Phenytoin

Phenytoin has been used for over 50 years. Thus, the characteristics and side-effects have been well elucidated. Its primary use is for treatment of partial epilepsy, including simple and complex partial seizures, as well as generalized tonic-clonic seizures, whether of primary or partial onset. Phenytoin can be initiated with a ‘loading dose’ of 13-20mg/kg, or with a starting dose of 3-5 mg/kg/day. Phenytoin was one of the first anti-epileptic drugs that became associated with a ‘therapeutic range’ (10-20 mg/1 in most laboratories), which represents serum concentrations most likely to produce a therapeutic effect without substantial dose-related side-effects. The phenytoin dose should be selected using therapeutic monitoring rather than a predetermined dose, such as 300 mg/day. As the serum level increases, side-effects such as lethargy, ataxia, dysarthria, fatigue, diplopia, abnormal movements, mental confusion and cognitive changes may occur. This is particularly true at concentrations above 20 mg/1. However, the therapeutic range represents an average. A number of patients may remain seizure-free at serum concentrations below the range, or may tolerate levels substantially above the range. However, it is very important to understand the properties of phenytoin metabolism. As serum concentrations rise, particularly to levels above 15 mg/1, the metabolism of phenytoin slows substantially. This is called ‘zero order kinetics’. At levels below 15 mg/1, doubling the dose will lead to a doubling of serum concentration, and the half-life is 24 h. As metabolism slows at higher concentrations, even a 50-mg change in dose can double the serum concentration, and the half-life increases to 48-70 h. Since the half-life is so prolonged, a steady state after dose adjustments may not occur for weeks, with serum levels slowly rising over this time. This can easily lead to serious phenytoin toxicity. Hospitalization due to phenytoin toxicity under these circumstances is not uncommon. Dosage adjustments must be made with great care, and levels should be repeated a month after any adjustment. In addition to dose-related toxicities, patients receiving phenytoin may experience side-effects that are relatively independent of dose. These include gingival hyperplasia, acne and hirsutism. Visits to the dentist every 6-12 months, accompanied by daily flossing, can help prevent gingival hypertrophy. There is now fairly substantial evidence that long-term phenytoin use can lead to reduced bone density and risk of fracture. Obviously, this is a major issue for patients who fall with their seizures. All patients receiving phenytoin should receive supplemental calcium and vitamin D, and should be screened with bone densitometry. Allergic rash may occur. Although idiosyncratic side-effects are not common, they can occur, and patients should be advised of this possibility. These include Stevens-Johnson syndrome, aplastic anaemia, hepatic failure and a lupus-like syndrome. Monitoring of blood counts, liver function tests and electrolytes are warranted for the first 6-12 months of therapy. Drug interactions are relatively common, both with other epilepsy drugs and with drugs taken for other conditions. Interactions with other anti-epileptic drugs are listed in Because of phenytoin’s relatively long half-life, it can be administered only once or twice a day.

Carbamazepine

Carbamazepine has long been considered a first-line agent for simple partial, complex partial and generalized tonic-clonic seizures. Recently, many studies have compared the newer anti-epileptic drugs to carbamazepine as the ‘gold standard’ in patients with newly diagnosed epilepsy, and to date, none has been found to be more effective.

Table Pharmacokinetic impact of old anti-epileptic drugs (anti-epileptic drugs) on new anti-epileptic drugs. -I, levels decrease (faster clearance); T, levels increase (slower clearance)

Table Pharmacokinetic impact of new anti-epileptic drugs (anti-epileptic drugs) on old anti-epileptic drugs. -I, levels decrease (faster clearance); T, levels increase (slower clearance)

However, lamotrigine, topiramate and oxcarbazepine all caused fewer dropouts due to side-effects than carbamazepine. Of note, it is considered ‘narrow spectrum’, and may actually worsen generalized epilepsies, particularly those associated with absence or myoclonus. Initiation must be done with titration, to avoid appearance of dose-related side-effects. Dose selection should be done using clinical response and serum levels. Typically, a level of 8-12mgA will provide the best response, and few patients will tolerate serum concentrations above 15mg/l. Dose-related adverse effects include ataxia, drowsiness, vertigo, difficulty concentrating, diplopia and blurred vision. Using sustained-release formulations of carbamazepine will reduce some of these side-effects by reducing peak serum concentrations. The other advantage is the ability to use twice-a-day dosing, rather than the three- to four-times-a-day dosing that would otherwise be necessary due to the short half-life of carbamazepine. Gastrointestinal symptoms such as nausea, vomiting, diarrhoea and constipation may also be seen. The other side-effects of carbamazepine are not necessarily linked to dose. These include more common, but less serious, effects such as leucopenia, hyponatraemia and rash as well as life-threatening but extremely rare idiosyncratic reactions such as Stevens-Johnson syndrome, aplastic anaemia and hepatic failure. Mild leucopenia can be disregarded. Rarely, more profound leucopenia (with leucocyte counts <2.5xl0⁹) may necessitate discontinuation of therapy. Hyponatraemia does not necessitate discontinuation in all patients, as it can often be managed with water restriction. However, in some patients water restriction does not work, or too severely impacts lifestyle, and in these patients an alternative anti-epileptic drug should be sought. Because of the potential for all of the above issues, monitoring of liver function tests, white blood counts and electrolytes are necessary during the first 6-12 months of therapy, and yearly thereafter. The potential for carbamazepine to produce decreased bone density is under study. Of note, chronic carbamazepine use has been associated with some reduction in serum testosterone levels and increases in cholesterol levels. The clinical implications of these changes are under study. As with phenytoin, carbamazepine is associated with many drug interactions affecting anti-epileptic drugs and other drugs. Because many drugs can inhibit or induce the metabolism of carbamazepine, and cause acute toxicity or reduced effect, it is a good idea to tell patients to inform their neurologist when starting any prescription drug. Carbamazepine, even in the extended-release formulations, is substantially less expensive than the newer anti-epileptic drugs.

Phenobarbital

Phenobarbital is the ‘grandfather of anti-epileptic drugs’. It has been available for over 100 years. It is effective for most seizure types and the fact that an intravenous (i.v.) formulation is available means it is often used for treatment of status epilepticus. In the modern era, it is rarely used as first-line therapy, as studies have demonstrated that it causes more dose-related side-effects, particularly sedation, than other options. Also, once started it is very difficult to withdraw without causing seizure exacerbation. Abrupt withdrawal is not recommended, and even slow withdrawal can lead to problems. The initial dose is 30-50 mg, which is best administered at bedtime. Titration to optimal dose can be achieved over several weeks. Optimal effect is usually achieved at serum concentrations of 15-45 mg/1. Other dose-related side-effects include irritability, difficulty concentrating, memory loss, sedation, dysarthria and ataxia. Other reported adverse reactions include hyperactivity, mostly in children, and depression. As with phenytoin and carbamazepine, hypersensitivity syndrome, rash, hepatic failure and aplastic anaemia may occur. Since many patients who are currently on phenobarbital have been on it long term, an understanding of long-term side-effects is important. Some unique side-effects occur with long-term phenobarbital use, affecting the skin and connective tissue. These may include contractures, frozen shoulder and general pain. Drug interactions may occur with phenobarbital . It is the least expensive anti-epileptic drug, costing pennies a day, and its long half-life permits once-a-day dosing, which is important for potentially non-compliant patients.

Primidone

Primidone is no longer considered a first-line drug, and its use has diminished substantially. It is metabolized to a number of active metabolites, including phenobarbital and phenylethylmalonamide, although the parent compound is also active. When obtaining serum levels, therapeutic effect will be associated with both the parent primidone levels and phenobarbital levels. In the presence of enzyme-inducing drugs, primidone levels will go down, and phenobarbital levels will rise. Primidone causes all the problems seen with phenobarbital use, described above.

Valproate

Valproate has been available since the 1970s, but remains the first-line drug for many epilepsy syndromes, including juvenile myoclonic epilepsy and syndromes associated with absence seizures. Valproate may be the only effective agent for some patients. A recent large randomized open-label trial demonstrated superior efficacy compared with lamotrigine, and superior tolerability compared with topiramate, in adults and children with idiopathic generalized or unclassified epilepsy. Seizure control was maintained in the majority for 5 years.

In some countries, valproate is also used as first-line therapy for partial seizures. In a head-to-head study, valproate was as effective for generalized tonic-clonic convulsions as carbamazepine in patients with partial epilepsy, but was found to be less effective for complex partial seizures. However, in other studies, the efficacy was equivalent in all seizure types, when valproate was compared with phenytoin, carbamazepine or oxcarbazepine. Valproate is available in a variety of formulations, including sustained release, sprinkles and i.v.. With the availability of i.v., valproate has become more popular for treatment of status epilepticus. Typical initiation in outpatients is at a dose of 10—15mg/ kg/day, with subsequent increases of 5-10mg/kg/week as needed to control seizures. Serum levels between 50 and 100 mg/1 are typically therapeutic and well tolerated, but higher concentrations may be necessary in some patients.

Skin rashes are less common with valproate than with carbamazepine, phenytoin and lamotrigine, and therefore valproate is a reasonable choice for patients with a history of hypersensitivity. The main side-effects are Gastrointestinal upset, nausea, vomiting, tremor, weight gain and hair loss. Tremor and weight gain are dose related. Gastrointestinal upset can sometimes be avoided by using alternative formulations, such as sustained release or sprinkles. Elevated ammonia levels can be seen commonly, affecting 20-50% of patients. In some patients this is well tolerated and not problematic, while in others elevated ammonia can be associated with encephalopathy, triphasic waves and even coma. It is not recommended to monitor ammonia in asymptomatic patients. However, if patients demonstrate encephalopathy, particularly in the presence of asteryxis and/or delta slowing on the electroencephalogram, it is reasonable to check for hyperammonaemia. Carnitine supplementation has been recommended to improve valproate-induced hyperammonaemia. Idiosyncratic side-effects include rare fatal hepatotoxicity. The incidence is 1 in 20 000 in adults on monotherapy, but much more common in polytherapy, in children under 10 years old, and even more so in children under 2 years old. Children who have seizures resulting from metabolic disorders may be at extremely high risk, and as a rule should not be treated with valproate. When children on polytherapy under the age of 2 are treated, the reported incidence is as high as 1 in 600-800. The greatest risk is in the first 6 months of use, and clinical as well as blood monitoring is indicated during this time. Pancreatitis may also occur, which may have a frequency of up to 1 in 3000. The risk of pancreatitis does not diminish over time. Aplastic anaemia is rare, but thrombocytopenia and altered bleeding time are common. These are usually not clinically worrisome, and low platelet counts can usually be tolerated as they do not portend more significant blood dyscrasias. Some case reports note increased risk of bleeding during surgery in patients on valproate, whereas many others note no increase in bleeding. Recently, a number of studies have reported adverse fetal outcomes in offspring of women receiving valproate. Spina bifida is seen in up to 2% of children exposed to valproate before birth. This makes valproate a poor choice for women contemplating pregnancy. In some studies, valproate has also been associated with development of polycystic ovarian syndrome. This appears to be more prevalent when valproate is initiated in women under 40. Reports of menstrual cycle irregularities are common.

One property of valproate that must be kept in mind is that it is a hepatic metabolic inhibitor. This has a number of consequences, including a number of interactions with other anti-epileptic drugs as well as drugs of different classes. In addition, intrinsic substances such as oestrogen may be inhibited. Valproate is highly protein bound. It may displace phenytoin from binding sites, causing emergence of phenytoin toxicity in the absence of an increased plasma level.

Ethosuximide

Ethosuximide has a very narrow therapeutic indication, with use limited to patients with absence seizures. In most cases, it should be used as the sole agent only in patients who experience this seizure type in isolation, a condition seen primarily in childhood. Occasionally, in patients with primary generalized epilepsy with seizure types other than absence, addition of ethosuximide as an adjunctive medication may improve seizure control. Ethosuximide can be started at 500 mg/day, and titrated as tolerated, with weekly increments. Serum concentrations of 40-100 mg/1 are usually optimal. The most common side-effects noted with ethosuximide use include nausea and abdominal discomfort, drowsiness, anorexia and headache. In rare cases, behavioural changes may be seen, including psychosis. Blood dyscrasias have been reported. Drug-drug interactions are minimal.

Benzodiazepines

Available benzodiazepines for chronic use include clonazepam, clorazepate and clobezam. Most benzodiazepines are not good choices for long-term therapy and should not be used as first-line agents. Patients may develop tolerance to the therapeutic effects of many of the benzodiazepines. Seizures may initially be decreased, but as tolerance develops over time, seizures may recur, necessitating dosage increases to regain control. Among the available benzodiazepines, clobezam has been touted as having less propensity for tolerance development. The most common dose-related side-effects of this drug class include drowsiness, ataxia and behavioural problems. Clonazepam is particularly useful for myoclonus. Clorazepate and clobezam may be used for both generalized and partial epilepsies. They tend to be used in patients with drug-resistant epilepsy. Starting dose for clonazepam is 0.5-1 mg twice daily, increasing as needed. Chlorazepate can be initiated at 7.5 mg twice daily or thrice daily. Clobezam can be started at 5mg twice daily and increased by 5-10 mg every 1-2 weeks to achieve the best seizure control without development of excessive sleepiness. Abrupt withdrawal from chronic benzodiazepines may precipitate status epilepticus. Even slow withdrawal may exacerbate seizures. Acute benzodiazepines such as diazepam, lorazepam and midazolam may be used as intermittent ‘rescue therapy’ in patients who experience seizure clusters or status epilepticus.

