Milrinone: Difference between revisions

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|clinicalTrials=
|clinicalTrials=
There is limited information regarding <i>Clinical Trial Experience</i> of {{PAGENAME}} in the drug label.
=====Body as a Whole=====


=====Cardiovascular=====
=====Cardiovascular=====


 
* In patients receiving milrinone in Phase II and III clinical trials, ventricular arrhythmias were reported in 12.1%: Ventricular ectopic activity, 8.5%; nonsustained ventricular tachycardia, 2.8%; sustained ventricular tachycardia, 1% and ventricular fibrillation, 0.2% (2 patients experienced more than one type of arrhythmia). Holter recordings demonstrated that in some patients injection of milrinone increased ventricular ectopy, including nonsustained ventricular tachycardia. Life-threatening arrhythmias were infrequent and when present have been associated with certain underlying factors such as preexisting arrhythmias, metabolic abnormalities (e.g., hypokalemia), abnormal digoxin levels and catheter insertion. Milrinone was not shown to be arrhythmogenic in an electrophysiology study. Supraventricular arrhythmias were reported in 3.8% of the patients receiving milrinone. The incidence of both supraventricular and ventricular arrhythmias has not been related to the dose or plasma milrinone concentration.
 
* Other cardiovascular adverse reactions include hypotension, 2.9% and angina/chest pain, 1.2%.
 
=====Digestive=====
 
 
 
 
=====Endocrine=====
 
 
 
 
=====Hematologic and Lymphatic=====
 
 
 
 
=====Metabolic and Nutritional=====
 
 
 
 
=====Musculoskeletal=====
 
 




=====Neurologic=====
=====Neurologic=====


 
* Headaches, usually mild to moderate in severity, have been reported in 2.9% of patients receiving milrinone.
 
 
=====Respiratory=====
 
 
 
 
=====Skin and Hypersensitivy Reactions=====
 
 
 
 
=====Special Senses=====
 
 
 
 
=====Urogenital=====
 
 
 


=====Miscellaneous=====
=====Miscellaneous=====


 
* Other adverse reactions reported, but not definitely related to the administration of milrinone include hypokalemia, 0.6%; tremor, 0.4%; and thrombocytopenia, 0.4%.


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|postmarketing=


There is limited information regarding <i>Postmarketing Experience</i> of {{PAGENAME}} in the drug label.
* In addition to adverse events reported from clinical trials, the following events have been reported from worldwide post-marketing experience with milrinone:
 
:* Isolated spontaneous reports of bronchospasm and anaphylactic shock.
=====Body as a Whole=====
 
 
 
=====Cardiovascular=====
 
 
 
=====Digestive=====
 
 
 
=====Endocrine=====
 
 
 
=====Hematologic and Lymphatic=====
 
 
 
=====Metabolic and Nutritional=====
 
 
 
=====Musculoskeletal=====
 
 
 
=====Neurologic=====
 
 
 
=====Respiratory=====
 
 
 
=====Skin and Hypersensitivy Reactions=====
 
 
 
=====Special Senses=====
 
 
 
=====Urogenital=====
 
 
 
=====Miscellaneous=====
 


:* Liver function test abnormalities and skin reactions such as rash.
:* Administration site conditions: Infusion site reaction.
:* In the post-marketing experience, there have been rare cases of “torsades de pointes” reported.


<!--Drug Interactions-->
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|useInPregnancyFDA=
|useInPregnancyFDA=
* '''Pregnancy Category'''
* '''Pregnancy Category C'''
:* Oral administration of milrinone to pregnant rats and rabbits during organogenesis produced no evidence of teratogenicity at dose levels up to 40 mg/kg/day and 12 mg/kg/day, respectively. Milrinone did not appear to be teratogenic when administered intravenously to pregnant rats at doses up to 3 mg/kg/day (about 2.5 times the maximum recommended clinical intravenous dose) or pregnant rabbits at doses up to 12 mg/kg/day, although an increased resorption rate was apparent at both 8 mg/kg/day and 12 mg/kg/day (intravenous) in the latter species. There are no adequate and well-controlled studies in pregnant women. Milrinone should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.


