Sonata 5 mg hard capsules

1. Name Of The Medicinal Product

Sonata 5 mg hard capsules

2. Qualitative And Quantitative Composition

Each capsule contains 5 mg of zaleplon.

Excipient: Lactose monohydrate 54 mg.

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Capsule, hard.

Capsules have an opaque white and opaque light brown hard shell with gold band, “W” and the strength “5 mg”.

4. Clinical Particulars

4.1 Therapeutic Indications

Sonata is indicated for the treatment of patients with insomnia who have difficulty falling asleep. It is indicated only when the disorder is severe, disabling or subjecting the individual to extreme distress.

4.2 Posology And Method Of Administration

For adults, the recommended dose is 10 mg.

Treatment should be as short as possible with a maximum duration of two weeks.

Sonata can be taken immediately before going to bed or after the patient has gone to bed and is experiencing difficulty falling asleep. As administration after food delays the time to maximal plasma concentration by approximately 2 hours no food should be eaten with or shortly before intake of Sonata.

The total daily dose of Sonata should not exceed 10 mg in any patient. Patients should be advised not to take a second dose within a single night.

Elderly

Elderly patients may be sensitive to the effects of hypnotics; therefore, 5 mg is the recommended dose of Sonata.

Paediatric patients

Sonata is contraindicated in children (see section 4.3).

Hepatic impairment

As clearance is reduced, patients with mild to moderate hepatic impairment should be treated with Sonata 5 mg. For severe hepatic impairment see section 4.3.

Renal impairment

No dosage adjustment is required in patients with mild to moderate renal insufficiency, because Sonata pharmacokinetics is not altered in such patients. Severe renal impairment is contraindicated (see section 4.3.).

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients

Severe hepatic impairment

Severe renal impairment

Sleep apnoea syndrome

Myasthenia gravis

Severe respiratory insufficiency

Children (under 18 years of age)

4.4 Special Warnings And Precautions For Use

Complex behaviours such as “sleep-driving” (i.e., driving while not fully awake after ingestion of a sedative-hypnotic, with amnesia for the event) have been reported in patients taking sedative-hypnotics. These events can occur in sedative-hypnotic-naive as well as in sedative-hypnotic experienced persons. Although behaviours such as sleep-driving may occur with a sedative-hypnotic alone at therapeutic doses, the use of alcohol and other central nervous system (CNS) depressants with sedative-hypnotics appears to increase the risk of such behaviours, as does exceeding the maximum recommended dose. Due to the risk to the patient and the community, discontinuation of zaleplon is recommended for patients who report a “sleep-driving” episode. Other complex behaviours (e.g., preparing and eating food, making phone calls, or having sex) have been reported in patients who are not fully awake after taking a sedative-hypnotic. As with sleep-driving, patients usually do not remember these events.

Severe anaphylactic/anaphylactoid reactions have been reported with the use of sedative-hypnotics, including zaleplon. Cases of angioedema involving the tongue, glottis or larynx have been reported in patients after taking the first or subsequent doses of sedative-hypnotics, including zaleplon. Some patients taking sedative-hypnotics have had additional symptoms such as dyspnoea, throat closing, or nausea and vomiting. Some patients have required medical therapy in the emergency department. If angioedema involves the tongue, glottis or larynx, airway obstruction may occur and be fatal. Patients who develop angioedema after treatment with zaleplon should not be rechallenged with the active substance.

Insomnia may represent an underlying physical or psychiatric disorder. Insomnia that persists or worsens after a short course of zaleplon treatment may indicate a need to re-evaluate the patient.

Due to zaleplon's short plasma half-life, alternative therapy should be considered if early morning awakening is experienced. Patients should be advised not to take a second dose within a single night.

Co-administration of Sonata with medicinal products known to influence CYP3A4 is expected to result in changes in zaleplon's plasma concentrations. (See section 4.5)

Tolerance

Some loss of efficacy to the hypnotic effects of short-acting benzodiazepines and benzodiazepine-like agents may develop after repeated use for a few weeks.

Dependence

Use of benzodiazepines and benzodiazepine-like agents may lead to physical and psychic dependence. The risk of dependence increases with dose and duration of treatment and is greater with patients having a history of alcohol and medicinal product abuse. Once physical dependence has developed, abrupt termination of treatment will be accompanied by withdrawal symptoms. These may consist of headaches, muscle pain, extreme anxiety, tension, restlessness, confusion and irritability. In severe cases the following symptoms may occur: unreality, depersonalisation, hyperacusis, numbness and tingling of the extremities, hypersensitivity to light, noise and physical contact, hallucinations or epileptic seizures. There have been post-marketing reports of dependence associated with zaleplon, predominantly in combination with other psychotropic agents.

Rebound insomnia and anxiety

A transient syndrome whereby the symptoms that led to the treatment with a benzodiazepine or benzodiazepine-like agent recur in an enhanced form, may occur on withdrawal of treatment. It may be accompanied by other reactions including mood changes, anxiety, or sleep disturbances and restlessness.

Duration of treatment

The duration of treatment should be as short as possible (see section 4.2), and should not exceed two weeks. Extension beyond these periods should not take place without clinical re-evaluation of the patient.

It may be useful to inform the patient when treatment is started that it will be of limited duration. It is important that patients be aware of the possibility of rebound phenomena, thereby minimising anxiety should such symptoms develop when the medicinal product is discontinued.

Memory and psychomotor impairment

Benzodiazepines and benzodiazepine-like agents may induce anterograde amnesia and psychomotor impairment. These occur most often up to several hours after ingesting the product. To reduce the risk, patients should not undertake activities requiring psychomotor co-ordination until 4 hours or more after taking Sonata (see section 4.7).

Psychiatric and “paradoxical” reactions

Reactions like restlessness, agitation, irritability, decreased inhibition, aggressiveness, abnormal thinking, delusion, rages, nightmares, depersonalisation, hallucinations, psychoses, inappropriate behaviour, extroversion that seems out of character and other behavioural effects are known to occur when using benzodiazepines or benzodiazepine-like agents. They may be active substance-induced, spontaneous in origin, or a result of an underlying psychiatric or physical disorder. These reactions are more likely to occur in the elderly. Should this occur, use of this product should be discontinued. Any new behavioural sign or symptom requires careful and immediate evaluation.

Specific patient groups

Alcohol and medicinal product abuse

Benzodiazepine and benzodiazepine-like agents should be used with extreme caution in patients with a history of alcohol or medicinal product abuse.

Hepatic impairment

Benzodiazepine and benzodiazepine-like agents are not indicated to treat patients with severe hepatic insufficiency as they may precipitate encephalopathy (see section 4.2). In patients with mild to moderate hepatic insufficiency, the bioavailability of zaleplon is increased because of reduced clearance, and the dose will therefore need to be modified in these patients.

Renal impairment

Sonata is not indicated to treat patients with severe renal impairment as it has not been adequately studied in those patients. In patients with mild to moderate renal impairment, the pharmacokinetic profile of zaleplon is not significantly different than that in healthy subjects. Hence, no dose adjustment is required in these patients.

Respiratory insufficiency

Caution should be observed when prescribing sedative medicinal products to patients with chronic respiratory insufficiency.

Psychosis

Benzodiazepine and benzodiazepine-like agents are not recommended for the primary treatment of psychotic illness.

Depression

Benzodiazepines and benzodiazepine-like agents should not be used alone to treat depression or anxiety associated with depression (suicide may be precipitated in such patients). Also, because of the increased risk for intentional overdose in patients with depression in general, the quantity of a medicinal product, including zaleplon, prescribed for such patients should be kept to the necessary minimum.

Sonata contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Concomitant intake with alcohol is not recommended. The sedative effect may be enhanced when the product is used in combination with alcohol. This affects the ability to drive or use machines (see section 4.7).

Combination with other CNS-acting compounds should be taken into account. Enhancement of the central sedation may occur in cases of concomitant use with antipsychotics (neuroleptics), hypnotics, anxiolytics/sedatives, antidepressant agents, narcotic analgesics, anti-epileptic medicinal products, anaesthetics, and sedative antihistamines.

