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Avastin dosing and administration in mRCC

Clinical benefits have been observed with Avastin given until disease progression or unacceptable toxicity1

Significant clinical benefit with Avastin plus IFN was observed in mRCC with Avastin given until disease progression or unacceptable toxicity at a recommended dose of 10 mg/kg IV q2w.1

Avastin dosing in mRCC1

Avastin dosing in RCC

The 10 mg/kg IV q2w dose is the only dose of Avastin proven to increase PFS and ORR in mRCC. Avastin should be administered continually and at its full dose, without scheduled treatment interruptions or dose reductions, until disease progression or unacceptable toxicity.1

AVOREN protocol allowed for IFN dose escalation, reduction, or discontinuation2,3
IFN dose reduction or discontinuation were allowed in AVOREN per rotocol
  • *After IFN held per protocol.

IFN dose reduction or discontinuation were allowed in AVOREN per rotocol

IFN dose reduction or discontinuation in AVOREN per protocol

Avastin was continued until disease progression or unacceptable toxicity in AVOREN even if IFN was escalated, reduced, or discontinued1,2

Avastin was continued until disease progression or unacceptable toxicity in AVOREN


In AVOREN, Avastin was continued until disease progression or unacceptable toxicity even if IFN was escalated, reduced, or discontinued. IFN was discontinued after a maximum of 52 weeks, but Avastin was continued until disease progression or unacceptable toxicity.1,2 In AVOREN, 31% (105/337) of patients in the Avastin plus IFN arm discontinued IFN after 52 weeks and received Avastin alone thereafter.2

Forty-nine percent (165/337) of patients in the Avastin plus IFN group received IFN dose reduction and 21% of those patients (71/337) discontinued IFN prior to 52 weeks.3 Avastin was not dose reduced but was discontinued in 21% (71/337) of patients (vs 6% discontinuation of placebo [17/304] in the placebo plus IFN group).3

Important treatment considerations—Dose modifications

  • There are no recommended dose reductions
  • Discontinue Avastin in patients with
    • Gastrointestinal (GI) perforations (GI perforations, fistula formation in the GI tract, intra-abdominal abscess)
    • Fistula formation involving an internal organ
    • Wound dehiscence and wound healing complications requiring medical intervention
    • Serious hemorrhage (ie, requiring medical intervention)
    • Severe arterial thromboembolic event (ATE)
    • Hypertensive crisis or hypertensive encephalopathy
    • Reversible posterior leukoencephalopathy syndrome (RPLS) (symptoms usually resolve or improve within days, although some patients have experienced ongoing neurologic sequelae)
    • Nephrotic syndrome
  • Temporarily suspend Avastin for at least 4 weeks prior to elective surgery, severe hypertension not controlled with medical management, moderate to severe proteinuria pending further evaluation, and severe infusion reactions
  • The safety of resumption of Avastin therapy in patients that experienced RPLS, ATE, and moderate to severe proteinuria is unknown

Important treatment considerations—Women of childbearing potential

  • Avastin increases 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 Avastin
  • Long-term effects of Avastin exposure on fertility are unknown
  • Prior to initiation of therapy, advise patients of the potential risk of Avastin to the developing fetus
  • Counsel patients who become pregnant about the possible risks, including hazard to the fetus and/or loss of pregnancy, of both continued treatment and prolonged exposure following discontinuation, keeping in mind the approximate half-life of Avastin (20 days; range 11–50 days). Patients should also be counseled to continue adequate contraception for at least 6 months following the last dose of Avastin
  • Nursing mothers should be advised to discontinue nursing or Avastin, taking into account the half-life of the product and the importance of Avastin to the mother
Indication

Avastin is indicated for the treatment of metastatic renal cell carcinoma in combination with interferon alfa.

Boxed WARNINGS
  • Gastrointestinal (GI) perforation
    • Serious and sometimes fatal GI perforation occurs at a higher incidence in Avastin-treated patients compared to controls
    • The incidences of GI perforation ranged from 0.3% to 2.4% across clinical studies
    • Discontinue Avastin in patients with GI perforation
  • Surgery and wound healing complications
    • The incidence of wound healing and surgical complications, including serious and fatal complications, is increased in Avastin-treated patients
    • Do not initiate Avastin for at least 28 days after surgery and until the surgical wound is fully healed. The appropriate interval between termination of Avastin and subsequent elective surgery required to reduce the risks of impaired wound healing/wound dehiscence has not been determined
    • Discontinue Avastin at least 28 days prior to elective surgery and in patients with wound healing complications requiring medical intervention
  • Hemorrhage
    • Severe or fatal hemorrhage, including hemoptysis, GI bleeding, hematemesis, central nervous system hemorrhage, epistaxis, and vaginal bleeding, occurred up to 5-fold more frequently in patients receiving Avastin. Across indications, the incidence of grade ≥3 hemorrhagic events among patients receiving Avastin ranged from 1.2% to 4.6%
    • Do not administer Avastin to patients with serious hemorrhage or recent hemoptysis (≥1/2 tsp of red blood)
    • Discontinue Avastin in patients with serious hemorrhage (ie, requiring medical intervention)
Additional serious adverse events
  • Additional serious and sometimes fatal adverse events with increased incidence in the Avastin-treated arm vs control included
    • Non-GI fistula formation (≤0.3%)
    • Arterial thromboembolic events (grade ≥3, 2.4%)
    • Proteinuria including nephrotic syndrome (<1%)
  • Additional serious adverse events with increased incidence in the Avastin-treated arm vs control included
    • Hypertension (grade 3–4, 5%–18%)
    • Reversible posterior leukoencephalopathy syndrome (RPLS) (<0.1%)
  • Infusion reactions with the first dose of Avastin were uncommon (<3%), and severe reactions occurred in 0.2% of patients
  • Inform females of reproductive potential of the risk of ovarian failure prior to starting treatment with Avastin
Most common adverse events
  • Most common adverse reactions observed in Avastin patients at a rate >10% and at least twice the control arm rate were
    – Epistaxis
    – Headache
    – Hypertension
    – Rhinitis
    – Proteinuria
    – Taste alteration
    – Dry skin
    – Rectal hemorrhage
    – Lacrimation disorder
    – Back pain
    – Exfoliative dermatitis
  • Across all studies, Avastin was discontinued in 8.4% to 21% of patients because of adverse reactions
Pregnancy warning
  • Avastin may impair fertility
  • Based on animal data, Avastin may cause fetal harm
  • Advise patients of the potential risk to the fetus during and following Avastin and the need to continue adequate contraception for at least 6 months following the last dose of Avastin
  • For nursing mothers, discontinue nursing or Avastin, taking into account the importance of Avastin to the mother
  • In mRCC, the most common grade 3–5 adverse events in AVOREN, occurring at a ≥2% higher incidence in Avastin-treated patients vs controls, were fatigue (13% vs 8%), asthenia (10% vs 7%), proteinuria (7% vs 0%), hypertension (6% vs 1%), and hemorrhage (3% vs 0.3%)

Please see full Prescribing Information, including Boxed WARNINGS, for additional important safety information.

Next: mRCC Resources

References:
  1. Avastin Prescribing Information. Genentech, Inc. September 2011.
  2. Escudier B, Pluzanska A, Koralewski P, et al. Lancet. 2007;370:2103-2111.
  3. Data on file. Genentech, Inc.