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|useInNursing=
|useInNursing=
There is no FDA guidance on the use of {{PAGENAME}} with respect to nursing mothers.
* Caution should be exercised when milrinone is administered to nursing women, since it is not known whether it is excreted in human milk.


|useInPed=
|useInPed=
There is no FDA guidance on the use of {{PAGENAME}} with respect to pediatric patients.
* Safety and effectiveness in pediatric patients have not been established.


|useInGeri=
|useInGeri=
There is no FDA guidance on the use of {{PAGENAME}} with respect to geriatric patients.
* There are no special dosage recommendations for the elderly patient. Ninety percent of all patients administered milrinone in clinical studies were within the age range of 45 to 70 years, with a mean age of 61 years. Patients in all age groups demonstrated clinically and statistically significant responses. No age-related effects on the incidence of adverse reactions have been observed. Controlled pharmacokinetic studies have not disclosed any age-related effects on the distribution and elimination of milrinone.


|useInGender=
|useInGender=

Revision as of 19:01, 26 July 2014

Milrinone
Adult Indications & Dosage
Pediatric Indications & Dosage
Contraindications
Warnings & Precautions
Adverse Reactions
Drug Interactions
Use in Specific Populations
Administration & Monitoring
Overdosage
Pharmacology
Clinical Studies
How Supplied
Images
Patient Counseling Information
Precautions with Alcohol
Brand Names
Look-Alike Names

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Gerald Chi

Disclaimer

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Overview

Milrinone is a inotropic agent and vasodilator that is FDA approved for the {{{indicationType}}} of acute decompensated heart failure. Common adverse reactions include hypotension, ventricular arrhythmia, and headache.

Adult Indications and Dosage

FDA-Labeled Indications and Dosage (Adult)

Acute Decompensate Heart Failure
  • Milrinone should be administered with a loading dose followed by a continuous infusion (maintenance dose) according to the following guidelines:
  • Dosing Information
  • Loading Dose
This image is provided by the National Library of Medicine.
  • The loading dose may be given undiluted, but diluting to a rounded total volume of 10 or 20 mL may simplify the visualization of the injection rate.
This image is provided by the National Library of Medicine.
  • Milrinone drawn from vials should be diluted prior to maintenance dose administration. The diluents that may be used are 0.45% Sodium Chloride Injection, 0.9% Sodium Chloride Injection, or 5% Dextrose Injection. The table below shows the volume of diluent in milliliters (mL) that must be used to achieve 200 mcg/mL concentration for infusion, and the resultant total volumes.
This image is provided by the National Library of Medicine.
  • The infusion rate should be adjusted according to hemodynamic and clinical response. Patients should be closely monitored. In controlled clinical studies, most patients showed an improvement in hemodynamic status as evidenced by increases in cardiac output and reductions in pulmonary capillary wedge pressure.
  • Maintenance Dose
  • The maintenance dose in mL/hr by patient body weight (kg) may be determined by reference to the following table.
This image is provided by the National Library of Medicine.
  • When administering milrinone lactate by continuous infusion, it is advisable to use a calibrated electronic infusion device.
Dosage Adjustment in Renally Impaired Patients
  • Data obtained from patients with severe renal impairment (creatinine clearance = 0 to 30 mL/min) but without congestive heart failure have demonstrated that the presence of renal impairment significantly increases the terminal elimination half-life of milrinone. Reductions in infusion rate may be necessary in patients with renal impairment. For patients with clinical evidence of renal impairment, the recommended infusion rate can be obtained from the following table:
This image is provided by the National Library of Medicine.
  • Intravenous drug products should be inspected visually and should not be used if particulate matter or discoloration is present.

Off-Label Use and Dosage (Adult)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Milrinone in adult patients.

Non–Guideline-Supported Use

Low Cardiac Output Syndrome, Pre-Transplantation
  • Dosing Information
  • Loading dose of 50mcg/kg; mean maintenance dose was 0.43 mcg/kg/minute for a mean of 12 days.[1]

Pediatric Indications and Dosage

FDA-Labeled Indications and Dosage (Pediatric)

  • Safety and effectiveness in pediatric patients have not been established.

Off-Label Use and Dosage (Pediatric)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Milrinone in pediatric patients.

Non–Guideline-Supported Use

Adjunctive Therapy in Septic Shock
  • In pediatric patients with nonhyperdynamic septic shock, intravenous milrinone (loading dose of 50 mg/kg followed by a continuous infusion of 0.5 mg/kg/min) improves cardiovascular function when administered with catecholamines.[2]

Contraindications

  • Milrinone is contraindicated in patients who are hypersensitive to it.

