VECTARION - VECTARION - CT 12442 - Version anglaise

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Description

Présentation VECTARION, lyophilisat et solution pour préparation injectable (code CIS : 60047143) Boîte de 12 flacons de lyophilisat et 12 ampoules de solvant - Code CIP : 3400932142798 Mis en ligne le 21 mai 2013 Substance active (DCI) almitrine (mésilate d') Le service médical rendu par VECTARION, lyophilisat et solution pour préparation injectable, dans l’hypoxémie et l’hypercapnie liées à une hypoventilation alvéolaire est faible lors du sevrage de l’assistance respiratoire artificielle. Le service médical rendu par VECTARION, lyophilisat et solution pour préparation injectable, dans l’hypoxémie et hypercapnie liées à une hypoventilation alvéolaire est insuffisant :- dans les épisodes de décompensation respiratoire aiguë compliquant les bronchopneumopathies chroniques obstructives ;- dans la dépression respiratoire momentanée induite par les analgésiques centraux, les neuroleptiques, le fluothane. Code ATC R07AB07 Laboratoire / fabricant SERVIER VECTARION, lyophilisat et solution pour préparation injectable (code CIS : 60047143) Boîte de 12 flacons de lyophilisat et 12 ampoules de solvant - Code CIP : 3400932142798 Mis en ligne le 21 mai 2013

Informations

• Publié par: haute-autorite-sante-maladies-appareil-respiratoire
• Publié le: 20 mars 2013
• Nombre de lectures: 20
• Licence : En savoir +
  Paternité, pas d'utilisation commerciale, partage des conditions initiales à l'identique
• Langue: English

Extrait

 

The legally binding text is the original French version  

    T RANSPARENCY C OMMITTEE   Opinion 20 March 2013       VECTARION, lyophilisate and solution for preparation for injection B/12 vials of lyophilisate and 12 ampoules of solvent (CIP code: 34009 321 4279 8)  

Applicant: SERVIER

INN

ATC Code (2012):

Reason for the review

List(s) concerned

Indication(s) concerned

         

almitrine bismesylate 

R07AB07 (respiratory stimulant)  Re-assessment of Actual Benefit in response to a request by the Directorate-General for Health and the Social Security Directorate, pursuant to Article R-163-19 of the Social Security Code 

Hospital use(French Public Health Code L.5123-2) 

“Hypoxaemia and hypercapnia associated with alveolar hypoventilation in the following situations: · episodes of acute respiratory decompensation as a complication of chronic obstructive pulmonary disease, · weaning off artificial ventilatory support, · temporary respiratory depression induced by central analgesics, neuroleptics and fluothane.”  

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Actual benefit

Improvement Actual Benefit

Therapeutic use

 

in

In view of its place in the therapeutic strate , endorsed b uidelines and b experts, in particular in hospitals that do not have appropriate ventilator support equipment, althou h its efficac is b no means proven in such cases, the actual benefit of VECTARION, l ophilisate and solution for preparation for in ection, in h poxaemia and h percapnia associated with alveolar h poventilation is low when weanin patients off artificial ventilator support.   In the absence of an uidelines, and accordin to expert opinion, the actual benefit of VECTARION, l ophilisate and solution for preparation for in ection, in h poxaemia and h percapnia associated with alveolar h poventilation is insufficient: -  as a complication ofin episodes of acute respirator decompensation chronic obstructive pulmonar disease; -  in temporary respiratory depression induced by central analgesics, neuroleptics and fluothane.    

Not applicable

According to guidelines (SFAR (French Society of Anaesthesia and Intensive Care and SRLF (French Language Intensive Care Society) and expert opinion, injectable VECTARION still has a place in the management of acute respiratory syndromes as an adjuvant therapy alongside mechanical ventilation, especially when patients are being weaned off ventilation in the most serious cases and in the absence of appropriate ventilatory support equipment. In the absence of guidelines and according to expert opinion, injectable VECTARION no longer has any place in the management of: ·  ensation as a com lication ofe isodes of acute res irator decom chronic obstructive pulmonar disease, · temporary respiratory depression induced by central analgesics, neuroleptics and fluothane.  

