chapter
Antiepileptics
Pages 19

Be aware and monitor levels. Watch for early features of phenytoin toxicity

CARBAMAZEPINE 1. ?ETHOSUXIMIDE 2. LAMOTRIGINE 3. TIAGABINE 4. TOPIRAMATE 5. VALPROATE 6. ZONISAMIDE

↓ levels of these antiepileptics Induction of metabolism Watch for poor response to these antiepileptics

CARBAMAZEPINE PHENYTOIN Variable effect on phenytoin levels. ↓ carbamazepine levels

Mutual induction of metabolism; uncertain why cases of ≠ phenytoin levels

Be aware and monitor levels. Watch for early features of phenytoin toxicity

ETHOSUXIMIDE PHENYTOIN Cases of ≠ phenytoin levels Uncertain Watch for early features of phenytoin toxicity

N ER

V O

U SSY

STEM D

R U

G S

A N

TIEPILEPTIC S

Mechanism Precautions

toxicity 2. Case of toxicity with oxcarbazepine

Uncertain Be aware; watch for early features of toxicity of carbamazepine and oxcarbazepine

OXCARBAZEPINE 1. BARBITURATES – phenobarbital 2. PHENYTOIN

≠ levels of these antiepileptics Uncertain Watch for early features of toxicity

OXCARBAZEPINE CARBAMAZEPINE Variable effect on carbamazepine levels

Uncertain Be aware; monitor carbamazepine levels

PHENYTOIN 1. LAMOTRIGINE 2. TIAGABINE 3. TOPIRAMATE 4. VALPROATE 5. ZONISAMIDE

↓ levels of these antiepileptics. Topiramate sometimes ≠ phenytoin levels

Induction of metabolism. Uncertain why phenytoin alters topiramate levels

Watch for poor response to these antiepileptics

VALPROATE 1. BARBITURATES – phenobarbital, primidone 2. ?ETHOSUXIMIDE 3. LAMOTRIGINE

≠ levels of these antiepileptics Uncertain Watch for early features of toxicity. Measure levels where possible

VALPROATE PHENYTOIN Variable effect on phenytoin levels Uncertain Be aware and monitor levels. Watch for early features of phenytoin toxicity

VIGABATRIN 1. BARBITURATES – phenobarbital, primidone 2. PHENYTOIN

↓ levels of these antiepileptics Possibly induction of metabolism Watch for poor response to these antiepileptics

INTERACTIONS WITH DRUGS THAT LOWER SEIZURE THRESHOLD

ANTIEPILEPTICS 1. ANTIMALARIALS – chloroquine, mefloquine 2. ANTIDEPRESSANTS – MAOIs, SSRIs, TCAs 3. ANTIPSYCHOTICS

≠ risk of seizures These drugs lower seizure threshold

Care with co-administration. Watch for ≠ fit frequency; warn patient of this risk when starting these drugs and take suitable precautions. Consider increasing dose of antiepileptic

N ER

V O

U SSY

STEM D

R U

G S

A N

TIEPILEPTIC S211

NERVOUS SYSTEM DRUGS ANTIEPILEPTICS Barbiturates

BARBITURATES 1. ANTIARRHYTHMICS – disopyramide, propafenone 2. ANTIBIOTICS – chloramphenicol, doxycycline, metronidazole, rifampicin, telithromycin 3. ANTICANCER AND IMMUNOMODULATING DRUGS – carmustine, ciclosporin, corticosteroids, doxorubicin, etoposide, imatinib, lomustine, paclitaxel, tacrolimus, tamoxifen, toremifene, vinca alkaloids 4. ANTICOAGULANTS – ORAL 5. ANTIDEPRESSANTS – mianserin, paroxetine 6. ANTIDIABETIC DRUGS – repaglinide, sulphonylureas 7. ANTIEMETICS – aprepitant 5-HT3-antagonists 8. ANTIFUNGALS – fluconazole, itraconazole, ketoconazole, voriconazole 9. ANTIPSYCHOTICS – apiprazole, chlorpromazine, haloperidol 10. BETA-BLOCKERS – metoprolol, propanolol, timolol 11. BRONCHODILATORS – montelukast, theophylline 12. CARDIAC GLYCOSIDES – digitoxin 13. CALCIUM CHANNEL BLOCKERS – felodipine, nifedipine, nimodipine, nisoldipine, verapamil 14. DIURETICS – eplerenone 15. 5-HT1 AGONISTS – almotriptan, eletriptan 16. GESTRINONE 17. OESTROGENS 18. PROGESTOGENS 19. THYROID HORMONES – levothyroxine

↓ levels of these drugs with risk of therapeutic failure. The ↓ anticoagulant effect of warfarin reaches a maximum after 3 weeks and can last up to 6 weeks after stopping barbiturates

