Axitinib

Axitinib is used to treat advanced renal cell carcinoma (RCC, a type of cancer that begins in the cells of the kidneys) in people who have not been treated successfully with another medication. Axitinib is in a class of medications called kinase inhibitors. It works by blocking the action of an abnormal protein that signals cancer cells to multiply. This helps slow or stop the spread of cancer cells.

Axitinib interferes with the growth of some cancer cells.

Axitinib is used to treat advanced kidney cancer.

Axitinib is usually given after other cancer medicine has been tried without success.

Axitinib may also be used for purposes not listed in this medication guide.

Axitinib can increase your risk of serious bleeding. Stop using axitinib and call your doctor at once if you have severe stomach pain, bloody or tarry stools, coughing up blood, or any heavy or unusual bleeding.

Some people taking axitinib have developed a perforation (a hole or tear) or a fistula (an abnormal passageway) within the stomach or intestines. Call your doctor if you have severe stomach pain, or if you feel like you are choking and gagging when you eat or drink.

You should not use axitinib if you are allergic to it.

To make sure axitinib is safe for you, tell your doctor if you have:

• liver disease;
• high blood pressure;
• a thyroid disorder;
• bleeding problems, or a wound that has not healed;
• recent stomach or intestinal bleeding;
• history of perforation (a hole or tear) in your stomach or intestines;
• history of a brain tumor; or
• a history of heart attack, heart failure, stroke, or blood clot.

Do not use axitinib if you are pregnant. It could harm the unborn baby. Use effective birth control, and tell your doctor if you become pregnant during treatment.

Use birth control to prevent pregnancy while you are receiving axitinib, whether you are a man or a woman. Axitinib use by either parent may cause birth defects or miscarriage.

Call your doctor at once if a pregnancy occurs while either sexual partner is taking axitinib.

It is not known whether axitinib passes into breast milk or if it could harm a nursing baby. You should not breast-feed while you are using axitinib.

Follow all directions on your prescription label. Your doctor may occasionally change your dose to make sure you get the best results. Do not take this medicine in larger or smaller amounts or for longer than recommended.

Axitinib should be taken at evenly spaced intervals, usually once every 12 hours. Follow your doctor's instructions.

Take this medicine with a full glass of water. You may take axitinib with or without food.

Do not crush, chew, or break an axitinib tablet. Swallow it whole.

Your blood pressure will need to be checked often. You may also need frequent medical tests to be sure this medicine is not causing harmful effects.

If you need surgery, tell the surgeon ahead of time that you are using axitinib. You will need to stop using the medicine at least 24 hours before a planned surgery.

Store at room temperature away from moisture and heat.

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

If you vomit after taking the medicine, or if you miss a dose, take the medicine at your next scheduled dose. Do not take extra medicine to make up the missed dose.

Tell your doctor if you:

• are pregnant or plan to become pregnant. Taking axitinib during pregnancy may cause the death of an unborn baby or birth defects. You should not become pregnant while taking axitinib. Talk to your doctor if you are pregnant or plan to become pregnant.
• are able to become pregnant. You should use effective birth control during your treatment with axitinib. Talk to your doctor about birth control methods to prevent pregnancy while you are taking axitinib.

Tell your doctor if you are breastfeeding or plan to breastfeed. It is not known if axitinib passes into your breast milk. You and your doctor should decide if you will take axitinib or breastfeed. You should not do both.

Dosage Forms & Strengths

tablet

• 1mg
• 5mg

Renal Cell Carcinoma

Indicated for treatment of advanced renal cell carcinoma after failure of 1 prior systemic therapy

Initial dose: 5 mg PO q12hr (see Dosage Modifications)

Dosage Modifications

Dose increase or reduction based on individual safety and tolerability

Dose escalation

• Criteria: Tolerated for at least 2 consecutive weeks with no adverse reactions (ie, not exceeding grade 2 toxicities) and are normotensive and not receiving antihypertension medications
• First dose increase: 7 mg PO BID
• Second dose increase: Using the same criteria, may further increase to 10 mg PO BID

