FULL PRESCRIBING INFORMATION,1 INDICATIONS AND USAGE. VARUBI is indicated in combination with other antiemetic agents in adults for the prevention of. delayed nausea and vomiting associated with initial and repeat courses of emetogenic cancer. chemotherapy including but not limited to highly emetogenic chemotherapy. 2 DOSAGE AND ADMINISTRATION, Prevention of Nausea and Vomiting Associated with Emetogenic Cancer Chemotherapy. The recommended dosage of VARUBI in adults in combination with a 5 HT3 receptor. antagonist and dexamethasone is shown in Table 1 There is no drug interaction between. rolapitant and dexamethasone so no dosage adjustment for dexamethasone is required. Administer a dexamethasone dose of 20 mg on Day 1 see Clinical Pharmacology 12 3. Administer VARUBI prior to the initiation of each chemotherapy cycle but at no less than 2. week intervals,Administer VARUBI without regards to meals. Table 1 Recommended Dosing Regimen,Day 1 Day 2 Day 3 Day 4. Prevention of Nausea and Vomiting Associated with Cisplatin Based Highly Emetogenic Cancer. Chemotherapy,VARUBI 180 mg None,Approximately 1 to 2 hours prior to. chemotherapy, Dexamethasone 20 mg 8 mg twice 8 mg twice 8 mg twice. 30 min prior to chemotherapy daily daily daily, 5 HT3 receptor See the prescribing information for the co None. antagonist administered 5 HT3 receptor antagonist for. appropriate dosing information, Prevention of Nausea and Vomiting Associated with Moderately Emetogenic Cancer Chemotherapy and. Combinations of Anthracycline and Cyclophosphamide. VARUBI 180 mg None,Approximately 1 to 2 hours prior to. chemotherapy,Dexamethasone 20 mg None,30 min prior to chemotherapy. 5 HT3 receptor See the prescribing information for the co See the prescribing information for the co. administered 5 HT3 receptor antagonist for administered 5 HT3 receptor antagonist for. antagonist appropriate dosing information,appropriate dosing information. 3 DOSAGE FORMS AND STRENGTHS, Tablets 90 mg rolapitant film coated capsule shaped blue tablets debossed with T0101 on one. side and 100 on the other side,Reference ID 3814176. 4 CONTRAINDICATIONS, VARUBI is contraindicated in patients receiving thioridazine a CYP2D6 substrate A significant. increase in plasma concentrations of thioridazine may result in QT prolongation and Torsades de. 5 WARNINGS AND PRECAUTIONS, 5 1 Interaction with CYP2D6 Substrates with a Narrow Therapeutic. The inhibitory effect of VARUBI on CYP2D6 lasts at least for 7 days and may last longer after a. single dose administration of VARUBI see Contraindications 4 Drug Interactions 7 Clinical. Pharmacology 12 3 Avoid use of BRANDNAME in patients who are receiving pimozide a. CYP2D6 substrate An increase in plasma concentrations of pimozide may result in QT. prolongation Monitor for adverse reactions if concomitant use of VARUBI and other CYP2D6. substrates with a narrow therapeutic index cannot be avoided. 6 ADVERSE REACTIONS,6 1 Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions adverse reaction rates. observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials. of another drug and may not reflect the rates observed in clinical practice. The safety of VARUBI was evaluated in approximately 2800 patients in 4 controlled clinical. trials in patients receiving emetogenic cancer chemotherapy VARUBI was given in combination. with a 5 HT3 receptor antagonist and dexamethasone On Day 1 of Cycle 1 of chemotherapy. 1567 patients were treated with VARUBI and 1198 of these patients continued into the optional. multiple cycle extension for up to 6 cycles of chemotherapy The median number of cycles. administered 180 mg of VARUBI was four VARUBI 180 mg was administered to 1294. In Cycle 1 adverse reactions were reported in approximately 7 of patients treated with. VARUBI compared with approximately 6 of patients treated with control therapy The most. common adverse reactions reported with an incidence of 3 and greater than control are listed. in Table 2 and Table 3, Table 2 Most Common Adverse Reactions in Patients Receiving Cisplatin Based. Highly Emetogenic Chemotherapy Cycle 1,VARUBI Regimen Control. VARUBI Dexamethasone and 5HT3 Placebo Dexamethasone and. Receptor Antagonist 5HT3 Receptor Antagonist,N 624 N 627. Neutropenia 9 8,Reference ID 3814176,VARUBI Regimen Control. VARUBI Dexamethasone and 5HT3 Placebo Dexamethasone and. Receptor