Amlodipine Besylate And Atorvastatin Calcium

Check Drug InteractionsCheck known drug interactions.

Amlodipine Besylate And Atorvastatin Calcium Prescribing Information

Warnings and Precautions, Myopathy and Rhabdomyolysis (

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 ].

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 ]. 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 ].

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.

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Warnings and Precautions, Immune-Mediated Necrotizing Myopathy (

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.

) 09/2020

Amlodipine besylate and atorvastatin calcium

Dosage of amlodipine besylate and atorvastatin calcium must be individualized on the basis of both effectiveness and tolerance for each individual component in the treatment of hypertension/angina and hyperlipidemia. Select doses of amlodipine and atorvastatin independently.

Amlodipine besylate and atorvastatin calcium may be substituted for its individually titrated components. Patients may be given the equivalent dose of amlodipine besylate and atorvastatin calcium or a dose of amlodipine besylate and atorvastatin calcium with increased amounts of amlodipine, atorvastatin, or both for additional antianginal effects, blood pressure lowering, or lipid-lowering effect.

Amlodipine besylate and atorvastatin calcium may be used to provide additional therapy for patients already on one of its components. Amlodipine besylate and atorvastatin calcium may be used to initiate treatment in patients with hyperlipidemia and either hypertension or angina.

Amlodipine

The usual initial antihypertensive oral dose of amlodipine is 5 mg once daily, and the maximum dose is 10 mg once daily.

Pediatric (age > 6 years), small adult, fragile, or elderly patients, or patients with hepatic insufficiency may be started on 2.5 mg once daily and this dose may be used when adding amlodipine to other antihypertensive therapy.

Adjust dosage according to blood pressure goals. In general, wait 7 to 14 days between titration steps. Titration may proceed more rapidly, however, if clinically warranted, provided the patient is assessed frequently.

Angina:

The recommended dose of amlodipine for chronic stable or vasospastic angina is 5 to 10 mg, with the lower dose suggested in the elderly and in patients with hepatic insufficiency. Most patients will require 10 mg for adequate effect.

Coronary Artery Disease

: The recommended dose range of amlodipine for patients with CAD is 5 to 10 mg once daily. In clinical studies, the majority of patients required 10 mg [see

Clinical Studies (

14.4 Amlodipine for Coronary Artery Disease

In PREVENT, 825 patients with angiographically documented CAD were randomized to amlodipine (5 to 10 mg once daily) or placebo and followed for 3 years. Although the study did not show significance on the primary objective of change in coronary luminal diameter as assessed by quantitative coronary angiography, the data suggested a favorable outcome with respect to fewer hospitalizations for angina and revascularization procedures in patients with CAD.

CAMELOT enrolled 1318 patients with CAD recently documented by angiography, without left main coronary disease and without heart failure or an ejection fraction <40%. Patients (76% males, 89% Caucasian, 93% enrolled at U.S. sites, 89% with a history of angina, 52% without PCI, 4% with PCI and no stent, and 44% with a stent) were randomized to double-blind treatment with either amlodipine (5 to 10 mg once daily) or placebo in addition to standard care that included aspirin (89%), statins (83%), beta-blockers (74%), nitroglycerin (50%), anticoagulants (40%), and diuretics (32%), but excluded other calcium channel blockers. The mean duration of follow-up was 19 months. The primary endpoint was the time to first occurrence of one of the following events: hospitalization for angina pectoris, coronary revascularization, myocardial infarction, cardiovascular death, resuscitated cardiac arrest, hospitalization for heart failure, stroke/TIA, or peripheral vascular disease. A total of 110 (16.6%) and 151 (23.1%) first events occurred in the amlodipine and placebo groups, respectively, for a hazard ratio of 0.691 (95% CI: 0.540– 0.884, p = 0.003). The primary endpoint is summarized in Figure 1 below. The outcome of this study was largely derived from the prevention of hospitalizations for angina and the prevention of revascularization procedures (see Table 8). Effects in various subgroups are shown in Figure 2.

In an angiographic substudy (n=274) conducted within CAMELOT, there was no significant difference between amlodipine and placebo on the change of atheroma volume in the coronary artery as assessed by intravascular ultrasound.

Figure 1. Kaplan-Meier Analysis of Composite Clinical Outcomes for Amlodipine versus Placebo

Referenced Image

Figure 2. Effects on Primary Endpoint of Amlodipine versus Placebo across Sub-Groups

Referenced Image

Table 8 below summarizes the significant composite endpoint and clinical outcomes from the composites of the primary endpoint. The other components of the primary endpoint including cardiovascular death, resuscitated cardiac arrest, myocardial infarction, hospitalization for heart failure, stroke/TIA, or peripheral vascular disease did not demonstrate a significant difference between amlodipine and placebo.

Table 8. Incidence of Significant Clinical Outcomes for CAMELOT

Clinical Outcomes N (%)	Amlodipine (N=663)	Placebo (N=655)	Risk Reduction (p-value)
Composite CV	110	151	31%
Endpoint	(16.6)	(23.1)	(0.003)
Hospitalization for	51	84	42%
Angina*	(7.7)	(12.8)	(0.002)
Coronary	78	103	27%
Revascularization*	(11.8)	(15.7)	(0.033)

* Total patients with these events.

)

Pediatrics:

The effective antihypertensive oral dose of amlodipine in pediatric patients ages 6 to 17 years is 2.5 mg to 5 mg once daily. Doses in excess of 5 mg daily have not been studied in pediatric patients [see

Clinical Pharmacology (

12.3 Pharmacokinetics

Absorption

Amlodipine:

After oral administration of therapeutic doses of amlodipine alone, absorption produces peak plasma concentrations between 6 and 12 hours. Absolute bioavailability has been estimated to be between 64% and 90%.

Atorvastatin:

After oral administration alone, atorvastatin is rapidly absorbed; maximum plasma concentrations occur within 1 to 2 hours. Extent of absorption increases in proportion to atorvastatin dose. The absolute bioavailability of atorvastatin (parent drug) is approximately 14% and the systemic availability of HMG-CoA reductase inhibitory activity is approximately 30%. The low systemic availability is attributed to presystemic clearance in gastrointestinal mucosa and/or hepatic first-pass metabolism. Plasma atorvastatin concentrations are lower (approximately 30% for C_maxand AUC) following evening drug administration compared with morning. However, LDL-C reduction is the same regardless of the time of day of drug administration [see

Dosage and Administration

Amlodipine besylate and atorvastatin calcium: Following oral administration of amlodipine besylate and atorvastatin calcium, peak plasma concentrations of amlodipine and atorvastatin are seen at 6 to 12 hours and 1 to 2 hours post dosing, respectively. The rate and extent of absorption (bioavailability) of amlodipine and atorvastatin from amlodipine besylate and atorvastatin calcium are not significantly different from the bioavailability of amlodipine and atorvastatin administered separately (see above).

The bioavailability of amlodipine from amlodipine besylate and atorvastatin calcium was not affected by food. Food decreases the rate and extent of absorption of atorvastatin from amlodipine besylate and atorvastatin calcium by approximately 32% and 11%, respectively, as it does with atorvastatin when given alone. LDL-C reduction is similar whether atorvastatin is given with or without food.

Distribution

Amlodipine: Ex vivo

studies have shown that approximately 93% of the circulating amlodipine drug is bound to plasma proteins in hypertensive patients. Steady-state plasma levels of amlodipine are reached after 7 to 8 days of consecutive daily dosing.

Atorvastatin:

Mean volume of distribution of atorvastatin is approximately 381 liters. Atorvastatin is ≥98% bound to plasma proteins. A blood/plasma ratio of approximately 0.25 indicates poor drug penetration into red blood cells. Based on observations in rats, atorvastatin calcium is likely to be secreted in human milk [see

Contraindications

and

Use in Specific Populations

Metabolism

Amlodipine:

Amlodipine is extensively (about 90%) converted to inactive metabolites via hepatic metabolism.

Atorvastatin:

Atorvastatin is extensively metabolized to ortho- and parahydroxylated derivatives and various beta-oxidation products.

In vitro

inhibition of HMG-CoA reductase by ortho- and parahydroxylated metabolites is equivalent to that of atorvastatin. Approximately 70% of circulating inhibitory activity for HMG-CoA reductase is attributed to active metabolites.

In vitro

studies suggest the importance of atorvastatin metabolism by cytochrome P4503A4, consistent with increased plasma concentrations of atorvastatin in humans following co-administration with erythromycin, a known inhibitor of this isozyme [see

Drug Interactions

]. In animals, the ortho-hydroxy metabolite undergoes further glucuronidation.

Excretion

Amlodipine:

Elimination from the plasma is biphasic with a terminal elimination half-life of about 30 to 50 hours. Ten percent of the parent amlodipine compound and 60% of the metabolites of amlodipine are excreted in the urine.

