Pocket Drug Guide

Posts Tagged ‘Stevens Johnson’

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.

Drugs are listed in order of approval in the USA, from oldest to newest.

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 .

Perdix7.5mg film-coated tablets Perdix 15mg film-coated tablets

Moexipril hydrochloride

1. What Perdix is for

Perdix belongs to a group of medicines called “ACE inhibitors”.

It works by blocking the effect of a substance called angiotensin-converting enzyme. This enzyme is important in the control of blood pressure. Perdix is used to treat high blood pressure.

High blood pressure often causes no symptoms, but if it is not treated it can damage blood vessels in the long-term. In some cases this can lead to heart attacks, kidney failure, stroke or blindness. This is why it is important not to stop taking this medicine without talking to your doctor.

2. Before you take Perdix Do not take Perdix if:

• You are allergic to moexipril hydrochloride or any of the other ingredients of Perdix, or any other ACE inhibitor

• You have ever suffered from a swelling of the tissues such as the face, lips, tongue or throat after taking medicines

• You suffer from hereditary or idiopathic angioneurotic oedema (very bad swelling of your skin especially around the face, lips, nose, tongue or throat). This means you were either born with this illness or your doctor does not know what causes it

• You are more than 3 months pregnant.

If any of the above apply to you talk to your doctor or pharmacist.

Check with your doctor before taking Perdix if:

• You suffer from low blood pressure

• You have kidney failure or any problems with your kidneys

• You are having dialysis

• You have recently had a kidney transplant

• You are on a low sodium diet

• You suffer from hyperkalaemia (increased levels of potassium in your blood)

• You suffer from liver disease

• You are going to hospital for an operation or general anaesthetic

• You suffer from heart valve problems such as aortic stenosis or a condition affecting the heart muscle (hypertropic cardiomyopathy)

• You suffer from diseases of your blood vessels.

• You are having a treatement called low density lipoprotein apheresis

• You are having treatment to make you less sensitive to insect poisons, such as bee or wasp stings

• You think you are (or might become) pregnant. Perdix is not recommended in early pregnancy, and must not be taken if you are more than 3 months pregnant, as it may cause serious harm to your baby if used at that stage.

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

• Water tablets (diuretics) that cause you to pass more urine than you usually do. If taken with Perdix, your blood pressure may fall too low.

• Anti-hypertensives, including nifedipine, used to help lower blood pressure. If taken with Perdix, your blood pressure may fall too low.

• Potassium supplements. Perdix can affect the amount of potassium you have in your blood.

• Lithium for manic depression. Perdix can increase the amount of lithium you have in your blood.

• Sleeping agents or other narcotics. If taken with Perdix, your blood pressure may fall too low.

• Antipsychotics for the treatment of mental illness. If taken with Perdix, your blood pressure may fall too low.

• Drugs which suppress the body’s defence reactions (e.g. anti-immune drugs, anticancer drugs, steroids). If taken with Perdix, they may reduce your body’s defence reaction further.

• Allopurinol for gout. If taken with Perdix, it may reduce your body’s defence reaction.

• Procainamide for irregular heart rhythms. If taken with Perdix, it may reduce your body’ s defence reaction.

• Painkillers (non-steroidal anti-inflammatory drugs). They may reduce the effect of Perdix.

• General anaesthetics. If taken with Perdix, your blood pressure may fall too low.

• Antacids. If taken with Perdix, they may reduce the effect of Perdix.

• Injectable gold, used to treat arthritis. If given to you with Perdix, it may cause your face to flush, for you to feel or be sick and/or reduce your blood pressure.

• Antidiabetic drugs. If taken with Perdix, these may reduce the amount of sugar in your blood.

• Any other medicine, including medicines obtained without a prescription.

Taking Perdix with food and drink

Do not drink alcohol when taking Perdix as the effect of the medicine may be increased, causing you to feel dizzy.

Pregnancy and breast-feeding Pregnancy

You must tell your doctor if you think you are (or might become) pregnant. Your doctor will normally advise you to stop taking Perdix before you become pregnant or as soon as you know you are pregnant and will advise you to take another medicine instead of Perdix. Perdix is not recommended in early pregnancy, and must not be taken when more than 3 months pregnant, as it may cause serious harm to your baby if used after the third month of pregnancy.

Breast-feeding

Tell your doctor if you are breast-feeding or about to start breast-feeding. Perdix is not recommended for mothers who are breastfeeding, and your doctor may choose another treatment for you if you wish to breast-feed, especially if your baby is newborn, or was born prematurely.

Driving and using machines

Perdix may cause you to feel dizzy. If this happens to you, do not drive or use machinery until this effect has worn off.

Information on sugar intolerance

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

3. How to take Perdix

Always take Perdix exactly as your doctor has told you.

Important: Your doctor will choose the dose that is right for you. Your dose will be shown clearly on the label that your pharmacist puts on your medicine. If it does not, or you are not sure, ask your doctor or pharmacist.

Adults

Take either one Perdix 7.5 mg or one Perdix 15 mg tablet once a day. Your doctor may prescribe up to 30 mg per day.

Your doctor may prescribe a lower dose of 3.75 mg if:

• You are elderly

• You are already taking another medicine for high blood pressure

• Your kidneys do not work very well

• You have liver problems.

If your doctor prescribes you a dose of 3.75 mg, break a 7.5 mg tablet in half and take one half.

While you are taking this medicine, your doctor may ask you to have blood-pressure check-ups. These are to make sure that your medicine is working properly and that the dose you are taking is right for you.

Children

This medicine is not suitable for children.

If you take more Perdix than you should

Do not take more Perdix than you should. If you accidentally take too much, immediately contact the nearest hospital casualty department or your doctor. Too much Perdix can lower your blood pressure too much and may make you feel dizzy, light-headed or faint.

If you forget to take Perdix

Do not take a double dose to make up for a missed dose. Simply take your next scheduled dose.

If you stop taking Perdix

Do not stop taking Perdix without first talking to your doctor. High blood pressure often causes no symptoms, but if it is not treated it can damage blood vessels in the long-term. In some cases this can lead to heart attacks, kidney failure, stroke or blindness.

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

4. Possible side effects

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

Seek immediate medical help if you have any of the following symptoms:

• Feeling faint

• Swelling of the face or throat or blistering of the skin, mouth, eyes and genitals

• Difficulty in breathing or wheezing, shortness of breath.

Common side effects (affects less than 1 in 10 people):

• Cough

• Headache

• Dizziness

• Tiredness

• Flushing

• Rash.

Uncommon side effects (affects less than 1 in 100 people):

• Those related to the heart and circulation: heart attack (myocardial infarction), chest pain (angina), feeling your heart beat (palpitations), rhythm disturbances (changes to the pattern of your heart beat), stroke and transient ischaemic attacks (temporary lack of blood flow to the brain), low blood pressure, fainting

• Those related to the stomach: inflammation of the pancreas (which causes severe pain in the abdomen and back), liver problems such as hepatitis, stomach ache, indigestion, constipation, feeling or being sick, diarrhoea, appetite or weight change, dry mouth

• Those related to the respiratory system: difficulty inbreathing or wheezing, shortness of breath, chest infection, sore throat, blocked sinuses or swelling and irritation inside the nose

• Those affecting the skin: serious illness with redness, swelling or blistering of the skin, mouth, eyes and genitals (e.g. Stevens- Johnson syndrome, toxic epidermal necrolysis, erythema multiforme, pemphigus), rash, itching, hair loss

• Kidney problems or proteinuria (presence of protein in your urine)

• Other possible side-effects: serious allergic reaction which causes swelling of the face or throat (angioedema), drowsiness, problems with sleep, depression, impotence, tingling or numbness, loss of balance, confusion, blurred vision, taste disturbances, ringing in the ears, sweating, flu-like symptoms, muscle and joint pain, a general feeling of being unwell. Changes in blood test results may also occur, including low red or white blood cell counts and low platelet counts. These may cause anaemia (weakness, breathlessness or pale skin), increased risk of bleeding or bruising, or make infections more likely. 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 Perdix

Keep out of the reach and sight of children.

Do not use Perdix after the expiry date on the carton. The expiry date refers to the last day of that month.

Keep Perdix in the original pack.

Medicines should not be disposed of via wastewater or household waste. Return any medicine you no longer need to your pharmacist.

6. Further information

• What Perdix contains

There are two strengths of Perdix – 7.5 mg or 15 mg. These contain 7.5 mg or 15 mg of the active substance moexipril hydrochloride respectively.

The other ingredients are lactose monohydrate, crospovidone, light magnesium oxide, gelatin, magnesium stearate, Hypromellose, hydroxypropylcellulose, gelatin, Macrogol 6000 and colours, titanium dioxide [E171] and ferric oxide [El72].

• What Perdix looks like

Perdix is a film coated pink tablet with a break line. Perdix comes in a blister pack of 28 tablets.