Induction of hepatic metabolism

1. Avoid co-administration of barbiturates with carmustine, eplerenone, etoposide, griseofulvin, imatinib, lomustine, tacrolimus, tamoxifen; consider alternative non-enzyme-inducing antiepileptics. Avoid co-administration of telithromycin for up to 2 weeks after stopping phenobarbital 2. With the other drugs, monitor for ↓ clinical efficacy and ≠ their dose as required (a) Monitor ciclosporin levels (b) With anticoagulants, monitor INR carefully. Dose of anticoagulant may need to be ≠ by up to 60% (c) With antidiabetic drugs, monitor capillary blood glucose and warn patients about symptoms of hyperglycaemia (d) Beta-blockers, calcium channel blockers and digitoxin – monitor PR and BP weekly until stable and watch for ≠ BP (e) Levothyroxine – monitor TFTs regularly (f) May need to ≠ dose of theophylline by 25% (g) With oestrogens and progestogens, advise patients to use additional contraception for period of intake and for 1 month after stopping co-administration with these drugs ➣ For signs and symptoms of hyperglycaemia, see Clinical Features of Some Adverse Drug Interactions, Hyperglycaemia

N ER

V O

U SSY

STEM D

R U

G S

A N

TIEPILEPTIC S

Mechanism Precautions

Additive sedative effect Warn patients about this effect BARBITURATES ANAESTHETICS – LOCAL –

PROCAINE SOLUTIONS Precipitation of drugs, which may not be immediately apparent

Pharmaceutical interaction Do not mix in the same infusion or syringe

BARBITURATES ANALGESICS – OPIOIDS 1. Barbiturates ≠ sedative effects of opioids 2. ↓ efficacy of fentanyl and methadone with phenobarbital and primidone

1. Additive sedative effect. 2. ≠ hepatic metabolism of fentanyl and methadone

1. Monitor respiratory rate and conscious levels 2. Be aware that the dose of fentanyl and methadone may need to ≠

BARBITURATES ANTICANCER AND IMMUNOMODULATING DRUGS

BARBITURATES IFOSFAMIDE ≠ rate of biotransformation to 4-hydroxyifosfamide, the active metabolite, but no change in AUC of 4-hydroxyifosfamide

Due to ≠ rate of metabolism and of clearance resulting from induction of CYP3A4 and CYP2D6

Be aware – clinical significance may be minimal or none

BARBITURATES PROCARBAZINE ≠ risk of hypersensitivity reactions in patients with brain tumours

Strong correlation between therapeutic antiepileptic level and hypersensitivity reactions

Consider using non-enzyme-inducing agents

BARBITURATES ANTIDEMENTIA DRUGS – MEMANTINE

Possible ↓ efficacy of primidone Uncertain Avoid co-administration

BARBITURATES ANTIDEPRESSANTS

BARBITURATES MAOIs – PHENELZINE Reports of prolonged hypnotic effects

Animal experiments showed that pretreatment with tranylcypromine prolonged amobarbital-induced hypnotic effects 2.5-fold. Inhibition of hepatic enzymes other than MAO has been proposed as an explanation for the exaggerated depressant effects associated with barbiturates and opioids

Be aware. Warn patients taking sleeping aids about activities requiring attention and co-ordination (e.g. driving or using machinery)

BARBITURATES ST JOHN’S WORT ↓ barbiturate levels ≠ metabolism Avoid co-administration

N ER

V O

U SSY

STEM D

R U

G S

A N

TIEPILEPTIC S213

NERVOUS SYSTEM DRUGS ANTIEPILEPTICS Barbiturates

BARBITURATES FLUCONAZOLE, ITRACONAZOLE, KETOCONAZOLE, VORICONAZOLE

↓ azole levels with risk of therapeutic failure

Barbiturates induce CYP3A4, which metabolizes itraconazole and the active metabolite of itraconazole. Primidone is metabolized to phenobarbitone

Watch for inadequate therapeutic effects and ≠ dose of azole if effect due to interaction

BARBITURATES MICONAZOLE ≠ phenobarbital levels Inhibition of metabolism Be aware; watch for early features of toxicity (e.g. ≠ sedation)

BARBITURATES OTHER ANTIFUNGALS – GRISEOFULVIN

↓ griseofulvin levels ↓ absorption Although the effect of ↓ plasma concentrations on therapeutic effect has not been established, concurrent use is preferably avoided

BARBITURATES ANXIOLYTICS AND HYPNOTICS

BARBITURATES BZDs – clonazepam ↓ barbiturate levels Induction of metabolism Watch for poor response to barbiturates

BARBITURATES SODIUM OXYBATE Risk of CNS depression – coma, respiratory depression

Additive depression of CNS Avoid co-administration. Caution even with relatively non-sedating antihistamines (cetrizine, desloratidine, fexofenadine, levocetirizine, loratidine, mizolastine) as they can impair performance of skilled tasks

N ER

V O

U SSY

STEM D

R U

G S

A N

TIEPILEPTIC S

Mechanism Precautions Additive hypotensive effect;

anxiolytics and hypnotics can cause postural ↓ BP

Watch for ↓ BP; monitor BP at least weekly until stable. Warn patients to report symptoms of hypotension (light-headedness, dizziness on standing, etc.)