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01 ADMINISTRATIVE AND REGULATORY INFORMATION  

  Marketing Authorisation  (procedure)  Prescribing and dispensing conditions / special status    

ATC Classification

 

Initial Marketing Authorisation: 25 July 1977 (national procedure) 7 October 2003: changed indication (present wording) and prescribing conditions (list II, reserved for hospital use). List II Medicinal product for hospital use only.

2012 R R07 R07A R07AB   R07AB07

02 B ACKGROUND  

Respiratory system Other respiratory system products Other respiratory system products Respiratory stimulants almitrine

VECTARION, lyophilisate and solution for preparation for injection, has only been on the list of medicinal products approved for use by hospitals and by various public services since 1978. At the request of the Directorate-General for Health and the Social Security Directorate, pursuant to Article R-163-19 of the Social Security Code dated 12 May 2012, the Transparency Committee is re-assessing the actual benefit of this proprietary medicinal product in a presentation for injection for hospital use only, as an addition to VECTARION tablets, which were re-assessed in 2011.  

03 T HERAPEUTIC INDICATIONS  

“Hypoxaemia and hypercapnia associated with alveolar hypoventilation in the following situations: · episodesof acute respiratory decompensation as a complication of chronic obstructive  pulmonary disease, · off artificial ventilatory support, weaning · respiratory depression induced by central analgesics, neuroleptics and fluothane.” temporary  

04 D OSAGE  

“Slow intravenous infusion: - preparing the solution,  Afterdilute in a bottle of isotonic glucose solution. Do not put any other products in this bottle as there is a possible risk of precipitation or denaturing. Infuse using an access cannula affording an adequate flow rate (greater than 18-gauge). - The direct intravenous (I.V.) route is not recommended; it does, however, remain an option; if it is used, administer the injection very slowly into a sufficiently large vein (maximum recommended flow-rate: 15 mg/minute, i.e. 1 bottle/minute). - Administration of injectable VECTARION is compatible with concomitant oxygen therapy.        

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The posology is variable, depending on the patient’s clinical condition: -3 mg/kg/24 h, by slow intravenous infusion (2 the treatment of alveolar hypoventilation: 1 to  in to 3 infusions per 24 h) at a rate of 2 to 4 bottles per 2 h infusion, without exceeding 12 bottles per 24 h; - anaesthesiology (recovery room): 0.5 to 1 mg/kg/24 h, i.e. 2 to 4 bottles of 15 mg. As an in induction treatment: slow direct intravenous injection: 2 bottles, to be repeated if needed.   Treatment by intravenous infusion should be restricted to the shortest possible time and should be replaced by the oral form as soon as possible.”  

05 T HERAPEUTIC STRATEGY  

Acute respiratory failure is an immediately life-threatening syndrome associated with an inability of the ventilatory system to maintain gas exchanges at a level compatible with survival   Acute respiratory failure is a medical emergency. It can have very different causes and occur during an episode of chronic respiratory decompensation in COPD, or acute asthma, or be triggered by the presence of a foreign body in the upper respiratory tract, trauma, state of shock, coma, postoperative effects, lung disease – whether infectious (pneumonia, lymphangitis, septicaemia) or non-infectious (interstitial disease, tumor) – neuromuscular disease, anaphylactic reaction, heart disease (congestive heart failure), pleural effusion and other causes.   Treatment includes: - correction of hypoxaemia with oxygen therapy -the aid of bronchodilators or physiotherapy reducing ventilatory effort with - reducing respiratory muscle fatigue through assisted ventilation (invasive or non-invasive) - aetiological treatment.   In the management of acute respiratory failure during exacerbations of COPD requiring hospitalisation, respiratory stimulants no longer have a place in the therapeutic strategy. 1  The recommended drug treatments in this clinical situation are short-acting bronchodilators, systemic corticosteroids, and antibiotics.   In the management of acute respiratory distress syndromes (ARDS), almitrine is an adjuvant treatment in mechanical ventilation, in particular when weaning patients off ventilation; however, it is not recommended for routine use. 2,3 Almitrine is reserved for use in the most severe cases, and should not be administered in cases of right ventricular failure or dysfunction, liver failure or lactic acidosis.     There is no recommendation for using injectable almitrine in temporary respiratory depression induced by central analgesics, neuroleptics or fluothane.              

