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).

• Antimuscarinic adverse effects can limit treatment success. Adverse effects can be reduced by starting at a low dose and gradually increasing until a satisfactory clinical response is achieved.
• For oxybutynin [ABPI Medicines Compendium, 2007a; ABPI Medicines Compendium, 2007c]:
• The usual starting dose is 5 mg two or three times a day.
• In elderly women, a starting dose of 2.5 mg or 3 mg twice daily is recommended by the manufacturers of oxybutynin.
• Increase the dose as necessary to a maximum of 5 mg four times a day.
• Modified-release preparations are effective and have fewer adverse effects than immediate-release preparations, but they are more expensive.
• Other antimuscarinic drugs should also be prescribed cautiously in frail and elderly people because of an increased risk of adverse effects. For further information, see Management of urgency incontinence symptoms/ overactive bladder.
• For dosage information, see Table 1.

• Dosages for the various antimuscarinic preparations are listed in Table 1.

• Do not prescribe an antimuscarinic to people with:
• Myasthenia gravis.
• Significant bladder outflow obstruction or urinary retention.
• Severe ulcerative colitis.
• Toxic megacolon.
• Gastrointestinal obstruction.
• Uncontrolled angle-closure glaucoma.
• Intestinal atony.

[BNF 57, 2009]

• Adverse effects of antimuscarinic drugs include dry mouth, gastrointestinal disturbances, blurred vision, dry eyes, drowsiness, dizziness, fatigue, difficulty in micturition, palpitation, and skin reactions (including dry skin, rash, and photosensitivity).
• Central nervous system stimulation, manifested as restlessness, disorientation, hallucination, and convulsion, can also occur.
• Antimuscarinic drugs can very rarely precipitate angle-closure glaucoma.

[BNF 57, 2009]

• For the management of stress urinary incontinence:
• The recommended dose of duloxetine is 40 mg twice a day.
• Re-assess after 2–4 weeks of treatment to evaluate the benefit and tolerability of the treatment.
• If adverse effects are likely to be a problem, consider starting treatment at a dose of 20 mg twice a day for 2 weeks before increasing to the recommended dose of 40 mg twice a day.
• For information on treatment reduction and discontinuation, see Drug withdrawal or dose reduction.

[ABPI Medicines Compendium, 2008a]

• Advise the person not to stop treatment abruptly.
• If duloxetine treatment is to be discontinued, reduce the dose gradually over at least 1 to 2 weeks to reduce the risk of withdrawal reactions.
• If intolerable withdrawal reactions occur after a dose reduction or on stopping treatment, resume the previously prescribed dose and continue decreasing the dose more gradually.

[ABPI Medicines Compendium, 2008a]

• Duloxetine is contraindicated in people:
• Taking monoamine oxidase inhibitors.
• Taking a CYP1A2 inhibitor (such as fluvoxamine or ciprofloxacin) — combination results in elevated plasma concentration of duloxetine.
• With hepatic impairment.
• With severe renal impairment (creatinine clearance less than 30 mL/min; approximately stage 4 CKD [chronic kidney disease]).
• With uncontrolled hypertension — there is a potential risk of hypertensive crisis.
• Prescribe duloxetine with caution in people with:
• Increased intra-ocular pressure, or those at risk of acute narrow-angle glaucoma — mydriasis has been reported in association with duloxetine.
• Epilepsy — concomitant treatment may precipitate seizures.
• A history of mania or a diagnosis of bipolar disorder — concomitant treatment may precipitate a mixed or manic episode. If this occurs, stop treatment with duloxetine.

[ABPI Medicines Compendium, 2008a]

• Duloxetine should not be used during pregnancy or breastfeeding.

• Data and experience with duloxetine are insufficient to recommend its use during pregnancy or breastfeeding [Schaefer et al, 2007].
• Complications consistent with serotonin-noradrenaline reuptake inhibitor (SNRI) toxicity, a possible drug discontinuation syndrome, or serotonin syndrome have been reported in neonates exposed to SNRIs in the third trimester [Micromedex, 2009].
• The manufacturer of duloxetine (Yentreve^®) recommends that duloxetine should be used in pregnancy only if the potential benefit justifies the potential risk to the fetus, and that the use of duloxetine while breastfeeding is not recommended [ABPI Medicines Compendium, 2008a].