PHENOBARBITONE CNS STIMULANTS – MODAFINIL

1. ↓ plasma concentrations of modafinil with possibility of ↓ therapeutic effect 2. May cause moderate≠ in plasma concentrations of phenobarbitone and primidone

1. Induction of CYP3A4, which has a partial role in the metabolism of modafinil 2. Modafinil is a reversible inhibitor of CYP2C19 when used in therapeutic doses

1 and 2. Be aware

BARBITURATES DIURETICS – CARBONIC ANHYDRASE INHIBITORS

Risk of osteomalacia Barbiturates have a small risk of causing osteomalacia; this may be ≠ by acetazolamide-induced urinary excretion of calcium

Be aware

BARBITURATES FOLIC ACID ↓ levels of these antiepileptics Uncertain; postulated that induction of CYP enzymes by these antiepileptics depletes folate reserves. Replacement of these reserves ≠ formation of CYP further, which ≠ metabolism of the antiepileptics

Watch for poor response to these antiepileptics and ≠ doses as necessary

BARBITURATES LOFEXIDINE ≠ sedation Additive effect Warn patients of risk of excessive sedation

BARBITURATES TIBOLONE ↓ tibolone levels Induction of metabolism of tibolone

Watch for poor response to tibolone; consider increasing its dose

BARBITURATES VITAMIN B6 ↓ plasma concentrations of these antiepileptics

Uncertain Watch for poor response to these antiepileptics if large doses of vitamin B6 are given

N ER

V O

U SSY

STEM D

R U

G S

A N

TIEPILEPTIC S215

NERVOUS SYSTEM DRUGS ANTIEPILEPTICS Carbamazepine

CARBAMAZEPINE 1. ANALGESICS – parecoxib, fentanyl, methadone, tramadol 2. ANTIBIOTICS – doxycycline, telithromycin 3. ANTICANCER AND IMMUNOMODULATING DRUGS – ciclosporin, corticosteroids, imatinib, irinotecan, paclitaxel, tamoxifen, toremifene, vinca alkaloids 4. ANTICOAGULANTS – ORAL 5. ANTIDEPRESSANTS – mirtazapine 6. ANTIDIABETIC DRUGS – glipizide, repaglinide 7. ANTIEMETICS – aprepitant, ondansetron 8. ANTIFUNGALS – itraconazole, ketoconazole, posaconazole, voriconazole, caspofungin 9. ANTIPROTOZOALS – mebendazole 10. ANTIPSYCHOTICS – apiprazole, clozapine, haloperidol, olanzapine, quetiapine, risperidone, sertindole 11. ANXIOLYTICS AND HYPNOTICS – zaleplon, zolpidem, zopiclone 12. BRONCHODILATORS – theophylline 13. CALCIUM CHANNEL BLOCKERS – felodipine, nifedipine, and possibly nimodipine and nisoldipine 14. CARDIAC GLYCOSIDES – digitoxin 15. DIURETICS – eplerenone 16. 5-HT1 AGONISTS almotriptan, eletriptan 17. GESTRINONE 18. OESTROGENS 19. PROGESTOGENS 20. THYROID HORMONES – levothyroxine

1. ↓ levels of these drugs with risk of therapeutic failure 2. Azoles also ≠ carbamazepine levels 3. Risk of serotonin syndrome with almotriptan and eletriptan

1. Induction of hepatic metabolism 2. Inhibition of P-gp ≠ bioavailability of carbamazepine 3. Triptans and carbamazepine are both stimulants of 5-HT receptors, and carbamazepine also prevents reuptake of 5-HT

1. Avoid co-administration of carbamazepine with azoles (consider using fluconazole), eplerenone, irinotecan (if not able to avoid, ≠ dose of irinotecan by 50%) or tamoxifen. Avoid co-administration of telithromycin for up to 2 weeks after stopping carbamazepine 2. With the other drugs, monitor for ↓ clinical efficacy and ≠ their dose as required (a) Monitor ciclosporin levels (b) With anticoagulants, monitor INR at least weekly until stable; dose of anticoagulant may need to be ≠ (c) With antidiabetic drugs, monitor capillary blood glucose and warn patients about symptoms of hyperglycaemia (d) Calcium channel blockers and digitoxin – monitor PR and BP weekly until stable and watch for ≠ BP (e) Levothyroxine – monitor TFTs regularly (f) ≠ dose of caspofungin to 70 mg daily (g) Be aware of the possibility of the occurrence of serotonin syndrome with 5-HT1 agonists (h) May need to ≠ dose of theophylline by 25% (i) With oestrogens and progestogens, advise patients to use additional contraception for period of intake and for 1 month after stopping co-administration with these drugs ➣ For signs and symptoms of hyperglycaemia, see Clinical Features of Some Adverse Drug Interactions, Hyperglycaemia