Dose reduction or discontinuation

• Hypertension: If persistent hypertension occurs despite antihypertensive medications, reduce dose; discontinue if hypertension is severe and persists despite dose reduction
• Hypertensive crisis: Discontinue axitinib
• Hemorrhage: If any bleeding requires medical intervention, temporarily interrupt axitinib dose
• Surgery: Discontinue at least 24 hr prior to scheduled surgery
• Reversible posterior leukoencephalopathy syndrome: Discontinue axitinib
• Moderate-to-severe proteinuria: Reduce dose or temporarily interrupt treatment
• Strong CYP3A4/5 inhibitors: Avoid coadministration if possible, if axitinib must be coadministered, decrease dose by ~50% and then adjust according to safety and tolerance; if strong CYP3A4/5 inhibitor is discontinued, may increase to prior axitinib dose after waiting 3-5 half-lives of the inhibitor

Renal & Hepatic Impairment

Renal impairment

• No dedicated renal impairment trial has been conducted
• Based on population pharmacokinetic analyses, no significant difference in clearance observed in patients with pre-existing mild-to-severe renal impairment

Hepatic impairment

• Mild (Child-Pugh A): No adjustment of initial dose is required
• Moderate (Child-Pugh B): Decrease initial dose by ~50%; subsequent doses can be increased or decreased based on individual safety and tolerability
• Severe (Child-Pugh C): Has not been studied

Administration

Administer twice daily approximately 12 hr apart

May be taken with or without food

Swallow whole with a glass of water; do not split, crush, or chew

If patient vomits or misses a dose, an additional dose should not be taken; the next prescribed dose should be taken at the usual time

<18 years: Safety and efficacy not established

In clinical trials, 34% of participants 65 years or older

No overall differences were observed in the safety or efficacy between elderly and younger patients

No dosage adjustment required in elderly patients

>10%

Diarrhea (55%)

Hypertension (40%)

Fatigue (39%)

Decreased appetite (34%)

Nausea (32%)

Dysphonia (31%)

Palmar-plantar erythrodysesthesia syndrome (27%)

Weight decreased (25%)

Vomiting (24%)

Asthenia (21%)

Constipation (20%)

Hypothyroidism (19%)

Cough (15%)

Mucosal inflammation (15%)

Arthralgia (15%)

Stomatitis (15%)

Dyspnea (15%)

Abdominal pain (14%)

Headache (14%)

Extremity pain (13%)

Rash (13%)

Proteinuria (11%)

Dysgeusia (11%)

1-10%

Dry skin (10%)

Dyspepsia (10%)

Dizziness (9%)

Upper abdominal pain (8%)

Myalgia (7%)

Pruritus (7%)

Dehydration (6%)

Epistaxis (6%)

Hypercalcemia (6%)

Anemia (4%)

Alopecia (4%)

Hemorrhoids (4%)

Hematuria (3%)

Tinnitus (3%)

Increased lipase (3%)

Glossodynia (3%)

Pulmonary embolism (2%)

Rectal hemorrhage (2%)

Hemoptysis (2%)

Erythema (2%)

DVT (1%)

Retinal vein occlusion/thrombosis (1%)

Polycythemia (1%)

TIA (1%)

<1%

Reversible posterior leukoencephalopathy syndrome

Pregnancy Category: D; can cause fetal harm when administered to a pregnant woman based on its mechanism of action; axitinib was teratogenic, embryotoxic, and fetotoxic in mice at exposures lower than human exposures at the recommended starting dose

Lactation: Unknown whether distributed in breast milk; because of the potential for serious adverse reactions in nursing infants from axitinib, a decision should be made whether to discontinue breast feeding or to discontinue the drug, taking into account the importance of the drug to the mother

Pregnancy Categories

A:Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B:May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C:Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D:Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X:Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA:Information not available.

