GASTROENTEROLOGY 1985;88:1026-33
Famotidine, a New, Potent, Long-Acting
Histamine H2-Receptor Antagonist:
Comparison With Cimetidine and
Ranitidine in the Treatment of Zollinger-
Ellison Syndrome
J. M. HOWARD, A. N. CHREMOS, M. J. COLLEN,
K. E. McARTHUR, J. A. CHERNER, P. N. MATON,
C. A. CIARLEGLIO, M. J. CORNELIUS, J. D. GARDNER,
and R. T. JENSEN
Digestive Diseases Branch, National Institute of Arthritis, Diabetes, and Digestive and Kidney
Diseases, National Institutes of Health, Bethesda, Maryland and Merck, Sharp and Dohme
Research Labs, West Point, Pennsylvania
Famotidine, a new, potent, long-acting histamine
H 2 -receptor antagonist was compared with cimeti-
dine and ranitidine in 9 patients with Zollinger-
Ellison syndrome. The mean minimum daily re-
quirement of fartlOtidine to control gastric acid
hypersecretion was 0.24 g (range 0.08-0.48 g) com-
pared with 2.1 g (range 0.6-3.6 g) for ranitidine and
7.8 g (range 1.2-13.2 g) for cimetidine. Equally
potent doses of the three drugs had similar onsets of
action, but the duration of action of famotidine was
30% longer than the duration of action of either
ranitidine or cimetidine (p < 0.05). Eight patients
were treated for up to 9 mo (mean 6 mo) with good
control of gastric acid hypersecretion and with no
evidence of biochemical or hematologic toxicity.
These studies demonstrate that famotidine is nine
times more potent than ranitidine and 32 times more
potent than cimetidine, has a longer duration of
action than ranitidine or cimetidine, and is both safe
and effective in the long-term therapy of Zollinger-
Ellison syndrome.
In thepast decade, the introduction of histamine H 2 -
receptor antagohists has markedly changed the ther-
apy of Zollinger-Ellison syndrome. Instead of rou-
tine total gastrectomy, gastric acid hypersecretion
can now be successfully treated in almost all pa-
Received June 27, 1984. Accepted November 13, 1984.
Address requests for reprints to: R. T. Jensen, M.D., Building 10,
Room 9C-I03, National Institutes of Health, Bethesda, Maryland
20205.
© 1985 by the American Gastroenterological Association
0016-5085/85/$3.30
tients using a histamine H 2 -receptor antagonist alone
or in combination with an anticholinergic agent (1-
6). There are problems, however, with the medical
therapy of gastric acid hypersecretion. In recent
studies (7,8), 25% of patients required >7 g of
cimetidine or >3 g of ranitidine to control gastric
acid secretion, doses of drugs that are over five times
the usual dose for peptic ulcer disease. Drugs often
have to be taken every 4 h (5) and usually in
combination with an anticholinergic agent, with its
inherent side effects, to control gastric acid hyperse-
cretion (4,5,7,8). Finally, increasing doses of hista-
mine H 2 -receptor antagonists are required, with con-
tinued medical management (9).
Famotidine (MK-208, YM-11170) is a new, potent,
histamine H 2 -receptor antagonist (10) that contains a
thiazole ring, whereas cimetidine and ranitidine
contain imidazole and furan rings, respectively (Fig-
ure 1). Famotidine also contains propionamidine,
instead of an ethyl guanidine (cimetidine) or ethyl-
ethenediamine group (ranitidine) (Figure 1). Famoti-
dine has been reported to be 20-fold to 160-fold more
potent than cimetidine (10-19) and threefold to 20-
fold more potent than ranitidine (15,16,20). In addi-
tion, famotidine has been reported to have a longer
duration of action than cimetidine (10,20,21) or
ranitidine (15). Therefore, because of its high poten-
cy and possible longer duration of action, famotidine
might be particularly useful in the therapy of pa-
tients with Zollinger-Ellison syndrome and other
gastric hypersecretory states.
In the present study we have compared famotidine
with cimetidine and ranitidine in terms of the poten-
April 1985 FAMOTIDINE IN ZOLLINGER-ELLISON SYNDROME 1027

H,C~ CH,SCH,CH,NHCNHCH,
,_, II
and December 1983. Within 12 mo of beginning the study,
HN N N-C=N all patients had been evaluated at the National Institutes of
V Health as part of an ongoing study of the investigation and
Cimetidine therapy of patients with gastric hypersecretory disorders.
