Support Care Cancer (1994) 2:389-392

9 Springer-Verlag 1994

M.
M.
M.
A.

Tomirotti
Dimaiuta
Confalonieri
Scanni

Efficacy and tolerability of nasally

administered compared to parenterally
administered metoclopramide
in the symptomatic treatment
of chemotherapy-induced emesis
in cancer outpatients
A controlled clinical study

M. Tomirotti, M. D. ([]) 9 M. Dimaiuta

M. Confalonieri 9 A. Scanni
Servizio di Oncologia Medica
et Chemioterapia,
Ospedale Fatebenefratelli,
Corso Porta Nuova, 23,
1-20121 Milan, Italy
Fax: 02/6363216

Abstract The clinical efficacy and

tolerability of a new nasal spray
formulation of metoclopramide
(MTC) was evaluated in terms of
its ability to prevent the nausea
and vomiting induced by a moderately emetic chemotherapy (cisplatin 20 mg/m 2 weekly as radioenhancer + radiotherapy for a fractionated total of 60 Gy) in 12 patients with non-small-cell lung cancer, stage IIIB. The first chemotherapy cycle was administered
without any prophylaxis in order to
identify those patients who experienced grade 2 nausea and/or vomiting. As prophylaxis during the
second cycle, these patients were
given MTC 20 mg i.v. at time zero,
and MTC 20 mg i.m. after 4 h and
8 h; during the third cycle, they received MTC 40 mg by nasal spray
2 h before chemotherapy, followed
by the same dose at 4 h and 8 h.
The two prophylactic treatments
(parenteral injections and nasal
spray) proved to be therapeutically
equivalent: complete protection, 6
and 6 patients respectively; major

Introduction
Although their intensity varies in relation to particular
drugs [3], nausea and vomiting are frequent and disturbing side-effects of all commonly used anticancer
chemotherapies, and often limit patient compliance

[81.

protection, 2 and 3 patients; minor

protection, 1 and 1 patient; no protection, 3 and 2 patients. The control of nausea was satisfactory,
with 7 and 9 patients respectively
experiencing grade 0-1 nausea.
Comparative analysis of individual
responses confirmed the similar
anti-emetic efficacy of the two regimens. No adverse reactions were
observed at any time during the
course of the study, and all 12 patients judged the acceptability of
the new formulation as optimal. It
can thus be concluded that the use
of metoclopramide nasal spray represents an effective, safe, easily
managed and low-cost therapeutic
alternative for the prophylaxis and
treatment of emesis induced by
low-dose chemotherapy. The results of the present study could
also promote a regular use of the
MTC nasal spray in other fields of
oncological supportive therapy.

Key words Chemotherapy

Cisplatin-induced emesis
Metoclopramide nasal spray

At therapeutic doses, cisplatin is a drug with highly

emetic effects that manifest themselves 1-6 h after administration and may continue for 24-72 h. These effects are dose-dependent and correlate with plasma
platinum levels [5].
Metoclopramide (MTC) is widely used in the prophylaxis and treatment of chemotherapy-induced emesis. Its anti-emetic action is due to the fact that it blocks

390

..

the d o p a m i n e r g i c (D2) receptors located in the chem o r e c e p t o r trigger zone, as well as the peripheral receptors in the s m o o t h - m u s c l e tissue of the gastroenteric
apparatus. A t the peripheral level, it also has cholinergic proPerties; and t h e r e is s o m e e x p e r i m e n t a l evidence
that suggests that it m a y act directly on the s m o o t h
muscle itself [1, 4]. R e c e n t studies have s h o w n that,
particularly w h e n used at high doses, M T C is also capable o f interacting with central 5HT3 serotininergic receptors [6].
T h e t r e a t m e n t schedules used so far involve the prevalently p a r e n t e r a l (intravenous or intramuscular) administration of M T C alone, or in association with o t h e r
drugs. O u r C e n t r e has c o n d u c t e d a pilot study in o r d e r
to verify the t h e r a p e u t i c efficacy and tolerability of a
n e w M T C nasal spray f o r m u l a t i o n in the prophylaxis of
emesis patients receiving a m o d e r a t e l y e m e t i c c h e m o t h e r a p y (cisplatin 20 m g / m 2 weekly). This schedule was
c h o s e n b e c a u s e its m o d e r a t e e m e t i c effects justified the
p r o p h y l a c t i c use of drugs o t h e r t h a n antiserotininergic
agents [2].
T h e p h a r m a c o k i n e t i c data relating to the nasal form u l a t i o n show d e l a y e d a b s o r p t i o n (tmax=2-3 h), a
bioavailability of 70% in relation to an equivalent i.v.
dose, and persistent t h e r a p e u t i c p l a s m a levels [7].
T h e p h a r m a c o t o x i c o l o g i c a l characteristics of the active substance have already b e e n well defined in the lite r a t u r e and are well k n o w n in daily clinical practice.
T h e results of local tolerability studies in animals show
the a b s e n c e of any h a r m f u l effects on the nasal m u c o s a
( R e y n o l d s J. A., study no. T85 M00466: Nasal m u c o s a l
irritation study of m e t o c l o p r a m i d e nasal in rabbits.
D a t a in Crinos files. R e y n o l d s J. A., study no. T85
M01676: 30-day nasal m u c o s a l irritation study of m e t o c l o p r a m i d e nasal in rabbits).

