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A - Drug Name

aflibercept

SYNONYM(S):   VEGF Trap; AVE0005; VEGF Trap R1R2

COMMON TRADE NAME(S):   Zaltrap® (Sanofi-aventis)

 
B - Mechanism of Action and Pharmacokinetics

Aflibercept is a recombinant fusion protein consisting of Vascular Endothelial Growth Factor (VEGF)-binding portions, fused to human IgG1. It binds to VEGF-A, VEGF-B and PIGF (placental growth factor), therefore preventing binding of these ligands to their cognate receptors.  Inhibition of VEGF results in decreased neovascularization and decreased vascular permeability. Aflibercept is approved only in combination therapy. The addition of aflibercept to FOLFIRI improved overall and progression-free survival in metastatic colorectal cancer patients (Van Custem, 2012).



Absorption
Aflibercept exhibits linear pharmacokinetics over the dose range of 2-9 mg/kg. An increase in exposure of 29% was observed in patients weighing 100 kg.  Age, gender, race did not have a clinically important effect on free aflibercept exposure.
Time to reach steady state By second dose

Distribution

No information found

Metabolism

Proteolytic catabolism to peptides, amino acids

Elimination
Half-life 6 days
 
C - Indications and Status
Health Canada Approvals:

In combination with irinotecan plus fluoropyrimidine-based chemotherapy for patients with metastatic colorectal cancer that is resistant to or has progressed following an oxaliplatin-containing regimen.

 
D - Adverse Effects

Emetogenic Potential:  

Moderate (with FOLFIRI)

Extravasation Potential:   Minimal

The following adverse events were reported in the phase III study of aflibercept in combination with FOLFIRI.

ORGAN SITE SIDE EFFECT* (%) ONSET**
Cardiovascular Arterial thromboembolism (3%) E
Cardiotoxicity (rare) E  D
Hypertension (41%) (may be severe) E
Venous thromboembolism (5%) E
Dermatological Hand-foot syndrome (11%) E
Rash (rare) E
Gastrointestinal Abdominal pain (27%) E
Anorexia (32%) E
Diarrhea (69%) (may be severe) E
Gastrointestinal fistula (1.5%) (may be non-GI) E
GI obstruction (2%) E
GI perforation (rare) E
Mucositis (50%) E
Nausea, vomiting (53%) I  E
General Fatigue (48%) E
Wound dehiscence (rare) E
Hematological Myelosuppression ± infection, bleeding (37%) (grade 3-4) E
Thrombotic microangiopathy (rare) E
Hepatobiliary ↑ LFTs (58%) E
Hypersensitivity Hypersensitivity (rare) I  E
Metabolic / Endocrine Hyperglycemia (rare) E  D
Musculoskeletal Musculoskeletal pain (12%) E
Osteonecrosis of jaw (rare) E  D
Neoplastic Secondary malignancy (rare) D  L
Nervous System Headache (22%) E
Peripheral neuropathy (6%) E
PRES (rare) E
Renal Proteinuria (62%) E
Renal failure (rare) E
Respiratory Pneumonitis (ARDS; rare) E


* "Incidence" may refer to an absolute value or the higher value from a reported range.
"Rare" may refer to events with < 1% incidence, reported in post-marketing, phase 1 studies,
isolated data or anecdotal reports.
Dose-limiting side effects are underlined.

** I = immediate (onset in hours to days)     E = early (days to weeks)
D = delayed (weeks to months)      L = late (months to years)

The most common side effects for aflibercept (combined with FOLFIRI) include myelosuppression +/- infection, bleeding, diarrhea, nausea/vomiting, mucositis, hypertension, fatigue, anorexia and abdominal pain.

Hypertension is common and may be severe. Blood pressure should be monitored regularly and treated appropriately. For a suggested treatment algorithm, see Appendix 8: Management of Angiogenesis Inhibitor (AI) Induced Hypertension.

Heart failure and decreased LVEF have been reported.

