Cleviprex (clevidipine butyrate)

Clevidipine dosage should be individualized to achieve the desired blood pressure reduction. The recommended initial adult IV dosage of clevidipine for the reduction of blood pressure when oral antihypertensive therapy is not feasible or desirable is 1-2 mg/hour. Initially, dosage may be doubled at short (90-second) intervals; as blood pressure approaches the desired value, dosage should be increased in smaller increments (less than doubling) at 5- to 10-minute intervals. An increase in dosage of approximately 1-2 mg/hour generally produces an additional 2- to 4-mm Hg decrease in systolic blood pressure. Blood pressure and heart rate should be monitored continuously during IV infusion and until vital signs are stable.

Desired therapeutic responses to clevidipine usually occur at IV dosages of 4-6 mg/hour. Patients with severe hypertension may require dosages up to 32 mg/hour. Most patients have received maximum dosages of 16 mg/hour or less; there is limited, short-term experience with dosages up to 32 mg/hour. Because each mL of emulsion contains 200 mg of lipids, the manufacturer recommends that no more than 1 L of clevidipine emulsion be administered in a 24-hour period (average clevidipine dosage of 21 mg/hour). In clinical studies, about 55 patients with hypertension received more than 500 mL of clevidipine emulsion in a 24-hour period. There is limited experience with infusion durations exceeding 72 hours at any dosage.

When IV clevidipine is used in adults who have a hypertensive emergency with a compelling indication (e.g., aortic dissection, severe preeclampsia or eclampsia+ , pheochromocytoma crisis+), systolic blood pressure should be reduced to less than 140 mm Hg during the first hour, and, in patients with acute aortic dissection, to less than 120 mm Hg within the first 20 minutes; beta-adrenergic blockade should precede clevidipine in such patients. In adults who have a hypertensive emergency without a compelling indication, systolic blood pressure should be reduced by no more than 25% within the first hour; then, if stable, to <160/100 mmHg within the next 2 to 6 hours, and then cautiously to 130 to 140 mmHg during the next 24 to 48 hours to limit target organ injury. If this blood pressure is well tolerated and the patient is clinically stable, further gradual reductions toward normal blood pressure can be implemented in the next 24-48 hours.

In patients being transferred to an oral antihypertensive agent, clevidipine should be discontinued or the dosage decreased while appropriate oral therapy is established; the lag time to onset of the oral antihypertensive agent's effects should be considered. Blood pressure monitoring should be continued until the desired effect is achieved. Patients who receive prolonged infusions of clevidipine and are not transferred to other antihypertensive therapies should be monitored for the possibility of rebound hypertension for at least 8 hours following discontinuance of the infusion.

Clevidipine injectable emulsion is administered by IV infusion into a central or peripheral vein using an infusion device allowing calibrated infusion rates. Commercially available standard plastic cannulae may be used to administer the infusion.

Vials of clevidipine injectable emulsion are intended for single use only. Aseptic technique should be maintained when handling clevidipine. Because the emulsion can support microbial growth, administration must be completed within 12 hours after initial puncture of the vial stopper; any unused portions remaining after the 12-hour time limit should be discarded.

Vials of clevidipine injectable emulsion should be inverted gently several times before use to ensure uniformity of the emulsion prior to administration.

Clevidipine should not be administered in the same IV line as other drugs. The commercially available emulsion should not be diluted; however, it may be administered with sterile water for injection, 0.9% sodium chloride injection, 5% dextrose injection, 5% dextrose and 0.9% sodium chloride injection, lactated Ringer's and 5% dextrose injection, lactated Ringer's injection, or 10% amino acid injection. Inspect parenteral drug products visually for particulate matter and discoloration prior to administration whenever solution and container permit.

Clevidipine injectable emulsion should be stored at 2-8degreesC; do not freeze. Store the single-use vials in the original cartons until use protected from light; protection from light during administration is not required. Vials may be removed from the refrigerator and stored at 25degreesC for <=2 months; however, the vials may not be returned to the refrigerator.

No dosing information is available for this tab.

There is no enhanced messaging for this drug.

There are no contraindication interactions for this drug.

