RANITIDINE IMMEDIATE RELEASE- ranitidine hydrochloride tablet
The active ingredient in ranitidine tablets, USP 150 mg and 300 mg is ranitidine hydrochloride (HCl), USP, a histamine H 2 -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:
Ranitidine HCl USP is a white to pale yellow crystalline powder that is soluble in water. It has a slightly bitter taste and sulfur-like odor.
Each ranitidine tablets, USP 150 mg for oral administration contains 168 mg of ranitidine HCl USP equivalent to 150 mg of ranitidine. Each tablet also contains the inactive ingredients magnesium stearate, microcrystalline cellulose, croscarmellose sodium, colloidal silicon dioxide, hypromellose, titanium dioxide, triacetin, and iron oxide red.
Each ranitidine tablets, USP 300 mg for oral administration contains 336 mg of ranitidine HCl USP equivalent to 300 mg of ranitidine. Each tablet also contains the inactive ingredients magnesium stearate, microcrystalline cellulose, croscarmellose sodium, colloidal silicon dioxide, hypromellose, titanium dioxide, triacetin, and iron oxide red.
Ranitidine is a competitive, reversible inhibitor of the action of histamine at the histamine H 2 -receptors, including receptors on the gastric cells. Ranitidine does not lower serum Ca++ in hypercalcemic states. Ranitidine is not an anticholinergic agent.
Absorption: Ranitidine is 50% absorbed after oral administration, compared with 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 is 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 ranitidine, probably by delaying gastric emptying and transit time. In one trial, simultaneous administration of high-potency antacid (150 mmol) in fasting subjects has been reported to decrease the absorption of ranitidine.
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. Trials 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 (aged from 1 month up to 16 years) 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 (t 1/2 , Vd, and CL) are similar to those observed with intravenous ranitidine use in pediatric patients. Estimates of C max and T max are displayed in Table 1.
|Population (age)||n||Dosage Form (dose)||C max (ng/mL)||T max (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 ranitidine (0.7 to 14 years, Single dose)||10||Syrup (2 mg/kg)||244||1.61|
|Otherwise healthy requiring ranitidine (0.7 to 14 years, Multiple dose)||10||Syrup (2 mg/kg)||320||1.66|
Plasma clearance measured in 2 neonatal patients (aged younger than 1 month) 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).
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 ranitidine are in this range up to 12 hours. However, blood levels bear no consistent relationship to dose or degree of acid inhibition
Antisecretory Activity:1. Effects on Acid Secretion: Ranitidine 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.
|Basal||Time After Dose (hours)||% Inhibition of Gastric Acid Output by Dose|
|75 to 80 mg||100 mg||150 mg||200 mg|
|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 ranitidine, 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 ranitidine does not affect pepsin secretion. Total pepsin output is reduced in proportion to the decrease in volume of gastric juice
Intrinsic Factor: Oral ranitidine has no significant effect on pentagastrin-stimulated intrinsic factor secretion
Serum Gastrin: Ranitidine has little or no effect on fasting or postprandial serum gastrin
Other Pharmacologic Actions:
- Gastric bacterial flora—increase in nitrate-reducing organisms, significance not known.
- Prolactin levels—no effect in recommended oral or IV dosage, but small, transient, dose-related increases in serum prolactin have been reported after IV bolus injections of 100 mg or more.
- Other pituitary hormones—no effect on serum gonadotropins, TSH, or GH. Possible impairment of vasopressin release.
- No change in cortisol, aldosterone, androgen, or estrogen levels.
- No antiandrogenic action.
- No effect on count, motility, or morphology of sperm.
Clinical Trials: Active Duodenal Ulcer: In a multicenter, double-blind, controlled, US trial of endoscopically diagnosed duodenal ulcers, earlier healing was seen in the patients treated with ranitidine as shown in Table 3.
|Outpatients||Ranitidine a||Placebo a|
|Number Entered||Healed/ Evaluable||Number Entered||Healed/ Evaluable|
|Week 2||195||69/182 (38%) b||188||31/164 (19%)|
|Week 4||137/187 (73%) b||76/168 (45%)|
In these trials, patients treated with ranitidine reported a reduction in both daytime and nocturnal pain, and they also consumed less antacid than the placebo-treated patients.
|Ulcer Healed||Ulcer Not Healed|
Foreign trials have shown that patients heal equally well with 150 mg twice daily and 300 mg at bedtime (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 twice daily as compared with 300 mg at bedtime (92% versus 87%, respectively).
Trials 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 ranitidine (150 mg at bedtime) than in patients treated with placebo over a 12-month period.
|Double-Blind, Multicenter, Placebo-Controlled Trials|
|Multicenter Trial||Drug||Duodenal Ulcer Prevalence||No. of Patients|
|0 to 4 Months||0 to 8 Months||0 to 12 Months|
|USA||RAN||20% a||24%||35% a||138|
|Foreign||RAN||12% a||21% a||28% a||174|
a = P<0.05 (ranitidine tablets, USP versus comparator).
RAN = ranitidine.
PLC = placebo.
As with other H 2 -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 trial of endoscopically diagnosed gastric ulcers, earlier healing was seen in the patients treated with ranitidine as shown in Table 6.
|Outpatients||Ranitidine *||Placebo *|
|Number Entered||Healed/ Evaluable||Number Entered||Healed/ Evaluable|
|Week 2||92||16/83 (19%)||94||10/83 (12%)|
|Week 6||50/73 (68%) †||35/69 (51%)|
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, ranitidine 150 mg at bedtime was significantly more effective than placebo in maintaining healing of gastric ulcers.
Pathological Hypersecretory Conditions (such as Zollinger-Ellison syndrome): Ranitidine 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 ranitidine 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, ranitidine 150 mg twice daily 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 ranitidine 150 mg twice daily 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, ranitidine 150 mg twice daily was shown to provide relief of heartburn pain within 24 hours of initiating therapy and a reduction in the frequency of severity of heartburn.
Erosive Esophagitis: In 2 multicenter, double-blind, randomized, placebo-controlled, 12-week trials performed in the United States, ranitidine 150 mg 4 times daily 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:
|Placebo a n = 229||Ranitidine 150 mg 4 times daily a n = 215|
|Week 4||43/198 (22%)||96/206 (47%) b|
|Week 8||63/176 (36%)||142/200 (71%) b|
|Week 12||92/159 (58%)||162/192 (84%) b|
b 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 4 times daily.
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, ranitidine 150 mg twice daily was significantly more effective than placebo in maintaining healing of erosive esophagitis.
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