Lansoprazole

Current therapy for peptic ulcer disease focuses on the eradication of H. pylori infection with maintenance therapy indicated in those patients who are not cured of H. pylori and those with ulcers resistant to healing. Lansoprazole 30mg combined with amoxicillin 1g, clarithromycin 250 or 500mg, or metronidazole 400mg twice daily was associated with eradication rates ranging from 71 to 94%, and ulcer healing rates were generally >80% in well designed studies. In addition, it was as effective as omeprazole- or rabeprazole-based regimens which included these antimicrobial agents. Maintenance therapy with lansoprazole 30 mg/day was significantly more effective than either placebo or ranitidine in preventing ulcer relapse. Importantly, preliminary data suggest that lansoprazole-based eradication therapy is effective in children and the elderly.

In the short-term treatment of patients with gastro-oesophageal reflux disease (GORD), lansoprazole 15, 30 or 60 mg/day was significantly more effective than placebo, ranitidine 300 mg/day or cisapride 40 mg/day and similar in efficacy to pantoprazole 40 mg/day in terms of healing of oesophagitis. Lansoprazole 30 mg/day, omeprazole 20 mg/day and pantoprazole 40 mg/day all provided similar symptom relief in these patients. In patients with healed oesophagitis, 12-month maintenance therapy with lansoprazole 15 or 30 mg/day prevented recurrence and was similar to or more effective than omeprazole 10 or 20 mg/day.

Available data in patients with NSAID-related disorders or acid-related dyspepsia suggest that lansoprazole is effective in these patients in terms of the prevention of NSAID-related gastrointestinal complications, ulcer healing and symptom relief.

Meta-analytic data and postmarketing surveillance in >30 000 patients indicate that lansoprazole is well tolerated both as monotherapy and in combination with antimicrobial agents. After lansoprazole monotherapy commonly reported adverse events included dose-dependent diarrhoea, nausea/vomiting, headache and abdominal pain. After short-term treatment in patients with peptic ulcer, GORD, dyspepsia and gastritis the incidence of adverse events associated with lansoprazole was generally ≤5%. Similar adverse events were seen in long-term trials, although the incidence was generally higher (≤10%). When lansoprazole was administered in combination with amoxicillin, clarithromycin or metronidazole adverse events included diarrhoea, headache and taste disturbance.

In conclusion, lansoprazole-based triple therapy is an effective treatment option for the eradication of H. pylori infection in patients with peptic ulcer disease. Preliminary data suggest it may have an important role in the management of this infection in children and the elderly. In the short-term management of GORD, lansoprazole monotherapy offers a more effective alternative to histamine H₂-receptor antagonists and initial data indicate that it is an effective short-term treatment option in children and adolescents. In adults lansoprazole maintenance therapy is also an established treatment option for the long-term management of this chronic disease. Lansoprazole has a role in the treatment and prevention of NSAID-related ulcers and the treatment of acid-related dyspepsia; however, further studies are needed to confirm its place in these indications. Lansoprazole has emerged as a useful and well tolerated treatment option in the management of acid-related disorders.

Lansoprazole inhibits gastric acid secretion via selective inhibition of the proton pump of the gastric parietal cell. Its active sulphenamide metabolites inactivate H⁺, K⁺-ATPase which catalyses the final step in the gastric acid secretion pathway.

Data from healthy volunteers showed that lansoprazole 30mg provided faster control of intragastric acidity than pantoprazole 40mg, rabeprazole 20mg and omeprazole 20 and 40mg administered once daily. However, in terms of mean intragastric 24-hour pH, lansoprazole 30mg was equivalent to omeprazole 40mg and better than pantoprazole 40mg and omeprazole 20mg. The duration of increased intragastric pH above pH 3 or 4 was significantly longer for lansoprazole 30mg versus pantoprazole 40mg or omeprazole 20mg; lansoprazole 15 mg/day and omeprazole 20 mg/day were equivalent.

Lansoprazole 30 mg/day significantly increased mean 24-hour gastric pH values compared with ranitidine 600 mg/day in a well designed crossover 5-day study. In addition, the percentage of time for which intragastric pH was maintained above 4 was significantly greater for lansoprazole than for ranitidine.

