NORVASC PROTECT Amlodipine Besilate / Atorvastatin Calcium 5mg / 10mg Tablet 1's

Amlodipine besilate/Atorvastatin calcium (Norvasc Protect) Tablet is indicated for the following patient populations: Patients at increased cardiovascular risk due to the presence of the two modifiable risk factors hypertension and dyslipidemia; and/or Patients at increased cardiovascular risk due to the presence of symptomatic Coronary Heart Disease (CHD) expressed as angina with the additional modifiable risk factor of dyslipidemia; and/or Prevention of cardiovascular complications in hypertensive patients (see Prevention of Cardiovascular Complications as follows).
In these patients with multiple cardiovascular risk factors, amlodipine/atorvastatin is indicated for: Hypertension: The amlodipine component is indicated for the first-line treatment of hypertension and can be used as the sole agent to control blood pressure (BP) in the majority of patients. Patients not adequately controlled on a single antihypertensive agent (other than amlodipine) may benefit from the addition of the amlodipine component of Amlodipine besilate/Atorvastatin calcium (Norvasc Protect), in the same manner as they would benefit from the addition of amlodipine alone.
Amlodipine is also indicated to reduce the risk of fatal CHD and non-fatal myocardial infarction (MI), and to reduce the risk of stroke.
Coronary Artery Disease: The amlodipine component is indicated to reduce the risk of coronary revascularization procedures and the need for hospitalization due to angina in patients with coronary artery disease (CAD).
Chronic Stable Angina: The amlodipine component is indicated for the first-line treatment of myocardial ischemia, whether due to fixed obstruction (stable angina) and/or vasospasm/vasoconstriction (Prinzmetal's or variant angina) of coronary vasculature. Amlodipine besilate/Atorvastatin calcium (Norvasc Protect) may be used where the clinical presentation suggests a possible vasospastic/vasoconstrictive component but where vasospasm/vasoconstriction has not been confirmed. Amlodipine besilate/Atorvastatin calcium (Norvasc Protect) may be used alone or in combination with other antianginal drugs in patients with angina that is refractory to nitrates and/or adequate doses of beta-blockers.
Dyslipidemia: The atorvastatin component is indicated as an adjunct to diet for the treatment of patients with elevated total cholesterol (total-C), low-density lipoprotein cholesterol (LDL-C), apolipoprotein B (apo B), and triglycerides (TG) and to increase high-density lipoprotein-cholesterol (HDL-C) in patients with primary hypercholesterolemia (heterozygous familial and nonfamilial hypercholesterolemia), combined (mixed) hyperlipidemia (Fredrickson Types IIa and IIb), elevated serum TG levels (Fredrickson Type IV), and in patients with dysbetalipoproteinemia (Fredrickson Type III) who do not respond adequately to diet.
The atorvastatin component is also indicated for the reduction of total C and LDL-C in patients with homozygous familial hypercholesterolemia (FH).
Prevention of Cardiovascular Complications: In patients without clinically evident cardiovascular disease (CVD), and with or without dyslipidemia, but with multiple risk factors for CHD such as smoking, hypertension, diabetes, low HDL-C, or a family history of early CHD, atorvastatin is indicated to: Reduce the risk of fatal CHD and non-fatal MI; Reduce the risk of stroke; Reduce the risk of revascularization procedures and angina pectoris.
In patients with clinically evident CHD, atorvastatin is indicated to: Reduce the risk of non-fatal MI; Reduce the risk of fatal and non-fatal stroke; Reduce the risk for revascularization procedures; Reduce the risk of hospitalization for congestive heart failure (CHF); Reduce the risk of angina.
Pediatric Patients (10-17 years of age): Atorvastatin is indicated as an adjunct to diet to reduce total-C, LDL-C, and apo B levels in boys and postmenarchal girls, 10 to 17 years of age, with heterozygous FH if after an adequate trial of diet therapy the following findings are present: LDL-C remains ≥190 mg/dL; or 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.

