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).

• Paracetamol is well tolerated and rarely causes adverse effects when used at the recommended daily dose [Aronson, 2006b].
• For women who are pregnant or breastfeeding, paracetamol is the preferred analgesic as it can be used at any time during pregnancy or breastfeeding [NTIS, 2004; Schaefer et al, 2007]. For further information, see Choice in pregnancy or breastfeeding.
• In older people, paracetamol is often a safer option than a nonsteroidal anti-inflammatory drug.
• Paracetamol is best avoided in people with hepatic impairment or alcohol dependence, because the risk of liver damage is increased.

[Schaefer et al, 2007]

• For a detailed discussion of the contraindications, adverse effects, monitoring issues, and interactions of nonsteroidal anti-inflammatory drugs (NSAIDs), see the CKS topic on NSAIDs - prescribing issues.
• Ibuprofen is generally the preferred NSAID because of its lower risk of gastrointestinal adverse effects [CSM, 2002].
• As with other NSAIDs, ibuprofen may worsen or precipitate gastrointestinal haemorrhage, asthma, hypertension, renal impairment, or cardiac failure. Avoid ibuprofen if there is a history of peptic ulcer.
• For use in women who are pregnant or breastfeeding, see Choice in pregnancy or breastfeeding.
• Ibuprofen and other NSAIDs are known to interact with ciclosporin, lithium, and methotrexate. NSAIDs should be initiated with caution in people taking these drugs. Consider seeking specialist advice.
• For people with epilepsy who are taking an NSAID, it may be best to avoid the concomitant use of a quinolone. For further information, see the section on Quinolone and an NSAID in the CKS topic on NSAIDs - prescribing issues.

[Aronson, 2006a; BNF 57, 2009]

• Paracetamol is the preferred analgesic as it can be used at the usual dosage and at any stage of pregnancy and during breastfeeding.
• If the use of ibuprofen is considered essential, it can be used in pregnant women, but it should not used beyond 27 weeks of gestation because of the increased risk of constriction of the ductus arteriosus.
• Constriction is related to gestational age; it is rare before week 27, but its incidence increases with advancing gestational age, to 50–70% at 32 weeks, and up to 100% with exposure from week 34 onwards.
• The effect appears not to be dose dependent.
• If use of ibuprofen is unavoidable, fetal circulation should be monitored regularly (once or twice weekly) with Doppler sonography, and medication use should be stopped as soon as signs of ductal constriction appear.
• Ibuprofen can be used in breastfeeding women.
• Levels of ibuprofen excreted in breast milk are negligible [Trent Drug Information Services, 2005].
• Ibuprofen was not detected in breast milk following administration of 800 mg to 1600 mg daily in two small studies. No adverse effects on breastfed children were reported in both studies and also in a prospective study covering 21 mother-child pairs.

[Schaefer et al, 2007]

• For treatment of urinary tract infection (UTI), prescribe trimethoprim 200 mg twice daily.
• For uncomplicated UTIs, treat for 3 days.
• For complicated UTIs, treat for 5–10 days.
• In pregnant women, treat for 7 days.
• For further information, see Choice of antibiotic, Screening for and managing asymptomatic bacteriuria in pregnancy, and Managing suspected acute cystitis during pregnancy.
• For long-term prophylaxis, prescribe 100 mg at night.
• Reduce the dose if the woman has severe renal impairment — particularly if treatment is prescribed for more than 3 days (for example, people with complicated urinary tract infection or for long-term prophylaxis).
• For a glomerular filtration rate (GFR) of 15–25 mL per minute, prescribe the normal dose for 3 days, then reduce the dose by half.
• For a GFR less than 15 mL per minute, prescribe half the normal dose.

Standard dose

• These doses are based on those recommended by the manufacturer of trimethoprim and the British National Formulary [Actavis, 2007; BNF 57, 2009].

Dose in renal failure

• Dose adjustment is recommended for people with severe renal impairment because of the risk of drug accumulation in these people — 40–60% of the trimethoprim dose (along with its metabolites) is excreted unchanged in the urine within 24 hours [Actavis, 2007].

• Avoid using trimethoprim in women with blood dyscrasias.

Because of its potential anti-folate effect, there have been reports that trimethoprim causes blood disorders. For further information, see Adverse effects. Consequently, trimethoprim is contraindicated in people with dyscrasias [Actavis, 2007; BNF 57, 2009].

