Atortonus, 20 mg tablets

Drug form: Tablets

ATC category: Agents affecting lipid metabolism

Trade name – atortonus International non-property name– atorvastatin COMPOSITION Each tablet contains: active ingredient: atorvastatin (as atorvastatin calcium trihydrate) - 20mg inactive ingredients: tablet core: microcrystalline cellulose, lactose monohydrate, povidone, maize starch, sodium starch glycolate, magnesium stearate, calcium hydrogen phosphate; tablet coating: hypromellose, titanium dioxide, propylene glycol, talc purified CHEMICAL NAME AND CAS NUMBER [R –(R*, R*)]-2-(4-fluorophenyl)-β,δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid calcium salt (2:1)tryhidrate: 134523-00-5. PHARMACOLOGICAL GROUP AND ATC CODE Нypolipidemic agent, inhibiors of GMG-CoA reductase. ATC code: C10AA05 PHARMACOLOGICAL ACTION Atorvastatin is a selective, competitive inhibitor of HMGCoA reductase, the rate-limiting enzyme responsible for the conversion of 3hydroxy-3methyl-glutaryl-coenzyme A to mevalonate, a precursor of sterols, including cholesterol. Triglycerides and cholesterol in the liver are incorporated into 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 high affinity LDL receptor. Atorvastatin lowers plasma cholesterol and lipoprotein levels by inhibiting HMGCoA reductase and cholesterol synthesis 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. Approximately 70% of circulating inhibitory activity for HMGCoA reductase is attributed to active metabolites. Atorvastatin has been shown to reduce totalC, LDLC, apolipoprotein B, and triglycerides while producing variable increases in HDLC in a dose-response study as shown in Table 1 below.
TABLE 1. Dose Response in Patients with Primary Hypercholesterolaemia
Lipitor Dose (mg) N Total-C LDL-C Apo B TG HDL-C
Placebo 12 5 8 6 -1 -2
10 11 -30 -41 -34 -14 4
20 10 -35 -44 -36 -33 12
40 11 -38 -50 -41 -25 -3
80 11 -46 -61 -50 -27 3
Adjusted Mean % Change from Baseline
Atorvastatin produced a variable but small increase in apolipoprotein A1. However, there was no clear dose response effect. Review of the current clinical database of 24 complete studies shows that atorvastatin increases HDL-cholesterol and reduces the LDL/HDL and total cholesterol/HDL ratios. These results are consistent in patients with heterozygous familial hypercholesterolaemia, nonfamilial forms of hypercholesterolaemia, and mixed hyperlipidaemia, including patients with noninsulin-dependent diabetes mellitus. Atorvastatin is effective in reducing LDL-C in patients with homozygous familial hypercholesterolaemia, a population that has not usually responded to lipid-lowering medication. In a compassionate use study, 41 patients aged 6 to 51 years with homozygous familial hypercholesterolaemia or with severe hypercholesterolaemia, who had 15% reduction in LDL-C in response to previous maximum dose combination drug therapy, received daily doses of 40 to 80 mg of Atorvastatin . Twenty four patients with homozygous familial hypercholesterolaemia received 80 mg Atorvastatin. Nineteen of these 24 patients responded with a greater than 15% reduction of LDL-C (mean 26%, range 18% to 42%). Atherosclerosis In the Reversing Atherosclerosis with Aggressive Lipid-Lowering Study (REVERSAL), the effect of atorvastatin 80 mg and pravastatin 40 mg on coronary atherosclerosis was assessed by intravascular ultrasound (IVUS), during angiography, in patients with coronary heart disease. In this randomized, 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 evaluated by the percentage change in atheroma volume in a pre-defined target vessel with a stenosis between 20% and 50%. 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 atovastatin were statistically significant (p=0.02). 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). The safety and tolerability profiles of the two treatment groups were comparable. The effect of intensive lipid lowering with atorvastatin on cardiovascular mortality and morbidity was not investigated in this 18-month study. Therefore, the clinical significance of these imaging results with regard to the primary and secondary prevention of cardiovascular events is unknown. Heterozygous Familial Hypercholesterolaemia in Paediatric Patients 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. Inclusion in the study required 1) a baseline LDL-C level 4.91 mmol/l or 2) a baseline LDL-C 4.14 mmol/l and positive family history of FH or documented premature cardiovascular disease in a first- or second degree relative. The mean baseline LDL-C value was 5.65 mmol/l (range: 3.58-9.96 mmol/l) in the atorvastatin group compared to 5.95 mmol/l (range: 4.14-8.39 mmol/l) in placebo group. The dosage if atorvastatin (once daily) was 10mg for the first 4 weeks and up-titrated to 20mg if the LDL-C level was>3.36 mmol/l. The number of atorvastatin-treated patients who required up-titration to 20mg after Week 4 during the double-blind phase was 80 (57.1%). Atorvastatin significantly decreased plasma levels of total-C, LDL-C, triglycerides, and apolipoprotein B during the 26 week double-blind phase (see Table 2).
