Pharmacopedia - User contributions [en]

Trazodone

2026-06-29T18:33:14Z

WikiSysop: Safety wave: priapism 4-hour emergency counseling (label + Warner 1987)

{{MedTemplate
| generic = Trazodone
| brand = Desyrel (original IR), Oleptro (ER), Trittico
| structure =
| classes = [[:Category:SARIs|Serotonin antagonist and reuptake inhibitor (SARI)]], [[:Category:Antidepressants|Antidepressant]], [[:Category:Sleep aids|Sleep aid]]
| uses = <vote slug="major-depressive-disorder-use">Major depressive disorder (FDA, original indication)</vote>, <vote slug="insomnia-trazodone-use">Insomnia (off-label; vastly more common in current practice than the depression indication)</vote>, <vote slug="anxiety-adjunct-use">Anxiety disorder adjunct (off-label)</vote>, <vote slug="ptsd-sleep-disturbance-use">PTSD-related sleep disturbance (off-label)</vote>
| starting_dose = Insomnia (off-label): 25-50 mg PO at bedtime, titrate to effect. Depression: 150 mg/day divided BID-TID; titrate to 400 mg/day outpatient or 600 mg/day inpatient
| preparations = IR tablets 50, 100, 150, 300 mg; Oleptro ER tablets 150, 300 mg
| fda_max = 400 mg/day outpatient; 600 mg/day inpatient
| pill_id =
| routes = Oral
| onset = Sleep effect within 30-60 minutes; antidepressant effect over 1-2 weeks
| duration = ~6-8 hours (IR); 24 hours (Oleptro ER)
| halflife = Biphasic: ~3-6 hours alpha, ~5-9 hours beta<ref name="trazodone-label">FDA Prescribing Information, Desyrel (trazodone hydrochloride), Apotex/various, current revision. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/018207s032lbl.pdf</ref>
| bioavailability = ~65% (oral)<ref name="trazodone-label" />
| pregnancy = Limited human data; observational signals inconclusive.{{citation needed}}
| legal = [[USLegal:Prescription only|Rx-only]] in US. Carries the antidepressant '''Boxed Warning''' for suicidality in children, adolescents, and young adults<ref name="trazodone-label" />
| mechanism = <vote slug="trazodone-mech-claim">Combined strong 5-HT2A antagonism with weaker serotonin reuptake inhibition (the SARI class signature). At the low doses used for insomnia (25-100 mg), 5-HT2A antagonism, H1 antihistaminergic effect, and α1-adrenergic antagonism dominate, producing sedation; at antidepressant doses (≥150 mg) the SRI contribution adds. The active metabolite mCPP is a 5-HT2C agonist that may contribute to anxiogenesis in some patients.</vote> '''Priapism''' is a recognized rare adverse effect via α1 antagonism in penile vasculature and is the marquee counseling point for male patients<ref name="trazodone-label" />.
| counseling = Priapism is a recognized, uncommon adverse effect of trazodone, attributed to alpha-1 adrenergic antagonism in penile vasculature; cases requiring surgical intervention or resulting in permanent erectile dysfunction have been reported.<ref>Trazodone hydrochloride prescribing information, Warnings and Precautions (priapism).</ref> Patients should be counseled that a prolonged erection, generally one lasting more than 4 hours, or any painful erection unrelated to sexual activity, is a medical emergency requiring immediate care, because delayed treatment risks permanent damage.<ref>Warner MD, Peabody CA, Whiteford HA, Hollister LE. Trazodone and priapism. J Clin Psychiatry. 1987;48(6):244-245.</ref>
}}

== References ==
<references />

[[Category:SARIs]]
[[Category:Antidepressants]]
[[Category:Sleep aids]]

Aripiprazole

2026-06-29T18:33:12Z

WikiSysop: Safety wave: FDA 2016 impulse-control labeled Warning (May 3 2016 DSC); labeled, not boxed

