CYRAMZA

Ramucirumab is a human monoclonal antibody (IgG1) against vascular endothelial growth factor receptor 2 (VEGFR2), a type II trans-membrane tyrosine kinase receptor expressed on endothelial cells.

By binding to

VEGFR2, ramucirumab prevents binding of its ligands (VEGF-A, VEGF-C, and VEGF-D), thereby preventing VEGF-stimulated receptor phosphorylation and downstream ligand-induced proliferation, permeability, and migration of human endothelial cells.

VEGFR stimulation also mediates downstream signalling required for angiogenesis and is postulated to be heavily involved in cancer progression, making it a highly likely drug target.

In contrast to other agents directed against VEGFR-2, ramucirumab binds a specific epitope on the extracellular domain of VEGFR-2, thereby blocking all VEGF ligands from binding to it.

Ramucirumab is indicated for us in advanced gastric or gastro-esophageal junction adenocarcinoma as a single agent or in combination with paclitaxel after prior fluoropyrimidine.

• or platinum-containing chemotherapy.

Ramucirumab is indicated for the treatment of advanced or metastatic gastric or gastro-esophageal junction adenocarcinoma as a single agent or in combination with paclitaxel for patients who progress after prior fluoropyrimidine.

• or platinum-containing chemotherapy.

It is indicated, in combination with erlotinib, for the first-line treatment of metastatic non-small cell lung cancer with epidermal growth factor exon 19 deletions or exon 21 (L858R) point mutations.

It is also indicated in combination with docetaxel for the treatment of metastatic non-small cell lung cancer in patients who have progressed following prior platinum-based chemotherapy.

Patients who have EGFR or

ALK genomic aberrations should also have disease progression following FDA-approved therapy for these aberrations.

Ramucirumab, in combination with FOLFIRI ( folinic acid, fluorouracil, and irinotecan ), is indicated for the treatment of metastatic colorectal cancer in patients who have progressed following therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine.

Lastly, ramucirumab is indicated for the treatment of hepatocellular carcinoma in patients with an alpha-fetoprotein level ≥400 ng/mL and have previously been treated with sorafenib.

Mechanism of Action Ramucirumab is a

VEGFR2 antagonist that specifically binds VEGFR2 and blocks binding of VEGFR ligands, VEGF-A, VEGF-C, and VEGF-D. As a result, ramucirumab inhibits ligand-stimulated activation of VEGFR2, thereby inhibiting ligand-induced proliferation, and migration of human endothelial cells.

Ramucirumab inhibited angiogenesis in an in vivo animal model. 12.3 Pharmacokinetics The pharmacokinetics (PK) of ramucirumab were studied in patients with various cancers over a dose range of 6-12 mg/kg administered every two or three weeks.

PK characteristics of ramucirumab are similar for patients across cancer types based on a population PK analysis.

Ramucirumab systemic exposure increased dose proportionally at doses of 8 mg/kg and above and steady state concentrations were achieved at approximately 12 weeks.

The mean (% coefficient of variation [CV%]) volume of distribution of ramucirumab at steady-state (Vss) was 5.4 L (15%).

The mean (CV%) clearance of ramucirumab was 0.015 L/hour (30%) and the mean elimination half-life was 14 days (20%).

Age (19-88 years), sex (68% male), race (70% White, 24% Asian), renal impairment (creatinine clearance [CLcr] calculated by Cockcroft-Gault, 15-89 mL/min, mild hepatic impairment (total bilirubin within ULN and AST>ULN or total bilirubin >1 to 1.5 times ULN and any AST), or moderate hepatic impairment (total bilirubin >1.5 to 3 times ULN) had no clinically meaningful effect on the PK of ramucirumab.

The effect of severe hepatic impairment (total bilirubin >3 times ULN and any AST) on the PK of ramucirumab is unknown.

No clinically meaningful changes in the exposure of either ramucirumab or its concomitant drugs in the approved combinations, including paclitaxel, docetaxel, irinotecan (or its active metabolite, SN-38), and erlotinib were observed in patients with solid tumors.

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Ramucirumab packaging includes warnings for arterial thromboembolic events, hypertension, infusion-related reactions, gastrointestinal perforation, clinical deterioration in patients with cirrhosis, and reversible posterior leukoencephalopathy syndrome.

The most common reactions observed in single-agent-treated patients at a rate of >10% and >2% higher than placebo were hypertension and diarrhea.

The most common adverse reactions observed in patients treated with ramucirumab plus paclitaxel at a rate of of >30% and >2% higher than placebo plus paclitaxel were fatigue, neutropenia, diarrhea, and epistaxis.

For intravenous infusion only.

