Zantac^® (Tablets, Solution) Instructions for Use

ATC Code

A02BA02 (Ranitidine)

Active Substance

Ranitidine (Rec.INN registered by WHO)

Clinical-Pharmacological Group

Histamine H₂-receptor blocker. Antiulcer drug

Pharmacotherapeutic Group

H2 histamine receptor blocker

Pharmacological Action

Histamine H₂-receptor blocker. Reduces basal and stimulated secretion of hydrochloric acid, induced by baroreceptor irritation, food load, action of histamine, gastrin and other biogenic stimulants.

It reduces both the volume of secretion and the content of hydrochloric acid and pepsin in it. It contributes to an increase in the pH of the gastric contents, which leads to a decrease in pepsin activity. The duration of action of ranitidine after a single dose is 12 hours.

Helicobacter pylori is detected in approximately 95% of patients with duodenal ulcers and in 80% of patients with gastric ulcers. When ranitidine is combined with amoxicillin and metronidazole, eradication of Helicobacter pylori is noted in approximately 90% of cases. This combination of drugs significantly reduces the frequency of exacerbations of duodenal ulcer.

Pharmacokinetics

Absorption

When taken orally, the bioavailability of ranitidine is approximately 50%. After oral administration of the drug at a dose of 150 mg, C_max is reached in 2-3 hours and is 300-550 ng/ml.

After intramuscular administration, C_max is reached within 15 minutes after administration and is 300-500 ng/ml.

Distribution

Binding to plasma proteins does not exceed 15%. Ranitidine penetrates the placental barrier. It is excreted in breast milk (concentration in breast milk is higher than in plasma). It poorly penetrates the blood-brain barrier.

Metabolism

It is not subject to intensive metabolism. The metabolism of ranitidine does not differ with parenteral administration and oral administration and proceeds with the formation of small amounts of N-oxide (6%), S-oxide (2%), desmethylranitidine (2%) and a furoic acid analogue (1-2%).

Excretion

T_1/2 is 2-3 hours.

After taking ³H-ranitidine at a dose of 150 mg, 60-70% of the drug is excreted in the urine and 26% in the feces; and 35% of the taken dose is excreted in the urine unchanged.

After intravenous administration of ³H-ranitidine at a dose of 150 mg, 93% of the drug is excreted in the urine and 5% in the feces; in the first 24 hours, 70% of the taken dose is excreted in the urine unchanged.

Pharmacokinetics in special clinical cases

In severe renal impairment, the plasma concentration of ranitidine increases.

Indications

• Duodenal ulcers and benign gastric ulcers, incl. those associated with NSAID use;
• Prevention of duodenal ulcers caused by NSAIDs (including acetylsalicylic acid), especially in patients with a history of peptic ulcer disease;
• Duodenal ulcers associated with Helicobacter pylori infection;
• Postoperative ulcers;
• Gastroesophageal reflux disease;
• Reflux esophagitis;
• Relief of pain in gastroesophageal reflux disease;
• Zollinger-Ellison syndrome;
• Chronic episodic dyspepsia characterized by epigastric or retrosternal pain that is related to food intake or disturbs sleep, but is not related to the above conditions;
• Prevention of stress gastric ulcers in severely ill patients;
• Prevention of recurrent bleeding from peptic ulcers;
• Prevention of Mendelson’s syndrome (aspiration of acidic gastric contents during anesthesia).

ICD codes

Dosage Regimen

Solution

Tablets and effervescent tablets

Orally for adults with exacerbation of duodenal ulcer and benign gastric ulcer, 150 mg 2 times/day or 300 mg at night is prescribed. In most cases, duodenal ulcers and benign gastric ulcers heal within 4 weeks. In patients with ulcers that have not healed during this period, healing usually occurs while continuing treatment for the next 4 weeks. In the treatment of duodenal ulcer, taking the drug at a dose of 300 mg 2 times/day is more effective than taking doses of 150 mg 2 times/day or 300 mg once at night. Increasing the dose does not lead to an increase in the frequency of side effects.

For long-term prevention of recurrences of duodenal and gastric ulcers, 150 mg once/day (at night) is prescribed. For smoking patients, increasing the dose to 300 mg at night is more preferable (since smoking is associated with a higher frequency of ulcer recurrence).

