Axitinib

Axitinib is a potent and selective tyrosine kinase inhibitor of the vascular endothelial growth factor receptors VEGFR-1, VEGFR-2 and VEGFR-3. These receptors take part in pathological angiogenesis (the growth of new blood vessels that feed tumours), in tumour growth and in the spread of cancer.

Mechanism of Action

• Receptor blockade: by blocking VEGFR-1, -2 and -3, axitinib potently inhibits VEGF-mediated proliferation and survival of endothelial cells.
• Preclinical effect: in experimental models it inhibited VEGFR-2 phosphorylation in tumour blood vessels and produced delayed tumour growth, regression and inhibition of metastases.
• Metabolites: the sulfoxide and N-glucuronide metabolites are about 400-fold and 8,000-fold less potent against VEGFR-2 than axitinib itself, so the parent drug carries the activity.
• Cardiac electrophysiology: exposure up to two-fold higher than expected after a 5 mg dose did not cause clinically significant QT interval prolongation.

Pharmacokinetics

• Absorption: absolute bioavailability about 58%. Peak concentrations are reached within about 4 hours (median 2.5 to 4.1 hours). Cmax and AUC rise in proportion to dose between 5 and 10 mg. A moderate-fat meal lowered exposure by 10% and a high-fat, high-calorie meal raised it by 19% compared with fasting, so tablets can be taken with or without food.
• Steady state: accumulation at 5 mg twice daily is under two-fold compared with a single dose, and steady state is expected within 2 to 3 days. In the fed state the geometric mean peak concentration was 27.8 ng/mL and the 24-hour AUC 265 ng·h/mL.
• Distribution: more than 99% bound to plasma proteins, mainly albumin and, to a moderate extent, α1-acid glycoprotein; apparent volume of distribution about 160 L.
• Metabolism: mainly in the liver by CYP3A4/5, and to a lesser extent by CYP1A2, CYP2C19 and UGT1A1. In plasma the N-glucuronide metabolite makes up about 50% of circulating radioactivity, and unchanged axitinib and the sulfoxide metabolite about 20% each.
• Elimination: half-life 2.5 to 6.1 hours; apparent oral clearance about 38 L/h. After a radiolabelled 5 mg dose, 30–60% of the radioactivity was recovered in faeces (unchanged axitinib 12% of the dose) and 23% in urine, mostly as the carboxylic acid and sulfoxide metabolites; no unchanged axitinib was found in urine.
• Special populations: moderate hepatic impairment (Child-Pugh class B) roughly doubles exposure. Age, race, sex and body weight do not call for dose changes.

• Advanced renal cell carcinoma (RCC): treatment of adults after failure of prior treatment with sunitinib or a cytokine. This is the indication of Inlyta itself.
• First-line combinations: axitinib is also used with avelumab (Bavencio) and with pembrolizumab for first-line treatment of adults with advanced RCC. These combinations are authorised in the product information of the partner medicines, not in Inlyta’s own indication; with avelumab, the axitinib dose is 5 mg twice daily.

• Hypersensitivity to axitinib or to any of the excipients.

Safety data come from a pooled dataset of 672 patients with renal cell carcinoma who received axitinib, plus post-marketing reports. The most common reactions (20% or more) were diarrhoea, hypertension, fatigue, decreased appetite, nausea, weight decreased, dysphonia, palmar-plantar erythrodysaesthesia (hand-foot syndrome), haemorrhage, hypothyroidism, vomiting, proteinuria, cough and constipation. The safety database is too small to detect rare and very rare reactions.

Very common (≥1/10): hypothyroidism, decreased appetite, headache, dysgeusia, hypertension, haemorrhage, dyspnoea, cough, dysphonia, diarrhoea, vomiting, nausea, abdominal pain, constipation, stomatitis, dyspepsia, palmar-plantar erythrodysaesthesia (hand-foot syndrome), rash, dry skin, arthralgia, pain in extremity, proteinuria, fatigue, asthenia, mucosal inflammation, weight decreased.

Common (≥1/100 to <1/10): anaemia, thrombocytopenia, polycythaemia, hyperthyroidism, dehydration, hyperkalaemia, hypercalcaemia, dizziness, tinnitus, cardiac failure events, venous embolic and thrombotic events, arterial embolic and thrombotic events, oropharyngeal pain, upper abdominal pain, flatulence, haemorrhoids, glossodynia, gastrointestinal perforation and fistula, hyperbilirubinaemia, cholecystitis, pruritus, erythema, alopecia, myalgia, renal failure, and raised lipase, alanine aminotransferase, amylase, aspartate aminotransferase, alkaline phosphatase, creatinine and thyroid-stimulating hormone.

