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Drug overview for CLONIDINE (clonidine):
Generic name: CLONIDINE (KLON-i-deen)
Drug class: Central Adrenolytics
Therapeutic class: Cardiovascular Therapy Agents
Clonidine hydrochloride, an imidazoline-derivative hypotensive agent, is a selective alpha2-adrenergic agonist.
No enhanced Uses information available for this drug.
Generic name: CLONIDINE (KLON-i-deen)
Drug class: Central Adrenolytics
Therapeutic class: Cardiovascular Therapy Agents
Clonidine hydrochloride, an imidazoline-derivative hypotensive agent, is a selective alpha2-adrenergic agonist.
No enhanced Uses information available for this drug.
DRUG IMAGES
CLONIDINE 0.2 MG/DAY PATCH
CLONIDINE 0.3 MG/DAY PATCH
CLONIDINE 0.1 MG/DAY PATCH
The following indications for CLONIDINE (clonidine) have been approved by the FDA:
Indications:
Hypertension
Professional Synonyms:
Elevated blood pressure
Essential hypertension
Hyperpiesia
Hyperpiesis
Hypertensive disorder
Systemic arterial hypertension
Indications:
Hypertension
Professional Synonyms:
Elevated blood pressure
Essential hypertension
Hyperpiesia
Hyperpiesis
Hypertensive disorder
Systemic arterial hypertension
The following dosing information is available for CLONIDINE (clonidine):
To avoid the possibility of precipitating the withdrawal syndrome, clonidine therapy should not be discontinued abruptly. (See Cautions: Withdrawal Effects.)
For the management of hypertension, the usual initial oral dosage of clonidine hydrochloride (as conventional tablets) in adults is 0.1 mg twice daily. Geriatric patients may benefit from a lower initial dosage of 0.05
mg twice daily. Dosage may be increased by 0.1 mg at weekly intervals until the desired response is achieved.
In clinical studies, the most commonly used dosages have ranged from 0.2-0.6 mg daily, administered in divided doses.
Some experts state that the usual dosage range for adults is 0.1-0.8 mg daily, administered in 2 divided doses.
The maximum effective dosage in adults is 2.4 mg daily.
For information on overall principles and expert recommendations for treatment of hypertension in pediatric patients, see Uses: Hypertension in Pediatric Patients, in the Thiazides General Statement 40:28.20.
Smaller than usual dosages of clonidine hydrochloride may be adequate in patients who are also receiving diuretics or other hypotensive drugs.
When transdermal clonidine therapy is used for the management of hypertension in adults, transdermal therapy is initiated with one system delivering 0.1 mg/24 hours applied once every 7 days. Because of interpatient variability in transdermal absorption, it is recommended that this initial dosage be used in all patients, including those who had been receiving oral clonidine hydrochloride therapy, and that dosage subsequently be titrated according to individual requirements; the relationship between the effective dosage of oral clonidine hydrochloride and that of transdermal clonidine is not predictable.
If the desired reduction in blood pressure is not achieved after 1 or 2 weeks with the initial dosage, dosage may be increased by using 2 systems delivering 0.1 mg/24 hours or a larger dosage system. Subsequent dosage adjustments may be made at weekly intervals.
Some experts state that the usual dosage range for transdermal clonidine is 0.1-0.3 mg/24 hours applied once every 7 days.
Transdermal dosages exceeding 0.6 mg/24 hours (2 systems each delivering 0.3 mg/24 hours) are usually not associated with additional efficacy. In patients who develop localized skin irritation during the intended period of use (7 days), it may be necessary to move the transdermal system to a different site or replace it with another system at shorter intervals (e.g., every 3-5 days).
Replacement of the transdermal system following a duration of less than 7 days may be required rarely to maintain blood pressure control.
When transdermal therapy is initiated in patients who have been receiving low dosages of oral clonidine hydrochloride, some clinicians recommend continuing the usual oral dosage the first day the initial transdermal system is applied. When transdermal clonidine therapy is administered to patients already receiving other hypotensive agents, dosage of the other hypotensive agents should be gradually reduced when transdermal therapy is initiated since the hypotensive effect of transdermal clonidine may not begin until 2-3 days after application of the initial system; the other hypotensive agents may have to be continued, particularly in patients with more severe hypertension.
When used for the relief of severe, intractable cancer pain that is unresponsive to epidural or spinal opiate analgesia or other more conventional methods of analgesia, the recommended initial epidural dosage of clonidine hydrochloride in adults is 30 mcg/hour, administered by continuous epidural infusion. The dosage may be adjusted based on clinical response and tolerance; however, clinical experience with infusion rates exceeding 40 mcg/hour is limited. Patients should be closely monitored, particularly during the first few days of epidural clonidine therapy.
The recommended initial dosage of epidural clonidine hydrochloride in pediatric patients is 0.5 mcg/kg of body weight per hour. The dosage of epidural clonidine in pediatric patients should be cautiously adjusted based on clinical response.
Oral clonidine hydrochloride dosages of 0.025-0.2 mg twice daily (as conventional tablets) have been employed in the management of vasomotor symptoms (e.g., hot flashes) associated with menopause+.
While comparative efficacy of various transdermal clonidine dosages have not been established, patients in clinical studies have received one transdermal system delivering 0.1 mg/24 hours applied once every 7 days.