                                                1 GOLD (2013) 2 Richard JC et al. Prise en charge ventilatoire du syndrome de détresse respiratoire aiguë de l’adulte et de l’enfant (nouveau-né exclu) - Recommandations d’Experts de la Société de Réanimation de Langue Françai 3  aux questions fréquemment posées. SFAR (2010). http://www.sfar.org/ar Réponses s t e i   c ( l 2 e 0 /4 05 1 ) 5   /prise-en- charge-du-sdra-en-dehors-de-la-ventilation

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06 C LINICALLY RELEVANT COMPARATORS  

  06.1 Medicinal products

There is one other respiratory stimulant with Marketing Authorisation for use in Intensive Care Units: DOPRAM 2%, solution for injection (doxapram). In practice, this proprietary medicinal product is not used in cases of profound acute respiratory failure. This proprietary medicinal product was included in the list approved for use by hospitals in 1982 and has not undergone an assessment by the Transparency Committee since that date.   06.2 Other health technologies

Oxygen therapy, assisted ventilation.  

07 I NTERNATIONAL INFORMATION ON THE MEDICINAL PRODUCT  

VECTARION, lyophilisate and solution for preparation for injection, is marketed only in France.  

08 S UMMARY OF PREVIOUS ASSESSMENTS  

Given that VECTARION, lyophilisate and solution for preparation for injection, is only included in the list of medicinal products approved for use by hospitals and other public services, and in the absence of any particular flag against it, this proprietary medicinal product has not been re-assessed since it was first listed in 1978.  

09 A NALYSIS OF AVAILABLE DATA  

  09.1 Efficacy

The Applicant has provided 32 studies in which the efficacy of injectable almitrine was assessed in patients with acute respiratory failure (see the table and references in the Appendix): -  11studies in patients with acute exacerbation of chronic respiratory failure; - 4 studies in patients recovering from general anaesthesia; - studies in toxic coma patients with respiratory depression; 2 - 11 studies in patients with acute respiratory distress syndrome;  4 studies in patients with acute respiratory failure due to various pulmonary causes. -   These studies showed a decrease in hypoxaemia and hypercapnia with almitrine in various different clinical situations of acute respiratory failure; however, their level of evidence is poor (old studies, for the most part non-comparative and in small patient populations).  

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09.2 Safety/Adverse effects

The adverse effects observed during clinical studies and mentioned in the SPC are: - breathing difficulties; paradoxical - digestive disturbances such as nausea, heartburn and bloating. possible These effects do not routinely entail the discontinuation of treatment. Injectable VECTARION should be administered for a limited time.   The Applicant forwarded the latest periodic pharmacovigilance update report covering the period from 26/11/2006 to 25/11/2009 and from 26/11/2009 to 25/11/2011 relating to almitrine for injection.  Over the period from 26/11/2006 to 25/11/2009, the number of treatment days was estimated at 44,079, and there were no pharmacovigilance reports submitted. Over the period from 26/11/2009 to 25/11/2011, exposure from the time the product came onto the market was estimated at 9453 patient-months. Two cases of adverse events were reported: one case of a non-serious increase in lactic acidaemia with a plausible causal link to VECTARION for injection, and one case of Stevens-Johnson syndrome in a polymedicated female patient under treatment with injectable VECTARION. No changes were made in the SPC based on the pharmacovigilance data.   09.3 Usage/prescription data

Injectable VECTARION is only prescribed in hospitals. During the period from June 2011 to May 2012, 12,057 boxes (B/12 ampoules) were sold. Sales data for the past 3 years show steady sales.   09.4 Summary & discussion

There have been many studies assessing the efficacy of almitrine in patients with acute respiratory failure. The results have shown a decrease in hypoxaemia and hypercapnia with almitrine in different clinical situations of acute respiratory failure; however, their level of evidence is poor (old studies, for the most part non-comparative, and in small patient populations).   The adverse effects observed with injectable almitrine are paradoxical breathing difficulties and possible digestive disturbances such as nausea, heartburn and bloating. Updated pharmacovigilance data for the injectable form do not reveal any new flags.  

