Цирамза

Gastric Cancer

Цирамза®as a single agent, or in combination with paclitaxel, is indicated for the treatment of patients with advanced or metastatic, gastric or gastro-esophageal junction adenocarcinoma with disease progression on or after prior fluoropyrimidine-or platinum-containing chemotherapy.

Non-Small Cell Lung Cancer

Цирамза, in combination with docetaxel, is indicated for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) with disease progression on or after platinum-based chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving Цирамза.

Colorectal Cancer

Цирамза, in combination with FOLFIRI (irinotecan, folinic acid, and 5-fluorouracil), is indicated for the treatment of patients with metastatic colorectal cancer (mCRC) with disease progression on or after prior therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine.

Do not administer Цирамза as an intravenous push or bolus.

Recommended Dose And Schedule

Gastric Cancer

• The recommended dose of Цирамза either as a single agent or in combination with weekly paclitaxel is 8 mg/kg every 2 weeks administered as an intravenous infusion over 60 minutes. Continue Цирамза until disease progression or unacceptable toxicity.
• When given in combination, administer Цирамза prior to administration of paclitaxel.

Non-Small Cell Lung Cancer

• The recommended dose of Цирамза is 10 mg/kg administered by intravenous infusion over 60 minutes on day 1 of a 21-day cycle prior to docetaxel infusion. Continue Цирамза until disease progression or unacceptable toxicity.

Colorectal Cancer

• The recommended dose of Цирамза is 8 mg/kg every 2 weeks administered by intravenous infusion over 60 minutes prior to FOLFIRI administration. Continue Цирамза until disease progression or unacceptable toxicity.

Premedication

• Prior to each Цирамза infusion, premedicate all patients with an intravenous histamine H1 antagonist (e.g., diphenhydramine hydrochloride).
• For patients who have experienced a Grade 1 or 2 infusion-related reaction, also premedicate with dexamethasone (or equivalent) and acetaminophen prior to each Цирамза infusion.

Dose Modifications

Infusion-Related Reactions (IRR)

• Reduce the infusion rate of Цирамза by 50% for Grade 1 or 2 IRRs.
• Permanently discontinue Цирамза for Grade 3 or 4 IRRs.

Hypertension

• Interrupt Цирамза for severe hypertension until controlled with medical management.
• Permanently discontinue Цирамза for severe hypertension that cannot be controlled with antihypertensive therapy.

Proteinuria

• Interrupt Цирамза for urine protein levels ≥ 2 g/24 hours. Reinitiate treatment at a reduced dose (see Table 1) once the urine protein level returns to < 2 g/24 hours. If the protein level ≥ 2 g/24 hours reoccurs, interrupt Цирамза and reduce the dose (see Table 1) once the urine protein level returns to < 2 g/24 hours.
• Permanently discontinue Цирамза for urine protein level > 3 g/24 hours or in the setting of nephrotic syndrome.

Table 1: Цирамза Dose Reductions for Proteinuria

Wound Healing Complications

• Interrupt Цирамза prior to scheduled surgery until the wound is fully healed.

Arterial Thromboembolic Events, Gastrointestinal Perforation, or Grade 3 or 4 Bleeding

• Permanently discontinue Цирамза.

For toxicities related to paclitaxel, docetaxel, or the components of FOLFIRI, refer to the current prescribing information.

Preparation For Administration

Inspect vial contents for particulate matter and discoloration prior to dilution. Discard the vial, if particulate matter or discolorations are identified. Store vials in a refrigerator at 2°C to 8°C (36°F to 46°F) until time of use. Keep the vial in the outer carton in order to protect from light.

• Calculate the dose and the required volume of Цирамза needed to prepare the infusion solution. Vials contain either 100 mg/10 mL or 500 mg/50 mL at a concentration of 10 mg/mL solution of Цирамза.
• Withdraw the required volume of Цирамза and further dilute with only 0.9% Sodium Chloride Injection in an intravenous infusion container to a final volume of 250 mL. Do not use dextrose containing solutions.
• Gently invert the container to ensure adequate mixing.
• DO NOT FREEZE OR SHAKE the infusion solution. DO NOT dilute with other solutions or co-infuse with other electrolytes or medications.
• Store diluted infusion for no more than 24 hours at 2°C to 8°C (36°F to 46°F) or 4 hours at room temperature (below 25°C [77°F]).
• Discard vial with any unused portion of Цирамза.

