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Training Grani-Denk i.v. 07.2013

Training Grani-Denk i.v. 07.2013. Contents. Introduction Product Information Key Selling P oints Visit Recommendations Therapeutic Indications Off-Label Use Mechanism of Action Posology & Administration Adverse Drug Reaction Special Warnings & Precautions Interactions

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Training Grani-Denk i.v. 07.2013

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  1. Training Grani-Denki.v. 07.2013

  2. Contents Introduction Product Information Key Selling Points Visit Recommendations Therapeutic Indications Off-Label Use Mechanism of Action Posology & Administration Adverse Drug Reaction Special Warnings & Precautions Interactions Take Home Messages Ondansetron Versus Granisetron Train the Brain – Quiz References Additional Information Click on thetitle toredirecttothepageswithfurtherinformation! Click toreturntothispage!

  3. 16. Contents – Additional Information • I. Physiology & Pharmacology • Nausea &Vomiting • Emesis • Emetic Risk Categories • Chemotherapeutic and Radiotherapy Emetic Potential • Postoperative Nausea & Vomiting: PONV • Pharmacology(Antiemetic Agents and Receptor Antagonists) • Granisetron Pharmacogenomics • Controlling Nausea & Vomiting • Efficencyof Granisetron • NK1R Antagonists • Other 5-HT3 Antagonists • II. Clinical studies • PONV in children – Studies • III. Guidelines & Recommendations • a) Clinical Practice Guidelines • b) Metoclopramide • c) MASCC Guideline • d) ASCO Guideline • e) RadiotherapyAntiemetic Guideline • f) PONV

  4. 1. Product to Meet Patient Needs Controlling Nausea & VomitingImproved Patient Outcome!

  5. 1. Product to Meet Patient Needs Granisetron: Grani-Denkiv. intravenous solution 2 Decades of Clinical Experience & Safety!

  6. 2. Product Information

  7. 3. Key Selling Points Guideline1listed 5-HT3R antagonists Benzyl Alcohol free solution2 - Grani-Denk suitable for babys! (off label; Compare your competitors!) low incidence of drug interactions safe and effective in elderly and children no dose reduction required when administered to patients with impaired renal or hepatic function and elderly Relieving Patients Safely for > 20 Years e.g. Grani-Denk

  8. 4. Visit Recommendations

  9. 5. Therapeutic Indication (1) Selective serotonin 5-HT3receptor blocker eg. Grani-Denk • CINVChemotherapy Induced Nausea & Vomiting Adults & Children ≥ 2 years • RINV Radiotherapy Induced Nausea & Vomiting • PONVPost-Operative Nausea & Vomiting

  10. 5. Therapeutic Indication (2)

  11. 6. ReportedOff-Label Use • Granisetron (oral) OCD 1 • 42 OCD Patients, 8 weeks • 1 mg Granisetron twice daily 100% response • Placebo 35% Response • Granisetron little effect in Migraine 2 • 18 subjects, 40-80 mg/kg

  12. 7. Mechanismof Action Mechanism of Action • highly selective antagonist of 5-hydroxytryptamine (5 HT3) receptorsnegligible affinity for other receptor types including 5 HT and dopamine D2 • Antiemetic effect prolonged but plasma levels are not clearly correlated with efficacy Clinical Pharmacology • Dose proportional exposure • t1/2 5.2 h healthy subjects, 8.7 h patients Chemotherapy • Hepatic metabolism CYP3A4 inhibited by ketoconazole • Moderate Protein Binding: 65%

  13. 8. Posology(1) • Chemo- and radiotherapy-induced nausea and vomiting (CINV and RINV*) • Prevention** acute and delayed nausea: 1-3 mg (10-40 µg/kg) as a slow i.v. injection or as a diluted i.v. infusion 5 minutes priorto the start of chemotherapy. Solution should be diluted to 5ml/mg. • Treatment (acute nausea): 1-3 mg (10-40 µg/kg)as a slow i.v. injection or as a diluted i.v. infusion administered over 5 minutes; Solution should be diluted to 5ml/mg; Further maintenance doses may be administered at least 10 minutes apart  max. dose over 24 hours ≤9 mg!

  14. 8. Posology (2) • Chemo- and radiotherapy-induced nausea and vomiting (CINV and RINV*) • Combination with adrenocortical steroid: The efficacy of parenteralgranisetron may be enhanced by an additional i.v. dose of an adrenocortical steroid -e.g. by 8-20 mg dexamethasoneadministered before the start of the cytostatic therapy -or by250 mg methyl-prednisoloneadministered prior to the start and shortly after the end of the chemotherapy.

