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At least 19 recordsLinked to original sources

PubMed1997

The influence of lithium on fluvoxamine therapeutic efficacy and pharmacokinetics in depressed patients on combined fluvoxamine-lithium therapy.

The influence of lithium on fluvoxamine therapeutic efficacy, plasma concentrations and pharmacokinetics was studied in 12 depressed inpatients. Six patients were on fluvoxamine monotherapy and six were on combined fluvoxamine-lithium therapy. The treatment response was determined using 17-item Hamilton Rating Scale for Depression. Blood samples were collected during 48 h after a single dose administration of 100 mg fluvoxamine, and five times at steady state after repeated doses of 100 mg fluvoxamine per day. The evaluation of 17-item Hamilton Rating Scale for Depression Scores showed a significant clinical improvement 2 and 4 weeks after the beginning of the therapy in both groups (p < 0.01). However, 2 weeks after the administration of the drug(s) had started, significant differences (p < 0.05) in efficacy between the two treatments in favour of the fluvoxamine-lithium combination were found. Plasma concentrations of fluvoxamine were measured by high-performance liquid chromatography. The comparison of the measured concentrations of fluvoxamine showed a similar course of the plasma concentration-time curves in both groups of patients. Pharmacokinetic parameters of fluvoxamine did not show any significant difference on the comparison between the groups. According to the results from this study, it is evident that lithium does not affect plasma concentrations and pharmacokinetics of fluvoxamine in depressed patients on concomitant treatment with these two drugs. However, the effect achieved with the combination was better.

Adult↗

PubMed1998

Fluvoxamine or placebo in the treatment of panic disorder and relationship to blood concentrations of fluvoxamine.

A six-week double-blind placebo-controlled trial of fluvoxamine was undertaken in 46 patients suffering from panic disorder with or without agoraphobia diagnosed by DSM-III-R guidelines. Average daily dosage of fluvoxamine was 160 mg, with a highest permitted dose of 300 mg/day. Weekly evaluation included a diary in which the number, severity, and duration of full-blown and limited panic attacks and the duration and severity of anticipating fear, CAS, GAS, CGI, HAM-D, adverse effects and the number of capsules not taken were noted. Fluvoxamine was not significantly superior to placebo with regard to the main outcome criterion, i.e., the reduction in the number of panic attacks, but it was significantly more effective with regard to the diminution in the number of limited panic attacks and showed a tendency to significance in respect of GAS and CGI. Plasma levels of fluvoxamine were measured at the end of week one and at the end of the study. Most patients with complete remission at the end of the study were found in the verum group with plasma fluvoxamine levels ranging from 10 to 100ng/ml. It is suggested that therapeutic response might be maximized by monitoring fluvoxamine concentrations in blood.

Adolescent↗

PubMed2004

[Postherpetic neuralgia alleviated by an SSRI fluvoxamine: two cases of PHN accompanied with depression were treated with fluvoxamine].

Case 1: female, age 76. Fluvoxamine (50 mg/day) initiated a reduction of pain on the 14th day of administration and completely ameliorated pain as well as depression. Case 2: female, age 76. Fluvoxamine (25 mg/day) was administered with tandospirone (15 mg/day) which augments the effect of an SSRI. This combination regimen induced a reduction of PHN-pain on the 10th day and as the analgesic effect attained nearly 50%, there occurred a reflaming of pain on the 35th day. Increasing fluvoxamine to 50 mg/day reameliorated pain on the 49th day, and a further increase to 75 mg/day finally eliminated pain and depression at the end of the 3rd month. The long latency of fluvoxamine action, its shortening by tandospirone and the parallel changes of PHN and depression are all indicative of that the same mechanism, namely renormalization of the dysfunctioned central serotonergic transmission would be underlying both the anti-PHN and antidepressant actions. It would be concluded that fluvoxamine alleviates PHN by restoration of the descending serotonergic inhibition of primary afferent activity that carries pain impulses.

Aged↗

PubMed2003

Relationship between clinical effects of fluvoxamine and the steady-state plasma concentrations of fluvoxamine and its major metabolite fluvoxamino acid in Japanese depressed patients.