• Concurrent use of duloxetine with a monoamine oxidase inhibitor or a reversible inhibitor of monoamine oxidase type A is contraindicated.
• Combination with a CYP1A2 inhibitor (such as fluvoxamine or ciprofloxacin) is also contraindicated.
• Concurrent use of duloxetine with other serotonergic drugs is not recommended.

• Duloxetine should not be started for 2 weeks after a monoamine oxidase inhibitor (MAOI) has been stopped, or for 24 hours after a reversible inhibitor of monoamine oxidase type A (RIMA [i.e. moclobemide]) has been stopped.
• An MAOI or RIMA should not be started for at least 1 week after duloxetine has been stopped.

[Taylor et al, 2007]

• Concurrent use of duloxetine with monoamine oxidase inhibitors and reversible inhibitors of monoamine oxidase type A can cause very toxic and sometimes fatal reactions similar to serotonin syndrome [Baxter, 2008].
• Concurrent use of duloxetine with selective serotonin reuptake inhibitors, tricyclic antidepressants, St John's wort, venlafaxine, triptans, tramadol, pethidine, and tryptophan can rarely cause serotonin syndrome [Baxter, 2008].
• Combination with a CYP1A2 inhibitor (such as fluvoxamine or ciprofloxacin) is not recommended by the manufacturer of duloxetine because this results in elevated plasma concentration of duloxetine [ABPI Medicines Compendium, 2008a].

• The most common adverse effects seen in clinical trials were nausea, dry mouth, fatigue, and constipation, which usually occur in the first week of treatment.
• Duloxetine treatment is associated with small increases in blood pressure (BP).
• Monitor BP in people with known hypertension or other cardiac disease and those whose conditions could be affected by an increase in BP (see the section on Monitoring in the CKS topic on Neuropathic pain - drug treatment).
• Consider reducing the dose or gradual discontinuation in people who experience a sustained increase in BP while taking duloxetine.
• Hyponatraemia is associated with all types of antidepressants (duloxetine is a serotonin-noradrenaline reuptake inhibitor).
• Consider hyponatraemia if the person develops dizziness, drowsiness, confusion, nausea, muscle cramps, or seizures.
• If hyponatraemia is suspected, stop duloxetine and manage according to severity and duration of symptoms, and state of hydration.
• Bleeding abnormalities have been reported with serotonin-noradrenaline reuptake inhibitors.
• This risk is increased in people who are also taking low-dose aspirin or nonsteroidal anti-inflammatory drugs (NSAIDs) — consider gastroprotection for people who are prescribed duloxetine with an NSAID or aspirin.
• This increased risk may also apply to those who are very old or those with a history of gastrointestinal bleeding — consider using an alternative drug in these groups.
• Exercise caution in people taking warfarin.
• Suicidal thoughts and suicide attempts have rarely been reported during duloxetine treatment or early after stopping treatment.
• Advise people to seek medical advice immediately if they notice any changes in mood, increased anxiety and agitation, negativity and hopelessness, or suicidal ideation.
• Treatment with duloxetine has been associated with an increase in fasting plasma glucose.
• The clinical significance of this is not clear, but it may be prudent to monitor blood glucose in people who are taking duloxetine to treat painful diabetic neuropathy.

[ABPI Medicines Compendium, 2008a]

• Recent data has shown high discontinuation rates during the first 4 weeks of duloxetine treatment caused by adverse effects [Women's Health Specialist Library, 2009].