For the treatment of ulcers associated with NSAID use, 150 mg 2 times/day or 300 mg at night is prescribed for 8-12 weeks; for prevention – 150 mg 2 times/day during NSAID treatment.

For the treatment of duodenal ulcers associated with Helicobacter pylori, 150 mg 2 times/day (morning and evening) or 300 mg once/day (at night) is prescribed in combination with amoxicillin at a dose of 750 mg 3 times/day and metronidazole 500 mg 3 times/day for 2 weeks. Treatment with Zantac^® should continue for another subsequent 2 weeks. This regimen significantly reduces the frequency of duodenal ulcer recurrence.

For postoperative ulcers, 150 mg 2 times/day is prescribed for 4 weeks. In patients with ulcers that have not healed during this period, healing usually occurs while continuing treatment for the next 4 weeks.

For gastroesophageal reflux disease for the treatment of acute reflux esophagitis, 150 mg 2 times/day or 300 mg at night is prescribed for 8 weeks; if necessary, the course of treatment can be extended to 12 weeks. For moderate and severe reflux esophagitis, the dose can be increased to 150 mg 4 times/day for up to 12 weeks. For preventive therapy for reflux esophagitis, the recommended dose is 150 mg 2 times/day.

For relief of pain in gastroesophageal reflux disease, 150 mg 2 times/day is prescribed for 2 weeks. If the effect is insufficient, treatment can be continued at the same dose for the next 2 weeks.

For Zollinger-Ellison syndrome, the initial dose is 150 mg 3 times/day, if necessary the dose can be increased. Doses up to 6 g/day were well tolerated.

For chronic episodes of dyspepsia, Zantac^® is prescribed at 150 mg 2 times/day for 6 weeks. In the absence of a positive effect from treatment, as well as in case of deterioration of the condition during treatment, a thorough examination should be carried out.

For the prevention of bleeding from stress ulcers in severely ill patients, as well as for the prevention of recurrent bleeding from peptic ulcers, after the patient is able to take food orally, parenteral use of Zantac^® can be replaced by oral administration of the drug at a dose of 150 mg 2 times/day.

For the prevention of the development of Mendelson’s syndrome, Zantac^® is prescribed at a dose of 150 mg 2 hours before anesthesia, and also, preferably, 150 mg the night before. Parenteral use of Zantac^® is possible.

For the prevention of Mendelson’s syndrome in women in labor during childbirth, 150 mg is prescribed every 6 hours, but if general anesthesia is required, then before it, along with Zantac^®, water-soluble antacids (for example, sodium citrate) should be used.

For children for the treatment of peptic ulcer, a dose of 2-4 mg/kg 2 times/day is recommended; the maximum daily dose is 300 mg.

In patients with severe renal failure (creatinine clearance less than 50 ml/min), accumulation and an increase in plasma concentration of ranitidine are noted. The recommended dose is 150 mg once/day.

For patients on long-term outpatient peritoneal dialysis or long-term hemodialysis, the drug is prescribed at a dose of 150 mg immediately after the end of the dialysis session.

Solution for injection can be administered as

• A slow (over 2 minutes) intravenous injection at a dose of 50 mg, which is diluted to a volume of 20 ml and administered every 6-8 hours;
• An intermittent intravenous infusion at a rate of 25 mg/hour for 2 hours, with repeated administration after 6-8 hours;
• An intramuscular injection at a dose of 50 mg every 6-8 hours.

For the prevention of bleeding from stress ulcers and recurrence of bleeding from peptic ulcers in severely ill patients, Zantac^® is administered at an initial dose of 50 mg as a slow intravenous injection, and then a long-term intravenous infusion is performed at a rate of 0.125-0.250 mg/kg/hour. Parenteral therapy continues until the patient is able to take food. Then a transition to oral Zantac^® is possible.

For the prevention of Mendelson’s syndrome, the recommended dose is 50 mg intramuscularly or slowly intravenously 45-60 minutes before anesthesia.

For patients with renal failure with creatinine clearance less than 50 ml/min, the recommended dose of Zantac^® for parenteral use is 25 mg.