Warnings

  • Whether given orally or by continuous or intermittent intravenous infusion, milrinone has not been shown to be safe or effective in the longer (greater than 48 hours) treatment of patients with heart failure. In a multicenter trial of 1088 patients with Class III and IV heart failure, long-term oral treatment with milrinone was associated with no improvement in symptoms and an increased risk of hospitalization and death. In this study, patients with Class IV symptoms appeared to be at particular risk of life-threatening cardiovascular reactions. There is no evidence that milrinone given by long-term continuous or intermittent infusion does not carry a similar risk.
  • The use of milrinone both intravenously and orally has been associated with increased frequency of ventricular arrhythmias, including nonsustained ventricular tachycardia. Long-term oral use has been associated with an increased risk of sudden death. Hence, patients receiving milrinone should be observed closely with the use of continuous electrocardiographic monitoring to allow the prompt detection and management of ventricular arrhythmias.

Precautions

  • General
  • Milrinone should not be used in patients with severe obstructive aortic or pulmonic valvular disease in lieu of surgical relief of the obstruction. Like other inotropic agents, it may aggravate outflow tract obstruction in hypertrophic subaortic stenosis.
  • Supraventricular and ventricular arrhythmias have been observed in the high-risk population treated. In some patients, injections of milrinone and oral milrinone have been shown to increase ventricular ectopy, including nonsustained ventricular tachycardia. The potential for arrhythmia, present in congestive heart failure itself, may be increased by many drugs or combinations of drugs. Patients receiving milrinone should be closely monitored during infusion.
  • Milrinone produces a slight shortening of AV node conduction time, indicating a potential for an increased ventricular response rate in patients with atrial flutter/fibrillation which is not controlled with digitalis therapy.
  • During therapy with milrinone, blood pressure and heart rate should be monitored and the rate of infusion slowed or stopped in patients showing excessive decreases in blood pressure.
  • If prior vigorous diuretic therapy is suspected to have caused significant decreases in cardiac filling pressure, milrinone should be cautiously administered with monitoring of blood pressure, heart rate, and clinical symptomatology.
  • There is no experience in controlled trials with infusions of milrinone for periods exceeding 48 hours. Cases of infusion site reactions have been reported with intravenous milrinone therapy. Consequently, careful monitoring of the infusion site should be maintained to avoid possible extravasation.
  • Use in Acute Myocardial Infarction
  • No clinical studies have been conducted in patients in the acute phase of post myocardial infarction. Until further clinical experience with this class of drugs is gained, milrinone is not recommended in these patients.
  • Laboratory Tests
  • Fluid and electrolyte changes and renal function should be carefully monitored during therapy with milrinone. Improvement in cardiac output with resultant diuresis may necessitate a reduction in the dose of diuretic. Potassium loss due to excessive diuresis may predispose digitalized patients to arrhythmias. Therefore, hypokalemia should be corrected by potassium supplementation in advance of or during use of milrinone.

Adverse Reactions

Clinical Trials Experience

Cardiovascular
  • In patients receiving milrinone in Phase II and III clinical trials, ventricular arrhythmias were reported in 12.1%: Ventricular ectopic activity, 8.5%; nonsustained ventricular tachycardia, 2.8%; sustained ventricular tachycardia, 1% and ventricular fibrillation, 0.2% (2 patients experienced more than one type of arrhythmia). Holter recordings demonstrated that in some patients injection of milrinone increased ventricular ectopy, including nonsustained ventricular tachycardia. Life-threatening arrhythmias were infrequent and when present have been associated with certain underlying factors such as preexisting arrhythmias, metabolic abnormalities (e.g., hypokalemia), abnormal digoxin levels and catheter insertion. Milrinone was not shown to be arrhythmogenic in an electrophysiology study. Supraventricular arrhythmias were reported in 3.8% of the patients receiving milrinone. The incidence of both supraventricular and ventricular arrhythmias has not been related to the dose or plasma milrinone concentration.
  • Other cardiovascular adverse reactions include hypotension, 2.9% and angina/chest pain, 1.2%.


Neurologic
  • Headaches, usually mild to moderate in severity, have been reported in 2.9% of patients receiving milrinone.
Miscellaneous
  • Other adverse reactions reported, but not definitely related to the administration of milrinone include hypokalemia, 0.6%; tremor, 0.4%; and thrombocytopenia, 0.4%.

