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Interactions with Valproic acid

Contents
Metoprolol, Pindolol, Prazosin, Timolol, Benztropine, Bupropion (oral), Buspirone, Chlorpheniramine, Diphenhydramine, Fentanyl topical, Fluphenazine, Hydromorphone (oral), Metoclopramide, Morphine, Oxycodone, Pentobarbital, Prochlorperazine, Secobarbital, Terazosin, Thioridazine (oral), Thiothixene, Trazodone, Doxazosin, Clemastine, Tripelennamine, Brompheniramine, Promethazine (oral), Cyproheptadine, Azatadine, Phenindamine, Levorphanol, Oxymorphone, Perphenazine, Thiethylperazine, Meclizine, Trimethobenzamide, Dronabinol, Sertraline, Phenelzine, Tranylcypromine, Mesoridazine, Trifluoperazine, Molindone, Loxapine, Pimozide (oral), Hydroxyzine, Zolpidem, Mephobarbital, Carisoprodol, Chlorphenesin, Chlorzoxazone, Cyclobenzaprine, Metaxalone, Methocarbamol, Orphenadrine, Baclofen, Dantrolene, Procyclidine, Trihexyphenidyl, Biperiden, Apraclonidine ophthalmic, Paroxetine, Venlafaxine (oral), Fluvoxamine, Carvedilol, Chloral hydrate, Chloral hydrate rectal, Fentanyl (buccal), Fentanyl citrate (oral transmucosal), Hydromorphone (injection), Hydromorphone (rectal), Meprobamate, Triprolidine, Promethazine (rectal), Promethazine (injection), Buprenorphine (oral), Buprenorphine (injection), Maprotiline, Isocarboxazid, Flavoxate, Mirtazapine, Pramipexole (oral), Ropinirole (oral), Quetiapine, Butorphanol, Sibutramine (oral), Tolcapone, Thalidomide, Citalopram (oral), St. John's wort, Zaleplon, Entacapone, Nabilone, Ziprasidone, Alfuzosin, Escitalopram, Aripiprazole, Duloxetine, Eszopiclone, Ziconotide, Pregabalin, Rotigotine (transdermal), Paliperidone

If you are currently being treated with any of the following medications, you should not use Valproic acid without reading these interactions.

Lamotrigine

ADJUST DOSE: Coadministration with valproic acid has been shown to significantly increase the plasma concentrations of lamotrigine and the risk of potentially serious and life-threatening rash induced by lamotrigine, including Stevens-Johnson syndrome and toxic epidermal necrolysis. Severe, disabling tremors and ataxia have also been reported. The mechanism is competitive inhibition of lamotrigine glucuronidation by valproic acid. Pharmacokinetic data indicate that valproic acid can more than double the elimination half-life of lamotrigine, whether given with or without enzyme-inducing antiepileptic drugs (EIAEDs) such as carbamazepine, phenytoin, and phenobarbital. In a study of eight patients treated with lamotrigine, half of whom also received EIAEDs, valproic acid 200 mg/day and 1000 mg/day (each for 3 weeks) increased the dose-corrected area under the plasma concentration-time curve (AUC) of lamotrigine by an average of 84% and 160%, respectively. Corresponding lamotrigine half-life increased by an average of 37% and 150%. Additive or synergistic pharmacodynamic effects may also contribute to the interaction, which some investigators suggest is responsible in some patients for enhanced antiepileptic efficacy beyond that attained from mere increases in plasma lamotrigine levels. Lamotrigine appears to have negligible to minor effects on the pharmacokinetics of valproic acid.

MANAGEMENT: When coadministered with valproic acid, the dosage of lamotrigine should be half that required in the absence of valproic acid. Patients should be advised to promptly notify their physician if they experience early manifestations of hypersensitivity such as fever, angioedema, and lymphadenopathy, even if a rash is not evident. Lamotrigine should be discontinued if an alternative etiology for these symptoms cannot be established. Likewise, the drug should be discontinued at the first sign of rash, unless the rash is clearly not drug-related.

Felbamate

ADJUST DOSE: Felbamate may increase steady-state plasma concentrations of valproate by decreasing its plasma clearance.

MANAGEMENT: When combination therapy involving felbamate and valproic acid or its derivatives is initiated, valproate dosage generally should be decreased 20% to 30%. Lower felbamate dosages may also be required. Close observation for clinical and laboratory evidence of altered effects is indicated, especially when changing the dose or discontinuing felbamate. Patients should be advised to report possible symptoms of valproate toxicity to their physician, including nausea, confusion, irritability, nervousness, restlessness, tremor, insomnia, headache, or somnolence.

Cholestyramine

ADJUST DOSING INTERVAL: Cholestyramine may interfere with the gastrointestinal absorption of valproic acid reducing serum concentrations, bioavailability and therapeutic effect of valproic acid.

MANAGEMENT: Valproic acid should be administered at least 3 hours before or 3 hours after a dose of cholestyramine. Patients should be monitored for clinical and laboratory evidence of altered valproate efficacy and the dose adjusted, if necessary.