For symptomatic relief of opiate withdrawal in opiate-dependent individuals+, various dosage regimens of oral clonidine hydrochloride (as conventional tablets) have been used. Some experts state that the usual clonidine hydrochloride dosage for opiate withdrawal management is 0.1-0.3
mg every 6-8 hours, with dosage guided by withdrawal symptoms and adverse effects. Other experts recommend administration of an initial 0.1-mg test dose of clonidine hydrochloride; a 0.2-mg
test dose may be considered for patients with severe manifestations of opiate withdrawal or for those weighing more than 200 pounds (91 kg). If blood pressure remains adequate (generally systolic and diastolic blood pressures of least 90 and 60 mm Hg, respectively) following the test dose, a clonidine hydrochloride dosage of 0.1-0.2
mg may be administered every 4-6 hours as needed; scheduled dosing may be considered in patients with severe withdrawal. Under this dosing method, the total dose administered during the initial 24 hours of treatment is tabulated to establish the patient's daily dosage requirement and is administered in 3 or 4 divided doses.
Doses of clonidine hydrochloride should be reduced, delayed, or omitted in individuals demonstrating greater sensitivity to the drug's adverse effects (e.g., hypotension, orthostasis, bradycardia). Individuals treated in the outpatient setting should be capable of performing self-monitoring for these adverse effects, and some experts suggest that lower dosages may be appropriate in this setting. As opiate withdrawal symptoms wane, clonidine hydrochloride dosage may be reduced gradually (e.g., by 0.1 mg per dose every 1-2 days).
Other tapering schedules also have been used to discontinue therapy (e.g., dosage has been reduced by decrements of 50% per day for 3 days and then discontinued, or reduced by 0.1-0.2 mg daily ). Clinicians should consult published protocols for more specific information.
For use in the cessation of smoking+, the initial adult oral dosage of clonidine hydrochloride is typically 0.1 mg twice daily (as conventional tablets). Therapy with the drug is initiated on the day set as the date of cessation of smoking or shortly before this date (e.g., up to 3 days prior).
Dosage may be increased each week by 0.1 mg daily, if needed. In clinical studies, oral dosages varied from 0.15-0.75
mg daily without a clear relationship to achievement of cessation of smoking. The duration of oral therapy with clonidine hydrochloride also varied in these studies, ranging from 3-10 weeks.
When transdermal clonidine is used for the cessation of smoking+, therapy is initiated typically in adults with one system delivering 0.1 mg/24 hours applied once every 7 days. Therapy with the drug is initiated on the day set as the date of cessation of smoking or shortly before this date (e.g., up to 3 days prior).
Dosage may be increased at weekly intervals by 0.1 mg/24 hours, if needed. In clinical studies, the transdermal dosage varied from 0.1-0.2
mg/24 hours without a clear relationship to achievement of cessation of smoking. The duration of transdermal clonidine therapy also varied in these studies, ranging from 3-10 weeks.
Smaller than usual dosages of clonidine or clonidine hydrochloride may be adequate in patients with renal impairment. Dosage should be adjusted according to the degree of renal impairment. Some clinicians suggest that adjustment of clonidine hydrochloride dosage is not necessary in patients with creatinine clearances of 10 mL/minute or greater, but those with lower clearances can receive 50-75% of the usual dosage. Supplemental doses after hemodialysis are not necessary.
For the management of hypertension, the usual initial oral dosage of clonidine hydrochloride (as conventional tablets) in adults is 0.1 mg twice daily. Geriatric patients may benefit from a lower initial dosage of 0.05
mg twice daily. Dosage may be increased by 0.1 mg at weekly intervals until the desired response is achieved.
In clinical studies, the most commonly used dosages have ranged from 0.2-0.6 mg daily, administered in divided doses.
Some experts state that the usual dosage range for adults is 0.1-0.8 mg daily, administered in 2 divided doses.
The maximum effective dosage in adults is 2.4 mg daily.
For information on overall principles and expert recommendations for treatment of hypertension in pediatric patients, see Uses: Hypertension in Pediatric Patients, in the Thiazides General Statement 40:28.20.
Smaller than usual dosages of clonidine hydrochloride may be adequate in patients who are also receiving diuretics or other hypotensive drugs.
When transdermal clonidine therapy is used for the management of hypertension in adults, transdermal therapy is initiated with one system delivering 0.1 mg/24 hours applied once every 7 days. Because of interpatient variability in transdermal absorption, it is recommended that this initial dosage be used in all patients, including those who had been receiving oral clonidine hydrochloride therapy, and that dosage subsequently be titrated according to individual requirements; the relationship between the effective dosage of oral clonidine hydrochloride and that of transdermal clonidine is not predictable.
If the desired reduction in blood pressure is not achieved after 1 or 2 weeks with the initial dosage, dosage may be increased by using 2 systems delivering 0.1 mg/24 hours or a larger dosage system. Subsequent dosage adjustments may be made at weekly intervals.
Some experts state that the usual dosage range for transdermal clonidine is 0.1-0.3 mg/24 hours applied once every 7 days.
Transdermal dosages exceeding 0.6 mg/24 hours (2 systems each delivering 0.3 mg/24 hours) are usually not associated with additional efficacy. In patients who develop localized skin irritation during the intended period of use (7 days), it may be necessary to move the transdermal system to a different site or replace it with another system at shorter intervals (e.g., every 3-5 days).
Replacement of the transdermal system following a duration of less than 7 days may be required rarely to maintain blood pressure control.
When transdermal therapy is initiated in patients who have been receiving low dosages of oral clonidine hydrochloride, some clinicians recommend continuing the usual oral dosage the first day the initial transdermal system is applied. When transdermal clonidine therapy is administered to patients already receiving other hypotensive agents, dosage of the other hypotensive agents should be gradually reduced when transdermal therapy is initiated since the hypotensive effect of transdermal clonidine may not begin until 2-3 days after application of the initial system; the other hypotensive agents may have to be continued, particularly in patients with more severe hypertension.
