Atorsan

Atorsan

atorvastatin

Manufacturer:

Sandoz

Distributor:

Zuellig Pharma
Full Prescribing Info
Contents
Atorvastatin calcium.
Description
Each 40 mg film-coated tablet contains atorvastatin calcium eq. to atorvastatin 40 mg.
Excipients/Inactive Ingredients: Microcrystalline cellulose, Lactose monohydrate, Croscarmellose sodium, Hydroxypropyl cellulose, Polysorbate 80, Magnesium oxide heavy, Colloidal anhydrous silica, Magnesium stearate, Hypromellose, Hydroxypropyl cellulose, Titanium dioxide, Macrogol 6000, Talc, Yellow ferric oxide (E172).
Action
Pharmacotherapeutic Group: Lipid modifying agents, HMG-CoA-reductase inhibitors. ATC Code: C10AA05.
Pharmacology: Pharmacodynamics: Atorvastatin is a selective, competitive inhibitor of HMG-CoA reductase, the rate-limiting enzyme that converts 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 lipoprotein (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 receptors).
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
Homozygous familial hypercholesterolaemia: In a multicenter 8 week open-label compassionate-use study with an optional extension phase of variable length, 335 patients were enrolled, 89 of which were identified as homozygous familial hypercholesterolaemia patients. From these 89 patients, the mean percent reduction in LDL-C was approximately 20%. Atorvastatin was administered at doses up to 80 mg/day.
Atherosclerosis: In the Reversing Atherosclerosis with Aggressive Lipid- Lowering Study (REVERSAL), the effect of intensive lipid lowering with atorvastatin 80 mg and standard degree of lipid lowering with pravastatin 40 mg on coronary atherosclerosis was assessed by intravascular ultrasound (IVUS), during angiography, in patients with coronary heart disease. In this randomised, double- blind, multicenter, controlled clinical trial, IVUS was performed at baseline and at 18 months in 502 patients. In the atorvastatin group (n=253), there was no progression of atherosclerosis.
The median percent change, from baseline, in total atheroma volume (the primary study criteria) was -0.4% (p=0.98) in the atorvastatin group and +2.7% (p=0.001) in the pravastatin group (n=249). When compared to pravastatin the effects of atorvastatin were statistically significant (p=0.02). The effect of intensive lipid lowering on cardiovascular endpoints (e. g. need for revascularisation, non fatal myocardial infarction, coronary death) was not investigated in this study.
In the atorvastatin group, LDL-C was reduced to a mean of 2.04 mmol/L ± 0.8 (78.9 mg/dl ± 30) from baseline 3.89 mmol/L ± 0.7 (150 mg/dl ± 28) and in the pravastatin group, LDL-C was reduced to a mean of 2.85 mmol/L ± 0.7 (110 mg/dl ± 26) from baseline 3.89 mmol/L ± 0.7 (150 mg/dl ± 26) (p<0.0001). Atorvastatin also significantly reduced mean TC by 34.1% (pravastatin: -18.4%, p<0.0001), mean TG levels by 20% (pravastatin: -6.8%, p<0.0009), and mean apolipoprotein B by 39.1% (pravastatin: -22.0%, p<0.0001). Atorvastatin increased mean HDL-C by 2.9% (pravastatin: +5.6%, p=NS). There was a 36.4% mean reduction in CRP in the atorvastatin group compared to a 5.2% reduction in the pravastatin group (p<0.0001).
Study results were obtained with the 80 mg dose strength. Therefore, they cannot be extrapolated to the lower dose strengths.
The safety and tolerability profiles of the two treatment groups were comparable.
The effect of intensive lipid lowering on major cardiovascular endpoints was not investigated in this study. Therefore, the clinical significance of these imaging results with regard to the primary and secondary prevention of cardiovascular events is unknown.
Acute coronary syndrome: In the MIRACL study, atorvastatin 80 mg has been evaluated in 3,086 patients (atorvastatin n=1,538; placebo n=1,548) with an acute coronary syndrome (non Q-wave MI or unstable angina). Treatment was initiated during the acute phase after hospital admission and lasted for a period of 16 weeks. Treatment with atorvastatin 80 mg/day increased the time to occurrence of the combined primary endpoint, defined as death from any cause, nonfatal MI, resuscitated cardiac arrest, or angina pectoris with evidence of myocardial ischaemia requiring hospitalization, indicating a risk reduction by 16% (p=0.048). This was mainly due to a 26% reduction in re-hospitalisation for angina pectoris with evidence of myocardial ischaemia (p=0.018). The other secondary endpoints did not reach statistical significance on their own (overall: Placebo: 22.2%, Atorvastatin: 22.4%).
The safety profile of atorvastatin in the MIRACL study was consistent with what is described in Adverse Reactions.
Prevention of cardiovascular disease: The effect of atorvastatin on fatal and non-fatal coronary heart disease was assessed in a randomized, double-blind, placebocontrolled study, the Anglo-Scandinavian Cardiac Outcomes Trial Lipid Lowering Arm (ASCOT-LLA). Patients were hypertensive, 40-79 years of age, with no previous myocardial infarction or treatment for angina, and with TC levels ≤6.5 mmol/L (251 mg/dl). All patients had at least 3 of the pre-defined cardiovascular risk factors: male gender, age ≥55 years, smoking, diabetes, history of CHD in a first-degree relative, TC:HDL-C >6, peripheral vascular disease, left ventricular hypertrophy, prior cerebrovascular event, specific ECG abnormality, proteinuria/albuminuria. Not all included patients were estimated to have a high risk for a first cardiovascular event.
