For decades, statins have been used for the treatment of hyperlipidemia
and prevention of primary and secondary cardiovascular events.1
Nearly one-third (31.8%) of individuals 55 to 64 years of age use
prescription cholesterol-lowering medications, most commonly statins.
Many of these individuals are also being treated for other conditions.2,3
As such, there is widespread use of statins in patients taking multiple
medications, and it is therefore important to consider the possible
risks involved in polypharmacy, including the potential for clinically
relevant drug interactions between statins and concomitant medications.
Pharmacologic Basis for Statin-Related Interactions
Of all medications metabolized, approximately 3 out of every 4 rely on
the cytochrome P450 isoenzymes for metabolism, and approximately half
of these rely on CYP3A4/5 isoenzymes.4,5 Because many commonly used statins rely on this same metabolic pathway,4,6
use of a statin with medications that inhibit isoenzymes such as CYP3A4
may lead to supratherapeutic statin levels and may increase the risk of
statin-related adverse events, such as myalgia, myositis, and, in rare
cases, rhabdomyolysis.7,8
The FDA released a public safety announcement highlighting this risk
for those statins that are sensitive in vivo cytochrome P450 3A4
(CYP3A4) substrates. Regarding other medications metabolized, strong
CYP3A4 inhibitors are predicted to significantly increase overall
exposures to certain statins. For example, itraconazole, a strong CYP3A4
inhibitor, increases maximal concentrations of simvastatin up to
13-fold and lovastatin exposure up to 20-fold, with the potential
interaction to result in rhabdomyolysis.9 Hence, other CYP3A4
inhibitors may significantly increase lovastatin and simvastatin
exposures based on metabolic dependency on the CYP450 system. Statins
may also inhibit CYP3A4, exposing patients to supratherapeutic levels of
other medications.4,7
Key Statin-Related Interactions
Pursuant to an FDA safety advisory communication released in 2011, restrictions, limitations, and contraindications were added to the labeling of simvastatin and simvastatin-containing agents. A later FDA communication, released in 2012, advised against use of statins in combination with human immunodeficiency virus or hepatitis C protease inhibitors (Table 19). Following these communications, the FDA added several contraindications and dose restrictions to the labeling of many statins (Table 210).9-11 Additionally, for patients taking commonly prescribed antihypertensive medications, the dose of simvastatin must be limited. Patients taking verapamil or diltiazem should take no more than 10 mg of simvastatin daily, and in patients taking amlodipine, simvastatin should not be administered at a dosage greater than 20 mg daily.11 Use of simvastatin or rosuvastatin with warfarin may affect coagulation parameters, such as prothrombin time (PT) and international normalized ratio (INR), further complicating therapy.11,12
Pursuant to an FDA safety advisory communication released in 2011, restrictions, limitations, and contraindications were added to the labeling of simvastatin and simvastatin-containing agents. A later FDA communication, released in 2012, advised against use of statins in combination with human immunodeficiency virus or hepatitis C protease inhibitors (Table 19). Following these communications, the FDA added several contraindications and dose restrictions to the labeling of many statins (Table 210).9-11 Additionally, for patients taking commonly prescribed antihypertensive medications, the dose of simvastatin must be limited. Patients taking verapamil or diltiazem should take no more than 10 mg of simvastatin daily, and in patients taking amlodipine, simvastatin should not be administered at a dosage greater than 20 mg daily.11 Use of simvastatin or rosuvastatin with warfarin may affect coagulation parameters, such as prothrombin time (PT) and international normalized ratio (INR), further complicating therapy.11,12
Unlike most other statins, pitavastatin (Livalo) is only minimally
metabolized by the CYP450 system, has no clinically relevant
interactions with strong CYP3A4 inhibitors, has no contraindication,
restriction or limitation in patients taking protease inhibitors, and
does not significantly affect coagulation parameters (ie, PT/ INR) in
patients taking warfarin.4,13 It has no dose-limitation
restriction when used with calcium channel blockers. Key clinically
relevant drug interactions with pitavastatin include a contraindication
for use with cyclosporine and limitation of the pitavastatin dose to 1
mg daily in patients taking erythromycin. As with other statins, due to
classwide effects, fibrates, niacin (≥1 gram daily), and colchicine
should be used with caution, and gemfibrozil should be avoided.13
Assessing Statin-Related Interactions
In the largest Internet-based survey to date on statin use, of more
than 10,000 individuals, which included 1220 former statin users and
8919 current statin users, drug interactions that involved statins
occurred in more than 8 of every 10 respondents (84%). For each
participant with an interaction, an average of 3 other products
interacted with the statin, including prescription medications, OTC
products, and dietary supplements. Nearly three-fourths (74%) of these
respondents never spoke with their physician about the possibility of
these drug interactions.6
Although a causal relationship between drug interactions and adverse
events (AEs) leading to treatment discontinuation was not evaluated in
this survey, in this population of patients with unaddressed drug
interactions, 1 of 4 current statin users and more than half (60%) of
former users reported experiencing muscle-related AEs. In former statin
users, AEs, including muscle pain and weakness, were responsible for
nearly two-thirds (62%) of statin discontinuations.6
Considering that patients prescribed statins who do not take them have
nearly 3 times greater mortality risk than patients who take statins as
prescribed, treatment discontinuation may have important clinical
consequences.14 In the modern treatment era, statins with
fewer drug interactions are available; they are worth consideration
because their interaction burden is lower than other medications in this
class while still providing potent efficacy.4
Role of the Pharmacist
In addition to advising and counseling patients about the importance
of adherence to statin therapy to reduce the risk of negative
cardiovascular outcomes, pharmacists are instrumental in recognizing and
managing drug interactions to achieve treatment regimen harmonization
for patients. To achieve this desirable end, pharmacists should not only
alert prescribers to drug interactions, but also provide
recommendations for alternative therapy to help resolve these drug
interactions whenever possible.
