Medicinal Products

DACLATASVIR 30 mg

Generic drug of the therapeutic class: Gastro-Entero-Hepatology
Active ingredients: Daclatasvir
laboratory: Bristol Myers Squibb

Coated tablet
Bottle of 33
All forms

Indication

Daclatasvir, used in a Cohort ATU, is indicated for the treatment of adult patients with chronic viral Infection C:

- presenting with advanced disease (with F3 / F4 liver fibrosis or with extrahepatic HCV manifestations) and for whom there are no suitable therapeutic alternatives

or

- Are on waiting list for liver or kidney transplant

or

Have undergone liver transplantation and have a recurrence of infection with hepatitis C virus.

For activity based on hepatitis C virus (HCV) genotype, see Warnings and Precautions and Pharmacodynamic Properties sections.

Dosage DACLATASVIR 30 mg Film-coated tablet Bottle of 33

Treatment with Daclatasvir should be initiated and monitored by a physician experienced in the management of patients with HCC.

Dosage

The recommended dose of daclatasvir is 60 mg once daily, orally with or without food (see section 5.2 ). In some co-administrations, a dosage adjustment is necessary (see section Interactions with other medicinal products and other forms of interaction ).

Daclatasvir should be used in combination with sofosbuvir 400 mg tablet (one tablet daily) for a duration of 24 weeks of treatment. Limited data from AI444040 does not support conclusion on the value of adding ribavirin to the regimen. The optimal pattern in advanced patients remains to be determined.

Virological rebound

In patients for whom virologic rebound has been confirmed (> 1 log 10 increase in HCV viral load compared to nadir), treatment should be discontinued.

Treatment stop

If sofosbuvir is permanently discontinued, other anti-HCV drugs should also be discontinued.

Dosage modification

It is not recommended to change the dosage of daclatasvir for the management of adverse effects. To change the dosage of other drugs in the treatment, refer to the respective Product Characteristics Summaries.

Missed doses

Patients should be advised that if they miss a dose of daclatasvir, the missed dose should be taken as soon as possible within 20 hours of the usual set time. However, if it is missed more than 20 hours after the usual time, the missed dose should not be taken and the next dose taken at the appropriate time.

Special populations


Renal failure

No dose adjustment of daclatasvir is required in patients with end-stage renal disease (ESRD) on hemodialysis or with mild renal impairment (see section 5.2 ). A study is ongoing in patients with moderate or severe renal impairment.

Hepatic insufficiency

No dosage adjustment of daclatasvir is required in patients with mild (Child-Pugh A, score 5-6), moderate (Child-Pugh B, score 7-9) or severe (Child-Pugh C, ≥ 10). Daclatasvir has not been studied in HCV-infected patients with decompensated cirrhosis (see section 5.2 ).

Elderly

No dose adjustment of daclatasvir is required in elderly patients (see section 5.2 ).

Pediatric population

The safety and effectiveness of daclatasvir in children and adolescents under 18 years of age have not yet been established. No data available.

Administration mode

Daclatasvir should be taken orally with or without food. The tablets should not be broken.

Against indications

Hypersensitivity to the active substance (s) or to any of the excipients listed under Composition .

Daclatasvir is contraindicated in combination with drugs strongly inducing CYP3A4 or P - gp and therefore likely to decrease the exposure and effectiveness of aclatasvir. These active substances include phenytoin, carbamazepine, phenobarbital, rifampicin, dexamethasone, and herbal St. John's Wort (Hypericum perforatum).

Reference should be made to the respective Product Characteristics Summaries of other treatment drugs for details of their contraindications.

Daclatasvir side effects

Summary of adverse effects

The overall safety profile of daclatasvir is based on data from 716 patients with chronic HCV infection who received Daclatasvir 60 mg once daily in combination with sofosbuvir with or without ribavirin (n = 211) or with combined with peginterferon alfa and ribavirin (n = 505, pooled data) in a total of seven clinical studies.

Daclatasvir in combination with sofosbuvir

The most commonly reported adverse reactions (greater than or equal to 10%) were fatigue, headache, and nausea. The overwhelming majority of adverse events were grade 1 or 2 and two patients (<1%) discontinued treatment due to adverse events considered to be unrelated to treatment in both cases.

Daclatasvir in combination with peginterferon and ribavirin

The most commonly reported adverse reactions (greater than or equal to 10%) are listed in Table 2. Adverse reactions with at least Grade 3 severity most commonly reported (frequency ≥ 1%) were neutropenia, lymphopenia, anemia and leukopenia.

The frequency of adverse events in cirrhotic patients treated with daclatasvir / peginterferon alfa / ribavirin was similar to that observed in patients treated with pla cebo / peginterferon alfa / ribavirin (94% [50/53] vs 95% respectively [18 / 19]) and the frequency of Grade 3-4 liver abnormalities in these patients was low (less than 10% in any of the clavasavir groups).

Summary table of adverse effects

The following side effects have been reported as related to treatment with daclatasvir in combination with sofosbuvir (with or without ribavirin) or in combination with peginterferon alfa and ribavarin. In this context, no adverse effects specific to daclatasvir could be identified.

The following adverse reactions are presented in Table 2 by system organ class (SOC) and frequency: very common (≥ 1/10), common (≥ 1/100 to <1/10), infrequent (≥ 1/1000 to <1/100). In each frequency group, adverse effects are presented in order of decreasing severity.

