Buy Vectibix solution 20 mg/ml 5 ml vial 1 pc.
  • Buy Vectibix solution 20 mg/ml 5 ml vial 1 pc.

Vectibix® [Panitumumab]

Amgen Manewackering Limited
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2019-09-19
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Clinical Pharmacology

Panitumumab is a human IgG2 monoclonal antibody obtained from a mammalian cell line (Chinese hamster ovaries) by recombinant DNA technology. Panitumumab has high affinity and specificity for human epithelial growth factor (EGF) receptors. The EGF receptor is a transmembrane glycoprotein from the type I tyrosine kinase receptor family, which also includes HER1 / c-ErbB-1, HER2, HER3 and HER4. The EGF receptor stimulates the growth of normal epithelial cells, including skin cells and hair follicles, and is expressed on various types of tumor cells.

Panitumumab binds to the ligand-binding domain of the EGF receptor and inhibits the process of autophosphorylation, which is induced by all known EGF receptor ligands. The binding of panitumumab to the EGF receptor leads to receptor internalization, inhibition of cell growth processes, induction of apoptosis and a decrease in the production of interleukin-8 and vascular endothelial growth factor. The KRAS gene (a homologue of viral oncogene rat Kirsten's sarcoma 2) encodes a small guanosine triphosphate-binding protein that is involved in signal transduction. KRAS is activated by various signals, including from the EGF receptor, and, in turn, stimulates the synthesis of other intracellular proteins involved in the processes of cell proliferation, survival and angiogenesis.

Activating mutations of the KRAS gene often occur in various human tumor cells and play a certain role, both in the process of carcinogenesis and in tumor progression.

Immunogenicity

The production of neutralizing antibodies to panitumumab was evaluated using two different immunoassay methods (ELISA - enzyme immunoassay, which allows to determine high-affinity antibodies, and Biosensor, which allows to determine high-and low-affinity antibodies); The results of the analysis showed that, in general, the occurrence of post-response response, assessed by the presence of antibodies to panitumumab, was low. Antibodies to panitumumab before drug administration were detected in 5 of 636 patients (<1%) and 16/635 patients (2.5%) according to ELISA and Biosensor immunoassays, respectively. Neutralizing antibodies to panitumuma after drug administration were detected in 1 of 447 patients (0.2%) and in 7 of 447 patients (1.6%) according to ELISA and Biosensor immunoassays, respectively. When compared with patients whose antibodies did not develop, the relationship between the presence of neutralizing antibodies to panitumumab and changes in pharmacokinetic parameters, efficacy and safety of the drug was not observed.

The detection of antibodies depends on the sensitivity and specificity of the method used. A positive result, by definition, of antibodies can be influenced by various factors, including the sampling technique, the use of concomitant drugs, and the nature of the underlying disease, so the comparison of the incidence of antibodies to panitumumab with this indicator for other drugs may be unreliable.

Clinical efficacy

The use of Vectibix in clinical studies in patients with metastatic colorectal cancer, who have experienced progression of the disease on the background or after a previous course of chemotherapy, leads to an increase in progression-free survival (PFS), while the absolute value of PFS was greater in patients with wild-type KRAS in tumor cells compared with a group of patients with tumors with KRAS mutations.

Pharmacokinetics

When prescribing Vectibix as monotherapy or in combination with chemotherapy, the pharmacokinetics of the drug is non-linear.

After a single injection of panitumumab in the form of a 1-hour infusion, the AUC increased to a greater degree than is typical with dose-proportional dependence, and the drug clearance decreased from 30.6 to 4.6 ml / day / kg with an increase in dose from 0.75 to 9 mg / kgHowever, with the introduction of panitumumab in doses of more than 2 mg / kg, the nature of the increase in AUC was close to dose-proportional dependence.

Subject to the recommended dosing regimen (6 mg / kg 1 time in 2 weeks as a 1-hour infusion) Css panitumumab is achieved by the third infusion with average C valuesmax 213 ± 59 mcg / ml and Cmin 39 ± 14 mcg / ml. The mean AUC was 1306 ± 374 μg × d / ml, the clearance was 4.9 ± 1.4 ml / kg / day. T1/2 the drug was approximately 7.5 days (range from 3.6 to 10.9 days).