Atorvastatin:

Atorvastatin and its metabolites are eliminated primarily in bile following hepatic and/or extra-hepatic metabolism; however, the drug does not appear to undergo enterohepatic recirculation. Mean plasma elimination half-life of atorvastatin in humans is approximately 14 hours, but the half-life of inhibitory activity for HMG-CoA reductase is 20 to 30 hours because of the contribution of active metabolites. Less than 2% of a dose of atorvastatin is recovered in urine following oral administration.

Specific Populations

Geriatric

Amlodipine:

Elderly patients have decreased clearance of amlodipine with a resulting increase in AUC of approximately 40 to 60%, and a lower initial dose of amlodipine may be required.

Atorvastatin:

Plasma concentrations of atorvastatin are higher (approximately 40% for C_maxand 30% for AUC) in healthy elderly subjects (age ≥65 years) than in young adults. Clinical data suggest a greater degree of LDL-lowering at any dose of atorvastatin in the elderly population compared to younger adults [see

Use in Specific Populations

Pediatric

Amlodipine:

Sixty-two hypertensive patients aged 6 to 17 years received doses of amlodipine between 1.25 mg and 20 mg. Weight-adjusted clearance and volume of distribution were similar to values in adults.

Atorvastatin:

Apparent oral clearance of atorvastatin in pediatric subjects appeared similar to that of adults when scaled allometrically by body weight as the body weight was the only significant covariate in atorvastatin population pharmacokinetics model with data including pediatric HeFH patients (ages 10 years to 17 years of age, n=29) in an open-label, 8-week study.

Gender

Atorvastatin:

Plasma concentrations of atorvastatin in women differ from those in men (approximately 20% higher for C_maxand 10% lower for AUC); however, there is no clinically significant difference in LDL-C reduction with atorvastatin between men and women.

Renal Impairment

Amlodipine:

The pharmacokinetics of amlodipine are not significantly influenced by renal impairment. Patients with renal failure may therefore receive the usual initial amlodipine dose.

Atorvastatin:

Renal disease has no influence on the plasma concentrations or LDL-C reduction of atorvastatin; thus, dose adjustment of atorvastatin in patients with renal dysfunction is not necessary [see

Dosage and Administration

and

Warnings and Precautions

Hemodialysis

While studies have not been conducted in patients with end-stage renal disease, hemodialysis is not expected to clear atorvastatin or amlodipine since both drugs are extensively bound to plasma proteins.

Hepatic Impairment

Amlodipine:

Elderly patients and patients with hepatic insufficiency have decreased clearance of amlodipine with a resulting increase in AUC of approximately 40 to 60%.

Atorvastatin:

In patients with chronic alcoholic liver disease, plasma concentrations of atorvastatin are markedly increased. C_maxand AUC are each 4-fold greater in patients with Childs-Pugh A disease. C_maxand AUC of atorvastatin are approximately 16-fold and 11-fold increased, respectively, in patients with Childs-Pugh B disease [see

Contraindications

Atorvastatin is contraindicated in patients with active liver disease.

Heart Failure

Amlodipine:

In patients with moderate to severe heart failure, the increase in AUC for amlodipine was similar to that seen in the elderly and in patients with hepatic insufficiency.

Effects of Other Drugs on Amlodipine besylate and atorvastatin calcium

Amlodipine:

Co-administered cimetidine, magnesium-and aluminum hydroxide antacids, sildenafil, and grapefruit juice have no impact on the exposure to amlodipine.

CYP3A inhibitors:

Co-administration of a 180 mg daily dose of diltiazem with 5 mg amlodipine in elderly hypertensive patients resulted in a 60% increase in amlodipine systemic exposure. Erythromycin co-administration in healthy volunteers did not significantly change amlodipine systemic exposure. However, strong inhibitors of CYP3A (e.g., itraconazole, clarithromycin) may increase the plasma concentrations of amlodipine to a greater extent [see

Drug Interactions (7.1)

Atorvastatin:

Atorvastatin is a substrate of the hepatic transporters, OATP1B1 and OATP1B3 transporter. Metabolites of atorvastatin are substrates of OATP1B1. Atorvastatin is also identified as a substrate of the efflux transporter BCRP, which may limit the intestinal absorption and biliary clearance of atorvastatin

Table 6 shows effects of other drugs on the pharmacokinetics of atorvastatin

Table 6. Effect of Co-administered Drugs on the Pharmacokinetics of Atorvastatin

Co-administered drug and dosing regimen	Atorvastatin
	Dose (mg)	Ratio of AUC^&	Ratio of C_max^&
^#Cyclosporine 5.2 mg/kg/day, stable dose	10 mg QD^afor 28 days	8.69	10.66
^#Tipranavir 500 mg BID^b/ritonavir 200 mg BID^b, 7 days	10 mg, SD^c	9.36	8.58
^#Glecaprevir 400 mg QD^a/pibrentasvir 120 mg QD^a, 7 days	10 mg QD^afor 7 days	8.28	22.00
^#Telaprevir 750 mg q8h^f, 10 days	20 mg, SD^c	7.88	10.60
^{#, ‡}Saquinavir 400 mg BID^b/ritonavir 400mg BID, 15 days	40 mg QD^afor 4 days	3.93	4.31
^#Elbasvir 50 mg QD^a/grazoprevir 200 mg QD^a, 13 days	10 mg SD^c	1.95	4.34
^#Simeprevir 150 mg QD^a, 10 days	40 mg SD^c	2.12	1.70
^#Clarithromycin 500 mg BID^b, 9 days	80 mg QD^afor 8 days	4.54	5.38
^#Darunavir 300 mg BID^b/ritonavir 100 mg BID, 9 days	10 mg QD^afor 4 days	3.45	2.25
^#Itraconazole 200 mg QD^a, 4 days	40 mg SD^c	3.32	1.20
^#Letermovir 480 mg QD^a, 10 days	20 mg SD^c	3.29	2.17
^#Fosamprenavir 700 mg BID^b/ritonavir 100 mg BID^b, 14 days	10 mg QD^afor 4 days	2.53	2.84
^#Fosamprenavir 1400 mg BID^b, 14 days	10 mg QD^afor 4 days	2.30	4.04
^#Nelfinavir 1250 mg BID^b, 14 days	10 mg QD^afor 28 days	1.74	2.22
^#Grapefruit Juice, 240 mL QD^a,*	40 mg, SD^c	1.37	1.16
Diltiazem 240 mg QD^a, 28 days	40 mg, SD^c	1.51	1.00
Erythromycin 500 mg QID^e, 7 days	10 mg, SD^c	1.33	1.38
Amlodipine 10 mg, single dose	80 mg, SD^c	1.18	0.91
Cimetidine 300 mg QID^e, 2 weeks	10 mg QD^afor 2 weeks	1.00	0.89
Colestipol 10 g BID^b, 24 weeks	40 mg QD^afor 8 weeks	NA	0.74**
Maalox TC^®30 mL QD^a, 17 days	10 mg QD^afor 15 days	0.66	0.67
Efavirenz 600 mg QD^a, 14 days	10 mg for 3 days	0.59	1.01
^#Rifampin 600 mg QD^a, 7 days (coadministered)^†	40 mg SD^c	1.12	2.90
^#Rifampin 600 mg QD^a, 5 days (doses separated)^†	40 mg SD^c	0.20	0.60
^#Gemfibrozil 600 mg BID^b, 7 days	40 mg SD^c	1.35	1.00
^#Fenofibrate 160 mg QD^a, 7 days	40 mg SD^c	1.03	1.02
Boceprevir 800 mg TID^d, 7 days	40 mg SD^c	2.32	2.66

Represents ratio of treatments (co-administered drug plus atorvastatin versus atorvastatin alone).

^#See Sections 5.1 and 7 for clinical significance.

* Greater increases in AUC (ratio of AUC up to 2.5) and/or C_max(ratio of C_maxup to 1.71) have been reported with excessive grapefruit consumption (≥ 750 mL to 1.2 liters per day).

** Ratio based on a single sample taken 8 to 16 h post dose.

† Due to the dual interaction mechanism of rifampin, simultaneous co-administration of atorvastatin with rifampin is recommended, as delayed administration of atorvastatin after administration of rifampin has been associated with a significant reduction in atorvastatin plasma concentrations.

‡ The dose of saquinavir plus ritonavir in this study is not the clinically used dose. The increase in atorvastatin exposure when used clinically is likely to be higher than what was observed in this study. Therefore, caution should be applied and the lowest dose necessary should be used.

^aOnce daily

^bTwice daily

^cSingle dose

^dThree times daily

^eFour times daily

^fEvery 8 hours

Effects of Amlodipine besylate and atorvastatin calcium on Other Drugs

Amlodipine:

Amlodipine is a weak inhibitor of CYP3A and may increase exposure to CYP3A substrates.

In vitro

data indicate that amlodipine has no effect on the human plasma protein binding of digoxin, phenytoin, warfarin, and indomethacin.

