Interactions : אינטראקציות

4.5     Interaction with other medicinal products and other forms of interaction

Effects of other medicinal products on valproic acid:
Enzyme-inducing anti-epileptics such as phenobarbital, primidone, phenytoin and carbamazepine reduce serum levels of valproic acid, thereby reducing the effect. In the case of combined therapy, the dosage should be adjusted in accordance with the clinical efficacy and serum level.

Valproic acid metabolites levels may be increased in case of concomitant use with phenytoin or phenobarbital. Therefore, patients treated with those two drugs should be carefully monitored for signs and symptoms of hyperammonemia.

Mefloquine increases the degradation of valproic acid and also has potential convulsant effects.
Concomitant use can therefore lead to epileptic seizures.

Decreases in serum concentrations of valproic acid have been reported when it is co-administered with carbapenems, resulting in a 60−100 % decrease in valproic acid levels in about two days. Due to the rapid onset and the extent of the decrease, the consequences of an interaction between valproic acid and carbapenems in patients stabilised on valproic acid are considered to be unmanageable and therefore co-administration should be avoided (see section 4.4). If treatment with these antibiotics cannot be avoided, the blood level of valproic acid should be closely monitored.

Serum valproic acid concentrations may be increased by concomitant administration of cimetidine or erythromycin, as a result of a reduced metabolism in the liver.

Serum valproic acid concentrations may also be increased by concomitant administration of fluoxetine. However, a decrease has also been reported.


Medicinal products with high plasma protein binding, such as acetylsalicylic acid, can competitively displace valproic acid from its protein binding sites and increase the concentration of free valproic acid in serum.
Medicinal products containing valproic acid and acetylsalicylic acid should not be administered concomitantly in infants and children with febrile disorders and only on the express instructions of a doctor in adolescents with febrile disorders.

If vitamin K antagonists are administered concomitantly, close monitoring of the INR is recommended.

Rifampicin may decrease the serum valproic acid levels, resulting in a lack of therapeutic effect.
Therefore, valproic acid dosage adjustment may be necessary when it is co-administered with rifampicin.

Valproate plasma level is decreased in case of concomitant use with protease inhibitors such as lopinavir or ritonavir.

Estrogen-containing products, including estrogen-containing hormonal contraceptives Estrogens are inducers of the UDP-glucuronosyl transferase (UGT) isoforms involved in valproate glucuronidation and may increase the clearance of valproate, which would result in decreased serum concentration of valproate and potentially decreased valproate efficacy (see section 4.4). Consider monitoring of valproate serum levels.
On the opposite, valproate has no enzyme inducing effect; as a consequence, valproate does not reduce efficacy of oestroprogestative agents in women receiving hormonal contraception.


Metamizole may decrease valproate serum levels when co-administered, which may result in potentially decreased valproate clinical efficacy. Prescribers should monitor clinical response (seizure control or mood control) and consider monitoring valproate serum levels as appropriate.

Some case reports describe a significant decrease in valproate serum levels after methotrexate administration, with occurrence of seizures. Prescribers should monitor clinical response (seizure control or mood control) and consider monitoring valproate serum levels as appropriate.

Effects of valproic acid on other medicinal products:
The valproic acid-induced increase in the phenobarbital concentration, which can manifest itself in the form of severe sedation (particularly in children), is of particular clinical significance. If this occurs, the phenobarbital or primidone dose must be reduced (primidone is partially metabolised to phenobarbital). Careful monitoring is therefore recommended, particularly in the first 15 days of combination treatment.

In patients who are already taking phenytoin, additional administration or an increase in the dose of medicinal products containing valproic acid can cause the amount of free phenytoin to rise (the concentration of the non-protein-bound active part) without an increase in total serum levels of phenytoin. This can increase the risk of undesirable effects, particularly brain damage (see section 4.8). Clinical monitoring is therefore recommended; if plasma phenytoin concentrations are determined, the free form should be measured.

During combination treatment with carbamazepine and valproic acid, symptoms have been described that may be attributable to potentiation of carbamazepine toxicity by valproic acid. Clinical monitoring is indicated, particularly at the start of combination treatment, and the dose should be adjusted if necessary.

