Caduet (Page 2 of 15)

3 DOSAGE FORMS AND STRENGTHS

CADUET tablets are formulated for oral administration in the following strength combinations:

Table 1
Atorvastatin (mg)
10 20 40 80

Amlodipine (mg)

5

X

X

X

X

10

X

X

X

X

Combinations of atorvastatin with 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

CADUET 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 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, and higher CADUET dosage [see Drug Interactions (7.3)].

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 (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 CADUET [see Drug Interactions (7.3)].

Discontinue CADUET if markedly elevated CK levels occur or myopathy is diagnosed or suspected. Muscle symptoms and CK increases 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. 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 CADUET, promptly interrupt therapy. If an alternate etiology is not found, do not restart CADUET.

Active liver disease or unexplained persistent transaminase elevations are contraindications to the use of CADUET [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.

5.6 Endocrine Function

Increases in HbA1c and fasting serum glucose levels have been reported with HMG-CoA reductase inhibitors, including atorvastatin.

Statins interfere with cholesterol synthesis and theoretically might blunt adrenal and/or gonadal steroid production. Clinical studies have shown that atorvastatin does not reduce basal plasma cortisol concentration or impair adrenal reserve. The effects of statins on male fertility have not been studied in adequate numbers of patients. The effects, if any, on the pituitary-gonadal axis in premenopausal women are unknown. Avoid a statin with drugs that may decrease the levels or activity of endogenous steroid hormones such as ketoconazole, spironolactone, and cimetidine.

5.7 CNS Toxicity

Brain hemorrhage was seen in a female dog treated with atorvastatin for 3 months at 120 mg/kg/day. Brain hemorrhage and optic nerve vacuolation were seen in another female dog that was sacrificed in moribund condition after 11 weeks of escalating doses up to 280 mg/kg/day. The 120 mg/kg dose resulted in a systemic exposure approximately 16 times the human plasma area-under-the-curve (AUC, 0–24 hours) based on the maximum human dose of 80 mg/day. A single tonic convulsion was seen in each of 2 male dogs (one treated at 10 mg/kg/day and one at 120 mg/kg/day) in a 2-year study. No CNS lesions have been observed in mice after chronic treatment for up to 2 years at doses up to 400 mg/kg/day or in rats at doses up to 100 mg/kg/day. These doses were 6 to 11 times (mouse) and 8 to 16 times (rat) the human AUC (0–24) based on the maximum recommended human dose (MRHD) of 80 mg/day.

CNS vascular lesions, characterized by perivascular hemorrhages, edema, and mononuclear cell infiltration of perivascular spaces, have been observed in dogs treated with other statins. A chemically similar drug in this class produced optic nerve degeneration (Wallerian degeneration of retinogeniculate fibers) in clinically normal dogs in a dose-dependent fashion at a dose that produced plasma drug levels about 30 times higher than the mean drug level in humans taking the highest recommended dose.

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