Repaglinide

A10B - Blood glucose lowering drugs, excl. insulins ATC A10BX02 Small molecule approved 1997 Oral Natural product

JFDA label: NovoNorm Tab

Mechanism of Action

Blocker of Sulfonylurea receptor 1, Kir6.2 — Sulfonylurea receptor 1, Kir6.2 blocker

Target	Action	Gene / class
Sulfonylurea receptor 1, Kir6.2 efficacy	BLOCKER

Indications

Approved

Diabetes mellitus, type 2

Class profile

mechanismClass	Meglitinide/glinide (rapid-acting secretagogue)
insulinSecretagogue	1
weightEffect	Slight gain
hypoglycemiaRisk	Moderate
renalContraindicated	0
cardioProtective	0
renalProtective	0
source	ADA-EASD2023/Maruthur2016

Contraindications

Source: Lexicomp

Additional contraindications (not in US labeling): Severe hepatic impairment Absolute
Hypersensitivity to repaglinide or any component of the formulation Absolute
concurrent gemfibrozil therapy Absolute
concurrent use with clopidogrel Absolute
diabetic ketoacidosis, with or without coma Absolute
type 1 diabetes (insulin dependent) 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 (2)

Common chest pain · Ischemia

Nervous system disorders (1)

Very Common Headache

Renal and urinary disorders (1)

Common Urinary tract infection

Immune system disorders (1)

Common Hypersensitivity reaction

Metabolism and nutrition disorders (1)

Very Common Hypoglycemia

Gastrointestinal disorders (2)

Common constipation · Diarrhea

Musculoskeletal and connective tissue disorders (2)

Common arthralgia · Back pain

Respiratory, thoracic and mediastinal disorders (3)

Very Common Upper respiratory tract infection

Common bronchitis · Sinusitis

Dosing

Source: Lexicomp

Diabetes mellitus, type 2: Oral: Patients whose HbA1c is Patients whose HbA1c is ≥8%: Initial: 1 or 2 mg before each meal (2, 3, or 4 times/day depending on number of meals); may double the dose with each meal at intervals of ≥1 week until adequate glycemic control is achieved; maximum: 4 mg/dose or 16 mg/day. Dosage adjustment for concomitant therapy: Clopidogrel: Avoid concomitant use; if concomitant use is necessary, initiate repaglinide at 0.5 mg before each meal; maximum: 4 mg/day. Cyclosporine: Maximum: 6 mg/day of repaglinide.

Refer to adult dosing.

CrCl ≥40 mL/minute: No dosage adjustment necessary. CrCl 20 to 40 mL/minute: Initial: 0.5 mg with meals; titrate carefully. CrCl Hemodialysis: There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).

There are no dosage adjustments provided in the manufacturer's labeling. Use with caution; consider longer intervals between dosage adjustments.

Warnings & Precautions

Source: Lexicomp

Hypoglycemia

Severe hypoglycemia may occur; risk may be increased by changes in meal patterns, changes in physical activity levels, changes to coadministered medications, and concomitant use with other antidiabetic agents. Disease-related concerns:

Cardiovascular effects

Some studies suggest oral hypoglycemic drugs may be associated with increased cardiovascular events. Theoretically, repaglinide may also increase cardiovascular events, but there are no long-term studies assessing this concern. Use in combination with NPH insulin is not indicated; in two studies, reports of myocardial ischemia (6 events) in patients using repaglinide plus insulin have caused concern. Further evaluation is required to assess the safety of this combination.

Hepatic impairment

Use with caution in patients with hepatic impairment; may be more susceptible to glucose-lowering effects.

Renal impairment

Use with caution in patients with severe renal impairment; may be more susceptible to glucose-lowering effects. Concurrent drug therapy issues:

Drug-drug interactions

Potentially significant drug-drug 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

Not for use in patients with diabetic ketoacidosis or patients with type 1 diabetes mellitus (insulin-dependent).

Pregnancy & Lactation

Pregnancy

FDA category C

Adverse events have been observed in some animal reproduction studies. Repaglinide was shown to have a low potential to cross the placenta using an ex vivo perfusion model (Tertti 2011). Information describing the effects of repaglinide on pregnancy outcomes is limited. In women with diabetes, maternal hyperglycemia can be associated with congenital malformations as well as adverse effects in the fetus, neonate, and the mother (ACOG 2005; ADA 2018c; Kitzmiller 2008; Metzger 2007). To prevent adverse outcomes, prior to conception and throughout pregnancy maternal blood glucose and HbA1c should be kept as close to target goals as possible but without causing significant hypoglycemia (ACOG 2013; ADA 2018c; Blumer 2013; Kitzmiller 2008). Agents other than repaglinide are currently recommended to treat diabetes in pregnant women (ADA 2018c).

