Amlodipine/ Atorvastatin

Registered South African indications:

• Increased cardiovascular risk due to concomitant hypertension and dyslipidaemia
• Angina and concomitant dyslipidaemia

Registered South African contraindications

• Hypersensitivity to the active ingredient or any of the excipients in this combination product
• Known hypersensitivity to dihydropyridines (amlodipine is a dihydropyridine calcium channel blocker)
• Active liver disease or unexplained persistent elevations of serum transaminases exceeding 3 times the upper limit of normal
• Pregnancy
• Breastfeeding
• Women of childbearing potential not using appropriate contraception
• Severe hypotension
• Shock (including cardiogenic shock)
• Left ventricular outflow tract obstruction (e.g., severe aortic stenosis)
• Haemodynamically unstable heart failure after acute myocardial infarction
• For dose combinations of amlodipine/ atorvastatin where the atorvastatin component is higher than 10mg: contraindicated in patients taking the HIV protease inhibitors tipranavir plus ritonavir or the hepatitis C protease inhibitor telaprevir
• Patients taking the hepatitis C antivirals glecaprevir/pibrentasvir

South African recommendations

Hepatic effects of amlodipine/ atorvastatin

• Atorvastatin therapy has been associated with elevations in serum transaminases (>3 times the upper limit of normal)
• Persistent increases in serum transaminases occurred in 0.7% of atorvastatin users, with varying incidences based on the dosage
• Liver function tests should be conducted before starting amlodipine/ atorvastatin and as needed thereafter
• If liver injury, hyperbilirubinaemia, or jaundice occurs, amlodipine/ atorvastatin treatment should be interrupted. If an alternate aetiology is not found, do not restart treatment with amlodipine/ atorvastatin
• Amlodipine/ atorvastatin is not recommended for patients with significant alcohol consumption, a history of liver disease, active liver disease, or unexplained persistent transaminase elevations

Skeletal muscle effects

• Myalgia has been reported in patients treated with the atorvastatin component of this combination product
• Myopathy, characterised by muscle pain or weakness and elevated creatine phosphokinase (CPK) values >10 times the upper limit of normal (ULN), should be considered for patients with diffuse myalgias, muscle tenderness or weakness, and/or marked elevation of CPK
• Patients are advised to report unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever
• Stop if there is a significant CPK increase, or if myopathy is diagnosed or suspected
• The risk of myopathy is higher when amlodipine/atorvastatin is used with certain medications including ciclosporin, fibric acid derivatives, erythromycin, niacin, azole antifungals, and various HIV or hepatitis C protease inhibitors. These drugs can affect the metabolism of atorvastatin
• Regular monitoring for muscle symptoms is advised, especially during the initial months and when increasing doses
• Consideration for lower starting and maintenance doses of atorvastatin is recommended when used with these medicines
• Discontinue treatment during fusidic acid treatment and resume seven days after the last fusidic acid dose
• Periodic CPK monitoring may be considered but doesn't guarantee prevention of severe myopathy
• Rhabdomyolysis with acute renal failure due to myoglobinuria has been reported. Patients with renal impairment should be closely monitored for skeletal muscle effects
• Temporarily withhold or discontinue in patients with acute conditions that may predispose to myopathy or 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

Risk of rhabdomyolysis

• Amlodipine/ atorvastatin should be used cautiously in patients with factors predisposing them to rhabdomyolysis
• Before starting statin therapy with amlodipine/atorvastatin, measure creatine phosphokinase (CPK) levels in patients with:
  • Renal impairment
  • Hypothyroidism
  • Personal or family history of hereditary muscular disorders
  • Previous muscular toxicity from statins or fibrates
  • History of liver disease or substantial alcohol consumption
  • Elderly patients (over 70 years), based on the presence of other rhabdomyolysis risk factors
• Regular clinical monitoring is advised for these patients
• Do not initiate treatment if baseline CPK levels are significantly elevated (> 5 times the upper limit of normal)

CPK measurement considerations

• Avoid CPK measurement post-strenuous exercise or in presence of other factors that can raise CPK, as this affects result interpretation
• If initial CPK is significantly high (> 5 times ULN), retest within 5-7 days