 

General Considerations: Amlodipine besilate/Atorvastatin calcium (Norvasc Protect) is a combination product targeting concomitant cardiovascular conditions, hypertension/angina and dyslipidemia.
The dosage range for Amlodipine besilate/Atorvastatin calcium (Norvasc Protect) is 5 mg/10 mg to a maximum dose of 10 mg/20 mg once daily. The starting dose and maintenance dose should be individualized on the basis of both effectiveness and tolerance for each individual component in the treatment of hypertension/angina and dyslipidemia. Current treatment guidelines should be consulted to establish treatment goals for patients based on their baseline characteristics. Doses may be taken at any time of day with or without food.
As a component of multiple risk factor intervention, amlodipine/atorvastatin should be used in addition to non-pharmacological measures, including an appropriate diet, exercise and weight reduction in obese patients, smoking cessation, and to treat underlying medical problems, when the response to these measures have been inadequate.
Following initiation and/or titration of amlodipine/atorvastatin, lipid levels should be analyzed and BP measured within 2 to 4 weeks, and dosage of amlodipine and atorvastatin components should be adjusted accordingly. Titration for BP response may proceed more rapidly if clinically warranted.
Initial Therapy: Amlodipine besilate/Atorvastatin calcium (Norvasc Protect) may be used to initiate treatment in patients with hyperlipidemia and either hypertension or angina. The recommended starting dose of Amlodipine besilate/Atorvastatin calcium (Norvasc Protect) should be based on the appropriate combination of recommendations for the amlodipine and atorvastatin components considered separately. The maximum dose of the amlodipine component of Amlodipine besilate/Atorvastatin calcium (Norvasc Protect) is 10 mg once daily. The maximum dose of the atorvastatin component of Amlodipine besilate/Atorvastatin calcium (Norvasc Protect) is 20 mg once daily.
Substitution Therapy: Amlodipine besilate/Atorvastatin calcium (Norvasc Protect) may be substituted for its individually titrated components. Patients may be given the equivalent dose of Amlodipine besilate and Atorvastatin calcium or a dose of Amlodipine besilate/Atorvastatin calcium (Norvasc Protect) with increased amounts of amlodipine, atorvastatin or both for additional antianginal effects, BP lowering, or lipid lowering effect.
Amlodipine besilate/Atorvastatin calcium (Norvasc Protect) may be used to provide additional therapy for patients already on one of its components. As initial therapy for one indication and continuation of treatment of the other, the recommended starting dose of Amlodipine besilate/Atorvastatin calcium (Norvasc Protect) should be selected based on continuation of the component being used previously and on the recommended starting dose for the component being added.
Concomitant Medication (see also Interactions): The amlodipine component of Amlodipine besilate/Atorvastatin calcium (Norvasc Protect) has been safely co-administered with thiazide diuretics, alpha blockers, beta blockers, angiotensin-converting enzyme (ACE) inhibitors, long-acting nitrates, and with sublingual nitroglycerine. Amlodipine besilate/Atorvastatin calcium (Norvasc Protect) has also been safely administered with the aforementioned medicines.
The atorvastatin component of Amlodipine besilate/Atorvastatin calcium (Norvasc Protect) may be used in combination with a bile acid-binding resin for additive effect on lipid lowering. The combination of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors and fibrates should generally be avoided (see Precautions and Interactions).
Special Populations and Special Considerations for Dosing: Coronary Artery Disease (Amlodipine Studies): For patients with CAD, the recommended dosage range is 5 mg to 10 mg of amlodipine once daily. In clinical studies, the majority of patients required 10 mg once daily (see Pharmacology: Pharmacodynamics: Amlodipine/Atorvastatin Pharmacodynamics: Use in Patients with Coronary Artery Disease under Actions).
Primary Hypercholesterolemia and Combined (Mixed) Hyperlipidemia (Atorvastatin Studies): The majority of patients are controlled with 10 mg of atorvastatin once daily. A therapeutic response is evident within 2 weeks, and the maximum response is usually achieved within 4 weeks. The response is maintained during chronic therapy.
Homozygous Familial Hypercholesterolemia (Atorvastatin Studies): In a compassionate-use study of patients with homozygous FH, most patients responded to 80 mg of atorvastatin with a greater than 15% reduction in LDL-C (18%-45%).
Use in Patients with Impaired Hepatic Function: Amlodipine besilate/Atorvastatin calcium (Norvasc Protect) should not be used in patients with hepatic impairment (see Contraindications and Precautions).
Use in Patients with Impaired Renal Function: No adjustment of the dose is required in patients with impaired renal function (see Precautions).
Use in the Elderly: No adjustment of the dose is required in elderly patients.
Use in Children: There have been no studies conducted to determine the safety or effectiveness of Amlodipine besilate/Atorvastatin calcium (Norvasc Protect) (combination product) in pediatric populations. However, there have been studies in pediatric populations with amlodipine alone and atorvastatin alone (see as follows).
Studies with amlodipine: The recommended antihypertensive oral dose in pediatric patients aged 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 Pharmacology: Pharmacodynamics and Pharmacokinetics under Actions).
The effect of amlodipine on BP in patients less than 6 years of age is not known.
Studies with atorvastatin: Use in Pediatric Patients with Severe Dyslipidemias: For patients aged 10 years and above, the recommended starting dose is 10 mg of atorvastatin per day. The dose may be increased to 80 mg daily according to the response and tolerability. Doses should be individualized according to the recommended goal of therapy (see Indications/Uses and Pharmacology: Pharmacodynamics under Actions). Adjustments should be made at intervals of 4 weeks or more.
Experience in pediatric patients younger than 10 years of age is derived from open-label studies (see Adverse Reactions and Pharmacology: Pharmacodynamics and Pharmacokinetics: Special Populations under Actions).
Use in Combination with Other Medicinal Compounds: Studies with atorvastatin: In cases where co-administration of atorvastatin with cyclosporine, telaprevir, the combination tipranavir/ritonavir, or glecaprevir/pibrentasvir is necessary, the dose of atorvastatin should not exceed 10 mg.
Use of atorvastatin is not recommended in patients taking letermovir co-administered with cyclosporine.
Pharmacokinetic drug interactions that result in increased systemic concentration of atorvastatin have also been noted with other human immunodeficiency virus (HIV) protease inhibitors (lopinavir/ritonavir, saquinavir/ritonavir, darunavir/ritonavir, fosamprenavir, fosamprenavir/ritonavir and nelfinavir), hepatitis C (HCV) protease inhibitors (boceprevir, elbasvir/grazoprevir, simeprevir), clarithromycin, itraconazole, and letermovir. Caution should be used when co-prescribing atorvastatin and appropriate clinical assessment is recommended to ensure that the lowest dose necessary of atorvastatin is employed (see Skeletal Muscle Effects under Precautions and Interactions).

