Minds On Meds

Mental Health Medications

Antidepressants

Fluvoxamine Maleate (Luvox, Faverin), Page 4

Fluvoxamine maleate (Luvox) tablets are indicated for the treatment of obsessions and compulsions in patients with obsessive compulsive disorder (OCD).

7.4 Effects of Smoking on Fluvoxamine Metabolism

Smokers had a 25% increase in the metabolism of fluvoxamine compared to nonsmokers.

7.5 Electroconvulsive Therapy (ECT)

There are no clinical studies establishing the benefits or risks of combined use of ECT and fluvoxamine maleate.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Teratogenic Effects — Pregnancy Category C

When pregnant rats were given oral doses of fluvoxamine (60, 120, or 240 mg/kg) throughout the period of organogenesis, developmental toxicity in the form of increased embryofetal death and increased incidences of fetal eye abnormalities (folded retinas) was observed at doses of 120 mg/kg or greater. Decreased fetal body weight was seen at the high dose. The no effect dose for developmental toxicity in this study was 60 mg/kg (approximately 2 times the MRHD on a mg/m2 basis).

In a study in which pregnant rabbits were administered doses of up to 40 mg/kg (approximately 2 times the MRHD on a mg/m2 basis) during organogenesis, no adverse effects on embryofetal development were observed.

In other reproduction studies in which female rats were dosed orally during pregnancy and lactation (5, 20, 80, or 160 mg/kg), increased pup mortality at birth was seen at doses of 80 mg/kg or greater and decreases in pup body weight and survival were observed at all doses (low effect dose approximately 0.1 times the MRHD on a mg/m2 basis).

Nonteratogenic Effects

Neonates exposed to fluvoxamine maleate and other SSRIs or serotonin and norepinephrine reuptake inhibitors (SNRIs) late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. These findings are based on postmarketing reports. Such complications can arise immediately upon delivery. Reported clinical findings have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability and constant crying. These features are consistent with either a direct toxic effect of SSRIs or SNRIs or, possibly, a drug discontinuation syndrome. It should be noted that, in some cases, the clinical picture is consistent with serotonin syndrome [see Warnings and Precautions (5.3)].

Infants exposed to SSRIs in late pregnancy may have an increased risk for persistent pulmonary hypertension of the newborn (PPHN). PPHN is associated with substantial neonatal morbidity and mortality. In a case control study of 377 women whose infants were born with PPHN and 836 women whose infants were born healthy, the risk for developing PPHN was approximately six fold higher for infants exposed to SSRIs after the 20th week of gestation compared to infants who had not been exposed to antidepressants during pregnancy. PPHN occurs in 1 to 2 per 1000 live births in the general population.

When treating a pregnant woman with fluvoxamine maleate during the third trimester, the physician should carefully consider both the potential risks and benefits of treatment [see Dosage and Administration (2.4)]. Physicians should note that in a prospective longitudinal study of 201 women with a history of major depression who were euthymic at the beginning of pregnancy, women who discontinued antidepressant medication during pregnancy were more likely to experience a relapse of major depression than women who continued antidepressant medication.

8.2 Labor and Delivery

The effect of fluvoxamine on labor and delivery in humans is unknown.

8.3 Nursing Mothers

As for many other drugs, fluvoxamine is secreted in human breast milk. The decision of whether to discontinue nursing or to discontinue the drug should take into account the potential for serious adverse effects from exposure to fluvoxamine in the nursing infant as well as the potential benefits of fluvoxamine maleate tablets therapy to the mother.

8.4 Pediatric Use

The efficacy of fluvoxamine maleate for the treatment of obsessive compulsive disorder was demonstrated in a 10 week multicenter placebo controlled study with 120 outpatients ages 8 to 17. In addition, 99 of these outpatients continued open label fluvoxamine maleate treatment for up to another one to three years, equivalent to 94 patient years. The adverse event profile observed in that study was generally similar to that observed in adult studies with fluvoxamine [see Adverse Reactions (6.3) and Dosage and Administration (2.2)].

Decreased appetite and weight loss have been observed in association with the use of fluvoxamine as well as other SSRIs. Consequently, regular monitoring of weight and growth is recommended if treatment of a child with an SSRI is to be continued long term.

The risks, if any, that may be associated with fluvoxamine’s extended use in children and adolescents with OCD have not been systematically assessed. The prescriber should be mindful that the evidence relied upon to conclude that fluvoxamine is safe for use in children and adolescents derives from relatively short term clinical studies and from extrapolation of experience gained with adult patients. In particular, there are no studies that directly evaluate the effects of long term fluvoxamine use on the growth, cognitive behavioral development, and maturation of children and adolescents. Although there is no affirmative finding to suggest that fluvoxamine possesses a capacity to adversely affect growth, development or maturation, the absence of such findings is not compelling evidence of the absence of the potential of fluvoxamine to have adverse effects in chronic use [see Warnings and Precautions, Clinical Worsening and Suicide Risk (5.1)].

