Top 26-50 drugs -BNF

Method of action
6.1.2 Antidiabetic drugs

Oral antidiabetic drugs are used for the treatment of type 2 diabetes mellitus. They should be prescribed only if the patient fails to respond adequately to at least 3 months’ restriction of energy and carbohydrate intake and an increase in physical activity. They should be used to augment the effect of diet and exercise, and not to replace them.

For patients not adequately controlled by diet and oral hypoglycaemic drugs, insulin may be added to the treatment regimen or substituted for oral therapy. When insulin is added to oral therapy, it is generally given at bedtime as isophane insulin, and when insulin replaces an oral regimen it is generally given as twice-daily injections of a biphasic insulin (or isophane insulin mixed with soluble insulin). Weight gain and hypoglycaemia may be complications of insulin therapy but weight gain may be reduced if the insulin is given in combination with metformin.An inhibitor of intestinal alpha glucosidases, delays the digestion and absorption of starch and sucrose
Acarbose, an inhibitor of intestinal alpha glucosidases, delays the digestion and absorption of starch and sucrose. It has a small but significant effect in lowering blood glucose and is used either on its own or as an adjunct to metformin or to sulphonylureas when they prove inadequate. Postprandial hyperglycaemia in type 1 diabetes can be reduced by acarbose, but it has been little used for this purpose. Flatulence deters some from using acarbose although this side-effect tends to decrease with time.
ACARBOSE
Additional information interactions (Acarbose).
Indications
diabetes mellitus inadequately controlled by diet or by diet with oral antidiabetic drugs
Cautions
monitor liver function; may enhance hypoglycaemic effects of insulin and sulphonylureas (hypoglycaemic episodes may be treated with oral glucose but not with sucrose); interactions: Appendix 1 (antidiabetics)
Contra-indications
inflammatory bowel disease, predisposition to partial intestinal obstruction; hernia, previous abdominal surgery; hepatic impairment; renal impairment (Appendix 3); pregnancy (Appendix 4); breast-feeding (Appendix 5)
Side-effects
flatulence, soft stools, diarrhoea (may need to reduce dose or withdraw), abdominal distention and pain; rarely, nausea, abnormal liver function tests and skin reactions; very rarely ileus, oedema, jaundice, and hepatitis
Note
Antacids unlikely to be beneficial for treating side-effects
Dose
Initially 50 mg daily increased to 50 mg 3 times daily, then increased if necessary after 6–8 weeks to 100 mg 3 times daily; max. 200 mg 3 times daily; child and adolescent under 18 years not recommended
Counselling
Tablets should be chewed with first mouthful of food or swallowed whole with a little liquid immediately before food. To counteract possible hypoglycaemia, patients receiving insulin or a sulphonylurea as well as acarbose need to carry glucose (not sucrose—acarbose interferes with sucrose absorption)

6.2.2 Antithyroid drugs
Antithyroid drugs are used for hyperthyroidism either to prepare patients for thyroidectomy or for long-term management. In the UK carbimazole is the most commonly used drug. Propylthiouracil may be used in patients who suffer sensitivity reactions to carbimazole as sensitivity is not necessarily displayed to both drugs. Both drugs act primarily by interfering with the synthesis of thyroid hormones.
CSM warning (neutropenia and agranulocytosis)
Doctors are reminded of the importance of recognising bone marrow suppression induced by carbimazole and the need to stop treatment promptly.
1. Patient should be asked to report symptoms and signs suggestive of infection, especially sore throat.
2. A white blood cell count should be performed if there is any clinical evidence of infection.
3. Carbimazole should be stopped promptly if there is clinical or laboratory evidence of neutropenia.
Carbimazole is given in a dose of 15 to 40 mg daily; occasionally a larger dose may be required. This dose is continued until the patient becomes euthyroid, usually after 4 to 8 weeks and the dose is then gradually reduced to a maintenance dose of 5 to 15 mg. Therapy is usually given for 12 to 18 months. Children may be given carbimazole in an initial dose of 250 micrograms/kg three times daily, adjusted according to response; treatment in children should be undertaken by a specialist. Rashes and pruritus are common but they can be treated with antihistamines without discontinuing therapy; alternatively propylthiouracil can be substituted. All patients should be advised to report any sore throat immediately because of the rare complication of agranulocytosis (see CSM warning, above).
Pregnancy and breast-feeding
Radioactive iodine therapy is contra-indicated during pregnancy. Propylthiouracil and carbimazole can be given but the blocking-replacement regimen (see above) is not suitable. Both propylthiouracil and carbimazole cross the placenta and in high doses may cause fetal goitre and hypothyroidism—the lowest dose that will control the hyperthyroid state should be used (requirements in Graves’ disease tend to fall during pregnancy). Rarely, carbimazole has been associated with aplasia cutis of the neonate.
Carbimazole and propylthiouracil appear in breast milk but this does not preclude breast-feeding as long as neonatal development is closely monitored and the lowest effective dose is used.
CARBIMAZOLE
Indications
hyperthyroidism
Cautions
liver disorders, pregnancy, breast-feeding (see notes above)
Side-effects
nausea, mild gastro-intestinal disturbances, headache, rashes and pruritus, arthralgia; rarely myopathy, alopecia, bone marrow suppression (including pancytopenia and agranulocytosis, see CSM warning above), jaundice
Dose
See notes above
Counselling
Warn patient to tell doctor immediately if sore throat, mouth ulcers, bruising, fever, malaise, or non-specific illness develops
Sub-sections
* *Neo-Mercazole®


5.1 Antibacterial drugs > 5.1.2 Cephalosporins and other beta-lactams
Cephalosporins
The cephalosporins are broad-spectrum antibiotics which are used for the treatment of septicaemia, pneumonia, meningitis, biliary-tract infections, peritonitis, and urinary-tract infections. The pharmacology of the cephalosporins is similar to that of the penicillins, excretion being principally renal. Cephalosporins penetrate the cerebrospinal fluid poorly unless the meninges are inflamed; cefotaxime is a suitable cephalosporin for infections of the CNS (e.g meningitis).
The principal side-effect of the cephalosporins is hypersensitivity and about 0.5–6.5% of penicillin-sensitive patients will also be allergic to the cephalosporins. Patients with a history of immediate hypersensitivity to penicillin should not receive a cephalosporin. If a cephalosporin is essential in these patients because a suitable alternative antibacterial is not available, then cefixime, cefotaxime, ceftazidime, ceftriaxone, or cefuroxime can be used with caution; cefaclor, cefadroxil, cefalexin, and cefradine should be avoided.
Antibiotic-associated colitis may occur with the use of broad-spectrum cephalosporins.
Cefradine (cephradine) has generally been replaced by the newer cephalosporins.
Cefuroxime is a ‘second generation’ cephalosporin that is less susceptible than the earlier cephalosporins to inactivation by beta-lactamases. It is, therefore, active against certain bacteria which are resistant to the other drugs and has greater activity against Haemophilus influenzae and Neisseria gonorrhoeae.
Cefotaxime, ceftazidime and ceftriaxone are ‘third generation’ cephalosporins with greater activity than the ‘second generation’ cephalosporins against certain Gram-negative bacteria. However, they are less active than cefuroxime against Gram-positive bacteria, most notably Staphylococcus aureus. Their broad antibacterial spectrum may encourage superinfection with resistant bacteria or fungi.
Ceftazidime has good activity against pseudomonas. It is also active against other Gram-negative bacteria.
Ceftriaxone has a longer half-life and therefore needs to be given only once daily. Indications include serious infections such as septicaemia, pneumonia, and meningitis. The calcium salt of ceftriaxone forms a precipitate in the gall bladder which may rarely cause symptoms but these usually resolve when the antibiotic is stopped.
Orally active cephalosporins
The orally active ‘first generation’ cephalosporins, cefalexin (cephalexin), cefradine, and cefadroxil and the ‘second generation’ cephalosporin, cefaclor, have a similar antimicrobial spectrum. They are useful for urinary-tract infections which do not respond to other drugs or which occur in pregnancy, respiratory-tract infections, otitis media, sinusitis, and skin and soft-tissue infections. Cefaclor has good activity against H. influenzae, but it is associated with protracted skin reactions especially in children. Cefadroxil has a long duration of action and can be given twice daily; it has poor activity against H. influenzae. Cefuroxime axetil, an ester of the ‘second generation’ cephalosporin cefuroxime, has the same antibacterial spectrum as the parent compound; it is poorly absorbed.
Cefixime has a longer duration of action than the other cephalosporins that are active by mouth. It is only licensed for acute infections.
Cefpodoxime proxetil is more active than the other oral cephalosporins against respiratory bacterial pathogens and it is licensed for upper and lower respiratory-tract infections.
For treatment of Lyme disease, see section 5.1.1.3.
Oral infections
The cephalosporins offer little advantage over the penicillins in dental infections, often being less active against anaerobes. Infections due to oral streptococci (often termed viridans streptococci) which become resistant to penicillin are usually also resistant to cephalosporins. This is of importance in the case of patients who have had rheumatic fever and are on long-term penicillin therapy. Cefalexin and cefradine have been used in the treatment of oral infections.
CEFACLOR
Additional information interactions (Cefaclor); pregnancy; breast-feeding.
Indications
infections due to sensitive Gram-positive and Gram-negative bacteria, but see notes above
Cautions
sensitivity to beta-lactam antibacterials (avoid if history of immediate hypersensitivity reaction, see also notes above and Hypersensitivity Reactions); renal impairment (Appendix 3); pregnancy and breast-feeding (but appropriate to use); false positive urinary glucose (if tested for reducing substances) and false positive Coombs’ test; interactions: Appendix 1 (cephalosporins)
Contra-indications
cephalosporin hypersensitivity
Side-effects
diarrhoea and rarely antibiotic-associated colitis (CSM has warned both more likely with higher doses), nausea and vomiting, abdominal discomfort, headache; allergic reactions including rashes, pruritus, urticaria, serum sickness-like reactions with rashes, fever and arthralgia, and anaphylaxis; Stevens-Johnson syndrome, toxic epidermal necrolysis reported; disturbances in liver enzymes, transient hepatitis and cholestatic jaundice; other side-effects reported include eosinophilia and blood disorders (including thrombocytopenia, leucopenia, agranulocytosis, aplastic anaemia and haemolytic anaemia); reversible interstitial nephritis, hyperactivity, nervousness, sleep disturbances, hallucinations, confusion, hypertonia, and dizziness
Dose
250 mg every 8 hours, doubled for severe infections; max. 4 g daily; child over 1 month, 20 mg/kg daily in 3 divided doses, doubled for severe infections, max. 1 g daily; or 1 month–1 year, 62.5 mg every 8 hours; 1–5 years, 125 mg; over 5 years, 250 mg; doses doubled for severe infections

CEFALEXIN
(Cephalexin)
Additional information interactions (Cefalexin); renal impairment; pregnancy; breast-feeding.
Indications, Cautions, Contra-indications, Side-effects
see under Cefaclor
Dose
250 mg every 6 hours or 500 mg every 8–12 hours increased to 1–1.5 g every 6–8 hours for severe infections; child 25 mg/kg daily in divided doses, doubled for severe infections, max. 100 mg/kg daily; or under 1 year 125 mg every 12 hours, 1–5 years 125 mg every 8 hours, 5–12 years 250 mg every 8 hours
Prophylaxis of recurrent urinary-tract infection, adult 125 mg at night
7.3 Contraceptives
The Fraser guidelines should be followed when prescribing contraception to women under 16 years.
Hormonal contraception is the most effective method of fertility control, but has major and minor side-effects, especially for certain groups of women.
Intra-uterine devices are a highly effective method of contraception but may produce undesirable local side-effects. They are most suitable for older parous women, but less appropriate for younger nulliparous women and for those with an increased risk of pelvic inflammatory disease.
Barrier methods alone (condoms, diaphragms, and caps) are less effective but can be very reliable for well-motivated couples if used in conjunction with a spermicide. Occasionally sensitivity reactions occur. A female condom (Femidom®) is also available; it is prelubricated but does not contain a spermicide.
7.3.1 Combined hormonal contraceptives
Additional information interactions (Oestrogens, Progestogens).
Oral contraceptives containing an oestrogen and a progestogen (‘combined oral contraceptives’) are the most effective preparations for general use. Advantages of combined oral contraceptives include:
reliable and reversible;
reduced dysmenorrhoea and menorrhagia;
reduced incidence of premenstrual tension;
less symptomatic fibroids and functional ovarian cysts;
less benign breast disease;
reduced risk of ovarian and endometrial cancer;
reduced risk of pelvic inflammatory disease, which may be a risk with intra-uterine devices.
Combined oral contraceptives containing a fixed amount of an oestrogen and a progestogen in each active tablet are termed ‘monophasic’; those with varying amounts of the two hormones according to the stage of the cycle are termed ‘biphasic’ and ‘triphasic’. A transdermal patch containing an oestrogen with a progestogen is also available.


