\
`
`I \
`
`I
`
`3312
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`Circulation December 17/24, 2002
`
`TableVI.2-2. Summary of BileAcid Sequestrants
`,.
`Cholestyramine,colestipol,colesevelam
`Available drugs
`_ ...
`................
`. .l. 15-30%
`LDLcholesterol
`lipid/lipoprotein effects
`-t 3-5%
`HDLcholesterol
`Triglycerides
`- no effect or increase
`Tolower LDLcholesterol
`
`Major use
`...-
`..... _., .-
`Contraindications
`n Absolute
`
`['l Relative
`Efficacy
`Safety
`
`Major side/adverse effects
`
`Usual daily dose
`
`Maximum daily dose
`
`Availablepreparations
`
`Familialdysbetalipoproteinemia
`Triglycerides>400 mg/dL
`
`Triglycerides>200 mg/dL
`Clinicaltrialevidenceof CHDriskreduction
`Clinicaltrialevidenceof lackof systemictoxicity;
`GI sideeffectscommon
`Upperand lowergastrointestinalcomplaintscommon
`Decreaseabsorption of other drugs
`- 4-16g
`Cholestyramine
`- 5-20g
`Colestipol
`- 2.6-38g
`Colesevelam
`- 24g
`Cholestyramine
`Colestipol
`- 30g
`- 4.4g
`Colesevelam
`- 9g packets (4g drug)
`Cholestyramine
`- 378g bulk
`- 5g packets (4g drug)
`- 21Ogbulk
`- 5g packets (5g drug)
`- 450g bulk
`- 19 tablets
`- 625 mg tablets
`
`Cholestyramine
`"light"
`Colestipol
`
`Colesevelam
`
`to a statin can further
`moderate dose of a sequestrant
`lower LDL cholesterol by 12-16 percent.839-841Thus,
`sequestrants are useful in combined drug therapy with
`statins. Further, sequestrants combined with plant stanol
`esters apparently enhance LDL lowering.842,843 Thus,
`sequestranrs
`in combination with TLC, including other
`dietary options for lowering LDL cholesterol
`(plant
`stanols/sterols and viscous fiber), should enable many
`persons to achieve their LDL-cholesterol goal without
`the need for an agent that
`is systemically absorbed.
`
`tend to raise serum trigl ycerides,
`Since sequestrants
`they are contraindicated
`as monotherapy
`in persons
`with high triglycerides
`(>400 mgldL) and in familial
`dysbetalipoproteinemia.844
`They generally should be
`used as monotherapy
`only in persons with triglyceride
`
`are not
`levels of <200 mgldL. Bile acid sequestrants
`contradicted in patients with type 2 diabetes.845
`
`therapy can produce a variety of gastroin-
`Sequestrant
`testinal symptoms,
`including constipation,
`abdominal
`pain, bloating,
`fullness, nausea, and flarulence.i-
`These symptoms often can be lessened by moderate
`doses of standard sequestrants or use of colesevelam.
`Sequestrants
`are not absorbed from the intestine,
`but
`can decrease the absorption of a number of drugs
`that
`are administered concomitantly. The general
`recom-
`mendation is that other drugs should be taken either
`au hour before or 4 hours after administration
`of the
`sequestrant. Colesevelam, which apparently
`does not
`decrease absorption of co-administered
`drugs, need
`not be administered separately from other drugs.
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`produce
`Bile acid sequestrants
`statements:
`Evidence
`(AI).
`in LDL cholesterol
`reductions
`moderate
`reduces
`risk for CHD (AI).
`':'erapy
`Sequestram
`in LDL-cholesterollowering
`They are adc.uve
`combination
`··..ith other
`cholesterol-lowering
`(C'l ). They h>k systemic
`toxicity
`(AI).
`
`in
`drugs
`
`should
`Bile acid sequestrants
`Recommend.·:~;on:
`for persons
`be considererl
`as LDL-lowering
`therapy
`with moderato:
`elevations
`in LDL cholesterol,
`for
`younger
`persons with elevated LD L cholesterol,
`for women with elevated LDL cholesterol
`who are
`considering
`pregnancy,
`for persons
`needing
`only
`modest
`reductions
`in LDL cholesterol
`to achieve
`target
`goals,
`and for combination
`therapy with
`sratins
`in persons with very high LDL-cholesterol
`levels.
`
`VI. Drug Therapy
`
`3313
`
`3) Nicotinic acid
`
`in Table VI.2-3. Nicotinic
`This drug is summarized
`affects
`all
`lipids
`and lipopro-
`acid or niacin favorably
`teins when given in pharmacological
`doses.
