INEXIUM - INEXIUM - CT 7094 - English version
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Introduction INEXIUM 10 mg, gastroresistant granules for oral suspension in single dose sachets Pack of 28 (CIP: 386 730-8) Posted on Nov 10 2009 Active substance (DCI) esomeprazole Gastro-entérologie - Pédiatrie - Nouvelle forme galénique Pas d’avantage clinique démontré chez l’enfant à partir de un an :– par rapport aux antiacides pour le traitement du reflux gastro-oesophagien (RGO)– par rapport à l’oméprazole pour l’oesophagite érosive par reflux INEXIUM 10 mg granulés pour suspension buvable en sachet-dose est une nouvelle présentation d’ésoméprazole indiquée chez l’enfant de 1 an à 11 ans, dans le traitement symptomatique du RGO et dans le traitement de l’oesophagite érosive par reflux confirmée par endoscopie.Cette présentation représente une alternative aux traitements utilisés chez l’enfant dans le traitement du RGO et de l’oesophagite. Pour en savoir plus, téléchargez la synthèse ou l'avis complet ci-dessous. ATC Code A02BC05 Laboratory / Manufacturer ASTRAZENECA INEXIUM 10 mg, gastroresistant granules for oral suspension in single dose sachets Pack of 28 (CIP: 386 730-8) Posted on Nov 10 2009
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| Publié par | haute-autorite-sante-maladies-appareil-digestif |
| Publié le | 21 octobre 2009 |
| Nombre de lectures | 53 |
| Licence : |
En savoir + Paternité, pas d'utilisation commerciale, partage des conditions initiales à l'identique
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| Langue | English |
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The legally binding text is the original French version
TRANSPARENCY COMMITTEE OPINION 21 October 2009 INEXIUM 10 mg, gastroresistant granules for oral suspension in single dose sachets Pack of 28 (CIP: 386 730-8) Applicant: ASTRAZENECA Esomeprazole List II Marketing authorisation date: August 19, 2008 Reason for request: Inclusion on the list of medicines reimbursed by National Insurance and approved for use by hospitals. Medical, Economic and Public Health Assessment Division
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CHARACTERISTICS OF THE MEDICINAL PRODUCT
1.1. Active ingredient Esomeprazole
1.2. Indication “INEXIUM for oral suspension in single dose sachets is indicated for the treatment of gastro-oesophageal reflux in children aged 1 to 11. Gastro-oesophageal reflux (GOR)
· Treatment of erosive reflux oesophagitis confirmed by endoscopy. · treatment of gastro-oesophageal reflux (GOR). Symptomatic INEXIUM for oral suspension in single dose sachets can also be used by patients who have difficulty swallowing INEXIUM gastroresistant tablets. For patients over the age of 12, see indications in INEXIUM gastroresistant tablet SPC.
1.3. Dosage “For a 10 mg dose, add the content of one 10 mg single dose sachet to a glass of 15 ml water. For a 20 mg dose, add the content of two 10 mg single dose sachets to a glass of 30 ml water. Do not use sparkling water. Stir the content until the granules have been dispersed and wait a few minutes to thicken. Stir again and drink within 30 minutes. The granules must not be bitten or chewed. Rinse with 15 ml water to ensure all granules are taken. Children aged 1 to 11 weighing less than 10 kg Gastro-oesophageal reflux (GOR): Doses exceeding 1 mg/kg/day have not been studied. Treatment of erosive reflux oesophagitis confirmed by endoscopy
· Weight³10 kg and < 20 kg: 10 mg once daily for 8 weeks. · Weight³20 kg: 10 mg or 20 mg once daily for 8 weeks. Symptomatic treatment of gastro-oesophageal reflux (GOR) 10 mg once daily for no more than 8 weeks. Doses exceeding 1 mg/kg/day have not been studied. Adults and adolescents over the age of 12 Dosage for patients over the age of 12: see INEXIUM gastroresistant tablet SPC. Infants under 1 year or < 10 kg Due to the absence of data, INEXIUM must not be given to children under 1 year or weighing <10 kg. Renal impairment No dose adjustment is necessary for patients with renal impairment. Due to limited data on patients suffering from severe renal impairment, INEXIUM should be used by these patients with caution [
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Hepatic impairment No dose adjustments are necessary for patients suffering from mild to moderate hepatic impairment. For patients over the age of 12 suffering from severe hepatic impairment, it is advisable not to exceed the maximum dose of 20 mg INEXIUM. For children aged 1 to 11 suffering from severe hepatic impairment, it is advisable not to exceed the maximum dose of 10 mg .