OBJECTIVES: The relationship between clinical effects of fluvoxamine (FLV) and the steady-state plasma concentrations (Css) of FLV and its major metabolite fluvoxamino acid (FLA) was studied. METHODS: The subjects were 49 Japanese patients with major depressive disorder receiving FLV 200 mg/day for 6 weeks. Depressive symptoms and side effects were evaluated by the Montgomery Asberg Depression Rating Scale (MADRS), and the UKU Side Effect Rating Scale, respectively. The Css of FLV and FLA were measured by HPLC, and the CYP2D6 genotyping was performed by PCR methods. RESULTS: The Css of FLV and FLV+FLA showed significant negative correlations with the final MADRS score. The Css of FLV, FLA and FLV+FLA were significantly higher in the responders (final MADRS score < or =10) than in non-responders. The proportion of responders was significantly higher in the patients with the Css of FLV, FLA and FLV+FLA above 150, 55 and 180 ng/ml, respectively. In the multiple regression, the Css of FLV+FLA showed a significant negative correlation with the final MADRS score. In the logistic regression, the Css of FLA had a significant effect on the differentiation of responders from non-responders. The incidence of side effects was low, and the development of nausea, the most frequent one, was not dependent on any Css. The number of mutated CYP2D6 alleles causing absent or decreased enzyme activity was not related to the therapeutic response or development of nausea. CONCLUSIONS: The present study suggests that there is a therapeutic threshold for the Css of FLV and probably also for the Css of FLA, and the Css of FLV+FLA above 180 ng/ml best predicts a good therapeutic response.

Adult↗

PubMed2000

Comparison of Fluvoxamine alone, Fluvoxamine and cognitive psychotherapy and psychotherapy alone in the treatment of panic disorder in Kelantan--implications for management by family doctors.

This paper reports the result of a brief therapy attempt at treating panic in a busy outpatient psychiatric clinic. The patients were cases of panic referred from the various outpatient clinics within the hospital complex. The patients were divided into three groups at random using one of three modalities of treatment, i.e. cognitive behaviour therapy (CBT), CBT and Fluvoxamine (FVX), and FVX alone. The therapy was aimed for a maximum of nine sessions after which the patients were to be discharged. There were 14 patients in each group. The results show that all the groups were similar in the severity and scores pre treatment but after the different types of treatment there was a significant difference among them. The FVX alone group, showed significant improvement from the pretreatment levels but did not show as much improvement as the other groups and the mean score was only 9.07 after nine sessions. The best group was the CBT in combination with FVX. This indicates that the best way to treat panic is to combine drug treatment and psychological treatment. It is also shown from the study that the combination group requires less FVX than the FVX alone group. This finding has implications for the treatment of panic at the family physician clinic.

Adult↗

PubMed1995

Fluvoxamine and tricyclic antidepressants (TCAs): how do the TCAs compare as "new" drugs with established fluvoxamine?

The tricyclic antidepressants (TCAs) are still considered as first-line treatment for depression, despite the availability of the selective serotonin reuptake inhibitors (SSRIs). This paper considers the current situation in reverse by assuming that only the SSRIs, in particular fluvoxamine, are available and the TCAs (amitriptyline, imipramine, clomipramine and dothiepin) are the potential "new" drugs. The criteria for an "ideal" antidepressant are discussed and the efficacy, safety and cost-effectiveness of these agents are compared.

Amitriptyline↗

PubMed2002

Low daily 10-mg and 20-mg doses of fluvoxamine inhibit the metabolism of both caffeine (cytochrome P4501A2) and omeprazole (cytochrome P4502C19).