  15. 8. Posology (3) • Chemo- and radiotherapy-induced nausea and vomiting (CINV and RINV*) • Paediatricpopolation: safety & efficacy for injection • in children aged 2 years and above established for the -prevention and treatment (control) ofacute nausea • and vomiting associated with chemotherapy. • -preventionof delayednausea and vomiting associated • with chemotherapy. • ->dose of 10-40 μg/kg body weight (up to 3 mg)as an i.v. infusion • -> diluted in 10-30 ml infusion fluid • ->administeredover 5 minutesprior to the start of chemo • -> one additional dose may be administered within a 24 hour-period • if required. This additional dose should not be administered until • at least 10 minutes after the initial infusion.

  16. 8. Posology (4) • PONV, adults: Dose of 1 mg (10 µg/kg) -should be administered by slow i.v. injection* • max. dose over 24 hours ≤3 mg • For the prevention of PONV, administration should be completed prior to induction of anaesthesia. (hospital guidelines recommend: 30 min before anesthesia, Induction or Reversal!)

  17. 8. Posology (5) • PONVin children: Currently available data are described in section 5.1, but no recommendation on a posology can be made. Study: Clinical application of granisetron was reported by Candiotti et al. A prospective, multicentre, randomized, double-blind, parallel-group study evaluated 157 children 2 to 16 years of age undergoing elective surgery. Total control of PONV during the first 2 hours after surgery was observed in most patients.

  18. 8. Posology (6) • Maximum Daily Dose adults: 9 mg CINV,RINV 3mg PONV children: 3 mg CINV • 10-40 µg/kg Adults and Children > 2 years* • No Dose Adjustment for Renal Impairment • No Dose Adjustment in Elderly • No Dose Adjustment for Hepatic Impairment Click here to see the Therapeutic indication slide again!

  19. Train the Brain - Quiz Should dose be changed for elderly or renal impaired patients? • No dose adjustment recommended for renal impairment or elderly.

  20. 8. Administration For Intravenous (i.v.) Administration Only • “slow i.v. injection” bolus dosing time ≥ 30 seconds • 1 mg ampoule dilute to 5 mL • 3 mg ampoule dilute to 15 mL • “intravenous infusion” short infusion dosing time over5 minutes • 1 mg ampoule dilute to 20-50 mL • 3 mg ampoule dilute to 20-50 mL Single Use Vials without benzyl alcohol!(less side effects; esp. for children)

  21. 8. Administration • Diluents for IV administration • 0.9 % w/v sodium chloride injection • 0.18 % w/v sodium chloride and 4% glucose injection • 5 % w/v glucose injection • Hartmann's solution • 1.87 % w/v sodium lactate injection • 10% mannitol injection • 1.4% w/v sodium hydrogen carbonate injection • 2.74% w/v sodium hydrogen carbonate injection • 4.2% w/v sodium hydrogen carbonate injection Use immediately, protect from direct light

  22. 8. Administration • Chemical & Physical Stability 24 h • Do not mix with other drug solutions! • PaediatricDosing10-40 µg/kg body weight • Withdraw appropriate volume • Dilute to 10-30 mL with infusion fluid • That means: no dose adjustment compared to adult dosing, only the maximum dose a day is lower (up to 3mg)

  23. Train the Brain - Quiz Is there a special posology for Grani-Denk in children? • Paediatricdosing: 10 – 40 µg/kg bodyweight • No dose adjustmentcomparedto adult dosing, but themaximum dose a dayislower (upto 3 mg)

  24. 9. Adverse Drug Reaction Granisetron • Headache 14% • Constipation 3% • Asthenia, Somnolence & Diarrhea • Fever 2-8%

  25. Train the Brain - Quiz Name some adversed drug reactions • Headache • Constipation • Asthenia, somnolence, diarrhea • fever

  26. 10. Special Warnings & Precautions • Hypotension with Apomorphine* Contraindicated with Apopmorphine • Reported Tramadol analgesia (Ondansetr.) • Rare Serotonergic Syndrome** 2 overdose cases, 39 total cases Unexplained mechanism, FDA watch list 2013 • Sensitivity to class or excipients Phenylketonuria Ondansetron Denk*** Other 5HT3 antagonists •  Intestinal motility Bowel obstruction

  27. 11. Interactions • No known clinically significant drug interactions requiring dose adjustment • Ketoconazole inhibited metabolism in vitro • Phenobarbital (CYP3A4 inducer) decreased plasma levels of Granisetron • Due to QTC prolongation, avoid with other drugs associated with arrhythmias

