Venlafaxine
JFDA label: Vaxor Tab
- Suicidality and antidepressant drugs:
Mechanism of Action
Venlafaxine and its active metabolite, O-desmethylvenlafaxine (ODV), are potent inhibitors of neuronal serotonin and norepinephrine reuptake and weak inhibitors of dopamine reuptake. Venlafaxine and ODV have no significant activity for muscarinic cholinergic, H1-histaminergic, or alpha2-adrenergic receptors. Venlafaxine and ODV do not possess MAO-inhibitory activity. Venlafaxine functions like an SSRI in low doses (37.5 mg/day) and as a dual mechanism agent affecting serotonin and norepinephrine at doses above 225 mg/day (Harvey 2000; Kelsey 1996).
Indications
Approved
- Generalized anxiety disorder (extended-release capsules only)
- Major depressive disorder
- Panic disorder (extended-release capsules only)
- Social anxiety disorder (extended-release capsules and tablets only)
Off-label
- Attention-deficit/hyperactivity disorder (adults)
- Attention-deficit/hyperactivity disorder (children/adolescents)
- Diabetic neuropathy
- Episodic migraine prevention
- Hot flashes
- Obsessive-compulsive disorder (OCD)
- Post-traumatic stress disorder (PTSD)
- Premenstrual dysphoric disorder
Contraindications
Source: Lexicomp
- Hypersensitivity to venlafaxine or any component of the formulation Absolute
- initiation in patients receiving linezolid or IV methylene blue Absolute
- initiation of MAOI intended to treat psychiatric disorders within 7 days of discontinuing venlafaxine Absolute
- use of MAOIs intended to treat psychiatric disorders (concurrently or within 14 days of discontinuing the MAOI) Absolute
Adverse Reactions
Cardiac disorders (5)
Common Elevated heart rate / palpitations · Hypertension · hypotension, yawning, anorgasmia, abnormal dreams, paresthesia, agitation, decreased libido, hypercholesterolemia, hypermenorrhea, constipation, diarrhea, vomiting, bruxism, impotence, abnormal uterin · increased pulse · Vasodilation
Vascular disorders (1)
Common Hypertension (dose-dependent, diastolic)
Nervous system disorders (8)
Very Common Discontinuation syndrome (severe, abrupt stop) · dizziness · drowsiness · Headache · Insomnia
Common Somnolence · Suicidal ideation
Rare Serotonin syndrome
Blood and lymphatic system disorders (2)
Common Hematoma · petechia
Metabolism and nutrition disorders (2)
Common Increased serum triglycerides
Uncommon Hyponatraemia (SIADH)
Gastrointestinal disorders (3)
Very Common Nausea · Nausea · xerostomia
Skin and subcutaneous tissue disorders (2)
Very Common Diaphoresis
Common Hyperhidrosis
Musculoskeletal and connective tissue disorders (1)
Very Common Weakness
Psychiatric disorders (1)
Common Insomnia
Eye disorders (2)
Common accommodation disturbance (Otic: Tinnitus (Frequency not defined: · Visual disturbance
Reproductive system and breast disorders (1)
Very Common Sexual dysfunction
Respiratory, thoracic and mediastinal disorders (1)
Common Epistaxis
Dosing
Source: Lexicomp
Warnings & Precautions
Source: Lexicomp
Suicidal thinking/behavior
Antidepressants increased the risk of suicidal thinking and behavior in children, adolescents, and young adults (18 to 24 years of age) in short-term studies of major depressive disorder (MDD) and other psychiatric disorders; consider risk prior to prescribing. Short-term studies did not show an increased risk in patients >24 years of age and showed a decreased risk in patients ≥65 years. Closely monitor patients of all ages for clinical worsening, suicidality, or unusual changes in behavior, particularly during the first few months of therapy or during periods of dosage adjustments (increases or decreases); the patient’s family or caregiver should be instructed to closely observe the patient and communicate condition with healthcare provider. A medication guide concerning the use of antidepressants in children and teenagers should be dispensed with each prescription. Venlafaxine is not approved for use in pediatric patients.
Anxiety/insomnia
May cause increase in anxiety, nervousness, and insomnia.
Bleeding risk
May impair platelet aggregation resulting in increased risk of bleeding events, particularly if used concomitantly with aspirin, NSAIDs, warfarin, or other anticoagulants. Bleeding related to SSRI or SNRI use has been reported to range from relatively minor bruising and epistaxis to life-threatening hemorrhage.
