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Re: ZOFRAN for hyperem... From: philip@ICSI.Net Fri Dec 8 09:06:21 1995 Messages sorted by: [ date ][ thread ][ subject ][ author ] Next message: Geff klein: "Re: Subarachnoid hemorrhage after delivery" Previous message: Dr MG Schoon - Obst & Gin.: "Subarachnoid hemorrhage after delivery" --kekale.icsi.net:818438852:757465518:664207401:1902772224 Content-Type: TEXT/PLAIN; charset=US-ASCII On Thu, 7 Dec 1995 19:59:38 -0600 Paul Prior MD wrote: > >> >>"ZOFRAN" seems to work...but it is very expen$ive >> >>Yes, it i understand, but i would like to know yours opinions about the >>teratogenic, and other questions about using this in pregnancy. > >I believe Zofran is category B. Paul, Zofran is indeed category B. I have attached the entire monograph on Zofran from our Physicians GenRx program to this message for those interested in all the details of the drug. Regards, Philip Philip Suarez, M.D. philip@icsi.net Fellow - American College Ob/Gyn Delegate - Texas Medical Association President - Internet Connect Services, Inc. Internet Connect Services, Inc. http://www.icsi.net Physicians GenRx on the World Wide Web Medicine's most complete drug compendium resource now available by subscription: http://www.icsi.net/GenRx 12/08/95 08:06:21 --kekale.icsi.net:818438852:757465518:664207401:1902772224 Content-Type: TEXT/plain; SizeOnDiskT065; name="ZOFRAN.TXT"; CHARSET=US-ASCII Content-Description: ZOFRAN.TXT ONDANSETRON HYDROCHLORIDE See From ZOFRAN Categories: Antiemetics, Cancer, Central_Nervous_System_Agents, Chemotherapy, Dementia*, FDA_Approved_1991_Jan, FDA_Class_1B_("Modest_Therapeutic_Advantage"), 5-HT3_Receptor_Antagonist, Gastrointestinal_Drugs, HCFA_Code_J2405_(Per_1_mg), Nausea, Nausea_and_Vomiting, Pregnancy_Category_B, Sales_>_$500_Million, Schizophrenia*, Serotonin_Antagonists, Top_100_Drugs, Vomiting, * Indication not approved by FDA BRAND NAMES: Zofran FORMULARIES: Kaiser; Medi-Cal COST OF THERAPY: $107.00 (Nausea; Tablet; 8 mg; 3/day; 2 days) DESCRIPTION: Injection and Tablets The active ingredient in Zofran is ondansetron hydrochloride, the racemic form of ondansetron and a selective blocking agent of the serotonin 5-HT3 receptor type. Chemically it is (&177) 1,2,3,9- tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]-4H-carbazol-4- one, monohydrochloride, dihydrate. The empirical formula is C18H19N3OHCl2H2O, representing a molecular weight of 365.9. Ondansetron HCl is a white to off-white powder that is soluble in water and normal saline. Injection Zofran Injection is a clear, colorless, nonpyrogenic, sterile solution for intravenous (IV) injection. Each 1 ml of aqueous solution contains 2 mg of ondansetron as the hydrochloride dihydrate; 8.3 mg of sodium chloride, USP; 0.5 mg of citric acid monohydrate, USP as buffers; and 1.2 mg of methylparaben, NF and 0.15 mg of propylparaben, NF as preservatives in water for injection, USP. The pH of the injection solution is 3.3 to 4.0. Tablets Each 4-mg Zofran Tablet for oral administration contains ondansetron HCl dihydrate equivalent to 4 mg of ondansetron. Each 8-mg Zofran Tablet for oral administration contains ondansetron HCl dihydrate equivalent to 8 mg ondansetron. Each tablet also contains the inactive ingredients lactose, microcrystalline cellulose, pregelatinized starch, hydroxypropyl methylcellulose, magnesium stearate, titanium dioxide, iron oxide yellow (8-mg tablet), and sodium benzoate (4-mg tablet only). CLINICAL PHARMACOLOGY: Injection and Tablets Pharmacodynamics: Ondansetron is a selective 5-HT3 receptor antagonist. While ondansetron's mechanism of action has not been fully characterized, it is not a dopamine-receptor agonist. Serotonin receptors of the 5-HT3 type are present both peripherally on vagal nerve terminals and centrally in the chemoreceptor trigger zone of the area postrema. It is not certain whether ondansetron's antiemetic action in chemotherapy-induced emesis is mediated centrally, peripherally, or in both sites. However, cytotoxic chemotherapy appears to be associated with release of serotonin from the enterochromaffin cells of the small intestine. In humans, urinary 5-HIAA (5-hydroxy- indoleacetic acid) excretion increases after cisplatin administration in parallel with the onset of emesis. The released serotonin may stimulate the vagal afferents through the 5-HT3 receptors and initiate the vomiting reflex. In animals, the emetic response to cisplatin can be prevented by pretreatment with an inhibitor of serotonin synthesis, bilateral abdominal vagotomy and greater splanchnic nerve section, or pretreatment with a serotonin 5-HT3 receptor antagonist. In normal volunteers, single IV doses of 0.15 mg/kg of ondansetron had no effect on esophageal motility, gastric motility, lower sphincter pressure, or small intestinal transit time. In another study in six normal male volunteers, a 16-mg dose infused over 5 minutes showed no effect of the drug on cardiac output., heart rate, stroke volume, blood pressure, or electrocardiogram (ECG). Multiday administration of ondansetron has been shown to slow colonic transit in normal volunteers. Ondansetron has no effect on plasma prolactin concentrations. Ondansetron does not alter the respiratory depressant effects produced by alfentanil or the degree of the neuromuscular blockade produced by atracurium. Interactions with general or local anesthetics have not been studied. Multiday esophageal administration of ondansetron has been shown to slow colonic transit in normal volunteers. Ondansetron has no effect on plasma prolactin concentrations. Pharmacokinetics: Ondansetron is extensively metabolized in humans, with approximately 5% of a radiolabeled dose recovered as the parent compound from the urine. The primary metabolic pathway is hydroxylation on the indole ring followed by glucuronide or sulfate