Neurologic drug-psychotropic drug update

Neurologic drug–psychotropic drug update

James J. Strain, M.D.a,*, Anwarul Karim, M.D.a, Gina Caliendo, Pharm.D., R.Ph.b,Matthew Brodsky, M.D.c, R. Sandlin Lowe III, M.D.a, Carol Himelein, B.S.R.Ph.d

aDivision of Behavioral Medicine and Consultation Psychiatry, Mount Sinai School of Medicine, Mount Sinai - NYU Medical Center/Health System,New York, NY, 10029 USA

bDepartment of Pharmacy, Mount Sinai Hospital, New York, NY, 10029 USAcDepartment of Neurology, Mount Sinai School of Medicine, Mount Sinai - NYU Medical Center/Health System, New York, NY, 10029 USA

dParmacia, Peapack, NJ 07977 USA

Abstract

It is essential that both the neurologist and the psychiatrist be aware of the neurology drug–psychotropic drug interactions becauseneurologists prescribe many psychotropic medications and psychiatric consultants often recommend the use of psychotropic drugs forneurology patients. Six methods of examining drug–drug interactions were employed: 1) PubMed (MEDLINE); 2)Hanston’s DrugInteraction Analysis and Management Text (July 2001 quarterly updated version); 3)Drug Interactions Facts (quarterly updated versionthrough July 2001); 4)Micromedex Drug-dex; 5) American Hospital Formulary Service Drug Information; 6) Food and Drug Adminis-tration (MedWatch) Dear Doctor Letters and new labeling. Over eighty important interactions of significance level 1 (major), or significancelevel 2 (minor) were found. Furthermore, over one-third of the neurologist’s most commonly administered medications were those alsoemployed by the psychiatrist, but not necessarily for the same reason, e.g., carbamazepine, for seizure control (neurologist) or moodstabilization (psychiatrist). © 2002 Elsevier Science Inc. All rights reserved.

1. Introduction

The concomitant use of neurologic and psychotropicmedications is ubiquitous in the general hospital setting, andin ambulatory practice. The aim of this literature drug - druginteraction analysis is to compare the most commonly pre-scribed neurologic and psychotropic drugs and their inter-actions if they were employed simultaneously. Furthermore,many of the same drugs are prescribed by both disciplines,but not necessarily for the same disorder, e.g., carbamaz-epine for seizure (neurology) and mood stabilization (psy-chiatry). This presented an opportunity to examine psycho-tropic drug–psychotropic drug interactions: Carbamazepinewith the benzodiazepines, antipsychotics including theatypicals. Psychiatrists also have to be informed of thepotential hazards of employing concomitantly psychotropicdrugs.

Neurologists frequently encounter patients with psychi-

atric conditions such as affective disorders or psychosis.Delirium and dementia are commonly observed in a neuro-logical practice. These patients are often on antidepressants,antipsychotics, mood stabilizers, or combinations of such.This may present a challenge when assessing which neuro-logical medication would be safe to prescribe, which wouldbe the most effective, and which would necessitate a doseadjustment from that usually prescribed or more carefulmonitoring of serum levels than is typically required.

The aim of the study group was to describe adverse druginteractions, enumerate the mechanisms of the interactionswhen possible, and given the interaction and the degree ofits severity, specify recommended action for the practitio-ners.

2. Materials and method

The drugs selected for review were from: 1) the Redbooklist of the 200 most often prescribed medications in theUnited States; 2) those medications most commonly em-ployed by the Department of Neurology, the Division ofBehavioral Medicine and Consultation Psychiatry, and theDepartment of Pharmacy (Mount Sinai–NYU Medical Cen-

* Corresponding author. Tel.:�1-212-659-8728; fax:�1-212-369-6817.

E-mail address: [email protected] (J.Strain).This work was funded by The Malcolm Gibbs Foundation, Inc., NY,

NY and Pharmacia, Peapack, New Jersey, 07977, USA.

General Hospital Psychiatry 24 (2002) 290–310

0163-8343/02/$ – see front matter © 2002 Elsevier Science Inc. All rights reserved.PII: S0163-8343(02)00192-5

ter/Health System) (Tables 1 and 2). The disciplines of theinvestigators were: neurology (MB), pharmacy-drug infor-mation (GC), pharmacy (CH) psychiatry (JJS, RSL, and aresearch assistant (AK). The search strategy utilized thefollowing indexing systems: 1) MEDLINE (PubMed) em-ploying the generic neurological drug name, the genericpsychotropic drug name, and the term “ interaction;” 2)Hanston’s Drug Interaction Analysis and Management Text(quarterly updated version) [2]; 3) Drug Interactions Facts(Facts and Comparisons) (July 2001 quarterly updated ver-sion) [3]; 4) Micromedex Drug-dex [4]; 5) American Hos-pital Formulary Service Drug Information [5]; and 6) Foodand Drug Administration (MedWatch) (Dear Doctor Lettersand new labeling) (www.fed.gov/medwatch for (1990through 2001). (Citations regarding children, reports in for-eign languages or about food, animals, invitro experiments,analgesics and naturalistic—herbal or natural products—

treatment interactions were excluded). The authors recog-nized that all of the above sources do not necessarily coverthe entire information database regarding drug–drug inter-actions.

Should one utilize the known mechanism of interactionand established pharmacokinetics and pharmacolgic princi-ples in order to extrapolate selectively to other drugs in agiven class for which the given interaction has not beenreported? For example, interactions involving selective se-rotonin reuptake inhibitors (SSRI’s) were generalized whenthe risk for the occurrence of the serotonin syndrome couldbe based on a potential pharmacological interaction. Forinteractions that were pharmacokinetic in nature, differ-ences in extreme impact were addressed individually. Sim-ilarity of action in a particular enzyme system might indi-cate possible interactions. Nefazodone is a known inhibitorof the cytochrome P3A4 isoenzyme. Yet, its use with cisa-pride was initially not contraindicated. Cisapride is a knownand established cytrochrome P3A4 substrate that could pro-duce cardiac arrthymias and/or death when prescribed withcytochrome P3A4 inhibitors. Judicious practice would havequestioned the use of nefazodone with cisapride despite thelack of a documented interaction. Eventually, the prescrip-tion of cisapride was officially contraindicated with nefaz-odone.

Table 1Commonly prescribed neurologic medications

AcetazolamideAmobarbitalAlprazolamAmantadineAmitriptylineAspirinAtropineBaclofenBenztropineBotulinumBromocriptineCarbamazepineCarbidopa/LevodopaChloral HydrateChlordiazepoxideClonazepamClonidineClopidogrelClozapineCyclobenzaprineDexamethasoneDiazepamDihydroergotamineDiphenhydramineDipyridamoleDipyridamole�ASADomperidoneEntacaponeEthosuximideFelbamateFosphenytoinGabapentinGlatiramer AcetateTacrineInterferon beta-1aInterferon beta-1bIVIGLamotrigineLevatiracetamLorazepamMeclizineMethylphenidate

MethylprednisoloneMetoclopramideMidazolamModafinilNaratriptanNimodipineNortriptylineOlanzapineOndansetranOxazepamOxcarbazepinePenicillaminePentobarbitalPergolidePerphenazinePhenelzinePhenobarbitalPhenytoinPramipexolePrednisolonePrimidoneProchlorperazinePromethazinePyridostigmineRiluzoleRopiniroleSelegilineSumatriptanTemazepamTiagabineTiclopidineTizanidineTolcaponeTopiramateTrihexyphenidylValproic AcidVigabatrinWarfarinZaleplonZolpidemZonisamide

Table 2Commonly prescribed psychotropic medications

AlprazolamAmantadineAmitriptylineAmphetamineAmobarbitalBenztropineBupropionBuspironeButalbitalCarbamazepineChoral HydrateChlordiazepoxideChlorpromazineCitalopramClomipramineClonazepamClozapineDesipramineDextroamphetamineDiazepamDiphenhydramineDivalproex SodiumDonepezilFluoxetineFluphenazineFluvoxamineGabapentinHaloperidolImipramineLamotrigineLithiumLorazepam

LoxapineMeprobamateMethylphenidateMolindoneNefazodoneNortriptylineOlanzapineOxazepamPargylineParoxetinePemolinePerphenazinePhenobarbitalQuetiapineRisperidoneSertindoleSertralineSildenafilSodium AmytalTarcineTemazepamThioridazineThiothixeneTrazodoneTranylcypromineTriazolamTrifluoperazineTrihexiphenidylValproic AcidVenlafaxineZaleplonZolpidem

291J.J. Strain et al. / General Hospital Psychiatry 24 (2002) 290–310

3. Dynamics of drug–drug interaction

Although the dynamics of drug–drug interaction(s) havebeen described before [1], it is important to review themhere as the neurologic drug-psychotropic drug interactionsummaries which follow are constructed with this algorithmin mind and a reader may not have access to the previouscommunication. It is necessary to determine the circum-stances in which drugs might interact, and when the clinicalsituation would be protective or aversive, by adding orsubtracting Drug A to or from Drug B, and vice versa. Forexample, if Drug A and Drug B were started simultaneouslyand Drug A had the potential to alter the metabolism ofDrug B, regular monitoring of the clinical response may beprotective in that the net effect of the interaction could beadjusted for as the clinician treated the patient either untilimprovement or toxicity.

Adding Drug A to Drug B where Drug A alters themetabolism of Drug B, might change (increase/decrease)the concentration of B, which is already in the patient’ssystem, and initiate an adverse drug response. Before add-ing A, drug B might have been at a stable therapeutic dose.Three situations may prevail: higher serum concentration ofB, less of B, or thirdly, a chemical interaction with anadditive incidence or severity of an adverse event. On theother hand, adding Drug B to a steady state of Drug A,where Drug A alters the metabolism of Drug B but Drug Ais not affected by Drug B, will not be aversive, as theclinician may add more or less of Drug B, depending uponthe clinical situation. Thus the clinician can compensate forthe interaction by adjusting the dose of Drug B. An ap-proach to observing drug–drug interactions is to outlineDrug A’s impact on Drug B when adding and subtractingone drug to or from the other.

Patient is on Add on

A (Drug A altersmetabolism ofDrug B)

B No impact as the effect of A on Bwill be accounted for as B isinitiated.

A&B � No action is necessary if there areno adverse effects present, thepatient is stable on both and theinteraction is accounted for.

B � A Dose of B may need to be adjustedas the effect of A on B is observed.

Removing Drug A from Drug B or Drug B from Drug A,where Drug A alters metabolism of Drug B, presents addi-tional issues. Discontinuing one drug may raise or lower theconcentration of another, may alter the clinical effects of theremaining drug and/or may precipitate toxicity. The practi-tioner needs to assess the clinical effects of the remainingdrug during withdrawal of the second drug.

In the appendix describing the drug interactions, thisalgorithm is employed to aid the physician when adding orterminating drugs which are known to have adverse reac-tions.

Patient on Take away

A�B (Drug A altersmetabolism ofDrug B)

B No change in the dose of A will benecessary.

A�B � A The dose of B may need to bealtered as the effect of A on Bdissipates.

4. Rating system: significance levels

Most rating systems indicate: 1) major significance; 2)moderate significance; and 3) minor significance. Signifi-cance level 1 indicates a major contraindication or a druginteraction that requires very careful monitoring. The clini-cian needs to document why he/she is prescribing this com-bination, and the medical necessity to use both drugs con-comitantly only if there is no alternative or the potentialbenefit outweighs the risk. Drug combinations producing aninteraction with a significance level 1 are combinations thatresult in serious and potentially life threatening adverseeffects such as arrhythmia and/or death. Obviously, if thiscombination is to be used the drug(s) in question must beprescribed with an explanation as to the need for theirconcurrent use and cautious monitoring. Documentation ofthe clinician’s awareness of the potential serious—level1—interaction should be accomplished at the time of pre-scribing this potentially lethal combination. In addition, it isobligatory to communicate to the other health care providersthe potential interactions and adverse outcomes they shouldbe on guard to observe. Obviously, the optimum choice, ifpossible, is to use another drug to avoid significance level 1interactions.

