PREVACID^® I.V.
(lansoprazole)
for Injection
30 mg/vial

R_x only

The active ingredient in PREVACID I.V. (lansoprazole) for Injection is a substituted benzimidazole, 2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl] methyl] sulfinyl] benzimidazole, a compound that inhibits gastric acid secretion. Its empirical formula is C₁₆H₁₄F₃N₃O₂S with a molecular weight of 369.37. The structural formula is:

Lansoprazole is a white to brownish-white odorless crystalline powder which melts with decomposition at approximately 166°C. Lansoprazole is freely soluble in dimethylformamide; soluble in methanol; sparingly soluble in ethanol; slightly soluble in ethyl acetate, dichloromethane and acetonitrile; very slightly soluble in ether; and practically insoluble in hexane and water.

Lansoprazole is stable when exposed to light for up to two months. The rate of degradation of the compound in aqueous solution increases with decreasing pH.

PREVACID I.V. for Injection contains 30 mg of the active ingredient lansoprazole, 60 mg mannitol, 10 mg meglumine, and 3.45 mg sodium hydroxide and is supplied as a sterile, lyophilized powder for I.V. (intravenous) use. The solution of PREVACID I.V. for Injection has a pH of approximately 11 following the first reconstitution with Sterile Water for Injection, USP, and approximately 10.2, 10.0, or 9.5 after further dilution with either 0.9% Sodium Chloride Injection, USP, Lactated Ringer's Injection, USP, or 5% Dextrose Injection, USP, respectively.

Following the administration of 30 mg of lansoprazole by intravenous infusion over 30 minutes to healthy subjects, plasma concentrations of lansoprazole declined exponentially with a mean (± standard deviation) terminal elimination half-life of 1.3 (± 0.5) hours. The mean peak plasma concentration of lansoprazole (C_max) was 1705 (± 292) ng/mL and the mean area under the plasma concentration versus time curve (AUC) was 3192 (± 1745) ng∙h/mL. The absolute bioavailability of lansoprazole following oral administration is over 80%, and C_max and AUC of lansoprazole are approximately proportional in doses from 15 mg to 60 mg after single oral administration. The pharmacokinetics of lansoprazole did not change with time after 7-day once daily repeated oral or intravenous administration of 30 mg lansoprazole.

During lifetime exposure of rats with up to 150 mg/kg/day of lansoprazole dosed orally seven days per week, marked hypergastrinemia was observed followed by ECL cell proliferation and formation of carcinoid tumors, especially in female rats. (Refer to PRECAUTIONS, Carcinogenesis, Mutagenesis, Impairment of Fertility.)

Gastric biopsy specimens from the body of the stomach from approximately 150 patients treated continuously with lansoprazole for at least one year did not show evidence of ECL cell effects similar to those seen in rat studies. Longer term data are needed to rule out the possibility of an increased risk of the development of gastric tumors in patients receiving long-term therapy with lansoprazole.

A multicenter, double-blind, two-period placebo-controlled, pharmacodynamic study was conducted to assess the ability of PREVACID I.V. for Injection to maintain gastric acid suppression in patients switched from the oral dosage form of lansoprazole to the intravenous dosage form. Erosive esophagitis patients (n=87; 18 to 78 years of age; 28 female; 69 Caucasian/non-Hispanic, 14 Hispanic, 3 African-American, and 1 Native American) received 30 mg of oral lansoprazole for 7 days in Period 1. Patients were then immediately switched to receive either 30 mg of intravenous lansoprazole or intravenous placebo (normal saline) for 7 days in Period 2. MAO and BAO were determined 21 hours following the last dose of oral medication and the last dose of intravenous administration. MAO was calculated from two hours of continuous collection of gastric spans following a subcutaneous injection of 6.0 µg/kg of pentagastrin. BAO was calculated from one hour of continuous collection of gastric spans.

This study demonstrated that, after seven days of repeated oral administration followed by 7 days of intravenous administration, the oral and intravenous dosage forms of PREVACID were similar in their ability to suppress MAO and BAO in patients with erosive esophagitis (refer to the table below). Also, patients receiving oral PREVACID, who were switched to intravenous placebo, experienced a significant increase in acid output within 48 hours of their last oral dose.