Reversible posterior/posterior reversible leukoencephalopathy syndrome (PRES/RPLS) has been reported during aflibercept monotherapy and in combination with other chemotherapies.

Hemorrhage is common and usually mild, but may include severe intracranial and pulmonary bleeding.

ONJ has been reported in patients with risk factors, including bisphosphonate use and/or invasive dental procedures.

Neutralizing antibodies have been reported with potential for immunogenicity (clinical significance unknown).

 
E - Dosing

Refer to protocol by which patient is being treated. A supply of loperamide should be provided for diarrhea.

Do not use in patients with ECOG PS of 3 or 4, nor in patients with moderate or severe increases in bilirubin. Consider a reduction in the starting dose of FOLFIRI for elderly patients (≥ 70 years), patients with prior abdominal or pelvic irradiation, patients with a poor performance status (ECOG of 2), patients with mild increases in bilirubin (including Gilbert’s syndrome), patients homozygous for UGT1A1*28 allele or patients with a history of myelosuppression with previous treatment.



Adults:

aflibercept Every 2 weeks:


Intravenous: 4 mg/kg over 1 hour on Day 1, followed by

FOLFIRI:
 
Irinotecan 180 mg/m2 over 90 minutes, day 1;
Leucovorin 400 mg/m2 over 2 hours, day 1;
5-fluorouracil 400 mg/m2 bolus, followed by 2400 mg/m2 continuous IV over 46 hours.

Dosage with Toxicity:

Aflibercept Dose levels: 4 mg/kg, 2 mg/kg
FOLFIRI dose levels: -1 = 15-20% dose reduction
Aflibercept/FOLFIRI should not be given until neutrophil count is ≥ 1.5 X 109/L and  platelet count ≥ 75 x 109/L, and other toxicity has recovered to ≤ grade 2 (or levels specified below).
Toxicity
Severity
Aflibercept dose modification
FOLFIRI dose modification
Febrile neutropenia or sepsis with neutropenia
 n/a
No change
↓ irinotecan 1 dose level.
If recurs, also ↓ 5-fluorouracil bolus and infusion by 1 dose level. Consider use of G-CSF.
 
Bleeding
Severe
Discontinue
Hold until recovery. Consider dosage reduction upon restart.
Hypersensitivity
Mild
Moderate
Hold until reaction resolves. Treat with corticosteroids and/or antihistamines. Consider pre-treatment in subsequent cycles; caution as may recur.
Hold until reaction resolves. Treat with corticosteroids and/or antihistamines. Consider pre-treatment in subsequent cycles.
Severe
Discontinue if related to aflibercept and treat agressively.
Discontinue if related to FOLFIRI and treat.
Surgery
 n/a
Hold for ≥ 4 weeks prior to elective surgery. Restart ≥ 4 weeks after major surgery and until surgical wound is fully healed. May restart once surgical wound is fully healed for minor surgery, biopsy or tooth extraction.
Follow institutional guidelines.
 
Wound healing issue required intervention
Discontinue
 Hold until recovery and then restart.
Hypertension
 
mild to moderate
Treat and monitor. If cannot control, hold until controlled. 
If recurs, hold until controlled and restart by ↓ 1 dose level
No change
Severe OR PRES/RPLS
Discontinue
No change
Proteinuria ≥ 2 grams/24 hours
Grade 2-3
Hold. Restart when proteinuria < 2 g/ 24 hours.  If recurs, hold until proteinuria < 2 g/ 24 hours and restart by ↓ 1 dose level
No change
Grade 4 (nephrotic syndrome)
Discontinue
No change
Stomatitis and/or hand-foot syndrome
 Grade 3-4
No change
↓ 5-fluorouracil bolus and infusion 1 dose level
Diarrhea
 Grade 3-4
No change
Treat with anti-diarrheals and rehydration as required. When recovered to baseline, ↓ irinotecan 1 dose level.
If severe diarrhea recurs, also ↓5-fluorouracil bolus and infusion 1 dose level.
If severe diarrhea persists with both dose reductions, discontinue FOLFIRI.
Venous thromboembolism
Grade 1-3
Treat appropriately and monitor patient. If recurs despite appropriate anticoagulation, discontinue.
Treat appropriately and monitor patient
Grade 4
Discontinue
Discontinue if considered related to FOLFIRI
GI perforation;  Fistula;
Arterial thromboembolism;
Thrombotic microangiopathy;
Cardiotoxicity / decreased LVEF
Any grade
Discontinue
Discontinue


