Portrazza

Percentages listed below are for all grades of toxicity unless otherwise noted

>10%

Hypomagnesemia (83%)

Hypocalcemia (45%)

Rash (44%)

Hypocalcemia (albumin corrected) (36%)

Hypophosphatemia (31%)

Vomiting (29%)

Hypokalemia (28%)

Hypomagnesemia, grade 3-4 (20%)

Diarrhea (16%)

Dermatitis acneiform (15%)

Weight decreased (13%)

Stomatitis (11%)

Headache (11%)

1-10%

Hemoptysis (10%)

Venous thromboembolic events (9%)

Acne (9%)

Hypophosphatemia, grade 3-4 (8%)

Paronychia (7%)

Conjunctivitis (7%)

Pruritus (7%)

Dry skin (7%)

Hypocalcemia, grade 3-4 (6%)

Hypokalemia, grade 3-4 (5%)

Skin fissures (5%)

Pulmonary embolism (5%)

Venous thromboembolic events, grade 3-4 (5%)

Hypocalcemia (albumin corrected), grade 3-4 (4%)

Vomiting, grade 3-4 (3%)

Diarrhea, grade 3-4 (2%)

Stomatitis, grade 3-4 (1%)

Necitumumab is a monoclonal antibody that blocks a certain protein in the body that can affect tumor cell growth. Monoclonal antibodies are made to target and destroy only certain cells in the body. This may help to protect healthy cells from damage.

Necitumumab is used to treat a certain type of non-small cell lung cancer. Necitumumab is usually given in combination with other cancer medications.

Necitumumab may also be used for purposes not listed in this medication guide.

Necitumumab can cause your electrolytes to become unbalanced. This can lead to serious heart problems, including cardiac arrest. You will need frequent blood tests to check your electrolytes (calcium, potassium, and magnesium).

You should not be treated with necitumumab if you are allergic to it.

To make sure necitumumab is safe for you, tell your doctor if you have:

• coronary artery disease (hardened arteries);
• high blood pressure;
• chronic obstructive pulmonary disease (COPD);
• an electrolyte imbalance (such as low levels of potassium or magnesium in your blood); or
• a history of heart attack or stroke.

Using necitumumab during pregnancy could harm the unborn baby. Tell your doctor if you are pregnant or plan to become pregnant. Use effective birth control to prevent pregnancy while you are using this medicine and for at least 3 months after your last dose.

It is not known whether necitumumab passes into breast milk or if it could harm a nursing baby. Do not breast-feed while you are being treated with necitumumab, and for at least 3 months after your last dose.

Portrazza is a prescription medication used with two other chemotherapy medications to treat advanced (metastatic) squamous non-small cell lung cancer (NSCLC) in patients who have not previously received medication specifically for treating their advanced lung cancer.

This medication may be prescribed for other uses. Ask your doctor or pharmacist for more information.

Avoid exposure to sunlight or tanning beds. Necitumumab can make you sunburn more easily. Wear protective clothing and use sunscreen (SPF 30 or higher) when you are outdoors.

General

Premedication for Infusion-related Reactions

• In patients who previously experienced a grade 1 or 2 infusion-related reaction to necitumumab, premedicate with an antihistamine (e.g., diphenhydramine or equivalent) prior to each subsequent infusion.1

• Following a second occurrence of a grade 1 or 2 infusion-related reaction, premedicate with an antihistamine (e.g., diphenhydramine or equivalent), acetaminophen (or equivalent), and dexamethasone (or equivalent) prior to each subsequent infusion.1 (See Infusion-related Reactions under Dosage and Administration and also under Cautions.)

Serum Electrolyte Monitoring

• Closely monitor serum electrolyte concentrations, including magnesium, potassium, and calcium, and aggressively correct electrolyte abnormalities as clinically appropriate prior to each necitumumab infusion and for ≥8 weeks following the last dose.1 (See Electrolyte Abnormalities under Dosage and Administration.)

Administration

IV Administration

For solution compatibility information, see Compatibility under Stability.

Administer by IV infusion via an infusion pump.1

Necitumumab injection concentrate must be diluted prior to administration.1 Use within 4 hours following dilution if stored at room temperature or within 24 hours if stored at 2–8°C.1 (See Storage under Stability.)

