CATEGORIES: Ulcer, duodenal; Esophagitis, erosive; Gastroesophageal Reflux Disease; Mastocytosis, systemic; Ulcer, gastric; Zollinger-Ellison syndrome; Pregnancy Category B; FDA Approved June 1983
Drug Classes: Antihistamines, H2; Gastrointestinals
BRAND NAMES: Zantac; Zantac 150; Zantac 300; Zantac EFFERdose
FOREIGN BRAND AVAILABILITY:
Acidex (Argentina);
Aciloc (India);
Acloral (Mexico);
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Aldin (India);
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Atural (Peru);
Ausran (Australia);
Avintac (Mexico);
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Consec (India);
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Microtid (Mexico);
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Neoceptin-R (South Africa, Singapore);
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Ptinolin (Greece);
Quantor (Spain);
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Radine (Philippines);
Ranacid (Norway);
Rancet (Colombia);
Randin (Israel);
Rani 2 (Australia);
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Ranidil (Italy);
Ranidine (Thailand);
Ranihexal (Australia);
Ranimex (Finland);
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Ranitab (Philippines);
Ranital (Slovenia);
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Ranitin (Bahrain, Republic of Yemen);
Ranolta (Hong Kong);
Rantac (Israel, India);
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Ratic (Thailand);
Raticina (Argentina);
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R-Loc (South Africa);
RND (Taiwan);
Rolan (Israel);
Rosimol (Argentina);
Simetac (Hong Kong);
Sostril (Germany);
Taural (Argentina, Costa Rica, Dominican Republic, Ecuador, El Salvador, Guatemala, Honduras, Nicaragua, Panama);
Terodul (Mexico);
Ulcaid (South Africa);
Ulceran (Peru);
Ulceranin (Indonesia);
Ulcex (Italy);
Ulcin (Philippines);
Ulsal (Austria);
Ultak (South Africa);
Urantac (Korea);
Verlost (Greece);
Vesyca (Taiwan);
Vizerul (Argentina);
Weichilin (Taiwan);
Weidos (Taiwan);
Xanidine (Singapore, Thailand);
Zantab (Israel);
Zantac FR (Philippines);
Zantac Relief (New Zealand);
Zantadin (Indonesia);
Zantic (Germany, Switzerland);
Zinetac (India)
COST OF THERAPY:
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The active ingredient in Zantac injection and injection premixed is ranitidine hydrochloride, 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, hydrochloride.
The empirical formula is C13H22N4O3S·HCl, representing a molecular weight of 350.87.
Ranitidine hydrochloride is a white to pale yellow, granular substance that is soluble in water.
Zantac injection is a clear, colorless to yellow, nonpyrogenic liquid. The yellow color of the liquid tends to intensify without adversely affecting potency. The pH of the injection solution is 6.7-7.3.
Pharmacy Bulk Package: A pharmacy bulk package is a container of a sterile preparation for parenteral use that contains many single doses. The contents are intended for use in a pharmacy admixture program and are restricted to the preparation of admixtures for IV infusion.
Sterile Injection for IM or IV Administration
Each 1 ml of aqueous solution contains ranitidine 25 mg (as the hydrochloride); phenol 5 mg as preservative; and 0.96 mg of monobasic potassium phosphate and 2.4 mg of dibasic sodium phosphate as buffers.
Sterile, Premixed Solution for IV Administration in Single-Dose, Flexible Plastic Containers
Each 50 ml contains ranitidine hydrochloride equivalent to 50 mg of ranitidine, sodium chloride 225 mg, and citric acid 15 mg and dibasic sodium phosphate 90 mg as buffers in water for injection. It contains no preservatives. The osmolarity of this solution is 180 mOsm/L (approx.), and the pH is 6.7-7.3.
The flexible plastic container is fabricated from a specially formulated, nonplasticized, thermoplastic co-polyester (CR3). Water can permeate from inside the container into the overwrap but not in amounts sufficient to affect the solution significantly. Solutions inside the plastic container also can leach out certain of the chemical components in very small amounts before the expiration period is attained. However, the safety of the plastic has been confirmed by tests in animals according to USP biological standards for plastic containers.
Ranitidine HCl is a competitive, reversible inhibitor of the action of histamine at the histamine H2-receptors, including receptors on the gastric cells. Ranitidine HCl does not lower serum Ca++ in hypercalcemic states. Ranitidine HCl is not an anticholinergic agent.
Pharmacokinetics
Absorption
Ranitidine HCl is absorbed very rapidly after IM injection. Mean peak levels of 576 ng/ml occur within 15 minutes or less following a 50-mg IM dose. Absorption from IM sites is virtually complete, with a bioavailability of 90-100% compared with IV administration. Following oral administration, the bioavailability of ranitidine HCl tablets is 50%.
