NDA 20-239/S-008
`Page 3
`
`KYTRIL®
`(granisetron hydrochloride)
`Injection
`
`DESCRIPTION
`KYTRIL (granisetron hydrochloride) Injection is an antinauseant and antiemetic agent. Chemically it
`is en do-N-( 9-methy 1-9-azabicyclo [3. 3.1] non-3-yl)-1-methyl-1 H-indazo l e-3 -carboxamide
`hydrochloride with a molecular weight of 348.9 (312.4 free base). Its empirical formula is
`Cl8H24N40•HCI, while its chemical structure is:
`
`granisetron hydrochloride
`
`Granisetron hydrochloride is a white to off-white solid that is readily soluble in water and normal
`saline at 20°C. KYT~ Injection is a clear, colorless, sterile, nonpyrogenic, aqueous solution for
`intravenous administration.
`
`KYT~ is available in 1 mL single-dose and 4 mL multi-dose vials.
`Single-Dose Vials
`Each 1 mL of preservative-free aqueous solution contains 1.12 mg granisetron hydrochloride
`equivalent to granisetron, I mg and sodium chloride, 9 mg. The solution's pH ranges from 4.7 to 7.3.
`Multi-Dose Vials
`Each 1 mL contains 1.12 mg granisetron hydrochloride equivalent to granisetron, l mg; sodium
`chloride, 9 mg; citric acid, 2 mg; and benzyl alcohol, 10 mg, as a preservative. The solution's pH
`ranges from 4.0 to 6.0.
`CLINICAL PHARMACOLOGY
`Granisetron is a selective 5-hydroxytryptamine3 (5-HT3) receptor antagonist with little or no affinity
`for other serotonin receptors, including 5-HTI; 5-HTIA; 5-HTIB/C; 5-HT2; for alpha!-, alpha2- or
`beta-adrenoreceptors; for dopamine-D2; or for histamine-HI ; benzodiazepine; picrotoxin or opioid
`receptors.
`
`Serotonin receptors of the 5-HT3 type are located peripherally on vagal nerve terminals and centrally
`in the chemoreceptor trigger zone of the area postrema. Dming chemotherapy-induced vomiting,
`mucosal enterochromaffin cells release serotonin, which stimulates 5
`or. Reddy's Laboratories, Ltd., et al.
`vagal afferent discharge and may induce vomiting. Animal studies de
`v.
`HT3 receptors, granisetron blocks serotonin stimulation and subsequ~::
`Helsinn Healthcare S.A., et al.
`U.S. Patent No. 8,729,094
`Reddy Exhibit 1054
`
`

`

`NDA 20-239/S-008
`Page 3
`
`KYTRIL®
`(granisetron hydrochloride)
`Injection
`
`DESCRIPTION
`KYTRIL (granisetron hydrochloride) Injection is an antinauseant and antiemetic agent. Chemically it
`is en do-N-( 9-methy 1-9-azabicyclo [3. 3.1] non-3-yl)-1-methyl-1 H-indazo l e-3 -carboxamide
`hydrochloride with a molecular weight of 348.9 (312.4 free base). Its empirical formula is
`Cl8H24N40•HCI, while its chemical structure is:
`
`granisetron hydrochloride
`
`Granisetron hydrochloride is a white to off-white solid that is readily soluble in water and normal
`saline at 20°C. KYT~ Injection is a clear, colorless, sterile, nonpyrogenic, aqueous solution for
`intravenous administration.
`
`KYT~ is available in 1 mL single-dose and 4 mL multi-dose vials.
`Single-Dose Vials
`Each 1 mL of preservative-free aqueous solution contains 1.12 mg granisetron hydrochloride
`equivalent to granisetron, I mg and sodium chloride, 9 mg. The solution's pH ranges from 4.7 to 7.3.
`Multi-Dose Vials
`Each 1 mL contains 1.12 mg granisetron hydrochloride equivalent to granisetron, l mg; sodium
`chloride, 9 mg; citric acid, 2 mg; and benzyl alcohol, 10 mg, as a preservative. The solution's pH
`ranges from 4.0 to 6.0.
`CLINICAL PHARMACOLOGY
`Granisetron is a selective 5-hydroxytryptamine3 (5-HT3) receptor antagonist with little or no affinity
`for other serotonin receptors, including 5-HTI; 5-HTIA; 5-HTIB/C; 5-HT2; for alpha!-, alpha2- or
`beta-adrenoreceptors; for dopamine-D2; or for histamine-HI ; benzodiazepine; picrotoxin or opioid
`receptors.
`
`Serotonin receptors of the 5-HT3 type are located peripherally on vagal nerve terminals and centrally
`in the chemoreceptor trigger zone of the area postrema. Dming chemotherapy-induced vomiting,
`mucosal enterochromaffin cells release serotonin, which stimulates 5-HT3 receptors. This evokes
`vagal afferent discharge and may induce vomiting. Animal studies demonstrate that, in binding to 5-
`HT3 receptors, granisetron blocks serotonin stimulation and subsequent vomiting after emetogenic
`
`Exh. 1054
`
`