Co-administered amlodipine does not affect the exposure to atorvastatin, digoxin, ethanol and the warfarin prothrombin response time.

Cyclosporine:

A prospective study in renal transplant patients (N=11) showed on an average of 40% increase in trough cyclosporine levels when concomitantly treated with amlodipine [see

Drug Interactions

Tacrolimus:

A prospective study in healthy Chinese volunteers (N=9) with CYP3A5 expressers showed a 2.5-to 4-fold increase in tacrolimus exposure when concomitantly administered with amlodipine compared to tacrolimus alone. This finding was not observed in CYP3A5 non-expressers (N= 6). However, a 3-fold increase in plasma exposure to tacrolimus in a renal transplant patient (CYP3A5 non-expresser) upon initiation of amlodipine for the treatment of post-transplant hypertension resulting in reduction of tacrolimus dose has been reported. Irrespective of the CYP3A5 genotype status, the possibility of an interaction cannot be excluded with these drugs [see

Drug Interactions ]

Atorvastatin:

Table 7 shows the effects of atorvastatin on the pharmacokinetics of other drugs.

Table 7. Effect of Atorvastatin on the Pharmacokinetics of Co-administered Drugs

Atorvastatin	Co-administered drug and dosing regimen
	Drug/Dose (mg)	Ratio of AUC	Ratio of C_max
80 mg QD^afor 15 days	Antipyrine, 600 mg SD^c	1.03	0.89
80 mg QD^afor 10 days	^#Digoxin 0.25 mg QD^a, 20 days	1.15	1.20
40 mg QD^afor 22 days	Oral contraceptive QD^a, 2 months – norethindrone 1 mg – ethinyl estradiol 35 mcg	1.281.19	1.231.30
10 mg, SD^c	Tipranavir 500 mg BID^b/ritonavir 200 mg BID^b, 7 days	1.08	0.96
10 mg QD^afor 4 days	Fosamprenavir 1400 mg BID^b, 14 days	0.73	0.82
10 mg QD^afor 4 days	Fosamprenavir 700 mg BID^b/ritonavir 100 mg BID^b, 14 days	0.99	0.94

# See Section 7 for clinical significance.

^aOnce daily

^bTwice daily

^cSingle dose

Atorvastatin had no clinically significant effect on prothrombin time when administered to patients receiving chronic warfarin treatment.

), Clinical Studies (

14.1 Amlodipine for Hypertension

Adult Patients

The antihypertensive efficacy of amlodipine has been demonstrated in a total of 15 double-blind, placebo-controlled, randomized studies involving 800 patients on amlodipine and 538 on placebo. Once daily administration produced statistically significant placebo-corrected reductions in supine and standing blood pressures at 24 hours postdose, averaging about 12/6 mmHg in the standing position and 13/7 mmHg in the supine position in patients with mild to moderate hypertension. Maintenance of the blood pressure effect over the 24-hour dosing interval was observed, with little difference in peak and trough effect. Tolerance was not demonstrated in patients studied for up to 1 year. The 3 parallel, fixed dose, dose response studies showed that the reduction in supine and standing blood pressures was dose related within the recommended dosing range. Effects on diastolic pressure were similar in young and older patients. The effect on systolic pressure was greater in older patients, perhaps because of greater baseline systolic pressure. Effects were similar in black patients and in white patients.

Pediatric Patients

Two hundred sixty-eight hypertensive patients aged 6 to 17 years were randomized first to amlodipine 2.5 or 5 mg once daily for 4 weeks and then randomized again to the same dose or to placebo for another 4 weeks. Patients receiving 2.5 mg or 5 mg at the end of 8 weeks had significantly lower systolic blood pressure than those secondarily randomized to placebo. The magnitude of the treatment effect is difficult to interpret, but it is probably less than 5 mmHg systolic on the 5 mg dose and 3.3 mmHg systolic on the 2.5 mg dose. Adverse events were similar to those seen in adults.

)

Atorvastatin (Hyperlipidemia)

Hyperlipidemia and Mixed Dyslipidemia:

The recommended starting dose of atorvastatin is 10 or 20 mg once daily. Patients who require a large reduction in LDL-C (more than 45%) may be started at 40 mg once daily. The dosage range of atorvastatin is 10 to 80 mg once daily. Atorvastatin can be administered as a single dose at any time of the day, with or without food. The starting dose and maintenance doses of atorvastatin should be individualized according to patient characteristics such as goal of therapy and response. After initiation and/or upon titration of atorvastatin, lipid levels should be analyzed within 2 to 4 weeks and dosage adjusted accordingly.

Homozygous Familial Hypercholesterolemia:

The dosage range of atorvastatin in patients with HoFH is 10 to 80 mg daily. Atorvastatin should be used as an adjunct to other lipid-lowering treatments (e.g., LDL apheresis) in these patients or if such treatments are unavailable.

Concomitant Lipid-Lowering Therapy:

Atorvastatin may be used with bile acid resins. Monitor for signs of myopathy in patients receiving the combination of HMG-CoA reductase inhibitors (statins) and fibrates [see

Warnings and Precautions (

5.1 Myopathy and Rhabdomyolysis

Risk Factors for Myopathy

Steps to Prevent or Reduce the Risk of Myopathy and Rhabdomyolysis

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 ].

), Drug Interactions (

7 DRUG INTERACTIONS

Data from a drug-drug interaction study involving 10 mg of amlodipine and 80 mg of atorvastatin in healthy subjects indicate that the pharmacokinetics of amlodipine are not altered when the drugs are co-administered. The effect of amlodipine on the pharmacokinetics of atorvastatin showed no effect on the C_max: 91% (90% confidence interval: 80 to 103%), but the AUC of atorvastatin increased by 18% (90% confidence interval: 109 to 127%) in the presence of amlodipine, which is not clinically meaningful.

No drug interaction studies have been conducted with amlodipine besylate and atorvastatin calcium and other drugs, although studies have been conducted in the individual amlodipine and atorvastatin components, as described below:

Amlodipine

Increased Risk of Myopathy and Rhabdomyolysis

Cyclosporine, tipranavir plus ritonavir, glecaprevir plus pibrentasvir	Avoid atorvastatin
Clarithromycin, itraconazole, saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir, elbasvir plus grazoprevir,letermovir	Do not exceed 20 mg atorvastatin daily
Nelfinavir	Do not exceed 40 mg atorvastatin daily
Lopinavir plus ritonavir, simeprevir, fibric acid derivatives, erythromycin, azole antifungals, lipid-modifying doses of niacin, colchicine	Consider the risk/benefit of concomitant use with atorvastatin

Other Lipid-Lowering Medications: Increased risk of myopathy (7).
Rifampin should be simultaneously co-administered with atorvastatin .
Oral Contraceptives: Norethindrone and ethinyl estradiol may be increased .
Digoxin: Patients should be monitored appropriately .

7.1 Impact of Other Drugs on Amlodipine

CYP3A Inhibitors

Co-administration with CYP3A inhibitors (moderate and strong) results in increased systemic exposure to amlodipine and may require dose reduction. Monitor for symptoms of hypotension and edema when amlodipine is co-administered with CYP3A inhibitors to determine the need for dose adjustment [see

Clinical Pharmacology

CYP3A Inducers

No information is available on the quantitative effects of CYP3A inducers on amlodipine. Blood pressure should be closely monitored when amlodipine is co-administered with CYP3A inducers.

Sildenafil

Monitor for hypotension when sildenafil is co-administered with amlodipine [see

Clinical Pharmacology

7.2 Impact of Amlodipine on Other Drugs

Immunosuppressants

Amlodipine may increase the systemic exposure of cyclosporine or tacrolimus when co-administered. Frequent monitoring of trough blood levels of cyclosporine and tacrolimus is recommended and adjust the dose when appropriate [see

Clinical Pharmacology

Atorvastatin

The risk of myopathy during treatment with statins is increased with concurrent administration of fibric acid derivatives, lipid-modifying doses of niacin, cyclosporine, or strong CYP3A4 inhibitors (e.g., clarithromycin, HIV and HCV protease inhibitors, and itraconazole) [see

Warnings and Precautions (5.1)and Clinical Pharmacology

7.3 Drug Interactions that may Increase the Risk of Myopathy and Rhabdomyolysis with Atorvastatin

Atorvastatin is a substrate of CYP3A4 and transporters (e.g., OATP1B1/1B3, P-gp, or BCRP). Atorvastatin plasma levels can be significantly increased with concomitant administration of inhibitors of CYP3A4 and transporters. Table 3 includes a list of drugs that may increase exposure to atorvastatin and may increase the risk of myopathy and rhabdomyolysis when used concomitantly and instructions for preventing or managing them [see

Warnings and Precautions (5.1) and Clinical Pharmacology (12.3)].

