LOTRONEX alosetron HCl Tablets:

1
LOTRONEX(alosetron HCl) Tablets

• Understanding the Benefits and Risks

PROMETHEUS, LOTRONEX, the LOTRONEX design mark,
and the Prescribing Program for LOTRONEX are
trademarks or registered trademarks of Prometheus
Laboratories Inc. Please see complete
Prescribing Information for LOTRONEX.
2
Table of Contents

• Section 1 Purpose 3
• Section 2 Indication and Usage 5
• Section 3 Important Safety Information 9
• Section 4 Ischemic Colitis 27
• Section 5 Clinical Update Information 36
• Section 6 Review of Efficacy 38
• Section 7 Mechanism of Action and
  Pharmacokinetics 52
• Section 8 How to Prescribe and
  Dispense LOTRONEX (alosetron HCl) Tablets 62
• Section 9 Prescribing Program for LOTRONEX 67

3
Section 1

• Purpose

4
Purpose of Educational Slide Set for LOTRONEX
(alosetron HCl)

• By reviewing this educational material for
  LOTRONEX, healthcare professionals should be able
  to understand
• Indication and usage
• The restricted conditions of use
• Important safety information
• The efficacy in women with chronic, severe
  diarrhea-predominant irritable bowel syndrome
  (IBS-D)
• The Prescribing Program for LOTRONEX

5
Section 2

• Indication and Usage

6
LOTRONEX (alosetron HCl) Indication and Usage

• Only for women with severe diarrhea-predominant
  IBS who have
• Chronic IBS symptoms (generally lasting 6 months
  or longer)
• Had anatomic or biochemical abnormalities of the
  GI tract excluded, and
• Not responded adequately to conventional therapy

7
LOTRONEX (alosetron HCl) Indication and Usage
(contd)

• For the purposes of prescribing LOTRONEX, IBS-D
  is severe if it includes diarrhea and at least
  one of the following
• Frequent and severe abdominal pain/discomfort
• Frequent bowel urgency or fecal incontinence
• Disability or restriction of daily activities due
  to IBS
• Because of infrequent but serious GI adverse
  events associated with LOTRONEX, the indication
  is restricted to those patients for whom the
  benefit-to-risk balance is most favorable
• Currently LOTRONEX is not indicated for use in men

8
Severe IBS in Literature

• Published clinical and epidemiologic literature
  on severe/refractory IBS was reviewed to evaluate
  the definition of severe IBS
• Severe/refractory IBS is not consistently defined
  in the literature
• GlaxoSmithKline/FDA have developed a definition
  for severe diarrhea-predominant IBS

9
Section 3

• Important Safety Information

10
LOTRONEX (alosetron HCl) Boxed Warning

• Warning Infrequent but serious gastrointestinal
  adverse events have been reported with the use of
  LOTRONEX. These events, including ischemic
  colitis and serious complications of
  constipation, have resulted in hospitalization,
  and rarely, blood transfusion, surgery, and
  death.
• The Prescribing Program for LOTRONEX was
  implemented to help reduce risks of serious
  gastrointestinal adverse events. Only physicians
  who have enrolled in the Prescribing Program for
  LOTRONEX, based on their understanding of the
  benefits and risks, should prescribe LOTRONEX.

11
LOTRONEX (alosetron HCl) Boxed Warning (contd)

• LOTRONEX is indicated only for women with severe
  diarrhea-predominant IBS who have not responded
  adequately to conventional therapy. Before
  receiving the initial prescription for LOTRONEX,
  the patient must read and sign the
  Patient-Physician Agreement for LOTRONEX.
• LOTRONEX should be discontinued immediately in
  patients who develop constipation or symptoms of
  ischemic colitis. Patients should immediately
  report constipation or symptoms of ischemic
  colitis to their physician. LOTRONEX should not
  be resumed in patients who develop ischemic
  colitis. Patients who have constipation should
  immediately contact their physician if the
  constipation does not resolve after LOTRONEX is
  discontinued. Patients with resolved constipation
  should resume LOTRONEX only on the advice of
  their treating physician.

