Euciton Complex

Clorazepate Dipotassium:

• Indications and usage
• Contraindications
• Warnings
• Precautions
• Adverse reactions
• Dosage and administration
• Drug interactions
• Overdosage
• Animal pharmacology and toxicology
• How supplied
• Medication guide
• Euciton Complex (Clorazepate Dipotassium) reviews

INDICATIONS AND USAGE

TRANXENE is indicated for the management of anxiety disorders or for the short-term relief of the symptoms of anxiety. Anxiety or tension associated with the stress of everyday life usually does not require treatment with an anxiolytic.

TRANXENE tablets are indicated as adjunctive therapy in the management of partial seizures.

The effectiveness of TRANXENE tablets in long-term management of anxiety, that is, more than 4 months, has not been assessed by systematic clinical studies. Long-term studies in epileptic patients, however, have shown continued therapeutic activity. The physician should reassess periodically the usefulness of the drug for the individual patient.

TRANXENE tablets are indicated for the symptomatic relief of acute alcohol withdrawal.

CONTRAINDICATIONS

TRANXENE tablets are contraindicated in patients with a known hypersensitivity to the drug and in those with acute narrow angle glaucoma.

WARNINGS

Risks from Concomitant Use with Opioids:

Concomitant use of benzodiazepines, including TRANXENE, and opioids may result in profound sedation, respiratory depression, coma, and death. Because of these risks, reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate.

Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drug-related mortality compared to use of opioids alone. If a decision is made to prescribe TRANXENE concomitantly with opioids, prescribe the lowest effective dosages and minimum durations of concomitant use, and follow patients closely for signs and symptoms of respiratory depression and sedation. In patients already receiving an opioid analgesic, prescribe a lower initial dose of TRANXENE than indicated in the absence of an opioid and titrate based on clinical response. If an opioid is initiated in a patient already taking TRANXENE, prescribe a lower initial dose of the opioid and titrate based upon clinical response.

Advise both patients and caregivers about the risks of respiratory depression and sedation when TRANXENE is used with opioids. Advise patients not to drive or operate heavy machinery until the effects of concomitant use with the opioid have been determined.

Use in Depressive Neuroses or Psychotic Reactions:

TRANXENE tablets are not recommended for use in depressive neuroses or in psychotic reactions.

Use in Children:

Because of the lack of sufficient clinical experience, TRANXENE tablets are not recommended for use in patients less than 9 years of age.

Interference with Psychomotor Performance:

Patients taking TRANXENE tablets should be cautioned against engaging in hazardous occupations requiring mental alertness, such as operating dangerous machinery including motor vehicles.

Concomitant Use with CNS Depressants:

Since TRANXENE has a central nervous system depressant effect, patients should be advised against the simultaneous use of other CNS depressant drugs, and cautioned that the effects of alcohol may be increased.

Physical and Psychological Dependence:

Withdrawal symptoms have occurred following abrupt discontinuance of clorazepate. Withdrawal symptoms associated with the abrupt discontinuation of benzodiazepines have included convulsions, delirium, tremor, abdominal and muscle cramps, vomiting, sweating, nervousness, insomnia, irritability, diarrhea, and memory impairment. The more severe withdrawal symptoms have usually been limited to those patients who had received excessive doses over an extended period of time. Generally milder withdrawal symptoms have been reported following abrupt discontinuance of benzodiazepines taken continuously at therapeutic levels for several months. Consequently, after extended therapy, abrupt discontinuation of clorazepate should generally be avoided and a gradual dosage tapering schedule followed.

Caution should be observed in patients who are considered to have a psychological potential for drug dependence.

Evidence of drug dependence has been observed in dogs and rabbits which was characterized by convulsive seizures when the drug was abruptly withdrawn or the dose was reduced; the syndrome in dogs could be abolished by administration of clorazepate.

Suicidal Behavior and Ideation:

Antiepileptic drugs (AEDs), including TRANXENE, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior.

Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different AEDs showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted Relative Risk 1.8, 95% CI:1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to placebo. In these trials, which had a median treatment duration of 12 weeks, the estimated incidence rate of suicidal behavior or ideation among 27,863 AED-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients, representing an increase of approximately one case of suicidal thinking or behavior for every 530 patients treated. There were four suicides in drug-treated patients in the trials and none in placebo-treated patients, but the number is too small to allow any conclusion about drug effect on suicide.

The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week after starting drug treatment with AEDs and persisted for the duration of treatment assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed.

The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed. The finding of increased risk with AEDs of varying mechanisms of action and across a range of indications suggests that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age (5-100 years) in the clinical trials analyzed. Table 1 shows absolute and relative risk by indication for all evaluated AEDs.

The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications.

Anyone considering prescribing TRANXENE or any other AED must balance the risk of suicidal thoughts or behavior with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated.

Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of the signs and symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers.

