Praluent Drug Information
Generic name: ALIROCUMAB
PCSK9 Inhibitor [EPC]
Uses of Praluent
- PRALUENT ® is indicated: To reduce the risk of major adverse cardiovascular (CV) events (coronary heart disease death, myocardial infarction, stroke, or unstable angina requiring hospitalization) in adults at increased risk for these events. As an adjunct to diet and exercise to reduce low- density lipoprotein cholesterol (LDL-C) in: adults with hypercholesterolemia. adults and pediatric patients aged 8 years and older with heterozygous familial hypercholesterolemia (HeFH). adults with homozygous familial hypercholesterolemia (HoFH).
Dosage & Administration of Praluent
Recommended Dosage in Pediatric Patients Aged 8 years and Older With HeFH The recommended dosage of PRALUENT for patients with a body weight less than 50 kg is 150 mg once every 4 weeks administered subcutaneously. If the LDL-C lowering response is inadequate, the dosage may be adjusted to 75 mg subcutaneously once every 2 weeks. The recommended dosage of PRALUENT for patients with a body weight of 50 kg or more is 300 mg once every 4 weeks administered subcutaneously.
Assess LDL-C when clinically appropriate. The LDL-lowering effect of PRALUENT may be measured as early as 4 weeks after initiation.
- Missed Doses If a dose is missed: Within 7 days from the missed dose, instruct the patient to administer PRALUENT and resume the patient's original schedule.
- More than 7 days after the missed dose: For every 2-week dosage, instruct the patient to wait until the next dose on the original schedule. For every 4-week dosage, instruct the patient to administer the dose and start a new schedule based on this date.
Important Administration Instructions
Train patients and/or caregivers on how to prepare and administer PRALUENT, according to the Instructions for Use and instruct them to read and follow the Instructions for Use each time they use PRALUENT. In children aged 12 to 17 years, it is recommended that PRALUENT be given by or under the supervision of an adult. In children aged 8 to 11 years, PRALUENT should be given by a caregiver.
Prior to use, allow PRALUENT to warm to room temperature for 30 to 40 minutes if PRALUENT has been refrigerated. Visually inspect PRALUENT prior to administration. PRALUENT is a clear, colorless to pale yellow solution.
Do not use if the solution is cloudy, discolored, or contains particles. Administer PRALUENT subcutaneously into areas of the thigh, abdomen, or upper arm that are not tender, bruised, red, or indurated. Rotate injection sites for each administration.
It may take up to 20 seconds to inject PRALUENT. To administer the 300 mg dose, give two 150 mg PRALUENT injections consecutively at two different injection sites.
Side Effects of Praluent
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Adverse reactions reported in at least 2% of PRALUENT-treated patients, and more frequently than in placebo-treated patients, are shown in Table 1. In an analysis of ezetimibe-controlled trials in which 864 patients were exposed to PRALUENT for a median of 27 weeks and 618 patients were exposed to ezetimibe for a median of 24 weeks, the types and frequencies of common adverse reactions were similar to those listed above.
Adverse Reactions in a Cardiovascular Outcomes Trial in Adults In a CV outcomes trial in which 9,451 patients were exposed to PRALUENT for a median of 31 months and 9,443 patients were exposed to placebo for a median of 32 months, common adverse reactions (greater than 5% of patients treated with PRALUENT and occurring more frequently than placebo) included myalgia (6% PRALUENT, 5% placebo). Adverse Reactions in Pediatric Patients with HeFH In a 24-week placebo-controlled clinical trial in which 101 pediatric patients aged 8 to 17 years with HeFH were exposed to PRALUENT and 52 pediatric patients with HeFH were exposed to placebo, the safety profile of PRALUENT observed in this population was consistent with the safety profile observed in adults with HeFH. Other Adverse Reactions Local Injection Site Reactions In a pool of placebo-controlled trials evaluating PRALUENT 75 mg and/or 150 mg administered every 2 weeks in adults, local injection site reactions including erythema/redness, itching, swelling, and pain/tenderness were reported more frequently in patients treated with PRALUENT (7.2% versus 5.1% for PRALUENT and placebo, respectively).
