1.1       Primary Hyperlipidemia

REPATHA™ is indicated as an adjunct to diet and maximally tolerated statin therapy for the treatment of adults with heterozygous familial hypercholesterolemia (HeFH) or clinical atherosclerotic cardiovascular disease (CVD), who require additional lowering of low density lipoprotein cholesterol (LDL-C).

1.2       Homozygous Familial Hypercholesterolemia

REPATHA is indicated as an adjunct to diet and other LDL-lowering therapies (e.g., statins, ezetimibe, LDL apheresis) for the treatment of patients with homozygous familial hypercholesterolemia (HoFH) who require additional lowering of LDL-C.

1.3       Limitations of Use

The effect of REPATHA on cardiovascular morbidity and mortality has not been determined.

2.1       Recommended Dosage

The recommended subcutaneous dosage of REPATHA in patients with HeFH or patients with primary hyperlipidemia with established clinical atherosclerotic CVD is either 140 mg every 2 weeks OR 420 mg once monthly. When switching dosage regimens, administer the first dose of the new regimen on the next scheduled date of the prior regimen.

The recommended subcutaneous dosage of REPATHA in patients with HoFH is 420 mg once monthly. In patients with HoFH, measure LDL-C levels 4 to 8 weeks after starting REPATHA, since response to therapy will depend on the degree of LDL-receptor function.  

If an every 2 week or once monthly dose is missed, instruct the patient to:

• Administer REPATHA as soon as possible if there are more than 7 days until the next scheduled dose, or,  
• Omit the missed dose and administer the next dose according to the original schedule. 

2.2       Important Administration Instructions

• To administer the 420 mg dose, give 3 REPATHA injections consecutively within 30 minutes.

• Provide proper training to patients and/or caregivers on how to prepare and administer REPATHA prior to use, according to the Instructions for Use, including aseptic technique. Instruct patients and/or caregivers to read and follow the Instructions for Use each time they use REPATHA.

• Keep REPATHA in the refrigerator. Prior to use, allow REPATHA to warm to room temperature for at least 30 minutes. Do not warm in any other way. Alternatively, for patients and caregivers, REPATHA can be kept at room temperature (up to 25°C (77°F)) in the original carton. However, under these conditions, REPATHA must be used within 30 days [see How Supplied/Storage and Handling (16)].

• Visually inspect REPATHA for particles and discoloration prior to administration. REPATHA is a clear to opalescent, colorless to pale yellow solution. Do not use if the solution is cloudy or discolored or contains particles.

• Administer REPATHA by subcutaneous injection into areas of the abdomen, thigh, or upper arm that are not tender, bruised, red, or indurated using a single-use prefilled syringe or single-use prefilled autoinjector.

• Do not co-administer REPATHA with other injectable drugs at the same injection site.

• Rotate the injection site with each injection. 

5.1       Allergic Reactions

Hypersensitivity reactions (e.g., rash, urticaria) have been reported in patients treated with REPATHA, including some that led to discontinuation of therapy. If signs or symptoms of serious allergic reactions occur, discontinue treatment with REPATHA, treat according to the standard of care, and monitor until signs and symptoms resolve. 

6.1       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 clinical practice. 

Adverse Reactions in Patients with Primary Hyperlipidemia and in Patients with Heterozygous Familial Hypercholesterolemia

REPATHA is not indicated for use in patients without familial hypercholesterolemia or atherosclerotic CVD [see Indications and Usage (1.1)].

The data described below reflect exposure to REPATHA in 8 placebo-controlled trials that included 2651 patients treated with REPATHA, including 557 exposed for 6 months and 515 exposed for 1 year (median treatment duration of 12 weeks). The mean age of the population was 57 years, 49% of the population were women, 85% White, 6% Black, 8% Asians, and 2% other races. 

Adverse Reactions in a 52-Week Controlled Trial

In a 52-week, double-blind, randomized, placebo-controlled trial (Study 2), 599 patients received 420 mg of REPATHA subcutaneously once monthly [see Clinical Studies (14.1)]. The mean age was 56 years (range: 22 to 75 years), 23% were older than 65 years, 52% women, 80% White, 8% Black, 6% Asian, and 6% Hispanic. Adverse reactions reported in at least 3% of REPATHA-treated patients, and more frequently than in placebo-treated patients in Study 2, are shown in Table 1. Adverse reactions led to discontinuation of treatment in 2.2% of REPATHA-treated patients and 1% of placebo-treated patients. The most common adverse reaction that led to REPATHA treatment discontinuation and occurred at a rate greater than placebo was myalgia (0.3% versus 0% for REPATHA and placebo, respectively).

