Inlita - instructions for use, doses, side effects, contraindications

Active substanceAksitinibAksitinib

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Inlita®

pills inwards

Pfizer Inc. USA

Inlita®

pills inwards

Pfizer Manufakchuring Deutschland GmbH Germany

Dosage form: & nbspfilm-coated tablets

Composition:

1 tablet contains:

active substance: axitinib 3 mg and 7 mg;

Excipients: cellulose microcrystalline 64,458 / 150,403 mg, lactose monohydrate 33,600 / 78,400 mg, croscarmellose sodium 3,150 / 7,350 mg, magnesium stearate 0,792 / 1,847 mg;

film sheath: Fall red 4,200 / 9,800 mg [hypromellose 1,176 / 2,744 mg, titanium dioxide 0.718 / 1.675 mg, lactose monohydrate 1.68 / 3.920 mg, triacetin 0.336 / 0.784 mg, ferric oxide red oxide 0.290 / 0.677 mg].

Description:

Dosage 3 mg: red, round tablets, covered with a film sheath with engraving "Pfizer"on one side and" 3 XNBOn the other side, two layers are visible on the cross section: the core of the tablet is white or almost white.

Dosage of 7 mg: red, diamond-shaped tablets covered with a film sheath with engraving "Pfizer"on one side and" 7 XNB"- on the other, two layers are visible on the cross section: the core of the tablet is white or almost white

Pharmacotherapeutic group:Antitumor agent - protein tyrosine kinase inhibitor

ATX: & nbsp

L.01.X.E.17 Aksitinib

Pharmacodynamics:

Mechanism of action

Aksitinib is a potent and selective tyrosine kinase inhibitor of receptors of vascular endothelial growth factor (VEGFR)-l, VEGFR-2 and VEGFR-3, involved in the mechanisms of pathological angiogenesis, tumor growth and metastasis of malignant neoplasms. It was shown that axitinib provides powerful inhibition VEGF-mediated proliferation and survival of endothelial cells. Aksitinib inhibits phosphorylation VEGFR-2 in the vessels of xenografts of malignant tumors that express target receptors in vivo and provides slowing of tumor growth, regression and inhibition of metastasis of many experimental models of malignant tumors.

Pharmacokinetics:

The half-life of axitinib from the blood plasma varies from 2.5 to 6.1 hours. Taking axitinib 5 mg twice daily leads to less than twice the accumulation of axitinib compared with a single dose. In view of the short half-life of axitinib, the equilibrium state is expected to be achieved within 2-3 days after initiation of therapy.

Suction and distribution

The maximum concentration of axitinib in the blood plasma (C_mOh) is usually achieved 4 hours after admission; the median time to reach the maximum concentration in the blood plasma (TS_mOh) varies from 2.5 to 4.1 hours.

Taking axitinib along with food with a moderate fat content leads to a decrease in exposure values by 10% compared with taking on an empty stomach. Taking axitinib along with high-calorie food leads to an increase in exposure values by 19% in comparison with reception on an empty stomach. In this way, axitinib can be taken regardless of the meal.

Mean values of C_mOh and the area under the "concentration-time" curve (AUC) increase proportionally to an increase in the dose of axitinib in the dose range from 5 mg to 10 mg. Binding axitinib in vitro with proteins of human blood plasma is> 99 % (predominantly with albumin, to a moderate extent with α₁acid glycoprotein). When taking axitinib in a dose of 5 mg 2 times a day after eating a geometric average FROM_mOh and daily value AUC in patients with advanced renal cell carcinoma were 27.8 ng / ml and 265 ng / ml, respectively. The geometric mean clearance and volume distribution corresponded to 38 l / h and 160 l, respectively.

Metabolism and excretion

Axitinib is mainly metabolized in the liver with the participation of isoenzymes CYP3A4/5 and, to a lesser extent, isoenzymes CYP1A2, CYP2C19 and uridine 5'-diphosphate-glucuronosyltransferase 1A1 (UGT1A1). After oral administration of radio-labeled axitinib in a dose of 5 mg, 30-60% of the administered dose of radioactivity was detected in feces and 23% in urine. The unchanged axitinib accounted for 12% of the administered dose, and it was the main component found in the feces, but was not found in the urine. In urine, a large proportion of radioactivity accounted for carboxylic acid - a derivative of axitinib and its sulfoxide metabolite. In blood plasma to share N-glucuronide accounted for the largest share of circulating radioactivity (50%), unchanged axitinib and its sulfoxide metabolite accounted for approximately 20% of the circulating radioactivity.