CNS depression
Has a low potential to impair cognitive or motor performance; caution operating hazardous machinery or driving.
Dyslipidemia
May cause significant increases in serum total cholesterol and triglycerides; monitor during long-term treatment.
Fractures
Bone fractures have been associated with antidepressant treatment. Consider the possibility of a fragility fracture if an antidepressant-treated patient presents with unexplained bone pain, point tenderness, swelling, or bruising (Rabenda, 2013; Rizzoli, 2012).
Hypertension
Dose-related increases in systolic and diastolic blood pressure have been documented. Monitor blood pressure regularly, and if sustained increases noted, consider dose reduction or discontinuation.
Ocular effects
May cause mild pupillary dilation which in susceptible individuals can lead to an episode of narrow-angle glaucoma. Consider evaluating patients who have not had an iridectomy for narrow-angle glaucoma risk factors.
Pulmonary events
Interstitial lung disease and eosinophilic pneumonia have been rarely reported. May present as progressive dyspnea, cough, and/or chest pain. Prompt evaluation and possible discontinuation of therapy may be necessary.
Serotonin syndrome
Potentially life-threatening serotonin syndrome (SS) has occurred with serotonergic agents (eg, SSRIs, SNRIs), particularly when used in combination with other serotonergic agents (eg, triptans, TCAs, fentanyl, lithium, tramadol, buspirone, St John’s wort, tryptophan) or agents that impair metabolism of serotonin (eg, MAO inhibitors intended to treat psychiatric disorders, other MAO inhibitors [ie, linezolid and intravenous methylene blue]). Monitor patients closely for signs of SS such as mental status changes (eg, agitation, hallucinations, delirium, coma); autonomic instability (eg, tachycardia, labile blood pressure, diaphoresis); neuromuscular changes (eg, tremor, rigidity, myoclonus); GI symptoms (eg, nausea, vomiting, diarrhea); and/or seizures. Discontinue treatment (and any concomitant serotonergic agent) immediately if signs/symptoms arise.
Sexual dysfunction
May cause or exacerbate sexual dysfunction.
SIADH and hyponatremia
SSRIs and SNRIs have been associated with the development of SIADH; hyponatremia has been reported rarely (including severe cases with serum sodium • Weight loss and anorectic effects: Dose-dependent weight loss has been observed in both pediatric and adult patients; weight loss was not limited to those experiencing reduced appetite. Disease-related concerns:
Cardiovascular disease
May cause sustained increase in blood pressure or tachycardia. Control pre-existing hypertension prior to initiation of venlafaxine. Use caution in patients with recent history of MI, unstable heart disease, cerebrovascular conditions, or hyperthyroidism. Hypertensive effect is dose related and increases are generally modest (12 to 15 mm Hg diastolic).
Hepatic impairment
Use caution; clearance is decreased and plasma concentrations are increased; dosage reduction recommended.
Mania/hypomania
May precipitate a shift to mania or hypomania in patients with bipolar disorder. Monotherapy in patients with bipolar disorder should be avoided. Patients presenting with depressive symptoms should be screened for bipolar disorder, including details regarding family history of suicide, bipolar disorder, and depression. Venlafaxine is not FDA approved for the treatment of bipolar depression.
Renal impairment
Use caution; clearance is decreased and plasma concentrations are increased; dosage reduction recommended.
Seizure disorders
Use caution in patients with a previous seizure disorder; discontinue in any patient who develops seizures. Concurrent drug therapy issues:
Drug-drug interactions
Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information. Special populations:
Elderly
Use with caution in the elderly; may have a higher risk of SIADH or hyponatremia.
Pediatric
Small differences in height and weight have been observed in pediatric patients receiving venlafaxine, particularly those Other warnings/precautions:
Discontinuation syndrome
Abrupt discontinuation or interruption of antidepressant therapy has been associated with a discontinuation syndrome. Symptoms arising may vary with antidepressant however commonly include nausea, vomiting, diarrhea, headaches, lightheadedness, dizziness, diminished appetite, sweating, chills, tremors, paresthesias, fatigue, somnolence, and sleep disturbances (eg, vivid dreams, insomnia). Less common symptoms include electric shock-like sensations, cardiac arrhythmias (more common with tricyclic antidepressants), myalgias, parkinsonism, arthralgias, and balance difficulties. Psychological symptoms may also emerge such as agitation, anxiety, akathisia, panic attacks, irritability, aggressiveness, worsening of mood, dysphoria, mood lability, hyperactivity, mania/hypomania, depersonalization, decreased concentration, slowed thinking, confusion, and memory or concentration difficulties. Greater risks for developing a discontinuation syndrome have been associated with antidepressants with shorter half-lives, longer durations of treatment, and abrupt discontinuation. For antidepressants of short or intermediate half-lives, symptoms may emerge within 2 to 5 days after treatment discontinuation and last 7 to 14 days (APA 2010; Fava 2006; Haddad 2001; Shelton 2001; Warner 2006).
