Vectibix (Concentrate) Instructions for Use

ATC Code

L01FE02 (Panitumumab)

Active Substance

Panitumumab (Rec.INN registered by WHO)

Clinical-Pharmacological Group

Antitumor drug. Monoclonal antibodies

Pharmacotherapeutic Group

Antineoplastic agents; monoclonal antibodies and their drug conjugates; EGFR inhibitors (epidermal growth factor receptor)

Pharmacological Action

Antitumor agent. Panitumumab is a recombinant human monoclonal antibody (Ig G2) with high affinity and specificity for epidermal growth factor receptors (EGFR).

The EGF receptor stimulates the growth of normal epithelial cells, including skin and hair follicle cells, and is expressed on various types of tumor cells. Panitumumab binds to the ligand-binding domain of the EGF receptor and inhibits the autophosphorylation process induced by all known EGF receptor ligands.

Binding of panitumumab to the EGF receptor leads to receptor internalization, inhibition of cell growth processes, induction of apoptosis, and decreased production of interleukin-8 and vascular endothelial growth factor.

The KRAS (Kirsten rat sarcoma viral oncogene homolog 2) and NRAS (neuroblastoma RAS viral oncogene homolog) genes belong to the RAS oncogene family. The KRAS and NRAS genes encode a small guanosine triphosphate-binding protein involved in signal transduction. KRAS and NRAS are activated by various signals, including from the EGF receptor, and in turn stimulate the synthesis of other intracellular proteins involved in cell proliferation, survival, and angiogenesis.

Activating mutations of RAS genes frequently occur in various human tumor cells and play a role in both oncogenesis and tumor progression.

In vitro and in vivo animal studies have shown that Panitumumab inhibits the growth and survival of tumor cells expressing EGFR. No antitumor activity of panitumumab was observed in experiments with human tumor xenografts that did not express EGFR. The addition of panitumumab to radiation, chemotherapy, or other targeted therapy in animal studies led to an enhanced antitumor effect compared to radiation, chemotherapy, or targeted therapy alone.

Like all therapeutic proteins, Panitumumab has potential immunogenicity. The production of neutralizing antibodies to panitumumab was assessed using two different immunoassay screening systems to detect antibodies binding to panitumumab.

Pharmacokinetics

The pharmacokinetics of panitumumab are nonlinear when panitumumab is used as monotherapy or in combination with chemotherapy.

After a single administration of panitumumab as a 1-hour infusion, the AUC increased to a greater extent than would be characteristic of direct proportional dose dependence, and the clearance of panitumumab decreased from 30.6 to 4.6 ml/day/kg with increasing dose from 0.75 to 9 mg/kg. However, when panitumumab was administered at doses above 2 mg/kg, the increase in AUC was close to proportional dose dependence.

At a dose of 6 mg/kg every 2 weeks as a 1-hour infusion, the steady-state concentration (C_ss) of panitumumab is reached by the third infusion, with mean (± standard deviation [SD]) maximum and minimum concentrations of 213 ± 59 and 39 ± 14 µg/ml, respectively. The mean (± SD) AUC_0-t and clearance were 1306 ± 374 µg×day/ml and 4.9 ± 1.4 ml/kg/day, respectively. The half-life (T_1/2) of panitumumab was approximately 7.5 days (range: from 3.6 to 10.9 days).

Indications

Treatment of metastatic colorectal cancer (mCRC) in adult patients with RAS wild-type tumors: as first-line therapy in combination with regimens containing fluorouracil, folinic acid, and oxaliplatin (FOLFOX) or fluorouracil, folinic acid, and irinotecan (FOLFIRI); as second-line therapy in combination with a regimen containing fluorouracil, folinic acid, and irinotecan (FOLFIRI) in patients who have previously received first-line fluoropyrimidine-based chemotherapy (excluding irinotecan); as monotherapy after failure of fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy regimens.

ICD codes

Dosage Regimen

Administer Vectibix as an intravenous infusion using an infusion pump. Do not administer as an intravenous push or bolus.

The recommended dose is 6 mg/kg administered every 14 days.

Infuse doses up to 1000 mg over 60 minutes through a low protein-binding 0.2 µm or 0.22 µm in-line filter.

Infuse doses greater than 1000 mg over 90 minutes.

Reduce the infusion rate by 50% in patients experiencing a mild or moderate (Grade 1 or 2) infusion reaction.

Immediately and permanently discontinue Vectibix for a severe (Grade 3) or life-threatening (Grade 4) infusion reaction.

Premedication is not required.

Withhold Vectibix for dermatologic toxicities of Grade 3 or higher. If toxicity does not improve to Grade 2 or lower within one month, permanently discontinue treatment.

Upon improvement of dermatologic toxicity to Grade 2 or lower, resume treatment at the original dose.

For a second occurrence of Grade 3 dermatologic toxicity, withhold Vectibix. If toxicity improves to Grade 2 or lower within one month, resume treatment at 80% of the original dose.

Permanently discontinue Vectibix after the third occurrence of Grade 3 dermatologic toxicity or for a Grade 4 dermatologic toxicity.

