Axitinib is an oral agent that works by inhibiting receptor tyrosine kinases, including vascular endothelial growth factor receptors (VEGFR)-1, VEGFR-2, and VEGFR-3. It is indicated for the treatment of advanced renal cell cancer (RCC) after the failure of one prior systemic therapy. Progression-free survival (PFS) was significantly improved with axitinib compared with sorafenib in a multicenter, randomized, phase 3 study in patients with progressive RCC after one first-line therapy including a sunitinib-, temsirolimus-, or cytokine-based regimen or bevacizumab plus interferon alfa. It is also indicated for the first-line treatment of advanced renal cell cancer in combination with either avelumab after demonstrating an improvement in PFS over sunitinib monotherapy, and in combination with pembrolizumab treatment showed a significant improvement in both overall survival and PFS compared with sunitinib monotherapy. Patients should not receive axitinib for at least 2 days before elective surgery due to wound healing complications that may be associated with treatment; do not administer axitinib for at least 2 weeks after major surgery and until adequate wound healing has occurred.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Hazardous Drugs Classification
-NIOSH 2016 List: Group 1
-NIOSH (Draft) 2020 List: Table 2
-Observe and exercise appropriate precautions for handling, preparation, administration, and disposal of hazardous drugs.
-Use double chemotherapy gloves and a protective gown. Prepare in a biological safety cabinet or compounding aseptic containment isolator with a closed system drug transfer device. Eye/face and respiratory protection may be needed during preparation and administration.
Emetic Risk
-Minimal/Low
-Administer prn antiemetic prophylaxis prior to treatment.
Route-Specific Administration
Oral Administration
Oral Solid Formulations
-Administer axitinib orally with or without food.
-Swallow tablet whole with a glass of water.
-If the patient vomits or misses a dose, an additional dose should not be taken. The next prescribed dose should be taken at the usual time.
Hypertension was reported in 40% of patients with renal cell cancer (grade 3 or 4, 16%) who received axitinib monotherapy in a randomized clinical trial; 2 patients (less than 1%) experienced hypertensive crisis. Increased blood pressure was observed as early as 4 days after initiating axitinib, with a median onset time for hypertension (systolic blood pressure greater than 150 mmHg or diastolic blood pressure greater than 100 mmHg) occurring within 1 month. The incidence of hypertension (including hypertensive crisis as well as labile hypertension) was slightly increased when axitinib was administered in combination with avelumab or pembrolizumab to patients with renal cell cancer in 2 other clinical trials (48% to 50%; grade 3 or 4, 24% to 26%). Monitor patients for hypertension during axitinib therapy; hypertension may be treated using standard antihypertensive medications.
Heart failure occurred in 2% of patients with renal cell carcinoma treated with axitinib monotherapy in a randomized clinical trial (grade 3 or 4, 1%); fatal cardiac failure was reported in 2 patients treated with axitinib (1%). Axitinib administered in combination with avelumab can cause severe and fatal cardiovascular events. Major adverse cardiovascular events occurred in 7% of patients with advanced renal cell carcinoma treated with axitinib plus avelumab in a randomized clinical trial, including death due to cardiac events (1.4%), grade 3 or 4 myocardial infarction (2.8%), and grade 3 or 4 congestive heart failure (1.8%). The median time to onset of major cardiovascular events was 4.2 months. Discontinue avelumab and axitinib for grade 3 or 4 cardiovascular events.
Arterial thromboembolic events (ATE) and venous thromboembolic events (VTE), some fatal, have been reported with axitinib use in patients with renal cell cancer. In clinical trials with axitinib monotherapy, 2% of patients experienced an ATE (e.g., transient ischemic attack, cerebrovascular accident, myocardial infarction, and retinal artery occlusion), with 2 deaths due to stroke. In one trial, 1% of patients treated with axitinib experienced a transient ischemic attack and 1% experienced retinal-vein occlusion/retinal thrombosis; fatal cerebrovascular accident was reported in one patient (less than 1%) receiving axitinib monotherapy. Venous thromboembolic events (e.g., pulmonary embolism, deep vein thrombosis, retinal vein occlusion and retinal vein thrombosis), were reported in 3% of patients who received axitinib monotherapy in clinical trials, including 3% with VTE, 2% with pulmonary embolism, and 1% with deep vein thrombosis; 2 deaths occurred due to pulmonary embolism. Venous thromboembolic disease occurred in 1.6% of patients with advanced renal cell cancer treated with axitinib in combination with avelumab.
Bleeding occurred in 16% of patients with advanced renal cell cancer treated with axitinib monotherapy in a randomized clinical trial (grade 3 or 4, 1%); grade 3 or 4 events included cerebral hemorrhage (intracranial bleeding), hematuria, hemoptysis, lower GI bleeding, and melena. Additionally, epistaxis (6%), hematuria (3%), rectal hemorrhage (2%), and hemoptysis (2%) were reported in patients who received axitinib monotherapy; fatal GI bleeding occurred in less than 1% of patients treated with axitinib.
Diarrhea occurred in 55% of patients with advanced renal cell cancer treated with axitinib monotherapy in a randomized clinical trial (grade 3 or 4, 11%). Additionally, constipation was reported in 20% (grade 3 or 4, 1%), abdominal pain in 14% (grade 3 or 4, 2%), upper abdominal pain in 8%, and hemorrhoids in 4% of these patients. The incidence of these adverse reactions was not meaningfully different when axitinib was administered in combination with avelumab or pembrolizumab. Diarrhea (including autoimmune colitis) occurred in 62% (grade 3 or 4, 8%) and abdominal pain in 22% (grade 3 or 4, 1.4%) of patients with advanced renal cell cancer who received axitinib plus avelumab in a randomized clinical trial. Diarrhea including colitis as well as hemorrhagic enterocolitis (56%; grade 3 or 4, 11%) and constipation (21%) were reported with similar frequencies in another trial of patients with advanced renal cell cancer who received axitinib plus pembrolizumab.
Hypothyroidism occurred in 19% of patients with advanced renal cell cancer treated with axitinib monotherapy (grade 3 or 4, less than 1%), in 25% of patients treated with axitinib in combination with avelumab (grade 3 or 4, 0.2%), and in 35% of patients who received axitinib plus pembrolizumab (grade 3 or 4, 0.2%) in separate clinical trials. Additionally, 32% of patients who had a thyroid stimulating hormone (TSH) level less than 5 microunits/mL prior to treatment experienced a TSH elevation to 10 microunits/mL or more with axitinib monotherapy. Monitor thyroid function tests prior to and periodically during axitinib therapy; treat thyroid disease with standard thyroid medications if clinically indicated. Hyperthyroidism occurred in 1% of patients treated with axitinib monotherapy.
Elevated hepatic enzymes occurred in 20% to 30% of patients with renal cell carcinoma treated with axitinib in a randomized clinical trial (grade 3 or 4, 1% or less); specific hepatic laboratory abnormalities included increased alkaline phosphatase (30%; grade 3 or 4, 1%), increased ALT (22%; grade 3 or 4, less than 1%), and increased AST (20%; grade 3 or 4, less than 1%). Monitor liver function tests prior to beginning treatment and periodically during therapy. Axitinib administered with pembrolizumab or avelumab can cause hepatotoxicity, including autoimmune hepatitis and fulminant hepatitis, more often than what would be expected with either drug alone (24% to 39%; grade 3 or 4, 9% to 20%). Axitinib in combination with avelumab caused increased ALT in 50% (grade 3 or 4, 9%) and increased AST in 47% (grade 3 or 4, 7%) of patients; resolution occurred in 92% of these patients. Hyperbilirubinemia occurred in 21% of patients who received axitinib plus avelumab (grade 3 or 4, 1.4%). Increased ALT (60%; grade 3 or 4, 20%), increased AST (57%; grade 3 or 4, 13%), increased alkaline phosphatase (26%; grade 3 or 4, 1.7%), and hyperbilirubinemia (22%; grade 3 or 4, 2.1%) were also reported in patients treated with axitinib plus pembrolizumab. Resolution of increased AST occurred in 94% of patients with an ALT of 3 or more times ULN; a recurrence occurred in 45% of patients who were rechallenged.
Headache occurred in 14% to 21% of patients with advanced renal cell cancer treated with axitinib monotherapy or in combination with avelumab in 2 randomized clinical trials (grade 3 or 4, 0.2% to 1%). Dizziness was also reported in 9% of patients who received monotherapy.
Proteinuria was reported in 11% of patients with advanced renal cell cancer who received axitinib monotherapy in a randomized clinical trial (grade 3, 3%).
Palmar-plantar erythrodysesthesia (hand and foot syndrome) was reported in 27% to 33% (grade 3 or 4, 5% to 6%) of patients with renal cell cancer treated with axitinib, either as monotherapy or in combination with avelumab or pembrolizumab, in randomized clinical trials. Rash (including maculopapular rash, erythematous rash, pustular rash, acneiform rash, exfoliative dermatitis, bullous rash, seborrheic dermatitis, and skin discoloration) occurred in 13% (grade 3 or 4, less than 1%) of patients receiving axitinib monotherapy and in 25% (grade 3 or 4, 0.9% to 1.4%) of those receiving axitinib plus either avelumab or pembrolizumab. Additionally, 10% of patients receiving axitinib reported xerosis, 7% reported pruritus, and 2% reported erythema.
Lymphopenia occurred in 33% of patients with advanced renal cell cancer treated with axitinib, either as monotherapy or in combination with pembrolizumab in separate clinical trials; the incidence of grade 3 or 4 lymphopenia was higher in those who received axitinib plus pembrolizumab (11% vs. 3%). Mild leukopenia was also reported in 11% of renal cell cancer patients treated with axitinib monotherapy.
Musculoskeletal adverse effects including arthralgia (15%; grade 3 or 4, 2%), pain in extremities (13%; grade 3 or 4, 1%), and myalgia (7%) were reported in patients with advanced renal cell cancer who received axitinib monotherapy in a randomized clinical trial. Musculoskeletal pain (including musculoskeletal chest pain, myalgia, back pain, bone pain, neck pain, and extremity pain) was reported in 40% of renal cell cancer patients treated with axitinib in combination with avelumab (grade 3 or 4, 3.2%); arthralgia occurred in less than 20% of these patients.
