Cerenia Tablets

Cerenia Tablets Indications

CERENIA (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

Administer CERENIA Tablets orally at a minimum dose of 2 mg/kg (0.9 mg/lb) body weight once daily for up to 5 consecutive days. For prevention of acute vomiting, CERENIA Tablets is recommended for use in dogs 8 weeks and older.

Prevention Of Acute Vomiting

Minimum of 2 mg/kg BW Dosing

Dog body weight		Number of Tablets
Pounds	Kilograms	16 mg	24 mg	60 mg
2.2 - 8.8	1.0 - 4	1/2
8.9 - 17.6	4.1 - 8	1
17.7 - 26.4	8.1 - 12		1
26.5 - 52.8	12.1 - 24		2
52.9 - 66	24.1 - 30			1
66.1 - 132	30.1 - 60			2

CERENIA Tablets may be used interchangeably with CERENIA Injectable Solution for once daily dosing for the prevention of acute vomiting.

For Prevention of Vomiting Due to Motion Sickness

Administer CERENIA Tablets orally at a minimum dose of 8 mg/kg (3.6 mg/lb) body weight once daily for up to 2 consecutive days. Dogs should be fasted 1 hour prior to administration of CERENIA Tablets. Administer CERENIA Tablets 2 hours prior to travel. For prevention of vomiting due to motion sickness, CERENIA Tablets is recommended for use in dogs 16 weeks and older.

Prevention Of Vomiting Due To Motion Sickness

Minimum of 8 mg/kg BW Dosing

Dog body weight		Number of Tablets
Pounds	Kilograms	16 mg	24 mg	60 mg	160 mg
2.2	1	1/2
2.3 - 3.3	1.1 - 1.5		1/2
3.4 - 4.4	1.6 - 2	1
4.5 - 6.6	2.1 - 3		1
6.7 - 8.8	3.1 - 4	2
8.9 - 13.2	4.1 - 6		2
13.3 - 16.5	6.1 - 7.5			1
16.6 - 22	7.6 - 10				1/2
22.1 - 33	10.1 - 15			2
33.1 - 44	15.1 - 20				1
44.1 - 66	20.1 - 30				1 1/2
66.1 - 88	30.1 - 40				2
88.1 - 132	40.1 - 60				3

Information For Use

CERENIA Tablets have been shown to be effective for the prevention of vomiting (see EFFECTIVENESS), however where the frequency of vomiting is high, orally administered CERENIA may not be absorbed before the next vomiting event occurs. Therefore, initiation of therapy with CERENIA Injectable Solution is recommended. If vomiting persists despite treatment, the case should be re-evaluated. CERENIA is most effective in preventing vomiting associated with chemotherapy if administered prior to the chemotherapeutic agent.

Warnings

Not for use in humans. Keep out of 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. CERENIA 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 CERENIA compared to control puppies. In puppies 16 weeks and older, bone marrow hypocellularity was not observed (see ANIMAL SAFETY).

Precautions

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

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

Use with caution in dogs with hepatic dysfunction because CERENIA is metabolized by CYP3A enzymes (see Pharmacokinetics). Use with caution with other medications that are highly protein bound. The concomitant use of CERENIA 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 CERENIA has not been evaluated. Drug compatibility should be monitored in patients requiring adjunctive therapy.

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

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 CERENIA 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)		CERENIA (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 CERENIA 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)		CERENIA (n=208)
	# dogs	% occurrence	# dogs	% occurrence
Hypersalivation	19	9.7	26	12.5
Vomiting1	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

¹ Not associated with motion sickness

The following adverse reactions were reported during a European field study for the prevention of vomiting due to motion sickness in dogs treated with CERENIA 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)		CERENIA (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

Post-Approval Experience

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 are listed in decreasing order of reporting frequency in dogs: depression/lethargy, anorexia, hypersalivation, vomiting, diarrhea, ataxia, and trembling.

Cases of ineffectiveness have been reported.

For a complete listing of adverse reactions for CERENIA Tablets reported to CVM see:

http://www.fda.gov/AnimalVeterinary/SafetyHealth/ProductSafetyInformation/ucm055369.htm

For a copy of the Material Safety Data Sheet (MSDS) or to report adverse reactions call Pfizer Animal Health at 1-800-366-5288.

CLINICAL EXPERIENCE: For motion sickness, prolonged fasting before administration should be avoided. Feeding dogs a small amount of food one hour prior to the administration of 8 mg/kg of CERENIA Tablets may mitigate vomiting that may occur within two hours post-dosing and prior to travel.

Clinical Pharmacology

Pharmacokinetics

The pharmacokinetic characterization associated with maropitant after oral (PO) or subcutaneous (SC) administration in adult Beagle dogs is provided in the table below.

