This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda

Black
PMS 1245
Non-varnish area inside
Label Size: 1 3/4” x 3 3/4”

Store at controlled room
temperature 20° to 25°C
(68° to 77°F) [see USP].
Manufactured for:Reliant Pharmaceuticals, Inc.
Liberty Corner, NJ 07938
by:Patheon Pharmaceuticals Inc.
Cincinnati, OH 45237

AXID

®

(nizatidine)
Capsules, USP

150 mgRx only
60 PULVULES

®

EXP.

Keep tightly closed.

NDC 65726-144-15

LOT

Usual Adult Dose:See accompanying literaturefor dosage.

1514M400

This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
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12:03 PM

Page 1

AXID®

(nizatidine) Capsules, USP®

2143400

214F400

DESCRIPTION
Axid® (Nizatidine, USP) is a histamine H2-receptor antagonist.
Chemically, it is N-[2-[[[2-[(dimethylamino)methyl]-4-thiazolyl]methyl]thio]ethyl]-Nı-methyl-2-nitro-1,1-ethenediamine.
The structural formula is as follows:

Nizatidine
Nizatidine has the empirical formula C12H21N5O2S2 representing amolecular weight of 331.47. It is an off-white to buff crystalline solidthat is soluble in water. Nizatidine has a bitter taste and mild sulfurlike odor. Each Pulvule® (capsule) contains for oral administration
gelatin, pregelatinized starch, dimethicone, starch, titanium dioxide,
yellow iron oxide, 150 mg (0.45 mmol) or 300 mg (0.91 mmol) of
nizatidine, and other inactive ingredients. The 150-mg Pulvule also
contains magnesium stearate, and the 300-mg Pulvule also contains
croscarmellose sodium, povidone, red iron oxide, and talc.
CLINICAL PHARMACOLOGY
Axid is a competitive, reversible inhibitor of histamine at the histamine H2-receptors, particularly those in the gastric parietal cells.
Antisecretory Activity —1. Effects on Acid Secretion: Axid significantly inhibited nocturnal gastric acid secretion for up to 12 hours.
Axid also significantly inhibited gastric acid secretion stimulated byfood, caffeine, betazole, and pentagastrin (Table 1).
Table 1
Effect of Oral Axid on Gastric Acid Secretion
Time After
Dose (h)% Inhibition of Gastric Acid
Output by Dose (mg)20-50

Nocturnal
Betazole
Pentagastrin
Meal
Caffeine

Up to 10
Up to 3Up to 6Up to 4Up to 3

75

57

100

150

300

100
64
98
85

90
99
67
97
96

73
93
25
64
73

41

2. Effects on Other Gastrointestinal Secretions —Pepsin: Oraladministration of 75 to 300 mg of Axid did not affect pepsin activity ingastric 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 Axid
increased betazole-stimulated secretion of intrinsic factor.
Serum Gastrin: Axid had no effect on basal serum gastrin. No
rebound of gastrin secretion was observed when food was ingested
12 hours after administration of Axid.
3. Other Pharmacologic Actions—a. Hormones: Axid was not shown to affect the serum concentrations of gonadotropins, prolactin, growth hormone, antidiuretic hormone, cortisol, triiodothyronine, thyroxin, testosterone, 5α-dihydrotestosterone, androstenedione, or
estradiol.
b. Axid had no demonstrable antiandrogenic action.
4. Pharmacokinetics—The absolute oral bioavailability of nizatidine exceeds 70%. Peak plasma concentrations (700 to 1,800 µg/L
for a 150-mg dose and 1,400 to 3,600 µg/L for a 300-mg dose) occur
from 0.5 to 3 hours following the dose. A concentration of 1,000 µg/L
is equivalent to 3 µmol/L; a dose of 300 mg is equivalent to905 µmoles. Plasma concentrations 12 hours after administration
are less than 10 µg/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. Axid exhibits dose proportionality
over the recommended dose range.
The oral bioavailability of nizatidine is unaffected by concomitantingestion of propantheline. Antacids consisting of aluminum andmagnesium hydroxides with simethicone decrease the absorption of
nizatidine by about 10%. With food, the AUC and Cmax increase byapproximately 10%.
In humans, less than 7% of an oral dose is metabolized as N2monodes-methylnizatidine, an H2-receptor antagonist, which is theprincipal metabolite excreted in the urine. Other likely metabolites
are the N2-oxide (less than 5% of the dose) and the S-oxide (lessthan 6% of the dose).
More than 90% of an oral dose of nizatidine is excreted in theurine 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 thehalf-life and decreases the clearance of nizatidine. In individuals who
are functionally anephric, the half-life is 3.5 to 11 hours, and theplasma clearance is 7 to 14 L/h. To avoid accumulation of the drugin individuals with clinically significant renal impairment, the amountand/or frequency of doses of Axid 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 α 1 -acid glycoprotein. Warfarin, diazepam, acetaminophen,
propantheline, phenobarbital, and propranolol did not affect plasma
protein binding of nizatidine in vitro.
Clinical Trials —1. Active Duodenal Ulcer: In multicenter, doubleblind, placebo-controlled studies in the United States, endoscopicallydiagnosed duodenal ulcers healed more rapidly following administration of Axid, 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 Axid
AXID
300 mg h.s.
NumberEnteredSTUDY 1
Week 2
Week 4STUDY 2
Week 2
Week 4STUDY 3
Week 2
Week 4
Week 8150 mg b.i.d.

