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).

• Before starting risperidone, olanzapine, or quetiapine:
• Record the person's height and body weight, and measure plasma glucose and lipids.
• If the person has cardiovascular disease or risk factors for cardiovascular disease, do an electrocardiogram.
• If risperidone is to be prescribed, measure prolactin levels.
• After starting risperidone, olanzapine, or quetiapine:
• Measure plasma glucose and lipids (preferably fasting levels) at 3 months (or within 1 month if taking olanzapine).
• Measure body weight at 3 months, or more often if the person is gaining weight rapidly.
• For people maintained on risperidone, olanzapine, or quetiapine:
• If levels of plasma glucose or lipids are elevated, monitor regularly (every 3 months), or more often if there is evidence of elevated levels.
• Monitor body weight every 3 months, or more often if the person is gaining weight rapidly.
• If the person is taking risperidone, measure prolactin level if symptoms of raised prolactin develop (these include low libido, sexual dysfunction, menstrual abnormalities, gynaecomastia, and galactorrhea).

• Hyperglycaemia and sometimes diabetes can occur in people taking atypical antipsychotics. Monitoring weight and plasma glucose may identify the development of hyperglycaemia [BNF 56, 2008].
• Risperidone, olanzapine, and quetiapine can all increase lipid levels [Taylor et al, 2007].
• Risperidone can cause elevated prolactin levels [ABPI Medicines Compendium, 2008d].

• Adverse effects of the atypical antipsychotics include weight gain, dizziness, and postural hypotension (especially during initial dose titration) which may be associated with syncope or reflex tachycardia in some people.
• Extrapyramidal symptoms may occur. These are usually mild and transient, and may respond to dose reduction or to an antimuscarinic drug (e.g. procyclidine).
• Tardive dyskinesia can occur on long-term administration. The drug should be discontinued on appearance of early signs.
• Risperidone can cause elevated prolactin levels.
• Hyperglycaemia, and sometimes diabetes, can occur, particularly with clozapine and olanzapine; monitoring weight and plasma glucose may identify the development of hyperglycaemia.
• Atypical antipsychotics may affect performance of skilled tasks (e.g. driving); effects of alcohol are enhanced.
• Olanzapine and risperidone are associated with an increased risk of stroke in elderly people with dementia. The Committee on Safety of Medicines has advised [CSM, 2004] that:
• Risperidone or olanzapine should not be used for treating behavioural symptoms of dementia.
• For acute psychotic conditions in elderly people with dementia, risperidone should be limited to short-term use under specialist advice; olanzapine is not licensed for acute psychosis.
• The possibility of cerebrovascular events should be considered carefully before treating people with a history of stroke or transient ischaemic attack; risk factors for cerebrovascular disease (e.g. hypertension, diabetes, smoking, and atrial fibrillation) should also be considered.

[BNF 56, 2008]

• People with known risk for narrow-angle glaucoma should not receive olanzapine [ABPI Medicines Compendium, 2008b].
• While atypical antipsychotics have not generally been associated with clinically significant prolongation of the QT interval, they should be used with care if prescribed with other drugs that increase the QT interval.
• Atypical antipsychotics should be used with caution in people with cardiovascular disease or a history of epilepsy [BNF 56, 2008].

• Atypical antipsychotics such as quetiapine, olanzapine, and risperidone have not generally been associated with clinically significant prolongation of the QT interval. However, they should be used with care if prescribed with other drugs that increase the QT interval (e.g. antiarrhythmics).
• There is an increased risk of central nervous system toxicity when antipsychotics are given with sibutramine, and the manufacturer of sibutramine advises against concomitant use.
• The plasma concentration of quetiapine may be increased by fluconazole, itraconazole, and ketoconazole, so the dose of quetiapine should be reduced.
• Smoking induces the metabolism of olanzapine and clozapine. If the person stops smoking, monitor for increased adverse effects and seek advice about dose adjustment if necessary.