Trimethoprim should be prescribed with caution in the following conditions:

• Severe renal impairment
• As the drug is predominantly excreted by the kidney, dose adjustment may be required. For further information, see Dosage.
• Folate deficiency
• Because of its potential anti-folate effect, there is a risk of further exacerbating folate deficiency in people who are folate deficient or who are predisposed to folate deficiency (for example elderly people). Consequently, consider prescribing a folate supplement (if this has not already been prescribed) — particularly if trimethoprim is prescribed long term.
• The risk of folate deficiency is also increased when trimethoprim is combined with certain drugs. For further information, see Drug interactions.
• Pregnancy
• See Pregnancy and breastfeeding with trimethoprim.
• Long-term trimethoprim treatment
• Because of the risk of haematological adverse effects (see Adverse effects), the British National Formulary (BNF) advises these people should be warned to seek immediate medical attention if the person develops signs of blood disorders.
• Although the manufacturer of trimethoprim recommends regular blood monitoring, the BNF found no practical evidence to support this.

[Actavis, 2007; BNF 57, 2009]

• For women who are pregnant:
• Trimethoprim can be used during pregnancy (although it should not be used first-line when other alternatives are available — for example, amoxicillin, if the bacterial sensitivity is known).
• For information on treating asymptomatic and symptomatic urinary tract infection in pregnancy, see Screening for and managing asymptomatic bacteriuria in pregnancy and Managing suspected acute cystitis during pregnancy.
• If trimethoprim is recommended for use during the first trimester:
• Ensure the woman is taking a folic acid supplement.
• For most women, prescribe folic acid 400 microgram daily.
• Consider a higher dose (5 mg daily) if the woman is at high risk of neural tube defects (for further information, see the section on Advice on folic acid in the CKS topic on Pre-conception - advice and management).
• For women who are breastfeeding
• Trimethoprim can be used in women who are breastfeeding.

These recommendations are based on information from the UK Teratology Information Service (UKTIS), (formerly the National Teratology Information Service [NTIS]), a reference text, and the manufacturers of trimethoprim [Actavis, 2007; Schaefer et al, 2007; NTIS, 2008].

Safety in pregnancy

• There is no strong evidence to suggest that trimethoprim is teratogenic and it has been used for many years in pregnant women [Schaefer et al, 2007].
• Concerns have been expressed about the use of trimethoprim during pregnancy because it is a folic acid antagonist, and low levels of folic acid have been associated with serious birth defects.
• The evidence on the risks of trimethoprim during pregnancy has been critically assessed by the UK Teratology Information Service (UKTIS), formerly the National Teratology Information Service (NTIS) [NTIS, 2008]. A similar systematic review was conducted by the Centers for Disease Control (CDC) in the USA, to assess the safety of trimethoprim-sulfamethoxazole used for prophylaxis in HIV-infected pregnant women [Forna et al, 2006]. The NTIS and CDC concluded that the benefits outweighed the risks, which were small. Additionally the NTIS concluded that:
• Trimethoprim should not be used in pregnant women who are folate deficient, or who are taking a folate antagonist (unless they are taking a folate supplement).
• In women with normal folate status, who are well nourished, use of trimethoprim for a short period is unlikely to induce folate deficiency.
• Trimethoprim is not licensed for use during pregnancy. This is reflected in the British National Formulary which recommends that it should avoided in the first trimester due to its anti-folate effect [BNF 57, 2009].

Folic acid supplement

• When trimethoprim is prescribed during the first trimester, the recommendation to co-prescribe a folic acid supplement is precautionary [Schaefer et al, 2007; NTIS, 2008].
• The standard folic acid dosage for pregnant women is usually recommended [Schaefer et al, 2007].
• In the UK, most pregnant women should be covered; folic acid supplementation (400 micrograms per day) is routinely recommended for women who wish to conceive and should be taken up to week 12 of pregnancy to prevent neural tube defects in the fetus. For some women at high risk of neural tube defects, a higher dose (5 mg per day) is recommended. For further information, see the section on Advice on folic acid in the CKS topic on Pre-conception - advice and management.

Breastfeeding

• Trimethoprim may be used during breastfeeding [Schaefer et al, 2007].
• Although it is excreted in breast milk, the manufacturer of trimethoprim states that short-term trimethoprim treatment is not contraindicated in women who are breastfeeding [Actavis, 2007].