Lanthanum carbonate

ADJUST DOSING INTERVAL: Theoretically, lanthanum carbonate may chelate with certain drugs in the gastrointestinal tract, resulting in reduced oral bioavailability of those drugs during coadministration. However, an in vitro study involving digoxin, enalapril, furosemide, metoprolol, phenytoin, and warfarin found no evidence that lanthanum carbonate forms insoluble complexes with these drugs in simulated gastric fluid. Studies in healthy subjects have also found no effect of lanthanum carbonate (1000 mg for 4 doses) on the absorption of a single dose of digoxin (0.5 mg), metoprolol (100 mg), or warfarin (10 mg).

MANAGEMENT: To minimize the potential for interaction, the product labeling recommends that drugs known to interact with antacids (e.g., ACE inhibitors, beta blockers, bisphosphonates, coumarin derivatives, digitalis glycosides, fluoroquinolones, iron, phenytoin, rifampin, tetracyclines, thyroid preparations, valproic acid) not be taken within 2 hours of administration of lanthanum carbonate.

Temozolomide (oral)

Administration of temozolomide with valproic acid decreases the clearance of temozolomide by about 5%. The clinical implication of this effect is unknown. The patient should be observed for increased adverse effects if these drugs are given concomitantly.

Cimetidine

Cimetidine may inhibit the hepatic metabolism of valproate. Reductions in valproate clearance of 2% to 17% have been reported. The clinical significance of this interaction is unknown. The interaction may be most significant in patients with serum valproic acid levels near the upper limit of the therapeutic range.

Evening primrose

Evening primrose oil contains gamolenic acid which lowers the seizure threshold, which may theoretically offset the beneficial effects of anticonvulsants. However, data have been conflicting and an interaction has not been clearly established. The possibility of an interaction should be considered if loss of seizure control occurs in patients taking anticonvulsants and evening primrose oil.

Apomorphine

GENERALLY AVOID: Central nervous system (CNS) depressant effects may be additively or synergistically increased in patients using apomorphine in combination with other drugs that can also cause these effects. Apomorphine alone has been frequently associated with somnolence and dizziness. Patients may suddenly fall asleep during activities of daily living.

MANAGEMENT: The use of other sedating drugs should generally be avoided during apomorphine treatment. Patients prescribed these agents concurrently should be monitored for potentially excessive or prolonged CNS depression, especially if they are elderly or debilitated. Ambulatory patients should be made aware of the possibility of additive CNS effects (e.g., drowsiness, dizziness, lightheadedness, confusion) and counseled to avoid activities requiring mental alertness until they know how these agents affect them. If patients experience increased episodes of falling asleep during normal daily activities, they should avoid driving and other potentially hazardous activities until they have contacted their physician.

Charcoal

GENERALLY AVOID: Charcoal may reduce the absorption of many drugs and can absorb enterohepatically circulated drugs. Clinical utility may be the reduction either of the effects or of the toxicity of many drugs. Activated charcoal may absorb any therapeutic agents administered while it is in the gastrointestinal tract.

MANAGEMENT: The regular ingestion of charcoal should be avoided by patients requiring maintenance medications. If concomitant use is necessary, the dosage or route of administration may need to be altered.

Naltrexone (oral), Naltrexone (injection)

GENERALLY AVOID: Coadministration of naltrexone with other agents known to induce hepatotoxicity may potentiate the risk of liver injury. Naltrexone, especially in larger than recommended doses (more than 50 mg/day), has been associated with hepatocellular injury, hepatitis, and elevations in liver transaminases and bilirubin.

MANAGEMENT: Concomitant use is generally not recommended unless the potential benefit outweighs the risk of hepatotoxicity. Periodic monitoring of hepatic function is advisable.

Mefloquine

GENERALLY AVOID: Mefloquine may increase the risk of seizures and decrease the effectiveness of anticonvulsant drugs in patients with epilepsy. The mechanism is unknown, and it is unclear whether the seizures occur due to drug-drug or drug-disease interactions, as mefloquine alone and in combination with other related drugs (e.g., quinine, quinidine, chloroquine) have also been associated with seizures in some patients. It has been proposed that mefloquine may reduce the plasma levels of certain anticonvulsants such as sodium valproate, phenobarbital, carbamazepine, and phenytoin.

MANAGEMENT: Because it can increase the risk of seizures in patients with epilepsy, mefloquine should only be used for curative treatment of malaria in such patients and only if there are compelling medical reasons for its use. Patient clinical status and anticonvulsant blood levels should be closely monitored if mefloquine is prescribed. Dosage adjustments may be required. Patients should be advised to notify their physician if they experience a loss of seizure control. Mefloquine should not be prescribed for malaria prophylaxis in patients with a history of convulsions.

Diazepam, Lorazepam, Alprazolam, Chlordiazepoxide, Clorazepate, Flurazepam, Temazepam, Triazolam, Halazepam, Estazolam, Quazepam, Diazepam rectal

GENERALLY AVOID: One case series has suggested that benzodiazepines may amplify the teratogenic effects of valproate in the offspring of epileptic women. Both drugs individually have been associated with adverse effects to the fetus. Another study has suggested that valproate may displace diazepam from plasma protein binding sites and inhibit its metabolism; however, the clinical significance has not been established. Other benzodiazepines may interact with valproate in a similar fashion.