  28. 12. Take Home Messages Guideline1 listed 5-HT3R antagonist Benzyl Alcohol free solution2 - suitable even for babys! (off label; Compare your competitors!) Low incidence of drug interactions Safe and effective in elderly and children no dose reduction required when administered to patients with impaired renal or hepatic function and elderly Relieving Patients Safely for > 20 Years

  29. Train the Brain - Quiz Name some advantages of Grani-Denk. • Guideline listed 5-HT3R antagonists • Benzyl Alcohol free solution - suitable even for babys! (off label; Compare your competitors!) • Low incidence of drug interactions • Safe and effective in elderly and children • no dose reduction required when administered to patients with impaired renal or hepatic function and elderly

  30. 13. OndansetronVersus Granisetron… … in the prevention of chemotherapy induced nausea and vomiting in children with acute lymphoblastic leukemia. Abstract Effect of ondansetron and granisetron were evaluated in sixty (60) children (age 4-11 years) irrespective of sex, diagnosed case of acute lymphoblastic leukemia (ALL) who received high dose methotrexate and did not receive any antiemetic 24 hours prior to HDMTX. This was a prospective, randomized, double-blind, single center study. Of 60 children, 30 received oral ondansetron (4mg) and rest 30 granisetron (1mg) half an hour before therapy. Drugs were randomly allocated with appropriate code. The patients were followed up from day 1 to day 5 of therapy. Episodes of nausea and vomiting were recorded and scorings was done every 24 hours following chemotherapy. No significant difference was found between two groups according to acute emesis (Day-1) (p=0.053). In day two and day three it was significant (p<0.05). In day four it was significant (p=0.002). Early chemotherapy induced nausea and vomiting (CINV) were controlled 90% in children who received granisetron and 70% in children who received ondansetron. Delayed (Day 2-4) CINV were controlled in 80% of children who received granisetron and 43.4% who received ondansetron (p<0.05). Granisetron group required additional doses only 3.3% cases and ondanseton group 30% cases on the second day (p<0.05). Result was significant between two groups. About 36.7% patients had episodes of nausea on day four of chemotherapy in ondansetron group and it was only 3.3% in granisetron group due to adverse effects of antiemetic drug itself (p=0.001). Maximum episodes of vomiting were found on the second day in ondansetron group 33.3% and in granisetron group 3.3% (p=0.003). Though adverse effects like headache, constipation, abdominal pain and loose motion were common in both group of children but their number was much less in children who received granisetron. On second day of therapy score of nausea and vomiting was maximum in ondansetronand minimum in granisetron treated on day 4 and the result was significant. So, to prevent acute and delayed CINV in children with ALL, oral graniseteron can be considered as more effective and well tolerated with minimum adverse effects compared with ondansetrons.

  31. 14. Train the Brain - Quiz Name some advantages of Grani-Denk. Is there a special posology for Grani-Denk in children? Should dose be changed for elderly or renal impaired patients? Name some adversed drug reactions. Has Granisetron been shown safe for fetus & effective in pregnant women? Ondansetron and Granisetron differ in rates of effectiveness. What genotype population might require higher Ondansetron dosing? 5HT3 receptor antagonists are effective against nausea & vomiting from: • vestibular motion sickness c. Therapeutic Radiation • Chemotherapy d. Surgery & Anesthesia Nausea & vomiting is treated only for patient comfort

  32. 14. Train the Brain - Quiz See slide 29 Paediatric dosing: 10 – 40 µg/kg body weight; No dose adjustment compared to adult dosing, but the maximum dose a day is lower (up to 3 mg) No dose adjustment recommended for renal impairment or elderly. Headache, constipation, asthenia, somnolence, diarrhea, fever Ondansetronhas been tested in pregnancy & shown safe False, ondansetron & granisetron are equally effective at recommended doses Ultrarapid metabolizers with duplicate CYP 2D6 alleles All except a False, treatment decreases discontinued therapy, dehydration & electrolyte imbalance, esophagus tears (rare), hospital costs

