Atorvastatin/ Perindopril/ Amlodipine

Registered South African indications:

• Essential hypertension and/ or stable coronary artery disease, in association with primary hypercholesterolaemia or mixed hyperlipidaemia, as substitution therapy in adult patients adequately controlled with atorvastatin, perindopril and amlodipine given concurrently at the same dose level as in the combination

Should a woman become pregnant while receiving atorvastatin/ perindopril/ amlodipine, the treatment must be stopped promptly and switched to a different class of antihypertensive medicine

South African registered contraindications

• Hypersensitivity to atorvastatin/perindopril/amlodipine or to any other ACE-inhibitor, dihydropyridine derivatives, or statin or to any of the other excipients
• Active liver disease or unexplained persistent elevations of serum transaminases exceeding 3 times the upper limit of normal
• Pregnancy
• Breastfeeding
• In women of child-bearing potential not using appropriate contraceptive measures
• Severe hypotension (in case of systolic and diastolic blood pressure <90/60 mmHg with related symptoms dizziness, fatigue, especially when standing up and in upright position)
• Shock (including cardiogenic shock)
• Obstruction of the outflow tract of the left ventricle (e.g., hypertrophic obstructive cardiomyopathy, high grade aortic stenosis and/or mitral valve stenosis)
• Haemodynamically unstable heart failure after acute myocardial infarction
• Hereditary or idiopathic angioedema
• Hypertrophic obstructive cardiomyopathy (HOCM)
• Severe renal function impairment (creatinine clearance less than 30ml/min)
• Bilateral renal artery stenosis
• Renal artery stenosis in patients with a single kidney
• A history of angioedema related to previous therapy with ACE-inhibitors or angiotensin receptor blockers (ARBs)
• History of angioedema (Quincke’s oedema) associated with previous ACE-inhibitor therapy
• Porphyria
• Coadministration with lithium therapy
• Coadministration with aliskiren-containing products in patients with diabetes mellitus or renal impairment (GFR<60ml/min/1.73m²)
• Coadministration with sacubitril/valsartan
• Extracorporeal treatments leading to contact of blood with negatively charged surfaces
• Significant bilateral renal artery stenosis or stenosis of the artery to a single functioning kidney
• Coadministration with fluoroquinolones with ACE-inhibitors/Angiotensin receptor blockers is contraindicated in patients with moderate to severe renal impairment (CrCl≤30ml/min) and in elderly patients

South African recommendations

Liver effects

• Regular liver tests required with atorvastatin/perindopril/amlodipine use. Caution for users with alcohol use or liver disease history. Discontinuation advised if abnormal liver tests or jaundice develops. Atorvastatin/perindopril/amlodipine is contraindicated in patients with active liver disease or unexplained persistent elevations of serum transaminases exceeding 3 times the upper limit of normal

Skeletal muscle effects

• Atorvastatin can cause muscle effects including myalgia, myositis, or rhabdomyolysis. Persistent muscle weakness and elevated creatine kinase levels may occur even after discontinuation

Creatine kinase measurement

• Avoid CK measurements post strenuous exercise or other CK-increase causes. If baseline CK is elevated (>5 times ULN), retest in 5-7 days

- Before treatment

• Caution with atorvastatin/perindopril/amlodipine in patients predisposed to rhabdomyolysis. Pre-treatment CK measurement is needed for renal impairment, hypothyroidism, personal or familial history of hereditary muscle disorders, history of muscle toxicity with a statin or fibrate, or liver disease, alcohol consumption, elderly (>70 years), interactions which may cause an increase in plasma level and certain genetic subpopulations. If baseline CK >5 times ULN, do not start treatment

- While on treatment

• Monitor for muscle pain, cramps, or weakness with malaise or fever. If these symptoms occur, measure CK levels. Stop treatment if CK >5 times ULN. Consider stopping if discomfort is severe and CK ≤5 times ULN. If symptoms and CK levels normalise, re-introduction at the lowest atorvastatin dose may be considered with appropriate monitoring. Discontinue immediately if CK >10 times ULN or rhabdomyolysis is suspected or diagnosed

