Amlodipine - Warnings and Precautions

5 WARNINGS AND PRECAUTIONS • Myopathy and Rhabdomyolysis: Risk factors include age 65 years or greater, uncontrolled hypothyroidism, renal impairment, concomitant use with certain other drugs, and higher CADUET dosage.

Discontinue CADUET if markedly elevated CK levels occur or myopathy is diagnosed or suspected.

Temporarily discontinue CADUET in patients experiencing an acute or serious condition at high risk of developing renal failure secondary to rhabdomyolysis.

Inform patients of the risk of myopathy and rhabdomyolysis when starting or increasing CADUET dosage.

Instruct patients to promptly report unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever ( 2 , 5.1 , 7.3 , 8.5 , 8.6 ). • Immune-Mediated Necrotizing Myopathy (IMNM): Rare reports of IMNM, an autoimmune myopathy, have been reported with statin use.

Discontinue CADUET if IMNM is suspected . • Hepatic Dysfunction: Increases in serum transaminases have occurred, some persistent.

Rare reports of fatal and non-fatal hepatic failure have occurred.

Consider testing liver enzymes before initiating therapy and as clinically indicated thereafter.

If serious hepatic injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs, promptly discontinue CADUET . • Angina or myocardial infarction may occur with initiation or dose increase . • Symptomatic hypotension is possible, particularly in patients with severe aortic stenosis.

However, acute hypotension is unlikely .

5.1 Myopathy and Rhabdomyolysis CADUET may cause myopathy (muscle pain, tenderness, or weakness associated with elevated creatine kinase [CK]) and rhabdomyolysis.

Acute kidney injury secondary to myoglobinuria and rare fatalities have occurred as a result of rhabdomyolysis in patients treated with statins, including CADUET.

Risk Factors for Myopathy Risk factors for myopathy include age 65 years or greater, uncontrolled hypothyroidism, renal impairment, concomitant use with certain other drugs (including other lipid-lowering therapies), and higher CADUET dosage [see Drug Interactions and Use in Specific Populations ( 8.5 , 8.6 )].

Steps to Prevent or Reduce the Risk of Myopathy and Rhabdomyolysis CADUET exposure may be increased by drug interactions due to inhibition of cytochrome P450 enzyme 3A4 (CYP3A4) and/or transporters (e.g., breast cancer resistant protein [BCRP], organic anion-transporting polypeptide [OATP1B1/OATP1B3] and P-glycoprotein [P-gp]), resulting in an increased risk of myopathy and rhabdomyolysis.

Concomitant use of cyclosporine, gemfibrozil, tipranavir plus ritonavir or glecaprevir plus pibrentasvir with CADUET is not recommended.

CADUET dosage modifications are recommended for patients taking certain anti-viral, azole antifungals, or macrolide antibiotic medications [see Dosage and Administration ] .

Cases of myopathy/rhabdomyolysis have been reported with atorvastatin co-administered with lipid modifying doses (> 1 gram/day) of niacin, fibrates, colchicine, and ledipasvir plus sofosbuvir [see Adverse Reactions ] .

Consider if the benefit of use of these products outweighs the increased risk of myopathy and rhabdomyolysis [see Drug Interactions ] .

Concomitant intake of large quantities, more than 1.2 liters daily, of grapefruit juice is not recommended in patients taking CADUET [see Drug Interactions ] .

Discontinue CADUET if markedly elevated CK levels occur or if myopathy is either diagnosed or suspected.

Muscle symptoms and CK elevations may resolve if CADUET is discontinued.

Temporarily discontinue CADUET in patients experiencing an acute or serious condition at high risk of developing renal failure secondary to rhabdomyolysis (e.g., sepsis; shock; severe hypovolemia; major surgery; trauma; severe metabolic, endocrine, or electrolyte disorders; or uncontrolled epilepsy).

Inform patients of the risk of myopathy and rhabdomyolysis when starting or increasing the CADUET dosage.

Instruct patients to promptly report any unexplained muscle pain, tenderness or weakness, particularly if accompanied by malaise or fever.

5.2 Immune-Mediated Necrotizing Myopathy There have been rare reports of immune-mediated necrotizing myopathy (IMNM), an autoimmune myopathy, associated with statin use, including reports of recurrence when the same or a different statin was administered.