When patients are unable to take the oral formulations, PREVACID I.V. for Injection is indicated as an alternative for the short-term treatment (up to 7 days) of all grades of erosive esophagitis. Once the patient is able to take medications orally, therapy can be switched to an oral formulation of PREVACID for a total of 6 to 8 weeks. The safety and efficacy of PREVACID I.V. for Injection as an initial treatment of erosive esophagitis have not been demonstrated. Refer to full prescribing information for the oral formulations of PREVACID.

PREVACID I.V. for Injection is contraindicated in patients with known hypersensitivity to any component of the formulation.

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

Treatment with PREVACID I.V. for Injection should be discontinued as soon as the patient is able to resume treatment with PREVACID oral formulations.

Lansoprazole is metabolized through the cytochrome P₄₅₀ system, specifically through the CYP3A and CYP2C19 isozymes. Studies have shown that lansoprazole does not have clinically significant interactions with other drugs metabolized by the cytochrome P₄₅₀ system, such as warfarin, antipyrine, indomethacin, ibuprofen, phenytoin, propranolol, prednisone, diazepam, or clarithromycin in healthy subjects. These compounds are metabolized through various cytochrome P₄₅₀ isozymes including CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A. When lansoprazole was administered concomitantly with theophylline (CYP1A2, CYP3A), a minor increase (10%) in the clearance of theophylline was seen. Because of the small magnitude and the direction of the effect on theophylline clearance, this interaction is unlikely to be of clinical concern. Nonetheless, individual patients may require additional titration of their theophylline dosage when lansoprazole is started or stopped to ensure clinically effective blood levels.

In a study of healthy subjects neither the pharmacokinetics of warfarin enantiomers nor prothrombin time were affected following single or multiple 60 mg doses of lansoprazole. However, there have been reports of increased International Normalized Ratio (INR) and prothrombin time in patients receiving proton pump inhibitors, including lansoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly may need to be monitored for increases in INR and prothrombin time.

Lansoprazole causes a profound and long-lasting inhibition of gastric acid secretion; therefore, it is theoretically possible that lansoprazole may interfere with the absorption of drugs where gastric pH is an important determinant of bioavailability (eg, ketoconazole, ampicillin esters, iron salts, digoxin).

In two 24-month carcinogenicity studies, Sprague-Dawley rats were treated orally with doses of 5 to 150 mg/kg/day, about 1 to 40 times the exposure on a body surface (mg/m²) basis, of a 50-kg person of average height (1.46 m² body surface area) given the recommended human dose of 30 mg/day (22.2 mg/m²). Lansoprazole produced dose-related gastric enterochromaffin-like (ECL) cell hyperplasia and ECL cell carcinoids in both male and female rats. It also increased the incidence of intestinal metaplasia of the gastric epithelium in both sexes. In male rats, lansoprazole produced a dose-related increase of testicular interstitial cell adenomas. The incidence of these adenomas in rats receiving doses of 15 to 150 mg/kg/day (4 to 40 times the recommended human dose based on body surface area) exceeded the low background incidence (range = 1.4 to 10%) for this strain of rat. Testicular interstitial cell adenoma also occurred in 1 of 30 rats treated with 50 mg/kg/day (13 times the recommended human dose based on body surface area) in a 1-year toxicity study.

In a 24-month carcinogenicity study, CD-1 mice were treated orally with doses of 15 to 600 mg/kg/day, 2 to 80 times the recommended human dose based on body surface area. Lansoprazole produced a dose-related increased incidence of gastric ECL cell hyperplasia. It also produced an increased incidence of liver tumors (hepatocellular adenoma plus carcinoma). The tumor incidences in male mice treated with 300 and 600 mg/kg/day (40 to 80 times the recommended human dose based on body surface area) and female mice treated with 150 to 600 mg/kg/day (20 to 80 times the recommended human dose based on body surface area) exceeded the ranges of background incidences in historical controls for this strain of mice. Lansoprazole treatment produced adenoma of rete testis in male mice receiving 75 to 600 mg/kg/day (10 to 80 times the recommended human dose based on body surface area).

Lansoprazole was not genotoxic in the Ames test, the ex vivo rat hepatocyte unscheduled DNA synthesis (UDS) test, the in vivo mouse micronucleus test or the rat bone marrow cell chromosomal aberration test. It was positive in in vitro human lymphocyte chromosomal aberration assays.

Lansoprazole at intravenous doses of up to 30 mg/kg/day (approximately 8 times the recommended human dose based on body surface area) was found to have no effect on fertility and reproductive performance in male and female rats.