[BNF 56, 2008; MHRA, 2009b]

• Measure full blood count, liver function tests, urea, and electrolytes before starting treatment and every 6 months during treatment.
• Stop treatment if leucopenia develops that is severe, progressive, or accompanied by clinical symptoms (e.g. fever or sore throat), or if there is any evidence of significant bone marrow depression.
• Stop treatment immediately if acute liver dysfunction develops.
• Monitor body weight in people who gain weight rapidly.
• Measure plasma levels of carbamazepine every 6 months to exclude toxicity, because therapeutic levels and toxic levels are close.
• A plasma level of at least 7 mg/L seems to be required in affective illness.
• Most adverse effects of carbamazepine increase in severity and frequency when the plasma level is greater that 12 mg/L, but this varies substantially from person to person.

• These recommendations are consistent with guidelines, expert opinion, and the manufacturer's recommendations [London and South East Medicines Information Service et al, 2008].
• Measuring plasma levels:
• These recommendations are taken from guidance published by the National Institute for Health and Clinical Excellence; Bipolar disorder: the management of bipolar disorder in adults, children and adolescents, in primary and secondary care [National Collaborating Centre for Mental Health, 2006].

• Advise the person and their carers how to recognize the signs and symptoms of:
• Blood disorders (e.g. unexplained bleeding, bruising, purpura, sore throat, fever, or malaise).
• Liver disorders (e.g. sudden loss of strength, malaise, anorexia, lethargy, oedema and drowsiness [sometimes associated with repeated vomiting and abdominal pain], and jaundice).
• The person should seek immediate medical help if these develop.

[National Collaborating Centre for Mental Health, 2006; BNF 56, 2008]

• Common adverse effects include nausea and vomiting, sedation, dizziness, and ataxia.
• These adverse effects are dose-related and are most common at the start of treatment.
• Allergic skin reactions (including urticaria, which may be severe) are also common.
• Withdraw carbamazepine if a skin reaction worsens or is accompanied by other symptoms.
• Rarely, serious dermatological adverse effects, including Stevens–Johnson syndrome and exfoliative dermatitis, can occur.
• People who are Han Chinese, Hong Kong Chinese, or of Thai origin should be screened for the presence of the HLA-B*1502 allele before taking carbamazepine.
• People who test positive should not start carbamazepine unless the benefits clearly outweigh the risks of Stevens–Johnson syndrome.
• Hyponatraemia occurs in 20% of people taking carbamazepine, but is usually mild.
• If the hyponatraemia is clinically significant, restriction of fluid intake or a slight reduction in the dose of carbamazepine usually resolves the issue.
• Leucopenia (very common) and other blood disorders, including thrombocytopenia, agranulocytosis, and aplastic anaemia (rare), can occur with carbamazepine treatment.
• There is a small risk of suicidal thoughts and behaviour, which may be seen as early as one week after starting treatment.
• People taking carbamazepine and healthcare professionals should be alert to any mood changes, distressing thoughts, or feelings about suicide or harming themselves at any point during treatment.

[ABPI Medicines Compendium, 2008c; BNF 56, 2008; MHRA, 2008a; Micromedex, 2009; MHRA, 2008b]

• Information regarding adverse effects is taken from the British National Formulary, Micromedex, the Summary of Product Characteristics for Tegretol^®, and the Medicines and Healthcare products Regulatory Agency [ABPI Medicines Compendium, 2008c; BNF 56, 2008; MHRA, 2008b; Micromedex, 2009].
• The recommendation to screen people who are Han Chinese, Hong Kong Chinese, or of Thai origin for the presence of the HLA-B*1502 allele before starting carbamazepine comes from the Medicines and Healthcare products Regulatory Agency [MHRA, 2008a].

• Carbamazepine is contraindicated in people:
• With atrioventricular block.
• With a history of bone marrow depression.
• Taking a monoamine oxidase inhibitor (MAOI).
• Who have porphyria.