Monitoring while on treatment

• Prompt reporting of muscle pain, cramps, or weakness, particularly with malaise or fever, is crucial
• Test CPK levels if such symptoms occur. Stop treatment if CPK levels are significantly high (>5 times ULN)
• Consider discontinuing treatment for severe muscular symptoms, even if CPK levels are only elevated up to ≤5 times ULN
• Reintroduction of atorvastatin or an alternative statin might be possible if symptoms resolve and CPK levels normalise, starting at the lowest dose

Discontinuation guidelines

• Amlodipine/ atorvastatin should be stopped if there's a clinically significant elevation in CPK (>10 times ULN) or if rhabdomyolysis is diagnosed or suspected

Increased rhabdomyolysis risk with concurrent medications

• The risk is higher when amlodipine/ atorvastatin is used with medications like ciclosporin, erythromycin, clarithromycin, itraconazole, ketoconazole, nefazodone, niacin, gemfibrozil, other fibric acid derivatives, or HIV-protease inhibitors
• Regular monitoring for muscle symptoms is recommended, especially during the start of therapy and dose increases

Risk of haemorrhagic stroke

• There's an increased risk of recurrent stroke and transient ischaemic attack associated with amlodipine/ atorvastatin

Impact on endocrine function

• Increases in HbA1c and fasting serum glucose levels have been noted with the atorvastatin component of amlodipine/ atorvastatin
• Statins, in general, may raise blood glucose levels, potentially leading to hyperglycaemia, particularly in patients at high risk of developing diabetes
• The vascular risk reduction benefits of statins typically outweigh the risk of increased blood glucose
• High-risk patients on amlodipine/ atorvastatin (identified by fasting glucose 5.6-6.9mmol/L, BMI>30kg/m², raised triglycerides, hypertension) should be regularly monitored for any deterioration in glycaemic control

Ability to drive and use machines

• Amlodipine/ atorvastatin may cause dizziness and syncope or muscle events that can impair a patient’s ability to drive or use machinery

Amlodipine

Patients with heart failure

• In patients with NYHA Class II and IV heart failure of non-ischemic origin, amlodipine use has been linked to a higher incidence of pulmonary oedema

Forms avail. in SA and covered in this monograph: fct

South African registered indications and dosages

Increased cardiovascular risk due to concomitant hypertension and dyslipidaemia
Angina and concomitant dyslipidaemia

Amlodipine/ Atorvastatin
5/10 (mg)
5/20 (mg)
10/10 (mg)
10/20 (mg)
10/40 (mg)
10/80 (mg) 

• Oral (fct): Dosage range: 5/10-10/80 (mg): 1 tab, dly; Individualise dosing; Max: 10/80mg/24hrs

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Doses may be taken at any time of day with or without food

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May be used either alone or in combination with other anti-hypertensive or anti-anginal medicines

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General considerations
Dosages should be personalised based on effectiveness and tolerance for treating hypertension/angina and dyslipidaemia. It's important to consult current treatment guidelines for setting patient-specific treatment goals based on baseline values

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Amlodipine/atorvastatin should be used as part of a comprehensive risk factor intervention, alongside non-pharmacological measures such as a suitable diet, exercise, weight reduction for obese patients, smoking cessation, and addressing underlying medical issues, especially when the response to these measures alone is insufficient

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Following initiation and/or titration of amlodipine/atorvastatin, lipid levels should be analysed, and blood pressure measured within 2-4 weeks, and dosage of the amlodipine and atorvastatin components should be adjusted accordingly. Titration for blood pressure response may proceed more rapidly if clinically warranted

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Use with ciclosporin
In cases where co-administration of atorvastatin with ciclosporin is necessary, the dose of atorvastatin should not exceed 10mg

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For initial therapy, substitution therapy and concomitant medication use see Additional Prescribing Points

Not established for use in children and adolescents

Pregnancy

South African recommendations

• Contraindicated
• Amlodipine/ atorvastatin is contraindicated in patients who are pregnant, or of childbearing potential not using appropriate contraceptive measures
• Should only be used in women of childbearing potential who are using appropriate contraceptive measures

