Necitumumab

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Solution, Intravenous [preservative free]:

Portrazza: 800 mg/50 mL (50 mL) [contains polysorbate 80]

Pharmacology

Mechanism of Action

Necitumumab is a recombinant human IgG1 EGFR monoclonal antibody which binds (with a high affinity) to the ligand binding site of the EGFR receptor to prevent receptor activation and downstream signaling (Thatcher 2015).

Pharmacokinetics/Pharmacodynamics

Distribution

V_dss: 7 L.

Excretion

Clearance (mean): 14.1 mL/hour.

Half-Life Elimination

~14 days.

Use: Labeled Indications

Non-small cell lung cancer (squamous), metastatic: First-line treatment of metastatic squamous non-small cell lung cancer (NSCLC) in combination with gemcitabine and cisplatin

Limitations of use: Not indicated for treatment of non-squamous NSCLC.

Contraindications

There are no contraindications listed in the manufacturer's labeling.

Dosage and Administration

Dosing: Adult

Note: For patients with a prior grade 1 or 2 infusion reaction, premedicate (prior to all subsequent necitumumab infusions) with diphenhydramine (or equivalent). For patients with a recurrent grade 1 or 2 infusion reaction, premedicate (prior to all subsequent necitumumab infusions) with diphenhydramine (or equivalent), acetaminophen, and dexamethasone (or equivalent).

Non-small cell lung cancer (squamous), metastatic: IV: 800 mg on days 1 and 8 of each 3-week treatment cycle (in combination with gemcitabine and cisplatin); continue until disease progression or unacceptable toxicity (Thatcher 2015).

In the study, gemcitabine and cisplatin were administered for a maximum of 6 cycles, while patients without disease progression continued necitumumab as single agent therapy (Thatcher 2015).

Dosing: Geriatric

Refer to adult dosing.

Dosing: Adjustment for Toxicity

Dermatologic toxicity:

Grade 3 rash or acneiform rash: Withhold necitumumab treatment until symptoms resolve to grade 2 or lower, then resume necitumumab with the dose reduced to 400 mg for at least 1 treatment cycle. If symptoms do not worsen, may increase the dose to 600 mg and then 800 mg in subsequent cycles.

Grade 3 rash or acneiform rash that does not resolve to grade 2 or lower within 6 weeks: Permanently discontinue necitumumab.

Grade 3 rash or acneiform rash that worsens or is intolerable at the 400 mg dose: Permanently discontinue necitumumab.

Grade 3 skin induration/fibrosis: Permanently discontinue necitumumab.

Grade 4 dermatologic toxicity: Permanently discontinue necitumumab.

Electrolyte abnormality: Grade 3 or 4 electrolyte abnormality: Withhold necitumumab treatment; may resume when electrolyte abnormality has improved to grade 2 or lower (replete electrolytes as appropriate).

Infusion-related reactions:

Grade 1: Reduce necitumumab infusion rate by 50%.

Grade 2: Interrupt necitumumab infusion until signs/symptoms have resolved to grade 1 or 0, then resume with the rate reduced by 50% for all subsequent infusions.

Grade 3 or 4: Permanently discontinue necitumumab.

Thromboembolic events: Serious or life-threatening venous thromboembolism or arterial thromboembolism: Discontinue treatment necitumumab.

Reconstitution

Dilute for infusion in NS to a total volume of 250 mL (do not use solutions containing dextrose). Gently invert to mix; do not shake.

Administration

IV: Infuse over 60 minutes using an infusion pump. Infuse through a separate line. Flush with sodium chloride 0.9% at the end of infusion. Do not infuse with other medications or with electrolytes. Monitor for infusion reactions; reduce infusion rate by 50% for grade 1 infusion reaction; interrupt infusion for grade 2 infusion reaction.

Necitumumab should be administered prior to gemcitabine and cisplatin (Thatcher 2015).

Storage

Store intact vials at 2°C to 8°C (36°F to 46°F). Do not freeze. Store in original carton to protect from light. Do not shake. Solutions diluted for infusion in NS are stable for up to 4 hours at room temperature or 24 hours at 2°C to 8°C (36°F to 46°F); do not freeze or shake.

Drug Interactions

There are no known significant interactions.

Adverse Reactions

Adverse reaction percentages reported as part of a combination regimen with gemcitabine and cisplatin.

>10%:

Central nervous system: Headache (11%)

Dermatologic: Skin toxicity (79%; grades 3/4: 8%), skin rash (44%; grades 3/4: 4%), acneiform eruption (15%; grades 3/4: 1%)

Endocrine & metabolic: Hypomagnesemia (43% to 83%; grades 3/4: 20%), hypocalcemia (45%; grades 3/4: 6%; with albumin corrected: 36%; grades 3/4: 4%), hypophosphatemia (31%; grades 3/4: 8%), hypokalemia (28%; grades 3/4: 5%), weight loss (13%)

Gastrointestinal: Vomiting (29%), diarrhea (16%), stomatitis (11%)

1% to 10%:

Cardiovascular: Venous thromboembolism (9%; grades 3/4: 5%), arterial thromboembolism (5%; grades 3/4: 4%), pulmonary embolism (5%), cardiorespiratory arrest (3%), deep vein thrombosis (2%), cerebrovascular accident (≤2%), ischemia (≤2%), myocardial infarction (1%)

Dermatologic: Acne vulgaris (9%), paronychia (7%), pruritus (7%), xeroderma (7%), skin fissure (5%)