MANAGEMENT: Both valproate and benzodiazepines should be avoided during pregnancy unless the potential benefits outweigh the risks to the fetus. In other patients, close observation for clinical evidence of benzodiazepine toxicity (excessive sedation) is recommended if valproate and a benzodiazepine must be used together.

Clofarabine

GENERALLY AVOID: Since the liver is a known target organ for clofarabine toxicity (i.e., hepatomegaly, jaundice), concomitant use of agents known to induce hepatotoxicity may potentiate the risk of liver injury.

MANAGEMENT: The use of clofarabine with other agents that are potentially hepatotoxic (e.g., alcohol; androgens and anabolic steroids; antituberculous agents; azole antifungal agents; ACE inhibitors; anticonvulsants such as carbamazepine, hydantoins, felbamate, and valproic acid; lipid-lowering medications such as fenofibrate, HMG-CoA reductase inhibitors, and niacin; nucleoside reverse transcriptase inhibitors; thiazolidinediones) should be avoided if possible.

Sodium oxybate

GENERALLY AVOID: The central nervous system (CNS)- and respiratory-depressant effects of sodium oxybate may be potentiated by other agents with CNS-depressant effects.

MANAGEMENT: Agents with CNS depressant effects should be avoided during sodium oxybate therapy.

Ginkgo

Ginkgo toxin (found in both the Ginkgo leaf and seed) is a known neurotoxin. Some investigators have concluded that the amount of toxin is too low to exert a detrimental effect. However, avoiding use of Ginkgo in known epileptics has been recommended because the Ginkgo toxin that is present may diminish the effectiveness of anticonvulsant medications.

Fluoxetine

Individual case reports suggest that fluoxetine may increase valproate levels, perhaps by inhibiting the hepatic metabolism of valproate. Another study of two patients suggests that valproate may enhance the therapeutic effects of fluoxetine. The mechanism is unknown. Patients should be monitored for altered pharmacologic effects and increased valproic acid levels if these drugs are administered concomitantly.

Calcium carbonate, Aluminum hydroxide, Aluminum carbonate, Magnesium hydroxide, Magnesium oxide

Limited data suggest that concurrent administration of antacids may increase the bioavailability of valproic acid. The mechanism of interaction is unknown. In seven healthy volunteers, coadministration of a single 500 mg dose of valproic acid one hour after breakfast and an antacid containing aluminum-magnesium hydroxide (dose equal to 160 mEq of neutralizing capacity) one and three hours after meals and at bedtime on the same day resulted in a mean 12% increase (range 3% to 28%) in the total area under the concentration-time curve (AUC) of valproic acid compared to administration alone. These changes are unlikely to be of clinical importance, and no special precautions appear to be necessary. Equivalent doses of antacids containing either aluminum hydroxide-magnesium trisilicate or calcium carbonate also increased the AUC of valproic acid, but the differences were not statistically significant.

Medroxyprogesterone, Estradiol oral, Estradiol transdermal, Conjugated estrogens, Esterified estrogens, Estropipate, Chlorotrianisene, Medroxyprogesterone (injectable), Estradiol topical (for use on skin), Estradiol vaginal (systemic), Estradiol injection, Progesterone, Progesterone vaginal, Norethindrone, Levonorgestrel, Levonorgestrel emergency contraceptive, Megestrol, Estradiol (topical), Estradiol vaginal (local), Conjugated estrogens (vaginal), Etonogestrel (implant)

MONITOR: A case report suggests that estrogens or progestins may decrease the serum concentrations and pharmacologic effects of valproic acid (VPA). The proposed mechanism is induction of hepatic glucuronidation by sex hormones. The case report involves a 26-year-old woman with a history of epilepsy since childhood. Petite mal seizures developed at age seven, which were treated with ethosuximide for approximately 2 years. She was seizure-free from age nine and did not require medication until age 13, when she had her first generalized convulsive seizure that corresponded with her first menstrual cycle. She continued to have one or two episodes each year under treatment with a variety of anticonvulsants, but had her last generalized convulsion at age 23 while taking VPA. Subsequently, she developed partial seizures that began around the time she was started on an oral contraceptive containing ethynodiol 1 mg and ethinyl estradiol 35 mcg. The patient's seizure charting indicated that her partial seizures occurred more frequently during the weeks she was taking active contraceptive pills than the weeks when she took the inactive pills. Specifically, over a 5-month period, she had 12 seizures during 105 days of active pill use and none during 35 days of inactive pill use. In two separate cycles, morning trough serum VPA level during the third week of active pill use was 39% and 64% of that between days 5 and 7 of inactive pill use. Conversely, VPA reportedly has no effects on the pharmacokinetics of contraceptive steroids. In one study, VPA given at a dosage of 200 mg twice daily for 2 months did not significantly affect the systemic exposure (AUC) of ethinyl estradiol or levonorgestrel in six women.