Choice
The oestrogen content of combined oral contraceptives ranges from 20 to 40 micrograms. Generally a preparation with the lowest oestrogen and progestogen content which gives good cycle control and minimal side-effects in the individual woman is chosen.
Low strength preparations (containing ethinylestradiol 20 micrograms) are particularly appropriate for women with risk factors for circulatory disease, provided a combined oral contraceptive is otherwise suitable. It is recommended that the combined oral contraceptive is not continued beyond 50 years of age since more suitable alternatives exist.
Standard strength preparations (containing ethinylestradiol 30 or 35 micrograms or in 30–40 microgram phased preparations) are appropriate for standard use—but see Risk of Venous Thromboembolism below. Phased preparations are generally reserved for women who either do not have withdrawal bleeding or who have breakthrough bleeding with monophasic products.
The progestogens desogestrel, drospirenone, and gestodene (in combination with ethinylestradiol) may be considered for women who have side-effects (such as acne, headache, depression, weight gain, breast symptoms, and breakthrough bleeding) with other progestogens. However, women should be advised that desogestrel and gestodene have also been associated with an increased risk of venous thromboembolism. Drospirenone, a derivative of spironolactone, has anti-androgenic and anti-mineralocorticoid activity; it should be used with care if an increased plasma-potassium concentration might be hazardous. The progestogen norelgestromin is combined with ethinylestradiol in a transdermal patch.
Risk of venous thromboembolism
There is an increased risk of venous thromboembolic disease (particularly during the first year) in users of oral contraceptives but this risk is considerably smaller than that associated with pregnancy (about 60 cases of venous thromboembolic disease per 100 000 pregnancies). In all cases the risk of venous thromboembolism increases with age and in the presence of other risk factors for venous thromboembolism (e.g. obesity).
The incidence of venous thromboembolism in healthy, non-pregnant women who are not taking an oral contraceptive is about 5–10 cases per 100 000 women per year. For those using combined oral contraceptives containing second-generation progestogens e.g. levonorgestrel, this incidence is about 15 per 100 000 women per year of use. The risk of venous thromboembolism with transdermal patches may be slightly increased compared to combined oral contraceptives that contain levonorgestrel. Some studies have reported a greater risk of venous thromboembolism in women using combined oral contraceptives containing the third-generation progestogens desogestrel and gestodene; the incidence in these women is about 25 per 100 000 women per year of use.
The absolute risk of venous thromboembolism in women using combined oral contraceptives containing these third-generation progestogens remains very small and well below the risk associated with pregnancy. Provided that women are informed of the relative risks of venous thromboembolism and accept them, the choice of oral contraceptive is for the woman together with the prescriber jointly to make in light of her individual medical history and any contra-indications.
Travel
Women taking oral contraceptives, or using the patch are at an increased risk of deep-vein thrombosis during travel involving long periods of immobility (over 5 hours). The risk may be reduced by appropriate exercise during the journey and possibly by wearing graduated compression hosiery.
Missed pill
The critical time for loss of contraceptive protection is when a pill is omitted at the beginning or end of a cycle (which lengthens the pill-free interval).
If a woman forgets to take a pill, it should be taken as soon as she remembers, and the next one taken at the normal time (even if this means taking 2 pills together). A missed pill is one that is 24 or more hours late. If a woman misses only one pill, she should take an active pill as soon as she remembers and then resume normal pill-taking. No additional precautions are necessary.
If a woman misses 2 or more pills (especially from the first 7 in a packet), she may not be protected. She should take an active pill as soon as she remembers and then resume normal pill-taking. In addition, she must either abstain from sex or use an additional method of contraception such as a condom for the next 7 days. If these 7 days run beyond the end of the packet, the next packet should be started at once, omitting the pill-free interval (or, in the case of everyday (ED) pills, omitting the 7 inactive tablets).
Emergency contraception (section 7.3.5) is recommended if 2 or more combined oral contraceptive tablets are missed from the first 7 tablets in a packet and unprotected intercourse has occurred since finishing the last packet.
Note
The missed pill information above offers the same advice regardless of the ethinylestradiol content of the woman’s contraceptive pill; it is a simplified version of advice issued by The Faculty of Sexual and Reproductive Healthcare.
Delayed application or detached patch
If a patch is partly detached for less than 24 hours, reapply to the same site or replace with a new patch immediately; no additional contraception is needed and the next patch should be applied on the usual change day. If a patch remains detached for more than 24 hours or if the user is not aware when the patch became detached then stop the current contraceptive cycle and start a new cycle by applying a new patch, giving a new ‘Day 1’; an additional non-hormonal contraceptive must be used concurrently for the first 7 days of the new cycle.
If application of a new patch at the start of a new cycle is delayed, contraceptive protection is lost. A new patch should be applied as soon as remembered giving a new ‘Day 1’; additional non-hormonal methods of contraception should be used for the first 7 days of the new cycle. If intercourse has occurred during this extended patch-free interval, a possibility of fertilisation should be considered. If application of a patch in the middle of the cycle is delayed (i.e. the patch is not changed on day 8 or day 15):
for up to 48 hours, apply a new patch immediately; next patch change day remains the same and no additional contraception is required.
for more than 48 hours, contraceptive protection may have been lost. Stop the current cycle and start a new 4-week cycle immediately by applying a new patch giving a new ‘Day 1’; additional non-hormonal contraception should be used for the first 7 days of the new cycle.
If the patch is not removed at the end of the cycle (day 22), remove it as soon as possible and start the next cycle on the usual ‘change day’, after day 28; no additional contraception is required.
Diarrhoea and vomiting
Vomiting and persistent, severe diarrhoea can interfere with the absorption of combined oral contraceptives. If vomiting occurs within 2 hours of taking a combined oral contraceptive another pill should be taken as soon as possible. In cases of persistent vomiting or severe diarrhoea lasting more than 24 hours, additional precautions should be used during and for 7 days after recovery (see also under Missed pill). If the vomiting and diarrhoea occurs during the last 7 tablets, the next pill-free interval should be omitted (in the case of ED tablets the inactive ones should be omitted).
Interactions
The effectiveness of both combined and progestogen-only oral contraceptives can be considerably reduced by interaction with drugs that induce hepatic enzyme activity (e.g. carbamazepine, griseofulvin, modafinil, nelfinavir, nevirapine, oxcarbazepine, phenytoin, phenobarbital, primidone, ritonavir, St John’s Wort, topiramate, and, above all, rifabutin and rifampicin). A condom together with a long-acting method, such as an injectable contraceptive, may be more suitable for patients with HIV infection or at risk of HIV infection; advice on the possibility of interaction with antiretroviral drugs should be sought from HIV specialists.
For a short course of an enzyme-inducing drug, the dose of combined oral contraceptives should be adjusted to provide ethinylestradiol 50 micrograms or more daily [unlicensed use]; furthermore, additional contraceptive precautions should be taken whilst taking the enzyme-inducing drug and for 4 weeks after stopping it.
Women requiring a long-term course of an enzyme-inducing drug should be encouraged to consider a contraceptive method that is unaffected by the interacting drug. In women unable to use an alternative method of contraception (for rifampicin and rifabutin see also below), a regimen of combined oral contraceptives should be taken which provides a daily intake of ethinylestradiol 50 micrograms or more [unlicensed use]; ‘tricycling’ (i.e. taking 3 or 4 packets of monophasic tablets without a break followed by a short tablet-free interval of 4 days) is recommended (but women should be warned of uncertainty about the effectiveness of this regimen). Rifampicin and rifabutin are such potent enzyme-inducing drugs that an alternative method of contraception (such as an IUD) is always recommended. Since enzyme activity does not return to normal for several weeks after stopping an enzyme-inducing drug, appropriate contraceptive measures are required for 4 to 8 weeks after stopping.
The effectiveness of contraceptive patches can also be reduced by drugs that induce hepatic enzyme activity. Additional contraceptive precautions are required whilst taking the enzyme-inducing drug and for 4 weeks after stopping. If concomitant administration runs beyond the 3 weeks of patch treatment, a new treatment cycle should be started immediately without a patch-free break. For women taking enzyme-inducing drugs over a long period, another method of contraception should be considered.
Some antibacterials that do not induce liver enzymes (e.g. ampicillin, doxycycline) may reduce the efficacy of combined oral contraceptives by impairing the bacterial flora responsible for recycling ethinylestradiol from the large bowel. Additional contraceptive precautions should be taken whilst taking a short course of an antibacterial drug that is not enzyme-inducing and for 7 days after stopping. If these 7 days run beyond the end of a packet the next packet should be started immediately without a break (in the case of ED tablets the inactive ones should be omitted). If the antibacterial course exceeds 3 weeks, the bacterial flora develop antibacterial resistance and additional precautions become unnecessary unless a new antibacterial is prescribed; additional precautions are also unnecessary if a woman starting a combined oral contraceptive has been on a course of antibacterial therapy for 3 weeks or more.
It is possible that some antibacterials affect the efficacy of contraceptive patches. Additional contraceptive precautions are recommended during concomitant use and for 7 days after discontinuation of an antibacterial that is not enzyme-inducing (except tetracycline). If concomitant administration runs beyond the 3 weeks of patch treatment, a new treatment cycle should be started immediately without a patch-free break. If the antibacterial course exceeds 3 weeks, additional precautions become unnecessary unless a new antibacterial is prescribed; additional precautions are also unnecessary if a woman starting a contraceptive patch has been on a course of antibacterial therapy for 3 weeks or more.
Surgery
Oestrogen-containing contraceptives should preferably be discontinued (and adequate alternative contraceptive arrangements made) 4 weeks before major elective surgery and all surgery to the legs or surgery which involves prolonged immobilisation of a lower limb; they should normally be recommenced at the first menses occurring at least 2 weeks after full mobilisation. A depot injection of a progestogen-only contraceptive may be offered and the oestrogen-containing contraceptive restarted later—if preferred before the next injection would be due. When discontinuation of an oestrogen-containing contraceptive is not possible, e.g. after trauma or if a patient admitted for an elective procedure is still on an oestrogen-containing contraceptive, thromboprophylaxis (with heparin and graduated compression hosiery) is advised. These recommendations do not apply to minor surgery with short duration of anaesthesia, e.g. laparoscopic sterilisation or tooth extraction, or to women using oestrogen-free hormonal contraceptives (whether by mouth or by injection).
Reason to stop immediately
Combined hormonal contraceptives or hormone replacement therapy (HRT) should be stopped (pending investigation and treatment), if any of the following occur:
sudden severe chest pain (even if not radiating to left arm);
sudden breathlessness (or cough with blood-stained sputum);
unexplained swelling or severe pain in calf of one leg;
severe stomach pain;
serious neurological effects including unusual severe, prolonged headache especially if first time or getting progressively worse or sudden partial or complete loss of vision or sudden disturbance of hearing or other perceptual disorders or dysphasia or bad fainting attack or collapse or first unexplained epileptic seizure or weakness, motor disturbances, very marked numbness suddenly affecting one side or one part of body;
hepatitis, jaundice, liver enlargement;
blood pressure above systolic 160 mmHg and diastolic 95 mmHg;
prolonged immobility after surgery or leg injury;
detection of a risk factor which contra-indicates treatment (see Cautions and Contra-indications under Combined Hormonal Contraceptives below or under Oestrogens for HRT (section 6.4.1.1)).
COMBINED HORMONAL CONTRACEPTIVES
Additional information interactions (Norethisterone, Desogestrel, Ethinylestradiol, Mestranol, Gestodene, Norelgestromin, Drospirenone, Norgestimate, Levonorgestrel).
Indications
contraception; menstrual symptoms (section 6.4.1.2)
Cautions
see notes above; also risk factors for venous thromboembolism (see below and also notes above), arterial disease and migraine, see below; personal or family history of hypertriglyceridaemia (increased risk of pancreatitis); hyperprolactinaemia (seek specialist advice); history of severe depression especially if induced by hormonal contraceptive; undiagnosed breast mass; gene mutations associated with breast cancer (e.g. BRCA 1); sickle-cell disease; inflammatory bowel disease including Crohn’s disease; reduced efficacy of contraceptive patch in women with body-weight ≥ 90 kg; interactions: see above and Appendix 1 (oestrogens, progestogens)
Risk factors for venous thromboembolism
See also notes above. Use with caution if any of following factors present but avoid if two or more factors present:
family history of venous thromboembolism in first-degree relative aged under 45 years (avoid contraceptive containing desogestrel or gestodene, or if known prothrombotic coagulation abnormality e.g. factor V Leiden or antiphospholipid antibodies (including lupus anticoagulant));
obesity—body mass index above 30 kg/m2 (avoid if body mass index above 39 kg/m2);
long-term immobilisation e.g. in a wheelchair (avoid if confined to bed or leg in plaster cast);
history of superficial thrombophlebitis.
Risk factors for arterial disease
Use with caution if any one of following factors present but avoid if two or more factors present:
family history of arterial disease in first degree relative aged under 45 years (avoid if atherogenic lipid profile);
diabetes mellitus (avoid if diabetes complications present);
hypertension—blood pressure above systolic 140 mmHg and diastolic 90 mmHg (avoid if blood pressure above systolic 160 mmHg and diastolic 95 mmHg);
smoking (avoid if smoking 40 or more cigarettes daily);
age over 35 years (avoid if over 50 years);
obesity (avoid if body mass index above 39 kg/m2);
migraine—see below.
Migraine
Women should report any increase in headache frequency or onset of focal symptoms (discontinue immediately and refer urgently to neurology expert if focal neurological symptoms not typical of aura persist for more than 1 hour—see also Reason to stop immediately in notes above); contra-indicated in
migraine with typical focal aura,
severe migraine regularly lasting over 72 hours despite treatment,
migraine treated with ergot derivatives;
use with caution in
migraine without focal aura,
migraine controlled with 5HT1 agonist (section 4.7.4.1).
Contra-indications
see notes above; also pregnancy (Appendix 4); personal history of venous or arterial thrombosis, severe or multiple risk factors for arterial disease or for venous thromboembolism (see above), heart disease associated with pulmonary hypertension or risk of embolus; sclerosing treatment for varicose veins; migraine (but see above); transient cerebral ischaemic attacks without headaches; liver disease including disorders of hepatic excretion (e.g. Dubin-Johnson or Rotor syndromes), infective hepatitis (until liver function returns to normal); systemic lupus erythematosus; acute porphyria (section 9.8.2); liver tumour; gallstones; active trophoblastic disease (until return to normal of urine and plasma gonadotrophin concentration); history of haemolytic uraemic syndrome or history during pregnancy of pruritus, cholestatic jaundice, chorea, pemphigoid gestationis; history of breast cancer but can be used after 5 years if no evidence of disease and non-hormonal methods unacceptable; undiagnosed vaginal bleeding; breast-feeding (until weaning or for 6 months after birth—Appendix 5)
Side-effects
see notes above; also nausea, vomiting, abdominal cramps, changes in body-weight, liver impairment, hepatic tumours; fluid retention, thrombosis (more common when factor V Leiden present or in blood groups A, B, and AB; see also notes above), hypertension, changes in lipid metabolism; headache, depression, chorea, nervousness, irritability; changes in libido, breast tenderness, enlargement, and secretion; reduced menstrual loss, ‘spotting’ in early cycles, absence of withdrawal bleeding, amenorrhoea after discontinuation, changes in vaginal discharge, cervical erosion; contact lenses may irritate, visual disturbances; leg cramps; skin reactions, chloasma, photosensitivity; rarely gallstones and systemic lupus erythematosus
Breast cancer
There is a small increase in the risk of having breast cancer diagnosed in women taking the combined oral contraceptive pill; this relative risk may be due to an earlier diagnosis. In users of combined oral contraceptive pills the cancers are more likely to be localised to the breast. The most important factor for diagnosing breast cancer appears to be the age at which the contraceptive is stopped rather than the duration of use; any increase in the rate of diagnosis diminishes gradually during the 10 years after stopping and disappears by 10 years.
Cervical cancer
Use of combined oral contraceptives for 5 years or longer is associated with a small increased risk of cervical cancer; the risk diminishes after stopping and disappears by about 10 years. The risk of cervical cancer with transdermal patches is not yet known.
Note
The possible small increase in the risk of breast cancer and cervical cancer should be weighed against the benefits and evidence of the protective effect against cancers of the ovary and endometrium
Dose
By mouth, each tablet should be taken at approximately same time each day; if delayed by longer than 24 hours contraceptive protection may be lost
21-day combined (monophasic) preparations, 1 tablet daily for 21 days; subsequent courses repeated after a 7-day interval (during which withdrawal bleeding occurs); first course usually started on day 1 of cycle—if starting on day 4 of cycle or later additional precautions (barrier methods) necessary during first 7 days
Every day (ED) combined (monophasic) preparations, 1 active tablet starting on day 1 of cycle (see also under preparations below)—if starting on day 4 of cycle or later additional precautions (barrier methods) necessary during first 7 days; withdrawal bleeding occurs when inactive tablets being taken; subsequent courses repeated without interval
Biphasic and triphasic preparations, see under individual preparations below
Changing to combined preparation containing different progestogen
21-day combined preparations: continue current pack until last tablet and start first tablet of new brand the next day. If a 7-day break is taken before starting new brand, additional precautions (barrier methods) should be used during first 7 days of taking the new brand.
Every Day (ED) combined preparations: start the new brand (first tablet of a 21-day preparation or the first active tablet of an ED preparation) the day after taking the last active tablet of previous brand (omitting the inactive tablets).
Changing from progestogen-only tablet
Start on day 1 of menstruation or any day if amenorrhoea present and pregnancy has been excluded.
Secondary amenorrhoea (exclude pregnancy)
Start any day, additional precautions (barrier methods) necessary during first 7 days.
After childbirth (not breast-feeding)
Start 3 weeks after birth (increased risk of thrombosis if started earlier); later than 3 weeks postpartum additional precautions (barrier methods) necessary for first 7 days.
Not recommended if woman breast-feeding—oral progestogen-only contraceptive preferred.
After abortion or miscarriage
Start same day.
By transdermal application, apply first patch on day 1 of cycle, change patch on days 8 and 15; remove third patch on day 22 and apply new patch after 7-day patch-free interval to start subsequent contraceptive cycle
Note
If first patch applied later than day 1, additional precaution (abstinence or barrier methods) should be used for the next 7 days
Changing from combined oral contraception
Apply patch on the first day of withdrawal bleeding; if no withdrawal bleeding within 5 days of taking last active tablet, rule out pregnancy before applying first patch. Unless patch is applied on first day of withdrawal bleeding, additional precautions (barrier methods) should be used concurrently for first 7 days
Changing from progestogen-only method
From an implant, apply first patch on the day implant removed; from an injection, apply first patch when next injection due; from oral progestogen, first patch may be started on any day after stopping pill. For all methods additional precautions (barrier methods) should be used concurrently for first 7 days
After childbirth (not breast-feeding)
Start 4 weeks after birth; if started later than 4 weeks after birth additional precautions (barrier methods) should be used for first 7 days
After abortion or miscarriage
Before 20 weeks’ gestation start immediately; no additional contraception required if started immediately. After 20 weeks’ gestation start on day 21 after abortion or on the first day of first spontaneous menstruation; additional precautions (barrier methods) should be used for first 7 days after applying the patch