Coadministration of a single zaleplon 10 mg dose and venlafaxine (extended release) 75 mg or 150 mg daily did not produce any interaction on memory (immediate and delayed word recall) or psychomotor performance (digit symbol substitution test). Additionally, there was no pharmacokinetic interaction between zaleplon and venlafaxine (extended release).

In the case of narcotic analgesics enhancement of the euphoria may occur leading to an increase in physiological dependence.

Cimetidine, a non-specific moderate inhibitor of several hepatic enzymes including both aldehyde oxidase and CYP3A4, produced an 85% increase in plasma concentrations of zaleplon because it inhibited both the primary (aldehyde oxidase) and secondary (CYP3A4) enzymes responsible for zaleplon's metabolism. Therefore, caution is advisable in co-administering cimetidine and Sonata.

Co-administration of Sonata with a single 800 mg dose of erythromycin, a strong, selective CYP3A4 inhibitor, produced a 34% increase in zaleplon's plasma concentrations. A routine dosage adjustment of Sonata is not considered necessary, but patients should be advised that the sedative effects might be enhanced.

In contrast, rifampicin, a strong inducer of several hepatic enzymes, including CYP3A4 resulted in a four fold reduction in zaleplon plasma concentration. Co-administration of Sonata together with inducers of CYP3A4 such as rifampicin, carbamazepine and phenobarbitone, may result in a reduction of zaleplon's efficacy.

Sonata did not affect the pharmacokinetic and pharmacodynamic profiles of digoxin and warfarin, two compounds with a narrow therapeutic index. In addition, ibuprofen, as an example of compounds that alter renal excretion, showed no interaction with Sonata.

4.6 Pregnancy And Lactation

Although animal studies have shown no teratogenic or embryotoxic effects, insufficient clinical data are available on Sonata to assess its safety during pregnancy and breastfeeding. Use of Sonata is not recommended during pregnancy. If the medicinal product is prescribed to a woman of child-bearing potential, she should be warned to contact her physician regarding discontinuance of the medicinal product if she intends to become or suspects that she is pregnant.

If for compelling medical reasons, the medicinal product is administered during the late phase of pregnancy, or during labour at high doses, effects on the neonate, such as hypothermia, hypotonia and moderate respiratory depression, can be expected, due to the pharmacological action of the compound.

Infants born to mothers who took benzodiazepine and benzodiazepine-like agents chronically during the latter stages of pregnancy may have developed physical dependence and may be at some risk for developing withdrawal symptoms in the postnatal period.

Because zaleplon is excreted in the breast milk, Sonata should not be administered to breast-feeding mothers.

4.7 Effects On Ability To Drive And Use Machines

Sonata has major influence on the ability to drive and use machines.

Sedation, amnesia, impaired concentration and impaired muscular function may adversely affect the ability to drive or to use machines. If insufficient sleep duration occurs, the likelihood of impaired alertness may be increased (see section 4.5). Caution is recommended for patients performing skilled tasks.

4.8 Undesirable Effects

The most frequent reported adverse drug reactions are amnesia, paraesthesia, somnolence and dysmenorrhea.

Frequencies are defined as

Very common (

Common (

Uncommon (

Rare (

Very rare (<1/10,000)

not known (cannot be estimated from the available data)

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Organ/System (Frequency)	Adverse Reactions
Nervous system disorders Common: Uncommon:	amnesia, paraesthesia, somnolence ataxia/coordination abnormal, dizziness, disturbance in attention, parosmia, speech disorder (dysarthria, slurred speech), hypo aesthesia
See also below under Amnesia
Eye disorders Uncommon:	visual impairment, diplopia
Ear and labyrinth disorders Uncommon:	hyperacusis
Gastrointestinal disorders Uncommon:	nausea
Skin and subcutaneous tissue disorders Uncommon: Frequency not known:	photosensitivity reaction angioedema
Metabolism and nutrition disorders Uncommon:	anorexia
General disorders and administration site conditions Uncommon:	asthenia, malaise
Immune system disorders Very rare:	anaphylactic/anaphylactoid reactions
Hepatobiliary disorders Frequency not known:	hepatotoxicity (mostly described as transaminase increased)
Reproductive system and breast disorders Common:	dysmenorrhea
Psychiatric disorders Uncommon: Frequency not known:	depersonalisation, hallucinations, depression, confusional state, apathy somnambulism
See also below under Depression and Psychiatric and “paradoxical” reactions

Amnesia

Anterograde amnesia may occur using recommended therapeutic dosages, the risk increasing at higher dosages. Amnestic effects may be associated with inappropriate behaviour (see section 4.4).

Depression

Pre-existing depression may be unmasked during benzodiazepine or benzodiazepine-like agent use.

Psychiatric and “paradoxical” reactions

Reactions like restlessness, agitation, irritability, decreased inhibition, aggressiveness, abnormal thinking, delusions, rages, nightmares, depersonalisation, hallucinations, psychoses, inappropriate behaviour, extroversion that seems out of character, and other adverse behavioural reactions are known to occur when using benzodiazepines or benzodiazepine-like agents. Such reactions are more likely to occur in the elderly.

Dependence

Use (even at therapeutic doses) may lead to the development of physical dependence: discontinuation of therapy may result in withdrawal or rebound phenomena (see section 4.4). Psychic dependence may occur. Abuse of benzodiazepines and benzodiazepine-like active substances has been reported.

4.9 Overdose

There is limited clinical experience with the effects of an acute overdose of Sonata, and overdose levels in humans have not been determined.

As with other benzodiazepines or benzodiazepine-like agents, overdose should not present a threat to life unless combined with other CNS depressants (including alcohol).

In the management of overdose with any medicinal product, it should be borne in mind that multiple agents may have been taken.

Following overdose with oral benzodiazepine or benzodiazepine-like agents, vomiting should be induced (within one hour) if the patient is conscious or gastric lavage undertaken with the airway protected if the patient is unconscious. If there is no advantage in emptying the stomach, activated charcoal should be given to reduce the absorption. Special attention should be paid to respiratory or cardiovascular functions in intensive care.

Overdose of benzodiazepine or benzodiazepine-like agents is usually manifested by degrees of central nervous system depression ranging from drowsiness to coma. In mild cases, symptoms include drowsiness, mental confusion, and lethargy, in more serious cases, symptoms may include ataxia, hypotonia, hypotension, respiratory depression, rarely coma and very rarely death.

Chromaturia (blue-green urine discolouration) has been reported with zaleplon overdose.

Flumazenil may be useful as an antidote. Animal studies suggest that flumazenil is an antagonist to zaleplon and should be considered in the management of Sonata overdose. However, there is no clinical experience with the use of flumazenil as an antidote to a Sonata overdose.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic Group: Benzodiazepine related drugs, ATC Code N05CF03

Zaleplon is a pyrazolopyrimidine hypnotic that is structurally different from benzodiazepines and other hypnotics. Zaleplon binds selectively to the benzodiazepine type I receptor.

Zaleplon's pharmacokinetic profile shows rapid absorption and elimination (see section 5.2). In combination with its subtype selective receptor-binding characteristics, with high selectivity and low affinity for the benzodiazepine type I receptor, these properties are responsible for the overall characteristics of Sonata.

Sonata's efficacy has been demonstrated in both sleep laboratory studies using objective polysomnography (PSG) measures of sleep and in outpatient studies using patient questionnaires to assess sleep. In these studies, patients were diagnosed with primary (psychophysiological) insomnia.

Sleep latency in outpatient studies was decreased for up to 4 weeks in non-elderly patients with Sonata 10 mg. In elderly patients, sleep latency was often significantly decreased with Sonata 5 mg and was consistently decreased with Sonata 10 mg compared with placebo in 2-week studies. This decreased sleep latency was significantly different from that observed with placebo. Results from the 2- and 4-week studies showed that no pharmacological tolerance developed with any dose of Sonata.

