Overview of Wart Inhibit Ointment
Dosage Strength of Wart Inhibit Ointment
Cimetidine / Imiquimod 10/5% 10 mL Pump
Cimetidine is a histamine H2-antagonist and inhibits actions of histamine mediated by H2-receptors such as gastric acid secretion and pepsin output. It is used where inhibition of gastric acid secretion may be beneficial, as in peptic ulcer disease, including stress ulceration (Gastrointestinal Drugs), gastro-oesophageal reflux disease (Gastrointestinal Drugs), selected cases of persistent dyspepsia (Gastrointestinal Drugs), scleroderma of the oesophagus, pathological hypersecretory states such as the Zollinger-Ellison syndrome (Gastrointestinal Drugs), and in patients at risk of acid aspiration (Gastrointestinal Drugs) during general anaesthesia or child birth. Cimetidine may also be used to reduce malabsorption and fluid loss in patients with the short bowel syndrome and to reduce the degradation of enzyme supplements given to patients with pancreatic insufficiency.
Mechanism of Action
Cimetidine blocks the effects of histamine at the receptor located on the basolateral membrane of the parietal cell (designated as the H2-receptor). The result is a reduction of both gastric acid volume and gastric acidity. Cimetidine also decreases the amount of gastric acid released in response to other stimuli including food, caffeine, insulin, betazole, or pentagastrin. Because gastric secretions respond to multiple stimuli, cimetidine does not reduce acid-output as dramatically as the proton-pump inhibiting medications (e.g., omeprazole). Cimetidine does not appear to alter gastric motility, gastric emptying, esophageal pressure, or the secretion rate of the gallbladder or pancreas. Cimetidine also exhibits weak anti-androgenic effects.
In combination with an H1-receptor antagonist, cimetidine can suppress the formation of edema, flare, and pruritus that results from histaminic activity. Human skin mast cells express both H1- and H2-receptors. Stimulation of H2-receptors leads to changes in membrane permeability (activating the cyclic AMP-PKA pathway) causing vasodilation.1 The resultant dilation develops more slowly and is more sustained, as compared to H1-stimulation. Combination therapy blocks both the initial and delayed histaminic response.2
Studies in mice and humans have shown that H2-antagonists have an immunoregulatory effect.1 T-lymphocyte suppressor cells have histamine H2 receptors and cimetidine has been reported to reduce activity of these cells, thus enhancing immune response.34 There is also some evidence that it enhances cellular immunity, notably natural killer cell activity.5 This discovery has led to the investigation of cimetidine in disorders associated with alteration of the immune response including eosinophilic fasciitis, herpesvirus infections, mucocutaneous candidiasis,6 hypogammaglobulinaemia,7 and various malignancies. 3
There are reports8 of benefit from the use of cimetidine in patients with viral warts (Dermatological Drugs and Sunscreens) and an 8-year retrospective analysis of 216 patients with plantar warts reported a success rate of about 80%, although warts recurred in 12 patients.9 However, controlled studies have failed to show significant benefit,1011 and a review concluded that use of H2-antagonists for warts could not be recommended based on the available evidence.12
Cimetidine is administered orally and parenterally. The drug distributes throughout body tissues, is found in breast milk, and crosses the placenta. Cimetidine has been shown to inhibit a number of CYP isoenzymes, including 1A2, 2C19, and to a lesser extent 2D6 and 3A4.1314 Half-life is roughly 2 hours in patients with normal renal function.
Affected cytochrome P450 isoenzymes: CYP1A2, CYP2C19, CYP2D6, and CYP3A4
Cimetidine is the classic example of a drug that inhibits cytochrome oxidative hepatic metabolism, and it inhibits this system non-selectively.15 Cimetidine has been shown to inhibit a number of CYP isoenzymes, including CYP1A2, CYP2C19, and to a lesser extent CYP2D6 and CYP3A4.14
H2 blockers can be used in combination with certain antibiotics to eradicate Helicobacter pylori.16 When cimetidine is used with antimicrobials, clinicians should be cognizant of possible pseudomembranous colitis occurring. Almost all antibacterial agents have been associated with pseudomembranous colitis (antibiotic-associated colitis) which may range in severity from mild to life-threatening. In the colon, overgrowth of Clostridia may exist when normal flora is altered subsequent to antibacterial administration. The toxin produced by Clostridium difficile is a primary cause of pseudomembranous colitis. It is known that systemic use of antibiotics predisposes patients to development of pseudomembranous colitis. Consideration should be given to the diagnosis of pseudomembranous colitis in patients presenting with diarrhea following antibacterial administration. Systemic antibiotics should be prescribed with caution to patients with inflammatory bowel disease such as ulcerative colitis or other GI disease. If diarrhea develops during therapy, the drug should be discontinued. Following diagnosis of pseudomembranous colitis, therapeutic measures should be instituted. In milder cases, the colitis may respond to discontinuation of the offending agent. In moderate to severe cases, fluids and electrolytes, protein supplementation, and treatment with an antibacterial effective against Clostridium difficile may be warranted. Products inhibiting peristalsis are contraindicated in this clinical situation. Practitioners should be aware that antibiotic-associated colitis has been observed to occur over two months or more following discontinuation of systemic antibiotic therapy; a careful medical history should be taken.
