Medicinal Products

ADCETRIS 50 mg

Generic drug of the therapeutic class: Oncology and Hematology
Active ingredients: Brentuximab vedotin
laboratory: Takeda Europe RD Center

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

Indication

ADCETRIS is indicated for the treatment of recurrent or refractory CD30 positive Hodgkin lymphoma (LH) in adults:

1. after autologous stem cell transplantation (ASCT) or 2. after at least two prior treatments when ASCT or multidrug therapy is not a treatment option.

ADCETRIS is indicated for the treatment of relapsed or refractory large-cell anaplastic systemic lymphoma (ALS) in adults.

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

Brentuximab vedotin should only be administered under the supervision of a physician experienced in cancer chemotherapy.

Dosage

The recommended dose is 1.8 mg / kg administered by intravenous infusion for 30 minutes every 3 weeks.

If the patient's weight is greater than 100 kg, use 100 kg for the calculation of the dose (see section Instructions for use, handling and disposal ).

A blood count should be performed before each treatment infusion (see Warnings and Precautions ).

Patients should be monitored during and after the infusion (see Warnings and Precautions ).

The treatment should be continued until the progression of the disease or until the occurrence of unacceptable toxicity (see section Warnings and precautions for use ).

Patients who achieve at least one disease stabilization should receive a minimum of 8 cycles and a maximum of 16 cycles (ie approximately 1 year) (see section 5.1 Pharmacodynamic properties ).

Dosage adjustments

neutropenia

If neutropenia develops during treatment, postpone treatment. The recommended dosage adjustments are shown in Table 1 below (see also Warnings and Precautions for Use ).

Table 1: Recommended Dosage Adjustments for Neutropenia

Grade of severity of neutropenia (signs and symptoms [short description of CTCAE a ])

Modification of the dosage schedule

Grade 1 ( 3

9 / l) or

Grade 2 (<1500-1000 / mm 3

<1.5-1.0 x 10 9 / l)

Continue the treatment at the same dosage.

Grade 3 (<1000-500 / mm 3

<1.0-0.5 x 10 9 / l) or

Grade 4 (<500 / mm 3

<0.5 x 10 9 / l)

Discontinue treatment until the toxicity is grade ≤ 2 or returned to baseline, then resume treatment at the same dose b .

Consider growth factor support (G-CSF or GM-CSF) in subsequent cycles for patients developing grade 3 or 4 neutropenia.

a Grades based on the National Cancer Institute (NCI) Common Criteria for Terminology for Adverse Events (CTCAE) v3.0; see neutrophils / granulocytes; LIN = lower limit of normal.

b Patients who develop grade 3 or 4 lymphopenia can continue treatment without interruption.

Peripheral neuropathy

Recommended dosage adjustments in the event of treatment emergence or worsening of sensory or motor peripheral neuropathy are indicated in Table 2 below (see Warnings and Precautions for Use section ).

Table 2: Recommended dosage adjustments in case of treatment emergence or worsening of peripheral sensory or motor neuropathy

Grade of severity of sensory peripheral neuropathy or

driving

(signs and symptoms [short description of CTCAE a ])

Modification of the dosage schedule

Grade 1 (paresthesia and / or loss of reflexes, without loss of function)

Continue the treatment at the same dosage.

Grade 2 (interfering with function but not activities of daily living) or

Grade 3 (interfering with activities of daily living)

Discontinue treatment until toxicity returns to grade ≤1 or returned to baseline and resumes treatment at the reduced dose of 1.2 mg / kg every 3 weeks.

Grade 4 (disabling sensitive neuropathy or life threatening motor neuropathy or leading to paralysis)

Stop the treatment.

a Grades based on the National Cancer Institute (NCI) Common Criteria for Terminology for Adverse Events (CTCAE) v3.0; see neuropathy: motor; neuropathy: sensitive; and neuropathic pain.

Renal failure

No studies have been performed in patients with renal impairment. No data derived from studies is currently available for this type of patient. Patients with renal insufficiency should be closely monitored (see section Pharmacokinetic properties ).

Hepatic insufficiency

No studies have been performed in patients with hepatic impairment. No data derived from studies is currently available for this type of patient. Hepatic impairment should be closely monitored (see section 5.2 Pharmacokinetic properties ).

Elderly patients

Tolerance and efficacy have not been established in patients aged 65 years or older. No data is available in these patients.

Pediatric population

Safety and effectiveness in children under the age of 18 have not yet been established. No data available.

In pre-clinical animal studies, thymic depletion has been observed (see section 5.3 ).

Administration mode

The recommended dose of ADCETRIS should be infused in 30 minutes.

For instructions on reconstitution and dilution of the drug before administration, see Instructions for Use, Handling and Disposal .

Brentuximab vedotin should not be administered as a direct intravenous injection or intravenous bolus. Brentuximab vedotin should be administered by separate intravenous tubing and should not be mixed with other medicinal products (see section 5.2 ).

Against indications

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

Concomitant use of Bleomycin and Brentuximab vedatin due to risk of pulmonary toxicity.

Adcetris side effects

Tolerance Profile Summary

Brentuximab vedotin has been studied as monotherapy in two pivotal phase 2 studies in 160 patients (SG035-0003 and SG035-0004) (see section 5.1).

Serious infections and opportunistic infections have been reported in patients treated with this drug (see Warnings and Precautions ). In the population of phase 2 studies, 16% of patients reported an event corresponding to an infection.

Serious adverse events included neutropenia, thrombocytopenia, constipation, diarrhea, vomiting, fever, peripheral motor neuropathy and peripheral sensory neuropathy, hyperglycemia, demyelinating polyneuropathy, tumor lysis syndrome, and Stevens-Johnson syndrome.

