Drug Safety-related Labeling Changes (SrLC)

Get Email Alerts | Guide

PRALUENT (BLA-125559)

(ALIROCUMAB)

Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)

Download Data

Expand all

03/08/2024 (SUPPL-39)

Approved Drug Label (PDF)

6 Adverse Reactions

6.1 Clinical Trials Experience

Extensive changes; please refer to label

8 Use in Specific Populations

8.4 Pediatric Use

Newly added information:

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. In the trial, 101 patients received PRALUENT and 52 patients received placebo; 26 patients (17%) were 8 to 9 years of age. This indication is supported by evidence from controlled trials in adults [see Adverse Reactions (6.1) and Clinical Studies (14.3)].

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 hyperlipidemia.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

Patient Information

Additions and revisions underlined:

What is PRALUENT?

PRALUENT is an injectable prescription medicine used:

• in adults with cardiovascular disease to reduce the risk of heart attack, stroke, and certain types of chest pain conditions (unstable angina) requiring hospitalization.

• along with diet, alone or together with other cholesterol-lowering medicines in adults with high blood cholesterol levels called primary hyperlipidemia (including a type of high cholesterol called heterozygous familial hypercholesterolemia [HeFH]), to reduce low-density lipoprotein cholesterol (LDL-C) or bad cholesterol.

• along with other LDL-lowering treatments in adults with a type of high cholesterol called homozygous familial hypercholesterolemia, who need additional lowering of LDL-C.

• along with diet and other LDL-lowering treatments in children aged 8 years and older with HeFH to reduce LDL-C.

It is not known if PRALUENT is safe and effective in children who are younger than 8 years of age or in children with other types of high cholesterol (hyperlipidemias).

. . .

• 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.

. . .

The common side effects of PRALUENT include:

• redness, itching, swelling, pain, or tenderness

  at the injection site                                               ·     muscle pain

• flu or flu-like symptoms                                         ·     muscle spasms

• diarrhea                                                              ·      bruising

04/01/2021 (SUPPL-29)

Approved Drug Label (PDF)

4 Contraindications

(Additions and/or revisions underlined)

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 [see Warnings and Precautions (5.1)].

5 Warnings and Precautions

5.1 Hypersensitivity Reactions

(Additions and/or revisions underlined)

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 [see Contraindications (4)].

6 Adverse Reactions

(Additions and/or revisions underlined)

The following adverse reactions are also discussed in the other sections of the labeling:

• Hypersensitivity Reactions [see Warnings and Precautions (5.1)]

6.1 Clinical Trials Experience

(Additions and/or revisions underlined)

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.

The data in Table 1 are derived from 9 primary hyperlipidemia placebo-controlled trials that included 2476 patients treated with PRALUENT 75 mg and/or 150 mg every 2 weeks, including 2135 exposed for 6 months and 1999 exposed for more than 1 year (median treatment duration of 65 weeks). The mean age of the population was 59 years, 40% of the population were women, 90% were White, 4% were Black or African American, and 3% were Asian.

Adverse reactions reported in at least 2% of PRALUENT-treated patients, and more frequently than in placebo-treated patients, are shown in Table 1.

Table 1: Adverse Reactions Occurring in >2% of PRALUENT-Treated Patients and More Frequently Than with Placebo

…

In the HoFH placebo-controlled trial in which 45 patients were exposed to PRALUENT for a median of 12 weeks and 24 patients were exposed to placebo for a median of 12 weeks, no additional adverse reactions were identified.

Local Injection Site Reactions

In a pool of placebo-controlled trials evaluating PRALUENT 75 mg and/or 150 mg administered every 2 weeks, 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 a 48-week placebo-controlled trial evaluating PRALUENT 300 mg every 4 weeks and 75 mg every 2 weeks, in which all patients received an injection of drug or placebo every 2 weeks, local injection site reactions were reported more frequently in patients treated with PRALUENT 300 mg every 4 weeks as compared to those receiving PRALUENT 75 mg every 2 weeks or placebo (16.6%, 9.6%, and 7.9%, respectively). Three patients (0.7%) treated with PRALUENT 300 mg every 4 weeks discontinued treatment due to local injection site reactions versus no patients (0%) in the other 2 treatment groups.

In a cardiovascular outcomes trial, local injection site reactions were reported in 3.8% of patients treated with PRALUENT versus 2.1% patients treated with placebo, and led to permanent discontinuation in 26 patients (0.3%) versus 3 patients (<0.1%), respectively.

Hypersensitivity Reactions

Hypersensitivity reactions were reported more frequently in 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 the primary hyperlipidemia trials, 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.

