Important aspects of prescribing information relevant to primary healthcare are covered in this section specifically for the drugs recommended in this CKS topic. For further information on contraindications, cautions, drug interactions, and adverse effects, see the electronic Medicines Compendium (eMC) (http://emc.medicines.org.uk), or the British National Formulary (BNF) (www.bnf.org).

• Amoxicillin should not be taken by people who have true penicillin allergy. However, gastrointestinal adverse effects alone (e.g. nausea, vomiting, or diarrhoea) do not constitute an allergy to penicillin [BNF 55, 2008]:
• An erythematous, maculopapular rash is common with amoxicillin, but this only indicates hypersensitivity to amoxicillin and not usually to other penicillins [Sweetman, 2005].
• Note: an urticarial rash does constitute true penicillin allergy.
• Drug interactions:
• Contraceptives: antibiotics may cause the combined oral contraceptive pill or patch to fail during the first few weeks of treatment [Baxter, 2006] (see the CKS topic on Contraception for information on the combined oral contraceptive pill or patch).
• Advise women to use additional contraception during the course of treatment and for 7 days afterwards. If this 7-day period runs beyond the end of the pack of contraceptive pills, advise the woman to start a new pack without a break (omitting any inactive tablets) [FFPRHC, 2005; FFPRHC, 2007].
• Anticoagulants: documented reports of oral anticoagulant/penicillin (including amoxicillin) interaction are relatively rare [Baxter, 2006]. However, the British National Formulary advises that common experience in anticoagulant clinics is that a course of broad-spectrum antibiotic can alter the international normalized ratio [BNF 55, 2008].

• Clarithromycin is generally well tolerated. It may cause gastrointestinal adverse effects (e.g. nausea, vomiting, diarrhoea) [ABPI Medicines Compendium, 2006].
• Drug interactions:
• Possible enhanced effect of aminophylline, theophylline, and carbamazepine (due to cytochrome P450 enzyme inhibition) [Aronson, 2006a]. Check levels if toxicity is suspected (e.g. palpitations, nausea, headache).
• Possible enhanced effect of warfarin: this is an established but unpredictable interaction. Monitor the international normalized ratio when both drugs are used (particularly in the elderly), and adjust the warfarin dose accordingly [Baxter, 2006]. There are reports of increased prothrombin times within three to five days after starting to take clarithromycin [Baxter, 2006].
• Possible QT interval prolongation: if possible, avoid giving erythromycin or clarithromycin if the person is already taking a drug that can potentially prolong the QT interval (e.g. antiarrhythmics, antipsychotics, tricyclic antidepressants) or if the person has hypokalaemia, which also increases the risk of QT prolongation [Baxter, 2006].
• Increased risk of myopathy in people taking atorvastatin or simvastatin (due to cytochrome P450 enzyme CYP3A4 inhibition) [CSM, 2004a].
• Stop atorvastatin or simvastatin for the duration of clarithromycin treatment [ABPI Medicines Compendium, 2009d; MHRA, 2008a].
• Contraceptives: antibiotics may cause the combined oral contraceptive pill or patch to fail during the first few weeks of treatment [Baxter, 2006] (see the CKS topic on Contraception for information on the combined oral contraceptive pill or patch).
• Advise women to use additional contraception during the course of treatment and for 7 days afterwards. If this 7-day period runs beyond the end of the pack of contraceptive pills, advise the woman to start a new pack without a break (omitting any inactive tablets) [FFPRHC, 2005; FFPRHC, 2007].

• Common adverse effects include a metallic taste and gastrointestinal irritation (in particular nausea and vomiting). These are more common at higher doses.
• Drug interactions:
• Alcohol: some people taking oral metronidazole experience disulfiram-like reactions to alcohol (flushing, increased respiratory rate, increased pulse rate). Although there is no conclusive evidence to support an interaction between metronidazole and alcohol, people taking metronidazole should be advised of the possible consequences of drinking alcohol [Baxter, 2006].
• Anticoagulants: metronidazole can markedly increase the anticoagulant effects of warfarin [ABPI Medicines Compendium, 2008; Baxter, 2006]. If concurrent use cannot be avoided, monitor the international normalized ratio and adjust the warfarin dose accordingly [Baxter, 2006].
• Contraceptives: antibiotics may cause the combined oral contraceptive pill or patch to fail during the first few weeks of treatment [Baxter, 2006] (see the CKS topic on Contraception for information on the combined oral contraceptive pill or patch).
• Advise women to use additional contraception during the course of treatment and for 7 days afterwards. If this 7-day period runs beyond the end of the pack of contraceptive pills, advise the woman to start a new pack without a break (omitting any inactive tablets) [FFPRHC, 2005; FFPRHC, 2007].

