DRUG INTERACTION MONITORING Iron Food decreases Should be taken BID: 6am - 6pm

preparation with water or

juice on an empty
Drug Interaction stomach
- Modification of the effects of one drug by the prior or May be
concomitant administration of another administered
- Object + Precipitant = DI with food to
prevent irritation
However, do not TID: 6am-2pm-
Benefits of DI Monitoring give with cereals, 10pm
Early Recognition or Detection of DI → Prevention dietary fiber, tea,
 Loss in treatment effect coffee, eggs, or
 Unexpected increases in pharmacologic activity milk
 Toxicity Tetracycline Milk and other Take on empty BID: 10 am – 10
dairy products stomach one hour pm
may reduce the before or two
DRUG-FOOD INTERACTION absorption of hours after meals.
- CP evaluates new drug orders for DFI using a List of most tetracycline If your stomach
Potential Clinically significant Drug-Food Interactions derivatives by gets upset, take
which shall serve as guide for Pharmacist, Dietitians, 50% or more with food
Doctors & Nurses in monitoring and detecting DFIs. Absorption may Do not take with QID: 6am-11am-
be decreased dairy products. 6pm-10pm
The list shall include only drugs that are: when given with Take one hour
1. included in the formulary iron and/or food before or 2 hours
2. frequently used/or chronically administered Products/foods after taking dairy
3. with numerous interactions with common food containing products
4. with DFIs resulting in severe outcomes calcium,
magnesium,
aluminum, iron, or
Potential Clinically Significant DFIs zinc decrease the
a. Drugs recommended to be given on an empty absorption
stomach Erythromycin Food alters To optimiza BID: 10am – 10
Generic name Rationale Recommendation Estimated time erythromycin erythromycin pm
Classification of concentrations efficacy, take on
administration an empty
ACE inhibitors Food Take on an empty TID: 6am-2pm- stomach, at least
decreases stomach, 1 hour 10pm 30 minutes
absorption by before or 2 hours before meals
30%-40% after meals BID: 6am-6pm Erythromycin base Erythromycin TID: 6am-2pm-
and stearate are ethyl succinate, 10pm
absorbed better in erythromycin
Alendronate Calcium in Take on an empty 6am the fasting state estolate, and
food binds stomach – first thing enteric-coated
with the drug in the morning, at erythromycin
and least 30 minutes may be
inactivates it before meals; give administered
without regard to QID: 6am-11am-
with a full glass of
meals 6pm-10pm
water
Reduce Patient should not lie
potential for down for approx. 1
esophageal hour after the dose
irritation Do not give to
patients at risk for
esophageal reflux Phenytoin Absorption may Administer Hold feedings
Quinolones Food Take on empty OD: 6am increase 27% phenytoin for 1-2 hours
decreases stomach one hour when taken with a consistently with prior to and 1-2
absorption before or two hours standard meal regard to meals hours afer
after meals. If your Serum phenytoin Do not administer phenytoin
stomach gets upset, conc. Maybe phenytoin administration
take with food decreased by concomitantly
Do not take with enteral feeding with an enteral
dairy products. Take preparations feeding 2 hours
one hour before or 2 and/or related before and after
hours after taking nutritional dosing
dairy products supplements
Taking these BID: 6am-6pm Tegaserod Food may reduce Take on an empty BID: 6am-6pm
medications with bioavailability by stomach 30
caffeine-containing 40 to 65%. minutes before
products may meals
increase caffeine
levels, leding to
excitability and
nervousness
Mycophenolate Food may Take on an empty BID: c. Drugs requiring Diet Modification
decrease Cmax stomach 6am- Generic name Rationale Recommendation
by 40% 6pm Allopurinol A low protein diet Avoid low protein
Proton pump Food decreases Take at least 1 hour OD: 6am will promote diet.