`Nicotinamide,
`which
`is sometimes
`confused with niacin
`or nicotinic
`acid, has only vitamin
`functions
`and does
`not affect
`lipid and lipoprotein
`levels. Nicotinic
`acid
`lowers
`serum total
`and LD L-cholesterol
`and triglyc-
`eride levels and also raises HDL-cholesterollevels.
`Smaller
`doses often increase HDL-cholesterollevels,
`but doses of 2-3 g/day are generally
`required
`to pro-
`of IS percent
`duce LDL-cholesterol
`reductions
`or
`greater.87,147,846-849
`Nicotinic
`acid can also lower Lp(a)
`up to 30 percent with high doses.283 Whether
`Lp(a)
`lowering
`by nicotinic
`acid therapy
`reduces
`risk for
`CHD is not known. Nicotinic
`acid was
`shown
`to
`in
`reduce
`the risk of recurrent myocardial
`infarction
`Drug Projecr.t-! and total mortality was
`the Coronary
`decreased
`in a IS-year
`followup
`of the persons who
`had originally
`received
`nicotinic
`acid.444 Decreased
`
`Crystalline nicotinic acid
`Sustained-release (or timed-release) nicotinic acid
`Extended-release nicotinic acid (Niaspan®)
`-.]. 5-25%
`LDLcholesterol
`- T 15-35%
`HDLcholesterol
`-.]. 20-50%
`Triglycerides
`Useful in most lipid and lipoprotein abnormalities
`
`=
`
`Chronic liver disease, severe gout
`Hyperuricemia; high doses in type 2 diabetes
`Clinicaltrial evidence of CHD risk reduction
`Serious long-term side effects rare for crystalline form; serious hepatotoxicy may be more
`common with sustained-release form
`Flushing, hyperglycemia. hyperuricemia or gout. upper gastrointestinal distress,
`hepatotoxicity, especially for sustained-release form
`Crystalline nicotinic acid
`- 1.5-3g
`Sustained-release nicotinic acid
`- 1-29
`Extended-release nicotinic acid (Niaspane) - 1-2g
`Crystalline nicotinic acid
`- 4.5g
`Sustained-release nicotinic acid
`- 2g
`Extended-release nicotinic acid (Niasparrs) - 2g
`
`Many OTe preparations by various manufacturers for both crystalline and sustained-release
`nicotinic acid, The extended-release preparation (Niasparrs) is a prescription drug,
`
`Table VI.2-3. Summary of Nicotinic Acid
`r:=::=::c'
`-'
`-"·'i__
`:~:
`- >
`Available drugs
`
`:
`
`j
`
`lipid/lipoprotein
`
`effects
`
`Major use
`Contra indications
`[J Absolute
`D Relative
`Efficacy
`Safety
`
`Malor side/adverse
`
`effects
`
`Usual daily dose
`
`Maximum daily dose
`
`Available preparations
`
`I
`
`II
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`I
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`I
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`1 I
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`3314
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`Circulation December 17/24, 2002
`
`)
`
`progression were also observed
`rates of atherosclerotic
`in tbree quantitative
`angiographic
`trials: FATS,!58
`HATS,159and CLAS1S7.In all of these trials, nicotinic
`acid was combined with other LDL-lowering drugs
`and effects were compared to placebo.
`
`of nicotinic acid are
`Many crystalline preparations
`and are inexpensive.
`available without
`a prescription
`Some preparations
`and a new formulation, Niaspans',
`are available by prescription. Niaspanv is a proprietary
`extended-release
`formulation
`of nicotinic acid; its use is
`associated with less flushing than occurs with usual
`crystalline preparations.
`
`Nicotinic acid appears to alter lipid levels by inhibiting
`lipoprotein synthesis and decreasing the production of
`VLDL particles by the liver. It inhibits the peripheral
`mobilization of free fatty acids, reducing hepatic seere-
`tion of VLDL.850,851It decreases the plasma concentra-
`tion of triglyceride, VLDL remnants, and IDL;88,138and
`it causes a shift in LDL composition from the small,
`denser LDL particles to the larger, more buoyant LDL
`particles.852 Nicotinic acid also is the most effective
`lipid-lowering drug for raising HDL levels.s? The
`changes in HDL cholesterol and triglyceride concentra-
`tions tend to be curvilinear
`(log-linear);
`thus, smaller
`doses of nicotinic acid still produce significant
`increases
`in HDL or reductions in triglyceride with fewer side
`effects. The increases in HDL cholesterol are generally
`in the range of 15-30 percent.s? but increases of
`40 percent have been noted with very high
`doses.B46,84',853,854The sustained-release preparations
`usually increase HDL cholesterol
`levels by only 10-15
`percentS53,854with the exception of Niaspan's which
`retains the HDL-raising potential of the crystalline
`form. Nicotinic acid typically reduces triglyceride levels
`by 20 to 35 percent, but reductions of 50 percent have
`been noted with high doses in hypertriglyceridemic
`per-
`sons.87,!47,846-849Among lipid-lowering agents, nicotinic
`acid appears
`to be the most effective for favorably
`modifying all of the lipoprotein abnormalities
`associat-
`ed with atherogenic dyslipidemia.
