Interactions between Disopyramide and Xermelo

MONITOR: Grapefruit or grapefruit juice may increase the plasma concentrations of orally administered drugs that are substrates of the CYP450 3A4 isoenzyme. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruit. Because grapefruit juice inhibits primarily intestinal rather than hepatic CYP450 3A4, the magnitude of interaction is greatest for those drugs that undergo significant presystemic metabolism by CYP450 3A4 (i.e., drugs with low oral bioavailability). In general, the effect of grapefruit juice is concentration-, dose- and preparation-dependent, and can vary widely among brands. Certain preparations of grapefruit juice (e.g., high dose, double strength) have sometimes demonstrated potent inhibition of CYP450 3A4, while other preparations (e.g., low dose, single strength) have typically demonstrated moderate inhibition. Pharmacokinetic interactions involving grapefruit juice are also subject to a high degree of interpatient variability, thus the extent to which a given patient may be affected is difficult to predict.

MANAGEMENT: Patients who regularly consume grapefruit or grapefruit juice should be monitored for adverse effects and altered plasma concentrations of drugs that undergo significant presystemic metabolism by CYP450 3A4. Grapefruit and grapefruit juice should be avoided if an interaction is suspected. Orange juice is not expected to interact with these drugs.

ADJUST DOSING INTERVAL: Food increases the systemic exposure to both telotristat ethyl and its active metabolite, telotristat. Following administration of a single 500 mg dose of telotristat ethyl (twice the recommended dose) with a high-fat meal, telotristat ethyl peak plasma concentration (Cmax) and systemic exposure (AUC) were 112% and 264% higher, respectively, compared to administration under fasted conditions. The Cmax and AUC values for telotristat were also increased by 47% and 33%, respectively. The in vitro inhibitory potency of telotristat towards tryptophan hydroxylase has been shown to be approximately 29 times higher than that of the parent drug.

MANAGEMENT: Telotristat ethyl should be administered with food.

Ethanol significantly increases the renal elimination of disopyramide, apparently by inducing diuresis (inhibition of antidiuretic hormone). Limited data show that ethanol does not, however, significantly affect the elimination half-life or total plasma clearance of disopyramide. No special precautions appear to be necessary.

The use of disopyramide is contraindicated in patients with cardiogenic shock, second- or third-degree AV block in the absence of a functional artificial pacemaker, or congenital QT prolongation. Therapy with disopyramide should be administered with extreme caution in patients with sick sinus syndrome (bradycardia-tachycardia), Wolff-Parkinson White syndrome, or bundle-branch block. The effect of disopyramide in these conditions has not been determined.

Antiarrhythmic agents can induce severe hypotension (particularly with IV administration) or induce or worsen congestive heart failure (CHF). Patients with primary cardiomyopathy or inadequately compensated CHF are at increased risk. Antiarrhythmic agents should be administered cautiously and dosage and/or frequency of administration modified in patients with hypotension or adequately compensated CHF. Alternative therapy should be considered unless these conditions are secondary to cardiac arrhythmia.

Disopyramide has anticholinergic activity, and therapy with disopyramide should be administered with extreme caution in patients who may be adversely affected by this. Disopyramide should not be used in patients with glaucoma, myasthenia gravis, or urinary retention unless adequate overriding measures are taken.

The use of disopyramide is contraindicated in patients with cardiogenic shock, second- or third-degree AV block in the absence of a functional artificial pacemaker, or congenital QT prolongation. Therapy with disopyramide should be administered with extreme caution in patients with sick sinus syndrome (bradycardia-tachycardia), Wolff-Parkinson White syndrome, or bundle-branch block. The effect of disopyramide in these conditions has not been determined.

Antiarrhythmic agents can induce severe hypotension (particularly with IV administration) or induce or worsen congestive heart failure (CHF). Patients with primary cardiomyopathy or inadequately compensated CHF are at increased risk. Antiarrhythmic agents should be administered cautiously and dosage and/or frequency of administration modified in patients with hypotension or adequately compensated CHF. Alternative therapy should be considered unless these conditions are secondary to cardiac arrhythmia.

