Sunitinib

When ATH:
L01XE04

Pharmacological action

Inhibiting receptor tyrosine kinases of various (more 80), processes involved in tumor growth, pathological angiogenesis and metastasis. Potent inhibitor of platelet derived growth factor receptor (alpha and beta), receptors vascular endothelial growth factor (1, 2 and 3), stem cell factor receptor, receptor Fms-like tyrosine kinase-3, 1R receptor-colony stimulating factor and glial-derived neurotrophic factor receptor.

Pharmacokinetics

Well absorbed by ingestion. TCmax - 6-12. The volume of distribution 2230 l. Метаболизируется при участии CYP3A4, whereby a main active metabolite, which is further metabolized by CYP3A4. The proportion of the active metabolite is 23-37% of the AUC. Css sunitinib and its active metabolite are achieved within 10-14 days. K 14 day total concentration of sunitinib and its active metabolite in plasma is 62,9-101 ng / ml. Contact sunitinib and its metabolite plasma proteins - 95 and 90% respectively, without an explicit dependence on the concentration in the range of 100 to 4000 ng / ml. T1 / 2 sunitinib and its active metabolite - 40-60 and 80-110 hours, respectively. Repeated daily application takes 3-4 fold accumulation of sunitinib and 7-10-fold accumulation of its major metabolite. The total clearance of ingestion - 34-62 l / h. Excreted in the feces (61%), urine (16% - As unchanged drug and metabolites).

Testimony

Gastrointestinal stromal tumors with no effect on imatinib treatment due to resistance or intolerance. Distribution and / or metastatic renal cell carcinoma patients, naïve specific treatment or no effect on cytokine therapy.

Contraindications

Hypersensitivity, pregnancy, lactation, childhood (efficacy and safety have not been established).

Carefully. QT prolongation in history, concomitant use of anti-arrhythmic drugs or potent inhibitors of CYP3A4 (may increase sunitinib plasma concentration), arrhythmia, bradycardia, electrolyte imbalance, renal / hepatic insufficiency.

Dosage regimen

Inside, usually 50 mg daily for 4 weeks, followed by a break in 2 Sun (mode 4/2). Daily dose - 25-87,5 mg. The full cycle of therapy - 6 Sun.

If the drug was omitted, to make up the missed dose should not be. It should take the usual prescribed dose of the drug the next day.

Side effect

Pulmonary embolism (1%), thrombocytopenia (1%), tumor hemorrhage (0,9%), febrile neutropenia (0,4%), increased blood pressure (0,4%).

Venous thromboembolism in patients with metastatic renal cell carcinoma (pulmonary embolism (4 Art.) and deep vein thrombosis (3 Art.)) - 2%, patients with gastrointestinal stromal tumor - 3%.

IN 20% cases: fatigue, diarrhea, nausea, stomatitis, dyspepsia (incl. vomiting), discolouration of the skin, taste disturbance, anorexia.

Frequency: Often (more 1/10), often (more 1/100 less 1/10), infrequently (more 1/1000 less 1/100), rarely (more 1/10000 less 1/1000), rarely (less 1/10000).

From the side of hematopoiesis: often and often - anemia, neutropenia, thrombocytopenia; often - leukopenia.

From the digestive system: very often - dysgeusia, diarrhea, nausea, vomiting, stomatitis, mukozit, dyspepsia, gastralgia; very often or often - anorexia, constipation, glossodiniya (neuralgia jazika), flatulence, dryness of the oral mucosa; often - pain in the mouth, gastroesophageal reflux эzofahealnыy; rarely - pancreatitis; rarely - gastrointestinal perforation.

For the skin: very often - to change the color of the skin, hand-foot syndrome (эritrodizesteziya), rash (эritematoznaya, Thistle, papular, otrubevidnom, generalized, psoriazopodobnye), Blisters; very often or often - to change the color of hair, xerosis, эritema; Parts - alopecia, peeling of the skin, itching, exfoliative dermatitis.