inhibitors absorption. before meals; best if
elevated Allopurinol
taken before breakfast.
levels.
H2 blocker Gastric acid If ordered once a day, OD: 9pm
production give at bedtime (unless
Antacids High protein meals Avoid high protein
increases at patient has symptoms may lead to a meals.
night. during the day) BID:  Al-/ Mg- decrease in the
6am- hydroxide/ neutralizing capacity
6pm Simethicone of the antacid.
Sucralfate Increase Should be taken on an QID:  CaCO3 -
efficacy empty stomach 6am- containing
11am-
6pm- Corticosteroids May cause Limit foods high in
10pm hypernatremia and sodium.
Thyroid Food decreases Should be taken on an OD: 6am- water retention
preparations absorption empty stomach, 11am- Cyclosporine May cause Limit potassium-rich
preferably at least 30 6pm- hyperkalemia and foods and limit
minutes before 10pm my induce sodium intake.
breakfast BID: hypertension
6am- Digoxin Hypokalemia may Maintain adequate
6pm increase the risk of amounts of
Domperidone In GI motility disorders, TID: Digoxin toxicity. potassium in the
should be taken 15-30 6am- diet.
minutes prior to meals 11am- Furosemide May cause Include potassium-
6pm
hypokalemia. rich foods in diet.
May cause minerals Limit/ avoid use of
Metoclopramide Take on an empty TID:
stomach 30 minutes 6am- and vitamins MSG
before meals 11am- depletion. Increases
6pm removal of excess
water. May be cause
Furosemide Food decreases Take on empty TID: MSG toxicity
Furosemide stomach. Maybe 6am- (tightening of the
sodium administered with food 11am- chest, flushing of
or milk if GI 6pm the face)
BID: Isoniazid May cause Avoid tyramine-
6am- hypertension containing foods
6pm Decreases folic acid Increase dietary
absorption intake of folate,
b. Drugs recommended to be given with meals niacin and
Generic name Rationale Recommendation magnesium.
Acarbose Inhibit food Take with first bite of Linezolid May cause sudden Avoid tyramine-
absorption food and severe high containing food,
Non steroidal anti- Food helps to Take with food or blood pressure caffeine and
inflammatory drugs decrease GI irritation large volume of water phenylalanine
(NSAIDs) or milk. Moclobemide May cause sudden Avoid tyramine-
Nitrofurantoin Food significantly Take with whole milk and severe high containing foods and
increases absorption or food blood pressure caffeine
Itraconazole Bioavailability of Take with meals Theophylline May result in Avoid large intake of
capsule formulation is manifestation of caffeine- contaning
maximal when taken some adverse beverages.
with a full meal effects which
Absorption of capsule includes
formulation can be nervousness and
increased after insomnia.
coadministration with Warfarin Alteration of Limit intake of foods
a cola beverage (AUC anticoagulant effect rich in vitamin k.
may increase by 75% Levodopa/Carbidopa High protein diets Avoid high protein
and Cmax may (>2 g/kg) may meals
increase by 95%) decrease the
Metformin Food decreases GI Take with food efficacy of levodopa
upset via competition with
amino acids in
crossing the blood-
brain barrier
Furazolidone May increase the Avoid tyramine- DRUG INTERACTIONS
risk of severe side containing foods and Pharmacokinetic interaction
effects (eg, beverages during and 1. Alteration of DRUG ABSORPTION
hypertensive for 4 days following a. Changes in gastric pH (antacid, alcohol and food)
reactions, serotonin therapy.
b. Changes in gastrointestinal motility/gastric
syndrome)
emptying time
Cilostazol May increase peak Avoid taking with c. Complexation and adsorption
concentration by high fat meals.
90%. 2. Alteration of DRUG DISTRIBUTION
Avoid concurrent MOA: Displacement from protein binding sites
ingestion of
grapefruit juice due 3. Alteration of DRUG METABOLISM
to the potential to a. Enzyme Induction
inhibit CYP3A4. b. Enzyme Inhibition

