Viberzi

VIBERZI- eluxadoline tablet, film coated
Actavis Pharma, Inc

1 INDICATIONS AND USAGE

VIBERZI is indicated in adults for the treatment of irritable bowel syndrome with diarrhea (IBS-D).

2 DOSAGE AND ADMINISTRATION

The recommended dosage of VIBERZI is 100 mg taken orally twice daily with food.

The recommended dosage of VIBERZI is 75 mg taken orally twice daily with food in patients who:

  • do not have a gallbladder [see Warnings and Precautions (5.1), Adverse Reactions (6.1)].
  • are unable to tolerate the 100 mg dose of VIBERZI [see Adverse Reactions (6.1)].
  • are receiving concomitant OATP1B1 inhibitors [see Drug Interactions (7)].
  • have mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment [see Use in Specific Population (8.6), Clinical Pharmacology (12.3)].

Discontinue VIBERZI in patients who develop severe constipation for more than 4 days.

Instruct patients if they miss a dose, take the next dose at the regular time and not to take 2 doses at the same time to make up for a missed dose.

3 DOSAGE FORMS AND STRENGTHS

  • 75 mg tablets: capsule-shaped tablets are coated in pale-yellow to light tan color debossed with “FX75” on one side. Each tablet contains 75 mg eluxadoline.
  • 100 mg tablets: capsule-shaped tablets are coated in pink-orange to peach color debossed with “FX100” on one side. Each tablet contains 100 mg eluxadoline.

4 CONTRAINDICATIONS

VIBERZI is contraindicated in patients with:

  • Known or suspected biliary duct obstruction; or sphincter of Oddi disease or dysfunction. These patients are at increased risk for sphincter of Oddi spasm [see Warnings and Precautions (5.1)].
  • Alcoholism, alcohol abuse or alcohol addiction, or in patients who drink more than 3 alcoholic beverages per day. These patients are at increased risk for acute pancreatitis [see Warnings and Precautions (5.2)].
  • A history of pancreatitis; or structural diseases of the pancreas, including known or suspected pancreatic duct obstruction. These patients are at increased risk for acute pancreatitis [see Warnings and Precautions (5.2)].
  • Severe hepatic impairment (Child-Pugh Class C). These patients are at risk for significantly increased plasma concentrations of eluxadoline [see Use in Specific Populations (8.6)]
  • A history of chronic or severe constipation or sequelae from constipation, or known or suspected mechanical gastrointestinal obstruction. These patients may be at risk for severe complications of bowel obstruction.

5 WARNINGS AND PRECAUTIONS

5.1 Sphincter of Oddi Spasm

Given the mu opioid receptor agonism of VIBERZI, there is a potential for increased risk of sphincter of Oddi spasm, resulting in pancreatitis or hepatic enzyme elevation associated with acute abdominal pain (e.g., biliary-type pain) with VIBERZI.

In clinical trials, sphincter of Oddi spasm occurred in less than 1% of patients receiving VIBERZI. The majority of these patients presented within the first week of treatment and the event resolved on discontinuation of VIBERZI. Patients without a gallbladder are at increased risk [see Adverse Reactions (6.1)].

Consider alternative therapies before using VIBERZI in patients without a gallbladder and evaluate the benefits and risks of VIBERZI in these patients in the context of their symptom severity. The recommended dosage of VIBERZI is 75 mg twice daily in patients without a gallbladder [see Dosage and Administration (2)]. If VIBERZI is used in such a patient, inform them that they may be at increased risk for adverse reactions and monitor them for symptoms of sphincter of Oddi spasm, such as elevated liver transaminases associated with abdominal pain or pancreatitis, especially during the first few weeks of treatment.

Instruct patients to stop VIBERZI and seek medical attention if they experience symptoms suggestive of sphincter of Oddi spasm such as acute worsening of abdominal pain, (e.g. acute epigastric or biliary [i.e., right upper quadrant] pain), that may radiate to the back or shoulder with or without nausea and vomiting, associated with elevations of pancreatic enzymes or liver transaminases. Do not restart VIBERZI in patients who developed biliary duct obstruction or sphincter of Oddi spasm while taking VIBERZI [see Contraindications (4)].

5.2 Pancreatitis

There is a potential for increased risk of pancreatitis, not associated with sphincter of Oddi spasm, when taking VIBERZI. Additional cases of pancreatitis, not associated with sphincter of Oddi spasm, were reported in less than 1% of patients receiving VIBERZI in clinical trials. The majority were associated with excessive alcohol intake. All pancreatic events, whether or not associated with sphincter of Oddi spasm, resolved upon discontinuation of VIBERZI; patients did not have organ failure or local or systemic complications [see Adverse Reactions (6.1)].

Instruct patients to avoid chronic or acute excessive alcohol use while taking VIBERZI. Monitor for new or worsening abdominal pain that may radiate to the back or shoulder, with or without nausea and vomiting. Instruct patients to stop VIBERZI and seek medical attention if they experience symptoms suggestive of pancreatitis such as acute abdominal or epigastric pain radiating to the back associated with elevations of pancreatic enzymes [see Contraindications (4)].

6 ADVERSE REACTIONS

The following adverse reactions described below and elsewhere in the labeling include:

  • Sphincter of Oddi Spasm [see Warnings and Precautions (5.1)]
  • Pancreatitis [see Warnings and Precautions (5.2)]

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates 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 practice.