• Five proton pump inhibitors (PPIs) are currently available in the UK: esomeprazole (an isomer of omeprazole), lansoprazole, omeprazole, pantoprazole, and rabeprazole.
• Differences between the PPIs in terms of clinical efficacy and safety are minimal [Aronson, 2006; MeReC, 2006].
• Of the five PPIs available, lansoprazole and omeprazole are both available generically and are considerably cheaper than other PPIs.
• For the eradication of Helicobacter pylori, evidence indicates omeprazole and lansoprazole are equally effective and are as effective as other PPIs.

• Recommended doses of proton pump inhibitors are outlined in Table 1.

• When gastric ulcer is suspected, exclude the possibility of malignancy before treatment with a proton pump inhibitor (PPI) is instituted, as treatment may alleviate symptoms and delay diagnosis.
• Stop or do not initiate PPIs at least 14 days before endoscopy, as they may mask gastric cancer.
• Check if the individual is taking omeprazole which has been brought over the counter. The 10 mg tablet is licensed for the relief of reflux-like symptoms (e.g. heartburn) in those aged 18 and over [ABPI Medicines Compendium, 2004].
• PPIs are generally well tolerated and adverse reactions have generally been mild and reversible.
• The type and frequency of adverse effects reported with lansoprazole, omeprazole, pantoprazole, and rabeprazole are comparable. The most common adverse effects include headache, diarrhoea, nausea, abdominal pain, constipation, dizziness, and skin rashes.
• Drug interactions:
• PPIs undergo extensive hepatic metabolism. In people with liver disease, do not exceed 20 mg daily for omeprazole, pantoprazole, and esomeprazole and 30 mg daily for lansoprazole. There are no data on the use of rabeprazole in people with severe hepatic impairment, and the manufacturer advises caution.
• Occasional and unpredictable bleeding have been reported with warfarin and certain proton pump inhibitors (esomeprazole, omeprazole and lansoprazole). The interaction is not thought to occur with rabeprazole or pantoprazole [Baxter, 2006].
• There are case reports of omeprazole, esomeprazole and lansoprazole interacting with phenytoin (causing an increase in phenytoin level). The mechanism is not well understood and information is very limited. No special precautions would normally seem necessary if lansoprazole or omeprazole is given with phenytoin but prescribers should be aware of this possible interaction if concurrent use is necessary. Pantoprazole and rabeprazole appear not to interact with warfarin [Baxter, 2006].
• Because of decreased intragastric acidity, the absorption of ketoconazole or itraconazole may be reduced during PPI treatment.
• PPIs can significantly reduce the efficacy of clopidogrel by inhibition of the CYP2C19 isoenzyme. The Medicines and Healthcare products Regulatory Agency (MHRA) has advised that concomitant use of clopidogrel and any PPI should be avoided unless considered essential [MHRA, 2009].

[NICE, 2005; Aronson, 2006; ABPI Medicines Compendium, 2008]