With significance level 2, the potential interaction mustalso be documented and the clinical outcome(s) must bemonitored carefully so that unacceptable, pernicious reac-tions may be halted as soon as possible. If possible, con-sideration should be given to an alternative agent that doesnot share the same interaction potential. It is essential thatthe clinician document that the potential drug interactionswere considered when using this combination. It is alsoessential to alert the patient’s health care providers of thepotential interactions so that they are observed early in theircourse.

Significance level 3 does not preclude the use of a spe-cific drug, but clinical decision making requires acknowl-edging if the adverse reactions, (e.g., nausea, rash, etc.)might be precluded by another drug option. The potentialinteraction and its mechanism(s) needs documentation inthe patient’s medical chart and the patient’s health careproviders need to be informed.

Another rating system is employed by Drug InteractionFacts which utilizes a five point significance classificationschema [3]:

1. Avoid combination - risk always outweighs benefit.

292 J.J. Strain et al. / General Hospital Psychiatry 24 (2002) 290–310

2. Usually avoid combination - use combination onlyunder special circumstances.

3. Minimize risk - take action as necessary to reducerisk.

4. No action needed - risk of adverse outcomes appearssmall; and

5. No interaction - evidence suggests no interaction.

When data were obtained from Drug Interaction Factsthe five point scale was converted to the three levels ofsignificance rating system described earlier which is em-ployed in the appendix.

5. Conclusion

We previously described methods to keep abreast ofnewly reported drug–drug interactions, and identified in-struments available to accomplish this task [1]. Each monthnew drug - drug interactions are described. This unfoldingof knowledge of neurological drug–psychotropic drug in-teractions illustrates the importance of methods of surveil-lance to ensure that information is current, accurate, andavailable. It is our intent to have the interactions describedin this paper available on the internet on a web site (www-.microcares.com), and as a part of the dictionaries in acomputerized medical record, MICROCARES, which iscurrently employed by Consultation-Liaison (C-L) psychi-atrists at the interface of medicine and psychiatry in thegeneral acute care inpatient and ambulatory setting. Thiswill permit medical students, house officers, fellows andattendings in neurology, psychiatry and primary care tohave immediate access to this essential drug–drug informa-tion as well as to new interactions as they are discoveredand reported through the variety of resources describedabove and the technical reports maintained by the pharma-ceutical laboratories.

The authors were impressed with the number and sever-ity of drug interactions when two or more psychotropic/neurologic drugs were employed simultaneously. Sinceneurology uses many psychotropic medications routinely,the psychiatric consultant has to be aware of interactionswhen he/she recommends additional psychotropic drugs.(Many of these interactions were not found on two com-monly employed software systems: Interact and ePocrates[6,7]).

Psychiatrists need to be aware of the potential interac-tions when two or more psychotropic medications are pre-scribed concomitantly to the same patient, and who may beon other neurological medications as well.

Pharmaceutical companies develop limited drug interac-tion profiles prior to the introduction of a new medication.Preclinical in-vitro and clinical studies are the basis for thisinformation. After the introduction of a new drug, additionalstudies are conducted and new drug interaction reports arecollected and continuously evaluated. This “ from use” data

offers a valuable insight into level one, two and three sig-nificant interactions and their frequencies. “From use” datamay provide early indications of potential drug interactionsthat have not been previously identified. After evaluation,reports can be the basis for a pharmacokinetic drug–druginteraction study to determine the significance of a collec-tion of single case reports. A well-designed pharmacokinec-tic drug interaction study can confirm the validity of a groupof single case reports. Single case reports were weighted tobe less significant than several case reports with similarfindings. Well-designed pharmacokinetic studies demon-strating a significant drug interaction were weighted signif-icantly higher in our review than single case reports.

Since the patient is the “guinea pig” for reactions notobserved during clinical trials and FDA approval, it is thisnatural experiment of the patient using a drug over time,using the medication with other drugs, herbal agents, andfoods, and in some cases acquiring additional medical ill-ness, etc., which provide the matrix for the interactions tooccur. Such data could compare and counter that presentedin “Prozac Backlash” in which the author argues that long-term effects of the SSRIs can be injurious to brain, memory,motor movements functioning, etc. [8]. Eli Lilly Co. has usedata from over 22 million initial and renewal prescriptionsof fluoxetine (1986–2002) that might answer some of thesequestions. They probably can never have a definitive state-ment about all adverse responses, because many are notreported, and many reported are not necessarily related tothe drug or drugs in question. Unfortunately, these are oftenself-report statements not verified by a physician.

It would be important to know about the long term use ofmedication, gender issues and age considerations. Healthcare workers might also know if the frequency of adversereactions is rare, occasional or frequent. And, such use datacan illuminate risk characteristics for adverse drug respond-ers, e.g., the elderly, women, those with heart disease, dia-betes, etc., to guide the physician and the patient with regardto the risk versus benefit from combined medication usage.

As one follows the evolution of antipsychotic medica-tions from reserpine (1940s), chlorpromazine (1950s), hal-operidol, fluphenazine, thioridazine (1960s), to the atypicalantipsychotics (loxapine, risperidone, olanzapine, quetiap-ine (1990s), and finally to the “atypical atypicals” (ziprasi-done, aripiprazole, iloperidone (2000) [9], it is understand-able that we need to wait and see what happens with thesetwenty first century medications with regard to drug–druginteractions. There has not been time for the “atypical atypi-cals” to run the “natural experiment” and be sufficientlyused by the human “guinea pig” in a variety of situations toknow their potentially significant interactions.

Since psychotropic medications are so frequently em-ployed by non psychiatric physicians, e.g., neurologists,primary care physicians, internists, and since large numbersof their patients are concurrently on medical drugs forsomatic reasons, the interactions listed above must be un-derstood before psychotropic medications are prescribed.


References

[1] Strain JJ, Caliendo G, Alexis JD, Lowe, III, RS, Karim A, LoigmanM. Part II: Cardiac drug and psychotropic drug interactions: signifi-cance and recommendations. General Hospital Psychiatry 1999;21:408–29.

[2] Hansten PD, Horn JR, Koda-Kimble MA, Young LY, editors. Druginteractions and analysis and management: facts and comparisons. St.Louis, MO, 2000, Quarterly Update.

[3] Tatro DS, editor. Drug interaction facts: Facts and Comparisons, StLouis, MO, 1998. Quarterly Update 1999.

[4] Micromedex Drugdex, Micromedex, Volume 97, 2000. Englewood,New Jersey.

[5] McEvoy GK, editor. American hospital formulary service drug in-formation 2000. American Society of Health System Pharmacists.Bethesda, MD, 2000.

[6] Goldman LS: Interact: psychotropic drug interactions. American Psy-chiatric Press, Inc. Washington, D.C., 1999.

[7] ePocrates Rx, Clinical Drug Database, 2000. Copyright ePocratesInc., www.jobs@ePocrates.

[8] Glenmullen J. Prozac backlash. Simon and Schuster, New York, NY,2000.

[9] Lieberman J. Treating psychotic disorders: what is the state of the art?American Psychiatric Association Annual Meeting, New Orleans,LA, May 2001.

Neurologic and psychotropic drug interactions

Acetazolamide/LithiumSignificance level 2: ModerateAdvice to Practitioner: Lithium renal elimination may be

increased by acetazolamide. Therefore, with patients onlithium, serum levels may decrease when acetazolamide isadded. No action is needed if a patient is stable on thecombination. If a patient is on acetazolamide and lithium isadded, no action is necessary, as the dose of lithium will bedetermined by serum levels.

Action: Monitor lithium levels when adding acetazol-amide to lithium therapy.

Acetazolamide/PhenobarbitalSignificance level 3: MinorAdvice to Practitioner: Acetazolamide causes urinary

alkalinization which can increase phenobarbital elimination.If a patient is on phenobarbital, serum levels may be de-creased when acetazolamide is added. If a patient is main-tained on the combination, no action is necessary. If apatient is on acetazolamide and phenobarbital is added, thedose of phenobarbital will be determined by serum levelsand clinical efficacy.

Action: Monitor serum phenobarbital levels when ac-etazolamide is added to phenobarbital therapy.

Acetazolamide/Tricyclic antidepressants (TCA)Significance level 3: MinorAdvice to Practitioner: Acetazolamide causes urinary

alkalinization which can decrease tricyclic antidepressantelimination. If a patient is on a TCA, serum levels may be

increased when acetazolamide is added. This may result inincreased TCA side effects. This interaction is unlikely toresult in significant effects, however, in patients on highdoses or with bothersome side effects it may be problematic.If a patient is maintained on the combination, no action isnecessary. If a patient is on acetazolamide and a TCA isadded, no action is necessary, as the dose of the TCA willbe determined by clinical efficacy.

Action: Monitor for TCA side affects when acetazol-amide is added to TCA therapy.

Acetazolamide/TopiramateSignificant level 2: ModerateAdvice to Practitioner: Both acetazolamide and topira-

mate are carbonic anhydrase inhibitors. Use of both agentstogether may increase the risk of renal stones.

Action: Use cautiously if necessary. Patients should beinstructed to drink plenty of water.

Alprazolam, Midazolam/CarbamazepineSignificance level 2: ModerateAdvice to Practitioner: Carbamazepine can increase the

metabolism of some benzodiazepines (alprazolam and mi-dazolam). Interactions of this type may take some time tooccur or dissipate. If a patient is on carbamazepine and abenzodiazepine is added, no intervention is required, as thedose of the benzodiazepine will be monitored by clinicalefficacy. If a patient is stabilized on the combination, noaction is necessary. If a patient is on a benzodiazepine andcarbamazepine is added, decrease benzodiazepinie activitymay be seen. Increased doses may be needed.

Action: Monitor benzodiazepine efficacy and adjustdose as needed as indicated above. An unaffected ben-zodiazepine may also be used.

Alprazolam/Selective Serotonin Reuptake Inhibitors(SSRI’s) (Fluoxetine, Fluvoxamine), Nefazodone

Significance level 2: ModerateAdvice to Practitioner: Fluoxetine, fluvoxamine, nefaz-

odone inhibits cytochrome P450 3A4 which metabolizesalprazolam. Interactions of this type may take some time toonset or dissipate. If a patient is on alprazolam, and any ofthe above named agents are added, increased benzodiaz-epine activity may be seen. If a patient is stabilized on thecombination, no action is necessary. If a patient is either onflouxetine, fluvoxamine or nefazodone and alprazolam isadded, no action is necessary, as the dose of alprazolam willbe determined by clinical efficacy.

Action: Monitor benzodiazepine efficacy and adjustdose as needed as indicated above. An unaffected ben-zodiazepine or paroxetine may be considered as alter-natives.

Amantadine/Anticholinergics (Benztropine, Trihexy-phenidyl)

Significance level 2: Moderate


Advice to Practitioner: The anticholinergic side effectsmay be intensified, probably by additive or synergistic tox-icity.

Action: When an interaction is observed, the anticho-linergic agent could be decreased observing for sideeffects.

Amantadine/ThioridazineSignificance level 3: MinorAdvice to Practitioner: In elderly patients, with Parkin-

sonian Syndrome, thioridazine has been associated withincreased tremor when added to amantadine. This has notbeen seen with other phenothiazines. Patients should beinformed of this possibility and alternative phenothiazinesor other antipsychotics used if it is problematic.

Action: Educate and monitor patient for increasetremor.

Amantadine/TCASignificance level 3: MinorAdvice to Practitioner: Amantadine has anticholinergic

effects. When used with a TCA, especially those with highanticholinergic effects, increased anticholinergic and centralnervous system (CNS) effects may occur. This interactionmay be a concern in patients on high doses of these agents.In a patient on a TCA, increased anticholinergic effectsshould be expected when amantadine is added. No action isnecessary if a patient is already maintained on the twoagents. If a TCA is being added to amantadine, increasedanticholinergic effects should be expected.

Action: Use a TCA with lower anticholinergic activityor from another class of antidepressant with amantadineif anticholinergic effects are potentially problematic.

Amitriptyline, Imipramine, Nortriptyline/VerapamilSignificance level 3: MinorAdvice to Practitioner: A controlled study has shown

that verapamil decreases amitriptyline, imipramine, andnortriptyline clearance by 25%. The addition of verapamilto amitriptyline, imipramine, or nortriptyline may lead totoxicity (arrythmia, dry mouth, sedation, and urinary reten-tion). When verapamil is given to a stable patient on ami-triptyline, imipramine, or nortriptyline, he or she should beaware of these side effects and a lower dose may be indi-cated. On the other hand, an increase in the dosage of a TCAmay be required if verapamil is discontinued from the com-bination.