This evaluation included measurement of serum gastrin
concentrations in the fasting state and in response to
H,C, secretin; upper gastrointestinal endoscopy; evaluation of
NCH~ CH,SCH,CH, NHCNHCH, tumor status by ultrasound, liver-spleen scan, computed
/ l II
H~ n CHN~ tomography, and selective celiac and superior mesenteric
angiography; and determination of basal and maximal acid
Ranitidine
output.
All determinations of gastric acid secretion were per-
formed as described previously (2,22). In brief, after posi-
~CH,SCH~H,CNH,
tioning a nasogastric tube in the gastric antrum, the stom-
,-\ II ach was emptied of all contents. Gastric fluid was
S~ NSO,NH,
collected in 15-min samples by continuous aspiration.
N
Samples were titrated to pH 7.0 with 0.01 N NaOH to
C
I determine the titratable acidity. Results are expressed in
H,N
/ \
NH,
milliequivalents of acid per hour.
The protocol was divided into two parts: short-term
Famotidine
Figure 1. Chemical structures of cimetidine. ranitidine. and fa-
studies to compare the effect of famotidine with the effects
motidine. of cimetidine and ranitidine on gastric acid secretion, and
long-term studies to determine the long-term efficacy and
cy, the time-course- for the onset of action, and the toxicity of famotidine.
duration of action in the inhibition of gastric acid
secretion in patients with Zollinger-Ellison syn-
drome. In addition, we have determined the long- Short-Term Acid Secretory' Studies
term safety and efficacy of famotidine. In contrast to our previous studies (2,7,8), the
short-term part of this study was specifically designed to
Materials and Methods investigate the kinetics of action of each of the histamine
Hz-receptor antagonists. Because the onset and duration of
Patients action can be a function of the relative potency of each
drug, this comparison had to be made with equipotent
Nine patients with Zollinger-Ellison syndrome
doses of each drug.
were studied. The clinical and laboratory characteristics of
Equipotent doses of famotidine, ranitidine, and cimeti-
the patients are listed in Table 1. Each patient had a basal
dine were determined for each patient by determining the
gastric acid output >15 mEq/h, a fasting serum gastrin
minimum dose of each drug taken every 6 h that inhibited
concentration of >100 pglml (normal <100 pglml), and a
gastric acid secretion to <10 mEq/h during the sixth hour
rise in the serum gastrin concentration of > 200 pglml after
after a dose of drug. The criterion of 10 mEq/h during the
intravenous infusion of 2 Ulkg of secretin (Secretin-Kabi,
Kabi Group, Greenwich, Conn.) (4). Eight patients had no
previous gastric surgery and 1 patient (patient 9) previous- Table 1. Clinical and Laboratory Characteristics of
ly had an antrectomy with a Billroth I anastomosis. Each Patients With Zollinger-Ellison Syndrome
patient gave written informed consent and the protocol Basal!
was approved by the Clinical Research Committee of the maximal Fasting
National Institute of Arthritis, Diabetes, and Digestive and Multiple Disease acid serum
Kidney Diseases, National Institutes of Health. Age endocrine duration output gastrin Tumor
Patient (yr) neoplasia (yr) (mEq/h) (pg/ml) status

Drugs 1 48 No 3 56/87 237

2 61 No 7 40/70 4,100 +
Drugs used in this study were famotidine (Merck, 3 55 No 1 34/81 260
Sharp and Dohme Research Laboratories, West Point, Pa.), 4 54 No 7 47/49 30,300 +
ranitidine (Zantac; Glaxo, Inc., Research Triangle Park, 5 65 No 6 35/74 1,780 +
N.C.), cimetidine (Tagamet: Smith, Kline and Beckman 6 22 Yes 2 44/76 630 +
7 44 No 5 24/49 430
Laboratories, Philadelphia, Pa.), and isopropamide iodide
(Darbid; Smith, Kline and Beckman Laboratories).
8 47 No 2 18/23 7,000 +
9 54 Yes 15 108/117 3,045 +
Investigations +, either biopsy-proven gastrinoma or gastrinoma suspected on
the basis of ultrasound, angiography, or computed tomography
The 9 patients with Zollinger-Ellison syndrome but not proven by surgery; -, no evidence of tumor found at
were entered into the present study between June 1983 surgery or on localization studies.
