Diltiazem
JFDA label: DILZACARD R 90 TABLETS
Mechanism of Action
Inhibits calcium ion from entering the “slow channels” or select voltage-sensitive areas of vascular smooth muscle and myocardium during depolarization; produces relaxation of coronary vascular smooth muscle and coronary vasodilation; increases myocardial oxygen delivery in patients with vasospastic angina.
Indications
Approved
- Chronic kidney disease (CKD) and hypertension
- Coronary artery disease (CAD) and hypertension
- Hypertension
- Injection
- Oral
Off-label
- Anal fissures (topical)
- Atrial fibrillation (rate control) (oral)
- Hypertension (Children)
- Hypertrophic cardiomyopathy
- Non-ST-elevation acute coronary syndrome
- Raynaud phenomenon
Contraindications
Source: Lexicomp · Curated
- Additional contraindications (not in US labeling): Pregnancy Absolute
- Oral: Hypersensitivity to diltiazem or any component of the formulation Absolute
- Severe hypotension or cardiogenic shock Absolute
- Sick sinus syndrome or second/third-degree AV block without pacemaker Absolute
- administration concomitantly or within a few hours of the administration of IV beta-blockers Absolute
- atrial fibrillation or flutter associated with accessory bypass tract (eg, Wolff-Parkinson-White syndrome, short PR syndrome) Absolute
- cardiogenic shock Absolute
- concurrent use with intravenous dantrolene Absolute
- concurrent use with ivabradine Absolute
- hypotension (systolic Intravenous (IV): Hypersensitivity to diltiazem or any component of the formulation Absolute
- second- or third-degree AV block (except in patients with a functioning artificial pacemaker) Absolute
- severe hypotension Absolute
- sick sinus syndrome (except in patients with a functioning artificial pacemaker) Absolute
- use in women of childbearing potential Absolute
- ventricular tachycardia (with wide-complex tachycardia [QRS ≥0.12 seconds], must determine whether origin is supraventricular or ventricular) Absolute
Adverse Reactions
Cardiac disorders (4)
Very Common Edema
Common Atrioventricular block · bradycardia · hypotension, pain, nervousness
Nervous system disorders (1)
Very Common Headache
Metabolism and nutrition disorders (1)
Common Gout
Gastrointestinal disorders (2)
Common constipation · Dyspepsia
Skin and subcutaneous tissue disorders (1)
Common Skin rash
Musculoskeletal and connective tissue disorders (2)
Common myalgia · Weakness
Other (1)
Not Known Frequencies represent ranges for various dosage forms. Patients with impaired ventricular function and/or conduction abnormalities may have higher incidence of adverse reactions
Respiratory, thoracic and mediastinal disorders (1)
Common Rhinitis (
Dosing
Source: Lexicomp
Warnings & Precautions
Source: Lexicomp
Conduction abnormalities
May cause first-, second-, and third-degree AV block or sinus bradycardia; risk increases with agents known to slow cardiac conduction.
Dermatologic reactions
Transient dermatologic reactions have been observed with use; if reaction persists, discontinue. Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme, and/or exfoliative dermatitis have been reported.
Hepatic effects
Mild elevations of transaminases with and without concomitant elevation in alkaline phosphatase and bilirubin have been observed and frequently resolve spontaneously. Significant elevations in hepatic transaminases (eg, alkaline phosphatase, LDH, AST, ALT) and signs of acute hepatic injury have also been observed 1 to 8 weeks after therapy initiation and have been reversible upon discontinuation.
Hypotension/syncope
Symptomatic hypotension with or without syncope can rarely occur; blood pressure must be lowered at a rate appropriate for the patient's clinical condition. Disease-related concerns:
Hepatic impairment
Use with caution in patients with hepatic impairment.
Hypertrophic obstructive cardiomyopathy (HOCM)
Use with caution in patients with HOCM; routine use is currently not recommended due to insufficient evidence (Maron 2003).
Left ventricular dysfunction
Use with caution in left ventricular dysfunction; due to negative inotropic effects, may exacerbate condition. The ACCF/AHA heart failure guidelines recommend to avoid use in patients with heart failure due to lack of benefit and/or worse outcomes with calcium channel blockers in general (ACCF/AHA [Yancy 2013]).
Renal impairment
Use with caution in patients with renal impairment. Concurrent drug therapy:
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:
Appropriate use
IV: Unless otherwise contraindicated, appropriate vagal maneuvers should be attempted prior to administration of IV diltiazem. Use with caution in patients hemodynamically compromised; continuously monitor ECG and blood pressure during administration (especially during continuous IV infusion). Initial use should be, if possible, in a setting where monitoring and resuscitation equipment, including DC cardioversion/defibrillation, are present.
Pregnancy & Lactation
Pregnancy
Adverse events have been observed in animal reproduction studies. Untreated chronic maternal hypertension is associated with adverse events in the fetus, infant, and mother. If treatment for hypertension during pregnancy is needed, other agents are preferred (ACOG 2013). Women with hypertrophic cardiomyopathy who are controlled with diltiazem prior to pregnancy may continue therapy, but increased fetal monitoring is recommended (Gersh 2011).
