Ranitak 150 mg & 300 mg Film Coated Tablets

Ranitidine HCI

Composition

– The active ingredient in RANITAK 150 mg & 300 mg Film Coated Tablets is Ranitidine as 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, HCI.

The empirical formula is C 13 H 22 N 4 0 3 S-HCI, representing a molecular weight of 350.87 mg.

– Ranitidine HCL is a white to pale yellow, granular substance that is soluble in water. It has a slightly bitter taste and sulfur-like odor.

Each RANITAK 150 mg for oral administration contains: 168 mg of ranitidine HCL equivalent to 150 mg Ranitidine.

Each RANITAK 300 mg for oral administration contains: 336 mg of ranitidine HCI equivalent to 300 mg Ranitidine.

Properties

Clinical pharmacology

RANITAK is a competitive, reversible inhibitor of the action of histamine at the histamine H2 – receptors, including receptors on the gastric cells.

RANITAK does not lower serum Ca++ in hypercalcemic states.

RANITAK is not an anticholinergic agent.

Antisecretory activity

  1. Effects on Acid Secretion

RANITAK inhibits both daytime and nocturnal basal gastric acid secretions as well as gastric acid secretion stimulated by food, betazole-stimulated secretions are most sensitive to RANITAK, responding almost completely to doses of 100 mg or less, while pentagastrin – and food – stimulated secretions are more difficult to suppress.

  1. Effects on Other Gastrointestinal Secretions:

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

Intrinsic Factor: Oral RANITAK has no significant effect on pentagastrin-stimulated intrinsic factor secretion.

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

Other pharmacological actions

  1. Gastric bacterial flora: increase in nitrate-reducing organisms, significance not known.
  2. Prolactin levels: no effect in recommended oral dosage.
  3. Other pituitary hormones: no effect on serum gonado-tropins,TSH,GH. Possible impairment of vasopressin release.
  4. No change in cortisol, aldosterone, androgen, or estrogen level.
  5. No antiandrogenic action..
  6. No effect on count, motility, or morphology of sperm.

Pharmacokinetics

RANITAK is 50% absorbed after oral administration, compared to an IV injection with mean peak levels of 440 to 545 mg/mL occurring at 2 to 3 hours after a 150 mg dose.

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 RANITAK, 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 RANITAK.

Serum concentrations necessary to inhibit 50% of stimulated gastric acid secretion are estimated to be 36 to 94 mg/mL.

Following a single oral dose of 150 mg, serum concentrations of RANITAK are in this range up to 12 hours. However, blood levels bear no consistent relationship to dose or degree of acid inhibition. The principle 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.

In man, the N-oxide is the principle 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.%

Indications and usage

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 yeas.

Treatment of GERD. Symptomatic relief commonly occurs within 24 hours after starting therapy with RANITAK 150 mg b.i.d.

Treatment of endoscopically diagnosed erosive esophagitis. Symptomatic relief of heartburn commonly occurs within 24 hours of therapy initiation with RANITAK 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.

Contra-indications

RANITAK is contraindicated for patients known to have hypersensitivity to the drug or any of the ingredients .

Side effects

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

  1. 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.

  1. Cardiovascular:

As with other H 2 -blockers, rare reports of arrhythmias such as tachycardia, bradycardia, atrioventricular block, and premature ventricular beats.

  1. Gastrointestinal:

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

  1. 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.

  1. Musculoskeletal:

Rare reports of arthralgias and myalgias.

  1. Hematologic:

Blood count changes (Ieukopenia, 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.

  1. Endocrine:

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

  1. Integumentary:

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

  1. -Other:

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

Drug interactions

Although RANITAK 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 RANITAK 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 pf 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.

As with other agents that lower gastric acidity, ranitidine has been shown to increase the absorption of triazolam resulting in increased plasma concentrations.

Carcinogenesis, Mutagenesis, Impairment of Fertility

There was no indication of tumorigenic or carcinogenic effects in life-span studies in mice and rats at dosages up to 2,000 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 1,000 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 RANITAK. 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

Ranitak is secreated in human milk. Caution should be exercised when RANITAK is administered to a nursing mother.

Pediatric use

Safety and effectiveness in pediatric patients have not been established.

Use in elderly patients

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.

Warnings and precautions

General:

Symptomatic response to therapy with RANITAK does not preclude the presence of gastric malignancy.

Since RANITAK is excreted primarily by the kidney, dosage should be adjusted in patients with impaired renal function.

Caution should be observed in patients with hepatic dysfunction since RANITAK is metabolized in the liver.

Rare reports suggest that RANITAK may precipitate acute porphyric attacks in patients with acute porphyria. RANITAK should therefore be avoided in patients with a history of acute porphyria.

Information for patients

Laboratory tests:

False-positive tests for urine protein with MUL TISTIX may occur during RANITAK therapy, and therefore testing with sulfosalicylic acid is recommended.

Overdose

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 . 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 RANITAK 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 LD 50 values in mice and rats were 77 and 83 mg/kg, respectively.

Dosage and administration

Active Duodenal Ulcer:

The current recommended adult oral dosage of RANITAK for duodenal ulcer is 150 mg twice daily. An alternative dosage of 300 mg 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 .

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 .

Maintenance of Healing of Duodenal Ulcers:

The current recommended adult oral dosage is 150 mg at bedtime.

Pathological Hypersecretory Conditions (such as Zollinger-Ellison syndrome):

The current recommended adult oral dosage is 150 mg twice a day.

In some patients it may be necessary to administer RANITAK 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 twice a day.

Maintenance of Healing of Gastric Ulcers:

The current recommended adult oral dosage is 150 mg at bedtime.

GERD:

The current recommended adult oral dosage is 150 mg twice a day.

Erosive Esophagitis:

The current recommended adult oral dosage is 150 mg four times a day.

Maintenance of Healing of Erosive Esophagitis:

The current recommended adult oral dosage is 150 mg 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 RANITAK, the recommended dosage in patients with a creatinine clearance <50 ml/min is 150 mg 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.

Storage

Store at temperature not exceeding 30° C, in a dry place, protected from light.