Atorvastatin

Registered South African indications:

• Hypercholesterolaemia 
• Reduction of cardiovascular complications

Contraindications 

South African recommendations

• Hypersensitivity to atorvastatin or to any of the ingredients
• Active liver disease or unexplained persistent increase of serum transaminases exceeding 3 times the upper limit of normal
• Concomitant use with rifampicin, diltiazem, and grapefruit juice
• Patients with Child-Pugh B and C (liver cirrhosis)
• Pregnancy
• Lactation

Recommendations in other jurisdictions

• Hypersensitivity to the active substance, peanut, or soya or to any of the excipients
• Active liver disease or unexplained persistent elevations of serum transaminases exceeding 3 times the upper limit of normal
• Pregnancy and in women of child-bearing potential not using appropriate contraceptive measures
• Breastfeeding
• Treated with the hepatitis C antivirals glecaprevir/pibrentasvir

Cautions

South African recommendations

• Renal impairment
  - History of renal impairment
• Risk factor predisposing to the development of renal failure secondary to rhabdomyolysis
  - Severe acute infection
  - Hypotension
  - Major surgery
  - Trauma
  - Severe metabolic, endocrine and electrolyte disorders
  - Uncontrolled seizures
• Consumption of substantial quantities of alcohol and/or history of hepatic disease
• Prior haemorrhagic stroke 
• Stroke or transient ischaemic attack (TIA) within the preceding 6 months
• Coadministration with immunosuppressive medicines, nicotinic acid, azole antifungals
• Galactose intolerance
• Lapp lactase deficiency
• Glucose-galactose malabsorption

Recommendations in other jurisdictions

• Renal impairment
• Hepatic impairment
• Pre-disposing factors for rhabdomyolysis
  - Renal impairment 
  - Hypothyroidism
  - Personal or familial history of hereditary muscular disorders
  - Previous history of muscular toxicity with a statin or fibrate 
  - Consumption of substantial quantities of alcohol and/or history of hepatic disease 
  - Elderly (age >70 years)
  - Situations where an increase in plasma levels may occur, such as interactions and special populations including genetic subpopulations
• Prior hemorrhagic stroke or lacunar infarct
• Recent stroke or transient ischemic attack (TIA)
• Long term therapy
• Galactose intolerance
• Total lactase deficiency
• Glucose-galactose malabsorption

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

Dosages below include:

• South African registered indications and dosages

South African registered indications and dosages

Primary hypercholesterolaemia and combined (mixed) hyperlipidaemia
- As an adjunct to diet for reduction of elevated total-cholesterol, LDL-cholesterol, apolipoprotein-B, triglyceride levels and to moderately increase HDL-cholesterol in patients with primary hypercholesterolaemia (heterozygous familial and non-familial hypercholesterolaemia) and combined/mixed dyslipidaemia
- To reduce total-C and LDL-C in patients with homozygous familial hypercholesterolaemia as an adjunct to other lipid-lowering treatments (e.g. LDL apheresis) or if such treatments are unavailable

• Oral (fct, tab): Initial: 10mg, dly with or without food (individualised according to baseline LDL-C levels, goal of therapy, and patient response); Adjust dosage after a minimum interval of 4 weeks

---

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

---

For homozygous familial hypercholesterolaemia, most patients responded to 80mg, dly with a greater than 15% reduction in LDL-C (18% - 45%) in  a compassionate-use, uncontrolled study

---

Reduction of cardiovascular complications
- In patients without clinically evident cardiovascular disease, and with or without dyslipidaemia, but with multiple risk factors for coronary heart disease such as smoking, hypertension, diabetes, low HDL-C, or a family history of early coronary heart disease
- To reduce the risk of ischaemic cardiovascular and cerebrovascular diseases
- Secondary reduction: Reduction of cardiovascular events in patients with clinically evident coronary heart disease and increased cholesterol levels

• Oral (fct, tab): 10-80mg, dly with or without food

---

Therapy with lipid-lowering agents should be a component of multiple-risk-factor intervention in individuals at increased risk of atherosclerotic vascular disease due to hypercholesterolaemia

---

In all cases, lipid-altering agents should be used in addition to a diet restricted in saturated fat and cholesterol only when the response to diet and other non-pharmacological measures has been inadequate. Secondary causes for hypercholesterolaemia should be excluded before initiating therapy with atorvastatin, and a lipid profile performed to measure total-C, LDL-C, HDL-C, and TG

