Topigen

Topigen may be available in the countries listed below.

Ingredient matches for Topigen

Topiramate

Topiramate is reported as an ingredient of Topigen in the following countries:

• Poland

International Drug Name Search

Xopenex

In the US, Xopenex (levalbuterol systemic) is a member of the drug class adrenergic bronchodilators and is used to treat Asthma - acute, Asthma - Maintenance, COPD - Acute and COPD - Maintenance.

US matches:

• Xopenex


• Xopenex HFA Aerosol


• Xopenex Solution


• Xopenex Concentrate


• Xopenex HFA


• Xopenex Pediatric

Ingredient matches for Xopenex

Levosalbutamol

Levosalbutamol hydrochloride (a derivative of Levosalbutamol) is reported as an ingredient of Xopenex in the following countries:

• United States

International Drug Name Search

Sedarest

Sedarest may be available in the countries listed below.

Ingredient matches for Sedarest

Estazolam

Estazolam is reported as an ingredient of Sedarest in the following countries:

• Peru

International Drug Name Search

Ranitidine

Dosage Form: tablets, capsules
Ranitidine Tablets, USP and Ranitidine Capsules

Ranitidine Description

Ranitidine hydrochloride (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, HCl.

It has the following structure:

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 sulfur like odor.

Each tablet, for oral administration contains 168 mg or 336 mg of Ranitidine hydrochloride equivalent to 150 mg and 300 mg of Ranitidine, respectively. Inactive ingredients: D & C Red #30 Aluminum Lake, hydroxypropyl cellulose, hydroxypropyl methylcellulose, magnesium stearate, microcrystalline cellulose, triethyl citrate, sodium starch glycolate, titanium dioxide and flavoring. The 300 mg also contains: D & C Yellow #10 Aluminum Lake.

Each capsule, for oral administration contains 168 mg or 336 mg of Ranitidine hydrochloride equivalent to 150 mg and 300 mg of Ranitidine, respectively. Inactive ingredients: Ammonium hydroxide, colloidal silicon dioxide, corn starch, FD & C Blue #1, FD & C Red #40, FD & C Yellow #6, gelatin, magnesium stearate, pharmaceutical glaze, propylene glycol, silicon dioxide, simethicone, sodium lauryl sulfate, sodium starch glycolate, and titanium dioxide.

Ranitidine - Clinical Pharmacology

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 a anticholinergic agent.

Pharmacokinetics

Absorption

Ranitidine tablets and Ranitidine capsules are 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. 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 (t1/2, Vd, and CL) are similar to those observed with intravenous Ranitidine use in pediatric patients. Estimates of Cmax and Tmax are displayed in Table 1.

Table 1. Ranitidine Pharmacokinetics in Pediatric Patients Following Oral Dosing

Population(age)	n	Dosage Form (dose)	Cmax (ng/mL)	Tmax (hours)
Gastric or duodenal ulcer (3.5 to 16 years)	12	Tablets (1 to 2 mg/kg)	54 to 492	2.0
Otherwise healthy requiring Ranitidine (0.7 to 14 years, Single dose)	10	Syrup (2 mg/kg)	244	1.61
Otherwise healthy requiring Ranitidine (0.7 to 14 years, Multiple dose)	10	Syrup (2 mg/kg)	320	1.66

Plasma clearance measured in two 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 Useand 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.

Table 2. Effect of Oral Ranitidine on Gastric Acid Secretion

	Time after Dose, h	% Inhibition of Gastric Acid Output by Dose, mg
		75-80	100	150	200
Basal	Up to 4		99	95
Nocturnal	Up to 13	95	96	92
Betazole	Up to 3		97	99
Pentagastrin	Up to 5	58	72	72	80
Meal	Up to 3		73	79	95

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

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

Intrinsic Factor

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

a. Gastric bacterial flora – increase in nitrate-reducing organisms, significance not known.

b. Prolactin levels – no effect in recommended dosage.

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.

Pediatrics

Oral doses of 6 to 10 mg/kg per day in two or three divided doses maintain gastric pH>4 throughout most of the dosing interval.

