EMEPREV- maropitant citrate tablet

Emeprev by

Drug Labeling and Warnings

Emeprev by is a Animal medication manufactured, distributed, or labeled by Dechra Vet Products, LLC. Drug facts, warnings, and ingredients follow.

Drug Details [pdf]

SPL UNCLASSIFIED SECTION

Antiemetic

For oral use in dogs only

SAFE HANDLING WARNING

CAUTION: Federal law restricts this drug to use by or on the order of a licensed veterinarian.

DESCRIPTION

DESCRIPTION: Maropitant is a neurokinin (NK1) receptor antagonist that blocks the pharmacological action of substance P in the central nervous system (CNS). Maropitant is the non-proprietary designation for a substituted quinuclidine. The empirical formula is C32H40N2O C6H8O7 H2O and the molecular weight 678.81. The chemical name is (2S,3S)-2-benzhydryl-N-(5-tert-butyl-2-methoxybenzyl) quinuclidin-3-amine citrate monohydrate. Each light peach to orange mottle colored oval tablet is scored and contains 16, 24, 60 or 160 mg of maropitant as maropitant citrate per tablet.

The chemical structure of maropitant citrate is:

VETERINARY INDICATIONS

INDICATIONS: Emeprev (maropitant citrate) Tablets are indicated for the prevention of acute vomiting and the prevention of vomiting due to motion sickness in dogs.

DOSAGE AND ADMINISTRATION:

For Prevention of Acute Vomiting

For Prevention of Acute Vomiting in dogs 2 -7 months of age: Administer Emeprev Tablets orally at a minimum dose of 2 mg/kg (0.9 mg/lb) body weight once daily for up to 5 consecutive days (see WARNINGS and Animal Safety).

For Prevention of Acute Vomiting in dogs 7 months of age and older: Administer Emeprev Tablets orally at a minimum dose of 2 mg/kg (0.9 mg/lb) body weight once daily until resolution of acute vomiting.

If vomiting persists despite treatment, the case should be re-evaluated. Emeprev is most effective in preventing acute vomiting associated with chemotherapy if administered prior to the chemotherapeutic agent.

For prevention of acute vomiting, dispense whole or half tablets in strength(s) that most closely result in a 2 mg/kg dose:

Dog body weight		Number of Tablets
Pounds	Kilograms	16 mg	24 mg	60 mg
8	4	1/2
15	8	1
25	12		1
50	24		2
65	30			1
130	60			2

Interchangeable use with Maropitant Citrate Injectable Solution for Prevention of Acute Vomiting:

In dogs that are actively vomiting, to ensure that the full initial dose is administered, maropitant citrate injectable solution is recommended at a dose of 1 mg/kg once daily. (See package insert for maropitant citrate injectable solution.) Thereafter, for the prevention of acute vomiting, Emeprev Tablets at a dose of 2 mg/kg once daily may be used interchangeably with maropitant citrate injectable solution for up to 5 days.

For Prevention of Vomiting Due to Motion Sickness in dogs 4 months and older

For Prevention of Vomiting due to motion sickness in dogs 4 months of age and older: Administer Emeprev Tablets orally at a minimum dose of 8 mg/kg (3.6 mg/lb) body weight once daily for up to 2 consecutive days (see WARNINGS and Animal Safety).

Administer Emeprev Tablets a minimum of two hours prior to travel with a small amount of food to mitigate vomiting associated with administration of the dose on an empty stomach; however, refrain from feeding a full meal prior to travel.

Prevention of Vomiting Due to Motion Sickness in Dogs 4 months of age and older:

Dispense whole or half tablets in strengths that most closely result in an 8 mg/kg dose once daily for up to 2 consecutive days :

Dog body weight		Number of Tablets
Pounds	Kilograms	16 mg	24 mg	60 mg	160 mg
2	1	1/2
3	1.5		1/2
4	2	1
6	3		1
8	4	2
13	6		2
16	7.5			1
22	10				1/2
33	15			2
44	20				1
66	30				1 1/2
88	40				2
132	60				3

Maropitant citrate injectable solution should not be used interchangeably with Emeprev Tablets for the prevention of vomiting due to motion sickness (8 mg/kg).

WARNINGS

WARNINGS: Not for use in humans. Keep out of the reach of children. In case of accidental ingestion, seek medical advice. Topical exposure may elicit localized allergic skin reactions in some individuals. Repeated or prolonged exposure may lead to skin sensitization. Wash hands with soap and water after administering drug. Emeprev is also an ocular irritant. In case of accidental eye exposure, flush with water for 15 minutes and seek medical attention.

