PREVACID (lansoprazole delayed-release capsules), and PREVACID FasTab (lansoprazole delayed-release tablets) are indicated in the treatment of conditions where a reduction of gastric acid secretion is required, such as:

Lansoprazole, in combination with clarithromycin plus amoxicillin as triple therapy, is indicated for the treatment of patients with H. pylori infection and active duodenal ulcer disease. Eradication of H. pylori has been shown to reduce the risk of duodenal ulcer recurrence (see Dosage and Administration).

(For additional information on triple therapy for the treatment of H. pylori infection and active duodenal ulcer recurrence, refer to the Hp-PAC Product Monograph.)

In patients with a recent history of duodenal ulcers who are H. pylori positive, eradication therapy may reduce the rate of recurrence of duodenal ulcers. The optimal timing for eradication therapy for such patients remains to be determined.

In patients who fail a therapy combination containing clarithromycin, susceptibility testing should be done. If resistance to clarithromycin is demonstrated or susceptibility testing is not possible, an alternative therapy combination is recommended.

Resistance to amoxicillin has not been demonstrated in clinical studies with lansoprazole delayed-release capsules and amoxicillin.

Table 1 summarizes the eradication rates for the H. pylori Triple Therapy treatment regimens.

Table 1: PREVACID

Eradication Rates for the H. pylori Triple Therapy Treatment Regimens

Treatment Regimen	Days/Study No.	Evaluable (Per Protocol)a % (n/N)	ITT (all data)b % (n/N)	ITT (Worst Case)c % (n/N)
PREVACID 30 mg capsules/Clarithromycin 500 mg/Amoxicillin 1 g (all b.i.d.)	14/M93-131 14/M95-392	92 (44/48) 86 (57/66)	94 (47/50) 87 (58/67)	86 (47/55) 83 (58/70)
PREVACID 30 mg capsules/Clarithromycin 500 mg/Amoxicillin 1 g (all b.i.d.)	10/M95-399	84 (103/123)	86 (110/128)	81 (110/135)
PREVACID 30 mg capsules/Clarithromycin 250 mg/Amoxicillin 1 g (all b.i.d.)	7/GB 94/110	90 (103/114)	90 (104/116)	86 (104/121)

^a. Based on evaluable patients with confirmed duodenal ulcer and/or gastritis and H. pylori infection at baseline defined as at least 2 of 3 positive endoscopic tests from CLOtest, histology and/or culture. Patients were included in the analysis if they completed the study. Additionally, if patients dropped out of the study due to an adverse event related to the study drug, they were included in the analysis as failures of therapy.
^b. Patients were included in the analysis if they had documented H. pylori infection at baseline as defined above and had a confirmed duodenal ulcer.
^c. “Worst case” included patients with no available data as failures.

Legend:

PREVACID is indicated for treatment of erosive and non-erosive GERD in children, aged 1 to 17 years. The clinical trial treatment period did not extend beyond 12 weeks.

• Patients with known hypersensitivity to any component of the formulations. For a complete listing, see Dosage Forms, Composition and Packaging.

  
  

• Amoxicillin is contraindicated in patients with a known hypersensitivity to any penicillin. (Please refer to the Amoxicillin Product Monograph before prescribing.)

  
  

• Clarithromycin is contraindicated in patients with known hypersensitivity to clarithromycin, erythromycin or other macrolide antibacterial agents. Clarithromycin is also contraindicated in patients receiving concurrent therapy with astemizole, terfenadine, cisapride or pimozide. (Please refer to the Clarithromycin tablets Product Monograph before prescribing.)

  
  

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

Pseudomembranous colitis has been reported with nearly all antibacterial agents, including clarithromycin and amoxicillin, and may range in severity from mild to life threatening. Therefore, it is important to consider this diagnosis in patients who present with diarrhea subsequent to the administration of antibacterial agents.

Treatment with antibacterial agents alters the normal flora of the colon and may permit overgrowth of clostridia. Studies indicate that a toxin produced by Clostridium difficile is a primary cause of “antibiotic-associated colitis”.

After the diagnosis of pseudomembranous colitis has been established, therapeutic measures should be initiated. Mild cases of pseudomembranous colitis usually respond to discontinuation of the drug alone. In moderate to severe cases, consideration should be given to management with fluids and electrolytes, protein supplementation, and treatment with an antibacterial drug effective against C. difficile.

To avoid failure of the eradication treatment with a potential for developing antimicrobial resistance and a risk of failure with subsequent therapy, patients should be instructed to follow closely the prescribed regimen.

