Ranitidine

DESCRIPTION

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

Oral

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, hydroxypropyl methylcellulose, 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, hydroxypropyl methylcellulose, magnesium stearate, microcrystalline cellulose, titanium dioxide, and triacetin.

Zantac 150 geldose capsules and Zantac 300 geldose capsules for oral administration are soft gelatin capsules containing 168 mg of ranitidine HCl equivalent to 150 mg of ranitidine and 336 mg of ranitidine HCl equivalent to 300 mg of ranitidine, respectively, in a nonaqueous matrix of synthetic coconut oil and synthetic triglycerides. The soft gelatin capsule shell contains gelatin, sorbitol special (sorbitol and sorbitol anhydrides), glycerin, purified water, titanium dioxide, FD&C yellow No. 6, FD&C blue No. 1, and FD&C red No. 40. The capsule shell may also contain mineral oil and soybean lecithin. The capsules are printed with edible ink.

Zantac 150 EFFERdose tablets and Zantac 150 EFFERdose granules for oral administration are effervescent formulations of ranitidine that must be dissolved in water before use. Each individual tablet or the contents of a packet contain 168 mg of ranitidine HCl 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, and the total sodium content of each packet of granules is 173.54 mg (7.55 mEq) per 150 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, hydroxypropyl methylcellulose, peppermint flavor, monobasic potassium phosphate, propylparaben, purified water, saccharin sodium, sodium chloride, and sorbitol.

Injection, Injection Premixed, and Injection Pharmacy Bulk Package¾Not for Direct Infusion

Ranitidine HCl 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 to 7.3.

Sterile Injection for Intramuscular or Intravenous Administration or Injection Pharmacy Bulk Package: 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.

Injection Pharmacy Bulk Package¾Not for Direct Infusion: 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 intravenous (IV) infusion.

Sterile, Premixed Solution for Intravenous Administration in Single-Dose, Flexible Plastic Containers: Each 50 ml contains ranitidine HCl 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 to 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.

CLINICAL PHARMACOLOGY

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.

Antisecretory Activity: Effects on Acid Secretion

Oral

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 1.

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.

Injection, Injection Premixed, and Injection Pharmacy Bulk Package¾Not for Direct Infusion

Ranitidine HCl injection inhibits basal gastric acid secretion as well as gastric acid secretion stimulated by betazole and pentagastrin, as shown in TABLE 2.

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

Pepsin: Ranitidine HCl does not affect pepsin secretion. Total pepsin output is reduced in proportion to the decrease in volume of gastric juice.

Intrinsic Factor: Ranitidine HCl has no significant effect on pentagastrin-stimulated intrinsic factor secretion.

Serum Gastrin: Ranitidine HCl has little or no effect on fasting or postprandial serum gastrin.

Other Pharmacologic Actions

a. Gastric bacterial flora: Increase in nitrate-reducing organisms, significance not known.

b. 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.

c. Other pituitary hormones: No effect on serum gonadotropins, TSH, or GH. Possible impairment of vasopressin release.

d. No change in cortisol, aldosterone, androgen, or estrogen levels.

e. No antiandrogenic action.

f. No effect on count, motility, or morphology of sperm.

Pharmacokinetics

Oral

Ranitidine HCl is 50% absorbed after oral administration, compared to an IV injection with mean peak levels of 440 to 545 ng/ml occurring at 2 to 3 hours after a 150-mg dose. The syrup, capsule, and effervescent formulations are bioequivalent to the tablets. In a pharmacodynamic comparison of the effervescent with the ranitidine HCl tablets, during the first hour after administration, the effervescent tablet formulation gave a significantly higher intragastric pH, by approximately 1 pH unit, compared to the ranitidine HCl tablets. The elimination half-life is 2.5 to 3 hours.

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.

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 HCl are in this range up to 12 hours. However, blood levels bear no consistent relationship to dose or degree of acid inhibition.

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 per minute, indicating active tubular excretion. Four patients with clinically significant renal function impairment (creatinine clearance 25 to 35 ml per minute) administered 50 mg of ranitidine intravenously had an average plasma half-life of 4.8 hours, a ranitidine clearance of 29 ml per minute, 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).

In man, 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.

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

Injection, Injection Premixed, and Injection Pharmacy Bulk Package-Not for Direct Infusion

Serum concentrations necessary to inhibit 50% of stimulated gastric acid secretion are estimated to be 36 to 94 ng/ml. Following single IV or intramuscular (IM) 50-mg doses, serum concentrations of ranitidine HCl are in this range for 6 to 8 hours.