DRUG-DRUG INTERACTION Common Enzyme Inducers & Inhibitors

Understanding DIs Inducing drugs/chemicals Inhibiting drugs
 Knowledge of DI mechanism Phenobarbital Cimetidine
 Recognition of High-Risk Patients Carbamazepine Erythromycin
 ID drugs with Narrow Treatment index Phenytoin Ketoconazole
Rifampicin
Tobacco smoke
Alcohol (chronic)

4. Alteration of DRUG EXCRETION

a. Changes in urinary pH
e.g salicylates + sodium bicarbonate
b. Competition at active transport site
e.g. probenecid + penicillin

1. Most significant are those involving drug metabolisms and

least significant are those involving drug distribution
2. Effect of an interacting drug can either:
INCREASE in drug conc → TOXICITY (increase in bioavailability,
effect of an enzyme inhibiting drug, decrease in excretion)

DECREASE in drug conc → TREATMENT FAILURE (decrease in

bioavailability, effect of an enzyme inducing drug, increase in
excretion)

Drug Interaction Mechanisms Altered GIT Absorption

 Pharmacokinetic – in vivo 1) Altered pH,
 Pharmacodynamic – in vivo 2) Formation of drug chelates or complexes,
 Physico-chemical (IV Incompatibilities) – in vitro 3) Drug induced mucosal damage
4) Altered GIT motility.
Pharmacokinetic vs Pharmacodynamic
Drug disposition in the body Related to pharmacologic 1) Altered pH,
activity of interacting drugs Sodium Bicarbonate (antacids) + Ketoconazole
Effect of 1 drug on the ADME Amount of drug in blood
of another drug remains the same, but its MOI: The dissolution of oral ketoconazole requires an acidic
effect is altered environment. Medications that decrease the acidity of the
stomach can reduce the bioavailability of ketoconazole by 75%
Seldom produce serious
to 80%. (drugs.com)
clinical effects
Often associated w/ changes
Object Drug: Ketoconazole
in plasma drug conc and
Precipitant Drug: Sodium Bicarbonate
altered clinical response
Most common
Management: Separation of doses by two or more hours is
recommended.
 One case of phenytoin toxicity has been reported in a patient
2) Complexation or chelation taking aspirin. However, clinical studies in healthy subjects and
Ciprofloxacin + aluminum hydroxide epileptic patients (taking phenytoin and 1500 mg aspirin/day)
have not reported significant pharmacokinetic changes, adverse
MOI: Oral preparations that contain magnesium, aluminum, or effects, or loss of seizure control.
calcium may significantly decrease the gastrointestinal
absorption of quinolone antibiotics. Absorption may also be Metabolism
reduced by sucralfate, which contains aluminum, as well as other 1) Induction
polyvalent cations such as iron and zinc. The mechanism is  CYP450 family is the major metabolizing enzyme in
chelation of quinolones by polyvalent cations, forming a complex phase I (oxidation process)
that is poorly absorbed from the gastrointestinal tract. The  Enzyme induction involves protein synthesis.
bioavailability of ciprofloxacin has been reported to decrease by Therefore, it needs time up to 3 weeks to reach a
as much as 90% when administered with antacids containing maximal effect
aluminum or magnesium hydroxide 2) Inhibition
Inhibition of the enzyme may be due to the competition on its
Precipitant Drug: Aluminum hydroxide binding sites, so the onset of action is short may be within 24h.
Object Drug: Ciprofloxacin
Phenytoin + warfarin
3) Drug induced mucosal damage MOI: Some oral anticoagulants have been reported to increase
Digoxin + Vincristine (other antineoplastic agent) phenytoin half-life and serum concentrations, possibly by
inhibiting CYP450 metabolism. The addition of phenytoin to
MOI: The use of some antineoplastic agents has been associated warfarin therapy has initially increased prothrombin time, but
with decreased gastrointestinal absorption of digoxin. The thereafter reduced anticoagulant effects. The mechanism is not
suspected mechanism is alteration of the gastrointestinal known, but may be due to initial CYP450 metabolic inhibition,
mucosa. The risk of an interaction is expected to be less with followed by isoenzyme induction. Data have been conflicting.
digoxin solution in capsules because absorption occurs rapidly in