`

`NDA 20-239/S-008
`Page 4
`
`stimuli such as cisplatin. In the ferret animal model, a single granisetron injection prevented vomiting
`due to high-dose cisplatin or arrested vomiting within 5 to 30 seconds.
`
`In most human studies, granisetron has had little effect on blood pressure, heart rate or ECG. No
`evidence of an effect on plasma prola,ctin or aldosterone concentrations has been found in other
`studies.
`
`KYTRIL Injection exhibited no effect on oro-cecal transit time in normal volunteers given a single
`intravenous infusion of 50 meg/kg or 200 meg/kg. Single and multiple oral doses slowed colonic
`transit in normal volunteers.
`Pharmacokinetics
`Chemotherapy-Induced Nausea and Vomiting
`In adult cancer patients undergoing chemotherapy and in volunteers, mean pbarmacokinetic data
`obtained from an infusion of a single 40 meg/kg dose ofKYTRlL Injection are shown in Table I.
`Table 1. Pharmacokinetic Parameters in Adult Cancer Patients Undergoing
`Chemotherapy and in Volunteers, Following a Single Intravenous 40 meg/kg
`Dose of KYTRI L Injection
`Peak Plasma
`Terminal Phase
`Plasma Half-Life
`Concentration
`(h)
`(n2/mL)
`
`Total
`Clearance
`(L/h/k!!)
`
`Volume of
`Distribution
`(L/1<2)
`
`63.8*
`l 8.0tol76
`
`64L3t
`11.2 to182
`
`Cancer Patients
`Mean
`Range
`Volunteers
`21 to 42 years
`Mean
`Range
`65 to 81 years
`57.0(
`Mean
`l4.6to 153
`Range
`*5-mmute mfus10n.
`t3-minute infusion.
`
`8.95*
`0.90 to 3l.l
`
`0.38*
`0.14to 1.54
`
`3.07*
`0.85 to 10.4
`
`4.91t
`0.88 to 15.2
`
`7.69(
`2.65 to 17.7
`
`0.79t
`0.20 to 2.56
`
`3.04t
`1.68 to 6.13
`
`0.44(
`0.17to l.06
`
`3.97t
`1.75 to 7.01
`
`Distribution:
`Plasma protein binding is approximately 65% and granisetron distributes freely between plasma and
`red blood cells.
`Metabolism:
`Granisetron metabolism involves N-demethylation and aromatic ring oxidation followed by
`conjugation. In vitro liver microsomal studies show that granisetron 's major route of metabolism is
`inhibited by ketoconazole, suggestive of metabolism mediated by the cytochrome P-450 3A subfamily.
`Animal studies suggest that some of the metabolites may also have 5-HT 3 receptor antagonist activity.
`Elimination:
`Clearance is predominantly by hepatic metabolism. In normal volunteers, approximately 12% of the
`administered dose is eliminated unchanged in the urine in 48 hours. The remainder of the dose is
`excreted as metabolites, 49% in the urine, and 34% in the feces.
`
`Exh. 1054
`
`

`

`NDA 20-239/S-008
`Page 5
`
`Sub populations
`
`Gender
`There was high inter- and intra-subject variability noted in these studies. No difference in mean AUC
`was found between males and females, although males had a higher Cmax generally.
`Geriatrics
`The ranges of the pharmacokinetic parameters in geriatric volunteers (mean age 71 years), given a
`single 40 meg/kg intravenous dose ofKYTRIL Injection, were generally similar to those in younger
`healthy volunteers; mean values were lower for clearance and longer for half-life in the geriatric
`patients (see Table 1).
`Pediatric Patients
`A pharmacokinetic study in pediatric cancer patients (2 to 16 years of age), given a single 40 meg/kg
`intravenous dose ofKYTRIL Injection, showed that volume of distribution and total clearance
`increased with age. No relationship with age was observed for peak plasma concentration or terminal
`phase plasma half-life. When volume of distribution and total clearance are adjusted for body weight,
`the pharmacokinetics of granisetron are similar in pediatric and adult cancer patients.
`Renal Failure Patients
`Total clearance of granisetron was not affected in patients with severe renal failure who received a
`single 40 meg/kg intravenous dose ofKYTRIL Injection.
`Hepatically Impaired Patients
`A pharmacokinetic study in patients with hepatic impairment due to neoplastic liver involvement
`showed that total clearance was approximately halved compared to patients without hepatic
`impairment. Given the wide variability in pharmacokinetic parameters noted in patients and the good
`tolerance of doses well above the recommended 10 meg/kg dose, dosage adjustment in patients with
`possible hepatic functional impairment is not necessary.
`Postoperative Nausea and Vomiting
`In adult patients (age range, 18 to 64 years) recovering from elective surgery and receiving general
`balanced anesthesia, mean pharmacokinetic data obtained from a single 1-mg dose ofKYTRJL
`Injection administered intravenously over 30 seconds are shown in Table 2.
`Table 2. Pharmacokinetic Parameters in 16 Adult Surgical Patients Following a Single
`Intravenous 1-mg Dose of KYTRIL Injection
`Terminal Phase
`Total
`Volume of
`Plasma Half-life
`Clearance
`Distribution
`(L/h/kg)
`(L/kg)
`(h)
`8.63
`0.28
`2.42
`1.77 to 17.73
`0.07 to 0.71
`0.71 to 4.13
`
`Mean
`Range
`
`The pharmacokinetics of granisetron in patients undergoing surgery were similar to those seen in
`cancer patients undergoing chemotherapy.
`
`Exh. 1054
`
`