Concomitant treatment with other medicines

• Rhabdomyolysis risk increases with atorvastatin/perindopril/amlodipine when combined with medicines that elevate atorvastatin plasma concentration, such as potent CYP3A4 or transport protein inhibitors
• Co-administration with gemfibrozil, other fibric acid derivatives, erythromycin, niacin, ezetimibe, telaprevir, or tipranavir/ritonavir also heightens myopathy risk
• Immune-mediated necrotising myopathy (IMNM) may occur during or after statin treatment
• Careful monitoring is needed when unavoidable co-administration occurs. A lower maximum dose of atorvastatin is recommended in such cases. Do not co-administer with systemic fusidic acid or within 7 days of stopping fusidic acid
• Discontinue atorvastatin/perindopril/amlodipine during fusidic acid treatment. Seek immediate medical advice for symptoms of muscle weakness, pain, or tenderness

Interstitial lung disease

• Interstitial lung disease may occur with long-term atorvastatin/perindopril/amlodipine therapy. Symptoms can include dyspnoea, non-productive cough, and general health deterioration. If suspected, discontinue the therapy

Diabetes mellitus

• Statins may increase blood glucose. Monitor at-risk patients (fasting glucose 5.6-6.9 mmol/L, BMI >30kg/m², raised triglycerides, hypertension) clinically and biochemically during atorvastatin/perindopril/amlodipine treatment. In diabetic patients on oral antidiabetic medicine or insulin, closely monitor glucose control during the first month of treatment

Cardiac failure

• Use atorvastatin/perindopril/amlodipine with caution in patients with heart failure (NYHA class III and IV). Higher incidence of pulmonary edema has been reported in patients with severe heart failure treated with amlodipine. This combination product should be used carefully in patients with congestive heart failure due to the potential increase in risk of future cardiovascular events and mortality

Hypotension

• Hypotension may occur with atorvastatin/perindopril/amlodipine, especially in patients who are volume-depleted (e.g. by diuretic therapy, dietary salt restriction, dialysis, diarrhoea or vomiting) or have severe renin-dependent hypertension. In patients with symptomatic heart failure, with or without associated renal insufficiency, symptomatic hypotension has been observed. Careful monitoring is required for patients at increased risk. If hypotension occurs, place the patient supine and administer intravenous sodium chloride if necessary

Aortic and mitral valve stenosis

• Atorvastatin/perindopril/amlodipine, containing the ACE-inhibitor perindopril, should be used cautiously in patients with significant mitral or aortic stenosis. It is contraindicated in severe left ventricular outflow obstruction

Kidney transplantation

• There is no established experience with the use of atorvastatin/perindopril/amlodipine in patients with recent kidney transplantation

Renovascular hypertension

• Hypotension and renal insufficiency risks are heightened in patients with bilateral renal artery stenosis or stenosis of a single functioning kidney artery, treated with ACE-inhibitors. Minor changes in serum creatinine may indicate loss of renal function in patients with unilateral renal artery stenosis

Renal impairment

• Atorvastatin/perindopril/amlodipine is suitable for patients with creatinine clearance ≥60ml/min but not for those with creatinine clearance <60ml/min. For patients with renal impairment, potassium and creatinine should be routinely monitored. ACE inhibitors such as perindopril may lead to further renal impairment or acute renal failure in patients with symptomatic heart failure. Concomitant use of perindopril and a diuretic can lead to increases in blood urea and serum creatinine in patient's with no apparent pre-existing renal vascular disease, however this is more likely to occur in those with pre-existing renal impairment. Dosage adjustments and/or discontinuation of the diuretic or atorvastatin/perindopril/amlodipine may be required

Amlodipine and renal failure

• Amlodipine can be used at recommended doses in patients with renal failure as changes in plasma concentration are not correlated with the degree of renal impairment. Amlodipine is not dialyzable

Hemodialysis patients

• Anaphylactoid reactions have been reported in patients dialyzed with high flux membranes and treated concomitantly with an ACE inhibitor. Consideration should be given to using a different type of dialysis membrane or a different class of antihypertensive agent

Hypersensitivity/ angioedema

• Angioedema has been reported in patients treated with ACE inhibitors, including perindopril. In case of such reactions, atorvastatin/perindopril/amlodipine should be promptly discontinued and appropriate monitoring should be initiated. Angioedema associated with laryngeal oedema may be fatal and requires emergency therapy, which may include the administration of adrenaline and/or the maintenance of a patent airway. Patients with a history of angioedema unrelated to ACE inhibitor therapy may be at increased risk while receiving atorvastatin/perindopril/amlodipine. Intestinal angioedema should also be considered in the differential diagnosis in patients presenting with abdominal pain

