Drugs that interfere with the clearance of carbamazepine, clobazam, ethosuximide, felbamate,
cenobamate and tiagabine as well a many other drugs such as Plaquenil (hydroxychlorquine) Viagra, Lipitor, Propecia etc by inhibiting cytochrome P-450 3A4
The inhibition of cenobamate (and the other antiepileptic drugs noted above as well as many drugs not used to treat epilepsy) metabolism leading to higher levels that might cause untoward symptoms can be seen with the use of grapefruit, Seville oranges and carambola [Starfruit] and many drugs including:
anticonvulsants: cannabidiol [Epidiolex], remacemide [Ecovia] and stiripentol [Diacomit].
Marijuana (due primarily to cannabidiol moiety; ironically tetrahyrocannibinol is a substrate for cannabidiol such that latter prolongs the brains exposure to the former)
loratidine [Claritin]
most macrolide antibiotics (clarithromycin [Biaxin], erythromycin, troleandomycin, josamycin, flurithromycin, ponsinomycin, telithromycin; one macrolide that does not interact is azithromycin [Zithromax]); norfloxacin, ciprofloxacin; chloramphenicol
metronidazole [Flagyl];
antifungal agents: fluconazole [Diflucan}, itraconazole, ketoconazole; voriconazole [Vfend],
isoniazid [INH];
antiretroviral agents: amprenavir, indinavir, nelfinavir, ritonavir, telaprevir, boceprevir, delaviridine and saquinavir
imatinib [Gleevec]
propoxyphene [Darvon];
Calcium channel antagonists: verapamil [Calan], diltiazem [Cardizem, Dilacor], mibefradil [Posicor, taken off the market] to lesser extent amlodipine (Norvasc) weak inhibitor 3A4 in vitro
some SSRI antidepressants: in particular fluvoxamine [Luvox], also fluoxetine [Prozac], nefazodone [Serzone, off
market in US and Canada], paroxetine [Paxil] (may not be clinically significant), and to a lesser extent sertraline [Zoloft])
danazol [Danocrine used to suppress pituitary-ovarian axis in treatment of endometriosis]
cimetadine [Tagamet, over the counter], omeprazole [Prilosec]
nicotinamide
sodium diethyldithiocarbamate [chelating agent]
amiodarone
aprepitan [Emend]
glyburide (mild inhibition) [eg. DiaBeta, Glucovance, Glynase, Micronase}
gestodene [progestin] used in many oral contraceptives
mifepristone [Mifegyne, Mifeprex, RU-486], progesterone receptor antagonist atorvastatin [Lipitor] http://dmd.aspetjournals.org/content/31/1/53.short
bold: Strong inhibitor is one that causes a > 5-fold increase in the plasma AUC values or more than 80% decrease in clearance.
Underline: moderate inhibitor is one that causes a > 2-fold increase in the plasma AUC values or 50-80% decrease in clearance.
anticonvulsants: cannabidiol [Epidiolex], remacemide [Ecovia] and stiripentol [Diacomit].