6.3.2 Glucocorticoid therapy
In comparing the relative potencies of corticosteroids in terms of their anti-inflammatory (glucocorticoid) effects it should be borne in mind that high glucocorticoid activity in itself is of no advantage unless it is accompanied by relatively low mineralocorticoid activity (see Disadvantages of Corticosteroids below). The mineralocorticoid activity of fludrocortisone (section 6.3.1) is so high that its anti-inflammatory activity is of no clinical relevance. The table below shows equivalent anti-inflammatory doses.
Equivalent anti-inflammatory doses of corticosteroids
This table takes no account of mineralocorticoid effects, nor does it take account of variations in duration of action
Prednisolone 5 mg
≡
Betamethasone 750 micrograms
≡
Cortisone acetate 25 mg
≡
Deflazacort 6 mg
≡
Dexamethasone 750 micrograms
≡
Hydrocortisone 20 mg
≡
Methylprednisolone 4 mg
≡
Triamcinolone 4 mg
The relatively high mineralocorticoid activity of cortisone and hydrocortisone, and the resulting fluid retention, make them unsuitable for disease suppression on a long-term basis. However, they can be used for adrenal replacement therapy (section 6.3.1); hydrocortisone is preferred because cortisone requires conversion in the liver to hydrocortisone. Hydrocortisone is used on a short-term basis by intravenous injection for the emergency management of some conditions. The relatively moderate anti-inflammatory potency of hydrocortisone also makes it a useful topical corticosteroid for the management of inflammatory skin conditions because side-effects (both topical and systemic) are less marked (section 13.4); cortisone is not active topically.
Prednisolone has predominantly glucocorticoid activity and is the corticosteroid most commonly used by mouth for long-term disease suppression.
Betamethasone and dexamethasone have very high glucocorticoid activity in conjunction with insignificant mineralocorticoid activity. This makes them particularly suitable for high-dose therapy in conditions where fluid retention would be a disadvantage.
Betamethasone and dexamethasone also have a long duration of action and this, coupled with their lack of mineralocorticoid action makes them particularly suitable for conditions which require suppression of corticotropin (corticotrophin) secretion (e.g. congenital adrenal hyperplasia). Some esters of betamethasone and of beclometasone (beclomethasone) exert a considerably more marked topical effect (e.g. on the skin or the lungs) than when given by mouth; use is made of this to obtain topical effects whilst minimising systemic side-effects (e.g. for skin applications and asthma inhalations).
Deflazacort has a high glucocorticoid activity; it is derived from prednisolone.
DEXAMETHASONE
Additional information interactions (Dexamethasone); pregnancy; breast-feeding.
Indications
suppression of inflammatory and allergic disorders; diagnosis of Cushing’s disease, congenital adrenal hyperplasia; cerebral oedema associated with malignancy; croup (section 3.1); nausea and vomiting with chemotherapy (section 8.1); rheumatic disease (section 10.1.2); eye (section 11.4.1); see also notes above
Cautions, Contra-indications
see notes above
Side-effects
see notes above; also perineal irritation may follow intravenous administration of the phosphate ester
Dose
By mouth, usual range 0.5–10 mg daily; child 10–100 micrograms/kg daily; see also Administration (above)
By intramuscular injection or slow intravenous injection or infusion (as dexamethasone phosphate), initially 0.5–24 mg; child 200–400 micrograms/kg daily
Cerebral oedema associated with malignancy (as dexamethasone phosphate), by intravenous injection, 10 mg initially, then 4 mg by intramuscular injection every 6 hours as required for 2–4 days then gradually reduced and stopped over 5–7 days
Adjunctive treatment of bacterial meningitis, (starting before or with first dose of antibacterial treatment, as dexamethasone phosphate) [unlicensed indication], by intravenous injection, 10 mg every 6 hours for 4 days; child 150 micrograms/kg every 6 hours for 4 days
Note
Dexamethasone 1 mg ≡ dexamethasone phosphate 1.2 mg ≡ dexamethasone sodium phosphate 1.3 mg
4.1.2 Anxiolytics
Benzodiazepine anxiolytics can be effective in alleviating anxiety states. Although these drugs are often prescribed to almost anyone with stress-related symptoms, unhappiness, or minor physical disease, their use in many situations is unjustified. In particular, they are not appropriate for treating depression or chronic psychosis. In bereavement, psychological adjustment may be inhibited by benzodiazepines. In children anxiolytic treatment should be used only to relieve acute anxiety (and related insomnia) caused by fear (e.g. before surgery).
Anxiolytic treatment should be limited to the lowest possible dose for the shortest possible time (see CSM advice, section 4.1). Dependence is particularly likely in patients with a history of alcohol or drug abuse and in patients with marked personality disorders.
Anxiolytics, particularly the benzodiazepines, have been termed ‘minor tranquillisers’. This term is misleading because not only do they differ markedly from the antipsychotic drugs (‘major tranquillisers’) but their use is by no means minor. Antipsychotics, in low doses, are also sometimes used in severe anxiety for their sedative action but long-term use should be avoided in view of a possible risk of tardive dyskinesia (section 4.2.1).
Some antidepressants (section 4.3) are licensed for use in anxiety and related disorders; see section 4.3 for a comment on their role in chronic anxiety, generalised and social anxiety disorder, and panic disorder. The use of antihistamines (e.g. hydroxyzine, section 3.4.1) for their sedative effect in anxiety is not considered to be appropriate.
Beta-blockers (e.g. propranolol, oxprenolol) (section 2.4) do not affect psychological symptoms, such as worry, tension, and fear, but they do reduce autonomic symptoms, such as palpitation and tremor; they do not reduce non-autonomic symptoms, such as muscle tension. Beta-blockers are therefore indicated for patients with predominantly somatic symptoms; this, in turn, may prevent the onset of worry and fear. Patients with predominantly psychological symptoms may obtain no benefit.
Benzodiazepines
Benzodiazepines are indicated for the short-term relief of severe anxiety; long-term use should be avoided (see CSM advice). Diazepam, alprazolam, chlordiazepoxide, and clobazam have a sustained action. Shorter-acting compounds such as lorazepam and oxazepam may be preferred in patients with hepatic impairment but they carry a greater risk of withdrawal symptoms.
In panic disorders (with or without agoraphobia) resistant to antidepressant therapy (section 4.3), a benzodiazepine (lorazepam 3–5 mg daily or clonazepam 1–2 mg daily (section 4.8.1) [both unlicensed]) may be used; alternatively, a benzodiazepine may be used as short-term adjunctive therapy at the start of antidepressant treatment to prevent the initial worsening of symptoms.
Diazepam or lorazepam are very occasionally administered intravenously for the control of panic attacks. This route is the most rapid but the procedure is not without risk (section 4.8.2) and should be used only when alternative measures have failed. The intramuscular route has no advantage over the oral route.
For guidelines on benzodiazepine withdrawal, see section 4.1.
DIAZEPAM
Additional information interactions (Diazepam).
Indications
short-term use in anxiety or insomnia (see CSM advice); adjunct in acute alcohol withdrawal; status epilepticus (section 4.8.2); febrile convulsions (section 4.8.3); muscle spasm (section 10.2.2); peri-operative use (section 15.1.4.1)
Cautions
respiratory disease, muscle weakness and myasthenia gravis, history of drug or alcohol abuse, marked personality disorder, pregnancy (Appendix 4), breast-feeding (Appendix 5); reduce dose in elderly and debilitated, and in hepatic impairment (avoid if severe; Appendix 2), renal impairment (Appendix 3); avoid prolonged use (and abrupt withdrawal thereafter); special precautions for intravenous injection (section 4.8.2); acute porphyria (section 9.8.2); when given parenterally, close observation required until full recovery from sedation; interactions: Appendix 1 (anxiolytics and hypnotics)
Driving
Drowsiness may affect performance of skilled tasks (e.g. driving); effects of alcohol enhanced
Contra-indications
respiratory depression; marked neuromuscular respiratory weakness including unstable myasthenia gravis; acute pulmonary insufficiency; sleep apnoea syndrome; severe hepatic impairment; not for chronic psychosis; should not be used alone in depression or in anxiety with depression; avoid injections containing benzyl alcohol in neonates (see under preparations below)
Side-effects
drowsiness and lightheadedness the next day; confusion and ataxia (especially in the elderly); amnesia; dependence; paradoxical increase in aggression (see also section 4.1); muscle weakness; occasionally: headache, vertigo, hypotension, salivation changes, gastro-intestinal disturbances, visual disturbances, dysarthria, tremor, changes in libido, incontinence, urinary retention; blood disorders and jaundice reported; skin reactions; on intravenous injection, pain, thrombophlebitis, and rarely apnoea; overdosage: see Emergency Treatment of Poisoning,
Dose
By mouth, anxiety, 2 mg 3 times daily increased if necessary to 15–30 mg daily in divided doses; elderly (or debilitated) half adult dose
Insomnia associated with anxiety, 5–15 mg at bedtime
By intramuscular injection or slow intravenous injection (into a large vein, at a rate of not more than 5 mg/minute), for severe acute anxiety, control of acute panic attacks, and acute alcohol withdrawal, 10 mg, repeated if necessary after not less than 4 hours

Note
Only use intramuscular route when oral and intravenous routes not possible; special precautions for intravenous injection section 4.8.2
By rectum as rectal solution, acute anxiety and agitation, 500 micrograms/kg repeated after 12 hours as required; elderly 250 micrograms/kg; child not recommended
As suppositories, anxiety when oral route not appropriate, 10–30 mg (higher dose divided); dose form not appropriate for less than 10 mg
6.3 Corticosteroids
6.3.1 Replacement therapy
The adrenal cortex normally secretes hydrocortisone (cortisol) which has glucocorticoid activity and weak mineralocorticoid activity. It also secretes the mineralocorticoid aldosterone.
In deficiency states, physiological replacement is best achieved with a combination of hydrocortisone (section 6.3.2) and the mineralocorticoid fludrocortisone; hydrocortisone alone does not usually provide sufficient mineralocorticoid activity for complete replacement.
In Addison’s disease or following adrenalectomy, hydrocortisone 20 to 30 mg daily by mouth is usually required. This is given in 2 doses, the larger in the morning and the smaller in the evening, mimicking the normal diurnal rhythm of cortisol secretion. The optimum daily dose is determined on the basis of clinical response. Glucocorticoid therapy is supplemented by fludrocortisone 50 to 300 micrograms daily.
In acute adrenocortical insufficiency, hydrocortisone is given intravenously (preferably as sodium succinate) in doses of 100 mg every 6 to 8 hours in sodium chloride intravenous infusion 0.9%.
In hypopituitarism glucocorticoids should be given as in adrenocortical insufficiency, but since production of aldosterone is also regulated by the renin-angiotensin system a mineralocorticoid is not usually required. Additional replacement therapy with levothyroxine (section 6.2.1) and sex hormones (section 6.4) should be given as indicated by the pattern of hormone deficiency.
FLUDROCORTISONE ACETATE
Additional information interactions (Fludrocortisone); pregnancy.
Indications
mineralocorticoid replacement in adrenocortical insufficiency
Cautions
section 6.3.2; interactions: Appendix 1 (corticosteroids)
Contra-indications
section 6.3.2
Side-effects
section 6.3.2
Dose
50–300 micrograms daily; child 5 micrograms/kg daily

6.3.2 Glucocorticoid therapy
In comparing the relative potencies of corticosteroids in terms of their anti-inflammatory (glucocorticoid) effects it should be borne in mind that high glucocorticoid activity in itself is of no advantage unless it is accompanied by relatively low mineralocorticoid activity (see Disadvantages of Corticosteroids below). The mineralocorticoid activity of fludrocortisone (section 6.3.1) is so high that its anti-inflammatory activity is of no clinical relevance. The table below shows equivalent anti-inflammatory doses.
Equivalent anti-inflammatory doses of corticosteroids
This table takes no account of mineralocorticoid effects, nor does it take account of variations in duration of action
Prednisolone 5 mg
≡
Betamethasone 750 micrograms
≡
Cortisone acetate 25 mg
≡
Deflazacort 6 mg
≡
Dexamethasone 750 micrograms
≡
Hydrocortisone 20 mg
≡
Methylprednisolone 4 mg
≡
Triamcinolone 4 mg
The relatively high mineralocorticoid activity of cortisone and hydrocortisone, and the resulting fluid retention, make them unsuitable for disease suppression on a long-term basis. However, they can be used for adrenal replacement therapy (section 6.3.1); hydrocortisone is preferred because cortisone requires conversion in the liver to hydrocortisone. Hydrocortisone is used on a short-term basis by intravenous injection for the emergency management of some conditions. The relatively moderate anti-inflammatory potency of hydrocortisone also makes it a useful topical corticosteroid for the management of inflammatory skin conditions because side-effects (both topical and systemic) are less marked (section 13.4); cortisone is not active topically.
Prednisolone has predominantly glucocorticoid activity and is the corticosteroid most commonly used by mouth for long-term disease suppression.
Betamethasone and dexamethasone have very high glucocorticoid activity in conjunction with insignificant mineralocorticoid activity. This makes them particularly suitable for high-dose therapy in conditions where fluid retention would be a disadvantage.
Betamethasone and dexamethasone also have a long duration of action and this, coupled with their lack of mineralocorticoid action makes them particularly suitable for conditions which require suppression of corticotropin (corticotrophin) secretion (e.g. congenital adrenal hyperplasia). Some esters of betamethasone and of beclometasone (beclomethasone) exert a considerably more marked topical effect (e.g. on the skin or the lungs) than when given by mouth; use is made of this to obtain topical effects whilst minimising systemic side-effects (e.g. for skin applications and asthma inhalations).
Deflazacort has a high glucocorticoid activity; it is derived from prednisolone.
4.3.3 Selective serotonin re-uptake inhibitors
Additional information interactions (Antidepressants, SSRI, Antidepressants, SSRI (related)).
Citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline selectively inhibit the re-uptake of serotonin (5-hydroxytryptamine, 5-HT); they are termed selective serotonin re-uptake inhibitors (SSRIs). For a general comment on the management of depression and on the comparison between tricyclic and related antidepressants and the SSRIs and related antidepressants, see section 4.3.
CSM advice (depressive illness in children and adolescents)
The CSM has advised that the balance of risks and benefits for the treatment of depressive illness in individuals under 18 years is considered unfavourable for the SSRIs citalopram, escitalopram, paroxetine, and sertraline, and for mirtazapine and venlafaxine. Clinical trials have failed to show efficacy and have shown an increase in harmful outcomes. However, it is recognised that specialists may sometimes decide to use these drugs in response to individual clinical need; children and adolescents should be monitored carefully for suicidal behaviour, self-harm or hostility, particularly at the beginning of treatment.
Only fluoxetine has been shown in clinical trials to be effective for treating depressive illness in children and adolescents. However, it is possible that, in common with the other SSRIs, it is associated with a small risk of self-harm and suicidal thoughts. Overall, the balance of risks and benefits for fluoxetine in the treatment of depressive illness in individuals under 18 years is considered favourable, but children and adolescents must be carefully monitored as above.
Cautions
SSRIs should be used with caution in patients with epilepsy (avoid if poorly controlled, discontinue if convulsions develop), cardiac disease, diabetes mellitus, susceptibility to angle-closure glaucoma, a history of mania or bleeding disorders (especially gastro-intestinal bleeding), and if used with other drugs that increase the risk of bleeding, hepatic impairment (Appendix 2), renal impairment (Appendix 3), pregnancy (Appendix 4), and breast-feeding (Appendix 5). They should also be used with caution in those receiving concurrent electroconvulsive therapy (prolonged seizures reported with fluoxetine). SSRIs may also impair performance of skilled tasks (e.g. driving). Interactions: see below and Appendix 1 (antidepressants, SSRI).
Withdrawal
Gastro-intestinal disturbances, headache, anxiety, dizziness, paraesthesia, sleep disturbances, fatigue, influenza-like symptoms, and sweating are the most common features of abrupt withdrawal of an SSRI or marked reduction of the dose; the dose should be tapered over a few weeks to avoid these effects.
Interactions
An SSRI or related antidepressant should not be started until 2 weeks after stopping an MAOI. Conversely, an MAOI should not be started until at least a week after an SSRI or related antidepressant has been stopped (2 weeks in the case of sertraline, at least 5 weeks in the case of fluoxetine). For guidance relating to the reversible monoamine oxidase inhibitor, moclobemide, see above. For other SSRI antidepressant interactions, see Appendix 1 (antidepressants, SSRI).
Contra-indications
SSRIs should not be used if the patient enters a manic phase.
Side-effects
SSRIs are less sedating and have fewer antimuscarinic and cardiotoxic effects than tricyclic antidepressants (section 4.3). Side-effects of the SSRIs include gastro-intestinal effects (dose-related and fairly common—include nausea, vomiting, dyspepsia, abdominal pain, diarrhoea, constipation), anorexia with weight loss (increased appetite and weight gain also reported) and hypersensitivity reactions including rash (consider discontinuation—may be sign of impending serious systemic reaction, possibly associated with vasculitis), urticaria, angioedema, anaphylaxis, arthralgia, myalgia and photosensitivity; other side-effects include dry mouth, nervousness, anxiety, headache, insomnia, tremor, dizziness, asthenia, hallucinations, drowsiness, convulsions (see Cautions above), galactorrhoea, sexual dysfunction, urinary retention, sweating, hypomania or mania (see Cautions above), movement disorders and dyskinesias, visual disturbances, hyponatraemia (see Hyponatraemia and Antidepressant Therapy), and bleeding disorders including ecchymoses and purpura. Suicidal behaviour has been linked with antidepressants (see Suicidal Behaviour and Antidepressant Therapy). Angle-closure glaucoma may very rarely be precipitated by treatment with SSRIs.
FLUOXETINE
Additional information interactions (Fluoxetine); hepatic impairment; breast-feeding.
Indications, Cautions , Contra-indications
see under Dose, see notes above
Side-effects
see notes above; also vasodilatation, postural hypotension, pharyngitis, dyspnoea, chills, taste disturbances, sleep disturbances, euphoria, confusion, yawning, impaired concentration, changes in blood sugar, alopecia, urinary frequency; rarely pulmonary inflammation and fibrosis; very rarely hepatitis, toxic epidermal necrolysis, and neuroleptic malignant syndrome-like event
Dose
Major depression, 20 mg once daily increased after 3–4 weeks if necessary, and at appropriate intervals thereafter; max. 60 mg once daily (elderly usual max. 40 mg once daily but 60 mg can be used); child 8–18 years, 10 mg once daily increased after 1–2 weeks if necessary, max. 20 mg once daily, discontinue if no improvement within 9 weeks; (but see also CSM advice)
Bulimia nervosa, adult over 18 years, 60 mg once daily
Obsessive-compulsive disorder, adult over 18 years, 20 mg once daily; if inadequate response after 2 weeks increase gradually to max. 60 mg once daily (elderly usual max. 40 mg once daily but 60 mg can be used)
Long duration of action
Consider the long half-life of fluoxetine when adjusting dosage (or in overdosage)
Sub-sections
Fluoxetine
Prozac®
6.1.2.1 Sulphonylureas
breast-feeding
The sulphonylureas act mainly by augmenting insulin secretion and consequently are effective only when some residual pancreatic beta-cell activity is present; during long-term administration they also have an extrapancreatic action. All may cause hypoglycaemia but this is uncommon and usually indicates excessive dosage. Sulphonylurea-induced hypoglycaemia may persist for many hours and must always be treated in hospital.
Sulphonylureas are considered for patients who are not overweight, or in whom metformin is contra-indicated or not tolerated. Several sulphonylureas are available and choice is determined by side-effects and the duration of action as well as the patient’s age and renal function. The long-acting sulphonylureas chlorpropamide and glibenclamide are associated with a greater risk of hypoglycaemia; for this reason they should be avoided in the elderly and shorter-acting alternatives, such as gliclazide or tolbutamide, should be used instead. Chlorpropamide also has more side-effects than the other sulphonylureas (see below) and therefore it is no longer recommended.
When the combination of strict diet and sulphonylurea treatment fails other options include:
· combining with metformin (section 6.1.2.2) (reports of increased hazard with this combination remain unconfirmed);
· combining with acarbose (section 6.1.2.3), which may have a small beneficial effect, but flatulence can be a problem;
· combining with pioglitazone or rosiglitazone, but see section 6.1.2.3;
· combining with bedtime isophane insulin (section 6.1.1) but weight gain and hypoglycaemia can occur.
Insulin therapy should be instituted temporarily during intercurrent illness (such as myocardial infarction, coma, infection, and trauma). Sulphonylureas should be omitted on the morning of surgery; insulin is required because of the ensuing hyperglycaemia in these circumstances.