OBJECTIVES: Fluvoxamine is metabolized by the polymorphic cytochrome P450 (CYP) 2D6 and the smoking-inducible CYP1A2. Therapeutic doses of fluvoxamine inhibit both CYP1A2 and CYP2C19. In this study we used extensive metabolizers (EMs) and poor metabolizers (PMs) of debrisoquin (INN, debrisoquine) (CYP2D6) and two probes, caffeine (CYP1A2) and omeprazole (CYP2C19), to investigate whether nontherapeutic doses of fluvoxamine inhibit CYP1A2 but possibly not CYP2C19. METHODS: Single oral doses of 100 mg caffeine and 20 mg omeprazole were given separately to 5 EMs and 5 PMs of debrisoquin to assess the activity of CYP1A2 and CYP2C19, respectively. Initially, a single oral dose of fluvoxamine (25 mg to PMs and 50 mg to EMs) was given, followed by 1 week of daily administration of 25 mg x 2 to EMs and 25 mg x 1 to PMs. Caffeine (day 6) and omeprazole (day 7) were again administered at the steady state of fluvoxamine. Later the study protocol was repeated with a lower dose of fluvoxamine, 10 mg x 2 to EMs and 10 mg x 1 to PMs for 1 week. Concentrations of fluvoxamine, caffeine, omeprazole, and their metabolites were analyzed by HPLC methods in plasma and urine. RESULTS: The kinetics of fluvoxamine were not significantly different in EMs and PMs after a single oral dose of the drug. At the higher but not the lower steady-state dose of fluvoxamine, a significantly lower clearance in PMs compared with EMs was observed (geometric mean, 0.86 versus 1.4 L/h per kilogram; P <.05). At steady state, the 25 mg x 1 or x 2 fluvoxamine dose caused a pronounced inhibition of about 75% to 80% for both CYP1A2 and CYP2C19, whereas the inhibition after the lower 10 mg x 1 or x 2 dose was about 40% to 50%. The area under the plasma concentration-versus-time curve from 0 to 24 hours [AUC(0-24)] of caffeine increased 5-fold (P <.001) after the higher dose of fluvoxamine and 2-fold (P <.05) after the lower dose. The area under the plasma concentration-time curve from time zero to 8 hours [AUC(0-8)] ratio of 5-hydroxyomeprazole/omeprazole decreased 3.4-fold (P <.001) and 2.4-fold (P <.001), respectively. One EM subject had a very low oral clearance of fluvoxamine after both single and multiple dosing of the drug. This subject might have a deficient transporter protein in the gut, leading to an increased absorption of fluvoxamine. CONCLUSION: No convincing evidence was found that CYP2D6 is an important enzyme for the disposition of fluvoxamine. Other factors seem to be more important. A nontherapeutic oral daily dose of fluvoxamine is sufficient to provide a marked inhibition of both caffeine (CYP1A2) and omeprazole (CYP2C19) metabolism. It was not possible to separate the inhibitory effects of fluvoxamine on these enzymes, even after such a low daily dose such as 10 mg x 1 or x 2 of fluvoxamine.

Adrenergic Agents↗

PubMed1995

Overview of the pharmacokinetics of fluvoxamine.

The pharmacokinetics of fluvoxamine, a selective serotonin reuptake inhibitor (SSRI) with antidepressant properties, are well established. After oral administration, the drug is almost completely absorbed from the gastrointestinal tract, and the extent of absorption is unaffected by the presence of food. Despite complete absorption, oral bioavailability in man is approximately 50% on account of first-pass hepatic metabolism. Peak plasma fluvoxamine concentrations are reached 4 to 12 hours (enteric-coated tablets) or 2 to 8 hours (capsules, film-coated tablets) after administration. Steady-state plasma concentrations are achieved within 5 to 10 days after initiation of therapy and are 30 to 50% higher than those predicted from single dose data. Fluvoxamine displays nonlinear steady-state pharmacokinetics over the therapeutic dose range, with disproportionally higher plasma concentrations with higher dosages. Plasma fluvoxamine concentrations show no clear relationship with antidepressant response or severity of adverse effects. Fluvoxamine undergoes extensive oxidative metabolism, most probably in the liver. Nine metabolites have been identified, none of which are known to be pharmacologically active. The specific cytochrome P450 (CYP) isoenzymes involved in the metabolism of fluvoxamine are unknown. CYP2D6, which is crucially involved in the metabolism of paroxetine and fluoxetine, appears to play a clinically insignificant role in the metabolism of fluvoxamine. The drug is excreted in the urine, predominantly as metabolites, with only negligible amounts ( < 4%) of the parent compound. Fluvoxamine shows a biphasic pattern of elimination with a mean terminal elimination half-life of 12 to 15 hours after a single oral dose; this is prolonged by 30 to 50% at steady-state. Plasma protein binding of fluvoxamine (77%) is low compared with that of other SSRIs. Fluvoxamine pharmacokinetics are substantially unaltered by increased age or renal impairment. However, its elimination is prolonged in patients with hepatic cirrhosis. Fluvoxamine inhibits oxidative drug metabolising enzymes (particularly CYP1A2, and less potently and much less potently CYP3A4 and CYP2D6, respectively) and has the potential for clinically significant drug interactions. Drugs whose metabolic elimination is impaired by fluvoxamine include tricyclic antidepressants (tertiary, but not secondary, amines), alprazolam, bromazepam, diazepam, theophylline, propranolol, warfarin and, possibly, carbamazepine. Fluvoxamine is a second generation antidepressant that selectively inhibits neuronal reuptake of serotonin (5-hydroxytryptamine; 5-HT). Fluvoxamine exhibits antidepressant activity similar to that of the tricyclic antidepressants, but has a somewhat improved tolerability profile, particularly with respect to a lower incidence of anticholinergic effects and reduced cardiotoxic potential. However, gastrointestinal adverse effects, especially nausea, are seen more frequently with fluvoxamine than with the tricyclic antidepressants. Fluvoxamine does not have an asymmetric carbon in its structure (fig. 1) and therefore does not exist as optical isomers. For this reason, the potentially confounding problem of stereoisomerism does not arise with fluvoxamine.