Do not administer as an intravenous push or bolus.

Premedicate before each infusion.

Administer CYRAMZA 8 mg/kg every 2 weeks as a single agent or in combination with weekly paclitaxel.

Administer CYRAMZA 10 mg/kg every 2 weeks with daily erlotinib.

CYRAMZA 10 mg/kg on Day of a 21-day cycle prior to docetaxel.

Administer CYRAMZA 8 mg/kg every 2 weeks prior to FOLFIRI.

Administer CYRAMZA 8 mg/kg every 2 weeks. 2.1 Premedication Prior to each CYRAMZA infusion, premedicate all patients with an intravenous histamine-1 receptor antagonist (e.g., diphenhydramine hydrochloride) .

For patients who have experienced a

Grade 1 or 2 IRR, premedicate with a histamine-1 receptor antagonist, dexamethasone (or equivalent), and acetaminophen prior to each CYRAMZA infusion. 2.2 Recommended Dosage for Gastric Cancer The recommended dosage of CYRAMZA, either as a single agent or in combination with weekly paclitaxel, is 8 mg/kg every 2 weeks administered by intravenous infusion over 60 minutes.

If the first infusion is tolerated, all subsequent CYRAMZA infusions may be administered over 30 minutes.

CYRAMZA until disease progression or unacceptable toxicity.

When given in combination with paclitaxel, administer CYRAMZA prior to administration of paclitaxel.

Refer to the prescribing information for paclitaxel for dosage information. 2.3 Recommended Dosage for Non-Small Cell Lung Cancer EGFR Exon 19 Deletions or Exon 21 (L858R) Substitution Mutations – CYRAMZA in Combination with Erlotinib The recommended dosage of CYRAMZA is 10 mg/kg every 2 weeks administered by intravenous infusion over 60 minutes.

Refer to the prescribing information for erlotinib for dosage information.

Chemotherapy – CYRAMZA in Combination with Docetaxel The recommended dosage of CYRAMZA is 10 mg/kg administered by intravenous infusion over 60 minutes on Day of a 21-day cycle prior to docetaxel infusion.

Refer to the prescribing information for docetaxel for dosage information. 2.4 Recommended Dosage for Colorectal Cancer The recommended dosage of CYRAMZA is 8 mg/kg every 2 weeks administered by intravenous infusion over 60 minutes prior to FOLFIRI administration.

Refer to the prescribing information for fluorouracil, leucovorin, and irinotecan for dosage information. 2.5 Recommended Dosage for Hepatocellular Carcinoma The recommended dosage of CYRAMZA is 8 mg/kg every 2 weeks administered by intravenous infusion over 60 minutes.

CYRAMZA until disease progression or unacceptable toxicity. 2.6 Dosage Modifications for Adverse Reactions Reduce dose, withhold dose, or discontinue CYRAMZA to manage adverse reactions as described in Table 1.

Table 1: Dosage Modifications for CYRAMZA Adverse Reaction Severity a Dosage Modification a National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI CTCAE) version 4.0 used to identify adverse reactions Hemorrhage Grade 3 or 4 Permanently discontinue CYRAMZA Gastrointestinal Perforation All Grades Permanently discontinue CYRAMZA Wound Healing Complications All Grades Withhold CYRAMZA for 28 days prior to elective surgery.

CYRAMZA no sooner than 2 weeks after surgery and until adequate wound healing.

The safety of resumption of

CYRAMZA after resolution of wound healing complications has not been established.

Arterial Thromboembolic Events All Grades Permanently discontinue CYRAMZA Hypertension Severe hypertension Withhold CYRAMZA until controlled with medical management Severe hypertension that cannot be controlled with antihypertensive therapy Permanently discontinue CYRAMZA Infusion-Related Reaction (IRR) Grade 1 or 2 IRR Reduce the infusion rate of CYRAMZA by 50% Grade 3 or 4 IRR Permanently discontinue CYRAMZA Posterior Reversible Encephalopathy Syndrome (PRES) All Grades Permanently discontinue CYRAMZA Proteinuria First occurrence of increased urine protein levels greater than or equal to 2 g per 24 hours Withhold CYRAMZA until urine protein level is less than 2 g per 24 hours Resume CYRAMZA at a reduced dose: Reduce 8 mg/kg dose to 6 mg/kg Reduce 10 mg/kg dose to 8 mg/kg Reoccurrence of urine protein level greater than 2 g per 24 hours following initial dose reduction Withhold CYRAMZA until urine protein level is less than 2 g per 24 hours Resume CYRAMZA at a reduced dose: Reduce 6 mg/kg dose to 5 mg/kg Reduce 8 mg/kg dose to 6 mg/kg Urine protein level greater than 3 g per 24 hours or in the setting of nephrotic syndrome Permanently discontinue CYRAMZA 2.7 Preparation and Administration Preparation Visually inspect vials for particulate matter and discoloration.