Cautions
Sulphonylureas can encourage weight gain and should be prescribed only if poor control and symptoms persist despite adequate attempts at dieting; metformin (section 6.1.2.2) is considered the drug of choice in obese patients. Caution is needed in the elderly and in those with mild to moderate hepatic impairment (Appendix 2) and mild to moderate renal impairment (Appendix 3) because of the hazard of hypoglycaemia. The short-acting tolbutamide can be used in renal impairment, as can gliclazide which is principally metabolised in the liver, but careful monitoring of blood-glucose concentration is essential; care is required to choose the smallest possible dose that produces adequate control of blood glucose.
Contra-indications
Sulphonylureas should be avoided where possible in severe hepatic impairment (Appendix 2) and in severe renal impairment (Appendix 3) and in acute porphyria (section 9.8.2). They should not be used while breast-feeding (Appendix 5), and insulin therapy should be substituted during pregnancy (see also Appendix 4). Sulphonylureas are contra-indicated in the presence of ketoacidosis.
Side-effects
Side-effects of sulphonylureas are generally mild and infrequent and include gastro-intestinal disturbances such as nausea, vomiting, diarrhoea and constipation.
Chlorpropamide has appreciably more side-effects, mainly because of its very prolonged duration of action and the consequent hazard of hypoglycaemia and it should no longer be used. It may also cause facial flushing after drinking alcohol; this effect does not normally occur with other sulphonylureas. Chlorpropamide may also enhance antidiuretic hormone secretion and very rarely cause hyponatraemia (hyponatraemia is also reported with glimepiride and glipizide).
Sulphonylureas can occasionally cause a disturbance in liver function, which may rarely lead to cholestatic jaundice, hepatitis and hepatic failure. Hypersensitivity reactions can occur, usually in the first 6–8 weeks of therapy, they consist mainly of allergic skin reactions which progress rarely to erythema multiforme and exfoliative dermatitis, fever and jaundice; photosensitivity has rarely been reported with chlorpropamide and glipizide. Blood disorders are also rare but may include leucopenia, thrombocytopenia, agranulocytosis, pancytopenia, haemolytic anaemia, and aplastic anaemia.
GLICLAZIDE
Additional information interactions (Gliclazide); liver disease; renal impairment.
Indications
type 2 diabetes mellitus
Cautions
see notes above; interactions: Appendix 1 (antidiabetics)
Contra-indications, Side-effects
see notes above
Dose
Initially, 40–80 mg daily, adjusted according to response; up to 160 mg as a single dose, with breakfast; higher doses divided; max. 320 mg daily
Sub-sections
· Gliclazide
· Diamicron®
· Modified release
Sulphonylureas
Theoretical possibility of hypoglycaemia in infant
6.1.1 Insulins
Insulin plays a key role in the regulation of carbohydrate, fat, and protein metabolism. It is a polypeptide hormone of complex structure. There are differences in the amino-acid sequence of animal insulins, human insulins and the human insulin analogues. Insulin may be extracted from pork pancreas and purified by crystallisation; it may also be extracted from beef pancreas, but beef insulins are now rarely used. Human sequence insulin may be produced semisynthetically by enzymatic modification of porcine insulin (emp) or biosynthetically by recombinant DNA technology using bacteria (crb, prb) or yeast (pyr).
All insulin preparations are to a greater or lesser extent immunogenic in man but immunological resistance to insulin action is uncommon. Preparations of human sequence insulin should theoretically be less immunogenic, but no real advantage has been shown in trials.
Insulin is inactivated by gastro-intestinal enzymes, and must therefore be given by injection; the subcutaneous route is ideal in most circumstances. Insulin is usually injected into the upper arms, thighs, buttocks, or abdomen; absorption from a limb site may be increased if the limb is used in strenuous exercise after the injection. Generally subcutaneous insulin injections cause few problems; fat hypertrophy does, however, occur but can be minimised by using different injection sites in rotation. Local allergic reactions are rare.
Insulin is needed by all patients with ketoacidosis, and it is likely to be needed by most patients with:
· rapid onset of symptoms;
· substantial loss of weight;
· weakness;
· ketonuria;
· a first-degree relative who has type 1 diabetes.
Insulin is required by almost all children with diabetes. It is also needed for type 2 diabetes when other methods have failed to achieve good control, and temporarily in the presence of intercurrent illness or peri-operatively. Pregnant women with type 2 diabetes should be treated with insulin when diet alone fails.
Management of diabetes with insulin
The aim of treatment is to achieve the best possible control of blood-glucose concentration without making the patient obsessional and to avoid disabling hypoglycaemia; close co-operation is needed between the patient and the medical team because good control reduces the risk of complications.
Mixtures of insulin preparations may be required and appropriate combinations have to be determined for the individual patient. For patients with acute-onset diabetes, treatment should be started with a short-acting insulin (e.g. soluble insulin, insulin aspart) given 3 times daily with intermediate-acting insulin at bedtime. For those less severely ill, treatment is usually started with a mixture of premixed short- and intermediate-acting insulins (most commonly in a proportion of 30% soluble insulin and 70% isophane insulin) given twice daily; 8 units twice daily is a suitable initial dose for most ambulant patients. The proportion of the short-acting soluble component can be increased in those with excessive postprandial hyperglycaemia.
The dose of insulin is increased gradually, taking care to avoid troublesome hypoglycaemic reactions.
Insulin preparations can be divided into 3 types:
· those of short duration which have a relatively rapid onset of action, namely soluble insulin, insulin lispro and insulin aspart;
· those with an intermediate action, e.g. isophane insulin and insulin zinc suspension; and
· those whose action is slower in onset and lasts for long periods, e.g. insulin zinc suspension.
The duration of action of a particular type of insulin varies considerably from one patient to another, and needs to be assessed individually.
Examples of recommended insulin regimens
· Short-acting insulin mixed with intermediate-acting insulin: twice daily (before meals)
· Short-acting insulin mixed with intermediate-acting insulin: before breakfast
Short-acting insulin: before evening meal
Intermediate-acting insulin: at bedtime
· Short-acting insulin: three times daily (before breakfast, midday, and evening meal)
Intermediate-acting insulin: at bedtime
· Intermediate-acting insulin with or without short-acting insulin: once daily either before breakfast or at bedtime suffices for some patients with type 2 diabetes who need insulin
Insulin requirements may be increased by infection, stress, accidental or surgical trauma, and during puberty. Requirements may be decreased in patients with renal impairment (Appendix 3) or hepatic impairment and in those with some endocrine disorders (e.g. Addison’s disease, hypopituitarism) or coeliac disease.
Pregnancy and breast-feeding
During pregnancy and breast-feeding, insulin requirements may alter and doses should be assessed frequently by an experienced diabetes physician. The dose of insulin generally needs to be increased in the second and third trimesters of pregnancy.
Insulin administration
Insulin is generally given by subcutaneous injection. Injection devices (‘pens’) (section 6.1.1.3), which hold the insulin in a cartridge and meter the required dose, are convenient to use. The conventional syringe and needle is still preferred by many and is also required for insulins not available in cartridge form.
For intensive insulin regimens multiple subcutaneous injections (3 to 4 times daily) are usually recommended.
Short-acting injectable insulins (soluble insulin, insulin aspart, insulin glulisine, and insulin lispro) can also be given by continuous subcutaneous infusion using a portable infusion pump. This device delivers a continuous basal insulin infusion and patient-activated bolus doses at meal times. This technique is appropriate only for patients who suffer recurrent hypoglycaemia or marked morning rise in blood-glucose concentration despite optimised multiple-injection regimens. NICE (February 2003) has also recommended continuous subcutaneous infusion as an option in those who suffer repeated or unpredictable hypoglycaemia despite optimal multiple-injection regimens (including the use of insulin glargine where appropriate). Patients on subcutaneous insulin infusion must be highly motivated, able to monitor their blood-glucose concentration, and have expert training, advice and supervision from an experienced healthcare team.
Soluble insulin by the intravenous route is reserved for urgent treatment, and for fine control in serious illness and in the peri-operative period (see under Diabetes and Surgery, below).
Units
The word ‘unit’ should not be abbreviated.
Monitoring
Many patients now monitor their own blood-glucose concentrations (section 6.1.6). Since blood-glucose concentrations vary substantially throughout the day, ‘normoglycaemia’ cannot always be achieved throughout a 24-hour period without causing damaging hypoglycaemia. It is therefore best to recommend that patients should maintain a blood-glucose concentration of between 4 and 9 mmol/litre for most of the time (4–7 mmol/litre before meals and less than 9 mmol/litre after meals), while accepting that on occasions, for brief periods, it will be above these values; strenuous efforts should be made to prevent the blood-glucose concentration from falling below 4 mmol/litre. Patients should be advised to look for ‘peaks’ and ‘troughs’ of blood glucose, and to adjust their insulin dosage only once or twice weekly. Overall it is ideal to aim for an HbA1c (glycosylated haemoglobin) concentration of 6.5–7.5% or less (reference range 4–6%) but this is not always possible without causing disabling hypoglycaemia; in those at risk of arterial disease, the aim should be to maintain the HbA1c concentration at 6.5% or less. HbA1c should be measured every 3–6 months. Fructosamine can also be used for assessment of control; this is simpler and cheaper but the measurement of HbA1c is generally a more reliable method.
The intake of energy and of simple and complex carbohydrates should be adequate to allow normal growth and development but obesity must be avoided. The carbohydrate intake needs to be regulated and should be distributed throughout the day. Fine control of plasma glucose can be achieved by moving portions of carbohydrate from one meal to another without altering the total intake.
Hypoglycaemia
Hypoglycaemia is a potential problem with insulin therapy. All patients must be carefully instructed on how to avoid it.
Loss of warning of hypoglycaemia is common among insulin-treated patients and can be a serious hazard, especially for drivers and those in dangerous occupations. Very tight control of diabetes lowers the blood-glucose concentration needed to trigger hypoglycaemic symptoms; increase in the frequency of hypoglycaemic episodes reduces the warning symptoms experienced by the patient. Beta-blockers can also blunt hypoglycaemic awareness (and also delay recovery).
To restore the warning signs, episodes of hypoglycaemia must be minimised; this involves appropriate adjustment of insulin type, dose and frequency together with suitable timing and quantity of meals and snacks.
Some patients have reported loss of hypoglycaemia warning after transfer to human insulin. Clinical studies do not confirm that human insulin decreases hypoglycaemia awareness. If a patient believes that human insulin is responsible for the loss of warning it is reasonable to revert to animal insulin and essential to educate the patient about avoiding hypoglycaemia. Great care should be taken to specify whether a human or an animal preparation is required.
Few patients are now treated with beef insulins; when undertaking conversion from beef to human insulin, the total dose should be reduced by about 10% with careful monitoring for the first few days. When changing between pork and human-sequence insulins, a dose change is not usually needed, but careful monitoring is still advised.
Diabetes and surgery
The following regimen is suitable when surgery in a patient with type 1 diabetes requires intravenous infusion of insulin for 12 hours or longer.
· Give an injection of the patient’s usual insulin on the night before the operation.
· Early on the day of the operation, start an intravenous infusion of glucose 5% or 10% containing potassium chloride 10 mmol/litre (provided that the patient is not hyperkalaemic) and infuse at a constant rate appropriate to the patient’s fluid requirements (usually 125 mL per hour); make up a solution of soluble insulin 1 unit/mL in sodium chloride 0.9% and infuse intravenously using a syringe pump piggy-backed to the intravenous infusion.
· The rate of the insulin infusion should normally be:
Blood glucose < 4 mmol/litre, give 0.5 units/hour
Blood glucose 4–15 mmol/litre, give 2 units/hour
Blood glucose 15–20 mmol/litre, give 4 units/hour
Blood glucose > 20 mmol/litre, review.
In resistant cases (such as patients who are in shock or severely ill or those receiving corticosteroids or sympathomimetics) 2–4 times these rates or even more may be needed.
If a syringe pump is not available soluble insulin 16 units/litre should be added to the intravenous infusion of glucose 5% or 10% containing potassium chloride 10 mmol per litre (provided the patient is not hyperkalaemic) and the infusion run at the rate appropriate to the patient’s fluid requirements (usually 125 mL per hour) with the insulin dose adjusted as follows:
· Blood glucose < 4 mmol/litre, give 8 units/litre
· Blood glucose 4–15 mmol/litre, give 16 units/litre
· Blood glucose 15–20 mmol/litre, give 32 units/litre
· Blood glucose > 20 mmol/litre, review.
The rate of intravenous infusion depends on the volume depletion, cardiac function, age, and other factors. Blood-glucose concentration should be measured pre-operatively and then hourly until stable, thereafter every 2 hours. The duration of action of intravenous insulin is only a few minutes and the infusion must not be stopped unless the patient becomes overtly hypoglycaemic (blood glucose < 3 mmol/litre) in which case it should be stopped for up to 30 minutes. The amount of potassium chloride required in the infusion needs to be assessed by regular measurement of plasma electrolytes. Sodium chloride 0.9% infusion should replace glucose 5% or 10% if the blood glucose is persistently above 15 mmol/litre.
Once the patient starts to eat and drink, give subcutaneous insulin before breakfast and stop intravenous insulin 30 minutes later; the dose may need to be 10–20% more than usual if the patient is still in bed or unwell. If the patient was not previously receiving insulin, an appropriate initial dose is 30–40 units daily in four divided doses using soluble insulin before meals and intermediate-acting insulin at bedtime and the dose adjusted from day to day. Patients with hyperglycaemia often relapse after conversion back to subcutaneous insulin calling for one of the following approaches:
· additional doses of soluble insulin at any of the four injection times (before meals or bedtime) or
· temporary addition of intravenous insulin infusion (while continuing the subcutaneous regimen) until blood-glucose concentration is satisfactory or
· complete reversion to the intravenous regimen (especially if the patient is unwell).
Sub-sections
· 6.1.1.1 Short-acting insulins
· 6.1.1.2 Intermediate- and long-acting insulins
· 6.1.1.3 Hypodermic equipment
6.1.1.1 Short-acting insulins
Soluble insulin is a short-acting form of insulin. For maintenance regimens it is usual to inject it 15 to 30 minutes before meals.
Soluble insulin is the most appropriate form of insulin for use in diabetic emergencies e.g. diabetic ketoacidosis (section 6.1.3) and at the time of surgery. It can be given intravenously and intramuscularly, as well as subcutaneously.
When injected subcutaneously, soluble insulin has a rapid onset of action (30 to 60 minutes), a peak action between 2 and 4 hours, and a duration of action of up to 8 hours.
When injected intravenously, soluble insulin has a very short half-life of only about 5 minutes and its effect disappears within 30 minutes.
The human insulin analogues, insulin aspart, insulin glulisine, and insulin lispro have a faster onset and shorter duration of action than soluble insulin; as a result, compared to soluble insulin, fasting and preprandial blood-glucose concentration is a little higher, postprandial blood-glucose concentration is a little lower, and hypoglycaemia occurs slightly less frequently. Subcutaneous injection of insulin analogues may be convenient for those who wish to inject shortly before or, when necessary, shortly after a meal. They can also help those susceptible to hypoglycaemia before lunch and those who eat late in the evening and are prone to nocturnal hypoglycaemia. They can also be administered by subcutaneous infusion (see Insulin Administration, above). Insulin aspart and insulin lispro can be administered intravenously and can be used as alternatives to soluble insulin for diabetic emergencies and at the time of surgery.
Sub-sections
INSULIN
(Insulin Injection; Neutral Insulin; Soluble Insulin)
Additional information interactions (Insulin); pregnancy.
A sterile solution of insulin (i.e. bovine or porcine) or of human insulin; pH 6.6–8.0
Indications
diabetes mellitus; diabetic ketoacidosis (section 6.1.3)
Cautions
see notes above; pregnancy (Appendix 4); reduce dose in renal impairment (Appendix 3); interactions: Appendix 1 (antidiabetics)
Side-effects
see notes above; transient oedema; local reactions and fat hypertrophy at injection site; rarely hypersensitivity reactions including urticaria, rash; overdose causes hypoglycaemia
Dose
By subcutaneous, intramuscular or intravenous injection or intravenous infusion, according to requirements
Sub-sections
· Highly purified animal
· Human sequence
· Mixed preparations
7.3 Contraceptives > 7.3.5 Emergency contraception
Hormonal methods
Additional information interactions (Levonorgestrel).
Hormonal emergency contraception involves the use of levonorgestrel. It is effective if taken within 72 hours (3 days) of unprotected intercourse; taking the dose as soon as possible increases efficacy. Levonorgestrel may also be used between 72 and 120 hours after unprotected intercourse [unlicensed use] but efficacy decreases with time. Hormonal emergency contraception is less effective than insertion of an intra-uterine device (see below).
If vomiting occurs within 2 hours of taking levonorgestrel, a replacement dose should be given. If an anti-emetic is required domperidone is preferred.
When prescribing hormonal emergency contraception the doctor should explain:
· that the next period may be early or late;
· that a barrier method of contraception needs to be used until the next period;
· the need to return promptly if any lower abdominal pain occurs because this could signify an ectopic pregnancy (and also in 3 to 4 weeks if the subsequent menstrual bleed is abnormally light, heavy or brief, or is absent, or if she is otherwise concerned).
Intra-uterine pregnancy despite treatment: see Appendix 4 (levonorgestrel).
Interactions
The effectiveness of hormonal emergency contraception is reduced by enzyme-inducing drugs; a copper intra-uterine device can be offered instead or the dose of levonorgestrel should be increased to a total of 3 mg taken as a single dose [unlicensed dose—advise women accordingly]. There is no need to increase the dose for emergency contraception if the patient is taking antibacterials that are not enzyme inducers.
Sub-sections
· LEVONORGESTREL
LEVONORGESTREL
Additional information interactions (Levonorgestrel).
Indications
emergency contraception
Cautions
see notes above; past ectopic pregnancy; severe malabsorption syndromes; active trophoblastic disease (until return to normal of urine- and plasma-gonadotrophin concentration); pregnancy (see notes above and Appendix 4); breast-feeding (Appendix 5); interactions: see notes above and Appendix 1 (progestogens)
Contra-indications
acute porphyria (section 9.8.2)
Side-effects
menstrual irregularities (see also notes above), nausea, low abdominal pain, fatigue, headache, dizziness, breast tenderness, vomiting
Dose
1.5 mg as a single dose as soon as possible after coitus (preferably within 12 hours but no later than after 72 hours)
Sub-sections
· Levonelle® One Step
· Levonelle® 1500
·
6.2.1 Thyroid hormones
Thyroid hormones are used in hypothyroidism (myxoedema), and also in diffuse non-toxic goitre, Hashimoto’s thyroiditis (lymphadenoid goitre), and thyroid carcinoma. Neonatal hypothyroidism requires prompt treatment for normal development. Levothyroxine sodium (thyroxine sodium) is the treatment of choice for maintenance therapy.
In infants and children with congenital hypothyroidism and juvenile myxoedema, the dose of levothyroxine should be titrated according to clinical response, growth assessment, and measurements of plasma thyroxine and thyroid-stimulating hormone. See BNF for Children (section 6.2.1) for suitable dosage regimens.
Liothyronine sodium has a similar action to levothyroxine but is more rapidly metabolised and has a more rapid effect; 20 micrograms is equivalent to 100 micrograms of levothyroxine. Its effects develop after a few hours and disappear within 24 to 48 hours of discontinuing treatment. It may be used in severe hypothyroid states when a rapid response is desired.
Liothyronine by intravenous injection is the treatment of choice in hypothyroid coma. Adjunctive therapy includes intravenous fluids, hydrocortisone, and treatment of infection; assisted ventilation is often required.
Sub-sections
· LEVOTHYROXINE SODIUM
· LIOTHYRONINE SODIUM
LEVOTHYROXINE SODIUM
(Thyroxine sodium)
Additional information interactions (Levothyroxine (thyroxine)).
Indications
hypothyroidism; see also notes above
Cautions
panhypopituitarism or predisposition to adrenal insufficiency (initiate corticosteroid therapy before starting levothyroxine), elderly, cardiovascular disorders (including hypertension, myocardial insufficiency or myocardial infarction, see Initial Dosage below), long-standing hypothyroidism, diabetes insipidus, diabetes mellitus (dose of antidiabetic drugs including insulin may need to be increased); pregnancy (Appendix 4); interactions: Appendix 1 (thyroid hormones)
Initial dosage

