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.
Adverse reactions seen in a European field study included ataxia, lethargy and injection site soreness in one dog treated with CERENIA
Injectable Solution.
Post-Approval Experience ( Rev. 2015)
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 reporting frequency for CERENIA Injectable Solution:
Pain/vocalization upon injection, depression/lethargy, anorexia, anaphylaxis/anaphylactoid reactions (including swelling of the head/face),
ataxia, convulsions, hypersalivation, tremors, fever, dyspnea, collapse/loss of consciousness, recumbency, injection site reactions (swelling,
inflammation) and sedation.
Cases of death (including euthanasia) have been reported.
CATS ( :CERENIA Injectable Solution)
The following adverse reactions were reported during the course of a US field study for the treatment of vomiting in cats treated with 1 mg/kg
CERENIA Injectable Solution subcutaneously once daily for up to five consecutive days:
Frequency of Adverse Reactions by Treatment
Adverse Reaction Placebo (n=62) CERENIA (n=133)
# cats % occurrence # cats % occurrence
Moderate Response to Injection
1,2 1 1.6 30 22.6
Significant Response to Injection1,3 1 1.6 15 11.3
Fever/Pyrexia 2 3.2 2 1.5
Dehydration 0 0 3 2.3
Lethargy 0 0 2 1.5
Anorexia 0 0 1 0.8
Hematuria 0 0 1 0.8
Hypersalivation 0 0 1 0.8
Injection site swelling 1 1.6 0 0
1
The clinician observed and graded each cat’s response to injection.
2
Cat objected to the injection by retreating and vocalizing
3
Cat objected to the injection by retreating, hissing, scratching, and vocalization
Post-Approval Experience (Rev. 2015)
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 cats are listed in decreasing order of reporting frequency for CERENIA Injectable Solution: Depression/
lethargy, anorexia, hypersalivation, pain/ vocalization upon injection, dyspnea, ataxia, fever, recumbency, vomiting, panting, convulsion, and
muscle tremor.
Cases of death (including euthanasia) have been reported.
To report suspected adverse events, for technical assistance or to obtain a copy of the SDS, contact Zoetis Inc. at 1-888-963-8471
or www.zoetis.com.
For additional information about adverse drug experience reporting for animal drugs, contact FDA at 1-888-FDA-VETS
or www.fda.gov/reportanimalae.
CLINICAL PHARMACOLOGY:
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(NK
1) receptor antagonist which acts by
inhibiting the binding of substance P, a neuropeptide of the tachykinin family. SubstanceP is found in significant concentrations in the nuclei
comprising the emetic center and is considered the key neurotransmitter involved in emesis.
1By 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] [60refs]. Drugs. 2000;60:533-46.
Pharmacokinetics (CERENIA Tablets):
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
Doses1
8 mg/kg Single
Dose
8 mg/kg
repeat Doses1
Tmax2
(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 2
(hr)
NC 7.69
(6.21 - 17.8)
NC 25.4
(6.06 - 30.0)
Accumulation Ratio
(R
ac)
3
NA 2.46
(1.68, 3.61)
NA 4.81
(3.28, 7.05)
1Following once daily doses of maropitant for 14 days.
2Median (Range)
3Ratio=Multiple Dose AUC(
0-24)/Single Dose AUC(0-24 ), Least square means (95% Confidence Interval)
NA= Not Applicable
NC= Not Calculated
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 enzyme kinetics, involvement of a high capacity enzyme in vitro
(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 enzyme kinetics data suggest that the non-linear kinetics may be partially in vitro
associated with saturation of the low capacity enzyme (CYP2D15). Plasma protein binding of maropitant was high (99.5%).
Pharmacokinetics (CERENIA Injectable):
CERENIA is formulated using sulphobutylether-ß-cyclodextrin (SBECD), which exhibits enhanced binding to maropitant at refrigerated
temperatures. The enhanced binding affinity reverses rapidly upon warming.
DOGS:
The pharmacokinetic (PK) characterization associated with maropitant after a single oral (PO), intravenous (IV), or subcutaneous (SC) dose
administration in adult Beagle dogs is provided in the table below.