The following drug interactions have been reported with trimethoprim, when it is combined:

• With methotrexate (a folate antagonist):
• Several cases of bone marrow suppression have been reported (some fatal) [Baxter, 2008].
• With azathioprine:
• Increased risk of haematological toxicity has been reported in some people with renal transplant and taking azathioprine — particularly if both drugs are given over a prolonged period [Baxter, 2008].
• Nevertheless, for most people, both drugs can be taken together. The combination is commonly used in practice.
• The reaction is also expected for mercaptopurine (a metabolite of azathioprine).
• With phenytoin:
• There is a small risk of phenytoin toxicity (particularly if the serum phenytoin levels are at the top end of the range) as trimethoprim can decrease the clearance of phenytoin [Baxter, 2008]. Signs of phenytoin toxicity include blurred vision, nystagmus, ataxia, or drowsiness.
• This interaction is also expected with fosphenytoin (a pro-drug of phenytoin).
• With ciclosporin:
• Increased nephrotoxicity has been reported. However, this interaction has not been firmly established [Baxter, 2008].
• With digoxin and warfarin. However the clinical significance of these interactions is still uncertain [Baxter, 2008].
• Digoxin: trimethoprim has been reported to increase digoxin levels by an average of 22% in nine elderly people after taking trimethoprim 200 mg daily for 14 days (although an increase of 75% was experienced by one person). Consider monitoring for signs of digoxin toxicity in the elderly if trimethoprim is given long term for prophylaxis [Baxter, 2008].
• Warfarin: the manufacturer of trimethoprim warns that it may potentiate the anticoagulant effect of warfarin. However, no case reports or controlled trials on this interaction have been reported. Although there is some indication of increased anticoagulant effect from two cohort studies, the interaction is likely to be small (if it occurs), requiring little or no adjustment in warfarin dose [Baxter, 2008].

[Baxter, 2008; BNF 57, 2009]

• Trimethoprim is generally well tolerated.
• Nausea, vomiting, pruritus, and skin rashes have occasionally been reported. These are generally mild and reversible when trimethoprim is withdrawn.
• Severe adverse drug reactions with trimethoprim are rare.
• There have been rare reports of trimethoprim causing haematological adverse effects, including [Aronson, 2006c]:
• Macrocytic and megaloblastic anaemia: this is more likely in people with pre-existing folate deficiency.
• Agranulocytosis — very rare. In people where leukocytes are monitored regularly, mild leukopenia has been reported in 0.4–10% of people taking trimethoprim or co-trimoxazole (trimethoprim plus sulfamethoxazole).
• Aplastic anaemia, neutropenia, thrombocytopenia, and pancytopenia.
• For people receiving long-term trimethoprim treatment, the British National Formulary advises that they should be warned to seek immediate medical attention if they develop signs of blood disorders such as fever, sore throat, rash, mouth ulcers, purpura, bruising, or bleeding [BNF 57, 2009].

[Aronson, 2006c; Actavis, 2007]

• For treatment of acute urinary tract infection (UTI), prescribe nitrofurantoin 50 mg four times daily, or 100 mg (modified-release), twice daily.
• For uncomplicated UTIs, treat for 3 days.
• For complicated UTIs, treat for 5–10 days.
• In pregnant women, treat for 7 days.
• For further information on duration of treatment, see Choice of antibiotic, Screening for and managing asymptomatic bacteriuria in pregnancy, and Managing suspected acute cystitis during pregnancy.
• For long-term prophylaxis, prescribe 50 mg to 100 mg at night.

These doses are based on those recommended by the manufacturer of nitrofurantoin [Goldshield Pharmaceuticals, 2002b; Goldshield Pharmaceuticals, 2002c; Goldshield Pharmaceuticals, 2007].

• Nitrofurantoin is available in the following oral formulations:
• Immediate-release tablets and capsules (50 mg and 100 mg).
• Modified-release capsules (100 mg).
• Oral suspension (25 mg/5 mL).
• For treatment of urinary tract infection:
• Both the immediate-release and modified-release formulations may be considered.
• If compliance is a problem, the modified-release formulation may be preferred with its twice-daily dosage (the other formulations need to be taken four times daily).
• If nausea and vomiting is a concern, a formulation that contains macrocrystalline nitrofurantoin (such as immediate-release capsules) may reduce the likelihood of these adverse effects, but the evidence-base to support this is weak.
• For long-term prophylaxis of UTIs:
• Prescribe an immediate-release formulation.
• The modified-release formulation is not licensed for long-term prophylaxis.
• The oral suspension may be considered for people with swallowing difficulties or requiring enteral-tube feeding.