conjugation. Pediatric Studies: Four open-label, non-comparative (one U.S., three foreign) trials have been performed with 209 pediatric cancer patients aged 4 to 18 years given a variety of cisplatin or non-cisplatin regimens. In the three foreign trials, the initial Zofran Injection dose ranged from 0.04 to 0.87 mg/kg for a total dose of 2.16 to 12 mg. This was followed by the oral administration of ondansetron ranging from 4 to 24 mg daily for 3 days. In the U.S. trial, Zofran was administered intravenously (only) in three doses of 0.15 mg/kg each for a total daily dose of 7.2 to 39 mg. In these studies, 58% of the 196 evaluable patients had a complete response (no emetic episodes) on day 1. Thus, prevention of emesis in these children was essentially the same as for patients older than 18 years of age. Overall, Zofran Injection was well tolerated in these pediatric patients. Injection In normal volunteers, the following mean pharmacokinetic data have been determined following a single 0.15-mg/kg IV dose (TABLE 1): TABLE 1 - Ondansetron HCl, Clinical Pharmacology Pharmacokinetics in Normal Volunteers Peak Plasma Mean Plasma Concentration Elimination Clearance Age-group n (ng/ml) Half-life (h) (L/h/kg) 19-40 11 102 3.5 0.381 61-74 12 106 4.7 0.319 &62 75 11 170 5.5 0.262 >From a single-dose infusion study, patients with severe hepatic impairment showed a five-fold and those with mild-to-moderate liver impairment a two-fold reduction in mean plasma clearance, with increases in the mean apparent volume of distribution of less than two-fold, as compared to normals. The mean half-life of 3.6 hours in normals increased in 9.2 hours in patients with mild-to-moderate hepatic impairment and was prolonged to 20.6 hours in patients with severe hepatic insufficiency. A reduction in clearance and increase in elimination half-life are seen in patients over 75 years old. In clinical trials with patients with cancer, there was neither a difference in safety nor efficacy between patients over 65 years of age and those under 65 years of age; an insufficient number of patients were over 75 years of age to permit conclusions in that age-group. No adjustment in dosage is recommended in the elderly. In adult cancer patients, the mean elimination half-life was 4.0 hours, and there was no difference in the multidose pharmacokinetics over a 4- day period. In a study of 21 pediatric cancer patients (aged 4 to 18 years) who received three IV doses of 0.15 mg/kg of ondansetron at 4-hour intervals, patients older than 15 years of age exhibited ondansetron pharmacokinetic parameters similar to those of adults. Patients aged 4 to 12 years generally showed higher clearance and somewhat larger volume of distribution than adults. Most pediatric patients younger than 15 years of age with cancer had a shorter (2.4 hours) ondansetron plasma half-life than patients older than 15 years of age. It is not known whether these differences in ondansetron plasma half-life may result in differences in efficacy between adults and some young children (see CLINICAL TRIALS: Pediatric Studies). Plasma protein binding on ondansetron as measured in vitro was 70% to 76%, with binding constant over the pharmacologic concentration range (10 - 500 ng/ml). Circulating drug also distributes into erythrocytes. A positive lymphoblast transformation test to ondansetron has been reported, which suggests immunologic sensitivity to ondansetron. CLINICAL TRIALS: Chemotherapy-Induced Nausea and Vomiting: In a double-blind study of three different dosing regimens of Zofran Injection, 0.015 mg/kg, 0.15 mg/kg, and 0.30 mg/kg, each given three times during the course of cancer chemotherapy, the 0.15-mg/kg dosing regimen was more effective than the 0.015-mg/kg dosing regimen. The 0.30-mg/kg dosing regimen was not shown to be more effective than the 0.15-mg/kg dosing regimen. Cisplatin-Based Chemotherapy: In a double-blind study in 28 patients, Zofran Injection (three 0.15-mg/kg doses) was significantly more effective than placebo in preventing nausea and vomiting induced by cisplatin-based chemotherapy. Treatment response was as follows (TABLE 2): TABLE 2 - Ondansetron HCl, Clinical Pharmacology Prevention of Chemotherapy-Induced Nausea and Emesis in Single-Day Cisplatin Therapy* Ondansetron HCl Injection Placebo p Value Number of patients 14 14 Treatment response 0 Emetic episodes 2 (14%) 0 (0%) 1-2 Emetic episodes 8 (57%) 0 (0%) 3-5 Emetic episodes 2 (14%) 1 (7%) More than 5 emetic episodes/rescued 2 (14%) 13 (93%) 0.001 Median number of emetic episodes 1.5 Undefined Median time to first emetic episode (h) 11.6 2.8 0.001 Median nausea scores (0-100)** 3 59 0.034 Global satisfaction with control of nausea and vomiting (0-100)*** 96 10.5 0.009 * Chemotherapy was high dose (100 and 120 mg/m2; Zofran Injection n=6, placebo n=5) or moderate dose (50 and 80 mg/m2; Zofran Injection n=8, placebo n=9). Other chemotherapeutic agents included fluorouracil, doxorubicin and cyclophosphamide. There was no difference between treatments in the types of chemotherapy that would account for differences in response. Efficacy based on "all patients treated" analysis. Median undefined since at least 50% of the patients were rescued or more than 5 emetic episodes. ** Visual analog scale assessment of nausea: 0=no nausea, 100=nausea as bad as it can be. *** Visual analog scale assessment of satisfaction: 0=not at all satisfied, 100=totally satisfied. Ondansetron was compared with metoclopramide in a single-blind trial in 307 patients receiving cisplatin &62 100 mg/m2 with or without other chemotherapeutic agents. Patients received the first dose of ondansetron or metoclopramide 30 minutes before cisplatin. Two additional ondansetron doses were administered 4 and 8 hours later, or five additional metoclopramide doses were administered 2, 4, 7, 10 and 13 hours