Isfahan University of Medical Sciences

Isfahan University of Medical Sciences
Drug Interactions Dr. Hajhashemi Dept. of Pharmacology Isfahan University of Medical Sciences

Types Multiple physician Prescription drugs + OTC drugs
Interactions in one prescription Multiple physician Prescription drugs + OTC drugs

Important factors Dose Age Other disease Onset of interactions
Duration Low therapeutic index

Low Therapeutic Index Drugs
Digoxin, Li, Theophylline Warfarine, Anticancer Drugs Anticonvulsants, Aminoglycosides

Drug interaction When 1 drug alters the effects of another drug
e.g. Drug A causes Drug B to have ... Increased or reduced effect Slower or more rapid effect New or increased side effects

Pharmacokinetic v Pharmacodynamic interactions
Me Pharmacokinetic: Amount of drug in blood is altered Pharmacodynamic: Amount of drug in blood remains the same, but its effect is altered

ADME Absorption Distribution Metabolism Excretion

Absorption based interactions
One drug make the absorption of another drug … Faster or slower Less or more complete

Mechanisms Gastric emptying and intestinal motility
pH (ketoconazole) Gastric emptying and intestinal motility Physico-chemical interaction

Gastric emptying and intestinal motility
Drug absorption from small intestine is much more efficient than from the stomach. Drug A alters rate of gastric emptying. Rate of absorption of drug B is also altered.

Drugs altering rate of gastric emptying
Opiate analgesics (e.g. Morphine, pethidine) Much slower Antimuscarinic drugs (e.g. Atropine, propantheline) Slower Tri-cyclic anti-depressants - antimuscarinic side-effects (e.g. Imipramine) Slower Muscarinic agents (e.g. Bethanechol) Faster Metoclopramide, Cisapride

Physico-chemical interactions
Two drugs bind together within the G.I.T. contents and then neither is absorbed. Examples: Tetracycline Colestyramine Antacids

Tetracyclines and polyvalent cations
e.g. Ca2+, Al3+, Mg2+ or Fe2+ Form non-absorbable chelates with tetracyclines. Iron tablets - Fe2+ Antacids - Al3+, Mg2+ etc Dairy products (Milk, cheese) - Ca2+ Effect is considerable. Antacids can reduce absorption of tetracyclines by 80%. Solution: Leave a 2 hour gap between the two drugs.

Effect of ferrous sulfate (325 mg) on plasma levodopa and carbidopa concentrations after ingestion of Sinemet (100/25) in patients with Parkinson's disease. Concentrations shown are mean values without (tirangles) and with (circles) ferrous sulfate administration simultaneously. Adapted from Campbell NRC et al: Br J clin Pharmacol 30: , 1990

Colestyramine and acidic drugs
Colestyramine: Basic anion exchange resin. Purpose: Bind to bile acids, prevent their re-absorption, force body to synthesis new bile acids from cholesterol, reduce cholesterol load in body. Problem: Non-selective. Binds any acidic molecule, inc. acidic drugs. Examples: Thyroxine, valproate, digoxin, statins may show reduced absorption.

Absorption Change in gut flora:
e.g. antibiotics  bacterial Vit K synthesis, potentiate anticoagulants Antibiotics and estrogen containing OCPs Enzyme inhibition: e.g. phenytoin blocks conversion of folate to absorbable form  folate deficiency

Interactions via Enterohepatic Circulation
Change in gastrointestinal flora Antibiotics with OCs Free drug Conjugate Liver Gut Bile Bacteria Reabsorption

Altered intestinal bacterial flora ;
EX., In 10% 0f patients receive digoxin…..40% or more of the administered dose is metabolized by the intestinal flora Antibiotics kill a large number of the normal flora of the intestine Increase digoxin conc. and increase its toxicity

Distribution: protein binding
Let B displace 10% of bound A: If A 30% bound, free A changes from 70-73% If A 98% bound, free A changes from 2-12%

Protein binding Bilirubin displaced by sulphonamides  brain damage in premature babies Anticoagulants, steroids, NSAIDs, thyroxine, sulphonylureas may displace one another

Unwanted effects on metabolism
Liver enzyme induction: e.g. by some anticonvulsants, alcohol increases metabolism of some other drugs Competition at liver enzymes: reduces metabolism of competing drugs e.g. warfarin vs sulphonylureas

Proportion Of Drugs Metabolized by the Major CYP Enzymes
*CYP2C metabolism reflects CYP2C9, CYP2C10, CYP2C18, and CYP2C19

Inhibitors of cytp450 3A4 CYP3A4 inhibitors mainly include macrolide antibiotics (eg, clarithromycin and erythromycin), anti-HIV agents (eg, ritonavir and delavirdine), antidepressants (eg, fluoxetine and fluvoxamine), calcium channel blockers (eg, verapamil and diltiazem), steroids and their modulators (eg, gestodene and mifepristone), Azole antifungals (ketoconazole) and several herbal and dietary components.