N ER

V O

U SSY

STEM D

R U

G S

A N

TIEPILEPTIC S

Mechanism Precautions

1. ≠ hepatic metabolism of fentanyl and methadone, and possibly an effect at the opioid receptor 2. ≠ metabolism of tramadol

1. Be aware that the dose of fentanyl and methadone may need to be ≠ 2. Watch for poor effect of tramadol. Consider using an alternative opioid

CARBAMAZEPINE ANTIBIOTICS

CARBAMAZEPINE ISONIAZID ≠ carbamazepine levels Inhibition of metabolism Monitor carbamazepine levels CARBAMAZEPINE MACROLIDES –

CLARITHROMYCIN, ERYTHROMYCIN, TELITHROMYCIN, ISONIAZID

≠ carbamazepine levels Inhibition of metabolism Monitor carbamazepine levels

CARBAMAZEPINE RIFABUTIN ↓ carbamazepine levels Induction of metabolism Monitor carbamazepine levels CARBAMAZEPINE ANTICANCER AND IMMUNOMODULATING DRUGS

CARBAMAZEPINE PLATINUM COMPOUNDS ↓ plasma concentrations of antiepileptic, which ≠ risk of seizures

Due to impaired absorption of antiepileptic

Monitor closely for seizure activity, and warn patient and carers. Need to adjust dosage using parameters such as blood levels to ensure therapeutic levels

CARBAMAZEPINE PROCARBAZINE ≠ risk of hypersensitivity reactions in patients with brain tumours

Strong correlation between therapeutic antiepileptic level and hypersensitivity reactions

Consider using non-enzyme-inducing agents

CARBAMAZEPINE ANTIDEPRESSANTS

CARBAMAZEPINE LITHIUM ≠ risk of neurotoxicity Uncertain; this may occur with normal lithium blood levels

Warn patient and carers to watch for drowsiness, ataxia and tremor

CARBAMAZEPINE ST JOHN’S WORT ↓ carbamazepine levels Induction of metabolism Avoid co-administration CARBAMAZEPINE SSRIs Risk of serotonin syndrome with

carbamazepine Carbamazepine ≠ serotonin concentrations in the brain

Avoid co-administration

N ER

V O

U SSY

STEM D

R U

G S

A N

TIEPILEPTIC S217

NERVOUS SYSTEM DRUGS ANTIEPILEPTICS Carbamazepine

concentrations of mianserin

1. Additive effects 2. ≠ metabolism of mianserin

1. Avoid concurrent use during chemotherapy 2. Be aware and watch for signs of ↓ antidepressant effect of mianserin

CARBAMAZEPINE ANTIFUNGALS – ITRACONAZOLE, KETOCONAZOLE, MICONAZOLE, POSACONAZOLE, VORICONAZOLE

↓ plasma concentrations of itraconazole and of its active metabolite, ketoconazole, posaconazole and voriconazole, with risk of therapeutic failure. ≠ carbamazepine plasma concentrations

These azoles are highly lipophilic, and clearance is heavily dependent upon metabolism by CYP isoenzymes. Carbamazepine is a powerful inducer of CYP3A4 and other CYP isoenzymes (CYP2C18/19, CYP1A2), and the result is very low or undetectable plasma levels. Inhibition of P-gp ≠ bioavailability of carbamazepine

Avoid co-administration of posaconazole or voriconazole with carbamazepine. Watch for inadequate therapeutic effects, and ≠ dose of itraconazole. Higher doses of itraconazole may not overcome this interaction. Consider use of the less lipophilic fluconazole, which is less dependent on CYP metabolism. Necessary to monitor carbamazepine levels

CARBAMAZEPINE ANTIGOUT DRUGS – ALLOPURINOL

High-dose allopurinol (600 mg/day) may ≠ carbamazepine levels over a period of several weeks. 300 mg/ day allopurinol does not seem to have this effect

Uncertain Monitor carbamazepine levels in patients taking long-term, high-dose allopurinol

CARBAMAZEPINE ANTIVIRALS

CARBAMAZEPINE NNRTIs Possible ↓ efficacy of carbamazepine

Uncertain Monitor carbamazepine levels and side-effects when initiating or changing treatment

CARBAMAZEPINE PROTEASE INHIBITORS Possibly ≠ adverse effects of carbamazepine with protease inhibitors

Inhibition of CYP3A4-mediated metabolism of carbamazepine

Use with caution. Monitor carbamazepine levels and side-effects when initiating or changing treatment

N ER

V O

U SSY

STEM D

R U

G S

A N

TIEPILEPTIC S

Mechanism Precautions

clonazepam

Induction of metabolism Watch for poor response to carbamazepine

CARBAMAZEPINE CALCIUM CHANNEL BLOCKERS

Diltiazem and verapamil ≠ plasma concentrations of carbamazepine (have been cases of toxicity)

Diltiazem and verapamil inhibit CYP3A4-mediated metabolism of carbamazepine. They also inhibit intestinal P-gp, which may ≠ bioavailability of carbamazepine

