CABOZANTINIB S-MALATE Drug Interactions: What You Need to Know

INTERACTIONS Strong CYP3A4 Inhibitors: Reduce the COMETRIQ dosage. ( 2.2 , 7.1 ) Strong CYP3A4 Inducers: Increase the COMETRIQ dosage. ( 2.2 , 7.2 )

7.1 Effect of CYP3A4 Inhibitors Administration of a strong CYP3A4 inhibitor, ketoconazole to healthy subjects increased single-dose plasma cabozantinib exposure by 38%. Avoid taking a strong CYP3A4 inhibitor (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole) while taking COMETRIQ or reduce the dosage of COMETRIQ if concomitant use with strong CYP3A4 inhibitors cannot be avoided <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.2 ), Clinical Pharmacology ( 12.3 )]</span> . Avoid ingestion of foods (e.g., grapefruit, grapefruit juice) or nutritional supplements that are known to inhibit cytochrome P450 while taking COMETRIQ.

7.2 Effect of CYP3A4 Inducers Administration of a strong CYP3A4 inducer, rifampin to healthy subjects decreased single-dose plasma cabozantinib exposure by 77%. Avoid chronic co-administration of strong CYP3A4 inducers (e.g., phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital, St. John’s Wort) with COMETRIQ or increase the dosage of COMETRIQ if concomitant use with strong CYP3A4 inducers cannot be avoided <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.2 ), Clinical Pharmacology ( 12.3 )]</span>.

7.3 Effect of MRP2 Inhibitors Concomitant administration of MRP2 inhibitors may increase the exposure to cabozantinib. Monitor patients for increased toxicity when MRP2 inhibitors (e.g., abacavir, adefovir, cidofovir, furosemide, lamivudine, nevirapine, ritonavir, probenecid, saquinavir, and tenofovir) are co-administered with COMETRIQ <span class="opacity-50 text-xs">[see Clinical Pharmacology ( 12.3 )]</span> .

None. None ( 4 )

AND PRECAUTIONS Hemorrhage: Do not administer CABOMETYX if recent history of hemorrhage. ( 5.1 ) Perforations and Fistulas: Monitor for symptoms. Discontinue CABOMETYX for Grade 4 fistula or perforation. ( 5.2 )

Thromboembolic

Events: Discontinue CABOMETYX for myocardial infarction or serious venous or arterial thromboembolic events. ( 5.3 ) Hypertension and Hypertensive Crisis: Monitor blood pressure regularly. Interrupt for hypertension that is not adequately controlled with anti-hypertensive therapy. Discontinue CABOMETYX for hypertensive crisis or severe hypertension that cannot be controlled with anti-hypertensive therapy. ( 5.4 )

Cardiac

Failure: Monitor patients for signs and symptoms of cardiac failure throughout treatment. ( 5.5 ) Diarrhea: May be severe. Interrupt CABOMETYX until diarrhea resolves or decreases to ≤Grade 1, resume at reduced dose. Recommend standard antidiarrheal treatments. ( 5.6 ) Palmar-Plantar Erythrodysesthesia (PPE): Interrupt CABOMETYX treatment until PPE resolves or decreases to Grade 1. ( 5.7 ) Hepatotoxicity: When used in combination with nivolumab, higher frequencies of Grade 3 and 4 ALT and AST elevation may occur than with CABOMETYX alone. Monitor liver enzymes before initiation of and periodically throughout treatment. Consider withholding CABOMETYX and/or nivolumab, initiating corticosteroid therapy, and/or permanently discontinuing the combination for severe or life- threatening hepatotoxicity. ( 5.8 )

Adrenal

Insufficiency: When used in combination with nivolumab, primary or secondary adrenal insufficiency may occur.

For Grade

2 or higher adrenal insufficiency, initiate symptomatic treatment, including hormone replacement as clinically indicated. Withhold CABOMETYX and/or nivolumab depending on severity. ( 5.9 ) Proteinuria: Monitor urine protein. Interrupt CABOMETYX until proteinuria resolves to ≤ Grade 1, resume CABOMETYX at a reduced dose. Discontinue for nephrotic syndrome. ( 5.10 ) Osteonecrosis of the jaw (ONJ): Withhold CABOMETYX for at least 3 weeks prior to invasive dental procedures and for development of ONJ. ( 5.11 )