Table 2: Adverse Reactions in Clinical Studies

Class of organ systems

Side effects

Daclatasvir in combination with sofosbuvir ± ribavirin *

N = 211

Daclatasvir in combination with peginterferon alfa and ribavirin

N = 505

Infections and infestations

frequent

flu, oral herpes §, sinusitis, otitis externa, nasopharyngitis

rare

§ pneumonia, anthrax §, furuncle §

Blood and lymphatic system disorders

very common

anemia §, neutropenia

frequent

anemia*

Leukopenia, lymphopenia, thrombocytopenia

rare

aplastic anemia §, autoimmune haemolytic anemia §, febrile neutropenia §

Metabolism and nutrition disorders

very common

decreased appetite

frequent

decreased appetite

Psychiatric disorders

very common

Depression §, insomnia

frequent

depression, anxiety, insomnia

anxiety, depressed mood, altered mood, sleep disorder, mood disorders, decreased libido

rare

schizophrenia, paranoid type §

Nervous system disorders

very common

headache

headache

frequent

dizziness, migraine

dizziness, disturbances of attention, memory problems, tremor, hypoesthesia, lethargy, dysgeusia, poor sleep, restless legs syndrome

O Phthalmological conditions

frequent

eye pruritus, blurred vision, dry eye, eye irritation, eye pain, decreased visual acuity

rare

retinal hemorrhage §

Affections of the ear and labyrinth

frequent

dizziness, tinnitus

rare

auricular perichondritis

Vascular disorders

frequent

hot flush

hot flush

Respiratory, thoracic and mediastinal disorders

very common

cough, dyspnea

frequent

cough, dyspnea, exertional dyspnea, nasal congestion

exercise dyspnea, nasal congestion, oropharyngeal pain, epistaxis, productive cough

Gastrointestinal disorders

very common

nausea

nausea, diarrhea

frequent

diarrhea e, upper abdominal pain, constipation, flatulence, gastroesophageal reflux, dry mouth, vomiting

abdominal pain, constipation, flatulence, gastroesophageal reflux, dry mouth, vomiting, abdominal discomfort, dyspepsia, stomatitis, abdominal discomfort, abdominal pain, oral ulcer, stomatitis, cheilitis

rare

anal fissure §, gastrointestinal inflammation §

Hepatobiliary disorders

rare

hyperbilirubinemia §

A ffections of the skin and subcutaneous tissue

very common

pruritus, dry skin, alopecia, rash

frequent

pruritus, dry skin, alopecia, rash

erythema, hyperhidrosis, generalized pruritus, dermatitis, eczema, night sweats, maculopapular rash, skin fissures, skin lesion

Musculoskeletal and systemic disorders

very common

arthralgia, myalgia

frequent

arthralgia, myalgia

back pain, muscle contractures, painful extremities

General disorders and administration site conditions **

very common

tired

fatigue, flu-like pathology §, irritability, asthenia, pyrexia

frequent

irritability, abnormal taste of the product

chills, pain, sensation of abnormal state, malaise, dryness of the mucosa

investigations

frequent

lowered weight

rare

Streptococcus positive test §

* Ninety (43%) of the 211 patients received ribavirin in addition to daclatasvir and sofosbuvir. In this study, there were no cases of anemia in treatment groups without ribavirin.

§ Includes adverse events assessed as serious by the investigator in subjects in clinical studies.

** Injection site reactions are not included since daclatasvir is administered orally.

Biological abnormalities


Table 4 presents the selected laboratory abnormalities under treatment (Grade 3-4 toxicity according to WHO criteria) that were observed in HCV-infected patients treated with daclatasvir combination therapy, depending on the treatment. associated.

Table 4: Biological abnormalities developed during treatment (Grade 3-4 toxicity according to WHO criteria) observed in patients infected with HCV

Daclatasvir in combination with sofosbuvir ± ribavirin * Daclatasvir in combination with peginterferon alfa and ribavirin
N = 211 N = 505
Biological parameters Percentage presenting the anomaly Percentage presenting the anomaly

Hepatoglobin Reduction, Grade 3-4

<1% *

5%

Thrombocytopenia Grade 3-4

0

3%

Neutropenia Grade 3-4

0

25%

ALT increase, Grade 3-4

0

2%

Increase ASAT Grade 3-4

0

3%

Increased Bilirubin, Grade 3-4

0

1%

* Ninety (43%) of the 211 patients received ribavirin in addition to daclatasvir and sofosbuvir. In this study, there were no cases of Grade 3-4 hemoglobin decline in treatment groups without ribavirin.

The severity grades of the biological results were evaluated using the Adverse Reaction Severity Score Chart in adult and pediatric patients from the "AIDS Division" ("DAIDS Adverse Event Evaluation Table"). ), Version 1.0.

Declaration of adverse effects

It is necessary to pay particular attention to any adverse effects that may occur in the context of the cohort ATU. In this context, the reporting of adverse effects is important given the limited decline in clinical data at this stage of development of the drug. It allows continuous monitoring of the benefit / risk ratio of the drug. Healthcare professionals must report any suspected adverse reactions using the corresponding sheet (see Annex D) of the Therapeutic Use and Information Collection Protocol (TUP).

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