{{MedTemplate
| generic = Aripiprazole
| brand = Abilify (oral), Abilify Maintena (monthly IM LAI), Aristada (aripiprazole lauroxil IM LAI), Abilify Asimtufii (bi-monthly IM LAI), Abilify MyCite (digital ingestion sensor)
| structure =
| classes = [[:Category:Neuroleptics|Neuroleptic]], [[:Category:Atypical neuroleptics|Atypical neuroleptic]], [[:Category:Third-generation neuroleptics|Third-generation neuroleptic]], [[:Category:Mood stabilizers|Mood stabilizer]]
| uses = <vote slug="schizophrenia-use">Schizophrenia (FDA, ages 13+)</vote>, <vote slug="bipolar-mania-mixed-use">Bipolar mania and mixed episodes (FDA)</vote>, <vote slug="bipolar-maintenance-use">Bipolar maintenance (FDA)</vote>, <vote slug="mdd-adjunct-use">Major depressive disorder adjunct (FDA)</vote>, <vote slug="autism-irritability-use">Autism spectrum disorder-associated irritability (FDA, pediatric ages 6-17)</vote>, <vote slug="tourette-syndrome-pediatric-use">Tourette syndrome (FDA, pediatric)</vote>
| starting_dose = Schizophrenia/bipolar mania: 10-15 mg PO once daily, target 15-30 mg. MDD adjunct: 2-5 mg/day, target 5-15 mg. Pediatric autism irritability: 2 mg, titrate to 5-15 mg. Maintena LAI: 400 mg IM every 4 weeks after oral overlap
| preparations = Tablets 2, 5, 10, 15, 20, 30 mg; ODT 10, 15 mg; oral solution 1 mg/mL; acute IM injection 9.75 mg/1.3 mL; Maintena LAI 300, 400 mg monthly; Aristada LAI 441, 662, 882, 1064 mg (4-8 week dosing); Asimtufii bi-monthly
| fda_max = 30 mg/day (adult schizophrenia); 15 mg/day (MDD adjunct)
| pill_id =
| routes = Oral, intramuscular (acute and long-acting)
| onset = Neuroleptic effect emerges over days to weeks; activation symptoms (akathisia, insomnia) often within days
| duration = 24 hours (oral); 4-8 weeks (LAI)
| halflife = ~75 hours (long, accumulates over weeks)<ref name="abilify-label">FDA Prescribing Information, Abilify (aripiprazole), Otsuka/Bristol-Myers Squibb, current revision. https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/021436s038,021713s030,021729s022,021866s023lbl.pdf</ref>
| bioavailability = ~87% (oral)<ref name="abilify-label" />
| pregnancy = Limited human data; signal for neonatal extrapyramidal symptoms and withdrawal with third-trimester exposure.{{citation needed}}
| legal = [[USLegal:Prescription only|Rx-only]] in US. Carries the atypical-neuroleptic '''Boxed Warning''' for increased mortality in elderly patients with dementia-related psychosis, and the antidepressant suicidality '''Boxed Warning''' when used for MDD adjunct in patients under 24<ref name="abilify-label" />
| mechanism = <vote slug="aripiprazole-mech-claim">'''D2 and D3 dopamine receptor partial agonist''' (the third-generation neuroleptic signature, distinct from olanzapine/risperidone full D2 antagonism), with additional 5-HT1A partial agonism and 5-HT2A receptor antagonism. The D2 partial agonism is the "dopamine system stabilizer" rationale: in hyperdopaminergic states (psychosis, mania) aripiprazole functions as a partial antagonist; in hypodopaminergic states (prefrontal cortex, MDD adjunct) it functions as a partial agonist.</vote> '''Akathisia''' is the most common dose-limiting adverse effect, particularly with the MDD-adjunct dose range. Lower weight gain, lower metabolic burden, and lower prolactin elevation than most second-generation neuroleptics, the principal pharmacological selling points. CYP2D6 and CYP3A4 metabolism; CPIC PGx guidance applies for CYP2D6 dose individualization<ref name="abilify-label" />.
| effects = In May 2016 the FDA warned that aripiprazole can cause intense, uncontrollable urges, most often compulsive gambling, but also compulsive eating, shopping, and hypersexuality; these urges can arise at any dose, are easily missed, and generally resolve when the dose is lowered or the medicine is stopped.<ref>U.S. Food and Drug Administration. Drug Safety Communication: FDA warns about new impulse-control problems associated with mental health drug aripiprazole (Abilify, Abilify Maintena, Aristada). May 3, 2016.</ref> The association is commonly linked to aripiprazole's dopamine D2 partial agonism, though the FDA stated the mechanism is not established. This is a labeled Warning, separate from the medicine's boxed warnings.
}}

