bo plus FOLFIRI, were neutropenia (12.5% versus 5.3%) and thrombocytopenia (4.2% versus 0.8%). The most common adverse reactions leading to treatment discontinuation of CYRAMZA were proteinuria (1.5%) and gastrointestinal perforation (1.7%).
The most common serious adverse events with CYRAMZA plus FOLFIRI were diarrhea (3.6%), intestinal obstruction (3.0%), and febrile neutropenia (2.8%).
Table 5 provides the frequency and severity of adverse reactions in Study 4.
Table 5: Adverse Reactions Occurring at Incidence Rate ≥5% and a ≥2% Difference Between Arms in Patients Receiving CYRAMZA in Study 4
a Includes 3 patients with nephrotic syndrome in the CYRAMZA plus FOLFIRI treatment group.
Clinically relevant adverse reactions reported in ≥1% and <5% of CYRAMZA plus FOLFIRI-treated patients in Study 4 consisted of gastrointestinal perforation (1.7% CYRAMZA plus FOLFIRI versus 0.6% for placebo plus FOLFIRI).
Thyroid stimulating hormone (TSH) levels were eva luated in 224 patients (115 CYRAMZA plus FOLFIRI-treated patients and 109 placebo plus FOLFIRI-treated patients) with normal baseline TSH levels. Patients underwent periodic TSH laboratory assessments until 30 days after the last dose of study treatment. Increased TSH levels were observed in 53 (46%) patients treated with CYRAMZA plus FOLFIRI compared with 4 (4%) patients treated with placebo plus FOLFIRI.
6.2 Immunogenicity
As with all therapeutic proteins, there is the potential for immunogenicity. In 23 clinical trials, 86/2890 (3.0%) of CYRAMZA-treated patients tested positive for treatment-emergent anti-ramucirumab antibodies by an enzyme-linked immunosorbent assay (ELISA). Neutralizing antibodies were detected in 14 of the 86 patients who tested positive for treatment-emergent anti-ramucirumab antibodies.
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 incidence of antibodies to CYRAMZA with the incidences of antibodies to other products may be misleading.
7 DRUG INTERACTIONS
No pharmacokinetic interactions were observed between ramucirumab and paclitaxel, between ramucirumab and docetaxel, or between ramucirumab and irinotecan or its active metabolite, SN-38 [see Clinical Pharmacology (12.3)].
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Risk Summary
Based on its mechanism of action [see Clinical Pharmacology (12.1)], CYRAMZA can cause fetal harm. Animal models link angiogenesis, VEGF and VEGF Receptor 2 (VEGFR2) to critical aspects of female reproduction, embryofetal development, and postnatal development. There are no available data on CYRAMZA use in pregnant women to inform any drug–associated risks. No animal studies have been conducted to eva luate the effect of ramucirumab on reproduction and fetal development. The background risk of major birth defects and miscarriage for the indicated populations are 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. Advise pregnant women of the potential risk to a fetus.
Data
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