`
`by nicotinic
`The degree of LDL-cholesterollowering
`acid has varied in different studies. Some studies
`in
`report
`little or no change in LD L levels.s? However,
`one carefully controlled study in patients with hyper-
`cholesterolemia,855 reductions
`in LDL cholesterol of
`5 percent, 16 percent, and 23 percent were noted with
`daily doses of 1.5, 3.0 and 4.5 grams,
`respectively.
`
`nicotinic acid (Niaspan'"], which is
`Extended-release
`administered as a single bedtime dose, has been
`shown to reduce LDL cholesterol by 15 percent at
`2 g/day.147,847,853,856Because many persons cannot
`tolerate higher doses, nicotinic acid is typically not
`used primarily to lower LDL levels. Instead,
`it is gener-
`ally used in combination with other drngs, especially
`the statins.s-?
`
`Nicotinic acid therapy can be accompanied by a num-
`ber of side effects. Flushing of the skin is common with
`the crystalline form and is intolerable for some per-
`sons. However, most persons develop tolerance to the
`flushing after more prolonged use of the drng. Less
`severe flushing generally occurs when the drug is taken
`during or after meals, or if aspirin is administered prior
`to drng ingestion. A newer preparation, Niaspant',
`is
`reporred to cause less flushing than crystalline nicotinic
`acid. A variety of gastrointestinal
`symptoms,
`including
`nausea, dyspepsia,
`flatulence, vomiting, diarrhea, and
`activation of peptic ulcer may occur. Three other major
`adverse effects include hepatotoxicity,
`hyperuricemia
`and gout, and hyperglycemia. The risk of all three
`is increased with higher doses, especially at doses of
`2g or higher. The risk of hepatotoxicity
`appears
`to be greater with the sustained-release
`preparations,
`although not with Niaspan'".
`Impending hepatotoxicity
`should be considered if there is a dramatic reduction
`in plasma lipids.858 Nicotinic acid reduces insulin
`sensitivity, and higher doses (>3 g/day) often worsen
`hyperglycemia
`in persons with type 2 diabetcs.s'?
`Recent studies suggest
`that
`lower doses do not unduly
`worsen hyperglycemia.S60,861 Other adverse effects
`include conjunctivitis, nasal stuffiness, acanthosis nigri-
`cans,
`ichthyosis, and retinal edema (toxic amblyopia).
`
`in two or three
`Nicotinic acid is usually administered
`doses a day, with the exception of Niaspanw, which is
`administered as a single dose at bedtime. Crystalline
`nicotinic acid is the least expensive drug, and small
`doses are especially useful for increasing HDL-choles-
`terollevels or lowering triglycerides. The timed-release
`(sustained-release)
`preparations
`are designed to mini-
`mize cutaneous
`flushing. When switching from crys-
`talline nicotinic acid to a sustained-release
`preparation,
`smaller doses should be used to reduce the risk of
`hepatotoxicity. The d.ose can then be carefully titrated
`upward, generally to a level not exceeding 2 g/day.
`Rare cases of fulminant hepatitis have been reponed
`with sustained-release
`preparations.862-864 Considerable
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`VI. Drug Therapy
`
`3315
`
`variation exists among different sustained-release
`preparations,
`and persons should be advised not to
`switch from one preparation to another. Niaspanw is an
`extended-release preparation; however, its more rapid-
`release than sus.ained-release preparation appears to
`reduce the risk of hepatotoxicity. Niasparrs also is
`associated with less flushing than with crystalline nico-
`tinic acid. Since many nicotinic acid preparations are
`available without a prescription, persons should be
`instructed that nicotinic acid is associated with many
`severe adverse cffects and regular monitoring by a
`health professional
`is essential.
