Important aspects of prescribing information relevant to primary healthcare are covered in this section specifically for the drugs recommended in this CKS topic. For further information on contraindications, cautions, drug interactions, and adverse effects, see the electronic Medicines Compendium (eMC) (http://emc.medicines.org.uk), or the British National Formulary (BNF) (www.bnf.org).

• Statins inhibit 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase, an enzyme involved in cholesterol synthesis. Inhibition of HMG CoA reductase reduces low-density lipoprotein (LDL) cholesterol levels by slowing down the production of cholesterol in the liver and increasing the liver's ability to remove the LDL cholesterol already in the blood [NICE, 2006].

• Simvastatin is recommended first-line for primary and secondary prevention of cardiovascular disease.
• Pravastatin is an alternative to simvastatin if there are significant interactions with drugs which interfere with cytochrome P450 metabolism.
• Atorvastatin should only be considered for people with acute coronary syndrome.

• For further information, see:
• First-line therapy for primary prevention of cardiovascular disease.
• First-line therapy for secondary prevention of cardiovascular disease.

• These recommendations are based on guidelines issued by the National Institute for Health and Clinical Excellence (NICE) [National Collaborating Centre for Primary Care, 2008a; NICE, 2008a].

• Offer simvastatin 40 mg daily for primary and secondary prevention of cardiovascular disease:
• Prescribe pravastatin 40 mg daily if simvastatin is not suitable.
• Consider prescribing a daily dose of less than 40 mg simvastatin in the following situations:
• People who can not tolerate a dose of simvastatin 40 mg daily.
• People with severe renal insufficiency (creatinine clearance less than 30 mL/min): doses above 10 mg daily should be used with caution.
• Risk of drug interaction:
• Avoid exceeding a simvastatin dosage of 10 mg daily in people receiving concomitant medication with ciclosporin, danazol, gemfibrozil (avoid this combination if possible), or a lipid-modifying dose (equal to or greater than 1 g/day) of nicotinic acid.
• Avoid exceeding a simvastatin dose of 20 mg daily in people taking amiodarone or verapamil. These combinations should be avoided unless clinical benefits outweigh the increased risk of myopathy.
• Re-initiation of simvastatin therapy in people who previously experienced elevated creatine kinase levels and muscular symptoms. If indicated, simvastatin should be re-introduced at the lowest dose with close monitoring.
• Simvastatin 80 mg daily should only be offered:
• For people with acute coronary syndrome.
• For secondary prevention, when simvastatin 40 mg daily is insufficient to reach a target total cholesterol level less than 4 mmol/L or a low-density lipoprotein cholesterol level less than 2 mmol/L.
• Atorvastatin 80 mg daily should only be offered for people with acute coronary syndrome.
• For further information, see First-line therapy.

• For further information, see:
• First-line therapy in primary prevention.
• First-line therapy in secondary prevention.
• Higher intensity therapies in secondary prevention.
• The effect of statins on serum total and low-density lipoprotein (LDL) cholesterol is drug- and dose-dependent.
• For a comparison of the potency of different doses for different statins, see evidence on Lipid lowering effects.

• These recommendations reflect guidance issued by the National Institute for Health and Clinical Excellence [National Collaborating Centre for Primary Care, 2008a; NICE, 2008a] and recommendations from the manufacturer of simvastatin [ABPI Medicines Compendium, 2009].
• For pravastatin, a dose of 40 mg daily is recommended because, in all preventive morbidity and mortality trials, this was the only studied starting and maintenance dose [ABPI Medicines Compendium, 2005b].

• Simvastatin and pravastatin should preferably be taken in the evening.
• Atorvastatin should be taken once daily. It is not affected by the time of administration.

• These recommendations are in line with those issued by the manufacturers of simvastatin, pravastatin and atorvastatin [ABPI Medicines Compendium, 2005b; ABPI Medicines Compendium, 2007c; ABPI Medicines Compendium, 2009].
• For simvastatin and pravastatin, the rationale for evening dosing is based on the fact that these statins have a short half-life (range: 1 to 5 hours) and that peak cholesterol biosynthesis occurs in the early morning hours [Plakogiannis and Cohen, 2007].
• For atorvastatin, timing is less crucial as it has a longer duration of action. The half-life of its inhibitory activity on HMG-CoA reductase is around 20 to 30 hours (due to the contribution of active metabolites) [ABPI Medicines Compendium, 2007c].
• The evidence to support evening and morning dosing for statins is poor.

• Do not prescribe a statin in:
• People with active liver disease or unexplained persistent elevations of serum transaminases.
• Women who are pregnant or breastfeeding.
• Do not initiate a statin in:
• People with transaminase levels that are three or more times the upper limit of normal:
• For further information, see Monitoring: LFTs and CK.
• People within the first 48 hours of an acute stroke.
• Seek specialist advice before initiating a statin in people with a history of haemorrhagic stroke, particularly those with inadequately controlled hypertension.