Safety and effectiveness in the pediatric population other than pediatric patients with OCD have not been established [see Boxed Warning and Warnings and Precautions, Clinical Worsening and Suicide Risk (5.1)]. Anyone considering the use of fluvoxamine maleate tablets in a child or adolescent must balance the potential risks with the clinical need.

8.5 Geriatric Use

Approximately 230 patients participating in controlled premarketing studies with fluvoxamine maleate tablets were 65 years of age or over. No overall differences in safety were observed between these patients and younger patients. Other reported clinical experience has not identified differences in response between the elderly and younger patients. However, SSRIs and SNRIs, including fluvoxamine maleate tablets, have been associated with several cases of clinically significant hyponatremia in elderly patients, who may be at greater risk for this adverse event [see Warnings and Precautions (5.13)]. Furthermore, the clearance of fluvoxamine is decreased by about 50% in elderly compared to younger patients [see Clinical Pharmacology, Elderly (12.3)], and greater sensitivity of some older individuals also cannot be ruled out. Consequently, a lower starting dose should be considered in elderly patients and fluvoxamine maleate tablets should be slowly titrated during initiation of therapy.

9 DRUG ABUSE AND DEPENDENCE

9.1 Controlled Substance Class

Fluvoxamine maleate tablets are not a controlled substance.

9.2 Physical and Psychological Dependence

The potential for abuse, tolerance and physical dependence with fluvoxamine maleate has been studied in a nonhuman primate model. No evidence of dependency phenomena was found. The discontinuation effects of fluvoxamine maleate tablets were not systematically evaluated in controlled clinical trials. Fluvoxamine maleate tablets were not systematically studied in clinical trials for potential for abuse, but there was no indication of drug-seeking behavior in clinical trials. It should be noted, however, that patients at risk for drug dependency were systematically excluded from investigational studies of fluvoxamine maleate. Generally, it is not possible to predict on the basis of preclinical or premarketing clinical experience the extent to which a CNS active drug will be misused, diverted, and/or abused once marketed. Consequently, physicians should carefully evaluate patients for a history of drug abuse and follow such patients closely, observing them for signs of fluvoxamine maleate misuse or abuse (i.e., development of tolerance, incrementation of dose, drug-seeking behavior).

10 OVERDOSAGE

10.1 Human Experience

Worldwide exposure to fluvoxamine includes over 45,000 patients treated in clinical trials and an estimated exposure of 50,000,000 patients treated during worldwide marketing experience (end of 2005). Of the 539 cases of deliberate or accidental overdose involving fluvoxamine reported from this population, there were 55 deaths. Of these, 9 were in patients thought to be taking fluvoxamine alone and the remaining 46 were in patients taking fluvoxamine along with other drugs. Among non-fatal overdose cases, 404 patients recovered completely. Five patients experienced adverse sequelae of overdosage, to include persistent mydriasis, unsteady gait, hypoxic encephalopathy, kidney complications (from trauma associated with overdose), bowel infarction requiring a hemicolectomy, and vegetative state. In 13 patients, the outcome was provided as abating at the time of reporting. In the remaining 62 patients, the outcome was unknown. The largest known ingestion of fluvoxamine involved 12,000 mg (equivalent to 2 to 3 months’ dosage). The patient fully recovered. However, ingestions as low as 1,400 mg have been associated with lethal outcome, indicating considerable prognostic variability.

Commonly (≥ 5%) observed adverse events associated with fluvoxamine maleate overdose include gastrointestinal complaints (nausea, vomiting and diarrhea), coma, hypokalemia, hypotension, respiratory difficulties, somnolence, and tachycardia. Other notable signs and symptoms seen with fluvoxamine maleate overdose (single or multiple drugs) include bradycardia, ECG abnormalities (such as heart arrest, QT interval prolongation, first degree atrioventricular block, bundle branch block, and junctional rhythm), convulsions, dizziness, liver function disturbances, tremor, and increased reflexes.

10.2 Management of Overdosage

Treatment should consist of those general measures employed in the management of overdosage with any antidepressant.

Ensure an adequate airway, oxygenation, and ventilation. Monitor cardiac rhythm and vital signs. General supportive and symptomatic measures are also recommended. Induction of emesis is not recommended. Gastric lavage with a large-bore orogastric tube with appropriate airway protection, if needed, may be indicated if performed soon after ingestion, or in symptomatic patients.