When used for the relief of severe, intractable cancer pain that is unresponsive to epidural or spinal opiate analgesia or other more conventional methods of analgesia, the recommended initial epidural dosage of clonidine hydrochloride in adults is 30 mcg/hour, administered by continuous epidural infusion. The dosage may be adjusted based on clinical response and tolerance; however, clinical experience with infusion rates exceeding 40 mcg/hour is limited. Patients should be closely monitored, particularly during the first few days of epidural clonidine therapy.
The recommended initial dosage of epidural clonidine hydrochloride in pediatric patients is 0.5 mcg/kg of body weight per hour. The dosage of epidural clonidine in pediatric patients should be cautiously adjusted based on clinical response.
Oral clonidine hydrochloride dosages of 0.025-0.2 mg twice daily (as conventional tablets) have been employed in the management of vasomotor symptoms (e.g., hot flashes) associated with menopause+.
While comparative efficacy of various transdermal clonidine dosages have not been established, patients in clinical studies have received one transdermal system delivering 0.1 mg/24 hours applied once every 7 days.
For symptomatic relief of opiate withdrawal in opiate-dependent individuals+, various dosage regimens of oral clonidine hydrochloride (as conventional tablets) have been used. Some experts state that the usual clonidine hydrochloride dosage for opiate withdrawal management is 0.1-0.3
mg every 6-8 hours, with dosage guided by withdrawal symptoms and adverse effects. Other experts recommend administration of an initial 0.1-mg test dose of clonidine hydrochloride; a 0.2-mg
test dose may be considered for patients with severe manifestations of opiate withdrawal or for those weighing more than 200 pounds (91 kg). If blood pressure remains adequate (generally systolic and diastolic blood pressures of least 90 and 60 mm Hg, respectively) following the test dose, a clonidine hydrochloride dosage of 0.1-0.2
mg may be administered every 4-6 hours as needed; scheduled dosing may be considered in patients with severe withdrawal. Under this dosing method, the total dose administered during the initial 24 hours of treatment is tabulated to establish the patient's daily dosage requirement and is administered in 3 or 4 divided doses.
Doses of clonidine hydrochloride should be reduced, delayed, or omitted in individuals demonstrating greater sensitivity to the drug's adverse effects (e.g., hypotension, orthostasis, bradycardia). Individuals treated in the outpatient setting should be capable of performing self-monitoring for these adverse effects, and some experts suggest that lower dosages may be appropriate in this setting. As opiate withdrawal symptoms wane, clonidine hydrochloride dosage may be reduced gradually (e.g., by 0.1 mg per dose every 1-2 days).
Other tapering schedules also have been used to discontinue therapy (e.g., dosage has been reduced by decrements of 50% per day for 3 days and then discontinued, or reduced by 0.1-0.2 mg daily ). Clinicians should consult published protocols for more specific information.
For use in the cessation of smoking+, the initial adult oral dosage of clonidine hydrochloride is typically 0.1 mg twice daily (as conventional tablets). Therapy with the drug is initiated on the day set as the date of cessation of smoking or shortly before this date (e.g., up to 3 days prior).
Dosage may be increased each week by 0.1 mg daily, if needed. In clinical studies, oral dosages varied from 0.15-0.75
mg daily without a clear relationship to achievement of cessation of smoking. The duration of oral therapy with clonidine hydrochloride also varied in these studies, ranging from 3-10 weeks.
When transdermal clonidine is used for the cessation of smoking+, therapy is initiated typically in adults with one system delivering 0.1 mg/24 hours applied once every 7 days. Therapy with the drug is initiated on the day set as the date of cessation of smoking or shortly before this date (e.g., up to 3 days prior).
Dosage may be increased at weekly intervals by 0.1 mg/24 hours, if needed. In clinical studies, the transdermal dosage varied from 0.1-0.2
mg/24 hours without a clear relationship to achievement of cessation of smoking. The duration of transdermal clonidine therapy also varied in these studies, ranging from 3-10 weeks.
Smaller than usual dosages of clonidine or clonidine hydrochloride may be adequate in patients with renal impairment. Dosage should be adjusted according to the degree of renal impairment. Some clinicians suggest that adjustment of clonidine hydrochloride dosage is not necessary in patients with creatinine clearances of 10 mL/minute or greater, but those with lower clearances can receive 50-75% of the usual dosage. Supplemental doses after hemodialysis are not necessary.
Clonidine hydrochloride is administered orally or by epidural infusion, and clonidine is administered percutaneously by topical application of a transdermal system. To ensure overnight blood pressure control with oral administration, the last dose of the day should be administered immediately before retiring. If oral clonidine therapy is to be discontinued, dosage of the drug should be slowly reduced over a period of 2-4 days to avoid the possibility of precipitating a withdrawal syndrome. (See Cautions: Withdrawal Effects.)
| DRUG LABEL | DOSING TYPE | DOSING INSTRUCTIONS |
|---|---|---|
| CLONIDINE 0.1 MG/DAY PATCH | Maintenance | Adults apply 1 patch by transdermal route once weekly |
| CLONIDINE 0.2 MG/DAY PATCH | Maintenance | Adults apply 1 patch by transdermal route once weekly |
| CLONIDINE 0.3 MG/DAY PATCH | Maintenance | Adults apply 1 patch by transdermal route once weekly |
| DRUG LABEL | DOSING TYPE | DOSING INSTRUCTIONS |
|---|---|---|
| CLONIDINE 0.1 MG/DAY PATCH | Maintenance | Adults apply 1 patch by transdermal route once weekly |
| CLONIDINE 0.2 MG/DAY PATCH | Maintenance | Adults apply 1 patch by transdermal route once weekly |
| CLONIDINE 0.3 MG/DAY PATCH | Maintenance | Adults apply 1 patch by transdermal route once weekly |
The following drug interaction information is available for CLONIDINE (clonidine):
There are 0 contraindications.