In Sonata studies using objective PSG measures, Sonata 10 mg was superior to placebo in decreasing sleep latency and increasing sleep duration during the first half of the night. Sonata has been shown to preserve sleep stages in controlled studies that measured the percentage of sleep time spent in each sleep stage.

5.2 Pharmacokinetic Properties

Absorption

Zaleplon is rapidly and almost completely absorbed after oral administration, and peak concentrations are reached in approximately 1 hour. At least 71% of the orally-administered dose is absorbed. Zaleplon undergoes presystemic metabolism, resulting in an absolute bioavailability of approximately 30%.

Distribution

Zaleplon is lipophilic with a volume of distribution of about 1.4±0.3 l/kg following intravenous administration. The in vitro plasma protein binding is approximately 60%, suggesting little risk of active substance interaction due to protein binding.

Metabolism

Zaleplon is primarily metabolised by aldehyde oxidase to form 5-oxo-zaleplon. Additionally, zaleplon is metabolised by CYP3A4 to form desethylzaleplon which is further metabolised by aldehyde oxidase to form 5-oxo-desethylzaleplon. The oxidative metabolites are further metabolised by conjugation via glucuronidation. All of zaleplon's metabolites are inactive in both animal behavioural models and in vitro activity assays.

Zaleplon plasma concentrations increased linearly with dose, and zaleplon showed no signs of accumulation following administration of up to 30 mg/day. The elimination half-life of zaleplon is approximately 1 hour.

Excretion

Zaleplon is excreted in the form of inactive metabolites, mainly in the urine (71%) and faeces (17%). Fifty-seven percent (57%) of the dose is recovered in urine in the form of 5-oxo-zaleplon and its glucuronide metabolite, an additional 9% is recovered as 5-oxo-desethylzaleplon and its glucuronide metabolite. The remainder of the urinary recovery consists of minor metabolites. The majority of the faecal recovery consists of 5-oxo-zaleplon.

Hepatic Impairment

Zaleplon is metabolised primarily by the liver and undergoes significant presystemic metabolism. Consequently, the oral clearance of zaleplon was reduced by 70% and 87% in compensated and decompensated cirrhotic patients, respectively, leading to marked increases in mean C_max and AUC (up to 4-fold and 7-fold in compensated and decompensated patients, respectively) relative to healthy subjects. The dose of zaleplon should be reduced in patients with mild to moderate hepatic impairment, and zaleplon is not recommended for use in patients with severe hepatic impairment.

Renal Impairment

The single dose pharmacokinetics of zaleplon were studied in patients with mild (creatinine clearance 40 to 89 ml/min) and moderate (20 to 39 ml/min) renal impairment, and in patients on dialysis. In patients with moderate impairment and those on dialysis there was a reduction of approximately 23% in peak plasma concentration compared to healthy volunteers. The extent of exposure to zaleplon was similar among all groups. Therefore, no dose adjustment is necessary in patients with mild to moderate renal impairment. Zaleplon has not been adequately studied in patients with severe renal impairment.

5.3 Preclinical Safety Data

Repeated oral administration of zaleplon to rats and dogs elicited increases in liver and adrenal weights; however, these increases occurred at high multiples of the maximum therapeutic dose, were reversible, were not associated with degenerative microscopic changes in liver or adrenal glands, and were consistent with effects in animals with other compounds that bind to benzodiazepine receptors. In a three month study in prepubescent dogs there was significant reduction in the weight of both prostate and testes at high multiples of the maximum therapeutic dose. Oral administration of zaleplon to rats for 104 consecutive weeks at dosage levels up to 20 mg/kg/day did not result in compound-related tumorigenicity. Oral administration of zaleplon to mice for 65 or 104 consecutive weeks at high dosage levels (

Overall, the results of the preclinical studies do not suggest any significant safety hazard for use of Sonata at recommended doses in humans.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Capsule core

Microcrystalline cellulose,

pregelatinised starch,

silicon dioxide,

sodium lauryl sulphate,

magnesium stearate,

lactose monohydrate,

indigo carmine (E132),

titanium dioxide (E171).

Capsule shell

gelatin,

titanium dioxide (E171),

red iron oxide (E172),

yellow iron oxide (E172),

black iron oxide (E172),

sodium lauryl sulphate,

silicon dioxide.

Printing inks on the shell contain the following (gold ink S-13050):

shellac,

lecithin,

simethicone,

yellow iron oxide (E172).

6.2 Incompatibilities

Not applicable.

6.3 Shelf Life

3 years.

6.4 Special Precautions For Storage

Do not store above 30ºC.

6.5 Nature And Contents Of Container

PVC / PVDC aluminium blister packages of 7, 10, 14 capsules in perforated unit-dose blisters. Not all pack sizes may be marketed.

6.6 Special Precautions For Disposal And Other Handling

No special requirements.

Sonata has been designed so that if the contents of the capsule are dissolved in a liquid, the liquid will change colour and become cloudy.

7. Marketing Authorisation Holder

Meda AB

Pipers väg 2A

S-170 09 Solna

Sweden

8. Marketing Authorisation Number(S)

EU/1/99/102/001-003

9. Date Of First Authorisation/Renewal Of The Authorisation

Date of first authorisation: 12 March 1999

Date of latest renewal: 12 March 2009

10. Date Of Revision Of The Text

February 2009

Detailed information on this medicinal product is available on the website of the European Medicines Agency (EMEA) http://www.emea.europa.eu/.

Sotalol 160 mg Tablets

1. Name Of The Medicinal Product

Sotalol 160mg Tablets

2. Qualitative And Quantitative Composition

Each tablet contains 160mg Sotalol hydrochloride

For Excipients see 6.1.

3. Pharmaceutical Form

Tablet

Round, blue coloured, flat bevelled edged tablets with a break line on one side.

4. Clinical Particulars

4.1 Therapeutic Indications

Sotalol 160mg Tablets are indicated for:

1. Ventricular arrhythmias:

• Treatment of life-threatening ventricular tachyarrhythmias;

• Treatment of symptomatic non-sustained ventricular tachyarrhythmias

2. Supraventricular arrhythmias:

• Prophylaxis of paroxysmal atrial tachycardia, paroxysmal atrial fibrillation, paroxysmal A-V nodal re-entrant tachycardia, paroxysmal A-V re-entrant tachycardia using accessory pathways, and paroxysmal supraventricular tachycardia after cardiac surgery;

• Maintenance of normal sinus rhythm following conversion of atrial fibrillation or atrial flutter

4.2 Posology And Method Of Administration

As with other antiarrhythmic agents, it is recommended that Sotalol 160mg Tablets be initiated and doses increased in a facility capable of monitoring and assessing cardiac rhythm. The dosage must be individualised and based on the patient's response. Proarrhythmic events can occur not only at initiation of therapy, but also with each upward dosage adjustment.

In view of its β-adrenergic blocking properties, treatment with Sotalol 160mg Tablets should not be discontinued suddenly, especially in patients with ischaemic heart disease (angina pectoris, prior acute myocardial infarction) or hypertension, to prevent exacerbation of the disease (see 4.4 Warnings).

The initiation of treatment or changes in dosage with sotalol should follow an appropriate medical evaluation including ECG control with measurement of the corrected QT interval, and assessment of renal function, electrolyte balance and concomitant medications (See 4.4 Warnings and precautions).

As with other antiarrhythmic agents, it is recommended that sotalol be initiated and doses increased in a facility capable of monitoring and assessing cardiac rhythm. The dosage must be individualised and based on the patient's response. Proarrhythmic events can occur not only at initiation of therapy, but also with each upward dosage adjustment.

In view of its β-adrenergic blocking properties, treatment with sotalol should not be discontinued suddenly, especially in patients with ischaemic heart disease (angina pectoris, prior acute myocardial infarction) or hypertension, to prevent exacerbation of the disease (see 4.4 Warnings).

The following dosing schedule can be recommended:

The initial dose is 80 mg, administered either singly or as two divided doses.