HAS - Medical, Economic and Public Health Assessment Division 

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010

T HERAPEUTIC USE  

Despite a low level of evidence owing to the age of the studies, according to the guidelines of the 4 SRLF and SFAR 5  societies of anaesthetists, and the opinion of experts, injectable VECTARION still has a place in the treatment of hypoxic and hypercapnic patients in the context of acute respiratory distress syndrome, and as an adjuvant treatment to mechanical ventilation, notably when patients are being weaned off ventilation in the most severe cases, especially in hospitals that do not have appropriate ventilatory support equipment.   In the absence of guidelines in these indications, injectable VECTARION no longer has any place in the management of: · episodes of acute respiratory decompensation as a complication of chronic obstructive pulmonary disease, · temporary respiratory depression induced by central analgesics, neuroleptics and fluothane.  

011

T RANSPARENCY C OMMITTEE CONCLUSIONS  

  In view of all the above information, and followin the debate and vote, the Committee’s opinion is as follows:   011.1 Actual benefit

respiratory failure is a life-threatening medical emergency.Acute This proprietary medicinal product is intended for symptomatic treatment. The efficacy/adverse effects ratio is low. There are alternative treatments. Therapeutic use of this medicinal product: According to the guidelines (SFAR and SRLF) and expert opinion, injectable VECTARION still has a place in the management of acute respiratory syndromes as an adjuvant therapy to mechanical ventilation, especially when weaning patients off ventilation in the most serious cases and in the absence of appropriate ventilatory support equipment. In the absence of guidelines, and according to expert opinion, VECTARION for injection no longer has any place in the management of: · episodes of acute respiratory decompensation as a complication in chronic obstructive pulmonary disease, · temporary respiratory depression induced by central analgesics, neuroleptics and fluothane.    

                                                4 Richard JC et al. respiratoire aiguë de l’adulte et de l’enfantPrise en charge ventilatoire du syndrome de détresse 5 (nouve o au n - s n e é s ex a cl u u x )   - q R u e e c s o ti m on m s a   n f d r a é ti q o u n e s m d’ m Ex e p n e t rts p   o d s e é la e   s S . oc S ié F té A   R d   e ( R 2 é 0 a 1 n 0 i ) m . ati h o tt n p   : d // e w L w an w g . u s e f   a F r r . a or n g ç / a a is rt e i   c ( l 2 e 0 / 0 4 5 1 ) 5   /prise-en- Rép charge-du-sdra-en-dehors-de-la-ventilation

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Public health benefit: VECTARION for injection is unlikely to provide any public health benefit given the existence of alternative treatments, and the fact that it has not been shown to have any impact on morbidity or mortality or on quality of life compared to existing treatments.   Taking account of these points, the Committee considers that:    In view of its therapeutic usefulness, as endorsed by guidelines and by experts, in particular in the case of hospitals that do not have appropriate ventilatory support equipment, and even though its efficacy is by no means proven in this situation, the actual benefit of VECTARION, lyophilisate and solution for preparation for injection, in hypoxaemia and hypercapnia associated with alveolar hypoventilation is low when patients are being weaned off artificial ventilatory support.    the absence of any guideline and according to expert opinion, the actual benefit of In VECTARION, lyophilisate and solution for preparation for injection, in hypoxaemia and hypercapnia associated with alveolar hypoventilation is insufficient: - episodes of acute respiratory decompensation as a complication of chronicin obstructive pulmonary disease; - in temporary respiratory depression induced by central analgesics, neuroleptics and fluothane.   The Committee recommends the continued inclusion of VECTARION, lyophilisate and solution for preparation for injection, in the list of medicines approved for hospital use in hypoxaemia and hypercapnia associated with alveolar hypoventilation when weaning patients off artificial ventilatory support and at the dosages indicated in the Marketing Authorisation.    The Committee does not recommend the continued inclusion of VECTARION, lyophilisate and solution for preparation for injection, on the list of medicines approved for hospital use in: - episodes of acute respiratory decompensation as a complication of chronic obstructive pulmonary disease; - temporary respiratory depression induced by central analgesics, neuroleptics and fluothane.  

