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

• Oestrogen-only preparations include:
• Oral tablet (daily).
• Transdermal patch (once weekly or twice weekly) or gel (daily).
• Vaginal ring (Estring^®), creams and pessaries.
• Implant (every 6 months).
• Combined oestrogen–progestogen preparations include:
• Oral tablet (daily).
• Transdermal patch (once weekly or twice weekly):
• In transdermal combined hormone replacement therapy (cyclical or continuous combined oestrogen plus progestogen), the progestogen is either combined into the patch, or given separately as a tablet.

[BNF 54, 2007]

• Choice of systemic oestrogen:
• 'Natural' oestrogens, such as conjugated oestrogen, estradiol, estrone, and estriol, are suitable for use as systemic hormone replacement therapy (HRT).
• Choice of vaginal oestrogen:
• Low dose oestrogens such as estriol (cream or pessary) or estradiol (tablet or ring) preparations are suitable for topical (vaginal) use. Endometrial effects should not be incurred. A progestogen is not needed with such low dose preparations [Rees and Purdie, 2006a].
• Synthetic or conjugated oestrogens should be avoided as they are well absorbed from the vagina and may potentially result in endometrial stimulation.
• Choice of progestogen:
• The progestogens most commonly used in HRT are almost all synthetic and include:
• Dydrogesterone and medroxyprogesterone.
• Norethisterone and levonorgestrel.
• Drospirenone.
• Women vary in their tolerance to progestogens.
• Medroxyprogesterone and dydrogesterone are sometimes better tolerated than norethisterone or levonorgestrel because they are less androgenic.
• Drospirenone is also considered to be less androgenic and has aldosterone antagonistic activities. It is useful for women who complain of fluid retention during the progestogen phase.
• Combined HRT tablets contain medroxyprogesterone, dydrogesterone, or drospirenone (less androgenic); or norethisterone, or levonorgestrel (more androgenic).
• Combined HRT patches only contain norethisterone or levonorgestrel (more androgenic). There are currently no patches containing less androgenic progestogens.
• The levonorgestrel-releasing intrauterine system is an alternative route of delivery of progestogen to protect the endometrium. Since levonorgestrel is delivered locally to the uterus, a much lower daily dose is used, which also results in low systemic levels of levonorgestrel.
• Tibolone is a synthetic steroidal agent with oestrogenic, progestogenic, and androgenic activity. It may be used as an alternative to combined therapy for postmenopausal women who wish to have amenorrhoea.
• Testosterone supplementation (patches and implants) can improve loss of libido, particularly after surgical menopause. Treatment is not always successful, other factors such as marital problems may be involved, and testosterone may cause potentially serious adverse effects [Rees and Purdie, 2006a].
• Testosterone patches are licensed for women with surgically induced menopause (in women receiving concomitant oestrogen therapy), but they are not recommended for women naturally menopausal or those taking conjugated oestrogens. Safety and efficacy of testosterone patches have not been established beyond 1 year of treatment [BNF 54, 2007].

• For the purposes of this guideline, 'natural oestrogen' is defined as one that is found in normal physiology, irrespective of whether it has been prepared by chemical synthesis or extraction from a plant or animal source.

• These recommendations are based on published expert opinion [Rees and Purdie, 2006a].
• Synthetic oestrogens, such as mestranol or ethinylestradiol, are generally considered not to be suitable for hormone replacement therapy (except in women with early ovarian failure) because of their greater metabolic impact.

• Offer oestrogen-only hormone replacement therapy (HRT) for women who do not have a uterus (usually taken continuously).
• Offer combined (oestrogen and progestogen) HRT to women with an intact uterus:
• For perimenopausal women, monthly or 3-monthly cyclical regimens may be used:
• A 3-monthly regimen may be more suitable for women with infrequent periods or who are intolerant of progestogens.
• A monthly regimen produces monthly bleeding and a 3-monthly regimen produces a bleed every three months.
• For postmenopausal women, monthly, 3-monthly cyclical regimens, or continuous combined regimens may be used. Continuous combined regimens may be preferred because they do not produce withdrawal bleeding:
• Continuous combined HRT may produce irregular bleeding or spotting the first 4–6 months of treatment. Bleeding should be investigated if it persists beyond 6 months, if it becomes heavier rather than less, or it if occurs after amenorrhoea.
• Tibolone is an alternative no-bleed regimen for postmenopausal women.
• It is preferable for the oestrogen and progestogen to be in combined form (e.g. in one tablet), because the adverse effects of the progestogen may lead to poor compliance if given separately. If oestrogen and progestogen are given separately, an explanation about the endometrial protective effect of progestogens is important to ensure compliance.