MANAGEMENT: Pharmacologic response and serum valproic levels should be monitored more closely whenever estrogen- and/or progestin-containing drugs are added to or withdrawn from therapy, and the valproic acid dosage adjusted as necessary. Patients should be advised to contact their physician if they experience loss of seizure control or symptoms of valproic acid toxicity such as tremors, ataxia, nystagmus, increased seizures, and changes in mental status. In patients receiving oral contraceptives, gradual transient increases in valproic acid levels will likely occur during the pill-free week for women not also taking an enzyme-inducing drug (e.g., carbamazepine, phenytoin, phenobarbital, primidone, rifampin). The increase in valproic acid levels will be greater if the dose of valproic acid is increased in the few days before or during the pill-free week.

Clarithromycin, Troleandomycin

MONITOR: A single case has been reported in which a patient developed seizures associated with elevated blood valproate levels after erythromycin was added to a stable valproate regimen. The seizures and elevated valproate levels resolved after both drugs were withheld. The patient subsequently tolerated her usual valproate dosage. The mechanism is suspected to be inhibition of the hepatic metabolism of valproate.

MANAGEMENT: While more data are needed, clinicians are encouraged to be aware that this interaction is possible when macrolide antimicrobial agents and valproate are coadministered. Patients should be advised to notify their physicians if they experience weakness, fatigue, confusion, ataxia, increased seizures, nausea, or vomiting.

Clonazepam

MONITOR: A single study has suggested that combination therapy with clonazepam and valproic acid may cause severe drowsiness and decreased seizure control. Other studies have not supported this finding. Several case reports have suggested that the combination of clonazepam and valproic acid may precipitate absence status; however, this combination has had beneficial effects in the treatment refractory absence seizures. The mechanism and causality have not been determined.

MANAGEMENT: Monitoring for altered efficacy and safety is recommended if valproic acid (or its derivatives) and clonazepam are used together. Alternative therapy may be appropriate if significant side effects or loss of seizure control occur.

Modafinil

MONITOR: Based on in vitro inhibition data, coadministration with modafinil may increase the plasma concentrations of drugs that are substrates of the CYP450 2C9 and/or 2C19 isoenzymes. The mechanism is decreased clearance due to inhibition of CYP450 2C9/2C19 activities by modafinil. Pharmacologic response to these drugs may be altered, particularly if they have a narrow therapeutic range. For example, modafinil was implicated in a case of clozapine toxicity, characterized by dizziness, ataxia, and tachycardia. Clozapine serum levels increased from 761 ng/mL to 1400 ng/mL several weeks after concurrent modafinil therapy was initiated.

MANAGEMENT: Patients should be monitored for altered efficacy and safety whenever modafinil is added to or withdrawn from therapy. Dosage adjustments may be required if an interaction is suspected.

Metoprolol, Pindolol, Prazosin, Timolol, Benztropine, Bupropion (oral), Buspirone, Chlorpheniramine, Diphenhydramine, Fentanyl topical, Fluphenazine, Hydromorphone (oral), Metoclopramide, Morphine, Oxycodone, Pentobarbital, Prochlorperazine, Secobarbital, Terazosin, Thioridazine (oral), Thiothixene, Trazodone, Doxazosin, Clemastine, Tripelennamine, Brompheniramine, Promethazine (oral), Cyproheptadine, Azatadine, Phenindamine, Levorphanol, Oxymorphone, Perphenazine, Thiethylperazine, Meclizine, Trimethobenzamide, Dronabinol, Sertraline, Phenelzine, Tranylcypromine, Mesoridazine, Trifluoperazine, Molindone, Loxapine, Pimozide (oral), Hydroxyzine, Zolpidem, Mephobarbital, Carisoprodol, Chlorphenesin, Chlorzoxazone, Cyclobenzaprine, Metaxalone, Methocarbamol, Orphenadrine, Baclofen, Dantrolene, Procyclidine, Trihexyphenidyl, Biperiden, Apraclonidine ophthalmic, Paroxetine, Venlafaxine (oral), Fluvoxamine, Carvedilol, Chloral hydrate, Chloral hydrate rectal, Fentanyl (buccal), Fentanyl citrate (oral transmucosal), Hydromorphone (injection), Hydromorphone (rectal), Meprobamate, Triprolidine, Promethazine (rectal), Promethazine (injection), Buprenorphine (oral), Buprenorphine (injection), Maprotiline, Isocarboxazid, Flavoxate, Mirtazapine, Pramipexole (oral), Ropinirole (oral), Quetiapine, Butorphanol, Sibutramine (oral), Tolcapone, Thalidomide, Citalopram (oral), St. John's wort, Zaleplon, Entacapone, Nabilone, Ziprasidone, Alfuzosin, Escitalopram, Aripiprazole, Duloxetine, Eszopiclone, Ziconotide, Pregabalin, Rotigotine (transdermal), Paliperidone

MONITOR: Central nervous system- and/or respiratory-depressant effects may be additively or synergistically increased in patients taking multiple drugs that cause these effects, especially in elderly or debilitated patients.