Paed. forms avail. in SA and covered in this monograph: fct, tab

Dosages below include:

• South African registered indications and dosages

South African registered indications and dosages

Heterozygous familial hypercholesterolaemia 
- As an adjunct to diet to reduce total-C and LDL-C and apolipoprotein-B, if after an adequate trial of diet therapy, the following findings are present: LDL-C remains ≥4.98mmol/l (190mg/dl) OR LDL-C remains ≥4.04mmol/l (160mg/dl) and there is a positive family history of premature cardiovascular disease or two or more other CVD risk factors are present 

Younger than 10 years

• No information available

Between 10-17 years

• Oral (fct, tab): Initial: 10mg, dly with or without food; Adjust dosage after a minimum interval of 4 weeks; Max: 20mg/24hrs

---

Experience in paediatrics is limited to a small number of patients (age 10-17 years) with severe dyslipidaemias, such as familial hypercholesterolaemia 

---

Lipid-altering agents should be used in addition to a diet restricted in saturated fat and cholesterol only when the response to diet and other non-pharmacological measures has been inadequate. Secondary causes for hypercholesterolaemia should be excluded before initiating therapy with atorvastatin, and a lipid profile performed to measure total-C, LDL-C, HDL-C, and TG

Pregnancy

South African recommendations

• Contraindicated
• Atorvastatin is contraindicated in pregnancy and in women of childbearing potential not using adequate contraceptive measures
• Atorvastatin should be administered to women of childbearing age only when such patients are using adequate contraception and have been informed of the potential hazards to the foetus. An interval of one month should be allowed from stopping atorvastatin treatment to conception in the event of planning a pregnancy

Recommendations in other jurisdictions

• Contraindicated
• Atorvastatin is contraindicated during pregnancy. Safety in pregnant women has not been established. No controlled clinical trials with atorvastatin have been conducted in pregnant women. Rare reports of congenital anomalies following intrauterine exposure to HMG-CoA reductase inhibitors have been received. Studies in animals have shown toxicity to reproduction
• Maternal treatment with atorvastatin may reduce the foetal levels of mevalonate which is a precursor of cholesterol biosynthesis. Atherosclerosis is a chronic process, and ordinarily, discontinuation of lipid-lowering medicinal products during pregnancy should have little impact on the long-term risk associated with primary hypercholesterolaemia
• For these reasons, atorvastatin should not be used in women who are pregnant, trying to become pregnant or suspect they are pregnant. Treatment with atorvastatin should be suspended for the duration of pregnancy or until it has been determined that the woman is not pregnant
• Women of child-bearing potential should use appropriate contraceptive measures during treatment

Breastfeeding

South African recommendations

• Contraindicated
• Atorvastatin is contraindicated in mothers breastfeeding their infants

Recommendations in other jurisdictions

• Contraindicated
• It is unknown 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. Atorvastatin is contraindicated during breastfeeding

Fertility

South African recommendations

• No information available

Recommendations in other jurisdictions

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

Renal Impairment

• Caution; no dose adjustment recommended  

Hepatic Impairment

South African recommendations

• Mild (Child-Pugh A): No dose adjustment recommended
• Moderate to severe (Child-Pugh B and C): Contraindicated 
  In patients with moderate to severe hepatic dysfunction, the therapeutic response to atorvastatin is unaffected but serum levels of the medicine are greatly increased. In patients with chronic alcoholic liver disease, plasma concentrations of atorvastatin are markedly increased. C_max and AUC are each 4-fold greater in patients with Child-Pugh A disease. Cmax and AUC are approximately 16-fold and 11-fold increased, respectively, in patients with Child-Pugh B disease. Therefore, caution with dosage should be exercised in patients who consume substantial quantities of alcohol and/or have a history of liver disease

Recommendations in other jurisdictions

• Caution; no dose adjustment recommended 
  Atorvastatin is contraindicated in patients with active liver disease

Elderly

• No dose adjustment recommended 

Porphyria Information

• Probably not porphyrinogenic (PNP) 

Drugs in Sport

• Permitted - No warnings 

Central Nervous System Disorders

• Nightmare
• Insomnia
• Headache
• Dizziness
• Paraesthesia
• Hypoaesthesia
• Dysgeusia
• Amnesia
• Peripheral neuropathy
• Malaise
• Depression

