4.1. Therapeutic indications

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

•Adjuvant treatment of stage III (Duke's C) colon cancer after complete resection of primary tumour.

•Treatment of metastatic colorectal cancer.

4.2. Posology and method of administration

The preparation of injectable solutions of cytotoxic agents must be carried out by trained specialist personnel with knowledge of the medicinal products used, in conditions that guarantee the integrity of the medicinal product, the protection of the environment and in particular the protection of the personnel handling the medicinal products, in accordance with the hospital policy. It requires a preparation area reserved for this purpose. It is forbidden to smoke, eat or drink in this area.

Posology

FOR ADULTS ONLY

The recommended dose for oxaliplatin in adjuvant setting is 85 mg/m² intravenously repeated every two weeks for 12 cycles (6 months).

The recommended dose for oxaliplatin in treatment of metastatic colorectal cancer is 85mg/m² intravenously repeated every 2 weeks until disease progression or unacceptable toxicity.

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

Oxaliplatin should always be administered before fluoropyrimidines, i.e. 5-fluorouracil.

Oxaliplatin is administered as a 2- to 6-hour intravenous infusion in 250 to 500 ml of 5% glucose solution to give a concentration between 0.2 mg/ml and 0.70 mg/ml; 0.70 mg/ml is the highest concentration in clinical practice for an oxaliplatin dose of 85 mg/m².

Oxaliplatin has mainly been 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 must not be administered in patients with severe renal impairment (see sections 4.3 and 5.2). In patients with mild to moderate renal impairment, the recommended dose of oxaliplatin is 85 mg/m2 (see sections 4.4 and 5.2).

•Hepatic insufficiency:

In a phase I study including patients with several levels of hepatic impairment, frequency and severity of hepato-biliary disorders appeared to be related to progressive disease and impaired 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.

•Paediatric patients:

There is no relevant indication for use of oxaliplatin in children. The effectiveness of oxaliplatin single agent in the paediatric populations with solid tumors has not been established (see section 5.1).

Method of administration

Oxaliplatin is administered by intravenous infusion.

The administration of oxaliplatin does not require hyperhydration.

Oxaliplatin diluted in 250 to 500 ml of 5% glucose solution to give a concentration not less than 0.2 mg/ml must be infused via a central venous line or peripheral vein over 2 to 6 hours. Oxaliplatin infusion must always precede the administration of 5-fluorouracil.

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

Instructions for use:

Oxaliplatin must be diluted before use. Only 5% glucose diluent is to be used to dilute the concentrated solution for infusion (see section 6.6).

4.3. Contraindications

Oxaliplatin is contraindicated in patients who

- have a known history of hypersensitivity to oxaliplatin.

- are breast feeding.

- have myelosuppression prior to starting first course, as evidenced by baseline neutrophils <2×109/l and/or platelet count of <100×109/l.

- have a peripheral sensory neuropathy with functional impairment prior to first course.

- have a severely impaired renal function (creatinine clearance less than 30 ml/min)(see section 5.2).

4.4. Special warnings and precautions for use

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

Renal impairment

Patients with mild to moderate renal impairment should be closely monitored for adverse reactions and dose adjusted according to toxicity (see section 5.2).

Hypersensitivity reactions

Special surveillance should be ensured for patients with a history of allergic manifestations to other products containing platinum. In case of anaphylactic manifestations the infusion should be interrupted immediately and an appropriate symptomatic treatment started. Re-administration of oxaliplatin to such patients is contraindicated. Cross reactions, sometimes fatal, have been reported with all platinum compounds.

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

Neurological Symptoms

Neurological toxicity of oxaliplatin should be carefully monitored, especially if co-administered with other medicinal products 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 infusion should be administered over 6 hours.

Peripheral neuropathy

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

- If symptoms last longer than seven days and are troublesome, the subsequent oxaliplatin dose should be reduced from 85 to 65 mg/m2 (metastatic setting) or 75mg/m2 (adjuvant setting).

