Lotronex (alosetron HCl)

Dosage of alosetron hydrochloride is expressed in terms of alosetron.

For the treatment of severe diarrhea-predominant irritable bowel syndrome (IBS) in women, the recommended initial dosage of alosetron is 0.5 mg twice daily. Data from a dose-ranging study indicate that risk of constipation is reduced with this dosage compared with a dosage of 1 mg twice daily; however, efficacy of the 0.5-mg twice-daily dosage in women with severe diarrhea-predominant IBS has not been adequately evaluated in clinical studies. If constipation occurs at a dosage of 0.5 mg twice daily, therapy should be withheld until constipation resolves; upon resolution, alosetron may be reinitiated at a reduced dosage of 0.5 mg once daily. If constipation recurs at a dosage of 0.5 mg once daily, treatment with alosetron should be immediately discontinued.

Patients may continue receiving an alosetron dosage of 0.5 mg once or twice daily as maintenance therapy if the dosage is well tolerated and symptoms of IBS are adequately controlled. If the patient tolerates but does not respond adequately to the dosage after 4 weeks, dosage may be increased up to 1 mg twice daily. If adequate control of symptoms is not achieved after 4 weeks of treatment on a dosage of 1 mg twice daily, alosetron therapy should be discontinued.

Alosetron should be discontinued immediately and permanently in patients who develop ischemic colitis. (See Ischemic Colitis under Warnings/Precautions: Warnings, in Cautions.)

If a dose of alosetron is missed, the dose should be skipped and the next dose should be taken at the regularly scheduled time. A double dose should not be taken to make up for the missed dose.

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Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

Alosetron/Selected Dual Cyp1a2 And Cyp3a4 Inhibitors

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Dual inhibitors of CYP1A2 and CYP3A4 may inhibit the metabolism of alosetron.(1,2)

CLINICAL EFFECTS: Concurrent administration with dual CYP1A2 and CYP3A4 inhibitors may result in 6-fold increases in alosetron levels and toxicity.(1,2)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturers of alosetron states that concurrent use is contraindicated.(1)

DISCUSSION: In a study in 40 healthy females, pretreatment with fluvoxamine (escalating doses from 50 mg to 200 mg daily for 16 days) increased the area-under-curve (AUC) and half-life of alosetron by 6-fold and 3-fold, respectively.(1,2) Selected dual CYP1A2 and CYP3A4 inhibitors linked include: enasidenib and fluvoxamine.(3,4)

Selected 5-Ht3 Antagonists/Apomorphine

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: The mechanism for risk of profound hypotension or loss of consciousness is not known.

CLINICAL EFFECTS: Concurrent use of apomorphine with a 5-HT3 antagonist may result in profound hypotension and loss of consciousness.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of apomorphine states that concurrent use with 5-HT3 antagonists is contraindicated. Alternative agents, such as trimethobenzamide, are recommended for prevention of nausea and vomiting caused by apomorphine.(3)

DISCUSSION: Profound hypotension and loss of consciousness have been reported with the concurrent use of apomorphine and ondansetron.(1,2) Selected 5-HT3 Antagonists linked to this monograph include: alosetron, azasetron, and ramosetron.

Selected Cyp1a2 Substrates/Viloxazine

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Viloxazine is a strong inhibitor of CYP1A2 and may increase the total exposure of sensitive CYP1A2 substrates.(1) The FDA defines strong inhibition as an increase in drug area-under-curve (AUC) greater than 5-fold.(2)

CLINICAL EFFECTS: Concurrent use of viloxazine with drugs primarily metabolized by CYP1A2 may lead to elevated drug levels and increase the risk of adverse reactions associated with the CYP1A2 substrate.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Drugs linked to this monograph have a narrow therapeutic window or are sensitive to CYP1A2 inhibition. Coadministration of viloxazine with sensitive CYP1A2 substrates or CYP1A2 substrates with a narrow therapeutic window is contraindicated.(1)

DISCUSSION: Concomitant use of viloxazine significantly increases the total exposure, but not peak exposure, of sensitive CYP1A2 substrates, which may increase the risk of adverse reactions associated with these CYP1A2 substrates. In a study, viloxazine increased the AUC of caffeine by almost 6-fold.(1) CYP1A2 substrates linked to this monograph include: agomelatine, alosetron, aminophylline, duloxetine, ramelteon, tasimelteon, and theophylline.(2,3)

There are no severe interactions for this drug.

Moderate Interaction: Assess the risk to the patient and take action as needed.

5-Ht3 Antagonists/Tramadol

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: The interaction may involve a reduction in the binding involving 5-HT3 receptors.(1)

CLINICAL EFFECTS: Concurrent use of 5-HT3 antagonists may decrease the effectiveness of tramadol, resulting in increased use of tramadol.(1-3) 5-HT3 antagonists may not be effective in reducing tramadol-induced nausea.(4)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Consider the use of alternative anti-emetics in patients receiving tramadol, or the use of other opioids in patients receiving 5-HT3 antagonists.