Usage in Pregnancy:

An increased risk of congenital malformations associated with the use of minor tranquilizers during the first trimester of pregnancy has been suggested in several studies. Euciton Complex (Clorazepate Dipotassium), a benzodiazepine derivative, has not been studied adequately to determine whether it, too, may be associated with an increased risk of fetal abnormality. Because use of these drugs is rarely a matter of urgency, their use during this period should almost always be avoided. The possibility that a woman of childbearing potential may be pregnant at the time of institution of therapy should be considered. Patients should be advised that if they become pregnant during therapy or intend to become pregnant they should communicate with their physician about the desirability of discontinuing the drug.

To provide information regarding the effects of in utero exposure to TRANXENE, physicians are advised to recommend that pregnant patients taking TRANXENE enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry. This can be done by calling the toll-free number 1-888-233-2334, and must be done by patients themselves. Information on the registry can also be found at the website http://www.aedpregnancyregistry.org/.

Usage during Lactation:

TRANXENE tablets should not be given to nursing mothers since it has been reported that nordiazepam is excreted in human breast milk.

PRECAUTIONS

In those patients in which a degree of depression accompanies the anxiety, suicidal tendencies may be present and protective measures may be required. The least amount of drug that is feasible should be available to the patient.

Patients taking TRANXENE tablets for prolonged periods should have blood counts and liver function tests periodically. The usual precautions in treating patients with impaired renal or hepatic function should also be observed.

In elderly or debilitated patients, the initial dose should be small, and increments should be made gradually, in accordance with the response of the patient, to preclude ataxia or excessive sedation.

Information for Patients:

To assure the safe and effective use of benzodiazepines, patients should be informed that, since benzodiazepines may produce psychological and physical dependence, it is essential that they consult with their physician before either increasing the dose or abruptly discontinuing this drug.

Patients, their caregivers, and families should be counseled that AEDs, including TRANXENE, may increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers.

Patients should be encouraged to enroll in the NAAED Pregnancy Registry if they become pregnant. This registry is collecting information about the safety of antiepileptic drugs during pregnancy. To enroll, patients can call the toll-free number 1-888-233-2334.

Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with Euciton Complex (Clorazepate Dipotassium) and should counsel them in its appropriate use. A patient Medication Guide is available for TRANXENE. The prescriber or health professional should instruct patients, their families, and their caregivers to read the Medication Guide and should assist them in understanding its contents. Patients should be given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have. The complete text of the Medication Guide is available at www.recordatirarediseases.com.

Pediatric Use:

See WARNINGS.

Geriatric Use:

Clinical studies of TRANXENE were not adequate to determine whether subjects aged 65 and over respond differently than younger subjects. Elderly or debilitated patients may be especially sensitive to the effects of all benzodiazepines, including TRANXENE. In general, elderly or debilitated patients should be started on lower doses of TRANXENE and observed closely, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and concomitant disease or other drug therapy. Dose adjustments should also be made slowly, and with more caution in this patient population (see PRECAUTIONS and DOSAGE AND ADMINISTRATION ).

ADVERSE REACTIONS

The side effect most frequently reported was drowsiness. Less commonly reported (in descending order of occurrence) were: dizziness, various gastrointestinal complaints, nervousness, blurred vision, dry mouth, headache, and mental confusion. Other side effects included insomnia, transient skin rashes, fatigue, ataxia, genitourinary complaints, irritability, diplopia, depression, tremor, and slurred speech.

There have been reports of abnormal liver and kidney function tests and of decrease in hematocrit.

Decrease in systolic blood pressure has been observed.

To report SUSPECTED ADVERSE REACTIONS, contact Recordati Rare Diseases Inc. at 1-888-575-8344 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

DOSAGE AND ADMINISTRATION

For the symptomatic relief of anxiety:

TRANXENE T-TAB tablets are administered orally in divided doses. The usual daily dose is 30 mg. The dose should be adjusted gradually within the range of 15 to 60 mg daily in accordance with the response of the patient. In elderly or debilitated patients it is advisable to initiate treatment at a daily dose of 7.5 to 15 mg.

TRANXENE tablets may also be administered in a single dose daily at bedtime; the recommended initial dose is 15 mg. After the initial dose, the response of the patient may require adjustment of subsequent dosage. Lower doses may be indicated in the elderly patient. Drowsiness may occur at the initiation of treatment and with dosage increment.

For the symptomatic relief of acute alcohol withdrawal:

The following dosage schedule is recommended:

Thereafter, gradually reduce the daily dose to 7.5 to 15 mg. Discontinue drug therapy as soon as patient’s condition is stable.

The maximum recommended total daily dose is 90 mg. Avoid excessive reductions in the total amount of drug administered on successive days.

As an Adjunct to Antiepileptic Drugs: In order to minimize drowsiness, the recommended initial dosages and dosage increments should not be exceeded.