Few patients discontinued treatment because of these reactions (0.2% versus 0.4% for PRALUENT and placebo, respectively), but patients receiving PRALUENT had a greater number of injection site reactions, had more reports of associated symptoms, and had reactions of longer average duration than patients receiving placebo. In the trial of pediatric patients with HeFH, local injection site reactions were reported in 5% of patients treated with PRALUENT versus 0% patients treated with placebo; no patients discontinued treatment due to injection site reactions. Hypersensitivity Reactions in Adults Hypersensitivity reactions were reported more frequently in adult patients treated with PRALUENT than in those treated with placebo (8.6% versus 7.8%).
The most common hypersensitivity reaction was pruritus (1.1% versus 0.4% for PRALUENT and placebo, respectively). The proportion of patients who discontinued treatment due to allergic reactions was higher among those treated with PRALUENT (0.6% versus 0.2%). Serious allergic reactions, such as hypersensitivity, nummular eczema, and hypersensitivity vasculitis were reported in patients using PRALUENT in controlled clinical trials.
Liver Enzyme Abnormalities in Adults In the hypercholesterolemia trials in adults, liver-related disorders (primarily related to abnormalities in liver enzymes) were reported in 2.5% of patients treated with PRALUENT and 1.8% of patients treated with placebo, leading to treatment discontinuation in 0.4% and 0.2% of patients, respectively. Increases in serum transaminases to greater than 3 times the upper limit of normal occurred in 1.7% of patients treated with PRALUENT and 1.4% of patients treated with placebo.
Postmarketing Experience
The following adverse reactions have been reported during post-approval use of PRALUENT. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Hypersensitivity reactions: Angioedema Influenza-like illness
| Adverse Reactions | Placebo (N=1,276) % | PRALUENT 75 mg every 2 weeks and 150 mg every 2 weeks combined (N=2,476) % |
|---|---|---|
| Injection site reactions Includes erythema/redness, itching, swelling, pain/tenderness | 5 | 7 |
| Influenza | 5 | 6 |
| Diarrhea | 4 | 5 |
| Myalgia | 3 | 4 |
| Muscle spasms | 2 | 3 |
| Contusion | 1 | 2 |
Warnings & Cautions for Praluent
Hypersensitivity Reactions
Hypersensitivity reactions, including hypersensitivity vasculitis, angioedema, and other hypersensitivity reactions requiring hospitalization, have been reported with PRALUENT treatment. If signs or symptoms of serious hypersensitivity reactions occur, discontinue treatment with PRALUENT, treat according to the standard of care, and monitor until signs and symptoms resolve. PRALUENT is contraindicated in patients with a history of a serious hypersensitivity reaction to alirocumab or any excipient in PRALUENT.
Pregnancy Safety for Praluent
Pregnancy Risk Summary Available data from clinical trials and postmarketing reports on PRALUENT use in pregnant women are insufficient to evaluate for a drug-associated risk of major birth defects, miscarriage or other adverse maternal or fetal outcomes. In animal reproduction studies, there were no effects on embryo-fetal development when rats were subcutaneously administered alirocumab during organogenesis at dose exposures up to 12-fold the exposure at the maximum recommended human dose of 150 mg every two weeks. In monkeys, suppression of the humoral immune response was observed in infant monkeys when alirocumab was dosed during organogenesis to parturition at dose exposures 13-fold the exposure at the maximum recommended human dose of 150 mg every two weeks.
