CADUET (amlodipine besylate/atorvastatin calcium)

There are 2 contraindications. Absolute contraindication.

Contraindication List
Hepatic failure
Lactation

There are 12 severe contraindications. Adequate patient monitoring is recommended for safer drug use.

Severe List
Acute renal failure
Alcohol use disorder
Disease of liver
Hemorrhagic stroke
Immune-mediated necrotizing myopathy
Intracerebral hemorrhage
Myopathy with CK elevation
Pregnancy
Rhabdomyolysis
Severe aortic valve stenosis
Severe hepatic disease
Severe hypotension

There are 4 moderate contraindications. Clinically significant contraindication, where the condition can be managed or treated before the drug may be given safely.

Moderate List
Hyperglycemia
Kidney disease with reduction in glomerular filtration rate (GFr)
Memory impairment
Untreated hypothyroidism

There are 39 severe adverse reactions.

More Frequent	Less Frequent
Arthralgia	Muscle spasm Myalgia

Rare/Very Rare

Abnormal hepatic function tests Acute myocardial infarction Anaphylaxis Angioedema Atrial fibrillation Bradycardia Cholestasis Depersonalization Depression Erythema multiforme Extrapyramidal disease Hepatic failure Hepatitis Hypotension Immune-mediated necrotizing myopathy Increased alanine transaminase Increased aspartate transaminase Interstitial lung disease Jaundice Leukopenia Muscle weakness Myasthenia gravis Myopathy Myositis Neck stiffness Pancreatitis Peripheral neuropathy Progressive angina pectoris Pulmonary edema Purpura Rhabdomyolysis Stevens-johnson syndrome Tendon rupture Thrombocytopenic disorder Toxic epidermal necrolysis Ventricular tachycardia

There are 81 less severe adverse reactions.

More Frequent	Less Frequent
Acute abdominal pain Diarrhea Drowsy Dyspepsia Edema Headache disorder Nausea Pain Peripheral edema Pharyngitis Urinary tract infection	Dizziness Fatigue Flushing Insomnia Musculoskeletal pain Nausea Palpitations Skin rash

Rare/Very Rare

Abnormal sexual function Acute abdominal pain Acute cognitive impairment Anorexia Arthralgia Back pain Blurred vision Chest pain Chills Conjunctivitis Constipation Cramps Depression Diarrhea Dream disorder Drug-induced hot flash Dysgeusia Dysphagia Dyspnea Epistaxis Eructation Fatigue Fever Flatulence General weakness Gingival hyperplasia Gynecomastia Hyperglycemia Hyperhidrosis Hypoesthesia Increased urinary frequency Insomnia Joint stiffness Maculopapular rash Malaise Memory impairment Myalgia Nervousness Nightmares Nocturia Ocular pain Osteoarthritis Paresthesia Peripheral ischemia Peripheral neuropathy Polydipsia Pruritus of skin Skin rash Sterile pyuria Symptoms of anxiety Syncope Tachycardia Tinnitus Tremor Urticaria Vasculitis Vertigo Visual changes Vomiting Weight gain Weight loss Xerostomia

All statins were previously contraindicated in pregnant women because the fetal risk with these drugs was thought to outweigh any possible benefit. This determination was based on several factors including safety signals from animal data. In addition, congenital anomalies including severe CNS defects and unilateral limb deficiencies were reported in a case series of pregnant women who were exposed to a lipophilic statin during the first trimester.

Because statins decrease synthesis of cholesterol and possibly other products of the cholesterol biosynthetic pathway, there is also a concern that these drugs can potentially cause fetal harm. More recent data from case series and observational cohort studies have not shown evidence of an increased risk of major birth defects with statin use during pregnancy, and this was observed after controlling for potential confounders such as maternal age, diabetes mellitus, hypertension, obesity, and alcohol and tobacco use. The overall evidence from animal studies suggests limited potential for statins to cause malformations or other adverse fetal effects.

While an increased risk of miscarriage has been reported in pregnant women exposed to statins, it is not clear whether this effect is related to the drugs or to other confounding factors. FDA conducted a comprehensive review of all available clinical and nonclinical data of statin use in pregnant women and concluded that the totality of evidence suggests limited potential for statins to cause malformations and other adverse embryofetal effects. Because statins may prevent serious or potentially fatal cardiovascular events in certain high-risk patients who are pregnant, FDA has requested that the contraindication in pregnant women be removed from the prescribing information for all statins.

While FDA still advises that most pregnant patients discontinue statins because of the possibility of fetal harm, there may be some patients (e.g., those with homozygous familial hypercholesterolemia or established cardiovascular disease) in whom continued therapy may be beneficial; therefore, decisions should be individualized based on the patient's risks versus benefits. Patients who become pregnant or suspect that they are pregnant while receiving a statin should notify their clinician who can advise them on the appropriate course of action. Category C. (See Users Guide.)

