Indications:
RECONCILE chewable tablets
are indicated for the treatment of canine separation anxiety in
conjunction with a behavior modification plan.
Dosage
and Administration:
The recommended dose of
RECONCILE chewable tablets is 1-2 mg/kg (0.5-0.9 mg/lb) administered
once daily, in conjunction with a behavior modification plan. A typical
behavior modification plan consists of the pet owner implementing
standard training techniques based on principles such as rewarding
appropriate behavior; coming and going in a manner that does not elicit
inappropriate responses from the dog; and teaching the dog to be content
while alone.
Table
1: Recommended Dose of RECONCILE Chewable Tablets
Dog Weight |
No. of
Tablets/day |
Tablet Strength
(mg) |
(lb) |
(kg) |
8.8 - 17.6 |
4.0 - 8.0 |
1 |
8 |
17.7 - 35.2 |
8.1 -16.0 |
1 |
16 |
35.3 - 70.4 |
16.1 - 32.0 |
1 |
32 |
70.5 - 140.8 |
32.1 - 64.0 |
1 |
64 |
The effectiveness and
safety of RECONCILE chewable tablets was demonstrated in a field study
in client-owned dogs (see EFFECTIVENESS and
ADVERSE REACTIONS). At the end of the 8-week study,
73% of dogs treated with RECONCILE chewable tablets showed significant
improvement (p=0.010), as compared to behavior modification alone (51%).
During the course of therapy, 42% of dogs showed improvement within the
first week, which was significantly greater (p=0.005) than with behavior
modification alone (18%). The patient's response to therapy should be
monitored. If no improvement is noted within 8 weeks, case management
should be reevaluated.
The effectiveness and
clinical safety of RECONCILE chewable tablets for long-term use (i.e.
for more than 8 weeks) has not been evaluated. RECONCILE chewable
tablets were evaluated at the recommended label dose for one year in a
laboratory safety study in dogs (see ANIMAL SAFETY).
Professional judgment
should be used in monitoring the patient's response to therapy to
determine the need to continue treatment with RECONCILE chewable tablets
beyond 8 weeks. To discontinue therapy, it is not necessary to taper or
reduce doses because of the long half-life of this product. Continued
behavioral modification is recommended to prevent recurrence of the
clinical signs.
RECONCILE chewable tablets
are readily consumed by dogs or can be administered like other tablet
medications, and can be given with or without food.
Professional discretion
should be used in determining the need for dose reduction in the event
of a possible adverse reaction. Approximately half of patients tolerate
a return to the previous dose after 1-2 weeks on a reduced schedule (see
ADVERSE REACTIONS).
If a dose is missed, the
next scheduled dose should be administered as prescribed. Do not
increase or double the dose.
Contraindications:
RECONCILE chewable tablets
are contraindicated for use in dogs with epilepsy or a history of
seizures. RECONCILE chewable tablets should not be given concomitantly
with drugs that lower the seizure threshold (e.g., phenothiazines such
as acepromazine or chlorpromazine).
RECONCILE chewable tablets
should not be given in combination with a monoamine oxidase inhibitor (MAOI)
[e.g., selegiline hydrochloride (L-deprenyl) or amitraz], or within a
minimum of 14 days of discontinuing therapy with an MAOI.
RECONCILE chewable tablets
are contraindicated in dogs with a known hypersensitivity to fluoxetine
HCl or other SSRIs.
Because fluoxetine and its
major metabolite, norfluoxetine, have long half-lives, a 6-week washout
interval should be observed following discontinuation of therapy with
RECONCILE chewable tablets prior to the administration of any drug that
may adversely interact with fluoxetine or norfluoxetine.
Human
Warnings:
Not for use in humans.
Keep out of reach of children. In case of accidental
ingestion seek medical attention immediately. In humans, the most common
symptoms associated with over dosage include seizures, somnolence,
nausea, tachycardia, and vomiting. In case of ingestion by a human,
contact a physician immediately. For a copy of the Material Safety Data
Sheet (MSDS) or to report adverse reactions call 1-888-545-5973.
