Special Warning : אזהרת שימוש

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 the dose adjusted according to toxicity (see section 5.2).

Hypersensitivity reactions
Special surveillance should be ensured for patients with a history of allergic reactions 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 7 days and are troublesome, the subsequent oxaliplatin dose should be reduced from 85 mg/m2 to 65 mg/m2 (metastatic setting) or 75 mg/m2 (adjuvant setting).
- If paraesthesia without functional impairment persists until the next cycle, the subsequent oxaliplatin dose should be reduced from 85 mg/m2 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. Localised 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) 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).

Nausea, vomiting, diarrhoea, dehydration and haematological 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 (5-FU).

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

If haematological toxicity occurs (neutrophils < 1.5 x 109/l or platelets < 50 x 109/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.
Patient 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 (FA)), the usual dose adjustments for 5-fluorouracil associated toxicities should apply.

If grade 4 diarrhoea, grade 3-4 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, temperature > 38.3°C or a sustained temperature > 38°C for more than 1 hour), or grade 3-4 thrombocytopenia (platelets < 50 x 109/l) occur, the dose of oxaliplatin should be reduced from 85 mg/m2 to 65 mg/m2 (metastatic setting) or 75 mg/m2 (adjuvant setting), in addition to any 5- fluorouracil (5-FU) dose reductions required.

Peritoneal haemorrhage may occur when oxaliplatin is administered by intraperitoneal route (off-label route of administration).
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 (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 hypokalaemia, 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 ulcer haemorrhage and perforation Oxaliplatin treatment can cause gastrointestinal ulcer and potential complications, such as gastrointestinal haemorrhage and perforation, which can be fatal. In case of gastrointestinal ulcer, oxaliplatin treatment should be discontinued and appropriate measures taken (see section 4.8).

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

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.

Effects on Driving

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 increased risk of dizziness, nausea and vomiting, and other neurologic symptoms that affect gait and balance may lead to 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.