Breastfeeding

South African recommendations

• Contraindicated
• Amlodipine/ atorvastatin is contraindicated in patients who are breastfeeding their infants

Fertility

South African recommendations

• No information available

South African recommendations

• No dose adjustment recommended

South African recommendations

• Contraindicated
  Contraindicated in the presence of  active liver disease or unexplained persistent elevations of serum transaminases exceeding 3 times the upper limit of normal
  Amlodipine/ atorvastatin should not be used in patients with hepatic impairment

South African recommendations

• No dose adjustment recommended
  Amlodipine/ atorvastatin is well tolerated at similar doses in elderly or younger patients. Therefore, normal dosage regimens are recommended

Combination products may have additional pharmacological effects not accounted for by the action of the individual ingredients

Amlodipine

Blood and Lymphatic System Disorders

Very rare

• Leukopenia
• Thrombocytopenia

Immune System Disorders

Very rare

• Allergic reaction

Metabolism and Nutrition Disorders

Very rare

• Hyperglycaemia

Psychiatric Disorders

Uncommon

• Insomnia
• Altered mood

Nervous System Disorders

Common

• Somnolence
• Dizziness
• Headaches

Uncommon

• Tremor
• Dysgeusia
• Syncope
• Hypoaesthesia
• Paraesthesia

Very rare

• Hypertonia
• Peripheral neuropathy

Eye Disorders

Uncommon

• Visual impairment

Ear and Labyrinth Disorders

Uncommon

• Tinnitus

Cardiac Disorders

Common

• Palpitations

Very rare

• Myocardial infarction
• Dysrhythmia (including bradycardia, ventricular tachycardia, and atrial fibrillation)

Vascular Disorders

Common

• Flushing

Uncommon

• Hypotension

Very rare

• Vasculitis

Respiratory, Thoracic, and Mediastinal Disorders

Uncommon

• Dyspnoea
• Rhinitis

Very rare

• Coughing

Gastrointestinal Disorders

Common

• Abdominal pain
• Nausea

Uncommon

• Vomiting
• Dyspepsia
• Change in bowel habits
• Dry mouth

Very rare

• Pancreatitis
• Gastritis
• Gingival hyperplasia

Hepatobiliary Disorders

Very rare

• Hepatitis
• Jaundice
• Hepatic enzyme elevations (mostly consistent with cholestasis)

Skin and Subcutaneous Tissue Disorders

Uncommon

• Alopecia
• Purpura
• Skin discolouration
• Hyperhidrosis
• Pruritus 
• Rash

Very rare

• Angioedema
• Erythema multiforme
• Urticaria

Musculoskeletal and Connective Tissue Disorders

Uncommon

• Arthralgia
• Myalgia
• Muscle spasms
• Back pain

Renal and Urinary Disorders

Uncommon

• Micturition disorder
• Nocturia
• Pollakiuria

Reproductive System and Breast Disorders

Uncommon

• Erectile dysfunction
• Gynaecomastia

General Disorders and Administration Site Conditions

Common

• Oedema
• Fatigue

Uncommon

• Chest pain
• Asthenia
• Pain
• Malaise

Investigations

Uncommon

• Increased weight
• Decreased weight

Atorvastatin

Blood and Lymphatic System Disorders

Uncommon

• Thrombocytopenia

Immune System Disorders

Common

• Allergic reaction (including anaphylaxis)

Infections and Infestations

Common

• Nasopharyngitis

Metabolism and Nutrition Disorders

Uncommon

• Hypoglycaemia
• Hyperglycaemia
• Anorexia
• Weight gain

Respiratory, Thoracic and Mediastinal Disorders

Common

• Pharyngolaryngeal pain
• Epistaxis (nosebleed)

Psychiatric Disorders

Common

• Insomnia

Uncommon

• Nightmare

Eye Disorders

Uncommon

• Blurred vision

Nervous System Disorders

Common

• Hypoaesthesia
• Paraesthesia
• Dizziness
• Headache

Uncommon

• Peripheral neuropathy
• Amnesia
• Dysgeusia

Ear and Labyrinth Disorders

Uncommon

• Tinnitus

Gastrointestinal Disorders

Common

• Nausea
• Diarrhoea
• Abdominal pain
• Dyspepsia
• Constipation
• Flatulence

Uncommon

• Vomiting
• Abdominal discomfort
• Eructation

Rare

• Pancreatitis

Hepatobiliary Disorders

Rare

• Hepatitis
• Cholestatic jaundice

Uncommon

• Cholestasis

Injury and Poisoning

Uncommon

• Tendon rupture

Skin and Subcutaneous Tissue Disorders:

Common

• Pruritus
• Rash

Uncommon

• Alopecia
• Urticaria

Rare

• Bullous rashes

Very rare

• Stevens-Johnson syndrome
• Toxic epidermal necrolysis
• Erythema multiforme

Musculoskeletal and Connective Tissue Disorders

Common

• Myalgia
• Arthralgia
• Back pain
• Pain in extremity
• Musculoskeletal pain
• Muscle spasms
• Joint swelling

Uncommon

• Muscle fatigue
• Neck pain

Rare

• Myositis
• Muscle cramps

Very rare

• Rhabdomyolysis
• Myopathy

Investigations

Common

• Abnormal liver function tests
• Increased blood creatine phosphokinase

Uncommon

• White blood cells in urine

Reproductive System and Breast Disorders

Uncommon

• Impotence

General Disorders and Administration Site Conditions

Common

• Asthenia
• Chest pain
• Fatigue

Uncommon

• Malaise
• Pyrexia

Rare

• Peripheral oedema

Combination products may have additional pharmacological effects not accounted for by the action of the individual ingredients

Amlodipine/Atorvastatin

• HIV protease inhibitors
• Tipranavir plus ritonavir
• Hepatitis C protease inhibitor, telaprevir
• Hepatitis C antivirals glecaprevir/pibrentasvir
• Saquinavir plus ritonavir
• Lopinavir plus ritonavir
• Darunavir plus ritonavir
• Fosamprenavir
• Fosamprenavir plus ritonavir
• Atazanavir plus ritonavir
• Ciclosporin
• Fibric acid derivatives
• Erythromycin
• Niacin (lipid lowering doses)
• Azole antifungals
• Colchicine
• Hepatitis C protease inhibitors
• Telaprevir
• Boceprevir
• Elbasvir/grazoprevir
• Immunosuppressive medicines
• Fusidic acid

Amlodipine

• CYP3A4 inhibitors
• Diltiazem
• Erythromycin
• Strong inhibitors of CYP3A4
• Ketoconazole
• Itraconazole
• Ritonavir
• CYP3A4 inducers
• Rifampicin
• Ciclosporin

Other interactions

• Grapefruit or grapefruit juice
• Hypericum perforatum (St. John's Wort)

Atorvastatin

• Ciclosporin
• Fibric acid derivatives
• Niacin
• Cytochrome P450 3A4 inhibitors
• Nefazodone
• Macrolide antibiotics
• Erythromycin
• Azole antifungals
• OATP1B1 inhibitors
• Clarithromycin
• Protease inhibitors
• HIV protease inhibitors
• Tipranavir plus ritonavir
• Hepatitis C protease inhibitor
• Telaprevir
• Lopinavir/ ritonavir
• Saquinavir plus ritonavir
• Darunavir plus ritonavir
• Fosamprenavir
• Fosamprenavir plus ritonavir
• Nelfinavir
• Boceprevir
• Diltiazem
• Itraconazole
• Cytochrome P450 3A4 inducers
• Efavirenz
• Rifampicin
• Antacids
• Digoxin
• Oral contraceptives containing norethindrone and ethinyloestradiol
• Warfarin
• Fusidic acid
• Colchicine
• Gemfibrozil
• Fibric acid derivatives

Other interactions

• Grapefruit juice

• Lipid levels
• Blood pressure (measured within 2-4 weeks)
  - Titration for blood pressure response may proceed more rapidly if clinically warranted
• Creatine phosphokinase (CPK) determinations (periodic)
• Hepatic function

Specific cases may require

• Blood glucose
• Ciclosporin levels

Additional observations

• 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 medicine) especially when coadministered with medicines inhibit cytochrome P450 3A4 metabolism and/or medicine-transport

