Viberzi

Name: Viberzi

Pregnancy & Lactation

Pregnancy

No studies in pregnant women

Animal reproduction studies

  • Oral and SC administration of eluxadoline to rats and rabbits during organogenesis at doses approximately 51 and 115 times the human exposure after a single oral dose of 100 mg, respectively, demonstrated no teratogenic effects. In a prenatal and postnatal development study in rats
  • No adverse effects were observed in offspring with oral administration of eluxadoline at doses approximately 10 times the human exposure

Lactation

Unknown if distributed in human breast milk

Secreted in rat milk

Consider the developmental and health benefits of breastfeeding along with the mother’s clinical need for the drug and any potential adverse effects on the breastfed infant from the drug or from the underlying maternal condition

Pregnancy Categories

A:Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B:May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C:Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D:Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X:Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA:Information not available.

Overdose

No reports of overdosage with VIBERZI have been reported.

In the event of acute overdose, the stomach should be emptied and adequate hydration maintained. The patient should be carefully observed and given standard supportive treatment as required. Given eluxadoline's action at opioid receptors, administration of a narcotic mu-opioid antagonist, such as naloxone, should be considered. Considering the short half-life of naloxone, repeated administration may be necessary. In the event of naloxone administration, subjects should be monitored closely for the return of overdose symptoms, which may indicate need for repeated naloxone injection.

Storage

Store the medicine in a closed container at room temperature, away from heat, moisture, and direct light. Keep from freezing.

Keep out of the reach of children.

Do not keep outdated medicine or medicine no longer needed.

Ask your healthcare professional how you should dispose of any medicine you do not use.

Viberzi Precautions

Serious side effects have been reported with Viberzi including the following:

  • Sphincter of Oddi Spasm. Tell your healthcare provider right away if you have some or all of the following symptoms of sphincter of Oddi spasm.
    • abdominal pain that may radiate to the back or shoulder
    • pancreatitis
    • nausea
    • vomiting
  • Pancreatitis that is not related to sphincter of Oddi spasm. Tell your healthcare provider right away if you have some or all of the following symptoms of pancreatits.
    • abdominal pain that may radiate to the back or shoulder
    • nausea
    • vomiting

Those who do not have a gallbladder have an increased risk of developing serious pancreatitis that could result in hospitalization or death. 

Viberzi can cause drowsiness. Do not drive or operate heavy machinery until you know how Viberzi affects you.

Do not take Viberzi if you:

  • are allergic to Viberzi or to any of its ingredients
  • have known or suspected biliary duct obstruction, or sphincter of Oddi disease or dysfunction
  • have a history of alcoholism, alcohol abuse, alcohol addiction, or drink more than 3 alcoholic beverages/day
  • have a history of pancreatitis or structural diseases of the pancreas, including known or suspected pancreatic duct obstruction
  • have severe hepatic impairment (Child-Pugh Class C)
  • have severe constipation or known or suspected mechanical gastrointestinal obstruction

Inform MD

Before taking Viberzi, tell your doctor about all of your medical conditions. Especially tell your doctor if you:

  • are allergic to Viberzi or to any of its ingredients
  • do not have a gallbladder
  • have liver problems
  • have a history of alcohol or drug abuse
  • are pregnant or breastfeeding

Tell your doctor about all the medicines you take including prescription and non-prescription medicines, vitamins, and herbal supplements.

Other Requirements

  • Store Viberzi at room temperature.
  • Keep this and all medicines out of the reach of children.
  • Do not use alcohol regularly or excessively while taking Viberzi.

What is eluxadoline?

Eluxadoline works directly in your intestines to slow the movement of food during digestion. Eluxadoline also makes the nerves in your intestines less sensitive to stimulation.

Eluxadoline is used to treat irritable bowel syndrome when the main symptom is diarrhea.

Eluxadoline may also be used for purposes not listed in this medication guide.

What should I avoid while taking eluxadoline?

Avoid drinking alcohol. It may increase your risk of pancreas problems.

Avoid taking anti-diarrhea medicine such as loperamide (Imodium) without your doctor's advice. Taking loperamide long-term while you are taking eluxadoline may cause severe constipation.

