Trazodone

Trazodone, sold under many brand names,[1] is an antidepressant medication.[13] It is used to treat major depressive disorder, anxiety disorders, and, with other medications, alcohol dependence.[13] It is taken by mouth.[13]

Trazodone
Clinical data
Trade namesMany brand names worldwide[1]
Other namesAF-1161
AHFS/Drugs.comMonograph
MedlinePlusa681038
License data
Dependence
liability		None[2]
Addiction
liability		None[2]
Routes of
administration		By mouth (tablets)
ATC code
Legal status
Legal status
  • AU: S4 (Prescription only)
  • CA: ℞-only
  • UK: POM (Prescription only)
  • US: ℞-only
  • In general: ℞ (Prescription only)
Pharmacokinetic data
BioavailabilityBy mouth: 65%[3]
Protein binding89–95%[4]
MetabolismLiver (CYP3A4, CYP2D6, CYP1A2?)[5][6][7][8][9]
MetabolitesmCPP[10]
Onset of actionBy mouth: 1 hour (Tmax)[11]
Elimination half-lifeTrazodone IR: 7 hours[3]
Trazodone ER: 10 hours[3]
mCPP: 4–14 hours[5][12]
ExcretionUrine: 70–75%[3]
Feces: 21%[3]
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.039.364
Chemical and physical data
FormulaC19H22ClN5O
Molar mass371.87 g·mol−1
3D model (JSmol)
Melting point87 °C (189 °F)
  (verify)

Common side-effects include dry mouth, feeling faint, vomiting, and headache.[13] More serious side effects may include suicide, mania, irregular heart rate, and pathologically prolonged erections.[13] It is unclear if use during pregnancy or breastfeeding is safe.[14] It is a phenylpiperazine compound of the serotonin antagonist and reuptake inhibitor (SARI) class.[15][16] Trazodone also has sedating effects.[17]

Trazodone was approved for medical use in the United States in 1981.[13] It is available as a generic medication.[13] In 2017, it was the 30th most commonly prescribed medication in the United States, with more than 22 million prescriptions.[18][19]

Medical uses

Trazodone has the following medical uses:

Depression

The primary use of trazodone is the treatment of major depression. Data from open and double-blind trials suggest the antidepressant efficacy of trazodone is comparable to that of amitriptyline, doxepin, and mianserin. Also, trazodone showed anxiolytic properties, low cardiotoxicity, and relatively mild side effects.[23]

Because trazodone has minimal anticholinergic activity, it was especially welcomed as a treatment for geriatric patients with depression when it first became available. Three double-blind studies reported trazodone has antidepressant efficacy similar to that of other antidepressants in geriatric patients. However, a side effect of trazodone, orthostatic hypotension, which may cause dizziness and increase the risk of falling, can have devastating consequences for elderly patients; thus, this side effect, along with sedation, often makes trazodone less acceptable for this population, compared with newer compounds that share its lack of anticholinergic activity but not the rest of its side-effect profile. Still, trazodone is often helpful for geriatric patients with depression who have severe agitation and insomnia.[23]

Trazodone is usually used at a dosage of 150 to 300 mg/day for the treatment of depression.[6][24] Lower doses have also been used to augment other antidepressants, or when initiating therapy.[6][24] Higher doses up to 600 mg/day have been used in more severe cases of depression, for instance in hospitalized patients.[25] Trazodone is usually administered multiple times per day, but once-daily administration may be similarly effective.[26]

Insomnia

Low-dose trazodone is used off-label in the treatment of insomnia.[27] Two recent reviews found that trazodone is the second most prescribed agent for insomnia, though most studies have been in depressed individuals.[24] Systematic reviews and meta-analyses published in 2017 and 2018 have found trazodone to be a significantly effective medication for insomnia, both in depressed and non-depressed individuals.[28][29] Trazodone is used at doses in the range of 25 to 100 mg/day for insomnia.[28][30] In the past, doses of more than 100 mg/day were also studied.[28]

Other off-label uses

Other off-label and investigational uses are listed below:[27]

Available forms

Trazodone is available in the form of 25 mg, 50 mg, 100 mg, 150 mg, and 300 mg tablets for oral ingestion.[40][41]

An extended release formulation at 150 mg and 300 mg as tablets is also available.[42][43]