`
`Although nicotinic acid can be highly efficacious and
`favorably modify the lipoprotein profile, especially in
`patients with atherogenic dyslipidemia,
`its long-term
`use is limited for many patients by side effects.865For
`this reason,
`the drug is generally reserved for patients
`at higher short-term risk, i.e., for those with CHD,
`CHD risk equivalents, or multiple (2+) risk factors
`with 10-year risk for CHD of 10-20 percent. Its use
`for long-term prevention of CHD in persons with
`lO-year risk dO percent is not well established, and
`in such persons, should be used more cautiously.
`For example,
`it is not known whether long-term use
`of nicotinic acid for lower-risk persons with isolated
`low HDL cholesterol
`is beneficial.
`
`Evidence statements: Nicotinic acid effectively
`modifies atherogenic dyslipidemia by reducing
`TGRLP, raising HDL cholesterol, and transforming
`small LDL into normal-sized LDL (Cl). Among
`lipid-lowering agents, nicotinic acid is the most
`effective HDL-raising drug (Cl). Nicorinic acid
`usually causes a moderate reduction in LDL-
`cholesterol
`levels (Cl), and it is the most effective
`drug for reducing Lp(a) levels (Cl).
`
`Evidence statements: Nicotinic acid 'therapy is
`commonly accompanied by a variety of side effects,
`including flushing and itching of the skin, gastroin-
`testinal distress, glucose intolerance, hepatotoxicity,
`hyperuricemia, and other rarer side effects (Cl).
`Hepatotoxicity is more common with sustained-
`release preparations
`(Dl).
`
`Evidence statement: Nicotinic acid therapy pro-
`duces a moderate reduction in CHD risk, either
`when used alone or in combination with other
`lipid-lowering drugs (A2, B2).
`
`Recommendation: Nicotinic acid should be
`considered as a therapeutic option for higher-risk
`persons with atherogenic dyslipidemia. It should
`be considered as a single agent in higher-risk
`persons with atherogenic dyslipidemia who do
`not have a substantial
`increase in LDL-cholesterol
`levels, and in combination therapy with other
`cholesterol-lowering drugs in higher-risk persons
`with atherogenic dyslipidemia combined with
`elevated LDL-choJesterollevels.
`
`Recommendation: Nicotinic acid should be used
`with caution in persons with active liver disease,
`recent peptic ulcer, hyperuricemia and gout, and
`type 2 diabetes. High doses of nicotinic acid
`(>3 g/day) generally should be avoided in persons
`with type 2 diabetes, although lower doses may
`effectively treat diabetic dyslipidemia without
`significantly worsening hyperglycemia.
`
`4) Fibric acid derivatives
`[enofibrate, clofibrate
`
`(fibrates); gemfibrozil,
`
`These drugs are summarized in Table VI.2-4. There
`are three fibrates-gemfibrozil,
`fenofibrate, and
`clofibrate-eurrently
`available in the United States.
`Other fibrate preparations,
`including bezafibrate and
`ciprofibrate, are available outside the United States.
`The fibrates are primarily used for lowering triglyc-
`erides because the LDL-cholesterol-lowering
`effects of
`gemfibrozil and clofibrate are generally in the range of
`10 percent or less in persons with primary hypercholes-
`terolemia. Only slight changes in LDL cholesterol are
`noted in persons with combined hyperlipidemia, and
`LDL-cholesterollevels
`generally rise on fibrate therapy
`in persons with hypertriglyceridemia.866,867Fenofibrate
`frequently reduces LDL-cholesterollevels
`by 15 to 20
`percent when triglycerides are not elevated; other
`fibrates not available in the United States are also more
`effective in lowering LDL cholesterol.868-87oTherapy
`with clofibrate and gemfibrozil reduced risk of fatal
`and non-fatal myocardial
`infarction in two large pri-
`mary prevention trials,139,149and gemfibrozil
`therapy
`reduced CHD death and non-fatal myocardial
`infarc-
`tion and stroke in a recently reported secondary
`this beneficial effect on
`prevention trial. 48 However,
`cardiovascular outcomes has not been observed in all
`large fibrate trials.14!,!53
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`ra rc
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`III
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`3316
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`Circulation December 17/24, 2002
`
`Table VI.2-4. Summary of Fibrie-Acid Derivatives
`=
`Gemfibrozil,fenofibrate,clofibrate
`Available drugs
`LDLcholesterol
`- L 5-20%