Continue treatment until disease progression or unacceptable toxicity occurs.

Adverse Reactions

Infections and infestations very common – conjunctivitis, paronychia; common – pustular rash, subcutaneous tissue inflammation, urinary tract infection, folliculitis, localized infection; uncommon – eye infection, eyelid infection.

Blood and lymphatic system disorders very common – anemia; common – leukopenia.

Immune system disorders common – hypersensitivity; uncommon – anaphylactic reaction.

Metabolism and nutrition disorders very common – hypokalemia, hypomagnesemia, decreased appetite, weight loss; common – hypocalcemia, dehydration, hyperglycemia, hypophosphatemia.

Psychiatric disorders very common – insomnia; common – anxiety.

Nervous system disorders common – headache, dizziness.

Eye disorders common – blepharitis, eyelash growth, increased lacrimation, eye hyperemia, dry eye, eye itching, eye irritation; uncommon – ulcerative keratitis, keratitis, eyelid irritation.

Cardiac disorders common – tachycardia, deep vein thrombosis, hypotension, hypertension, hyperemia; uncommon – cyanosis.

Respiratory, thoracic and mediastinal disorders very common – dyspnea, cough; common – pulmonary embolism, epistaxis; uncommon – interstitial lung disease, bronchospasm, dryness of nasal mucosa.

Gastrointestinal disorders very common – diarrhea, nausea, vomiting, abdominal pain, stomatitis, constipation; common – rectal bleeding, dry mouth, dyspepsia, aphthous ulcers, cheilitis, GERD; uncommon – chapped lips; dry lips.

Skin and subcutaneous tissue disorders very common – acneiform dermatitis, skin rash, erythema, skin itching, dry skin, skin fissures, acne, alopecia; common – skin ulceration, exfoliative skin lesions, exfoliative skin rash, dermatitis, papular skin rash, pruritic skin rash, erythematous skin rash, generalized skin rash, maculopapular skin rash, skin lesions, skin toxicity, crusts, hypertrichosis, onychoclasis, nail disorder, hyperhidrosis, palmar-plantar erythrodysesthesia syndrome; uncommon – toxic epidermal necrolysis, Stevens-Johnson syndrome, skin necrosis, angioedema, hirsutism, ingrown nail, onycholysis.

Musculoskeletal and connective tissue disorders very common – back pain; common – pain in extremity.

General disorders and administration site conditions very common – fatigue, pyrexia, asthenia, mucositis, peripheral edema.

Contraindications

History of hypersensitivity to panitumumab; interstitial pneumonitis or pulmonary fibrosis; renal failure; hepatic failure; combination with oxaliplatin-containing chemotherapy regimen in patients with mCRC and RAS gene mutations or in patients with mCRC with unspecified RAS gene mutation status; children and adolescents under 18 years of age; pregnancy, breastfeeding period.

Use with caution

Keratitis, ulcerative keratitis, severe dry eye.

Use in Pregnancy and Lactation

Contraindicated for use during pregnancy and breastfeeding.

Use in Hepatic Impairment

Pharmacokinetic studies in patients with hepatic impairment have not been conducted.

Use in Renal Impairment

Pharmacokinetic studies in patients with renal impairment have not been conducted.

Pediatric Use

Contraindicated for use in children and adolescents under 18 years of age.

Geriatric Use

No differences in the safety or efficacy of panitumumab were observed in elderly patients (> 65 years). However, an increase in the number of serious adverse events was noted in elderly patients receiving Panitumumab in combination with chemotherapy.

Special Precautions

During treatment, the occurrence of dermatological reactions should be monitored and appropriate symptomatic therapy should be administered. To reduce the severity of these reactions, patients are advised to limit sun exposure and use sun-protective clothing.

During infusion, anaphylactic reactions, bronchospasm, and arterial hypotension are possible. In such cases, the infusion should be stopped immediately. Hypersensitivity reactions, including angioedema, have been reported more than 24 hours after infusion.

Interstitial lung disease, development of acute or worsening of existing pulmonary symptoms have been observed with the use of EGFR inhibitors. If such symptoms occur, treatment with panitumumab should be interrupted and an appropriate examination should be performed. If pneumonitis or pulmonary infiltrates are confirmed, Panitumumab should be discontinued and the patient should receive appropriate therapy.

Renal function impairment has been observed in patients with severe diarrhea and dehydration.

Visual status should be monitored during treatment.

Electrolyte balance, especially blood magnesium levels, should be monitored during treatment.

Safety of use in pediatrics has not been studied.

Effect on ability to drive vehicles and operate machinery

In case of adverse reactions from the organs of vision and/or decreased ability to concentrate and speed of reactions, patients are advised to refrain from driving vehicles or working with complex equipment until these adverse reactions resolve.

Drug Interactions

Concomitant use of panitumumab with a chemotherapy regimen including bevacizumab is not recommended, as it may increase the frequency of toxicity and fatal outcomes.

Storage Conditions

Store at 2°C (36°F) to 8°C (46°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.