Zalitin 50 mg/10 ml/100 mg/20 ml Solution

ZALITIN 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 ZALITIN 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:

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). Dosage given should be adjusted according to tolerability (see section 4.4 and 4.8).

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

ZALITIN is administered as a 2- to 6-hour intravenous infusion in 250 to 500 ml of 5 % glucose solution. ZALITIN was 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 oxaliplatin as in ZALITIN (2-hour IV infusion every two weeks for a maximum of 12 cycles) in combination with 5FU/FA (FOLFOX4), oxaliplatin as in ZALITIN 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 ZALITIN is 85 mg/mu00b2. In patients with severe renal impairment, ZALITIN should not be used.

Hepatic impairment: ZALITIN has not been studied in patients with severe hepatic impairment. No increase in ZALITIN 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. A phase I study of oxaliplatin as in ZALITIN single agent, 2-hour IV infusion q3w, included adult cancer patients with different degrees of hepatic impairment (none to severe). The initial oxaliplatin as in ZALITIN dose was based upon the degree of liver dysfunction and was then increased up to 130 mg/mu00b2 whatever the degree of liver impairment (none to severe). Overall, the types of toxicities observed were toxicities expected with oxaliplatin as in ZALITIN (see section 4.8). The frequencies of adverse events were increased in patients with liver impairment.

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

Method of administration: ZALITIN is administered by intravenous infusion. The administration of ZALITIN does not require hyperhydration. ZALITIN infusion should always precede that of 5-fluorouracil (5-FU). ZALITIN 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 medicines 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 ZALITIN administration. In the event of extravasation, administration must be discontinued immediately.

• Hypersensitivity to oxaliplatin or to any of the ingredients of ZALITIN listed in section 6.1.
• Breastfeeding.
• Bone marrow failure.
• Myelosuppression prior to starting treatment.
• Peripheral sensory neuropathy with functional impairment before treatment.
• Severe renal impairment (Clcr < 30 mL/min).

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

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

For ZALITIN combined with 5-fluorouracil (with or without folinic acid), the usual dose adjustments for 5-fluorouracil associated toxicities should apply.

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 ZALITIN dose is 65 mg/mu00b2 (see section 4.2: Special populations).

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 ZALITIN, the infusion should be immediately discontinued, and appropriate symptomatic treatment initiated. ZALITIN re-challenge is contraindicated.

Neurological symptoms: Sensory peripheral neurotoxicity of ZALITIN should be carefully monitored, especially if co-administered with other medications with specific neurological toxicity. A neurological examination should be performed before each administration and periodically thereafter.

If neurological symptoms (paraesthesia, dysaesthesia) occur, the following recommended ZALITIN 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 ZALITIN 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 ZALITIN 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, ZALITIN administration should be discontinued. If these symptoms improve following discontinuation of ZALITIN 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.

For patients who develop acute laryngopharyngeal dysaesthesia (see section 4.8), during or within the hours following the 2-hour infusion, the next ZALITIN 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 ZALITIN administration.

Signs and symptoms of reversible posterior leucoencephalopathy 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.

Gastrointestinal toxicity: 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 ZALITIN with 5-fluorouracil (5-FU).

Intestinal ischaemia: Cases of intestinal ischaemia, including fatal outcomes, have been reported with ZALITIN treatment. In case of intestinal ischaemia, ZALITIN treatment should be discontinued and appropriate measures initiated (see section 4.8).

Haematological toxicity: If haematological toxicity occurs (neutrophils < 1,5 x 109/L or platelets < 50 x 109/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.

If severe/life-threatening diarrhoea, severe neutropenia (neutrophils < 1,0 x 109/L), febrile neutropenia (fever of unknown origin without clinically or microbiologically documented infection with an absolute neutrophil count < 1,0 x 109/L, a single temperature of > 38,3 u00b0C or a sustained temperature of > 38 u00b0C for more than one hour), or severe thrombocytopenia (platelets < 50 x 109/L) occurs, ZALITIN must be discontinued until improvement or resolution, and the dose of ZALITIN 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.

Patients must be adequately informed of the risk of diarrhoea/emesis and neutropenia after ZALITIN/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 109/L.

Infection: Sepsis, neutropenic sepsis and septic shock have been reported in patients treated with ZALITIN, including fatal outcomes (see section 4.8). If any of these events occurs, ZALITIN should be discontinued.

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

Haemolytic-uraemic syndrome (HUS): Haemolytic-uraemic syndrome (HUS) is a life-threatening side effect (see section 4.8). ZALITIN 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): Disseminated intravascular coagulation (DIC), including fatal outcomes, has been reported in association with ZALITIN treatment. If DIC is present, ZALITIN treatment should be discontinued, and appropriate treatment should be administered (see section 4.8).

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

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, ZALITIN treatment should be discontinued (see sections 4.5 and 4.8).

Cardiac disorders: Post-marketing reports with ZALITIN use include acute coronary syndrome (including myocardial infarction, coronary arteriospasm, and cardiac arrest). In case of acute coronary syndrome, treatment with ZALITIN may need to be interrupted or discontinued based on the individual benefit-risk assessment (see section 4.8). Post-marketing reports with oxaliplatin include cardiac dysrhythmias (including bradyarrhythmia, tachycardia and atrial fibrillation). In case of cardiac dysrhythmias, treatment with ZALITIN may need to be interrupted or discontinued based on the individual benefit-risk assessment (see section 4.8).

Rhabdomyolysis: Rhabdomyolysis has been reported in patients treated with ZALITIN, including fatal outcomes. In case of muscle pain and swelling, in combination with weakness, fever or darkened urine, ZALITIN 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 ZALITIN (see sections 4.5 and 4.8).

