Cyramza ® (ramucirumab)

This information is intended for UK registered healthcare professionals only as a scientific exchange in response to your search for information. Please refer to the link for full prescribing information: Cyramza Summary of Product Characteristics (SmPC)

Cyramza® (ramucirumab): Proteinuria

Monitor for proteinuria during ramucirumab therapy. Permanently discontinue if urine protein level >3g/24 hours or in the event of nephrotic syndrome.

Incidence of Proteinuria

The incidence of any grade and grade ≥3 proteinuria in phase 3 clinical trials are presented in Table 1.

Table 1. Incidence of Any Grade and Grade ≥3 Proteinuria in the Phase 3 Clinical Studies1-6


Any Grade (%)

Grade ≥3 (%)

REGARD (second-line gastric cancer)

Ramucirumab (n=236)



Placebo (n=115)



RAINBOW (second-line gastric cancer)

Ramucirumab + Paclitaxel (n=327)



Paclitaxel + Placebo (n=329)



REVEL (second-line NSCLC)

Ramucirumab + Docetaxel (n=627)



Docetaxel + Placebo (n=618)



RAISE (second-line CRC)a

Ramucirumab + FOLFIRI (n=529)



FOLFIRI + Placebo (n=528)



REACH-2 (second-line HCC)

Ramucirumab (n=197)



Placebo (n=95)



RELAY (first-line EGFR mutation+ NSCLC)

Ramucirumab + Erlotinib (n=221)



Erlotinib + Placebo (n=225)



Abbreviations: CRC = colorectal cancer; EGFR = epidermal growth factor receptor; FOLFIRI = irinotecan, folinic acid, and 5-fluorouracil; HCC = hepatocellular carcinoma; NSCLC = non-small cell lung cancer.

a Proteinuria includes proteinuria and nephrotic syndrome.

Monitoring for Proteinuria

Patients should be monitored for the development or worsening of proteinuria during ramucirumab therapy. If the urine protein is ≥2+ on a dipstick, a 24 hour urine collection should be performed. Ramucirumab therapy should be temporarily discontinued if the urine protein level is ≥2 g/24 hours. Once the urine protein level returns to <2 g/24 hours, treatment should be resumed at a reduced dose level (see Table 2). A second dose reduction (see Table 2) is recommended if a urine protein level ≥2 g/24 hours reoccurs.7

Clinical Trial Protocols

In the REGARD trial, urinalysis was performed every 6 weeks, and in the RAINBOW and REACH-2 trials, urinalysis was performed prior to each ramucirumab treatment (days 1 and 15 of a 28-day cycle). In the REVEL trial, routine dipstick measurements were done within 72 hours prior to treatment on day 1 of every second cycle (screening period, before cycle 3, cycle 5, and every 2 cycles thereafter). In the RAISE trial, urinalysis was done at baseline and prior to every third cycle. In the RELAY trial, urinalysis was done at baseline and prior to every cycle. A patient’s urinary protein was measured by routine urinalysis or dipstick in clinical trials.1,2,5,6,8

Proteinuria and Dose Adjustments

Ramucirumab therapy should be permanently discontinued if the urine protein level is >3 g/24 hours or in the event of nephrotic syndrome.7

Ramucirumab dose modifications for proteinuria are summarized in Table 2.

Table 2. Ramucirumab dose reductions for proteinuria7

Initial ramucirumab dose:

First dose reduction to:

Second dose reduction to:

8 mg/kg

6 mg/kg

5 mg/kg

10 mg/kg

8 mg/kg

6 mg/kg


1. Fuchs CS, Tomasek J, Yong CJ, et al. Ramucirumab monotherapy for previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (REGARD): an international, randomised, multicentre, placebo-controlled, phase 3 trial. Lancet. 2014;383(9911):31-39.

2. Wilke H, Muro K, Van Cutsem E, et al. Ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (RAINBOW): a double-blind, randomised phase 3 trial. Lancet Oncol. 2014;15(11):1224-1235.

3. Garon EB, Ciuleanu TE, Arrieta O, et al. Ramucirumab plus docetaxel versus placebo plus docetaxel for second-line treatment of stage IV non-small-cell lung cancer after disease progression on platinum-based therapy (REVEL): a multicentre, double-blind, randomised phase 3 trial. Lancet. 2014;384(9944):665-673.

4. Tabernero J, Yoshino T, Cohn AL, et al. Ramucirumab versus placebo in combination with second-line FOLFIRI in patients with metastatic colorectal carcinoma that progressed during or after first-line therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine (RAISE): a randomised, double-blind, multicentre, phase 3 study. Lancet Oncol. 2015;16(5):499-508.

5. Zhu AX, Kang YK, Yen CJ, et al. Ramucirumab after sorafenib in patients with advanced hepatocellular carcinoma and increased α-fetoprotein concentrations (REACH-2): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2019;20(2):282-296.

6. Nakagawa K, Garon EB, Seto T, et al. Ramucirumab plus erlotinib in patients with untreated, EGFR-mutated, advanced non-small-cell lung cancer (RELAY): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2019;20(12):1655-1669.

7. Cyramza [summary of product characteristics]. Eli Lilly Nederland B.V., The Netherlands.

8. Data on file, Eli Lilly and Company and/or one of its subsidiaries.


CRC = colorectal cancer

FOLFIRI = irinotecan, folinic acid, and 5-fluorouracil

HCC = hepatocellular carcinoma

NSCLC = non-small cell lung cancer

Date of Last Review: October 07, 2019

Contact Lilly

Call or Email us

If you want to ask a Medical Information question or you want to report an adverse event or product complaint you can call us or email us at

Available Mon - Fri, 10am - 4pm, excluding Bank Holidays

Or you can

Chat with Us

Click to Chat is Offline

If you have a question, you can chat online with a Lilly Medical Information professional.

Submit a request