Cilostazol

J01 - Antibacterials for systemic use Small molecule approved 1999 Oral Natural product Black-box warning

JFDA label: CladitolÂ®

⚠ Black-Box Warning

Contraindicated in heart failure patients:

Mechanism of Action

Inhibitor of cGMP-inhibited 3',5'-cyclic phosphodiesterase 3A — Phosphodiesterase 3A inhibitor

Target	Action	Gene / class
cGMP-inhibited 3',5'-cyclic phosphodiesterase 3A efficacy	INHIBITOR	PDE3A

Indications

Approved

Intermittent claudication

Off-label

Elective PCI with bare metal or drug eluting stent placement (alternative agent)
Prevention of stent thrombosis and restenosis after coronary stent placement (adjunct with aspirin and clopidogrel)
Secondary prevention of noncardioembolic ischemic stroke or transient ischemic attack (TIA)

Contraindications

Source: Lexicomp

Hypersensitivity to cilostazol or any component of the formulation Absolute
heart failure of any severity 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)

Common atrial fibrillation, vertigo , anxiety, dyspepsia, abdominal pain, flatulence, anorexia, myalgia, arthralgia, cough, asthma (Miscellaneous: Fever (Postmarketing and/or case reports: Abnormal hepatic f · Palpitations · peripheral edema · tachycardia

Nervous system disorders (1)

Very Common Headache

Gastrointestinal disorders (2)

Very Common abnormal stools · Diarrhea

Infections and infestations (1)

Very Common Infection

Respiratory, thoracic and mediastinal disorders (1)

Very Common Rhinitis

Dosing

Source: Lexicomp

Intermittent claudication: Oral: 100 mg twice daily. Note: The American College of Chest Physicians recommends use when refractory to exercise therapy and smoking cessation; use in combination with either aspirin or clopidogrel (ACCP [Guyatt 2012]). Note: Discontinue treatment if symptoms are not improved after 3 months of therapy. PCI (following elective stent placement) (off-label use): Oral: 100 mg twice daily in combination with aspirin or clopidogrel. Note: Only recommended in patients with an allergy or intolerance to either aspirin or clopidogrel (ACCP [Guyatt 2012]). Secondary prevention of noncardioembolic stroke or TIA (off-label use): Oral: 100 mg twice daily. Note: Clopidogrel or aspirin/extended release dipyridamole recommended over the use of cilostazol (ACCP [Guyatt 2012]). Dosage adjustment with concomitant medications: CYP2C19 inhibitors (eg, fluconazole, omeprazole, ticlopidine): Reduce cilostazol to 50 mg twice daily. Strong or moderate CYP3A4 inhibitors (eg, diltiazem, erythromycin, itraconazole, ketoconazole): Reduce cilostazol to 50 mg twice daily.

Refer to adult dosing.

No dosage adjustment necessary. Severe renal impairment increases metabolite concentrations; use with caution. End-stage renal disease (ESRD) on dialysis: There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied). Not dialyzable (NCS/SCCM [Frontera 2016])

Mild impairment: No dosage adjustment necessary. Moderate to severe impairment: There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied); use with caution.

Warnings & Precautions

Source: Lexicomp

Cardiovascular effects

May induce tachycardia, palpitation, tachyarrhythmia, and/or hypotension. Left ventricular outflow tract obstruction has been reported in patients with sigmoid shaped interventricular septum; monitor for the development of a new systolic murmur or cardiac symptoms after initiating therapy.

Hematologic effects

Cases of thrombocytopenia or leukopenia progressing to agranulocytosis, reversible upon discontinuation, have been reported when not immediately discontinued; monitor platelets and white blood cell counts periodically. Disease-related concerns:

Hemostatic disorders

Avoid use in patients with active pathological bleeding or hemostatic disorders (has not been studied).

Cardiovascular disease

Cilostazol is contraindicated in patients with heart failure of any severity. Phosphodiesterase inhibitors have caused decreased survival compared with placebo in patients with class III to IV heart failure. Patients with history of ischemic heart disease may be at increased risk for exacerbation of angina pectoris or myocardial infarction.