Activated charcoal should be administered. Due to the large volume of distribution of this drug, forced diuresis, dialysis, hemoperfusion and exchange transfusion are unlikely to be of benefit. No specific antidotes for fluvoxamine are known.

A specific caution involves patients taking, or recently having taken, fluvoxamine who might ingest excessive quantities of a tricyclic antidepressant. In such a case, accumulation of the parent tricyclic and/or an active metabolite may increase the possibility of clinically significant sequelae and extend the time needed for close medical observation [see Drug Interactions (7.2).]

In managing overdosage, consider the possibility of multiple drug involvement. The physician should consider contacting a poison control center for additional information on the treatment of any overdose. Telephone numbers for certified poison control centers are listed in the Physicians’Desk Reference (PDR).

11 DESCRIPTION

Fluvoxamine maleate is a selective serotonin (5-HT) reuptake inhibitor (SSRI) belonging to the chemical series, the 2-aminoethyl oxime ethers of aralkylketones.

It is chemically designated as 5-methoxy-4′-(trifluoromethyl)valerophenone-(E)-O-(2-aminoethyl)oxime maleate (1:1).

The structural formula is:

Fluvoxamine Maleate Tablets Chemical Formula
(click image for full-size original)

C15H21O2N2F3•C4H4O4 M. W. 434.41

Fluvoxamine maleate is a white to off-white, odorless, crystalline powder which is sparingly soluble in water, freely soluble in ethanol and chloroform and practically insoluble in diethyl ether.

Fluvoxamine maleate tablets, USP are available in 25 mg, 50 mg and 100 mg strengths for oral administration. In addition to the active ingredient, fluvoxamine maleate, each tablet contains the following inactive ingredients: mannitol, methylcellulose, pregelatinized starch, silicon dioxide, starch and sodium stearyl fumarate.

The 25 mg also contains FD&C blue no. 2 aluminum lake, FD&C red no. 40 aluminum lake, FD&C yellow no. 6 aluminum lake, hypromellose, polyethylene glycol, polysorbate 80 and titanium dioxide.

The 50 mg also contains D&C yellow no. 10 aluminum lake, FD&C yellow no. 6 aluminum lake, hypromellose, polyethylene glycol, polysorbate 80 and titanium dioxide.

The 100 mg also contains hypromellose, polyethylene glycol, polysorbate 80, synthetic black iron oxide, synthetic red iron oxide, synthetic yellow iron oxide and titanium dioxide.

Fluvoxamine maleate meets USP Related Compounds Test 2.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

The mechanism of action of fluvoxamine maleate in obsessive compulsive disorder is presumed to be linked to its specific serotonin reuptake inhibition in brain neurons. Fluvoxamine has been shown to be a potent inhibitor of the serotonin reuptake transporter in preclinical studies, both invitro and in vivo.

12.2 Pharmacodynamics

In in vitro studies, fluvoxamine maleate had no significant affinity for histaminergic, alpha- or beta-adrenergic, muscarinic, or dopaminergic receptors. Antagonism of some of these receptors is thought to be associated with various sedative, cardiovascular, anticholinergic, and extrapyramidal effects of some psychotropic drugs.

12.3 Pharmacokinetics

Absorption

The absolute bioavailability of fluvoxamine maleate is 53%. Oral bioavailability is not significantly affected by food.

In a dose proportionality study involving fluvoxamine maleate at 100, 200 and 300 mg/day for 10 consecutive days in 30 normal volunteers, steady state was achieved after about a week of dosing. Maximum plasma concentrations at steady state occurred within 3 to 8 hours of dosing and reached concentrations averaging 88, 283 and 546 ng/mL, respectively. Thus, fluvoxamine had nonlinear pharmacokinetics over this dose range, i.e., higher doses of fluvoxamine maleate produced disproportionately higher concentrations than predicted from the lower dose.

Distribution

The mean apparent volume of distribution for fluvoxamine is approximately 25 L/kg, suggesting extensive tissue distribution.

Approximately 80% of fluvoxamine is bound to plasma protein, mostly albumin, over a concentration range of 20 to 2000 ng/mL.