Following IV injection, approximately 70% of the dose is recovered in the urine as unchanged drug. Renal clearance averages 530 ml per minute, with a total clearance of 760 ml per minute. The volume of distribution is 1.4 l/kg, and the elimination half-life is 2 to 2.5 hours.

Four patients with clinically significant renal function impairment (creatinine clearance 25 to 35 ml per minute) administered 50 mg of ranitidine intravenously had an average plasma half-life of 4.8 hours, a ranitidine clearance of 29 ml per minute, 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).

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% to 100% compared with IV administration. Following oral administration, the relative bioavailability of ranitidine HCl tablets is 50%.

In humans, the N-oxide is the principal metabolite in the urine; however, this amounts to less than 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.

Serum protein binding averages 15%.

CLINICAL STUDIES

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 3.

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 (TABLE 4).

Oral

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 two independent, double-blind, multicenter, controlled trials, the number of duodenal ulcers observed was significantly less in patients treated with ranitidine HCl (150 mg h.s.) than in patients treated with placebo over a 12-month period (TABLE 5).

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 the following table (TABLE 6):

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 h.s. 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 United States and Europe, ranitidine HCl 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 ranitidine HCl 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 two additional US multicenter, double-blind, placebo-controlled, 2-week trials, ranitidine HCl 150 mg b.i.d. was shown to provide relief of heartburn pain wihtin 24 hours of initiating therapy and a reduction in the frequency of severity of heartburn. In these trials, ranitidine HCl 150mg 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 United States, ranitidine HCl 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 are in TABLE 7.

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

Injection

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 per hour.

INDICATIONS

Oral

Ranitidine HCl is Indicated in:

1. Short-term treatment of active duodenal ulcer. Most patients heal within 4 weeks. Studies available to date have not assessed the safety of ranitidine in uncomplicated duodenal ulcer for periods of more than 8 weeks.

2. Maintenance therapy for duodenal ulcer patients at reduced dosage after healing of acute ulcers. No placebo-controlled comparative studies have been carried out for periods of longer than 1 year.

3. The treatment of pathological hypersecretory conditions (e.g., Zollinger-Ellison syndrome and systemic mastocytosis).

4. Short-term treatment of active, benign gastric ulcer. Most patients heal within 6 weeks and the usefulness of further treatment has not been demonstrated. Studies available to date have not assessed the safety of ranitidine in uncomplicated, benign gastric ulcer for periods of more than 6 weeks.

5. Maintenance therapy for gastric ulcer patients at reduced dosage after healing of acute ulcers. Placebo-controlled studies have been carried out for 1 year.

6. Treatment of GERD. Symptomatic relief commonly occurs within 1 or 2 weeks after starting therapy with ranitidine HCl 150 mg b.i.d.

7. Treatment of endoscopically diagnosed erosive esophagitis. Symptomatic relief of heartburn commonly occurs within 24 hours of therapy initiation with ranitidine HCl 150 mg q.i.d.

8. Maintenance of healing of erosive esophagitis. Placebo-controlled trials have been carried out for 48 weeks.

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.

Injection, Injection Premixed, and Injection Pharmacy Bulk Package¾Not for Direct Infusion

Ranitidine HCl injection is 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.

DOSAGE AND ADMINISTRATION

Oral

Active Duodenal Ulcer: The current recommended adult oral dosage of ranitidine HCl for duodenal ulcer is 150 mg or 10 ml (2 teaspoonfuls equivalent to 150 mg of ranitidine) twice daily. An alternative dosage of 300 mg or 20 ml (4 teaspoonfuls 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 b.i.d. 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 (2 teaspoonfuls 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 (2 teaspoonfuls 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 per day have been employed in patients with severe disease.

Benign Gastric Ulcer: The current recommended adult oral dosage is 150 mg or 10 ml (2 teaspoonfuls 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 (2 teaspoonfuls equivalent to 150 mg of ranitidine) at bedtime.

GERD: The current recommended adult oral dosage is 150 mg or 10 ml (2 teaspoonfuls equivalent to 150 mg of ranitidine) twice a day.

Erosive Esophagitis: The current recommended adult oral dosage is 150 mg or 10 ml (2 teaspoonfuls equivalent to 150 mg of ranitidine) four times a day.