• Duloxetine has been associated with small increases in blood pressure and clinically significant hypertension in some people [ABPI Medicines Compendium, 2008a; Micromedex, 2009].
• In clinical trials, treatment with duloxetine led to a mean increase in blood pressure of up to 2.1 mmHg systolic and 2.3 mmHg diastolic, compared with placebo.
• Cases of hypertensive crisis have been reported with duloxetine, especially in people with pre-existing hypertension.
• The recommendation regarding antidepressants and hyponatraemia is in line with advice from the Committee on Safety of Medicines (now the Commission on Human Medicines) [MHRA, 1994].
• Most of the evidence for an increased risk of bleeding is from observational studies of selective serotonin reuptake inhibitors (SSRIs) [de Abajo et al, 1999; van Walraven et al, 2001; Dalton et al, 2003; Meijer et al, 2004]. However, there have also been reports of bleeding abnormalities with serotonin-noradrenaline reuptake inhibitors [Micromedex, 2009]. Recommendations for minimizing this adverse effect are expert opinion extrapolated from managing this adverse effect with SSRIs [Paton and Ferrier, 2005].
• Isolated cases of suicidal thoughts and suicide attempts have been reported during duloxetine therapy or early after treatment discontinuation. The Commission on Human Medicines recommends that people be monitored frequently for the emergence of suicidal thoughts or behaviour during treatment with duloxetine [CSM, 2006].

• In people with hypertension or other cardiac disease and those whose condition could be affected by an increase in blood pressure (BP), monitor BP before starting treatment and regularly throughout treatment, especially during the first month.
• If a sustained increase in BP occurs, consider either a dose reduction or a gradual discontinuation of duloxetine.
• In people taking warfarin, monitor the international normalized ratio (INR) when duloxetine is started or stopped, or after an increase in dose.

• Duloxetine has been associated with an increase in blood pressure and clinically significant hypertension in some people. This may be due to the noradrenergic effect of duloxetine. Cases of hypertensive crisis have been reported with duloxetine, especially in people with pre-existing hypertension [Micromedex, 2009].
• For people who experience a sustained increase in blood pressure while receiving duloxetine, the manufacturer recommends that either a dose reduction or a gradual discontinuation should be considered [ABPI Medicines Compendium, 2008a].
• Increases in the international normalized ratio (INR) have been reported when duloxetine was co-administered with warfarin [ABPI Medicines Compendium, 2008a]. It would therefore seem prudent to monitor the INR in anyone taking warfarin concomitantly with duloxetine.

• Prescribe 200 micrograms at bedtime, increasing to 400 micrograms if the lower dose is not effective [BNF 57, 2009].
• Desmopressin is not licensed for nocturia in women with idiopathic urinary incontinence. Informed consent to treatment should be obtained and documented [National Collaborating Centre for Women's and Children's Health, 2006].

• Desmopressin should not be used in women with heart failure, psychogenic polydipsia, or polydipsia associated with alcohol dependence.
• Desmopressin should be used cautiously in people at higher risk of hyponatraemia, including those with [Micromedex, 2009]:
• The syndrome of inappropriate antidiuretic hormone secretion.
• Dipsogenic diabetes insipidus.
• Hepatic cirrhosis.
• Adrenal insufficiency.
• Hyperglycaemia.
• AIDS.
• Other drugs known to cause hyponatraemia.
• Desmopressin can also be used cautiously in women taking diuretics for conditions other than heart failure.

• Older people, particularly those who are hospitalized or living in long-term care facilities, are more at risk of drug-induced hyponatraemia [Kugler and Hustead, 2000; Palmer et al, 2003].
• Symptoms of hyponatraemia include [Baylis, 2003; Palmer et al, 2003]:
• Mild: anorexia, headache, nausea, vomiting, lethargy, oedema.
• Moderate: personality change, muscle cramps, muscle weakness, confusion, ataxia.
• Severe: drowsiness, convulsions, coma, death.
• Several drugs have been reported to cause hyponatraemia; those that are more commonly implicated include [Palmer et al, 2003; Liamis et al, 2008]:
• Diuretics: thiazides (such as bendroflumethiazide), indapamide, amiloride, loop diuretics (such as furosemide).
• Antidepressants: tricyclic antidepressants (such as amitriptyline), selective serotonin reuptake inhibitors (such as fluoxetine), monoamine oxidase inhibitors (such as phenelzine), venlafaxine.
• Antipsychotic drugs: phenothiazines (such as trifluoperazine), butyrophenones (such as haloperidol).
• Antiepileptics: carbamazepine, oxcarbazepine, sodium valproate.
• Desmopressin.

