Clonidine Hcl (clonidine HCl)

Regardless of the route of administration, to avoid the possibility of precipitating the withdrawal syndrome, clonidine therapy should not be discontinued abruptly.

Dosage of clonidine is expressed in terms of clonidine and clonidine hydrochloride.

Clonidine hydrochloride is administered orally or by epidural infusion; clonidine is administered orally or percutaneously by topical application of a transdermal system.

There is no enhanced messaging for this drug.

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

Agents Affecting Growth Hormone/Macimorelin

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: Agents affecting growth hormone may impact the accuracy of the macimorelin diagnostic test.(1)

CLINICAL EFFECTS: Concurrent use of agents affecting growth hormone may impact the accuracy of the macimorelin diagnostic test.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of macimorelin states concurrent use with agents affecting growth hormone may impact the accuracy of the macimorelin diagnostic test. Discontinue growth hormone products at least 1 week before administering the macimorelin diagnostic test. Sufficient washout time of drugs affecting growth hormone release prior to administration of macimorelin is recommended.(1) Agents affecting growth hormone include: - Drugs that directly affect the pituitary secretion of growth hormone (e.g. somatostatin, insulin, glucocorticoids, cyclooxygenase inhibitors) - Drugs that may transiently elevate growth hormone concentrations (e.g. clonidine, levodopa, insulin) - Drugs that may blunt the growth hormone response (e.g. muscarinic antagonists, anti-thyroid medications, growth hormone products)

DISCUSSION: Concurrent use of agents affecting growth hormone may impact the accuracy of the macimorelin diagnostic test.(1)

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

Agents That Cause Bradycardia/Camizestrant

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

MECHANISM OF ACTION: Camizestrant 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 camizestrant recommends avoiding concurrent use of camizestrant and other agents known to cause bradycardia.(1) If combination therapy is unavoidable, monitor heart rate and blood pressure regularly. Monitor heart rate more frequently during the first 30 days of treatment with camizestrant in patient with bradycardia (heart rate less than 60 beats per minute (bpm)) and those on concomitant medications known to lower heart rate.(1) If bradycardia occurs, symptomatic or Grade 2 or above, withhold camizestrant until symptoms resolve. Obtain an ECG to evaluate the etiology of the symptomatic bradycardia. If a contributing concomitant medication is identified, modify the dosage or discontinue the medication as appropriate until bradycardia symptoms resolve and then resume camizestrant. Consider reassessing the heart rate after restarting camizestrant. Permanently discontinue camizestrant for persistent bradycardia.(1) The manufacturer of camizestrant recommends performing an ECG prior to initiating camizestrant, then every week for the first 2 weeks of treatment, and periodically during treatment as clinically indicated.(1)

DISCUSSION: In a clinical trial, bradycardia occurred in 8% of patients on camizestrant. The mean heart rate decrease from baseline was approximately 13 beats per minute with camizestrant, with the maximum decrease observed on Day 15. The median time to onset of adverse reaction was 17 days (range 13 to 283 days) after starting camizestrant. Bradycardia led to dose interruption of camizestrant in 3.9% of patients.(1) Agents that may cause bradycardia and linked to this monograph include: beta-blockers, non-dihydropyridine calcium channel blockers, clonidine, digoxin, and moxonidine.

Agents That Cause Bradycardia/Crizotinib

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, digoxin, and moxonidine.(1)

Agents That Cause Bradycardia/Etrasimod

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)

Agents That Cause Bradycardia/Fexinidazole

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

MECHANISM OF ACTION: Fexinidazole has been shown to prolong the QTc interval. Concurrent use with agents that cause bradycardia may increase the risk of QTc prolongation.(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 fexinidazole recommends avoiding concurrent use of fexinidazole and other agents known to cause bradycardia.(1) Avoid use of fexinidazole in patients who have a baseline QTcF interval greater than 470 msec, a history of torsade de pointes, congenital long QT syndrome, cardiac arrhythmias, uncompensated heart failure, or family history of sudden death, or uncorrected hypokalemia.(1) If patients are, or need to be, treated with drugs known to induce bradycardia or prolong the QTc interval do not initiate therapy with fexinidazole until such drugs are eliminated from the body (allow a washout period of 5 half-lives for such other drugs). Do not start such drugs until fexinidazole therapy is eliminated (allow a washout period of 7 days).(1)