• These recommendations are based on those issued by the National Institute for Health and Clinical Excellence [National Collaborating Centre for Chronic Conditions, 2008; NICE, 2008a] and the manufacturers of statins [ABPI Medicines Compendium, 2005b; Pfizer Ltd, 2007; ABPI Medicines Compendium, 2009].

• The combination of a fibrate and statin should be used with caution, as there is an increased risk of muscular adverse effects (e.g. myopathy and rhabdomyolysis) [MHRA, 2007].
• Simvastatin and atorvastatin are metabolized by cytochrome P450 isoenzymes and interact with drugs which inhibit these liver enzymes.
• For simvastatin, see Table 1 for prescribing advice.
• For atorvastatin, the manufacturer recommends the following maximum doses [Pfizer Ltd, 2007]:
• With ciclosporin: do not exceed 10 mg atorvastatin.
• With clarithromycin: do not exceed 20 mg atorvastatin (consider temporary cessation of atorvastatin if antibiotic treatment is short term).
• With itraconazole: do not exceed 40 mg atorvastatin.
• Grapefruit juice:
• Avoid grapefruit juice when taking simvastatin.
• Concomitant intake of large quantities of grapefruit juice and atorvastatin is not recommended.
• In contrast, pravastatin is not extensively metabolized by cytochrome P450 isoenzymes and does not share these interactions (except with ciclosporin) [ABPI Medicines Compendium, 2005b]:
• The manufacturer of pravastatin warns that co-administration with ciclosporin can elevate the plasma level of pravastatin and advises closer clinical and biochemical monitoring in these people (no dose adjustment was recommended).

• Before initiating a statin:
• Measure baseline liver enzymes (transaminases):
• Do not initiate a statin if transaminase levels are three or more times the upper limit of normal:
• People with liver enzymes (transaminases) that are elevated but are less than three times the upper limit of normal should not be routinely excluded from statin therapy.
• Check creatine kinase if the person is at high risk of muscle toxicity. This is not routinely necessary in other people.
• After initiating a statin:
• Repeat liver function tests (LFTs) within 3 months of starting treatment, again at 12 months, and after each dose increase, but not again unless clinically indicated (e.g. signs or symptoms of hepatotoxicity):
• For management of abnormal LFT results, see Abnormal LFT results.
• Check creatine kinase as soon as possible if the person reports muscular symptoms (rhabdomyolysis and myopathy are rare but serious adverse effects of statins):
• For management of abnormal creatine kinase results, see Raised creatine kinase.

• Pretreatment baseline creatine kinase:
• The Scottish Intercollegiate Guidelines Network recommends pretreatment baseline creatine kinase measurement for people at high risk of muscle toxicity (e.g. older individuals or when combining a statin with a drug known to increase myotoxicity) [SIGN, 2007].
• The manufacturer of simvastatin recommends that this should be checked in people with predisposing factors for rhabdomyolysis [ABPI Medicines Compendium, 2009]:
• Elderly (more than 70 years of age).
• Renal impairment.
• Uncontrolled hypothyroidism.
• Personal or familial history of hereditary muscular disorders.
• History of muscular toxicity with a statin or fibrate.
• Alcohol abuse.

• These recommendations are based on guidance issued by the National Institute for Health and Clinical Excellence (NICE), the Scottish Intercollegiate Guidelines Network (SIGN), and expert opinion [Smellie et al, 2005; Smellie, 2006; SIGN, 2007; NICE, 2008a].
• Pretreatment baseline creatine kinase (CK) only for people at high risk of experiencing muscle toxicity:
• NICE does not make any recommendation regarding the need for pretreatment, baseline CK measurement [NICE, 2008a].
• This recommendation is based on that from SIGN [SIGN, 2007], following the consensus recommendations issued by the National Lipid Association Statin Safety Task Force [McKenney et al, 2006; SIGN, 2007]. This US group reviewed evidence from the US Food and Drug Administration (FDA), cohort and clinical trials, and administrative claims database information. Four of its expert panels assessed statin safety with regard to liver, muscle, renal, and neurological systems.
• This recommendation is consistent with the manufacturer of simvastatin which recommends that CK should be measured in people with predisposing factors for rhabdomyolysis [ABPI Medicines Compendium, 2009].
• Repeat liver function tests (LFTs):
• The recommendation to repeat LFTs within 3 months of starting statin treatment and again at 12 months is based on the expert consensus of the NICE Guidance Development Group [NICE, 2008a]. Evidence for the monitoring of LFTs is sparse.
• CKS did not find any evidence to support the need for long-term monitoring of liver function in people taking statins (for more than 12 months).
• The recommendation to repeat LFTs after a dose increase is also based on expert opinion [Smellie et al, 2005; Smellie, 2006].