In a well designed crossover study in patients with gastro-oesophageal reflux disease (GORD), lansoprazole 30 mg/day and omeprazole 20 mg/day increased median daytime and night-time intragastric pH to a similar extent. Although, on day 5 of treatment the total time spent with a mean oesophageal pH value of <4 was significantly shorter for lansoprazole than for omeprazole.

In vitro, lansoprazole has demonstrated antibacterial activity against up to 113 Helicobacter pylori strains isolated from endoscopic biopsies. The minimum inhibitory concentrations required to inhibit the growth of 50% (MIC₅₀) of H. pylori were generally within the range of 1 to 1.56 mg/L. Comparative MIC₅₀values for other proton pump inhibitors were 12.5 to 16 mg/L for omeprazole and 50 mg/L for pantoprazole.

Lansoprazole is rapidly and completely absorbed, and displays linear kinetics over a dose range of 15 to 60mg. Maximum plasma concentrations (C_max) of 0.75 to 1.15 mg/L were reached 1.5 to 2.2 hours after administration of a single dose of lansoprazole 30mg. Administration with food reduces both C_max and area under the plasma concentration-time-curve (AUC) by 50% and delays the time to reach Cmax by 3.5 to 3.7 hours. Like all proton pump inhibitors, lansoprazole is highly protein bound (97%), rapidly metabolised in the liver by cytochrome P450 and has negligible renal clearance. Lansoprazole is also converted to its active metabolites in the gastric parietal cells. The elimination half-life (t½) of lansoprazole 30mg is approximately 0.9 to 1.6 hours. After a single oral dose of [¹⁴C]-lansoprazole one-third was excreted in the urine and two-thirds in the faeces.

In patients with renal impairment, t½ and AUC were decreased after administration of lansoprazole 60mg. AUC at steady state and t½ were increased in patients with varying degrees of hepatic impairment. In elderly patients t½ and AUC may be prolonged and clearance may be reduced. In one study, C_max, AUC and t½ were increased after multiple doses of lansoprazole 30mg in patients with GORD compared with healthy volunteers.

Coadministration of lansoprazole 30mg, amoxicillin 1g and clarithromycin 500mg twice daily significantly prolongs t½ and increases the AUC of lansoprazole while increasing the C_max, AUC₁₂ and t_max of clarithromycin. The C_max of paracetamol (acetaminophen) 1g was increased and the t_max was reduced when coadministered with lansoprazole 30mg. There were no clinically significant interactions when lansoprazole 30mg was coadministered with the following agents: roxithromycin 300mg twice daily, warfarin, indomethacin, ibuprofen, prednisolone, diazepam or terfenadine. Lansoprazole 60mg had no clinically significant effect on the pharmacokinetics of intravenous phenytoin, oral propranolol or theophylline, and multiple dose lansoprazole 60mg plus metronidazole 1g did not effect the pharmacokinetic properties of either agent.

Peptic ulcer disease

Eradication therapy combining a proton pump inhibitor and two antimicrobial agents is currently the most effective therapy, curing peptic ulcer disease and preventing ulcer recurrence in the majority of patients.

One-week triple therapy regimens with various combinations of lansoprazole 30mg or omeprazole 20mg plus amoxicillin 1g and/or clarithromycin 250 or 500mg and/or metronidazole 400mg administered twice daily generally show ulcer healing rates of >80%. Preliminary results obtained in a subgroup of patients indicate a greater incidence of ulcer healing was observed with a two-week lansoprazole-based triple therapy regimen although this was not significantly different compared with a one-week regimen.

There are few available data on the efficacy of eradication regimens in elderly patients and in children. Lansoprazole-based triple therapy regimens including a combination of amoxicillin, clarithromycin or metronidazole were equally effective in elderly patients, with eradication rates in the order of 80%. Similar eradication rates were observed after one weeks treatment with lansoprazole 30mg, omeprazole 20mg or pantoprazole 40mg all administered twice daily in combination with amoxicillin 1g twice daily and metronidazole 250mg 4 times daily for 1 week.