later. Cisplatin was administered over a period of 3 hours or less. Episodes of vomiting and retching were tabulated over the period of 24 hours after cisplatin. The results of this study are summarized below (TABLE 3): TABLE 3 - Ondansetron HCl, Clinical Pharmacology Prevention of Emesis Induced by Cisplatin (&62 100 mg/m2) Single-Day Therapy* Ondansetron HCl Injection Metoclopramide p Value Dose 0.15 mg/kg x 3 2 mg/kg x 6 Number of patients in efficacy population 136 138 Treatment response Emetic episodes 54 (40%) 41 (30%) 1-2 Emetic episodes 34 (25%) 30 (22%) 3-5 Emetic episodes 19 (14%) 18 (13%) More than 5 emetic episodes/rescued 29 (21%) 49 (36%) Comparison of treatments with respect to 0 Emetic episodes 54/136 41/138 0.083 More than 5 emetic episodes/rescued 29/136 49/138 0.009 Median number of emetic episodes 1 2 0.005 Median time to first emetic episode (h) 20.5 4.3 < 0.001 Global Satisfaction with control of nausea and vomiting (0 - 100) 85 63 0.001 Acute dystonic reactions 0 8 0.005 Akathisia 0 10 0.002 * In addition to cisplatin, 68% of patients received other chemotherapeutic agents, including cyclophosphamide, etoposide, and fluorouracil. There was no difference between treatments in the types of chemotherapy that would account for differences in response. Visual analog scale assessment: 0=not at all satisfied, 100=totally satisfied. Forty-one of the ondansetron patients were over 65 years of age. The complete response rate (zero emetic episodes) was 41% in this group compared with 40% in those 65 years old or younger. In a stratified, randomized, double-blind, parallel group, multicenter study, a single 32-mg dose of ondansetron was compared with three 15- mg/kg doses in patients receiving cisplatin doses of either 50 to 70 mg/m2 or &62 100 mg/m2. Patients received the first ondansetron dose 30 minutes before cisplatin. Two additional ondansetron doses were administered 4 and 8 hours later to the group receiving three 0.15 mg/kg doses. In both strata, significantly fewer patients on the single 32-mg dose than those receiving the three-dose regimen failed (TABLE 4): TABLE 4 - Ondansetron HCl, Clinical Pharmacology Prevention of Chemotherapy-Induced Nausea and Emesis in Single-Dose Therapy Ondansetron HCl Dose 0.15 mg/kg 32 mg x 3 x 1 p Value High-dose cisplatin (&62100 mg/m2) Number of Patients 100 102 Treatment Response 0 Emetic episodes 41% (41%) 49 (48%) 0.315 1-2 Emetic episodes 19 (19%) 25 (25%) 3-5 Emetic episodes 4 (4%) 8 (8%) More than 5 emetic episodes/rescued 36 (36%) 20 (20%) 0.009 Median time to first emetic episode (h) 21.7 23 0.173 Median nausea scores (0 - 100)* 28 13 0.004 Medium-dose cisplatin (50-70 mg/m2) Number of Patients 101 93 Treatment Response 0 Emetic episodes 62 (61%) 68 (73%) 0.083 1-2 Emetic episodes 11 (11%) 14 (15%) 3-5 Emetic episodes 6 (6%) 3 (3%) More than 5 emetic episodes/rescued 22 (22%) 8 (9%) 0.011 Median time to first emetic episode (h) Undefined Undefined 0.084 Median nausea scores (0 - 100)* 9 3 0.131 * Visual analog scale assessment: 0 = no nausea, 100 = nausea as bad as it can be. Median undefined since at least 50% of patients did not have any emetic episodes. Cyclophosphamide-Based Chemotherapy: In a double-blind, placebo-controlled study of Zofran Injection (three 0.15-mg/kg doses) in 20 patients receiving cyclophosphamide (500-600 mg/m2) chemotherapy, Zofran Injection was significantly more effective than placebo in preventing nausea and vomiting. The results are summarized below (TABLE 5): TABLE 5 - Ondansetron HCl, Clinical Pharmacology Prevention of Chemotherapy-Induced Nausea and Emesis in Single-Day Cyclophosphamide Therapy* Ondansetron HCl Inj. Placebo p Value Number of Patients 10 10 Treatment response 0 Emetic episodes 7(70%) 0 (0%) 0.001 1-2 Emetic episodes 0(0%) 2 (20%) 3-5 Emetic episodes 2(20%) 4 (40%) More than 5 emetic episodes/rescued 1 (10%) 4 (40%) 0.131 Median number of emetic episodes 0 4 0.008 Median time to first emetic episode (h) Undefined 8.79 Median nausea scores (0-100)** 0 60 0.001 Global Satisfaction with control of nausea and vomiting (0-100)*** 100 52 0.008 * Chemotherapy consisted of cyclophosphamide in all patients, plus other agents, including fluorouracil, doxorubicin, methotrexate, and vincristine.There was no difference between treatments in the type of chemotherapy that would account for differences in response. Efficacy based on "all patients treated" analysis. Median undefined since at least 50% of patients did not have any emetic episodes. ** Visual analog scale assessment of nausea: 0=no nausea, 100=nausea as bad as it can be. ***Visual analog scale assessment of satisfaction: 0=not at all satisfied, 100=totally satisfied. Retreatment: In uncontrolled trials, 127 patients receiving cisplatin (median dose, 100 mg/m2) and ondansetron who had two or fewer emetic episodes were retreated with ondansetron and chemotherapy, mainly cisplatin, for a total of 269 retreatment courses (median 2; range, 1 to 10). No emetic episodes occurred in 160 (59%), and two or fewer emetic episodes occurred in 217 (81%) retreatment courses. Postoperative Nausea and Vomiting: Prevention of Postoperative Nausea and Vomiting: Surgical patients who received ondansetron immediately before the induction of general balanced anesthesia (barbiturate: thiopental, methohexital or thiamylal; opioid; alfentanil or fentanyl; nitrous oxide; neuromuscular blockade; succinylcholine/curare and/or vecuronium or atracurium; and supplemental isoflurane) were evaluated in two double-blind US studies involving 554 patients. Zofran Injection (4 mg) IV given over 2 to 5 minutes was significantly more effective than placebo. The results of these studies are summarized below (TABLE 6). TABLE 6 - Ondansetron HCl, Clinical Pharmacology Prevention of Postoperative Nausea and Vomiting Ondansetron Placebo p value Study 1 Emetic Episodes: Number of patients 136 139 Treatment response over 24-hour postoperative period 0 Emetic episodes 103 (76%) 64 (46%) < 0.001 1 Emetic episodes 13 (10%) 17 (12%) More than 1 emetic episode/rescued 20 (15%) 58 (42%) Nausea assessments: Number of patients 134 136 No nausea over 24-hr postoperative period 56 39 (29%) Study 2 Emetic episodes: Number of patients 136 143 Treatment response over 24-hr postoperative period 0 Emetic episodes 85 (63%) 63 (44%) 0.002 1 Emetic episodes 16 (12%) 29 (20%) More than 1 emetic episodes/rescued 35 (26%) 51 (36%) Nausea assessments: Number of patients 125 133 No nausea over 24-hr postoperative period 48 (38%) 42 (32%) (See paragraph below). (From TABLE 6): The study populations in all trials thus far consisted of mainly women undergoing laparoscopic procedures. While some men were included in some trials with similar results, clearance of the drug is more rapid in men and sufficient numbers of men have not been clinically studied to be certain that efficacy and safety have been established. Few patients undergoing major abdominal surgery have been studied. Prevention of Further Postoperative Nausea and Vomiting: Surgical patients receiving general balanced anesthesia (barbiturate: thiopental, methohexital or thiamylal; opioid; alfentanil or fentanyl; nitrous oxide; neuromuscular blockade; succinyl choline/curare and/or vecuronium or atracurium; and supplemental isoflurane) who received no prophylactic antiemetics and who experienced nausea and/or vomiting within 2 hours postoperatively were evaluated in two double-blind US studies involving 441 patients. Patients who experienced an episode of postoperative nausea and/or vomiting were given Zofran Injection (4 mg) IV over 2 to 5 minutes, and this was significantly more effective than placebo. The results of these studies are summarized below (TABLE 7). TABLE 7 - Ondansetron HCl, Clinical Pharmacology Prevention of Further Postoperative Nausea and Vomiting Ondansetron 4 mg IV Placebo p value Study 1 Emetic Episodes: Number of patients 104 117 Treatment response 24 hours after study drug 0 Emetic episodes 49 (47%) 19 (16%) < 0.001 1 Emetic episodes 12 (12%) 9 (8%) More than 1 emetic episode/rescued 43 (41%) 89 (76%) Median time to first emetic episode (min)* 55.0 43.0 Nausea assessments: Number of patients 98 102 Mean nausea score over 24-hr postoperative period 1.7 3.1 Study 2 Emetic Episodes: Number of patients 112 108 Treatment response 24 hours after study drug 0 Emetic episodes 49 (44%) 28 (26%) 0.006 1 Emetic episodes 14 (13%) 3 (3%) More than 1 emetic episode/rescued 49 (44%) 58 (71%) Median time to first emetic episode (min)* 60.5 34.0 Nausea assessments: Number of patients 105 85 Mean nausea score over 24-hr postoperative period 1.9 2.9 * After administration of study drug. Nausea measured on a scale of 0-10 with 0 = no nausea, 10 = nausea as bad as it can be. (See paragraph in previous column). (From Table 7). The study populations in all trials thus far consisted of mainly women undergoing laparoscopic procedures. While some men were included in some trials with similar results, clearance of the drug is more rapid in men and sufficient numbers of men have not been clinically studied to be certain that efficacy and safety have been established. Few patients undergoing major abdominal surgery have been studied. Tablets Oral ondansetron is well absorbed and undergoes limited first-pass metabolism. Following the administration of a single 8-mg ondansetron tablet to healthy young, male volunteers and from pooled studies, the time to peak plasma ondansetron concentration is approximately 1.7 hours, the terminal elimination half life is approximately 3 hours and the bioavailability is approximately 56%. Gender differences were shown in the disposition of ondansetron given as a single dose. The extent and rate of ondansetron's absorption is greater in women than men. Slower clearance in women, a smaller apparent volume of distribution (adjusted for weight) and higher absolute bioavailability resulted in higher plasma ondansetron levels. These higher plasma levels may in part be explained by differences in body weight between men and women. It is not known whether these gender related differences were clinically important. More detailed pharmacokinetic information is contained in the following table (TABLE 8) taken from one study. TABLE 8 - Ondansetron HCl, Clinical Pharmacology Pharmacokinetics in Normal Volunteers: Single 8-mg Oral Dose Peak Time of Mean Systemic Plasma Peak Elimi- Plasma Age- Mean Concen- Plasma nation Clear- Absolute group Weight tration Concen- Half- ance Bioavail- (years) (kg) n (ng/ml) tration (h) life (h) L/h/kg ability 18-40 M 69.0 6 26.2 2.0 3.1 0.403 0.483 F 62.7 5 42.7 1.7 3.5 0.354 0.663 61-74 M 77.5 6 24.1 2.1 4.1 0.384 0.585 F 60.2 6 52.4 1.9 4.9 0.255 0.643 &62 75 M 78.0 5 37.0 2.2 4.5 0.277 0.619 F 67.6 6 46.1 2.1 6.2 0.249 0.747 The administration of oral ondansetron with food increases significantly (about 17%) the extent of absorption of ondansetron. The peak plasma concentration are not significantly affected. This change in the extent of absorption is not believed to be of any clinical relevance. There was no significant effect of antacid administration on the pharmacokinetics of orally administered ondansetron. Because ondansetron undergoes extensive metabolism, the modest reduction in clearance in the over 75 age-group was not expected. However, since there was neither a difference in safety nor efficacy between patients over 65 years of age and those under 65 years of age, no adjustment in dosage is required in the elderly. Plasma protein binding of ondansetron as measured in vitro was 70% to 76% over the concentration range of 10 to 500 ng/ml. Circulating drug also distributes into erythrocytes. Clinical Trials: In two double-blind U.S. studies in 304 