TABLE 2. Lipid Lowering effects of atorvastatin in adolescent boys and girls with heterozygous familial hypercholesterolaemia or severe hypocholesterolaemia (mean percent change from baseline at endpoint in intention- to-treat-population)
Placebo 47 -1.5 -0.4 -1.9 1.0 0.7
Atorvastatin 140 -31.4 -39.6 2.8 -12.0 -34.0
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. In this limited controlled study, there was no detectable effect on growth or sexual maturation in boys or on menstrual length in girls. Atorvastatin has not been studied in controlled clinical trials involving pre-pubertal patients or patients younger than 10 years of age. The safety and efficacy of doses above 20mg have not been studied in controlled trials in children. The long-term efficacy of atorvastatin therapy in childhood to reduce morbidity and mortality in adulthood has not been established. Prevention of Cardiovascular Disease In the Anglo Scandinavian Cardiac Outcomes Trial Lipid Lowering Arm (ASCOT-LLA), the effect of atorvastatin on fatal and non-fatal coronary heart disease was assessed in 10,305 hypertensive patients 40-79 years of age, with no previous myocardial infarction or treatment for angina, and with TC levels 6.5mmol/l (251 mg/dl). Additionally, all patients had at least 3 of the predefined cardiovascular risk factors: male gender, age 55 years, smoking, diabetes, history of CHD in a first degree relative, TC:HDL 6, peripheral vascular disease, left ventricular hypertrophy, prior cerebrovascular event, specific ECG abnormality, proteinuria/albuminuria. In this randomised, double-blind, placebo-controlled study, patients were treated with anti-hypertensive therapy and either atorvastatin 10mg daily (n=5168) or placebo (n=5137). After 3 years treatment with amlodipine or atenolol-based regimen, mean blood pressure fell from 164.2/94.9 to 138.9/80.1 mmHg (atorvastatin) and 164.2/94.3 to 138.9/80.0 mmHg (placebo). After a median of 3.3 years of treatment, there was a statistically significant reduction in the rate of myocardial infarction (a component of the primary endpoint), 1.2% on atorvastatin versus 2.1% on placebo. Fatal and non-fatal ischaemic strokes tended to be lower in the atorvastatin group with a relative risk reduction of 26% (89 vs. 119 events) and an absolute risk reduction of 0.6%. The difference did not reach pre-defined levels of statistical significance. Women constituted 20% of the trial population and a subgroup analysis did not demonstrate any benefit on the primary endpoint of coronary events (fatal CHD plus non-fatal MI) (RR 1.11, 95% CI 0.58-2.13). In the Collaborative Atorvastatin Diabetes Study (CARDS), the effect of atorvastatin on fatal and nonfatal cardiovascular disease was assessed in 2838 patients with type 2 diabetes 40-75 years of age, without prior history of cardiovascular disease and with LDL 4.14 mmol/l (160 mg/dl) and TG 6.78mmol/l (600mg/dl). Additionally, all patients had at least 1 of the following risk factors: hypertension, current smoking, retinopathy, microalbuminuria or macroalbuminuria. In this randomised, double-blind, multi-centre, placebo-controlled trial, patients were treated with either atorvastatin 10 mg daily (n=1428) or placebo (n=1410) for a median follow-up of 3.9 years. The absolute and relative risk reduction effect of atorvastatin is as follows:
Event Relative Risk Reduction (%) Absolute Risk Reduction1 (%) No of events (atorvastatin vs.placebo) p-value
Major cardiovascular events (fatal and non-fatal AMI, silent MI, acute CHD death, unstable angina, CABG, PTCA, revascularisation, stroke) 37% 3.2% 83 vs. 127 0.001
MI (fatal and non-fatal AMI, silent MI) 42% 1.9% 38 vs. 64 0.007
Strokes (Fatal and non-fatal) 48% 1.3% 21 vs. 39 0.016
