Cimetidine

A02B - Drugs for peptic ulcer and GORD ATC A02BA01 Small molecule approved 1977 Oral Parenteral Natural product

JFDA label: CIMEDINE400 TAB.

Mechanism of Action

Antagonist of Histamine H2 receptor — Histamine H2 receptor antagonist

Target	Action	Gene / class
Histamine H2 receptor efficacy	ANTAGONIST	HRH2

Indications

Approved

Duodenal ulcer
Gastric ulcer
Gastroesophageal reflux disease
Heartburn (OTC only)
Pathological hypersecretory conditions

Off-label

Interstitial cystitis (bladder pain syndrome)
Stress ulcer prophylaxis in critically-ill patients

Contraindications

Source: Lexicomp

Hypersensitivity to cimetidine or any component of the formulation OTC labeling: When used for self-medication (OTC), do not use if trouble or pain when swallowing food, vomiting with blood, or bloody or black stools, allergic to cimetidine or other acid reducers. Do not use with other acid reducers. Documentation of allergenic cross-reactivity for histamine H2 antagonists is limited. However, because of similarities in chemical structure and/or pharmacologic actions, the possibility of cros 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 (5)

Not Known Atrioventricular block · bradycardia · hypotension · tachycardia · vasculitis

Nervous system disorders (6)

Common agitation · dizziness · drowsiness · Headache

Not Known Confusion · decreased sexual activity

Hepatobiliary disorders (3)

Not Known Hepatic fibrosis (case report) · increased serum ALT · increased serum AST

Renal and urinary disorders (3)

Not Known Breast swelling · Increased serum creatinine · interstitial nephritis

Blood and lymphatic system disorders (6)

Not Known Agranulocytosis · aplastic anemia · hemolytic anemia (immune-based) · neutropenia · pancytopenia · thrombocytopenia

Immune system disorders (1)

Not Known Anaphylaxis

Metabolism and nutrition disorders (1)

Common Gynecomastia

Gastrointestinal disorders (3)

Not Known Nausea · pancreatitis · vomiting

Skin and subcutaneous tissue disorders (6)

Not Known Alopecia · erythema multiforme · exfoliative dermatitis · skin rash · Stevens-Johnson syndrome · toxic epidermal necrolysis

Musculoskeletal and connective tissue disorders (3)

Not Known Arthralgia · myalgia · polymyositis

General disorders and administration site conditions (1)

Not Known Fever

Respiratory, thoracic and mediastinal disorders (1)

Not Known Pneumonia (causal relationship not established)

Dosing

Source: Lexicomp

Duodenal ulcer, active: Oral: 300 mg 4 times daily or 800 mg at bedtime or 400 mg twice daily for up to 8 weeks Note: Higher doses of 1,600 mg at bedtime for 4 weeks may be beneficial for a subpopulation of patients with larger duodenal ulcers (>1 cm defined endoscopically) who are also heavy smokers (≥1 pack/day). Duodenal ulcer, prophylaxis: Oral: 400 mg at bedtime Gastric ulcer, active: Oral: 300 mg 4 times daily or 800 mg at bedtime for up to 8 weeks Gastroesophageal reflux disease: Oral: 400 mg 4 times daily or 800 mg twice daily for 12 weeks Heartburn (OTC labeling): Prevention: Oral: 200 mg daily up to 30 minutes prior to eating foods or beverages that cause heartburn (maximum: 400 mg per 24 hours). Relief of symptoms: Oral: 200 mg daily; maximum: 400 mg per 24 hours. Pathological hypersecretory conditions: Oral: 300 mg 4 times daily; adjust dose to patient response; maximum 2,400 mg/day Interstitial cystitis (bladder pain syndrome) (off-label use): Oral: 200 mg 3 times daily or 300 to 400 mg twice daily (Dasgupta 2001; Seshadri 1994; Thilagarajah 2001) Stress ulcer prophylaxis in critically ill patients (off-label use): Oral or NG tube: 300 mg 4 times daily (ASHP 1999). Note: Intended for patients with associated risk factors (eg, coagulopathy, mechanical ventilation for >48 hours, sepsis/septic shock); discontinue use once risk factors have resolved (Rhodes 2017).