• Gastric malignancy should be excluded prior to initiation of therapy with a H₂-receptor antagonist (H₂RA). Symptomatic response to H₂RA therapy does not preclude the presence of gastric malignancy.
• Stop or do not initiate H₂RA at least 14 days before endoscopy, as they may mask gastric cancer.
• Four H₂RAs are available in the UK: cimetidine, famotidine, nizatidine, and ranitidine. Licensed indications differs between H₂RAs for the management of dyspepsia:
• All four H₂RAs are licensed for the treatment and symptomatic relief of gastro-oesphageal reflux disease.
• However, only cimetidine and ranitidine are both licensed for persistent symptoms of dyspepsia with or without ulceration (including meal-related upper abdominal pain).
• Choice of H₂RA:
• Famotidine, nizatidine and ranitidine may be considered (see Table 1 for indications and dosage). Of these, ranitidine is preferred because it is also licensed for persistent symptoms of dyspepsia and is considerably cheaper than famotidine and nizatidine.
• Cimetidine is less preferred, given the higher risk of drug interaction with this drug (inhibition of the cytochrome P450 enzymes). The other three H₂RAs do not share the drug metabolism inhibitory properties of cimetidine [BNF 55, 2008].
• Availability over the counter:
• Only famotidine and ranitidine are available over-the-counter, and both are licensed for the relief of heartburn, indigestion, and hyperacidity.
• Proprietary and generic versions of ranitidine 75 mg tablets are widely available.
• Proprietary famotidine is available as 10 mg tablets (alone or in combination with antacids).
• Drug interactions:
• Cimetidine should be avoided by people taking erythromycin, warfarin, amiodarone, theophylline, carbamazepine, phenytoin, or sodium valproate; cimetidine inhibits hepatic drug metabolism by binding to microsomal cytochrome P450.
• Due to the decreased intragastric acidity, the absorption of ketoconazole or itraconazole may be reduced during H₂RA treatment.
• Adverse effects are uncommon and include diarrhoea, headache, dizziness, rash, and tiredness.

[ABPI Medicines Compendium, 2003; ABPI Medicines Compendium, 2005; ABPI Medicines Compendium, 2009; ABPI Medicines Compendium, 2008c]

• Examples of antacid and alginate preparations listed in the British National Formulary are shown in Table 1.

• Antacids work by neutralizing gastric acid. However, the effect is only for a relatively short period, requiring frequent administration [Maton and Burton, 1999].
• Alginates are added to antacid preparations to relieve reflux symptoms by forming a floating viscous raft on top of the gastric contents, thus providing a physical barrier to reflux.
• Administration:
• Antacids are best given when symptoms occur or are expected, that is after meals and at bedtime. They also remain in the stomach for longer at these times, and therefore have longer to act. They have a duration of action of up to 3 hours when given with or 1 hour after a meal. When ingested on an empty stomach, the duration of action is reduced to 20 to 60 minutes [Maton and Burton, 1999].
• For maximum benefits, alginate preparations should be taken after meals, otherwise the alginate rapidly exits the stomach; this provides only transient relief of symptoms courtesy of the antacid component [de Caestecker, 2001].
• Choice of preparations:
• A variety of antacids, with or without alginates, are available on prescription and for sale over-the-counter.
• There is limited evidence on the efficacy of antacids in the management of dyspepsia [Maton and Burton, 1999; de Caestecker, 2001]. The evidence for antacids in relieving dyspeptic symptoms is poor.
• Antacids containing combinations of aluminium salts with magnesium salts may be preferable to magnesium salts alone (which may cause diarrhoea) or aluminium salts alone (which may cause constipation) [BNF 55, 2008].
• Compound alginate preparations are useful for people with mild reflux symptoms. Evidence from a systematic review found alginates to be more effective than placebo in relieving symptoms of gastro-oesophageal reflux.
• Antacids containing sodium bicarbonate should be avoided in those on salt-restricted diets.
• Antacids containing only calcium salts are less preferred due to concerns that they might induce acid rebound (although the clinical significance is uncertain at low doses) [BNF 55, 2008].
• Formulation:
• Liquid antacid preparations may be more effective than tablet preparations [BNF 55, 2008] although CKS found no evidence to support this.
• Drug interactions:
• All antacids can produce drug interactions by changing gastric pH, thus affecting drug absorption.
• This can be avoided by taking antacids at different times to other drugs.
• Adverse effects:
• Most adverse effects are minor, if antacids are used only periodically and in small amounts.
• However, when large doses are taken for long periods of time, significant adverse effects may occur especially in those with underlying diseases such as chronic renal failure (avoid aluminium-containing antacids in this group) [Maton and Burton, 1999]. Prolonged high doses of calcium-containing antacids can cause hypercalcaemia and alkalosis, and precipitate milk-alkali syndrome [BNF 55, 2008].

