Nighttime Heartburn פרופ רם דיקמן סגן מנהל המערך לגסטרואנטרולוגיה מרכז רפואי רבין

Transcription

1 Nighttime Heartburn פרופ רם דיקמן סגן מנהל המערך לגסטרואנטרולוגיה מרכז רפואי רבין יולי 2016

2 Disclaimer: This presentation is sponsored by Takeda The data on this presentation is based on published clinical studies This presentation is provided for your information and is not intended to recommend or encourage any off label use of the product

3 GERD Common: 15-20% 1/week Abnormal LES Relaxation PPI: Standard of care

4 Therapy: What do we Need? Acid control - 24h Symptoms control - 24h Healing of erosions Compliance with treatment Prevention of complications

5 Nocturnal Acid Breakthrough סקר בקרב 123 רופאי משפחה ו 40 גסטרואנטרולוגים, מרץ 2016 "איזה אחוז מהחולים שלך מתלוננים על סימפטומים גם בלילה?" רופאי גסטרו רופאי משפחה ממוצע 30% ממוצע 31%

6 האם לדעתך יש מגבלות לתרופות הקיימות היום לטיפול ברפלוקס?, מרץ 2016 סקר בקרב 123 רופאי משפחה ו 40 גסטרואנטרולוגים 1 מכל 4 רופאי גסטרו מציין כי המגבלה העיקרית בתרופות הנוכחיות לטיפול ברפלוקס הינה העדר כיסוי של 24 שעות

7 Nocturnal acid breakthrough: How to diagnose? Last Meal UPRIGHT PERIOD SUPINE PERIOD 24-Hours ph Monitoring

8 Why Nocturnal acid breakthrough? (Mean plasma concentration, 44 healthy subjects, single dose) Kukulka M, et al. Clin Exp Gastroenterol 2011;4:

9 TLESR = Transient LES Relaxation Relaxed LES Esophagitis Acid Reflux

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11 Normal Esophageal Manometry Normal Peristalsis

12 Esophageal Manometry Normal LES Relaxation

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14 Scleroderma Esophagus

15 Other systemic diseases Diabetes mellitus Hypothyroidism Parkinson Myasthenia Gravis

16 Hernia Lower Esophageal Sphincter Diaphragm

17 PPIs Poor Flexibility Reduced / poor compliance due to: Fixed timing and dosing On empty stomach Problems:» Skip breakfast» Nighttime snacking» Shift workers» Multiple medications

18 Acid Pocket

19 Nocturnal acid breakthrough: What is the risk? Peptic stricture Barrett s esophagus Adenocarcinoma

20 Peptic stricture

21 Barrett s Esophagus

22 Esophageal Adenocarcinoma

23 Nocturnal acid breakthrough Summary Poor compliance & adherence Defective esophageal sphincter Defective esophageal motility Reduced bioavailability

24 Nocturnal acid breakthrough What to do? 1. Improve compliance & adherence 2. Insist on life style modifications 3. Add on demand at bedtime: H2 Blocker 4. Push down the acid pocket 5. Prokinetics? 6. Improve bioavailability of PPI 7. Surgery

25 Nocturnal acid breakthrough What to do? (Dexlansoprazole) Dexilant מאושרת FDA מ 2009 שחרור מושהה כפול של החומר הפעיל: לאחר שעה ושחרור שני 1 כעבור 4-5 שעות. לא תלויה במזון Indications 1 Dexilant 30 is indicated in adults for the following: Maintenance of healed erosive reflux esophagitis and relief of heartburn Short-term treatment of heartburn and acid regurgitation associated with symptomatic Nonerosive reflux disease Dexilant 60 is indicated in adults for the following: Treatment of erosive reflux esophagitis 1. Dexilant Prescribing Information

