chapter
H2 receptor blockers
Pages 10

Uncertain. Monitor more closely. No toxicity reported to date with bupivacaine. If using intravenous lidocaine, monitor closely for symptoms of toxicity; ↓ dose may be required

H2 RECEPTOR BLOCKERS ANALGESICS – OPIOIDS

CIMETIDINE ALFENTANIL, FENTANYL, PETHIDINE, TRAMADOL

Cimetidine may ≠ fentanyl, pethidine and tramadol levels

Cimetidine inhibits CYP2D6mediated metabolism of these opioids. Ranitidine weakly inhibits CYP2D6

Watch for excessive narcotization

CIMETIDINE CODEINE Cimetidine may ↓ efficacy of codeine

Due to initiation of enzymatic conversion to active metabolite

Watch for poor response to codeine. Consider using an alternative opioid or acid suppression therapy

CIMETIDINE, RANITIDINE ANTIARRHYTHMICS – AMIODARONE, FLECAINIDE, MEXILETINE, PROCAINAMIDE, PROPAFENONE

Likely ≠ plasma concentrations of these antiarrhythmics and risk of adverse effects

Cimetidine inhibits CYP2D6mediated metabolism of flecainide, mexiletine, procainamide and propafenone. Ranitidine is a much weaker CYP2D6 inhibitor. Cimetidine is a potent inhibitor of organic cation transport in the kidney, and the elimination of procainamide is impaired

Monitor PR and BP at least weekly until stable. Warn patients to report symptoms of hypotension (lightheadedness, dizziness on standing, etc.). Consider alternative acid suppression therapy

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DOXYCYCLINE

↓ absorption of cephalosporin as ≠ gastric pH

Avoid concomitant use. If unable to avoid combination, take H2 antagonists at least 2-3 hours after cephalosporin. Consider an alternative antibiotic or separate the doses by at least 2 hours and give with an acidic drink, e.g. a carbonated drink; ≠ dose may be required

CIMETIDINE CHLORAMPHENICOL ≠ adverse effects of chloramphenicol, e.g. bone marrow depression

Additive toxicity Use with caution; monitor FBC regularly

CIMETIDINE MACROLIDES – ERYTHROMYCIN

≠ efficacy and adverse effects of erythromycin, including hearing loss

≠ bioavailability Consider an alternative antibiotic, e.g. clarithromycin. Deafness has been reversible with cessation of erythromycin

CIMETIDINE METRONIDAZOLE ≠ metronidazole levels Inhibited metabolism Watch for ≠ side-effects of metronidazole

CIMETIDINE RIFAMPICIN ↓ efficacy of cimetidine ≠ metabolism Change to alternative acid suppression, e.g. rabeprazole, or ≠ dose and/or frequency

H2 RECEPTOR BLOCKERS ANTICANCER AND IMMUNOMODULATING DRUGS

CIMETIDINE BUSULFAN, CARMUSTINE, CHLORAMBUCIL, CYCLOPHOSPHAMIDE, ESTRAMUSTINE, IFOSFAMIDE, LOMUSTINE, THIOTEPA, TREOSULFAN

≠ adverse effects of cytotoxic, e.g. myelosuppression

Additive toxicity. Possible minor inhibition of cyclophosphamide metabolism via CYP2C9

Monitor more closely; monitor FBC regularly. Avoid co-administration of cimetidine with cyclophosphamide

Famotidine ≠ metabolism of dasatinib

Consider using alternative acid suppression therapy

CIMETIDINE DOXORUBICIN ≠ risk of myelosuppression due to ≠ plasma concentrations

Due to ↓ metabolism of doxorubicin by CYP3A4 isoenzymes due to inhibition of those enzymes

Monitor for ≠ myelosuppression, peripheral neuropathy, myalgias and fatigue

CIMETIDINE EPIRUBICIN ≠ epirubicin levels, with risk of toxicity

Attributed to inhibition of hepatic metabolism of epirubicin by cimetidine

Avoid concurrent treatment and consider using an alternative H2 receptor blocker, e.g. ranitidine, famotidine

CIMETIDINE FLUOROURACIL Altered efficacy of fluorouracil Inhibition of metabolism and altered action

Monitor more closely. May be of clinical benefit. No additional toxicity was noted in one study

CIMETIDINE IFOSFAMIDE ↓ plasma concentrations of 4-hydroxyifosfamide, the active metabolite of ifosfamide, and risk of inadequate therapeutic response

Due to inhibition of the isoenzymatic conversion to active metabolites

Monitor clinically the efficacy of ifosfamide, and ≠ dose accordingly

CIMETIDINE IMATINIB ≠ imatinib levels with ≠ risk of toxicity (e.g. abdominal pain, constipation, dyspnoea) and of neurotoxicity (e.g. taste disturbances, dizziness, headache, paraesthesia, peripheral neuropathy)