Cough occurred in 15% to 23% of patients with renal cell cancer who received axitinib, either as monotherapy or in combination with avelumab or pembrolizumab, in randomized clinical trials (grade 3 or 4, 0.2% to 1%). Dyspnea was also reported in 15% to 23% of patients who received avelumab monotherapy or in combination with avelumab (grade 3 or 4, 3%).
Hyponatremia (13%; grade 3 or 4, 4%) and hyperkalemia (15%; grade 3 or 4, 3%) occurred in patients with advanced renal cell cancer treated with axitinib monotherapy in a randomized clinical trial. The incidence of both hyponatremia (35%; grade 3 or 4, 8%) and hyperkalemia (34%; grade 3 or 4, 6%) was higher when axitinib was administered to renal cell cancer patients in combination with pembrolizumab; decreases from baseline in sodium (38%; grade 3 or 4, 9%) and increases in potassium (35%; grade 3 or 4, 3%) were also reported in patients who received axitinib plus avelumab. Additional electrolyte abnormalities reported both with axitinib monotherapy and in combination with pembrolizumab include hypocalcemia (39% vs. 22%; grade 3 or 4, 1% vs. 0.2%), hypophosphatemia (13% vs. 26%; grade 3 or 4, 2% vs. 6%), and hypercalcemia (6% vs. 27%; grade 3 or 4, 0% vs. 0.7%). Decreased bicarbonate (44%; grade 3 or 4, less than 1%) and hypernatremia (17%; grade 3 or 4, 1%) also occurred in patients receiving axitinib monotherapy.
Fatigue was reported in 39% of patients with advanced renal cell cancer treated with axitinib monotherapy in a randomized clinical trial (grade 3 or 4, 11%); asthenia was separately reported in 21% of patients (grade 3 or 4, 5%). Fatigue (including asthenia) was slightly more common in patients with advanced renal cell cancer who received axitinib in combination with either avelumab or pembrolizumab in 2 other clinical trials (52% to 53%; grade 3 or 4, 5% to 6%).
Tinnitus was reported in 3% of patients with advanced renal cell cancer who received axitinib monotherapy in a randomized clinical trial.
Hyperamylasemia occurred in 25% of patients with advanced renal cell cancer treated with axitinib monotherapy in a randomized clinical trial (grade 3 or 4, 2%); increased lipase occurred in 2% to 27% of axitinib-treated patients in this trial (grade 3 or 4, 5%). Increased lipase occurred more often in another randomized trial of patients with advanced renal cell cancer who received axitinib in combination with avelumab (37%; grade 3 or 4, 14%).
Hypoalbuminemia was reported in 15% (grade 3 or 4, less than 1%) of patients with advanced renal cell cancer who received axitinib monotherapy in a randomized clinical trial. Hypoalbuminemia occurred more often in patients with renal cell cancer who received axitinib in combination with pembrolizumab (32%; grade 3 or 4, 0.5%).
In clinical trials with axitinib, 1% of patients had a GI perforation and 1% of developed a gastrointestinal fistula; there was 1 report of death resulting from a GI perforation. In one controlled clinical trial with axitinib for the treatment of renal cell carcinoma, a GI perforation occurred in one patient (less than 1%). Patients should be periodically monitored for symptoms of GI perforation or fistula.
Decreased appetite or anorexia was reported in 26% to 34% of patients with renal cell cancer treated with axitinib, either as monotherapy or in combination with avelumab or pembrolizumab, in clinical trials (grade 3 or 4, 2.1% to 5%). Weight loss occurred in 25% of these patients who received axitinib monotherapy (grade 3 or 4, 2%) and in less than 20% of those treated with axitinib plus avelumab. Dysgeusia (11%) and dyspepsia (10%) were also reported in patients treated with axitinib monotherapy.
Nausea was reported in 28% to 34% of patients with advanced renal cell cancer treated with axitinib, either as monotherapy or in combination with avelumab or pembrolizumab (grade 3 or 4, 0.9% to 3%). Vomiting occurred in 24% of patients who received axitinib monotherapy (grade 3 or 4, 3%).
Mucosal inflammation (15%; grade 3 or 4, 1%), stomatitis (15%; grade 3 or 4, 1%), and glossodynia (3%) were reported in patients with advanced renal cell cancer treated with axitinib monotherapy in a randomized clinical trial. Mucositis (including mucosal inflammation and stomatitis) was more common (27% to 34%; grade 3 or 4, 1.6% to 2.8%) in patients who received axitinib in combination with either avelumab or pembrolizumab in 2 other clinical trials.
Dehydration occurred in 6% of patients with advanced renal cell cancer treated with axitinib monotherapy in a randomized clinical trial. Serious cases of dehydration were also reported in 1% of patients who received axitinib in combination with pembrolizumab in another clinical trial.
Dysphonia occurred in 25% to 31% of patients with advanced renal cell cancer treated with axitinib, either as monotherapy or in combination with avelumab or pembrolizumab, in randomized clinical trials (grade 3 or 4, 0.5% or less).
Alopecia occurred in 4% of patients with advanced renal cell cancer treated with axitinib monotherapy in a randomized clinical trial.
Reversible posterior leukoencephalopathy syndrome (RPLS) occurred in 1 patient with advanced renal cell cancer (less than 1%) who received axitinib monotherapy in a randomized clinical trial (n = 355); there have been 2 additional cases of RPLS in patients who received axitinib on other clinical trials. Symptoms of RPLS can include headache, seizure, lethargy, confusion, blindness, and other visual or neurologic changes; hypertension may also be present. Discontinue axitinib if RPLS develops; it is not known whether axitinib may be safely reinitiated in patients who experienced RPLS.
Hypertriglyceridemia and hypercholesterolemia have occurred in patients receiving axitinib in combination with either avelumab or pembrolizumab. In one clinical trial, 71% of patients with advanced renal cell cancer treated with axitinib in combination with avelumab had an increase in triglycerides compared to baseline (grade 3 or 4, 13%). In another trial, 57% of those who received axitinib plus pembrolizumab had an increase in cholesterol from baseline (grade 3 or 4, 1.9%).
Hyperglycemia occurred in 28% of patients with advanced renal cell cancer treated with axitinib monotherapy (grade 3 or 4, 2%) and in 62% of renal cell cancer patients who received axitinib in combination with pembrolizumab (grade 3 or 4, 9%) in separate clinical trials. Hypoglycemia was also reported in 11% of patients treated with axitinib monotherapy (grade 3 or 4, 1%).
Generally mild increases in creatinine occurred in 43% to 62% of patients with advanced renal cell cancer treated with axitinib, either as monotherapy or in combination with avelumab or pembrolizumab, in a randomized clinical trial (grade 3 or 4, 4.3% or less). Acute kidney injury or renal failure (unspecified) occurred in 1.4% to 2.3% of patients with advanced renal cell who received treatment with axitinib plus avelumab or pembrolizumab.
Prolonged bleeding time (aPTT) occurred in 22% of patients with advanced renal cell cancer treated with axitinib in combination with pembrolizumab (n = 429) in a randomized clinical trial (grade 3 or 4, 1.2%). Two patients with a grade 3 elevation in aPTT were also reported as having hepatotoxicity.
Arterial (including aortic) aneurysms, dissections (aortic dissection), and rupture have occurred in postmarketing experience with axitinib.
Anemia occurred in 4% of patients with advanced renal cell cancer treated with axitinib monotherapy in a randomized clinical trial; a decrease in hemoglobin from baseline occurred in 35% of these patients (grade 3 or 4, less than 1%). Anemia occurred more often in renal cell cancer patients who received axitinib in combination with pembrolizumab in another clinical trial (29%; grade 3 or 4, 2.1%). A decrease in hemoglobin from baseline occurred in 21% of patients with advanced renal cell cancer treated with axitinib plus avelumab.
Polycythemia occurred in 1% of patients with advanced renal cell cancer treated with axitinib monotherapy in a randomized clinical trial; an increase in hemoglobin from baseline also occurred in 9% of patients.
Thrombocytopenia occurred in 15% of patients with advanced renal cell cancer treated with axitinib monotherapy in a randomized clinical trial (grade 3 or 4, less than 1%). The incidence was slightly higher in renal cell cancer patients who received axitinib in combination with pembrolizumab in another clinical trial (27%; grade 3 or 4, 1.4%). A decreased platelet count from baseline occurred in 27% of patients with renal cell cancer treated with axitinib plus avelumab (grade 3 or 4, 0.7%).
Serious pneumonia (infection) occurred in 1.2% of patients with advanced renal cell cancer treated with axitinib in combination with avelumab in a randomized clinical trial.
Chills occurred in less than 20% of patients with advanced renal cell cancer treated with axitinib in combination with avelumab in a randomized clinical trial.
Serious cases of pneumonitis occurred in 1% of patients with advanced renal cell cancer treated with axitinib in combination with pembrolizumab in a randomized clinical trial.
Monitor patients for signs and symptoms of venous thromboembolism (e.g., pulmonary embolism, deep vein thrombosis, retinal vein occlusion, retinal vein thrombosis). Use axitinib with caution in patients who are risk for or have a history of thromboembolic disease because arterial thromboembolism (eg, cerebrovascular accident, transient ischemic attack, myocardial infarction, and retinal artery occlusion) and venous thromboembolism have been reported in clinical trials, sometimes with fatal outcomes. Patients who had an arterial thromboembolic event within the previous 12 months or a venous thromboembolic event within the previous 6 months were excluded from clinical trials. Permanently discontinue axitinib therapy for patients who experience an arterial thrombotic event. Interrupt axitinib therapy and either reduce the dose or discontinue therapy depending on the severity of any venous thromboembolic event.
Serious hemorrhagic events have been reported with axitinib use including cerebral hemorrhage, hematuria, and hemoptysis. Axitinib has not been studied in patients with untreated brain metastasis and should not be used in patients with this condition due to the risk of bleeding. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary depending on the severity and persistence of hemorrhage.