Respiratory Disorders

• Nasopharyngitis
• Pharyngolaryngeal pain 
• Epistaxis
• Chest pain
• Interstitial lung disease

Gastrointestinal Disorders

• Constipation
• Flatulence
• Dyspepsia
• Nausea and vomiting
• Diarrhoea
• Upper and lower abdominal pain 
• Eructation
• Pancreatitis

Hepatobiliary Disorders

• Hepatitis
• Cholestasis
• Hepatic failure
• Abnormal liver function test 
• Increased serum transaminases

Genitourinary Disorders

• Positive white blood cells urine
• Sexual dysfunction

Endocrine and Metabolic Disorders

• Hyperglycaemia
• Hypoglycaemia
• Increased weight 
• Anorexia
• Gynaecomastia
• Diabetes mellitus

Musculoskeletal Disorders

• Myalgia
• Arthralgia
• Pain in extremity
• Muscle spasms
• Joint swelling
• Back pain
• Neck pain
• Muscle fatigue
• Myopathy
• Myositis
• Rhabdomyolysis
• Muscle rupture
• Tendonopathy
• Lupus-like syndrome
• Immune-mediated necrotising myopathy 
• Increased creatine kinase

Skin and Subcutaneous Tissue Disorders

• Urticaria
• Skin rash
• Pruritus
• Alopecia
• Angioneurotic oedema
• Bullous dermatitis
  - Erythema multiforme
• Stevens-Johnson syndrome
• Toxic epidermal necrolysis

Immune, Blood and Lymphatic System Disorders

• Thrombocytopenia
• Allergic reactions
• Anaphylaxis
• Peripheral oedema
• Pyrexia
• Infections

Sensory Disorders

• Blurred vision
• Visual disturbance
• Tinnitus
• Hearing loss

• Rifampicin
• Diltiazem
• Glecaprevir/ pibrentasvir
• Moderate CYP3A4 inhibitors 
• Erythromycin
• Verapamil 
• Fluconazole
• Amiodarone
• Verapamil
• CYP3A4 inducers
• Efavirenz
• Potent CYP3A4 inhibitors
• Organic anion-transporting polypeptide 1B1 (OATP1B1) and 1B3 (OATP1B3) transporters
• Ciclosporin
• Telithromycin
• Clarithromycin
• Delavirdine
• Stiripentol
• Ketoconazole
• Voriconazole
• Itraconazole
• Posaconazole
• Some antivirals used in the treatment of HCV 
• Elbasvir/ grazoprevir
• HIV protease inhibitors 
• Ritonavir
• Lopinavir
• Atazanavir
• Indinavir
• Darunavir
• Transport protein inhibitors
• Letermovir
• Fibric acid derivatives
• Gemfibrozil
• Ezetimibe
• Colestipol
• Fusidic acid
• Colchicine
• Digoxin
• Oral contraceptives
• Warfarin
• Tipranavir/ ritonavir
• Telaprevir
• Lopinavir/ ritonavir
• Saquinavir/ ritonavir
• Darunavir/ ritonavir
• Fosamprenavir/ ritonavir
• Fosamprenavir
• Nelfinavir
• Fenofibrate
• Boceprevir

Other interactions

• Grapefruit juice
• St. John's wort

• Lipid profile (Fasting or nonfasting before initiating treatment, fasting lipid profile should be rechecked 4-12 weeks after therapy initiation and every 3-12 months thereafter)
• Hepatic function

Specific cases may require

• Creatine phosphokinase (CPK)
• Neuromuscular and serologic assessment (if immune-mediated necrotizing myopathy is suspected)

Additional observations

• Signs and symptoms of myopathy/rhabdomyolysis
• New-onset diabetes mellitus

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 catabolized primarily through the receptor with high affinity to LDL (LDL receptor). Atorvastatin lowers plasma cholesterol and lipoprotein serum concentrations by inhibiting HMG-CoA reductase and subsequently cholesterol biosynthesis in the liver and increases 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. Atorvastatin produces a profound and sustained increase in LDL receptor activity coupled with a beneficial change in the quality of circulating LDL particles. Atorvastatin is effective in reducing LDL-C in patients with homozygous familial hypercholesterolaemia, a population that has not usually responded to lipid-lowering medicinal products. Atorvastatin has been shown to reduce concentrations of total-C (30% - 46%), LDL-C (41% - 61%), apolipoprotein B (34% - 50%), and triglycerides (14% - 33%) while producing variable increases in HDL-C and apolipoprotein A1 in a dose response study. These results are consistent in patients with heterozygous familial hypercholesterolaemia, nonfamilial forms of hypercholesterolaemia, and mixed hyperlipidaemia, including patients with noninsulin-dependent diabetes mellitus. Reductions in total-C, LDL-C, and apolipoprotein B have been proven to reduce risk for cardiovascular events and cardiovascular mortality.

