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).

• Any topical artificial saliva and saliva stimulant product available on prescription in the UK can be tried to treat the symptoms of dry mouth.
• Salinum^® and SST^® Saliva Stimulating Tablets are classified as appliances. The remaining products are all borderline substances so the prescriber must endorse prescriptions 'ACBS' when these products are used for dry mouth in this situation.
• In people with their own teeth, the use of acidic artificial saliva products (e.g. Glandosane^® aerosol spray) should generally be avoided in order to minimize damage to tooth enamel.

• Some products have been reported to be superior to others, but nearly all the published trials that have investigated topical artificial saliva substitutes were found to be of poor quality. Therefore, from an evidence-based perspective, it is difficult to recommend the use of one product over another.
• Choice of product will therefore be influenced by:
• Patient preference.
• Product experience and familiarity of the prescriber.
• People with cancer and dry mouth are at a higher risk of damaged mucosal membranes. Acidic products (e.g. Glandsone^® spray, Salivix^® pastilles, and SST^® tablets) may cause discomfort compared with products with a neutral pH.

• Topical artificial saliva and saliva stimulant products should generally used as frequently as needed, including before and during meals.
• Enough artificial saliva should be used to cover the whole mouth [Davies et al, 1998]. Applying the artificial saliva under the tongue can help to spread the artificial saliva around the whole mouth [Davies, 2000].
• When using Biotene Oralbalance^® saliva replacement gel, it is recommended to avoid using toothpastes containing detergents (including foaming agents) [BNF 52, 2006].

• Long-term use of acidic products (e.g. Glandsone^® spray, Salivix^® pastilles, and SST^® tablets) may cause demineralization of tooth enamel, especially if used long term [Miller and Kearney, 2001]. The importance of this depends on the person's prognosis and whether they still have teeth.

Pilocarpine is a muscarinic agonist and should not be used by people who:

• Have asthma.
• Have chronic obstructive pulmonary disease.
• Have uncontrolled cardiovascular and/or renal disease.
• Have acute iritis.
• Are pregnant.
• Are breastfeeding.

[ABPI Medicines Compendium, 2006c]

• Pilocarpine is effective only in people who have residual salivary gland function, and treatment should be withdrawn if there is no response [BNF 52, 2006].
• For people who tolerate pilocarpine but have not responded sufficiently after four weeks, the dose may be increased up to a maximum of 30 mg daily [ABPI Medicines Compendium, 2006c].
• It may take up to three months before dry mouth improves. If there is no improvement by three months, pilocarpine treatment should be discontinued [ABPI Medicines Compendium, 2006c].

• Advise people taking pilocarpine that very common adverse effects include:
• Sweating.
• Headache.
• Increased urinary frequency.
• Flu-like symptoms.
• The incidence of adverse effects appears to be dose related.
• If dizziness or blurred vision are reported, the person should avoid driving or operating machinery.

[ABPI Medicines Compendium, 2006c]

• Topical nystatin or topical miconazole are recommended for first-line treatment of oral candida infection.

• Few trials have compared the use of topical anticandidal treatments in people with cancer in palliative care [Pankhurst, 2005].
• Nystatin is recommended as it only needs to be prescribed for 7 days and resistance to nystatin is uncommon [Davies and Finlay, 2005].
• Miconazole also only needs to be prescribed for 7 days it is an imidazole antifungal which provides a different therapeutic option to nystatin as it belongs to a different antifungal class. However, resistance to miconazole is becoming increasingly common, especially in people who are immunocompromised [Davies and Finlay, 2005].
• Amphotericin is not recommended as it needs to be prescribed for 14 days and as like nystatin it is a polyene antifungal, it therefore offers no therapeutic advantage over nystatin.

• For adults, the recommended and licensed dose for treatment of oral candidiasis is 100,000 U four times daily after food for seven days.
• Treatment should be continued for at least 48 hours after the lesions have healed [ABPI Medicines Compendium, 2005b].

• Nystatin suspension:
• Take after food or drink.
• Keep in contact with the affected areas for as long as possible.
• No food should be taken for 30 minutes after the use of nystatin suspension.
• Dentures should be removed before using a topical antifungal.

• As nystatin is not absorbed when given orally, adverse effects tend to be gastrointestinal and include diarrhoea, gastrointestinal distress, nausea, and vomiting.

• As nystatin is not absorbed via the gastrointestinal tract when given orally, systemic drug interactions are unlikely.
• However, the combined use of nystatin and chlorhexidine mouthwash is not recommended because they will inactivate each other [Ellepola and Samaranayake, 2001]. They should be used 1 hour apart. Also, note that the use of chlorhexidine should not be used for 30 minutes after the use of toothpaste [Kinley, Personal Communication, 2007].