If liver function test (LFT) results are abnormal while on a statin:

• If less than three times the upper limit of normal:
• Continue the statin, but recheck LFTs within 4–6 weeks to exclude further increases in transaminase levels.
• No extra monitoring is required if values are stable.
• If transaminase levels are three times the upper limit of normal or more, consider the following options, depending on the concentration:
• Stop the statin and recheck LFTs within 4–6 weeks to ensure that values settle (consider re-introducing the statin cautiously at a later date) or
• Reduce the statin dosage and recheck LFTs within 4–6 weeks:
• Stop the statin if transaminase levels continue to be three times the upper limit of normal or more.

• These recommendations are based on expert opinion [Smellie et al, 2005; Smellie, 2006].

• If creatine kinase (CK) is five or more times the upper limit of normal:
• Stop statin treatment immediately.
• Check renal function.
• Monitor creatine kinase fortnightly.
• Consider secondary causes of myopathy if the CK level remains elevated:
• Underlying muscle disorders, renal impairment, hypothyroidism, or alcohol abuse.
• Concomitant use of other lipid-modifying drugs (e.g. fibrates and nicotinic acid).
• Concomitant use of cytochrome P450 inhibitors (e.g. ciclosporin, macrolide antibiotics [e.g. erythromycin and clarithromycin], azole antifungal [e.g. itraconazole and ketoconazole], grapefruit juice).
• If symptoms resolve and CK levels return to normal, then re-introduction of the statin or introduction of an alternative statin may be considered at the lowest dose, and with close monitoring.
• If the CK level is less than five times the upper limit of normal:
• If there are no muscle symptoms:
• Continue the statin.
• Advise the individual to report immediately any unexplained muscular symptoms.
• Consider further checks of CK to ensure that values are not increasing.
• If there are muscle symptoms:
• Continue the statin.
• Monitor symptoms.
• Check CK concentrations regularly (for example, fortnightly) if CK values continue to increase.
• Stop the statin, or seek specialist advice if muscle symptoms are severe or CK values continue to increase.

• Statins and other lipid-modifying drugs can rarely cause myopathy and rhabdomyolysis. The exact mechanism is uncertain, but risk factors include [CSM, 2004]:
• Underlying muscle disorders.
• Renal impairment.
• Untreated hypothyroidism: this is known to increase the risk of statin-induced myopathy [Bar et al, 2007] and is a recognized cause of dyslipidaemia [BTA et al, 2006].
• Alcohol abuse.
• Older age (older than 70 years of age).
• Concomitant use of other lipid-modifying drugs (i.e. fibrates, nicotinic acid).
• A history of myopathy with any lipid-modification therapy.
• Drug interactions (e.g. with drugs inhibiting cytochrome P450 enzymes).

• These recommendations are based on expert opinion [Smellie et al, 2005; Smellie, 2006] and information from the manufacturers of statins [ABPI Medicines Compendium, 2005b; ABPI Medicines Compendium, 2009].

• Advise the person to seek medical advice and to stop the statin:
• If they develop unexplained muscle symptoms (pain, tenderness, weakness).
• If they develop unexplained peripheral neuropathy.
• If they develop presenting features of interstitial lung disease such as dyspnoea, non-productive cough, and deterioration in general health (e.g. fatigue, weight loss, and fever).
• For further information and management, see Adverse effects.
• Emphasize the importance of compliance with treatment.
• Not all people who are prescribed statins will take them for any length of time. Between 5 and 15% are likely to discontinue therapy within the first year, and at the end of five years as many as 30% are likely to have discontinued [NICE, 2005].
• Additional advice:
• Avoid grapefruit juice with simvastatin. Concomitant intake of large quantities of grapefruit juice and atorvastatin is not recommended.
• Simvastatin and pravastatin should be taken in the evening (atorvastatin can be taken at any time). For further information, see Time of administration.