perienced nausea (grade 2) or vomiting during the run-in phase,

were considered eligible for the study.
The exlusion criteria were: pregnancy, a history of psychiatric
disturbances or overt psychosis, known hypersensitivity to metoclopramide, extrapyramidal or degenerative CNS diseases, or epilepsy.
Also excluded were patients treated with anti-emetics, sedatives, hypnotic drugs, antidepressants, neuroleptic agents or steroids during the 12 h preceeding the beginning of the study (or
who required the administration of these drugs during the course
of the study itself); patients with nausea and/or vomiting of noniatrogenic origin; and patients who had taken food or drink in the
12 h preceding the beginning of the study.
In order to ensure the correct absorption of the drug, patients
with allergic or vasomotor rhinitis, or anatomical alterations of
the nasal cavities, were also excluded.

Study design
Phase 1 (run-in)

A. During the days immediately preceding their enrolment, all of

the patients considered eligible for the study had to undergo a
series of preliminary examinations including a complete medical
history, general physical examination, an evaluation of the main
haematochemical parameters, complete urinalysis and rhinoscopy. This last examination had to be repeated at the end of the
treatment with metoclopramide nasal spray (phase 3).
B. Patients received one cycle of chemotherapy without antiemetic prophylaxis.

Phase 2 (parenteral MTC)

Patients underwent a second cycle of chemotherapy+metoclopramide 20 mg i.v. at time zero + metoclopramide 20 mg i.m. at
home, 4 h and 8 h after the anticancer treatment.

Phase 3 (MTC nasal spray)

Patients and methods

The aim of the present study was to evaluate anti-emetic prophylaxis in the 24 h following chemotherapy in 12 outpatients with
non-small-cell lung cancer stage IIIB, being treated with cisplatin
20 mg/m 2 i.v. every 7 days as a radioenhancer + ratiotherapy for a
fractionated total of 60 Gy.
The study design consisted of balanced blocks in which each
patient acted as his own control, and included three phases corresponding to three chemotherapeutic cycles. Given the moderate
emetic effects of the dose of cisplatin used, no anti-emetic prophylaxis was given during the initial run-in phase; this was to ensure that only those patients who presented nausea (grade 2) or
vomiting (grade 1) were enrolled for the subsequent phases in
which prophylaxis was given (parenteral MTC in phase 2 and
MTC nasal spray in phase 3).
All of the patients gave their informed consent before entering the study.
/

Two hours before the third chemotherapy cycle, patients received

metoclopramide 40 mg by nasal spray (n.s.; one spray dose in one
nostril), and 4 h and 8 h after chemotherapy, they administered
metoclopramide 40 mg n.s. at home. This schedule, with its "early" administration of the drug and higher doses, was chosen because pharmacokinetic data indicate slower drug absorption after
nasal administration and a bioavailability of 70% in relation to an
equivalent intravenous dose.
Each of the study phases included a washout period of 7
days.
The use of dexamethasone was strictly forbidden during all of
the three phases. The self-administration of one or two vials of
metoclopramide i.m. was allowed "as needed", but any such administration had to be reported to the Investigator at the subsequent visit, and then recorded in the case record form for use in
the efficacy evaluation.

Inclusion and exclusion criteria

Symptom assessment

Patients aged between 18 and 75 years, who had been treated

with cisplatin 20 mg/m 2 weekly as a radioenhancer, and had ex-

For the purpose of evaluating therapeutic efficacy, the following

data were collected for each phase of the study:

391

1. The number o~ vomiting episodes (non-productive retching

episodes were n o t included here, but classified as episodes of nausea)
2. The duration and severity of nausea (graded as 0=absent;
1 = mild; 2 = moderate; 3 = severe)
3. The number of self-administrations of metoclopramide i.m., in
addition to those established in the protocol
4. Any adverse events occurring during the course of anti-emetic
therapy.
Anti-emetic efficacy over the 24 h was evaluated as: complete
protection = no vomiting episodes; major protection = 1 or 2 vomiting episodes; minor protection=3-5 vomiting episodes; failure = more than 5 vomiting episodes
Statistical analysis
Given the small size of the sample and the fact that this was a
pilot study, no inferential statistical analysis was performed.

