Soksplat

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT SOXPLAT (Soxplat)

Composition:

Active substance: oxaliplatin;

1 ml of solution contains 5 mg of oxaliplatin; 1 vial contains 50 mg or 100 mg or 200 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: L01X A03.

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 the single enantiomer cis-[(1R,2R)-1,2-diaminocyclohexane-N,N'] oxalato(2-)-O,O'] platinum.

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

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

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

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

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

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

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

Table 1

Response rates with FOLFOX4 regimen compared to LV5FU2 regimen

• NA: not applicable.

Table 2

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

• NA: not applicable.

Table 3

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

* NA: not applicable.

Among patients who had symptoms of the disease at the beginning of the study and who had previously received anticancer therapy (EF04584), a statistically significant improvement in symptoms was observed more frequently in the group receiving oxaliplatin with 5-FU/FA than in the group receiving only 5-FU/FA (27.7% vs. 14.6%, p = 0.0033).

In patients who had not received prior treatment (EFC2962), no statistically significant difference between the two groups was observed for any quality-of-life parameter. 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 assignment of adjuvant therapy during the phase III comparative MOSAIC study (EFC3313), 2246 patients were randomized into 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 monotherapy with 5-FU/FA (LV5FU2, N = 1123 (B2/C = 448/675)) or combination therapy with oxaliplatin and 5-FU/FA (FOLFOX4, N = 1123 (B2/C) = 451/672).

Table 4

EFC3313: 3-year disease-free survival (ITT analysis)* for all patient groups

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

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

Table 5

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

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

Overall survival (ITT analysis). At the time of analysis of 3-year disease-free survival, which was the primary endpoint of the MOSAIC study, 85.1% of patients remained alive in the FOLFOX4 treatment group compared to 83.8% of patients in the LV5FU2 treatment group. This indicated an overall 10% reduction in the risk of death in favor of FOLFOX4, which did not reach statistical significance (hazard ratio = 0.9).

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

Monotherapy with oxaliplatin was evaluated in children during two phase I studies (69 patients) and two phase II studies (166 patients). A total of 235 children (aged from 7 months to 22 years) with solid tumors received treatment. The efficacy of oxaliplatin monotherapy in treated children has not been established. Enrollment in both phase II studies was discontinued due to lack of tumor response. During clinical trials, efficacy of oxaliplatin (85 mg/m² every 2 weeks) in combination with 5-FU/folinic acid was demonstrated in patients with metastatic colorectal cancer.

Pharmacokinetics.

The pharmacokinetics of individual active metabolites has not been defined. The pharmacokinetics of ultrafiltered platinum, i.e., the mixture of all forms of non-conjugated active and inactive platinum species in blood plasma, after 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 below.

Table 6

Summary of results from the assessment of pharmacokinetic parameters of platinum 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

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

The mean values of AUC, Vss, clearance, and clearance R0-48 were determined during cycle 1.

Cfinal, Cmax, AUC, AUC0-48, Vss, and clearance values were determined by noncompartmental analysis.

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

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

Irreversible binding to erythrocytes and plasma proteins results in elimination half-lives of these matrices being close to the natural lifespan of erythrocytes and serum albumin. No accumulation of the drug was observed in plasma ultrafiltrate, either when administered at 85 mg/m² every 2 weeks or at 130 mg/m² every 3 weeks, with steady-state levels achieved in this matrix during the first treatment cycle. Values vary only slightly between different patients and within the same patient.

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

Oxaliplatin undergoes extensive biotransformation and is not detected in unchanged form in plasma ultrafiltrate at the end of the 2-hour infusion. At later time points, individual cytotoxic metabolites were detected in systemic circulation, including mono-chloro, di-chloro, and diaqua derivatives of DACH-platinum, along with some inactive conjugates.

Platinum is excreted predominantly 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.

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 the drug was 9, 4, 6, and 3 cycles, respectively, and pharmacokinetic data during cycle 1 were obtained from 11, 13, 10, and 4 patients, respectively.