No additional effects on pregnancy or neonatal/infant development were observed at dose exposures up to 81-fold the maximum recommended human dose of 150 mg every two weeks. Measurable alirocumab serum concentrations were observed in the infant monkeys at birth at comparable levels to maternal serum, indicating that alirocumab, like other IgG antibodies, crosses the placental barrier. Monoclonal antibodies are transported across the placenta in increasing amounts especially near term; therefore, alirocumab has the potential to be transmitted from the mother to the developing fetus.
The estimated background risk of major birth defects and miscarriage for the indicated population(s) is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2%-4% and 15%-20%, respectively. There is a pregnancy safety study for PRALUENT.
If PRALUENT is administered during pregnancy, healthcare providers should report PRALUENT exposure by contacting Regeneron at 1-844-734-6643. Data Animal data In Sprague Dawley rats, no effects on embryo-fetal development were observed when alirocumab was dosed at up to 75 mg/kg/dose by the subcutaneous route on gestation days 6 and 12 at exposures 12-fold the maximum recommended human dose of 150 mg every two weeks, based on serum AUC. The lowest dose tested in the monkey resulted in humoral immune suppression; therefore, it is unknown if this effect would be observed at clinical exposure.
No study designed to challenge the immune system of infant monkeys was conducted. No additional embryo-fetal, prenatal or postnatal effects were observed in infant monkeys, and no maternal effects were observed, when alirocumab was dosed at up to 75 mg/kg/week by the subcutaneous route, corresponding to maternal exposure of 81-fold the exposure at the maximum recommended human dose of 150 mg every two weeks, based on serum AUC.
Pediatric Use of Praluent
Pediatric Use The safety and effectiveness of PRALUENT as an adjunct to diet and other LDL-C-lowering therapies for the treatment of HeFH have been established in pediatric patients aged 8 years and older. Use of PRALUENT for this indication is based on data from a 24-week, randomized, placebo-controlled, double-blind trial in pediatric patients with HeFH. This indication is supported by evidence from controlled trials in adults.
The safety and effectiveness of PRALUENT have not been established in pediatric patients with HeFH who are younger than 8 years of age or in pediatric patients with other types of hypercholesterolemia.
Contraindications for Praluent
PRALUENT is contraindicated in patients with a history of a serious hypersensitivity reaction to alirocumab or any of the excipients in PRALUENT. Hypersensitivity vasculitis, angioedema, and hypersensitivity reactions requiring hospitalization have occurred.
Clinical Studies of Praluent
Patients had an acute coronary syndrome (ACS) event 4 to 52 weeks prior to randomization and were treated with a lipid-modifying therapy (LMT) regimen that was statin-intensive (defined as atorvastatin 40 or 80 mg, or rosuvastatin 20 or 40 mg) or at maximally tolerated dose of a statin, with or without other LMT. Patients were randomized to receive either PRALUENT 75 mg or placebo once every two weeks. Patients on 75 mg every 2 weeks who had two consecutive LDL-C values below 15 mg/dL were switched to placebo in a blinded fashion.
Overall, 730 (7.7%) of 9,451 patients switched to placebo. A total of 99.5% of patients were followed for survival until the end of the trial. The median follow-up duration was 33 months.
The index ACS event was a myocardial infarction in 83% of patients and unstable angina in 17% of patients. Prior to the index ACS event, 19% had prior myocardial infarction and 23% had coronary revascularization procedures (CABG/PCI). Most patients (89%) were receiving statin-intensive therapy with or without other LMT at randomization.
The mean LDL-C value at baseline was 92.4 mg/dL. Endpoint Results PRALUENT significantly reduced the risk for the primary composite endpoint (time to first occurrence of coronary heart disease death, non-fatal myocardial infarction, fatal and non-fatal ischemic stroke, or unstable angina requiring hospitalization: p=0.0003). The results are presented in Table 2.
Table 2: Cardiovascular Outcomes in Adult Patients with Established Cardiovascular Disease 0.85 The Kaplan-Meier estimates of the cumulative incidence of the primary endpoint over time is presented in Figure 1. All patients were taking maximally tolerated doses of statins with or without other lipid-modifying therapy and required additional LDL-C reduction. The average LDL-C at baseline was 122 mg/dL.
