Xilaz Concentrate For Solution for Infusion

XILAZ 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 XILAZ 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/m2 intravenously repeated every 2 weeks.

Adjuvant treatment of colon cancer

The recommended dose is 85 mg/m2 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).

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

XILAZ 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 XILAZ (2-hour IV infusion every two weeks for a maximum of 12 cycles) in combination with 5-FU/FA (FOLFOX4), oxaliplatin as in XILAZ 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 XILAZ is 85 mg/m2. In patients with severe renal impairment, XILAZ should not be used.

Hepatic insufficiency: XILAZ 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.

A phase I study of oxaliplatin single agent, 2-hour IV infusion q3w, included adult cancer patients with different degrees of hepatic impairment (none to severe). The initial oxaliplatin dose was based upon the degree of liver dysfunction and was then increased up to 130 mg/m2 whatever the degree of liver impairment (none to severe). Overall the types of toxicities observed were toxicities expected with oxaliplatin (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 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

XILAZ is administered by intravenous infusion. The administration of oxaliplatin does not require hyperhydration.

XILAZ infusion should always precede that of 5-fluorouracil (5-FU).

XILAZ 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 XILAZ administration.

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

Instructions for use: XILAZ 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 XILAZ 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)

XILAZ 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 XILAZ dose is 65 mg/m2 (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 XILAZ, the infusion should be immediately discontinued and appropriate symptomatic treatment initiated. Re-administration of XILAZ to such patients is contra-indicated. Cross reactions, sometimes fatal, have been reported with all platinum compounds.

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

Neurological Symptoms

Sensory neurological toxicity of XILAZ 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 XILAZ, 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 XILAZ administration.

Dysaesthesia/paraesthesia of extremities and peripheral neuropathy:

• The dose-limiting toxicity of XILAZ 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/m2 (10 cycles) is 10 % and 20 % for a cumulative dose of 1020 mg/m2 (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 XILAZ 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.

In patients who have received a single dose of 85 mg/m2 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 XILAZ 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 XILAZ 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 sections 4.4).

Women of childbearing potential

Effective contraceptive measures should be taken in potentially fertile patients prior to initiating chemotherapy with XILAZ. 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, XILAZ 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. XILAZ is contraindicated during breastfeeding; therefore, if treatment with this medicine is required, breastfeeding must be discontinued (see section 4.3).

Fertility

XILAZ 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, XILAZ 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

SYSTEM ORGAN CLASS ADVERSE REACTION FREQUENCY Infections and infestations Infection, neutropenic sepsis + Frequent Sepsis + Less frequent Blood and lymphatic Disorders $ Anaemia, neutropenia, thrombocytopenia, leukopenia, lymphopenia, febrile neutropenia Frequent Immuno-allergic thrombocytopenia, haemolytic anaemia, disseminated intravascular coagulation (DIC) Less frequent 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 Frequent Metabolism and nutrition disorders Anorexia, hyperglycaemia, hypokalaemia, natraemia abnormalities, dehydration, hypocalcaemia Frequent Metabolic acidosis Less frequent Psychiatric disorders Depression, insomnia Frequent Nervousness Less frequent Nervous system disorders Dysaesthesia/paraesthesia of extremities and peripheral neuropathy, headache, acute neuro-sensory manifestations ** , dysgeusia, dizziness, motor neuritis, flushing, meningism Frequent Dysarthria, loss of deep tendon reflexes, Lhermitteu2019s sign, reversible posterior leukoencephalopathy syndrome (RPLS or PRES) ** Less frequent Eye disorders Conjunctivitis, abnormal vision Frequent Visual acuity reduced transiently, visual field disturbances, optic neuritis, transient vision loss (reversible following therapy discontinuation) Less frequent Ear and labyrinth disorders Ototoxicity, deafness Less frequent Vascular disorders Epistaxis, haemorrhage of the nose, haematuria, deep thrombophlebitis, pulmonary embolism, haemorrhage of the rectum, deep vein thrombosis, thromboembolic events, hypertension Frequent Respiratory, thoracic and mediastinal disorders Dyspnoea, cough, rhinitis, hiccups, pulmonary embolism, upper respiratory infection Frequent Acute interstitial lung diseases, which may be fatal and pulmonary fibrosis ** Less frequent Gastrointestinal disorders * Nausea, vomiting and diarrhoea, stomatitis/mucositis, abdominal pain, constipation, dehydration, ileus, intestinal obstruction, renal disorders may be associated with severe diarrhoea/vomiting, particularly when combined with 5-FU **, dyspepsia, Frequent gastro-oesophageal reflux and gastrointestinal haemorrhage Colitis including clostridium difficile, diarrhoea, pancreatitis Less frequent 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. Less frequent Skin and subcutaneous tissue disorders Skin disorder, alopecia, skin exfoliation (i.e. Hand & Foot syndrome), erythematous rash, rash, hyperhidrosis, nail disorder Frequent Musculoskeletal and connective tissue disorders Back pain *** , arthralgia, skeletal pain Frequent Renal and urinary disorders Dysuria, abnormal micturition frequency Frequent Acute tubular necrosis, acute interstitial nephritis and acute renal failure Less frequent General disorders and administration site conditions Fatigue, fever +++ , asthenia, pain, weight increase, injection site reaction ++++ Frequent Investigations Mild to moderate hepatic enzymes (ALT/AST) increase, and alkaline phosphatase, bilirubin increase, LDH increase, blood creatinine increase, weight decrease (metastatic setting) Frequent Injury, poisoning, and procedural complications Fall Frequent $ The frequency increases when XILAZ is administered (85 mg/m2 every 2 weeks) in combination with 5-FU+/-folinic acid, as compared to a single medicine administration (130 mg/m2 every 3 weeks), e.g. anaemia (80 % vs 60 % of patients), neutropenia (70 % vs 15 %), thrombocytopenia (80 % vs 40 %). Severe anaemia (haemoglobin <8,0 g/dL) or thrombocytopenia (platelets < 50 x 109/L) occurs with a similar frequency (<5 % of patients) when XILAZ is administered as a single medicine or in combination with 5-FU. Severe neutropenia (neutrophils < 1,0 x 109/L) occurs with a greater frequency when XILAZ is administered in combination with 5-FU than as a single medicine (40 % vs < 3 % of patients). ** See section 4.4. *** In case of such adverse reaction, haemolysis which has been rarely reported should be investigated + including fatal outcomes. ++ Frequent allergies/allergic reactions, occurring mainly during infusion, sometimes fatal. Allergic reactions include skin rash, particularly urticaria, conjunctivitis, and rhinitis. Anaphylactic or anaphylactoid reactions include bronchospasm, angioedema, hypotension, sensation of chest pain and anaphylactic shock. Delayed hypersensitivity has also been reported with oxaliplatin hours or even days after the infusion. +++ Frequent fever, rigors (tremors), either from infection (with or without febrile neutropenia) or possibly from immunological mechanism. ++++ Injection site reactions including local pain, redness, swelling and thrombosis have been reported. Extravasation may also result in local pain and inflammation which may be severe and lead to complications including necrosis, especially when oxaliplatin is infused through a peripheral vein (see section 4.4).

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