AXID

AXID- nizatidine solution
Braintree Laboratories, Inc.

Rx only

Description

Nizatidine (USP) is a histamine H2 -receptor 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:

Structural Formula

Nizatidine has the empirical formula C12 H21 N5 O2 S2 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.

Axid Oral Solution is formulated as a clear, yellow, oral solution with bubble gum flavor and each 1 mL contains 15 mg of nizatidine. Axid Oral Solution also contains the inactive ingredients methylparaben, propylparaben, glycerin, sodium alginate, purified water, sodium chloride, saccharin sodium, sodium citrate dihydrate, citric acid anhydrous, sucrose, bubble gum flavor, artificial sweetness enhancer, and sodium hydroxide.

Clinical Pharmacology in Adults: Nizatidine 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: 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 AfterDose (h) % Inhibition of Gastric AcidOutput by Dose (mg)
20-50 75 100 150 300
NocturnalBetazolePentagastrinMealCaffeine Up to 10Up to 3Up to 6Up to 4Up to 3 57––41– –93256473 73–––– –100649885 9099679796

2. Effects on Other Gastrointestinal SecretionsPepsin: 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 Concentration: Nizatidine had no effect on basal serum gastrin concentration. No rebound of gastrin secretion was observed when food was ingested 12 hours after administration of nizatidine.

3. Other Pharmacologic Actions

  1. Hormones: Nizatidine was not shown to affect the serum concentrations of gonadotropins, prolactin, growth hormone, antidiuretic hormone, cortisol, triiodo-thyronine, thyroxin, testosterone, 5 α-dihydro-testosterone, androstenedione, or estradiol.
  2. Nizatidine 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. 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. Nizatidine exhibits dose proportionality over the recommended dose range.

The oral bioavailability of nizatidine is unaffected by concomitant ingestion of the anticholinergic 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-monodesmethylnizatidine, 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 orally administered 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 α 1 -acid glycoprotein. Warfarin, diazepam, acetaminophen, propantheline, phenobarbital, and propranolol did not affect plasma protein binding of nizatidine in vitro.

At a dose of 150 mg, the Axid Oral Solution (15 mg/mL) is bioequivalent to nizatidine capsules.

Clinical Pharmacology in Pediatric Patients:

Pharmacokinetics

Table 2 presents pharmacokinetic data of nizatidine administered orally to adolescents with gastroesophageal reflux (GER) and healthy adults. Pharmacokinetic parameters for adolescent patients ages 12 to 18 years are comparable to those obtained for adults.

Table 2. Pharmacokinetics of Oral Nizatidine

SD=single dose SS=steady state

Administration of nizatidine capsules in apple juice results in 27% reduction of nizatidine bioavailability.

Age Range Formulation Dose C max (ng/mL) T max (h) AUC 0- (ng•h/mL) CL F (L/h) Vd F (L) T 1/2 (h)
12-18 yr Capsule 150 mg SD 1422.9 1.3 3764.2 41.0 71.4 1.2
Adolescents 150 mg SS 1480.2 1.4 3776.1 41.1 74.2 1.3
with GER
Healthy Capsule 150 mg SD 1367.6 1.0 3703.1 41.9 83.4 1.4
Adults Oral Solution 150 mg SD 1340.6 0.8 3610.9 43.0 86.4 1.4
Apple Juice 150 mg SD 762.8 1.3 2694.1 57.5 142.3 1.7
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