== References ==
<references />

[[Category:Neuroleptics]]
[[Category:Atypical neuroleptics]]
[[Category:Third-generation neuroleptics]]
[[Category:Mood stabilizers]]

Diazepam

2026-06-29T18:33:10Z

WikiSysop: Safety wave: 2020 FDA benzo-class boxed warning (Sept 23 2020)

{{MedTemplate
| generic = Diazepam
| brand = Valium (oral, IV/IM, rectal), Diastat (rectal gel for breakthrough seizures), Valtoco (nasal spray for breakthrough seizures), Libervant (buccal film)
| structure =
| classes = [[:Category:Benzodiazepines|Benzodiazepine (long-acting)]], [[:Category:Anxiolytics|Anxiolytic]], [[:Category:Anticonvulsants|Anticonvulsant]], [[:Category:Skeletal muscle relaxants|Skeletal muscle relaxant]], [[:Category:Schedule IV controlled substances|Schedule IV controlled substance]]
| uses = <vote slug="anxiety-disorders-broad-use">Anxiety disorders (FDA)</vote>, <vote slug="alcohol-withdrawal-use">Alcohol withdrawal (FDA; the classic indication for long-acting benzodiazepines)</vote>, <vote slug="preoperative-sedation-use">Preoperative sedation (FDA)</vote>, <vote slug="status-epilepticus-use">Status epilepticus (FDA, IV)</vote>, <vote slug="breakthrough-seizures-use">Breakthrough seizures (FDA, Diastat rectal gel; Valtoco intranasal)</vote>, <vote slug="acute-muscle-spasm-use">Acute muscle spasm (FDA, IV/IM)</vote>, <vote slug="cerebral-palsy-spasticity-use">Cerebral palsy spasticity (FDA)</vote>
| starting_dose = Anxiety: 2-10 mg PO 2-4 times daily. Alcohol withdrawal: 10-20 mg PO/IV every 4-6 hours, symptom-triggered. Status epilepticus: 5-10 mg IV. Breakthrough seizures: Diastat rectal 0.2-0.5 mg/kg or Valtoco intranasal 5-20 mg
| preparations = Tablets 2, 5, 10 mg; oral solution 1, 5 mg/mL; injection 5 mg/mL; Diastat rectal gel 2.5, 5, 10, 20 mg; Valtoco nasal spray 5, 7.5, 10 mg/dose; Libervant buccal film
| fda_max = 40 mg/day (oral, anxiety)
| pill_id =
| routes = Oral, IV, IM, rectal, intranasal, buccal
| onset = 15-60 minutes (oral); 1-5 minutes (IV); 4-10 minutes (rectal or intranasal)
| duration = 6-24 hours (parent); much longer when accounting for the long-lived active metabolites
| halflife = Diazepam 20-50 hours; '''N-desmethyldiazepam (nordazepam) 30-200 hours''' is the major active metabolite and accumulates substantially with chronic dosing<ref name="valium-label">FDA Prescribing Information, Valium (diazepam), Roche/Bausch, current revision. https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/013263s094lbl.pdf</ref>
| bioavailability = ~93% (oral); ~90% (rectal)<ref name="valium-label" />
| pregnancy = Some signal for cleft palate with first-trimester exposure (debated); neonatal sedation and withdrawal with third-trimester exposure.{{citation needed}}
| legal = [[USLegal:Schedule IV|Schedule IV controlled substance]] in US. Carries the benzodiazepine class '''Boxed Warning''' for risk of fatal respiratory depression, coma, and death when combined with opioids<ref name="valium-label" />
| mechanism = <vote slug="diazepam-mech-claim">Classic positive allosteric modulator of the GABA-A receptor at the benzodiazepine binding site (α-γ subunit interface), enhancing chloride ion conductance and producing the full benzodiazepine effect spectrum: anxiolysis, anticonvulsant activity, skeletal muscle relaxation, and sedation. The very long elimination half-life combined with the even-longer-lived active metabolite nordazepam is the clinical signature, producing stable plasma levels with infrequent dosing.</vote> The pharmacokinetic profile produces '''self-tapering withdrawal''' as plasma levels gradually decline, the basis of diazepam's preference in alcohol withdrawal protocols. CYP3A4 and CYP2C19 substrate; CYP3A4 inhibitors substantially raise exposure<ref name="valium-label" />.
| monitoring = '''Boxed warning:''' in September 2020 the FDA required an updated boxed warning across the benzodiazepine class for the risks of abuse, misuse, addiction, physical dependence, and withdrawal reactions.<ref>U.S. Food and Drug Administration. Drug Safety Communication: FDA requiring Boxed Warning updated to improve safe use of benzodiazepine drug class. September 23, 2020.</ref> Physical dependence can develop with continued use even at prescribed doses, and abrupt discontinuation or rapid dose reduction can precipitate acute, sometimes life-threatening withdrawal (including seizures), so prolonged use requires a gradual, individualized taper. This is in addition to the earlier boxed warning for fatal respiratory depression, coma, and death when benzodiazepines are combined with opioids or other CNS depressants.<ref>U.S. Food and Drug Administration. Drug Safety Communication: FDA warns about serious risks and death when combining opioid pain or cough medicines with benzodiazepines. August 31, 2016.</ref>
}}