Marijuana (due primarily to cannabidiol moiety; ironically tetrahyrocannibinol is a substrate for cannabidiol such that latter prolongs the brains exposure to the former)
loratidine [Claritin]
most macrolide antibiotics (clarithromycin [Biaxin], erythromycin, troleandomycin, josamycin, flurithromycin, ponsinomycin, telithromycin; one macrolide that does not interact is azithromycin [Zithromax]); norfloxacin, ciprofloxacin; chloramphenicol
metronidazole [Flagyl];
antifungal agents: fluconazole [Diflucan}, itraconazole, ketoconazole; voriconazole [Vfend],
isoniazid [INH];
antiretroviral agents: amprenavir, indinavir, nelfinavir, ritonavir, telaprevir, boceprevir, delaviridine and saquinavir
imatinib [Gleevec]
propoxyphene [Darvon];
Calcium channel antagonists: verapamil [Calan], diltiazem [Cardizem, Dilacor], mibefradil [Posicor, taken off the market] to lesser extent amlodipine (Norvasc) weak inhibitor 3A4 in vitro
some SSRI antidepressants: in particular fluvoxamine [Luvox], also fluoxetine [Prozac], nefazodone [Serzone, off
market in US and Canada], paroxetine [Paxil] (may not be clinically significant), and to a lesser extent sertraline [Zoloft])
danazol [Danocrine used to suppress pituitary-ovarian axis in treatment of endometriosis]
cimetadine [Tagamet, over the counter], omeprazole [Prilosec]
nicotinamide
sodium diethyldithiocarbamate [chelating agent]
amiodarone
aprepitan [Emend]
glyburide (mild inhibition) [eg. DiaBeta, Glucovance, Glynase, Micronase}
gestodene [progestin] used in many oral contraceptives
mifepristone [Mifegyne, Mifeprex, RU-486], progesterone receptor antagonist atorvastatin [Lipitor] http://dmd.aspetjournals.org/content/31/1/53.short
bold: Strong inhibitor is one that causes a > 5-fold increase in the plasma AUC values or more than 80% decrease in clearance.
Underline: moderate inhibitor is one that causes a > 2-fold increase in the plasma AUC values or 50-80% decrease in clearance.
Drugs that are metabolized by (substrates for) cytochrome P-450 2D6
alprenolol
amitriptyline, Elavil, tricyclic antidepressant
amphetamine
aripriprazole, Abilify
atomoxetine, Strattera (a selective norepinephrine reuptake inhibitor or NRI)
bufuradol
carvedilol, Coreg (both a beta blocker (β1, β2) and alpha blocker (α1), inhibits P-glycoprotein (P-gp), a drug efflux pump
cholpheniramine (first-generation antihistamine)
chlorpromazine, Thorazine
clomipramine, Anafranil, tricyclic antidepressant
codeine, a prodrug, converted to morphine by 2D6, thus ineffective for pain control in poor metabolizer phenotypes and
overdose potential in ultra-rapid metabolizer phenotype
debrisoquine, antihypertensive guanethidine, used for phenotyping the CYP2D6 enzyme
desipramine, Norpramin, tricyclic antidepressant, inhibits reuptake norepinephrine>>serotonin
dextromethorphan, cough suppressant, active ingredient in many over-the-counter cold and cough medicines: Mucinex DM,
Robitussin, NyQuil, Dimetapp, Vicks, Coricidin, Delsym, also used recreationally, exceeding label-specified maximum
dosages acts as a dissociative hallucinogen
dexfenfluramine, diet pill, removed from the market in 1997
diltiazem, Cardizem, Dilacor, Tiazac, calcium channel blocker
disopyramide, Norpace, Rythmodan
donepezil, Aricept, centrally acting reversible acetylcholinesterase inhibitor
duloxetine, Cymbalta
encainide, antiarrhythmic, no longer marketed
flecainide, antiarrhythmic, Tambocor,Almarytm, Apocard, Ecrinal, Flécaine
fluoxetine, Prozac
haloperidol, Haldol
hydroxychloroquine
ilperidone, Fanapt, Fanapta, Zomaril, atypical antipsychotic
imipramine, Tofranil
labetalol, Normodyne, Trandate, mixed alpha/beta adrenergic antagonist
lidocaine, Xylocaine, local anesthetic, class 1B antiarrhythmic drug
metoclopramide, Reglan
metoprolol, Lopressor, Toprol-xl, selective β1 receptor blocker
mexiletine, Mexitil, IB anti-arrhythmic
minaprine, Brantur, Cantor, antidepressant used in France, reversible inhibitor of MAO-A
mirtazapine, Remeron
nebivolol, Bystolic, β1 receptor blocker with nitric oxide-potentiating vasodilatory effect
nortriptyline, Pamelor, Aventyl, tricyclic antidepressant