Precautions:
RECONCILE chewable tablets
are not recommended for the treatment of aggression. RECONCILE chewable
tablets have not been clinically tested for the treatment of other
behavioral disorders. Studies to determine the effects of RECONCILE
chewable tablets in breeding, pregnant, or lactating dogs and in
patients less than 6 months of age have not been conducted.
Seizures may occur in dogs
treated with RECONCILE chewable tablets, even in dogs without a history
of epilepsy or seizures (see ADVERSE REACTIONS).
Before prescribing
RECONCILE chewable tablets, a comprehensive physical examination should
be conducted to rule out causes of inappropriate behavior unrelated to
separation anxiety. The examination should include a thorough history
and assessment of the patient's household environment and standard
practice laboratory tests as appropriate for the patient's age and
health status. Veterinarians should be familiar with the risks and
benefits of the treatment of behavioral disorders in dogs before
initiating therapy. Inappropriate use of RECONCILE chewable tablets,
i.e. in the absence of a diagnosis or without concurrent behavior
modification, may expose the animal to unnecessary adverse reactions and
may not provide any lasting benefit of therapy.
RECONCILE chewable tablets
have not been evaluated with drugs that affect the cytochrome P450
enzyme system. RECONCILE chewable tablets should be used with caution
when co-administered with any drug that affects the cytochrome P450
enzyme system (for example, ketoconazole). Studies to assess the
interaction of RECONCILE chewable tablets with tricyclic antidepressants
(TCAs) (for example, amitriptyline and clomipramine) have not been
conducted. The minimum washout period to transition dogs from TCAs to
RECONCILE chewable tablets has not been evaluated. Published
pharmacokinetic data demonstrates that TCAs are cleared 4 days following
discontinuation. 1,2
Adverse
Reactions:
In two North American
multi-site field studies, which included a total of 427 dogs, the
following adverse reactions were observed:
Seizures: In one study, one of 112 dogs in the control group and
three of 117 dogs that received RECONCILE chewable tablets experienced
the serious adverse reaction of seizures. One of the three dogs treated
with RECONCILE chewable tablets experienced two seizures 10 days after
the end of therapy.
Despite escalating
phenobarbital doses, the seizures continued and this dog died in status
epilepticus approximately six months after the first seizure. Another of
the three dogs treated with RECONCILE chewable tablets had experienced
one seizure approximately 1 1/2 years prior to study enrollment
immediately after receiving head trauma.
No additional seizures
were reported to have occurred until 45 days after concluding treatment
with RECONCILE chewable tablets. During the 11/2-year period since the
second seizure, this dog's seizure activity increased from single
seizures to cluster seizures despite increasing doses of phenobarbital
and the addition of oral potassium bromide and rectal diazepam. The
third dog treated with RECONCILE chewable tablets and the control dog
experienced one seizure 24 days and 35 days, respectively, after the
start of therapy; no anticonvulsant therapy was initiated and no further
seizures were reported in either dog.
In the second study, one
of 99 dogs treated with RECONCILE chewable tablets and one of 99 dogs
treated with the control tablet experienced the serious adverse reaction
of seizures 9 and 27 days, respectively, after initiation of therapy.
The dog treated with RECONCILE chewable tablets was subsequently
diagnosed with vestibular disease and the control dog had a history of
recurrent hind leg weakness.
1
Plumb DC. Amitriptyline. Veterinary Drug Handbook 5th Edition (Pocket
Edition). Iowa State Press. Ames, IA. Page 39, 2002.
2
Hewson CJ, et.al. The pharmacokinetics of clomipramine and
desmethylclomipramine in dogs: parameter estimates following a single
oral dose and 28 consecutive daily doses of clomipramine. J Vet
Pharmacol Therap 21:214-222, 1998.
In a European multi-site
study, 234 dogs were treated with daily doses of fluoxetine chewable
tablets ranging from 0.25 mg/kg to 4 mg/kg.
