How to Safely Stop Praluent (Alirocumab): Discontinuation Protocol

Does Praluent need to be tapered?

The labeled dosing options step up rather than down: 75 mg every 2 weeks or 300 mg every 4 weeks to start in adults, with 150 mg every 2 weeks if the LDL-C response is inadequate [1]. No smaller doses or longer intervals are described for winding treatment down.

The label reports a median apparent half-life at steady state of 17 to 20 days, with two elimination phases: saturable binding to PCSK9 at low concentrations, and non-saturable proteolysis at higher concentrations [1]. Alirocumab is a protein expected to degrade to small peptides and individual amino acids, and no specific metabolism studies were conducted [1].

In ODYSSEY OUTCOMES, the alirocumab dose was adjusted under blinded conditions toward an LDL-C target of 25 to 50 mg/dL [3]. In the label's account, 2,615 Praluent-treated patients (27.7%) had their dose increased to 150 mg every 2 weeks, and 805 of them later had it reduced [1]. In the same trial, 730 Praluent-treated patients (7.7%) were switched to placebo after two LDL-C measurements below 15 mg/dL; this was a trial rule for very low LDL-C [1].

What the label says about stopping

If signs or symptoms of serious hypersensitivity reactions occur, the label says to discontinue treatment with Praluent, treat according to the standard of care, and monitor until signs and symptoms resolve [1]. A history of a serious hypersensitivity reaction to alirocumab or any excipient is a contraindication [1]. The label carries no boxed warning [1].

The label also reports patients who stopped treatment in trials because of allergic reactions, elevated liver enzymes and injection site reactions (rates are in the side effects section below) [1].

For a missed dose, the label says that within 7 days you give the dose and resume the usual schedule. If it is later than 7 days, wait for the next dose on the every-2-week schedule, or give the dose and start a new schedule on the every-4-week schedule [1].

How long alirocumab stays in the body

After a subcutaneous dose of 75 to 300 mg, peak concentrations arrive in 3 to 7 days and absolute bioavailability is about 85%; steady state is reached after 2 to 3 doses, with accumulation up to about 2-fold [1]. Free PCSK9 is maximally suppressed within 4 to 8 hours of a single 75 or 150 mg dose and returns to baseline when alirocumab concentrations drop below the limit of quantitation [1]. The median apparent half-life at steady state is 17 to 20 days [1].

How does Praluent lower LDL-C?

Alirocumab binds PCSK9, the protein that promotes degradation of LDL receptors on the surface of hepatocytes. Blocking that binding increases the number of receptors available to clear LDL, which lowers LDL-C [1]. The pharmacodynamic data show free PCSK9 returning to baseline once alirocumab is no longer measurable [1].

What the label says about checking LDL-C

The label says to assess LDL-C when clinically appropriate, and the LDL-lowering effect may be measured as early as 4 weeks after starting [1]. On the 300 mg every 4 weeks regimen, LDL-C is measured just before the next scheduled dose because it can vary between doses in some patients [1].

What the outcomes trial measured

ODYSSEY OUTCOMES compared continued alirocumab with placebo; it was not designed to test stopping. It enrolled 18,924 adults who had an acute coronary syndrome 1 to 12 months earlier, with LDL-C of at least 70 mg/dL (or non-HDL-C of at least 100 mg/dL, or apolipoprotein B of at least 80 mg/dL) on a high-intensity or maximally tolerated statin; mean baseline LDL-C was 92.4 mg/dL [3]. Over a median 2.8 years, the primary composite of coronary heart disease death, non-fatal myocardial infarction, ischemic stroke or unstable angina requiring hospitalization occurred in 903 patients (9.5%) on alirocumab versus 1,052 (11.1%) on placebo, HR 0.85 (95% CI 0.78 to 0.93) [3][1]. All-cause death was 3.5% versus 4.1% (HR 0.85, 0.73 to 0.98) and was not statistically significant under the trial's pre-specified method for controlling type I error [1][3].

In ODYSSEY LONG TERM (2,341 high-risk patients, 150 mg every 2 weeks versus placebo, 2:1, for 78 weeks), the difference between the alirocumab and placebo groups in mean percentage change in calculated LDL-C at week 24 was minus 62 percentage points [4].

Side effects that lead to stopping in the first place

In nine placebo-controlled hypercholesterolemia trials (2,476 patients on Praluent 75 or 150 mg every 2 weeks for a median of 65 weeks versus 1,276 on placebo), adverse reactions led to discontinuation in 5.3% versus 5.1%; the leading causes were allergic reactions (0.6% versus 0.2%) and elevated liver enzymes (0.3% versus under 0.1%) [1]. Injection site reactions were 7% versus 5%, and influenza 6% versus 5% [1]. Hypersensitivity reactions overall were 8.6% versus 7.8%, with pruritus the most common at 1.1% versus 0.4% [1]. In ODYSSEY OUTCOMES, injection site reactions led to permanent discontinuation in 0.3% versus under 0.1% [1].