Prozamel

Storage And Handling

Store at Controlled Room Temperature, 15° to 30°C (59° to 86°F).

Marketed by: Lilly USA, LLC, Indianapolis, IN 46285, USA. Revised: Oct 2014

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Prozamel interactions

See also:
What other drugs will affect Prozamel?

The potential for interaction by a variety of mechanisms (for example, pharmacodynamic, pharmacokinetic drug inhibition or enhancement, etc.) is a possibility.

Monoamine Oxidase Inhibitors (MAOI)

Concomitant use of Prozamel (Prozamel) in patients taking MAOIs is contraindicated. There have been reports of serious, sometimes fatal, reactions (including hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations of vital signs, and mental status changes that include extreme agitation progressing to delirium and coma) in patients receiving Prozamel in combination with a monoamine oxidase inhibitor (MAOI), and in patients who have recently discontinued Prozamel and are then started on an MAOI. Some cases presented with features resembling neuroleptic malignant syndrome. Therefore, Prozamel, including Prozamel, should not be used in combination with an MAOI, or within a minimum of 14 days of discontinuing therapy with an MAOI. Since Prozamel and its major metabolite have very long elimination half-lives, at least 5 weeks (perhaps longer, especially if Prozamel has been prescribed chronically and/or at higher doses ) should be allowed after stopping Prozamel before starting an MAOI.

CNS Acting Drugs

Caution is advised if the concomitant administration of Prozamel, including Prozamel, and other CNS acting drugs is required. In evaluating individual cases, consideration should be given to using lower initial doses of the concomitantly administered drugs, using conservative titration schedules, and monitoring of clinical status.

Serotonergic Drugs

Based on the mechanism of action of SNRIs and SSRIs, including Prozamel, and the potential for serotonin syndrome, caution is advised when Prozamel is coadministered with other drugs that may affect the serotonergic neurotransmitter systems, such as triptans, linezolid (an antibiotic which is a reversible non-selective MAOI), lithium, tramadol, or St. John's Wort. The concomitant use of Prozamel with SNRIs, SSRIs, or tryptophan is not recommended.

Triptans

There have been rare postmarketing reports of serotonin syndrome with use of an SSRI and a triptan. If concomitant treatment of Prozamel with a triptan is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases.

Tryptophan

Five patients receiving Prozamel in combination with tryptophan experienced adverse reactions, including agitation, restlessness, and gastrointestinal distress. The concomitant use with tryptophan is not recommended.

Drugs That Interfere With Hemostasis (for example, NSAIDS, Aspirin, Warfarin)

Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies of the case-control and cohort design that have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding have also shown that concurrent use of an NSAID or aspirin may potentiate this risk of bleeding. Altered anticoagulant effects, including increased bleeding, have been reported when SNRIs or SSRIs are coadministered with warfarin. Patients receiving warfarin therapy should be carefully monitored when Prozamel is initiated or discontinued.

Electroconvulsive Therapy (ECT)

There are no clinical studies establishing the benefit of the combined use of ECT and Prozamel. There have been rare reports of prolonged seizures in patients on Prozamel receiving ECT treatment.

Potential For Other Drugs To Affect Prozamel

Drugs Tightly Bound to Plasma Proteins

Because Prozamel is tightly bound to plasma proteins, adverse effects may result from displacement of protein-bound Prozamel by other tightly bound drugs.

Potential For Prozamel To Affect Other Drugs

Pimozide

Concomitant use of Prozamel in patients taking pimozide is contraindicated. Clinical studies of pimozide with other antidepressants demonstrate an increase in drug interaction or QTc prolongation. While a specific study with pimozide and Prozamel has not been conducted, the potential for drug interactions or QTc prolongation warrants restricting the concurrent use of pimozide and Prozamel.

Thioridazine

Concomitant use of Prozamel in patients taking thioridazine is contraindicated. Thioridazine should not be administered with Prozamel or within a minimum of 5 weeks after Prozamel has been discontinued.

In a study of 19 healthy male subjects, which included 6 slow and 13 rapid hydroxylators of debrisoquin, a single 25 mg oral dose of thioridazine produced a 2.4-fold higher Cmax and a 4.5-fold higher AUC for thioridazine in the slow hydroxylators compared with the rapid hydroxylators. The rate of debrisoquin hydroxylation is felt to depend on the level of CYP2D6 isozyme activity. Thus, this study suggests that drugs which inhibit CYP2D6, such as certain SSRIs, including Prozamel, will produce elevated plasma levels of thioridazine.

Thioridazine administration produces a dose-related prolongation of the QTc interval, which is associated with serious ventricular arrhythmias, such as torsades de pointes-type arrhythmias, and sudden death. This risk is expected to increase with Prozamel-induced inhibition of thioridazine metabolism.

Drugs Metabolized by CYP2D6

Prozamel inhibits the activity of CYP2D6, and may make individuals with normal CYP2D6 metabolic activity resemble a poor metabolizer. Coadministration of Prozamel with other drugs that are metabolized by CYP2D6, including certain antidepressants (for example, tricyclic antidepressants (TCAs)), antipsychotics (for example, phenothiazines and most atypicals), and antiarrhythmics (for example, propafenone, flecainide, and others) should be approached with caution. Therapy with medications that are predominantly metabolized by the CYP2D6 system and that have a relatively narrow therapeutic index should be initiated at the low end of the dose range if a patient is receiving Prozamel concurrently or has taken it in the previous 5 weeks. Thus, his/her dosing requirements resemble those of poor metabolizers. If Prozamel is added to the treatment regimen of a patient already receiving a drug metabolized by CYP2D6, the need for decreased dose of the original medication should be considered. Drugs with a narrow therapeutic index represent the greatest concern (for example, flecainide, propafenone, vinblastine, and TCAs). Due to the risk of serious ventricular arrhythmias and sudden death potentially associated with elevated plasma levels of thioridazine, thioridazine should not be administered with Prozamel or within a minimum of 5 weeks after Prozamel has been discontinued.