Patients were treated with anti-hypertensive therapy (either amlodipine or atenolol-based regimen) and either atorvastatin 10 mg daily (n=5,168) or placebo (n=5,137).
The relative risk reduction effect of atorvastatin was as follows: (See Table 1.)

Click on icon to see table/diagram/image

Total mortality and cardiovascular mortality were not significantly reduced (185 vs. 212 events, p=0.17 and 74 vs. 82 events, p=0.51). In the subgroup analyses by gender (81% males, 19% females), a beneficial effect of atorvastatin was seen in males but could not be established in females possibly due to the low event rate in the female subgroup. Overall and cardiovascular mortality were numerically higher in the female patients (38 vs. 30 and 17 vs. 12), but this was not statistically significant. There was significant treatment interaction by antihypertensive baseline therapy. The primary endpoint (fatal CHD plus non-fatal MI) was significantly reduced by atorvastatin in patients treated with amlodipine (HR 0.47 (0.32-0.69), p=0.00008), but not in those treated with atenolol (HR 0.83 (0.59-1.17), p=0.287).
The effect of atorvastatin on fatal and non-fatal cardiovascular disease was also assessed in a randomized, double-blind, multicenter, placebo-controlled trial, the Collaborative Atorvastatin Diabetes Study (CARDS) in patients with type 2 diabetes, 40-75 years of age, without prior history of cardiovascular disease, and with LDL-C ≤4.14 mmol/L (160 mg/dl) and TG ≤6.78 mmol/L(600 mg/dl). All patients had at least 1 of the following risk factors: hypertension, current smoking, retinopathy, microalbuminuria or macroalbuminuria.
Patients were treated with either atorvastatin 10 mg daily (n=1,428) or placebo (n=1,410) for a median follow-up of 3.9 years.
The relative risk reduction effect of atorvastatin was as follows: (See Table 2.)

Click on icon to see table/diagram/image

There was no evidence of a difference in the treatment effect by patient's gender, age, or baseline LDL-C level. A favourable trend was observed regarding the mortality rate (82 deaths in the placebo group vs. 61 deaths in the atorvastatin group, p=0.0592).
Recurrent stroke: In the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) study, the effect of atorvastatin 80 mg daily or placebo on stroke was evaluated in 4731 patients who had a stroke or transient ischemic attack (TIA) within the preceding 6 months and no history of coronary heart disease (CHD). Patients were 60% male, 21-92 years of age (average age 63 years), and had an average baseline LDL of 133 mg/dl (3.4 mmol/l). The mean LDL-C was 73 mg/dl (1.9 mmol/l) during treatment with atorvastatin and 129 mg/dl (3.3 mmol/l) during treatment with placebo. Median follow-up was 4.9 years.
Atorvastatin 80 mg reduced the risk of the primary endpoint of fatal or non-fatal stroke by 15% (HR 0.85; 95% CI, 0.72-1.00; p=0.05 or 0.84; 95% CI, 0.71-0.99; p=0.03 after adjustment for baseline factors) compared to placebo. All cause mortality was 9.1% (216/2365) for atorvastatin versus 8.9% (211/2366) for placebo.
In a post-hoc analysis, atorvastatin 80 mg reduced the incidence of ischemic stroke (218/2365, 9.2% vs. 274/2366, 11.6%, p=0.01) and increased the incidence of hemorrhagic stroke (55/2365, 2.3% vs. 33/2366, 1.4%, p=0.02) compared to placebo.
The risk of hemorrhagic stroke was increased in patients who entered the study with prior hemorrhagic stroke (7/45 for atorvastatin versus 2/48 for placebo; HR 4.06; 95% CI, 0.84-19.57), and the risk of ischemic stroke was similar between groups (3/45 for atorvastatin versus 2/48 for placebo; HR 1.64; 95% CI, 0.27-9.82).
The risk of hemorrhagic stroke was increased in patients who entered the study with prior lacunar infarct (20/708 for atorvastatin versus 4/701 for placebo; HR 4.99; 95% CI, 1.71-14.61), but the risk of ischemic stroke was also decreased in these patients (79/708 for atorvastatin versus 102/701 for placebo; HR 0.76; 95% CI, 0.57-1.02). It is possible that the net risk of stroke is increased in patients with prior lacunar infarct who receive atorvastatin 80 mg/day.
All cause mortality was 15.6% (7/45) for atorvastatin versus 10.4% (5/48) in the subgroup of patients with prior hemorrhagic stroke. All cause mortality was 10.9% (77/708) for atorvastatin versus 9.1% (64/701) for placebo in the subgroup of patients with prior lacunar infarct.
Paediatric Population: Heterozygous Familial Hypercholesterolaemia in Paediatric Patients aged 6-17 years old: An 8-week, open-label study to evaluate pharmacokinetics, pharmacodynamics, and safety and tolerability of atorvastatin was conducted in children and adolescents with genetically confirmed heterozygous familial hypercholesterolemia and baseline LDLC ≥4 mmol/L. A total of 39 children and adolescents, 6 to 17 years of age, were enrolled. Cohort A included 15 children, 6 to 12 years of age and at Tanner Stage 1. Cohort B included 24 children, 10 to 17 years of age and at Tanner Stage ≥2.