The optimal treatment regimen in children has not been established. Based on preliminary data in children and adolescents (2 to 18 years) triple therapy regimens using a lansoprazole dosage of >0.75 mg/kg/day combined with amoxicillin and clarithromycin had the highest eradication rates (87 and 92% in two trials), and ulcer healing was evident in 92% of children.

Gastro- Oesophageal reflux disease

For short-term treatment of patients with GORD, lansoprazole 15, 30 or 60 mg/day was significantly more effective in healing oesophagitis than placebo, ranitidine 300 or 600 mg/day or cisapride 20mg twice daily. Lansoprazole also reduced the percentage of days and nights with heartburn compared with ranitidine and placebo; the latter comparison was significantly in favour of lansoprazole. Lansoprazole and pantoprazole were equivalent in terms of endoscopically confirmed healing, and omeprazole and pantoprazole provided similar symptom relief to lansoprazole therapy in terms of the proportion of patients free of heartburn. However, in comparison with omeprazole, ranitidine and cisapride, lansoprazole provided significantly greater relief from heartburn.

In patients with healed oesophagitis, lansoprazole 15 or 30 mg/day administered as maintenance therapy prevented recurrence. However, data from 12-month studies offer no firm consensus on the most effective lansoprazole dosage for maintenance treatment.

Oesophagitis recurrence rates were <10% for both lansoprazole 30 mg/day and omeprazole 20 mg/day after 12 months’ maintenance therapy. The lower dosage of lansoprazole 15mg once daily was significantly more effective than omeprazole 10mg once daily in preventing relapse.

H. pylori status may affect the relapse rate in patients with GORD. In a randomised trial, all patients received lansoprazole 30mg daily for 10 days and H. pylori-positive patients also received amoxicillin and clarithromycin for 10 days then all patients received lansoprazole 30mg for 8 weeks. After 6 months of follow-up H. pylori-positive patients had a significantly faster relapse rate compared with either patients who had successful eradication therapy or patients who were H. pylori-negative. Severity of oesophagitis also significantly affected the relapse rate.

Lansoprazole 15 or 30mg once daily for 8 to 12 weeks healed erosive GORD in 27 children aged 1 to 12 years enrolled in a noncomparative trial. In a randomised double-blind trial in 63 children, lansoprazole 15mg relieved symptoms in only 69% of patients. Lansoprazole 1.3 to 1.5 mg/kg/day for 12 weeks resulted in endoscopically confirmed healing in 75% of children (n = 12) after treatment failure with ranitidine.

NSAID- related ulcers

In patients with NSAID-related gastric ulcers lansoprazole 15 and 30 mg/day was associated with a significantly higher incidence of ulcer healing, a lower incidence of daytime and night-time abdominal pain and a lower severity of day- or night-time abdominal pain and less antacid use per day than ranitidine 150mg twice daily. In over 2400 patients enrolled in randomised double-blind trials overall ulcer healing rates ranged from 64 to 76% with both dosages of lansoprazole compared with 47 to 53% for ranitidine recipients.

Lansoprazole 30 mg/day reduced ulcer relapse, irrespective of H. pylori status, in 61 patients with healed ulcers who continued to take naproxen 750 mg/day. An approximately 5-fold difference in relapse rates was noted between lansoprazole who had undergone H. pylori eradication and placebo recipients.

In a randomised double-blind study in 455 evaluable patients reported as an abstract, lansoprazole 15 and 30 mg/day was as effective as misoprostol 200μg four times daily in preventing NSAID-related ulcers.

Acid- related dyspepsia

In 562 patients with acid-related dyspepsia, lansoprazole 15mg once daily provided significantly greater symptom relief (daytime heartburn and epigastric pain) compared with omeprazole 10mg once daily after 2 weeks of treatment in a randomised double-blind study; however, both agents were similarly effective at 4 weeks in an intention-to-treat analysis. Additional analyses suggest an interaction between the type of dyspepsia and treatment; at week 4 lansoprazole was more likely to provide symptom relief for patients with ulcer-like dyspepsia and omeprazole was more likely to be effective for those with reflux-like dyspepsia.