Table 3: Drug Interactions that may Increase the Risk of Myopathy and Rhabdomyolysis with

Atorvastatin

Cyclosporine or Gemfibrozil
Clinical Impact:	Atorvastatin plasma levels were significantly increased with concomitant administration of atorvastatin and cyclosporine, an inhibitor of CYP3A4 and OATP1B1 [ see Clinical Pharmacology ]. Cases of myopathy and rhabdomyolysis have been reported with concomitant use of ledipasvir plus sofosbuvir with atorvastatin.
Intervention :	Concomitant use of tipranavir plus ritonavir or glecaprevir plus pibrentasvir with atorvastatin is not recommended. In patients taking lopinavir plus ritonavir, or simeprevir, consider the risk/benefit of concomitant use with atorvastatin. In patients taking saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir,fosamprenavir plus ritonavir, elbasvir plus grazoprevir or letermovir, do not exceed atorvastatin 20 mg. In patients taking nelfinavir, do not exceed atorvastatin 40 mg [see Dosage and Administration ].Consider the risk/benefit of concomitant use of ledipasvir plus sofosbuvir with atorvastatin. Monitor all patients for signs and symptoms of myopathy particularly during initiation of therapy and during upward dose titration of either drug.
Examples:	Tipranavir plus ritonavir, glecaprevir plus pibrentasvir, lopinavir plus ritonavir, simeprevir, saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir, elbasvir plus grazoprevir, letermovir, nelfinavir, and ledipasvir plus sofosbuvir.
Select Azole Antifungals or Macrolide Antibiotics
Clinical Impact:	Atorvastatin plasma levels were significantly increased with concomitant administration of atorvastatin with select azole antifungals or macrolide antibiotics, due to inhibition of CYP3A4 and/or transporters [ see Clinical Pharmacology ].
Intervention:	In patients taking clarithromycin or itraconazole, do not exceed atorvastatin 20 mg [ see Dosage and Administration ]. Consider the risk/benefit of concomitant use of other azole antifungals or macrolide antibiotics with atorvastatin. Monitor all patients for signs and symptoms of myopathy particularly during initiation of therapy and during upward dose titration of either drug.
Examples:	Erythromycin, clarithromycin, itraconazole, ketoconazole, posaconazole, and voriconazole.
Niacin
Clinical Impact:	Cases of myopathy and rhabdomyolysis have been observed with concomitant use of lipid modifying dosages of niacin (>1 gram/day niacin) with atorvastatin.
Intervention:	Consider if the benefit of using lipid modifying dosages of niacin concomitantly with atorvastatin outweighs the increased risk of myopathy and rhabdomyolysis. If concomitant use is decided, monitor patients for signs and symptoms of myopathy particularly during initiation of therapy and during upward dose titration of either drug.
Fibrates (other than Gemfibrozil)
Clinical Impact:	Fibrates may cause myopathy when given alone. The risk of myopathy and rhabdomyolysis is increased with concomitant use of fibrates with atorvastatin.
Intervention:	Consider if the benefit of using fibrates concomitantly with atorvastatin outweighs the increased risk of myopathy and rhabdomyolysis. If concomitant use is decided, monitor patients for signs and symptoms of myopathy particularly during initiation of therapy and during upward dose titration of either drug.
Colchicine
Clinical Impact:	Cases of myopathy and rhabdomyolysis have been reported with concomitant use of colchicine with atorvastatin.
Intervention :	Consider the risk/benefit of concomitant use of colchicine with atorvastatin. If concomitant use is decided, monitor patients for signs and symptoms of myopathy particularly during initiation of therapy and during upward dose titration of either drug.
Grapefruit Juice
Clinical Impact:	Grapefruit juice consumption, especially excessive consumption, more than 1.2 liters/daily, can raise the plasma levels of atorvastatin and may increase the risk of myopathy and rhabdomyolysis.
Intervention:	Avoid intake of large quantities of grapefruit juice, more than 1.2 liters daily, when taking atorvastatin.

7.4 Drug Interactions that may Decrease Exposure to
Atorvastatin

Table 4 presents drug interactions that may decrease exposure to atorvastatin and instructions for preventing or managing them.

Table 4: Drug Interactions that may Decrease Exposure to

Atorvastatin

Rifampin
Clinical Impact:	Concomitant administration of atorvastatin with rifampin, an inducer of cytochrome P450 3A4 and inhibitor of OATP1B1, can lead to variable reductions in plasma concentrations of atorvastatin. Due to the dual interaction mechanism of rifampin, delayed administration of atorvastatin after administration of rifampin has been associated with a significant reduction in atorvastatin plasma concentrations.
Intervention :	Administer atorvastatin and rifampin simultaneously.

7.5 Atorvastatin Effects on Other Drugs

Table 5 presents atorvastatin effect on other drugs and instructions for preventing or managing them.

Table 5:

Atorvastatin Effects on Other Drugs

Oral Contraceptives
Clinical Impact:	Co-administration of atorvastatin and an oral contraceptive increased plasma concentrations of norethindrone and ethinyl estradiol [ see Clinical Pharmacology ( 12.3 )].
Intervention:	Consider this when selecting an oral contraceptive for patients taking atorvastatin.
Digoxin
Clinical Impact :	When multiple doses of atorvastatin and digoxin were co-administered, steady state plasma digoxin concentrations increased [ see Clinical Pharmacology ].
Intervention:	Monitor patients taking digoxin appropriately.

)

Patients with Renal Impairment:

Renal disease does not affect the plasma concentrations nor LDL-C reduction of atorvastatin; thus, dosage adjustment in patients with renal dysfunction is not necessary [see

Warnings and Precautions (

5.1 Myopathy and Rhabdomyolysis

Risk Factors for Myopathy

Steps to Prevent or Reduce the Risk of Myopathy and Rhabdomyolysis

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 ].

), Clinical Pharmacology (

12.3 Pharmacokinetics

Absorption

Amlodipine:

Atorvastatin:

Dosage and Administration

Distribution

Amlodipine: Ex vivo

Atorvastatin:

Contraindications

and

Use in Specific Populations

Metabolism

Amlodipine:

Amlodipine is extensively (about 90%) converted to inactive metabolites via hepatic metabolism.

Atorvastatin:

Atorvastatin is extensively metabolized to ortho- and parahydroxylated derivatives and various beta-oxidation products.

In vitro

Drug Interactions

]. In animals, the ortho-hydroxy metabolite undergoes further glucuronidation.

Excretion

Amlodipine:

Atorvastatin:

Specific Populations

Geriatric

Amlodipine:

Elderly patients have decreased clearance of amlodipine with a resulting increase in AUC of approximately 40 to 60%, and a lower initial dose of amlodipine may be required.

Atorvastatin:

Use in Specific Populations

Pediatric

Amlodipine:

Sixty-two hypertensive patients aged 6 to 17 years received doses of amlodipine between 1.25 mg and 20 mg. Weight-adjusted clearance and volume of distribution were similar to values in adults.

Atorvastatin:

Gender

Atorvastatin:

Renal Impairment

Amlodipine:

The pharmacokinetics of amlodipine are not significantly influenced by renal impairment. Patients with renal failure may therefore receive the usual initial amlodipine dose.

Atorvastatin:

Renal disease has no influence on the plasma concentrations or LDL-C reduction of atorvastatin; thus, dose adjustment of atorvastatin in patients with renal dysfunction is not necessary [see

Dosage and Administration

and

Warnings and Precautions

Hemodialysis

Hepatic Impairment

Amlodipine:

Elderly patients and patients with hepatic insufficiency have decreased clearance of amlodipine with a resulting increase in AUC of approximately 40 to 60%.

Atorvastatin:

Contraindications

Atorvastatin is contraindicated in patients with active liver disease.

Heart Failure

Amlodipine:

In patients with moderate to severe heart failure, the increase in AUC for amlodipine was similar to that seen in the elderly and in patients with hepatic insufficiency.

Effects of Other Drugs on Amlodipine besylate and atorvastatin calcium

Amlodipine:

Co-administered cimetidine, magnesium-and aluminum hydroxide antacids, sildenafil, and grapefruit juice have no impact on the exposure to amlodipine.

