Aspen Oxaliplatin Injection

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

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

DOSAGE AND DIRECTIONS FOR USE
FOR ADULTS ONLY
Dosage
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 SIDE EFFECTS).
ASPEN OXALIPLATIN should always be administered before fluoropyrimidines.
ASPEN OXALIPLATIN 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.
Special populations
Renal impairment
ASPEN OXALIPLATIN has not been studied in patients with severe renal impairment (see CONTRAINDICATIONS). In patients with moderate renal impairment, treatment may be initiated at the normally recommended dose (see SIDE EFFECTS and WARNINGS AND SPECIAL PRECAUTIONS). There is no need for dose adjustment in patients with mild renal dysfunction.
Hepatic insufficiency
ASPEN OXALIPLATIN has not been studied in patients with severe hepatic impairment. No specific dose adjustment is required in patients with abnormal liver function tests.
Elderly patients
No increase in severe toxicities was observed when oxaliplatin, as contained in ASPEN OXALIPLATIN, was used as a single agent or in combination with 5-fluorouracil in patients over the age of 65. Dosage adjustment is thus not required for the elderly.

• History of allergy to oxaliplatin or other platinum compounds
• Myelosuppression prior to starting treatment
• Severe renal impairment (creatinine clearance less than 30 ml/min)
• Pregnancy
• Breastfeeding (see PREGNANCY AND LACTATION)
• Peripheral sensory neuropathy with functional impairment before treatment
• Bone-marrow failure.

Warnings
ASPEN OXALIPLATIN should only be used in specialised departments of oncology and administered under the supervision of an experienced oncologist.
ASPEN OXALIPLATIN may have an antifertility effect, which could be irreversible. Male patients are therefore advised not to father a child up to 6 months after treatment and to seek advice on conservation of sperm prior to treatment.

Allergic reactions
Allergic reactions are usually managed with standard epinephrine (adrenaline), corticosteroid or antihistamine therapy and require discontinuation of ASPEN OXALIPLATIN therapy. Re-challenge of ASPEN OXALIPLATIN is contraindicated in these patients.

Neurologic toxicity
Reversible posterior leukoencephalopathy syndrome: Reversible posterior leukoencephalopathy syndrome (RPLS, also known as PRES, posterior reversible encephalopathy syndrome) has been observed with the use of ASPEN OXALIPLATIN.

Special precautions
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. Patients with a history of allergic reaction to platinum compounds should be monitored for allergic symptoms. In case of an anaphylactic-like reaction to ASPEN OXALIPLATIN, the infusion should be immediately discontinued and appropriate symptomatic treatments initiated. ASPEN OXALIPLATIN re-challenge is contraindicated. In case of ASPEN OXALIPLATIN extravasations, the infusion must be stopped immediately and usual local symptomatic treatment initiated. Sensory peripheral neurological toxicity of ASPEN OXALIPLATIN 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 Side effects), during or within the hours following the 2 hour infusion, the next ASPEN OXALIPLATIN infusion should be administered over 6 hours. To prevent 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 ASPEN OXALIPLATIN administration.

In patients who have received a single dose of 85 mg/m2 of ASPEN OXALIPLATIN, immediately before administration of 5-fluorouracil, no change in the level of exposure to the 5-fluorouracil has been observed. In vitro, no significant displacement of oxaliplatin, as contained in ASPEN OXALIPLATIN, 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 concurrently or consecutively. Because normal defence mechanisms may be suppressed by treatment with ASPEN OXALIPLATIN 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 vaccine. Immunisation of patients treated with ASPEN OXALIPLATIN should be undertaken with extreme caution.

ASPEN OXALIPLATIN is contraindicated in pregnancy and lactation (see CONTRAINDICATIONS).
Pregnancy
There is no available information on safety of the use in pregnant women. Based on pre-clinical findings, ASPEN OXALIPLATIN is likely to be lethal and/or teratogenic to the human foetus at the recommended therapeutic dose, and is consequently not recommended during pregnancy. Effective contraceptive measures should be taken in potentially fertile patients prior to initiating chemotherapy with ASPEN OXALIPLATIN and after cessation of treatment for a period of 4 months in women, and 6 months for men.
Lactation
Excretion in breast milk has not been studied. Breastfeeding is contraindicated during ASPEN OXALIPLATIN therapy (see CONTRAINDICATIONS).

No studies on the effect of the ability to drive and use machines have been performed. However, ASPEN OXALIPLATIN treatment resulting in an increase of dizziness, nausea and 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 a patientu2019s ability to drive and use machines. Therefore patients should be warned of the potential effect of these events on the ability to drive, use machines or engage in dangerous activities.

