Recoxali Adverse Reactions

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 as follows are derived from clinical trials in the metastatic and adjuvant settings (having included 416 and 1,108 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 after the table. (See Table 7.)

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Description of selected adverse reactions: Blood and lymphatic system disorders: See Table 8.

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Rare (>1/10,000, <1/1,000): Disseminated intravascular coagulation (DIC), including fatal outcomes (see Precautions).
Postmarketing experience with frequency not known: Hemolytic uremic syndrome, Autoimmune pancytopenia, Pancytopenia, Secondary leukemia.
Infections and infestations: Incidence by patient (%): See Table 9.

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Postmarketing experience with frequency not known: Septic shock, including fatal outcomes.
Immune system disorders: Incidence of allergic reactions by patient (%), by grade: See Table 10.

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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 Precautions).
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 1,020 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 Pharmacology: Toxicology: Preclinical safety data under Actions) 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 Precautions). 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 previously 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.
Post-marketing 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 Precautions).
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: Post-marketing experience with frequency not known: Laryngospasm.
Pneumonia and bronchopneumonia, including fatal outcomes.
Gastrointestinal disorders: Incidence by patient (%), by grade: See Table 11.

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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 Precautions).
Postmarketing experience with frequency not known: Intestinal ischaemia, including fatal outcomes (see Precautions).
Gastrointestinal ulcer and perforation, which can be fatal. (see Precautions).
Oesophagitis.
Hepato-biliary disorders: 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.
Musculoskeletal and connective tissue disorders: Post-marketing experience with frequency not known: Rhabdomyolysis, including fatal outcomes (see Precautions).
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 to pharmacovigilance@aurobindo.com.