Adults: The maximum recommended initial dose in patients over 12 years old is 7.5 mg three times a day. Dosage should be increased by no more than 7.5 mg every week and should not exceed 90 mg/day.

Children (9-12 years): The maximum recommended initial dose is 7.5 mg two times a day. Dosage should be increased by no more than 7.5 mg every week and should not exceed 60 mg/day.

DRUG INTERACTIONS

The concomitant use of benzodiazepines and opioids increases the risk of respiratory depression because of actions at different receptor sites in the CNS that control respiration. Benzodiazepines interact at GABA_A sites and opioids interact primarily at mu receptors. When benzodiazepines and opioids are combined, the potential for benzodiazepines to significantly worsen opioid-related respiratory depression exists. Limit dosage and duration of concomitant use of benzodiazepines and opioids, and monitor patients closely for respiratory depression and sedation.

If TRANXENE is to be combined with other drugs acting on the central nervous system, careful consideration should be given to the pharmacology of the agents to be employed. Animal experience indicates that Euciton Complex (Clorazepate Dipotassium) prolongs the sleeping time after hexobarbital or after ethyl alcohol, increases the inhibitory effects of chlorpromazine, but does not exhibit monoamine oxidase inhibition. Clinical studies have shown increased sedation with concurrent hypnotic medications. The actions of the benzodiazepines may be potentiated by barbiturates, narcotics, phenothiazines, monoamine oxidase inhibitors or other antidepressants.

If TRANXENE tablets are used to treat anxiety associated with somatic disease states, careful attention must be paid to possible drug interaction with concomitant medication.

In bioavailability studies with normal subjects, the concurrent administration of antacids at therapeutic levels did not significantly influence the bioavailability of TRANXENE tablets.

OVERDOSAGE

Overdosage is usually manifested by varying degrees of CNS depression ranging from slight sedation to coma. As in the management of overdosage with any drug, it should be borne in mind that multiple agents may have been taken.

The treatment of overdosage should consist of the general measures employed in the management of overdosage of any CNS depressant. Gastric evacuation either by the induction of emesis, lavage, or both, should be performed immediately. General supportive care, including frequent monitoring of the vital signs and close observation of the patient, is indicated. Hypotension, though rarely reported, may occur with large overdoses. In such cases the use of agents such as norepinephrine bitartrate injection, USP or metaraminol bitartrate injection, USP should be considered.

While reports indicate that individuals have survived overdoses of Euciton Complex (Clorazepate Dipotassium) as high as 450 to 675 mg, these doses are not necessarily an accurate indication of the amount of drug absorbed since the time interval between ingestion and the institution of treatment was not always known. Sedation in varying degrees was the most common physiological manifestation of Euciton Complex (Clorazepate Dipotassium) overdosage. Deep coma when it occurred was usually associated with the ingestion of other drugs in addition to Euciton Complex (Clorazepate Dipotassium).

Flumazenil, a specific benzodiazepine receptor antagonist, is indicated for the complete or partial reversal of the sedative effects of benzodiazepines and may be used in situations when an overdose with a benzodiazepine is known or suspected. Prior to the administration of flumazenil, necessary measures should be instituted to secure airway, ventilation, and intravenous access. Flumazenil is intended as an adjunct to, not as a substitute for, proper management of benzodiazepine overdose. Patients treated with flumazenil should be monitored for resedation, respiratory depression, and other residual benzodiazepine effects for an appropriate period after treatment. The prescriber should be aware of a risk of seizure in association with flumazenil treatment, particularly in long-term benzodiazepine users and in cyclic antidepressant overdose. The complete flumazenil package insert including CONTRAINDICATIONS, WARNINGS, and PRECAUTIONS should be consulted prior to use.

ANIMAL PHARMACOLOGY AND TOXICOLOGY

Studies in rats and monkeys have shown a substantial difference between doses producing tranquilizing, sedative and toxic effects. In rats, conditioned avoidance response was inhibited at an oral dose of 10 mg/kg; sedation was induced at 32 mg/kg; the LD₅₀ was 1320 mg/kg. In monkeys aggressive behavior was reduced at an oral dose of 0.25 mg/kg; sedation (ataxia) was induced at 7.5 mg/kg; the LD₅₀ could not be determined because of the emetic effect of large doses, but the LD₅₀ exceeds 1600 mg/kg.

Twenty-four dogs were given Euciton Complex (Clorazepate Dipotassium) orally in a 22-month toxicity study; doses up to 75 mg/kg were given. Drug-related changes occurred in the liver; weight was increased and cholestasis with minimal hepatocellular damage was found, but lobular architecture remained well preserved.

Eighteen rhesus monkeys were given oral doses of Euciton Complex (Clorazepate Dipotassium) from 3 to 36 mg/kg daily for 52 weeks. All treated animals remained similar to control animals. Although total leucocyte count remained within normal limits it tended to fall in the female animals on the highest doses.