  33. 15. References Almazrou, Alnaim. Evaluation of Adherence to Chemotherapy-Induced Nausea and Vomiting Guidelines. An Observational Study. Journal of Cancer Therapy,2012, 3, 613-620. 2012. American Society of Clinical Oncology. ASCO antiemetics guideline. 2011. Arumugham, Reddy. Augmentation Strategies in Obsessive-Compulsive Disorder CME. Medscape. 2013. Basch, Prestrud, Hesketh, Kris, Feyer, Somerfield, Chesney, Clark-Snow, Flaherty, Freundlich, Morrow, Rao, Schwartz, Lyman. Antiemetics: American Society of Clinical Oncology Clinical Practice Guideline Update. Journal of Clinical Oncology. Nov 2011. Broder. Metoclopramide, Ondansetron Cut Nausea in Cesarean Delivery. Medscape. Feb 07, 2013. De Witte, Dammers. Clinical overview of Ondansetron 4/8 mg. Module 2.5. 2006. Dempsey, Coop, Shillington, Farley, Eberhardt, O’Briant. Antiemetic Effectiveness of Ondansetron and Granisetron in Patients with Breast Cancer Treated With Cyclophosphamide. Medscape. 2004. Gan, Kovac, Lubarsky, Philip. PONV Management: Tackling the Practical Issues. Medscape. 2006. Gralla, Roila, Tonato, Herrstedt. MASCC/ESMO Antiemetic Guideline 2013. Multinational Association of Supportive Care in Cancer. 2013 Grunberg, Ades, Moukharskaya. Management of Nausea and Vomiting.CancerNetwork. 2013. Hand.Ondansetron Not Associated With Adverse Fetal Events. Medscape. Feb 27, 2013. Janicki, Schuler, Jarzembowski, Rossi. Prevention of Postoperative Nausea and Vomiting with Granisetron and Dolasetron in Relation to CYP2D6 Genotype. Anesthesia and Analgesia. 2006. Johnson. Genes Predict Success of Ondansetron Treatment for Alcoholism. Medscape. Jan 25, 2011. Kaunitz. Is Ondansetron Safe for Preventing Vomiting in Pregnancy? Medscape. Mar 01, 2013. (2) Kelley, Tepper. Rescue Therapy for Acute Migraine, Part 2. Medscape.Headache. 2012;52(2):292-306. 2012.

  34. 15. References Mike Harlos. Management Of Nausea and Vomiting in Palliative Care. 2010. Moon, Joo, Kim, Lee. Anti-emetic Effect of Ondansetron and Palonosetron in Thyroidectomy. Medscape. 2012. Myklejord, Yao, Llang, Glurich. Consensus Guideline Adoption for Managing Postoperative Nausea and Vomiting. Wisconsin Medical Journal. 2012. Nelson. FDA Issues Update on QT Prolongation Risk With Ondansetron. Medscape. Jun 29, 2012. Ondansetron. Drug Information Online. Dec 2012. Pasternak B, Swanström H, Hviid A. Ondansetron in pregnancy and risk of adverse fetal outcomes. N Engl J Med.368:814-823, 2013. Patka, Wu, Abraham, Sobel. Randomized Controlled Trial of Ondansetron vs. Prochlorperazine in Adults in the Emergency Department. Medscape. Western J Emerg Med. 2011;12(1):1-5. 2011. Pierre, Whelan. Nausea and Vomiting After Surgery.Cont Edu AnaesthCrit Care & Pain. 2013;13(1):28-32. Medscape. 2013. Piescik-Lech, Shamir, Guarino, Szajewska. Review Article: The Management of Acute Gastroenteritis in Children. Medscape. Aliment PharmacolTher. 2013;37(3):289-303. 2013. Santos, Souza, Brunetto, Sasse, Lima. Neurokinin-1 Receptor Antagonists for Chemotherapy-Induced Nausea and Vomiting. Medscape. J NatlCancerInst. 2012;104(17):1280-1292. 2012 Spanik. Module 2.5 Clinical Overview Granisetron 1 mg/ml. Hameln rds GmbH. 2008. Pfizer. SPC Ondansetron 8 mg orodispersible tablets. 2013. Transcript 3.14.13.: Towbin. Pediatric advisory committee meeting. United States Food and Drug Administration. 2012 WHO. Promoting safety of medicines for children. World Health Organisation. 2007.