There are 5 severe interactions.
These drug interactions can produce serious consequences in most patients. Actions required for severe interactions include, but are not limited to, discontinuing one or both agents, adjusting dosage, altering administration scheduling, and providing additional patient monitoring. Review the full interaction monograph for more information.
| Drug Interaction | Drug Names |
|---|---|
| Clonidine/Beta-Blockers SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Withdrawal of clonidine triggers increased catecholamine release. Beta-blockers inhibit the vasodilation mediated by the beta 2 receptor, leaving the vasoconstriction mediated by the alpha 2 receptor unopposed. In addition, concurrent use is expected to produce additive effects on blood pressure and heart rate requiring standard monitoring precautions. CLINICAL EFFECTS: Severe hypertension may occur upon abrupt discontinuation of clonidine in patients receiving both clonidine and beta-blockers. In addition, concurrent use is expected to produce additive effects on blood pressure and heart rate requiring standard monitoring precautions. PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: In a patient receiving both drugs, discontinuation of the beta-blocker prior to clonidine may decrease the occurrence of rebound hypertension. If clonidine is discontinued first, rebound hypertension can be treated by restarting the clonidine or by the IV administration of phentolamine, phenoxybenzamine or prazosin. When adding either of these agents to the drug regimen of the patient, monitor blood pressure. Since labetalol has both alpha and beta activity, administration of labetalol may prevent rebound hypertension in patients undergoing clonidine withdrawal, although conflicting reports exist. In addition, concurrent use is expected to produce additive effects on blood pressure and heart rate requiring standard monitoring precautions. DISCUSSION: Increased blood pressure has been observed in patients following: 1) the discontinuation of clonidine in patients receiving beta-blockers, 2) the replacement of clonidine therapy with beta-blockers, 3) the simultaneous discontinuation of both drugs. Conflicting reports exist on the development of increased blood pressure after clonidine withdrawal in patients receiving labetalol. Patients receiving labetalol who are being withdrawn from clonidine should still be closely monitored. |
ACEBUTOLOL HCL, ATENOLOL, ATENOLOL-CHLORTHALIDONE, BETAPACE, BETAPACE AF, BETAXOLOL HCL, BETIMOL, BETOPTIC S, BISOPROLOL FUMARATE, BISOPROLOL-HYDROCHLOROTHIAZIDE, BREVIBLOC, BRIMONIDINE TARTRATE-TIMOLOL, BYSTOLIC, CARTEOLOL HCL, CARVEDILOL, CARVEDILOL ER, COMBIGAN, COREG, COREG CR, CORGARD, COSOPT, COSOPT PF, DORZOLAMIDE-TIMOLOL, ESMOLOL HCL, ESMOLOL HCL-SODIUM CHLORIDE, ESMOLOL HCL-WATER, HEMANGEOL, INDERAL LA, INDERAL XL, INNOPRAN XL, ISTALOL, KAPSPARGO SPRINKLE, LABETALOL HCL, LABETALOL HCL-WATER, LEVOBUNOLOL HCL, LOPRESSOR, METOPROLOL SUCCINATE, METOPROLOL TARTRATE, METOPROLOL-HYDROCHLOROTHIAZIDE, NADOLOL, NEBIVOLOL HCL, PINDOLOL, PROPRANOLOL HCL, PROPRANOLOL HCL ER, PROPRANOLOL-HYDROCHLOROTHIAZID, RAPIBLYK, SOTALOL, SOTALOL AF, SOTALOL HCL, SOTYLIZE, TENORETIC 100, TENORETIC 50, TENORMIN, TIMOLOL, TIMOLOL MALEATE, TIMOLOL-BIMATOPROST, TIMOLOL-BRIMONI-DORZOL-BIMATOP, TIMOLOL-BRIMONIDIN-DORZOLAMIDE, TIMOLOL-DORZOLAMIDE-BIMATOPRST, TIMOPTIC OCUDOSE, TOPROL XL |
| Siponimod/Agents That Cause Bradycardia SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Initiation of siponimod has caused transient decreases in heart rate and atrioventricular conduction delays after the first dose. Decreases in heart rate start within the first hour and maximal decrease in heart rate was seen at approximately 3-4 hours. The first dose has also been associated with heart block. Additional agents that cause bradycardia further increase the risk for symptomatic bradycardia.(1) CLINICAL EFFECTS: The heart rate lowering effect of siponimod is transient and is usually seen with the first dose. Bradycardia may be associated with an increase in the QTc interval, increasing the risk for torsade de pointes.(1) PREDISPOSING FACTORS: Pre-existing cardiovascular disease (e.g. heart failure, ischemic heart disease, history of myocardial infarction, stroke, history of torsades de pointes, or heart block), severe untreated sleep apnea, a prolonged QTc interval prior to siponimod initiation, or factors associated with QTc prolongation (e.g. hypokalemia, hypomagnesemia, bradycardia, female gender, or advanced age) may increase risk for cardiovascular toxicity due to siponimod.(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 prescribing information states siponimod treatment should generally not be initiated in patients who are concurrent therapy with additional agents that cause bradycardia. If treatment with siponimod is considered, advice from a cardiologist should be sought regarding switching to non-heart rate lowering drugs or recommendations for monitoring for treatment initiation. Treatment initiation recommendations include: - Obtain an ECG in all patients to determine whether preexisting conduction abnormalities are present. - In all patients, a dose titration is recommended for initiation of siponimod treatment to help reduce cardiac effects. - In patients with sinus bradycardia (HR less than 55 bpm), first- or second-degree [Mobitz type I] AV block, or a history of myocardial infarction or heart failure with onset > 6 months prior to initiation, ECG testing and first dose monitoring is recommended. - Since significant bradycardia may be poorly tolerated in patients with history of cardiac arrest, cerebrovascular disease, uncontrolled hypertension, or severe untreated sleep apnea, siponimod is not recommended in these patients. If treatment is considered, advice from a cardiologist should be sought prior to initiation of treatment in order to determine the most appropriate monitoring strategy. - Use of siponimod in patients with a history of recurrent syncope or symptomatic bradycardia should be based on an overall benefit-risk assessment. If treatment is considered, advice from a cardiologist should be sought prior to initiation of treatment in order to determine the most appropriate monitoring. - If a titration dose is missed or if 4 or more consecutive daily doses are missed during maintenance treatment, reinitiate Day 1 of the dose titration and follow titration monitoring recommendations.