Paclitaxel 6 mg/ml concentrate for solution for infusion

1. WHAT PACLITAXEL CONCENTRATE FOR SOLUTION FOR INFUSION IS AND WHAT IT IS USED FOR

Paclitaxel concentrate for solution for infusion is used in the treatment of a number of different types of cancer including ovarian cancer and breast cancer (after surgery or in advanced/spreading state) and non-small cell lung cancer (advanced state). It may be used in combination with other treatments or after other treatments have failed. It may also be used in the treatment of patients with advanced AIDS (Acquired Immuno-Deficiency Syndrome)-related Kaposi’s sarcoma where previous other treatments have not been effective. Paclitaxel works by preventing the growth of certain cancer cells.

2. BEFORE YOU USE PACLITAXEL CONCENTRATE FOR SOLUTION FOR INFUSION

You may need to have laboratory tests (eg blood tests) to ensure that you can be given this medicinal product. Some patients may also need to have heart tests.

Do not use Paclitaxel concentrate for solution for infusion

• If you are allergic to paclitaxel, polyoxyl castor oil or any of the other ingredients of Paclitaxel concentrate for solution for infusion
• If you are pregnant or breast-feeding
• If your white blood cell or platelet count is very low (this is checked by blood tests)
• If you have a serious, uncontrolled infection and paclitaxel is to be given for the treatment of Kaposi’s sarcoma

Take special care with Paclitaxel concentrate for solution for infusion

• If you notice marked allergic reaction which may cause shortness of breath, dizziness (caused by low blood pressure), swelling of the face or rash
• If you have heart disease or liver problems (if liver damage is severe, paclitaxel is not recommended)
• If your blood cell counts are abnormal
• If you experience irregular heart beats, dizziness or faintness during treatment
• If you experience tingling, burning or numbness in your fingers and/or toes
• If this product is given to you along with radiation treatment (radiotherapy) of the lungs (see 4. Possible side effects)
• If diarrhoea occurs during or shortly after treatment with this product as your colon could be inflamed
• If you have Kaposi’s sarcoma and have a sore or inflamed mouth

Taking/using other medicines

Special care should be taken if you are taking other medicinal products which could interact with paclitaxel.

The following drugs may increase the level of paclitaxel in the blood:

• erythromycin (antibiotic)
• fluoxetine (used to treat nervous disorders such as depression)
• gemfibrozil (used to prevent heart disease)
• nelfmavir and ritonavir (antiviral treatments for HIV/AIDS infection)

The following drugs may decrease the level of paclitaxel in the blood:

• rifampicin (antibiotic)
• carbamazepine, phenytoin and phenobarbital (used to control epilepsy)
• efavirenz and nevirapine (antiviral treatments for HIV/AIDS infection)

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

Pregnancy and breast-feeding

Do not use Paclitaxel concentrate for solution for infusion if you are pregnant or if you and your partner are attempting to become pregnant. This medicine may cause birth defects if either partner is taking it at the time of conception or if it is taken during pregnancy. Use contraception whilst you are receiving treatment with paclitaxel and for six months after treatment has finished. If pregnancy occurs during treatment, or within the six months after treatment has finished, inform your doctor immediately.

Do not use Paclitaxel concentrate for solution for infusion if you are breast feeding or if you wish to start breast feeding whilst you are receiving treatment with paclitaxel.

Driving and using machines

Immediately after a course of treatment, the amount of alcohol in this medicinal product may affect your ability to drive or use machines. In addition, some side effects such as dizziness, nausea or tiredness may affect your ability to drive or operate machinery.

Important information about some of the ingredients of Paclitaxel 6 mg/ml concentrate for solution for infusion

This medicinal product contains polyoxyl castor oil which may cause severe allergic reactions.

It also contains 49.7% vol ethanol (alcohol), i.e. up to 21 g per average dose, equivalent to 740 ml of a 3.5% vol beer, 190 ml of a 14% vol wine per dose. This may be harmful to patients suffering from alcoholism. It should also be taken into account when considering using this medicine in children and high risk groups such as those with liver disease or epilepsy. The alcohol in this medicine may also affect the way other medicines work.

3. HOW TO USE  PACLITAXEL   CONCENTRATE  FOR  SOLUTION  FOR INFUSION

Your treatment will usually be given to you in hospital. Paclitaxel will be given under supervision of a doctor, who can give you more information.

Before you receive your paclitaxel injection you will be given other medicines to prevent allergic reactions (a corticosteroid, e.g. dexamethasone, an antihistamine, e.g. diphenhydramine and an H₂-receptor antagonist, e.g. cimetidine or ranitidine).

Paclitaxel may be given alone or in combination with other anti-cancer medicines. Your doctor will decide on the dose of product you should have and how many doses you will be given. If you are receiving combination treatment with paclitaxel and cisplatin, the paclitaxel should be administered before the cisplatin in order to reduce the possibility of side effects. If you are receiving combination treatment with paclitaxel and doxorubicin, the paclitaxel should be administered 24 hours after doxorubicin.

You will be given paclitaxel as an infusion (slow injection via a drip) into a vein. Tell your doctor or nurse at once if you notice any pain at the injection site during or shortly after treatment. Pain around the injection site could mean the needle has not been properly inserted into the vein.

The dose of paclitaxel will depend on the illness for which you are being treated, the results of your blood tests and any side effects you have had to previous doses. The dose also depends on your body surface area (expressed as mg/m²) which is calculated from your height and weight. Depending on your illness, dosing is typically between 100 mg/m² and 220 mg/m² of paclitaxel given over 3 or 24 hours and repeated every two or three weeks.

As paclitaxel is most likely to be given to you in hospital, under the supervision of a doctor, it is unlikely that you will receive an incorrect dose. However if you have any concerns about the dose you receive, please tell your doctor.

4. POSSIBLE SIDE EFFECTS

Like all medicines, Paclitaxel 6 mg/ml concentrate for solution for infusion can have side effects although not everybody gets them.

If you experience any of the following side effects, tell your doctor immediately as these are all serious. You may need urgent medical attention or hospitalisation.

Uncommon side-effects which may affect more than 1 person in 1000 are listed below:

• Severe chest pains possibly radiating to the jaw or arm, sweating, breathlessness and nausea (heart attack)
• Severe infection including sepsis (blood poisoning) with a state of shock
• Feeling unusually hot or cold (fever or chills)
• Blood clots in the veins (thrombosis) and inflammation of the veins associated with blood clots (thrombophlebitis) – this may present as pain and/or swelling in your arms or legs or inflammation of the vein
• Severe allergic reactions causing low blood pressure, breathing problems, severe itching and/or back pain.

Rare side-effects which may affect less than 1 person in 1000 are listed below:

• Severe allergic reaction (anaphylactic reaction): you may experience a sudden itchy rash (hives), swelling of the hands, feet, ankles, face, lips, mouth or throat (which may cause difficulty in swallowing or breathing), and you may feel you are going to faint
• Shortness of breath, cough, coughing up blood or pain in the chest or shoulder (eg pulmonary embolism). Some of these effects may not occur immediately (lung fibrosis)

Very Rare side-effects which may affect less than 1 person in 10000 are listed below:

• Life-threatening allergic reaction (anaphylactic shock)

Seizures (‘fits’)

• Rapid formation of a rash followed by the appearance of skin lesions on the soles of the feet and palms and ulcers in the mouth (erythema multiforme, Stevens-Johnson syndrome, epidermal necrolysis). Severe skin peeling (exfoliative dermatitis)
• Persistent diarrhoea

Tell your doctor as soon as possible if you notice any of the following:

Very Common side-effects which may affect more than 1 person in 10 are listed below:

• Joint or muscle weakness, pain, aching or loss of sensation in the limbs. These usually reduce or disappear several months after stopping treatment with paclitaxel
• Infection – this may be associated with low blood cell count resulting from receiving paclitaxel
• Bone marrow suppression, which can lead to decreased blood cell counts and may result in infections, anaemia with paleness and weakness, and bruising and bleeding
• Low blood pressure which may cause you to feel light-headed, particularly when standing up
• Pain in the muscle or joints
• Hair loss
• Nausea and vomiting
• Mild diarrhoea
• Soreness of the mouth or tongue
• Mild allergic reactions including flushing and skin rash
• Nerve problems – these may appear as pins and needles in the hands and feet

Common side-effects which may affect more than 1 person in 100 are listed below:

• Slow heart-beat
• Injection site reactions (local swelling, pain, redness, hardening of tissues, extravasation (leaking of drug outside the vein) resulting in cellulitis (painful swelling and redness)
• Temporary mild changes to the nails and skin

Uncommon side-effects which may affect more than 1 person in 1000 are listed below:

• Irregular heartbeats
• Fainting
• High blood pressure (may give you headaches)
• Yellowing of whites of eyes and skin
• Pain in the middle of your chest which may be caused by heart disease
• Pain or weakness in heart muscles (heart muscle degeneration)
• Irregular heartbeat (may be caused by irregular impulse conduction)

