Medicinal Products

PEMBROLIZUMAB 50 mg

Generic drug of the therapeutic class: Oncology and Hematology
Active ingredients: Pembrolizumab
laboratory: Msd France

Powder for IV infusion solution
Box of 1 vial of 50 mg
All forms

Indication

Single-agent treatment of adult patients (≥ 18 years of age) with unresectable (stage III) or metastatic (stage IV) melanoma

❖ previously treated by ipilimumab

❖ and after treatment with BRAF inhibitor or MEK inhibitor for patients with BRAF v600 mutation.

Patients should have an ECOG performance index of 0 or 1, and adequate organ functions defined by hematological and biochemical criteria.

Given the delay in response, and adverse effects (AE), treatment is reserved for patients with a life expectancy greater than 3 months and whose general condition is preserved.

The temporary authorization for use is based on data from a single open-label study of the overall response rate. Clinical trials are still in progress. An improvement in survival is not established at this stage.

Dosage PEMBROLIZUMAB 50 mg Powder for solution for infusion IV Box of 1 vial of 50 mg

Treatment with PEMBROLIZUMAB MSD FRANCE should be initiated and supervised by a medical specialist experienced in the treatment of cancer.

Dosage

The recommended dose of PEMBROLIZUMAB MSD FRANCE is 2 mg / kg administered intravenously (IV) over a period of 30 minutes every 3 weeks.

The treatment must be continued as long as the risk-benefit ratio remains favorable without exceeding 24 months. Atypical responses (ie, an initial and transient increase in tumor size, or the appearance of new small lesions during the first few months, followed by tumor regression), were observed. Clinically stable patients with initial evidence of disease progression should continue treatment until confirmation of disease progression.

Precautions should be taken before starting treatment (see Warnings and Precautions ) and treatment should be evaluated regularly.

Dosage adjustment

Final cessation of treatment or suspension of treatment:

• Management of immunological adverse events may require treatment continuation or definitive discontinuation of PEMBROLIZUMAB therapy. Decreasing the dose is not recommended. Recommendations for definitive cessation of treatment or suspension of treatment are described in Tables 1A and 1B. Detailed recommendations for the management of adverse events of immunological origin are described in the Warnings and Precautions for Use section .

Table 1A When to definitively stop PEMBROLIZUMAB?

Permanently discontinue PEMBROLIZUMAB in patients with the following signs and symptoms suggestive of adverse immunological effects. Management of these toxicities may also require treatment with high dose corticosteroids.

Severe or life-threatening side effects

Grade according to NCI-CTCAE v4 a

Gastrointestinal:

Severe symptoms (abdominal pain, severe diarrhea or a significant change in the number of stools, blood in the stool, gastrointestinal bleeding, gastrointestinal perforation) of known or suspected immunological origin

- Grade 2 Diarrhea without resolution

(grade ≤ 1) ≤ 12 weeks after treatment with corticosteroids

- Diarrhea or grade 3 or 4 colitis without resolution (Grade ≤ 1) within ≤ 12 weeks after treatment with corticosteroids

Or

-Resolution of IE (grade ≤ 1) but impossible weaning of corticosteroid therapy 12 weeks after its introduction

Hepatic:

Very important elevation of ASAT and ALT, or total bilirubin or symptoms of hepatic toxicity of known or suspected immunological origin

- ASAT or ALAT> 5 x ULN and / or total bilirubin> 3 x ULN in absence of cholestasis or haemolysis

Infusion reactions

- grade 2 recidivating despite appropriate premedication

- grade 3 or 4

Inflammatory pneumonitis

- recurring grade 2

- grade 3 or 4

Other organ system b :

nephritis, uveitis, skin rashes

- adverse effect of immunological origin grade ≥ 3 for nephritis and uveitis, grade 4 for rash

- immunological condition of grade 1-2 immunological origin NOT SATISFIED with topical treatment

Permanently stop PEMBROLIZUMAB in case

■ - progression of the disease confirmed by radiological examination, according to irRC criteria (immune related Response Criteria),

■ - confirmed pregnancy,

■ inability to reduce the dose of corticosteroids when dealing with adverse effects of immunological origin at a dose <10 mg prednisone or equivalent per day,

■ - Grade 2 adverse effect related to the drug and considered of immunological origin which persists without improvement over a period> 4 weeks.

- a) Toxicities are graded according to the National Cancer Institute's Common Terminology Criteria for Adverse Events classification. Version 4.0 (NCI-CTCAE v4) available at this address: //ctep.cancer.gov.