Lansoprazole or its metabolites are excreted in the milk of rats. It is not known whether lansoprazole is excreted in human milk. Because many drugs are excreted in human milk, because of the potential for serious adverse reactions in nursing infants from lansoprazole, and because of the potential for tumorigenicity shown for lansoprazole in rodent carcinogenicity studies, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

The safety and effectiveness of PREVACID I.V. for Injection have not been established for pediatric patients. For further information, please see the PREVACID package insert for the oral formulations.

Among intravenous lansoprazole treated subjects, similar percentages of adverse events were reported in males and females.

Over 4,000 women were treated with oral lansoprazole. Ulcer healing rates in females were similar to those in males. The incidence rates of adverse events were also similar to those seen in males.

Data in elderly patients administered intravenous lansoprazole is limited; however, with oral lansoprazole, ulcer healing rates in elderly patients are similar to those in a younger age group. The incidence rates of adverse events and laboratory test abnormalities are also similar to those seen in younger patients. For elderly patients, dosage and administration of lansoprazole need not be altered for a particular indication.

More than 1,000 patients and subjects have participated in domestic and foreign clinical trials. Treatment with PREVACID I.V. for Injection was well tolerated.

In four U.S. trials involving 161 subjects exposed to PREVACID I.V. for Injection, the following treatment-related adverse events were reported in ≥1% of subjects: headache (1.0%), injection site pain (1.0%), injection site reaction (1.0%) and nausea (1.3%). Treatment-related adverse events occurring in <1% of subjects included abdominal pain, vasodilatation, diarrhea, dyspepsia, vomiting, dizziness, paresthesia, rash, and taste perversion. No additional adverse drug reactions were reported with the intravenous formulation that had not been reported previously with the oral formulations.

Worldwide, over 10,000 patients have been treated with oral lansoprazole in Phase 2-3 clinical trials involving various dosages and durations of treatment. In general, lansoprazole treatment has been well-tolerated in both short-term and long-term trials.

The following adverse events were reported by the treating physician to have a possible or probable relationship to drug in 1% or more of PREVACID-treated patients and occurred at a greater rate in PREVACID-treated patients than placebo-treated patients:

Headache was also seen at greater than 1% incidence but was more common on placebo. The incidence of diarrhea was similar between patients who received placebo and patients who received lansoprazole 15 mg and 30 mg, but higher in the patients who received lansoprazole 60 mg (2.9%, 1.4%, 4.2%, and 7.4%, respectively).

Additional adverse experiences occurring in <1% of patients or subjects in domestic trials are shown below. Refer to Postmarketing for adverse reactions occurring since the drug was marketed.

Body as a Whole - abdomen enlarged, allergic reaction, asthenia, back pain, candidiasis, carcinoma, chest pain (not otherwise specified), chills, edema, fever, flu syndrome, halitosis, infection (not otherwise specified), malaise, neck pain, neck rigidity, pain, pelvic pain; Cardiovascular System - angina, arrhythmia, bradycardia, cerebrovascular accident/cerebral infarction, hypertension/ hypotension, migraine, myocardial infarction, palpitations, shock (circulatory failure), syncope, tachycardia, vasodilation; Digestive System - abnormal stools, anorexia, bezoar, cardiospasm, cholelithiasis, colitis, dry mouth, dyspepsia, dysphagia, enteritis, eructation, esophageal stenosis, esophageal ulcer, esophagitis, fecal discoloration, flatulence, gastric nodules/fundic gland polyps, gastritis, gastroenteritis, gastrointestinal anomaly, gastrointestinal disorder, gastrointestinal hemorrhage, glossitis, gum hemorrhage, hematemesis, increased appetite, increased salivation, melena, mouth ulceration, nausea and vomiting, nausea and vomiting and diarrhea, oral moniliasis, rectal disorder, rectal hemorrhage, stomatitis, tenesmus, thirst, tongue disorder, ulcerative colitis, ulcerative stomatitis; Endocrine System - diabetes mellitus, goiter, hypothyroidism; Hemic and Lymphatic System - anemia, hemolysis, lymphadenopathy; Metabolic and Nutritional Disorders - gout, dehydration, hyperglycemia/hypoglycemia, peripheral edema, weight gain/loss; Musculoskeletal System - arthralgia, arthritis, bone disorder, joint disorder, leg cramps, musculoskeletal pain, myalgia, myasthenia, synovitis; Nervous System - abnormal dreams, agitation, amnesia, anxiety, apathy, confusion, convulsion, depersonalization, depression, diplopia, dizziness, emotional lability, hallucinations, hemiplegia, hostility aggravated, hyperkinesia, hypertonia, hypesthesia, insomnia, libido decreased/increased, nervousness, neurosis, paresthesia, sleep disorder, somnolence, thinking abnormality, tremor, vertigo; Respiratory System - asthma, bronchitis, cough increased, dyspnea, epistaxis, hemoptysis, hiccup, laryngeal neoplasia, pharyngitis, pleural disorder, pneumonia, respiratory disorder, upper respiratory inflammation/infection, rhinitis, sinusitis, stridor; Skin and Appendages - acne, alopecia, contact dermatitis, dry skin, fixed eruption, hair disorder, maculopapular rash, nail disorder, pruritus, rash, skin carcinoma, skin disorder, sweating, urticaria; Special Senses - abnormal vision, blurred vision, conjunctivitis, deafness, dry eyes, ear disorder, eye pain, otitis media, parosmia, photophobia, retinal degeneration, taste loss, taste perversion, tinnitus, visual field defect; Urogenital System - abnormal menses, breast enlargement, breast pain, breast tenderness, dysmenorrhea, dysuria, gynecomastia, impotence, kidney calculus, kidney pain, leukorrhea, menorrhagia, menstrual disorder, penis disorder, polyuria, testis disorder, urethral pain, urinary frequency, urinary tract infection, urinary urgency, urination impaired, vaginitis.