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
Following IV injection, approximately 70% of the dose is recovered in the urine as unchanged drug. Renal clearance averages 530 ml/min, with a total clearance of 760 ml/min. The elimination half-life is 2.0-2.5 hours.
Four patients with clinically significant renal function impairment (creatinine clearance 25-35 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 3.1 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 pharmacokinetics of ranitidine HCl in pediatric patients are summarized in TABLE 1.
Plasma clearance in neonatal patients (less than 1 month of age) receiving ECMO was considerably lower (3-4 ml/min/kg) than observed in children or adults. The elimination half-life in neonates averaged 6.6 hours as compared to approximately 2 hours in adults and pediatric patients.
Pharmacodynamics
Serum concentrations necessary to inhibit 50% of stimulated gastric acid secretion are estimated to be 36-94 ng/ml. Following single IV or IM 50-mg doses, serum concentrations of ranitidine HCl are in this range for 6-8 hours.
Antisecretory Activity
Effects on Acid Secretion
Ranitidine HCl injection inhibits basal gastric acid secretion as well as gastric acid secretion stimulated by betazole and pentagastrin, as shown in TABLE 2.
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In a group of 10 known hypersecretors, ranitidine plasma levels of 71, 180, and 376 ng/ml inhibited basal acid secretion by 76%, 90%, and 99.5%, respectively.
It appears that basal- and betazole-stimulated secretions are most sensitive to inhibition by ranitidine HCl, while pentagastrin-stimulated secretion is more difficult to suppress.
Effects on Other Gastrointestinal Secretions
Other Pharmacologic Actions
Pediatrics
The ranitidine concentration necessary to suppress basal acid secretion by at least 90% has been reported to be 40-60 ng/ml in pediatric patients with duodenal or gastric ulcers.
In a study of 20 critically ill pediatric patients receiving ranitidine IV at 1 mg/kg every 6 hours, 10 patients with a baseline pH ≥4 maintained this baseline throughout the study. Eight (8) of the remaining 10 patients with a baseline of pH ≤2 achieved pH ≥4 throughout varying periods after dosing. It should be noted, however, that because these pharmacodynamic parameters were assessed in critically ill pediatric patients, the data should be interpreted with caution when dosing recommendations are made for a less seriously ill pediatric population.
In another small study of neonatal patients (n=5) receiving ECMO, gastric pH <4 pretreatment increased to >4 after a 2-mg/kg dose and remained above 4 for at least 15 hours.
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 oral ranitidine HCl as shown in TABLE 3.
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| * All patients were permitted prn antacids for relief of pain. | |||||||||||||||||||
| † p <0.0001. | |||||||||||||||||||
In these studies, patients treated with oral ranitidine HCl reported a reduction in both daytime and nocturnal pain, and they also consumed less antacid than the placebo-treated patients.
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Pathological Hypersecretory Conditions (such as Zollinger-Ellison syndrome)
Ranitidine HCl 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 oral ranitidine HCl was followed by healing of ulcers in 8 of 19 (42%) patients who were intractable to previous therapy.
In a retrospective review of 52 Zollinger-Ellison patients given ranitidine HCl as a continuous IV infusion for up to 15 days, no patients developed complications of acid-peptic disease such as bleeding or perforation. Acid output was controlled to ≤10 mEq/h.
Ranitidine HCl injection and injection premixed are indicated in some hospitalized patients with pathological hypersecretory conditions or intractable duodenal ulcers, or as an alternative to the oral dosage form for short-term use in patients who are unable to take oral medication.
Non-FDA Approved Indications
While not FDA approved indications, ranitidine is also used in the management of upper gastrointestinal bleeding and for stress ulcer prophylaxis in the ICU.
Ranitidine HCl injection and injection premixed are contraindicated for patients known to have hypersensitivity to the drug.
General
Symptomatic response to therapy with ranitidine HCl does not preclude the presence of gastric malignancy.
Since ranitidine HCl is excreted primarily by the kidney, dosage should be adjusted in patients with impaired renal function (see DOSAGE AND ADMINISTRATION). Caution should be observed in patients with hepatic dysfunction since ranitidine HCl is metabolized in the liver.
In controlled studies in normal volunteers, elevations in SGPT have been observed when H2-antagonists have been administered intravenously at greater than recommended dosages for 5 days or longer. Therefore, it seems prudent in patients receiving IV ranitidine at dosages ≥100 mg qid for periods of 5 days or longer to monitor SGPT daily (from Day 5) for the remainder of IV therapy.
Bradycardia in association with rapid administration of ranitidine HCl injection has been reported rarely, usually in patients with factors predisposing to cardiac rhythm disturbances. Recommended rates of administration should not be exceeded (see DOSAGE AND ADMINISTRATION).
