Fluvoxamine toxicity

FLUVOXAMINE FOOD-CHARGRILLED MEAT, BROCCOLI, CABBAGE, SPROUTS 1 plasma concentrations of fluvoxamine with loss of therapeutic efficacy Fluvoxamine and fluoxetine are metabolized mainly by CYP1A2 isoenzymes, while the role of CYP1A2 in the metabolism of sertraline is probably not clinically significant Monitor for lack of therapeutic effect. When inducers are withdrawn, monitor for fluvoxamine toxicity... 

Carbamazepine Some, but not all, reports indicate that carbamazepine serum levels can be increased by fluoxetine and fluvoxamine. Toxicity may develop. Sertraline normally appears not to affect carbamazepine, but sertraline levels may be reduced by carbamazepine. Isolated cases of Par-kinson-like and serotonin syndrome have occurred with fluoxetine and carbamazepine, while an isolated case of pancytopenia has been reported with sertraline and carbamazepine. The metabolism of citalopram may be increased. 

Clozapine Fluoxetine, paroxetine, sertraline, and possibly citalopram can raise serum clozapine levels. Particularly large increases can occur with fluvoxamine. Toxicity has been seen in some patients. 

Theophylline serum levels can be markedly and rapidly increased by fluvoxamine. Toxicity will develop if the theophylline dosage is not suitably reduced. Some preliminary clinical evidence su ests that fluoxetine and citalopram may not interact, and in vitro evidence su ests that paroxetine and sertraline are also unlikely to interact... 

Theophylline Ciprofloxacin, fluvoxamine, etc. CYP1A2 Theophylline toxicity... 

Certain medications (e.g., cimetidine, diltiazem, erythromycin, fluoxetine, fluvoxamine, isoniazid, itraconazole, ketoconazole, nefazodone, propoxyphene, and verapamil) added to carbamazepine therapy may cause carbamazepine toxicity. 

Other Antidepressants. Antidepressant refinements for the next 30 years primarily consisted of the development of new TCAs. However, in 1988, a novel antidepressant class, the selective serotonin reuptake inhibitors (SSRIs), was introduced in the United States. The chief innovation of the SSRIs was that they afforded the comparable effectiveness of the TCAs with fewer side effects and minimal toxicity. The debut of the SSRIs coincided with the reworking of the nosology of the anxiety disorders in DSM-III and DSM-IV. As a result, the SSRIs have been studied extensively in each of the respective anxiety disorders and in many cases have obtained FDA approval for the treatment of one or more of these anxiety syndromes. The SSRIs currently available in the United States include citalopram (Celexa), escitalo-pram (Lexapro), fluoxetine (Prozac), fluvoxamine (Luvox), paroxetine (Paxil), and sertraline (Zoloft). 

SSRIs—fluvoxamine, fluoxetine, and paroxetine, more than sertraline and citalopram Inhibition of metabolism at CYP2D6 isoenzyme TCA toxicity due to up to 10-fold increase in TCA levels with coadministration Lower TCA dose Baumann, 1996... 

In contrast to anticonvulsants and alcohol, drugs such as bupropion, fluoxetine, fluvoxamine, nefazodone, quinidine, paroxetine, and some antipsychotics can inhibit specific CYP enzymes (7, 11, 36, 37, 41, 42, 43 and 44). Thus, TCAs, certain BZDs, bupropion, some steroids, and antipsychotics can all have their metabolism inhibited by drugs such as fluoxetine. For example, fluoxetine at 20 mg/day produces on average a 500% increase in the levels of coprescribed drugs which are principally dependent on CYP 2D6 for their clearance. That can lead to serious or even life-threatening toxicity if the drug has a narrow therapeutic index and the dose is not adjusted for the change in clearance caused by the coadministration of fluoxetine. 

All SSRIs have an antipanic effect. Their advantages are limited adverse effects and lack of toxicity. Because of more acceptable adverse effect profiles, the SSRIs are usually the drugs of choice. Several studies consistently indicate that SSRIs such as fluoxetine, sertraline, paroxetine, fluvoxamine, as well as agents such as clomipramine and trazodone, all possess antipanic efficacy, although the last may be less effective than imipramine ( 24, 105, 106, 107, 108 and 109). 

BZD hypnotics such as midazolam and triazolam are primarily metabolized via the P450 3A3/4 microenzyme system. Other BZDs often used as hypnotics, such as diazepam, can also be metabolized by CYP 33/4 and CYP 2C19. Any drugs that act as inhibitors or inducers of these isoenzymes could increase or decrease BZD levels, respectively (350). Thus, ketoconazole, macrolide antibiotics (e.g., erythromycin), SSRIs (e.g., fluoxetine-norfluoxetine and fluvoxamine), and other antidepressants (especially nefazodone) may decrease clearance and increase BZD levels to potentially toxic ranges. Conversely, rifampacin, CBZ, and dexamethasone may increase clearance and decrease BZD levels to potentially subtherapeutic ranges. 

Ramelteon Activates and MT2 receptors in suprachiasmatic nuclei in the CNS Rapid onset of sleep with minimal rebound insomnia or withdrawal symptoms Sleep disorders, especially those characterized by difficulty in falling asleep not a controlled substance Oral activity forms active metabolite via CYP1A2 Toxicity Dizziness fatigue endocrine changes Interactions Fluvoxamine inhibits metabolism... 

