Somatuline Autogel 60 mg, Somatuline Autogel 90 mg, Somatuline Autogel 120 mg

1. Name Of The Medicinal Product

Somatuline Autogel 60mg, solution for injection in a pre-filled syringe.

Somatuline Autogel 90mg, solution for injection in a pre-filled syringe.

Somatuline Autogel 120mg, solution for injection in a pre-filled syringe.

2. Qualitative And Quantitative Composition

Lanreotide (I.N.N.), 60mg, 90mg or 120mg (as acetate).

Each pre-filled syringe contains a supersaturated solution of lanreotide acetate corresponding to 0.246mg lanreotide base/mg of solution, which ensures an actual injection dose of 60mg, 90mg or 120mg respectively, of lanreotide.

For excipients, see 6.1.

3. Pharmaceutical Form

Solution for injection in a pre-filled syringe.

White to pale yellow semi-solid formulation.

4. Clinical Particulars

4.1 Therapeutic Indications

Somatuline Autogel is indicated for the treatment of individuals with acromegaly when the circulating levels of Growth Hormone (GH) and/or Insulin-like Growth Factor-1 (IGF-1) remain abnormal after surgery and/or radiotherapy, or in patients who otherwise require medical treatment. The goal of treatment in acromegaly is to reduce GH and IGF-1 levels and where possible to normalise these values.

Somatuline Autogel is also indicated for the treatment of symptoms associated with neuroendocrine (particularly carcinoid) tumours.

4.2 Posology And Method Of Administration

Posology

Acromegaly

In patients receiving a somatostatin analogue for the first time, the recommended starting dose is 60mg of Somatuline Autogel administered every 28 days.

In patients previously treated with Somatuline LA 30mg once every 14 days, the initial dose of Somatuline Autogel should be 60mg every 28 days; in patients previously treated with Somatuline LA 30mg once every 10 days, the initial dose of Somatuline Autogel should be 90mg every 28 days; and in patients treated with Somatuline LA 30mg once every 7 days, the initial dose of Somatuline Autogel should be 120mg every 28 days.

Thereafter, for all patients, the dose should be individualised according to the response of the patient (as judged by a reduction in symptoms and/or a reduction in GH and/or IGF-1 levels).

If the desired response is not obtained, the dose may be increased.

For patients whose GH concentrations are below 1ng/mL (approx 2mU/L), whose IGF-1 serum concentrations have normalised, and in whom most reversible signs of acromegaly have disappeared the monthly dose should be decreased. If appropriate, this may be achieved by giving Somatuline Autogel 120mg at increased intervals of 42-56 days.

For patients on Somatuline Autogel 60mg or 90mg every 28 days who are well controlled (GH concentrations less than 2.5ng/mL (approx 5 mU/L) but above 1ng/mL (approx 2mU/L) and normalised IGF-1 levels) the dose should be maintained, or alternatively Somatuline Autogel 120mg may be given at increased intervals of 56 or 42 days respectively.

For patients in whom clinical symptoms and biochemical parameters are not adequately controlled (GH concentrations still above 2.5ng/mL (approx 5mU/L) or IGF-1 greater than (age matched) normal) the dose of Somatuline Autogel may be increased to a maximum of 120mg at 28 day intervals.

Long term monitoring of symptoms, GH and IGF-1 levels should be routinely carried out in all patients.

Neuroendocrine tumours:

The recommended starting dose is 60 to 120mg administered every 28 days.

The dose should be adjusted according to the degree of symptomatic relief obtained.

Paediatric population:

Somatuline Autogel is not recommended for use in children and adolescents due to lack of data on safety and efficacy.

Renal and /or hepatic impairment:

In patients with impaired renal or hepatic function, no dosage adjustment is necessary due to the wide therapeutic window of lanreotide (see section 5.2).

Elderly patients:

In elderly patients, no dosage adjustment is necessary due to the wide therapeutic window of lanreotide (see section 5.2).