Treatment guidance

Initial therapy

• Amlodipine/ atorvastatin may be used to start treatment in patients with hyperlipidemia and either hypertension or angina
• Recommended starting dose should be based on individual recommendations for amlodipine and atorvastatin components
• Maximum dose for amlodipine in amlodipine/ atorvastatin: 10mg once daily
• Maximum dose for atorvastatin in amlodipine/ atorvastatin: 80mg once daily

Substitution therapy

• Amlodipine/ atorvastatin can replace its individual components (amlodipine and atorvastatin) for patients already on these medications
• Patients may receive an equivalent dose of amlodipine/ atorvastatin or a dose with increased amlodipine, atorvastatin, or both for enhanced antianginal effects, blood pressure reduction, or lipid-lowering effects
• Amlodipine/ atorvastatin is suitable for additional therapy in patients currently treated with either amlodipine or atorvastatin
• For starting amlodipine/ atorvastatin therapy, the dose should be based on the ongoing treatment component and the recommended starting dose for the new component being added

Concomitant medications

• Amlodipine in amlodipine/ atorvastatin can be safely co-administered with:
  • Thiazide diuretics
  • ACE inhibitors
  • Alpha-blockers
  • Beta-blockers
  • Long-acting nitrates
  • Sublingual nitroglycerine
• Amlodipine/ atorvastatin can be safely used with the medications mentioned above
• Atorvastatin in amlodipine/ atorvastatin can be combined with a bile acid binding resin for enhanced lipid-lowering effects
• The combination of HMG-CoA reductase inhibitors (like atorvastatin) and fibrates is generally advised to be avoided

Atorvastatin/amlodipine has a dual mechanism of action, the dihydropyridine calcium antagonist (calcium ion antagonist or slow-channel blocker) action of amlodipine and the HMG-CoA reductase inhibition of atorvastatin.

Amlodipine
Amlodipine inhibits the transmembrane influx of calcium ions into vascular smooth muscle and cardiac muscle. The mechanism of the antihypertensive action of amlodipine is due to a direct relaxant effect on vascular smooth muscle. The precise mechanism by which amlodipine relieves angina has not been fully determined but amlodipine reduces total ischaemic burden by the following two actions:

• Amlodipine dilates peripheral arterioles and thus, reduces the total peripheral resistance (afterload) against which the heart works. Since the heart rate remains stable, this unloading of the heart reduces myocardial energy consumption and oxygen requirements.
• The mechanism of action of amlodipine also probably involves dilatation of the main coronary arteries and coronary arterioles, both in normal and ischaemic regions. This dilatation increases myocardial oxygen delivery in patients with coronary artery spasm (Prinzmetal's or variant angina) and blunts smoking induced coronary vasoconstriction.

Atorvastatin
Atorvastatin is a selective, competitive inhibitor of HMG-CoA reductase, the rate-limiting enzyme that converts 3-hydroxy3-methylglutaryl-coenzyme A to mevalonate, a precursor of sterols, including cholesterol. In patients with homozygous and heterozygous familial hypercholesterolaemia (FH), nonfamilial forms of hypercholesterolaemia, and mixed dyslipidaemia, atorvastatin reduces total-C (total cholesterol), LDL-C (low-density lipoprotein cholesterol), and apo B (apolipoprotein B). Atorvastatin also reduces VLDL-C (very-low-density lipoprotein cholesterol) and TG (triglycerides) and produces variable increases in HDL-C (high-density lipoprotein cholesterol). 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 for enhanced uptake and catabolism of LDL. Atorvastatin reduces LDL production and the number of LDL particles.

COMBINATION PREPARATION

Atorvastatin/ Amlodipine

Tablet 10mg/5mg 

• Caduet (Pfizer) originator

Tablet 20mg/5mg 

• Caduet (Pfizer) originator

Tablet 10mg/10mg 

• Caduet (Pfizer) originator

Tablet 20mg/10mg 

• Caduet (Pfizer) originator

Tablet 40mg/10mg

• Caduet (Pfizer) originator

Tablet 80mg/10mg 

• Caduet (Pfizer) originator (Discontinued - 19 Oct 2018)