Effexor Interactions
- Amitriptyline
- Amphetamine
- Aripiprazole
- Atomoxetine
- Buspirone
- Cevimeline
- Cimetidine
- Clomipramine
- Clozapine
- Cocaine
- Delavirdine
- Desipramine
- Dexfenfluramine
- Dexmethylphenidate
- Dextroamphetamine
- Dextromethorphan
- Doxepin
- Duloxetine
- Fenfluramine
- Fluconazole
- Furazolidone
- Gefitinib
- Haloperidol
- Imatinib, STI-571
- Imipramine
- Indinavir
- Itraconazole
- Kava Kava, Piper methysticum
- Ketoconazole
- Linezolid
- Lithium
- Melatonin
- Methylphenidate
- Metoclopramide
Monoamine oxidase inhibitors (MAOIs)
- Nefazodone
- Nortriptyline
- Pentazocine
Phenothiazines
- Phentermine
- Procarbazine
- Propafenone
- Protriptyline
- Risperidone
- Ritonavir
Selective serotonin reuptake inhibitors (SSRIs)
Serotonin-Receptor Agonists
- Sibutramine
- St. John’s Wort, Hypericum perforatum
- Tramadol
- Trazodone
- Tryptophan, 5-Hydroxytryptophan
- Valerian, Valeriana officinalis
- Voriconazole
- Warfarin
- Zolpidem
Effexor (Venlafaxine) Interactions
NOTE: Venlafaxine is a substrate of the hepatic CYP450 isoenzyme CYP2D6 (major) and CYP3A4 (minor). Venlafaxine is likely metabolized to a minor, less active metabolite by CYP3A4 and the potential for a clinically significant drug interactions between CYP3A4 inhibitors and venlafaxine is small. However, drugs that inhibit CYP2D6 may result in elevated venlafaxine plasma concentrations. Additionally, the use of venlafaxine with a drug that is a potent inhibitor of both CYP2D6 and CYP1A2 may increase the risk for venlafaxine toxicity. Venlafaxine is a weak inhibitor CYP2D6 in vivo. In clinical studies involving CYP2D6-poor and -extensive metabolizers, the total concentration of active compounds (venlafaxine plus O-desmethylvenlafaxine [ODV]), was similar in the two metabolizer groups. Therefore, the manufacturer suggests no dosage adjustment is required when venlafaxine is coadministered with a CYP2D6 inhibitor. Venlafaxine does not appear to inhibit other CYP hepatic isoenzymes, based on in vitro studies, to any clinically significant degree.
Due to similarity of pharmacology and the potential for additive adverse effects, including serotonin syndrome, duloxetine should not be administered with other serotonin norepinephrine reuptake inhibitors like venlafaxine.
Due to similarity of pharmacology and the potential for additive adverse effects, including serotonin syndrome, selective serotonin reuptake inhibitors (SSRIs) should generally not be administered with serotonin norepinephrine reuptake inhibitors like venlafaxine or duloxetine.
Coadministration of venlafaxine and cimetidine resulted in a decreased first-pass metabolism of venlafaxine. Maximum concentrations of venlafaxine were increased and clearance reduced. At present, the manufacturer recommends no dosage adjustments in normal patients, but caution should be observed in the elderly and in patients with preexisting hypertension and/or hepatic disease or impairment because the results of this interaction can be more pronounced. O-desmethylvenlafaxine pharmacokinetics were not altered by cimetidine.
Documentation is not available on the concurrent use of venlafaxine with many CNS agents. Venlafaxine and its active metabolite, O-desmethylvenlafaxine (ODV), exert their antidepressant effects by inhibiting the reuptake of both serotonin and norepinephrine. Concomitant use of two serotonin-augmenting drugs has been associated with serotonin syndrome. Caution should be observed when administering venlafaxine with drugs that have CNS serotonergic properties. Examples of these drugs include: serotonin-receptor agonists for migraine; the SSRIs; St. John’s wort, Hypericum perforatum; amphetamine and dextroamphetamine; buspirone; cocaine; dexfenfluramine and fenfluramine; duloxetine; lithium; phentermine; sibutramine; nefazodone and trazodone; and some tricyclic antidepressants (e.g., amitriptyline, clomipramine, desipramine, doxepin, imipramine, nortriptyline, protriptyline). The manufacturer reports that no pharmacokinetic interaction was seen between venlafaxine and lithium. Coadministration of venlafaxine with weight loss products is not recommended. Venlafaxine is not indicated for weight loss alone or in combination with other agents.
Serotonin norepinephrine reuptake inhibitors (e.g., venlafaxine) should not be administered to patients receiving non-selective monoamine oxidase inhibitors (MAOIs). Concurrent use of venlafaxine with MAOIs may be associated with serotonin syndrome, which is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, and mental status changes that can include coma and delirium. The manufacturer of venlafaxine recommends an interval of 14 days elapse between the discontinuation of an MAOI and the initiation of venlafaxine. Before initiating a MAOI after the discontinuation of an serotonergic drug, a sufficient amount of time must be allowed for the clearance of the serotonergic drug and its active metabolites. Based on the half-life of venlafaxine, at least 7 days should be allowed after stopping venlafaxine before starting a MAOI. In addition, selegiline, although selective for MAO type B at usual doses, may inhibit MAO type A at higher doses and should also be avoided in patients receiving selected serotonin-reuptake inhibitors. Finally, isoniazid, INH (antituberculosis drug), furazolidone, linezolid (antibiotic) and procarbazine (chemotherapy agent) also possess weak non-selective MAO-inhibiting activity and should be combined with any serotonergic agent with caution.
Venlafaxine could potentially interfere with dextromethorphan metabolism leading to clinical toxicity mimicking the serotonin syndrome. Dextromethorphan should be used in lower doses in patients receiving serotonin-potentiating medications which are inhibitors of hepatic CYP2D6 metabolism, the hepatic isoenzyme responsible for metabolism of dextromethorphan. Venlafaxine is a weak inhibitor of CYP2D6 and could potentially interact with dextromethorphan; although no clinical drug interactions have been reported. Melperone (a neuroleptic 2D6 inhibitor not available in the US) has been shown to inhibit CYP2D6 metabolism of dextromethorphan, corroborating the fact that dextromethorphan can be affected by CYP2D6 inhibitors.
Melatonin may potentially interact with medications the inhibit serotonin reuptake such as venlafaxine. Other serotonergic agents, like certain SSRI-type medications, have been reported to interact with melatonin. The possibility that serotonin norepinephrine reuptake inhibitors could interact with melatonin should be considered until more data are available.
The German Commission E and other groups warn that any substances that act on the CNS, including psychopharmacologic agents like venlafaxine, may interact with the phytomedicinals kava kava, Piper methysticum or valerian, Valeriana officinalis. These interactions are probably pharmacodynamic in nature, or result from additive mechanisms of action.
The combination of SSRI-type medications and tramadol has been associated with serotonin syndrome and an increased risk of seizures; post-marketing reports implicate the concurrent use of tramadol in some cases of seizures. Several cases of serotonin syndrome have been reported following the administration of tramadol with paroxetine or sertraline. Venlafaxine, a serotonin-norepinephrine reuptake inhibitor, has actions similar to the SSRIs and thus may also have the potential to interact with tramadol. Venlafaxine may inhibit the formation of the active M1 metabolite of tramadol by inhibiting cytochrome P450 2D6. The inhibition of this metabolite may decrease the analgesic effectiveness of tramadol but increase the level of the parent compound, which has more serotonergic activity than the metabolite.
Cevimeline is metabolized by cytochrome P450 (CYP) 3A4 and CYP2D6. Venlafaxine is a mild inhibitor of CYP2D6 and could lead to an increase in cevimeline plasma concentrations. Clinical interactions have not been documented at this time.
In some patients taking serotonin-reuptake inhibiting medications, like venlafaxine, zolpidem has been associated with rare reports of disorientation, delusions, or hallucinations when administered concomitantly. In most cases the visual hallucinations were short lived (i.e., 30 minutes) but in some patients the symptoms persisted up to 7 hours in duration. The mechanism for the interaction has not been established, but is thought to be primarily pharmacodynamic in nature, although pharmacokinetic interactions have also been reported.
In a study of 9 healthy volunteers, venlafaxine administered under steady-state conditions at 150 mg/day resulted in a 28% decrease in the AUC of a single 800 mg oral dose of indinavir and a 36% decrease in indinavir Cmax. Indinavir did not affect the pharmacokinetics of venlafaxine or its metabolite (i.e., ODV). The clinical significance of this interaction is unknown. Other anti-retroviral protease inhibitors have not been formally studied in combination with venlafaxine. However, ritonavir may be expected to decrease the metabolism of venlafaxine; ritonavir is a potent inhibitor of CYP3A4 and 2D6, and venlafaxine is a substrate for both of these enzymes. The risk of elevated plasma concentrations and toxicity may be greater when ritonavir is given with venlafaxine.
Patients receiving concurrent pentazocine and drugs which inhibit serotonin reuptake, like venlafaxine, may be at increased risk for developing serotonin syndrome; pentazocine should be used cautiously, if at all, in these patients.
Documentation is not available on the concurrent use of venlafaxine with many CNS agents. However, caution should be observed when administering venlafaxine with drugs that have CNS active properties. In one case report, the initiation of venlafaxine in a patient taking trifluoperazine resulted in symptoms consistent with neuroleptic malignant syndrome (NMS). After discontinuation of all psychiatric medications and treatment for NMS, the patient recovered and was able to reinitiate trifluoperazine without further problems. Venlafaxine was not administered a second time. This case report, thought isolated, may signal the need to be cautious in combining venlafaxine with the antipsychotic phenothiazines.
Delavirdine and imatinib, STI-571 are potent inhibitors of cytochrome P450 2D6 and might decrease venlafaxine metabolism leading to increased adverse reactions. Additionally, imatinib, STI-571 is a potent inhibitor of CYP 3A4, and venlafaxine is a substrate for both 2D6 and 3A4. The risk of elevated plasma concentrations and toxicity may be greater when imatinib, STI-571 is given with venlafaxine.
Since tryptophan is converted to serotonin (5-hydroxytryptamine), the use of tryptophan in patients receiving venlafaxine could lead to serotonin excess and, potentially, the ‘serotonin syndrome’ (presenting as agitation, restlessness, aggressive behavior, insomnia, poor concentration, headache, paresthesia, incoordination, worsening of obsessive thoughts or compulsive behaviors, nausea, abdominal cramps, diarrhea, palpitations, or chills). The discontinuation of tryptophan usually resolves symptoms.
Drugs that are inhibitors of the hepatic cytochrome P450 isoenzyme CYP2D6 may increase the risk of developing risperidone-induced side effects or extrapyramidal symptoms. Agents that may inhibit CYP2D6 include venlafaxine. Until more data are available, clinicians should remain aware of the possibility of such interactions. Closely monitor patients who begin or stop taking venlafaxine while taking risperidone.
It is possible that methylphenidate or dexmethylphenidate could interact with venlafaxine. These interactions could lead to serotonin excess and, potentially, the ‘serotonin syndrome’. The manufacturers of methylphenidate have noted that an NMS-like event occurred in a child who had been taking methylphenidate chronically, 45 minutes after ingesting a dose of venlafaxine. It is unclear if the reaction was the result of a drug-drug interaction. If serotonin syndrome is suspected, offending agents should be discontinued. While serotonergic agents like venlafaxine have occasionally been prescribed for the treatment of ADHD, the concurrent use of methylphenidate or dexmethylphenidate with venlafaxine should be approached with caution until more data are available.
Venlafaxine mildly inhibits the hepatic CYP450 isoenzyme CYP2D6 in vivo, thereby inhibiting the metabolism of a number of drugs. Atomoxetine is primarily a substrate for the cytochrome P450 (CYP) isozyme CYP2D6. A dosage adjustment of atomoxetine may be needed in normal populations (also known as extensive metabolizers) when atomoxetine is administered with inhibitors of the CYP2D6 enzyme, such as venlafaxine. In vitro studies suggest that coadministration of CYP2D6 inhibitors to poor metabolizers will not further increase the plasma concentrations of atomoxetine.
