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Date Printed: October 23, 2017: 07:22 AM

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09-J2000-36

Original Effective Date: 08/01/15

Reviewed: 04/12/17

Revised: 08/15/17

Subject: PCSK9 Inhibitors

THIS MEDICAL COVERAGE GUIDELINE IS NOT AN AUTHORIZATION, CERTIFICATION, EXPLANATION OF BENEFITS, OR A GUARANTEE OF PAYMENT, NOR DOES IT SUBSTITUTE FOR OR CONSTITUTE MEDICAL ADVICE. ALL MEDICAL DECISIONS ARE SOLELY THE RESPONSIBILITY OF THE PATIENT AND PHYSICIAN. BENEFITS ARE DETERMINED BY THE GROUP CONTRACT, MEMBER BENEFIT BOOKLET, AND/OR INDIVIDUAL SUBSCRIBER CERTIFICATE IN EFFECT AT THE TIME SERVICES WERE RENDERED. THIS MEDICAL COVERAGE GUIDELINE APPLIES TO ALL LINES OF BUSINESS UNLESS OTHERWISE NOTED IN THE PROGRAM EXCEPTIONS SECTION.

           
Dosage/ Administration Position Statement Billing/Coding Reimbursement Program Exceptions Definitions
           
Related Guidelines Other References Updates  
           

DESCRIPTION:

In late 2013, the American College of Cardiology (ACC) and the American Heart Association (AHA) jointly released new guidelines on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular disease (ASCVD) risk in adults. The guidelines promoted a major change in hypercholesterolemia management. Specific low-density lipoprotein cholesterol (LDL-C) treatment goals were abandoned and focus was placed on appropriate intensity of HMG-CoA reductase inhibitor (statin) therapy in those persons most likely to benefit (i.e., the four “statin benefit groups”). This paradigm shift was based on the fact that, among the cholesterol reducing medications, only statins had proven cardiovascular outcome benefits at that time. In 2015, the results of the IMPROVE-IT trial demonstrated that ezetimibe (Zetia) plus simvastatin vs. simvastatin alone in patients with recent acute coronary syndrome (ACS) led to reduced LDL-C (~16 mg/dL), as expected, but also a reduction in cardiovascular adverse events (32.7% vs. 34.7%). Some clinicians suggest that this data supports the “lower is better” approach to treating hypercholesterolemia; however, this extrapolation to all LDL-C lowering medications may be premature. In contrast to the ACC/AHA guidelines, the National Lipid Association (NLA) published guidelines in 2014 that support the use of non-HDL-C and LDL-C treatment goals. Goals and consideration for drug therapy are based on risk stratification of low, moderate, high, or very high. The LDL-C treatment goals and thresholds to consider drug therapy for each group, respectively, are as follows, low: <100 mg/dL/≥160 mg/dL, moderate: <100 mg/dL/≥130 mg/dL, high: <100 mg/dL/≥100 mg/dL, and very high: <70 mg/dL/≥70 mg/dL. A 2015 update includes drug therapy recommendations for patients with residual risk despite statin treatment and lifestyle modification.

A novel class of medications, the proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, are a recent addition to the treatment options available for hypercholesterolemia. PCSK9 is a serine protease that regulates the amount of plasma LDL-C by interacting with LDL receptors. PCSK9 binding leads to degradation of LDL receptors and a corresponding inhibition of LDL-C breakdown. Numerous trials of the three PCSK9 inhibitors in late stage devolvement, alirocumab (Praluent, Sanofi/Regeneron), bococizumab (Pfizer), and evolocumab (Repatha, Amgen); have shown potent lowering of LDL-C. The optimal clinical role for PCSK9 inhibitors is being debated; however, they have been studied in patients with primary hypercholesterolemia (with and without concurrent statin therapy), statin intolerance, and familial hypercholesterolemia (both the heterozygous and homozygous forms). In July 2015, alirocumab was the first PCSK9 inhibitor to be FDA approved. It has an indication of “as an adjunct to diet and maximally tolerated statin therapy for the treatment of adults with heterozygous familial hypercholesterolemia or clinical atherosclerotic cardiovascular disease, who require additional lowering of LDL-C. In August 2015, evolocumab was approved with the same indication as alirocumab with the addition of use in patients with homozygous familial hypercholesterolemia (HoFH). The FDA had previously granted evolocumab orphan drug designation for the treatment of homozygous familial hypercholesterolemia in September 2013. In late 2016, Pfizer discontinued the global clinical development program for bococizumab. This was based on an emerging clinical profile that included an unanticipated attenuation of LDL-C lowering over time, as well as a higher level of immunogenicity and higher rate of injection-site reactions with bococizumab vs. other agents in the class. Regarding outcomes data, exploratory post-hoc analyses of pooled trial data initially suggested about a 50% relative reduction in composite cardiovascular events (~1% vs. 2%) at 12 to 18 months vs. controls in a range of patient populations. Two large outcomes trials, FOURIER (adding evolocumab to statins for people with preexisting heart disease), and ODYSSEY Outcomes (comparing alirocumab to placebo atop medical and lifestyle management after a recent acute coronary syndrome), were conducted.