Metabolism

Fluvoxamine maleate is extensively metabolized by the liver; the main metabolic routes are oxidative demethylation and deamination. Nine metabolites were identified following a 5 mg radio-labelled dose of fluvoxamine maleate, constituting approximately 85% of the urinary excretion products of fluvoxamine. The main human metabolite was fluvoxamine acid which, together with its N-acetylated analog, accounted for about 60% of the urinary excretion products. A third metabolite, fluvoxethanol, formed by oxidative deamination, accounted for about 10%. Fluvoxamine acid and fluvoxethanol were tested in an in vitro assay of serotonin and norepinephrine reuptake inhibition in rats; they were inactive except for a weak effect of the former metabolite on inhibition of serotonin uptake (1 to 2 orders of magnitude less potent than the parent compound). Approximately 2% of fluvoxamine was excreted in urine unchanged. [see Drug Interactions (7).]

Elimination

Following a 14C-labelled oral dose of fluvoxamine maleate (5 mg), an average of 94% of drug related products was recovered in the urine within 71 hours.

The mean plasma half-life of fluvoxamine at steady state after multiple oral doses of 100 mg/day in healthy, young volunteers was 15.6 hours.

Elderly Subjects

In a study of fluvoxamine maleate tablets at 50 and 100 mg comparing elderly (ages 66 to 73) and young subjects (ages 19 to 35), mean maximum plasma concentrations in the elderly were 40% higher. The multiple dose elimination half-life of fluvoxamine was 17.4 and 25.9 hours in the elderly compared to 13.6 and 15.6 hours in the young subjects at steady state for 50 and 100 mg doses, respectively. In elderly patients, the clearance of fluvoxamine was reduced by about 50% and, therefore, Fluvoxamine maleate tablets should be slowly titrated during initiation of therapy [see Dosage and Administration (2.3].

Pediatric Subjects

The multiple dose pharmacokinetics of fluvoxamine were determined in male and female children (ages 6 to 11) and adolescents (ages 12 to 17). Steady state plasma fluvoxamine concentrations were 2 to 3 fold higher in children than in adolescents. AUC and Cmax in children were 1.5 to 2.7 fold higher than that in adolescents (See TABLE 4). As in adults, both children and adolescents exhibited nonlinear multiple-dose pharmacokinetics. Female children showed significantly higher AUC(0 to 12) and Cmax compared to male children and, therefore, lower doses of fluvoxamine maleate tablets may produce therapeutic benefit (See TABLE 5). No gender differences were observed in adolescents. Steady state plasma fluvoxamine concentrations were similar in adults and adolescents at a dose of 300 mg/day, indicating that fluvoxamine exposure was similar in these two populations (See TABLE 4). Dose adjustment in adolescents (up to the adult maximum dose of 300 mg) may be indicated to achieve therapeutic benefit [see Dosage and Administration (2.2)].

TABLE 4 COMPARISON OF MEAN (SD) FLUVOXAMINE PHARMACOKINETIC PARAMETERS BETWEEN CHILDREN, ADOLESCENTS, AND ADULTS

Pharmacokinetic Parameter

(body weight corrected)

Dose = 200 mg/day

(100 mg b.i.d.)

Dose = 300 mg/day

(150 mg b.i.d.)

Children

(n = 10)

Adolescent

(n = 17)

Adolescent

(n = 13)

Adult

(n = 16)
AUC(0 to 12) (ng•h/mL/kg) 155.1 (160.9) 43.9 (27.9) 69.6 (46.6) 59.4 (40.9)
Cmax (ng/mL/kg) 14.8 (14.9) 4.2 (2.6) 6.7 (4.2) 5.7 (3.9)
Cmin (ng/mL/kg) 11 (11.9) 2.9 (2.0) 4.8 (3.8) 4.6 (3.2)
TABLE 5 COMPARISON OF MEAN (SD) FLUVOXAMINE PHARMACOKINETIC PARAMETERS BETWEEN MALE AND FEMALE CHILDREN (6 TO 11 YEARS)

Pharmacokinetic Parameter

(body weight corrected)
Dose = 200 mg/day (100 mg b.i.d.)

Male Children

(n = 7)

Female Children

(n = 3)
AUC(0 to 12) (ng•h/mL/kg) 95.8 (83.9) 293.5 (233)
Cmax (ng/mL/kg) 9.1 (7.6) 28.1 (21.1)
Cmin (ng/mL/kg) 6.6 (6.1) 21.2 (17.6)

Hepatic and Renal Disease

A cross study comparison (healthy subjects versus patients with hepatic dysfunction) suggested a 30% decrease in fluvoxamine clearance in association with hepatic dysfunction. The mean minimum plasma concentrations in renally impaired patients (creatinine clearance of 5 to 45 mL/min) after 4 and 6 weeks of treatment (50 mg b.i.d., n = 13) were comparable to each other, suggesting no accumulation of fluvoxamine in these patients [see Warnings and Precautions, Use in Patients with Concomitant Illness (5.13)].