Rare side-effects which may affect less than 1 person in 1000 are listed below:

• Pneumonia
• Effect on nerves that control the muscles, resulting in muscle weakness in arms and legs (motor neuropathy)
• Itching, skin rash/redness
• Accumulation of fluid in the whole body (oedema)
• Dehydration
• Loss of energy

Problems with your lungs such as inflammation or accumulation of fluids, which may make it difficult to breathe

Very Rare side-effects which may affect less than 1 person in 10000 are listed below:

• Increased frequency of heartbeat
• Nettle rash (urticaria)
• Effect on the brain (encephalopathy)
• Damage to the liver which may be severe (hepatic necrosis). This may have an effect on brain function (hepatic encephalopathy)
• Loss of hearing or ringing in the ears
• Balance problems
• Visual disturbances
• Staggering when walking
• Dizziness
• Headache
• Constipation
• Abdominal pain which may be caused by accumulation of fluid in the abdomen (ascites), inflammation in your bowel, bowel obstruction, blood clot in the blood vessels to your bowel or perforation of the wall of your bowel
• Inflammation of your pancreas (pancreatitis)
• Loss of appetite
• Confusion
• Shock
• Loosening of finger or toe nails (you are advised to wear protection on your hands and feet when exposed to the sun)
• Heartburn, nausea and/or vomiting which may be caused by inflammation of the gullet
• Cough
• Muscle weakness, cramps, severe bowel or abdominal pain or dizziness when standing up which may be caused by a disease of the nervous system
• Acute leukaemia (blood cancer) or related condition (myelodysplastic syndrome) which your doctor will check for
• Like many other anti-cancer medicines, paclitaxel may cause sterility, which could be permanent.

Paclitaxel may cause inflammation of the lungs when used in combination with, or after, radiotherapy.

Laboratory tests (eg blood tests) may be performed to check for changes in liver activity, kidney function and blood cells, which are side effects of paclitaxel treatment.

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 PACLITAXEL CONCENTRATE FOR SOLUTION FOR INFUSION

Keep out of the reach and sight of children.

Do not use Paclitaxel concentrate for solution for infusion after the expiry date printed on the vial label and carton. The expiry date refers to the last day of that month.

Do not store above 25°C. Keep the vial in the outer carton, in order to protect from light.

The infusion should be clear and colourless to pale yellow. Infusions which contain clear particles or are strongly coloured should not be used.

6. FUTHER INFORMATION

What Paclitaxel concentrate for solution for infusion contains

The active substance is paclitaxel. Each ml of concentrate contains 6 mg of paclitaxel.

The other ingredients are macrogolglycerol ricinoleate (polyoxyl castor oil), ethanol (49.7% v/v) and citric acid anhydrous.

What Paclitaxel concentrate for solution for infusion looks like and contents of the pack

This medicinal product is a concentrate for solution (sterile concentrate). This means that the concentrated solution in the vial must be diluted prior to use. Once diluted it is given as a slow injection into a vein. The sterile concentrate is a clear, colourless to pale yellow solution.

This medicinal product contains 6 mg of paclitaxel per ml of concentrate. It is available in four vial sizes: 30 mg/5 ml, 100 mg/16.7 ml, 150 mg/25 ml, or 300 mg/50 ml. Each presented in packs containing a single vial. Not all presentations may be marketed.

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

Further to the information included in section 3 practical information on the preparation/handling of the medicinal product is provided here.

Instructions for use, handling and disposal

Handling: Paclitaxel is a cytotoxic anticancer medicinal product and caution should be exercised in handling paclitaxel. Dilution should be carried out under aseptic conditions, by trained personnel in a designated area. Appropriate gloves should be used. Contact of paclitaxel with skin and mucous membranes should be avoided.

If paclitaxel solution contacts the skin, wash the skin immediately and thoroughly with soap and water. Following topical exposure, events have included tingling, burning, and redness. If paclitaxel contacts mucous membranes, the membranes should be flushed thoroughly with water. Upon inhalation, dyspnoea, chest pain, burning throat, and nausea have been reported.

Preparation for IV Administration: During dilution of the concentrate for infusion, cytostatic dispensing needles or similar devices with spikes should not be used with vials of paclitaxel since they can cause the stopper to collapse resulting in loss of sterile integrity of the solution.

Prior to infusion, paclitaxel must be diluted to a ready-to-use solution for infusion (0.3 to 1.2 mg/ml) using aseptic techniques with one of the following solutions:

•   9 mg/ml (0.9%) sodium chloride solution for infusion,

•   50 mg/ml (5%) glucose solution for infusion,

•   50 mg/ml glucose- and 9 mg/ml sodium chloride solution for infusion, or

•   Ringer’s solution containing 50 mg/ml glucose.

Once diluted, the ready-to-use infusions are for single use only.

After dilution chemical and physical in-use stability has been demonstrated for 72 hours at 25°C, stored under normal lighting conditions.

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

After first use and following multiple needle entries and product withdrawals, any unused concentrate maintains microbial, chemical and physical stability when stored below 25 °C, protected from light for up to 28 days. Other in-use storage times and conditions are the responsibility of the user.

The ready-to-use infusion should be visually inspected for particulate matter and discoloration.

Upon preparation, solutions may show haziness, which is attributed to the formulation vehicle, and is not removed by filtration. However haziness does not affect the potency of the product. The solution for infusion should be administered through an in-line filter with microporous membrane not greater than 0.22 microns. No significant losses in potency have been noted following simulated delivery of the solution through I.V. tubing containing an inline (0.22 micron) filter.

There have been some reports of precipitation during paclitaxel infusions, with precipitation usually taking place towards the end of a 24-hour infusion period. To reduce the risk of precipitation, paclitaxel should be used as soon as possible after dilution and excessive shaking or agitation should be avoided. The infusion solution should be regularly inspected during infusion and the infusion should be discontinued if precipitation occurs.

To minimise patient exposure to DEHP which may be leached from plasticised PVC infusion bags, sets, or other medical instruments, diluted paclitaxel solutions should be stored in non-PVC bottles (glass, polypropylene) or plastic bags (polypropylene, polyolefin) and administered through polyethylene-lined administration sets. Use of filter devices which incorporate short inlet and/or outlet plasticised PVC tubing has not resulted in significant leaching of DEHP.

Disposal: All items used for preparation, administration, infusion, or otherwise coming into contact with paclitaxel should be placed in an appropriate safety container and disposed according     to     local     guidelines     for     the     handling     of    cytotoxic     compounds.

Litak 2 mg/ml solution for injection

Cladribine

1. What Litak is and what it is used for

Litak contains the active substance cladribine. Cladribine is a cytostatic agent. It affects the growth of malignant (cancerous) white blood cells which play a role in hairy cell leukaemia. Litak is used to treat this disease.

2. Before you use Litak

Do not use Litak

• if you are allergic (hypersensitive) to cladribine or any of the other ingredients of Litak
• if you are pregnant or breast-feeding
• if you are less than 18 years of age
• if you have moderate to severe kidney or liver impairment
• if you are using other medicines which affect the production of blood cells in the bone marrow (myelosuppression).

Take special care with Litak

Tell your doctor if you have or have had: liver or kidney problems infections

• if you suffer from an infection, this will be treated before you start using Litak.
• if you notice any signs of infections (such as flu-like symptoms or fever) during or after treatment with Litak, inform your doctor immediately.
• fever

Before and during treatment with Litak, you will have regular blood tests to check whether it is safe for you to continue with your treatment. Your doctor may decide that you should receive blood transfusions to improve your level of blood cells. In addition, the proper function of your liver and your kidneys will be checked.

If you want to father a child, please tell your doctor before treatment with Litak is started. You should not father a child during treatment and up to 6 months after treatment with Litak. Your doctor may advise you about the possibility to store deep-frozen sperm (cryoconservation).

Using other medicines

Please tell your doctor if you are taking or have recently taken any other medicines, including medicines obtained without a prescription. In particular, tell your doctor if you are using any medicines containing:

• corticosteroids, commonly used to treat inflammation
• antiviral agents, used to treat viral infections

You must not use Litak with other medicines that affect the production of blood cells in the bone marrow (myelosuppression).

Pregnancy and breast-feeding

Your must not use Litak if you are pregnant. You must take adequate contraceptive precautions during therapy and for at least six months after your last Litak dose. If pregnancy occurs during your treatment, you must immediately inform your doctor.

You must not breast-feed while you are treated with Litak and for at least six months after your last Litak dose.

Driving and using machines

Litak has a major effect on the ability to drive and use machines. If you feel drowsy, which may occur due to a low number of red blood cells caused by Litak treatment, or dizzy, you should not drive or use machines.

3. How to use Litak

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

Your doctor will calculate your dose according to your body weight and explain the treatment schedule in detail. The recommended daily dose is 0.14 mg per kg body weight for five consecutive days (single treatment course).