The results of the FOURIER trial were released in March 2017. A total of 27,564 patients with ASCVD and LDL ≥70 mg/dL despite statin therapy were randomized to evolocumab (either 140 mg every 2 weeks or 420 mg monthly) or matching placebo as subcutaneous injections. The primary efficacy end point was the composite of CV death, MI, stroke, hospitalization for unstable angina, or coronary revascularization. The key secondary efficacy end point was the composite of CV death, MI, or stroke. The median duration of follow-up was 2.2 years. At 48 weeks, the reduction in LDL-C with evolocumab vs. placebo was 59%, from a median baseline value of 92 mg/dL to 30 mg/dL (p<0.001). Relative to placebo, evolocumab treatment reduced the relative risk of the primary end point by 15% (9.8% vs.11.3%; NNT=67; HR 0.85, 95% CI, 0.79 to 0.92; p<0.001) and the key secondary end point by 20% (5.9% vs. 7.4%; NNT=67; HR 0.80; 95% CI, 0.73 to 0.88; p<0.001). The results were consistent across key subgroups. There was no significant difference between the study groups with regard to adverse events with the exception of injection-site reactions. Final results for the ODYSSEY trial are expected in early in 2018.

Familial hypercholesterolemia (FH) is an inherited genetic defect that results in severe elevations of blood cholesterol levels and increases the risk of CHD about 20-fold in untreated patients. Recent population data show that the heterozygous and homozygous forms of FH affect one in 200 to 500 and one in 160,000 to 300,000 people, respectively, worldwide. Untreated total cholesterol concentrations in heterozygous FH (HeFH) patients (genetic defect inherited from one parent) are typically in the range of 200 to 450 mg/dL and in homozygotes (genetic defects inherited from both parents) range from 650 to 1,000 mg/dL. Aggressive lipid lowering is necessary to achieve target LDL-C levels (ideally <100 mg/dL or at least a 50% reduction from baseline). Current drug treatments include high-dose statin therapy alone or in combination with other cholesterol lowering medications such as ezetimibe and bile acid sequestrants. Statins, on average, decrease LDL-C 15% (range 0 to 48%) in individuals with HoFH. In phase III trials of patients with HoFH and HeFH, evolocumab, when added to intensive statin therapy, reduced LDL-C on average by an additional 30% and 60%, respectively, vs. placebo. When desired reductions in LDL-C are not achieved with pharmacological therapy, LDL-C apheresis may be used. LDL apheresis can reduce LDL-C by more than 50%; however, the procedure is expensive, not readily available, and inconvenient as it has to be done every two weeks. Preliminary data have shown that use of PCSK9 inhibitors can reduce the need for apheresis in patients with FH.

POSITION STATEMENT:

Alirocumab (Praluent)

The initiation of alirocumab (Praluent) meets the definition of medical necessity when ALL of the follow criteria are met (“1” to “8”):

1. Initiation of therapy is prescribed by a cardiologist, endocrinologist, or lipidologist

2. Dosage does not exceed 150 mg every 2 weeks

3. Member is not taking ANY of the following medications concurrently:

a. Lomitapide (Juxtapid)

b. Mipomersen (Kynamro)

c. Another PCSK9 inhibitor [e.g., evolocumab (Repatha)]

4. Member has not previously had an inadequate therapeutic response with PCSK9 inhibitor treatment

5. Documentation of baseline LDL-C level is provided - measurement must occur within 90 days prior to treatment with alirocumab AND after at least 120 consecutive days of concurrent therapy with criteria-specified prerequisite lipid-lowering medications (as assessed by claims history when possible). If the member is not a candidate for a specific drug, the 120-day treatment requirement does not apply for that drug.

6. Treatment with alirocumab will be used in combination with maximally tolerated HMG-CoA reductase inhibitor (statin) therapy unless the member has a documented contraindication or complete intolerance as defined below. The specific contraindication or intolerance must be specified.

7. Member has EITHER the following indications (“a” or “b”) and meets ALL indication-specific criteria:

a. Clinical atherosclerotic cardiovascular disease (ASCVD), and the member’s ASCVD is defined by evidence of at least ONE of the following (medical record documentation must be provided):

• Acute coronary syndrome (ACS)

• Coronary or other arterial revascularization

• History of myocardial infarction (MI)

• Peripheral arterial disease (PAD) presumed to be of atherosclerotic origin

• Stable or unstable angina

• Stroke

• Transient ischemic attack (TIA)

b. Heterozygous familial hypercholesterolemia (HeFH), and the diagnosis is confirmed as “definite” by a score of 9 or higher using the Dutch Lipid Clinic Network criteria (see “Other Section” for the scoring algorithm). Documentation of ALL of the following must be provided to calculate an accurate score:

• Member’s first-degree relatives with any of the following:

o Tendon xanthoma

o Corneal arcus

o Known LDL-C >95th percentile by age and gender for country

o Known premature (<55 years, men; <60 years, women) coronary heart disease (CHD)

• Member’s child(ren) <18 years with LDL-C >95th percentile by age and gender for country

• Member’s baseline LDL-C level prior to the use of ALL cholesterol lowering medications

• Member history of CHD

• Member history of cerebral or peripheral vascular disease

• Physical exam finding of tendon xanthoma

• Physical exam finding of corneal arcus

• Results of molecular genetic testing

8. Member’s LDL-C is ≥100 mg/dL [if without existing clinical atherosclerotic cardiovascular disease (ASCVD)] or ≥70 mg/dL [if with existing clinical ASCVD] despite current therapy with BOTH maximally tolerated statin therapy AND ezetimibe (Zetia) for at least 120 days of consecutive therapy (as assessed by claims history when possible) (see drug-specific requirements below - “a” and “b”). Use of fewer medications is permissible if the member is not a candidate for a given drug (documentation of reason(s) must be provided):

a. Statin treatment at the maximally tolerated dosage unless contraindicated, OR member has a complete intolerance. The specific contraindication or intolerance must be specified. If there is no evidence of partial intolerance, maximally tolerated means that the member must be using the maximum FDA-approved dosage of a high-intensity statin (i.e., atorvastatin 80 mg/day or rosuvastatin 40 mg/day). See the definitions that must be met in “i”, “ii”, or “iii”.

i. Complete intolerance to a statin (ALL of the following are met - “1”, “2”, and “3”):

1. Persistent (>2 weeks) and intolerable skeletal muscle-related discomfort, OR creatine kinase (CK) ≥10-time the upper limit of normal (ULN), that is not diagnosed as rhabdomyolysis, despite BOTH of the following:

• Use of at least TWO different statins at the lowest FDA-approved dosage

• At least one statin must be a hydrophilic statin (i.e., pravastatin, rosuvastatin, or fluvastatin)

2. Other reasons (i.e., untreated hypothyroidism, interacting drugs, concurrent illnesses, significant changes in physical activity/exercise, and underlying muscle disease) have been ruled out as the cause of the muscle symptoms and/or elevated CK level

3. Muscle symptoms and/or elevated CK levels resolved upon statin discontinuation

ii. Partial intolerance (BOTH of the following are met - “1” and “2”):

1. Member is unable to tolerate the maximum FDA-approved approved dosage of a high-intensity statins (i.e., atorvastatin 80 mg/day or rosuvastatin 40 mg/day).

2. Member is able to tolerate a lower dosage of a high-intensity statin, OR any dosage of a different statin.

iii. Contraindications (ANY of the following):

1. Decompensated liver disease (i.e., patients with symptomatic complications such as jaundice, ascites, variceal hemorrhage, or hepatic encephalopathy). This does NOT include patients with stable, chronic liver disease (e.g., hepatitis B and C infection, non-alcoholic fatty liver disease, etc.).

2. Immune-mediated hypersensitivity to the HMG-CoA reductase inhibitor drug class as evidence by an allergic reaction occurring with at least one statin.

3. Previous history of laboratory-confirmed acute liver injury resulting from statin treatment (see “Other Section”)

4. Previous history of laboratory-confirmed rhabdomyolysis resulting from statin treatment (see “Other Section”)

5. Women who are pregnant or are actively trying to become pregnant

b. Ezetimibe (Zetia) treatment unless use is contraindicated, OR, for members with a documented inability to take a statin, ezetimibe monotherapy is unlikely to achieve the member’s goal LDL-C level (i.e., LDL-C reduction of 25% or more).* See the specific requirements below (“i” or “ii”):

i. Contraindications (EITHER of the following):

1. Immune-mediated hypersensitivity to the specific product or any of its components

2. Moderate to severe hepatic impairment (Child-Pugh grade B and C)

ii. For members unable to take a statin (ONE of the following):

1. LDL-C goal <70 mg/dL - if the submitted LDL-C level is ≥95 mg/dL, a trial of ezetimibe monotherapy is not required

2. LCL-C goal i<100 mg/dL - if the submitted LDL-C level is ≥130 mg/dL, a trial of ezetimibe monotherapy is not required

*Average LDL-C reduction with ezetimibe monotherapy is ~18% with a standard deviation (SD) of ± ~13%. As such, some members may see LDL-C reductions greater than 25 to 30%.

Duration of approval: 6 months

The continuation of alirocumab (Praluent) meets the definition of medical necessity when ALL of the following criteria are met:

1. Initial approval by Florida Blue for the treatment of clinical ASCVD or HeFH, OR member previously met ALL indication-specific initiation criteria

2. At least ONE of the following:

a. Minimum 30% reduction in LDL-C since the beginning of treatment with alirocumab

b. Achievement of LDL-C goal of <100 mg/dL (if HeFH without ASCVD) or <70 mg/dL (if ASCVD or HeFH with ASCVD)

3. The member is NOT using ANY of the following:

a. Lomitapide (Juxtapid)

b. Mipomersen (Kynamro)

c. Another PCSK9 inhibitor [e.g., evolocumab (Repatha)]

4. Treatment with alirocumab will be used in combination with maximally tolerated statin therapy (as shown by the past 120 days of claims history) unless the member has a documented contraindication or complete intolerance.