Results
Twelve patients with non-small-cell lung cancer, stage
IIIB, treated by means of radiotherapy+cisplatin 20
mg m -2 week -1 as radioenhancer, were enrolled in
this block-design pilot study. Because the chemotherapy regimen adopted does not induce hyperemesis in all
patients treated, a run-in phase was necessary to be
able to identify those subjects responding to the requirements of a controlled study. All of the patients who
experienced nausea and vomiting of iatrogenic origin
during the first cycle of chemotherapy were therefore
entered in the subsequent phases of the study.
The patients enrolled were 9 men and 3 women,
with a mean age of 64 years (range 44-76) and a mean
body surface area of 1.54 m 2. None of them prematurely discontinued the study treatments.
During the prophylaxis-free 24 h following chemotherapy (run-in phase), all of the patients (12/12) reported a mean of 4 (median 4, range 1-11) productive
vomiting episodes, and 8/12 also reported nausea of
varying intensity (median 2, range 1-3) lasting for a
mean of 8.25 h (range 3-18).
The results obtained with parenteral and nasal spray
metoclopramide respectively, in comparison with the
run-in phase, show that there was no clinically significant difference in terms of vomiting control between
the two prophylactic treatments (parenteral and nasal
spray). Both provided good protection: no episodes of
vomiting in 6/12 and 6/12 patients respectively; major
protection in 2/12 and 3/12; minor protection in 1/12
and 1/12; no protection in 3/12 and 2/12. Comparative
analysis of individual data shows that the therapeutic
response to the two treatments was identical in 9/12 patients; there was a better response to the nasal spray
formulation in 2/12 cases and, in only one case did the
nasal spray prove to be less efficacious.

Where present (6/12 patients), vomiting occurred

during the first 6 h after chemotherapy in 5/6 patients
after parenteral MTC, and in 4/6 patients after MTC
nasal administration. In the remaining 1/6 and 2/6 patients respectively, the first vomiting episode occurred
in the subsequent 18 h.
The control of nausea was satisfactory with both
routes of administration: 7/12 parenterally and 9/12 nasally administered patients experienced grade 0-1 nausea, and 5/12 and 3/12 respectively experienced grade
2-3 nausea.
Comparative analysis of the individual nausea data
shows that 7/12 patients received the same degree of
protection from both treatments; 2/12 showed better
symptom control on nasal MTC (grade 0 compared to
grade 3 and grade 2) and 3/12 patients experienced no
nausea with parenteral MTC, but grade 1 nausea with
the nasal administration.
The mean duration of the symptom was more or less
the same both for the two treatments (9 compared to
8.25 h) and in comparison with the mean value observed during the run-in phase (8.25 h).
As a whole, the results show the therapeutic efficacy
of metoclopramide in antiemetic prophylaxis, as well as
the bioequivalence of the two pharmaceutical formulations studied.
Provided that they recorded the fact on their individual cards, all of the patients were allowed to administer one or more vials of MTC i.m. themselves, in addition to those established by the protocol, after the 8th h
following chemotherapy. Analysis of the reported data
shows that, during the run-in phase, all of the patients
self-administered one or two vials of MTC i.m. during
the 24-h period; during the phases of parenteral and
nasal MTC treatment, the number of self-prescribers
was respectively 1 (1 vial) and 4 (1 or 2 vials). These
self-administrations were all carried out within the first
8 h following chemotherapy; none of the patients required further administrations after the completion of
the study dose schedule (8 h after chemotherapy). It
would therefore seem (and this is in line with pharmacokinetic data on the nasal spray formulation mentioned above) that delayed absorption allows adequate
protection to be achieved only some hours after the administration of the drug.
Examination of the nasal mucosa both before and
after the nasal administration of MTC revealed no alterations, nor did any patient report any local disturbances following treatment; local tolerability was therefore optimal.
Patient judgements concerning the use of the new
nasal spray formulation of metoclopramide were satisfactory, all of them judging it "easier to use". The medical judgements were; highly efficacious (1 patient), efficacious (8), inefficacious (2), and undefined (1).

392

During the course of the study, none of the patients

manifested any side-effects related to the active substance.

