BEVACIZUMAB Drug Interactions: What You Need to Know

INTERACTIONS Effects of VEGZELMA on Other Drugs No clinically meaningful effect on the pharmacokinetics of irinotecan or its active metabolite SN38, interferon alfa, carboplatin or paclitaxel was observed when bevacizumab was administered in combination with these drugs; however, 3 of the 8 patients receiving bevacizumab with paclitaxel and carboplatin had lower paclitaxel exposure after four cycles of treatment (at Day 63) than those at Day 0, while patients receiving paclitaxel and carboplatin alone had a greater paclitaxel exposure at Day 63 than at Day 0.

None. None ( 4 )

AND PRECAUTIONS Gastrointestinal Perforations and Fistula : Discontinue for gastrointestinal perforations, tracheoesophageal fistula, grade 4 fistula, or fistula formation involving any organ ( 5.1 ) Surgery and Wound Healing Complications : In patients who experience wound healing complications during Avastin treatment, withhold Avastin until adequate wound healing. Withhold for at least 28 days prior to elective surgery. Do not administer Avastin for at least 28 days following a major surgery, and until adequate wound healing. The safety of resumption of AVASTIN after resolution of wound healing complication has not been established. Discontinue for wound healing complication of necrotizing fasciitis. ( 5.2 ) Hemorrhage: Severe or fatal hemorrhages have occurred. Do not administer for recent hemoptysis. Discontinue for Grade 3-4 hemorrhage ( 5.3 )

Arterial Thromboembolic

Events (ATE) : Discontinue for severe ATE. ( 5.4 )

Venous Thromboembolic

Events (VTE) : Discontinue for Grade 4 VTE. ( 5.5 ) Hypertension : Monitor blood pressure and treat hypertension. Withhold if not medically controlled; resume once controlled. Discontinue for hypertensive crisis or hypertensive encephalopathy. ( 5.6 )

Posterior Reversible Encephalopathy

Syndrome (PRES ) : Discontinue. ( 5.7 )

Renal

Injury and Proteinuria : Monitor urine protein. Discontinue for nephrotic syndrome. Withhold until less than 2 grams of protein in urine. ( 5.8 ) Infusion-Related Reactions : Decrease rate for infusion-related reactions. Discontinue for severe infusion-related reactions and administer medical therapy. ( 5.9 ) Embryo-Fetal Toxicity : May cause fetal harm. Advise females of potential risk to fetus and need for use of effective contraception. ( 5.10 , 8.1 , 8.3 )

Ovarian

Failure : Advise females of the potential risk. ( 5.11 , 8.3 )

Congestive Heart

Failure (CHF) : Discontinue Avastin in patients who develop CHF. ( 5.12 )

5.1 Gastrointestinal Perforations and Fistulae Serious, and sometimes fatal, gastrointestinal perforation occurred at a higher incidence in patients receiving Avastin compared to patients receiving chemotherapy. The incidence ranged from 0.3% to 3% across clinical studies, with the highest incidence in patients with a history of prior pelvic radiation. Perforation can be complicated by intra-abdominal abscess, fistula formation, and the need for diverting ostomies. The majority of perforations occurred within 50 days of the first dose <span class="opacity-50 text-xs">[see Adverse Reactions (6.1) ]</span> . Serious fistulae (including, tracheoesophageal, bronchopleural, biliary, vaginal, renal and bladder sites) occurred at a higher incidence in patients receiving Avastin compared to patients receiving chemotherapy. The incidence ranged from &lt; 1% to 1.8% across clinical studies, with the highest incidence in patients with cervical cancer. The majority of fistulae occurred within 6 months of the first dose. Patients who develop a gastrointestinal vaginal fistula may also have a bowel obstruction and require surgical intervention, as well as a diverting ostomy.