For the eradication of H. pylori, amoxicillin and clarithromycin should not be administered to patients with renal impairment since the appropriate dosage in this patient population has not yet been established.

Safety concerns of long-term treatment relate to hypergastrinemia, possible enterochromaffin-like (ECL) effect and carcinoid formation. ECL cell hyperplasia and gastric carcinoid tumours were observed in four animal studies.

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 entero-chromaffin-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 rats. 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 one 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. Lansoprazole also induced a low, non-dose-related incidence of carcinoid tumours in the gastric mucosa in several dose groups (one female mouse in the 15 mg/kg/day group, one male mouse in the 150 mg/kg/day group, and 2 males and 1 female in the 300 mg/kg/day group). It also produced an increased incidence of liver tumours (hepatocellular adenoma plus carcinoma). The tumour 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).

Analysis of gastric biopsy specimens from patients after short-term treatment of proton pump inhibitors have not detected ECL cell effects similar to those seen in animal studies. Longer term studies in humans revealed a slight increase in the mean ECL-cell density, although there was no microscopic evidence of cell hyperplasia. Similar results were seen in the maintenance treatment studies, where patients received up to 15 months of lansoprazole therapy. Serum gastrin values increased significantly from their baseline values but reached a plateau after two months of therapy. By one month post-treatment, fasting serum gastrin values returned to lansoprazole therapy baseline. Moreover, results from gastric biopsies from short-term, long-term and maintenance treatment studies indicate that there are no clinically meaningful effects on gastric mucosa morphology among lansoprazole-treated patients.

When gastric ulcer is suspected, the possibility of malignancy should be excluded before therapy with lansoprazole delayed-release capsules or lansoprazole delayed-release tablets are instituted as treatment with these drugs may alleviate symptoms and delay diagnosis.

In the 24-month toxicology study in rats, after 18 months of treatment, Leydig cell hyperplasia increased above the concurrent and historical control level at dosages of 15 mg/kg/day or higher.

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 one-year toxicity study.

These changes are associated with endocrine alterations which have not been, to date, observed in humans.

It is recommended that the initial dosing regimen need not be altered for patients with mild or moderate liver disease, but for patients with moderate impairment, doses higher than 30 mg per day should not be administered unless there are compelling clinical indications. Dose reduction in patients with severe hepatic disease should be considered.

Allergic reactions (including anaphylaxis) have been reported in patients receiving clarithromycin orally.

Serious and occasionally fatal hypersensitivity (anaphylactic) reactions have been reported in patients on penicillin therapy. These reactions are more apt to occur in individuals with a history of penicillin hypersensitivity and/or a history of sensitivity to multiple allergens.

There have been well documented reports of individuals with a history of penicillin hypersensitivity reactions who have experienced severe hypersensitivity reactions when treated with a cephalosporin. Before initiating therapy with any penicillin, careful inquiry should be made concerning previous hypersensitivity reactions to penicillins, cephalosporins, and other allergens. If an allergic reaction occurs, amoxicillin should be discontinued and the appropriate therapy instituted.

Serious anaphylactic reactions require immediate emergency treatment with epinephrine, oxygen, corticosteroids, and airway management, including intubation, as indicated.

In animal studies, retinal atrophy was observed in rats dosed orally for 2 years with lansoprazole at doses of 15 mg/kg/day and above. These changes in rats are believed to be associated with the effects of taurine imbalance and phototoxicity in a susceptible animal model.

Clinical data available from long-term PREVACID (lansoprazole delayed-release capsules) studies are not suggestive of any drug-induced eye toxicity in humans. In humans, there are presently no concerns for ocular safety with short-term lansoprazole treatment and the risks associated with long-term use for nearly five years appear to be negligible.

The finding of drug-induced retinal atrophy in the albino rat is considered to be species-specific with little relevance for humans.

No dosage modification of lansoprazole is required in patients with renal insufficiency.

For the eradication of H. pylori, amoxicillin and clarithromycin should not be administered to patients with renal impairment since the appropriate dosage in this patient population has not yet been established.

Three patients 3/82 (3.7%) who had isolates susceptible to clarithromycin pretreatment and were treated with the triple therapy regimen remained H. pylori positive posttreatment. None of the isolates from these three patients had susceptibility results available after treatment with triple therapy; therefore, it is unknown whether or not these patients developed resistance to clarithromycin. Sixteen percent of the patients treated with the dual therapy regimen developed clarithromycin resistance post-treatment. Therefore, development of clarithromycin resistance should be considered as a possible risk.