The initial dose of atorvastatin was 5 mg daily of a chewable tablet in Cohort A and 10 mg daily of a tablet formulation in Cohort B. The atorvastatin dose was permitted to be doubled if a subject had not attained target LDL-C of <3.35 mmol/L at Week 4 and if atorvastatin was well tolerated.
Mean values for LDL-C, TC, VLDL-C, and Apo B decreased by Week 2 among all subjects. For subjects whose dose was doubled, additional decreases were observed as early as 2 weeks, at the first assessment, after dose escalation. The mean percent decreases in lipid parameters were similar for both cohorts, regardless of whether subjects remained at their initial dose or doubled their initial dose. At Week 8, on average, the percent change from baseline in LDL-C and TC was approximately 40% and 30%, respectively, over the range of exposures.
Heterozygous Familial Hypercholesterolaemia in Paediatric Patients aged 10-17 years old: In a double-blind, placebo controlled study followed by an open-label phase, 187 boys and postmenarchal girls 10-17 years of age (mean age 14.1 years) with heterozygous familial hypercholesterolaemia (FH) or severe hypercholesterolaemia were randomised to atorvastatin (n=140) or placebo (n=47) for 26 weeks and then all received atorvastatin for 26 weeks. The dosage of atorvastatin (once daily) was 10 mg for the first 4 weeks and up-titrated to 20 mg if the LDL-C level was >3.36 mmol/l. Atorvastatin significantly decreased plasma levels of total-C, LDL-C, triglycerides, and apolipoprotein B during the 26 week double-blind phase. The mean achieved LDL-C value was 3.38 mmol/l (range: 1.81-6.26 mmol/l) in the atorvastatin group compared to 5.91 mmol/l (range: 3.93-9.96 mmol/l) in the placebo group during the 26-week double-blind phase.
An additional paediatric study of atorvastatin versus colestipol in patients with hypercholesterolaemia aged 10-18 years demonstrated that atorvastatin (N=25) caused a significant reduction in LDL-C at week 26 (p<0.05) compared with colestipol (N=31).
A compassionate use study in patients with severe hypercholesterolaemia (including homozygous hypercholesterolaemia) included 46 paediatric patients treated with atorvastatin titrated according to response (some subjects received 80 mg atorvastatin per day). The study lasted 3 years: LDL-cholesterol was lowered by 36%.
The long-term efficacy of atorvastatin therapy in childhood to reduce morbidity and mortality in adulthood has not been established.
Pharmacokinetics: Absorption: Atorvastatin is rapidly absorbed after oral administration; maximum plasma concentrations (Cmax) occur within 1 to 2 hours. Extent of absorption increases in proportion to atorvastatin dose. After oral administration, atorvastatin film-coated tablets are 95% to 99% bioavailability compared to the oral solution. The absolute bioavailability of atorvastatin (parent medicinal product) is approximately 12% and the systemic availability of HMG-CoA reductase inhibitory activity is approximately 30%. The low systemic availability is attributed to presystemic clearance in gastrointestinal mucosa and/or hepatic first-pass metabolism.
Distribution: Mean volume of distribution of atorvastatin is approximately 381 liters. Atorvastatin is ≥98% bound to plasma proteins.
Biotransformation: Atorvastatin is metabolized by cytochrome P450 3A4 to ortho- and parahydroxylated derivatives and various beta-oxidation products. Apart from other pathways these products are further metabolized via glucuronidation. In vitro inhibition of HMG-CoA reductase by ortho- and parahydroxylated metabolites is equivalent to that of atorvastatin. Approximately 70% of circulating inhibitory activity for HMG-CoA reductase is attributed to active metabolites.
Elimination: Atorvastatin is eliminated primarily in bile following hepatic and/or extrahepatic metabolism; However, atorvastatin does not appear to undergo significant enterohepatic recirculation. Mean plasma elimination half-life of atorvastatin in humans is approximately 14 hours. The half-life of inhibitory activity for HMG-CoA reductase is approximately 20 to 30 hours due to the contribution of active metabolites.
Special populations: Elderly: Plasma concentrations of atorvastatin and its active metabolites are higher in healthy elderly subjects than in young adults while the lipid effects were comparable to those seen in younger patient populations.
Paediatric: In an open-label, 8-week study, Tanner Stage 1 (N=15) and Tanner Stage ≥2 (N=24) paediatric patients (ages 6-17 years) with heterozygous familial hypercholesterolemia and baseline LDL-C ≥4 mmol/l were treated with 5 or 10 mg of chewable or 10 or 20 mg of film-coated atorvastatin tablets once daily, respectively. Body weight was the only significant covariate in atorvastatin population PK model. Apparent oral clearance of atorvastatin in paediatric subjects appeared similar to adults when scaled allometrically by body weight. Consistent decreases in LDL-C and TC were observed over the range of atorvastatin and ohydroxyatorvastatin exposures.