• Combined hormone replacement therapy regimens:
• Monthly cyclical regimens: oestrogen is taken daily and progestogen given at the end of the cycle for 10–14 days.
• Three-monthly cyclical regimens: oestrogen is taken every day and progestogen is given for 14 days every 13 weeks.
• Continuous combined regimens: oestrogen and progestogen are taken every day.

• These recommendations are based on expert published opinion [Rees and Purdie, 2006a].
• Hysterectomy:
• Women who have a had a hysterectomy do not usually require the addition of progestogen. Progestogens are added to hormone replacement therapy regimens to reduce the increased risk of endometrial hyperplasia and cancer which occurs with unopposed oestrogen.
• Perimenopausal women:
• Continuous regimens are not recommended because they often cause unpredictable bleeding in these women.

• Oral or transdermal preparations may be used to treat urogenital symptoms or vasomotor symptoms (e.g. flushes or sweats) with or without urogenital symptoms.
• Transdermal preparations may be appropriate if:
• The woman prefers this route.
• Symptom control is poor with oral treatment.
• Oral treatment causes adverse effects (e.g. nausea).
• History of or risk of venous thromboembolism (in this situation, consider hormone replacement therapy [HRT] only after full discussion and appropriate investigation).
• The woman is taking a hepatic enzyme–inducing drug (e.g. anticonvulsant therapy).
• The woman has a bowel disorder which may affect absorption of oral therapy.
• The woman has a history of migraine (when steadier hormone levels may be beneficial).
• The woman has lactose sensitivity (most HRT tablets contain lactose).
• Low-dose vaginal oestrogen (tablet, cream, pessary, or vaginal ring) may be used for urogenital symptoms alone.
• Offer the levonorgestrel-releasing intrauterine system (Mirena^®) when:
• The woman is experiencing persistent progestogenic adverse effects from systemic HRT despite changes in type and route of progestogen.
• Contraception is required along with HRT in the perimenopause.
• Withdrawal bleeds on sequential HRT are heavy, after investigation if indicated.
• Estradiol implants are usually offered as a last resort in women post-hysterectomy when symptoms are not controlled by other means. Implants release estradiol over many months (replaced every 6 months) so that the woman does not have to remember to take medication. However, they can scar the skin and cannot be easily removed.

• These recommendations are based on pragmatic advice and published expert opinion [Rees and Purdie, 2006a].
• Oral oestrogens are more likely to cause nausea than other forms of oestrogen.
• Vaginal oestrogen:
• Systemic absorption of low-dose vaginal oestrogen is very low and does not relieve other menopausal symptoms, such as hot flushes.
• Patches:
• Hormone levels delivered by patch are more constant than if given orally; oestrogen is absorbed directly through the skin into the systemic circulation, bypassing the liver.
• Some patches come in four strengths of oestrogen, allowing titration to the optimal dose.
• Mirena^®:
• Mirena^® provides adequate endometrial protection. The oestrogen dose and route can be tailored to meet individual needs.
• Progestogenic systemic absorption is minimal, reducing systemic progestogenic side effects. The endometrial effect of Mirena^® can significantly reduce bleeding when used as part of a hormone replacement therapy regimen: 30–60% of women become amenorrhoeic. Although Mirena used for contraception is licensed for 5 years, the license for use for the progestogen part of hormone replacement therapy is currently 4 years.
• Estradiol implants:
• Recurrence of vasomotor symptoms at supraphysiological plasma concentrations may occur. Moreover, there is evidence of prolonged endometrial stimulation after discontinuation (calling for continuous cyclical progestogen) [BNF 54, 2007].

• The lowest effective dose of hormone replacement therapy should be used for the shortest time possible.
• Oestrogen dose for symptom control:
• Older women may be less tolerant of oestrogen and need to start (and are usually maintained) on a lower dose (e.g. oral estradiol 1 mg, or transdermal estradiol 25–50 micrograms). Younger women may require higher doses (e.g. 2–4 mg estradiol, or transdermal estradiol 100 micrograms) to remain symptom-free. The dose should be tailored to the symptoms since the ingested or applied dose may not be well absorbed.
• Oestrogen dose for osteoporosis:
• The 'standard' bone-conserving doses of oestrogen are considered to be estradiol 2 mg, conjugated equine oestrogens 0.625 mg, or transdermal 50 microgram patch. However, it is now evident that lower doses also conserve bone mass.
• Progestogens for endometrial protection: several different progestogens used in combined hormone replacement therapy provide adequate endometrial protection. See Table 1 for more information.
• Tibolone: the standard dose is 2.5 mg daily.