(1) DISCUSSION: Initiation of siponimod treatment has been associated with transient atrioventricular (AV) conduction delays that follow a similar temporal pattern as the observed decrease in heart rate during dose titration. The AV conduction delays manifested in most of the cases as first-degree AV block (prolonged PR interval on ECG), which occurred in 5.1% of siponimod treated patients and in 1.9 % of patients receiving placebo in Study 1. Second-degree AV blocks, usually Mobitz type I (Wenckebach), have been observed at the time of treatment initiation with siponimod in less than 1.7% of patients in clinical trials. The conduction abnormalities typically were transient, asymptomatic, resolved within 24 hours, rarely required treatment with atropine, and did not require discontinuation of siponimod treatment.(1) |
MAYZENT |
| Crizotinib/Agents That Cause Bradycardia SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Crizotinib may cause symptomatic bradycardia. Additional agents that cause bradycardia further increase the risk for symptomatic bradycardia.(1) CLINICAL EFFECTS: Bradycardia may be associated with an increase in the QTc interval, increasing the risk for torsade de pointes.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The manufacturer of crizotinib recommends avoiding concurrent use of crizotinib and other agents known to cause bradycardia to the extent possible. If combination therapy is required, monitor heart rate and blood pressure regularly. If bradycardia occurs, withhold crizotinib until heart rate recovers to 60 bpm or above, or patient is asymptomatic. Re-evaluate the use of the concomitant medication. If the concomitant medication is discontinued or its dose is reduced, resume crizotinib at the previous dose upon patient's recovery. If the concomitant medication is not discontinued or dose adjusted, resume crizotinib at a reduced dose upon patient's recovery. If life-threatening bradycardia occurs, discontinue or reduce the dose of the concomitant medication. Upon the patient's recovery, lower the dose of crizotinib to 250 mg daily. Monitor blood pressure and heart rate frequently.(1) DISCUSSION: Across clinical trials, bradycardia occurred in 13 % of patients on crizotinib, and grade 3 syncope occurred in 2.4 % of patients on crizotinib compared with 0.6 % on chemotherapy.(1) Agents that may cause bradycardia and linked to this monograph include: beta-blockers, non-dihydropyridine calcium channel blockers, clonidine, and digoxin.(1) |
XALKORI |
| Ponesimod/Agents That Cause Bradycardia SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Initiation of ponesimod has caused transient decreases in heart rate and atrioventricular conduction delays after the first dose. Decreases in heart rate start within the first hour and maximal decrease in heart rate was seen at approximately 2-4 hours. The first dose has also been associated with heart block. Additional agents that cause bradycardia further increase the risk for symptomatic bradycardia.(1) CLINICAL EFFECTS: The heart rate lowering effect of ponesimod is transient and is usually seen with the first dose. Bradycardia may be associated with an increase in the QTc interval, increasing the risk for torsade de pointes.(1) PREDISPOSING FACTORS: Pre-existing cardiovascular disease (e.g. heart failure, ischemic heart disease, history of myocardial infarction, stroke, history of torsades de pointes, or heart block), severe untreated sleep apnea, a prolonged QTc interval prior to siponimod initiation, or factors associated with QTc prolongation (e.g. hypokalemia, hypomagnesemia, bradycardia, female gender, or advanced age) may increase risk for cardiovascular toxicity due to siponimod.(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 prescribing information states ponesimod treatment should generally not be initiated in patients who are on concurrent therapy with additional agents that cause bradycardia. If treatment with ponesimod is considered, advice from a cardiologist should be sought regarding switching to non-heart rate lowering drugs or monitoring during treatment initiation. Treatment initiation recommendations include: - Obtain an ECG in all patients to determine whether preexisting conduction abnormalities are present. - In all patients, a dose titration is recommended for initiation of ponesimod treatment to help reduce cardiac effects. - In patients with sinus bradycardia (HR less than 55 bpm), first- or second-degree [Mobitz type I] AV block, or a history of myocardial infarction or heart failure with onset > 6 months prior to initiation, ECG testing and first dose monitoring is recommended. - Since significant bradycardia may be poorly tolerated in patients with history of cardiac arrest, cerebrovascular disease, uncontrolled hypertension, or severe untreated sleep apnea, ponesimod is not recommended in these patients. If treatment is considered, advice from a cardiologist should be sought prior to initiation of treatment in order to determine the most appropriate monitoring strategy. - Use of ponesimod in patients with a history of recurrent syncope or symptomatic bradycardia should be based on an overall benefit-risk assessment. If treatment is considered, advice from a cardiologist should be sought prior to initiation of treatment in order to determine the most appropriate monitoring. - If a titration dose is missed or if 4 or more consecutive daily doses are missed during maintenance treatment, reinitiate Day 1 of the dose titration and follow titration monitoring recommendations.(1) DISCUSSION: Initiation of ponesimod treatment has been associated with transient atrioventricular (AV) conduction delays that follow a similar temporal pattern as the observed decrease in heart rate during dose titration. The AV conduction delays manifested in most of the cases as first-degree AV block (prolonged PR interval on ECG), which occurred in 3.4% of ponesimod treated patients and in 1.2% of patients receiving teriflunomide in Study 1. Second-degree or third-degree AV blocks have not been reported in patients in clinical trials. The conduction abnormalities typically were transient, asymptomatic, resolved within 24 hours, and did not require discontinuation of ponesimod treatment.(1) |