`

`NDA 20-239/S-008
`Page 6
`
`CLINICAL TRIALS
`Chemotherapy Induced Nausea and Vomiting
`
`Single-Day Chemotherapy
`Cisplatin-Based Chemotherapy
`In a double-blind, placebo-controlled study in 28 cancer patients, KYTRIL Injection, administered as a
`single intravenous infusion of 40 meg/kg, was significantly more effective than placebo in preventing
`nausea and vomiting induced by cisplatin chemotherapy (see Table 3).
`Table 3. Prevention of Chemotherapy-Induced Nausea and Vomiting- Single-Day
`Cisplatin Therapy 1
`KYTRIL
`Injection
`14
`
`14
`
`Number of Patients
`Response Over 24 Hours
`Complete Response2
`<0.001
`7%
`93%
`No Vomiting
`<0.001
`14%
`93%
`No More Than Mild Nausea
`<0.001
`7%
`93%
`1. Cisplatin administration began within 10 minutes ofKYTRa Injection infusion and continued for
`1.5 to 3.0 hours. Mean cisplatin dose was 86 mg/m2 in the KYTRIL Injection group and 80 mg/m2
`in the placebo group.
`2. No vomiting and no moderate or severe nausea.
`
`Placebo
`
`P-Value
`
`KYTRIL Injection was also evaluated in a randomized dose response study of cancer patients
`receiving cisplatin '2:.75 mg/m2
`. Additional chemotherapeu6c agents included: anthracyclines,
`carboplatin, cytostatic antibiotics, folic acid derivatives, methylhydrazine, nitrogen mustard analogs,
`podophyllotoxin derivatives, pyrimidine analogs, and vinca alkaloids. KYTRIL Injection doses of 10
`and 40 meg/kg were superior to 2 meg/kg in preventing cisplatin-induced nausea and vomiting, but 40
`meg/kg was not significantly superior to 10 meg/kg (see Table 4).
`Table 4. Prevention of Chemotherapy-Induced Nausea and Vomiting- Single-Day
`High,-Dose Cisplatin Therapy1
`KYTRIL Injection
`meg/kg;
`10
`52
`
`2
`52
`
`40
`53
`
`Number of Patients
`Response Over 24 Hours
`Complete Response2
`<0.002 <0.001
`68%
`62%
`31%
`No Vomiting
`<0.001 <0.001
`74%
`65%
`38%
`No More Than Mild Nausea
`0.007
`79%
`75%
`58%
`NS
`..
`1. Ctsplatm admmtstrattOn began wttbm 10 mmutes ofKYTRa lnjectton mfusion and continued for
`2.6 holl.lrs (mean). Mean cisplatin doses were 96 to 99 mg/m2.
`2. No vomiting and no moderate or severe nausea.
`
`P-Value
`( vs. 2 mcg/lkg)
`10
`40
`
`Exh. 1054
`
`