Monitor carbamazepine levels when initiating calcium channel blockers, particularly diltiazem/verapamil

CARBAMAZEPINE CNS STIMULANTS – MODAFINIL

↓ plasma concentrations of modafinil, with possibility of ↓ therapeutic effect

Induction of CYP3A4, which has a partial role in the metabolism of modafinil

Be aware

CARBAMAZEPINE DANAZOL ≠ plasma concentrations of carbamazepine, with risk of toxic effects

Inhibition of carbamazepine metabolism

Watch for toxic effects of carbamazepine

CARBAMAZEPINE GRAPEFRUIT JUICE ≠ efficacy and ≠ adverse effects Grapefruit juice irreversibly inhibits intestinal CYP3A4. Transport via P-gp and the MRP-2 efflux pumps is also inhibited

Monitor for ≠ side-effects/toxicity and check carbamazepine levels. If levels or control of fits are variable remove grapefruit juice and grapefruit from the diet

CARBAMAZEPINE H2 RECEPTOR BLOCKERS – CIMETIDINE, FAMOTIDINE, RANITIDINE

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

Inhibition of metabolism via CYP2C9 and CYP2C19

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

CARBAMAZEPINE LIPID-LOWERING DRUGS – FIBRATES

Gemfibrozil may ≠ carbamazepine levels

Uncertain at present Watch for features of carbamazepine toxicity

N ER

V O

U SSY

STEM D

R U

G S

A N

TIEPILEPTIC S219

NERVOUS SYSTEM DRUGS ANTIEPILEPTICS Oxcarbazepine

Unclear; possibly via ↓ clearance Use with caution. Monitor carbamazepine levels when starting or stopping and use proton pump inhibitor regularly not PRN. Not reported with pantoprazole or rabeprazole

CARBAMAZEPINE TIBOLONE ↓ tibolone levels Induction of metabolism of tibolone

Watch for poor response to tibolone; consider increasing its dose

ETHOSUXIMIDE

ETHOSUXIMIDE ANTIBIOTICS – ISONIAZID Case of ≠ ethosuximide levels with toxicity

Inhibition of metabolism Watch for early features of ethosuximide toxicity

GABAPENTIN

GABAPENTIN ANTACIDS ↓ gabapentin levels ↓ absorption Separate doses by at least 3 hours LAMOTRIGINE

LAMOTRIGINE 1. ANTIBIOTICS – rifampicin 2. OESTROGENS 3. PROGESTOGENS

↓ lamotrigine levels ≠ metabolism Monitor levels

OXCARBAZEPINE

OXCARBAZEPINE OESTROGENS Marked ↓ contraceptive effect Induction of metabolism of oestrogens

Advise patients to use additional contraception for period of intake and for 1 month after stopping co-administration

OXCARBAZEPINE PROGESTOGENS ↓ progesterone levels, which may lead to failure of contraception or poor response to treatment of menorrhagia

Possibly induction of metabolism of progestogens

Advise patients to use additional contraception for period of intake and for 1 month after stopping co-administration

N ER

V O

U SSY

STEM D

R U

G S

A N

TIEPILEPTIC S

Mechanism Precautions

PHENYTOIN 1. ANALGESICS – parecoxib, fentanyl, methadone 2. ANTIARRHYTHMICS – amiodarone, disopyramide, mexiletine 3. ANTIBIOTICS – doxycycline, telithromycin 4. ANTICANCER AND IMMUNOMODULATING DRUGS – busulfan, ciclosporin, corticosteroids, etoposide, ifosfamide, imatinib, irinotecan, paclitaxel, tacrolimus, tamoxifen, topotecan, toremifene, vinca alkaloids 5. ANTICOAGULANTS – ORAL 6. ANTIDEPRESSANTS – mirtazapine, TCAs 7. ANTIDIABETIC DRUGS – repaglinide 8. ANTIEMETICS – aprepitant, ondansetron 9. ANTIFUNGALS – itraconazole, ketoconazole, posaconazole, voriconazole, caspofungin 10. ANTIPROTOZOALS – mebendazole 11. ANTIPSYCHOTICS – apiprazole, clozapine, quetiapine, sertindole 12. ANXIOLYTICS AND HYPNOTICS – zaleplon, zolpidem, zopiclone 13. BETA-BLOCKERS – propanolol 14. BRONCHODILATORS – theophylline 15. CALCIUM CHANNEL BLOCKERS – diltiazem, felodipine, nisoldipine, verapamil, possibly nimodipine 16. CARDIAC GLYCOSIDES – digitoxin, digoxin 17. 5-HT1 AGONISTS – almotriptan, eletriptan 18. GESTRINONE 19. OESTROGENS 20. PROGESTOGENS

1. ↓ levels of these drugs, with risk of therapeutic failure 2. Report of ≠ phenytoin levels with celecoxib, mianserin, diltiazem and possibly nifedipine and isradipine 3. Phenytoin levels may be ↓ by amiodarone and theophylline

