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Zantac (Ranitidine Hydrochloride) - Description and Clinical Pharmacology

 
 



DESCRIPTION

The active ingredient in ZANTAC 150 Tablets, ZANTAC 300 Tablets, ZANTAC 25 EFFERdose Tablets, and ZANTAC Syrup is ranitidine hydrochloride (HCl), USP, a histamine H2-receptor antagonist. Chemically it is N[2-[[[5-[(dimethylamino)methyl]-2-furanyl]methyl]thio]ethyl]-N′-methyl-2-nitro-1,1-ethenediamine, HCl. It has the following structure:

The empirical formula is C13H22N4O3S•HCl, representing a molecular weight of 350.87.

Ranitidine HCl is a white to pale yellow, granular substance that is soluble in water. It has a slightly bitter taste and sulfurlike odor.

Each ZANTAC 150 Tablet for oral administration contains 168 mg of ranitidine HCl equivalent to 150 mg of ranitidine. Each tablet also contains the inactive ingredients FD&C Yellow No. 6 Aluminum Lake, hypromellose, magnesium stearate, microcrystalline cellulose, titanium dioxide, triacetin, and yellow iron oxide.

Each ZANTAC 300 Tablet for oral administration contains 336 mg of ranitidine HCl equivalent to 300 mg of ranitidine. Each tablet also contains the inactive ingredients croscarmellose sodium, D&C Yellow No. 10 Aluminum Lake, hypromellose, magnesium stearate, microcrystalline cellulose, titanium dioxide, and triacetin.

ZANTAC 25 EFFERdose Tablets for oral administration is an effervescent formulation of ranitidine that must be dissolved in water before use. Each individual tablet contains 28 mg of ranitidine HCl equivalent to 25 mg of ranitidine and the following inactive ingredients: aspartame, monosodium citrate anhydrous, povidone, and sodium bicarbonate. Each tablet also contains sodium benzoate. The total sodium content of each tablet is 30.52 mg (1.33 mEq) per 25 mg of ranitidine.

Each 1 mL of ZANTAC Syrup contains 16.8 mg of ranitidine HCl equivalent to 15 mg of ranitidine. ZANTAC Syrup also contains the inactive ingredients alcohol (7.5%), butylparaben, dibasic sodium phosphate, hypromellose, peppermint flavor, monobasic potassium phosphate, propylparaben, purified water, saccharin sodium, sodium chloride, and sorbitol.

CLINICAL PHARMACOLOGY

ZANTAC is a competitive, reversible inhibitor of the action of histamine at the histamine H2-receptors, including receptors on the gastric cells. ZANTAC does not lower serum Ca++ in hypercalcemic states. ZANTAC is not an anticholinergic agent.

Pharmacokinetics

Absorption

ZANTAC is 50% absorbed after oral administration, compared to an intravenous (IV) injection with mean peak levels of 440 to 545 ng/mL occurring 2 to 3 hours after a 150-mg dose. The syrup and EFFERdose formulations are bioequivalent to the tablets. Absorption is not significantly impaired by the administration of food or antacids. Propantheline slightly delays and increases peak blood levels of ZANTAC, probably by delaying gastric emptying and transit time. In one study, simultaneous administration of high-potency antacid (150 mmol) in fasting subjects has been reported to decrease the absorption of ZANTAC.

Distribution

The volume of distribution is about 1.4 L/kg. Serum protein binding averages 15%.

Metabolism

In humans, the N-oxide is the principal metabolite in the urine; however, this amounts to <4% of the dose. Other metabolites are the S-oxide (1%) and the desmethyl ranitidine (1%). The remainder of the administered dose is found in the stool. Studies in patients with hepatic dysfunction (compensated cirrhosis) indicate that there are minor, but clinically insignificant, alterations in ranitidine half-life, distribution, clearance, and bioavailability.

Excretion

The principal route of excretion is the urine, with approximately 30% of the orally administered dose collected in the urine as unchanged drug in 24 hours. Renal clearance is about 410 mL/min, indicating active tubular excretion. The elimination half-life is 2.5 to 3 hours. Four patients with clinically significant renal function impairment (creatinine clearance 25 to 35 mL/min) administered 50 mg of ranitidine intravenously had an average plasma half-life of 4.8 hours, a ranitidine clearance of 29 mL/min, and a volume of distribution of 1.76  L/kg. In general, these parameters appear to be altered in proportion to creatinine clearance (see DOSAGE AND ADMINISTRATION).

Geriatrics

The plasma half-life is prolonged and total clearance is reduced in the elderly population due to a decrease in renal function. The elimination half-life is 3 to 4 hours. Peak levels average 526 ng/mL following a 150-mg twice daily dose and occur in about 3 hours (see PRECAUTIONS: Geriatric Use and DOSAGE AND ADMINISTRATION: Dosage Adjustment for Patients With Impaired Renal Function).