PONVORY |
| Etrasimod/Agents That Cause Bradycardia SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Initiation of etrasimod has caused transient decreases in heart rate and atrioventricular conduction delays after the first dose. The first dose has also been associated with heart block. Additional agents that cause bradycardia further increase the risk for symptomatic bradycardia.(1) CLINICAL EFFECTS: The heart rate lowering effect of etrasimod is transient and is usually seen with the first dose. Bradycardia may be associated with an increase in the QTc interval, increasing the risk for torsade de pointes.(1) PREDISPOSING FACTORS: Pre-existing cardiovascular disease (e.g. heart failure, ischemic heart disease, history of myocardial infarction, stroke, history of torsades de pointes, or heart block), severe untreated sleep apnea, a prolonged QTc interval prior to etrasimod initiation, or factors associated with QTc prolongation (e.g. hypokalemia, hypomagnesemia, bradycardia, female gender, or advanced age) may increase risk for cardiovascular toxicity due to etrasimod.(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 prescribing information for etrasimod treatment states that advice from a cardiologist should be sought before initiating etrasimod treatment in patients currently taking additional agents that cause bradycardia or in patients with preexisting heart and cerebrovascular conditions, with resting heart rate of less than 50 bpm, history of symptomatic bradycardia, recurrent cardiogenic syncope, severe untreated sleep apnea, or history of Mobitz type 1 second-degree AV block (unless has functioning pacemaker).(1) Monitor blood pressure during treatment.(1) DISCUSSION: Initiation of etrasimod treatment has been associated with transient atrioventricular (AV) conduction delays. The AV conduction delays manifested as first or second degree AV block (prolonged PR interval on ECG), which occurred in 0.7% of etrasimod treated patients in UC-1 and in 0.8% of patients in UC-2 and UC-3 compared to 0% for placebo in all studies.(1) |
VELSIPITY |
There are 4 moderate interactions.
The clinician should assess the patient’s characteristics and take action as needed. Actions required for moderate interactions include, but are not limited to, discontinuing one or both agents, adjusting dosage, altering administration.
| Drug Interaction | Drug Names |
|---|---|
| Clonidine/Tricyclic Compounds; Mirtazapine SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Clonidine decreases blood pressure via alpha-2 agonism.(1) Tricyclic compounds(2) and mirtazapine(3) antagonize alpha-2, which may result in a loss of effect of clonidine. CLINICAL EFFECTS: The concurrent use of clonidine and tricyclic compounds(1,3,4-16) and mirtazapine(3,17) may result in decreased effectiveness of clonidine and hypertensive crisis. PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: If possible, avoid concurrent use of clonidine with tricyclic compounds or mirtazapine. Consider using an alternative agent in patients maintained on clonidine. If concurrent administration is warranted, blood pressure should be carefully monitored, particularly in the first two weeks of therapy, when this interaction is most likely to occur. The dosage of clonidine may need to be adjusted or the tricyclic compound or mirtazapine may need to be discontinued. DISCUSSION: This interaction has been reported in patients receiving amitriptyline,(6) clomipramine,(7,8) desipramine,(2,9-11) imipramine(12-16), and protriptyline.(11) In one patient, a hypertensive crisis resulted. Other patients experienced a decrease in blood pressure control. A controlled trial demonstrated a decrease in anti-hypertensive effect when desipramine was added to a clonidine regimen. This decrease in hypertensive-control may be overcome by increasing the dose of clonidine and monitoring blood pressure closely. Cyclobenzaprine is structurally related to the tricyclic antidepressants and, especially at higher dosages, has similar effects.(18) Therefore, it is prudent to consider cyclobenzaprine in this interaction. Hypertensive crisis has been reported during concurrent clonidine and mirtazapine therapy.(3,17) Mianserin(19,20) and maprotiline,(21) tetracyclic antidepressants, have been shown not to affect the antihypertensive effects of clonidine. |
AMITRIPTYLINE HCL, AMOXAPINE, AMRIX, ANAFRANIL, CHLORDIAZEPOXIDE-AMITRIPTYLINE, CLOMIPRAMINE HCL, CYCLOBENZAPRINE HCL, CYCLOBENZAPRINE HCL ER, CYCLOPAK, CYCLOTENS, DESIPRAMINE HCL, DOXEPIN HCL, FEXMID, IMIPRAMINE HCL, IMIPRAMINE PAMOATE, MIRTAZAPINE, MIRTAZAPINE ANHYDROUS, NORPRAMIN, NORTRIPTYLINE HCL, PAMELOR, PERPHENAZINE-AMITRIPTYLINE, PROTRIPTYLINE HCL, PRUDOXIN, REMERON, SILENOR, TRIMIPRAMINE MALEATE, ZONALON |