†includes erythema, pain, bruising

Adverse Reactions in Seven Pooled 12-Week Controlled Trials

In seven pooled 12-week, double-blind, randomized, placebo-controlled trials, 993 patients received 140 mg of REPATHA subcutaneously every 2 weeks and 1059 patients received 420 mg of REPATHA subcutaneously monthly.  The mean age was 57 years (range: 18 to 80 years), 29% were older than 65 years, 49% women, 85% White, 5% Black, 9% Asian, and 5% Hispanic. Adverse reactions reported in at least 1% of REPATHA-treated patients, and more frequently than in placebo-treated patients, are shown in Table 2. 

†140 mg every 2 weeks and 420 mg once monthly combined

Adverse Reactions in Eight Pooled Controlled Trials (Seven 12-Week Trials and One 52-Week Trial)

The adverse reactions described below are from a pool of the 52-week trial (Study 2) and seven 12-week trials. The mean and median exposure durations of REPATHA in this pool of eight trials were 20 weeks and 12 weeks, respectively.

Local Injection Site Reactions

Injection site reactions occurred in 3.2% and 3.0% of REPATHA-treated and placebo-treated patients, respectively. The most common injection site reactions were erythema, pain, and bruising. The proportions of patients who discontinued treatment due to local injection site reactions in REPATHA-treated patients and placebo-treated patients were 0.1% and 0%, respectively.

Allergic Reactions

Allergic reactions occurred in 5.1% and 4.7% of REPATHA-treated and placebo-treated patients, respectively. The most common allergic reactions were rash (1.0% versus 0.5% for REPATHA and placebo, respectively), eczema (0.4% versus 0.2%), erythema (0.4% versus 0.2%), and urticaria (0.4% versus 0.1%).

Neurocognitive Events

In placebo-controlled trials, neurocognitive events were reported in less than or equal to 0.2% in REPATHA-treated and placebo-treated patients. 

Low LDL-C Levels

In a pool of placebo- and active-controlled trials, as well as open-label extension studies that followed them, a total of 1988 patients treated with REPATHA had at least one LDL-C value < 25 mg/dL. Changes to background lipid-altering therapy were not made in response to low LDL-C values, and REPATHA dosing was not modified or interrupted on this basis. Although adverse consequences of very low LDL-C were not identified in these trials, the long-term effects of very low levels of LDL-C induced by REPATHA are unknown.

Musculoskeletal Events

Musculoskeletal adverse reactions were reported in 14.3% of REPATHA-treated patients and 12.8% of placebo-treated patients. The most common adverse reactions that occurred at a rate greater than placebo were back pain (3.2% versus 2.9% for REPATHA and placebo, respectively), arthralgia (2.3% versus 2.2%), and myalgia (2.0% versus 1.8%).

Adverse Reactions in Patients with Homozygous Familial Hypercholesterolemia

In a 12-week, double-blind, randomized, placebo-controlled trial of 49 patients with HoFH (Study 4), 33 patients received 420 mg of REPATHA subcutaneously once monthly [see Clinical Studies (14.3)]. The mean age was 31 years (range: 13 to 57 years), 49% were women, 90% White, 4% Asian, and 6% other. The adverse reactions that occurred in at least two (6.1%) REPATHA-treated patients, and more frequently than in placebo-treated patients, included:

• Upper respiratory tract infection (9.1% versus 6.3%)
• Influenza (9.1% versus 0%)
• Gastroenteritis (6.1% versus 0%)
• Nasopharyngitis (6.1% versus 0%)

6.2       Immunogenicity

As with all therapeutic proteins, there is potential for immunogenicity. The immunogenicity of REPATHA has been eva luated using an electrochemiluminescent bridging screening immunoassay for the detection of binding anti-drug antibodies. For patients whose sera tested positive in the screening immunoassay, an in vitro biological assay was performed to detect neutralizing antibodies. 

In a pool of placebo- and active-controlled clinical trials, 0.1% of patients treated with at least one dose of REPATHA tested positive for binding antibody development. Patients whose sera tested positive for binding antibodies were further eva luated for neutralizing antibodies; none of the patients tested positive for neutralizing antibodies.

There was no evidence that the presence of anti-drug binding antibodies impacted the pharmacokinetic profile, clinical response, or safety of REPATHA, but the long-term consequences of continuing REPATHA treatment in the presence of anti-drug binding antibodies are unknown.

The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of 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 REPATHA with the incidence of antibodies to other products may be misleading.