Impaired Wound

Healing: Withhold CABOMETYX for at least 3 weeks before elective surgery. Do not administer for at least 2 weeks following major surgery and adequate wound healing. The safety of resumption of CABOMETYX after resolution of wound healing complications has not been established. ( 5.12 )

Reversible Posterior Leukoencephalopathy

Syndrome (RPLS): Discontinue CABOMETYX. ( 5.13 )

Thyroid

Dysfunction: Monitor thyroid function before and during treatment with CABOMETYX. ( 5.14 ) Hypocalcemia: Withhold CABOMETYX and resume at reduced dose upon recovery or permanently discontinue CABOMETYX depending on severity. ( 5.15 ) Embryo-Fetal Toxicity: Can cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus and to use effective contraception. ( 5.16 , 8.1 , 8.3 )

5.1 Hemorrhage CABOMETYX can cause severe and fatal hemorrhages. Do not administer CABOMETYX to patients who have a recent history of hemorrhage, including hemoptysis, hematemesis, or melena. The incidence of Grade 3 to 5 hemorrhagic events was 5% in CABOMETYX-treated patients in RCC, HCC, and DTC studies <span class="opacity-50 text-xs">[see Adverse Reactions (6.1) ]</span> . Withhold CABOMETYX for 3 weeks prior to scheduled surgery, including dental surgery to reduce the risk of hemorrhage. Permanently discontinue CABOMETYX for Grade 3 or 4 hemorrhage and prior to surgery as recommended <span class="opacity-50 text-xs">[see Dosage and Administration (2.3) , Warnings and Precautions (5.11 , 5.12) ]</span> .

5.2 Perforations and Fistulas CABOMETYX can cause gastrointestinal (GI) perforations and fistulas. Fistulas, including fatal cases, occurred in 1% of CABOMETYX-treated patients <span class="opacity-50 text-xs">[see [see Adverse Reactions (6.1) ]</span> . GI perforations, including fatal cases, occurred in 1% of CABOMETYX-treated patients. Monitor patients for signs and symptoms of fistulas and perforations, including abscess and sepsis. Discontinue CABOMETYX in patients who experience a Grade 4 fistula or a GI perforation <span class="opacity-50 text-xs">[see Dosage and Administration (2.3) ]</span> .

5.3 Thromboembolic Events CABOMETYX can cause arterial or venous thromboembolic events. Venous thromboembolism occurred in 7% (including 4% pulmonary embolism) and arterial thromboembolism occurred in 2% of CABOMETYX-treated patients. Fatal thromboembolic events occurred in CABOMETYX-treated patients <span class="opacity-50 text-xs">[see Adverse Reactions (6.1) ]</span> . Discontinue CABOMETYX in patients who develop an acute myocardial infarction or serious arterial or venous thromboembolic events that require medical intervention <span class="opacity-50 text-xs">[see Dosage and Administration (2.3) ]</span> .

5.4 Hypertension and Hypertensive Crisis CABOMETYX can cause hypertension, including hypertensive crisis <span class="opacity-50 text-xs">[see Adverse Reactions (6.1)]</span>. Hypertension was reported in 37% (16% Grade 3 and &lt;1% Grade 4) of CABOMETYX-treated patients. In CABINET (n=195) <span class="opacity-50 text-xs">[see Clinical Studies (14.4) ]</span> , hypertension was reported in 65% (26% Grade 3) of CABOMETYX-treated patients. Do not initiate CABOMETYX in patients with uncontrolled hypertension. Monitor blood pressure regularly during CABOMETYX treatment. Withhold CABOMETYX for hypertension that is not adequately controlled with medical management; when controlled, resume CABOMETYX at a reduced dose <span class="opacity-50 text-xs">[see Dosage and Administration (2.3) ]</span> . Permanently discontinue CABOMETYX for severe hypertension that cannot be controlled with anti-hypertensive therapy or for hypertensive crisis <span class="opacity-50 text-xs">[see Dosage and Administration (2.3) ]</span> .

5.5 Cardiac Failure CABOMETYX can cause severe and fatal cardiac failure <span class="opacity-50 text-xs">[see Adverse Reactions (6.1) ]</span> . Cardiac failure occurred in 0.5% of patients treated with CABOMETYX as a single agent, including fatal cardiac failure in 0.1% of patients. Median time to onset of cardiac failure was 73 days (range: 44 days to 159 days). Consider baseline and periodic evaluations of left ventricular ejection fraction. Monitor for signs and symptoms of cardiovascular events. Withhold and resume at a reduced dose upon recovery or permanently discontinue CABOMETYX depending on the severity <span class="opacity-50 text-xs">[see Dosage and Administration (2.3) ]</span> .