• Desmopressin is well tolerated at recommended doses.
• Adverse effects can include headache, abdominal pain, and nausea. Isolated cases of allergic skin reactions and more severe general allergic reactions have been reported.
• Water retention/hyponatraemia (due to fluid overload) occurs if treatment with desmopressin is undertaken without concomitant reduction of fluid intake.

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

• The manufacturer of desmopressin tablets warns that there may be an increased risk of water retention and/or hyponatraemia with [ABPI Medicines Compendium, 2008b]:
• Drugs known to induce syndrome of inappropriate antidiuretic hormone secretion (SIADH) (such as tricyclic antidepressants, selective serotonin re-uptake inhibitors, chlorpromazine, and carbamazepine).
• Concomitant treatment with loperamide — leading to an increased plasma concentration of desmopressin.
• However, the clinical significance of these interactions is unknown as CKS did not find any documented reports of these interactions in a standard reference textbook on drug interactions [Baxter, 2008].

• Topical oestrogens should be used in the lowest effective amount to minimize systemic absorption.
• Review at least annually to re-assess the need for continued treatment and to monitor for symptoms of endometrial hyperplasia or carcinoma in women with a uterus. For further information, see Adverse effects.
• Long term treatment may be required as symptoms can recur on cessation of therapy.
• For the treatment of atrophic vaginitis in post-menopausal women, licensed doses for intravaginal oestrogen preparations are:
• Intravaginal cream:
• Ovestin^® (estriol 0.1%): insert one applicatorful daily for 2–3 weeks, reducing to twice a week.
• Pessaries/vaginal tablets:
• Ortho-Gynest^® pessaries (estriol 500 micrograms): insert 1 pessary daily (preferably in the evening) until improvement occurs, reducing to a maintenance dose of one pessary twice a week.
• Vagifem^® vaginal tablets (estradiol 25 micrograms): insert one vaginal tablet daily for 2 weeks then reduce to one vaginal tablet twice a week.
• Vaginal ring:
• Estring^® (releasing approximately estradiol 7.5 micrograms over 24 hours): insert the ring into the upper third of the vagina. The ring is then worn continuously for 3 months before replacing with a new ring.
• For information on the duration of treatment, see Management of urgency incontinence symptoms/ overactive bladder.

[BNF 57, 2009]

• The manufacturers of topical oestrogens advise that these preparations are contraindicated in people with:
• Known, past, or suspected breast cancer.
• Known or suspected oestrogen-dependent malignant tumours (such as endometrial cancer).
• Undiagnosed genital bleeding.
• Untreated endometrial hyperplasia.
• Previous idiopathic or current venous thromboembolism (deep venous thrombosis, pulmonary embolism).
• Active or recent arterial thromboembolic disease (such as angina, myocardial infarction).
• Acute liver disease or a history of liver disease (if liver function tests have failed to return to normal).
• Known hypersensitivity to the active substances or to any of the excipients.
• Porphyria.
• If use is indicated in these people, consider seeking specialist advice.

[ABPI Medicines Compendium, 2006; ABPI Medicines Compendium, 2008c; ABPI Medicines Compendium, 2009a]

• Intravaginal oestrogens may cause local irritation or itching at the beginning of treatment. In general, these symptoms are transient.
• The British National Formulary advises that the endometrial safety of long-term or repeated use of topical vaginal oestrogens is uncertain.
• Consequently, treatment should be interrupted as least annually to re-assess the need for continued treatment. If breakthrough bleeding or spotting appears at any time on therapy, the reason should be investigated and may include endometrial biopsy to exclude endometrial malignancy.

[BNF 57, 2009]

• Manufacturers of intravaginal oestrogen preparations reported no clinical drug interactions with these products.

• Advise the woman that:
• Topical oestrogens should be used in the lowest effective dose to minimize systemic absorption.
• Medical advice should be sought if she experiences breakthrough bleeding or spotting at any time during treatment (see Adverse effects).
• Warn the woman that certain intravaginal oestrogen preparations can damage latex condoms and diaphragms (for example Ortho-Gynest^® cream and pessaries, and Ovestin^® cream).
• If in doubt, check the Summaries of Product Characteristics (SPCs) or the patient information leaflets.