Over 4000 women were treated with lansoprazole. Ulcer healing rates in females are similar to those in males. The incidence rates of adverse events are also similar to those seen in males.

Reproductive studies conducted in pregnant rats at oral doses up to 150 mg/kg/day (40 times the recommended human dose based on body surface area), and in rabbits at oral doses up to 30 mg/kg/day (16 times the recommended human dose based on body surface area), did not disclose any evidence of a teratogenic effect. Maternal toxicity and a significant increase in fetal mortality were observed in the rabbit study at doses above 10 mg/kg/day. In rats, maternal toxicity and a slight reduction in litter survival and weights were noted at doses above 100 mg/kg/day.

There are no adequate or well-controlled studies in pregnant women. Therefore, lansoprazole should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Lansoprazole or its metabolites are excreted in the milk of rats. It is not known whether lansoprazole is excreted in human milk. Because drugs are excreted in human milk, lansoprazole should not be given to nursing mothers unless its use is considered essential.

Safety and effectiveness have been established in pediatric patients 1 year to 17 years for short-term up to 12 weeks of symptomatic GERD and erosive esophagitis. Use of lansoprazole in this population is supported by evidence of adequate and well controlled studies of lansoprazole in adults with additional clinical, pharmacokinetic, pharmacodynamic, and safety studies performed in pediatric patients. The adverse events (AEs) profile in pediatric patients is similar to that of adults. There were no adverse events reported in U.S. clinical studies that were not previously observed in adults. Dose safety and effectiveness have not been established in patients <1 year.

Ulcer healing rates in elderly patients are similar to those in younger age groups. The incidence rates of adverse events and laboratory test abnormalities are also similar to those seen in other age groups. The initial dosing regimen need not be altered for elderly patients, but subsequent doses higher than 30 mg per day should not be administered unless additional gastric acid suppression is necessary.

Since 1991, lansoprazole has been approved in over 100 countries around the world, and about 250 million patients have been treated. Worldwide, over 10 000 patients have been treated with lansoprazole during Phase II-III short-term and long-term clinical trials involving various dosages and duration of treatment. In general, lansoprazole treatment has been well tolerated.

Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.

The following adverse events were reported to have a possible or probable relationship to drug as described by the treating physician in 1% or more of lansoprazole delayed-release capsules-treated patients who participated in placebo- and positive-controlled trials ( Table 2 and Table 3, respectively). Numbers in parentheses indicate the percentage of the adverse events reported.

Table 2: PREVACID

Incidence of Possibly or Probably Treatment-related Adverse Events in Short-term, Placebo-controlled Studies in TAP^a Safety Database

Body System/Adverse Eventb	PREVACIDc (n=817), N (%)	Placebo (n=254), N (%)
Body as a Whole
Headache	63 (7.7)	31 (12.2)
Abdominal Pain	19 (2.3)	3 (1.2)
Digestive System
Diarrhea	29 (3.5)	6 (2.4)
Nausea	9 (1.1)	5 (2.0)
Vomiting	7 (0.9)	3 (1.2)
Liver Function Tests Abnormal	2 (0.2)	3 (1.2)
Nervous System
Dizziness	8 (1.0)	2 (0.8)

^a. TAP Pharmaceuticals Inc.
^b. Events reported by at least 1% of patients on either treatment are included.
^c. Doses 15 mg, 30 mg and 60 mg q.d. for 4-8 weeks.

In the TAP Safety Database, all short-term, Phase II/III studies, one or more treatment-emergent AEs were reported by 715/1359 (52.6%) PREVACID-treated patients; of those considered to be possibly or probably treatment-related AEs, one or more were reported by 276/1359 (20.3%) PREVACID-treated patients. In all short-term, Phase II/III studies, one or more treatment-emergent AEs were reported by 150/254 (59.1%) placebo-treated patients; of those considered to be possibly or probably treatment-related AEs, one or more were reported by 56/254 (22.0%).

The most frequent AEs reported in the European short-term studies were diarrhea (3.3%), laboratory test abnormal (2.3%), headache (1.5%), constipation (1.2%), asthenia (1.1%), dizziness (1.1%), and abdominal pain (1.0%). The most frequent AEs reported in the Asian short-term studies were unspecified laboratory test abnormalities (7.3%), eosinophilia (1.0%), and increased ALT (1.0%).

