Dyspepsia Gastroesophageal reflux Gastrointestinal hemorrhage Rectal hemorrhage	Ileus Intestinal obstruction	Colitis, including diarrhea caused by Clostridium difficile Pancreatitis	Esophagitis
Renal and urinary disorders		Hematuria Dysuria Urination frequency disturbance
Skin and subcutaneous tissue disorders	Skin reactions Alopecia	Skin exfoliation (i.e., hand-foot syndrome) Erythematous rash Rash Hyperhidrosis Nail disorders
Musculoskeletal and connective tissue disorders	Back pain	Arthralgia Bone pain
Metabolism and nutrition disorders	Anorexia Hypoglycemia Hypokalemia Hypernatremia	Dehydration Hypocalcemia	Metabolic acidosis
Infections and infestations*	Infection	Rhinitis Upper respiratory tract infections Neutropenic sepsis+	Sepsis+
Vascular disorders		Bleeding Flushing Deep vein thrombophlebitis Arterial hypertension Thromboembolism
General disorders and administration site conditions	Fatigue Fever+++ Asthenia Pain Injection site reactions++++
Immune system disorders*	Allergy/allergic reactions++
Psychiatric disorders		Depression Insomnia	Anxiety
Cardiac disorders					Acute coronary syndrome, including myocardial infarction, coronary artery spasm, and angina in patients receiving oxaliplatin in combination with 5-FU or bevacizumab
Injury, poisoning and procedural complications		Fall

* See detailed information provided below in this same section.

** See section "Special precautions".

• Neutropenic sepsis, including fatal cases, is frequently observed.

++ Very common allergic/allergic reactions, which occurred predominantly during infusion and sometimes resulted in death. Common allergic reactions include skin rashes (particularly urticaria), conjunctivitis, and rhinitis. Frequent anaphylactic or anaphylactoid reactions, including bronchospasm, angioneurotic edema, arterial hypotension with chest pain, and anaphylactic shock. Hypersensitivity reactions of delayed type have been reported, occurring several hours or even days after oxaliplatin 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, particularly when oxaliplatin is administered via peripheral vein infusion (see section "Special precautions").

Disorders of the blood and lymphatic system

Table 8

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

Oxaliplatin in combination with 5-FU/FA at a dose of 85 mg/m2 every 2 weeks	Antimetastatic therapy			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	5.0	3.6	1.4	0.7	0.7	0.0
Neutropenic sepsis	1.1	0.7	0.4	1.1	0.6	0.4

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

Post-marketing experience with unknown frequency: hemolytic uremic syndrome, autoimmune pancytopenia, pancytopenia, secondary leukemia, bleeding caused by prolonged prothrombin time and increased international normalized ratio (INR) in patients receiving anticoagulants, hyponatremia, vaginal bleeding.

Infections and infestations

Table 9

Frequency of adverse reactions in patients (%)

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

Experience from post-marketing use with unknown frequency of occurrence: septic shock, including fatal cases, gingivitis.

Immune system disorders

Table 10

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

Oxaliplatin in combination with 5-FU/FA at a dose of 85 mg/m2 every 2 weeks	Antimetastatic therapy			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 manifests as peripheral sensory neuropathy characterized by dysesthesia and/or paresthesia of the extremities, with or without spasms, often triggered by cold. These symptoms occur in 95% of patients receiving treatment. The duration of such symptoms, which usually regress between treatment cycles, increases with the number of treatment cycles.

The onset of pain and/or functional impairment warrants dose modification or even discontinuation of treatment, depending on the duration of symptoms (see section "Special precautions").

This functional impairment includes difficulty in performing fine motor tasks and may result from sensory disturbances. The risk of persistent symptoms at a cumulative dose of approximately 850 mg/m² (10 cycles) is about 10%; at a cumulative dose of 1020 mg/m² (12 cycles), it is approximately 20%.

In most cases, neurological signs and symptoms decrease or completely resolve after treatment cessation. In adjuvant therapy of colorectal cancer, 87% of patients had no symptoms or only mild symptoms 6 months after treatment discontinuation. After 3 or more years of follow-up following cessation of adjuvant therapy, approximately 3% of patients experienced persistent localized moderate-intensity paresthesia (2.3%), or paresthesia interfering with functional activity (0.5%).

Acute neurosensory disturbances have been reported. These begin within several hours after drug infusion and are often triggered by cold. Such manifestations are usually transient and include paresthesia, dysesthesia, and hypesthesia. Acute pharyngolaryngeal dysesthesia syndrome occurs in 1–2% of patients and is characterized by subjective sensations of dysphagia or dyspnea/choking without objective signs of respiratory insufficiency (absence of cyanosis or hypoxia), or laryngospasm or bronchospasm (absence of stridor or wheezing). In such cases, symptoms rapidly resolve even without treatment, regardless of the use of antihistamines or bronchodilators. Prolonging the infusion duration helps reduce the frequency of this syndrome (see section "Special precautions").