DISCUSSION: Bradycardia increases the risk of QTc interval prolongation and torsade de pointes.(1) In clinical studies, fexinidazole was associated with a concentration-dependent QTcF prolongation. At recommended therapeutic doses, the mean (upper 90% confidence interval) increase in QTcF is predicted to be 19.0 msec (23.3 msec). The observed increase in QTcF appears to be associated with the M2 (sulfone) metabolite of fexinidazole.(1) Agents that may cause bradycardia and linked to this monograph include: beta-blockers, clonidine, digoxin and moxonidine.(1)

Agents That Cause Bradycardia/Ponesimod

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)

Agents That Cause Bradycardia/Siponimod

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)

Alpha-2 Agonists/Tizanidine

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

MECHANISM OF ACTION: Tizanidine is an alpha-2 agonist. Concurrent use with other alpha-2 agonists may result in additive effects on blood pressure.(1)

CLINICAL EFFECTS: Concurrent use of alpha-2 agonists and tizanidine may result in hypotension.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of tizanidine states concurrent use with other alpha-2 agonists is not recommended.(1) 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) Alpha-2 agonists linked include: clonidine, dexmedetomidine, guanabenz, guanadrel, guanethidine, guanfacine, methyldopa, and moxonidine.

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

Clonidine/Beta-Blockers

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

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.

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.

Selected Antihypertensive Agents/Selected Maois

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, moxonidine, and sparsentan.

Selected Antihypertensives And Vasodilators/Apomorphine

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)

*Clonidine is contraindicated in patients with known hypersensitivity to the drug or to any ingredient or component in the formulation.

*Administration of epidural clonidine is contraindicated in patients receiving anticoagulant therapy, in those with a bleeding diathesis, and in the presence of an injection site infection.

*Administration of epidural clonidine above the C4 dermatome is contraindicated because of inadequate safety data supporting such use.

*Administration of epidural clonidine also is not recommended in most patients with severe cardiovascular disease or in patients who are hemodynamically unstable.

There are no contraindication contraindications for this drug.

• Atrioventricular block
• Hypotension
• Invasive surgical procedure
• Sinus bradycardia

• Acute myocardial infarction
• Cerebrovascular disorder
• Chronic kidney disease stage 5 (failure) GFr<15 ml/min
• Chronic myocardial ischemia
• Dry eye

Most adverse effects with clonidine are mild in nature and tend to decrease with continuation of therapy. The most common, dose-related adverse effects include dry mouth, drowsiness, dizziness, constipation, and sedation.

Adverse effects with transdermal clonidine are generally similar to those with oral therapy. The most frequent adverse effects with transdermal clonidine were dry mouth, drowsiness, and local adverse dermatologic effects.

The most frequent adverse effects occurring with clonidine hydrochloride epidural infusion for severe intractable cancer pain were hypotension, postural hypotension, dizziness, anxiety, and dry mouth; asymptomatic bradycardia was also observed in 1 patient. Mean heart rate and blood pressure reductions were also observed in patients receiving clonidine hydrochloride epidural infusion. Upon withdrawal of clonidine, 4 patients also experienced rebound hypertension, of which 1 suffered a cerebrovascular accident.

Adverse effects occurring in >=5% of patients receiving clonidine as monotherapy for ADHD include somnolence, fatigue, irritability, nightmares, insomnia, constipation, and dry mouth. When used as adjunctive therapy to stimulants in ADHD, adverse effects reported in >=5% of patients include somnolence, fatigue, decreased appetite, and dizziness.