Concomitant use of mTOR inhibitors (e.g., sirolimus, everolimus, temsirolimus)

• Patients undergoing therapy with mTOR inhibitors (e.g., sirolimus, everolimus, temsirolimus) while taking the combination of atorvastatin, perindopril, and amlodipine may be at an increased risk for angioedema (swelling of the airways or tongue, with or without respiratory impairment)

Anaphylactoid reactions during low-density lipoproteins (LDL) apheresis

• Patients receiving ACE inhibitors during LDL apheresis with dextran sulphate have experienced life-threatening anaphylactoid reactions. Temporarily discontinuing the ACE inhibitor therapy before each apheresis can help prevent these reactions

Anaphylactoid reactions during desensitisation

• Patients undergoing desensitisation treatments (e.g. hymenoptera venom) while on an ACE inhibitor, such as perindopril, have experienced anaphylactoid reactions. These reactions can be avoided by temporarily stopping the ACE inhibitor, but may reappear upon re-exposure to the agent

Neutropenia/ agranulocytosis/ thrombocytopenia/ anaemia

• Neutropenia/agranulocytosis, thrombocytopenia, and anaemia have been reported in patients receiving ACE inhibitors. These complications are rare in patients with normal renal function without other complicating factors. The combination of atorvastatin, perindopril, and amlodipine should be used with caution in patients with collagen vascular disease, immunosuppressant therapy, treatment with allopurinol or procainamide, or a combination of these factors, especially if there is pre-existing impaired renal function. Periodic monitoring of white blood cell counts is advised in such patients

Race

• ACE inhibitors, such as perindopril, are associated with a higher rate of angioedema in black patients compared to non-black patients. The combination of atorvastatin, perindopril, and amlodipine may be less effective in lowering blood pressure in black people due to a higher prevalence of low-renin states in the black hypertensive population

Cough

• Coughing, particularly a non-productive and persistent cough, has been associated with the use of ACE inhibitors like perindopril. This symptom typically resolves after discontinuation of therapy. Therefore, a cough induced by ACE inhibitors should be considered when diagnosing a cough in patients treated with atorvastatin/perindopril/amlodipine

Surgery/ anaesthesia

• In patients undergoing major surgery or during anaesthesia with medicines that cause low blood pressure, atorvastatin/perindopril/amlodipine could block angiotensin II formation as a result of compensatory renin release. Therefore, the medication should be stopped one day before the surgery. If low blood pressure occurs and is considered due to this mechanism, it can be corrected by volume expansion

Hyperkalaemia

• Elevated levels of serum potassium have been observed in patients treated with ACE inhibitors, including perindopril. Risk factors for developing high potassium levels include renal insufficiency, worsening of renal function, age (>70 years), diabetes mellitus, certain concurrent events (e.g. dehydration, acute cardiac decompensation, metabolic acidosis), and the use of potassium-sparing diuretics (e.g. spironolactone, eplerenone, triamterene, or amiloride), potassium supplements or potassium-containing salt substitutes, or other medicines associated with increases in serum potassium (e.g. heparin, co-trimoxazole). Regular monitoring of serum potassium levels is necessary if these medicines are used in combination with atorvastatin/perindopril/amlodipine, especially in patients with impaired renal function

Dual blockade of the renin-angiotensin-aldosterone system (RAAS)

• Simultaneous use of ACE inhibitors (like perindopril), angiotensin II receptor blockers, or aliskiren can increase the risk of low blood pressure, high potassium levels, and decreased kidney function, including acute kidney failure. Therefore, dual blockade of the RAAS with ACE inhibitors, angiotensin II receptor blockers, or aliskiren is not recommended. If considered necessary, it should be done under specialist supervision with close monitoring of kidney function, electrolytes, and blood pressure. The concurrent use of ACE inhibitors and angiotensin II receptor blockers is not recommended in patients with diabetic nephropathy

Concomitant use of fluoroquinolones

• Simultaneous use of fluoroquinolones and ACE-inhibitors/angiotensin receptor blockers like atorvastatin/perindopril/amlodipine may lead to acute kidney injury in patients, particularly those with moderate to severe renal impairment and elderly patients. Renal function should be assessed before starting treatment and monitored during treatment with fluoroquinolones or ACE-inhibitors/Angiotensin receptor blockers, whether used separately or concomitantly

