Inlyta

/ Pfizer

The recommended starting oral dose is 5 mg twice daily approximately 12 hours apart with or without food, with a full glass of water. If the patient vomits or misses a dose, an additional dose should not be taken. Advise the patient to take the next prescribed dose should be taken at the usual time.

Dose increase or reduction is recommended based on individual safety and tolerability.

Over the course of treatment, patients who tolerate Axitinib    for at least two consecutive weeks with no adverse reactions >Grade >2 (according to the Common Toxicity Criteria for Adverse Events [CTCAE]), are normotensive, and are not receiving anti-hypertension medication, may have their dose increased. When a dose increase from 5 mg twice daily is recommended, the Axitinib   dose may be increased to 7 mg twice daily, and further to 10 mg twice daily using the same criteria.

Over the course of treatment, management of some adverse drug reactions may require temporary interruption or permanent discontinuation and/or dose reduction of Axitinib therapy. If dose reduction from 5 mg twice daily is required, the recommended dose is 3 mg twice daily. If additional dose reduction is required, the recommended dose is 2 mg twice daily.

Strong CYP3A4/5 Inhibitors

The concomitant use of strong CYP3A4/5 inhibitors should be avoided (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, and voriconazole). Selection of an alternate concomitant medication 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 by approximately half is recommended, as this dose reduction is predicted to adjust the axitinib area under the plasma concentration vs time curve (AUC) to the range observed without inhibitors. The subsequent doses can be increased or decreased based on individual safety and tolerability. If co–administration of the strong inhibitor is discontinued, the Axitinib dose should be returned (after 3 – 5 half-lives of the inhibitor) to that used prior to initiation of the strong CYP3A4/5 inhibitor.

Hepatic Impairment

No starting dose adjustment is required when administering Axitinib to patients with mild hepatic impairment (Child-Pugh class A). Based on the pharmacokinetic data, the Axitinib starting dose should be reduced by approximately half in patients with baseline moderate hepatic impairment (Child-Pugh class B). The subsequent doses can be increased or decreased based on individual safety and tolerability. Axitinib has not been studied in patients with severe hepatic impairment (Child–Pugh class C).

Treatment of advanced renal cell carcinoma (RCC) after failure of one prior systemic therapy.

Hypersensitivity to the active substance or to any of the excipients.

Hypertension and Hypertensive Crisis

Blood pressure should be well-controlled prior to initiating axitinib. Patients should be monitored for hypertension and treated as needed with standard anti-hypertensive therapy. In the case of persistent hypertension despite use of anti-hypertensive medications, reduce the Axitinib dose. Discontinue Axitinib if hypertension is severe and persistent despite anti-hypertensive therapy and dose reduction of Axitinib, and discontinuation should be considered if there is evidence of hypertensive crisis. If Axitinib is interrupted, patients receiving anti-hypertensive medications should be monitored for hypotension.

Arterial Thromboembolic Events

Use Axitinib 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 thromboembolic event within the previous 12 months.

Venous Thromboembolic Events

Use Axitinib 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 thromboembolic event within the previous 6 months.

Hemorrhage

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.

Cardiac Failure

Monitor for signs or symptoms of cardiac failure throughout treatment with Axitinib. Management of cardiac failure may require permanent discontinuation of Axitinib.

Gastrointestinal Perforation and Fistula Formation

Monitor for symptoms of gastrointestinal perforation or fistula periodically throughout treatment with Axitinib.

Thyroid Dysfunction 

Monitor thyroid function before initiation of, and periodically throughout, treatment with Axitinib. Treat hypothyroidism and hyperthyroidism according to standard medical practice to maintain euthyroid state.

Risk of Impaired Wound Healing

Impaired wound healing can occur in patients who receive drugs that inhibit the vascular endothelial growth factor (VEGF) signaling pathway. Therefore, Axitinib has the potential to adversely affect wound healing.

Withhold Axitinib for at least 2 days prior to elective surgery. Do not administer for at least 2 weeks following major surgery and until adequate wound healing. The safety of resumption of Axitinib after resolution of wound healing complications has not been established.

Reversible Posterior Leukoencephalopathy Syndrome

RPLS 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 RPLS. Discontinue Axitinib in patients developing RPLS. The safety of reinitiating Axitinib therapy in patients previously experiencing RPLS is not known.

Proteinuria

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.

Hepatotoxicity

The drug may elevate liver enzymes.

ALT, aspartate aminotransferase (AST) and bilirubin should be monitored before initiation of and periodically throughout treatment with Axitinib.

Aneurysms and artery dissections

The use of vascular endothelial growth factor (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.

 See prescribing formation for full details.

The most common (≥20%) adverse reactions observed following treatment with INLYTA were diarrhea, hypertension, fatigue, decreased appetite, nausea, dysphonia, palmar-plantar erythrodysesthesia (hand-foot) syndrome, weight decreased, vomiting, asthenia, and constipation.
See prescribing information for full details.

Axitinib is metabolized primarily in the liver by CYP3A4/5. Additionally, the aqueous solubility of axitinib is pH dependent, with higher pH resulting in lower solubility.

Effects of Axitinib on Other Drugs

In vitro studies demonstrated that axitinib has the potential to inhibit CYP1A2 and CYP2C8. However, co-administration of axitinib with paclitaxel, a CYP2C8 substrate, did not increase plasma concentrations of paclitaxel in patients.

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 in human hepatocytes indicated that axitinib does not induce CYP1A1, CYP1A2, or CYP3A4/5.

Axitinib is an inhibitor of the efflux transporter P-glycoprotein (P-gp) in vitro. However, Axitinib is not expected to inhibit P-gp at therapeutic plasma concentrations. See prescribing formation for full details.

Pregnancy

There are no available human data to inform the drug-associated risk. In developmental toxicity studies, axitinib was teratogenic, embryotoxic and fetotoxic in mice at exposures lower than human exposures at the recommended starting dose. See prescribing formation for full details.

Lactation

There are no data on the presence of axitinib in human milk, or its effects on the breastfed child or on milk production.

See prescribing formation for full details.

There is no specific treatment for I Axitinib overdose.

In a controlled clinical study with Axitinib for the treatment of patients with RCC, 1 patient inadvertently received a dose of 20 mg twice daily for 4 days and experienced dizziness (Grade 1).

In a clinical dose finding study with Axitinib, subjects who received starting doses of 10 mg twice daily or 20 mg twice daily experienced adverse reactions which included hypertension, seizures associated with hypertension, and fatal hemoptysis.

In cases of suspected overdose, Axitinib should be withheld and supportive care instituted.

Storage: Store below 30°C.
Shelf life after first opening the bottle: 6 months.