Note: Descriptions are shown in the official language in which they were submitted.
WO 92/12716 ~ ~ ~,~ ~f ~~ ,,~ r~ PCT/GB92/00091
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Pharmaceutical composition containing granisetron
and dexamethasone
This invention relates to the use of a compound having 5-HT3
receptor antagonist activity and dexamethasone in the
treatment of emesis, and to pharmaceutical compositions
containing the two compounds.
EP-A-200449 tBeecham Group p.l.c.), Example 6 discloses
granisetron, and its use as an anti-emetic, especially
1o useful in treating cytotoxic agent-induced nausea and
vomiting. All references herein to granisetron include
pharmaceutically acceptable salts, such as the
hydrochloride, and solvates, such as hydrates.
i5 The anti-emetic properties of granisetron are potentially
enhanced by administering the compound in conjunction with
systemic corticosteraids, such as dexamethasone.
Dexamethasone is a systemic anti-inflammatory
corticosteroid, which is known to have anti-emetic
20 properties and to be useful in the treatment of emesis
resulting from chemotherapy, especially cancer chemotherapy
involving the use of, for example, cisplatin.
Accordingly, the present invention provides a pharmaceutical
25 product comprising granisetron and dexamethasone as a
combined preparation for simultaneous, separate or
sequential use in the treatment and/or prevention of nausea
and vomiting.
3o The present invention also provides a method of treatment
and/or prophylaxis of nausea and vomiting, which comprises
administering to a human or animal subject, granisetron and
dexamethasone or a pharmaceutically acceptable salt or ester
thereof.
The invention further provides the use of granisetron for
the manufacture of a medicament for administration in
WO 92/12716 ~~/~~~ PCT/GB92/00091
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conjunction with dexame'thasone or a pharmaceutically
acceptable salt or ester thereof, for the treatment and/or
prevention of nausea and vomiting.
Co-administration of granisetron with dexamethasone is
particularly useful for the treatment and/or prevention of
nausea and vomiting associated with chemotherapy using
cytotoxic drugs, especially cancer chemotheraphy involving
the use of, for example, platinum complexes such as
cisplatin or carboplatin, or cylcophosphamide or
doxorubicin. Such co-administration may also reduce delayed
or prolonged nausea and vomiting associated with this type
of chemotherapy. Particular note should also be made of the
use in the treatment of nausea and vomiting associated with
other cytotoxic agents, such as that associated with
radiation treatment.
Granisetron and dexamethasone or a pharmaceutically
acceptable salt or ester thereof, may be administered as a
2o single pharmaceutical composition comprising effective
amounts of the two active ingredients. Alternatively the
two active ingredients may be co-administered in the form of
two separate pharmaceutical compositions for simultaneous or
sequential use.
Suitable pharmaceutically acceptable salts of granisetron
for use according to the invention include acid addition
salts formed with organic or inorganic acids for example,
hydrochlorides, hydrobromides, sulphates, phosphates,
3o citrates, fumarates and maleates. The solvates may, for
example, be hydrates. A preferred form of granisetron for -
use according to the invention is the hydrochloride.
Dexamethasone may be administered according to the invention
as dexamethasone alcohol or in the form of a
pharmaceutically acceptable salt or ester. Suitable salts
and esters include the acetate, isonicotinoate,
WO 92/12716 ~ ~~ ( '~ PCT/GB92/00091
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phenylpropionate, pivalate, t-butyl acetate,
trioxaundecanoate, disodium metasulphobenzoate and disodium
phosphate.
A proposed dosage of granisetron for use according to the
invention for administration to man (of approximately 70kg
body weight), is 0.05 to 25mg., more preferably 0.05 to
20mg, and most preferably 0.1 to lOmg per unit dose,
expressed as the weight of free base. A preferred dose of
dexamethasone for use according to the invention is in the
range of 0.5 to 20mg per dosage unit, expressed as the
weight of the alcohol.
The unit doses may be administered, for example, 1 to 4
times per day. The exact dose will depend on the route of
administration and the condition being treated, and it will
be appreciated that it may be necessary to make routine
variations to the dosage depending on the age and weight of
the patient as well as the severity of the condition to be
treated.