For treatment of urinary tract infections (UTIs):

• CKS identified no strong evidence to prefer one nitrofurantoin formulation over another.
• There is weak evidence from two small RCTs and one retrospective case series that the macrocrystalline formulation of nitrofurantoin (Macrodantin^® capsules) causes less nausea than the crystalline formulation (Furadantin^® tablets) in people with a UTI. However, these results should be interpreted with caution as there are a number of methodological weaknesses with these studies.
• No other studies comparing the modified-release nitrofurantoin formulation (Macrobid^®) with immediate-release formulations of nitrofurantoin were found.
• Given its twice-daily dosage, the modified-release preparation may be preferred if compliance is problem.

For long-term prophylaxis:

• Unlike the modified-release preparations, the immediate-release formulations are preferred as they are licensed for this indication [Goldshield Pharmaceuticals, 2002b; Goldshield Pharmaceuticals, 2002c; Goldshield Pharmaceuticals, 2007].
• Long-term prophylaxis only requires one dose to be taken at night. For further information, see Preventive treatments.

• Avoid prescribing nitrofurantoin to people with creatinine clearance less than 60 mL per minute, or elevated serum creatinine.

[Goldshield Pharmaceuticals, 2002b; Goldshield Pharmaceuticals, 2002c; Goldshield Pharmaceuticals, 2007]

• Peripheral neuropathy
• Nitrofurantoin should be used with caution in people with anaemia, diabetes mellitus, electrolyte imbalance, debilitating conditions, and vitamin B (particularly folate) deficiency since these conditions may enhance the occurrence of peripheral neuropathy.
• The manufacturer of nitrofurantoin advises stopping the drug at the first signs of neural involvement (paraesthesiae).
• People with a deficiency of glucose-6-phosphate dehydrogenase
• This is found in 10% of black people and a variable percentage of ethnic groups of Mediterranean, near Eastern, and Asian origin. It is rare in Caucasians.
• Avoid nitrofurantoin in these people as it may cause haemolysis.
• Discontinue nitrofurantoin if there is any sign of haemolysis (which ceases when the drug is withdrawn).
• If the person develops unexplained pulmonary, hepatotoxic, haematological, or neurologic syndromes, discontinue treatment with nitrofurantoin.

[Goldshield Pharmaceuticals, 2002b; Goldshield Pharmaceuticals, 2002c; Goldshield Pharmaceuticals, 2007]

• Nitrofurantoin can be used in women who are pregnant or breastfeeding.
• Because it is excreted in milk, avoid breastfeeding during treatment with nitrofurantoin if the newborn is glucose-6-phosphate dehydrogenase deficient.

Safety in pregnancy

• Nitrofurantoin has been used for many years for the prophylaxis and treatment of urinary tract infection and asymptomatic bacteriuria in pregnancy [NTIS, 2005; Schaefer et al, 2007].
• The drug is concentrated in the urinary tract. Consequently, significant transfer across the placenta does not occur.
• Although it is not licensed for use in pregnancy, the manufacturer of nitrofurantoin reported that the drug has been used extensively clinically since 1952 and its suitability in pregnancy has been well documented [Goldshield Pharmaceuticals, 2002a; Goldshield Pharmaceuticals, 2002b]. The efficacy and safety profiles of nitrofurantoin are further supported by a recent large multicentre study undertaken by the World Health Organization (WHO) in which 778 pregnant women with asymptomatic bacteriuria were treated with nitrofurantoin [Lumbiganon et al, 2009].
• There have been no reports of increased risk of congenial malformations [Schaefer et al, 2007].
• Haemolytic reactions are rare. There has been one case report of haemolytic anaemia in a newborn baby (with glucose-6-phosphate dehydrogenase deficiency) after in utero exposure to nitrofurantoin [Bruel et al, 2000; Schaefer et al, 2007].

Breastfeeding

• Nitrofurantoin may be used in women who are breastfeeding [Schaefer et al, 2007].
• Because it is excreted in milk, there is a potential to cause haemolytic anaemia in newborns who are glucose-6-phosphate dehydrogenase deficient. However, this is rare, and only one case report has been documented [Schaefer et al, 2007]. The recommendation to temporarily cease breastfeeding is pragmatic advice.