`Lipid/lipoprotein effects
`(in nonhypertriglyceridemicpersons);may be increasedin hypertriglyceridemicpersons
`- T 10-35%
`HDLcholesterol
`(more in severehypertriglyceridemia)
`-.l- 20-50%
`Triglycerides
`Hypertriglyceridemia,atherogenicdyslipidemia
`
`Major uses
`
`insufficiency
`Severe hepatic or renal
`trials indicate a moderate reduction in CHD risk
`Clinical
`Serioussideeffectsseeminglydo not occur in the long term, although earlystudies
`suggested an increasein non-CHDmortality
`Dyspepsia,variousupper gastrointestinalcomplaints,cholesterolgallstones,myopathy
`- 600 mg bid
`Gemfibrozil
`- 200 mg daily
`Fenofibrate
`- 1000 mg bid
`Clofibrate
`- 1200 mg
`Gemfibrozil
`- 200 mg
`Fenofibrate
`- 2000 mg
`Clofibrate
`Gemfibrozil
`- 600 mg tablets
`Fenofibrate
`- 67 and 200 mg tablets
`- 500 mg capsules
`Clofibrate
`
`Contraindications
`Effieacy
`Safety
`
`Major side/adverse effects
`Usual daily dose
`
`Maximum daily dose
`
`Available preparations
`
`)I
`
`the short-term
`There has been some concern about
`safety of the fibrates. Although nonfatal myocardial
`infarction fell by 25 percent
`in the WHO Clofibrate
`Study, a primary prevention study,
`total mortality was
`significantly higher in the clofibrate group, due to an
`increase in non-CHD deaths.t''? The use of clofibrate in
`general medical practice decreased markedly after this
`study. The Helsinki Heart Study, a primary prevention
`trial employing gemfibrozil, demonstrated
`a 37 percent
`reduction in fatal and non-fatal myocardial
`infarctions
`and no change in total mortality during the course of
`the study.U" After 8.5-10 years of followup, non-car-
`diac death and all cause mortality were numerically
`higher in the group that had received gemfibrozil dur-
`ing the study.4!2 However,
`this increase was 110t statisti-
`cally significant. Moreover, after 10 years of followup,
`no difference in cancer rates was observed between
`those who had received gemfibrozil or placebo.
`In the
`Veterans Administration HDL Intervention Trial (VA-
`HIT),48 a secondary prevention trial, gemfibrozil
`thera-
`py reduced risk for CHD death and nonfatal myocar-
`dial infarction
`by 22 percent;
`stroke rates also were
`
`there
`In this study,
`therapy.
`reduced by gemfibrozil
`was no suggestion of an increased risk of non-CHD
`mortality. Neither was there an increase in non-CHD
`mortality from fibrate therapy in the recently reported
`Bezafibrate Infarction Prevention (BIP) study.!S3
`Furthermore, worldwide
`clinical experience with
`various fibrates is vast. No evidence of specific toxicity
`that enhances non-CHD mortality has emerged. This
`experience,
`taken in the light of all the clinical
`trials,
`provides little support
`for the concern that fibrates
`carry significant short-term toxicity that precludes
`their use for appropriately
`selected persons.
`
`is complex and
`The mechanism of action of the fibrates
`there may be some variation among the drugs in this
`class. Recent research shows fibrates to be agonists
`for
`the nuclear
`transcription
`factor peroxisome
`prolifera-
`tor-activated receptor-alpha (PPAR-alpha}.871 Through
`this mechanism,
`fibrates downregulate
`the apolipopro-
`tein C-llI gene and upregulate genes for apolipoprotein
`A-I, fatty acid transport protein,
`fatty acid oxidation,
`and possibly lipoprotein lipase.i72 Its effects on
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`VI. DrugTherapy
`
`3317
`
`lipase and apolipoprotein C-III (an
`lipoprotein
`of lipoprotein lipase) enhance the catabolism
`inhibitor
`of TGRLP, whereas increased fatty acid oxidation
`rednces formation of VLDL triglycerides. These effects
`account
`for serum triglyceride lowering, which is the
`major action of [ibrates. Serum triglyceride lowering
`combined with increased synthesis of apolipoprotein
`A-I and A-II tend to raise HDL-cholesterollevels.873
`Triglyceride
`lowering also transforms
`small, dense
`LDL into normal-sized LDL.874The effect of PPAR
`activity on other atherogenic mechanisms
`is now
`being evaluated,875,876
`
`typically reduce triglyceride by 25-50
`The fibrates
`percent;
`the greater
`reductions generally occur in
`severely hypertriglyceridemic
`individuals.w? Fibrates
`usually raise HD L cholesterol by 10-15 percent, but
`greater
`increases can occur in persons with very high
`triglyceride levels and very low HDL-cholesterol
`levels.