• Statin intolerance is common. It is thought to affect around 5 to 10% of people taking a statin [Ara et al, 2008; Nair et al, 2008].
• Statin intolerance is defined by the National Institute for Health and Clinical Excellence as the presence of clinically significant adverse effects from statin therapy that are considered to represent an unacceptable risk to the patient or that may result in compliance with therapy being compromised [NICE, 2007].
• These adverse effects include new-onset muscle pain (often associated with levels of muscle enzymes in the blood indicative of muscle damage), significant gastrointestinal disturbance or alterations of liver function tests.
• For people intolerant of a particular statin, there is very limited evidence from a small retrospective study (n = 40) which indicates switching to a different statin may be helpful — particularly from a lipophilic statin (e.g. simvastatin, atorvastatin, or fluvastatin) to a more water soluble (hydrophilic) statin (e.g. pravastatin or rosuvastatin) [Nair et al, 2008].
• Serious muscular adverse effects are rare.
• For further information on the incidence of rhabdomyolysis and myopathy and elevation of liver transaminase (greater than three times the upper limit of normal [ULN]), see Serious adverse effects with lower intensity statin therapy.
• Advise the person to seek medical advice and to stop the statin if they develop unexplained muscle symptoms (pain, tenderness, weakness). Check creatine kinase.
• For the management of abnormal liver enzymes and abnormal creatine kinase in people taking a statin, see:
• Abnormal LFT results
• Raised creatine kinase
• Check if there is untreated hypothyroidism as this increases the risk of statin-induced myopathy [Bar et al, 2007].
• Headache and gastrointestinal adverse effects are common.
• Headache has been reported as an adverse effect of all statins in clinical trials.
• Gastrointestinal adverse effects include abdominal pain, flatulence, constipation, diarrhoea, and nausea and vomiting. These usually settle with time.
• Other less common adverse effects include:
• Sleep disturbances, including insomnia and nightmares:
• The Medicines and Healthcare products Regulatory Agency (MHRA) has advised that sleep disturbances are likely to be a class effect of all statins [MHRA, 2009b].
• Postmarketing data suggest that sleep disturbances have commonly been reported with atorvastatin and fluvastatin [MHRA, 2009c]. Post marketing reports have also been received with pravastatin, simvastatin, and rosuvastatin, but it is not possible to determine whether there is any statin with which sleep disturbances are least likely.
• Experts have previously suggested that a hydrophilic statin (pravastatin, fluvastatin, or rosuvastatin) may be less likely to cause sleep disturbance because it would be less likely to cross the blood-brain barrier than a lipophilic statin (simvastatin or atorvastatin) [Chong, 2002].
• Memory loss
• The MHRA has advised that memory loss is likely to be a class effect of all statins [MHRA, 2009b].
• When assessing someone with memory loss, consider whether a statin could be the cause or a contributing factor.
• With the exception of rosuvastatin, which had a higher incidence rate (3.0 cases per 1000 patient-years with rosuvastatin compared with 0 cases with placebo), the incidence rates of memory loss with statin use compared to placebo were similar. However, because there was insufficient information regarding confounding factors, causality with all statins cannot be ruled out because all statins have post-marketing reports of memory loss reoccurring after re-challenge with statin [MHRA, 2009c].
• Sexual dysfunction
• The MHRA has advised that sexual dysfunction is likely to be a class effect of all statins [MHRA, 2009b].
• A case-control study reported that 12.1% of patients receiving lipid-lowering therapy reported erectile dysfunction compared with 5.6% of controls [Bruckert et al, 1996; MHRA, 2009c].
• People should be directly questioned about whether they are having sexual problems because this adverse effect is often not volunteered because of embarrassment.
• Depression
• The MHRA has advised that depression may be a class effect of all statins [MHRA, 2009b].
• Consider whether a statin may be a contributing factor in someone presenting with depression.
• Atorvastatin and rosuvastatin had a higher incidence rate of depression compared with placebo in clinical trials. Although a direct causal link between other statins and depression could not be established, the MHRA identified one study that suggested that depression may be related to low levels of cholesterol, which suggests that causality cannot be ruled out [MHRA, 2009c].
• Other rare adverse effects of statins include:
• Peripheral neuropathy
• Peripheral neuropathy has rarely been reported.
• It is usually reversible on stopping treatment. NICE recommends that statins should be discontinued and specialist advice sought if a person develops an unexplained peripheral neuropathy [National Collaborating Centre for Primary Care, 2008a].
• Interstitial lung disease
• It is difficult to establish whether there is a causal relationship between statins and interstitial lung disease because this is a very rare adverse event [MHRA, 2009c].
• However, the MHRA has issued the following advice because interstitial lung disease is a potentially life-threatening adverse reaction: 'people on statins should be advised to seek medical advice if they develop presenting features of interstitial lung disease such as dyspnoea, non-productive cough, and deterioration in general health (e.g. fatigue, weight loss, and fever)' [MHRA, 2009b].
• Skin rashes and hair loss
• These may occasionally occur, necessitating stopping or switching treatment [Aronson, 2006a; BNF 55, 2008].

• The mechanism of action of fibrates is complex; they are thought to:
• Reduce plasma triglycerides by inhibiting their hepatic synthesis and increasing their catabolism.
• Increase high-density lipoprotein cholesterol by increasing apoA-I and apoA-II gene transcription.

[Aronson, 2006a]

• For primary and secondary prevention of cardiovascular disease, fibrates should only be used when a statin is not tolerated.
• Fibrates should only be considered as first-line therapy in people with isolated severe hypertriglyceridaemia.
• Combination therapy with a statin and a fibrate should be only initiated under specialist advice.