1. Induction of hepatic metabolism 2. Inhibition of phenytoin metabolism (parecoxib – CYP2C9; calcium channel blockers – CYP3A4; mianserin – unknown) 3. Uncertain; amiodarone inhibits CYP2C9, which plays a role in phenytoin metabolism and inhibits intestinal P-gp, which may ≠ bioavailability of phenytoin. Theophylline ↓ absorption of phenytoin

1. Avoid co-administration of phenytoin with azoles (consider using fluconazole), etoposide, irinotecan (if not able to avoid, ≠ dose of irinotecan by 50%), tacrolimus, tamoxifen. Avoid co-administration of telithromycin for up to 2 weeks after stopping phenytoin 2. With the other drugs, monitor for ↓ clinical efficacy and ≠ their dose as required (a) Monitor ciclosporin levels (b) With anticoagulants, monitor INR at least weekly until stable; dose of anticoagulant may need to be ≠ (c) With antidiabetic drugs, monitor capillary blood glucose and warn patients about symptoms of hyperglycaemia (d) Antiarrhythmics, beta-blockers, calcium channel blockers and cardiac glycosides – monitor PR and BP weekly until stable, and watch for ≠ BP (e) ≠ dose of caspofungin to 70 mg daily (f) May need to ≠ dose of theophylline by 25% (g) With oestrogens and progestogens, advise patients to use additional contraception for period of intake and for 1 month after stopping co-administration with these drugs 3. Monitor phenytoin levels when co-administered with amiodarone, diltiazem, isradipine, mianserin, nifedipine, parecoxib or theophylline ➣ For signs and symptoms of hyperglycaemia, see Clinical Features of Some Adverse Drug Interactions, Hyperglycaemia

N ER

V O

U SSY

STEM D

R U

G S

A N

TIEPILEPTIC S221

NERVOUS SYSTEM DRUGS ANTIEPILEPTICS Phenytoin/fosphenytoin

A pharmaceutical interaction Do not mix in the same infusion or syringe

PHENYTOIN ANALGESICS – OPIOIDS 1. ↓ efficacy of fentanyl and methadone 2. Risk of pethidine toxicity

1. ≠ hepatic metabolism of fentanyl and methadone, and possibly an effect at the opioid receptor 2. Phenytoin induces metabolism of pethidine, which causes ≠ levels of a neurotoxic metabolite

1. Be aware that the dose of fentanyl and methadone may need to be ≠ 2. Co-administer with caution; the effect may be ↓ by administering pethidine intravenously

PHENYTOIN ANTACIDS ↓ phenytoin levels ↓ absorption Separate doses by at least 3 hours PHENYTOIN ANTIARRHYTHMICS –

AMIODARONE Phenytoin levels may be ≠ by amiodarone; conversely, amiodarone levels may be ↓ by phenytoin

Uncertain; amiodarone inhibits CYP2C9, which plays a role in phenytoin metabolism, while phenytoin is a known hepatic enzyme inducer. Also, amiodarone inhibits intestinal P-gp, which may ≠ bioavailability of phenytoin

↓ phenytoin dose by 25-30% and monitor levels; watch for amiodarone toxicity. Note that phenytoin and amiodarone share similar features of toxicity, such as arrhythmias and ataxia

PHENYTOIN ANTIBIOTICS

PHENYTOIN CHLORAMPHENICOL, CLARITHROMYCIN, ISONIAZID, METRONIDAZOLE, SULPHONAMIDES, TRIMETHOPRIM

≠ phenytoin levels Inhibited metabolism Monitor phenytoin levels

PHENYTOIN CIPROFLOXACIN Variable effect on phenytoin levels Unknown Monitor phenytoin levels

PHENYTOIN RIFAMPICIN, RIFABUTIN ↓ phenytoin levels Induced metabolism Monitor phenytoin levels

N ER

V O

U SSY

STEM D

R U

G S

A N

TIEPILEPTIC S

Mechanism Precautions

with high-dose and long-term use of methotrexate. Likely ↓ in phenytoin levels and ≠ risk of folic acid deficiency. High-dose and long-term therapy with methotrexate ≠ risk of liver injury with other potentially hepatotoxic drugs. Additive antifolate effects. Cytotoxics in general ↓ absorption of phenytoin

High doses of methotrexate ↓ elimination of phenytoin and risk of folic acid deficiency

Monitor phenytoin levels and clinically watch for signs and symptoms of phenytoin toxicity, e.g. nausea, vomiting, insomnia, tremor, acne and hirsutism

PHENYTOIN PLATINUM COMPOUNDS ↓ phenytoin levels with risk of seizures

Impaired absorption of antiepileptic

Monitor closely for seizure activity, and warn patients and carers. Need to adjust dosage using parameters such as blood levels to ensure therapeutic levels

PHENYTOIN PROCARBAZINE ≠ risk of hypersensitivity reactions in patients with brain tumours

Strong correlation between therapeutic antiepileptic level and hypersensitivity reactions