Antagonist 5HT3 Receptor Antagonist,N 624 N 627. Hiccups 5 4,Abdominal Pain 3 2, all reactions occurring at 3 in the VARUBI group and for which the rate for VARUBI exceeds the rate for. Table 3 Most Common Adverse Reactions in Patients Receiving Moderately. Emetogenic Chemotherapy and Combinations of Anthracycline and. Cyclophosphamide Cycle 1,VARUBI Regimen Control, VARUBI Dexamethasone and 5HT3 Placebo Dexamethasone and. Receptor Antagonist 5HT3 Receptor Antagonist,N 670 N 674. Decreased appetite 9 7,Neutropenia 7 6,Dizziness 6 4. Dyspepsia 4 2,Urinary tract infection 4 3,Stomatitis 4 2. Anemia 3 2, all reactions occurring at 3 in the VARUBI group and for which the rate for VARUBI exceeds the rate for. Adverse reactions in the multiple cycle extensions of highly and moderately emetogenic. chemotherapy studies for up to 6 cycles of chemotherapy were generally similar to that. observed in Cycle 1,7 DRUG INTERACTIONS,7 1 Effect of VARUBI on Other Drugs. Rolapitant is not an inhibitor or inducer of CYP3A4 Therefore no dosage adjustment for. dexamethasone CYP3A4 substrate is needed when co administered with VARUBI see Dosage. and Administration 2, Rolapitant is a moderate CYP2D6 inhibitor an inhibitor of Breast Cancer Resistance Protein. BCRP and an inhibitor of P glycoprotein P gp Clinical Pharmacology 12 3. Reference ID 3814176, CYP2D6 Substrates with a Narrow Therapeutic Index Increased plasma concentration of. CYP2D6 substrates may result in potential adverse reactions A three fold increase in the. exposure of dextromethorphan a CYP2D6 substrate was observed 7 days after a single dose of. VARUBI The duration of CYP2D6 inhibition was not studied beyond 7 days and may last. longer Clinical Pharmacology 12 3 Concomitant use with Thioridazine is contraindicated. see Contraindications 4 Avoid use of VARUBI with pimozide see Warnings and. Precautions 5 1 Monitor for QT prolongation if concomitant use with pimozide cannot be. avoided Monitor for adverse reactions if concomitant use with CYP2D6 substrates with a. narrow therapeutic index cannot be avoided, BCRP Substrates with a Narrow Therapeutic Index e g Methotrexate topotecan or irinotecan. Increased plasma concentrations of BRCP substrates may result in potential adverse reactions. Monitor for adverse reactions related to the concomitant drug if use of VARUBI cannot be. avoided Use the lowest effective dose of rosuvastatin see prescribing information for additional. information on recommended dosing, P gp Substrates with a Narrow Therapeutic Index Increased plasma concentrations of digoxin. or other P gp substrates may result in potential adverse reactions see Clinical Pharmacology. 12 3 Monitor for increased digoxin concentrations Monitor for adverse reactions if. concomitant use of VARUBI with other P gp substrates with a narrow therapeutic index cannot. be avoided,7 2 Effect of Other Drugs on VARUBI, Strong CYP3A4 Inducers e g rifampin significantly reduced plasma concentrations of. rolapitant can decrease the efficacy of VARUBI avoid use of VARUBI in patients who require. chronic administration of such drugs,8 USE IN SPECIFIC POPULATIONS. 8 1 Pregnancy,Risk Summary, There are no available data on VARUBI use in pregnant women to inform any drug associated. risks In animal reproduction studies there were no teratogenic or embryo fetal effects observed. with oral administration of rolapitant hydrochloride in rats and rabbits during the period of. organogenesis at doses up to 1 2 times and 2 9 times respectively the maximum recommended. human dose MRHD see Data In the U S general population the estimated background risk. of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4 and 15 to. 20 respectively,Animal Data, The potential embryo fetal toxicity of rolapitant hydrochloride was assessed in pregnant rats. administered oral doses equivalent to up to 22 5 mg kg per day rolapitant free base throughout. organogenesis Rats administered doses equivalent to 13 5 or 22 5 mg kg per day rolapitant free. Reference ID 3814176, base exhibited evidence of maternal toxicity including decreased body weight gain and or body. weight loss and a concomitant decrease in food consumption during the first week of dosing No. teratogenic or embryo fetal effects were observed at doses equivalent to up to 22 5 mg kg per. day rolapitant free base approximately 1 2 times the recommended