- If paraesthesia without functional impairment persists until the next cycle, the subsequent oxaliplatin dose should be reduced from 85 to 65 mg/m2 (metastatic setting) or 75 mg/m2 (adjuvant setting).

- If paraesthesia with functional impairment persists until the next cycle, oxaliplatin should be discontinued.

- If these symptoms improve following discontinuation of oxaliplatin 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. Localized moderate paresthesias or paresthesias that may interfere with functional activities can persist after up to 3 years following treatment cessation in the adjuvant setting.

Reversible Posterior Leukoencephalopathy Syndrome (RPLS)

Cases of Reversible Posterior Leukoencephalopathy Syndrome (RPLS, also known as PRES, Posterior Reversible Encephalopathy Syndrome) have been reported in patients receiving oxaliplatin in combination chemotherapy. RPLS is a rare, reversible, rapidly evolving neurological condition, which can include seizure, hypertension, headache, confusion, blindness, and other visual and neurological disturbances (see section 4.8). Diagnosis of RPLS is based upon confirmation by brain imaging, preferably MRI (Magnetic Resonance Imaging)

Immunosuppressant Effects/Increased Susceptibility to Infections

Administration of live or live attenuated vaccines in patients immunocompromised by chemotherapeutic agents, may results in serious or fatal infections. Vaccination with a live vaccine should be avoided in patients receiving oxaliplatin. Killed or inactivated vaccines may be administered; however, the response to such vaccines may be diminished.

Nausea, vomiting, diarrhoea, dehydration, and hematologic 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, hypokalemia, metabolic acidosis and renal impairment may be caused by severe diarrhoea/emesis particularly when combining oxaliplatin with 5-fluorouracil.

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

If haematological toxicity occurs (neutrophils < 1.5x109/l or platelets < 50x109/l), administration of the next course of therapy should be postponed until haemotological values return to acceptable levels. A full blood count with white cell differential should be performed prior to start of therapy and before each subsequent course. Myelosuppressive effects may be additive to those of concomitant chemotherapy. Patients with severe and persistent myelosuppression are at high risk of infectious complications. Sepsis, neutropenic sepsis and septic shock have been reported in patients treated with oxaliplatin including fatal outcomes (see section 4.8.). If any of these events occurs, oxaliplatin should be discontinued.

Patients must be adequately informed of the risk of diarrhoea/emesis, mucositis/stomatitis and neutropenia after oxaliplatin and 5-fluorouracil administration so that they can urgently contact their treating physician 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 ≥ 1.5 x 109/l.

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

If grade 4 diarrhoea, grade 3-4 neutropenia (neutrophils < 1.0x109/l), febrile neutropenia (fever of unknown origin without clinically or microbiologically documented infection with an absolute neutrophil count < 1.0x109/L, a single temperature of >38.3℃ or a sustained temperature of >38℃ for more than one hour), or grade 3-4 thrombocytopenia (platelets < 50x109/L) occur, the dose of oxaliplatin should be reduced from 85 to 65 mg/m² (metastatic setting) or 75 mg/m² (adjuvant setting), 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, oxaliplatin should be discontinued until further pulmonary investigations exclude an interstitial lung disease or pulmonary fibrosis (see section 4.8).

Blood disorders

Haemolytic-uraemic syndrome (HUS) is a life-threatening side effect (frequency not known).

Oxaliplatin 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 treatment. If DIC is present, oxaliplatin treatment should be discontinued and appropriate treatment should be administered. (see section 4.8)

QT prolongation

QT prolongation may lead to an increased risk for ventricular arrhythmias including Torsade de Pointes, which can be fatal (see section 4.8). The QT interval should be closely monitored on a regular basis before and after administration of oxaliplatin. Caution should be exercised in patients with a history or a predisposition for prolongation of QT, those who are taking medicinal products known to prolong QT interval, and those with electrolyte disturbances such as hypokalemia, hypocalcaemia, or hypomagnesaemia. In case of QT prolongation, oxaliplatin treatment should be discontinued. (see sections 4.5 and 4.8).