12
LOTRONEX (alosetron HCl) Warnings

• Some patients have experienced the following
  without warning
• Constipation
• Serious complications of constipation
• Clinical trials obstruction, ileus, impaction,
  toxic megacolon, and secondary bowel ischemia
• Postmarketing In addition to the above, rarely,
  intestinal perforation and death
• In some cases, complications of constipation
  required intestinal surgery, including colectomy

13
LOTRONEX (alosetron HCl) Warnings (contd)

• Constipation (contd)
• In IBS clinical trials
• 10 of patients on LOTRONEX withdrew prematurely
  because of constipation
• Incidence of serious complications of
  constipation in women who received either
  LOTRONEX or placebo was approximately 1 per 1,000
  patients
• Patients who are elderly, debilitated, or taking
  additional medications that decrease GI motility
  may be at greater risk for complications of
  constipation
• LOTRONEX should be discontinued immediately in
  patients who develop constipation

14
LOTRONEX (alosetron HCl) Warnings (contd)

• Ischemic Colitis
• Ischemic colitis has been reported in patients
  receiving LOTRONEX in clinical trials as well as
  during marketed use of the drug
• In IBS clinical trials
• Cumulative incidence of ischemic colitis in women
  receiving LOTRONEX was
• 0.2, or 2 per 1,000 patients (95 CI 1-3), over
  3 months
• 0.3, or 3 per 1,000 patients (95 CI 1-4), over
  6 months
• Patient experience in controlled clinical trials
  is insufficient to estimate the incidence of
  ischemic colitis in patients taking LOTRONEX for
  longer than 6 months

15
LOTRONEX (alosetron HCl) Warnings (contd)

• Ischemic Colitis (contd)
• LOTRONEX should be discontinued immediately in
  patients with signs of ischemic colitis such as
  rectal bleeding, bloody diarrhea, or new or
  worsening abdominal pain
• Because ischemic colitis can be life-threatening,
  patients with signs or symptoms of ischemic
  colitis should be evaluated promptly and have
  appropriate diagnostic testing performed
• Treatment with LOTRONEX should not be resumed in
  patients who develop ischemic colitis

16
LOTRONEX (alosetron HCl) Contraindications

• Do not initiate LOTRONEX when constipation is
  present
• LOTRONEX is contraindicated in patients with a
  history of the following
• Chronic or severe constipation or sequelae from
  constipation
• Intestinal obstruction, stricture, toxic
  megacolon, gastrointestinal perforation, and/or
  adhesions
• Ischemic colitis, impaired intestinal
  circulation, thrombophlebitis, or hypercoagulable
  state

17
LOTRONEX (alosetron HCl) Contraindications
(contd)

• LOTRONEX is contraindicated in patients with a
  history of the following
• Crohns disease or ulcerative colitis
• Diverticulitis or active disease
• Severe hepatic impairment
• Hypersensitivity to any component of the product
• Patients who are unable to understand or comply
  with the Patient-Physician Agreement
• Concomitant administration of LOTRONEX with
  fluvoxamine is contraindicated. Fluvoxamine, a
  known strong inhibitor of CYP1A2, has been shown
  to increase mean LOTRONEX plasma concentrations
  (AUC) approximately 6-fold and prolong the
  half-life by approximately 3-fold.

18
LOTRONEX (alosetron HCl) Precautions
Drug Interactions
Because LOTRONEX is metabolized by a variety of
hepatic CYP drug-metabolizing enzymes, inducers
or inhibitors of these enzymes may change the
clearance of LOTRONEX

• Concomitant administration of LOTRONEX and
  fluvoxamine is contraindicated
• Concomitant administration of LOTRONEX and
  moderate CYP1A2 inhibitors, including quinolone
  antibiotics and cimetidine, has not been
  evaluated, but should be avoided unless
  clinically necessary because of similar potential
  drug interactions

19
LOTRONEX (alosetron HCl) Precautions (contd)
Drug Interactions (contd)

• Inhibition of CYP3A4 with ketoconazole increases
  LOTRONEX AUC by 29. Caution should be used when
  LOTRONEX and ketoconazole are administered
  concomitantly
• Coadministration of LOTRONEX and strong CYP3A4
  inhibitors, such as clarithromycin,
  telithromycin, protease inhibitors, voriconazole,
  and itraconazole has not been evaluated but
  should be undertaken with caution because of
  similar potential drug interactions
• The effect of induction or inhibition of other
  pathways on exposure to LOTRONEX and its
  metabolites is not known

20
Drug Interactions (contd)
LOTRONEX (alosetron HCl) Precautions (contd)

• LOTRONEX is unlikely to inhibit the hepatic
  metabolic clearance of drugs metabolized by CYP
  enzymes 3A4, 2D6, 2C9, 2C19, 2E1, or 1A2
• LOTRONEX does not appear to induce the major
  cytochrome P450 (CYP) drug metabolizing enzyme
  3A, and does not appear to induce CYP enzymes 2E1
  or 2C19. It is not known whether LOTRONEX might
  induce other enzymes