Litak has to be injected under your skin (subcutaneous injection), at about the same time each day. If you are injecting Litak yourself, first you must receive adequate training by your doctor or nurse. You will find detailed instructions for injection at the end of this leaflet.

You may also receive an additional medicine containing the active substance allopurinol in order to reduce excess of uric acid.

• If you use more Litak than you should

In case you inject an incorrect dose, tell your doctor immediately.

• If you forget to use Litak

Do not inject a double dose to make up for a forgotten dose. In case you miss an injection of a dose, tell your doctor immediately.

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

4. Possible side effects

Like all medicines, Litak can have side effects, although not everybody gets them.

Tell your doctor immediately if you have any of the following during or after treatment with Litak: any signs of infections (such as flu-like symptoms) fever

Repeated occurrence of malignant (cancerous) disease cannot be excluded. This means that the risk that you develop a malignant disease in the future is slightly higher than for healthy people. This slightly increased risk can be due to hairy cell leukaemia or to therapies used to treat the disease including Litak.

Side effects may occur with certain frequencies, which are defined as follows: very common: affects more than 1 user in 10 common: affects 1 to 10 users in 100 uncommon: affects 1 to 10 users in 1,000 rare: affects 1 to 10 users in 10,000 very rare: affects less than 1 user in 10,000 not known: frequency cannot be estimated from the available data.

Very common side effects

• Infections.
• Fever.
• Low numbers of certain white blood cells (neutrophils and lymphocytes) and platelets in blood tests.
• Low number of red blood cells, which may result in anaemia, with symptoms such as tiredness and drowsiness.
• Reduced function of your body’ s immune system.
• Headache, dizziness.
• Abnormal breath sounds, abnormal chest sounds, cough.
• Feeling sick, vomiting, constipation and diarrhoea.
• Skin eruption (rash), swelling, redness as well as soreness around the site of injection, sweating. Skin reactions are mostly mild to moderate and usually resolve within a few days.
• Tiredness, chills, decreased appetite.
• Weakness.

Common side effects

• Repeated occurrence of malignant (cancerous) disease.
• Low number of platelets, which can cause unusual bleeding (for example nose or skin bleeds).
• Sleeplessness, anxiety.
• Increased heart rate, abnormal heart sound, low blood pressure, decreased blood supply to the heart muscle.
• Shortness of breath, swelling in lung tissue due to infection, inflammation of mouth and tongue.
• Abdominal pain and presence of excessive amount of gas in the stomach or bowels, mostly mild increases in liver laboratory values (bilirubin, transaminases) which will return to normal values once treatment is over.
• Itching, itching skin eruption (urticaria), redness of the skin and skin pain.
• Swelling in tissues (oedema), not feeling well, pain (muscle pain, joint pain, and bone pain).

Uncommon side effects

• Anaemia caused by destruction of red blood cells.
• Sleepiness, numbness and tingling of the skin, feebleness, inactivity, disorder of peripheral nerves, confusion, impaired ability to coordinate movements.
• Eye inflammation.
• Sore throat.
• Inflammation of a vein.
• Severe weight loss.
• Rare side effects
• Reduced liver function.
• Reduced kidney function.
• Complications caused by cancer treatment due to break-down of cancer cells.
• Rejection response to blood transfusions.
• Increased number of certain white blood cells (eosinophils). Stroke.
• Disturbances in speech and swallowing.
• Heart failure.
• Abnormal heart rhythm.
• Inability of the heart to maintain adequate blood circulation.
• Obstruction of the bowels.
• Serious allergic skin reaction (Stevens-Johnson syndrome or Lyell syndrome).

Very rare side effects

• Depression, epileptic attack.
• Swelling of the eyelid.
• Blood clot in the lung.
• Inflammation of the gallbladder.

Reduced function of organs due to high amounts of a specific substance produced by the body (a glycoprotein).

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 Litak

Keep out of the reach and sight of children.

Store in a refrigerator (2°C-8°C). Do not freeze.

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

From a microbiological point of view, unless the opening precludes the risk of microbiological contamination, the product should be used immediately. If not used immediately, in-use storage times and conditions are the responsibility of the user.

Do not use Litak if you notice that the vial is damaged or that the solution is not clear or contains any particles.

Any unused product or waste material should be disposed of in accordance with local requirements.

6. Further information

• What Litak contains

The active substance is cladribine. Each ml solution contains 2 mg cladribine. Each vial contains 10 mg cladribine in 5 ml solution.

The other ingredients are sodium chloride, sodium hydroxide (for pH adjustment), hydrochloric acid (for pH adjustment) and water for injections.

• Instructions for injection

This section contains information on how to give an injection of Litak. It is important that you do not try to give yourself the injection unless you have been instructed by your doctor or nurse. Your doctor will tell you how much Litak you need and how often and when you have to inject yourself. Litak should be injected into the tissue just under the skin (subcutaneous injection). If you have any question with regard to giving the injection, please ask your doctor or nurse for help.

Litak is a cytotoxic and should therefore be handled with caution. When Litak is not self-administered by the patient, the use of disposable gloves and protective garments is recommended when handling and administering Litak. If Litak contacts the skin or eyes, rinse the involved surface immediately with copious amounts of water. Pregnant women must avoid contact with Litak.

What do I need for the injection?

To give yourself a subcutaneous injection, you will need:

• one vial of Litak (or two vials if you need to inject more than 5 ml). Do not use vials which are damaged, or if the solution is not clear or if it contains any particles.
• one sterile syringe (e.g. 10 ml LUER syringe),
• one sterile injection needle (e.g. 0.5 x 19 mm, 25 G x %”),
• alcohol wipes,
• a puncture-proof container for safe disposal of the used syringe.

What should I do before I give myself a subcutaneous injection of Litak?

1. Before injection, allow Litak to warm up to room temperature.

2. Wash your hands thoroughly.

3. Find a comfortable, well-lit place and put everything you need where you can reach it. How do I prepare the injection?

Before you inject Litak, you must do the following:

1. Remove the red protective cap from the Litak vial. Do not remove the rubber stopper of the vial. Clean the rubber top of the vial with an alcohol wipe. Remove the syringe from the wrapping without touching the tip of the syringe. Remove the injection needle from the wrapping and place it firmly on the tip of the syringe. Remove the needle guard without touching the needle.

2. Push the needle through the rubber stopper of the vial and turn the vial and the syringe upside down. Be sure that the tip of the needle is in the solution.

3. Draw the correct volume of Litak into the syringe by pulling back the plunger (your doctor will inform you how many ml of Litak you need to inject).

4. Pull the needle out of the vial.

5. Make sure there is no air left in the syringe: point the needle upwards and push the air out.

6. Check you have the right volume.

7. Inject straight away. Where should I give my injection?

The most suitable places to inject yourself are shown here: the top of your thighs and the abdomen, except for the area around the navel. If someone else is injecting you, they can also use the outer surface of the upper arms or the buttocks.

How do I give my injection?

1. Disinfect your skin by using an alcohol wipe, wait for the area to dry and pinch the skin between your thumb and forefinger, without squeezing it.

2. Put the needle fully into the skin at an angle of about 45°, as shown in the picture.

3. Pull slightly on the plunger to check that no blood vessel has been punctured. If you see blood in the syringe, remove the needle and re-insert it in another place.

4. Inject the liquid slowly and evenly for approximately one minute, always keeping the skin pinched.

5. After injecting the liquid, remove the needle.

6. Put the used syringe in the puncture-proof container. Use a new syringe and injection needle for each injection. The vials are for single use only. Return any portion of the contents remaining after use to your doctor or pharmacist for proper disposal.

Disposing of used syringes

Put used syringes into a puncture-proof container and keep it out of the reach and sight of children.

Dispose the puncture-proof container as instructed by your doctor, nurse or pharmacist. Do not put used syringes into the normal household garbage bin.

Leustat injection

Cladribine

1. What Leustat is and what it is used for

Leustat contains a medicine called cladribine. This belongs to a group of medicines used to treat cancer (called ‘cytotoxic drugs’).

Leustat is for:

• An illness caused by the abnormal growth of white blood cells. This is called ‘hairy cell leukaemia’

• An illness caused by the abnormal growth of a type of white blood cell called ‘lymphocytes’. This illness is called ‘B-cell chronic lymphocytic leukaemia’. In this case, Leustat is used when the first treatment (called an ‘alkylating agent’) has not worked or has stopped working

Leustat works by killing abnormal white blood cells.

2. Before you are given Leustat

Do not have Leustat if:

•  You are allergic to anything in Leustat.

Take special care

Talk to your doctor before you are given Leustat if:

• You are suffering from any infection or fever

• You have ever had kidney or liver problems

• You have ever had bone marrow or blood problems

You may still be able to have Leustat, but you should discuss this with your doctor first.

