Zaltrap (ziv-aflibercept)

If toxicities occur, temporary or permanent discontinuance of ziv-aflibercept may be required based on causality.

Ziv-aflibercept should be discontinued in patients who develop severe hemorrhage, GI perforation, compromised wound healing, fistula formation, hypertensive crisis or hypertensive encephalopathy, arterial thromboembolic events, nephrotic syndrome or thrombotic microangiopathy, or reversible posterior leukoencephalopathy syndrome (RPLS). (See Cautions: Warnings/Precautions.)

Ziv-aflibercept therapy should be temporarily suspended at least 4 weeks prior to elective surgery. Therapy also should be temporarily interrupted in patients who develop recurrent or severe hypertension or proteinuria. (See Hypertension and also Proteinuria under Dosage: Dosage Modification for Toxicity, in Dosage and Administration.) Ziv-aflibercept therapy should be delayed in patients with a neutrophil count of less than 1500/mm3. (See Neutropenia and Neutropenic Complications under Warnings/Precautions: Other Warnings and Precautions, in Cautions.)

No dosing information is available for this tab.

No dosing information is available for this tab.

No formal drug interaction studies have been performed to date.

There are no contraindication interactions for this drug.

Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

Myelosuppressives; Immunomodulators/Sodium Iodide I 131

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Sodium iodide I 131 can cause depression of the hematopoetic system. Myelosuppressives and immunomodulators also suppress the immune system.(1)

CLINICAL EFFECTS: Concurrent use of sodium iodide I 131 with agents that cause bone marrow depression, including myelosuppressives or immunomodulators, may result in an enhanced risk of hematologic disorders, including anemia, blood dyscrasias, bone marrow depression, leukopenia, and thrombocytopenia. Bone marrow depression may increase the risk of serious infections and bleeding.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of sodium iodide I 131 states that concurrent use with bone marrow depressants may enhance the depression of the hematopoetic system caused by large doses of sodium iodide I 131.(1) Sodium iodide I 131 causes a dose-dependent bone marrow suppression, including neutropenia or thrombocytopenia, in the 3 to 5 weeks following administration. Patients may be at increased risk of infections or bleeding during this time. Monitor complete blood counts within one month of therapy. If results indicate leukopenia or thrombocytopenia, dosimetry should be used to determine a safe sodium iodide I 131 activity.(1)

DISCUSSION: Hematologic disorders including death have been reported with sodium iodide I 131. The most common hematologic disorders reported include anemia, blood dyscrasias, bone marrow depression, leukopenia, and thrombocytopenia.(1)

Selected Myelosuppressive Agents/Clozapine

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Clozapine and other myelosuppressive agents may be associated with neutropenia or agranulocytosis.(2)

CLINICAL EFFECTS: Moderate neutropenia, even if due to combination therapy, may require abrupt discontinuation of clozapine resulting in decompensation of the patient's psychiatric disorder (e.g. schizophrenia). The disease treated by the myelosuppressive agent may be compromised if myelosuppression requires dose reduction, delay, or discontinuation of the myelosuppressive agent. Undetected severe neutropenia or agranulocytosis may be fatal.

PREDISPOSING FACTORS: Low white blood counts prior to initiation of the myelosuppressive agent may increase risk for clinically significant neutropenia.

PATIENT MANAGEMENT: If a patient stabilized on clozapine therapy requires treatment with a myelosuppressive agent, the clozapine prescriber should consult with prescriber of the myelosuppressive agent (e.g. oncologist) to discuss treatment and monitoring options.(2) More frequent absolute neutrophil count (ANC) monitoring or treatment alternatives secondary to neutropenic episodes may need to be considered. The U.S. Food and Drug Administration (FDA) recommends that prescribers monitor patients' ANC according to the monitoring frequencies described in the prescribing information. Severe neutropenia remains a serious, potentially fatal risk that is greatest in the first several months of clozapine treatment. ANC monitoring can help identify neutropenia early to allow for timely intervention.(1-2) Australia, Canada, and U.K.: Clozapine is only available through a restricted distribution system which requires documentation of the ANC prior to dispensing. For most clozapine patients, clozapine treatment must be interrupted for a suspected clozapine-induced ANC < 1000 cells/microliter. For patients with benign ethnic neutropenia (BEN), treatment must be interrupted for suspected clozapine-induced neutropenia < 500 cells/microliter.(2)

DISCUSSION: Concurrent use of clozapine and selected myelosuppressive agents may require more frequent ANC monitoring or consideration of treatment alternatives secondary to neutropenic episodes. Agents linked to this interaction generally have > 5% risk for neutropenia and/or warnings describing risk for myelosuppression in manufacturer prescribing information.(3-26)

Selected Myelosuppressive Agents/Deferiprone

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Concurrent use of deferiprone with other drugs known to be associated with neutropenia or agranulocytosis may increase the frequency or risk for severe toxicity.(1)

CLINICAL EFFECTS: Concurrent use of deferiprone and myelosuppressive agents may result in severe neutropenia or agranulocytosis, which may be fatal.