| Selected MAOIs/Selected Antihypertensive Agents SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Both MAOIs and antihypertensive agents may increase the risk of postural hypotension.(1,2) CLINICAL EFFECTS: Postural hypotension may occur with concurrent therapy of MAOIs and antihypertensive agents.(1,2) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The manufacturer of phenelzine states all patients should be followed closely for symptoms of postural hypotension. Hypotensive side effects have occurred in patients who have been hypertensive and normotensive, as well as hypotensive at initiation of phenelzine.(1) The manufacturer of tranylcypromine states hypotension has been observed most commonly but not exclusively in patients with pre-existing hypertension. Tranylcypromine doses greater than 30 mg daily have a major side effect of postural hypotension and can lead to syncope. Gradual dose titration is recommended to decrease risk of postural hypotension. Combined use with other agents known to cause hypotension have shown to have additive side effects and should be monitored closely.(2) Monitor the patient for signs and symptoms of postural hypotension including dizziness, lightheadedness, or weakness, especially upon standing. Monitor blood pressure as well as orthostatic vitals and adjust antihypertensive therapy, including decreasing the dose, dividing doses, or scheduling doses at bedtime, as needed to maintain goal blood pressure. If blood pressure remains hypotensive, consider decreasing the dose of phenelzine or tranylcypromine. In some cases, discontinuation of one or both agents may be necessary.(3) Normotensive patients on stable antihypertensive therapy who are started on either phenelzine or tranylcypromine may be at increased risk for hypotension. Hypertensive patients on stable phenelzine or tranylcypromine who require antihypertensive therapy would be at decreased risk for hypotension. DISCUSSION: A review article describes the pharmacology of phenelzine and tranylcypromine as non-selective MAOIs which inhibit both type A and type B substrates. Orthostatic hypotension is described as the most common MAOI side effect and usually occurs between initiation and the first 3-4 weeks of therapy.(3) In a double-blind study, 71 patients were randomized to receive a 4-week trial of either tranylcypromine, amitriptyline, or the combination. The number of patients reporting dizziness at 4 weeks was not different between the three treatment groups (tranylcypromine 52.4%; amitriptyline 65%; combination 66.7%). Blood pressure (BP) assessment noted a significant drop in standing BP in the tranylcypromine group compared to baseline (systolic BP change = -10 mmHg; p<0.02 and diastolic BP change = -9 mmHg; p<0.02). Combination therapy also had a significant drop in standing BP compared to baseline (systolic BP change = -9 mmHg; p<0.02). Patients receiving amitriptyline had no significant change in BP from baseline at 4 weeks. All three groups had a trend toward increasing orthostatic hypotension in BP changes from lying to standing. The change in orthostatic hypotension was significant in the amitriptyline group with an average systolic BP orthostatic drop of -9 mmHg (p<0.05).(4) A randomized, double-blind study of 16 inpatients with major depressive disorder were treated with either phenelzine or tranylcypromine. Cardiovascular assessments were completed at baseline and after 6 weeks of treatment. After 6 weeks, 5/7 patients (71%) who received phenelzine had a decrease in standing systolic BP greater than 20 mmHg from baseline. Head-up tilt systolic and diastolic BP decreased from baseline in patients on phenelzine (98/61 mmHg v. 127/65 mmHg, respectively; systolic change p=0.02 and diastolic change p=0.02). After 6 weeks, 6/9 patients (67%) who received tranylcypromine had a decrease in standing systolic BP greater than 20 mmHg from baseline. Head-up tilt systolic and diastolic BP decreased from baseline in patients on tranylcypromine (113/71 mmHg v. 133/69 mmHg, respectively; systolic change p=0.09 and diastolic change p=0.07).(5) Selected MAOIs linked to this monograph include: phenelzine and tranylcypromine. Selected antihypertensive agents include: ACE inhibitors, alpha blockers, ARBs, beta blockers, calcium channel blockers, aprocitentan, clonidine, hydralazine and sparsentan. |
NARDIL, PARNATE, PHENELZINE SULFATE, TRANYLCYPROMINE SULFATE |
| Tizanidine/Clonidine; Guanadrel; Guanethidine SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Tizanidine is an alpha-2 agonist. Concurrent use with antihypertensive agents may result in additive effects on blood pressure.(1) CLINICAL EFFECTS: Concurrent use of antihypertensives and tizanidine may result in hypotension.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Patients receiving concurrent therapy should be monitored for hypotension. The risk of hypotension may be decreased by careful titration of tizanidine dosages and monitoring for hypotension prior to dose advancement. Counsel patients about the risk of orthostatic hypotension.(1) DISCUSSION: Severe hypotension has been reported following the addition of tizanidine to existing lisinopril therapy.(2-4) |
TIZANIDINE HCL, ZANAFLEX |
| Apomorphine/Selected Antihypertensives and Vasodilators SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Apomorphine causes dose-dependent decreases in blood pressure. Concurrent use with antihypertensive agents may result in additive effects on blood pressure.(1) CLINICAL EFFECTS: Concurrent use of antihypertensives and apomorphine may result in orthostatic hypotension with or without dizziness, nausea, or syncope.(1) PREDISPOSING FACTORS: The risk of orthostatic hypotension may be increased during dose escalation of apomorphine and in patients with renal or hepatic impairment.(1) PATIENT MANAGEMENT: Patients receiving concurrent therapy should be monitored for hypotension. Counsel patients about the risk of orthostatic hypotension.(1) DISCUSSION: Healthy volunteers who took sublingual nitroglycerin (0.4 mg) concomitantly with apomorphine experienced a mean largest decrease in supine systolic blood pressure (SBP) of 9.7 mm Hg and in supine diastolic blood pressure (DBP) of 9.3 mm Hg, and a mean largest decrease in standing SBP and DBP of 14.3 mm Hg and 13.5 mm Hg, respectively. The maximum decrease in SBP and DBP was 65 mm Hg and 43 mm Hg, respectively. When apomorphine was taken alone, the mean largest decrease in supine SBP and DBP was 6.1 mm Hg and 7.3 mm Hg, respectively, and in standing SBP and DBP was 6.7 mm Hg and 8.4 mm Hg, respectively.(1) |
APOKYN, APOMORPHINE HCL, ONAPGO |
The following contraindication information is available for CLONIDINE (clonidine):
Drug contraindication overview.