MANAGEMENT: During concomitant use of these drugs, patients should be monitored for potentially excessive or prolonged CNS and respiratory depression. Ambulatory patients should be counseled to avoid hazardous activities requiring complete mental alertness and motor coordination until they know how these agents affect them, and to notify their physician if they experience excessive or prolonged CNS effects that interfere with their normal activities.

Brimonidine ophthalmic

MONITOR: Central nervous system (CNS) depressant effects may be additively or synergistically increased in patients using brimonidine ophthalmic solution in combination with other drugs that can also cause these effects, especially in elderly or debilitated patients.

MANAGEMENT: Patients prescribed brimonidine ophthalmic drops with other agents that can cause CNS depression should be made aware of the possibility of additive CNS effects (e.g., drowsiness, dizziness, lightheadedness, confusion) and counseled to avoid activities requiring mental alertness until they know how these agents affect them. Patients should be advised to contact their physician if they experience excessive or prolonged CNS depression.

Propoxyphene

MONITOR CLOSELY: Sedatives, tranquilizers, muscle relaxants, antidepressants, and other central nervous system (CNS) depressants may have additive CNS- and/or respiratory-depressant effects with propoxyphene. Misuse of propoxyphene, either alone or in combination with other CNS depressants, has been a major cause of drug-related deaths, particularly in patients with a history of emotional disturbances, suicidal ideation, or alcohol and drug abuse. In a large Canadian study, propoxyphene use was also associated with a 60% increased risk of hip fracture in the elderly, and the risk was further increased by concomitant use of psychotropic agents (sedatives, antidepressants, neuroleptics), presumably due to additive psychomotor impairment. Therefore, these drugs may constitute a dangerous combination in certain susceptible populations. Pharmacokinetically, propoxyphene is an inhibitor of CYP450 2D6 and may increase the plasma concentrations of many psychotropic agents that are metabolized by the isoenzyme such as phenothiazines, haloperidol, risperidone, phenobarbital, and some tricyclic antidepressants and serotonin reuptake inhibitors.

MANAGEMENT: Caution is advised if propoxyphene is used with sedatives, tranquilizers, muscle relaxants, antidepressants, and other CNS depressants, particularly in the elderly and in patients with a history of emotional disturbances, suicidal ideation, or alcohol and drug abuse. Dosage reductions may be appropriate. Patients should be monitored for potentially excessive or prolonged CNS and respiratory depression and other CNS adverse effects. Patients should be warned not to exceed recommended dosages, to avoid alcohol, and to avoid activities requiring mental alertness until they know how these agents affect them.

Vorinostat

MONITOR CLOSELY: Severe thrombocytopenia and gastrointestinal bleeding have been reported during concomitant use of vorinostat and other histone deacetylase (HDAC) inhibitors such as valproic acid, presumably due to additive pharmacodynamic effects.

MANAGEMENT: Blood cell counts, including platelets, should be performed every two weeks during the first two months of vorinostat therapy, then monthly thereafter. If abnormalities develop, the dosage should be reduced or therapy discontinued.

Interferon beta-1b, Interferon beta-1a

MONITOR: Coadministration of beta interferons with other agents known to induce hepatotoxicity may potentiate the risk of liver injury. Use of beta interferons has been associated with rare cases of liver injury, including autoimmune hepatitis and severe liver damage leading to hepatic failure, some of which required transplantation. In some cases, these events have occurred in the presence of other drugs that have been associated with hepatic injury. Symptoms of liver dysfunction typically began from 1 to 6 months following the initiation of therapy. Asymptomatic elevation of hepatic transaminases (particularly SGPT) have also been reported but is common with interferon therapy.

MANAGEMENT: The risk of hepatic injury should be considered when beta interferons are used in combination with other agents that are potentially hepatotoxic (e.g., alcohol; androgens and anabolic steroids; antituberculous agents; azole antifungal agents; ACE inhibitors; anticonvulsants such as carbamazepine, hydantoins, felbamate, and valproic acid; lipid-lowering medications such as fenofibrate, HMG-CoA reductase inhibitors, and niacin; nucleoside reverse transcriptase inhibitors; thiazolidinediones). Liver function tests should be monitored at regular intervals and the interferon dosage reduced if SGPT rises above 5 times the upper limit of normal. The dosage may be gradually re-escalated when enzyme levels return to normal. Patients should be advised to notify their physician if they experience signs and symptoms of hepatotoxicity such as fever, rash, anorexia, nausea, vomiting, fatigue, right upper quadrant pain, dark urine, and jaundice. If liver injury is suspected, interferon therapy should be promptly discontinued due to the potential for rapid progression to liver failure.

Topiramate (oral)

MONITOR: Coadministration of topiramate with valproic acid has been reported to decrease mean area under the plasma concentration-time curve (AUC) of valproic acid by 11% and that of topiramate by 14%. The mechanism of interaction may involve increased metabolism of both drugs.

MANAGEMENT: Pharmacologic response to the drugs should be monitored more closely following addition or withdrawal of one or the other drug. Dose adjustments may be required if an interaction is suspected. Patients should be advised to notify their physician if they experience loss of seizure control.