21
Drug Interactions (contd)
LOTRONEX (alosetron HCl) Precautions (contd)

• Further interaction studies
• Theophylline (CYP1A2 substrate) No effect on
  metabolism of theophylline was observed
• Oral contraceptive agents ethinyl estradiol and
  levonorgestrel (CYP3A4 substrate) No clinically
  significant effect on plasma concentrations of
  the oral contraceptives
• Cisapride (CYP3A4 substrate) No effects on
  cisapride metabolism or QT interval were noted

22
LOTRONEX (alosetron HCl) Precautions (contd)
Other Considerations

• Increased exposure to LOTRONEX and/or its
  metabolites is likely to occur in patients with
  hepatic insufficiency. LOTRONEX should not be
  used in patients with severe hepatic impairment
  and should be used with caution in patients with
  mild or moderate hepatic impairment.
• Pregnancy Category B
• It is not known whether LOTRONEX is excreted in
  human milk caution should be exercised for
  nursing mothers receiving LOTRONEX
• Safety and effectiveness of LOTRONEX have not
  been established in pediatric patients
• Elderly patients may be at greater risk for
  complications of constipation

23
Adverse Events (1) Reported in IBS Patients
a Data reported from 22 repeat-dose studies in
patients with IBS treated for 8 to 24
weeks. b Plt0.0001 vs placebo.
24
LOTRONEX (alosetron HCl) Adverse Events

• Constipation is a frequent and dose-related side
  effect
• In clinical trials in patients on 1 mg BID
  (n9,316), constipation was reported in 29 of
  patients with LOTRONEX and 11 withdrew from the
  study
• Although the number treated with 0.5 mg BID is
  small (n243), only 11 reported constipation and
  4 withdrew from study

25
LOTRONEX (alosetron HCl) Overdosage

• No specific antidote available for overdosage of
  LOTRONEX
• Patients should be managed with appropriate
  supportive therapy
• Doses of 16 mg (8 times higher than recommended
  total daily dose) administered in clinical trials
  without significant adverse events

26
For information on the Prescribing Program for
LOTRONEX

• Please see Section 9 of this presentation

27
Section 4

• Ischemic Colitis
• In the Prescribing Information for LOTRONEX
  (alosetron HCl), the term ischemic colitis is
  used to describe the full spectrum of disorders
  in intestinal ischemia.

28
Intestinal IschemiaClinical Features

• Colonic Ischemia 75
• Typically self-limited, without sequelae
• Mild/moderate pain (gt80)
• Diarrhea (50)
• Hematochezia (87)

• Chronic Mesenteric Ischemia 5
• Insidious
• Post-prandial pain
• Weight loss

• Acute Mesenteric Ischemia 20
• Severe abdominal pain
• Significant morbidity/mortality
• Hx CVD/emboli/CHF
• Hx cardiac surgery

Brandt LJ, Boley SJ. Gastroenterology.
2000118(5)954-968. Cohn SM, Birnbaum EH. In
Yamada T, Alpers DH, Owyang C, Laine L, Powell
DW, eds. Textbook of Gastroenterology. 3rd ed.
Philadelphia, Pa Lippincott Williams Wilkins
19991767.
29
Colonic IschemiaSpectrum of Injury

• Reversible (most cases)
• Reversible ischemic colopathy or transient
  ischemic colitis
• Usually self-limitedblood flow to tissues often
  restored before symptoms appear
• Irreversible
• Chronic ulcerative ischemic colitis
• Ischemic colonic stricture
• Colonic gangrene
• Fulminant universal ischemic colitis (rare)

Brandt LJ, Boley SJ. Gastroenterology.
2000118(5)954-968. Greenwald DA, Brandt LJ. J
Clin Gastroenterol. 199827(2)122-128.
30
Colonic IschemiaDiagnosis

• Clinical presentation
• Colonoscopyideally within 48 hours
• Allows direct visualization of mucosa
• Allows biopsy to confirm clinical impression
• Barium enemaif colonoscopy not readily
  accessible
• Flexible sigmoidoscopypotentially of limited use
  given lack of findings in left colon in up to 40
  
• CT scan and flat plate of abdomenless helpful
• Angiographynot indicated as large vessels
  typically are not involved