[ABPI Medicines Compendium, 2008a; BNF 56, 2008]

• The plasma concentration of carbamazepine may be increased (increasing the risk of toxicity) by the concomitant use of:
• Azole antifungals.
• Cimetidine.
• Danazol.
• Macrolide antibiotics (clarithromycin and erythromycin).
• Selective serotonin reuptake inhibitors (fluoxetine and fluvoxamine).
• Carbamazepine accelerates the metabolism of:
• Ciclosporin — leading to reduced levels of ciclosporin.
• Clozapine — leading to reduced plasma concentration of clozapine; also avoid concomitant use of drugs with a potential for causing agranulocytosis.
• Corticosteroids (systemic) — leading to reduced steroidal effect.
• Oestrogens and progestogens — oral contraceptives become less effective, so recommend alternative method of contraception.
• Tricyclic antidepressants (TCAs) — leading to reduced effect of TCAs.
• Warfarin — leading to reduced anticoagulant effect.
• The use of carbamazepine is not recommended in combination with monoamine oxidase inhibitors (MAOIs), or for 2 weeks after stopping an MAOI.
• St John's wort reduces plasma levels of carbamazepine.

[ABPI Medicines Compendium, 2008c; Baxter, 2008; BNF 56, 2008; Micromedex, 2009]

• Advise the person to seek medical attention urgently if a rash develops or there are symptoms and signs of bone marrow failure (e.g. anaemia, bruising, or infection).

[National Collaborating Centre for Mental Health, 2006; BNF 56, 2008]

• Skin rash:
• All people (adults and children) who develop a rash should be promptly evaluated and lamotrigine withdrawn immediately unless the rash is clearly not drug related.
• Rash has been reported in up to 10% of people taking lamotrigine in clinical trials. These rashes were maculopapular in appearance, generally appeared within 8 weeks of starting treatment, and resolved on withdrawal of lamotrigine.
• Serious, potentially life threatening, skin rashes, including Stevens–Johnson syndrome and toxic epidermal necrolysis (Lyell Syndrome) have been reported. The approximate incidence of serious skin rashes reported as Stevens–Johnson syndrome in adults and children older than 12 years of age is 1 in 1000. Children younger than 12 years of age are at higher risk. Available data from a number of studies suggest that the incidence in children younger than 12 years of age requiring hospitalization due to rash ranges from 1 in 300 to 1 in 100.
• In children, the initial presentation of a rash can be mistaken for an infection; clinicians should consider the possibility of a drug reaction in children that develop symptoms of rash and fever during the first 8 weeks of therapy.
• Factors associated with increased risk of serious skin reactions include:
• Concomitant use of valproate, initial lamotrigine dosage higher than recommended, and more rapid dose escalation than recommended.
• Rash is sometimes associated with hypersensitivity syndrome and is more common in people with a history of allergy or rash from other antiepileptic drugs.
• Other adverse effects reported include headache, tiredness, nausea, dizziness, drowsiness and insomnia, diplopia, blurred vision, conjunctivitis, gastrointestinal disturbance (including vomiting and diarrhoea), irritability or aggression, tremor, agitation, confusion, and hallucinations.
• Rarely reported adverse effects include:
• Hypersensitivity syndrome: rash, fever, lymphadenopathy, hepatic dysfunction, blood disorders, disseminated intravascular coagulation, and multiorgan dysfunction.
• Blood disorders: leucopenia, thrombocytopenia, pancytopenia.
• Lupus-like reactions.
• There is a small risk of suicidal thoughts and behaviour, which may be seen as early as one week after starting treatment [MHRA, 2008b].
• People taking lamotrigine and healthcare professionals should be alert to any mood changes, distressing thoughts, or feelings about suicide or harming themselves at any point during treatment.

• Plasma concentration of lamotrigine is reduced by phenytoin, primidone, oestrogens, and progestogens. The dose of lamotrigine may need to be increased.
• Plasma concentration of lamotrigine is increased by valproate.