Method of Administration:

Somatuline Autogel should be injected, via the deep subcutaneous route, into the superior, external quadrant of the buttock.

The injection may be given by a healthcare professional or, for patients considered by their healthcare professional to be stabilised on their treatment with Somatuline Autogel, by an appropriately trained friend or relative of the patient (see section 5.1). Alternatively, such patients may self-administer the product after appropriate training. In this case the injection should be given in the upper, outer thigh.

Regardless of the site of administration, the skin should be stretched prior to injection. The needle should be inserted rapidly to its full length, perpendicularly to the skin.

The injection site should be alternated between the right and left sides.

4.3 Contraindications

Hypersensitivity to lanreotide or related peptides or any of the excipients

4.4 Special Warnings And Precautions For Use

Lanreotide may reduce gall bladder motility and lead to gallstone formation. Therefore, patients may need to be monitored periodically.

Pharmacological studies in animals and humans show that lanreotide, like somatostatin and other somatostatin analogues, inhibits the secretion of insulin and glucagon. Hence, patients treated with lanreotide may experience hypoglycaemia or hyperglycaemia. Blood glucose levels should be monitored when lanreotide treatment is initiated, or when the dose is altered and any anti-diabetic treatment should be adjusted accordingly.

Slight decreases in thyroid function have been seen during treatment with lanreotide in patients with acromegaly, although clinical hypothyroidism is rare (<1%). Tests of thyroid function should be done where clinically indicated.

In patients without underlying cardiac problems, lanreotide may lead to a decrease of heart rate without necessarily reaching the threshold of bradycardia. In patients suffering from cardiac disorders prior to lanreotide treatment, sinus bradycardia may occur. Care should be taken when initiating treatment with lanreotide in patients with bradycardia (see section 4.5).

In patients with carcinoid tumours, lanreotide must not be prescribed before excluding the presence of an obstructive intestinal tumour.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

The pharmacological gastrointestinal effects of lanreotide may reduce the intestinal absorption of co-administered drugs including ciclosporin. Concomitant administration of ciclosporin with lanreotide may decrease the relative bioavailability of ciclosporin and therefore may necessitate the adjustment of ciclosporin dose to maintain therapeutic levels.

Interactions with highly plasma bound drugs are unlikely in view of the moderate binding of lanreotide to serum proteins.

Limited published data indicate that concomitant administration of somatostatin analogues and bromocriptine may increase the availability of bromocriptine.

Concomitant administration of bradycardia-inducing drugs (e.g. beta blockers) may have an additive effect on the slight reduction of heart rate associated with lanreotide. Dose adjustments of such concomitant medicines may be necessary.

The limited published data available indicate the somatostatin analogues may decrease the metabolic clearance of compounds known to be metabolised by cytochrome P450 enzymes, which may be due to the suppression of growth hormone. Since it cannot be excluded that lanreotide may have this effect, other drugs mainly metabolised by CYP3A4 and which have a low therapeutic index (e.g. quinidine, terfenadine) should therefore be used with caution.

4.6 Pregnancy And Lactation

Non-clinical data

Studies in animals showed no evidence of teratogenic effects associated with lanreotide during organogenesis. Reduced fertility was observed in female rats due to the inhibition of GH secretion at doses in excess of those achieved in humans at therapeutic doses.

Clinical data:

Data on a limited number of exposed pregnancies indicate no adverse effects of lanreotide on pregnancy or on the health of the foetus/newborn child. To date, no other relevant epidemiological data are available.

Because animal studies are not always predictive of human responses, lanreotide should be administered to pregnant women only if clearly needed.

Breast feeding:

It is not known whether this drug is excreted in human milk.

Because many drugs are excreted in human milk, caution should be exercised when lanreotide is administered during lactation.

4.7 Effects On Ability To Drive And Use Machines

While no effect on the ability to drive and use machines has been established, dizziness has been reported with Somatuline Autogel. If a patient is affected, he/she should not drive or operate machinery.

