Irritable Bowel Syndrome: Treatment Disclosure Overview Focusing on Newly Approved Medications • I, or an immediate family member, including spouse or partner, have no financial relationship(s) relevant to the contents of this Southwest Florida Society of Health System Pharmacists continuing education activity

Jose Barboza, Pharm.D., C.D.E. Faculty Pharmacotherapeutics & Clinical Research University of South Florida College of Pharmacy

Objectives Irritable Bowel Syndrome: Definition • Gastrointestinal (GI) syndrome 1. Describe the pathophysiology of Irritable – Altered bowel function – Abdominal pain or discomfort Bowel Syndrome • Diarrhea predominant – Altered bowel habits (IBS‐D) 2. Review the treatments for Irritable Bowel – Absence of organic cause • Constipation Syndrome • Recurring symptoms predominant (IBS‐C) – Incomplete evacuation • Constipation/ diarrhea 3. Discuss the use of rifaximin and – Urgency (IBS‐M) eluxadoline in treating diarrhea – Bloating • Undefined (IBS‐U) predominant irritable bowel syndrome

Compare and Contrast: IBS/IBD Irritable Bowel Syndrome: Diagnosis

Irritable Bowel Inflammatory Bowel Rome III Criteria for Irritable Bowel Syndrome Syndrome (IBS) Disease (IBD) Recurrent abdominal pain or discomfort Three episodes per month Pain/ Discomfort Last 3 months associated Chronic inflammation Change in Bowel habits Two or more of… of the intestines Absence of organic cause 1 Improvement with defecation

2 Onset associated with change in frequency of stool Diarrhea (IBS‐D) Crohn’s disease (CD) Constipation (IBS‐C) Ulcerative colitis (UC) 3 Onset associated with a change in form of stool Alternating/Mixed (IBS‐M) Am J Gastroenterol, 2009. 104 Suppl 1: p. S1‐35.

1 Irritable Bowel Syndrome: IBS Epidemiology Pathophysiology • Prevalence in US: 10‐15% • Disturbed GI motility – More common • Visceral hypersensitivity • Females (~2:1) • Psychological stress • Young adulthood • Intestinal microflora and – 15% of those affected seek inflammation medical attention • Altered levels of 5HT • Most commonly diagnosed GI • 5HT3 and 5HT4 are extensively condition found in the gut, responsible for – 25‐50% of gastroenterologist secretion, sensitization, and referrals motility

Clin Epidemiol. 2014; 6: 71–80.

Physiological distribution of 5‐HT

• Prucalopride CNS – 5% • 5HT4 agonist • IBS-C • Alosetron

• 5HT3 antagonist • IBS-D GI tract – 95%

• Causes altered GI Pathophysiology: • Motility • Sensitivity Drugs. 2014 Oct;74(16):1849-70. • Secretions Gershon, Aliment Pharmacol Ther.,1999

IBS –Positive Diagnosis and Outcome IBS: Dietary Modifications

• Identify concerns • Avoid caffeine, alcohol, and artificial • Basis for patient’s symptoms sweeteners • Reassurance – Can irritate the gut > laxative effect • Cost effective evaluation • Evaluate lactose intolerance • Involve patient in decision making • Rule out Celiac sprue (1%) • Provide continuity • Rule out gluten intolerance (6%) • Set realistic limits • Low FODMAP diet • No association between negative colonoscopy and – Fermentable Oligosaccharides, Disaccharides, improved health related quality of life Monosaccharides and Polyols – Poorly absorbed by some Gastrointest Endosc 2005; 62:892-9.

2 IBS: Fiber IBS‐C: Non‐Pharmacologic MOA/ Role in Therapy • Secondary constipation: Correct the cause • MOA: Contain hydrophilic polysaccharide • Dietary modification: Basis of therapy derivatives – Gradually increase fiber – 20‐25 grams/day – Absorb water to: Increase bulk, soften the stool, and facilitate peristalsis and elimination • Other lifestyle – Exercise – Effects seen in 2‐3 days – Adjust bowel habits • Role in therapy: – Increase fluid intake – Safest – Acceptable in pregnancy

IBS: Fiber IBS: Fiber Agents and Availability Adverse Effects/Drug Interactions • Agents (Not FDA approved for IBS) • Adverse effects – Methylcellulose (Citrucel) – Abdominal distention, cramping, and flatulence – Calcium Polycarbophil (FiberCon) • Minimized by gradual increase, resolved with continued use – Psyllium (Metamucil) • Drug Interactions – Barley malt extract (Maltsupex) – Possible binding to digoxin and warfarin • Powders, flakes, granules, tablets, and liquids – May bind with tetracyclines • Doses vary, typically administered in divided doses – Separate other medications by 1‐2 hours

IBS: Fiber IBS: Fiber Precautions Evidence

• Severely fluid restrictions • Psyllium/ispaghula husk showed • May cause hypersentitivity improvement over placebo • Diabetes – NNT=6 (IBS type not differentiated) • Other agents are similar to placebo • Fecal impaction or intestinal obstruction • Psyllium/ispaghula husk (20‐30 g/day) – Avoid: intestinal ulcerations, stenosis, and disabling improves constipation adhesions

Drugs. 2014 Oct;74(16):1849-70.