Taking other medicines

Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines. This includes medicines that you buy without a prescription or herbal medicines. In particular tell your doctor if you are already taking or are to be given:

• A live vaccine while being treated with Leustat

• Medicines to treat viral infections including HIV (such as didanosine, tenofovir, adefovir)

Blood tests

• Your doctor will arrange regular blood tests before and during your treatment. The blood tests check that your liver and kidneys are working properly. They also check how the Leustat treatment is working

• If you visit another hospital or your family doctor for a blood test, tell them that you have been given Leustat. This is because Leustat may affect the result of blood tests

Pregnancy and breast-feeding

Do not use this medicine if you are pregnant, think you may be pregnant or might become pregnant. This is because it may affect the baby.

You must not breast-feed while you are being treated with Leustat, or for 6 months after your treatment ends.

Ask your doctor or pharmacist for advice before taking any medicine if you are pregnant or breast-feeding.

Family planning

Men should not father a child until at least 6 months after the last dose of Leustat.

Driving or using machines

Your illness and its treatment may affect you being able to drive. Do not drive or use any tools or machines without discussing this with your doctor first.

Important information about an ingredient of Leustat

If you need to control your salt intake (controlled sodium diet) be aware that:

• Each Leustat vial contains 1.55 mmol sodium (35.4 mg)

• The contents of the vial are diluted in a salt solution (called ‘saline’) before

being given to you. This salt solution also contains sodium

3. How Leustat is used

Leustat is put in a drip and given slowly into a vein. It is normally diluted in a salt solution (called ‘saline’). A doctor experienced at using this type of medicine will give it to you. Check with your doctor or nurse if you are not sure about anything.

Adults and the elderly

The dose of Leustat is based on your body weight in kilograms.

For abnormal growth of hairy white blood cells:

•The usual dose is 0.09 mg per kilogram each day

• The dose is given over 24 hours every day for 7 days, without a break

For abnormal growth of lymphocyte white blood cells:

• The usual dose is 0.12 mg per kilogram each day

• The dose is given every day for 5 days

• Each dose is normally given over 2 hours

• The 5 day course is repeated every 28 days

• You can receive a maximum of 6 of these courses

Children

Leustat has not been fully tested for use in children.

If you have too much Leustat

Tell your doctor or nurse straight away if you think you have been given too much Leustat.

4. Possible side effects

Like all medicines, Leustat can cause side effects, although not everybody gets them. Some side effects may be the same as symptoms of the illness. Your doctor may decide to delay or stop using Leustat if you get side effects.

Tell your doctor or nurse straight away if you notice any of the following serious side effects. You may need urgent medical treatment.

• The sudden appearance of rash, itching, hives (also known as nettle rash or urticaria), swollen face or lips, or shortness of breath. These may be signs of an allergic reaction.

• Fever and chills (affects more than 1 in 10 people). These may be the first signs that you have an infection. The infection may happen because of a fall in the number of white blood cells (neutropenia). Some infections are more common than others. Infection can happen anywhere in your body including:

• Your chest (cough, shortness of breath or difficulty breathing, noisy breathing, pneumonia)

• Your urinary system (pain or discomfort on passing water)

• Your skin (bacterial, fungal or viral infections that may leave the skin tender, hot or red)

• Your mouth (a fungal infection called thrush)

• Your gut (infection or inflammation of the intestines)

• Your blood (septicaemia)

• Easier bruising and bleeding under the skin (thrombocytopenia) or red or purple spots under the skin (petechiae). This can be caused by a fall in the number of small blood cells called platelets (affects more than 1 in 10 people) or problems with blood clotting.

• Feeling weak or breathless. This can be caused by a fall in the number of red blood cells (anaemia). The anaemia may be severe (affects more than 1 in 10 people)

• Build-up of fluid under the skin called oedema (affects more than 1 in 10 people)

• Swelling and clotting in a vein called phlebitis (affects less than 1 in 10 people)

• Stevens-Johnson syndrome (a serious illness with blistering of the skin, mouth, eyes and genitals) (affects less than 1 in 100 people)

• Tumour lysis syndrome (a serious condition resulting from breakdown of tumour cells. This can lead to heart and kidney problems, weakness and fits) (affects less than 1 in 100 people)

Tell your doctor or nurse at your next appointment if you notice any of the following side effects:

Very common (affects more than 1 in 10 people)

• Feeling dizzy or tired

• Headache

• Rash, sweating

• Feeling sick (nausea), being sick (vomiting)

• Redness, swelling or pain where the injection was given

Common (affects less than 1 in 10 people)

• Faster heart beat

• Stomach pain or wind (flatulence)

• Having less appetite

• Constipation or diarrhoea

• Joint pain, muscle pains or weakness

• Generalised pain

• Anxiety or difficulty sleeping (insomnia)

• Itching (pruritus)

• Conjunctivitis

• Generally feeing unwell

Uncommon (affects less than 1 in 100 people)

• A problem that affects the body being able to produce white blood cells, red blood cells and small blood cells (platelets). The effects may need further treatment

• An increase in a particular type of white blood cell (eosinophil)

• A decrease in the ability of your kidneys being able to get rid of waste products from the blood, and a decrease in urine production

• Serious nerve damage. The effects include partial or complete paralysis and may be permanent

• An increase in liver enzymes (shown in blood tests)

• Confusion, reduced consciousness, co-ordination problems (ataxia)

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

5. How Leustat is stored

The vials are stored unopened in a hospital refrigerator where children can’t see or reach them. Vials should be protected from light.

Do not use Leustat after the expiry date stated on the label. The expiry date refers to the last day of that month.

Do not use Leustat if:

• The seal is broken or a dose has already been taken from the vial

• The liquid is coloured or you can see particles floating in it

• It has been diluted and refrigerated for more than 8 hours

• It has been diluted with a solution of 5% dextrose

6. Further information

The active substance in Leustat is cladribine (1 mg/ml).

The other ingredients are sodium chloride, phosphoric acid, dibasic sodium phosphate heptahydrate and water for injection.

What Leustat looks like and contents of the pack

Leustat is supplied in a clear glass vial containing 10 ml of a clear, colourless liquid.

Doribax 500 mg powder for solution for infusion

Doripenem

1.  WHAT DORIBAX IS AND WHAT IT IS USED FOR

Doribax is an antibiotic. Doribax works by killing different types of bacteria (germs) that cause infections in various parts of the body.

Doribax is used for the following infections:

Pneumonia (a serious type of chest or lung infection) that you catch in a hospital or similar setting.

This includes pneumonia that you catch when on a machine that helps you breathe

Complicated infections of the area around your stomach (abdominal infections)

Complicated urinary tract infections, including kidney infections and cases that have spread to the bloodstream.

2.  BEFORE YOU USE DORIBAX

Do not use Doribax

• If you are allergic (hypersensitive) to doripenem
• If you are allergic to other antibiotics such as penicillins, cephalosporins or carbapenems (which are used to treat various infections) as you may also be allergic to Doribax.

Do not use Doribax if any of the above applies to you. If you are not sure, talk to your doctor or pharmacist before being given Doribax.

Take special care with Doribax

If you have:

• Kidney problems. Your doctor may need to lower your dose of Doribax
• Diarrhoea. It is important that you tell your doctor if you have bloody diarrhoea before, during or after your treatment with Doribax. This is because you may have a condition known as colitis (an inflammation of the bowel). Do not take any medicine to treat diarrhoea without first checking with your doctor.
• Convulsions have infrequently been reported during treatment with closely related antibiotics.

While antibiotics including Doribax kill certain bacteria, other bacteria and fungi may continue to grow more than normal. This is called overgrowth. Your doctor will monitor you for overgrowth and treat you if necessary.

Tell your doctor if you are taking medicines called valproic acid or sodium valproate (see Taking other medicines below).

Doribax should not be inhaled as it may cause inflammation of the lung (pneumonitis).

Doribax should not be given to children or adolescents (under 18 years of age) as there is not enough information to be sure that Doribax can be used safely in children or adolescents.

• Taking other medicines

Always tell your doctor or pharmacist if you are taking or have recently taken any other medicines, This includes medicines you get without a prescription or herbal medicines. Tell your doctor if you are taking medicines called valproic acid or sodium valproate (used to treat epilepsy, bipolar disorder, migraines or schizophrenia) or probenecid (used to treat gout or high levels of uric acid in the blood) as these medicines may affect Doribax.

• Pregnancy and breast-feeding

Tell your doctor or pharmacist before using Doribax if:

-    You are pregnant or think you may be pregnant. Your doctor will decide whether you should use

Doribax

-    You are breast-feeding or if you plan to breast-feed. Small amounts of this medicine may pass into

breast milk and it may affect the baby. Therefore, your doctor will decide whether you should use Doribax while breastfeeding.

Driving and using machines

Doribax is not likely to affect your ability to drive or operate machinery.

