Fluvoxamine

Fluvoxamine (Luvox) is an antidepressant which functions pharmacologically as a selective serotonin reuptake inhibitor. Though it is in the same class as other SSRI drugs, it is most often used to treat obsessive-compulsive disorder.

History
Fluvoxamine was one of the first of the SSRI antidepressants to be launched (1984 - Switzerland) and was developed by Solvay Pharmaceuticals. It was launched in the US in December 1994 and in Japan in June 1999. As of the end of 1995, more than 10 million patients worldwide have been treated with fluvoxamine. In 1999, fluvoxamine came under great public scrutiny after it was discovered that Eric Harris, one of the two teenage shooters involved in the Columbine High School massacre, had been taking the drug. Many immediately pointed fingers at fluvoxamine and its manufacturer Solvay Pharmaceuticals. Sales fell, and Solvay withdrew the medication from the U.S. market in 2002. In 2007 Solvay re-introduced Luvox, which is now manufactured by Palo Alto, California-based Jazz Pharmaceuticals Inc.

Fluvoxamine was the first SSRI to be registered for the treatment of Obsessive Compulsive Disorder in children by FDA in 1997.

Fluvoxamine was the first drug approved for the treatment of social anxiety disorder in Japan in 2005.

On February 28, 2008, the US FDA approved a controlled-release formulation of fluvoxamine, to be marketed in the US as LUVOX CR.

Approved
Fluvoxamine is widely prescribed to treat depression, and anxiety disorders such as Obsessive-Compulsive Disorder, Obsessive-Compulsive Spectrum Disorder, Panic Disorder, Social Phobia, and Post-Traumatic Stress Disorder.

Fluvoxamine is indicated for children and adolescents with OCD.

Unapproved/Off-label/Investigational
Fluvoxamine is also used for the treatment of children and adolescents with social phobia, separation anxiety disorder, or generalized anxiety disorder.

Fluvoxamine may help in the treatment of Irritable Bowel Syndrome.

Mode of Action
Fluvoxamine is one of the few SSRI class of drugs to have a monocyclic structure.

Although all SSRIs inhibit the reuptake of serotonin, fluvoxamine has different pharmacological and side effects profiles from other drugs in its class. Fluvoxamine has been shown to be selective for serotonin reuptake, and has little effect on dopamine and noradrenaline uptake systems compared to other SSRIs. For this reason, fluvoxamine can be of benefit to patients who experience unusual or limiting side-effects from other antidepressants. It appears to cause fewer side effects than other SSRIs. In addition, these differences also are a result of the lack of direct effects at other neurotransmitter receptors compared to other SSRIs. Affinity for these receptors, for example cholinergic muscarinic (dry mouth, constipation) sites, histaminergic (sedation) sites, alpha (postural hypertension) sites and dopamine (extrapyramidal)sites, leads to many side effects. Compared to other SSRIs, fluvoxamine has a very low affinity to all of these sites.

Among the SSRIs, fluvoxamine has the highest affinity for sigma receptor subtype 1 (σ1receptors) , suggesting that it may have particular benefits in the treatment of depressed patients who show features of anxiety/stress and for whom memory impairment is particularly undesirable (such as in depressed elderly patients, and also in treating psychotic depression).

Absorption
The oral absorption of fluvoxamine is equal to or more than 94%.

Distribution
The plasma protein binding is only about 76%.

Metabolism
Fluvoxamine is extensively metabolised in the liver. It has no active metabolites.

Elimination
Fluvoxamine has the shortest half-life of all the SSRIs. Its mean serum half-life is 15 hours after a single dose, and 17 to 22 hours after repeated doses.

Dosage & Administration
The normal dosage for depression and anxiety starts at 50mg per day, rising to 100mg after a few days. It may be raised after evaluation of the effects by a doctor.

Fluvoxamine has shown generally effective for OCD at 150mg and above, and dosages can reach 300mg or more for some patients.

Drug Interactions
Fluvoxamine has a low potential for the drug interactions which are based on inhibition of enzyme Cytochrome P450 CYP2D6. Fluvoxamine shows the least interaction of the SSRIs, in regard to this specific enzyme. Naturally the other SSRIs which are metabolized by CYP2D6 will have more CYP2D6-based interactions with TCAs, antiarrythmics, B-blockers, phenytoin, opiates (eg. codeine, dextromethorphan, morphine, tramadol) and neuroleptics (eg. haloperidol, risperidon).

Fluvoxamine does, however, inhibit Cytochrome P450 enzyme CYP1A2, which metabolises caffeine, clozapine, haloperidol, phenacetin, tacrine, theophylline, and olanzapine. These substances can cause increased serum levels when administered together with fluvoxamine. Of major concern is the fact that the polycyclic aromatic hydrocarbons found in tobacco smoke are potent inducers of CYP1A2 so that smokers may require significant modification of medication dosage. A recent warning has been published regarding potentially serious interaction with Tizanidine, based on CYP1A2 metabolism.

Fluvoxamine inhibits metabolism of diazepam and phenytoin via CYP2C19 and inhibits metabolism of aripiprazole, chlorpromazine, clozapine, haloperidol, olanzapine, perphenazine, risperidone, thioridazine and zuclopenthixol via CYP2D6 as well as inhibiting metabolism of aripiprazole, clozapine, haloperidol, quetiapine, risperidone and ziprasidone via CYP3A4.

The plasma protein binding of fluvoxamine is about 77%. Drugs with low protein binding are less likely to displace other protein bound drugs, and therefore have a lower potential to cause protein binding-related drug interactions.

Side effects
Side effects of fluvoxamine can include: decreased sex drive or ability, drowsiness, tiredness, diarrhea, dizziness or light-headedness, constipation, headache, nausea, nervousness, sleep problems, increased sweating, tremors, serious skin rash, vomiting, stomach pain, dry mouth, heart burn, loss of appetite, pins and needles, abnormal taste, increased heart beat, weight gain or loss, unusual bruising and other allergic problems such as difficulty breathing, fever, confusion, severe weakness,  intense agitation or anxiety, restlessness, hypomania, mania,  seizures.

Fluvoxamine has been found to delay ejaculation in a manner similar to but less than other SSRIs including fluoxetine, paroxetine and sertraline.