Fluoxetine

Overview

Fluoxetine (Prozac®, Reconcile®) is a selective serotonin reuptake inhibitor (SSRI) widely used in veterinary medicine for the management of behavioral disorders. It is FDA-approved for use in dogs, particularly for separation anxiety, and is commonly used extra-label in cats.

Fluoxetine is typically the first-choice SSRI in veterinary behavioural medicine, has fewer adverse effects than other antidepressant drugs, and has a prolonged duration of action. Clinical improvement is gradual, and several weeks (typically 4–8 weeks) may be required before full therapeutic effects are observed.

Fluoxetine and its active metabolite (norfluoxetine) have long half-lives, allowing for once-daily dosing but also requiring consideration of prolonged drug effects and washout periods when switching therapies.

Mechanism of Action (MOA): Fluoxetine selectively inhibits the presynaptic reuptake of serotonin in the central nervous system, increasing serotonin availability. This results in anxiolytic and anticompulsive effects and may reduce behavioral reactivity and aggression.

Indications

Fluoxetine is used in dogs and cats for the management of a variety of behavioral disorders. It should be used in conjunction with a structured behavior modification program.

• Canine separation anxiety: FDA-approved indication in dogs; used in combination with behavior modification to reduce anxiety-related behaviors.
• Aggression: May help reduce inappropriate or pathologic aggression in both dogs and cats by decreasing behavioral reactivity, although the licensed product is not recommended for treating aggression and use in an aggressive patient should be part of a specifically constructed behaviour modification plan.
• Obsessive-compulsive and stereotypic behaviors: Used to manage repetitive or compulsive behaviors, including excessive licking and other self-directed behaviours.
• Anxiety-related disorders: Includes generalized anxiety, noise aversion, and stress-related behavioral issues.
• Inappropriate elimination (cats): May be useful in managing urine marking or other elimination-related behavioral problems.
• Feline hyperesthesia and overgrooming: Cats with self-directed licking or biting of the flank and tail, twitching and tail swishing, when a primary behavioural disorder is suspected; psychogenic alopecia is managed the same way.
• Hereditary Scottie cramp: Episodic muscle hypertonicity or cramping in Scottish terriers, thought to arise from disordered serotonin metabolism, may be reduced by fluoxetine.

Dosage (Reference)

Dog

In dogs, fluoxetine is given by mouth: once daily for behavioural disorders, and every 12 hours for hereditary Scottie cramp. It is FDA-approved for separation anxiety and also used extra-label for other behavioral disorders. Clinical response is gradual and should be evaluated over several weeks.

Cat

In cats, fluoxetine is used extra-label for behavioral disorders. Response may take several weeks, and dose adjustments should be based on clinical improvement and tolerance.

Warnings & Precautions

Fluoxetine is generally well tolerated, but careful patient selection and monitoring are required due to its effects on the central nervous system and its long half-life.

• Contraindications: Do not use in animals with known hypersensitivity to fluoxetine or other SSRIs, or in those receiving monoamine oxidase inhibitors (MAOIs).
• Seizure disorders: Contraindicated in animals with a history of seizures. The licensed canine product is specifically contraindicated in dogs with epilepsy or a history of seizures, and seizures have also occurred in treated dogs with no previous seizure history.
• Drug combinations affecting seizure threshold: Avoid concurrent use with drugs considered to lower the seizure threshold, including phenothiazines such as acepromazine and chlorpromazine. Although the effect of phenothiazines on seizure susceptibility remains uncertain, particularly for acepromazine, this combination should be avoided.
• Diabetes mellitus: May alter blood glucose levels; careful monitoring and dose adjustments may be required.
• Hepatic impairment: Dose reduction may be necessary in animals with severe liver disease because clearance can be reduced; renal impairment does not significantly affect elimination rates.
• Long half-life: Fluoxetine and its active metabolite persist in the body; effects may continue after discontinuation.
• Washout period: Allow approximately 6 weeks after stopping fluoxetine before starting a drug that may interact with it or with norfluoxetine, and at least 14 days after stopping a monoamine oxidase inhibitor before fluoxetine is started.
• Use in young animals: Safety has not been established in dogs younger than 6 months, and the licensed chewable tablets are intended only for dogs of that age or older weighing at least 4.0 kg.
• Aggression: Fluoxetine is not recommended for routine treatment of aggression. It may be considered in selected aggressive dogs as part of a specifically designed behavioral management plan and under close professional supervision. Use with caution because behavioral disinhibition may occur and aggression may worsen; owners should be advised of this risk.
• Drug confusion: Take care not to confuse fluoxetine with famotidine, fluvoxamine or paroxetine, and the brand Prozac with Prilosec.
• Pregnancy, lactation and breeding: Safety in pregnancy, lactation and breeding animals has not been established, and no studies have been conducted in breeding, pregnant or lactating dogs. Fluoxetine crosses the placenta and is excreted in human milk; the implications for nursing animal offspring are unclear. SSRIs as a class have been associated with increased litter mortality and possible birth defects, and pulmonary hypertension has been produced in experimental animals dosed late in pregnancy. Use only when the maternal benefit outweighs the potential risk to the offspring.
• Anaesthesia and other CNS-active drugs: Use caution when a patient on fluoxetine receives other CNS-active drugs, including general anaesthesia and neuroleptic, anticholinergic and sympathomimetic agents.
• Flea and tick collars: Ask whether the animal has worn a flea-and-tick collar in the previous 2 weeks, and do not put one on during fluoxetine treatment without discussing it first.

