Recotaxin 50 Mg/10 Ml/100 Mg/20 Ml/200 Mg/40 Ml Solution

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

• Treatment of metastatic colorectal cancer.
• Adjuvant treatment of stage III (Dukeu2019s C) colon cancer after complete resection of primary tumour.

The preparation of RECOTAXIN must be carried out by trained specialist personnel with knowledge of the medicines used, in conditions that guarantee the protection of the environment and in particular the protection of the personnel handling the medicines. It requires a preparation area reserved for this purpose. It is forbidden to smoke, eat or drink in this area.

Posology

FOR ADULTS ONLY

Dosing regimen

Treatment of metastatic colorectal cancer

The recommended dose is 85 mg/mu00b2 intravenously repeated every 2 weeks.

Adjuvant treatment of colon cancer

The recommended dose is 85 mg/mu00b2 intravenously repeated every 2 weeks for 12 cycles (6 months). The dosage given should be adjusted according to tolerability (See section 4.4 and 4.8).

RECOTAXIN should always be administered before fluoropyrimidines (5-FU).

RECOTAXIN is administered as a 2 to 6-hour intravenous infusion in 250 to 500 mL of 5 % glucose solution. It is mainly used in combination with continuous infusion 5-fluorouracil based regimens. For the two - weekly treatment schedule 5 - fluorouracil regimens combining bolus and continuous infusion were used.

Special populations:

Renal impairment: In gastrointestinal cancer patients with varying degrees of renal impairment, treated with RECOTAXIN (2-hour IV infusion every two weeks for a maximum of 12 cycles) in combination with 5-FU/FA (FOLFOX4), oxaliplatin as in RECOTAXIN showed minimal clinical impact on renal function as assessed by mean creatinine clearance (see sections 4.3, 4.4 and 5.2). The duration of exposure was shorter in patients with renal impairment. The median exposure was 4, 6 and 3 cycles for mild, moderate and severe renal impairment patients, respectively. In patients with normal renal function, the median exposure was 9 cycles. However, 7/13 with mild and 5/11 with moderate to severe renal impairment withdrew due to adverse effects. In patients with normal renal function or mild to moderate renal impairment, the recommended dose of RECOTAXIN is 85 mg/mu00b2. In patients with severe renal impairment, RECOTAXIN should not be used.

Hepatic insufficiency: RECOTAXIN has not been studied in patients with severe hepatic impairment. No increase in oxaliplatin acute toxicities was observed in the subset of patients with abnormal liver function tests at baseline. No specific dose adjustment for patients with abnormal liver function tests was performed during clinical development.

Elderly patients: No increase in severe toxicities was observed when oxaliplatin was used as a single agent or in combination with 5-fluorouracil in patients over the age of 65. In consequence no specific dose adaptation is required for elderly patients.

Method of administration

RECOTAXIN is administered by intravenous infusion. The administration of oxaliplatin does not require hyperhydration. RECOTAXIN infusion should always precede that of 5-fluorouracil (5-FU). RECOTAXIN diluted in 250 to 500 mL of 5 % glucose solution to give a concentration of not less than 0,2 mg/mL must be infused either via a peripheral vein or central venous line at the same time as folinic acid intravenous infusion in 5 % glucose solution, over 2 to 6 hours, using a Y-line placed immediately before the site of infusion. The two medicinal products should not be combined in the same infusion bag. Folinic acid must not contain trometamol as an excipient and must only be diluted using isotonic 5 % glucose solution, and NOT in alkaline solutions or sodium chloride or chloride-containing solutions (see section 6.2 for incompatibilities). Flush the line after RECOTAXIN administration.

In the event of extravasation, administration must be discontinued immediately.

Instructions for use: RECOTAXIN must be further diluted before use. DO NOT administer undiluted. Only the recommended diluent (5 % glucose) should be used (see Method of administration above and section 6.2).

Precautions to be taken before manipulation or administering the product: Caution should be exercised when handling and preparing RECOTAXIN solutions, see section 6.6.

Oxaliplatin is contraindicated in patients who:

• have a known history of hypersensitivity to oxaliplatin or any of the other ingredients (see Section 6.1).
• are breast feeding.
• have bone marrow failure.
• have myelosuppression prior to starting treatment.
• have a peripheral sensory neuropathy with functional impairment prior to starting treatment.
• have a severely impaired renal function (creatinine clearance less than 30 mL/min) (See section 5.2).

RECOTAXIN should only be used in specialised departments of oncology and should be administered under the supervision of an experienced oncologist.

