OXALIPLATIN Concentrate for solution Ref.[7987] Active ingredients: Oxaliplatin

Oxaliplatin 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 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.

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 medications 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 several hours after a 2-hour infusion, the subsequent oxaliplatin infusion must 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 75 mg/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 about the possibility of persistent symptoms of peripheral sensory neuropathy after the end of the treatment. Localised moderate paraesthesia or paraesthesia 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 Undesirable effects).

Diagnosis of RPLS is based upon confirmation by brain imaging, preferably MRI (Magnetic Resonance Imaging).

Nausea, vomiting, diarrhoea, dehydration

Gastrointestinal toxicity of oxaliplatin, i.e. symptoms such as nausea and vomiting, requires prophylactic and/or therapeutic use of antiemetics (see section 4.8 Undesirable effects).

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).

Hematologic changes

If haematological toxicity occurs (neutrophils < 1.5 × 10⁹/l or platelets < 50 × 10⁹/l), administration of the next course of therapy should be postponed until haematological values return to acceptable levels. A full blood count with white cell differential should be performed prior to start therapy and before each subsequent course.

Patients must be adequately informed about the risk of diarrhoea/emesis, mucositis/stomatitis and neutropenia following oxaliplatin and 5-fluorouracil (5-FU) administration so 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 I or less and/or until the neutrophil count is ≥ 1.5 × 10⁹/l.

For oxaliplatin combined with 5-fluorouracil (5-FU) (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 < 1.0 × 10⁹/l), grade 3-4 thrombocytopenia (platelets < 50 × 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.

Pulmonary

In cases 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 Undesirable effects).

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.

Pregnancy

For use in pregnant women, see section 4.6 Pregnancy and lactation.

Fertility

Genotoxic effects were observed with oxaliplatin in 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 Pregnancy and lactation).

Immunosuppressant Effects/Increased Susceptibility to Infections

Administration of live or live-attenuated vaccines in patients immunocompromised by chemotherapeutic agents including oxaliplatin, may result 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.

In patients who have received a single dose of 85 mg/m² of oxaliplatin, immediately before administration of 5-fluorouracil (5-FU), no change in plasma levels of 5-fluorouracil (5-FU) 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.

Pregnancy/Women of childbearing potential

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.

Contraception

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 contraindicated during oxaliplatin therapy.

Fertility

Oxaliplatin may have an anti-fertility effect (see section 4.4 Special warnings and precautions for use).

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 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 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.

The most frequent adverse events of oxaliplatin in combination with 5-fluorouracil and folinic acid (5-FU and FA) were of gastrointestinal (diarrhoea, nausea, vomiting and mucositis), haematological (neutropenia, thrombocytopenia) and neurological (acute and dose cumulative peripheral sensory neuropathy) nature.

Overall, these adverse events were more frequent and severe when 5-FU/FA was administered in combination with oxaliplatin compared to 5-FU/FA alone.

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 arms) 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 (≥1/1,000 <1/100), rare (≥1/10,000 <1/1,000), very rare (<1/10,000), not known (cannot be estimated from the available data).

Further details are given following this table.

Infections and infestations*

Very common: Infection

Common: Rhinitis, Upper respiratory tract infection, Neutropenic sepsis

Blood and lymphatic system disorders*

Very common: Anemia, Neutropenia, Thrombocytopenia, Leukopenia, Lymphopenia

Common: Febrile neutropenia

Rare: Haemolytic anemia, Immunoallergic thrombocytopenia

Immune system disorders*

Very common: Allergy/allergic reaction+

Metabolism and nutrition disorders

Very common: Anorexia, Hyperglycemia, Hypokalaemia, Hypernatraemia

Common: Dehydration

Uncommon: Metabolic acidosis

Psychiatric disorders

Common: Depression, Insomnia

Uncommon: Nervousness

Nervous system disorders*

Very common: Peripheral sensory, europathy, Headache, Sensory disturbance, Dysgeusia

Common: Dizziness, Motor neuritis, Meningism

Rare: Dysarthria, Reversible Posterior Leukoencephalopathy syndrome (RPLS – also known as PRES)**

Eye disorders

Common: Conjunctivitis, Visual disturbance

Rare: Visual acuity reduced transiently, visual field disturbances, optic neuritis, transient vision loss (reversible following therapy discontinuation)