Animals↗

PubMed2000

Fluvoxamine. An updated review of its use in the management of adults with anxiety disorders.

UNLABELLED: Fluvoxamine is a potent and selective serotonin reuptake inhibitor (SSRI) that has little or no effect on other monoamine reuptake mechanisms. Relative to other SSRIs, fluvoxamine is a weak inhibitor of cytochrome P450 (CYP) 2D6, a moderate inhibitor of CYP2C19 and CYP3A4 and a potent inhibitor of CYP1A2. In randomised, double-blind trials. fluvoxamine 100 to 300 mg/day for 6 to 10 weeks significantly reduced symptoms of obsessive-compulsive disorder (OCD) compared with placebo. Response rates of 38 to 52% have been reported with fluvoxamine, compared with response rates of 0 to 18% with placebo. In patients with OCD, fluvoxamine had similar efficacy to that of clomipramine and, in smaller trials, the SSRIs paroxetine and citalopram and was significantly more effective than desipramine. Maintenance therapy with fluvoxamine may reduce the likelihood of relapses in up to 67% of patients with OCD. Fluvoxamine < or = 300 mg/day for 6 to 8 weeks was as effective as imipramine in patients with panic disorder, and significantly more effective than placebo. In addition, treatment with fluvoxamine < or = 300 mg/day for > or = 8 weeks improved symptoms of social phobia (social anxiety disorder), post-traumatic stress disorder (PTSD), pathological gambling, compulsive buying, trichotillomania, kleptomania, body dysmorphic disorder, eating disorders and autistic disorder. Large trials comparing the efficacy of fluvoxamine and other SSRIs in patients with anxiety disorders are warranted. Fluvoxamine is generally well tolerated; in postmarketing studies, nausea was the only adverse event occurring in >10% of patients with less commonly reported events including somnolence, asthenia, headache, dry mouth and insomnia. Fluvoxamine is associated with a low risk of suicidal behaviour, sexual dysfunction and withdrawal syndrome. Fewer anticholinergic or cardiovascular events are associated with fluvoxamine than tricyclic antidepressants. Although comparative data are lacking, the tolerability profile of fluvoxamine appears to be broadly similar to those of other SSRIs. CONCLUSION: Fluvoxamine has demonstrated short term efficacy in the treatment of OCD, panic disorder, social phobia, PTSD and in a range of obsessive-compulsive spectrum disorders. The drug is as effective as clomipramine in patients with OCD but appears to have a better tolerability profile. On the basis of current treatment guidelines, fluvoxamine, like other SSRIs, is recommended as first-line treatment for a number of anxiety disorders. It appears to offer some pharmacokinetic advantages and a different drug interaction profile to the other SSRIs with a broadly similar spectrum of adverse events. However, direct comparisons are required to assess the relative efficacy and tolerability of the different agents of this drug class.

Adult↗

PubMed2004

Effects of concomitant fluvoxamine on the plasma concentration of etizolam in Japanese psychiatric patients: wide interindividual variation in the drug interaction.

Administration of fluvoxamine with concomitant benzodiazepines is common in clinical situations. This study investigated the effects of the coadministration of fluvoxamine on plasma concentrations of etizolam and evaluated the effects of various fluvoxamine doses on drug interactions with etizolam. Subjects were 18 Japanese outpatients concomitantly treated with fluvoxamine before or after monotherapy with etizolam. Plasma concentrations of etizolam were measured using a column-switching high-performance liquid chromatographic method with ultraviolet detection. In 17 subjects treated concomitantly with fluvoxamine at 25 mg or 50 mg, the ranges of plasma concentrations of etizolam corrected for the dose increased from 2.0-13.3 (mean 6.3 +/- 3.6, n = 17) in monotherapy to 2.7-18.2 (mean 9.6 +/- 5.1, n = 17) ng/mL/mg in concomitant doses. Wide variations were observed in the drug interactions; however, coadministration with fluvoxamine produced significant changes in the plasma concentrations of etizolam (P < 0.0001) with a median of 42.9% (range 0.0 to 235.0%). Although the sleepiness of the subjects was evaluated using the Stanford Sleepiness Scale, no changes in sleepiness were found between the etizolam-monotherapy and the fluvoxamine-concomitant states. Of the 12 subjects treated concomitantly with fluvoxamine at 25 mg, 2 subjects received fluvoxamine at a dose increased up to 150 mg, and another received fluvoxamine at a dose increased up to 200 mg. They showed an increase in the plasma concentrations of etizolam in a fluvoxamine dose-dependent manner; more particularly, the increased dose of fluvoxamine (150 mg and 200 mg) resulted in about a twofold variation in plasma concentrations of etizolam.