Inhibitors of Hepatic Cytochrome P450
1A C9/ D A4 Fluvoxamine Amiodarone Fluoxetine Erythromycin Cimetidine Fluconazole Paroxetine Azole antifungal Ciprofloxacin Fluvastatin Quinidine Nefazodone Fluoxetine Ritonavir Clarithromycin Isoniazid Bupropion Ritonavir Sertraline Cimetidine Cimetidine Omeprazole Cimetidine

Inhibitors of Drug Metabolism
Clarithromycin Erythromycin Diltiazem Verapamil Amiodarone Cimetidine Omeprazole Fluoxetine Protease inhibitors Delavirdine Fluconazole Itraconazole Ketoconazole Voriconazole Isoniazid Ciprofloxacin Grapefruit juice

Example: Erythromycin + theophylline
Enzyme inhibition; It is the decrease of the rate of metabolism of a drug by another one.This will lead to the increase of the concentration of the target drug and leading to the increase of its toxicity . Inhibition of the enzyme may be due to the competition on its binding sites , so the onset of action is short may be within 24h. Example: Erythromycin + theophylline Impact: Erythromycin reduces the clearance of theophylline causing an increase in adverse effects

- Clopidogrel is a prodrug that is converted in the liver to an
active thiol metabolite, which irreversibly inhibits the platelet P2Y12 ADP receptor. PPI - P450 2C19 Angiolillo, D. J. et al. J Am Coll Cardiol 2007;0:j.jacc v Copyright ©2007 American College of Cardiology Foundation. Restrictions may apply.

Clopidogrel+PPI : Clopidogrel alone=3:1
Risk of AMI: Clopidogrel+PPI : Clopidogrel alone=3:1 We sought to characterize whether the concomitant use of a proton pump inhibitor with clopidogrel was associated with adverse outcomes among older patients discharged from hospital after acute myocardial infarction.

P450 Enzyme Inducers Carbamazepine, phenytoin, primidone, phenobarbital, rifampicin Valproate is not inducer Smoking, Alcohol

Withdrawal of inducer Patient taking barbiturates and warfarin
Barbiturates cause induction - warfarin clearance increased Warfarin dose titrated above normal dose (Blood levels normal) Barbiturates suddenly withdrawn and replaced by valproate Warfarin clearance falls - blood levels rise above normal Patient dies

Excretion Transport: Penicillin  methotrexate excretion
pH or electrolyte effects: diuretics  K+  digoxin toxicity NaHCO3  salicylate & barbiturate excr.

Pharmacodynamic interactions;
It means alteration of the dug action without change in its serum concentration by pharmacokinetic factors. EX., Propranolol + verapamil Synergistic or additive effect Synergism means =1+1=3 On the other hand Additive means= 1+1=2 Effect at the receptor site Antiadrenegic anticholinergic Potentiation means= 1+0=2 Antagonism means 1+1=0 or 0.5

Pharmacodynamic Interactions
Similar Clinical Responses • Beta-blockers/verapamil/amiodarone/digoxin ( AV block ) • ACEIs/ARBs /K+/K-sparing diuretics (hyperkalemia ) • Alcohol/CNS depressants • CNS depressants/CNS depressants • Nitrates with silendafil • Additive antihypotensive effects • “Serotonin syndrome”

Histamine-2-blocker with the greatest number of drug interactions

Cimetidine (Tagamet) Inhibits 2C9 and 2D6 isoenzymes
Combination increases toxicity potential of theophylline, phenytoin, quinidine, metronidazole, warfarin, TCA’s, BZDs Other H-2 blockers (ranitidine, famotidine, nizatidine) do NOT cause these interactions

Antacids Quinolones Tetracyclines digoxin H2 blockers quinidine
ketoconazole isoniazid

NSAIDs

Indomethacin In some patients, the administration of INDOCIN can reduce the diuretic, natriuretic, and antihypertensive effects of loop, potassium-sparing, and thiazide diuretics. Therefore, when Indomethacin and diuretics are used concomitantly, the patient should be observed closely to determine if the desired effect of the diuretic is obtained.