5. The member’s dosage does not exceed 150 mg every 2 weeks.

Duration of approval: 1 year

Evolocumab (Repatha)

The initiation of evolocumab (Repatha) meets the definition of medical necessity when ALL of the follow criteria are met (“1” to “8”):

1. The member’s dosage does not exceed EITHER of the following:

• 140 mg (one prefilled syringe or one SureClick autoinjector) every 2 weeks

• 420 mg* (one Pushtronex system) once monthly

*The use of a 420 mg dose via three 140-mg SureClick autoinjectors or three 140-mg prefilled syringes is NOT considered medically necessary

2. Initiation of therapy is prescribed by a cardiologist, endocrinologist, or lipidologist.

3. Member is not taking ANY of the following medications concurrently:

a. Lomitapide (Juxtapid)

b. Mipomersen (Kynamro)

c. Another PCSK9 inhibitor [e.g., alirocumab (Praluent)]

4. Member has not previously had an inadequate therapeutic response with PCSK9 inhibitor treatment.

5. Documentation of baseline LDL-C level is provided - measurement must occur within 90 days prior to treatment with evolocumab AND after at least 120 consecutive days of concurrent therapy with criteria-specified prerequisite lipid-lowering medications (as assessed by claims history when possible). If the member is not a candidate for a specific drug, the 120-day treatment requirement does not apply for that drug.

6. Treatment with evolocumab will be used in combination with maximally tolerated HMG-CoA reductase inhibitor (statin) therapy unless the member has a documented contraindication or complete intolerance as defined below. The specific contraindication or intolerance must be specified.

7. Member has ANY of the following indications (“a”, “b”, or “c”) and meets ALL indication-specific criteria:

a. Clinical atherosclerotic cardiovascular disease (ASCVD), and the member’s ASCVD is defined by evidence of at least ONE of the following (medical record documentation must be provided):

• Acute coronary syndrome (ACS)

• Coronary or other arterial revascularization

• History of myocardial infarction (MI)

• Peripheral arterial disease (PAD) presumed to be of atherosclerotic origin

• Stable or unstable angina

• Stroke

• Transient ischemic attack (TIA)

b. Heterozygous familial hypercholesterolemia (HeFH), and the diagnosis is confirmed as “definite” by a score of 9 or higher using the Dutch Lipid Clinic Network criteria (see “Other Section” for the scoring algorithm). Documentation of ALL of the following must be provided to calculate an accurate score:

• Member’s first-degree relatives with any of the following:

o Tendon xanthoma

o Corneal arcus

o Known LDL-C >95th percentile by age and gender for country

o Known premature (<55 years, men; <60 years, women) coronary heart disease (CHD)

• Member’s child(ren) <18 years with LDL-C >95th percentile by age and gender for country

• Member’s baseline LDL-C level prior to the use of ALL cholesterol lowering medications

• Member history of CHD

• Member history of cerebral or peripheral vascular disease

• Physical exam finding of tendon xanthoma

• Physical exam finding of corneal arcus

• Results of molecular genetic testing

c. Homozygous familial hypercholesterolemia (HoFH), and the diagnosis is confirmed by meeting ANY of the following (medical record documentation must be provided):

• Genetic confirmation of two mutant alleles at the LDL-R, Apo-B, PCSK9, or ARH adaptor protein gene locus

• Untreated LDL-C >500 mg/L AND cutaneous or tendinous xanthoma before age 10 years

• Untreated LDL-C >500 mg/L AND both parents with elevated LDL-C before lipid-lowering therapy consistent with heterozygous familial hypercholesterolemia (e.g., untreated LDL‐C >190 mg/dL)

• Treated LDL-C ≥300 mg/dL or non-HDL-C ≥330 mg/dL AND cutaneous or tendinous xanthoma before age 10 years

• Treated LDL-C ≥300 mg/dL or non-HDL-C ≥330 mg/dL AND both parents with elevated LDL-C before lipid-lowering therapy consistent with heterozygous familial hypercholesterolemia (e.g., untreated LDL‐C >190 mg/dL)

8. Member’s LDL-C is ≥100 mg/dL [if without existing clinical atherosclerotic cardiovascular disease (ASCVD)] or ≥70 mg/dL [if with existing clinical ASCVD] despite current therapy with BOTH maximally tolerated statin therapy AND ezetimibe (Zetia) for at least 120 days of consecutive therapy (as assessed by claims history when possible) (see drug-specific requirements below - “a” and “b”). Use of fewer medications is permissible if the member is not a candidate for a given drug (documentation of reason(s) must be provided):

a. Statin treatment at the maximally tolerated dosage unless contraindicated, OR member has a complete intolerance. The specific contraindication or intolerance must be specified. If there is no evidence of partial intolerance, maximally tolerated means that the member must be using the maximum FDA-approved dosage of a high-intensity statin (i.e., atorvastatin 80 mg/day or rosuvastatin 40 mg/day). See the definitions that must be met in “i”, “ii”, or “iii”.