== References ==
<references />

[[Category:Benzodiazepines]]
[[Category:Anxiolytics]]
[[Category:Anticonvulsants]]
[[Category:Skeletal muscle relaxants]]
[[Category:Schedule IV controlled substances]]

Lorazepam

2026-06-29T18:33:08Z

WikiSysop: Safety wave: 2020 FDA benzo-class boxed warning (Sept 23 2020) + propylene-glycol IV toxicity monitoring (Wilson 2005)

{{MedTemplate
| generic = Lorazepam
| brand = Ativan (oral, injectable), Loreev XR
| structure =
| classes = [[:Category:Benzodiazepines|Benzodiazepine]], [[:Category:Anxiolytics|Anxiolytic]], [[:Category:Schedule IV controlled substances|Schedule IV controlled substance]]
| uses = <vote slug="anxiety-disorders-broad-use">Anxiety disorders (FDA)</vote>, <vote slug="preoperative-sedation-use">Preoperative sedation (FDA, IV)</vote>, <vote slug="status-epilepticus-use">Status epilepticus (FDA, IV; first-line per current guidelines)</vote>, <vote slug="alcohol-withdrawal-use">Alcohol withdrawal (off-label, often first-line in hepatic impairment)</vote>, <vote slug="agitation-acute-use">Acute agitation (off-label, IM)</vote>, <vote slug="chemotherapy-induced-nausea-use">Chemotherapy-induced nausea (off-label adjunct)</vote>
| starting_dose = Anxiety: 0.5-1 mg PO BID-TID. Insomnia: 1-2 mg PO at bedtime. Status epilepticus: 4 mg IV (adult), repeat after 5-10 minutes if needed. Acute agitation: 1-2 mg IM
| preparations = Tablets 0.5, 1, 2 mg; oral concentrate 2 mg/mL; injection 2 mg/mL and 4 mg/mL; Loreev XR capsules 1, 2, 3 mg
| fda_max = 10 mg/day (anxiety, oral)
| pill_id =
| routes = Oral, intramuscular, intravenous
| onset = 30-60 minutes (oral); 5 minutes (IV); 15-30 minutes (IM)
| duration = 6-8 hours
| halflife = 12-15 hours (intermediate); '''no active metabolites''' (key clinical feature)<ref name="ativan-label">FDA Prescribing Information, Ativan (lorazepam), Bausch/Pfizer, current revision. https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/017794s044lbl.pdf</ref>
| bioavailability = ~90% (oral)<ref name="ativan-label" />
| pregnancy = Some signal for cleft lip/palate with first-trimester exposure (debated); neonatal sedation and withdrawal with third-trimester exposure.{{citation needed}}
| legal = [[USLegal:Schedule IV|Schedule IV controlled substance]] in US. Carries the benzodiazepine class '''Boxed Warning''' for risk of fatal respiratory depression, coma, and death when combined with opioids<ref name="ativan-label" />