  35. Join DenkPharma Our contributions to keeping you* healthy: • affordable pharmaceuticals for your therapy • German high premium quality for tablets, sachets, • packaging, studies, consultation, availability, support, etc… • raise awareness by conducting Check Up Days (blood glucose, • blood pressure, cholesterol and triglyceride) • constantly enhancing the product portfolio *patients, doctors, pharmacists, sales reps

  36. 16. Contents – Additional Information • I. Physiology & Pharmacology • Nausea &Vomiting • Emesis • Emetic Risk Categories • Chemotherapeutic and Radiotherapy Emetic Potential • Postoperative Nausea & Vomiting: PONV • Pharmacology (Antiemetic Agents and Receptor Antagonists) • Granisetron Pharmacogenomics • Controlling Nausea & Vomiting • Efficiency of Granisetron • NK1R Antagonists • Other 5-HT3 Antagonists • Controlling Nausea & Vomiting • II. Clinical studies • PONV in children - Studies • III. Guidelines & Recommendations • a) Clinical Practice Guidelines • b) Metoclopramide • c) MASCC Guideline • d) ASCO Guideline • e) RadiotherapyAntiemetic Guideline • f) PONV

  37. I. Physiology & Pharmacology Nausea &Vomiting • Clinical Scenarios • Risks • Patient Perspective 2. Emesis • Emesis Signalling Pathways • Mechanisms of Chemotherapy-induced Nausea & Vomiting (CINV) • Neurotransmitters involved in CINV • Antiemetic agents • Clinical Practice Guidelines • Emetic Risk Categories • Chemotherapeutic and Radiotherapy Emetic Potential • Postoperative Nausea & Vomiting: PONV • Risk Factors PONV • Incidence of PONV (adults) 6. Pharmacology (Antiemetic Agents and Receptor Antagonists) 7. Granisetron Pharmacogenomics 8. Controlling Nausea & Vomiting 9. Efficency of Granisetron 10. NK1R Antagonists 11. Other 5-HT3 Antagonists

  38. 1. Nausea ≠ Vomiting Clinical Scenarios Incidence Nausea > Emesis Subjective vs. Objective Are symptoms important to treat? Yes!* What are control pathways? CNS, peripheral Antiemetic Categories Treatment Decisions Therapy with 5-HT3 antagonists Options Specific Considerations

  39. a) EmesisClinical Scenarios e.g. On.setron-Denk ODT e.g. Grani-Denk e.g. On.setron-Denk ODT e.g. Grani-Denk

  40. b) Nausea & Vomiting Risks1,2 • Patient discomfort & stress • Discontinued Therapy • Anticipatory N & V • Esophagus tears • Dehydration & electrolyte imbalance • Malnutrition • Increased Hospital costs (Personnel, Supplies, Discharge Delays)

  41. c) Patient Perspective • CINV most feared aspect of Chemotherapy • PONV considered worse side effect of anesthesia & pain relief medications • Prefer PONV prevention over Complete Pain Control 1

  42. 2. EmesisPathways Cortex • Sensory input • Anxiety, memory • Meningeal irritation • Increased ICP* CTZ opioids, toxins, drugs dorsal vagal complex VOMITING CENTRE GI Vestibular • motion • CNS lesions • opioids • aggravates most nausea • Serotonin (5HT) release from mucosal enterochromaffin cells (vomiting reflex/ activating vagal afferents) • Obstruction (blockage), etc. Vomiting Center(Central Pattern Generator)

  43. a) Emesis Signalling Pathways

  44. b) Mechanisms of Chemotherapy-Induced Nausea and Vomiting (CINV) • Central mechanism • Chemotherapeutic agent activates the chemoreceptor trigger zone (CTZ) • Activated CTZ invokes release of various neurotransmitters, which stimulate vomiting center • Peripheral mechanism • Chemotherapeutic agent causes irritation and damage to gastrointestinal (GI) mucosa, resulting in the release of neurotransmitters • Activated receptors send signals to vomiting center via vagal afferents

  45. Serotonin Histamine EmeticReflex Endorphins Substance P Acetylcholine Dopamine c) Neurotransmitters Involved in CINV

  46. d) AntiemeticAgents e.g. promethacine,diphenhydramin, dimenhydrinate, doxylamine e.g. metoclopramide, domperidone, chlor-promazine, haloperidol, droperidol, alizapride e.g. On.setron- Denk ODT e.g. Grani-Denk e.g. aprepitant, fosaprepitant

  47. 3. EmeticRiskCategories Guideline1,2 emetic risk categories: • High (>90%) • Moderate (30%-90%) • Low (10%-30%) • Minimal (<10%) *Antiemetic risk categories were developed from historic studies 1Multinational Association of Supportive Care in Cancer 2013 2American Society of Clinical Oncology 2011

  48. 4. ChemotherapeuticsEmetic Potential

  49. 4. RadiotherapyEmetic Potential

  50. 5. Postoperative Nausea & Vomiting: PONV • Early 0-4 or 6 hours Anesthesia recovery unit • Opioid-Induced • Late >6 hours Post Anesthesiarecovery

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