Meropenem, Ertapenem

MONITOR: Coadministration with carbapenems may substantially decrease the serum concentrations of valproic acid (VPA). The exact mechanism of interaction is unknown. In vitro and animal studies suggest that carbapenems may increase the metabolism of VPA to VPA glucuronide; inhibit the hydrolysis of VPA glucuronide in the liver; increase the renal clearance of VPA glucuronide; and inhibit the intestinal absorption of VPA. Clinically, the interaction has been reported with meropenem and panipenem, often resulting in subtherapeutic levels of VPA promptly following initiation of the carbapenem and despite increases in the VPA dosage. Seizures have been reported in several cases. VPA levels typically begin to increase soon after discontinuation of the carbapenem.

MANAGEMENT: Caution is advised if valproic acid must be used concomitantly with a carbapenem. Pharmacologic response and serum valproate levels should be monitored more closely whenever a carbapenem is added to or withdrawn from therapy, and the valproic acid dosage adjusted as necessary. Use of another antiepileptic agent such as phenytoin may be appropriate in some cases.

Vardenafil

MONITOR: Coadministration with drugs that are inhibitors of CYP450 3A4 and/or 2C9 may increase the plasma concentrations of vardenafil, which is metabolized primarily by 3A4 and, to a lesser degree, by 2C9. The possibility of prolonged and/or increased pharmacologic effects of vardenafil should be considered.

MANAGEMENT: Dosage adjustments may be appropriate for vardenafil whenever a CYP450 3A4 and/or 2C9 inhibitor is added to or withdrawn from therapy based on efficacy and side effects. The manufacturer recommends that an initial vardenafil dosage of 2.5 to 5 mg be used in patients treated concomitantly with a potent CYP450 3A4 inhibitor such as erythromycin, itraconazole, ketoconazole, indinavir, and ritonavir. Patients should be advised to promptly notify their physician if they experience pain or tightness in the chest or jaw, irregular heartbeat, nausea, shortness of breath, visual disturbances, syncope, or prolonged erection (greater than 4 hours).

Risperidone (oral)

MONITOR: Coadministration with risperidone may alter the serum concentrations of valproic acid, although data are conflicting. The mechanism is unknown but may be related to risperidone displacement of valproate from plasma proteins. In one pediatric patient, serum valproate level rose from 143 mg/L to 191 mg/L five days following the addition of risperidone, necessitating a 43% dosage reduction of valproic acid. The level declined to 108 mg/L within 3 days and stabilized thereafter. In another patient, the addition of risperidone was associated with a drop in serum valproate level. The combination has also been associated with the development of edema in one patient. In contrast, a group of investigators found no difference in the mean valproate serum concentration-to-dose ratio (C/D) in 4 patients treated concomitantly with risperidone compared to that of 172 patients who did not receive risperidone. In two of the four patients, serum valproate concentrations measured on occasions when they were not taking risperidone also indicate no change in valproate C/D. Another group of investigators compared trough serum valproate levels in 45 patients, 29 of whom received concurrent treatment with atypical antipsychotics, and found no significant difference among those receiving divalproex with risperidone versus those receiving divalproex alone or with olanzapine.

MANAGEMENT: Until further data are available, clinicians may consider monitoring the pharmacologic response and serum valproate levels more closely whenever risperidone is added to or withdrawn from therapy. Ambulatory patients should be made aware of the possibility of additive central nervous system effects (e.g., drowsiness, dizziness, lightheadedness, confusion) and counseled to avoid activities requiring mental alertness until they know how these agents affect them.

Cetirizine

MONITOR: Concurrent use of cetirizine or levocetirizine with alcohol or other central nervous system (CNS) depressants may result in additive impairment of mental alertness and performance. Several studies have shown no effect of racemic cetirizine on cognitive function, motor performance, or sleep latency as indicated by objective measurements. However, there have been reports of somnolence, fatigue, and asthenia in some patients treated with cetirizine or levocetirizine in clinical trials.

MANAGEMENT: Concomitant use of cetirizine or levocetirizine with alcohol or other CNS depressants should generally be avoided if possible. In the event that they are used together, patients should be counseled to avoid hazardous activities requiring complete mental alertness and motor coordination until they know how these agents affect them, and to notify their physician if they experience excessive or prolonged CNS effects that interfere with their normal activities.

Olanzapine

MONITOR: Concurrent use of olanzapine and valproic acid may potentiate the risk of hepatotoxicity. The exact mechanism of interaction is unknown. In a retrospective study of 52 children, combined treatment with olanzapine and divalproex was associated with more frequent elevations of hepatic enzymes than either agent alone, and mean and peak hepatic enzyme levels during the observed course of treatment were also higher. All 12 patients who received combined treatment had at least one peak enzyme elevation above the normal range, versus 10 of 17 who received olanzapine alone and 6 of 23 who received divalproex alone. With the exception of 2 patients who required discontinuation of combination treatment (due to development of pancreatitis in one and steatohepatitis in the other), the observed peak and mean enzyme levels were less than 3 times the upper limit of normal (ULN) and were asymptomatic. The long-term significance of these findings is unknown.