Felbamate

Felbamate is a broad-spectrum anti-epileptic drug. It is not considered to be a first-line drug because of its potential for serious idiosyncratic side-effects, including potentially fatal aplastic anaemia (incidence of 1 in 3000) and hepatic failure (incidence of 1 in 10000). Recent analyses indicate that aplastic anaemia and liver failure occur almost exclusively within the first year of therapy. During this period, safety monitoring consisting of liver function tests and blood counts is recommended with a frequency of up to twice monthly, despite lack of evidence that early detection of changes will prevent serious health problems, even if the drug is discontinued. Yet, felbamate may still be an important drug in the armamentarium for refractory patients, because it may control seizures when other drugs fail, and tends to be alerting rather than sedating. It has been found to be particularly effective in patients with Lennox-Gastaut syndrome. Felbamate should be started at 300-600 mg twice daily, and increased as necessary over several weeks, up to 3600 mg, or higher in some cases. Drug levels maybe useful, and serum concentrations of 30-80mg/1 are recommended. Three-times-a-day dosing may improve tolerability. Dose-related side-effects include insomnia, decreased appetite and weight loss, ataxia, Gastrointestinal upset and headache. Other serious idiosyncratic adverse events include rash and Stevens-Johnson syndrome. Felbamate has a complex metabolism and elimination, by both the hepatic and renal routes, and inhibits the metabolism of some drugs while inducing others. Adjustments in these medications may be necessary.

Lamotrigine

Lamotrigine is a broad-spectrum anti-epileptic drug that has been widely accepted as a first-line drug for both partial and generalized epilepsy syndromes. Clinical trials have supported its use in partial seizures, primary generalized tonic-clonic seizures, absence seizures and seizures associated with Lennox-Gastaut syndrome. There is some controversy regarding the use of lamotrigine in juvenile myoclonic epilepsy. It is commonly used, but may worsen myoclonus in some patients. Lamotrigine has been the subject of a number of head-to-head studies in newly diagnosed partial and generalized epilepsy. Lamotrigine was equally effective but better tolerated than phenytoin and carbamazepine in several somewhat under-powered studies. Several studies indicated that lamotrigine is better tolerated than carbamazepine in the elderly. A recent very large, randomized open-label study indicated that lamotrigine might be the drug of choice in patients with partial epilepsy, as it was equally effective but better tolerated, but in a companion study it was substantially less effective than valproate in patients with generalized or unclassified epilepsy. Some studies have advocated combining lamotrigine with valproate in refractory patients, to achieve maximum efficacy through a favourable pharmacodynamic interaction. However, side-effects are also enhanced when the drugs are combined. Initiation of lamotrigine is somewhat more complex than for other drugs. Slow titration is mandatory to reduce occurrence of serious rash. In monotherapy, initiation with 25mg/day for 2 weeks, then 50mg/day for another 2 weeks, followed by increases of 25-50 mg/week is appropriate. If the patient is receiving valproate at the time of initiation, starting doses and doses during titration should be cut in half, whereas if they are receiving enzyme-inducing anti-epileptic drugs such as phenytoin, carbamazepine or phenobarbital, doses can be doubled. Doses can then be increased as necessary. Typical doses for patients with newly diagnosed epilepsy are 100-200 mg/day. In refractory patients, doses may be as high as 500-1000 mg/day. There is a great deal of variability in serum concentrations that produce optimal effects. Some patients may do well at serum concentrations of 2mg/l, while others may need levels of up to 20 mg/1. Common dose-related side-effects of lamotrigine include mild tremor, double vision, headache and insomnia. Rash, including Stevens-Johnson syndrome and toxic epidermal necrolysis, can occur. Risk is increased for children under 16, and is also more common with concomitant valproate use, and in patients who have experienced rash on other anti-epileptic drugs. Rash almost always occurs within the first 8 weeks of therapy. Other hypersensitivity reactions, although much rarer, may be seen, including lymphadenopathy, fever, hepatic or renal failure, disseminated intravascular coagulation and arthritis. Discontinuation of lamotrigine is recommended in the presence of rash or other indication of hypersensitivity, and it is very important to tell patients to call immediately with such symptoms. Rapid discontinuation can prevent a more severe, potentially life-threatening reaction. In the absence of any clinical symptoms of hypersensitivity, it is unclear that routine monitoring of liver function tests, blood counts or electrolytes is useful. Lamotrigine does not alter the metabolism of other drugs that are given concomitantly. However, other drugs may impact on the metabolism of lamotrigine. One important and common drug interaction that bears noting is that with oral contraceptives, which double the clearance and halve the half-life of lamotrigine. Women on lamotrigine should be told to notify their doctor of any changes in oral contraceptive pill use, something they might not otherwise think to do.

Gabapentin

Gabapentin is a narrow-spectrum drug. It is useful only in patients with partial epilepsy, that is those with simple or complex partial seizures, or partial-onset generalized tonic-clonic convulsions. Gabapentin is felt to be more useful in newly diagnosed patients with mild epilepsy and in the elderly, who benefit from the relatively mild side-effect profile and lack of drug interactions, but less useful in patients with refractory epilepsy. Although gabapentin can be initiated at a therapeutic dose of 1200-2400 mg/day, it appears to be better tolerated when titrated. Typically, 300 mg two times a day is well tolerated as a starting dose, but lower starting doses are needed in some patients. Clinical trials have only tested efficacy to 2400 mg/day. However, in clinical experience, higher doses can be useful. However, gabapentin displays dose-dependent, saturable absorption. At higher doses, less may be absorbed across the gut, leading to diminishing returns. The amount of absorption varies from person to person. Determining if serum levels are rising after dose increments can help ascertain whether increasing doses are futile. Gabapentin is not bound to plasma proteins, is eliminated renally and does not interfere with the metabolism of other medications, including anti-epileptic drugs or psychotropic agents. This makes it an ideal drug for the elderly and patients with chronic illness, who are likely to be taking other drugs. Common dose-related side-effects include somnolence, dizziness, ataxia and fatigue. Weight gain is also seen, and appears to be dose related. Peripheral oedema may occur in some patients. Occurrence of myoclonus has been reported, as well as occasional behavioural disturbance in children. There are no reports of serious idiosyncratic side-effects. Therefore, routine monitoring of liver function tests, blood counts and electrolytes is probably not warranted.

Topiramate

Topiramate is another anti-epileptic drug that is felt to be broad spectrum. It has been studied and found effective in patients with partial-onset or primary generalized tonic-clonic seizures, and in patients with seizures associated with Lennox-Gastaut syndrome. Topiramate is felt to be first-line therapy in all these conditions. One head-to-head study in newly diagnosed patients found topiramate to be equal in efficacy with valproate in patients with mostly generalized seizures, and with carbamazepine in patients with mostly partial seizures, although the study was under-powered and has been criticized methodologically. A recent open-label randomized study in newly diagnosed adults and children indicated that topiramate was as efficacious as any other drug for partial and generalized seizures, but was less well tolerated. However, the open-label nature of the study could have produced some bias. Topiramate should be started at a low dose and slowly titrated for best tolerability, although there are no safety concerns related to starting more rapidly. It is best tolerated when initiated at 25 mg/day and increased by 25 mg/week. Typical doses necessary for newly diagnosed patients are in the range of 100-200 mg, while, as is the case for most drugs, refractory patients may require much higher doses. Up to 1000 mg has been tested in clinical trials, although few can tolerate such high doses. As with lamotrigine, serum levels needed to achieve control are variable, from 2 to 20 mg/1. Monitoring serum levels may be useful. Topiramate is well absorbed and has minimal protein binding. Topiramate is partially metabolized by the liver and approximately 60% is excreted unchanged in the urine. The more common dose-related adverse events include somnolence, paraesthesias (especially of fingertips), fatigue, taste perversion, weight loss and dizziness. One of the side-effects that is relatively specific to topiramate is psychomotor slowing, which particularly affects speech. Patients may complain of word-finding difficulty or slowing of speech. Academic performance can be affected. This side-effect is significant in some patients, while others may escape it entirely, even at high doses. Potential, more serious side-effects that occur infrequently include nephrolithiasis, open-angle glaucoma, causing transient and reversible visual loss, and hypohidrosis in children. Rarely, the hypohidrosis has caused heat stroke with serious consequences. Children receiving topiramate have also rarely developed clinically significant metabolic acidosis. Milder forms are common. Topiramate has rarely been associated with hepatic failure, and this seems to happen more commonly when topiramate is combined with valproate. Topiramate does not impact the metabolism of most concomitant drugs, but it does raise phenytoin levels when added to patients with baseline higher phenytoin levels (e.g. above 15 mg/1), which can potentially cause phenytoin toxicity. Therefore, phenytoin levels should be monitored. In addition, the classic hepatic enzyme-inducing antiepileptic drugs, such as phenytoin and carbamazepine, will increase the metabolism of topiramate, and higher doses may be required.

Oxcarbazepine

Oxcarbazepine, an analogue of carbamazepine, is a narrow-spectrum drug that is considered to be a first-line therapy for the treatment of partial seizures. Although it is similar to carbamazepine, it is effective in some patients for whom carbamazepine has failed and is believed to have additional mechanisms of action. Oxcarbazepine is actually a prodrug for a mono-hydroxylated form, to which it is rapidly converted after oral administration. Several studies have been performed in patients with newly diagnosed epilepsy, comparing oxcarbazepine with older anti-epileptic drugs. In all of these studies, oxcarbazepine was equally efficacious. It was better tolerated than phenytoin and carbamazepine, and as well tolerated as valproate. Oxcarbazepine has been noted to exacerbate myoclonic seizures as well as absence.

Oxcarbazepine should be initiated with titration to avoid side-effects. However, in one inpatient study, 2400 mg/day was started, and caused few dropouts, thus rapid initiation in an emergency is possible. In outpatients, initiation of 300 mg twice daily and titration of 600mg/week is usually well tolerated. Effective doses range from 900 to 2400mg, but higher doses are not well tolerated in combination with other drugs, particularly those with similar side-effect profiles. If side-effects develop as the dose is being increased, spacing out dosing to three times daily, or even four times daily sometimes permits achievement of higher, more efficacious doses. Plasma concentrations of up to 45 mg/1 have been well tolerated. Frequent dose-related adverse events include somnolence, dizziness, headache, ataxia, nausea and vomiting, diplopia, blurred vision, vertigo and tremor. One problematic potential adverse event is hyponatraemia. In a recent study, hyponatraemia was substantially more common for oxcarbazepine (29.9%) than carbamazepine (35.5%), and serum sodium levels of <128mEqA occurred in 12.4%. Risk factors for hyponatraemia include older age and diuretic use. Hypersensitivity syndromes, including rash and Stevens-Johnson syndrome are rare consequences of oxcarbazepine use. Oxcarbazepine does not have the strong enzyme-inducing properties of carbamazepine, and also does not induce its own metabolism. Oxcarbazepine also acts as an inhibitor of phenytoin metabolism, and its own metabolism is induced by the classic inducing anti-epileptic drugs such as phenytoin and carbamazepine.

Tiagabine

Tiagabine is a drug that is considered second-line therapy, and is effective for partial seizures only. Like other drugs that work via y-aminobutyric acid enhancement, tiagabine may exacerbate absence and myoclonic seizures. Tiagabine was compared with carbamazepine in a study of newly diagnosed patients with partial seizures, and was found to be less efficacious. However, it was fairly effective as add-on therapy in patients with refractory epilepsy. Nonetheless, its use has waned in recent years. Of note, some reports of seizures have surfaced when tiagabine has been used off-label for psychiatric indications. Tiagabine is best tolerated when titrated. Initiation of 4 mg once or twice daily is recommended, with dose increments of 4mg/week. A three-four-times-a-day regimen is recommended, due to the short half-life. Doses of up to 64 mg have been used in add-on trials. Patients receiving enzyme inducers will need higher doses than patients taking non-inducing anti-epileptic drugs. Serum levels have not been very clinically useful, due to the short half-life, which results in wide fluctuations in levels from peak to trough. Tiagabine is 96% protein bound, but no protein-binding interactions have been identified clinically. Common dose-related side-effects include tiredness, nervousness, dizziness, headache, tremor and abnormal thinking. An unusual side-effect has been identified, consisting of a stuporous state accompanied by a slow wave or spike-wave pattern on electroencephalogram. This resolves promptly with discontinuation of the drug. Another atypical side-effect is described as weakness or asthenia. No metabolic, hepatic or blood-related adverse events have been identified. Therefore, monitoring of complete blood counts, electrolytes and liver function tests is not clinically warranted. Tiagabine does not impact on the metabolism of other drugs. Other anti-epileptic drugs can impact on the metabolism of tiagabine.

Levetiracetam

Levetiracetam is a broad-spectrum drug that has undergone extensive testing. Therefore, more syndromes have been explored than for some of the other newer anti-epileptic drugs. It is effective in partial seizures. A study of patients with newly diagnosed partial or generalized tonic-clonic seizures showed no differences in efficacy or tolerability between levetiracetam and carbamazepine. Levetiracetam is the only newer anti-epileptic drug approved for use in juvenile myoclonic epilepsy. It was also effective for idiopathic generalized tonic-clonic seizures in an add-on situation. Case series have indicated efficacy in other idiopathic epilepsy syndromes.

One reason levetiracetam has become a very popular choice, for both initial and add-on therapy, is that it is easy to use. It can be started at a therapeutic dose, and data indicate that onset of action is within a day. Patients can be started on either 500mg once daily or 500 mg twice daily. The dose can then be increased gradually as necessary, with maximal dose typically being 3000 mg/day. If necessary, it can be started at a higher dose, although it is not clear if this is clinically necessary. In one study, levetiracetam was started at 4000 mg/ day, and was well tolerated. Serum levels are typically within the range of 10—40mgA, but will vary substantially over the course of a day, because of the short half-life of the drug. Another advantage of levetiracetam is that it is associated with no drug interactions because it is predominantly renally excreted, and shows limited metabolism in humans. As with other renally excreted drugs, lower doses should be used in the elderly, because they have a reduced creatinine clearance .