3. HOW TO USE DORIBAX

• How Doribax is given

Doribax will be prepared and given to you by a doctor or nurse over one or four hours as an intravenous infusion into one of your veins (this is sometimes known as a “drip”)

• How much Doribax is given

-     Your doctor will decide how much Doribax you need and for how long

Adults (including people over 65 years of age)

The usual dose is 500 mg every eight hours. Each dose is given over a period of one or four hours The course usually lasts 5 to 14 days

If you have kidney problems, your doctor may lower your dose of Doribax to 250 mg given over one or four hours every eight or 12 hours

If you use more Doribax than you should

If you are concerned that you may have been given too much Doribax, talk to your doctor or pharmacist straight away.

If a Doribax dose has been missed

If you are concerned that you may have missed a dose of Doribax, talk to your doctor or pharmacist straight away. It is important that you receive treatment with Doribax as long as your doctor feels it is necessary.

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

4.  POSSIBLE SIDE EFFECTS

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

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

very common (affects more than 1 user in 10)

common (affects 1 to 10 users in 100)

uncommon (affects 1 to 10 users in 1,000)

rare (affects 1 to 10 users in 10,000)

very rare (affects less than 1 user in 10,000)

not known (frequency cannot be estimated from the available data).

Very common

Headache

Common

Rash, itching or hives

Diarrhoea. Tell your doctor straight away if you get bloody diarrhoea before, during or after your

treatment with Doribax

Feeling sick (nausea)

Vein wall inflammation where the intravenous infusion (or “drip”) goes into your vein (phlebitis)

Fungal infections (thrush) in your mouth or vagina

Increase in the level of some liver enzymes in your blood

Uncommon

Inflammation of the bowel with diarrhoea (Clostridium difficile colitis)

Decrease of blood platelet count

Decrease of white blood cells which may increase your risk of infections

Sudden swelling of your lips, face, throat or tongue, a rash, swallowing or breathing problems. These may be signs of a severe allergic reaction (anaphylaxis) and may be life-threatening. Tell your doctor straight away if you get these as you may need urgent medical treatment.

The following side effects we res also seen in a small number of patients:

Serious skin reactions, with a widespread rash with peeling skin and blistering in the mouth, eyes and genitals (toxic epidermal necrolysis or Stevens-Johnson syndrome)

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 DORIBAX

Keep out of the reach and sight of children.

Do not use this medicine after the expiry date stated on the container. The first two numbers indicate the month. The next four numbers indicate the year. The expiry date refers to the last day of that month.

This medicinal product does not require any special storage conditions.

Medicines should not be disposed of via wastewater or household waste. These measures will help to protect the environment.

6.  FURTHER INFORMATION

• What Doribax contains

The active substance is doripenem. Each vial contains doripenem monohydrate equivalent to 500 mg doripenem

• What Doribax looks like and contents of the pack

Doribax is a white to slightly yellowish off-white crystalline powder in a glass vial. Doribax is supplied in packs of 10 vials.

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

Each vial is for single use only.

Doribax is reconstituted and then further diluted prior to infusion.

Preparation of 500 mg dose of solution for infusion using the 500mg vial

1.  Add 10 ml of sterile water for injections or sodium chloride 9 mg/ml (0.9%) solution for injection to the 500mg vial and shake it to form a suspension

2.  Inspect the suspension visually for foreign matter. Note: the suspension is not for direct infusion.

3.  Withdraw the suspension using a syringe and needle and add it to an infusion bag containing 100 ml of either sodium chloride 9 mg/ml (0.9%) solution for injection or dextrose 50 mg/ml (5%) solution for injection and mix to complete dissolution. Infuse all of this solution to administer a 500 mg dose of doripenem.

Preparation of 250 mg dose of solution for infusion using the 500mg vial

1.  Add 10 ml of sterile water for injections or sodium chloride 9 mg/ml (0.9%) solution for injection to the 500mg vial and shake it to form a suspension.

2.  Inspect the suspension visually for foreign matter. Note: the suspension is not for direct infusion.

3.  Withdraw the suspension using a syringe and needle and add it to an infusion bag containing 100 ml either sodium chloride 9 mg/ml (0.9%) solution for injection or dextrose 50 mg/ml (5%) solution for injection and mix to complete dissolution.

4.  Remove 55 ml of this solution from the infusion bag and discard. Infuse all of the remaining solution to administer a 250 mg dose of doripenem.

Doribax solutions for infusion range from clear, colourless solutions to solutions that are clear and slightly yellow. Variations in colour within this range do not affect the potency of the product.

Storage of reconstituted solutions

Upon reconstitution with sterile water for injections or sodium chloride 9 mg/ml (0.9%) solution for injection, Doribax suspension in the vial may be held for up to 1 hour below 30°C prior to transfer and dilution in the infusion bag.

Following dilution in the infusion bag with sodium chloride 9 mg/ml (0.9%) solution for injection or dextrose 50 mg/ml (5%) solution for injection, Doribax infusions stored at room temperature or under refrigeration should be completed according to the times in the following table:

Time by which reconstitution, dilution and infusion must be completed for Doribax infusions solutions

*Once removed from the refrigerator, infusions should be completed within the room temperature stability time, provided the total refrigeration time, time to reach room temperature and infusion time does not exceed refrigeration stability time.

⁺ Dextrose 50 mg/ml (5%) solution for injection should not be used for infusion durations greater than 1 hour.

Chemical and physical in-use stability has been demonstrated for the times and solutions shown in the above Table.

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

Any unused product or waste material should be disposed of in accordance with local requirements.

Augmentin 125/31 SF Suspension

Co-amoxiclav (Amoxicillin and Clavulanic Acid)

Augmentin is an antibiotic and works by killing bacteria that cause infections. It contains two different medicines called amoxicillin and clavulanic acid. Amoxicillin belongs to a group of medicines called “penicillins” that can sometimes be stopped from working (made inactive). The other active component (clavulanic acid) stops this from happening.

Augmentin is used in babies and children to treat the following infections:

•   middle ear and sinus infections

•   respiratory tract infections

•   urinary tract infections

•   skin and soft tissue infections including dental infections

•   bone and joint infections.

Do not give your child Augmentin:

•   if they are allergic (hypersensitive) to amoxicillin, clavulanic acid or any of the other ingredients of Augmentin (listed in section 6)

•   if they have ever had a severe allergic (hypersensitive) reaction to any other antibiotic. This can include a skin rash or swelling of the face or neck

•   if they have ever had liver problems or jaundice (yellowing of the skin) when taking an antibiotic.

Do not give Augmentin to your child if any of the above apply to your child.

If you are not sure, talk to their doctor or pharmacist before giving  Augmentin.

Take special care with Augmentin

Check with their doctor or pharmacist before giving your child this medicine if they:

•   have glandular fever

•   are being treated for liver or kidney problems

•   are not passing water regularly.

If you are not sure if any of the above apply to your child, talk to their doctor or pharmacist before giving Augmentin.

In some cases, your doctor may investigate the type of bacteria that is causing your child’s infection. Depending on the results, your child may be given a different strength of Augmentin or a different medicine.

Conditions you need to look out for

Augmentin can make some existing conditions worse, or cause serious side effects. These include allergic reactions, convulsions (fits) and inflammation of the large intestine. You must look out for certain symptoms while your child is taking Augmentin, to reduce the risk of any problems.

Blood or urine tests

If your child is having blood tests (such as red blood cell status tests or liver function tests) or urine tests, let the doctor or nurse know that they are taking Augmentin. This is because Augmentin can affect the results of these types of tests.

Using other medicines

Please tell your doctor or pharmacist if your child is taking or has recently taken any other medicines. This includes medicines that can be bought without a prescription and herbal medicines.

If your child is taking allopurinol (used for gout) with Augmentin, it may be more likely that they will have an allergic skin reaction.

If your child is taking probenecid (used for gout), your doctor may decide to adjust the dose of Augmentin.

If medicines to help stop blood clots (such as warfarin) are taken with Augmentin then extra blood tests may be needed.

Augmentin can affect how methotrexate (a medicine used to treat cancer or rheumatic diseases) works.

Pregnancy and breast-feeding

If your child who is about to take this medicine is pregnant or breast-feeding, please tell your doctor or pharmacist.

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

Important information about some of the ingredients of Augmentin

•  Augmentin contains aspartame (E951) which is a source of phenylalanine. This may be harmful for children born with a condition called ‘phenylketonuria’.

•  Augmentin contains maltodextrin (glucose). If you have been told by your doctor that your child has an intolerance to some sugars, contact your doctor before taking this medicinal product.

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

Adults and children weighing 40 kg or over

•  This suspension is not usually recommended for adults and children weighing 40 kg and over. Ask your doctor or pharmacist for advice.

Children weighing less than 40 kg

All doses are worked out depending on the child’s bodyweight in kilograms.

•  Your doctor will advise you how much Augmentin you should give to your baby or child.

•  You may be provided with a plastic measuring spoon or measuring cup. You should use this to give the correct dose to your baby or child.