On-going Safety Surveillance: Additional adverse experiences have been reported since oral lansoprazole has been marketed. The majority of these cases are foreign-sourced and a relationship to lansoprazole has not been established. Because these events were reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These events are uled below by COSTART body system.

Body as a Whole - anaphylactoid-like reaction; Digestive System - hepatotoxicity, pancreatitis, vomiting; Hemic and Lymphatic System - agranulocytosis, aplastic anemia, hemolytic anemia, leukopenia, neutropenia, pancytopenia, thrombocytopenia, and thrombotic thrombocytopenic purpura; Skin and Appendages– severe dermatologic reactions including erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis (some fatal); Special Senses - speech disorder; Urogenital System - urinary retention.

There were no clinically important changes identified in any laboratory parameter with PREVACID I.V. for Injection.

The following changes in laboratory parameters for oral lansoprazole were reported as adverse events:

Abnormal liver function tests, increased SGOT (AST), increased SGPT (ALT), increased creatinine, increased alkaline phosphatase, increased globulins, increased GGTP, increased/decreased/abnormal WBC, abnormal AG ratio, abnormal RBC, bilirubinemia, eosinophilia, hyperlipemia, increased/decreased electrolytes, increased/decreased cholesterol, increased glucocorticoids, increased LDH, increased/decreased/abnormal platelets, and increased gastrin levels. Urine abnormalities such as albuminuria, glycosuria, and hematuria were also reported. Additional isolated laboratory abnormalities were reported.

In the placebo controlled studies, when SGOT (AST) and SGPT (ALT) were evaluated, 0.4% (4/978) placebo patients and 0.4% (11/2677) lansoprazole patients had enzyme elevations greater than three times the upper limit of normal range at the final treatment visit. None of these lansoprazole patients reported jaundice at any time during the study.

Single intravenous doses of lansoprazole at 218 mg/kg in mice (approximately 30 times the recommended human dose based on body surface area) and 167 mg/kg in rats (approximately 46 times the recommended human dose based on body surface area) were lethal. The symptoms of acute toxicity were decreased locomotor response, ataxia, ptosis and tonic convulsions.

Lansoprazole is not removed from the circulation by hemodialysis.

PREVACID I.V. for Injection admixtures should be administered intravenously using the in-line filter provided. The filter must be used to remove precipitate that may form when the reconstituted drug product is mixed with I.V. solutions. Studies have shown that filtration does not alter the amount of drug that is available for administration. Read the following instructions carefully.

There are two methods for preparing PREVACID I.V. for Injection:

• 1.Reconstitution in Vial and Preparation of Admixture.
  
                                                  OR
  
  
• 2.Direct reconstitution with Baxter's MINI-BAG Plus Container.

There are two steps for preparing Prevacid I.V. for Injection.