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

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

An increase in the beta-phase 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 data 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 fluorouracil and folinic acid, oxaliplatin is recommended for:

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

Contraindications.

• Hypersensitivity to oxaliplatin or to any of the excipients of the medicinal product in history;
• breastfeeding period;
• myelosuppression (neutrophil count <2x10⁹/L and/or platelet count <100x10⁹/L) prior to the first treatment cycle;
• peripheral sensory neuropathy associated with functional impairments prior to the first treatment cycle;
• severe renal impairment (creatinine clearance <30 mL/min).

Special precautions.

When handling the medicinal product, the rules for working with cytostatic agents must be observed.

Handling this cytotoxic substance requires healthcare personnel to follow all precautionary measures to ensure protection of the worker and his or her surroundings.

Preparation of injectable solutions of cytotoxic substances must be performed by an experienced specialist familiar with the use of these medicinal products, under conditions ensuring protection of the environment and, above all, of personnel working with these medicinal products. A specially designated area for carrying out preparatory operations is required. Smoking, eating, or drinking are prohibited in this designated area.

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

Particular caution is necessary when in contact with patient excreta and vomitus.

Pregnant individuals should be warned about the necessity of avoiding work with cytotoxic substances.

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

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

Disposal.

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

Interaction with other medicinal products and other forms of interactions.

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

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

Special precautions for use.

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

Hypersensitivity reactions. Close monitoring is required in patients with a history of allergic reactions to other platinum compounds. In case of a hypersensitivity reaction to oxaliplatin resembling anaphylaxis, the infusion must be stopped immediately and appropriate symptomatic treatment initiated. Re-administration of oxaliplatin to such patients is contraindicated. Cases of cross-reactions with all platinum compounds have been reported, sometimes resulting in fatal outcomes.

In case of drug extravasation, the infusion should 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 medicinal products having specific neurotoxic properties. A neurological examination should be performed before each administration and periodically thereafter.

In patients who develop acute pharyngolaryngeal dysesthesia during or within several hours after the 2-hour infusion (see section "Adverse reactions"), the next dose of the drug should be administered no earlier than 6 hours after the previous one. To prevent such dysesthesia, patients should be informed about the necessity to avoid cold exposure and swallowing cold or fresh food and/or drinks for several hours after drug administration.

Peripheral neuropathy. If neurological symptoms (e.g., 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 associated with pain, the next dose of oxaliplatin should be reduced from 85 to 65 mg/m² (metastatic treatment) or to 75 mg/m² (adjuvant therapy);
• if paresthesia without functional impairment persists until the next treatment cycle, the next dose of oxaliplatin should be reduced from 85 to 65 mg/m² (metastatic treatment) or to 75 mg/m² (adjuvant therapy);
• 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 symptoms of sensory peripheral neuropathy may persist after treatment discontinuation. Mild localized paresthesia or paresthesia that may interfere with functional activity can be observed for more than 3 years after completion of adjuvant therapy.

Reversible posterior leukoencephalopathy syndrome (RPLS). Cases of reversible posterior leukoencephalopathy syndrome (RPLS), also known as posterior reversible encephalopathy syndrome (PRES), have been reported in patients receiving oxaliplatin as part of combination chemotherapy. RPLS is a rare, reversible neurological disorder that rapidly develops and may present with seizures, arterial hypertension, headache, confusion, blindness, and other visual and neurological disturbances (see section "Adverse reactions"). Diagnosis of RPLS is confirmed by brain imaging techniques, preferably 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.

In case of hematological toxicity (neutrophil count <1.5x10⁹/L or platelet count <75x10⁹/L), the next treatment cycle should be delayed until acceptable hematological parameters are restored. A complete blood count with differential should be performed before the start of oxaliplatin therapy and prior to each subsequent cycle.

Patients should be informed that in case of diarrhea/vomiting, mucositis/stomatitis, or neutropenia occurring after administration of oxaliplatin and 5-FU, they should seek immediate medical attention for appropriate management of these symptoms.