 

Overdosage

May be taken with or without food.

Amlodipine besilate/Atorvastatin calcium (Norvasc Protect) is contraindicated in patients who: Have known hypersensitivity to dihydropyridines,* amlodipine, atorvastatin, or any component of this medication including: calcium carbonate, croscarmellose sodium, microcrystalline cellulose, pregelatinized starch, polysorbate 80, magnesium stearate, silicon dioxide and hydroxypropylcellulose.
Have active liver disease or unexplained persistent elevations of serum transaminases >3 x the upper limit of normal [ULN].
Are pregnant, breast-feeding, or of childbearing potential who are not using adequate contraceptive measures. Amlodipine besilate/Atorvastatin calcium (Norvasc Protect) should be administered to women of childbearing age only when such patients are highly unlikely to conceive and have been informed of the potential hazards to the fetus.
*Amlodipine is a dihydropyridine calcium channel blocker.

Use in Patients with Heart Failure: In a long-term, placebo-controlled study (PRAISE-2) of amlodipine-treated patients with New York Heart Association (NYHA) class III-IV heart failure of nonischemic etiology, amlodipine was associated with increased reports of pulmonary edema despite no significant difference in the incidence of worsening heart failure as compared to placebo (see Pharmacology: Pharmacodynamics under Actions).
Use in Patients with Impaired Hepatic Function (see also Contraindications): Hepatic Effects: As with other lipid-lowering agents of the HMG-CoA reductase inhibitor class, moderate (>3 x ULN) elevations of serum transaminases have been reported following therapy with atorvastatin. Liver function was monitored during pre-marketing as well as post-marketing clinical studies of atorvastatin given at doses of 10 mg, 20 mg, 40 mg and 80 mg.
Persistent increases in serum transaminases (>3 x ULN on two or more occasions) occurred in 0.7% of patients who received atorvastatin in these clinical trials. The incidence of these abnormalities was 0.2%, 0.2%, 0.6%, and 2.3% for 10 mg, 20 mg, 40 mg and 80 mg respectively. Increases were generally not associated with jaundice or other clinical signs or symptoms. When the dosage of atorvastatin was reduced, or drug treatment interrupted or discontinued, transaminase levels returned to pre-treatment levels. Most patients continued treatment on a reduced dose of atorvastatin without sequelae.
Liver function tests should be performed before the initiation of treatment and periodically thereafter. Patients who develop any signs or symptoms suggesting liver injury should have liver function tests performed. Patients who develop increased transaminase levels should be monitored until the abnormality(ies) resolve(s). Should an increase in alanine transaminase (ALT) or aspartate transaminase (AST) >3 x ULN persist, reduction of dose or withdrawal of Amlodipine besilate/Atorvastatin calcium (Norvasc Protect) is recommended. Atorvastatin can cause an elevation in transaminases (see Adverse Reactions).
Amlodipine besilate/Atorvastatin calcium (Norvasc Protect) should be used with caution in patients who consume substantial quantities of alcohol and/or have a history of liver disease. Active liver disease or unexplained persistent transaminase elevations are contraindications to the use of Amlodipine besilate/Atorvastatin calcium (Norvasc Protect) (see Contraindications).
Skeletal Muscle Effects: Myalgia has been reported in atorvastatin-treated patients (see Adverse Reactions). Myopathy, defined as muscle aching or muscle weakness in conjunction with increases in creatine phosphokinase (CPK) values >10 x ULN, should be considered in any patient with diffuse myalgias, muscle tenderness or weakness, and/or marked elevation of CPK. Patients should be advised to promptly report unexplained muscle pain, tenderness or weakness, particularly if accompanied by malaise or fever. Amlodipine besilate/Atorvastatin calcium (Norvasc Protect) therapy should be discontinued if markedly elevated CPK levels occur or myopathy