Side effects
See also: List of adverse effects of trazodone

Because of its lack of anticholinergic side effects, trazodone is especially useful in situations in which antimuscarinic effects are particularly problematic (e.g., in patients with benign prostatic hyperplasia, closed-angle glaucoma, or severe constipation). Trazodone's propensity to cause sedation is a dual-edged sword. For many patients, the relief from agitation, anxiety, and insomnia can be rapid; for other patients, including those individuals with considerable psychomotor retardation and feelings of low energy, therapeutic doses of trazodone may not be tolerable because of sedation. Trazodone elicits orthostatic hypotension in some people, probably as a consequence of α1-adrenergic receptor blockade. The unmasking of bipolar disorder may occur with trazodone[13] and other antidepressants.[44]

Precautions for trazodone include known hypersensitivity to trazodone and under 18 years and combined with other antidepressant medications, it may increase the possibility of suicidal thoughts or actions.[45]

Trazodone has been reported to cause seizures in a small number of patients who took it concurrently with medications to control seizures.

While trazodone is not a true member of the SSRI class of antidepressants, it does still share many properties of the SSRIs, especially the possibility of discontinuation syndrome if the medication is stopped too quickly.[46] Care must, therefore, be taken when coming off the medication, usually by a gradual process of tapering down the dose over a period of time.

Suicide

Antidepressants increase the risk of suicidal thoughts and behaviors in children and young adults. Close monitoring for emergence of suicidal thoughts and behaviors is thus recommended.[47]

Sedation

Since trazodone may impair the mental and/or physical abilities required for performance of potentially hazardous tasks, such as operating an automobile or machinery, the patient should be cautioned not to engage in such activities while impaired. Compared to the reversible MAOI antidepressant drug moclobemide, more impairment of vigilance occurs with trazodone.[48]

Heart

Case reports have noted cardiac arrhythmias emerging in relation to trazodone treatment, both in patients with pre-existing mitral valve prolapse and in patients with negative personal and family histories of cardiac disease.[49]

QT prolongation has been reported with trazodone therapy. Arrhythmia identified include isolated PVCs, ventricular couplets, and in two patients short episodes (three to four beats) of ventricular tachycardia. Several post-marketing reports have been made of arrhythmia in trazodone-treated patients who have pre-existing cardiac disease and in some patients who did not have pre-existing cardiac disease. Until the results of prospective studies are available, patients with pre-existing cardiac disease should be closely monitored, particularly for cardiac arrhythmias. Trazodone is not recommended for use during the initial recovery phase of myocardial infarction. Concomitant administration of drugs that prolong the QT interval or that are inhibitors of CYP3A4 may increase the risk of cardiac arrhythmia.[50][51]

Priapism

A relatively rare side effect associated with trazodone is priapism, likely due to its antagonism at α-adrenergic receptors.[52] More than 200 cases have been reported, and the manufacturer estimated that the incidence of any abnormal erectile function is about one in 6,000 male patients treated with trazodone. The risk for this side effect appears to be greatest during the first month of treatment at low dosages (i.e. <150 mg/day). Early recognition of any abnormal erectile function is important, including prolonged or inappropriate erections, and should prompt discontinuation of trazodone treatment. Clinical reports have also described trazodone-associated psychosexual side effects in women, including increased libido, priapism of the clitoris, and spontaneous orgasms.[49][53]

Other

Rare cases of liver toxicity have been observed, possibly due to the formation of reactive metabolites.[54]

Elevated prolactin concentrations have been observed in people taking trazodone.[25][55] They appear to be increased by around 1.5- to 2-fold.[25][55]

Pregnancy and lactation

Sufficient data in humans are lacking. Use should be justified by the severity of the condition to be treated.[56][57]

Overdose

There are reported cases of high doses of trazodone precipitating serotonin syndrome.[58] There are also reports of patients taking multiple SSRIs with trazodone and precipitating serotonin syndrome.[58]

Trazodone appears to be relatively safer than TCAs, MAOIs, and a few of the other second-generation antidepressants in overdose situations, especially when it is the only agent taken. Fatalities are rare, and uneventful recoveries have been reported after ingestion of doses as high as 6,000–9,200 mg. In one report, 9 of 294 cases of overdose were fatal, and all nine patients had also taken other central nervous system (CNS) depressants. When trazodone overdoses occur, clinicians should carefully monitor for low blood pressure, a potentially serious toxic effect. In a report of a fatal trazodone overdose, torsades de pointes and complete atrioventricular block developed, along with subsequent multiple organ failure, with a trazodone plasma concentration of 25.4 mg/L on admission.[23][59][60][61]