CYP3A inhibitors:

Drug Interactions (7.1)

Atorvastatin:

Table 6 shows effects of other drugs on the pharmacokinetics of atorvastatin

Table 6. Effect of Co-administered Drugs on the Pharmacokinetics of Atorvastatin

Co-administered drug and dosing regimen	Atorvastatin
	Dose (mg)	Ratio of AUC^&	Ratio of C_max^&
^#Cyclosporine 5.2 mg/kg/day, stable dose	10 mg QD^afor 28 days	8.69	10.66
^#Tipranavir 500 mg BID^b/ritonavir 200 mg BID^b, 7 days	10 mg, SD^c	9.36	8.58
^#Glecaprevir 400 mg QD^a/pibrentasvir 120 mg QD^a, 7 days	10 mg QD^afor 7 days	8.28	22.00
^#Telaprevir 750 mg q8h^f, 10 days	20 mg, SD^c	7.88	10.60
^{#, ‡}Saquinavir 400 mg BID^b/ritonavir 400mg BID, 15 days	40 mg QD^afor 4 days	3.93	4.31
^#Elbasvir 50 mg QD^a/grazoprevir 200 mg QD^a, 13 days	10 mg SD^c	1.95	4.34
^#Simeprevir 150 mg QD^a, 10 days	40 mg SD^c	2.12	1.70
^#Clarithromycin 500 mg BID^b, 9 days	80 mg QD^afor 8 days	4.54	5.38
^#Darunavir 300 mg BID^b/ritonavir 100 mg BID, 9 days	10 mg QD^afor 4 days	3.45	2.25
^#Itraconazole 200 mg QD^a, 4 days	40 mg SD^c	3.32	1.20
^#Letermovir 480 mg QD^a, 10 days	20 mg SD^c	3.29	2.17
^#Fosamprenavir 700 mg BID^b/ritonavir 100 mg BID^b, 14 days	10 mg QD^afor 4 days	2.53	2.84
^#Fosamprenavir 1400 mg BID^b, 14 days	10 mg QD^afor 4 days	2.30	4.04
^#Nelfinavir 1250 mg BID^b, 14 days	10 mg QD^afor 28 days	1.74	2.22
^#Grapefruit Juice, 240 mL QD^a,*	40 mg, SD^c	1.37	1.16
Diltiazem 240 mg QD^a, 28 days	40 mg, SD^c	1.51	1.00
Erythromycin 500 mg QID^e, 7 days	10 mg, SD^c	1.33	1.38
Amlodipine 10 mg, single dose	80 mg, SD^c	1.18	0.91
Cimetidine 300 mg QID^e, 2 weeks	10 mg QD^afor 2 weeks	1.00	0.89
Colestipol 10 g BID^b, 24 weeks	40 mg QD^afor 8 weeks	NA	0.74**
Maalox TC^®30 mL QD^a, 17 days	10 mg QD^afor 15 days	0.66	0.67
Efavirenz 600 mg QD^a, 14 days	10 mg for 3 days	0.59	1.01
^#Rifampin 600 mg QD^a, 7 days (coadministered)^†	40 mg SD^c	1.12	2.90
^#Rifampin 600 mg QD^a, 5 days (doses separated)^†	40 mg SD^c	0.20	0.60
^#Gemfibrozil 600 mg BID^b, 7 days	40 mg SD^c	1.35	1.00
^#Fenofibrate 160 mg QD^a, 7 days	40 mg SD^c	1.03	1.02
Boceprevir 800 mg TID^d, 7 days	40 mg SD^c	2.32	2.66

Represents ratio of treatments (co-administered drug plus atorvastatin versus atorvastatin alone).

^#See Sections 5.1 and 7 for clinical significance.

* Greater increases in AUC (ratio of AUC up to 2.5) and/or C_max(ratio of C_maxup to 1.71) have been reported with excessive grapefruit consumption (≥ 750 mL to 1.2 liters per day).

** Ratio based on a single sample taken 8 to 16 h post dose.

^aOnce daily

^bTwice daily

^cSingle dose

^dThree times daily

^eFour times daily

^fEvery 8 hours

Effects of Amlodipine besylate and atorvastatin calcium on Other Drugs

Amlodipine:

Amlodipine is a weak inhibitor of CYP3A and may increase exposure to CYP3A substrates.

In vitro

data indicate that amlodipine has no effect on the human plasma protein binding of digoxin, phenytoin, warfarin, and indomethacin.

Co-administered amlodipine does not affect the exposure to atorvastatin, digoxin, ethanol and the warfarin prothrombin response time.

Cyclosporine:

A prospective study in renal transplant patients (N=11) showed on an average of 40% increase in trough cyclosporine levels when concomitantly treated with amlodipine [see

Drug Interactions

Tacrolimus:

Drug Interactions ]

Atorvastatin:

Table 7 shows the effects of atorvastatin on the pharmacokinetics of other drugs.

Table 7. Effect of Atorvastatin on the Pharmacokinetics of Co-administered Drugs

Atorvastatin	Co-administered drug and dosing regimen
	Drug/Dose (mg)	Ratio of AUC	Ratio of C_max
80 mg QD^afor 15 days	Antipyrine, 600 mg SD^c	1.03	0.89
80 mg QD^afor 10 days	^#Digoxin 0.25 mg QD^a, 20 days	1.15	1.20
40 mg QD^afor 22 days	Oral contraceptive QD^a, 2 months – norethindrone 1 mg – ethinyl estradiol 35 mcg	1.281.19	1.231.30
10 mg, SD^c	Tipranavir 500 mg BID^b/ritonavir 200 mg BID^b, 7 days	1.08	0.96
10 mg QD^afor 4 days	Fosamprenavir 1400 mg BID^b, 14 days	0.73	0.82
10 mg QD^afor 4 days	Fosamprenavir 700 mg BID^b/ritonavir 100 mg BID^b, 14 days	0.99	0.94

# See Section 7 for clinical significance.

^aOnce daily

^bTwice daily

^cSingle dose

Atorvastatin had no clinically significant effect on prothrombin time when administered to patients receiving chronic warfarin treatment.

)

Use with Cyclosporine, Clarithromycin, Itraconazole, Letermovir, or Certain Protease Inhibitors: In patients taking cyclosporine or the human immunodeficiency virus (HIV) protease inhibitor tipranavir plus ritonavir or the hepatitis C virus (HCV) protease inhibitor glecaprevir plus pibrentasvir, or letermovir when co-administered with cyclosporine, therapy with atorvastatin should be avoided. In patients with HIV taking lopinavir plus ritonavir, use the lowest dose necessary of atorvastatin. In patients taking clarithromycin, itraconazole, elbasvir plus grazoprevir, or in patients with HIV taking a combination of saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir, or letermovir therapy with atorvastatin should be limited to 20 mg, and appropriate clinical assessment is recommended to ensure that the lowest dose necessary of atorvastatin is used. In patients taking the HIV protease inhibitor nelfinavir therapy with atorvastatin should be limited to 40 mg.

[see Warnings and Precautions (

5.1 Myopathy and Rhabdomyolysis

Risk Factors for Myopathy

Steps to Prevent or Reduce the Risk of Myopathy and Rhabdomyolysis

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 ].

), Drug Interactions (

7.3 Drug Interactions that may Increase the Risk of Myopathy and Rhabdomyolysis with Atorvastatin

Warnings and Precautions (5.1) and Clinical Pharmacology (12.3)].

Table 3: Drug Interactions that may Increase the Risk of Myopathy and Rhabdomyolysis with

Atorvastatin

Cyclosporine or Gemfibrozil
Clinical Impact:	Atorvastatin plasma levels were significantly increased with concomitant administration of atorvastatin and cyclosporine, an inhibitor of CYP3A4 and OATP1B1 [ see Clinical Pharmacology ]. Cases of myopathy and rhabdomyolysis have been reported with concomitant use of ledipasvir plus sofosbuvir with atorvastatin.
Intervention :	Concomitant use of tipranavir plus ritonavir or glecaprevir plus pibrentasvir with atorvastatin is not recommended. In patients taking lopinavir plus ritonavir, or simeprevir, consider the risk/benefit of concomitant use with atorvastatin. In patients taking saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir,fosamprenavir plus ritonavir, elbasvir plus grazoprevir or letermovir, do not exceed atorvastatin 20 mg. In patients taking nelfinavir, do not exceed atorvastatin 40 mg [see Dosage and Administration ].Consider the risk/benefit of concomitant use of ledipasvir plus sofosbuvir with atorvastatin. Monitor all patients for signs and symptoms of myopathy particularly during initiation of therapy and during upward dose titration of either drug.
Examples:	Tipranavir plus ritonavir, glecaprevir plus pibrentasvir, lopinavir plus ritonavir, simeprevir, saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir, elbasvir plus grazoprevir, letermovir, nelfinavir, and ledipasvir plus sofosbuvir.
Select Azole Antifungals or Macrolide Antibiotics
Clinical Impact:	Atorvastatin plasma levels were significantly increased with concomitant administration of atorvastatin with select azole antifungals or macrolide antibiotics, due to inhibition of CYP3A4 and/or transporters [ see Clinical Pharmacology ].
Intervention:	In patients taking clarithromycin or itraconazole, do not exceed atorvastatin 20 mg [ see Dosage and Administration ]. Consider the risk/benefit of concomitant use of other azole antifungals or macrolide antibiotics with atorvastatin. Monitor all patients for signs and symptoms of myopathy particularly during initiation of therapy and during upward dose titration of either drug.
Examples:	Erythromycin, clarithromycin, itraconazole, ketoconazole, posaconazole, and voriconazole.
Niacin
Clinical Impact:	Cases of myopathy and rhabdomyolysis have been observed with concomitant use of lipid modifying dosages of niacin (>1 gram/day niacin) with atorvastatin.
Intervention:	Consider if the benefit of using lipid modifying dosages of niacin concomitantly with atorvastatin outweighs the increased risk of myopathy and rhabdomyolysis. If concomitant use is decided, monitor patients for signs and symptoms of myopathy particularly during initiation of therapy and during upward dose titration of either drug.
Fibrates (other than Gemfibrozil)
Clinical Impact:	Fibrates may cause myopathy when given alone. The risk of myopathy and rhabdomyolysis is increased with concomitant use of fibrates with atorvastatin.
Intervention:	Consider if the benefit of using fibrates concomitantly with atorvastatin outweighs the increased risk of myopathy and rhabdomyolysis. If concomitant use is decided, monitor patients for signs and symptoms of myopathy particularly during initiation of therapy and during upward dose titration of either drug.
Colchicine
Clinical Impact:	Cases of myopathy and rhabdomyolysis have been reported with concomitant use of colchicine with atorvastatin.
Intervention :	Consider the risk/benefit of concomitant use of colchicine with atorvastatin. If concomitant use is decided, monitor patients for signs and symptoms of myopathy particularly during initiation of therapy and during upward dose titration of either drug.
Grapefruit Juice
Clinical Impact:	Grapefruit juice consumption, especially excessive consumption, more than 1.2 liters/daily, can raise the plasma levels of atorvastatin and may increase the risk of myopathy and rhabdomyolysis.
Intervention:	Avoid intake of large quantities of grapefruit juice, more than 1.2 liters daily, when taking atorvastatin.