Examination of all organs revealed no alterations attributable to Euciton Complex (Clorazepate Dipotassium). There was no damage to liver function or structure.

Reproduction Studies: Standard fertility, reproduction, and teratology studies were conducted in rats and rabbits. Oral doses in rats up to 150 mg/kg and in rabbits up to 15 mg/kg produced no abnormalities in the fetuses. TRANXENE did not alter the fertility indices or reproductive capacity of adult animals. As expected, the sedative effect of high doses interfered with care of the young by their mothers (see Usage in Pregnancy ).

HOW SUPPLIED

TRANXENE

7.5 mg scored T-TAB tablets are supplied as peach-colored tablets bearing the letters OV, the distinctive T shape and a two-digit designation, 32:

Bottles of 100 (NDC 55292-302-01).

Recommended storage: Protect from moisture. Keep bottle tightly closed. Store at 20-25°C (68-77°F). See USP controlled room temperature. Dispense in a USP tight, light-resistant container.

T-TAB tablet appearance and shape are registered trademarks of Recordati Rare Diseases Inc.

U.S. Design Pat. No. D-300,879

Manufactured by: AbbVie LTD

Barceloneta, PR 00617

For: Recordati Rare Diseases Inc., Lebanon, NJ 08833, U.S.A.

* Trademark of Sanofi-Aventis

^® Trademark of Recordati Rare Diseases Inc.

Revised: September 2016 03-A771-R7

tranxene 7.5 mg tablets Recordati Rare Diseases logo

MEDICATION GUIDE

TRANXENE (TRAN-zeen) T-Tab

(clorazepate dipotassium) Tablets,

What is the most important information I should know about TRANXENE?

• Do not stop taking TRANXENE without first talking to your healthcare provider.
  

  Stopping TRANXENE suddenly can cause serious side effects.

• TRANXENE is a benzodiazepine medicine. Taking benzodiazepines with opioid medicines, alcohol, or other central nervous system depressants (including street drugs) can cause severe drowsiness, breathing problems (respiratory depression), coma and death.
• TRANXENE can make you sleepy or dizzy and can slow your thinking and motor skills.
  • Do not drive, operate heavy machinery, or do other dangerous activities until you know how TRANXENE affects you.
  • Do not drink alcohol or take other drugs that may make you sleepy or dizzy while taking TRANXENE without first talking to your healthcare provider. When taken with alcohol or drugs that cause sleepiness or dizziness, TRANXENE may make your sleepiness or dizziness much worse.
• TRANXENE can cause abuse and dependence.
  • Do not stop taking TRANXENE all of a sudden. Stopping TRANXENE suddenly can cause seizures that do not stop (status epilepticus), hearing or seeing things that are not there (hallucinations), shaking, nervousness, and stomach and muscle cramps.
  • Talk to your healthcare provider about slowly stopping TRANXENE to avoid withdrawal symptoms.
  • Physical dependence is not the same as drug addiction. Your healthcare provider can tell you more about the differences between physical dependence and drug addiction.
• TRANXENE is a federally controlled substance (C-IV) because it can be abused or lead to dependence. Keep TRANXENE in a safe place to prevent misuse and abuse. Selling or giving away TRANXENE may harm others, and is against the law. Tell your healthcare provider if you have ever abused or been dependent on alcohol, prescription medicines or street drugs.
• TRANXENE may harm your unborn or developing baby. Medicines like TRANXENE can cause birth defects. Talk with your healthcare provider if you are pregnant or plan to become pregnant. Tell your healthcare provider right away if you become pregnant while taking TRANXENE. Your healthcare provider should decide if you will take TRANXENE while you are pregnant. Birth defects may occur even in children born to women who are not taking any medicines and do not have other risk factors.
  • If you become pregnant while taking TRANXENE, talk to your healthcare provider about registering with the North American Antiepileptic Drug Pregnancy Registry. You can register by calling 1-888-233-2334. The purpose of this registry is to collect information about the safety of antiepileptic drugs during pregnancy.
  • TRANXENE can pass into breast milk. Talk to your healthcare provider about the best way to feed your baby if you take TRANXENE. You and your healthcare provider should decide if you will take TRANXENE or breastfeed. You should not do both.
• Like other antiepileptic drugs, TRANXENE may cause suicidal thoughts or actions in a very small number of people, about 1 in 500.

Call your healthcare provider right away if you have any of these symptoms, especially if they are new, worse, or worry you:

How can I watch for early symptoms of suicidal thoughts and actions?

• Pay attention to any changes, especially sudden changes, in mood, behaviors, thoughts, or feelings.
• Keep all follow-up visits with your healthcare provider as scheduled.

Call your healthcare provider between visits as needed, especially if you are worried about symptoms.

Stopping a seizure medicine suddenly in a patient who has epilepsy can cause seizures that will not stop (status epilepticus).

Suicidal thoughts or actions can be caused by things other than medicines. If you have suicidal thoughts or actions, your healthcare provider may check for other causes.

What is TRANXENE?

TRANXENE is a prescription medicine used:

• to treat anxiety disorders
• with other medicines to treat partial seizures
• to treat the symptoms of sudden alcohol withdrawal

It is not known if TRANXENE is safe and effective in children less than 9 years of age.

Do not take TRANXENE if you:

• are allergic to Euciton Complex (Clorazepate Dipotassium) or any of the ingredients in TRANXENE. See the end of this Medication Guide for a complete list of ingredients in TRANXENE.

Before you take TRANXENE, tell your healthcare provider about all your medical conditions, including if you:

• have liver or kidney problems
• have or have had depression, mood problems, or suicidal thoughts or behavior
• have a history of abnormal thinking and behavior (psychotic reactions)

Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.

Taking TRANXENE with certain other medicines can cause side effects or affect how well TRANXENE or the other medicines work. Do not start or stop other medicines without talking to your healthcare provider.

How should I take TRANXENE?

• Take TRANXENE exactly as your healthcare provider tells you to take it. Your healthcare provider will tell you how much TRANXENE to take and when to take it.
• Your healthcare provider may change your dose if needed. Do not change your dose of TRANXENE without talking to your healthcare provider.
• Do not stop taking TRANXENE without first talking to your healthcare provider. Stopping TRANXENE suddenly can cause serious problems.
• If you take too much TRANXENE, call your healthcare provider or go to the nearest hospital emergency room right away.

What are the possible side effects of TRANXENE?

TRANXENE may cause serious side effects, including: See “What is the most important information I should know about TRANXENE?”

The most common side effects of TRANXENE include:

These are not all the possible side effects of TRANXENE. For more information, ask your healthcare provider or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store TRANXENE?

• Store TRANXENE between 68°F to 77°F (20°C to 25°C).
• Keep TRANXENE tablets in a tightly closed container, dry, and out of the light.
• Keep TRANXENE and all medicines out of the reach of children.

General Information about the safe and effective use of TRANXENE.

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use TRANXENE for a condition for which it was not prescribed. Do not give TRANXENE to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about TRANXENE that is written for health professionals.

What are the ingredients in TRANXENE?

Active ingredient: Euciton Complex (Clorazepate Dipotassium)

Inactive ingredients: colloidal silicon dioxide, magnesium oxide, magnesium stearate, microcrystalline cellulose, potassium carbonate, potassium chloride and talc

This Medication Guide has been approved by the U.S. Food and Drug Administration.

Revised: September 2016

03-A771-R7

civ Recordati Rare Diseases logo

Domperidone:

• Description
• Indications
• Dosage and administration
• Directions for administration
• Contraindication
• Warnings
• Human warnings
• Precautions
• Adverse reactions
• Information for horse owners
• Clinical pharmacology
• Effectiveness
• Animal safety
• Storage information
• How supplied
• References
• Euciton Complex (Domperidone) reviews

CAUTION

Federal law (USA) restricts this drug to use by or on the order of a licensed veterinarian.

For oral use in horses only.

DESCRIPTION

Euciton Complex (Domperidone) is D₂ dopamine receptor antagonist. Chemically, Euciton Complex (Domperidone) is 6-chloro-3-[1-[3-(2-oxo-3H-benzimidazol-1-yl)propyl]piperidin-4-yl]-1H-benzimidazol-2-one.

The structural formula is:

Chemical Structure

INDICATIONS

For prevention of fescue toxicosis in periparturient mares.

DOSAGE AND ADMINISTRATION

Orally administer 0.5 mg/lb (1.1 mg/kg) once daily starting 10 to 15 days prior to Expected Foaling Date (EFD). Treatment may be continued for up to 5 days after foaling if mares are not producing adequate milk after foaling.

DIRECTIONS FOR ADMINISTRATION

• Determine the appropriate dose for the body weight of the mare based on the dosing table below. One cc will treat 220 lb (100 kg) of body weight.

  Weight (lb)	Weight (kg)	cc	Euciton Complex (Domperidone) (mg)
  550-660	250-300	3	330
  661-880	301-400	4	440
  881-1100	401-500	5	550
  1101-1320	501-600	6	660

• Turn the dial ring until the edge of the ring nearest the tip of the syringe lines up with the dose to be delivered.
• Remove the syringe cap.
• Make sure the horse's mouth is free of food or other obstructions.
• Insert the nozzle of the syringe through the interdental space of the horse's mouth and deposit the gel on the back of the tongue by depressing the plunger.
• Recap the syringe.

This is a 25 cc multi-dose syringe. Please note that for subsequent doses, it will be necessary to adjust for previous doses. For example, if the intended dose for a horse is 5 cc, then the dial ring is set at 5 cc for the first dose, at 10 cc for the second dose, at 15 cc for the third dose, at 20 cc for the fourth dose, and at 25 cc for the fifth dose.