Serious gastrointestinal toxicity has been reported with axitinib use including GI bleeding, GI perforation, and fistula. Axitinib has not been studied in patients with recent, active GI bleeding and should not be used in patients with this condition due to the risk of bleeding. Axitinib should be used with caution in patients at risk for GI perforation or fistula. Monitor patients for symptoms of GI perforation or fistula and temporarily discontinue therapy if a patient develops any bleeding that requires medical intervention.
Impaired wound healing can occur in patients treated with vascular endothelial growth factor (VEGF) inhibitors such as axitinib. Discontinue axitinib at least 2 days prior to elective surgery; do not administer axitinib for at least 2 weeks following major surgery and until adequate wound healing. The safety of resuming axitinib after resolution of wound healing complications has not been established. After wound healing, a dose reduction or discontinuation of therapy may be necessary depending on the severity and persistence of impaired healing.
Reduce the dose of axitinib in patients with moderate hepatic disease (Child-Pugh B) at baseline; axitinib has not been studied in patients with severe hepatic disease (Child-Pugh C). Increased liver function tests have been reported during axitinib treatment; monitor liver function tests prior to starting axitinib and periodically during therapy. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary. Consider more frequent monitoring when axitinib is administered in combination with avelumab or pembrolizumab as the incidence of hepatotoxicity is higher; administration of corticosteroids may be necessary for severe hepatotoxicity in addition to interruption of therapy, dose reduction, and/or discontinuation of therapy.
Blood pressure should be well controlled before starting axitinib. Monitor patients for hypertension and administer antihypertensive therapy as necessary prior to and during axitinib therapy. An interruption of therapy is necessary for systolic blood pressure greater than 150 mmHg or diastolic blood pressure greater than 100 mmHg; reduce the dose or discontinue therapy depending on the severity of hypertension.
Hyperthyroidism and hypothyroidism have been reported with axitinib use. Monitor thyroid function tests prior to and periodically during axitinib therapy; treat thyroid disease if necessary with standard thyroid medications.
Proteinuria has been reported with axitinib use. Monitor for proteinuria prior to and periodically during axitinib therapy. An interruption of therapy, dose reduction, or discontinuation of therapy is necessary for patients who develop moderate to severe proteinuria.
Use axitinib with caution in patients with end-stage renal impairment (CrCL less than 15 mL/min). No significant change in axitinib clearance was demonstrated in healthy volunteers and patients with pre-existing mild to severe (CrCL 15 to 88 mL/min) renal impairment in a population pharmacokinetic study. However, only one patient with end-stage renal impairment was evaluated in this study.
Reversible Posterior Leukoencephalopathy Syndrome (RPLS), also known as Posterior Reversible Encephalopathy Syndrome (PRES), has been reported with axitinib use. Symptoms of RPLS include seizures, headache, visual disturbances, confusion, and altered mental status. Permanently discontinue axitinib therapy if RPLS is suspected or diagnosed; this syndrome may be confirmed on magnetic resonance imaging. The safety of reinitiating axitinib therapy in patients previously experiencing RPLS is not known.
Use caution in patients with cardiac disease or risk factors for heart failure. Heart failure has been reported in 2% of patients treated with axitinib in a controlled, clinical study, including 2 fatalities (1%). Monitor patients for signs or symptoms consistent with heart failure throughout treatment; evaluate and treat as necessary. If heart failure occurs, permanent discontinuation of axitinib may be required. When administered in combination with avelumab, severe and fatal cardiovascular events have been reported including myocardial infarction and congestive heart failure. Optimize management of cardiovascular risk factors such as hypertension, diabetes mellitus, or hyperlipidemia when administering combination therapy; consider baseline and periodic evaluations of left ventricular ejection fraction. Monitor for signs and symptoms of cardiovascular events. Permanently discontinue both axitinib and avelumab for grade 3 or 4 cardiovascular events.
The safety and efficacy of axitinib has not been studied in adolescents, children, infants, or neonates. Thickening growth plates (in mice and dogs at doses of 15 mg/kg or more) and incisor teeth abnormalities (in mice at doses of 5 mg/kg or more) were observed in immature mice and dogs who received twice daily axitinib for 1 month or longer.
Pregnancy should be avoided by females of reproductive potential during axitinib treatment and for at least 1 week after the last dose. Although there are no adequately controlled studies in pregnant humans, axitinib can cause fetal harm or death when administered during pregnancy based on its mechanism of action and animal studies. Women who are pregnant or who become pregnant while receiving axitinib should be apprised of the potential hazard to the fetus. In developmental toxicity studies, axitinib was teratogenic, embryotoxic, and fetotoxic in mice at exposures lower than human exposures at the recommended starting dose. When administered to female mice prior to mating and through the first week of pregnancy at approximately 10 times the AUC in patients at the recommended starting dose, oral axitinib caused an increase in postimplantation loss. In another study, the following embryo-fetal toxicities were observed in the absence of maternal toxicity when axitinib was administered to pregnant mice during organogenesis: malformation (cleft palate) at approximately 0.5 times the AUC in patients at the recommended starting dose, and variation in skeletal ossification at approximately 0.15 times the AUC in patients at the recommended starting dose.
Counsel patients about the reproductive risk and contraception requirements during axitinib treatment. Axitinib can be teratogenic if taken by the mother during pregnancy. Females and males with female partners of reproductive potential should avoid pregnancy and use effective contraception during and for at least 1 week after treatment with axitinib. Females of reproductive potential should undergo pregnancy testing prior to initiation of axitinib. Women who become pregnant while receiving axitinib should be apprised of the potential hazard to the fetus. Although there are no data regarding the effect of axitinib on human fertility, male and female infertility has been observed in animal studies including delayed sexual maturity, reduced or absent corpora lutea, decreased uterine weighs and uterine atrophy in females, and decreased organ weight, atrophy or degeneration, decreased number of germinal cells, hypospermia or abnormal sperm forms, and reduced sperm density/count in males.
Due to the potential for serious adverse reactions in nursing infants from axitinib, advise women to discontinue breast-feeding during treatment and for 2 weeks after the final dose. It is not known whether axitinib is present in human milk, although many drugs are excreted in human milk.
For the treatment of renal cell cancer:
-for the first-line treatment of advanced renal cell cancer, in combination with pembrolizumab:
Oral dosage:
Adults: Initially, give axitinib 5 mg PO twice daily in combination with pembrolizumab (200 mg IV on day 1 every 3 weeks OR 400 mg IV on day 1 every 6 weeks). The axitinib dosage may be increased to 7 mg twice daily and then to 10 mg twice daily at intervals of 6 weeks or longer in normotensive patients (BP less than or equal to 150/90) who tolerate the lower dosage for at least 2 consecutive weeks with no greater than grade 2 adverse reactions. Continue treatment until disease progression or unacceptable toxicity, or for pembrolizumab, up to 24 months in patients without progression. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Pembrolizumab therapy may need to be temporarily withheld or permanently discontinued in patients who develop immune-related reactions; permanently discontinue therapy for severe or life-threatening infusion-related reactions. Combination therapy with pembrolizumab and axitinib significantly improved median overall survival (45.7 months vs. 40.1 months) and median progression-free survival (15.7 months vs. 11.1 months) compared with sunitinib in patients with advanced renal cell cancer in the final analysis of an open-label, phase 3 clinical trial (KEYNOTE-426). The objective response rate was 60.4% (complete response [CR], 10%) versus 39.6% (CR, 3.5%), respectively; the median duration of response was 23.6 months in patients receiving combination therapy compared with 15.3 months for patients treated with sunitinib.
-for the first-line treatment of advanced renal cell cancer, in combination with avelumab:
Oral dosage:
Adults: 5 mg PO twice daily initially, in combination with avelumab (800 mg IV over 1 hour every 2 weeks), until disease progression or unacceptable toxicity. The axitinib dosage may be increased to 7 mg twice daily and then to 10 mg twice daily in normotensive patients (not receiving antihypertensive medications) who tolerate the lower dosage for at least 2 consecutive weeks with no greater than grade 2 adverse reactions. All patients should receive premedication with an antihistamine and acetaminophen 30 to 60 minutes prior to the first 4 avelumab infusions; premedication may be administered prior to subsequent doses based upon clinical judgment and presence/severity of prior infusion reactions. Avelumab therapy may need to be temporarily withheld or permanently discontinued in patients who develop immune-related reactions. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Permanently discontinue therapy for severe or life-threatening infusion-related reactions. In the first interim analysis of an open-label phase 3 clinical trial (JAVELIN Renal 101), first-line combination therapy with avelumab and axitinib significantly improved PFS in patients with advanced renal cell carcinoma and PD-L1 expression of 1% or more compared with sunitinib monotherapy; the confirmed objective response rate almost doubled with combination therapy. Overall survival was not reached in either group and continues to be monitored.
-for the first-line treatment of advanced or metastatic renal cell cancer (RCC)*:
Oral dosage:
Adults: Initially, give 5 mg PO twice daily (at approximately 12 hour intervals). Dose increase or reduction is based on individual safety and tolerability. The axitinib dosage may be increased to 7 mg twice daily and then to 10 mg twice daily in normotensive patients (BP less than or equal to 150/90) who tolerate the lower dosage for at least 2 consecutive weeks with no greater than grade 2 adverse reactions. In clinical trials, dose reductions to 3 mg twice were allowed, and then to 2 mg twice daily if necessary. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Axitinib significantly improved the objective response rate in patients with previously untreated, metastatic clear cell RCC compared with sorafenib (32% vs. 15%) in a multicenter, randomized, open-label phase 3 clinical trial. An improvement in median progression-free survival (PFS) was not statistically significant in the intent-to-treat population (10.1 months vs. 6.5 months); however, the improvement was significant in a subgroup analysis of patients with ECOG score of 0 (13.7 months vs. 6.6 months).