The sulfoxide and N-glucuronide metabolites possessed approximately 400 and 8000 times less activity in vitro, respectively, with respect to VEGFR-2 in comparison with the unchanged axitinib.

Special patient groups

Effect of sex, race and age

The absence of a clinically significant effect of age, sex, body weight, race, renal function, genotypes UGT1A1 or CYP2C19 on the parameters of pharmacokinetics of axitinib.

Use in children

The use of axitinib in patients under the age of 18 years has not been investigated.

Impaired liver function

In studies in vitro and in vivo it was shown that axitinib it is metabolized primarily in the liver. Compared with patients with normal liver function, the values of systemic exposure to axitinib in patients with mild liver function disorder (class A Child-Pugh classification) were identical, and in patients with impaired liver function of moderate severity (class B by Child-Pugh classification) is higher. The use of axitinib in patients with severe hepatic impairment (Child-Pugh class C) has not been investigated.

Impaired renal function

The use of axitinib in patients with impaired renal function has not been studied. Based on the pharmacokinetic population analysis, there was no significant difference in the clearance of axitinib in patients with an existing impairment of renal function of moderate and severe severity (15 ml / min ≤ creatinine clearance <89 ml / min).

Indications:Common renal cell carcinoma (as second-line therapy).

Contraindications:

- Hypersensitivity to axitinib and other components of the drug;

- severe liver dysfunction (Child-Pugh class C);

- arterial thromboembolism during the previous 12 months;

- venous thromboembolism during the previous 6 months;

- metastatic brain damage, for which there was no appropriate treatment;

- recent or currently existing gastrointestinal bleeding;

- pregnancy and the period of breastfeeding;

- children under 18 years of age (safety and efficacy not studied).

Carefully:

Aksitinib should be used with caution in patients with risk factors for arterial thromboembolism (such as transient ischemic attack, myocardial infarction and cerebral circulation impairment), venous thromboembolism (such as pulmonary embolism, deep vein thrombosis and occlusion or central retinal vein thrombosis) or having them in the anamnesis.

In addition, caution should be exercised when using axitinib in patients with lactase deficiency, lactose intolerance or glucose-galactose malabsorption.

In patients with impaired renal function of a serious degree (creatinine clearance < 15 ml / min) caution should be exercised when using axitinib.

Pregnancy and lactation:

Adequate and well-controlled studies of axitinib when used in period of pregnancy in humans was not carried out. Aksitinib may cause damage to the fetus during pregnancy.

Women of childbearing age should be informed about the need to avoid pregnancy with the background of therapy with axitinib and within 1 week after therapy with axitinib.

Studies of the effects of axitinib on the production of breast milk in women, its ability to penetrate breast milk or to have a negative impact on the infant breastfed were not conducted. Given that many medications penetrate the breast milk, as well as the possibility of developing serious adverse reactions in a breastfeeding baby, either stop breastfeeding or complete axitinib therapy, taking into account the importance of this drug for the mother.

According to the results of pre-clinical studies, axitinib is able to disrupt reproductive function and fertility in humans.

Dosing and Administration:

Aksitinib taken inside, swallowing whole, washed down with a glass of water, regardless of food intake.

The recommended initial dose is 5 mg 2 times a day with an interval between doses of about 12 hours.

When developing vomiting or skipping the dose, you should not take an additional dose of the drug, but take the next dose at the usual time for it.

Therapy is continued until there is a positive effect from the treatment or until there is a development of severe toxicity that can not be controlled by the appointment of additional therapy or with the help of dose adjustment of axitinib.

Recommendations for dose adjustment

Increase and decrease in the dose of the drug is recommended to be carried out depending on the individual safety assessment and tolerability.

Patients carrying the preparation of Inlita® in the initial dose (5 mg twice daily) without developing adverse reactions above 2 degrees of severity (according to the General criteria for severity assessment of adverse events [Common Terminology Criteria for Adverse Events - STSAE]) for two consecutive weeks, provided that the arterial pressure does not exceed 150/90 mm Hg. and there is no need for standard antihypertensive therapy, it is possible to increase the dose to 7 mg 2 times a day. Then, using the same criteria, patients who suffer axitinib in a dose of 7 mg twice a day, it is possible to further increase the dose of the drug to 10 mg twice a day as much as possible.