•   Usual dose – 20 mg/5 mg to 60 mg/15 mg for each kilogram of bodyweight a day, given in three divided doses.

Patients with kidney and liver problems

•   If your child has kidney problems the dose might be lowered. A different strength or a different medicine may be chosen by your doctor.

•   If your child has liver problems they may have more frequent blood tests to see how their liver is working.

How to give Augmentin

•  Always shake the bottle well before each dose

•   Give at the start of a meal or slightly before

•  Space the doses evenly during the day, at least 4 hours apart. Do not take 2 doses in 1 hour.

•   Do not give your child Augmentin for more than 2 weeks. If your child still feels unwell they should go back to see the doctor.

If you give more Augmentin than you should

If you give your child too much Augmentin, signs might include an upset stomach (feeling sick, being sick or diarrhoea) or convulsions. Talk to their doctor as soon as possible. Take the medicine bottle to show the doctor.

If you forget to give Augmentin

If you forget to give your child a dose, give it as soon as you remember. You should not give your child the next dose too soon, but wait about 4 hours before giving the next dose.

If your child stops taking Augmentin

Keep giving your child Augmentin until the treatment is finished, even if they feel better. Your child needs every dose to help fight the infection. If some bacteria survive they can cause the infection to come back.

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

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

Conditions you need to look out for

Allergic reactions:

•  skin rash

•   inflammation of blood vessels (vasculitis) which may be visible as red or purple raised spots on the skin, but can affect other parts of the body

•  fever, joint pain, swollen glands in the neck, armpit or groin

•  swelling, sometimes of the face or mouth (angioedema), causing difficulty in breathing

•  collapse.

Contact a doctor immediately if your child gets any of these symptoms. Stop taking Augmentin.

Inflammation of large intestine

Inflammation of the large intestine, causing watery diarrhoea usually with blood and mucus, stomach pain and/or fever. Contact your doctor as soon as possible for advice if your child gets these symptoms.

Very common side effects

These may affect more than 1 in 10 people

•  diarrhoea (in adults).

Common side effects

•  These may affect up to 1 in 10 people

•  thrush (Candida – a yeast infection of the vagina, mouth or skin folds)

•  feeling sick (nausea), especially when taking high doses

-    if affected take Augmentin before food

•  vomiting

•  diarrhoea (in children).

Uncommon side effects

These may affect up to 1 in 100 people

•  skin rash, itching

•   raised itchy rash (hives)

•   indigestion

•  dizziness

•   headache.

Uncommon side effects that may show up in blood tests:

•   increase in some substances (enzymes) produced by the liver.

Rare side effects

These may affect up to 1 in 1000 people

•  skin rash, which may blister, and looks like small targets (central dark spots surrounded by a paler area, with a dark ring around the edge – erythema multiforme)

- if you notice any of these symptoms contact a doctor urgently.

Rare side effects that may show up in blood tests:

•   low number of cells involved in blood clotting

•   low number of white blood cells.

Other side effects

Other side effects have occurred in a very small number of people but their exact frequency is unknown.

•  Allergic reactions (see above)

•   Inflammation of the large intestine (see above)

•  Serious skin reactions:

-    a widespread rash with blisters and peeling skin, particularly around the mouth, nose, eyes and genitals {Stevens-Johnson syndrome), and a more severe form, causing  extensive peeling of the skin (more than 30% of the body surface – toxic epidermal necrolysis)

- widespread red skin rash with small pus-containing blisters {bullous exfoliative dermatitis)

- a red, scaly rash with bumps under the skin and blisters {exanthemouspustulosis).

Contact a doctor immediately if your child gets any of these symptoms.

•   inflammation of the liver (hepatitis)

•  jaundice, caused by increases in the blood of bilirubin (a substance produced in the liver) which may make your child’s skin and whites of the eyes appear yellow

•   inflammation of tubes in the kidney

•   blood takes longer to clot

•   hyperactivity

•   convulsions (in people taking high doses of Augmentin or who have kidney problems)

•   black tongue which looks hairy

•   stained teeth (in children), usually removed by brushing.

Side effects that may show up in blood or urine tests:

•   severe reduction in the number of white blood cells

•   low number of red blood cells {haemolytic anaemia)

•   crystals in urine.

If your child gets side effects

•  Tell your doctor or pharmacist if any of the side effects become severe or troublesome, or if you notice any side effects not listed in this post.

•   Keep out of the reach and sight of children.

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

•  The expiry date which is stated on the bottle label is for the pharmacist’s use. The pharmacist will have made up your medicine. It should be used within 7 days.

•   Store in the fridge, but do not freeze.

•   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.

What Augmentin contains

•  The active substances are 125 mg amoxicillin and 31.25 mg clavulanic acid (present as potassium clavulanate) in every 5 ml of suspension

•  The other ingredients are xanthan gum (E415), hydroxypropyl methylcellulose (E464), aspartame (see section 2), silicon dioxide, colloidal silica, succinic acid, raspberry, orange and golden syrup flavours and water.

What Augmentin looks like and contents of the pack

A clear glass bottle containing 100 ml of an off-white liquid mixture called a suspension. The bottle is supplied in a carton.

Advice/medical education

Antibiotics are used to treat infections caused by bacteria. They have no effect against infections caused by viruses.

Sometimes an infection caused by bacteria does not respond to a course of an antibiotic. One of the commonest reasons for this to occur is because the bacteria causing the infection are resistant to the antibiotic that is being taken. This means that they can survive and even multiply despite the antibiotic.

Bacteria can become resistant to antibiotics for many reasons. Using antibiotics carefully can heta to reduce the chance of bacteria becomina

When your doctor prescribes a course of an antibiotic it is intended to treat only your current illness. Paying attention to the following advice will help prevent the emergence of resistant bacteria that could stop the antibiotic working.

1.  It is very important that you take the antibiotic at the right dose, at the right times and for the right number of days. Read the instructions on the label and if you do not understand anything ask your doctor or pharmacist to explain.

2. You should not take an antibiotic unless it has been prescribed specifically for you and you should use it only to treat the infection for which it was prescribed.

3. You should not take antibiotics that have been prescribed for other people even if they had an infection that was similar to yours.

4. You should not give antibiotics that were prescribed for you to other people.

5.  If you have any antibiotic left over when you have taken the course as directed by your doctor you should take the remainder to a pharmacy

Asacol Foam Enema
(Mesalazine)

1. WHAT ASACOL FOAM ENEMA IS AND WHAT IT IS USED FOR

Asacol Foam Enema contains the active substance mesalazine (also known as 5-aminosalicylic acid) which is an anti-inflammatory drug used in the treatment of Ulcerative colitis.

Ulcerative colitis is a disease of the large bowel (colon) and back passage (rectum) in which the lining of the bowel becomes inflamed (red and swollen). Symptoms can include rectal bleeding, frequent diarrhoea and abdominal pain. The enema acts locally in the lower part of the colon to reduce the inflammation.

2. BEFORE YOU USE ASACOL FOAM ENEMA

Do not use Asacol Foam Enema if you:

•   are allergic (hypersensitivity) to any of the ingredients in the product

•   are allergic to aspirin or any other salicylate

•   had kidney problems or blood abnormalities while taking other medicines such as sulphasalazine

•   have confirmed severe kidney impairment.

Do not use the foam in children under 2 years of age.

Take special care with Asacol Foam Enema

•   Asacol should be used with extreme caution in patients with confirmed mild to moderate kidney impairment

•   Asacol should be used with caution in the elderly.

Taking other medicines

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

Use of non-steroidal anti-inflammatory drugs (NSAIDs such as ibuprofen, aspirin, Cox-ll inhibitors) and azathioprine in particular may increase the risk of kidney reactions.

• Pregnancy and breast-feeding

Women who are pregnant or breast-feeding should not use Asacol Foam Enema unless advised otherwise by their doctor. Ask your doctor or pharmacist for advice before taking any medicine.

• Driving and using machines

Asacol Foam Enema is not expected to affect your ability to drive or operate machinery.

3. HOW TO USE ASACOL FOAM ENEMA

Please read these instructions carefully, even if you have used Asacol Foam Enema before, as these instructions have recently changed.

Asacol Foam Enema should not be swallowed.

Please use the product with care as it may cause staining to clothing and household articles.

DOSE FOR ADULTS AND THE ELDERLY: Please read the pharmacist’s label carefully as your doctor will have instructed you whether to use one or two doses each day.

This medicine should be delivered to the back passage (rectum) as described below:

1. Before using the enema for the first time, thoroughly mix the contents by shaking the can vigorously for 15 seconds. Rest for about 30 seconds, and then shake the can vigorously for another 15 seconds.

2. Also, before using the enema for the first time, remove the safety tag from under the dome.

3.  Push the plastic applicator firmly onto the spout of the can and align the notch beneath the dome with the spout.

4.  Hold the can in the palm of one hand with the dome pointing downwards.This product must only be dispensed when the can is upside down, with the dome nearest the ground (if the can is not upside down, the foam will not come out properly).