Drug Interactions

Fluoxetine has multiple clinically significant drug interactions, primarily related to its effects on serotonin pathways and hepatic metabolism. Careful consideration and monitoring are required when combining with other medications.

• Monoamine oxidase inhibitors (MAOIs; e.g., selegiline, amitraz, linezolid): Contraindicated due to high risk of serotonin syndrome; strict washout periods required.
• Serotonergic drugs (e.g., trazodone, tramadol, buspirone, dextromethorphan, St. John’s Wort): Increased risk of serotonin syndrome.
• Tricyclic antidepressants (e.g., clomipramine, amitriptyline): Increased drug concentrations and risk of toxicity or serotonin syndrome; the combination has not been formally studied.
• Benzodiazepines (e.g., alprazolam, diazepam): May increase plasma concentrations and prolong sedative effects.
• Beta-blockers (e.g., propranolol, metoprolol): Increased plasma levels and risk of exaggerated pharmacologic effects; atenolol may be a safer choice if a beta-blocker is needed alongside fluoxetine.
• Methadone: Increased plasma concentrations and exposure may occur.
• NSAIDs and anticoagulants (e.g., aspirin, clopidogrel, warfarin): Increased risk of bleeding and of gastrointestinal ulceration; the risk extends to bleeding in the case of tissue trauma, and carprofen, meloxicam and robenacoxib are named specifically.
• Cyproheptadine: May reduce or reverse the therapeutic effects of fluoxetine.
• Insulin: May alter insulin requirements.
• Diuretics: Increased risk of hyponatremia.
• Drugs cleared by the liver: Fluoxetine inhibits cytochrome P450, so use it cautiously with drugs that undergo extensive hepatic metabolism, including phenobarbital, benzodiazepines and tricyclic antidepressants.
• Scottie cramp (indication-specific): Serotonin antagonists increase the severity of clinical signs, and aspirin, indomethacin, phenylbutazone, flunixin meglumine and penicillin may also exacerbate them.

Side Effects & Overdose

Side Effects

Adverse effects are seen in both dogs and cats. They were common in the canine field trials and become more frequent in dogs at higher doses; in feline urine-spraying trials few adverse effects were reported. Many effects are mild and transient, but some may require dose adjustment or discontinuation.

• Dogs: Anorexia, weight loss, lethargy, vomiting, diarrhea, restlessness, tremors, excessive vocalization, and panting. In the licensing field trials the commonest were lethargy in about a third of dogs, weight loss in about a third, anorexia in about a quarter and vomiting in about one in six; loss of 5% or more of body weight occurred in 29.6% of treated dogs against 13.0% of controls.
• Behavioral changes: Anxiety, irritability or increased aggression may occur in some animals; owners should be warned about the possibility, although in the licensing trials aggression occurred no more often than in dogs given a placebo.
• Neurologic effects: Seizures have been reported, although causality is not always clear; they occurred in 0.4% to 2.5% of dogs in the licensing field trials and have occurred in dogs with no previous seizure history.
• Other effects: Mydriasis, confusion, incoordination, and hypersalivation.
• Cats: Behavioral changes (e.g., anxiety, irritability, sleep disturbances), anorexia, diarrhea, and changes in elimination patterns; nervousness or increased anxiousness has also been described, and urine retention and constipation are reported.
• Transdermal use (cats): Skin irritation may occur at the application site.
• Managing an adverse reaction: Lowering the dose may eliminate or reduce these effects, and about half of dogs then tolerate a return to the previous dose after 1 to 2 weeks. In some dogs, persistent anorexia precludes further treatment.

Overdose

Fluoxetine overdose can result in significant neurologic and gastrointestinal effects. Clinical signs vary depending on dose and individual sensitivity.