Consider using non-enzyme-inducing agents

PHENYTOIN ANTIDEPRESSANTS

PHENYTOIN LITHIUM ≠ risk of neurotoxicity Uncertain; this may occur with normal lithium blood levels

Warn patients and carers to watch for drowsiness, ataxia and tremor

CARBAMAZEPINE ST JOHN’S WORT ↓ phenytoin levels Induction of metabolism Avoid co-administration PHENYTOIN SSRIs ≠ phenytoin levels Phenytoin is a substrate of

CYP2C9 and CYP2C19. SSRIs are known to inhibit CYP2C9/10

Monitor plasma phenytoin levels

PHENYTOIN ANTIDIABETIC DRUGS – METFORMIN, SULPHONYLUREAS

↓ hypoglycaemic efficacy Hydantoins are considered to ↓ release of insulin

Monitor capillary blood glucose closely; higher doses of antidiabetic drugs needed

N ER

V O

U SSY

STEM D

R U

G S

A N

TIEPILEPTIC S223

NERVOUS SYSTEM DRUGS ANTIEPILEPTICS Phenytoin/fosphenytoin

posaconazole and voriconazole, with risk of therapeutic failure. ≠ phenytoin levels but clinical significance uncertain

These azoles are highly lipophilic, and clearance is heavily dependent upon metabolism by CYP isoenzymes. Phenytoin is a powerful inducer of CYP3A4 and other CYP isoenzymes (CYP2C18/19, CYP1A2), and the result is very low or undetectable plasma levels. Phenytoin extensively ↓ AUC of itraconazole by more than 90%

Watch for inadequate therapeutic effects and ≠ dose of itraconazole. Higher doses of itraconazole may not overcome this interaction. Consider use of the less lipophilic fluconazole, which is less dependent on CYP metabolism. Necessary to monitor phenytoin levels

PHENYTOIN ANTIGOUT DRUGS – ALLOPURINOL, SULFINPYRAZONE

Phenytoin levels may be ≠ in some patients

Uncertain Monitor phenytoin levels

PHENYTOIN ANTIMALARIALS – PYRIMETHAMINE

1. ↓ efficacy of phenytoin 2. ≠ antifolate effect

1. Uncertain 2. Additive effect 1. Care with co-administration; ≠ dose of antiepileptic if ≠ incidence of fits 2. Monitor FBC closely; the effect may take a number of weeks to occur

PHENYTOIN ANTIPARKINSON’S DRUGS – LEVODOPA

Possibly ↓ levodopa levels Uncertain Watch for poor response to levodopa and consider increasing its dose

PHENYTOIN ANTIPLATELET AGENTS – ASPIRIN

Possible ≠ phenytoin levels Possibly ≠ unbound phenytoin fraction in the blood

Monitor phenytoin levels when co-administering high-dose aspirin

PHENYTOIN ANTIPROTOZOALS – LEVAMISOLE

Possible ≠ phenytoin levels Uncertain; case report of this interaction when levamisole and fluorouracil were co-administered with phenytoin

Monitor phenytoin levels and ↓ phenytoin dose as necessary

N ER

V O

U SSY

STEM D

R U

G S

A N

TIEPILEPTIC S

Mechanism Precautions

TRANSCRIPASE INHIBITORS – DIDANOSINE, STAVUDINE, ZIDOVUDINE

≠ peripheral neuropathy) with didanosine, stavudine and zidovudine

Additive effect Monitor closely for peripheral neuropathy during prolonged combination

PHENYTOIN PROTEASE INHIBITORS Possibly ↓ efficacy of phenytoin, with a risk of fits when coadministered with indinavir, nelfinavir and ritonavir (with or without lopinavir)

Uncertain; ↓ plasma levels of phenytoin

Use with caution. Monitor phenytoin levels weekly. Adjust doses at 7-10day intervals. Maximum suggested dose adjustment each time is 25 mg

PHENYTOIN ACICLOVIR/VALACICLOVIR ↓ efficacy of phenytoin Unclear Warn patients and monitor seizure frequency

PHENYTOIN ANXIOLYTICS AND HYPNOTICS – BZDs – clonazepam

↓ phenytoin levels Induction of metabolism Watch for poor response to phenytoin

PHENYTOIN CNS STIMULANTS – MODAFINIL

May ↓ modafinil levels Induction of CYP3A4, which has a partial role in the metabolism of modafinil

Be aware

PHENYTOIN DIURETICS

PHENYTOIN CARBONIC ANHYDRASE INHIBITORS

Risk of osteomalacia Phenytoin is associated with a small risk of causing osteomalacia; this may be ≠ by acetazolamideinduced urinary excretion of calcium

Be aware

PHENYTOIN LOOP DIURETICS – FUROSEMIDE

↓ efficacy of furosemide Uncertain Be aware; watch for poor response to furosemide