Pharmacokinetic Parameters in Beagle Dogs (Mean±SD or Mean and Range)
PK Parameter SC at 1 mg/kg
(n=8)
IV at 1 mg/kg
(n=8)
PO at 2 mg/kg
(n=8)
PO at 8 mg/kg
(n=8)
AUC0-inf (hr*ng/mL) 759.08±189.49 693.83±137.25 561±322 7840±5600
Cmax (ng/mL) 102.99±46.06 296.62±60.77 81±32 776±604
T1/2
(hr) 8.84 a (6.15-20.48) 6.85 a
(4.87-11.30) 4.03 (2.48-7.09) 5.46 (3.39-7.65)
Tmax (hr) 0.56±0.40 n/a 1.9±0.5 1.7±0.7
a Harmonic mean
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 1499.13 mL/hr/kg at a dose of 1 mg/kg. An accumulation
ratio of 1.5 was observed following once-daily use of maropitant for five consecutive days at 1 (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 enzyme kinetics, involvement of a high capacity enzyme (CYP3A12) may contribute to this return to dose linearity. Plasma in vitro
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.
CATS:
The pharmacokinetic characterization associated with maropitant after a single subcutaneous (SC) or intravenous (IV) dose administration in cats
is provided in the table below.
Pharmacokinetic Parameters for a Single Dose in 6-7 Month Old Cats (Mean±SD or Mean and Range)
PK Parameter SC at 1 mg/kg
(n=6)
IV at 1 mg/kg
(n=6)
AUC0-inf (hr*ng/mL) 2016.07±516.65 2116.53±706.72
Cmax (ng/mL) 257.84±49.95 987.65±421.75
T1/2
(hr) 6.57 a (5.09-8.60) 4.86a (3.44-6.79)
Tmax (hr) 0.43±0.33 n/a
a Harmonic mean
There appears to be an age-related effect on the pharmacokinetics of maropitant in cats; kittens (4 months) have a higher clearance than adults.
In multiple IV and SC studies, the mean maropitant half-life in kittens (4-7 months old) is 7.83 hours, compared to 17.2 hours in adults. The mean
bioavailability of maropitant after subcutaneous administration in cats was 91.3%. The mean total body clearance (CL) and volume of distribution at
steady-state (Vss) determined after IV administration of 1.0 mg/kg to 6 cats was 510 (388 to 603) mL/hr/kg and 2.3 (1.4 to 3.6) L/kg, respectively.
Maropitant displays linear kinetics when administered SC within the 0.25–3 mg/kg dose range. Following SC administration of once daily doses
of 1 mg/kg body weight for 5 consecutive days, accumulation was 250%. Maropitant undergoes cytochrome P450 (CYP) metabolism in the liver.
CYP1A and CYP3A-related enzymes were identified as the feline isoforms involved in the hepatic biotransformation of maropitant. Renal and fecal
clearances are minor routes of elimination for maropitant, with less than 1% of a 1 mg/kg SC dose appearing in the urine or feces as maropitant.
For the major metabolite, 10.4% of the maropitant dose was recovered in urine and 9.3% in feces. Plasma protein binding of maropitant in cats
was estimated to be 99.1%.
EFFECTIVENESS:
Prevention of Acute Vomiting (CERENIA Tablets)
In laboratory model studies, CERENIA Tablets dosed at a minimum of 2mg/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% (12of 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% (10of 12) of Beagle dogs treated with placebo tablets.
In a study of 275canine 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 2mg/kg orally or Injectable Solution at 1mg/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 199dogs included in the analysis for effectiveness, 27of 54dogs (50%) in the placebo group displayed vomiting at some time
during the study and 31of 145dogs (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. 143was 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 (CERENIA Tablets)
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
8mg/kg BW or placebo tablets 2hours prior to the journey, 67 of 122(55%) of dogs vomited during the journey when treated with placebo
while 8of 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.
CERENIA INJECTABLE:
DOGS:
In laboratory model studies, CERENIA Injectable Solution administered subcutaneously at 1 mg/kg in Beagle dogs 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 16.7% (2 of 12) of dogs treated with CERENIA Injectable Solution and 83.3% (10 of 12) of placebo-treated
dogs. Following administration of syrup of ipecac (peripheral emetic stimuli) vomiting was observed in 25% (3 of 12) of dogs treated with
CERENIA Injectable Solution and in 100% (12 of 12) of dogs treated with placebo.
In a study of veterinary cancer patients, dogs were treated with CERENIA Injectable Solution or placebo either 1 hour prior to cisplatin (prevention)
or after the first vomiting episode following cisplatin (treatment) and monitored for 5 hours. In the groups evaluated for prevention of vomiting,
94.9% (37/39) of the dogs administered CERENIA Injectable Solution and 4.9% (2/41) of the dogs administered placebo did not vomit. In the
groups evaluated for treatment, 21% (8/38) of the dogs administered CERENIA Injectable Solution and 5.1% (2/39) of the dogs administered
placebo had no further episodes of vomiting following treatment.