DISCUSSION: In a randomized study in 59 post-surgical patients in recovery, compared to tramadol alone, patients receiving concurrent ondansetron required significantly larger doses of tramadol at four hours (223 mg versus 71 mg), at 8 hours (285 mg versus 128 mg), and at 12 hours (406 mg versus 190 mg). Vomiting rates at 4 hours and 8 hours were significantly higher with tramadol and concurrent ondansetron compared to tramadol alone.(1) In a randomized, double-blind study in 40 surgical patients undergoing lumbar laminectomy, compared to tramadol alone, cumulative tramadol consumption with concurrent ondansetron during the first 24 hours was significantly increased (between 26% and 35%) as well as thereafter (22% to 25%).(2) In another randomized study in 120 post-surgical patients, it was discovered that tramadol consumption was increased in those patients receiving concurrent ondansetron compared to tramadol alone.(3) In a prospective, randomized, double-blinded study in dental patients, patients received one of four treatments: fentanyl and metoclopramide, tramadol and metoclopramide, fentanyl and ondansetron, or tramadol and ondansetron. The patients who received tramadol and ondansetron had the highest nausea scores among the treatment groups. There were no significant differences in the incidences of pain or nausea in the 24 hours following the procedure.(4) In a randomized, controlled trial in 40 surgical patients undergoing hernioplasty or thyroidectomy, compared to tramadol alone, cumulative tramadol consumption was higher at the 2-hour time point with concurrent ondansetron (0.24 +/- 0.1 vs. 0.17 +/- 0.16; p = 0.01).(5) A systematic review and meta-analysis of randomized controlled trials in the postoperative setting comparing tramadol alone and in combination with ondansetron were included. At 4-hours, 8-hours, 12-hours, and 24-hours post-procedure, patients had increased tramadol requirements when administered with concurrent ondansetron compared to tramadol alone.(6) 5-HT3 antagonists linked to this monograph include: alosetron, azasetron, dolasetron, granisetron, ondansetron, palonosetron, ramosetron, and tropisetron.

Current constipation, history of chronic or severe constipation, or history of complications related to constipation. History of intestinal obstruction, stricture, toxic megacolon, GI perforation, and/or adhesions. History of ischemic colitis, impaired intestinal circulation, thrombophlebitis, or hypercoagulable state. History of Crohn's disease, ulcerative colitis, or diverticulitis.

History of severe hepatic impairment.

Concomitant use of fluvoxamine. (See Drug Interactions: Fluvoxamine.)

• Adhesion of gastrointestinal tract
• Child-pugh class C hepatic impairment
• Constipation
• Crohn's disease
• Diverticulitis of gastrointestinal tract
• Gastrointestinal obstruction
• Gastrointestinal perforation
• Ischemic bowel disease
• Thrombophilia
• Thrombophlebitis
• Toxic megacolon
• Ulcerative colitis

• Disease of liver

There are no moderate contraindications for this drug.

Adverse effects occurring in 2% or more of patients with IBS receiving alosetron in clinical studies include constipation, abdominal discomfort or pain, nausea, GI discomfort or pain, abdominal distention, regurgitation and reflux, and hemorrhoids. In women with severe diarrhea-predominant IBS, diarrhea, hemorrhoidal hemorrhage, and flatulence also were reported in addition to the adverse effects observed in the general IBS population.

Less Frequent

• Bleeding hemorrhoids
• Severe constipation

Rare or Very Rare

• Abnormal hepatic function tests
• Bacterial infection
• Cardiac arrhythmia
• Extrasystoles
• Fecal impaction
• Gastrointestinal obstruction
• Gastrointestinal perforation
• Gastrointestinal ulcer
• Hyperbilirubinemia
• Hypertension
• Hypothalamic-pituitary insufficiency
• Ileus
• Intussusception of intestine
• Ischemic bowel disease
• Ischemic colitis
• Tachyarrhythmia
• Toxic megacolon
• Ulcerative colitis
• Urticaria

More Frequent

• Constipation

Less Frequent

• Acute abdominal pain
• Diarrhea
• Flatulence
• Upper respiratory infection
• Urinary tract infection

Rare or Very Rare

• Abdominal distension
• Abnormal sexual function
• Abnormal vaginal bleeding
• Acne vulgaris
• Allergic rhinitis
• Cough
• Depression
• Dysgeusia
• Dyspepsia
• Dyspnea
• Fatigue
• Folliculitis
• Gastritis
• Gastroesophageal reflux disease
• Headache disorder
• Hematoma
• Hemorrhoids
• Hyperhidrosis
• Hypnagogic hallucination
• Hypoesthesia
• Increased urinary frequency
• Insomnia
• Irregular menstrual periods
• Malaise
• Nausea
• Parosmia
• Pharyngitis
• Photophobia
• Polyuria
• Proctitis
• Sedation
• Sinusitis
• Skin rash
• Sore throat
• Symptoms of anxiety
• Viral infection
• Xerostomia

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Safety and efficacy of alosetron have not been established in pediatric patients younger than 18 years of age. The drug is not recommended for use in the pediatric population because of the risk of serious GI complications.

Category B. (See Users Guide.) There are no adequate and well-controlled studies of alosetron in pregnant women; animal reproduction studies using alosetron doses up to 160-240 times the recommended human dose have not demonstrated any evidence of fetal harm. Alosetron should be used during pregnancy only if clearly needed.

Alosetron and/or its metabolites are distributed into milk in rats; it is not known whether alosetron is distributed into milk in humans. Caution is advised if the drug is administered in nursing women.

In some studies in healthy individuals, plasma concentrations of alosetron were increased by approximately 40% in those 65 years of age or older compared with younger adults.

Because of evidence suggesting that geriatric patients may be at greater risk for complications of constipation, alosetron should be used with caution and appropriate follow-up in such patients.