Pharmacokinetic Parameters in Beagle Dogs (Mean±SD or range)
	SC at 1 mg/kg (n=6)	PO at 2 mg/kg (n=8)	PO at 8 mg/kg (n=8)
AUC0-inf (hr*ng/mL)	860±137	561±322	7840±5600
Cmax (ng/mL)	92±34	81±32	776±604
T1/2 (hr)	8.84 (6.07-17.7)	4.03 (2.48-7.09)	5.46 (3.39-7.65)
Tmax (hr)	0.75±1.11	1.9±0.5	1.7±0.7

The absolute bioavailability of maropitant was much higher following SC injection (91% at 1 mg/kg) than after PO administration (24% at 2 mg/kg). Oral bioavailability may be underestimated due to the presence of nonlinear kinetics and the resulting longer T_1/2 seen after intravenous (IV) administration. Although hepatic first-pass metabolism contributed to the relatively low bioavailability 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). 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. An accumulation ratio of 1.5 was observed following once-daily use of maropitant for five consecutive days at 1 mg/kg (SC) or 2 mg/kg (PO). 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. Based on in vitro enzyme kinetics data, it is believed that the non-linear kinetics may be partially associated with saturation of the low capacity enzyme (CYP2D15). However as doses increase (20-50 mg/kg PO), 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. Plasma protein binding of maropitant was high (99.5%).

Based on differences in plasma trough concentrations from a single study, the exposure of 10 week old puppies to maropitant may be lower than that observed in adult dogs, particularly after doses of 1 or 2 mg/kg.

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.

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

Effectiveness

Prevention of Acute Vomiting

In laboratory model studies, CERENIA Tablets dosed at a minimum of 2 mg/kg BW reduced the number of emetic events associated with established neural (central) and humoral (peripheral) stimuli. Following administration of apomorphine (central emetic stimuli), vomiting was observed in 33% (4 of 12) of Beagle dogs treated with CERENIA Tablets and 100% (12 of 12) of Beagle dogs treated with placebo tablets. Following administration of syrup of ipecac (peripheral emetic stimuli) vomiting was observed in 33% (4 of 12) of Beagle dogs treated with CERENIA Tablets and in 83% (10 of 12) of Beagle dogs treated with placebo tablets.

In a study of 275 canine patients presented to veterinary hospitals with a history of acute vomiting, dogs were initially administered CERENIA Injectable Solution or placebo on Day 0. Following the initial dose, dogs allocated to the CERENIA group were treated with either CERENIA Tablets at a minimum of 2 mg/kg orally or Injectable Solution at 1 mg/kg subcutaneously once daily at the discretion of the clinician. Dogs allocated to the placebo group were treated using either an injectable placebo solution or placebo tablets once daily at the discretion of the clinician. Of the 199 dogs included in the analysis for effectiveness, 27 of 54 dogs (50%) in the placebo group displayed vomiting at some time during the study and 31 of 145 dogs (21.4%) in the treated group displayed vomiting during the study period.

Percent Of Vomiting For Each Study Day, Based Upon Treatment And Route Of Administration.

Days	Treatment	Route	# dogs	# vomited	% vomited
Day 0	Placebo (54)	SC	54	15	28%
	CERENIA (145)	SC	145 (143*)	14	10%
Day 1	Placebo (45)	PO	22	3	14%
		SC	23	16	70%
	CERENIA (108)	PO	67	2	3%
		SC	41	16	39%
Day 2	Placebo (16)	PO	7	2	29%
		SC	9	6	67%
	CERENIA (37)	PO	24	0	0%
		SC	13	8	62%
Day 3	Placebo (6)	PO	2	0	0%
		SC	4	1	25%
	CERENIA (21)	PO	14	0	0%
		SC	7	5	71%
Day 4	Placebo (2)	PO	1	0	0%
		SC	1	1	100%
	CERENIA (7)	PO	5	0	0%
		SC	2	1	50%
Day 5	CERENIA (1)	SC	1	0	0%

*2 dogs administered CERENIA were not observed on Day 0. Their vomiting status was unknown. 143 was used in the denominator for % vomited.

In US field studies in veterinary patients, CERENIA Tablets and Injectable Solution were well tolerated in dogs presenting with various conditions including parvovirus, gastroenteritis, and renal disease. There were no notable differences in mean laboratory values between CERENIA-treated and placebo-treated patients.

CERENIA Tablets were used safely in dogs receiving other frequently used veterinary products such as fluid and electrolyte replacement solutions, antimicrobial agents, vaccines, antacids, and antiparasitic agents.

Prevention of Vomiting due to Motion Sickness

In a study of canine veterinary patients taken on a one-hour car journey and treated with either CERENIA Tablets at a minimum dose of 8 mg/kg BW or placebo tablets 2 hours prior to the journey, 67 of 122 (55%) of dogs vomited during the journey when treated with placebo while 8 of 122 (7%) vomited during the journey after treatment with CERENIA Tablets. The probability that a dog in this study, prone to motion sickness would NOT vomit during a journey if treated with CERENIA Tablets was 93%, while the probability was 48% if treated with placebo.