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SIMILAR MEDICINAL PRODUCTS
ATC Classification (2005) : Alimentary tract and metabolism : Antacids, drugs for treatment of peptic ulcer and flatulence : Drugs for peptic ulcer : Proton pump inhibitors 05 : Esomeprazole
2.1. A A02 A02B A02BC A02BC
2.2. Medicines in the same therapeutic category Children over the age of 1: Omeprazole: MOPRAL, ZOLTUM and their generics1, in the indication “symptomatic ulcerative or erosive oesophagitis due to gastro-oesophageal reflux. No other pharmaceutical specifically for the paediatric population is available in the PPI drug class.
2.3. Medicines with a similar therapeutic aim In the indication “Treatment of erosive reflux oesophagitis for children and infants: Cimetidine (TAGAMET 200 mg effervescent) and ranitidine (ZANTAC). In the indication “Treatment of proven gastro-oesophageal reflux disease, refractory to other treatments, in newborn babies, infants and children up to 36 months. cisapride (PREPULSID 1 mg/ml oral suspension children infants) In the indication: “Symptomatic treatment of gastro-oesophageal reflux“: sodium alginate+sodium bicarbonate (GAVISCON Infant oral suspension).
1Pharmaceutical form not suitable for paediatric use
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ANALYSIS OF AVAILABLE DATA
Three randomised clinical studies have been submitted: - one pharmacokinetic study on children under 24 months, study SH-NEC-0001 (not presented in this document); - one efficacy study (phase III), study D9614C00096; involving children under 1 year, a population not complying with the MA population; - a safety study (phase III), D9614C00097.
3.1. Efficacy -Study D9614C00096: Randomised, double-blind, parallel-group, placebo-controlled phase III study. Esomeprazole was administered open-label for 2 weeks. Infants whose symptoms responded favourably to treatment were randomised to be given esomeprazole or the placebo. The maximum double-blind treatment duration was 4 weeks. The primary aim was to determine the efficacy of esomeprazole on oesophageal and supraoesophageal symptoms of GOR in infants aged 1 to 12 months. This study concerns an age category for which the product does not have an MA. The primary endpoint was the time between the start of randomisation and the cessation of treatment linked to an exacerbation of symptoms. The infants included had to be suffering from endoscopic oesophagitis or GOR. The symptoms (vomiting/regurgitation, irritability, feeding difficulties) had to occur at least twice weekly over the four weeks prior to inclusion. The dose of esomeprazole was 2.5 mg/day for children weighing 3 to 5 kg, 5 mg/day for children weighing 5 to 7.5 kg and 10 mg/day for children weighing between 7.5 and 12 kg. Esomeprazole and the placebo were administered in the form of open capsules and mixed with compote of apples. Results: Out of 98 patients aged 4.9 months on average and weighing 6.6 kg on average, 18 (18.4%) stopped treatment after two weeks of open-label treatment (5 due to adverse effects, 4 withdrew consent, 9 due to a lack of efficacy). The remaining 80 were randomised: 39 in the esomeprazole group and 41 in the placebo group. The time between the start of randomisation and the cessation of treatment in relation to an exacerbation of symptoms was not significantly different in the two groups (HR=0.69 95%CI=0.35-1.35). 15 patients ceased the study treatment early due to exacerbated symptoms with esomeprazole and 20 with the placebo (see table 1).