There is no specific antidote for trazodone. Management of overdosage should, therefore, be symptomatic and supportive. Any person suspected of having taken an overdosage should be evaluated at a hospital as soon as possible. Activated charcoal, and forced diuresis may be useful in facilitating elimination of the drug, gastric lavage has been shown to not be useful unless done during the first hour after intake.

Interactions

Trazodone is metabolized by several liver enzymes, including CYP3A4, CYP2D6, and CYP1A2.[5][62] Its active metabolite meta-chlorophenylpiperazine is known to be formed by CYP3A4 and metabolized by CYP2D6.[5] Inhibition or induction of the aforementioned enzymes by various other substances may alter the metabolism of trazodone and/or mCPP, leading to increased and/or decreased blood concentrations.[6][24] The enzymes in question are known to be inhibited and induced by many medications, herbs, and foods, and as such, trazodone may interact with these substances. Potent CYP3A4 inhibitors such as clarithromycin, erythromycin, fluvoxamine, grapefruit juice, ketoconazole, and ritonavir may lead to increased concentrations of trazodone and decreased concentrations of mCPP, while CYP3A4 inducers like carbamazepine, enzalutamide, phenytoin, phenobarbital, and St. John's wort may result in decreased trazodone concentrations and increased mCPP concentrations.[6][24][7] CYP2D6 inhibitors may result in increased concentrations of both trazodone and mCPP while CYP2D6 inducers may decrease their concentrations.[5][6][8] Examples of potent CYP2D6 inhibitors include bupropion, cannabidiol, duloxetine, fluoxetine, paroxetine, quinidine, and ritonavir, while CYP2D6 inducers include dexamethasone, glutethimide, and haloperidol. CYP1A2 inhibitors may increase trazodone concentrations while CYP1A2 inducers may decrease trazodone concentrations. Examples of potent CYP1A2 inhibitors include ethinylestradiol (found in hormonal birth control) fluoroquinolones (e.g., ciprofloxacin), fluvoxamine, and St. John's wort, while potent CYP1A2 inducers include phenytoin, rifampin, ritonavir, and tobacco.

A study found that ritonavir, a strong CYP3A4 and CYP2D6 inhibitor and moderate CYP1A2 inducer, increased trazodone peak levels by 1.34-fold, increased area-under-the-curve levels by 2.4-fold, and decreased the clearance of trazodone by 50%.[6][7] This was associated with adverse effects such as nausea, hypotension, and syncope.[6] Another study found that the strong CYP3A4 inducer carbamazepine reduced concentrations of trazodone by 60 to 74%.[6] The strong CYP2D6 inhibitor thioridazine has been reported to increase concentrations of trazodone by 1.36-fold and concentrations of mCPP by 1.54-fold.[5][63] On the other hand, CYP2D6 genotype has not been found to predict trazodone or mCPP concentrations with trazodone therapy, although it did correlate with side effects like dizziness and prolonged corrected prolonged corrected QT interval.[64][65][66]

Combination of trazodone with selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants (TCAs), or monoamine oxidase inhibitors has a theoretical risk of serotonin syndrome.[6][24] However, trazodone has been studied in combination with SSRIs and seemed to be safe in this context.[6][24] On the other hand, cases of excessive sedation and serotonin syndrome have been reported with the combinations of trazodone and fluoxetine or paroxetine.[5] This may be due to combined potentiation of the serotonin system.[5] However, it may also be related to the fact that fluoxetine and paroxetine are strong inhibitors of CYP2D6 and fluoxetine is additionally a weak or moderate inhibitor of CYP3A4.[5][67] Accordingly, fluoxetine has been reported to result in increased levels of trazodone and mCPP by 1.31- to 1.65-fold and by 2.97- to 3.39-fold, respectively.[5][68]