Rhabdomyolysis

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

Gastrointestinal ulcer/ Gastrointestinal haemorrhage and perforation

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

Liver disorders

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

Pregnancy

For use in pregnant women, see section 4.6.

Fertility

Genotoxic effects were observed with oxaliplatin in the preclinical studies. Therefore male patients treated with oxaliplatin are 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 because oxaliplatin may have an anti-fertility effect which could be irreversible.

Women should not become pregnant during treatment with oxaliplatin and should use an effective method of contraception (see section 4.6).

Peritoneal hemorrhage may occur when oxaliplatin is administered by intraperitoneal route (off-label route of administration).

4.5. Interaction with other medicinal products and other forms of interaction

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

Caution is advised when oxaliplatin treatment is co-administered with other medicinal products known to cause QT interval prolongation. In case of combination with such medicinal products, the QT interval should be closely monitored (see section 4.4). Caution is advised when oxaliplatin treatment is administered concomitantly with other medicinal products known to be associated with rhabdomyolysis. (see section 4.4).

Vaccination with live or live attenuated vaccines should be avoided in patients receiving oxaliplatin (see section 4.4).

4.6. Fertility, pregnancy and lactation

Pregnancy

To date there is no available information on safety of use in pregnant women. In animal studies, reproductive toxicity was observed. Consequently, oxaliplatin is not recommended during pregnancy and in women of childbearing potential not using contraceptive measures.

The use of oxaliplatin should only be considered after suitably appraising the patient of the risk to the foetus and with the patient's consent.

Appropriate contraceptive measures must be taken during and after cessation of therapy during 4 months for women and 6 months for men.

Breast-feeding

Excretion in breast milk has not been studied. Breast-feeding is contra-indicated during oxaliplatin therapy.

Fertility

Oxaliplatin may have an anti-fertility effect (see section 4.4).

4.7. Effects on ability to drive and use machines

No studies on the effects on the ability to drive and use machines have been performed. However oxaliplatin treatment resulting in an increase risk of dizziness, nausea and vomiting, and other neurologic 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 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.

4.8. Undesirable effects

Summary of the safety profile

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

Tabulated list of adverse reactions

The frequencies reported in the table below are derived from clinical trials in the metastatic and adjuvant settings (having included 416 and 1108 patients respectively in the oxaliplatin + 5-FU/FA treatment arm) and from post marketing experience.

Frequencies in this table are defined using the following convention: very common (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1000, <1/100), rare (≥1/10000, <1/1000), very rare (<1/10000), not known (cannot be estimated from the available data).

Further details are given after the table.

MedDRA Organ system classes

Very common

Common

Uncommon

Rare

Infections and infestations *

- Infection

- Rhinitis

-Upper respiratory tract infection

-Neutropenic sepsis

Sepsis+

Blood and lymphatic system disorders*

- Anaemia

- Neutropenia

- Thrombocyto-penia

- Leukopenia

- Lymphopenia

- Febrile neutropenia

- Immunoallergic thrombocytopenia

- Haemolytic anaemia***[rare]

Immune system disorders*

-Allergy/ allergic reaction ++

Metabolism and nutrition disorders

- Anorexia

- Hyperglycaemia

- Hypokalaemia

- Hypernatraemia

- Dehydration

- Hypocalcaemia

- Metabolic acidosis

Psychiatric disorders

- Depression

- Insomnia

- Nervousness

Nervous system disorders*

- Peripheral sensory neuropathy

- Sensory disturbance

- Dysgeusia

- Headache

- Dizziness

- Motor neuritis

- Meningism

- Dysarthria

- Reversible Posterior Leukoencephalopathy syndrome (RPLS or PRES) (see section 4.4)