1Based on difference in crude events rates occurring over a median follow-up of 3.9 years. AMI= acute myocardial infarction; CABG= coronary artery bypass graft; CHD=coronary heart disease; MI=myocardial infarction; PTCA=percutaneous transluminal coronary angioplasty. Although the relative risk reduction in the primary end-point was similar between men and women, the absolute benefit for the women was less since the primary event rate on placebo was approximately 1/3 of the male event rate. 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 haemorrhagic stroke (55/2365, 2.3% vs. 33/2366, 1.4%, p=0.02) compared to placebo. • The risk of haemorrhagic stroke was increased in patients who entered the study with prior haemorrhagic 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 haemorrhagic 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 haemorrhagic 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. PHARMACOKINETICS Absorption: Atorvastatin is rapidly absorbed after oral administration; maximum plasma concentrations occur within 1 to 2 hours. Extent of absorption increases in proportion to atorvastatin dose. Atorvastatin tablets are bioequivalent to atorvastatin solutions. The absolute bioavailability of atorvastatin 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 L. Atorvastatin is 98% bound to plasma proteins. Metabolism: Atorvastatin is metabolised by cytochrome P450 3A4 to ortho- and parahydroxylated derivatives and various beta-oxidation products. 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. Excretion: Atorvastatin and atorvastatin metabolites are substrates of P-glycoprotein (see section 4.5). Atorvastatin is eliminated primarily in bile following hepatic and/or extrahepatic metabolism. However, the drug 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 HMGCoA reductase is approximately 20 to 30 hours due to the contribution of active metabolites. Special Populations Geriatric: Plasma concentrations of atorvastatin are higher in healthy elderly subjects than in young adults while the lipid effects were comparable to those seen in younger patient populations. Paediatric: Pharmacokinetic data in the paediatric population are not available. Gender: Concentrations of atorvastatin in women differ (approximately 20% higher for Cmax and 10% lower for AUC) from those in men. These differences were of no clinical significance, resulting in no clinically significant differences in lipid effects among men and women. Renal Insufficiency: Renal disease has no influence on the plasma concentrations or lipid effects of atorvastatin. Hepatic Insufficiency: Plasma concentrations of atorvastatin are markedly increased (approximately 16-fold in Cmax and 11fold in AUC) in patients with chronic alcoholic liver disease (ChildsPugh B). USES Hypercholesterolaemia: Atorvastatin is indicated as an adjunct to diet for reduction of elevated total cholesterol, LDL-cholesterol, apolipoprotein B, and triglycerides in adults and children aged 10 years and older with primary hypercholesterolaemia, heterozygous familial hypercholesterolaemia or combined (mixed) hyperlipidaemia when response to diet and other nonpharmacological measures is inadequate. Atorvastatin also raises HDL-cholesterol and lowers the LDL/HDL and total cholesterol/HDL ratios. Atorvastatin is also indicated as an adjunct to diet and other non-dietary measures in reducing elevated total cholesterol, LDL-cholesterol, and apolipoprotein B in patients with homozygous familial hypercholesterolaemia when response to these measures is inadequate. Primary prevention in type II diabetes: Atorvastatin is indicated for reducing the risk of cardiovascular events in diabetic patients with at least 1 additional risk factor, without clinically evident coronary heart disease irrespective of whether cholesterol is raised. DOSAGE AND ADMINISTRATION 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 usual starting dose is 10 mg once a day. Doses should be individualised according to baseline LDLC levels, the goal of therapy, and patient response. Adjustment of dosage should be made at intervals of 4 weeks or more. The maximum dose is 80 mg once a day. For patients taking interacting drugs that increase plasma exposure to atorvastatin, the starting dose should be 10 mg once a day, and a maximum dose of less than 80mg may need to be considered. In some cases a dose reduction, or where not practical, a temporary dose suspension may be considered. Doses above 20mg/day have not been investigated in patients aged Primary Hypercholesterolaemia and Combined (Mixed) Hyperlipidaemia Adults: The majority of patients are controlled with 10 mg Atorvastatin once a day. 