Uncommon (≥1/1,000 to <1/100): neutropenia, leukopenia, posterior reversible encephalopathy syndrome (PRES).

Not known: aneurysms and artery dissections.

Among the high-grade reactions, grade 3 hypertension occurred in 22.0% of patients, grade 3 diarrhoea in 10.1%, grade 3 fatigue in 10.6% and grade 3 hand-foot syndrome in 7.6%. Cardiac failure, arterial and venous thromboembolism, haemorrhage, gastrointestinal perforation, PRES, proteinuria and raised liver enzymes are described under Special Instructions.

Axitinib is metabolised mainly by CYP3A4/5, so strong inhibitors or inducers of these enzymes change its levels. Further in vitro interaction data are in the SmPC.

• Strong CYP3A4/5 inhibitors (ketoconazole, itraconazole, clarithromycin, erythromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin): ketoconazole 400 mg once daily for 7 days doubled the AUC and raised Cmax 1.5-fold after a single 5 mg dose of axitinib. A co-medication with no or minimal CYP3A4/5 inhibition is preferred; if a strong inhibitor is unavoidable, the axitinib dose is reduced (see Administration and Dosage).
• Grapefruit: may also raise axitinib levels and should be avoided.
• CYP1A2 and CYP2C19 inhibitors: these are minor pathways (under 10% each) and the effect of strong inhibitors has not been studied; caution is advised because axitinib levels may rise.
• Strong CYP3A4/5 inducers (rifampicin, dexamethasone, phenytoin, carbamazepine, rifabutin, rifapentine, phenobarbital, St John’s wort): rifampicin 600 mg once daily for 9 days cut the AUC by 79% and Cmax by 71%. A co-medication with no or minimal induction is preferred; if one is unavoidable, a gradual axitinib dose increase is recommended. St John’s wort should be avoided.
• Avelumab: when axitinib 5 mg was given with avelumab, exposure to each medicine was unchanged compared with either alone.
• Food: tablets can be taken with or without food and are swallowed whole with a glass of water.

Treatment should be conducted by a physician experienced in the use of anticancer therapies. The tablets are taken by mouth twice daily, about 12 hours apart, with or without food, and swallowed whole with a glass of water.

Recommended Dose

• 5 mg twice daily is the starting dose. Treatment continues for as long as clinical benefit is seen, or until toxicity that cannot be managed with concomitant medicines or dose adjustment becomes unacceptable.
• With avelumab (first-line RCC): 5 mg twice daily together with avelumab 800 mg every 2 weeks, until disease progression or unacceptable toxicity. For the pembrolizumab combination, follow the pembrolizumab product information.

Dose Adjustments

• Increase: a patient who tolerates 5 mg twice daily for two consecutive weeks with no adverse reaction above grade 2 (CTCAE version 3.0) may increase to 7 mg twice daily, unless blood pressure is above 150/90 mmHg or an antihypertensive is being taken. By the same criteria, 7 mg twice daily can go up to a maximum of 10 mg twice daily.
• Reduction: where a reaction requires it, the dose can be reduced to 3 mg twice daily and then to 2 mg twice daily. Some reactions call for a temporary or permanent stop.
• Age, race, sex and body weight: no adjustment is required.

With Strong CYP3A4/5 Inhibitors or Inducers

• Inhibitors: avoid where possible. If one must be given, reduce the axitinib dose to about half (for example from 5 mg to 2 mg twice daily). After the inhibitor is stopped, a return to the previous axitinib dose should be considered.
• Inducers: avoid where possible. If one must be given, raise the axitinib dose gradually (maximal induction occurs within a week of starting a high-dose inducer) and monitor carefully for toxicity. After the inducer is stopped, return immediately to the previous dose.

Special Populations

• Elderly (65 years and over): no dose adjustment. In the controlled study 34% of patients were 65 or older; no major differences in safety or effectiveness were seen, although greater sensitivity in some older patients cannot be ruled out.
• Renal impairment: no dose adjustment; virtually no data in patients with creatinine clearance below 15 mL/min.
• Hepatic impairment: no adjustment in mild impairment (Child-Pugh class A); a lower dose is recommended in moderate impairment (Child-Pugh class B), for example from 5 mg to 2 mg twice daily; not studied in severe impairment (Child-Pugh class C) and should not be used.
• Children and adolescents: safety and efficacy below 18 years have not been established; no data are available.

Missed or Vomited Dose

Do not take an additional dose. Take the next prescribed dose at the usual time.

Specific safety events are monitored before treatment starts and periodically throughout it.