oxycodone, Percocet (when combined with acetaminophen), Percodan (when combined aspirin), primary metabolic pathway N-
Demethylation via CYP 3A4 (what is unclear is whether the parent compound or like codeine the portion metabolized by 2D6 to oxymorphone results in most of the analgesia)
ondansetron, Zofran
paroxetine, Paxil
pergolide, Permax, agonist at dopamine D2, D1 and serotonin 5-HT1A, 5-HT1B, 5-HT2A, 5-HT2B, and 5-HT2C receptors
perhexiline, prophylactic antianginal agent, particularly dangerous and poor metabolizers
promethazine, Phenergan, Promethegan, Romergan, Fargan, Farganesse, Prothiazine, Avomine, Atosil, Receptozine, Lergigan,
and Sominex in the UK
phenformin, anti-diabetic drug replaced by considerably safer metformin
pimozide, Orap, diphenylbutylpiperidine class antipsychotics with risk of akathisia, tardive dyskinesia and rarely neuroleptic
malignant syndrome and prolongation of QT interval
propafenone, Rythmol SR, Rytmonorm, anti-arrhythmic him him him him him
propranolol, Inderal
risperidone, Risperdal
sertraline, Zoloft, cleared via multiple metabolic pathways thus poor metabolizers unlikely to have difficulty
tamoxifen, Nolvadex, Istubal, Valodex, like codeine this is a prodrug, it is activated primarily by 2D6 to its active metabolite,
hydroxytamoxifen, an estrogen receptor antagonist used in the treatment of breast cancer, evidence suggests that it is
not as effective in poor metabolizers
thioridazine, Mellaril
tegaserod, Zelnorm, 5-HT4 agonist, used for the management of irritable bowel syndrome and constipation common taken off
the market, still available online
timolol,timoptic, non-selective beta-adrenergic receptor blocker, used to treat blood pressure,migraine and open angle
glaucoma
tramadol, Ultram, can cause seizures but unclear which metabolite is the culprit, nevertheless should be particularly avoided
by slow metabolizers and ironically also possibly by ultra-rapid metabolizers
venlafaxine, Effexor
March 12th, 2010 FDA announces boxed warning for clopidogrel (Plavix)
Clopidogrel (Plavix) approved for use in 1997 is one of the most commonly prescribed medicines in the US. Genetic variations (polymorphisms) of an enzyme, cytochrome P450 2C19, play a role in determining how effective clopidogrel may be with respect to preventing undesirable clotting. This enzyme plays a roll in the metabolism of some anticonvulsants including clobazam, lacosamide, mephenytoin, mephobarbital, phenytoin, phenobarbital and primidone and some antidepressants, in particular citalopram and escitalopram and as well other drugs (see list below). Knowing which polymorphisms a patient inherited can be potentially useful when it comes to adjusting the dose and predicting interactions with some of these medications (see required prescribing information for clobazam and escitalopram). The evaluation of patients with epilepsy therefore at times can lead to information that is potentially helpful in other areas. For instance knowing an individuals 2C19 genotype allows one to make predictions about how they will respond to clopidogrel if it is prescribed after stenting for an acute coronary syndrome. Being an intermediate metabolizer increases the risk of developing a "stent thrombosis" by more than two and half times whereas a poor metabolizer has close to 4 times the risk. http://www.clinchem.org/content/58/1/154.full.pdf+html On the other hand an ultrarapid metabolizer is more likely to have problems with bleeding http://circ.ahajournals.org/content/121/4/512.short
Boxed warning on clopidogrel (Plavix)
•WARNING: DIMINISHED EFFECTIVENESS IN POOR METABOLIZERS
•Effectiveness of Plavix depends on activation to an active metabolite by the cytochrome P450 (CYP) system, principally CYP2C19.
•Poor metabolizers treated with Plavix at recommended doses exhibit higher cardiovascular event rates following acute coronary syndrome (ACS) or percutaneous coronary intervention (PCI) than patients with normal CYP2C19 function.
•Tests are available to identify a patient's CYP2C19 genotype and can be used as an aid in determining therapeutic strategy. •Consider alternative treatment or treatment strategies in patients identified as CYP2C19 poor metabolizers.