Viberzi Pharmacokinetics

Absorption

Bioavailability

Poorly absorbed after oral administration; some data suggest moderate hepatic first-pass extraction occurs.2 8 Absolute oral bioavailability not established.1

Exhibits substantial interpatient variability in pharmacokinetic parameters.1 7

Median time to peak plasma concentration is 1.5 (range: 1–8) or 2 (range: 0.5–6) hours under fed or fasting conditions, respectively, following a single oral 100-mg dose in healthy individuals.1

Exhibits approximately linear pharmacokinetics with no evidence of accumulation with twice-daily dosing.1 7

Food

High-fat meal decreases peak plasma concentration and AUC by 50 and 60%, respectively.1 7

Special Populations

Hepatic impairment: Plasma concentrations increased by 6-, 4-, and 16-fold in patients with mild, moderate, or severe (Child-Pugh class A, B, or C) hepatic impairment, respectively.1

Distribution

Extent

Distributed into milk in rats; not known whether distributed into human milk.1

Plasma Protein Binding

81%.1

Elimination

Metabolism

Not fully established; an acyl glucuronide metabolite has been detected in urine.1 7

Elimination Route

Excreted principally in feces (approximately 82%); <1% excreted in urine.1

Half-life

3.7–6 hours.1 7

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Subject to control under the Federal Controlled Substances Act of 1970 as a schedule IV (C-IV) drug.1

Eluxadoline

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets, film-coated

75 mg

Viberzi ( C-IV)

Actavis

100 mg

Viberzi ( C-IV)

Actavis

Before Using Viberzi

In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For this medicine, the following should be considered:

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to this medicine or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.

Pediatric

Appropriate studies have not been performed on the relationship of age to the effects of eluxadoline in the pediatric population. Safety and efficacy have not been established.

Geriatric

Appropriate studies performed to date have not demonstrated geriatric-specific problems that would limit the usefulness of eluxadoline in the elderly. However, elderly patients are more likely to have unwanted side effects and stomach problems, which may require caution in patients receiving eluxadoline.

Breast Feeding

There are no adequate studies in women for determining infant risk when using this medication during breastfeeding. Weigh the potential benefits against the potential risks before taking this medication while breastfeeding.

Interactions with Medicines

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are taking this medicine, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using this medicine with any of the following medicines is usually not recommended, but may be required in some cases. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

  • Alfentanil
  • Atazanavir
  • Cyclosporine
  • Dihydroergotamine
  • Eltrombopag
  • Ergotamine
  • Fentanyl
  • Flibanserin
  • Gemfibrozil
  • Lopinavir
  • Pimozide
  • Quinidine
  • Rifampin
  • Ritonavir
  • Rosuvastatin
  • Saquinavir
  • Sirolimus
  • Tacrolimus
  • Temsirolimus
  • Tipranavir

Interactions with Food/Tobacco/Alcohol

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using this medicine with any of the following is not recommended. Your doctor may decide not to treat you with this medication, change some of the other medicines you take, or give you special instructions about the use of food, alcohol, or tobacco.

  • Ethanol

Other Medical Problems

The presence of other medical problems may affect the use of this medicine. Make sure you tell your doctor if you have any other medical problems, especially:

  • Alcohol abuse or addiction or
  • Bowel or stomach blockage, known or suspected or
  • Constipation (severe), history of or
  • Gallbladder blockage, known or suspected or
  • Liver disease, severe or
  • Pancreas problems (eg, blockage in the pancreas) or
  • Pancreatitis (inflammation of the pancreas), history of or
  • Patients who drink more than 3 alcoholic beverages a day or
  • Patients without a gallbladder or
  • Sphincter of Oddi disease, known or suspected—Should not be used in patients with these conditions.
  • Liver disease, mild to moderate—Use with caution. The effects may be increased because of slower removal of the medicine from the body.

What are some things I need to know or do while I take Viberzi?

  • Tell all of your health care providers that you take Viberzi. This includes your doctors, nurses, pharmacists, and dentists.
  • Talk with your doctor before you drink alcohol.
  • Avoid driving and doing other tasks or actions that call for you to be alert until you see how this medicine affects you.
  • This medicine may affect how much of some other drugs are in your body. If you are taking other drugs, talk with your doctor. You may need to have your blood work checked more closely while taking Viberzi with your other drugs.
  • A very bad and sometimes deadly pancreas problem (pancreatitis) has happened with this medicine. Talk with your doctor.
  • A problem with the part of your body that controls the flow of bile and pancreas juice to the small bowels (sphincter of Oddi) has happened with Viberzi. Sometimes, people have had to go to the hospital. Talk with the doctor.
  • If you are 65 or older, use this medicine with care. You could have more side effects.
  • Tell your doctor if you are pregnant or plan on getting pregnant. You will need to talk about the benefits and risks of using Viberzi while you are pregnant.
  • Tell your doctor if you are breast-feeding. You will need to talk about any risks to your baby.