`Thus fibrates,
`like nicotinic acid, primarily target
`atherogenic dyslipidemia,
`In addition,
`the ability of
`fibrates to lower triglycerides has led to their wide
`usage in persons having very high triglyceride levels
`and chylomicrouemia.se? The purpose of fibrate
`therapy in such persons is to reduce the risk for acute
`pancreatitis. Their value for this purpose is well
`recognized. Finally, fibrates are highly effective for
`reducing beta- VLDL concentrations
`in persons with
`dysbetali poproteinemia. 877
`
`of atherogenic dyslipi-
`fibrate modification
`Whether
`demia reduces risk for CHD is an important
`issue.
`Results of clinical
`trials with fibrates are summarized
`in Tables 11.3-3 and 11.3-4. The major primary preven-
`tion trials were the WHO clofibrate trial and the
`Helsinki Heart Study gemfibrozil
`trial.'39,149 In both
`trials, CHD incidence was significantly reduced by
`fibrare therapy. Early secondary prevention trials with
`clofibrate therapy gave suggestive evidence of CHD
`risk reduction.
`In another
`secondary prevention trial,
`the Coronary Drug Project, clofibrate
`therapy failed to
`significantly reduce risk for CHD.14! Likewise,
`in the
`BIP trial, bezafibrate therapy did not significantly
`reduce recurrent major coronary events in persons with
`established CHD,153 In contrast, gemfibrozil
`therapy in
`the VA-HIT48 trial showed wide benefit by significantly
`reducing CHD events and strokes in persons with
`
`established CHD (Table II.3-4 and Table II.8-3b).
`Thus,
`taken as a whole, clinical
`trials of fibrate
`therapy strongly suggest a reduction in CHD incidence,
`although results are less robust
`than with statin
`therapy. Further, a reduction
`in total mortality, which
`would have required a greater
`reduction in CHD mor-
`tality than observed, has not been demonstrated with
`fibrate therapy (see Table 11.9-1). This failure does not
`rule out a benefit of fibrate therapy but certainly sug-
`gests less efficacy than with statin therapy.
`
`Several studies have employed fibrates in combination
`with LDL-Iowering drugs in persons with combined
`(elevated LDL + atherogenic
`hyperlipidemia
`dyslipi-
`demia). Combination
`therapy improves the overall
`lipoprotein profile compared
`to either Iibrates or LDL-
`lowering drugs alone. This finding has led to a move-
`ment for considering use of fibrates in combination
`with statins in high-risk individuals whose triglyceride
`levels are still elevated.
`In some persons,
`this combina-
`tion may better achieve the secondary target
`for non-
`HDL cholesterol
`than will statins alone. Nonetheless,
`to date no clinical
`trials have been published that com-
`pare statins vs. statins + fibrates on CHD outcomes.
`
`in most per-
`The fibrates are generally well-tolerated
`sons. Gastrointestinal
`complaints
`are the most common
`complaints. All drugs in this class appear
`to increase
`the lithogenicity of bile, increasing the likelihood of
`cholesterol gallstones.878 A portion of the excess deaths
`reported in the WHO Clofibrate Study was related to
`gallstone disease.s?? The fibrates bind strongly to serum
`albumin and so may displace other drugs that bind
`with albumin. For example,
`fibrates displace warfarin
`from its albumin-binding
`sites, thereby increasing the
`latter's anticoagulant
`effect. Fibrates are excreted
`primarily by the kidney; consequently,
`elevated serum
`levels occur in persons with renal failure and risk for
`myopathy is greatly increased. The combination
`of
`a fibrate with a statin also increases the risk for
`myopathy, which can lead to rhabdomyolysis.823,88o
`None of these well-established
`side effects can account
`for the increased total mortality observed in the WHO
`clofibrate study.'8!,882 The increase in non-CHD
`deaths remains unexplained. An increase in non-CHD
`mortality has not been confirmed by subsequent
`trials
`with fibrate therapy.
`
`(
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`

`II
`
`F
`
`I
`is no longer available in the United States and I t
`
`c. Other drugs
`
`Probucol
`in most other countries. This drug has powerful
`antioxidant
`properties, which is theoretically beneficial.