Boxed warning on clopidogrel (Plavix)
•WARNING: DIMINISHED EFFECTIVENESS IN POOR METABOLIZERS
•Effectiveness of Plavix depends on activation to an active metabolite by the cytochrome P450 (CYP) system, principally CYP2C19.
•Poor metabolizers treated with Plavix at recommended doses exhibit higher cardiovascular event rates following acute coronary syndrome (ACS) or percutaneous coronary intervention (PCI) than patients with normal CYP2C19 function.
•Tests are available to identify a patient's CYP2C19 genotype and can be used as an aid in determining therapeutic strategy. •Consider alternative treatment or treatment strategies in patients identified as CYP2C19 poor metabolizers.
March 3rd 2012 FDA Announces boxed warning for citalopram (Celexa)
Revised recommendations for Celexa (citalopram hydrobromide) related to a potential risk of abnormal heart rhythms with doses greater than 20 mg in patients: taking cytochrome 2C19 inhibitors or those who are 2C19 poor metabolizers, those older than 60 and those with liver disease. Risk is that there can be a dose dependent prolongation of QT interval http://www.fda.gov/drugs/drugsafety/ucm297391.htm
Revised recommendations for Celexa (citalopram hydrobromide) related to a potential risk of abnormal heart rhythms with doses greater than 20 mg in patients: taking cytochrome 2C19 inhibitors or those who are 2C19 poor metabolizers, those older than 60 and those with liver disease. Risk is that there can be a dose dependent prolongation of QT interval http://www.fda.gov/drugs/drugsafety/ucm297391.htm
Drugs that are substrates for (metabolized by) cytochrome P-450 2C19
Prodrugs, activated by 2C19:
clopidogrel*, Plavix, prodrug metabolized to its active thiol derivative (see above FDA boxed warning)
carisoprodol, Soma (popular muscle relaxant), prodrug for meprobamate, Miltown, Equanil, (rapid metabolizers have higher levels of meprobamate, formerly a sleeping pill marketed as Miltown and Equanil)
proguanil, prodrug converted to active metabolite cycloguanil, usually taken in combination with another anti-malarial drug
atovaquone making the drug Malarone (potential for drug to be less effective in slow metabolizers)
Drugs cleared by 2C19:
Anticonvulsants:
clobazam, Frisium, Onfi, Urbanyl
desmethylclobazam, active metabolite of clobazam
diazepam, Valium
lacosamide, Vimpat, primarily cleared renally
mephenytoin, Mesantoin
mephobarbital, Mebaral
phenobarbital, Luminal
phenytoin, Dilantin
primidone, Mysoline
Proton pump inhibitors:
esomeprazole, Nexium
lansoprazole, Prevacid
omeprazole, Prilosec
pantoprazole, Prontonix
rabeprazole, Aciphex, much less affected by 2C19 activity than the others http://onlinelibrary.wiley.com/doi/10.1111/j.1365-2036.2004.02161.x/full
Antidepressants:
amitriptyline, Elavil
citalopram, Celexa
clomipramine, Anafranil
escitalopram, Lexapro
imipramine, Tofranil
moclobemide, Aurorix, Manerix, reversible monoamine oxidase inhibitor (MAOI)
sertraline (Zoloft)
Other drugs:
chloramphenicol
cyclophosphamide, Cytoxan
indomethacin, Indocin
nelfinavir, Viracept
nilutamide Nilandron, Anandron, antiandrogen used to treat prostate cancer
progesterone
propranolol, Inderal
teniposide Vumon, VM-26, chemotherapeutic agent
warfarin (R), Coumadin
*see FDA Boxed Warning for Plavix above. Controversial but slow metabolizers of clopidogrel are probably better served by either increasing dose http://jama.jamanetwork.com/article.aspx?articleid=1104664 or using alternate treatment particularly if they are taking medications that inhibit other enzymes (3A4, 2B6, 1A2) that metabolize clopidogrel http://www.sciencedirect.com/science/article/pii/S0140673612601615
Ultrarapid metabolizers of clopidogrel who develop bleeding problems may also need to change treatments http://circ.ahajournals.org/content/121/4/512.short