Do not administer with any other drug or electrolytes simultaneously in the same IV line.1

Flush IV line with 0.9% sodium chloride injection at end of infusion.1

Withdraw appropriate volume of necitumumab injection concentrate from vial labeled as containing 800 mg in 50 mL and add to infusion container containing the appropriate volume of 0.9% sodium chloride injection to yield a final volume of 250 mL.1 Mix by gentle inversion; do not shake.1

Do not dilute in dextrose-containing or other solutions or admix with any other drug or electrolytes.1

Discard any partially used vials.1

Administer over 60 minutes.1

Dosage

Adults

800 mg on days 1 and 8 of each 3-week cycle; use in combination with gemcitabine and cisplatin.1

Administer necitumumab prior to IV infusion of gemcitabine and cisplatin.1

Continue therapy until disease progression or unacceptable toxicity occurs.1

If grade 1 infusion-related reaction occurs, reduce infusion rate by 50%.1

If grade 2 infusion-related reaction occurs, interrupt infusion until resolution to grade 1 or less; resume at 50% reduced rate for subsequent infusions.1

If grade 3 or 4 infusion-related reaction occurs, permanently discontinue therapy.1 (See Infusion-related Reactions under Cautions.)

If grade 3 rash or acneiform rash develops, interrupt therapy.1 If toxicity improves to grade 2 or less, resume necitumumab at reduced dosage of 400 mg for at least 1 cycle.1 May increase dosage to 600 mg, then to 800 mg in subsequent cycles if symptoms do not worsen.1 If dermatologic toxicity worsens or becomes intolerable at a dosage of 400 mg, permanently discontinue therapy.1 If grade 3 rash or acneiform rash does not improve to grade 2 or less within 6 weeks, permanently discontinue therapy.1

If grade 3 skin induration/fibrosis or grade 4 dermatologic toxicity occurs, permanently discontinue therapy.1 (See Dermatologic Toxicity under Cautions.)

If grade 3 or 4 electrolyte abnormalities occur, interrupt therapy.1 Resume therapy at previous dosage upon improvement of hypomagnesemia and related electrolyte abnormalities to grade 2 or less.1 (See Cardiopulmonary Arrest and also see Hypomagnesemia under Cautions.)

Special Populations

Hepatic Impairment

No specific dosage recommendations at this time.1 (See Hepatic Impairment under Cautions.)

Renal Impairment

No specific dosage recommendations at this time.1 (See Renal Impairment under Cautions.)

Geriatric Patients

No specific dosage recommendations at this time.1 (See Geriatric Use under Cautions.)

Body Weight, Race, and Gender

No dosage adjustment required.1 (See Special Populations under Pharmacokinetics.)

Absorption

Bioavailability

Steady-state concentrations predicted to be reached approximately 100 days following IV infusion of necitumumab 800 mg on days 1 and 8 of each 21-day cycle.1

Special Populations

Systemic exposure not affected by renal function in a population pharmacokinetic analysis.1

Systemic exposure not affected by mild or moderate hepatic impairment in a population pharmacokinetic analysis.1 Patients with severe hepatic impairment not enrolled in clinical trials.1

Gender, age (range: 19–84 years), and race do not substantially affect systemic exposure.1

Effect of body weight on necitumumab exposure not clinically important.1 (See Special Populations under Dosage and Administration.)

Distribution

Extent

Not known whether necitumumab distributes into milk.1

Elimination

Half-life

Approximately 14 days.1

• Risk of electrolyte abnormalities, including hypomagnesemia, hypokalemia, and hypocalcemia.1 Importance of advising patients to take electrolyte replacement therapy exactly as advised by their clinician.1

• Risk of venous and arterial thromboembolic events.1

• Risk of skin reactions.1 Importance of minimizing sun exposure with protective clothing and use of sunscreen during therapy.1

• Risk of infusion-related reactions.1 Importance of informing patients to report signs and symptoms of infusion reactions (e.g., fever, chills, breathing problems) to a healthcare professional.1

• Risk of fetal harm.1 Advise women of childbearing potential to use effective methods of contraception while receiving necitumumab and for 3 months after the last dose.1 If pregnancy occurs, apprise patient of potential fetal hazard.1

• Importance of advising women to avoid breast-feeding during therapy and for 3 months following the last dose.1

• Importance of informing patients of other important precautionary information.1 (See Cautions.)