Healed/Evaluable

108

24/103 (23%)*
65/97 (67%)*92

22/90 (24%)†52/85 (61%)*
68/83 (82%)*

PlaceboNumberEnteredHealed/Evaluable

NumberEnteredHealed/Evaluable

276

93/265 (35%)*
198/259 (76%)*279

55/260 (21%)
95/243 (39%)

106

27/101 (27%)*
66/97 (68%)*101

9/93 (10%)
24/84 (29%)

98

13/92 (14%)
29/88 (33%)
39/79 (49%)*P <0.01 as compared with placebo.
†P <0.05 as compared with placebo.

2. Maintenance of Healed Duodenal Ulcer:
Treatment with a reduced dose of Axid has been shown to beeffective as maintenance therapy following healing of active duodenal ulcers. In multicenter, double-blind, placebo-controlled studies
conducted in the United States, 150 mg of Axid 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
MonthAxid, 150 mg h.s.

Placebo361213% (28/208)*
24% (45/188)*
34% (57/166)*

40% (82/204)
57% (106/187)
64% (112/175)*P <0.001 as compared with placebo.

3. Gastroesophageal Reflux Disease (GERD):
In 2 multicenter, double-blind, placebo-controlled clinical trials performed in the United States and Canada, Axid was more effective
than placebo in improving endoscopically diagnosed esophagitis andin healing erosive and ulcerative esophagitis.
In patients with erosive or ulcerative esophagitis, 150 mg b.i.d. of
Axid given to 88 patients compared with placebo in 98 patients inStudy 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 Axid 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 patientstreated with Axid. Patients treated with Axid consumed fewer
antacids than did patients treated with placebo.
4. Active Benign Gastric Ulcer:
In a multicenter, double-blind, placebo-controlled study conductedin the United States and Canada, endoscopically diagnosed benign
gastric ulcers healed significantly more rapidly following administration of nizatidine than of placebo (Table 4).

Week

Treatment

Table 4
Healing Rate4

Niz 300 mg h.s.
Niz 150 mg b.i.d.
PlaceboNiz 300 mg h.s.
Niz 150 mg b.i.d.
Placebo

52/153 (34%)
65/151 (43%)
48/151 (32%)
99/153 (65%)
105/151 (70%)
78/151 (52%)

8

vs. Placebo
p-value*
0.342
0.022
0.011
<0.001*P-values are one-sided, obtained by Chi-square test, and not adjusted for
multiple comparisons.

In a multicenter, double-blind, comparator-controlled study inEurope, healing rates for patients receiving nizatidine (300 mg h.s.
or 150 mg b.i.d.) were equivalent to rates for patients receiving acomparator drug, and statistically superior to historical placebo control rates.
INDICATIONS AND USAGE
Axid is indicated for up to 8 weeks for the treatment of active duodenal ulcer. In most patients, the ulcer will heal within 4 weeks.
Axid is indicated for maintenance therapy for duodenal ulcer
patients, at a reduced dosage of 150 mg h.s. after healing of anactive duodenal ulcer. The consequences of continuous therapy with
Axid for longer than 1 year are not known.
Axid is indicated for up to 12 weeks for the treatment of endoscopically diagnosed esophagitis, including erosive and ulcerativeesophagitis, and associated heartburn due to GERD.
Axid is indicated for up to 8 weeks for the treatment of active
benign gastric ulcer. Before initiating therapy, care should be taken
to exclude the possibility of malignant gastric ulceration.
CONTRAINDICATION
Axid is contraindicated in patients with known hypersensitivity to
the drug. Because cross sensitivity in this class of compounds has
been observed, H2-receptor antagonists, including Axid, should not
be administered to patients with a history of hypersensitivity to other
H2-receptor antagonists.
PRECAUTIONSGeneral —1. Symptomatic response to nizatidine therapy does notpreclude the presence of gastric malignancy.
2. Because nizatidine is excreted primarily by the kidney, dosage
should be reduced in patients with moderate to severe renal insufficiency (see Dosage and Administration).
3. Pharmacokinetic studies in patients with hepatorenal syndrome
have not been done. Part of the dose of nizatidine is metabolized in
the liver. In patients with normal renal function and uncomplicatedhepatic dysfunction, the disposition of nizatidine is similar to that innormal subjects.
Laboratory Tests — False-positive tests for urobilinogen with
Multistix ® may occur during therapy with nizatidine.
Drug Interactions — No interactions have been observed between
Axid and theophylline, chlordiazepoxide, lorazepam, lidocaine,
phenytoin, and warfarin. Axid does not inhibit the cytochrome P-450linked drug-metabolizing enzyme system; therefore, drug interactions mediated by inhibition of hepatic metabolism are not expected
to occur. In patients given very high doses (3,900 mg) of aspirin daily,
increases in serum salicylate levels were seen when nizatidine,
150 mg b.i.d., was administered concurrently.
Carcinogenesis, Mutagenesis, Impairment of Fertility — A 2-year
oral carcinogenicity study in rats with doses as high as
500 mg/kg/day (about 80 times the recommended dailyt h e r a p e u t i c d o s e ) showed no evidence of a carcinogenic effect.
There was a dose-related increase in the density of enterochromaffin-like (ECL) cells in the gastric oxyntic mucosa. In a 2-year study inmice, there was no evidence of a carcinogenic effect in male mice;although hyperplastic nodules of the liver were increased in the highdose males as compared with placebo. Female mice given the highdose of Axid (2,000 mg/kg/day, about 330 times the human dose)
showed marginally statistically significant increases in hepatic carcinoma and hepatic nodular hyperplasia with no numerical increase
seen in any of the other dose groups. The rate of hepatic carcinoma
in the high-dose animals was within the historical control limits seen
for the strain of mice used. The female mice were given a dose larger
than the maximum tolerated dose, as indicated by excessive (30%)
weight decrement as compared with concurrent controls and evidence of mild liver injury (transaminase elevations). The occurrenceof a marginal finding at high dose only in animals given an excessive
and somewhat hepatotoxic dose, with no evidence of a carcinogenic
effect in rats, male mice, and female mice (given up to
360 mg/kg/day, about 60 times the human dose), and a negative
mutagenicity battery are not considered evidence of a carcinogenic
potential for Axid.
Axid was not mutagenic in a battery of tests performed to evaluate
its potential genetic toxicity, including bacterial mutation tests,
unscheduled DNA synthesis, sister chromatid exchange, mouse lymphoma assay, chromosome aberration tests, and a micronucleus
test.
In a 2-generation, perinatal and postnatal fertility study in rats,
doses of nizatidine up to 650 mg/kg/day produced no adverse
effects on the reproductive performance of parental animals or theirprogeny.
Pregnancy —Teratogenic Effects —Pregnancy Category B — Oralreproduction studies in pregnant rats at doses up to 1500 mg/kg/day(9000 mg/m2/day, 40.5 times the recommended human dose basedon body surface area) and in pregnant rabbits at doses up to
275 mg/kg/day (3245 mg/m2/day, 14.6 times the recommended
human dose based on body surface area) have revealed no evidence of impaired fertility or harm to the fetus due to nizatidine.
There are, however, no adequate and well-controlled studies inpregnant women. Because animal reproduction studies are notalways predictive of human response, this drug should be used during pregnancy only if clearly needed.
Nursing Mothers — Studies conducted in lactating women haveshown that 0.1% of the administered oral dose of nizatidine issecreted in human milk in proportion to plasma concentrations.
Because of the growth depression in pups reared by lactating rats
treated with nizatidine, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account theimportance of the drug to the mother.
Pediatric Use — Safety and effectiveness in pediatric patients havenot been established.