Due to inhibition of CYP3A4mediated metabolism of imatinib

Monitor for clinical efficacy and for the signs of toxicity listed, along with convulsions, confusion and signs of oedema (including pulmonary oedema). Monitor electrolytes, liver function and for cardiotoxicity

CIMETIDINE IRINOTECAN ≠ plasma concentrations of SN-38 (active metabolite of irinotecan) and ≠ toxicity of irinotecan, e.g. diarrhoea, acute cholinergic syndrome, interstitial pulmonary disease

Due to inhibition of the metabolism of irinotecan by CYP3A4 isoenzymes by cimetidine

Peripheral blood counts should be checked before each course of treatment. Monitor lung function. Recommendation is to ↓ dose of irinotecan by 25%

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DRUGS ACTING ON THE GASTROINTESTINAL TRACT H2 RECEPTOR BLOCKERS

response to melphalan

Cimetidine causes a change in gastric pH, which ↓ absorption of melphalan

Avoid concurrent use

CIMETIDINE VINCA ALKALOIDS ≠ adverse effects of vinblastine and vincristine

Inhibition of CYP3A4-mediated metabolism. Also inhibition of P-gp efflux of vinblastine

Monitor FBCs and watch for early features of toxicity (pain, numbness, tingling in the fingers and toes, jaw pain, abdominal pain, constipation, ileus). Consider selecting an alternative drug

CIMETIDINE TOREMIFENE ≠ plasma concentrations of toremifene

Due to inhibition of metabolism of toremifene by the CYP3A4 isoenzymes by cimetidine

Clinical relevance is uncertain. Need to monitor for clinical toxicities

CIMETIDINE CICLOSPORIN ≠ plasma concentrations of ciclosporin, with risk of nephrotoxicity, myelosuppression, neurotoxicity and excessive immunosuppression, with risk of infection and post-transplant lymphoproliferative disease

Inhibition of CYP3A4-mediated metabolism of ciclosporin; these inhibitors vary in potency. Cimetidine is classified as a potent inhibitor

Avoid co-administration with cimetidine. Consider an alternative H2 blocker but need to monitor plasma ciclosporin levels to prevent toxicity

CIMETIDINE CORTICOSTEROIDS ≠ adrenal suppressive effects of corticosteroids, which may ≠ risk of infections and produce an inadequate response to stress scenarios

Due to inhibition of metabolism of corticosteroids

Monitor cortisol levels and warn patients to report symptoms such as fever and sore throat

hepatotoxicity

Ciclosporin, tacrolimus and sirolimus are metabolized primarily by CYP3A4 isoenzymes, which are inhibited by cimetidine. Cimetidine is also an inhibitor of CYP2D6, CYP2C19 and CYP1A2. Sirolimus has multiple pathways of metabolism, which would be inhibited by cimetidine. Ciclosporin is also a substrate of P-gp

Consider alternative acid suppression, e.g. alginate suspension or rabeprazole. Not thought to be clinically significant. Ensure close monitoring of immunosuppressant levels and renal function

CIMETIDINE, FAMOTIDINE ANTICOAGULANTS – ORAL ≠ anticoagulant effect with cimetidine and possibly famotidine

Inhibition of metabolism via CYP1A2, CYP2C9 and CYP2C19

Use alternative acid suppression, e.g. another H2 antagonist or proton pump inhibitor (not esomeprazole, lansoprazole or omeprazole) or monitor INR more closely; ↓ dose may be required. Take acid suppression regularly and not PRN if affects INR control

H2 RECEPTOR BLOCKERS ANTIDEPRESSANTS

CIMETIDINE MAOIs – MOCLOBEMIDE ≠ plasma concentrations of moclobemide (by up to 40%)

Due to cimetidine inhibiting metabolism

↓ dose of moclobemide to one-half to one-third of original and then alter as required

CIMETIDINE MIRTAZAPINE ≠ efficacy and adverse effects of mirtazapine

Inhibition of metabolism via CYP1A2, CYP2D6 and CYP3A4

Consider alternative acid suppression, e.g. H2 antagonist (proton pump inhibitors will interact in poor CYP2D6 metabolizers) or monitor more closely for side-effects; ↓ dose as necessary

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DRUGS ACTING ON THE GASTROINTESTINAL TRACT H2 RECEPTOR BLOCKERS

Inhibition of metabolism Not thought to be clinically significant, but take care in elderly people and patients with hepatic impairment

CIMETIDINE SSRIs ≠ efficacy and adverse effects e.g. nausea, diarrhoea, dyspepsia, dizziness, sexual dysfunction

≠ bioavailability Use with caution; monitor for ≠ side-effects. ↓ dose may be necessary