• For adults: place 5 mL to 10 mL in the mouth after food and retain near lesions, four times daily for seven days.
• Treatment should be continued for 48 hours after the lesions have healed [ABPI Medicines Compendium, 2006a].
• Dentures should be removed before using a topical antifungal drug.

• To maximize effectiveness, the oral gel should be kept in the mouth for as long as possible and be given after food and drink.
• For localized lesions of the mouth, a small amount of gel may be applied directly to the affected area with a clean finger.
• Dentures should be removed at night and brushed with the gel.
• Note: miconazole oral gel is adhesive.

• Systemic absorption of topical miconazole may occur. Potential drug interactions still need to be considered [ABPI Medicines Compendium, 2006a; BNF 52, 2006]:
• Miconazole can inhibit the metabolism of drugs metabolized by the cytochrome P450-3A and -2C9 families. This can increase and/or prolong the effects of these drugs [ABPI Medicines Compendium, 2006a].
• Warfarin. Interaction between miconazole oral gel and warfarin has been reported, resulting in an increase in the international normalized ratio (INR) [Pemberton et al, 2004]:
• People prescribed warfarin should inform the INR clinic when using miconazole oral gel, especially if the medication is bought over the counter.
• Tolbutamide and sulphonylureas. The interaction between miconazole and these antidiabetic drugs is established and clinically important, but of uncertain (and probably low) incidence [Baxter, 2006]. The interaction can result in hypoglycaemia:
• Concurrent use need not be avoided, but it should be monitored and the dosage of the sulphonylurea reduced if necessary. People taking these antidiabetic drugs should be warned of this interaction.
• The manufacturer of miconazole oral gel advises that CYP3A4 metabolized HMG-CoA reductase inhibitors, such as simvastatin, should not be used during treatment with the topical antifungal [ABPI Medicines Compendium, 2006a].

• In immunocompetent people, oral fluconazole is recommended for second-line treatment if candidiasis persists.
• In immunocompromised people, oral fluconazole is generally preferred for first-line treatment.

[BNF 52, 2006]

• Oral antifungals are reserved for widespread (e.g. evidence of oesophageal candidiasis) or severe infection, or when topical anticandidals are not tolerated or are ineffective [BNF 52, 2006]:
• Ketoconazole is less commonly used, following the Committee on Safety of Medicines (CSM) advice that it should not be used for superficial fungal infections because of rare reports of liver damage [CSM, 1983; CSM, 1984].
• Itraconazole is an alternative but it should only be used in cases of fluconazole-resistant candidiasis. It is less suitable for people at high risk of heart failure. Although reports of heart failure have been rare, the risk seems to be higher in elderly people, people with cardiac disease, people taking negative inotropic drugs (e.g. calcium-channel blockers), and people taking high doses or receiving longer treatment courses [CSM, 2001].
• Fluconazole is more reliably absorbed and has a lower risk of systemic adverse effects and drug interactions than itraconazole and it is therefore the preferred treatment when an oral antifungal is considered appropriate.
• CKS recommends seeking specialist advice before initiating itraconazole in people who have not responded to a course of fluconazole due to the possibility of underlying disease and the increased risk of drug interactions and adverse effects.

• For the treatment of oral candidiasis:
• Adults with mild oral candidiasis not responding to topical therapy: fluconazole 50 mg daily for 7 days.
• Adults who have severe oral candidiasis: fluconazole 100 mg daily for 7 to 14 days depending on response.
• Oral suspension is the preferred formulation because this can be swirled in the mouth before swallowing, producing both topical and systemic effects.
• As fluconazole is predominately excreted by the kidneys, the dose needs to be adjusted for those with renal impairment:
• For people with impaired renal function, the normal recommended dose should be given on the first day, followed by a daily dose based on [ABPI Medicines Compendium, 2005a]:
• Creatinine clearance greater than 50 mL/min: dose remains as the standard recommended dose.
• Creatinine clearance less than 50 mL/min (no dialysis): reduce the dose by 50%.
• Regular dialysis: give 100% of recommended dose after each dialysis.

• The most common adverse effects associated with fluconazole are nausea, diarrhoea, abdominal discomfort, flatulence, headache, and rash [ABPI Medicines Compendium, 2005a].

