This is the AMRN Prior Auth template they give to physicians to use.
Note to requesting physician: This letter responds to your request for information on an appropriate format and/or topics in a PA letter. It is being provided to you per your request for suggested language to provide to Health Plans that have formulary restrictions in place for VASCEPA. This letter is not promotional in nature but merely provides scientifically accurate and balanced information for your consideration. Please include Important Safety Information and Disclosures (pages 5 to 14) when you send your letter to Health Plans.
RE: Vascepa® (icosapent ethyl) Capsules, for oral use
Dear [Formulary Decision Maker],
I am the prescribing physician for patient [Name]. This patient has triglycerides (TGs) 135-499 mg/dL and other cardiovascular (CV) risk factors and requires VASCEPA as the most suitable therapy, based on the available evidence from clinical trials. For the reasons stated below [tailor points below to the patient-specific situation], in my medical judgment, other available TG-lowering products are not suitable for this patient.
1. Need to reduce cardiovascular (CV) events in patient with residual risk1
In the REDUCE-IT™ trial, VASCEPA was proven to reduce CV events:
o Primary composite endpoint demonstrated a highly statistically significant (P=0.00000001) 25% relative risk reduction (RRR) (4.8% absolute risk reduction [ARR]), with a number needed to treat (NNT) of 21 over 4.9 years
o Key secondary composite endpoint (3-point MACE of CV death, nonfatal myocardial infarction [MI], nonfatal stroke) demonstrated a highly statistically significant (P=0.0000006) 26% RRR (3.6% ARR) with an NNT of 28 over 4.9 years
o Significant reductions in prespecified secondary endpoints were also demonstrated, including a 20% reduction in CV death, 31% reduction in MI, and a 28% reduction in stroke
o The Food and Drug Administration (FDA) has not reviewed and opined on a supplemental new drug application related to REDUCE IT. FDA has thus not reviewed the information herein or determined whether to approve VASCEPA for use to reduce the risk of major adverse cardiovascular events in the REDUCE-IT patient population
o As with any cardiovascular outcomes trial result, further REDUCE-IT data assessment and data release could yield additional useful information to inform greater understanding of study outcome
o Overall adverse event (AE) rates were similar across treatment groups:
— Adverse events (AE) and serious adverse event (SAE) rates leading to study drug discontinuation were similar to placebo
— A single serious adverse event (SAE) occurred at a frequency of at least 2%, which was pneumonia (2.6% in the VASCEPA group and 2.9% in the placebo group, P=0.42)
o These adverse events (AE) occurred in ≥5% of VASCEPA patients and were statistically more frequent with VASCEPA than placebo:
— Peripheral edema occurred in 6.5% VASCEPA patients versus 5.0% placebo patients
— Constipation occurred in 5.4% VASCEPA patients versus 3.6% placebo patients
— Atrial fibrillation occurred in 5.3% VASCEPA patients versus 3.9% placebo patients but heart attack, cardiac arrest and sudden death each decreased in VASCEPA patients
o Regarding bleeding:
— The rate of treatment-emergent serious adverse events for bleeding was 2.7% in the VASCEPA group versus 2.1% in the placebo group, with a nonsignificant, but trending P-value of 0.06
2. Icosapent ethyl is recommended by the American Diabetes Association® (ADA) for cardiovascular (CV) risk reduction2
o The ADA 2019 Standards of Medical Care in Diabetes was updated following the results of REDUCE-IT™2
— REDUCE-IT was a CV outcomes trial that evaluated the effects of icosapent ethyl in statin-treated adults with well-controlled low-density lipoprotein cholesterol (LDL-C) and CV risk factors including TG ≥ 135 mg/dL and either established cardiovascular disease (CVD) or diabetes and other risk factors1
o Based on the primary and secondary prevention results of REDUCE-IT, the Standards of Care now include the following:
— The ADA Standards of Care give icosapent ethyl level “A” TOP TIER recommendation
· For CV risk reduction, consider icosapent ethyl, marketed as VASCEPA, for patients with diabetes and atherosclerotic cardiovascular disease (ASCVD) or other CV risk factors on a statin with controlled LDL-C and elevated triglycerides (135-499 mg/dL)1,2
· “It should be noted that data are lacking with other omega-3 fatty acids, and results of the REDUCE-IT trial should not be extrapolated to other products”2
o Combination therapy (statin/fibrate) has not been shown to improve atherosclerotic cardiovascular disease outcomes and is generally not recommended2