Adult↗

PubMed1997

19F magnetic resonance spectroscopy investigation in vivo of acute and steady-state brain fluvoxamine levels in obsessive-compulsive disorder.

OBJECTIVE: The purpose of this study was to investigate the pharmacokinetics of fluvoxamine in the human brain by using fluorine-19 magnetic resonance spectroscopy (19F MRS) and to assess the relationships among fluvoxamine brain levels, fluvoxamine plasma levels, and clinical efficacy. METHOD: Eight subjects with DSM-IV obsessive-compulsive disorder were entered into a prospective, open-label treatment trial of fluvoxamine. 19F MRS measurements of whole brain drug and metabolite concentrations and spin-lattice (T1) relaxation times were performed serially in seven subjects for up to 5 months. A psychiatric determination of clinical response and a blood sample for plasma fluvoxamine measurement were obtained at each 19F MRS session. RESULTS: The subjects achieved steady-state brain concentrations of fluvoxamine within 30 days after consistent daily dosing, as determined by stabilization of brain fluvoxamine concentrations. The mean brain-to-plasma ratio at steady state was 24 to 1. Brain fluvoxamine T1 values from 140 to 230 msec were observed. All but one subject experienced substantial improvement in symptoms. The one nonresponder exhibited several-fold higher plasma and brain fluvoxamine levels. CONCLUSIONS: Brain fluvoxamine levels were substantially higher than plasma levels. Steady-state brain levels correlated to plasma levels but not to dose. Systematic assessment of treatment response in relation to brain or plasma fluvoxamine level was not feasible because of the marked and rapid clinical response during open-label treatment. These data suggest that fluvoxamine attains brain steady-state levels substantially faster than fluoxetine, with corresponding clinical implications.

Adolescent↗

PubMed2002

Spotlight on fluvoxamine in anxiety disorders in children and adolescents.

Fluvoxamine is a selective serotonin reuptake inhibitor (SSRI) which may be used for the management of anxiety disorders in children and adolescents. Absorption of fluvoxamine was similar in adolescents to that in adults, which suggests that the maximum dosage of the drug for patients aged between 12 and 17 years can be as high as 300 mg/day. However, steady-state plasma fluvoxamine concentrations were 2 to 3 times higher in children (aged between 6 and 11 years) than in adolescents; thus, the maximum fluvoxamine dosage recommended for children is 200 mg/day. Fluvoxamine (50 to 300 mg/day) for 8 to 16 weeks significantly reduced symptoms of obsessive-compulsive disorder (OCD) [measured across multiple assessment scales] compared with placebo in a well controlled trial in paediatric patients (n = 120) or from baseline in noncomparative trials in adolescent (n = 20) or paediatric (n = 16) patients. Improvements with fluvoxamine (up to 200 mg/day) were observed for up to 1 year in 98 patients with OCD in a noncomparative trial. The drug (up to 250 or 300 mg/day) also improved symptoms of anxiety compared with placebo in an 8-week well controlled trial in 128 paediatric patients with social phobia, separation anxiety disorder or generalised anxiety disorder (GAD). Fluvoxamine (50 to 300 mg/day) appears to be well tolerated in paediatric patients, with most adverse events with the drug (except abdominal discomfort, which occurred more often in patients receiving fluvoxamine) occurring with a similar incidence to those with placebo. The most common adverse events involved the CNS or gastrointestinal system. Most adverse events reported by paediatric patients with OCD were similar to those reported by adults. In conclusion, fluvoxamine is generally well tolerated and has demonstrated short-term efficacy compared with placebo in the treatment of OCD, and social phobia, separation anxiety disorder or GAD in well controlled trials in paediatric patients. Reductions in symptoms of anxiety with fluvoxamine have been observed for up to 1 year in children and adolescents with OCD. However, there are currently no comparative trials of fluvoxamine with other pharmacological agents. In the absence of such trials, current consensus opinion recommends that when pharmacotherapy is indicated, fluvoxamine, like other SSRIs, can be used as first-line treatment for anxiety disorders, particularly OCD, in paediatric patients. However, direct comparisons are required to assess the relative efficacy and tolerability of pharmacological agents in order to make firm recommendations for the treatment of anxiety disorders in this patient group.