3 IBS: Antispasmodics/Anticholinergics IBS: Antidepressants

• MOA: Relax smooth muscles in the colon and • MOA: Improve dysregulation of neuroenteric pathway small bowel • Symptomatic treatment: Abdominal pain • – Reserved for patients with severe or refractory pain Symptomatic relief –Pain • Visceral analgesia, changes in motility, smooth muscle • Agents: Peppermint oil, hyoscine, cimetropium, relaxation pinaverium, mebeverine, and otilonium • Agents: – Paroxetine, fluoxetine, citalopram, amitriptyline, and • Side effects: Anticholinergic, generally safe imipramine • Adverse effects (antibiotic dependent): – insomnia, restlessness, sexual dysfunction, nausea, constipation, diarrhea

Drugs. 2014 Oct;74(16):1849-70. Drugs. 2014 Oct;74(16):1849-70.

IBS: Probiotics • MOA: restore normal flora – Alterations may cause Diarrhea‐Predominant IBS (IBS‐D) • Increased fermentation of food • Changes in intestinal motor and sensory function, • Mucosal immune activation • Malabsorption • Agents: – Lactobacillus, bifidobacterium, streptococcus, others – Limitations in clinical trials • Generally safe

IBS‐D: Alosetron IBS‐D: Loperamide MOA/Agent • Evaluated in randomized controlled trials for • MOA: Potent and selective 5‐HT3 antagonist IBS‐D – Results in modulation of the enteric nervous system – Effective for treatment of diarrhea • Alosetron (Lotronex) – Not FDA approved for IBS – Approved in chronic, severe IBS‐D for patients who • No impact on abdominal bloating or global IBS failed to responded to conventional treatments – Starting dose: 0.5mg BID symptoms – Reassess at 4 weeks • Acute diarrhea: Oral: Initial: 4 mg, followed by • No adequate control of symptoms: Increase to 1mg BID 2 mg after each loose stool, up to 16 mg/day – Re‐assess at 4 weeks • No adequate control of symptoms: Discontinue medication

ACG Task Force on IBS. Am J Gastro. 2009

4 IBS‐D: Alosetron IBS‐D: Alosetron Restricted Use/Precautions Contraindications

• Adverse effects (dose related) • Constipation – Constipation • intestinal obstruction, stricture, toxic megacolon, gastrointestinal perforation, and/or adhesions – GI discomfort/pain • Ischemic colitis, impaired intestinal circulation, • Restricted FDA use thrombophlebitis, or hypercoagulable state – Females only • Crohn's disease or ulcerative colitis – Enroll in Prometheus prescribing program • Diverticulitis • Ischemic colitis (FDA warning) • Severe hepatic impairment – 1.1 cases/1,000 patient‐years • Concomitant fluvoxamine use • Precautions: Constipation, ischemic colitis

Chang L et al. Am J Gastro 2010

IBS‐D: Rifaximin

• Broad spectrum antibiotic with low bioavailability – <0.4% absorbed • FDA approved • Dose: 550mg TID for 2 weeks – May be repeated up to 2 times – Improvement shown in up to 10 weeks • Showed to improve global IBS symptoms: TARGET 1 & 2 • Adverse effects: Flatulence, abdominal pain, tenesmus, fecal incontinence, nausea, and headaches • High Cost, Xifaxan 550mg (#60)~ $2000

IBS‐D: Eluxadoline (Viberzi) IBS‐D: Eluxadoline • MOA: kappa and mixed mu and opioid receptor agonist, delta opioid receptor antagonist • Adverse effects – Decrease pain and intestine contractility – Constipation (~8% vs. 2.4%), nausea (~7.5% vs. 4.8), – Shown to improve stool consistency and pain vomiting • Global symptoms, QOL, and adequate relief • Contraindications: • FDA Approved: IBS3001 and 3002 – Severe hepatic impairment, biliary duct obstruction, • Dose: 100mg BID diseases of the pancreas, alcoholism • Unable to tolerate, no gallbladder, mild hepatic impairment: 75mg BID