Significant drug interactions with fluconazole include:

• Warfarin:
• On the basis of kinetic studies, it has been determined that an approximately 20% reduction in the warfarin dose may be needed when using fluconazole 50 mg daily, although this can vary considerably between people [Baxter, 2006].
• Consequently, prothrombin times should be closely monitored and the anticoagulant dosage reduced as necessary [Baxter, 2006].
• Sulphonylureas:
• The increased plasma concentration of sulphonylureas in people receiving this combination requires monitoring for possible hypoglycaemic episodes.
• However, there are only case reports of fluconazole causing episodes of hypoglycaemia in people taking glipizide or glibenclamide [Baxter, 2006].
• Interactions with antineoplastics, antivirals, and immunosuppressants:
• Antineoplastics. Preliminary evidence suggests that the pharmacokinetics of fluconazole are less likely than itraconazole to be affected by antineoplastics. Fluconazole may be the antifungal drug of choice in people receiving chemotherapy [Baxter, 2006].
• Antiviral drugs. There are few clinically significant drug interactions with fluconazole.
• Immunosuppressants:
• Serum levels of tacrolimus given orally may be considerably increased by oral fluconazole, and tacrolimus dose reductions may be needed.
• Increased plasma concentration of ciclosporin has been observed. Monitor for possible toxicity and dose adjustment.

[Baxter, 2006; BNF 52, 2006]

• Chlorhexidine is the most effective antiseptic gel/mouthwash for reducing plaque, gingivitis, and gingival bleeding [Grossman et al, 1989; Overholser et al, 1990].
• In the UK, products available for the prevention and treatment of gingivitis include chlorhexidine gluconate mouthwash (0.12% and 0.2%), spray (0.2%), and gel (1%).

• Chlorhexidine can stain teeth brown when used regularly.
• The stain is not usually permanent and can be reduced by avoiding drinks that contain tannin (e.g. tea, coffee, or red wine) and by brushing teeth before use.
• If usual tooth brushing does not remove the discolouration, it can be easily removed by a dentist or dental hygienist.

• The combined use of nystatin and chlorhexidine mouthwash is not recommended, as they will inactivate each other. They should be used 1 hour apart.
• Some ingredients in toothpaste can inactivate chlorhexidine, therefore rinse the mouth well with water after brushing the teeth therefore rinse the mouth well with water after brushing the teeth and also do not use chlorhexidine for 30 minutes after the use of toothpaste.

[Kinley, Personal Communication, 2007]

• As corticosteroid use for aphthous ulcers is short-term, potential problems often associated with corticosteroid use (e.g. osteoporosis) are not relevant.
• Beclometasone spray or betamethasone soluble tablets are more potent than hydrocortisone lozenges, but they have an increased risk of systemic adverse effects and oral candidiasis. They are generally reserved for use when ulceration is extensive or at a difficult-to-reach site.

• Topical aciclovir and topical penciclovir are recommended in immunocompetent people who are in the early stages of an uncomplicated herpes simplex infection in the locality of the lips.
• Oral aciclovir is recommended in:
• Immunocompetent people who are in the early stages of an intraoral herpes infection.
• All immunocompromised people whether herpes simplex infection is in the locality of the lips, or in the mouth.

[Doyle et al, 2004; Regnard and Hockley, 2004; Davies and Finlay, 2005]

• Topical antiviral preparations are not recommended for treatment of intraoral herpes infection as they are difficult to apply, they may be irritant, and oral antivirals are more effective [Worrall, 2006].
• Oral antivirals are not usually needed in managing uncomplicated herpes simplex infection. There is limited evidence that oral aciclovir or valaciclovir can reduce the duration of symptoms by about one day if taken early in the attack (that is, at prodrome) [Jensen et al, 2004; Worrall, 2006]. Any effect on the duration of pain is very small [Spruance et al, 1990; Rooney et al, 1993; Whitley et al, 1998].
• Famciclovir is not licensed for the treatment of oral herpes simplex.
• Inosine pranobex tablets are licensed for the treatment of mucocutaneous herpes simplex, but there is little evidence of symptom relief or reduction in time to healing in immunocompetent people.

• Topical aciclovir and penciclovir may cause transient stinging, burning, itchiness and numbing of the skin.
• Oral aciclovir is generally well tolerated. Gastrointestinal adverse effects (e.g. nausea, vomiting, diarrhoea, and abdominal pain) and skin rashes (including photosensitivity and urticaria) are the most common adverse effects.

• Common adverse effects include a metallic taste and gastrointestinal irritation (in particular nausea and vomiting). These are more common at higher doses.
• Some people taking oral metronidazole experience disulfiram-like reactions to alcohol (flushing, increased respiratory rate, increased pulse rate). Although no conclusive evidence supports an interaction between metronidazole and alcohol, people taking metronidazole should be advised to avoid alcohol because of the possible interaction.

[Baxter, 2006]