In discussing these interactions with prescribers, rather than focusing only on the increased risk of rhabdomyolysis with statins and interacting medications, pharmacists should emphasize the risk of drug interactions leading to statin-related AEs and statin discontinuation. Approximately 8 in 10 patients taking statins are using an average of 3 interacting medications. These interactions may increase the risk of AEs such as myalgia, weakness, myositis, and myopathy.6,7 Harmonizing treatment regimens may help patients continue taking statins. By applying their specialized knowledge about the subtle but clinically significant differences between individual statins, pharmacists can help align patients with the most appropriate statin and associated dose to help achieve improved long-term outcomes.
In discussing these interactions with prescribers, rather than focusing only on the increased risk of rhabdomyolysis with statins and interacting medications, pharmacists should emphasize the risk of drug interactions leading to statin-related AEs and statin discontinuation. Approximately 8 in 10 patients taking statins are using an average of 3 interacting medications. These interactions may increase the risk of AEs such as myalgia, weakness, myositis, and myopathy.6,7 Harmonizing treatment regimens may help patients continue taking statins. By applying their specialized knowledge about the subtle but clinically significant differences between individual statins, pharmacists can help align patients with the most appropriate statin and associated dose to help achieve improved long-term outcomes.
INDICATIONS AND USAGE
Drug therapy should be one component of multiple-risk-factor intervention in individuals who require modifications of their lipid profile. Lipid-altering agents should be used in addition to a diet restricted in saturated fat and cholesterol only when the response to diet and other nonpharmacological measures has been inadequate.
PRIMARY HYPERLIPIDEMIA AND MIXED DYSLIPIDEMIA
LIVALO (pitavastatin) is indicated as an adjunctive therapy to diet to reduce elevated total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), apolipoprotein B (Apo B), triglycerides (TG), and to increase high-density lipoprotein cholesterol (HDL-C) in adult patients with primary hyperlipidemia or mixed dyslipidemia.
LIMITATIONS OF USE
- Doses of LIVALO greater than 4 mg once daily were associated with an increased risk for severe myopathy in premarketing clinical studies. Do not exceed 4-mg, once-daily dosing of LIVALO
- The effect of LIVALO on cardiovascular morbidity and mortality has not been determined
- LIVALO has not been studied in Fredrickson Type I, III, and V dyslipidemias
CONTRAINDICATIONS
LIVALO is contraindicated in patients with a known hypersensitivity to product components, in patients with active liver disease (which may include unexplained persistent elevations in hepatic transaminase levels), in women who are pregnant or may become pregnant, in nursing mothers, or in co-administration with cyclosporine.
WARNINGS AND PRECAUTIONS
Skeletal Muscle Effects
Cases of myopathy and rhabdomyolysis with acute renal failure secondary to myoglobinuria have been reported with HMG-CoA reductase inhibitors, including LIVALO. These risks can occur at any dose level, but increase in a dose-dependent manner.
- LIVALO should be prescribed with caution in patients with predisposing factors for myopathy.
- The risk of skeletal muscle effects (e.g., myopathy and rhabdomyolysis) increases in a dose-dependent manner with advanced age (≥65 years), renal impairment, inadequately treated hypothyroidism, and in combination use with fibrates or lipid-modifying doses of niacin (≥1 g/day).
- LIVALO should be administered with caution in patients with impaired renal function, in elderly patients, or when used concomitantly with fibrates or lipid-modifying doses of niacin.
- Concomitant administration of LIVALO with gemfibrozil should be avoided.
- LIVALO therapy should be discontinued if markedly elevated CK levels occur or myopathy is diagnosed or suspected. LIVALO therapy should also be temporarily withheld in any patient with an acute, serious condition suggestive of myopathy or predisposing to the development of renal failure secondary to rhabdomyolysis (e.g., sepsis; hypotension; dehydration; major surgery; trauma; severe metabolic, endocrine, and electrolyte disorders; or uncontrolled seizures).
- Advise patients to promptly report unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever, and to discontinue LIVALO if these signs or symptoms appear.
- Cases of myopathy, including rhabdomyolysis, have been reported with HMG-CoA reductase inhibitors coadministered with colchicine, and caution should be exercised when prescribing LIVALO with colchicine
- There have been rare reports of immune-mediated necrotizing myopathy (IMNM), an autoimmune myopathy, associated with statin use. IMNM is characterized by: proximal muscle weakness and elevated serum creatine kinase, which persist despite discontinuation of statin treatment; muscle biopsy showing necrotizing myopathy without significant inflammation; improvement with immunosuppressive agents. IMNM has not been reported with LIVALO therapy.
- Advise patients to promptly report if muscle signs and symptoms persist after discontinuing LIVALO as this may be a sign of IMNM requiring immediate medical attention.
Increases in serum transaminases have been reported with HMG-CoA reductase inhibitors, including LIVALO.
- It is recommended that liver enzyme tests be performed before the initiation of LIVALO and if signs or symptoms of liver injury occur.
- There have been rare postmarketing reports of fatal and non-fatal hepatic failure in patients taking statins, including pitavastatin. If serious liver injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs during treatment with LIVALO, promptly interrupt therapy. If an alternate etiology is not found do not restart LIVALO.
- Advise patients to promptly report any symptoms that may indicate liver injury, including fatigue, anorexia, right upper abdominal discomfort, dark urine or jaundice.
- LIVALO should be used with caution in patients who consume substantial quantities of alcohol and/or have a history of chronic liver disease.
Increases in HbA1c and fasting serum glucose levels have been reported with HMG-CoA reductase inhibitors, including LIVALO.
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