Cimetidine with warfarin

Cimetidine, erythromycin, and dextropropoxyphene had no effect on the pharmacokinetics of MHD. Results with warfarin show no evidence of interaction with either single or repeated doses of oxcarbazepine. 

A number of studies and case reports have confirmed this interaction with warfarin. In the studies, plasma warfarin levels were reported to rise by 25% and 80%, and prothrombin times were increased by 18% and 20% by cimetidine 1.2 g daily. In the case reports, severe bleeding (haematuria, internal haemorrhages) and very prolonged prothrombin times have been seen in few patients given cimetidine 900 mg or 1.2 g daily 4,e-s jjj Qjjg 7 out of 14 patients stabilised on warfarin had a... 

The interaction between warfarin and cimetidine is well documented, well established and potentially clinically important. Its effects are generally modest, but rarely, patients have shown a marked interaction. Because of this unpredictability, and to avoid bleeding, the response should be monitored well in every patient when cimetidine is first added, being alert for the need to reduce the warfarin dosage. The onset of the interaction appears rapid effects have been seen within days, and even as early as 24 hours. The effect of low non-prescription doses of cimetidine on warfarin do not appear to have been studied. Acenocoumarol is reported to in-teraet similarly, and there is one case of phenindione being affected. Expect other coumarins and indanediones to behave in the same way, with the possible exception of phenprocoumon, which was not affected in one study. 

Hetzel D, BirkettD, Miners J. Cimetidine interaction with warfarin. Lancet (1979) ii, 639. 

Phenytoin interacts widi many different drugp. For example isoniazid, chloramphenicol, sulfonamides, benzodiazepines, succinimides, and cimetidine all increase phenytoin blood levels. The barbiturates, rifampin, theophylline, and warfarin decrease phenytoin blood levels. When administering the hydantoins with meperidine, die analgesic effect of meperidine is decreased. 

The effects of warfarin may increase when administered with acetaminophen, NSAIDs, beta blockers, disulfiram, isoniazid, chloral hydrate, loop diuretics, aminoglycosides, cimetidine, tetracyclines, and cephalosporins. Oral contraceptives, ascorbic acid, barbiturates, diuretics, and vitamin K decrease the effects of warfarin. Because die effects of warfarin are influenced by many drugp, die patient must notify die nurse or die primary healdi care provider when taking a new drug or discontinuing... 

Ranitidine is a H2-receptor antagonist, which reduces the gastric output. Unlike cimetidine, ranitidine does not interact with cytochrome P450, so does not retard hepatic metabolism of certain drugs, such as warfarin. Ranitidine may be administered as 150 mg twice daily or 300 mg at night. 

Il.b.l.1. Adverse effects of anti-secretory treatment. Histamine H2 antagonists and proton pump inhibitors are very safe as well as effective treatments. Cimetidine has small effects on hepatic drug metabolism which are only of clinical signiflcance with drugs used in doses close to toxic levels, notably phenytoin, aminophylline and warfarin. Other adverse effects such as headache, rash and thrombocytopenia are rare. 

Concurrent administration of propafenone with digoxin, warfarin, propranolol, or metoprolol increases the serum concentrations of the latter four drugs. Cimetidine slightly increases the propafenone serum concentrations. Additive pharmacological effects can occur when lidocaine, procainamide, and quinidine are combined with propafenone. 

Clinicians should be aware of a few drug interactions with Zolpidem. Flumazenil acts as an antagonist to the hypnotic effects of zolpidem. There is decreased alertness when zolpidem is combined with cimetidine. There is an increase in anterograde amnesia in volunteers treated with a combination of imipramine and zolpidem. Haloperidol, ranitidine, chlorpromazine, warfarin, and digoxin, along with cimetidine and flumazenil, do not alter the pharmacokinetics of zolpidem (Salva and Costa, 1995). 

Warfarin antagonists include vitamin K, barbiturates, glutethimide. rifampin, and cholestyramine. Warfarin potentiators include phenylbutazone. oxyphenbutazone, anabolic steroids, clofibrate, aspirin, hepatotoxins, disnlfirain, and metronidazole. In patients undergoing anticoagulation therapy with warfann, it has been found that cimetidine (used in therapy of duodenal ulcer) may increase anticoagulant blood levels and consequently prolong the prothrombin time. 

Numerous drugs have been reported not to interact with repaglinide, including cimetidine, theophylline, and warfarin (58). 

Donepezil is both excreted in the urine intact and extensively metabolized to four major metabolites, two of which are known to be active, and a number of minor metabolites, not all of which have been identified. Three of the human metabolites of donepezil have not undergone extensive safety tests in animals. These comprise two O-demethylated derivatives and an N-oxidation product. Donepezil is metabolized by CYP 450 isoenzymes 2D6 and 3A4 and undergoes glucuronidation. The rate of metabolism of donepezil is slow and does not appear to be saturable. These findings are consistent with the results from formal pharmacokinetic studies which showed that donepezil and/or its metabolites do not inhibit the metabolism of theophylline, warfarin, cimetidine, or digoxin... 