Clinical Trials

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 as shown in Table 3.

Table 3. Duodenal Ulcer Patient Healing Rates

* All patients were permitted antacids as needed for relief of pain. † P <0.0001.
	Ranitidine*		Placebo*
	Number Entered	Healed/ Evaluable	Number Entered	Healed/ Evaluable
Outpatients Week 2		69/182		31/164
		(38%)†		(19%)
	195		188
Week 4		137/187		76/168
		(73%)†		(45%)

In these studies, patients treated with Ranitidine reported a reduction in both daytime and nocturnal pain, and they also consumed less antacid than the placebo-treated patients.

Table 4. Mean Daily Doses of Antacid

	Ulcer Healed	Ulcer Not Healed
Ranitidine	0.06	0.71
Placebo	0.71	1.43

Foreign studies have shown that patients heal equally well with 150 mg two times a day and 300 mg at bedtime (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 two times a day as compared to 300 mg at bedtime (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 (150 mg at bedtime) than in patients treated with placebo over a 12-month period.

Table 5. Duodenal Ulcer Prevalence

* RAN = Ranitidine. † % = Life Table estimate. ‡ P<0.05 (Ranitidine versus comparator). § PLC = placebo.
Double-blind, Multicenter, Placebo-Controlled Trials
Multicenter Trial	Drug	Duodenal Ulcer Prevalence			No. of Patients
		0-4 Months	0-8 Months	0-12 Months
	RAN*	20%†‡	24%†‡	35%†‡	138
USA	PLC§	44%†	54%†	59%†	139
	RAN*	12%†‡	21%†‡	28%†‡	174
Foreign	PLC§	56%†	64%†	68%†	165

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 as shown in Table 6.

Table 6. Gastric Ulcer Patient Healing Rates

* All patients were permitted antacids as needed for relief of pain. † P = 0.009.
	Ranitidine*		Placebo*
	Number Entered	Healed/ Evaluable	Number Entered	Healed/ Evaluable
Outpatients Week 2	92	16/83 (19%)	94	10/83 (12%)
Week 6		50/73 (68%)†		35/69 (51%)

In this multicenter trial, significantly more patients treated with Ranitidine 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 tablets or Ranitidine capsules 150 mg at bedtime were significantly more effective than placebo in maintaining healing of gastric ulcers.

Pathological Hypersecretory Conditions (such as Zollinger-Ellison syndrome)

Ranitidine 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 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 150 mg two times a day 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 150 mg two times a day 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 150 mg two times a day was shown to provide relief of heartburn pain within 24 hours of initiating therapy and a reduction in the frequency and severity of heartburn.

Erosive Esophagitis

In two multicenter, double-blind, randomized, placebo-controlled, 12-week trials performed in the United States, Ranitidine 150 mg 4 times daily was significantly more effective than placebo in healing endoscopically diagnosed erosive esophagitis and in relieving associated heartburn. The erosive esophagitis healing rates were as follows:

Table 7. Erosive Esophagitis Patient Healing Rates

* All patients were permitted antacids as needed for relief of pain. † p<0.001 versus placebo.
	Healed/Evaluable
	Placebo* (n = 229)		Ranitidine 150 mg 4 times daily* (n = 215)
Week 4	43/198	(22%)	96/206	(47%)†
Week 8	63/176	(36%)	142/200	(71%)†
Week 12	92/159	(58%)	162/192	(84%)†

No additional benefit in healing of esophagitis or in relief of heartburn was seen with a Ranitidine dose of 300 mg 4 times daily.

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 150 mg two times a day was significantly more effective than placebo in maintaining healing of erosive esophagitis.

Indications and Usage for Ranitidine

Ranitidine 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 24 hours after starting therapy with Ranitidine 150 mg two times a day.


7. Treatment of endoscopically diagnosed erosive esophagitis. Symptomatic relief of heartburn commonly occurs within 24 hours of therapy initiation with Ranitidine 150 mg 4 times daily.


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.