The use of disopyramide is contraindicated in patients with cardiogenic shock, second- or third-degree AV block in the absence of a functional artificial pacemaker, or congenital QT prolongation. Therapy with disopyramide should be administered with extreme caution in patients with sick sinus syndrome (bradycardia-tachycardia), Wolff-Parkinson White syndrome, or bundle-branch block. The effect of disopyramide in these conditions has not been determined.

Disopyramide has anticholinergic activity, and therapy with disopyramide should be administered with extreme caution in patients who may be adversely affected by this. Disopyramide should not be used in patients with glaucoma, myasthenia gravis, or urinary retention unless adequate overriding measures are taken.

Disopyramide has anticholinergic activity, and therapy with disopyramide should be administered with extreme caution in patients who may be adversely affected by this. Disopyramide should not be used in patients with glaucoma, myasthenia gravis, or urinary retention unless adequate overriding measures are taken.

The use of telotristat reduces bowel movement frequency and may cause gastrointestinal effects including, constipation, intestinal perforation and obstruction. It is recommended to monitor for the development of constipation and/or severe, persistent, or worsening abdominal pain in patients taking telotristat and to discontinue its use if severe constipation or severe persistent or worsening abdominal pain develops. Care is recommended when using telotristat in patients suffering from constipation. .

Rare cases of hypoglycemia have been reported during administration of disopyramide. Therapy with disopyramide should be administered cautiously in patients with diabetes mellitus or other conditions that alter normal glucoregulatory mechanisms such as chronic malnutrition, congestive heart failure, renal or hepatic dysfunction, or drugs (beta blockers).

Population pharmacokinetic (PK) analysis showed that creatine clearance does not affect the PK of telotristat. Care is recommended when using telotristat in patients with end-stage renal disease (ESRD) who require dialysis as this agent has not been studied in this patient population.

Electrolyte imbalance can alter the therapeutic effectiveness of antiarrhythmic agents. Hypokalemia and hypomagnesemia can reduce the effectiveness of antiarrhythmic agents. In some cases, these disorders can exaggerate the degree of QTc prolongation and increase the potential for torsade de pointes. Hyperkalemia can potentiate the toxic effects of antiarrhythmic agents. Electrolyte imbalance should be corrected prior to initiating antiarrhythmic therapy. Clinical monitoring of cardiac function and electrolyte concentrations is recommended.

Electrolyte imbalance can alter the therapeutic effectiveness of antiarrhythmic agents. Hypokalemia and hypomagnesemia can reduce the effectiveness of antiarrhythmic agents. In some cases, these disorders can exaggerate the degree of QTc prolongation and increase the potential for torsade de pointes. Hyperkalemia can potentiate the toxic effects of antiarrhythmic agents. Electrolyte imbalance should be corrected prior to initiating antiarrhythmic therapy. Clinical monitoring of cardiac function and electrolyte concentrations is recommended.

Disopyramide is partially metabolized by the liver. The plasma half-life of disopyramide is prolonged in patients with hepatic dysfunction. Therapy with disopyramide should be administered cautiously and dosages reduced in patients with compromised hepatic function. Clinical monitoring of cardiac function (ECG) and hepatic function is recommended.

Population pharmacokinetic analysis showed that mild hepatic impairment does not affect the pharmacokinetics of telotristat. Care is recommended when using telotristat in patients with moderate or severe hepatic impairment as this agent has not been studied in this patient population.

Electrolyte imbalance can alter the therapeutic effectiveness of antiarrhythmic agents. Hypokalemia and hypomagnesemia can reduce the effectiveness of antiarrhythmic agents. In some cases, these disorders can exaggerate the degree of QTc prolongation and increase the potential for torsade de pointes. Hyperkalemia can potentiate the toxic effects of antiarrhythmic agents. Electrolyte imbalance should be corrected prior to initiating antiarrhythmic therapy. Clinical monitoring of cardiac function and electrolyte concentrations is recommended.

Disopyramide is primarily eliminated by the kidney. Approximately 50% of disopyramide is excreted in the urine as unchanged drug. The serum concentration of disopyramide is increased and the elimination half-life is prolonged in patients with renal impairment. Patients with renal impairment may be at increased risk of disopyramide-associated toxicity such as hypotension, conduction disturbances, or worsening of congestive heart failure. Therapy with disopyramide should be administered cautiously and dosage and/or frequency of administration modified in patients with compromised renal function. Clinical monitoring of cardiac function (ECG) and renal function is recommended.