1028 HOWARD ET AL.
last hour before the next dose was used because previous
studies have shown that inhibition to this level allows
healing of peptic ulcers and prevents further acid-peptic
complications (2,23). Anticholinergic agents were stopped
at least 3 days before the study and famotidine (0.02-0.06
g) was begun every 6 h replacing the patient's previous
histamine H 2 -receptor antagonist. After the patient had
received at least four doses of famotidine, gastric acid
secretion was measured during the sixth hour after a dose.
If gastric acid secretion was > 10 mEq/h, the dose of
famotidine was increased by 0.02 g and gastric acid
secretion was measured the following day. In this manner,
the 6-h dose of famotidine was increased by 0.02 g each
day until gastric acid secretion in the sixth hour after a
dose was <10 mEq/h. This dose was defined as the
minimum 6-h dose requirement of famotidine for that
patient. After the minimum 6-h dose requirement of famo-
tidine was found, gastric acid secretion was measured on
the next day to ensure suppression of gastric acid secretion
to < 10 mEq/h by that dose. If the initial measurement of
gastric acid secretion was <10 mEq/h the dose of famoti-
dine was reduced until gastric acid secretion was > 10
mEq/h , and the dose of famotidine was then increased as
described. The minimum 6-h dose requirements of cimeti-
dine and ranitidine were then determined using a proce-
dure identical to that described for famotidine except the
dose increments were 0.3 g every 6 h for cimetidine and
0.15 g every 6 h for ranitidine. If > 0.16 g of famotidine,
> 1.5 g of ranitidine, or >3.6 g of cimetidine was required
every 6 h, the patient was defined as resistant to the
respective drug and the anticholinergic agent, isopropa-
mide , was administered every 6 h in addition to the
histamine H 2 -receptor antagonist. The minimum 6-h dose
requirements of each histamine H 2 -receptor was then
determined as described previously while the patient was
taking an anticholinergic agent. Because the minimum 6-h
drug requirements described doses of each drug that
reduced gastric acid secretion to the same degree (to <10
mEq/h during the sixth hour after a dose), these doses were
considered equipotent.
To compare the time-course for the onset of action of
famotidine with those for equipotent doses of cimetidine
and ranitidine, gastric acid secretion was measured before
and after drug administration in 4 patients (patients 1, 3, 5,
9; Table 1). The dosage of drug administered was the
minimum 6-h drug requirement defined previously. On
three separate days, after the patient had received no
anti secretory medications for 24 h, gastric acid secretion
was measured for 1 h. Then famotidine, cimetidine, or
ranitidine was administered and the nasogastric tube was
clamped for 2 h. Gastric contents were emptied complete-
ly, aspirated continuously, and pooled every 15 min for 5
h.
To compare the duration of action of famotidine with the
durations of action of ranitidine and cimetidine, gastric
acid secretion was measured from 5 to 12 h after discontin-
uing equipotent drug regimens . Five patients (patients I, 2,
5, 7, 9; Table 1) were studied on three separate occasions.
On each occasion the patient was treated with an equipo-
tent dose of each of the histamine H 2 -receptor antagonists
given every 6 h. After the patient had received at least
GASTROENTEROLOGY Vol. 88 , No.4
eight doses, the drug was stopped and gastric acid secre-
tion was measured from the beginning of the sixth hour to
the end of the 12th hour after the last dose.
Long-Term Study
After completion of the short-term study, 8 patients
(patients 1, 2, 3,4,5,7,8 , 9) were treated with famotidine
alone and evaluated at 2 wk, 2 mo, and thereafter at 2-mo
intervals after beginning famotidine therapy . The dose
used was the minimum dose requirement defined in the
short-term study administered every 6 h. At each evalua-
tion a detailed review of symptoms was taken; serum
concentrations of creatinine, serum glutamic oxaloacetic
transferase, and serum glutamic pyruvic transferase, and
serum gastrin were measured; a complete blood count was
performed; and urinary creatinine clearance and 24-h
protein excretion were determined. Stools were tested for
occult blood and gastric acid secretion was measured
during the sixth hour after a dose of medication. If patients
complained of heartburn, abdominal pain, or diarrhea,
which lasted longer than 1 wk and remained unexplained,
or if stools were positive for occult blood, upper gastroin-
testinal endoscopy was performed . The dose of famotidine
was increased if gastric acid secretion was >10 mEq/h. If
0.16 g offamotidine every 6 h did not suppress gastric acid
secretion to <10 mEq/h in the hour tested, then the
anticholinergic agent, isopropamide, 5 mg every 6 h, was
administered in addition.
Results
The clinical and laboratory characteristics for
the 9 patients studied with Zollinger-Ellison syn-
drome are listed in Table 1. The mean age was 50 yr
(range 22-65 yr). Two patients had multiple endo-
crine neoplasia type 1 (patients 6 and 9). The diagno-
sis of Zollinger-Ellison syndrome had been present
for a mean of 5.3 yr (range 1-15 yr). The mean basal
acid output was 45 mEq/h (range 18-108 mEq/h) and
the mean maximal acid output was 57 mEq/h (range
23-117 m~q/h). The median fasting serum gastrin
was 1780 pg/ml (range 260-30,300 pg/ml). Five pa-
tients had proven gastrinoma on the basis of histolo-
gy showing islet cell tumor. The characteristics of
these patients are representative of the entire group
of patients followed by the Digestive Diseases
Branch of the National Institutes of Health (4).
To determine equipotent doses of each histamine
H 2 -receptor antagonist, we established the minimum
dose of each drug (given every 6 h) that inhibited
gastric acid secretion to < 10 mEq/h during the last
hour immediately preceding the next dose. Figure 2
illustrates the results in 1 patient (patient 1, Table 1),
and is representative of all other studies. Initially,
famotidine (0.02 g) was administered every 6 h. The
following day after the patient had received four
doses of famotidine, gastric acid secretion during the
April 1985 FAMOTIDINE IN ZOLLINGER-ELLISON SYNDROME 1029

that for cimetidine (y = 0.34 + 0.25x, r = 0.81, P =

PaI ICOIIII
8AO - 5SmE.qh

.75 0.02, data not shown) .

The time-course for the onset of action of equipo-
.02 .60
1.5
tent doses of each of the three histamine H 2 -receptor
.04 1.8 2.1 antagonists was studied in 4 patients (patients 1, 3,
5, 9, Table 2). On three separate occasions, each
-- -- -- - - ---
patient received a single equipotent dose of famoti-

Ii
FAMOTIDINE RANITIOINE
DRUG TAKEN EVERY 6 HOURS
'fl CIMETIOINE
n dine, ranitidine, or cimetidine after the patient had
received no antisecretory medication for 24 h. The
dose of each drug administered was the minimum
Figure 2. Determination of the minimum 6-h dose requirement
dose that controlled gastric acid secretion when
for each histamine H 2 -receptor antagonist in patient 1. given every 6 h, i.e., one-fourth of the total daily dose
The numbers on the top of the vertical bars indicate the shown in Table 2. Maximum suppression of gastric
dose of drug in grams given every 6 h. Gastric acid acid secretion occurred with each drug 3-4 h after
output was measured during the sixth hour after each administration (Figure 4). Famotidine suppressed
indicated dose of drug. The dotted line at 10 mEq/h
indicates the level of control of gastric hypersecretion
gastric acid secretion by a mean of 88% after 3 h,
used in this study. which was not significantly different from the 80%
suppression of acid secretion caused by equipotent
sixth hour after a dose was 17 mEq/h. The dose of doses of cimetidine or the 72% suppression caused
famotidine was increased to 0.04 g every 6 hand by equipotent doses of ranitidine. With each of the
gastric acid secretion was 14 mEq/h the following three drugs, significant suppression of gastric acid
day. The dose of famotidine was increased to 0.06 g secretion persiste<;i for up to 7 h after administration
and gastric acid secretion the following day was 6 (Figure 4).
mEq/h. This degree of inhibition was confirmed the To compare the duration of action of famotidine
following day and as 0.06 g of famotidine was the with the duration of action of ranitidine and cimeti-
minimum 6-h drug requirement for famotidine that dine, gastric acid secretion was measured from 5 to
controlled gastric acid secretion in patient 1, this 12 h after discontinuing equipotent doses of each
was used in all studies on patient 1. Figure 2 also drug (one-quarter of the daily dose requirement
illustrates similar drug adiustments for ranitidine shown in Table 2 given every 6 h). The mean gastric
and cimetidine. In this patient the minimum 6-h acid secretion for the sixth hour afterdisc-ontinuing
dose of ranitidine that inhibited gastric acid secre- famotidine was 4.3 ± 1.2 mEq/h (mean ± SEM) ,
tion to < 10 mEq/h during the sixth hour was 0.9 g which was not significantly different from the mean
and the minimum 6-h dose for cimetidine was 2.4 g. gastric acid secretion for the sixth hour after stop-
The minimum daily famotidine doses (expressed as
grams required per day) that suppressed gastric acid Table 2. Minimum Daily Dose of Famotidine, Ranitidine,
secretion to <10 mEq/h during the sixth hour are and Cimetidine in Each Patient
shown for each patient in Table 2 along with the Famotidine Ranitidine Cimetidine
equipotent doses of cimetidine and ranitidine. The Patient (g/day) (g/day) (g/da y)
mean minimum daily dose requirement of famoti- 1 0.24 3.6 9.6
dine was 0.24 g/day (range 0.08-0.48 g/day) com- 2 0.32 3.6 13 .2
pared with 2.1 g/day (range 0.6-3.6 g/day) for raniti- 3 0.08 0.6 3.6
dine and 7.8 g/day (range 1.2-13.2 g/day) for 4 0.08 1.2 6.0
5 0.24 3.0 7.2
cimetidine. Gastric acid secretion in 1 patient (pa- 6 0.32a 3.0 a 7.2 a
tient 6, Table 2) could not be suppressed to <10 7 0.24 2.4 12.0
mEq/h by 0.16 g offamotidine, by 1.5 g ofranitidine, 8 0.08 0.6 1.2
or by 3.6 g of cimetidine given every 6 h; therefore, 9 0.48 1.2 9.6
results shown are the minimum daily drug require- Mean ± SD 0.24 ± 0.14 2.1 ± 1.2 7.8 ± 3.9
ments of each histamine H 2 -receptor antagonist giv-
The minimum dose of drug (given every 6 h) that inhibited gastric
en in addition to isopropamide (5 mg) taken every 6 acid secretion to < 10 mEq/h in the sixth hour after a dose was
h. There was a positive linear correlation between determined. The minimum daily dose was the total amount of
the individual minimum daily dose requirement for each drug required per day (Le., four times the 6-h drug require-
famotidine and the corresponding individual dose ments) . aPatient's gastric acid secretion could only be controlled
with these doses of histamine H2 -receptor antagonist when iso-
requirement for cimetidine (p < 0.05) and for raniti-
propamide (20 mg/day) was administered. In patient 6 gastric acid
dine (p < 0.01) (Figure 3). In addition, there was a secretion could not be controlled to < 10 mEq/h with 0.64 g/day of
positive linear correlation between the individual famotidine, 6.0 g/day of ranitidine. or 14.4 g/day of cimetidine
minimal daily dose requirement for ranitidine and when administered alone.
1030 HOWARD ET AL. GASTROENTEROLOGY Vol. 88,No. 4

0.4
v = .049 + .020x 60

~ '78 ..
'" /'
~O.3

~
. p<.cJ5 :c
3
E
QQ.2 z
b 0
::;; E
~ 0.1
0:

• • f,l
'"0
-L I U
5 10 15 «
CIM£TIDINE Ig/doy) u
ir'

..
D.4
y - .029 + .016x
r =.93
p <.D1
• • •
RANITIDINE Ig/doyJ
Figure 3. Comparison between the minimum daily dose require-
ment for famotidine and that for cimetidine (top) and
b etween the minimum daily dose requirement for
famotidine and that for ranitidine (bottom) in patients
1-8. Minimum daily doses are from Table 2. The
correlation coefficient (rl. and the equation for the best
fit were calculated using least-squares analysis. Data
from patient 9 were excluded from analysis because the
famotidine vs. ranitidine ratio was > 2 SD from the line
of best fit.
ping cimetidine (4.7 ± 1.3 mEq/h, mean ± SEM), or
ranitidine (4 .7 ± 1.6 mEq/h, mean ± SEM) , thus
confirming that equipotent doses of drugs were be-
ing evaluated (Figure 5). In each patient gastric acid
secretion after discontinuing famotidine increased
more slowly than after discontinuing cimetidine or
ranitidine. The mean time required for gastric acid
secretion to reach 20 mEq/h was 12.2 ± 0.9 h (mean
± SEM) after discontinuing famotidine, which was
significantly longer than that after discontinuing
either ranitidine (9.8 ± 0.5 h, p < 0.05) or cimetidine
(9.3 ± 0.6 h) (p < 0.01) (Figure 5). In contrast, the
mean time required to reach 20 mEq/h after discon-
tinuing cimetidine was not significantly different
from that after discontinuing ranitidine (9.8 vs. 9.3 ,
P > 0.3). At 12 h after discontinuing equipotent
doses of drugs, inhibition of gastric acid secretion by
famotidine was 58% ± 9% (mean ± SEM) of the
basal gastric acid secretory rate which was signifi-
cantly greater than the 27% ± 9% inhibition caused
by cimetidine (p < 0.01) and the 38% ± 12%
inhibition caused by ranitidine (p < 0.05) (Figure 5).
Whereas the total percentage inhibition for cimeti-
dine during the 7 h measured was not different from
that seen with ranitidine, the percent inhibition with
famotidine was significantly greater than with either
of the other two drugs (p < 0.05).
To assess the efficacy of famotidine to suppress
gastric acid secretion during long-term treatment
and to assess the toxicity of high doses of famotidine,
f-
'"«
"
TIME Ihou<sJ._..
Figure 4. Time-course for the onset of action of single equipotent
doses of famotidine, ranitidine, and cimetidine in 4
patients. The dose of each drug was one-quarter of the
minimum daily dose of that drug indicated in Table 2.
Vertical bars represent 1 SEM. The initial gastric acid
secretion (time 0-1 h) before the time drugs were
administered was 43 ± 6 mEq/h for ranitidine, 40 ± 7
mEq/h for cimetidine, and 53 ± 32 mEq/h for famoti-
dine, values that were not statistically significantly
different (p > 0 .1).
8 patients (patients 1, 2, 3, 4, 5, 7,8,9; Table 1) were
treated for up to 9 mo (mean 6 mol with famotidine.
The dose of famotidine used in each patient was the
minimum daily dose that controlled gastric acid
secretion for that patient (Table 2). A single increase
in drug dosage was required in 3 patients (patients 4,
5, 9; Table 1) and 2 patients required two dosage
increases (patients 1 , 3; Table 1) to maintain gastric
acid output at <10 mEq/h during the sixth hour after
a previous dose. An anticholinergic agent was re-
quired as part of these drug adjustments in 2 patients
(patients 1, 9; Table 1) because, in each case, gastric
40
~
. ~~
z
o
E
a:
f,l
"'20
o
~
u
ir'
f-
~ 10
"
o ri ------I !- --:';;
10,---------01!o-'2
TIME AFTER LAST DOSE ''''''ns l
Figure 5. Duration of action of equipotent doses of famotidine.
ranitidine. and cimetidine in 5 patients. After discon-
tinuing equipotent dose schedules of each drug, gastric
acid secretion was measured from the beginning of the
sixth hour to the end of the 12th h after the last dose.
The dose schedule of each drug was one-quarter of the
minimum daily requirement of that drug indicated in
Table 2 given every 6 h. Vertical bars represent 1 SEM.
April 1985
acid secretion was not controlled by 0.64 g/day of
famotidine which was the upper allowable dose.
Famotidine alone or with an anticholinergic agent
was able to inhibit gastric acid secretion to <10 mEq/
h during the last hour before the next dose in all 8
patients studied for the follow-up period.
During iong-term famotidine therapy, patients
were assessed at 2 wk, at 2 mo, and thereafter at 2-mo
intervals with a complete symptomatic, biochemi-
cal, and hematologic assessment. During treatment
with famotidine, no patient developed gastrointesti~
nal ulceration and all patients remained asympto-
matic when famotidine was used at doses that con-
trolled gastric acid secretion. One patient (patient 2,
Table 1) developed a worsening of preexisting alope-
cia but this was thought by a dermatology consultant
to be related to the removal of the antiandrogenic
effects of the previous high"dose therapy with cime-
tidine and not due to famotidine per se. Of the
remaining 7 patients, none developed symptoms of
signs that could be attributed to famotidine therapy.
In particular; none of the 5 male patients developed
antiandrogen side effects. During the long-term
maintenance study in which doses up to 0.64 g/day
of famotidine were required, there were no signifi-
cant changes in the mean levels of serum glutamic
pyruvic transaminase or serum glutamic oxaloacetic
transaminase from the mean pretreatment values at
any follow-up time (2, a, 26, or 33 wk). No patient
with normal pretreatment values developed elevated
levels of transaminases during famotidine therapy.
Two patients (patients 3, 8) had elevations of serum
glutamic oxaloacetic transaminase or serum glutam-
ic pyruvic transaminase, or both, before famotidine
therapy and one or both values remained elevated
during famotidine treatment. During farrtotidine
treatment there was no significant change in the
mean levels of serum creatinine concentrations or
white blood cell count from the mean pretreatment
values at any of the follow-up times. In the individ-
ual patients, 1 patient had a transient elevation of
white blood cell count that could not be accounted
for by any concomitant infection, and 3 patients
(patients 4, 5, 7) had borderline leukopenia at some
time during famotidine treatment. One of the 3
patients with leukopenia consistently had leukope-
nia before famotidlne treatment (patient 5), whereas
2 patients had intermittent leukopenia before famoti-
dine (patients 4, 7) in that 13 of 20 white blood cell
counts in patient 4, and 2 of 10 white blood cell
counts in patient 7 before entering the study demon-
-strated leukopenia. As has been reported previously
with ranitidine (7,8) or cimetidine therapy (2), serum
gastrin concentrations remained unchanged in all
patients during famotidine treatment.
FAMOTIDINE IN ZOLLINGER-ELLISON SYNDROME 1031
Discussion
The present study demonstrates that famoti-
dine has both similarities with and differences from
other histamine H 2 -receptor antagonists in its ability
to inhibit gastric acid secretion in patients with
Zollinger-Ellison syndrome. Equipotent doses of fa-
motidine, cimetidine, or ranitidine are similar in the
time-course for the onset of action, with each drug
showing maximum activity by 3-4 h. Like cimeti-
dine (2,7,8) and ranitidine (7,8), fainotidine re-
mained effective in controlling gastric acid hyperse-
cretion for up to 9 mo. High doses of famotidine are
well tolerated and, as previously reported with high
doses of cimetidine and ranitidine (2 ,7,8), there was
no evidence of hepatoxicity. Leukopenia occurred in
3 patients treated with famotidine. In each case the
leukopenia had been documented more than once
within the year before the study when the patient
was not being treated with famotidine, demonstrat-
ing that the leukopenia was not clearly related to
famotidine therapy. Thus, high doses of famotidine,
like high doses cif cimetidine and ranitidine (4,7,8),
did not cause hematologic toxicity. Famotidine is
similar to ranitidine and cimetidine in that periodic
dose adjustments are required, but the frequency of
dose adjustments of famotidine in the present study
was approximately the same as that reported for
these latter two drugs (7-9), suggesting that rapid
tolerance does not develop. As reported in other
studies (2,7,8), gastric acid secretlon could be inhib-
ited in 8 of 9 patients by each histamine H 2 -receptor
antagonist alone, but to adequately control gastric
acid hypersecretion, all patients required more than
the usual dose used for the treatment of duodenal
ulcer disease, i.e., > 1.2 g/day for oimetidine, 0.3 g/
day for ranitidine, and 0.02-0.04 g/day for famoti-
dine. As previously reported with cimetidine and
ranitidine (7,8), there is a close correlation between
the individual daily dose of famotidine required to
control gastric acid secretion and the corresponding
individual daily dose of cimetidine and ranitidine.
Thus, patients whose acid secretion is controlled
with low doses of cimetidine or ranitidine can also
be controlled with low doses of famotidine; whereas
patients who require high doses of either cimetidine
or ranitidine also require high doses of famotidine. A
recent review has suggested a number of different
mechanisms that might account for the high and
variable cimetidine and ranitidine dose require-
ments in patients with gastric hypersecretory states
(6). The close correlation between the daily doses of
famotidine with those of cimetidine or ranitidine
required to control gastric acid hypersecretion sug-
gests that whatever the mechanism of relative resist-
1032 HOWARD ET AL.
ance, it is shared by all histamine H 2 -receptor antag-
onists.
Famotidine differs from cimetidine or ranitidine
in its potency, duration of action, and the occurrence
of antiandrogen side effects in men during long-term
treatment. In the present study famotidine was 32-
fold more potent than cimetidine and ninefold more
potent than ranitidine. These results are consistent
with previous in vitro studies (11,13,15,16,19) and
in vivo animal studies (10,12,14,15,19), which re-
ported that famotidine is 23-fold to 150-fold more
potent than cimetidine and threefold to 48-fold more
potent than ranitidine. In preliminary studies in
humans (17-20) famotidine is reported to be 10-fold
to 60-fold more potent than cimetidine and eightfold
more potent than ranitidine.