is diagnosed or suspected. The risk of myopathy is increased with concurrent administration of drugs that increase the systemic concentration of atorvastatin (see Interactions and Pharmacology: Pharmacokinetics under Actions). Many of these drugs inhibit cytochrome P450 3A4 metabolism and/or drug-transport. CYP3A4 is the primary hepatic isozyme known to be involved in the biotransformation of atorvastatin. Physicians considering combined therapy with atorvastatin and fibric acid derivatives, erythromycin, immunosuppressive drugs, azole antifungals, HIV/HCV protease inhibitors, HCV NS5A/NS5B inhibitors, letermovir, or lipid-modifying doses of niacin should carefully weigh the potential benefits and risks and should carefully monitor patients for any signs and symptoms of muscle pain, tenderness, or weakness, particularly during the initial months of therapy and during any periods of upward dosage titration of either drug. Therefore, lower starting and maintenance doses of the atorvastatin component should also be considered when taken concomitantly with the aforementioned drugs (see Dosage & Administration). The concurrent use of atorvastatin and fusidic acid is not recommended, therefore, temporary suspension of atorvastatin is advised during fusidic acid therapy (see Interactions). Periodic CPK determinations may be considered in such situations, but there is no assurance that such monitoring will prevent the occurrence of severe myopathy. Amlodipine besilate/Atorvastatin calcium (Norvasc Protect) may cause an elevation of CPK due to the atorvastatin component (see Adverse Reactions).
There have been very rare reports of an immune-mediated necrotizing myopathy (IMNM) during or aftertreatment with some statins (see Adverse Reactions). IMNM is clinically characterized by persistent proximal muscle weakness and elevated serum creatine kinase, which persist despite discontinuation of statin treatment, positive anti-HMG CoA reductase antibody and improvement with immunosuppressive agents.
As with other drugs in the class of HMG-CoA reductase inhibitors, rare cases of rhabdomyolysis with acute renal failure secondary to myoglobinuria, have been reported. A history of renal impairment may be a risk factor for the development of rhabdomyolysis. Such patients merit closer monitoring for skeletal muscle effects. Amlodipine besilate/Atorvastatin calcium (Norvasc Protect) therapy should be temporarily withheld or discontinued in any patient with an acute, serious condition suggestive of a myopathy or having a risk factor predisposing to the development of renal failure secondary to rhabdomyolysis (e.g., severe acute infection; hypotension; major surgery; trauma; severe metabolic, endocrine and electrolyte disorders; and uncontrolled seizures). Control of hypertension may be continued with the appropriate dose of amlodipine.
Hemorrhagic Stroke: A post-hoc analysis of a clinical study in 4,731 patients without CHD who had a stroke or transient ischemic attack (TIA) within the preceding 6 months and were initiated on atorvastatin 80 mg revealed a higher incidence of hemorrhagic stroke in the atorvastatin 80 mg group compared to placebo (55 atorvastatin vs. 33 placebo). Patients with hemorrhagic stroke on entry appeared to be at increased risk for recurrent hemorrhagic stroke (7 atorvastatin vs. 2 placebo). However, in patients treated with atorvastatin 80 mg there were fewer strokes of any type (265 atorvastatin vs. 311 placebo) and fewer CHD events (123 atorvastatin vs. 204 placebo) (see Pharmacology: Pharmacodynamics: Recurrent Stroke under Actions).
Endocrine Function: Increases in glycated hemoglobin (HbA1c) and fasting serum glucose levels have been reported with HMG-CoA reductase inhibitors, including atorvastatin. The risk of hyperglycemia, however, is outweighed by the reduction in vascular risk with statins.
Effects on Ability to Drive and Use Machines: Based on the available information on amlodipine and atorvastatin, this medication is unlikely to impair a patient's ability to drive or use machinery.

