The incidence of adverse reactions described below is described in accordance with the following gradation: very often (≥ 1/10), often (≥ 1/100 and <1/10), infrequently (≥ 1/1000 and <1/100), rarely (≥ 1/10000 and <1/1000), very rarely (<1/10000), including individual messages; the frequency is unknown - according to the available data, it is not possible to determine the frequency of occurrence.
Combined therapy with oxaliplatin and fluorouracil / calcium folinate
Laboratory and instrumental data: very often - increased activity of "hepatic" transaminases, alkaline phosphatase, hyperbilirubinemia, increased lactate dehydrogenase activity, weight gain (with adjuvant therapy); often - hypercreatininaemia, weight loss (in the treatment of metastatic tumors).
Infectious and parasitic diseases: very often - infections; often - infections of the upper respiratory tract,neutropenic sepsis (including fatal outcomes); infrequently - sepsis (including fatal outcomes).
Violations from the blood and lymphatic system: very often - anemia, neutropenia, thrombocytopenia, leukopenia, lymphopenia; often - febrile neutropenia (including grade 3-4); rarely - immuno-allergic hemolytic anemia and thrombocytopenia, disseminated intravascular coagulation, including lethal outcomes (see section "Special instructions").
Disorders from the gastrointestinal tract: very often - nausea, vomiting, diarrhea, constipation, stomatitis or mucositis (inflammation of the mucous membranes), abdominal pain; often - dyspepsia, gastroesophageal reflux disease, gastrointestinal bleeding, rectal bleeding; infrequently - intestinal obstruction, incl. paralytic; rarely - colitis, including cases of pseudomembranous colitis (called Clostridium difficile), pancreatitis.
Disorders from the liver and bile ducts: very rarely - a syndrome of hepatic sinusoidal obstruction, also known as veno-occlusive disease of the liver, perisinusoidal fibrosis, which in rare cases can progress.
Disorders of the psyche: often - depression, insomnia; infrequently - nervousness.
Impaired nervous system: very often - acute neurosensory manifestations, dysesthesia or paresthesia of the extremities and peripheral sensory neuropathy, sensitivity disorders, headache, paresthesia of the extremities, dysgeusia (a violation of taste sensations); often - dizziness, meningism; rarely - dysarthria, disappearance of deep tendon reflexes, a symptom of Lermitt, a syndrome of a posterior reversible leukoencephalopathy (see section "Special instructions").
Disturbances from the musculoskeletal and connective tissue: very often - back pain; often - arthralgia, pain in the bones.
Disturbances from the respiratory system, chest and mediastinal organs: very often - cough, shortness of breath, nosebleed; often - hiccough, pulmonary embolism, rhinitis, infections of the upper respiratory tract; rarely - acute interstitial lung involvement, sometimes fatal, pulmonary fibrosis (see section "Special instructions").
Vascular disorders: often - bleeding, hot flushes, deep vein thrombosis, pulmonary artery thromboembolism, increased blood pressure.
Disorders from the kidneys and urinary tract: often - hematuria, dysuria, frequent urination; very rarely - acute tubular necrosis, acute interstitial nephritis, acute renal failure.
Disturbances from the skin and subcutaneous tissues: very often - skin lesions; often - alopecia (less than 5% of patients with monotherapy), palmar-plantar erythrodysesthesia, erythematous rashes, excessive sweating, changes from the nails.
Disorders from the side of the organ of vision: often - conjunctivitis, visual impairment; rarely - transient reduction in visual acuity, narrowing and / or loss of visual fields, optic neuritis, transient loss of vision, reversible after discontinuation of treatment.
Hearing disorders and labyrinthine disturbances: infrequently - ototoxicity; rarely - deafness.
Immune system disorders: very often - allergic reactions, such as skin rash (especially urticaria); often - anaphylactic reactions, including bronchospasm, angioedema, hypotension, a feeling of pain in the chest and anaphylactic shock.