Smokers have lower levels of trazodone and higher ratios of mCPP to trazodone.[5][69] Trazodone levels were 30% lower in smokers and mCPP to trazodone ratio was 1.29-fold higher in smokers, whereas mCPP concentrations were not different between smokers and non-smokers.[69] Smoking is known to induce CYP1A2, and this may be involved in these findings.[5]

Pharmacology

Pharmacodynamics
Trazodone (and metabolite)[70]
SiteTrazodonemCPPSpeciesRef
SERT160–>10,000[71]202–432Human[70][72][73]
NET≥8,500≥1,940Human[73][72]
DAT≥7,400NDHuman[73][70]
5-HT1A96–11844–400Human[70][74][75]
5-HT1B>10,00089–501Human[70][76]
5-HT1D106210–1,300Human[70][75][77]
5-HT1E>10,000NDHuman[70]
5-HT1FNDNDNDND
5-HT2A20–4532–398Human[70][78][79][80]
5-HT2B74–1893.2–63Human[70][78][81][82]
5-HT2C224–4023.4–251Human[78][83][84][80]
5-HT3>10,000427Human[70]
5-HT4NDNDNDND
5-HT5A>10,0001,354Human[70]
5-HT6>10,0001,748Human[70]
5-HT71,782163Human[70]
α112–4297–2,900Human[72][74][75][85]
  α1A1531,386Human[70]
  α1BND915Human[70]
  α1DNDNDNDND
α2106–490112–570Human[74][72][75][85]
  α2A728145Human[70]
  α2BND106Human[70]
  α2C155124Human[70]
β>10,0002,500Human[70][75]
  β1>10,0002,359Human[70]
  β2>10,0003,474Human[70]
D13,7307,000Human[70][75]
D2≥3,500>10,000Human[70][74][86][75]
D3353>10,000Rat[70][75]
D4703NDHuman[70]
D5>10,000>10,000Human[70][75]
H1220–1,100326Human[70][85][74]
H23,290NDHuman[70]
H3>10,000NDGuinea pig[70]
H4>10,000NDHuman[70]
mAChRs>10,000>10,000Human[70][86][74][75]
nAChRs>10,000>10,000Human[70]
σ1>10,000NDRat[70]
σ25368,350Rat[70]
I1ND759Rat[70]
NMDAR
(MK-801)		>10,000NDRat[70]
VDCCs>10,0006,043Rat[70]
Values are Ki (nM). The smaller the value, the more strongly the drug binds to the site.

Trazodone is a mixed agonist and antagonist of various serotonin receptors, antagonist of adrenergic receptors, weak histamine H1 receptor antagonist, and weak serotonin reuptake inhibitor.[7][24] More specifically, it is an antagonist of 5-HT2A and 5-HT2B receptors, a partial agonist of the 5-HT1A receptor, and an antagonist of the α1- and α2-adrenergic receptors.[24][7] It is also a ligand of the 5-HT2C receptor with lower affinity than for the 5-HT2A receptor.[7][24] However, it is unknown whether trazodone acts as a full agonist, partial agonist, or antagonist of the 5-HT2C receptor.[7] Trazodone is a 5-HT1A receptor partial agonist similarly to buspirone and tandospirone but with comparatively greater intrinsic activity.[70][87][88] A range of weak affinities (Ki) have been reported for trazodone at the human histamine H1 receptor, including 220 nM,[70] 350 nM,[85] 500 nM,[89] and 1,100 nM.[74]

Trazodone has a minor active metabolite known as meta-chlorophenylpiperazine (mCPP), and this metabolite may contribute to some degree to the pharmacological properties of trazodone.[5][90] In contrast to trazodone, mCPP is an agonist of various serotonin receptors.[91] It has relatively low affinity for α1-adrenergic receptors unlike trazodone, but does high affinity for α2-adrenergic receptors and weak affinity for the H1 receptor.[7] In addition to direct interactions with serotonin receptors, mCPP is a serotonin releasing agent similarly to agents like fenfluramine and MDMA.[7][92][93][68] In contrast to these serotonin releasing agents however, mCPP does not appear to cause long-term serotonin depletion (a property thought to be related to serotonergic neurotoxicity).[7]

Trazodone's 5-HT2A receptor antagonism and weak serotonin reuptake inhibition form the basis of its common label as an antidepressant of the serotonin antagonist and reuptake inhibitor (SARI) type.[64]