The most common adverse events observed in patients receiving this treatment were: peripheral sensory neuropathy, fatigue, nausea, diarrhea, neutropenia, vomiting, fever, and upper respiratory infection.

Adverse events motivated discontinuation of brentuximab vedotin in 19% of patients. Serious adverse events leading to discontinuation in at least two patients with LH or LAGCs were peripheral sensory neuropathy (6%) and peripheral motor neuropathy (2%).

Tolerance data from phase 1 dose escalation studies and clinical pharmacology (n = 15) and compassionate program (n = 26) studies in patients with recurrent or refractory LH who do not had not received an autologous stem cell transplant (see Pharmacodynamic properties ), and treated with the recommended dose of 1.8 mg / kg every three weeks, were similar to the safety profile of the pivotal clinical studies.

Table listing adverse effects

Adverse reactions reported with ADCETRIS are listed according to the MedDRA classification by organ class and absolute frequency (see Table 3). In each class of organs, the adverse effects are grouped according to the frequencies defined as follows: very frequent (> 1/10); frequent (> 1/100, 1/1 000, 1/10 000, <1/1 000); very rare (<1 / 10, 000).

Table 3: Adverse Reactions Reported with ADCETRIS in the Population of Phase 2 Studies

Class of organ systems

Adverse reactions

Infections and infestations

Very common :

Infection a

Frequent

Upper respiratory tract infection,

shingles, pneumonia

Rare :

Oral candidiasis, Pneumocystis pneumonia

jiroveci, Staphylococcus bacteremia

Blood and lymphatic system disorders

Very common :

neutropenia

Frequent

Anemia, thrombocytopenia

Metabolism and nutrition disorders

Frequent

hyperglycemia

Rare :

Tumor lysis syndrome *

Nervous system disorders

Very common :

Peripheral peripheral neuropathy

Frequent

Motor Peripheral Neuropathy,

dizziness, polyneuropathy

demyelinating *

Respiratory, thoracic and mediastinal disorders

Frequent

Cough dyspnea

Gastrointestinal disorders

Very common :

Diarrhea, nausea, vomiting

Frequent

Constipation

Skin and subcutaneous tissue disorders

Very common :

Alopecia, pruritus

Frequent

Skin rash

Rare :

Stevens-Johnson Syndrome *

Musculoskeletal and systemic disorders

Very common :

myalgia

Frequent

Arthralgia, backache

General disorders and administration site conditions

Very common :

Fatigue, fever, infusion-related reactions b

Frequent

Chills

* Reported as a serious adverse event only

at. Preferred terms that have been reported in the Infections and Infestations organ system class are: upper respiratory infection, shingles, pneumonia.

b. Preferred terms associated with infusion-related reactions were: chills (4%), nausea, dyspnea, pruritus (3% each), cough (2%).

Description of selected side effects

The undesirable effects leading to a postponement of treatment of up to 3 weeks in more than 5% of patients were neutropenia (14%) and peripheral sensory neuropathy (11%).

The undesirable effect leading to a decrease in the dose in more than 5% of patients was peripheral sensory neuropathy (8%). Ninety percent (90%) of patients admitted to phase 2 studies maintained the recommended dose of 1.8 mg / kg throughout the treatment period.

Severe and prolonged (≥ 1 week) neutropenia with this treatment may increase the risk of developing serious infections. The median duration of Grade 3 or Grade 4 neutropenia was limited (1 week); 2% of patients had Grade 4 neutropenia that lasted 7 days or more. Less than half of the patients admitted to Phase 2 or Grade 4 neutropenia also had concomitant infections, and the majority of these infections were Grade 1 or Grade 2.

In patients with peripheral neuropathy, the median duration of follow-up from the end of treatment to the last assessment was approximately 10 weeks. At the time of the last assessment, 62% of the 84 affected patients experienced resolution or improvement of peripheral neuropathy symptoms. The median duration between onset and resolution or improvement for any event was 6.6 weeks (range 0.3 weeks to 54.4 weeks).

Cases of PML have been reported outside the Phase 2 pivotal trials described in this section (see Warnings and Precautions ).

Cases of anaphylactic reactions have been reported outside the phase 2 pivotal trials described in this section. Symptoms of anaphylaxis may include urticaria, angioedema, hypotension and bronchospasm, among others.

Cases of febrile neutropenia have been reported outside of pivotal phase 2 trials described in this section (see section 4.2 ). A patient enrolled in a dose escalation Phase 1 trial experienced Grade 5 febrile neutropenia after receiving a single dose of 3.6 mg / kg brentuximab vedotin.

immunogenicity

Antibodies to brentuximab vedotin were investigated by electrochemiluminescent immunoassay every 3 weeks in patients with recurrent or refractory LH or LAGCs admitted to phase 2 studies. Approximately 35% of participants developed antibodies to brentuximab vedotin. In the majority of cases, patients became positive before the second dose; A persistent positivity for the anti-drug antibodies (ATA) was reported in 7% of them and 62% of the ATA-positive patients were carriers of neutralizing antibodies. Adverse reactions such as infusion-related reactions leading to discontinuation of treatment have been reported in one (1) per cent of patients.

The presence of antibodies to brentuximab vedotin is not correlated with a clinically significant reduction in serum levels of brentuximab vedotin and does not result in a decrease in treatment efficacy. The detection of antibodies against brentuximab vedotin is not necessarily predictive of the development of an infusion-related reaction (IRP). However, the incidence of RLP was higher in patients with persisting ATA positivity (30%) than those with temporary ATA (12%) have never been detected (7%).

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