ANIMAL SAFETY: Laboratory and field studies have demonstrated that CERENIA Tablets are well tolerated in dogs after oral administration.

Target Animal Safety Study for Acute Vomiting

Fifty six Beagle dogs (28 males and 28 females) approximately 16 weeks of age were administered CERENIA Tablets orally once daily for 15 days at 0, 2, 6, and 10 mg/kg. There were 8 dogs (4 males and 4 females) in the 2 mg/kg group and 16 dogs (8 males and 8 females) in all other groups. CERENIA Tablets caused decreases in food consumption and body weight that were not dose-dependent and did not persist after cessation of treatment.

Beagle dogs approximately 8 weeks of age were administered CERENIA Tablets orally once daily for 15 days at 0, 2, 6, and 10 mg/kg using a protocol similar to the previous study. A dose dependent increase in severity of bone marrow hypoplasia was observed histologically. Interpretation of these study results is complicated by the health status of study animals. Dogs used in the study were weaned early, minimally acclimated to the test facility, many of the dogs in the study tested positive for coccidia and some tested positive for canine parvovirus.

Beagle dogs approximately 10 weeks of age were administered either placebo tablets for 2 days, CERENIA Tablets at 8 mg/kg for 2 days, placebo (saline) subcutaneously (SC) for 5 days, CERENIA Injectable Solution at 1 mg/kg SC for 5 days, or CERENIA Tablets at 2 mg/kg for 5 days (8 dogs in each dose group). Mild pain associated with injection was noted in more dogs and lasted longer in dogs that received maropitant injections compared to saline. Males administered CERENIA at 8 mg/kg orally for 2 days had a decrease in food consumption. Body weight and food consumption were variable throughout the 4 week acclimation period. Two dogs that received 8 mg/kg maropitant orally for 2 days were below the reference range for reticulocyte counts. Decreases in reticulocyte counts were also seen in 4 (of 8) placebo treated dogs (SC saline for 5 days). Hypocellular femoral bone marrow described as “minimal” was seen in 1 male that received 1 mg/kg maropitant SC for 5 days; reticulocyte counts were not available for this dog.

Target Animal Safety Study for Motion Sickness

Forty Beagle dogs (20 males and 20 females) between 16 - 18 weeks of age were administered CERENIA Tablets orally once daily for 6 days at 0, 8 and 24 mg/kg. There were 16 dogs (8 males and 8 females) in the 0 and 24 mg/kg groups and 8 dogs (4 males and 4 females) in the 8 mg/kg group.

At 24 mg/kg, CERENIA Tablets caused decreases in food consumption, with decreases in body weight, liver and testis weight; and an increase in RBC count indicating hemoconcentration, but the effects on feed consumption, body weight, and RBCs did not persist in the post-treatment recovery period (beyond Day 5).

Beagle dogs approximately 8 weeks of age were administered CERENIA Tablets orally once daily for 6 days at 0, 8, and 24 mg/kg using a protocol similar to the previous study. One dog in the 24 mg/kg/day group died of unknown causes on study day 2 and a dose dependent increase in occurrence and severity of bone marrow hypoplasia and lymphoid depletion was observed histologically. Interpretation of these study results is complicated by the health status of study animals. Dogs used in the study were weaned early, minimally acclimated to the test facility, and many of the dogs in the study tested positive for coccidia. Additionally, some dogs in the study tested positive for canine parvovirus, however, clinical parvoviral disease was not definitively diagnosed.

Tolerance Study

Twenty four Beagle dogs (14 males and 10 females) between 11 and 25 weeks of age were administered CERENIA Tablets in 2 phases with 8 dogs per group. In the first phase the dogs were administered 0, 20 or 30 mg/kg orally once daily for 7 days and in the second phase 0, 40, or 50 mg/kg once daily for 7 days. CERENIA Tablets administered at 20 and 30 mg/kg caused occasional vomiting. CERENIA Tablets administered at 40 mg/kg and 50 mg/kg caused clinically relevant signs of weight loss, vomiting, soft stools, weakness, lethargy, salivation and hypokalemia. Additionally, leukopenia characterized by a neutropenia and a trend toward decreasing plasma phosphorus values was seen. Decreased heart rate and prolonged corrected QT intervals were seen in all treatment groups in a dose dependent manner.

STORAGE CONDITIONS: CERENIA Tablets should be stored at controlled room temperature 20°-25°C (68°-77°F) with excursions between 15°-30°C (59°-86°F).

How Supplied

CERENIA peach-colored tablets are scored with a break line, and contain 16, 24, 60 or 160 mg of maropitant as maropitant citrate per tablet. Each tablet is marked with “MPT” and the tablet strength on one side and the Pfizer logo on the other. Each tablet size is packaged in blister packs containing 4 tablets per perforated sheet.

NADA #141-262, Approved by FDA

Made in France

Distributed by: Pfizer Animal Health, Div. of Pfizer Inc, NY, NY 10017

Revised: March 2012

8814121

NAC No.: 36902402