PHENYTOIN DRUG DEPENDENCE THERAPIES – DISULFIRAM

≠ phenytoin levels Inhibited metabolism Monitor phenytoin levels closely

N ER

V O

U SSY

STEM D

R U

G S

A N

TIEPILEPTIC S225

NERVOUS SYSTEM DRUGS ANTIEPILEPTICS Phenytoin/fosphenytoin

Uncertain; postulated that induction of CYP enzymes by these antiepileptics depletes folate reserves. Replacement of these reserves ≠ formation of CYP further, which ≠ metabolism of the antiepileptics

Watch for poor response to phenytoin and ≠ dose as necessary

PHENYTOIN H2 RECEPTOR BLOCKERS – CIMETIDINE, FAMOTIDINE, RANITIDINE

≠ phenytoin levels with risk of adverse effects

Inhibition of metabolism via CYP2C9 and CYP2C19

Use alternative acid suppression (e.g. ranitidine) or warn patients that effects last about 1 week

PHENYTOIN PROTON PUMP INHIBITORS Possible ≠ efficacy and adverse effects of phenytoin

Unclear; possible altered metabolism via CYP2C19

↓ dose may be required. Use the proton pump inhibitor regularly, not PRN; monitor phenytoin levels when starting or stopping treatment. Patients have received omeprazole for 3 weeks without altered phenytoin levels. Effect not reported with pantoprazole or rabeprazole

PHENYTOIN SUCRALFATE ↓ phenytoin levels ↓ absorption of phenytoin Give phenytoin at least 2 hours after sucralfate

PHENYTOIN TIBOLONE ↓ tibolone levels Induction of metabolism of tibolone

Watch for poor response to tibolone; consider ≠ its dose

PHENYTOIN VASODILATOR ANTIHYPERTENSIVES

Co-administration of diazoxide and phenytoin ↓ phenytoin levels and possibly ↓ efficacy of diazoxide

Uncertain at present Monitor phenytoin levels and BP closely

PHENYTOIN VITAMIN B6 ↓ phenytoin levels Uncertain Watch for poor response to phenytoin if large doses of vitamin B6 are given

PHENYTOIN VITAMIN D ↓ efficacy of vitamin D Uncertain Be aware; consider increasing dose of vitamin D

N ER

V O

U SSY

STEM D

R U

G S

A N

TIEPILEPTIC S

Mechanism Precautions

Additive sedative effect Warn patients about this effect TOPIRAMATE ANTICANCER AND

IMMUNOMODULATING DRUGS – IMATINIB

≠ topiramate levels Imatinib is a potent inhibitor of CYP2C9-mediated metabolism of topiramate

Watch for the early features of toxicity. If necessary, consider using alternative drugs while the patient is being given imatinib

TOPIRAMATE ANTIDIABETIC DRUGS – METFORMIN

≠ metformin levels Unknown mechanism Watch for and warn patients about hypoglycaemia ➣ For signs and symptoms of hypoglycaemia, see Clinical Features of Some Adverse Drug Interactions, Hypoglycaemia

TOPIRAMATE OESTROGENS Marked ↓ contraceptive effect Induction of metabolism of oestrogens

Advise patients to use additional contraception for period of intake and for 1 month after stopping coadministration with topiramate

TOPIRAMATE PROGESTOGENS ↓ progesterone levels, which may lead to failure of contraception or poor response to treatment of menorrhagia

Possibly induction of metabolism of progestogens

Advise patients to use additional contraception for period of intake and for 1 month after stopping coadministration with topiramate

VALPROATE

VALPROATE ANTIBIOTICS

VALPROATE ERTAPENEM, MEROPENEM ↓ valproate levels Induced metabolism Monitor levels VALPROATE ERYTHROMYCIN ≠ valproate levels Inhibited metabolism Monitor levels

N ER

V O

U SSY

STEM D

R U

G S

A N

TIEPILEPTIC S227

NERVOUS SYSTEM DRUGS ANTIEPILEPTICS Valproate

seizures

Impaired absorption of valproate Monitor for seizure activity closely, and warn patients and carers. Monitor valproate levels

VALPROATE PROCARBAZINE ≠ risk of hypersensitivity reactions in patients with brain tumours

Strong correlation between therapeutic antiepileptic level and hypersensitivity reactions

Consider using non-enzyme-inducing agents

VALPROATE ANTIDEPRESSANTS – TCAs ≠ amitriptyline and nortriptyline levels

Uncertain Be aware; watch for clinical features of ≠ levels of these TCAs (e.g. sedation, dry mouth, etc.)

VALPROATE ANTIDIABETIC DRUGS – ACARBOSE

Case of ↓ valproate levels Uncertain Monitor valproate levels

VALPROATE ANTIPLATELET AGENTS – ASPIRIN

Possible ≠ levels of phenytoin and valproate

Possibly ≠ unbound phenytoin or valproate fraction in the blood

Monitor phenytoin or valproate levels when co-administering high-dose aspirin

VALPROATE ANTIPSYCHOTICS – OLANZAPINE

Risk of bone marrow toxicity Additive effect Monitor FBC closely; warn patients to report sore throat, fever, etc.