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PROZAC                                          
Chemical- Fluoxetine Hydrochloride 


Adverse Effects- Adverse effects reported with Fluoxetine include gastro-intestinal disturbances such as nausea, vomiting, dyspepsia, dry mouth, and diarrhea. Anorexia and weight loss may also occur although these properties have led to the indication for fluoxetine's use in bulimia nervosa. Neurological side-effects have included either anxiety, nervousness, and insomnia or drowsiness and fatigue- headache, tremor, dizziness, convulsions, and decreased libido have also occurred. Excessive sweating and pruritus or skin rashes such as urticaria have also been reported. In some patients with rashes, systemic events involving the lungs, kidneys, or liver, and possibly related to vasculitis, have developed- it has therefore been advised that Fluoxetine therapy should be discontinued in any patient who develops a skin rash. In overdosage nausea, vomiting, and excitation of the central nervous system are considered to be prominent features- death has been reported. Treatment involves emesis induction or gastric lavage followed by symptomatic and supportive therapy. Forced diuresis, dialysis, haemoperfusion, and exchange transfusion are considered unlikely to be of benefit. Effects on Mental State- Although there have been allegations concerning the ability of Fluoxetine to increase suicidal ideation, meta-analysis, (1) opinion, (2) and experience (3) indicate that there is no such increased risk. However, it has been said that it is not known whether Fluoxetine can increase hostility or aggression. 

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1. Beasley CM, et al. Fluoxetine and suicide: a meta-analysis of controlled trials of treatment for depression. Br Med J 1991- 303: 685-92. 
2. Anonymous. Fluoxetine, suicide and aggression. Drug Ther Bull 1992- 30: 5-6. 
3. Committee on Safety of Medicines. Safety of Fluoxetine (Prozac): comparison with fluvoxamine (Faverin). Current Problems 34 1992.

Epileptogenic Effect- References. 
1. Weber JJ. Seizure activity associated with Fluoxetine therapy. Clin Pharm 1989- 8: 296-8. 
2. Ware MR, Stewart RB. Seizures associated with Fluoxetine therapy. DICP Ann Pharmacother 1989- 23: 428. 

Precautions- As Fluoxetine undergoes hepatic metabolism and renal excretion it should be used with caution and in reduced doses in patients with impaired hepatic or renal function (see below under Uses and Administration).  Because of its epileptogenic effect it should be used with caution in patients with epilepsy or a history of such disorders. Fluoxetine may alter glycemia control and therefore caution is also warranted in diabetic subjects. Depressed patients with suicidal tendencies should be carefully supervised during treatment.  Fluoxetine is not usually considered a suitable form of therapy for the depressive component of bipolar (manic-depressive) illness as mania may be precipitated. Fluoxetine should be discontinued in patients who develop a rash since systemic effects, possibly related to vasculitis, have occurred in such patients. Interactions have occurred between Fluoxetine and other antidepressants. Enhancement of the serotonergic effects resulting in the serotonin syndrome has been reported in patients receiving Fluoxetine and monoamine oxidase inhibitors concurrently or within a short interval of each other (see below). Consequently at least 14 days should elapse between discontinuation of a monoamine oxidase inhibiting antidepressant and the introduction of Fluoxetine. Because of the long half-lives of Fluoxetine and its metabolite, norfluoxetine, it is also advised that at least 5 weeks should elapse between discontinuation of Fluoxetine and the introduction of a monoamine oxidase inhibitor. Enhancement of the serotonergic effects may also occur if Fluoxetine is given with Tryptophan or lithium (see below). There have also been reports of Fluoxetine causing both increased and decreased concentrations of lithium. Increases in previously stable concentrations of other antidepressants have also been stated to have occurred when Fluoxetine was added to the therapy. Interactions- In the UK the CSM has warned (1) that enhanced serotonergic effects may result from combination therapy of highly selective serotonin re-uptake inhibitors, such as Fluoxetine and fluvoxamine, with other antidepressants, including monoamine oxidase inhibitors, lithium, or Tryptophan. Although such an enhancement may be beneficial in some instances it can produce a life-threatening serotonin syndrome comprising hypothermia, tremor, and convulsions. Indeed, such fatal effects have been reported in a patient receiving Fluoxetine, tranylcypromine, and Tryptophan along with other multiple drug therapies. (2) 
1. Committee on Safety of Medicines. Fluvoxamine and Fluoxetine-interaction with monoamine oxidase inhibitors, lithium and Tryptophan. Current Problems 26 1989. (Correction stating that hypothermia should have read hypothermia. Current Problems 27 1989). 
2. Kline SS, et al. Serotonin syndrome versus neuroleptic malignant syndrome as a cause of death. Clin Pharm 1989- 8: 