Pregnancy & Lactation
Pregnancy
Caution
SNRI — NAS more frequent and severe than SSRIs in some reports. Taper before delivery if possible
Lactation
Venlafaxine and the active metabolite ODV are present in breast milk. In one study, the mean relative infant dose (RID) of venlafaxine + ODV was 8.1% (range: 5% to 13%) when compared to a mean weight-adjusted maternal dose of 194 mg/day (range: 37.5 to 300 mg/day). In general, breastfeeding is considered acceptable when the RID is The mean RID of venlafaxine + ODV was calculated by the authors of a study using mean milk concentrations of 803.9 ng/mL (venlafaxine) and 1,424.2 ng/mL (ODV), pro
Monitoring
| Clinical pearl | Blood pressure should be regularly monitored, especially in patients with a high baseline blood pressure; may cause mean increase in heart rate of 4-9 beats/minute; cholesterol; mental status for depression, suicide ideation (especially at the beginning of therapy or when doses are increased or decreased), anxiety, social functioning, mania, panic attacks; signs/symptoms of serotonin syndrome, hyponatremia, discontinuation symptoms; height and weight should be monitored in children; intraocular pressure and mydriasis (in patients with raised ocular pressure or at risk of acute narrow angle glaucoma) (APA, 2010) |
|---|
Chemistry & Properties
| Formula | C17H27NO2 |
|---|---|
| Molecular weight | 277.41 g/mol |
| IUPAC name | 1-[2-(dimethylamino)-1-(4-methoxyphenyl)ethyl]cyclohexan-1-ol |
| CAS | 93413-69-5 |
| PubChem CID | 5656 |
| InChIKey | PNVNVHUZROJLTJ-UHFFFAOYSA-N |
| logP | 3.04 (XLogP 2.9) |
| Polar surface area | 32.7 Ų |
| H-bond acceptors / donors | 3 / 1 |
| Drug-likeness (QED) | 0.90 |
| Lipinski violations | 0 |
SMILES
COc1ccc(C(CN(C)C)C2(O)CCCCC2)cc1Biology & Pharmacokinetics
Pharmacokinetics
| BBB penetrant | Yes (logBB 0.62) |
|---|
Enzyme interactions
| Enzyme | Role | Detail |
|---|---|---|
| CYP1A2 | Substrate | — |
| CYP2C19 | Substrate | — |
| CYP2C9 | Substrate | — |
| CYP2D6 | Substrate | — |
| CYP3A4 | Substrate | — |
Receptor binding (top 13)
| Target | Action | Affinity |
|---|---|---|
| SERT (SLC6A4) | Inhibitor | pIC50 7.6 |
| 5-HT Transporter (SLC6A4) | Binding | pKi 7.4 |
| NET (SLC6A2) | Inhibitor | pIC50 6.3 |
| adrenergic Alpha2A (ADRA2A) | Binding | pKi 6.0 |
| Cholinergic, muscarinic M1 (CHRM1) | Binding | pKi 6.0 |
| Cholinergic, muscarinic M2 (CHRM2) | Binding | pKi 6.0 |
| NPY-Y1 (NPY1R) | Binding | pKi 6.0 |
| adrenergic Alpha1A (ADRA1A) | Binding | pKi 6.0 |
| Norepinephrine transporter (SLC6A2) | Binding | pKi 5.8 |
| 5-HT2C (HTR2C) | Binding | pKi 5.7 |
| 5-HT2A (HTR2A) | Binding | pKi 5.7 |
| 5-HT6 (HTR6) | Binding | pKi 5.6 |
| Dopamine Transporter (SLC6A3) | Binding | pKi 5.2 |
Transporters
BCRP (Inhibitor)BSEP (Inhibitor)BSEP (Inhibitor)MDR1 (Inhibitor)MRP1 (Inhibitor)MRP2 (Inhibitor)MRP3 (Inhibitor)MRP4 (Inhibitor)OATP1B1 (Inhibitor)OATP1B3 (Inhibitor)OCTN2 (Inhibitor)P-gp (Inhibitor)MDR1 (Substrate)P-gp (Substrate)