`

`NDA 20-239/S-008
`Page 7
`
`KYTRIL Injection was also evaluated in a double-blind, randomized dose response study of353
`patients stratified for high (2:80 to 120 mg/m2
`
`) or low (50 to 79 mg/m2) cisplatin dose. Response rates
`of patients for both cisplatin strata are given in Table 5.
`Table 5. Prevention of Chemotherapy-Induced Nausea and Vomiting- Single-Day
`High-Dose and Low-Dose Cisplatin Therapy1
`KYTRIL Injection
`P-Value
`(mc2/k2)
`(vs. 5 mc21k2)
`10
`20
`10
`20
`40
`
`40
`
`5
`
`40
`
`18%
`28%
`15%
`
`42
`
`49
`
`41%
`47%
`35%
`
`41
`
`48
`
`40%
`44%
`38%
`
`40
`
`47
`
`47%
`53%
`43%
`
`46
`
`0.018
`NS
`0.036
`
`0.025
`NS
`0.019
`
`0.004
`0.016
`0.005
`
`High-Dose Cisplatin
`Number of Patients
`Response Over 24 Hours
`Complete Response2
`No Vomiting
`No Nausea
`Low-Dose Cisplatin
`Number of Patients
`Response Over 24 Hours
`Complete Response2
`NS
`0.009
`0 .. 012
`41%
`58%
`56%
`29%
`0.012
`43%
`65%
`63%
`36%
`No Vomiting
`0.008
`NS
`NS
`NS
`0.012
`33%
`38%
`56%
`29%
`No Nausea
`1. Cisplatin administration began within 10 minutes ofKYTRU., Injection infusion and continued for 2
`hours (mean). Mean ,cisplatin doses were 64 and 98 mg/m2 for low and high strata.
`2. No vomiting and no use of rescue antiemetic.
`
`For both the low and high cisplatin strata, the 10, 20, and 40 meg/kg doses were more effective than
`the 5 meg/kg dose in preventing nausea and vomiting within 24 hours of chemotherapy administration.
`The 10 meg/kg dose was at least as effective as the higher doses.
`Moderately Emetogenic Chemotherapy
`KYTRIL Injection, 40 meg/kg, was compared with the combination of chlorpromazine (50 to 200
`mg/24 hours) and dexamethasone (12 mg) in patients treated with moderately emeto~enic
`chemotherapy, including primarily carboplatin >300 mg/m2
`, cisplatin 20 to 50 mg/m and
`cyclophosphamide >600 mg/m2
`. KYTRIL Injection was superior to the chlorpromazine regimen in
`preventing nausea and vomiting (see Table 6).
`
`Exh. 1054
`
`

`

`NDA 20-239/S-008
`Page 8
`
`Table 6. Prevention of Chemotherapy-Induced Nausea and Vomiting-Single-Day
`Moderately Emetogenic Chemotherapy
`KYTRIL
`Chlorp romazine•
`In.iection
`133
`
`Number of Patients
`Response Over 24 Hours
`Complete Response2
`68%
`73%
`No Vomiting
`77%
`No More Than Mild Nausea
`1. Patients also received dexamethasone, 12 mg.
`2. No vomiting and no moderate or severe nausea.
`
`P-Value
`
`133
`
`47%
`53%
`59%
`
`<0.001
`<0.001
`<0.001
`
`In other studies of moderately emetogenic chemotherapy, no significant difference in efficacy was
`found between KYTRIL doses of 40 meg/kg and 160 meg/kg.
`Repeat-Cycle Chemotherapy
`In an uncontrolled trial,. 512 cancer patients received KYTRIL Injection, 40 meg/kg, prophylactically,
`for two cycles of chemotherapy, 224 patients received it for at least four cycles, and 108 patients
`received it for at least six cycles. KYTRIL Injection efficacy remained relatively constant over the first
`six repeat cycles, with complete response rates (no vomiting and no moderate or severe nausea in 24
`hours) of60% to 69%. No patients were studied for more than 15 cycles.
`Pediatric Studies
`A randomized double-blind study evaluated the 24-hour response of 80 pediatric cancer patients (age 2
`to 16 years) to KYTRIL Injection 10, 20 or 40 meg/kg. Patients were treated with cisplatin ~60 mg/m 2,
`cytarabine ~3 g/m2, cyclophosphamide ~1 g/m2 or nitrogen mustard ~6 mg/m2 (see Table 7).
`Table 7. Prevention of Chemotherapy-Induced Nausea and Vomiting in Pediatric
`Patients
`
`Number of Patients
`Median Number of Vomiting
`Episodes
`Complete Response Over 24
`H
`.ours
`t
`1. No vomttmg and no moderate or severe nausea.
`
`KYTRIL Injection Dose (meg/k g)
`10
`20
`40
`26
`25
`29
`2
`1
`3
`
`21%
`
`31%
`
`32%
`
`0
`
`0
`
`A second pediatric study compared KYTRIT.- Injection 20 meg/kg to chlorpromazine plus
`dexamethasone in 88 patients treated with ifosfamide ~3 g/m2/day for two or three days. KYTRIL
`Injection was administered on each day of ifosfamide treatment. At 24 hours, 22% ofKYTRIL
`Injection patients achieved complete response (no vomiting and no moderate or severe nausea in 24
`hours) compared with 10% on the chlorpromazine regimen. The median number of vomiting episodes
`with KYTRIT.- Injection was 1.5; with chlorpromazine it was 7.0.
`
`Exho 1054
`
`