Primary aldosteronism

• Patients with primary hyperaldosteronism will not respond to anti-hypertensive medicines acting through inhibition of the renin-angiotensin system. Therefore, the use of atorvastatin/perindopril/amlodipine is not recommended

Excipients

• Because of the presence of lactose, atorvastatin/perindopril/amlodipine should not be taken by patients with rare hereditary problems of galactose intolerance (e.g., galactosaemia), glucose-galactose malabsorption, or total lactase deficiency

Level of sodium

• The combination of atorvastatin/perindopril/amlodipine contains less than 1mmol sodium (23mg) per tablet, i.e., essentially 'sodium-free'

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

South African registered indications and dosages

Essential hypertension and/ or stable coronary artery disease, in association with primary hypercholesterolaemia or mixed hyperlipidaemia, as substitution therapy in adult patients adequately controlled with atorvastatin, perindopril and amlodipine given concurrently at the same dose level as in the combination

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

• Oral (fct): 1 tab, dly

---

Not suitable for initial therapy. If a change of posology is required, titration should be done with the individual components

---

The tablets should be taken as a single dose once daily in the morning before a meal

Not established for use in children and adolescents ≤18 years of age

Pregnancy

South African recommendations

• Contraindicated
• Women of childbearing potential should use appropriate contraceptive measures during treatment as use is contraindicated in women of childbearing potential not using appropriate contraceptive measures

Atorvastatin

• Safety in pregnant women has not been established
• No controlled clinical trials in pregnant women
• Reports of congenital anomalies following intrauterine exposure
• Animal studies show toxicity to reproduction
• May reduce fetal levels of mevalonate, a precursor of cholesterol biosynthesis
• Not for use in women who are pregnant, trying to become pregnant, or suspected to be pregnant

Perindopril

• Pregnant women should be informed of the potential hazards to the foetus
• Patients planning pregnancy should switch to alternative anti-hypertensive treatments with an established safety profile for use in pregnancy
• Treatment should be stopped immediately when pregnancy is diagnosed
• Foetal exposure during the first trimester has been associated with an increased risk of various malformations
• Atorvastatin/ Perindopril/ Amlodipine can pass through the placenta and interfere with foetal blood pressure regulatory mechanisms

Amlodipine

• Safety in human pregnancy has not been established
• Reproductive toxicity was observed in animal studies at high doses

Breastfeeding

South African recommendations

• Contraindicated

Atorvastatin

• It is not known whether atorvastatin or its metabolites are excreted in human milk
• In rats, plasma concentrations of atorvastatin and its active metabolites are similar to those in milk
• Because of the potential for serious adverse reactions, women taking atorvastatin should not breastfeed their infants

Perindopril

• No information is available regarding the use of perindopril during breastfeeding
• Perindopril should not be used during breastfeeding, and alternative treatments with better-established safety profiles should be considered instead

Amlodipine

• Amlodipine is excreted in human milk
• The proportion of the maternal dose received by the infant has been estimated with an interquartile range of 3–7%, with a maximum of 15%
• The effect of amlodipine on infants is unknown

Fertility

South African recommendations

Atorvastatin

• In animal studies, atorvastatin had no effect on male or female fertility

Perindopril

• No effect on reproductive performance or fertility has been reported

Amlodipine

• Reversible biochemical changes in the head of spermatozoa have been reported in some patients treated by calcium channel blockers
• Clinical data are insufficient regarding the potential effect of amlodipine on fertility
• In one rat study, adverse effects were found on male fertility at doses comparable to that in humans based on a mg/kg basis
• Decreased plasma follicle-stimulating hormone (FSH) and plasma testosterone were found, as well as decreases in sperm density and in the number of mature spermatids and Sertoli cells