Oral dosage of sotalol should be adjusted gradually allowing 2-3 days between dosing increments in order to attain steady-state, and to allow monitoring of QT intervals. Most patients respond to a daily dose of 160 to 320 mg administered in two divided doses at approximately 12 hour intervals. Some patients with life-threatening refractory ventricular arrhythmias may require doses as high as 480 - 640 mg/day. These doses should be used under specialist supervision and should only be prescribed when the potential benefit outweighs the increased risk of adverse events, particularly proarrhythmias (see 4.4 Warnings).

Children

Sotalol is not intended for administration to children.

Dosage in renally impaired patients

Because sotalol is excreted mainly in urine, the dosage should be reduced when the creatinine clearance is less than 60 ml/min according to the following table:

Creatinine clearance (ml/min)	Adjusted doses
> 60	Recommended Dose
30-60	½ recommended Dose
10-30	¼ recommended Dose
< 10	Avoid Sotalol

Dosage in hepatically impaired patients

No dosage adjustment is required in hepatically impaired patients.

4.3 Contraindications

Sotalol should not be used where there is evidence of:

• sick sinus syndrome

• second and third degree AV heart block unless a functioning pacemaker is present

• congenital or acquired long QT syndromes

• torsades de pointes

• symptomatic sinus bradycardia

• uncontrolled congestive heart failure

• cardiogenic shock

• anaesthesia that produces myocardial depression

• untreated phaeochromocytoma

• hypotension (except due to arrhythmia)

• Raynaud's phenomenon and severe peripheral circulatory disturbances

• history of chronic obstructive airway disease or bronchial asthma

• hypersensitivity to any of the components of the formulation

• metabolic acidosis

• renal failure (creatinine clearance < 10 ml/min).

• Contraindicated Combination: Sotalol should not be administered in combination with drugs like class Ia antiarrhythmics, class II antiarrhythmics such as amiodarone, dofetilide, ibutilide etc; neuroleptics such as trimipramine, phenobarbitone, chlorpromazine etc; and antibiotics such as erythromycin IV and moxifloxacin

4.4 Special Warnings And Precautions For Use

Abrupt Withdrawal

Hypersensitivity to catecholamines is observed in patients withdrawn from beta-blocker therapy. Occasional cases of exacerbation of angina pectoris, arrhythmias, and in some cases, myocardial infarction have been reported after abrupt discontinuation of therapy. Patients should be carefully monitored when discontinuing chronically administered sotalol, particularly those with ischaemic heart disease. If possible the dosage should be gradually reduced over a period of one to two weeks, if necessary at the same time initiating replacement therapy. Abrupt discontinuation may unmask latent coronary insufficiency. In addition, hypertension may develop.

Proarrhythmias

The most dangerous adverse effect of Class III antiarrhythmic drugs (such as sotalol) is the aggravation of pre-existing arrhythmias or the provocation of new arrhythmias. Drugs that prolong the QT-interval may cause torsades de pointes, a polymorphic ventricular tachycardia associated with prolongation of the QT-interval. Experience to date indicates that the risk of torsades de pointes is associated with the prolongation of the QT-interval, slow heart rate, reduction in serum potassium and magnesium, high plasma sotalol concentrations and with the concomitant use of sotalol and other medications which have been associated with torsades de pointes (see 4.5: Interactions). Females may be at increased risk of developing torsades de pointes.

Other risk factors for torsades de pointes were excessive prolongation of the QTc and history of cardiomegaly or congestive heart failure.

The incidence of torsades de pointes is dose dependent. Torsades de pointes usually occurs early after initiating therapy or escalation of the dose and can progress to ventricular fibrillation.

In clinical trials of patients with sustained VT/VF the incidence of severe proarrhythmia (torsades de pointes or new sustained VT/VF) was <2% at doses up to 320 mg. The incidence more than doubled at higher doses.

Patients with sustained ventricular tachycardia and a history of congestive heart failure have the highest risk of serious proarrhythmia (7%).

Proarrhythmic events must be anticipated not only on initiating therapy but with every upward dose adjustment. Initiating therapy at 80 mg with gradual upward dose titration thereafter reduces the risk of proarrhythmia. In patients already receiving sotalol caution should be used if the QTc exceeds 500msec whilst on therapy, and serious consideration should be given to reducing the dose or discontinuing therapy when the QTc-interval exceeds 550 msec. Due to the multiple risk factors associated with torsades de pointes, however, caution should be exercised regardless of the QTc-interval.

Electrolyte Disturbances

Sotalol should not be used in patients with hypokalaemia or hypomagnesaemia prior to correction of imbalance; these conditions can exaggerate the degree of QT prolongation, and increase the potential for torsades de pointes. Special attention should be given to electrolyte and acid-base balance in patients experiencing severe or prolonged diarrhoea or patients receiving concomitant magnesium- and/or potassium-depleting drugs.

Congestive Heart Failure

Beta-blockade may further depress myocardial contractility and precipitate more severe heart failure. Caution is advised when initiating therapy in patients with left ventricular dysfunction controlled by therapy (i.e. ACE Inhibitors, diuretics, digitalis, etc); a low initial dose and careful dose titration is appropriate.

Recent MI

In post-infarction patients with impaired left ventricular function, the risk versus benefit of sotalol administration must be considered. Careful monitoring and dose titration are critical during initiation and follow-up of therapy. Sotalol should be avoided in patients with left ventricular ejection fractions <40% without serious ventricular arrhythmias.

Electrocardiographic Changes

Excessive prolongation of the QT-interval,>500 msec, can be a sign of toxicity and should be avoided (see Proarrhythmias above). Sinus bradycardia has been observed very commonly in arrhythmia patients receiving sotalol in clinical trials. Bradycardia increases the risk of torsades de pointes. Sinus pause, sinus arrest and sinus node dysfunction occur in less than 1% of patients. The incidence of 2nd- or 3rd-degree AV block is approximately 1%.

Anaphylaxis

Patients with a history of anaphylactic reaction to a variety of allergens may have a more severe reaction on repeated challenge while taking beta-blockers. Such patients may be unresponsive to the usual doses of adrenaline used to treat the allergic reaction.

Anaesthesia

As with other beta-blocking agents, Sotalol 160mg Tablets should be used with caution in patients undergoing surgery and in association with anaesthetics that cause myocardial depression, such as cyclopropane or trichloroethylene.

Diabetes Mellitus

Sotalol should be used with caution in patients with diabetes (especially labile diabetes) or with a history of episodes of spontaneous hypoglycaemia, since beta-blockade may mask some important signs of the onset of acute hypoglycaemia, e.g. tachycardia.

Thyrotoxicosis

Beta-blockade may mask certain clinical signs of hyperthyroidism (e.g., tachycardia). Patients suspected of developing thyrotoxicosis should be managed carefully to avoid abrupt withdrawal of beta-blockade which might be followed by an exacerbation of symptoms of hyperthyroidism, including thyroid storm.

Renal Impairment

As sotalol is mainly eliminated via the kidneys the dose should be adjusted in patients with renal impairment (see dosage section 4.2).

Psoriasis

Beta-blocking drugs have been reported rarely to exacerbate the symptoms of psoriasis vulgaris.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Contraindicated Combinations

Class 1a antiarrhythmic drugs, such as disopyramide, quinidine and procainamide and other antiarrhythmic drugs such as amiodarone and bepridil are not recommended as concomitant therapy with sotalol, because of their potential to prolong refractoriness (see 4.4 Special Warnings and Precautions). The concomitant use of other beta-blocking agents with sotalol may result in additive Class II effects.

Not recommended combinations

Other drugs prolonging the QT-interval

Sotalol 160mg Tablets should be given with extreme caution in conjunction with other drugs known to prolong the QT-interval such as phenothiazines, tricyclic antidepressants, terfenadine and astemizole. Other drugs that have been associated with an increased risk for torsades de pointes include erythromycin IV, halofantrine, pentamidine, and quinolone antibiotics.