Rare reports suggest that ranitidine HCl may precipitate acute porphyric attacks in patients with acute porphyria. Ranitidine HCl should therefore be avoided in patients with a history of acute porphyria.
Laboratory Tests
False-positive tests for urine protein with Multistix may occur during therapy with ranitidine HCl, and therefore testing with sulfosalicylic acid is recommended.
Carcinogenesis, Mutagenesis, and Impairment of Fertility
There was no indication of tumorigenic or carcinogenic effects in life-span studies in mice and rats at oral dosages up to 2000 mg/kg/day.
Ranitidine was not mutagenic in standard bacterial tests (Salmonella, Escherichia coli) for mutagenicity at concentrations up to the maximum recommended for these assays.
In a dominant lethal assay, a single oral dose of 1000 mg/kg to male rats was without effect on the outcome of 2 matings per week for the next 9 weeks.
Pregnancy, Teratogenic Effects, Pregnancy Category B
Reproduction studies have been performed in rats and rabbits at oral doses up to 160 times the human oral dose and have revealed no evidence of impaired fertility or harm to the fetus due to ranitidine HCl. There are, however, no adequate and well-controlled studies in pregnant 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
Ranitidine HCl is secreted in human milk. Caution should be exercised when ranitidine HCl is administered to a nursing mother.
Pediatric Use
The safety and effectiveness of ranitidine HCl injection have been established in the age-group of 1 month to 16 years for the treatment of duodenal ulcer. Use of ranitidine HCl in this age-group is supported by adequate and well-controlled studies in adults, as well as additional pharmacokinetic data in pediatric patients, and an analysis of the published literature.
Safety and effectiveness in pediatric patients for the treatment of pathological hypersecretory conditions have not been established.
Limited data in neonatal patients (less than 1 month of age) receiving ECMO suggest that ranitidine HCl may be useful and safe for increasing gastric pH for patients at risk of gastrointestinal hemorrhage.
Geriatric Use
Clinical studies of ranitidine HCl injection did not include sufficient numbers of subjects aged 65 and over to determine whether they responded differently from younger subjects. However, in clinical studies of oral formulations of ranitidine HCl, of the total number of subjects enrolled in US and foreign controlled clinical trials, for which there were subgroup anaylses, 4197 were 65 and over, while 899 were 75 and older. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and 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 and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, caution should be exercised in dose selection, and it may be useful to monitor renal function (see CLINICAL PHARMACOLOGY, Pharmacokinetics, Geriatrics and DOSAGE AND ADMINISTRATION, Dosage Adjustment for Patients With Impaired Renal Function).
Although ranitidine HCl has been reported to bind weakly to cytochrome P-450 in vitro, recommended doses of the drug do not inhibit the action of the cytochrome P-450-linked oxygenase enzymes in the liver. However, there have been isolated reports of drug interactions that suggest that ranitidine HCl may affect the bioavailability of certain drugs by some mechanism as yet unidentified (e.g., a pH-dependent effect on absorption or a change in volume of distribution).
Increased or decreased prothrombin times have been reported during concurrent use of ranitidine and warfarin. However, in human pharmacokinetic studies with dosages of ranitidine up to 400 mg/day, no interaction occurred; ranitidine had no effect on warfarin clearance or prothrombin time. The possibility of an interaction with warfarin at dosages of ranitidine higher than 400 mg/day has not been investigated.
In a ranitidine-triazolam drug-drug interaction study, triazolam plasma concentrations were higher during bid dosing of ranitidine than triazolam given alone. The mean area under the triazolam concentration-time curve (AUC) values, in 18- to 60-year-old subjects were 10% and 28% higher following administration of 75-mg and 150-mg ranitidine tablets, respectively, than triazolam given alone. In subjects older than 60 years of age, the mean AUC values were approximately 30% higher following administration of 75- and 150-mg ranitidine tablets. It appears that there were no changes in pharmacokinetics of triazolam and α-hydroxytriazolam, a major metabolite, and in their elimination. Reduced gastric acidity due to ranitidine may have resulted in an increase in the availability of triazolam. The clinical significance of this triazolam and ranitidine pharmacokinetic interaction is unknown.
Transient pain at the site of IM injection has been reported. Transient local burning or itching has been reported with IV administration of ranitidine HCl.
The following have been reported as events in clinical trials or in the routine management of patients treated with oral or parenteral ranitidine HCl. The relationship to therapy with ranitidine HCl has been unclear in many cases. Headache, sometimes severe, seems to be related to administration of ranitidine HCl.
There has been virtually no experience with overdosage with ranitidine HCl injection and limited experience with oral doses of ranitidine. Reported acute ingestions of up to 18 g orally have been associated with transient adverse effects similar to those encountered in normal clinical experience (see ADVERSE REACTIONS). In addition, abnormalities of gait and hypotension have been reported.