Administration

• Visually inspect the diluted solution for particulate matter and discoloration prior to administration. If particulate matter or discolorations are identified, discard the solution.
• Administer diluted Цирамза infusion via infusion pump over 60 minutes through a separate infusion line. Use of a protein sparing 0.22 micron filter is recommended. Flush the line with sterile sodium chloride (0.9%) solution for injection at the end of the infusion.

None

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Hemorrhage

Цирамза increased the risk of hemorrhage and gastrointestinal hemorrhage, including severe and sometimes fatal hemorrhagic events. In Study 1, the incidence of severe bleeding was 3.4% for Цирамза and 2.6% for placebo. In Study 2, the incidence of severe bleeding was 4.3% for Цирамза plus paclitaxel and 2.4% for placebo plus paclitaxel.

Patients with gastric cancer receiving nonsteroidal anti-inflammatory drugs (NSAIDs) were excluded from enrollment in Studies 1 and 2; therefore, the risk of gastric hemorrhage in Цирамза-treated patients with gastric tumors receiving NSAIDs is unknown.

In Study 3, the incidence of severe bleeding was 2.4% for Цирамза plus docetaxel and 2.3% for placebo plus docetaxel. Patients with NSCLC receiving therapeutic anticoagulation or chronic therapy with NSAIDS or other anti-platelet therapy other than once daily aspirin or with radiographic evidence of major airway or blood vessel invasion or intratumor cavitation were excluded from Study 3; therefore the risk of pulmonary hemorrhage in these groups of patients is unknown.

In Study 4, the incidence of severe bleeding was 2.5% for Цирамза plus FOLFIRI and 1.7% for placebo plus FOLFIRI.

Permanently discontinue Цирамза in patients who experience severe bleeding.

Arterial Thromboembolic Events

Serious, sometimes fatal, arterial thromboembolic events (ATEs) including myocardial infarction, cardiac arrest, cerebrovascular accident, and cerebral ischemia occurred in clinical trials including 1.7% of 236 patients who received Цирамза as a single agent for gastric cancer in Study 1. Permanently discontinue Цирамза in patients who experience a severe ATE.

Hypertension

An increased incidence of severe hypertension occurred in patients receiving Цирамза as a single agent (8%) as compared to placebo (3%), in patients receiving Цирамза plus paclitaxel (15%) as compared to placebo plus paclitaxel (3%), in patients receiving Цирамза plus docetaxel (6%) as compared to placebo plus docetaxel (2%), and in patients receiving Цирамза plus FOLFIRI (11%) as compared to placebo plus FOLFIRI (3%).

Control hypertension prior to initiating treatment with Цирамза. Monitor blood pressure every two weeks or more frequently as indicated during treatment.

Temporarily suspend Цирамза for severe hypertension until medically controlled. Permanently discontinue Цирамза if medically significant hypertension cannot be controlled with antihypertensive therapy or in patients with hypertensive crisis or hypertensive encephalopathy.

Infusion-Related Reactions

Prior to the institution of premedication recommendations across clinical trials of Цирамза, IRRs occurred in 6 out of 37 patients (16%), including two severe events. The majority of IRRs across trials occurred during or following a first or second Цирамза infusion. Symptoms of IRRs included rigors/tremors, back pain/spasms, chest pain and/or tightness, chills, flushing, dyspnea, wheezing, hypoxia, and paresthesia. In severe cases, symptoms included bronchospasm, supraventricular tachycardia, and hypotension.

Monitor patients during the infusion for signs and symptoms of IRRs in a setting with available resuscitation equipment. Immediately and permanently discontinue Цирамза for Grade 3 or 4 IRRs.