Drug/Drug Class	Severity	Precaution Description	Pregnancy Category Description
Amlodipine	2		No fda rating but may have precautions or warnings; may have animal and/or human studies or pre or post marketing information.
Atorvastatin	D	Insuff human data avail;Theoretical risk based on mech of action	Positive evidence of human fetal risk based on investigation or marketing information but potential benefits may warrant use of drug in pregnant women despite potential risks.

Atorvastatin is distributed into milk in rats. It is not known whether atorvastatin is distributed into human milk; however, the drug is probably distributed into human milk because a small amount of another statin is distributed into human milk. Because of the potential for serious adverse reactions from atorvastatin in nursing infants, the drug is contraindicated in nursing women.

Women who require atorvastatin therapy should not breast-feed their infants. Many patients can stop statin therapy temporarily until breast-feeding is complete; patients who require ongoing statin treatment should not breast-feed and should use alternatives such as infant formula. It is not known whether amlodipine is distributed into milk; the manufacturer recommends discontinuance of nursing if amlodipine is used.

Contraindicated
Absolute contraindication. (Human data usually available to support recommendations.) This drug should not be given to breast feeding mothers.

Drug Name	Excretion Potential	Effect on Infant	Notes
Atorvastatin	Unknown. It is unknown whether the drug is excreted in human breast milk.	It is not known whether this drug has an adverse effect on the nursing infant. (No data or inconclusive human data)	Mfr does not recommend; other hmg-coa reductase inhibitors excreted in milk

No Known Risk
No known risk. This drug has no known risks to nursing infants and does not adversely affect lactation.

Drug Name	Excretion Potential	Effect on Infant	Notes
Amlodipine	Excreted.This drug is known to be excreted in human breast milk.	This drug has been shown not to have an adverse effect on the nursing infant.	Milk levels low; undetectable in breastfed infants; no adv eff reported

Of the 39,828 patients receiving atorvastatin in clinical studies, 40% were 65 years of age or older, and 7% were 75 years of age or older. Although no overall differences in efficacy or safety were observed between geriatric and younger patients, and other clinical experience has not revealed age-related differences in response, the possibility that some geriatric patients may exhibit increased sensitivity to the drug cannot be ruled out. Data from a pharmacokinetic study indicate that peak plasma concentration and area under the plasma concentration-time curve (AUC) of atorvastatin were 40 or 30% higher, respectively, in geriatric individuals (65 years of age or older) compared with younger adults.

In addition, mean reductions in LDL-cholesterol concentrations appear to be higher in geriatric patients receiving any dose of atorvastatin compared with younger patients. Because patients older than 75 years of age may have a higher risk of adverse effects and lower adherence to therapy, the expected benefits versus adverse effects of statin therapy should be considered before initiating statin therapy in this population. Safety and efficacy of atorvastatin in fixed combination with amlodipine (Caduet(R)) have not been established in geriatric patients.

In geriatric patients, amlodipine clearance is decreased and AUC is increased by about 40-60%. Therefore, amlodipine dosage should be selected carefully, usually initiating therapy with dosages at the lower end of the recommended range. The greater frequency of decreased hepatic, renal, and/or cardiac function and of concomitant disease and drug therapy observed in the elderly also should be considered.

(See Geriatric Patients under Dosage and Administration: Special Populations.) Clinical studies of amlodipine did not include sufficient numbers of patients 65 years of age and older to determine whether geriatric patients respond differently than younger patients; however, other clinical experience has not revealed age-related differences in response or tolerance. No substantial differences in safety and efficacy relative to younger adults have been observed in geriatric patients receiving amlodipine in fixed combination with benazepril, olmesartan (with or without hydrochlorothiazide), telmisartan, or valsartan (with or without hydrochlorothiazide), but increased sensitivity cannot be ruled out. The manufacturer states that use of amlodipine in fixed combination with perindopril in geriatric patients is not recommended, as insufficient data are available to support dosage recommendations. The manufacturers state that safety and efficacy of amlodipine in fixed combination with atorvastatin have not been established in geriatric patients.

Precaution Exists
Geriatric management or monitoring precaution exists.

Drug Name	Narrative	REN	HEP	CARDIO	NEURO	PULM	ENDO
Amlodipine	General-Not recommended as first line therapy in the elderly. Cardiovascular-Start at 2.5 mg/day and slowly titrate upward. Peripheral edema may be common. Lower drug clearance may result in increased sensitivity to blood pressure lowering effects. Gastrointestinal-May cause or worsen pre-existing constipation.	N	Y	Y	N	N	N
Atorvastatin	Musculoskeletal-Higher incidence of myopathy in patients greater than 65 years of age. Hepatic-Monitor LFTs for liver dysfunction.	Y	Y	N	N	N	N