Adverse Reactions

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

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

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.

Pancreatitis

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.

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

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.

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 Viberzi
100 mg twice daily
(N= 1032)
%
Viberzi
75 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

Use in specific populations

Pregnancy

Risk Summary

There are no studies with Viberzi in pregnant women that inform any drug-associated risks. The background risk of major birth defects and miscarriage for the indicated population is unknown. However, the background risk in the U.S. general population of major birth defects is 2 to 4% and of miscarriage is 15 to 20% of clinically recognized pregnancies. In animal reproduction studies, oral and subcutaneous administration of eluxadoline to rats and rabbits during organogenesis at doses approximately 51 and 115 times the human exposure after a single oral dose of 100 mg, respectively, demonstrated no teratogenic effects. In a pre- and postnatal development study in rats, no adverse effects were observed in offspring with oral administration of eluxadoline at doses approximately 10 times the human exposure [see Data].

Data

Animal Data

Eluxadoline administered as combined oral (1000 mg/kg/day) and subcutaneous (5 mg/kg/day) doses during the period of organogenesis to rats and rabbits (exposures about 51 and 115 times, respectively, the human AUC of 24 ng.h/mL after a single oral dose of 100 mg) did not cause any adverse effects on embryofetal development. A pre- and postnatal development study in rats showed no evidence of any adverse effect on pre- and postnatal development at oral doses of eluxadoline up to 1000 mg/kg/day (with exposures about 10 times the human AUC of 24 ng.h/mL after a single oral dose of 100 mg). In the same study, eluxadoline was detected in the milk of lactating rats administered oral doses of 100, 300 and 1000 mg/kg/day (with exposures about 1.8, 3 and 10 times, respectively, the human AUC of 24 ng.h/mL after a single oral dose of 100 mg). Milk samples were collected from six lactating females per group on lactation day 12. Mean concentrations of eluxadoline in the milk of lactating rats on lactation day 12 were 2.78, 5.49 and 44.02 ng/mL at 100, 300 and 1000 mg/kg/day, respectively.

Lactation

Risk Summary

No data are available regarding the presence of eluxadoline in human milk, the effects of eluxadoline on the breastfed infant, or the effects of eluxadoline on milk production. However, eluxadoline is present in rat milk [see Use in Specific Populations (8.1)].

The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for Viberzi and any potential adverse effects on the breastfed infant from Viberzi or from the underlying maternal condition.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Juvenile Toxicology Data

Eluxadoline was orally administered to juvenile rats at 500, 750, and 1500 mg/kg/day (about 16, 54 and 30 times, respectively, the human AUC of 24 ng.h/mL after a single oral dose of 100 mg) for 4 weeks. There were no adverse physiologic effects related to eluxadoline. Based on these results, the NOAEL for male and female juvenile rats was 1500 mg/kg/day (about 30 times the human AUC of 24 ng.h/mL after a single oral dose of 100 mg).

Geriatric Use

Of 1795 IBS-D patients in clinical trials of Viberzi who received 75 mg or 100 mg twice daily, 139 (7.7%) were at least 65 years of age, while 15 (0.8%) were at least 75 years old. No overall differences in effectiveness were observed between these patients and younger patients. There were no overall differences in the types of adverse reactions observed between elderly and younger patients; however, a higher proportion of elderly patients than younger patients experienced adverse reactions (66% vs 59%), serious adverse reactions (9% vs 4%), and gastrointestinal adverse reactions (39% vs 28%).

Hepatic Impairment

Plasma concentrations of eluxadoline increase in patients with hepatic impairment [see Clinical Pharmacology (12.3)].

Viberzi is contraindicated in patients with severe hepatic impairment (Child-Pugh Class C) as plasma concentrations of eluxadoline increase significantly (16-fold) and there is no information to support the safety of Viberzi in these patients.

In patients with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment, plasma concentrations of eluxadoline increase to a lesser extent (6- and 4-fold, respectively). Administer Viberzi at a reduced dose of 75 mg twice daily to these patients [see Dosage and Administration (2)]. Monitor patients with any degree of hepatic impairment for impaired mental or physical abilities needed to perform potentially hazardous activities such as driving a car or operating machinery and for other eluxadoline-related adverse reactions [see Adverse Reactions (6.1)].

What is Viberzi?

Viberzi (eluxadoline) works directly in your intestines to slow the movement of food during digestion. Eluxadoline also makes the nerves in your intestines less sensitive to stimulation.