 

Use In Pregnancy & Lactation

Combination therapy with amlodipine and atorvastatin has been evaluated for safety in 1,092 patients in double blind, placebo-controlled studies treated for concomitant hypertension and dyslipidemia. In clinical trials, no adverse events peculiar to combination therapy with amlodipine and atorvastatin have been observed. Adverse events have been limited to those that were reported previously with amlodipine and/or atorvastatin (please see respective adverse event experiences as follows).
In general, combination therapy with amlodipine and atorvastatin was well tolerated. For the most part, adverse events have been mild or moderate in severity. In controlled clinical trials, discontinuation of therapy due to adverse events or laboratory abnormalities was required in 5.1% of patients treated with both amlodipine and atorvastatin compared to 4.0% of patients given placebo.
The following information is based on clinical trials and postmarketing experience with amlodipine and atorvastatin.
Amlodipine Experience: Amlodipine is well tolerated. In placebo-controlled clinical trials involving patients with hypertension or angina, the most commonly observed side effects were: See Table 13.

In these clinical trials no pattern of clinically significant laboratory test abnormalities related to amlodipine has been observed.
Less commonly observed side effects in marketing experience with amlodipine include: See Table 14.

Rarely reported events were allergic reactions including pruritus, rash, angioedema, and erythema multiforme.
Hepatitis, jaundice and hepatic enzyme elevations have also been reported very infrequently (mostly consistent with cholestasis). Some cases severe enough to require hospitalization have been reported in association with use of amlodipine. In many instances, causal association is uncertain.
As with other calcium channel blockers, the following adverse events have been rarely reported and cannot be distinguished from the natural history of the underlying disease: MI, arrhythmia (including bradycardia, ventricular tachycardia and atrial fibrillation) and chest pain.
Pediatric Patients (Aged 6-17 years): Amlodipine is well tolerated in children. Adverse events were similar to those seen in adults. In a study of 268 children, the most frequently reported adverse events were: See Table 15.

The majority of adverse events were mild or moderate. Severe adverse events (predominantly headache) were experienced by 7.2% with amlodipine 2.5 mg, 4.5% with amlodipine 5 mg, and 4.6% with placebo. The most common cause of discontinuation from the study was uncontrolled hypertension. There were no discontinuations due to laboratory abnormalities. There was no significant change in heart rate.
Atorvastatin Experience: Atorvastatin is generally well-tolerated. Adverse reactions have usually been mild and transient. In the atorvastatin placebo-controlled clinical trial database of 16,066 (8,755 atorvastatin vs. 7,311 placebo) patients treated for a median period of 53 weeks, 5.2% of patients on atorvastatin discontinued due to adverse reactions compared to 4.0% of the patients on placebo.
The most frequent (≥1%) adverse effects that may be associated with atorvastatin therapy, reported in patients participating in placebo-controlled clinical studies include: Infections and infestations: Nasopharyngitis.
Metabolism and nutrition disorders: Hyperglycemia.
Respiratory, thoracic and mediastinal disorders: Pharyngolaryngeal pain, epistaxis.
Gastrointestinal disorders: Diarrhea, dyspepsia, nausea, flatulence.
Musculoskeletal and connective tissue disorders: Arthralgia, pain in extremity, musculoskeletal pain, muscle spasms, myalgia, joint swelling.
Investigations: Liver function test abnormal, blood creatine phosphokinase increased.
Additional adverse effects reported in atorvastatin placebo-controlled clinical trials include: Psychiatric disorders: Nightmare.
Eye disorders: Blurred vision.
Ear and labyrinth disorders: Tinnitus.
Gastrointestinal disorders: Abdominal discomfort, eructation.
Hepatobiliary disorders: Hepatitis, cholestasis.
Skin and subcutaneous tissue disorders: Urticaria.
Musculoskeletal and connective tissue disorders: Muscle fatigue, neck pain.
General disorders and administration site conditions: Malaise, pyrexia.
Investigations: White blood cells positive in urine.
Not all effects listed previously have been causally associated with atorvastatin therapy.
Pediatric Patients: Patients treated with atorvastatin had an adverse experience profile generally similar to that of patients treated with placebo. The most common adverse experiences observed in both groups, regardless of causality assessment, were infections.
No clinically significant effect on growth and sexual maturation was observed in a 3-year study in children ages 6 and above based on the assessment of overall maturation and development, assessment of Tanner Stage, and measurement of height and weight. The safety and tolerability profile in pediatric patients was similar to the known safety profile of atorvastatin in adult patients.
Post-marketing Experience: In post-marketing experience, the following additional undesirable effects have been reported with atorvastatin: Blood and lymphatic system disorders: Thrombocytopenia.
Immune system disorders: Allergic reactions (including anaphylaxis).
Injury, poisoning and procedural complications: Tendon rupture.
Metabolism and nutrition disorders: Weight gain.
Nervous system disorders: Hypoesthesia, amnesia, dizziness, dysgeusia.
Gastrointestinal disorders: Pancreatitis.
Skin and subcutaneous tissue disorders: Stevens-Johnson syndrome, toxic epidermal necrolysis, angioedema, erythema multiforme, bullous rashes.
Musculoskeletal and connective tissue disorders: Rhabdomyolysis, immune-mediated necrotizing myopathy, myositis, back pain.
General disorders and administration site conditions: Chest pain, peripheral edema, fatigue.