In case of mucositis/stomatitis, with or without neutropenia, the next administration of the drug should be delayed until mucositis/stomatitis regresses to grade ≤1 and/or neutrophil count recovers to >1.5x10⁹/L. When oxaliplatin is combined with 5-FU (with or without leucovorin), dose adjustments of 5-FU are generally recommended due to its toxicity.

In case of grade 4 diarrhea (WHO classification), grade 3–4 neutropenia (neutrophil count <1x10⁹/L), or grade 3–4 thrombocytopenia (platelet count <50x10⁹/L), the dose of oxaliplatin should be reduced by 25% along with dose reduction of 5-FU.

Pulmonary manifestations. In case of respiratory symptoms of unknown etiology such as non-productive cough, dyspnea, crackles, or pulmonary infiltrates on X-ray, oxaliplatin treatment should be discontinued until interstitial pneumonitis is ruled out by additional lung investigations (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 vascular disorders in the liver induced by the drug should be considered.

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

Use during pregnancy or breastfeeding.

Pregnancy. There are no data on the safety of oxaliplatin use in pregnant women. Reproductive toxicity has been observed in animal studies. Oxaliplatin is not recommended during pregnancy and in women of childbearing potential who are not using contraception.

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

Patients must use effective contraceptive measures during treatment. These measures should be continued after completion of therapy: in women — for 4 months, in men — for 6 months.

Oxaliplatin may have a negative effect on fertility.

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

Ability to affect driving and operating machinery.

Studies on the effect of the drug on the ability to drive or operate machinery have not been conducted.

Adverse reactions such as dizziness, nausea, visual disturbances (including transient loss of vision that resolves after discontinuation of therapy), vomiting, and other neurological symptoms affecting gait and balance may occur during treatment. Therefore, the drug may impair the ability to drive or operate machinery.

Patients should therefore refrain from driving or operating machinery during treatment, especially when high concentration of attention is required.

Method of Administration and Dosage.

The medicinal product is intended only for the treatment of adults.

The recommended dose of oxaliplatin for adjuvant therapy is 85 mg/m² administered intravenously, repeated every 2 weeks for 12 cycles (6 months).

The recommended dose of oxaliplatin for the treatment of metastatic colorectal cancer is 85 mg/m² administered intravenously, repeated every 2 weeks until disease progression or until signs of intolerable toxicity occur. The dose should be adjusted according to individual patient tolerance (see section "Special Warnings and Precautions for Use").

Oxaliplatin must always be administered before fluoropyrimidines, for example, prior to 5-FU administration.

Oxaliplatin, diluted in 250–500 mL of 5 % glucose solution to achieve a concentration of 0.2 to 0.7 mg/mL, should be administered as a 2–6 hour intravenous infusion; 0.7 mg/mL corresponds to the highest concentration used clinically at the oxaliplatin dose of 85 mg/m².

Oxaliplatin is usually administered in combination with continuous infusion of 5-FU. For a treatment regimen repeated every 2 weeks, a dosing schedule involving bolus administration of 5-FU followed by continuous infusion of 5-FU is recommended.

Method of administration. Before administration, oxaliplatin must be diluted. Only the recommended diluent – 5 % glucose solution – should be used for dilution 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 to achieve a concentration of not less than 0.2 mg/mL should be administered via central or peripheral vein over 2–6 hours.

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

In case of extravasation, administration must be immediately discontinued.

Patients at Risk.

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

Patients with hepatic impairment. In a study involving patients with various degrees of hepatic impairment, the frequency and severity of hepatobiliary disorders were related to disease progression and pre-existing liver function abnormalities (no specific dose adjustment was performed for patients with hepatic impairment).

Elderly patients. No increase in oxaliplatin toxicity has been observed when used as monotherapy or in combination with 5-FU in patients aged 65 years and older. Therefore, no special dose adjustment is required for elderly patients.

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

Instructions for Preparation and Disposal. Precautions must be taken during the preparation of oxaliplatin solutions, as with all potentially toxic substances (for further details, see section "Special Precautions for Handling").

Special Precautions for Administration.

