The following important adverse reactions have been observed and are discussed in detail in other sections of the label:
- Risk of hepatotoxicity [see WARNINGS AND PRECAUTIONS]
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of a drug cannot be directly compared to rates in the clinical trial of another drug and may not reflect the rates observed in patients in clinical practice.
Safety data are based on pooled results from four Phase 3, randomized, double-blind, placebo-controlled trials with a total of 390 patients of which 261 patients received weekly subcutaneous injections of 200 mg of KYNAMRO and 129 patients received placebo for a median treatment duration of 25 weeks (age range 12-81 years, 47% women, 84% Caucasian, 10% Blacks, 3% Asian, 3% other). For the 141 participants who subsequently were treated in the open-label extension trial, the mean length of study treatment, including exposure to KYNAMRO in the index study, was 19.8 months and the median was 18.2 months. A total of 41 individuals with HoFH were exposed to KYNAMRO for at least 6 months and 25 were exposed for at least 12 months.
Eighteen percent of patients on KYNAMRO and 2% of patients on placebo discontinued treatment due to adverse reactions. The five most common adverse reactions in patients treated with KYNAMRO that led to treatment discontinuation and occurred at a rate greater than placebo were: injection site reactions (5.0%), alanine aminotransferase increased (3.4%), flu-like symptoms (2.7%), aspartate aminotransferase increased (2.3%), and liver function test abnormal (1.5%).
Common Adverse Reactions
Table 2 enumerates adverse reactions that occurred among pooled Phase 3 patients treated with KYNAMRO at an incidence that was at least 2% more than that observed in the placebo-treated patients, listed by system organ class and frequency (MedDRA v.13.0). Similar types and severities of adverse reactions were observed across all populations in this pooled table including the subset of patients with HoFH.
Table 2: Summary of Adverse Reactions for Pooled Phase 3 Placebo-Controlled Trials
|System Organ Class
|Total Patients with Events||95%||85%|
|General disorders and administration site conditions||87%||47%|
|Injection site reactions*||84%||33%|
|Influenza like illness||13%||3%|
|Alanine aminotransferase increased||10%||1%|
|Aspartate aminotransferase increased||6%||2%|
|Liver function test abnormal||5%||1%|
|Hepatic enzyme increased||3%||1%|
|Musculoskeletal and connective tissue disorders||26%||26%|
|Pain in extremity||7%||3%|
|Nervous system disorders||25%||17%|
|* Preferred Terms include: Injection site erythema, Injection site pain, Injection site hematoma, Injection site pruritus, Injection site swelling, Injection site discoloration, Injection site nodule, Injection site rash, Injection site warmth, Injection site induration, Injection site recall reaction, Injection site edema, Injection site hemorrhage, Injection site discomfort, Injection site reaction, Injection site papule, Injection site inflammation, Injection site macule, Injection site vesicles, Injection site urticaria|
In the pooled Phase 3 trials, neoplasms (benign and malignant) were reported in 4% of patients receiving KYNAMRO and 0% of patients receiving placebo. In addition, 9% of patients receiving KYNAMRO and 3% of patients receiving placebo developed 1+ or greater proteinuria by dipstick measurement by the end of the trial.
In the open-label extension trial, one case of hypersensitivity reaction with angioedema and one case of glomerular nephritis were reported.
In the phase 3 trial in patients with HoFH, the mean change in platelet count from baseline to Week 28/Early Termination was -30.6 x 103/uL in the mipomersen group and +8.1 x 103/uL in the placebo group. In the pooled Phase 3 trials the mean change in platelet count from baseline to Week 28/Early Termination was -23.8 x 103/μL in the mipomersen group and -3.5 x 103/μL in the placebo group.
In the pooled, placebo-controlled clinical trials with KYNAMRO, elevated serum transaminase levels, mainly ALT, have been observed as presented in Table 3. Elevated ALT levels ≥ 3X ULN have been reported on two consecutive occasions at least 7 days apart in 8.4% of patients receiving KYNAMRO therapy (versus 0% of placebo patients) with 16.5% of patients receiving KYNAMRO therapy having at least 1 result that was ≥ 3X ULN (versus 0.8% for placebo patients). The ALT elevations observed in the pooled, placebo-controlled trials were generally accompanied by lesser AST elevations and were not associated with increased total bilirubin, changes in INR or PTT, nor by decreased albumin levels. After stopping therapy, in the patients in whom an elevation was observed, transaminase elevations trended toward baseline over a period of weeks to months.