According to the results of the analysis of pharmacokinetics in individual groups of patients (mainly aged 21-88 years), patient's age, race, liver and kidney function, the use of concomitant chemotherapeutic drugs and EGF intensive membrane staining (1+, 2+, 3+) in tumor The cells do not have a clear effect on the pharmacokinetics of panitumumab.

Panitumumab pharmacokinetics have not been studied in patients with impaired renal or hepatic function.

Indications

Monotherapy of metastatic colorectal cancer with expression of EGF receptors and non-mutant (wild) type of KRAS, with disease progression on the background or after a previous course of fluorotherapy with fluoropyrimidine, oxaliplatin and irinotecan-containing regimens.

Composition

1 ml (1 bottle) contains:

Active substances: Panitumumab 20 mg 100 mg.

Excipients: sodium acetate trihydrate, sodium chloride, glacial acetic acid, water d / u.

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Vectibix® [Panitumumab]

Dosage and Administration

The recommended dose of Vectibix is 6 mg / kg of body weight 1 time in 2 weeks.

Safety and efficacy of Vectibix not evaluated in patients with impaired renal or hepatic function.

In case of drug administration elderly patients dose adjustment is not required.

Experience in the use of Vectibix in children missing; the drug should not be prescribed patients under 18 years old.

Recommendations for dose adjustment and mode of administration

With the appearance of weak or moderate signs of an infusion reaction (grade 1 or 2), the rate of drug administration should be reduced by 50%. At the onset of pronounced symptoms of an infusion reaction (grade 3 or 4), the introduction of Vectibix should be stopped immediately.

With the development of a dermatological reaction of severity 3 and above (according to the NCI-CTC / CTCAE classification) or regarded by the patient as an “intolerable dermatological reaction”, it is necessary to temporarily suspend the use of Vektibix until the severity of this reaction decreases (≤ 2 severity). After reducing the severity of the observed dermatological reaction to ≤ 2 degrees, the administration of Vektibix is ​​resumed at a dose equal to 50% of the initial dose. In the absence of re-development of the reaction, the dose of Vektibix must be gradually increased by 25% until the recommended dose is reached. If the severity of the reaction does not decrease (to ≤ 2 degrees of severity) after skipping 1 or 2 doses of Vectibix, or in case of a relapse or an intolerable reaction occurs at a dose of the drug equal to 50% of the initial dose, taking the Vectibix drug should be completely canceled.

Instructions for the preparation and administration of the solution for infusion

Before infusion, Vektibix is ​​diluted in 0.9% sodium chloride solution for injection using the aseptic dilution technique. It is not recommended to shake or shake the bottle. Do not enter the drug, if there is a change in the color of the contents of the bottle. The required amount of Vectibix is taken from the drug bottle to obtain a dose of 6 mg / kg, which is then dissolved in a total volume of 100 ml. The final concentration should not exceed 10 mg / ml. Doses higher than 1000 mg should be dissolved in 150 ml of 0.9% sodium chloride solution for injection. The resulting solution is mixed by gently turning the bottle over, do not shake.

Vektibix should be injected iv with an infusion pump into a peripheral probe or permanent catheter through a 0.2 or 0.22 μm inline filter with a low degree of protein binding. The recommended duration of infusion is approximately 60 minutes. The duration of administration of the drug in doses of more than 1000 mg should be approximately 90 minutes.

Before and after the introduction of Vektibix, the infusion system must be washed with saline to avoid mixing Vectibix with other drugs or solutions for intravenous administration. Jet or bolus administration of Vectibix is not recommended.

Adverse reactions

The most frequent undesirable reactions in the application of Vectibix monotherapy were dermatological reactions, observed in approximately 93% of cases. These reactions are due to the pharmacological properties of Vectibix and usually have mild or moderate severity; only in 12% of cases dermatological reactions are severe (severity 3 and higher, according to the NCI-CTC classification).