Hepatic impairment

Use with caution in patients with moderate to severe hepatic impairment (has not been studied).

Renal impairment

Use with caution in patients with severe renal impairment. Concurrent drug therapy issues:

Drug-drug interactions

Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information. Other warnings/precautions:

Elective surgery

Time required to recover adequate platelet function is ~2 days (Hill 2011). Of note, bleeding times were not significantly altered by cilostazol after 3 to 14 days of treatment (Kim 2004; Wilhite 2003).

Pregnancy & Lactation

Pregnancy

FDA category C

Adverse events have been observed in animal reproduction studies.

Lactation

It is not known if cilostazol is present in breast milk. Due to the potential for serious adverse reactions in the breastfed infant, the manufacturer recommends a decision be made whether to discontinue breastfeedig or to discontinue the drug, taking into account the importance of treatment to the mother.

LactMed: monitor the infant.

Monitoring

Clinical pearl	Platelets and WBC counts periodically; monitor for the development of a new systolic murmur or cardiac symptoms.

Chemistry & Properties

Formula	C20H27N5O2
Molecular weight	369.47 g/mol
IUPAC name	6-[4-(1-cyclohexyltetrazol-5-yl)butoxy]-3,4-dihydro-1H-quinolin-2-one
CAS	73963-72-1
PubChem CID	2754
InChIKey	`RRGUKTPIGVIEKM-UHFFFAOYSA-N`
logP	3.46 (XLogP 3.1)
Polar surface area	81.93 Å²
H-bond acceptors / donors	6 / 1
Drug-likeness (QED)	0.76
Lipinski violations	0

SMILES

O=C1CCc2cc(OCCCCc3nnnn3C3CCCCC3)ccc2N1

Biology & Pharmacokinetics

Pharmacokinetics

BBB penetrant	No

Enzyme interactions

Enzyme	Role	Detail
CYP2C19	Substrate	—
CYP2C9	Inhibitor	IC₅₀ 10.0 µM
CYP3A4	Inhibitor	—
CYP3A4	Substrate	—

Receptor binding (top 2)

Target	Action	Affinity
phosphodiesterase 3A (PDE3A)	Inhibitor	pIC50 6.7
phosphodiesterase 3B (PDE3B)	Inhibitor	pIC50 6.4

Transporters

BCRP (Inhibitor)BCRP (Inhibitor)BSEP (Inhibitor)BSEP (Inhibitor)MDR1 (Inhibitor)MRP1 (Inhibitor)MRP2 (Inhibitor)MRP3 (Inhibitor)MRP4 (Inhibitor)OATP1B1 (Inhibitor)OATP1B3 (Inhibitor)OATP1B3 (Inhibitor)P-gp (Inhibitor)MDR1 (Substrate)OAT (Substrate)OAT1 (Substrate)OAT2 (Substrate)OAT3 (Substrate)P-gp (Substrate)

Drug–drug interactions (100+, DDInter)

Interacting drug	Severity	Management
Acalabrutinib	major
Amisulpride	major
Amprenavir	major
Apixaban	major
Aprepitant	major
Ardeparin	major
Argatroban	major
Arsenic trioxide	major
Atazanavir	major
Avapritinib	major
Bedaquiline	major
Bepridil	major
Berotralstat	major
Betrixaban	major
Bivalirudin	major
Boceprevir	major
Cabozantinib	major
Ceritinib	major
Chloroquine	major
Cisapride	major
Clarithromycin	major
Clozapine	major
Cobicistat	major
Conivaptan	major
Crizotinib	major
Dalfopristin	major
Dalteparin	major
Danaparoid	major
Darunavir	major
Dasatinib	major
Deferasirox	major
Defibrotide	major
Delavirdine	major
Desirudin	major
Diltiazem	major
Disopyramide	major
Dofetilide	major
Dolasetron	major
Dronedarone	major
Droperidol	major

Showing 40 of 100+.

Registered Products (1)

Brand	Form / strength	Pack	Agent	Citizen (JOD)
CladitolÂ®	Tablet 50.0 mg	60 tab	/ UNITED PHARM.MFG.CO.LTD(UPM)/JORDAN / General	—