Film-coated tablet 10mg

• Adco-Atorvastatin 10mg (Adcock Ingram)
• Astor (Watson)
• Atorvastatin Winthrop (Zentiva)
• Cholmin 10 (Trinity Pharma)

Tablet 10mg 

• Alipto 10 (Unimed Healthcare)
• Aspavor 10 (UpJohn)
• Atolip (Ranbaxy)
• Atorvastatin LHC 10 ( LHC Pharmaceuticals)
• Atorvastatin Sun (Ranbaxy)
• Atorvastatin Unicorn (Pharmacia)
• Dezzolip 10 (Dezzo Trading 392)
• Dynator (Pharma Dynamics)
• Lestavor 10 ( Activo Health)
• Lipitor (UpJohn) originator
• Lipogen (Ranbaxy)
• Ran-Atorvastatin (Ranbaxy)
• Vastor 10 (Mylan)

Film-coated tablet 20mg

• Astor (Watson)
• Atorvastatin Winthrop (Zentiva)

Tablet 20mg 

• Adco-Atorvastatin Adco Atorvastatin 20mg (Adcock Ingram)
• Alipto 20 (Unimed Healthcare)
• Aspavor (Pfizer)
• Atolip (Ranbaxy)
• Atorvastatin LHC 20 (LHC Pharmaceuticals)
• Atorvastatin Sun (Ranbaxy)
• Atorvastatin Unicorn (Pharmacia)
• Cholmin 20 (Trinity Pharma)
• Dezzolip 20 (Dezzo Trading 392)
• Dynator (Pharma Dynamics)
• Lestavor 20 ( Activo Health)
• Lipitor (Pfizer) originator
• Lipogen (Ranbaxy)
• Ran-Atorvastatin (Ranbaxy)
• Vastor 20 (Mylan)

Film-coated tablet 40mg

• Astor (Watson)
• Atorvastatin Winthrop (Zentiva)

Tablet 40mg 

• Adco-Atorvastatin Adco Atorvastatin 40mg (Adcock Ingram)
• Alipto 40 (Unimed Healthcare
• Aspavor 40 (UpJohn)
• Atolip (Ranbaxy)
• Atorvastatin LHC 40 (LHC Pharmaceuticals)
• Atorvastatin Sun (Ranbaxy)
• Atorvastatin Unicorn (Pharmacia)
• Cholmin 40 (Trinity Pharma)
• Dezzolip 40 (Dezzo Trading 392)
• Dynator (Pharma Dynamics)
• Lestavor 40 ( Activo Health)
• Lipitor (UpJohn) originator
• Lipogen (Ranbaxy)
• Ran-Atorvastatin (Ranbaxy)
• Vastor 40 (Mylan)

Film-coated tablet 80mg

• Astor (Watson)
• Lestavor 80 ( Activo Health)

Tablet 80mg

• Aspavor 80 (UpJohn)
• Atolip (Ranbaxy)
• Atorvastatin Sun (Ranbaxy)
• Cholmin 80 (Trinity Pharma)
• Dezzolip 80 (Dezzo Trading 392)
• Dynator (Pharma Dynamics)
• Lipitor (UpJohn) originator
• Lipogen (Ranbaxy)
• Ran-Atorvastatin (Ranbaxy)
• Vastor 80 (Mylan)

COMBINATION PREPARATIONS

Atorvastatin/ Amlodipine

Tablet 10mg/10mg 

• Caduet (Pfizer) originator

Tablet 20mg/10mg 

• Caduet (Pfizer) originator

Tablet 10mg/5mg 

• Caduet (Pfizer) originator

Tablet 20mg/5mg 

• Caduet (Pfizer) originator

Tablet 40mg/10mg

• Caduet (Pfizer) originator

Tablet 80mg/10mg 

• Caduet (Pfizer) originator