• These recommendations are based on published expert opinion [Rees and Purdie, 2006a; MHRA and CHM, 2007b].

• Reassure the woman that weight gain is very common around the time of the menopause and that hormone replacement therapy does not cause significant further weight gain.

• These recommendations are based on published expert opinion [Kongnyuy et al, 1999; Rees and Purdie, 2006a].
• Weight gain is often cited as a major reason why women are reluctant to start or continue hormone replacement therapy.

• Oestrogen-related adverse effects include fluid retention, bloating, breast tenderness or enlargement, nausea, headaches, leg cramps, and dyspepsia. They may occur continuously or randomly throughout the cycle.
• Encourage the woman to persist with therapy for about 3 months to await resolution, as most adverse effects resolve with increased duration of use:
• Leg cramps can improve with lifestyle changes, including exercise and regular stretching of the calf muscles.
• Nausea/gastric upset may be helped by adjusting the timing of the oestrogen dosage or taking with food.
• Breast tenderness may be alleviated by a low-fat, high-carbohydrate diet. Gamolenic acid (evening primrose oil) is no longer available as a licensed medicinal product because of lack of efficacy.
• Migraine triggered by fluctuating oestrogen levels may respond to transdermal therapy, as this produces more stable oestrogen levels.
• For persistent adverse effects, consider:
• Reducing the dosage or
• Changing the oestrogen type (e.g. swap between the two main forms of oestrogen, that is, estradiol and conjugated oestrogens) or
• Changing the route of delivery (e.g. tablets may cause nausea, but patches and gels generally do not).

• These recommendations are based on published expert opinion [Bundred, 2003; Rees and Purdie, 2006a; Menopause Matters, 2007a].
• The recommended management strategies have not been assessed in clinical trials.

• Progestogen-related adverse effects tend to occur in a cyclical pattern during the progestogen phase of cyclical hormone replacement therapy (HRT). They include fluid retention, breast tenderness, headaches or migraine, mood swings, depression, acne, lower abdominal pain, and backache.
• Encourage the woman to persist with therapy for about 3 months to await possible resolution of adverse effects.
• For persistent or troublesome symptoms, consider the following options. Many of these are the opposite of what may be needed to better control bleeding:
• Changing the progestogen type, for example from more androgenic ones, such as norethisterone and norgestrel, to less androgenic ones, such as medroxyprogesterone or dydrogesterone.
• Changing the route of progestogen, for example from oral to transdermal, vaginal, or intrauterine progestogen. This may be most beneficial when the woman is nauseous while receiving oral HRT. If the oestrogen is to be delivered by a different route to the progestogen, the woman can easily miss out the progestogen as desired if it is causing unpleasant adverse effects. However, the woman must fully understand that the progestogen is being given to provide endometrial protection.
• Reducing the duration of progestogen administration: progestogens can be taken for 12–14 days of each monthly sequential regimen, so swapping from a 14-day to a 12-day product may provide benefit.
• Changing to a product with a lower dose of progestogen (dosages are preparation dependent).
• Reducing the frequency of progestogen dosing. This can be achieved by switching to a long-cycle regimen administering progestogen for 14 days every 3 months (but this strategy is suitable only for women without natural regular periods).
• Changing to continuous combined therapy or tibolone often reduces progestogenic adverse effects with established use (as these products contain lower dosages of progestogen), but this is suitable only for postmenopausal women.

• These recommendations are based on published expert opinion [Rees and Purdie, 2006a; Menopause Matters, 2007a].

• Examine the woman, visualize the cervix and check smears are up to date, and refer for transvaginal ultrasound to exclude pelvic abnormalities before changing treatment.
• Check for compliance with therapy, drug interactions (e.g. anticonvulsants), or gastrointestinal upset.
• Altering the progestogen part of the regimen may improve bleeding:
• Heavy or prolonged bleeding: increase the duration or dosage of the progestogen, or change the type of progestogen. Idiopathic menorrhagia may be helped by using the levonorgestrel-releasing intrauterine system combined with an oestrogen delivered orally or transdermally.
• Bleeding early in the progestogen phase: increase dosage or change the type of progestogen.
• Irregular bleeding: change regimen or increase the dosage of progestogen.
• No bleeding whilst taking a cyclical regimen reflects an atrophic endometrium and occurs in 5% of women. Pregnancy needs to be excluded in perimenopausal women. Check compliance if the progestogen component is taken separately.

• It is mandatory to investigate before changing treatment because pelvic pathology can be missed. Changing treatment before examination is unsafe practice and can lead to delayed diagnosis of endometrial cancer.