Tricyclic Antidepressants (TCAs)

In 2 studies, previously stable plasma levels of imipramine and desipramine have increased greater than 2- to 10-fold when Prozamel has been administered in combination. This influence may persist for 3 weeks or longer after Prozamel is discontinued. Thus, the dose of TCAs may need to be reduced and plasma TCA concentrations may need to be monitored temporarily when Prozamel is coadministered or has been recently discontinued.

Benzodiazapines

The half-life of concurrently administered diazepam may be prolonged in some patients. Coadministration of alprazolam and Prozamel has resulted in increased alprazolam plasma concentrations and in further psychomotor performance decrement due to increased alprazolam levels.

Antipsychotics

Some clinical data suggests a possible pharmacodynamic and/or pharmacokinetic interaction between SSRIs and antipsychotics. Elevation of blood levels of haloperidol and clozapine has been observed in patients receiving concomitant Prozamel.

Anticonvulsants

Patients on stable doses of phenytoin and carbamazepine have developed elevated plasma anticonvulsant concentrations and clinical anticonvulsant toxicity following initiation of concomitant Prozamel treatment.

Lithium

There have been reports of both increased and decreased lithium levels when lithium was used concomitantly with Prozamel. Cases of lithium toxicity and increased serotonergic effects have been reported. Lithium levels should be monitored when these drugs are administered concomitantly.

Drugs Tightly Bound to Plasma Proteins

Because Prozamel is tightly bound to plasma proteins, the administration of Prozamel to a patient taking another drug that is tightly bound to protein (for example, warfarin, digitoxin) may cause a shift in plasma concentrations potentially resulting in an adverse effect.

Drugs Metabolized by CYP3A4

In an in vivo interaction study involving coadministration of Prozamel with single doses of terfenadine (a CYP3A4 substrate), no increase in plasma terfenadine concentrations occurred with concomitant Prozamel.

Additionally, in vitro studies have shown ketoconazole, a potent inhibitor of CYP3A4 activity, to be at least 100 times more potent than Prozamel or norfluoxetine as an inhibitor of the metabolism of several substrates for this enzyme, including astemizole, cisapride, and midazolam. These data indicate that Prozamel's extent of inhibition of CYP3A4 activity is not likely to be of clinical significance.

Drug Abuse And Dependence

Dependence

Prozamel has not been systematically studied, in animals or humans, for its potential for abuse, tolerance, or physical dependence. While the pre-marketing clinical experience with Prozamel did not reveal any tendency for a withdrawal syndrome or any drug seeking behavior, these observations were not systematic and it is not possible to predict on the basis of this limited experience the extent to which a CNS active drug will be misused, diverted, and/or abused once marketed. Consequently, physicians should carefully evaluate patients for history of drug abuse and follow such patients closely, observing them for signs of misuse or abuse of Prozamel (for example, development of tolerance, incrementation of dose, drug-seeking behavior).

Prozamel side effects

See also:
What are the possible side effects of Prozamel?

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 Prozamel chewable tablets experienced the serious adverse reaction of seizures. One of the three dogs treated with Prozamel 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 Prozamel chewable tablets had experienced one seizure approximately 1½ 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 Prozamel chewable tablets. During the 1½-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 Prozamel 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 Prozamel 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 Prozamel 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 Prozamel 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 Prozamel 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 Prozamel 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.

Other adverse reactions:

Additional adverse reactions observed in dogs treated with Prozamel chewable tablets at a rate of 1% or greater were:

Dose Reduction:

Twenty dogs in the Prozamel 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 Prozamel chewable tablet group only. Resumption of the full dose of Prozamel 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 Prozamel chewable tablets. Effectiveness was maintained in a majority of those dogs in which a dose reduction was necessary.

Prozamel contraindications

See also:
What is the most important information I should know about Prozamel?

Prozamel® is contraindicated in patients known to be hypersensitive to it.

Monoamine Oxidase Inhibitors

There have been reports of serious, sometimes fatal, reactions (including hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations of vital signs, and mental status changes that include extreme agitation progressing to delirium and coma) in patients receiving Prozamel in combination with a monoamine oxidase inhibitor (MAOI), and in patients who have recently discontinued Prozamel and are then started on an MAOI. Some cases presented with features resembling neuroleptic malignant syndrome. Therefore, Prozamel should not be used in combination with an MAOI, or within a minimum of 14 days of discontinuing therapy with an MAOI. Since Prozamel and its major metabolite have very long elimination half-lives, at least 5 weeks [perhaps longer, especially if Prozamel has been prescribed chronically and/or at higher doses ] should be allowed after stopping Prozamel before starting an MAOI.

Pimozide

Concomitant use in patients taking pimozide is contraindicated.

Thioridazine

Thioridazine should not be administered with Prozamel® or within a minimum of 5 weeks after Prozamel® has been discontinued.

Active ingredient matches for Prozamel:

Fluoxetine in Ireland.

Fluoxetine hydrochloride in Ireland.