5 IBS‐C: Osmotic Laxatives MOA/ Role in Therapy Constipation‐Predominant IBS (IBS‐C) • MOA: Osmotic agent, causes water retention in the stool and increases stool frequency – Not absorbed systemically – Onset 1‐4 days  Role in therapy  Low doses for constipation  Bowel cleansing before diagnostic or colorectal procedures  Safe use chronically, studied in up to 6 months  Agent: Polyethylene Glycol 3350 (Miralax): Rx or OTC

IBS‐C: Osmotic Laxatives: IBS‐C: Chloride Channel Activator Dose/ Side Effects/ Contraindications Lubiprostone‐ MOA/ Agent

 Available with and without electrolytes • MOA: Chloride channel activator – Open chloride channels locally on the GI luminal  PEG: Constipation epithelium  10–30 g or 17–34 g per 120–240 mL QD or BID – Stimulates chloride‐rich fluid secretion into the lumen  Not FDA Approved for IBS – Results in softening of the stool and increased motility  Side effects – Onset: 24‐48 hours  Bloating, abdominal discomfort, cramping,  Agent: Lubiprostone (Amitiza) flatulence  FDA Approved to treat chronic constipation in adults (Rx)  Contraindications  IBS‐C: 8 mcg BID with food  GI Obstruction  Constipation: 24mcg BID with food

IBS‐C: Lubiprostone IBS‐C: Guanylate Cyclase‐C agonist Lubiprostone‐ Role in Therapy/ Adverse Effects Linaclotide‐ MOA/ Agents • MOA: Guanylate cyclase‐C agonist • Role in therapy – Stimulates the secretion of chloride and bicarbonate into – Chronic constipation in those who fail first‐line agents the intestinal lumen • Adverse effects – Increased intestinal fluid and accelerated GI transit – Decreased visceral pain – Nausea (dose dependent), diarrhea, abdominal pain, flatulence, headaches, dyspnea • Agent: Linaclotide (Linzess) – Pregnancy category C – FDA Approved for IBS‐C: • 290mcg PO QD on an empty stomach • Contraindication • ≥30 minutes prior to the first meal of the day – GI obstruction • Chronic Constipation: 145 mcg PO QD on an empty stomach at least 30 minutes prior to the first meal of the day

6 IBS‐C: Linaclotide IBS‐C: Serotonin Agonists Side Effects/ Contraindications Prucalopride

• MOA  Safety • Side effects:  Tegaserod‐ withdrawn from – Selective high affinity 5‐HT4 – Diarrhea, abdominal pain, flatulence receptor agonist the market due to CV adverse events likely due to its actions • Pregnancy category C – Promotes enteric neurons to stimulate the peristaltic reflex, on hERG channel • Contraindicated intestinal secretions, and GI  Prucalopride: no actions on hERG channel and higher – GI obstruction motility affinity to ‐5HT • Agents 4 – Children <6 years old  Prucalopride has been safely – Prucalopride‐ Not available in tolerated in clinical trials USA, available in Europe  No adverse CV effects compared to placebo

Altered Bowel Motility: IBS-D Altered Bowel Motility: IBS-C Rifaximin, loperamide, 5HT3 Psyllium, osmotic laxatives receptor antagonists (PEG), sorbitol/lactulose, Treatment Algorithm Emerging Therapies: lubiprostone, linaclotide, 5HT4 •Bile acid sequestrants receptor agonists, STW5 •Crofelemer Emerging Therapies •ASA derivatives •IBAT Symptomatic treatment Stress management and patient educations Altered Bowel Constipation Predominant Diarrhea Predominant Motility Diet: Lactose‐fee and caffeine‐free diet, Pain: Increase: Fiber and Liquid intake Antispasmodics, avoid other diarrhea causing agents antidepressants, probiotics, STW5, Add bulk‐forming laxatives, melatonin consider antispasmodic agents Add loperamide or antispasmodic agents Emerging Therapies •Mixed visceral Mu- Pain Bloating opioid Add 5HT‐3 •Receptor Add 5HT‐4 agonists agonists/antagonists, antagonists •Pregabalin (prucalopride) or Bloating: (alosetron) •Selective visceral K Antispasmodics, guanylate cyclase‐c opioid receptor agonist Add psychotherapeutic antiflatulents, •H1 receptor agonist (linaclotide) behavior modifications, probiotics, linaclotide, antagonists rifaximin, consider antidepressants •NK receptor antidepressants: antagonists Drugs. 2014 Oct;74(16):1849-70. Drugs. 2014 Oct;74(16):1849-70. citalopram, fluxoetine

Summary Questions? • IBS and IBD result in similar symptoms and can be difficult to manage – Diagnosis can be difficult – IBS: Increased morbidity – IBD: Increased morbidity and mortality • Cost of therapy can be high • Monitor for medication adverse effects, precautions, and contraindications [email protected]

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