Adolescent↗

PubMed2001

Fluvoxamine: a review of its therapeutic potential in the management of anxiety disorders in children and adolescents.

Fluvoxamine is a selective serotonin reuptake inhibitor (SSRI) which may be used for the management of anxiety disorders in children and adolescents. Absorption of fluvoxamine was similar in adolescents to that in adults, which suggests that the maximum dosage of the drug for patients aged between 12 and 17 years can be as high as 300 mg/day. However, steady-state plasma fluvoxamine [corrected] concentrations were 2 to 3 times higher in children (aged between 6 and 11 years) than in adolescents; thus, the maximum fluvoxamine dosage recommended for children is 200 mg/day. Fluvoxamine (50 to 300 mg/day) for 8 to 16 weeks significantly reduced symptoms of obsessive-compulsive disorder (OCD) [measured across multiple assessment scales] compared with placebo in a well controlled trial in paediatric patients (n = 120) or from baseline in noncomparative trials in adolescent (n = 20) or paediatric (n = 16) patients. Improvements with fluvoxamine (up to 200 mg/day) were observed for up to 1 year in 98 patients with OCD in a noncomparative trial. The drug (up to 250 or 300 mg/day) also improved symptoms of anxiety compared with placebo in an 8-week well controlled trial in 128 paediatric patients with social phobia, separation anxiety disorder or generalised anxiety disorder (GAD). Fluvoxamine (50 to 300 mg/day) appears to be well tolerated in paediatric patients, with most adverse events with the drug (except abdominal discomfort, which occurred more often in patients receiving fluvoxamine) occurring with a similar incidence to those with placebo. The most common adverse events involved the central nervous system or gastrointestinal system. Most adverse events reported by paediatric patients with OCD were similar to those reported by adults. In conclusion, fluvoxamine is generally well tolerated and has demonstrated short-term efficacy compared with placebo in the treatment of OCD, and social phobia, separation anxiety disorder or GAD in well controlled trials in paediatric patients. Reductions in symptoms of anxiety with fluvoxamine have been observed for up to 1 year in children and adolescents with OCD. However, there are currently no comparative trials of fluvoxamine with other pharmacological agents. In the absence of such trials, current consensus opinion recommends that when pharmacotherapy is indicated, fluvoxamine, like other SSRIs, can be used as first-line treatment for anxiety disorders, particularly OCD, in paediatric patients. However, direct comparisons are required to assess the relative efficacy and tolerability of pharmacological agents in order to make firm recommendations for the treatment of anxiety disorders in this patient group.

Adolescent↗

PubMed2001

[Effects of fluvoxamine on both the desired anxiolytic effect and the adverse motor incoordination and amnesia induced by benzodiazepines].

Fluvoxamine, a selective serotonin reuptake inhibitor, is frequently used along with benzodiazepine anxiolytics in clinics. In this study, the effects of fluvoxamine on the anxiolytic effects as well as adverse effects of benzodiazepines were examined in the light/dark box, rota-rod and passive avoidance tests using mice. Diazepam, ethyl loflazepate and its active metabolite, CM7116, were used as benzodiazepine anxiolytics. The anxiolytic effects of diazepam, ethyl loflazepate and CM7116 were potentiated by intraperitoneal treatment with fluvoxamine at 10 mg/kg, whereas only those of ethyl loflazepate were potentiated by fluvoxamine at 45 mg/kg. The motor incoordination and amnesia induced by ethyl loflazepate and CM7116 were not affected by fluvoxamine, although these adverse effects of diazepam were potentiated by fluvoxamine at 45 mg/kg. Fluvoxamine itself showed no effects in any of the tests. These results suggest that low-dose fluvoxamine potentiates the anxiolytic effects of benzodiazepines, while high-dose fluvoxamine augments the adverse effects depending on the benzodiazepine used. Consequently, when fluvoxamine is administered along with benzodiazepines, the doses of both fluvoxamine and benzodiazepines should be carefully chosen to achieve anxiolytic effects without any adverse results.