012

T RANSPARENCY C OMMITTEE RECOMMENDATIONS  

Packaging Appropriate for the prescription conditions.  

HAS - Medical, Economic and Public Health Assessment Division 

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Study

APPENDIX: Tabulated summary of the studies on VECTARION, lyophilisate and solution for preparation for injection

SADOUL 1973 1  

MORERE 1973 1  

BERTRAND 1973 1  

MAIRESSE 2 1978

Design

Studies in acute respiratory decompensation in patients with chronic respiratory failure

Treatment

Open-label, 0.85-3  mg/kg/day   n c o o n nt - rolled   (mean: 2 mg) 

    Asso e ci n a a t t e io d  n   N* Duration oxyg    

By mask or nasal prongs

Open-label, non- 60 mg/day - controlled Bird n c O o o p n n e t - r n o -l ll a e b d e   l,  0.5-1.50 mg/kg/day r ( e 2 s 7) p   i g r o a r s   t   n ( o 3 r a   ) s   al  (mean: 1 mg) pron

abel,  / or n O o p n e t - n- l l led  0 3 . 0 5     m m in g u k t g e   s f   con ro

GERMOUTY Open-label, 1979 3 ello d   non- contr TENAILLON Open-label, 1980 4 rolled    on-n octn SERGYSELS Open-label,   (NAEIJE) 1981 5 octn on   -n ed roll

- 

rtificial ntilation

1 mg/kg for 1 hour - 0.5 mg/kg for A 1 hour ve 0.25-0.5 mg/kg for - 30 minutes

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53

30

6

10

13

12

9 days

5-6 days

4 days

1 day

1 day

1 day

1 day

Population

Acute exacerbation of chronic respiratory failure

Acute exacerbation of chronic respiratory failure

Acute exacerbation of chronic respiratory failure

Acute exacerbation of chronic respiratory failure

Acute exacerbation of chronic respiratory failure

Acute exacerbation of chronic respiratory failure

Acute exacerbation of chronic respiratory failure

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Blood gas parameters

PaO 2 : +18% (p<0.001) SaO 2 : +16% (p<0.001) PaCO 2 : -13% (p<0.001) Blood pH: +1.05% (p<0.001) PaO 2 : +17% (p<0.001) SaO 2 :   +10% (p<0.001) PaCO 2 : -15% (p<0.001) Blood pH: +0.4% (p<0.001) PaO 2 : from +55 to +66 mmHg aO 2 : fro   S m +82 to +90% PaCO 2 : from -62.2 to -54 mmHg Blood pH: from +7.34 to +7.37 PaO 2 : from 41.3 to 48.8 mmHg, +7.5% (p<0.05) SaO 2 : from 71.8 to 82.7%; +10.8% (p<0.05) PaCO 2 : from 56.6 to 49.3 mmHg; -7.3% (p<0.01) Blood pH: from 7.36 to 7.40; +0.04% (p<0.02) PaO 2 : from 52.2 to 56.9 mmHg (p<0.05) SaO 2 : from 84.7 to 88.4% (p<0.05) PaCO 2 : from 57.0 à 48.9 mmHg (p<0.001) Blood pH: from 7.39 to 7.45 (p<0.001) aO 2 : from 105 to 133 mmHg (p<0.001) P PaCO 2 : from 42 to 41 mmHg (NS) PaO 2 : from +43.7 to +53.9 mmHg (p<0.001) SaO 2 : from +78.5 to +86.9% (p<0.001) PaCO 2 : from -55.0 to -50.0 mmHg (p<0.001) Blood pH: from 7.39 to 7.43 (p<0.001)