One dog treated with a
daily dose of 0.4 mg/kg for one month experienced one seizure one week
after discontinuing therapy. No anticonvulsant therapy was initiated and
no further seizures were reported.
Weight
loss: Of the dogs in the two North American field studies with body
weight measurements throughout the study (n=196 and n=185 in the
RECONCILE chewable tablets and control group, respectively), a 5% or
greater weight loss (when compared to initial, pre-study body weight)
was observed in 58 (29.6%) of dogs treated with RECONCILE chewable
tablets and 24 (13.0%) of dogs in the control group. No dogs were
withdrawn from clinical studies due to weight loss alone. The following
table shows the number of dogs with weight loss, stratified by percent
weight loss relative to initial body weight.
Table
2: Dogs with Weight Loss (stratified by percent loss relative to initial
body weight)
Treatment Group |
? 5% to < 10%
Number (%) |
? 10 to < 15%
Number (%) |
? 15%
Number (%) |
RECONCILE
chewable tablets |
44 (22.5%) |
13 (6.6%) |
1a
(0.5%) |
Control |
20 (10.8%) |
4 (2.2%) |
0 (0%) |
a
This dog lost 20% of its initial body weight and was the same dog that
died in status epilepticus.
Other adverse reactions: Additional adverse reactions observed in
dogs treated with RECONCILE chewable tablets at a rate of 1% or greater
were:
Table
3: Adverse Reactions Reported in the North American Field Studies
|
RECONCILE Chewable Tablets,N=216 |
Control,* N=211 |
Adverse Reaction |
n |
% |
n |
% |
Calm/Lethargy/Depression |
71 |
32.9 |
22 |
10.4 |
Decreased
Appetite |
58 |
26.9 |
13 |
6.2 |
Vomiting |
37 |
17.1 |
28 |
13.3 |
Shaking/Shivering/Tremor |
24 |
11.1 |
4 |
1.9 |
Diarrhea |
21 |
9.7 |
17 |
8.1 |
Restlessness |
16 |
7.4 |
8 |
3.8 |
Excessive
Vocalization (Including Whining) |
13 |
6.0 |
7 |
3.3 |
Aggression |
9 |
4.2 |
13 |
6.2 |
Otitis Externa |
6 |
2.8 |
2 |
0.9 |
Disorientation |
5 |
2.3 |
1 |
0.5 |
Incoordination |
5 |
2.3 |
0 |
0.0 |
Constipation |
3 |
1.4 |
0 |
0.0 |
Excessive
Salivation |
3 |
1.4 |
4 |
1.9 |
* The control group
received the tablet formulation without fluoxetine.
Dose
Reduction: Twenty dogs in the RECONCILE chewable tablet group and
five dogs in the control group required a reduction in dose due to
unacceptable adverse reactions, generally anorexia, vomiting, shaking
and depression. Lowering the dose eliminated or reduced the severity of
these adverse reactions in the RECONCILE chewable tablet group only.
Resumption of the full dose of RECONCILE chewable tablets resulted in a
return of the initial adverse reactions in approximately half of the
affected dogs. The majority of these adverse reactions were intermittent
and mild. However, one dog experienced recurrence of severe adverse
reactions, which necessitated withdrawal from the study for that dog.
Additionally, two dogs
required a second dose reduction of RECONCILE chewable tablets.
Effectiveness was maintained in a majority of those dogs in which a dose
reduction was necessary.
Clinical Pharmacology:
Fluoxetine exerts its
effect by inhibiting the reuptake of serotonin at the pre-synaptic
neuron. Fluoxetine does not act as a sedative. Fluoxetine is well
absorbed after oral administration (~72%). It is largely metabolized in
the liver by cytochrome P-450 enzyme system to norfluoxetine, an
equipotent SSRI that contributes to the efficacy of RECONCILE chewable
tablets.
After a single dose,
and also at steady state, calculations were made as follows:
Table 4:
Single Dose* Pharmacokinetic Parameters of Fluoxetine Hydrochloride
(mean � standard error).
|
AUC0-?
(�g�hr/mL) |
Cmax (ng/mL) |
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|