`

`NDA 20-239/S-008
`Page 9
`
`Postoperative Nausea and Vomiting:
`
`Prevention of Postoperative Nausea and Vomiting:
`
`The efficacy of KYTRIL Injection for prevention of postoperative nausea and vomiting was evaluated
`in 868 patients, of which 833 were women, 35 men, 484 Caucasians, 348 Asians, 18 Blacks, 18 Other,
`with 61 patients 65 years or older. KYTRIL was evaluated in two randomized, double-blind, placebo-
`controlled studies in patients who underwent elective gynecological surgery or cholecystectomy and
`received general anesthesia. Patients received a single intravenous dose ofKYTRIL Injection
`(0.1 mg, 1 mg, or 3 mg) or placebo either 5 minutes before induction of anesthesia or immediately
`before reversal of anesthesia. The primary endpoint was the proportion of patients with no vomiting for
`24 hours after surgery. Episodes of nausea and vomiting and use of rescue antiemetic therapy were
`recorded for 24 hours after surgery. In both studies, KYTRIL Injection (1 mg) was more effective than
`placebo in preventing postoperative nausea and vomiting (see Table 8). No additional benefit was seen
`in patients who received the 3-mg dose.
`
`Exh. 1054
`
`

`

`NDA 20-239/S-008
`Page 10
`
`Table 8. Prevention of Postoperative Nausea and Vomiting in Adult Patients
`
`Study and Efficacy Endpoint
`
`Placebo
`
`KYTRIL
`0.1 mg
`
`KYTRIL
`1 mg
`
`KYTRIL
`3mg
`
`133
`
`34%
`
`22%
`
`18%
`
`60%
`
`117
`
`56%
`
`37%
`
`132
`
`45%
`
`28%
`
`27%
`
`67%
`
`-
`
`-
`
`-
`
`Study 1
`Number of Patients
`No Vomiting
`0 to 24 hours
`No Nausea
`0 to 24 hours
`No Nausea or Vomiting
`0 to 24 hours
`No Use of Rescue Antiemetic
`Therapy
`0 to 24 hours
`Study 2
`Number of Patients
`No Vomiting
`0 to 24 hours
`No Nausea
`0 to 24 hours
`*P < 0.05
`**P < 0.001 versus placebo
`Note: No Vomiting= no vomiting and no use of rescue antiemetic therapy; No Nausea= no nausea
`and no use of rescue antiemetic therapy
`Gender/Race
`There were too few male and Black patients to adequately assess differences in effect in either
`population.
`
`134
`
`128
`
`63%**
`
`62%**
`
`50%**
`
`49%**
`
`75%*
`
`110
`
`77%**
`
`59%**
`
`42%**
`
`42%**
`
`77%*
`
`114
`
`75%*
`
`56%*
`
`Treatment of Postoperative Nausea and Vomiting:
`
`The efficacy of KYTRIT.., Injection for treatment of postoperative nausea and vomiting was evaluated
`in 844 patients, of which 731 were women, 113 men, 777 Caucasians, 6 Asians, 41 Blacks, 20 Other
`with 107 patients 65 years or older. KYTRIT.., Injection was evaluated in two randomized, double-
`blind, placebo-controlled studies of adult surgical patients who received general anesthesia with no
`prophylactic antiemetic agent, and who experienced nausea or vomiting within 4 hours
`postoperatively. Patients received a single intravenous dose of KYTRIT.., Injection
`(0.1 mg, l mg, or 3 mg) or placebo after experiencing postoperative nausea or vomiting. Episodes of
`nausea and vomiting and use of rescue antiemetic therapy were recorded for 24 hours after
`administration of study medication. KYTRIT.., Injection was more effective than placebo in treating
`postoperative nausea and vomiting (see Table 9). No additiional benefit was seen in patients who
`received the 3-mg dose.
`
`Exh. 1054
`
`