-for the treatment of advanced renal cell cancer after failure of 1 prior systemic therapy:
Oral dosage:
Adults: Initially, give 5 mg PO twice daily (at approximately 12 hour intervals). Dose increase or reduction is based on individual safety and tolerability. The axitinib dosage may be increased to 7 mg twice daily and then to 10 mg twice daily in normotensive patients (not receiving antihypertensive medications) who tolerate the lower dosage for at least 2 consecutive weeks with no greater than grade 2 adverse reactions. Reduce axitinib to 3 mg twice daily if a dose reduction is necessary; if further reduction is necessary, reduce axitinib to 2 mg twice daily. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Progression-free survival (primary endpoint) was significantly improved with axitinib 5 mg twice daily (increased up to 10 mg twice daily if no hypertension or greater than grade 2 adverse events) compared with sorafenib 400 mg twice daily (6.7 months vs. 4.7 months) in patients with progressive renal cell cancer in a multicenter, randomized, phase 3 study (n = 723).
Therapeutic Drug Monitoring:
Dosage Adjustment for Treatment-Related Toxicities:
-First dose reduction (from 5 mg twice daily): 3 mg PO twice daily.
-Second dose reduction: 2 mg PO twice daily.
Hypertension
-Systolic blood pressure (SBP) greater than 150 mmHg or diastolic blood pressure (DBP) greater than 100 mmHg despite antihypertensive treatment: Reduce the dose of axitinib by 1 level.
-SBP greater than 160 mmHg or DBP greater than 105 mmHg: Hold axitinib therapy. When blood pressure is less than 150/100 mmHg, resume axitinib therapy at a reduced dose.
-Grade 4 hypertension or hypertensive crisis: Permanently discontinue axitinib therapy.
Bleeding
-Grade 3 or 4: Hold axitinib therapy. When bleeding resolves to grade 1 or less, either resume axitinib therapy at a reduced dose or discontinue therapy, depending on the severity and persistence of bleeding.
Heart Failure
-Asymptomatic cardiomyopathy (left ventricular ejection fraction [LVEF] 21% to 49% below baseline, or below the lower limit of normal if a baseline LVEF was not obtained): Hold axitinib therapy. When cardiomyopathy resolves to grade 1 or less, resume axitinib therapy at a reduced dose.
-Clinically manifested congestive heart failure: Permanently discontinue axitinib therapy.
Impaired Wound Healing
-Any grade: The safety of resumption of axitinib therapy after resolution of wound healing has not been established. Either resume at a reduced dose or discontinue axitinib therapy depending on the severity and persistence of the reaction.
Proteinuria
-2 or more grams in 24 hours: Hold axitinib therapy. When proteinuria improves to less than 2 grams per 24 hours, resume axitinib therapy at a reduced dose.
Reversible Posterior Leukoencephalopathy Syndrome (RPLS)
-Any grade: Permanently discontinue axitinib therapy.
Thromboembolic Events
-Arterial thromboembolic events: Permanently discontinue axitinib therapy.
-Venous thromboembolic events: Hold axitinib therapy. When resolved, either resume therapy at a reduced dose or discontinue axitinib therapy depending on the severity of the event.
Other Adverse Reactions
-Grade 3: Reduce axitinib dose by 1 level.
-Grade 4: Hold axitinib therapy. When the adverse reaction resolves to grade 2 or less, resume axitinib therapy at a reduced dose.
In combination with avelumab or pembrolizumab
Diarrhea
-Grade 1 or 2: Initiate symptomatic treatment for diarrhea.
-Grade 3: Hold axitinib therapy and initiate symptomatic treatment for diarrhea. When diarrhea is controlled, either continue the same dose or reduce the dose of axitinib by 1 level and resume treatment.
-Grade 4: Hold axitinib therapy and initiate symptomatic treatment for diarrhea. When diarrhea resolves to grade 2 or less, reduce the dose of axitinib by 1 level and resume treatment.
In combination with avelumab
Major Adverse Cardiac Event (MACE)
-Grade 3 or 4: Permanently discontinue axitinib plus avelumab therapy.
Maximum Dosage Limits:
-Adults
20 mg/day PO.
-Geriatric
20 mg/day PO.
-Adolescents
Safety and efficacy have not been established.
-Children
Safety and efficacy have not been established.
-Infants
Safety and efficacy have not been established.
-Neonates
Safety and efficacy have not been established.
Patients with Hepatic Impairment Dosing
Baseline Hepatic Impairment:
-Mild impairment (Child-Pugh class A): No dose adjustment to the starting dose is required.
-Moderate impairment (Child-Pugh class B): Reduce the starting dose by approximately one-half, and then adjust the dose upwards or downwards based on safety and tolerability.
-Severe impairment (Child-Pugh class C): No studies have been performed; dosing recommendations are not available from the manufacturer.
Treatment-Related Hepatotoxicity:
In combination with avelumab or pembrolizumab
-AST/ALT 3 to 9.9 times the upper limit of normal (ULN) with concurrent total bilirubin less than 2 times ULN: Hold both axitinib and avelumab or pembrolizumab. Consider corticosteroid therapy. When AST/ALT recover to grade 1 or less, consider a rechallenge with axitinib and avelumab or pembrolizumab. If rechallenging, consider reducing the dose of axitinib by 1 dose level; additionally consider a sequential rechallenge.
-AST/ALT more than 3 times ULN with concurrent total bilirubin at least 2 times ULN; OR AST/ALT more than 10 times ULN: Permanently discontinue both axitinib and avelumab or pembrolizumab. Consider corticosteroid therapy.
Patients with Renal Impairment Dosing
Baseline Renal Impairment:
No dosage adjustment to the starting dose is necessary for patients with mild, moderate, or severe renal impairment. Data are not available for patients with end-stage renal disease (ESRD). A baseline urinalysis to monitor for proteinuria is recommended before axitinib administration and periodically during treatment.
Treatment-Related Nephrotoxicity:
-If moderate to severe proteinuria develops, reduce the dose of axitinib or temporarily withhold treatment.
-If dose reduction from 5 mg twice daily is required due to adverse drug reactions, the recommended dose is 3 mg twice daily; reduce the dose to 2 mg twice daily if an additional dose reduction is necessary.
*non-FDA-approved indication
Adagrasib: (Major) Avoid coadministration of axitinib with adagrasib due to the risk of increased axitinib-related adverse reactions. If coadministration is unavoidable, decrease the dose of axitinib by approximately half; subsequent doses can be increased or decreased based on individual safety and tolerability. Resume the original dose of axitinib approximately 3 to 5 half-lives after adagrasib is discontinued. Axitinib is a CYP3A substrate and adagrasib is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor significantly increased the plasma exposure of axitinib in healthy volunteers.
Amobarbital: (Major) Avoid coadministration of axitinib with amobarbital if possible due to the risk of decreased efficacy of axitinib. Selection of a concomitant medication with no or minimal CYP3A4 induction potential is recommended. Axitinib is a CYP3A4/5 substrate and amobarbital is a moderate CYP3A4 inducer.
Amoxicillin; Clarithromycin; Omeprazole: (Major) Avoid coadministration of axitinib with clarithromycin due to the risk of increased axitinib-related adverse reactions. If coadministration is unavoidable, decrease the dose of axitinib by approximately half; subsequent doses can be increased or decreased based on individual safety and tolerability. Resume the original dose of axitinib approximately 3 to 5 half-lives after clarithromycin is discontinued. Axitinib is a CYP3A4/5 substrate and clarithromycin is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4/5 inhibitor significantly increased the plasma exposure of axitinib in healthy volunteers.
Apalutamide: (Major) Avoid coadministration of axitinib with apalutamide due to the risk of decreased efficacy of axitinib. Selection of a concomitant medication with no or minimal CYP3A4 induction potential is recommended. Axitinib is a CYP3A4/5 substrate and apalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4/5 inducer significantly decreased the plasma exposure of axitinib in healthy volunteers.
Artesunate: (Moderate) Monitor for an increase in artesunate-related side effects if coadministered with axitinib. Coadministration may increase the exposure of the active metabolite of artesunate, dihydroartemisinin (DHA). DHA is a UGT substrate, and axitinib is a strong UGT inhibitor.
Aspirin, ASA; Butalbital; Caffeine: (Major) Avoid coadministration of axitinib with butalbital if possible due to the risk of decreased efficacy of axitinib. Selection of a concomitant medication with no or minimal CYP3A4 induction potential is recommended. Axitinib is a CYP3A4/5 substrate and butalbital is a moderate CYP3A4 inducer.
Atazanavir: (Major) Avoid coadministration of axitinib with atazanavir due to the risk of increased axitinib-related adverse reactions. If coadministration is unavoidable, decrease the dose of axitinib by approximately half; subsequent doses can be increased or decreased based on individual safety and tolerability. Resume the original dose of axitinib approximately 3 to 5 half-lives after atazanavir is discontinued. Axitinib is a CYP3A4/5 substrate and atazanavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4/5 inhibitor significantly increased the plasma exposure of axitinib in healthy volunteers.
Atazanavir; Cobicistat: (Major) Avoid coadministration of axitinib with atazanavir due to the risk of increased axitinib-related adverse reactions. If coadministration is unavoidable, decrease the dose of axitinib by approximately half; subsequent doses can be increased or decreased based on individual safety and tolerability. Resume the original dose of axitinib approximately 3 to 5 half-lives after atazanavir is discontinued. Axitinib is a CYP3A4/5 substrate and atazanavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4/5 inhibitor significantly increased the plasma exposure of axitinib in healthy volunteers. (Major) Avoid coadministration of axitinib with cobicistat due to the risk of increased axitinib-related adverse reactions. If coadministration is unavoidable, decrease the dose of axitinib by approximately half; subsequent doses can be increased or decreased based on individual safety and tolerability. Resume the original dose of axitinib approximately 3 to 5 half-lives after cobicistat is discontinued. Axitinib is a CYP3A4/5 substrate and cobicistat is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4/5 inhibitor significantly increased the plasma exposure of axitinib in healthy volunteers.
Bexarotene: (Major) Avoid coadministration of axitinib with bexarotene if possible due to the risk of decreased efficacy of axitinib. Selection of a concomitant medication with no or minimal CYP3A4 induction potential is recommended. Axitinib is a CYP3A4/5 substrate and bexarotene is a moderate CYP3A4 inducer.