Gastrointestinal Perforations

Цирамза is an antiangiogenic therapy that can increase the risk of gastrointestinal perforation, a potentially fatal event. Four of 570 patients (0.7%) who received Цирамза as a single agent in clinical trials experienced gastrointestinal perforation. In Study 2, the incidence of gastrointestinal perforation was also increased in patients that received Цирамза plus paclitaxel (1.2%) as compared to patients receiving placebo plus paclitaxel (0.3%). In Study 3, the incidence of gastrointestinal perforation was 1% for Цирамза plus docetaxel and 0.3% for placebo plus docetaxel. In Study 4, the incidence of gastrointestinal perforation was 1.7% for Цирамза plus FOLFIRI and 0.6% for placebo plus FOLFIRI. Permanently discontinue Цирамза in patients who experience a gastrointestinal perforation.

Impaired Wound Healing

Impaired wound healing can occur with antibodies inhibiting the VEGF pathway. Цирамза has not been studied in patients with serious or non-healing wounds. Цирамза, an antiangiogenic therapy, has the potential to adversely affect wound healing. Discontinue Цирамза therapy in patients with impaired wound healing.

Withhold Цирамза prior to surgery. Resume following the surgical intervention based on clinical judgment of adequate wound healing. If a patient develops wound healing complications during therapy, discontinue Цирамза until the wound is fully healed.

Clinical Deterioration In Patients with Child-Pugh B or C Cirrhosis

Clinical deterioration, manifested by new onset or worsening encephalopathy, ascites, or hepatorenal syndrome was reported in patients with Child-Pugh B or C cirrhosis who received single-agent Цирамза. Use Цирамза in patients with Child-Pugh B or C cirrhosis only if the potential benefits of treatment are judged to outweigh the risks of clinical deterioration.

Reversible Posterior Leukoencephalopathy Syndrome

Reversible Posterior Leukoencephalopathy Syndrome (RPLS) has been reported with a rate of < 0.1% in clinical studies with Цирамза. Confirm the diagnosis of RPLS with MRI and discontinue Цирамза in patients who develop RPLS. Symptoms may resolve or improve within days, although some patients with RPLS can experience ongoing neurologic sequelae or death.

Proteinuria Including Nephrotic Syndrome

In Study 4, severe proteinuria occurred more frequently in patients treated with Цирамза plus FOLFIRI compared to patients receiving placebo plus FOLFIRI. Severe proteinuria was reported in 3% of patients treated with Цирамза plus FOLFIRI (including 3 cases [0.6%] of nephrotic syndrome) compared to 0.2% of patients treated with placebo plus FOLFIRI.

Monitor proteinuria by urine dipstick and/or urinary protein creatinine ratio for the development of worsening of proteinuria during Цирамза therapy.

Withhold Цирамза for urine protein levels that are 2 or more grams over 24 hours. Reinitiate Цирамза at a reduced dose once the urine protein level returns to less than 2 grams over 24 hours. Permanently discontinue Цирамза for urine protein levels greater than 3 grams over 24 hours or in the setting of nephrotic syndrome.

Thyroid Dysfunction

Monitor thyroid function during treatment with Цирамза. In Study 4, the incidence of hypothyroidism reported as an adverse event was 2.6% in the Цирамза plus FOLFIRI treated patients and 0.9% in the placebo plus FOLFIRI treated patients.

Embryofetal Toxicity

Based on its mechanism of action, Цирамза can cause fetal harm when administered to pregnant women. Animal models link angiogenesis, VEGF and VEGF Receptor 2 (VEGFR2) to critical aspects of female reproduction, embryofetal development, and postnatal development. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with Цирамза and for at 3 least months after the last dose of Цирамза.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

No animal studies have been performed to test ramucirumab for potential carcinogenicity or genotoxicity.

Inhibition of VEGFR2 signaling in animal models was shown to result in changes to hormone levels critical for pregnancy, and, in monkeys, an increased duration of the follicular cycle. In a 39 week animal study, female monkeys treated with ramucirumab showed dose dependent increases in follicular mineralization of the ovary.