i. Complete intolerance to a statin (ALL of the following are met - “1”, “2”, and “3”):

1. Persistent (>2 weeks) and intolerable skeletal muscle-related discomfort, OR creatine kinase (CK) ≥10-time the upper limit of normal (ULN), that is not diagnosed as rhabdomyolysis, despite BOTH of the following:

• Use of at least TWO different statins at the lowest FDA-approved dosage

• At least one statin must be a hydrophilic statin (i.e., pravastatin, rosuvastatin, or fluvastatin)

2. Other reasons (i.e., untreated hypothyroidism, interacting drugs, concurrent illnesses, significant changes in physical activity/exercise, and underlying muscle disease) have been ruled out as the cause of the muscle symptoms and/or elevated CK level

3. Muscle symptoms and/or elevated CK levels resolved upon statin discontinuation

ii. Partial intolerance (BOTH of the following are met - “1” and “2”):

1. Member is unable to tolerate the maximum FDA-approved approved dosage of a high-intensity statins (i.e., atorvastatin 80 mg/day or rosuvastatin 40 mg/day).

2. Member is able to tolerate a lower dosage of a high-intensity statin, OR any dosage of a different statin.

iii. Contraindications (ANY of the following):

1. Decompensated liver disease (i.e., patients with symptomatic complications such as jaundice, ascites, variceal hemorrhage, or hepatic encephalopathy).This does NOT include patients with stable, chronic liver disease (e.g., hepatitis B and C infection, non-alcoholic fatty liver disease, etc.).

2. Immune-mediated hypersensitivity to the HMG-CoA reductase inhibitor drug class as evidence by an allergic reaction occurring with at least one statin.

3. Previous history of laboratory-confirmed acute liver injury resulting from statin treatment (see “Other Section”)

4. Previous history of laboratory-confirmed rhabdomyolysis resulting from statin treatment (see “Other Section”)

5. Women who are pregnant or are actively trying to become pregnant

b. Ezetimibe (Zetia) treatment unless use is contraindicated, OR, for members with a documented inability to take a statin, ezetimibe monotherapy is unlikely to achieve the member’s goal LDL-C level (i.e., LDL-C reduction of 25% or more).* See the specific requirements below (“i” or “ii”):

i. Contraindications (EITHER of the following):

1. Immune-mediated hypersensitivity to the specific product or any of its components

2. Moderate to severe hepatic impairment (Child-Pugh grade B and C)

ii. For members unable to take a statin (EITHER of the following):

1. LDL-C goal <70 mg/dL - if the submitted LDL-C level is ≥95 mg/dL, a trial of ezetimibe monotherapy is not required

2. LCL-C goal <100 mg/dL - if the submitted LDL-C level is130 mg/dL, a trial of ezetimibe monotherapy is not required

*Average LDL-C reduction with ezetimibe monotherapy is ~18% with a standard deviation (SD) of ± ~13%. As such, some members may see LDL-C reductions greater than 25 or 30%.

Duration of approval: 6 months

The continuation of evolocumab (Repatha) meets the definition of medical necessity when ALL of the following criteria are met:

1. Initial approval by Florida Blue for the treatment of clinical ASCVD, HeFH or HoFH, OR member previously met ALL indication-specific initiation criteria

2. At least ONE of the following:

a. An indication-specific reduction in LDL-C since the beginning of treatment with evolocumab:

i. Clinical ASCVD or heterozygous FH - minimum 30% reduction

ii. Homozygous FH – minimum 10% reduction

b. Achievement of LDL-C goal of <300 mg/dL* (HoFH only), <100 mg/dL (HeFH without ASCVD) or <70 mg/dL (ASCVD or HeFH with ASCVD)

*NLA cholesterol thresholds for the initiation of LDL apheresis in patients with HoFH. Treatment to below these thresholds should reduce the need for LDL apheresis.