When the two active ingredients are administered as separate
preparations, they are preferably given enterally, such as
orally or parenterally (e. g. intramuscularly or, more
particularly, intravenously).
According to a further aspect the invention provides a
pharmaceutical composition, for use in human or veterinary
medicine, comprising the granisetron, and dexamethasone or a
3o pharmaceutically acceptable salt or ester thereof.
Compositions according to the invention may be formulated in
conventional manner using one or more physiologically
acceptable carriers or excipients. Thus the compositions
may, for example, be formulated for oral, buccal, parenteral
WO 92/12716 PCT/GB92100091
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2~.~fl'~7'~
or rectal administration. Compositions for administration
by the oral route, in the form of for example tablets or
capsules, are preferred.
Compositions for oral use such as tablets and capsules may
be prepared by conventional means. with pharmaceutically
acceptable excipients such as binding agents (e. g.
pregelatinised maize starch, polyvinylpyrrolidone or
hydroxypropyl methylcellulose): fillers (e. g. lactose,
to microcrystalline cellulose or calcium hydrogen phosphate)
lubricant (e. g. magnesium stearate, talc or silica);
disintegrants (e. g. potato starch or sodium starch
glycollate); or wetting agent (e. g. sodium lauryl sulphate).
Tablets may be coated by methods well known in the art.
Liquid preparations for oral administration may take the
form of, for example, solutions, syrups or suspensions, or
they may be presented as a dry product for constitution with
water or other suitable vehicle before use. Such liquid
preparations may be prepared by conventional means with
2o pharmaceutically acceptable additives such as suspending
agents (e.g. sorbitol syrup, cellulose derivatives or
hydrogenated edible fats): emulsifying agents (e. g. lecithin
or acacia); non-aqueous vehzcles (e. g. almond oil, oily
esters, ethyl alcohol or fractionated vegetable oils) and
preservatives (e.g. methyl or propyl-~-hydroxybenzoates or
sorbic acid). The preparations may also contain buffer
salts, flavouring, colouring and sweetening agents as
appropriate.
Preparations for oral administration may be suitably
formulated to give controlled release of one or both active
ingredients.
For parenteral administration the compositions may be.
presented in a form suitable for bolus injection or
continuous infusion. Formulations for injection may be
WO 92/12716 ~ ~ ~ ~ ~ ~ ~ PCf/GB92/00091
presented in unit dosage form e.g. in syringes, ampoules or
in multi-dose containers, with an added preservative. The
compositions may take such forms as suspensions, solutions
or emulsions in oily or aqueous vehicles, and may contain
formulatory agents such as suspending, stabilising and/or
dispersing agents. Alternatively, the active ingredients
may be in powder form for constitution with a suitable
vehicle, e.g. sterile pyrogen-free Water, before use.
E'or rectal administration the compositions may be formulated
as suppositories or retention enemas, e.g. containing
conventional suppository bases such as cocoa butter or other
glycerides.
The pharmaceutical compositions of the invention may be
prepared according to conventional techniques well known in
the pharmaceutical industry. Thus, for example, the
granisetron and the dexamethasone or dexamethasone salt or
ester may be admixed together, if desired, with suitable
excipients. Tablets may be prepared, for example, by direct
compression of such a mixture. Capsules may be prepared by
filling the blend along with suitable excipients into
gelatin capsules, using a suitable filling machine.
Controlled release forms for oral or rectal administration
may be formulated in a conventional manner associated with
controlled release forms.
The compositions for use according to the invention may, if
desired, be presented in a pack or dispenser device which
may contain one or more unit dosage forms containing the
active ingredients. The pack may for example comprise metal
or plastic foil, such as a blister pack. The pack or
dispenser device may be accompanied by instructions for
administration. Where the granisetron and the dexamethasone
are intended fox administration as two separate compositions
these may be presented in the form of, for example, a twin
pack.