Avoid

Avastin in patients with ovarian cancer who have evidence of recto-sigmoid involvement by pelvic examination or bowel involvement on CT scan or clinical symptoms of bowel obstruction. Discontinue in patients who develop gastrointestinal perforation, tracheoesophageal fistula or any Grade 4 fistula. Discontinue in patients with fistula formation involving any internal organ .

5.2 Surgery and Wound Healing Complications In a controlled clinical study in which Avastin was not administered within 28 days of major surgical procedures, the incidence of wound healing complications, including serious and fatal complications, was 15% in patients with mCRC who underwent surgery while receiving Avastin and 4% in patients who did not receive Avastin. In a controlled clinical study in patients with relapsed or recurrent GBM, the incidence of wound healing events was 5% in patients who received Avastin and 0.7% in patients who did not receive Avastin <span class="opacity-50 text-xs">[see Adverse Reactions (6.1) ]</span>. In patients who experience wound healing complications during Avastin treatment, withhold Avastin until adequate wound healing. Withhold for at least 28 days prior to elective surgery. Do not administer for at least 28 days following major surgery and until adequate wound healing. The safety of resumption of AVASTIN after resolution of wound healing complications has not been established <span class="opacity-50 text-xs">[see Dosage and Administration (2.9) ]</span> . Necrotizing fasciitis including fatal cases, has been reported in patients receiving Avastin, usually secondary to wound healing complications, gastrointestinal perforation or fistula formation.

Discontinue

Avastin in patients who develop necrotizing fasciitis .

5.3 Hemorrhage Avastin can result in two distinct patterns of bleeding: minor hemorrhage, which is most commonly Grade 1 epistaxis, and serious hemorrhage, which in some cases has been fatal. Severe or fatal hemorrhage, including hemoptysis, gastrointestinal bleeding, hematemesis, CNS hemorrhage, epistaxis, and vaginal bleeding, occurred up to 5-fold more frequently in patients receiving Avastin compared to patients receiving chemotherapy alone. Across clinical studies, the incidence of Grades 3-5 hemorrhagic events ranged from 0.4% to 7% in patients receiving Avastin <span class="opacity-50 text-xs">[see Adverse Reactions (6.1) ]</span>. Serious or fatal pulmonary hemorrhage occurred in 31% of patients with squamous NSCLC and 4% of patients with non-squamous NSCLC receiving Avastin with chemotherapy compared to none of the patients receiving chemotherapy alone. An evaluation for the presence of varices is recommended within 6 months of initiation of Avastin in patients with HCC. There is lack of clinical data to support the safety of Avastin in patients with variceal bleeding within 6 months prior to treatment, untreated or incompletely treated varices with bleeding, or high risk of bleeding because these patients were excluded from clinical trials of Avastin in HCC <span class="opacity-50 text-xs">[see Clinical Studies (14.10) ]</span> . Do not administer Avastin to patients with recent history of hemoptysis of 1/2 teaspoon or more of red blood. Discontinue in patients who develop a Grades 3-4 hemorrhage.

5.4 Arterial Thromboembolic Events Serious, sometimes fatal, arterial thromboembolic events (ATE) including cerebral infarction, transient ischemic attacks, myocardial infarction, and angina, occurred at a higher incidence in patients receiving Avastin compared to patients receiving chemotherapy. Across clinical studies, the incidence of Grades 3-5 ATE was 5% in patients receiving Avastin with chemotherapy compared to ≤2% in patients receiving chemotherapy alone; the highest incidence occurred in patients with GBM. The risk of developing ATE was increased in patients with a history of arterial thromboembolism, diabetes, or &gt;65 years <span class="opacity-50 text-xs">[see Use in Specific Populations (8.5) ]</span>. Discontinue in patients who develop a severe ATE. The safety of reinitiating Avastin after an ATE is resolved is not known.

5.5 Venous Thromboembolic Events An increased risk of venous thromboembolic events (VTE) was observed across clinical studies <span class="opacity-50 text-xs">[see Adverse Reactions (6.1) ]</span> .