Postmarketing Experience

  • In addition to adverse events reported from clinical trials, the following events have been reported from worldwide post-marketing experience with milrinone:
  • Isolated spontaneous reports of bronchospasm and anaphylactic shock.
  • Liver function test abnormalities and skin reactions such as rash.
  • Administration site conditions: Infusion site reaction.
  • In the post-marketing experience, there have been rare cases of “torsades de pointes” reported.

Drug Interactions

  • Drug Interactions
  • No untoward clinical manifestations have been observed in limited experience with patients in whom milrinone was used concurrently with the following drugs: digitalis glycosides; lidocaine, quinidine; hydralazine, prazosin; isosorbide dinitrate, nitroglycerin; chlorthalidone, furosemide, hydrochlorothiazide, spironolactone; captopril; heparin, warfarin, diazepam, insulin; and potassium supplements.
  • Chemical Interactions
  • There is an immediate chemical interaction which is evidenced by the formation of a precipitate when furosemide is injected into an intravenous line of an infusion of milrinone. Therefore, furosemide should not be administered in intravenous lines containing milrinone.

Use in Specific Populations

Pregnancy

Pregnancy Category (FDA):

  • Pregnancy Category C
  • Oral administration of milrinone to pregnant rats and rabbits during organogenesis produced no evidence of teratogenicity at dose levels up to 40 mg/kg/day and 12 mg/kg/day, respectively. Milrinone did not appear to be teratogenic when administered intravenously to pregnant rats at doses up to 3 mg/kg/day (about 2.5 times the maximum recommended clinical intravenous dose) or pregnant rabbits at doses up to 12 mg/kg/day, although an increased resorption rate was apparent at both 8 mg/kg/day and 12 mg/kg/day (intravenous) in the latter species. There are no adequate and well-controlled studies in pregnant women. Milrinone should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.


Pregnancy Category (AUS):

  • Australian Drug Evaluation Committee (ADEC) Pregnancy Category

There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Milrinone in women who are pregnant.

Labor and Delivery

There is no FDA guidance on use of Milrinone during labor and delivery.

Nursing Mothers

  • Caution should be exercised when milrinone is administered to nursing women, since it is not known whether it is excreted in human milk.

Pediatric Use

  • Safety and effectiveness in pediatric patients have not been established.

Geriatic Use

  • There are no special dosage recommendations for the elderly patient. Ninety percent of all patients administered milrinone in clinical studies were within the age range of 45 to 70 years, with a mean age of 61 years. Patients in all age groups demonstrated clinically and statistically significant responses. No age-related effects on the incidence of adverse reactions have been observed. Controlled pharmacokinetic studies have not disclosed any age-related effects on the distribution and elimination of milrinone.

Gender

There is no FDA guidance on the use of Milrinone with respect to specific gender populations.

Race

There is no FDA guidance on the use of Milrinone with respect to specific racial populations.

Renal Impairment

There is no FDA guidance on the use of Milrinone in patients with renal impairment.

Hepatic Impairment

There is no FDA guidance on the use of Milrinone in patients with hepatic impairment.

Females of Reproductive Potential and Males

There is no FDA guidance on the use of Milrinone in women of reproductive potentials and males.

Immunocompromised Patients

There is no FDA guidance one the use of Milrinone in patients who are immunocompromised.

Administration and Monitoring

Administration

  • Oral
  • Intravenous

Monitoring

There is limited information regarding Monitoring of Milrinone in the drug label.

  • Description

IV Compatibility

There is limited information regarding IV Compatibility of Milrinone in the drug label.

Overdosage

Acute Overdose

Signs and Symptoms

  • Description

Management

  • Description

Chronic Overdose

There is limited information regarding Chronic Overdose of Milrinone in the drug label.

Pharmacology

Template:Px
Milrinone
Systematic (IUPAC) name
6-methyl-2-oxo-5-pyridin-4-yl-1H-pyridine-3-carbonitrile
Identifiers
CAS number 78415-72-2
ATC code C01CE02
PubChem 4197
DrugBank APRD00010
Chemical data
Formula Template:OrganicBox atomTemplate:OrganicBox atomTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBox atomTemplate:OrganicBoxTemplate:OrganicBox atomTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBox 
Mol. mass 211.219 g/mol
Pharmacokinetic data
Bioavailability 100% (as IV bolus, infusion)
Protein binding 70 to 80%
Metabolism Hepatic (12%)
Half life 2.3 hours
Excretion Urine (85% as unchanged drug) within 24 hours
Therapeutic considerations
Pregnancy cat.

