You are now connected to the following file: HAZARDOUS SUBSTANCES DATA BANK ==RANITIDINE - HSDB== 1 - HSDB NAME OF SUBSTANCE RANITIDINE CAS REGISTRY NUMBER 66357-35-5 SYNONYMS N-(2-(((-5-((DIMETHYLAMINO)METHYL)-2-FURAN YL)METHYL)THIO)ETHYL)-N'-METHYL-2 -NITRO-1,1-ETHENEDIAMINE **PEER REVIEWED** SYNONYMS 1,1-ETHENEDIAMINE, N-(2-(((5-((DIMETHYLAMINO)METHYL)-2-FURANY L)METHYL)THIO) ETHYL)-N-METHYL-2-NITRO- **PEER REVIEWED** MAJOR USES MEDICATION [CITATION] **QC REVIEWED** HUMAN TOXICITY EXCERPTS A 63 yr old woman developed anicteric hepatitis after two wk of therapy with ranitidine. Despite continuation of therapy, her symptoms resolved within 5 days and transaminase levels returned to normal in the next 4 weeks, at which time use of the drug ceased. No other cause for the reaction could be found. [Barr GD, Piper DW; Med J Aust 2 (8): 421 (1981)] **PEER REVIEWED** HUMAN TOXICITY EXCERPTS In a study of 51 male patients with duodenal ulcer, treatment with ranitidine, produced no decrease in basal levels of serum testosterone, as did cimetidine. [Peden NR et al; Acta Endocrinol (Copenh) 96 (4): 564-8 (1981)] **PEER REVIEWED** HUMAN TOXICITY EXCERPTS Ranitidine inhibited in a dose-dependent manner acetylcholinesterases from human erythrocytes and gastric mucosa. The concn for half-max inhibition was 1.5X10-6 and 1.4X10-6 M/l, which resembles levels seen during therapy. The inhibitory constant measured 1.6X10-6 M/l. Pseudocholinesterase in serum was also inhibited, the levels required were about 25 times higher. A stimulation of cholinergic mechanisms in ranitidine treatment should occur, eg, stimulation of glandular secretion or incr of gastrointestinal motility. [Hansen WE, Bertl S; Z Gastroenterol 21 (4): 164-7 (1983)] **PEER REVIEWED** HUMAN TOXICITY EXCERPTS Headache (sometimes severe) occurs in approx 3% of patients receiving the drug. Malaise, dizziness, somnolence, insomnia, and vertigo have been reported less frequently. Reversible mental confusion, agitation, mental depression, and hallucinations have occurred, mainly in debilitated geriatric patients. A child who was receiving prolonged, high-dose oral ranitidine therapy (8 mg/kg once daily for 10 mo) developed altered consciousness, drowsiness, dysarthria, hyporeflexia, positive Babinski's sign, diaphoresis, and bradycardia, which resolved within 24 hr after discontinuance of the drug. [McEvoy G.K. (ed.). American Hospital Formulary Service-Drug Information 96. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 1996 (Plus Supplements)., p. 2182] **PEER REVIEWED** HUMAN TOXICITY EXCERPTS Constipation, nausea, vomiting, and abdominal discomfort or pain have occurred in patients receiving ranitidine. Pancreatitis has been reported rarely. [McEvoy G.K. (ed.). American Hospital Formulary Service-Drug Information 96. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 1996 (Plus Supplements)., p. 2182] **PEER REVIEWED** HUMAN TOXICITY EXCERPTS Rash, which may be urticarial, maculopapular, and/or pruritic, has been reported during ranitidine therapy. Rash suggestive of mild erythema multiforme has occurred rarely. Urticaria at the site of injection has occurred following IV admin of ranitidine. Alopecia has occurred rarely. [McEvoy G.K. (ed.). American Hospital Formulary Service-Drug Information 96. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 1996 (Plus Supplements)., p. 2182] **PEER REVIEWED** HUMAN TOXICITY EXCERPTS Leukopenia, granulocytopenia, agranulocytosis, thrombocytopenia, aplastic anemia, acquired immune hemolytic anemia, and pancytopenia, which may be accompanied by bone marrow hypoplasia, have been reported rarely in patients receiving ranitidine. Alterations in blood cell counts ... usually were reversible. At least one case of leukocytosis has been reported 6-8 days after initiating ranitidine therapy, which resolved following discontinuance ... aplastic anemia has occurred in at least one patient receiving ranitidine. [McEvoy G.K. (ed.). American Hospital Formulary Service-Drug Information 96. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 1996 (Plus Supplements)., p. 2182] **PEER REVIEWED** HUMAN TOXICITY EXCERPTS Small increases in serum creatinine, without concomitant increases in BUN, have been reported during ranitidine therapy. ... Increases in serum aminotransferase ... alkaline phosphatase, LDH, total bilirubin, and gamma-glutamyl transferase ... conc have been reported and reversible hepatitis, which may be hepatocellular, hepatocanalicular, or both and may or may not be accompanied by jaundice, has occurred occasionally in individuals receiving ranitidine and usually was reversible; however, death has been reported rarely. [McEvoy G.K. (ed.). American Hospital Formulary Service-Drug Information 96. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 1996 (Plus Supplements)., p. 2182] **PEER REVIEWED** HUMAN TOXICITY EXCERPTS ... Cardiac arrhythmias have occurred rarely in patients receiving ranitidine. Bradycardia, sometimes assoc with dyspnea, has occurred. ... Tachycardia, AV block, asystole, and ventricular premature complexes have also been reported rarely. [McEvoy G.K. (ed.). American Hospital Formulary Service-Drug Information 96. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 1996 (Plus Supplements)., p. 2182] **PEER REVIEWED** HUMAN TOXICITY EXCERPTS Arthralgias, myalgias, and hypersensitivity reactions such as bronchospasm, fever, rash, and eosinophilia have occurred rarely in patients receiving ranitidine. Anaphylaxis, characterized by severe urticaria and a decrease in blood pressure in one patient following admin of a single dose of ranitidine, has occurred rarely; exacerbation of asthma and angioedema also has occurred. Mild erythema multiforme-like rash and alopecia also have occurred rarely. Rare reports suggest that ranitidine may precipitate acute attacks of porphyria in patients with acute porphyria; therefore, the drug should be avoided in patients with a history of acute porphyria. [McEvoy G.K. (ed.). American Hospital Formulary Service-Drug Information 96. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 1996 (Plus Supplements)., p. 2182] **PEER REVIEWED** HUMAN TOXICITY EXCERPTS Reported acute oral ingestions /of ranitidine/ of up to 18 g have been assoc with transient adverse effects similar to those encountered in usual clinical experience. In addition, gait abnormalities and hypotension have been reported. [McEvoy G.K. (ed.). American Hospital Formulary Service-Drug Information 96. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 1996 (Plus Supplements)., p. 2183] **PEER REVIEWED** HUMAN TOXICITY EXCERPTS ... Was suspected in one patient to have caused rise of intraocular pressure and discomfort similar to when cimetidine was used, associated with pressure up to 24 mm Hg. [Grant, W.M. Toxicology of the Eye. 3rd ed. Springfield, IL: Charles C. Thomas Publisher, 1986., p. 789] **PEER REVIEWED** HUMAN TOXICITY EXCERPTS Rapid iv injections of both cimetidine and ranitidine occasionally may produce profound bradycardia and cardiotoxic effects. [Haddad, L.M., Clinical Management of Poisoning and Drug Overdose. 2nd ed. Philadelphia, PA: W.B. Saunders Co., 1990., p. 824] **PEER REVIEWED** HUMAN TOXICITY EXCERPTS Symptoms of acute intoxication with both cimetidine and ranitidine are bradycardia and tachycardia; CNS disturbances, including confusion, delirium, drowsiness, slurred speech, flushing, and sweating; dermatologic lesions; endocrine abnormalities; GI disorders; and liver dysfunction. [Haddad, L.M., Clinical Management of Poisoning and Drug Overdose. 2nd ed. Philadelphia, PA: W.B. Saunders Co., 1990., p. 824] **PEER REVIEWED** HUMAN TOXICITY EXCERPTS Although ranitidine appears to only minimally affect the secretion of gastric intrinsic factor, malabsorption of, and resultant deficiency in , vitamin B12 may occur during long-term ranitidine therapy. [McEvoy G.K. (ed.). American Hospital Formulary Service-Drug Information 96. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 1996 (Plus Supplements)., p. 2184] **PEER REVIEWED** HUMAN TOXICITY EXCERPTS Following admin of a single 150 mg oral or 50-mg IM or IV dose, serum ranitidine conc remain in the IC50 range /SRP: IC50 is the serum concentrations of ranitidine necessary to inhibit 50% of pentagastrin-stimulated gastric acid secretion/ for up to 12 hr and 6-8 hr, respectively. Following chronic oral admin of 150 mg of ranitidine twice daily, trough serum conc range between 53-57 ng/ml. In one study following intraduodenal admin of ranitidine in individuals with duodenal ulcers, the IC50 of the drug was estimated to be 100 ng/ml. Substantial inhibition of gastric acid secretion reportedly continues for about 9.5 hr after ingestion of a single 150-mg dose of the drug. [McEvoy G.K. (ed.). American Hospital Formulary Service-Drug Information 96. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 1996 (Plus Supplements)., p. 2180] **PEER REVIEWED** HUMAN TOXICITY EXCERPTS Most controlled studies in humans indicate that ranitidine does not alter theophylline metabolism, even at high doses. However, there have been several case reports published recently which demonstrate the development of theophylline toxicity mostly in older patients receiving stable oral doses of this drug when ranitidine was administered simultaneously. We studied eleven elderly (mean age, 69.0 + or - 6.2 years) patients with chronic obstructive pulmonary disease. During one week the patients took slow-release theophylline, 200 mg every 12 hr, followed by one week intake of the same dose of theophylline plus ranitidine tablets, 150 mg every 12 hr. At the end of each period, blood samples were obtained 0, 1, 2, 3, 4, 5, 6, 7, 8 and 12 hr after the morning dose for the determination of serum theophylline levels. The peak theophylline concentration (Tmax) was achieved after 4.1 + or - 0.9 hr while the patients were taking theophylline, and after 2.9 + or - 1.4 hr with the combined regimen. This difference was statistically significant (P < 0.01). In only 3/11 subjects did Tmax remain unchanged during both phases of the study. The mean theophylline clearance rates while the patients were receiving theophylline alone (39.58 + or - 19.89 ml/min) and when they were receiving both medications 134.42 + or - 10.55 ml/min) were similar. The mean serum levels while the patients were receiving theophylline alone were slightly higher but not statistically different. These results suggest that the reported increases in serum theophylline levels in older patients receiving theophylline and ranitidine cannot be ascribed to slower theophylline metabolism in the geriatric patients with chronic obstructive pulmonary disease who is also given ranitidine. [Cukier A et al; Braz J Med Biol Res 28 (8): 875-9 (1995)] **PEER REVIEWED** HUMAN TOXICITY EXCERPTS Peripheral venous blood from 12 patients with colorectal cancer and eight healthy volunteers was used to identify the lowest in vitro dose of human, recombinant interleukin-2 with immunoactivity on NK-cell lysis of K562 tumor cells. Subsequently, this dosage of 200 units/ml recombinant interleukin-2, which may respond to 10(6) units in vivo, was used alone or in combination with ranitidine (0.02 mg/ml, which may correspond to 100 mg in vivo) to improve in vitro NK-cell activity in peripheral blood from 25 patients with liver metastases from colorectal cancer. A standard 4-hour Cr51-release assay of K562 tumor cells was used for the analyses. Spontaneous NK-cell activity was 19.0% (6.5-33.2), while ranitidine-induced NK-cell activity was 23.6% (7.8-46.2), and without statistical difference from spontaneous activity. Recombinant IL-2-induced NK-cell activity was 37.1 (11.1-71.7) (P < 0.05 compared to spontaneous activity), and recombinant interleukin-2 plus ranitidine-induced NK-cell activity was 52.7 (18.9-85.6) (P < 0.05 compared to spontaneous and to recombinant interleukin-2-induced activity, respectively). These results suggest a synergistic increase of low-dose recombinant interleukin-2-induced NK-cell activity by ranitidine. Therefore, the combination of low-dose recombinant interleukin-2 and ranitidine may be beneficial to improve post-operative immune competence, and should be considered in future adjuvant treatment regimens of cancer patients. [Nielsen HJ et al; Eur J Surg Oncol 21 (5): 526-30 (1995)] **PEER REVIEWED** HUMAN TOXICITY EXCERPTS The involvement of immunological reactivity to ranitidine base (R-b) and ranitidine hydrochloride in the development of occupationally related symptomatology was analyzed in 40 subjects employed in a pharmaceutical plant producing ranitidine and in 33 nonexposed controls, using a specific dose-response lymphocyte proliferative test (lymphocyte transformation test:). Of the 40 workers, 11 (28% ) gave positive reactions to lymphocyte transformation test: 3/11 to ranitidine-base, 4/11 to ranitidine-hydrochloride, and 4/11 to both compounds. None of the controls gave positive reactions. Cutaneous, oculonasal, or respiratory work-related symptoms were cited by 23 of the 40 (58%) subjects; ten of these 23 subjects (43%) were lymphocyte transformation test positive. One asymptomatic case was lymphocyte transformation test positive. The present results indicate that specific immune reactivity to ranitidine, analyzed by lymphocyte transformation test, is associated with the presence of occupational symptomatology; ranitidine-hydrochloride and ranitidine-base seem to share some antigenic determinants, because of the partial cross-reactivity shown by the examined compounds. Nonimmunological, probably