General disorders and disorders at the site of administration: very often - weakness and fatigue, fever, fever, chills (trembling) or due to the development of infections (with or without febrile neutropenia) or due to a possible immune reaction, asthenia, reaction at the injection site.
Disorders from the metabolism and nutrition: very often - hypokalemia, hyponatremia, hypernatremia, hyperglycemia, anorexia; often - dehydration, hypocalcemia; infrequently - metabolic acidosis.
Post-registration experience of using oxaliplatin preparations:
Infectious and parasitic diseases: frequency unknown - septic shock, including fatal outcomes.
Disturbances from the musculoskeletal and connective tissue: the frequency is unknown - rhabdomyolysis, including fatal outcomes (see section "Special instructions").
Heart Disease: frequency unknown - interval elongation QT, which can lead to the development of severe ventricular arrhythmias, including ventricular pirouette tachycardia, possibly with a fatal outcome.
Violations from the blood and lymphatic system: frequency unknown - hemolytic-uremic syndrome, increased prothrombin time and INR in patients receiving anticoagulants.
Disturbances from the respiratory system, chest and mediastinal organs: frequency is unknown - laryngospasm.
Impaired nervous system: frequency is unknown - convulsions.
Disturbances from the gastrointestinal tract, liver and bile ducts: frequency is unknown - intestinal ischemia (including fatal outcomes), duodenal ulcer and its potential complications, such as ulcerative bleeding and perforation of the ulcer (including fatal outcomes) (see section "Special instructions").
Disturbances from the skin and subcutaneous tissues: frequency is unknown - itching of the skin.
Disorders from the metabolism and nutrition: frequency unknown - hypocalcemia.
When combined with oxaliplatin / calcium folinate therapy (FOLFOX) and bevacizumab
Safety of application of combination of oxaliplatin with fluorouracil / calcium folinate (FOLFOX) and bevacizumab as first-line therapy was evaluated in 71 patients with metastatic colorectal cancer (study TREE). In addition to the undesirable reactions expected as a result of the application of the regime FOLFOX, undesired reactions in combination FOLFOX with bevacizumab included:
Violations from the blood and lymphatic system: frequency unknown - bleeding.
Violations from the heart and blood vessels: frequency is unknown - hypertension.
Disorders from the gastrointestinal tract: frequency unknown - gastrointestinal perforation.
Disorders from the kidneys and urinary tract: frequency unknown - proteinuria.
General disorders: frequency unknown - deterioration of wound healing.
Description of individual adverse reactions
Hematological toxicity
The incidence of side effects from the blood and lymphatic system increases with treatment with oxaliplatin (85 mg / m2 every 2 weeks) in combination with fluorouracil ± calcium folinate in comparison with monotherapy with preparations of oxaliplatin in a dose of 130 mg / m2 every 3 weeks, for example, the incidence of anemia (80% compared to 60%), the incidence of neutropenia (70% compared to 15%), the rate of thrombocytopenia (80% compared to 40%).
Severe anemia (hemoglobin <80 g / l) or severe thrombocytopenia (platelets <50 * 109/ l) occurred with the same frequency (<5% of patients when oxaliplatin preparations were used as monotherapy or in combination with fluorouracil).
Severe neutropenia (number of neutrophils <1x109/ l) occurred more frequently with oxaliplatin preparations in combination with fluorouracil compared with oxaliplatin alone (40% compared with <3% of patients).
Severe diarrhea, vomiting
Severe diarrhea and / or vomiting can be associated with the development of dehydration, hypokalemia, metabolic acidosis, intestinal obstruction, renal dysfunction, especially with a combination of platinum and fluorouracil.
Syndrome of hepatic sinusoidal obstruction
Syndrome of hepatic sinusoidal obstruction, also known as veno-occlusive disease of the liver or pathological manifestations associated with this liver disease, including peliosis hepatitis, nodal regenerative hyperplasia, perisinusoidal fibrosis, whose clinical manifestations may be portal hypertension or increased activity of "hepatic" transaminases, alkaline phosphatase in the blood serum.