human dose on a body. surface area basis In rabbits administered rolapitant hydrochloride throughout the period of. organogenesis oral doses equivalent to up to 27 mg kg per day rolapitant free base. approximately 2 9 times the recommended human dose on a body surface area basis were. without effects on the developing fetus, The pre and postnatal developmental effects of rolapitant hydrochloride were assessed in rats. administered oral doses equivalent to 2 25 9 or 22 5 mg kg per day rolapitant free base during. the periods of organogenesis and lactation Maternal toxicity was evident based on. mortality moribund condition decreased body weight and food consumption total litter loss. prolonged parturition decreased length of gestation and increased number of unaccounted for. implantation sites at a dose equivalent to 22 5 mg kg per day free base approximately 1 2 times. the recommended human dose on a body surface area basis Effects on offspring at this dose. included decreased postnatal survival and decreased body weights and body weight gain and. may be related to the maternal toxicity observed At a maternal dose equivalent to 9 mg kg per. day rolapitant free base approximately 0 5 times the recommended human dose on a body. surface area basis there was a decrease in memory in female pups in a maze test and a decrease. in pup body weight,8 2 Lactation,Risk Summary, There are no data on the presence of rolapitant in human milk the effects of rolapitant in the. breastfed infant or the effects of rolapitant on milk production Rolapitant hydrochloride. administered orally to lactating female rats was present in milk see Data The developmental. and health benefits of breastfeeding should be considered along with the mother s clinical need. for B RAND N AME and any potential adverse effects on the breastfed infant from VARUBI or. from the underlying maternal condition or the use of concomitant chemotherapy. Radioactivity from labeled 14C rolapitant hydrochloride was transferred into milk of lactating. rats following a single oral dose equivalent to 22 5 mg kg rolapitant free base and the maximum. radioactivity in milk was observed at 12 hours post dose The mean milk plasma radioactivity. concentration ratios in dams at 1 to 48 hours post dose ranged from 1 24 to 3 25 Based on. average daily consumption of milk 2 mL day and the maximum milk radioactivity determined. pup exposure is expected to be 0 32 of the orally administered dose. 8 4 Pediatric Use, Safety and efficacy of VARUBI have not been established in pediatric patients. Reference ID 3814176,8 5 Geriatric Use, Of the 1294 subjects treated with VARUBI 25 were 65 years and over while 5 were 75 and. over No overall differences in safety or efficacy were reported between the elderly subjects and. younger subjects but greater sensitivity of some older individuals cannot be ruled out. 8 6 Hepatic Impairment, No dosage adjustment is needed in patients with mild Child Pugh Class A or moderate Child. Pugh Class B hepatic impairment There are no clinical or pharmacokinetic data in patients. with severe hepatic impairment Child Pugh Class C Avoid use of VARUBI in patients with. severe hepatic impairment If use cannot be avoided monitor patients for adverse reactions. related to rolapitant see Adverse Reactions 6 1,10 OVERDOSAGE. There are no data on overdose with VARUBI, There is no antidote for VARUBI overdose Discontinue VARUBI in the event of overdose and. institute general supportive measures and close observation. 11 DESCRIPTION, VARUBI tablets contain 90 mg rolapitant equivalent to 100 mg rolapitant hydrochloride a. substance P neurokinin 1 NK1 receptor antagonist Rolapitant hydrochloride is chemically. described as 5S 8S 8 1R 1 3 5 bis trifluoromethyl phenyl ethoxy methyl 8 phenyl. 1 7 diazaspiro 4 5 decan 2 one monohydrochloride monohydrate Its empirical formula is. C25H26F6N2O2 HCl H2O and its structural formula is. rolapitant hydrochloride, Rolapitant hydrochloride is a white to off white powder with a molecular weight of 554 95. Solubility of rolapitant hydrochloride in aqueous solution is pH dependent and is more soluble at. lower pH Rolapitant hydrochloride has good solubility in common pharmaceutical solvents such. as ethanol propylene glycol and 40 hydroxypropyl beta cyclodextrin. Each tablet for oral administration contains 90 mg rolapitant and the following inactive. ingredients lactose monohydrate pregelatinized starch microcrystalline cellulose povidone. croscarmellose sodium colloidal silicon dioxide and magnesium stearate The tablets are coated. in non functional blue and clear coats The tablet coating comprises the following inactive. Reference ID 3814176, ingredients polyvinyl alcohol titanium dioxide polyethylene glycol talc FD C Blue No 2. Indigo Carmine Lake and polysorbate 80,12 CLINICAL PHARMACOLOGY. 