• Metoclopramide is licensed for the following conditions:
• Restoring normal co-ordination and tone to the upper digestive tract.
• Relieving symptoms of gastro-duodenal dysfunction (e.g. dyspepsia, heartburn, flatulence, sickness) in condition such as: peptic ulcer, duodenitis, reflux oesophagitis, hiatus hernia, gastritis.
• Contraindications:
• Metoclopramide should not be used in those with gastrointestinal obstruction, perforation or haemorrhage.
• Avoid using metoclopramide during the first three to four days following gastrointestinal surgery as vigorous muscular contractions may not help healing.
• Avoid using the drug in those with phaeochromocytoma as it may induce an acute hypertensive response.
• Dose:
• Adults 20 years and over: 10 mg three times daily.
• For the elderly: avoid prolonged therapy to minimize the risk of adverse reactions.
• Reduce dose in those with significant degrees of renal or hepatic impairment.
• Drug interaction:
• The risk of extrapyramidal adverse effect is increased if metoclopramide is prescribed to those on neuroleptics such as the phenothiazines.
• Metoclopramide (a dopamine antagonist) should be used with care in association with other drugs acting at central dopamine receptors (e.g. levodopa, bromocriptine and pergolide).
• Adverse reactions:
• Extrapyramidal adverse reactions, usually of the dystonic type, have been reported.
• The majority of reactions occur within 36 hours of starting treatment and the effects usually disappear within 24 hours of withdrawal of the drug.
• Neuroleptic malignant syndrome is very rare. This syndrome is potentially fatal and must be treated urgently. Metoclopramide should be stopped immediately if this syndrome occurs (hyperpyrexia, altered consciousness, muscle rigidity and autonomic instability with elevated levels of creatine phosphokinase).
• Tardive dyskinesia has been reported during prolonged treatment in a small number of mainly elderly patients. People on prolonged treatment should be regularly reviewed.
• Raised serum prolactin levels have been observed during metoclopramide therapy: this may result in galactorrhoea, irregular periods and gynaecomastia.

[ABPI Medicines Compendium, 2008b]

• Domperidone is licensed for the relief of the symptoms of nausea and vomiting, epigastric sense of fullness, upper abdominal discomfort and regurgitation of gastric contents. This indication is licensed for use in adults and in children aged over 12 years of age, weighing 35 kg or more.
• Domperidone is also available over the counter, licensed for the relief of post-prandial symptoms of fullness, nausea, epigastric bloating and belching that is occasionally accompanied by epigastric discomfort and heartburn. Maximum duration of course of treatment 2 weeks. It is licensed for use in those aged 16 and above.
• Contraindications:
• Avoid using domperidone in those where stimulation of the gastric motility could be harmful e.g. gastrointestinal haemorrhage, mechanical obstruction or perforation.
• Avoid in those with prolactin-releasing pituitary tumour (prolactinoma).
• Since domperidone is highly metabolized in the liver, it should be not be used in those with hepatic impairment.
• Dose:
• For adults and adolescents (over 12 years and weighing 35 kg or more): 10 mg to 20 mg; to be taken three to four times per day. Maximum daily dose: 80 mg.
• For those with severe renal impairment, the dose may need to be reduced.
• The initial duration of treatment is four weeks. Patients should be re-evaluated after four weeks and the need for continued treatment re-assessed.
• Domperidone should be taken 15 to 30 minutes before meals. If taken after meals, absorption of the drug is delayed.
• Drug interaction:
• The manufacturer advises avoiding the concomitant use of domperidone and ketoconazole (a slight increase of the QT interval has been reported).
• Adverse effects:
• Domperidone is generally very well tolerated with few undesirable effects.
• It may cause an increase in prolactin levels. In rare cases, this hyperprolactinaemia may lead to neuro-endocrinological side effects such as galactorrhoea, gynaecomastia and amenorrhoea.
• Extrapyramidal side effects are very rare as domperidone does not readily cross the blood-brain barrier. These side effects reverse spontaneously and completely as soon as the treatment is stopped.

[ABPI Medicines Compendium, 2004; ABPI Medicines Compendium, 2007]