[BNF 56, 2008]

• Always prescribe lithium by brand name.
• Lithium is available as two salts, lithium carbonate and lithium citrate, which are not dose equivalent.
• Lithium carbonate is supplied in tablet form (Camcolit^®, Liskonum^®, and Priadel^®).
• Lithium citrate is supplied as a liquid (Priadel^® liquid and Li-Liquid^®).
• One 5 mL spoonful of Priadel^® liquid (520 mg lithium citrate) is equivalent to 204 mg lithium carbonate.
• One 5 mL spoonful of Li-Liquid^® (509 mg lithium citrate) is equivalent to 200 mg lithium carbonate.
• All lithium preparations vary widely in bioavailability and lack of clarity over which preparation is intended can lead to the person receiving a subtherapeutic or toxic dose.
• The lithium dose is usually adjusted to achieve a plasma level of 0.6 mmol/L to 1 mmol/L.
• A serum lithium level of 0.6–0.8 mmol/L is suitable for people who are being prescribed lithium for the first time.
• Higher serum lithium levels (0.8–1.0 mmol/L) are suitable for people who have relapsed previously while taking lithium or who still have sub-threshold symptoms with functional impairment while receiving lithium.

[National Collaborating Centre for Mental Health, 2006; BNF 56, 2008; MHRA, 2009a; ABPI Medicines Compendium, 2010]

• People taking lithium should be advised:
• To carry a lithium card.
• That regular blood tests are important and the results should be recorded in their lithium record booklet.
• About what adverse effects to expect.
• How to recognize the symptoms of lithium toxicity.
• Not to take over-the-counter nonsteroidal anti-inflammatory drugs.
• That episodes of diarrhoea or vomiting, or any form of dehydration, will lead to sodium depletion and therefore increased plasma lithium levels.
• To maintain their fluid intake, particularly after sweating (for example, after exercise, in hot climates, or if they have a fever), if they are immobile for long periods, or — in the case of older people — if they develop a chest infection or pneumonia.
• That if a dose is missed they should take it as soon as possible; but if yesterday's dose was missed then they should not double today's dose.
• Not to stop taking lithium abruptly, and that non-compliance may lead to a relapse.
• Women of childbearing age should be advised to use reliable contraception.

[National Collaborating Centre for Mental Health, 2006; National Patient Safety Agency, 2009]

• Lithium levels are normally measured 1 week after starting therapy, 1 week after every dose change, and weekly thereafter until the levels are stable. Once the person is stable, lithium levels are measured every 3 months.
• Levels should be measured 12 hours post-dose.
• Baseline renal function tests, thyroid function tests, and a full blood count are normally measured at the start of treatment. Thereafter thyroid and renal function tests should be monitored every 6 months (or more often if there is evidence of impaired renal function).
• If there is a risk factor for, or existing, cardiovascular disease, an electrocardiogram is normally performed before treatment begins.
• The person's height and body weight should be recorded at the start of treatment. Monitoring of weight is only required after this if there is rapid weight gain.
• Record the results of blood tests in the persons lithium record booklet.
• Copies of this booklet can be obtained from nhsforms@spsl.uk.com.

[National Collaborating Centre for Mental Health, 2006; National Patient Safety Agency, 2009]

• Lithium toxicity occurs at serum lithium concentrations of about 1.5 mmol/L and above, but may occur despite an apparently normal plasma level.
• Signs of toxicity include increasing diarrhoea, vomiting, anorexia, muscle weakness, lethargy, giddiness, ataxia, lack of coordination, tinnitus, blurred vision, coarse tremor of the extremities and lower jaw, muscle hyper-irritability, choreoathetoid movements, dysarthria, and drowsiness.
• Severe lithium toxicity occurs at serum lithium concentrations of about 2 mmol/L and above. Signs include, hyper-reflexia and hyperextension of limbs, syncope, toxic psychosis, seizures, polyuria, renal failure, electrolyte imbalance, dehydration, circulatory failure, coma, and occasionally death.
• The risk of toxicity is greater in people with hypertension, diabetes, congestive heart failure, chronic renal failure, schizophrenia, or Addison's disease.

