amlodipine/atorvastatin (Caduet)

Dosing and uses of Caduet (amlodipine/atorvastatin)

• Adult
• Pediatric
• Geriatric

 

Adult dosage forms and strengths

amlodipine/atorvastatin

tablet

• 2.5/10mg
• 2.5/20mg
• 2.5/40mg
• 5/10mg
• 5/20mg
• 5/40mg
• 5/80mg
• 10/10mg
• 10/20mg
• 10/40mg
• 10/80mg

 

Hypertension/Angina & Hyperlipidemia

Dosage must be individualized for each individual component for treatment of hypertension, angina, and/or hyperlipidemia; amlodipine dose may be titrated after 1-2 weeks and the atorvastatin dose after 2-4 weeks; not to exceed 10 mg amlodipine or 80 mg atorvastatin

2.5-10 mg amlodipine; 10-80 mg atorvastatin PO qDay

 

Renal Impairment

Dose adjustment not necessary

 

Hepatic Impairment

Contraindicated in active liver disease

 

Pediatric dosage forms and strengths

amlodipine/atorvastatin

tablet

• 2.5/10mg
• 2.5/20mg
• 5/10mg
• 5/20mg

 

Hypertension & Hyperlipidemia

Dosage must be individualized for each individual component for treatment of hypertension/hyperlipidemia; amlodipine dose may be titrated after 1-2 weeks and the atorvastatin dose after 2-4 weeks; not to exceed 5 mg amlodipine or 20 mg atorvastatin

<6 years: Safety and efficacy not established

>6 years: 2.5-5 mg amlodipine; 10-20 mg atorvastatin PO qDay

 

Geriatric dosage forms and strengths

Consider initiating amlodipine dose at lower end of the spectrum due to possible decrease in renal or hepatic clearance

 

Caduet (amlodipine/atorvastatin) adverse (side) effects

>10%

Amlodipine

• Peripheral edema (2-15%)

Atorvastatin

• Arthralgia (4-12%)
• Diarrhea (5-14%)
• Nasopharingitis (4-13%)

 

1-10%

Amlodipine

• Palpitation (1-5%)
• Dizziness (1-3%)
• Flushing (1-5%)
• Somnolence (1-2%)
• Rash (1-2%)
• Fatigue (5%)
• Pruritus (1-2%)
• Male sexual dysfunction (1-2%)
• Nausea (3%)
• Dyspepsia (1-2%)
• Dyspnea (1-2%)
• Weakness (1-2%)

Atorvastatin

• Nausea (4-7%)
• Dyspepsia (3-6%)
• Increased transaminases (2-3% with 80 mg/day)
• Urinary tract infection (4-8%)
• Insomnia (1-5%)
• Myalgia (3-8%)
• Musculoskeletal pain (2-5%)
• Respiratory pharyngeal pain (1-4%)

 

<1%

Amlodipine

• Abnormal vision
• Arthralgia
• Chest pain
• Abnormal dreams
• Increased apetite
• Acute interstitial nephritis
• Alopecia
• Conjunctivitis
• Cough
• Depression
• Dysphagia
• Flatulence

Atorvastatin

• Amnesia
• Alopecia
• Anorexia
• Colitis
• Confusion
• Bullous rash
• Biliary pain
• Anemia
• Cholestatic jaundice
• Duodenal ulcer

 

Postmarketing reports

Myositis

Extrapyramidal disorder

 

Warnings

Contraindications

Hypersensitivity to amlodipine or atorvastatin

Active liver disease, or unexplained elevated transminases

Pregnancy, lactation

 

Cautions

Hypotension with or without syncope is possible (particularly with severe aortic stenosis)

CHF

Persistent progressive dermatologic reactions

Exacerbation of angina and/or MI (during initiation of treatment, after dose increase, or withdrawal of beta blocker)

Caution in liver impairment

Heavy alcohol use, history of liver disease, renal failure

Rhabdomyolysis with acute renal failure secondary to myoglobinuria have been reported with the atorvastatin

Myopathy, risk of myopathy increased by coadministration with CYP3A4 inhibiors (eg, fibrates, niacin, cyclosporine, macrolides, azole antifungals); therapy should be discontinued if myopathy diagnosed or suspected

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

Rare reports of immune-mediated necrotizing myopathy (IMNM), characterized by increased serum creatine kinase that persist despite discontinuing statin

Withhold or discontinue if myopathy, renal failure, or transaminase levels >3x ULN develops

Use in patients with recent stroke or TIA: SPARCL study observed higher incidence of hemorrhagic stroke with atorvastatin 80 mg (compared with placebo)

Increased HbA1c and fasting serum glucose levels reported with HMG-CoA reductase inhibitors

Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir) may increase risk of myopathy/rhabdomyolysis; do not exceed 20 mg atorvastatin

Amlodipine may increase systemic exposure of cyclosporine or tacrolimus when co-administered; frequent monitoring of trough blood levels of cyclosporine and tacrolimus recommended; adjust dose when appropriate

 

Pregnancy and lactation

Pregnancy category: X

Lactation: It is not known whether atorvastatin is excreted into human milk. Because statins have the potential for serious adverse reactions in nursing infants, women taking this drug should not breastfeed their infants

 

Pregnancy categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

 

Pharmacology of Caduet (amlodipine/atorvastatin)

Mechanism of action

Amlodipine: Ca channel blocker: inhibits extracellular Ca ions across the membranes of myocardial cells and vascular smooth muscle cells, without changing serum calcium concentrations, resulting in inhibition of cardiac & vascular smooth muscle contraction, thereby dilating the main coronary and systemic arteries

Atorvastatin: HMG-CoA reductase inhibitor, inhibits rate-limiting step in cholesterol biosynthesis by competitively inhibiting HMG-CoA reductase

 

Pharmacogenomics

SLCO1B1 (OATP1B1) CC genotype significantly increases AUCs of parent drug and metabolites compared with the CT or TT genotypes

This polymorphism is proposed to reduced transport into the liver, the main site of statin metabolism and elimination, resulting in elevated plasma concentrations

SLCO1B1 polymorphism is thought to have a lesser effect on the more hydrophilic statins (eg, rosuvastatin, fluvastatin) compared with more those that are more lipophilic (eg, atorvastatin, pravastatin, simvastatin)

Other genetic polymorphisms of elimination (eg, CYP450, P-glycoprotein) for each individual drug must also be considered to explain variability for statin clearance among patients that exhibit SCLO1B1 polymorphism

SLCO1B1 CC genotype is most common in Caucasians and Asians (15%)

Risk of myopathy is 2.6- to 4.3-fold higher if the C allele is present and 16.9-fold higher in CC homozygotes compared with TT homozygotes

Genetic testing laboratories

• Optivia Biotechnology, Inc (https://optiviabio.com/index.html)

 

Pharmacokinetics

Amlodipine

• Duration: 24 hr (antihypertensive effects)
• Vd: 21 L/kg
• Bioavailability: 64-90%
• Half-life: 30-50 hr
• Metabolism: Liver (>90%)
• Protein binding: 93-98%
• Peak plasma time: 6-12 hr
• Excretion: Urine (70%)

Atorvastatin

• Bioavailability: 30 %
• Vd: 381 L
• Protein binding: >98%
• Half-life: 14 hr (parent drug); 20-30 hr (active metabolites)
• Peak plasma time: 1-2 hr
• Onset of action: 3-5 days
• Excretion: Bile; urine (< 2% as unchanged drug)