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For current labeling information, please visit https://www.fda.gov/drugsatfda
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Page 2

AXID®

(nizatidine) Capsules, USP
Geriatric Use — Of the 955 patients in clinical studies who weretreated with nizatidine, 337 (35.3%) were 65 and older. No overall
differences in safety or effectiveness were observed between theseand younger subjects. Other reported clinical experience has not
identified differences in responses between the elderly and younger
patients, but greater sensitivity of some older individuals cannot be
ruled out.
This drug is known to be substantially excreted by the kidney, andthe risk of toxic reactions to this drug may be greater in patients with
impaired renal function. Because elderly patients are more likely tohave decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function (see Dosage andAdministration).
ADVERSE REACTIONSWorldwide, controlled clinical trials of nizatidine included over
6,000 patients given nizatidine in studies of varying durations. Placebocontrolled trials in the United States and Canada included over 2,600
patients given nizatidine and over 1,700 given placebo. Among theadverse events in these placebo-controlled trials, anemia (0.2% vs0%) and urticaria (0.5% vs 0.1%) were significantly more common in
the nizatidine group.
Incidence in Placebo-Controlled Clinical Trials in the UnitedStates and Canada —Table 5 lists adverse events that occurred at afrequency of 1% or more among nizatidine-treated patients who participated in placebo-controlled trials. The cited figures provide somebasis for estimating the relative contribution of drug and nondrug factors to the side effect incidence rate in the population studied.
Table 5
INCIDENCE OF TREATMENT-EMERGENTADVERSE EVENTS IN PLACEBO-CONTROLLED
CLINICAL TRIALSIN THE UNITED STATES AND CANADA
Percentage of Patients Reporting Event
Body System/Adverse Event* Nizatidine(N=2,694) Placebo(N=1,729)
Body as a Whole
Headache
Abdominal pain
Pain
Asthenia
Back pain
Chest pain
Infection
Fever
Surgical procedure
Injury, accident
Digestive
Diarrhea
NauseaFlatulence
Vomiting
Dyspepsia
Constipation
Dry mouth
Nausea and vomiting
Anorexia
Gastrointestinal disorder
Tooth disorder
Musculoskeletal
Myalgia
NervousDizziness
Insomnia
Abnormal dreams
SomnolenceAnxiety
Nervousness
Respiratory
RhinitisPharyngitis
Sinusitis
Cough, increased
Skin and Appendages
Rash
Pruritus
Special Senses
Amblyopia

16.6
7.5
4.2
3.1
2.4
2.3
1.7
1.6
1.4
1.2

15.6
12.5
3.8
2.9
2.6
2.1
1.1
2.3
1.5
0.9

7.2
5.4
4.9
3.6
3.6
2.5
1.4
1.2
1.2
1.1
1.0

6.9
7.4
5.4
5.6
4.4
3.8
1.3
1.9
1.6
1.2
0.8

1.7

1.5

4.6
2.7
1.9
1.9
1.6
1.1

3.8
3.4
1.9
1.6
1.4
0.8

9.8
3.3
2.4
2.0

9.6
3.1
2.1
2.0

1.9
1.7

2.1
1.3

1.0

0.9

*Events reported by at least 1% of nizatidine-treated patients are included.