- b) Any other inflammatory effect considered to be of immunological origin must be graded according to CTCAE. The decision to discontinue PEMBROLIZUMAB therapy should be based on the severity of the effect.

LSN = upper limit of normal

Table 1B When to suspend treatment with PEMBROLIZUMAB?

Suspend treatment with PEMBROLIZUMAB a in patients with the following signs or symptoms suggestive of an immunological adverse effect. Management of these toxicities may also require treatment with high dose corticosteroids.

Mild to moderate side effects

Action

1. Suspend treatment with Pembrolizumab until resolution of grade 1 or grade 0 toxicity (or return to baseline). 2. If the resolution of the toxicity occurs before the next dose is given, resume treatment at the next scheduled administration. Non-administered doses following the emergence of immunological adverse events should not be taken up. 3. If the resolution did not occur before the next scheduled administration, continue the suspension of treatment until resolution and resume treatment. The interval of administration between the following cycles may be increased by 1 week (for example, up to an interval of 4 weeks). Non-administered doses following the emergence of immunological adverse events should not be taken up. 4. Permanently discontinue Pembrolizumab if not resolved (grade ≤ 1) ≤ 12 weeks.

Gastrointestinal:

Moderate symptoms, such as diarrhea or colitis, no

controlled by medical treatment (including persistent symptoms [5-7 days] or recurrence of mild to moderate symptoms [Grade 1 or 2] b ) of proven or suspected immunologic origin

Endocrine:

Severe adverse effects in the endocrine glands, such as hypophysitis and thyroid called not sufficiently controlled by hormone replacement therapy or immunosuppressive treatment at high doses.

Inflammatory pneumonitis:

Moderate inflammatory pneumonia (Grade 2) 1st appearance

Renal:

El grade 1 in the absence of improvement under symptomatic EI treatment of grade 2

Other IEs of immunological origin c

a) Decreasing doses of PEMBROLIZUMAB is not recommended

b) IAs are graded according to the National Cancer Institute Common Terminology Criteria for Version 4.1 (NCI-CTCAE v4) classification available at this address: //ctep.cancer.gov.

c) Any other inflammatory effect considered to be of immunological origin must be graded according to CTCAE. The decision to discontinue PEMBROLIZUMAB therapy should be based on the severity of the effect.

LSN = upper limit of normal

è Discontinuation of treatment may be considered in patients who have achieved a complete response confirmed according to irRC criteria and who have been treated for at least 24 weeks by PEMBROLIZUMAB MSD FRANCE.

Special populations

The safety and efficacy of PEMBROLIZUMAB MSD FRANCE have not been studied in patients with uveal or choroidal melanoma or in patients with active brain metastases.

The elderly

No differences in safety or efficacy were reported between elderly patients (> 65 years) and younger patients (<65 years). No dose adjustment is necessary in this population.

Renal failure

The safety and efficacy of PEMBROLIZUMAB MSD FRANCE have not been studied in patients with severe or moderate renal impairment.

No dosage adjustment is necessary for patients with mild to moderate renal impairment. Hepatic insufficiency

The safety and efficacy of PEMBROLIZUMAB MSD FRANCE have not been studied in patients with moderate or severe hepatic impairment.

No dose adjustment is required in patients with mild hepatic impairment.

Pediatric population: The safety and efficacy of PEMBROLIZUMAB MSD FRANCE in children under 18 years of age have not been established. No data available.

Administration mode

This medication should be given by intravenous infusion over a period of 30 minutes. Due to the risk of infusion-related reactions, appropriate resuscitation equipment should be available in the room and a physician should be immediately available when administering the medication. (see section monitoring during treatment). PEMBROLIZUMAB MSD FRANCE should not be injected with fast direct intravenous or IV bolus. A central catheter is not necessary for infusion. However, if the patient has a central venous catheter in place, it is recommended to use it for infusion. The use of PVC plasticized material or medical devices with DEHP (di-2-ethylhexylphthalate) may result in release of DEHP in the presence of pembrolizumab. In order to minimize the patient's exposure to DEHP, it is recommended to perform the final dilution and administration of pembrolizumab using bags and sets that do not contain DEHP. The following infusion materials are compatible with pembrolizumab: • PVC perfusion kit and bis (2-ethylhexyl) tri-phthalate trimellitate (TOTM) o Polyethylene-coated PVC infusion set

o Polyurethane

o PVC and DEHT infusion set

• Sterile, non-pyrogenic, low-adsorption 0.2 to 5 μm protein filters, made of polyethersulfone, should be used during administration. • Prepare the infusion tubing either with saline or with an infusion solution according to local procedures.