Side-effects of levetiracetam include irritability, somnolence, dizziness, asthenia and headache. Other uncommon adverse events include behavioural problems, depression and psychosis. Levetiracetam does not often cause rash, and is therefore a reasonable choice in patients with a history of hypersensitivity syndrome. To date, there has been no indication that levetiracetam can cause idiosyncratic safety problems such as aplastic anaemia or hepatic failure. Therefore, routine monitoring of liver function tests, blood counts and electrolytes is not clinically warranted.

Levetiracetam was recently approved in an i.v. formulation. It is being used more frequently for inpatients with other medical conditions who require immediate anti-epileptic drug therapy, and in status epilepticus, but no formal studies have been done.

Zonisamide

Zonisamide is felt to be broad spectrum. Unfortunately, trials in generalized seizure syndromes have not been performed to confirm this clinical impression. The only randomized controlled trials were performed in adults with partial seizures. Randomized trials in patients with newly diagnosed epilepsy have also not been done. Case series and open studies support a role for zonisamide in the treatment of syndromes associated with myoclonus, including juvenile myoclonic epilepsy and progressive myoclonic epilepsies. Zonisamide is better tolerated when it is titrated at initiation. It can be started at 50mg/day or 100 mg/day. The dose should then be titrated by 50mg/week or 100 mg every other week. Doses of 200-300 mg are common, and up to 500 mg can be necessary in difficult-to-treat patients. Serum concentrations of 20-40 mg/1 are considered therapeutic. Since the half-life is long (up to 60 h), serum concentrations can be expected to be steady over the course of the day. Common dose-related adverse events include fatigue, weight loss, dizziness, somnolence, anorexia and abnormal thinking, and decreased sweating. Zonisamide has also been associated with idiosyncratic side-effects. These include hypersensitivity syndromes such as rash and Stevens-Johnson syndrome and renal calculi. Patients living in hot climates, who are on high doses and have a family history of renal calculi may be at higher risk. Patients receiving zonisamide should be advised to drink plenty of fluids. The recurrence rate, even if zonisamide is continued, is not 100%. Hypohidrosis has also been seen, again more common in hot climates, and may infrequently lead to heat stroke in children. Zonisamide is well absorbed and is not extensively bound to plasma proteins. Since enzyme-inducing drugs such as carbamazepine and phenytoin can significantly reduce the half-life of zonisamide, higher doses will be needed in patients taking them in combination. Zonisamide metabolism can also be inhibited by a number of medications as well as by grapefruit juice. Zonisamide has essentially no impact on the pharmacokinetic parameters of other drugs.

Pregabalin

Pregabalin has a similar efficacy profile to gabapentin, that is to say its use is restricted to partial seizures. No formal monotherapy studies have been completed, in either newly diagnosed or refractory patients. An advantage of pregabalin when compared to gabapentin, is that it is highly bioavailable, and does not require active dose-dependent transport in the Gastrointestinal tract. Pregabalin is better tolerated when titrated. A recent study indicated that starting at the highest dose of 600 mg, while safe, led to 32% dropouts. Pregabalin can be initiated at 50-75 mg twice daily, and titrated by 50-75 mg every week or two weeks. There are very few clinical data available regarding the safety and tolerability of doses above 600mg/day. Twice-daily dosing is commonly used, despite the short half-life of the drug. A study comparing efficacy and tolerability of the same total daily dose, given as twice daily or thrice daily showed no statistically significant difference, but there was a trend to both better efficacy and tolerability when thrice daily was used. Therefore, it is reasonable to start off with a twice-daily regimen, and switch to thrice daily only if side-effects are present and/or breakthrough seizures are occurring. Pregabalin levels have only recently become available, and their clinical utility is unknown. Common dose-related side-effects predominantly affecting the central nervous system include dizziness, somnolence and ataxia. Weight gain and peripheral oedema are also seen. Weight gain is also dose related. To date, no idiosyncratic side-effects have been identified. Need for routine monitoring of liver functions, electrolytes and blood counts is therefore not established. Pregabalin is almost exclusively excreted unchanged in the urine, and does not undergo metabolic changes. To date, no drug-drug interactions have been uncovered, and none are expected.

Vigabatrin (not approved in the usa)

Vigabatrin, like felbamate, is an anti-epileptic drug that has been associated with a significant adverse drug effect (irreversible visual field restriction) that limits its use to those patients who have severe epilepsy which has not responded to other anti-epileptic drugs. In adults, vigabatrin appears to have a narrow spectrum of action, and its use is primarily restricted to those patients with refractory partial epilepsy. It has been found inferior in efficacy to carbamazepine in trials of newly diagnosed patients. It has also been known to worsen myoclonus. In infants, however, vigabatrin was found to be highly effective in the devastating childhood epilepsy known as infantile spasms, or West syndrome [99]. In a randomized trial, there was a 78% reduction in seizures on vigabatrin, compared with 26% on placebo. Moreover, in the open-label phase, 38% of children were completely spasm free. Vigabatrin is particularly effective in patients with spasms associated with tuberous sclerosis. Vigabatrin can be initiated at 500-1000mg, given once or twice a day. The dose can be increased in 500-1000 mg weekly increments, up to 3000 mg. Some patients worsen at higher doses. Vigabatrin has unique pharmacokinetic properties, in that its mechanism of action involves changes in brain chemistry that far outlast its presence in the bloodstream. Therefore, vigabatrin levels are not useful for therapeutic monitoring.

As noted, the main safety concern relates to irreversible peripheral visual field defects. This problem is estimated to occur in 30-50% of patients receiving the drug. Often, this will be picked up on screening visual field testing, but the patients will not spontaneously report any problem. Since early development of this problem has not been seen in controlled studies, there may be a 3-month ‘window of opportunity’ to see if the drug works before there is a risk of the visual field defect. However, once it occurs, it is not reversible.

Other side-effects of vigabatrin include drowsiness, depression, weight gain, dizziness and rare psychosis .

Approximately 25% of patients will achieve seizure freedom below the recognized therapeutic range, and about the same number will require serum concentrations above the range to obtain the maximum seizure benefit, often with few side-effects.

Many of the new anti-epileptic drugs are considered to have a wide therapeutic range. The range of serum concentrations that can be beneficial varies widely from one individual to another, yet for a particular individual it may be very important to maintain serum concentrations with minimal variability. For example, one patient on lamotrigine may have excellent seizure control within a range of 2-4 mg/1, but may experience dizziness and diplopia if the level increases to 5 mg/1. Another patient, in contrast, may have breakthrough seizures if their level drops below 7mg/l, but may tolerate levels up to 10mg/l.

Another area of confusion relates to timing of levels. Some anti-epileptic drugs have short half-lives, but nonetheless are dosed two times a day. In some cases, there is reasonably good scientific evidence that the drug has a longer duration of action in the central nervous system than would be expected based on its half-life. This has led to the common practice of dosing these drugs two times a day. It seems that other anti-epileptic drugs must be present at relatively constant serum concentrations throughout the day, to prevent seizure breakthroughs. Carbamazepine and phenytoin seem to fall in this category. What does this mean in terms of levels? For drugs that are dosed less frequently than their half-lives, the levels will be expected to vary substantially over the course of a day. Thus, levels can only be compared if they are measured at the same time of day. Take, for example, a patient who is receiving levetiracetam 1000 mg two times a day, at 8 a.m. and 8 p.m. He always gets his serum levels measured at his physician’s office at the time of his appointments, 2h after his dose. The levels would therefore be close to the peak. When measured, they are 20-25 mg/1. The patient now has a seizure at 7 p.m. and the level in the emergency room is 10 mg/1. One interpretation would be that the patient is non-compliant or the levels have dropped, but this would be incorrect. In fact, the levels were measured at trough, and are exactly where they should be. Now consider a patient on sustained-release carbamazepine, who receives 400 mg two times a day, at 8 a.m. and 8 p.m.. In this case, serum concentrations would be expected to vary very little over the course of a day, and a treating physician will have to investigate the cause of any major fluctuations. This can be very confusing for a treating physician. Nonetheless, levels can be useful if employed properly.

The following strategy may be recommended for using serum levels:

•   When initiating therapy, increase doses slowly, until seizure control is achieved or side-effects occur. If seizures are controlled, obtain a serum concentration at that time. This will identify the patient’s ‘therapeutic optimal level’.

•   Measure all levels at the same time of day, if possible. This will provide some indication of compliance, and also of variability in a given patient.

•   For drugs with sustained-release formulations, or long half-lives, serum concentrations should remain within a small range (no more than 20-25% change), even if obtained at different times of day, once a steady state is achieved (e.g. phenobarbital, phenytoin (administered two times a day), Tegretol XR™ or Carbatrol™ (sustained-release carbamazepine formulations), zonisamide, Depakote ER™ (sustained-release valproate formulation), topiramate and lamotrigine (administered two times a day in patients who are not receiving enzyme-inducing anti-epileptic drugs). If a breakthrough seizure occurs in the setting of a low serum concentration, consider non-compliance or inappropriate dosing schedule.

•   For drugs with short half-lives and no sustained-release formulation, serum concentrations should be consistent when taken at trough, but may vary by >50% if taken at other times, and should not be interpreted as indication of non-compliance (e.g. non-sustained-release valproate, gabapentin, levetiracetam, carbamazepine [administered two times a day], tiagabine and pregabalin).

Allopurinol

1 What Zyloric is and what it is used for

Zyloric tablets contain a medicine called Allopurinol. It works by slowing down the speed of certain chemical reactions in your body. Zyloric is used:

•  to prevent gout. This is a disease where your body produces too much of a substance called ‘uric acid’. The uric acid builds up in your joints and tendons as crystals. These crystals cause an inflammatory reaction. The inflammation causes the skin around certain joints to become swollen, tender and sore when only slightly touched. You can also fine you get severe pain when the joint is moved.

•  to prevent other conditions where there is a build up of uric acid in the body. These include kidney stones and certain other types of kidney problem and when you are having treatment for cancer.

2 Before you take Zyloric

Do not take Zyloric if:

•  you are allergic (hypersensitive) to Allopurinol or any of the other ingredients of Zyloric. Do not take Zyloric if the above applies to you. If you are not sure, talk to your doctor or pharmacist before taking Zyloric.

Take special care with Zyloric

Check with your doctor or pharmacist before taking your medicine if:

•  you have problems with your liver or kidneys. Your doctor may give you a lower dose or ask you to take it less often than each day. They will also monitor you more closely

•  You have heart problems or high blood pressure

•  you are currently having an attack of gout

•  you have been told by your doctor that you have an intolerance to lactose. Zyloric tablets contain a small amount of lactose. If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicinal product.

If you are not sure if any of the above applies to you, talk to your doctor or pharmacist before taking Zyloric.

Taking other medicines

Tell your doctor or pharmacist if you are taking any of the following:

•  aspirin

•  theophylline, used for breathing problems

•  medicines used for fits (epilepsy)

•  antibiotics

•  didanosine, used to treat HIV infection

•  medicines for cancer

•  medicines used to reduce your immune response (immunosuppressants)

•  medicines used to treat diabetes

•  medicines for heart problems or high blood pressure such as ‘ACE inhibitors’ or water tablets (diuretics)

•  medicines used to thin your blood (anticoagulants), such as warfarin

•  any other medicine to treat gout.

Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines. This includes medicines obtained without a prescription, including herbal medicines. This is because Zyloric can affect the way some medicines work. Also some other medicines can affect the way Zyloric works. Taking Zyloric with food and drink Take Zyloric with food and water.

Pregnancy and breast-feeding

Talk to your doctor before taking this medicine if you are pregnant, might become pregnant or are breast-feeding.

Driving and using machines

You may feel drowsy, giddy or have problems with your co-ordination. If this happens, do not drive or use any tools or machines.

3 How to take Zyloric

Always take Zyloric exactly as your doctor has told you. You should check with your doctor or pharmacist if you are not sure.

Taking this medicine

•  Swallow the tablet with a drink of water.

•  Take with or just after food. Children (under 15 years)

•  The usual dose ranges from 100 to 400 mg each day. Adults (over 18 years)

•  The usual dose ranges from 100 to 900 mg each day.

You will usually start on a dose of 100 to 300 mg each day. Elderly (over 65 years)

•  Your doctor will prescribe the lowest dose of Zyloric tablets that best controls your symptoms.

If you have a serious kidney problem

•  you may be asked to take less than 100 mg each day

•  or you may be asked to take 100 mg at longer intervals than one day.

If you have dialysis two or three times a week, your doctor may prescribe a dose of 300 or 400 mg which is to be taken straight after your dialysis.

If you take more Zyloric than you should

If you take more Zyloric than you should, talk to a doctor or go to hospital straight away. Take the medicine pack with you.

If you forget to take Zyloric

•  If you forget a dose, take it as soon as you remember it. However, if it is nearly time for the next dose, skip the missed dose.

•  Do not take a double dose to make up for a forgotten dose. If you stop taking Zyloric

Do not stop taking your Zyloric without talking to your doctor.

If you have any further questions on the use of this product, ask your doctor or pharmacist.

