axid 300mg

DESCRIPTION
Axid® (Nizatidine, USP) is a histamine H 2 -receptor antagonist axid 300mg. Chemically,it is N-[2-[[[2-[(dimethylamino)methyl]-4- thiazolyl] methyl]thio]ethyl]-N'-methyl-2-nitro-1,1-ethene-diamine axid 300mg.

The structural formula is as follows:

Nizatidine

Nizatidine has the empirical formula C 12 H 21 N 5 O 2 S 2 representing a molecularweight of 331.47 axid 300mg. It is an off-white to buff crystalline solid that is solublein water axid 300mg. Nizatidine has a bitter taste and mild sulfur-like odor axid 300mg. 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 (0.91mmol) of nizatidine, and other inactive ingredients axid 300mg. The 150-mg Pulvule alsocontains magnesium stearate, and the 300-mg Pulvule also contains croscarmellosesodium, povidone, red iron oxide, and talc axid 300mg.

CLINICAL PHARMACOLOGY
Axid is a competitive, reversible inhibitor of histamine at the histamine H2 -receptors, particularly those in the gastric parietal cells axid 300mg.

Antisecretory Activity-- 1 axid 300mg. Effects on Acid Secretion: Axid significantly inhibitednocturnal gastric acid secretion for up to 12 hours axid 300mg. Axid also significantlyinhibited gastric acid secretion stimulated by food, caffeine, betazole, andpentagastrin (Table 1) axid 300mg.

Table 1
Effect of Oral Axid 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

2 axid 300mg. Effects on Other Gastrointestinal Secretions --Pepsin: Oral administrationof 75 to 300 mg of Axid did not affect pepsin activity in gastric secretions axid 300mg. Total pepsin output was reduced in proportion to the reduced volume of gastricsecretions axid 300mg.

Intrinsic Factor: Oral administration of 75 to 300 mg of Axid increased betazole-stimulatedsecretion of intrinsic factor axid 300mg.

Serum Gastrin: Axid had no effect on basal serum gastrin axid 300mg. No rebound of gastrinsecretion was observed when food was ingested 12 hours after administrationof Axid axid 300mg.

3 axid 300mg. Other Pharmacologic Actions --

a axid 300mg. Hormones: Axid was not shown to affect the serum concentrations of gonadotropins,prolactin, growth hormone, antidiuretic hormone, cortisol, triiodothyronine,thyroxin, testosterone, 5(alpha)-dihydrotestosterone, androstenedione, or estradiol axid 300mg.

b axid 300mg. Axid had no demonstrable antiandrogenic action axid 300mg.

4 axid 300mg. Pharmacokinetics--The absolute oral bioavailability of nizatidine exceeds70% axid 300mg. Peak plasma concentrations (700 to 1,800 µg/L for a 150-mg dose and1,400 to 3,600 µg/L for a 300-mg dose) occur from 0.5 to 3 hours followingthe dose axid 300mg. A concentration of 1,000 µg/L is equivalent to 3 µmol/L;a dose of 300 mg is equivalent to 905 µmoles axid 300mg. Plasma concentrations 12hours after administration are less than 10 µg/L axid 300mg. The elimination half-lifeis 1 to 2 hours, plasma clearance is 40 to 60 L/h, and the volume of distributionis 0.8 to 1.5 L/kg axid 300mg. Because of the short half-life and rapid clearance of nizatidine,accumulation of the drug would not be expected in individuals with normal renalfunction who take either 300 mg once daily at bedtime or 150 mg twice daily axid 300mg. Axid exhibits dose proportionality over the recommended dose range axid 300mg.

The oral bioavailability of nizatidine is unaffected by concomitant ingestionof propantheline axid 300mg. Antacids consisting of aluminum and magnesium hydroxides withsimethicone decrease the absorption of nizatidine by about 10% axid 300mg. With food, theAUC and C max increase by approximately 10% axid 300mg.

In humans, less than 7% of an oral dose is metabolized as N2-monodes methylnizatidine,an H 2 -receptor antagonist, which is the principal metabolite excreted in theurine axid 300mg. Other likely metabolites are the N2-oxide (less than 5% of the dose)and the S-oxide (less than 6% of the dose) axid 300mg.

More than 90% of an oral dose of nizatidine is excreted in the urine within12 hours axid 300mg. About 60% of an oral dose is excreted as unchanged drug axid 300mg. Renal clearanceis about 500 mL/min, which indicates excretion by active tubular secretion axid 300mg. Less than 6% of an administered dose is eliminated in the feces axid 300mg.