It is very important that your doctor check your progress at regular visits to make sure this medicine is working properly and to check for unwanted effects. Blood tests may be needed to check for unwanted effects.

Using this medicine while you are pregnant can harm your unborn baby. Use an effective form of birth control to keep from getting pregnant during therapy and for 3 months after the last dose of this medicine. If you think you have become pregnant while using the medicine, tell your doctor right away.

Hypomagnesemia may occur while you are receiving this medicine. Tell your doctor right away if you have drowsiness, mood or mental changes, muscle spasms or twitching, seizures, or unusual tiredness or weakness after receiving this medicine.

Blood clots may occur while you are receiving this medicine. Call your doctor if you have chest pain that may spread to your arms, jaw, back, or neck, coughing up blood, nausea, numbness or weakness in your arm or leg, or on one side of your body, sudden or severe headache, problems with vision, speech, or walking, trouble breathing, or unusual sweating.

This medicine may make your skin more sensitive to sunlight. Use a sunscreen when you are outdoors. Avoid sunlamps and tanning beds.

Infusion-related reactions may occur while you are receiving this medicine. Tell your doctor right away if you have the following symptoms: back pain, chest tightness, chills, fever, flushing, headache, nausea and vomiting, weakness, or trouble breathing.

Squamous Non-Small Cell Lung Cancer (NSCLC)

Portrazza™ is indicated, in combination with gemcitabine and cisplatin, for first-line treatment of patients with metastatic squamous non-small cell lung cancer.

Limitation of Use

Portrazza is not indicated for treatment of non-squamous non-small cell lung cancer [see Warnings and Precautions (5.6) and Clinical Studies (14.2)].

The following adverse drug reactions are discussed in greater detail in other sections of the label:

• Cardiopulmonary Arrest [see Boxed Warning and Warnings and Precautions (5.1)].
• Hypomagnesemia [see Boxed Warning and Warnings and Precautions (5.2)].
• Venous and Arterial Thromboembolic Events [see Warnings and Precautions (5.3)].
• Dermatologic Toxicities [see Dosage and Administration (2.3) and Warnings and Precautions (5.4)].
• Infusion-Related Reactions [see Dosage and Administration (2.2, 2.3) and Warnings and Precautions (5.5)].
• Non-Squamous NSCLC - Increased Toxicity and Increased Mortality [see Warnings and Precautions (5.6) and Clinical Studies (14.2)].

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The safety of Portrazza was evaluated in two randomized, open-label trials comparing Portrazza plus gemcitabine and cisplatin to gemcitabine and cisplatin alone in patients with squamous NSCLC (Study 1), and Portrazza plus pemetrexed and cisplatin to pemetrexed and cisplatin alone in patients with non-squamous NSCLC (Study 2). Since the data in Study 2 demonstrated similar incidence of adverse reactions over control as observed in Study 1, the safety data from Study 1 alone is described below.

For patients who received at least 1 dose of treatment in Study 1, the median age was 62 years (range 32 to 84), 83% were male; 84% were Caucasian; and 92% were smokers. Baseline ECOG performance status was 0 or 1 for 91%, and 2 for 9% of patients; 90% had metastatic disease in 2 or more sites. Patients received Portrazza 800 mg intravenously on days 1 and 8 of each 21 day cycle in combination with up to six cycles of gemcitabine (1250 mg/m2 on days 1 and 8) and cisplatin (75 mg/m2 on day 1). Patients received Portrazza until progressive disease or unacceptable toxicity.

Patients in the gemcitabine and cisplatin alone arm received a maximum of 6 cycles, while patients in the Portrazza plus gemcitabine and cisplatin arm demonstrating at least stable disease were permitted to continue to receive additional cycles of Portrazza until disease progression or unacceptable toxicity. The median duration of exposure to Portrazza in 538 patients who received at least 1 dose of treatment in Study 1 was 4.6 months (range 0.5 months to 34 months), including 182 patients exposed for at least 6 months and 41 patients exposed for greater than 1 year. Patients were monitored for safety until 30 days after treatment discontinuation and resolution of treatment-emergent adverse events.