Amnesia↗

PubMed2004

Fluvoxamine drastically increases concentrations and effects of tizanidine: a potentially hazardous interaction.

OBJECTIVE: Our objective was to study the effect of fluvoxamine on the pharmacokinetics and pharmacodynamics of tizanidine, a centrally acting skeletal muscle relaxant. METHODS: In a double-blind, randomized, 2-phase crossover study, 10 healthy volunteers took 100 mg fluvoxamine or placebo orally once daily for 4 days. On day 4, each ingested a single 4-mg dose of tizanidine. Plasma concentrations of tizanidine and fluvoxamine and pharmacodynamic variables were measured. A caffeine test was performed on day 3 to examine the role of cytochrome P450 (CYP) 1A2 in tizanidine pharmacokinetics. RESULTS: On average, fluvoxamine increased the total area under the concentration-time curve [AUC(0- infinity )] of tizanidine 33-fold (range, 14-fold to 103-fold; P =.000002) and the peak plasma concentration 12-fold (range, 5-fold to 32-fold; P =.000001). The mean elimination half-life of tizanidine was prolonged from 1.5 to 4.3 hours (P =.00004) by fluvoxamine. The AUC(0- infinity ) of tizanidine and its increase by fluvoxamine correlated with the caffeine/paraxanthine ratio and its increase, respectively (P <.03). All pharmacodynamic variables revealed a significant difference between the fluvoxamine and placebo phases, eg, in the maximal effects on systolic blood pressure (-35 mm Hg, P =.000009), diastolic blood pressure (-20 mm Hg, P =.00002), heart rate (-4 beats/min, P =.007), Digit Symbol Substitution Test (P =.0003), subjective drug effect (P =.0000001), and drowsiness (P =.0002). In particular, the decrease in systolic blood pressure, to the level of 80 mm Hg or even less, was an alarming finding. CONCLUSIONS: Fluvoxamine seriously affects the pharmacokinetics of tizanidine and increases the intensity and duration of its effects. Inhibition of tizanidine-metabolizing enzyme(s), mainly CYP1A2, by fluvoxamine seems to explain the observed interaction. Because of the potentially hazardous consequences, the concomitant use of tizanidine with fluvoxamine, or other potent inhibitors of CYP1A2, should be avoided.

Administration, Oral↗

PubMed1997

Influence of the CYP1A2 inhibitor fluvoxamine on tacrine pharmacokinetics in humans.

OBJECTIVE: Tacrine is extensively metabolized by cytochrome P4501A2 (CYP1A2). Fluvoxamine, a potent CYP1A2 inhibitor, may be coadministered with tacrine. The aim of this study was to examine the influence of fluvoxamine administration on the disposition kinetics of single-dose tacrine administration. METHODS: Thirteen healthy volunteers participated in this double-blind, randomized crossover study, which compared the effects of fluvoxamine (100 mg/day during 6 days) and placebo on the pharmacokinetics of a single oral dose of tacrine (40 mg). RESULTS: Fluvoxamine caused a significant increase in tacrine area under the plasma concentration versus time curve (AUC): arythmetic mean, 27 (95% confidence interval [CI], 19 to 38) ng.hr/ml versus 224 (95% CI, 166 to 302) ng. hr/ml. Fluvoxamine caused a decrease in the apparent oral clearance of tacrine from 1683 +/- 802 to 200 +/- 106 L/hr (mean +/- SD), which was explained by a decrease in its nonrenal clearance. Five subjects had gastrointestinal side effects during fluvoxamine administration. Fluvoxamine administration was associated with significant increases in the plasma AUC values of three monohydroxylated tacrine metabolites and in the total urinary recovery measurements of tacrine and its metabolites (9.1% +/- 4.6% versus 24.0% +/- 2.6% of recovery). These results may be attributable to fluvoxamine-dependent inhibition of CYP1A/, which is responsible of the biotransformation of tacrine into its monohydroxylated metabolites and further into dihydroxylated and reactive metabolites. CONCLUSION: Fluvoxamine inhibits the metabolism of tacrine. CYP1A2 may be the target of this inhibition. Fluvoxamine may modulate the hepatotoxicity of tacrine, depending on the relative contribution of tacrine and its reactive metabolites to this toxicity.

Adult↗

PubMed1998

Determinants of interindividual variability and extent of CYP2D6 and CYP1A2 inhibition by paroxetine and fluvoxamine in vivo.

