NEODOSE

INDICATIONS

• Retinopathy of Prematurity (ROP): A systematic review (5 randomized or semi-randomized studies) demonstrated no reduction in retinal detachment or recurrent ROP in infants treated with intravitreal bevacizumab (n=4 studies) or ranibizumab (n=1 studies) compared with laser therapy; however, refractive errors were reduced. In a subgroup analysis, the risk of recurrence was lower in type 1, but higher in type 2 ROP. Intravitreal bevacizumab was well tolerated but long-term systemic effects are unknown. If bevacizumab is offered, consider only for type 1 ROP treatment in patients with zone I or posterior zone II disease. In infants with stage 3+ ROP in each eye, intravitreal 0.625 mg bevacizumab significantly reduced the rate of recurrence compared with conventional laser therapy (6% vs 26%; P=0.002) at 54 weeks’ postmenstrual age in a randomized trial (N=143 infants). However, a significant treatment effect was observed for zone I but not zone II posterior ROP. (Bevacizumab Eliminates the Angiogenic Threat of ROP (BEAT-ROP) Trial). At 2.5 years of age (n=109), a follow-up of the BEAT-ROP trial detected more myopia and very high myopia in laser-treated eyes compared with bevacizumab-treated eyes. In a retrospective study of 241 infants, the ROP recurrence rate was 8.3% with bevacizumab. The recurrence rate was higher in those infants with APROP (31.6%) compared with infants with stage 3+ ROP (6.3%; P less than 0.001). A follow-up (n=39 eyes) with fluorescein angiograph in infants at 4 years of age detected significant ocularvascular abnormalities in bevacizumab (0.5 mg)-treated eyes compared with laser-treated eyes treated for type 1, zone I ROP For 2 months after intravitreal bevacizumab (0.625 mg/dose per eye or 0.25 mg/dose per eye), serum vascular endothelial growth factor (VEGF) and insulin-like growth factor-1 concentrations had greater suppression compared with laser surgery in 24 infants. Serum vascular endothelial growth factor concentrations for intravitreal bevacizumab groups (0.5 mg and 1.25 mg) were 50% lower from day 2 to day 60 compared with laser-treated groups (no bevacizumab). There were no significant differences in serum VGEF concentrations between the 2 bevacizumab doses. The clinical significance of these findings is unknown

FDA APPROVED INDICATION

Safety and effectiveness have not been established in pediatric patients.

IV Administration:

• Cardiovasculer
  • Increased risk for severe (Grade 3 or 4) hypertension; interruption or discontinuation may be necessary.
  • Congestive heart failure (CHF) has been reported; discontinue if CHF develops.
• Gastrointestinal:
  • Gastrointestinal fistulae, including gastrointestinal-vaginal fistula, have been reported and may be accompanied by bowel obstruction requiring surgical interventions. Avoid use in patients with ovarian cancer who have recto-sigmoid involvement by pelvic examination or bowel involvement on CT scan.
• Hamatological:
  • Thrombotic microangiopathy has been reported.
  • Serious and sometimes fatal arterial thrombotic events (ie, cerebral infarction, angina, transient ischemic attack, myocardial infarction) have been reported, with an increased risk in patients with a history of arterial thromboembolism or diabetes. The highest incidence was reported in patients with glioblastoma. Discontinue use if severe event is suspected.
  • Venous thromboembolic events have been reported; discontinuation required if life-threatening (grade 4) thromboembolism or pulmonary embolism occur.
• Infusion reactions:
  • Infusion reactions (ie, hypertension, hypertensive crisis with neurological signs and symptoms, wheezing, oxygen desaturation, hypersensitivity reaction (grade 3), chest pain, headache, rigors, and diaphoresis) have been reported; if severe reaction occurs, stop infusion and institute appropriate therapy.
• Neurologic:
  • Posterior reversible encephalopathy syndrome (PRES) has been reported, occurring from 16 hours up to 1 year after treatment initiation. MRI is required to confirm diagnosis; discontinue use in patients developing PRES
• Non-gastrointestinal fistulae:
  • Non-gastrointestinal fistulae (ie, tracheoesophageal, bronchopleural, biliary, vaginal, renal, bladder), which may be serious and/or fatal, have been reported; discontinuation required for fistula formation involving internal organs, tracheoesophageal fistula or any grade 4 fistula.
• Renal:
  • Nephrotic syndrome, sometimes fatal, has been reported; discontinue use.
  • Proteinuria has been reported; interruption of therapy may be necessary.
• Reproductive:
  • Ovarian failure has been reported.
• Respiratory:
  • Serious and/or fatal pulmonary hemorrhage has been reported.