Greenwald DA et al. Gastroenterol Clin North Am.
200130(2)445-473.
31
Ischemic Colitis in IBS Clinical Trials Prior to
Product Withdrawal and Reintroduction

• Total number of patients 10,805
• Reported cases of IC 17
• Femalemale ratio 161
• Serious cases (per regulatory definition)
  12
• Age range (median), years 20-75 (51)
• Age gt65 years 1
• Age lt50 years 8

• Dose (mg BID) Total Subjects Reports
• 1 9,316 15
• 0.5a 243 1
• Othera 1,246 1b

a These doses were not approved for use in the
United States at the time these data were
generated. b 2 mg BID.
Briefing document on LOTRONEX (alosetron HCl)
for the FDA Joint GI Drugs Advisory Committee
and Drug Safety and Risk Management Subcommittee.
April 23, 2002. http//www.fda.gov/ohrms/dockets/a
c/02/briefing/3848B1_01_GSK20Briefing20Pkg.pdf.
32
Regulatory Definition of Serious

• 21 CFR 312.32(a) defines serious adverse drug
  experience as any adverse drug experience
  occurring at any dose that results in any of the
  following outcomes Death, a life-threatening
  adverse drug experience, inpatient
  hospitalization or prolongation of existing
  hospitalization, a persistent or significant
  disability/incapacity, or a congenital
  anomaly/birth defect. Important medical events
  that may not result in death, be
  life-threatening, or require hospitalization may
  be considered a serious adverse drug experience
  when, based upon appropriate medical judgement,
  they may jeopardize the patient or subject and
  may require medical or surgical intervention to
  prevent one of the outcomes listed in this
  definition.

33
Ischemic Colitis Reported inClinical Trialsa for
LOTRONEX (alosetron HCl)

• Clinical Presentation
• Acute, mild-moderate pain and hematochezia
• Inpatient management in 53 (9/17) of the cases
• Hospital duration, range 1-7 days (median 3)
• Conservative treatment in all cases
• Constipation in 18 (3/17) of the cases
• Estrogen use in 50 (8/16 females) of the cases

a Clinical trials completed or terminated prior
to reintroduction in November 2002.
34
Ischemic Colitis Reporteda in Postmarketing
Experience With LOTRONEX (alosetron HCl)

• Number of reports 80
• Approximate number of patients 275,000
• Female/Male/Unknown 75/2/3
• Median age, years 55
• Median time to onset 14 days(range) (12 h 6
  mos)
• Onset within first month 74
• Age gt65 years 23
• Age lt50 years 24

a Reported by GlaxoSmithKline at FDA/GI Advisory
Committee in April 2002. Cutoff reporting date
February 18, 2002. Data not reported in all cases.
35
Summary of Ischemic Colitis Reported With
LOTRONEX (alosetron HCl)

• Postmarketing
• IBS Since
• Clinical Trialsa Postmarketingb
  Reintroductionc
• Patients 10,805 275,000 10,000
• Ischemic Colitis 17 80 8
• Outcomes
• Hospitalization 9 48 3
• Surgery 0 6 0
• Death 0 0 0

a Completed and terminated when LOTRONEX was
withdrawn in November 2000. b Spontaneous
reports received in relation to previous
marketing cycle in 2000. Reported by
GlaxoSmithKline at FDA/GI Advisory Committee in
April 2002. c Spontaneous reports received
following reintroduction. Reported at May 5, 2004
DSRM Committee Meeting. http//www.fda.gov/ohrms/
dockets/ac/04/slides/1
36
Section 5

• Clinical Update Information

37
LOTRONEX (alosetron HCl) Postmarketing Data
Since Reintroduction

• Data presented by GlaxoSmithKline to FDA Drug
  Safety and Risk Management Advisory Committee on
  May 5, 2004. Info available at
• www.fda.gov/ohrms/dockets/ac/04/slides/2004/4040s1
  _08_glaxosmithkline.ppt

• November 22, 2002, to February 2, 2004
• 34,000 prescriptions dispensed
• Approximately 10,000 patients
• 8 reported cases of ischemic colitis 7 resolved
  and 1 outcome unknown
• No reports of mesenteric ischemia, occlusion, or
  infarction
• 8 reported cases of complications of constipation
  including fecal impaction, intestinal
  obstruction, ileus, and intestinal ulceration
• No drug-related deaths, confirmed surgeries, or
  blood transfusions