irritative, mechanisms are also present in some of the symptomatic subjects. [Riviera AP et al; Int Arch Occup Environ Health 66 (6): 407-11 (1995)] **PEER REVIEWED** HUMAN TOXICITY EXCERPTS Acute interstitial nephritis is a disease characterized by renal inflammation and is thought to be secondary to a hypersensitivity reaction. Although the causes of acute interstitial nephritis are numerous, adverse reactions to many common drugs, particularly antibiotics and nonsteroidal anti-inflammatory agents, are important etiological factors. Acute interstitial nephritis has many clinical manifestations, most notably fever and rash. Flank pain is an uncommon presentation. A case of acute, severe, low-back pain and rash in a healthy woman found to be secondary to acute interstitial nephritis is reported. The etiology of acute interstitial nephritis in this patient's case is suspected to be ranitidine (Zantac; Glaxo Pharmaceuticals, Research Triangle Park, NC), which has not been previously associated with this syndrome. [Karras DJ; Am J Emerg Med 12 (1) 67-8 (1994)] **PEER REVIEWED** HUMAN TOXICITY EXCERPTS Cyclosporin is currently the main immunosuppressive agent used in organ transplantation with considerable improvement in graft survival. Oral cyclosporin solution is highly lipophilic, and its bioavailability may be reduced in cystic fibrosis (CF) heart-lung transplant recipients with pancreatic, gastrointestinal, and hepatic insufficiency. The bioavailability of oral cyclosporin solution in 7 cystic fibrosis transplant recipients (5 male and 2 female with a mean age of 27 years and a mean weight of 49 kg) and 3 non-cystic fibrosis heart-lung recipients (1 male and 2 female with a mean age of 41 years and a mean weight of 60 kg) was studied. Following intravenous cyclosporin administration, the kinetic curves were similar with no significant difference in the volume of distribution and clearance of cyclosporin demonstrated between the cystic fibrosis and non-cystic fibrosis groups. The mean daily dose of oral cyclosporin in 7 cystic fibrosis subjects (23.3 mg/kg) was significantly higher than the 3 non-cystic fibrosis heart-lung recipients (4.8 mg/kg). The mean maximum blood concentration of cystic fibrosis for the oral dose was 776 ng/ml for the 7 cystic fibrosis subjects, which was comparable with the mean peak values of 789 ng/ml for the 3 non-cystic fibrosis control subjects. Poor enteral absorption of cylosporin probably accounts for the significantly lower mean bioavailability in the 7 cystic fibrosis subjects (14.9%) compared with the 3 non-cystic fibrosis control subjects (39.4%). The effects on the bioavailability of oral cyclosporin solution by pancreatic enzymes (Creon) and histamine-2 antagonist (ranitidine) were also evaluated in the 7 cystic fibrosis subjects. No significant difference was demonstrated. [Tsang VT et al; Eur J Clin Pharmacol 46 (3): 261-5 (1994)] **PEER REVIEWED** HUMAN TOXICITY EXCERPTS We report a case of acute cholestatic hepatitis associated with rash and hypereosinophilia, in which the absence of transfusion, intercurrent viral infection, alcohol consumption or other hepatotoxic drugs are suggestive of ranitidine-induced hepatotoxicity. The pathogenesis of the disorder is unknown, but the lack of a dose-effect relationship, the rarity and unpredictability of the reaction, as well as the clinical signs suggest that hypersensitivity is involved. Physicians should be aware of this rare and idiosyncratic side-effect of ranitidine. [Devuyst C et al; Acta Clin Belg 48 (2): 109-14 (1993)] **PEER REVIEWED** HUMAN TOXICITY EXCERPTS Although acute interstitial nephritis has been well described with the histamine H2-receptor antagonist cimetidine, we found only one previous case report of ranitidine-induced interstitial nephritis in the literature. We describe an additional patient who developed acute interstitial nephritis after taking ranitidine. Electron microscopy showed focal fusion of the epithelial cell foot processes that was not described in the previous report of ranitidine-induced interstitial nephritis. [Gaughan WJ et al; Am J Kidney Dis 22 (2): 337-40 (1993)] **PEER REVIEWED** HUMAN TOXICITY EXCERPTS Reversible hematologic abnormalities including hemolytic anemia [1] with a positive direct Coombs' test have been associated with ranitidine. In addition to the case report cited above, the US Food and Drug Administration had received five other cases of hemolysis associated with recent intake of ranitidine as of February 1991. To investigate