12 1 Mechanism of Action, Rolapitant is a selective and competitive antagonist of human substance P NK1 receptors. Rolapitant does not have significant affinity for the NK2 or NK3 receptors or for a battery of. other receptors transporters enzymes and ion channels Rolapitant is also active in animal. models of chemotherapy induced emesis,12 2 Pharmacodynamics. NK1 Receptor Occupancy, A human Positron Emission Tomography PET study with rolapitant demonstrated that. rolapitant crosses the blood brain barrier and occupies brain NK1 receptors A dose dependent. increase in mean NK1 receptor occupancy was observed in the dose range from 4 5 mg to 180. mg of rolapitant At the 180 mg dose of rolapitant the mean NK1 receptor occupancy was 73. in the striatum at 120 hours after a single dose administration in healthy subjects The. relationship between NK1 receptor occupancy and the clinical efficacy of rolapitant has not been. established,Cardiac Electrophysiology, In a thorough QT study rolapitant at doses up to four times higher than the recommended dose. had no significant effects on the QT intervals,12 3 Pharmacokinetics. Absorption, Following a single dose administration of 180 mg VARUBI under fasting conditions to healthy. subjects rolapitant was measurable in plasma between 30 minutes and the peak plasma. concentration Cmax for rolapitant was reached in about 4 hours and mean Cmax was 968. ng mL CV 28, Following multiple oral doses 9 to 45 mg once daily of rolapitant accumulation of rolapitant was. approximately 5 fold, The systemic exposures Cmax and AUC to rolapitant increased in a dose proportional manner. when the dose of rolapitant increased from 4 5 mg to 180 mg With an increase in dose by four. times from the recommended clinical dose of 180 mg the Cmax and AUC of rolapitant increased. by 3 1 fold and 3 7 fold respectively, Concomitant administration of a high fat meal did not significantly affect the pharmacokinetics. of rolapitant after administration of 180 mg VARUBI see Dosage and Administration 2. Distribution,Reference ID 3814176, Rolapitant was highly protein bound to human plasma 99 8 The apparent volume of. distribution Vd F was 460 L in healthy subjects indicating an extensive tissue distribution of. rolapitant In a population pharmacokinetic analysis of rolapitant the Vd F was 387 L in cancer. Elimination, Following single oral doses 4 5 to 180 mg of rolapitant the mean terminal half life t1 2 of. rolapitant ranged from 169 to 183 hours approximately 7 days and was independent of dose In. a population pharmacokinetic analysis the apparent total clearance CL F of rolapitant was 0 96. L hour in cancer patients,Metabolism, Rolapitant is metabolized primarily by CYP3A4 to form a major active metabolite M19 C4. pyrrolidine hydroxylated rolapitant In a mass balance study the metabolite M19 was the major. circulating metabolite The formation of M19 was significantly delayed with the median Tmax. of 120 hours range 24 168 hours and the mean half life of M19 was 158 hours. The exposure ratio of M19 to rolapitant was approximately 50 in plasma. Rolapitant is eliminated primarily through the hepatic biliary route Following administration of. a single oral 180 mg dose of 14C rolapitant on average 14 2 range 9 to 20 and 73. range 52 to 89 of the dose was recovered in the urine and feces respectively over 6 weeks. In pooled samples collected over 2 weeks 8 3 of the dose was recovered in the urine primarily. as metabolites and 37 8 of the dose was recovered in the feces primarily as unchanged. rolapitant Unchanged rolapitant or M19 were not found in pooled urine sample. Specific Populations,Age Sex and Race Ethnicity, Population pharmacokinetic analyses indicated that age sex and race had no significant impact. on the pharmacokinetics of rolapitant,Hepatic Impairment. Following administration of a single dose of 180 mg rolapitant to patients with mild