PROPRANOLOL-HYDROCHLOROTHIAZID (propranolol hcl/hydrochlorothiazide)

There are 5 contraindications. These drug combinations generally should not be dispensed or administered to the same patient. A manufacturer label warning that indicates the contraindication warrants inclusion of a drug combination in this category, regardless of clinical evidence or lack of clinical evidence to support the contraindication.

Drug Interaction	Drug Names
Thioridazine/Pindolol; Propranolol 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: Pindolol and propranolol may inhibit the metabolism of thioridazine at CYP3A4.(1) CLINICAL EFFECTS: Concurrent use of pindolol or propranolol with thioridazine may result in elevated levels of thioridazine and prolongation of the QTc interval, which may result in potentially life-threatening arrhythmias,(1) and elevated levels of the beta blocker. PREDISPOSING FACTORS: The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(4) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentration of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(4) PATIENT MANAGEMENT: The manufacturer of thioridazine states that concurrent use with pindolol or propranolol is contraindicated.(1) If concurrent therapy is deemed medically necessary, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting. DISCUSSION: In one study, two patients receiving thioridazine (600 mg/day to 800 mg/day) developed thioridazine levels that were in the potentially toxic range following the administration of propranolol. In one patient, thioridazine levels increased 433% over 40 days of concurrent therapy. The other patient's level increased 275% after 26 days of concurrent therapy. Neither patient exhibited any signs or symptoms of thioridazine toxicity.(2) In another study, administration of pindolol (40 mg/day) to eight patients receiving thioridazine (150 mg/day) resulted in an increase in thioridazine levels by 36%, as well as increases in the levels of the thioridazine metabolites. In addition, in seven patients, pindolol levels were found to be increased when administered with thioridazine.(3)	THIORIDAZINE HCL, THIORIDAZINE HYDROCHLORIDE
Dofetilide/Thiazide Diuretics 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: Thiazide diuretics may decrease the excretion of dofetilide and may decrease potassium levels.(1) CLINICAL EFFECTS: Concurrent use of dofetilide with a thiazide diuretic may result in elevated levels and clinical effects of dofetilide, as well as prolongation of the QT interval.(1) PREDISPOSING FACTORS: Renal impairment may increase risk for excessive QTc prolongation as dofetilide is primarily renally eliminated. To prevent increased serum levels and risk for ventricular arrhythmias, dofetilide must be dose adjusted for creatinine clearance < or = to 60 mL/min.(1) The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, and advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2) PATIENT MANAGEMENT: The manufacturer of dofetilide states that the concurrent use of dofetilide with hydrochlorothiazide, alone or in combination with triamterene, is contraindicated.(1) Other thiazides should also be considered contraindicated as well. If concurrent therapy is deemed medically necessary, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting. DISCUSSION: In a study, hydrochlorothiazide (50 mg daily) alone or hydrochlorothiazide/triamterene (50 mg/100 mg daily) was administered with dofetilide (500 mcg twice daily) for 5 days following 2 days of diuretic use at half-dose. In patients receiving hydrochlorothiazide alone, the area-under-curve (AUC) and maximum concentration (Cmax) of dofetilide increased by 27% and by 21%, respectively. The pharmacodynamic effects of dofetilide increased by 197% (QTc increase over time) and by 95% (maximum QTc increase). In patients on combination hydrochlorothiazide/triamterene, dofetilide AUC and Cmax increased by 30% and by 16%, respectively. The pharmacodynamic effects of dofetilide increased by 190% (QTc increase over time) and by 84% (maximum QTc increase).(1) Dofetilide clearance was 16% lower in patients receiving thiazide diuretics.(1)	DOFETILIDE, TIKOSYN
Disopyramide/Class IB, II, and IV Antiarrhythmics 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: Disopyramide has been shown to prolong the QTc interval. Concurrent use with other agents that affect the heart rate and rhythm may result in unpredictable effect on heart rhythm.(1-2) CLINICAL EFFECTS: The concurrent use of disopyramide with other agents that affect the heart rate and rhythm may result in in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(1-2) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The US manufacturer of disopyramide states that concurrent use of disopyramide with antiarrhythmic agents should be reserved for patients with life-threatening arrhythmias who are demonstrably unresponsive to single-agent antiarrhythmic therapy.(3) The Australian manufacturer of disopyramide states that the concurrent use of other antiarrhythmics, such as Class I, II, III, or IV is contraindicated.(1) The US manufacturer of verapamil states that disopyramide should not be administered within 48 hours before or 24 hours after verapamil.(2) The Australian manufacturer of celiprolol states that the concurrent use of antiarrhythmics such as disopyramide is contraindicated during treatment with celiprolol (exception: intensive care).(4) If concurrent therapy is deemed medically necessary, obtain serum calcium, magnesium, and potassium levels and monitor ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting. DISCUSSION: Because combinations of antiarrhythmics are not well researched and concurrent use may result in unpredictable effects, the Australian manufacturer of disopyramide states that the concurrent use of other antiarrhythmics, such as Class I, II, III, or IV is contraindicated.(1)	DISOPYRAMIDE PHOSPHATE, NORPACE, NORPACE CR
