New Drug Approvals

The Pharmacology and Toxicology of Reboxetine

Michael J. Burns, MD
Division of Toxicology
Department of Emergency Medicine
Beth Israel Deaconess Medical Center
330 Brookline Avenue
Boston, MA 02215
Phone: (617) 667-5198
Fax: (617) 667-8726
Email:

Int J Med Toxicol 2000; 3(4): 26
See also Editor's Note, 3(4): 25


Financial source: none

There are no financial, litigational, or other relationships that may lead to a conflict of interest, particularly with Pharmacia & Upjohn, manufacturer of reboxetine (VestraTM)

Introduction

All antidepressants that are currently available for clinical use are effective for the treatment of depression but vary significantly in terms of tolerability and side effect profile. Monoamine oxidase inhibitors (MAOIs) and tricyclic antidepressants (TCAs) are limited by their high incidence of side effects at therapeutic doses and life-threatening toxicity following overdose. Selective serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs), although much safer than TCAs and MAOIs, are limited by certain side effects, drug-drug interactions, and response failure in patients with severe depression. Reboxetine is a novel, selective norepinephrine reuptake inhibitor (NRI) that provides a new therapeutic alternative and, perhaps, advance for the treatment of depression. Unlike other antidepressants, reboxetine has no serotonin-potentiating effects. (1) The results of numerous premarketing studies demonstrate that reboxetine is clinically effective, well-tolerated, and does not have significant drug-drug interactions. (2-7) Based on its pharmacologic selectivity and specificity, reboxetine should have a wide therapeutic index and is likely to be safer following overdose. (6, 7) The following is a description of the pharmacology, pharmacokinetics, and toxicology of reboxetine.

Structure and Pharmacology

Reboxetine mesylate (Vestra, Edronax, Prolift, Integrex, NoreboxTM) is internationally marketed by Pharmacia & Upjohn and is currently available for clinical use as an antidepressant in Europe. (7, 8) It should be available for use in the United States by the end of this year (personal communication, Pharmacia & Upjohn, May 18, 2000) Reboxetine is a racemic mixture of RR- and SS-([2-[a [2-ethoxyphenoxy]benzyl]-morpholine sulphonate]) (Figure 1); structurally similar antidepressants include fluoxetine and viloxazine. (9- 11)


Figure 1. Structure of reboxetine

It is the first selective and specific norepinephrine or noradrenaline reuptake inhibitor (NRI or NARI) available for clinical use. Based on in vitro data, reboxetine dose-dependently and potently inhibits presynaptic norepinephrine reuptake (Ki = 8 nmol/L) in the central nervous system (CNS); it has over 1000 and 130 times greater selectivity for blocking norepinephrine (NE) as compared to dopamine (D) and serotonin (5-HT) reuptake, respectively. (1) In vivo, reboxetine is approximately 30 times more potent at blocking noradrenergic neurons as compared to serotonergic neurons (1) Unlike TCAs and similar to SSRIs and SNRIs, reboxetine has weak affinity (Ki > 1000 nmol/L) for a 1-adrenergic, H1-histaminergic, and M1-muscarinic CNS receptors. (1, 11, 12) In addition, reboxetine has an affinity at the NE transporter that is more than 1000-fold greater than all subtypes of CNS adrenergic, dopaminergic, histaminergic, muscarinic, and serotonergic receptors (1, 11, 12) Reboxetine also antagonizes presynaptic a 2 -adrenergic receptor effects and prevents clonidine-induced hypothermia in mice. (1, 9-14) This latter effect is indirect; it results from increased synaptic concentrations of NE and not from direct a 2-adrenergic receptor antagonism. (1, 11, 12, 14) Reboxetine has no monoamine oxidase A inhibitory properties; as such, it may be safe to administer MAOIs to patients who are already taking reboxetine. (9, 11, 15, 16) Reboxetine does not appear to have any affect on nitric oxide synthase and, thus, is less likely than SSRIs to produce erectile dysfunction. (1, 17)

Reboxetine has minimal direct effects on cardiovascular functioning. Although studies have not been performed to determine affinity for cardiac ionic channels, therapeutic doses have not been associated with arrhythmias or conduction disturbances. (2-8, 18, 19) At therapeutic doses in humans, reboxetine increases heart rate and blood pressure; these effects are consistent with a sympathomimetic effect that results from NE reuptake inhibition in peripheral tissues. (7, 14, 18, 19) A heart rate greater than 100 beats per minute was present in over 20 percent of patients treated with reboxetine in one study. (18) In addition, reboxetine increases resting pupil diameter and shortens the recovery time of the light reflex, effects consistent with NE reuptake blockade in the iris. (14, 20) Reboxetine reduces salivation, which likely reflects enhancement of noradrenergic inhibition of central parasympathetic nuclei. (14) Like SSRIs and unlike TCAs, reboxetine has minimal effects on psychomotor function and does not produce behavioral toxicity at therapeutic doses. (21)