Increased aripiprazole blood levels are expected when aripiprazole is coadministered with inhibitors of CYP2D6, such as venlafaxine. A dosage adjustment of aripiprazole is necessary when these drugs are used concomitantly, and conversely, when venlafaxine is discontinued in a patient taking aripiprazole (see Aripiprazole Dosage).
Gefitinib may inhibit cytochrome P450 (CYP) 2D6 at clinical doses. Caution is recommended when administering gefitinib with other CYP2D6 substrates, such as venlafaxine, that have a narrow therapeutic range or where large increases in serum concentrations may be associated with severe adverse reactions.
Post-marketing reports have indicated there may be the potential for seizure activity if venlafaxine is added to established clozapine therapy. Clozapine serum concentrations have risen following the addition of venlafaxine. Although the mechanism of this interaction has not been described, clozapine is a CYP2D6 substrate and venlafaxine is a weak inhibitor of CYP2D6. A temporal relationship was noted in this interaction.
Elevations in prothrombin time, activated partial thromboplastin and INR values have been reported post-marketing when venlafaxine was added to established warfarin therapy. The causality and mechanism of this potential interaction have not been established. The clinician may want to more closely monitor INR levels when venlafaxine is added to or discontinued from warfarin therapy.
An elderly women exhibited psychosis 2 weeks after an increase in her dose of venlafaxine from 225 to 300 mg/day and initiation of propafenone at 600 mg/day. Upon evaluation it was found that her serum concentrations of venlafaxine had increased > 6-fold. Although the mechanism of this interaction has not been described, it is possible that strong inhibition of CYP2D6 by propafenone led to elevated serum concentrations of venlafaxine, a CYP2D6 substrate. Additionally, propafenone is also a substrate for CYP2D6, and competitive inhibition may have played a role. Serum concentrations of venlafaxine and the clinical response to therapy should be monitored if adding propafenone to the regimen.
There may be a potential for rare drug interactions between metoclopramide and selective serotonin reuptake inhibitors (SSRIs) and selected other drugs that inhibit serotonin reuptake (i.e., venlafaxine). The few published case reports of possible interactions have resulted in either ‘serotonin-syndrome’ type events and/or movement disorders (e.g., dystonia). The mechanism of the interactions is elusive but is thought to be a pharmacodynamic interaction; the interactions do not appear common. In most of the cases reported, a singular drug effect was not ruled out; however, the time course of the events are enough to raise suspicion that a drug interaction might be possible. Patients receiving metoclopramide concomitantly with an SSRI or venlafaxine should report any unusual movements or other unusual side effects to their health care professionals promptly.
Venlafaxine administered at 150 mg/day in 24 subjects decreased total oral clearance of a 2 mg dose of haloperidol by 42%, which resulted in a 70% increase in haloperidol AUC. In addition, the haloperidol Cmax increased 88% when coadministered with venlafaxine, but the haloperidol elimination half-life (T1/2) was unchanged. The mechanism explaining this finding is unknown; however, venlafaxine may have slight CYP2D6 inhibitory activity and could lead to elevated plasma concentrations of haloperidol, which is strongly metabolized by CYP2D6. Additionally, competitive inhibition could come into play as both drugs are substrates of CYP2D6. Monitor patients who are started on haloperidol for CNS toxicity if they have previously also been on venlafaxine.
Venlafaxine is a substrate of the hepatic CYP450 isoenzyme CYP2D6 (major) and CYP3A4 (minor). Venlafaxine is likely metabolized to a minor, less active metabolite by CYP3A4 and, normally, the potential for clinically significant drug interactions between CYP3A4 inhibitors and venlafaxine is small. However, in patients who are poor CYP2D6 metabolizers, the CYP3A4 pathway may become more important and administration of potent CYP3A4 inhibitors can result in elevated venlafaxine plasma concentrations. Administration of venlafaxine and ketoconazole, a potent CYP3A4 inhibitor, to patients identified as CYP2D6 poor metabolizers resulted in a significant increase in venlafaxine mean AUC; there was no effect on venlafaxine half-life. Fluconazole, itraconazole, and voriconazole are also known to inhibit CYP3A4 and may also interact with venlafaxine in a similar manner.
[ Last revised: 12/16/2005 2:26:00 PM ]
References
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