Dosage with Hepatic Impairment:

No dosage adjustment is required for leucovorin. No dosage adjustment is required for aflibercept in mild to moderate hepatic impairment; no data is available in severe hepatic impairment.
Transaminases
Bilirubin
Irinotecan
5FU
any 
1-1.5 X ULN
Consider ↓ dose
No change
 > 3 X ULN*
2-4 X ULN
Omit
No change
 any
> 4 XULN
Omit
Omit
* or 5 X ULN with liver metastases


Dosage with Renal Impairment:

No dosage adjustment is required for leucovorin or aflibercept.
Creatinine Clearance (mL/min)
Fluorouracil (% previous dose)
Irinotecan (% previous dose)
>60
No change
No change
30-60                         
 No change
Caution; no data available
<30
 Caution; consider dose ↓
Caution; no data available


Dosage in the elderly:

No dose adjustment required for patients ≥ 65 years of age.  The elderly experienced higher incidences of diarrhea, dizziness, asthenia, decreased weight, and dehydration. Monitor closely for diarrhea and dehydration.



Children:

Safety and effectiveness have not been established.



 
F - Administration Guidelines
  • Administer as an IV infusion over 1 hour using a 0.2 micron polyethersulfone filter
  • Do not use filters made of polyvinylidene fluoride (PVDF) or nylon
  • DO NOT administer undiluted or as an IV push or bolus
  • NOT for intravitreal injection
  • Dilute in 0.9% sodium chloride USP or 5% dextrose solution for injection
  • Final concentration of 0.6 to 8 mg/mL
  • May administer using an infusion set made up of one of the following materials:
    • PVC containing DEHP
    • DEHP free PVC containing trioctyl-trimellitate (TOTM)
    • polypropylene
    • polyethylene-lined PVC
    • polyurethane
  • Do not combine aflibercept with other drugs in the same infusion bag or intravenous line.
  • Refrigerate unused vials at 2-8oC.  Keep vials in original outer carton to protect from light.

 

 
G - Special Precautions
Contraindications:

  • Patients with severe hemorrhage
  • Patients who have a hypersensitivity to this drug or any of its components
  • Patients with contraindications to irinotecan, 5-fluorouracil or leucovorin (refer to the individual drug monographs for details)
  • ZaltrapTM formulation is contraindicated for intravitreal use

 

Other Warnings/Precautions:

  • Use with caution in patients with significant cardiovascular disease as drug-induced hypertension may exacerbate this condition. Aflibercept has not been studied in patients with NYHA class III or IV heart failure. Heart failure has been reported.
  • Compromised wound healing has been observed.  Hold aflibercept for at least 4 weeks prior to elective surgery and do not restart until 4 weeks after surgery (refer to Dosing section).
  • Use with caution when re-treating patients with prior hypersensitivity reactions as recurrent reactions have been observed despite prophylaxis.
  • Use with caution in patients with risk factors for ONJ, including bisphosphonate use.


Other Drug Properties:

  • Carcinogenicity: Unknown

Pregnancy and Lactation:
  • Embryotoxicity: Documented in animals
  • Teratogenicity: Documented in animals
  • Fetotoxicity: Documented in animals

    Aflibercept is not recommended for use in pregnancy.  Adequate contraception should be used by both sexes during treatment, and for at least 6 months after the last dose.

  • Excretion into breast milk: Unknown

    Breastfeeding is not recommended.