Frequent adverse reactions occurring in> 20% of patients were gastrointestinal disorders: nausea (30%), diarrhea (27%) and vomiting (22%); general reactions: increased fatigue (35%); infections and invasions: paronychia (21%); pathology of skin and subcutaneous tissue: itching (53%), erythema (52%), acneiform dermatitis (51%) and rash (38%).

Below are data on adverse events observed in patients with metastatic colorectal cancer (mCRC) who received panitumumab as monotherapy.The safety profile of panitumumab in patients expressing wild-type KRAS in tumor cells was generally similar to that for the mCRC monotherapy group. The only difference was that the pathology of the nails and hypomagnesaemia in the group of patients with increased expression of wild-type KRAS was higher (≥ 1/10) than in patients in the general mRDC monotherapy population (≥ 1/100, <1/10), and stomatitis and acne were classified as frequent in the wild type KRAS group and very common in the general population of mCRC monotherapy. In addition, bronchospasm, hypotension and hypertension were classified as infrequent (≥ 1/1000, <1/100) in the general population of mCRC monotherapy and as frequent (≥ 1/100, <1/10) in the group with wild type KRAS.

Undesirable reactions are presented in accordance with the following gradation of the frequency of their occurrence: very often (≥ 1/10), often (≥ 1/100, <1/10), rarely (≥ 1/1000 to <1/100), very rarely ( ≥ 1/10 000, <1/1000).

Infections and invasions: very often - paronychia; often - pustular rash, cellulitis, eye infection, infection of the eyelids.

On the part of the skin: very often - eel rash, acne, erythema, peeling of the skin, exfoliative rash, pruritus, dry skin, skin cracks, acneiform dermatitis; often - papular rash, erythematous rash, macular rash, maculo-papular rash, itchy rash, skin ulcers, nail disease (onicoclasia, onycholysis), hypertrichosis, alopecia, scabies, palm-erythrodestosis syndrome very rarely - angioedema.

The skin rash that developed during treatment with Vectibix was most often localized on the face, upper chest, and back, but in some cases it also spread to the extremities. As a consequence of severe dermatological reactions, the development of infectious complications, such as sepsis, in rare cases with fatal outcome, cellulitis, and local abscesses requiring surgical intervention and drainage were also noted. The median time to the development of the first manifestations of dermatological reactions was 10 days, and the median time to their resolution since the last injection of Vektibix was 28 days.

Paronychia was accompanied by swelling of the side nail rollers of the fingers and toes.

Dermatological reactions (including effects on the nails), observed in patients who received Vektibix or other EGF inhibitors, are known pharmacological effects of these drugs. According to the general population of mCRC monotherapy, severe (grade 3 and 4) reactions were attributed to: acneiform dermatitis (5%), erythema (4%), rash (3%), itching (2%), exfoliative rash (1%), acne rash (1%), skin cracks (1%), peeling skin <1%), dry skin (<1%), skin ulcers (<1%), scabies (<1%), erythematous rash (<1%) , papular rash (<1%) and maculo-papular rash (<1%). Paronychia was observed in 1% of patients who received Vectibix.

From the digestive system: very often - diarrhea, nausea, vomiting, abdominal pain, constipation, stomatitis; often - dryness of the oral mucosa.

In most cases, diarrhea was mild or moderate, and in only 2% of patients with wild-type KRAS expression was severe diarrhea. The development of acute renal failure with severe diarrhea and dehydration has been reported.

On the part of the respiratory system: very often - shortness of breath, cough; often - dry nasal mucosa, nasal bleeding, pulmonary embolism; rarely - bronchospasm.

On the part of the organ of vision: often - conjunctivitis, increased tearing, hyperemia of the eyeball, dryness and irritation of the eyes, irritation of the eyelids, itchy eyes, increased growth of eyelashes.

From the nervous system: often - headache, dizziness.

Metabolic disorders: often - hypomagnesemia, hypocalcemia, hypokalemia, dehydration.