`

`NDA 20-239/S-008
`Page 11
`
`Table 9. Treatment of Postoperative Nausea and Vomiting in Adult Patients
`
`Study and Efficacy Endpoint
`
`Placebo
`
`KYTRIL
`0.1 mg
`
`KYTRIL
`1mg
`
`KYTRIL
`3mg
`
`125
`
`60%***
`49%***
`
`42%***
`37%***
`
`-
`61%***
`
`- --- -- -- --- --
`
`Exh. 1054
`
`133
`
`26%
`20%
`
`17%
`13%
`
`-
`33%
`
`162
`
`-
`20%
`14%
`
`13%
`9%
`
`13%
`9%
`
`-
`24%
`86
`
`21%
`14%
`
`128
`
`133
`
`53%***
`38%***
`
`40%***
`27%**
`
`-
`51%**
`
`58%***
`46%***
`
`41%***
`30%**
`
`-
`61%***
`
`ll63
`
`-
`32%*
`23%*
`
`18%
`14%
`
`18%
`14%
`
`-
`34%*
`103
`
`27%
`20%
`
`-
`
`-
`-
`-
`-
`-
`-
`-
`
`-
`-
`-
`
`-
`-
`
`Study 3
`Number of Patients
`No Vomiting
`0 to 6 hours
`0 to 24 hours
`No Nausea
`0 to 6 hours
`0 to 24 hours
`No Use of Rescue Antiemetic
`Therapy
`0 to 6 hours
`0 to 24 hours
`Study 4
`Number of Patients (All
`Patients)
`No Vomiting
`0 to 6 hours
`0 to 24 hours
`No Nausea
`0 to 6 hours
`0 to 24 hours
`No Nausea or Vomiting
`0 to 6 hours
`0 to 24 hours
`No Use of Rescue Antiemetic
`Therapy
`0 to 6 hours
`0 to 24 hours
`Number of Patients
`(Treated for Vomiting)1
`No Vomiting
`0 to 6 hours
`0 to 24 hours
`* P<0.05
`** p <0.01
`*** P<O.OOl versus placebo.
`1Protocol Specified Analysis: Patients who had vomiting prior to treatment
`Note: No vomiting = no vomiting and no use of rescue antiemetic therapy; No nausea= no nausea and
`no use of rescue antiemetic therapy
`Gender/Race
`There were too few male and Black patients to adequately assess differences in effect in either
`population.
`
`