  • Fertility effects: Documented in animals
 
H - Interactions

No specific drug-drug interaction studies were performed with aflibercept.  No clinically significant interactions were found between aflibercept and irinotecan/SN-38, 5-FU, oxaliplatin, cisplatin, docetaxel, pemetrexed, gemcitabine and erlotinib.

 
I - Recommended Clinical Monitoring

Treating physicians may decide to monitor more or less frequently for individual patients but should always consider recommendations from the product monograph.

Recommended Clinical Monitoring

Monitor Type Monitor Frequency

CBC with differential count

Baseline and before each cycle

Urine dipstick

Baseline and before each cycle; patients with dipstick >/= 2+ for protein or urinary protein creatinine ratio (UPCR) > 1 should undergo a 24 hour urine collection

Blood pressure

Baseline and every two weeks or more frequently as clinically indicated

LVEF

Baseline and as clinically indicated

Clinical toxicity assessment for signs and symptoms of bleeding, heart failure, GI perforation or obstruction, delayed wound healing and diarrhea

At each visit

Grade toxicity using the current NCI-CTCAE (Common Terminology Criteria for Adverse Events) version



Suggested Clinical Monitoring

Monitor Type Monitor Frequency

Blood glucose in patients with diabetes

Baseline and as clinically indicated
 
K - References

FOLFIRI regimen monograph, Cancer Care Ontario.

Product monograph. ZaltrapTM (aflibercept). Sanofi-aventis Canada Inc., Aug 3, 2016.

Van Cutsem E, Tabernero J, Lakomy R, et al. Addition of aflibercept to fluorouracil, leucovorin, and irinotecan improves survival in a phase III randomized trial in patients with metastatic colorectal cancer previously treated with an oxaliplatin-based regimen. J Clin Oncol. 2012 Oct 1;30(28):3499-506.


October 2017 added cardiotoxicity and ONJ to adverse effects and precautions sections; added heart failure to monitoring

 
L - Disclaimer

Refer to the New Drug Funding Program or Ontario Public Drug Programs websites for the most up-to-date public funding information.

The information set out in the drug monographs, regimen monographs, appendices and symptom management information (for health professionals) contained in the Drug Formulary (the "Formulary") is intended for healthcare providers and is to be used for informational purposes only. The information is not intended to cover all possible uses, directions, precautions, drug interactions or adverse effects of a particular drug, nor should it be construed to indicate that use of a particular drug is safe, appropriate or effective for a given condition. The information in the Formulary is not intended to constitute or be a substitute for medical advice and should not be relied upon in any such regard. All uses of the Formulary are subject to clinical judgment and actual prescribing patterns may not follow the information provided in the Formulary.

The format and content of the drug monographs, regimen monographs, appendices and symptom management information contained in the Formulary will change as they are reviewed and revised on a periodic basis. The date of last revision will be visible on each page of the monograph and regimen. Since standards of usage are constantly evolving, it is advised that the Formulary not be used as the sole source of information. It is strongly recommended that original references or product monograph be consulted prior to using a chemotherapy regimen for the first time.

Some Formulary documents, such as the medication information sheets, regimen information sheets and symptom management information (for patients), are intended for patients. Patients should always consult with their healthcare provider if they have questions regarding any information set out in the Formulary documents.

While care has been taken in the preparation of the information contained in the Formulary, such information is provided on an “as-is” basis, without any representation, warranty, or condition, whether express, or implied, statutory or otherwise, as to the information’s quality, accuracy, currency, completeness, or reliability.

CCO and the Formulary’s content providers shall have no liability, whether direct, indirect, consequential, contingent, special, or incidental, related to or arising from the information in the Formulary or its use thereof, whether based on breach of contract or tort (including negligence), and even if advised of the possibility thereof. Anyone using the information in the Formulary does so at his or her own risk, and by using such information, agrees to indemnify CCO and its content providers from any and all liability, loss, damages, costs and expenses (including legal fees and expenses) arising from such person’s use of the information in the Formulary.