In puppies younger than 11 weeks of age, histological evidence of bone marrow hypocellularity was observed at higher frequency and greater severity in puppies treated with maropitant citrate compared to control puppies. In puppies 16 weeks and older, bone marrow hypocellularity was not observed (see ANIMAL SAFETY).

Keep Emeprev Tablets in a secure location out of reach of dogs, cats, and other animals to prevent accidental ingestion or overdose.

PRECAUTIONS

PRECAUTIONS: The safe use of Emeprev Tablets has not been evaluated in dogs used for breeding, or in pregnant or lactating bitches.

The safe use of Emeprev has not been evaluated in dogs with gastrointestinal obstruction, or dogs that have ingested toxins.

Use with caution in dogs with hepatic dysfunction because maropitant citrate is metabolized by CYP3A enzymes (see Pharmacokinetics). Use with caution with other medications that are highly protein bound. The concomitant use of Emeprev with other protein bound drugs has not been studied in dogs. Commonly used protein bound drugs include NSAIDs, cardiac, anticonvulsant, and behavioral medications. The influence of concomitant drugs that may inhibit the metabolism of Emeprev has not been evaluated. Drug compatibility should be monitored in patients requiring adjunctive therapy.

Maropitant citrate causes dose related decreases in appetite and body weight (see ANIMAL SAFETY). To maximize therapeutic potential of Emeprev, the underlying cause of vomiting should be identified and addressed in dogs receiving Emeprev.

ADVERSE REACTIONS:

Prevention of Acute Vomiting (minimum of 2 mg/kg)

The following adverse reactions were reported during the course of a US field study for the prevention of acute vomiting in dogs treated with maropitant citrate tablets at a minimum of 2 mg/kg orally and/or injectable solution at 1 mg/kg subcutaneously once daily for up to 5 consecutive days:

Frequency of Adverse Reactions by Treatment

Adverse Reaction	Placebo (n=69)		maropitant citrate (n=206)
	# dogs	% occurrence	# dogs	% occurrence
Death during study	4	5.8	10	4.9
Euthanized during study	0	0	2	1
Diarrhea	6	8.7	8	3.9
Hematochezia/bloody stool	5	7.2	4	1.9
Anorexia	2	2.9	3	1.5
Otitis/Otorrhea	0	0	3	1.5
Endotoxic Shock	1	1.4	2	1
Hematuria	0	0	2	1
Excoriation	0	0	2	1

Other clinical signs were reported but were <0.5% of dogs.

Prevention of Vomiting Due to Motion Sickness (minimum of 8 mg/kg)

The following adverse reactions were reported during US studies for the prevention of vomiting due to motion sickness in dogs treated with maropitant citrate tablets at a minimum of 8 mg/kg orally one time. Dogs may have experienced more than one of the observed adverse reactions.

Frequency of Adverse Reactions by Treatment

Adverse Reaction	Placebo (n=195)		maropitant citrate (n=208)
	# dogs	% occurrence	# dogs	% occurrence
* Not associated with motion sickness.
Hypersalivation	19	9.7	26	12.5
Vomiting*	0	0	11	5.3
Muscle Tremors	1	0.5	2	1
Sedation/Depression	3	1.5	2	1
Retching	3	1.5	1	0.5
Flatulence	0	0	1	0.5

The following adverse reactions were reported during a European field study for the prevention of vomiting due to motion sickness in dogs treated with maropitant citrate tablets at a minimum of 8 mg/kg orally once daily for 2 consecutive days. Dogs may have experienced more than one of the observed adverse reactions.

Frequency of Adverse Reactions by Treatment

Adverse Reaction	Placebo (n=106)		maropitant citrate (n=107)
	# dogs	% occurrence	# dogs	% occurrence
Vomiting	4	4	10	9
Drowsiness/Lethargy/Apathy	1	1	8	8
Hypersalivation	2	2	5	5
Anxiety	0	0	2	2
Trembling/Tremors	0	0	2	2
Inappetence	0	0	2	2
Mucus in stool	0	0	1	1

The following Adverse Reactions were reported during the conduct of a US clinical field trial where maropitant citrate tablets were administered once daily for 28 consecutive days to 32 dogs: lethargy, vomiting, inappetence, corneal edema, and enlarged lymph nodes.

Post-Approval Experience (Revised May 2019)

The following adverse events are based on post-approval adverse drug experience reporting. Not all adverse events are reported to FDA CVM. It is not always possible to reliably estimate the adverse event frequency or establish a causal relationship to product exposure using these data.