Discard if particulate matter or discolorations are identified.

Calculate the dose and the required volume of CYRAMZA needed for the calculated dose.

Withdraw the required volume of

CYRAMZA 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.

Do not shake.

Gently invert the container to ensure adequate mixing.

Do not dilute with other solutions or co-infuse with other electrolytes or medications.

Do not freeze.

Store diluted solution 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 any unused portion of

Visually inspect the diluted solution for particulate matter and discoloration prior to administration.

Do not administer

CYRAMZA as an intravenous push or bolus.

Administer diluted

CYRAMZA solution via infusion pump through a separate infusion line.

Use of a protein sparing 0.22 micron filter is recommended.

Flush the line with sterile 0.9% Sodium Chloride Injection at the end of the infusion.

(ramucirumab) injection is a clear to slightly opalescent and colorless to slightly yellow, preservative-free solution supplied in single-dose vials.

NDC 0002-7669-01 100 mg/10 mL (10 mg/mL), individually packaged in a carton NDC 0002-7678-01 500 mg/50 mL (10 mg/mL), individually packaged in a carton Store vials in a refrigerator at 2°C to 8°C (36°F to 46°F) in the original carton to protect from light until time of use.

Do not freeze or shake the vial.

Based on its mechanism of action, CYRAMZA can cause fetal harm when administered to a pregnant woman.

There are no available data on

CYRAMZA use in pregnant women.

Animal models link angiogenesis, VEGF and VEGFR2 to critical aspects of female reproduction, embryo-fetal development, and postnatal development.

No animal studies have been conducted to evaluate the effect of ramucirumab on reproduction and fetal development.

Advise a pregnant woman of the potential risk to a fetus.

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.

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 embryo-fetal 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 feto-placental 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.

The safety and effectiveness of

CYRAMZA in pediatric patients have not been established.

CYRAMZA were assessed but not established in a single-arm, multicenter, open-label trial [NCT02564198] that included 23 pediatric patients aged 1 year to <17 years with relapsed or refractory solid tumors who received CYRAMZA as a single agent and two multicenter, randomized, controlled trials [NCT04145700 and NCT04145349] that included 16 pediatric patients aged to <17 years with relapsed, recurrent, or progressive desmoplastic small round cell tumors or synovial sarcoma who received CYRAMZA in combination with chemotherapy versus chemotherapy alone.

The effect on open tibial growth plates in pediatric patients who received CYRAMZA has not been adequately studied; however, one patient had progressive widening of distal femoral growth plate.

No other new safety signals were observed in pediatric patients.

The pharmacokinetic (PK) parameters for these pediatric patients who received CYRAMZA as a single agent or in combination was within the range of the values previously observed in adults given the same dose per body weight.

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.

Of the 563 CYRAMZA-treated patients in REGARD and RAINBOW, 205 (36%) were and over, while 41 (7%) were and over.

No overall differences in safety or effectiveness were observed between these subjects and younger subjects.

Of the 221 patients who received CYRAMZA with erlotinib in RELAY, 119 (54%) were and over, while 29 (13%) were and over.

Overall, no clinically meaningful differences in effectiveness were observed between these patients and younger patients.

Adverse reactions occurring at a 10% or higher incidence in patients receiving CYRAMZA with erlotinib and with a 10% or greater difference between patients aged 65 or older compared to patients aged less than 65 years were: diarrhea (75% versus 65%), hypertension (50% versus 40%), increased ALT (49% versus 35%), increased AST (49% versus 33%), stomatitis (46% versus 36%), decreased appetite (32% versus 19%), dysgeusia (23% versus 12%), and weight loss (19% versus 6%).

Of the 1253 patients in REVEL, 455 (36%) were and over and 84 (7%) were and over.

Of the 627 patients who received CYRAMZA with docetaxel in REVEL, 237 (38%) were and over, while 45 (7%) were and over.

In an exploratory subgroup analysis of

REVEL, 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 and over was 1.10 (95% CI: 0.89, 1.36).

Of the 529 patients who received CYRAMZA with FOLFIRI in RAISE, 209 (40%) were and over, while 51 (10%) were and over.

Overall, no differences in safety or effectiveness were observed between these subjects and younger subjects.

Of the 197 patients who received CYRAMZA in REACH-2, 95 (48%) were 65 years and over, while 37 (19%) were 75 years and over.

Overall, no differences in efficacy were observed between these subjects and younger subjects.