Contraindications

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

Precautions

General

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


2. Since Ranitidine 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 is metabolized in the liver.


3. Rare reports suggest that Ranitidine may precipitate acute porphyric attacks in patients with acute porphyria. Ranitidine 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 Ranitidine therapy, and therefore testing with sulfosalicylic acid is recommended.

Drug Interactions

Ranitidine has been reported to affect the bioavailability of other drugs through several different mechanisms such as competition for renal tubular secretion, alteration of gastric pH, and inhibition of cytochrome P450 enzymes.

Procainamide: Ranitidine, a substrate of the renal organic cation transport system, may affect the clearance of other drugs eliminated by this route. High doses of Ranitidine (e.g., such as those used in the treatment of Zollinger-Ellison syndrome) have been shown to reduce the renal excretion of procainamide and N-acetylprocainamide resulting in increased plasma levels of these drugs. Although this interaction is unlikely to be clinically relevant at usual Ranitidine doses, it may be prudent to monitor for procainamide toxicity when administered with oral Ranitidine at a dose exceeding 300 mg per day.

Warfarin: There have been reports of altered prothrombin time among patients on concomitant warfarin and Ranitidine therapy. Due to the narrow therapeutic index, close monitoring of increased or decreased prothrombin time is recommended during concurrent treatment with Ranitidine.

Ranitidine may alter the absorption of drugs in which gastric pH is an important determinant of bioavailability. This can result in either an increase in absorption (e.g., triazolam, midazolam, glipizide) or a decrease in absorption (e.g., ketoconazole, atazanavir, delavirdine, gefitinib). Appropriate clinical monitoring is recommended.

Atazanavir: Atazanavir absorption may be impaired based on known interactions with other agents that increase gastric pH. Use with caution. See atazanavir label for specific recommendations.

Delavirdine: Delavirdine absorption may be impaired based on known interactions with other agents that increase gastric pH. Chronic use of H2-receptor antagonists with delavirdine is not recommended.

Gefitinib: Gefitinib exposure was reduced by 44% with the coadministration of Ranitidine and sodium bicarbonate (dosed to maintain gastric pH above 5.0). Use with caution.

Glipizide: In diabetic patients, glipizide exposure was increased by 34% following a single 150-mg dose of oral Ranitidine. Use appropriate clinical monitoring when initiating or discontinuing Ranitidine.

Ketoconazole: Oral ketoconazole exposure was reduced by up to 95% when oral Ranitidine was coadministered in a regimen to maintain a gastric pH of 6 or above. The degree of interaction with usual dose of Ranitidine (150 mg twice daily) is unknown.

Midazolam: Oral midazolam exposure in 5 healthy volunteers was increased by up to 65% when administered with oral Ranitidine at a dose of 150 mg twice daily. However, in another interaction study in 8 volunteers receiving IV midazolam, a 300 mg oral dose of Ranitidine increased midazolam exposure by about 9%. Monitor patients for excessive or prolonged sedation when Ranitidine is coadministered with oral midazolam.

Triazolam: Triazolam exposure in healthy volunteers was increased by approximately 30% when administered with oral Ranitidine at a dose of 150 mg twice daily. Monitor patients for excessive or prolonged sedation.

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 Ranitidine. 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 is secreted in human milk. Caution should be exercised when Ranitidine is administered to a nursing mother.

Pediatric Use

The safety and effectiveness of Ranitidine has 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 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: 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 one month of age) have not been established (see CLINICAL PHARMACOLOGY: Pediatrics).

Geriatric Use

Of the total number of subjects enrolled in US and foreign controlled clinical trials of oral formulations of Ranitidine, for which there were subgroup analyses, 4,197 were 65 and over, while 899 were 75 and over. 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).

Adverse Reactions

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 4 times daily intravenously for 7 days, and in 4 of 24 subjects receiving 50 mg 4 times daily 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. Rare cases of breast symptoms and conditions, including galactorrhea and gynecomastia, have been reported in both males and females.

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, acute interstitial nephritis, and small increases in serum creatinine.

Overdosage

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.