ADVERSE EFFECTS

• Cardiovascular: Hypotension was reported in a male preterm infant twin 1 day after intravitreal bevacizumab for retinopathy of prematurity. At 9 weeks, intravitreal injection of bevacizumab 0.625 mg/0.025 mL was administered in each eye under IV ketamine (0.3 mg) and local atropine (0.25%). Feeding intolerance, hypotension (42/24 mmHg), and oxygen desaturation (arterial oxygen saturation, 80%) were observed 22 hours after bevacizumab administration and continued the following day. Shortness of breath with apnea and lethargy were also noted. Intubation for mechanical ventilation, treatment with DOPamine, and prophylactic antibiotics were instituted. Blood pressure normalized on day 3 and his general condition improved. On day 6, DOPamine and antibiotics were discontinued. He was successfully extubated on day 7 and arterial oxygen saturation was normal. The sibling received bevacizumab with no episodes of hypotension.
• Musculoskeletal: Non-mandibular osteonecrosis has been reported in patients younger than 18 years who received IV bevacizumab.
• Neurologic: In a retrospective study (n=125), the adjusted odds ratio was 3.1 (95% CI, 1.2 to 8.4) for severe neurodevelopmental disability in intravitreal bevacizumab-treated compared with laser-treated preterm infants at 18 months corrected age after adjusting for gestational age, gender, maternal education, Score for Neonatal Acute Physiology-II score, bronchopulmonary dysplasia, sepsis, and severe brain injury.
• Ophthalmic: More high myopia was seen in eyes treated with bevacizumab (14.6%) than those treated with ranibizumab (0%; p=0.03) at 1 year of age in a retrospective study (n=37 infants).

BLACK BOX WARNING

• Gastrointestinal Perforation: The incidence of gastrointestinal perforation, some fatal, in patients receiving bevacizumab ranged from 0.3 to 3%. Discontinue bevacizumab in patients who develop gastrointestinal perforation.
• Surgery and Wound Healing Complications: The incidence of wound healing and surgical complications, including serious and fatal complications, is increased in patients receiving bevacizumab. Discontinue bevacizumab in patients who develop wound healing complications that require medical intervention. Withhold bevacizumab at least 28 days prior to elective surgery. Do not administer bevacizumab for at least 28 days after surgery and until the wound is fully healed.
• Hemorrhages: Severe or fatal hemorrhage, including hemoptysis, gastrointestinal bleeding, hematemesis, central nervous systems (CNS) hemorrhage, epistaxis, and vaginal bleeding occur up to 5-fold more frequently in patients receiving bevacizumab. Do not administer bevacizumab to patients with a recent history of hemoptysis. Discontinue in patients who develop Grade 3 to 4 hemorrhage.

ADMINISTRATION

Intravitreal Administration:

• Bevacizumab concentration was 25 mg/mL. Diluted concentrations, 3.1 mg/mL to 12.5 mg/mL, have been used with smaller doses.
• In pediatric patients a sterile 30-gauge, 31-gauge, or 32-gauge 4-mm needle injected intravitreally 0.75 mm to 1 mm or 1.5 mm to 2 mm posterior to the temporal limbus into the vitreous cavity.

MONITORING

The duration for follow-up is unknown but will require longer follow-up compared with laser treatment due to delayed or incomplete vascularization, significant rates of recurrence and need for retreatment, and potential for developmentally abnormal or atypical retinal vascular features. In a retrospective case series recurrent ROP occurred a mean of 51.2 weeks (range, 45.7 to 64.9 weeks) adjusted age after intravitreal bevacizumab in 20 infants. Additionally retinal detachment had occurred in 2 treated patients at the age of 2.5 years and 3 years.