Warfarin sodium may be adsorbed to PVC and intravenous infusion sets but may be minimized with glass containers or polyethylene-lined containers. Warfarin sodium is incompatible with solutions of adrenaline hydrochloride, amikacin sulfate, metaraminol tartrate, oxytocin, promazine hydrochloride, tetracycline hydrochloride, aminophylline, bretylium tosylate, ceftazidime, cimetidine hydrochloride, ciprofloxacin lactate, dobutamine hydrochloride, esmolol hydrochloride, gentamicin sulfate, labetalol hydrochloride, metronidazole hydrochloride, and vancomycin hydrochloride.130131... 

Simultaneous administration of sucralfates with other nonantacid medication should be given after an interval of at least 2 hours. Sucralfates interact with rantidine, cimetidine, digoxin, quinidine, theophylline, and warfarin. Sulfasalazine should be administered with caution with antibacterials and antineoplastics.179... 

Drug interactions The effect of antacids and cations on the absorption of these agents was considered above. Ciprofloxacin, ofloxacin and enoxacin can increase the serum levels of theophylline by inhibiting its metabolism. They also may raise levels of warfarin, caffeine and cyclosporine. Cimetidine interferes with the... 

Pharmacokinetics. Carbamazepine is extensively metabolised one of the main products, an epoxide (a chemically reactive form), has anticonvulsant activity similar to that of the parent drug but may also cause some of its adverse effects. The t) of carbamazepine falls from 35 h to 20 h over the first few weeks of therapy due to induction of hepatic enzymes that metabolise it as well as other drugs, including corticosteroids (adrenal and contraceptive), theophylline and warfarin. Cimetidine and valproate inhibit its metabolism. There are complex interactions with other antiepilepsy drugs, which constitute a reason for monodrug therapy. 

Adverse effects include nausea, headache, diarrhoea, constipation and rash but are uncommon. Omeprazole inhibits the 2C family of the cytochrome P450 system, decreasing the metabolism of warfarin, diazepam, carbamazepine and phenytoin, and enhancing the action of these drugs (but inhibition is less than with cimetidine). 

The overall safety record of the currently marketed agents, particularly cimetidine and ranitidine, which have had extensive worldwide use, is excellent, and in practice safety issues seldom affect drug choice (1), except perhaps when it is necessary to avoid interactions with phenytoin, theophylline, or warfarin. Surveillance studies, which have been going on for a quarter of a century (including 10-year studies in many patients, mainly involving cimetidine and ranitidine), have failed to detect any serious adverse effects other than those recognized by 1980, or any adverse effect on mortality (2). 

Omeprazole is a proton pump inhibitor. Headache, skin rash, and diarrhea have all been recorded by adverse event registries sufficiently often to suggest causal relations (1). Omeprazole is a modest inhibitor of CYP isoforms. Interactions are less likely than with cimetidine and are probably of no practical importance. However, omeprazole reduces the absorption of drugs that require a low gastric pH (ketoconazole, iron salts, ampicilhn) and can inhibit the hepatic clearance of some drugs (diazepam, warfarin, phenytoin) (2). 

A 71-year-old woman taking a stable dose of warfarin and cimetidine was treated with terbinafine, and 32 days later developed profuse intestinal bleeding associated with a prothrombin time of 120 seconds, suggestive of an interaction between warfarin and terbinafine, either directly or through the mediation of cimetidine (which can reduce terbinafine clearance by 33%) (74). 

Drug interactions Cimetidine is a CYP450 inhibitor and can inhibit the metabolism of phenytoin, warfarin, and theophylline. Famotidine, nizatidine, and ranitidine are unlikely to cause clinically significant drug interactions. All antagonists have the potential to interact with other drugs that require gastric acid for absorption (e.g., ketoconazole, itraconazole). 

You are presented with a prescription for Mrs Smith for warfarin 3 mg daily and cimetidine 400 mg bd. 

Before ringing the GP to query the interaction you decide to obtain more information by consulting Stockley s Drug Interactions. Here you find that the interaction between warfarin and cimetidine can cause severe bleeding, but in some patients there is no problem at all. Ranitidine and nizatidine seem to be the preferred alternative H2 receptor antagonists, but even with these bleeding has occurred with a small number of patients. 

Clinically important, potentially hazardous interactions with alfuzosin, alprazolam, amphotericin B, anisindione, antacids, aprepitant, astemizole, atorvastatin, bosentan, ciclesonide, cimetidine, clorazepate, conivaptan, cyproterone, dasatinib, dexamethasone, dicumarol, didanosine, eplerenone, erythromycin, ethotoin, fentanyl, fesoterodine, fosamprenavir, fosphenytoin, grapefruit juice, HMG-CoA reductase inhibitors, imatinib, ixabepilone, lapatinib, lopinavir, lovastatin, mephenytoin, methylprednisolone, micafungin, midazolam, nilotinib, pimozide, prednisolone, prednisone, quinidine, rifampin, rimonabant, rivaroxaban, sildenafil, silodosin, simvastatin, sirolimus, solifenacin, temsirolimus, terfenadine, tolvaptan, triazolam, vardenafil, vinblastine, vincristine, warfarin... 

Clinically important, potentially hazardous interactions with allopurinol, cimetidine, clozapine, metronidazole, phenytoin, warfarin... 

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