Action: Monitor for anticholinergic effects if vera-pamil is added to a patient previously stabilized onamitriptyline, imipramine, or nortriptyline. Adjust thedose (upward) if verapamil is discontinued from combi-nation therapy. Consider an alternative antidepressantother than TCA.

Aspirin/FluoxetineSignificance level 3: Minor

Advice to Practitioner: Aspirin may result in the reap-pearance of hives initially caused by fluoxetine. The mech-anism for this allergic reaction is unknown and can bemoderately severe.

Action: Be aware of potential reactions.

Aspirin/ImipramineSignificance level 3: MinorAdvice to Practitioner: In a recent small study, addition

of aspirin to imipramine resulted in increased severity ofimipramine side effects. Increased free imipramine levelswere noted when aspirin was administered. This interactionis not likely to have long-term significance as free imipra-mine will be metabolized and eliminated until a new steadystate is achieved.

Action: Initiate aspirin slowly in patients who havesignificant imipramine side effects. Since this interactionwas noted with aspirin 500 mg po q12h, it is unknown ifit would be seen at lower doses.

Aspirin/Valproic acid (VPA)Significance level 2: ModerateAdvice to Practitioner: Aspirin may displace valproic

acid from protein binding sites. This may result in increasedfree VPA concentration without any change in the totalconcentration. A second mechanism may be that aspirinmay alter the metabolic pathways of VPA. Because aspirinis highly protein bound, it can be displaced or displace otherdrugs from binding sites. The acetylation of albumin byaspirin could alter protein binding of other drugs and thismust be a caution in its use. Increased risk of bleeding hasalso been reported.

Action: Monitoring of VPA, total and free concentra-tions, should be conducted if salicylates are prescribedcontemporaneously. Changes in liver enzymes and evi-dence of VPA toxicity should also be monitored.

Baclofen/Tricyclic Antidepressant (TCA)Significance level 3: MinorAdvice to Practitioner: Baclofen has anticholinergic ef-

fects. When used with a TCA, especially those with highanticholinergic effects, increased anticholinergic and centralnervous system (CNS) effects may occur. This interactionmay be a concern in patients on high doses of these agents.If a patient is on a TCA, increased anticholinergic effectsshould be expected when baclofen is added. No action isnecessary if a patient is already maintained on the twoagents. If a tricyclic is being added to baclofen, increasedanticholinergic effects should be expected. In case reports,addition of baclofen to imipramine, amitriptyline, or clomi-pramine has resulted in short-term memory loss. Addition-ally, when used with imipramine, additive muscle relaxanteffects have occurred.

Action: Monitor for anticholinergic side effects whencombinations are used. If the side effects become intol-


erable to the patients, switching of antidepressants maybe suggested.

For example, use a TCA with lower anticholinergicactivity, or another class of antidepressant with baclofenif anticholinergic effects are potentially problematic.

Benztropine/ClozapineSignificance level 2: ModerateAdvice to Practitioner: Benztropine has anticholinergic

effects. When used with clozapine, increased anticholin-ergic and CNS effects may occur. This interaction may be aconcern in patients on high doses of these agents. In apatient on clozapine, increased anticholinergic effectsshould be expected when benztropine is added. No action isnecessary if a patient is already maintained on the twoagents. If clozapine is being added to benztropine, increasedanticholinergic effects should be expected.

Action: Avoid routine use of benztropine with cloza-pine. Consider atypical antipsychotics with reduced in-cidence of extrapyramidal symptoms (EPS) if it is prob-lematic. Combined use should be limited to patients withsigns and symptoms of EPS.

Benztropine/HaloperidolSignificance level 2: ModerateAdvice to Practitioner: Both haloperidol and benztropine

have anticholinergic effects. The combination of haloperi-dol and other anticholingeric agents have resulted in wors-ening of schizophrenic symptoms and may increase the riskof tardive dyskinesias.

Action: Avoid routine use of benztropine with halo-peridol. Consider atypical antipsychotics with reducedincidence of EPS if it is problematic. Combined useshould be limited to patients with signs and symptoms ofEPS.

Benztropine/PhenothiazinesSignificance level 2: ModerateAdvice to Practitioner: Benztropine has anticholinergic

effects. When used with a phenothiazine antidepressant,especially those with high anticholinergic effects, increasedanticholinergic and CNS effects may occur. This interactionmay be a concern in patients on high doses of these agents.In a patient on a phenothiazine, increased anticholinergiceffects should be expected when benztropine is added. Noaction is necessary if a patient is already maintained on thetwo agents. If a phenothiazine is being added to benztro-pine, increased anticholinergic effects should be expected.Additionally, oral absorption of the phenothiazine may bedecreased. It is unknown if spacing the doses of these agentswould diminish this effect, but it is unlikely to have animpact as direct interference with absorption is not postu-lated to be the mechanism.

Action: Avoid routine use of benztropine with phe-nothiazines. Consider atypical antipsychotics with re-duced incidence of EPS if it is problematic. Combined

use should be limited to patients with signs and symp-toms of EPS.

Bromocriptine/Mesoridazine, ThioridazineSignificance level 2: ModerateAdvice to Practitioner: Phenothiazines can increase pro-

lactin levels. Since some of bromocriptine’s efficacy may berelated to reduction in prolactin levels, increased doses ofbromocriptine may be needed. If a patient is on bromocrip-tine and a phenothiazine is added, the dose of bromocriptinemay need to be increased. If a patient is stabilized on thecombination, no action is necessary. If a patient is on aphenothiazine and bromocriptine is added, no action isneeded, as the dose of bromocriptine will be determined bythe therapeutic response. It is unknown if other atypicalantipsychotics would have this effect, however, an agentthat can increase prolactin may interfere with the efficacy ofbromocriptine.

Action: Use an antipsychotic with minimal effect onprolactin. Monitor response to bromocriptine as above.

Carbamazepine/BupropionSignificance level 2: ModerateAdvice to Practitioner: Addition of carbamazepine to

buproprion has been associated with a significance reduc-tion (up to 90%) of the buproprion area under the curve. Itis believed to be due to carbamazepine induction of bupro-prion metabolism via the cytochrome P450 system. Inter-actions of this type may take some time to onset or dissipate.If a patient is on carbamazepine and buproprion is added, nointervention is required, as the dose of buproprion will bedetermined by clinical efficacy. If a patient is stabilized onthe combination, no action is necessary. If a patient is onbuproprion and carbamazepine is added, decreased bupro-prion activity may be seen, and increased doses may beneeded.

Action: Monitor patients for symptoms of decreasedbuproprion concentration and adjust dose as needed.Obtaining serum levels of buproprion may be helpful.

Carbamazepine/DonepezilSignificance level 3: MinorAdvice to Practitioner: Carbamazepine induces the me-

tabolism of donepezil via induction of the cytochrome P4503A4 and 2D6 isoenzymes. Interactions of this type may takesome time to onset or dissipate. If a patient is on carbam-azepine and donepezil is added, no intervention is required,as the dose of donepezil will be determined by clinicalefficacy. If a patient is stabilized on the combination, noaction is necessary. If a patient is on donepezil and carbam-azepine is added, decrease donepezil activity may be seen,and increased doses may be needed.

Action: Patients should be monitored for clinical re-sponse to donepezil when carbamazepine is added. Thedose of donepezil may need to be adjusted when car-bamazepine is added or removed from the regimen.


Carbamazepine/HaloperidolSignificance level 2: ModerateAdvice to Practitioner: Carbamazepine induces the me-

tabolism of haloperidol via the cytochrome P450 3A4 and2D6 isoenzymes. Interactions of this type may take sometime to onset or dissipate. If a patient is on carbamazepineand haloperidol is added, no intervention is required, as thedose of haloperidol will be determined by clinical efficacy.If a patient is stabilized on the combination, no action isnecessary. If a patient is on haloperidol and carbamazepineis added, decreased haloperidol effectiveness may be seen,and increased doses may be needed.

Action: Patients should be monitored for clinical re-sponse to haloperidol when carbamazepine is added.The dose of haloperidol may need to be adjusted whencarbamazepine is added or removed from the regimen.

Carbamazepine/LithiumSignificance level 2: ModerateAdvice to Practitioner: The combination of lithium and

carbamazepine has resulted in neurotoxicity, even with ther-apeutic concentrations. Reported symptoms include: un-steady gait, truncal tremors, ataxia, horizontal nystagmus,hyperflexia, muscle fasiculations, confusion, drowsiness,weakness, lethargy, and coarse tremor. When used together,patients must be educated and closely monitored.

Action: Monitor patients for symptoms listed above ifthe combination is necessary.

Carbamazepine/Monoamine Oxidase Inhibitors (MAOIs)Significance level 1: MajorAdvice to Practitioner: Use of carbamazepine with a

MAOI is contraindicated by the manufacturer, with a rec-ommendation that at least 14 days elapse between the dis-continuation of the MAOI and introduction of carbamaz-epine. Concomitant use has resulted in increased bloodpressure, hyperpyrexia, and seizures. However, in refractorycases use of a MAOI with carbamazepine may be employedwith appropriate monitoring and patient education.

Action: Avoid combination whenever possible. Atleast 14 days should elapse after discontinuing a MAOIbefore carbamazepine is introduced. If the combinationis essential, closely monitor patient for the signs andsymptoms listed above.

Carbamazepine/NefazodoneSignificance level 2: ModerateAdvice to Practitioner: This combination represents a

complex interaction. Nefazodone inhibits the metabolism ofcarbamazepine via inhibition of the cytochrome P450 3A4isoenzyme. Carbamazepine concentrations may increase by23%, with a 21% reduction of the carbamazepine epoxideconcentration. However, carbamazepine induces the metab-olism of nefazodone by cytochrome P450 3A4 induction.The area under the curve (AUC) of nefazodone may bereduced by as much as 93%.

Action: Patients should be monitored for clinical re-sponse to both nefazodone and carbamazepine. It isdifficult to predict the impact of this combination due tothe competitive and divergent effect on the same enzymesystem. Monitoring of serum carbamazepine levels isessential when nefazodone is added, discontinued, ordose adjusted.

Carbamazepine/OlanzapineSignificance level 2: ModerateAdvice to Practitioner: Carbamazepine induces the me-

tabolism of olanzapine via induction of the cytochromeP450 1A2 isoenzyme. Olanzapine clearance may be in-creased by 50%, and serum olanzapine levels may thereforebe decreased significantly. Interactions of this type may takesome time to onset or dissipate. If a patient is on carbam-azepine and olanzapine is added, no intervention is required,as the dose of olazapine will be determined by clinicalefficacy. If a patient is stabilized on the combination, noaction is necessary. If a patient is on olazapine and carbam-azepine is added, decreased olazapine activity may be seen,and increased doses may be required.

Action: Patients should be monitored for clinical re-sponse to olanzapine when carbamazepine is added. Thedose of olanzapine may need to be adjusted when car-bamazepine is added or removed from the regimen.

Carbamazepine/PhenobarbitalSignificance level 2: ModerateAdvice to Practitioner: Phenobarbital stimulates

CYP450 3A4 which metabolizes carbamazepine. The in-crease in metabolism significantly reduces plasma concen-trations of carbamazepine. If a patient is on a stabilized doseof both drugs, no action is necessary. When phenobarbital isadded to carbamazepine, monitor patients for increased sei-zure activity and increase the carbamazepine dose if neces-sary. However, phenobarbital levels are not affected bycarbamazepine.

Action: Monitor for increased seizure activity andincrease the dose of carbamazepine if necessary.

Carbamazepine/RisperidoneSignificance level 2: ModerateAdvice to Practitioner: Carbamazepine induces the me-

tabolism of risperidone via induction of the cytochromeP450 2D6 and 3A4 isoenzyme. Risperidone serum levelswill decrease when carbamazepine is added, and have beenreported to double when carbamazepine was discontinued.Interactions of this type may take some time to onset ordissipate. If a patient is on carbamazepine and risperidone isadded, no intervention is required, as the dose of risperidonewill be determined by clinical efficacy. If a patient is sta-bilized on the combination, no action is necessary. If apatient is on risperidone and carbamazepine is added, de-creased risperidone activity may be seen, and increaseddoses may be needed.