Pharmacokinetics

Reboxetine is marketed as a mixture of (R,R) and (S,S) enantiomers. Although the latter is more potent, there are no qualitative differences in pharmacodynamic and pharmacokinetic properties between the two enantiomers. (9, 10) Reboxetine is formulated as 1, 2, 3, 4, and 5 mg capsules or tablets; the dissolution properties for each are similar. (9, 10) After oral administration, reboxetine is well absorbed with a bioavailability of approximately 92 percent. (22) Food does not affect bioavailability. (9) Absorption is rapid with a tmax of 1.5 to 2 hours. (9, 10, 23) Once absorbed, reboxetine is extensively bound (97%) to plasma proteins, mainly to a 1-acid glycoprotein. Volume of distribution is 0.5 L/kg. (7, 9) The mean steady-state plasma concentrations depend on the dose but range from 50 to 160 ng/mL. (9, 10, 23) At steady state, accumulation is approximately two times that found following a single dose. (9, 23) Reboxetine is extensively metabolized in the liver to four inactive metabolites. (9) The principal metabolite, O-desethylreboxetine, is produced by CYP3A4 isoenzyme oxidative dealkylation of the parent drug. Little unchanged drug is excreted in the urine (9%).  (9, 10 23) Reboxetine has linear elimination kinetics across the normal dose range with a terminal half-life of 13 ± 5 hours in healthy human volunteers. (9, 10, 23) This allows for twice-daily dose administration. The recommended therapeutic dose of reboxetine is 8 mg per day, in two divided doses. The maximum daily dose is 12 mg. (7)

Repeated administration of reboxetine is not associated with a significant induction of the CYP3A4 isoenzyme (no auto-induction).  (23, 24) In addition, repeated administration of reboxetine does not appreciably inhibit any CYP P450 isoenzymes, even when plasma concentrations are eight times greater than those following a single dose. (24)

Special Populations. Gender has no significant effect on the pharmacokinetics of reboxetine. (9, 22, 23) Elderly patients have reduced clearance rates of reboxetine and may require dose reduction with repeated administration. (7, 9) Patients with severe liver and renal impairment have elimination half-lives of reboxetine that are approximately doubled from those of healthy volunteers (26 to 31 hours versus 13 to 17 hours). (9, 25) A reduction of the starting dose of reboxetine to 4 mg per day, in two divided doses, is recommended for elderly patients and those with hepatic and renal impairment. (7, 9) Data is not available with respect to the use of reboxetine in children and pregnant or lactating women.

Clinical Efficacy

In numerous double-blind, controlled studies, reboxetine has demonstrated superior efficacy to that of placebo and similar or greater efficacy to that of imipramine, desipramine, and fluoxetine for the treatment of depression. (2-7, 26) Reboxetine is also efficacious for treating hospitalized patients with severe depression. (2-4, 7) Evidence suggests that the onset of therapeutic effect occurs earlier with reboxetine than with other antidepressants. (1, 3) In long-term treatment studies, reboxetine-treated depressed patients remain in remission significantly more often than those taking placebo. (27) In all clinical efficacy studies, reboxetine has been well-tolerated with minimal adverse effects. (2-7)

Toxicology

Animal Toxicity Data. In mouse studies, reboxetine is well-tolerated. Oral doses from 2 to 10 mg/kg produce effects predictive of clinical antidepressant activity (therapeutic dose range) (1) Mild mydriasis is observed between 50 and 400 mg/kg. (1) CNS stimulation (e.g., shaking, tremors, and increased flexor reflexes) does not occur until 100 mg/kg of reboxetine has been administered orally. (1) Generalized clonic seizures occur following toxic oral doses of 400 mg/kg. (1) Toxic effects begin 20 minutes after oral administration, peak at 60 minutes, and last approximately 120 minutes. A wide margin of safety is evident from the 10- to 40-fold dose ratio that separates therapeutic and toxic doses in the mouse.

Human Toxicity Data. In healthy human volunteer, placebo-controlled studies, reboxetine has been shown to significantly increase resting heart rate and pupil diameter, shorten the recovery time of the pupillary light reflex response, and significantly reduce salivation and pupillary light reflex amplitude at therapeutic doses. (14, 18-20, 28) Although not significant, reboxetine increases both diastolic and systolic blood pressure in human volunteers. (14, 18, 19) These clinical signs reflect NE reuptake blockade in central and peripheral tissues.