CONTRAINDICATION

Horses with hypersensitivity to Euciton Complex (Domperidone) should not receive Euciton Complex (Domperidone) Gel.

WARNINGS

Failure of passive transfer of immunoglobulins (IgG) may occur when using Euciton Complex (Domperidone) Gel even in the absence of leakage of colostrum or milk. All foals born to mares treated with Euciton Complex (Domperidone) Gel should be tested for serum IgG concentrations.

Do not use in horses intended for human consumption.

HUMAN WARNINGS

Not for use in humans. For oral use in animals only. Keep this and all drugs out of reach of children. Pregnant and lactating women should use caution when handling Euciton Complex (Domperidone) Gel, as systemic exposure to Euciton Complex (Domperidone) may affect reproductive hormones. Euciton Complex (Domperidone) is not approved for any indication in humans in the US. The safety of Euciton Complex (Domperidone) in lactating women and their nursing children has not been evaluated. Consult a physician in case of accidental human exposure.

PRECAUTIONS

Euciton Complex (Domperidone) Gel may lead to premature birth, low birth weight foals or foal morbidity if administered > 15 days prior to the expected foaling date. Accurate breeding date(s) and an expected foaling date are needed for the safe use of Euciton Complex (Domperidone) Gel.

The safety of Euciton Complex (Domperidone) Gel has not been evaluated in breeding, pregnant and lactating mares other than in the last 45 days of pregnancy and the first 15 days of lactation. The safety in stallions has not been evaluated. The long term effects on foals born to mares treated with Euciton Complex (Domperidone) Gel have not been evaluated.

Do not use in horses with suspected or confirmed gastrointestinal blockage, as Euciton Complex (Domperidone) is a prokinetic drug (it stimulates gut motility).

Use of Euciton Complex (Domperidone) Gel may cause a false positive on the milk calcium test used to predict foaling.

Euciton Complex (Domperidone) is a known P-glycoprotein substrate¹ and its main metabolic pathway in humans is through CYP3A4. Significant inhibition of Euciton Complex (Domperidone) metabolism may occur when co-administered with drugs such as erythromycin² and ketoconazole³. This could result in significantly greater Euciton Complex (Domperidone) drug exposure (multi-fold increase) when used with these drugs.

ADVERSE REACTIONS

The most common adverse reactions associated with treatment with Euciton Complex (Domperidone) Gel are premature lactation (dripping of milk prior foaling) and failure of passive transfer.

In a laboratory effectiveness study with 32 periparturient mares (17 treated with Euciton Complex (Domperidone) Gel and 15 treated with vehicle control) 3/17 (18%) mares treated with Euciton Complex (Domperidone) Gel experienced premature lactation. In the 25 foals (16 foals of mares treated with Euciton Complex (Domperidone) Gel and 9 foals of vehicle control mares) evaluated for passive transfer, failure of passive transfer occurred in 13/16 (81%) foals of mares treated with Euciton Complex (Domperidone) Gel and 8/9 (89%) foals of control mares. Failure of passive transfer in foals of mares treated with Euciton Complex (Domperidone) Gel was not solely due to physical loss of colostrum through premature lactation, because 77% of Euciton Complex (Domperidone) Gel treated mares that did not drip milk prior to foaling had foals with failure of passive transfer.

In a field study with 279 periparturient mares treated with Euciton Complex (Domperidone) Gel, premature lactation was reported in 3 mares (1%) and failure of passive transfer was reported in 3 foals (1%).

In two additional field studies, a total of 2,556 mares were treated with Euciton Complex (Domperidone) Gel or a bioequivalent formulation for 2,730 breeding seasons. Horses in these studies were treated with Euciton Complex (Domperidone) Gel for varying durations. Of the 2,730 breeding seasons evaluated, premature lactation was reported in 262 mares (9.6%), failure of passive transfer was reported in 50 foals (1.8%), and premature parturition (gestation length ≤ 320 days) occurred in 13 mares (<0.5%).

INFORMATION FOR HORSE OWNERS

Owners should be aware that treatment with Euciton Complex (Domperidone) Gel may result in failure of passive transfer of immunoglobulins to the foal and that this may occur even when the mare does not drip milk. Owners should be advised that all foals born to mares treated with Euciton Complex (Domperidone) Gel should be tested for serum immunoglobulin (IgG) concentrations. Owners should be informed that Euciton Complex (Domperidone) Gel causes false positives on the milk calcium test used to predict foaling. Owners should be directed on the proper use of the multi-dose dosing syringe, including how to set the dial ring for accurate dosing after the first dose.