Action: Patients should be monitored for their clini-cal response to risperidone when carbamazepine isadded. The dose of risperidone may need to be adjustedwhen carbamazepine is added or removed from theregimen.

Carbamazepine/Selective Serotonin Reuptake Inhibitors(SSRI)

Significance level 2: ModerateAdvice to Practitioner: Carbamazepine levels may be

increased by the addition of fluoxetine, fluvoxamine, andsertraline. In addition, serum levels of citalopram may bedecreased by carbamazepine since it is metabolized by theP450 3A4 isoenzyme, which is induced by carbamazepine.Paroxetine has not been reported to be affected by carbam-azepine, and does not itself appear to affect carbamazepine.

Action: Monitor patient for symptoms of increasedcarbamazepine concentration and adjust doses asneeded. If using citalopram, monitor patients for inad-equate therapeutic efficacy and increase dosage ifneeded. Use of paroxetine may be considered.

Carbamazepine/TrazodoneSignificance level 2: ModerateAdvice to Practitioner: Trazodone inhibits the metabo-

lism of carbamazepine via induction of the cytochromeP450 3A4 isoenzyme. Carbamazepine clearance may bedecreased, resulting in carbamazepine toxicity. Also,plasma levels of trazodone and its active metabolite may bedecreased from enhanced metabolism. Interactions of thistype may take some time to onset or dissipate. If a patient ison carbamazepine and trazodone is added, increased car-bamazepine concentration and toxicity may be seen. If apatient is stabilized on the combination, no action is neces-sary. If a patient is on trazodone, and carbamazepine isadded, no action is necessary as the dose of carbamazepinewill be determined by serum levels and clinical efficacy.

Action: Carbamazepine serum levels should be mon-itored when trazodone is added to or removed fromcarbamazepine therapy. Patients should be monitoredfor clinical signs and symptoms of carbamazepine tox-icity.

Carbamazepine /TCASignificance level 2: ModerateAdvice to Practitioner: Addition of carbamazepine to a

TCA has been associated with a significant (up to 40%)reduction in serum concentration of the TCA. Reductionshave been reported with amitriptyline, nortriptyline, imip-ramine, and desipramine. It is believed to be due to carbam-azepine induced metabolism of TCAs. Interaction of thistype may take some time to onset or dissipate. If a patient ison carbamazepine and TCA is added, no intervention isrequired, as the dose of TCA will be determined by clinicalefficacy. If a patient is stabilized on the combination, noaction is necessary. If a patient is on TCA and carbamaz-

epine is added, decreased TCA activity may be seen, andincreased doses may be needed.

Action: Monitor patient for symptoms of decreasedTCA concentration and adjust dose as needed. Obtain-ing serum levels of the TCA may be helpful.

Carbamazepine/VerapamilSignificance level 2: ModerateAdvice to Practitioner: Co-administration of carbamaz-

epine and verapamil has resulted in increased carbamaz-epine levels and toxicity (ataxia, nystagmus, diplopia, head-ache, vomiting, apnea, seizures, and coma). The probablemechanism is decreased carbamazepine metabolism by ve-rapamil. If the patient were stable on this combination, noaction would be necessary. Decrease or increase in carbam-azepine dose may be required when verapamil is adminis-tered or withdrawn respectively.

Action: Reduction in the dose of carbamazepine maybe required when verapamil is added, and considerhigher dose of carbamazepine when verapamil is with-drawn from the combination therapy to avoid epilepticseizures.

Clozapine/BenzodiazepinesSignificance level 2: ModerateAdvice to Practitioner: There have been reports of car-

diorespiratory collapse when benzodiazepines have beenused with clozapine. It is unclear what the mechanism ofthis reaction is and it has been rarely reported.

Action: Monitor patient when this combination isused.

Clozapine/CarbamazepineSignificance level 2: ModerateAdvice to Practitioner: Both clozapine and carbamaz-

epine are associated with agranulocytosis and bone marrowsuppression. Additionally, carbamazepine is an enzyme in-ducer and may decrease clozapine serum levels. Interactionsof this type may take some time to onset or dissipate. If apatient is maintained on the combination of carbamazepinewith clozapine, no action is necessary. If a patient is oncarbamazepine and clozapine is added, no action is neces-sary as the dose of clozapine will be determined by serumlevels and clinical response. If a patient is on clozapine andcarbamazepine is added, clozapine levels and toxicityshould be monitored as the metabolism of clozapine will beincreased and serum levels may decrease.

Action: Use this combination only if necessary, andthen monitor complete blood counts (CBC) and cloza-pine levels as indicated above.

Clozapine/Hydantoins (Phenytoin, Fosphentoin, Mephe-nytoin)

Significance level 2: ModerateAdvice to Practitioner: Phenytoin is an enzyme inducer,

which has been reported to decrease serum levels of cloza-


pine. Interactions of this type may take some time to occuror dissipate. If a patient is maintained on the combination ofphenytoin with clozapine, no action is necessary. If a patientis on phenytoin and clozapine is added, no action is neces-sary as the dose of clozapine will be determined by serumlevels and clinical response. If a patient is on clozapine andphenytoin is added, clozapine levels and toxicity should bemonitored as the metabolism of clozapine will be increasedand serum levels may decrease.

Action: Monitor serum levels of clozapine when add-ing or removing phenytoin from a patient’s regimen.

Clozapine/LithiumSignificance level 2: ModerateAdvice to Practitioner: When lithium has been added to

antipsychotic agents, encephalopathic symptoms have oc-curred. In addition, weakness, dyskinesia and increasedEPS, and brain damage have been reported. Some datasuggest that lithium levels � 0.5 mg/dL minimize this risk,however this has not been fully established. This interactionis not commonly seen, and lithium is frequently added tomany antipsychotic agents without any interaction.

Action: When using lithium and clozapine together,monitor patient for weakness, EPS and encephalopathicsymptoms.

Clozapine/PhenobarbitalSignificance level 2: ModerateAdvice to Practitioner: Phenobarbital is an enzyme in-

ducer and may decrease clozapine serum levels. Interactionsof this type may take some time to be observed or dissipate.If a patient is maintained on the combination of phenobar-bital with clozapine, no action is necessary. If a patient is onphenobarbital and clozapine is added, no action is necessaryas the dose of clozapine will be determined by serum levelsand clinical response. If a patient is on clozapine and phe-nobarbital is added, clozapine levels should be monitored asthe metabolism of clozapine will be increased and serumlevels may decrease with consequent diminished effective-ness.

Action: Monitor clozapine serum levels and responsewhen adding or removing phenobarbital from a pa-tient’s medication regimen.

Clozapine/Selective Serotoin Reuptake Inhibitors(SSRI)

Significance level 2: ModerateAdvice to Practitioner: Clozapine is hepatically metab-

olized via the cytochrome P450 2D6 and 1A2 pathway.Fluoxetine and sertraline are inhibitors of the 2D6 enzymeand fluvoxamine inhibits the 1A2 enzyme, and they mayincrease clozapine levels resulting in toxicity when used incombination. Interactions of this type may take some time tooccur or dissipate. If a patient is maintained on the combi-nation of fluoxetine, sertraline or fluvoxamine, with cloza-pine, no action is necessary. If a patient is on fluoxetine,

fluvoxamine or sertraline and clozapine is added, no actionis necessary as the dose of clozapine will be determined byserum levels and the clinical response. If a patient is onclozapine and fluoxetine, fluvoxamine or sertraline is added,clozapine levels and toxicity should be monitored as themetabolism of clozapine will be decreased and serum levelsmay increase to toxic levels.

Action: Monitor patient and clozapine levels as abovewith dose adjustments made as required. Alternatively,paroxetine or citalopram may be used as they are lesslikely to impact the 2D6 or 1A2 enzymes.

Clonidine/TCASignificance level 1: MajorAdvice to Practitioner: Clonidine exerts its antihyper-

tensive effect by inhibiting presynaptic release of noradren-aline through alfa-2 adrenoreceptors. On the other handTCAs block the re-uptake of noradrenaline and prolong itsaction. Therefore, the drugs counteract each other. If apatient is stabilized on clonidine and a TCA is added, theremay be life-threatening elevation of blood pressure.

Action: Combination of these two drugs should beavoided. Alternative antidepressant agents should beused.

Corticosteroids (Prednisone, Dexamethasone, Methyl-prednisone)/Barbiturates (Phenobarbital, Amobarbital)

Significance level 2: ModerateAdvice to Practitioner: Barbiturates like phenobarbital

significantly increase the metabolism of corticosteroids,namely prednisolone, dexamethasone, methylprednisolone.The possible mechanism is the induction of enzymes bybarbiturates.

Action: Carefully monitor the patients receiving cor-ticosteroids if a barbiturate is added as the level will fallor if the barbiturate is discontinued from combinationtherapy, the dose of corticosteroid may need to be de-creased accordingly. During the short-term pulse ther-apy it is unlikely to require any dose alteration. If cor-ticosteroids are used for maintenance therapy addingbarbiturates may require the increase of the dose ofcorticosteroid.

Cyclobenzaprine/FluoxetineSignificance level 2: ModerateAdvice to Practitioner: Cyclobenzaprine is structurally

related to TCA. Fluoxetine inhibits cytochrome P450 2D6,which may metabolize cyclobenzaprine. This may lead toincreased cyclobenzaprine levels. In a patient stabilized oncyclobenzaprine, increased cyclobenzaprine effects may beseen when fluoxetine is added. If a patient is on fluoxetineand cyclobenzaprine is added, no action is needed, as thedose of cyclobenzaprine will be adjusted based on response.If a patient is currently receiving both agents, no action isnecessary. In one case report, a patient developed symp-tomatic QT prolongation and in another, a patient developed


torsade de pointes when droperidol was added to the com-bination of cyclobenzaprine and fluoxetine.

Action: Monitor patient’s response to cyclobenza-prine as above.

Cyclobenzaprine/Monoamine Oxidase Inhibitors (MAOI)Signifiance level 1: MajorAdvice to Practitioner: Cyclobenzaprine is structurally

related to TCA and has some of the same pharmacologiceffects. Although this specific interaction has not been re-ported, use of monoamine oxidase inhibitors (MAOI’s) withTCA is contraindicated. Use of a MAOI should be discon-tinued at least 14 days before cyclobenzaprine is addedwhenever possible. If it is necessary to use a MAOI, bloodpressure should be monitored as a hypertensive crisis withor without seizures may occur.

Action: Avoid combination whenever possible.

Diazepam/SSRI (Fluoxetine, Fluvoxamine, Sertraline)Significance level 2: ModerateAdvice to Practitioner: Fluoxetine, fluvoxamine, and ser-

traline inhibit cytochrome P450 3A4 which metabolizesdiazepam. Interactions of this type may take some time tooccur or dissipate. If a patient is on diazepam and one ofthese SSRI’s are added, increased benzodiazepine activitymay be seen. If a patient is stabilized on the combination, noaction is necessary. If a patient is on any one of the abovenamed SSRI’s and diazepam is added, no action is neces-sary, as the dose of diazepam will be determined by clinicalefficacy.

Action: Monitor benzodiazepine efficacy and adjustdose as needed as indicated above. An unaffected ben-zodiazepine or paroxetine may be considered as alter-natives.

Diphenhydramine/AmitriptylineSignificance level 2: ModerateAdvice to Practitioner: Amitriptyline and diphenhydra-

mine have anticholinergic effects. Use of both agents mayresult in adynamic ileus, urinary retention, or chronic glau-coma. This may be more problematic in the elderly or inpatients sensitive to anticholinergic effects.

Action: In patients where additional anticholinergiceffects are undesirable, or in elderly patients, use of aTCA with lower anticholinergic activity or an antide-pressant of a different class is recommended.

Diphenhydramine/ClomipramineSignificance level 2: ModerateAdvice to Practitioner: Clomipramine and diphenhydra-

mine have anticholinergic effects. Use of both agents mayresult in adynamic ileus, urinary retention, or chronic glau-coma. This may be more problematic in the elderly or inpatients sensitive to anticholinergic effects.