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. Current consensus guidelines should be consulted to establish treatment goals for individual patients. Children aged 10-17 years: Doses above 20mg/day have not been investigated. Heterozygous Familial Hypercholesterolaemia Adults: Patients should be started with 10 mg Atorvastatin 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 (eg, colestipol) may be combined with 40 mg Atorvastatin Children aged 10-17 years: Doses above 20mg/day and combination therapies have not been investigated. Homozygous Familial Hypercholesterolaemia Adults: In a compassionate-use study of patients with homozygous familial hypercholesterolaemia, most patients responded to a dose of 80 mg of Atorvastatin Children: Treatment experience in a paediatric population with doses of Atorvastatin up to 80 mg/day is limited. Dosage in Patients With Renal Insufficiency Renal disease has no influence on the plasma concentrations nor lipid effects of Atorvastatin thus, no adjustment of dose is required. Dosage in Patients With Hepatic Dysfunction In patients with moderate to severe hepatic dysfunction, the therapeutic response to Atorvastatin is unaffected but exposure to the drug is greatly increased. Cmax increases by approximately 16 fold and AUC (0-24) by approximately 11 fold. Therefore, caution should be exercised in patients who consume substantial quantities of alcohol and/or have a history of liver disease. Geriatric Use Adequate treatment experience in adults age 70 or older with doses of Atorvastatin up to 80 mg/day has been obtained. Efficacy and safety in older patients using recommended doses is similar to that seen in the general population. Prevention of Cardiovascular disease In the primary prevention trials, the dose was 10mg/day ADVERSE EFFECTS Adverse reactions have usually been mild and transient. In the atorvastatin placebo-controlled clinical trial database of 16,066 (8755 Atorvastatin vs. 7311 placebo) patients treated for a median period of 53 weeks , 5.2% of patients on atorvastatin discontinued due to adverse reactions compared to 4.0% of the patients on placebo. The most frequent (1% or more) adverse effects that may be associated with Atorvastatin therapy, reported in patients participating in controlled clinical studies include: Infections and infestations: nasopharyngitis. Metabolism and nutrition disorders:hyperglycemia. Respiratory, thoracic and mediastinal disorders:pharyngolaryngeal pain, epistaxis. Gastrointestinal disorders : abdominal pain, constipation, diarrhoea, dyspepsia, nausea, flatulence. Musculoskeletal and connective tissue disorders: arthralgia, pain in extremity, musculoskeletal pain, muscle spasms, myalgia, joint swelling. Investigations: liver function test abnormal, blood creatine phosphokinase increased. Psychiatric Disorders: insomnia. Nervous System Disorders: headache. General Disorders and Administration Site Conditions: asthenia. Elevated serum ALT levels have been reported in 1.3% of patients receiving Atorvastatin Clinically important (>3 times upper normal limit) elevations in serum ALT levels occurred in 19 of the 2483 (0.8%) patients on Atorvastatin It was dose related and was reversible in all 19 patients. In 10 cases, the increase was first observed within 12 weeks of starting the treatment. Only 1 case occurred after 36 weeks and only 1 patient had symptoms suggestive of hepatitis. Treatment was discontinued in only 9 of these 19 cases. Elevated serum CPK levels (>3 times upper normal limit) occurred in 62 of the 2452 (2.5%) patients on Atorvastatin compared with 3.1% with other HMGCoA reductase inhibitors in clinical trials. Levels above 10 times the normal upper range occurred in only 11 (0.4%) Atorvastatin -treated patients. Only 3 (0.1%) of