MANAGEMENT: The authors of the study recommend monitoring liver function tests every 3 to 4 months during the first year of treatment with either olanzapine or valproic acid, at least in pediatric patients. If no elevations of liver enzymes or marked weight gain occur after one year, a decrease in frequency of monitoring to every 6 months can be considered. Patients should be advised to notify their physician if they experience signs and symptoms of hepatotoxicity such as fever, rash, anorexia, nausea, vomiting, fatigue, right upper quadrant pain, dark urine, and jaundice.

Pemoline

MONITOR: Decreased seizure threshold has been reported in patients receiving pemoline concomitantly with antiepileptic medications. The mechanism of this interaction has not been reported.

MANAGEMENT: These drugs should be coadministered cautiously with careful clinical monitoring. Patients should be advised to notify their physician if they experience loss of seizure control.

Aspirin (oral), Salsalate, Magnesium salicylate, Aspirin (rectal), Diflunisal

MONITOR: Salicylates, particularly aspirin, may displace valproate from protein binding sites and inhibit its clearance. Four-fold increases in the free fraction of valproate have been reported in children. Increased therapeutic and toxic effects may be expected to occur. This interaction is more likely with large or prolonged doses of salicylates.

MANAGEMENT: Small single doses of salicylates are unlikely to cause significant effects. However, patients who take large doses of salicylates or over a prolonged period of time should be closely monitored for clinical and laboratory evidence of valproate toxicity and hepatotoxicity. Free fraction of valproate may be particularly helpful in detecting this interaction. Patients should be advised to notify their physician if they experience possible symptoms of toxicity (e.g., malaise, weakness, lethargy, drowsiness, nausea, vomiting, or abdominal pain).

Tizanidine

MONITOR: Sedation is a major side effect of tizanidine and may be potentiated by coadministration with other substances that have central nervous system-depressant effects or that may commonly cause drowsiness.

MANAGEMENT: Use of tizanidine with other substances that commonly cause sedation should be approached with caution, particularly in elderly or debilitated patients. Ambulatory patients should be counseled to avoid hazardous activities requiring complete mental alertness and motor coordination until they know how these agents affect them, and to notify their physician if they experience excessive or prolonged CNS effects that interfere with their normal activities.

Isoniazid

MONITOR: Several case reports suggest that combining valproic acid (or its derivatives) and isoniazid may increase the toxicity of both drugs. The mechanism, while not established, is probably inhibition by isoniazid of the hepatic metabolism of valproic acid. Case reports suggest that the risk of this interaction may be greater for slow acetylators of isoniazid.

MANAGEMENT: Valproic acid dosage may need to be reduced if isoniazid is added to the therapy. Additional monitoring for altered valproic acid response may be prudent when isoniazid therapy is started or stopped. Patients should be advised to notify their caregiver if they experience weakness, fatigue, confusion, ataxia, increased seizures, nausea, or vomiting during concomitant use.

Celecoxib (oral)

MONITOR: The coadministration with drugs that are inhibitors of the CYP450 2C9 enzymatic pathway may increase the plasma concentrations of celecoxib, which is metabolized by CYP450 2C9. The possibility of prolonged and/or increased pharmacologic effects of celecoxib should be considered.

MANAGEMENT: Monitoring for clinical and laboratory evidence of altered effects of celecoxib is recommended. Patients should be advised to notify their physician if they experience abdominal pain, tarry stools, nausea, vomiting, lethargy or drowsiness.

Nortriptyline, Desipramine, Amitriptyline, Doxepin, Imipramine, Trimipramine, Amoxapine, Protriptyline, Clomipramine

MONITOR: The concomitant administration of valproic acid or its derivatives may increase serum concentrations of tricyclic antidepressants. In one study, the amitriptyline area under the curve was increased 31% in subjects taking divalproex sodium (n=15). A case report has described increased nortriptyline levels and toxicity after sodium valproate was added to the regimen. The proposed mechanism of action is inhibition of CYP450 hepatic metabolism. CNS and/or respiratory depressant effects may be additively or synergistically increased in patients taking multiple drugs which cause these effects. Other tricyclic antidepressants may exhibit a similar interaction. Additionally, tricyclic antidepressants may counteract the anticonvulsive effects of valproic acid and divalproex by lowering the seizure threshold.

MANAGEMENT: It may be advisable to monitor patients for altered efficacy and safety. Dose adjustments or alternate therapy may be necessary if an interaction is suspected.

Leflunomide (oral)

MONITOR: The concomitant or sequential use of leflunomide (without the recommended washout period) with agents known to induce hepatotoxicity may potentiate the risk of liver injury. Leflunomide has been associated with hepatotoxicity, including elevated liver transaminases, hepatitis, jaundice/cholestasis, hepatic failure, and acute hepatic necrosis,

MANAGEMENT: Baseline and frequent monitoring of hepatic function is recommended during concurrent use.