Hypertension

Hypertension was very commonly reported, with a median onset within the first month and rises seen as early as 4 days after starting. Blood pressure should be well controlled before starting and monitored throughout, with standard antihypertensive treatment as needed. If hypertension persists despite treatment, the axitinib dose is reduced; in severe hypertension axitinib is interrupted and restarted at a lower dose once blood pressure is normal, with monitoring for low blood pressure in patients taking antihypertensives. A brain MRI should be considered for severe or persistent hypertension with symptoms suggesting PRES.

Cardiac Failure

Cardiac failure events (including reduced ejection fraction and left or right ventricular failure) were reported. Signs and symptoms are monitored periodically; management may need temporary interruption, permanent discontinuation or a lower dose.

Thyroid Dysfunction

Hypothyroidism and, less often, hyperthyroidism occurred. Thyroid function is checked before starting and periodically, and treated by standard practice to keep the patient euthyroid.

Thromboembolic Events

Arterial events (transient ischaemic attack, myocardial infarction, stroke, retinal artery occlusion) and venous events (pulmonary embolism, deep vein thrombosis, retinal vein occlusion or thrombosis) were reported. Axitinib is used with caution in patients at risk of, or with a history of, these events, and has not been studied in patients who had an arterial event within the previous 12 months or a venous event within the previous 6 months.

Haemoglobin and Haematocrit

Haemoglobin and haematocrit may rise (polycythaemia), which can increase the risk of embolic and thrombotic events. They are checked before starting and periodically, and raised values are treated by standard practice.

Haemorrhage

Haemorrhagic events were reported. Axitinib has not been studied in patients with untreated brain metastasis or recent active gastrointestinal bleeding and should not be used in them. Bleeding that needs medical intervention means a temporary interruption.

Aneurysms and Artery Dissections

VEGF pathway inhibitors, in patients with or without hypertension, may promote aneurysms and artery dissections. This risk is considered carefully before starting in patients with risk factors such as hypertension or a history of aneurysm.

Gastrointestinal Perforation, Fistula and Wound Healing

Gastrointestinal perforation and fistulas were reported, and patients are monitored periodically for symptoms. The effect of axitinib on wound healing has not been formally studied: treatment should be stopped at least 24 hours before scheduled surgery, and restarted on clinical judgement that the wound has healed adequately.

Posterior Reversible Encephalopathy Syndrome (PRES)

PRES is a neurological disorder that can present with headache, seizure, lethargy, confusion, blindness and other visual or neurological disturbances, sometimes with hypertension. MRI is needed to confirm it. Axitinib is temporarily interrupted or permanently stopped in patients with signs or symptoms; the safety of restarting after PRES is not known.

Proteinuria

Proteinuria, including grade 3 and 4, was reported. Urine protein is monitored before starting and periodically; in moderate to severe proteinuria the dose is reduced or interrupted, and axitinib is discontinued if nephrotic syndrome develops.

Liver Function and Hepatic Impairment

Raised ALT, AST and bilirubin were the most commonly reported liver-related reactions. One patient given 20 mg twice daily (four times the recommended starting dose) developed concurrent rises in ALT and bilirubin considered to be drug-related hepatotoxicity. Liver function tests are done before starting and periodically. In moderate hepatic impairment (Child-Pugh class B) exposure is about two-fold higher and a lower dose is recommended; axitinib has not been studied in severe impairment (Child-Pugh class C) and should not be used.

Pregnancy, Breastfeeding and Fertility

• Contraception: women of childbearing potential must use effective contraception during treatment and up to 1 week afterwards.
• Pregnancy: there are no data in pregnant women. Given its pharmacology it may cause foetal harm, and animal studies showed reproductive toxicity including malformations. It should not be used in pregnancy unless the woman’s condition requires it.
• Breastfeeding: it is unknown whether axitinib passes into human milk and a risk to the infant cannot be excluded, so it should not be used during breastfeeding.
• Fertility: on non-clinical findings, axitinib may impair reproductive function and fertility in humans.

Lactose and Sodium

The tablets contain lactose (33.6 to 82.3 mg per tablet, depending on strength). Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take them. Each tablet contains less than 1 mmol (23 mg) of sodium, so it is essentially sodium-free.

Effect on Driving

Axitinib has a minor influence on the ability to drive and use machines. Dizziness and fatigue can occur during treatment.

Inlyta tablets do not require any special storage conditions. They are supplied in aluminium blister packs and in HDPE bottles with a silica gel desiccant. Keep out of the sight and reach of children.

3 years. Do not use after the expiry date.

Prescription only (Rx), on the prescription of a physician experienced in the use of anticancer therapies. Axitinib tablets are taken at home, so they are supplied to the patient or to the treating clinic on prescription.