Major depression may require antidepressant treatment for several years. This necessitates consideration of the long-term effects of antidepressants on multiple clinical endpoints. The antidepressants paroxetine and fluvoxamine are potent in vitro inhibitors of CYP2D6 and CYP1A2 isozymes, respectively. CYP2D6 and CYP1A2 are important for the clearance of 30 or more frequently used medications. Moreover, CYP1A2 also contributes to metabolism of 17beta-estradiol and metabolic activation of environmental procarcinogens (e.g., arylamines in cigarette smoke). The aim of this study was to assess the determinants of interindividual variability and extent of CYP2D6 and CYP1A2 inhibition during paroxetine and fluvoxamine treatment. Healthy volunteers and patients received caffeine (100 mg) and dextromethorphan (30 mg) at baseline and at steady state of paroxetine (10-20 mg/day, 5-74 days, N = 13) or fluvoxamine (50-100 mg/day, 5-43 days, N = 8). The caffeine metabolic ratio (CMR) and the log O-demethylation ratio (ODMR) of dextromethorphan in overnight urine were used as in vivo indices of the CYP1A2 and CYP2D6 isozyme activities, respectively. All subjects had an extensive metabolizer phenotype for CYP2D6. After fluvoxamine treatment, baseline CMR 5.1 +/- 1.4 (mean +/- SD) decreased to 2.7 +/- 1.1 (p < 0.01). Paroxetine did not have a significant effect on CMR (p > 0.05). In seven of eight subjects in the fluvoxamine group, posttreatment CMR was comparable with the minimum CMR value (2.0) attainable in nonsmoking healthy volunteers. After paroxetine treatment, log ODMR changed from a baseline value of -2.28 +/- 0.37 to -1.13 +/- 0.44, indicating significant inhibition of CYP2D6 (p < 0.001). Subjects' CYP2D6 phenotype did not change after paroxetine treatment. Fluvoxamine had no significant effect on log ODMR (p > 0.05). The extent of inhibition of CYP2D6 and CYP1A2 by paroxetine and fluvoxamine, respectively, displayed a positive correlation with baseline enzyme activity (p < 0.05). In addition, a negative association was found between the plasma paroxetine concentration and the CYP2D6 activity after paroxetine treatment (r = -0.47, p < 0.05). These data indicate that paroxetine and fluvoxamine treatment with minimum clinically effective doses significantly inhibit CYP2D6 and CYP1A2, respectively. The extent of inhibition of CYP2D6 by paroxetine and of CYP1A2 by fluvoxamine is dependent in part on the baseline enzyme activity. The interindividual variability in CYP2D6 inhibition by paroxetine can also be explained by variability in plasma paroxetine concentration. Most patients treated with fluvoxamine (50-100 mg/day) will reach population minimums for CYP1A2 activity. These results have potential implications for interindividual variability in the risk for drug-drug interactions mediated by CYP2D6 and CYP1A2 as well as for the disposition of 17beta-estradiol and environmental procarcinogens.

Adult↗

PubMed1998

Brain elimination half-life of fluvoxamine measured by 19F magnetic resonance spectroscopy.

OBJECTIVE: This study used fluorine-19 magnetic resonance spectroscopy (19F MRS) to characterize the elimination of fluvoxamine from the human brain after abrupt drug discontinuation. The elimination half-lives of fluvoxamine in brain and plasma were determined to assess their interdependence and the relationship of brain half-life to the clinical practice of drug holidays and reports of acute withdrawal symptoms. METHODS: Six subjects completing clinical treatment with fluvoxamine were enrolled in the study. Spectroscopic quantification of whole brain fluvoxamine concentrations and chromatographic determination of plasma fluvoxamine levels were performed serially for up to 10 days after drug withdrawal. Psychiatric evaluation to assess withdrawal symptoms was also done at each scanning session. RESULTS: Elimination of fluvoxamine in the brain and plasma was optimally described by first-order kinetics; the mean elimination half-lives were 58 hours and 26 hours, respectively. The mean ratio of fluvoxamine brain elimination half-life to plasma half-life was 2.4. Three of the six subjects experienced mild to moderate withdrawal symptoms between the third and fifth days of the study, which corresponded to between one and two brain half-lives of fluvoxamine. CONCLUSIONS: The brain elimination half-life for fluorinated psychotropic compounds can be measured noninvasively by 19F MRS. The elimination half-life of fluvoxamine was found to be substantially longer for the brain than for plasma. The time course of withdrawal symptom onset and the rationale for drug holidays with fluvoxamine appear to be well explained by the brain elimination half-life.

Brain↗