Bosentan: (Major) Avoid coadministration of axitinib with bosentan if possible due to the risk of decreased efficacy of axitinib. Selection of a concomitant medication with no or minimal CYP3A4 induction potential is recommended. Axitinib is a CYP3A4/5 substrate and bosentan is a moderate CYP3A4 inducer.
Butalbital; Acetaminophen: (Major) Avoid coadministration of axitinib with butalbital if possible due to the risk of decreased efficacy of axitinib. Selection of a concomitant medication with no or minimal CYP3A4 induction potential is recommended. Axitinib is a CYP3A4/5 substrate and butalbital is a moderate CYP3A4 inducer.
Butalbital; Acetaminophen; Caffeine: (Major) Avoid coadministration of axitinib with butalbital if possible due to the risk of decreased efficacy of axitinib. Selection of a concomitant medication with no or minimal CYP3A4 induction potential is recommended. Axitinib is a CYP3A4/5 substrate and butalbital is a moderate CYP3A4 inducer.
Butalbital; Acetaminophen; Caffeine; Codeine: (Major) Avoid coadministration of axitinib with butalbital if possible due to the risk of decreased efficacy of axitinib. Selection of a concomitant medication with no or minimal CYP3A4 induction potential is recommended. Axitinib is a CYP3A4/5 substrate and butalbital is a moderate CYP3A4 inducer.
Butalbital; Aspirin; Caffeine; Codeine: (Major) Avoid coadministration of axitinib with butalbital if possible due to the risk of decreased efficacy of axitinib. Selection of a concomitant medication with no or minimal CYP3A4 induction potential is recommended. Axitinib is a CYP3A4/5 substrate and butalbital is a moderate CYP3A4 inducer.
Carbamazepine: (Major) Avoid coadministration of axitinib with carbamazepine due to the risk of decreased efficacy of axitinib. Selection of a concomitant medication with no or minimal CYP3A4 induction potential is recommended. Axitinib is a CYP3A4/5 substrate and carbamazepine is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4/5 inducer significantly decreased the plasma exposure of axitinib in healthy volunteers.
Cenobamate: (Major) Avoid coadministration of axitinib with cenobamate if possible due to the risk of decreased efficacy of axitinib. Selection of a concomitant medication with no or minimal CYP3A4 induction potential is recommended. Axitinib is a CYP3A4/5 substrate and cenobamate is a moderate CYP3A4 inducer.
Ceritinib: (Major) Avoid coadministration of axitinib with ceritinib due to the risk of increased axitinib-related adverse reactions. If coadministration is unavoidable, decrease the dose of axitinib by approximately half; subsequent doses can be increased or decreased based on individual safety and tolerability. Resume the original dose of axitinib approximately 3 to 5 half-lives after ceritinib is discontinued. Axitinib is a CYP3A4/5 substrate and ceritinib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4/5 inhibitor significantly increased the plasma exposure of axitinib in healthy volunteers.
Chloramphenicol: (Major) Avoid coadministration of axitinib with chloramphenical due to the risk of increased axitinib-related adverse reactions. If coadministration is unavoidable, decrease the dose of axitinib by approximately half; subsequent doses can be increased or decreased based on individual safety and tolerability. Resume the original dose of axitinib approximately 3 to 5 half-lives after chloramphenical is discontinued. Axitinib is a CYP3A4/5 substrate and chloramphenical is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4/5 inhibitor significantly increased the plasma exposure of axitinib in healthy volunteers.
Cholera Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the live cholera vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to cholera bacteria after receiving the vaccine.
Clarithromycin: (Major) Avoid coadministration of axitinib with clarithromycin due to the risk of increased axitinib-related adverse reactions. If coadministration is unavoidable, decrease the dose of axitinib by approximately half; subsequent doses can be increased or decreased based on individual safety and tolerability. Resume the original dose of axitinib approximately 3 to 5 half-lives after clarithromycin is discontinued. Axitinib is a CYP3A4/5 substrate and clarithromycin is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4/5 inhibitor significantly increased the plasma exposure of axitinib in healthy volunteers.
Cobicistat: (Major) Avoid coadministration of axitinib with cobicistat due to the risk of increased axitinib-related adverse reactions. If coadministration is unavoidable, decrease the dose of axitinib by approximately half; subsequent doses can be increased or decreased based on individual safety and tolerability. Resume the original dose of axitinib approximately 3 to 5 half-lives after cobicistat is discontinued. Axitinib is a CYP3A4/5 substrate and cobicistat is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4/5 inhibitor significantly increased the plasma exposure of axitinib in healthy volunteers.
Cocaine: (Moderate) Use caution if coadministration of axitinib with cocaine is necessary, due to the risk of increased axitinib-related adverse reactions. Axitinib is a CYP3A4 substrate and cocaine is a weak CYP3A4 inhibitor. Coadministration with a strong CYP3A4/5 inhibitor, ketoconazole, significantly increased the plasma exposure of axitinib in healthy volunteers. The manufacturer of axitinib recommends a dose reduction in patients receiving strong CYP3A4 inhibitors, but recommendations are not available for moderate or weak CYP3A4 inhibitors.
Dabrafenib: (Major) Avoid coadministration of axitinib with dabrafenib if possible due to the risk of decreased efficacy of axitinib. Selection of a concomitant medication with no or minimal CYP3A4 induction potential is recommended. Axitinib is a CYP3A4/5 substrate and dabrafenib is a moderate CYP3A4 inducer.
Darunavir: (Major) Avoid coadministration of axitinib with darunavir due to the risk of increased axitinib-related adverse reactions. If coadministration is unavoidable, decrease the dose of axitinib by approximately half; subsequent doses can be increased or decreased based on individual safety and tolerability. Resume the original dose of axitinib approximately 3 to 5 half-lives after darunavir is discontinued. Axitinib is a CYP3A4/5 substrate and darunavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4/5 inhibitor significantly increased the plasma exposure of axitinib in healthy volunteers.
Darunavir; Cobicistat: (Major) Avoid coadministration of axitinib with cobicistat due to the risk of increased axitinib-related adverse reactions. If coadministration is unavoidable, decrease the dose of axitinib by approximately half; subsequent doses can be increased or decreased based on individual safety and tolerability. Resume the original dose of axitinib approximately 3 to 5 half-lives after cobicistat is discontinued. Axitinib is a CYP3A4/5 substrate and cobicistat is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4/5 inhibitor significantly increased the plasma exposure of axitinib in healthy volunteers. (Major) Avoid coadministration of axitinib with darunavir due to the risk of increased axitinib-related adverse reactions. If coadministration is unavoidable, decrease the dose of axitinib by approximately half; subsequent doses can be increased or decreased based on individual safety and tolerability. Resume the original dose of axitinib approximately 3 to 5 half-lives after darunavir is discontinued. Axitinib is a CYP3A4/5 substrate and darunavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4/5 inhibitor significantly increased the plasma exposure of axitinib in healthy volunteers.
Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Major) Avoid coadministration of axitinib with cobicistat due to the risk of increased axitinib-related adverse reactions. If coadministration is unavoidable, decrease the dose of axitinib by approximately half; subsequent doses can be increased or decreased based on individual safety and tolerability. Resume the original dose of axitinib approximately 3 to 5 half-lives after cobicistat is discontinued. Axitinib is a CYP3A4/5 substrate and cobicistat is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4/5 inhibitor significantly increased the plasma exposure of axitinib in healthy volunteers. (Major) Avoid coadministration of axitinib with darunavir due to the risk of increased axitinib-related adverse reactions. If coadministration is unavoidable, decrease the dose of axitinib by approximately half; subsequent doses can be increased or decreased based on individual safety and tolerability. Resume the original dose of axitinib approximately 3 to 5 half-lives after darunavir is discontinued. Axitinib is a CYP3A4/5 substrate and darunavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4/5 inhibitor significantly increased the plasma exposure of axitinib in healthy volunteers.
Delavirdine: (Major) Avoid coadministration of axitinib with delavirdine due to the risk of increased axitinib-related adverse reactions. If coadministration is unavoidable, decrease the dose of axitinib by approximately half; subsequent doses can be increased or decreased based on individual safety and tolerability. Resume the original dose of axitinib approximately 3 to 5 half-lives after delavirdine is discontinued. Axitinib is a CYP3A4/5 substrate and delavirdine is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4/5 inhibitor significantly increased the plasma exposure of axitinib in healthy volunteers.
Dengue Tetravalent Vaccine, Live: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the dengue virus vaccine. When feasible, administer indicated vaccines at least 2 weeks prior to initiating immunosuppressant medications. If vaccine administration is necessary, consider revaccination following restoration of immune competence. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure after receiving the vaccine.
Efavirenz: (Major) Avoid coadministration of axitinib with efavirenz if possible due to the risk of decreased efficacy of axitinib. Selection of a concomitant medication with no or minimal CYP3A4 induction potential is recommended. Axitinib is a CYP3A4/5 substrate and efavirenz is a moderate CYP3A4 inducer.
Efavirenz; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Avoid coadministration of axitinib with efavirenz if possible due to the risk of decreased efficacy of axitinib. Selection of a concomitant medication with no or minimal CYP3A4 induction potential is recommended. Axitinib is a CYP3A4/5 substrate and efavirenz is a moderate CYP3A4 inducer.
Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Major) Avoid coadministration of axitinib with efavirenz if possible due to the risk of decreased efficacy of axitinib. Selection of a concomitant medication with no or minimal CYP3A4 induction potential is recommended. Axitinib is a CYP3A4/5 substrate and efavirenz is a moderate CYP3A4 inducer.
Elagolix: (Major) Avoid coadministration of axitinib with elagolix if possible due to the risk of decreased efficacy of axitinib. Selection of a concomitant medication with no or minimal CYP3A4 induction potential is recommended. Axitinib is a CYP3A4/5 substrate and elagolix is a weak to moderate CYP3A4 inducer.