• These recommendations are based on guidance issued by the National Institute for Health and Clinical Excellence (NICE) [National Collaborating Centre for Primary Care, 2008a; NICE, 2008a] and jointly by the Medicines and Healthcare products Regulatory Agency (MHRA) and Commission on Human Medicines (CHM) [MHRA, 2007].
• In a Drug Safety Update, issued jointly by the MHRA and CHM, the review considered published and unpublished data and relevant clinical guidelines and concluded that [MHRA, 2007]:
• There is limited evidence to support the long-term clinical benefit of fibrate treatment in the primary or secondary prevention of cardiovascular disease (CVD). Given the robust evidence for statins in these indications, the use of fibrates as a first-line treatment is no longer justified.
• However, the effects of fibrates (mainly on triglycerides, and to a smaller extent on other lipid parameters) suggest that some subgroups of people may still benefit from a fibrate. In these subgroups, the overall benefit-risk balance of fibrates for specific indications remains positive.
• Combination therapy with a statin should only be used with caution due to a lack of robust evidence for their long-term clinical benefit, and the increased risk of myopathy and rhabdomyolysis. CKS recommends that combination therapy should only be initiated by specialists.
• The recommendation to use fibrates in people who can not tolerate a statin is supported by NICE. The Guidance Development Group did not find sufficient evidence to recommend the use of fibrates as a first-line treatment for primary or secondary prevention of CVD [National Collaborating Centre for Primary Care, 2008a; NICE, 2008a].

• Four fibrates are licensed in the UK: bezafibrate, ciprofibrate, fenofibrate, and gemfibrozil (see Table 1).
• Although all four fibrates may be considered, bezafibrate and fenofibrate are preferred.

• The licensed indications for fibrates available in the UK are shown in Table 1.

• The National Institute for Health and Clinical Excellence does not recommend any particular fibrate for use in the primary or secondary prevention of cardiovascular disease (CVD) for people who can not tolerate a statin [National Collaborating Centre for Primary Care, 2008a; NICE, 2008a].
• CKS could find no randomized controlled trials comparing different fibrates for primary and secondary prevention of CVD.
• CKS does not recommended a particular fibrate based on the very limited evidence for fibrates for primary and secondary prevention of CVD.
• However, of the four fibrates, bezafibrate and fenofibrate are preferred:
• There is a greater risk of drug interactions with gemfibrozil, and it is considerably more expensive than other fibrates.
• Dose titration is less flexible for ciprofibrate as it is only available in one dose (100 mg daily).

• Do not prescribe a fibrate in people who have, or have had:
• Severe hepatic impairment (including biliary cirrhosis).
• Severe renal impairment.
• Gallbladder disease.
• Known photoallergy or phototoxic reaction during treatment with a fibrate.
• Chronic or acute pancreatitis with the exception of acute pancreatitis due to severe hypertriglyceridemia.
• Pregnancy and lactation.

[ABPI Medicines Compendium, 2006b; ABPI Medicines Compendium, 2007b; ABPI Medicines Compendium, 2007d; ABPI Medicines Compendium, 2007e; ABPI Medicines Compendium, 2008b]

• Licensed dosages for fibrates licensed in the UK can be found in Table 1.
• Note: as fibrates are not licensed for the primary and secondary prevention of cardiovascular disease (with the exception of gemfibrozil for primary prevention in men), only licensed dosages are offered.

• The combination of a fibrate and a statin should be used with caution because of the increased risk of serious muscular adverse effects (myopathy and rhabdomyolysis) [MHRA, 2007]:
• Do not prescribe gemfibrozil with a statin, as the risk of muscular adverse effects is higher than with other fibrates.
• One meta-analysis found that the incidence of rhabdomyolysis increased 10-fold when statins (other than cerivastatin) were combined with gemfibrozil [Law and Rudnicka, 2006].
• Interaction between fibrates and oral anticoagulants [Baxter, 2008]:
• There have been reports of increased bleeding and increased prothrombin times in people taking a fibrate and an oral anticoagulant.
• Apart from clofibrate (which is no longer available in the UK), the clinical significance of this interaction for other fibrates is uncertain as information is generally limited to case reports.
• Overall, the evidence suggests that it would be prudent to monitor the international normalized ratio in people taking a fibrate and an oral coagulant.
• Interaction with ciclosporin:
• Severe cases of reversible renal impairment have been reported during concomitant administration of ciclosporin and certain fibrates (e.g. bezafibrate and fenofibrate). The manufacturer of these fibrates advises close monitoring of renal function when these drugs are used together and to stop the fibrate if there is severe alteration in laboratory values.
• For gemfibrozil:
• Gemfibrozil potently inhibits several cytochrome P450 enzymes (CYP2C8 [an enzyme important for the metabolism of, for example, repaglinide, rosiglitazone, and paclitaxel], CYP2C9 [an enzyme involved in the metabolism of, for example, warfarin and glimepiride], CYP2C19, CYP1A2) and other hepatic enzymes (UGTA1 and UGTA3):
• Do not prescribe gemfibrozil with repaglinide.
• The manufacturer of gemfibrozil advises caution when combining gemfibrozil with rosiglitazone, as increased rosiglitazone levels have been reported (2.3-fold increase).
• Because of the number of enzymes inhibited by gemfibrozil, the manufacturer warns that the interaction profile of gemfibrozil can be complex and can result in an increased plasma level of many medicinal products if administered concomitantly with gemfibrozil.
• With hypoglycaemic agents (oral drugs and insulin): hypoglycaemic reactions have been reported with gemfibrozil and these drugs. The manufacturer advises monitoring glucose levels.