 

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 [CI]: 80%-103%), but the AUC of atorvastatin increased by 18% (90% CI: 109%-127%) in the presence of amlodipine.
No drug interaction studies have been conducted with Amlodipine besilate/Atorvastatin calcium (Norvasc Protect) and other drugs, although studies have been conducted using the individual amlodipine and atorvastatin components, as described as follows: Amlodipine Interactions: Amlodipine has been safely administered with thiazide diuretics, alpha blockers, beta blockers, ACE inhibitors, long-acting nitrates, sublingual nitroglycerine, non-steroidal anti-inflammatory drugs, antibiotics, and oral hypoglycemic drugs.
CYP3A4 Inhibitors: Co-administration of a 180 mg daily dose of diltiazem with 5 mg of amlodipine in elderly hypertensive patients (69-87 years of age) resulted in a 57% increase in amlodipine systemic exposure. Erythromycin co-administration in healthy volunteers (18-43 years of age) did not significantly change amlodipine systemic exposure (22% increase in AUC). Although the clinical relevance of these findings is uncertain, the pharmacokinetic variations may be more pronounced in the elderly.
Strong inhibitors of CYP3A4 (e.g., ketoconazole, itraconazole, ritonavir) may increase the plasma concentrations of amlodipine to a greater extent than diltiazem. Amlodipine should be used with caution together with CYP3A4 inhibitors.
Clarithromycin: Clarithromycin is an inhibitor of CYP3A4. There is an increased risk of hypotension in patients receiving clarithromycin with amlodipine. Close observation of patients is recommended when amlodipine is co-administered with clarithromycin.
CYP3A4 Inducers: There are no data available regarding the effect of CYP3A4 inducers on amlodipine. The concomitant use of CYP3A4 inducers (e.g., rifampicin, Hypericum perforatum) may give a lower plasma concentration of amlodipine. Amlodipine should be used with caution together with CYP3A4 inducers.
Grapefruit Juice: Co-administration of 240 mL of grapefruit juice with a single oral dose of amlodipine 10 mg in 20 healthy volunteers had no significant effect on the pharmacokinetics of amlodipine. The study did not allow examination of the effect of genetic polymorphism in CYP3A4, the primary enzyme responsible for metabolism of amlodipine; therefore, administration of amlodipine with grapefruit or grapefruit juice is not recommended as bioavailability may be increased in some patients resulting in increased BP-lowering effects.
In vitro data from studies with human plasma indicate that amlodipine has no effect on protein binding of the drugs tested (digoxin, phenytoin, warfarin, or indomethacin).
In the following studies, there were no significant changes in the pharmacokinetics of either amlodipine or another drug within the study, when co-administered.
Special Studies: Effect of Other Agents on Amlodipine: Cimetidine: Co-administration of amlodipine with cimetidine did not alter the pharmacokinetics of amlodipine.
Aluminum/Magnesium (Antacid): Co-administration of an aluminum/magnesium antacid with a single dose of amlodipine had no significant effect on the pharmacokinetics of amlodipine.
Sildenafil: A single 100 mg dose of sildenafil in subjects with essential hypertension had no effect on the pharmacokinetic parameters of amlodipine. When amlodipine and sildenafil were used in combination, each agent independently exerted its own BP-lowering effect.
Special Studies: Effect of Amlodipine on Other Agents: Digoxin: Co-administration of amlodipine with digoxin did not change serum digoxin levels or digoxin renal clearance in normal volunteers.
Ethanol (Alcohol): Single and multiple 10 mg doses of amlodipine had no significant effect on the pharmacokinetics of ethanol.
Warfarin: Co-administration of amlodipine with warfarin did not change the warfarin prothrombin response time.
Cyclosporine: No drug interaction studies have been conducted with cyclosporine and amlodipine in healthy volunteers or other populations with the exception of renal transplant patients. Various studies in renal transplant patients report that amlodipine co-administration with cyclosporine affect trough concentrations of cyclosporine from no change up to an average increase of 40%. Consideration should be given for monitoring cyclosporine levels in renal transplant patients on amlodipine.