• The use of alkalinizing agents (such as potassium citrate) should be avoid in people taking nitrofurantoin. The antibacterial activity of the nitrofurantoin is reduced when the pH of the urine is increased [SIGN, 2006].
• Although the manufacturer of nitrofurantoin advises against concomitant administration of magnesium trisilicate with nitrofurantoin (due to reduced absorption), the clinical significance is uncertain as only one very small study in 6 people has reported this effect [Baxter, 2008].

Adverse effects associated with nitrofurantoin

• Pulmonary: nitrofurantoin-associated pulmonary reactions are reported in less than 1% of people treated with nitrofurantoin. Common manifestations are dry cough, chest pain, dyspnoea, and hypoxemia. Skin rash, arthralgia, and elevated liver enzymes are occasionally present. Chest imaging shows patchy infiltrates and fibrosis. Treatment includes stopping the medication and prescribing a course of corticosteroids [Vahid and Wildemore, 2006].
• Gastrointestinal: nausea and anorexia have been reported. Vomiting, abdominal pain, and diarrhoea are less common gastrointestinal reactions.
• Peripheral neuropathy (including optical neuritis), with symptoms of sensory as well as motor involvement, has been reported infrequently.
• Stop treatment at the first sign of neurological involvement.

Dosage

• For adults: prescribe amoxicillin 250 mg three times daily, increasing to 500 mg three times daily for more severe infections.
• For the treatment of symptomatic or asymptomatic urinary tract infections in pregnancy, a 7-day course is recommended.
• For further information, see Screening for and managing asymptomatic bacteriuria in pregnancy and Managing suspected acute cystitis during pregnancy.

Contraindications

• Amoxicillin should not be taken by people who have true penicillin allergy. However, gastrointestinal adverse effects alone (such as nausea, vomiting, or diarrhoea) do not constitute an allergy to penicillin [BNF 57, 2009].

Use in pregnancy and breastfeeding

• Amoxicillin can be used in women who are pregnant or breastfeeding [Schaefer et al, 2007; ABPI Medicines Compendium, 2008].
• Amoxicillin is licensed for the treatment of bacteriuria in pregnancy [ABPI Medicines Compendium, 2008].

Adverse effects

• Adverse effects that are commonly reported are gastrointestinal (such as nausea, vomiting, and diarrhoea), and skin rash.

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 sections on Antibiotics and Drug interactions in 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 penicillin can alter the international normalized ratio [BNF 57, 2009].

[ABPI Medicines Compendium, 2008; BNF 57, 2009]

Cefalexin is a first generation cephalosporin.

Dosage

• For uncomplicated urinary tract infections: prescribe cefalexin 250 mg every 6 hours, or 500 mg every 12 hours.
• For treatment of symptomatic or asymptomatic urinary tract infections (UTIs) in pregnancy, a 7-day course is recommended.
• For further information, see Screening for and managing asymptomatic bacteriuria in pregnancy and Managing suspected acute cystitis during pregnancy.

Contraindications and precautions

• Cefalexin should not be taken by people with known allergy to the cephalosporin group of antibiotics.
• Cephalosporins should given cautiously to penicillin-sensitive people. The British National Formulary advises that about 10% of penicillin-sensitive people will also be allergic to cephalosporins [BNF 57, 2009].
• The Health Protection Agency advises that broad spectrum antibiotics (such as co-amoxiclav, quinolones, and cephalosporins) should be avoided when narrow spectrum antibiotics remain effective, as they increase risk of Clostridium difficile, meticillin-resistant Staphylococcus aureus (MRSA), and resistant UTIs [HPA, 2009].

Use in pregnancy and breastfeeding

• Although cefalexin is not licensed in these groups, the manufacturer reported no evidence of teratogenicity in clinical studies [ABPI Medicines Compendium, 2005].
• Cephalosporins (such as cefalexin) can be used in women who are pregnant or breastfeeding [Schaefer et al, 2007].

Adverse effects

• Gastrointestinal adverse effects (such as nausea, vomiting, and diarrhoea), are commonly reported.
• The manufacturer of cefalexin advises that pseudomembranous colitis should be considered in people who develop antibiotic-associated diarrhoea [ABPI Medicines Compendium, 2005]. It can be mild, or can be life threatening. Mild cases of pseudomembranous colitis usually respond to drug discontinuation alone.

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 sections on Antibiotics and Drug interactions in 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 penicillin can alter the international normalized ratio [BNF 57, 2009].

[ABPI Medicines Compendium, 2005; BNF 57, 2009]