Endpoint Results At week 24, the treatment difference between PRALUENT and placebo in mean LDL-C percent change was p-value: ˂0.0001. The proportion of patients who prematurely discontinued trial drug prior to the 24-week primary endpoint was 8% among those treated with PRALUENT and 8% among those treated with placebo. For additional results see Table 3 and Figure 2.
Table 3: Mean Percent Change from Baseline and Difference Difference is PRALUENT minus Placebo from Placebo in Lipid Parameters at Week 24 in ODYSSEY LONG TERM A pattern-mixture model approach was used with multiple imputation of missing post-treatment values based on a patient's own baseline value and multiple imputation of missing on-treatment values based on a model including available on-treatment values Trial 3 (ODYSSEY COMBO I, NCT01644175) was a multicenter, double-blind, placebo-controlled trial that randomly assigned 209 adult patients to PRALUENT and 107 adult patients to placebo. Mean baseline LDL-C was 102 mg/dL. At week 12, if additional LDL-C lowering was required based on pre-specified LDL-C criteria, PRALUENT was up-titrated to 150 mg every 2 weeks for the remainder of the trial.
The trials were similar with regard to both design and eligibility criteria. The diagnosis of HeFH was made either by genotyping or clinical criteria ("definite FH" using either the Simon Broome or WHO/Dutch Lipid Network criteria). The LDL-C-lowering effect was sustained to week 52.
For additional results see Table 4 and Figure 3. Table 4: Mean Percent Change from Baseline and Difference Difference is PRALUENT minus Placebo from Placebo in Lipid Parameters at Week 12 and Week 24 in Adult Patients with HeFH (ODYSSEY FH I and FH II Pooled) A pattern-mixture model approach was used with multiple imputation of missing post-treatment values based on a patient's own baseline value and multiple imputation of missing on-treatment values based on a model including available on-treatment values Trial 6 (ODYSSEY HIGH FH, NCT01617655) was a multicenter, double-blind, placebo-controlled trial that randomly assigned 72 adult patients to PRALUENT 150 mg every 2 weeks and 35 adult patients to placebo. Patients had HeFH with a baseline LDL-C ≥160 mg/dL while taking a maximally tolerated dose of statin with or without other lipid-modifying therapy.
Patients were stratified based on whether or not they were treated concomitantly with statin. Endpoint Results In the cohort of patients on background statin, the mean LDL-C at baseline was 113 mg/dL. The treatment difference between PRALUENT and placebo were similar to the cohort of patients treated with a concomitant statin.
Trial 8 (ODYSSEY ESCAPE, NCT02326220) was a multicenter, double-blind, placebo-controlled trial that randomly assigned adult patients with HeFH who were undergoing LDL apheresis to PRALUENT 150 mg every 2 weeks (N=41) or placebo (N=21). Patients were treated in combination with their usual LDL apheresis schedule for 6 weeks. The mean LDL-C at baseline, measured before the apheresis procedure, was 181 mg/dL.
Endpoint Results At week 6, the mean percent change from baseline in pre-apheresis LDL-C was -53% in patients in the PRALUENT group compared to 1% in patients who received placebo. Patients were taking a maximally tolerated dose of a statin and required additional LDL-C reduction. Mean baseline LDL-C was 107 mg/dL.
At week 24, the mean percent change from baseline in LDL-C was -48% with PRALUENT and -20% with ezetimibe, and the treatment difference between PRALUENT and ezetimibe in mean LDL-C percent change was p-value: <0.0001. Mean baseline LDL-C was 140 mg/dL. The proportion of patients who prematurely discontinued trial drug prior to the 24-week endpoint was 15% among those treated with PRALUENT and 14% among those treated with ezetimibe.