Gender: Concentrations of atorvastatin and its active metabolites in women differ from those in men (Women: approximately 20% higher for Cmax and approx. 10% lower for AUC). These differences were of no clinically significance, resulting in on clinically significant differences in lipid effects among men and women.
Patients with renal impairment: Renal disease has no influence on the plasma concentrations or lipid effects of atorvastatin and its active metabolites.
Hemodialysis: While studies have not been conducted in patients with end-stage renal disease, hemodialysis is not expected to significantly enhance clearance of atorvastatin since the medicinal product is extensively bound to plasma proteins.
Patients with hepatic impairment: Plasma concentrations of atorvastatin and its active metabolites are markedly increased (approx. 16-fold in Cmax and approx. 11-fold in AUC) in patients with chronic alcoholic liver disease (Child-Pugh B).
SLOC1B1 polymorphism: Hepatic uptake of all HMG-CoA reductase inhibitors including atorvastatin, involves the OATP1B1 transporter. In patients with SLCO1B1 polymorphism there is a risk of increased exposure of atorvastatin, which may lead to an increased risk of rhabdomyolysis (see Precautions). Polymorphism in the gene encoding OATP1B1 (SLCO1B1 c.521CC) is associated with a 2.4-fold higher atorvastatin exposure (AUC) than in individuals without this genotype variant (c.521TT). A genetically impaired hepatic uptake of atorvastatin is also possible in these patients. Possible consequences for the efficacy are unknown.
Toxicology: Preclinical safety data: Atorvastatin was negative for mutagenic and clastogenic potential in a battery of 4 in vitro tests and 1 in vivo assay. Atorvastatin was not found to be carcinogenic in rats, but high doses in mice (resulting in 6-11 fold the AUC0-24h reached in humans at the highest recommended dose) showed hepatocellular adenomas in males and hepatocellular carcinomas in females.
There is evidence from animal experimental studies that HMG-CoA reductase inhibitors may affect the development of embryos or fetuses. In rats, rabbits and dogs atorvastatin had no effect on fertility and was not teratogenic, however, at maternally toxic doses fetal toxicity was observed in rats and rabbits. The development of the rat offspring was delayed and post-natal survival reduced during exposure of the dams to high doses of atorvastatin. In rats, there is evidence of placental transfer. In rats, plasma concentrations of atorvastatin are similar to those in milk.
It is not known whether atorvastatin or its metabolites are excreted in human milk.
Indications/Uses
Hypercholesterolaemia: Atorvastatin is indicated as an adjunct to diet for reduction of elevated total cholesterol (total-C), LDL-cholesterol (LDL-C), apolipoprotein B, and triglycerides in adults, adolescents and children aged 10 years or older with primary hypercholesterolaemia including familial hypercholesterolaemia (heterozygous variant) or combined (mixed) hyperlipidaemia (Corresponding to Types IIa and IIb of the Fredrickson classification) when response to diet and other nonpharmacological measures is inadequate.
Atorvastatin is also indicated to reduce total-C and LDL-C in adults with homozygous familial hypercholesterolaemia as an adjunct to other lipid-lowering treatments (e.g. LDL apheresis) or if such treatments are unavailable.
Prevention of cardiovascular disease: Atorvastatin is used to prevent cardiovascular events in patients without clinical evidence of cardiovascular disease who have multiple risk factors for a first cardiovascular event (see Pharmacology: Pharmacodynamics under Actions), as an adjunct to correction of other risk factors.
Chronic Kidney Disease: In patients with diabetes with moderately decreased estimated glomerular filtration rate (eGFR), atorvastatin is indicated to reduce the risk for cardiovascular disease.
In patients with clinically evident coronary heart disease and CKD not requiring dialysis, atorvastatin is indicated to reduce the risk of major cardiovascular events including stroke.
In patients with clinically evident coronary heart disease and/or diabetes with microalbuminuria, atorvastatin is indicated to reduce the rate of GFR decline and progression of CKD.
Paediatric Patients (10-17 years of age): Atorvastatin is indicated as adjunct to diet to reduce total cholesterol, LDL-C and apo B levels in boys and post-menarchal girls, 10 to 17 years of age, with heterozygous familial hypercholesterolemia 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 cardiovascular disease or two or more other CVD risk factors are present in the paediatric patient.
Dosage/Direction for Use
Posology: The patient should be placed on a standard cholesterol-lowering diet before receiving atorvastatin and should continue on this diet during treatment with atorvastatin.
The dose should be individualised according to baseline LDL-C levels, the goal of therapy, and patient response.
The usual starting dose is 10 mg once a day. Adjustment of dose should be made at intervals of 4 weeks or more. The maximum dose is 80 mg once a day.
Primary hypercholesterolaemia and combined (mixed) hyperlipidaemia: The majority of patients are controlled with atorvastatin 10 mg once a day. A therapeutic response is evident within 2 weeks, and the maximum therapeutic response is usually achieved within 4 weeks. The response is maintained during chronic therapy.
Heterozygous familial hypercholesterolaemia: Patients should be started with atorvastatin 10 mg daily. Doses should be individualised and adjusted every 4 weeks to 40 mg daily. Thereafter, either the dose may be increased to a maximum of 80 mg daily or a bile acid sequestrant may be combined with 40 mg atorvastatin once daily.
Homozygous familial hypercholesterolaemia: Only limited data are available.