Action: In patients where additional anticholinergiceffects are undesirable, or in elderly patients, use of a

TCA with lower anticholinergic activity or an antide-pressant of a different class is recommended.

Domperidone/LithiumSignificance level 1: MajorAdvice to Practitioner: Weakness, dyskinesias, increased

extrapyramidal symptoms, encephalopathy, and brain dam-age have been reported with concomitant use of lithium andantipsychotic drugs. This is especially true if high doses ofantipsychotics or lithium are used, although it may happenwith therapeutic doses as well. Chronic lithium treatmentdecreases neostriatal dopaminergic activity. If domperidoneis added to lithium, observe for adverse effects. If lithium isadded to domperidone, examine for adverse effects.

Action: Monitor for signs of toxicity or EPS, espe-cially if high doses of either antipsychotics and/or lith-ium are prescribed concomitantly.

Entacapone/nonselective Monoamine Oxidase Inhibitors(Phenelzine, Tranylcypromine)

Significance level 1: MajorAdvice to Practitioner: Two of the major enzyme sys-

tems involved in the metabolism of catecholamines aremonoamine oxidase (MAO) and catechol-o-methyltransfer-aase (COMT). It is theoretically possible that the combina-tion of entacapone and a nonselective MAO inhibitor wouldcause the inhibition of normal catecholamine metabolism.This could lead to hypertensive crisis and death.

Action: The concurrent administration of entacaponeand a nonselective MAO inhibitor should be avoided.Entacapone may be given with a MAO-B inhibitor, suchas selegiline, in the treatment of Parkinson’s disease.

Ethosuximide/VPASignificance level 2: ModerateAdvice to Practitioner: In the therapy of the epilepsies, a

combination of ethosuximide and VPA is sometimes nec-essary for successful seizure control. A published reportdemonstrated that VPA levels dropped 28.3% with the ad-dition of ethosuximide, and when both were used togetherand ethosuxuimide was discontinued, VPA serum concen-trations rose about 36.7%. The mechanism of ethosuximideto influence the serum levels of VPA remains unknown.

Action: Serum VPA levels should be monitored andadjusted accordingly when used in combination withethosuximide. The levels should be monitored eitherwhen VPA is given to a patient taking ethosuximide, orwhen ethosuximide is given to a patient taking VPA.

Ethosuximide/CarbamazepineSignificance level 2: ModerateAdvice to Practitioner: Patients receiving concurrent

therapy with carbamazepine and ethosuximide may achievelower serum ethosuximide concentrations compared to pa-tients not taking carbamazepine, leading to a decreased


therapeutic effect. Carbamazeine induces the cytochromeP450 enzymes.

Action: If these two agents are used concomitantly,regardless of which one is started first, careful evalua-tion of clinical response may be necessary. If the patientis on carbamazepine and ethosuximide is added, then adose higher than usually given of ethosuximide may benecessary. If a patient is on ethosuximide then the doseshould be increased accordingly if carbamazepine isadded.

Felbamate/CarbamazepineSignificance level 2: ModerateAdvice to Practitioner: Administration of felbamate to

patients stabilized on monotherapy with carbamazepine de-creases carbamazepine serum concentrations.

Action: If these two agents are used together, observepatients for changes in seizure control. Serum drugmonitoring is necessary when felbamate is added tocarbamazepine. When carbamazepine is added to fel-bamate, carbamazepine levels should be monitored untilappropriate steady-state serum levels are attained. If apatient is started on both agents concurrently, then se-rum levels should be monitored appropriately.

Felbamate/LamotrigineSignificance level 3: MinorAdvice to Practitioner: Lamotrigine levels were found to

increase maximum serum concentration (Cmax) by 13%and area under the curve (AUC) by 14% with the additionof felbamate.

Action: Potential side effects from increased lam-otrigine serum levels should be monitored when felbam-ate is added. Monitoring efficacy of lamotrigine shouldbe considered when added to felbamate.

Felbamate/PhenobarbitalSignificance level 2: ModerateAdvice to Practitioner: It has been reported that pheno-

barbital levels will increase, by as much as 42%, with theaddition of Felbamate. Phenobarbital was found to decreasefelbamate concentrations by 29% in another publishedstudy.

Action: Obtain serum phenobarbital concentrationswhen adding or discontinuing felbamate therapy. Adjustphenobarbital dosage as needed. When phenobarbital isadded to felbamate, phenobarbital levels should be mon-itored until appropriate steady-state serum levels areattained. If a patient is already at therapeutic levels ofboth agents, then maintain steady dosing and monitorlevels intermittently.

Felbamate/VPASignificance level 2: ModerateAdvice to Practitioner: VPA serum levels were shown to

increase, up to 54%, with the addition of felbamate in a

published study. Increased valproate levels can cause nau-sea, dizziness and ataxia.

Action: Monitor serum valproate levels and adjustdose accordingly when adding or discontinuing felbam-ate therapy. If VPA is added to felbamate, VPA levelsshould be monitored until appropriate steady-state lev-els are attained. If started on both drugs concurrently,then VPA levels should still be monitored until steadystate levels are achieved.

Lamotrigine/Carbamazepine, OxcarbamazepineSignificance level 2: ModerateAdvice to Practitioner: Concurrent use of lamotrigine

and carbamazepine can result in a 40% decrease in lam-otrigine steady state levels and a doubling of lamotrigineclearance leading to a decreased pharmacologic effect oflamotrigine. Reduced lamotrigine efficacy can lead to theloss of seizure control and mood stabilization. The exactmechanism is not known, but it maybe due to carbamaz-epine’s potent ability to induce CYP3A4 and other enzymesin the liver accelerating the metabolism of lamotrigine. Lossof seizure control is more likely to occur when the initialdose of carbamazepine is high and lamotrigine is added.Oxcarbamazepine has a less pronounced effect on lam-otrigine levels, but the effect is still significant.

Action: Monitor for loss of efficacy. May need toconsider increasing lamotrigine dose and/or decreasingthe carbamazepine/oxcarbamazepine dose.

Lamotrigine/PhenobarbitalSignificance level 2: ModerateAdvice to Practitioner: The administration of phenobar-

bital significantly decreases the half-life (24–30 h to 15 h)of lamotrigine due to its ability to induce hepatic enzymes.If a patient is on lamotrigine and phenobarbital is added, anincrease in lamotrigine dose may be necessary. If a patientis on the combination and phenobarbital is discontinued thelamotrigine dose may need to be decreased. If a patient is onboth drugs and well maintained, no action is necessary.

Action: Monitor for loss of seizure control and theneed to increase or decrease the lamotrigine dose. Whenpatients are receiving concurrent therapy and the phe-nobarbital dose is decreased or discontinued, monitorpatients carefully for lamotrigine toxicity and the needto lower the lamotrigine dose.

Lamotrigine/VPASignificance level 2: ModerateAdvice to Practitioner: Concurrent use of lamotrigine

and VPA can result in a two fold increase in the normal halflife of lamotrigine with a significant rise in plasma concen-trations. An increase in clinical effects is likely to occur.This may be viewed as a benefit to the patient by achievingimproved symptom control, but if this is not the case areduction of the lamtorigine dosage should be considered.


The mechanism of interaction is competitive inhibition be-tween lamotrigine and VPA for hepatic glucuronidation.

Action: With concurrent use, patients should be mon-itored for altered lamotrigine effects as VPA is initiated,discontinued or changed in dosage. A decrease dosage oflamotrigine may be needed.

Midazolam, Alprazolam/Carbamazepine(See Carbmazepine/Alprazolam, Midazolam above).

Midazolam/Fluvoxamine(See Diazepam or Alprazolam/SSRI’s).

Modafilnil/TCAs (Clomipramine, Desipramine)Significance level 2: ModerateAdvice to Practitioner: Patients on TCA who are

CYP2D6 deficient (7–10% population) may experience anincrease in tricyclic concentrations when modafilnil is co-administered. Modafinil reversibly inhibits CYP2C19 thatserves as an alternate pathway for TCA metabolism inCYP2D6 deficient patients. Increased tricyclic serum con-centrations can occur is this subset of patients.

Action: Monitor TCA levels and decrease dose asnecessary when co-administered with modafilnil.

Nimodipine/Carbamazepine, PhenobarbitalSignificance level 2: ModerateAdvice to Practitioner: Concurrent use of nimodipine

and carbamazepine or phenobarbital can result in an 8–10fold decrease in nimodipine plasma concentration. The mostlikely mechanism is hepatic enzyme inducing effects ofcarbamazepine and phenobarbital.

Action: Monitor cardiovascular response to nimodip-ine and observe need for increasing nimodipine dose orchanging the mood stabilizer dose.

Nimodipine/VPASignificance level 2: ModerateAdvice to Practitioner: Plasma concentrations of nimo-

dipine may increase by 50% in patients taking VPA leadingto nimodipine toxicity, i.e., dizziness, flushing, headache,peripheral edema. The mechanism of interaction may be theresult of VPA inhibition of the first pass metabolism ofnimodipine with the resulting increase in nimodipine oralbioavailability.

Action: With concurrent use, patients should be mon-itored for altered nimodipine effects as VPA is initiated,discontinued, or changed in dosage. Consider an alter-native mood stabilizer.

Nortriptyline/CarbamazepineSignificance level 2: ModerateAdvice to Practitioner: Carbamazepine induces the

CYP3 A4 hepatic enzyme which may increase the clearanceof nortriptyline and significantly decrease nortriptyline lev-els. When carbamazepine is added to nortriptyline, monitor

the patient for decreased nortriptyline efficacy and the needto increase the nortriptyline dose. If a patient is on combi-nation therapy and carbamazepine is discontinued, monitorthe patient for increased nortriptyline side effects and theneed to decrease the nortriptyline dose. No action is neces-sary if a patient is already maintained on the two agents.

Action: Monitor the clinical efficacy of nortriptylineand signs for carbamazepine toxicity when the drugs aregiven together. Dosage adjustments may be necessary.

Nortriptyline/ChlorpromazineSignificance level 2: ModerateAdvice to Practitioner: Plasma chlorpromazine concen-

trations rose when nortriptyline was added and the anti-pyrine plasma half-life was prolonged. The addition ofnortriptyline dramatically reversed the therapeutic actionsof chlorpormazine, mainly via pharmcodynamic interaction.

Action: This combination should be monitored andmust be used with caution.

Nortriptyline/Monoamine Oxidase Inhibitor (Tranyl-cypromine)

Significance level 1: MajorAdvice to Practitioner: Tranylcypromine, a monoamine

oxidase inhibitor, in combination with nortriptyline canresult in a serotonin syndrome (hypertension, hyperthermia,myoclonus and mental status changes). In rare cases thesyndrome can be fatal. Another antidepressant should beconsidered.

Action: Do not prescribe nortriptyline and tranyl-cypromine in combination.

Nortriptyline/Phenothiazines (Haldoperidol/Thiorida-zine/Triflurpromazine)

Significance level 2: ModerateAdvice to Practitioner: Nortriptyline and phenothiazines

have been showed to interfere with the metabolism of eachother increasing the opportunity of toxicity of either drug.Increased nortriptyline and/or haldoperidol/thioridazineblood levels and anticholingeric side effects are possible.

Action: Monitor for side effects from toxicity of eitherdrug.

Nortriptyline TCA/SSRI (Fluoxetine, Paroxetine, Ser-traline)

Significance level 2: ModerateAdvice to Practitioner: Concurrent use of a TCA and

SSRI can significantly increase the plasma levels of theTCA. Elevated nortriptyline levels can lead to increasedsigns of nortriptyline toxicity (urinary retention, dry mouth,sedation). Most SSRIs are inhibitors of the cyctochromeP450 2D6 leading to increased nortriptyline levels. Fluox-etine and paroxetine are potent inhibitors of P450 2D6,sertraline to a lesser degree. When a SSRI inhibitor thatsignificantly inhibits 2D6 is added to a TCA, monitor forTCA toxicity and the need to decrease the TCA dose. When


administered together and the SSRI is discontinued, monitorfor decreased plasma TCA levels and the need to increasethe TCA dose. Plasma concentrations of the TCA should bemonitored. No action is necessary, if the patient is alreadymaintained successfully on the two drugs.

Action: Monitor tricyclic blood levels, for signs ofTCA toxicity or decreased TCA efficacy when adding ordiscontinuing a SSRI regimen. Consider a dosage ad-justment.