Thioguanine

MONITOR: The concomitant or sequential use of thioguanine with agents known to induce hepatotoxicity may potentiate the risk of liver injury. Thioguanine has been associated with hepatotoxicity, including elevated liver transaminases, hyperbilirubinemia, hepatomegaly, portal hypertension, hepatoportal sclerosis, peliosis hepatitis, and fibrosis.

MANAGEMENT: Frequent monitoring of hepatic function is recommended during concurrent use.

Phenobarbital

MONITOR: Valproate may increase plasma levels of phenobarbital. The mechanism may be related to decreased CYP450 hepatic metabolism of the barbiturate.

MANAGEMENT: Patients started on combination therapy should be closely monitored for clinical and laboratory evidence of toxicity. They should be advised to notify their physician if they experience excessive sedation or lethargy. Reductions in the phenobarbital dosage may be required.

Primidone

MONITOR: Valproate may increase the plasma levels of primidone's major metabolite, phenobarbital. The mechanism may be related to decreased CYP450 hepatic metabolism of the barbiturate.

MANAGEMENT: Patients started on combination therapy should be closely monitored for clinical and laboratory evidence of toxicity. They should be advised to notify their physician if they experience excessive sedation or lethargy.

Mephenytoin, Ethotoin

MONITOR: Valproic acid and its derivatives may increase the pharmacologic effects of hydantoins. Toxicity may result, despite normal hydantoin levels. Phenytoin is the only hydantoin specifically studied in this regard. The mechanism may be related to displacement of the hydantoin from plasma proteins.

MANAGEMENT: Patients on combination therapy should be closely monitored for clinical and laboratory evidence of altered effects. Patients should be advised to notify their physician if they experience symptoms of toxicity (e.g., drowsiness, visual disturbances, change in mental status, seizures, nausea, or ataxia).

Phenytoin (oral)

MONITOR: Valproic acid (and its derivatives) may increase the pharmacologic effects of phenytoin. Toxicity may result, despite normal phenytoin levels. The mechanism may be related to displacement of phenytoin from plasma proteins. Also, phenytoin may induce the CYP450 metabolism of valproic acid. Similar interactions may occur with other hydantoins.

MANAGEMENT: Patients on combination therapy should be closely monitored for clinical and laboratory evidence of altered phenytoin and valproate effects. It may be more useful to monitor plasma free-phenytoin levels than to monitor total plasma concentrations. Patients should be advised to notify their physician if they experience symptoms of toxicity (e.g., drowsiness, visual disturbances, change in mental status, seizures, nausea, or ataxia).

Nitazoxanide

Nitazoxanide may increase the potential for toxicity of other highly plasma protein bound drugs. The mechanism of action is competition for plasma protein binding sites. Tizoxanide, its active metabolite, is over 99.9% plasma protein bound. The clinical significance is unknown. Caution is recommended when highly protein bound drugs with narrow therapeutic indices are administered concurrently. Additionally, total plasma concentrations should be interpreted cautiously, because a greater amount of free drug may be present.

Clozapine

Several reports have suggested that valproate may slightly increase serum clozapine levels and levels of clozapine metabolites. Increased sedation and functional impairment may result. The mechanism of this interaction is unknown, as is its clinical significance. If clozapine and valproic acid or any of its derivatives must be used together, close observation for altered clozapine effect is recommended.

Oxcarbazepine

Some antiepileptic drugs may moderately decrease plasma concentrations of MHD, the active metabolite of oxcarbazepine. The mechanism may be related to induction of CYP450 hepatic metabolism. The effect of oxcarbazepine on plasma concentrations some antiepileptic drugs is variable. Oxcarbazepine doses greater than 1200 mg/day may increase phenytoin levels by up to 40% and phenobarbital levels by 15%. Dosage adjustments may be indicated if an interaction is suspected.

Esomeprazole

The coadministration of esomeprazole and drugs that are substrates of the CYP450 2C19 enzymatic pathway may result in elevated plasma concentrations of those drugs. The mechanism is decreased clearance due to competitive inhibition of CYP450 2C19 activity by esomeprazole. The clinical significance of this potential interaction, if any, is unknown. Caution is advised if esomeprazole is used concomitantly with medications that undergo metabolism by CYP450 2C19, particularly those with a narrow therapeutic range.

Tiagabine

Tiagabine has been reported to cause a 10% decrease in serum valproate concentrations. Additionally, valproic acid decreased tiagabine protein binding in vitro from 96.3% to 94.4% which resulted in a 40% increase in free tiagabine levels. The clinical significance of either interaction is unknown. However, clinical and/or laboratory monitoring for evidence of altered effect of both drugs is recommended if this combination is used.

Ethosuximide

Valproate has been reported variously to increase, decrease, and not affect blood ethosuximide levels. When these drugs must be used concurrently, it may be helpful to monitor ethosuximide levels.

Tolbutamide

Valproate may displace tolbutamide from plasma protein-binding sites. However, the clinical significance of the increased refraction of tolbutamide in plasma has not been determined.

Nimodipine

Valproic acid and its derivatives may increase the effects of nimodipine by decreasing first-pass metabolism and increasing bioavailability. Patients who must take both drugs should be carefully monitored for increased nimodipine effect.

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