patients, Zofran Tablets were significantly effective in preventing nausea and vomiting induced by cyclophosphamide-based chemotherapy containing either methotrexate or doxorubicin. Treatment response is based on the total number of emetic episodes over the 3-day study period. The results of these studies are summarized below (TABLE 9): TABLE 9 - Ondansetron HCl, Clinical Pharmacology Emetic Episodes Treatment* Ondansetron 8 t.i.d. Oral* Placebo p Value Study 1 Number of Patients 79 81 Treatment Response 0 Emetic episodes 52 (66%) 15 (19%) < 0.001 1-2 Emetic episodes 9 (11%) 10 (12%) 3-5 Emetic episodes 5 (6%) 5 (6%) More than 5 emetic episodes/rescued 13 (16%) 51 (63%) < 0.001 Median number of emetic episodes 0.0 Undefined Median time to first emetic episode (h) Undefined 11.1 Median nausea scores (0-100)** 5 40 <0.001 Study 2 Number of Patients 71 73 Treatment Response 0 Emetic episodes 47 (66%) 9 (12%) < 0.001 1-2 Emetic episodes 9 (13%) 11 (15%) 3-5 Emetic episodes 4 (6%) 6 (8%) More than 5 emetic 11 (15%) 47 (64%) < 0.001 episodes/rescued Median number of emetic episodes 0.0 Undefined Median time to first Undefined 9.5 emetic episode (h) Median nausea scores (0-100)** 5 55 <0.001 *The first dose was administered 30 minutes before the start of emetogenic chemotherapy, with subsequent doses 4 and 8 hours after the first dose. An 8 mg tablet was administered three times a day for 2 days after completion of chemotherapy. In adults, Ondansetron 4 mg t.i.d, was also studied with the following results: Study 1: 0 emetic episodesS/81 (65%); more than 5 emetic episodes/ rescued/81 (23%). Study 2: 0 emetic episodesH/75 (64%); more than 5 emetic episodes/rescued = 14/75 (19%). In analysis of patients receiving &62 600 mg/m2 of cyclophosphamide, there were more failures on the 4 mg dose than on the 8 mg dose, 26% vs. 0% in one study and 14% vs. 4% in the second study. Median undefined since at least 50% of the patients were rescued or had more than five emetic episodes Median undefined since at least 50% of patients did not have any emetic episodes. ** Visual analog scale assessment: 0=no nausea, 100=nausea as bad as it can be. In both studies, the ondansetron-treated group was statistically significantly (p< 0.001) superior to placebo with respect to complete treatment response, treatment failure, the number of emetic episodes, and nausea scores. Retreatment: In uncontrolled trials, 148 patients receiving cyclophosphamide-based chemotherapy were retreated with 8 mg t.i.d. of oral ondansetron during subsequent chemotherapy for a total of 396 retreatment courses. No emetic episodes occurred in 314 (79%) of the retreatment courses, and only one to two emetic episodes occurred in 43 (11%) of the retreatment courses. Elderly Patients: One hundred thirty-seven (137) patients 65 years of age or older have received oral ondansetron. Prevention of emesis was similar to that in patients younger than 65 years of age and adverse reactions were not seen in increased frequency. Clinical Trials: Radiation-Induced Nausea and Vomiting: Total Body Irradiation: In a randomized, double-blind study in 20 patients, Zofran Tablets (8 mg given 1.5 hours before each fraction of radiotherapy for 4 days) was significantly more effective than placebo in preventing vomiting induced by total body irradiation. Total body irradiation consisted of 11 fractions (120 cGy per fraction) over 4 days for a total of 1,320 cGy. Patients received three fractions for 3 days, than two fractions on day 4. Single High-Dose Fraction Radiotherapy: Ondansetron was significantly more effective than metoclopramide with respect to complete control of emesis (0 emetic episodes) in a double-blind trial in 105 patients receiving single high-dose radiotherapy (800 to 1,000 cGy) over an anterior or posterior field size of &6280 cm2 to the abdomen. Patients received the first dose of ondansetron (8 mg) or metoclopramide (10 mg) 1 to 2 hours before radiotherapy. If radiotherapy was given in the morning, two additional doses of study treatment were given (one tablet late afternoon and one tablet before bedtime). If radiotherapy was given in the morning, two additional doses of study treatment were given (one tablet late afternoon and one tablet before bedtime). If radiotherapy was given in the afternoon, patients took only one further tablet that day before bedtime. Patients continued the oral medication on a t.i.d. basis for 3 days. Daily Fractionated Radiotherapy: Ondansetron was significantly more effective than prochlorperazine with respect to complete control of emesis (0 emetic episodes) in a double-blind trial in 135 patients receiving a 1- to 4-week course of fractionated radiotherapy (180 cGy doses) over a field size of &6280 cm2 to the abdomen. Patients received the first dose of ondansetron (8 mg) or prochlorperazine (10 mg) 1 to 2 hours before the patient received the first daily radiotherapy fraction, with two subsequent doses on a t.i.d. basis. Patients continued the oral medication on a t.i.d. basis on each day of radiotherapy. INDICATIONS AND USAGE: Injection 1. Prevention of nausea and vomiting associated with initial and repeat courses of emetogenic cancer chemotherapy, including high-dose cisplatin. Efficacy of the 32-mg single dose beyond 24 hours in these patients has not yet been established. 2. Prevention of postoperative nausea and/or vomiting. As with other antiemetics, routine prophylaxis is not recommended for patients in whom there is little expectation that nausea and/or vomiting will occur postoperatively. In patients where nausea and/or vomiting must be avoided postoperatively, Zofran Injection is recommended even where the incidence of postoperative nausea and/or vomiting is low. For patients who have nausea and/or vomiting postoperatively, Zofran Injection may be given to prevent further episodes (see CLINICAL PHARMACOLOGY: CLINICAL TRIALS). Tablets 1. Prevention of nausea and vomiting associated with initial and repeat courses of moderately emetogenic cancer chemotherapy. 