Maintenance of Healing of Erosive Esophagitis: The current recommended adult oral dosage is 150 mg or 10 ml (2 teaspoonfuls equivalent to 150 mg of ranitidine) twice a day.

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 per minute is 150 mg or 10 ml (2 teaspoonfuls 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.

Preparation of Ranitidine HCl 150 Effervescent Tablets and Ranitidine HCl 150 Effervescent Granules: Dissolve each dose in approximately 6 to 8 o of water before drinking.

Injection

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 to 8 hours. (No dilution necessary.)

Intermittent Intravenous Injection

1. Intermittent Bolus: 50 mg (2 ml) every 6 to 8 hours. Dilute ranitidine HCl injection, 50 mg, in 0.9% sodium chloride injection or other compatible IV solution (see

DOSAGE AND ADMINISTRATION

2. Intermittent Infusion: 50 mg (2 ml) every 6 to 8 hours. Dilute ranitidine HCl injection, 50 mg, in 5% dextrose injection or other compatible IV solution (see

DOSAGE AND ADMINISTRATION

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 it generally should not exceed 400 mg per day.

Continuous Intravenous Infusion

Add ranitidine HCl injection to 5% dextrose injection or other compatible IV solution (see

DOSAGE AND ADMINISTRATION

For Zollinger-Ellison patients, dilute ranitidine HCl injection in 5% dextrose injection or other compatible IV solution (see DOSAGE AND ADMINISTRATION, Stability) to a concentration no greater than 2.5 mg/ml. Start the infusion at a rate of 1.0 mg/kg per hour. If after 4 hours either a measured gastric acid output is > 10 mEq or the patient becomes symptomatic, the dose should be adjusted upward in 0.5-mg/kg per hour increments, and the acid output should be remeasured. Dosages up to 2.5 mg/kg per hour and infusion rates as high as 220 mg per hour have been used.

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.

Preparation for Administration: Use aseptic technique.

1. Close wflow control clamp of administration set.

2. Remove cover from outlet port at bottom of container.

3. Insert piercing pin of administration set into port with a twisting motion until the pin is firmly seated. NOTE: See full directions on administration set carton.

4. Suspend container from hanger.

5. Squeeze and release drip chamber to establish proper fluid level in chamber during infusion of Zantac Injection Premixed.

6. Open wflow control clamp to expel air from set. Close clamp.

7. Attach set to venipuncture device. If device is not indwelling, prime and make venipuncture.

8. Perform venipuncture.

9. Regulate rate of administration with wflow control clamp.

Caution: Zantac Injection Premixed in flexible plastic containers is to be administered by 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 Zantac 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 wiht 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 to 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.

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.

Directions for Dispensing

Pharmacy Bulk Package¾Not for Direct Infusion: The pharmacy bulk package is for use in a pharmacy admixture service only under a laminar flow hood. The closure should be penetrated only once with a sterile transfer set or other sterile dispensing device, which allows measured distribution of the contents, and the contents dispensed in aliquots using aseptic technique. CONTENTS SHOULD BE USED AS SOON AS POSSIBLE FOLLOWING INITIAL CLOSURE PUNCTURE. DISCARD ANY UNUSED PORTION WITHIN 24 HOURS OF FIRST ENTRY. Following closure puncture, container should be maintained below 30°C (86°F) under a laminar flow hood until contents are dispensed.

HOW SUPPLIED

Oral

Zantac 150 tablets are peach, film-coated, five-sided tablets embossed with "Zantac 150" on one side and "Glaxo" on the other. Zantac 300 tablets are yellow, film-coated, capsule-shaped tablets embossed with "Zantac 300" on one side and "Glaxo" on the other.

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 150 geldose capsules are beige, soft gelatin capsules imprinted with "Zantac 150" on one side and "Glaxo" on the other. Zantac 300 geldose capsules are beige, soft gelatin capsules imprinted with "Zantac 300" on one side and "Glaxo" on the other.

Store between 2° and 25°C (36° and 77°F) in a dry place. Protect from light. Replace cap securely after each opening.

Zantac 150 EFFERdose tablets are white to pale yellow, round, flat-faced, bevel-edged tablets embossed with "Zantac 150" on one side and "427" on the other. Zantac 150 EFFERdose granules are white to pale yellow granules.

Storage: Store between 2° and 30°C (36° and 86°F).

Zantac syrup, a clear, peppermint-flavored liquid, contains 16.8 mg of ranitidine HCl equivalent to 15 mg of ranitidine per 1 ml in bottles of 16 fluid ounces (one pint).