When overdosage occurs, clinical monitoring and supportive therapy should be employed.
Studies in dogs receiving dosages of ranitidine HCl in excess of 225 mg/kg/day have shown muscular tremors, vomiting, and rapid respiration. Single oral doses of 1000 mg/kg in mice and rats were not lethal. Intravenous LD50 values in mice and rats were 77 and 83 mg/kg, respectively.
Parenteral Administration
In some hospitalized patients with pathological hypersecretory conditions or intractable duodenal ulcers, or in patients who are unable to take oral medication, ranitidine HCl may be administered parenterally according to the following recommendations:
Intramuscular Injection
50 mg (2 ml) every 6-8 hours. (No dilution necessary.)
Intermittent IV Injection
Intermittent Bolus
50 mg (2 ml) every 6-8 hours. Dilute ranitidine HCl injection, 50 mg, in 0.9% sodium chloride injection or other compatible IV solution (see Stability) to a concentration no greater than 2.5 mg/ml (20 ml). Inject at a rate no greater than 4 ml/min (5 minutes).
Intermittent Infusion
50 mg (2 ml) every 6-8 hours. Dilute ranitidine HCl injection, 50 mg, in 5% dextrose injection or other compatible IV solution (see Stability) to a concentration no greater than 0.5 mg/ml (100 ml). Infuse at a rate no greater than 5-7 ml/min (15-20 minutes).
Ranitidine HCl injection premixed solution, 50 mg, in 0.45% sodium chloride, 50 ml, requires no dilution and should be infused over 15-20 minutes.
In some patients it may be necessary to increase dosage. When this is necessary, the increases should be made by more frequent administration of the dose, but generally should not exceed 400 mg/day.
Continuous IV Infusion
Add ranitidine HCl injection to 5% dextrose injection or other compatible IV solution (see Stability). Deliver at a rate of 6.25 mg/h [e.g., 150 mg (6 ml) of ranitidine HCl injection in 250 ml of 5% dextrose injection at 10.7 ml/h].
For Zollinger-Ellison patients, dilute ranitidine HCl injection in 5% dextrose injection or other compatible IV solution (see Stability) to a concentration no greater than 2.5 mg/ml. Start the infusion at a rate of 1.0 mg/kg/h. If after 4 hours either a measured gastric acid output is >10 mEq/h or the patient becomes symptomatic, the dose should be adjusted upward in 0.5 mg/kg/h increments, and the acid output should be remeasured. Dosages up to 2.5 mg/kg/h and infusion rates as high as 220 mg/h have been used.
Pediatric Use
While limited data exist on the administration of IV ranitidine to children, the recommended dose in pediatric patients is for a total daily dose of 2-4 mg/kg, to be divided and administered every 6-8 hours, up to a maximum of 50 mg given every 6-8 hours. This recommendation is derived from adult clinical studies and pharmacokinetic data in pediatric patients. Limited data in neonatal patients (less than 1 month of age) receiving ECMO have shown that a dose of 2 mg/kg is usually sufficient to increase gastric pH to >4 for at least 15 hours. Therefore, doses of 2 mg/kg given every 12-24 hours or as a continuous infusion should be considered.
Ranitidine HCl Injection Premixed in Flexible Plastic Containers
Instructions for Use
To Open
Tear outer wrap at notch and remove solution container. Check for minute leaks by squeezing container firmly. If leaks are found, discard unit as sterility may be impaired.
Caution
Ranitidine HCl injection premixed in flexible plastic containers is to be administered by slow IV drip infusion only. Additives should not be introduced into this solution. If used with a primary IV fluid system, the primary solution should be discontinued during ranitidine HCl injection premixed infusion.
Do not administer unless solution is clear and container is undamaged.
Warning
Do not use flexible plastic container in series connections.
Dosage Adjustment for Patients With Impaired Renal Function
The administration of ranitidine as a continuous infusion has not been evaluated in patients with impaired renal function. On the basis of experience with a group of subjects with severely impaired renal function treated with ranitidine HCl, the recommended dosage in patients with a creatinine clearance <50 ml/min is 50 mg every 18-24 hours. Should the patient's condition require, the frequency of dosing may be increased to every 12 hours or even further with caution. Hemodialysis reduces the level of circulating ranitidine. Ideally, the dosing schedule should be adjusted so that the timing of a scheduled dose coincides with the end of hemodialysis.
Elderly patients are more likely to have decreased renal function, therefore caution should be exercised in dose selection, and it may be useful to monitor renal function (see CLINICAL PHARMACOLOGY, Pharmacokinetics, Geriatrics and PRECAUTIONS, Geriatric Use).