[Sweetman, 2005; ABPI Medicines Compendium, 2006b]

The National Patient Safety Agency has developed a lithium patient information booklet. Copies can be obtained from nhsforms@spsl.uk.com.

• This information is taken from Martindale: the complete drug reference [Sweetman, 2005] and from information published by manufacturers of lithium [ABPI Medicines Compendium, 2006b].

• Stop lithium therapy and refer the person urgently to secondary care.
• There is no specific antidote to lithium poisoning. In secondary care the treatment is supportive and lithium levels are normally redetermined every 6–12 hours.

• Referral to secondary care is recommended because the person will require supportive treatment. This may include measuring their lithium levels every 6–12 hours, and administering generous amounts of sodium salts and fluids. Depending on the severity, dialysis may be required [NPIS, 2005].

• Initial adverse effects of lithium therapy include nausea, diarrhoea, vertigo, muscle weakness, and a dazed feeling. These effects often abate with continued therapy. Fine hand tremors, polyuria, and polydipsia may persist.
• Adverse effects tend to be directly related to plasma levels and their frequency increases dramatically at levels greater than 1 mmol/L. For more information see Recognizing lithium toxicity.
• Longer-term adverse effects include:
• Hypothyroidism: there is a small risk that people taking lithium at therapeutic doses may develop clinical goitre, hypothyroidism, or both; the risk appears to be greatest in the first 2 years of treatment. Although this may occur, it should not be a reason for stopping lithium treatment. Levothyroxine replacement is usually indicated. Thyroxine function tests usually return to normal when lithium is discontinued.
• Hyperthyroidism: lithium-associated thyrotoxicosis is rare and occurs mainly after long-term use. It should not constitute an absolute contraindication to lithium treatment. Specialist advice should be sought regarding management.
• Hyperparathyroidism: lithium use has been associated with hypercalcaemia accompanied by elevations in circulating parathyroid hormone (PTH). The coexistence of hypercalcaemia and elevated PTH levels suggests primary hyperparathyroidism. However, significantly greater serum levels of calcium are probably required to inhibit PTH secretion during lithium therapy. The presence of mild hypercalcaemia with elevated PTH is consistent with lithium-induced hyperparathyroidism. Parathyroid surgery is not indicated in this situation, and withdrawal of lithium will result in prompt normalization of serum calcium and PTH levels.
• Nephrotoxicity: a small reduction in glomerular filtration rate is seen in 20% of people taking lithium. In the vast majority of these people this effect is benign. A very small number of people taking lithium may develop interstitial nephritis. Lithium can also cause a reduction in urinary concentrating capacity (nephrogenic diabetes insipidus, with symptoms of thirst and polyuria) which is reversible in the short-to-medium term, but may be irreversible after long-term treatment (greater than 15 years).

[Bocchetta and Loviselli, 2006; BTA et al, 2006; Taylor et al, 2007]

The National Patient Safety Agency has developed a lithium patient information booklet. Copies can be obtained from nhsforms@spsl.uk.com.

• People who should not take lithium include those:
• With cardiac disease.
• With clinically significant renal impairment.
• With untreated hypothyroidism.
• Who are breastfeeding.
• With low body-sodium levels, including for example people that are dehydrated and those on low-sodium diets.
• With Addison's disease.

[ABPI Medicines Compendium, 2006a]