hepatic. impairment Child Pugh Class A the pharmacokinetics of rolapitant were comparable with. those of healthy subjects In patients with moderate hepatic impairment Child Pugh Class B. the mean Cmax was 25 lower while mean AUC of rolapitant was similar compared to those of. healthy subjects The median Tmax for M19 was delayed to 204 hours in patients with mild or. moderate hepatic impairment compared to 168 hours in healthy subjects The pharmacokinetics. of rolapitant was not studied in patients with severe hepatic impairment Child Pugh Class C. see Use in Specific Population 8 6,Renal Impairment. In population pharmacokinetic analyses creatinine clearance CLcr at baseline did not show a. significant effect on rolapitant pharmacokinetics in cancer patients with mild CLcr 60 to 90. mL min or moderate CLcr 30 to 60 mL min renal impairment compared to cancer patients. with normal kidney function Information is insufficient for the effect of severe renal. Reference ID 3814176, impairment The pharmacokinetics of rolapitant was not studied in patients with end stage renal. disease requiring hemodialysis,Drug Interaction Studies. Effect of Other Drugs on VARUBI,Rolapitant is a substrate for CYP3A4. CYP3A4 inducers, Concomitant administration of a CYP3A4 inducer significantly decreased the systemic exposure. to rolapitant When 600 mg rifampin was administered once daily for 7 days before and 7 days. after administration of a single dose of 180 mg rolapitant the mean Cmax of rolapitant was. reduced by 30 and the mean AUC was reduced by 85 compared to administration of. rolapitant alone The mean half life of rolapitant decreased from 176 hours without rifampin to. 41 hours with concurrent rifampin see Drug Interactions 7. CYP3A4 inhibitors, No clinically significant effect was seen on the pharmacokinetics of rolapitant when. ketoconazole a strong CYP3A4 inhibitor was administered with rolapitant Concurrent. administration of 400 mg ketoconazole once daily for 21 days following a single 90 mg dose of. rolapitant did not significantly affect the Cmax of rolapitant while the AUC increased by 21. Effect of VARUBI on Other Drugs, The effect of VARUBI on CYP450 enzymes and transporters is summarized below See Table 4. for a summary of the effects of the clinical dose of VARUBI on the pharmacokinetics of co. administered drugs,CYP3A4 substrates, Rolapitant is neither an inhibitor nor an inducer of CYP3A4. Midazolam A single dose 180 mg rolapitant had no significant effects on the pharmacokinetics. of midazolam when oral midazolam 3 mg was co administered on Day 1 and administered alone. on Days 6 and 9, Ondansetron Rolapitant had no significant effects on the pharmacokinetics of intravenous. ondansetron when concomitantly administered with a single 180 mg dose of rolapitant on the. Dexamethasone Rolapitant had no significant effects on the pharmacokinetics of. dexamethasone when oral dexamethasone was administered on Days 1 to 3 after a single 180 mg. dose of rolapitant was co administered on Day 1 see Dosage and Administration 2. CYP2D6 substrates, Rolapitant is a moderate inhibitor of CYP2D6 see Contraindications 4 Warning and. Precautions 5 1 Drug Interactions 7,BCRP transporter. Rolapitant is an inhibitor of BCRP transporter see Drug Interactions 7. P glycoprotein substrates,Reference ID 3814176, Rolapitant is an inhibitor of P gp transporter see Drug Interactions 7. Substrates for other CYP enzymes, In vitro studies suggest that rolapitant is not an inhibitor of CYP1A2 and CYP2E1 A clinically. meaningful drug interaction via an inhibition of CYP2A6 appears unlikely based on in vitro. No clinically significant interaction was seen on the pharmacokinetics of the following drugs. when administered with a single dose of 180 mg rolapitant on Day 1 and without rolapitant on. Day 8 repaglinide CYP2C8 substrate no effect on repaglinide 0 25 mg on Day 1 on Day 8. 