6.2 Immunogenicity

(Additions and/or revisions underlined)

As with all therapeutic proteins, there is a potential for immunogenicity with PRALUENT. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to PRALUENT in the studies described below with the incidence of antibodies in other studies or to other products may be misleading.

In a cardiovascular outcomes trial, 5.5% (504/9091) of patients treated with PRALUENT 75 mg and/or 150 mg every 2 weeks had anti-drug antibodies (ADA) detected after initiating treatment compared with 1.6% (149/9097) of patients treated with placebo. Persistent ADA responses, defined as at least 2 consecutive post-baseline samples with positive ADA separated by at least a 16-week period, were observed in 0.7% of patients treated with PRALUENT and 0.4% of patients treated with placebo. Neutralizing antibody (NAb) responses were observed in 0.5% of patients treated with PRALUENT and in <0.1% of patients treated with placebo. Efficacy based on reductions in LDL-C was mostly similar in patients with or without ADA. However, some patients treated with PRALUENT with persistent or neutralizing antibodies experienced attenuation in LDL-C efficacy.

A higher incidence of injection site reactions were observed in patients with treatment-emergent ADA compared to patients who were ADA negative (7.5% vs 3.6%). In a pool of ten placebo- controlled and active-controlled trials of patients treated with PRALUENT 75 mg and/or 150 mg every 2 weeks as well as in a separate clinical study of patients treated with PRALUENT 75 mg every 2 weeks or 300 mg every 4 weeks (including some patients with dose adjustment to 150 mg every 2 weeks), the incidence of detecting ADA and NAb was similar to the results from the trial described above.

The long-term consequences of continuing PRALUENT treatment in the presence of ADA are unknown.

6.3 Postmarketing Experience

(Additions and/or revisions underlined)

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

8 Use in Specific Populations

8.1 Pregnancy

(Additions and/or revisions underlined)

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.

…

8.4 Pediatric Use

(Additions and/or revisions underlined)

The safety and effectiveness of PRALUENT have not been established in pediatric patients.

8.5 Geriatric Use

(Additions and/or revisions underlined)

In controlled trials, 3663 patients treated with PRALUENT were greater than or equal to 65 years of age and 734 patients treated with PRALUENT were greater than or equal to 75 years of age. No overall differences in safety or effectiveness were observed between these patients and younger patients, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

PATIENT COUNSELING INFORMATION

(Additions and/or revisions underlined)

Advise the patient to read the FDA-Approved Patient Labeling (Patient Information and Instructions for Use).

Pregnancy

Advise women who are exposed to PRALUENT during pregnancy that there is a pregnancy safety study that monitors pregnancy outcomes. Encourage these patients to report their pregnancy to Regeneron at 1 844-734-6643 [see Use in Specific Populations (8.1)].

Hypersensitivity Reactions

Inform patients that serious hypersensitivity reactions (e.g., angioedema) have been reported in patients treated with PRALUENT. Advise patients on the symptoms of hypersensitivity reactions and instruct them to discontinue PRALUENT and seek medical attention promptly, if such symptoms occur.

Administration

Provide guidance to patients and caregivers on proper subcutaneous injection technique and how to use the pre-filled pen. Inform patients that it may take up to 20 seconds to inject PRALUENT. Inform patients the pre-filled pen should be allowed to warm to room temperature for 30 to 40 minutes prior to use if refrigerated.

PATIENT INFORMATION

(Additions and/or revisions underlined)

What is PRALUENT?

PRALUENT is an injectable prescription medicine used:

• in adults with cardiovascular disease to reduce the risk of heart attack, stroke, and certain types of chest pain conditions (unstable angina) requiring hospitalization.

• along with diet, alone or together with other cholesterol-lowering medicines in adults with high blood cholesterol levels called primary hyperlipidemia (including a type of high cholesterol called heterozygous familial hypercholesterolemia), to reduce low-density lipoprotein cholesterol (LDL-C) or bad cholesterol.

• along with other LDL-lowering treatments in adults with a type of high cholesterol called homozygous familial hypercholesterolemia, who need additional lowering of LDL-C.

It is not known if PRALUENT is safe and effective in children.

…

What should I tell my healthcare provider before using PRALUENT?

Before you start using PRALUENT, tell your healthcare provider about all of your medical conditions, including allergies, and if you:

• are pregnant or plan to become pregnant. It is not known if PRALUENT will harm your unborn baby. Tell your healthcare provider if you become pregnant while taking PRALUENT.