(For additional information see "Cimetidine: Pediatric drug information") Duodenal ulcer, active: Children ≥5 years of age and Adolescents Adolescents ≥16 years of age: Oral: Refer to adult dosing. Duodenal ulcer, prophylaxis: Adolescents ≥16 years of age: Oral: Refer to adult dosing. Gastric ulcer, active: Adolescents ≥16 years of age: Oral: Refer to adult dosing. Gastroesophageal reflux disease: Infants, Children, and Adolescents Adolescents ≥16 years of age: Oral: Refer to adult dosing. Heartburn (OTC labeling): Prevention: Children ≥12 years of age and Adolescents: Oral: Refer to adult dosing. Relief of symptoms: Children ≥12 years of age and Adolescents: Oral: Refer to adult dosing. Pathological hypersecretory conditions: Adolescents ≥16 years of age: Oral: Refer to adult dosing.

Refer to adult dosing.

Manufacturer's labeling: Mild to moderate renal impairment: There are no dosage adjustments provided in the manufacturer’s labeling; use with caution. Severe renal impairment: 300 mg every 12 hours; may increase frequency with caution. When hepatic impairment is also present, further reductions in dosage may be necessary. Alternate recommendations: Adults (Aronoff 2007): GFR >50 mL/minute: No dosage adjustment necessary. GFR 10 to 50 mL/minute: Administer 50% of normal dose GFR 300 mg every 8 to 12 hours Hemodialysis: Dose after dialysis CCRT: Administer 50% of normal dose Peritoneal dialysis: 300 mg every 8 to 12 hours Geriatric patients ≥65 years: CrCl Stress ulcer prophylaxis in critically ill patients (off-label use): CrCl

There are no dosage adjustments provided in the manufacturer’s labeling; use with caution. Dosage adjustments may be needed in patients with both renal and hepatic impairment.

Warnings & Precautions

Source: Lexicomp

Confusion

Rare cases of reversible confusion have been associated with cimetidine; usually elderly or severely ill patients, or in patients with renal or hepatic impairment.

Vitamin B12 deficiency

Prolonged treatment (≥2 years) may lead to vitamin B12 malabsorption and subsequent vitamin B12 deficiency. The magnitude of the deficiency is dose-related and the association is stronger in females and those younger in age ( Disease-related concerns:

Gastric malignancy

Relief of symptoms does not preclude the presence of a gastric malignancy.

Hepatic impairment

Use with caution in patients with hepatic impairment.

Renal impairment

Use with caution in patients with renal impairment; dosage adjustment recommended. 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. Special populations:

Elderly

Use caution in this age group due to risk of confusion and other CNS effects.

Immunocompromised patients

May have increased risk of hyperinfection of strongyloidiasis.

Pediatric

Use of gastric acid inhibitors, including proton pump inhibitors and H2 blockers, has been associated with an increased risk for development of acute gastroenteritis and community-acquired pneumonia in pediatric patients (Canani 2006). Other warnings/precautions:

OTC labeling

When used for self-medication (OTC), notify health care provider before use if any of the following are present: Frequent chest pain; frequent wheezing particularly with heartburn; nausea/vomiting; unexplained weight loss; stomach pain; heartburn >3 months; heartburn with light-headedness, sweating, or dizziness; chest pain or shoulder pain with shortness of breath; sweating or pain that spreads to arms, neck, or shoulders; light-headedness. Stop use and notify health care provider if heartburn continues or worsens, stomach pain continues, or if use is required >14 days.

Pregnancy & Lactation

Pregnancy

FDA category B

Adverse events have not been observed in animal reproduction studies. Cimetidine crosses the placenta (Howe 1981). Histamine H2 antagonists have been evaluated for the treatment of gastroesophageal reflux disease (GERD), as well as gastric and duodenal ulcers during pregnancy (Cappell 2003; Richter 2003). Histamine H2 antagonists may be used for aspiration prophylaxis prior to cesarean delivery (ASA 2007).

Lactation

Avoid

Cimetidine is excreted in breast milk. Breastfeeding is not recommended by the manufacturer.

Monitoring

Clinical pearl	CBC, gastric pH; monitor renal function to correct dose; occult blood with GI bleeding; signs of confusion.