Immunologic: Antibody development (4%; neutralizing: 1%)

Ophthalmic: Conjunctivitis (7%)

Respiratory: Hemoptysis (10%)

Miscellaneous: Infusion related reaction (2%; grade 3: <1%)

Warnings/Precautions

Concerns related to adverse effects:

• Cardiopulmonary arrest: [US Boxed Warning]: Cardiopulmonary arrest and/or sudden death occurred in a small percentage of patients treated with necitumumab in combination with gemcitabine and cisplatin. Monitor serum electrolytes closely, including serum magnesium, potassium, and calcium, with aggressive replacement when warranted during and after necitumumab administration. Continue electrolyte monitoring for at least 8 weeks after the last dose. Some cardiopulmonary events were fatal; many of those patients had comorbid conditions (including a history of coronary artery disease, hypomagnesemia, chronic obstructive pulmonary disease, and/or hypertension). Patients with significant coronary artery disease, MI within 6 months, uncontrolled hypertension or uncontrolled heart failure were excluded from the squamous cell non-small cell lung cancer (NSCLC) study.
• Dermatologic toxicity: Dermatologic toxicity, including rash, dermatitis acneiform, acne, dry skin, pruritus, generalized rash, skin fissures, maculo-papular rash, and/or erythema occurs commonly; may be severe. Skin toxicity usually developed within the first 2 weeks of treatment and resolved within 17 weeks after onset. May require treatment interruption, dose reduction, or discontinuation. Patients should minimize exposure to the sun.
• Hypomagnesemia: [US Boxed Warning]: Hypomagnesemia occurred in a majority of patients receiving necitumumab in combination with gemcitabine and cisplatin; hypomagnesemia was severe in one-fifth of patients. Monitor for hypomagnesemia, hypocalcemia, and hypokalemia prior to each dose of necitumumab during treatment and for at least 8 weeks following completion of necitumumab. Withhold necitumumab for Grade 3 or 4 electrolyte abnormalities. Replete electrolytes as appropriate. May resume treatment when hypomagnesemia and related electrolyte abnormalities are improved to grade 2 or lower. The median time to development of hypomagnesemia was 6 weeks after treatment initiation.
• Infusion reactions: Infusion-related reactions have been reported with necitumumab, usually after the first or second infusion. Premedication was not routinely administered prior to the first dose in the squamous cell NSCLC study. Monitor for signs/symptoms of infusion reaction. Discontinue for serious or life-threatening reactions.
• Thromboembolism: Venous and arterial thromboembolic events (VTE and ATE) were observed with necitumumab, including grades 3 and 4 events and some fatalities. The most common VTEs were deep vein thrombosis and pulmonary embolism and the most common ATEs were cerebral stroke and ischemia and MI. Discontinue necitumumab for serious or life-threatening VTE or ATE. The incidence of VTE may be higher in patients ≥70 years of age (compared to patients under age 70).

Disease-related concerns:

• Non-squamous NSCLC: Necitumumab is not indicated for use in patients with non-squamous NSCLC. In a study of necitumumab in combination with pemetrexed and cisplatin for the treatment of metastatic non-squamous NSCLC, patients experienced increased serious and fatal toxicities and cardiopulmonary arrest/sudden death within 30 days of the last dose of necitumumab (compared to pemetrexed and cisplatin without necitumumab).

Dosage form specific issues:

• Polysorbate 80: Some dosage forms may contain polysorbate 80 (also known as Tweens). Hypersensitivity reactions, usually a delayed reaction, have been reported following exposure to pharmaceutical products containing polysorbate 80 in certain individuals (Isaksson 2002; Lucente 2000; Shelley 1995). Thrombocytopenia, ascites, pulmonary deterioration, and renal and hepatic failure have been reported in premature neonates after receiving parenteral products containing polysorbate 80 (Alade 1986; CDC 1984). See manufacturer's labeling.

Monitoring Parameters

Serum electrolytes, including magnesium, potassium, and calcium (prior to each dose during treatment and for at least 8 weeks following completion). Signs/symptoms of infusion-related reactions, dermatologic toxicity, and thromboembolism.

Pregnancy

Pregnancy Considerations

Necitumumab is expected to cross the placenta. Based on the mechanism of action and data from animal reproduction studies, in utero exposure to necitumumab may cause fetal harm. Females of reproductive potential should use effective contraception during therapy and for 3 months after the last necitumumab dose.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)
• Patient may experience vomiting, diarrhea, mouth sores, weight loss, headache, acne, itching, dry skin, or redness. Have patient report immediately to prescriber signs of blood clots (numbness or weakness on one side of the body; pain, redness, tenderness, warmth, or swelling in the arms or legs; change in color of an arm or leg; chest pain; shortness of breath; fast heartbeat; or coughing up blood), signs of low magnesium (mood changes; muscle pain or weakness; muscle cramps or spasms; seizures; tremors; lack of appetite; severe nausea or vomiting; or an abnormal heartbeat), signs of infusion reaction, signs of severe cerebrovascular disease (change in strength on one side is greater than the other, difficulty speaking or thinking, change in balance, or vision changes), signs of electrolyte problems (mood changes, confusion, muscle pain or weakness, abnormal heartbeat, seizures, lack of appetite, or severe nausea or vomiting), severe dizziness, passing out, nail changes, chills, vision changes, eye pain, severe eye irritation, or severe skin irritation (HCAHPS).
• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.