• These recommendations are based on published expert opinion [Rees and Purdie, 2006a; Menopause Matters, 2007a].
• Monthly cyclical regimens should produce regular predictable bleeding starting towards or soon after the end of the progestogen phase. Unpredictable or unacceptable bleeding may be due to non-adherence to therapy, drug interactions, or gastrointestinal upset (or cancer, if not already excluded).

• Irregular breakthrough bleeding or spotting is common in the first 3–6 months of therapy, but bleeding beyond 6 months or after a spell of amenorrhoea requires further investigation or referral.

• These recommendations are based on published expert opinion [Rees and Purdie, 2006a; Menopause Matters, 2007a].

• Contraindications to HRT are:
• Hormone-dependent cancer (e.g. endometrial cancer, current or past breast cancer).
• Active or recent arterial thromboembolic disease (e.g. angina or myocardial infarction).
• Venous thromboembolic disease, pulmonary embolism, or current pregnancy.
• Severe active liver disease.
• Undiagnosed breast mass.
• Uninvestigated abnormal vaginal bleeding.

• Some women do not notice any symptoms even with abrupt cessation of hormone replacement therapy (HRT), while others may experience a recurrence of hot flushes and sweats.
• Some experts suggest that HRT should be gradually reduced rather than stopped abruptly. Suggested strategies are:
• Oestrogen-only tablets: reduce from a 2 mg to a 1 mg tablet for 1–2 months, then use 1 mg on alternate days for a further 1–2 months.
• Oestrogen-only patches: reduce the dose gradually to 25 micrograms daily (e.g. step the dose down a patch strength each month). Half a matrix-type patch (12.5 micrograms daily) can be used for a further 1–2 months.
• Cyclical combined HRT tablets: reduce to a cyclical HRT pack containing 1 mg estradiol for 1–2 months. Cut the tablet in half for the next 1–2 months; this will ensure that the woman still receives oestrogen combined with a progestogen.
• Cyclical combined HRT patches: reduce the dose as for oestrogen-only patches, but ensure that the woman still uses the oestrogen-only patches for 2 weeks of the cycle followed by the combined patches for a further 2 weeks, to ensure endometrial protection.
• Continuous combined HRT tablets or patches: reduce the dose gradually every 1–2 months to the lowest strength tablet or patch. Then, take half a tablet or patch daily for a further 1–2 months.
• If symptoms are severe after HRT is stopped or persist for several months after stopping, the woman may wish to restart HRT after reassessment and counselling. Often a lower dose of HRT can be used (e.g. estradiol 1 mg) if HRT is restarted.

• This recommendation is based on published expert opinion [NZGG, 2004; ICSI, 2006].
• In older women, sleep disorders rather than hot flushes may be the major manifestation of renewed menopausal symptoms [ICSI, 2006].

• Offer a selective serotonin reuptake inhibitor, such as paroxetine, fluoxetine, or citalopram, or a serotonin–norepinephrine reuptake inhibitor, such as venlafaxine:
• There is evidence that paroxetine, fluoxetine, citalopram, and venlafaxine are effective for treating hot flushes, but no evidence that one is more effective than the other.
• All are unlicensed for treating hot flushes.

[Rees and Purdie, 2006a]

• Antidepressants are unlicensed for treating menopausal symptoms. However, the following dosages have been assessed and found to be effective for hot flushes in short-term studies:
• Citalopram 20 mg daily.
• Paroxetine 20 mg daily.
• Fluoxetine 20 mg daily.
• Venlafaxine 37.5 mg twice daily.