Renal impairment: Due to limited information on safety in patients with severely impaired renal function, administration should only be considered after suitable appraisal of the benefit/risk for the patient. In this situation, renal function should be closely monitored and the recommended initial RECOTAXIN dose is 65 mg/mu00b2 (see section 4.2 and 5.2).

Hypersensitivity reactions: Patients with a history of allergic reaction to platinum compounds should be monitored for allergic symptoms. Allergic reactions can occur during any cycle. In case of an anaphylactic-like reaction to RECOTAXIN , the infusion should be immediately discontinued and appropriate symptomatic treatment initiated. Re-administration of RECOTAXIN to such patients is contra-indicated. Cross reactions, sometimes fatal, have been reported with all platinum compounds.

In case of RECOTAXIN extravasation, the infusion must be stopped immediately and usual local symptomatic treatment initiated.

Neurological Symptoms: Sensory neurological toxicity of RECOTAXIN should be carefully monitored, especially if co-administered with other medicines with specific neurological toxicity. A neurological examination should be performed before each administration and periodically thereafter. For patients who develop acute laryngopharyngeal dysaesthesia (see Section 4.8), during or within the hours following the 2-hour infusion, the next oxaliplatin, as in RECOTAXIN, infusion should be administered over 6 hours. To reduce such dysaesthesia, inform the patient to avoid exposure to cold and to avoid ingesting fresh/cold food and/or beverages during or within hours following RECOTAXIN administration.

Dysaesthesia/paraesthesia of extremities and peripheral neuropathy:

• The dose-limiting toxicity of RECOTAXIN is neurological. It involves a sensory peripheral neuropathy characterised by peripheral dysaesthesia and/or paraesthesia with or without cramps, often triggered by the cold. The symptoms occur in 95 % of patients treated.
• The duration of these symptoms, which usually recede between the cycles of treatment, increases with the number of treatment cycles. The onset of pain and/or a functional disorder and their duration are indications for dose adjustment, or even treatment discontinuation. This functional disorder includes difficulties in executing delicate movements and is a possible consequence of sensory impairment. The risk of occurrence of a functional disorder for cumulative dose of approximately 850 mg/mu00b2 (10 cycles) is 10 % and 20 % for a cumulative dose of 1020 mg/mu00b2 (12 cycles).
• In the majority of cases, the neurological signs and symptoms improve or totally recover when treatment is discontinued. In the adjuvant setting of colon cancer, 6 months after recovery cessation, 87 % of patients had no or mild symptoms. After up to 3 years of follow-up, about 3 % of patients presented either with persisting localised paraesthesias of moderate intensity or with paraesthesias that interfere with functional activities.

Acute neurosensory manifestations: These symptoms usually develop at the end of the 2-hour RECOTAXIN infusion or within a few hours, abate spontaneously within the next hours or days, and frequently recur with further cycles. They may be precipitated or exacerbated by exposure to cold temperatures or objects. They usually present as transient paraesthesia, dysaesthesia and hypaesthesia.

An acute syndrome of pharyngolaryngeal dysaesthesia occurs in 1 u2013 2 % of patients, and is characterised by subjective sensations of dysphagia or dyspnoea/feeling of suffocation, without any evidence of respiratory distress (no cyanosis or hypoxia) or of laryngospasm or bronchospasm (no stridor or wheezing). Although antihistamines and bronchodilators have been administered in such cases, the symptoms are rapidly reversible even in the absence of treatment. Prolongation of the infusion helps to reduce the incidence of this syndrome.

Other symptoms occasionally observed, particularly of cranial nerve dysfunction, may be either associated with above-mentioned events, or also occur isolated such as ptosis, diplopia, aphonia/dysphonia/hoarseness, sometimes described as vocal cord paralysis, abnormal tongue sensation or dysarthria, sometimes described as aphasia, trigeminal neuralgia/facial pain/eye pain, decrease of visual acuity, and visual field disorders. In addition, the following symptoms have been observed: jaw spasm/muscle spasms/involuntary muscle contractions/muscle twitching/myoclonus, coordination abnormal/abnormal gait/ataxia/balance disorders, throat or chest tightness/pressure/discomfort/pain.