4.  Possible side effects

Like all medicines, Zyloric can cause side effects, although not everybody gets them. The following side effects may happen with this medicine:

Allergic reactions (affects less than 1 in 10,000 people) If you have an allergic reaction, stop taking Zyloric and see a doctor straight way. The signs may include:

•   skin rash, flaking skin, boils or sore lips and mouth

•   very rarely signs may include sudden wheeziness, fluttering or tightness in the chest and collapse.

Do not take any more tablets unless your doctor tells you to do so.

If you experience any of the following, stop your tablets and tell your doctor as soon as possible:

Rare (affects less than 1 in 1000 people)

•  joint pain or painful swelling in your groin, armpits or neck

•   yellowing of the skin and eyes (jaundice)

• liver or kidney problems

•   feeling sick (nausea) or being sick (vomiting), occasionally    with blood

. •   you notice any changes to your skin, for example blisters or   peeling

•   fever and chills, aching muscles and generally feeling unwell

•   bleeding in the lips, eyes, mouth, nose or genitals Very rare (affects less than 1 in 10,000 people)

•   bruising more easily than usual, or you may develop a sore throat or other signs of an infection. Tell your doctor as soon as possible. Occasionally Zyloric tablets may affect your blood or lymph system. These effects usually occur in people with liver or kidney problems

•   high temperature

•   blood in your urine (haematuria)

•   high levels of cholesterol in your blood (hyperlipidaemia)

•   a general feeling of being unwell

•   weakness, numbness, unsteadiness on your feet, feeling unable to move muscles (paralysis) or loss of consciousness

•   headache, dizziness, drowsiness or disturbance of your vision

•   chest pain, high blood pressure or a slow pulse

•   male infertility or erectile dysfunction

•   enlargement of the breasts, in men as well as women

•   a change in your normal bowel habit

•   a change in taste

•   cataracts

•   hair loss or discolouration

•   fits (convulsions)

•   depression

•   build up of fluid leading to swelling (oedema) particularly of your ankles

•   feeling thirsty, tired and losing weight; these may be symptoms of diabetes. Your doctor may wish to measure the level of sugar in your blood to check if this is happening.

If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist.

5. How to store Zyloric

•   Keep out of the reach and sight of children.

•   Do not use Zyloric after the expiry date which is stated on the carton after ‘EXP’. The expiry date refers to the last day of that month.

•   Keep your tablets in the original packaging.

•   Do not store above 25°C.

•   Medicines should not be disposed of via wastewater or household waste.

•   Return any unused or unwanted tablets to your pharmacist for disposal. Only keep them if your doctor tells you to. These measures will help to protect the environment.

6. Further information

What Zyloric contains

•  The active substance is Allopurinol.

•  The other ingredients are lactose, maize starch, povidone and magnesium stearate.

What Zyloric looks like and contents of the pack

Zyloric tablets contain 100 or 300 mg Allopurinol. Each 100 mg tablet is white, round and marked with a score line, ‘GXCM2′.

Each 300 mg tablet is white, round and marked with a score line, ‘GXCM7′.

Zyloric 100 mg tablets come in 4 strips of 25 tablets.

Zyloric 300 mg tablets come in calendar packs of 2 x 14 tablets.

Simvastatin

1 What the medicine is for

Zocor Heart-Pro is a medicine which is used to reduce the risk of a first heart attack in people who have a moderate risk of coronary heart disease (heart disease caused by a build up of plaques in the coronary arteries). Moderate risk means that your chances of having a heart attack in the next 10 years are at least 1 in 10 (10%). The tablets contain simvastatin, which belongs to a group of medicines known as statins. Statins significantly reduce the amount of cholesterol in your blood.

You will need to take these tablets regularly for a long period of time to get the maximum benefit from them.

Who is at moderate risk of coronary heart disease?

■  You are likely to be at moderate risk if you are a man aged 55 or over.

■  You are also likely to be at moderate risk if you are a man aged between 45 and 54 or a woman aged 55 or over and you answer yes to one or more of the questions below:

■  Do you have a parent, brother or sister who suffered a heart attack younger than 55 for men or 65 for women?

■  Do you smoke or have you smoked within the last 5 years?

■  Are you overweight?

This means you have a body mass index (BMI) over 25kg/m² (this is your weight in kilos divided by your height in metres squared), OR

■  Men – your waist is greater than 40 inches or 102cm OR

■  Women -your waist is greater than 35 inches or 88cm

Your pharmacist can help you answer this question if you are in any doubt.

■  Are you of South Asian origin (from the Indian subcontinent that includes Bangladesh, India, Pakistan or Sri Lanka)?

■  In addition, if you take no physical exercise other than normal daily activities, your risk of heart attack is further increased.

How does the medicine work?

Zocor Heart-Pro works by reducing the level of LDL (bad) cholesterol and fatty substances called triglycerides in your blood and raises HDL (good) cholesterol.

LDL (bad) cholesterol clogs your coronary arteries.

HDL (good) cholesterol helps to protect against heart disease.

How LDL (bad) Cholesterol can cause a heart attack

If too much cholesterol in your blood builds up in the walls of the coronary arteries, then plaques will form. This leads to narrowing of the coronary arteries, just like hard water furs up a water pipe. Heart attacks can then happen when a blood clot forms in a narrowed coronary artery.

How this medicine can help reduce the likelihood of a heart attack

By taking these tablets you can significantly reduce LDL (bad) cholesterol levels and help reduce the build up of artery-narrowing plaques.

2 Before taking this medicine

This medicine is suitable for most adults, but a few people should not use it. If you are in any doubt, talk to your doctor or pharmacist.

Do not use this medicine.

■  If you have ever had a bad reaction to statins or any of the ingredients in this medicine.

■  If you have liver disease or have been told that you have abnormal liver function blood tests.

■  If you are already taking prescription drugs to lower your cholesterol (such as gemfibrozil, bezafibrate).

■  If you are pregnant, planning to become pregnant or think you may be pregnant, or if you are breast-feeding.

■  If you discover you are pregnant while taking Zocor Heart-Pro. In this case you should stop taking the tablets immediately and contact your doctor.

■  If you have had muscle problems in the past after taking a cholesterol lowering medicine.

■  If you are taking any of the following medicines:

■  Oral antifungal medicines (drugs taken by mouth which are used to treat fungal infections such as itraconazole or ketoconazole).

Erythromyrin, Telithromycin and Clarithromyrin (these are a type of antibiotic medicine).

■  Protease inhibitors (drugs used to treat HIV infections such as indinavir, nelfinavir, ritonavir or saquinavir). Nefazodone (a drug used to treat depression).

If any of these apply to you, get advice from a doctor or pharmacist without using Zocor Heart-Pro.

Talk to your doctor or pharmacist before taking this medicine.

■  If you have an under active thyroid gland (hypothyroidism).

■  If you have kidney problems.

■  If you have a family history of muscle disorders.

■  If you already have angina or have had a heart attack.

■  If you have diabetes.

■  If you have had a stroke.

■  If you have disease of the arteries of your legs or neck (peripheral vascular disease).

■  If you have inherited very high blood cholesterol levels.

■  If you have high blood pressure.

■  If you are aged over 70.

■  If you drink more than 4 units of alcohol a day (for men) or 3 units a day (for women). One unit is Yi pint of lager, a small glass of wine or one short.

■  If you eat grapefruit or drink grapefruit juice.

■  If you are taking any other medicines, including:

■  Anti-coagulants (drugs that thin the blood, such as warfarin).

■  High doses of niacin or nicotinic acid (more than 1000 mg a day) for poor blood flow to the hands and feet.

■  Cidosporin (an immunosuppressant medicine).

■ Danazol (a steroid often used to treat endometriosis).

■ Fusidic acid (an antibiotic used to treat bacterial infections).

If you are not sure about any of the medicines you are taking, show the bottle or pack to your pharmacist.

■  If your doctor prescribes a new medicine while you are taking this medicine, you should mention that you are taking Zocor Heart-Pro.

If any of these bullets apply to you now or in the past, talk to a doctor or pharmacist.

If you have your cholesterol levels checked and you find that you have a fasting LDL cholesterol measurement greater than 5.5 mmol/l, you should talk to your doctor because you may need more than Zocor Heart-Pro to reduce your cholesterol levels.

If you are pregnant or breast-feeding

■  Do not take this medicine if you are pregnant, think you may be pregnant, trying to become pregnant or breast-feeding.

Some of the ingredients can cause problems

■  This product contains lactose. If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicine.

Special warnings about this medicine

■  This medicine can cause dizziness. If affected, do not drive or operate machinery.

■  Do not drink grapefruit juice while you are taking these tablets.

3 How to take this medicine

Check the table below to see how much medicine to take.

■  For oral use only.

■  Do not use more than the stated dose shown in the table.

■  Do not give to children.

■  Swallow the tablet whole with a drink of water.

■  Zocor Heart-Pro should betaken regularly and on a long term basis in order to gain the full benefits of treatment.

Children (under 18 years):

This medicine is not recommended for children under 18 years of age.

Adults and the elderly:

Special warnings whilst taking Zocor Heart-Pro

■  Very rarely these tablets can affect the muscles. Symptoms of this are generalised muscle pain, tenderness or weakness unless clearly related to the flu, unaccustomed exercise or recent injury or strains. If you develop these symptoms you should stop taking your tablets immediately and contact your doctor.

■  The chances of getting the muscle disorder mentioned above are greater if you drink grapefruit juice, have kidney problems or are taking tidosporin, danazol or prescription drugs to lower your cholesterol. If you are in any doubt whether to take the medicine or whether any symptoms you have are related to the medicine you should talk to your doctor or pharmacist.

■  if you are going into hospital for major surgery, you should tell your doctor you are taking these tablets, as you will need to stop taking them a few days beforehand.

■  if your cholesterol is checked whilst you are taking these tablets and your fasting LDL-cholesterol is above 5.5 mmol/lyou should talk to your doctor as it may mean that you need more than 10 mg of Zocor Heart-Pro to reduce your cholesterol.

If anyone has too much of the medicine

If anyone has taken too many Zocor Heart-Pro tablets, contact a doctor or your nearest Accident and Emergency Department (Casualty) taking this post and pack with you.

If you forget to take the medicine

You should only take this medicine as required following the dosage instructions above carefully. If you forget to take a dose, take one tablet the next evening you remember. Do not take a double dose to make up.

4 Possible side-effects

Zocor Heart-Pro tablets can have side-effects, like all medicines, although these don’t affect everyone and are usually mild.

If you experience any of the following, stop using the medicine and seek immediate medical help:

■  Allergic reactions such as swelling of the face or neck, muscle and joint pains, joint and blood vessel inflammation, itchy, lumpy rash (hives, nettle rash), a high temperature, sensitivity to light, flushing, difficulty in breathing or tiredness.

■  Muscle aches and pains, cramps, tenderness or weakness which can be severe (see section 3 Special warnings while you are taking Zocor Heart-Pro).

■  Yellowing of the skin or the whites of the eyes, dark coloured urine. This may mean you have a problem with your liver.

■  Abdominal pain felt just behind the ribs and spreading through to your back which may be due to pancreatitis (inflammation of the pancreas).

If you experience any of the following stop using the medicine and talk to your doctor:

■  Tiredness, faintness or breathlessness that may be due to anaemia (not enough red blood cells).

■  Tingling and numbness, dizziness, painful heavy pins and needles.

■  Rash, itching, hair loss.

■  Abnormal blood test results for liver or muscle function.

Other effects which occur are listed below:

■  Commonly stomach pain, wind, constipation, weakness, indigestion and headache.

■  Diarrhoea, feeling sick or being sick.

If you experience any side-effects not included in this leaflet or are not sure about anything, talk to your doctor or pharmacist.

5 Storing this medicine

Keep the product out of the reach and sight of children.

Do not store above 30°C.

Do not put them in another container as they might get mixed up.

Do not use your medicine if the pack is damaged, or after the expiry date on the packaging.

6 Further information

What’s in this medicine?

The active ingredient in Zocor Heart-Pro is: 10 mg simvastatin.

Other ingredients are: Ascorbic acid (E300), Butylated hydroxyanisole (E320), Citric acid monohydrate (E330), Lactose,

Magnesium stearate (E572), Microcrystalline cellulose (E460), Pregelatinised maize starch, Hydroxypropylcellulose (E463),

Methylhydroxy-propylcellulose (E464), Talc (E553b), Titanium dioxide (E171), Red iron oxide (E172), Yellow iron oxide (E172).

What the medicine looks like

Zocor Heart-Pro are peach coloured, oval shaped film coated tablets marked “MSD-735″. They are available in packs of

28 tablets.

7 What you can do to help reduce your risk of heart attack

At the same time as taking Zocor Heart-Pro tablets, try to reduce your risk of coronary heart disease by doing the following:

■  Stop smoking – there is strong evidence to link cigarette smoking with heart disease. The risks increase with the number of cigarettes you smoke each day, but risks still exist even if you smoke as little as five a day. It is better to stop smoking altogether rather than just cut down on how much you smoke. Your pharmacist can advise you on a suitable programme to help you stop smoking.

■  Eat a healthy diet – this will not only help towards preventing coronary heart disease, but has also been shown to reduce the risk of stroke and a number of cancers. Try to increase the amount of fruit and vegetables in your diet and reduce the amount of sugar, salt and fat.

■  Lose weight – being overweight can cause a rise in your blood pressure, increase your risk of developing diabetes and increase the risk of developing heart disease due to high cholesterol levels. Try to change your diet as described above and take more exercise.

■  Exercise – a brisk walk to the shops can help. Swimming is a good all round exercise that you could do as it is something you can gradually build up without overdoing it to start with. You could try adding the following to your daily routine: vigorous housework, walk upstairs more often and gardening.