Infusion reactions: During clinical trials and in the post-marketing period, the following adverse reactions were observed within 24 hours after the infusion: abdominal pain, anaphylactic reactions, angioedema, back pain, bronchospasm, cardiac arrest, chest pain, chills, cyanosis, shortness of breath , flushing, hypertension, hypotension, pyrexia, tachycardia, vomiting.Reactions to infusion (developing within 24 hours from the moment of the first injection of the drug) were observed in 3% of patients who received Vectibix in clinical studies. The frequency of severe reactions (degrees 3 and 4) was <1%. Post-marketing studies have reported serious infusion reactions, including reports of rare lethal outcomes. The development of a case of lethal angineurotic edema was reported in a patient with recurrent metastatic squamous cell carcinoma of the head treated with Vektibix. A fatal complication developed with the resumption of therapy after a previous episode of angioedema. Both reactions were recorded more than 24 hours after drug administration. Hypersensitivity reactions that developed more than 24 hours after the infusions were also reported in the post-marketing period.

Other: very often - increased fatigue, pyrexia; often - infusion reactions, inflammation of the oral mucosa, chills, chest discomfort, hypersensitivity, tachycardia, back pain; rarely - anaphylactic reactions, flushing, hypotension, hypertension, cyanosis.

Vectibix in combination with other anticancer drugs and / or as monotherapy.

In all clinical studies in combination with other anticancer drugs and / or as monotherapy, the most serious side effects associated with Vectibix were: pulmonary embolism, severe dermatological toxicity complicated by infection, and death as a result of sepsis, infusion reactions and hypomagnemia. Adverse reactions requiring withdrawal of Vectibix included infusion reactions, severe skin toxicity, and paronychia.

Contraindications

  • Vectibix is ​​contraindicated in patients with a history of the development of life-threatening hypersensitivity reactions to any of the components of the drug.
  • interstitial pneumonitis or pulmonary fibrosis;
  • children's age (efficacy and safety in children under 18 years old has not been established);
  • pregnancy;
  • breastfeeding period.

Drug interactions

Studies of drug interactions was not conducted.

Combined administration of Vektibix with chemotherapy regimens based on irinotecan, fluoropyrimidine and calcium folinate (leucovorin) (IFL mode) or chemotherapy regimens including bevacizumab is not recommended. When prescribing panitumumab in combination with a chemotherapy regimen that included bevacizumab, there was an increase in mortality.

Vektibix should not be given in combination with chemotherapy containing oxaliplatin in patients with mCRC (metastatic colorectal cancer) with tumors characterized by mutant KRAS, or in the case of unspecified status of KRAS tumors. In a clinical trial in patients with tumors with mutated KRAS who received panitumumab and folfox, there was a decrease in survival without a progression of the total survival time.

Pregnancy and Lactation

The EGF receptor is involved in the control of prenatal development of the fetus and plays a role in the processes of normal organogenesis, proliferation and differentiation of the cells of a developing embryo. Thus, Vectibix can be potentially harmful to the fetus when prescribed to pregnant women. It is known that human IgG antibodies are able to penetrate the placental barrier, so panitumumab can penetrate from the mother's body into the developing fetus. Therefore, women with intact reproductive function during treatment with Vectibix and for 6 months after its termination should use reliable contraceptive means. If the pregnancy has developed during therapy, it is necessary to explain to the patient the potential risk of abortion and the potential risk to the fetus.

It is not known whether panitumumb penetrates breast milk. Sincehuman IgG antibodies penetrate into breast milk; it can be assumed that panitumumab can also pass into breast milk. The possibility of absorption of the drug and its potential harm to the child has not been established. During the period of treatment with Vektibix and for 3 months after its termination, breastfeeding is not recommended.

Experimental studies have shown a reversible effect of the drug on the menstrual cycle and a decrease in fertility of female monkeys. In this regard, panitumumab may affect the possibility of pregnancy in women.

Special instructions

Treatment with Vectibix should be made under the supervision of the attending physician who has experience in prescribing antineoplastic drugs.