these 11 patients had concurrent muscle pain, tenderness, or weakness. Adverse events reported in atorvastatin clinical trials and in post marketing experience are categorised below according to system organ class and frequency. Frequencies are defined as: very common (>10%), common (>1% and <10%), uncommon (>0.1% and <1%), rare (>0.01% and <0.1%) and very rare (<0.01%). Gastrointestinal disorders Common: constipation, flatulence, dyspepsia, nausea, diarrhoea Uncommon: anorexia, vomiting, pancreatitis, abdominal discomfort Rare: eructation Blood and lymphatic system disorders Uncommon: thrombocytopenia. Immune system disorders Common: allergic reactions (including anaphylaxis). Endocrine disorders Uncommon: alopecia, hyperglycaemia, hypoglycaemia. Psychiatric Common: insomnia. Uncommon: amnesia, nightmare. Nervous system disorders Common: headache, dizziness, paraesthaesia, hypoesthesia. Uncommon: peripheral neuropathy. Very rare: dysgeusia. Eye disorders Uncommon: vision blurred Very rare: visual disturbance. Hepato-biliary disorders Rare: hepatitis, cholestasis. Very rare: hepatic failure. Skin/Appendages Common: Skin rash, pruritus Uncommon: urticaria, alopecia. Very rare: angioneurotic oedema, bullous rashes (including erythema multiforme, Stevens-Johnson syndrome and toxic epidermal necrolysis). Ear and Labyrinth Disorders Uncommon: tinnitus. Very rare: hearing loss. Musculoskeletal disorders Common: myalgia, arthralgia. Uncommon: myopathy, muscle cramps, neck pain. Rare: myositis, rhabdomyolysis, muscle fatigue. Very rare: tendon rupture. Reproductive system and breast disorders Uncommon: impotence. Very rare: gynecomastia. General disorders Common: asthenia, chest pain, back pain, fatigue. Uncommon: malaise, weight gain. Rare: peripheral oedema, pyrexia Investigations Rare: white blood cells urine positive The following adverse events have been reported with some statins: • Sleep disturbances, including insomnia and nightmares. • Memory loss. • Sexual dysfunction. • Depression. • Exceptional cases of interstitial lung disease, especially with long term therapy OVERDOSAGE Specific treatment is not available for Atorvastatin overdosage. Should an overdose occur, the patient should be treated symptomatically and supportive measures instituted, as required. Liver function tests and serum CPK levels should be monitored. Due to extensive drug binding to plasma proteins, haemodialysis is not expected to significantly enhance atorvastatin clearance. Contraindications Atorvastatin is contraindicated in patients with hypersensitivity to any component of this medication, active liver disease or unexplained persistent elevations of serum transaminases exceeding 3 times the upper limit of normal, during pregnancy, while breast-feeding, and in women of child-bearing potential not using appropriate contraceptive measures. 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 ALT or AST of greater than 3 times the upper limit of normal persist, reduction of dose or withdrawal of Lipitor is recommended. 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 CHD who had a recent stroke or TIA there was a higher incidence of haemorrhagic stroke in patients initiated on atorvastatin 80 mg compared to placebo. The increased risk was particularly noted in patients with prior haemorrhagic stroke or lacunar infarct at study entry. For patients with prior haemorrhagic stroke or lacunar infarct, the balance of risks and benefits of atorvastatin 80 mg is uncertain and the potential risk of haemorrhagic stroke should be carefully considered before initiating treatment Muscle effects Treatment with HMG-CoA reductase inhibitors (statins) has been associated with the onset of myalgia, myopathy, and very rarely rhabdomyolysis. Myopathy must be considered in any patient under statin therapy presenting with unexplained muscle symptoms such as pain or tenderness, muscle weakness or muscle cramps. In such cases creatine kinase (CK) levels should be measured Creatine phosphokinase measurement Creatine phosphokinase (CPK) should not be measured following strenuous exercise or in the presence of any plausible alternative cause of CPK increase as this makes value interpretation difficult. If CPK levels are significantly elevated at baseline (>5 times ULN), levels should be remeasured within 5 to 7 days later to confirm the results. Before treatment As with other statins atorvastatin should be prescribed with caution in patients with pre-disposing factors for rhabdomyolysis. A creatine phosphokinase (CPK) level should be measured before starting 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