Ranitidine Dosage and Administration

Active Duodenal Ulcer

The current recommended adult oral dosage of Ranitidine 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 (see CLINICAL PHARMACOLOGY: 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 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 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 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

Bactrim DS

Generic Name: sulfamethoxazole/trimethoprim (Oral route)

sul-fa-meth-OX-a-zole, trye-METH-oh-prim

Commonly used brand name(s)

In the U.S.

• Bactrim


• Bactrim DS


• Septra


• Septra DS


• Sulfatrim


• Sulfatrim Pediatric

In Canada

• Apo-Sulfatrim


• Novo-Trimel


• Nu-Cotrimox


• Septa Pediatric


• Septra Pediatric Suspension

Available Dosage Forms:

• Tablet


• Suspension

Therapeutic Class: Sulfonamide Combination

Pharmacologic Class: Folic Acid Antagonist

Chemical Class: Sulfonamide

Uses For Bactrim DS

Sulfamethoxazole and trimethoprim combination is used to treat infections such as urinary tract infections, middle ear infections (otitis media), bronchitis, traveler's diarrhea, and shigellosis (bacillary dysentery). This medicine is also used to prevent or treat Pneumocystis carinii pneumonia (PCP), a very serious kind of pneumonia. This type of pneumonia occurs more commonly in patients whose immune systems are not working normally, such as cancer patients, transplant patients, and patients with acquired immune deficiency syndrome (AIDS).

Sulfamethoxazole and trimethoprim combination is an antibiotic. It works by eliminating the bacteria that cause many kinds of infections. This medicine will not work for colds, flu, or other virus infections.

This medicine is available only with your doctor's prescription.

Before Using Bactrim DS

In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For this medicine, the following should be considered:

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to this medicine or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.

Pediatric

Appropriate studies performed to date have not demonstrated pediatric-specific problems that would limit the usefulness of sulfamethoxazole and trimethoprim combination in children and infants 2 months of age and older. Because of the toxicity of the combination of sulfamethoxazole and trimethoprim, use in infants younger than 2 months of age is not recommended.

Geriatric

Appropriate studies performed to date have not demonstrated geriatric-specific problems that would limit the usefulness of sulfamethoxazole and trimethoprim combination in the elderly. However, elderly patients are more likely to have a folate deficiency, age-related kidney or liver problems, and may be more likely to experience unwanted side effects (e.g., severe skin rash, increased potassium in the body, or problems with blood clotting or the immune system). There may be a dose adjustment for elderly patients receiving sulfamethoxazole and trimethoprim combination.

Pregnancy

	Pregnancy Category	Explanation
All Trimesters	C	Animal studies have shown an adverse effect and there are no adequate studies in pregnant women OR no animal studies have been conducted and there are no adequate studies in pregnant women.

Breast Feeding

Sulfamethoxazole

There are no adequate studies in women for determining infant risk when using this medication during breastfeeding. Weigh the potential benefits against the potential risks before taking this medication while breastfeeding.

Trimethoprim

Studies in women suggest that this medication poses minimal risk to the infant when used during breastfeeding.

Interactions with Medicines

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are taking this medicine, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using this medicine with any of the following medicines is not recommended. Your doctor may decide not to treat you with this medication or change some of the other medicines you take.

• Bepridil


• Cisapride


• Dofetilide


• Levomethadyl


• Mesoridazine


• Pimozide


• Terfenadine


• Thioridazine

Using this medicine with any of the following medicines is usually not recommended, but may be required in some cases. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Acecainide