clopidogrel*, Plavix, prodrug metabolized to its active thiol derivative (see above FDA boxed warning)
carisoprodol, Soma (popular muscle relaxant), prodrug for meprobamate, Miltown, Equanil, (rapid metabolizers have higher levels of meprobamate, formerly a sleeping pill marketed as Miltown and Equanil)
proguanil, prodrug converted to active metabolite cycloguanil, usually taken in combination with another anti-malarial drug
atovaquone making the drug Malarone (potential for drug to be less effective in slow metabolizers)
Drugs cleared by 2C19:
Anticonvulsants:
clobazam, Frisium, Onfi, Urbanyl
desmethylclobazam, active metabolite of clobazam
diazepam, Valium
lacosamide, Vimpat, primarily cleared renally
mephenytoin, Mesantoin
mephobarbital, Mebaral
phenobarbital, Luminal
phenytoin, Dilantin
primidone, Mysoline
Proton pump inhibitors:
esomeprazole, Nexium
lansoprazole, Prevacid
omeprazole, Prilosec
pantoprazole, Prontonix
rabeprazole, Aciphex, much less affected by 2C19 activity than the others http://onlinelibrary.wiley.com/doi/10.1111/j.1365-2036.2004.02161.x/full
Antidepressants:
amitriptyline, Elavil
citalopram, Celexa
clomipramine, Anafranil
escitalopram, Lexapro
imipramine, Tofranil
moclobemide, Aurorix, Manerix, reversible monoamine oxidase inhibitor (MAOI)
sertraline (Zoloft)
Other drugs:
chloramphenicol
cyclophosphamide, Cytoxan
indomethacin, Indocin
nelfinavir, Viracept
nilutamide Nilandron, Anandron, antiandrogen used to treat prostate cancer
progesterone
propranolol, Inderal
teniposide Vumon, VM-26, chemotherapeutic agent
warfarin (R), Coumadin
*see FDA Boxed Warning for Plavix above. Controversial but slow metabolizers of clopidogrel are probably better served by either increasing dose http://jama.jamanetwork.com/article.aspx?articleid=1104664 or using alternate treatment particularly if they are taking medications that inhibit other enzymes (3A4, 2B6, 1A2) that metabolize clopidogrel http://www.sciencedirect.com/science/article/pii/S0140673612601615
Ultrarapid metabolizers of clopidogrel who develop bleeding problems may also need to change treatments http://circ.ahajournals.org/content/121/4/512.short
Drugs that may interfere with (inhibit) the metabolism of drugs handled by 2C19
Anticonvulsants:
cannabidiol (Epidiolex)
cenobamate (Xcopri)
eslicarbazepine acetate (Aptiom, in Europe called Zebinix)
felbamate (Felbatol)
oxcarbazepine, Trileptal
topiramate, Topamax
Of interest is that five of these antconvulsants (all except Epidiolex which also inhibits cytochrome P-450 3A4 and 1A2) have the opposite effect (induction) on cytochrome P450 3A4 and tend to lower the levels of any substance which is a substrate for (metabolized by) 3A4. A mnemonic for remembering these four (using their brand names) is FAT² (Felbamate, Aptiom, Topamax, Trileptal)
On some websites valproate, valproic acid, Depakote, Depakene is mentioned as inhibiting 2C19 but there is no evidence that it does though it does inhibit 2C9 (the enzyme that metabolizes drugs in the NSIAD family such as Motrin, Advil, Alleve etc) http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2014611/)
Other drugs that inhibit 2C19
Strong inhibitors: chloramphenicol, fluvoxamine, moclobemide
Proton pump inhibitors: lansoprazole, omeprazole, pantoprazole, rabeprazole
Other drugs: cimetidine, clopidogrel http://jcp.sagepub.com/content/49/5/574.short etravirine (reported interaction with clobazamhttp://www.ntkinstitute.org/news/content.nsf/PaperFrameSet?OpenForm&pp=1&id=F0AEE4F167E103588525773D0070651C&refid=3914&specid=59&newsid=852571020057CCF685257A690029996A&locref=ntkwatch&u=http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=22293514, fluoxetine, indomethacin, ketoconazole, modafinil, probenecid, ticlopidine