3. The member is NOT using ANY of the following:

a. Lomitapide (Juxtapid)

b. Mipomersen (Kynamro)

c. Another PCSK9 inhibitor [e.g., alirocumab (Praluent)]

4. Treatment with evolocumab will be used in combination with maximally tolerated statin therapy (as shown by the past 120 days of claims history) unless the member has a documented contraindication or complete intolerance

5. The member’s dosage does not exceed EITHER of the following:

a. 140 mg (one prefilled syringe or one SureClick autoinjector) every 2 weeks

b. 420 mg* (one Pushtronex system) once monthly

*The use of a 420 mg dose via three 140 mg SureClick autoinjectors or three 140 mg prefilled syringes is NOT considered medically necessary

Duration of approval: 1 year

DOSAGE/ADMINISTRATION:

THIS INFORMATION IS PROVIDED FOR INFORMATIONAL PURPOSES ONLY AND SHOULD NOT BE USED AS A SOURCE FOR MAKING PRESCRIBING OR OTHER MEDICAL DETERMINATIONS. PROVIDERS SHOULD REFER TO THE MANUFACTURER’S FULL PRESCRIBING INFORMATION FOR DOSAGE GUIDELINES AND OTHER INFORMATION RELATED TO THIS MEDICATION BEFORE MAKING ANY CLINICAL DECISIONS REGARDING ITS USAGE.

FDA-approved

• Alirocumab - indicated as an adjunct to diet and maximally tolerated statin therapy for the treatment of adults with heterozygous familial hypercholesterolemia or clinical atherosclerotic cardiovascular disease, who require additional lowering of LDL-C. The effect on cardiovascular morbidity and mortality has not been determined. The recommended starting dose is 75 mg administered subcutaneously once every 2 weeks, since the majority of patients achieve sufficient LDL-C reduction with this dosage. If the LDL-C response is inadequate, the dosage may be increased to the maximum dosage of 150 mg administered every 2 weeks. Measure LDL-C levels within 4 to 8 weeks of initiating or titrating to assess response and adjust the dose, if needed. Allow alirocumab to warm to room temperature for 30 to 40 minutes prior to use. Do NOT use if it has been at room temperature for 24 hours or longer.

• Evolocumab – indicated as, (1) an adjunct to diet and maximally tolerated statin therapy for treatment of adults with heterozygous familial hypercholesterolemia (HeFH) or clinical atherosclerotic cardiovascular disease (CVD), who require additional lowering of LDL-C, and (2) an adjunct to diet and other LDL-lowering therapies (e.g., statins, ezetimibe, LDL apheresis) in patients with homozygous familial hypercholesterolemia (HoFH) who require additional lowering of LDL-C. The effect on cardiovascular morbidity and mortality has not been determined. For members with a CVD or HeFH indication, the recommended dosage is either 140 mg every 2 weeks or 420 mg once monthly administered subcutaneously in the abdomen, thigh, or upper arm. For the HoFH indication, the recommended dosage is 420 mg once monthly. In members with HoFH, measure LDL-C levels 4 to 8 weeks after starting treatment, since response to therapy will depend on the degree of LDL-receptor function.

Dose Adjustments

• Alirocumab - no dose adjustment is needed for patients with mild or moderately impaired renal function. No data are available in patients with severe renal impairment. No dose adjustment is needed for patients with mild or moderate hepatic impairment. No data are available in patients with severe hepatic impairment.

• Evolocumab -no dose adjustment is needed for patients with mild or moderately impaired renal function. No data are available in patients with severe renal impairment. No dose adjustment is needed for patients with mild or moderate hepatic impairment. No data are available in patients with severe hepatic impairment.

Drug Availability

• Alirocumab – 75 mg/mL and 150 mg/mL single-dose pre-filled pens and pre-filled syringes. Store in a refrigerator at 36°F to 46°F (2°C to 8°C) in the outer carton in order to protect from light. Do NOT freeze. Do NOT expose to extreme heat. Do NOT shake.

• Evolocumab - 140 mg/mL single-use pre-filled syringes and single-use prefilled SureClick® autoinjectors. Store in a refrigerator at 36°F to 46°F (2°C to 8°C) in the outer carton in order to protect from light. Alternatively, evolocumab can be kept at room temperature [up to 25°C (77°F)] in the original carton; however, under these conditions, it must be used within 30 days. Do NOT freeze. Do NOT shake.

PRECAUTIONS:

Boxed Warning

• None

Contraindications

• Hypersensitivity to the specific PCSK9 inhibitor

Precautions/Warnings

Alirocumab

• Allergic Reactions: Hypersensitivity reactions (e.g., pruritus, rash, urticaria), including some serious events (e.g., hypersensitivity vasculitis and hypersensitivity reactions requiring hospitalization), have been reported with treatment. If signs or symptoms of serious allergic reactions occur, discontinue treatment, treat according to the standard of care, and monitor until signs and symptoms resolve.

• Pregnancy: There are no available data on use in pregnant women to inform a drug-associated risk. In animal reproduction studies, there were no effects on embryo-fetal development when rats were subcutaneously administered alirocumab during organogenesis at dose exposures up to 12-fold the exposure at the maximum recommended human dose. Suppression of the humoral immune response was observed in infant monkeys.

Evolocumab

• Allergic Reactions: Hypersensitivity reactions (e.g., rash, urticaria) have been reported with treatment, including some that led to discontinuation of therapy. If signs or symptoms of serious allergic reactions occur, discontinue treatment, treat according to the standard of care, and monitor until signs and symptoms resolve.