[ABPI Medicines Compendium, 2006b; ABPI Medicines Compendium, 2007b; ABPI Medicines Compendium, 2007d; ABPI Medicines Compendium, 2007e; ABPI Medicines Compendium, 2008b]

• Gastrointestinal adverse effects (e.g. abdominal pain, nausea, vomiting, diarrhoea, and flatulence) are the most commonly reported adverse effects.
• Moderately elevated levels of serum transaminases have been reported with fibrate treatment:
• Discontinue the fibrate if serum transaminases are three or more times the upper limit of the normal.
• Serious muscular adverse effects (e.g. rhabdomyolysis and myopathy) are rare:
• Advise the person to seek medical advice and to stop the statin if they develop unexplained muscle symptoms (pain, tenderness, weakness).
• Check creatine kinase if myopathy or rhabdomyolysis is suspected.
• As with statins, discontinue treatment if the creatine kinase level is five times the upper limit of normal or greater.
• The risk of serious adverse effects is increased when combined with a statin. Do not combine gemfibrozil with a statin [MHRA, 2007].

[ABPI Medicines Compendium, 2006b; ABPI Medicines Compendium, 2007b; ABPI Medicines Compendium, 2007d; ABPI Medicines Compendium, 2007e; ABPI Medicines Compendium, 2008b]

• Bile acid sequestrants form non-absorbable complexes with bile acids in the gastrointestinal tract and increase their faecal excretion, thereby preventing their reabsorption and removing them from the enterohepatic circulation. Consequently, bile acid sequestrants diminish the ability of bile acids to solubilize dietary lipids and stimulate the liver to convert endogenous cholesterol into bile acids in an attempt to maintain bile acid pool size [Staels and Kuipers, 2007].
• Bile acid sequestrants can be combined with these drugs to provide complementary cholesterol reduction because they do not inhibit cholesterol synthesis like fibrates and statins.

• Colestyramine is the preferred bile acid sequestrant.
• Other licensed bile acid sequestrants (colesevelam and colestipol) (see Table 1) may be considered if the person is poorly compliant on colestyramine.

• The formulation and licensed indications and for bile acid sequestrants available in the UK are shown in Table 1.

• The National Institute for Health and Clinical Excellence does not recommend any particular bile acid sequestrant for use in the primary or secondary prevention of cardiovascular disease (CVD) for people who can not tolerate a statin [National Collaborating Centre for Primary Care, 2008a; NICE, 2008a].
• CKS could find no randomized controlled trials comparing the different bile acid sequestrants for primary and secondary prevention of CVD.
• Colestyramine is preferred over colesevelam and colestipol because:
• There is limited trial evidence supporting the use of colestyramine for primary (but not secondary) prevention of CVD (as reflected in its product licence — see Table 1).
• For colesevelam and colestipol, CKS could find no trials that reported health-related quality of life or clinical endpoints such as cardiovascular morbidity and mortality. Neither colesevelam nor colestipol are licensed for primary or secondary prevention of CVD.
• Colestyramine is available generically and is less expensive than the other two bile acid sequestrants.
• Colesevelam is currently under intensive post-marketing surveillance by the Commission on Human Medicines (black triangle drug).

• For colestyramine, the dosage should be titrated from 4 g daily to 24 g daily, if tolerated.
• For colesevelam and colestipol, use the licensed dosages outlined in Table 1.

• The licensed dosages (for adults) and advice regarding administration for bile acid sequestrants available in the UK are shown in Table 1.

• The target dosage of 24 g daily for colestyramine is extrapolated from clinical trials for primary and secondary prevention of cardiovascular disease (CVD). These dosages are consistent with licensed dosages (see Table 1).
• For colesevelam and colestipol, CKS could find no trials that reported health-related quality of life or clinical endpoints such as cardiovascular morbidity and mortality. Consequently, only licensed dosages are recommended.

• Contraindications:
• Manufacturers differ in their recommendations regarding who should not use bile acid sequestrants:
• Colesevelam should not be used in people with bowel or biliary obstruction.
• Colestyramine should not be used in people with complete biliary obstruction (since the drug is likely to be ineffective if bile is not secreted into the intestine).
• Colestipol: none specified.
• Given that all these drugs work similarly, and are not systematically absorbed, CKS recommends that bile acid sequestrants should not be used in people with bowel or biliary obstruction.
• Precautions:
• Although it has not been supported by studies, the manufacturers of bile acid sequestrants warn that these drugs may interfere with normal fat absorption and thus may alter the absorption of fat soluble vitamins (vitamins A, D, E, and K) if taken long term (particularly in people with malabsorption disorders).
• When prescribing colestyramine for people with diabetes, the sugar-free preparation is preferred:
• Each colestyramine sachet (Questran^®) contains 3.79 g sucrose. A sugar-free version is available (Questran Orange^®).