Baseline ECG is valuable because changes induced by hypothyroidism can be confused with ischaemia. If metabolism increases too rapidly (causing diarrhoea, nervousness, rapid pulse, insomnia, tremors and sometimes anginal pain where there is latent myocardial ischaemia), reduce dose or withhold for 1–2 days and start again at a lower dose
Contra-indications
Thyrotoxicosis



Side-effects
usually at excessive dosage (see Initial Dosage above) include diarrhoea, vomiting, anginal pain, arrhythmias, palpitation, tachycardia, tremor, restlessness, excitability, insomnia; headache, flushing, sweating, fever, heat intolerance, weight-loss, muscle cramp, and muscular weakness; transient hair loss in children; hypersensitivity reactions including rash, pruritus and oedema also reported
Dose
adult, initially 50–100 micrograms once daily, preferably before breakfast, adjusted in steps of 25–50 micrograms every 3–4 weeks according to response (usual maintenance dose 100–200 micrograms once daily); in cardiac disease, severe hypothyroidism, and patients over 50 years, initially 25 micrograms once daily, adjusted in steps of 25 micrograms every 4 weeks according to response; usual maintenance dose 50–200 micrograms once daily; child under 12 years see BNF for Children (section 6.2.1)
Congenital hypothyroidism and juvenile myxoedema, see BNF for Children (section 6.2.1)
3.4.1 Antihistamines
Additional information interactions (Antihistamines).
pregnancy; breast-feeding
All antihistamines are of potential value in the treatment of nasal allergies, particularly seasonal allergic rhinitis (hay fever), and they may be of some value in vasomotor rhinitis. They reduce rhinorrhoea and sneezing but are usually less effective for nasal congestion. Antihistamines are used topically in the eye (section 11.4.2), in the nose (section 12.2.1), and on the skin (section 13.3).
Oral antihistamines are also of some value in preventing urticaria and are used to treat urticarial rashes, pruritus, and insect bites and stings; they are also used in drug allergies. Injections of chlorphenamine (chlorpheniramine) or promethazine are used as an adjunct to adrenaline (epinephrine) in the emergency treatment of anaphylaxis and angioedema (section 3.4.3). For the use of antihistamines (including cinnarizine, cyclizine, and promethazine teoclate) in nausea and vomiting, see section 4.6. Buclizine is included as an anti-emetic in a preparation for migraine (section 4.7.4.1). For reference to the use of antihistamines for occasional insomnia, see section 4.1.1.
All older antihistamines cause sedation but alimemazine (trimeprazine) and promethazine may be more sedating whereas chlorphenamine and cyclizine (section 4.6) may be less so. This sedating activity is sometimes used to manage the pruritus associated with some allergies. There is little evidence that any one of the older, ‘sedating’ antihistamines is superior to another and patients vary widely in their response.
Non-sedating antihistamines such as cetirizine, desloratadine (an active metabolite of loratadine), fexofenadine (an active metabolite of terfenadine), levocetirizine (an isomer of cetirizine), loratadine, and mizolastine cause less sedation and psychomotor impairment than the older antihistamines because they penetrate the blood brain barrier only to a slight extent.
Dental surgery
Antihistamines are used widely as anti-emetics (section 4.6) but diazepam is likely to be more effective in patients with an overactive gag reflex. See also Anaphylaxis under Medical Emergencies in Dental Practice.
Cautions and contra-indications
Sedating antihistamines have significant antimuscarinic activity and they should therefore be used with caution in prostatic hypertrophy, urinary retention, susceptibility to angle-closure glaucoma, and pyloroduodenal obstruction. Antihistamines should be used with caution in hepatic disease (Appendix 2). Caution may be required in epilepsy. Children and the elderly are more susceptible to side-effects. Many antihistamines should be avoided in acute porphyria although some (e.g. chlorphenamine and cetirizine) are thought to be safe (section 9.8.2). Interactions: Appendix 1 (antihistamines).
Side-effects
Drowsiness is a significant side-effect with most of the older antihistamines although paradoxical stimulation may occur rarely, especially with high doses or in children and the elderly. Drowsiness may diminish after a few days of treatment and is considerably less of a problem with the newer antihistamines (see also notes above). Side-effects that are more common with the older antihistamines include headache, psychomotor impairment, and antimuscarinic effects such as urinary retention, dry mouth, blurred vision, and gastro-intestinal disturbances.
Other rare side-effects of antihistamines include hypotension, extrapyramidal effects, dizziness, confusion, depression, sleep disturbances, tremor, convulsions, palpitation, arrhythmias, hypersensitivity reactions (including bronchospasm, angioedema, and anaphylaxis, rashes, and photosensitivity reactions), blood disorders, liver dysfunction, and angle-closure glaucoma.
Sub-sections
· Non-sedating antihistamines
· Sedating antihistamines
Non-sedating antihistamines
Driving
Although drowsiness is rare, nevertheless patients should be advised that it can occur and may affect performance of skilled tasks (e.g. driving); excess alcohol should be avoided.
Sub-sections
· CETIRIZINE HYDROCHLORIDE
· DESLORATADINE
· FEXOFENADINE HYDROCHLORIDE
· LEVOCETIRIZINE HYDROCHLORIDE
· LORATADINE
· MIZOLASTINE
LORATADINE
Additional information interactions (Loratadine).
Indications
symptomatic relief of allergy such as hay fever, chronic idiopathic urticaria
Cautions
see notes above
Contra-indications
see notes above; also pregnancy (Appendix 4) and breast-feeding (Appendix 5)
Side-effects
see notes above
Dose
adult and child over 6 years 10 mg once daily; child 2–6 years 5 mg once daily
Sub-sections
· Loratadine
6.1.2 Antidiabetic drugs
Oral antidiabetic drugs are used for the treatment of type 2 diabetes mellitus. They should be prescribed only if the patient fails to respond adequately to at least 3 months’ restriction of energy and carbohydrate intake and an increase in physical activity. They should be used to augment the effect of diet and exercise, and not to replace them.
For patients not adequately controlled by diet and oral hypoglycaemic drugs, insulin may be added to the treatment regimen or substituted for oral therapy. When insulin is added to oral therapy, it is generally given at bedtime as isophane insulin, and when insulin replaces an oral regimen it is generally given as twice-daily injections of a biphasic insulin (or isophane insulin mixed with soluble insulin). Weight gain and hypoglycaemia may be complications of insulin therapy but weight gain may be reduced if the insulin is given in combination with metformin.
Sub-sections
· 6.1.2.1 Sulphonylureas
· 6.1.2.2 Biguanides
· 6.1.2.3 Other antidiabetic drugs

6.1.2.2 Biguanides
Metformin, the only available biguanide, has a different mode of action from the sulphonylureas, and is not interchangeable with them. It exerts its effect mainly by decreasing gluconeogenesis and by increasing peripheral utilisation of glucose; since it acts only in the presence of endogenous insulin it is effective only if there are some residual functioning pancreatic islet cells.
Metformin is the drug of first choice in overweight patients in whom strict dieting has failed to control diabetes, if appropriate it may also be considered as an option in patients who are not overweight. It is also used when diabetes is inadequately controlled with sulphonylurea treatment. When the combination of strict diet and metformin treatment fails, other options include:
· combining with acarbose (section 6.1.2.3), which may have a small beneficial effect, but flatulence can be a problem;
· combining with insulin (section 6.1.1) but weight gain and hypoglycaemia can be problems (weight gain minimised if insulin given at night);
· combining with a sulphonylurea (section 6.1.2.1) (reports of increased hazard with this combination remain unconfirmed);
· combining with pioglitazone or rosiglitazone (section 6.1.2.3);
· combining with repaglinide or nateglinide (section 6.1.2.3).
Insulin treatment is almost always required in medical and surgical emergencies; insulin should also be substituted before elective surgery (omit metformin on the morning of surgery and give insulin if required).
Hypoglycaemia does not usually occur with metformin; other advantages are the lower incidence of weight gain and lower plasma-insulin concentration. It does not exert a hypoglycaemic action in non-diabetic subjects unless given in overdose.
Gastro-intestinal side-effects are initially common with metformin, and may persist in some patients, particularly when very high doses such as 3 g daily are given.
Metformin can provoke lactic acidosis which is most likely to occur in patients with renal impairment; it should not be used in patients with even mild renal impairment.
Metformin is used for the symptomatic management of polycystic ovary syndrome [unlicensed indication]; it improves insulin sensitivity, may aid weight reduction, helps to normalise menstrual cycle (increasing the rate of spontaneous ovulation), and may improve hirsutism.
Sub-sections
· METFORMIN HYDROCHLORIDE
METFORMIN HYDROCHLORIDE
Additional information interactions (Metformin).
Indications
diabetes mellitus (see notes above); polycystic ovary syndrome [unlicensed indication]
Cautions
see notes above; determine renal function (using an appropriately sensitive method) before treatment and once or twice annually (more frequently in the elderly or if deterioration suspected); interactions: Appendix 1 (antidiabetics)
Contra-indications
renal impairment (Appendix 3), ketoacidosis, withdraw if tissue hypoxia likely (e.g. sepsis, respiratory failure, recent myocardial infarction, hepatic impairment (Appendix 2)), use of iodine-containing X-ray contrast media (do not restart metformin until renal function returns to normal) and use of general anaesthesia (suspend metformin on the morning of surgery and restart when renal function returns to normal), pregnancy (Appendix 4) and breast-feeding (Appendix 5)
Side-effects
anorexia, nausea, vomiting, diarrhoea (usually transient), abdominal pain, metallic taste; rarely lactic acidosis (withdraw treatment), decreased vitamin-B12 absorption, erythema, pruritus and urticaria; hepatitis also reported
Dose
Diabetes mellitus, adult and child over 10 years initially 500 mg with breakfast for at least 1 week then 500 mg with breakfast and evening meal for at least 1 week then 500 mg with breakfast, lunch and evening meal; usual max. 2 g daily in divided doses
Polycystic ovary syndrome [unlicensed], initially 500 mg with breakfast for 1 week, then 500 mg with breakfast and evening meal for 1 week, then 1.5–1.7 g daily in 2–3 divided doses

Note
Metformin doses in the BNF may differ from those in the product literature
Sub-sections
· Metformin
· Glucophage®
· Modified release
· With pioglitazone
· With rosiglitazone
2.6.2 Calcium-channel blockers
Calcium-channel blockers (less correctly called ‘calcium-antagonists’) interfere with the inward displacement of calcium ions through the slow channels of active cell membranes. They influence the myocardial cells, the cells within the specialised conducting system of the heart, and the cells of vascular smooth muscle. Thus, myocardial contractility may be reduced, the formation and propagation of electrical impulses within the heart may be depressed, and coronary or systemic vascular tone may be diminished.
Calcium-channel blockers differ in their predilection for the various possible sites of action and, therefore, their therapeutic effects are disparate, with much greater variation than those of beta-blockers. There are important differences between verapamil, diltiazem, and the dihydropyridine calcium-channel blockers (amlodipine, felodipine, isradipine, lacidipine, lercanidipine, nicardipine, nifedipine, nimodipine, and nisoldipine). Verapamil and diltiazem should usually be avoided in heart failure because they may further depress cardiac function and cause clinically significant deterioration.
Verapamil is used for the treatment of angina (section 2.6), hypertension (section 2.5), and arrhythmias (section 2.3.2). It is a highly negatively inotropic calcium channel-blocker and it reduces cardiac output, slows the heart rate, and may impair atrioventricular conduction. It may precipitate heart failure, exacerbate conduction disorders, and cause hypotension at high doses and should not be used with beta-blockers (see under VERAPAMIL). Constipation is the most common side-effect.
Nifedipine relaxes vascular smooth muscle and dilates coronary and peripheral arteries. It has more influence on vessels and less on the myocardium than does verapamil, and unlike verapamil has no anti-arrhythmic activity. It rarely precipitates heart failure because any negative inotropic effect is offset by a reduction in left ventricular work. Short-acting formulations of nifedipine are not recommended for angina or long-term management of hypertension; their use may be associated with large variations in blood pressure and reflex tachycardia. Nicardipine has similar effects to those of nifedipine and may produce less reduction of myocardial contractility. Amlodipine and felodipine also resemble nifedipine and nicardipine in their effects and do not reduce myocardial contractility and they do not produce clinical deterioration in heart failure. They have a longer duration of action and can be given once daily. Nifedipine, nicardipine, amlodipine, and felodipine are used for the treatment of angina (section 2.6) or hypertension. All are valuable in forms of angina associated with coronary vasospasm. Side-effects associated with vasodilatation such as flushing and headache (which become less obtrusive after a few days), and ankle swelling (which may respond only partially to diuretics) are common.
Isradipine, lacidipine, lercanidipine and nisoldipine have similar effects to those of nifedipine and nicardipine; isradipine, lacidipine, and lercanidipine are only indicated for hypertension whereas nisoldipine is indicated for angina and hypertension.
Nimodipine is related to nifedipine but the smooth muscle relaxant effect preferentially acts on cerebral arteries. Its use is confined to prevention and treatment of vascular spasm following aneurysmal subarachnoid haemorrhage.
Diltiazem is effective in most forms of angina (section 2.6); the longer-acting formulation is also used for hypertension. It may be used in patients for whom beta-blockers are contra-indicated or ineffective. It has a less negative inotropic effect than verapamil and significant myocardial depression occurs rarely. Nevertheless because of the risk of bradycardia it should be used with caution in association with beta-blockers.
Unstable angina
Calcium-channel blockers do not reduce the risk of myocardial infarction in unstable angina. The use of diltiazem or verapamil should be reserved for patients resistant to treatment with beta-blockers.
Withdrawal
There is some evidence that sudden withdrawal of calcium-channel blockers may be associated with an exacerbation of angina.
Sub-sections
NIFEDIPINE
Additional information interactions (Nifedipine).
Indications
prophylaxis of angina; hypertension; Raynaud’s phenomenon
Cautions
see notes above; also withdraw if ischaemic pain occurs or existing pain worsens shortly after initiating treatment; poor cardiac reserve; heart failure or significantly impaired left ventricular function (heart failure deterioration observed); severe hypotension; elderly; diabetes mellitus; hepatic impairment (Appendix 2); may inhibit labour; pregnancy (Appendix 4); breast-feeding (Appendix 5); avoid grapefruit juice (may affect metabolism); interactions: Appendix 1 (calcium-channel blockers)
Contra-indications
cardiogenic shock; advanced aortic stenosis; within 1 month of myocardial infarction; unstable or acute attacks of angina; acute porphyria (section 9.8.2)
Side-effects
gastro-intestinal disturbances; hypotension, oedema, vasodilatation, palpitation; headache, dizziness, lethargy, asthenia; less commonly tachycardia, syncope, chills, nasal congestion, dyspnoea, anxiety, sleep disturbances, vertigo, migraine, paraesthesia, tremor, polyuria, dysuria, nocturia, erectile dysfunction, epistaxis, myalgia, joint swelling, visual disturbances, sweating, hypersensitivity reactions (including angioedema, jaundice, pruritus, urticaria, and rash); rarely anorexia, gum hyperplasia, mood disturbances, hyperglycaemia, male infertility, purpura, and photosensitivity reactions; also reported dysphagia, intestinal obstruction, intestinal ulcer, bezoar formation (with some modified-release preparations), gynaecomastia, agranulocytosis, and anaphylaxis
Dose
See preparations below
· Nifedipine (Non-proprietary)
Capsules, nifedipine 5 mg, net price 84-cap pack = £3.76; 10 mg, 84-cap pack = £4.91


