Venlafaxine, without having an increased bond with blood plasma proteins, practically does not increase the concentration of concomitant medications, which are characterized by a high bond with plasma proteins.Clinically significant interaction with antihypertensive drugs (many pharmacological groups, including beta-blockers, angiotensin-converting enzyme inhibitors and diuretics) and antidiabetic drugs have not been detected. Care should be taken when concomitant administration with other drugs affecting the central nervous system (CNS), since combinations of venlafaxine with all such drugs have not been studied.
Inhibitors of monoamine oxidase (MAO)
Contraindicated concomitant use of venlafaxine with MAO inhibitors, as well as within 14 days after their withdrawal (likely the risk of severe adverse effects up to a lethal outcome). Therapy with MAO inhibitors can be prescribed not less than 7 days after discontinuation of the drug Venlafaxine. Reception of the drug Venlafaxine should be discontinued at least 7 days before the onset of reversible selective MAO inhibitors (moclobemide). Weakly reversible and non-selective MAO inhibitor linezolid (antimicrobial drugs) and methylene blue (intravenous dosage form) are also not recommended for simultaneous use with venlafaxine.
Serotonergic agents
Caution should be exercised at the simultaneous use of drugs that affect the serotonin system of mediators, such as triptans (sumatriptan, zolmitriptan and others), selective serotonin reuptake inhibitors (SSRIs) and SSRIs (prolonged seizures were noted), tricyclic antidepressants, lithium, sibutramine or fentanyl (and its analogues dextromethorphan, tramadol and others), as well as an excess of tryptophan sources due to the increased potential risk of the occurrence of serotonin syndrome.
Alcohol
During treatment with venlafaxine, alcohol should be completely ruled out. Alcohol enhances the disturbances of psychomotor functions that can cause venlafaxine.
Lithium
Lithium preparations have no significant effect on the pharmacokinetics of venlafaxine.
Diazepam
There was no effect of orally administered diazepam on the pharmacokinetics of venlafaxine and EFA, and, conversely, venlafaxine did not alter the pharmacokinetics of diazepam and its metabolite desmethyldiazepam. In addition, the appointment of both these drugs does not impair the psychomotor and psychometric effects caused by diazepam.
Cimetidine
Simultaneous administration of cimetidine and venlafaxine was manifested in a delay in metabolism during the "first passage" of venlafaxine. The venlafaxine clearance for oral administration decreased by 43%, and the area under the pharmacokinetic curve (AUC) and the maximum concentration (CmOh) of this drug increased by 60%. However, such an impact did not manifest itself with regard to EFA. Since the total activity of venlafaxine and EFA is expected to increase only to a small extent, dose adjustments for most of the usual patients will not be required. However, patients with existing (identified) hypertension, elderly patients and those who have a violation of the liver or kidney function, it is possible to adjust the dose of venlafaxine.
Haloperidol
In the study, where venlafaxine was prescribed in the stage of equilibrium concentration at a dose of 150 mg / day, there was a decrease in total clearance of oral haloperidol by 42% after a dose of 2 mg orally; the area under the pharmacokinetic curve (AUC) increased by 70%, and CmOh increased by 88%, while the half-life of haloperidol (T1/2) did not change. This should be considered for the correct choice of a dose of haloperidol.
Imipramine
Venlafaxine does not impair the pharmacokinetics of imipramine and 2-hydroxyimipramine. but AUC, FROMmOh and Cmin desipramine (an active metabolite of imipramine) increased by approximately 35% with concurrent administration of venlafaxine. It also rises from 2.5 to 4.5 times (depending on the dose of venlafaxine: 37.5 mg for 12 hours or 75 mg for 12 hours), the concentration of 2-hydroxydesipramine, but the clinical significance of this fact is not known.
Metoprolol
With the simultaneous use of metoprolol and venlafaxine, care should be taken, because of the pharmacokinetic interaction, the concentration of metoprolol in the blood plasma increases by about 30-40%, without changing the concentration of its active metabolite α-hydroxymethoprolol. The clinical significance of this interaction has not been studied. Metoprolol does not affect AUC venlafaxine and EFA.
Risperidone
With simultaneous application with risperidone (despite the increase AUC risperidone), the pharmacokinetics of a pair of active molecules (risperidone and 9-hydroxyrisperidone) does not change significantly when combined with venlafaxine.
Clozapine
During the post-marketing study of venlafaxine, it was found that with simultaneous use with clozapine, its concentration in the blood plasma increases.This was manifested by an increase in the side effects of clozapine, especially with respect to the incidence of seizures.