`In one angiographic
`trial, probucol
`therapy failed to
`retard femoral atherogenesis; neither was a reduction
`in CHD risk observed. There is some current
`interest
`in reports that probucol
`reduced the restenosis rates
`following angioplasty.883,884
`
`d. n-3 (omega) fatty acids
`
`n-3 fatty acids (linolenic acid, DHA, and EPA) have
`two potential uses. In higher doses, DHA and EPA
`lower serum triglycerides by reducing hepatic secretion
`of triglyceride-rich
`lipoproteins. They represent alterna-
`tives to fibrates or nicotinic acid for treatment of
`hypertriglyceridemia,
`particularly chylornicronemia.
`They are available in capsules of fish oil, and doses of
`3-12 g/day have been used depending on tolerance and
`severity of hypertriglyceridemia.
`
`that relatively high
`trials also suggest
`Recent clinical
`intakes of n-3 fatty acids (1-2 g/day) in the form of
`fish, fish oils, or high-linolenic
`acid oils will reduce risk
`for major coronary events in persons with established
`CHD (see Section V.3.c). Although this usage falls out-
`side the realm of "cholesterol management,"
`the ATP
`III panel recognizes that n-3 fatty acids can be a thera-
`peutic option in secondary prevention. The n-3 fatty
`acids are recommended
`only as an option because the
`strength of the clinical
`trial evidence is moderate
`at
`present. The n-3 fatty acids can be derived from either
`foods (n-3 rich vegetable oils or fatty fish) or from fish-
`oil supplements.
`In the view of the ATP III panel, more
`definitive clinical
`trials are required before relatively
`high intakes of n-3 fatty acids (1-2 g/day) can be
`strongly recommended for either primary or secondary
`prevention.
`
`e. Hormone replacement
`
`therapy (HRT)
`
`Risk for CHD is increased in postmenopausal women
`whether
`the menopause
`is natural,
`surgical, or prerna-
`ture.885-887Loss of estrogen has been proposed as a
`cause for increased risk. This putative mechanism was
`strengthened by results of numerous case-control
`and
`epidemiological
`studies which suggested that either
`
`3318
`
`Circulation
`
`December
`
`17/24, 2002
`
`Evidence statements: Fibrates are effective for
`modifying atherogenic dyslipidemia,
`and particu-
`larly for lowering serum triglycerides
`(C1). They
`produce moderate
`elevations of HDL cholesterol
`(C1). Fibrates also are effective for treatment of
`dysbetalipoproteinemia
`(elevated beta-VLDL)
`(C1).
`They also can produce some lowering of LD L, the
`degree of which may vary among different
`fibrate
`preparations
`(Cl). Fibrates also can be combined
`with LDL-lowering drugs in treatment of combined
`hyperlipidemia
`to improve the lipoprotein profile,
`although there is no clinical-trial evidence of effica-
`cy for CHD risk reduction with combined druzc
`therapy (Cl, Dl).
`
`Evidence statements: Fibrate therapy moderately
`reduces risk for CHD (A2, B1). It may also reduce
`risk for stroke in secondary prevention (A2).
`
`Evidence statements: Evidence for an increase in
`total mortality due to an increased non-CHD mor-
`tality, observed in the first large primary prevention
`trial with clofibrate, has not been substantiated
`in
`subsequent primary or secondary prevention trials
`with other fibrates (gemfibrozil or bezafibrate)
`(A2,
`Bl). Nonetheless,
`fibrates have the potential
`to
`produce some side effects. Fibrate therapy alone
`carries an increased risk for cholesterol gallstones
`(A2), and the combination
`of fibrate and statin
`imparts an increased risk for myopathy (B2).
`
`Recommendations: Fibrates can be recommended
`for persons with very high triglycerides
`to reduce
`risk for acute pancreatitis. They also can be recom-
`mended for persons with dysbetalipoproteinemia
`(elevated beta-VLDL). Fibrate therapy should be
`considered an option for treatment of persons with
`esrablished CHD who have low levels of LDL
`cholesterol and atherogenic dyslipidemia. They
`also should be considered in combination with
`stat in therapy in persons who have elevated LDL
`cholesterol and atherogenic dyslipidernia.