Stability
Undiluted, ranitidine HCl injection tends to exhibit a yellow color that may intensify over time without adversely affecting potency. Ranitidine HCl injection is stable for 48 hours at room temperature when added to or diluted with most commonly used IV solutions, e.g., 0.9% sodium chloride injection, 5% dextrose injection, 10% dextrose injection, lactated Ringer's injection, or 5% sodium bicarbonate injection.
Ranitidine HCl injection premixed in flexible plastic containers is sterile through the expiration date on the label when stored under recommended conditions.
Note: Parenteral drug products should be inspected visually for particulate matter and discoloration before administration whenever solution and container permit.
Zantac Injection
Zantac injection, 25 mg/ml, containing phenol 0.5% as preservative, is available in 2-ml single-dose vials and 6-ml multi-dose vials.
Storage
Store between 4 and 25°C (39 and 77°F); excursions permitted to 30°C (86°F). Protect from light.
Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat; however, brief exposure up to 40°C does not adversely affect the product. Protect from freezing.
Zantac Injection Premixed
Zantac injection premixed, 50 mg/50 ml, in 0.45% sodium chloride, is available as a sterile, premixed solution for IV administration in single-dose, flexible plastic containers. It contains no preservatives.
Storage
Store between 2 and 25°C (36 and 77°F). Protect from light.
Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat; however, brief exposure up to 40°C does not adversely affect the product. Protect from freezing.
Zantac Pharmacy Bulk Package
Zantac injection, 25 mg/ml, containing phenol 0.5% as preservative, is supplied in a 40 ml pharmacy bulk package.
Storage:
Store between 4 and 25°C (39 and 77°F); excursions permitted to 30°C (86°F). Protect from light. Store vial in carton until time of use.
The active ingredient in Zantac 150 tablets, 300 tablets, 25 Efferdose tablets, 150 Efferdose tablets, and syrup is ranitidine hydrochloride, 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, hydrochloride.
The empirical formula is C13H22N4O3S·HCl, representing a molecular weight of 350.87.
Ranitidine hydrochloride is a white to pale yellow, granular substance that is soluble in water. It has a slightly bitter taste and sulfurlike odor.
Tablets
Each Zantac 150 tablet for oral administration contains 168 mg of ranitidine hydrochloride 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 hydrochloride 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.
Efferdose Tablets
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 hydrochloride 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.
Zantac 150 Efferdose tablets for oral administration is an effervescent formulation of ranitidine that must be dissolved in water before use. Each individual tablet contains 168 mg of ranitidine hydrochloride equivalent to 150 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 183.12 mg (7.96 mEq) per 150 mg of ranitidine.
Syrup
Each 1 ml of Zantac syrup contains 16.8 mg of ranitidine hydrochloride 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.
Ranitidine HCl is a competitive, reversible inhibitor of the action of histamine at the histamine H2-receptors, including receptors on the gastric cells. Ranitidine HCl does not lower serum Ca++ in hypercalcemic states. Ranitidine HCl is not an anticholinergic agent.
Pharmacokinetics
Absorption
Ranitidine HCl is 50% absorbed after oral administration, compared to an IV injection with mean peak levels of 440-545 ng/ml occurring 2-3 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 ranitidine HCl, 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 ranitidine HCl.
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 2.5-3 hours. Four patients with clinically significant renal function impairment (creatinine clearance 25-35 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 3-4 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 (T½, Vd, and CL) are similar to those observed with IV ranitidine use in pediatric patients. Estimates of Cmax and Tmax are displayed in TABLE 5.
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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 36-94 ng/ml. Following a single oral dose of 150 mg, serum concentrations of ranitidine HCl 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 ranitidine HCl 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 ranitidine HCl tablets.
Antisecretory Activity
Effects on Acid Secretion
Ranitidine HCl 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 6.
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It appears that basal-, nocturnal-, and betazole-stimulated secretions are most sensitive to inhibition by ranitidine HCl, responding almost completely to doses of 100 mg or less, while pentagastrin- and food-stimulated secretions are more difficult to suppress.
Effects on Other Gastrointestinal Secretions
Other Pharmacologic Actions
Pediatrics
Oral doses of 6-10 mg/kg/day in 2 or 3 divided doses maintain gastric pH >4 throughout most of the dosing interval.
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 ranitidine HCl as shown in TABLE 7.
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| * All patients were permitted prn antacids for relief of pain. | |||||||||||||||||||
| † p <0.0001. | |||||||||||||||||||
In these studies, patients treated with ranitidine HCl reported a reduction in both daytime and nocturnal pain, and they also consumed less antacid than the placebo-treated patients.