The most common interactions with SSRIs are pharmacokinetic interactions. For example, paroxetine and fluoxetine are potent CYP2D6 inhibitors (Table 30-4). Thus, administration with 2D6 substrates such as TCAs can lead to dramatic and sometimes unpredictable elevations in the tricyclic drug concentration. The result may be toxicity from the TCA. Similarly, fluvoxamine, a CYP3A4 inhibitor, may elevate the levels of concurrently administered substrates for this enzyme such as diltiazem and induce bradycardia or hypotension. Other SSRIs, such as citalopram and escitalopram, are relatively free of pharmacokinetic interactions. The most serious interaction with the SSRIs are pharmacodynamic interactions with MAOIs that produce a serotonin syndrome (see below). 

Fluoxetine Highly selective blockade of serotonin transporter (SERT) little effect on norepinephrine transporter (NET) Acute increase of serotonergic synaptic activity slower changes in several signaling pathways and neurotrophic activity Major depression, anxiety disorders panic disorder obsessive-compulsive disorder post-traumatic stress disorder perimenopausal vasomotor symptoms eating disorder (bulimia) Half-lives from 15-75 h oral activity Toxicity Well tolerated but cause sexual dysfunction Interactions Some CYP inhibition (fluoxetine 2D6, 3A4 fluvoxamine 1A2 paroxetine 2D6)... 

An example of a potentially important drug interaction is that which occurs when fluvoxamine is given along with theophyllin (Figure 6—13). In that case, the theo-phyllin dose must be lowered or else the blood levels of theophyllin will rise and possibly cause side effects, even toxic side effects such as seizures. The same may occur with caffeine. Fluvoxamine also affects the metabolism of atypical anti-psychotics. 

FIGURE 6—18. The antidepressants fluoxetine, fluvoxamine, and nefazodone are all inhibitors of CYP450 3A4. More potent inhibitors of this enzyme include the nonpsychotropic drugs ketoconazole, erythromycin, and protease inhibitors. If a 3A4 inhibitor is given with cisapride or astemazole, levels of these substrates can rise to toxic levels. Thus, fluoxetine, fluvoxamine, and nefazodone cannot be given with cisapride or astemazole. 

In contrast, decreases in theophylline metabolism by selective inhibitors of CYP1A2, such as fluvoxamine and some quinolone antibiotics, or by selective and potent inhibitors of CYP3A4, such as the macrolide antibiotics, have resulted in serious theophylline toxicity (22). It is postulated that taken over time, the macrolide antibiotics act as mechanism-based inhibitors of CYP isoforms other than just CYP3A4. Some nonselective inhibitors of P450s, such as cimetidine, some p-blockers and calcium channel blockers, and others (19,22), also appear to inhibit the metabolism of theophylline enough to cause toxicity. 

Interactions are similar to those of opioid analgesics. Methadone has interactions with enzyme inducers. Withdrawal symptoms of methadone are observed upon concurrent administration with phenobarbitone, phenytoin, and rifampicin. Methadone toxicity increases if administered with cimetidine and fluvoxamine. 

Fluvoxamine has little inhibitory effect on CYP2D6 but is a potent inhibitor of CYP1A2 and CYP2C19. It also is a moderate inhibitor of CYP3A4, which is involved in the metabolism of haloperidol. When fluvoxamine (25, 75, and 150 mg/day, each for 2 weeks) was added to haloperidol in 12 patients with schizophrenia aged 22-59 years, plasma haloperidol concentrations rose dose-relatedly after fluvoxamine 25 mg/day haloperidol concentrations rose by about 20%, with additional 20% increases with each increment in fluvoxamine dose however, this was not associated with overt clinical toxicity (104). 

A case of toxic epidermal necrolysis after fluvoxamine has been described although the patient was taking other drugs, the authors concluded that the skin reaction was probably due to fluvoxamine (SEDA-18, 20). 

METOPROLOL SSRIs T plasma concentrations of metoprolol SSRIs inhibit metabolism of metoprolol (paroxetine, fluoxetine, sertraline, fluvoxamine via CYP2D6, and (es)citalopram via mechanism uncertain at present) Monitor PR and BP at least weekly watch for metoprolol toxicity, in particular loss of its cardioselectivity... 

LITHIUM SSRIs Lithium may enhance the pharmacologic effects of SSRIs and potentiate the risk of serotonin syndrome. Excessive somnolence has been reported with fluvoxamine. However, there are reports of both T and l plasma concentrations of lithium. There are reports of lithium toxicity and of serotonergic effects Lithium is a direct stimulant of 5-HT receptors, while SSRIs i the reuptake of 5- HT these are considered to t the effects of serotonin in the brain. Seizures are a neurotoxic effect of lithium and could occur even with plasma lithium concentrations within the normal range. SSRIs and lithium may have additive effects to cause seizures Be aware of the possibility of serotonin syndrome. Also need to monitor lithium levels with appropriate dose adjustments during co-administration > For signs and symptoms of serotonin toxicity, see Clinical Features of Some Adverse Drug Interactions, Serotonin toxicity and serotonin syndrome... 

FLUVOXAMINE ANTIPARKINSON S DRUGS - ROPINIROLE t ropinirole levels Inhibition of CYP1 A2-mediated metabolism Watch for early features of toxicity (nausea, drowsiness)... 

ESCITALOPRAM, FLUOXETINE, FLUVOXAMINE, PAROXETINE, SERTRALINE BUPROPION T plasma concentrations of these SSRIs, with risk of toxic effects Bupropion and its metabolite hydroxybupropion inhibit CYP2D6 Initiate therapy of these drugs at the lowest effective dose. Interaction is likely to be important with substrates for which CYP2D6 is considered the only metabolic pathway (e.g. paroxetine)... 

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