Eye disorders

- Conjunctivitis

- Visual

disturbance

- Visual acuity reduced transiently

- Visual field disturbances

- Optic neuritis

- Transient vision loss, reversible following therapy discontinuation

Ear and labyrinth disorders

- Ototoxicity

- Deafness

Vascular disorders

- Haemorrhage

- Flushing

- Deep vein thrombosis

- Hypertension

Respiratory, thoracic and mediastinal disorders

- Dyspnoea

- Cough

- Epistaxis

- Hiccups

- Pulmonary

embolism

- Interstitial lung disease, sometimes fatal

- Pulmonary fibrosis**

Gastrointestinal disorders*

- Nausea

- Diarrhoea

- Vomiting

- Stomatitis /Mucositis

- Abdominal pain

- Constipation

- Dyspepsia

- Gastro-esophageal reflux

- Gastrointestinal hemorrhage

- Rectal haemorrhage

- Ileus

- Intestinal

obstruction

- Colitis including clostridium difficile diarrhoea

- Pancreatitis

Skin and subcutaneous tissue disorders

- Skin disorder

- Alopecia

- Skin exfoliation (i.e. Hand & Foot syndrome)

- Rash erythematous

- Rash

- Hyperhidrosis

- Nail disorder

Musculoskeletal and connective tissue disorders

- Back pain

- Arthralgia

- Bone pain

Renal and urinary disorders

- Haematuria

- Dysuria

- Micturition frequency abnormal

General disorders and administration site conditions

- Fatigue

- Fever +++

- Asthenia

- Pain

- Injection site reaction++++

Investigations

- Hepatic enzyme increase

- Blood alkaline phosphatase increase

- Blood bilirubin increase

- Blood lactate dehydrogenase increase

- Weight increase (adjuvant setting)

- Blood creatinine increase

- Weight decrease (metastatic setting)

Injury, poisoning, and procedural complications

- Fall

* See detailed section below.

** See section 4.4.

*** Microangiopathic haemolytic anaemia associated with haemolytic uraemic syndrome (HUS) or Coombs positive haemolytic anaemia, see section 4.4)

+ Including fatal outcomes.

++ Very common allergies/allergic reactions, occurring mainly during infusion, sometimes fatal. Common allergic reactions include skin rash, particularly urticaria, conjunctivitis, and rhinitis. Common anaphylactic or anaphylactoid reactions, include bronchospasm, angioeodema, hypotension, sensation of chest pain and anaphylactic shock. Delayed hypersensitivity has also been reported with oxaliplatin hours or even days after the infusion.

+++Very common 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).

Description of selected adverse reactions

Blood and lymphatic system disorders

Incidence by patient (%), by grade

Oxaliplatin and 5-FU/FA 85 mg/m²

every 2 weeks

Metastatic Setting

Adjuvant Setting

All grades

Gr 3

Gr 4

All grades

Gr 3

Gr 4

Anaemia

82.2

3

<1

75.6

0.7

0.1

Neutropenia

71.4

28

14

78.9

28.8

12.3

Thrombocytopenia

71.6

4

<1

77.4

1.5

0.2

Febrile neutropenia

5.0

3.6

1.4

0.7

0.7

0.0

Neutropenic sepsis

1.1

0.7

0.4

1.1

0.6

0.4

Rare (≥1/10000, <1/1000)

Disseminated intravascular coagulation (DIC), including fatal outcomes (see section 4.4).

Postmarketing experience with frequency not known

Hemolytic uremic syndrome

Autoimmune pancytopenia

Pancytopenia

Secondary leukemia

Infections and infestations

Incidence by patients (%)

Oxaliplatin and 5-FU/FA 85 mg/m2

Every 2 weeks

Metastatic Setting

Adjuvant Setting

All grades

All grades

Sepsis (including sepsis and neutropenic sepsis)

1.5

1.7

Postmarketing experience with frequency not known

Septic shock, including fatal outcomes.

Immune system disorders

Incidence of allergic reactions by patient (%), by grade

Oxaliplatin and 5-FU/FA 85 mg/m²

every 2 weeks

Metastatic Setting

Adjuvant Setting

All grades

Gr 3

Gr 4

All grades

Gr 3

Gr 4

Allergic reactions /Allergy

9.1

1.0

<1

10.3

2.3

0.6

Nervous system disorders

The dose limiting toxicity of oxaliplatin is neurological. It involves a sensory peripheral neuropathy characterised by dysaesthesia and/or paraesthesia of the extremities with or without cramps, often triggered by the cold. These symptoms occur in up to 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 are indications, depending on the duration of the symptoms, for dose adjustment, or even treatment discontinuation (see section 4.4).