Peripheral neuropathy: If neurological symptoms (paraesthesia, dysaesthesia) occur, the following recommended RECOTAXIN dosage adjustment, based on the duration and severity of these symptoms, should be performed:

• If symptoms last longer than seven days and are troublesome, the subsequent RECOTAXIN dose should be reduced from 85 to 65 mg/mu00b2 (metastatic setting) or 75 mg/mu00b2 (adjuvant setting).
• If paraesthesia without functional impairment persists until the next cycle, the subsequent RECOTAXIN dose should be reduced from 85 to 65 mg/mu00b2 (metastatic setting) or 75 mg/mu00b2 (adjuvant setting).
• If paraesthesia with functional impairment persists until the next cycle, RECOTAXIN administration should be discontinued.
• If these symptoms improve following discontinuation of RECOTAXIN therapy, resumption of therapy may be considered. Patients should be informed of the possibility of persistent symptoms of peripheral sensory neuropathy after the end of the treatment. Localised moderate paraesthesias or paraesthesias that may interfere with functional activities can persist after up to 3 years following treatment cessation of adjuvant setting.

Nausea, vomiting, diarrhoea, dehydration, and haematological changes: Gastrointestinal toxicity, which manifests as nausea and vomiting, warrants prophylactic and/or therapeutic anti-emetic therapy (see section 4.8). Dehydration, paralytic ileus, intestinal obstruction, hypokalaemia, metabolic acidosis and renal impairment may be associated with severe diarrhoea/emesis particularly when combining RECOTAXIN with 5-fluorouracil (5-FU).

Cases of intestinal ischaemia, including fatal outcomes, have been reported with oxaliplatin as in RECOTAXIN treatment. In case of intestinal ischaemia, RECOTAXIN treatment should be discontinued and appropriate measures initiated (see section 4.8). If haematological toxicity occurs (neutrophils < 1,5 x 10 9 /L or platelets < 50 x 10 9 /L), after a course of therapy or if myelosuppression is present prior to the start (first course) of therapy (see section 4.3), administration of the next course or the first course of therapy should be postponed until the haematological values return to acceptable levels. A full blood count with white cell differential should be performed prior to the start of therapy and before each subsequent course.

Sepsis, neutropenic sepsis and septic shock have been reported in patients treated with oxaliplatin as in RECOTAXIN , including fatal outcomes (see section 4.8). If any of these events occurs, RECOTAXIN should be discontinued. Patients must be adequately informed of the risk of diarrhoea/emesis and neutropenia after RECOTAXIN /5-fluorouracil administration in order to contact their treating doctor urgently for appropriate management. If mucositis/stomatitis occurs with or without neutropenia, the next treatment should be delayed until recovery from mucositis/ stomatitis to grade 1 or less and/or until the neutrophil count is u2265 1,5 x 10 9 /L. For RECOTAXIN combined with 5-fluorouracil (with or without folinic acid), the usual dose adjustments for 5-fluorouracil associated toxicities should apply. If severe/life-threatening diarrhoea, severe neutropenia (neutrophils < 1,0 x 10 9 /L), febrile neutropenia (fever of unknown origin without clinically or microbiologically documented infection with an absolute neutrophil count 38,3 u00b0C or a sustained temperature of > 38 u00b0C for more than one hour), or severe thrombocytopenia(platelets < 50 x 10 9 /L) occurs, RECOTAXIN must be discontinued until improvement or resolution, and the dose of RECOTAXIN should be reduced from 85 to 65 mg/mu00b2 (metastatic setting) or 75 mg/mu00b2 (adjuvant setting) at subsequent cycles, in addition to any 5-fluorouracil dose reductions required.

Pulmonary: In the case of unexplained respiratory symptoms such as non-productive cough, dyspnoea, crackles or radiological pulmonary infiltrates, RECOTAXIN should be discontinued until further pulmonary investigations exclude an interstitial lung disease (see section 4.8).

Blood disorders: Haemolytic-uraemic syndrome (HUS) is a life-threatening side effect (see section 4.8). RECOTAXIN should be discontinued at the first signs of any evidence of microangiopathic haemolytic anaemia, such as rapidly falling haemoglobin with concomitant thrombocytopenia, elevation of serum bilirubin, serum creatinine, blood urea nitrogen, or LDH. Renal failure may not be reversible with discontinuation of therapy and dialysis may be required. Disseminated intravascular coagulation (DIC), including fatal outcomes, has been reported in association with oxaliplatin as in RECOTAXIN treatment. If DIC is present, RECOTAXIN treatment should be discontinued and appropriate treatment should be administered (see section 4.8).

Hepatic: In case of abnormal liver function test results or portal hypertension which does not obviously result from liver metastases, cases of drug-induced hepatic vascular disorders should be considered.

Reversible posterior leukoencephalopathy syndrome (RPLS): Signs and symptoms of reversible posterior leukoencephalopathy syndrome (RPLS, also known as PRES, posterior reversible encephalopathy syndrome), could be induced headache, altered mental functioning, seizures, abnormal vision from blurriness to blindness, associated with or without hypertension (see section 4.8). Diagnosis of RPLS/PRES is based upon confirmation by brain imaging.