38
Section 6

• Review of Efficacy

39
Women With Severe Diarrhea-Predominant IBS
LOTRONEX is indicated only for women with severe
diarrhea-predominant IBS who have

• Chronic IBS symptoms (generally lasting 6 months
  or longer)
• Had anatomic or biochemical abnormalities of the
  GI tract excluded, and
• Not responded adequately to conventional therapy
• For the purposes of prescribing LOTRONEX, IBS-D
  is severe if it includes diarrhea and at least
  one of the following
• Frequent and severe abdominal pain/discomfort
• Frequent bowel urgency or fecal incontinence
• Disability or restriction of daily activities due
  to IBS

40
Women With Severe Diarrhea-Predominant IBS
(contd)

• Because of infrequent but serious GI adverse
  events associated with LOTRONEX, the indication
  is restricted to those patients for whom the
  benefit-to-risk balance is most favorable
• Currently LOTRONEX is not indicated for use in
  men
• Prospective and retrospective analyses support
  efficacy of LOTRONEX in women with severe
  diarrhea-predominant IBS

41
Prospective Analysis to Support Efficacy in Women
With Diarrhea-Predominant IBS

• Two 12-week multicenter trials (Studies 1 and 2)
  in non-constipated women with IBS for at least
  6 months
• 633 women randomized to LOTRONEX and 640 to
  placebo
• Approximately two-thirds of the women had
  diarrhea-predominant IBS

42
Prospective Analysis of Diarrhea-Predominant IBS
in WomenRate of Adequate Relief of IBS Pain and
Discomfort
Study 2
Study 1
c 60
b 58
d 61
d 59
e 59
a 50
43
Placebo
47
41
45
39
40
LOTRONEX 1 mg BID
d Plt0.001 vs placebo. e P0.013 vs placebo.
a P0.022 vs placebo. b P0.003 vs placebo.
c Plt0.001 vs placebo.
Data on file, Prometheus Laboratories Inc., San
Diego, Calif.
43
Retrospective Analysis of Severe
Diarrhea-Predominant IBS in Women Rate of
Adequate Relief of IBS Pain and Discomfort

• Adequate Relief Rate of IBS Pain and Discomfort
  Over 12 Weeks Stratified by Increasing Severity
  of Baseline Abdominal PainIntegrated Analysis
  From 6 Studies Involving Female IBS-D Patients

56a
52a
Placebo
47a
41
LOTRONEX
39
36
Weeks With Adequate Relief
(n85)
(n107)
(n184)
(n147)
(n192)
(n189)
Pain 1.75 lt2.5
Pain 2.5 (Severe IBS-D)
Pain 1.0 lt1.75
a Plt0.05 vs placebo.
Data on file, Prometheus Laboratories Inc., San
Diego, Calif.
44
Prospective Analysis in Females With Severe
IBS-Da Satisfactory Control of Urgency
Percentage of Days Subjects ReportedSatisfactory
Control of Bowel Urgency
Study 42
Study 31
Treatment
Follow-up
Treatment
Follow-up
100 90 80 70 60 50 40 30 20 10 0
100 90 80 70 60 50 40 30 20 10 0
b
b
b
b
b
b
b
b
b
b
LOTRONEX (n532)
c
c
c
c
c
c
c
c
c
b
c
c
b
LOTRONEX (n246)
c
Percentage of Days (Median)
Percentage of Days (Mean)
Placebo (n269)
Placebo (n246)
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14
Week
Week
c Plt0.003
b Plt0.001 a Urgency on 50 of days during
screening.
1. Lembo T et al. Am J Gastroenterol.
200196(9)2662-2670. 2. Lembo AJ et al. Clin
Gastroenterol Hepatol. 20042(8)675-682.
45
Retrospective Analysis in Females With More
Frequent Severe IBS-DRate of Satisfactory
Control of Urgency

• In further analyses of Studies 1 and 2, 57 of
  patients had urgency at baseline on 5 or more
  days per week
• In Studies 3 and 4, 66 of patients had urgency
  at baseline on 5 or more days per week

46
Retrospective Analysis in Females With More
Frequent Severe IBS-DaRate of Satisfactory
Control of Urgency (contd)
50
Percent of Patients
32
29
19
a This subset included only patients with
urgency on gt5 days/week at baseline who improved
to no more than 1 day in the final week.
Lembo AJ et al. Clin Gastroenterol Hepatol.
20042(8)675-682.
47
Prospective Analysis in Females With Severe
IBS-DRate of Stool Frequency