In such situations, the risk of treatment should be considered in relation to possible benefit and clinical monitoring is recommended. If CPK levels are significantly elevated (>5 times ULN) at baseline, treatment should not be started. Whilst on treatment
− If muscular pain, weakness or cramps occur whilst a patient is receiving treatment with a statin, their CPK 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 CPK levels are elevated to 5 times ULN, treatment discontinuation should be considered. − If symptoms resolve and CPK 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.
These CPK elevations should be considered when evaluating the possibility of myocardial infarction in the differential diagnosis of chest pain. As with other drugs in this class, rhabdomyolysis with acute renal failure has been reported. A history of renal impairment may be a risk factor for the development of rhabdomyolysis. Such patients merit closer monitoring for skeletal muscle effects. Children aged 10-17 years In patients aged 52 weeks' duration and effects on long-term cardiovascular outcomes are unknown. The effects of atorvastatin in children aged Long term effects on cognitive development, growth and pubertal maturation are unknown. Risk of dose-related side effects including rhabdomyolysis is increased when atorvastatin is administered concomitantly with certain medications that may increase the plasma concentration of atorvastatin such as: ciclosporin, erythromycin, clarithromycin, itraconazole, ketoconazole, nefazodone, niacin, gemfibrozil, other fibrates or HIV-protease inhibitors. The risk of myopathy may also be increased with the concomitant use of ezetimibe. If possible alternative (non-interacting) therapies should be considered instead of these medications. In cases where co-administration of these medications with atorvastatin is only necessary for a few days, a dose reduction or where not practical, a temporary suspension of treatment with atorvastatin may be considered. If co-administration with interacting drugs is unavoidable, the starting dose of atorvastatin should be 10 mg once a day. In the case of ciclosporin, clarithromycin and itraconazole, a lower maximum dose of atorvastatin should be used. Lipid levels should be monitored to ensure that the lowest dose necessary of atorvastatin is employed. Patients with rare hereditary problems of galactose intolerance, Lapp lactose deficiency or glucose-galactose malabsorption should not take this medicine. Temporary suspension of atorvastatin may be appropriate during fusidic acid therapy . Interstitial lung disease Exceptional cases of interstitial lung disease have been reported with some statins, especially with long term therapy.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. PREGNANCY AND BREAST FEEDING Atorvastatin is contraindicated in pregnancy and while breast-feeding. Women of child-bearing potential should use appropriate contraceptive measures. An interval of 1 month should be allowed from stopping Atorvastatin treatment to conception in the event of planning a pregnancy. In animal studies atorvastatin had no effect on fertility and was not teratogenic, however, at maternally toxic doses foetal 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 atorvastatin equivalent to 6 and 21 times that expected in man, respectively. In rats, plasma concentrations of atorvastatin are similar to those in milk. It is not known whether this drug or its metabolites is excreted in human milk.