The dose of atorvastatin in patients with homozygous familial hypercholesterolemia is 10 to 80 mg daily (see Pharmacology: Pharmacodynamics under Actions). Atorvastatin should be used as an adjunct to other lipid-lowering treatments (e.g. LDL apheresis) in these patients or if such treatments are unavailable.
Prevention of cardiovascular disease: In the primary prevention trials the dose was 10 mg/day. Higher doses may be necessary in order to attain (LDL-) cholesterol levels according to current guidelines.
Renal impairment: No adjustment of dose is required (see Precautions).
Hepatic impairment: Atorvastatin should be used with caution in patients with hepatic impairment (see Precautions). Atorvastatin is contraindicated in patients with active liver disease (see Contraindications).
Use in the elderly: Efficacy and safety in geriatric patients (65 years of age and older) using recommended doses are similar to those seen in the general population.
Paediatric use: Hypercholesterolaemia: Paediatric use should only be carried out by physicians experienced in the treatment of paediatric hyperlipidaemia and patients should be re-evaluated on a regular basis to assess progress.
For patients aged 10 years and above, the recommended starting dose of atorvastatin is 10 mg per day with titration up to 20 mg per day. Titration should be conducted according to the individual response and tolerability in paediatric patients. Safety information for paediatric patients treated with doses above 20 mg, corresponding to about 0.5 mg/kg, is limited.
There is limited experience in children between 6-10 years of age. Atorvastatin is not indicated in the treatment of patients below the age of 10 years.
Other pharmaceutical forms/strengths may be more appropriate for this population.
Method of administration: Atorvastatin is for oral administration. Each daily dose of atorvastatin is given all at once and may be given at any time of day with or without food.
Overdosage
Specific treatment is not available for atorvastatin overdose. Should an overdose occur, the patient should be treated symptomatically and supportive measures instituted, as required. Liver function tests should be performed and serum CK levels should be monitored. Due to extensive atorvastatin binding to plasma proteins, haemodialysis is not expected to significantly enhance atorvastatin clearance.
Contraindications
Atorvastatin is contraindicated in patients: with hypersensitivity to the active substance or to any of the excipients of this medicinal product,
with active liver disease or unexplained persistent elevations of serum transaminases exceeding 3 times the upper limit of normal,
treated with hepatitis C antivirals glecaprevir/pibrentasvir,
during pregnancy, while breast-feeding and in women of child-bearing potential not using appropriate contraceptive measures (see Use in Pregnancy & Lactation).
Special Precautions
Liver effects: Liver function tests should be performed before the initiation of treatment and periodically thereafter. Patients who develop any signs or symptoms suggestive of liver injury should have liver function tests performed. Patients who develop increased transaminase levels should be monitored until the abnormality (ies) resolve. Should an increase in transaminases of greater than 3 times the upper limit of normal (ULN) persist, reduction of dose or withdrawal of atorvastatin is recommended (see Adverse Reactions).
Atorvastatin should be used with caution in patients who consume substantial quantities of alcohol and/or have a history of liver disease.
Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL): In a post-hoc analysis of stroke subtypes in patients without coronary heart disease (CHD) who had a recent stroke or transient ischemic attack (TIA) there was a higher incidence of hemorrhagic stroke in patients initiated on atorvastatin 80 mg compared to placebo. The increased risk was particularly noted in patients with prior hemorrhagic stroke or lacunar infarct at study entry. For patients with prior hemorrhagic stroke or lacunar infarct, the balance of risks and benefits of atorvastatin 80 mg is uncertain, and the potential risk of hemorrhagic stroke should be carefully considered before initiating treatment (see Pharmacology: Pharmacodynamics under Actions).
Skeletal muscle effects: Atorvastatin, like other HMG-CoA reductase inhibitors, may in rare occasions affect the skeletal muscle and cause myalgia, myositis, and myopathy that may progress to rhabdomyolysis, a potentially life-threatening condition characterised by markedly elevated creatine kinase (CK) levels (> 10 times ULN), myoglobinaemia and myoglobinuria which may lead to renal failure.
There have been very rare reports of an immune-mediated necrotising myopathy (IMNM) during or after treatment with some statins. IMNM is clinically characterised by persistent proximal muscle weakness and elevated serum creatine kinase, which persist despite discontinuation of statin treatment.
Before the treatment: Atorvastatin should be prescribed with caution in patients with pre-disposing factors for rhabdomyolysis. A CK level should be measured before starting statin treatment in the following situations: Renal impairment,
Hypothyroidism,
Personal or familial history of hereditary muscular disorders,
Previous history of muscular toxicity with a statin or fibrate,
Previous history of liver disease and/or where substantial quantities of alcohol are consumed,
In elderly (age > 70 years), the necessity of such measurement should be considered, according to the presence of other predisposing factors for rhabdomyolysis,
Situations where an increase in plasma levels may occur, such as interactions (see Interactions) and special populations including genetic subpopulations (see Pharmacology: Pharmacokinetics under Actions).
In such situations, the risk of treatment should be considered in relation to possible benefit, and clinical monitoring is recommended.
If CK levels are significantly elevated (> 5 times ULN) at baseline, treatment should not be started.