`

`NDA 20-239/S-008
`Page 12
`
`INDICATIONS AND USAGE
`KYTRlL Injection is indicated for:
`
`• The prevention of nausea and/or vomiting associated with initial and repeat courses of emetogenic
`cancer therapy, including high-dose cisplatin.
`
`• The prevention and treatment of postoperative nausea and vomiting. As with other anti emetics,
`routine prophylaxis is not recommended in 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 during the postoperative period, KYTRlL Injection is recommended even where the
`incidence of postoperative nausea and/or vomiting is low.
`
`CONTRAINDICATIONS
`KYTRIL Injection is contraindicated in patients with known hypersensitivity to the drug or to any of
`its components.
`
`WARNINGS
`Hypersensitivity reactions may occur in patients who have exhibited hypersensitivity to other selective
`5-HT 3 receptor antagonists.
`
`PRECAUTIONS
`KYTRIL is not a drug that stimulates gastric or intestinal peristalsis. It should not be used instead of
`nasogastric suction. The use ofKYTRIL in patients following abdominal surgery or in patients with
`chemotherapy-induced nausea and vomiting may mask a progressive ileus and/or gastric distention.
`
`Drug Interactions
`Granisetron does not induce or inhibit the cytochrome P-450 drug-metabolizing enzyme system. There
`have been no definitive drug-drug interaction studies to examine pharmacokinetic or
`pharmacodynamic interaction with other drugs, but in humans, KYTRJL Injection bas been safely
`administered with drugs representing benzodiazepines, neuroleptics and anti-ulcer medications
`commonly prescribed with antiemetic treatments. KYTRJL Injection also does not appear to interact
`with emetogenic cancer chemotherapies. Because granisetron 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 granisetron.
`Carcinogenesis, Mutagenesis, Impairment of Fertility
`In a 24-month carcinogenicity study, rats were treated orally with granisetron 1, 5 or 50 mg/kg/day (6,
`30 or 300 mg/m2/day). The 50 mg/kg/day dose was reduced to 25 mg/kg/day (150 mg/m2/day) during
`week 59 due to toxicity. For a 50 kg person of average height ( 1.46 m2 bod:i' surface area), these doses
`represent 16, 81 and 405 times the recommended clinical dlose (0.37 mg/m , iv) on a body surface area
`basis. There was a statistically significant increase in the incidence of hepatocellular carcinomas and
`adenomas in males treated with 5 mg/kg/day (30 mg/m2/day, 81 times the recommended human dose
`based on body surface area) and above, and in females treated with 25 mg/kg/day (150 mg/m2/day, 405
`
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`NDA 20-239/S-008
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`
`times the recommended human dose !based on body surface area). No increase in liver tumors was
`observed at a dose of 1 mglkg/day (6 mg/m2/day, 16 times the recommended human dose based on
`body surface area) in males and 5 mg/kg/day (30 mg/m2/day, 81 times the recommended human dose
`based on body surface area) in females. In a 12-month oral toxicity study, treatment with granisetron
`100 mg/kg/day (600 mg/m2/day, 1622 times the recommended human dose based on body surface
`area) produced hepatocellular adenomas in male and female rats while no such tumors were found in
`the control rats. A 24-month mouse carcinogenicity study of granisetron did not show a statistically
`significant increase in tumor incidence, but the study was not conclusive.
`
`Because of the tumor findings in rat studies, KYTRIL Injection should be prescribed only at the dose
`and for the indication recommended (see INDICATIONS AND USAGE and DOSAGE AND
`ADMINISTRATION).
`
`Granisetron was not mutagenic in an in vitro Ames test and mouse lymphoma cell forward mutation
`assay, and in vivo mouse micronucleus test and in vitro and ex vivo rat hepatocyte UDS assays. It,
`however, produced a significant increase in UDS in HeLa cells in vitro and a significant increased
`incidence of cells with polyploidy in an in vitro human lymphocyte chromosomal aberration test.
`
`Granisetron at subcutaneous doses up to 6 mg/kg/day (36 mg/m2/day, 97 times the recommended
`human dose based on body surface area) was found to have no effect on fertility and reproductive
`performance of male and female rats.
`Pregnancy
`Teratogenic Effects. Pregnancy Category B. Reproduction studies have been performed in
`pregnant rats at intravenous doses up to 9 mg/kg/day (54 mg/m2/day, 146 times the recommended
`human dose based on body surface area) and pregnant rabbits at intravenous doses up to 3 mglkg/day
`(35.4 mg/m2/day, 96 times the recommended human dose based on body surface area) and have
`revealed no evidence of impaired fertility or harm to the fetus due to granisetron. There are, however,
`no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are
`not always predictive of human response, this drug should be used during pregnancy only if clearly
`needed.
`Nursing Mothers
`It is not known whether granisetron is excreted in human milk. Because many drugs are excreted in
`human milk, caution should be exercised when KYTRIL Injection is administered to a nursing woman.
`Pediatric Use
`See DOSAGE AND ADMINISTRATION for use in chemotherapy-induced nausea and vomiting in
`pediatric patients 2 to 16 years of age. Safety and effectiveness in pediatric patients under 2 years of
`age have not been established. Safety and effectiveness ofKYTRIL Injection have not been
`established in pediatric patients for the prevention or treatment of postoperative nausea or vomiting.
`
`Geriatric Use
`During chemotherapy clinical trials, 713 patients 65 years of age or older received KYTRIL Injection.
`Effectiveness and safety were similar in patients of various ages
`
`During postoperative nausea and vomiting clinical trials , 168 patients 65 years of age or older, of
`which 47 were 75 years of age or older, received KYTRIL Injection. Clinical studies ofKYTRIL
`Injection did not include sufficient numbers of subjects aged 65 years and over to determine whether
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`NDA 20-239/S-008
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`
`they respond differently from younger subjects. Other reported clinical experience has not identified
`differences in responses between the elderly and younger patients.