A variety of less common events were also reported; it was notpossible to determine whether these were caused by nizatidine.
Hepatic — Hepatocellular injury, evidenced by elevated liver
enzyme tests (SGOT [AST], SGPT [ALT], or alkaline phosphatase),occurred in some patients and was possibly or probably related tonizatidine. In some cases there was marked elevation of SGOT,
SGPT enzymes (greater than 500 IU/L) and, in a single instance,
SGPT was greater than 2,000 IU/L. The overall rate of occurrencesof elevated liver enzymes and elevations to 3 times the upper limit of
normal, however, did not significantly differ from the rate of liver
enzyme abnormalities in placebo-treated patients. All abnormalities
were reversible after discontinuation of Axid. Since market introduction, hepatitis and jaundice have been reported. Rare cases ofcholestatic or mixed hepatocellular and cholestatic injury with jaundice have been reported with reversal of the abnormalities after discontinuation of Axid.
Cardiovascular — In clinical pharmacology studies, short episodesof asymptomatic ventricular tachycardia occurred in 2 individuals
administered Axid and in 3 untreated subjects.
CNS — Rare cases of reversible mental confusion have beenreported.
Endocrine — Clinical pharmacology studies and controlled clinical
trials showed no evidence of antiandrogenic activity due to Axid.
Impotence and decreased libido were reported with similar frequency
by patients who received Axid and by those given placebo. Rarereports of gynecomastia occurred.
Hematologic — Anemia was reported significantly more frequently
in nizatidine- than in placebo-treated patients. Fatal thrombocytopenia was reported in a patient who was treated with Axid and another
H2-receptor antagonist. On previous occasions, this patient had
experienced thrombocytopenia while taking other drugs. Rare casesof thrombocytopenic purpura have been reported.
Integumental — Sweating and urticaria were reported significantly
more frequently in nizatidine- than in placebo-treated patients. Rashand exfoliative dermatitis were also reported. Vasculitis has beenreported rarely.
Hypersensitivity — As with other H2-receptor antagonists, rare casesof anaphylaxis following administration of nizatidine have beenreported. Rare episodes of hypersensitivity reactions (eg, bronchospasm, laryngeal edema, rash, and eosinophilia) have beenreported.
Body as a Whole — Serum sickness-like reactions have occurredrarely in conjunction with nizatidine use.
Genitourinary — Reports of impotence have occurred.
Other — Hyperuricemia unassociated with gout or nephrolithiasis
was reported. Eosinophilia, fever, and nausea related to nizatidine
administration have been reported.
OVERDOSAGE
Overdoses of Axid have been reported rarely. The following is provided to serve as a guide should such an overdose be encountered.
Signs and Symptoms —There is little clinical experience with overdosage of Axid in humans. Test animals that received large doses ofnizatidine have exhibited cholinergic-type effects, including lacrimation, salivation, emesis, miosis, and diarrhea. Single oral doses of
800 mg/kg in dogs and of 1,200 mg/kg in monkeys were not lethal.
Intravenous median lethal doses in the rat and mouse were
301 mg/kg and 232 mg/kg respectively.
Treatment —To obtain up-to-date information about the treatmentof overdose, a good resource is your certified Regional Poison Control Center. Telephone numbers of certified poison control centers
are listed in the Physicians’ Desk Reference (PDR). In managing
overdosage, consider the possibility of multiple drug overdoses,interaction among drugs, and unusual drug kinetics in your patient.
If overdosage occurs, use of activated charcoal, emesis, or lavage
should be considered along with clinical monitoring and supportive
therapy. The ability of hemodialysis to remove nizatidine from thebody has not been conclusively demonstrated; however, due to its
large volume of distribution, nizatidine is not expected to be efficiently
removed from the body by this method.
DOSAGE AND ADMINISTRATION
Active Duodenal Ulcer —The recommended oral dosage for adults
is 300 mg once daily at bedtime. An alternative dosage regimen is
150 mg twice daily.
Maintenance of Healed Duodenal Ulcer —The recommended oral
dosage for adults is 150 mg once daily at bedtime.
Gastroesophageal Reflux Disease —The recommended oral
dosage in adults for the treatment of erosions, ulcerations, and associated heartburn is 150 mg twice daily.
Active Benign Gastric Ulcer —The recommended oral dosage is
300 mg given either as 150 mg twice daily or 300 mg once daily at
bedtime. Prior to treatment, care should be taken to exclude the possibility of malignant gastric ulceration.
Dosage Adjustment for Patients With Moderate to Severe Renal
Insufficiency —The dose for patients with renal dysfunction should
be reduced as follows:
Active Duodenal Ulcer, GERD and Benign Gastric Ulcer
Ccr
Dose
20-50 mL/min
150 mg daily<20 mL/min
150 mg every other day
Maintenance Therapy
Ccr
Dose
20-50 mL/min
150 mg every other day<20 mL/min
150 mg every 3 days
Some elderly patients may have creatinine clearances of less than
50 mL/min, and, based on pharmacokinetic data in patients withrenal impairment, the dose for such patients should be reduced
accordingly. The clinical effects of this dosage reduction in patientswith renal failure have not been evaluated.
HOW SUPPLIED
Axid® Pulvules®* are available in:
The 150-mg Pulvules are imprinted with “150” on the opaque dark
yellow cap and “AXID” and “Reliant” on the opaque pale yellow
body, using black ink. They are available as follows:
Bottles of 60
NDC 65726-144-15
The 300-mg Pulvules are imprinted with “300” on the opaque brown
cap and “AXID” and “Reliant” on the opaque pale yellow body, using
black ink. They are available as follows:
Bottles of 30
NDC 65726-145-10*Pulvules® (filled gelatin capsules, Lilly)

Store at controlled room temperature 20° to 25°C (68° to 77°F) ina tightly closed container [see USP].
The USP defines controlled room temperature as: A temperature
maintained thermostatically that encompasses the usual and customary working environment of 20° to 25°C (68° to 77°F); that
results in a mean kinetic temperature calculated to be not morethan 25°C; and that allows for excursions between 15° and 30°C
(59° and 86°F) that are experienced in pharmacies, hospitals, andwarehouses.