Floctafenine

beta-adrenergic blocking agents may impede the compensatory cardiovascular reactions associated with hypotension or shock that may be induced by Floctafenine.

Calcium channel blocking drugs

Concurrent administration of beta-blocking agents and calcium channel blockers has resulted in hypotension, bradycardia, conduction defects, and cardiac failure. Beta-blockers should be avoided in combination with cardiodepressant calcium-channel blockers such as verapamil and diltiazem because of the additive effects on atrioventricular conduction, and ventricular function.

Associations requiring precautions for use

Potassium-Depleting Diuretics

Hypokalaemia or hypomagnesaemia may occur, increasing the potential for torsade de pointes (see Special Warnings and Precautions for Use).

Other potassium-depleting drugs

Amphotericin B (IV route), corticosteroids (systemic administration), and some laxatives may also be associated with hypokalaemia; potassium levels should be monitored and corrected appropriately during concomitant administration with sotalol.

Clonidine

Beta-blocking drugs may potentiate the rebound hypertension sometimes observed after discontinuation of clonidine; therefore, the beta-blocker should be discontinued slowly several days before the gradual withdrawal of clonidine.

Digitalis glycosides

Single and multiple doses of sotalol do not significantly affect serum digoxin levels. Proarrhythmic events were more common in sotalol treated patients also receiving digitalis glycosides; however, this may be related to the presence of CHF, a known risk factor for proarrhythmia, in patients receiving digitalis glycosides. Association of digitalis glycosides with beta-blockers may increase auriculo-ventricular conduction time.

Catecholamine-depleting agents

Concomitant use of catecholamine-depleting drugs, such as reserpine, guanethidine, or alpha methyldopa, with a beta-blocker may produce an excessive reduction of resting sympathetic nervous tone. Patients should be closely monitored for evidence of hypotension and/or marked bradycardia which may produce syncope.

Insulin and oral hypoglycaemics

Hyperglycaemia may occur, and the dosage of antidiabetic drugs may require adjustment. Symptoms of hypoglycaemia (tachycardia) may be masked by beta-blocking agents

Neuromuscular blocking agents like Tubocurarin

The neuromuscular blockade is prolonged by beta-blocking agents

Beta-2-receptor stimulants

Patients in need of beta-agonists should not normally receive sotalol. However, if concomitant therapy is necessary beta-agonists may have to be administered in increased dosages.

Drug/Laboratory interaction

The presence of sotalol in the urine may result in falsely elevated levels of urinary metanephrine when measured by photometric methods. Patients suspected of having phaeochromocytoma and who are treated with sotalol should have their urine screened utilising the HPLC assay with solid phase extraction.

4.6 Pregnancy And Lactation

Pregnancy

Animal studies with sotalol hydrochloride have shown no evidence of teratogenicity or other harmful effects on the foetus. Although there are no adequate and well-controlled studies in pregnant women, sotalol hydrochloride has been shown to cross the placenta and is found in amniotic fluid. Beta-blockers reduce placental perfusion, which may result in intrauterine foetal death, immature and premature deliveries. In addition, adverse effects (especially hypoglycaemia and bradycardia) may occur in foetus and neonate. There is an increased risk of cardiac and pulmonary complications in the neonate in the postnatal period. Therefore, sotalol should be used in pregnancy only if the potential benefits outweigh the possible risk to the foetus. The neonate should be monitored very carefully for 48 - 72 hours after delivery if it was not possible to interrupt maternal therapy with sotalol 2-3 days before the birthdate.

Lactation

Most beta-blockers, particularly lipophilic compounds, will pass into breast milk although to a variable extent. Breast feeding is therefore not recommended during administration of these compounds.

4.7 Effects On Ability To Drive And Use Machines

There are no data available, but the occasional occurrence of side-effects such as dizziness and fatigue should be taken into account (see 4.8 Undesirable effects).

4.8 Undesirable Effects

The most frequent adverse effects of sotalol arise from its beta-blockade properties. Adverse effects are usually transient in nature and rarely necessitate interruption of, or withdrawal from treatment. If they do occur, they usually disappear when the dosage is reduced. The most significant adverse effects, however, are those due to proarrhythmia, including torsades de pointes (see Warnings).

The following are adverse events considered related to therapy, occurring in 1% or more of patients treated with sotalol.

Cardiovascular

Bradycardia, dyspnoea, chest pain, palpitations, oedema, ECG abnormalities, hypotension, proarrhythmia, syncope, heart failure, presyncope.

Dermatologic

Rash

Gastro-intestinal

Nausea/vomiting, diarrhoea, dyspepsia, abdominal pain, flatulence

Musculoskeletal

Cramps

Nervous/psychiatric

Fatigue, dizziness, asthenia, lightheadedness, headache, sleep disturbances, depression, paraesthesia, mood changes, anxiety

Urogenital

Sexual dysfunction

Special Senses

Visual disturbances, taste abnormalities, hearing disturbances

Body as a whole

Fever

In trials of patients with cardiac arrhythmia, the most common adverse events leading to discontinuation of sotalol were fatigue 4%, bradycardia ( <50 bpm) 3%, dyspnoea 3%, proarrhythmia 2%, asthenia 2%, and dizziness 2%.

Cold and cyanotic extremities, Raynaud's phenomenon, increase in existing intermittent claudication and dry eyes have been seen in association with other beta-blockers.

4.9 Overdose

Intentional or accidental overdosage with sotalol has rarely resulted in death. Haemodialysis results in a large reduction of plasma levels of sotalol.

Symptoms and treatment of overdosage: The most common signs to be expected are bradycardia, congestive heart failure, hypotension, bronchospasm and hypoglycaemia. In cases of massive intentional overdosage (2-16 g) of sotalol the following clinical findings were seen: hypotension, bradycardia, prolongation of QT-interval, premature ventricular complexes, ventricular tachycardia, torsades de pointes.

If overdosage occurs, therapy with SOTALOL should be discontinued and the patient observed closely. In addition, if required, the following therapeutic measures are suggested:

Bradycardia

Atropine (0.5 to 2 mg IV), another anticholinergic drug, a beta-adrenergic agonist (isoprenaline, 5 microgram per minute, up to 25 microgram, by slow IV injection) or transvenous cardiac pacing

Heart Block (second and third degree)

Transvenous cardiac pacing

Hypotension

Adrenaline rather than isoprenaline or noradrenaline may be useful, depending on associated factors

Bronchospasm

Aminophylline or aerosol beta-2-receptor stimulant

Torsades de pointes

DC cardioversion, transvenous cardiac pacing, adrenaline, and/or magnesium sulphate.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

ATC Code - C70A A07

D,l-sotalol is a non-selective hydrophilic β-adrenergic receptor blocking agent, devoid of intrinsic sympathomimetic activity or membrane stabilising activity.

sotalol has both beta-adrenoreceptor blocking (Vaughan Williams Class II) and cardiac action potential duration prolongation (Vaughan Williams Class III) antiarrhythmic properties. Sotalol has no known effect on the upstroke velocity and therefore no effect on the depolarisation phase.

Sotalol uniformly prolongs the action potential duration in cardiac tissues by delaying the repolarisation phase. Its major effects are prolongation of the atrial, ventricular and accessory pathway effective refractory periods.

The Class II and III properties may be reflected on the surface electrocardiogram by a lengthening of the PR, QT and QTc (QT corrected for heart rate) intervals with no significant alteration in the QRS duration.

The d- and l-isomers of sotalol have similar Class III antiarrhythmic effects while the l-isomer is responsible for virtually all of the beta-blocking activity. Although significant beta-blockade may occur at oral doses as low as 25 mg, Class III effects are usually seen at daily doses of greater than 160 mg.

Its β-adrenergic blocking activity causes a reduction in heart rate (negative chronotropic effect) and a limited reduction in the force of contraction (negative inotropic effect). These cardiac changes reduce myocardial oxygen consumption and cardiac work. Like other β-blockers, sotalol inhibits renin release. The renin-suppressive effect of sotalol is significant both at rest and during exercise. Like other beta adrenergic blocking agents, sotalol produces a gradual but significant reduction in both systolic and diastolic blood pressures in hypertensive patients. Twenty-four-hour control of blood pressure is maintained both in the supine and upright positions with a single daily dose.