Olanzapine/CarbamazepineSignificance level 2: ModerateAdvice to Practitioner: Addition of carbamazepine (200

mg) to a previously stable olanzapine regimen resulted in a50% increase in olanzapine clearance. Higher doses of car-bamazepine may result in a greater increase in olanzapineclearance. Carbamazepine decreases olanzapine levels byinducing cytochrome P450 1A2 isoenzyme, which is par-tially responsible for olazepine metabolism. This may resultin a significant decrease in olanzapine efficacy. If carbam-azepine is added to olanzapine, decreased olanzapine effi-cacy can occur along with the need to increase the olanzpinedosing. If a patient is stabilized on the combination, noaction is necessary. If a patient is on the combination andcarbamazepine is discontinued, monitor for increased olan-zapine levels and the need to decrease the olanzapine dose.

Action: Careful monitoring of olanzapine efficacyand adverse reactions are needed. Adjust doses accord-ingly.

Olanzapine/FluvoxamineSignificance level 2: ModerateAdvice to Practitioner: Concurrent use of olanzapine and

fluvoxamine may cause an increase in olanzapine levels.Fluvoxamine inhibits P450 1A2 isoenzyme that is partiallyresponsible for olanzapine metabolism. Monitor for in-creased olanzapine adverse reactions (tachycardia, ortho-static hypertension, seizures). If a patient is on olanzapineand fluvoxamine is added, monitor for increased olanzapinelevels and the need to decrease the dose of olanzapine. If apatient is stabilized on the combination, no action is neces-sary. If a patient is on the combination and fluovoxamine isdiscontinued, monitor for decreased olanzapine efficacy andthe need to adjust the dose.

Action: Monitor for olanzapine efficacy and adjustdose as needed

Oxazepam/PhenobarbitalSignificance level 2: ModerateAdvice to Practitioner: Concurrent use of oxazepam and

phenobarbital results in a shorten elimination half-life andhigher clearance of oxazepam. The mechanism of action isenhanced activity of glycuronyl transferase activity. If phe-nobarbital is added to oxazepam it may be necessary toincrease the dose of oxazepam. If a patient is stabilized onthe combination no action is necessary.

Action: Increased dosage of oxazepam may be neededif phenobarbital is added.

Oxcarbazepine/Lamotrigine(See Lamotrigine/Carbamazepine, Oxcarbamazepine

above).

Phenobarbital/Carbamazepine (See Carbamazepine/Phenobarbital above).

Phenobarbital/ClonazepamSignificance level 2: ModerateAdvice to Practitioner: Concurrent use decreases the

steady state plasma concentration of clonazepam by 20%. Ifa patient is on a stabilized dose of both drugs, no action isnecessary. When phenobarbital is added to clonazepamthere may be a loss of efficacy and a dosage adjustment maybe needed. If phenobarbital is withdrawn from the combi-nation there may be an increase in clonazepam levels andside effects. Dose adjustment may be necessary. The addi-tion of clonazepam to phenobarbital does not effect pheno-barbital plasma concentrations.

Action: Monitor patients for decreased efficacy ofclonazepam if phenobarbital is added and increasedclonazepam levels if phenobarbital is withdrawn. Dos-age adjustments may be necessary.

Phenobarbital/ClozapineSignificance level 2: ModerateAdvice to Practitioner: Phenobarbital induces CYP 450

1A2 which metabolizes clozapine. When phenobarbital isadded to clozapine, patients experience a 35% decrease inclozapine concentrations. Patients should be monitoredclosely for increased psychotic symptoms and the need toincrease the clozapine dose. When patients receive concur-rent therapy and the dose of phenobarbital is decreased ordiscontinued, monitor patients for increased clozapine lev-els and the need to reduce its dose.

Action: Monitor patients for increased or decreasedclozapine levels depending on the addition or discontin-uation of phenobarbital. Adjust dose accordingly.

Phenobarbital/HaloperidolSignificance level 2: ModerateAdvice to Practitioner: Phenobarbital induces enzyme

stimulation which can significantly lower haloperidol bloodlevels. When phenobarbital is added to haloperidol, patientsexperience a 22% decrease in plasma concentrations. Whenadding phenobarbital to haloperidol, patients should bemonitored for decreased efficacy of and lower plasma levelsof haloperidol. The doses of haloperidol may need to beincreased when phenobarbital is given. When patients re-ceive concurrent therapy and the dose of phenobarbital isdecreased or discontinued, monitor patients for increasedhaloperidol levels and the need for a decreased dose.


Action: Monitor patients for increased or decreasedhaloperidol levels depending upon the addition or dis-continuation of phenobarbital.

Phenobarbital/Lamotrigine(See Lamotrigine/Phenobarbital above).

Phenobarbital/ParoxetineSignificance level 3: MinorAdvice to Practitioner: Phenobarbital induces hepatic

isoenzymes that may decrease serum concentrations of par-oxetine. If a patient is maintained on the combination ofphenobarbital with paroxetine, no action is necessary. Ifphenobarbital is added to paroxetine, monitor the patient fordecreased paroxetine efficacy and the need to increase theparoxetine dose.

Action: Monitor paroxetine efficacy and adjust thedose as indicated above.

Phenobarbital/Phenlezine, Tranylcypromine (MAOIs)Significance level 2: ModerateAdvice to Practitioner: MAOIs may inhibit the metabo-

lism of phenobarbital resulting in a prolonged effect ofphenobarbital. Hypotension, increased CNS and respiratoryeffects may be observed. When an MAOI is added to phe-nobarbital, consider the need to decrease the phenobarbitaldose. In patients, receiving concurrent therapy and theMAOI dose is lowered or discontinued, consider increasingthe dose of phenobarbital.

Action: Monitor patients for increased or decreasedphenobarbital levels depending on the addition or dis-continuation of the MAOI.

Phenobarbital/ThioridazineSignificance level 2: ModerateAdvice to Practitioner: Concomitant administration has

resulted in reports of decreased effectiveness of both phe-nobarbital and thioridazine. In addition, phenobarbital maydecrease thioridazine levels due to the induction of hepaticenzymes. Patients should be monitored for decreased ther-apeutic effects for one or both drugs when adding one to theother. If a patient is maintained on the combination noaction is necessary, but if one drug is discontinued thepatient should be monitored for increase levels and adversereactions.

Action: Monitor patients for increased or decreaseddrug effects depending on the addition or discontinua-tion of either drug. Adjust doses accordingly.

Phenobarbital/TCAs (Amitriptyline, Imipramine)Significance level 2: ModerateAdvice to Practitioner: Tricyclic antidepressants have

been reported to reduce seizure threshold resulting in pos-sible loss of seizure control. When adding a TCA to phe-nobarbital, patients should be monitored closely for loss ofseizure control. An increase in phenobarbital dose may be

necessary. If a TCA is discontinued from combination ther-apy, monitor patients for increased phenobarbital adversereactions and the need to decrease the dose of phenobarbital.In combination, additive CNS and respiratory depressanteffects are also possible, resulting in the need to adjust thedose of one or both drugs. It has been reported that pheno-barbital may stimulate the metabolism of TCA resulting indecreased serum levels of the TCA and their therapeuticeffectiveness. When adding phenobarbital to a TCA, it maybe necessary to increase the TCA dose to maintain thera-peutic levels. If phenobarbital is discontinued from combi-nation therapy, it maybe necessary to decrease the TCAdose.

Action: Monitor patients for reduced seizure control,CNS and respiratory depressant effects, and changes inTCA levels and efficacy. Dosage adjustments may benecessary.

Phenobarbital/VPASignificance level 2: ModerateAdvice to Practitioner: Concomitant administration of

phenobarbital and VPA results in the inhibition of pheno-barbital metabolism and increased serum levels of pheno-barbital. Patients should be monitored for serum levels andsigns of phenobarbital toxicity. When adding VPA to phe-nobarbital it may be necessary to decrease the phenobarbitaldose. If a patient is on the combination and VPA is discon-tinued phenobarbital levels may decrease requiring a doseadjustment.

Concurrent phenobartial and VPA therapy shortens theserum half-life of valproate due to hepatic enzyme induc-tion. This results in a 10% increase in VPA clearance.

Monitoring VPA serum concentrations should be consid-ered.

Action: Monitor patients for changes in phenobarbi-tal serum concentration when adding or discontinuingVPA. Concurrent use may also increases VPA clearance.Adjust doses accordingly.

Phenobarbital/VerapamilSignificance level 3: MinorAdvice to Practitioner: Concurrent use of oral phenobar-

bital resulted in a significant decrease in the concentrationof verapamil. A possible mechanism is the increase in firstpass hepatic metabolism of verapamil by phenobarbital. Ifphenobarbital is added to verapamil, the amounts of thelatter may need to be increased in order to maintain anoptimum effect; and, a higher dose of verapamil may berequired when it is added to a patient currently takingphenobarbital.

Action: An increase in verapamil may be required ina previously stabilized patient when phenobarital is add-ed; the verapamil dose should be adjusted (decreased)when phenobarbital is withdrawn from the combina-tion.


Phenytoin - Fosphenytoin/BenzodiazepinesSignificance level 3: MinorAdvice to Practitioner: When benzodiazepines have

been used with phenytoin, inconsistent interactions havebeen reported. Increases and decreases in phenytoin levels,as well as decreased benzodiazepine levels have been ob-served. Patients who are on phenytoin should have theirserum phenytoin levels monitored when a benzodiazepine isadded. If a patient is on a benzodiazepine and phenytoin isadded, patients should be monitored for decreases in ben-zodiazepine activity.

Action: Monitor serum phenytoin levels when addinga benzodiazepine. Monitor benzodiazepine responsewhen adding phenytoin.

Phenytoin/CarbamazepineSignificance level 2: ModerateAdvice to Practitioner: Combination of these two drugs

has complex interactions, which might lead to unpredictableeffects. If the two drugs are administered at the same time,carbamazepine levels may be reduced as a result of theenhanced cytochrome P450 enzyme induction by phenyt-oin. On the other hand, carbamazepine has variable effectson phenytoin. In one study, phenytoin levels were increasedby 81.3% in 50% of the patients when carbamazepine wasadded which resulted in acute phenytoin toxicity. In anotherstudy increased phenytoin levels in turn decreased carbam-azepine plasma concentration to subtherapeutic levels.Moreover, they also increase epoxide/parent drug ratio,which has been associated with increased teratogenicity.

Action: Avoid this combination. If this combination isnecessary both carbamazepine and phenytoin levelsneed to be monitored, even after withdrawal or additionof one or the other drugs.

Phenytoin/PhenobarbitalSignificance level 3: MinorAdvice to Practitioner: Combination of these two drugs

has variable effects on each other. The addition of pheno-barbital may increase, decrease or cause no change in phe-nytoin serum levels. Phenobarbital induces hepatic enzymesand may cause enhanced metabolism, but it also appears toinhibit phenytoin metabolism competitively when it is givenin high doses thereby resulting in phenytoin toxicity. Also,the addition of phenytoin increased the serum barbituratelevel. More studies are needed to clarify the different as-pects (dose, time course and individual variations) of theinteractions between these two drugs.

Action: Closely monitor the levels of both drugs whencombined therapy is prescribed.

Phenytoin/SSRI (Fluoxetine/Fluvoxamine/Sertraline)Significance level 2: ModerateAdvice to Practitioner: Fluoxetine, fluvoxamine, and ser-

traline significantly increase phenytoin serum levels whichcan result in toxicity (ataxia, tremor, nystagmus, nausea,

seizure) if they are prescribed for a previously stabilizedpatient. A possible mechanism is the inhibition of the cy-tochrome P450 enzyme system (3A4, 2C9, 2C19) by theSSRI’s.

Action: Monitor for phenytoin side effects, if SSRI’sare added to a regimen stable on phenytoin.

Phenytoin/TCASignificance level 2: ModerateAdvice to Practitioner: There are case reports where

TCA increased phenytoin levels and resulted in toxicity,i.e., ataxia, hypereflexia, nystagmus, tremors. Theoretically,phenytoin may increase TCA metabolism because of itsknown enzyme induction. Additional studies are needed tofurther elucidate the interaction between these two drugs.