A per-protocol analysis in 283 patients with acid-related dyspepsia showed that lansoprazole 30mg once daily was significantly more effective than ranitidine 150mg twice daily in improving dyspepsia symptoms including freedom from daytime and night-time heartburn and night-time epigastric pain after 4 weeks of treatment in a randomised study.

Data from two abstracts also confirm that lansoprazole 15 and 30mg are superior in efficacy to placebo in providing symptomatic relief from dyspepsia in patients with nonulcer dyspepsia.

In the US, the UK and The Netherlands, a review of clinical trials and postmarketing surveillance have evaluated the tolerability profile of lansoprazole in over 30 000 patients with GORD, gastric or duodenal ulcers, dyspepsia, Barrett’s oesophagus or Zollinger-Ellison syndrome. The most commonly reported adverse events,with lansoprazole 15, 30 and 60 mg/day therapy in patients with GORD or gastric or duodenal ulcer, were diarrhoea, which appears to be dose dependent, nausea, headache and abdominal pain.

A US review of clinical trials of ≤2 months’ duration found no significant differences between lansoprazole 15, 30 or 60 mg/day and omeprazole 20 mg/day with respect to headache, diarrhoea and nausea; these adverse events occurred with a frequency of ≤5%.

In 8-week trials in patients with GORD, NSAID-related gastric ulcers and acid-related dyspepsia lansoprazole 15 or 30 mg/day were generally associated with a similar incidence of adverse events compared with ranitidine 300 or 600 mg/day. In patients with GORD, nausea/vomiting, diarrhoea, abdominal pain and headache were most commonly reported; diarrhoea was the most frequently reported adverse event in patients with an NSAID-related ulcer.

Similar adverse events were observed in trials of 1 to 4 years’ duration in patients with GORD, peptic ulcer, gastritis or dyspepsia. However, the frequency of adverse events such as diarrhoea, headache, nausea/vomiting, dizziness and abdominal pain was generally higher (>10%) in longer-term trials. A similar type and frequency of events was observed in a 1-year trial in patients with duodenal ulcer administered lansoprazole 15 or 30 mg/day or ranitidine 150 mg/day.

The most commonly reported adverse events were diarrhoea, headache and taste disturbance when lansoprazole was administered in combination with amoxicillin, clarithromycin or metronidazole. Omeprazole-based triple therapy was generally similar in the type and frequency of adverse events observed. Notably, lansoprazole in combination with amoxicillin and clarithromycin had the highest incidence of diarrhoea, while lansoprazole plus clarithromycin and metronidazole had the lowest.

For short-term treatment of GORD, 30 mg/day for 4 to 8 weeks is recommended in the UK; in the US treatment should be initiated with 15 mg/day for up to 8 weeks and this dosage may be increased to 30 mg/day for patients with erosive oesophagitis. Lansoprazole 15 mg/day is recommended for maintenance treatment to prevent recurrence in patients with healed GORD; this dosage may be increased to 30 mg/day in the UK.

US guidelines recommend administration of lansoprazole 30 mg/day for 8 weeks for the treatment of NSAID-related ulcers; according to UK guidelines lansoprazole 15 to 30 mg/day should be administered for 4 to 8 weeks. In the US, lansoprazole 15 mg/day for up to 12 weeks is recommended as prophylactic treatment in patients at risk of developing NSAID-related ulcers. Lansoprazole 15 to 30 mg/day may be administered to these patients according to UK guidelines.

At present there are no US recommendations for the treatment of acid-related dyspepsia. The UK prescribing guidelines recommend 2 to 4 weeks’ treatment with lansoprazole 15 to 30 mg/day as required.

Of note, lansoprazole should be taken before meals to avoid a reduction in the rate and extent of absorption. Although lansoprazole is usually administered once daily, it may be administered in two divided doses in the morning and evening in patients receiving ≥120mg daily.

Dosage adjustment of lansoprazole is not necessary in elderly patients or patients with mild renal or hepatic impairment, although, in patients with severe hepatic dysfunction a dosage reduction should be considered. There are currently no recommendations available concerning the use of lansoprazole in children.