5.2 Pharmacokinetic Properties

The bioavailability of oral sotalol is essentially complete (greater than 90%). After oral administration, peak levels are reached in 2.5 to 4 hours, and steady-state plasma levels are attained within 2-3 days. The absorption is reduced by approximately 20% when administered with a standard meal, in comparison to fasting conditions. Over the dosage range 40-640 mg/day sotalol displays dose proportionality with respect to plasma levels. Distribution occurs to a central (plasma) and a peripheral compartment, with an elimination half-life of 10-20 hours. Sotalol does not bind to plasma proteins and is not metabolised. There is very little inter-subject variability in plasma levels. Sotalol crosses the blood brain barrier poorly, with cerebrospinal fluid concentrations only 10% of those in plasma. The primary route of elimination is renal excretion. Approximately 80 to 90% of a dose is excreted unchanged in the urine, while the remainder is excreted in the faeces. Lower doses are necessary in conditions of renal impairment (see Dosage and Administration in patients with renal dysfunction). Age does not significantly alter the pharmacokinetics, although impaired renal function in geriatric patients can decrease the excretion rate, resulting in increased drug accumulation.

5.3 Preclinical Safety Data

No further particulars.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Each tablet contains the following excipients:

Calcium hydrogen phosphate dihydrate

Maize Starch

Povidone K30

Sodium starch glycollate (Type A)

Talc

Magnesium stearate

Indigocarmine Aluminium Salt E132

6.2 Incompatibilities

None

6.3 Shelf Life

36 months

6.4 Special Precautions For Storage

Do not store above 25°C. Store in original package.

6.5 Nature And Contents Of Container

The tablets are packed in 14's blisters constituted from a PVC/ PVdC and aluminium foil. Two such blisters are packed in a carton for a pack of 28 tablets.

6.6 Special Precautions For Disposal And Other Handling

None

7. Marketing Authorisation Holder

Milpharm Limited,

Ares,

Odyssey Business Park,

West End Road,

South Ruislip HA4 6QD,

United Kingdom

8. Marketing Authorisation Number(S)

PL 16363/0129

9. Date Of First Authorisation/Renewal Of The Authorisation

21 July 2003

10. Date Of Revision Of The Text

17/06/2008

Seractil 400mg Film-Coated Tablets

1. Name Of The Medicinal Product

Seractil

2. Qualitative And Quantitative Composition

Each film-coated tablet contains 400 mg of dexibuprofen. For excipients, see 6.1.

3. Pharmaceutical Form

Film-coated tablet

White, oblong, both-sided scored film-coated tablet.

4. Clinical Particulars

4.1 Therapeutic Indications

Symptomatic treatment for the relief of pain and inflammation associated with osteoarthritis.

Acute symptomatic treatment of pain during menstrual bleeding (primary dysmenorrhoea).

Symptomatic treatment of other forms of mild to moderate pain, such as muscular-skeletal pain or dental pain.

4.2 Posology And Method Of Administration

The dosage should be adjusted to the severity of the disorder and the complaints of the patient. During chronic administration, the dosage should be adjusted to the lowest maintenance dose that provides adequate control of symptoms.

For individual dosage film-coated tablets with 200, 300 and 400 mg dexibuprofen are available.

The recommended dosage is 600 to 900 mg dexibuprofen daily, divided in up to three single doses.

For the treatment of mild to moderate pain, initially single doses of 200 mg dexibuprofen and daily doses of 600 mg dexibuprofen are recommended.

The maximum single dose is 400 mg dexibuprofen.

The dose may be temporarily increased up to 1200 mg dexibuprofen per day in patients with acute conditions or exacerbations. The maximum daily dose is 1200 mg.

For dysmenorrhoea a daily dose of 600 to 900 mg dexibuprofen, divided in up to three single doses, is recommended. The maximum single dose is 300 mg, the maximum daily dose is 900 mg.

Dexibuprofen has not been studied in children and adolescents (< 18 years): Safety and efficacy have not been established and therefore it is not recommended in these age groups.

In elderly patients it is recommended to start the therapy at the lower end of the dosage range. The dosage may be increased to that recommended for general population only after good general tolerance has been ascertained.

Hepatic dysfunction: Patients with mild to moderate hepatic dysfunction should start therapy at reduced doses and be closely monitored. Dexibuprofen should not be used in patients with severe hepatic dysfunction (see 4.3. Contraindications).

Renal dysfunction: The initial dosage should be reduced in patients with mild to moderate impaired renal function. Dexibuprofen should not be used in patients with severe renal dysfunction (see 4.3. Contraindications).

The film coated tablets can be taken with or without a meal (see 5.2.). In general NSAIDs (non-steroidal anti-inflammatory drugs) are preferably taken with food to reduce gastrointestinal irritation, particularly during chronic use. However, a later onset of action in some patients may be anticipated when the tablets are taken with or directly after a meal.

The score in the 200 and 400 mg tablets makes it possible to divide the tablets before administration so as to assist with swallowing.

Dividing the tablets will not provide an exact "half" dose.

4.3 Contraindications

Dexibuprofen must not be administered in the following cases:

- Patients previously sensitive to dexibuprofen, to any other NSAID, or to any of the

excipients of the product.

- Patients in whom substances with a similar action (e.g. aspirin or other NSAIDs)

precipitate attacks of asthma, bronchospasm, acute rhinitis, or cause nasal polyps,

urticaria or angioneurotic oedema.

- Patients with active or suspected gastrointestinal ulcer or history of recurrent

gastrointestinal ulcer.

- Patients who have gastrointestinal bleeding or other active bleedings or bleeding

disorders.

- Patients with active Crohn's disease or active ulcerative colitis.

- Patients with severe heart failure.

- Patients with severe renal dysfunction (GFR < 30ml/min).

- Patients with severely impaired hepatic function.

- Patients with haemorrhagic diathesis and other coagulation disorders, or patients

receiving anticoagulant therapy.

- From the beginning of 6^th month of pregnancy (see 4.6).

4.4 Special Warnings And Precautions For Use

Care is recommended in conditions that predispose patients to the gastrointestinal adverse effects of NSAIDs such as dexibuprofen, including existing gastrointestinal disorders, previous gastric or duodenal ulcer, ulcerative colitis, Crohn's disease and alcoholism.

These patients should be closely monitored for digestive disturbances, especially gastrointestinal bleeding, when taking dexibuprofen or any other NSAID.

Gastrointestinal bleeding or ulceration/perforation have in general more serious consequences in the elderly. They can occur at any time during treatment with or without warning symptoms or a previous history of serious gastrointestinal events.

In the rare instances where gastrointestinal bleeding or ulceration occurs in patients receiving dexibuprofen, treatment should be immediately discontinued (see 4.3. Contraindications).

As with other NSAIDs, allergic reactions, including anaphylactic/anaphylactoid reactions, can also occur without earlier exposure to the drug.

In the treatment of patients with heart failure, hypertension, renal or hepatic disease, especially during concomitant diuretic treatment, the risk of fluid retention and a deterioration in renal function must be taken into account. If used in these patients, the dose of dexibuprofen should be kept as low as possible and renal function should be regularly monitored.

Caution must be exercised in the treatment of elderly patients, who generally have a greater tendency to experience side effects to NSAIDs.

Dexibuprofen should only be given with care to patients with systemic lupus erythematosus and mixed connective tissue disease, because such patients may be predisposed to NSAID-induced CNS and renal side effects.

Caution is required in patients suffering from, or with a previous history of, bronchial asthma since NSAIDs can cause bronchospasm in such patients (see 4.3 Contraindications).

NSAIDs may mask the symptoms of infections.