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Foreign studies have shown that patients heal equally well with 150 mg bid and 300 mg hs (85% vs 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 bid as compared to 300 mg hs (92% vs 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 two independent, double-blind, multicenter, controlled trials, the number of duodenal ulcers observed was significantly less in patients treated with ranitidine HCl (150 mg hs) than in patients treated with placebo over a 12-month period.
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| * p <0.05 (ranitidine HCl versus comparator). | |||||||||||||||||||||||||||||||||||||||||||||
| % = Life table estimate. | |||||||||||||||||||||||||||||||||||||||||||||
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 ranitidine HCl as shown in TABLE 10.
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| * All patients were permitted prn antacids for relief of pain. | |||||||||||||||||||
| † p=0.009. | |||||||||||||||||||
In this multicenter trial, significantly more patients treated with ranitidine HCl became pain free during therapy.
Maintenance of Healing of Gastric Ulcers
In two multicenter, double-blind, randomized, placebo-controlled, 12-month trials conducted in patients whose gastric ulcers had been previously healed, ranitidine HCl 150 mg hs was significantly more effective than placebo in maintaining healing of gastric ulcers.
Pathological Hypersecretory Conditions (such as Zollinger-Ellison syndrome)
Ranitidine HCl 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 HCl was followed by healing of ulcers in 8 of 19 (42%) patients who were intractable to previous therapy.
Gastroesophageal Reflux Disease (GERD)
In two multicenter, double-blind, placebo-controlled, 6-week trials performed in the US and Europe, ranitidine HCl 150 mg bid 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 HCl 150 mg bid significantly reduced the frequency of heartburn attacks and severity of heartburn pain within 1-2 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 two additional US multicenter, double-blind, placebo-controlled, 2-week trials, ranitidine HCl 150 mg bid 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, ranitidine HCl Efferdose tablets were shown to provide heartburn relief within 45 minutes of dosing.
Erosive Esophagitis
In two multicenter, double-blind, randomized, placebo-controlled, 12-week trials performed in the US, ranitidine HCl 150 mg qid was significantly more effective than placebo in healing endoscopically diagnosed erosive esophagitis and in relieving associated heartburn. The erosive esophagitis healing rates are shown in TABLE 11.
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| * All patients were permitted prn 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 qid.
Maintenance of Healing of Erosive Esophagitis
In two multicenter, double-blind, randomized, placebocontrolled, 48-week trials conducted in patients whose erosive esophagitis had been previously healed, ranitidine HCl 150 mg bid was significantly more effective than placebo in maintaining healing of erosive esophagitis.
Ranitidine HCl is indicated in:
Concomitant antacids should be given as needed for pain relief to patients with active duodenal ulcer; active, benign gastric ulcer; hypersecretory states; GERD; and erosive esophagitis.
Ranitidine HCl is contraindicated for patients known to have hypersensitivity to the drug or any of the ingredients (see PRECAUTIONS).
General
Symptomatic response to therapy with ranitidine HCl does not preclude the presence of gastric malignancy.
Since ranitidine HCl is excreted primarily by the kidney, dosage should be adjusted in patients with impaired renal function (see DOSAGE AND ADMINISTRATION). Caution should be observed in patients with hepatic dysfunction since ranitidine HCl is metabolized in the liver.
Rare reports suggest that ranitidine HCl may precipitate acute porphyric attacks in patients with acute porphyria. Ranitidine HCl should therefore be avoided in patients with a history of acute porphyria.
Information for the Patient
Phenylketonurics: Ranitidine HCl 25 Efferdose tablets contain phenylalanine 2.81 mg/25 mg of ranitidine. Ranitidine HCl 150 Efferdose tablets contain phenylalanine 16.84 mg/150 mg of ranitidine.
Laboratory Tests
False-positive tests for urine protein with Multistix may occur during ranitidine HCl therapy, and therefore testing with sulfosalicylic acid is recommended.
Carcinogenesis, Mutagenesis, and Impairment of Fertility
There was no indication of tumorigenic or carcinogenic effects in life-span studies in mice and rats at dosages up to 2000 mg/kg/day.
Ranitidine was not mutagenic in standard bacterial tests (Salmonella, Escherichia coli) for mutagenicity at concentrations up to the maximum recommended for these assays.
In a dominant lethal assay, a single oral dose of 1000 mg/kg to male rats was without effect on the outcome of 2 matings per week for the next 9 weeks.
Pregnancy, Teratogenic Effects, Pregnancy Category B
Reproduction studies have been performed in rats and rabbits at doses up to 160 times the human dose and have revealed no evidence of impaired fertility or harm to the fetus due to ranitidine HCl. There are, however, no adequate and well-controlled studies in pregnant 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
Ranitidine HCl is secreted in human milk. Caution should be exercised when ranitidine HCl is administered to a nursing mother.