Following both short- and long-term treatment, reboxetine is well-tolerated. In many studies, the overall incidence of adverse effects for patients treated with reboxetine have been similar to those treated with placebo. Adverse events that have occurred significantly more often in reboxetine-treated patients as compared to placebo-treated patients include blurred vision, constipation, dry mouth, insomnia, sweating, sinus tachycardia, and urinary hesitancy. (2-8) These effects appear to reflect autonomic disturbances created by NE reuptake blockade. (14)

Clinically important changes in vital signs and ECG have not been reported with therapeutic reboxetine treatment. (2-8, 18, 19) In one study, the QTc increase for reboxetine was only 7 to 8 msec and the mean heart rate increase was only 5 beats per minute. (19) Mild orthostatic hypotension has been infrequently reported with reboxetine treatment. (2, 10) Clinically relevant changes in laboratory parameters have been reported only once with reboxetine therapy. A single case report relates hyponatremia due to the inappropriate secretion of antidiuretic hormone to reboxetine therapy. (29) In addition, reboxetine is non-sedative, does not impair psychomotor performance and is not associated with an increased incidence of seizures in healthy volunteers. (6, 18, 21) These findings suggest that reboxetine may prove safe following overdose.

Little information is available on the safety of reboxetine in overdose but early clinical experience suggests low toxicity. (30) During preclinical studies, four reboxetine overdoses were reported to the manufacturer; all made a full recovery. (8, 31) There were no reports of ECG abnormalities, coma, or seizures following overdose with reboxetine alone. In one patient who had ingested 52 mg reboxetine as the sole agent, toxicity was minimal. Subsequent to its clinical availability in Europe, there have been very few reports of overdose with reboxetine alone; none have proven fatal despite ingestion of up to 240 mg of reboxetine. (30, 31) One fatal overdose has been reported in a patient who ingested reboxetine in combination with amitriptyline (doses unknown). (31)

The clinical effects that occur following acute reboxetine overdose are expected to be an exaggeration of the drug’s known pharmacological effects. Acute NE reuptake inhibition should produce sympathomimetic effects. Signs and symptoms may variably include sinus tachycardia, hypertension or hypotension, diaphoresis, mydriasis, tremulousness, anxiety, agitation, and confusion. More serious intoxication may result in significant neuromuscular hyperactivity, seizures, hyperthermia, and rhabdomyolysis. Although sufficient human toxicity data are lacking, seizures are a theoretical concern following reboxetine overdose since NE reuptake blockade is partly implicated in seizures that occur with other cyclic antidepressants (e.g., TCAs, SNRIs) Coma, marked respiratory depression, arrhythmias, and death are expected to occur only rarely with isolated reboxetine toxicity. Cardiac conduction disturbances are not expected to occur.

The specificity of reboxetine for NE reuptake inhibition is so great that, even following overdose, it is highly unlikely that reboxetine would obtain concentrations in plasma necessary to bind to and produce effects at other CNS receptors (supramicromolar inhibitory constants [Ki]). (1) For instance, even with rapid and complete gastrointestinal absorption, an overdose of 20, 4-mg tablets of reboxetine (total, 80 mg) in a 70-kg individual would result in a free peak plasma concentration of 220 nmol/L. This concentration is still well below the in vitro Ki values reported for reboxetine at CNS a 1- and a 2-adrenergic (Ki = 10, 43 m mol/L, respectively), D2-dopaminergic (Ki = 9 m mol/L), H1-histaminergic (Ki = 1.4 m mol/L), M1-muscarinic (Ki = 3.9 m mol/L), and 5-HT2A-serotonergic (Ki = 1.5 m mol/L) receptors. ( 1, 11)

Drug Interactions

To date, no clinically significant pharmacodynamic or pharmacokinetic drug-drug or drug-food interactions have been described with reboxetine. (9) No significant additive effect on cognitive or psychomotor function was observed when alcohol or lorazepam was given with therapeutic doses of reboxetine. (9, 32, 33) Although not clinically proven, it may be possible to administer a MAOI to a patient taking reboxetine. Reboxetine does not itself inhibit MAO and, as an NRI, should protect against tyramine reactions associated with MAOI therapy; the blockade of the NE reuptake transporter by reboxetine should prevent the release of an expanded presynaptic pool of NE. (9, 11, 15, 16) Conversely, however, the administration of reboxetine to a patient taking a MAOI may be dangerous and could precipitate a life-threatening sympathomimetic reaction by further increasing the amount of NE in the synapse. Until more data is available, the concomitant administration of reboxetine and MAOIs is not recommended.

