Carafate (Sucralfate)

Sucralfate is a basic nonabsorbable aluminum salt of sucrose octasulfate. Despite weak antacid properties, the protective effect of sucralfate is not mediated by acid suppression or neutralization but by a mucosal protective effect on the gastric mucosa. The mucosal protection afforded by sucralfate is mediated by several mechanisms, including the formation of a protective barrier, stimulation of gastric mucosal blood flow, prostaglandin-mediated increase in mucus and bicarbonate secretion, and the stimulation of a variety of growth factors that have been implicated in ulcer healing.

Despite this theoretical benefit, the role of sucralfate in preventing clinically significant stress-related erosive syndrome bleeding is controversial. Although some studies suggest that sucralfate is an effective prophylactic agent with a benign side effect profile that possibly includes a lower incidence of nosocomial pneumonia, in many of the studies reviewed, sucralfate was not statistically superior to the control group in preventing stress-related erosive syndrome hemorrhage.

In a large study by Cook and colleagues (1998), including 1,200 mechanically ventilated patients, sucralfate was inferior to ranitidine in preventing upper gastrointestinal bleeding, and there were no significant differences in ventilator-associated pneumonia rates between the two agents. Sucralfate (Carafate) is available as tablets or as liquid administered 1 g orally or by nasogastric tube every 4 to 6 hours. Although usually well tolerated, constipation occurs in 2 to 4% of patients receiving sucralfate, and aluminum toxicity has occurred in patients with chronic renal failure.

Despite some theoretical advantages of sucralfate, including its ease of use, lack of need for monitoring, lack of need for supplemental antacid therapy, and cost-effectiveness, this agent cannot be recommended as the drug of choice in stress-related erosive syndrome because of discordant study results.

Prostaglandin Analogues

Despite the promise demonstrated in earlier trials, synthetic prostaglandin derivatives, such as misoprostol (Cytotec), are ineffective in preventing stress-related erosive syndrome. Synthetic prostaglandin analogs exert a cytoprotective effect at low doses and have been demonstrated to protect the gastric mucosa from various agents. Given the relatively high cost and significant side effects associated with their use, it is unlikely that any large-scale randomized clinical trial will be performed to investigate the role of prostaglandin analogs in stress-related erosive syndrome bleeding; therefore, the use of these agents in the prevention of SERS cannot be recommended.

Pharmacokinetics

Sucralfate is only slightly absorbed from the gastrointestinal tract after oral doses. However, there can be some release of aluminum ions and sucrose sulfate. Small quantities of sucrose sulfate may then be absorbed and excreted, primarily in the urine; some absorption of aluminum may also occur.

Uses and Administration

Sucralfate is a cytoprotective drug that, under acid gastrointestinal conditions, forms an adhesive complex with proteins that coat the gastric mucosa and is reported to have a particular affinity for ulcer sites. It also inhibits the action of pepsin and adsorbs bile salts. Sucralfate has been used to treat peptic ulcer disease and chronic gastritis. It is given orally and should be taken on an empty stomach before meals and at bedtime. The usual dose is 1 g four times or 2 g twice daily for 4 to 8 weeks; if necessary, the dose may be increased to a maximum of 8 g daily. If longer-term therapy is required, sucralfate may be given for up to 12 weeks. Where appropriate, a maintenance dose of 1 g twice daily may be given to prevent the recurrence of duodenal ulcers. To prevent gastrointestinal bleeding from stress ulceration, the usual sucralfate dose is 1 g six times daily; a dose of 8 g daily should not be exceeded.

Administration in Children

Although sucralfate is not licensed in the UK for use in children under 15 years, the BNFC recommends the following oral doses for the treatment of peptic ulcer disease or the prevention of stress ulceration in children in intensive care:

• 1 month to 2 years: 250 mg four to six times daily;
• 2 to 12 years: 500 mg four to six times daily;
• 12 to 18 years: 1 g four to six times daily.

The oral suspension blocks fine-bore feeding tubes, and tablets should be crushed and dispersed in water instead.

Gastrointestinal Bleeding

Sucralfate is an effective drug for preventing and managing stress-induced gastrointestinal bleeding in severely ill patients. However, whether it should be chosen over an H2-antagonist has been debated. One study suggested it might reduce the risk of late-onset pneumonia compared with ranitidine. Another study found ranitidine to be more effective than sucralfate in reducing the risk of gastrointestinal bleeding. At the same time, there was a trend towards a lower rate of pneumonia among patients receiving sucralfate, and the difference was insignificant.

However, meta-analyses found an increased risk of pneumonia with ranitidine compared with sucralfate but no difference in the rate of pneumonia with sucralfate and placebo; insufficient data were available to conduct a meta-analysis of sucralfate’s efficacy in terms of rates of bleeding, and a re-assessment of recommendations for the prevention of stress ulcers was called for. Later guidelines concluded that the use of sucralfate did not influence the incidence of ventilator-associated pneumonia compared with placebo. There is also evidence from a study that sucralfate reduces gastrointestinal bleeding associated with NSAID use, although it does not prevent drug-induced gastric erosion.

In a study to assess whether oral prophylactic sucralfate could ease the symptoms of acute radiation proctitis, sucralfate was found to increase the incidence of rectal bleeding compared with placebo; the cause of this increased bleeding was unclear.