Indomethacin Blunting of the antihypertensive effect of beta-adrenoceptor blocking agents by non-steroidal antiinflammatory drugs including INDOCIN has been reported. Therefore, when using these blocking agents to treat hypertension, patients should be observed carefully in order to confirm that the desired therapeutic effect has been obtained. INDOCIN can reduce the antihypertensive effects of captopril and losartan.

Indomethacin It has been reported that the addition of triamterene to a maintenance schedule of INDOCIN resulted in reversible acute renal failure in two of four healthy volunteers. INDOCIN and triamterene should not be administered together.

Indomethacin INDOCIN and potassium-sparing diuretics each may be associated with increased serum potassium levels. The potential effects of INDOCIN and potassium-sparing diuretics on potassium kinetics and renal function should be considered when these agents are administered concurrently. Most of the above effects concerning diuretics have been attributed, at least in part, to mechanisms involving inhibition of prostaglandin synthesis by INDOCIN.

Indomethacin Capsules INDOCIN 50 mg t.i.d. produced a clinically relevant elevation of plasma lithium and reduction in renal lithium clearance in psychiatric patients and normal subjects with steady state plasma lithium concentrations. This effect has been attributed to inhibition of prostaglandin synthesis. As a consequence, when INDOCIN and lithium are given concomitantly, the patient should be carefully observed for signs of lithium toxicity.

Indomethacin Administration of non-steroidal anti-inflammatory drugs concomitantly with cyclosporine has been associated with an increase in cyclosporine-induced toxicity, possibly due to decreased synthesis of renal prostacyclin. NSAIDs should be used with caution in patients taking cyclosporine, and renal function should be carefully monitored.

Indomethacin Caution should be used if INDOCIN is administered simultaneously with methotrexate. INDOCIN has been reported to decrease the tubular secretion of methotrexate and to potentiate its toxicity.

Indomethacin Clinical studies have shown that INDOCIN does not influence the hypoprothrombinemia produced by anticoagulants. However, when any additional drug, including INDOCIN, is added to the treatment of patients on anticoagulant therapy, the patients should be observed for alterations of the prothrombin time. In post-marketing experience, bleeding has been reported in patients on concomitant treatment with anticoagulants and INDOCIN. Caution should be exercised when INDOCIN and anticoagulants are administered concomitantly.

Indomethacin The concomitant use of INDOCIN with other NSAIDs is not recommended due to the increased possibility of gastrointestinal toxicity, with little or no increase in efficacy.

Cardiovascular Drugs

Diuretics Acetazolamide Thiazides and Li Thiazides and digoxin
Furosemide and Amino. Spironolactone and ACEIs

May have to reduce digoxin dose by 50% if you give it with this antihypertensive agent

Verapamil, Diltiazem, Nifedepine, or Nicardipine
These agents inhibit the renal and nonrenal clearance of digoxin Effect of verapamil is most predictable Amlodipine is NOT reported to increase digoxin levels

Phenytoin-Amiodarone Unless you reduce the phenytoin dosage by 25% or more, you can expect ataxia, nystagmus, sedation, possibly seizures in 1-8 weeks after starting this antiarrhythmic agent

Amiodarone (Cordarone)
Combination can produce 2-3 fold increase in serum concentration Due to inhibition of 2C9 and 3A4 Delayed interaction due to long half-life of amiodarone ( days) Other significant amiodarone DIs warfarin, quinidine, procainamide, digoxin also beta blockers, CCBs, statins

Beta blockers Ca blockers + propronolol ACEI + Li ACEI + K (K sparing) Losartan + Li Losartan + K (K sparing)

Losartan As with other drugs that block angiotensin II or its effects, concomitant use of potassium-sparing diuretics (e.g., spironolactone, triamterene, amiloride), potassium supplements, or salt substitutes containing potassium may lead to increases in serum potassium. As with other antihypertensive agents, the antihypertensive effect of losartan may be blunted by the non-steroidal anti-inflammatory drug indomethacin.