2. Prevention of nausea and vomiting associated with radiotherapy in patients receiving either total body irradiation, single high-dose fraction, or daily fractions to the abdomen. CONTRAINDICATIONS: Injection and Tablets Zofran is contraindicated for patients known to have hypersensitivity to the drug. PRECAUTIONS: Injection Ondansetron is not a drug that stimulates gastric or interstitial peristalsis. It should not be used instead of nasogastric suction. As with other antiemetics, the use of ondansetron in abdominal surgery may mask a progressive ileus and /or gastric distension. Injection and Tablets Carcinogenesis, Mutagenesis, Impairment of Fertility: Carcinogenic effects were not seen in 2-year studies in rats and mice with oral ondansetron doses up to 10 and 30 mg/kg per day, respectively. Ondansetron was not mutagenic in standard tests for mutagenicity. Oral administration of ondansetron up to 15 mg/kg per day did not affect fertility or general reproductive performance of male and female rats. Pregnancy: Teratogenic Effects: Pregnancy Category B: Reproduction studies have been performed in pregnant rats and rabbits at daily doses up to 4 mg/kg per day and have revealed no evidence of impaired fertility or harm to the fetus. There are no adequate and well- controlled studies in pregnant women. Ondansetron should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Nursing Mothers: Ondansetron is excreted in the breast milk of rats. It is not known whether ondansetron is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when ondansetron is administered to a nursing woman. Pediatric Use: Little information is available about dosage in children 4 years of age or younger (see DOSAGE AND ADMINISTRATION for use in children 4 to 18 years of age receiving cancer chemotherapy.) Use in Elderly Patients: Dosage adjustment is not needed in patients over the age of 65 (see CLINICAL PHARMACOLOGY). Prevention of nausea and vomiting in elderly patients was no different than in younger age-groups. DRUG INTERACTIONS: Injection and Tablets Ondansetron does not itself appear to induce or inhibit the cytochrome p-450 drug-metabolizing enzyme system of the liver. Because ondansetron is metabolized by hepatic cytochrome p-450 drug metabolizing enzymes, inducers, or inhibitors of these enzymes may change the clearance and, hence, the half-life of ondansetron. On the basis of available data, no dosage adjustment is recommended for patients on these drugs. Tumor response to chemotherapy in the P 388 mouse leukemia model is not affected by ondansetron. In humans, carmustine, etoposide, and cisplatin do not affect the pharmacokinetics of ondansetron. ADVERSE REACTIONS: Injection Chemotherapy-Induced Nausea and Vomiting: The following adverse events have been reported in individuals receiving ondansetron at a dosage of three 0.15 mg/kg doses or as a single 32-mg dose in clinical trials. These patients were receiving concomitant chemotherapy, primarily cisplatin, and IV fluids. Most were receiving a diuretic (TABLE 10): TABLE 10 - Ondansetron HCl, Adverse Reactions Principal Adverse Events in Comparative Trials Number of Patients With Event Ondansetron HCl Ondansetron HCl Injection Injection Metoclopramide Placebo 0.15 mg/kg x 3 32 mg x 1 nA9 n"0 n6 n4 Diarrhea 16% 8% 44% 18% Headache 17% 25% 7% 15% Fever 8% 7% 5% 3% Akathisia 0% 0% 6% 0% Acute dystonic reactions* 0% 0% 5% 0% * See Central Nervous System below. Gastrointestinal: Constipation has been reported in 11% of chemotherapy patients receiving multi-day ondansetron. Hepatic: In comparative trials in cisplatin chemotherapy patients with normal baseline values of aspartate transaminase (AST) and alanine transaminase (ALT), these enzymes have been reported to exceed twice the upper limit of normal in approximately 5% of patients. The increases were transient and did not appear to be related to dose or duration of therapy. On repeat exposure, similar transient elevations in transaminase values occurred in some courses, but symptomatic hepatic disease did not occur. There have been reports of liver failure and death in patients with cancer receiving concurrent medications including potentially hepatotoxic cytotoxic chemotherapy and antibiotics. The etiology of the liver failure is unclear. Integumentary: Rash has occurred in approximately 1% of patients receiving ondansetron. Central Nervous System: There have been three reports consistent with, but not diagnostic of, an extrapyramidal reaction in patients receiving ondansetron. Cardiovascular: Rare instances tachycardia, angina (chest pain), bradycardia, hypotension, syncope, and electrocardiographic alterations. In many cases the relationship to Zofran Injection was unclear. Special Senses: Transient blurred vision, in some cases associated with abnormalities of accommodation, and transient dizziness during or shortly after IV infusion. Local Reactions: Pain, redness, and burning at site of injection. Other: Rare cases of hypokalemia and grand mal seizures have been reported. The relationship to Zofran Injection is unclear. Rare cases of hypersensitivity reactions, sometimes severe (e.g., anaphylaxis, bronchospasm, shortness of breath, hypotension, shock, angioedema, urticaria), have also been reported. Postoperative Nausea and Vomiting: The following adverse events have been reported in &62 2% of people receiving ondansetron at a dosage of 4 mg IV over 2-5 minutes in clinical trials. Rates of these vents were not significantly different in the ondansetron and placebo groups. These patients were receiving multiple concomitant perioperative and postoperative medications. TABLE 11 - Ondansetron HCl, Adverse Reactions Zofran