Valproic acid inhibits the metabolism of lamotrigine and almost doubles its mean half-life.
Combination of lamotrigine and medicinal products containing valproic acid may increase the risk of skin reactions; individual cases of severe skin reactions have been reported occurring within 6 weeks of starting combination treatment and, in some cases, not regressing until the medication was withdrawn or appropriate treatment administered. Clinical monitoring is therefore recommended and, if necessary, the lamotrigine dosage should be adjusted (reduction of the lamotrigine dosage).

In combination with benzodiazepines, barbiturates and neuroleptics, MAO inhibitors and antidepressants, valproic acid can increase the central depressant effect of these medicinal products.
Patients taking corresponding combinations should be monitored carefully and doses adjusted if necessary.

Depalept Chrono has no effect on the lithium serum level.

The metabolism and protein binding of other active substances, such as codeine, are also affected.
Valproic acid may increase the serum concentration of zidovudine, which can lead to an increase in zidovudine toxicity.

Concomitant administration of medicinal products containing valproic acid and anticoagulants or anti-aggregants can result in an increased tendency to bleed. Regular monitoring of blood coagulation is therefore recommended in the event of concomitant use (see also section 4.4).

In healthy subjects, valproate displaces diazepam from its plasma albumin binding sites and inhibits its metabolism. In patients receiving combination treatment, the concentration of unbound diazepam can be elevated, and the plasma clearance and volume of distribution of the free diazepam fraction reduced (by 25 % and 20 % respectively). However, the half-life remains unchanged.

In healthy subjects, concomitant treatment with valproate and lorazepam reduced the plasma clearance of lorazepam by up to 40 %.

In children, serum levels of phenytoin may increase after concomitant administration of clonazepam and valproic acid.

Valproic acid may decrease the olanzapine plasma concentration.

Valproic acid may lead to an increase in plasma level of rufinamide. This increase is dependent on concentration of valproic acid. Caution should be exercised, in particular in children, as this effect is larger in this population.

Valproic acid may lead to an increased blood level of propofol. When co-administered with valproate, a reduction of the dose of propofol should be considered.

Other interactions

Risk of liver damage
The concomitant use of salicylates should be avoided in children under 12 years due to the risk of liver toxicity (see section 4.4).
Concomitant use of valproate and multiple anticonvulsant therapy increases the risk of liver damage, especially in young children (see section 4.4).
Concomitant use with cannabidiol increases the incidence of transaminases enzyme elevation. In clinical trials in patients of all ages receiving concomitantly cannabidiol at doses 10 to 25 mg/kg and valproate, ALT increases greater than 3 times the upper limit of normal have been reported in 19% of patients. Appropriate liver monitoring should be exercised when valproate is concomitantly used with other anticonvulsants with potential hepatotoxicity, including cannabidiol, and dose reductions or discontinuation should be considered in case of significant anomalies of liver parameters (see section 4.4).

It is pointed out that potentially hepatotoxic medicinal products as well as alcohol can increase the hepatotoxicity of valproic acid.

With concomitant administration of valproic acid and topiramate, encephalopathy and/or an increase in ammonia blood levels (hyperammonaemia) has been reported. Also, concomitant use of valproic acid and acetazolamide may lead to hyperammonaemia and therefore there might be an increased risk of encephalopathy. Patients treated with those two drugs should be carefully monitored for signs and symptoms of hyperammonaemic encephalopathy.

Pivalate-conjugated medicinal products
Concomitant administration of valproate and pivalate-conjugated medicines (such as cefditorenpivoxil, adefovir dipivoxil, pivmecillinam and pivampicillin) should be avoided due to an increased risk of carnitine depletion (see section 4.4 “Patients at risk of hypocarnitinaemia”). Patients in whom coadministration cannot be avoided should be carefully monitored for signs and symptoms of hypocarnitinaemia.

Co-administration of valproate and quetiapine may increase the risk of neutropenia/leucopenia.

The effect of hormonal contraceptives (“the Pill”) is not reduced by valproic acid, as valproic acid has no enzyme-inducing effect.

As valproic acid is partially metabolised to ketone bodies, consideration should be given to the possibility of a false positive reaction to a test for ketone bodies in diabetics with suspected ketoacidosis.

Absences occurred in patients with a history of this type of seizure after concomitant treatment with medicinal products containing valproic acid and clonazepam.

Catatonia occurred in a female patient with a schizoaffective disorder after concomitant treatment with valproic acid, sertraline (antidepressant) and risperidone (neuroleptic).

The bioavailability of sodium valproate/valproic acid in the prolonged-release formulation is not significantly affected by the concomitant intake of food.