Cimetidine is contraindicated in any patient hypersensitive to the drug or its components. Cross-sensitivity in this class of compounds has been observed, so cimetidine should be administered with caution to patients with a history of H2-blocker hypersensitivity. An incidence of cross-reactivity among this class of agents is not currently available. Cimetidine injection multidose vials contain benzyl alcohol as a preservative and should be avoided in patients with benzyl alcohol hypersensitivity.17
Cimetidine non-selectively inhibits the hepatic cytochrome P450 oxidative enzymes system and many drug interactions have been described when cimetidine was added to, or discontinued from an established drug regimen. The clinician should review potential drug interactions prior to prescribing cimetidine. Cimetidine should be used cautiously in patients with hepatic disease such as cirrhosis, or in those with renal impairment or renal failure, because cimetidine clearance can be reduced. Reduced doses of cimetidine are recommended in patients with renal impairment; further dose reduction may be necessary if liver impairment is also present.1518 Various types of reversible confusional states have been attributed to cimetidine. While decreased clearance would seem to predispose patients to adverse reactions, hepatic disease and/or renal disease have not been shown conclusively to increase the risk for central nervous system reactions.19
Cimetidine is classified as FDA pregnancy risk category B.15 Animal studies have not demonstrated a risk to the fetus but there are no adequate studies in pregnant women. Epidemiological evidence based on the use of cimetidine during the first trimester of human gestation does not suggest an increase in fetal malformations compared to the normal population.20 However, cimetidine, is known to cross the placenta. Unlike other H2-blockers, cimetidine pharmacologically exhibits some weak anti-androgenic activity that could result in feminism of male fetuses. However, conflicting evidence from in utero exposure in animals exists regarding anti-androgenic effects. There are documented data of efficacy in human pregnancy for ranitidine, and many experts consider this H-2 blocker an effective and safe alternative during pregnancy.20
Cimetidine is secreted into breast milk, usually in concentrations that exceed maternal plasma concentrations. Cimetidine is not usually recommended for use during lactation by the manufacturer. However, in the absence of reported adverse events in infants, the American Academy of Pediatrics and other experts consider the drug usually compatible with breast-feeding.2122 Although also excreted in breast milk, other H2-blockers might be considered alternatives due to the fact that they do not typically have anti-androgenic actions, and would not inhibit infant hepatic enzyme activity should the infant be prescribed an interacting medication. Galactorrhea and hyperprolactinemia have been reported in patients taking cimetidine. In one case, a patient with galactorrhea and hyperprolactinemia on cimetidine was switched to ranitidine with resolution of her symptoms.23 Of all H2-blockers, famotidine is excreted least in breast milk.20
Adverse Reactions/Side Effects
Mild to severe headache occurred in 2.1% of patients who received cimetidine 800 mg/day (n = 2225) and 3.5% of patients who received 1600 mg/day (n = 924) compared with 2.3% of patients who received placebo (n = 1897) in clinical trials. Dizziness and drowsiness, most cases mild, were reported in approximately 1% of patients who received 800 mg/day or 1600 mg/day in clinical trials. Mental confusion, agitation, psychosis, depression, anxiety, hallucinations, disorientation, have been reported mostly in severely ill patients. These central nervous system adverse effects usually developed within 2—3 days after starting and resolved within 3—4 days of stopping cimetidine therapy.2425
Rare cases of thrombocytopenia (3 cases per million patients) and decreased white blood counts such as neutropenia and leukopenia (1 case per 100,000 patients) or agranulocytosis (3 cases per million patients) have been reported with cimetidine therapy. Some cases have recurred on rechallenge. Pancytopenia, aplastic anemia, and immune hemolytic anemia have also been reported rarely.2425
Gynecomastia has been reported in patients who received cimetidine therapy for longer than 1 month. Gynecomastia occurred in approximately 4% of adult patients with pathological hypersecretory conditions and in 0.3% to 1% of patients with other conditions in clinical trials.2425 Galactorrhea and hyperprolactinemia have been reported in patients taking cimetidine. In one case, a patient with galactorrhea and hyperprolactinemia on cimetidine was switched to ranitidine with resolution of her symptoms.23 Although reversible impotence (erectile dysfunction) was reported in patients with pathological hypersecretory conditions (e.g., Zollinger-Ellison syndrome) and mostly in patients who received high doses of cimetidine for > 12 months (mean, 38 months; range, 12-79 months), large surveillance studies have not shown an increased risk of erectile dysfunction in patients who received a regular cimetidine dosage.2425
Dose-related elevated hepatic enzymes (e.g., increased transaminase levels) have been reported with cimetidine therapy; however, most transaminase level elevations did not worsen with continued therapy and returned to normal by the end of therapy. Cholestatic (cholestasis) or mixed cholestatic hepatocellular effects and pancreatitis have also occurred rarely, most cases reversible. There has been 1 report of biopsy proven periportal hepatic fibrosis. Rarely, fatal hepatic injury has been reported with H2-receptor antagonist use.2425
Store this medication in its original container at 68°F to 77°F (20°C to 25°C) and away from heat, moisture and light. Keep all medicine out of the reach of children. Throw away any unused medicine after the beyond use date. Do not flush unused medications or pour down a sink or drain.