Randomization was stratified by LDL apheresis treatment status. The diagnosis of HoFH was made by either clinical diagnosis, which included a history of an untreated total cholesterol concentration >500 mg/dL together with either xanthoma before 10 years of age or with a history of total cholesterol >250 mg in both parents, or by genetic testing. Endpoint Results At week 12, the treatment difference between PRALUENT and placebo in mean LDL-C percent change from baseline was (see Figure 5 ).
For the effect of PRALUENT on lipid parameters as compared to placebo, see Table 5. No patient discontinued from the trial prior to the 12-week primary endpoint. Patients with two LDL-receptor negative alleles (little to no residual function) had a minimal to absent response to PRALUENT.
Patients were on a low-fat diet and receiving background lipid-lowering therapy. Patients were randomized in a 2:1 ratio to receive PRALUENT or placebo. The 40 mg dosage every 2 weeks is not approved.
Baseline Disease and Demographic Characteristics The diagnosis of HeFH was made based on criteria from Simon Broome Register Group or by genetic testing. Mean body weight was 53 kg. Of the patients receiving PRALUENT once every 4 weeks with an optional up-titration, 91% were on statins and 20% were on ezetimibe at baseline.
| Endpoint | PRALUENT N=9,462 | Placebo N=9,462 | Hazard Ratio (95% CI) Cox-proportional hazards model with treatment as a factor and stratified by geographic region | ||
|---|---|---|---|---|---|
| n (%) | Incidence Rate per 100 Patient Years (95% CI) | n (%) | Incidence Rate per 100 Patient Years (95% CI) | ||
| Primary composite endpoint Primary composite endpoint defined as: time to first occurrence of coronary heart disease death, non-fatal myocardial infarction, fatal and non-fatal ischemic stroke, or unstable angina requiring hospitalization | 903 (9.5%) | 3.5 (3.3 to 3.8) | 1052 (11.1%) | 4.2 (3.9 to 4.4) | 0.85 (0.78, 0.93) |
| Components of the Primary Composite Endpoint First occurrence of specified event at any time; patients may have experienced more than one adjudicated event | |||||
| CHD death | 205 (2.2%) | 0.8 (0.7 to 0.9) | 222 (2.3%) | 0.8 (0.7 to 0.9) | 0.92 (0.76, 1.11) |
| Non-fatal MI Statistical testing performed outside hierarchy; therefore not considered statistically significant | 626 (6.6%) | 2.4 (2.2 to 2.6) | 722 (7.6%) | 2.8 (2.6 to 3.0) | 0.86 (0.77, 0.96) |
| Fatal or non-fatal ischemic stroke | 111 (1.2%) | 0.4 (0.3 to 0.5) | 152 (1.6%) | 0.6 (0.5 to 0.7) | 0.73 (0.57, 0.93) |
| Unstable angina requiring hospitalization | 37 (0.4%) | 0.1 (0.1 to 0.2) | 60 (0.6%) | 0.2 (0.2 to 0.3) | 0.61 (0.41, 0.92) |
| Mortality Endpoint (not statistically significant per pre-specified method to control for type I error) | |||||
| All-cause mortality | 334 (3.5%) | 1.2 (1.1 to 1.4) | 392 (4.1%) | 1.5 (1.3 to 1.6) | 0.85 (0.73, 0.98) |
| Treatment Group | LDL-C | Total-C | Non-HDL-C | Apo B |
|---|---|---|---|---|
| Week 24 (Mean Percent Change from Baseline) | ||||
| Placebo (n=788) | 1 | 0 | 1 | 1 |
| PRALUENT 150 mg (n=1,553) | -58 | -36 | -49 | -50 |
| Difference from placebo (LS Mean) (95% CI) | -58 (-61, -56) | -36 (-37, -34) | -50 (-52, -47) | -51 (-53, -48) |