As with all NSAIDs, dexibuprofen can increase plasma urea nitrogen and creatinine. As with other NSAIDs, dexibuprofen can be associated with adverse effects on the renal system, which can lead to glomerular nephritis, interstitial nephritis, renal papillary necrosis, nephrotic syndrome and acute renal failure (see 4.2. Posology, 4.3. Contraindications and 4.5 Interactions).

As with other NSAIDs, dexibuprofen can cause transient small increases in some liver parameters, and also significant increases in SGOT and SGPT. In case of a relevant increase in such parameters, therapy must be discontinued (see 4.2. Posology and 4.3. Contraindications).

In common with other NSAIDs dexibuprofen may reversibly inhibit platelet aggregation and function and prolong bleeding time. Caution should be exercised when dexibuprofen is given concurrently with oral anticoagulants (see section 4.5).

Patients receiving long-term treatment with dexibuprofen should be monitored as a precautionary measure (renal, hepatic functions and haematologic function/blood counts).

During long-term, high dose, off-label treatment with analgesic drugs, headaches can occur which must not be treated with higher doses of the medicinal product.

In general the habitual use of analgesics, especially the combination of different analgesic drug substances, can lead to lasting renal lesions with the risk of renal failure (analgesic nephropathy). Thus combinations with racemic ibuprofen or other NSAIDs (including OTC products) should be avoided.

The use of dexibuprofen, as with any other drug known to inhibit cyclooxygenase / prostaglandin synthesis, may impair fertility reversibly and is not recommended in women attempting to conceive. In women who have difficulty conceiving or who are undergoing investigation of infertility, withdrawal of Seractil should be considered.

Data of preclinical studies indicate that inhibition of platelet aggregation by low-dose acetylsalicylic acid may be impaired if ibuprofen is administrated concurrently;

this interaction could reduce the cardiovascular-protective effect. Therefore if concomitant administration of low-dose acetylsalicylic acid is indicated special precaution is required if duration of treatment exceeds short term use.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

The information in this section is based upon previous experience with racemic ibuprofen and other NSAIDs.

In general, NSAIDs should be used with caution with other drugs that can increase the risk of gastrointestinal ulceration or gastrointestinal bleeding or renal impairment.

Concomitant use not recommended:

Anticoagulants: The effects of anticoagulants on bleeding time can be potentiated by NSAIDs. If concomitant treatment can not be avoided blood coagulation tests (INR, bleeding time) should be performed during the initiation of dexibuprofen treatment and the dosage of the anticoagulant should be adjusted if necessary (see section 4.4).

Methotrexate used at doses of 15 mg/week or more: If NSAIDs and methotrexate are given within 24 hours of each other plasma levels of methotrexate may increase, via a reduction in its renal clearance thus increasing the potential for methotrexate toxicity. Therefore, in patients receiving high-dose treatment with methotrexate, the concomitant use of dexibuprofen is not recommended (see section 4.4).

Lithium: NSAIDs can increase the plasma levels of lithium, by reducing its renal clearance. The combination is not recommended (see section 4.4). Frequent lithium monitoring should be performed. The possibility of reducing the dose of lithium should be considered.

Other NSAIDs and salicylates ( acetylsalicylic acid at doses above those used for anti-thrombotic treatment, approximately 100 mg/day ): The concomitant use with other NSAIDs should be avoided, since simultanous administration of different NSAIDs can increase the risk of gastrointestinal ulceration and haemorrhage.

Precautions:

Acetylsalicylic acid: Concomitant administration of ibuprofen may impair inhibition of platelet aggregation by low-dose acetylsalicylic acid.

Antihypertensives : NSAIDs may reduce the efficacy of beta-blockers, possibly due to inhibition of the formation of vasodilatory prostaglandins.

The concomitant use of NSAIDs and ACE inhibitors or angiotensin-II receptor antagonists may be associated with an increased risk of acute renal failure, especially in patients with pre-existing impairment of renal function. When given to the elderly and/or dehydrated patients, such a combination can lead to acute renal failure by acting directly on glomerular filtration. At the beginning of the treatment, a careful monitoring of renal function is recommended.

Furthermore, chronic administration of NSAIDs can theoretically reduce the antihypertensive effect of angiotensin-II receptor antagonists, as reported with ACE inhibitors. Therefore, caution is required when using such a combination and at the start of treatment, renal function should be carefully monitored (and patients should be encouraged to maintain adequate fluid intake).

Ciclosporin, tacrolimus: Concomitant administration with NSAIDs may increase the risk of nephrotoxicity on account of reduced synthesis of prostaglandins in the kidney. During combination treatment renal function must be closely monitored, especially in the elderly.

Corticosteroids: The risk of gastrointestinal ulceration may be increased by the concomitant administration of NSAIDs and corticosteroids.

Digoxin : NSAIDs can increase the plasma levels of digoxin and increase the risk of digoxin toxicity.

Methotrexate used at doses lower than 15 mg/week : Ibuprofen has been reported to increase methotrexate levels. If dexibuprofen is used in combination with low doses of methotrexate, then the patient's blood count should be monitored carefully, particularly during the first weeks of coadministration. An increased surveillance is required in the presence of even mildly impaired renal function, notably in the elderly, and renal function should be monitored to anticipate any reductions in the clearance of methotrexate.

Phenytoin:Ibuprofen may displace phenytoin from protein-binding sites, possibly leading to increased phenytoin serum levels and toxicity. Although clinical evidence for this interaction is limited, phenytoin dosage adjustment, based on monitoring of plasma concentrations and/or observed signs of toxicity, is recommended.

Thiazides, thiazide-related substances, loop diuretics and potassium-sparing diuretics: Concurrent use of an NSAID and a diuretic may increase the risk of renal failure secondary to a reduction in renal blood flow.

Drugs increasing potassium plasma levels:

As with other NSAIDs, concomitant treatment with drugs increasing potassium plasma levels, like potassium-sparing diuretics, ACE inhibitors, angiotensin-II receptors antagonists, immunosuppressants like cyclosporin or tacrolimus, trimethoprime, heparins, etc… may be associated with increased serum potassium levels; hence serum potassium levels should be monitored.

Thrombolytics, ticlopidine and antiplatelet agents: Dexibuprofen inhibits platelet aggregation via inhibition of platelet cyclooxygenase. Therefore, caution is required when dexibuprofen is combined with thrombolytics, ticlopidine and other antiplatelet agents, because of the risk of increased antiplatelet effect.

4.6 Pregnancy And Lactation

Pregnancy:

For dexibuprofen, no clinical data on exposed pregnancies are available. Animal studies with ibuprofen and other NSAIDs have shown reproductive toxicity (see 5.3 Preclinical Safety Data).

Inhibition of prostaglandin synthesis may adversely affect the pregnancy and/or the embryo/fetal development, and as the consequences of inhibiting the synthesis of prostaglandins are not fully known, dexibuprofen, like other drugs of this class, should only be administered in the first 5 months of pregnancy if clearly needed, in the lowest effective dose and as short as possible.

During the third trimester of pregnancy, all prostaglandin synthesis inhibitors may expose the fetus to:

- cardiopulmonary toxicity (with premature closure of the ductus arteriosus and

pulmonary hypertension),

- renal dysfunction, which may progress to renal failure with oligo-hydroamniosis,

the mother and the neonate, at the end of pregnancy, to:

- possible prolongation of bleeding time,

- inhibition of uterine contractions resulting in delayed or prolonged labour.

Therefore, from the beginning of the 6^th month of pregnancy onward dexibuprofen is contraindicated.

The use of dexibuprofen, as with any drug substance known to inhibit cyclooxygenase / prostaglandin synthesis is not recommended in women attempting to conceive (see 4.4).

Lactation:

Ibuprofen is slightly excreted in human milk. Breast-feeding is possible with dexibuprofen if dosage is low and the treatment period is short.

4.7 Effects On Ability To Drive And Use Machines

During treatment with dexibuprofen the patient's reaction capacity may be reduced when dizziness or fatigue appear as side effects. This should be taken into consideration when increased alertness is required, e.g. when driving or operating machinery. For a single or short term use of Dexibuprofen no special precautions are necessary.