Use In Specific Populations

Pregnancy

Risk Summary

Based on its mechanism of action , Цирамза 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 Цирамза use in pregnant women to inform any drug–associated risks. No animal studies have been conducted to evaluate 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

Animal Data

No animal studies have been specifically conducted to evaluate the effect of ramucirumab on reproduction and fetal development. In mice, loss of the VEGFR2 gene resulted in embryofetal death and these fetuses lacked organized blood vessels and blood islands in the yolk sac. In other models, VEGFR2 signaling was associated with development and maintenance of endometrial and placental vascular function, successful blastocyst implantation, maternal and fetoplacental vascular differentiation, and development during early pregnancy in rodents and non-human primates. Disruption of VEGF signaling has also been associated with developmental anomalies including poor development of the cranial region, forelimbs, forebrain, heart, and blood vessels.

Lactation

Risk Summary

There is no information on the presence of ramucirumab in human milk, the effects on the breast-fed infant, or the effects on milk production. Human IgG is present in human milk, but published data suggest that breast milk antibodies do not enter the neonatal and infant circulation in substantial amounts. Because of the potential risk for serious adverse reactions in nursing infants from ramucirumab, advise women that breastfeeding is not recommended during treatment with Цирамза.

Females And Males Of Reproductive Potential

Contraception

Females

Based on its mechanism of action, Цирамза can cause fetal harm. Advise females of reproductive potential to use effective contraception while receiving Цирамза and for at least 3 months after the last dose of Цирамза.

Infertility

Females

Advise females of reproductive potential that based on animal data Цирамза may impair fertility.

Pediatric Use

The safety and effectiveness of Цирамза in pediatric patients have not been established. In animal studies, effects on epiphyseal growth plates were identified. In cynomolgus monkeys, anatomical pathology revealed adverse effects on the epiphyseal growth plate (thickening and osteochondropathy) at all doses tested (5-50 mg/kg). Ramucirumab exposure at the lowest weekly dose tested in the cynomolgus monkey was 0.2 times the exposure in humans at the recommended dose of ramucirumab as a single agent.

Geriatric Use

Of the 563 Цирамза-treated patients in two randomized gastric cancer clinical studies, 36% were 65 and over, while 7% were 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects.

Of the 1253 patients in Study 3, 455 (36%) were 65 and over and 84 (7%) were 75 and over. Of the 627 patients who received Цирамза plus docetaxel in Study 3, 237 (38%) were 65 and over, while 45 (7%) were 75 and over. In an exploratory subgroup analysis of Study 3, the hazard ratio for overall survival in patients less than 65 years old was 0.74 (95% CI: 0.62, 0.87) and in patients 65 years or older was 1.10 (95% CI: 0.89, 1.36).

Of the 529 patients who received Цирамза plus FOLFIRI in Study 4, 209 (40%) were 65 and over, while 51 (10%) were 75 and over. Overall, no differences in safety or effectiveness were observed between these subjects and younger subjects.

Renal Impairment

No dose adjustment is recommended for patients with renal impairment based on population pharmacokinetic analysis.

Hepatic Impairment

No dose adjustment is recommended for patients with mild (total bilirubin within upper limit of normal [ULN] and aspartate aminotransferase [AST] > ULN, or total bilirubin > 1.0-1.5 times ULN and any AST) or moderate (total bilirubin > 1.5-3.0 times ULN and any AST) hepatic impairment based on population pharmacokinetic analysis. Clinical deterioration was reported in patients with Child-Pugh B or C cirrhosis who received single-agent Цирамза.

The following adverse drug reactions are discussed in greater detail in other sections of the label:

• Hemorrhage.
• Arterial Thromboembolic Events.
• Hypertension.
• Infusion-Related Reactions.
• Gastrointestinal Perforation.
• Impaired Wound Healing.
• Patients with Child-Pugh B or C Cirrhosis.
• Reversible Posterior Leukoencephalopathy Syndrome.
• Proteinuria Including Nephrotic Syndrome.
• Thyroid Dysfunction.