Although speculative, the potential for a serious adverse pharmacodynamic interaction is a concern when reboxetine is combined with other drugs. In particular, when reboxetine is combined with other agents that increase synaptic NE concentrations (e.g., TCAs, SNRIs, cocaine, amphetamines, phenylpropanolamine, pseudoephedrine), a life-threatening hyperadrenergic state could result. For instance, an adverse drug interaction cannot be excluded as the cause of the reported postmarketing fatality of a patient who ingested reboxetine in combination with amitriptyline. (31) In addition, the therapeutic combination of reboxetine with other cyclic antidepressants (e.g., TCAs, bupropion, SNRIs, SSRIs) may produce synergistic neurotoxic effects (e.g., seizures, agitation, confusion). Venlafaxine pharmacologically is both a NRI and 5HT reuptake inhibitor. In overdose a severe serotonin-like syndrome can result. Therefore, while an overdose of reboxetine or an SSRI alone may not result in severe toxicity, the combination may. In general, since reboxetine does not itself potentiate serotonin neurotransmission, it is not expected to precipitate the serotonin syndrome when combined with agents that increase CNS serotonin levels.

Reboxetine is primarily metabolized by CYP 3A4 and its clearance may be significantly increased and decreased by inducers and inhibitors of this enzyme, respectively. Ketoconazole and papaverine, potent CYP3A4 inhibitors, have been shown to significantly increase plasma reboxetine concentrations; these effects have not been shown to be clinically significant. (7, 24, 34) At high in vitro concentrations, reboxetine is a competitive inhibitor of both CYP2D6 (Ki = 2.5 m mol/L) and CYP3A4 (Ki = 11 m mol/L). (24) With therapeutic doses of reboxetine, however, plasma concentrations of reboxetine are not likely to be high enough (submicromolar) to produce clinically significant inhibition of CYP3A4 and CYP2D6. (24) It is not known whether reboxetine overdose will interfere with the metabolism of other drugs metabolized by CYP3A4 or CYP2D6. Repeated administration of reboxetine does not significantly induce or inhibit CYP P450 enzymes. (9, 23)

Overdose Management

Diagnosis of reboxetine overdose is based on a positive history of ingestion, suggestive physical findings, and confirmatory laboratory testing. Sympathomimetic findings on physical exam may suggest overdose with this agent. The presence of reboxetine in the plasma may be confirmed and quantitated by high-performance liquid chromatography (HPLC).  (35) The correlation between serum reboxetine concentrations and therapeutic or toxic effects are unknown. Routine drug quantification is not recommended, particularly since clinical effects are unlikely to be severe following reboxetine overdose.

Treatment is primarily supportive and should allow for complete recovery when provided in a timely fashion for the vast majority of patients. Sinus tachycardia and asymptomatic hypertension, when present, do not require any specific treatment. When hypertension is associated with end-organ dysfunction (e.g., confusion, agitation, chest pain, electrocardiographic changes, and pulmonary edema), intravenous sodium nitroprusside or phentolamine is recommended. Phentolamine is pharmacologically attractive due to its ability to block alpha-adrenergic receptors and antagonize the effects of NE. As for other sympathomimetic intoxications, liberal doses of benzodiazepines (e.g., diazepam or lorazepam) are recommended as first-line therapy for patients with neuromuscular hyperactivity, agitation, and seizures associated with reboxetine intoxication or adverse interaction.

Gastrointestinal decontamination should be initiated as soon as possible after patient stabilization. For the vast majority of patients, the administration of a single dose of activated charcoal with or without a cathartic is the preferred method of decontamination following reboxetine overdose.

Conclusion

Reboxetine, a selective NRI, is a novel antidepressant with similar or greater therapeutic efficacy to current antidepressants. It has a wide margin of safety and is well-tolerated at therapeutic doses. To date, reboxetine has no clinically significant drug-drug or drug-food interactions. The combination or reboxetine with other sympathomimetic agents, however, could produce synergistic hyperadrenergic effects. Although experience is limited, the clinical effects that result from reboxetine overdose are likely to be mild to moderate in severity and manifest as an exaggeration of pharmacologic effects. If they occur, toxic effects should be evident within a few hours of acute ingestion and are likely to be characterized by mydriasis, diaphoresis, anxiety, mild hypertension, sinus tachycardia, and tremor. Timely supportive care should prevent death in the overwhelming majority of patients with reboxetine poisoning.

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Int J Med Toxicol 2000; 3(4): 26
See also Editor's Note, 3(4): 25

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