Ear and labyrinth disorders

Uncommon: Ototoxicity

Rare: Deafness

Vascular disorders

Common: Haemorrhage, Flushing, Deep vein thrombosis, Hypertension

Respiratory, thoracic and mediastinal disorders

Very common: Dyspnoea, Cough, Epistaxis

Common:Hiccups, Pulmonary embolism

Rare: Interstitial lung disease, sometimes fatal, Pulmonary fibrosis**

Gastrointestinal disorders*

Very common: Diarrhea, Nausea, Vomiting, Stomatitis/Mucositis, Abdominal pain, Constipation

Common:Dyspepsia, Gastroesophageal reflux, Gastrointestinal haemorrhage, Rectal haemorrhage

Uncommon: Ileus, Intestinal obstruction

Rare: Colitis including Clostridium difficile diarrhea, Pancreatitis

Hepato-biliary disorders

Very rare: Liver sinusoidal obstruction syndrome (see below)

Skin and subcutaneous tissue disorders

Very common: Skin disorder, Alopecia

Common: Skin exfoliation (i.e. hand and foot syndrome), Rash erythematous, Rash, Hyperhidrosis, Nail disorder

Musculoskeletal system, connective tissue and bone disorders

Very common: Back pain

Common: Arthralgia, Bone pain

Renal and urinary disorders

Common: Haematuria, Dysuria, Micturition frequency abnormal

General disorders and administration site conditions

Very common: Fever++, Injection site reaction+++, Fatigue, Asthenia, Pain

Investigations

Very common: Blood alkaline phosphatase increase, Blood bilirubin increase, Blood lactate dehydrogenase (LDH) increase, Hepatic enzymes increase, Weight increase (adjuvant setting)

Common:Blood creatinine increase, Weight decrease

* See detailed information in the section below
** See section 4.4.
⁺ Very common: frequent allergy/allergic reactions, occurring mainly during perfusion, sometimes fatal (frequent allergic reactions such as skin rash, in particularly urticaria, conjunctivitis, rhinitis. Common anaphylactic or anaphylactoid reactions, include bronchospasm, angioedema, hypotension, sensation of chest pain, and anaphylactic shock.
⁺⁺ Very commonly fever, rigors (tremor), either from infection (with or without febrile neutropenia) or possibly from immunological mechanism.
⁺⁺⁺ Injection site reactions including local pain, reddening, swelling and thrombosis have been reported. Extravasation may 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 4.4).

Blood and lymphatic system disorders

Incidence by patient (%) and by grade:

Postmarketing experience with frequency unknown:

Hemolytic uremic syndrome

Gastrointestinal disorders

Incidence by patient (%) and by grade:

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).

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 functional disorders is an indication for dose adjustments or even treatment discontinuation, depending on the duration of these symptoms (see section 4.4).

These functional disorders include difficulties in executing delicate movements and are a possible consequence of sensory impairment. The risk of occurrence of persistent symptoms for a cumulative dose of 850mg/m² (10 cycles) is approximately 10% and 20% for a cumulative dose of 1,020 mg/m² (12 cycles).

In the majority of the cases, the neurological signs and symptoms improved or totally recovered when treatment was 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 persistent localised paraesthesia of moderate intensity (2.3%) or with paraesthesia with functional impairment (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 paraesthesia, dysaesthesia and hypoesthesia. An acute syndrome of pharyngolaryngeal dysaesthesia occurs in 1% and 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 were rapidly reversible even in the absence of treatment. Prolongation of the infusion helps to reduce the incidence of this syndrom (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 the 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 unknown:

Convulsion

Immune system disorders

Incidence by patient (%) and by grade:

Hepatobiliary disorders

Very rare (<1/10,000): Hepatic sinusoidal obstruction syndrome, also known as veno-occlusive liver disease, or pathological manifestations related to such liver disorder, including peliosis hepatis, nodular regenerative hyperplasia and perisinusoidal fibrosis. Clinical manifestations may be portal hypertension and/or increased transaminases.

Renal and urinary disorders

Very rare (<1/10,000): Acute tubular necrosis, acute interstitial nephritis and acute renal failure.

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 (www.mhra.gov.uk/yellowcard).

This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.

• DO NOT mix with alkaline medicinal products or solutions, in particular 5-fluorouracil, trometamol and folinic acid products containing trometamol as an excipient and trometamol salts of other medicinal products. Alkaline medicinal products or solutions will adversely affect the stability of oxaliplatin (see section 6.6).
• DO NOT dilute oxaliplatin with saline or other solutions containing chloride ions (including calcium, potassium or sodium chlorides)
• DO NOT mix with other medicinal products in the same infusion bag or infusion line (see section 6.6 for instructions concerning simultaneous administration with folinic acid).
• DO NOT use injection equipment containing aluminium.