| Treatment Group | LDL-C | Total-C | Non-HDL-C | Apo B |
|---|---|---|---|---|
| Week 12 (Mean Percent Change from Baseline) | ||||
| Placebo (n=245) | 5 | 4 | 5 | 2 |
| PRALUENT 75 mg (n=490) | -43 | -27 | -38 | -34 |
| Difference from placebo (LS Mean) (95% CI) | -48 (-52, -44) | -31 (-34, -28) | -42 (-46, -39) | -36 (-39, -33) |
| Week 24 (Mean Percent Change from Baseline) | ||||
| Placebo (n=245) | 7 | 5 | 7 | 2 |
| PRALUENT 75 mg/150 mg Dose was up-titrated to 150 mg every 2 weeks in 196 (42%) patients treated for at least 12 weeks (n=490) | -47 | -30 | -42 | -40 |
| Difference from placebo (LS Mean) (95% CI) | -54 (-59, -50) | -36 (-39, -33) | -49 (-53, -45) | -42 (-45, -39) |
| Treatment Group | LDL-C | Apo B | Non-HDL-C | Total Cholesterol |
|---|---|---|---|---|
| Placebo (n=24) | 9 | 7 | 8 | 7 |
| PRALUENT 150 mg every 2 weeks (n=45) | -27 | -23 | -25 | -20 |
| Difference from placebo (LS Mean) (95% CI) | -36 (-51, -20) | -30 (-42, -17) | -33 (-48, -18) | -27 (-39, -14) |
| Treatment Group The percent of missing data was 5% in the every 2 week group and 13% in the every 4 week group | LDL-C | Apo B | Non-HDL-C | Total Cholesterol |
|---|---|---|---|---|
| PRALUENT once every 4 weeks (150 mg for body weight less than 50 kg or 300 mg for body weight 50 kg or more) In the PRALUENT group 52 patients received a dose of 150 mg every 4 weeks (body weight less than 50 kg) or 300 mg every 4 weeks (body weight 50 kg or more). At week 12, a total of 15 (28.8%) patients had an automatic blinded dose adjustment to 75 mg every 2 weeks (body weight less than 50 kg) or 150 mg every 2 weeks (body weight 50 kg or more). | ||||
| LS Mean: Placebo (n=27) | -5.2 | -3.3 | -4.1 | -4.4 |
| LS Mean: PRALUENT (n=52) | -36.6 | -33.0 | -34.2 | -26.7 |
| LS Mean Difference from Placebo A pattern-mixture approach was used with multiple imputation of missing post-treatment values based on a patient's own baseline value and multiple imputation of missing on-treatment values based on a model including available on-treatment values (97.5% CI) | -31.4 (-45.0, -17.9) | -29.7 (-41.1, -18.2) | -30.1 (-43.0, -17.2) | -22.3 (-33.0, -11.6) |
| PRALUENT once every 2 weeks (40 mg for body weight less than 50 kg or 75 mg for body weight 50 kg or more) In the PRALUENT group dosed every 2 weeks, 49 patients received a dose of 40 mg for body weight less than 50 kg or 75 mg for body weight 50 kg or more. At week 12, a total of 22 (44.9%) patients had an automatic blinded dose adjustment to 75 mg every 2 weeks (body weight less than 50 kg) or 150 mg every 2 weeks (body weight 50 kg or more)., The 40 mg dosage every 2 weeks is not approved | ||||
| LS Mean: Placebo (n=25) | 9.7 | 10.4 | 9.7 | 7.4 |
| LS Mean: PRALUENT (n=49) | -31.9 | -25.7 | -29.5 | -22.4 |
| LS Mean Difference from Placebo (97.5% CI) | -41.7 (-54.2, -29.1) | -36.2 (-45.8, -26.5) | -39.2 (-50.6, -27.8) | -29.8 (-38.7, -21.0) |
Drug information sourced from the FDA. This content is for informational purposes only and does not constitute medical advice. Consult a healthcare professional before making any medication decisions.
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