Storage: Store between 4° and 25°C (39° and 77°F). Dispense in tight, light-resistant containers as defined in the USP/NF.

Injection, Injection Premixed, and Injection Pharmacy Bulk Package-Not for Direct Infusion

Zantac injection, 25 mg/ml, contains phenol 0.5% as preservative.

Storage: Store between 4° and 30°C (39° and 86°F). Protect from light.

Zantac injection premixed, 50 mg/50 ml, in 0.45% sodium chloride, 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.

Injection Pharmacy Bulk Package¾Not for Direct Infusion: Zantac injection, 25 mg/ml, containing phenol 0.5% as preservative, in a 40-ml pharmacy bulk package.

Storage: Store between 4° and 30°C (39° and 86°F). Protect from light. Store vial in carton until time of use.

SIDE EFFECTS

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 therapy has been unclear in many cases. Headache, sometimes severe, seems to be related to administration of ranitidine HCl.

Central Nervous System: Rarely, malaise, dizziness, somnolence, insomnia, and vertigo. Rare cases of reversible mental confusion, agitation, depression, and hallucinations have been reported, predominantly in severely ill elderly patients. Rare cases of reversible blurred vision suggestive of a change in accommodation have been reported. Rare reports of reversible involuntary motor disturbances have been received.

Cardiovascular: As with other H₂-blockers, rare reports of arrhythmias such as tachycardia, bradycardia, asystole (injection only), atrioventricular block, and premature ventricular beats.

Gastrointestinal: Constipation, diarrhea, nausea/vomiting, abdominal discomfort/pain, and rare reports of pancreatitis.

Hepatic: In normal volunteers, SGPT values were increased to at least twice the pretreatment levels in 6 of 12 subjects receiving 100 mg q.i.d. intravenously for 7 days, and in 4 of 24 subjects receiving 50 mg q.i.d. intravenously for 5 days. There have been occasional reports of hepatocellular, cholestatic, or mixed hepatitis, with or without jaundice. In such circumstances, ranitidine should be immediately discontinued. These events are usually reversible, but in exceedingly rare circumstances death has occurred. Rare cases of hepatic failure have also been reported.

Musculoskeletal: Rare reports of arthralgias and myalgias.

Hematologic: Blood count changes (leukopenia, granulocytopenia, and thrombocytopenia) have occurred in a few patients. These were usually reversible. Rare cases of agranulocytosis, pancytopenia, sometimes with marrow hypoplasia, and aplastic anemia and exceedingly rare cases of acquired immune hemolytic anemia have been reported.

Endocrine: Controlled studies in animals and humans have shown no stimulation of any pituitary hormone by ranitidine HCl and no antiandrogenic activity, and cimetidine-induced gynecomastia and impotence in hypersecretory patients have resolved when ranitidine HCl has been substituted. However, occasional cases of gynecomastia, impotence, and loss of libido have been reported in male patients receiving ranitidine HCl, but the incidence did not differ from that in the general population.

Integumentary: Rash, including rare cases of erythema multiforme, and, rarely, alopecia.

Other: Rare cases of hypersensitivity reactions (e.g., bronchospasm, fever, rash, eosinophilia), anaphylaxis, angioneurotic edema, and small increases in serum creatinine.

Injection, Injection Premixed, and Injection Pharmacy Bulk Package¾Not for Direct Infusion: 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.

DRUG INTERACTIONS

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 per 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 per 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 18-60 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-mg and 150-mg ranitidine tablets. It appears that there were no changes in pharmacokinetics of triazolam and a-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.

WARNINGS

No information provided.

PRECAUTIONS

General

1. Symptomatic response to ranitidine HCl therapy does not preclude the presence of gastric malignancy.

2. 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.

3. 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.

4. Injection only: 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 ³100 mg q.i.d. for periods of 5 days or longer to monitor SGPT daily (from day 5) for the remainder of IV therapy.

5. Injection only: 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).

Information for the Patient

Phenylketonurics: Zantac 150 efferdose tablets and Zantac 150 efferdose granules contain phenylalanine 16.84 mg per 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 per 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 two 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

Safety and effectiveness in pediatric patients have not been established.

Geriatric Use

Ulcer healing rates in elderly patients (65 to 82 years of age) were no different from those in younger age-groups. The incidence rates for adverse events and laboratory abnormalities were also not different from those seen in other age-groups.