Elagolix; Estradiol; Norethindrone acetate: (Major) Avoid coadministration of axitinib with elagolix if possible due to the risk of decreased efficacy of axitinib. Selection of a concomitant medication with no or minimal CYP3A4 induction potential is recommended. Axitinib is a CYP3A4/5 substrate and elagolix is a weak to moderate CYP3A4 inducer.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Major) Avoid coadministration of axitinib with cobicistat due to the risk of increased axitinib-related adverse reactions. If coadministration is unavoidable, decrease the dose of axitinib by approximately half; subsequent doses can be increased or decreased based on individual safety and tolerability. Resume the original dose of axitinib approximately 3 to 5 half-lives after cobicistat is discontinued. Axitinib is a CYP3A4/5 substrate and cobicistat is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4/5 inhibitor significantly increased the plasma exposure of axitinib in healthy volunteers.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Avoid coadministration of axitinib with cobicistat due to the risk of increased axitinib-related adverse reactions. If coadministration is unavoidable, decrease the dose of axitinib by approximately half; subsequent doses can be increased or decreased based on individual safety and tolerability. Resume the original dose of axitinib approximately 3 to 5 half-lives after cobicistat is discontinued. Axitinib is a CYP3A4/5 substrate and cobicistat is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4/5 inhibitor significantly increased the plasma exposure of axitinib in healthy volunteers.
Encorafenib: (Major) Avoid coadministration of axitinib with encorafenib due to the risk of decreased efficacy of axitinib. Selection of a concomitant medication with no or minimal CYP3A induction potential is recommended. Axitinib is a CYP3A substrate and encorafenib is a strong CYP3A inducer. Coadministration with another strong CYP3A inducer significantly decreased the plasma exposure of axitinib in healthy volunteers.
Enzalutamide: (Major) Avoid coadministration of axitinib with enzalutamide due to the risk of decreased efficacy of axitinib. Selection of a concomitant medication with no or minimal CYP3A4 induction potential is recommended. Axitinib is a CYP3A4/5 substrate and enzalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4/5 inducer significantly decreased the plasma exposure of axitinib in healthy volunteers.
Eslicarbazepine: (Major) Avoid coadministration of axitinib with eslicarbazepine if possible due to the risk of decreased efficacy of axitinib. Selection of a concomitant medication with no or minimal CYP3A4 induction potential is recommended. Axitinib is a CYP3A4/5 substrate and eslicarbazepine is a moderate CYP3A4 inducer.
Etravirine: (Major) Avoid coadministration of axitinib with etravirine if possible due to the risk of decreased efficacy of axitinib. Selection of a concomitant medication with no or minimal CYP3A4 induction potential is recommended. Axitinib is a CYP3A4/5 substrate and etravirine is a moderate CYP3A4 inducer.
Fosamprenavir: (Major) Avoid coadministration of axitinib with fosamprenavir due to the risk of increased axitinib-related adverse reactions. If coadministration is unavoidable, decrease the dose of axitinib by approximately half; subsequent doses can be increased or decreased based on individual safety and tolerability. Resume the original dose of axitinib approximately 3 to 5 half-lives after fosamprenavir is discontinued. Axitinib is a CYP3A4/5 substrate and fosamprenavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4/5 inhibitor significantly increased the plasma exposure of axitinib in healthy volunteers.
Fosphenytoin: (Major) Avoid coadministration of axitinib with fosphenytoin due to the risk of decreased efficacy of axitinib. Selection of a concomitant medication with no or minimal CYP3A4 induction potential is recommended. Axitinib is a CYP3A4/5 substrate and fosphenytoin is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4/5 inducer significantly decreased the plasma exposure of axitinib in healthy volunteers.
Grapefruit juice: (Major) Avoid administration of axitinib with grapefruit or grapefruit juice due to the risk of increased axitinib-related adverse reactions. Axitinib is a CYP3A4/5 substrate and grapefruit juice is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4/5 inhibitor significantly increased the plasma exposure of axitinib in healthy volunteers.
Idelalisib: (Major) Avoid coadministration of axitinib with idelalisib due to the risk of increased axitinib-related adverse reactions. If coadministration is unavoidable, decrease the dose of axitinib by approximately half; subsequent doses can be increased or decreased based on individual safety and tolerability. Resume the original dose of axitinib approximately 3 to 5 half-lives after idelalisib is discontinued. Axitinib is a CYP3A4/5 substrate and idelalisib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4/5 inhibitor significantly increased the plasma exposure of axitinib in healthy volunteers.
Indinavir: (Major) Avoid coadministration of axitinib with indinavir due to the risk of increased axitinib-related adverse reactions. If coadministration is unavoidable, decrease the dose of axitinib by approximately half; subsequent doses can be increased or decreased based on individual safety and tolerability. Resume the original dose of axitinib approximately 3 to 5 half-lives after indinavir is discontinued. Axitinib is a CYP3A4/5 substrate and indinavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4/5 inhibitor significantly increased the plasma exposure of axitinib in healthy volunteers.
Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Avoid coadministration of axitinib with rifampin due to the risk of decreased efficacy of axitinib. Selection of a concomitant medication with no or minimal CYP3A4 induction potential is recommended. Axitinib is a CYP3A4/5 substrate and rifampin is a strong CYP3A4 inducer. Coadministration with rifampin significantly decreased the plasma exposure of axitinib in healthy volunteers.
Isoniazid, INH; Rifampin: (Major) Avoid coadministration of axitinib with rifampin due to the risk of decreased efficacy of axitinib. Selection of a concomitant medication with no or minimal CYP3A4 induction potential is recommended. Axitinib is a CYP3A4/5 substrate and rifampin is a strong CYP3A4 inducer. Coadministration with rifampin significantly decreased the plasma exposure of axitinib in healthy volunteers.
Itraconazole: (Major) Avoid axitinib during and for 2 weeks after discontinuation of itraconazole treatment. If coadministration is unavoidable, decrease the dose of axitinib by approximately 50%; subsequent doses can be increased or decreased based on individual safety and tolerability. Resume the original dose of axitinib approximately 3 to 5 half-lives after itraconazole is discontinued. Axitinib is a CYP3A4/5 substrate and itraconazole is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4/5 inhibitor significantly increased the plasma exposure of axitinib in healthy volunteers.
Ketoconazole: (Major) Avoid coadministration of axitinib with ketoconazole due to the risk of increased axitinib-related adverse reactions. If coadministration is unavoidable, decrease the dose of axitinib by approximately half; subsequent doses can be increased or decreased based on individual safety and tolerability. Resume the original dose of axitinib approximately 3 to 5 half-lives after ketoconazole is discontinued. Axitinib is a CYP3A4/5 substrate and ketoconazole is a strong CYP3A4 inhibitor. Coadministration with ketoconazole significantly increased the plasma exposure of axitinib in healthy volunteers.
Lansoprazole; Amoxicillin; Clarithromycin: (Major) Avoid coadministration of axitinib with clarithromycin due to the risk of increased axitinib-related adverse reactions. If coadministration is unavoidable, decrease the dose of axitinib by approximately half; subsequent doses can be increased or decreased based on individual safety and tolerability. Resume the original dose of axitinib approximately 3 to 5 half-lives after clarithromycin is discontinued. Axitinib is a CYP3A4/5 substrate and clarithromycin is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4/5 inhibitor significantly increased the plasma exposure of axitinib in healthy volunteers.
Letermovir: (Moderate) Avoid coadministration of axitinib with letermovir if the patient is also taking cyclosporine due to the risk of increased axitinib-related adverse reactions. If coadministration is unavoidable, decrease the dose of axitinib by approximately half; subsequent doses can be increased or decreased based on individual safety and tolerability. Resume the original dose of axitinib approximately 3 to 5 half-lives after letermovir or cyclosporine is discontinued. Axitinib is a CYP3A4/5 substrate. Letermovir is a moderate CYP3A4 inhibitor which requires no dose adjustment with axitinib; however, the combined effect of letermovir and cyclosporine on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4/5 inhibitor significantly increased the plasma exposure of axitinib in healthy volunteers.
Levoketoconazole: (Major) Avoid coadministration of axitinib with ketoconazole due to the risk of increased axitinib-related adverse reactions. If coadministration is unavoidable, decrease the dose of axitinib by approximately half; subsequent doses can be increased or decreased based on individual safety and tolerability. Resume the original dose of axitinib approximately 3 to 5 half-lives after ketoconazole is discontinued. Axitinib is a CYP3A4/5 substrate and ketoconazole is a strong CYP3A4 inhibitor. Coadministration with ketoconazole significantly increased the plasma exposure of axitinib in healthy volunteers.
Lonafarnib: (Major) Avoid coadministration of axitinib with lonafarnib due to the risk of increased axitinib-related adverse reactions. If coadministration is unavoidable, decrease the dose of axitinib by approximately half; subsequent doses can be increased or decreased based on individual safety and tolerability. Resume the original dose of axitinib approximately 3 to 5 half-lives after lonafarnib is discontinued. Axitinib is a CYP3A4/5 substrate and lonafarnib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4/5 inhibitor significantly increased the plasma exposure of axitinib in healthy volunteers.
Lopinavir; Ritonavir: (Major) Avoid coadministration of axitinib with ritonavir due to the risk of increased axitinib-related adverse reactions. If coadministration is unavoidable, decrease the dose of axitinib by approximately half; subsequent doses can be increased or decreased based on individual safety and tolerability. Resume the original dose of axitinib approximately 3 to 5 half-lives after ritonavir is discontinued. Axitinib is a CYP3A4/5 substrate and ritonavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4/5 inhibitor significantly increased the plasma exposure of axitinib in healthy volunteers.
Lorlatinib: (Major) Avoid coadministration of axitinib with lorlatinib if possible due to the risk of decreased efficacy of axitinib. Selection of a concomitant medication with no or minimal CYP3A4 induction potential is recommended. Axitinib is a CYP3A4/5 substrate and lorlatinib is a moderate CYP3A4 inducer.
