Cometriq

Warnings and Precautions, Hypocalcemia
(

COMETRIQ is indicated for the treatment of patients with progressive, metastatic medullary thyroid cancer (MTC).

Capsules:

20-mg gelatin capsules, grey with "XL184 20mg" printed in black on the body of the capsule.

80-mg gelatin capsules, Swedish orange with "XL184 80mg" printed in black on the body of the capsule.

• Lactation: Advise not to breastfeed. (
  8.2 Lactation

  Risk Summary

  There is no information regarding the presence of cabozantinib or its metabolites in human milk, or their effects on the breastfed infant, or milk production. Because of the potential for serious adverse reactions in a breastfed infant from COMETRIQ, advise a lactating woman not to breastfeed during treatment with COMETRIQ and for 4 months after the final dose.
  )

• Perforations and Fistulas: Monitor for symptoms. Discontinue COMETRIQ
  for Grade 4 fistula or perforation. (
  5.1 Perforations and Fistulas

  Gastrointestinal (GI) perforations and fistulas, including fatal cases, were reported in 3% and 1% of COMETRIQ-treated patients (N=214), respectively. Non-GI fistulas including tracheal/esophageal, including fatal cases, were reported in 4% of COMETRIQ-treated patients.

  Monitor patients for symptoms of perforations and fistulas, including abscess and sepsis. Discontinue COMETRIQ in patients who experience a Grade 4 fistula or a GI perforation

  [see Dosage and Administration (2.2)]

  .
  )
• Hemorrhage: Do not administer COMETRIQ if recent history of hemorrhage. (
  5.2 Hemorrhage

  Severe and fatal hemorrhage occurred with COMETRIQ. The incidence of Grade ≥ 3 hemorrhagic events was higher in COMETRIQ-treated patients compared with placebo (3% vs. 1%).

  Discontinue COMETRIQ for Grade 3 or 4 hemorrhage

  [see Dosage and Administration (2.2)]

  . Do not administer COMETRIQ to patients with a recent history of hemorrhage, including hemoptysis, hematemesis, or melena.
  )
• Thrombotic Events: Discontinue COMETRIQ for myocardial infarction or serious arterial or venous thromboembolic events. (
  5.3 Thrombotic Events

  COMETRIQ increased the incidence of thrombotic events (venous thromboembolism: 6% vs. 3% and arterial thromboembolism: 2% vs. 0% in COMETRIQ-treated and placebo-treated patients, respectively).

  Discontinue COMETRIQ in patients who develop an acute myocardial infarction or arterial or venous thromboembolic events that require medical intervention

  [see Dosage and Administration (2.2)]

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

  Wound complications have been reported with COMETRIQ. Withhold COMETRIQ for at least 3 weeks prior to elective surgery. Do not administer COMETRIQ for at least 2 weeks after major surgery and until adequate wound healing. The safety of resumption of COMETRIQ after resolution of wound healing complications has not been established.
  )
• Hypertension and hypertensive crisis: Monitor blood pressure regularly. Interrupt for hypertension that is not adequately controlled with anti- hypertensive therapy. Discontinue COMETRIQ for hypertensive crisis or severe hypertension that cannot be controlled with anti-hypertensive therapy. (
  5.5 Hypertension and Hypertensive Crisis

  COMETRIQ can cause hypertension, including hypertensive crisis. Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (modified JNC criteria) stage 1 or 2 hypertension was identified in 61% in COMETRIQ-treated patients compared with 30% of placebo-treated patients in the randomized trial

  [see Adverse Reactions (6.1)]

  .

  Do not initiate COMETRIQ in patients with uncontrolled hypertension. Monitor blood pressure regularly during COMETRIQ treatment. Withhold COMETRIQ for hypertension that is not adequately controlled with medical management; when controlled, resume COMETRIQ at a reduced dose. Discontinue COMETRIQ for severe hypertension that cannot be controlled with anti-hypertensive therapy and for hypertensive crisis

  [see Dosage and Administration (2.2)]

  .
  )
• Osteonecrosis of the Jaw (ONJ): Withhold COMETRIQ for at least 3 weeks prior to invasive dental procedure and for development of ONJ. (
  5.6 Osteonecrosis of the Jaw

  Osteonecrosis of the jaw (ONJ) occurred in 1% of COMETRIQ-treated patients. 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 COMETRIQ and periodically during COMETRIQ therapy. Advise patients regarding good oral hygiene practices. Withhold COMETRIQ treatment for at least 3 weeks prior to scheduled dental surgery, or invasive dental procedures, if possible. Withhold COMETRIQ for development of ONJ until complete resolution

  [see Dosage and Administration (2.2)]

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  )
• Diarrhea: May be severe. Interrupt COMETRIQ immediately until diarrhea resolves or decreases to Grade 1. Recommend standard antidiarrheal treatments. (
  5.7 Diarrhea

  Diarrhea occurred in 63% of patients treated with COMETRIQ. Grade 3-4 diarrhea occurred in 16% of patients treated with COMETRIQ

  [see Adverse Reactions (6.1)]

  .

