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Venlafaxine

N06A - Antidepressants ATC N06AX16 Small molecule approved 1993 Oral Natural product Black-box warning

JFDA label: Vaxor Tab

⚠ Black-Box Warning
  • 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

Very Common >10%Common 1–10%Uncommon 0.1–1% Rare 0.01–0.1%Very Rare <0.01%Not Known

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

Depression: Oral: Immediate-release tablets: Initial: 37.5 to 75 mg/day, administered in 2 or 3 divided doses; may increase in ≤75 mg/day increments at intervals of ≥4 days as tolerated; usual dosage: 75 to 225 mg/day (maximum dose: 375 mg/day) (APA 2010) Extended-release capsules or tablets: Initial: 37.5 to 75 mg once daily; in patients who are initiated at 37.5 mg once daily, may increase to 75 mg once daily after 4 to 7 days; dose may then be increased by ≤75 mg/day increments at intervals of ≥4 days as tolerated; usual dosage: 75 to 225 mg once daily (maximum dose: 225 mg/day) Note: Patients treated with a therapeutic dose with venlafaxine immediate release may be switched to venlafaxine extended release (ER) at the nearest equivalent dose (mg/day). Following the formulation switch individual dosage adjustments may be necessary. Generalized anxiety disorder: Oral: Extended-release capsules: Initial: 37.5 to 75 mg once daily; in patients who are initiated at 37.5 mg once daily, may increase to 75 mg once daily after 4 to 7 days; may then be increased by ≤75 mg/day increments at intervals of ≥4 days as tolerated; usual dosage: 75 to 225 mg once daily (maximum dose: 225 mg/day) Panic disorder: Oral: Extended-release capsules: Initial: 37.5 mg once daily for 1 week; may increase to 75 mg once daily after 7 days, may then be increased by ≤75 mg/day increments at intervals of ≥7 days; usual dosage: 75 to 225 mg once daily (maximum dose: 225 mg/day). Social anxiety disorder: Oral: Extended-release capsules or tablets: 75 mg once daily; no evidence that doses >75 mg/day offer any additional benefit. Attention-deficit disorder (off-label use): Oral: Immediate release: Initial: 18.75 to 37.5 mg/day in 1 or 2 divided doses; may increase every 1 to 2 weeks based on response and tolerability up to a maximum of 225 mg/day (Adler 1995; Hedges 1995). Additional data may be necessary to further define the role of venlafaxine in this condition. Diabetic neuropathy (off-label use): Extended release: Oral: Initial: 37.5 mg or 75 mg once daily; increase by 75 mg each week to a maximum dosage of 225 mg daily based on tolerance and effect. An adequate duration to determine effect and to accomplish titration has been documented to be 4 to 6 weeks (Bril 2011; Kadiroglu 2008; Rowbotham 2004). Episodic migraine prevention (off-label use): Extended release: Oral: Initial: 37.5 once daily for 3 days; based on response and tolerability continue to increase at 75 mg increments to a target dose of 75 to 150 mg once daily (Bulut 2004; EFNS [Evers 2009]; Pringsheim 2012). Additional data may be necessary to further define the role of venlafaxine in this condition. Hot flashes (off-label use): Oral: Immediate-release and extended release: Dosage range studied: 37.5 to 150 mg daily; therapy usually initiated with 37.5 mg daily to minimize adverse effects; dose may remain at 37.5 mg daily or titrated by 37.5 mg per week to a dose of 75 mg or 150 mg daily administered in a singl
(For additional information see "Venlafaxine: Pediatric drug information") Attention-deficit/hyperactivity disorder (off-label use) (Olvera 1996): Children and Adolescents: Oral: Initial: 12.5 mg/day Children Children ≥40 kg: Increase by 25 mg/week to maximum of 75 mg/day in 3 divided doses Mean dose: 60 mg or 1.4 mg/kg administered in 2 to 3 divided doses Discontinuation of therapy: Refer to adult dosing. MAO inhibitor recommendations: Refer to adult dosing.
Refer to adult dosing. No specific recommendations for elderly; use with caution Discontinuation of therapy: Refer to adult dosing. MAO inhibitor recommendations: Refer to adult dosing.
GFR 10 to 70 mL/minute: Extended release: Reduce total daily dose by 25% to 50% Immediate release: Reduce total daily dose by 25% Hemodialysis: Reduce total daily dose by 50% or more
Mild to moderate impairment (Child-Pugh class A and B): Reduce total daily dose by 50%. There is variability in clearance for patients with cirrhosis; therefore, a reduction in total daily dose of more than 50% may be necessary. Severe impairment (Child-Pugh class C): There are no dosage adjustments provided in the manufacturer’s labeling; however, a reduction in total daily dose of at least 50% or more is prudent in patients with cirrhosis.

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

FDA category C

Caution

SNRI — NAS more frequent and severe than SSRIs in some reports. Taper before delivery if possible

Lactation

RID 8.1%

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 pearlBlood 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

2D structure
FormulaC17H27NO2
Molecular weight277.41 g/mol
IUPAC name1-[2-(dimethylamino)-1-(4-methoxyphenyl)ethyl]cyclohexan-1-ol
CAS93413-69-5
PubChem CID5656
InChIKeyPNVNVHUZROJLTJ-UHFFFAOYSA-N
logP3.04 (XLogP 2.9)
Polar surface area32.7 Ų
H-bond acceptors / donors3 / 1
Drug-likeness (QED)0.90
Lipinski violations0
SMILESCOc1ccc(C(CN(C)C)C2(O)CCCCC2)cc1

Biology & Pharmacokinetics

Pharmacokinetics

BBB penetrantYes (logBB 0.62)

Enzyme interactions

EnzymeRoleDetail
CYP1A2Substrate
CYP2C19Substrate
CYP2C9Substrate
CYP2D6Substrate
CYP3A4Substrate

Receptor binding (top 13)

TargetActionAffinity
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 drugSeverityManagement
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)

BrandForm / strengthPackAgentCitizen (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