Target occupancy studies

Studies have estimated occupancy of target sites by trazodone based on trazodone concentrations in blood and brain and on the affinities of trazodone for the human targets in question.[94][38][7] Roughly half of brain 5-HT2A receptors are blocked by 1 mg of trazodone and essentially all 5-HT2A receptors are saturated at 10 mg of trazodone, but the clinically effective hypnotic doses of trazodone are in the 25–100 mg range.[28][30] The occupancy of the serotonin transporter (SERT) by trazodone is estimated to be 86% at 100 mg/day and 90% at 150 mg/day.[6][94] Trazodone may almost completely occupy the 5-HT2A and 5-HT2C receptors at doses of 100 to 150 mg/day.[6][94] Significant occupancy of a number of other sites may also occur.[6][94] However, another study estimated much lower occupancy of the SERT and 5-HT2A receptors by trazodone.[7]

Estimated occupancy of biological targets by trazodone at different doses[94][38]
Target Estimated target occupancy
50 mg/day 100 mg/day 150 mg/day
SERT 75% 86% 90%
5-HT1A 91% 95% 97%
5-HT1D 91% 95% 97%
5-HT2A 97% 98% 99%
5-HT2B 94% 97% 98%
5-HT2C 83% 91% 94%
5-HT7 39% 56% 66%
α1A 88% 94% 96%
α2A 61% 75% 82%
α2C 88% 94% 96%
D4 62% 76% 83%
H1 84% 91% 94%
Very low (<25–33%): NET, DAT, 5-HT1B, 5-HT1E, 5-HT3, 5-HT5A, 5-HT6, β1, β2, D5, H4, mAChRs, nAChRs. Low (<50%): D1, D2. Not determined: α1B, α2B, D3. Note: Another study estimated much lower occupancies.[7]

Correspondence to clinical effects

Trazodone may act predominantly as a 5-HT2A receptor antagonist to mediate its therapeutic benefits against anxiety and depression.[95] Its inhibitory effects on serotonin reuptake and 5-HT2C receptors are comparatively weak.[95] In relation to these properties, trazodone does not have similar properties to selective serotonin reuptake inhibitors (SSRIs)[95] and is not particularly associated with increased appetite and weight gain—unlike other 5-HT2C antagonists like mirtazapine.[96][97] Moderate 5-HT1A partial agonism may contribute to trazodone's antidepressant and anxiolytic actions to some extent as well.[87][88][98]

The combined actions of 5-HT2A and 5HT2C receptor antagonism with serotonin reuptake inhibition only occur at moderate to high doses of trazodone.[99] Doses of trazodone lower than those effective for antidepressant action are frequently used for the effective treatment of insomnia.[99] Low doses exploit trazodone's potent actions as a 5-HT2A receptor antagonist, and its properties as an antagonist of H1 and α1-adrenergic receptors, but do not adequately exploit its SERT or 5-HT2C inhibition properties, which are weaker.[99] Since insomnia is one of the most frequent residual symptoms of depression after treatment with an SSRI, a hypnotic is often necessary for patients with a major depressive episode.[99] Not only can a hypnotic potentially relieve the insomnia itself, but treating insomnia in patients with major depression may also increase remission rates due to improvement of other symptoms such as loss of energy and depressed mood.[99] Thus, the ability of low doses of trazodone to improve sleep in depressed patients may be an important mechanism whereby trazodone can augment the efficacy of other antidepressants.[99]

Trazodone's potent α1-adrenergic blockade may cause some side effects like orthostatic hypotension and sedation.[100] Conversely, along with 5-HT2A and H1 receptor antagonism, it may contribute to its efficacy as a hypnotic. Trazodone lacks any affinity for the muscarinic acetylcholine receptors, so does not produce anticholinergic side effects.

mCPP, a non-selective serotonin receptor modulator and serotonin releasing agent, is an active metabolite of trazodone and has been suggested to possibly play a role in its therapeutic benefits.[7][92][93][68] However, research has not supported this hypothesis and mCPP might actually antagonize the efficacy of trazodone as well as produce additional side effects.[101][102][103][104][105]

Pharmacokinetics

Trazodone is well-absorbed after oral administration.[7] Its bioavailability is 65 to 80%.[7] Peak blood levels of trazodone occur 1 to 2 hours after ingestion and peak levels of the metabolite mCPP occur after 2 to 4 hours.[7][5] Absorption is somewhat delayed and enhanced by food.