Metabolized principally by CYP3A4/5 and, to a lesser extent, by CYP1A2, CYP2C19, and uridine diphosphate-glucurosyltransferase (UGT) 1A1.1 6

Has potential to inhibit CYP isoenzymes 1A2 and 2C8 in vitro.1

In vitro studies indicate that axitinib does not inhibit CYP2A6, 2C9, 2C19, 2D6, 2E1, 3A4/5, or UGT1A1 at therapeutic plasma concentrations.1

Inhibition of P-glycoprotein (P-gp) not expected at therapeutic plasma concentrations.1

Axitinib does not induce CYP1A1, CYP1A2, or CYP3A4/5 in human hepatocytes in vitro.1

Drugs and Foods Affecting Hepatic Microsomal Enzymes

Potent CYP3A4/5 inhibitors: Possible pharmacokinetic interaction (increased plasma concentrations of axitinib).1 6 Avoid concomitant use; select an alternative agent with no or minimal enzyme inhibition potential.1 6 If concomitant therapy cannot be avoided, reduce axitinib dosage by approximately 50%; may increase or decrease subsequent dosages based on individual safety and tolerability.1 If the potent CYP3A4/5 inhibitor is discontinued, resume axitinib (after 3–5 elimination half-lives of the CYP3A4/5 inhibitor) at the dosage used prior to initiation of the potent CYP3A4/5 inhibitor.1 (See Specific Drugs and Foods under Interactions.)

CYP3A4/5 inducers: Possible pharmacokinetic interaction (decreased plasma concentrations of axitinib).1 Avoid concomitant use of potent CYP3A4/5 inducers; select an alternative agent with no or minimal enzyme induction potential.1 Also avoid concomitant use of moderate CYP3A4/5 inducers if possible.1 (See Specific Drugs and Foods under Interactions.)

Drugs Metabolized by Hepatic Microsomal Enzymes

Substrates of CYP isoenzymes 1A2 or 2C8: Clinically important pharmacokinetic interactions unlikely.1

Drugs Affecting Gastric Acidity

Pharmacokinetic interaction (possible decreased solubility of axitinib) with drugs that increase pH of upper GI tract.1 9 Clinically important pharmacokinetic interaction unlikely.1 9

Specific Drugs and Foods

Absorption

Bioavailability

Readily absorbed following oral administration; peak plasma concentrations are attained within 2.5–4.1 hours.1 8

Steady-state concentrations expected within 2–3 days.1

Mean absolute bioavailability after single-dose oral administration is 58%.1

Food

Administration with a high-fat, high-calorie meal increased AUC by 19% compared with overnight fasting; administration with a moderate fat meal decreased AUC by 10%.1

Special Populations

Mild hepatic impairment (Child-Pugh class A) does not substantially affect systemic exposure.1 Moderate hepatic impairment (Child-Pugh class B) increases systemic exposure.1 Not studied in severe hepatic impairment (Child-Pugh class C).1 (See Hepatic Impairment under Dosage and Administration.)

Distribution

Extent

Not known whether distributed into human milk.1

Plasma Protein Binding

>99% (preferentially to albumin and moderately to α1-acid glycoprotein).1

Elimination

Metabolism

Predominantly metabolized in liver by CYP3A4/5 and, to a lesser extent, by CYP1A2, CYP2C19, and UGT1A1.1 8

Elimination Route

Primarily eliminated in feces (approximately 41%), mainly as unchanged drug, and in urine (approximately 23%), mainly as carboxylic acid and sulfoxide metabolites.1

Half-life

2.5–6.1 hours.1

Special Populations

Mild to severe renal impairment did not substantially alter clearance of axitinib in a population pharmacokinetic analysis.1 Data in end-stage renal disease very limited.1

Storage

Oral

20–25°C.1

• Importance of reading the manufacturer’s patient information prior to beginning axitinib therapy and rereading it each time the prescription is refilled.1

• If a dose of axitinib is missed or vomited, take the next dose at the regularly scheduled time.1 Do not take more than one dose at a time.1

• Importance of swallowing axitinib tablets whole with a glass of water.1 Avoid grapefruit or grapefruit juice while taking the drug.1