Pediatrics

There are no significant differences in the pharmacokinetic parameter values for ranitidine in pediatric patients (from 1 month up to 16 years of age) and healthy adults when correction is made for body weight. The average bioavailability of ranitidine given orally to pediatric patients is 48% which is comparable to the bioavailability of ranitidine in the adult population. All other pharmacokinetic parameter values (t1/2, Vd, and CL) are similar to those observed with intravenous ranitidine use in pediatric patients. Estimates of Cmax and Tmax are displayed in Table 1.

Table 1. Ranitidine Pharmacokinetics in Pediatric Patients Following Oral Dosing

Population

(age)

n

Dosage Form (dose)

Cmax

(ng/mL)

Tmax

(hours)

Gastric or duodenal ulcer

(3.5 to 16 years)

12

Tablets

(1 to 2 mg/kg)

54 to 492

2.0

Otherwise healthy requiring ZANTAC

(0.7 to 14 years, Single dose)

10

Syrup

(2 mg/kg)

244

1.61

Otherwise healthy requiring ZANTAC

(0.7 to 14 years, Multiple dose)

10

Syrup

(2 mg/kg)

320

1.66

Plasma clearance measured in 2 neonatal patients (less than 1 month of age) was considerably lower (3 mL/min/kg) than children or adults and is likely due to reduced renal function observed in this population (see PRECAUTIONS: Pediatric Use and DOSAGE AND ADMINISTRATION: Pediatric Use).

Pharmacodynamics

Serum concentrations necessary to inhibit 50% of stimulated gastric acid secretion are estimated to be 36 to 94 ng/mL. Following a single oral dose of 150 mg, serum concentrations of ZANTAC are in this range up to 12 hours. However, blood levels bear no consistent relationship to dose or degree of acid inhibition.

In a pharmacodynamic comparison of the EFFERdose with the ZANTAC Tablets, during the first hour after administration, the EFFERdose tablet formulation gave a significantly higher intragastric pH, by approximately 1 pH unit, compared to the ZANTAC tablets.

Antisecretory Activity

1. Effects on Acid Secretion

ZANTAC inhibits both daytime and nocturnal basal gastric acid secretions as well as gastric acid secretion stimulated by food, betazole, and pentagastrin, as shown in Table 2.

Table 2. Effect of Oral ZANTAC on Gastric Acid Secretion

Time After Dose, h

% Inhibition of Gastric Acid Output by Dose, mg

75-80

100

150

200

Basal

Up to 4

99

95

Nocturnal

Up to 13

95

96

92

Betazole

Up to 3

97

99

Pentagastrin

Up to 5

58

72

72

80

Meal

Up to 3

73

79

95

It appears that basal-, nocturnal-, and betazole-stimulated secretions are most sensitive to inhibition by ZANTAC, responding almost completely to doses of 100 mg or less, while pentagastrin- and food-stimulated secretions are more difficult to suppress.

2. Effects on Other Gastrointestinal Secretions

Pepsin

Oral ZANTAC does not affect pepsin secretion. Total pepsin output is reduced in proportion to the decrease in volume of gastric juice.

Intrinsic Factor

Oral ZANTAC has no significant effect on pentagastrin-stimulated intrinsic factor secretion.

Serum Gastrin

ZANTAC has little or no effect on fasting or postprandial serum gastrin.

Other Pharmacologic Actions

  1. Gastric bacterial flora—increase in nitrate-reducing organisms, significance not known.
  2. Prolactin levels—no effect in recommended oral or intravenous (IV) dosage, but small, transient, dose-related increases in serum prolactin have been reported after IV bolus injections of 100 mg or more.
  3. Other pituitary hormones—no effect on serum gonadotropins, TSH, or GH. Possible impairment of vasopressin release.
  4. No change in cortisol, aldosterone, androgen, or estrogen levels.
  5. No antiandrogenic action.
  6. No effect on count, motility, or morphology of sperm.

Pediatrics

Oral doses of 6 to 10 mg/kg per day in 2 or 3 divided doses maintain gastric pH>4 throughout most of the dosing interval.

Clinical Trials

Active Duodenal Ulcer

In a multicenter, double-blind, controlled, US study of endoscopically diagnosed duodenal ulcers, earlier healing was seen in the patients treated with ZANTAC as shown in Table 3.

Table 3. Duodenal Ulcer Patient Healing Rates

ZANTAC*

Placebo*

Number

Entered

Healed/

Evaluable

Number

Entered

Healed/

Evaluable

Outpatients

195

69/182

(38%)

188

31/164

(19%)

Week 2

Week 4

137/187

(73%)

76/168

(45%)

*All patients were permitted p.r.n. antacids for relief of pain.

P <0.0001.

In these studies, patients treated with ZANTAC reported a reduction in both daytime and nocturnal pain, and they also consumed less antacid than the placebo-treated patients.

Table 4. Mean Daily Doses of Antacid

Ulcer Healed

Ulcer Not Healed

ZANTAC

0.06

0.71

Placebo

0.71

1.43

Foreign studies have shown that patients heal equally well with 150 mg b.i.d. and 300 mg h.s. (85% versus 84%, respectively) during a usual 4-week course of therapy. If patients require extended therapy of 8 weeks, the healing rate may be higher for 150 mg b.i.d. as compared to 300 mg h.s. (92% versus 87%, respectively).