DRUG INTERACTIONS The risk of myopathy during treatment with HMG-CoA reductase inhibitors is increased with concurrent administration of ciclosporin, fibrates, macrolide antibiotics including erythromycin, azole antifungals, HIV-protease inhibitors or niacin and on rare occasions has resulted in rhabdomyolysis with renal dysfunction secondary to myoglobinuria. In cases where co-administration of these medications with atorvastatin is necessary, the benefit and the risk of concurrent treatment should be carefully considered. When patients are receiving drugs that increase the plasma concentration of atorvastatin, the starting dose of atorvastatin should be 10 mg once a day. In the case of ciclosporin, clarithromycin and itraconazole, a lower maximum dose of atorvastatin should be used.Lipid levels should be monitored to ensure that the lowest dose necessary of atorvastatin is used. Transporter Inhibitors: Atorvastatin and atorvastatin-metabolites are substrates of the OATP1B1 transporter. Concomitant administration of atorvastatin 10 mg and ciclosporin 5.2 mg/kg/day resulted in an 8.7 fold increase in atorvastatin AUC. In cases where co-administration of atorvastatin with ciclosporin is necessary, the dose of atorvastatin should not exceed 10 mg. Clarithromycin: Clarithromycin is a known inhibitor of cytochrome P450 3A4. Co-admistration of atorvastatin 80 mg OD and clarithromycin (500 mg BID) resulted in a 4.4 fold increase in atorvastatin AUC. In cases where co-administration of clarithromycin with atorvastatin is necessary, the maintenance dose of atorvastatin should not exceed 20 mg daily. Patients who normally require 40mg or 80mg of atorvastatin should either reduce their dosage during concomitant clarithromycin treatment, or alternatively (for short courses of this antibiotic) where not practical, a temporary suspension of treatment with atorvastatin may be considered. Erythromycin: Erythromycin is a known inhibitor of cytochrome P450 3A4. Co-administration of atorvastatin 10 mg OD and erythromycin (500 mg QID) resulted in a 33% increase in exposure to total atorvastatin activity. Azithromycin:Co-administration of atorvastatin (10 mg OD) and azithromycin (500 mg OD) did not alter the plasma concentrations of atorvastatin. Itraconazole:Concomitant administration of atorvastatin 20 to 40 mg and itraconazole 200 mg daily resulted in a 2.5-3.3 fold increase in atorvastatin AUC. In cases where co-administration of itraconazole with atorvastatin is necessary, the maintenance dose of atorvastatin should not exceed 40 mg daily. Patients who normally require 80 mg of atorvastatin should either reduce their dosage during concomitant itraconazole treatment, or alternatively (for short courses of this antibiotic) where not practical, a temporary suspension of treatment with atorvastatin may be considered. Protease inhibitors: Co-administration of atorvastatin and protease inhibitors, known inhibitors of cytochrome P450 3A4, was associated with an approximately two-fold increase in plasma concentrations of atorvastatin. Lipid levels should be monitored to ensure that the lowest dose necessary of atorvastatin is used. Diltiazem hydrochloride: Co-administration of atorvastatin 40 mg with diltiazem 240 mg resulted in a 51% increase in atorvastatin AUC. After initiation of diltiazem or following dosage adjustment, lipid levels should be monitored to ensure that the lowest dose necessary of atorvastatin is used. Ezetimibe: The use of ezetimibe alone is associated with myopathy. The risk of myopathy may therefore be increased with concomitant use of ezetimibe and atorvastatin. Grapefruit juice: Contains one or more components that inhibit CYP3A4 and can increase plasma concentrations of drugs metabolised by CYP3A4. Intake of one 240 ml glass of grapefruit juice resulted in an increase in atorvastatin AUC of 37 % and a decreased AUC of 20.4 % for the active orthohydroxy metabolite. However, large quantities of grapefruit juice (over 1.2L daily for 5 days) increased AUC of atorvastatin 2.5 fold and AUC of active (atorvastatin