• The solution for infusion should be administered within 30 minutes, with a possible deviation of -5 to +10 minutes, with an infusion pump.

• The maximum infusion rate should not exceed 6.7 mL / min through a central or permanent catheter.

• After infusion, purge the IV tubing according to local procedures. • Note: If institutional recommendations do not allow the infusion tubing to be flushed after infusion, please prepare an additional volume of infusion solution in the infusion bag to compensate for the volume lost in the catheter. • For example, if a volume of 100 mL infusion solution is prepared and 18 mL remains in the infusion set, the pharmacist should prepare 118 mL of infusion solution in the infusion bag to ensure 100 mL will be administered to the patient.

For instructions on the preparation of the medicinal product before administration, see section Instructions for use, handling and disposal ).

Against indications

- Hypersensitivity to the active substance or to any of the excipients listed in the Composition section,

- Eastern Cooperative Oncology Group (ECOG) performance index ≥ 2,

- Severe inflammatory diseases are likely to worsen under PEMBROLIZUMAB MSD

LA FRANCE,

- Patients with any of the following autoimmune diseases should not receive PEMBROLIZUMAB

MSD FRANCE:

■ History of clinically severe autoimmune diseases (eg ulcerative colitis, lupus) (eg requiring chronic immunosuppressive therapy), ■ History of inflammatory pneumonitis, organ transplantation, positive status for human immunodeficiency virus ( HIV), hepatitis B or active C, ■ History of serious or life-threatening adverse events of immunological origin during treatment with other immunotherapy (eg ipilimumab)

Patient requiring systemic treatment with corticosteroids for the management of adverse effects of immunological origin occurring during previous immunotherapy or antineoplastic treatment,

- Active metastasis (s) of the central nervous system, especially carcinomatous meningitis,

- Pregnancy, breastfeeding,

- Active infection requiring systemic treatment,

- Patient who received a live virus vaccine within 30 days prior to the planned start of treatment with PEMBROLIZUMAB MSD FRANCE,

- Surgical intervention during the 4 weeks preceding the initiation of treatment with PEMBROLIZUMAB MSD FRANCE

Pembrolizumab side effects

Tolerance Profile Summary

The safety of PEMBROLIZUMAB MSD FRANCE was studied in an open, uncontrolled study (three defined cohorts from study P001) for the treatment of unresectable or metastatic melanoma. Tolerance is described for a total population of 411 pretreated (n = 221) or naive patients treated with ipilimumab (n = 190). Of the 411 patients treated, patients were exposed to 2 mg / kg every 3 weeks (n = 162), 10 mg / kg every 3 weeks (n = 192), or 10 mg / kg every 2 weeks (n = 57). In the treated patient population, 39% were 65 years of age or older (18 to 94 years old), 60% were male, and all but 11 patients were Caucasian. The average duration of treatment was 213 days (1 to 680 days), including 63 patients treated for more than one year. Of the 162 patients receiving 2 mg / kg PEMBROLIZUMAB MSD FRANCE, 35% were 65 years of age or older (18-88 years old), 58% were men, and all but 3 patients were Caucasian; the mean duration of treatment with PEMBROLIZUMAB MSD FRANCE was 196 days (range 1 to 526 days), including 16 patients treated for more than one year.

PEMBROLIZUMAB MSD FRANCE was discontinued for treatment-related adverse events in 3% of patients who received a dose of 2 mg / kg every 3 weeks.

Treatment-related serious adverse events (SAEs) reported up to 90 days after the last dose occurred in 10% of patients treated at 2 mg / kg every 3 weeks. Among these serious treatment-related adverse events, those occurring in more than one patient (out of 162) are: hypophysitis (n = 2) and colitis (n = 2). The most common treatment-related adverse events (reported in more than 10% of patients) included arthralgia, diarrhea, fatigue, nausea, pruritus, and rash.

Tabulated list of adverse effects

Adverse reactions reported in more than 1 patient with advanced melanoma treated with PEMBROLIZUMAB MSD FRANCE at a dose of 2 mg / kg every 3 weeks (n = 162) are presented in Table 1. These effects are presented by system class -organ and in order of frequency. Frequencies are defined as follows: very common (≥ 1/10); frequent (≥ 1/100 to <1/10); uncommon (≥ 1/1000 to <1/100); rare (≥ 1/10000 to <1/1000); very rare (<1/10000).

