DRUG INTERACTIONS

A drug interaction study was performed in which irinotecan was administered as part of the FOLFIRI regimen with or without bevacizumab.

The results demonstrated no significant effect of bevacizumab on the pharmacokinetics of irinotecan or its active metabolite SN38. In a randomized study in 99 patients with NSCLC, based on limited data, there did not appear to be a difference in the mean exposure of either carboplatin or paclitaxel when each was administered alone or in combination with bevacizumab.

However, 3 of the 8 patients receiving bevacizumab plus paclitaxel/carboplatin had substantially lower paclitaxel exposure after four cycles of treatment (at Day 63) than those at Day 0, while patients receiving paclitaxel/carboplatin without bevacizumab had a greater paclitaxel exposure at Day 63 than at Day 0.

In Study 8, there was no difference in the mean exposure of interferon alfa administered in combination with bevacizumab when compared to interferon alfa alone.

ADVERSE REACTIONS

­ Most common adverse reactions incidence (>10% and at least twice the control arm rate)

are epistaxis, headache, hypertension, rhinitis, proteinuria, taste alteration, dry skin, rectal hemorrhage, lacrimation disorder, back pain and exfoliative dermatitis.

CONTRAINDICATIONS

­ None

WARNINGS AND PRECAUTIONS

­ • Perforation or Fistula: Discontinue MVASI if perforation or fistula occurs. 

• Arterial Thromboembolic Events (e.g., myocardial infarction, cerebral infarction): Discontinue MVASI for severe ATE.

• Venous Thromboembolic Events: Discontinue MVASI for life-threatening VTE 

• Hypertension: Monitor blood pressure and treat hypertension. Temporarily suspend MVASI if not medically controlled. Discontinue MVASI for hypertensive crisis or hypertensive encephalopathy. 

• Posterior Reversible Encephalopathy Syndrome (PRES): Discontinue MVASI. 

• Proteinuria: Monitor urine protein. Discontinue MVASI for nephrotic syndrome. Temporarily suspend MVASI for moderate proteinuria. 

• Infusion Reactions: Stop MVASI for severe infusion reactions.

• Embryo-fetal Toxicity: Advise females of potential risk to a fetus and the need for use of effective contraception. 

• Ovarian Failure: Advise females of the potential risk. 

  INDICATIONS AND USAGE

 PATIENT COUNSELING INFORMATION

Advise patients: 

i.To undergo routine blood pressure monitoring and to contact their health care provider if blood pressure is elevated.

ii. To immediately contact their health care provider for unusual bleeding, high fever, rigors, sudden onset of worsening neurological function, or persistent or severe abdominal pain, severe constipation, or vomiting.

iii. Of increased risk of wound healing complications during and following MVASI.

iv. Of increased risk of an arterial thromboembolic event.

v. Of the increased risk for ovarian failure following MVASI treatment. Embryo-fetal Toxicity

vi. Advise female patients that MVASI may cause fetal harm and to inform their healthcare provider with a known or suspected pregnancy.

vii Advise females of reproductive potential to use effective contraception during treatment with MVASI and for 6 months after the last dose of MVASI

viii.Lactation - Advise nursing women that breastfeeding is not recommended during treatment with MVASI 

Manufactured by:

Amgen Inc. One Amgen Center Drive Thousand Oaks, CA 91320-1799

Marketed by Amgen Inc. ? 2017 Amgen Inc. All rights reserved. 1xxxxxx- v1

CLINICAL PHARMACOLOGY

1. Mechanism of Action

Bevacizumab products bind VEGF and prevent the interaction of VEGF to its receptors (Flt-1 and KDR) on the surface of endothelial cells. The interaction of VEGF with its receptors leads to endothelial cell proliferation and new blood vessel formation in in vitro models of angiogenesis.

Administration of bevacizumab products to xenotransplant models of colon cancer in nude (athymic) mice caused reduction of microvascular growth and inhibition of metastatic disease progression.

2.Pharmacokinetics

The pharmacokinetic profile of bevacizumab was assessed using an assay that measures total serum bevacizumab concentrations (i.e., the assay did not distinguish between free bevacizumab and bevacizumab bound to VEGF ligand).

Based on a population pharmacokinetic analysis of 491 patients who received 1 to 20 mg/kg of bevacizumab weekly, every 2 weeks, or every 3 weeks, the estimated  half-life of bevacizumab was approximately 20 days (range 11-50 days). The predicted time to reach steady state was 100 days.

 USE IN SPECIFIC POPULATIONS

1. Pregnancy Risk Summary

Bevacizumab products may cause fetal harm based on findings from animal studies and the drug’s mechanism of action

 Limited postmarketing reports describe cases of fetal malformations with use of bevacizumab products in pregnancy; however, these reports are insufficient to determine drug associated risks.

 Advise pregnant women of the potential risk to a fetus.

The background risk of major birth defects and miscarriage for the indicated population is 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.

2.Lactation

No data are available regarding the presence of bevacizumab products in human milk, the effects on the breast fed infant, or the effects on milk production

Because of the potential for serious adverse reactions in breastfed infants from bevacizumab products, advise a nursing woman that breastfeeding is not recommended during treatment with MVASI.

3. Females and Males of Reproductive Potential Contraception

Females                                                                                                               Bevacizumab products may cause fetal harm when administered to a pregnant woman. Advise female patients of reproductive potential to use effective contraception during treatment with MVASI and for 6 months following the last dose of MVASI

Infertility Females                                                                                                Bevacizumab products increase the risk of ovarian failure and may impair fertility.

Inform females of reproductive potential of the risk of ovarian failure prior to starting treatment with MVASI. Long term effects of bevacizumab products exposure on fertility are unknown.

4.Pediatric patients-                                                                                                             The safety, effectiveness and pharmacokinetic profile of bevacizumab products in pediatric patients have not been established.

In published literature reports, cases of non-mandibular osteonecrosis have been observed in patients under the age of 18 years who have received bevacizumab.

Bevacizumab products are not approved for use in patients under the age of 18 years.

5.Geriatric Use                                                                                                                  In Study 1, severe adverse events that occurred at a higher incidence (=2%) in patients aged =65 years as compared to younger patients were asthenia, sepsis, deep thrombophlebitis, hypertension, hypotension, myocardial infarction, congestive heart failure, diarrhea, constipation, anorexia, leukopenia, anemia, dehydration, hypokalemia, and hyponatremia

. The effect of bevacizumab products on overall survival was similar in elderly patients as compared to younger patients.

In Study 2, patients aged =65 years receiving bevacizumab plus FOLFOX4 had a greater relative risk as cvents: nausea, emesis, ileus, and fatigue. In Study 5, patients aged =65 years receiving carboplatin, paclitaxel, and bevacizumab had a greater relative risk for proteinuria as compared to younger patients

OVERDOSAGE                                                                                                               The highest dose tested in humans (20 mg/kg IV) was associated with headache in nine of 16 patients and with severe headache in three of 16 patients.