)].

Heterozygous Familial Hypercholesterolemia in Pediatric Patients (10 Years to 17 Years of Age):

The recommended starting dose of atorvastatin is 10 mg/day; the usual dose range is 10 to 20 mg orally once daily [see

Clinical Studies (

14.11 Atorvastatin for Heterozygous Familial Hypercholesterolemia in Pediatric Patients

In a double-blind, placebo-controlled study followed by an open-label phase, 187 boys and post-menarchal girls 10 years to 17 years of age (mean age 14.1 years) with HeFH or severe hypercholesterolemia, were randomized to atorvastatin (n=140) or placebo (n=47) for 26 weeks and then all received atorvastatin for 26 weeks. Inclusion in the study required 1) a baseline LDL-C level ≥ 190 mg/dL or 2) a baseline LDL-C level ≥ 160 mg/dL and positive family history of FH or documented premature cardiovascular disease in a first or second-degree relative. The mean baseline LDL-C value was 218.6 mg/dL (range: 138.5 to 385 mg/dL) in the atorvastatin group compared to 230 mg/dL (range: 160 to 324.5 mg/dL) in the placebo group. The dosage of atorvastatin (once daily) was 10 mg for the first 4 weeks and uptitrated to 20 mg if the LDL-C level was > 130 mg/dL. The number of atorvastatin-treated patients who required uptitration to 20 mg after Week 4 during the double-blind phase was 78 (55.7%).

Atorvastatin significantly decreased plasma levels of total-C, LDL-C, TG, and apolipoprotein B during the 26-week double-blind phase (see Table 14).

Table 14. Lipid-Altering Effects of Atorvastatin in Adolescent Boys and Girls with Heterozygous Familial Hypercholesterolemia or Severe Hypercholesterolemia (Mean Percentage Change from Baseline at Endpoint in Intention-to-Treat Population)

DOSAGE	N	Total-C	LDL-C	HDL-C	TG	Apo B
Placebo	47	-1.5	-0.4	-1.9	1	0.7
Atorvastatin	140	-31.4	-39.6	2.8	-12	-34

The mean achieved LDL-C value was 130.7 mg/dL (range: 70 to 242 mg/dL) in the atorvastatin group compared to 228.5 mg/dL (range: 152 to 385 mg/dL) in the placebo group during the 26-week double-blind phase.

Atorvastatin was also studied in a three year open-label, uncontrolled trial that included 163 patients with HeFH who were 10 years to 15 years old (82 boys and 81 girls). All patients had a clinical diagnosis of HeFH confirmed by genetic analysis (if not already confirmed by family history). Approximately 98% were Caucasian, and less than 1% were Black or Asian. Mean LDL-C at baseline was 232 mg/dL. The starting atorvastatin dosage was 10 mg once daily and doses were adjusted to achieve a target of <130 mg/dL LDL-C. The reductions in LDL-C from baseline were generally consistent across age groups within the trial as well as with previous clinical studies in both adult and pediatric placebo-controlled trials.

)

]. Doses should be individualized according to the recommended goal of therapy [see

Indications and Usage (

1.4 Hyperlipidemia

Atorvastatin is indicated:

As an adjunct to diet to reduce elevated total cholesterol (total-C), low-density lipoprotein cholesterol (LDL-C), apolipoprotein B (apo B), and triglycerides (TG) levels and to increase HDL-C in adult patients with primary hypercholesterolemia (heterozygous familial and nonfamilial) and mixed dyslipidemia (
Fredrickson
Types IIa and IIb)
As an adjunct to diet for the treatment of adult patients with elevated serum TG levels (
Fredrickson
Type IV);
For the treatment of adult patients with primary dysbetalipoproteinemia (
Fredrickson
Type III) who do not respond adequately to diet
To reduce total-C and LDL-C in patients with homozygous familial hypercholesterolemia (HoFH) as an adjunct to other lipid-lowering treatments (e.g., LDL apheresis) or if such treatments are unavailable
As an adjunct to diet to reduce total-C, LDL-C, and apo B levels in pediatric patients, 10 years to 17 years of age, with heterozygous familial hypercholesterolemia (HeFH) if after an adequate trial of diet therapy the following findings are present:

a. LDL-C remains ≥ 190 mg/dL or

b. LDL-C remains ≥ 160 mg/dL and:

there is a positive family history of premature CVD or
two or more other CVD risk factors are present in the pediatric patient

) and Clinical Pharmacology (

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Amlodipine besylate and atorvastatin calcium is a combination of two drugs, a dihydropyridine calcium channel blocker (amlodipine) and an HMG-CoA reductase inhibitor (atorvastatin). The amlodipine component of amlodipine besylate and atorvastatin calcium inhibits the transmembrane influx of calcium ions into vascular smooth muscle and cardiac muscle. The atorvastatin component of amlodipine besylate and atorvastatin calcium is a selective, competitive inhibitor of HMG-CoA reductase, the rate-limiting enzyme that converts 3-hydroxy-3-methylglutaryl-coenzyme A to mevalonate, a precursor of sterols, including cholesterol.

Amlodipine

Amlodipine binds to both dihydropyridine and nondihydropyridine binding sites. The contractile processes of cardiac muscle and vascular smooth muscle are dependent upon the movement of extracellular calcium ions into these cells through specific ion channels. Amlodipine inhibits calcium ion influx across cell membranes selectively, with a greater effect on vascular smooth muscle cells than on cardiac muscle cells. Negative inotropic effects can be detected

in vitro

but such effects have not been seen in intact animals at therapeutic doses. Serum calcium concentration is not affected by amlodipine.

Amlodipine is a peripheral arterial vasodilator that acts directly on vascular smooth muscle to cause a reduction in peripheral vascular resistance and reduction in blood pressure. The precise mechanisms by which amlodipine relieves angina have not been fully delineated, but are thought to include the following:

Exertional Angina:

In patients with exertional angina, amlodipine reduces the total peripheral resistance (afterload) against which the heart works and reduces the rate pressure product, and thus myocardial oxygen demand, at any given level of exercise.

Vasospastic Angina:

Amlodipine has been demonstrated to block constriction and restore blood flow in coronary arteries and arterioles in response to calcium, potassium epinephrine, serotonin, and thromboxane A2 analog in experimental animal models and in human coronary vessels

in vitro

. This inhibition of coronary spasm is responsible for the effectiveness of amlodipine in vasospastic (Prinzmetal’s or variant) angina.

Atorvastatin

Atorvastatin is a selective, competitive inhibitor of HMG-CoA reductase, the rate-limiting enzyme that converts 3-hydroxy-3-methylglutaryl-coenzyme A to mevalonate, a precursor of sterols, including cholesterol. In animal models, atorvastatin lowers plasma cholesterol and lipoprotein levels by inhibiting HMG-CoA reductase and cholesterol synthesis in the liver and by increasing the number of hepatic LDL receptors on the cell surface to enhance uptake and catabolism of LDL; atorvastatin also reduces LDL production and the number of LDL particles.