Lactation

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

LactMed: monitor the infant.

Monitoring

Efficacy	HbA1c every 3 months initially, then every 6–12 months when stable; fasting and post-prandial blood glucose; patient-reported hypoglycaemia episodes
Toxicity	Hypoglycaemia symptoms; eGFR for renally-cleared agents; weight; blood pressure
Clinical pearl	Individualise HbA1c targets based on patient age, comorbidities, and hypoglycaemia risk. Targets of < 7% are appropriate for most patients but < 8% may be safer in frail elderly.
Counseling	Monitor blood glucose regularly. Know how to recognise and treat hypoglycaemia. Keep carbohydrate snacks available.

Chemistry & Properties

Formula	C27H36N2O4
Molecular weight	452.6 g/mol
IUPAC name	2-ethoxy-4-[2-[[(1S)-3-methyl-1-(2-piperidin-1-ylphenyl)butyl]amino]-2-oxoethyl]benzoic acid
CAS	135062-02-1
PubChem CID	65981
InChIKey	`FAEKWTJYAYMJKF-QHCPKHFHSA-N`
logP	5.22 (XLogP 5.2)
Polar surface area	78.87 Å²
H-bond acceptors / donors	4 / 2
Drug-likeness (QED)	0.52
Lipinski violations	1

SMILES

CCOc1cc(CC(=O)N[C@@H](CC(C)C)c2ccccc2N2CCCCC2)ccc1C(=O)O

Biology & Pharmacokinetics

Pharmacokinetics

BBB penetrant	No

Enzyme interactions

Enzyme	Role	Detail
CYP2C19	Substrate	—
CYP3A4	Substrate	—

Receptor binding (top 1)

Target	Action	Affinity
ATP-binding cassette, sub-family C (CFTR/MRP), member 8 (ABCC8)	Inhibitor	pIC50 7.0

Transporters

BCRP (Inhibitor)BSEP (Inhibitor)BSEP (Inhibitor)MDR1 (Inhibitor)MRP1 (Inhibitor)MRP2 (Inhibitor)MRP3 (Inhibitor)MRP4 (Inhibitor)OATP1B1 (Inhibitor)OATP1B1 (Inhibitor)OATP1B3 (Inhibitor)OATP1B3 (Inhibitor)OATP2B1 (Inhibitor)OCT1 (Inhibitor)P-gp (Inhibitor)PEPT1 (Inhibitor)MDR1 (Substrate)OATP (Substrate)OATP1B1 (Substrate)P-gp (Substrate)Transporter(unspecified) (Substrate)

Drug–drug interactions (100+, DDInter)

Interacting drug	Severity	Management
Cinoxacin	major
Ciprofloxacin	major
Clopidogrel	major
Cyclosporine	major
Delafloxacin	major
Enoxacin	major
Gatifloxacin	major
Gemfibrozil	major
Gemifloxacin	major
Grepafloxacin	major
Levofloxacin	major
Lomefloxacin	major
Moxifloxacin	major
Nalidixic acid	major
Norfloxacin	major
Ofloxacin	major
Sparfloxacin	major
Trovafloxacin	major
Abametapir (topical)	moderate
Abiraterone	moderate
Acebutolol	moderate
Acetazolamide	moderate
Acetylsalicylic acid	moderate
Albiglutide	moderate
Alimemazine	moderate
Aloe Vera Leaf	moderate
Alogliptin	moderate
Alpelisib	moderate
Aminoglutethimide	moderate
Amiodarone	moderate
Amobarbital	moderate
Amprenavir	moderate
Apalutamide	moderate
Aprepitant	moderate
Aripiprazole	moderate
Armodafinil	moderate
Asenapine	moderate
Asparaginase Erwinia chrysanthemi	moderate
Asparaginase Escherichia coli	moderate
Atazanavir	moderate

Showing 40 of 100+.

Registered Products (6)

Brand	Form / strength	Pack	Agent	Citizen (JOD)
NovoNorm	Tablet 0.5 mg	30 tab pack varies	Khoury Drug Store	4.640
NovoNorm	Tablet 1 mg	30 tab pack varies	Khoury Drug Store	5.190
NovoNorm Tab	Tablet 2 mg	30 tab pack varies	Khoury Drug Store	5.610
NovoNorm	Tablet 0.5 mg	90 tab pack varies	Khoury Drug Store	13.080
NovoNorm	Tablet 1 mg	90 tab pack varies	Khoury Drug Store	14.640
NovoNorm Tab	Tablet 2 mg	90 tab pack varies	Khoury Drug Store	15.790