Injection 4 mg IV Placebo n = 547 patients n = 547 patients Headache 92 (17%) 77 (14%) Dizziness 67 (12%) 88 (16%) Musculoskeletal pain 57 (10%) 59 (11%) Drowsiness/sedation 44 (8%) 37 (7%) Shivers 38 (7%) 39 (7%) Malaise/fatigue 25 (5%) 30 (5%) Injection site reaction 21 (4%) 18 (3%) Urinary retention 17 (3%) 15 (3%) Postoperative CO2-related pain* 12 (2%) 16 (3%) Chest pain (unspecified) 12 (2%) 15 (3%) Anxiety/agitation 11 (2%) 16 (3%) Dysuria 11 (2%) 9 (2%) Hypotension 10 (2%) 12 (2%) Fever 10 (2%) 6 (1%) Cold sensation 9 (2%) 8 (1%) Pruritus 9 (2%) 3 (< 1%) Paresthesia 9 (2%) 2 (< 1%) * Sites of pain included abdomen, stomach, joints, rib cage, shoulder. Tablets Chemotherapy-Induced Nausea and Vomiting: The following adverse events have been reported in adults receiving 4 or 8 mg of ondansetron three times a day for 3 days in two U.S. placebo-controlled trials. These patients were receiving concurrent chemotherapy, primarily cyclophosphamide-based regimens (TABLE 12): TABLE 12 - Ondansetron HCl, Adverse Reactions Principal Adverse Events in US Placebo-Controlled Trials: 3 Days of Oral Therapy Ondansetron Ondansetron 8 mg t.i.d. 4 mg t.i.d Placebo Event n!5 n!5 n"1 Headache 46 (21%) 49 (23%) 24 (11%) Constipation 15 (7%) 10 (5%) 0 (0%) Abdominal Pain 11 (5%) 7 (4%) 1 (<1%) Weakness 7 (3%) 5 (2%) 1 (<1%) Xerostomia 4 (2%) 3 (1%) 0 (0%) Central Nervous System: There have been three reports consistent with but not diagnostic of, an extrapyramidal reaction in patients receiving ondansetron. Hepatic: In 723 patients receiving cyclophosphamide-based chemotherapy in US clinical trials, AST and/or ALT values have been reported to exceed twice the upper limit of normal in approximately 1% to 2% of patients receiving oral ondansetron. The increases were transient and did not appear to be related to dose or duration of therapy. On repeat exposure, similar transient elevations in transaminase values occurred in some courses, but symptomatic hepatic disease did not occur. The role of cancer chemotherapy in these biochemical changes cannot clearly be determined. There have been reports of liver failure and death in patients with cancer receiving concurrent medications including potentially hepatotoxic cytotoxic chemotherapy and antibiotics. The etiology of the liver failure is unclear. Integumentary: Rash has occurred in approximately 1% of patients receiving ondansetron. Other: Rare cases of anaphylaxis, bronchospasm, tachycardia, angina (chest pain), hypokalemia, electrocardiographic alterations, vascular occlusive events, and grand mal seizures have been reported. Except for bronchospasm and anaphylaxis, the relationship to Zofran was unclear. Radiation-Induced Nausea and Vomiting: The adverse events reported in patients receiving ondansetron and concurrent radiotherapy were similar to those reported in patients receiving ondansetron and concurrent chemotherapy. The most frequently reported adverse events were headache, constipation, and diarrhea. DRUG ABUSE AND DEPENDENCE: Injection and Tablets Animal studies have shown that ondansetron is not discriminated as a benzodiazepine nor does it substitute for benzodiazepines in direct addiction studies. OVERDOSAGE: Injection and Tablets There is not specific antidote for ondansetron overdose. Patients should be managed with appropriate supportive therapy. Individual doses as large as 145 mg and total daily dosages (three dosages) as large as 252 mg have been administrated intravenously without significant adverse events. These doses are more than 10 times the recommended daily dose. "Sudden blindness" (amaurosis) of 2-3 minutes' duration plus severe constipation occurred in one patient that was administered 72 mg of ondansetron intravenously as a single dose. Hypotension (and faintness) occurred in another patient that took 48 mg of oral ondansetron. In both instances, the events were resolved completely. DOSAGE AND ADMINISTRATION: Injection Cancer Chemotherapy: DILUTE BEFORE USE. Zofran Injection should be diluted in 50 ml of 5% dextrose injection or 0.9% sodium chloride injection before administration. The recommended IV dosage of Zofran Injection is a single 32-mg dose or three 0.15 mg/kg doses. A single 32- mg dose is infused over 15 minutes beginning 30 minutes before the start of emetogenic chemotherapy. The recommended infusion rate should not be exceeded (see OVERDOSAGE). With the three-dose (0.15-mg/kg) regimen, the first dose is infused over 15 minutes beginning 30 minutes before the start of emetogenic chemotherapy. Subsequent doses (0.15 mg/kg) are administered 4 and 8 hours after the first dose of Zofran Injection. Zofran Injection should not be mixed with solutions for which physical and chemical compatibility has not yet been established. In particular, this applies to alkaline solutions as a precipitate may form. Pediatric Use: DILUTE BEFORE USE. On the basis of the limited available information (see CLINICAL PHARMACOLOGY, CLINICAL TRIALS: Pediatric Studies, and Pharmacokinetics), the dosage in children 4 to 18 years of age should be three 0.15-mg/kg doses (see above). Little information is available about dosage in children 3 years of age or younger. Use in the Elderly: DILUTE BEFORE USE. The dosage is the same as for the general population. Prevention of Postoperative Nausea and/or Vomiting: NO DILUTION NECESSARY. Immediately before induction of anesthesia, or postoperatively of the patient experiences nausea and/or vomiting occurring shortly after surgery, administer 4 mg undiluted intravenously in not less than 30 seconds, preferably over 2-5 minutes. repeat dosing for patients who continue to experience nausea and/or vomiting postoperatively has not been studied. While recommended as a fixed dose for all, few patients above 80 kg or below 40 kg have been studied. Pediatric Use: There is no experience with the use of