Discussion
Pharmacological prophylaxis given during and after the
administration of anticancer chemotherapy is the most
effective means of counteracting iatrogenic nausea and
vomiting. In the case of moderately emetic chemotherapeutic regimens, such prophylaxis is commonly given
by means of the parenteral (intravenous or intramuscular) or oral administration of drugs such as metoclopramide.
On the basis of such preliminary considerations, and
bearing in mind that the invasiveness of parenteral prophylactic treatment makes it uncomfortable for patients, as well as the fact that the bioavailability of nasally administered MTC is 70% that of an equivalent intravenous dose, the present study was designed to verify the therapeutic efficacy and tolerability of the new
pharmaceutical formulation. A moderately emetic anticancer regimen (cisplatin 20 mg -2 week -1) with a
fixed dose for all of the patients studied was used not
only to ensure more homogeneous results, but also because it does not require the use of antiserotininergic
drugs for prophylaxis of acute emesis.
The study did not aim to ascertain the superiority of
one of the two regimens over the other; its objective
was simply to verify the validity of a new means of administering the same active substance, metoclopramide,
the therapeutic efficacy of which has already been
widely demonstrated. It is for this reason that no formal
sizing of the sample was undertaken.
The results obtained using the new formulation
show that the control over vomiting it provides (complete or major protection in 9/12 patients) is the same
as that offered by parenterally administered metoclopramide (8/12 patients). Comparative analysis of the
two regimens in each subject shows that the therapeutic
response was absolutely identical in 9/12 patients and,

in the remaining 3, the differences are in favour of the

nasal spray (2/3 cases). In the case of nausea, the results
provided by the two regimens were also similar: both
provided good control of the severity (grade 0-1 nausea in 7/12 patients on parenteral MTC and in 9/12 on
the nasal formulation) even though, where present, the
duration of the symptom remained substantially the
same as that observed during the run-in phase. Once
again, individual responses to the two regimens were
the same in the majority of cases (7/12). The slight superiority of the injected formulation during the first
hours after chemotherapy (as demonstrated by the
number of self-administrations made particularly during the nasal-spray phase of the study) is fully consistent with its different pharmacokinetic profile, the nasal
spray being characterised by slow absorption and a delayed haematic peak (tmax 2--3 h).
The results of the present study indicate that the administration of metoclopramide by nasal spray at a
dose of 40 mg three times daily is effective in preventing the hypermesis induced by a moderately emetic
chemotherapy, and also show that there is a substantial
therapeutic equivalence between the two regimens
studied.
As far as patient compliance is concerned, all of the
patients (12/12) expressed an extremely favourable
judgement concerning the greater ease of administration of the new formulation, which also proved to be
absolutely well tolerated.
In conclusion, it can be said that the new metoclopramide nasal spray formulation represents a valid alternative post-chemotherapy anti-emetic prophylaxis to
both the parenteral and oral formulations (although
equally efficacious, the former is certainly more invasive; the latter is often impracticable precisely because
of the symptoms of the patients). Given the pharmacodynamic and pharmacokinetic charatceristics of MTC
therapy by nasal spray, as well as its safety, ease of administration and low cost, it is possible to imagine its
use also in other areas of oncological support treatment.

References
1. Desmond PV, Watson KJR (1986) Metoclopramide - a review. Med J Aust
144:366-369
2. Du Bois A, Meerpohl HG, Vach V, et
al (1992) Course, patterns and risk factors for chemotherapy-induced emesis
in cisplatin-pretreated patients: a study
with ondansetron. Eur J Cancer
28: 450-457
3. Powis G, Macker MP (1991) The toxicity of anticancer drugs. Pergamon
Press, New York

4. Guslandi M (1989) Drugs for upper digestive motility disorders. Drugs Today 25:101-110
5. Mc Dermed J, Cohen J, Huang C, et
al (1985) Correlative data relating serum metoclopramide levels and serum
cisplatin levels: preliminary results.
Proc Am Soc Clin Oncol 4:261
6. Mitchelson F (1992) Pharmacological
agents affecting emesis. A review.
Drugs 43: 295-315

7. Scaglione F, Scanni A, Tomirotti M, et

al (1993) Pharmacokinetics and bioavailability of metoclopramide nasal
spray vs metoclopramide intravenous
in helathy volunteers and cancer patients. Arzneimittelforschung/Drug Res
43 : 986-991
8. Seynaeve C, De Mulder PHM, Verweij
J, Gralla RJ (1991) Controlling cancer
chemotherapy-induced emesis. An update. Pharm Weekbl Sci 13:189-197