5. You may find the easiest way to use the enema is to raise one foot onto a firm surface such as a stool or chair, and insert the applicator into the rectum as far as is comfortable. You can apply a lubricating jelly to the tip of the applicator for comfort if you wish.

6.   To administer one dose, fully push the dome down once and release it. The foam will not come out of the can until you release the dome. To administer a second dose, press  and release the dome again. Wait for 15 seconds before withdrawing the applicator. Note, the can will only work properly when held with the dome pointing downwards.

7. Remove the applicator and dispose of it in one of the plastic bags provided. Do not  flush it down the toilet. Wash your hands.

8. Before using the enema again, mix the contents of the can by shaking vigorously for 5 seconds only, before continuing to use the enema as instructed above.

DO NOT use Asacol Foam Enema more than twice in 12 hours.

Do not use this medicine in children under 2 years of age.

Keep using the foam until your prescribed course is finished. Your symptoms may come back if you stop treatment too early. Your doctor will normally recommend that you take treatment for between 4 and 6 weeks.

If you use more Asacol Foam Enema than you should

Do not exceed the recommended dose. You should only use as much enema as your doctor has instructed on the pharmacist’s label. If you use too much, tell your doctor immediately or go to your nearest Accident & Emergency Department (take the foam enema pack with you if possible).

If you forget to use Asacol Foam Enema

If you forget to use your enema at the required time, take the dose as soon as you remember and continue using the foam as before. Do not use Asacol Foam Enema more than twice in 12 hours.

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

4. POSSIBLE SIDE EFFECTS

Like all medicines, Asacol Foam Enema can cause side effects, although not everybody gets them.

Allergic reactions to the enema can occur. Tell your doctor if you get a rash (with or without itching), any shortness of breath, palpitations (rapid heart beat) or chest pain. These effects will usually disappear when you stop using the medicine.

Tell your doctor immediately if you experience any of the following symptoms:

•   fever, sore throat, mouth or lip ulcers, spots underneath your skin anywhere on your body, including the genital and anal regions, become very pale, swollen ankles or have unusual bleeding (e.g. unexpected nosebleeds or bleeding gums)

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

•   bruising more easily or suspect blood abnormalities

•   problems with kidney function.

Common side effects:

•   diarrhoea                             •  nausea (feeling sick)

•   abdominal pain                       •  headache.

Rare side effects:

•   problems with heart, lung, liver or kidney function

•  hair loss

•   inflammation of the pancreas                                                    •  skin rash

•   blood abnormalities                                                                   •  local irritation at site of application.

•   numbness and tingling of the fingers and toes due to damaged nerves

Very rare side effects:

•   worsening of symptoms of colitis

•   Erythema multiforme and Stevens-Johnson syndrome (skin and mucous membrane disease).

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

5. HOW TO STORE ASACOL FOAM ENEMA

Keep out of the reach and sight of children.

Store Asacol Foam Enema below 30°C (86°F).

Keep the medicine away from flames or sparks (including cigarettes) and protect from direct sunlight. Do not pierce or burn the product, even when it is empty.

Do not use the enema after the expiry date stated on the pack 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 Asacol Foam Enema contains

The active substance is mesalazine (5-aminosalicylic acid). Each metered dose contains 1 g of mesalazine. The other ingredients are sorbitan mono-oblate, polysorbate 20, emulsifying wax, colloidal anhydrous silica, sodium metabisulphite (E223), disodium edetate, methylhydroxybenzoate (E218), propylhydroxybenzoate (E216), sodium phosphate dodecahydrate or heptahydrate, sodium acid phosphate, glycerol (E422), macrogol 300, purified water, propane, iso-butane, n-butane (see also end of Section 2 on ‘Important information about some of the ingredients of Asacol Foam Enema’).

What Asacol Foam Enema looks like and contents of the pack

Asacol Foam Enema is a white foam. It is supplied in an aerosol can containing 14 metered doses with 14 disposable applicators and 14 disposable plastic bags.

(British Approved Name, US Adopted Name, rINN)

Drug Nomenclature

International Nonproprietary Names (INNs) in main languages (French, Latin, Russian, and Spanish):

Adverse Effects, Treatment, and Precautions

The most frequent adverse effects are gastrointestinal disturbances including anorexia, nausea and vomiting, and diarrhoea; asthenia; hot flushes; dizziness; drowsiness; headache; and rash. Other reported effects include hair thinning, vaginal dryness or bleeding, myalgia, arthralgia, and bone fractures, Abnormalities in liver enzyme values, thromboembolism, and increases in total cholesterol, have occurred in some patients receiving anastrozole. Very rare cases of erythema multiforme, Stevens-Johnson syndrome, and allergic reactions (including angioedema, urticaria, and anaphylaxis) have occurred.

Reductions in bone mineral density can occur during use of anastrozole. Patients with or at risk of osteoporosis should therefore have their bone density assessed at the start of therapy and at regular intervals thereafter. Treatment or prophylaxis for osteoporosis should be started as appropriate and carefully monitored. The use of anastrozole is contra-indicated in premeno-pausal women (particularly in pregnancy).

Effects on the liver. A case of acute hepatitis was attributed to anastrozole, 3 weeks after starting therapy.

Effects on the musculoskeletal system. In a series of 77 postmenopausal women treated with anastrozole for metastatic breast cancer, 12 complained of joint pains within 2 months of beginning therapy. Based on this experience and the incidence of arthralgia reported during clinical studies, the authors estimated that arthralgia occurs in 10 to 15% of patients treated with anastrozole, possibly as a result of the very low oestrogen concentrations achieved.

Adjuvant anastrozole therapy for postmenopausal women with early breast cancer was associated with accelerated bone loss, but the risk appeared to be confined to those with osteopenia at baseline. These patients should be assessed for the risk of osteoporosis before starting therapy, and the decision to treat should be made on an individual basis.

Pharmacokinetics

Anastrozole is rapidly and almost completely absorbed from the gastrointestinal tract after oral doses, with peak plasma concentrations within about 2 hours. Food decreases the rate of absorption, though this is not considered clinically significant. Anastrozole is 40% bound to plasma proteins. It is metabolised in the liver, and excreted in urine, chiefly as metabolites. The terminal plasma elimination half-life is about 40 to 50 hours, and steady-state concentrations are achieved after about 7 days in patients receiving once-daily doses.

Uses and Administration

Anastrozole is a potent and selective nonsteroidal inhibitor of the aromatase (oestrogen synthetase) system, which converts adrenal androgens to oestrogens in peripheral tissue. It is used in the treatment of advanced or locally advanced breast cancer, and as adjuvant treatment in early breast cancer, in postmenopausal women in an oral dose of 1 mg daily. Responses are unlikely in patients with oestrogen receptor-negative disease. Adjuvant therapy may be continued for up to 5 years, although the optimum duration is uncertain.

Endometriosis. In a small, open-label study, oral anastrozole 1 mg, given daily with a low-strength oral contraceptive for 6 months, reduced pelvic pain scores in women with refractory endometriosis. Adverse effects were mild, although most patients had breakthrough bleeding, which exacerbated pain. The authors supposed that a higher dose of oral contraceptive should be considered in future studies.

In a small pilot study of patients with rectovaginal endometriosis, anastrozole 250 micrograms was given vaginally once daily for 6 months. Dysmenorrhoea improved significantly although chronic pelvic pain was unchanged. Adverse effects were mild.

Gynaecomastia. Anastrozole has been reported to be under investigation for the treatment of gynaecomastia, but controlled studies suggest that it may be no better than placebo — see Gynaecomastia and Gynaecomastia under Adverse Effects and Precautions of Flutamide.

Single-ingredient Preparations

The symbol ¤ denotes a preparation which is discontinued or no longer actively marketed.

Argentina: Anaskebir; Anastraze; Arimidex; Aromenal; Asiolex¤; Distalene; Gondonar; Leprofen; Lezole¤; Pantestone; Trozolite; Australia: Arimidex; Austria: Arimidex; Belgium: Arimidex; Brazil: Arimidex; Canada: Arimidex; Chile: Arimidex; Trozolet; Czech Republic: Arimidex; Denmark: Arimidex; Finland: Arimidex; France: Arimidex; Germany: Arimidex; Greece: Arimidex; Hong Kong: Arimidex; Hungary: Arimidex; India: Altraz; Armotraz; Ireland: Arimidex; Israel: Arimidex; Italy: Arimidex; Malaysia: Arimidex; Mexico: Arimidex; Netherlands: Arimidex; Norway: Arimidex; New Zealand: Arimidex; Portugal: Arimidex; Russia: Arimidex (Аримидекс); South Africa: Arimidex; Singapore: Arimidex; Spain: Arimidex; Sweden: Arimidex; Switzerland: Arimidex; Thailand: Arimidex; United Kingdom: Arimidex; United States: Arimidex; Venezuela: Arimidex