On the part of the musculoskeletal system: often - pain in the extremities, arthralgia, myalgia.

From the nervous system: very often - headache; often - dizziness, paresthesia, insomnia or hypersomnia, depression.

From the CCC: very often - increased blood pressure; often - reduced LVEF, venous thromboembolism (pulmonary embolism, deep vein thrombosis); infrequently - CHF, incl. congestive, LV dysfunction, rarely - QT prolongation, flickering and fluttering of the ventricles of the type "pirouette".

From the urinary system: often - to change the color of urine.

The respiratory system: very often or often - nosebleeds; often - shortness of breath, sore throat, glotke.

On the part of the endocrine system: often - hypothyroidism, Increasing the concentration of TSH.

Other: ocheny part - asthenia; very often or often - increased activity of lipase; often - tearing, weight loss, fever, chills, peripheral edema, periorbital edema, dehydration, Increase CPK and amylase; rarely - bleeding tumors, flu-like symptoms. Patients with brain metastases or reversible leukoencephalopathy syndrome described cases of seizures.

Overdose

Treatment: symptomatic, induction of vomiting, gastric lavage, No specific antidote.

Drug Interactions

Ketoconazole (CYP3A4 inhibitor) increases Cmax and AUC sunitinib and its active metabolite at 49% and 51% respectively. Dr.. CYP3A4 inhibitors (incl. ritonavir, itraconazole, Erythromycin, clarithromycin or greypfrutovыy juice) increase the concentration of sunitinib. Avoid simultaneous reception CYP3A4 inhibitors or select a drug with minimal inhibitory activity against CYP3A4.

Rifampicin (CYP3A4 inducer) reduces Cmax and AUC by 23% and 46% respectively. Dr.. индукторы CYP3A4 (incl. Dexamethasone, phenytoin, karʙmazepin, phenobarbital or St. John's wort preparations) can reduce the concentration of sunitinib. Avoid simultaneous reception with CYP3A4 inducers or select an alternative drug with minimal inducing activity against CYP3A4.

Cautions

Treatment should be under medical supervision, with experience in anti-cancer drugs.

At the beginning of each treatment cycle should be carried out a full analysis of hematological parameters, tk. possible bleeding from the tumor.

During therapy, patients should be observed periodically in order to identify the symptoms of heart failure; LVEF should be assessed before initiating therapy and periodically during treatment. When the manifestation of clinical signs of heart failure treatment with sunitinib should be discontinued. In the absence of clinical signs of heart failure, but with a performance LV ejection fraction less 50% or reduction of this index more 20% compared with the original (prior to initiating therapy), the dose of sunitinib is recommended to reduce or stop taking the drug.

At concentrations, about 2 times higher than therapeutic, sunitinib sposobstvuet udlineniyu QT interval, so before the beginning of therapy and during treatment ECG monitoring is recommended.

During treatment requires monitoring of blood pressure. In patients with severe hypertension, not treatable, It recommended the suspension of treatment. Therapy resume, as soon as possible to normalize blood pressure.

Patients with symptoms of hypothyroidism is necessary to control the function of the thyroid gland.

During treatment, there may be a change in color of the skin due to the presence of the dye formulation (yellow), It may also be discoloration of the skin or hair.

During the treatment it is necessary to control the activity of amylase and lipase in blood serum.

Patients with brain metastases, a history of seizures and / or symptoms of reversible posterior leukoencephalopathy (intracranial hypertension, headache, lethargy, infringement of intellectual activity, loss of sight, including cortical blindness), requires monitoring, including BP. In the case of seizures or symptoms of reversible posterior leukoencephalopathy during therapy it is recommended to temporarily stop taking the drug.

Men and women of childbearing age during treatment and during, at least, 3 Months after its termination must use reliable methods of contraception.

In the period of treatment should refrain from driving and Occupation potentially hazardous activities, require high concentration and speed of psychomotor reactions.