Less Frequent

• Depression

Rare or Very Rare

• Abnormal ECG
• Angioedema
• Atrioventricular block
• Bradycardia
• Chronic heart failure
• Hepatitis
• Hypotension
• Nightmares
• Raynaud's phenomenon
• Syncope

More Frequent

• Constipation
• Dizziness
• Drowsy
• Fatigue
• General weakness
• Irritability
• Xerostomia

Less Frequent

• Abnormal sexual function
• Acute abdominal pain
• Anorexia
• Dry eye
• Earache
• Erectile dysfunction
• Nasal congestion
• Nausea
• Nervousness
• Ocular irritation
• Ocular itching
• Orthostatic hypotension
• Sore throat
• Tremor
• Upper abdominal pain
• Vomiting

Rare or Very Rare

• Accommodation disorder
• Agitation
• Blurred vision
• Cramps in legs
• Delirium
• Delusional disorder
• Dry nose
• Fever
• Gynecomastia
• Hallucinations
• Headache disorder
• Insomnia
• Myalgia
• Nocturia
• Pallor
• Paresthesia
• Sleep disorder
• Symptoms of anxiety
• Urinary retention
• Weight gain

No enhanced messaging available.

The safety and efficacy of extended-release clonidine tablets and extended-release oral suspension (Onyda(TM) XR) for the treatment of ADHD have been established in pediatric patients 6-17 years of age. Use for this indication is based on evidence from 3 adequate, well-controlled studies, a short-term, placebo-controlled monotherapy study, a short-term, adjunctive therapy study, and a long-term randomized monotherapy study.

Safety and efficacy of oral clonidine hydrochloride, extended-release clonidine (Nexiclon(TM) XR), and clonidine transdermal system for the management of hypertension in children have not been established.

The safety and efficacy of clonidine hydrochloride epidural infusion have been established in pediatric patients who are old enough to tolerate placement and management of an epidural catheter, based on evidence from adequate, well-controlled studies in adults and experience with the use of clonidine in pediatric patients for other indications. Epidural clonidine should be used only in pediatric patients with severe, intractable cancer pain that is unresponsive to epidural or spinal opiates and to other conventional analgesic therapy.

Children may be more likely to experience CNS depression associated with clonidine overdosage than adults. In children, signs of toxicity have occurred with clonidine doses as low as 0.1 mg. Rare cases of clonidine toxicity (many involving children) associated with accidental or deliberate mouthing or ingestion of clonidine transdermal systems have been reported.

The manufacturer of oral clonidine states that because children frequently experience vomiting associated with GI illnesses, they may be particularly susceptible to hypertensive episodes resulting from sudden inability to ingest the drug.

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.

There is a pregnancy exposure registry available that monitors pregnancy outcomes in women exposed to ADHD medications, including clonidine, during pregnancy. Patients can register by calling the National Pregnancy Registry for Psychiatric Medications at 1-866-961-2388 or by visiting https://womensmentalhealth.org/research/pregnancyregistry/adhd-medications/ .

Since clonidine is distributed into milk, the drug should be used with caution in nursing women. The drug is excreted into milk at relative infant doses ranging from 4.1-8.4% of the maternal weight-adjusted dosage. Although in most cases, there were no reported adverse effects in breast-fed infants exposed to clonidine, one infant developed sedation, hypotonia, and apnea after clonidine exposure through breast milk. Monitor infants exposed to clonidine through breast milk for symptoms of hypotension and bradycardia, such as sedation, lethargy, tachypnea and poor feeding. Consider the developmental and health benefits of breast-feeding along with the mother's clinical need for the drug and any potential adverse effects on the breast-fed infant from exposure to clonidine or the underlying maternal condition.

When conventional clonidine tablets are used for hypertension, the manufacturer states that geriatric patients may benefit from a lower initial dosage of 0.05 mg twice daily. Geriatric patients with hypertension may also benefit from an initial lower dosage when extended-release clonidine tablets (Nexiclon(R) XR) are used.

Geriatric patients may benefit from lower initial dosages of clonidine.