• Acenocoumarol


• Ajmaline


• Amiodarone


• Amisulpride


• Amitriptyline


• Amoxapine


• Aprindine


• Arsenic Trioxide


• Astemizole


• Azimilide


• Bretylium


• Chloral Hydrate


• Chloroquine


• Chlorpromazine


• Clarithromycin


• Desipramine


• Dibenzepin


• Disopyramide


• Dolasetron


• Doxepin


• Droperidol


• Eltrombopag


• Enflurane


• Erythromycin


• Flecainide


• Fluconazole


• Fluoxetine


• Foscarnet


• Gemifloxacin


• Halofantrine


• Haloperidol


• Halothane


• Hydroquinidine


• Ibutilide


• Imipramine


• Isoflurane


• Isradipine


• Lidoflazine


• Lorcainide


• Mefloquine


• Methotrexate


• Nortriptyline


• Octreotide


• Pentamidine


• Pirmenol


• Prajmaline


• Probucol


• Procainamide


• Prochlorperazine


• Propafenone


• Pyrimethamine


• Quetiapine


• Quinidine


• Risperidone


• Sematilide


• Sertindole


• Sotalol


• Spiramycin


• Sultopride


• Tedisamil


• Telithromycin


• Trifluoperazine


• Trimipramine


• Vasopressin


• Warfarin


• Zotepine

Using this medicine with any of the following medicines may cause an increased risk of certain side effects, but using both drugs may be the best treatment for you. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Acetohexamide


• Anisindione


• Chlorpropamide


• Didanosine


• Digoxin


• Enalaprilat


• Enalapril Maleate


• Fosphenytoin


• Glipizide


• Glyburide


• Phenytoin


• Quinapril


• Repaglinide


• Rifabutin


• Rosiglitazone


• Tolazamide


• Tolbutamide

Interactions with Food/Tobacco/Alcohol

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using this medicine with any of the following is usually not recommended, but may be unavoidable in some cases. If used together, your doctor may change the dose or how often you use this medicine, or give you special instructions about the use of food, alcohol, or tobacco.

• Ethanol

Other Medical Problems

The presence of other medical problems may affect the use of this medicine. Make sure you tell your doctor if you have any other medical problems, especially:

• Alcohol abuse, history of or


• Folate (vitamin B9) deficiency or


• HIV or AIDS or


• Kidney disease or


• Liver disease or


• Malabsorption syndrome (difficulty of absorbing food in the body) or


• Malnutrition state (nutrition disorder)—Use with caution. May have an increased chance of serious side effects.

• Anemia, megaloblastic (caused by not enough folic acid) or


• Drug-induced thrombocytopenia (low platelets in the blood) after using this medicine or


• Kidney disease, severe or


• Liver disease, severe—Should not be used in patients with these conditions.

• Asthma or


• Diabetes or


• Hyperkalemia (high potassium in the blood) or


• Porphyria (enzyme problem) or


• Severe allergies or


• Thyroid problems—Use with caution. May make these conditions worse.

• Glucose-6-phosphate dehydrogenase (G6PD) deficiency (an enzyme problem)—May cause hemolytic anemia (blood disorder) in patients with this condition.

• Streptococcal infection (group A β-hemolytic)—Sulfonamides should not be used in patients with this condition.

Proper Use of trimethoprim and sulfamethoxazole

This section provides information on the proper use of a number of products that contain trimethoprim and sulfamethoxazole. It may not be specific to Bactrim DS. Please read with care.

Take this medicine exactly as directed by your doctor. Do not take more of it, do not take it more often, and do not take it for a longer time than your doctor ordered. To do so may increase the chance of side effects.

Sulfamethoxazole and trimethoprim combination is best taken with a full glass (8 ounces) of water. Several additional glasses of water should be taken every day, unless otherwise directed by your doctor. Drinking extra water will help to prevent some unwanted effects. .

For patients taking the oral liquid, use a specially marked measuring spoon or other device to measure each dose accurately. The average household teaspoon may not hold the right amount of liquid.

To help clear up your infection completely, keep using this medicine for the full time of treatment, even if you begin to feel better after a few days. If you stop taking this medicine too soon, your symptoms may return.

Dosing

The dose of this medicine will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of this medicine. If your dose is different, do not change it unless your doctor tells you to do so.

The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.

• For oral dosage forms (liquid or tablets):
  
  • For treatment of bacterial infections:
    
    • Adults and children weighing 40 kilograms (kg) or more—800 milligrams (mg) of sulfamethoxazole and 160 mg of trimethoprim every 12 hours. Your doctor may adjust this dose if needed.
    