Dose
Angina prophylaxis (but not recommended, see notes above) and Raynaud’s phenomenon, initially 5 mg 3 times daily, adjusted according to response to 20 mg 3 times daily
Hypertension, not recommended therefore no dose stated
6.4.1.2 Progestogens
Additional information interactions (Progestogens).
There are two main groups of progestogen, progesterone and its analogues (dydrogesterone and medroxyprogesterone) and testosterone analogues (norethisterone and norgestrel). The newer progestogens (desogestrel, norgestimate, and gestodene) are all derivatives of norgestrel; levonorgestrel is the active isomer of norgestrel and has twice its potency. Progesterone and its analogues are less androgenic than the testosterone derivatives and neither progesterone nor dydrogesterone causes virilisation.
Where endometriosis requires drug treatment, it may respond to a progestogen, e.g. norethisterone, administered on a continuous basis. Danazol, gestrinone, and gonadorelin analogues are also available (section 6.7.2).
Although oral progestogens have been used widely for menorrhagia they are relatively ineffective compared with tranexamic acid (section 2.11) or, particularly where dysmenorrhoea is also a factor, mefenamic acid (section 10.1.1); the levonorgestrel-releasing intra-uterine system (section 7.3.2.3) may be particularly useful for women also requiring contraception. Oral progestogens have also been used for severe dysmenorrhoea, but where contraception is also required in younger women the best choice is a combined oral contraceptive (section 7.3.1).
Progestogens have also been advocated for the alleviation of premenstrual symptoms, but no convincing physiological basis for such treatment has been shown.
Progestogens have been used for the prevention of spontaneous abortion in women with a history of recurrent miscarriage (habitual abortion) but there is no evidence of benefit and they are not recommended for this purpose. In pregnant women with antiphospholipid antibody syndrome who have suffered recurrent miscarriage, administration of low-dose aspirin (section 2.9) and a prophylactic dose of a low molecular weight heparin (section 2.8.1) may decrease the risk of fetal loss (use under specialist supervision only).
Hormone replacement therapy
In women with a uterus a progestogen needs to be added to long-term oestrogen therapy for hormone replacement, to prevent cystic hyperplasia of the endometrium and possible transformation to cancer; it can be added on a cyclical or a continuous basis (see section 6.4.1.1). Combined packs incorporating suitable progestogen tablets are available, see Oestogens for HRT.
Oral contraception
Desogestrel, etynodiol (ethynodiol), gestodene, levonorgestrel, norethisterone, and norgestimate are used in combined oral contraceptives and in progestogen-only contraceptives (section 7.3.1 and section 7.3.2).
Cancer
Progestogens also have a role in neoplastic disease (section 8.3.2).
Cautions
Progestogens should be used with caution in conditions that may worsen with fluid retention e.g. epilepsy, hypertension, migraine, asthma, cardiac or renal dysfunction, and in those susceptible to thromboembolism (particular caution with high dose). Care is also required in liver impairment (avoid if severe), and in those with a history of depression. Progestogens can decrease glucose tolerance and diabetes should be monitored closely. For interactions see Appendix 1 (progestogens).
Contra-indications
Progestogens should be avoided in patients with a history of liver tumours, and in severe liver impairment. They are also contra-indicated in those with genital or breast cancer (unless progestogens are being used in the management of these conditions), severe arterial disease, undiagnosed vaginal bleeding and acute porphyria (section 9.8.2). Progestogens should not be used if there is a history during pregnancy of idiopathic jaundice, severe pruritus, or pemphigoid gestationis.
Side-effects
Side-effects of progestogens include menstrual disturbances, premenstrual-like syndrome (including bloating, fluid retention, breast tenderness), weight change, nausea, headache, dizziness, insomnia, drowsiness, depression, change in libido; also skin reactions (including urticaria, pruritus, rash, and acne), hirsutism and alopecia. Jaundice and anaphylactoid reactions have also been reported.
Sub-sections
· DYDROGESTERONE
· MEDROXYPROGESTERONE ACETATE
· NORETHISTERONE
· PROGESTERONE
NORETHISTERONE
Additional information interactions (Norethisterone); hepatic impairment.
Indications
see under Dose; HRT (section 6.4.1.1); contraception (section 7.3.1 and section 7.3.2); malignant disease (section 8.3.2)
Cautions
see notes above; breast-feeding (Appendix 5)
Contra-indications
see notes above; pregnancy (Appendix 4)
Side-effects
see notes above
Dose
Endometriosis, by mouth, 10–15 mg daily for 4–6 months or longer, starting on day 5 of cycle (if spotting occurs increase dose to 20–25 mg daily, reduced once bleeding has stopped)
Dysfunctional uterine bleeding, menorrhagia (but see notes above), by mouth, 5 mg 3 times daily for 10 days to arrest bleeding; to prevent bleeding 5 mg twice daily from day 19 to 26
Dysmenorrhoea (but see notes above), by mouth, 5 mg 3 times daily from day 5 to 24 for 3–4 cycles
Premenstrual syndrome (but not recommended, see notes above), by mouth, 5 mg 2–3 times daily from day 19 to 26 for several cycles
Postponement of menstruation, by mouth, 5 mg 3 times daily starting 3 days before expected onset (menstruation occurs 2–3 days after stopping)
Sub-sections
· Tablets of 5mg
· Combined preparations
4.3.1 Tricyclic and related antidepressant drugs
Additional information interactions (Antidepressants, Tricyclic, Antidepressants, Tricyclic (related)).
This section covers tricyclic antidepressants and also 1-, 2-, and 4-ring structured drugs with broadly similar properties.
Some tricyclic antidepressants are used in the management of panic disorder (section 4.3). For reference to the role of some tricyclic antidepressants in some forms of neuralgia, see section 4.7.3, and in nocturnal enuresis in children, see section 7.4.2.
Dosage
About 10 to 20% of patients fail to respond to tricyclic and related antidepressant drugs and inadequate dosage may account for some of these failures. It is important to use doses that are sufficiently high for effective treatment but not so high as to cause toxic effects. Low doses should be used for initial treatment in the elderly (see under Side-effects, below).
In most patients the long half-life of tricyclic antidepressant drugs allows once-daily administration, usually at night; the use of modified-release preparations is therefore unnecessary.
Choice
Tricyclic and related antidepressants block the re-uptake of both serotonin and noradrenaline, although to different extents. For example, clomipramine is more selective for serotonergic transmission, and imipramine is more selective for noradrenergic transmission. Tricyclic and related antidepressant drugs can be roughly divided into those with additional sedative properties and those that are less sedating. Agitated and anxious patients tend to respond best to the sedative compounds, whereas withdrawn and apathetic patients will often obtain most benefit from the less sedating ones. Those with sedative properties include amitriptyline, clomipramine, dosulepin (dothiepin), doxepin, mianserin, trazodone, and trimipramine. Those with less sedative properties include imipramine, lofepramine, and nortriptyline.
Tricyclic and related antidepressants also have varying degrees of antimuscarinic side-effects and cardiotoxicity in overdosage, which may be important in individual patients. Lofepramine has a lower incidence of side-effects and is less dangerous in overdosage but is infrequently associated with hepatic toxicity. Imipramine is also well established, but has more marked antimuscarinic side-effects than other tricyclic and related antidepressants. Amitriptyline and dosulepin (dothiepin) are effective but they are particularly dangerous in overdosage (see Overdosage, below) and are not recommended for the treatment of depression; dosulepin (dothiepin) should only be prescribed by specialists.
Children and adolescents
Evidence of the efficacy of tricyclic antidepressants for depression in children has not been established; see also CSM advice.
Side-effects
Arrhythmias and heart block occasionally follow the use of tricyclic antidepressants, particularly amitriptyline, and may be a factor in the sudden death of patients with cardiac disease. They are also sometimes associated with convulsions (and should be prescribed with special caution in epilepsy as they lower the convulsive threshold). Hepatic and haematological reactions may occur and have been particularly associated with mianserin.
Other side-effects of tricyclic and related antidepressants include drowsiness, dry mouth, blurred vision (very rarely precipitation of angle-closure glaucoma), constipation, and urinary retention (all attributed to antimuscarinic activity), and sweating. The patient should be encouraged to persist with treatment as some tolerance to these side-effects seems to develop. They are reduced if low doses are given initially and then gradually increased, but this must be balanced against the need to obtain a full therapeutic effect as soon as possible. Gradual introduction of treatment is particularly important in the elderly, who, because of the hypotensive effects of these drugs, are prone to attacks of dizziness or even syncope. Another side-effect to which the elderly are particularly susceptible is hyponatraemia (see Hyponatraemia and Antidepressant Therapy, section 4.3).
Neuroleptic malignant syndrome (section 4.2.1) may, very rarely, arise in the course of antidepressant treatment.
Suicidal behaviour has been linked with antidepressants (see Suicidal Behaviour and Antidepressant Therapy).
Overdosage
Limited quantities of tricyclic antidepressants should be prescribed at any one time because their cardiovascular effects are dangerous in overdosage. In particular, overdosage with dosulepin (dothiepin) and amitriptyline is associated with a relatively high rate of fatality. For advice on overdosage see Emergency Treatment of Poisoning.
Withdrawal
If possible tricyclic and related antidepressants should be withdrawn slowly (see also section 4.3).
Interactions
A tricyclic or related antidepressant (or an SSRI or related antidepressant) should not be started until 2 weeks after stopping an MAOI (3 weeks if starting clomipramine or imipramine). Conversely, an MAOI should not be started until at least 7–14 days after a tricyclic or related antidepressant (3 weeks in the case of clomipramine or imipramine) has been stopped. For guidance relating to the reversible monoamine oxidase inhibitor, moclobemide, see section 4.3.2. For other tricyclic antidepressant interactions, see Appendix 1 (antidepressants, tricyclic and antidepressants, tricyclic (related)).
Sub-sections
· Tricyclic antidepressants
· Related antidepressants
AMITRIPTYLINE HYDROCHLORIDE
Additional information interactions (Amitriptyline).
Indications
depressive illness (but not recommended, see notes above); nocturnal enuresis in children (section 7.4.2); neuropathic pain [unlicensed] (section 4.7.3); migraine prophylaxis [unlicensed] (section 4.7.4.2)
Cautions
cardiac disease (particularly with arrhythmias, see Contra-indications below), history of epilepsy, pregnancy (Appendix 4), breast-feeding (Appendix 5), elderly, hepatic impairment (avoid if severe; Appendix 2), thyroid disease, phaeochromocytoma, history of mania, psychoses (may aggravate psychotic symptoms), susceptibility to angle-closure glaucoma, history of urinary retention, concurrent electroconvulsive therapy; if possible avoid abrupt withdrawal; anaesthesia (increased risk of arrhythmias and hypotension, see surgery section 15.1); acute porphyria (section 9.8.2); see section 7.4.2 for additional nocturnal enuresis warnings; interactions: Appendix 1 (antidepressants, tricyclic)
Driving

Drowsiness may affect performance of skilled tasks (e.g. driving); effects of alcohol enhanced
Contra-indications
recent myocardial infarction, arrhythmias (particularly heart block), not indicated in manic phase, severe liver disease

Side-effects

dry mouth, sedation, blurred vision (disturbance of accommodation, increased intra-ocular pressure), constipation, nausea, difficulty with micturition; cardiovascular side-effects (such as ECG changes, arrhythmias, postural hypotension, tachycardia, syncope, particularly with high doses); sweating, tremor, rashes and hypersensitivity reactions (including urticaria, photosensitivity), behavioural disturbances (particularly children), hypomania or mania, confusion or delirium (particularly elderly), headache, interference with sexual function, blood sugar changes; increased appetite and weight gain (occasionally weight loss); endocrine side-effects such as testicular enlargement, gynaecomastia, galactorrhoea; also convulsions (see also Cautions), movement disorders and dyskinesias, dysarthria, paraesthesia, taste disturbances, tinnitus, fever, agranulocytosis, leucopenia, eosinophilia, purpura, thrombocytopenia, hyponatraemia (see Hyponatraemia and Antidepressant Therapy, section 4.3), abnormal liver function tests (jaundice); for a general outline of side-effects see also notes above; overdosage: see Emergency Treatment of Poisoning (high rate of fatality—see notes above)
Dose
Depression (but not recommended, see notes above), initially 75 mg (elderly and adolescents 30–75 mg) daily in divided doses or as a single dose at bedtime increased gradually as necessary to 150–200 mg; child under 16 years not recommended for depression
Nocturnal enuresis, child 7–10 years 10–20 mg, 11–16 years 25–50 mg at night; max. period of treatment (including gradual withdrawal) 3 months—full physical examination before further course
Neuropathic pain [unlicensed indication], initially 10–25 mg daily at night, increased if necessary to 75 mg daily; higher doses under specialist supervision
Migraine prophylaxis [unlicensed indication], initially 10 mg at night, increased if necessary to maintenance of 50–75 mg at night
Sub-sections
6.4.1.1 Oestrogens and HRT
Oestrogens are necessary for the development of female secondary sexual characteristics; they also stimulate myometrial hypertrophy with endometrial hyperplasia.
In terms of oestrogenic activity natural oestrogens (estradiol (oestradiol), estrone (oestrone), and estriol (oestriol)) have a more appropriate profile for hormone replacement therapy (HRT) than synthetic oestrogens (ethinylestradiol (ethinyloestradiol) and mestranol). Tibolone has oestrogenic, progestogenic and weak androgenic activity.
Oestrogen therapy is given cyclically or continuously for a number of gynaecological conditions. If long-term therapy is required in women with a uterus, a progestogen should normally be added to reduce the risk of cystic hyperplasia of the endometrium (or of endometriotic foci in women who have had a hysterectomy) and possible transformation to cancer.
Oestrogens are no longer used to suppress lactation because of their association with thromboembolism.
Sub-sections
· Hormone replacement therapy
· OESTROGENS FOR HRT
· TIBOLONE
· Ethinylestradiol
· Raloxifene
OESTROGENS FOR HRT
Additional information interactions (Oestrogens).
Note

Relates only to small amounts of oestrogens given for hormone replacement therapy
Indications
see notes above and under preparations
Cautions
prolonged exposure to unopposed oestrogens may increase risk of developing endometrial cancer (see notes above); migraine (or migraine-like headaches); diabetes (increased risk of heart disease); history of breast nodules or fibrocystic disease—closely monitor breast status (risk of breast cancer, see notes above); risk factors for oestrogen-dependent tumours (e.g. breast cancer in first-degree relative); uterine fibroids may increase in size, symptoms of endometriosis may be exacerbated; factors predisposing to thromboembolism (see notes above); presence of antiphospholipid antibodies (increased risk of thrombotic events); increased risk of gall-bladder disease reported; hypophyseal tumours; acute porphyria (see section 9.8.2); interactions: Appendix 1 (oestrogens)
Other conditions