Creatine kinase measurement: Creatine kinase (CK) should not be measured following strenuous exercise or in the presence of any plausible alternative cause of CK increase as this makes value interpretation difficult. If CK levels are significantly elevated at baseline (> 5 times ULN), levels should be remeasured within 5 to 7 days later to confirm the results.
Whilst on treatment: Patients must be asked to promptly report muscle pain, cramps, or weakness especially if accompanied by malaise or fever.
If such symptoms occur whilst a patient is receiving treatment with atorvastatin, their CK levels should be measured. If these levels are found to be significantly elevated (> 5 times ULN), treatment should be stopped.
If muscular symptoms are severe and cause daily discomfort, even if the CK levels are elevated to ≤ 5 x ULN, treatment discontinuation should be considered.
If symptoms resolve and CK levels return to normal, then re-introduction of atorvastatin or introduction of an alternative statin may be considered at the lowest dose and with close monitoring.
Atorvastatin must be discontinued if clinically significant elevation of CK levels (> 10 x ULN) occur, or if rhabdomyolysis is diagnosed or suspected.
Concomitant treatment with other medicinal products: Risk of rhabdomyolysis is increased when atorvastatin is administered concomitantly with certain medicinal products that may increase the plasma concentration of atorvastatin such as potent inhibitors of CYP3A4 or transport proteins (e.g. ciclosporine, telithromycin, clarithromycin, delavirdine, stiripentol, ketoconazole, voriconazole, itraconazole, posaconazole and HIV protease inhibitors including ritonavir, lopinavir, atazanavir, indinavir, darunavir, tipranavir/ritonavir etc). The risk of myopathy may also be increased with the concomitant use of gemfibrozil and other fibric acid derivates, antivirals for the treatment of hepatitis C (HCV) (boceprevir, telaprevir, elbasvir/grazoprevir), erythromycin, niacin or ezetimibe. If possible, alternative (non-interacting) therapies should be considered instead of these medicinal products.
In cases where co-administration of these medicinal products with atorvastatin is necessary, the benefit and the risk of concurrent treatment should be carefully considered. When patients are receiving medicinal products that increase the plasma concentration of atorvastatin, a lower maximum dose of atorvastatin is recommended. In addition, in the case of potent CYP3A4 inhibitors, a lower starting dose of atorvastatin should be considered and appropriate clinical monitoring of these patients is recommended (see Interactions).
Atorvastatin must not be co-administered with systemic formulations of fusidic acid or within 7 days of stopping fusidic acid treatment. In patients where the use of systemic fusidic acid is considered essential, statin treatment should be discontinued throughout the duration of fusidic acid treatment. There have been reports of rhabdomyolysis (including some fatalities) in patients receiving fusidic acid and statins in combination (see Interactions). The patient should be advised to seek medical advice immediately if they experience any symptoms of muscle weakness, pain or tenderness.
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.
Interstitial lung disease: Exceptional cases of interstitial lung disease have been reported with some statins, especially with long term therapy (see Adverse Reactions). Presenting features can include dyspnoea, non-productive cough and deterioration in general health (fatigue, weight loss and fever). If it is suspected a patient has developed interstitial lung disease, statin therapy should be discontinued.
Diabetes Mellitus: Some evidence suggests that statins as a class raise blood glucose and in some patients, at high risk of future diabetes, may produce a level of hyperglycaemia where formal diabetes care is appropriate. This risk, however, is outweighed by the reduction in vascular risk with statins and therefore should not be a reason for stopping statin treatment. Patients at risk (fasting glucose 5.6 to 6.9 mmol/L, BMI > 30kg/m2, raised triglycerides, hypertension) should be monitored both clinically and biochemically according to national guidelines.
Excipients: Atorvastatin contains lactose. Patients with rare hereditary problems of galactose intolerance, Lapp lactose deficiency or glucose-galactose malabsorption should not take this medicine.
Effects on ability to drive and use machines: Atorvastatin has negligible influence on the ability to drive and use machines.
Use in Children: No clinically significant effect on growth and sexual maturation was observed in a 3-year study based on the assessment of overall maturation and development, assessment of Tanner Stage, and measurement of height and weight (see Adverse Reactions).
Use In Pregnancy & Lactation
Women of childbearing potential: Women of child-bearing potential should use appropriate contraceptive measures during treatment (see Contraindications).
Pregnancy: Atorvastatin is contraindicated during pregnancy (see Contraindications). 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 (see Pharmacology: Toxicology: Preclinical safety data under Actions).
Maternal treatment with atorvastatin may reduce the fetal 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 (see Contraindications).
Breast-feeding: 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 (see Pharmacology: Toxicology: Preclinical safety data under Actions). Because of the potential for serious adverse reactions, women taking atorvastatin should not breast-feed their infants (see Contraindications). Atorvastatin is contraindicated during breast-feeding (see Contraindications).
Fertility: In animal studies atorvastatin had no effect on male or female fertility (see Pharmacology: Toxicology: Preclinical safety data under Actions).
Adverse Reactions
In the atorvastatin placebo-controlled clinical trial database of 16,066 (8755 atorvastatin vs. 7311 placebo) patients treated for a mean period of 53 weeks, 5.2% of patients on atorvastatin discontinued due to adverse reactions compared to 4.0% of the patients on placebo.
Based on data from clinical studies and extensive post-marketing experience, the following list presents the adverse reaction profile for atorvastatin.