5.6 Diarrhea CABOMETYX can cause diarrhea. Diarrhea occurred in 62% of patients treated with CABOMETYX.

Grade

3 diarrhea occurred in 10% of patients treated with CABOMETYX [see Adverse Reactions (6.1) ] . Monitor and manage patients using antidiarrheals as indicated. Withhold CABOMETYX until improvement to ≤Grade 1, resume CABOMETYX at a reduced dose [see Dosage and Administration (2.3) ] .

5.7 Palmar-Plantar Erythrodysesthesia CABOMETYX can cause palmar-plantar erythrodysesthesia (PPE). PPE occurred in 45% of patients treated with CABOMETYX <span class="opacity-50 text-xs">[see Adverse Reactions (6.1) ]</span> .

Grade

3 PPE occurred in 13% of patients treated with CABOMETYX. Withhold CABOMETYX until improvement to Grade 1 and resume CABOMETYX at a reduced dose for intolerable Grade 2 PPE or Grade 3 PPE [see Dosage and Administration (2.3) ] .

5.8 Hepatotoxicity CABOMETYX in combination with nivolumab can cause hepatic toxicity with higher frequencies of Grades 3 and 4 ALT and AST elevations compared to CABOMETYX alone. Monitor liver enzymes before initiation of and periodically throughout treatment. Consider more frequent monitoring of liver enzymes as compared to when the drugs are administered as single agents. For elevated liver enzymes, interrupt CABOMETYX and nivolumab and consider administering corticosteroids <span class="opacity-50 text-xs">[see Dosage and Administration (2.3) ]</span> . With the combination of CABOMETYX and nivolumab, Grades 3 and 4 increased ALT or AST were seen in 11% of patients <span class="opacity-50 text-xs">[see Adverse Reactions (6.1) ]</span> . ALT or AST &gt;3 times ULN (Grade ≥2) was reported in 83 patients, of whom 23 (28%) received systemic corticosteroids; ALT or AST resolved to Grades 0-1 in 74 (89%). Among the 44 patients with Grade ≥2 increased ALT or AST who were rechallenged with either CABOMETYX (n=9) or nivolumab (n=11) as a single agent or with both (n=24), recurrence of Grade ≥2 increased ALT or AST was observed in 2 patients receiving CABOMETYX, 2 patients receiving nivolumab, and 7 patients receiving both CABOMETYX and nivolumab. Withhold and then resume CABOMETYX at a reduced dose based on severity <span class="opacity-50 text-xs">[see Dosage and Administration (2.3) ]</span> .

5.9 Adrenal Insufficiency CABOMETYX in combination with nivolumab can cause primary or secondary adrenal insufficiency. Adrenal insufficiency occurred in 4.7% (15/320) of patients treated with the combination of CABOMETYX and nivolumab including Grade 3 (2.2%), and Grade 2 (1.9%) adverse reactions <span class="opacity-50 text-xs">[see Adverse Reactions (6.1) ]</span> . Adrenal insufficiency led to permanent discontinuation of CABOMETYX and nivolumab in 0.9% and withholding of CABOMETYX and nivolumab in 2.8% of patients with RCC.

Approximately

80% (12/15) of patients with adrenal insufficiency received hormone replacement therapy, including systemic corticosteroids. Adrenal insufficiency resolved in 27% (n=4) of the 15 patients. Of the 9 patients in whom CABOMETYX with nivolumab was withheld for adrenal insufficiency, 6 reinstated treatment after symptom improvement; of these, all (n=6) received hormone replacement therapy and 2 had recurrence of adrenal insufficiency.

For Grade

2 or higher adrenal insufficiency, initiate symptomatic treatment, including hormone replacement as clinically indicated. Withhold CABOMETYX and/or nivolumab and resume CABOMETYX at a reduced dose depending on severity [see Dosage and Administration (2.3) ] .

5.10 Proteinuria CABOMETYX can cause proteinuria. Proteinuria was observed in 8% of patients receiving CABOMETYX <span class="opacity-50 text-xs">[see Adverse Reactions (6.1) ]</span> . Monitor urine protein regularly during CABOMETYX treatment.

