Oxaliplatin Key 50 mg, 100 mg Powder for injection

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

• Treatment of metastatic colorectal cancer
• Adjuvant treatment of colon cancer.

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 4.8).

OXALIPLATIN KEY should always be administered before fluoropyrimidines. OXALIPLATIN KEY is administered as a 2- to 6- hour intravenous infusion in 250 to 500 ml of 5 % glucose solution. OXALIPLATIN KEY 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: OXALIPLATIN KEY has not been studied in patients with severe renal impairment (see 4.3). In patients with moderate renal impairment, treatment may be initiated at the normally recommended dose (see section 4.8). There is no need for dose adjustment in patients with mild renal dysfunction.

Hepatic insufficiency: OXALIPLATIN KEY has not been studied in patients with severe hepatic impairment. No specific dose adjustment is required for patients with abnormal liver function tests.

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

Method of administration

OXALIPLATIN KEY is administered by intravenous infusion. The administration of OXALIPLATIN KEY does not require hyperhydration. OXALIPLATIN KEY 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 venous line over 2 to 6 hours. OXALIPLATIN KEY infusion should always precede that of 5-fluorouracil. In the event of extravasation, administration must be discontinued immediately.

Instruction for use/handling: OXALIPLATIN KEY must be reconstituted and further diluted before use. Only the recommended diluents should be used to reconstitute and then dilute the freeze-dried product. Caution should be exercised when handling and preparing OXALIPLATIN KEY solutions.

• History of hypersensitivity to oxaliplatin and excipients of OXALIPLATIN KEY or other platinum compounds.
• Pregnancy and breastfeeding.
• Bone marrow failure.
• Myelosuppression prior to starting treatment.
• Peripheral sensory neuropathy with functional impairment before treatment.
• Severe renal impairment (creatinine clearance less than 30 ml/min).
• Pulmonary toxicity.

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

Fertility

OXALIPLATIN KEY may have an antifertility effect, which could be irreversible. Male patients are therefore advised not to father a child during and up to 6 months after treatment and to seek advice on conservation of sperm prior to treatment (see section 4.6).

Renal impairment

Due to limited information on safety in patients with moderately 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 dose adjusted according to toxicity (see section 4.2 and 4.3).

Hypersensitivity reactions

Patients with a history of allergic reaction to platinum compounds should be monitored for allergic symptoms. In case of an anaphylactic-like reaction to OXALIPLATIN KEY, the infusion should be immediately discontinued and appropriate symptomatic treatment initiated. OXALIPLATIN KEY re-challenge is contraindicated. Cross reactions, sometimes fatal, have been reported with all platinum compounds. Allergy/allergic reactions, occurring mainly during perfusion, sometimes fatal (frequent allergic reactions such as skin rash, in particularly urticaria, conjunctivitis, rhinitis and frequent anaphylactic reactions, including bronchospasm, angioedema, low blood pressure and anaphylactic shock) has been reported. Delayed hypersensitivity has also been reported with oxaliplatin hours or even days after the infusion.

There have been frequent reports of fever, rigors (tremors), either from infection (with or without febrile neutropenia) or possibly from immunological mechanism. In case of OXALIPLATIN KEY extravasations, the infusion must be stopped immediately and usual local symptomatic treatment initiated. 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 KEY is infused through a peripheral vein.

Neurological symptoms

Neurological toxicity of OXALIPLATIN KEY 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. For patients who develop acute laryngo-pharyngeal dysaesthesia (see section 4.8 Side- effects), during or within the hours following the 2-hour infusion, the next OXALIPLATIN KEY 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 OXALIPLATIN KEY administration.

OXALIPLATIN KEY may have interactions with the following medicines:

• Bone marrow depressants.
• Anticoagulants (prolongation of prothrombin time and of INR in patients with concomitant use).
• Nephrotoxic medicine.
• Ototoxic medicine.
• Vaccination with live or live attenuated vaccines should be avoided in patients receiving OXALIPLATIN KEY (see section 4.4).

In patients who have received a single dose of 85 mg/mu00b2 of OXALIPLATIN KEY, immediately before administration of 5-fluorouracil, no change in the level of exposure to 5-flourouracil has been observed. In vitro, no significant displacement of OXALIPLATIN KEY binding to plasma proteins has been observed with the following agents: erythromycin, salicylates, granisetron, paclitaxel, and sodium valproate. Additive bone marrow depression and gastrointestinal adverse events may occur when two or more bone marrow depressants, including radiation, are used concomitantly or consecutively. For bone marrow failure see section 4.3. Vaccine immunisation of patients treated with OXALIPLATIN KEY should be undertaken with extreme caution, because normal defense mechanisms may be suppressed by treatment with OXALIPLATIN KEY and concurrent use with a live virus vaccine may potentiate the replication of the vaccine virus and/or may decrease the patientu2019s antibody response to the immunisation. The interval between discontinuation of OXALIPLATIN KEY and restoration of the patientu2019s ability to respond to the vaccine, depends on the intensity and type of immunosuppression-causing medicine used, the underlying disease, and other factors; estimates vary from 3 months to 1 year. Caution is advised when OXALIPLATIN KEY 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).

Women of childbearing potential/ Contraception in males and females

Effective contraceptive measures must be taken in potentially fertile patients prior to initiating chemotherapy with OXALIPLATIN KEY and after cessation of treatment, for a period of 4 months in women and 6 months in men.

Pregnancy

There is no available information on safety of use in pregnant women. Based on pre-clinical findings, OXALIPLATIN KEY is likely to be lethal and/or teratogenic to the human foetus at the recommended therapeutic dose and is consequently not recommended during pregnancy.