To correct some unwanted reactions, temporary or complete cancellation and / or reduction of the axitinib dose may be required. If necessary, a dose of axitinib can be reduced to 3 mg twice a day, then to 2 mg twice a day.

Correction of the dose, depending on the race, sex or body weight of the patient is not required.

Simultaneous application with powerful inhibitors of isoenzymes CYP3A4/5

It is recommended to select alternative drugs that do not inhibit isoenzymes CYP3A4/5 or inhibiting their activity to a minimum.

The dosage correction regimens of axitinib in its use in patients receiving potent inhibitors of isoenzymes CYP3A4/5, have not been studied. If it is necessary to simultaneously use the dose of axitinib, it is recommended to reduce approximately half (for example, from an initial dose of 5 mg twice a day to 2 mg twice a day).Subsequent doses of the drug should be increased or decreased, depending on individual tolerability and safety. After the withdrawal of the potent inhibitor (after 3-5 half-lives of the inhibitor), consideration should be given to returning to the dose of axitinib, which the patient received before the start of therapy with a potent inhibitor of isoenzymes CYP3A4/5.

Simultaneous application with powerful inductors of isoenzymes CYP3A4/5

It is recommended to select alternative drugs that do not induce isoenzymes CYP3A4/5 or their inducing activity to a minimum, for combination with axitinib.

Dose correction regimens for axitinib when used in patients receiving potent inducers of isoenzymes CYP3A4/5, were also not studied. If it is necessary to simultaneously use it is recommended to gradually increase the dose of axitinib with careful monitoring of the patient's condition for the development of symptoms of toxicity. After the cancellation of the powerful isoenzyme inducer CYP3A4/5, you must immediately return to the dose of axitinib, which the patient received before the start of combination therapy.

Impaired liver function

Correction of dose in patients with mild liver function disorder (class A according to the Child-Pugh classification) is not required.

In patients with impaired liver function of moderate severity (class B according to the Child-Pugh classification) it is recommended to reduce the dose of axitinib approximately twice. Application of the drug Inlita^® It was not studied in patients with impaired liver function of severe severity (class C according to the Child-Pugh classification).

Impaired renal function

In patients with impaired renal function of mild and moderate severity, dose adjustment is not required. In patients with impaired renal function of severe degree (creatinine clearance <15 ml / min), the preparation of Inlita ® should be taken with caution.

Elderly patients

Correction of the dose is not required.

Side effects:

The most frequent (≥20%), adverse reactions seen with the combination of axitinib therapy included diarrhea, increased blood pressure, fatigue, decreased appetite, nausea, weight loss, dysphonia, palmar dyspnoea syndrome, bleeding, vomiting, proteinuria, cough, and constipation.The frequency of unwanted reactions is represented by the following classification:

Often	≥ 10%
Often	≥ 1% and <10%
Infrequently	≥0.1% and <1%
Rarely	≥0.01% and <0.1%
Rarely	<0,01%
Frequency unknown	It is impossible to determine from the available data

Violations from the heart and blood vessels: very often - increased blood pressure, bleeding (including nasal bleeding, hematuria, rectal bleeding, cerebral hemorrhage, gastric bleeding and bleeding in the lower gastrointestinal tract); often venous embolic and thrombotic events (including pulmonary embolism, retinal vein occlusion / thrombosis and deep vein thrombosis), arterial embolic and thrombotic events (including transient ischemic attack and acute cerebrovascular accident), heart failure (including heart failure, congestive heart failure, cardiopulmonary failure, left ventricular dysfunction, reduced ejection fraction and right ventricular failure), in some cases with lethal outcome; infrequently hypertensive crisis.

Disorders from the endocrine system: Often - hypothyroidism; often - hyperthyroidism.

Disorders from the side of the organ of vision: infrequently - occlusion or thrombosis of the central vein of the retina.

Hearing disorders and labyrinthine disturbances: often - noise in ears.

Disorders from the gastrointestinal tract: Often - diarrhea, vomiting, nausea, abdominal pain, stomatitis, constipation, dyspepsia; often - hemorrhoids, pain in the upper abdomen, perforation of the gastrointestinal tract, fistula, flatulence, glossodynia.