• Never administer the medicinal product in undiluted form.
• Oxaliplatin may be administered simultaneously with 5-FU using a Y-type infusion system with a side port immediately before the injection site (intravenous infusion of 85 mg/m² oxaliplatin diluted in 250–500 mL of 5 % glucose solution is given simultaneously with intravenous infusion of 5-FU diluted in 5 % glucose solution over 2–6 hours). Sospplat and 5-FU must not be mixed in the same infusion bottle. 5-FU must not contain tromethamine as an excipient. 5-FU must be diluted with isotonic infusion solutions such as 5 % glucose solution, but must never be diluted with saline or alkaline solutions. The infusion system should be flushed after administration of oxaliplatin.
• Oxaliplatin must always be administered before fluoropyrimidines (e.g., 5-FU). The infusion system should be flushed after administration of oxaliplatin. For additional information regarding medicinal products that can be combined with oxaliplatin, refer to the summary of product characteristics provided by the respective manufacturer.
• Use only the recommended diluents (see below).

Concentrate for solution for infusion.

Visual inspection must be performed before use. Only clear, particle-free solutions should be used.

The medicinal product is intended 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 with 5 % glucose solution to a final volume of 250–500 mL to achieve an oxaliplatin concentration of 0.2 to 0.7 mg/mL. The physical and chemical stability of oxaliplatin has been demonstrated at concentrations ranging from 0.2 to 2 mg/mL. The solution should be administered as an intravenous infusion.

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

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

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

The compatibility of oxaliplatin infusion solution has been tested with standard polyvinyl chloride infusion systems.

Infusion.

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

Children.

The medicinal product is intended for use in adults only. The efficacy and safety of Sospplat in children have not been established; therefore, the medicinal product should not be administered to this patient population.

Overdose.

In case of overdose, an increased incidence and severity of adverse effects may be expected.

Treatment: hematological monitoring along with symptomatic treatment of other manifestations of intoxication. There is no known antidote for oxaliplatin.

Adverse reactions.

During combination therapy with oxaliplatin and 5-FU/FA, the most commonly observed adverse effects were gastrointestinal effects (diarrhea, nausea, vomiting, and mucositis), hematological disorders (neutropenia, thrombocytopenia), and neurological syndromes (acute and dose-dependent sensory peripheral neuropathy). 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 trials 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 (>1/1000, <1/100); rare (>1/10,000, <1/1000); very rare (>1/10,000); frequency not known (cannot be estimated from available data).

Table 7

• Very common allergies/allergic reactions (mostly occurred during infusion and sometimes ended fatally), such as skin rash (especially urticaria), conjunctivitis, rhinitis. Typical anaphylactic reactions, such as bronchospasm, chest pain, angioneurotic edema, angioedema, arterial hypotension, and anaphylactic shock or anaphylactoid reactions.

++ Very common: fever, chills (shivering) or infection-related (with or without febrile neutropenia) or isolated temperature increase due to immunological mechanism.

+++ Injection site reactions include local pain, redness, swelling, and thrombosis. Extravasation may also lead to local pain and inflammation, which in severe cases may result in necrosis, especially when oxaliplatin is administered intravenously via peripheral vein infusion.

* More detailed information is provided below.

** More detailed information is provided in the section "Special precautions for use".

Disorders of the blood and lymphatic system.

Table 8

Frequency in patients (%), by grades

Post-marketing experience with unknown frequency of occurrence: hemolytic uremic syndrome.

Disorders of the immune system.

Table 9

Disorders of the nervous system.

Neurological toxicity of oxaliplatin is dose-dependent. It mainly manifests as sensory peripheral neuropathies characterized by dysesthesia and/or paresthesia of the extremities, with or without associated muscle spasms, often triggered by cold. These symptoms are observed in approximately 95 % of patients 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 "Special instructions"), dose adjustment or even discontinuation of treatment may be required.

Functional impairment, such as difficulty performing fine motor tasks, may result from sensory dysfunction. The risk of developing persistent symptoms at a cumulative dose of approximately 850 mg/m² (i.e., 10 cycles) is about 10 %; at a cumulative dose of 1020 mg/m² (i.e., 12 cycles), the risk increases to approximately 20 %.