South African recommendations

• CrCl≥60ml/min: No dose adjustment recommended
  Atorvastatin/ perindopril/ amlodipine can be administered in patients with CrCl≥60ml/min
• CrCl 30-<60ml/min: Caution; dose adjustment recommended
  Atorvastatin/ perindopril/ amlodipine is not suitable for these patients; individual dose titration with the monocomponents is recommended; routine monitoring of potassium and creatinine is required
• CrCl<30ml/min: Contraindicated
  Atorvastatin/ perindopril/ amlodipine is contraindicated in patients with severe renal function impairment
  Concomitant use of fluoroquinolones with ACE-inhibitors/ angiotensin receptor blockers is also contraindicated in these patients
• Renal artery stenosis (bilateral or in patients with a single kidney): Contraindicated
  Atorvastatin/ perindopril/ amlodipine is contraindicated in patients with significant bilateral renal artery stenosis or stenosis of the artery to a single functioning kidney
• GFR<60ml/min/1.73m² and concomitant use with aliskiren-containing products: Contraindicated
  Atorvastatin/ perindopril/ amlodipine is contraindicated for use with aliskiren-containing products in patients with renal impairment or diabetes mellitus
• Extracorporeal treatments leading to contact of blood with negatively charged surfaces: Contraindicated
  Atorvastatin/ perindopril/ amlodipine is contraindicated in patients undergoing extracorporeal treatments leading to contact of blood with negatively charged surfaces
• Haemodialysis patients
  Anaphylactoid reactions have been reported in patients dialysed with high flux membranes, and treated concomitantly with an ACE-inhibitor as contained in atorvastatin/ perindopril/ amlodipine; consideration should be given to using a different type of dialysis membrane or different class of antihypertensive agent

 

South African recommendations

• Mild to moderate: Caution; no dose adjustment recommended
  Use atorvastatin/ perindopril/ amlodipine with caution in patients with mild to moderate hepatic impairment
• Severe: Caution; not recommended
  Active liver disease or unexplained persistent elevations of serum transaminases exceeding 3 times the upper limit of normal: Contraindicated

 

South African recommendations

• Caution; dose adjustment recommended
  ≥65 years of age can be treated with atorvastatin/ perindopril/ amlodipine however, dosage should be adjusted according to the patient's renal function
  The concomitant use of fluoroquinolones with ACE-inhibitors/ angiotensin receptor blockers is contraindicated in patients with moderate to severe renal impairment (CrCl≤30ml/min) and in elderly patients. These drugs should not be used under these circumstances

Infections and Infestation

• Nasopharyngitis (Atorvastatin: Common)
• Rhinitis (Perindopril: Very rare, Amlodipine: Uncommon)

Blood and Lymphatic System Disorders

• Thrombocytopenia (Atorvastatin: Rare, Perindopril: Very rare, Amlodipine: Very rare)
• Leucopenia/ neutropenia (Perindopril: Very rare, Amlodipine: Very rare)
• Eosinophilia (Perindopril: Uncommon*)
• Agranulocytosis or pancytopenia (Perindopril: Very rare)
• Haemolytic anaemia in patients with a congenital deficiency of G-6PDH (Perindopril: Very rare)

Immune System Disorders

• Hypersensitivity (Atorvastatin: Common, Amlodipine: Very rare)
• Anaphylaxis (Atorvastatin: Very rare)

Metabolism and Nutrition Disorders

• Hyperglycaemia (Atorvastatin: Common, Amlodipine: Very rare)
• Hypoglycaemia (Atorvastatin: Uncommon, Perindopril: Uncommon*)
• Hyponatraemia (Perindopril: Uncommon*)
• Hyperkalaemia reversible on discontinuation (Perindopril: Uncommon*)
• Anorexia (Atorvastatin: Uncommon)

Psychiatric Disorders

• Insomnia (Atorvastatin: Uncommon, Amlodipine: Uncommon)
• Mood altered (Including Anxiety) (Perindopril: Uncommon, Amlodipine: Uncommon)
• Sleep disorder (Perindopril: Uncommon)
• Depression (Amlodipine: Uncommon)
• Nightmares (Atorvastatin: Uncommon)
• Confusional state (Perindopril: Very rare, Amlodipine: Rare)

Nervous System Disorders

• Somnolence (Perindopril: Uncommon*, Amlodipine: Common)
• Dizziness (Atorvastatin: Uncommon, Perindopril: Common, Amlodipine: Common)
• Headache (Atorvastatin: Common, Perindopril: Common, Amlodipine: Common)
• Tremor (Amlodipine: Uncommon)
• Dysgeusia (Atorvastatin: Uncommon, Perindopril: Common, Amlodipine: Uncommon)
• Syncope (Perindopril: Uncommon*, Amlodipine: Uncommon)
• Hypoaesthesia (Atorvastatin: Uncommon, Amlodipine: Uncommon)
• Paraesthesia (Atorvastatin: Uncommon, Perindopril: Common, Amlodipine: Uncommon)
• Hypertonia (Amlodipine: Very rare)
• Neuropathy peripheral (Atorvastatin: Rare, Amlodipine: Very rare)
• Stroke possible secondary to excessive hypotension (Perindopril: Very rare)
• Amnesia (Atorvastatin: Uncommon)
• Extrapyramidal disorder (extrapyramidal syndrome) (Amlodipine: Not known)