the possible association of ranitidine with autoimmune hemolytic anemia, a study was conducted to determine how often diagnoses of hemolytic anemia or abnormal Coombs' test results followed dispensing of ranitidine using the automated medical and pharmacy records of a large health maintenance organization. No occurrences of hemolytic anemia were identified among 12,054 individuals following 38,686 prescriptions for this medication. The 95% upper confidence bound was 3.1 cases/10,000 exposed persons. Ore abnormal direct Coombs test with mild anemia was discovered during routine prenatal testing of an asymptomatic patient who was dispensed ranitidine two and a half months previously. Hemolysis, however, was not demonstrated and an association with prior ranitidine use could not be confirmed. Additional analyses indicate that in only 30% of ranitidine courses was a blood count obtained. In those courses with hematocrits below 40%, less than 1% had a Coombs' test performed. Chart review suggests that the majority of individuals with severe anemia have alternative explanations other than autoimmune hemolysis for their anemia. This analysis indicates that ranitidine is unlikely to be a common cause of clinically recognized autoimmune hemolytic anemia and demonstrates the utility of large automated medical and pharmacy data bases to conduct post-marketing studies of spontaneously reported drug effects. [Choo PW et al; J Clin Epidemiol 47 (lO): 1175-9 (1994)] **PEER REVIEWED** HUMAN TOXICITY EXCERPTS Ranitidine hydrochloride, a histamine H2-receptor antagonist, was intravenously administered to 61 pregnant women at a dose of 50 mg as premedication for cesarean section; its effects on gastric secretion were studied in the mother and the newborn. The volume of the maternal gastric juice collected immediately after the induction of anesthesia averaged 14.0 + or - 10.0 ml with pH 3.48 + or - 1.70, and at the time of extubation, 3.6 + or - 2.8 ml with pH 4.19 + or - 1.79, respectively. Forty-four full-term neonates whose mothers had received ranitidine were selected to investigate the effects of ranitidine. Another 45 full-term normal newborns delivered vaginally, and 14 by cesarean section, served as controls. No effects of ranitidine infusion in the mothers were detected in the newborn children. The gastric pH of the newborn at birth and 24 hours after birth, gastrointestinal symptoms and the general growth checked at the regular one-month work-up after birth did not differ in test and control groups. [Ikenoue T et al; Aliment Pharmacol Ther 5 (3): 315-8 (1991)] **PEER REVIEWED** HUMAN TOXICITY EXCERPTS [Koren G et al; Am J Perinatol 8 (1): 37-8 H2 antagonists are widely prescribed medications and are often consumed by women who are unaware of being pregnant. In 23 cases reported to the Motherisk program there were two spontaneous abortions, two therapeutic abortions, 18 normal births, and one infant with a large hemangioma of the upper right eyelid. The hemangioma was removed without incident. Our data suggest that cimetidine and ranitidine may not be teratogenic risk in humans. [CITATION] **PEER REVIEWED** HUMAN TOXICITY EXCERPTS The involvement of immunological reactivity to ranitidine base and ranitidine hydrochloride in the development of occupationally related symptomatology was analyzed in 40 subjects employed in a pharmaceutical plant producing ranitidine and in 33 nonexposed controls, using a specific dose-response lymphocyte proliferative test (lymphocyte transformation test: LTT). Of the 40 workers, 11 (28%) gave positive reactions to lymphocyte transformation test: 3/11 to ranitidine base, 4/11 to ranitidine hydrochloride, and 4/11 to both compounds. None of the controls gave positive reactions. Cutaneous, oculonasal, or respiratory work-related symptoms were cited by 23 of the 40 (58%) subjects; ten of these 23 subjects (43%) were lymphocyte transformation test positive. One asymptomatic case was lymphocyte transformation test positive. The present results indicate that specific immune reactivity to ranitidine, analyzed by lymphocyte transformation test, is associated with the presence of occupational symptomatology; ranitidine hydrochloride and ranitidine base seem to share some antigenic determinants, because of the partial cross-reactivity shown by the examined compounds. Nonimmunological, probably irritative, mechanisms are also present in some of the symptomatic subjects. [Riviera AP et al; Int Arch Occup Environ Health 66 (6): 407-11 (1995)] **PEER REVIEWED**