Estimated frequencies of reactions are ranked according to the following convention: common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (≤ 1/10,000), not known (cannot be estimated from the available data).
Infections and infestations: Common: Nasopharyngitis.
Blood and lymphatic system disorders: Rare: Thrombocytopenia.
Immune system disorders: Common: Allergic reactions. Very rare: Anaphylaxis.
Metabolism and nutrition disorders: Common: Hyperglycaemia. Uncommon: Hypoglycaemia, weight gain, anorexia.
Psychiatric disorders: Uncommon: Nightmare, insomnia.
Nervous system disorders: Common: Headache. Uncommon: Dizziness, paraesthesia, hypoaesthesia, dysgeusia, amnesia. Rare: Peripheral neuropathy.
Eye disorders: Uncommon: Vision blurred. Rare: Visual disturbance.
Ear and labyrinth disorders: Uncommon: Tinnitus. Very rare: Hearing loss.
Respiratory, thoracic and mediastinal disorders: Common: Pharyngolaryngeal pain, epistaxis.
Gastrointestinal disorders: Common: Constipation, flatulence, dyspepsia, nausea, diarrhoea. Uncommon: Vomiting, abdominal pain upper and lower, eructation, pancreatitis
Hepatobiliary disorders: Uncommon: Hepatitis. Rare: Cholestasis. Very rare: Hepatic failure.
Skin and subcutaneous tissue disorders: Uncommon: Urticaria, skin rash, pruritus, alopecia. Rare: Angioneurotic oedema, dermatitis bullous including erythema multiforme, Stevens-Johnson syndrome and toxic epidermal necrolysis.
Musculoskeletal and connective tissue disorders: Common: Myalgia, arthralgia, pain in extremity, muscle spasms, joint swelling, back pain. Uncommon: Neck pain, muscle fatigue. Rare: Myopathy, myositis, rhabdomyolysis, muscle rupture, tendonopathy, sometimes complicated by rupture. Very rare: Lupus-like syndrome. Not known: Immune mediated necrotising myopathy (see Precautions).
Reproductive system and breast disorders: Very rare: Gynecomastia.
General disorders and administration site conditions: Uncommon: Malaise, asthenia, chest pain, peripheral oedema, fatigue, pyrexia.
Investigations: Common: Liver function test abnormal, blood creatine kinase increased. Uncommon: White blood cells urine positive.
As with other HMG-CoA reductase inhibitors elevated serum transaminases have been reported in patients receiving atorvastatin. These changes were usually mild, transient, and did not require interruption of treatment. Clinically important (>3 times upper normal limit) elevations in serum transaminases occurred in 0.8% patients on atorvastatin. These elevations were dose related and were reversible in all patients.
Elevated serum creatine kinase (CK) levels greater than 3 times upper limit of normal occurred in 2.5% of patients on atorvastatin, similar to other HMG-CoA reductase inhibitors in clinical trials. Levels above 10 times the normal upper range occurred in 0.4% atorvastatin-treated patients (see Precautions).
Paediatric population: Paediatric patients aged from 10 to 17 years of age 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 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 paediatric patients was similar to the known safety profile of atorvastatin in adult patients.
The clinical safety database includes safety data for 520 paediatric patients who received atorvastatin, among which 7 patients were < 6 years old, 121 patients were in the age range of 6 to 9, and 392 patients were in the age range of 10 to 17.
Based on the data available, the frequency, type and severity of adverse reactions in children is similar to adults.
The following adverse events have been reported with some statins: Sexual dysfunction,
Depression,
Exceptional cases of interstitial lung disease, especially with long term therapy (see Precautions),
Diabetes mellitus: Frequency will depend on the presence or absence of risk factors (fasting blood glucose ≥ 5.6 mmol/l, BMI > 30kg/m2, raised triglycerides, history of hypertension),
Memory loss.
Drug Interactions
Effect of co-administered medicinal products on atorvastatin: Atorvastatin is metabolized by cytochrome P450 3A4 (CYP3A4) and is a substrate of the hepatic transporters, organic anion-transporting polypeptide 1B1 (OATP1B1) and 1B3 (OATP1B3) transporter. Metabolites of atorvastatin are substrates of OATP1B1. Atorvastatin is also identified as a substrate of the multi-drug resistance protein 1 (MDR1) and breast cancer resistance protein (BCRP), which may limit the intestinal absorption and biliary clearance of atorvastatin (see Pharmacology: Pharmacokinetics under Actions). Concomitant administration of medicinal products that are inhibitors of CYP3A4 or transport proteins may lead to increased plasma concentrations of atorvastatin and an increased risk of myopathy. The risk might also be increased at concomitant administration of atorvastatin with other medicinal products that have a potential to induce myopathy, such as fibric acid derivates and ezetimibe (see Precautions).
CYP3A4 inhibitors: Potent CYP3A4 inhibitors have been shown to lead to markedly increased concentrations of atorvastatin (see Table 3 and specific information as follows). Co-administration of potent CYP3A4 inhibitors (e.g. ciclosporin, telithromycin, clarithromycin, delavirdine, stiripentol, ketoconazole, voriconazole, itraconazole, posaconazole, some antivirals used in the treatement of HCV (e.g. elbasvir/grazoprevir) and HIV protease inhibitors including ritonavir, lopinavir, atazanavir, indinavir, darunavir, etc.) should be avoided if possible. In cases where co-administration of these medicinal products with atorvastatin cannot be avoided lower starting and maximum doses of atorvastatin should be considered and appropriate clinical monitoring of the patient is recommended (see Table 3).