o Fenofibrates and VASCEPA are not FDA-approved for co-administration with statins to affect lipid, lipoprotein, or inflammation parameters with the aim of reducing CV mortality or morbidity
o No head-to-head, randomized, well-controlled studies have been conducted to compare the effects of VASCEPA with other FDA-approved TG-lowering therapies
o The complete, annotated Standards of Care, which includes the recent updated findings, can be accessed online on Diabetes Care. The Abridged Standards of Medical Care in Diabetes have also been updated and can be accessed online on Clinical Diabetes
o The Food and Drug Administration (FDA) has not reviewed and opined on a supplemental new drug application related to REDUCE-IT. The FDA has thus not reviewed the information herein or determined whether to approve VASCEPA for use to reduce the risk of major adverse CV events in the REDUCE-IT patient population
o As with any CV outcomes trial result, further REDUCE-IT data assessment and data release could yield additional useful information to inform greater understanding of study outcome
3. Fenofibrates are inappropriate
o Fibrates have been shown to increase LDL-C (“bad” cholesterol) by approximately 45% in some patients with very high triglyceride (VHTG) levels—complicating efforts to improve overall lipid health and requiring added or stronger-dose statin intervention in eligible patients3
o Side effects reported for fenofibrate include serious conditions such as myopathy (e.g., muscle weakness), cholelithiasis (i.e., gallstones) and rhabdomyolysis (i.e., muscle breakdown that can result in kidney damage)—the muscle-related risks may be increased when taken with a statin, which patients with persistent high TGs may require. Myopathy and rhabdomyolysis have been reported in patients taking fenofibrate. The risks for myopathy and rhabdomyolysis are increased when fibrates are co-administered with a statin, particularly in elderly patients and patients with diabetes, renal failure, or hypothyroidism3
o In April of 2015, the FDA removed the following indication from the Trilipix® package insert (PI): Trilipix is indicated as an adjunct to diet in combination with a statin to reduce TG and increase HDL-C in patients with mixed dyslipidemia and CHD (coronary heart disease) or a CHD risk equivalent who are on optimal statin therapy to achieve their LDL-C goal4
o In addition, in April 2016, the FDA announced the removal of the indication for co-therapy with statin from all generic Trilipix products. The reason the Agency gave was that the “FDA has determined that the benefits of niacin ER tablets and fenofibric acid DR capsules for coadministration with statins no longer outweigh the risks, and the approvals for this indication should be withdrawn”4
o Fenofibrate is not indicated or approved for concomitant or adjunctive use with a statin4
o For the reasons listed above, fenofibrates are not, in my opinion, the most appropriate therapy for this patient
o Fenofibrates, niacin, and VASCEPA are not FDA-approved for co-administration with statins to affect lipid, lipoprotein, or inflammation parameters with the aim of reducing CV mortality or morbidity
o No head-to-head, randomized, well-controlled studies have been conducted to compare the effects of VASCEPA with other FDA-approved TG-lowering therapies
4. Docosahexaenoic acid (DHA)-containing omega-3 combination products are inappropriate
o DHA-containing omega-3 combination products do not currently have cardiovascular (CV) outcomes trials showing reduction in CV events5
o DHA-containing omega-3 agents tend to increase levels of LDL-C in some patients with VHTG, by approximately 45%5
o An article published in March 2018 in JAMA titled “Associations of Omega-3 Fatty Acid Supplement Use With Cardiovascular Disease Risks” reported that most of the studies included in this meta-analysis utilized mixed EPA and DHA omega-3 products administered daily at a low dose, and were not positive, including prescription therapy and dietary supplements6
o The ASCEND trial, which used Lovaza® (named Omacor in Europe)—a prescription omega- 3 mixture of EPA, DHA, and other ingredients—administered at a low dose of 1 gram/day in the omega-3 arms of the study, did not find a reduction of serious vascular events in patients with diabetes and without diagnosed CV disease7
o Similar analysis has been conducted and published by other sources, including the Cochrane review.8 Failed results with omega-3 mixtures on top of statin therapy was again demonstrated in the results of the VITAL study published in November 2018 in the NEJM—in which Lovaza again failed to demonstrate CV benefit9
For the reasons listed above, DHA-containing omega-3 combination products, including omega-3-acid ethyl esters, are not, in my medical opinion, the most appropriate therapy for this patient.