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

Agents That Affect Catecholamines/Iobenguane I 131

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

MECHANISM OF ACTION: Many compounds that reduce catecholamine uptake or that deplete catecholamine stores may interfere with iobenguane uptake into cells.(1)

CLINICAL EFFECTS: Compounds that reduce catecholamine uptake or that deplete catecholamine stores may impact the dosimetry calculations or effectiveness of iobenguane.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Discuss the use of agents that affect catecholamines. Discontinue drugs that reduce catecholamine uptake or deplete catecholamine stores for at least 5 half-lives before administration of either the dosimetry or a therapeutic dose of iobenguane. Do not administer these drugs until at least 7 days after each iobenguane dose.(1)

DISCUSSION: Many agents may reduce catecholamine uptake or deplete catecholamine stores.(1) Examples include: - CNS stimulants or amphetamines (e.g. cocaine, methylphenidate, dextroamphetamine) - norepinephrine and dopamine reuptake inhibitors (e.g. phentermine) - norepinephrine and serotonin reuptake inhibitors (e.g. tramadol) - monoamine oxidase inhibitors (e.g. phenelzine, linezolid) - central monoamine depleting drugs (e.g. reserpine) - non-select beta adrenergic blocking drugs (e.g. labetalol) - alpha agonists or alpha/beta agonists (e.g. pseudoephedrine, phenylephrine, ephedrine, phenylpropanolamine, naphazoline) - tricyclic antidepressants or norepinephrine reuptake inhibitors (e.g. amitriptyline, bupropion, duloxetine, mirtazapine, venlafaxine) - botanicals that may inhibit reuptake of norepinephrine, serotonin or dopamine (e.g. ephedra, ma huang, St. John's Wort, yohimbine) - calcium channel blockers

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

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)

Selected Antihypertensives/Tizanidine

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)

*Defective lipid metabolism (e.g., pathologic hyperlipemia, lipoid nephrosis, acute pancreatitis associated with hyperlipemia).

*Severe aortic stenosis because afterload reduction may be expected to reduce myocardial oxygen delivery.

*Known hypersensitivity to soybeans, soy products, eggs, or egg products.

• Acute pancreatitis
• Hyperlipidemia
• Hypertriglyceridemia
• Minimal change glomerulonephritis
• Severe aortic valve stenosis

• Hypotension

• Heart failure
• Tachyarrhythmia

Most common adverse reactions (>2%) reported with clevidipine are headache, nausea, and vomiting.

Rare or Very Rare

• Acute myocardial infarction
• Acute renal failure
• Atrial fibrillation
• Dyspnea
• Hypotension
• Tachycardia
• Worsening of chronic heart failure

More Frequent

• Headache disorder

Less Frequent

• Nausea
• Vomiting

Rare or Very Rare

• Hypertriglyceridemia
• Ileus
• Syncope

No enhanced messaging available.

Safety and efficacy not established in children younger than 18 years of age.

There are insufficient available data derived from post-marketing reports with clevidipine use in pregnant women to inform a drug-associated risk for major birth defects, miscarriage, or adverse maternal or fetal outcomes.

Clevidipine has been shown to cross the placenta in rats. In animal studies, clevidipine was associated with increased incidences of intrauterine deaths, slightly reduced fetal weight, retarded skeletal development, abortion, and embryolethality at doses higher than the expected human dose. A dose-related increase in mortality, length of gestation, and prolonged parturition at dose levels of 13, 35, and 55 mg/kg per day was observed when clevidipine was administered to pregnant rats. There was no evidence that clevidipine was teratogenic at the highest dose levels studied in pregnant rats and rabbits.

There are risks to the mother (e.g., pre-eclampsia, gestational diabetes, premature delivery, delivery complications (e.g., need for cesarean section and postpartum hemorrhage)) and fetus (e.g., intrauterine growth restriction, intrauterine death) associated with poorly controlled hypertension in pregnancy; carefully monitor and manage pregnant women with hypertension accordingly.

There are no data on the presence of clevidipine in human milk; the effects of the drug on milk production or on the breastfed infant are also unknown.

The manufacturer makes no specific dosage recommendations for geriatric patients. The greater frequency of decreased hepatic, renal, and/or cardiac function and of concomitant disease and drug therapy observed in geriatric patients should be considered.

No substantial differences in safety and efficacy relative to younger adults. While other reported clinical experience has not revealed age-related differences in response, dosage generally should be titrated carefully in geriatric patients, usually initiating therapy at the low end of the dosage range. The greater frequency of decreased hepatic, renal, and/or cardiac function and of concomitant disease and drug therapy observed in geriatric patients also should be considered.