The most common adverse reactions (all grades) observed in Portrazza-treated patients at a rate of ≥15% and ≥2% higher than gemcitabine and cisplatin alone were rash (44%), vomiting (29%), diarrhea (16%), and dermatitis acneiform (15%). The most common severe (Grade 3 or higher) adverse events that occurred at a ≥2% higher rate in Portrazza-treated patients compared to patients treated with gemcitabine and cisplatin alone were venous thromboembolic events (5%; including pulmonary embolism), rash (4%), and vomiting (3%).

Table 1 contains selected adverse drug reactions observed in Study 1 at an incidence of ≥5% in the Portrazza arm and at ≥2% higher incidence than the control arm.

Clinically relevant adverse reactions (all grades) reported in ≥1% and <5% of patients treated with Portrazza were: dysphagia (3%), oropharyngeal pain (1%), muscle spasms (2%), phlebitis (2%), and hypersensitivity/IRR (1.5%).

In Study 1, 12% of the patients on the Portrazza arm discontinued study treatment due to an adverse reaction. The most common Portrazza related toxicity leading to Portrazza discontinuation was skin rash (1%).

Table 2 contains selected electrolyte abnormalities observed in Study 1 according to laboratory assessment at an incidence of >10% in the Portrazza arm and at >2% higher incidence than the control arm.

The median time to onset of hypomagnesemia was 6 weeks (25th percentile 4 weeks; 75th percentile 9 weeks). Hypomagnesemia was reported as resolved in 43% of the patients who received Portrazza. In Study 1, 32% of the patients in the Portrazza arm and 16% of the patients who received gemcitabine and cisplatin alone received magnesium replacement.

Immunogenicity

As with all therapeutic proteins, there is the potential for immunogenicity. In clinical trials, treatment-emergent anti-necitumumab antibodies (ADA) were detected in 4.1% (33/814) of patients using an enzyme-linked immunosorbent assay (ELISA). Neutralizing antibodies were detected in 1.4% (11/814) of patients post exposure to Portrazza. No relationship was found between the presence of ADA and incidence of infusion-related reactions. The impact of ADA on efficacy (overall survival) could not be assessed due to the limited number of patients with treatment-emergent ADA. In Study 1, the exposure to necitumumab was lower in patients with ADA post-treatment than in patients without detectable ADA [see Clinical Pharmacology (12.3)].

The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of incidence of antibodies to Portrazza with the incidences of antibodies to other products may be misleading.

Squamous Non-Small Cell Lung Cancer

Study 1 was a randomized, multi-center open-label, controlled trial conducted in 1093 patients receiving gemcitabine and cisplatin first-line chemotherapy for metastatic squamous NSCLC. Patients were randomized (1:1) to receive Portrazza plus gemcitabine and cisplatin or gemcitabine and cisplatin alone. Stratification factors were ECOG performance status (0, 1 versus 2) and geographic region (North America, Europe, and Australia versus South America, South Africa, and India versus Eastern Asia). Gemcitabine (1250 mg/m2, Days 1 and 8) plus cisplatin (75 mg/m2, Day 1) were administered every 3 weeks (1 cycle) for a maximum of 6 cycles in the absence of disease progression or unacceptable toxicity. Portrazza (800 mg by intravenous infusion on Days 1 and 8 of each 3-week cycle) was administered prior to gemcitabine and cisplatin. Patients demonstrating at least stable disease on Portrazza plus gemcitabine and cisplatin were to continue Portrazza as a single agent in the absence of disease progression or unacceptable toxicity after completion of 6 planned courses of chemotherapy or if chemotherapy was discontinued for toxicity.

Of the 1093 randomized patients, the median age was 62 years (range 32 to 86), 83% were male; 84% were Caucasian; and 91% were smokers. The majority of the patients (87%) were enrolled in North America, Europe and Australia, 36 patients (3%) were enrolled at clinical sites in the U.S., 6% of the patients were enrolled in South America, South Africa and India and 8% enrolled at clinical sites in Eastern Asia. Baseline ECOG performance status was 0 or 1 for 91%, and 2 for 9% of patients; 91% had metastatic disease in 2 or more sites. In the Portrazza plus gemcitabine and cisplatin arm, 51% of patients continued Portrazza after completion or discontinuation of chemotherapy. Use of post-study systemic therapy was 47% in the Portrazza plus gemcitabine and cisplatin arm, and 45% in the gemcitabine and cisplatin arm.