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Table 1:Accumulated percentage of patients withdrawing from the study due to exacerbated symptoms ITT population
Variable
Total patients leaving study n(%) Discontinued or event-free n(%)
Esomeprazole (n=39)
15 (38.5) 24 (61.5)
Placebo (n=41)
20 (48.8) 21 (51.2)
Accumulated % of patients Week 0 0 0 Week 1 2.6 14.6 Week 2 20.5 29.3 Week 3 23.1 31.7 Week 4 39.4 49.3 -Study D9614C0097:Randomised, double-blind safety study Primary aimevaluate the safety of daily treatment with esomeprazole among children: to aged 1 to 11. Secondary endpoints: - daily evaluation of symptoms by parents/legal guardian, using a Likert scale2. - endoscopic evaluation of healing of oesophagitis when oesophagitis was certain upon inclusion. Inclusion criteriaweighing more than 8 kg and suffering from: children from 1 to 11 years GOR. An endoscopy was conducted on all the children upon inclusion, except for those having had an endoscopy during the 2 weeks prior to inclusion. Treatment administered: esomeprazole granules. The doses used were as follows, according to patient weight: Weight < 20 kg: esomeprazole 5 or 10 mg once a day. Weight≥20 kg: esomeprazole 10 or 20 mg once a day. Children weighing less than 20 kg were randomised into 2 groups: 5 or 10 mg esomeprazole per day. Patients weighing more than 20 kg were randomised into 2 groups: 10 or 20 mg esomeprazole per day. Results: 109 children were randomised, of which 53 (48.6%) suffered from erosive oesophagitis confirmed by endoscopy. The analysis was conducted on an intention-to-treat (ITT) basis at 8 weeks. Children with pyrosis, regurgitations and epigastric pain at inclusion experienced an improvement in their symptoms with esomeprazole 5 mg, 10 mg and 20 mg (secondary endpoint). Of the 453 who had an endoscopy during the follow-up, the erosive children oesophagitis healed (secondary endpoint) in 43 cases (93.3%) at 8 weeks4.
24 to 7-point scale whereby individuals are asked to express their level of agreement orPsychometric disagreement with the statement given. 3as diagnosis was modified during or upon leaving8 of the 53 patients did not undergo an endoscopy the trial. 4According to Los Angeles classification criteria
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3.2. Adverse effects In study SH-NEC-0001, 12 of the 50 children included had 15 mild to moderate non-serious adverse events. The main adverse events were nasopharyngitis (3 cases), urine infection (1 case), neutropenia (1 case). The frequency of the adverse events was similar in the esomeprazole 0.25 mg/kg and 1 mg/kg groups. In the D9614C00096 study, 7 infants had a serious adverse event but none were deemed to be due to treatment. Seven infants had adverse events that led to treatment being discontinued: 5 during the study’s open-label phase (abdominal phase, otitis, rotavirus infection, retarded weight gain, pulmonary infection), and 2 during the double-blind phase (abdominal phase/vomiting and gastroenteritis). These events were not deemed to be due to treatment. Four infants had non-serious adverse effects (abdominal pain, regurgitations, tachypnoea, elevated ALTs) with esomeprazole during the open-label phase. During the randomisation phase, there was one adverse effect in each group. In safety study D9614C00097, 82 children out of 109 had at least one adverse event of which 10 were considered to be due to treatment but none were serious. 4 treatments were discontinued due to adverse events, of which one (asthenia, nausea and viral infection) due to treatment. The most frequent adverse events were: vomiting (18.5%), fever (13.9%), diarrhoea (12%), cough (12%) and headaches (11.1%). No relationship could be established between dose and frequency of the adverse events. The SPC stipulates that frequent adverse effects (³1/100 and <1/10) are abdominal pain, constipation, diarrhoea, flatulence, nausea, vomiting and headaches.
3.3. Conclusion In one comparative phase III study, the aim of which was to evaluate the efficacy of esomeprazole capsules versus placebo, and including 98 infants aged 1 to 12 months (i.e. a population different to the MA), no statistically significant difference was observed in the study withdrawal times due to exacerbated symptoms (primary endpoint) between the esomeprazole group and the placebo group. In a safety study including 109 children aged 1 to 11 suffering from GOR confirmed by endoscopy and treated with INEXIUM once daily for no more than 8 weeks, out of 45 children that had an endoscopy during follow-up, the erosive oesophagitis healed (secondary endpoint) for 93.3% after 8 weeks. The most common adverse effects were abdominal pain, constipation, diarrhoea, flatulence, vomiting and headaches. This data does not enable the benefit of the granule form to be quantified in terms of efficacy compared to other forms of omeprazole or other anti-secretory drugs. The benefit of the granule form in terms of patient compliance has not been quantified.
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TRANSPARENCY COMMITTEE CONCLUSIONS
4.1. Actual benefit The symptoms of GOR are not usually serious; however, GOR can deteriorate the quality of life and result in oesophagitis, which exposes the patient to the risk of oesophageal stenosis, bleeding and Barret’s oesophagus. Consequences on growth, chronic ENT or respiratory events and malaise can also be observed
GOR-induced erosive or ulcerative oesophagitis in children over the age of one is a rare and serious condition, particularly when the children suffer from a neurological condition or after surgery for atresia of the oesophagus. This product is used as a form of symptomatic treatment. The efficacy/safety ratio of this product is high in this indication. This product is used in second-line symptomatic treatment of GOR and first-line treatment of erosive oesophagitis. There are alternatives to this product. Public health benefit: Gastro-oesophageal reflux (GOR) is a relatively common condition in children, but prognosis is generally good. The public health burden that it represents is deemed low. The improvement in the treatment of GOR in children is not a public health priority because other GOR treatments that can be given to children already exist. For this reason, and given clinical trial data, INEXIUM is not expected to have any impact on public health in this indication. Consequently, INEXIUM is not expected to benefit public health with respect to this indication. The actual benefit of this product in this indication is substantial.
4.2.Improvement in actual benefit In the absence of any direct comparison between esomeprazole and other treatment options used for symptomatic GOR (antacids) and erosive oesophagitis (omeprazole), INEXIUM 10 mg gastroresistant granules does not improve actual benefit (IAB V) in the MA indication.
4.3. Therapeutic use Uncomplicated GOR, manifested mainly by regurgitations or vomiting, is common during the first year of life and tends to diminish with age. Its frequency in children is related to the immaturity of the oesophagus and stomach and the high volume of fluids ingested. Certain cases of GOR can lead to oesophagitis, which exposes the patient to the risk of oesophageal stenosis and bleeding and Barret’s oesophagus. Consequences on growth, chronic ENT or respiratory events and malaise can also be observed. Treatment depends on the child’s age and the severity of symptoms. The aim of the treatment is to reduce the frequency of reflux, to heal the oesophagitis lesions, to prevent complications and to maintain height and weight growth. Uncomplicated GOR:
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Case history and the clinical examination enable uncomplicated reflux to be diagnosed. If the reflux does not affect growth and if the clinical examination is normal, no further tests are necessary. Parental reassurance and dietary measures (splitting up meals to decrease quantities, thickening bottle milk) generally enough for children under 36 months. Patients usually progress well, with symptoms decreasing or disappearing when the child starts to walk. Simple regurgitations among infants (28 days to 18 months) do not warrant PPI treatment. If symptoms are typical and far apart (< once a week), PPI are not recommended as they do not have an immediate effect. It is advisable to use any of the following fast-acting treatments from time to time, adhering to the ages in the MA: - either an antacid, - or an alginate, - or an H2blocker. If symptoms are typical and close together (once a week or more), it is advisable to prescribe a PPI, usually for 4 weeks5. In the event of acid GOR evidenced by pH monitoring or with endoscopic oesophageal lesions, long-term treatment (2 to 3 months) with PPI can be initiated. Complicated GOR: The GOR is diagnosed based on symptoms such as crying on swallowing, refusal to feed, excessive salivation, irritability, or on symptoms of oesophagitis complications (haematemesis or melaena, no weight change). Symptoms can also be respiratory (infections, cough, asthma), ENT (hoarseness, stridor, pharyngitis, laryngitis) serious malaise of infants. When such symptoms are present, the patient should consult a paediatric gastroenterologist to treat the GOR and manage complications. 24-hour oesophageal pH monitoring is a reliable method of measuring acid reflux in children. An oesogastroduodenal fibroscopy with biopsy is recommended to look for oesophagitis. Medical treatment must be introduced. A proton pump inhibitor (PPI) is given as first-line treatment (professional consensus). Surgery is only indicated when the patient is refractory to optimal medical treatment. Omeprazole was the only PPI benefiting from an MA for children over the age of one. INEXIUM 10 mg gastroresistant granules for oral suspension in single dose sachets are a therapeutic alternative in this case. No PPI benefits from an MA for infants under the age of 1 year.
4.4. Target population Given the product’s indication and its therapeutic use in the management of complicated or uncomplicated GOR, the target population is comprised of children aged 1 to 11 suffering from GOR refractory to appropriate dietary and lifestyle measures and presenting with frequent symptoms (i.e. at least once a week)6. There is no French epidemiological data on paediatric GOR. On January 1, 2008 in France there were 8.4 million children aged 1-11 (source: INSEE [French Institute of Statistics and Economic Studies]).
5French Healthcare Product Safety Agency (AFSSAPS). Anti-gastric secretory drugs for adults. Good Practice Guidelines. Saint-Denis: AFSSAPS; 2007 6 N Vakilet al:Definition and Classification of Gastroesophageal Reflux Disease: A Montreal The global evidence-based consensus. The American Journal of Gastroenterology 2006; 101: 1900-1920.
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Paediatric investigations conducted in the United States and Australia have demonstrated a prevalence of GOR symptoms of between 1.4% and 12.6% depending on the age category78. A descriptive unpublished observational study was conducted by AstraZeneca in France in 2008 on 404 general practitioners and 180 paediatricians9, with the aim of: - assessing the prevalence of GOR in children aged 1 to 11, - describing children with GOR, their symptoms and their management in terms of diagnosis and treatment. In this study, 8.1% of children aged 1 to 11 had GOR; for 95% of them, the symptoms occurred at least once a week. If we extrapolate this prevalence to the 8.4 million children aged 1 to 11 in France in 2009, we reach an estimation of 200,000 to 680,000 children in this age category. If we consider that around 95% of them have frequent symptoms, the target population of INEXIUM can be estimated as 190,000 to 640,000. 7% of patients suffering from GOR have erosive and/or ulcerative oesophagitis diagnosed by endoscopy, i.e. 13,300 to 44,800 patients.
4.5. Transparency Committee recommendations The Transparency Committee recommends inclusion on the list of medicines reimbursed by National Insurance and on the list of medicines approved for use by hospitals and various public services in the indications and at the dosage in the MA. 4.5.1. Packaging: appropriate for the prescription conditions. 4.5.2. Reimbursement rate: 65%.
7N, Kennedy JD, Ryan P, Ruffin R, Miles H, Marley J. Natural history and familial J, Pratt Martin relationships of infant spilling to 9 years of age. Pediatrics 2002; 109: 1061-1067. 8 Nelson SP, Chen EH, Syniar GM and Christoffel KK, for the Pediatric Practice research Group. Prevalence of Symptoms of Gastroesophageal Reflux during Childhood. Arch Pediatr Adolesc Med 2000; 154:150-154. 9 Cross-sectional observational study conducted by AstraZeneca and TNS Healthcare on 584 physicians (August 2008).
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