Ranitidine Syrup (Ranitidine Oral Solution, USP)

DESCRIPTION

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displayName: DESCRIPTION SECTION
FDA Article Code: 34089-3

The active ingredient in Ranitidine Syrup (Ranitidine Oral Solution, USP) is ranitidine hydrochloride (HCl), USP, a histamine H₂-receptor antagonist. Chemically it is N[2-[[[5-[(dimethylamino)methyl]-2-furanyl]methyl]thio]ethyl]-N’-methyl-2-nitro-1,1-ethenediamine, HCl. It has the following structure:

The molecular formula is C₁₃H₂₂N₄O₃SHCl, representing a molecular weight of 350.87.

Ranitidine HCl is a white to pale yellow, crystalline, practically odorless powder that is very soluble in water, sparingly soluble in alcohol.

Each 1 mL of ranitidine oral solution contains 16.8 mg of ranitidine HCl equivalent to 15 mg of ranitidine. Ranitidine oral solution also contains the inactive ingredients dehydrated alcohol (7.5%), butylparaben, dibasic sodium phosphate anhydrous, hypromellose, monobasic potassium phosphate, noncrystallizing sorbitol solution (70%), peppermint flavour, propylparaben, purified water, saccharin sodium, sodium chloride.

CLINICAL PHARMACOLOGY

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displayName: CLINICAL PHARMACOLOGY SECTION
FDA Article Code: 34090-1

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

Pharmacokinetics:

Absorption:
Ranitidine
is 50% absorbed after oral administration, compared to an intravenous
(IV) injection with mean peak levels of 440 to 545 ng/mL occurring 2 to
3 hours after a 150-mg dose. The oral solution formulation 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 study, 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. Studies in patients with
hepatic dysfunction (compensated cirrhosis) indicate that there are
minor, but clinically insignificant, alterations in ranitidine
half-life, distribution, clearance, and bioavailability.  

Excretion:

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

Geriatrics:


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

Pediatrics:
There are no significant differences in the pharmacokinetic parameter values for ranitidine in pediatric patients (from 1 month up to 16 years of age) and healthy adults when correction is made for body weight. The average bioavailability of ranitidine given orally to pediatric patients is 48% which is comparable to the bioavailability of ranitidine in the adult population. All other pharmacokinetic parameter values (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.

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

Pharmacodynamics: Serum concentrations necessary to inhibit 50% of stimulated gastric acid secretion are estimated to be 36 to 94 ng/mL. Following a single oral dose of 150 mg, serum concentrations of 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.

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:

INDICATIONS AND USAGE

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displayName: INDICATIONS & USAGE SECTION
FDA Article Code: 34067-9

Ranitidine oral solution is indicated in: 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.
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.
The treatment of pathological hypersecretory conditions (e.g., Zollinger-Ellison syndrome and systemic mastocytosis).
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.
Maintenance therapy for gastric ulcer patients at reduced dosage after healing of acute ulcers. Placebo-controlled studies have been carried out for 1 year.
Treatment of GERD. Symptomatic relief commonly occurs within 24 hours after starting therapy with ranitidine 150 mg b.i.d.
Treatment of endoscopically diagnosed erosive esophagitis. Symptomatic relief of heartburn commonly occurs within 24 hours of therapy initiation with ranitidine 150 mg q.i.d.
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.

CONTRAINDICATIONS

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displayName: CONTRAINDICATIONS SECTION
FDA Article Code: 34070-3

Ranitidine is contraindicated for patients known to have hypersensitivity to the drug or any of the ingredients (see PRECAUTIONS).

PRECAUTIONS

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displayName: PRECAUTIONS SECTION
FDA Article Code: 42232-9

ADVERSE REACTIONS

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displayName: ADVERSE REACTIONS SECTION
FDA Article Code: 34084-4

The following have been reported as events in clinical trials or in the routine management of patients treated with ranitidine. The relationship to therapy with ranitidine has been unclear in many cases. Headache, sometimes severe, seems to be related to administration of ranitidine.

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, atrioventricular block, and premature ventricular beats.

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

Hepatic: 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 rare circumstances death has occurred. Rare cases of hepatic failure have also been reported. 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.

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

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

Respiratory: A large epidemiological study suggested an increased risk of developing pneumonia in current users of histamine-2-receptor antagonists (H₂RAs) compared to patients who had stopped H₂RA treatment, with an observed adjusted relative risk of 1.63 (95% CI, 1.07-2.48). However, a causal relationship between use of H₂RAs and pneumonia has not been established.

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

OVERDOSAGE

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displayName: OVERDOSAGE SECTION
FDA Article Code: 34088-5

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 in excess of 225 mg/kg per day have shown muscular tremors, vomiting, and rapid respiration. Single oral doses of 1,000 mg/kg in mice and rats were not lethal. Intravenous LD₅₀ values in mice and rats were 77 and 83 mg/kg, respectively.

DOSAGE AND ADMINISTRATION

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displayName: DOSAGE & ADMINISTRATION SECTION
FDA Article Code: 34068-7

Active Duodenal Ulcer: The current recommended adult oral dosage of ranitidine oral solution for duodenal ulcer is 150 mg or 10 mL of oral solution (2 teaspoonfuls of oral solution equivalent to 150 mg of ranitidine) twice daily. An alternative dosage of 300 mg or 20 mL of oral solution (4 teaspoonfuls of oral solution 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 Trials: 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 oral solution (2 teaspoonfuls of oral solution 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 oral solution (2 teaspoonfuls of oral solution equivalent to 150 mg of ranitidine) twice a day. In some patients it may be necessary to administer ranitidine 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 oral solution (2 teaspoonfuls of oral solution 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 oral solution (2 teaspoonfuls of oral solution equivalent to 150 mg of ranitidine) at bedtime.

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

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

Pediatric Use: The safety and effectiveness of ranitidine have been established in the age-group of 1 month to 16 years. There is insufficient information about the pharmacokinetics of ranitidine 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.

Treatment of Duodenal and Gastric Ulcers:


The recommended oral dose for the treatment of active duodenal and gastric ulcers is 2 to 4 mg/kg 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 to 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 to 10 mg/kg per 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, the recommended dosage in patients with a creatinine clearance <50 mL/min is 150 mg or 10 mL of oral solution (2 teaspoonfuls of oral solution 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).

HOW SUPPLIED

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displayName: HOW SUPPLIED SECTION
FDA Article Code: 34069-5

Ranitidine Syrup (Ranitidine Oral Solution, USP) a clear, pale yellow, 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 ounces (one pint) (NDC 64679-694-01).

Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature].

Manufactured by:
Wockhardt Limited,
Mumbai, India.

Distributed by:

Wockhardt USA LLC.
20 Waterview Blvd.
Parsippany, NJ 07054
USA.

Rev.070909