4.8 Undesirable Effects

Clinical experience has shown that the risk of undesirable effects induced by dexibuprofen is comparable to that of racemic ibuprofen. The most common adverse events are gastrointestinal in nature.

It should be noted that the adverse events listed below include those reported predominantly for racemic ibuprofen, even though in some cases the adverse event has either not yet been observed with dexibuprofen or has not yet been reported in the frequency mentioned.

Gastrointestinal :

Very common (>1/10): Dyspepsia, diarrhoea.

Common (>1/100, <1/10): Nausea, vomiting, abdominal pain.

Uncommon (>1/1,000, <1/100): Gastrointestinal ulcers and bleeding, ulcerative stomatitis.

Rare (>1/10,000, <1/1,000): Gastrointestinal perforation, flatulence, constipation, esophagitis, esophageal strictures. Exacerbation of diverticular disease, unspecific haemorrhagic colitis, colitis ulcerosa or Crohn's disease.

If gastrointestinal blood loss occurs, this may cause anaemia and haematemesis.

Skin and hypersensitivity reaction:

Common: Rash.

Uncommon: Urticaria, pruritus, purpura (including allergic purpura), angiooedema, rhinitis, bronchospasm.

Rare: Anaphylactic reaction

Very rare ( <1/10,000): Erythema multiforme, epidermal necrolysis, systemic lupus erythematosus, alopecia, photosensitivity reactions, severe skin reactions like Stevens-Johnson-Syndrome, acute toxic epidermal necrolysis (Lyell-Syndrome) and allergic vasculitis.

Generalized hypersensitivity reactions have not yet been reported with dexibuprofen but their occurrence cannot be excluded considering the clinical experience with racemic ibuprofen. The symptoms may include fever with rash, abdominal pain, headache, nausea and vomiting, signs of liver injury and even aseptic meningitis. In the majority of cases in which aseptic meningitis has been reported with ibuprofen, some form of underlying auto-immune disease (such as systemic lupus erythematosus or other collagen diseases) was present as a risk factor. In case of a severe generalized hypersensitivity reaction swelling of face, tongue and larynx, bronchospasm, asthma, tachycardia, hypotension and shock can occur.

Central nervous system:

Common: Fatigue or drowsiness, headache, dizziness, vertigo.

Uncommon: Insomnia, anxiety, restlessness, visual disturbances, tinnitus.

Rare: Psychotic reaction, agitation, irritability, depression, confusion or disorientation, reversible toxic amblyopia, impaired hearing.

Very rare: Aseptic meningitis (see hypersensitivity reactions).

Haematological:

Bleeding time may be prolonged. Rare cases of blood disorders include: Thrombocytopenia, leucopenia, granulocytopenia, pancytopenia, agranulocytosis, aplastic anemia or haemolytic anaemia.

Cardiovascular:

Peripheral oedema has been reported in association with dexibuprofen treatment.

Patients with hypertension or renal impairment seem to be predisposed to fluid retention.

Hypertension or cardiac failure (especially in the elderly) may occur.

Renal:

According to the experience with NSAIDs in general, interstitial nephritis, nephrotic syndrome or renal failure cannot be excluded.

Hepatic:

Rare cases of abnormal liver function, hepatitis and jaundice have been observed with racemic ibuprofen.

Others:

In very rare cases infection related inflammation may be aggravated.

4.9 Overdose

Dexibuprofen has a low acute toxicity and patients have survived after single doses as high as 54 g of racemic ibuprofen. Most overdoses have been asymptomatic. There is a risk of symptoms at doses>80 - 100 mg/kg racemic ibuprofen.

The onset of symptoms usually occurs within 4 hours. Mild symptoms are most common, including abdominal pain, nausea, vomiting, lethargy, drowsiness, headache, nystagmus, tinnitus and ataxia. Rarely, moderate or severe symptoms include gastrointestinal bleeding, hypotension, hypothermia, metabolic acidosis, seizures, impaired kidney function, coma, adult respiratory distress syndrome and transient episodes of apnea (in very young children following large ingestions).

Treatment is symptomatic, and there is no specific antidote. Amounts not likely to produce symptoms (less than 50 mg/kg dexibuprofen) may be diluted with water to minimize gastrointestinal upset. In case of ingestion of a significant amount, activated charcoal should be administered.

Emptying of the stomach by emesis may only be considered if the procedure can be undertaken within 60 minutes of ingestion. Gastric lavage should not be considered unless a patient has ingested a potentially life-threatening amount of the drug and the procedure can be undertaken within 60 minutes of ingestion. Forced diuresis, hemodialysis or hemoperfusion are unlikely to be of assistance because dexibuprofen is strongly bound to plasma proteins.

5. Pharmacological Properties

Pharmacotherapeutic group: Antiinflammatory and antirheumatic products, non-steroids, propionic acid derivatives.

ATC code: M01AE14

5.1 Pharmacodynamic Properties

Dexibuprofen (= S(+)-ibuprofen) is considered to be the pharmacologically active enantiomer of racemic ibuprofen. Racemic ibuprofen is a non-steroidal substance with antiinflammatory and analgesic effects. Its mechanism of action is thought to be due to inhibition of prostaglandin synthesis. Bridging studies in order to compare the efficacy of racemic ibuprofen and dexibuprofen in osteoarthritis over a treatment period of 15 days and in dysmenorrhea, including symptoms of pain, have demonstrated at least non-inferiority of dexibuprofen versus racemic ibuprofen at the recommended dosage.

5.2 Pharmacokinetic Properties

Dexibuprofen is absorbed primarily from the small intestine. After metabolic transformation in the liver (hydroxylation, carboxylation), the pharmacologically inactive metabolites are completely excreted, mainly by the kidneys (90%), but also in the bile. The elimination half-life is 1.8 – 3.5 hours; the plasma protein binding is about 99 %. Maximum plasma levels are reached about 2 hours after oral administration.

The administration of dexibuprofen with a meal delays the time to reach maximum concentrations (from 2.1 hours after fasting conditions to 2.8 hours after non-fasting conditions) and decreases the maximum plasma concentrations (from 20.6 to 18.1 µg/ml, which is of no clinical relevance), but has no effect on the extent of absorption.

5.3 Preclinical Safety Data

Bridging studies on single and repeated dose toxicity, reproduction toxicity and mutagenicity have shown that the toxicological profile of dexibuprofen is comparable to that of racemic ibuprofen.

Racemic ibuprofen inhibited ovulation in the rabbit and impaired implantation in different animal species (rabbit, rat, mouse). Administration of prostaglandin synthesis inhibitors including ibuprofen (mostly in doses higher than used therapeutically) to pregnant animals has been shown to result in increased pre- and postimplantation loss, embryo-fetal lethality and increased incidences of malformations.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Tablet core: Hypromellose, microcrystalline cellulose, carmellose calcium, colloidal anhydrous silica, talc.

Film-coating material: Hypromellose, titanium dioxide (E171), glycerol triacetate, talc, macrogol 6000.

6.2 Incompatibilities

Not applicable.

6.3 Shelf Life

3 years (PVC/PVDC/aluminium blisters)

18 months (PE jars)

6.4 Special Precautions For Storage

Do not store above 25 °C.

6.5 Nature And Contents Of Container

10, 20, 30, 50, 60, 90, 100, 100x1 and 500x1 film-coated tablets in PVC/PVDC/aluminium blisters.

150 film-coated tablets in PE jars with dosing hole and hinged closure.

Not all pack sizes may be marketed.

6.6 Special Precautions For Disposal And Other Handling

No special requirements.

7. Marketing Authorisation Holder

Gebro Pharma GmbH, A-6391 Fieberbrunn

Austria

8. Marketing Authorisation Number(S)

PL 04536/0007

9. Date Of First Authorisation/Renewal Of The Authorisation

31 October 2000

10. Date Of Revision Of The Text

April 2004

11. Legal Category

POM