CIMETIDINE TCAs ≠ efficacy and adverse effects, e.g. dry mouth, urinary retention, blurred vision, constipation

↓ metabolism Use alternative acid suppression or monitor more closely and ↓ dose. Rapid hydroxylators may be at ≠ risk

H2 RECEPTOR BLOCKERS ANTIDIABETIC DRUGS

RANITIDINE ACARBOSE ↓ blood levels of ranitidine Possibly due to ↓ absorption of ranitidine

Be aware

H2 RECEPTOR BLOCKERS METFORMIN ≠ level of metformin and risk of lactic acidosis. The onset of lactic acidosis is often subtle with symptoms of malaise, myalgia, respiratory distress and ≠ non-specific abdominal distress. There may be hypothermia and resistant bradyarrhythmias

Metformin is not metabolized in humans and is not protein bound. Competition for renal tubular excretion is the basis for ≠ activity or retention of metformin. Cimetidine competes for excretory pathway

Theoretical possibility. Requires ↓ metformin dose to be considered or to avoid co-administration. Warn patients about hypoglycaemia ➣ For signs and symptoms of hypoglycaemia, see Clinical Features of Some Adverse Drug Interactions, Hypoglycaemia

CIMETIDINE NATEGLINIDE, REPAGLINIDE

Likely to ≠ plasma concentrations of these antidiabetic drugs and ≠ risk of hypoglycaemic episodes

Due to inhibition of CYP3A4mediated metabolism of nateglinide and repaglinide

hypoglycaemic episodes

Cimetidine and ranitidine ↓ renal elimination of glimepride and ≠ intestinal absorption of glimepride. Cimetidine is also an inhibitor of CYP2D6 and CYP3A4

Consider alternative acid suppression, e.g. a proton pump inhibitor (not omeprazole), and monitor more closely

CIMETIDINE, FAMOTIDINE, RANITIDINE

ANTIEPILEPTICS – CARBAMAZEPINE PHENYTOIN

≠ plasma concentrations of phenytoin and risk of adverse effects, including phenytoin toxicity, bone marrow depression and skin reactions

Inhibition of metabolism via CYP2C9 and CYP2C19

Use alternative acid suppression, e.g. ranitidine, or warn the patient that the effects last 1 week. Consider monitoring carbamazepine levels and adjust dose as necessary

H2 RECEPTOR BLOCKERS ANTIFUNGALS

H2 RECEPTOR BLOCKERS ITRACONAZOLE, KETOCONAZOLE, MICONAZOLE

↓ plasma concentrations and risk of treatment failure

↓ absorption of these antifungals as ≠ gastric pH

Avoid concomitant use. If unable to avoid combination, take H2 blockers at least 2-3 hours after antifungals. Use an alternative antifungal or separate the doses by at least 2 hours and give with an acidic drink, e.g. a carbonated drink; ≠ dose of the antifungal may be required

CIMETIDINE TERBINAFINE ≠ efficacy and adverse effects of terbinafine

≠ bioavailability Consider alternative acid suppression or monitor more closely and consider ↓ dose

H2 RECEPTOR BLOCKERS ANTIHISTAMINES – LORATIDINE

Possibly ≠ loratidine levels Inhibition of metabolism Be aware

H2 RECEPTOR BLOCKERS ANTIHYPERTENSIVES AND HEART FAILURE DRUGS – ALPHA-BLOCKERS

↓ efficacy of tolazoline Uncertain; possibly ↓ absorption

Watch for poor response to tolazoline

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DRUGS ACTING ON THE GASTROINTESTINAL TRACT H2 RECEPTOR BLOCKERS

Inhibition of metabolism and excretion

Consider ranitidine as alternative or take cimetidine at least 2 hours after chloroquine

CIMETIDINE ANTIMALARIALS OTHER THAN PROGUANIL

≠ efficacy and adverse effects of antimalarials

Inhibition of metabolism, some definitely via CYP3A4

Avoid co-administration

CIMETIDINE PROGUANIL ↓ efficacy of proguanil ↓ absorption and ↓ formation of active metabolite

Avoid concomitant use. Clinical significance not established; effectiveness of malarial prophylaxis may be ↓

CIMETIDINE ANTIPARKINSON’S DRUGS – PRAMIPEXOLE, ROPINIROLE

≠ efficacy and adverse effects of pramipexole

↓ renal excretion of pramipexole by inhibition of cation transport system. Inhibition of CYP1A2mediated metabolism of ropinirole

Monitor closely; ↓ dose of pramipexole may be required. Adjust the dose of ropinirole as necessary or use alternative acid suppression, e.g. H2 antagonist or proton pump inhibitor (not omeprazole or lansoprazole)