Viberzi is used to treat irritable bowel syndrome when the main symptom is diarrhea.

Viberzi may also be used for purposes not listed in this medication guide.

What should I avoid while taking Viberzi?

Avoid drinking alcohol. It may increase your risk of pancreas problems.

Avoid taking anti-diarrhea medicine such as loperamide (Imodium) without your doctor's advice. Taking loperamide long-term while you are taking Viberzi may cause severe constipation.

For Healthcare Professionals

Applies to eluxadoline: oral tablet

General

The most commonly reported adverse reactions included constipation, nausea, and abdominal pain.[Ref]

Gastrointestinal

Common (1% to 10%): Constipation, nausea, abdominal pain, vomiting, abdominal distention, flatulence, viral gastroenteritis
Uncommon (0.1% to 1%): Sphincter of Oddi spasm, pancreatitis
Frequency not reported: Gastroesophageal reflux disease
Postmarketing reports: Hospitalizations and deaths due to pancreatitis, particularly in patients without a gallbladder[Ref]

As of February 2017, the US FDA has received 120 reports of serious pancreatitis or death associated with this drug; 76 of these patients were hospitalized and 2 died. Both patients who died did not have a gallbladder; 56 of the 68 patients who reported gallbladder status did not have a gallbladder and had been receiving the recommended dose. Also reported among these cases were 6 with sphincter of Oddi spasm and 16 with abdomen pain.

Sphincter of Oddi spasm occurred in 0.2% (n=807) and 0.8% (n=1032) of patients receiving 75 mg and 100 mg twice a day, respectively. Sphincter of Oddi spasm manifested as abdominal pain with lipase elevation of less than 3 times the upper limit of normal in 1 patient, and elevated hepatic enzymes associated with abdominal pain in the second patient. For the 8 patients taking 100 mg twice a day, sphincter of Oddi spasm manifested in 1 patient as pancreatitis and as elevated hepatic enzymes associated with abdominal pain in the other 7 patients. Of 1317 patients with a gallbladder, no patients experienced a sphincter of Oddi spasm, while 2 of 165 patients and 8 of 184 patients in the 75 mg and 100 mg twice a day groups, respectively, experienced sphincter of Oddi spasm. Onset of symptoms occurred within the first week in 80% (8 of 10) of patients and no cases occurred greater than 1 month after treatment onset. The 1 case of sphincter of Oddi spasm-induced pancreatitis occurred within minutes of taking the first dose of the drug and resolved within 24 hours of discontinuation.

Pancreatitis not associated with sphincter of Oddi spasm was reported in 0.2% (n=807) and 0.3% (n=1032) of patients receiving 75 mg and 100 mg twice a day, respectively. Of these 5 cases, 3 were associated with excessive alcohol intake, 1 with biliary sludge, and 1 was reported 2 weeks after the patient discontinued therapy. All resolved within 1 week of therapy discontinuation.

Constipation was the most commonly reported adverse event in clinical trials with 50% of case reported within the first 2 weeks, and the majority within the first 3 months. Rates of severe constipation were less than 1%. After 3 months, the incidence of constipation was similar across active treatment and placebo groups.

Gastroesophageal reflux disease was reported in 2% or less of patients in clinical trials.[Ref]

Hepatic

Increased AST was reported in 2% or less of patients in clinical trials.[Ref]

Frequency not reported: Increased AST, increased ALT[Ref]

Respiratory

Common (1% to 10%): Upper respiratory tract infection, nasopharyngitis, bronchitis
Frequency not reported: Asthma, bronchospasm, respiratory failure, wheezing[Ref]

Asthma, bronchospasm, respiratory failure, and wheezing were reported in 2% or less of patients in clinical trials.[Ref]

Dermatologic

Common (1% to 10%): Rash[Ref]

Rash included terms such as dermatitis, dermatitis allergic, rash, rash erythematous, rash generalized, rash maculopapular, rash popular, rash pruritic, urticaria, and idiopathic urticaria.[Ref]

Nervous system

Common (1% to 10%): Dizziness
Frequency not reported: Sedation, somnolence[Ref]

Sedation and somnolence was reported in 2% or less of patients in clinical trials.[Ref]

Psychiatric

Euphoric mood was reported in 2% or less of patients in clinical trials.[Ref]

Frequency not reported: Euphoric mood[Ref]

Other

Feeling drunk was reported in 2% or less of patients in clinical trials.[Ref]

Common (1% to 10%): Fatigue
Frequency not reported: Feeling drunk[Ref]

Some side effects of Viberzi may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.

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