Rx Only
March 2005

Distributed by:
Reliant Pharmaceuticals, Inc.
Liberty Corner, NJ 07938, USA
Address Medical Inquiries to:
Reliant Pharmaceuticals, Inc.
Medical Affairs
110 Allen Road
Liberty Corner, NJ 07938, USA© 2005 Reliant Pharmaceuticals, Inc.
214F400

PRINTED IN U.S.A.

This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda

AXID®

AXID®

AXID®

Description: Axid® (Nizatidine, USP) is a histamine H2receptor antagonist. Chemically, it is N-[2-[[[2[(dimethylamino)methyl]-4-thiazolyl]methyl]thio]ethyl]-N'methyl-2-nitro-1,1-ethenediamine.
The structural formula is as follows: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 clinicallysignificant renal impairment, the amount and/or frequency ofdoses of Axid should be reduced in proportion to the severityof dysfunction (see Dosage and Administration).
Approximately 35% of nizatidine is bound to plasma
protein, mainly to α1-acid glycoprotein. Warfarin, diazepam,
acetaminophen, propantheline, phenobarbital, and propranolol did not affect plasma protein binding of nizatidine in vitro.
Clinical Trials —1. Active Duodenal Ulcer: In multicenter,double-blind, placebo-controlled studies in the UnitedStates, endoscopically diagnosed duodenal ulcers healed
more rapidly following administration of Axid, 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.

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 tohistorical placebo control rates.

(nizatidine) Capsules, USP(nizatidine) Capsules, USP

Nizatidine has the empirical formula C 12H 21N 5O 2S 2
representing a molecular weight of 331.47. It is an off-white
to buff crystalline solid that is soluble in water. Nizatidine
has a bitter taste and mild sulfur-like odor. Each Pulvule®
(capsule) contains for oral administration gelatin, pregelatinized starch, dimethicone, starch, titanium dioxide, yellow
iron oxide, 150 mg (0.45 mmol) or 300 mg (0.91 mmol) of
nizatidine, and other inactive ingredients. The 150-mg
Pulvule also contains magnesium stearate, and the 300-mg
Pulvule also contains croscarmellose sodium, povidone,
red iron oxide, and talc.
Clinical Pharmacology: Axid is a competitive, reversible
inhibitor of histamine at the histamine H 2-receptors,
particularly those in the gastric parietal cells.
Antisecretory Activity—1. Effects on Acid Secretion: Axid
significantly inhibited nocturnal gastric acid secretion for
up to 12 hours. Axid also significantly inhibited gastric acidsecretion stimulated by food, caffeine, betazole, and pentagastrin (Table 1).
Table 1.—Effect of Oral Axid on Gastric Acid Secretion
Time After
Dose (h)Nocturnal
Betazole
Pentagastrin
Meal
Caffeine

Up to 10
Up to 3Up to 6Up to 4Up to 3

% Inhibition of Gastric Acid
Output by Dose (mg)20-50 75 100 150 300
57
73
90
93
100 99
25
64 67
41
64
98 97
73
85 96

2. Effects on Other Gastrointestinal Secretions—Pepsin:
Oral administration of 75 to 300 mg of Axid did not affectpepsin activity in gastric secretions. Total pepsin output was
reduced in proportion to the reduced volume of gastricsecretions.
Intrinsic Factor: Oral administration of 75 to 300 mg of Axid
increased betazole-stimulated secretion of intrinsic factor.
Serum Gastrin: Axid had no effect on basal serum gastrin.
No rebound of gastrin secretion was observed when food
was ingested 12 hours after administration of Axid.
3. Other Pharmacologic Actions—a. Hormones: Axid was not shown to affect the serum
concentrations of gonadotropins, prolactin, growth
hormone, antidiuretic hormone, cortisol, triiodothyronine, thyroxin, testosterone, 5α-dihydrotestosterone, androstenedione, or estradiol.
b. Axid had no demonstrable antiandrogenic action.
4. Pharmacokinetics—The absolute oral bioavailability ofnizatidine exceeds 70%. Peak plasma concentrations (700
to 1,800 µg/L for a 150-mg dose and 1,400 to 3,600 µg/L for
a 300-mg dose) occur from 0.5 to 3 hours following thedose. A concentration of 1,000 µg/L is equivalent to 3 µmol/L;a dose of 300 mg is equivalent to 905 µmoles. Plasma
concentrations 12 hours after administration are less than
10 µg/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. Axid exhibits dose proportionality over the recommended dose range.
The oral bioavailability of nizatidine is unaffected byconcomitant ingestion of propantheline. Antacids consistingof 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-monodesmethylnizatidine, an H 2 -receptor
antagonist, which is the principal metabolite excreted in theurine. Other likely metabolites are the N2-oxide (less than
5% of the dose) and the S-oxide (less than 6% of the dose).

(nizatidine) Capsules, USP

Table 2.—Healing Response of Ulcers to Axid
Axid
Placebo
300 mg h.s.
150 mg b.i.d.
NumberHealed/NumberHealed/NumberHealed/EnteredEvaluable
EnteredEvaluable
EnteredEvaluable
STUDY 1
Week 2276 93/265 (35%)*
279 55/260 (21%)
95/243 (39%)
Week 4
198/259 (76%)*
STUDY 2
Week 2 108
24/103 (23%)* 106 27/101 (27%)*101
9/93 (10%)
Week 465/97 (67%)*
66/97 (68%)*
24/84 (29%)
STUDY 3
Week 2 92
22/90 (24%)†98
13/92 (14%)
29/88 (33%)
Week 452/85 (61%)*
39/79 (49%)
Week 868/83 (82%)*†P<0.05 as compared with placebo.
*P<0.01 as compared with placebo.