WO 92/12716 PCT/GB92/00091
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2~.0~"~7'~ ._ ,
Clinical Studies
FIRST STUDY
A randomised, double blind, parallel group study comparing
the use of granisetron and/or dexamethasone for prophylactic
control of cisplatin (>_ 50 mglm2) induced nausea and
vomiting is carried out for a period of seven days.
Randomisation is stratified by cisplatin dose (50-79 mg/m2
and >_ 75 mg/m2). Patients receive either granisetron for
seven days, granisetron and dexamethasone for seven days, or
granisetron and dexamethasone for one day followed by
dexamethasone for six days.
The following are evaluated:
o The improvement by dexamethasone of the efficacy of
granisetron when both medications are given over a
period of 24 hours and seven days.
o The efficacy improvement of dexamethasone in
preventing delayed onset nausea and/or vomiting when
granisetron is administered from day 2-7.
Patients receiving cisplatin (>_50 mg/m2) therapy for
malignant disease are randomised in a double blind fashion,
stratified according to cisplatin dosage, to receive the
study medication.
The study design consists of 3 treatment arms:
1. Placebo (saline) 15 minutes infusion to be completed
20 minutes prior to cisplatin infusion (TIME 0) and
granisetron 3 mg I.V. 15 minute infusion to be
completed 5 min prior to TIME 0 followed by
granisetron 1 mg p.o. at 6 and 12h. Granisetron 1 mg
p.o. B.I.D. begins at 24h for 6 consecutive days.
PGT/G B92/00091
W0 92/12716
2. Dexamethasone 10 mg I.V. 15 minute infusion to be
completed 20 munutes prior to cisplatin infusion (TIME
0) and granisetron 3 mg I.V. 15 minute infusion to be
completed 5 min prior to TIME ) followed by
granisetron 1 mg p.o. at 6 and 12h.
Granisetron 1 mg p.o. B.I.D. and dexamethasone 8 mg
p.o. B.I.D. begins at 24h for 6 consecutive days.
io
3. Dexamethasone lOmg I.V. 15 minute infusion to be
completed 20 minutes prior to cisplatin infusion (TIME
0) and granisetron 3 mg I.V. 15 minute infusion to be
completed 5 min prior to TIME 0 followed by
granisetron 1 mg p.o. at 6 and 12. Dexamethasone 8 mg
p.o. B.I.D. begins at 24h for 6 consecutive days.
Patients disease state is assessed using the WHO
classification and they must have a score of 2 or less. All
2o patients are naive to cytotoxic therapy to avoid
anticipatory emesis.
Patients who develop nausea and vomiting after their
cisplatin therapy may be given up to four doses of
prochlorperazine (10 mg suppositories) per day. If nausea
and vomiting continue after this such that other
anti-emetics have to be given, the physician decides whether
or not to stop the study medication and/or treat with
standard anti-emetics. As far as is medically safe,
3o patients remain on the study medication for as much of the 7
day treatment period as possible.
The primary efficacy assessments in the study are the
percentage of Complete Responders, the time to first
WO 92/12716 PCT/GB92100091
vomiting, and the use of other anti-emetics over the seven
day period.
Secondary efficacy assessments of nausea and vomiting during
s the first 24 hours determine the increase in efficacy of
granisetron by dexamethasone. As well, nausea and vomiting
assessments after the first 29 hours determine the increase
in efficacy of dexamethasone by granisetron in the
maintenance phase of treatment.
SECOND STUDY
A randomised, double blind, parallel group study is carried
out, comparing oral granisetron (1.0 mg bd) with oral
granisetron in combination with dexamethasone (12 mg iv) on
the first day only and a conventional anti-emetic therapy,
(metoclopramide 7mg/kg iv plus dexamethasone 12 mg iv on the
first day, followed by metoclopramide 10 mg tds po) over a 7
day period in controlling cisplatin induced nausea and
2o vomiting.
The following are primary efficacy assessments:
o The percentage of complete responders over the seven
2s day period.
o The time to less than complete response and use of
other antiemetics using survival methods over the
seven day period.
The following are secondary efficacy assessments:
o The percentage of complete responders over the crtical
24 hour period.
o Subjective symptom scoring for nausea and vomiting.