Infections and infestations
Frequent: Infection
Blood and the lymphatic system disorders
Frequent: Haemorrhage (nose, rectum), anaemia, neutropenia, thrombocytopenia, leukopenia, lymphocytopenia, leukaemia, febrile neutropenia, neutropenic sepsis, haematuria, thrombophlebitis
Immune system disorders
Frequent: Fever of unknown origin, immune mediated haemolytic anaemia and thrombocytopenia, anaphylactic or anaphylactoid reactions (include bronchospasm, angioedema, hypotension, sensation of chest pain and anaphylactic shock)
Metabolism and nutrition disorders
Frequent: Metabolic acidosis
Psychiatric disorders
Frequent: Depression, insomnia
Less frequent: Nervousness
Nervous system disorders
Frequent: Dysaestesia/paraesthesia, peripheral sensory neuropathy, headache, acute neuro-sensory disturbances, dizziness, neuritis motor, meningism, cranial nerve palsies (see details below)
Less frequent: Dysarthria, loss of deep tendon reflexes, Lhermitteu2019s sign
Dysaesthesia/paraesthesia of extremities and peripheral sensory neuropathy
The dose limiting toxicity of ASPEN OXALIPALTIN is neurological. It involves a sensory peripheral neuropathy, characterised by peripheral dysaesthesia and/or paraesthesia with or without cramps, often triggered by cold. The symptoms occur in 95 % of patients treated. The duration of these symptoms, which usually regress between courses 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 a 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 (2,3 %) or with paraesthesias that interfere with functional activities (0,5 %).
Acute neuro-sensory manifestations
Symptoms usually start within hours of administration and often occur on exposure to cold. They usually present as transient paraesthesia, dysaesthesia and hypoaesthesia. An acute syndrome of pharyngolaryngeal dysaesthesia occurs in 1 u2013 2 % of patients and is characterised by subjective sensations of dysphagia of dyspnoea/feeling of suffocation, without any objective 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. Occasionally other symptoms that have been observed included jaw spasm, muscle spasms, involuntary muscle contractions, muscle twitching, myoclonus, abnormal coordination, abnormal gait, ataxia, balance disorders, throat or chest tightness, pressure, discomfort, pain. In addition, cranial nerve dysfunctions may be associated with above mentioned events, or also occur as an isolated event 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 in visual acuity or visual field disorders.
Eye disorders
Frequent: Conjunctivitis, abnormal vision, abnormal lacrimation
Less frequent: Decrease of visual acuity, visual field disturbance, optic neuritis
Ear disorders
Frequent: Ototoxicity
Less frequent: Deafness
Vascular disorders
Frequent: Flushing, hypotension, thromboembolism
Respiratory, thoracic and mediastinal disorders
Frequent: Epistaxis, bronchospasm, bronchoconstriction, chest pain, dyspnoea, coughing, rhinitis, pharyngitis, upper respiratory infection, pulmonary embolism, pulmonary fibrosis
Less frequent: Interstitial lung disease
Gastrointestinal disorders
Frequent: Anorexia, nausea, vomiting, diarrhoea, stomatitis, mucositis, abdominal pain, constipation, dehydration, ileus, intestinal obstruction, dyspepsia, gastroesophageal reflux disease, hiccup, flatulence, haemolytic uraemic syndrome, taste perversion
Less frequent: Colitis including Clostridium difficile diarrhoea, pancreatitis
Hepato-biliary disorders
Less frequent: Liver sinusoidal obstruction syndrome (also known as veno-occlusive disease of the liver) or pathological manifestations related to such liver disorder, including peliosis hepatis, nodular regenerative hyperplasia or perisinusoidal fibrosis. Clinical manifestations may be portal hypertension and/or increased transaminases
Skin and subcutaneous tissue disorders
Frequent: Alopecia, skin exfoliation (hand and foot syndrome), skin rash, urticaria, erythematous rash, increased sweating, nail disorder.
Musculoskeletal, connective tissue and bone disorders
Frequent: Back pain, arthralgia, skeletal pain, myelosuppression.
Renal and urinary disorders
Frequent: Dysuria, abnormal micturition frequency
Less frequent: Acute tubular necrosis, acute interstitial nephritis and acute renal failure
General disorders and administrative site conditions
Frequent: Fever, rigors (tremors), oedema, chest pain, asthenia, fatigue, weight decrease (metastatic setting), increased weight (adjuvant setting), injection site reaction. Extravasation may result in local pain, inflammation and thrombosis which may be severe and lead to complications including necrosis, especially when ASPEN OXALIPLATIN is infused through a peripheral vein
Investigations
Frequent: Increased alkaline phosphatase, increased bilirubin, glycaemia abnormalities, disturbance of glucose metabolism, increased LDH, hypokalaemia, increased hepatic enzymes ALAT/ASAT), natraemia abnormalities, disturbance of sodium metabolism, increased creatinine

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