The following adverse events reported for dogs are listed in decreasing order of frequency: anorexia, depression/lethargy, hypersalivation, vomiting, diarrhea, trembling, ataxia, allergic reactions, weight loss, convulsion, hyperactivity, and panting.

Cases of ineffectiveness have been reported.

Cases of death (including euthanasia) have been reported.

Contact Information

To report suspected adverse events, for technical assistance or to obtain a copy of the Safety Data Sheet (SDS), contact Dechra Veterinary Products at (866) 933-2472. For additional information about adverse drug experience reporting for animal drugs, contact FDA at 1-888-FDA-VETS or http://www.fda.gov/reportanimalae

CLINICAL PHARMACOLOGY:

Pharmacokinetics

Mean (±SD) Plasma Pharmacokinetic Parameters for Maropitant in Beagle Dogs after single dose and repeat oral doses of Maropitant:

PK Parameter	2 mg/kg Single Dose	2 mg/kg repeat Doses *	8 mg/kg Single Dose	8 mg/kg repeat Doses*
NA= Not Applicable; NC= Not Calculated
* Following once daily doses of maropitant for 14 days. † Median (Range) ‡ Ratio=Multiple Dose AUC(0-24)/Single Dose AUC(0-24), Least square means (95% Confidence Interval)
Tmax†; (hr)	2.0; (1.5 – 3.0)	1.5; (1.0 – 3.0)	1.5; (1.0 – 3.0)	2.5; (1.5 – 7.0)
Cmax; (ng/mL)	154; (111)	304; (165)	588; (416)	1409; (516)
AUC(0-24); (ng*hr/mL)	1440; (982)	3890; (3030)	6730; (5030)	26600; (9200)
T1/2†; (hr)	NC	7.69; (6.21 - 17.8)	NC	25.4; (6.06 - 30.0)
Accumulation Ratio (Rac)‡	NA	2.46; (1.68, 3.61)	NA	4.81; (3.28, 7.05)

Following oral administration, median time to reach Cmax was within 2.5 hr. The absolute bioavailability of maropitant was low (24%) following oral administration of 2 mg/kg maropitant. After an oral dose, prandial status does not significantly affect the extent of oral bioavailability. Greater than dose-proportional drug exposure can be expected with an increase in dose (1-16 mg/kg PO). However as doses increase (20-50 mg/kg PO), the dose proportionality is re-established. Based upon in vitro enzyme kinetics, involvement of a high capacity enzyme (CYP3A12) may contribute to this return to dose linearity. Due to dose dependent pharmacokinetics, the maropitant concentrations reached steady state approximately after 4 and 8 days following 2 and 8 mg/kg, respectively. The observed drug accumulation ratios were 2.46 and 4.81, after oral administration of 2 and 8 mg/kg, respectively. The exposure of 10 week old puppies to maropitant was lower than that observed in adult dogs, particularly after repeat doses of 1 or 2 mg/kg. Systemic clearance of maropitant following IV administration was 970, 995, and 533 mL/hr/kg at doses of 1, 2 and 8 mg/kg, respectively.

Urinary recovery of maropitant and its major metabolite was minimal (<1% each). The hepatic metabolism of maropitant involves two cytochrome P-450 isoenzymes: CYP2D15 and CYP3A12. In in vitro enzyme kinetics data suggest that the non-linear kinetics may be partially associated with saturation of the low capacity enzyme (CYP2D15). Plasma protein binding of maropitant was high (99.5%).

Pharmacodynamics

Vomiting is a complex process coordinated centrally by the emetic center which consists of several brainstem nuclei (area postrema, nucleus tractus solitarius, dorsal motor nucleus of the vagus) that receive and integrate sensory stimuli from central and peripheral sources and chemical stimuli from the circulation and the cerebro-spinal fluid. Maropitant is a neurokinin 1 (NK1) receptor antagonist which acts by inhibiting the binding of substance P, a neuropeptide of the tachykinin family. Substance P is found in significant concentrations in the nuclei comprising the emetic center and is considered the key neurotransmitter involved in emesis.1 By inhibiting the binding of substance P within the emetic center, maropitant provides broad-spectrum effectiveness against neural (central) and humoral (peripheral) causes of vomiting.

In vivo model studies in dogs have shown that maropitant has antiemetic effectiveness against both central and peripheral emetogens including apomorphine, and syrup of ipecac.

1 Diemunsch P, Grelot L. Potential of substance P antagonists as antiemetics. [Review] [60 refs]. Drugs. 2000;60:533-46.