Tablets

It is set individually. Orally for the treatment of adults and children over 14 years of age, it is used in a daily dose of 300-450 mg, if necessary the daily dose is increased to 600-900 mg; frequency of administration – 2-3 times/day. For the prevention of exacerbations of diseases, 150 mg/day before bedtime is used. The duration of treatment is determined by the indications for use. For patients with renal failure with a creatinine level of more than 3.3 mg/100 ml – 75 mg 2 times/day.

Intravenously or intramuscularly – 50-100 mg every 6-8 hours.

Adverse Reactions

From the digestive system nausea, dry mouth, constipation, vomiting, abdominal pain, transient and reversible changes in liver function tests; in some cases – development of hepatitis (hepatocellular, cholestatic or mixed), accompanied or not accompanied by jaundice (usually reversible); rarely – diarrhea, acute pancreatitis.

From the hematopoietic system leukopenia, thrombocytopenia; rarely – agranulocytosis, pancytopenia, sometimes – hypo- and aplasia of the bone marrow, immune hemolytic anemia.

From the cardiovascular system decreased blood pressure, arrhythmia, bradycardia, AV block; rarely – vasculitis.

From the central nervous system headache (sometimes severe), dizziness, increased fatigue, drowsiness; rarely – irritability, tinnitus, blurred vision, possibly associated with a change in accommodation, involuntary reversible movement disorders, involuntary movements; predominantly in severely ill and elderly patients – confusion, depression and hallucinations.

From the musculoskeletal system rarely – arthralgia, myalgia.

Dermatological reactions alopecia.

Allergic reactions skin rash, multiforme erythema, urticaria, angioedema, anaphylactic shock, bronchospasm, arterial hypotension, fever, chest pain.

From the endocrine system hyperprolactinemia, gynecomastia, amenorrhea, decreased libido; rarely – reversible impotence, appearance of swelling or discomfort in the mammary glands in men.

Contraindications

• Acute porphyria (including history);
• Pregnancy;
• Lactation period (breastfeeding);
• Children under 12 years of age;
• Hypersensitivity to ranitidine and other components of the drug.

With caution, the drug should be prescribed for renal and hepatic insufficiency, for liver cirrhosis with a history of portosystemic encephalopathy.

Use in Pregnancy and Lactation

Ranitidine penetrates the placenta and is excreted in breast milk (concentration in breast milk is higher than in plasma).

Use of the drug during pregnancy is possible only if the intended benefit to the mother outweighs the potential risk to the fetus.

If it is necessary to prescribe the drug during lactation, the issue of stopping breastfeeding should be decided.

Use in Hepatic Impairment

With caution, the drug should be prescribed for hepatic insufficiency, for liver cirrhosis with a history of portosystemic encephalopathy.

Use in Renal Impairment

In patients with severe renal failure (creatinine clearance less than 50 ml/min), accumulation and an increase in plasma concentration of ranitidine are noted. The recommended dose is 150 mg once/day.

For patients on long-term outpatient peritoneal dialysis or long-term hemodialysis, the drug is prescribed at a dose of 150 mg immediately after the end of the dialysis session.

Pediatric Use

The drug is contraindicated in children under 12 years of age.

Geriatric Use

Regular monitoring of elderly patients taking Ranitidine in combination with NSAIDs is necessary.

Special Precautions

Treatment with Zantac^® may mask symptoms associated with gastric carcinoma. Therefore, in patients with gastric ulcer (and in middle-aged and elderly patients with changes or the appearance of new symptoms of dyspepsia), before starting treatment with Zantac^®, the possibility of malignancy must be excluded.

The drug should not be abruptly discontinued; there is a risk of a “rebound” syndrome.

With long-term treatment of debilitated patients under stress, bacterial lesions of the stomach are possible with subsequent spread of infection.

Regular monitoring of patients (especially the elderly and patients with a history of peptic ulcer disease) taking Ranitidine in combination with NSAIDs is necessary.

There are isolated reports that Ranitidine may contribute to the development of an acute attack of porphyria, therefore it is necessary to avoid its use in patients with a history of acute porphyria.

Zantac^® effervescent tablets contain sodium, so caution should be exercised when treating patients who are indicated for sodium restriction.

Since Zantac^® effervescent tablets contain aspartame, they should be used with caution in patients with phenylketonuria.