Lactation
Diltiazem is excreted in breast milk in concentrations similar to those in the maternal plasma (Okada 1985). Breast-feeding is not recommended by the manufacturer.
Monitoring
| Clinical pearl | Liver function tests, kidney function, blood pressure, ECG, heart rate; consult individual institutional policies and procedures. Ventricular rate control in patients with atrial fibrillation or flutter: Patients who respond, usually have at least a 20% decrease in ventricular response rate or a rate |
|---|
Chemistry & Properties
| Formula | C22H26N2O4S |
|---|---|
| Molecular weight | 414.53 g/mol |
| IUPAC name | [(2S,3S)-5-[2-(dimethylamino)ethyl]-2-(4-methoxyphenyl)-4-oxo-2,3-dihydro-1,5-benzothiazepin-3-yl] acetate |
| CAS | 42399-41-7 |
| PubChem CID | 39186 |
| InChIKey | HSUGRBWQSSZJOP-RTWAWAEBSA-N |
| logP | 3.37 (XLogP 3.1) |
| Polar surface area | 59.08 Ų |
| H-bond acceptors / donors | 6 / 0 |
| Drug-likeness (QED) | 0.68 |
| Lipinski violations | 0 |
SMILES
COc1ccc([C@@H]2Sc3ccccc3N(CCN(C)C)C(=O)[C@@H]2OC(C)=O)cc1Biology & Pharmacokinetics
Pharmacokinetics
| BBB penetrant | Yes (logBB 0.3) |
|---|
Enzyme interactions
| Enzyme | Role | Detail |
|---|---|---|
| CYP1A2 | Substrate | — |
| CYP2C19 | Substrate | — |
| CYP2C9 | Substrate | — |
| CYP2D6 | Substrate | — |
| CYP3A4 | Inhibitor | Ki 0.4791419857062785 µM |
| CYP3A4 | Substrate | — |
Receptor binding (top 1)
| Target | Action | Affinity |
|---|---|---|
| 5-HT2A (HTR2A) | Binding | pKi 5.6 |
Transporters
ASBT (Inhibitor)BCRP (Inhibitor)BCRP (Inhibitor)BSEP (Inhibitor)BSEP (Inhibitor)MATE1 (Inhibitor)MATE2 (Inhibitor)MDR1 (Inhibitor)MRP1 (Inhibitor)MRP2 (Inhibitor)MRP3 (Inhibitor)MRP4 (Inhibitor)NTCP (Inhibitor)OATP1B1 (Inhibitor)OATP1B1 (Inhibitor)OATP1B3 (Inhibitor)OATP1B3 (Inhibitor)OATP2B1 (Inhibitor)OCT1 (Inhibitor)OCTN1 (Inhibitor)OCTN2 (Inhibitor)P-gp (Inhibitor)MCT1 (Substrate)MDR1 (Substrate)OCT1 (Substrate)P-gp (Substrate)
Drug–drug interactions (100+, DDInter)
| Interacting drug | Severity | Management |
|---|---|---|
| Acalabrutinib | major | |
| Betrixaban | major | |
| Bosutinib | major | |
| Brigatinib | major | |
| Ceritinib | major | |
| Cilostazol | major | |
| Cisapride | major | |
| Cobimetinib | major | |
| Deflazacort | major | |
| Docetaxel | major | |
| Dolasetron | major | |
| Edoxaban | major | |
| Eliglustat | major | |
| Encorafenib | major | |
| Entrectinib | major | |
| Erythromycin | major | |
| Everolimus | major | |
| Fingolimod | major | |
| Halofantrine | major | |
| Hydrocodone | major | |
| Ibrutinib | major | |
| Ivacaftor | major | |
| Ivosidenib | major | |
| Loperamide | major | |
| Naloxegol | major | |
| Neratinib | major | |
| Olaparib | major | |
| Pazopanib | major | |
| Simvastatin | major | |
| Siponimod | major | |
| Sonidegib | major | |
| Venetoclax | major | |
| Abemaciclib | moderate | |
| Acetylsalicylic acid | moderate | |
| Afatinib | moderate | |
| Albendazole | moderate | |
| Aldesleukin | moderate | |
| Alectinib | moderate | |
| Alimemazine | moderate | |
| Alpelisib | moderate |
Showing 40 of 100+.
Registered Products (3)
| Brand | Form / strength | Pack | Agent | Citizen (JOD) |
|---|---|---|---|---|
| Dilzacard 60 TABLETS | Tablet 60 mg | 50 tab | Dar Al Dawa Development and Investment Co Ltd/Jordan | 2.570 |
| DILZACARD R 90 TABLETS | Tablet 90 mg | 30 tab | Dar Al Dawa Development and Investment Co Ltd/Jordan | 4.620 |
| Dilzem Retard | Tablet 90 mg | 30 tab | Khoury Drug Store | 4.620 |