Use and Administration- Fluoxetine is an antidepressant. It selectively inhibits the re-uptake of serotonin but has relatively little effect on noradrenaline re-uptake. It is reported to cause fewer antimuscarinic side effects than tricyclic antidepressants. Its mode of action in depression is not fully understood. In the treatment of depression Fluoxetine is given by mouth as Fluoxetine hydrochloride. In the UK doses and strengths are expressed in terms of Fluoxetine hydrochloride whereas in the USA they are expressed in terms of Fluoxetine. The usual dose of Fluoxetine or the hydrochloride is 20 mg daily- doses of up to 80 mg daily in divided doses may be employed if necessary. A recommended maximum dose for elderly patients is 60 mg daily. Because Fluoxetine is subject to hepatic metabolism, lower doses, such as alternate-day dosing, have been recommended in patients with significant hepatic impairment. Similar recommendations, because of renal excretion, have been made for patients with mild to moderate renal failure (where the glomerular filtration-rate is 10 to 50 ml per minute)- it should not, however, be used at all in patients with severe renal failure (glomerular filtration-rate of less than 10 ml per minute). It should be noted that the prolonged half-lives of Fluoxetine and norfluoxetine will result in the need for several weeks of therapy to be employed before steady-state concentrations are attained- similarly after dosage adjustments a time lag will occur before steady-state concentrations are again achieved. Fluoxetine is also used in doses of 60 mg daily in the management of bulimia nervosa. 

Some general references. 
1. Anonymous. Fluoxetine: another new antidepressive. Drug Ther Bull 1990- 28: 33-4. 
2. Anonymous. 5-HT blockers and all that. Lancet 1990- 336: 345-6. 
3. Anonymous. Fluoxetine (Prozac) revisited. Med Lett Drugs Ther 1990- 32: 83-5. Like many other antidepressants, the use of Fluoxetine has been investigated in a variety of disorders in addition to depression. Beneficial responses have been reported in obsessive compulsive disorders, (1-3) pain syndromes including diabetic neuropathy (4) and fibrosis, (5) panic disorders, (6) sleep disorders such as narcolepsy and cataplexy, (7) and bulimia nervosa. (8)

For mention of the use of Fluoxetine in cataplexy and sleep paralysis associated with narcolepsy, see Amitriptyline, Ref. 

1. Turner SM, et al. Fluoxetine treatment of obsessive-compulsive disorder. J Clin Psychopharmacol 1985- 5: 207-12. 
2. Fontaine R, Chouinard G. An open clinical trial of Fluoxetine in the treatment of obsessive-compulsive disorder. J Clin Psychopharmacol 1986-6: 98-101. 
3. Granet RB. Fluoxetine treatment of obsessive compulsive disorder. J Clin Psychiatry 1989- 50: 436. 
4. Theesen KA, Marsh WR. Relief of diabetic neuropathy with Fluoxetine. DICP Ann Pharmacother 1989- 23: 572-4. 
5. Geller SA. Treatment of fibrosis with Fluoxetine hydrochloride (Prozac). Am J Med 1989- 87: 594-5 
6. Schneier FR, et al. Fluoxetine in panic disorder. J Clin Psychopharmacol 1990- 10: 119-21. 
7. Langdon N, et al. Fluoxetine in the treatment of cataplexy. Sleep 1986- 9: 371-3. 
8. Ramirez LC, et al. Effective treatment of bulimia with Fluoxetine, a serotonin reuptake inhibitor, in a patient with type I diabetes mellitus. Am J Med 1990- 88: 540-1.

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