Indinavir
With simultaneous use, the pharmacokinetics of indinavir (AUC decreases by 28%, and CmOh decreases by 36%). In venlafaxine, there is no change in pharmacokinetics. The clinical significance of this fact is unknown.
Ketoconazole
A study of pharmacokinetics in combination with ketoconazole showed an increase in plasma concentrations of venlafaxine and EFA in subjects in whom the initial metabolism involving isoenzyme CYP2D6 is both good (X-Met) and bad (P-Met). In particular, CmOh venlafaxine increased by 26% in X-Meth and by 48% in P-Meth. The values of CmOh EFA increased by 14% and 29% in subjects X-Met and P-Meth, respectively. AUC venlafaxine increased by 21% in X-Meth and by 70% in P-Meth. Values AUC EFA increased by 23% and 33% in subjects X-Met and P-Meth, respectively.
Means that affect blood clotting and platelet function (NSAIDs, acetylsalicylic acid preparations and other anticoagulants)
Serotonin, released by platelets, plays an important role in hemostasis (stopping bleeding).Epidemiological studies demonstrate the relationship between the intake of psychotropic drugs that interfere with the reuptake of serotonin, and the frequency of bleeding in the upper sections of the gastrointestinal tract. This relationship is enhanced if non-steroidal anti-inflammatory drugs (NSAIDs), drugs with acetylsalicylic acid or other anticoagulants are used simultaneously. The risk of bleeding in the appointment of SSRIs and SSRIs (including venlafaxine) concomitantly with warfarin. Patients assigned warfarin, should be carefully monitored for prothrombin time and / or partial thromboplastin time, especially when the combined use with venlafaxine begins or ends.
Interaction with other drugs at the level of the studied metabolism with cytochrome P450 isoenzymes
The main ways of metabolism of venlafaxine include isozymes CYP2D6 and CYP3A4: The first one turns venlafaxine in its active metabolite EFA, and the second is less important in the metabolism of venlafaxine compared with CYP2D6 and forms a product N-desmethylvenlafaxine with little pharmacological activity. Preclinical studies showed, and then it was clinically confirmed that venlafaxine is a relatively weak inhibitor CYP2D6. Therefore, even when administered with moderately suppressing activity of this enzyme with drugs (see the example with imipramine above), or in patients with genetically determined function decline CYP2D6, dose correction of venlafaxine is not required, since the total concentration of active substance and active metabolite (venlafaxine and EFA) does not change significantly. This positively characterizes venlafaxine when compared with other antidepressants. Care should be taken when concomitant administration with such inhibitors CYP2D6, as quinidine, paroxetine, fluoxetine, haloperidol, perphenazine, levomepromazine, since in this case venlafaxine can potentially increase the plasma concentration of these substrates CYP2D6. In combination with drugs that inhibit both enzymes (CYP2D6 and CYP3A4), special care must be taken. Such drug interactions have not been sufficiently investigated, and in this case such a combination of drugs is not recommended.
Also venlafaxine does not suppress enzyme activity CYP3A4, CYP1A2 and CYP2C9, so with drugs such as alprozolam, caffeine, carbamazepine, diazepam, tolbutamide, terfenadine no significant interaction is observed.
Interaction ketoconazole described above. A similar effect may have such inhibitors CYP3A3/4 as itraconazole, ritonavir.
Other interactions with various concomitant therapeutic factors and food
Against the background of venlafaxine use, special care should be taken with electroconvulsive therapy, since there is no experience with venlafaxine in these conditions.
Significant influence of different types of food on the absorption of venlafaxine and its subsequent transformation into EFA was not revealed. Food (usually high in protein, for example: hard cheeses, fish caviar, turkey), as well as dietary supplements and fitness rations, which are an increased source of tryptophan, potentially contributes to greater production of serotonin in the body, which may increase the side effects of serotonergic effects of venlafaxine .
Unwanted pharmacodynamic interaction may occur when taking venlafaxine simultaneously with a medicinal plant, St. John's wort (grass or various kinds of preparations from it),this combination is not recommended.
There are reports of false positive results of an immunochromatographic urine test (test strip) test on phencyclidine and amphetamines in patients taking venlafaxine, and even a few days after the withdrawal of venlafaxine. This can be explained by the lack of specificity of this test. Distinguish between venlafaxine from phencyclidine and amphetamines can only confirm the test in a specialized anti-doping laboratory.
According to the data available to date, venlafaxine has not proved to be a drug that induces drug abuse or addiction (both in the pre-clinical study of affinity for receptors and in clinical practice).