In most cases, neurological symptoms show positive progression or complete resolution by the time treatment is discontinued.

Six months after completion of adjuvant therapy for colorectal cancer, 87 % of patients had no symptoms or only mild symptoms. After 3 years or more, persistent localized paresthesia of moderate severity was observed in approximately 3 % of patients (2.3 %), or paresthesia interfering with functional activity in 0.5 % of patients.

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, or may present as an acute laryngopharyngeal dysesthesia syndrome. This acute 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); jaw spasms, tongue sensory disturbances, dysarthria, and chest tightness.

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 "Special instructions").

Other observed symptoms include jaw spasms, muscle spasms, involuntary muscle contractions, myoclonus, coordination disorders, gait disturbances, ataxia, balance disorders, throat or chest tightness, lethargy, discomfort, and pain. Additionally, damage to cranial nerves may occur either simultaneously or separately, presenting as eyelid ptosis, diplopia, aphonia, dysphonia, hoarseness (sometimes referred to as vocal cord paralysis), tongue dysesthesia or dysarthria (sometimes referred to as aphasia), trigeminal neuralgia, facial or ocular pain, decreased visual acuity, or visual field disturbances.

Other neurological symptoms such as dysarthria, loss of tendon reflexes, and Lhermitte's sign have been observed during oxaliplatin treatment. Isolated cases of optic neuritis have also been reported.

Post-marketing experience with unknown frequency: seizures, laryngospasm.

Gastrointestinal disorders.

Table 10

Frequency in patients (%), by severity grade

Treatment or prophylactic administration of potent antiemetic agents is indicated.

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

Hepatobiliary disorders.

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

Renal and urinary disorders.

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

Shelf life. 2 years.

After opening the vial

Each vial is intended for single use and should be used immediately after opening. If the medicinal product is not used immediately, the user is responsible for the duration and conditions of storage.

After addition of the medicinal product to the infusion solution

From a microbiological standpoint, the medicinal product should be used immediately. If not used immediately, the user is responsible for the duration and conditions of storage.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 °C.

Keep out of the reach of children.

Do not freeze.

After dilution with 5% glucose solution, the physico-chemical stability of the solution is maintained for 48 hours at a temperature of 2°C to 8°C or for 24 hours at a temperature of 25°C.

However, from a microbiological standpoint, the reconstituted solution should be used immediately. If the solution is not administered immediately after preparation, responsibility for compliance with storage conditions and duration lies solely with the healthcare professional administering the solution. The storage period should not exceed 24 hours at a temperature of 2°C to 8°C, provided that dilution was performed under aseptic conditions in controlled and standardized settings.

The medicinal product is for single use only. The infusion solution should be used immediately. Any unused solution must be discarded.

Incompatibilities.

Do not use solvents not specified in the section “Dosage and method of administration”.

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

Alkaline solutions and medicinal products negatively affect the stability of oxaliplatin. Therefore, oxaliplatin should not be administered simultaneously with alkaline medicinal products or solutions (especially 5-FU, alkaline solutions, trometamol, and medicinal products containing fluoride and trometamol as excipients).

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

Do not use injectable preparations containing aluminium.

Packaging.

10 ml, 20 ml or 40 ml of medicinal product in a glass vial stoppered with a rubber plug and sealed with an aluminium crimp cap fitted with a flip-off cap ensuring tamper evidence.

1 vial in a cardboard box.

Prescription category. Prescription only.

For hospital use only by oncology specialists.

Manufacturer.

MYLAN LABORATORIES LIMITED (OTL)

MYLAN LABORATORIES LIMITED (OTL)

Manufacturer's address and location of its business operations.

Plot No. 284-B, Bommasandra Jigani Link Road, Industrial Area, Anekal Taluk, Bangalore, Karnataka 560105, India (IND)

Marketing Authorisation Holder.

M. Biotech Ltd

M. Biotech Ltd

Address of the Marketing Authorisation Holder.

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