12.2 Pharmacodynamics

Amlodipine

Following administration of therapeutic doses to patients with hypertension, amlodipine produces vasodilation resulting in a reduction of supine and standing blood pressures. These decreases in blood pressure are not accompanied by a significant change in heart rate or plasma catecholamine levels with chronic dosing. Although the acute intravenous administration of amlodipine decreases arterial blood pressure and increases heart rate in hemodynamic studies of patients with chronic stable angina, chronic oral administration of amlodipine in clinical trials did not lead to clinically significant changes in heart rate or blood pressures in normotensive patients with angina.

With chronic once daily oral administration, antihypertensive effectiveness is maintained for at least 24 hours. Plasma concentrations correlate with effect in both young and elderly patients. The magnitude of reduction in blood pressure with amlodipine is also correlated with the height of pretreatment elevation; thus, individuals with moderate hypertension (diastolic pressure 105 to 114 mmHg) had about a 50% greater response than patients with mild hypertension (diastolic pressure 90 to 104 mmHg). Normotensive subjects experienced no clinically significant change in blood pressures (+1/–2 mmHg).

In hypertensive patients with normal renal function, therapeutic doses of amlodipine resulted in a decrease in renal vascular resistance and an increase in glomerular filtration rate and effective renal plasma flow without change in filtration fraction or proteinuria.

As with other calcium channel blockers, hemodynamic measurements of cardiac function at rest and during exercise (or pacing) in patients with normal ventricular function treated with amlodipine have generally demonstrated a small increase in cardiac index without significant influence on dP/dt or on left ventricular end diastolic pressure or volume. In hemodynamic studies, amlodipine has not been associated with a negative inotropic effect when administered in the therapeutic dose range to intact animals and man, even when co-administered with beta-blockers to man. Similar findings, however, have been observed in normal or well-compensated patients with heart failure with agents possessing significant negative inotropic effects.

Amlodipine does not change sinoatrial nodal function or atrioventricular conduction in intact animals or man. In patients with chronic stable angina, intravenous administration of 10 mg did not significantly alter A-H and H-V conduction and sinus node recovery time after pacing. Similar results were obtained in patients receiving amlodipine and concomitant beta-blockers. In clinical studies in which amlodipine was administered in combination with beta-blockers to patients with either hypertension or angina, no adverse effects on electrocardiographic parameters were observed. In clinical trials with angina patients alone, amlodipine therapy did not alter electrocardiographic intervals or produce higher degrees of AV blocks.

Atorvastatin

Atorvastatin, as well as some of its metabolites, are pharmacologically active in humans. The liver is the primary site of action and the principal site of cholesterol synthesis and LDL clearance. Drug dosage, rather than systemic drug concentration, correlates better with LDL-C reduction. Individualization of drug dosage should be based on therapeutic response [see

Dosage and Administration

Drug interactions

Sildenafil:

When amlodipine and sildenafil were used in combination, each agent independently exerted its own blood pressure lowering effect [see

Drug Interactions (7.1)

12.3 Pharmacokinetics

Absorption

Amlodipine:

Atorvastatin:

Dosage and Administration

Distribution

Amlodipine: Ex vivo

Atorvastatin:

Contraindications

and

Use in Specific Populations

Metabolism

Amlodipine:

Amlodipine is extensively (about 90%) converted to inactive metabolites via hepatic metabolism.

Atorvastatin:

Atorvastatin is extensively metabolized to ortho- and parahydroxylated derivatives and various beta-oxidation products.

In vitro

Drug Interactions

]. In animals, the ortho-hydroxy metabolite undergoes further glucuronidation.

Excretion

Amlodipine:

Atorvastatin:

Specific Populations

Geriatric

Amlodipine:

Elderly patients have decreased clearance of amlodipine with a resulting increase in AUC of approximately 40 to 60%, and a lower initial dose of amlodipine may be required.

Atorvastatin:

Use in Specific Populations

Pediatric

Amlodipine:

Sixty-two hypertensive patients aged 6 to 17 years received doses of amlodipine between 1.25 mg and 20 mg. Weight-adjusted clearance and volume of distribution were similar to values in adults.

Atorvastatin:

Gender

Atorvastatin:

Renal Impairment

Amlodipine:

The pharmacokinetics of amlodipine are not significantly influenced by renal impairment. Patients with renal failure may therefore receive the usual initial amlodipine dose.

Atorvastatin:

Renal disease has no influence on the plasma concentrations or LDL-C reduction of atorvastatin; thus, dose adjustment of atorvastatin in patients with renal dysfunction is not necessary [see

Dosage and Administration

and

Warnings and Precautions

Hemodialysis

Hepatic Impairment

Amlodipine:

Elderly patients and patients with hepatic insufficiency have decreased clearance of amlodipine with a resulting increase in AUC of approximately 40 to 60%.

Atorvastatin:

Contraindications

Atorvastatin is contraindicated in patients with active liver disease.

Heart Failure

Amlodipine:

In patients with moderate to severe heart failure, the increase in AUC for amlodipine was similar to that seen in the elderly and in patients with hepatic insufficiency.

Effects of Other Drugs on Amlodipine besylate and atorvastatin calcium

Amlodipine:

Co-administered cimetidine, magnesium-and aluminum hydroxide antacids, sildenafil, and grapefruit juice have no impact on the exposure to amlodipine.

CYP3A inhibitors:

Drug Interactions (7.1)

Atorvastatin:

Table 6 shows effects of other drugs on the pharmacokinetics of atorvastatin

Table 6. Effect of Co-administered Drugs on the Pharmacokinetics of Atorvastatin

Co-administered drug and dosing regimen	Atorvastatin
	Dose (mg)	Ratio of AUC^&	Ratio of C_max^&
^#Cyclosporine 5.2 mg/kg/day, stable dose	10 mg QD^afor 28 days	8.69	10.66
^#Tipranavir 500 mg BID^b/ritonavir 200 mg BID^b, 7 days	10 mg, SD^c	9.36	8.58
^#Glecaprevir 400 mg QD^a/pibrentasvir 120 mg QD^a, 7 days	10 mg QD^afor 7 days	8.28	22.00
^#Telaprevir 750 mg q8h^f, 10 days	20 mg, SD^c	7.88	10.60
^{#, ‡}Saquinavir 400 mg BID^b/ritonavir 400mg BID, 15 days	40 mg QD^afor 4 days	3.93	4.31
^#Elbasvir 50 mg QD^a/grazoprevir 200 mg QD^a, 13 days	10 mg SD^c	1.95	4.34
^#Simeprevir 150 mg QD^a, 10 days	40 mg SD^c	2.12	1.70
^#Clarithromycin 500 mg BID^b, 9 days	80 mg QD^afor 8 days	4.54	5.38
^#Darunavir 300 mg BID^b/ritonavir 100 mg BID, 9 days	10 mg QD^afor 4 days	3.45	2.25
^#Itraconazole 200 mg QD^a, 4 days	40 mg SD^c	3.32	1.20
^#Letermovir 480 mg QD^a, 10 days	20 mg SD^c	3.29	2.17
^#Fosamprenavir 700 mg BID^b/ritonavir 100 mg BID^b, 14 days	10 mg QD^afor 4 days	2.53	2.84
^#Fosamprenavir 1400 mg BID^b, 14 days	10 mg QD^afor 4 days	2.30	4.04
^#Nelfinavir 1250 mg BID^b, 14 days	10 mg QD^afor 28 days	1.74	2.22
^#Grapefruit Juice, 240 mL QD^a,*	40 mg, SD^c	1.37	1.16
Diltiazem 240 mg QD^a, 28 days	40 mg, SD^c	1.51	1.00
Erythromycin 500 mg QID^e, 7 days	10 mg, SD^c	1.33	1.38
Amlodipine 10 mg, single dose	80 mg, SD^c	1.18	0.91
Cimetidine 300 mg QID^e, 2 weeks	10 mg QD^afor 2 weeks	1.00	0.89
Colestipol 10 g BID^b, 24 weeks	40 mg QD^afor 8 weeks	NA	0.74**
Maalox TC^®30 mL QD^a, 17 days	10 mg QD^afor 15 days	0.66	0.67
Efavirenz 600 mg QD^a, 14 days	10 mg for 3 days	0.59	1.01
^#Rifampin 600 mg QD^a, 7 days (coadministered)^†	40 mg SD^c	1.12	2.90
^#Rifampin 600 mg QD^a, 5 days (doses separated)^†	40 mg SD^c	0.20	0.60
^#Gemfibrozil 600 mg BID^b, 7 days	40 mg SD^c	1.35	1.00
^#Fenofibrate 160 mg QD^a, 7 days	40 mg SD^c	1.03	1.02
Boceprevir 800 mg TID^d, 7 days	40 mg SD^c	2.32	2.66

Represents ratio of treatments (co-administered drug plus atorvastatin versus atorvastatin alone).

^#See Sections 5.1 and 7 for clinical significance.

* Greater increases in AUC (ratio of AUC up to 2.5) and/or C_max(ratio of C_maxup to 1.71) have been reported with excessive grapefruit consumption (≥ 750 mL to 1.2 liters per day).