• Common signs: Vomiting, hypersalivation, mydriasis, and vocalization.
• Neurologic effects: Tremors, agitation, and seizures may occur.
• Other signs: Serotonin toxicosis may also cause tachycardia, hypotension, hyperthermia, disorientation, ataxia, hyperreflexia and myoclonus. In humans, serotonin syndrome is characterised by at least three of myoclonus, altered mentation, agitation, hyperreflexia, tremors, diarrhoea, ataxia or hyperthermia.
• Cats: May show vomiting, diarrhea, agitation, and tremors; in a retrospective series only about a quarter of exposed cats showed any signs, about half were hospitalised for a mean of 15 hours, and all survived.
• Toxic doses: Reported toxic doses vary widely and are not well defined in veterinary medicine. In dogs, signs of SSRI toxicosis have been reported at a median dose of about 15.9 mg/kg, with tremors, anorexia, aggression, nystagmus, vomiting and ataxia at 10 to 20 mg/kg and seizures above 25 mg/kg. In cats, 3 mg/kg produced anorexia and vomiting, doses as low as 3.7 mg/kg caused signs of toxicity and 5 mg/kg produced tremors – yet in urine-spraying trials few adverse effects were reported and cats tolerated doses up to 50 mg/kg.
• Management: Supportive care based on clinical signs. Induce emesis only if the patient is asymptomatic and the ingestion recent, or lavage if a large number of tablets was swallowed; give activated charcoal with a cathartic, and if severe signs are expected repeat administration may be needed because of the long half-life. Give intravenous fluids to support blood pressure and body temperature and to protect the kidneys. For tremors, give methocarbamol 50 to 150 mg/kg intravenously, titrated upward as needed. For a known or suspected overdose, consult a 24-hour poison information service that gives veterinary-specific advice.
• Serotonin antagonism: Cyproheptadine may be used as a serotonin antagonist in cases of serotonin syndrome: 1.1 mg/kg in dogs, or 2 to 4 mg per cat by mouth every 4 to 6 hours, given rectally if the patient is vomiting. Acepromazine 0.025 to 0.05 mg/kg intravenously, titrated to effect, may be used for agitation.
• Prognosis and monitoring: Most patients recover within 12 to 24 hours, but those presenting in status epilepticus or with severe hyperthermia carry a guarded prognosis, and young and elderly animals are more at risk of serious toxicosis. Monitor blood pressure, heart rate and urine colour hourly at first, since rhabdomyolysis can lead to renal failure and hyperthermia to disseminated intravascular coagulation.

Key Notes

Practical clinical points that help optimize the use of fluoxetine in dogs and cats:

• Behavior modification is essential: Fluoxetine should always be used alongside a structured behavior modification program for optimal results.
• Active metabolite effect: Norfluoxetine contributes significantly to the drug’s clinical effect, resulting in prolonged therapeutic activity. In dogs the elimination half-lives of fluoxetine and norfluoxetine are about 6 to 18 hours and 49 hours; in cats they are about 47 and 52 hours.
• Delayed peak response: Maximum clinical improvement may not be seen until several weeks after starting therapy; early response may be subtle.
• Formulation considerations: Available as veterinary chewable tablets of 8 mg, 16 mg, 32 mg and 64 mg (the only licensed presentation, approved for dogs) and as human products: tablets of 10 mg, 20 mg and 60 mg, capsules of 10 mg, 20 mg and 40 mg, delayed-release capsules of 90 mg, and an oral solution of 20 mg/5 mL (4 mg/mL) in 120 mL and 473 mL. Store tablets and capsules in well-closed containers at room temperature and the oral solution in a tight, light-resistant container, and do not remove the desiccant from the chewable-tablet bottle.
• Transdermal limitations (cats): Transdermal formulations achieve only about 10% of the bioavailability of the oral route in cats and are not recommended: absorption is low and unpredictable and the preparation can irritate the pinna. Compounded transdermal products lack evidence of efficacy and safety.
• Treatment duration: Long-term therapy is often required for chronic behavioral conditions and periodic reassessment is recommended; note that the licensed product has not been evaluated beyond 8 weeks, so continuing past that point is a clinical judgement rather than a labelled use.
• Dose titration strategy: Starting at a lower dose and gradually increasing may improve tolerance and reduce adverse effects.
• Absorption and food: Oral bioavailability in dogs is about 72% to 88%, food changes the rate but not the extent of absorption, and capsules and liquid are bioequivalent, so the drug may be given with or without food. The chewable tablet gives about 15% greater exposure than the same dose in a gelatin capsule.
• Monitoring: Track the target behaviour and the patient’s appetite and body weight. For canine separation anxiety, weekly follow-up is best in the early stages to assess both efficacy and owner compliance, and in aggression cases weekly to biweekly contact is recommended in the early phase. In cats treated for urine marking, obtain a CBC and biochemistry profile 3 to 4 weeks after starting and then every 6 to 12 months.
• Not established for pain: SSRIs have been used in dogs and cats for pain syndromes such as neuropathic pain, but no published studies confirm efficacy for that use, and fluoxetine is not a sedative.