Leitlinien & Arzneimittelsicherheit

HOS-096162 · has-adverse-reaction-information · PDF-Seite 8

Summary of the safety profile The following risks, including appropriate action to be taken, are discussed in greater detail in section 4.4: cardiac failure events, hypertension, thyroid dysfunction, arterial thromboembolic events, venous thromboembolic events, elevation of haemoglobin or haematocrit, haemorrhage, 8 gastrointestinal perforation and fistula formation, wound healing complications, PRES, proteinuria, and elevation of liver enzymes. The most common (≥ 20%) adverse reactions observed following treatment with axitinib were diarrhoea, hypertension, fatigue, decreased appetite, nausea, weight decreased, dysphonia, palmar-plantar erythrodysaesthesia (hand-foot) syndrome, haemorrhage, hypothyroidism, vomiting, proteinuria, cough, and constipation. Tabulated list of adverse reactions Table 1 presents adverse reactions reported in a pooled dataset of 672 patients who received axitinib in clinical studies for the treatment of patients with RCC (see section 5.1). Post-marketing adverse reactions identified in clinical studies are also included. The adverse reactions are listed by system organ class, frequency category and grade of severity. Frequency categories are defined as: 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), and not known (cannot be estimated from the available data). The current safety database for axitinib is too small to detect rare and very rare adverse reactions. Categories have been assigned based on absolute frequencies in the pooled clinical studies data. Within each system organ class, adverse reactions with the same frequency are presented in order of decreasing seriousness. Table 1. Adverse reactions reported in RCC studies in patients who received axitinib (N = 672) All System organ Frequency Grade 3b Grade 4b Adverse reactionsa Gradesb class category % % % Blood and Common Anaemia 6.3 1.2 0.4 lymphatic system Thrombocytopenia 1.6 0.1

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HOS-096158 · has-contraindication-information · PDF-Seite 4

Hypersensitivity to axitinib or to any of the excipients listed in section 6.1.

HOS-096157 · has-indication-information · PDF-Seite 3

Inlyta is indicated for the treatment of adult patients with advanced renal cell carcinoma (RCC) after failure of prior treatment with sunitinib or a cytokine.

HOS-096160 · has-interaction-information · PDF-Seite 7

In vitro data indicate that axitinib is metabolised primarily by CYP3A4/5 and, to a lesser extent, CYP1A2, CYP2C19, and uridine diphosphate-glucuronosyltransferase (UGT) 1A1. CYP3A4/5 inhibitors Ketoconazole, a strong inhibitor of CYP3A4/5, administered at a dose of 400 mg once daily for 7 days, increased the mean area under the curve (AUC) 2-fold and Cmax 1.5-fold of a single 5-mg oral dose of axitinib in healthy volunteers. Co-administration of axitinib with strong CYP3A4/5 inhibitors (e.g. ketoconazole, itraconazole, clarithromycin, erythromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, and telithromycin) may increase axitinib plasma concentrations. Grapefruit may also increase axitinib plasma concentrations. Selection of concomitant medicinal products with no or minimal CYP3A4/5 inhibition potential is recommended. If a strong CYP3A4/5 inhibitor must be co-administered, a dose adjustment of axitinib is recommended (see section 4.2). CYP1A2 and CYP2C19 inhibitors CYP1A2 and CYP2C19 constitute minor (< 10%) pathways in axitinib metabolism. The effect of strong inhibitors of these isozymes on axitinib pharmacokinetics has not been studied. Caution should be exercised due to the risk of increased axitinib plasma concentrations in patients taking strong inhibitors of these isozymes. CYP3A4/5 inducers Rifampicin, a strong inducer of CYP3A4/5, administered at a dose of 600 mg once daily for 9 days, reduced the mean AUC by 79% and Cmax by 71% of a single 5 mg dose of axitinib in healthy volunteers. Co-administration of axitinib with strong CYP3A4/5 inducers (e.g. rifampicin, dexamethasone, phenytoin, carbamazepine, rifabutin, rifapentin, phenobarbital, and Hypericum perforatum [St. John’s wort]) may decrease axitinib plasma concentrations. Selection of concomitant medicinal products with 7 no or minimal CYP3A4/5 induction potential is recommended. If a strong CYP3A4/5 inducer must be co-administered, a dose adjustment of axitinib is recommended (see section 4.2). In vitro studies of CYP and UGT inhibition and induction In vitro studies indicated that axitinib does not inhibit CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4/5, or UGT1A1 at therapeutic plasma concentrations. In vitro studies indicated that axitinib has a potential to inhibit CYP1A2. Therefore, co-administration of axitinib with CYP1A2 substrates may result in increased plasma concentrations of CYP1A2 substrat

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HOS-096161 · has-pregnancy-information · PDF-Seite 8

Pregnancy There are no data regarding the use of axitinib in pregnant women. Based on the pharmacological properties of axitinib, it may cause foetal harm when administered to a pregnant woman. Studies in animals have shown reproductive toxicity including malformations (see section 5.3). Axitinib should not be used during pregnancy unless the clinical condition of the woman requires treatment with this medicinal product. Women of childbearing potential must use effective contraception during and up to 1 week after treatment. Breast-feeding It is unknown whether axitinib is excreted in human milk. A risk to the suckling child cannot be excluded. Axitinib should not be used during breast-feeding. Fertility Based on non-clinical findings, axitinib has the potential to impair reproductive function and fertility in humans (see section 5.3).

HOS-096159 · has-warning-information · PDF-Seite 4

Specific safety events should be monitored before initiation of, and periodically throughout, treatment with axitinib as described below. Cardiac failure events In clinical studies with axitinib for the treatment of patients with RCC, cardiac failure events (including cardiac failure, cardiac failure congestive, cardiopulmonary failure, left ventricular dysfunction, ejection fraction decreased, and right ventricular failure) were reported (see section 4.8). Signs or symptoms of cardiac failure should periodically be monitored throughout treatment with axitinib. Management of cardiac failure events may require temporary interruption or permanent discontinuation and/or dose reduction of axitinib therapy. Hypertension In clinical studies with axitinib for the treatment of patients with RCC, hypertension was very commonly reported (see section 4.8). 4 In a controlled clinical study, the median onset time for hypertension (systolic blood pressure > 150 mmHg or diastolic blood pressure > 100 mmHg) was within the first month of the start of axitinib treatment and blood pressure increases have been observed as early as 4 days after starting axitinib. Blood pressure should be well-controlled prior to initiating axitinib. Patients should be monitored for hypertension and treated as needed with standard antihypertensive therapy. In the case of persistent hypertension, despite use of antihypertensive medicinal products, the axitinib dose should be reduced. For patients who develop severe hypertension, temporarily interrupt axitinib and restart at a lower dose once the patient is normotensive. If axitinib is interrupted, patients receiving antihypertensive medicinal products should be monitored for hypotension (see section 4.2). In case of severe or persistent arterial hypertension and symptoms suggestive of posterior reversible encephalopathy syndrome (PRES) (see below), a diagnostic brain magnetic resonance image (MRI) should be considered. Thyroid dysfunction In clinical studies with axitinib for the treatment of patients with RCC, events of hypothyroidism and, to a lesser extent, hyperthyroidism, were reported (see section 4.8). Thyroid function should be monitored before initiation of, and periodically throughout, treatment with axitinib. Hypothyroidism or hyperthyroidism should be treated according to standard medical practice to maintain euthyroid state. Arterial embolic and thrombotic events In clin

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