When hypertension is difficult to control, be sure to ask about use of these OTC agents

NSAIDs, phenylpropanolamine, pseudoephedrine, ephedrine, caffeine, or
NSAIDs, phenylpropanolamine, pseudoephedrine, ephedrine, caffeine, or ?herbals NSAIDs increase MAP by  5mm, antagonize effects of BBs, diuretics, ACE I’s especially Ask about use of OTC cold preparations (including excessive use of nasal sprays), diet aids, “no-doze” products, and any “non-traditional” remedies

Warfarin (Coumadin) Subject to interactions with drugs affecting P-450 system (3A4, 2C9) Other “red flag” drugs that cause serious drug interactions MAO inhibitors Cyclosporine Theophylline, digoxin, anticonvulsants

Warfarin Mechanism of Action
Vitamin K Antagonism of Vitamin K VII Synthesis of Non Functional Coagulation Factors IX X Warfarin acts as an anticoagulant by blocking the ability of Vitamin K to carboxylate the Vitamin K dependent clotting factors, thereby reducing their coagulant activity. II Warfarin

Drug Interaction (cont.)
Warfarine Chloramphenicol + Erythromycin + Nalidixic Acid + Ciprofloxacin + Co-trimoxazole + Azole Antifungals + Metronidazle + Rifampin

Cotrimoxazole (Bactrim, Septra)
Oral antibiotics that DON’T interact with warfarin Nitrofurantoin Penicillin/Amox./Ampicillin Azithromycin Cephalosporins

Drug-Drug Interactions With Warfarin
Interacting Drug Mechanism Anticoagulant Effect Aspirin PD  Barbiturate PK  Cimetidine PK  Dipyridamole PD  Fibrates PD  Fluvoxamine PK  Macrolides PK  Phenytoin PK  Quinolones PK  Rifampin PK  Sulfinpyrazone PK/PD  Thyroid hormones PD  Ticlopidine PD  N Engl J Med. 2003; 14;349:675-83; JAPHA 2004;44:142-51

Lovastatin CYP3A4 Interactions
Lovastatin is metabolized by CYP3A4 . Potent inhibitors of CYP3A4 increase the risk of myopathy by reducing the elimination of lovastatin. Ketoconazole Erythromycin Clarithromycin HIV protease inhibitors Nefazodone Cyclosporine Large quantities of grapefruit juice (>1 quart daily)

Myalgias and myopathy are more likely if itraconazole (Sporanox) is given with this drug

In the UK, simvastatin is contra-indicated in patients receiving potent CYP3A4 inhibitors.

Lovastatin, Simvastatin, Atorvastatin
AVOID COMBINATION Due to 3A4 isoenzyme interaction Most common with lovastatin Alternative to itraconazole: terbinafine Alternative statins: pravastatin, fluvastatin Other 3A4 inhibitors: nefazodone, erythromycin, clarithromycin, protease inhibitors

Lovastatin Danazol: The risk of myopathy/rhabdomyolysis is increased by concomitant administration of danazol particularly with higher doses of lovastatin Myopathy/Rhabdomyolysis). Amiodarone or Verapamil: The risk of myopathy/rhabdomyolysis is increased when either amiodarone or verapamil is used concomitantly with a closely related member of the HMG-CoA reductase inhibitor class.

Lovastatin Interactions with lipid- lowering drugs that can cause myopathy when given alone The risk of myopathy is also increased by the following lipid-lowering drugs that are not potent CYP3A4 inhibitors, but which can cause myopathy when given alone. Gemfibrozil Other fibrates Niacin (nicotinic acid) (>1 g/day)

Lithium Caution should be used when lithium and diuretics are used concomitantly because diuretic-induced sodium loss may reduce the renal clearance of lithium and increase serum lithium levels with risk of lithium toxicity. Patients receiving such combined therapy should have serum lithium levels monitored closely and the lithium dosage adjusted if necessary.

Lithium In some cases, lithium toxicity has resulted from interactions between an NSAID and lithium. Indomethacin and piroxicam have been reported to increase significantly, steady state plasma lithium concentrations. There is also evidence that other NSAIDs including the selective cyclooxygenase-2 (COX-2) inhibitors, have the same effect. In a study conducted in healthy subjects, mean steady-state lithium plasma levels increased approximately 17% in subjects receiving lithium 450 b.i.d. with celecoxib 200 mg b.i.d. as compared to subjects receiving lithium alone.

Lithium Concurrent use of metronidazole with lithium may provoke lithium toxicity due to reduced renal clearance. Patients receiving such combined therapy should be monitored closely.