  Withhold COMETRIQ until improvement to Grade 1 and resume COMETRIQ at a reduced dose for intolerable Grade 2 diarrhea, Grade 3 diarrhea that cannot be managed with standard antidiarrheal treatments, or Grade 4 diarrhea.
  )
• Palmar-Plantar Erythrodysesthesia (PPE): Interrupt COMETRIQ until PPE resolves or decreases to Grade 1. (
  5.8 Palmar-Plantar Erythrodysesthesia

  Palmar-plantar erythrodysesthesia (PPE) occurred in 50% of patients treated with COMETRIQ, including 13% Grade 3

  [see Adverse Reactions (6.1)]

  .

  Withhold COMETRIQ until improvement to Grade 1 and resume COMETRIQ at a reduced dose for intolerable Grade 2 PPE or Grade 3 PPE.
  )
• Proteinuria: Monitor urine protein. Discontinue for nephrotic syndrome. (
  5.9 Proteinuria

  Proteinuria was observed in 2% of patients receiving COMETRIQ, including one with nephrotic syndrome. Monitor urine protein regularly during COMETRIQ treatment. Discontinue COMETRIQ in patients who develop nephrotic syndrome.
  )
• Reversible Posterior Leukoencephalopathy Syndrome (RPLS): Discontinue COMETRIQ. (
  5.10 Reversible Posterior Leukoencephalopathy Syndrome

  Reversible Posterior Leukoencephalopathy Syndrome (RPLS), a syndrome of subcortical vasogenic edema diagnosed by characteristic finding on MRI, occurred in one (<1%) patient. Perform an evaluation for RPLS in any patient presenting with seizures, headache, visual disturbances, confusion or altered mental function. Discontinue COMETRIQ in patients who develop RPLS

  [see Dosage and Administration (2.2)]

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  )
• Embryo-Fetal Toxicity: Can cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus and to use effective contraception. (
  5.11 Embryo-Fetal Toxicity

  Based on data from animal studies and its mechanism of action, COMETRIQ 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 COMETRIQ and for 4 months after the last dose

  [see Use in Specific Populations, , and Clinical Pharmacology]

  .
  ,
  8.1 Pregnancy

  Risk Summary

  Based on findings from animal studies and its mechanism of action, COMETRIQ can cause fetal harm when administered to a pregnant woman

  [see Clinical Pharmacology]

  . There are no available data in pregnant women to inform the drug-associated risk. In animal developmental and reproductive toxicology studies administration of cabozantinib to pregnant rats and rabbits during organogenesis resulted in embryofetal lethality and structural anomalies at exposures that were below those occurring clinically at the recommended dose

  (see

  Data

  )

  . Advise pregnant women or women of childbearing potential of the potential hazard to a fetus.

  The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

  Data

  Animal Data

  In an embryo-fetal development study in pregnant rats, daily oral administration of cabozantinib throughout organogenesis caused increased embryo-fetal lethality compared to controls at a dose of 0.03 mg/kg (less than 1% of the human exposure by AUC at the 140 mg dose). Findings included delayed ossifications and skeletal variations at a dose of 0.01 mg/kg/day (approximately 0.03% of the human exposure by AUC at the 140 mg dose).

  In pregnant rabbits, daily oral administration of cabozantinib throughout organogenesis resulted in findings of visceral malformations and variations including reduced spleen size and missing lung lobe at 3 mg/kg (approximately 11% of the human exposure by AUC at the 140 mg dose).

  In a pre- and postnatal study in rats, cabozantinib was administered orally from gestation day 10 through postnatal day 20. Cabozantinib did not produce adverse maternal toxicity or affect pregnancy, parturition or lactation of female rats, and did not affect the survival, growth or postnatal development of the offspring at doses up to 0.3 mg/kg/day (approximately 0.02 times the recommended clinical dose of 140 mg based on body surface area).
  ,
  8.3 Females and Males of Reproductive Potential

  Pregnancy Testing

  Verify the pregnancy status of females of reproductive potential prior to initiating COMETRIQ

  [see Use in Specific Populations (8.1)]

  .

  Contraception

  COMETRIQ can cause fetal harm when administered to a pregnant woman

  [see Use in Specific Populations (8.1)]

  .

  Females

  Advise females of reproductive potential to use effective contraception during treatment with COMETRIQ and for 4 months after the final dose.

  Infertility

  Females and Males

  Based on findings in animals, COMETRIQ may impair fertility in females and males of reproductive potential

  [see Nonclinical Toxicology]

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  )
• Hypocalcemia: Monitor blood calcium levels and replace calcium as necessary during treatment. Withhold COMETRIQ and resume at reduced dose upon recovery or permanently discontinue COMETRIQ depending on severity. (
  5.12 Hypocalcemia

  COMETRIQ can cause hypocalcemia. Based on the safety population

  [see Clinical Trial Experience]

  , hypocalcemia occurred in 52% of patients treated with COMETRIQ, including Grade 3 or 4 in 12% of patients.

  Monitor blood calcium levels and replace calcium as necessary during treatment. Withhold and resume at a reduced dose upon recovery or discontinue COMETRIQ depending on severity

  [see Dosage and Administration]

  .
  )