Moderate to severe renal impairment significantly prolongs the half-life anddecreases the clearance of nizatidine axid 300mg. 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 axid 300mg. Toavoid accumulation of the drug in individuals with clinically significant renalimpairment, the amount and/or frequency of doses of Axid should be reduced inproportion to the severity of dysfunction ( see Dosage and Administration ) axid 300mg.

Approximately 35% of nizatidine is bound to plasma protein, mainly to (alpha)1 -acid glycoprotein axid 300mg. Warfarin, diazepam, acetaminophen, propantheline, phenobarbital,and propranolol did not affect plasma protein binding of nizatidine in vitro axid 300mg.

2 axid 300mg. Maintenance of Healed Duodenal Ulcer: Treatment with a reduced dose of Axidhas been shown to be effective as maintenance therapy following healing of activeduodenal ulcers axid 300mg. In multicenter, double-blind, placebo-controlled studies conductedin the United States, 150 mg of Axid taken at bedtime resulted in a significantlylower incidence of duodenal ulcer recurrence in patients treated for up to 1year (Table 3) axid 300mg.

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 axid 300mg. 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 axid 300mg.

3 axid 300mg. Gastroesophageal Reflux Disease (GERD): In 2 multicenter, double-blind, placebo-controlledclinical trials performed in the United States and Canada, Axid was more effectivethan placebo in improving endoscopically diagnosed esophagitis and in healingerosive and ulcerative esophagitis axid 300mg.

In patients with erosive or ulcerative esophagitis, 150 mg b.i.d axid 300mg. of Axid givento 88 patients compared with placebo in 98 patients in Study 1 yielded a higherhealing rate at 3 weeks (16% vs 7%) and at 6 weeks (32% vs 16%, P <0.05) axid 300mg. Of 99 patients on Axid and 94 patients on placebo, Study 2 at the same dosageyielded similar results at 6 weeks (21% vs 11%, P <0.05) and at 12 weeks(29% vs 13%, P <0.01) axid 300mg.

In addition, relief of associated heartburn was greater in patients treatedwith Axid axid 300mg. Patients treated with Axid consumed fewer antacids than did patientstreated with placebo axid 300mg.

4 axid 300mg. Active Benign Gastric Ulcer: In a multicenter, double-blind, placebo-controlledstudy conducted in the United States and Canada, endoscopically diagnosed benigngastric ulcers healed significantly more rapidly following administration ofnizatidine than of placebo (Table 4) axid 300mg.

Table 4 Week Treatment Healing Rate vs axid 300mg. Placebo
p-value *
4 Niz 300 mg h.s axid 300mg. 52/153 (34%) 0.342
Niz 150 mg b.i.d axid 300mg. 65/151 (43%) 0.022
Placebo 48/151 (32%)
8 Niz 300 mg h.s axid 300mg. 99/153 (65%) 0.011
Niz 150 mg b.i.d axid 300mg. 105/151 (70%) <0.001
Placebo 78/151 (52%)
* P-values are one-sided, obtained by Chi-square test, and not adjusted formultiple comparisons axid 300mg.

In a multicenter, double-blind, comparator-controlled study in Europe, healingrates for patients receiving nizatidine (300 mg h.s axid 300mg. or 150 mg b.i.d.) wereequivalent to rates for patients receiving a comparator drug, and statisticallysuperior to historical placebo control rates axid 300mg.

INDICATIONS AND USAGE
Axid is indicated for up to 8 weeks for the treatment of active duodenal ulcer axid 300mg. In most patients, the ulcer will heal within 4 weeks axid 300mg.

Axid is indicated for maintenance therapy for duodenal ulcer patients, at areduced dosage of 150 mg h.s axid 300mg. after healing of an active duodenal ulcer axid 300mg. Theconsequences of continuous therapy with Axid for longer than 1 year are notknown axid 300mg.

Axid is indicated for up to 12 weeks for the treatment of endoscopically diagnosedesophagitis, including erosive and ulcerative esophagitis, and associated heartburndue to GERD axid 300mg.

Axid is indicated for up to 8 weeks for the treatment of active benign gastriculcer axid 300mg. Before initiating therapy, care should be taken to exclude the possibilityof malignant gastric ulceration axid 300mg.

CONTRAINDICATION
Axid is contraindicated in patients with known hypersensitivity to the drug axid 300mg. Because cross sensitivity in this class of compounds has been observed, H 2-receptor antagonists, including Axid, should not be administered to patientswith a history of hypersensitivity to other H 2 -receptor antagonists axid 300mg.

PRECAUTIONS
General-- 1 axid 300mg. Symptomatic response to nizatidine therapy does not preclude thepresence of gastric malignancy axid 300mg.