• Median Stools per Day by Week in Female Patients
  With Severe IBS-D

Stools Per Day
Lembo T et al. Am J Gastroenterol.
200196(9)2662-2670. Data on file, Prometheus
Laboratories Inc., San Diego, Calif.
48
Prospective Analyses in Females With Severe
IBS-D Rate of Stool Frequency and Consistency

• For patients receiving LOTRONEX during the 12
  weeks of treatment, stool frequency decreased by
  approximately 1 stool per day compared with 0.5
  stools per day for patients receiving placebo
• For patients receiving LOTRONEX during the 12
  weeks of treatment, stool consistency changed
  from a stool consistency of 4 to 3. Patients
  receiving placebo had stool changed from 4 to 3.5

1very hard, 2hard, 3formed, 4loose, 5watery
49
Retrospective Analyses in Females With Severe
IBS-D Long-term Efficacy

• LOTRONEX 1 mg BID in a 48-week multinational,
  double-blind, placebo-controlled study
• LOTRONEX (alosetron HCl) (n198) placebo
  (n219)
• Provided a greater average rate of satisfactory
  control of bowel urgency (60 vs 48) and greater
  average rate of adequate relief of IBS pain and
  discomfort (52 vs 41) compared with placebo
• Significant improvement of these symptoms
  occurred for most of the 48-week period with no
  evidence of tachyphylaxis

50
Retrospective Analysis in Females With Severe
IBS-D
Patient-Reported Subjective Outcomes Related to
IBS

• As compared with patients on placebo, patients
  who received LOTRONEX (alosetron HCl) reported
• Less sleeping difficulty
• Less tiredness
• Fewer eating problems
• Less interference with social activities and
  work activities
• Change in impact of IBS symptoms and problems on
  emotional and mental distress and on physical and
  sexual activity were not statistically different
  between the placebo group and the group receiving
  LOTRONEX.

51
Summary of Efficacy of LOTRONEX (alosetron HCl)
in Females With Severe IBS-D

• Rate of adequate relief of IBS pain and
  discomfort
• Significantly greater relief in females with
  severe IBS-D during 12-48 weeks of treatment
• Rate of satisfactory control of bowel urgency
• Significantly greater control of urgency in
  females with severe IBS-D during 12-48 weeks of
  treatment
• Frequency of bowel movements
• Decreased frequency and improved stool
  consistency of bowel movements in females with
  severe IBS-D during 12-48 weeks of treatment
• Patient-reported subjective outcomes
• Less interference with daily activities due to
  IBS symptoms

52
Section 7

• Mechanism of Action and Pharmacokinetics

53
The Cause of IBS Is Unknown

• IBS is characterized by visceral hypersensitivity
  and hyperactivity of the GI tract leading to
  abnormal
• Sensations of pain
• Motor activity
• Following distention of the rectum, IBS patients
  exhibit pain and discomfort at lower volumes than
  healthy volunteers
• Following such distention, LOTRONEX reduced pain
  and exaggerated motor responses, possibly due to
  blockade of 5-HT3 receptors

54
LOTRONEX (alosetron HCl) Mechanism of Action

• LOTRONEX is a potent and selective 5-HT3
  receptor antagonist
• 5-HT3 receptors are ligand-gated cation channels
  that are extensively distributed on enteric
  neurons in the human gastrointestinal tract, as
  well as other peripheral and central locations

55
LOTRONEX (alosetron HCl) Mechanism of Action
(contd)

• Activation of these channels and the resulting
  neuronal depolarization affect the regulation of
  visceral pain, colonic transit, and GI
  secretions, processes that relate to the
  pathophysiology of IBS
• 5-HT3 receptor antagonists such as LOTRONEX
  inhibit activation of non-selective cation
  channels, which results in the modulation of the
  enteric nervous system

56
LOTRONEX (alosetron HCl) Mechanism of Action
(contd)

• In healthy volunteers and IBS patients, LOTRONEX
  (2 mg orally BID for 8 days) increased colonic
  transit time without affecting orocecal transit
  time
• In healthy volunteers, LOTRONEX also increased
  basal jejunal water and sodium absorption after
  a single 4-mg dose
• In IBS patients, multiple oral doses of LOTRONEX
  (4 mg BID for 6.5 days) significantly increased
  colonic compliance