    
    • Children and infants 2 months of age and older, and weighing up to 40 kg—Dose is based on body weight and must be determined by your doctor. The usual dose is 40 milligrams (mg) of sulfamethoxazole and 8 milligrams (mg) of trimethoprim per kilogram of body weight, given in two divided doses every 12 hours.
    
    
    • Infants younger than 2 months of age—Use is not recommended.
    
    
  
  
  • For chronic bronchitis:
    
    • Adults—800 milligrams (mg) of sulfamethoxazole and 160 mg of trimethoprim every 12 hours. Your doctor may adjust this dose if needed.
    
    
    • Children and infants 2 months of age and older—Use and dose must be determined by your doctor.
    
    
    • Infants younger than 2 months of age—Use is not recommended.
    
    
  
  
  • For treatment of Pneumocystis carinii pneumonia (PCP):
    
    • Adults and children 2 months of age and older—Dose is based on body weight and must be determined by your doctor. The usual dose is 75 to 100 milligrams (mg) of sulfamethoxazole and 15 to 20 milligrams (mg) of trimethoprim per kilogram of body weight each day, given in equally divided doses every 6 hours.
    
    
    • Infants younger than 2 months of age—Use is not recommended.
    
    
  
  
  • For prevention of Pneumocystis carinii pneumonia (PCP):
    
    • Adults—800 milligrams (mg) of sulfamethoxazole and 160 mg of trimethoprim once a day. Your doctor may adjust this dose if needed.
    
    
    • Children and infants 2 months of age and older—Dose is based on body size and must be determined by your doctor. The dose is 750 mg of sulfamethoxazole and 150 mg of trimethoprim per square meter (m[2]) of body surface each day. This is given in equally divided doses two times a day for 3 days a week on consecutive days (e.g., Monday, Tuesday, Wednesday).
    
    
    • Infants younger than 2 months of age—Use is not recommended.
    
    
  
  
  • For traveler's diarrhea:
    
    • Adults—800 milligrams (mg) of sulfamethoxazole and 160 mg of trimethoprim every 12 hours. Your doctor may adjust this dose if needed.
    
    
    • Children and infants 2 months of age and older—Use and dose must be determined by your doctor.
    
    
    • Infants younger than 2 months of age—Use is not recommended.
    
    
  
  

Missed Dose

If you miss a dose of this medicine, take it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not double doses.

Storage

Store the medicine in a closed container at room temperature, away from heat, moisture, and direct light. Keep from freezing.

Keep out of the reach of children.

Do not keep outdated medicine or medicine no longer needed.

Ask your healthcare professional how you should dispose of any medicine you do not use.

Precautions While Using Bactrim DS

It is very important that your doctor check the progress of you or your child at regular visits to make sure that this medicine is working properly. Blood and urine tests may be needed to check for unwanted effects.

Using this medicine while you are pregnant can harm your unborn baby. Use an effective form of birth control to keep from getting pregnant. If you think you have become pregnant while using the medicine, tell your doctor right away.

Very rarely, this medicine has caused severe side effects. If you or your child start to have a skin rash, or if you think you are having a severe skin reaction, stop taking this medicine and call your doctor right away. Symptoms of a severe reaction may include a skin rash, skin color that is very pale or yellow, or skin with purple spots, along with a sore throat, fever, muscle pain, cough, and trouble with breathing.

This medicine, especially if you are receiving high doses or for a long period of time, may lower the number of platelets in your body, which are necessary for proper blood clotting. Because of this, you may bleed or get infections more easily. Talk with your doctor if you have concerns about this.

This medicine may cause diarrhea, and in some cases it can be severe. It may occur 2 months or more after you stop taking this medicine. Do not take any medicine to treat diarrhea without first checking with your doctor. If you have any questions or if mild diarrhea continues or gets worse, check with your doctor.

Check with your doctor right away if you or your child have abdominal or stomach cramps; bloating; watery and severe diarrhea, which may also be bloody; nausea or vomiting; or unusual tiredness or weakness. These may be symptoms of a serious intestinal infection.