Determining the expression of non-mutant KRAS should be carried out by experienced laboratory technicians using a validated technique.

Dermatological reactions

Dermatological reactions - the class effect of EGF receptor inhibitors, due to pharmacological properties - were observed in almost all patients (approximately 90%) who received Vektibix.

Patients who developed severe dermatologic reactions during treatment with Vektibix or worsened the course of other dermatologic reactions should be monitored for the development of inflammatory or infectious complications (including cellulitis); if necessary, such patients should be given appropriate treatment. It is recommended to use sunscreen and headgear during treatment with Vektibix and with the development of dermatological reactions / skin rash. sunlight can increase the severity of dermatological reactions that occur during the use of the drug.

Lung complications

Interstitial lung diseases occurred during therapy with other inhibitors of the EGF receptor, therefore, when lung symptoms occur or worsen, treatment with Vectibix should be stopped, and the observed symptoms should be immediately and thoroughly studied. When pneumonitis or infiltrates are detected in the lung tissue, Vectibix should be canceled and appropriate treatment should be prescribed.

Electrolyte imbalance

Some patients had a progressive decrease in serum magnesium concentrations, leading to severe (grade 4) hypomagnesemia. Periodic monitoring of the patient’s condition for the development of hypomagnesaemia and concomitant hypocalcemia every 2 weeks during the period of treatment with Vectibix and for 8 weeks after its termination is necessary. Recommended medication magnesium (if necessary).

Disturbances in the balance of other electrolytes, including hypokalemia, were also noted. It is recommended to adequately maintain serum concentrations of other electrolytes.

The drug contains 0.15 mmol of sodium (which corresponds to 3.45 mg of sodium) per 1 ml of concentrate. In this regard, patients adhering to a diet with reduced sodium content during the period of treatment must control the amount of sodium in their diet.

Infusion reactions

In a clinical study, 4% of patients had infusion reactions, while in 1% of patients, these reactions were classified as severe (degrees 3 and 4 by NCI-CTC). In all clinical studies, infusion reactions (occurring within 24 hours after any infusion) were observed in 3% of patients who received Vectibix, of which <1% were severe (grades 3 and 4 by NCI-CTC). Post-marketing studies have reported serious infusion reactions, including rare post-marketing fatal reports. Infusion should be discontinued if a severe or life-threatening reaction occurs (for example, if bronchospasm, angioedema, hypotension, or anaphylaxis occur). Depending on the severity and / or duration of the reaction, the question of the permanent withdrawal of Vectibix should be resolved.

In patients with mild or moderate (grade 1 and 2 on the NCI-CTC) infusion reactions should reduce the rate of infusion throughout the infusion. It is recommended to maintain a reduced infusion rate during all subsequent infusions.

Hypersensitivity reactions have been reported that occurred more than 24 hours after the infusions, including fatal angioedema, which developed more than 24 hours after the infusions. Patients should be warned about the possibility of late development of the reaction and instructed to contact their doctor in case of symptoms of hypersensitivity reaction.

Vectibix in combination with chemotherapy regimens

When using Vektibix in combination with bevacizumab and the IFL regimen, there was a significant increase in the incidence of pulmonary embolism, infectious complications (mainly of dermatological origin), diarrhea, electrolyte imbalance and dehydration. Additional analysis of efficacy data, depending on KRAS status, did not reveal the advantages of adding Vectibix to chemotherapy regimens based on oxaliplatin or irinotecan and bevacizumab. There was a tendency to a decrease in survival in groups on modes containing oxaliplatin or irinotecan, regardless of the status of the KRAS mutation.

In this regard, it is necessary to avoid combining Vectibix with chemotherapy regimens containing bevacizumab.