PREDISPOSING FACTORS: Agranulocytosis may be less common in patients receiving deferiprone for thalassemia, and more common in patients treated for other systemic iron overload conditions (e.g. myelodysplastic syndromes, sickle cell disease).(2,3) Inadequate monitoring appears to increase the risk for severe outcomes. Manufacturer post market surveillance found that in all fatal cases of agranulocytosis reported between 1999 and 2005, data on weekly white blood count (WBC) monitoring was missing. In three fatal cases, deferiprone was continued for two to seven days after the detection of neutropenia or agranulocytosis.(2)

PATIENT MANAGEMENT: If possible, discontinue one of the drugs associated with risk for neutropenia or agranulocytosis. If alternative therapy is not available, documentation and adherence to the deferiprone monitoring protocol is essential. Baseline absolute neutrophil count (ANC) must be at least 1,500/uL prior to starting deferiprone. Monitor ANC weekly during therapy. If infection develops, interrupt deferiprone therapy and monitor ANC more frequently. If ANC is less than 1,500/uL but greater than 500/uL, discontinue deferiprone and any other drugs possibly associated with neutropenia. Initiate ANC and platelet counts daily until recovery (i.e. ANC at least 1,500/uL). If ANC is less than 500/uL, discontinue deferiprone, evaluate patient and hospitalize if appropriate. Do not resume deferiprone unless potential benefits outweigh potential risks.(1)

DISCUSSION: Drugs linked to this monograph have an FDA Boxed Warning for risk of neutropenia, agranulocytosis, or pancytopenia, or have > 5% risk for neutropenia and/or warnings describing risk for myelosuppression in manufacturer prescribing information.(1-25) In pooled clinical studies submitted to the FDA, 6.1% of deferiprone patients met criteria for neutropenia and 1.7% of patients developed agranulocytosis.(1) The time to onset of agranulocytosis was highly variable with a range of 65 days to 9.2 years (median, 161 days).(3)

Selected Myelosuppressive Agents/Dipyrone

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Concurrent use of dipyrone with other drugs known to be associated with neutropenia or agranulocytosis may increase the frequency or risk for severe toxicity.(1-29)

CLINICAL EFFECTS: Concurrent use of dipyrone with agents that cause bone marrow depression, including myelosuppressives, may result in an enhanced risk of hematologic disorders, including anemia, blood dyscrasias, bone marrow depression, leukopenia, and thrombocytopenia. Bone marrow depression may increase the risk of serious infections and bleeding. Undetected severe neutropenia or agranulocytosis may be fatal.(1-29)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Concurrent use of dipyrone and myelosuppressive agents should be avoided. The European Medicines Agency states dipyrone is contraindicated in patients with a prior medical history of dipyrone-induced agranulocytosis (or from other pyrazolones/pyrazolidines), impaired bone marrow function or diseases of the hematopoietic system.(3) International labeling for dipyrone and methotrexate state that co-administration may increase the hematotoxicity of methotrexate, especially in elderly patients, and therefore should be avoided.(1-2) The European Medicines Agency advises if agranulocytosis is suspected with dipyrone, a complete blood count (including differential blood count) should be performed immediately, and treatment must be stopped while waiting for the results. If confirmed, treatment must not be reintroduced.(1-3)

DISCUSSION: A retrospective cohort study analyzed new users of dipyrone (n=444,972), non-steroidal anti-inflammatory drugs (n=3,814,367) which served as a reference cohort, and opioids-paracetamol (n=3,129,221) which was the negative control. During continuous treatment over a median of 37-40 days, 26 cases of hospitalized agranulocytosis occurred. With the assumption that agranulocytosis onset was 7 days prior to admission, the hazard ratio of agranulocytosis associated with dipyrone was 4.40 [0.90-21.57] compared to NSAIDs and 2.45 [0.68-8.83] compared to opioid-paracetamol. HR of neutropenia from dipyrone was 2.98 [1.57-5.65] compared to NSAIDs and not statistically significant compared to opioids-paracetamol. In a sensitivity analysis assuming that the onset of agranulocytosis was the date of hospitalization, the HR of dipyrone-induced agranulocytosis was 7.20 [95% confidence interval: 1.92-26.99] compared to NSAIDs and 3.31 [1.17-9.34] compared to opioids-paracetamol. Agranulocytosis was very rare but more than 4 times more common with dipyrone than other analgesics.(4) In a review of 1,448 reports of agranulocytosis attributed to dipyrone, patients with fatal outcomes were older and more often had also received methotrexate compared to those with non-fatal outcomes (odds ratio: 5.18; 95% confidence interval: 3.06-8.78).(5) Agents linked to this interaction generally have > 5% risk for neutropenia and/or warnings describing risk for myelosuppression in manufacturer prescribing information.(2,6-26)

There are no moderate interactions for this drug.