This medicine may cause serious allergic reactions, including anaphylaxis. Anaphylaxis can be life-threatening and requires immediate medical attention. Check with your doctor right away if you or your child have a rash; itching; swelling of the face, tongue, and throat; trouble with breathing; shortness of breath; or chest pain after you use the medicine.

Before you have any medical tests, tell the medical doctor in charge that you or your child are taking this medicine. The results of some tests may be affected by this medicine.

Patients receiving anticonvulsant therapy (medicines to prevent seizures) may be at risk for a folate (vitamin B9) deficiency, which may increase the risk for side effects. Talk with your doctor if you have concerns about this.

Do not take other medicines unless they have been discussed with your doctor. This includes prescription or nonprescription (over-the-counter [OTC]) medicines and herbal or vitamin supplements.

Bactrim DS Side Effects

Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur:

Rare

• Abdominal or stomach pain


• black, tarry stools


• blistering, peeling, or loosening of the skin


• changes in skin color


• chest pain


• chills


• cough or hoarseness


• dark urine


• diarrhea


• dizziness


• fever with or without chills


• general feeling of tiredness or weakness


• headache


• itching


• joint or muscle pain


• light-colored stools


• loss of appetite


• lower back or side pain


• nausea


• pain, tenderness, or swelling of the foot or leg


• painful or difficult urination


• pale skin


• rash


• red irritated eyes


• red skin lesions, often with a purple center


• shortness of breath


• sore throat


• sores, ulcers, or white spots in the mouth or on the lips


• swollen or painful glands


• tightness in the chest


• unpleasant breath odor


• unusual bleeding or bruising


• vomiting of blood


• wheezing


• yellow eyes or skin

Incidence not known

• Abdominal or stomach tenderness


• back, leg, or stomach pains


• bleeding gums


• blindness or vision changes


• blisters, hives, or itching


• bloating


• blood in the urine or stools


• bluish-colored lips, fingernails, or palms


• burning, crawling, itching, numbness, painful, prickling, "pins and needles", or tingling feelings


• burning of the face or mouth


• chest pain


• cloudy urine


• confusion


• constipation


• continuing ringing or buzzing or other unexplained noise in the ears


• convulsions


• cracks in the skin


• decreased frequency or amount of urine


• diarrhea, watery and severe, which may also be bloody


• difficulty with breathing


• difficulty with swallowing


• fainting spells


• general body swelling


• general feeling of discomfort or illness


• hair loss


• hearing loss


• hives


• increased blood pressure


• increased thirst


• indigestion


• irregular heartbeat


• large, flat, blue, or purplish patches in the skin


• large, hive-like swelling on the face, eyelids, lips, tongue, throat, hands, legs, feet, or sex organs


• loss of heat from the body


• muscle or joint pain


• nosebleeds


• not able to pass urine


• numbness or tingling in the hands, feet, or lips


• pain or burning while urinating


• pinpoint red spots on the skin


• puffiness or swelling of the eyelids or around the eyes, face, lips, or tongue


• raised red swellings on the skin, the buttocks, legs, or ankles


• redness of the white part of the eyes


• redness, swelling, or soreness of the tongue


• sores, ulcers, or white spots on the lips or in the mouth


• soreness of the muscles


• stiff neck or back


• swelling of the face, hands, legs, and feet


• unsteadiness, trembling, or other problems with muscle control or coordination


• unusual weight loss


• weakness in the hands or feet


• weakness or heaviness of the legs


• weight gain

Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

More common

• Passing of gas

Incidence not known

• Discouragement


• feeling of constant movement of self or surroundings


• feeling sad or empty


• increased sensitivity of skin to sunlight


• irritability


• lack of feeling or emotion


• loss of interest or pleasure


• nervousness


• redness or other discoloration of the skin


• seeing, hearing, or feeling things that are not there


• sensation of spinning


• severe sunburn


• sleeplessness


• trouble concentrating


• trouble sleeping


• unable to sleep


• uncaring


• weight loss

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

See also: Bactrim DS side effects (in more detail)

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