Chemistry & Properties

Formula	C10H16N6S
Molecular weight	252.35 g/mol
IUPAC name	1-cyano-2-methyl-3-[2-[(5-methyl-1H-imidazol-4-yl)methylsulfanyl]ethyl]guanidine
CAS	51481-61-9
PubChem CID	2756
InChIKey	`AQIXAKUUQRKLND-UHFFFAOYSA-N`
logP	0.6 (XLogP 0.4)
Polar surface area	88.89 Å²
H-bond acceptors / donors	4 / 3
Drug-likeness (QED)	0.23
Lipinski violations	0

SMILES

CN/C(=N\CCSCc1nc[nH]c1C)NC#N

Biology & Pharmacokinetics

Pharmacokinetics

BBB penetrant	No (logBB -1.4)

Enzyme interactions

Enzyme	Role	Detail
CYP1A2	Inhibitor	—
CYP1A2	Substrate	—
CYP2C19	Inhibitor	—
CYP2C19	Substrate	—
CYP2D6	Inhibitor	Ki 77.00000000000007 µM
CYP3A4	Inhibitor	IC₅₀ 15.000000000000004 µM
CYP3A4	Substrate	—

Receptor binding (top 5)

Target	Action	Affinity
H2 receptor (HRH2)	Antagonist	pKi 6.8
HISTAMINE H2 (HRH2)	Binding	pKi 6.2
Multidrug and toxin extrusion (SLC47A1)	Inhibitor	pKi 6.0
5-HT2A (HTR2A)	Binding	pKi 5.2
MATE2 (SLC47A2)	Inhibitor	pKi 5.1

Transporters

BCRP (Inhibitor)BCRP (Inhibitor)BSEP (Inhibitor)BSEP (Inhibitor)MATE1 (Inhibitor)MATE2 (Inhibitor)MCT6 (Inhibitor)MDR1 (Inhibitor)MRP1 (Inhibitor)MRP2 (Inhibitor)MRP4 (Inhibitor)NTCP (Inhibitor)OAT (Inhibitor)OAT1 (Inhibitor)OAT2 (Inhibitor)OAT3 (Inhibitor)OAT4 (Inhibitor)OATP1B1 (Inhibitor)OATP1B1 (Inhibitor)OATP1B3 (Inhibitor)OATP1B3 (Inhibitor)OATP2B1 (Inhibitor)OCT(unspecified) (Inhibitor)OCT1 (Inhibitor)OCT2 (Inhibitor)OCT3 (Inhibitor)OCTN1 (Inhibitor)OCTN2 (Inhibitor)P-gp (Inhibitor)Transporter(unspecified) (Inhibitor)BCRP (Substrate)MATE1 (Substrate)MATE2 (Substrate)MDR1 (Substrate)OAT (Substrate)OAT1 (Substrate)OAT2 (Substrate)OAT3 (Substrate)OCT(unspecified) (Substrate)OCT1 (Substrate)OCT2 (Substrate)OCTN2 (Substrate)P-gp (Substrate)Transporter(unspecified) (Substrate)

Drug–drug interactions (100+, DDInter)

Interacting drug	Severity	Management
Astemizole	major
Atazanavir	major
Benzhydrocodone	major
Brexpiprazole	major
Carmustine	major
Cisapride	major
Citalopram	major
Dasatinib	major
Dofetilide	major
Eliglustat	major
Epirubicin	major
Fosphenytoin	major
Halofantrine	major
Hydrocodone	major
Lemborexant	major
Levacetylmethadol	major
Lomustine	major
Lonafarnib	major
Loperamide	major
Neratinib	major
Oxycodone	major
Pazopanib	major
Phenytoin	major
Pimozide	major
Rilpivirine	major
Selpercatinib	major
Siponimod	major
Tamoxifen	major
Terfenadine	major
Thioridazine	major
Tizanidine	major
Acalabrutinib	moderate
Acebutolol	moderate
Acetohexamide	moderate
Alfentanil	moderate
Alosetron	moderate
Alprazolam	moderate
Altretamine	moderate
Aminophylline	moderate
Amiodarone	moderate

Showing 40 of 100+.

Registered Products (5)

Brand	Form / strength	Pack	Agent	Citizen (JOD)
CIMEDINE400 TAB.	Tablet 400 mg	24 tab pack varies	Dar Al Dawa Development and Investment Co Ltd/Jordan	4.000
CIMEDINE 200 TAB.	Tablet 200 mg	50 tab pack varies	Dar Al Dawa Development and Investment Co Ltd/Jordan	4.700
DYSPAMET SUSP	Suspension 200 mg	100 ml	Sukhtian Group	4.890
CIMEDINE 200 TAB.	Tablet 200 mg	500 tab pack varies	Dar Al Dawa Development and Investment Co Ltd/Jordan	42.300
CIMEDINE400 TAB.	Tablet 400 mg	504 tab pack varies	Dar Al Dawa Development and Investment Co Ltd/Jordan	71.400