Praluent (Alirocumab): What to Expect Week by Week in Your First Month

Week 1: The First Injection and the First Few Days

Praluent is injected under the skin. Adults with hypercholesterolemia, including heterozygous familial hypercholesterolemia (HeFH), start at either 75 mg every 2 weeks or 300 mg every 4 weeks [1]. The 300 mg dose is not one large shot: it is two consecutive 150 mg injections at two different sites [1]. Adults with homozygous familial hypercholesterolemia (HoFH), or with HeFH who are undergoing LDL apheresis, are dosed at 150 mg every 2 weeks, and the injection can be given without regard to the timing of apheresis [1]. Children 8 and older with HeFH use weight-based dosing: 150 mg every 4 weeks under 50 kg, or 300 mg every 4 weeks at 50 kg or more [1].

The label says to let the pen warm to room temperature for 30 to 40 minutes before injecting, and that the injection itself can take up to 20 seconds [1]. Praluent comes in 75 mg/mL and 150 mg/mL strengths as prefilled pens, and the pen's needle shield is not made with natural rubber latex [1][2].

What happens inside the first hours

Alirocumab is a human monoclonal antibody that binds PCSK9. PCSK9 binds LDL receptors on hepatocytes and promotes their degradation in the liver; blocking that binding increases the number of LDL receptors available to clear LDL, which lowers LDL-C [1]. After a single 75 mg or 150 mg dose, maximal suppression of free PCSK9 occurred within 4 to 8 hours [1]. Blood levels peak at a median of 3 to 7 days, and absolute bioavailability after a subcutaneous dose is about 85% [1].

The earliest checkpoint the label names is the lab: the LDL-lowering effect may be measured as early as 4 weeks after starting [1].

What you may notice at the injection site

In nine placebo-controlled trials covering 2,476 adults on 75 mg or 150 mg every 2 weeks (median treatment 65 weeks), injection-site reactions (redness, itching, swelling, pain or tenderness) were reported in 7% versus 5% on placebo [1]. A separate pooled analysis put them at 7.2% versus 5.1%, with few discontinuations for that reason (0.2% versus 0.4%) [1].

Hypersensitivity reactions as a group were reported in 8.6% versus 7.8% on placebo, with itching the most common single reaction (1.1% versus 0.4%); allergic reactions led to discontinuation in 0.6% versus 0.2% [1].

The one serious reaction the label warns about

Hypersensitivity reactions are the only Warning and Precaution in the Praluent label [1]. Hypersensitivity vasculitis, angioedema, and hypersensitivity reactions requiring hospitalization have been reported [1]. The label says that if signs or symptoms of a serious hypersensitivity reaction occur, treatment should be discontinued, treated according to standard of care, and monitored until signs and symptoms resolve [1]. A history of a serious hypersensitivity reaction to alirocumab or to an excipient in Praluent is a contraindication [1].

Week 2: The Second Dose

On every-2-week dosing, week 2 is the second injection. Steady state is reached after 2 to 3 doses, with an accumulation ratio of up to about 2-fold, and the median apparent half-life at steady state is 17 to 20 days [1]. The first two or three injections are therefore still building toward steady state.

For a missed dose, the label directs that within 7 days of the missed dose, the dose is given and the usual schedule resumed. After more than 7 days, on the every-2-week schedule the label says to wait for the next dose; on the every-4-week schedule it says to give the dose and start a new schedule [1].

On 300 mg every 4 weeks there is no week-2 injection: both 150 mg injections are given on the same day, every 4 weeks [1].

Week 3: Between Doses

Praluent remains in the body between doses during week 3. The label says LDL-C can be assessed when clinically appropriate, and that its lowering effect may be measured as early as week 4 [1].

One specific instruction applies to 300 mg every 4 weeks: the label says to measure LDL-C just before the next scheduled dose, because LDL-C can vary between doses in some patients [1]. That places the measurement at the end of the dosing interval.

Week 4: Your First Lipid Panel

By week 4, Praluent's LDL-lowering effect may be measurable [1]. The week-24 figures from the trials show where the response ends up. In the label's analysis of ODYSSEY LONG TERM (788 on placebo, 1,553 on 150 mg every 2 weeks), alirocumab produced a mean 58% reduction in LDL-C from baseline at week 24, a difference from placebo of -58 percentage points (95% CI -61 to -56) [1]. The published report of that trial, which randomized 2,341 high-risk patients on maximally tolerated statins to alirocumab 150 mg every 2 weeks or placebo for 78 weeks, gave a difference of -62 percentage points at week 24 [3].