Pediatric Use
The safety and effectiveness of ranitidine HCl have been established in the age-group of 1 month to 16 years for the treatment of duodenal and gastric ulcers, gastroesophageal reflux disease and erosive esophagitis, and the maintenance of healed duodenal and gastric ulcer. Use of ranitidine HCl in this age-group is supported by adequate and well-controlled studies in adults, as well as additional pharmacokinetic data in pediatric patients and an analysis of the published literature (see CLINICAL PHARMACOLOGY, Pharacokinetics, Pediatrics and DOSAGE AND ADMINISTRATION, Pediatric Use).
Safety and effectiveness in pediatric patients for the treatment of pathological hypersecretory conditions or the maintenance of healing of erosive esophagitis have not been established.
Safety and effectiveness in neonates (less than 1 month of age) have not been established (see CLINICAL PHARMACOLOGY, Pharmacokinetics, Pediatrics).
Geriatric Use
Of the total number of subjects enrolled in US and foreign controlled clinical trials of oral formulations of ranitidine HCl, for which there were subgroup analyses, 4197 were 65 and over, while 899 were 75 and older. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and 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 and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, caution should be exercised in dose selection, and it may be useful to monitor renal function (see CLINICAL PHARMACOLOGY, Pharmacokinetics, Geriatrics and DOSAGE AND ADMINISTRATION, Dosage Adjustment for Patients With Impaired Renal Function).
Although ranitidine HCl has been reported to bind weakly to cytochrome P-450 in vitro, recommended doses of the drug do not inhibit the action of the cytochrome P-450-linked oxygenase enzymes in the liver. However, there have been isolated reports of drug interactions that suggest that ranitidine HCl may affect the bioavailability of certain drugs by some mechanism as yet unidentified (e.g., a pH-dependent effect on absorption or a change in volume of distribution).
Increased or decreased prothrombin times have been reported during concurrent use of ranitidine and warfarin. However, in human pharmacokinetic studies with dosages of ranitidine up to 400 mg/day, no interaction occurred; ranitidine had no effect on warfarin clearance or prothrombin time. The possibility of an interaction with warfarin at dosages of ranitidine higher than 400 mg/day has not been investigated.
In a ranitidine-triazolam drug-drug interaction study, triazolam plasma concentrations were higher during bid dosing of ranitidine than triazolam given alone. The mean area under the triazolam concentration-time curve (AUC) values in 18- to 60-year-old subjects were 10% and 28% higher following administration of 75-mg and 150-mg ranitidine tablets, respectively, than triazolam given alone. In subjects older than 60 years of age, the mean AUC values were approximately 30% higher following administration of 75- and 150-mg ranitidine tablets. It appears that there were no changes in pharmacokinetics of triazolam and α-hydroxytriazolam, a major metabolite, and in their elimination. Reduced gastric acidity due to ranitidine may have resulted in an increase in the availability of triazolam. The clinical significance of this triazolam and ranitidine pharmacokinetic interaction is unknown.
The following have been reported as events in clinical trials or in the routine management of patients treated with ranitidine HCl. The relationship to therapy with ranitidine HCl has been unclear in many cases. Headache, sometimes severe, seems to be related to administration of ranitidine HCl.
There has been limited experience with overdosage. Reported acute ingestions of up to 18 g orally have been associated with transient adverse effects similar to those encountered in normal clinical experience (see ADVERSE REACTIONS). In addition, abnormalities of gait and hypotension have been reported.
When overdosage occurs, the usual measures to remove unabsorbed material from the gastrointestinal tract, clinical monitoring, and supportive therapy should be employed.
Studies in dogs receiving dosages of ranitidine HCl in excess of 225 mg/kg/day have shown muscular tremors, vomiting, and rapid respiration. Single oral doses of 1000 mg/kg in mice and rats were not lethal. Intravenous LD50 values in mice and rats were 77 and 83 mg/kg, respectively.
Active Duodenal Ulcer
The current recommended adult oral dosage of ranitidine HCl for duodenal ulcer is 150 mg or 10 ml of syrup (2 teaspoonfuls of syrup equivalent to 150 mg of ranitidine) twice daily. An alternative dosage of 300 mg or 20 ml of syrup (4 teaspoonfuls of syrup equivalent to 300 mg of ranitidine) once daily after the evening meal or at bedtime can be used for patients in whom dosing convenience is important. The advantages of one treatment regimen compared to the other in a particular patient population have yet to be demonstrated (see CLINICAL STUDIES, Active Duodenal Ulcer). Smaller doses have been shown to be equally effective in inhibiting gastric acid secretion in US studies, and several foreign trials have shown that 100 mg twice daily is as effective as the 150-mg dose.
Antacid should be given as needed for relief of pain (see CLINICAL PHARMACOLOGY, Pharmacokinetics).