Table 3: PREVACID

Incidence of Possibly or Probably Treatment-related Adverse Events in Short-term, Positive-controlled Studies in TAP Safety Database

Body System/Adverse Eventa	PREVACIDb (n=647), N (%)	Ranitidine (n=393), N (%)
Body as a Whole
Headache	26 (4.0)	14 (3.6)
Abdominal Pain	8 (1.2)	3 (0.8)
Digestive System
Diarrhea	27 (4.2)	8 (2.0)
Nausea	7 (1.1)	4 (1.0)
Nervous System
Dizziness	8 (1.2)	3 (0.8)
Skin and Appendages
Rash	7 (1.1)	1 (0.3)

^a. Events reported by at least 1% of patients on either treatment are included.
^b. Doses 15 mg, 30 mg and 60 mg q.d. for 4-8 weeks.

The following tables summarize the most frequently reported treatment-emergent AEs in the two (2) Healing studies and the Reduction of Risk study ( Table 4 and Table 5, respectively).

Table 4: PREVACID

Most Frequently Reported^a Treatment-emergent AEs by Treatment Group and Dose in the Principal Healing of NSAID-associated Gastric Ulcer Studies^b

	Treatment Group % (n)
Body System/ COSTART Term	Ranitidine 150 mg b.i.d. (N=235)	Lansoprazole 15 mg q.d. (N=235)	Lansoprazole 30 mg q.d. (N=231)
Any Event	47% (110)	43% (102)	52% (120)
Body as a Whole
Abdominal Pain	7% (17)	3% (7)	5% (11)
Digestive System
Diarrhea	8% (19)	11% (25)	9% (21)
Respiratory System
Pharyngitis	7% (16)	6% (13)	7% (17)

^a. Reported by ≥5% of patients in any treatment group.
^b. Treatment duration: 8 weeks.



Table 5: PREVACID

Most Frequently Reported^a Treatment-emergent Adverse Events by Treatment Group and Dose in the Principal Reduction of Risk of NSAID-associated Gastric Ulcer Study^e

	Treatment Group % (n)
Body System/ COSTART Term	Placebo (N=133)	Misoprostol 200 µg q.i.d. (N=134)	Lansoprazole 15 mg q.d. (N=136)	Lansoprazole 30 mg q.d. (N=132)
Body as a Whole
Abdominal Pain	7% (9)	10% (14)	7% (9)	6% (8)
Digestive System
Diarrhea	7% (9)	25% (33)b , c , d	10% (14)	13% (17)
Nausea	5% (6)	6% (8)	1% (2)	5% (6)
Respiratory System
Pharyngitis	3% (4)	9% (12)	7% (10)	9% (12)b
Sinusitis	2% (3)	2% (3)	5% (7)	6% (8)
Urogenital System
Urinary Tract Infection	2% (2)	7% (9)d	4% (6)	1% (1)

^a. Reported by ≥5% of patients in any treatment group.
^b. Statistically significant difference vs placebo (p≤0.05).
^c. Statistically significant difference vs lansoprazole 15 mg q.d. (p≤0.05).
^d. Statistically significant difference vs lansoprazole 30 mg q.d. (p≤0.05).
^e. Treatment duration: 12 weeks.

All adverse events considered possibly/probably treatment-related with an incidence of at least 5% in any treatment group are displayed by COSTART body system and term and by treatment group in Table 6.

Table 6: PREVACID

Adverse Events Possibly/Probably Related to Treatment, Reported by ≥5% of Patients in the US Placebo-controlled Non-erosive GERD Studies

Body System/COSTART Term	Placebo N=71 % (n)	Lansoprazoleb N=249 % (n)
Total Patients
Any Event	16.9 (12)	28.5 (71)a
Body as a Whole
Abdominal Pain	1.4 (1)	6.0 (15)
Headache	7.0 (5)	7.6 (19)
Digestive System
Diarrhea	2.8 (2)	5.2 (13)

^a. Statistically significantly different vs placebo at p=0.05 level.
^b. Doses 15 mg and 30 mg q.d. for 8 weeks.

The most commonly reported (incidence ≥5% in any treatment group) treatment-emergent adverse events for lansoprazole patients were headache (14.9%), pharyngitis (9.6%), abdominal pain (8.8%), diarrhea (7.6%) and rhinitis (6.4%) and for placebo patients were headache (9.9%) and pharyngitis (9.9%). There were no clinically or statistically significant differences between lansoprazole and placebo when evaluated for treatment-emergent adverse events.

All possibly/probably treatment-related adverse events with an incidence of at least 5% in either treatments are displayed by body system, COSTART term, and treatment in Table 7.