2. Maintenance of Healed Duodenal Ulcer: Treatment
with a reduced dose of Axid has been shown to be effective
as maintenance therapy following healing of active
duodenal ulcers. In multicenter, double-blind, placebocontrolled studies conducted in the United States, 150 mg
of Axid taken at bedtime resulted in a significantly lower
incidence of duodenal ulcer recurrence in patients treatedfor 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
MonthAxid, 150 mg h.s.
Placebo3
13% (28/208)*
40% (82/204)
624% (45/188)*
57% (106/187)
1234% (57/166)*
64% (112/175)*P<0.001 as compared with placebo.

3. Gastroesophageal Reflux Disease (GERD): In 2 multicenter, double-blind, placebo-controlled clinical trials
performed in the United States and Canada, Axid was more
effective than placebo in improving endoscopicallydiagnosed esophagitis and in healing erosive andulcerative esophagitis.
In patients with erosive or ulcerative esophagitis, 150 mg
b.i.d. of Axid 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 Axid 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 inpatients treated with Axid. Patients treated with Axid consumed fewer antacids than did patients treated with placebo.
4. Active Benign Gastric Ulcer: In a multicenter, doubleblind, placebo-controlled study conducted in the UnitedStates and Canada, endoscopically diagnosed benign
gastric ulcers healed significantly more rapidly following
administration of nizatidine than of placebo (Table 4).
Table 4.
Week
48Treatment

Healing Rate

Niz 300 mg h.s.
52/153 (34%)
Niz 150 mg b.i.d. 65/151 (43%)
Placebo
48/151 (32%)
Niz 300 mg h.s.
99/153 (65%)
Niz 150 mg b.i.d. 105/151 (70%)
Placebo
78/151 (52%)

vs. Placebo
p-value*
0.342
0.022
0.011
<0.001*P-values are one-sided, obtained by Chi-square test, and not adjusted for
multiple comparisons.

Indications and Usage: Axid is indicated for up to 8 weeks
for the treatment of active duodenal ulcer. In most patients,
the ulcer will heal within 4 weeks.
Axid is indicated for maintenance therapy for duodenal
ulcer patients at a reduced dosage of 150 mg h.s. after
healing of an active duodenal ulcer. The consequences ofcontinuous therapy with Axid for longer than 1 year are
not known.
Axid is indicated for up to 12 weeks for the treatment ofendoscopically diagnosed esophagitis, including erosive
and ulcerative esophagitis, and associated heartburn due
to GERD.
Axid is indicated for up to 8 weeks for the treatment ofactive benign gastric ulcer. Before initiating therapy, careshould be taken to exclude the possibility of malignant
gastric ulceration.
Contraindication: Axid is contraindicated in patients withknown hypersensitivity to the drug. Because cross sensitivity in this class of compounds has been observed, H2receptor antagonists, including Axid, should not be
administered to patients with a history of hypersensitivity toother H2-receptor antagonists.
Precautions: General —1. Symptomatic response to
nizatidine therapy does not preclude the presence ofgastric malignancy.
2. Because nizatidine is excreted primarily by the kidney,
dosage should be reduced in patients with moderate tosevere renal insufficiency (see Dosage and Administration).
3. Pharmacokinetic studies in patients with hepatorenal
syndrome have not been done. Par t of the dose of
nizatidine is metabolized in the liver. In patients with normal
renal function and uncomplicated hepatic dysfunction, thedisposition of nizatidine is similar to that in normal subjects.
Laboratory Tests —False-positive tests for urobilinogenwith Multistix® may occur during therapy with nizatidine.
Drug Interactions —No interactions have been observed
between Axid and theophylline, chlordiazepoxide,lorazepam, lidocaine, phenytoin, and warfarin. Axid does
not inhibit the cytochrome P-450-linked drug-metabolizing
enzyme system; therefore, drug interactions mediated byinhibition of hepatic metabolism are not expected to occur.
In patients given very high doses (3,900 mg) of aspirin
daily, increases in serum salicylate levels were seen when
nizatidine, 150 mg b.i.d., was administered concurrently.
Carcinogenesis, Mutagenesis, Impairment of Fertility—A
2-year oral carcinogenicity study in rats with doses as highas 500 mg/kg/day (about 80 times the recommended daily
therapeutic dose) showed no evidence of a carcinogenic
effect. There was a dose-related increase in the density ofenterochromaffin-like (ECL) cells in the gastric oxyntic
mucosa. In a 2-year study in mice, there was no evidenceof a carcinogenic effect in male mice; although hyperplastic
nodules of the liver were increased in the high-dose males
as compared with placebo. Female mice given the highdose of Axid (2,000 mg/kg/day, about 330 times the humandose) showed marginally statistically significant increases
in hepatic carcinoma and hepatic nodular hyperplasia withno numerical increase seen in any of the other dosegroups. The rate of hepatic carcinoma in the high-doseanimals was within the historical control limits seen for thestrain of mice used. The female mice were given a doselarger than the maximum tolerated dose, as indicated byexcessive (30%) weight decrement as compared withconcurrent controls and evidence of mild liver injury(transaminase elevations). The occurrence of a marginal
finding at high dose only in animals given an excessive andsomewhat hepatotoxic dose, with no evidence of a
carcinogenic effect in rats, male mice, and female mice
(given up to 360 mg/kg/day, about 60 times the humandose), and a negative mutagenicity battery are notconsidered evidence of a carcinogenic potential for Axid.
Axid was not mutagenic in a battery of tests performed toevaluate its potential genetic toxicity, including bacterial
mutation tests, unscheduled DNA synthesis, sister
chromatid exchange, mouse lymphoma assay, chromosome aberration tests, and a micronucleus test.
In a 2-generation, perinatal and postnatal fertility study inrats, doses of nizatidine up to 650 mg/kg/day produced noadverse effects on the reproductive performance ofparental animals or their progeny.
Pregnancy—Teratogenic Effects—Pregnancy Category
B— Oral reproduction studies in pregnant rats at doses upThis label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda

AXID®

AXID®

AXID®

to 1500 mg/kg/day (9000 mg/m 2/day, 40.5 times therecommended human dose based on body surface area)
and in pregnant rabbits at doses up to 275 mg/kg/day (3245
mg/m2/day, 14.6 times the recommended human dose
based on body surface area) have revealed no evidence ofimpaired fertility or harm to the fetus due to nizatidine. There
are, however, no adequate and well-controlled studies inpregnant women. Because animal reproduction studies are
not always predictive of human response, this drug should
be used during pregnancy only if clearly needed.
Nursing Mothers — Studies conducted in lactating
women have shown that 0.1% of the administered oral
dose of nizatidine is secreted in human milk in proportion toplasma concentrations. Because of the growth depressionin pups reared by lactating rats treated with nizatidine, adecision should be made whether to discontinue nursing or
discontinue the drug, taking into account the importance ofthe drug to the mother.
Pediatric Use— Safety and effectiveness in pediatricpatients have not been established.
Geriatric Use— Of the 955 patients in clinical studies who
were treated with nizatidine, 337 (35.3%) were 65 andolder. No overall differences in safety or effectiveness wereobserved between these and younger subjects. Other
reported clinical experience has not identified differencesin responses between the elderly and younger patients,
but greater sensitivity of some older individuals cannot be
ruled out.
This drug is known to be substantially excreted by thekidney, and the risk of toxic reactions to this drug may begreater in patients with impaired renal function. Because
elderly patients are more likely to have decreased renal
function, care should be taken in dose selection, and it may
be useful to monitor renal function (see Dosage andAdministration).

A variety of less common events were also reported; it
was not possible to determine whether these were causedby nizatidine.
Hepatic—Hepatocellular injury, evidenced by elevatedliver enzyme tests (SGOT [AST], SGPT [ALT], or alkaline
phosphatase), occurred in some patients and was possiblyor probably related to nizatidine. In some cases, there wasmarked elevation of SGOT, SGPT enzymes (greater than
500 IU/L) and, in a single instance, SGPT was greater than
2,000 IU/L. The overall rate of occurrences of elevated liver
enzymes and elevations to 3 times the upper limit of
normal, however, did not significantly differ from the rate ofliver enzyme abnormalities in placebo-treated patients. All
abnormalities were reversible after discontinuation of Axid.
Since market introduction, hepatitis and jaundice havebeen repor ted. Rare cases of cholestatic or mixed
hepatocellular and cholestatic injury with jaundice havebeen reported with reversal of the abnormalities after
discontinuation of Axid.
Cardiovascular—In clinical pharmacology studies, shortepisodes of asymptomatic ventricular tachycardia occurredin 2 individuals administered Axid and in 3 untreated subjects.
CNS—Rare cases of reversible mental confusion havebeen reported.
Endocrine — Clinical pharmacology studies andcontrolled clinical trials showed no evidence ofantiandrogenic activity due to Axid. Impotence anddecreased libido were reported with similar frequency bypatients who received Axid and by those given placebo.
Rare reports of gynecomastia occurred.
Hematologic —Anemia was reported significantly more
frequently in nizatidine- than in placebo-treated patients.
Fatal thrombocytopenia was reported in a patient who wastreated with Axid and another H2-receptor antagonist. On
previous occasions, this patient had experienced thrombocytopenia while taking other drugs. Rare cases of thrombocytopenic purpura have been reported.
Integumental — Sweating and urticaria were reported
significantly more frequently in nizatidine- than in placebotreated patients. Rash and exfoliative dermatitis were also
reported. Vasculitis has been reported rarely.
Hypersensitivity — As with other H2-receptor antagonists,rare cases of anaphylaxis following administration of
nizatidine have been repor ted. Rare episodes ofhypersensitivity reactions (eg, bronchospasm, laryngeal
edema, rash, and eosinophilia) have been reported.
Body as a Whole—Serum sickness-like reactions haveoccurred rarely in conjunction with nizatidine use.
Genitourinary—Reports of impotence have occurred.
Other—Hyperuricemia unassociated with gout or nephrolithiasis was reported. Eosinophilia, fever, and nausea
related to nizatidine administration have been reported.

Dosage and Administration:
Active Duodenal Ulcer —The recommended oral dosage
for adults is 300 mg once daily at bedtime. An alternative
dosage regimen is 150 mg twice daily.
Maintenance of Healed Duodenal Ulcer —The recommended oral dosage for adults is 150 mg once daily at
bedtime.
Gastroesophageal Reflux Disease —The recommended
oral dosage in adults for the treatment of erosions, ulcerations, and associated heartburn is 150 mg twice daily.
Active Benign Gastric Ulcer—The recommended oral
dosage is 300 mg given either as 150 mg twice daily or 300
mg once daily at bedtime. Prior to treatment, care should betaken to exclude the possibility of malignant gastriculceration.
Dosage Adjustment for Patients With Moderate to
Severe Renal Insufficiency —The dose for patients withrenal dysfunction should be reduced as follows:
Active Duodenal Ulcer, GERD, and Benign Gastric Ulcer
Ccr
Dose
20-50 mL/min
150 mg daily<20 mL/min
150 mg every other day
Maintenance Therapy
Ccr
Dose
20-50 mL/min
150 mg every other day<20 mL/min
150 mg every 3 days
Some elderly patients may have creatinine clearances ofless than 50 mL/min, and, based on pharmacokinetic datain patients with renal impairment, the dose for such patientsshould be reduced accordingly. The clinical effects of thisdosage reduction in patients with renal failure have notbeen evaluated.

