Important Safety Information
WARNING: PERFORATIONS AND FISTULAS, and HEMORRHAGE
- Perforations and Fistulas: Gastrointestinal perforations occurred in 3% and fistula formation in 1% of COMETRIQ®-treated patients. Discontinue COMETRIQ® in patients with perforation or fistula.
- Hemorrhage: Severe, sometimes fatal, hemorrhage including hemoptysis and gastrointestinal hemorrhage occurred in 3% of COMETRIQ®-treated patients. Monitor patients for signs and symptoms of bleeding. Do not administer COMETRIQ® to patients with severe hemorrhage.
Perforations and Fistulas: Serious gastrointestinal (GI) perforations and fistulas were reported, of which one GI fistula was fatal. Non-GI fistulas including tracheal/esophageal were reported in 4% of COMETRIQ®-treated patients. Two of these were fatal. Monitor patients for symptoms of perforations and fistulas.
Hemorrhage: Serious and sometimes fatal hemorrhage occurred with COMETRIQ®. Events Grade ≥3 occurred in 3% COMETRIQ® patients vs 1% receiving placebo. Do not administer COMETRIQ® to patients with a recent history of hemorrhage or hemoptysis.
Thrombotic Events: COMETRIQ® treatment results in an increased incidence vs placebo of venous thromboembolism (6% vs 3%) and arterial thromboembolism (2% vs 0%). Discontinue COMETRIQ® in patients who develop an acute myocardial infarction, cerebral infarction, or other serious arterial thromboembolic event.
Wound Complications: Wound complications have been reported with COMETRIQ®. Stop treatment with COMETRIQ® at least 28 days prior to scheduled surgery. Resume COMETRIQ® therapy after surgery based on clinical judgment of adequate wound healing. Withhold COMETRIQ® in patients with dehiscence or wound healing complications requiring medical intervention.
Hypertension: COMETRIQ® treatment results in an increased incidence of treatment-emergent hypertension vs placebo (61% vs 30%). Monitor blood pressure prior to initiation and 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 hypertensive crisis or severe hypertension that cannot be controlled with anti-hypertensive therapy.
Osteonecrosis of the Jaw (ONJ): 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. For invasive dental procedures, withhold COMETRIQ® treatment for at least 28 days prior to scheduled surgery, if possible. Discontinue COMETRIQ® in patients who develop ONJ.
Palmar-Plantar Erythrodysesthesia Syndrome (PPES): PPES occurred in 50% of patients treated with COMETRIQ® and was severe (Grade 3) in 13% of patients. Withhold COMETRIQ® in patients who develop intolerable Grade 2 PPES or Grade 3 PPES until improvement to Grade 1; resume COMETRIQ® at a reduced dose.
Proteinuria: Proteinuria was observed in 2% of patients receiving COMETRIQ®, including 1 patient with nephrotic syndrome, vs 0% in placebo. Monitor urine protein regularly during COMETRIQ® treatment. Discontinue COMETRIQ® in patients who develop nephrotic syndrome.
Reversible Posterior Leukoencephalopathy Syndrome (RPLS): RPLS occurred in 1 patient. Evaluate for RPLS in patients presenting with seizures, headache, visual disturbances, confusion, or altered mental function. Discontinue COMETRIQ® in patients who develop RPLS.
Embryo-fetal Toxicity: COMETRIQ® can cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during COMETRIQ® treatment and for 4 months after the last dose.
The most commonly reported adverse drug reactions (≥25% and ≥5% difference from placebo) were diarrhea (63% vs 33%), stomatitis (51% vs 6%), PPES (50% vs 2%), decreased weight (48% vs 10%), decreased appetite (46% vs 16%), nausea (43% vs 21%), fatigue (41% vs 28%), oral pain (36% vs 6%), hair color changes (34% vs 1%), dysgeusia (34% vs 6%), hypertension (33% vs 4%), abdominal pain (27% vs 13%), and constipation (27% vs 6%).
The most common laboratory abnormalities (≥25%) were increased AST (86% vs 35%), increased ALT (86% vs 41%), lymphopenia (53% vs 51%), increased ALP (52% vs 35%), hypocalcemia (52% vs 27%), neutropenia (35% vs 15%), thrombocytopenia (35% vs 4%), hypophosphatemia (28% vs 10%), and hyperbilirubinemia (25% vs 14%).
Increased levels of thyroid stimulating hormone (TSH) were observed in 57% of patients receiving COMETRIQ® (vs 19% receiving placebo).
In clinical trials, the dose was reduced in 79% of patients receiving COMETRIQ® compared to 9% of patients receiving placebo. The median number of dosing delays was one in patients receiving COMETRIQ® compared to none in patients receiving placebo. Adverse reactions led to study treatment discontinuation in 16% of patients receiving COMETRIQ® and in 8% of patients receiving placebo.
Drug Interactions: Strong CYP3A4 inhibitors—Reduce the dosage of COMETRIQ® if concomitant use with strong CYP3A4 inhibitors cannot be avoided. Strong CYP3A4 inducers—Increase the dosage of COMETRIQ® if concomitant use with strong CYP3A4 inducers cannot be avoided.
Lactation: Advise a lactating woman not to breastfeed during COMETRIQ® treatment with COMETRIQ® and for 4 months after the final dose.
Reproductive Potential: Infertility—COMETRIQ® may impair fertility in females and males of reproductive potential.
Hepatic Impairment: Reduce the COMETRIQ® dosage in patients with mild to moderate hepatic impairment. COMETRIQ® is not recommended for use in patients with severe hepatic impairment.
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MET=hepatocyte growth factor receptor; VEGFR=vascular endothelial cell growth factor receptor; RET=rearranged during transfection. HGF=hepatocyte growth factor; GDNF=glial cell line–derived neurotrophic factor; GFRα-1=glial cell line–derived neurotrophic factor receptor.