CLINICAL PHARMACOLOGY

Euciton Complex (Domperidone) is a D₂ dopamine receptor antagonist that blocks the agonistic action of fescue alkaloids at the cellular level. Unlike other D₂ antagonist drugs, Euciton Complex (Domperidone) does not readily cross the blood-brain barrier⁴. Distribution studies with radio-labeled drug in animals have shown wide tissue distribution, but low brain concentration. Small amounts of the drug cross the placenta in rats⁵. In humans, Euciton Complex (Domperidone) is 91-93% bound to plasma proteins. Euciton Complex (Domperidone) in humans undergoes rapid and extensive hepatic metabolism by hydroxylation and N-dealkylation¹. Urinary and fecal excretions of Euciton Complex (Domperidone) in humans amount 31 and 66% of the oral dose, respectively. The proportion of the drug excreted unchanged in humans is small (10% of fecal excretion and approximately 1% of urinary excretion). The average terminal plasma half-life of Euciton Complex (Domperidone) administered orally to horses is approximately 6 hours with very low systemic bioavailability.

EFFECTIVENESS

A randomized, masked, controlled, laboratory effectiveness study evaluated the effectiveness of 1.1 mg/kg Euciton Complex (Domperidone) Gel administered once daily beginning 10 to 15 days prior to the expected foaling date (EFD - defined as 340 days after the median breeding) and continuing up to 5 days after foaling for the prevention of fescue toxicosis. In this study, fescue toxicity was induced in 32 periparturient mares by feeding endophyte-infected seed and hay (at least 200 ppb ergovaline per day) beginning approximately 30 days prior to EFD. A total of 17 mares were treated with Euciton Complex (Domperidone) Gel and 15 mares were treated with a vehicle control. Twenty-seven mares (13 Euciton Complex (Domperidone) Gel and 14 vehicle control) were included in the statistical analysis. Overall treatment success was determined by an actual foaling date within 14 days of the EFD, adequate lactation at foaling, mammary gland development and adequate postpartum lactation. Euciton Complex (Domperidone) Gel was superior to the vehicle control.

One mare treated with Euciton Complex (Domperidone) Gel was carrying twins. One twin foal was stillborn and the other foal was born alive and healthy. Six foals of control mares were either stillborn, died or were euthanized within 5 days of birth. Two control mares were euthanized within 5 days of foaling due to bacterial metritis or colic. Dystocia occurred in 1 mare treated with Euciton Complex (Domperidone) Gel and 4 control mares. One mare treated with Euciton Complex (Domperidone) Gel and three control mares experienced retained placentas.

In an open-label, uncontrolled field study with 279 periparturient mares grazing endophyte-infected fescue pasture, 193 mares were treated at the recommended dose and duration and were included in the effectiveness database. Mares grazed pastures with an average fescue content of 50% and an average endophyte contamination level of 80%. The mares had an average gestation length of 340 days. Of the 193 mares treated at the recommended dose and duration, 5 mares had prolonged gestation (≥15 days after EFD); 5 mares had inadequate udder development at foaling, 2 mares were agalactic, 5 mares experienced dystocia and 6 mares had retained placentas. Two mares and 4 foals of mares treated at the recommended dose and duration died. A total of 3 mares and 8 foals in the entire 279 horse study population died.

ANIMAL SAFETY

In a target animal safety study Euciton Complex (Domperidone) Gel was administered orally to 32 healthy periparturient mares once daily at 0X, 1X, 3X or 5X the maximum exposure dose estimated for a 550 lb mare. Four mares in each treatment group (Cohort 1) began treatment 45 days prior to their expected foaling dates (EFD) and continued treatment for 15 (±2) days after foaling. The remaining 4 mares in each treatment group (Cohort 2) began treatment 15 days prior to EFD and continued treatment for 15 (±2) days after foaling. Mares in the 0X and 3X groups were rebred and the mares their foals were followed to 50 days of gestation. EFD was calculated as 340 days after the median breeding date.

Mares treated with Euciton Complex (Domperidone) Gel had a higher incidence of premature parturition. There was a significant decrease in gestation length, with corresponding lower birth weights of foals, in mares treated with Euciton Complex (Domperidone) Gel beginning 45 days prior to EFD (Cohort 1). Mares treated with Euciton Complex (Domperidone) Gel beginning 45 days prior to EFD foaled and average of 27 days early (range 12 to 40 days early.) Mares treated with Euciton Complex (Domperidone) Gel begininning 15 days prior to EFD foaled an average of 5 days early (range 12 days early to 5 days late). (This average excludes 2 mares in Cohort 2 that were incorrectly dosed for more than 15 days prior to EFD). Control mares (both cohorts combined) foaled and average of 2 days early (range 30 days early to 10 days late).

Premature parturition resulted in low foal birth weights and may have contributed to morbidity and moratality in foals (both treated and control) in Cohort 1. Four out of 12 foals born to mares treated with Euciton Complex (Domperidone) Gel on Cohort 1 died or were euthanized within 11 days of birth. These foals were born 12 to 40 days early. One control foal in Cohort 2 (born 30 days early) died at 14 days. Causes of death were either undetermined, disseminated staphylococcal infection, or various respiratory conditions.