- 1. Moscati RM, Hood F, Moore GP, et al. Comparison of cimetidine and diphenhydramine in the treatment of acute urticaria. Ann Emerg Med 1990;19:12-15.
- 2. Skidgel RA, Erdos EG. Autocoids: Drug therapy of inflammation. In: Goodman and Gilman's Pharmacological Basis of Therapeutics. 11th ed. The McGraw-Hill Companies, Inc; 2006
- 3. a. b. Kumar A. Cimetidine: an immunomodulator. DICP Ann Pharmacother 1990; 24: 289-95.
- 4. Snyman JR, et al. Cimetidine as modulator of the cell-mediated immune response in vivo using the tuberculin skin test as parameter. Br J Clin Pharmacol 1990; 29: 257-60.
- 5. Katoh J, et al. Cimetidine and immunoreactivity. Lancet 1996; 348: 404-5.
- 6. Polizzi B, et al. Successful treatment with cimetidine and zinc sulphate in chronic mucocutaneous candidiasis. Am J Med Sci 1996; 311: 189-90.
- 7. White WB, Ballow M. Modulation of suppressor-cell activity by cimetidine in patients with common variable hypogammaglobulinemia. N Engl J Med 1985; 312: 198-202.
- 8. Glass AT, et al. Cimetidine therapy for recalcitrant warts in adults. Arch Dermatol 1996; 132: 680-2.
- 9. Mullen BR, et al. Cimetidine as a first-line therapy for pedal verruca: eight-year retrospective analysis. J Am Podiatr Med Assoc 2005; 95: 229-34.
- 10. Karabulut AA, et al. Is cimetidine effective for nongenital warts: a double-blind, placebo-controlled study. Arch Dermatol 1997; 133: 533-4.
- 11. Rogers CJ, et al. Cimetidine therapy for recalcitrant warts in adults: is it any better than placebo? J Am Acad Dermatol 1999; 41: 123-7.
- 12. Fit KE, Williams PC. Use of histamine2-antagonists for the treatment of verruca vulgaris. Ann Pharmacother 2007; 41: 1222-6.
- 13. Welage LS, Berardi RR. Drug interactions with antiulcer agents: considerations in treatment of acid-peptic disease. J Pharm Pract 1994;7:177-95.
- 14. a. b. Humphries TJ, Merritt GJ. Review article: drug interactions with agents used to treat acid-related diseases. Aliment Pharmacol Ther 1999;13:18-26.
- 15. a. b. c. Tagamet (cimetidine) package insert. Research Triangle Park, NC: GlaxoSmithKline; 2019 March.
- 16. Malfertheiner P, Megraud F, O'Morain C, et al. Current concepts in the management of Helicobacter pylori infection: the Maastricht III Consensus Report. Gut 2007;56:772-81.
- 17. Cimetidine injection solution package insert. Lake Forest, IL: Hospira, Inc.; 2006 Aug.
- 18. Cimetidine package insert. Sellersville, PA: Teva Pharmaceuticals USA; 2010 Oct.
- 19. Cantu TG, Korek JS. Central nervous system reactions to histamine-2 receptor blockers. Ann Intern Med 1991;114:1027-34.
- 20. a. b. c. Mahadevan U, Kane S. American Gastroenterological Association Institute technical review on the use of gastrointestinal medications in pregnancy. Gastroenterology 2006;131:283-311.
- 21. American Academy of Pediatrics (AAP) Committee on Drugs. Transfer of drugs and other chemicals into human milk. Pediatrics 2001;108(3):776-789.
- 22. Cimetidine. In: Drugs in Pregnancy and Lactation. A Reference Guide to Fetal and Neonatal Risk. Briggs GG, Freeman RK, Yaffee SJ, (eds). 9th ed., Philadelphia PA: Lippincott Williams and Wilkins; 2011: 279-82.
- 23. a. b. Ehrinpreis MN, Dhar R, Narula A. Cimetidine-induced galactorrhea. Am J Gastroenterol 1989;84:563-5.
- 24. a. b. c. d. e. Cimetidine tablets package insert. Sellersville, PA:Teva Pharmaceuticals USA Inc.;2010 Oct.
- 25. a. b. c. d. e. Cimetidine hydrochloride injection package insert. Lake Forest, IL:Hospira, Inc.; 2006 Aug.