If you would like to receive other advice and information on a healthy lifestyle and reducing your risk of a heart attack, register on the Healthy Heart Programme. This is a free on line service designed to help you understand your heart attack risk, lower it and keep it low.

WHAT IS IN ZIMBACOL XL TABLETS?

The name of your medicine is Zimbacol XL tablets.

Zimbacol XL tablets contain bezafibrate 400mg as the active ingredient. They also contain maize starch, sodium starch glycolate, lactose, poly(ethyl aery late-methyl methacrylate), magnesium stearate, polysorbate 80, hypromellose (E464), talc, calcium carbonate (E170), povidone, arabic gum, titanium dioxide (E171), glucose, sucrose, purified water and macrogol 6000.

WHEN SHOULD YOU NOT TAKE ZIMBACOL XL TABLETS?

You should not take Zimbacol XL tablets:

•    if you have received bezafibrate previously and had a bad reaction such as an allergy or wheezing,

•    if you have a severe liver disease (except that caused by increased fat in the liver),

•    if you have a gall bladder disease,

•    if you have poor kidney function or kidney disease.

BEFORE TAKING YOUR MEDICINE

Tell your doctor or pharmacist if any of the following apply:

•    if you are being treated for diabetes or depression,

•    if you are being treated with any other lipid-regulating drugs,

•    if you are taking medicine to ‘thin’ your blood,

•    if you are currently taking any other medicines,

•    if you are pregnant or trying to become pregnant,

•    if you are breast-feeding.

HOW TO TAKE YOUR MEDICINE

It is important that you take your medicine as directed by your doctor.

Normally your doctor will tell you to take one tablet a day, and the tablet should be swallowed whole with a little fluid after a meal, either in the morning or the evening.

Keep taking the medicine until your doctor tells you to stop. If you forget to take a dose take another as soon as you remember and then carry on as before.

The length of time needed for the medicine to work can vary from person to person and your doctor will check from time to time how well it is working.

In the event of an accidental overdose, consult your nearest hospital casualty department or doctor immediately.

DO ZIMBACOL XL TABLETS HAVE ANY SIDE EFFECTS?

As well as benefits, all medicines may occasionally have unwanted effects in some patients. These are called side effects.

Zimbacol XL tablets may cause side effects. These may include nausea and vomiting, loss of appetite, diarrhoea, indigestion, flatulence (wind) and stomach discomfort, particularly when you first start taking your medicine. These effects should not last for long, if they do consult your doctor.

Other effects which occur less frequently include weight gain, headache, dizziness, tiredness or drowsiness, skin rashes, itching or hair loss. Rarely, muscle cramps or weakness may occur.

If you notice any of these side effects or any other changes in your health whilst taking this medicine tell your doctor immediately.

Do not be alarmed by this list of possible events. Most people take Zimbacol XL tablets without any problems.

EXPIRY DATE

You must not take these tablets after the expiry date. This is given on the carton and the blister as ‘EXP’ followed by the month and year. Tablets should not be used after the end of that month. If you are not sure when this is check with your doctor or pharmacist.

STORAGE OF YOUR ZIMBACOL XL TABLETS

Keep your medicine in a safe place where children cannot reach it. These tablets are not prescribed for children and could be dangerous for them.

Do not store your medicine above 25°C.

When your doctor tells you to stop taking the tablets return any left over to your pharmacist.

REMEMBER: This medicine is only for you. Only a doctor can prescribe it for you. Never give it to someone else. It may harm them even if their symptoms are similar to yours.

Zerit 30 mg hard capsules

Zerit 40 mg hard capsules

Stavudine

1. WHAT ZERIT IS AND WHAT IT IS USED FOR

Zerit belongs to a group of antiviral medicines, also known as antiretrovirals, called nucleoside reverse transcriptase inhibitors (NRTIs).

These are used to treat Human Immunodeficiency Virus (HIV) infection.

This medicinal product, in combination with other antiretrovirals, reduces the HIV viral load and keeps it at a low level. It also increases CD4 cell counts. These CD4 cells play an important role in maintaining a healthy immune system to help fight infection. Response to treatment with Zerit varies between patients. Your doctor will therefore be monitoring the effectiveness of your treatment.

Zerit may improve your condition, but it is not a cure for your HIV infection. Treatment with Zerit has not been shown to reduce the risk of passing HIV infection on to others by sexual contact or by blood transfer. Therefore, you must continue to take appropriate precautions to avoid giving the virus to others.

During your treatment, other infections linked to your weakened immunity (opportunistic infections) may arise. These will require specific and sometimes preventive treatment.

2. BEFORE YOU TAKE ZERIT

Do not take Zerit:

If you are allergic (hypersensitive) to stavudine or any of the other ingredients of Zerit. Contact your doctor or pharmacist for advice.

Take special care with Zerit:

Before treatment with Zerit, you should have told your doctor:

■  if you suffer from kidney disease or liver disease (such as hepatitis),

■  if you have had peripheral neuropathy (persistent numbness, tingling, or pain in the feet and/or hands), or

■  if you have suffered from pancreatitis (inflammation of the pancreas).

The class of medicines to which Zerit belongs (NRTIs) can cause a sometimes fatal condition called lactic acidosis, together with an enlarged liver. This condition usually does not occur until a few months after onset of treatment. This rare, but very serious side effect occurs more often in women, particularly if very overweight. In addition, rare cases of liver failure/renal failure or fatal hepatitis have been reported.

Patients with chronic hepatitis B or C and treated with antiretroviral agents are at increased risk for severe and potentially fatal liver adverse events and may require blood tests for control of liver function.

If you develop one of the following, contact your doctor:

■  persistent numbness, tingling or pain in feet and/or hands (this may indicate the beginning of peripheral neuropathy, an adverse effect on the nerves), muscular weakness or

■  abdominal pain, nausea or vomiting, or

■  rapid deep breathing, drowsiness (which may indicate pancreatitis, liver disturbance such as hepatitis, or lactic acidosis).

In some patients with advanced HIV infection (AIDS) and a history of opportunistic infection, signs and symptoms of inflammation from previous infections may occur soon after anti-HIV treatment is started. It is believed that these symptoms are due to an improvement in the body’s immune response, enabling the body to fight infections that may have been present with no obvious symptoms. If you notice any symptoms of infection, please inform your doctor immediately.

Redistribution, accumulation, or loss of body fat may occur in patients receiving antiretroviral therapy. Some NRTIs, such as stavudine, have been associated with a loss of body fat (lipoatrophy). Contact your doctor if you notice changes in body fat.

Bone problems: some patients taking combination antiretroviral therapy may develop a bone disease called osteonecrosis (death of bone tissue caused by loss of blood supply to the bone). The length of combination antiretroviral therapy, corticosteroid use, alcohol consumption, severe immunosuppression, higher body mass index, among others, may be some of the many risk factors for developing this disease. Signs of osteonecrosis are joint stiffness, aches and pains (especially of the hip, knee and shoulder) and difficulty in movement. If you notice any of these symptoms please inform your doctor.

Taking other medicines

Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines, including medicines obtained without a prescription.

Except for zidovudine, which interferes with the activity of stavudine, Zerit may be taken with many of the other medicines commonly used in patients with HIV infection. These include the protease inhibitors (such as nelfinavir) and NRTIs. Please tell your doctor if you are taking doxorubicin or ribavirin as undesirable interactions may occur.

Taking Zerit with food and drink:

For maximum effect, Zerit should be taken on an empty stomach, and preferably at least one hour before a meal. If this is not possible, the capsules may also be taken with a light meal.

Pregnancy and breast-feeding:

Pregnancy

If you become pregnant, or are planning to become pregnant, you must contact your doctor to discuss the potential adverse effects and the benefits and risks of your antiretroviral therapy to you and your child. Lactic acidosis (sometimes fatal) has been reported in pregnant women who received stavudine in combination with other antiretroviral treatment.

If you have taken Zerit during your pregnancy, your doctor may request regular visits to monitor the development of your child. Such visits may include blood tests and other diagnostic tests.

In children whose mother took nucleoside and nucleotide analogues during pregnancy, the benefit from the reduced chance of being infected with HIV is greater than the risk of suffering from side effects.

Breast-feeding

Tell your doctor if you are breast-feeding. It is recommended that HIV-infected women should not breast-feed under any circumstances in order to avoid transmission of HIV to the baby.

Driving and using machines:

It is unlikely that Zerit affects the ability to drive or operate machinery.

Important information about some of the ingredients of Zerit:

These capsules contain lactose. If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicinal product.

3. HOW TO TAKE ZERIT

Always take Zerit exactly as your doctor has told you. You should check with your doctor if you are not sure. Your doctor has defined your daily dose based on your weight and individual characteristics.

Please follow these recommendations closely as they will give you the best chance to delay development of a resistance to the medicinal product. Do not change the dose on your own. Continue to take this medicine until your doctor tells you otherwise.

For adults whose body weight is 30 kg or more, the usual starting dose is 30 or 40 mg given twice daily (with approximately 12 hours between each dose).

To obtain optimal absorption, the capsules should be swallowed with a glass of water, preferentially at least one hour before a meal and on an empty stomach. If this is not possible, Zerit may also be taken with a light meal.

If you have problems swallowing capsules you should ask your doctor about the possibility of changing to the solution form of this medicine or you could carefully open the capsule and mix its contents with some food.

Use in Children

For children whose body weight is 30 kg or more, the usual starting dose is 30 or 40 mg given twice daily (with approximately 12 hours between each dose).

Children older than 3 months, whose body weight is less than 30 kg, should receive 1 mg/kg twice daily.

If you take more Zerit than you should:

If you have taken too many capsules or if someone accidentally swallows some, there is no immediate danger. However, you should contact your doctor or the nearest hospital for advice.

If you forget to take Zerit:

If you accidentally miss a dose, then simply take your normal dose when the next one is due. Do not take a double dose to make up for a forgotten dose.

If you stop taking Zerit:

The decision to stop using Zerit should be discussed with your doctor.

If you have any further questions on the use of this product, ask your doctor or pharmacist.

4. POSSIBLE SIDE EFFECTS

Like all medicines, Zerit can cause side effects, although not everybody gets them.

When treating HIV infection, it is not always possible to differentiate between unwanted effects caused by Zerit, or those caused by any other medicines you may be taking at the same time, or by the complications of the infection. For this reason, it is important that you inform your doctor of any change in your health.

Therapy for HIV including stavudine often causes changes in body shape due to changes in fat distribution. These may include loss of fat from legs, arms and face (lipoatrophy), and development of fatty lumps on the back of the neck (“buffalo hump”). Loss of body fat has been shown to be not fully reversible after discontinuation of stavudine. It occurs more often with Zerit compared to other HIV medicines. Your doctor should monitor for clinical signs and symptoms of changes in your body shape. Tell your doctor if you notice any changes in your body shape or loss of fat from your legs, arms, and face. When these signs occur, consideration should be given to discontinuing ZERIT treatment.

The frequency of possible side effects listed below is defined using the following convention:

Patients treated with Zerit have reported the following side effects: Common:

■  asymptomatic hyperlactatemia (build up of acid in your blood)

■  lipoatrophy or lipodystrophy syndrome (body changes due to fat redistribution, accumulation, or loss of body fat),

■  depression

■  peipheral neurologic symptoms including peripheral neuropathy, paresthesia, and peripheral neuritis (numbness, weakness, tingling or pain in the arms and legs)

■  dizziness, abnormal dreams, headache

■  insomnia (difficulty sleeping), somnolence (sleepiness), abnormal thinking,

■  diarrhoea, abdominal pain (stomach pain of discomfort),

■  nausea, dyspepsia (indigestion)

■  rash, pruritus (itching)

■  fatigue (extreme tiredness)

Uncommon:

■  lactic acidosis (build up of acid in your blood) in some cases involving motor weakness (weakness in your arms, legs or hands)

■  gynaecomastia (breast enlargement in men)

■  anorexia (loss of appetite), anxiety, emotional lability

■  pancreatitis (inflammation of the pancreas), vomiting

■  hepatitis, jaundice (yellow of the skin or eyes)

■  urticaria (itchy rash), arthralgia (joint pain)

■  myalgia (aching muscles), asthenia (unusual tiredness or weakness)

Frequency not known:

■  anemia, thrombocytopenia, neutropenia (blood disorders)

■  diabetes mellitis, hyperglycaemia (high sugar levels in the blood)

■  motor weakness (most often reported in the setting of symptomatic hyperlacetatemia or lactic acidosis syndrome

■  liver failure, hepatitis (infiamation of the liver) and hepatic steatosis (fat in the liver)

If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell you doctor or pharmacist.

5. HOW TO STORE ZERIT

Keep out of the reach and sight of children.

Store below 25 °C (aclar/alu blisters) Do not store above 30°C. (HDPE bottles) Store in the original package.

Do not use Zerit after the expiry date which is stated on the carton, the bottle label and/or the blister after EXP. The expiry date refers to the last day of that month.

Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. These measures will help to protect the environment.

6. FURTHER INFORMATION

What Zerit contains

The active substance is stavudine

The other ingredients of the powder contained in the hard capsule are: lactose (120 mg, 180mg, or 240mg), magnesium stearate, microcrystalline cellulose and sodium starch glycolate.

The ingredients of the capsule shell are gelatine, iron oxide colorant (E172), silicon dioxide, sodium laurilsulphate and titanium dioxide colorant (El71).

The capsule shells are marked using edible black printing ink containing shellac, propylene glycol, purified water, potassium hydroxide and iron oxide (El72).

What Zerit looks like and content of the pack

Zerit 20 mg hard capsules are brown and marked with “BMS 1965″ on one side and “20″ on the other side.

Zerit 30 mg hard capsules are light and dark orange and marked with “BMS 1966″ on one side and “30″ on the other side.