Zofran Injection in the prevention or treatment of postoperative nausea and vomiting in children. Use in the Elderly: NO DILUTION NECESSARY. The dosage recommendation is the same as for the general population. Dosage Adjustments for Patients With Impaired Renal Function: No specific studies have been conducted in patients with renal insufficiency. Dosage Adjustment for Patients with Impaired Hepatic Function: In patients with severe hepatic impairment according to Child-Pugh1 criteria, a single maximal daily dose of 8 mg to be infused over 15 minutes beginning 30 minutes before the start of emetogenic chemotherapy is recommended. There is no experience beyond first-day administration of ondansetron. Stability: Zofran injection is stable at room temperature under normal lighting conditions for 48 hours after dilution with the following IV fluids: 0.9% sodium chloride injection, 5% dextrose injection, 5% dextrose and 0.9% sodium chloride injection, 5% dextrose and 0.45% sodium chloride injection, and 3% sodium chloride injection. Although Zofran Injection is chemically and physically stable when diluted as recommended, sterile precautions should be observed because diluents generally do not contain preservative. After dilution, do not use beyond 24 hours Note: Parenteral drug products should be inspected visually for particulate matter and discoloration before administration whenever solution and container permit. Precaution: Occasionally, ondansetron precipitates at the stopper/vial interface in vials stored upright. Potency and safety are not affected. If a precipitate is observed, resolubilize by shaking the vial vigorously. Tablets Prevention of Nausea and Vomiting Associated With Moderately Emetogenic Cancer Chemotherapy: The recommended oral dosage of Zofran Tablets is one 8-mg tablet given three times a day. The first dose should be administered 30 minutes before the start of emetogenic chemotherapy, with subsequent doses 4 and 8 hours after the first dose. One 8-mg Zofran Tablet should be administered three times a day (every 8 hours) for 1 to 2 days after completion of chemotherapy. Pediatric Use: For patients 12 years of age and older, the dosage is the same as for adults. For patients 4-12 years of age, the recommended oral dosage is one 4-mg tablet given three times a day. The method and frequency of administration is the same as for adults. Use in the Elderly: The dosage is the same as for the general population. Prevention of Nausea and Vomiting Associated With Radiotherapy, Either Total Body Irradiation, or Single High-Dose Fraction or Daily Fractions to the Abdomen: The recommended oral dosage of Zofran Tablets is one 8-mg tablet given three times a day. For total body irradiation, an 8-mg dose should be administered 1 to 2 hours before each fraction of radiotherapy administered each day. For single high-dose fraction radiotherapy to the abdomen, an 8- mg dose should be administered 1 to 2 hours before radiotherapy, with subsequent doses every 8 hours after the first dose for 1 to 2 days after completion of radiotherapy. For daily fractionated radiotherapy to the abdomen, an 8-mg dose should be administered 1 to 2 hours after the first dose for each day radiotherapy is given. Pediatric Use: There is no experience with the use of Zofran Tablets in the prevention of radiation-induced nausea and vomiting in children. Use in the Elderly: The dosage recommendation is the same as for the general population. Dosage Adjustment for Patients With Impaired Renal Function: No specific studies have been conducted in patients with renal insufficiency. Dosage Adjustment for Patients with Impaired Hepatic Function: In patients with severe hepatic insufficiency, clearance is reduced, apparent volume of distribution is increased with a resultant increase in plasma half-life, and bioavailability approaches 100%. In such patients, a total daily dose of 8 mg should not be exceeded. HOW SUPPLIED: Injection Zofran Injection, 2 mg/ml, is supplied in 2-ml single-dose vials (NDC 0173-0442-02) and in 20-ml multidose vials (NDC 0173-0442-00). Tablets Zofran Tablets, 4 mg (ondansetron HCl dihydrate equivalent to 4 mg of ondansetron), are white, oval, film-coated tablets engraved with "Glaxo" on one side and "4" on the other in daily unit dose packs of 3 tablets (NDC 0173-0446-04), bottles of 30 tablets (NDC 0173-0446-00), and unit dose packs of 100 tablets (NDC 0173-0446-02). Zofran Tablets, 8 mg (ondansetron HCl dihydrate equivalent to 8 mg of ondansetron), are yellow, oval, film-coated tablets engraved with "Glaxo" on one side and "8" on the other in daily unit dose packs of 3 tablets (NDC 0173-0447-04), bottles of 30 tablets (NDC 0173-0447-00), and unit dose packs of 100 tablets (NDC 0173-0447-02). Store between 2o and 30oC (36o and 86oF). Protect from light. Store blisters and bottles in carton. REFERENCES: 1. Pugh RNH, Murray-Lyon IM, Dawson JL, Pietroni MC, Williams R. Transection of the oesophagus for bleeding oesophageal varices. Brit J Surg. 1973;60:646-649. (Tablets: Glaxo, 9/94, RL-140) (Injection: Glaxo, 6/94, RL-123) (94/09) HOW SUPPLIED - EQUIVALENTS NOT AVAILABLE: Injection, Solution - Intravenous - 2 mg/ml 2 ml x 5 $103.75ZOFRAN, Glaxo 00173-0442-02 20 ml $214.76ZOFRAN, Glaxo 00173-0442-00 Tablet, Coated - Oral - 4 mg 3's $32.10ZOFRAN, U.D., Glaxo 00173-0446-04 30's $314.70ZOFRAN, Glaxo 00173-0446-00 100's $1070.40ZOFRAN, U.D., Glaxo 00173-0446-02 Tablet, Coated - Oral - 8 mg 3's $53.50ZOFRAN, U.D., Glaxo 00173-0447-04 30's $524.26ZOFRAN, Glaxo 00173-0447-00 100's $1783.20ZOFRAN, U.D., Glaxo 00173-0447-02 --kekale.icsi.net:818438852:757465518:664207401:1902772224-- Next message: Geff klein: "Re: Subarachnoid hemorrhage after delivery" Previous message: Dr MG Schoon - Obst & Gin.: "Subarachnoid hemorrhage after delivery"

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