Eye Disorders

• Visual impairment (Atorvastatin: Rare, Perindopril: Common, Amlodipine: Common)
• Diplopia (Amlodipine: Common)
• Vision blurred (Atorvastatin: Uncommon)

Ear and Labyrinth Disorders

• Tinnitus (Atorvastatin: Uncommon, Perindopril: Common, Amlodipine: Uncommon)
• Vertigo (Perindopril: Common)
• Hearing loss (Atorvastatin: Very Rare)

Cardiac Disorders

• Myocardial infarction secondary to excessive hypotension in high-risk patients (Perindopril: Very rare, Amlodipine: Very rare)
• Angina pectoris (Perindopril: Very rare)
• Dysrhythmia (including bradycardia, ventricular tachycardia and atrial fibrillation) (Perindopril: Very rare, Amlodipine: Uncommon)
• Tachycardia (Perindopril: Uncommon*)
• Palpitations (Perindopril: Uncommon*, Amlodipine: Common)

Vascular Disorders

• Hypotension (and effects related to hypotension) (Perindopril: Common, Amlodipine: Uncommon)
• Vasculitis (Perindopril: Uncommon*, Amlodipine: Very rare)
• Flushing (Amlodipine: Common)

Respiratory, Thoracic and Mediastinal Disorders

• Pharyngolaryngeal pain (Atorvastatin: Common)
• Epistaxis (Atorvastatin: Common)
• Cough (Perindopril: Common, Amlodipine: Uncommon)
• Dyspnoea (Perindopril: Common, Amlodipine: Common)
• Bronchospasm (Perindopril: Uncommon)
• Eosinophilic pneumonia (Perindopril: Very rare)

Gastrointestinal Disorders

• Nausea (Atorvastatin: Common, Perindopril: Common, Amlodipine: Common)
• Vomiting (Atorvastatin: Uncommon, Perindopril: Common, Amlodipine: Uncommon)
• Abdominal pain upper and lower (Atorvastatin: Uncommon, Perindopril: Common, Amlodipine: Common)
• Dyspepsia (Atorvastatin: Common, Perindopril: Common, Amlodipine: Common)
• Diarrhoea (Atorvastatin: Common, Perindopril: Common, Amlodipine: Common)
• Constipation (Atorvastatin: Common, Perindopril: Common, Amlodipine: Common)
• Dry mouth (Perindopril: Uncommon, Amlodipine: Uncommon)
• Pancreatitis (Atorvastatin: Uncommon, Perindopril: Very rare, Amlodipine: Very rare)
• Gastritis (Amlodipine: Very rare)
• Gingival hyperplasia (Amlodipine: Very rare)
• Change of bowel habit (Amlodipine: Common)
• Eructation (Atorvastatin: Uncommon)
• Flatulence (Atorvastatin: Common)

Hepato-biliary Disorders

• Hepatitis either cytolytic or cholestatic (Atorvastatin: Uncommon, Perindopril: Very rare, Amlodipine: Very rare)
• Jaundice (Amlodipine: Very rare)
• Cholestasis (Atorvastatin: Rare)
• Hepatic failure (Atorvastatin: Very rare)

Skin and Subcutaneous Tissue Disorders

• Rash (Atorvastatin: Uncommon, Perindopril: Common, Amlodipine: Uncommon)
• Pruritus (Atorvastatin: Uncommon, Perindopril: Common, Amlodipine: Uncommon)
• Urticaria (Atorvastatin: Uncommon, Perindopril: Uncommon, Amlodipine: Uncommon)
• Purpura (Amlodipine: Uncommon)
• Skin discolouration (Amlodipine: Uncommon)
• Hyperhidrosis (Perindopril: Uncommon, Amlodipine: Uncommon)
• Exanthema (Amlodipine: Uncommon)
• Alopecia (Atorvastatin: Uncommon, Amlodipine: Uncommon)
• Angioedema (Atorvastatin: Rare, Perindopril: Uncommon, Amlodipine: Very rare)
• Exfoliative dermatitis (Amlodipine: Very rare)
• Pemphigoid (Perindopril: Uncommon*)
• Psoriasis aggravation (Perindopril: Rare*)
• Stevens-Johnson syndrome (Atorvastatin: Rare, Amlodipine: Very rare)
• Photosensitivity reactions (Perindopril: Uncommon*, Amlodipine: Very rare)
• Toxic epidermal necrolysis (Atorvastatin: Rare, Amlodipine: Not known)
• Erythema multiforme (Atorvastatin: Rare, Perindopril: Very rare, Amlodipine: Very rare)