• Because of lithium's narrow therapeutic index, interactions with other drugs can be very important. The most commonly encountered interactions are with:
• Diuretics: thiazide diuretics can increase serum lithium levels by reducing clearance of lithium. People who are stabilized on lithium and begin taking thiazide diuretics are at significant risk of developing lithium toxicity. Toxic lithium concentrations may be seen within 3–5 days. Loop diuretics also cause lithium retention but are less likely to result in lithium toxicity.
• Nonsteroidal anti-inflammatory drugs (NSAIDs) may increase serum lithium levels by up to 40%. The mechanism of this interaction is thought to be related to the effects of NSAIDs on fluid balance. This is particularly important if NSAIDs are added to a long-standing prescription of lithium.
• Haloperidol: although severe neurotoxicity has been reported with this combination, if lithium levels are maintained in the therapeutic range (0.6–1.0 mmol/L) and the haloperidol dose is not increased rapidly above the recommended maximum, the chance of inducing a toxic state is very low.
• Carbamazepine in combination with lithium has been reported to cause neurotoxic reactions. Higher (greater than 1 mmol/L) plasma lithium levels were involved than are now thought acceptable, so a neurotoxic reaction to lithium alone was a risk factor. Carbamazepine and lithium may therefore be usefully co-prescribed.
• Antidepressants with a serotonergic action (such as selective serotonin reuptake inhibitors, tricyclic antidepressants, venlafaxine, duloxetine) have rarely been linked to an increased incidence of central nervous system toxicity when used with lithium. The mechanism of this interaction is not well understood. Prescribers should check lithium levels soon after starting treatment with a serotonergic antidepressant, although there are some reports of neurotoxic reactions in the absence of raised lithium levels.
• ACE inhibitors decrease the excretion of lithium. They can also precipitate renal failure. If these two drugs are prescribed together, extra care is required in monitoring both serum creatinine and lithium.

[Sweetman, 2005; ABPI Medicines Compendium, 2006a; Taylor et al, 2007]

• Monitor the person closely in the early stages of treatment, irrespective of which antidepressant is prescribed, to assess response, adverse effects, compliance, and suicide risk. People considered at increased risk of suicide should be seen at least once a week.
• Hyponatraemia has been associated with all types of antidepressant [CSM, 2000b].
• Consider hyponatraemia in people taking antidepressants who develop drowsiness, confusion, nausea, muscle cramps, or seizures.
• Risk factors for developing hyponatraemia include a history of hyponatraemia, extreme old age, diuretics, diabetes mellitus, hypertension, reduced renal function, and chronic obstructive pulmonary disease.

[Taylor et al, 2007]

• Advise the person that:
• Craving and tolerance do not occur, and that taking medication should not be seen as a sign of weakness.
• Manic or hypomanic switching may occur.
• There may be a delay in the onset of effect, with a gradual and fluctuating improvement.
• Medication should be taken as prescribed.
• Stopping the treatment may result in withdrawal symptoms such as gastrointestinal disturbances, headache, anxiety, dizziness, paraesthesia, sleep disturbances, fatigue, influenza-like symptoms, and sweating.
• The dose is usually tapered down over a few weeks to avoid withdrawal effects.
• They should be aware of symptoms of akathisia (e.g. restlessness), suicidal ideation, and increased anxiety and agitation (particularly in the initial stages of treatment). They should seek help promptly if these adverse effects are distressing.

[National Collaborating Centre for Mental Health, 2006]

• Common adverse effects of selective serotonin reuptake inhibitors (SSRIs) include:
• Gastrointestinal effects (dose-related and fairly common — including nausea, vomiting, dyspepsia, abdominal pain, diarrhoea, and constipation), and anorexia with weight loss. Increased appetite and weight gain have also been reported.
• Hypersensitivity reactions may also occur. These include rash (consider discontinuation — rash may be a sign of an impending serious systemic reaction, possibly associated with vasculitis), urticaria, angioedema, anaphylaxis, arthralgia, myalgia, and photosensitivity.
• Other less common adverse effects include dry mouth, nervousness, anxiety, headache, insomnia, tremor, dizziness, asthenia, hallucinations, drowsiness, convulsions, galactorrhoea, sexual dysfunction, urinary retention, sweating, hypomania or mania, movement disorders and dyskinesias, visual disturbances, hyponatraemia, and bleeding disorders including ecchymoses and purpura.
• Suicidal behaviour has been linked with antidepressants.
• Angle-closure glaucoma may very rarely be precipitated by treatment with SSRIs.

[BNF 56, 2008]

• Antidepressants should be avoided for people with depressive symptoms who have:
• Rapid-cycling bipolar disorder.
• Recent hypomanic episode.
• Recent functionally-impairing rapid mood fluctuations.