Vectibix in combination with oxaliplatin-based chemotherapy in the treatment of patients with metastatic colorectal cancer (mCRC)

Vectibix should not be given in combination with chemotherapy containing oxaliplatin, in patients with mCRC, with tumors characterized by mutant KRAS, or in the case of unspecified status of KRAS tumors. During the phase III study (n = 1183, 656 patients with wild type KRAS and 440 patients with mutated type KRAS in tumors) assessed by panitumumab in combination with infusion 5-fluorouracil, leucovorin (FOLFOX), compared only with FOLFOX as therapy first line with mCRC in patients with tumors with mutated KRAS treated with panitumumab and FOLFOX (n = 221) compared with only FOLFOX (n = 219), there was a decrease in survival without a progression of the overall survival time.

Acute renal failure

Acute renal failure was observed in patients with severe diarrhea and dehydration.

Impact on the ability to drive vehicles and other mechanisms that require high concentration of attention

Special studies of the effect of the drug on the ability to drive and use complex equipment have not been conducted. If undesirable reactions develop on the part of the organs of vision and / or reduce the ability to concentrate and react quickly, patients are advised to refrain from driving or working with complex equipment until these adverse reactions are resolved.

Overdosage

Symptoms: when the recommended therapeutic dose was exceeded, approximately 2 times toxic reactions from the skin, diarrhea, dehydration and increased fatigue were observed, which corresponded to the safety profile of the drug at the recommended dose.

Treatment: symptomatic overdose therapy.

  • Brand name: Vectibix
  • Active ingredient: Panitumumab
  • Dosage form: Concentrate for solution for infusion.
  • Manufacturer: Amgen Manewackering Limited
  • Country of Origin: USA

Studies and clinical trials of Panitumumab (Click to expand)

  1. Panitumumab monotherapy in patients with previously treated metastatic colorectal cancer
  2. Panitumumab, a Fully Human Anti-EGFR Monoclonal Antibody, Augments Radiation Response in Xenograft Models of Upper Aerodigestive Tract Cancers
  3. Integration of panitumumab into the treatment of colorectal cancer
  4. Improving disease control in advanced colorectal cancer: Panitumumab and cetuximab
  5. Augmentation of Radiation Response by Panitumumab in Models of Upper Aerodigestive Tract Cancer
  6. A Phase I Study of Capecitabine, Oxaliplatin, Panitumumab, and External Beam Radiation Therapy (RT) for Patients with Esophagogastric Carcinoma (EC)
  7. Immunogenicity of panitumumab in combination chemotherapy clinical trials
  8. Le panitumumab, une nouvelle arme dans le traitement du cancer colorectal métastatique!
  9. Successful re-challenge with panitumumab in patients who developed hypersensitivity reactions to cetuximab: report of three cases and review of literature
  10. Successful desensitization with cetuximab after an infusion reaction to panitumumab in patients with metastatic colorectal cancer
  11. Health-related quality of life and colorectal cancer-specific symptoms in patients with chemotherapy-refractory metastatic disease treated with panitumumab
  12. Sweeping KRAS generalizations: are we depriving patients of an effective treatment? A novel KRAS mutation and dramatic response to panitumumab in a patient with metastatic colorectal cancer
  13. Cetuximab and panitumumab in KRAS wild-type colorectal cancer: a meta-analysis
  14. First-line panitumumab plus irinotecan/5-fluorouracil/leucovorin treatment in patients with metastatic colorectal cancer
  15. Safety and pharmacokinetics of panitumumab in Japanese patients with advanced solid tumors
  16. Le panitumumab (Vectibix®) en oncologie digestive: quel rationnel pharmacologique et pharmacocinétique ?
  17. Safety and efficacy of panitumumab following cetuximab: retrospective review of the Memorial Sloan-Kettering experience
  18. Zulassung für Kombinationstherapien mit Panitumumab
  19. Clinical outcome of panitumumab for metastatic colorectal cancer with wild-type KRAS status: a meta-analysis of randomized clinical trials
  20. Panitumumab: An Arrow on Target
  21. Panitumumab
  22. A Q-TWiST analysis comparing panitumumab plus best supportive care (BSC) with BSC alone in patients with wild-type KRAS metastatic colorectal cancer
  23. From XenoMouse technology to panitumumab, the first fully human antibody product from transgenic mice
  24. Panitumumab

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