Disorders from the liver and bile ducts: infrequently hyperbilirubinemia.

Disorders from the metabolism and nutrition: Often - decreased appetite; often - Dehydration, hyperkalemia, hypercalcemia, hypocalcemia.

Impaired nervous system: Often - headache, dysgeusia; often - dizziness; infrequently - a syndrome of reversible posterior leukoencephalopathy, stroke.

Disturbances from the musculoskeletal and connective tissue: Often - arthralgia, pain in the limbs; often - myalgia.

Violations from the blood and lymphatic system: often - Anemia, polycythemia, thrombocytopenia; infrequently - neutropenia, leukopenia.

Disturbances from the respiratory system, organs of the thorax and mediastinum: Often - dyspnea (in some cases, with a fatal outcome), cough, dysphonia; often hemoptysis, pain in the oropharynx.

Disturbances from the skin and subcutaneous tissues: Often - Syndrome of palmar-plantar erythrodysesthesia (palmar-plantar syndrome), skin rash, dry skin; often - erythema, itchy skin, alopecia.

Disorders from the kidneys and urinary tract: Often - proteinuria; often - Renal failure.

General disorders and disorders at the site of administration: Often - increased fatigue, asthenia (in some cases with a fatal outcome), inflammation of the mucous membranes.

Laboratory and instrumental data: Often - decreased body weight; often - Increased creatinine concentration, increased activity alanine aminotransferase (ALT), aspartate aminotransferase (ACT), alkaline phosphatase, lipase, amylase; hypoglycaemia, hyperglycemia, decreased bicarbonate concentration, hypernatremia, hyponatremia, hypoalbuminemia, hypophosphatemia, decreased platelet count, white blood cells, lymphocytes, decreased hemoglobin, increased thyroid-stimulating hormone concentration.

Overdose:

Symptoms: reported a case of unintentional drug overdose in one patient when he was taking axitinib in a dose of 20 mg twice a day for 4 days, after which he had dizziness (1 degree of severity).

In a clinical study of axitinib with a choice of doses, patients received the drug at an initial dose of 10 mg twice a day or 20 mg twice a day. At the same time, they noted an increase in blood pressure, associated with it the development of convulsions, and fatal hemoptysis.

Treatment: specific treatment for an overdose of axitinib has not been developed. If an overdose is suspected, axitinib therapy should be suspended and necessary supportive care should be provided.

Interaction:

Inhibitor inhibitors CYP3A4/5

It should avoid the simultaneous use of axitinib with potent inhibitors of isoenzymes CYP3A4/5 (in particular with ketoconazole, itraconazole, clarithromycin, erythromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin and voriconazole). Simultaneous use with ketoconazole (a potent inhibitor of isoenzymes CYP3A4/5), leads to an increase in the concentration of axitinib in the blood plasma in healthy volunteers.

Grapefruit or grapefruit juice can also increase the concentration of axitinib in blood plasma, and their simultaneous use should also be avoided. It is recommended to select alternative drugs that do not inhibit isoenzymes CYP3A4/5 or inhibiting their activity to a minimum. If it is necessary to combine axitinib with powerful inhibitors of isoenzymes CYP3A4/5, it is recommended to reduce its dose (see the section "Method of administration and dose").

Inhibitor inhibitors CYP1A2 and CYP2C19

Isozymes CYP1A2 and CYP2C19 support a smaller part (<10%) of the metabolites of axitinib. The effect of potent inhibitors of these isoenzymes on the pharmacokinetics of axitinib has not been studied. Caution should be exercised with the simultaneous use of axitinib and potent inhibitors of isoenzymes CYP1A2 and CYP2C19, since in this case the concentration of axitinib in the blood plasma can increase.

Inductors of isoenzymes CYP3A4/5

It should avoid simultaneous application of axitinib with powerful isozyme inducers CYP3A4/5 (in particular, rifampicin,dexamethasone, phenytoin, carbamazepine, rifabutin, rifapentin, phenobarbital and preparations of St. John's wort perfumed [Hypericum perforatum]). Rifampicin (a powerful inductor of isoenzymes CYP3A4/5) reduces the average values AUC axitinib in healthy volunteers. It is recommended to select alternative drugs that do not induce isoenzymes CYP3A4/5 or their inducing activity to a minimum, for combination with axitinib. Medium inhibitors of isoenzymes CYP3A4/5 (such as bosentan, efavirenz, etravirine, modafinil and nafcillin) can also reduce the concentration of axitinib in the blood plasma, and their simultaneous use should be avoided whenever possible.