Rare cases of bradycardia are known with rapid parenteral administration of Zantac^®, which was usually observed in patients with predisposing factors for the development of cardiac arrhythmias. The recommended rate of drug administration should not be exceeded.

It should be taken into account that Ranitidine is excreted through the kidneys, and therefore the level of the drug in plasma increases in severe renal failure. Therefore, it is necessary to adjust the dosage regimen.

With parenteral administration of the drug in high doses for more than 5 days, an increase in the activity of liver enzymes may be observed.

Zantac^® should be taken 2 hours after taking itraconazole or ketoconazole to avoid a significant decrease in their absorption.

While taking the drug, the activity of glutamyl transpeptidase may increase.

Taking Zantac^® may be the cause of a false-positive reaction when testing for the presence of protein in the urine.

Histamine H₂-receptor blockers (including Zantac^®) may counteract the effect of pentagastrin and histamine on the acid-forming function of the stomach, so it is not recommended to use Zantac^® within 24 hours preceding the test.

Histamine H₂-receptor blockers may suppress the skin reaction to histamine, thus leading to false-negative results. Therefore, before conducting diagnostic skin tests to detect an immediate allergic skin reaction, Zantac^® should be discontinued.

During treatment, consumption of foods, drinks and other medicines that may cause irritation of the gastric mucosa should be avoided.

Smoking reduces the effectiveness of Zantac^® use.

Unused mixtures must be destroyed within 24 hours after preparation.

Since compatibility studies of solutions were conducted only in polyvinyl chloride infusion bags (in glass for sodium bicarbonate) and polyvinyl chloride systems, it is assumed that adequate stability can also be achieved when using polyethylene bags.

Use in pediatrics

The safety and efficacy of Zantac^® in children under 12 years of age have not been established.

Effect on ability to drive vehicles and mechanisms

During the period of taking the drug Zantac^®, it is necessary to refrain from engaging in potentially hazardous activities that require increased concentration and speed of psychomotor reactions.

Overdose

Symptoms convulsions, bradycardia, ventricular arrhythmias.

Treatment symptomatic therapy is carried out; if convulsions develop – diazepam intravenously, for bradycardia and ventricular arrhythmias – atropine, lidocaine are administered. Ranitidine can be removed from plasma by hemodialysis.

Drug Interactions

With simultaneous use of Zantac^® with antacids, sucralfate in high doses (2 g), impaired absorption of ranitidine is possible, so the interval between taking these drugs should be at least 2 hours.

With simultaneous use of Zantac^® and drugs that suppress the bone marrow, the risk of developing neutropenia increases.

Zantac^® does not suppress the activity of cytochrome P₄₅₀ isoenzymes, so it does not enhance the effect of drugs metabolized with the participation of this enzyme system, such as diazepam, lidocaine, phenytoin, propranolol, theophylline, warfarin.

Ranitidine inhibits the metabolism of phenazone, aminophenazone, hexobarbital, indirect anticoagulants, glipizide, buformin, and calcium antagonists.

Due to an increase in the pH of gastric contents during concurrent use with Zantac^®, the absorption of itraconazole and ketoconazole may be decreased.

When taken concomitantly with Zantac^®, the AUC and serum concentration of metoprolol increase (by 80% and 50%, respectively), while the T_1/2 of metoprolol increases from 4.4 to 6.5 hours.

No interaction of ranitidine with metronidazole and amoxicillin has been noted.

Pharmaceutical Interactions

Zantac^® injection solution is compatible with the following infusion solutions: 0.9% sodium chloride solution, 5% dextrose solution, 0.18% sodium chloride and 4% dextrose solution, 4.2% sodium bicarbonate solution, and Hartmann’s solution.

Storage Conditions

Tablets should be stored in a place inaccessible to children at a temperature not exceeding 30°C (86°F). The tube with effervescent tablets should be tightly closed with a cap.

Shelf Life

The shelf life of 150 mg tablets is 5 years, 300 mg tablets is 3 years, and effervescent tablets is 2 years.

The injection solution should be stored in a place inaccessible to children at a temperature not exceeding 25°C (77°F). The shelf life is 3 years.

Dispensing Conditions

The drug is dispensed by prescription.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.