`
`ADVERSE REACTIONS
`Chemotherapy-Induced Nausea and Vomiting
`The following have been reported during controlled clinical trials or in the routine management of
`patients. The percentage figures are based on clinical trial experience only. Table 10 g1ves the
`comparative frequencies of the five most commonly reported adverse events (~3%) in patients
`receiving KYTRJL Injection, in single-day chemotherapy trials. These patients received chemotherapy,
`primarily cisplatin, and intravenous fluids during the 24-hour period following KYTRIL Injection
`administration. Events were generally recorded over seven days post-KYTRIL Injection
`administration. In the absence of a placebo group, there is uncertainty as to how many of these events
`should be attributed to KYTRIL, except for headache, which was clearly more frequent than in
`companson groups.
`Table 10. Principal Adverse Events in Clinical Trials - Single-Day Chemotherapy
`Percent of Patients With Event
`Comparatort
`KYTRIL Injection
`40 meg/kg
`(n=422)
`(n=1268)
`14%
`Headache
`6%
`6%
`5%
`Asthenia
`15%
`4%
`Somnolence
`6%
`4%
`Diarrhea
`3%
`3%
`Constipation
`1. Metoclopramide/dexamethasone and phenothiazines/dexamethasone.
`
`In over 3,000 patients receiving KYTRIL Injection (2 to 160 meg/kg) in single-day and multiple-day
`clinical trials with emetogenic cancer therapies, adverse events, other than those in Table 10, were
`observed; attribution of many of these events to KYTRIL is uncertain.
`
`Hepatic: In comparative trials, mainly with cisplatin regimens, elevations of AST and ALT (>2 times
`the upper limit of normal) following administration ofKYTRIL Injection occurred in 2.8% and 3.3%
`of patients, respectively. These frequencies were not significantly different from those seen with
`comparators (AST: 2.1%; ALT: 2.4%).
`
`Cardiovascular: Hypertension (2%); hypotension, arrhythmias such as sinus bradycardia, atrial
`fibrillation, varying degrees of A-V block, ventricular ectopy including non-sustained tachycardia, and
`ECG abnonnalities have been observed rarely.
`
`Central Nervous System: Agitation, anxiety, CNS stimulation and insomnia were seen in less than
`2% of patients. Extrapyramidal syndrome occurred rarely and only in the presence of other drugs
`associated with this syndrome.
`
`Hypersensitivity: Rare cases of hypersensitivity reactions, sometimes severe (eg, anaphylaxis,
`shortness of breath, hypotension, urticaria) have been reported.
`
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`NDA 20-239/S-008
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`
`Other: Fever (3%), taste disorder (2%), skin rashes (1 %). In multiple-day comparative studies, fever
`occurred more frequently with KYTRIL Injection (8.6%) than with comparative drugs (3.4%,
`P<0.014), which usually included dexamethasone.
`Postoperative Naus,ea and Vomiting
`The adverse events listed in Table 11 were reported in 2::2% of adults receiving KYTRIL Injection
`1 mg during controlled clinical trials.
`Table 11. Adverse Events ~2%
`
`Percent of Patients With Event
`KYTRIL I njection
`Placebo
`1 mg
`(n=267)
`10.1
`9.4
`9.4
`8.6
`7.9
`6.0
`5.6
`4.9
`4.5
`4.1
`3.7
`3.4
`3.4
`3.4
`3.0
`3.0
`3.0
`2.6
`2.6
`2.2
`2.2
`
`(n=266)
`8.3
`12.0
`10.2
`7.1
`4.5
`6.0
`4.1
`6.0
`5.3
`3.4
`4.1
`3.8
`3.8
`1.1
`3.0
`2.3
`1.9
`4.1
`3.4
`1.5
`1.1
`
`Pain
`Constipation
`Anemia
`Headache
`Fever
`Abdominal Pain
`Hepatic Enzymes Increased
`Insomnia
`Bradycardia
`Dizziness
`Leukocytosis
`Anxiety
`Hypotension
`Diarrhea
`Flatulence
`Infection
`Dyspepsia
`Hypertension
`Urinary Tract Infection
`Oliguria
`Coughing
`
`In a clinical study conducted in Japan, the types of adverse events differed notably from those reported
`above in Table 11. The adverse events in the Japanese study that occurred in ~2% of patients and were
`more frequent with KYTRIL I mg than with placebo were: fever (56% to 50%), sputum increased
`(2.7% to 1.7%), and dermatitis (2.7% to 0%).
`OVERDOSAGE
`There is no specific antidote for KYTRIL Injection overdosage. In case of overdosage, symptomatic
`treatment should be given. Overdosage of up to 38.5 mg of granisetron hydrochloride injection has
`been reported without symptoms or only the occurrence of a slight headache.
`DOSAGE AND ADMINISTRATION
`Prevention of Chemotherapy-Induced Nausea and Vomiting
`The recommended dosage for KYTRIL Injection is 10 meg/kg administered intravenously within 30
`minutes before initiation of chemotherapy, and only on the day(s) chemotherapy is given.
`
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`
`Infusion Preparation
`KYTRlL Injection may be administered intravenously either undiluted over 30 seconds, or diluted with
`0.9% Sodium Chloride or 5% Dextrose and infused over 5 minutes.
`
`Stability
`Intravenous infusion ofKYTRIL Injection should be prepared at the time of administration. However,
`KYTRlL Injection has been shown to be stable for at least 24 hours when diluted in 0.9% Sodium
`Chloride or 5% Dextrose and stored at room temperature under normal lighting conditions.
`
`As a general precaution, KYTRIL Injection should not be mixed in solution with other drugs.
`Parenteral drug products should be inspected visually for particulate matter and discoloration before
`administration whenever solution and container permit
`
`Pediatric Patients
`The recommended dose in pediatric patients 2 to 16 years of age is 10 meg/kg (see CLINICAL
`TRIALS). Pediatric patients under 2 years of age have not been studied.
`
`Geriatric Patients, Renal Failure Patients or Hepatically Impaired Patients
`No dosage adjustment is recommended (see CLINICAL PHARMACOLOGY: Pharmacokinetics).
`
`Prevention and Treatment of Postoperative Nausea and Vomiting
`The recommended dosage for prevention of postoperative nausea and vomiting is l mg ofKYT~,
`undiluted, administered intravenously over 30 seconds, before induction of anesthesia or immediately
`before reversal of anesthesia.
`The recommended dosage for the treatment of nausea and/or vomiting after surgery is 1 mg of
`KYTRIL, undiluted, administered intravenously over 30 seconds.
`Pediatric Patients
`Safety and effectiveness ofKYTRIL Injection have not been established in pediatric patients for the
`prevention or treatment of postoperative nausea or vomiting.
`
`Geriatric Patients, Renal Failur