Induction of isoenzyme CYP1A2 during smoking

Isozyme CYP1A2 supports a smaller part (<10%) of the pathways of metabolism of axitinib. Effect of induction of isoenzyme CYP1A2, caused by smoking, the pharmacokinetics of axitinib has not been fully studied. One should consider the possibility of reducing the concentration of axitinib in the blood plasma when using axitinib in smokers.

Studies of the ability of axitinib to inhibit and induce cytochrome P450 and uridine 5'-diphosphate-glucuronosyltransferase (UGT) in vitro

Was shown in vitro, what axitinib in therapeutic concentrations in blood plasma does not inhibit the activity of isoenzymes CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4/5 or UGT1A1.

In studies in vitro It was also noted that axitinib has the potential to inhibit isoenzyme activity CYP1A2. Therefore, simultaneous reception of axitinib with isoenzyme substrates CYP1A2 can lead to an increase in the concentration of the latter (for example, theophylline) in blood plasma.

In studies in vitro It was also shown that axitinib has the potential to inhibit isoenzyme CYP2C8. However, simultaneous application of axitinib with paclitaxel, which is a substrate of isoenzyme CYP2C8, did not lead to an increase in the concentration of the latter in blood plasma in patients with advanced malignant neoplasms, which indicates the absence of clinically significant inhibition of the isoenzyme CYP2C8 in the given conditions.

In studies in vitro Using human hepatocytes, it was noted that axitinib does not induce isoenzymes CYP1A1, CYP1A2 or CYP3A4/5. Therefore, the concentration in the blood plasma of the substrates of these isoenzymes is not expected to decrease with their simultaneous application with axitinib in vivo.

Studies of the ability of axitinib to interact with P-glycoprotein in vitro

In studies in vitro it was shown that axitinib is able to inhibit P-glycoprotein, but this effect is not expected in the presence of axitinib in blood plasma at therapeutic concentrations. Therefore, against the background of therapy with axitinib, the concentration of digoxin or other substrates of P-glycoprotein in the blood plasma is not expected to increase in vivo.

Special instructions:

Phenomena of heart failure

During therapy with axitinib, signs and symptoms of heart failure should be periodically monitored. Treatment of heart failure may require temporary or permanent cessation of taking axitinib and / or reducing its dose.

Arterial hypertension

There are reports of increased blood pressure when using the drug Inlita®. In general, this side effect is noted during the first month of therapy, mainly in the first four days. Before the beginning of therapy with axitinib, blood pressure should be adjusted. In the future, careful monitoring of patients to increase blood pressure and, if necessary, the appointment of standard antihypertensive therapy.With the development of persistent arterial hypertension, despite the use of antihypertensive drugs, a dose reduction of axitinib is necessary. Should cease therapy with axitinib in the development of severe and persistent arterial hypertension that does not lend itself to antihypertensive therapy and does not stop when the dose of Inlita® is reduced. It is also necessary to evaluate the feasibility of canceling therapy with axitinib when symptoms of hypertensive crisis appear. It should be borne in mind that after the abolition of axitinib, patients receiving antihypertensive drugs should be observed for arterial hypotension.

Arterial thromboembolism

There are reports of the development of arterial thromboembolism (including transient ischemic attack, cerebral circulatory disorders, myocardial infarction and retinal artery occlusion), including 2 fatal cases associated with impaired cerebral circulation.

Caution should be exercised when using the preparation of Inlita ® in patients with risk factors for arterial thromboembolism or having similar episodes in the anamnesis. It should be taken into account that the preparation of Inlita® has not been studied in patients who underwent arterial thromboembolism in the previous 12 months.

Venous thromboembolism

There are also reports of venous thromboembolism (including pulmonary embolism, deep vein thrombosis, retinal vein occlusion, and retinal vein occlusion), including cases of pulmonary embolism with lethal outcome.