the upper GI tract. Management: Phenytoin serum concentrations and INR/PT
should be monitored in patients receiving this combination and
Precipitant Drug: Vincristine whenever the dosage is changed or discontinued. Patients
Object Drug: Digoxin should be advised to promptly report any signs of bleeding (e.g.,
pain, swelling, headache, dizziness, weakness, prolonged
Management: Digoxin serum levels and effectiveness should be bleeding from cuts, nosebleeds, bleeding of gums from brushing,
monitored closely following the initiation or discontinuation of red or brown urine, or red or black stools) or hydantoin toxicity
antineoplastic agents, and the dosage adjusted as necessary. (e.g., drowsiness, visual disturbances, change in mental status,
seizures, nausea, or ataxia) to their physician.
4) Altered GIT Motility
Cyclosporine + Metoclopramide Excretion
Active tubular secretion;
MOI: Concomitant administration of single-dose cyclosporine  It occurs in the proximal tubules (a portion of renal
and metoclopramide increases cyclosporine bioavailability. tubules).
Although the exact mechanism is not well understood,  The drug combines with a specific protein to pass
metoclopramide-induced increase in gastric emptying may through the proximal tubules.
interfere with gastrointestinal degradation of cyclosporine.  When a drug has a competitive reactivity to the
Serum cyclosporine concentrations and risk of toxicity may be protein that is responsible for active transport of
increased another drug .This will reduce such a drug excretion
increasing its con. and hence its toxicity
Precipitant Drug: Metoclopramide
Object Drug: Cyclosporine Probenecid + methotrexate
MOI: Probenecid inhibits the renal elimination of methotrexate.
Management: Cyclosporine levels and renal function, including The pharmacologic effect and toxicity of methotrexate may be
serum creatinine, should be carefully monitored, during increased, especially in patients receiving high-dose
concurrent therapy. Cyclosporine dosage should be adjusted as methotrexate.
needed. Patients should be advised to notify their physician if
they experience nausea, vomiting, diarrhea, abdominal pain, Management: If this combination must be used, a reduction in
dizziness, fatigue, or headache methotrexate dosage may be needed and the patient should be
closely monitored for signs and symptoms of bone marrow
Distribution suppression, hepatotoxicity, and nephrotoxicity. Patients should
1) Displaced protein binding be advised to promptly report symptoms including fever, chills,
Aspirin + Phenytoin sore throat, bruising, bleeding, stomatitis, malaise, shortness of
breath, lower extremity edema, jaundice, or change in stool or
MOI: In vitro studies suggest that salicylates may displace urine color to their physician.
phenytoin from plasma protein-binding sites. The potential for
phenytoin toxicity exists. The clinical significance is unknown.
Passive tubular reabsorption Recommendation: Monitor for increased effects of warfarin
 Excretion and reabsorption of drugs occur in the (possibly transient), and significantly decreased effects of
tubules by passive diffusion which is regulated by dicumarol, if phenytoin is initiated/dose increased, and the
concentration and lipid solubility opposite effects if phenytoin is discontinued/dose decreased.
Monitor for increased serum concentrations/toxic effects of
Sodium Bicarbonate + Aspirin phenytoin if a coumarin derivative is initiated/dose increased, or
MOI: Agents that cause urinary alkalinization can reduce serum decreased serum concentrations/effects if a coumarin derivative
salicylate concentrations in patients receiving anti-inflammatory is discontinued/dose decreased
dosages of aspirin or other salicylates. The mechanism involves Results/Action: MD ordered to hold Warfarin temporarily
reduction in salicylate renal tubular reabsorption due to
increased urinary pH, resulting in increased renal salicylate Atorvastatin 40 mg PO OD HS + Phenytoin 100 mg IV q8
clearance especially above urine pH of 7. This interaction is Object Drug: Atorvastatin
sometimes exploited in the treatment of salicylate toxicity. Precipitant Drug: Phenytoin