| mechanism = <vote slug="lorazepam-mech-claim">Positive allosteric modulator of the GABA-A receptor at the benzodiazepine binding site (α-γ subunit interface), enhancing chloride ion conductance and consequent neuronal inhibition. The intermediate half-life sits between short-acting alprazolam and long-acting diazepam/clonazepam, making lorazepam a clinically versatile choice.</vote> Metabolized by '''glucuronidation rather than CYP''', so unlike alprazolam and diazepam, lorazepam has minimal CYP-mediated interactions, and the lack of active metabolites makes it the preferred benzodiazepine in elderly patients and in hepatic impairment. Tolerance, dependence, and significant withdrawal syndrome on abrupt discontinuation; slow taper essential after extended use<ref name="ativan-label" />.
| monitoring = '''Boxed warning:''' in September 2020 the FDA required an updated boxed warning across the benzodiazepine class for the risks of abuse, misuse, addiction, physical dependence, and withdrawal reactions.<ref>U.S. Food and Drug Administration. Drug Safety Communication: FDA requiring Boxed Warning updated to improve safe use of benzodiazepine drug class. September 23, 2020.</ref> Physical dependence can develop with continued use even at prescribed doses, and abrupt discontinuation or rapid dose reduction can precipitate acute, sometimes life-threatening withdrawal (including seizures), so prolonged use requires a gradual, individualized taper. This is in addition to the earlier boxed warning for fatal respiratory depression, coma, and death when benzodiazepines are combined with opioids or other CNS depressants.<ref>U.S. Food and Drug Administration. Drug Safety Communication: FDA warns about serious risks and death when combining opioid pain or cough medicines with benzodiazepines. August 31, 2016.</ref> The intravenous formulation of lorazepam is solubilized in propylene glycol; high-dose or prolonged continuous infusion (for example in refractory status epilepticus or prolonged intensive-care sedation) can cause propylene glycol to accumulate, producing a high-anion-gap metabolic (lactic) acidosis, hyperosmolarity, and acute kidney injury. The osmolar gap and serum lactate should be monitored when large cumulative intravenous doses are given.<ref>Wilson KC, Reardon C, Theodore AC, Farber HW. Propylene glycol toxicity: a severe iatrogenic illness in ICU patients receiving intravenous benzodiazepines. Chest. 2005;128(3):1674-1681.</ref>
}}

== References ==
<references />

[[Category:Benzodiazepines]]
[[Category:Anxiolytics]]
[[Category:Schedule IV controlled substances]]

Tramadol

2026-06-29T18:33:05Z

WikiSysop: Safety wave: 2017 FDA boxed warning + pediatric/breastfeeding contraindications (FDA DSC April 20 2017); M1 affinity framing + CPIC 2021 cite