• Risk of hypertension.1 Importance of monitoring BP regularly during treatment.1

• Risk of arterial and venous thromboembolic events.1 Importance of getting emergency help and contacting clinician if any symptoms suggestive of a thromboembolic event occur (e.g., chest pain or pressure, shortness of breath, unilateral numbness or weakness, difficulty talking, headache, vision changes, or arm, back, neck, or jaw pain).1

• Risk of bleeding.1 Importance of promptly informing clinician of any episodes of bleeding (e.g., unusual bleeding, bruising).1

• Risk of GI disorders.1 Importance of advising patients that GI disorders such as diarrhea, nausea, vomiting, and constipation may develop and to seek immediate medical attention if symptoms of GI perforation or fistula (e.g., persistent or severe abdominal pain, vomiting blood, red or black stools) occur.1

• Risk of thyroid dysfunction.1 Importance of informing clinician if symptoms of thyroid dysfunction occur (e.g., persistent or worsening fatigue, deepened voice, hair loss, weight gain or loss, myalgia, feeling hot or cold).1

• Risk of wound healing complications.1 Importance of informing clinician of any scheduled surgery or wounds that do not heal.1

• Risk of reversible posterior leukoencephalopathy syndrome (RPLS).1 Importance of immediately informing clinician if headache, seizures, weakness, lethargy, confusion, hypertension, blindness, or other visual and neurologic disturbances occur.1

• Risk of fetal harm and fetal loss.1 Importance of women informing their clinicians if they are or plan to become pregnant.1 Importance for men who are taking axitinib to inform their clinician if their female partner becomes pregnant.1 Necessity of advising women and men receiving axitinib to use effective methods of contraception during axitinib therapy.1 Necessity of advising women to avoid pregnancy during therapy.1 Advise women of the potential risk to the fetus (e.g., birth defects) and/or the potential risk for loss of the pregnancy.1

• Importance of advising women to avoid breast-feeding while receiving axitinib.1

• Risk of proteinuria and importance of monitoring for proteinuria before and during therapy.1

• Risk of hepatotoxicity; importance of liver function test monitoring during therapy.1

• Importance of informing clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements (e.g., St. John’s wort), as well as any concomitant illnesses (e.g., hypertension or other cardiovascular disease, cerebrovascular disease, thyroid disease, hepatic disease, bleeding disorders).1

• Importance of informing patients of other important precautionary information.1 (See Cautions.)

All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if any of these side effects or any other side effects bother you or do not go away:

• Belly pain.
• Change in taste.
• Loose stools (diarrhea).
• Feeling tired or weak.
• Headache.
• Upset stomach or throwing up.
• Weight loss.
• Not hungry.
• Mouth irritation or mouth sores.
• Hard stools (constipation).
• Joint pain.
• Dry skin.
• Cough.

These are not all of the side effects that may occur. If you have questions about side effects, call your doctor. Call your doctor for medical advice about side effects.

You may report side effects to the FDA at 1-800-FDA-1088. You may also report side effects at http://www.fda.gov/medwatch.

(ax I ti nib)

Renal cell carcinoma, advanced: Treatment of advanced renal cell carcinoma after failure of one prior systemic therapy.

Concerns related to adverse effects:

• Cardiac effects: Cardiac failure, including fatal events, has been observed rarely. Monitor for signs/symptoms of cardiac failure throughout therapy; management may require permanent therapy discontinuation.

• Gastrointestinal events: Gastrointestinal perforation and fistulas (including a fatality) have been reported. Monitor for signs/symptoms throughout treatment.

• Hemorrhage: Hemorrhagic events (cerebral hemorrhage, gastrointestinal hemorrhage, hematuria, hemoptysis, and melena) have been reported (with some fatalities). Temporarily interrupt treatment with any hemorrhage requiring medical intervention.

