Axitinib

Chemical formula: C₂₂H₁₈N₄OS  Molecular mass: 386.47 g/mol  PubChem compound: 6450551

Interactions

Axitinib interacts in the following cases:

CYP2C8 substrates

In vitro studies also indicated that axitinib has the potential to inhibit CYP2C8. However, co-administration of axitinib with paclitaxel, a known CYP2C8 substrate, did not result in increased plasma concentrations of paclitaxel in patients with advanced cancer, indicating lack of clinical CYP2C8 inhibition.

CYP1A2 substrates

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 substrates (e.g. theophylline).

P-glycoprotein substrates

In vitro studies indicated that axitinib inhibits P-glycoprotein. However, axitinib is not expected to inhibit P-glycoprotein at therapeutic plasma concentrations. Therefore, co-administration of axitinib is not expected to increase the plasma concentration of digoxin, or other P-glycoprotein substrates, in vivo.

Strong CYP3A4, CYP3A5 inhibitors

Co-administration of axitinib with strong CYP3A4/5 inhibitors may increase axitinib plasma concentrations. Selection of an alternate concomitant medicinal product with no or minimal CYP3A4/5 inhibition potential is recommended.

Although axitinib dose adjustment has not been studied in patients receiving strong CYP3A4/5 inhibitors, if a strong CYP3A4/5 inhibitor must be co-administered, a dose decrease of axitinib to approximately half the dose (e.g. the starting dose should be reduced from 5 mg twice daily to 2 mg twice daily) is recommended. Management of some adverse reactions may require temporary or permanent discontinuation of axitinib therapy. If co-administration of the strong inhibitor is discontinued, a return to the axitinib dose used prior to initiation of the strong CYP3A4/5 inhibitor should be considered.

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.

Strong CYP3A4, CYP3A5 inducers

Co-administration of axitinib with strong CYP3A4/5 inducers may decrease axitinib plasma concentrations. Selection of an alternate concomitant medicinal product with no or minimal CYP3A4/5 induction potential is recommended.

Although axitinib dose adjustment has not been studied in patients receiving strong CYP3A4/5 inducers, if a strong CYP3A4/5 inducer must be co-administered, a gradual dose increase of axitinib is recommended. Maximal induction with high-dose strong CYP3A4/5 inducers has been reported to occur within one week of treatment with the inducer. If the dose of axitinib is increased, the patient should be monitored carefully for toxicity. Management of some adverse reactions may require temporary or permanent discontinuation and/or dose reduction of axitinib therapy. If co-administration of the strong inducer is discontinued, the axitinib dose should be immediately returned to the dose used prior to initiation of the strong CYP3A4/5 inducer.

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 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.

CYP1A2, CYP2C19 strong 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.

Moderate hepatic impairment

A dose decrease is recommended when administering axitinib to patients with moderate hepatic impairment (Child-Pugh class B) (e.g. the starting dose should be reduced from 5 mg twice daily to 2 mg twice daily).

Severe hepatic impairment

Axitinib has not been studied in patients with severe hepatic impairment (Child-Pugh class C) and should not be used in this population.

Fertility

Based on non-clinical findings, axitinib has the potential to impair reproductive function and fertility in humans.

Hypothyroidism, hyperthyroidism

In clinical studies with axitinib for the treatment of patients with RCC, events of hypothyroidism and, to a lesser extent, hyperthyroidism, were reported.

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.

Haemorrhage

In clinical studies with axitinib, haemorrhagic events were reported. Axitinib has not been studied in patients who have evidence of untreated brain metastasis or recent active gastrointestinal bleeding, and should not be used in those patients. If any bleeding requires medical intervention, temporarily interrupt the axitinib dose.

Hypertension

In clinical studies with axitinib for the treatment of patients with RCC, hypertension was very commonly reported.

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.

In case of severe or persistent arterial hypertension and symptoms suggestive of posterior reversible encephalopathy syndrome (PRES), a diagnostic brain magnetic resonance image (MRI) should be considered.

Venous embolic and thrombotic events

In clinical studies with axitinib, venous embolic and thrombotic events (including pulmonary embolism, deep vein thrombosis, and retinal vein occlusion/thrombosis) were reported.

Axitinib should be used with caution in patients who are at risk for, or who have a history of, these events. Axitinib has not been studied in patients who had a venous embolic or thrombotic event within the previous 6 months.

Wound complications, surgical procedure

No formal studies of the effect of axitinib on wound healing have been conducted. Treatment with axitinib should be stopped at least 24 hours prior to scheduled surgery. The decision to resume axitinib therapy after surgery should be based on clinical judgment of adequate wound healing.

Proteinuria

In clinical studies with axitinib, proteinuria, including that of Grade 3 and 4 severity, was reported.

Monitoring for proteinuria before initiation of, and periodically throughout, treatment with axitinib is recommended. For patients who develop moderate to severe proteinuria, reduce the dose or temporarily interrupt axitinib treatment. Axitinib should be discontinued if the patient develops nephrotic syndrome.

Aneurysms, artery dissections

The use of VEGF pathway inhibitors in patients with or without hypertension may promote the formation of aneurysms and/or artery dissections. Before initiating axitinib, this risk should be carefully considered in patients with risk factors such as hypertension or history of aneurysm.

Posterior reversible encephalopathy syndrome (PRES)

In clinical studies with axitinib, events of PRES were reported.

PRES is a neurological disorder which can present with headache, seizure, lethargy, confusion, blindness and other visual and neurologic disturbances. Mild to severe hypertension may be present. Magnetic resonance imaging is necessary to confirm the diagnosis of PRES. In patients with signs or symptoms of PRES, temporarily interrupt or permanently discontinue axitinib treatment. The safety of reinitiating axitinib therapy in patients previously experiencing PRES is not known.

Gastrointestinal perforation, fistula

In clinical studies with axitinib, events of gastrointestinal perforation and fistulas were reported. Symptoms of gastrointestinal perforation or fistula should be periodically monitored for throughout treatment with axitinib.

Arterial embolic and thrombotic events

In clinical studies with axitinib, arterial embolic and thrombotic events (including transient ischemic attack, myocardial infarction, cerebrovascular accident and retinal artery occlusion) were reported.

Axitinib should be used with caution in patients who are at risk for, or who have a history of, these events. Axitinib has not been studied in patients who had an arterial embolic or thrombotic event within the previous 12 months.

Cardiac failure

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.

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.

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. 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.

Nursing mothers

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.

Carcinogenesis, mutagenesis and fertility

Fertility

Based on non-clinical findings, axitinib has the potential to impair reproductive function and fertility in humans.

Effects on ability to drive and use machines

Axitinib has minor influence on the ability to drive and use machines. Patients should be advised that they may experience events such as dizziness and/or fatigue during treatment with axitinib.

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