[ABPI Medicines Compendium, 2005a; ABPI Medicines Compendium, 2007a; ABPI Medicines Compendium, 2008a; ABPI Medicines Compendium, 2008d]

• Bile acid sequestrants could delay or reduce the absorption of certain drugs in the gastrointestinal tract (e.g. digoxin, verapamil, levothyroxine, tetracycline).
• To minimize possible interference with absorption, other medications should be taken at least 1 hour before, or 4–6 hours after, taking a bile acid sequestrant.
• These drugs may also interfere with normal fat absorption and thus may alter the absorption of fat soluble vitamins (vitamins A, D, E, and K) (for further information, see Cautions and contraindications).
• Bile acid sequestants and warfarin:
• If concurrent use with colestyramine is necessary, close monitoring of the international normalized ratio (INR) should be considered because:
• Colestyramine can reduce the anticoagulant effects of warfarin by interfering with warfarin absorption (directly and via the enterohepatic circulation pathway). This interaction is established, but the magnitude and clinical importance is uncertain. Giving colestyramine 3 to 6 hours after warfarin has been shown to minimize the effects of this interaction [Baxter, 2006].
• Colestyramine may have some direct hypoprothrombinaemic effects by reducing the absorption of vitamin K [Baxter, 2006].
• Isolated and unexplained reports of paradoxical increases in the effects of warfarin have also been documented [Baxter, 2006].
• Colesevelam and colestipol: although these drugs have not been shown to have an effect on the bioavailability of warfarin, the manufacturers advise that anticoagulant therapy should be monitored closely. Specific clinical interaction studies with colesevelam and vitamin K have not been performed.

[ABPI Medicines Compendium, 2005a; ABPI Medicines Compendium, 2007a; ABPI Medicines Compendium, 2008a; ABPI Medicines Compendium, 2008d]

• Adverse effects are predominantly gastrointestinal (GI) in nature.
• Constipation is the most common adverse effect and is usually mild, transient, and responsive to usual adjunctive measures. Severe constipation (accompanied by impaction) has been reported.
• Other, less frequent, GI complaints are abdominal discomfort, belching, flatulence, indigestion, nausea, and vomiting. Diarrhoea can also occur, especially when large doses of colestyramine are used.
• Bile acid sequestrants may elevate serum triglyceride levels when used as sole therapy.
• This elevation is generally transient but may persist in some people.
• The manufacturer of colestipol recommends that a significant increase in triglycerides should be considered as an indication for dose reduction, drug discontinuation, or combined or alternate therapy.
• Bile acid sequestrants may interfere with normal fat absorption and thus may alter the absorption of fat soluble vitamins (vitamins A, D, E, and K). Case reports of increased prothrombin time (hypoprothrombinaemia associated with vitamin K deficiency) have been reported.
• Transient and modest elevation in serum transaminase levels have been reported with colesevelam and colestipol.

[ABPI Medicines Compendium, 2005a; ABPI Medicines Compendium, 2007a; ABPI Medicines Compendium, 2008a; ABPI Medicines Compendium, 2008d]

• Nicotinic acid is a water-soluble B-complex vitamin, which is a naturally occurring constituent of foods.
• The mechanism of action by which nicotinic acid modifies the lipid profile has not been fully elucidated.

[ABPI Medicines Compendium, 2006a]

• Two nicotinic acid preparations are licensed in the UK: Niaspan^® tablets (containing modified-release nicotinic acid) and Olbetam^® capsules (containing acipimox — a derivative of nicotinic acid).
• Of these, modified-release nicotinic acid tablets are preferred.

• The National Institute for Health and Clinical Excellence (NICE) does not recommend any particular nicotinic acid preparation for use in the primary or secondary prevention of cardiovascular disease (CVD) for people who can not tolerate a statin [National Collaborating Centre for Primary Care, 2008a; NICE, 2008a].
• The NICE recommendation is based on trial evidence using immediate-release nicotinic acid preparations.
• Currently, Two nicotinic acid preparations are licensed in the UK: Niaspan^® tablets (containing modified-release nicotinic acid) and Olbetam^® capsules (containing acipimox — a derivative of nicotinic acid).
• CKS could find no trials for either product that reported health-related quality of life or clinical endpoints such as cardiovascular morbidity and mortality. Neither preparation is licensed for primary or secondary prevention of CVD.
• Of the two, nicotinic acid modified-release tablets are preferred because:
• There is indirect evidence using the immediate-release nicotinic acid preparation (see above).
• Niaspan^® is less expensive than acipimox.
• Although it has been suggested that acipimox may be associated with fewer adverse effects than nicotinic acid [BNF 55, 2008], CKS found no strong evidence to support this.
• CKS only identified one very small trial (n = 32) which found 22 people completed 6 months of treatment with acipimox without adverse effects (after 10 participants withdrew from the study) [Aronson, 2006b].