Lumacaftor; Ivacaftor: (Major) Avoid coadministration of axitinib with lumacaftor; ivacaftor due to the risk of decreased efficacy of axitinib. Selection of a concomitant medication with no or minimal CYP3A4 induction potential is recommended. Axitinib is a CYP3A4/5 substrate and lumacaftor is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4/5 inducer significantly decreased the plasma exposure of axitinib in healthy volunteers.
Lumacaftor; Ivacaftor: (Major) Avoid coadministration of axitinib with lumacaftor; ivacaftor due to the risk of decreased efficacy of axitinib. Selection of a concomitant medication with no or minimal CYP3A4 induction potential is recommended. Axitinib is a CYP3A4/5 substrate and lumacaftor is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4/5 inducer significantly decreased the plasma exposure of axitinib in healthy volunteers.
Mavacamten: (Major) Avoid coadministration of axitinib with mavacamten if possible due to the risk of decreased efficacy of axitinib. Selection of a concomitant medication with no or minimal CYP3A induction potential is recommended. Axitinib is a CYP3A substrate and mavacamten is a moderate CYP3A inducer.
Methohexital: (Major) Avoid coadministration of axitinib with methohexital if possible due to the risk of decreased efficacy of axitinib. Selection of a concomitant medication with no or minimal CYP3A4 induction potential is recommended. Axitinib is a CYP3A4/5 substrate and methohexital is a moderate CYP3A4 inducer.
Mifepristone: (Major) Avoid coadministration of axitinib with mifepristone due to the risk of increased axitinib-related adverse reactions. If coadministration is unavoidable, decrease the dose of axitinib by approximately half; subsequent doses can be increased or decreased based on individual safety and tolerability. Resume the original dose of axitinib approximately 3 to 5 half-lives after mifepristone is discontinued. Axitinib is a CYP3A4/5 substrate and mifepristone is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4/5 inhibitor significantly increased the plasma exposure of axitinib in healthy volunteers. The clinical significance of this interaction with the short-term use of mifepristone for termination of pregnancy is unknown.
Mitotane: (Major) Avoid coadministration of axitinib with mitotane due to the risk of decreased efficacy of axitinib. Selection of a concomitant medication with no or minimal CYP3A4 induction potential is recommended. Axitinib is a CYP3A4/5 substrate and mitotane is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4/5 inducer significantly decreased the plasma exposure of axitinib in healthy volunteers.
Modafinil: (Major) Avoid coadministration of axitinib with modafinil if possible due to the risk of decreased efficacy of axitinib. Selection of a concomitant medication with no or minimal CYP3A4 induction potential is recommended. Axitinib is a CYP3A4/5 substrate and modafinil is a moderate CYP3A4 inducer.
Nafcillin: (Major) Avoid coadministration of axitinib with nafcillin if possible due to the risk of decreased efficacy of axitinib. Selection of a concomitant medication with no or minimal CYP3A4 induction potential is recommended. Axitinib is a CYP3A4/5 substrate and nafcillin is a moderate CYP3A4 inducer.
Nefazodone: (Major) Avoid coadministration of axitinib with nefazodone due to the risk of increased axitinib-related adverse reactions. If coadministration is unavoidable, decrease the dose of axitinib by approximately half; subsequent doses can be increased or decreased based on individual safety and tolerability. Resume the original dose of axitinib approximately 3 to 5 half-lives after nefazodone is discontinued. Axitinib is a CYP3A4/5 substrate and nefazodone is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4/5 inhibitor significantly increased the plasma exposure of axitinib in healthy volunteers.
Nelfinavir: (Major) Avoid coadministration of axitinib with nelfinavir due to the risk of increased axitinib-related adverse reactions. If coadministration is unavoidable, decrease the dose of axitinib by approximately half; subsequent doses can be increased or decreased based on individual safety and tolerability. Resume the original dose of axitinib approximately 3 to 5 half-lives after nelfinavir is discontinued. Axitinib is a CYP3A4/5 substrate and nelfinavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4/5 inhibitor significantly increased the plasma exposure of axitinib in healthy volunteers.
Nirmatrelvir; Ritonavir: (Major) Avoid coadministration of axitinib with ritonavir due to the risk of increased axitinib-related adverse reactions. If coadministration is unavoidable, decrease the dose of axitinib by approximately half; subsequent doses can be increased or decreased based on individual safety and tolerability. Resume the original dose of axitinib approximately 3 to 5 half-lives after ritonavir is discontinued. Axitinib is a CYP3A4/5 substrate and ritonavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4/5 inhibitor significantly increased the plasma exposure of axitinib in healthy volunteers.
Omeprazole; Amoxicillin; Rifabutin: (Major) Avoid coadministration of axitinib with rifabutin due to the risk of decreased efficacy of axitinib. Selection of a concomitant medication with no or minimal CYP3A4 induction potential is recommended. Axitinib is a CYP3A4/5 substrate and rifabutin is a CYP3A4 inducer. Coadministration with a strong CYP3A4/5 inducer significantly decreased the plasma exposure of axitinib in healthy volunteers.
Pentobarbital: (Major) Avoid coadministration of axitinib with pentobarbital if possible due to the risk of decreased efficacy of axitinib. Selection of a concomitant medication with no or minimal CYP3A4 induction potential is recommended. Axitinib is a CYP3A4/5 substrate and pentobarbital is a moderate CYP3A4 inducer.
Pexidartinib: (Major) Avoid coadministration of axitinib with pexidartinib if possible due to the risk of decreased efficacy of axitinib. Selection of a concomitant medication with no or minimal CYP3A4 induction potential is recommended. Axitinib is a CYP3A4/5 substrate and pexidartinib is a moderate CYP3A4 inducer.
Phenobarbital: (Major) Avoid coadministration of axitinib with phenobarbital due to the risk of decreased efficacy of axitinib. Selection of a concomitant medication with no or minimal CYP3A4 induction potential is recommended. Axitinib is a CYP3A4/5 substrate and phenobarbital is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4/5 inducer significantly decreased the plasma exposure of axitinib in healthy volunteers.
Phenobarbital; Hyoscyamine; Atropine; Scopolamine: (Major) Avoid coadministration of axitinib with phenobarbital due to the risk of decreased efficacy of axitinib. Selection of a concomitant medication with no or minimal CYP3A4 induction potential is recommended. Axitinib is a CYP3A4/5 substrate and phenobarbital is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4/5 inducer significantly decreased the plasma exposure of axitinib in healthy volunteers.
Phenytoin: (Major) Avoid coadministration of axitinib with phenytoin due to the risk of decreased efficacy of axitinib. Selection of a concomitant medication with no or minimal CYP3A4 induction potential is recommended. Axitinib is a CYP3A4/5 substrate and phenytoin is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4/5 inducer significantly decreased the plasma exposure of axitinib in healthy volunteers.
Posaconazole: (Major) Avoid coadministration of axitinib with posaconazole due to the risk of increased axitinib-related adverse reactions. If coadministration is unavoidable, decrease the dose of axitinib by approximately half; subsequent doses can be increased or decreased based on individual safety and tolerability. Resume the original dose of axitinib approximately 3 to 5 half-lives after posaconazole is discontinued. Axitinib is a CYP3A4/5 substrate and posaconazole is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4/5 inhibitor significantly increased the plasma exposure of axitinib in healthy volunteers.
Primidone: (Major) Avoid coadministration of axitinib with primidone due to the risk of decreased efficacy of axitinib. Selection of a concomitant medication with no or minimal CYP3A4 induction potential is recommended. Axitinib is a CYP3A4/5 substrate and primidone is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4/5 inducer significantly decreased the plasma exposure of axitinib in healthy volunteers.
Repotrectinib: (Major) Avoid coadministration of axitinib with repotrectinib if possible due to the risk of decreased efficacy of axitinib. Selection of a concomitant medication with no or minimal CYP3A induction potential is recommended. Axitinib is a CYP3A substrate and repotrectinib is a moderate CYP3A inducer.
Ribociclib: (Major) Avoid coadministration of axitinib with ribociclib due to the risk of increased axitinib-related adverse reactions. If coadministration is unavoidable, decrease the dose of axitinib by approximately half; subsequent doses can be increased or decreased based on individual safety and tolerability. Resume the original dose of axitinib approximately 3 to 5 half-lives after ribociclib is discontinued. Axitinib is a CYP3A4/5 substrate and ribociclib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4/5 inhibitor significantly increased the plasma exposure of axitinib in healthy volunteers.
Ribociclib; Letrozole: (Major) Avoid coadministration of axitinib with ribociclib due to the risk of increased axitinib-related adverse reactions. If coadministration is unavoidable, decrease the dose of axitinib by approximately half; subsequent doses can be increased or decreased based on individual safety and tolerability. Resume the original dose of axitinib approximately 3 to 5 half-lives after ribociclib is discontinued. Axitinib is a CYP3A4/5 substrate and ribociclib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4/5 inhibitor significantly increased the plasma exposure of axitinib in healthy volunteers.
Rifabutin: (Major) Avoid coadministration of axitinib with rifabutin due to the risk of decreased efficacy of axitinib. Selection of a concomitant medication with no or minimal CYP3A4 induction potential is recommended. Axitinib is a CYP3A4/5 substrate and rifabutin is a CYP3A4 inducer. Coadministration with a strong CYP3A4/5 inducer significantly decreased the plasma exposure of axitinib in healthy volunteers.
Rifampin: (Major) Avoid coadministration of axitinib with rifampin due to the risk of decreased efficacy of axitinib. Selection of a concomitant medication with no or minimal CYP3A4 induction potential is recommended. Axitinib is a CYP3A4/5 substrate and rifampin is a strong CYP3A4 inducer. Coadministration with rifampin significantly decreased the plasma exposure of axitinib in healthy volunteers.
Rifapentine: (Major) Avoid coadministration of axitinib with rifapentine due to the risk of decreased efficacy of axitinib. Selection of a concomitant medication with no or minimal CYP3A4 induction potential is recommended. Axitinib is a CYP3A4/5 substrate and rifapentine is a strong CYP3A4 inducer. Coadministration with a strong CYP3A4/5 inducer significantly decreased the plasma exposure of axitinib in healthy volunteers.