[National Collaborating Centre for Mental Health, 2006]

• St John's wort should be stopped in people taking a selective serotonin reuptake inhibitor (SSRI) because of the risk of increased serotonergic effects and the increased incidence of adverse effects [CSM, 2000a]. Advise people that they should not take St John's wort while they are taking an SSRI.
• 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 [Baxter, 2008].
• 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 the 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, 2007].

• Valproate is available in the UK in three forms:
• Semisodium valproate (Depakote^®) is licensed for the treatment of acute mania (but is not licensed for use in children).
• Sodium valproate (Epilim^®) and valproic acid (Convulex^®) are both unlicensed for the treatment of bipolar disorder at the time of writing.
• However, a more recent review of valproate for bipolar disorder by the European Medicines Agency (EMEA) has concluded that the benefits of valproate for bipolar disorder outweigh the risks and has concluded that all product licences for medicines containing valproate should be amended to include the treatment of manic episodes in bipolar disorders when lithium is contraindicated or not tolerated [EMEA, 2009].
• Both semisodium and sodium valproate are metabolized to valproic acid, which is responsible for the pharmacological activity of all three preparations.

• Advise the person and their carers how to recognize the signs and symptoms of:
• Blood disorders (e.g. any unexplained bleeding, bruising, purpura, sore throat, fever, or malaise that occurs during treatment).
• Liver disorders (e.g. sudden onset of asthenia, malaise, anorexia, lethargy, oedema and drowsiness [which are sometimes associated with repeated vomiting and abdominal pain], and jaundice).
• Pancreatitis (e.g. abdominal pain, nausea, and vomiting).
• They should seek immediate medical help if these develop.

[National Collaborating Centre for Mental Health, 2006; BNF 56, 2008]

• Before starting treatment, a full blood count, baseline liver function tests (LFTs), height, and body weight are usually measured.
• LFTs and a full blood count should be repeated 6 months after treatment has been initiated. Monitoring of weight is only required in people who gain weight rapidly.
• Valproate levels are not routinely measured unless there is evidence of ineffectiveness, poor adherence, or toxicity.

[National Collaborating Centre for Mental Health, 2006]

• Adverse effects include:
• Gastric irritation, which can lead to intense nausea.
• Lethargy and confusion. This can occur with starting doses of more than 750 mg a day.
• Weight gain (which may be significant).
• Hair loss, with curly regrowth and peripheral oedema.
• Very rarely, fulminant hepatic failure.
• Hyperandrogenism in women. This has been linked to the development of polycystic ovaries.
• Thrombocytopenia, leucopenia, red cell hypoplasia, and pancreatitis.
• There is a small risk of suicidal thoughts and behaviour, which may be seen as early as one week after starting treatment.
• People taking valproate and healthcare professionals should be alert to any mood changes, distressing thoughts, or feelings about suicide or harming themselves at any point during treatment.

[Taylor et al, 2007; MHRA, 2008b]

• People who should not receive valproate include those with:
• Active liver disease.
• Personal or family history of severe, drug-related, hepatic dysfunction.
• Porphyria.
• Valproate should not be prescribed for women who are of childbearing age, or who are pregnant.

[National Collaborating Centre for Mental Health, 2006; ABPI Medicines Compendium, 2007]

• Valproate is highly protein bound (up to 94%), and other drugs that are also highly protein bound (e.g. aspirin) may displace valproate from albumin and precipitate toxicity.
• Other less strongly protein-bound drugs (e.g. warfarin) can be displaced by valproate; this may lead to higher free levels and increased therapeutic effect or toxicity of the concomitant drug.
• Valproate is metabolized by the liver, so drugs that inhibit cytochrome P450 enzymes (e.g. erythromycin, fluoxetine, and cimetidine) can increase valproate levels.
• Valproate can increase the plasma levels of some drugs, possibly by inhibition of their metabolism (e.g. tricyclic antidepressants, particularly clomipramine).

[Taylor et al, 2007]