29 and 24 increase in Cmax and AUC respectively efavirenz CYP2B6 substrate 18. decrease in Cmax and no effect on AUC of efavirenz 600 mg on Day 1 on Day 8 no effect on. Cmax and 28 increase in AUC tolbutamide CYP2C9 substrate no effect on tolbutamide 500. mg on Day 1 and on Day 8 or omeprazole CYP2C19 substrate 44 increase in Cmax and. 23 increase in AUC of omeprazole 40 mg on Day 1 on Day 8 37 and 15 increase in Cmax. and AUC respectively, Table 4 Effect of VARUBI on the Pharmacokinetics of Coadministered Drugs. Co administered drug Change for Coadministered Drug. Enzyme Day 1 with rolapitant Day 8 without rolapitant. transporter,Change in Change in Change in Change in. Cmax AUC Cmax AUC,CYP2D6 Dextromethorphan 30mg 120 160 180 230. BCRP Sulfasalazine 500 mg 140 130 17 32,P gp Digoxin 0 5 mg 70 30 n a n a. A single dose of 180 mg rolapitant was administered on day 1 the interacting drug was administered on day 1 with. rolapitant and alone on day 8, Denotes an average increase in exposure by the percentage indicated. n a Not studied,13 NONCLINICAL TOXICOLOGY, 13 1 Carcinogenesis Mutagenesis Impairment of Fertility. Carcinogenic potential of rolapitant hydrochloride was assessed in 2 year carcinogenicity studies. in CD 1 mice and Sprague Dawley rats In mice there were no drug related neoplastic findings. at doses equivalent to up to 135 mg kg per day rolapitant free base approximately 3 6 times the. recommended human dose on a body surface area basis In rats there were no drug related. neoplastic findings at doses equivalent to up to 90 mg kg per day rolapitant free base. approximately 4 9 times the recommended human dose on a body surface area basis. Rolapitant hydrochloride was not genotoxic in an Ames test a human peripheral blood. lymphocyte chromosome aberration test and a mouse micronucleus test. In a fertility and early embryonic development study in female rats rolapitant hydrochloride at. an oral dose equivalent to 9 mg kg per day free base approximately 0 5 times the recommended. Reference ID 3814176, human dose on a body surface area basis caused a transient decrease in maternal body weight. gain and increases in the incidence of pre and post implantation loss At a dose equivalent to 4 5. mg kg per day free base approximately 0 2 times the recommended human dose on a body. surface area basis there were slight decreases in the number of corpora lutea and implantation. sites Rolapitant hydrochloride did not affect the fertility or general reproductive performance of. male rats at doses equivalent to up to 90 mg kg per day rolapitant free base approximately 4 9. times the recommended human dose on a body surface area basis. 14 CLINICAL STUDIES, Cisplatin Based Highly Emetogenic Chemotherapy HEC. In two multicenter randomized double blind parallel group controlled clinical studies Study 1. and Study 2 the VARUBI regimen VARUBI granisetron and dexamethasone was compared. with control therapy placebo granisetron and dexamethasone in patients receiving a. chemotherapy regimen that included cisplatin 60 mg m2 See Table 5 for the treatment. Table 5 Treatment Regimens in Studies 1 and 2,Day 1 Day 2 to 4. VARUBI Regimen,180 mg none,Oral VARUBI,Oral Dexamethasone 8 mg twice daily. Intravenous Granisetron none,Control Regimen,Oral Dexamethasone 8 mg twice daily. Intravenous Granisetron none,VARUBI placebo was used to maintain blinding. VARUBI was administered 1 to 2 hours prior to chemotherapy treatment on Day 1. Dexamethasone was administered 30 minutes prior to chemotherapy on Day 1 There is no drug interaction. between VARUBI and dexamethasone so no dosage adjustment for dexamethasone is required see Clinical. Pharmacology 12 3, The dose of granisetron was administered 30 minutes prior to chemotherapy on Day 1. A total of 532 patients were randomized to either the VARUBI regimen N 266 or control. therapy N 266 A total of 526 patients were included in the evaluation of efficacy Of those. randomized 42 were women 58 men 67 White 23 Asian 1 Black and 9 multi. racial other unknown The proportion of patients from North America was 16 Patients in this. clinical study ranged from 20 to 90 years of age with a mean age of 57 years In Study 1 26 of. patients were 65 years or older with 3 of patients being 75 years or older The mean cisplatin. dose was 77 mg m2,Reference ID 3814176, During this study 82 of the patients received a concomitant chemotherapeutic agent in. addition to protocol mandated cisplatin The most common concomitant chemotherapeutic. agents administered during Cycle 1 were gemcitabine 17 paclitaxel 12 fluorouracil. 