The manufacturer states there are no known contraindications to the use of ziv-aflibercept.

• Acute arterial thromboembolism
• Gastrointestinal perforation
• Hypertensive crisis
• Lactation
• Nephrotic syndrome
• Posterior reversible encephalopathy syndrome
• Thrombotic thrombocytopenic purpura
• Transient cerebral ischemia

• Angina
• Gastrointestinal fistula
• Hemorrhage
• Hypertension
• Impaired wound healing
• Invasive surgical procedure
• Neutropenic disorder
• New fistula formation involving an internal organ
• Pregnancy
• Proteinuria
• Severe diarrhea
• Severe infection
• Stomatitis
• Thrombocytopenic disorder

There are no moderate contraindications for this drug.

The most common adverse effects reported in 20% or more of patients receiving ziv-aflibercept in combination with FOLFIRI and at an incidence that is at least 2% higher than that reported with placebo in combination with FOLFIRI include leukopenia, diarrhea, neutropenia, proteinuria, elevated aminotransferase (i.e., AST, ALT) concentrations, stomatitis, fatigue, thrombocytopenia, hypertension, weight loss, decreased appetite, epistaxis, abdominal pain, dysphonia, elevated serum creatinine concentration, and headache.

The most common grade 3 or 4 adverse effects reported in 5% or more of patients receiving ziv-aflibercept in combination with FOLFIRI and at an incidence that is at least 2% higher than that reported with placebo in combination with FOLFIRI include neutropenia, diarrhea, hypertension, leukopenia, stomatitis, fatigue, proteinuria, and asthenia.

More Frequent

• Hemorrhage
• Hypertension
• Increased alanine transaminase
• Increased aspartate transaminase
• Leukopenia
• Neutropenic disorder
• Palmar-plantar erythrodysesthesia
• Severe diarrhea
• Thrombocytopenic disorder

Less Frequent

• Angina
• Dehydration
• Gastrointestinal hemorrhage
• Hematuria
• Kidney disease with reduction in glomerular filtration rate (GFr)
• Pneumonia
• Rectal bleeding
• Thromboembolic disorder
• Transient cerebral ischemia

Rare or Very Rare

• Acute arterial thromboembolism
• Aortic aneurysm with dissection
• Arterial aneurysm
• Arterial dissection
• Aseptic necrosis of jaw bone
• Cerebrovascular accident
• Gastrointestinal fistula
• Gastrointestinal perforation
• Heart failure
• Impaired wound healing
• Intracranial bleeding
• Nephrotic syndrome
• Posterior reversible encephalopathy syndrome
• Pulmonary hemorrhage
• Thrombotic thrombocytopenic purpura

More Frequent

• Acute abdominal pain
• Diarrhea
• Dyspnea
• Epistaxis
• Fatigue
• General weakness
• Headache disorder
• Proteinuria
• Stomatitis
• Voice change
• Weight loss

Less Frequent

• Anorexia
• Dyschromia
• Hemorrhoids
• Rectal pain
• Rhinorrhea
• Skin pigmentation enhancement
• Sore throat
• Tooth disorder
• Upper respiratory infection
• Urinary tract infection

No enhanced messaging available.

Safety and efficacy of ziv-aflibercept have not been established in pediatric patients younger than 18 years of age.

Category C. (See Users Guide.) (See Advice to Patients.)

It is not known whether ziv-aflibercept is distributed into milk in humans. Because of the potential for serious adverse reactions to ziv-aflibercept in nursing infants, a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the woman.

In the VELOUR study, 34% of patients were 65 years of age or older and 5% were 75 years of age or older. Although no overall differences in efficacy (i.e., overall survival) were observed between geriatric and younger patients, the incidences of diarrhea, dizziness, asthenia, weight loss, and dehydration were higher among patients 65 years of age or older compared with younger patients. Geriatric patients should be monitored more closely for diarrhea and dehydration. (See Diarrhea and Dehydration under Warnings/Precautions: Other Warnings and Precautions, in Cautions.) Dosage adjustment is not required in patients 65 years of age or older.