Over 1700 patients with IBS-D have been treated with 75 or 100 mg of VIBERZI twice daily in controlled trials. Exposures from placebo-controlled clinical trials in adult patients with IBS-D included 1391 exposed for 3 months, 1001 exposed for 6 months and 488 exposed for one year.

Demographic characteristics were comparable between the treatment groups [see Clinical Studies (14)]. Data described below represent pooled data compared to placebo across the randomized trials.

Sphincter of Oddi Spasm

In clinical trials, sphincter of Oddi spasm occurred in 0.2% (2/807) of patients receiving 75 mg and 0.8% (8/1032) of patients receiving 100 mg VIBERZI twice daily.

  • Among patients receiving 75 mg, 1/807 (0.1%) patient experienced a sphincter of Oddi spasm presenting with abdominal pain but with lipase elevation less than 3 times the upper limit of normal (ULN) and 1/ 807 (0.1%) patient experienced a sphincter of Oddi spasm manifested as elevated hepatic enzymes associated with abdominal pain
  • Among patients receiving 100 mg, 1/1032 (0.1%) patient experienced a sphincter of Oddi spasm manifested as pancreatitis and 7/1032 (0.7%) patients experienced sphincter of Oddi spasm manifested as elevated hepatic enzymes associated with abdominal pain

In patients without a gallbladder, 2/165 (1.2%) and 8/184 (4.3%) of patients receiving 75 mg and 100 mg, respectively, experienced a sphincter of Oddi spasm vs 0/1317 (0%) in patients with a gallbladder who had received either 75 mg or 100 mg treatment.

Of those patients who experienced a sphincter of Oddi spasm, 80% (8/10) reported their first onset of symptoms within the first week of treatment. The case of sphincter of Oddi spasm-induced pancreatitis occurred within minutes of taking the first dose of VIBERZI. No cases of sphincter of Oddi spasm occurred greater than 1 month after treatment onset. All events resolved upon discontinuation of VIBERZI, with symptoms typically improved by the following day.

Pancreatitis

Additional cases of pancreatitis, not associated with sphincter of Oddi spasm, were reported in 2/807 (0.2%) of patients receiving 75 mg and 3/1032 (0.3%) of patients receiving 100 mg VIBERZI twice daily in clinical trials. Of these 5 cases, 3 were associated with excessive alcohol intake, one was associated with biliary sludge, and in one case the patient discontinued VIBERZI 2 weeks prior to the onset of symptoms. All pancreatic events resolved with lipase normalization upon discontinuation of VIBERZI, with 80% (4/5) resolving within 1 week of treatment discontinuation. The case of sphincter of Oddi spasm-induced pancreatitis resolved within 24 hours of discontinuation.

Common Adverse Reactions

Table 1 provides the incidence of common adverse reactions reported in > 2% of IBS-D patients in either VIBERZI treatment group and at an incidence greater than in the placebo group.

Table 1: Common* Adverse Reactions in the Placebo-Controlled Studies in IBS-D Patients

* Reported in > 2% of VIBERZI-treated patients at either dose and at an incidence greater than in placebo-treated patients

** Abdominal Pain” term includes: abdominal pain, abdominal pain lower, and abdominal pain upper

*** Rash” term includes: dermatitis, dermatitis allergic, rash, rash erythematous, rash generalized, rash maculo-papular, rash papular, rash pruritic, urticaria, and idiopathic urticaria

Adverse Reactions VIBERZI100 mg twice daily (N= 1032) % VIBERZI75 mg twice daily (N=807) % Placebo (N=975) %
Constipation 8 7 2
Nausea 7 8 5
Abdominal Pain** 7 6 4
Upper Respiratory Tract Infection 5 3 4
Vomiting 4 4 1
Nasopharyngitis 3 4 3
Abdominal Distention 3 3 2
Bronchitis 3 3 2
Dizziness 3 3 2
Flatulence 3 3 2
Rash*** 3 3 2
Increased ALT 3 2 1
Fatigue 2 3 2
Viral gastroenteritis 1 3 2

Constipation was the most commonly reported adverse reaction in VIBERZI-treated patients in these trials. Approximately 50% of constipation events occurred within the first 2 weeks of treatment while the majority occurred within the first 3 months of therapy. Rates of severe constipation were less than 1% in patients receiving 75 mg and 100 mg VIBERZI. Similar rates of constipation occurred between the active and placebo arms beyond 3 months of treatment.

Adverse Reactions Leading to Discontinuation

Eight percent of patients treated with 75 mg, 8% of patients treated with 100 mg VIBERZI and 4% of patients treated with placebo discontinued prematurely due to adverse reactions. In the VIBERZI treatment groups, the most common reasons for discontinuation due to adverse reactions were constipation (1% for 75 mg and 2% for 100 mg) and abdominal pain (1% for both 75 mg and 100 mg). In comparison, less than 1% of patients in the placebo group withdrew due to constipation or abdominal pain.

Less Common Adverse Reactions

Adverse reactions that were reported in ≤ 2% of VIBERZI-treated patients are listed below by body system.

Gastrointestinal: gastroesophageal reflux disease

General Disorders and administration site conditions: feeling drunk

Investigations: increased AST

Nervous system: sedation, somnolence

Psychiatric disorders: euphoric mood

Respiratory: asthma, bronchospasm, respiratory failure, wheezing

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