Table 3: Transaminase Results for Pooled Phase 3 Placebo-Controlled Trials
|Parameter||Statistic||Kynamro (%) (N=261)||Placebo (%) (N=129)|
|ALT maximum||Incidence rate, %|
|≥ 3 x ULN and < 5 x ULN||12%||1%|
|≥ 5 x ULN and < 10 x ULN||3%||0%|
|≥ 10 x ULN||1%||0%|
|ALT||≥ 3 x ULN, two consecutive results (at least 7 days apart), %||8%||0%|
|AST maximum||Incidence rate, %|
|≥ 3 x ULN and < 5 x ULN||7%||1%|
|≥ 5 x ULN and < 10 x ULN||3%||0%|
|≥ 10 x ULN||0%||0%|
|AST||≥ 3 x ULN, two consecutive results (at least 7 days apart), %||4%||0%|
|Adults: ALT ULN= 41 U/L; AST ULN = 34 U/L|
Increases in liver fat as measured by MRI were greater in patients receiving KYNAMRO therapy than in patients receiving placebo. Data from Phase 3 supportive trials in patients with heterozygous familial hypercholesterolemia and coronary artery disease and in patients with high risk hypercholesterolemia demonstrated after 26 weeks of treatment, a median nominal increase in fat fraction of 9.6% relative to baseline following KYNAMRO therapy versus a nominal 0.02% change in the placebo group (mean increases were 12.2% mipomersen vs 0.4% placebo). The maximum change in fat fraction was 46% for the KYNAMRO group and 28% for the placebo group. Sixty-two percent of patients receiving KYNAMRO developed a 5% or greater increase in hepatic fat versus 8% of patients receiving placebo. In general, these elevations in fat fraction decreased when assessed by MRI performed 24 weeks after cessation of KYNAMRO in the Phase 3 trial of patients with high-risk hypercholesterolemia. In the open-label extension trial, among individuals with a measurement at baseline and at 12 months or longer on KYNAMRO, 25% had an average liver fat fraction > 20% on at least one occasion.
Injection Site Reactions
The most commonly-reported adverse reactions were injection site reactions occurring in 84% of patients receiving KYNAMRO versus 33% of placebo treated patients. The most common injection site reactions were erythema (59%), pain (56%), hematoma (32%), pruritus (29%), swelling (18%) and discoloration (17%). Injection site reactions did not occur with every injection. Injection site reactions resulted in discontinuation of KYNAMRO in 5% of patients. Recall reactions, consisting of local erythema, tenderness and/or pruritus at previous injection sites when subsequent injections were administered, were observed in 8% of patients, all of whom were receiving KYNAMRO.
Flu-like symptoms, defined as any one of the following: influenza-like illness, pyrexia, chills, myalgia, arthralgia, malaise or fatigue and occurring within 2 days of injection, have been reported more frequently in patients receiving KYNAMRO (29.9%) versus placebo (16.3%) in the pooled Phase 3 studies. Flu-like symptoms did not occur with all injections. Flu-like symptoms resulted in discontinuation of KYNAMRO in 2.7% of patients. In the open-label extension trial, in which all patients received KYNAMRO therapy, 66% reported flu-like symptoms, 25% discontinued treatment due to flu-like symptoms and 9% experienced severe flu-like symptoms.
In the pooled Phase 3 trials, 38% of KYNAMRO-treated patients tested positive for anti-KYNAMRO antibodies during the 6-month trials. Efficacy results in the Phase 3 trials in patients who tested positive for anti-KYNAMRO antibodies were similar to patients who remained negative for antibodies (mean LDL-C percent change from baseline was -32% for antibody-positive and -34% for antibody-negative participants). In the open-label extension trial, approximately 72% of patients receiving KYNAMRO therapy tested positive for anti-KYNAMRO antibodies (35% with titers > 3200). The incidence of flu-like symptoms and the incidence of discontinuation of KYNAMRO were higher in antibody-positive patients. Antibodies to KYNAMRO were associated with higher trough levels for the drug. 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 KYNAMRO with the incidence of antibodies to other products may be misleading.
The following adverse reactions have been identified during post-approval use of KYNAMRO. 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.
- Idiopathic thrombocytopenic purpura