** Ratio based on a single sample taken 8 to 16 h post dose.

^aOnce daily

^bTwice daily

^cSingle dose

^dThree times daily

^eFour times daily

^fEvery 8 hours

Effects of Amlodipine besylate and atorvastatin calcium on Other Drugs

Amlodipine:

Amlodipine is a weak inhibitor of CYP3A and may increase exposure to CYP3A substrates.

In vitro

data indicate that amlodipine has no effect on the human plasma protein binding of digoxin, phenytoin, warfarin, and indomethacin.

Co-administered amlodipine does not affect the exposure to atorvastatin, digoxin, ethanol and the warfarin prothrombin response time.

Cyclosporine:

A prospective study in renal transplant patients (N=11) showed on an average of 40% increase in trough cyclosporine levels when concomitantly treated with amlodipine [see

Drug Interactions

Tacrolimus:

Drug Interactions ]

Atorvastatin:

Table 7 shows the effects of atorvastatin on the pharmacokinetics of other drugs.

Table 7. Effect of Atorvastatin on the Pharmacokinetics of Co-administered Drugs

Atorvastatin	Co-administered drug and dosing regimen
	Drug/Dose (mg)	Ratio of AUC	Ratio of C_max
80 mg QD^afor 15 days	Antipyrine, 600 mg SD^c	1.03	0.89
80 mg QD^afor 10 days	^#Digoxin 0.25 mg QD^a, 20 days	1.15	1.20
40 mg QD^afor 22 days	Oral contraceptive QD^a, 2 months – norethindrone 1 mg – ethinyl estradiol 35 mcg	1.281.19	1.231.30
10 mg, SD^c	Tipranavir 500 mg BID^b/ritonavir 200 mg BID^b, 7 days	1.08	0.96
10 mg QD^afor 4 days	Fosamprenavir 1400 mg BID^b, 14 days	0.73	0.82
10 mg QD^afor 4 days	Fosamprenavir 700 mg BID^b/ritonavir 100 mg BID^b, 14 days	0.99	0.94

# See Section 7 for clinical significance.

^aOnce daily

^bTwice daily

^cSingle dose

Atorvastatin had no clinically significant effect on prothrombin time when administered to patients receiving chronic warfarin treatment.

)

]. Adjustments should be made at intervals of 4 weeks or more.

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.

•

Active Liver Disease,

Which May Include Unexplained Persistent Elevations in Hepatic Transaminase Levels

•

Pregnancy

[see

Use in

Specific Populations (

8.1 Pregnancy

Risk Summary

Amlodipine besylate and atorvastatin calcium tablets are contraindicated in women who are pregnant.

Atorvastatin

Atorvastatin is contraindicated for use in pregnant women since safety in pregnant women has not been established and there is no apparent benefit of lipid lowering drugs during pregnancy. Because HMG-CoA reductase inhibitors decrease cholesterol synthesis and possibly the synthesis of other biologically active substances derived from cholesterol, atorvastatin may cause fetal harm when administered to a pregnant woman. Amlodipine besylate and atorvastatin calcium tablets should be discontinued as soon as pregnancy is recognized [see

Contraindications

]. Limited published data on the use of atorvastatin are insufficient to determine a drug-associated risk of major congenital malformations or miscarriage. In animal reproduction studies in rats and rabbits there was no evidence of embryo-fetal toxicity or congenital malformations at doses up to 30 and 20 times, respectively, the human exposure at the MRHD of 80 mg, based on body surface area (mg/m²). In rats administered atorvastatin during gestation and lactation, decreased postnatal growth and development was observed at doses ≥6 times the MRHD (

see Data

Amlodipine

The limited available data based on post-marketing reports with amlodipine use in pregnant women are not sufficient to inform a drug-associated risk for major birth defects and miscarriage. There are risks to the mother and fetus associated with poorly controlled hypertension in pregnancy (

see Clinical Considerations

). In animal reproduction studies, there was no evidence of adverse developmental effects when pregnant rats and rabbits were treated orally with amlodipine maleate during organogenesis at doses approximately 10 and 20 times MRHD, respectively. However for rats, litter size was significantly decreased (by about 50%) and the number of intrauterine deaths was significantly increased (about 5-fold). Amlodipine has been shown to prolong both the gestation period and the duration of labor in rats at this dose (

see Data

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Clinical Considerations

Disease-associated maternal and/or embryo/fetal risk

Hypertension in pregnancy increases the maternal risk for pre-eclampsia, gestational diabetes, premature delivery, and delivery complications (e.g., need for cesarean section and post-partum hemorrhage). Hypertension increases the fetal risk for intrauterine growth restriction and intrauterine death. Pregnant women with hypertension should be carefully monitored and managed accordingly.

Data

Human Data

Atorvastatin

Limited published data on atorvastatin calcium from observational studies, meta-analyses and case reports have not shown an increased risk of major congenital malformations or miscarriage. Rare reports of congenital anomalies have been received following intrauterine exposure to other HMG-CoA reductase inhibitors. In a review of approximately 100 prospectively followed pregnancies in women exposed to simvastatin or lovastatin, the incidences of congenital anomalies, spontaneous abortions, and fetal deaths/stillbirths did not exceed what would be expected in the general population. The number of cases is adequate to exclude a ≥3 to 4-fold increase in congenital anomalies over the background incidence. In 89% of the prospectively followed pregnancies, drug treatment was initiated prior to pregnancy and was discontinued at some point in the first trimester when pregnancy was identified.

Animal Data

Atorvastatin

Atorvastatin crosses the rat placenta and reaches a level in fetal liver equivalent to that of maternal plasma. When administered to pregnant rats and rabbits during organogenesis at oral doses up to 300 mg/kg/day and 100 mg/kg/day, respectively, atorvastatin was not teratogenic in rats at doses up to 300 mg/kg/day or in rabbits at doses up to 100 mg/kg/day. These doses resulted in multiples of about 30 times (rat) or 20 times (rabbit) the human exposure at the MRHD based on surface area (mg/m²). In rats, the maternally toxic dose of 300 mg/kg resulted in increased post-implantation loss and decreased fetal body weight. At the maternally toxic doses of 50 and 100 mg/kg/day in rabbits, there was increased post-implantation loss, and at 100 mg/kg/day fetal body weights were decreased.

In a study in pregnant rats administered atorvastatin calcium at doses equivalent to 20, 100, or 225 mg/kg/day, from gestation day 7 through to lactation day 20 (weaning), there was decreased survival at birth, postnatal day 4, weaning, and post-weaning in pups of mothers dosed with 225 mg/kg/day, a dose at which maternal toxicity was observed. Pup body weight was decreased through postnatal day 21 at 100 mg/kg/day, and through postnatal day 91 at 225 mg/kg/day. Pup development was delayed (rotorod performance at 100 mg/kg/day and acoustic startle at 225 mg/kg/day; pinnae detachment and eye-opening at 225 mg/kg/day). These doses of atorvastatin correspond to 6 times (100 mg/kg) and 22 times (225 mg/kg) the human exposure at the MRHD, based on AUC.

Amlodipine

No evidence of teratogenicity or other embryo/fetal toxicity was found when pregnant rats and rabbits were treated orally with amlodipine maleate at doses up to 10 mg amlodipine/kg/day (approximately 10 and 20 times the MRHD based on body surface area, respectively) during their respective periods of major organogenesis. However, for rats, litter size was significantly decreased (by about 50%) and the number of intrauterine deaths was significantly increased (about 5-fold) in rats receiving amlodipine maleate at a dose equivalent to 10 mg amlodipine/kg/day for 14 days before mating and throughout mating and gestation. Amlodipine maleate has been shown to prolong both the gestation period and the duration of labor in rats at this dose.

)

]

•

Lactation

[see

Use in

Specific Populations (

8.2 Lactation

Risk Summary

Amlodipine besylate and atorvastatin calcium tablets are contraindicated during breastfeeding.

Atorvastatin

Atorvastatin use is contraindicated during breastfeeding [see

Contraindications (

)]

There is no available information on the effects of the drug on the breastfed infant or the effects of the drug on milk production. It is not known whether atorvastatin is present in human milk, but it has been shown that another drug in this class passes into human milk and atorvastatin is present in rat milk. Because of the potential for serious adverse reactions in a breastfed infant, advise women that breastfeeding is not recommended during treatment with amlodipine besylate and atorvastatin calcium.

Amlodipine

Limited available data from a published clinical lactation study reports that amlodipine is present in human milk at an estimated median relative infant dose of 4.2%. No adverse effects of amlodipine on the breastfed infant have been observed. There is no available information on the effects of amlodipine on milk production.

)

]

The following serious adverse reactions are discussed in greater detail in other sections of the label:

Myopathy and Rhabdomyolysis [see
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 ].
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 ]. 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 ].
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.
)
]
Liver enzyme abnormalities [see
Warnings and Precautions (
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
].
)
]

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