Drug–drug interactions (100+, DDInter)
| Interacting drug | Severity | Management |
|---|---|---|
| Anagrelide | major | |
| Arsenic trioxide | major | |
| Bupropion | major | |
| Cabozantinib | major | |
| Ceritinib | major | |
| Chloroquine | major | |
| Cisapride | major | |
| Crizotinib | major | |
| Dexfenfluramine | major | |
| Dextromethorphan | major | |
| Diethylpropion | major | |
| Dolasetron | major | |
| Doxepin | major | |
| Doxepin (topical) | major | |
| Fenfluramine | major | |
| Fingolimod | major | |
| Granisetron | major | |
| Halofantrine | major | |
| Hydroxychloroquine | major | |
| Iobenguane (I-131) | major | |
| Iohexol | major | |
| Iopamidol | major | |
| Ivosidenib | major | |
| Lorcaserin | major | |
| Lumefantrine | major | |
| Macimorelin | major | |
| Mazindol | major | |
| Methylene blue | major | |
| Nilotinib | major | |
| Ondansetron | major | |
| Osimertinib | major | |
| Palonosetron | major | |
| Panobinostat | major | |
| Papaverine | major | |
| Pasireotide | major | |
| Phentermine | major | |
| Phenylpropanolamine | major | |
| Procarbazine | major | |
| Sibutramine | major | |
| Siponimod | major |
Showing 40 of 100+.
Registered Products (18)
| Brand | Form / strength | Pack | Agent | Citizen (JOD) |
|---|---|---|---|---|
| Venzor XR 75 | Tablet 75 mg | 10 tab pack varies | Savvy Pharma | 2.890 |
| Zytik XR | Capsule (as hydrochloride)75 mg | 14 cap | Hikma Pharmaceuticals Co.Ltd/Jordan | 4.050 |
| Zytik XR | Capsule (as hydrochloride) 37.5 mg | 14 cap | Hikma Pharmaceuticals Co.Ltd/Jordan | 4.050 |
| EFEXOR XR 75 Mg Caps. | Capsule 75 mg | 14 cap | Sabbagh Drug Store | 5.050 |
| Venzor XR | Tablet 150 mg | 10 tab pack varies | Savvy Pharma | 5.200 |
| Venlamac XR-75 | Capsule 75 mg | 28 cap | Sun Set Drug Store | 6.730 |
| EFEXOR XR 150 Mg Caps. | Capsule 150 mg | 14 cap | Sabbagh Drug Store | 6.890 |
| Zytik XR | Capsule (as hydrochloride)150 mg | 14 cap | Hikma Pharmaceuticals Co.Ltd/Jordan | 7.280 |
| Vaxor Tab | Tablet (Hcl)37.5 mg | 30 tab | Hayat Pharmaceutical Industries CO.PLC/JORDAN | 7.600 |
| Zytik XR | Capsule 37.5 mg | 28 cap | Hikma Pharmaceuticals Co.Ltd/Jordan | 7.700 |
| Zytik XR | Capsule 75 mg | 28 cap | Hikma Pharmaceuticals Co.Ltd/Jordan | 7.700 |
| Venzor XR 75 | Tablet 75 mg | 30 tab pack varies | Savvy Pharma | 8.150 |
| Vaxor Tab | Tablet (as Hcl) 75 mg | 30 tab | Hayat Pharmaceutical Industries CO.PLC/JORDAN | 9.430 |
| Vaxor Tab | Tablet (Hcl)50 mg | 30 tab | Hayat Pharmaceutical Industries CO.PLC/JORDAN | 9.430 |
| Venexor | Tablet 75 mg | 30 tab | UNITED PHARM.MFG.CO.LTD(UPM)/JORDAN | 9.430 |
| Venexor | Tablet 37.5 mg | 30 tab | UNITED PHARM.MFG.CO.LTD(UPM)/JORDAN | 12.350 |
| Zytik XR | Capsule 150 mg | 28 cap | Hikma Pharmaceuticals Co.Ltd/Jordan | 13.830 |
| Venzor XR | Tablet 150 mg | 30 tab pack varies | Savvy Pharma | 14.660 |