This functional disorder includes difficulties in executing delicate movements and is a possible consequence of sensory impairment. The risk of occurrence of persistent symptoms for a cumulative dose of 850 mg/m² (10 cycles) is approximately 10% and 20% for a cumulative dose of 1020 mg/m² (12 cycles).

In the majority of the cases, the neurological signs and symptoms improve or totally recover when treatment is discontinued. In the adjuvant setting of colon cancer, 6 months after treatment 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 localized paresthesias of moderate intensity (2.3%) or with paresthesias that may interfere with functional activities (0.5%).

Acute neurosensory manifestations (see section 5.3) have been reported. They start within hours of administration and often occur on exposure to cold. They usually present as transient paresthesia, dysesthesia and hypoesthesia. An acute syndrome of pharyngolaryngeal dysesthesia occurs in 1% - 2% of patients and is characterised by subjective sensations of dysphagia or 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 (see section 4.4). Occasionally other symptoms that have been observed include jaw spasm/muscle spasms/muscle contractions-involuntary/muscle twitching/myoclonus, coordination abnormal/gait abnormal/ 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, visual field disorders.

Other neurological symptoms such as dysarthria, loss of deep tendon reflex and Lhermitte's sign were reported during treatment with oxaliplatin. Isolated cases of optic neuritis have been reported.

Postmarketing experience with frequency not known

Convulsion

Ischemic or haemorrhagic cerebrovascular disorder

Cardiac disorders

Post-marketing experience with frequency not known

QT prolongation, which may lead to ventricular arrhythmias including Torsade de Pointes, which may be fatal (see section 4.4).

Acute coronary syndrome, including myocardial infarction and coronary arteriospasm and angina pectoris in patients treated with oxaliplatin in combination with 5- FU and bevacizumab.

Respiratory, thoracic and mediastinal disorders

Postmarketing experience with frequency not known

Laryngospasm

Pneumonia and bronchopneumonia, including fatal outcomes

Gastrointestinal disorders

Incidence by patient (%), by grade

Oxaliplatin and 5-FU/FA 85mg/m²

every 2 weeks

Metastatic Setting

Adjuvant Setting

All grades

Gr 3

Gr 4

All grades

Gr 3

Gr 4

Nausea

69.9

8

<1

73.7

4.8

0.3

Diarrhoea

60.8

9

2

56.3

8.3

2.5

Vomiting

49.0

6

1

47.2

5.3

0.5

Mucositis/Stomatitis

39.9

4

<1

42.1

2.8

0.1

Prophylaxis and/or treatment with potent antiemetic agents is indicated.

Dehydration, paralytic ileus, intestinal obstruction, hypokalemia, metabolic acidosis and renal impairment may be caused by severe diarrhoea/emesis particularly when combining oxaliplatin with 5-fluorouracil (5-FU) (see section 4.4).

Post-marketing experience with frequency not known

Intestinal ischaemia, including fatal outcomes (see section 4.4).

Gastrointestinal ulcer and perforation, which can be fatal (see section 4.4).

Oesophagitis

Hepato-biliary disorders

Very common (>1/10)

Hepatic enzyme increase, blood bilirubin increase

Very rare (<1/10,000)

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

Frequency not known

Focal nodular hyperplasia

Musculoskeletal and connective tissue disorders

Post-marketing experience with frequency not known

Rhabdomyolysis, including fatal outcomes (see section 4.4).

Renal and urinary disorders

Very rare (<1/10,000)

Acute tubular necrosis, acute interstitial nephritis and acute renal failure.

Skin and Subcutaneous tissue disorders

Post-marketing experience with frequency not known

Hypersensitivity vasculitis

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

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