Duodenal ulcer: ZALITIN 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, ZALITIN treatment should be discontinued and appropriate measures taken (see section 4.8).

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

In patients who have received a single dose of 85 mg/mu00b2 of ZALITIN, 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 agents: erythromycin, salicylates, granisetron, paclitaxel and sodium valproate.

Caution is advised when ZALITIN 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 ZALITIN 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 ZALITIN. 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, ZALITIN is likely to be lethal and/or teratogenic to the human fetus 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 fetus and with the patientu2019s consent.

Breastfeeding: Excretion in breast milk has not been studied. Breastfeeding is contraindicated during ZALITIN therapy.

Fertility: ZALITIN 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, ZALITIN treatment is associated with increased risk of dizziness, nausea and vomiting, and other neurological symptoms that affect gait and balance, which may lead to an impaired ability to drive and use machines. Vision abnormalities, in particular transient vision loss (reversible following therapy discontinuation), may affect the patientu2019s 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.

MeDRA system organ classification

Frequent

Less Frequent

Frequency Unknown

Infections and infestations

• infection, neutropenic sepsis, including fatal outcomes
• sepsis, including fatal outcomes

Blood and lymphatic system disorders

• anaemia, neutropenia, thrombocytopenia, leucopoenia and lymphopenia, febrile neutropenia
• immuno-allergic thrombocytopenia and haemolytic anaemia, disseminated intravascular coagulation (DIC), including fatal outcomes (see section 4.4)
• haemolytic uraemic syndrome, autoimmune pancytopenia, pancytopenia, secondary leukaemia

Immune system disorders

• allergic reactions such as skin rash (particularly urticaria), conjunctivitis, rhinitis, anaphylactic reactions including bronchospasm, angioedema, hypotension, sensation of chest pain and anaphylactic shock
• delayed hypersensitivity

Metabolism and nutrition disorders

• anorexia, hyperglycaemia, hypokalaemia, natraemia abnormalities, metabolic acidosis, dehydration, hypocalcaemia

Psychiatric disorders

• Depression, Insomnia
• Nervousness

Nervous system disorders

• dysaesthesia/paraesthesia of extremities and peripheral neuropathy, headache, acute neuro-sensory manifestations (see section 4.4) and dysgeusia, dizziness, motor neuritis, flushing and meningism
• dysarthria, loss of deep tendon reflexes, Lhermitteu2019s sign, reversible posterior leucoencephalopathy syndrome (RPLS, also known as PRES) (see section 4.4)
• convulsion, ischaemic and haemorrhagic cerebrovascular disorder

Eye disorders

• conjunctivitis and abnormal vision
• visual acuity reduced transiently, visual field disturbances and optic neuritis. Transient vision loss, reversible following therapy discontinuation.

Ear and labyrinth disorders

• ototoxicity, deafness

Cardiac Disorders

• QT prolongation, which may lead to ventricular dysrhythmias including Torsade de Pointes, which may be fatal (see sections 4.4 and 4.5), acute coronary syndrome including myocardial infarction and coronary arteriospasm and cardiac arrest; cardiac dysrhythmias including bradyarrhythmia, tachycardia and atrial fibrillation.

Vascular disorders

• epistaxis, haematuria, deep thrombophlebitis, rectum haemorrhage, deep vein thrombosis, thromboembolic events (including pulmonary embolism), and hypertension

Respiratory, thoracic and mediastinal disorders

• Dyspnoea, cough, rhinitis, hiccups and upper respiratory infection
• acute interstitial lung diseases, which may be fatal and pulmonary fibrosis (see section 4.4)
• laryngospasm, pneumonia and bronchopneumonia, including fatal outcomes

Gastrointestinal disorders

• Nausea, vomiting and diarrhoea, stomatitis/mucositis, abdominal pain and constipation. Dehydration, hypokalaemia, metabolic acidosis, ileus, intestinal obstruction, renal disorders may be associated with severe diarrhoea/vomiting, particularly when ZALITIN is combined with 5-FU (see section 4.4).
• intestinal ischaemia, including fatal outcomes, duodenal ulcer, and complications, such as duodenal ulcer haemorrhage or perforation, which can be fatal (see section 4.4), oesophagitis

Hepato-biliary disorders

• liver sinusoidal obstruction syndrome, also known as veno-occlusive disease of the liver, or pathological manifestations related to such liver disorder, including peliosis hepatitis, nodular regenerative hyperplasia, perisinusoidal fibrosis. Clinical manifestations may be portal hypertension and/or increased transaminases.

Skin and subcutaneous tissue disorders

• skin disorder and alopecia, skin exfoliation (hand and foot syndrome), erythematous rash, rash, increased sweating and nail disorder
• hypersensitivity vasculitis

Musculo-skeletal and connective tissue disorders

• back pain. In case of such adverse reaction, haemolysis which has been rarely reported should be investigated, arthralgia and skeletal pain
• rhabdomyolysis, including fatal outcomes (see sections 4.4 and 4.5).

Injury, poisoning, and procedural complications: fall and fall-related injuries

Renal and urinary disorders

• dysuria and abnormal micturition frequency

Less Frequent: Acute tubular necrosis, acute interstitial nephritis, acute renal failure

General disorders and administration site conditions

• fatigue, fever, rigors (tremors) either from infection (with or without febrile neutropenia) or possibly from immunological mechanism; asthenia, pain, weight increase (adjuvant setting).

Injection site reactions including local pain, redness, swelling and thrombosis have been reported. Extravasation may result in local pain and inflammation, which may be severe and lead to complications including necrosis, especially when ZALITIN is infused through a peripheral vein.

Investigations: mild to moderate elevation of hepatic enzymes (ALT/AST) and alkaline phosphatase, increased bilirubin, increased LDH, increased creatinine, decreased weight (metastatic setting)

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