The product literature advises caution in other conditions including hypertension, renal disease, asthma, epilepsy, sickle-cell disease, melanoma, otosclerosis, multiple sclerosis, and systemic lupus erythematosus (but care required if antiphospholipid antibodies present, see above). Evidence for caution in these conditions is unsatisfactory and many women with these conditions may stand to benefit from HRT.
Contra-indications
pregnancy; oestrogen-dependent cancer, history of breast cancer, active thrombophlebitis, active or recent arterial thromboembolic disease (e.g. angina or myocardial infarction), venous thromboembolism, or history of recurrent venous thromboembolism (unless already on anticoagulant treatment), liver disease (where liver function tests have failed to return to normal), Dubin-Johnson and Rotor syndromes (or monitor closely), untreated endometrial hyperplasia, undiagnosed vaginal bleeding, breast-feeding
Side-effects
see notes above for risks of long-term use; nausea and vomiting, abdominal cramps and bloating, weight changes, breast enlargement and tenderness, premenstrual-like syndrome, sodium and fluid retention, cholestatic jaundice, glucose intolerance, altered blood lipids—may lead to pancreatitis, rashes and chloasma, changes in libido, depression, mood changes, headache, migraine, dizziness, leg cramps (rule out venous thrombosis), vaginal candidiasis, contact lenses may irritate; transdermal delivery systems may cause contact sensitisation (possible severe hypersensitivity reaction on continued exposure), and headache has been reported on vigorous exercise
Withdrawal bleeding

Cyclical HRT (where a progestogen is taken for 12–14 days of each 28-day oestrogen treatment cycle) usually results in regular withdrawal bleeding towards the end of the progestogen. The aim of continuous combined HRT (where a combination of oestrogen and progestogen is taken, usually in a single tablet, throughout each 28-day treatment cycle) is to avoid bleeding, but irregular bleeding may occur during the early treatment stages (if it continues endometrial abnormality should be excluded and consideration given to cyclical HRT instead)
Dose
See under preparations
Counselling on patches

Patch should be removed after 3–4 days (or once a week in case of 7-day patch) and replaced with fresh patch on slightly different site; recommended sites: clean, dry, unbroken areas of skin on trunk below waistline; not to be applied on or near breasts or under waistband. If patch falls off in bath allow skin to cool before applying new patch
Sub-sections
· Conjugated oestrogens with progestogen
· Estradiol with progestogen
· Conjugated oestrogens only
· Estradiol only
· Estradiol, estriol and estrone
· Estriol only
· Estropipate only
1.3 Antisecretory drugs and mucosal protectants
Peptic ulceration commonly involves the stomach, duodenum, and lower oesophagus; after gastric surgery it involves the gastro-enterostomy stoma.
Healing can be promoted by general measures, stopping smoking and taking antacids and by antisecretory drug treatment, but relapse is common when treatment ceases. Nearly all duodenal ulcers and most gastric ulcers not associated with NSAIDs are caused by Helicobacter pylori.
The management of H. pylori infection and of NSAID-associated ulcers is discussed below.
Sub-sections
· Helicobacter pylori infection
· NSAID-associated ulcers
· 1.3.1 H2-receptor antagonists
· 1.3.2 Selective antimuscarinics
· 1.3.3 Chelates and complexes
· 1.3.4 Prostaglandin analogues
· 1.3.5 Proton pump inhibitors

1.3.5 Proton pump inhibitors
renal impairment
Proton pump inhibitors inhibit gastric acid secretion by blocking the hydrogen-potassium adenosine triphosphatase enzyme system (the ‘proton pump’) of the gastric parietal cell. Proton pump inhibitors are effective short-term treatments for gastric and duodenal ulcers; they are also used in combination with antibacterials for the eradication of Helicobacter pylori (see Recommended Regimens for Helicobacter pylori Eradication). Following endoscopic treatment of severe peptic ulcer bleeding, an intravenous, high-dose proton pump inhibitor reduces the risk of rebleeding and the need for surgery [unlicensed use]. Proton pump inhibitors can be used for the treatment of dyspepsia and gastro-oesophageal reflux disease.
Proton pump inhibitors are also used for the prevention and treatment of NSAID-associated ulcers (see NSAID-associated Ulcers). In patients who need to continue NSAID treatment after an ulcer has healed, the dose of proton pump inhibitor should normally not be reduced because asymptomatic ulcer deterioration may occur.
A proton pump inhibitor can be used to control excessive secretion of gastric acid in Zollinger–Ellison syndrome; high doses are often required.
Cautions
Proton pump inhibitors should be used with caution in patients with liver disease (Appendix 2), in pregnancy (Appendix 4) and in breast-feeding (Appendix 5). Proton pump inhibitors may mask the symptoms of gastric cancer; particular care is required in those presenting with ‘alarm features’ (see Dyspepsia), in such cases gastric malignancy should be ruled out before treatment.
Side-effects
Side-effects of the proton pump inhibitors include gastro-intestinal disturbances (including nausea, vomiting, abdominal pain, flatulence, diarrhoea, constipation), and headache. Less frequent side-effects include dry mouth, peripheral oedema, dizziness, sleep disturbances, fatigue, paraesthesia, arthralgia, myalgia, rash, and pruritus. Other side-effects reported rarely or very rarely include taste disturbance, stomatitis, hepatitis, jaundice, hypersensitivity reactions (including anaphylaxis, bronchospasm), fever, depression, hallucinations, confusion, gynaecomastia, interstitial nephritis, hyponatraemia, blood disorders (including leucopenia, leucocytosis, pancytopenia, thrombocytopenia), visual disturbances, sweating, photosensitivity, alopecia, Stevens-Johnson syndrome, and toxic epidermal necrolysis.
Sub-sections
· ESOMEPRAZOLE
· LANSOPRAZOLE
· OMEPRAZOLE
· PANTOPRAZOLE
· RABEPRAZOLE SODIUM
OMEPRAZOLE
Additional information interactions (Omeprazole); hepatic impairment; pregnancy; breast-feeding.
Indications
see under Dose
Cautions
see notes above; interactions: Appendix 1 (proton pump inhibitors)
Side-effects
see notes above; also agitation and impotence
Dose

By mouth, benign gastric and duodenal ulcers, 20 mg once daily for 4 weeks in duodenal ulceration or 8 weeks in gastric ulceration; in severe or recurrent cases increase to 40 mg daily; maintenance for recurrent duodenal ulcer, 20 mg once daily; prevention of relapse in duodenal ulcer, 10 mg daily increasing to 20 mg once daily if symptoms return
NSAID-associated duodenal or gastric ulcer and gastroduodenal erosions, 20 mg once daily for 4 weeks, continued for further 4 weeks if not fully healed; prophylaxis in patients with a history of NSAID-associated duodenal or gastric ulcers, gastroduodenal lesions, or dyspeptic symptoms who require continued NSAID treatment, 20 mg once daily
Duodenal or benign gastric ulcer associated with Helicobacter pylori, see Recommended Regimens for Helicobacter pylori Eradication
Zollinger–Ellison syndrome, initially 60 mg once daily; usual range 20–120 mg daily (above 80 mg in 2 divided doses)
Gastric acid reduction during general anaesthesia (prophylaxis of acid aspiration), 40 mg on the preceding evening then 40 mg 2–6 hours before surgery
Gastro-oesophageal reflux disease, 20 mg once daily for 4 weeks, continued for further 4–8 weeks if not fully healed; 40 mg once daily has been given for 8 weeks in gastro-oesophageal reflux disease refractory to other treatment; maintenance 20 mg once daily
Acid reflux disease (long-term management), 10 mg daily increasing to 20 mg once daily if symptoms return
Acid-related dyspepsia, 10–20 mg once daily for 2–4 weeks according to response
Severe ulcerating reflux oesophagitis, child over 1 year, body-weight 10–20 kg, 10 mg once daily increased if necessary to 20 mg once daily for 4–12 weeks; body-weight over 20 kg, 20 mg once daily increased if necessary to 40 mg once daily for 4–12 weeks; to be initiated by hospital paediatrician
By intravenous injection over 5 minutes or by intravenous infusion, prophylaxis of acid aspiration, 40 mg completed 1 hour before surgery
Benign gastric ulcer, duodenal ulcer and gastro-oesophageal reflux, 40 mg once daily until oral administration possible
Counselling

Swallow whole, or disperse MUPS® tablets in water, or mix capsule contents or MUPS® tablets with fruit juice or yoghurt
Sub-sections
· Omeprazole
· Losec®
7.3.2.1 Oral progestogen-only contraceptives
Additional information interactions (Progestogens).
Oral progestogen-only preparations may offer a suitable alternative when oestrogens are contra-indicated (including those patients with venous thrombosis or a past history or predisposition to venous thrombosis), but have a higher failure rate than combined preparations. They are suitable for older women, for heavy smokers, and for those with hypertension, valvular heart disease, diabetes mellitus, and migraine. Menstrual irregularities (oligomenorrhoea, menorrhagia) are more common but tend to resolve on long-term treatment.
Interactions
Effectiveness of oral progestogen-only preparations is not affected by antibacterials that do not induce liver enzymes. The efficacy of oral progestogen-only preparations is, however, reduced by enzyme-inducing drugs and an additional or alternative contraceptive method is recommended during treatment with an enzyme-inducing drug and for at least 4 weeks afterwards—see section 7.3.1 and Appendix 1 (progestogens).
Surgery
All progestogen-only contraceptives (including those given by injection) are suitable for use as an alternative to combined oral contraceptives before major elective surgery, before all surgery to the legs, or before surgery which involves prolonged immobilisation of a lower limb.
Starting routine
One tablet daily, on a continuous basis, starting on day 1 of cycle and taken at the same time each day (if delayed by longer than 3 hours contraceptive protection may be lost). Additional contraceptive precautions are not necessary when initiating treatment.
Changing from a combined oral contraceptive

Start on the day following completion of the combined oral contraceptive course without a break (or in the case of ED tablets omitting the inactive ones).
After childbirth

Start any time after 3 weeks postpartum (increased risk of breakthrough bleeding if started earlier)—lactation is not affected.
Missed pill
The following advice is now recommended by family planning organisations:
‘If you forget a pill, take it as soon as you remember and carry on with the next pill at the right time. If the pill was more than 3 hours (12 hours for Cerazette®) overdue you are not protected. Continue normal pill-taking but you must also use another method, such as the condom, for the next 2 days.’
The Faculty of Sexual and Reproductive Healthcare recommends emergency contraception (see Emergency contraception (Hormonal Methods, Intra-uterine device)) if one or more progestogen-only contraceptive tablets are missed or taken more than 3 hours (12 hours for Cerazette®) late and unprotected intercourse has occurred before 2 further tablets have been correctly taken.
Diarrhoea and vomiting
Vomiting and persistent, severe diarrhoea can interfere with the absorption of oral progestogen-only contraceptives. If vomiting occurs within 2 hours of taking an oral progestogen-only contraceptive, another pill should be taken as soon as possible. If a replacement pill is not taken within 3 hours (12 hours for Cerazette®) of the normal time for taking the progestogen-only pill, or in cases of persistent vomiting or very severe diarrhoea, additional precautions should be used during illness and for 2 days after recovery (see also under Missed pill above).
Sub-sections
· ORAL PROGESTOGEN-ONLY CONTRACEPTIVES
2.5.5.1 Angiotensin-converting enzyme inhibitors
Additional information interactions (ACE Inhibitors).
Angiotensin-converting enzyme inhibitors (ACE inhibitors) inhibit the conversion of angiotensin I to angiotensin II. They have many uses and are generally well tolerated. The main indications of ACE inhibitors are shown below.
Heart failure
ACE inhibitors are used in all grades of heart failure, usually combined with a beta-blocker (section 2.5.5). Potassium supplements and potassium-sparing diuretics should be discontinued before introducing an ACE inhibitor because of the risk of hyperkalaemia. However, a low dose of spironolactone may be beneficial in severe heart failure (section 2.5.5) and can be used with an ACE inhibitor provided serum potassium is monitored carefully. Profound first-dose hypotension may occur when ACE inhibitors are introduced to patients with heart failure who are already taking a high dose of a loop diuretic (e.g. furosemide 80 mg daily or more). Temporary withdrawal of the loop diuretic reduces the risk, but may cause severe rebound pulmonary oedema. Therefore, for patients on high doses of loop diuretics, the ACE inhibitor may need to be initiated under specialist supervision, see below. An ACE inhibitor can be initiated in the community in patients who are receiving a low dose of a diuretic or who are not otherwise at risk of serious hypotension; nevertheless, care is required and a very low dose of the ACE inhibitor is given initially.
Hypertension
An ACE inhibitor may be the most appropriate initial drug for hypertension in younger Caucasian patients; Afro-Caribbean patients, those aged over 55 years, and those with primary aldosteronism respond less well (see section 2.5). ACE inhibitors are particularly indicated for hypertension in patients with type 1 diabetics with nephropathy (see also section 6.1.5). They may reduce blood pressure very rapidly in some patients particularly in those receiving diuretic therapy (see Cautions, below); the first dose should preferably be given at bedtime.
Diabetic nephropathy
For comment on the role of ACE inhibitors in the management of diabetic nephropathy, see section 6.1.5.
Prophylaxis of cardiovascular events
ACE inhibitors are used in the early and long-term management of patients who have had a myocardial infarction, see section 2.10.1. ACE inhibitors may also have a role in preventing cardiovascular events.
Initiation under specialist supervision
ACE inhibitors should be initiated under specialist supervision and with careful clinical monitoring in those with severe heart failure or in those:
· receiving multiple or high-dose diuretic therapy (e.g. more than 80 mg of furosemide daily or its equivalent);
· with hypovolaemia;
· with hyponatraemia (plasma-sodium concentration below 130 mmol/litre);
· with hypotension (systolic blood pressure below 90 mmHg);
· with unstable heart failure;
· receiving high-dose vasodilator therapy;
· known renovascular disease.
Renal effects
Renal function and electrolytes should be checked before starting ACE inhibitors (or increasing the dose) and monitored during treatment (more frequently if features mentioned below present); hyperkalaemia and other side-effects of ACE inhibitors are more common in those with impaired renal function and the dose may need to be reduced (Appendix 3). Although ACE inhibitors now have a specialised role in some forms of renal disease, including chronic kidney disease, they also occasionally cause impairment of renal function which may progress and become severe in other circumstances (at particular risk are the elderly). A specialist should be involved if renal function is significantly reduced as a result of treatment with an ACE inhibitor.
Concomitant treatment with NSAIDs increases the risk of renal damage, and potassium-sparing diuretics (or potassium-containing salt substitutes) increase the risk of hyperkalaemia.
In patients with severe bilateral renal artery stenosis (or severe stenosis of the artery supplying a single functioning kidney), ACE inhibitors reduce or abolish glomerular filtration and are likely to cause severe and progressive renal failure. They are therefore not recommended in patients known to have these forms of critical renovascular disease.
ACE inhibitor treatment is unlikely to have an adverse effect on overall renal function in patients with severe unilateral renal artery stenosis and a normal contralateral kidney, but glomerular filtration is likely to be reduced (or even abolished) in the affected kidney and the long-term consequences are unknown.
ACE inhibitors are therefore best avoided in patients with known or suspected renovascular disease, unless the blood pressure cannot be controlled by other drugs. If ACE inhibitors are used, they should be initiated only under specialist supervision and renal function should be monitored regularly.
ACE inhibitors should also be used with particular caution in patients who may have undiagnosed and clinically silent renovascular disease. This includes patients with peripheral vascular disease or those with severe generalised atherosclerosis.
Cautions
ACE inhibitors need to be initiated with care in patients receiving diuretics (important: see Concomitant diuretics, below); first doses can cause hypotension especially in patients taking high doses of diuretics, on a low-sodium diet, on dialysis, dehydrated or with heart failure (see above). They should also be used with caution in peripheral vascular disease or generalised atherosclerosis owing to risk of clinically silent renovascular disease; for use in known renovascular disease, see Renal Effects above. The risk of agranulocytosis is possibly increased in collagen vascular disease (blood counts recommended). ACE inhibitors should be used with care in patients with severe or symptomatic aortic stenosis (risk of hypotension) and in hypertrophic cardiomyopathy. They should also be used with care (or avoided) in those with a history of idiopathic or hereditary angioedema. ACE inhibitors should be used with caution in breast-feeding (Appendix 5). Interactions: Appendix 1 (ACE inhibitors).
Anaphylactoid reactions
To prevent anaphylactoid reactions, ACE inhibitors should be avoided during dialysis with high-flux polyacrylonitrile membranes and during low-density lipoprotein apheresis with dextran sulphate; they should also be withheld before desensitisation with wasp or bee venom.
Concomitant diuretics
ACE inhibitors can cause a very rapid fall in blood pressure in volume-depleted patients; treatment should therefore be initiated with very low doses. If the dose of diuretic is greater than 80 mg furosemide or equivalent, the ACE inhibitor should be initiated under close supervision and in some patients the diuretic dose may need to be reduced or the diuretic discontinued at least 24 hours beforehand (may not be possible in heart failure—risk of pulmonary oedema). If high-dose diuretic therapy cannot be stopped, close observation is recommended after administration of the first dose of ACE inhibitor, for at least 2 hours or until the blood pressure has stabilised.
Contra-indications
ACE inhibitors are contra-indicated in patients with hypersensitivity to ACE inhibitors (including angioedema). ACE inhibitors should not be used in pregnancy (Appendix 4).
Side-effects
ACE inhibitors can cause profound hypotension (see Cautions) and renal impairment (see Renal effects above), and a persistent dry cough. They can also cause angioedema (onset may be delayed; higher incidence reported in Afro-Caribbean patients), rash (which may be associated with pruritus and urticaria), pancreatitis, and upper respiratory-tract symptoms such as sinusitis, rhinitis, and sore throat. Gastro-intestinal effects reported with ACE inhibitors include nausea, vomiting, dyspepsia, diarrhoea, constipation, and abdominal pain. Altered liver function tests, cholestatic jaundice, and hepatitis have been reported. Hyperkalaemia, hypoglycaemia, and blood disorders including thrombocytopenia, leucopenia, neutropenia, and haemolytic anaemia have also been reported. Other reported side-effects include headache, dizziness, fatigue, malaise, taste disturbance, paraesthesia, bronchospasm, fever, serositis, vasculitis, myalgia, arthralgia, positive antinuclear antibody, raised erythrocyte sedimentation rate, eosinophilia, leucocytosis, and photosensitivity.
Combination products
Products incorporating an ACE inhibitor with a thiazide diuretic or a calcium-channel blocker are available for the management of hypertension. Use of these combination products should be reserved for patients whose blood pressure has not responded adequately to a single antihypertensive drug and who have been stabilised on the individual components of the combination in the same proportions.
Sub-sections
· CAPTOPRIL
· CILAZAPRIL
· ENALAPRIL MALEATE
· FOSINOPRIL SODIUM
· IMIDAPRIL HYDROCHLORIDE
· LISINOPRIL
· MOEXIPRIL HYDROCHLORIDE
· PERINDOPRIL ERBUMINE
· QUINAPRIL
· RAMIPRIL
· RAMIPRIL WITH FELODIPINE
· TRANDOLAPRIL
RAMIPRIL
Additional information interactions (Ramipril); renal impairment; pregnancy; breast-feeding.
Indications