Lithium There is evidence that angiotensin-converting enzyme inhibitors, such as enalapril and captopril, may substantially increase steady-state plasma lithium levels, sometimes resulting in lithium toxicity. When such combinations are used, lithium dosage may need to be decreased, and plasma lithium levels should be measured more often.

Lithium Concurrent use of calcium channel blocking agents with lithium may increase the risk of neurotoxicity in the form of ataxia, tremors, nausea, vomiting, diarrhea and/or tinnitus. Caution is recommended.

Lithium The concomitant administration of lithium with SSRI should be undertaken with caution as this combination has been reported to result in symptoms such as diarrhea, confusion, tremor, dizziness, and agitation.

Lithium Hydrochlorothiazide Indomethacin Increased concn. Piroxicam
Diclofenac Na Ibuprofen Aspirin & Sulindac No effect ACEIs Increased conc. Sartans Increased conc.

Theophylline Aminoglutethimide 25% Carbamazepine 30%
Drugs increasing theophylline clearance Aminoglutethimide 25% Carbamazepine 30% Phenobarbital (PB) 25% Phenytoin 40% Rifampin 20-40% Hypericum perforatum

Theophylline Drugs decreasing theophylline clearance Cimetidine 70%
Ciprofloxacin % Erythromycin % Clarithromycin % Disulfiram % Tacrine % Ticlopidine % Fluvoxamine

Clinically Significant Drug-Drug Interactions with AEDs
Object Drug Interacting Drug Outcome Carbamazepine Danazol  CBZ level Carbamazepine Diltiazem  CBZ level Carbamazepine Macrolides  CBZ level Carbamazepine Propoxyphene  CBZ level Carbamazepine Verapamil  CBZ level Phenytoin Amiodarone  DPH level Phenytoin Cimetidine  DPH level Phenytoin Fluoxetine  DPH level Phenytoin INH  DPH level Phenytoin Omeprazole  DPH level Neuropharmacology 2002;5:280-9

MAO Inhibitors SSRI Serotonine syndrom Clomipramine Serotonine syndrom
Tramadol Serotonine syndrom Oral Hypoglycemic Increased hypogly. Adult Cold Hypertension Antihistamine-Decong. Hypertension Phenylephrine Hypertension Pethidine Toxic dextromethorphan Toxic

Serteraline Cases of serious sometimes fatal reactions have been reported in patients receiving ZOLOFT (sertraline hydrochloride), in combination with a monoamine oxidase inhibitor (MAOI). These reactions have also been reported in patients who have recently discontinued an SSRI and have been started on an MAOI. Therefore, ZOLOFT should not be used in combination with an MAOI, or within 14 days of discontinuing treatment with an MAOI. Similarly, at least 14 days should be allowed after stopping ZOLOFT before starting an MAOI.

Serotonin syndrom Symptoms of a drug interaction between an SSRI and an MAOI include: hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations of vital signs, mental status changes that include confusion, irritability, and extreme agitation progressing to delirium and coma.

Tramadol Use With Carbamazepine
Patients taking carbamazepine may have a significantly reduced analgesic effect of tramadol. Because carbamazepine increases tramadol metabolism and because of the seizure risk associated with tramadol, concomitant administration of Tramadol Hydrochloride and carbamazepine is not recommended.

Tramadol Use With Inhibitors of CYP2D6
In vitro drug interaction studies in human liver microsomes indicate that concomitant administration with inhibitors of CYP2D6 such as fluoxetine, paroxetine, and amitriptyline could result in some inhibition of the metabolism of tramadol.

Tramadol Use With MAO Inhibitors
Interactions with MAO Inhibitors , due to interference with detoxification mechanisms, have been reported for some centrally acting drugs.

Quinolones Absorption of all quinolones is reduced significantly by sucralfate, iron, zinc, calcium, antacids Administer PO quinolone 2 hr before and 4-6 hr after interacting agent Reduced absorption due to DIs can contribute to increasing quinolone resistance patterns

Triazole antifungals Ketoconazole, fluconazole, and itraconazole are triazole antifungal agents. Ketoconazole and itraconazole are much more potent CYP3A4 inhibitors than fluconazole and have about equal potency in this regard. All three agents can block metabolism of drugs that use CYP3A4 as a substrate for metabolism (eg, astemizole, terfenadine, loratadine, cisapride, cyclosporine, erythromycin, clarithromycin, omeprazole, lansoprazole, theophylline, warfarin, statins).