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.

Gastric Cancer

Safety data are presented from two randomized, placebo controlled clinical trials in which patients received Цирамза: Study 1, a randomized (2:1), double-blind, clinical trial in which 351 patients received either Цирамза 8 mg/kg intravenously every two weeks or placebo every two weeks and Study 2, a double-blind, randomized (1:1) clinical trial in which 656 patients received paclitaxel 80 mg/m² on days 1, 8, and 15 of each 28-day cycle plus either Цирамза 8 mg/kg intravenously every two weeks or placebo every two weeks. Both trials excluded patients with Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 2 or greater, uncontrolled hypertension, major surgery within 28 days, or patients receiving chronic anti-platelet therapy other than once daily aspirin. Study 1 excluded patients with bilirubin ≥ 1.5 mg/dL and Study 2 excluded patients with bilirubin > 1.5 times the upper limit of normal.

Цирамза Administered as a Single Agent

Among 236 patients who received Цирамза (safety population) in Study 1, median age was 60 years, 28% were women, 76% were W hite, and 16% were Asian. Patients in Study 1 received a median of 4 doses of Цирамза; the median duration of exposure was 8 weeks, and 32 (14% of 236) patients received Цирамза for at least six months.

In Study 1, the most common adverse reactions (all grades) observed in Цирамза-treated patients at a rate of ≥ 10% and ≥ 2% higher than placebo were hypertension and diarrhea. The most common serious adverse events with Цирамза were anemia (3.8%) and intestinal obstruction (2.1%). Red blood cell transfusions were given to 11% of Цирамза-treated patients versus 8.7% of patients who received placebo.

Table 2 provides the frequency and severity of adverse reactions in Study 1.

Table 2: Adverse Reactions Occurring at Incidence Rate ≥ 5% and a ≥ 2% Difference Between Arms in Patients Receiving Цирамза in Study 1

Clinically relevant adverse reactions reported in ≥ 1% and < 5% of Цирамза-treated patients in Study 1 were: neutropenia (4.7% Цирамза versus 0.9% placebo), epistaxis (4.7% Цирамза versus 0.9% placebo), rash (4.2% Цирамза versus 1.7% placebo), intestinal obstruction (2.1% Цирамза versus 0% placebo), and arterial thromboembolic events (1.7% Цирамза versus 0% placebo).

Across clinical trials of Цирамза administered as a single agent, clinically relevant adverse reactions (including Grade ≥ 3) reported in Цирамза-treated patients included proteinuria, gastrointestinal perforation, and infusion-related reactions.

In Study 1, according to laboratory assessment, 8% of Цирамза-treated patients developed proteinuria versus 3% of placebo-treated patients. Two patients discontinued Цирамза due to proteinuria. The rate of gastrointestinal perforation in Study 1 was 0.8% and the rate of infusion-related reactions was 0.4%.

Цирамза Administered in Combination with Paclitaxel

Among 327 patients who received Цирамза (safety population) in Study 2, median age was 61 years, 31% were women, 63% were White, and 33% were Asian. Patients in Study 2 received a median of 9 doses of Цирамза; the median duration of exposure was 18 weeks, and 93 (28% of 327) patients received Цирамза for at least six months.

In Study 2, the most common adverse reactions (all grades) observed in patients treated with Цирамза plus paclitaxel at a rate of ≥ 30% and ≥ 2% higher than placebo plus paclitaxel were fatigue, neutropenia, diarrhea, and epistaxis. The most common serious adverse events with Цирамза plus paclitaxel were neutropenia (3.7%) and febrile neutropenia (2.4%); 19% of patients treated with Цирамза plus paclitaxel received granulocyte colony-stimulating factors. Adverse reactions resulting in discontinuation of any component of the Цирамза plus paclitaxel combination in 2% or more patients in Study 2 were neutropenia (4%) and thrombocytopenia (3%).

Table 3 provides the frequency and severity of adverse reactions in Study 2.