Musculoskeletal and Connective Tissue Disorders

• Joint swelling (Atorvastatin: Common)
• Ankle swelling (Amlodipine: Common)
• Pain in extremity (Atorvastatin: Common)
• Arthralgia (Atorvastatin: Common, Perindopril: Uncommon*, Amlodipine: Uncommon)
• Muscle spasms (Atorvastatin: Common, Perindopril: Common, Amlodipine: Common)
• Myalgia (Atorvastatin: Common, Perindopril: Uncommon*, Amlodipine: Uncommon)
• Back pain (Atorvastatin: Common, Amlodipine: Uncommon)
• Neck pain (Atorvastatin: Uncommon)
• Muscle fatigue (Atorvastatin: Uncommon)
• Myopathy (Atorvastatin: Rare)
• Myositis (Atorvastatin: Rare)
• Rhabdomyolysis (Atorvastatin: Rare)
• Tendinopathy sometimes complicated by rupture (Atorvastatin: Rare)
• Immune-mediated necrotising myopathy (Atorvastatin: Not known)

Renal and Urinary Disorders

• Micturition disorder (Amlodipine: Uncommon)
• Nocturia (Amlodipine: Uncommon)
• Pollakiuria (Amlodipine: Uncommon)
• Renal failure (Perindopril: Uncommon)
• Renal failure acute (Perindopril: Very rare)
• Erectile dysfunction (Perindopril: Uncommon, Amlodipine: Uncommon)

Reproductive System and Breast Disorders

• Gynaecomastia (Atorvastatin: Very rare, Amlodipine: Uncommon)

General Disorders and Administration Site Conditions

• Asthenia (Atorvastatin: Uncommon, Perindopril: Common, Amlodipine: Common)
• Fatigue (Atorvastatin: Uncommon, Amlodipine: Common)
• Oedema (Amlodipine: Very common)
• Chest pain (Atorvastatin: Uncommon, Perindopril: Uncommon*, Amlodipine: Uncommon)
• Pain (Amlodipine: Uncommon)
• Malaise (Atorvastatin: Uncommon, Perindopril: Uncommon*, Amlodipine: Uncommon)
• Oedema peripheral (Atorvastatin: Uncommon, Perindopril: Uncommon*)
• Pyrexia (Atorvastatin: Uncommon, Perindopril: Uncommon*)

Investigations

• Blood urea increased (Perindopril: Uncommon*)
• Blood creatinine increased (Perindopril: Uncommon*)
• Hepatic enzymes increased (Perindopril: Rare, Amlodipine: Very rare**)
• Blood bilirubin increased (Perindopril: Rare)
• Weight increased (Atorvastatin: Uncommon, Amlodipine: Uncommon)
• White blood cells urine positive (Atorvastatin: Uncommon)
• Weight decreased (Amlodipine: Uncommon)
• Liver function test abnormal (Atorvastatin: Common)
• Blood creatine kinase increased (Atorvastatin: Common)
• Haemoglobin decreased and haematocrit decreased (Perindopril: Very rare)

Injury, Poisoning, and Procedural Complications

• Fall (Perindopril: Uncommon*)

* Frequency calculated from clinical trials for adverse events detected from spontaneous report
**Mostly consistent with cholestasis

Atorvastatin/ Perindopril/ Amlodipine

• Fluoroquinolones
• ACE-inhibitors
• Angiotensin II receptor blockers
• Aliskiren
• Agents inducing hyperkalaemia
• Potassium salts
• Potassium-sparing diuretics
• Non-steroidal anti-inflammatory drugs (NSAIDs)
• Heparins
• Immunosuppressant agents
• Ciclosporin
• Tacrolimus
• Trimethoprim
• Tipranavir/ritonavir

