Chemical formula: C₈H₁₂N₂O₄Pt Molecular mass: 397.294 g/mol PubChem compound: 6857599
Oxaliplatin interacts in the following cases:
Caution is advised when oxaliplatin treatment is co-administered with other medicinal products known to cause QT prolongation. When combined with these medicines, the QT interval should be closely monitored.
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.
Oxaliplatin may have an anti-fertility effect.
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.
Gastrointestinal toxicity of oxaliplatin, i.e. symptoms such as nausea and vomiting, requires prophylactic and/or therapeutic use of antiemetics.
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).
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.
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.
Diagnosis of RPLS is based upon confirmation by brain imaging, preferably MRI (Magnetic Resonance Imaging).
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.
Excretion in breast milk has not been studied. Breast-feeding is contraindicated during oxaliplatin therapy.
Oxaliplatin may have an anti-fertility effect.
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 list 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 list 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 list.
Very common: Infection
Common: Rhinitis, Upper respiratory tract infection, Neutropenic sepsis
Very common: Anemia, Neutropenia, Thrombocytopenia, Leukopenia, Lymphopenia
Common: Febrile neutropenia
Rare: Haemolytic anemia, Immunoallergic thrombocytopenia
Very common: Allergy/allergic reaction+
Very common: Anorexia, Hyperglycemia, Hypokalaemia, Hypernatraemia
Common: Dehydration
Uncommon: Metabolic acidosis
Common: Depression, Insomnia
Uncommon: Nervousness
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)
Common: Conjunctivitis, Visual disturbance
Rare: Visual acuity reduced transiently, visual field disturbances, optic neuritis, transient vision loss (reversible following therapy discontinuation)
Uncommon: Ototoxicity
Rare: Deafness
Common: Haemorrhage, Flushing, Deep vein thrombosis, Hypertension
Very common: Dyspnoea, Cough, Epistaxis
Common:Hiccups, Pulmonary embolism
Rare: Interstitial lung disease, sometimes fatal, Pulmonary fibrosis
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
Very rare: Liver sinusoidal obstruction syndrome (see below)
Very common: Skin disorder, Alopecia
Common: Skin exfoliation (i.e. hand and foot syndrome), Rash erythematous, Rash, Hyperhidrosis, Nail disorder
Very common: Back pain
Common: Arthralgia, Bone pain
Common: Haematuria, Dysuria, Micturition frequency abnormal
Very common: Fever++, Injection site reaction+++, Fatigue, Asthenia, Pain
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
+ 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.
Incidence by patient (%) and by grade:
| Oxaliplatin/5 FU/FA, 85 mg/m² every 2 weeks | Treatment of metastases | Adjuvant therapy | ||||
|---|---|---|---|---|---|---|
| All grades | Grade 3 | Grade 4 | All grades | Grade 3 | Grade 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 |
Postmarketing experience with frequency unknown:
Hemolytic uremic syndrome
Incidence by patient (%) and by grade:
| Oxaliplatin/5 FU/FA, 85 mg/m² every 2 weeks | Treatment of metastases | Adjuvant therapy | ||||
|---|---|---|---|---|---|---|
| All grades | Grade 3 | Grade 4 | All grades | Grade 3 | Grade 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).
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.
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 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. 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
Incidence by patient (%) and by grade:
| Oxaliplatin/5 FU/FA, 85mg/m2 every 2 weeks | Treatment of metastases | Adjuvant therapy | ||||
|---|---|---|---|---|---|---|
| All grades | Grade 3 | Grade 4 | All grades | Grade 3 | Grade 4 | |
| Allergic reactions/Allergy | 9.1 | 1 | <1 | 10.3 | 2.3 | 0.6 |
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.
Very rare (<1/10,000): Acute tubular necrosis, acute interstitial nephritis and acute renal failure.
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