Tacrolimus: There is a risk of increased tacrolimus blood levels when co-administered with amlodipine. In order to avoid toxicity of tacrolimus, administration of amlodipine in a patient treated with tacrolimus requires monitoring of tacrolimus blood levels and dose adjustment of tacrolimus when appropriate.
Mechanistic Target of Rapamycin (mTOR) Inhibitors: mTOR inhibitors such as sirolimus, temsirolimus, and everolimus are CYP3A substrates. Amlodipine is a weak CYP3A inhibitor. With concomitant use of mTOR inhibitors, amlodipine may increase exposure of mTOR inhibitors.
Drug/Laboratory Test Interactions: None known.
Atorvastatin Interactions: The risk of myopathy during treatment with HMG-CoA reductase inhibitors is increased with concurrent administration of cyclosporine, fibric acid derivatives, lipid-modifying doses of niacin or cytochrome P450 3A4/transporter inhibitors (e.g., erythromycin and azole antifungals) (see as follows and also Use in Combination with Other Medicinal Compounds under Dosage & Administration and Skeletal Muscle Effects under Precautions).
Inhibitors of Cytochrome P450 3A4: Atorvastatin is metabolized by cytochrome P450 3A4. Concomitant administration of atorvastatin with inhibitors of cytochrome P450 3A4 can lead to increases in plasma concentrations of atorvastatin. The extent of interaction and potentiation of effects depend on the variability of effect on cytochrome P450 3A4.
Erythromycin/Clarithromycin: Co-administration of atorvastatin and erythromycin (500 mg four times daily) or clarithromycin (500 mg twice daily), known inhibitors of cytochrome P450 3A4, was associated with higher plasma concentrations of atorvastatin (see Skeletal Muscle Effects under Precautions and Pharmacology: Pharmacokinetics under Actions).
Protease Inhibitors: Co-administration of atorvastatin and protease inhibitors, known inhibitors of cytochrome P450 3A4, was associated with increased plasma concentrations of atorvastatin (see Pharmacology: Pharmacokinetics under Actions).
Diltiazem Hydrochloride: Co-administration of atorvastatin (40 mg) with diltiazem (240 mg) was associated with higher plasma concentrations of atorvastatin (see Pharmacology: Pharmacokinetics under Actions).
Cimetidine: An atorvastatin interaction study with cimetidine was conducted, and no clinically significant interactions were seen (see Pharmacology: Pharmacokinetics under Actions).
Itraconazole: Concomitant administration of atorvastatin (20-40 mg) and itraconazole (200 mg) was associated with an increase in atorvastatin AUC (see Pharmacology: Pharmacokinetics under Actions).
Grapefruit Juice: Contains one or more components that inhibit CYP3A4 and can increase plasma concentrations of atorvastatin, especially with excessive grapefruit juice consumption (>1.2 L/day) (see Pharmacology: Pharmacokinetics under Actions).
Transporter Inhibitors: Atorvastatin is a substrate of the hepatic transporters (see Pharmacology: Pharmacokinetics under Actions).
Concomitant administration of atorvastatin 10 mg and cyclosporine 5.2 mg/kg/day resulted in an increase in exposure to atorvastatin (ratio of AUC: 8.7; see Pharmacology: Pharmacokinetics under Actions). Cyclosporine is an inhibitor of organic anion-transporting polypeptide 1B1 (OATP1B1), OATP1B3, multi-drug resistance protein 1 (MDR1), and breast cancer resistance protein (BCRP) as well as CYP3A4, thus it increases exposure to atorvastatin. Do not exceed 10 mg atorvastatin daily (see Use in Combination with Other Medicinal Compounds under Dosage & Administration).
Glecaprevir and pibrentasvir are inhibitors of OATP1B1, OATP1B3, MDR1 and BCRP, thus they increase exposure to atorvastatin. Do not exceed 10 mg atorvastatin daily (see Use in Combination with Other Medicinal Compounds under Dosage & Administration).
Concomitant administration of atorvastatin 20 mg and letermovir 480 mg daily resulted in an increase in exposure to atorvastatin (ratio of AUC: 3.29; see Pharmacology: Pharmacokinetics under Actions). Letermovir inhibits efflux transporters P-gp, BCRP, MRP2, OAT2 and hepatic transporter OATP1B1/1B3, thus it increases exposure to atorvastatin. Do not exceed 20 mg atorvastatin daily (see Use in Combination with Other Medicinal Compounds under Dosage & Administration).