11 etoposide 10 vinorelbine 9 docetaxel 9 pemetrexed 7 doxorubicin 6. and cyclophosphamide 5, A total of 555 patients were randomized to either the VARUBI regimen N 278 or control. therapy N 277 A total of 544 patients were included in the evaluation of efficacy Of those. randomized 32 were women 68 men 81 White 14 Asian 1 Black and 5 multi. racial other unknown The proportion of patients from North America was 7 Patients in this. clinical study ranged from 18 to 83 years of age with a mean age of 58 years In this study 27. of patients were 65 years or older with 3 of patients being 75 years or older The mean. cisplatin dose was 76 mg m2, During this study 85 of the patients received a concomitant chemotherapeutic agent in. addition to protocol mandated cisplatin The most common concomitant chemotherapeutic. agents administered during Cycle 1 were vinrorelbine 16 gemcitabine 15 fluorouracil. 12 etoposide 11 pemetrexed 9 docetaxel 7 paclitaxel 7 epirubicin 5 and. capecitabine 4, The primary endpoint in both studies was complete response defined as no emetic episodes and. no rescue medication in the delayed phase 25 to 120 hours of chemotherapy induced nausea. and vomiting, Moderately Emetogenic Chemotherapy and Combinations of Anthracycline and. Cyclophosphamide Chemotherapy, In Study 3 a multicenter randomized double blind parallel group controlled clinical study in. moderately emetogenic chemotherapy MEC the VARUBI regimen VARUBI granisetron and. dexamethasone was compared with control therapy placebo granisetron and dexamethasone. in patients receiving a moderately emetogenic chemotherapy regimen that included at least 50. of patients receiving a combination of anthracycline and cyclophosphamide The percentage of. patients who received carboplatin in Cycle 1 was 30 Treatment regimens for the VARUBI and. control arms are summarized in Table 6,Table 6 Treatment Regimens in Study 3. Day 1 Day 2 to 3,VARUBI Regimen,180 mg none,Oral VARUBI. Reference ID 3814176,Oral Dexamethasone none,Oral Ganisetron 2 mg once daily. Control Regimen,Oral Dexamethasone none,Oral Ganisetron 2 mg once daily. VARUBI placebo was used to maintain blinding, VARUBI was administered 1 to 2 hours prior to chemotherapy treatment on Day 1. Dexamethasone was administered 30 minutes prior to chemotherapy on Day 1 There is no drug interaction. between VARUBI and dexamethasone so no dosage adjustment for dexamethasone is required see Clinical. Pharmacology 12 3, The dose of ganisetron was administered 30 minutes prior to chemotherapy on Day 1. A total of 1369 patients were randomized to either the VARUBI regimen N 684 or control. therapy N 685 A total of 1332 patients were included in the evaluation of efficacy Of those. randomized 80 were women 20 men 77 White 13 Asian 4 Black and 6 multi. racial other unknown The proportion of patients from North America was 33 Patients in this. clinical study ranged from 22 to 88 years of age with a mean age of 57 years In this study 28. of patients were 65 years or older with 7 of patients being 75 years or older. The primary endpoint was complete response defined as no emetic episodes and no rescue. medication in the delayed phase 25 to 120 hours of chemotherapy induced nausea and. A summary of the study results from HEC Studies 1 and 2 and for the MEC Study 3 is shown in. Table 7 Percent of Patients Receiving Emetogenic Chemotherapy Responding by. Treatment Group for the HEC Studies 1 and 2 and for the MEC Study 3. Endpoint HEC Study 1 HEC Study 2 MEC Study 3,P Value P Value P Value. Treatment Treatment VARUBI Control Treatment,VARUBI Control Difference VARUBI Control. N 264 N 262 N 271 N 273 Difference N 666 N 666 Difference. Rate Rate 95 C I Rate Rate 95 C I Rate Rate 95 C I. Primary 72 7 58 4 0 001 70 1 61 9 0 043 71 3 61 6 0 001. Complete 14 3 8 2 0 3 9 8 4 7,Response 6 3 22 4 16 1 14 8. Granisetron and dexamethasone were used as concomitant drugs. Results were obtained based on the Cochran Mantel Haenszel test stratified by gender. Multiple Cycle Extension In Studies 1 2 and 3 patients had the option of continuing into a. multiple cycle extension for up to 5 additional cycles of chemotherapy receiving the same. treatment as assigned in cycle 1 At day 6 to 8 following initiation of chemotherapy patients. Reference ID 3814176, were asked to recall whether they had any episode of vomiting or retching or nausea that. interfered with normal daily life The results are summarized by study and treatment group in the. figure below, Figure 1 No Emesis and No Nausea Interfering with Daily Life over Cycles 2 6.
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