Caution should be exercised when using the preparation of Inlita® in patients with risk factors for venous thromboembolism or having similar episodes in the anamnesis.

It should also be taken into account that the preparation of Inlita® has not been studied in patients who have had venous thromboembolism in the previous 6 months.

Thyroid dysfunction

It is recommended to perform a thyroid gland function before beginning therapy with axitinib, and then periodically during the treatment. Correction of hypothyroidism and hyperthyroidism should be carried out in accordance with standard principles until the euthyroid state is reached.

Assessment of hemoglobin or hematocrit concentration

On the background of therapy with axitinib, an increase in the concentration of hemoglobin or hematocrit may be observed, reflecting the increase in erythrocyte mass in the body. This phenomenon may increase the risk of thromboembolism.

It is recommended to monitor the concentration of hemoglobin or hematocrit before the initiation of therapy with axitinib and periodically during it. Correction of an increase in the concentration of hemoglobin or hematocrit above the upper limit of the norm is made in accordance with standard principles.

Bleeding

There have been reports of cases of bleeding in patients who received axitinib (including intracranial hemorrhage, hematuria, hemoptysis, hemorrhage from the lower gastrointestinal tract and melena), including one fatal case (gastric bleeding).

Please be aware that the drug Inlita® has not been studied in patients with evidence of metastatic lesions of the brain, about which has not been appropriate treatment, as well as in patients with a recent history of, or currently available gastrointestinal bleeding. In this regard, do not use the drug Inlita ® in these groups of patients. With the development of any bleeding that requires medical attention, axitinib therapy should be temporarily discontinued.

Perforation of the gastrointestinal tract and fistula formation

In clinical trials, cases of perforation of the gastrointestinal tract and fistula formation have been reported, including fatal cases. Against the background of therapy with axitinib, periodic monitoring is necessary for the clinical manifestations of these conditions.

Wound healing disorders

Formal studies of the influence of axitinib on the processes of wound healing were not conducted.

Therapy with axitinib should be stopped at least 24 hours before the scheduled surgical intervention. The decision to resume therapy with axitinib in the postoperative period should be based on the results of a clinical evaluation of the course of the wound process.

Syndrome of reversible posterior leukoencephalopathy (COPD)

PSSD is a neurological disorder that can be manifested by headache, seizures, inhibition, confusion, blindness and other visual and neurological disorders. It is possible to increase blood pressure from mild to severe severity. The diagnosis of COPD is confirmed by magnetic resonance imaging. It should stop using the drug Inlita® in patients with clinical manifestations of COPD.

The safety of the resumption of axitinib therapy in patients with a previous history of COPD is unknown.

Proteinuria

It is recommended to screen for proteinuria before the beginning of therapy with axitinib and periodically on the background of treatment. With the development of proteinuria of moderate or severe severity, a dose reduction or temporary discontinuation of the Inlita® preparation is necessary.

Increased activity of "liver" enzymes

It is recommended to study the activity of ALT and ACT and the concentration of bilirubin before the initiation of therapy with axitinib and periodically on the background of treatment.

Effect on the ability to drive transp. cf. and fur:

Studies of the influence of axitinib on the ability to drive a car and work with mechanisms requiring increased concentration of attention have not been carried out. Patients should be informed about the possibility of developing some undesirable effects, in particular dizziness and / or fatigue, against the background of therapy with the drug Inlita®.

Form release / dosage:

Tablets, film-coated, 3 mg and 7 mg.

Packaging:

For 14 tablets in a blister of aluminum foil.

2 or 4 blisters together with instructions for use in a cardboard pack with the control of the first opening.

Storage conditions:

Store at a temperature not exceeding 30 ° C.

Keep out of the reach of children.

Shelf life:

3 of the year.

Do not use the product after the expiry date printed on the package.

Terms of leave from pharmacies:On prescription

Registration number:LP-003983

Date of registration:29.11.2016

Expiration Date:29.11.2021

The owner of the registration certificate:Pfizer Manufakchuring Deutschland GmbH Pfizer Manufakchuring Deutschland GmbH Germany

Manufacturer: & nbsp

PFIZER MANUFACTURING DEUTSCHLAND, GmbH Germany

Representation: & nbspPfizer LtdPfizer LtdUSA

Information update date: & nbsp31.10.2017

Illustrated instructions

Instructions

Inlita® (Inlyta®)