Zerit 40 mg hard capsules are dark orange and marked with “BMS 1967″ on one side and “40″ on the other side.

Zerit 20 mg, 30 mg & 40 mg hard capsules are supplied in blister packs of 56 hard capsules or bottles of 60 hard capsules. To help protect the capsules from excessive moisture, the bottle includes a desiccant canister.

Idarubicin HC1

1. What Zavedos is and what it is used for

•    Zavedos contains an active ingredient called idarubicin, which belongs to a group of medicines called anthracyclines. Zavedos interferes with ways in which the cells of your body grow and increase in number and is used in the treatment of cancers (chemotherapy).

•    Zavedos is used for the treatment of leukaemia.

2. Before you are given Zavedos

Do not take Zavedos if:

You have ever had an allergic (hypersensitivity) reaction to idarubicin or any of the other ingredients of Zavedos other anthracyclines You have an infection which is not under control. Your liver or kidneys are not working properly.

You have an intolerance to sugars? If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicinal product.

Take special care with Zavedos

Tell your doctor if you:

Suffer from bone marrow depression caused by previous therapy. -    Have suffered from heart trouble in the past or are presently receiving treatment for this. Zavedos might not be a suitable treatment for you, or a reduced dose might have to be used.

Taking other medicines

Please tell your doctor or pharmacist if you:

Are given medicines that have a similar action to Zavedos. They can make the effects of Zavedos stronger.

Are receiving radiotherapy.

Pregnancy

Avoid becoming pregnant while you or your partner is being treated with Zavedos. If you are sexually active, you are advised to use effective birth control to prevent pregnancy during treatment, whether you are male or female. Zavedos may harm an unborn child, so it is important to tell your doctor if you think you are pregnant.

Breast-feeding

You should not breast-feed whilst receiving Zavedos, as some of the drug may get into your milk and possibly harm your child.

Ask your doctor or pharmacist for advice before taking any medicine.

Driving and using machinery

Special care should be taken if it is essential that you drive or operate machinery while undergoing treatment especially if you are lacking strength or are in a debilitated condition.

3.   How Zavedos will be given to you.

Zavedos will be given to you by injection.

•    Your doctor will prescribe the required amount (the dose). The dose is decided by taking into account your condition being treated, your height and weight.

•    From your height and weight the doctor will work out your body surface area; this is necessary because the dose is usually calculated as “… milligrams per square metre” (mg/m2), given by injection, on 3 days running.

•    However, your doctor may alter the dose and number of days treatment depending on your condition and any other treatment you may receive.

Regular checks by your doctor during Zavedos treatment

During treatment you will need regular checks including blood tests. Your doctor will be making regular checks of:

•    Your blood, to check for low blood cell counts that may need treatment.

•    Your heart function, as Zavedos can have effects upon this.

•    Your liver and kidneys – again using blood tests – to check that Zavedos is not affecting the way they functions in a harmful way.

•    Blood uric acid levels – Zavedos may increase uric acid levels in the blood, which might cause gout. Another medicine may be given if your uric acid levels are too high.

You will find more information on some of these effects in Section 4 ‘Possible Side Effects’.

If you receive high doses of Zavedos:

High doses can worsen side effects like sores in the mouth or may decrease the number of white blood cells and platelets (these help the blood to clot) in the blood. Should this happen, you may need antibiotics or blood transfusions. Mouth ulcers can be treated to make them less uncomfortable as they heal.

Heart damage can occur when high doses of Zavedos are given. This may not be detected for several weeks, so regular tests may be required during this period.

4. Possible side effects

Like all medicines Zavedos can have side effects.

Allergic reactions can occur- you may feel dizzy, feverish, short of breath with a tight chest or throat or have an itchy rash. If this happens, tell your doctor or nurse immediately as this type of reaction can be very serious.

Low numbers of the following blood cells

•    Red cells causing anaemia that can leave you feeling tired and lethargic.

•    White cells(which fight infection) increasing the chance of infections, a raised temperature or fever and chills (like flu). Severe infections can occur after treatment with idarubicin alone or in combination, and may be fatal.

•    Platelets (these help the blood to clot) making you bruise more easily, or bleed more than usual if you hurt yourself.

It is important to seek medical advice if this happens.

You may also notice the following side effects:

Effects on your heart

•    Symptoms of damage to the heart muscles, which include tiredness, shortness of breath, weight gain and swollen ankles.

Effects on your kidneys and bladder

•    A red colour in your urine may appear when you pass water for a few days after treatment. This is quite normal and should not be cause for concern.

Effects on your skin and hair:

•    You may lose all or part of your hair, which usually grows back after treatment has finished.

•    You may get skin rashes.

Effects on your mouth, stomach and intestines:

•Soreness or ulcers in the mouth, which may not appear until 3-10 days after treatment, heartburn, feeling sick (nausea) being sick (vomiting) or diarrhoea.

If any of the side effects get serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist.

5.    How to store Zavedos

•    Keep out of the reach and sight of children.

•    Do not use Zavedos after the expiry date, which is stated on the vial. The expiry date refers to the last date of that month.

•    Zavedos should be given to you by injection within 24 hours of being made up from the dry powder in the vial. It should be kept in the fridge during this time.

6.    Further information

What Zavedos contains

Zavedos is supplied as an orange-red powder in a vial containing either 5mg or lOmg of the active ingredient, idarubicin hydrochloride. Your medicine also contains lactose monohydrate. The vials are packed singly in cartons. Your doctor or nurse will make up the Zavedos with water into an injection.

Zavedos

Idarubicin hydrochloride Powder for Solution for Injection

Biological activity

Idarubicin, an original anthracycline, is a DNA inter-calating agent which interacts with topoisomerase II and has an inhibitory effect on nucleic acid synthesis.

The modification in position 4 of the anthracycline structure gives the compound a high lipophilicity which results in an increased rate of cellular uptake compared with doxorubicin and daunorubicin.

Idarubicin has been shown to have a higher potency with respect to daunorubicin and to be an effective agent against murine leukemia and lymphomas both by i.v. and oral routes. Studies in-vitro on human and murine anthracycline-resistant cells have shown a lower degree of cross-resistance for idarubicin compared with doxorubicin and daunorubicin.

Cardiotoxicity studies in animals have indicated that idarubicin has a better therapeutic index than daunorubicin and doxorubicin. The main metabolite, idarubicinol, has shown in-vitro and in-vivo, antitumoural activity in experimental models. In the rat, darubicinol, administered at the same doses as the parent drug, is clearly less cardiotoxic than idarubicin.

Clinical pharmacology

After i.v. administration to patients with normal renal and hepatic function, idarubicin is eliminated from systemic circulation with a terminal plasma t 1/2 ranging between 11-25 hours and is extensively metabolized to an active metabolite, idarubicinol, which is more slowly eliminated with a plasma t 1/2 ranging between 41 and 69 hours. The drug is eliminated by biliary and renal excretion, mostly in the form of idarubicinol. Studies of cellular (nucleated blood and bone marrow cells) drug concentrations in leukemic patients have shown that peak cellular idarubicin concentrations are reached a few minutes after injection.

Idarubicin and idarubicinol concentrations in nucleated blood and bone marrow cells are more than a hundred times the plasma concentrations.

Idarubicin disappearance rates in plasma and cells were almost comparable with a terminal half life of about 15 hours. The terminal half life of idarubicinol in cells was about 72 hours.

Presentation

Sterile, pyrogen-free, orange-red, freeze-dried powder in vials containing 5 mg and 10 mg of idarubicin hydrochloride with 50 mg and 100 mg of lactose respectively.

Uses

Antimitotic and cytotoxic agent. Acute non-lymphocytic leukemia (ANLL) in adults for remission induction in untreated patients or for remission induction in relapsed or refractory patients.

Acute lymphocytic leukemia (ALL) as second line treatment in adults and children.

Zavedos may be used in combination chemotherapy regimens involving other cytotoxic agents.

Dosage and Administration

For reconstitution, the contents of the 5 mg vial should be dissolved in 5 ml of Water for Injections, the 10 mg vial in 10 ml of Water for Injections. Zavedos must be administered only by the intravenous route and the reconstituted solution should be given via the tubing of a freely running intravenous infusion of 0.9% Sodium Chloride Injection taking 5 to 10 minutes over the injection.

This technique minimises the risk of thrombosis or perivenous extravasation which can lead to severe cellulitis and necrosis. Venous sclerosis may result from injection into small veins or repeated injections into the same vein.

Dosage is usually calculated on the basis of body surface area.

Acute non-lymphocytic leukemia (ANLL)

In adult ANLL the dose schedule suggested is 12 mg/m2 i.v. daily for 3 days in combination with cytarabine.

Another dose-schedule which has been used in ANLL as a single agent and in combination is 8 mg/m2 i.v. daily for 5 days.

Acute lymphocytic leukemia (ALL)

As a single agent in ALL the suggested dose in adults is 12 mg/m2 i.v. daily for 3 days and in children is 10 mg/m2 i.v. daily for 3 days.

All of these dosage schedules should, however, take into account the haematological status of the patient and the dosages of other cytotoxic drugs when used in combination.

Warning: this product is not for intrathecal use.

Contra-indications, warnings, etc.:

Contra-indications

-    hypersensitivity to idarubicin or any other component of the product, other anthracyclines or anthracenediones

-    severe hepatic impairment

-    severe renal impairment

-    severe myocardial insufficiency

-    recent myocardial infarction

-    severe arrhythmias

-    persistent myelosuppression

-    previous treatment with maximum cumulative doses of idarubicin and/or other anthracyclines and anthracenediones .

-Breast-feeding should be stopped during drug therapy .

Uncontrolled infections Warnings and Precautions General. Idarubicin should be administered only under the supervision of physicians

experienced in the use of cytotoxic chemotherapy.

This ensures that immediate and effective treatment of severe complications of the disease and/or its treatment (e.g. hemorrhage, overwhelming infections) may be carried out.

Patients should recover from acute toxicities of prior cytotoxic treatment (such as stomatitis, neutropenia, thrombocytopenia, and generalized infections) before beginning treatment with idarubicin.

Cardiac Function. Cardiotoxicity is a risk of anthracycline treatment that may be manifested by early (i.e., acute) or late (i.e., delayed) events.

Early (i.e., Acute) Events. Early cardiotoxicity of idarubicin consists mainly of sinus tachycardia and/or electrocardiogram (ECG) abnormalities, such as non-specific ST-T wave changes. Tachyarrhythmias, including premature ventricular contractions and ventricular tachycardia, bradycardia, as well as atrioventricular and bundle-branch block have also been reported. These effects do not usually predict subsequent development of delayed cardiotoxicity, are rarely of clinical importance, and are generally not a reason for the discontinuation of idarubicin treatment.

Late (i.e., Delayed) Events. Delayed cardiotoxicity usually develops late in the course of therapy or within 2 to 3 months after treatment termination, but later events, several months to years after completion of treatment have also been reported. Delayed cardiomyopathy is manifested by reduced left ventricular ejection fraction (LVEF) and/or signs and symptoms of congestive heart failure (CHF) such as dyspnea, pulmonary edema, dependent edema, cardiomegaly, hepatomegaly, oliguria, ascites, pleural effusion, and gallop rhythm. Subacute effects such as pericarditis/myocarditis have also been reported. Life-threatening CHF is the most severe form of anthracycline-induced cardiomyopathy and represents the cumulative dose-limiting toxi city of the drug. Cumulative dose limits for IV or oral idarubicin have not been defined. However, idarubicin-related cardiomyopathy was reported in 5% of patients who received cumulative IV doses of 150 to 290 mg/m2. Available data on patients treated with oral idarubicin total cumulative doses up to 400 mg/m2 suggest a low probability of cardiotoxicity.

Cardiac function should be assessed before patients undergo treatment with idarubicin and must be monitored throughout therapy to minimize the risk of incurring severe cardiac impairment. The risk may be decreased through regular monitoring of LVEF during the course of treatment with prompt discontinuation of idarubicin at the first sign of impaired function. The appropriate quantitative method for repeated assessment of cardiac function (evaluation of LVEF) includes Multiple Gated Acquisition (MUGA) scan or echocardiography (ECHO). A baseline cardiac evaluation with an ECG and either a MUGA scan or an ECHO is recommended, especially in patients with risk factors for increased cardiotoxicity. Repeated MUGA or ECHO determinations of LVEF should be performed, particularly with higher, cumulative anthracycline doses. The technique used for assessment should be consistent throughout follow-up.

Risk factors for cardiac toxicity include active or dormant cardiovascular disease, prior or

concomitant radiotherapy to the mediastinal/pericardial area, previous therapy with other anthracyclines or anthracenediones, and concomitant use of drugs with the ability to suppress cardiac contractility or cardiotoxic drugs (e.g., trastuzumab). Anthracyclines including idarubicin should not be administered in combination with other cardiotoxic agents unless the patient’s cardiac function is closely monitored. Patients receiving anthracyclines after stopping treatment with other cardiotoxic agents, especially those with long half-lives such as trastuzumab, may also be at an increased risk of developing cardiotoxicity. The half-life of trastuzumab is approximately 28.5 days and may persist in the circulation for up to 24 weeks. Therefore, physicians should avoid anthracycline-based therapy for up to 24 weeks after stopping trastuzumab when possible. If anthracyclines are used before this time, careful monitoring of cardiac function is recommended.

Cardiac function monitoring must be particularly strict in patients receiving high cumulative doses and in those with risk factors. However, cardiotoxicity with idarubicin may occur at lower cumulative doses whether or not cardiac risk factors are present.