• are breastfeeding or plan to breastfeed. You and your healthcare provider should decide if you will take PRALUENT or breastfeed. You should not do both without talking to your healthcare provider first.

If you are pregnant during PRALUENT treatment, you are encouraged to call Regeneron at 1-844-734- 6643 to share information about the health of you and your baby.

Tell your healthcare provider or pharmacist about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.

…

03/10/2020 (SUPPL-24)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 Allergic Reactions

Additions and/or revisions underlined:

Hypersensitivity reactions (e.g., pruritus, rash, urticaria), including some serious events (e.g., hypersensitivity vasculitis, angioedema, and hypersensitivity reactions requiring hospitalization), have been reported with PRALUENT treatment …

6 Adverse Reactions

6.3 Postmarketing Experience

Newly added information:

• Allergic reactions

  • Angioedema

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

PATIENT INFORMATION

Additions and/or revisions underlined:

What are the possible side effects of PRALUENT?

PRALUENT can cause serious side effects, including:

• allergic reactions. PRALUENT may cause allergic reactions that can be severe and require

treatment in a hospital. Stop using PRALUENT and call your healthcare provider or go to the

nearest hospital emergency room right away if you have any symptoms of an allergic reaction

including:

• hives

• swelling of the face, lips, throat or tongue

04/26/2019 (SUPPL-19)

Approved Drug Label (PDF)

6 Adverse Reactions

6.1 Clinical Trials Experience

Extensive changes; please refer to label for complete information.

6.2 Immunogenicity

Extensive changes; please refer to label for complete information.

8 Use in Specific Populations

8.5 Geriatric Use

Additions and/or revisions underlined:

In primary hypercholesterolemia controlled trials, 1158 patients treated with PRALUENT were greater than or equal to 65 years of age and 241 patients treated with PRALUENT were greater than or equal to 75 years of age. In a cardiovascular outcomes trial, 2505 patients treated with PRALUENT were greater than or equal to 65 years of age and 493 patients treated with PRALUENT were greater than or equal to 75 years of age. No overall differences in safety or effectiveness were observed between these patients and younger patients, and other …

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

PATIENT INFORMATION

Additions and/or revisions underlined:

PRALUENT is an injectable prescription medicine used:

• in adults with cardiovascular disease to reduce the risk of heart attack, stroke, and certain types of chest pain conditions (unstable angina) requiring hospitalization.

• along with diet, alone or together with other cholesterol-lowering medicines in adults with high blood cholesterol levels called primary hyperlipidemia (including a type of high cholesterol called heterozygous familial hypercholesterolemia), to reduce low-density lipoprotein cholesterol (LDL-C) or bad cholesterol.

11/06/2018 (SUPPL-18)

Approved Drug Label (PDF)

6 Adverse Reactions

Newly added subsection:

6.3 Postmarketing Experience

The following adverse reactions have been reported during postapproval 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.

• General disorders and administration site conditions

  • Flu-like illness

07/20/2018 (SUPPL-15)

Approved Drug Label (PDF)

8 Use in Specific Populations

8.1 Pregnancy

Pregnancy Exposure Registry

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to PRALUENT during pregnancy.

…

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

PATIENT COUNSELING INFORMATION

(addition underlined)

See FDA-Approved Patient Labeling (Patient Information and Instructions for Use).

Pregnancy Registry

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to PRALUENT during pregnancy. Encourage participation in the registry.

…

09/20/2017 (SUPPL-6)

Approved Drug Label (PDF)

6 Adverse Reactions

6.2 Immunogenicity

(subsection revised, additions underlined)

As with all therapeutic proteins, there is a potential for immunogenicity with PRALUENT. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay.

Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to PRALUENT in the studies described below with the incidence of antibodies in other studies or to other products may be misleading.

In a pool of ten placebo- and active-controlled trials, 4.8% (147/3033) of patients treated with PRALUENT 75 mg and/or 150 mg every 2 weeks (Q2W) had anti-drug antibodies (ADA) newly detected at least once after initiating treatment compared with 0.6% (10/1708) of patients treated with control. For 1.9% (57/3033) of patients treated with PRALUENT and 0.5% (8/1708) of patients treated with control, ADA were detected in at least 2 samples separated by at least 12 weeks or were detected only at the last sampling time point. Patients treated with PRALUENT 75 mg and/or 150 mg Q2W who ever developed ADA had a higher incidence of injection site reactions compared with patients who never had ADA detected (10.2% vs 5.9%).