Table 11: Adverse effects in patients treated with PEMBROLIZUMAB MSD FRANCE at a dose of 2 mg / kg every 3 weeks *

Infections and infestations

Frequent

nasopharyngitis

Blood and lymphatic system disorders

Frequent

anemia

Endocrine disorders

Frequent

hypophysitis, hypothyroidism, thyroiditis

Metabolism and nutrition disorders

Frequent

decreased appetite, dehydration

Nervous system disorders

Frequent

dizziness, dysgeusia, headache, hypoesthesia, lethargy

Eye disorders

Frequent

ocular dryness, increased tearing, decreased visual acuity

Respiratory, thoracic and mediastinal disorders

Frequent

cough, dyspnea, exercise dyspnea, inflammatory pneumopathy, productive cough

Gastrointestinal disorders

Very common

diarrhea, nausea

Frequent

abdominal pain, colitis, constipation, gastroesophageal reflux, vomiting

Skin and subcutaneous tissue disorders

Very common

pruritus, rash

Frequent

acne-like dermatitis, dry skin, erythema, night sweats, pigmentation disorders, maculopapular rash, vitiligo

Musculoskeletal and systemic disorders

Very common

arthralgia

Frequent

back pain, muscle spasms, muscle weakness, musculoskeletal stiffness, myalgia, extremity pain

General disorders and administration site conditions

Very common

tired

Frequent

asthenia, chills, facial oedema, inflammation, inflammation of the mucous membranes, edema

peripheral, pain, pyrexia, xerosis.

investigations

Frequent

increased transaminases (ASAT, ALT), isolated increases in ASAT, increased serum calcium, decreased thyroid stimulating hormone (TSH), increased thyroid stimulating hormone (TSH), increased triiodothyronine (T3), weight loss, weight gain

* No treatment-related adverse events of grade 5 have been reported.

All doses studied

The overall tolerability profile of the 411 patients studied at 3 doses (2 mg / kg every 3 weeks and 10 mg / kg every 2 or 3 weeks) was generally similar to that observed for the group of patients receiving the recommended dose. 2 mg / kg every 3 weeks. PEMBROLIZUMAB MSD FRANCE was discontinued for treatment-related adverse events in 4% of patients, treatment-related SAEs were described up to 90 days after the last dose and occurred in 9% of patients. Of these treatment-related SAEs, those that occurred in more than 1 patient were hyperthyroidism (n = 2), hypophysitis (n = 2), colitis (including microscopic colitis) (n = 5), nausea (n = 2), vomiting (n = 2), pyrexia (n = 4), dehydration (n = 2), confusion (n = 2), kidney failure (including acute renal failure ) (n = 4), dyspnea (n = 2) and inflammatory pneumonia (n = 3).

Overall, the safety profile was similar between patients pretreated with ipilimumab and naive patients treated with ipilimumab.

Selection of adverse effects of immunological origin

Table 12 presents a selection of adverse effects of immunological origin, which occurred in patients treated with PEMBROLIZUMAB MSD FRANCE.

Table 12: Selection of adverse effects related to treatment of potential immunological origin

PEMBROLIZUMAB MSD FRANCE 2 mg / kg every 3 weeks

n = 162

PEMBROLIZUMAB MSD FRANCE

2 mg / kg every 3 weeks

or 10 mg / kg every 2 or 3 weeks

n = 411

Side effects

All grades (%)

Grade 3 (%)

Grade 4 * (%)

All grades (%)

Grade 3 (%)

Grade 4 * (%)

Colitis

1.2

1.2

0

1.0

0.5

0

Hepatitis

1.2

0

0.6

0.5

0

0.2

hyperthyroidism

0.6

0

0

1.0

0.2

0

Hypothyroidism

9.3

0

0

8.3

0.2

0

Inflammatory pneumonitis

1.2

0.6

0

2.7

0.2

0

* No adverse effects related to the treatment of potential immunological origin reported with PEMBROLIZUMAB MSD FRANCE

Includes microscopic colitis

Includes autoimmune hepatitis

Reporting of suspected adverse reactions

Reporting of suspected adverse reactions is important. It allows continuous monitoring of the benefit / risk ratio of the drug. Health professionals should report any suspected adverse reactions using the adverse reaction reporting form available in the Therapeutic Use and Information Collection Protocol (see Annex C of the TIP).

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