Overdosage: Overdoses of Axid have been reported
rarely. The following is provided to serve as a guide shouldsuch an overdose be encountered.
Signs and Symptoms —There is little clinical experience
with overdosage of Axid in humans. Test animals thatreceived large doses of nizatidine have exhibitedcholinergic-type effects, including lacrimation, salivation,
emesis, miosis, and diarrhea. Single oral doses of 800
mg/kg in dogs and of 1,200 mg/kg in monkeys were notlethal. Intravenous median lethal doses in the rat andmouse were 301 mg/kg and 232 mg/kg respectively.
Treatment —To obtain up-to-date information about thetreatment of overdose, a good resource is your certified
Regional Poison Control Center. Telephone numbers ofcertified poison control centers are listed in the Physicians’
Desk Reference (PDR). In managing overdosage, consider
the possibility of multiple drug overdoses, interaction
among drugs, and unusual drug kinetics in your patient.
If overdosage occurs, use of activated charcoal, emesis,or lavage should be considered along with clinicalmonitoring and suppor tive therapy. The ability ofhemodialysis to remove nizatidine from the body has notbeen conclusively demonstrated; however, due to its large
volume of distribution, nizatidine is not expected to beefficiently removed from the body by this method.

The USP defines controlled room temperature as: A
temperature maintained thermostatically that encompasses
the usual and customary working environment of 20° to
25°C (68° to 77°F); that results in a mean kinetic
temperature calculated to be not more than 25°C; and thatallows for excursions between 15° and 30°C (59° and 86°F)
that are experienced in pharmacies, hospitals, andwarehouses.

(nizatidine) Capsules, USP(nizatidine) Capsules, USP

Adverse Reactions: Worldwide, controlled clinical trials ofnizatidine included over 6,000 patients given nizatidine instudies of varying durations. Placebo-controlled trials in the
United States and Canada included over 2,600 patients
given nizatidine and over 1,700 given placebo. Among theadverse events in these placebo-controlled trials, anemia(0.2% vs 0%) and ur ticaria (0.5% vs 0.1%) weresignificantly more common in the nizatidine group.
Incidence in Placebo-Controlled Clinical Trials in the
United States and Canada —Table 5 lists adverse events
that occurred at a frequency of 1% or more among
nizatidine-treated patients who participated in placebocontrolled trials. The cited figures provide some basis for
estimating the relative contribution of drug and nondrug
factors to the side-effect incidence rate in the population
studied.
Table 5.
Incidence of Treatment-Emergent Adverse Events
in Placebo-Controlled Clinical Trials in
the United States and Canada

Body System/
Adverse Event*

Percentage ofPatients Reporting
Event
Nizatidine Placebo(N=2,694) (N=1,729)

Body as a Whole
Headache
16.6
Abdominal pain 7.5
Pain
4.2
Asthenia
3.1
Back pain
2.4
Chest pain
2.3
Infection
1.7
Fever
1.6
Surgicalprocedure
1.4
Injury, accident
1.2
Digestive
Diarrhea
7.2
Nausea5.4
Flatulence
4.9
Vomiting
3.6
Dyspepsia
3.6
Constipation
2.5
Dry mouth
1.4
Nausea andvomiting
1.2
Anorexia
1.2
Gastrointestinal
disorder1.1
Tooth disorder
1.0

15.6
12.5
3.8
2.9
2.6
2.1
1.1
2.3
1.5
0.9
6.9
7.4
5.4
5.6
4.4
3.8
1.3

Percentage ofPatients Reporting
Event
Body System/ Nizatidine Placebo
Adverse Event* (N=2,694) (N=1,729)
Musculoskeletal
Myalgia
1.7
1.5
NervousDizziness
4.6
3.8
Insomnia
2.7
3.4
Abnormal dreams 1.9
1.9
Somnolence
1.9
1.6
Anxiety
1.6
1.4
Nervousness
1.1
0.8
Respiratory
Rhinitis
9.8
9.6
Pharyngitis
3.3
3.1
Sinusitis
2.4
2.1
Cough, increased 2.0
2.0
Skin andAppendages
Rash
1.9
2.1
Pruritus
1.7
1.3
Special Senses
Amblyopia
1.0
0.9

1.9
1.6
1.2
0.8

*Events reported by at least 1% of nizatidine-treated patients are included.

(nizatidine) Capsules, USP

How Supplied:
Axid® Pulvules®* are available in:
The 150-mg Pulvules are imprinted with “150” on theopaque dark yellow cap and “AXID” and “Reliant” on theopaque pale yellow body, using black ink. They areavailable as follows:
Bottles of 60

NDC 65726-144-15

The 300-mg Pulvules are imprinted with “300” on theopaque brown cap and “AXID” and “Reliant” on the opaquepale yellow body, using black ink. They are available asfollows:
Bottles of 30
NDC 65726-145-10*Pulvules® (filled gelatin capsules, Lilly)
Store at controlled room temperature 20° to 25°C (68° to77°F) in a tightly closed container [see USP].

Rx Only
March 2005

Distributed by:
Reliant Pharmaceuticals, Inc.
Liberty Corner, NJ 07938, USA
Address Medical Inquiries to:
Reliant Pharmaceuticals, Inc.
Medical Affairs
110 Allen Road
Liberty Corner, NJ 07938, USA© 2005 Reliant Pharmaceuticals, Inc.
214R400

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