• Pregnancy: There are no available data on use in pregnant women to inform a drug-associated risk. In animal reproduction studies, there were no effects on pregnancy or neonatal/infant development when monkeys were subcutaneously administered evolocumab from organogenesis through parturition at dose exposures up to 12-fold the exposure at the maximum recommended human dose. Suppression of the humoral immune response was observed in infant monkeys.

BILLING/CODING INFORMATION:

The following codes may be used to describe:

HCPCS Coding

Alirocumab (Praluent)

C9399

Unclassified drugs or biologics (Hospital Outpatient Use ONLY)

J3590

Unclassified biologics

Evolocumab (Repatha)

C9399

Unclassified drugs or biologics (Hospital Outpatient Use ONLY)

J3590

Unclassified biologics

ICD-10 Diagnoses Codes That Support Medical Necessity

Alirocumab (Praluent)

E78.00

Pure hypercholesterolemia, unspecified

E78.01

Familial hypercholesterolemia

E78.2

Mixed hyperlipidemia

E78.4

Other hyperlipidemia

E78.5

Hyperlipidemia, unspecified

Evolocumab (Repatha)

E78.00

Pure hypercholesterolemia, unspecified

E78.01

Familial hypercholesterolemia

E78.2

Mixed hyperlipidemia

E78.4

Other hyperlipidemia

E78.5

Hyperlipidemia, unspecified

REIMBURSEMENT INFORMATION:

Refer to section entitled POSITION STATEMENT.

PROGRAM EXCEPTIONS:

Federal Employee Program (FEP): Follow FEP guidelines.

State Account Organization (SAO): Follow SAO guidelines.

Medicare Part D: BCBSF has delegated to Prime Therapeutics authority to make coverage determinations for the Medicare Part D services referenced in this guideline.

Medicare Advantage: No National Coverage Determination (NCD) and/or Local Coverage Determination (LCD) were found at the time of the guideline creation.

DEFINITIONS:

Clinical atherosclerotic cardiovascular disease (ASCVD): The ACC/AHA Guidelines for Preventing ASCVD define as patients with acute coronary syndromes (ACS); or a history of myocardial infarction (MI), stable or unstable angina (UA), coronary or other arterial revascularization, stroke, transient ischemia attack (TIA), or peripheral arterial disease (PAD) presumed to be of atherosclerotic origin.

Familial hypercholesterolemia (FH): A recessive genetic disorder caused by a defect on chromosome 19 that makes the liver incapable of metabolizing (or removing) excess LDL. The result is very high LDL levels which can lead to premature cardiovascular disease. There are two forms of FH. If inherited from one parent, the result is heterozygous FH (HeFH). HeFH occurs in 1 in 200 to 500 people worldwide. If inherited from both parents, it is much more severe in its consequences. This form of FH is called homozygous FH (HoFH). It is very rare, occurring in about 1 in 160,000 to one million people worldwide.

RELATED GUIDELINES:

Apheresis, Plasmapheresis and Plasma Exchange, 02-33000-17
Lomitapide (Juxtapid) Oral, 09-J1000-92

Mipomersen Sodium (Kynamro) Injection, 09-J1000-93

OTHER:

Child-Pugh Classification of Severity of Liver Disease: Using the table below, a total score of 5 to 6 is considered grade A (well-compensated disease); 7 to 9 is grade B (significant functional compromise); and 10 to 15 is grade C (decompensated disease).

Parameter

Points assigned

1

2

3

Ascites

Absent

Slight

Moderate

Bilirubin, mg/dL

</= 2

2-3

>3

Albumin, g/dL

>3.5

2.8-3.5

<2.8

Prothrombin time

* Seconds over control

* INR

1-3

<1.8

4-6

1.8 – 2.3

>6

>2.3

Encephalopathy

None

Grade 1-2

Grade 3-4

Dutch Lipid Clinic Network criteria for diagnosis of HeFH in adults:

(NOTE: Only one score, the highest applicable, can be chosen per group)

Criteria

Score

Group 1: family history

First-degree relative with known premature (<55 years, men; <60 years, women) coronary heart disease (CHD)

1

First-degree relative with known LDL cholesterol >95th percentile by age and gender for country

1

First-degree relative with tendon xanthoma and/or corneal arcus

2

Child(ren) <18 years with LDL cholesterol >95th percentile by age and gender for country

2

Group 2: clinical history

Subject has premature (<55 years, men; <60 years, women) CHD

2

Subject has premature (<55 years, men; <60 years, women) cerebral or peripheral vascular disease

1

Group 3: physical examination

 

Tendon xanthoma

6

Corneal arcus in a person <45 years

4

Group 4: biochemical results (LDL cholesterol)

 

>325 mg/dL

8

251 to 325 mg/dL

5

191 to 250 mg/dL

3

155 to 190 mg/dL

1

Group 5: molecular genetic testing (DNA analysis)

 

Causative mutation shown in the LDLR, APOB, or PCSK9 genes

8

Diagnostic total score:

• Definite: >8

• Probable: 6 to 8

• Possible: 3 to 5

• Unlikely: 0 to 2

Laboratory-confirmed rhabdomyolysis resulting from statin treatment

ALL of the following must be documented:

• Member’s creatinine kinase (CK) level was ≥10 times the upper limit of normal (ULN)

• Member’s symptoms were consistent with rhabdomyolysis (e.g., muscle pain, swelling, and weakness, dark urine)

• Member was receiving a statin at the time of the event

• Symptoms and elevated CK level resolved upon discontinuation of the statin

Laboratory-confirmed acute liver injury resulting from statin treatment

ALL of the following must be documented:

• Member’s ALT was ≥ 10 times the ULN, or ALT was >3 times the ULN plus a total bilirubin >2 times the ULN

• Member was receiving a statin at the time of the event

• Elevated liver function tests resolved within 6 weeks of discontinuation of the statin

• Other causes of liver injury were ruled out

REFERENCES:

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  2. Al-Rasadi K, Al-Waili K, Al-Sabti HA, et al. Criteria for Diagnosis of Familial Hypercholesterolemia: A Comprehensive Analysis of the Different Guidelines, Appraising their Suitability in the Omani Arab Population. Oman Med J. 2014 Mar;29(2):85-91. doi: 10.5001/omj.2014.22.
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  5. Blom DJ, Hala T, Bolognese M, et al. A 52-week placebo-controlled trial of evolocumab in hyperlipidemia. N Engl J Med. 2014 May 8;370(19):1809-19. doi: 10.1056/NEJMoa1316222. Epub 2014 Mar 29.
  6. Cannon CP, Blazing MA, Giugliano RP, et al. Ezetimibe Added to Statin Therapy after Acute Coronary Syndromes. N Engl J Med. 2015 Jun 18;372(25):2387-97. Epub 2015 Jun 3.
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  10. Ito MK, McGowan MP, Moriarty PM; National Lipid Association Expert Panel on Familial Hypercholesterolemia. Management of familial hypercholesterolemias in adult patients: recommendations from the National Lipid Association Expert Panel on Familial Hypercholesterolemia. J Clin Lipidol. 2011 Jun;5(3 Suppl):S38-45. doi: 10.1016/j.jacl.2011.04.001. Epub 2011 Apr 8.
  11. Jacobson TA, Ito MK, Maki KC, et al. National lipid association recommendations for patient-centered management of dyslipidemia: part 1--full report. J Clin Lipidol. 2015 Mar-Apr;9(2):129-69. doi: 10.1016/j.jacl.2015.02.003. Epub 2015 Apr 7.
  12. Jacobson TA, Maki KC, Orringer CE, et al; NLA Expert Panel. National Lipid Association Recommendations for Patient-Centered Management of Dyslipidemia: Part 2. J Clin Lipidol. 2015 Nov-Dec;9(6 Suppl):S1-122.e1.
  13. Koren MJ, Lundqvist P, Bolognese M, et al. Anti-PCSK9 monotherapy for hypercholesterolemia: the MENDEL-2 randomized, controlled phase III clinical trial of evolocumab. J Am Coll Cardiol. 2014 Jun 17;63(23):2531-40. doi: 10.1016/j.jacc.2014.03.018. Epub 2014 Mar 29.
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  26. Stroes E, Colquhoun D, Sullivan D, et al. Anti-PCSK9 antibody effectively lowers cholesterol in patients with statin intolerance: the GAUSS-2 randomized, placebo-controlled phase 3 clinical trial of evolocumab. J Am Coll Cardiol. 2014 Jun 17;63(23):2541-8. doi: 10.1016/j.jacc.2014.03.019. Epub 2014 Mar 30.
  27. US Preventive Services Task Force., Bibbins-Domingo K, Grossman DC, Curry SJ, et al. Statin Use for the Primary Prevention of Cardiovascular Disease in Adults: US Preventive Services Task Force Recommendation Statement. JAMA. 2016 Nov 15;316(19):1997-2007.

COMMITTEE APPROVAL:

This Medical Coverage Guideline (MCG) was approved by the BCBSF Pharmacy Policy Committee on 07/12/17.

GUIDELINE UPDATE INFORMATION:

08/01/15

New Medical Coverage Guideline.

09/15/15

Revision to guidelines consisting of updating description, position statement, dosage/administration, precautions, billing/coding, and references.

12/15/15

Revision to guidelines consisting of updating position statement, definitions, and references.

05/15/16

Review and revision to guideline consisting of description section, position statement, and references.

09/15/16

Revision to guideline consisting of updating the position statement.

10/01/16

Revision: ICD-10 code updates

03/01/17

Revision to guideline consisting of updating the position statement to include coverage of ASCVD.

05/15/17

Review and revision to guideline consisting of the description section, position statement, and references.

08/15/17

Revision to guideline consisting of updating the position statement and references in relation to ezetimibe treatment.

Date Printed: October 23, 2017: 07:22 AM