In

Study GOG-0240, Grades 3-4 VTE occurred in 11% of patients receiving Avastin with chemotherapy compared with 5% of patients receiving chemotherapy alone. In EORTC 26101, the incidence of Grades 3-4 VTE was 5% in patients receiving Avastin with chemotherapy compared to 2% in patients receiving chemotherapy alone.

Discontinue

Avastin in patients with a Grade 4 VTE, including pulmonary embolism .

5.6 Hypertension Severe hypertension occurred at a higher incidence in patients receiving Avastin as compared to patients receiving chemotherapy alone. Across clinical studies, the incidence of Grades 3-4 hypertension ranged from 5% to 18%. Monitor blood pressure every two to three weeks during treatment with Avastin. Treat with appropriate anti-hypertensive therapy and monitor blood pressure regularly. Continue to monitor blood pressure at regular intervals in patients with Avastin-induced or -exacerbated hypertension after discontinuing Avastin.

Withhold

Avastin in patients with severe hypertension that is not controlled with medical management; resume once controlled with medical management. Discontinue in patients who develop hypertensive crisis or hypertensive encephalopathy.

5.7 Posterior Reversible Encephalopathy Syndrome Posterior reversible encephalopathy syndrome (PRES) was reported in &lt; 0.5% of patients across clinical studies. The onset of symptoms occurred from 16 hours to 1 year after the first dose. PRES is a neurological disorder which can present with headache, seizure, lethargy, confusion, blindness and other visual and neurologic disturbances. Mild to severe hypertension may be present. Magnetic resonance imaging is necessary to confirm the diagnosis of PRES.

Discontinue

Avastin in patients who develop PRES. Symptoms usually resolve or improve within days after discontinuing Avastin, although some patients have experienced ongoing neurologic sequelae. The safety of reinitiating Avastin in patients who developed PRES is not known.

5.8 Renal Injury and Proteinuria The incidence and severity of proteinuria was higher in patients receiving Avastin as compared to patients receiving chemotherapy.

Grade

3 (defined as urine dipstick 4+ or > 3.5 grams of protein per 24 hours) to Grade 4 (defined as nephrotic syndrome) ranged from 0.7% to 7% in clinical studies. The overall incidence of proteinuria (all grades) was only adequately assessed in Study BO17705, in which the incidence was 20%. Median onset of proteinuria was 5.6 months (15 days to 37 months) after initiating Avastin. Median time to resolution was 6.1 months (95% CI: 2.8, 11.3). Proteinuria did not resolve in 40% of patients after median follow-up of 11.2 months and required discontinuation of Avastin in 30% of the patients who developed proteinuria [see Adverse Reactions (6.1) ] . In an exploratory, pooled analysis of patients from seven randomized clinical studies, 5% of patients receiving Avastin with chemotherapy experienced Grades 2-4 (defined as urine dipstick 2+ or greater or > 1 gram of protein per 24 hours or nephrotic syndrome) proteinuria.

Grades

2-4 proteinuria resolved in 74% of patients. Avastin was reinitiated in 42% of patients. Of the 113 patients who reinitiated Avastin, 48% experienced a second episode of Grades 2-4 proteinuria. Nephrotic syndrome occurred in < 1% of patients receiving Avastin across clinical studies, in some instances with fatal outcome. In a published case series, kidney biopsy of 6 patients with proteinuria showed findings consistent with thrombotic microangiopathy. Results of a retrospective analysis of 5805 patients who received Avastin with chemotherapy and 3713 patients who received chemotherapy alone, showed higher rates of elevated serum creatinine levels (between 1.5 to 1.9 times baseline levels) in patients who received Avastin. Serum creatinine levels did not return to baseline in approximately one-third of patients who received Avastin. Monitor proteinuria by dipstick urine analysis for the development or worsening of proteinuria with serial urinalyses during Avastin therapy. Patients with a 2+ or greater urine dipstick reading should undergo further assessment with a 24-hour urine collection. Withhold for proteinuria greater than or equal to 2 grams per 24 hours and resume when less than 2 grams per 24 hours. Discontinue in patients who develop nephrotic syndrome. Data from a postmarketing safety study showed poor correlation between UPCR (Urine Protein/Creatinine Ratio) and 24-hour urine protein [Pearson Correlation 0.39 (95% CI: 0.17, 0.57)] .