The main outcome measure was overall survival (OS). Investigator-assessed progression-free survival (PFS) and overall response rate (ORR) were also assessed. Overall survival and PFS were statistically significantly improved in patients randomized to receive Portrazza plus gemcitabine and cisplatin compared to gemcitabine and cisplatin alone. There was no difference in ORR between arms, with an ORR of 31% (95% CI 27, 35) for Portrazza plus gemcitabine and cisplatin arm and an ORR of 29% (95% CI 25, 33) for gemcitabine and cisplatin arm, p-value 0.40.

Efficacy results are shown in Table 3 and Figure 1.

Figure 1: Kaplan-Meier Curves of Overall Survival in Patients with Metastatic Squamous Non-Small Cell Lung Cancer

Non-Squamous NSCLC - Lack of Efficacy

Lack of efficacy of Portrazza in combination with pemetrexed and cisplatin for the treatment of patients with metastatic non-squamous non-small cell lung cancer was determined in one randomized, open-label, multicenter trial (Study 2). The study was closed prematurely after 633 patients were enrolled due to increased incidence of death due to any cause and of thromboembolic events in the Portrazza arm. Patients with no prior chemotherapy for metastatic disease were randomized (1:1) to receive Portrazza plus pemetrexed and cisplatin or pemetrexed and cisplatin alone. Stratification factors were smoking status (non-smokers versus light smokers versus smokers), ECOG performance status (0 - 1 versus 2), histology (adenocarcinoma/large cell versus others), and geographic region. Portrazza (800 mg, Days 1 and 8 of each 3-week cycle) was administered prior to pemetrexed and cisplatin. Patients demonstrating at least stable disease on Portrazza plus pemetrexed and cisplatin were to continue Portrazza as a single agent in the absence of disease progression or unacceptable toxicity after completion of 6 planned courses of chemotherapy.

Of the 633 patients, 315 were randomized to Portrazza plus pemetrexed and cisplatin arm and 318 in the pemetrexed and cisplatin arm. The median age was 61 years, 67 % were male, 93% were Caucasian and 94% had ECOG PS 0 or 1. More than 75% were smokers and 89% had adenocarcinoma histology.

The main efficacy outcome was OS. Progression-free survival and ORR were also assessed. Addition of Portrazza to pemetrexed and cisplatin did not improve OS [HR=1.01; 95%CI (0.84, 1.21); p-value = 0.96)]; PFS [HR=0.96; 95% CI (0.8, 1.16)] or ORR (31% in the Portrazza plus pemetrexed and cisplatin arm and 32% in the pemetrexed and cisplatin alone arm).

Applies to necitumumab: intravenous solution

Along with its needed effects, necitumumab (the active ingredient contained in Portrazza) may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor or nurse immediately if any of the following side effects occur while taking necitumumab:

• Abdominal or stomach cramps
• confusion
• convulsions
• decreased urine
• difficulty with breathing
• drowsiness
• dry mouth
• increased thirst
• irregular heartbeat
• loss of appetite
• mood or mental changes
• muscle cramps in the hands, arms, feet, legs, or face
• muscle pain or muscle spasms (tetany) or twitching
• nausea or vomiting
• numbness and tingling around the mouth, fingertips, or feet
• tremor
• unusual tiredness or weakness

• Anxiety
• back pain
• chest pain or discomfort
• chest tightness
• chills
• cough
• difficulty with speaking
• dizziness or lightheadedness
• double vision
• fainting
• fast heartbeat
• fever
• flushing
• headache
• heart stops
• inability to move the arms, legs, or facial muscles
• no breathing
• no pulse or blood pressure
• pain or discomfort in the arms, jaw, back, or neck
• pain, redness, or swelling in the arm or leg
• pains in the chest, groin, or legs, especially the calves of the legs
• severe headaches of sudden onset
• slow speech
• sudden loss of coordination
• sudden onset of slurred speech
• sudden shortness of breath or troubled breathing
• sudden vision changes
• sweating
• trouble breathing
• unconscious

Some side effects of necitumumab may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

• Blemishes on the skin
• burning, dry, or itching eyes
• decreased weight
• diarrhea
• discharge or excessive tearing
• dry skin
• itching skin or rash
• loosening of the fingernails
• pimples
• rash with flat lesions or small raised lesions on the skin
• redness or soreness around the fingernails
• redness, pain, or swelling of the eye, eyelid, or inner lining of the eyelid
• swelling or inflammation of the mouth