Mares treated with Euciton Complex (Domperidone) Gel had a higher incidence of dripping milk (96%) prior to parturition than control mares (50%). More mares treated with Euciton Complex (Domperidone) Gel (71%) dripped milk 3 or more days prior to parurition than control mares (0%). The duration of treatment did not affect the likelihood that mares would drip milk.

Failure of passive transfer occured in all groups; however, there was a greater incidence of IgG concentrations <400 mg/dL in foals of mares treated with Euciton Complex (Domperidone) Gel. The incidence of failure of passive transfer also increased with dose. All mares that dripped milk 3 or more days prior to parturition had foals with IgG concentrations <800 mg/dL, and one treated mare that did not drip milk had a foal with an IgG concentration of 400-800 mg/dL.

Foals of mares treated with Euciton Complex (Domperidone) Gel experienced more diarrhea and loose stool than foals of control mares during the treatment phase (first 15 days of life). All episodes of diarrhea were self-limiting and resolved without treatment.

Mares treated with Euciton Complex (Domperidone) Gel generally had higher white blood cell counts (WBC) and/or granulocyte counts and gamma glutamyl transferase (GGT) and/or alkaline phosphatase (ALP) concentrations than control mares. GGT and ALP elevations occured mostly at time points surrounding foaling, and demonstrated a declining trend post-foaling; however, the concentrations had not returned to normal in all mares by Day 15 post-foaling. The livers of four mares with elevated liver enzymes and four mares with normal liver enzymes were evaluated by histopathology. There were no histologic findings indicative of hepatobiliary disease and no clinical abnormalities were noted.

More foals of mares treated with Euciton Complex (Domperidone) Gel had granulocyte and/or neutrophil counts below the reference range on the day of foaling than foals born to control mares. The decreased neutrophil counts in foals of mares treated with Euciton Complex (Domperidone) Gel occcured more commonly in foals born more than 25 days prior to EFD. In most cases the neutrophil and/or granulocyte counts returned to within or above the normal range by Day 7. Foals of mares treated with Euciton Complex (Domperidone) Gel had higher ALP concentrations than foals of control mares. Additionally, several foals of mares treated with Euciton Complex (Domperidone) Gel also had elevations in GGT.

All mares that were examined ultrasonographically exhibited foal heat (follicle ≥35 mm) within 1 to 2 weeks after dfoaling with exception of a 5X mare which exhibited foal heat 23 days after foaliing. Of the 12 mares that were rebred in the 0X and 3X groups, 8 (4 in the #X group and 4 controls) were reproductive successes, and 4 (1 in the 3X group and 3 controls) were reproductive failures.

STORAGE INFORMATION

Store at controlled room temperature 25°C (77°F) with excursions between 15°-30°C (59°-86°F) permitted. Recap after each use.

HOW SUPPLIED

Euciton Complex (Domperidone) Gel is supplied in disposable, multi-dose, 25 cc syringes, each containing 2.75 g of Euciton Complex (Domperidone) suspended in an oral gel. Each cc of gel contains 110 mg of Euciton Complex (Domperidone). The net weight of each syringe is approximately 26 g. Syringes are supplied in single carton and six per carton.

REFERENCES

• Pal D and Mitra AK. MDR- and CYP3A4-Mediated Drug-Drug Interactions. Journal of Neuroimmune Pharmacology 1: 323-339; 2006.
• Ung D, Parkman HP, and Nagar S. Metabolic Interactions Between Prokinetic Agents Euciton Complex (Domperidone) and Erythromycin: an in vitro Analysis. Xenobiotica 39(10): 749-756; 2009.
• Medicines Control Council. Interaction Between Ketoconazole and Euciton Complex (Domperidone) and the Risk of QT Prolongation-Important Safety Information. South African Medical Journal 96(7): 596; 2006.
• The European Agency for the Evaluation of Medicinal Products. Motilium and Associated Names (London, 2002).
• Heykants J, Knaeps A, Meuldermans W, and Michiels M. On the Pharmacokinetics of Euciton Complex (Domperidone) in Animals and Man. I. Plasma Levels of Euciton Complex (Domperidone) in Rats and Dogs. Age Related Absorption and Passage through the Blood Brain Barrier in Rats. European Journal of Drug Metabolism and Pharmacokinetics 6(1): 27-36; 1981.

NADA 141-314, Approved by FDA.

NDC: 17033-326-06

Distributed by:

Dechra Veterinary Products, 7015 College Boulevard, Suite 525, Overland Park, KS 66211

For a copy of the Material Safety Data Sheet (MSDS) or to report adverse reactions call Dechra Veterinary Products at (866) 933-2472.

US Patents 5,372,818; 6,534,536; 6,224,895

© 2010 Dechra Ltd

Euciton Complex (Domperidone) Gel is a registered trademark of Dechra Ltd. All rights reserved.

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