Studies have been limited to short-term treatment of acute duodenal ulcer. Patients whose ulcers healed during therapy had recurrences of ulcers at the usual rates.

Maintenance Therapy in Duodenal Ulcer

Ranitidine has been found to be effective as maintenance therapy for patients following healing of acute duodenal ulcers. In 2 independent, double-blind, multicenter, controlled trials, the number of duodenal ulcers observed was significantly less in patients treated with ZANTAC (150 mg h.s.) than in patients treated with placebo over a 12-month period.

Table 5. Duodenal Ulcer Prevalence

Double-Blind, Multicenter, Placebo-Controlled Trials

Multicenter

Trial

Drug

Duodenal Ulcer Prevalence

No. of

Patients

0-4

Months

0-8

Months

0-12

Months

USA

RAN

20%*

24%*

35%*

138

PLC

44%

54%

59%

139

Foreign

RAN

12%*

21%*

28%*

174

PLC

56%

64%

68%

165

% = Life table estimate.

* =  P <0.05 (ZANTAC versus comparator).

RAN = ranitidine (ZANTAC).

PLC = placebo.

As with other H2-antagonists, the factors responsible for the significant reduction in the prevalence of duodenal ulcers include prevention of recurrence of ulcers, more rapid healing of ulcers that may occur during maintenance therapy, or both.

Gastric Ulcer

In a multicenter, double-blind, controlled, US study of endoscopically diagnosed gastric ulcers, earlier healing was seen in the patients treated with ZANTAC as shown in Table 6.

Table 6. Gastric Ulcer Patient Healing Rates

ZANTAC*

Placebo*

Number

Entered

Healed/

Evaluable

Number

Entered

Healed/

Evaluable

Outpatients

92

94

Week 2

16/83

(19%)

10/83

(12%)

Week 6

50/73

(68%)

35/69

(51%)

*All patients were permitted p.r.n. antacids for relief of pain.

= 0.009.

In this multicenter trial, significantly more patients treated with ZANTAC became pain free during therapy.

Maintenance of Healing of Gastric Ulcers

In 2 multicenter, double-blind, randomized, placebo-controlled, 12-month trials conducted in patients whose gastric ulcers had been previously healed, ZANTAC 150 mg h.s. was significantly more effective than placebo in maintaining healing of gastric ulcers.

Pathological Hypersecretory Conditions (such as Zollinger-Ellison syndrome)

ZANTAC inhibits gastric acid secretion and reduces occurrence of diarrhea, anorexia, and pain in patients with pathological hypersecretion associated with Zollinger-Ellison syndrome, systemic mastocytosis, and other pathological hypersecretory conditions (e.g., postoperative, "short-gut" syndrome, idiopathic). Use of ZANTAC was followed by healing of ulcers in 8 of 19 (42%) patients who were intractable to previous therapy.

Gastroesophageal Reflux Disease (GERD)

In 2 multicenter, double-blind, placebo-controlled, 6-week trials performed in the United States and Europe, ZANTAC 150 mg b.i.d. was more effective than placebo for the relief of heartburn and other symptoms associated with GERD. Ranitidine-treated patients consumed significantly less antacid than did placebo-treated patients.

The US trial indicated that ZANTAC 150 mg b.i.d. significantly reduced the frequency of heartburn attacks and severity of heartburn pain within 1 to 2 weeks after starting therapy. The improvement was maintained throughout the 6-week trial period. Moreover, patient response rates demonstrated that the effect on heartburn extends through both the day and night time periods.

In 2 additional US multicenter, double-blind, placebo-controlled, 2-week trials, ZANTAC 150 mg b.i.d. was shown to provide relief of heartburn pain within 24 hours of initiating therapy and a reduction in the frequency of severity of heartburn. In these trials, ZANTAC EFFERdose Tablets were shown to provide heartburn relief within 45 minutes of dosing.

Erosive Esophagitis

In 2 multicenter, double-blind, randomized, placebo-controlled, 12-week trials performed in the United States, ZANTAC 150 mg q.i.d. was significantly more effective than placebo in healing endoscopically diagnosed erosive esophagitis and in relieving associated heartburn. The erosive esophagitis healing rates were as follows:

Table 7. Erosive Esophagitis Patient Healing Rates

Healed/Evaluable

Placebo*

n = 229

ZANTAC

150 mg q.i.d.*

n = 215

Week 4

43/198 (22%)

96/206 (47%)

Week 8

63/176 (36%)

142/200 (71%)

Week 12

92/159 (58%)

162/192 (84%)

*All patients were permitted p.r.n. antacids for relief of pain.

P <0.001 versus placebo.

No additional benefit in healing of esophagitis or in relief of heartburn was seen with a ranitidine dose of 300 mg q.i.d.

Maintenance of Healing of Erosive Esophagitis

In 2 multicenter, double-blind, randomized, placebo-controlled, 48-week trials conducted in patients whose erosive esophagitis had been previously healed, ZANTAC 150 mg b.i.d. was significantly more effective than placebo in maintaining healing of erosive esophagitis.

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