Action: Monitor levels of both drugs when given con-currently.

Phenytoin/VPASignificance level 2: ModerateAdvice to Practitioner: The phenytoin and VPA combi-

nation has complex interactions, the ultimate result beingphenytoin toxicity and the loss of seizure control fromdecreased VPA levels. Valrpoic acid displaces phenytoinfrom the protein binding sites and also interrupts phenytoinmetabolism (by enzyme inhibition).

Action: Levels of both drugs should be monitored toobserve necessary adjustment in medication doses ifcombination therapy is employed.

Primidone/CarbamazepineSignificance level 2: ModerateAdvice to Practitioner: Concurrent use of primidone (a

prodrug that is metabolized to phenobarbital) and carbam-azepine results in decreased serum concentrations of car-bamazepine and primidone with loss of therapeutic effect(this interaction is particularly pronounced in children andadolescents). The exact mechanism of this drug interactionis unknown but most likely involves co induction of CYPisoenzymes (particularly 2C9, 2C19 and 3A4), epoxide hy-drolase (EH) and uridine diphosphate glucuronosyltrans-ferase (UDGPT) by both primidone and carbamazepine. If apatient is on the combination and stable, no action is re-quired. Caution should be used when adding either primi-done to carbamazepine or carbamazepine to primidone asthe co induction of isoenzymes, EH and UDGPT results inincreased metabolism of both drugs and loss of clinicalefficacy. This combination increases the epoxide/parentdrug ratio, and in pregnant women, the teratogenicity ofthese drugs is directly related to the levels of reactiveepoxide metabolites. Be aware that withdrawing one drugfrom the other will result in a lessening of hepatic inductionwith concomitant decrease in metabolism and greater bio-availabilty of the remaining drug.

Action: When adding either primidone to carbamaz-epine or carbamazepine to primidone observe for the


loss of clinical and therapeutic efficacy (seizure control,mood and affect stabilization). When withdrawing onedrug from the other observe for potential increases inadverse side effects including toxicity. Monitor serumconcentrations and adjust dosages accordingly. The useof this combination in pregnancy can increase the riskfor major birth defects 10 fold above background rates.

Primidone/LamotrigineSignificance level 2: ModerateAdvice to Practitioner: Addition of primidone to lam-

otrigine resulted in a 40% decrease in lamotrigine steady-state plasma concentration. The mechanism of this druginteraction is thought to be the induction of hepatic CYPisoenzymes and conjugating enzymes by primidone therebyincreasing lamotrigine metabolism and reducing its thera-peutic efficacy. Be aware that withdrawing primidone willresult in a lessening of hepatic induction with a concomitantdecrease in metabolism and greater bioavailabilty of lam-otrigine.

Action: Monitor patients for clinical efficacy or sideeffects of lamotrigine when adding or withdrawingprimidone. Examine lamotrigine plasma levels and ad-just dosages accordingly.

Primidone/VPASignificance level 2: ModerateAdvice to Practitioner: Concurrent use of primidone and

VPA results in an increase in serum concentrations of primi-done-derived phenobarbital, which may produce severecentral nervous system depression. The exact mechanism ofthis drug interaction is unknown but it is thought to besecondary to impairment of nonrenal phenobarbital clear-ance.

Action: When co-administering primidone and VPA,observe for excessive central nervous system depressionand neurological toxicity. Serum levels of primidone-derived phenobarbital should be monitored and the dos-age of primidone decreased if necessary.

Prochlorperazine/LithiumSignificance level 2: ModerateAdvice to Practitioner: Concurrent use of lithium with a

number of antipsychotic drugs has produced encephalopa-thy (at times with brain damage), EPS, dyskinesias andweakness in a number of case reports. In most of thesecases, the adverse effects occurred with therapeutic lithiumlevels. However, in clinical practice the use of lithium incombination with a neuroleptic has resulted in no seriousadverse effects in the vast majority of cases where thesecombinations were used. The mechanism of these druginteractions is not fully understood, but chronic lithiumtreatment decreases neostriatal dopaminergic activity (mostlikely by affecting G proteins and their ability to stimulateadenyl cyclase) and thereby could predispose susceptiblepatients to adverse effects.

Action: Monitor for weakness, confusion, dyskinesias,EPS and toxic encephalopathic states especially if higherdoses of lithium and the neuroleptic are given. Serumlithium levels should be monitored routinely; some cli-nicians recommend maintaining lithium levels in the lowtherapeutic range when using the combination.

Prochlorperazine/PimozideSignificance level 1: MajorAdvice to Practitioner: Concurrent use of prochlopera-

zine (and phenothiazines as a class) with pimozide is notrecommended as the additive effects on the prolongation ofthe QT interval increase the risk for torsades de pointes andcardiac arrest.

Action: Avoid concurrent use of a phenothiazine andpimozide as the risk for cardiotoxicity (QT prolonga-tion) and resulting dysrrhythmias is significant.

Quetiapine/LorazepamSignificance level 3: MinorAdvice to Practitioner: Co-administration of quetiapine

and lorazepam decreased the mean oral clearance of loraz-epam by 20% resulting in increased lorazepam serum con-centrations. The mechanism of this drug interaction is un-known. Caution should be used when adding quetiapine tolorazepam. If a patient is on the combination and stable, noaction is required. When adding lorazepam to quetiapinemonitor for the clinical efficacy of lorazepam.

Action: When co-administering quetiapine and loraz-epam, monitor patients for excessive lorazepam adverseeffects including sedation, dizziness and ataxia.

Quetiapine/ThioridazineSignificance level 3: MinorAdvice to Practitioner: Co-administration of quetiapine

and thioridazine increased the oral clearance of quetiapineby 65% resulting in decreased quetiapine serum concentra-tions. The mechanism of this drug interaction is unknown. Ifa patient is on the combination and stable, no action isrequired. Caution should be used when adding thioridazineas quetiapine efficacy can be decreased. When addingquetiapine to thioridazine monitor for the clinical affects ofquetiapine.

Action: When co-administering quetiapine and thio-ridazine, monitor patients for quetiapine efficacy. Anincrease in quetiapine dose may be necessary.

Riluzole/AmitriptylineSignificance level 3: MinorAdvice to Practitioner: Concurrent use of riluzole and

amitriptyline results in increased serum concentrations ofriluzole and possible toxicity (asthenia, nausea, dizziness,somnolence, and circumoral paresthesia). The mechanism isthought to be inhibition of CYP 1A2 isoenzyme metabolismof riluzole by amitriptyline. If the patient is stable on thecombination, no action is needed. Caution should be used


when adding amitriptyline to riluzole as increased plasmalevels of riluzole can occur. Be aware that when addingriluzole to amitriptyline a lower dose of riluzole will obtaintherapeutic efficacy.

Action: When co-administering riluzole and amitrip-tyline, monitor patients for excessive riluzole adverseeffects including toxicity (asthenia, nausea, dizziness,somnolence, and circumoral paresthesia). Be aware thata lower dose of riluzole may be clinically effective whenadding it to amitriptyline.

Riluzole/TacrineSignificance level 2: ModerateAdvice to Practitioner: Riluzole and tacrine are both

metabolized by CYP 1A2 isoenzymes, and concurrent useresults in a competitive inhibition of metabolism of bothagents resulting in increased risk of riluzole toxicity (asthe-nia, nausea, dizziness, somnolence, circumoral paresthesia)and tacrine (nausea, vomiting, diarrhea, elevations in serumtransaminases). If the patient is stable on the combination,no action is required. Caution should be used when addingeither riluzole to tacrine or tacrine to riluzole, as the com-petitive inhibition of CYP 1A2 results in increased plasmalevels of both agents.

Action: Monitor patients closely for signs and symp-toms of riluzole toxicity (asthenia, nausea, dizziness,somnolence, circumoral paresthesia and tacrine toxicity(nausea, vomiting, diarrhea, elevations in serum trans-aminases) when adding either drug to the other. Beaware that reduced clinical efficacy of one agent mayoccur when the other agent is withdrawn.

Selegiline/Monoamine Oxidase-A Inhibitors (MAOAI)(Isocarboxazid, Phenelzine, Tranylcypromine)

Significance level 1: MajorAdvice to Practitioner: Concurrent use of selegiline (a

selective MAO-B inhibitor) and a monoamine oxidase-Ainhibitor antidepressant is potentially hazardous and mayresult in synergistic pharmacologic effects leading to exces-sive monoamine oxidase inhibition causing hypertensivecrisis, fever, marked sweating, tremor, excitation, seizures,delirium, coma and circulatory collapse. This is particularlymore likely to occur if the dose of selegiline exceeds 10 mgdaily, above which dose the drug can inhibit the MAO-Aenzyme and acts as a nonselective MAO inhibitor. If thepatient is stable on the combination, no action is needed.Caution should be used however when adding selegiline toan MAO-AI or an MAO-AI to selegiline as both drugspotentiate inhibition of monoamine oxidase.

Action: Closely monitor patients for adverse effects ofsynergistic monoamine oxidase inhibition if concurrentuse is necessary. Severe adverse interactions may occur(hypertensive crisis, fever, marked sweating, tremor, ex-citation, seizures, delirium, coma and circulatory col-lapse).

Selegiline/SSRI (Citalopram, Fluoxetine, Fluvoxamine,Paroxetine, Sertraline), mixed SSRI atypicals (Nefaz-odone and Venlafaxine), and Buspirone


selective MAO-B inhibitor) and an SSRI or a serotoninaffinity antidepressant is potentially hazardous and mayresult in synergistic pharmacologic effects leading to exces-sive serotonergic stimulation causing serotonin syndrome(hypertension, hyperthermia, myoclonus and mental statuschanges). This is particularly more likely to occur if thedose of selegiline exceeds 10 mg daily, above which dosethe drug can inhibit the MAO-A enzyme and acts as anonselective MAO inhibitor. If the patient is stable on thecombination, no action is needed. Caution should be usedhowever when adding selegiline to an SSRI or an SSRI toselegiline as both drugs potentiate serotonin effects.

Action: Closely monitor patients for adverse seroto-nergic effects if concurrent use is necessary. Severe in-teractions –the serotonin syndrome could occur (hyper-tension, hyperthermia, myoclonus and mental statuschanges).

Selegiline/Tricyclic antidepressants (Amitriptyline, Clo-mipramine, Imipramine and Nortriptyline)


selective MAO-B inhibitor) and a TCA antidepressant ispotentially hazardous and may result in synergistic pharma-cologic effects leading to excessive serotonergic stimulationcausing the serotonin syndrome (hypertension, hyperther-mia, myoclonus and mental status changes). This is partic-ularly more likely to occur if the dose of selegiline exceeds10 mg daily, above which dose the drug can inhibit theMAO-A enzyme and acts as a nonselective MAO inhibitor.If the patient is stable on the combination, no action isneeded. Caution should be used however when adding sele-giline to a TCA or TCA to selegiline as both drugs poten-tiate serotonin effects.

Action: Closely monitor patients for adverse seroto-nergic effects if concurrent use is necessary. Severe in-teractions –the serotonin syndrome could occur (hyper-tension, hyperthermia, myoclonus and mental statuschanges).

Sumatriptan/SSRI (Citalopram, Fluoxetine, Fluvoxam-ine, Paroxetine, Sertraline) and mixed SSRI atypicals(Nefazodone and Venlafaxine)

Significance level 2: ModerateAdvice to Practitioner: Concurrent use of sumatriptan

and SSRI antidepressants has resulted in synergistic phar-macologic effects leading to excessive serotonergic stimu-lation causing weakness, incoordination and hypereflexia inpatients. If the patient is stable on the combination, noaction is needed. Caution should be used however when


adding sumatriptan to SSRI or SSRI to sumatriptan as bothdrugs potentiate serotonin effects.

Action: Closely monitor patients for adverse seroto-nergic effects if concurrent use is necessary. In severeinteractions serotonin syndrome (hypertension, hyper-thermia, myoclonus and mental status changes) couldoccur.