In infants and children there appears to be a greater susceptibility to anthracycline induced cardiac toxicity, and a long-term periodic evaluation of cardiac function has to be performed. It is probable that the toxicity of idarubicin and other anthracyclines or anthracenediones is additive.

Hematologic Toxicity. Idarubicin is a potent bone marrow suppressant. Severe myelosuppression will occur in all patients given a therapeutic dose of this agent. Hematologic profiles should be assessed before and during each cycle of therapy with idarubicin, including differential white blood cell (WBC) counts. A dose-dependent, reversible leukopenia and/or granulocytopenia (neutropenia) is the predominant manifestation of idarubicin hematologic toxicity and is the most common acute doselimiting toxicity of this drug. Leukopenia and neutropenia are usually severe; thrombocytopenia and anemia may also occur. Neutrophil and platelet counts usually reach their nadir 10 to 14 days after drug administration; however, cell counts generally return to normal levels during the third week. Clinical consequences of severe myelosuppression include fever, infections, sepsis/septicemia, septic shock, hemorrhage, tissue hypoxia, or death.

Secondary Leukemia. Secondary leukemia, with or without a preleukemic phase, has been reported in patients treated with anthracyclines, including idarubicin. Secondary leukemia is more common when such drugs are given in combination with DNA damaging antineoplastic agents, when patients have been heavily pretreated with cytotoxic drugs, or when doses of the anthracyclines have been escalated. These leukemias can have a 1- to 3-year latency period.

Gastrointestinal. Idarubicin is emetigenic. Mucositis (mainly stomatitis, less often esophagitis) generally appears early after drug administration and, if severe, may progress over a few days to mucosal ulcerations. Most patients recover from this adverse event by the third week of therapy.

Occasionally, episodes of serious gastrointestinal events (such as perforation or bleeding) have been observed in patients receiving oral idarubicin who had acute leukemia or a history of other pathologies or had received medications known to lead to gastrointestinal complications. In patients with active gastrointestinal disease with increased risk of bleeding and/or perforation, the physician must balance the benefit of oral idarubicin therapy against the risk.

Hepatic and/or Renal Function. Since hepatic and/or renal function impairment can affect the disposition of idarubicin, liver and kidney function should be evaluated with conventional clinical laboratory tests (using serum bilirubin and serum creatinine as indicators) prior to, and during, treatment. In a number of Phase III clinical trials, treatment was contraindicated if bilirubin and/or creatinine serum levels exceeded 2.0-mg %. With other anthracyclines a 50% dose reduction is generally used if bilirubin levels are in the range 1.2 to 2.0-mg %

Effects at Site of Injection. Phlebosclerosis may result from an injection into a small vessel or from previous injections into the same vein. Following the recommended administration procedures may minimize the risk of phlebitis/thrombophlebitis at the injection site .

Extravasation. Extravasation of idarubicin during intravenous injection may cause local pain, severe tissue lesions (vesication, severe cellulitis), and necrosis. Should signs or symptoms of extravasation occur during intravenous administration of idarubicin, the drug infusion should be immediately stopped.

Tumor Lysis Syndrome. Idarubicin may induce hyperuricemia as a consequence of the extensive purine catabolism that accompanies rapid drug-induced lysis of neoplastic cells (‘tumor lysis syndrome’). Blood uric acid levels, potassium, calcium phosphate, and creatinine should be evaluated after initial treatment. Hydration, urine alkalinization, and prophylaxis with allopurinol to prevent hyperuricemia may minimize potential complications of tumor lysis syndrome.

Immunosuppressant Effects/Increased Susceptibility to Infections. Administration of live or live-attenuated vaccines in patients immunocompromised by chemotherapeutic agents including idarubicin, may result in serious or fatal infections. Vaccination with a live vaccine should be avoided in patients receiving idarubicin. Killed or inactivated vaccines may be administered; however, the response to such vaccines may be diminished.

Reproductive system: Men treated with idarubicin hydrochloride are advised to adopt contraceptive measures during therapy and, if appropriate and available, to seek advice on sperm preservation due to the possibility of irreversible infertility caused by the therapy.

Other. As with other cytotoxic agents, thrombophlebitis and thromboembolic phenomena, including pulmonary embolism have been coincidentally reported with the

Patients with rare hereditary problems of galactose intolerance, the Lapp la deficiency or glucose-galactose malabsorption should not take this medicii

Adverse reactions

The frequencies of undesirable effects are based on the following categoric

Very common (>1/10)

Common (>1/100 to <1/10)

Uncommon (>1/1,000 to <1/100)

Rare (>1/10,000 to <1/1,000)

Very rare (< 1/10,000)

Not known (cannot be estimated from the available data)

Infections and infestations

Neoplasms benign, malignant and unspecified (including cysts and polyps)

Blood and lymphatic system disorders

Immune system disorders

Endocrine disorders

Nervous system disorders

Cardiac disorders

Vascular disorders

Gastrointestinal disorders

Hepatobiliary disorders

Skin and subcutaneous tissue disorders

Renal and urinarv disorders

General disorders and administration site conditions

Hematopoietic system

Pronounced myelosuppression is the most severe adverse effect of idarubicin treatment.

However, this is necessary for the eradication of leukemic cells.

Leukocyte and thrombocyte counts usually reach their nadir 10-14 days after the administration of idarubicin hydrochloride. Cell counts generally return to normal levels during the third week. During the phase of severe myelosuppression, deaths due to infections and/or hemorrhages have been reported.

Clinical consequences of myelosuppression may be fever, infections, sepsis, septic shock, hemorrhages, and tissue hypoxia, which can lead to death. If febrile neutropenia occurs, treatment with an IV antibiotic is recommended.

Cardiotoxicity

Life-threatening CHF is the most severe form of anthracycline-induced cardiomyopathy and

represents the cumulative dose-limiting toxicity of the drug .

Use During pregnancy and lactation

Impairment of Fertility. Idarubicin can induce chromosomal damage in human spermatozoa. For this reason, males undergoing treatment with idarubicin should use effective contraceptive methods

Pregnancy: The embryotoxic potential of idarubicin has been demonstrated in both in vitro and in vivo studies. However, there are no adequate and well-controlled studies in pregnant women. Women of childbearing potential should be advised not to become pregnant during treatment and adopt adequate contraceptive measures during therapy as suggested by a physician. Idarubicin should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. The patient should be informed of the potential hazard to the fetus. Patients desiring to have children after completion of therapy should be advised to obtain genetic counselling first if appropriate and available.

Lactation: It is not known whether idarubicin or its metabolites are excreted in human milk. Mothers should not breast-feed during treatment with idarubicin hydrochloride.

Interactions

Idarubicin is a potent myelosuppressant and combination chemotherapy regimens including other agents with similar action may be expected to induce additive myelosuppressant effects .. The use of idarubicin in combination chemotherapy with other potentially cardiotoxic drugs, as well as the concomitant use of other cardioactive compounds (e.g., calcium channel blockers), requires monitoring of cardiac function throughout treatment.

Changes in hepatic or renal function induced by concomitant therapies may affect idarubicin metabolism, pharmacokinetics, and therapeutic efficacy and/or toxicity.

An additive myelosuppressant effect may occur when radiotherapy is given concomitantly or within 2-3 weeks prior to treatment with idarubicin.

Overdose

Although the single-dose packaging is designed to minimise the risk of overdosage and no data on overdosage exists, should this occur gastric lavage should be carried out as soon as possible.

Patients treated with oral idarubicin should be observed for possible gastro-intestinal hemorrhage and severe mucosal damage. Very high doses of idarubicin may be expected to cause acute myocardial toxicity within 24 hours and severe myelosuppression within one or two weeks. Treatment should further aim to support the patient during this period and should utilise such measures as blood transfusions and reverse-barrier nursing. Delayed cardiac failure has been seen with the anthracyclines up to several months after the overdose. Patients should be observed carefully and if signs of cardiac failure arise, should be treated along conventional lines.

Pharmaceutical precautions

The vial contents are under a negative pressure to minimise aerosol formation during reconstitution; particular care should be taken when the needle is inserted. Inhalation of any aerosol produced during reconstitution must be avoided.

The following protective recommendations which are valid for all cytotoxic agents are given:

- Personnel should be trained in good technique for reconstitution and handling.

- Pregnant staff should be excluded from working with this drug.

- Personnel handling the drug should wear protective clothing; goggles, gowns and disposable gloves and masks.

- A designated area should be defined for reconstitution (preferably under a vertical laminar flow system). The work surface should be protected by disposable, plasticbacked, absorbent paper.

All items used for reconstitution, administration or cleaning, including gloves, should be placed in high-risk, waste disposal bags for high temperature incineration.

Accidental contact with the skin or eyes should be treated immediately by copious lavage with water or sodium bicarbonate solution.

Spillage or leakage should be treated with dilute sodium hypochlorite (1% available chlorine) solution, preferably by soaking, and then water. All cleaning materials should subsequently be disposed of as indicated previously.

When aseptically prepared, the product may be stored for up to 24 hours at 2°C to 8°C.

The product does not contain an antimicrobial preservative. Therefore if aseptic preparation cannot be ensured, the product must be prepared immediately before use and any unused portion discarded.

Prolonged contact with any solution of an alkaline pH should be avoided as it will result in degradation of the drug. Zavedos should not be mixed with heparin as a precipitate may form and it is not recommended that it be mixed with other drugs.

Package quantities

5 mg and 10 mg vials for injection.

Yondelis 1 mg powder for concentrate for solution for infusion

Trabectedin

1.WHAT YONDELIS IS AND WHAT IT IS USED FOR

Yondelis is an anti-cancer medicine that works by preventing the tumour cells from multiplying.

Yondelis is used for the treatment of patients with advanced soft tissue sarcoma, when previous medicines have been unsuccessful or the patients are unsuited to receive them. Soft tissue sarcoma is a malignant disease that starts somewhere in the soft tissues, such as the muscles, fat or other tissues (for example cartilages or vessels).

Yondelis in combination with pegylated liposomal doxorubicin (PLD: another anti-cancer medicine) is used for the treatment of patients with ovarian cancer that has come back after at least 1 previous therapy and are not resistant to platinum based anti-cancer medicines.

2.BEFORE YOU ARE GIVEN YONDELIS

Do not use Yondelis:

• if you are allergic (hypersensitive) to trabectedin or any of the other ingredients of Yondelis.
• if you have any serious infections.
• if you are breast-feeding.
• if you will receive yellow fever vaccine.

Take special care with Yondelis:

Yondelis or its combination with PLD must not be used if you have severe liver or kidney damage. Tell your doctor if you know or suspect that you have any liver or kidney problems before starting the treatment with Yondelis.

You should seek medical attention immediately if any of the following conditions appear:

•     If you develop a fever as Yondelis may cause side-effects affecting your blood and liver.

•      If you still feel sick, vomit or are unable to drink fluids and therefore pass less urine despite being given anti-sickness medicines.

•      If you experience severe muscle pain or weakness as it could be a sign of damage to your muscles .

•      If you notice that Yondelis infusion leaks out of your vein while you are being given it. It could lead to damage and death of your tissue cells around the injection site which may require surgery.

Yondelis must not be used in children and adolescents since safety and efficacy have not yet been studied in this age group.

Using other medicines

Please tell your doctor if you plan to take, are taking or have recently taken any other medicines, including medicines obtained without a prescription, vaccines and herbal medicines.

You must not use Yondelis if you will receive yellow fever vaccine and it is not recommended that you use Yondelis if you will receive a vaccine containing live virus particles. The effect of medicines containing phenytoin (for epilepsy) may be decreased if given together with Yondelis and this is therefore not recommended.

If you use other medicines, you may need to be closely monitored as the effects of Yondelis might be decreased (examples are medicines containing rifampicin (for bacterial infections), phenobarbital (for epilepsy) or St. John’s Wort (Hypericumperforatum, an herbal medicine for depression)) or increased (examples are medicines containing ketoconazole or fluconazole (for fungal infections), ritonavir (for HIV infection), clarithromycin (for bacterial infections), aprepitant (to prevent nausea and vomiting), ciclosporin (inhibit the defensive system of the body) or verapamil (for high blood pressure and heart conditions)) as a result.

If you are given Yondelis or the combination Yondelis+PLD together with a medicine that might cause damage to the liver or to the muscles (rhabdomyolysis), you may need to be closely monitored, when using Yondelis together with this medicine, as there could be an increased risk of damage. Medicines containing statins (for lowering cholesterol levels and preventing cardiovascular disease) is an example of medicines that may cause muscle damage.

Using Yondelis with food and drink

Alcohol consumption must be avoided during treatment with Yondelis as this may harm the liver.

Pregnancy and breast-feeding

Pregnancy

You should not use Yondelis if you are pregnant or if you are trying to become pregnant as Yondelis may harm the unborn baby. If you are pregnant or you think you may be pregnant, you must tell your doctor immediately. The doctor may prescribe Yondelis during pregnancy in certain circumstances.

Adequate contraceptive precautions must be used by men in fertile age and women of childbearing potential when receiving Yondelis and for 3 months following the end of treatment for women and 5 months following the end of treatment for men. If a pregnancy should occur you must tell your doctor immediately and genetic counselling is recommended since Yondelis can cause genetic damage.

Genetic counselling is also recommended for patients wishing to have children after therapy. Male patients should seek advice on sperm conservation prior to treatment because of the risk of irreversible infertility due to therapy with Yondelis.

Breast-feeding

Yondelis must not be given to patients who are breast-feeding. Therefore you must stop breast-feeding before you start your treatment and you must not begin breast-feeding again until your doctor has confirmed that it is safe to do so.

