Xaliptine 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 (diarrhoea, nausea, vomiting and mucositis), haematological (neutropenia, thrombocytopenia) and neurological (acute and dose cumulative peripheral sensory neuropathy). Overall, these adverse events were more frequent and severe with oxaliplatin and 5-FU/FA combination than with 5-FU/FA alone.
List of adverse reactions: The frequencies reported 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 arm) and from post-marketing experience.
Frequencies are defined using the following convention: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000), not known (cannot be estimated from the available data).
Further details are given after the list.
Infections and infestations^*: Very common: Infection. Common: Rhinitis, upper respiratory tract infection, neutropenic sepsis⁺. Uncommon: Sepsis⁺.
Blood and lymphatic system disorders^*: Very common: Anaemia, neutropenia, thrombocytopenia, leukopenia, lymphopenia. Common: Febrile neutropenia. Rare: Immunoallergic thrombocytopenia, haemolytic anaemia. Not known: Autoimmune pancytopenia.
Immune system disorders^*: Very common: Allergy/allergic reaction⁺⁺.
Metabolism and nutrition disorders: Very common: Anorexia, hyperglycaemia, hypokalaemia, hypernatraemia. Common: Dehydration, hypocalcaemia. Uncommon: Metabolic acidosis.
Psychiatric disorders: Common: Depression, insomnia. Uncommon: Nervousness.
Nervous system disorders^*: Very common: Peripheral sensory neuropathy, sensory disturbance, dysgeusia, headache. Common: Dizziness, motor neuritis, meningism. Rare: Dysarthria, Reversible Posterior Leukoencephalopathy Syndrome (RPLS or PRES) (see Precautions).
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: Nausea, diarrhoea, vomiting, stomatitis/mucositis, abdominal pain, constipation. Common: Dyspepsia, gastrooesophageal reflux, gastrointestinal haemorrhage, rectal haemorrhage. Uncommon: Ileus, intestinal obstruction. Rare: Colitis including Clostridium difficile diarrhoea, pancreatitis.
Skin and subcutaneous tissue disorders: Very common: Skin disorder, alopecia. Common: Skin exfoliation (i.e. Hand & Foot syndrome), rash erythematous, rash, hyperhidrosis, nail disorder. Not known: Hypersensitivity vasculitis.
Musculoskeletal and connective tissue 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: Fatigue, fever⁺⁺⁺, asthenia, pain, injection site reaction⁺⁺⁺⁺.
Investigations: Very common: Hepatic enzyme increase, blood alkaline phosphatase increase, blood bilirubin increase, blood lactate dehydrogenase increase, weight increase (adjuvant setting). Common: Blood creatinine increase, weight decrease (metastatic setting).
*See detailed section as follows.
**See Precautions.
⁺Common neutropenic sepsis, 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, angioedema, 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 Precautions).
Description selected adverse reactions: Blood and lymphatic system disorders: Incidence by patient (%), by grade: See Table 7.

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Rare (>1/10,000 to <1/1,000): Disseminated intravascular coagulation (DIC), including fatal outcomes (see Precautions).
Post-marketing experience with frequency not known: Haemolytic uraemic syndrome; Autoimmune pancytopenia.
Infections and infestations: Incidence by patient (%): See Table 8.

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Post-marketing experience with frequency not known: Septic shock, including fatal outcomes.
Immune system disorders: Incidence of allergic reactions by patient (%), by grade: See Table 9.

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Nervous system disorders: The dose limiting toxicity of oxaliplatin is neurological. It involves a sensory peripheral neuropathy characterised by dysaethesia and/or paraesthesia of 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 persisiting localised paraesthesias of moderate intensity (2.3%) or with paraesthesias 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 paraesthesia, dysaethesia and hypoaesthesia. 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 laryngospam 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.
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).
Respiratory, thoracic and mediastinal disorders: Post-marketing experience with frequency not known: Laryngospasm.
Gastrointestinal disorders: Incidence by patient (%), by grade: See Table 10.

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Prophylaxis and/or treatment with potent antiemetic agents in indicated.
Dehydration, paralytic ileus, intestinal obstruction, hypokalaemia, 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).
Hepatobiliary 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: Allergic vasculitis.