Sumatriptan/Monoamine Oxidase-A Inhibitors (MAO-AI) (Isocarboxazid, Phenelzine, Tranylcypromine)

Significance level 1: MajorAdvice to Practitioner: Monoamine oxidase is important

in the presystemic clearance of sumatriptan, particularly theA isoenzyme (MAO-A). Concurrent use of a MAO-A in-hibitor and injectable sumatriptan resulted in a 40% increasein the half-life of sumatriptan, a marked decrease insumatriptan clearance and a two-fold increase in plasmaconcentrations (in contrast MAO-B inhibitors had no effecton sumatriptan metabolism). This two-fold elevation inplasma sumatriptan increases endogenous serotonin in theCNS (and periphery), and the serotonin syndrome can oc-cur. It is believed that the above effects of MAO-A inhib-itors would be even greater with oral or nasal sumatriptanusage.

Action: Concurrent use of oral/nasal sumatriptanwith MAO-A inhibitors or within 2 weeks of discontin-uation of MAO-AI therapy is contraindicated. The useof injectable sumatriptan concurrently with a MAO-Ainhibitor is not recommended; however if clinically war-ranted, a reduced dose of sumatriptan injection shouldbe used, and the patient should be closely observed forserotonin syndrome signs and symptoms (hypertension,hyperthermia, myoclonus, and/or mental status changes).

Tacrine/FluvoxamineSignificance level 3: MinorAdvice to Practitioner: Two studies involving healthy

volunteers and using a single dose of tacrine found thatfluvoxamine inhibited the metabolism of tacrine causing anincrease in its plasma concentration and three of its metab-olites. The probable mechanism is inhibition of CYP 1A2isoenzymes by fluvoxamine.

Action: Although the exact clinical implications ofthis drug interaction are uncertain, patients receivingconcurrent tacrine and fluvoxamine should be moni-tored for excessive tacrine adverse effects (includingcholinergic effects) and liver function tests monitoredfor hepatotoxicity.

Tacrine/HaloperidolSignificance level 3: MinorAdvice to Practitioner: Concurrent use of tacrine and

haloperidol has resulted in Parkinsonian syndrome in twoseparate case reports. The mechanism is thought to be asynergistic effect of these drugs resulting in an increase inacetylcholine activity in the striatal region of the brain. The

adverse effects of akinesia, shuffling gait, masked facies,slurred speech, lead-pipe rigidity, and/or cogwheel signs arethought to be caused by this increase in acetylcholine ac-tivity. If patients are on the combination and stable, noaction is necessary. As both drugs increase acetylcholineactivity in the striatal region caution should be used whenadding either drug to the other.

Action: Monitor patients closely for the signs andsymptoms of Parkinsonian syndrome when adding ei-ther tacrine to haloperidol or haloperidol to tacrine.

Tiagabine/CarbamazepineSignificance level 2: ModerateAdvice to Practitioner: Concurrent use of tiagabine and

carbamazepine had no effects on carbamazepine plasmasteady state concentrations or its epoxide metabolite, butpharmacokinetic studies show that tiagabine clearance is60% greater resulting in decreased plasma concentration oftiagabine in patients taking both drugs. The mechanism isthought to be induction of CYP 3A isoenzyme metabolismof tiagabine by carbamazepine.

Action: Monitor patients for clinical efficacy or sideeffects of tiagabine when adding or withdrawing car-bamazepine. Monitoring tiagabine plasma levels may behelpful.

Tiagabine/PhenobarbitalSignificance level 2: ModerateAdvice to Practitioner: Concurrent use of tiagabine and

phenobarbital had no effect on plasma phenobarbital con-centrations in three well controlled studies, but pharmaco-kinetic studies show that tiagabine clearance is 60% greaterresulting in decreased plasma concentrations of tiagabine inpatients on both agents. The mechanism is thought to bephenobarbital induction of CYP 3A isoenzymes therebyincreasing the metabolism of tiagabine.

Action: Monitor patients for clinical efficacy or sideeffects of tiagabine when adding or withdrawing pheno-barbital. Monitoring tiagabine plasma levels may behelpful.

Tiagabine/VPASignificance level 3: MinorAdvice the Practitioner: Concurrent use of tiagabine and

VPA resulted in a 10% decrease in plasma steady stateconcentrations of VPA. The mechanism of this interaction isunknown, and the clinical implications probably are not thatsignificant given the broad therapeutic range (50–100 mg/mL) of VPA. In addition, concurrent use in in vitro studiesshowed decreased protein binding of tiagabine resulting in a40% increase in unbound tiagabine concentration which didin one study lead to increased tiagabine adverse effects(dizziness, lightheadedness, somnolence, nausea).

Action: Monitor patients for clinical efficacy or sideeffects of tiagabine when adding or withdrawing VPA.Assessing tiagabine plasma levels may be helpful.


Tolcapone/nonselective Monoamine Oxidase Inhibitors(Phenelzine, Tranylcypromine)

Significance level 1: MajorAdvice to Practitioner: Two of the major enzyme sys-

tems involved in the metabolism of catecholamines aremonoamine oxidase (MAO) and catechol-o-methyltransfer-aase (COMT). It is theoretically possible that the combina-tion of entacapone and a nonselective MAO inhibitor wouldcause the inhibition of normal catecholamine metabolism.This could lead to a hypertensive crisis and death.

Action: The concurrent administration of tolcaponeand a nonselective MAO inhibitor should be avoided.Tolcapone may be given with a MAO-B inhibitor, suchas selegiline, in the treatment of Parkinson’s disease.

Tolcapone/SSRI/TCASignificance level 1: MajorAdvice to Practitioner: Caution is advised if tolcapone is

administered with other drugs that affect brain monoamin-ergic (e.g., nonselective MAO inhibitors, TCA, SSRIs, oranticholinergic systems) since a symptom complex resem-bling neuroleptic malignant syndrome has been reported inpatients receiving such combinations.

Action: Use tolcapone with SSRI/TCAs cautiouslyand keep in mind the possibility of a neuroleptic malig-nant syndrome with their combined usage.

Topiramate/CarbamazepineSignificance level 1: MajorAdvice to Practitioner: In controlled, clinical pharmaco-

kinetic studies, patients with epilepsy showed a 40% de-crease in topiramate concentrations when carbamazepinewas added. Oral and nonrenal clearance is twofold to three-fold higher during concurrent carbamazepine therapy. Car-bamazepine reduces topiramate levels.

Action: If carbamazepine is added to a regimen oftopiramate, the latter’s increased clearance will have to bemonitored and the dose adjusted upward accordingly.

Topiramate/VPASignificance level 2: ModerateAdvice to Practitioner: An 11% decrease in the concen-

tration of VPA occurred when topiramate was added. How-ever, the concentration of topiramate decreased by 14%when VPA was added. Therefore, there could be a decreasein topiramate or VPA values when either is added to theother.

Action: Dosage adjustments of either or both topira-mate or VPA may be required with concomitant drugadministration. Therefore, it is necessary to monitor forseizure control and excessive adverse effects.

Trihexyphenidyl/PhenothiazinesSignificance level 3: MinorAdvice to Practitioner: Phenothiazine levels will be re-

duced in the presence of trihexyphenidyl because of reduced

oral absorption. Therefore, there is a decrease in phenothi-azine levels and decreased effectiveness when used in com-bination.

Action: Do not routinely use trihexyphenidyl as pro-phylaxis against possible EPS. Use only when EPS hasoccurred and there is evidence for its need.

VPA/LorazepamSignificance level 2: ModerateAdvice to Practitioner: VPA can significantly decrease

lorazepam clearance by 50%. This leads to lorazepamplasma concentrations that are two times higher for at least12 h after the valproate is administered. Co-administrationdoes not affect the steady state pharmacokinectics of val-proate. The mechanism of the interaction is likely to be theimpairment of hepatic glucuronidation.

Action: The dose of lorazepam should be reducedwhen prescribed with VPA.

VPA/TCASignificance level 2: ModerateAdvice to Practitioner: VPA results in the increase of

TCA levels if administered concomitantly and may produceside effects. The underlying mechanism is not determined,but it is presumed to be the inhibition of hepatic metabolismof TCA by VPA.

Action: Monitor for TCA side effects if VPA is addedto a patient stabilized on TCA. The TCA dose may needto be increased when VPA is withdrawn from the com-bination therapy.

Verapamil/Phenobarbital(See Phenobarbital/Verapamil above).

Warfarin/amobarbital, butalbital, phenobarbitalSignificance level 2: ModerateAdvice to Practitioner: Phenobarbital may increase the

metabolism of warfarin resulting in reduced warfarin activ-ity. An interaction of this type presents problems when theenzyme-altering drug is added to a previously stable patient.Interactions due to this mechanism may take a few days toweeks to become evident or dissipate, as it may take timebefore the enzyme alteration occurs or resolves. When war-farin is added to a regimen containing phenobarbital, nointervention would be required, as the dose of warfarinwould be determined by prothrombin times (PT) or inter-national normalized ratios (INR).

Action: monitor PT or INR as indicated above. Mayneed to switch to a benzodiazepine to avoid interaction.

Warfarin/CarbamazepineSignificance level 2: ModerateAdvice to Practitioner: Carbamazepine may increase the

metabolism of warfarin, resulting in reduced warfarin ac-tivity. (See warfarin/phenobarbital for additional informa-tion).


Action: Monitor PT and international normalized ra-tio (INR) as indicated. Adjust the warfarin dose asneeded.

Warfarin/ChloradiazepoxideSignificance level 2: ModerateAdvice to Practitioner: Chlordiazepoxide has been re-

ported to decrease PT times when used with warfarin (Seewarfarin/chlorpromazine for additional information).

Action: Monitor PT when adding chlordiazepoxide asrecommended above.

Warfarin/Chloral hydrateSignificance level 2: ModerateAdvice to Practitioner: Chloral hydrate may increase the

PT times when used with warfarin. The mechanism of theinteraction is unknown. When chloral hydrate is added to apreviously stable regimen of warfarin, warfarin activity maybe decreased. When warfarin is added to a regimen con-taining chloral hydrate no intervention would be required,as the dose of warfarin would be determined by PT times orINR.

Action: Monitor PT times or INR.

Warfarin/ChlorpromazineSignificance level 2: ModerateAdvice to Practitioner: Chlorpromazine has been re-

ported to decrease PT times when used with warfarin. Themechanism of this interaction is unknown. When chlor-promazine is added to a previously stable regimen of war-farin, warfarin activity may be decreased. When warfarin isadded to a regimen containing chlorpromazine, no interven-tion would be required, as the dose of warfarin would bedetermined by the PT times or INR.

Action: Monitor PT when adding chlorpromazine, asrecommended above.

Warfarin/ParoxetineSignificance level 2: ModerateAdvice to Practitioner: Use of paroxetine with warfarin

has been associated with increased bleeding, without alter-ations in the PT times. When paroxetine is added to a

previously stable regimen of warfarin, warfarin activity maybe decreased. When warfarin is added to a regimen con-taining paroxetine, no action would be required, as the doseof warfarin would be determined by PT times or INR.

Action: Use cautiously and inform the patient to beaware of increased bruisabilty. Consider an alternativeSSRI.

Warfarin/TrazodoneSignificance level 2: ModerateAdvice to Practitioner: Trazodone can decrease the PT

and INR when used with warfarin. The mechanism of thisinteraction is unknown and it is not widely reported.

Action: Monitor PT when adding trazodone to war-farin or stopping trazodone while receiving warfarin.

Warfarin/TCASignificance level 2: ModerateAdvice to Practitioner: Use of some TCAs have been

associated with increases in PT and increased bleeding. Themechanism of this interaction is unclear: reduced absorptionand decreased metabolism have been suggested. When aTCA is added to a previously stable regimen of warfarin,warfarin activity may be decreased. When warfarin is addedto a regimen containing a TCA, no intervention would berequired, as the dose of warfarin would be determined by PTtimes or INR.

Action: Monitor PT when adding a TCA as recom-mended above.

Zolmitriptan/Mono Amine Oxidase InhibitorSignificance level 1: MajorAdvice to Practitioner: A MAO-A inhibitor is suspected

of inhibiting zolmitriptan metabolism. The combination ofthese two drugs may induce cardiac toxicity (coronary ar-tery vasospasm/myocardial ischemia).

Action: Closely monitor patients for adverse seroto-nergic effects if concurrent use is necessary. In severeinteractions serotonin syndrome (hypertension, hyper-thermia, myoclonus and mental status changes) couldoccur.


Neurologic drug-psychotropic drug update

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