Management: Patients treated chronically with urinary Rationale: PPIs may increase the serum concentration of
alkalinizers and large doses of salicylates (i.e. 3 g/day or more) Warfarin
should be monitored for potentially diminished or inadequate Recommendation: Substitute Atorvastatin with Rosuvastatin
analgesic and anti-inflammatory effects, and the salicylate and monitor for subtherapeutic effects of Atorvastatin.
dosage adjusted if necessary. Results/Action: MD acknowledged the recommendation

Pharmacodynamic Interaction Digoxin 0.25 mg ½ tab OD + Amiodarone 200 mg PO BID

1. ADDITIVE/SYNERGISTIC effects Object Drug: Digoxin
e.g. benzodiazepines + sedating antihistamines Precipitant Drug: Amiodarone
2. ANTAGONISTIC effects
e.g. propranolol + B2 agonist Rationale: Amiodarone may increase the serum conc of Cardiac
3. Indirect effects Glycosides by decreasing Digoxin clearance as well as potentially
e.g. digoxin + diuretics increasing Digoxin BA
Recommendation: Consider reducing the dose of cardiac
Phenytoin 100 mg IV q8 + Omeprazole 40 mg IV BID glycosides by one-third to one-half when initiating concomitant
Object Drug: Phenytoin amiodarone therapy
Precipitant Drug: Omeprazole Results/Action: CFOD ordered to decrease dose of Digoxin
0.25mg ½ Tab every other day.
Rationale: PPI may increase the serum conc of Phenytoin by
inhibiting Phenytoin metabolism Carvedilol 6.24 mg PO BID + Amiodarone 200 mg PO BID
Recommendation: Monitor for increased levels of phenytoin if Object Drug: Carvedilol
omprazole is initiated/dose increased and decreased levels if Precipitant Drug: Amiodarone
omeprazole is D/C / dose decreased. This interaction is probably
of concern with daily dose of at least 40mg. Rationale: Amiodarone may enhance the bradycardic effect of
Substitute with Pantoprazole, Esomeprazole or Lanzoprazole Beta-Blockers. Possibly to the point of cardiac arrest
Results/Action: MD opted to monitor patient for increased Recommendation: Monitor for increased signs and symptoms of
effects of phenytoin bradycardia with beta-blockers if amiodarone is initiated/dose
increased, or decreased effects if amiodarone is
Warfarin 1.5 mg PO OD + Omeprazole 40 mg IV BID discontinued/dose decreased.
Object Drug: Warfarin Results/Action: CFOD ordered to decrease dose of Carvedilol to
Precipitant Drug: Omeprazole 6.25mg PO OD

Rationale: PPIs may increase the serum concentration of Amiodarone 200 mg PO BID + Azithromycin 500 mg PO OD
Warfarin by inhibiting R-warfarin metabolism. Object Drug: Amiodarone
Recommendation: Monitor for increased effects of warfarin if Precipitant Drug: Azithromycin
omprazole is initiated/dose increased and decreased effects if
omeprazole is D/C / dose decreased. Rationale: Azithromycin may enhance the QTc-prolonging effect
Substitute with Esomeprazole of Amiodarone
Results/Action: MD ordered to hold Warfarin temporarily Recommendation: Patients should be carefully monitored for
the development of this effect as QTc prolongation can result in
Warfarin 1.5 mg PO OD + Phenytoin 100 mg IV q8 TdP.
Object Drug: Warfarin Results/Action: CFOD ordered to continue Azithromycin while
Precipitant Drug: Phenytoin awaiting ECG results but was subsequently D/C the next day

Rationale: Phenytoin may enhance the anticoagulant effect of

warfarin (transient) due to protein binding displacement.
Warfarin may increase the serum conc of Phenytoin due to
competition fro CYP2C9 thus decreasing metabolism of
Phenytoin