{{MedTemplate
| generic = Tramadol
| brand = Ultram (IR), Ultram ER, ConZip ER
| structure =
| classes = [[:Category:Opioid analgesics|Opioid analgesic (atypical, weak μ-agonist with serotonin/norepinephrine reuptake inhibition)]], [[:Category:Schedule IV controlled substances|Schedule IV controlled substance]], [[:Category:Analgesics|Analgesic]]
| uses = <vote slug="moderate-severe-pain-use">Moderate to moderately severe pain (FDA)</vote>, <vote slug="chronic-pain-tramadol-use">Chronic pain in opioid-sparing regimens (off-label)</vote>, <vote slug="restless-legs-syndrome-use">Restless legs syndrome (off-label, second-line)</vote>, <vote slug="neuropathic-pain-broad-use">Neuropathic pain (off-label)</vote>
| starting_dose = IR: 25-50 mg PO every 4-6 hours as needed, titrate as tolerated. ER: 100 mg PO once daily, titrate by 100 mg every 5 days
| preparations = IR tablets 50 mg; ER tablets 100, 200, 300 mg (Ultram ER, ConZip); oral solution 5 mg/mL; combination products with acetaminophen (Ultracet)
| fda_max = 400 mg/day (IR, adult); 300 mg/day (ER); 300 mg/day in elderly >75 years
| pill_id =
| routes = Oral
| onset = 30-60 minutes (IR)
| duration = 4-6 hours (IR); 24 hours (ER)
| halflife = Tramadol 6-7 hours; M1 active metabolite 7-9 hours<ref name="ultram-label">FDA Prescribing Information, Ultram (tramadol hydrochloride), Janssen, current revision. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/020281s048lbl.pdf</ref>
| bioavailability = ~75% (IR, rises with multi-dose administration due to saturable first-pass)<ref name="ultram-label" />
| pregnancy = Chronic third-trimester exposure produces neonatal opioid withdrawal syndrome and respiratory depression at delivery.{{citation needed}}
| legal = [[USLegal:Schedule IV|Schedule IV controlled substance]] in US (federally scheduled 2014); some states schedule higher<ref name="ultram-label" />
| mechanism = <vote slug="tramadol-mech-claim">Tramadol acts partly as a prodrug for opioid effect: CYP2D6 converts it to O-desmethyltramadol (M1), which binds the mu-opioid receptor with substantially higher affinity than the parent compound (reported on the order of 200-fold, with estimates varying by assay), so M1 is the dominant opioid-active moiety while parent tramadol contributes serotonin and norepinephrine reuptake inhibition.<ref>Grond S, Sablotzki A. Clinical pharmacology of tramadol. Clin Pharmacokinet. 2004;43(13):879-923.</ref> Pharmacogenomic guidance on CYP2D6 metabolizer status for opioid selection is provided by the Clinical Pharmacogenetics Implementation Consortium.<ref>Crews KR, Monte AA, Huddart R, et al. Clinical Pharmacogenetics Implementation Consortium Guideline for CYP2D6, OPRM1, and COMT Genotypes and Select Opioid Therapy. Clin Pharmacol Ther. 2021;110(4):888-896.</ref></vote> CYP2D6 ultra-rapid metabolizers produce dangerously high M1 levels with risk of fatal respiratory depression, particularly in children; CYP2D6 poor metabolizers get reduced opioid analgesic benefit and rely on the serotonin/norepinephrine reuptake component. '''Serotonin syndrome''' risk with SSRIs, SNRIs, MAOIs, and other serotonergic agents. '''Seizure''' risk is dose-dependent and elevated in patients with epilepsy, head trauma, or concurrent serotonergic medicines.
| monitoring = '''Boxed warning:''' tramadol carries an FDA boxed warning for life-threatening respiratory depression arising from ultra-rapid CYP2D6 metabolism to the active metabolite O-desmethyltramadol (M1), alongside the opioid-class warnings for addiction, abuse, and misuse and for fatal interaction with benzodiazepines and other CNS depressants.<ref>U.S. Food and Drug Administration. Drug Safety Communication: FDA restricts use of prescription codeine pain and cough medicines and tramadol pain medicines in children; recommends against use in breastfeeding women. April 20, 2017.</ref> Tramadol is contraindicated for any use in children younger than 12 years, and contraindicated in children younger than 18 years to treat pain after tonsillectomy and/or adenoidectomy; use in adolescents 12 to 18 years is not recommended when they have obesity, obstructive sleep apnea, or severe lung disease.<ref>FDA Drug Safety Communication, April 20, 2017 (as above); tramadol prescribing information, Boxed Warning.</ref> Use is not recommended in breastfeeding women because M1 passes into breast milk and can cause sedation and life-threatening respiratory depression in the infant, especially of an ultra-rapid metabolizer.<ref>American College of Obstetricians and Gynecologists. Committee Opinion No. 711: Opioid Use and Opioid Use Disorder in Pregnancy. Obstet Gynecol. 2017;130(2):e81-e94.</ref>
}}

== References ==
<references />

[[Category:Opioid analgesics]]
[[Category:Schedule IV controlled substances]]
[[Category:Analgesics]]