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`

`17~_~,=-VI.2-5.Major Char~cteristics
`
`and Outcomes
`
`of HERS Trial
`
`Patient Characteristics
`
`2,763 postmenopausal women
`
`Study Design
`Randomized, double-blind
`
`Placebo vs. 0.625 mg of conjugated
`equine estrogens and 2.5 mg
`medroxyprogesterone acetate (E+P)
`
`Age <80 years (mean age 67
`years)
`
`History of CHD
`
`Absent hysterectomy
`
`8MI >27 kg/m2
`
`45% on lipid-lowering drugs
`at entry
`
`VI. DrugTherapy
`
`3319
`
`Clinical Outcomes
`(E+P vs. Placebo)
`
`·li
`
`I Side-Effects'
`
`CHD events 172 vs. 176
`
`CHD death 71 vs. 58
`
`Thromboembolic events
`(E+P" placebo)
`
`Gallbladder disease
`(E+P " placebo)
`
`Duration: 4.1 years
`
`Non-fatal MI 116 vs. 129
`
`(
`
`estrogen alone, or in combination with progestin,
`reduces risk for CHD in primary and secondary pre-
`vention. However, benefit of estrogen replacement was
`not confirmed in a secondary prevention trial,
`the
`Heart and Estrogen/progestin Replacement Study
`(HERS).493 A subsequent
`angiographic
`study also
`revealed no apparent benefit from HRT.888 The major
`features of the HERS trial are shown in Table VI.2-5.
`
`replacement
`As shown in the table, estrogen/progestin
`produced no overall benefit for the entire duration of
`the trial. Moreover, both CHD death and non-fatal
`myocardial
`infarction were increased, especially during
`the first year. Estrogen/progestin
`(E+P) replacement
`increased risk for thromboembolic
`events and caused
`more gallbladder disease.493,889Thus, E+P produced no
`overall benefit for the entire study and increased risk
`for CHD events,
`thromboembolic
`events, and gallblad-
`der disease in the early phase of the trial. There was
`a suggestion, however,
`that E+P reduced non-fatal
`myocardial
`infarction in the latter years of the trial.
`A 3-year followup study is currently in progress. The
`overall interpretation
`of the trial by the investigators
`was that HRT should not be initiated in post-
`menopausal women with CHD for the purpose of
`reducing risk of CHD, but
`if women had already been
`on HR T for a period of time,
`they could continue, with
`the expectation that
`there may be some later benefit.
`The mechanism for the early increase in CHD events
`and increased thromboembolic
`events has not been
`clearly defined, but it appears that E+P administration
`was associated with a prothrombotic
`tendency.
`
`Estrogen therapy favorably influences lipid and lipopro-
`tein levels, but this did not
`translate into a reduction in
`CHD risk in the HERS trial. In postmenopausal
`women, orally administered
`estrogen preparations
`(0.625 mg of conjugated estrogen or 2 mg of
`by
`micronized estradiol)
`reduce LDL-cholesterollevels
`up
`10-15 percent and increase HDL-cholesterollevels
`to 15 percent.890-892Co-administration
`of progestin may
`decrease the HDL-cholesterol-raising
`effect of estrogen.
`In the HERS trial,
`the mean difference between E+P
`minus placebo was an 11 percent decrease in LDL
`cholesterol, a 10 percent
`increase in HDL cholesterol
`and an 8 percent
`increase in triglycerides.
`
`for why the epidemi-
`There is no definitive explanation
`ologic/observational
`studies provided markedly differ-
`ent results from the HERS trial. The HERS trial clearly
`demonstrates
`the need for controlled clinical
`trials.
`Some investigators postulate
`that
`if lower doses of
`estrogen, different progestins, younger age group,
`estrogen only, or women without CHD had been
`employed,
`the results may have been different. The
`NHLBI Women's Health Initiative is utilizing the same
`hormonal preparation
`in a wide range of ages in an
`estrogen-only and in an estrogen/progestin group in
`women without CHD.683 This trial may answer some of
`the questions, but the results will probably not be avail-
`able before 2003. There is also a possibility of an
`increased risk of breast cancer with prolonged HRT.893-897
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`

`I P
`Ie:
`11',_
`I)
`II'
`'I'
`I(
`\'
`II:
`II.
`I,I
`
`I
`
`II
`I,
`
`IiIi
`
`tions. Persons with severe forms of hypercholes-
`terolemia or other hyperlipidemias who cannot be ade-
`quately controlled should be referred to a center spe-
`cializing in lipid disorders. LDL apheresis
`is now avail-
`able for persons with very high LDL levels, but the
`procedure
`is costly and time-consuming. The FDA
`recently approved two commercial
`techniques
`for this
`purpose:
`extracorporeallipopro-
`(1) a heparin-induced
`rein precipitation,
`and (2) a dextran sulfate cellulose
`adsorbent
`for removal of lipoproteins.
`
`3. Selection of drugs for elevated LDL cholesterol
`
`of LDL cholesterol
`Reduction in serum concentrations
`is the primary approach to lowering the risk of CHD
`in both primary and secondary prevention.
`In persons
`w