and metabolites) HMG-CoA reductase inhibitors 1.3 fold. Concomitant intake of large quantities of grapefruit juice and atorvastatin is therefore not recommended. Inducers of cytochrome P450 3A4: Concomitant administration of atorvastatin with inducers of cytochrome P450 3A4 (eg 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 3A4 induction and inhibition of hepatocyte uptake transporter OATP1B1), simultaneous co-administration of atorvastatin with rifampin is recommended, as delayed administration of atorvastatin after administration of rifampin has been associated with a significant reduction in atorvastatin plasma concentrations. Verapamil and Amiodarone: Interaction studies with atorvastatin and verapamil or amiodarone have not been conducted. Both verapamil and amiodarone are known to inhibit CYP3A4 activity and co-administration with atorvastatin may result in increased exposure to atorvastatin. Lipid levels should be monitored to ensure that the lowest dose necessary of atorvastatin is used. Other concomitant therapy Gemfibrozil/fibrates: The use of fibrates alone is occasionally associated with myopathy. The risk of atorvastatin-induced myopathy may be increased with the concomitant use of fibrates. Concomitant administration of gemfibrozil 600 mg BID resulted in a 24% increase in atorvastatin AUC. Digoxin: When multiple doses of digoxin and 10 mg atorvastatin were co-administered, steady state plasma digoxin concentrations were unaffected. However, digoxin concentrations increased approximately 20% following administration of digoxin with 80 mg atorvastatin daily. Patients taking digoxin should be monitored appropriately. Oral contraceptives: Administration of atorvastatin with an oral contraceptive containing norethisterone and ethinyl oestradiol produced increases in plasma concentrations of norethisterone and ethinyl oestradiol. These increased concentrations should be considered when selecting oral contraceptive doses. Colestipol: Plasma concentrations of atorvastatin were lower (approximately 25%) when colestipol was administered with atorvastatin. However, lipid effects were greater when atorvastatin and colestipol were administered together than when either drug was given alone. Antacid: Administration of atorvastatin with an oral antacid suspension containing magnesium and aluminium hydroxides decreased atorvastatin plasma concentrations approximately 35%; however, LDLC reduction was not altered. Warfarin: Administration of atorvastatin with warfarin caused a minimal decrease in prothrombin time (mean ± SE of 1.7 ± 0.4 seconds) during the first 4 days of dosing with 80 mg atorvastatin. Dosing continued for 15 days and prothrombin time returned to normal by the end of atorvastatin treatment. Nevertheless, patients receiving warfarin should be closely monitored when atorvastatin is added to their therapy. Phenazone:Co-administration of multiple doses of atorvastatin and phenazone showed little or no detectable effect in the clearance of phenazone. Cimetidine: An interaction study with cimetidine and atorvastatin was conducted, and no interaction was seen. Amlodipine:In a drug-drug interaction study in healthy subjects, co-administration of atorvastatin 80 mg and amlodipine 10 mg resulted in an 18% increase in atorvastatin AUC. Fusidic acid: Although interaction studies with atorvastatin and fusidic acid have not been conducted, severe muscle problems such as rhabdomyolysis have been reported in post-marketing experience with this combination. Patients should be closely monitored and temporary suspension of atorvastatin treatment may be appropriate. Other: In clinical studies in which atorvastatin was administered with antihypertensives or hypoglycaemic agents no clinically significant interactions were seen.
PRESCRIPTION STATUS To be dispensed with prescription. PRESENTATION 3 blister packets with 10 tablets in each and leaflet inserted in the cardboard box STORAGE conditions Store at a temperature (15-250C), in a dry place, out of the reach of children. Protect from light. EXPIRY DATE 3 years.