Atorvastatin

• CYP3A4 inhibitors
• Fibric acid derivates
• Gemfibrozil
• Ezetimibe
• Fusidic acid
• Moderate CYP3A4 inhibitors
• Erythromycin
• Diltiazem
• Verapamil
• Fluconazole
• Amiodarone
• Potent CYP3A4 inhibitors
• Transport protein inhibitors
• Ciclosporin
• Telithromycin
• Clarithromycin
• Delavirdine
• Stiripentol
• Ketoconazole
• Voriconazole
• Itraconazole
• Posaconazole
• HIV protease inhibitors
• Ritonavir
• Lopinavir
• Atazanavir
• Indinavir
• Darunavir
• CYP3A4 inducers
• Efavirenz
• Rifampicin
• St. John's Wort
• Colchicine
• Colestipol
• Oral contraceptives
• Warfarin
• Digoxin

Perindopril

• Extracorporeal treatments
• Dialysis or haemofiltration with certain high-flux membranes (e.g., polyacrylonitrile membranes) and low-density lipoprotein apheresis with dextran sulphate
• Sacubitril/valsartan
• Aliskiren
• ACE-inhibitors
• Angiotensin-receptor blocker
• Estramustine
• Lithium
• Trimethoprim/sulfamethoxazole
• Potassium-sparing diuretics
• Triamterene
• Amiloride
• Eplerenone
• Spironolactone
• Potassium salts
• Gliptins
• Linagliptin
• Saxagliptin
• Sitagliptin
• Vildagliptin
• Antidiabetic agents
• Insulins
• Oral hypoglycaemic agents
• Baclofen
• NSAIDs
• Aspirin (≥3g/day)
• Cyclooxygenase-2 inhibitors
• Non-selective NSAIDs
• Sympathomimetics
• Racecadotril
• mTOR inhibitors
• Sirolimus
• Everolimus
• Temsirolimus
• Tricyclic antidepressants
• Antipsychotics
• Anaesthetics
• Gold

Amlodipine

• Dantrolene (infusion)
• Verapamil
• Moderate CYP3A4 inhibitors
• Protease inhibitors
• Azole antifungals
• Macrolides
• Erythromycin
• Clarithromycin
• Verapamil
• Diltiazem
• CYP3A4 inducers
• Rifampicin
• Hypericum perforatum
• Digoxin
• Atorvastatin
• Warfarin
• Tacrolimus
• mTOR inhibitors
• Sirolimus
• Everolimus
• Temsirolimus
• Ciclosporin

Atorvastatin/ Amlodipine

• Grapefruit or grapefruit juice

Perindopril/ Amlodipine

• Antihypertensive medicines
• Vasodilators
• Nitroglycerin and other nitrates

None routine. Specific cases may require

• Hepatic function tests
• Creatine phosphokinase (CK)
• Potassium level
• Creatinine level

Specific cases may require

• Blood glucose
• White blood cell count
• Renal function
• Electrolytes
• Blood pressure

Atorvastatin
Atorvastatin is a selective, competitive inhibitor of HMG-CoA reductase, the rate-limiting enzyme responsible for the conversion of 3-hydroxy-3-methyl-glutaryl-coenzyme A to mevalonate, a precursor of sterols, including cholesterol. Triglycerides and cholesterol in the liver are incorporated into very low-density lipoproteins (VLDL) and released into the plasma for delivery to peripheral tissues. Low-density lipoprotein (LDL) is formed from VLDL and is catabolised primarily through the receptor with high affinity to LDL (LDL receptor).

Perindopril
Perindopril is an inhibitor of the enzyme that converts angiotensin I into angiotensin II (Angiotensin Converting Enzyme ACE). The converting enzyme, or kinase, is an exopeptidase that allows conversion of angiotensin I into the vasoconstrictor angiotensin II as well as causing the degradation of the vasodilator bradykinin into an inactive heptapeptide. Inhibition of ACE results in a reduction of angiotensin II in the plasma, which leads to increased plasma renin activity (by inhibition of the negative feedback of renin release) and reduced secretion of aldosterone. Since ACE inactivates bradykinin, inhibition of ACE also results in an increased activity of circulating and local kallikrein-kinin systems (and thus also activation of the prostaglandin system). It is possible that this mechanism contributes to the blood pressure lowering action of ACE-inhibitors and is partially responsible for certain of their side effects (e.g., cough). Perindopril acts through its active metabolite, perindoprilat. The other metabolites show no inhibition of ACE activity in vitro.

Amlodipine
Amlodipine is a calcium ion influx inhibitor of the dihydropyridine group (slow channel blocker or calcium ion antagonist) and inhibits the transmembrane influx of calcium ions into cardiac and vascular smooth muscle.