Fezolinetant/CYP1A2 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: Inhibitors of CYP1A2 may inhibit the metabolism of fezolinetant.(1-4) CLINICAL EFFECTS: Concurrent use of a CYP1A2 inhibitor may increase levels of and adverse effects from fezolinetant.(1-4) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Recommendations for concurrent use of fezolinetant with CYP1A2 inhibitors differ in different regions. The US manufacturer of fezolinetant states that concurrent use with strong, moderate, and weak CYP1A2 inhibitors is contraindicated.(1) The Australian, Canadian, and UK manufacturers of fezolinetant state that concurrent use with strong and moderate CYP1A2 inhibitors is contraindicated, while weak CYP1A2 inhibitors are not predicted to cause clinically relevant changes in fezolinetant exposure.(2-4) DISCUSSION: In a study, fluvoxamine, a strong CYP1A2 inhibitor, increased fezolinetant maximum concentration (Cmax) and area-under-curve (AUC) by 80% and 840%, respectively. Mexiletine (400 mg every 8 hours), a moderate CYP1A2 inhibitor, increased fezolinetant Cmax and AUC by 40% and 360%, respectively. Cimetidine (300 mg every 6 hours), a weak CYP1A2 inhibitor, increased fezolinetant Cmax and AUC by 30% and 100%, respectively.(1) Strong CYP1A2 inhibitors linked to this monograph include angelica root, ciprofloxacin, enasidenib, enoxacin, fluvoxamine, and rofecoxib. Moderate CYP1A2 inhibitors linked to this monograph include capmatinib, dipyrone, fexinidazole, genistein, hormonal contraceptives, methoxsalen, mexiletine, osilodrostat, phenylpropanolamine, pipemidic acid, rucaparib, troleandomycin, vemurafenib, and viloxazine. Weak CYP1A2 inhibitors linked to this monograph include acyclovir, allopurinol, artemisinin, belumosudil, caffeine, cannabidiol, cimetidine, curcumin, dan-shen, deferasirox, disulfiram, Echinacea, famotidine, ginseng, norfloxacin, obeticholic acid, parsley, piperine, propafenone, propranolol, ribociclib, simeprevir, thiabendazole, ticlopidine, triclabendazole, valacyclovir, verapamil, and zileuton.(5-7)	VEOZAH
Rizatriptan (Greater Than 5 mg)/Propranolol 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 exact mechanism is unknown. CLINICAL EFFECTS: Concurrent administration of rizatriptan and propranolol may increase the levels of rizatriptan.(1,2) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Patients on concurrent propranolol should not use the 10 mg-dose of rizatriptan.(1) For adult patients receiving propranolol, the manufacturer of rizatriptan states that the 5 mg dose of rizatriptan should be used and that a maximum of three doses (15 mg) should be administered in a 24 hour period.(1) For pediatric patients 6-17 years old who weigh less than 40 kg (88 lb) and are receiving propranolol, rizatriptan should not be given.(1) For pediatric patients 6-17 years old who weigh at least 40 kg (88 lb) and are receiving propranolol, a single 5 mg dose of rizatriptan is recommended (maximum dose of 5 mg in a 24 hour period).(1) DISCUSSION: In a study in 11 subjects, the concurrent use of rizatriptan (10 mg) with propranolol (240 mg daily) resulted in an increase in the area-under-curve (AUC) of rizatriptan by 70%. A 4-fold increase was observed in one subject. The AUC of the rizatriptan N-monodesmethyl metabolite was not affected by the concurrent administration of propranolol.(1,2) In a study in 12 healthy subjects, concurrent use of propranolol (80 mg twice daily) with almotriptan (12.5 mg) resulted in statistically significant changes in almotriptan AUC; however, the change was less than 7% and considered unlikely to be clinically significant.(3) In a study in 10 healthy subjects, concurrent propranolol (80 mg twice daily) with sumatriptan (300 mg) had no effects on the pharmacokinetics or pharmacodynamics of sumatriptan.(4) In a study in 12 healthy subjects, concurrent use of propranolol (160 mg daily) with zolmitriptan (10 mg) increased the AUC and maximum concentration (Cmax) of zolmitriptan by 56% and 37%, respectively. Propranolol had no effect on the pressor response to zolmitriptan. The authors stated that the effects are unlikely to be clinically significant and that no dosage adjustment is required during concurrent therapy.(5)	MAXALT, MAXALT MLT, RIZATRIPTAN, SYMBRAVO

Drug contraindication overview.

No enhanced Contraindications information available for this drug.

Adverse reaction overview.

No enhanced Common Adverse Effects information available for this drug.

No enhanced Pediatric Use information available for this drug.

Contraindicated

None

Severe Precaution

None

Management or Monitoring Precaution

None