Table 3: Adverse Reactions Occurring at Incidence Rate ≥ 5% and a ≥ 2% Difference Between Arms in Patients Receiving Цирамза plus Paclitaxel in Study 2

Clinically relevant adverse reactions reported in ≥ 1% and < 5% of the Цирамза plus paclitaxel treated patients in Study 2 were sepsis (3.1% Цирамза plus paclitaxel versus 1.8% placebo plus paclitaxel) and gastrointestinal perforations (1.2% Цирамза plus paclitaxel versus 0.3% for placebo plus paclitaxel).

Non-Small Cell Lung Cancer

Цирамза Administered in Combination with Docetaxel

Study 3 was a multinational, randomized, double-blind study conducted in patients with NSCLC with disease progression on or after one platinum-based therapy for locally advanced or metastatic disease. Patients received either Цирамза 10 mg/kg intravenously plus docetaxel 75 mg/m² intravenously every 3 weeks or placebo plus docetaxel 75 mg/m² intravenously every 3 weeks. Due to an increased incidence of neutropenia and febrile neutropenia in patients enrolled in East Asian sites, Study 3 was amended and 24 patients (11 Цирамза plus docetaxel, 13 placebo plus docetaxel) at East Asian sites received a starting dose of docetaxel at 60 mg/m² every 3 weeks.

Study 3 excluded patients with an ECOG PS of 2 or greater, bilirubin greater than the upper limit of normal (ULN), uncontrolled hypertension, major surgery within 28 days, radiographic evidence of major airway or blood vessel invasion by cancer, radiographic evidence of intra-tumor cavitation, or gross hemoptysis within the preceding 2 months, and patients receiving therapeutic anticoagulation or chronic anti-platelet therapy other than once daily aspirin. The study also excluded patients whose only prior treatment for advanced NSCLC was a tyrosine kinase (epidermal growth factor receptor [EGFR] or anaplastic lymphoma kinase [ALK]) inhibitor.

The data described below reflect exposure to Цирамза plus docetaxel in 627 patients in Study 3. Demographics and baseline characteristics were similar between treatment arms. Median age was 62 years; 67% of patients were men; 84% were W hite and 12% were Asian; 33% had ECOG PS 0; 74% had non-squamous histology and 25% had squamous histology. Patients received a median of 4.5 doses of Цирамза; the median duration of exposure was 3.5 months, and 195 (31% of 627) patients received Цирамза for at least six months.

In Study 3, the most common adverse reactions (all grades) observed in Цирамза plus docetaxel-treated patients at a rate of ≥ 30% and ≥ 2% higher than placebo plus docetaxel were neutropenia, fatigue/asthenia, and stomatitis/mucosal inflammation. Treatment discontinuation due to adverse reactions occurred more frequently in Цирамза plus docetaxel-treated patients (9%) than in placebo plus docetaxel-treated patients (5%). The most common adverse events leading to treatment discontinuation of Цирамза were infusion-related reaction (0.5%) and epistaxis (0.3%). For patients with non-squamous histology, the overall incidence of pulmonary hemorrhage was 7% and the incidence of ≥ Grade 3 pulmonary hemorrhage was 1% for Цирамза plus docetaxel compared to 6% overall incidence and 1% for ≥ Grade 3 pulmonary hemorrhage for placebo plus docetaxel. For patients with squamous histology, the overall incidence of pulmonary hemorrhage was 10% and the incidence of ≥ Grade 3 pulmonary hemorrhage was 2% for Цирамза plus docetaxel compared to 12% overall incidence and 2% for ≥ Grade 3 pulmonary hemorrhage for placebo plus docetaxel.

The most common serious adverse events with Цирамза plus docetaxel were febrile neutropenia (14%), pneumonia (6%), and neutropenia (5%). The use of granulocyte colony-stimulating factors was 42% in Цирамза plus docetaxel-treated patients versus 37% in patients who received placebo plus docetaxel. In patients ≥ 65 years, there were 18 (8%) deaths on treatment or within 30 days of discontinuation for Цирамза plus docetaxel and 9 (4%) deaths for placebo plus docetaxel. In patients < 65 years, there were 13 (3%) deaths on treatment or within 30 days of discontinuation for Цирамза plus docetaxel and 26 (6%) deaths for placebo plus docetaxel.