cannabidiol (Epidiolex)
cenobamate (Xcopri)
eslicarbazepine acetate (Aptiom, in Europe called Zebinix)
felbamate (Felbatol)
oxcarbazepine, Trileptal
topiramate, Topamax
Of interest is that five of these antconvulsants (all except Epidiolex which also inhibits cytochrome P-450 3A4 and 1A2) have the opposite effect (induction) on cytochrome P450 3A4 and tend to lower the levels of any substance which is a substrate for (metabolized by) 3A4. A mnemonic for remembering these four (using their brand names) is FAT² (Felbamate, Aptiom, Topamax, Trileptal)
On some websites valproate, valproic acid, Depakote, Depakene is mentioned as inhibiting 2C19 but there is no evidence that it does though it does inhibit 2C9 (the enzyme that metabolizes drugs in the NSIAD family such as Motrin, Advil, Alleve etc) http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2014611/)
Other drugs that inhibit 2C19
Strong inhibitors: chloramphenicol, fluvoxamine, moclobemide
Proton pump inhibitors: lansoprazole, omeprazole, pantoprazole, rabeprazole
Other drugs: cimetidine, clopidogrel http://jcp.sagepub.com/content/49/5/574.short etravirine (reported interaction with clobazamhttp://www.ntkinstitute.org/news/content.nsf/PaperFrameSet?OpenForm&pp=1&id=F0AEE4F167E103588525773D0070651C&refid=3914&specid=59&newsid=852571020057CCF685257A690029996A&locref=ntkwatch&u=http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=22293514, fluoxetine, indomethacin, ketoconazole, modafinil, probenecid, ticlopidine
Drugs that may increase (induce) the metabolism of drugs handled by 2C19
Carbamazepine (Tegretol), rifampicin (treatment of TB), artemisinin (treatment of malaria), norethisterone (part of several birth control pills) and prednisone. Phenobarbital, phenytoin and primidone induce some members of the cytochrome P-450 subfamily 2C but whether polypeptide 19, ie 2C19 is one of these has not been well studied.
Obtaining clobazam (Onfi) and desmethylclobazam levels
Though clobazam (Frisium, Onfi, Ubanyl) was first marketed abroad in the 1970s it has only been available in pharmacies in the United States since January 1st 2012. The usefulness of levels has yet to be fully determined. As is the case with a few other anticonvulsants (oxcarbazepine, primidone) it has an active metabolite (desmethylclobazam) which itself is an anticonvulsant. Not all laboratories (e.g. Quest) measure this level, though LabCorp does. If level is being done at local hospital ask which lab they use for send outs. Many will do the metabolite as well as parent compound:
In New Jersey:
Chilton Memorial Hospital, Pompton Plains
Holy Name hospital, Teaneck
Newton medical center, Newton
Valley Hospital, Ridgewood
Overlook Hospital, Summit
In NYC:
Lenox Hill Hospital
In Connecticut:
Stamford Hospital
Obtaining cannabidiol (Epidiolex) levels +/- other cannabinoids including tetrahydrocannabinol
Lab Corp:
Obtaining brivaracetam (Briviact) levels
NMS laboratories or any hospital that uses NMS as a reference laboratory including the Mayo Clinic or any hospital that uses the Mayo Clinic as their reference laboratory.
In New Jersey:
Chilton Memorial Hospital, Pompton Plains
Holy Name hospital, Teaneck
Newton medical center, Newton
Valley Hospital, Ridgewood
Overlook Hospital, Summit
In NYC:
Lenox Hill Hospital
In Connecticut:
Stamford Hospital
Obtaining cannabidiol (Epidiolex) levels +/- other cannabinoids including tetrahydrocannabinol
Lab Corp:
Obtaining brivaracetam (Briviact) levels
NMS laboratories or any hospital that uses NMS as a reference laboratory including the Mayo Clinic or any hospital that uses the Mayo Clinic as their reference laboratory.