Driving and using machines

During your treatment with Yondelis you may feel tired and experience a loss of strength. Do not drive or use any tools or machines if you are experiencing any of these side effects.

Important information about some of the ingredients of Yondelis

This medicine contains potassium, less than 1 mmol (39 mg) per vial, and can therefore be considered as essentially “potassium-free”.

3. HOW TO USE YONDELIS

Yondelis is given to you under the supervision of a physician experienced in the use of chemotherapy. Its use should be confined to qualified oncologists or other health professionals specialised in the administration of cytotoxic medicines.

For the treatment of soft tissue sarcoma, the usual dose is 1.5 mg/m² of body surface area. During the treatment period, your doctor will carefully monitor you and decide the most appropriate dosage of Yondelis to give to you.

For the treatment of ovarian cancer, the usual dose is 1.1 mg/m² body surface area after the administration of 30 mg/m² body surface area of PLD.

Before Yondelis is given to you, it is reconstituted and diluted for intravenous use. Every time you are given Yondelis for the treatment of soft tissue sarcoma, it will take about 24 hours for all of the solution to enter your blood. It will take 3 hours for the treatment of ovarian cancer.

In order to avoid irritation at the site of injection it is recommended that Yondelis is given to you through a central venous line.

You will be given medicine before and as needed during the treatment with Yondelis in order to protect your liver and to reduce the risk of side effects such as feeling sick (nausea) and vomiting.

The infusion is given to you every 3 weeks, although occasionally your doctor may recommend dose delays to ensure that you receive the most appropriate dosage of Yondelis.

The length of your whole treatment period will depend on your progress and how well you feel. Your doctor will tell you how long your treatment lasts. If you have any further questions on the use of this medicine, ask your doctor.

4. POSSIBLE SIDE EFFECTS

Like all medicines, Yondelis or its combination with PLD can cause side effects, although not everybody gets them.

If you are not sure what the side effects below are, you should ask your doctor to explain them to you in more detail.

Side effects caused by the single treatment with Yondelis: Very common (occurring in at least 1 in 10 patients):

• You may:

•    feel tired

•    feel short of breath (dyspnoea)

•    bruise more easily

•    have nose bleeds

•    be more prone to infections. An infection could also give you a raised temperature (fever).

If you develop any of these symptoms you should seek medical attention immediately.

• Your doctor may require blood tests in certain situations in order to avoid that you develop muscle damage (rhabdomyolysis). In very severe cases this could lead to kidney failure. If you

experience severe muscle pain or weakness, you should seek medical attention immediately.

• You could have increased levels of the yellow pigment bilirubin in the blood which might cause jaundice (a yellowing of the skin, mucous membranes and eyes).

• You may experience headache and a loss of strength.

• You may also lose your appetite, feel sick (nausea) or vomit, and become constipated. If you

still feel sick, vomit or are unable to drink fluids and therefore pass less urine, despite being given anti-sickness medication, you should immediately seek medical help.

• Your doctor will order regular blood tests to detect any abnormalities in the blood. Common (occurring in at least 1 in 100 patients):

• You may have fever. If you have a raised temperature you should seek medical attention immediately.

• You could also feel pain in your back, muscles and joints. There could be damage to your nerves which may result in muscle pain, weakness and numbness. You could experience general swelling or swelling of the limbs and a sensation of creeping on the skin.

• You may experience diarrhoea, loss of water from the body, inflammation of the mouth (stomatitis), pain in the abdomen, weight loss, digestive discomfort and a change in your sense of taste.

• You could have coughing.

• You may lose hair (alopecia).

• You could also experience dizziness, sleeping problems, low blood pressure and flushing.

• You may have a reaction at the site of injection. Yondelis infusion may leak out of your vein while you are being given it, leading to damage and death of your tissue cells around the injection site (tissue necrosis, see also section 2 “Take special care with Yondelis”) which may require surgery.

Other side effects that may occur with the combination of Yondelis and PLD:

When Yondelis is used in combination with PLD some of these side effects are more likely to occur and some may occcur in a more severe way.

Very common (occurring in at least 1 in 10 patients):

• You may have the hand and foot syndrome. It may present as red skin of the palms, fingers, and soles of the feet that later may become swelling and violaceous. The lesions may either dry out and desquamate, or blister with ulceration.

Common (occurring in at least 1 in 100 patients):

• You may have a higher skin pigmentation and rash.

• You could have mucosal inflammation as a swelling redness of the inside of the mouth leading to painful ulcers and mouth sores or as an inflammation of the gastrointestinal tract.

• You may also have blood infections (neutropenic infection and neutropenic sepsis). Your doctor will order regular blood tests to detect any abnormalities in the blood.

• You may have syncope also called fainting.

• You could have a weakness in the ventricles, the heart’s major pumping chambers (left ventricular dysfunction), sudden blockage in a lung artery (pulmonary embolism) and an abnormal build up of fluid in the lungs, which leads to swelling (pulmonary oedema).

If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor.

5. HOW TO STORE YONDELIS

Keep out of the reach and sight of children.

Do not use Yondelis after the expiry date which is stated on the carton and the vial label after EXP. The expiry date refers to the last day of that month.

Store in a refrigerator (2°C – 8°C).

Information on in-use stability of the reconstituted and diluted solutions is included in the section for medical and healthcare professionals.

6. FURTHER INFORMATION

• What Yondelis contains:

The active substance is trabectedin.

Yondelis 0.25 mg: Each vial contains 0.25 mg of trabectedin.

Yondelis 1 mg: Each vial contains 1 mg of trabectedin.

The other ingredients are sucrose, potassium dihydrogen phosphate, phosphoric acid (for pH-adjustment) and potassium hydroxide (for pH-adjustment).

• What Yondelis looks like and contents of the pack

Yondelis is a powder for concentrate for solution for infusion. The powder has a white to off-white colour and comes in a glass vial.

Each carton contains 1 vial of either 0.25 mg or 1 mg of trabectedin.

The following information is intended for medical or healthcare professionals only:

Instructions for use – preparation, handling and disposal

Appropriate procedures for proper handling and disposal of cytotoxic medicines must be followed. Any unused medicine or waste material should be disposed of in accordance with local requirements for cytotoxic medicines.

You should have received training on the correct techniques to reconstitute and dilute Yondelis or its combination with PLD and you should wear protective clothing including mask, goggles and gloves during the reconstitution and dilution. Accidental contact with the skin, eyes or mucous membranes must be treated immediately with copious amounts of water. You should not work with this medicine if you are pregnant.

Preparation for intravenous infusion:

Yondelis must be reconstituted and further diluted prior to infusion (see also section 3). Appropriate aseptic techniques must be used.

Yondelis must not be administered as a mixture with other medicines in the same infusion apart from the diluent. No incompatibilities have been observed between Yondelis and type I glass bottles, polyvinylchloride (PVC) and polyethylene (PE) bags and tubing, polyisoprene reservoirs and titanium implantable vascular access systems.

When Yondelis is used in combination with PLD, the intravenous line should be flushed well with 50 mg/ml (5%) glucose solution for infusion after administration of PLD and before administration of Yondelis. The use of any diluent other than 50 mg/ml (5%) glucose solution for infusion may cause precipitation of PLD. (See also PLD Summary Products Characteristics for specific handling instructions).

Instructions for reconstitution:

Yondelis 0.25 mg: Inject 5 ml of sterile water for injections into the vial.

Yondelis 1 mg: Inject 20 ml of sterile water for injections into the vial.

A syringe is used to inject the correct amount of sterile water for injections into the vial. Shake the vial until complete dissolution. The reconstituted solution results in a clear, colourless or slightly yellowish solution, essentially free of visible particles.

This reconstituted solution contains 0.05 mg/ml of trabectedin. It requires further dilution and is for single-use only.

Instructions for dilution:

Dilute the reconstituted solution with sodium chloride 9 mg/ml (0.9%) solution for infusion or glucose 50 mg/ml (5%) solution for infusion. Calculate the required volume as follows:

Volume (ml) = BSA (m²) x individual dose (mg/m²)

0.05 mg/ml

BSA = Body Surface Area

Withdraw the appropriate amount of reconstituted solution from the vial. If administration is to be made via a central venous line, add the reconstituted solution to an infusion bag containing > 50 ml of diluent (sodium chloride 9 mg/ml (0.9%) solution for infusion or glucose 50 mg/ml (5%) solution for infusion), the concentration of trabectedin in the infusion solution being < 0.030 mg/ml.

If central venous access is not feasible and a peripheral venous line has to be used, add the reconstituted solution to an infusion bag containing > 1,000 ml of diluent (sodium chloride 9 mg/ml (0.9%) solution for infusion or glucose 50 mg/ml (5%) solution for infusion).

Inspect the parenteral solution visually for particles prior to administration. Once the infusion is prepared, it should be administered immediately.

In-use stability of the solutions:

Reconstituted solution:

After reconstitution, chemical and physical stability has been demonstrated for 30 hours up to 25°C.

From a microbiological point of view, the reconstituted solution should be diluted and used immediately. If not diluted and used immediately, in-use storage times and conditions prior to use of the reconstituted solution are the responsibility of the user and would normally not be longer than 24 hours at 2°C to 8°C, unless reconstitution has taken place in controlled and validated aseptic conditions.

Diluted solution:

After dilution, chemical and physical stability has been demonstrated for 30 hours up to 25°C.

Podophyllotoxin

1. What Warticon Cream is and what it is used for

Warticon Cream contains a medicine called podophyllotoxin. This is a plant extract which belongs to a group of medicines called ‘antivirals’.

Warticon Cream is used to treat genital warts. It is used for warts on the penis in men and external warts on the vagina in women.

2.  Before you use Warticon Cream

Do not use Warticon Cream if:

•    you are allergic to podophyllotoxin or any of the other ingredients of Warticon Cream .

•    you are pregnant or breast-feeding a baby

•    your warts surround an open wound (such as after surgery).

•    the patient is a child

•    you are already using another medicine containing podophyllotoxin.

Do not use Warticon Cream if any of the above apply to you. If you are not sure, ask your doctor or pharmacist before using this medicine.

Take special care

Talk to your doctor before using this medicine if: •   any of your warts are bigger than a 4 centimetre area (approximately the size of a postage stamp).

You may need to have this medicine applied by a trained health professional. If you are not sure, talk to your doctor or pharmacist.

Important information about some of the ingredients in Warticon Cream:

Warticon Cream contains butylated hydroxyanisole (E320), stearyl and cetyl alcohols which may cause local skin reactions (e.g.contact dermatitis). Butylated hydroxyanisole may also cause irritation to the eyes and mucous membranes. Warticon Cream also contains methyl and propyl parahydroxybenzoates, E218 and E216, which may cause allergic reactions (possibly delayed).

3.   How to use Warticon Cream

Always use Warticon Cream exactly as your doctor has told you. You should check with your doctor or pharmacist if you are not sure.

Using Warticon Cream

•    Apply Warticon Cream twice a day, in the morning and evening for 3 days.

•    Do not apply any cream for the next 4 days. This completes one treatment course.

•    If you still have any warts remaining 7 days after you started using the cream, repeat the treatment course (twice a day for 3 days followed by 4 days where you do not use the cream).

•    A maximum of 4 treatment courses may be applied.

•    If any warts remain after 4 treatment courses consult your doctor.

How to apply Warticon Cream

1.   Wash the affected areas with soap and water. Dry the area well with a clean towel.

2.   It may help you to view the area to be treated, if you sit down and place the mirror as shown in the diagram below.

3.   Using a fingertip, apply Warticon Cream to cover each wart. Use only enough cream to cover each wart.

4.   Rub the cream into the wart. Be careful not to get the cream onto healthy skin. If this happens, wash the cream off with soap and water.

5.   Wash your hands thoroughly.

6.   Make sure you have screwed the lid back on tightly.

If you get Warticon Cream in your eyes or if you swallow it

•    If you get Warticon Cream in your eye, rinse the eye thoroughly with water and talk to your doctor.

•    If you accidentally swallow some of the cream see your doctor or go to hospital straight away. Take the tube of cream with you so that the doctor knows what you have swallowed.

Having sex when using Warticon Cream

You should not have sex when you are still treating your warts. You should wait until your warts have gone and your skin has healed. If you do have sex, you must use a condom.

4.   Possible side effects

Like all medicines, Warticon Cream can cause side effects, although not everybody gets them. The following side effects may happen with this medicine: •   irritation, burning and tenderness. If these happen, they are likely to occur on the second or third day of treatment as the warts begin to disappear. In most cases these effects are mild and will pass. If these effects do not go away and cause severe

discomfort, stop using the medicine and see your doctor.

If you notice any other side effects not listed in this leaflet, please tell your doctor or pharmacist.

5.  How to store Warticon Cream

•     Keep out of the reach and sight of children

•     Do not use Warticon Cream after the

expiry date which is stated on the tube and carton (after “Exp:”). The expiry date refers to the last day of that month.

•    Warticon cream does not require any special storage conditions.

•     Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. These measures will help to protect the environment.

6. Further information

What Warticon Cream contains

•    The active substance is podophyllotoxin 0.15% w/w (1.5 miligram per gram of Warticon Cream).

•    The other ingredients are: purified water, methyl parahydroxybenzoate (E218), propyl parahydroxybenzoate (E216), sorbic acid, phosphoric acid, stearyl alcohol, cetyl alcohol, isopropyl myristate, liquid paraffin, fractionated coconut oil, butylhydroxyanisole (E320), macrogol – 7 stearyl ether, macrogol – 10 stearyl ether.

What Warticon Cream looks like and contents of the pack

Warticon Cream comes in tubes containing 5 grams of a white cream.

A small mirror is provided in each pack.