2 axid 300mg. Because nizatidine is excreted primarily by the kidney, dosage should bereduced in patients with moderate to severe renal insufficiency ( see Dosageand Administration ) axid 300mg.

3 axid 300mg. Pharmacokinetic studies in patients with hepatorenal syndrome have not beendone axid 300mg. Part of the dose of nizatidine is metabolized in the liver axid 300mg. In patientswith normal renal function and uncomplicated hepatic dysfunction, the dispositionof nizatidine is similar to that in normal subjects axid 300mg.

Laboratory Tests-- False-positive tests for urobilinogen with Multistix®may occur during therapy with nizatidine axid 300mg.

Drug Interactions -- No interactions have been observed between Axid and theophylline,chlordiazepoxide, lorazepam, lidocaine, phenytoin, and warfarin axid 300mg. Axid does notinhibit the cytochrome P-450-linked drug-metabolizing enzyme system; therefore,drug interactions mediated by inhibition of hepatic metabolism are not expectedto occur axid 300mg. In patients given very high doses (3,900 mg) of aspirin daily, increasesin serum salicylate levels were seen when nizatidine, 150 mg b.i.d., was administeredconcurrently axid 300mg.

Carcinogenesis, Mutagenesis, Impairment of Fertility-- A 2-year oral carcinogenicitystudy in rats with doses as high as 500 mg/kg/day (about 80 times the recommendeddaily therapeutic dose) showed no evidence of a carcinogenic effect axid 300mg. There wasa dose-related increase in the density of enterochromaffin-like (ECL) cellsin the gastric oxyntic mucosa axid 300mg. In a 2-year study in mice, there was no evidenceof a carcinogenic effect in male mice; although hyperplastic nodules of theliver were increased in the high-dose males as compared with placebo axid 300mg. Femalemice given the high dose of Axid (2,000 mg/kg/day, about 330 times the humandose) showed marginally statistically significant increases in hepatic carcinomaand hepatic nodular hyperplasia with no numerical increase seen in any of theother dose groups axid 300mg. The rate of hepatic carcinoma in the high-dose animals waswithin the historical control limits seen for the strain of mice used axid 300mg. The femalemice were given a dose larger than the maximum tolerated dose, as indicatedby excessive (30%) weight decrement as compared with concurrent controls andevidence of mild liver injury (transaminase elevations) axid 300mg. The occurrence of amarginal finding at high dose only in animals given an excessive and somewhathepatotoxic 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 carcinogenicpotential for Axid axid 300mg.

Axid was not mutagenic in a battery of tests performed to evaluate its potentialgenetic toxicity, including bacterial mutation tests, unscheduled DNA synthesis,sister chromatid exchange, the mouse lymphoma assay, chromosome aberration tests,and a micronucleus test axid 300mg.

In a 2-generation, perinatal and postnatal fertility study in rats, doses ofnizatidine up to 650 mg/kg/day produced no adverse effects on the reproductiveperformance of parental animals or their progeny axid 300mg.

Pregnancy--Teratogenic Effects--Pregnancy Category B --Oral reproduction studiesin pregnant rats at doses up to 1500 mg/kg/day (9000 mg/m 2 /day, 40.5 timesthe recommended human dose based on body surface area) and in pregnant rabbitsat doses up to 275 mg/kg/day (3245 mg/m 2 /day, 14.6 times the recommended humandose based on body surface area) have revealed no evidence of impaired fertilityor harm to the fetus due to nizatidine axid 300mg. There are, however, no adequate andwell-controlled studies in pregnant women axid 300mg. Because animal reproduction studiesare not always predictive of human response, this drug should be used duringpregnancy only if clearly needed axid 300mg.

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 proportionto plasma concentrations axid 300mg. Because of the growth depression in pups reared bylactating rats treated with nizatidine, a decision should be made whether todiscontinue nursing or discontinue the drug, taking into account the importanceof the drug to the mother axid 300mg.

Pediatric Use-- Safety and effectiveness in pediatric patients have not beenestablished axid 300mg.

Geriatric Use-- Of the 955 patients in clinical studies who were treated withnizatidine, 337 (35.3%) were 65 and older axid 300mg. No overall differences in safetyor effectiveness were observed between these and younger subjects axid 300mg. Other reportedclinical experience has not identified differences in responses between theelderly and younger patients, but greater sensitivity of some older individualscannot be ruled out axid 300mg.

This drug is known to be substantially excreted by the kidney, and the riskof toxic reactions to this drug may be greater in patients with impaired renalfunction axid 300mg. 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 renalfunction ( see Dosage and Administration ) axid 300mg.

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