57
LOTRONEX (alosetron HCl) Mechanism of Action
(contd)

• Single oral doses of LOTRONEX administered to
  healthy men produced a dose-dependent reduction
  in the flare response seen after intradermal
  injection of serotonin
• Urinary 6-b-hydroxycortisol excretion decreased
  by 52 in elderly subjects after 27.5 days of
  LOTRONEX 2 mg orally twice daily
• This decrease was not statistically significant

58
LOTRONEX (alosetron HCl) Pharmacokinetics

• Rapidly absorbed after oral administration with
  mean absolute bioavailability of 50-60
• LOTRONEX can be taken with or without food
• Volume of distribution 65-95 L
• Plasma protein binding 82

59
LOTRONEX (alosetron HCl) Pharmacokinetics
(contd)

• Proportional increase of plasma concentrations up
  to 8 mg
• Plasma clearance 600 mL/min
• Terminal half-life 1.5 hours
• No accumulation with BID dosing

60
LOTRONEX (alosetron HCl) Pharmacokinetics
(contd)

• LOTRONEX extensively metabolized by CYP P450
  enzymes
• 30 2C9 18 3A4 10 1A2
• 11 non-CYP mediated
• See Important Safety InformationSection 3
• 73 renal excretion of drug and metabolites
• Only 7 of the dose was recovered as unchanged
  drug

61
LOTRONEX (alosetron HCl) Pharmacokinetics
(contd)

• Plasma concentrations are 30 to 50 lower and
  less variable in men compared with women given
  the same oral dose
• In Japanese men, an N-desmethyl metabolite was
  found circulating in plasma in all subjects and
  accounted for up to 30 of the dose in one subject

62
Section 8

• How to Prescribe and Dispense LOTRONEX
  (alosetron HCl) Tablets

63
LOTRONEX (alosetron HCl) Dosage and
Administration

• For safety reasons, only physicians who enroll in
  the Prescribing Program for LOTRONEX should
  prescribe LOTRONEX
• Usual Dose in Adults
• To lower the risk of constipation, LOTRONEX
  should be started at 0.5 mg BID
• Patients well controlled on 0.5 mg BID may be
  maintained on this regimen
• If, after 4 weeks, the 0.5 mg BID dosage is
  tolerated but does not adequately control IBS
  symptoms, increase dose to 1 mg BID, the dose
  used in controlled clinical trials

64
LOTRONEX (alosetron HCl) Dosage and
Administration (contd)

• Usual Dose in Adults
• LOTRONEX should be discontinued in patients who
  have not had adequate control of IBS symptoms
  after 4 weeks of treatment with 1 mg BID
• LOTRONEX should be discontinued immediately in
  patients who develop constipation or signs of
  ischemic colitis
• LOTRONEX should not be restarted in patients who
  develop ischemic colitis

65
LOTRONEX (alosetron HCl) Dosage and
Administration (contd)

• Clinical trial and postmarketing experience
  suggest that debilitated patients or patients
  taking additional medications that decrease GI
  motility may be at greater risk of serious
  complications of constipation
• Therefore, appropriate caution and follow-up
  should be exercised if LOTRONEX is prescribed for
  these patients
• LOTRONEX can be taken with or without food

66
LOTRONEX (alosetron HCl) Dosage and
Administration in Other Patient Populations

• Pediatric Safety and effectiveness have not been
  established
• Geriatric Caution and follow-up should be
  exercised with LOTRONEX, as elderly patients may
  be at greater risk for complications of
  constipation
• Renal impairment Insufficient data available
• Hepatic impairment Use caution in patients with
  mild or moderate hepatic impairment, as increased
  exposure to LOTRONEX is likely to occur and may
  increase the risk of serious adverse events.
  LOTRONEX is contraindicated in patients with
  severe hepatic impairment.

67
Section 9

• Prescribing Program for LOTRONEX(As noted in
  the PRECAUTIONS section of the complete
  Prescribing Information for LOTRONEX)

68
Prescribing Program for LOTRONEX
69
Prescribing Program forLOTRONEX (contd)

• To prescribe LOTRONEX (alosetron HCl),
  physicians must be enrolled in the Prescribing
  Program for LOTRONEX.
• To enroll, physicians must understand the
  benefits and risks of treatment with LOTRONEX for
  severe diarrhea-predominant IBS, including the
  information in the Prescribing Information,
  Medication Guide, and Patient-Physician Agreement
  for LOTRONEX.
• Stickers are provided to physicians when they
  enroll in the Prescribing Program for LOTRONEX.
• To enroll in the Prescribing Program for
  LOTRONEX call [phone] Opt. 1 or visit
  www.lotronex.com to complete the Physician
  Enrollment Form.