Trazodone is not sequestered into any tissue.[7] The medication is 89 to 95% protein-bound.[5][106] The volume of distribution of trazodone is 0.8 to 1.5 L/kg.[7] Trazodone is highly lipophilic.[5]

The metabolic pathways involved in the metabolism are not well-characterized.[6][64] In any case, the cytochrome P450 enzymes CYP3A4, CYP2D6, and CYP1A2 may all be involved to varying extents.[5][6][7][8] Trazodone is known to be extensively metabolized by the liver via hydroxylation, N-oxidation, and N-dealkylation.[5] Several metabolites of trazodone have been identified, including a dihydrodiol metabolite (via hydroxylation), a metabolite hydroxylated at the para position of the meta-chlorophenyl ring (via CYP2D6), oxotriazolepyridinepropionic acid (TPA) and mCPP (both via N-dealkylation of the piperazinyl nitrogen mediated by CYP3A4), and a metabolite formed by N-oxidation of the piperazinyl nitrogen.[5][62] CYP1A2, CYP2D6, and CYP3A4 genotypes all do not seem to predict concentrations of trazodone or mCPP.[64][65][66][107] In any case, there are large interindividual variations in the metabolism of trazodone.[5] In addition, poor metabolizers of dextromethorphan, a CYP2D6 substrate, eliminate mCPP more slowly and have higher concentrations of mCPP than do extensive metabolizers.[5]

mCPP is formed from trazodone by CYP3A4 and is metabolized via hydroxylation by CYP2D6 (to a para-hydroxylated metabolite).[6][7][8][5] It may contribute to the pharmacological actions of trazodone.[7][6][108] mCPP levels are only 10% of those of trazodone during therapy with trazodone, but is nonetheless present at concentrations known to produce psychic and physical effects in humans when mCPP has been administered alone.[5][109] In any case, the actions of trazodone, such as its serotonin antagonism, might partially overwhelm those of mCPP.[6] As a consequence of the production of mCPP as a metabolite, patients administered trazodone may test positive on EMIT II urine tests for the presence of MDMA ("ecstasy").[110]

The mean blood elimination half-life of trazodone is biphasic: the first phase's half-life is 3 to 6 hours, and the following phase's half-life is 5 to 9 hours.[5] The elimination half-life of mCPP is 4 to 14 hours and is longer than that of trazodone.[5] Metabolites are conjugated to gluconic acid or glutathione and around 70 to 75% of 14C-labelled trazodone was found to be excreted in the urine within 72 hours.[111] The remaining drug and its metabolites are excreted in the faeces via biliary elimination. Less than 1% of the drug is excreted in its unchanged form.[106] After an oral dose of trazodone, it was found to be excreted 20% in the urine as TPA and conjugates, 9% as the dihydrodiol metabolite, and less than 1% as unconjugated mCPP.[5] mCPP is glucuronidated and sulfated similarly to other trazodone metabolites.[5]

Chemistry

Trazodone is a triazolopyridine derivative and a phenylpiperazine that is chemically related to nefazodone and etoperidone, each of which are derivatives of it.[112][113][25]

History

Trazodone was developed in Italy, in the 1960s, by Angelini Research Laboratories as a second-generation antidepressant.[114][115] It was developed according to the mental pain hypothesis, which was postulated from studying patients and which proposes that major depression is associated with a decreased pain threshold.[116] In sharp contrast to most other antidepressants available at the time of its development, trazodone showed minimal effects on muscarinic cholinergic receptors. Trazodone was patented and marketed in many countries all over the world. It was approved by the Food and Drug Administration (FDA) in 1981[117] and was the first non-tricyclic antidepressant approved in the US.[118]

Society and culture

Generic names

Trazodone is the generic name of the drug and its INN, BAN, and DCF, while trazodone hydrochloride is its USAN, USP, BANM, and JAN.[119][120][121][122]

Brand names

Trazodone has been marketed under a large number of brand names throughout the world.[120][122] Major brand names include Desyrel (worldwide), Donaren (Brazil), Molipaxin (Ireland, United Kingdom), Oleptro (United States), Trazorel (Canada), and Trittico (worldwide).[120][122]

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