26 Thank you!!!!

27 Highlights of prescribing information These highlights do not include all the information needed to use Dexilant safely and effectively. NAME OF THE MEDICINAL PRODUCT DEXILANT is available as capsules in 30 mg and 60 mg strengths for adult use. DEXILANT (dexlansoprazole) modified-release capsules, for oral use. Therapeutic indications Dexilant 30 is indicated in adults for the following: Maintenance of healed erosive reflux oesophagitis and maintenance of relief of heartburn Short-term treatment of heartburn and acid regurgitation associated with symptomatic nonerosive gastro-oesophageal reflux disease (GORD). Dexilant 60 is indicated in adults for the following: Treatment of erosive reflux oesophagitis Dosage and administration Treatment of erosive reflux oesophagitis: One 60 mg capsule once daily for up to 8 weeks. Maintenance of healed erosive reflux oesophagitis and maintenance of relief of heartburn: One 30 mg capsule once daily (controlled studies did not extend beyond 6 months). Symptomatic non-erosive gastro-oesophageal reflux disease (GORD): One 30 mg capsule once daily for 4 weeks. Contraindications DEXILANT is contraindicated in patients with known hypersensitivity to any component of the formulation. DEXILANT is contraindicated with rilpivirine-containing products. Warnings and precautions Presence of Gastric Malignancy Symptomatic response with DEXILANT does not preclude the presence of gastric malignancy. Acute Interstitial Nephritis Acute interstitial nephritis has been observed in patients taking PPIs including lansoprazole. Acute interstitial nephritis may occur at any point during PPI therapy and is generally attributed to an idiopathic hypersensitivity reaction. Discontinue DEXILANT if acute interstitial nephritis develops. Cyanocobalamin (Vitamin B-12) Deficiency Daily treatment with any acid-suppressing medications over a long period of time (e.g., longer than 3 years) may lead to malabsorption of cyanocobalamin (Vitamin B-12) caused by hypo- or achlorhydria. Rare reports of cyanocobalamin deficiency occurring with acid-suppressing therapy have been reported in the literature. This diagnosis should be considered if clinical symptoms consistent with cyanocobalamin deficiency are observed in patients treated with DEXILANT. Clostridium Difficile Associated Diarrhea Published observational studies suggest that PPI therapy like DEXILANT may be associated with an increased risk of Clostridium difficile associated diarrhea, especially in hospitalized patients. This diagnosis should be considered for diarrhea that does not improve. Patients should use the lowest dose and shortest duration of PPI therapy appropriate to the condition being treated. Bone Fracture Several published observational studies suggest that PPI therapy may be associated with an increased risk for osteoporosis-related fractures of the hip, wrist or spine. The risk of fracture was increased in patients who received high-dose, defined as multiple daily doses, and long-term PPI therapy (a year or longer). Patients should use the lowest dose and shortest duration of PPI therapy appropriate to the conditions being treated. Patients at risk for osteoporosis-related fractures should be managed according to established treatment guidelines.