• CKS could find no trials for nicotinic acid modified-release tablets that reported health-related quality of life or clinical endpoints such as cardiovascular morbidity and mortality. Consequently, only licensed dosages are recommended.
• Nicotinic acid is only available as modified-release tablets (Niaspan^®) in the following strengths: 375 mg, 500 mg, 750 mg, and 1000 mg.
• A starter pack (containing seven 375 mg tablets, seven 500 mg tablets and seven 750 mg tablets) is also available.
• The manufacturer advises that the different tablet strengths have different bioavailability and are not interchangeable.
• Dose titration:
• Start with 375 mg daily for 1 week.
• Niaspan^® should be taken at bedtime, after a low fat snack (e.g. an apple, low fat yoghurt, slice of bread).
• Titrate the dose to 500 mg daily in the second week, 750 mg in third week, and then 1000 mg (two 500 mg tablets) in the fourth week.
• The recommended maintenance dose is 1000 mg (two 500 mg tablets) to 2000 mg (two 1000 mg tablets) daily, depending on response and tolerance.
• The daily dosage should not be increased by more than 500 mg in any 4-week period after the initial titration to 1000 mg. The maximum dose is 2000 mg per day.
• If therapy is discontinued for an extended period or transferred from a different nicotinic acid product, the manufacturer advises that re-institution of therapy must include a dose escalation.
• No dose adjustment is necessary for the elderly.

[ABPI Medicines Compendium, 2006a]

• Avoid prescribing nicotinic acid in people with:
• Significant hepatic dysfunction.
• Active peptic ulcer disease.
• Arterial bleeding.
• Precautions:
• Nicotinic acid should be prescribed with caution in people who consume substantial quantities of alcohol or who have a history of liver disease.
• Treatment has been associated with abnormal liver function tests:
• Elevated liver transaminases have been observed with nicotinic acid modified-release tablets (Niaspan^®). Transaminase elevations were reversible upon discontinuation of therapy.
• Stop treatment if there is evidence of a progressive increase in transaminase levels, particularly if they rise to three times the upper limit of normal.
• The manufacturer of Niaspan^® advises caution when prescribing nicotinic acid to:
• People with diabetes or at high risk of diabetes, as there may be a dose-related increase in glucose intolerance. Adjustment of diet, oral antihyperglycaemics, and insulin therapy may be necessary.
• People with unstable angina or in the acute phase of myocardial infarction, particularly when they are also receiving vasoactive drugs such as nitrates, calcium-channel blockers, or adrenergic blocking agents.
• People undergoing surgery, as nicotinic acid may affect platelet count and prothrombin time.
• People on anticoagulants (closer monitoring of prothrombin time and platelet count are recommended).
• People predisposed to gout, as elevated uric acid levels have been reported with nicotinic acid therapy.

[ABPI Medicines Compendium, 2006a]

• There are case reports that nicotinic acid may increase the risk of muscle toxicity (e.g. rhabdomyolysis) in people taking a statin [Baxter, 2008].
• People on this combination should be warned to seek urgent medical advice if they experience any unexplained muscular adverse effects.
• The manufacturer of Niaspan^® advises that concomitant alcohol or hot drinks may increase undesirable flushing and pruritus and should be avoided around the time of Niaspan^® ingestion.
• The manufacturer warns that Niaspan^® has been associated with small dose-related reductions in platelet count (mean of –11% with 2000 mg) and small increases in prothrombin time (mean of approximately +4%).
• The clinical significance of this is uncertain.
• For people on anticoagulants (e.g. warfarin), the manufacturer of Niaspan^® advises that prothrombin time and platelet counts should be monitored closely.

[ABPI Medicines Compendium, 2006a]

• Flushing reactions (warmth, redness, itching, tingling) are the most common adverse effects with nicotinic acid (incidence of more than 1 in 10).
• They generally occur during early treatment and the dose titration phase, and are thought to be mediated by the release of prostaglandin D₂ (nicotinic acid is a potent vasodilator). Tolerance to flushing usually develops over the course of several weeks.
• The manufacturer advises that concomitant alcohol or hot drinks may increase undesirable flushing and pruritus, and should be avoided around the time of Niaspan^® ingestion.
• Other common adverse effects are (incidence between 1 in 10 and 1 in 100):
• Diarrhoea, nausea, vomiting, abdominal pain, dyspepsia.
• Pruritus, rash.
• There have been case reports of hepatotoxicity (apparently a dose-related direct toxic effect), hyperglycaemia, and hyperuricaemia [Aronson, 2006b].
• Muscular adverse effects (e.g. myopathy, myalgia) are very rare (incidence between 1 in 1000 and 1 in 10,000).
• Advise the person to seek urgent medical advice if they develop unexplained muscular symptoms after starting nicotinic acid therapy.

[ABPI Medicines Compendium, 2006a]