The magnitude of CYP3A- and OATP1B1/1B3-mediated drug interactions on co-administered drugs may be different when letermovir is co-administered with cyclosporine. Use of atorvastatin is not recommended in patients taking letermovir co-administered with cyclosporine.
Elbasvir and grazoprevir are inhibitors of OATP1B1, OATP1B3, MDR1 and BCRP, thus they increase exposure to atorvastatin. Use with caution and lowest dose necessary (see Use in Combination with Other Medicinal Compounds under Dosage & Administration).
Inducers of Cytochrome P450 3A4: Concomitant administration of atorvastatin with inducers of cytochrome P450 3A4 (e.g., efavirenz, rifampin) can lead to variable reductions in plasma concentrations of atorvastatin. Due to the dual interaction mechanism of rifampin (cytochrome P450 3A4 induction and inhibition of hepatocyte uptake transporter OATP1B1), 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 (see Pharmacology: Pharmacokinetics under Actions).
Antacids: Co-administration of atorvastatin with an oral antacid suspension containing magnesium and aluminum hydroxides decreased atorvastatin plasma concentrations (ratio of AUC: 0.66); however, LDL-C reduction was not altered.
Antipyrine: Because atorvastatin does not affect the pharmacokinetics of antipyrine, interactions with other drugs metabolized via the same cytochrome isozymes are not expected.
Colestipol: Plasma concentrations of atorvastatin were lower (ratio of concentration: 0.74) when colestipol was administered with atorvastatin. However, lipid effects were greater when atorvastatin and colestipol were co-administered than when either drug was given alone.
Digoxin: When multiple doses of digoxin and 10 mg of atorvastatin were co-administered, steady-state plasma digoxin concentrations were unaffected. However, digoxin concentrations increased (ratio of AUC: 1.15) following administration of digoxin with 80 mg of atorvastatin daily. Patients taking digoxin should be monitored appropriately.
Azithromycin: Co-administration of atorvastatin (10 mg once daily) and azithromycin (500 mg once daily) did not alter the plasma concentrations of atorvastatin.
Oral Contraceptives: Co-administration of atorvastatin with an oral contraceptive containing norethindrone and ethinyl estradiol increased the area under the concentration versus time curve (AUC) values for norethindrone (ratio of AUC: 1.28) and ethinyl estradiol (ratio of AUC: 1.19), respectively. These increases should be considered when selecting an oral contraceptive for a woman taking atorvastatin.
Warfarin: An atorvastatin interaction study with warfarin was conducted, and no clinically significant interactions were observed.
Fusidic Acid: Although interaction studies with atorvastatin and fusidic acid have not been conducted, there is an increased risk of rhabdomyolysis in patients receiving a combination of statins, including atorvastatin, and fusidic acid. The mechanism of this interaction is not known. In patients where the use of systemic fusidic acid is considered essential, statin treatment should be discontinued throughout the duration of fusidic acid treatment. Statin therapy may be re-introduced seven days after the last dose of fusidic acid.
In exceptional circumstances, where prolonged systemic fusidic acid is needed, e.g., for the treatment of severe infections, the need for co-administration of atorvastatin and fusidic acid should only be considered on a case by case basis and under close medical supervision. The patient should be advised to seek medical advice immediately if they experience any symptoms of muscle weakness, pain or tenderness.
Colchicine: Although interaction studies with atorvastatin and colchicine have not been conducted, cases of myopathy have been reported with atorvastatin co-administered with colchicine, and caution should be exercised when prescribing atorvastatin with colchicine.
Other Concomitant Therapy: In clinical studies, atorvastatin was used concomitantly with antihypertensive agents and estrogen replacement therapy without evidence of clinically significant adverse interactions. Interaction studies with specific agents have not been conducted.

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Calcium Antagonists / Dyslipidaemic Agents