28 Highlights of prescribing information (cont) Hypomagnesemia Hypomagnesemia symptomatic and asymptomatic, has been reported rarely in patients treated with PPIs for at least three months, in most cases after a year of therapy. Serious adverse events include tetany, arrhythmias, and seizures. In most patients, treatment of hypomagnesemia required magnesium replacement and discontinuation of the PPI. For patients expected to be on prolonged treatment or who take PPIs with medications such as digoxin or drugs that may cause hypomagnesemia (e.g., diuretics), health care professionals may consider monitoring magnesium levels prior to initiation of PPI treatment and periodically. Interactions with Diagnostic Investigations for Neuroendocrine Tumors Serum chromogranin A (CgA) levels increase secondary to drug-induced decreases in gastric acidity. The increased CgA level may cause false positive results in diagnostic investigations for neuroendocrine tumors. Healthcare providers should temporarily stop dexlansoprazole treatment at least 14 days before assessing CgA levels and consider repeating the test if initial CgA levels are high. If serial tests are performed (e.g. for monitoring), the same commercial laboratory should be used for testing, as reference ranges between tests may vary Interaction with Methotrexate Literature suggests that concomitant use of PPIs with methotrexate (primarily at high dose) may elevate and prolong serum levels of methotrexate and/or its metabolite, possibly leading to methotrexate toxicities. In high-dose methotrexate administration, a temporary withdrawal of the PPI may be considered in some patients. Subacute cutaneous lupus erythematosus (SCLE) Proton pump inhibitors are associated with very infrequent cases of SCLE. If lesions occur, especially in sun-exposed areas of the skin, and if accompanied by arthralgia, the patient should seek medical help promptly and the healthcare professional should consider stopping Dexilant capsules. SCLE after previous treatment with a proton pump inhibitor may increase the risk of SCLE with other proton pump inhibitors. Drug Interactions Antiretrovirals: The effect of PPIs on antiretroviral drugs is variable. The clinical importance and the mechanisms behind these interactions are not always known. Warfarin: Increased INR and prothrombin time in patients receiving PPIs and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Methotrexate : Concomitant use of PPIs with methotrexate (primarily at high dose) may elevate and prolong serum concentrations of methotrexate and/or its metabolite hydroxymethotrexate, possibly leading to methotrexate toxicities. No formal drug interaction studies of high-dose methotrexate with PPIs have been conducted Digoxin: Potential for increased exposure of digoxin. Drugs Dependent on Gastric ph for Absorption: Dexlansoprazole can reduce the absorption of other drugs due to its effect on reducing intragastric acidity. Tacrolimus: Potentially increased exposure of tacrolimus, especially in transplant patients who are intermediate or poor metabolizers of CYP2C19. Interactions with Investigations of Neuroendocrine Tumors: CgA levels increase secondary to PPI-induced decreases in gastric acidity. The increased CgA level may cause false positive results in diagnostic investigations for neuroendocrine tumors. Interaction with Secretin Stimulation Test: Hyper-response in gastrin secretion in response to secretin stimulation test, falsely suggesting gastrinoma. False Positive Urine Tests for THC: There have been reports of false positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving PPIs. CYP2C19 or CYP3A4 Inducers: Decreased exposure of dexlansoprazole when used concomitantly with strong inducers. CYP2C19 or CYP3A4 Inhibitors: Increased exposure of dexlansoprazole is expected when used concomitantly with strong inhibitors.

29 Highlights of prescribing information (cont) Use in specific populations Pediatric use Safety and effectiveness of DEXILANT have not been established in pediatric patients. The use of DEXILANT is not recommended for sympstomatic non-erosive GORD in pediatric patients less than 1 year of age because studies in this class of drugs have not demonstrated efficacy. Geriatric Use Of the total number of patients (n=4548) in clinical studies of DEXILANT, 11% of patients were aged 65 years and over, while 2% were 75 years and over. No overall differences in safety or effectiveness were observed between these patients and younger patients and other reported clinical experience has not identified significant differences in responses between geriatric and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Hepatic impairment No dosage adjustment for DEXILANT capsules is necessary for patients with mild hepatic impairment (Child-Pugh Class A). For adult patients with moderate hepatic impairment (Child-Pugh Class B) the recommended dosage of DEXILANT capsules for the treatment of erosive reflux oesophagitis is 30 mg once daily for up to 8 weeks. No studies have been conducted in patients with severe hepatic impairment (Child-Pugh Class C) and therefore the use of DEXILANT capsules is not recommended for these patients. Pregnancy There are no studies with dexlansoprazole use in pregnant women to inform a drug-associated risk. In animal reproduction studies, no effects on embryo-fetal development were observed with the administration of oral dexlansoprazole to rabbits during organogenesis at doses up to 9 times the maximum recommended human dose (MRHD) (based on body surface area) or with administration of oral lansoprazole to rats and rabbits during organogenesis at doses up to 40 and 16 times the MRHD (based on body surface area), respectively. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Lactation There is no information regarding the presence of dexlansoprazole in human milk, the effects on the breastfed infant, or the effects on milk production. However, lansoprazole and its metabolites are present in rat milk. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for DEXILANT and any potential adverse effects on the breastfed child from DEXILANT or from the underlying maternal condition. Adverse Reactions: The following serious adverse reactions were observed: Acute Interstitial Nephritis Cyanocobalamin (Vitamin B-12) Deficiency Clostridium difficile Associated Diarrhea Bone Fracture Hypomagnesemia Common adverse reactions: The most common adverse reactions ( 2%) that occurred at a higher incidence for DEXILANT capsules than placebo in the controlled studies are: diarrhea, abdominal pain, nausea, upper respiratory tract infection, vomiting, flatulence For further information, please refer to the full prescribing information as approved by the Israeli MOH. טקדה ישראל בע"מ, אפעל 25, קריית אריה, פתח תקוה, , טלפון: