CLINICAL PHARMACOLOGY
Nizatidine is a competitive, reversible inhibitor
of histamine at the histamine H2-receptors, particularly
those in the gastric parietal cells.
Antisecretory Activity
Effects on Acid Secretion: Nizatidine significantly
inhibited nocturnal gastric acid secretion for up to 12
hours. Nizatidine also significantly inhibited gastric acid
secretion stimulated by food, caffeine, betazole, and pentagastrin
(TABLE 1).
| TABLE 1
Effect of Oral Nizatidine on Gastric Acid Secretion |
| |
Time After Dose (h) |
% Inhibition of Gastric
Acid |
Output by Dose (mg) |
|
|
|
| |
|
20-50 |
75 |
100 |
150 |
300 |
| Nocturnal |
Up to 10 |
57 |
|
73 |
|
90 |
| Betazole |
Up to 3 |
|
93 |
|
100 |
99 |
| Pentagastrin |
Up to 6 |
|
25 |
|
64 |
67 |
| Meal |
Up to 4 |
41 |
64 |
|
98 |
97 |
| Caffeine |
Up to 3 |
|
73 |
|
85 |
96 |
Effects on Other Gastrointestinal Secretions
Pepsin: Oral administration of 75 to 300
mg of nizatidine did not affect pepsin activity in gastric
secretions. Total pepsin output was reduced in proportion
to the reduced volume of gastric secretions.
Intrinsic Factor: Oral administration of 75 to
300 mg of nizatidine increased betazole-stimulated secretion
of intrinsic factor.
Serum Gastrin: Nizatidine had no effect
on basal serum gastrin. No rebound of gastrin secretion
was observed when food was ingested 12 hours after administration
of nizatidine.
Other Pharmacologic Actions
Hormones: Nizatidine was not shown to affect
the serum concentrations of gonadotropins, prolactin, growth
hormone, antidiuretic hormone, cortisol, triiodothyronine,
thyroxin, testosterone, 5a-dihydrotestosterone, androstenedione,
or estradiol.
Nizatidine had no demonstrable antiandrogenic action.
Pharmacokinetics
The absolute oral bioavailability of nizatidine exceeds
70%. Peak plasma concentrations (700 to 1800 mcg/L for
a 150-mg dose and 1400 to 3600 mcg/L for a 300-mg dose)
occur from 0.5 to 3 hours following the dose. A concentration
of 1000 mcg/L is equivalent to 3 mcgmol/L; a dose of 300
mg is equivalent to 905 mcgmoles. Plasma concentrations
12 hours after administration are less than 10 mcg/L.
The elimination half-life is 1 to 2 hours, plasma clearance
is 40 to 60 L/h, and the volume of distribution is 0.8
to 1.5 L/kg. Because of the short half-life and rapid
clearance of nizatidine, accumulation of the drug would
not be expected in individuals with normal renal function
who take either 300 mg once daily at bedtime or 150 mg
twice daily. Nizatidine exhibits dose proportionality
over the recommended dose range.
The oral bioavailability of nizatidine is unaffected
by concomitant ingestion of propantheline. Antacids consisting
of aluminum and magnesium hydroxides with simethicone
decrease the absorption of nizatidine by about 10%. With
food, the AUC and Cmax increase by approximately 10% .
In humans, less than 7% of an oral dose is metabolized
as N2-monodes- methylnizatidine, an H2-receptor antagonist,
which is the principal metabolite excreted in the urine.
Other likely metabolites are the N2-oxide (less than 5%
of the dose) and the S-oxide (less than 6% of the dose).
More than 90% of an oral dose of nizatidine is excreted
in the urine within 12 hours. About 60% of an oral dose
is excreted as unchanged drug. Renal clearance is about
500 ml/min, which indicates excretion by active tubular
secretion. Less than 6% of an administered dose is eliminated
in the feces.
Moderate to severe renal impairment significantly prolongs
the half-life and decreases the clearance of nizatidine.
In individuals who are functionally anephric, the half-life
is 3.5 to 11 hours, and the plasma clearance is 7 to 14
L/h. To avoid accumulation of the drug in individuals
with clinically significant renal impairment, the amount
and/or frequency of doses of nizatidine should be reduced
in proportion to the severity of dysfunction (see DOSAGE
AND ADMINISTRATION).
Approximately 35% of nizatidine is bound to plasma protein,
mainly to a1-acid glycoprotein. Warfarin, diazepam, acetaminophen,
propantheline, phenobarbital, and propranolol did not
affect plasma protein binding of nizatidine in vitro.
CLINICAL STUDIES
Active Duodenal Ulcer
In multicenter, double-blind, placebo-controlled studies
in the United States, endoscopically diagnosed duodenal
ulcers healed more rapidly following administration of
nizatidine, 300 mg h.s. or 150 mg b.i.d., than with placebo
(TABLE 2). Lower doses, such as 100 mg h.s., had slightly
lower effectiveness.
TABLE 2 Healing Response of Ulcers to Nizatidine
|
| |
300 mg h.s. |
150 mg b.i.d. |
Placebo |
| |
Number Entered |
Healed/ Evaluable |
Number Entered |
Healed/ Evaluable |
Number Entered |
Healed/ Evaluable |
| STUDY 1 |
| Week 2 |
|
|
276 |
93/265 (35%)* |
279 |
55/260 (21%) |
| Week 4 |
|
|
|
198/259 (76%)* |
|
95/243 (39%) |
| STUDY 2 |
| Week 2 |
108 |
24/103 (23%)* |
106 |
27/101 (27%)* |
101 |
9/93 (10%) |
| Week 4 |
|
65/97 (67%)* |
|
66/97 (68%)* |
|
24/84 (29%) |
| STUDY 3 |
| Week 2 |
92 |
22/90 (24%)† |
|
|
98 |
13/92 (14%) |
| Week 4 |
|
52/85 (61%)* |
|
|
|
29/88 (33%) |
| Week 8 |
|
68/83 (82%)* |
|
|
|
39/79 (49%) |
| * P
<0.01 as compared with placebo. |
| † P
<0.05 as compared with placebo. |
Maintenance of Healed Duodenal Ulcer
Treatment with a reduced dose of nizatidine has been shown
to be effective as maintenance therapy following healing
of active duodenal ulcers. In multicenter, double-blind,
placebo-controlled studies conducted in the United States,
150 mg of nizatidine taken at bedtime resulted in a significantly
lower incidence of duodenal ulcer recurrence in patients
treated for up to 1 year (TABLE 3).
| TABLE 3
Percentage of Ulcers Recurring by 3, 6, and 12 Months
in Double-Blind Studies Conducted in the United
States |
| Month |
Axid, 150 mg h.s. |
Placebo |
| 3 |
13% (28/208)* |
40% (82/204) |
| 6 |
24% (45/188)* |
57% (106/187) |
| 12 |
34% (57/166)* |
64% (112/175) |
| * P
<0.001 as compared with placebo. |
Gastroesophageal Reflux Disease (GERD):
In 2 multicenter, double-blind, placebo-controlled
clinical trials performed in the United States and Canada,
nizatidine was more effective than placebo in improving
endoscopically diagnosed esophagitis and in healing erosive
and ulcerative esophagitis.
In patients with erosive or ulcerative esophagitis, 150
mg b.i.d. of nizatidine given to 88 patients compared with
placebo in 98 patients in Study 1 yielded a higher healing
rate at 3 weeks (16% vs 7%) and at 6 weeks (32% vs 16%,
P <0.05). Of 99 patients on nizatidine and 94 patients
on placebo, Study 2 at the same dosage yielded similar results
at 6 weeks (21% vs 11%, P < 0.05) and at 12 weeks (29%
vs 13%, P <0.01).
In addition, relief of associated heartburn was greater
in patients treated with nizatidine. Patients treated with
nizatidine consumed fewer antacids than did patients treated
with placebo.
Active Benign Gastric Ulcer
In a multicenter, double-blind, placebo-controlled
study conducted in the United States and Canada, endoscopically
diagnosed benign gastric ulcers healed significantly more
rapidly following administration of nizatidine than of placebo
(TABLE 4).
| TABLE 4 |
| Week |
Treatment |
Healing Rate |
vs. Placebo p-value* |
| 4 |
Niz 300 mg h.s. |
52/153 (34%) |
0.342 |
| |
Niz 150 mg b.i.d. |
65/151 (43%) |
0.022 |
| |
Placebo |
48/151 (32%) |
|
| 8 |
Niz 300 mg h.s. |
99/153 (65%) |
0.011 |
| |
Niz 150 mg b.i.d. |
105/151 (70%) |
<0.001 |
| |
Placebo |
78/151 (52%) |
|
| * P-values
are one-sided, obtained by Chi-square test, and
not adjusted for multiple comparisons. |
In a multicenter, double-blind, comparator-controlled study
in Europe, healing rates for patients receiving nizatidine
(300 mg h.s. or 150 mg b.i.d.) were equivalent to rates
for patients receiving a comparator drug, and statistically
superior to historical placebo control rates.
| |