Breastfeeding

Excretion in breast milk has not been studied. Breastfeeding is contraindicated during OXALIPLATIN KEY therapy.

Fertility

Male patients who are treated with OXALIPLATIN KEY are advised not to conceive a child during and until 6 months after the end of oxaliplatin therapy.

No studies on the effects on the ability to drive and use machines have been performed. However, OXALIPLATIN KEY treatment resulting in an increase of dizziness, nausea, vomiting and other neurological symptoms that affect gait and balance may lead to a minor or moderate influence on the ability to drive and use machines. Vision abnormalities, in particular transient vision loss (reversible following therapy discontinuation) may affect patientu2019s ability to drive and use machines. Therefore, patients should be warned of the potential effect of these events on the ability to drive and use machines or engage in dangerous activities.

Summary of the safety profile

The most frequent adverse events of OXALIPLATIN KEY 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 KEY and 5-FU/FA combination than with 5-FU/FA alone.

Tabulated list of adverse reactions

Body System Undesirable effect Frequent Less frequent Frequency not known

Infections and Infestations: Infection, neutropenic sepsis + , upper respiratory infection, rhinitis Sepsis + Septic shock *+

Blood and the lymphatic system disorders: Anaemia, neutropenia, thrombocytopenia, leukopenia, lymphocytopenia, febrile neutropenia, thrombophlebitis Immuno-allergic thrombocytopenia, haemolytic anaemia. Disseminated intravascular coagulation (DIC) + Haemolytic uremic syndrome, autoimmune pancytopenia, pancytopenia, secondary leukaemia*

Immune system disorders: Isolated fever from immunological mechanism, anaphylactic or anaphylactoid reactions, including bronchospasm, angioedema, hypotension, sensation or chest pain and anaphylactic shock.

Metabolism and nutrition disorders: Anorexia, hyperglycaemia, hypokalaemia, hyponatraemia, dehydration, hypocalcaemia Metabolic acidosis

Psychiatric disorders: Depression and insomnia Nervousness

Nervous system disorders: Dysaethesia/paraesthesia, peripheral sensory neuropathy, headache, fasciculations, acute sensory disturbances, dizziness, motor Dysarthria, loss of deep tendon reflexes, Lhermitteu2019s sign. Reversible posterior leukoencephalopathy syndrome Cranial nerve palsies, fasciculations, convulsion, ischemic or haemorrhagic cerebrovascular disorder*

Eye disorders: Conjunctivitis, abnormal vision, abnormal lachrymation. Visual acuity reduced transiently, visual field disturbances, optic neuritis, transient vision loss (reversible following therapy discontinuation)

Ear and labyrinth disorders: Deafness, ototoxicity

Cardiac disorders: Chest pain Acute coronary syndrome, including myocardial infarction and coronary arteriospasm and angina pectoris in patients treated with oxaliplatin in combination with 5-FU and bevacizumab; QT prolongation which may lead to ventricular dysrhythmias including Torsade de Pointes *

Vascular disorders: Flushing, hypertension, thromboembolism.

Respiratory, thoracic and mediastinal disorders: Epistaxis, bronchospasm, bronchoconstriction, chest pain, Interstitial lung diseases and pulmonary fibrosis. Laryngospasm, pneumonia and broncho-pneumonia *+

Gastrointestinal disorders: Haemorrhage (rectum), anorexia, nausea, vomiting and diarrhoea, stomatitis/mucositis, abdominal pain and constipation, dehydration, metabolic acidosis, intestinal obstruction, dyspepsia, gastroesophageal reflux, hiccup, flatulence, abdominal pain, gastroesophageal reflux, gastrointestinal haemorrhage

Hepato-biliary disorders: Clinical manifestations may be portal hypertension and/or increased transaminases. 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, ascites, hepatic lesions

Skin and subcutaneous tissue disorders: Alopecia, skin exfoliation (hand and foot syndrome), skin rash, urticaria, erythematous rash, increased sweating and nail disorder. Hypersensitivity vasculitis *

Musculoskeletal, connective tissue and bone disorders: Back pain, arthralgia, skeletal pain; myelosuppression. Rhabdomyolysis *

Renal and urinary disorders: Dysuria, abnormal micturition frequency. Renal disorders may be associated with severe diarrhoea/vomiting. Haematuria Acute tubular necrosis, acute interstitial nephritis and acute renal failure.

General disorders and administrative site conditions: Fever +++ , rigors (tremors), oedema, chest pain, asthenia, fatigue, injection site reaction. Extravasation may result in local pain and inflammation and thrombosis, which may be severe and lead to complications including necrosis, especially when OXALIPLATIN KEY is infused through a peripheral vein.

Investigations: Increased alkaline phosphatase, increased bilirubin, increased LDH, increased hepatic enzymes (SGPT/ALT/SGOT/AST), increased creatinine, weight decrease (metastatic setting), increased weight (adjuvant setting)

Injury and poisoning: Fall + including fatal outcomes. ++ Very frequent allergies/allergic reactions, occurring mainly during infusion, sometimes fatal. Frequent allergic reactions include skin rash, particularly urticaria, conjunctivitis and rhinitis. Frequent anaphylactic or anaphylactoid reactions, include bronchospasm, angioedema, hypotension, sensation of chest pain and anaphylactic shock. Delayed hypersensitivity has also been reported with OXALIPLATIN KEY hours or even days after the infusion. +++ Very 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).

In overdose, side effects can be precipitated and/or be of increased severity (see section 4.8). There is no known antidote to OXALIPLATIN KEY. In cases of overdose, exacerbation of adverse events can be expected. Monitoring of haematological parameters should be initiated and symptomatic treatment given. Treatment should be symptomatic and supportive.