QT prolongation: QT prolongation may lead to an increased risk for ventricular dysrhythmias including Torsade de Pointes, which can be fatal. Caution should be exercised in patients with a history or a predisposition for prolongation of QT, those who are taking medicines known to prolong QT interval and those with electrolyte disturbances such as hypokalaemia, hypocalcaemia, or hypomagnesaemia. In case of QT prolongation, RECOTAXIN treatment should be discontinued (see sections 4.5 and 4.8).

Rhabdomyolysis: Rhabdomyolysis has been reported in patients treated with oxaliplatin as in RECOTAXIN , including fatal outcomes. In case of muscle pain and swelling, in combination with weakness, fever or darkened urine, RECOTAXIN treatment should be discontinued. If rhabdomyolysis is confirmed, appropriate measures should be taken. Caution is recommended if medicines associated with rhabdomyolysis are administered concomitantly with RECOTAXIN (see sections 4.5 and 4.8).

Gastrointestinal ulcer, gastrointestinal ulcer haemorrhage and perforation: RECOTAXIN treatment can cause duodenal ulcer (DU) and potential complications, such as duodenal ulcer haemorrhage and perforation, which can be fatal. In case of duodenal ulcer, RECOTAXIN treatment should be discontinued and appropriate measures taken (see section 4.8).

Do not use intraperitoneal route of administration: Do not use RECOTAXIN intraperitoneally. Peritoneal haemorrhage may occur when RECOTAXIN is administered by intraperitoneal route (off-label route of administration).

In patients who have received a single dose of 85 mg/mu00b2 of oxaliplatin, immediately before administration of 5-fluorouracil, no change in the level of exposure to 5-fluorouracil has been observed.

In vitro , no significant displacement of oxaliplatin binding to plasma proteins has been observed with the following medicines: erythromycin, salicylates, granisetron, paclitaxel, and sodium valproate.

Caution is advised when RECOTAXIN treatment is co-administered with other medicines known to cause QT interval prolongation (such as quinidine, disopyramide, amiodarone, sotalol, dofetilide and ibutilide). In case of combination with such medicines, the QT interval should be closely monitored (see section 4.4).

Caution is advised when RECOTAXIN treatment is administered concomitantly with other medicines known to be associated with rhabdomyolysis (such as statins, antipsychotics, zidovudine, colchicine, selective serotonin reuptake inhibitors, and lithium) (see section 4.4).

Women of childbearing potential: Effective contraceptive measures should be taken in potentially fertile patients prior to initiating chemotherapy with RECOTAXIN . Further, barrier contraceptive measures must be taken during and after cessation of therapy (4 months for women and 6 months for men) (see section 4.4).

Pregnancy: To date there is no available information on the safety of use in pregnant women. Based on pre-clinical findings, RECOTAXIN is likely to be lethal and/or teratogenic to the human foetus at the recommended therapeutic doses, and is consequently not recommended during pregnancy and should only be considered after suitably appraising the patient of the risk to the foetus and with the patientu2019s consent.

Breastfeeding: Excretion in breast milk has not been studied. RECOTAXIN is contraindicated during breastfeeding; therefore, if treatment with this medicine is required, breastfeeding must be discontinued (see section 4.3).

Fertility: RECOTAXIN may have an anti-fertility effect which could be irreversible, and patients are advised to seek advice on conservation of sperm prior to treatment (see section 4.4).

No studies on the effects on the ability to drive and use machines have been performed. However, RECOTAXIN treatment resulting in an increased risk of dizziness, nausea and vomiting, and other neurologic symptoms that affect gait and balance may lead to an impaired ability to drive and use machines. Vision abnormalities, in particular transient vision loss (reversible following therapy discontinuation), may affect patients' ability to drive and use machines. Therefore, patients should be warned of the potential effect of these events on the ability to drive or use machines.

a) Summary of the safety profile: The most frequent adverse events of oxaliplatin in combination with 5-fluorouracil/folinic acid (5- FU/FA) were gastrointestinal (diarrhoea, nausea, vomiting and mucositis), haematological (neutropenia, thrombocytopenia) and neurological (acute and dose cumulative peripheral sensory neuropathy). Overall, these adverse events were more frequent and severe with oxaliplatin and 5-FU/FA combination than with 5-FU/FA alone.

b) Tabulated list of adverse drug reactions:

There is no known antidote to RECOTAXIN . In cases of overdose, exacerbation of adverse events can be expected. Monitoring of haematological parameters should be initiated and symptomatic treatment given.