C(US)

Legal status

Rx Only

Routes IV only

Mechanism of Action

Structure

This image is provided by the National Library of Medicine.

Pharmacodynamics

There is limited information regarding Pharmacodynamics of Milrinone in the drug label.

Pharmacokinetics

There is limited information regarding Pharmacokinetics of Milrinone in the drug label.

Nonclinical Toxicology

  • Carcinogenesis, Mutagenesis, Impairment of Fertility
  • Twenty-four months of oral administration of milrinone to mice at doses up to 40 mg/kg/day (about 50 times the human oral therapeutic dose in a 50 kg patient) was unassociated with evidence of carcinogenic potential. Neither was there evidence of carcinogenic potential when milrinone was orally administered to rats at doses up to 5 mg/kg/day (about 6 times the human oral therapeutic dose) for twenty-four months or at 25 mg/kg/day (about 30 times the human oral therapeutic dose) for up to 18 months in males and 20 months in females. Whereas the Chinese Hamster Ovary Chromosome Aberration Assay was positive in the presence of a metabolic activation system, results from the Ames Test, the Mouse Lymphoma Assay, the Micronucleus Test, and the in vivo Rat Bone Marrow Metaphase Analysis indicated an absence of mutagenic potential. In reproductive performance studies in rats, milrinone had no effect on male or female fertility at oral doses up to 32 mg/kg/day.


  • Animal Toxicity
  • Oral and intravenous administration of toxic dosages of milrinone to rats and dogs resulted in myocardial degeneration/fibrosis and endocardial hemorrhage, principally affecting the left ventricular papillary muscles. Coronary vascular lesions characterized by periarterial edema and inflammation have been observed in dogs only. The myocardial/endocardial changes are similar to those produced by beta-adrenergic receptor agonists such as isoproterenol, while the vascular changes are similar to those produced by minoxidil and hydralazine. Doses within the recommended clinical dose range (up to 1.13 mg/kg/day) for congestive heart failure patients have not produced significant adverse effects in animals.

Clinical Studies

There is limited information regarding Clinical Studies of Milrinone in the drug label.

How Supplied

  • Milrinone Lactate Injection is supplied as 10 mL (1 mg/mL) NDC 55390-019-10, box of 10; 20 mL (1 mg/mL) NDC 55390-020-10, box of 10; and 50 mL (1 mg/mL) NDC 55390-021-01, individually-boxed, single-dose vials containing a sterile, clear, colorless to pale yellow solution. Each mL contains milrinone lactate equivalent to 1 mg milrinone.
  • Discard unused portion after initial use. Store at controlled room temperature 15° to 30°C (59° to 86°F). Avoid freezing.
  • Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. Protect from freezing.

Storage

There is limited information regarding Milrinone Storage in the drug label.

Images

Drug Images

{{#ask: Page Name::Milrinone |?Pill Name |?Drug Name |?Pill Ingred |?Pill Imprint |?Pill Dosage |?Pill Color |?Pill Shape |?Pill Size (mm) |?Pill Scoring |?NDC |?Drug Author |format=template |template=DrugPageImages |mainlabel=- |sort=Pill Name }}

Package and Label Display Panel

{{#ask: Label Page::Milrinone |?Label Name |format=template |template=DrugLabelImages |mainlabel=- |sort=Label Page }}

Patient Counseling Information

There is limited information regarding Patient Counseling Information of Milrinone in the drug label.

Precautions with Alcohol

  • Alcohol-Milrinone interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

Brand Names

Look-Alike Drug Names

Drug Shortage Status

Price

References

The contents of this FDA label are provided by the National Library of Medicine.

  1. Milfred-LaForest, S. K. (1999-10-15). "Tolerability of extended duration intravenous milrinone in patients hospitalized for advanced heart failure and the usefulness of uptitration of oral angiotensin-converting enzyme inhibitors". The American Journal of Cardiology. 84 (8): 894–899. ISSN 0002-9149. PMID 10532506. Unknown parameter |coauthors= ignored (help)
  2. Barton, P. (1996-05). "Hemodynamic effects of i.v. milrinone lactate in pediatric patients with septic shock. A prospective, double-blinded, randomized, placebo-controlled, interventional study". Chest. 109 (5): 1302–1312. ISSN 0012-3692. PMID 8625683. Unknown parameter |coauthors= ignored (help); Check date values in: |date= (help)
  3. "MILRINONE LACTATE injection".
  4. "http://www.ismp.org". External link in |title= (help)


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