    ciated N  Duration * Study Design Treatment  o A x s y s g o enation           Comparative, WEITZENBLUM open-label,  our   for  -   14  6 v   s  1 day  1982 6 h 1 el l g r k a / l g a m h   t 5.0  wi p groups vs placebo Single-blind, randomised, Infusion for 30 comparative minutes:  /kg  8 vs MARCQ 1979 7  -  0.5 mg Almitrine  study with parallel or doxapram  8 groups vs  1 mg/kg doxapram Double-blind, randomised, comparative 2  mg/kg/day By nasal TOUATY 1980 8  with study parallel or placebo prongs groups vs placebo Double-blind, randomised, Infusion for 30 RAVEZ comparative,  minutes: 1982 9  -  0.5 mg/kg Almitrine crossover study vs or placebo placebo * N: number of subjects treated with almitrine I.V. versus (vs) the control group

12 vs  3 days 12

HAS - Medical, Economic and Public Health Assessment Division 

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1 day

Population

Chronic bronchitis with respiratory decompensation (PaO 2 <65 mmHg PaCO 2 ≥45 mmHg)

Acute exacerbation of chronic respiratory failure

Acute exacerbation of chronic respiratory failure

Acute exacerbation of chronic respiratory failure

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Blood gas parameters

PaO 2 : from +51.9 to +61.9 mmHg, p<0.001 vs placebo PaCO 2 : from -52.8 to -45.7 mmHg, p<0.001 vs placebo Blood pH: from +7.39 to +7.43, p<0.001 vs placebo

PaO 2 : from 51.8 to 67.4 mmHg SaO 2 : from 86.0 to 92.7% PaCO 2 : from 53.2 to 46.9 mmHg Almitrine better than doxapram (p<0.05)

PaO 2 : +9.8 ± 4.1 mmHg SaO 2 : +5.6 ± 3.8% PaCO 2 : -6.45 ± 4.1 mmHg pH: +0.03 ± 0.04 Almitrine better than placebo (p<0.02)

PaO 2 : from 50.0 to 58.4 mmHg, p<0.001 vs placebo PaCO 2 : from -52.5 to -42.3 mmHg, p<0.001 vs placebo Blood pH: from 7.39 à 7.45, p<0.001 vs placebo

  Study

BIMAR 1 1976

SABATHIE 1978 10  

PAROTTE 1980 11  

LAXENAIRE 1980 12  

Design

Open-label, non-controlled  

Open-label, non-controlled

Open-label, comparative study with parallel groups vs absence of treatment

Comparative, randomised, double-blind study with parallel groups vs placebo

Studies in hypoventilation after anaesthesia, surgery and extubation

Treatment

0.5-1 mg/kg in 1 or 2 slow intravenous injections

0.5 mg/kg

1.5 mg/kg for 1 hour

Almitrine 0.5 mg/kg for 1 minute then almitrine 2.0 mg/kg for 2 hours Or placebo in the same infusion line

N*

140

16

10 vs 10

14 vs 14

Duration Population

1 day

1 day

1 day

1 day

Patients recovering from general anaesthesia

Patients recovering from general anaesthesia

Patients recovering from general anaesthesia (extubation)

Patients recovering from general anaesthesia (extubation)

* N: number of subjects treated with almitrine I.V. versus (vs) the control group

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Main results Significant increase in minute ventilation (>100%), tidal volume and respiratory rate Significant changes in PaCO 2 and blood pH; 10 minutes after the injection: regression of the acidosis and hypercapnia Significant increase in minute ventilation Significant fall in PaCO 2 from 43.87 to 30.65 mmHg (p<0.001) Significant rise in the pH of arterial blood from 7.38 to 7.42 (p<0.001)   Significant fall in PaCO 2 in the almitrine group from 46.1 to 38.4 mmHg, p<0.005. In contrast, no significant fall in PaCO 2 in the control group (from 48.7 to 45.2 mmHg) Significant rise in PaO 2 from 85.2 to 108.1 mmHg in the almitrine group Small and non-significant increase in the respiratory rate for the first 15 minutes Significant increase in the tidal volume throughout the entire study, p<0.01 versus placebo Significant increase in minute ventilation, from 8.7 to 12.2 l/min, p<0.001 versus placebo Significant fall in PaCO 2 , p<0.001 versus placebo