Moderate CYP3A4 inhibitors (e.g. erythromycin, diltiazem, verapamil and fluconazole) may increase plasma concentrations of atorvastatin (see Table 3). An increased risk of myopathy has been observed with the use of erythromycin in combination with statins. Interaction studies evaluating the effects of amiodarone or verapamil on atorvastatin have not been conducted. Both amiodarone and verapamil are known to inhibit CYP3A4 activity and co-administration with atorvastatin may result in increased exposure to atorvastatin. Therefore, a lower maximum dose of atorvastatin should be considered and appropriate clinical monitoring of the patient is recommended when concomitantly used with moderate CYP3A4 inhibitors. Appropriate clinical monitoring is recommended after initiation or following dose adjustments of the inhibitor.
CYP3A4 inducers: Concomitant administration of atorvastatin with inducers of cytochrome P450 3A (e.g. efavirenz, rifampin, St. John's Wort) can lead to variable reductions in plasma concentrations of atorvastatin. Due to the dual interaction mechanism of rifampin, (cytochrome P450 3A 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. The effect of rifampin on atorvastatin concentrations in hepatocytes is, however, unknown and if concomitant administration cannot be avoided, patients should be carefully monitored for efficacy.
Transport protein inhibitors: Inhibitors of transport proteins (e.g. ciclosporin) can increase the systemic exposure of atorvastatin (see Table 3). The effect of inhibition of hepatic uptake transporters on atorvastatin concentrations in hepatocytes is unknown. If concomitant administration cannot be avoided, a dose reduction and clinical monitoring for efficacy is recommended (see Table 3).
Gemfibrozil/fibric acid derivatives: The use of fibrates alone is occasionally associated with muscle related events, including rhabdomyolysis. The risk of these events may be increased with the concomitant use of fibric acid derivatives and atorvastatin. If concomitant administration cannot be avoided, the lowest dose of atorvastatin to achieve the therapeutic objective should be used and the patients should be appropriately monitored (see Precautions).
Ezetimibe: The use of ezetimibe alone is associated with muscle related events, including rhabdomyolysis. The risk of these events may therefore be increased with concomitant use of ezetimibe and atorvastatin. Appropriate clinical monitoring of these patients is recommended.
Colestipol: Plasma concentrations of atorvastatin and its active metabolites were lower (ratio of atorvastatin concentration: 0.74) when colestipol was coadministered with atorvastatin. However, lipid effects were greater when atorvastatin and colestipol were co-administered than when either medicinal product was given alone.
Fusidic acid: The risk of myopathy including rhabdomyolysis may be increased by the concomitant administration of systemic fusidic acid with statins. The mechanism of this interaction (whether it is pharmacodynamic or pharmacokinetic, or both) is yet unknown. There have been reports of rhabdomyolysis (including some fatalities) in patients receiving this combination.
If treatment with systemic fusidic acid is necessary, atorvastatin treatment should be discontinued throughout the duration of the fusidic acid treatment. Also see Precautions.
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.
Effect of atorvastatin on co-administered medicinal products: Digoxin: When multiple doses of digoxin and 10 mg atorvastatin were co-administered, steady-state digoxin concentrations increased slightly. Patients taking digoxin should be monitored appropriately.
Oral contraceptives: Co-administration of atorvastatin with an oral contraceptive produced increases in plasma concentrations of norethindrone and ethinyl oestradiol.
Warfarin: In a clinical study in patients receiving chronic warfarin therapy, co-administration of atorvastatin 80 mg daily with warfarin caused a small decrease of about 1.7 seconds in prothrombin time during the first 4 days of dosing which returned to normal within 15 days of atorvastatin treatment. Although only very rare cases of clinically significant anticoagulant interactions have been reported, prothrombin time should be determined before starting atorvastatin in patients taking coumarin anticoagulants and frequently enough during early therapy to ensure that no significant alteration of prothrombin time occurs. Once a stable prothrombin time has been documented, prothrombin times can be monitored at the intervals usually recommended for patients on coumarin anticoagulants. If the dose of atorvastatin is changed or discontinued, the same procedure should be repeated. Atorvastatin therapy has not been associated with bleeding or with changes in prothrombin time in patients not taking anticoagulants.
Paediatric population: Drug-drug interaction studies have only been performed in adults. The extent of interactions in the paediatric population is not known. The above mentioned interactions for adults and the warnings in Precautions should be taken into account for the paediatric population.
Drug Interaction: (See Tables 3 & 4.)

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Click on icon to see table/diagram/image
Caution For Usage
Special precautions for disposal: No special precautions.
Incompatibilities: Not applicable.
Storage
Do not store above 30°C, protected from moisture.
Store in the original package.
ATC Classification
C10AA05 - atorvastatin ; Belongs to the class of HMG CoA reductase inhibitors. Used in the treatment of hyperlipidemia.
Presentation/Packing
FC tab 40 mg (light yellow, round, biconvex, debossed with HLA 40 on one side) x 10 x 10's.
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