5. Fish oil dietary supplements are inappropriate
o As reflected in the Orange Book (www.fda.gov/cder/ob), there are no FDA-approved “OTC” omega-3 dietary supplements available to treat medical conditions10
o Dietary supplements are not regulated as drugs by the FDA; they are regulated as food. Therefore, supplements do not have to meet stringent FDA drug standards, and the FDA does not review any clinical trial data before supplements are sold to patients making any omega-3 supplement efficacy claims regarding lowering triglycerides unverified10
o The quantity and quality of ingredients in omega-3 dietary supplements are reported to be highly variable.10 Top-selling supplements contain only ~30% omega-3,11 and many contain lower omega-3 amounts than specified on the label.12 Many supplements contain DHA, which has the potential to raise LDL-C levels in some patients.13,14 Remaining ingredients are unknown/uncharacterized on the label,11,15 and some supplements may contain up to one-third saturated fat.12 In addition, if fish oil is exposed to air during poor manufacturing conditions, it may oxidize16
o There is a significant pill burden to attempt to achieve 4 grams of EPA. Given that the most commonly sold omega-3 dietary supplements are only ~30% omega-3, patients would need to
ingest 10 or more capsules per day to achieve the equivalent 4 grams of pure EPA found in one daily dose of prescription VASCEPA11,13
o The health benefits of dietary supplements are unproven. Dietary supplements may contain oxidized components that interfere with their potential biological benefits13
o Organizations such as the American Diabetes Association, American Society of Health-System Pharmacists, and American Association of Clinical Endocrinologists do not recommend omega-3 supplements to treat disease17-19
For the reasons listed above, omega-3 dietary supplements are not, in my medical opinion, the most appropriate therapy for this patient.
6. Extended-release (ER) niacin and ER niacin-statin combinations are inappropriate
o Although it can be used for the treatment of persistent high TGs, the tolerability profile of this class of products may make it difficult for compliance and meaningful clinical use20
o In April of 2015, the FDA removed the following indication from the Niaspan® PI:
— Niaspan in combination with simvastatin or lovastatin is indicated for the treatment of primary hyperlipidemia (heterozygous familial and nonfamilial) and mixed dyslipidemia (Fredrickson Types Ila and Ilb) when treatment with Niaspan, simvastatin, or lovastatin monotherapy is considered inadequate4
o In addition, in April 2016, the FDA announced the removal of the indication for co-therapy with statin from all generic Niaspan products. The reason the Agency gave was that the “FDA has determined that the benefits of niacin ER tablets and fenofibric acid DR capsules for coadministration with statins no longer outweigh the risks, and the approvals for this indication should be withdrawn”4
o Further, in April 2016, the FDA publicly announced that Advicor® & Simcor® (niacin XR + lovastatin and niacin XR + simvastatin, respectively) have also been removed from the market. In an entry published within the Federal Register, the FDA stated that it has determined that “benefits of ADVICOR and SIMCOR no longer outweigh the risks, and approval should be withdrawn”21
For the reasons listed above, Niacin is not, in my medical opinion, the most appropriate therapy for this patient.
7. VASCEPA use in combination with statins is desirable therapy for this patient
o [60%] [please update percent to your practice] or more of my patients are started on a statin to control their LDL-C levels. When TG levels are at a level studied in REDUCE-IT (135-499 mg/dL), I want to add VASCEPA to help address residual CV event risk beyond cholesterol management1
8. Request to remove prior authorization requirement
o I am sensitive to formulary prior authorization restrictions, as they create more work for myself and my staff, which decreases quality time spent with patients. That said, as a physician, I believe that patients with TG levels 135-499 mg/dL be allowed prescription VASCEPA therapy with the least possible restrictions. There is no AB-Rated alternative for VASCEPA
Please see Indication, Limitations of Use, ISI, additional Important Information for Healthcare Professionals, and a synopsis of the REDUCE-IT study attached. Additionally, going forward, I would recommend that VASCEPA be included in Tier-2 formulary coverage with no restrictions in order to support patient-care options and reduce the potential need for increased statin dose.
I appreciate your consideration to approve my request for [Name].
Please contact me at [xxx-xxxx] if I can be of further assistance.
Sincerely,
[PHYSICIAN NAME
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