• Hypertension: May cause hypertension; the median onset is within the first month, and has been observed as early as 4 days after treatment initiation. Hypertensive crisis has been reported. Blood pressure should be well-controlled prior to treatment initiation. Monitor blood pressure and treat with standard antihypertensive therapy. Persistent hypertension (despite antihypertensive therapy) may require dose reduction; discontinue if severe and persistent despite concomitant antihypertensives (or dose reduction), or with evidence of hypertensive crisis. Monitor for hypotension if on antihypertensive therapy and axitinib is withheld or discontinued.

• Proteinuria: Proteinuria is associated with use. Monitor for proteinuria at baseline and periodically throughout therapy. If moderate or severe proteinuria occurs, reduce dose or temporarily withhold treatment.

• Reversible posterior leukoencephalopathy syndrome (RPLS): Cases of RPLS have been reported. Symptoms of RPLS include confusion, headache, hypertension (mild-to-severe), lethargy, seizure, blindness and/or other vision or neurologic disturbances; interrupt treatment and manage hypertension. MRI is recommended to confirm RPLS diagnosis. Discontinue axitinib if RPLS is confirmed. The safety of reinitiating axitinib in patients previously experiencing RPLS is unknown.

• Thrombotic events: Arterial thrombotic events (cerebrovascular accident, MI, retinal artery occlusion, and transient ischemic attack), with fatalities, have been reported. Venous thrombotic events, including pulmonary embolism, deep vein thrombosis, retinal vein occlusion and retinal vein thrombosis, have been observed (with some fatalities). Use with caution in patients with a history of or risks for arterial or venous thrombotic events; has not been studied in patients within 12 months of an arterial thrombotic event or within 6 months of a venous thrombotic event.

• Thyroid dysfunction: Hypothyroidism occurs commonly with tyrosine kinase inhibitors, including axitinib. Hyperthyroidism has also been reported. Monitor thyroid function at baseline and periodically throughout therapy. Thyroid disorders should be treated according to standard practice to achieve/maintain euthyroid state.

• Wound healing complications: Although the effect on wound healing has not been studied with axitinib, vascular endothelial growth factor (VEGF) receptor inhibitors are associated with impaired wound healing. Discontinue treatment at least 24 hours prior to scheduled surgery; treatment reinitiation should be guided by clinical judgment and wound assessment.

Disease-related concerns:

• Brain metastases: Has not been studied in patients with evidence of untreated brain metastases; use is not recommended.

• Gastrointestinal bleeding: Has not been studied in patients with recent active gastrointestinal bleeding; use is not recommended.

• Hepatic impairment: Systemic exposure to axitinib is increased in patients with moderate impairment (Child-Pugh class B); dose reductions are recommended. Has not been studied in patients with severe impairment (Child-Pugh class C). Increases in ALT have been observed; monitor liver function tests prior to therapy initiation and periodically throughout treatment.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

• Kidney Cancer

Applies to axitinib: oral tablet

General

The most common adverse reactions included diarrhea, hypertension, fatigue, decreased appetite, nausea, dysphonia, hand-foot syndrome, decreased weight, vomiting, asthenia, and constipation.[Ref]

Cardiovascular

Very common (10% or more): Hypertension (40%)
Common (1% to 10%): Deep vein thrombosis, cardiac failure events, venous thromboembolic events, arterial thromboembolic events, myocardial infarction
Rare (less than 0.1%): Hypertensive crisis[Ref]

Hypertension has been reported in up to 40% or patients, with grade 3 or 4 hypertension and hypertensive crisis in 16% and less than 1% of those patients, respectively. The median onset time for hypertension was within the first month, with increases observed as early as 4 days after starting the drug. Less than 1% of patients discontinued therapy due to hypertension.

Arterial thromboembolic events including transient ischemic attacks, cerebrovascular accidents, myocardial infarctions, and retinal artery occlusions were reported in 2% of patients (17 of 715) and venous thromboembolic events including pulmonary embolism, deep vein thrombosis, retinal vein occlusion, and retinal vein thrombosis were reported in 3% of patients (22 of 715).