Other symptoms occasionally observed include jaw spasm, muscle spasms, involuntary muscle contractions, myoclonus, coordination disorders, gait disturbances, ataxia, loss of balance, tightness, depression, discomfort, and throat or chest pain. Additionally, the above phenomena may be accompanied by cranial nerve dysfunction or may occur as isolated events such as eyelid ptosis, diplopia, aphonia, dysphonia, hoarseness sometimes described as vocal cord paralysis, abnormal tongue sensation or dysarthria sometimes described as aphasia, trigeminal neuralgia, facial or ocular pain, decreased visual acuity, or visual field disturbances.

Other neurological symptoms reported during oxaliplatin treatment include dysarthria, loss of deep tendon reflexes, and Lhermitte's sign. There have been reports of isolated cases of optic neuritis.

Post-marketing experience with unknown frequency of occurrence: seizures, ischemic or hemorrhagic cerebrovascular disorders, falls, cranial nerve paralysis, peripheral edema, somnolence.

Cardiac disorders

Post-marketing experience with unknown frequency of occurrence: QT interval prolongation, which may lead to ventricular arrhythmias, including polymorphic ventricular tachycardia (Torsade de Pointes), sometimes fatal (see section "Special precautions").

Acute coronary syndrome, including myocardial infarction, coronary artery spasm, and angina in patients receiving oxaliplatin in combination with 5-FU and bevacizumab.

Respiratory, thoracic and mediastinal disorders

Post-marketing experience with unknown frequency of occurrence: laryngospasm, pneumonia, and bronchopneumonia, including fatal cases, hemoptysis.

Gastrointestinal disorders

Table 11

Incidence in patients (%), by severity grade

Oxaliplatin in combination with 5-FU/FA at a dose of 85 mg/m2 every 2 weeks	Antimetastatic therapy			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	49.0	6	1	47.2	5.3	0.5
Mucositis/stomatitis	39.9	4	<1	42.1	2.8	0.1

Prophylaxis and/or treatment with potent antiemetic agents are indicated.

Dehydration, paralytic ileus, intestinal obstruction, hypokalemia, metabolic acidosis, and renal impairment may result from severe diarrhea/vomiting, particularly when oxaliplatin is combined with 5-FU (see section "Special precautions").

Post-marketing experience with unknown frequency of occurrence: intestinal ischemia, including fatal cases (see section "Special precautions"), esophagitis, flatulence, dry mouth, melena, proctitis.

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 pathological manifestations associated with such liver disorder, including hepatic peliosis, nodular regenerative hyperplasia, perisinusoidal fibrosis, ascites, hemorrhoids. Clinical manifestations may include portal hypertension and/or elevated transaminase levels.

Renal and urinary disorders.

Very rare (<1/10,000):

Acute tubular necrosis, acute interstitial nephritis, acute renal failure, urinary incontinence.

Musculoskeletal and connective tissue disorders.

Post-marketing experience with unknown frequency of occurrence: rhabdomyolysis, including fatal cases (see section "Special precautions"), myalgia, abdominal distension.

Skin and subcutaneous tissue disorders.

Post-marketing experience with unknown frequency of occurrence: leukocytoclastic vasculitis, alopecia, dry skin, pruritus.

Reporting of suspected adverse reactions

It is important to report suspected adverse reactions after the medicinal product has been authorized. This allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are requested to report any suspected adverse reactions through the national reporting system.

Shelf life.

Unopened vial: 4 years.

After dilution in 5% glucose solution, chemical and physical stability has been demonstrated for 24 hours at 2 to 8°C and for 6 hours at temperatures not exceeding 25°C.

From a microbiological standpoint, the infusion solution should be used immediately. If not used immediately, the user is responsible for the storage duration and conditions. If dilution has not been carried out under controlled and validated aseptic conditions, the storage period should generally not exceed 24 hours at 2 to 8°C.

Storage conditions.

Keep out of the reach and sight of children. Store in the original packaging to protect from light at temperatures not exceeding 25°C. Do not freeze.

Incompatibilities.

The diluted preparation must never be mixed with other medicinal products in the same vial or infusion system unless specifically indicated in the instructions for medical use.

Do not administer simultaneously with alkaline medicinal products or solutions (particularly with 5-FU, alkaline solutions, trometamol, and medicinal products containing folic acid and trometamol as excipients).

Alkaline solutions and medicinal 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 preparations containing aluminum.

Packaging.

10 ml, 20 ml, or 40 ml in a vial; 1 vial in a cardboard box.

Prescription category.

Prescription only.

Manufacturer.

AqVida GmbH.

Manufacturer's address.

Kaiser-Wilhelm-Str. 89, 20355 Hamburg, Germany.

Marketing Authorization Holder.

Amaxa Ltd.

Address of the Marketing Authorization Holder.

31 John Islip Street, London SW1P 4FE, United Kingdom.