Rosuvastatin

Mechanism of Action

The mechanism of action of rosuvastatin is inhibition of 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase. This enzyme is the rate-limiting step in cholesterol synthesis, which reduces the production of mevalonic acid from HMG-CoA. Furthermore, this results in an increase of low-density lipoprotein receptors on hepatocyte membranes and stimulation of low-density lipoprotein catabolism. HMG-CoA reductase inhibitors also decrease levels of high sensitivity C-reactive protein (CRP). They also possess pleiotropic properties, including inhibition of platelet aggregation, anticoagulant effects, reduced inflammation at the site of a coronary plaque, and improved endothelial function.[1][2]

Rosuvastatin is not extensively metabolized, with approximately 10% of a radiolabeled dose being recoverable as a metabolite. The pharmacokinetic properties of statin medications vary; however, rosuvastatin is unique in that its half-life is 19 hours, bioavailability is 20%, protein binding is 88%, possesses hydrophilic solubility, metabolized by CYP2C9, and primarily fecally excreted (90%) with only 10% urinary excretion.[3]

Administration

The administration of rosuvastatin is via capsule or tablet. The capsule can be administered orally or via a nasogastric tube. The oral route can be taken with or without food, at any time of the day, and should be swallowed whole. The capsule should never be crushed or chewed. If opening the capsule, it is recommended to empty the contents into one teaspoonful of applesauce and then swallowed immediately without chewing.

For administration with a nasogastric tube, the capsule can be opened, emptied into a 60 ml catheter-tipped syringe. The recommendation is to add 40 milliliters of water, replace the plunge, shake the syringe for 15 seconds. Then attach the syringe to at least a 16 French nasogastric tube and administer with an additional flush of the tube with 20 milliliters of water. The mixture needs to be used promptly after preparation.

Dosage for the oral tablet is the same for the generic and trade name:

• 5 mg, 10 mg, 20 mg, 40 mg

Dosage recommendations: Dosing is individualized based on the low-density lipoprotein (LDL) levels at baseline and the goal of therapy. The patient’s response and medication adherence is an important determinant of therapeutic success. Adjustments should be made at a regular interval of four weeks or more depending on the underlying pathology of the disease and whether the treatment is for primary versus secondary prevention. Due to the risk of significant drug-drug interactions, the adjustment in dosing should be part of medication reconciliation with the current literature and a pharmacist. In renal impairment, if the creatinine clearance is greater or equal to 30 ml/minute, then no dosage adjustment is necessary; however, if lower than this cutoff, the recommendation is to start the lowest possible dose of 5 mg once daily with a maximum dosage of 10 mg per day.

Adverse Effects

Clinically Relevant Adverse Effects[4]

• Creatinine kinase of greater than ten times the upper limit of normal
• Severe myopathy
• Rhabdomyolysis
• AST or ALT elevations of greater than three times the upper limit of normal
• Renal failure

Rare adverse effects include diabetes mellitus, hematuria, proteinuria, and hypersensitivity.

Other reported symptomatic adverse effects include headache, dizziness, nausea, constipation, interstitial cystitis, arthralgia, and weakness.

Drug-Drug Interactions:

1. The following medications may enhance the myopathic effect of rosuvastatin: acipimox, bezafibrate, ciprofibrate, colchicine, daptomycin, fenofibrate, fusidic acid, gemfibrozil, niacin, niacinamide, raltegravir, red yeast rice, rupatadine.
2. The following medications may decrease the serum concentration of rosuvastatin: antacids, apalutamide, elagolix, eslicarbazepine.
3. The following medications may increase the serum concentrations of rosuvastatin: asunaprevir, clopidogrel, cobicistat, cyclosporine, daclatasvir, dasabuvir, dronedarone, elbasvir, eltrombopag, eluxadoline, fostamatinib, glecaprevir, pibrentasvir, grazoprevir, itraconazole, ledipasvir, letermovir, ombitasvir, paritaprevir, ritonavir, osimertinib, protease inhibitors, simeprevir, teriflunomide, velpatasvir, voxilaprevir.

Contraindications

As with many drugs, if the patient has a hypersensitivity to rosuvastatin or any component of the drug formulation, they must discontinue the drug. Other contraindications are listed below[5][6]: 

• Pregnancy (pregnancy category X)
• There are reports of congenital anomalies
• Breastfeeding
• Active liver disease
• Unexplained persistent elevations of serum transaminases

Monitoring

The following monitoring parameters are from the American College of Cardiology and the American Heart Association Cholesterol Guideline Recommendations.[7]

Creatinine phosphokinase (CPK) levels should not be routinely measured; however, the clinician can base special considerations for measuring CPK on family history of statin intolerance, drug-drug interactions leading to increased risk of myopathy, or other clinical presentations that create a high index of suspicion of myopathy.

Aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase, and total bilirubin levels do not need to be measured routinely. Only if symptoms suggest underlying hepatotoxicity during therapy, it may be beneficial to obtain these levels.

Lipid panel testing, including low-density lipoprotein, high-density lipoprotein, triglycerides, and total cholesterol, should be obtained on an initial visit to establish a baseline. Thereafter, a fasting lipid profile should be obtained within four to twelve weeks after initiation or dose adjustment. Furthermore, after receiving these initial two levels, further fasting lipid profiles are only necessary every three to twelve months or as clinically indicated. If two consecutive low-density lipoprotein levels are less than 40 milligrams per deciliter, the clinician should decrease the dose.

Toxicity

The most common toxic side effect of rosuvastatin is myalgia. If the patient has mild to moderate muscle symptoms, the drug should be discontinued to evaluate other causes of myalgia. If there is a resolution of the underlying etiology, the patient can restart the original or a lower dose of rosuvastatin; however, if symptoms reoccur for a second time, then discontinue rosuvastatin indefinitely. Switching to a different statin medication at a lower dose may relieve muscle symptoms.

It is clear that if severe muscle symptoms or fatigue occur, the provider should discontinue the medication and order a creatinine phosphokinase level, serum creatinine, and a urinalysis to evaluate for myoglobinuria.

Enhancing Healthcare Team Outcomes

Rosuvastatin is a widely used medication for serum lipid-lowering. The drug is known to be effective for elevated lipid levels and the prevention of cardiovascular disease. Prescribing and monitoring the patient will require interprofessional collaboration and communication between the clinicians (including NPs and PAs), pharmacists, nursing staff, and other subspecialties such as cardiologists who may have a role in adjusting the dosage of the medication. Monitoring for the effect of the drug and dose adjustment is best accomplished via an interprofessional approach, although it is manageable by a single provider. The drug does have multiple drug-drug interactions; therefore, it is helpful for pharmacists to check and flag any interactions. If any drug-drug interactions are present, the pharmacist must notify the provider immediately. Nursing also bears responsibility for monitoring for adverse reactions, helping assess therapeutic effectiveness, offering counsel to the patient, and serving as a liaison between the pharmacist and other providers and the prescriber. The prescribing provider should determine the risks versus benefits of the medication in conjunction with the patient after an informed consent discussion with shared decision making. Only with a collaborative interprofessional team approach can rosuvastatin therapy be optimized to deliver the appropriate therapeutic results for the patient. [Level 5]