STEP ONE - Reconstitution in Vial

• -First Prevacid I.V. MUST be reconstituted with Sterile Water for Injection, USP.
• -Inject 5 mL of ONLY Sterile Water for Injection, USP into a 30 mg vial of PREVACID I.V. for Injection. The resulting solution will contain lansoprazole 6 mg/mL (30 mg/5 mL).
• -Failure to reconstitute with Sterile Water may result in formation of precipitation/particulates.
• -Mix gently until the powder is dissolved.

The pH of this reconstituted solution is approximately 11. The reconstituted solution can be held for 1 hour when stored at 25°C (77°F) prior to further dilution.

STEP TWO - Preparation of Admixture

• -Dilute the reconstituted solution in either 50 mL of 0.9% Sodium Chloride Injection, USP, Lactated Ringer's Injection, USP, or 5% Dextrose Injection, USP.
• -The admixture should be stored at 25°C (77°F) and should be administered within the designated time period as uled in the Table below. No refrigeration is required.

• -Once the admixture is prepared, proceed toInstructions for Priming and Use of Filter.

• -PREVACID I.V. for Injection can be reconstituted directly into 50 mL of 0.9% Sodium Chloride for Injection, USP or 5% Dextrose Injection, USP utilizing Baxter's MINI-BAG Plus Container.
• -Refer to separate instructions that are provided with Baxter's MINI-BAG Plus Container.
• -Once the admixture is prepared, proceed to Instructions for Priming and Use of Filter.

The admixture should be stored at 25°C (77°F) and should be administered within the designated time period as uled in the Table below. No refrigeration is required.

TO PRIME FILTER

• -Prime administration set in usual manner and close administration set clamp.
• -Connect luer adapter of administration set to filter inlet using a twisting motion. Over-tightening should be avoided.
• -Hold filter below the level of solution container.
• -Open administration set clamp and slowly prime filter.
• -Close administration set clamp. Verify no air bubbles are present on patient side of filter.
• -If air bubbles are observed, open set clamp slightly to re-establish flow then gently tap filter housing. Observe that no air bubbles are present and close clamp.
• -Connect to patient and regulate flow. Filter may be primed using a syringe and saline.
• -The administration set can then be connected to inlet of filter.

PRECAUTIONS WITH USE OF FILTER

Follow instructions carefully:

• -Use Aseptic technique. For single use only. Do not resterilize or reuse. Do not use if package is damaged.
• -If repositioning of filter is required, loosen luer locking collar, reposition, then retighten locking collar firmly.
• -Maximum working pressure is 1500 mmHg (30 psi, 2 bar). When the working limits of the filter are exceeded, causes of the added resistance should be investigated and corrected.
• -The internal volume of the filter is approx. 0.7 mL.
• -The administration set clamp should be closed during solution container change.
• -Pumps should not be used downstream of filter.

IN-LINE FILTER THAT IS PROVIDED MUST BE USED when administering PREVACID I.V. for Injection via an administration set.

As lansoprazole may be incompatible with other drugs and/or diluents, follow these steps:

• Flush the PREVACID I.V. for Injection administration port before administration of PREVACID I.V. for Injection with either:
  • 0.9% Sodium Chloride Injection, USP,
  • Lactated Ringer’s Injection, USP, or
  • 5% Dextrose Injection, USP.
• Attach the filter and administration set.
• Administer the drug over 30 minutes.
• Remove and discard the administration set, including the filter, used for PREVACID I.V. for Injection.
• Flush the administration port.

If the administration port is not flushed and the administration set is not removed, lansoprazole degradation may occur with time, and black or brown particulate may be observed in the tubing or on the filter.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

The recommended adult dose (when patients are unable to take the oral therapy) is 30 mg of lansoprazole (1 vial of PREVACID I.V. for Injection) per day administered by I.V. infusion over 30 minutes for up to 7 days. Once the patient is able to take medications orally, therapy can be switched to an oral PREVACID formulation for a total of 6 to 8 weeks. Refer to full prescribing information for the oral formulations of PREVACID.

No dosage adjustment is necessary in patients with renal insufficiency or the elderly. For patients with severe liver disease, dosage adjustment should be considered.

PREVACID I.V. for Injection contains 30 mg of lansoprazole as white to pale yellow friable masses and powder in a vial and is available as follows:

Store PREVACID I.V. for Injection at 25°C (77°F); excursions permitted to 15-30°C (59-86°F). Protect from light. Use carton to protect spans from light.