Maintenance of Healing of Duodenal Ulcers
The current recommended adult oral dosage is 150 mg or 10 ml of syrup (2 teaspoonfuls of syrup equivalent to 150 mg of ranitidine) at bedtime.
Pathological Hypersecretory Conditions (such as Zollinger-Ellison syndrome)
The current recommended adult oral dosage is 150 mg or 10 ml of syrup (2 teaspoonfuls of syrup equivalent to 150 mg of ranitidine) twice a day. In some patients it may be necessary to administer ranitidine HCl 150-mg doses more frequently. Dosages should be adjusted to individual patient needs, and should continue as long as clinically indicated. Dosages up to 6 g/day have been employed in patients with severe disease.
Benign Gastric Ulcer
The current recommended adult oral dosage is 150 mg or 10 ml of syrup (2 teaspoonfuls of syrup equivalent to 150 mg of ranitidine) twice a day.
Maintenance of Healing of Gastric Ulcers
The current recommended adult oral dosage is 150 mg or 10 ml of syrup (2 teaspoonfuls of syrup equivalent to 150 mg of ranitidine) at bedtime.
GERD
The current recommended adult oral dosage is 150 mg or 10 ml of syrup (2 teaspoonfuls of syrup equivalent to 150 mg of ranitidine) twice a day.
Erosive Esophagitis
The current recommended adult oral dosage is 150 mg or 10 ml of syrup (2 teaspoonfuls of syrup equivalent to 150 mg of ranitidine) 4 times a day.
Maintenance of Healing of Erosive Esophagitis
The current recommended adult oral dosage is 150 mg or 10 ml of syrup (2 teaspoonfuls of syrup equivalent to 150 mg of ranitidine) twice a day.
Pediatric Use
The safety and effectiveness of ranitidine HCl have been established in the age-group of 1 month to 16 years. There is insufficient information about the pharmacokinetics of ranitidine HCl in neonatal patients (less than 1 month of age) to make dosing recommendations.
The following 3 subsections provide dosing information for each of the pediatric indications. Also, see Preparation of Ranitidine HCl 25 Efferdose Tablets.
Treatment of Duodenal and Gastric Ulcers
The recommended oral dose for the treatment of active duodenal and gastric ulcers is 2-4 mg/kg/day twice daily to a maximum of 300 mg/day. This recommendation is derived from adult clinical studies and pharmacokinetic data in pediatric patients.
Maintenance of Healing of Duodenal and Gastric Ulcers
The recommended oral dose for the maintenance of healing of duodenal and gastric ulcers is 2-4 mg/kg once daily to a maximum of 150 mg/day. This recommendation is derived from adult clinical studies and pharmacokinetic data in pediatric patients.
Treatment of GERD and Erosive Esophagitis
Although limited data exist for these conditions in pediatric patients, published literature supports a dosage of 5-10 mg/kg/day, usually given as 2 divided doses.
Dosage Adjustment for Patients With Impaired Renal Function
On the basis of experience with a group of subjects with severely impaired renal function treated with ranitidine HCl, the recommended dosage in patients with a creatinine clearance <50 ml/min is 150 mg or 10 ml of syrup (2 teaspoonfuls of syrup equivalent to 150 mg of ranitidine) every 24 hours. Should the patient's condition require, the frequency of dosing may be increased to every 12 hours or even further with caution. Hemodialysis reduces the level of circulating ranitidine. Ideally, the dosing schedule should be adjusted so that the timing of a scheduled dose coincides with the end of hemodialysis.
Elderly patients are more likely to have decreased renal function, therefore caution should be exercised in dose selection, and it may be useful to monitor renal function (see CLINICAL PHARMACOLOGY, Pharmacokinetics, Geriatrics and PRECAUTIONS, Geriatric Use).
Preparation of Ranitidine HCl 25 Efferdose Tablets
Dissolve 1 tablet in no less than 5 ml (1 teaspoonful) of water in an appropriate measuring cup. Wait until the tablet is completely dissolved before administering the solution to the infant/child. The solution may be administered by medicine dropper for infants.
Preparation of Ranitidine HCl 150 Efferdose Tablets
Dissolve each dose in approximately 6-8 oz of water before drinking.
Zantac Tablets
Storage: Store between 15 and 30°C (59 and 86°F) in a dry place. Protect from light. Replace cap securely after each opening.
Zantac Efferdose Tablets
Storage: Store between 2 and 30°C (36 and 86°F).
Zantac Syrup
Zantac syrup, a clear, peppermint-flavored liquid, contains 16.8 mg of ranitidine HCl equivalent to 15 mg of ranitidine per 1 ml (75 mg/5 ml) in bottles of 16 fluid oz (1 pint).
Storage: Store between 4 and 25°C (39 and 77°F). Dispense in tight, light-resistant containers.
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