For Grade

2 or 3 proteinuria, withhold CABOMETYX until improvement to ≤Grade 1 proteinuria, resume CABOMETYX at a reduced dose. Discontinue CABOMETYX in patients who develop nephrotic syndrome [see Dosage and Administration (2.3) ] .

5.11 Osteonecrosis of the Jaw CABOMETYX can cause osteonecrosis of the jaw (ONJ). ONJ occurred in &lt;1% of patients treated with CABOMETYX <span class="opacity-50 text-xs">[see Adverse Reactions (6.1) ]</span> . ONJ can manifest as jaw pain, osteomyelitis, osteitis, bone erosion, tooth or periodontal infection, toothache, gingival ulceration or erosion, persistent jaw pain or slow healing of the mouth or jaw after dental surgery. Perform an oral examination prior to initiation of CABOMETYX and periodically during CABOMETYX. Advise patients regarding good oral hygiene practices. Withhold CABOMETYX for at least 3 weeks prior to scheduled dental surgery or invasive dental procedures, if possible. Withhold CABOMETYX for development of ONJ until complete resolution, resume at a reduced dose <span class="opacity-50 text-xs">[see Dosage and Administration (2.3) ]</span> .

5.12 Impaired Wound Healing CABOMETYX can cause impaired wound healing <span class="opacity-50 text-xs">[see Adverse Reactions (6.1) ]</span> . Withhold CABOMETYX for at least 3 weeks prior to elective surgery <span class="opacity-50 text-xs">[see Dosage and Administration (2.1) ]</span> . Do not administer CABOMETYX for at least 2 weeks after major surgery and until adequate wound healing. The safety of resumption of CABOMETYX after resolution of wound healing complications has not been established <span class="opacity-50 text-xs">[see Dosage and Administration (2.1 , 2.3 )]</span> .

5.13 Reversible Posterior Leukoencephalopathy Syndrome CABOMETYX can cause reversible Posterior Leukoencephalopathy Syndrome (RPLS), a syndrome of subcortical vasogenic edema diagnosed by characteristic finding on MRI. Perform an evaluation for RPLS in any patient presenting with seizures, headache, visual disturbances, confusion or altered mental function. Discontinue CABOMETYX in patients who develop RPLS <span class="opacity-50 text-xs">[see Dosage and Administration (2.3) ]</span> .

5.14 Thyroid Dysfunction CABOMETYX can cause thyroid dysfunction, primarily hypothyroidism. Thyroid dysfunction occurred in 19% of patients treated with CABOMETYX, including Grade 3 in 0.4% of patients <span class="opacity-50 text-xs">[see Adverse Reactions (6.1) ]</span> . Assess patients for signs of thyroid dysfunction prior to the initiation of CABOMETYX and monitor for signs and symptoms of thyroid dysfunction during CABOMETYX treatment. Thyroid function testing and management of dysfunction should be performed as clinically indicated <span class="opacity-50 text-xs">[see Dosage and Administration (2.3) ]</span> .

5.15 Hypocalcemia CABOMETYX can cause hypocalcemia. Hypocalcemia occurred in 13% of patients treated with CABOMETYX, including Grade 3 in 2% and Grade 4 in 1% of patients <span class="opacity-50 text-xs">[see Adverse Reactions (6.1) ]</span> . Laboratory abnormality data were not collected in CABOSUN and CABINET. In COSMIC-311 (n=125) <span class="opacity-50 text-xs">[see Clinical Studies (14.3) ]</span> , hypocalcemia occurred in 36% of patients treated with CABOMETYX, including Grade 3 in 6% and Grade 4 in 3% of patients. Monitor blood calcium levels and replace calcium as necessary during treatment. Withhold and resume at reduced dose upon recovery or permanently discontinue CABOMETYX depending on severity <span class="opacity-50 text-xs">[see Dosage and Administration (2.3) ]</span> .

5.16 Embryo-Fetal Toxicity Based on data from animal studies and its mechanism of action, CABOMETYX can cause fetal harm when administered to a pregnant woman. Cabozantinib administration to pregnant animals during organogenesis resulted in embryolethality at exposures below those occurring clinically at the recommended dose, and in increased incidences of skeletal variations in rats and visceral variations and malformations in rabbits. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with CABOMETYX and for 4 months after the last dose <span class="opacity-50 text-xs">[see Use in Specific Populations (8.1 , 8.3) , Clinical Pharmacology (12.1) ]</span> .