70
Prescribing Program forLOTRONEX (contd)

• Physicians need to
• Enroll in the Prescribing Program for LOTRONEX
• Understand the requirements and submit the
  Physician Enrollment Form
• Identify appropriate patients and do the
  following
• Counsel on therapy with LOTRONEX
• Review the Medication Guide and give a copy to
  the patient
• Review and sign the Patient-Physician Agreement
  Form with the patient, place the original in the
  patients file, and give a copy of signed
  agreement to the patient
• Give the patient a prescription for LOTRONEX
  affixed with Prescribing Program Sticker
• Encourage the patient to enroll in the Follow-Up
  Survey for LOTRONEX
• Report serious adverse events to Prometheus at
  1-888-423-5227 Opt. 6 or the FDA at
  1-800-FDA-1088

71
Prescribing Program for LOTRONEX (contd)

• No telephone, facsimile, or computerized
  prescriptions are permitted with this program.
• Refills are permitted to be written on
  prescriptions.

72
Prescribing Program for LOTRONEX (contd)
73
Prescribing Program for LOTRONEX (contd)

• Patients who are prescribed LOTRONEX should be
  instructed to
• Read the Medication Guide before starting
  LOTRONEX and each time they refill their
  prescription
• Not start taking LOTRONEX if they are constipated
• Immediately discontinue LOTRONEX and contact
  their physician if they become constipated or
  have symptoms of ischemic colitis such as new or
  worsening abdominal pain, bloody diarrhea, or
  blood in the stool

74
Prescribing Program for LOTRONEX (contd)

• Patients who are prescribed LOTRONEX should be
  instructed to
• Immediately contact their physician again if
  their constipation does not resolve after
  discontinuation of LOTRONEX
• Resume LOTRONEX only if their constipation has
  resolved and after discussion with and the
  agreement of their treating physician
• Stop taking LOTRONEX and contact their
  physicianif LOTRONEX does not adequately control
  IBS symptoms after 4 weeks of taking 1-mg tablet
  BID

75
Follow-Up Survey for LOTRONEX (alosetron HCl)

• Prometheus is sponsoring a patient survey to
  evaluate the use of LOTRONEX in clinical practice
  called the Follow-Up Survey for LOTRONEX
• The survey is important for monitoring the
  Prescribing Program for LOTRONEX
• Patients should be encouraged to enroll in the
  Follow-Up Survey for LOTRONEX

76
Patient Profiles

• Patty
• 39-year-old mother of 2 whose primary complaint
  is bowel urgency but also suffers from stool
  frequency and abdominal pain associated with
  diarrhea-predominant IBS
• Diagnosed with IBS-D a year ago and had anatomic
  and biochemical abnormalities ruled out symptoms
  have persisted for more than 6 months
• Has taken hyoscyamine and loperamide for relief
  of abdominal pain, but it does not treat her
  symptoms of bowel urgency
• Otherwise healthy female

77
Patient Profiles

• Patty
• Mother of 2 children
• Her symptoms interfere with her ability to keep
  up with her energetic young boys, and she has
  had to stop volunteering at a senior center
• Chronic IBS-D symptoms have persisted for more
  than 6 months
• Not responded adequately to conventional therapy

Excellent candidate for a starting dose of
LOTRONEX 0.5 mg BID for IBS pain, urgency, and
frequency
78
Patient Profiles

• Maria
• 25-year-old teacher experiencing IBS-D symptoms
  of abdominal pain and bowel urgency. She has to
  go to the bathroom 3 to 4 times a day
• Symptoms have persisted for more than 6 months
• Symptoms have affected her work schedule and
  social life
• She has often had to take both diphenoxylate and
  dicyclomine 4 times a day to get relief from her
  symptoms

79
Patient Profiles

• Maria
• She worries about having to remember her
  medications and finding time to take them during
  her busy day.
• Being a teacher, she is also concerned about
  having to leave a room full of students
  unattended to use the bathroom multiple times
  during the day.
• In contrast to her conventional therapy, LOTRONEX
  would be a good fit for Marias busy lifestyle.
• The 0.5-mg BID dose offers Maria the dosing
  convenience that works with her hectic daily
  schedule.
• In addition, for patients like Maria, LOTRONEX
  provides relief from symptoms that restrict
  daily activities such as work.

?2008 Prometheus Laboratories Inc. All
rights reserved. LO7024 01/08