Ketoconazole Ketoconazole is a potent inhibitor of the cytochrome P450 3A4 enzyme system. Ketoconazole tablets inhibit the metabolism of terfenadine, astemizole, cisapride and can result in prolongation of the QT interval on the ECG.

Ketoconazole Ketoconazole tablets may alter the metabolism of cyclosporine, tacrolimus, and methylprednisolone, resulting in elevated plasma concentrations of the latter drugs.

Ketoconazole Coadministration of NIZORAL® Tablets with midazolam or triazolam has resulted in elevated plasma concentrations of the latter two drugs. This may potentiate and prolong hypnotic and sedative effects, especially with repeated dosing or chronic administration of these agents.

Ketoconazole Concomitant administration of ketoconazole tablets with phenytoin may alter the metabolism of one or both of the drugs. It is suggested to monitor both ketoconazole and phenytoin. Concomitant administration of rifampin with ketoconazole tablets reduces the blood levels of the latter. INH (Isoniazid) is also reported to affect ketoconazole concentrations adversely. These drugs should not be given concomitantly.

Ketoconazole (Nizoral) or Itraconazole (Sporanox)
Absorption is significantly reduced by agents that increase gastric pH Omeprazole or Other PPIs H2 blockers antacids sucralfate Can use with fluconazole (Diflucan)

Fluconazole In general, fewer interactions are considered to occur with fluconazole than with either itraconazole or ketoconazole. Fluconazole may interfere with the metabolism of some drugs if given concomitantly, mainly through inhibition of the cytochrome P450 isoenzymes CYP3A4 and CYP2C9. This may account for the reported increases in plasma concentrations of ciclosporin, midazolam, amitriptyline, nortriptyline, phenytoin, sulfonylurea hypoglycaemics and nateglinide, selective cyclo-oxygenase-2-inhibitors such as celecoxib and parecoxib, tacrolimus, triazolam, warfarin, and zidovudine.

Fluconazole Increases in terfenadine concentrations following high doses of fluconazole have been associated with ECG abnormalities. A similar effect may be anticipated with astemizole. Use of fluconazole with cisapride could result in increased cisapride concentrations and associated toxicity. The use of fluconazole with astemizole, cisapride, or terfenadine should therefore be avoided because of the risk of cardiac arrhythmias. Syncope attributed to increased amitriptyline concentrations has occurred when amitriptyline was given with fluconazole.

Tetracyclines Bactericides Tetracyclines Antacids Tetracyclines Ferrous Salts Tetracyclines Zinc Sulfate Doxycycline Carbamazepine + Phenytoin + Rifampin

Fluoroquinolones Antacids + Calcium salts + Ferrous sulfate + Zinc sulfate + Theophylline Erythromycin Theophylline + Terfenadine + Astemizole

Warfarine Chloramphenicol + Erythromycin + Nalidixic Acid + Ciprofloxacin + Co-trimoxazole + Azole Antifungals + Metronidazle + Rifampin

Macrolide with the greatest number of drug interactions

Erythromycin Inhibits 3A4 isoenzyme
Significant elevations in levels of: warfarin, Carbamazepine, cyclosporine, Digoxin, theophylline, lovastatin, warfarine, bromocriptine, valproate, terfenadine and astemizole. Clarithromycin also inhibits 3A4 Azithromycin - no reports of problems thus far

Nonsedating antihistamines
Terfenadine and astemizole are prodrugs that undergo extensive (>99%) first-pass elimination to active and inactive metabolites by the CYP3A subfamily. Cardiotoxicity occurs when this metabolism is inhibited. Erythromycin, clarithromycin, ketoconazole and itraconazole should not be used with them. Loratadine is not interacting.

OCPs LD, HD, Triphasic with broad spectrum antibiotics
With anticonvulsants MPA, Oral progestins, Norplant do not interact

Strategies to Prevent/Manage Drug Interactions
Encourage patients to report all prescription, over-the- counter and complementary and alternative drugs at every health care encounter. When adding a new drug to regimen, screen for potential drug-drug interactions.

Strategies to Prevent/Manage Drug Interactions
3. Select a non-interacting drug 4. If drug interaction can not be avoided, adjust doses and or/dosage intervals for affected medication and monitor the patient closely. 5. Carefully monitor other drug therapy when withdrawing a drug that can inhibit or induce hepatic metabolism. 6. Regularly review the need for chronic medications- reduce polypharmacy

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