Anti-Diarrheal (loperamide HCl)

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There are no contraindication interactions for this drug.

Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

Loperamide/Saquinavir

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: The exact mechanism is unknown, but loperamide may decrease saquinavir absorption.(1) Saquinavir may increase loperamide absorption.(2)

CLINICAL EFFECTS: Concurrent use may result in decreased levels and effectiveness of saquinavir(1,2) and elevated levels of loperamide, which may result in respiratory depression.(2)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Consider avoiding the use of loperamide, especially for long-term use, in patients receiving saquinavir.(1) If concurrent use is warranted, monitor for decrease saquinavir levels and efficacy.(2) The dosage of saquinavir may need adjusting. Consider lower doses of loperamide in these patients and monitor for adverse effects, including respiratory depression.

DISCUSSION: In a study in 12 healthy subjects, administration of a single dose of loperamide (16 mg) with a single dose of saquinavir (600 mg) decreased the saquinavir area-under-curve (AUC) and maximum concentration (Cmax) by 54% and 46%, respectively.(1) Loperamide AUC increased by 40%.(1)

Selected P-Glycoprotein (P-GP) Substrates/Venetoclax

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Venetoclax is an inhibitor of the P-glycoprotein (P-gp) system and may increase the absorption of P-gp substrates.(1)

CLINICAL EFFECTS: Concurrent use of venetoclax with P-gp substrates may result in elevated levels and toxicities of the substrate.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of venetoclax states that the concurrent use of P-gp substrates should be avoided. If concurrent therapy cannot be avoided, the P-gp substrate should be taken at least 6 hours before venetoclax.(1) If concurrent therapy with afatinib is unavoidable and not tolerated, the US manufacturer of afatinib states that the afatinib dose should be reduced by 10 mg. Resume the previous dose of afatinib if venetoclax is discontinued.(2) The manufacturer of ubrogepant recommends a dosage adjustment of ubrogepant when coadministered with P-gp inhibitors. The initial dose of ubrogepant should not exceed 50 mg. If a second dose of ubrogepant is needed, the dose should not exceed 50 mg.(8)

DISCUSSION: In vitro data suggests venetoclax is a P-gp inhibitor at therapeutic doses in the gut.(1) Administration of a single venetoclax 100 mg dose with digoxin increased the maximum concentration (Cmax) and area-under-the-curve of digoxin by 35% and 9%, respectively.(1) Selected P-gp substrates linked to this monograph include: afatinib, aliskiren, betrixaban, bilastine, cyclosporine, dabigatran, digoxin, edoxaban, everolimus, loperamide, sirolimus, talazoparib, topotecan, and ubrogepant.(1-9)

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

Loperamide/Cyp3a4; Cyp2c8; P-Glycoprotein (P-GP) Inhibitors

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

MECHANISM OF ACTION: Inhibitors of CYP3A4, CYP2C8, and/or P-gp may increase loperamide systemic absorption and facilitate entry into central nervous system (CNS).(1)

CLINICAL EFFECTS: Concurrent use of inhibitors of CYP3A4, CYP2C8, and/or P-gp may increase levels of loperamide, resulting in respiratory depression.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Use loperamide with caution in patients receiving inhibitors of CYP3A4, CYP2C8, and/or P-gp. Consider lower doses of loperamide in these patients and monitor for adverse effects. The manufacturer of lonafarnib recommends starting loperamide at a dose of 1 mg and slowly increasing the dose as needed.(2)

DISCUSSION: In a randomized, cross-over study in 12 healthy subjects, itraconazole (100 mg twice daily for 5 days - first dose 200 mg), gemfibrozil (600 mg twice daily), and the combination of itraconazole and gemfibrozil (same dosages) increased the area-under-curve (AUC) of single doses of loperamide (4 mg) by 2.9-fold, 1.6-fold, and 4.2-fold, respectively.(3) In a study of healthy subjects, lonafarnib (100 mg twice daily for 5 days) increased the AUC and maximum concentration (Cmax) of single dose loperamide (2 mg) by 299% and 214%, respectively.(3) In a study in 18 healthy males, quinidine increased the AUC of a single dose of loperamide by 2.2-fold and markedly decreased pupil size.(4) In a study in 8 healthy subjects, subjects experienced respiratory depression when a single dose of loperamide (16 mg) was administered with a single dose of quinidine (600 mg) but not when loperamide was administered alone.(6) Loperamide plasma levels increased 2-fold to 3-fold.(5) Coadministration of trofinetide 12,000 mg twice daily with 4 mg of loperamide increased the AUC of loperamide by 1.73-fold and the Cmax by 1.95-fold. Administration of trofinetide 2 hours prior to loperamide increased the AUC of loperamide by 1.22-fold and the Cmax by 1.44-fold.(7)

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• Paralytic ileus

• Bloody diarrhea
• Infectious diarrhea

• Disease of liver

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Rare or Very Rare

• Allergic dermatitis
• Anaphylaxis
• Angioedema
• Erythema multiforme
• Paralytic ileus
• Skin rash
• Stevens-johnson syndrome
• Toxic epidermal necrolysis
• Toxic megacolon
• Urinary retention

Less Frequent

• Abdominal distension
• Abdominal pain with cramps
• Constipation
• Dizziness
• Pruritus of skin

Rare or Very Rare

• Anticholinergic toxicity
• Drowsy
• Dyspepsia
• Flatulence
• Nausea
• Urticaria
• Vomiting
• Xerostomia

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