In the same pool, 1.2% (36/3033) of patients treated with PRALUENT 75 mg and/or 150 mg Q2W had neutralizing antibodies (NAb) detected at least once, and 0.3% (9/3033) exhibited some attenuation in efficacy. No patients treated with control developed NAb. The long-term consequences of continuing PRALUENT treatment in the presence of persistent NAb are unknown.

In a separate clinical study of patients treated with PRALUENT 75 mg Q2W or 300 mg every 4 weeks (including some patients with dose adjustment to 150 mg Q2W), the incidence of detecting ADA and NAb was qualitatively similar to the results from the pooled trials described above.

04/24/2017 (SUPPL-1)

Approved Drug Label (PDF)

6 Adverse Reactions

6.1 Clinical Trials Experience

Additions and/or revisions underlined:

… The safety of PRALUENT was evaluated in 9 placebo-controlled trials that included 2476 patients treated with PRALUENT 75 mg and/or 150 mg every 2 weeks, including 2135 exposed for 6 months and 1999 exposed for more than 1 year (median treatment duration of 65 weeks).

Following Table 1:

Local Injection Site Reactions

In a pool of placebo-controlled trials evaluating PRALUENT 75 mg and/or 150 mg administered every 2 weeks (Q2W), local injection site reactions including … and had reactions of longer average duration than patients receiving placebo.

Addition of the following:

In a 48-week placebo-controlled trial evaluating PRALUENT 300 mg every 4 weeks (Q4W) and 75 mg Q2W, in which all patients received an injection of drug or placebo every 2 weeks to maintain the blind, local injection site reactions were reported more frequently in patients treated with PRALUENT 300 mg Q4W as compared to those receiving PRALUENT 75 mg Q2W or placebo (16.6%, 9.6%, and 7.9%, respectively). Three patients (0.7%) treated with PRALUENT 300 mg Q4W discontinued treatment due to local injection site reactions versus no patients (0%) in the other 2 treatment groups.

Low LDL-C Values

Additions and/or revisions underlined:

In the placebo- and active-controlled clinical trials using an every 2 week or every 4 week dosing interval, 914 PRALUENT-treated patients had two consecutive calculated LDL-C values <25 mg/dL, and 335 had two consecutive calculated LDL-C values <15 mg/dL. LDL-C values < 25 mg/dL and <15 mg/dL were observed more frequently in patients treated with the PRALUENT 150 mg Q2W or 300 mg Q4W dosing regimens. Changes to background …

6.2 Immunogenicity

Additions and/or revisions underlined:

As with all therapeutic proteins, there is a potential for immunogenicity with PRALUENT. In a pool of ten placebo- and active-controlled trials, 4.8% of patients treated with PRALUENT 75 mg and/or 150 mg every 2 weeks (Q2W) exhibited anti-drug antibodies (ADA) newly detected after initiating treatment as compared with 0.6% of patients treated with control. In a separate study, 6.3% of patients treated with PRALUENT 75 mg Q2W or 300 mg every 4 weeks (Q4W) (including some patients with dose adjustment to 150 mg Q2W) exhibited a newly detected ADA versus 2.6% of patients treated with placebo.

In a pool of ten placebo- and active-controlled trials, patients treated with PRALUENT 75 mg and/or 150 mg Q2W who developed ADA had a higher incidence …

A total of 1.2% of patients treated with PRALUENT 75 mg and/or 150 mg Q2W developed neutralizing antibodies (NAb) … or prolonged loss of efficacy. In a separate study, 0.9% of patients treated with PRALUENT 75 mg Q2W or 300 mg Q4W (including some patients with dose adjustment to 150 mg Q2W) developed NAb on at least one occasion; no NAb were observed in patients treated with placebo. The long-term consequences …

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

PATIENT INFORMATION

How should I use PRALUENT?

Additions and/or revisions underlined:

• PRALUENT is injected under the skin (subcutaneously) every 2 weeks or every 4 weeks (monthly).

• If your healthcare provider prescribes you the monthly dose, you will give yourself 2 separate injections in a row, using a different syringe or pen for each injection and two different injection sites.

• If you forget to use PRALUENT or are not able to take the dose at your regular time, inject your missed dose as soon as you remember, within 7 days. Then, if you inject every 2 weeks take your next dose in 2 weeks from the day you missed your dose or if you inject every 4 weeks take your next dose in 4 weeks from the day you missed your dose. This will put you back on your original schedule.

• If you missed a dose  by more than 7 days and you inject every 2 weeks wait until your next scheduled dose to re-start PRALUENT or if you inject every 4 weeks start a new schedule from the time you remember to take your dose.