No enhanced Contraindications information available for this drug.
No enhanced Contraindications information available for this drug.
There are 1 contraindications.
Absolute contraindication.
| Contraindication List |
|---|
| Magnetic resonance imaging |
There are 6 severe contraindications.
Adequate patient monitoring is recommended for safer drug use.
| Severe List |
|---|
| Atrioventricular block |
| Chronic kidney disease stage 4 (severe) GFR 15-29 ml/min |
| Chronic kidney disease stage 5 (failure) GFr<15 ml/min |
| Hypotension |
| Invasive surgical procedure |
| Sinus bradycardia |
There are 4 moderate contraindications.
Clinically significant contraindication, where the condition can be managed or treated before the drug may be given safely.
| Moderate List |
|---|
| Acute myocardial infarction |
| Cerebrovascular disorder |
| Myocardial ischemia |
| Raynaud's phenomenon |
The following adverse reaction information is available for CLONIDINE (clonidine):
Adverse reaction overview.
No enhanced Common Adverse Effects information available for this drug.
No enhanced Common Adverse Effects information available for this drug.
There are 11 severe adverse reactions.
| More Frequent | Less Frequent |
|---|---|
|
Erythema Pruritus of skin Skin inflammation |
Body fluid retention Depression Edema |
| Rare/Very Rare |
|---|
|
Atrioventricular block Bradycardia Nightmares Raynaud's phenomenon Skin burn caused by transdermal patch worn during MRI |
There are 17 less severe adverse reactions.
| More Frequent | Less Frequent |
|---|---|
|
Constipation Dizziness Drowsy Fatigue General weakness Xerostomia |
Abnormal sexual function Anorexia Dry eye Erectile dysfunction Nausea Nervousness Ocular irritation Ocular itching Orthostatic hypotension Skin thickening Vomiting |
| Rare/Very Rare |
|---|
| None. |
The following precautions are available for CLONIDINE (clonidine):
No enhanced Pediatric Use information available for this drug.
Contraindicated
Severe Precaution
Management or Monitoring Precaution
Contraindicated
| None |
Severe Precaution
| None |
Management or Monitoring Precaution
| None |
Reproduction studies in rabbits using oral clonidine hydrochloride dosages up to about 3 times the maximum recommended human dosage have not revealed evidence of teratogenicity or embryotoxicity. However, in female rats receiving the drug continuously for 2 months prior to mating, an increased incidence of fetal resorptions occurred with oral dosages as low as one-third the maximum recommended human dosage (1/15th the maximum recommended human dosage on a mg/m2 basis); resorptions were not increased when these or higher dosages (up to 3 times the maximum recommended human dosage) were administered during days 6-15 of gestation. An increased incidence of fetal resorptions was observed when much higher dosages (40 times the maximum recommended human dosage on a mg/kg basis and 4-8 times the maximum recommended human dosage on a mg/m2 basis) were administered to mice and rats during days 1-14 of gestation; the lowest dosage used in the study was 0.5
mg/kg. There are no adequate and controlled studies to date using clonidine in pregnant women, and the drug should be used during pregnancy only when clearly needed.
mg/kg. There are no adequate and controlled studies to date using clonidine in pregnant women, and the drug should be used during pregnancy only when clearly needed.
Since clonidine is distributed into milk, the drug should be used with caution in nursing women. The manufacturer of parenteral clonidine states that because of the potential for serious adverse reactions to clonidine in nursing infants, a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the woman.
No enhanced Geriatric Use information available for this drug.
The following prioritized warning is available for CLONIDINE (clonidine):
No warning message for this drug.
No warning message for this drug.
The following icd codes are available for CLONIDINE (clonidine)'s list of indications:
| Hypertension | |
| I10 | Essential (primary) hypertension |
| I11 | Hypertensive heart disease |
| I11.0 | Hypertensive heart disease with heart failure |
| I11.9 | Hypertensive heart disease without heart failure |
| I12 | Hypertensive chronic kidney disease |
| I12.0 | Hypertensive chronic kidney disease with stage 5 chronic kidney disease or end stage renal disease |
| I12.9 | Hypertensive chronic kidney disease with stage 1 through stage 4 chronic kidney disease, or unspecified chronic kidney disease |
| I13 | Hypertensive heart and chronic kidney disease |
| I13.0 | Hypertensive heart and chronic kidney disease with heart failure and stage 1 through stage 4 chronic kidney disease, or unspecified chronic kidney disease |
| I13.1 | Hypertensive heart and chronic kidney disease without heart failure |
| I13.10 | Hypertensive heart and chronic kidney disease without heart failure, with stage 1 through stage 4 chronic kidney disease, or unspecified chronic kidney disease |
| I13.11 | Hypertensive heart and chronic kidney disease without heart failure, with stage 5 chronic kidney disease, or end stage renal disease |
| I13.2 | Hypertensive heart and chronic kidney disease with heart failure and with stage 5 chronic kidney disease, or end stage renal disease |
| I15.1 | Hypertension secondary to other renal disorders |
Formulary Reference Tool