5.9 Infusion-Related Reactions Infusion-related reactions reported across clinical studies and postmarketing experience include hypertension, hypertensive crises associated with neurologic signs and symptoms, wheezing, oxygen desaturation, Grade 3 hypersensitivity, anaphylactoid/anaphylactic reactions, chest pain, headaches, rigors, and diaphoresis. In clinical studies, infusion-related reactions with the first dose occurred in &lt; 3% of patients and severe reactions occurred in 0.4% of patients. Decrease the rate of infusion for mild, clinically insignificant infusion-related reactions. Interrupt the infusion in patients with clinically significant infusion-related reactions and consider resuming at a slower rate following resolution. Discontinue in patients who develop a severe infusion-related reaction and administer appropriate medical therapy (e.g., epinephrine, corticosteroids, intravenous antihistamines, bronchodilators and/or oxygen).

5.10 Embryo-Fetal Toxicity Based on its mechanism of action and findings from animal studies, Avastin may cause fetal harm when administered to pregnant women. Congenital malformations were observed with the administration of bevacizumab to pregnant rabbits during organogenesis every 3 days at a dose as low as a clinical dose of 10 mg/kg. Furthermore, animal models link angiogenesis and VEGF and VEGFR2 to critical aspects of female reproduction, embryo-fetal 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 Avastin and for 6 months after the last dose <span class="opacity-50 text-xs">[see Use in Specific Populations (8.1 , 8.3) ]</span>.

5.11 Ovarian Failure The incidence of ovarian failure was 34% vs. 2% in premenopausal women receiving Avastin with chemotherapy as compared to those receiving chemotherapy alone for adjuvant treatment of a solid tumor. After discontinuing Avastin, recovery of ovarian function at all time points during the post-treatment period was demonstrated in 22% of women receiving Avastin. Recovery of ovarian function is defined as resumption of menses, a positive serum β-HCG pregnancy test, or an FSH level &lt; 30 mIU/mL during the post-treatment period. Long-term effects of Avastin on fertility are unknown. Inform females of reproductive potential of the risk of ovarian failure prior to initiating Avastin <span class="opacity-50 text-xs">[see Adverse Reactions (6.1) , Use in Specific Populations (8.3) ]</span>.

5.12 Congestive Heart Failure (CHF) Avastin is not indicated for use with anthracycline-based chemotherapy. The incidence of Grade ≥ 3 left ventricular dysfunction was 1% in patients receiving Avastin compared to 0.6% of patients receiving chemotherapy alone. Among patients who received prior anthracycline treatment, the rate of CHF was 4% for patients receiving Avastin with chemotherapy as compared to 0.6% for patients receiving chemotherapy alone. In previously untreated patients with a hematological malignancy, the incidence of CHF and decline in left ventricular ejection fraction (LVEF) were increased in patients receiving Avastin with anthracycline-based chemotherapy compared to patients receiving placebo with the same chemotherapy regimen. The proportion of patients with a decline in LVEF from baseline of ≥ 20% or a decline from baseline of 10% to &lt; 50%, was 10% in patients receiving Avastin with chemotherapy compared to 5% in patients receiving chemotherapy alone. Time to onset of left-ventricular dysfunction or CHF was 1 to 6 months after the first dose in at least 85% of the patients and was resolved in 62% of the patients who developed CHF in the Avastin arm compared to 82% in the placebo arm.

Discontinue

Avastin in patients who develop CHF.