Acute neurosensory manifestations
Acute neurosensory manifestations usually occur at the end of a 2-hour infusion of oxaliplatin preparations or within a few hours after the administration of drugs and self-decrease for the next few hours or days and often reappear in subsequent cycles.They can arise or intensify when exposed to low temperatures or cold objects. Usually they are expressed in the appearance of transient paresthesia, dysesthesia and hypesthesia. Acute syndrome of laryngeal dysaesthesia occurs in 1-2% of patients and is characterized by subjective sensations of dysphagia or dyspnea / sensation of suffocation without any objective signs of respiratory disorders (absence of cyanosis or hypoxia) or laryngospasm or bronchospasm (absence of stridor or wheezing). Other, sometimes encountered symptoms, in particular, disorders of the cranial nerves, or associated with the above undesirable phenomena or occur in isolation: ptosis; diplopia (double vision); aphonia, dysphonia, hoarseness, sometimes described as paralysis of the vocal cords; a violation of the sensitivity of the tongue or dysarthria, sometimes described as aphasia; neuralgia of the trigeminal nerve, facial pain, eye pain, decreased visual acuity, narrowing of the visual fields. In addition, the following symptoms were observed: spasm of masticatory muscles, muscle spasms, involuntary muscle contractions, muscle twitching,myoclonus; impaired coordination, gait disturbance, ataxia, imbalance; feeling of pressure / feeling of pressure / discomfort / pain in the pharynx or chest.
Neurological Toxicity
The limiting toxicity of oxaliplatin is neurological toxicity. It manifests itself in the form of peripheral sensory neuropathy characterized by peripheral dysaesthesia and / or paresthesia with or without the development of convulsive muscle contractions, which is often provoked by cold (85 to 95% of patients). The time of maintenance of these symptoms, which usually decrease between treatment cycles, increases with the number of treatment cycles that have been performed. The occurrence of pain or functional disorders and their duration are indications for correcting the dosing regimen or even canceling the treatment (see section "Dosage and administration, recommendations for correcting the dosage regimen of oxaliplatin").
These functional disorders, including difficulties in performing accurate movements are the consequences of sensory disturbances. Risk of occurrence functional disorders for a cumulative dose of approximately 800 mg / m2 (for example, 10 cycles) is ≤ 15%. In most cases, neurologic manifestations and symptoms decrease after discontinuation of treatment. In most cases, these neurological symptoms are weakened or they completely stop. However, in 3% of patients 3 years after the end of treatment, either stable localized paresthesias of moderate intensity (2.3%) or paresthesia, affecting functional activity (0.5%) were observed.
The symptom of Lermitt, a syndrome of reversible posterior leukoencephalopathy
The symptom of Lermitt is a sudden feeling of electric shock, spreading downwards along the spine and into both legs. It occurs when the head is tilted, other neck movements or coughing. Possible variants of Lermitt's symptom are tingling with neck movements or pain during neck movements, the spreading of unpleasant sensations in both hands and the appearance of unpleasant sensations during movements in the lumbar spine. Signs and symptoms of reversible parieto-occipital leukoencephalopathy can be headache, mental impairment, convulsions, visual impairment (from blurred images to blindness), combined or not with increasing blood pressure.The diagnosis of reversible posterior leukoencephalopathy is confirmed by magnetic resonance imaging or computed tomography of the brain.
Back pain
In case of back pain, the patient should be examined to exclude hemolysis, as there were rare reports of his development.
Reactions at the injection site, extravasation
It was reported on the development of reactions at the site of administration, including pain, flushing, edema and thrombosis. Extravasation (getting the infusion solution with the drug into surrounding tissues) can lead to local pain and inflammation, which can be severe and lead to complications, including necrosis, especially when the drug is injected into the peripheral vein.
Interval lengthening QT
Interval lengthening QT can lead to the development of severe ventricular arrhythmias, including ventricular tachycardia such as pirouette, possibly with a fatal outcome.