Cardiac failure was reported in 2% (6 of 359) patients; grade 3 or 4 in 1% (2 of 359).[Ref]

Nervous system

Very common (10% or more): Headache (15%), dysgeusia (11%)
Common (1% to 10%): Dizziness, transient ischemic attack
Rare (less than 0.1%): Posterior reversible encephalopathy syndrome
Frequency not reported: Cerebrovascular accidents[Ref]

Arterial thromboembolic events including transient ischemic attacks, cerebrovascular accidents, myocardial infarctions, and retinal artery occlusions were reported in 2% of patients (17 of 715).

Three cases of reversible posterior leukoencephalopathy syndrome (RPLS), also known as posterior reversible encephalopathy syndrome (PRES) were reported during clinical trials.[Ref]

Ocular

Arterial thromboembolic events including transient ischemic attacks, cerebrovascular accidents, myocardial infarctions, and retinal artery occlusions were reported in 2% of patients (17 of 715). Venous thromboembolic events including pulmonary embolism, deep vein thrombosis, retinal vein occlusion, and retinal vein thrombosis were reported in 3% of patients (22 of 715).[Ref]

Common (1% to 10%): Retinal vein occlusion/thrombosis
Frequency not reported: Retinal artery occlusions[Ref]

Gastrointestinal

Very common (10% or more): Diarrhea (55%), nausea (32%), vomiting (24%), constipation (20%), stomatitis (15%), abdominal pain (14%), increased lipase (27%), increased amylase (25%)
Common (1% to 10%): Upper abdominal pain, hemorrhoids, glossodynia, rectal hemorrhage, dyspepsia, flatulence
Uncommon (0.1% to 1%): Gastrointestinal perforation, fistulas
Frequency not reported: Lower gastrointestinal hemorrhage, melena[Ref]

Hepatic

Very common (10% or more): Transaminase increases (20% to 22%), alkaline phosphatase increases (30%), hypoalbuminemia (15%)[Ref]

Renal

Very common (10% or more): Increased creatinine (55%), proteinuria (11%)
Common (1% to 10%): Hematuria, renal failure[Ref]

Other

Very common (10% or more): Fatigue (39%), asthenia (21%),
Common (1% to 10%): Tinnitus[Ref]

Dermatologic

Very common (10% or more): Hand-foot syndrome (27%), rash (13%)
Common (1% to 10%): Pruritus, alopecia, erythema, dry skin[Ref]

Endocrine

Hypothyroidism was reported in 20.9% of patients and hyperthyroidism in 1.1%. Among patients with TSH levels less than 5 micromoles/mL prior to treatment, elevations to greater 10 micromoles/mL occurred in greater than 32.2%[Ref]

Very common (10% or more): Hypothyroidism (20%),
Common (1% to 10%): Hyperthyroidism, increased thyroid stimulating hormone (TSH)[Ref]

Hematologic

Very common (10% or more): Decreased hemoglobin (35%), decreased lymphocytes (33%) decreased platelets (15%), WBC decreased (11%)
Common (1% to 10%): Anemia, polycythemia, increased hemoglobin
Uncommon (0.1% to 1%): Neutropenia, leukopenia[Ref]

Metabolic

Very common (10% or more): Decreased appetite (34%), weight loss (25%), decreased bicarbonate (44%), hypocalcemia (39%), hyperglycemia (28%), hypernatremia (17%), hyperkalemia (15%), hypoglycemia (11%), hyponatremia (13%), hypophosphatemia (13%)
Common (1% to 10%): Dehydration[Ref]

Musculoskeletal

Very common (10% or more): Arthralgia (15%), extremity pain (14%),
Common (1% to 10%): Myalgia,[Ref]

Respiratory

Very common (10% or more): Dysphonia (31%), cough (15%), mucosal inflammation (15%), dyspnea (15%)
Common (1% to 10%): Epistaxis, pulmonary embolism, hemoptysis[Ref]

Venous thromboembolic events including pulmonary embolism, deep vein thrombosis, retinal vein occlusion, and retinal vein thrombosis were reported in 3% of patients (22 of 715).[Ref]

Some side effects of axitinib may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.