Ritonavir: (Major) Avoid coadministration of axitinib with ritonavir due to the risk of increased axitinib-related adverse reactions. If coadministration is unavoidable, decrease the dose of axitinib by approximately half; subsequent doses can be increased or decreased based on individual safety and tolerability. Resume the original dose of axitinib approximately 3 to 5 half-lives after ritonavir is discontinued. Axitinib is a CYP3A4/5 substrate and ritonavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4/5 inhibitor significantly increased the plasma exposure of axitinib in healthy volunteers.
Saquinavir: (Major) Avoid coadministration of axitinib with saquinavir due to the risk of increased axitinib-related adverse reactions. If coadministration is unavoidable, decrease the dose of axitinib by approximately half; subsequent doses can be increased or decreased based on individual safety and tolerability. Resume the original dose of axitinib approximately 3 to 5 half-lives after saquinavir is discontinued. Axitinib is a CYP3A4/5 substrate and saquinavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4/5 inhibitor significantly increased the plasma exposure of axitinib in healthy volunteers.
SARS-CoV-2 (COVID-19) vaccines: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
SARS-CoV-2 Virus (COVID-19) Adenovirus Vector Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
SARS-CoV-2 Virus (COVID-19) mRNA Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
SARS-CoV-2 Virus (COVID-19) Recombinant Spike Protein Nanoparticle Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
Secobarbital: (Major) Avoid coadministration of axitinib with secobarbital if possible due to the risk of decreased efficacy of axitinib. Selection of a concomitant medication with no or minimal CYP3A4 induction potential is recommended. Axitinib is a CYP3A4/5 substrate and secobarbital is a moderate CYP3A4 inducer.
Sotorasib: (Major) Avoid coadministration of axitinib with sotorasib if possible due to the risk of decreased efficacy of axitinib. Selection of a concomitant medication with no or minimal CYP3A4 induction potential is recommended. Axitinib is a CYP3A4/5 substrate and sotorasib is a moderate CYP3A4 inducer.
St. John's Wort, Hypericum perforatum: (Major) Avoid coadministration of axitinib with St. Johns Wort due to the risk of decreased efficacy of axitinib. Selection of a concomitant medication with no or minimal CYP3A4 induction potential is recommended. Axitinib is a CYP3A4/5 substrate and St. Johns Wort is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4/5 inducer significantly decreased the plasma exposure of axitinib in healthy volunteers.
Tipranavir: (Major) Avoid coadministration of axitinib with tipranavir due to the risk of increased axitinib-related adverse reactions. If coadministration is unavoidable, decrease the dose of axitinib by approximately half; subsequent doses can be increased or decreased based on individual safety and tolerability. Resume the original dose of axitinib approximately 3 to 5 half-lives after tipranavir is discontinued. Axitinib is a CYP3A4/5 substrate and tipranavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4/5 inhibitor significantly increased the plasma exposure of axitinib in healthy volunteers.
Tucatinib: (Major) Avoid coadministration of axitinib with tucatinib due to the risk of increased axitinib-related adverse reactions. If coadministration is unavoidable, decrease the dose of axitinib by approximately half; subsequent doses can be increased or decreased based on individual safety and tolerability. Resume the original dose of axitinib approximately 3 to 5 half-lives after tucatinib is discontinued. Axitinib is a CYP3A4/5 substrate and tucatinib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4/5 inhibitor significantly increased the plasma exposure of axitinib in healthy volunteers.
Vonoprazan; Amoxicillin; Clarithromycin: (Major) Avoid coadministration of axitinib with clarithromycin due to the risk of increased axitinib-related adverse reactions. If coadministration is unavoidable, decrease the dose of axitinib by approximately half; subsequent doses can be increased or decreased based on individual safety and tolerability. Resume the original dose of axitinib approximately 3 to 5 half-lives after clarithromycin is discontinued. Axitinib is a CYP3A4/5 substrate and clarithromycin is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4/5 inhibitor significantly increased the plasma exposure of axitinib in healthy volunteers.
Voriconazole: (Major) Avoid coadministration of axitinib with voriconazole due to the risk of increased axitinib-related adverse reactions. If coadministration is unavoidable, decrease the dose of axitinib by approximately half; subsequent doses can be increased or decreased based on individual safety and tolerability. Resume the original dose of axitinib approximately 3 to 5 half-lives after voriconazole is discontinued. Axitinib is a CYP3A4/5 substrate and voriconazole is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4/5 inhibitor significantly increased the plasma exposure of axitinib in healthy volunteers.
Axitinib is an oral kinase inhibitor. At therapeutic concentrations, axitinib inhibits receptor tyrosine kinases including vascular endothelial growth factor receptors (VEGFR)-1, VEGFR-2, and VEGFR-3. Axitinib inhibited tumor growth and phosphorylation of VEGFR-2 in tumor xenograft mouse models and VEGF-mediated endothelial cell proliferation and survival in vitro and in mouse models. Inactivation of the von-Hippel Lindau (VHL) gene, reported in up to 91% of patients with noninherited clear-cell renal cell cancer (RCC), results in hypoxia inducible factors (HIF) accumulation. Elevated HIF levels trigger increased gene transcription of VEGF and platelet-derived growth factor that control cell proliferation, glucose uptake, and angiogenesis.
Axitinib is administered orally. It is highly protein bound (> 99%), mostly to albumin with moderate binding to alpha-1 acid glycoprotein. Carboxylic acid, sulfoxide, and N-glucuronide metabolites have been identified. N-glucuronide and sulfoxide metabolites are >= 400 times less potent against VEGFR-2 in vitro compared with axitinib. Following a radioactive 5-mg oral dose, 41% and 23% of the radioactivity was recovered in the feces and urine, respectively. Unchanged axitinib accounted for 12% of dose recovered in the feces. Unchanged axitinib was not found in urine; however, carboxylic acid and sulfoxide metabolites were responsible for most of the radioactivity in urine. The N-glucuronide metabolite accounted for 50% of the radioactivity in plasma with unchanged axitinib and the sulfoxide metabolite each accounting for 20% of the radioactivity. The plasma half-life ranges from 2.5 to 6.1 hours and steady state is estimated to occur within 2 to 3 days.
Affected cytochrome P450 isoenzymes and drug transporter: CYP3A4, CYP1A2, CYP2C19, UGT1A1
Axitinib is metabolized in the liver primarily via CYP3A4/5 and to a lesser extent, by CYP1A2, CYP2C19, and UGT1A1. In vitro studies suggest that axitinib has the potential to inhibit CYP1A2 and CYP2C8, but in vivo studies did not demonstrate this for CYP2C8. It is also an inhibitor of P-glycoprotein (P-gp) in vitro; however, it is not expected to inhibit P-gp at therapeutic plasma concentrations. Axitinib does not inhibit CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4/5 or UGT1A1 in vitro. It also does not induce CYP1A1, CYP1A2, or CYP3A4/5 in vitro.
-Route-Specific Pharmacokinetics
Oral Route
A 2-compartment disposition model with first order absorption and lag time was determined from pooled data in a population pharmacokinetic analysis in patients and healthy subjects who received axitinib in 17 trials. Following a single oral 5-mg axitinib dose, the mean absolute bioavailability was 58% and the median Tmax ranged from 2.5 to 4.1 hours. Linear kinetics are exhibited over a dosage range of 1 mg to 20 mg at steady state. Axitinib 5 mg twice daily dosing led to about 1.4 times the accumulation compared with a single 5-mg dose.
In 20 patients with advanced renal cell carcinoma who received axitinib 5 mg twice daily with food (fed state), the geometric mean Cmax was 27.8 ng/mL (coefficient of variation (CV%), 79%), AUC (0 to 24 hour) was 265 ng x hour/mL (CV%, 77%), total clearance was 38 L/hr (CV%, 80%), and apparent volume of distribution was 160 L (CV%, 105%). Compared with patients who received axitinib after fasting overnight, 10% lower AUC and 19% higher AUC values were observed following the administration of axitinib with a moderate fat meal and a high fat, high-calorie meal, respectively. Axitinib may be given with or without food. Although the solubility of axitinib is pH dependent, with higher pH resulting in lower solubility, coadministration with rabeprazole did not significantly alter the Cmax or AUC of axitinib; no dose adjustment is recommended for concomitant use with antacids, H2 antagonists, or proton pump inhibitors.
-Special Populations
Hepatic Impairment
In a pharmacokinetic (PK) study that evaluated the effect of hepatic impairment on axitinib PK parameters, systemic exposure (AUC and Cmax) was similar in patients with baseline mild hepatic impairment (Child-Pugh class A) and higher in patients with baseline moderate hepatic impairment (Child-Pugh class B) compared with subjects with normal hepatic function. An axitinib dose reduction is necessary in patients with moderate hepatic impairment. Axitinib has not been evaluated in patients with severe hepatic impairment (Child-Pugh class C).
Renal Impairment
Axitinib clearance was not significantly effected by any degree of renal dysfunction in a population pharmacokinetic analysis that included healthy subjects (n=590) and patients with pre-existing mild (n=139; CrCL, 60 to 89 mL/min), moderate (n=64; CrCL, 30 to 59 mL/min), or severe (n=5; CrCL, 15 to 29 mL/min) renal impairment. Caution should be used in patients with end stage renal disease (ESRD) (CrCl less than 15 mL/min) as axitinib has only been evaluated in 1 patient with ESRD.
Pediatrics
Axitinib has not been studied in pediatric patients.
Geriatric
Age had no clinically significant impact on the clearance of axitinib in population pharmacokinetic analyses.
Gender Differences
Gender had no clinically significant impact on the clearance of axitinib in population pharmacokinetic analyses.
Ethnic Differences
Race had no clinically significant impact on the clearance of axitinib in population pharmacokinetic analyses.
Obesity
Body weight and body surface area had no clinically significant impact on the clearance of axitinib in population pharmacokinetic analyses.
Other
Genotype Differences
UGT1A1 or CYP2C19 genotypes had no clinically significant impact on the clearance of axitinib in population pharmacokinetic analyses.