H2 RECEPTOR BLOCKERS ANTIPLATELET AGENTS – DIPYRIDAMOLE

Possible ↓ bioavailability of dipyridamole

Dipyridamole tablets require an acidic environment for adequate dissolution; ≠ pH of the stomach impairs dissolution and may therefore ↓ absorption of drug

≠ dose of dipyridamole or consider using an alternative antiplatelet drug

CIMETIDINE ANTIPROTOZOALS – MEBENDAZOLE

≠ mebendazole levels Inhibition of metabolism Be aware; case reports of where this interaction has been used therapeutically

CLOZAPINE, HALOPERIDOL, OLANZAPINE, PERPHENAZINE, RISPERIDONE, SERTINDOLE, THIORIDAZINE, ZUCLOPENTHIXOL

Cimetidine is an inhibitor of CYP3A4 (sertindole, haloperidol, risperidone) CYP2D6 (chlorpromazine, risperidone, zuclopenthixol, thioridazine, perphenazine) and CYP1A2 (clozapine, olanzapine, sertindole, haloperidol)

Avoid concomitant use. Choose alternative acid suppression

H2 RECEPTOR BLOCKERS ANTIVIRALS

CIMETIDINE ACICLOVIR/VALACICLOVIR ≠ efficacy and adverse effects of antivirals

Competition for renal excretion Use doses of valaciclovir 4 g/day with caution or consider alternative acid suppression. For doses 1 g/day, interaction is not thought to be clinically significant. Studies only reported with valaciclovir

H2 RECEPTOR BLOCKERS AMPRENAVIR, ATAZANAVIR

↓ efficacy of amprenavir; possible ≠ levels of cimetidine

↓ absorption of amprenavir and atazanavir. Uncertain mechanism of action on cimetidine

Amprenavir: separate doses by at least 1 hour. Take atazanavir at least 2 hours before or 10 hours after an H2 blocker. In both cases, monitor viral load closely

CIMETIDINE ZALCITABINE ≠ efficacy and adverse effects of zalcitabine

↓ excretion via inhibition of tubular secretion

Clinical significance unclear. Monitor more closely

H2 RECEPTOR BLOCKERS ANXIOLYTICS AND HYPNOTICS

CIMETIDINE, RANITIDINE BZDs (NOT LORAZEPAM OR TEMAZEPAM)

≠ efficacy and adverse effects of BZDs, e.g. sedation

Cimetidine is an inhibitor of CYP3A4, CYP2D6, CYP2C19 and CYP1A2

Not clinically significant for most patients. Conflicting information for some BZDs. Monitor more closely; ↓ dose if necessary

CIMETIDINE CHLORMETHIAZOLE ≠ efficacy and adverse effects, e.g. sedation, ‘hangover’ effect

Inhibition of metabolism Monitor closely; ↓ dose may be required

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effects of timolol eye drops

Cimetidine is an inhibitor of CYP3A4, CYP2D6, CYP2C19 and CYP1A2

Monitor BP and PR

NIZATIDINE BETA-BLOCKERS ≠ bradycardia when nizatidine is added to atenolol. Other betablockers have not been studied

Uncertain Monitor PR when administering nizatidine to patients on betablockers

CIMETIDINE FAMOTIDINE NIZATIDINE, RANITIDINE

BRONCHODILATORS – THEOPHYLLINE

≠ efficacy and adverse effects, including seizures. There is conflicting information associated with ranitidine, famotidine and nizatidine

Inhibition of metabolism via CYP1A2, cimetidine being the best known inhibitor

Use alternative acid suppression, e.g. a proton pump inhibitor (not omeprazole or lansoprazole) or monitor closely; considerable patient variation. Check levels on day 3 and then at 1 week. A 30-50% ↓ dose of theophylline may be required. For doses400 mg/day, the interaction may not be clinically significant

CIMETIDINE CALCIUM CHANNEL BLOCKERS

≠ levels of calcium channel blockers, especially diltiazem and nifedipine

Inhibition of CYP3A isoformmediated metabolism

Monitor BP closely; be aware of possibility of significant ↓ BP. Consider ↓ dose of diltiazem and nifedipine by up to 50%

FAMOTIDINE CALCIUM CHANNEL BLOCKERS

Reports of heart failure and ↓ BP when famotidine given with nifedipine

Additive negative inotropic effects Caution with co-administering famotidine with calcium channel blockers, especially in elderly people

H2 RECEPTOR BLOCKERS DRUG DEPENDENCE THERAPIES – BUPROPION

≠ plasma concentrations of cimetidine and ranitidine

Bupropion and its metabolite hydroxybupropion inhibit CYP2D6

Initiate therapy of these drugs at the lowest effective dose

CIMETIDINE ERGOT ALKALOIDS ≠ ergotamine/methysergide levels, with risk of toxicity

Inhibition of metabolism via CYP3A4

Avoid co-administration