Table 4 provides the frequency and severity of adverse reactions in Study 3.

Table 4: Adverse Reactions Occurring at Incidence Rate ≥ 5% and a ≥ 2% Difference Between Arms in Patients Receiving Цирамза in Study 3

Clinically relevant adverse drug reactions reported in ≥ 1% and < 5% of the Цирамза plus docetaxel-treated patients in Study 3 were hyponatremia (4.8% Цирамза plus docetaxel versus 2.4% for placebo plus docetaxel) and proteinuria (3.3% Цирамза plus docetaxel versus 0.8% placebo plus docetaxel).

Colorectal Cancer

Цирамза Administered in Combination with FOLFIRI

Study 4 was a multinational, randomized, double-blind study conducted in patients with metastatic colorectal cancer with disease progression on or after therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine. Patients received either Цирамза 8 mg/kg intravenously plus FOLFIRI intravenously every 2 weeks or placebo plus FOLFIRI intravenously every 2 weeks.

Study 4 excluded patients with an ECOG PS of 2 or greater, uncontrolled hypertension, major surgery within 28 days, and those who experienced any of the following during first-line therapy with a bevacizumab-containing regimen: an arterial thrombotic/thromboembolic event; Grade 4 hypertension; Grade 3 proteinuria; a Grade 3-4 bleeding event; or bowel perforation.

Demographics and baseline characteristics for the treated population were similar between treatment arms (n=1057). Median age was 62 years; 57% of patients were men; 76% were White and 20% were Asian; 48% had ECOG PS 0.

The data described in this section reflect exposure to Цирамза plus FOLFIRI in 529 patients in Study 4. Patients received a median of 8 doses (range 1-68) of Цирамза; the median duration of exposure was 4.4 months, and 169 (32% of 529) patients received Цирамза for at least six months. The most common adverse reactions (all grades) observed in Цирамза plus FOLFIRI-treated patients at a rate of ≥ 30% and ≥ 2% higher than placebo plus FOLFIRI were diarrhea, neutropenia, decreased appetite, epistaxis, and stomatitis. Twenty percent of patients treated with Цирамза plus FOLFIRI received granulocyte colony-stimulating factors. Treatment discontinuation of any study drug due to adverse reactions occurred more frequently in Цирамза plus FOLFIRI-treated patients (29%) than in placebo plus FOLFIRI-treated patients (13%).

The most common adverse reactions leading to discontinuation of any component of Цирамза plus FOLFIRI as compared to placebo 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 Цирамза were proteinuria (1.5%) and gastrointestinal perforation (1.7%).

The most common serious adverse events with Цирамза 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 Цирамза in Study 4

Clinically relevant adverse reactions reported in ≥ 1% and < 5% of Цирамза plus FOLFIRI-treated patients in Study 4 consisted of gastrointestinal perforation (1.7% Цирамза plus FOLFIRI versus 0.6% for placebo plus FOLFIRI).

Thyroid stimulating hormone (TSH) levels were evaluated in 224 patients (115 Цирамза 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 Цирамза plus FOLFIRI compared with 4 (4%) patients treated with placebo plus FOLFIRI.

Immunogenicity

As with all therapeutic proteins, there is the potential for immunogenicity. In 23 clinical trials, 86/2890 (3.0%) of Цирамза-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 Цирамза with the incidences of antibodies to other products may be misleading.

There are no data on overdose in humans. Цирамза was administered at doses up to 10 mg/kg every two weeks without reaching a maximum tolerated dose.

The pharmacokinetic (PK) characteristics of ramucirumab are similar for patients with gastric cancer, NSCLC, and mCRC based on a population PK analysis. The mean (% coefficient of variation [CV%]) clearance for ramucirumab was 0.015 L/hour (30%) and the mean terminal half-life was 14 days (20%).