Amlodipine Besylate and Atorvastatin Calcium (Page 2 of 13)

3 DOSAGE FORMS AND STRENGTHS

Amlodipine besylate and atorvastatin calcium tablets are formulated for oral administration in the following strength combinations:

Amlodipine besylate and atorvastatin calcium tablets 2.5 mg/10 mg are white to off-white, round, film coated tablets debossed ‘R’ on one side and ‘407’ on other side.

Amlodipine besylate and atorvastatin calcium tablets 2.5 mg/20 mg are white to off-white, round, film coated tablets debossed ‘R’ on one side and ‘408’ on other side.

Amlodipine besylate and atorvastatin calcium tablets 2.5 mg/40 mg are white to off-white, round, film coated tablets debossed ‘R’ on one side and ‘409’ on other side.

Amlodipine besylate and atorvastatin calcium tablets 5 mg/10 mg are white to off-white, oval shaped, film coated tablets debossed ‘R’ on one side and ‘410’ on other side.

Amlodipine besylate and atorvastatin calcium tablets 5 mg/20 mg are white to off-white, oval shaped, film coated tablets debossed ‘R’ on one side and ‘411’ on other side.

Amlodipine besylate and atorvastatin calcium tablets 5 mg/40 mg are white to off-white, oval shaped, film coated tablets debossed ‘R’ on one side and ‘412’ on other side.

Amlodipine besylate and atorvastatin calcium tablets 5 mg/80 mg are white to off-white, oval shaped, film coated tablets debossed ‘R’ on one side and ‘413’ on other side.

Amlodipine besylate and atorvastatin calcium tablets 10 mg/10 mg are blue, oval shaped, film coated tablets debossed ‘R’ on one side and ‘414’ on other side.

Amlodipine besylate and atorvastatin calcium tablets 10 mg/20 mg are blue, oval shaped, film coated tablets debossed ‘R’ on one side and ‘415’ on other side.

Amlodipine besylate and atorvastatin calcium tablets 10 mg/40 mg are blue, oval shaped, film coated tablets debossed ‘R’ on one side and ‘416’ on other side.

Amlodipine besylate and atorvastatin calcium tablets 10 mg/80 mg are blue, oval shaped, film coated tablets debossed ‘R’ on one side and ‘417’ on other side.

Combinations of atorvastatin with 2.5 mg and 5 mg amlodipine are film-coated white, and combinations of atorvastatin with 10 mg amlodipine are film-coated blue.

4 CONTRAINDICATIONS

• Active Liver Disease, Which May Include Unexplained Persistent Elevations in Hepatic Transaminase Levels

• Pregnancy [see Use in Specific Populations (8.1)]

• Lactation [see Use in Specific Populations (8.2)]

5 WARNINGS AND PRECAUTIONS

5.1 Myopathy and Rhabdomyolysis

​ Amlodipine and atorvastatin may cause myopathy (muscle pain, tenderness, or weakness with creatine kinase (CK) above ten times the upper limit of normal) and rhabdomyolysis (with or without acute renal failure secondary to myoglobinuria). Rare fatalities have occurred as a result of rhabdomyolysis with statin use, including amlodipine and atorvastatin.

Risk Factors for Myopathy

​ Risk factors for myopathy include age 65 years or greater, uncontrolled hypothyroidism, renal impairment, concomitant use with certain other drugs, and higher amlodipine and atorvastatin dosage [see Drug Interactions (7.3)].

Steps to Prevent or Reduce the Risk of Myopathy and Rhabdomyolysis

​ Amlodipine and atorvastatin 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 amlodipine and atorvastatin is not recommended. Amlodipine and atorvastatin dosage modifications are recommended for patients taking certain anti-viral, azole antifungals, or macrolide antibiotic medications [see Dosage and Administration (2)]. 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. Consider if the benefit of use of these products outweighs the increased risk of myopathy and rhabdomyolysis [see Drug Interactions (7.3)].

​ Concomitant intake of large quantities, more than 1.2 liters daily, of grapefruit juice is not recommended in patients taking amlodipine and atorvastatin tablets[see Drug Interactions (7.3)].

​ Discontinue amlodipine and atorvastatin tablets if markedly elevated CK levels occur or myopathy is diagnosed or suspected. Muscle symptoms and CK increases may resolve if amlodipine and atorvastatin tablets are discontinued. Temporarily discontinue amlodipine and atorvastatin tablets 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 amlodipine and atorvastatin 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. IMNM is characterized by: proximal muscle weakness and elevated serum creatine kinase, which persist despite discontinuation of statin treatment; positive anti-HMG CoA reductase antibody; muscle biopsy showing necrotizing myopathy; and improvement with immunosuppressive agents. Additional neuromuscular and serologic testing may be necessary. Treatment with immunosuppressive agents may be required. Consider risk of IMNM carefully prior to initiation of a different statin. If therapy is initiated with a different statin, monitor for signs and symptoms of IMNM.

5.3 Liver Dysfunction

Statins, like atorvastatin, and some other lipid-lowering therapies, have been associated with biochemical abnormalities of liver function. Persistent elevations (>3 times the upper limit of normal [ULN] occurring on 2 or more occasions) in serum transaminases occurred in 0.7% of patients who received atorvastatin in clinical trials. The incidence of these abnormalities was 0.2%, 0.2%, 0.6%, and 2.3% for 10, 20, 40, and 80 mg, respectively.

One patient in clinical trials with atorvastatin developed jaundice. Increases in liver function tests (LFT) in other patients were not associated with jaundice or other clinical signs or symptoms. Upon dose reduction, drug interruption, or discontinuation, transaminase levels returned to or near pretreatment levels without sequelae. Eighteen of 30 patients with persistent LFT elevations continued treatment with a reduced dose of atorvastatin.

It is recommended that liver enzyme tests be obtained prior to initiating therapy with atorvastatin and repeated as clinically indicated. There have been rare postmarketing reports of fatal and non-fatal hepatic failure in patients taking statins, including atorvastatin. If serious liver injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs during treatment with amlodipine besylate and atorvastatin calcium, promptly interrupt therapy. If an alternate etiology is not found, do not restart amlodipine besylate and atorvastatin calcium.

Active liver disease or unexplained persistent transaminase elevations are contraindications to the use of amlodipine besylate and atorvastatin calcium [see Contraindications (4)].

5.4 Increased Angina and Myocardial Infarction

Worsening angina and acute myocardial infarction can develop after starting or increasing the dose of amlodipine, particularly in patients with severe obstructive coronary artery disease.

5.5 Hypotension

Symptomatic hypotension is possible with use of amlodipine, particularly in patients with severe aortic stenosis. Because of the gradual onset of action, acute hypotension is unlikely.