Milrinone

C01C - Cardiac stimulants excl. cardiac glycosides ATC C01CE02 Small molecule approved 1987 Parenteral Natural product

JFDA label: Primalon

Mechanism of Action

A selective phosphodiesterase inhibitor in cardiac and vascular tissue, resulting in vasodilation and inotropic effects with little chronotropic activity.

Indications

Approved

Heart failure
Inotropic support in heart failure

Off-label

Bridge to heart transplantation
Cardiogenic shock
Palliation of symptoms in end-stage heart failure
Postoperative inotropic support for heart transplant recipients

Contraindications

Source: Lexicomp

Hypersensitivity to milrinone or any component of the formulation Absolute

Adverse Reactions

Very Common >10%Common 1–10%Uncommon 0.1–1% Rare 0.01–0.1%Very Rare <0.01%Not Known

Cardiac disorders (4)

Very Common angina pectoris · chest pain · hypotension · Supraventricular cardiac arrhythmia

Nervous system disorders (1)

Very Common Headache

Other (1)

Very Common Cardiovascular: Ventricular arrhythmia (ventricular ectopy: 9%, nonsustained ventricular tachycardia: 3%, ventricular tachycardia: 1%, ventricular fibrillation: 1% to 10%:

Dosing

Source: Lexicomp

Inotropic support in heart failure: IV: Loading dose (optional, not recommended by ACCF/AHA 2013 heart failure guidelines; also see "Note"): 50 mcg/kg administered over 10 minutes followed by a maintenance dose titrated according to hemodynamic and clinical response; Maintenance dose: IV infusion: 0.375 to 0.75 mcg/kg/minute; lower initial doses of 0.1 mcg/kg/minute (with final maintenance doses of 0.2 to 0.3 mcg/kg/minute) have also been recommended (HFSA [Lindenfeld 2010]). The ACCF/AHA 2013 heart failure guidelines recommend a maintenance dose of 0.125 to 0.75 mcg/kg/minute (ACCF/AHA [Yancy 2013]). Note: When initiating an infusion of 0.5 mcg/kg/minute without a loading dose, significant hemodynamic changes seen at 30 minutes with similar effects on pulmonary capillary wedge pressure and cardiac index seen at 2 and 3 hours, respectively, compared to loading dose regimen (Baruch 2011). Bridge to heart transplantation (off-label use): IV: 0.1 to 0.75 mcg/kg/minute; titrate to optimize clinical condition (Aranda 2003; Bhat 2006; Upadya 2004) Cardiogenic shock (off-label use): IV: 0.125 to 0.75 mcg/kg/minute (AHA [van Diepen 2017]) Postoperative inotropic support in heart transplant recipients (off-label use): IV: 0.375 to 0.75 mcg/kg/minute; use the lowest effective dose and wean as tolerated over the first 3 to 5 days (ISHLT [Costanzo 2010]).

(For additional information see "Milrinone: Pediatric drug information") PALS Guidelines (cardiac output maintenance and postresuscitation stabilization) (off-label use): Infants, Children, and Adolescents: IV, IO: Loading dose: 50 mcg/kg over 10 to 60 minutes followed by a maintenance infusion of 0.25 to 0.75 mcg/kg/minute (AHA [Kleinman 2010])

Refer to adult dosing.

Manufacturer recommended adjustment: CrCl 50 mL/minute/1.73 m2: Administer 0.43 mcg/kg/minute CrCl 40 mL/minute/1.73 m2: Administer 0.38 mcg/kg/minute CrCl 30 mL/minute/1.73 m2: Administer 0.33 mcg/kg/minute CrCl 20 mL/minute/ 1.73 m2: Administer 0.28 mcg/kg/minute CrCl 10 mL/minute/1.73 m2: Administer 0.23 mcg/kg/minute CrCl 5 mL/minute/1.73 m2: Administer 0.2 mcg/kg/minute Alternative Dosing Adjustments in Patients with Renal Impairment1 CrCl (mL/min) Starting dose (mcg/kg/minute) 0.375 0.5 0.75 1Based on expert opinion 50 0.25 0.375 0.5 40 0.125 0.25 0.375 30 0.0625 0.125 0.25 20 Consider alternative therapy 0.0625 0.125 10 Consider alternative therapy 0.0625 5 Consider alternative therapy

There are no dosage adjustments provided in the manufacturer’s labeling.

Warnings & Precautions

Source: Lexicomp

Arrhythmias

Ventricular arrhythmias, including nonsustained ventricular tachycardia and supraventricular arrhythmias, have been reported. Observe closely for arrhythmias in this very high-risk patient population; sudden cardiac death has been observed. Due to the prolonged half-life as compared to other inotropic agents, ventricular or atrial arrhythmias may persist even after discontinuation of milrinone especially in patients with renal dysfunction (Cox 2013; Leier 1998). Ensure that ventricular rate is controlled in atrial fibrillation/flutter before initiating; may increase ventricular response rate. In heart transplant candidates, institute appropriate measures to protect patient against risks of sudden cardiac death (Brozena 2004).