A week-4 result is therefore an early reading, not the week-24 result. The label says that if the LDL-C response is inadequate, the dosage may be adjusted to 150 mg every 2 weeks [1].

Side Effects: What the Trials Counted

In the nine placebo-controlled trials (2,476 adults on 75 or 150 mg every 2 weeks versus 1,276 on placebo) [1]:

• Injection-site reactions: 7% versus 5%
• Influenza: 6% versus 5%
• Diarrhea: 5% versus 4%
• Myalgia: 4% versus 3%
• Muscle spasms: 3% versus 2%
• Contusion: 2% versus 1%

Treatment was discontinued in 5.3% of patients on Praluent and 5.1% on placebo; the leading causes were allergic reactions (0.6% versus 0.2%) and elevated liver enzymes (0.3% versus under 0.1%) [1]. Liver-related disorders were reported in 2.5% versus 1.8%, and transaminases above 3 times the upper limit of normal occurred in 1.7% versus 1.4% [1].

Dosing schedule matters at the injection site. In a 48-week trial comparing 300 mg every 4 weeks with 75 mg every 2 weeks and placebo, local injection-site reactions were reported in 16.6%, 9.6% and 7.9% respectively, and three patients (0.7%) on the 300 mg every-4-week regimen stopped treatment because of them [1].

In the cardiovascular outcomes trial, with 9,451 patients on Praluent for a median of 31 months, myalgia was reported in 6% versus 5% on placebo, and injection-site reactions in 3.8% versus 2.1%, leading to permanent discontinuation in 0.3% versus under 0.1% [1]. ODYSSEY LONG TERM reported injection-site reactions in 5.9% versus 4.2%, myalgia in 5.4% versus 2.9%, neurocognitive events in 1.2% versus 0.5%, and ophthalmologic events in 2.9% versus 1.9% [3].

On muscle symptoms specifically: ODYSSEY ALTERNATIVE enrolled statin-intolerant patients, and 361 entered a placebo run-in. Patients who continued were randomized (2:2:1) to alirocumab 75 mg every 2 weeks, ezetimibe 10 mg daily, or an atorvastatin 20 mg rechallenge for 24 weeks [4]. Skeletal muscle-related events were less frequent with alirocumab than with atorvastatin (hazard ratio 0.61, 95% CI 0.38 to 0.99) [4].

What the First Month Is For

ODYSSEY OUTCOMES enrolled 18,924 adults who had an acute coronary syndrome 1 to 12 months earlier and were on high-intensity or maximally tolerated statins, randomizing them to alirocumab 75 mg every 2 weeks (with blinded adjustment toward an LDL-C of 25 to 50 mg/dL) or placebo [5]. 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 on alirocumab (9.5%) versus 1,052 on placebo (11.1%), hazard ratio 0.85 (95% CI 0.78 to 0.93), p=0.0003 [1][5]. Ischemic stroke was 1.2% versus 1.6% (HR 0.73, 95% CI 0.57 to 0.93) [1].

All-cause death was 3.5% versus 4.1% (HR 0.85, 95% CI 0.73 to 0.98), but the label states this was not statistically significant under the trial's pre-specified method for controlling type I error [1]. The trial therefore did not establish a survival benefit.

That outcome benefit was measured over years, not weeks.

Statins, Other Drugs and Dose Adjustments

In clinical studies of alirocumab given with atorvastatin or rosuvastatin, there were no relevant changes in statin concentrations, indicating that CYP enzymes (mainly CYP3A4 and CYP2C9) and transporters such as P-gp and OATP were not affected by alirocumab [1]. Alirocumab is a protein and is expected to degrade to small peptides and amino acids; age, body weight, sex, race and creatinine clearance did not significantly affect its pharmacokinetics across 2,799 patients [1]. The label lists no dose adjustment for renal impairment or mild to moderate hepatic impairment [1].

On pregnancy, the label states that available human data are insufficient to evaluate a drug-associated risk [1]. In monkeys dosed from organogenesis to parturition, suppression of the humoral immune response was seen in infants at exposures 13 times the human exposure at 150 mg every 2 weeks, and it is unknown whether this occurs at clinical exposure [1].