• The most common adverse effects associated with selective serotonin reuptake inhibitors (SSRIs) are gastrointestinal effects (nausea and diarrhoea), central nervous system effects (dizziness, agitation, insomnia, and tremor), and sexual dysfunction [Taylor et al, 2005].
• Observational studies have shown that SSRIs increase the risk of upper gastrointestinal bleeding, probably by altering platelet function [de Abajo et al, 1999; van Walraven et al, 2001; Dalton et al, 2003; Meijer et al, 2004]. This observed increase in risk may also apply to other types of bleeding:
• This risk is increased in people who are also taking low-dose aspirin or nonsteroidal anti-inflammatory drugs (NSAIDs) [Dalton et al, 2003]. Consider gastroprotection for all people who are prescribed both an SSRI and an NSAID or aspirin [Paton and Ferrier, 2005].
• This increased risk may also apply to very old people or those with a history of gastrointestinal bleeding. Consider using an antidepressant with a low affinity for the serotonin transporter [Paton and Ferrier, 2005].
• People receiving warfarin should receive careful coagulation monitoring when treatment with an SSRI is initiated or stopped.
• Extrapyramidal symptoms are relatively rare and seem to be most common with paroxetine [CSM, 2000].
• Co-administration of SSRIs with other serotonergic drugs (e.g. tramadol, triptans) or with dopaminergic drugs (e.g. selegiline) may also increase the risk of serotonin syndrome, and close monitoring is advised [Stockley, 2002].
• SSRIs have a low proconvulsant effect, the seizure risk being dose-related, and are a good choice of antidepressant for people with epilepsy. However, fluoxetine and paroxetine (and to a lesser extent sertraline) can increase serum levels of phenytoin and carbamazepine through inhibition of hepatic enzymes. Serum phenytoin levels should be monitored and the dosage adjusted accordingly when starting, stopping, or changing the dose of these SSRIs. Citalopram is a weak enzyme inhibitor and has a low potential for clinically significant interactions [Taylor et al, 2005].

• Nausea, insomnia, dry mouth, somnolence, dizziness, constipation, sweating, nervousness, and asthenia are the most common adverse effects. They are thought to be dose related and transient.
• Do not prescribe venlafaxine for people with:
• Uncontrolled hypertension.
• A high risk of serious cardiac arrhythmias.
• A recent myocardial infarction.
• Prescribe venlafaxine in people with pre-existing hypertension only if their blood pressure is controlled in line with the current National Institute for Health and Clinical Excellence (NICE) guidelines for hypertension. For more information, see the CKS topic on Hypertension - not diabetic.
• Monitor people taking venlafaxine (including those with pre-existing hypertension) for signs and symptoms of cardiac dysfunction and any increase in blood pressure:
• Check blood pressure on initiation of therapy and regularly during treatment (especially during dose titration). If there is a sustained increase in blood pressure:
• Reduce the dose or
• Discontinue treatment.

[ABPI Medicines Compendium, 2006; NICE, 2007]

• When stopping or reducing the dose of an antidepressant, some people experience such symptoms as dizziness, nausea, paraesthesiae, anxiety, diarrhoea, flu-like symptoms, and headaches. These symptoms occur with all classes of antidepressants, and are often referred to as discontinuation (or withdrawal) symptoms:
• Discontinuation symptoms are more common with longer treatment courses and rarely occur with treatments lasting less than 6 weeks.
• Onset is usually within 5 days of stopping treatment. Occasionally, symptoms occur during tapering or after missed doses.
• Symptoms are usually mild and self limiting, rarely lasting for more than 1–2 weeks. However, they can be severe, particularly if the drug is stopped abruptly.
• Discontinuation symptoms are more likely with: antidepressants with a short half-life, such as paroxetine; in people who developed anxiety symptoms at the start of treatment; and in people taking other centrally-acting drugs.
• Reduce the dose or frequency of antidepressant gradually over 4 weeks:
• More rapid discontinuation may be necessary in people with severe adverse reactions to treatment.
• In people who have been receiving longer-term treatment, taper the dose over 6 months.
• Fluoxetine can be stopped abruptly if the dose is 20 mg daily, as it has a long half-life and active metabolites.
• When stopping an antidepressant, ask the person to seek advice if they experience significant discontinuation symptoms.
• If discontinuation symptoms are mild, reassure the person that the symptoms usually pass in a few days.
• If discontinuation symptoms are severe, consider reintroducing the original antidepressant and then tapering more slowly while monitoring symptoms.

[Anderson et al, 2000; Haddad, 2001; Taylor et al, 2003; NICE, 2004]

• Use 50 micrograms twice daily and increase to 75 micrograms twice daily after 2 weeks if necessary for vasomotor symptoms (licensed use).

[BNF 54, 2007]

• Hypotension, dizziness, sedation, dry mouth, fluid retention, and nausea are the most common adverse effects.
• Clonidine may also aggravate depression or produce insomnia:
• Tricyclic antidepressants (TCAs) can antagonize the effects of clonidine, and a higher dose of clonidine (75 micrograms twice daily) may be required.
• Clonidine may potentiate bradyarrhythmic conditions:
• Avoid in women with sinus bradycardia or atrioventricular block.
• Avoid concomitant use of beta-blockers or cardiac glycosides if possible.
• There is a risk of rebound hypertension when a beta-blocker or a TCA is stopped in someone taking clonidine. Withdraw the beta-blocker or TCA slowly over a few days to avoid this. Clonidine should also be reduced gradually over a few days if used at high dose.

[ABPI Medicines Compendium, 2002]