The present study confirms the findings of some
(10,20,21) but not other researchers (24), that famoti-
dine has a longer duration of action than cimetidine
and, in addition, demonstrates in humans that famo-
tidine has a longer duration of action than ranitidine.
Because the duration of action can be a function of
the dose as well as the potency of the drugs com-
pared, the present study was designed specifically to
compare equipotent doses of each histamine H 2 -
receptor antagonist. Each drug gave equal suppres-
sion in the sixth hour after the last dose, confirming
that equipotent doses were used; therefore, an effect
of potency on dose contributing to the duration was
exciuded. In the present study the duration of action
of famotidine was ~30% longer than that of cimeti-
dine or ranitidine. This finding is identical to the
result reported in histamine-stimulated acid secre-
tion in dogs (10). The mechanism of the increased
duration of action of famotidine was not specifically
investigated in these studies but possible mecha-
nisms include delayed gastric emptying, delayed or
prolonged intestinal absorption, decreased drug
elimination, or prolonged persistence of famotidine
at the gastric histamine H 2 -receptor. Delayed gastric
emptying is unlikely because the time-courses for
the onset of action of each histamine H 2 -receptor
antagonist are the same. In addition, delayed gastric
emptying or prolonged intestinal absorption is un-
likely as famotidine has a 30% longer duration of
action than cimetidine whether given intravenously
or orally (10). The available information on the
pharmacokinetics of famotidine indicates a variable
half-life offrom 1.5 to 4.5 h with a mean of 3.2 h (19),
which may not be significantly longer than the
elimination half-life of 1.7-2.1 h for cimetidine and
2.1-3.1 h for ranitidine (25). On the other hand, there
is evidence for a possible persistence of action of
famotidine at the histamine H 2 -receptor from studies
on guinea pig atria (15). In contrast to the rapid and
GASTROENTEROLOGY Vol. 88. No. 4
complete reversal of the inhibition caused by raniti-
dine, removing famotidine from the incubation me-
dium results in only a gradual and incomplete rever-
sal of histamine H 2 -receptor blockade, suggesting
slower dissociation of famotidine from the atrial
histamine H 2 -receptor (15). Similar studies have not
been reported using gastric mucosa. The longer dura-
tion of action of famotidine has the potential advan-
tage that less frequent dosing intervals may be re-
quired; therefore, famotidine may prove to be a
useful antisecretory agent in patients who require
cimetidine or ranitidine every 4 h to maintain con-
trol of acid secretion.
Famotidine differs from cimetidine (26,27), but
resembles ranitidine (7,8 ,26,27) in that long-term,
high-dose treatment in men is not associated with
antiandrogen side effects (gynecomastia, impotence,
breast tenderness). In previous studies (8,26,27) it is
reported that up to 60% of men with gastric hyper-
secretory states treated with cimetidine develop an·
tiandrogen side effects, whereas these side effects do
not occur with ranitidine. These observations are
consistent with studies that demonstrate that neither
famotidine (28) nor ranitidine (29,30) inhibit dihy-
drotestosterone binding to androgen receptors,
whereas cimetidine does (29-31). In addition, high
doses of cimetidine decrease the weight of seminal
vesicles and the prostate in rats and dogs (12,32-34),
whereas famotidine (12) and ranitidine (30,34) do
not.
In conclusion, our study demonstrates that famoti-
dine can inhibit gastric acid secretion in patients
with Zollinger-Ellison syndtome during both short-
and long-term treatment. Famotidine is more potent
and has a 30% longer duration of action than either
cimetidine or ranitidine. Famotidine is safe at high
doses and does not cause antiandrogen side effects in
men. Although famotidine has a longer duration of
action, this study does not establish that this will
necessar~ly be clinically important and result in a
less frequent dosing interval. In addition, all patients
that required large doses of cimetidine or ranitidine
also required proportionately high doses of famoti-
dine. Because the drug requirements increase with
time, these studies suggest that even very potent
histamine H 2 -receptor antagonists may be more lim-
ited than newer antisecretory agents such as the
substituted benzimidazoles which have a very long
duration of action (35 ,36).
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