Gastro-oesophageal Reflux Disease

Although sucralfate has been tried for gastro-oesophageal reflux disease, the results of studies have been inconsistent. However, if lifestyle or dietary measures prove insufficient for managing heartburn in pregnancy, sucralfate may be considered for first-line therapy.

Mouth Ulceration

Sucralfate has been investigated as a mouth rinse in treating and preventing stomatitis induced by cancer chemotherapy, although evidence of benefit for any drug is ambiguous (see Mucositis). One study in 40 patients found a significant reduction in symptoms among 23 evaluable patients given sucralfate prophylactically. Seven patients withdrew due to aggravation of chemotherapy-induced nausea. It was suggested that to overcome this problem, the suspension should have a neutral taste, should not be swallowed after rinsing, and that rinsing should not be started until nausea has stopped.

However, another study involving 80 patients treated with fluorouracil for colorectal cancer found no significant difference in self-reported mucositis symptoms between patients given sucralfate suspension and those given a placebo. Sucralfate has also been reported to benefit patients with recurrent aphthous stomatitis (mouth ulceration). A study involving 21 such patients over two years found that topical application of sucralfate suspension four times daily was superior to treatment with an antacid (aluminum hydroxide with magnesium hydroxide) or placebo.

In patients with Behcefs syndrome, topical sucralfate suspension significantly decreased the frequency, healing time, and pain of oral ulceration, as well as the healing time and pain of genital ulceration, compared with placebo.

Skin Ulceration

Sucralfate has reportedly been applied topically with some success to treat bleeding skin ulcers associated with malignancy and to promote the healing of venous stasis ulcers. It has been suggested that sucralfate promotes angiogenesis by binding to and preventing the degradation of basic fibroblast growth factor (bFGF). Topical sucralfate 7% cream was also reported to decrease pain and speed wound healing after open surgical removal of hemorrhoids.

Adverse Effects and Precautions

Constipation is sucralfate’s most frequently reported adverse effect, although diarrhea, nausea, vomiting, flatulence, or gastric discomfort may also occur. Other adverse effects include dry mouth, dizziness, drowsiness, headache, vertigo, back pain, and skin rashes. Hypersensitivity reactions such as pruritus, edema, urticaria, respiratory difficulty, rhinitis, laryngospasm, and facial swelling have been reported. Great caution is needed in patients with renal impairment (below), as absorption and accumulation of aluminum may cause adverse effects.

Bezoar Formation

As of March 1999, the UK CSM was aware of 7 reports worldwide of bezoar formation associated with sucralfate use in intensive care patients. It advised caution in using sucralfate in seriously ill patients because of the risks of bezoar formation and intestinal obstruction. Patients with delayed gastric emptying or receiving concomitant enteral feeds may be at increased risk. A report by the French Pharmacovigilance System at about the same time made similar recommendations but also contra-indicated the use of sucralfate in premature and immature neonates.

Renal Impairment

Under acid conditions, sucralfate can release aluminum ions that may be absorbed systemically. Significant increases in the urinary excretion of aluminum have been seen in healthy subjects given sucralfate 4g daily, reflecting gastrointestinal absorption of aluminum concentrations in serum and urine was significantly higher in patients with chronic renal impairment than in subjects with normal renal function and similar serum increases have been seen in children with acute renal failure.

Aluminum toxicity in patients with normal renal function receiving sucralfate would not be expected. Still, seizures, muscle weakness, bone pain, and severe aluminum encephalopathy have been reported in patients with end-stage renal disease requiring dialysis. Sucralfate should be used with caution in patients with renal impairment, especially if other aluminum-containing agents are also taken, and such patients should be monitored for signs of aluminum toxicity.

Interactions

Sucralfate may interfere with the absorption of other drugs, and it has been suggested that there should be 2 hours between giving sucralfate and other non-antacid medication. Some of the drugs reported to be affected by sucralfate include cimetidine, ranitidine, digoxin, fluoroquinolone antibacterials, ketoconazole, levothyroxine, phenytoin, tetracycline, quinidine, theophylline, and possibly warfarin. The recommended interval between sucralfate and antacids is 30 minutes. An interval of 1 hour should elapse between giving sucralfate and enteral feeding.

Drug Approvals

(British Approved Name, US Adopted Name, rINN)

Synonyms: Sucralfato; Sucralfatum; Sukralfaatti; Sukralfat

BAN: Sucralfate

USAN: Sucralfate

INN: Sucralfate [rINN (en)]

INN: Sucralfato [rINN (es)]

INN: Sucralfate [rINN (fr)]

INN: Sucralfatum [rINN (la)]

INN: Сукральфат [rINN (ru)]

Chemical name: Sucrose hydrogen sulfate basic aluminum salt; Sucrose octakis(hydrogen sulfate) aluminum complex; β-d-Fructofuranosyl-αd-glucopyranoside octakis (hydrogen sulfate) aluminum complex

Molecular formula: C12HmAl16OnS8

CAS: 54182-58-0

ATC code: A02BX02

Read code: y01Q0

Pharmacopoeias. In China, Japan, and the US.

The United States Pharmacopeia 31, 2008 (Sucralfate). The hydrous basic aluminum salt of sucrose octasulfate. Store in airtight containers.