Table 7: PREVACID

Most Frequently^a Reported Possibly/Probably Treatment-related Adverse Events by Treatment in the Positive-controlled Non-erosive GERD Studies

	Treatment % (n)
Body System/ COSTART Term	RAN (N=283)	LANc (N=572)
Any Event	17 (49)	16 (91)
Body as a Whole
Abdominal Pain	2 (5)	5 (29)b
Digestive System
Diarrhea	6 (18)	4 (23)

^a. Reported by ≥5% of patients in any treatment.
^b. Statistically significantly different vs ranitidine at p=0.05 level.
^c. Doses 15 mg and 30 mg q.d. for 8 weeks.

Legend:

The most frequently reported (≥5% of patients in any treatment) treatment-emergent adverse events for lansoprazole-treated patients were abdominal pain (9%), diarrhea (7%), and headache (6%) and for ranitidine-treated patients were diarrhea (9%), abdominal pain (7%), and headache (7%). There were no clinically or statistically significant differences between lansoprazole- and ranitidine-treated patients in the percentage of patients reporting specific treatment-emergent adverse events.

Treatment-emergent AEs with an incidence of at least 2% in any treatment group of the maintenance treatment studies occurring from the start of maintenance treatment to the first recurrence of disease are displayed by body system and COSTART term, and by treatment group in Table 8.

There were no frequently reported (≥2.0%, incidence) severe AEs in the treatment-emergent or the possibly/probably treatment-related event categories with onset at any point from the start of maintenance treatment to the time of first recurrence of disease.

Table 8: PREVACID

Treatment-emergent Adverse Effects Reported by ≥2% of the Placebo and Lansoprazole Patients to the Time of First Recurrence of Disease^a in the Maintenance Treatment Studies

^a. Until time of first recurrence, withdrawal or end of maintenance treatment.
^b. CUM=cumulative.

The AEs reported by at least 2% of patients in any treatment group are displayed by COSTART body system and term and by treatment group for controlled long-term European Studies in Table 9.

Table 9: PREVACID

Treatment-emergent Adverse Effects Reported by ≥2% of Patients Treated with H₂-Receptor Antagonists or Lansoprazole in Long-term, Phase II/III H₂-Receptor Antagonist Controlled European Studies

The AEs reported by at least 1% of patients receiving lead-in open-label lansoprazole treatment in long-term European Studies are diarrhea (5.7%), esophagitis (2.5%), abdominal pain (2.1%), gastritis (2.1%), flatulence (1.3%), headache (1.1%), constipation (1.0%), and nausea (1.0%). The incidence of AEs reported in the lead-in open-label period of the European studies was similar to that seen in controlled studies, however, the overall incidence was lower for the lead-in open-label studies than for the H₂-RA controlled studies (27.5% versus 49.8%, respectively).

Adverse events from two bioequivalency studies performed in healthy volunteers are listed in Table 10.

The incidence of adverse events between the test 15 mg lansoprazole delayed-release orally disintegrating tablets and the reference 15 mg lansoprazole delayed-release capsule (8% and 3%, respectively) was similar and are summarized in Table 10.

The incidence of adverse events between the test 30 mg lansoprazole delayed-release orally disintegrating tablets and the reference 30 mg lansoprazole delayed-release capsule (0% and 2%, respectively) was similar and are summarized in Table 10.

Table 10: PREVACID FasTab

Summary of Adverse Events by Regimen, COSTART Term, Number of Subjects, Percentage, and Incidence

Regimen/N	COSTART term	N [percentage]	Overall N [incidence]
15 mg lansoprazole delayed-release orally disintegrating tablets (test)/60	Headache	4 [7%]	5 [8%]
	Nausea	2 [3%]
	Epistaxis	1 [2%]
15 mg lansoprazole delayed-release capsules (reference)/60	Headache	2 [3%]	2 [3%]
	Nausea	1 [2%]
30 mg lansoprazole delayed-release orally disintegrating tablets (test)/60	N/A	0 [0%]	0 [0%]
30 mg lansoprazole delayed-release capsules (reference)/60	Hyperlipemia	1 [2%]	1 [2%]

The adverse event profile in pediatric patients resembled that of adults taking lansoprazole. The most frequently reported (2 or more patients) treatment-related adverse events in patients 1 to 11 years of age (N=66) were constipation (5%) and headache (3%). There were no adverse events reported in this U.S. clinical study that were not previously observed in adults.

The most