Hypotension

Hypotension may occur. Monitor blood pressure closely. Hypotension may be prolonged especially in patients with renal dysfunction (Cox 2013; Leier 1998). Vigorous diuresis may contribute to hypotension; cautious administration of fluids may be required to prevent hypotension. Omitting the bolus dose may decrease the risk of hypotension (Baruch 2001; Cuffe 2002). If hypotension occurs, consider dose reduction or temporary discontinuation. Disease-related concerns:

Cardiovascular disease

Avoid use in patients with severe obstructive aortic or pulmonic valvular disease in lieu of surgical relief of the obstruction; may aggravate outflow tract obstruction in hypertrophic cardiomyopathy with outflow tract obstruction.

Electrolyte imbalance

Correct electrolyte disturbances, especially hypokalemia or hypomagnesemia, prior to use and throughout therapy to minimize the risk of arrhythmias.

Renal impairment

Use with caution in patients with renal impairment; reduction in infusion rate recommended. Hypotension may be prolonged in patients with renal dysfunction (Cox 2013; Leier 1998). Other warnings/precautions:

Appropriate use

A facility for immediate treatment of potential cardiac events, including life-threatening ventricular arrhythmias, must be available. Safe and effective use beyond 48 hours (prolonged use) has not been demonstrated. An increased risk of death and hospitalization has been observed with prolonged use in NYHA Class III/IV heart failure patients. Sudden cardiac death has been reported with prolonged use. Continuous electrocardiographic monitoring is recommended.

Long-term therapy

According to the ACCF/AHA 2013 heart failure guidelines, long-term use of intravenous inotropic therapy without a specific indication or for reasons other than palliation is potentially harmful (ACCF/AHA [Yancy 2013]).

Pregnancy & Lactation

Pregnancy

FDA category C

Adverse events have not been observed in animal reproduction studies; however, increased resorption was reported in some studies.

Lactation

It is not known if milrinone is present in breast milk. The manufacturer recommends that caution be exercised when administering milrinone to breastfeeding women.

Monitoring

Clinical pearl	Platelet count, electrolytes (especially potassium and magnesium) and fluid status, renal function; ECG, blood pressure, heart rate; infusion site If pulmonary artery catheter is in place, monitor cardiac index, stroke volume, systemic vascular resistance, pulmonary capillary wedge pressure and pulmonary vascular resistance. Consult individual institutional policies and procedures.

Chemistry & Properties

Formula	C12H9N3O
Molecular weight	211.22 g/mol
IUPAC name	6-methyl-2-oxo-5-pyridin-4-yl-1H-pyridine-3-carbonitrile
CAS	78415-72-2
PubChem CID	4197
InChIKey	`PZRHRDRVRGEVNW-UHFFFAOYSA-N`
logP	1.62 (XLogP 0.0)
Polar surface area	69.54 Å²
H-bond acceptors / donors	3 / 1
Drug-likeness (QED)	0.78
Lipinski violations	0

SMILES

Cc1[nH]c(=O)c(C#N)cc1-c1ccncc1

Biology & Pharmacokinetics

Pharmacokinetics

BBB penetrant	No

Enzyme interactions

Enzyme	Role	Detail
CYP1A2	Substrate	—
CYP2C8	Inhibitor	—
CYP2C9	Substrate	—
CYP3A4	Substrate	—

Receptor binding (top 3)

Target	Action	Affinity
phosphodiesterase 5A (PDE5A)	Inhibitor	pIC50 7.3
phosphodiesterase 2A (PDE2A)	Inhibitor	pIC50 6.5
phosphodiesterase 3B (PDE3B)	Inhibitor	pIC50 6.0

Transporters

BCRP (Inhibitor)BSEP (Inhibitor)MRP1 (Inhibitor)OATP1B1 (Inhibitor)OATP1B3 (Inhibitor)P-gp (Inhibitor)P-gp (Substrate)

Drug–drug interactions (5, DDInter)

Interacting drug	Severity	Management
Amifostine	moderate
Anagrelide	moderate
Diatrizoate	moderate
Ozanimod	moderate
Procarbazine	moderate

Registered Products (2)

Brand	Form / strength	Pack	Agent	Citizen (JOD)
Marolan 10mg/10ml Solution for IV Injection/Infusion	Infusion 10 mg/10 ml	1 vial	MS PHARMA/JORDAN	—
Primalon	Tablet 10 mg/10 ml	1 tab	HIKMA PHARMACEUTICALS FREE ZONE/JORDAN	—