mild to moderate hypertension; congestive heart failure (adjunct—see section 2.5.5); following myocardial infarction in patients with clinical evidence of heart failure; susceptible patients over 55 years, prevention of myocardial infarction, stroke, cardiovascular death or need of revascularisation procedures (consult product literature)
Cautions
see notes above; hepatic impairment (Appendix 2)
Contra-indications
see notes above


Side-effects
see notes above; arrhythmias, angina, chest pain, syncope, cerebrovascular accident, myocardial infarction, loss of appetite, stomatitis, dry mouth, skin reactions including erythema multiforme and pemphigoid exanthema; precipitation or exacerbation of Raynaud’s syndrome; conjunctivitis, onycholysis, confusion, nervousness, depression, anxiety, impotence, decreased libido, alopecia, bronchitis and muscle cramps
Dose

Hypertension, initially 1.25 mg once daily, increased at intervals of 1–2 weeks; usual range 2.5–5 mg once daily; max. 10 mg once daily; if used in addition to diuretic see notes above
Heart failure (adjunct), initially 1.25 mg once daily under close medical supervision (see notes above), increased gradually at intervals of 1–2 weeks to max. 10 mg daily if tolerated (daily doses of 2.5 mg or more may be taken in 1–2 divided doses)
Prophylaxis after myocardial infarction (started in hospital 3 to 10 days after infarction), initially 2.5 mg twice daily, increased after 2 days to 5 mg twice daily; maintenance 2.5–5 mg twice daily
Note

If initial 2.5-mg dose not tolerated, give 1.25 mg twice daily for 2 days before increasing to 2.5 mg twice daily, then 5 mg twice daily
Prophylaxis of cardiovascular events or stroke, initially 2.5 mg once daily, increased after 1 week to 5 mg once daily, then increased after a further 3 weeks to 10 mg once daily
Sub-sections
· Ramipril
· Tritace®
1.3.1 H2-receptor antagonists
Additional information interactions (Histamine H2-antagonists).
Histamine H2-receptor antagonists heal gastric and duodenal ulcers by reducing gastric acid output as a result of histamine H2-receptor blockade; they are also used to relieve symptoms of gastro-oesophageal reflux disease (section 1.1). H2-receptor antagonists should not normally be used for Zollinger-Ellison syndrome because proton pump inhibitors (section 1.3.5) are more effective.
Maintenance treatment with low doses for the prevention of peptic ulcer disease has largely been replaced in Helicobacter pylori positive patients by eradication regimens (section 1.3).
H2-receptor antagonists are used for the treatment of functional dyspepsia (section 1.1). Treatment of uninvestigated dyspepsia with H2-receptor antagonists used regularly or on an intermittent basis, may be acceptable in younger patients but care is required in older people because of the possibility of gastric cancer in these patients.
H2-receptor antagonist therapy can promote healing of NSAID-associated ulcers (particularly duodenal) (section 1.3).
Treatment with a H2-receptor antagonist has not been shown to be beneficial in haematemesis and melaena, but prophylactic use reduces the frequency of bleeding from gastroduodenal erosions in hepatic coma, and possibly in other conditions requiring intensive care. H2-receptor antagonists also reduce the risk of acid aspiration in obstetric patients at delivery (Mendelson’s syndrome).
Cautions
H2-receptor antagonists should be used with caution in renal impairment (Appendix 3), pregnancy (Appendix 4), and in breast-feeding (Appendix 5). H2-receptor antagonists might mask symptoms of gastric cancer; particular care is required in those whose symptoms change and in those who are middle-aged or older.
Side-effects
Side-effects of the H2-receptor antagonists include diarrhoea and other gastro-intestinal disturbances, altered liver function tests (rarely liver damage), headache, dizziness, rash, and tiredness. Rare side-effects include acute pancreatitis, bradycardia, AV block, confusion, depression, and hallucinations particularly in the elderly or the very ill, hypersensitivity reactions (including fever, arthralgia, myalgia, anaphylaxis), blood disorders (including agranulocytosis, leucopenia, pancytopenia, thrombocytopenia), and skin reactions (including erythema multiforme and toxic epidermal necrolysis). There have been occasional reports of gynaecomastia and impotence.
Interactions
Cimetidine retards oxidative hepatic drug metabolism by binding to microsomal cytochrome P450. It should be avoided in patients stabilised on warfarin, phenytoin, and theophylline (or aminophylline), but other interactions (see Appendix 1) may be of less clinical relevance. Famotidine, nizatidine, and ranitidine do not share the drug metabolism inhibitory properties of cimetidine.
Sub-sections
· CIMETIDINE
· FAMOTIDINE
· NIZATIDINE
· RANITIDINE
RANITIDINE
Additional information interactions (Ranitidine); renal impairment; pregnancy; breast-feeding.
Indications
see under Dose, other conditions where reduction of gastric acidity is beneficial (see notes above and section 1.9.4)
Cautions
see notes above; also acute porphyria; interactions: Appendix 1 (histamine H2-antagonists) and notes above
Side-effects
see notes above; also rarely tachycardia, agitation, visual disturbances, alopecia, vasculitis; very rarely interstitial nephritis
Dose
By mouth, benign gastric and duodenal ulceration, chronic episodic dyspepsia, adult and child over 12 years, 150 mg twice daily or 300 mg at night for 4–8 weeks in benign gastric and duodenal ulceration, up to 6 weeks in chronic episodic dyspepsia, and up to 8 weeks in NSAID-associated ulceration (in duodenal ulcer 300 mg can be given twice daily for 4 weeks to achieve a higher healing rate); child 3–12 years, (benign gastric and duodenal ulceration) 2–4 mg/kg (max. 150 mg) twice daily for 4–8 weeks
Prophylaxis of NSAID-associated gastric or duodenal ulcer [unlicensed dose], adult and child over 12 years, 300 mg twice daily
Gastro-oesophageal reflux disease, adult and child over 12 years, 150 mg twice daily or 300 mg at night for up to 8 weeks or if necessary 12 weeks (moderate to severe, 600 mg daily in 2–4 divided doses for up to 12 weeks); long-term treatment of healed gastro-oesophageal reflux disease, 150 mg twice daily; child 3–12 years, 2.5–5 mg/kg (max. 300 mg) twice daily
Zollinger–Ellison syndrome (but see notes above), adult and child over 12 years, 150 mg 3 times daily; doses up to 6 g daily in divided doses have been used
Gastric acid reduction (prophylaxis of acid aspiration) in obstetrics, adult and child over 12 years, by mouth, 150 mg at onset of labour, then every 6 hours; surgical procedures, by intramuscular or slow intravenous injection, 50 mg 45–60 minutes before induction of anaesthesia (intravenous injection diluted to 20 mL and given over at least 2 minutes), or by mouth, 150 mg 2 hours before induction of anaesthesia and also when possible on the preceding evening
By intramuscular injection, 50 mg every 6–8 hours
By slow intravenous injection, adult and child over 12 years, 50 mg diluted to 20 mL and given over at least 2 minutes; may be repeated every 6–8 hours
By intravenous infusion, 25 mg/hour for 2 hours; may be repeated every 6–8 hours
Prophylaxis of stress ulceration, adult and child over 12 years, initial slow intravenous injection of 50 mg (as above) then continuous infusion, 125–250 micrograms/kg/hour (may be followed by 150 mg twice daily by mouth when oral feeding commences)
Sub-sections
· Ranitidine
· Zantac®
6.1 Drugs used in diabetes > 6.1.2 Antidiabetic drugs > 6.1.2.3 Other antidiabetic drugs
REPAGLINIDE
Additional information interactions (Repaglinide); hepatic impairment.
Indications
type 2 diabetes mellitus (as monotherapy or in combination with metformin when metformin alone inadequate)
Cautions
substitute insulin during intercurrent illness (such as myocardial infarction, coma, infection, and trauma) and during surgery (omit repaglinide on morning of surgery and recommence when eating and drinking normally); debilitated and malnourished patients; renal impairment; interactions: Appendix 1 (antidiabetics)
Contra-indications
ketoacidosis; severe hepatic impairment; pregnancy (Appendix 4) and breast-feeding (Appendix 5)
Side-effects
abdominal pain, diarrhoea, constipation, nausea, vomiting; rarely hypoglycaemia, hypersensitivity reactions including pruritus, rashes, vasculitis, urticaria, and visual disturbances
Dose
Initially 500 micrograms within 30 minutes before main meals (1 mg if transferring from another oral hypoglycaemic), adjusted according to response at intervals of 1–2 weeks; up to 4 mg may be given as a single dose, max. 16 mg daily; child and adolescent under 18 years and elderly over 75 years, not recommended
Sub-sections
· Prandin®
ROSIGLITAZONE
Additional information interactions (Rosiglitazone).
Indications
type 2 diabetes mellitus (alone or combined with metformin or with a sulphonylurea or with both—see also notes above)
Cautions
monitor liver function (see below); cardiovascular disease or in combination with insulin (risk of heart failure and ischaemic heart disease—see MHRA/CHM advice); substitute insulin during peri-operative period (omit rosiglitazone on morning of surgery and recommence when eating and drinking normally); increased risk of bone fracture in females in feet, hands, and upper arms; renal impairment (Appendix 3); interactions: Appendix 1 (antidiabetics)
Liver toxicity

Rare reports of liver dysfunction reported; monitor liver function before treatment and periodically thereafter; advise patients to seek immediate medical attention if symptoms such as nausea, vomiting, abdominal pain, fatigue, anorexia and dark urine develop; discontinue if jaundice occurs or liver enzymes significantly raised
Contra-indications
hepatic impairment, history of heart failure or acute coronary syndrome, pregnancy (Appendix 4), breast-feeding (Appendix 5)
Side-effects
gastro-intestinal disturbances, cardiac ischaemia, headache, anaemia, altered blood lipids, weight gain, oedema, hypoglycaemia, bone fracture; less commonly increased appetite, heart failure, fatigue, paraesthesia, alopecia, dyspnoea; rarely pulmonary oedema, onset or worsening of macular oedema; very rarely angioedema, urticaria; see also Liver Toxicity above
Dose
Initially 4 mg daily; may be increased after 8 weeks to 8 mg daily (in 1–2 divided doses) according to response; child and adolescent under 18 years not recommended
Sub-sections
· Avandia®
· With metformin
4.7.4.1 Treatment of acute migraine
Treatment of a migraine attack should be guided by response to previous treatment and the severity of the attacks. A simple analgesic such as aspirin, paracetamol (preferably in a soluble or dispersible form) or a NSAID is often effective; concomitant antiemetic treatment may be required. If treatment with an analgesic is inadequate, an attack may be treated with a specific antimigraine compound such as a 5HT1 agonist (‘triptan’). Ergot alkaloids are rarely required now; oral and rectal preparations are associated with many side-effects and they should be avoided in cerebrovascular or cardiovascular disease.
Excessive use of acute treatments for migraine (opioid and non-opioid analgesics, 5HT1 agonists, and ergotamine) is associated with medication-overuse headache (analgesic-induced headache); therefore, increasing consumption of these medicines needs careful management.
Sub-sections
· Analgesics
· 5HT1 agonists
· Ergot alkaloids
· Antiemetics
5HT1 agonists
renal impairment
A 5HT1 agonist is of considerable value in the treatment of an acute migraine attack. The 5HT1 agonists (‘triptans’) act on the 5HT (serotonin) 1B/1D receptors and they are therefore sometimes referred to as 5HT1B/1D-receptor agonists. A 5HT1 agonist may be used during the established headache phase of an attack and is the preferred treatment in those who fail to respond to conventional analgesics.
The 5HT1 agonists available for treating migraine are almotriptan, eletriptan, frovatriptan, naratriptan, rizatriptan, sumatriptan, and zolmitriptan. Sumatriptan is also of value in cluster headache (section 4.7.4.3).
Cautions
5HT1 agonists should be used with caution in conditions which predispose to coronary artery disease (pre-existing cardiac disease, see Contra-indications below); hepatic impairment (see Appendix 2); pregnancy (see Appendix 4) and breast-feeding (see Appendix 5). 5HT1 agonists are recommended as monotherapy and should not be taken concurrently with other therapies for acute migraine; see also interactions: Appendix 1 (5HT1 agonists). Little information is available on the use of these drugs in the elderly (over 65 years).
Contra-indications
5HT1 agonists are contra-indicated in ischaemic heart disease, previous myocardial infarction, coronary vasospasm (including Prinzmetal’s angina), and uncontrolled or severe hypertension.
Side-effects
Side-effects of the 5HT1 agonists include sensations of tingling, heat, heaviness, pressure, or tightness of any part of the body (including throat and chest—discontinue if intense, may be due to coronary vasoconstriction or to anaphylaxis; see also CSM advice under Sumatriptan); flushing, dizziness, feeling of weakness; fatigue; nausea and vomiting also reported.
Sub-sections
· ALMOTRIPTAN
· ELETRIPTAN
· FROVATRIPTAN
· NARATRIPTAN
· RIZATRIPTAN
· SUMATRIPTAN
· ZOLMITRIPTAN
SUMATRIPTAN
Additional information interactions (Sumatriptan); hepatic impairment; pregnancy; breast-feeding.
Indications
treatment of acute migraine; cluster headache (subcutaneous injection only)
Cautions
see under 5HT1 agonists above; history of seizures; renal impairment; sensitivity to sulphonamides; interactions: Appendix 1 (5HT1 agonists)
Driving

Drowsiness may affect performance of skilled tasks (e.g. driving)
Contra-indications
see under 5HT1 agonists above; previous cerebrovascular accident or transient ischaemic attack; peripheral vascular disease; moderate and severe hypertension
Side-effects
see under 5HT1 agonists above; also drowsiness, transient increase in blood pressure; very rarely ischaemic colitis, hypotension, bradycardia or tachycardia, palpitation, arrhythmias, myocardial infarction, Raynaud’s syndrome, seizures, tremor, dystonia, nystagmus, and visual disturbances; erythema at injection site; nasal irritation and epistaxis with nasal spray
CSM advice

Following reports of chest pain and tightness (coronary vasoconstriction) CSM has emphasised that sumatriptan should not be used in ischaemic heart disease or Prinzmetal’s angina, and that use with ergotamine should be avoided (see also Cautions).
Dose
By mouth, 50 mg (some patients may require 100 mg); dose may be repeated after at least 2 hours if migraine recurs; max. 300 mg in 24 hours; child and adolescent under 18 years, see BNF for Children
By subcutaneous injection using auto-injector, 6 mg; dose may be repeated once after at least 1 hour if migraine recurs; max. 12 mg in 24 hours; child and adolescent under 18 years not recommended
Important

Not for intravenous injection which may cause coronary vasospasm and angina
Intranasally, 10–20 mg (adolescent 12–17 years 10 mg) into one nostril; dose may be repeated once after at least 2 hours if migraine recurs; max. 40 mg (adolescent 12–17 years 20 mg) in 24 hours
Note

Patient not responding to initial dose should not take second dose for same attack
Sub-sections
· Sumatriptan
· Imigran®
· Imigran® RADIS