4.8 Undesirable Effects

Undesirable effects reported by patients suffering from acromegaly treated with lanreotide in clinical trials are listed under the corresponding body organ systems according to the following classification: Very common (

The most commonly expected adverse drug reactions following treatment with lanreotide are gastrointestinal disorders (most commonly reported are diarrhoea and abdominal pain, usually mild or moderate and transient), cholelithiasis (often asymptomatic) and injection site reactions (pain, nodules and indurations).

The profile of undesirable effects is similar for other indications.

System organ class	Very common (	Common (	Uncommon (
Investigations		ALAT increased, ASAT abnormal, ALAT abnormal, blood bilirubin increased, blood glucose increased, glycosylated haemoglobin increased, weight decreased	ASAT increased, blood alkaline phosphatase increased, blood bilirubin abnormal, blood sodium decreased
Cardiac disorders		Sinus bradycardia
Nervous system disorders		Dizziness, headache
Gastrointestinal disorders	Diarrhoea, loose stools, abdominal pain	Nausea, vomiting, constipation, flatulence, abdominal distension, abdominal discomfort, dyspepsia	Faeces discoloured
Skin and subcutaneous tissue disorders		Alopecia, hypotrichosis
Metabolism and nutrition disorders		Hypoglycaemia	Diabetes mellitus, hyperglycaemia
Vascular disorders			Hot flush
General disorders and administration site conditions		Fatigue, injection site reactions (pain, mass, induration, nodule, pruritus)	Asthenia
Hepatobiliary disorders	Cholelithiasis	Biliary dilatation
Psychiatric disorders			Insomnia

Post-marketing safety experience

Post-marketing safety experience has not identified any other relevant information other than occasional reports of pancreatitis.

4.9 Overdose

If overdose occurs, symptomatic management is indicated.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Antigrowth hormones, ATC code: H01C B03.

Lanreotide is an octapeptide analogue of natural somatostatin. Like somatostatin, lanreotide is an inhibitor of various endocrine, neuroendocrine, exocrine and paracrine functions. Lanreotide has high binding affinity for human somatostatin receptors (SSTR) 2 and 5, and a reduced binding affinity for human SSTR 1, 3 and 4. Activity at SSTR 2 and 5 is the primary mechanism considered to be responsible for GH inhibition.

Lanreotide, like somatostatin, exhibits a general exocrine anti-secretory action. It inhibits the basal secretion of motilin, gastric inhibitory peptide and pancreatic polypeptide, but has no significant effect on fasting secretin or gastrin secretion. Lanreotide markedly inhibits meal-induced increases in superior mesenteric artery blood flow and portal venous blood flow. Lanreotide significantly reduces prostaglandin E1-stimulated jejunal secretion of water, sodium, potassium and chloride. Lanreotide reduces prolactin levels in patients with acromegaly treated long term.

Lanreotide is clearly more active than natural somatostatin and shows a much longer duration of action.

During an open label, controlled study involving patients with acromegaly treated with a stable dose of Somatuline Autogel for at least 4 months, 93% of the patients who received self or partner administered injections of Somatuline Autogel after appropriate training were considered competent to perform unsupervised injections (maintenance of GH and IGF-1 levels).

5.2 Pharmacokinetic Properties

Intrinsic pharmacokinetic parameters of lanreotide after intravenous administration in healthy volunteers indicated limited extravascular distribution, with a steady-state volume of distribution of 16.1L. Total clearance was 23.7L/h, terminal half-life was 1.14 hours and mean residence time was 0.68 hours.

In studies evaluating excretion, less than 5% of lanreotide was excreted in urine and less than 0.5% was recovered unchanged in faeces indicating some biliary excretion.

After deep subcutaneous administration of Somatuline Autogel 60, 90 and 120mg to healthy volunteers, lanreotide concentrations increase to achieve average maximum serum concentrations of 4.25, 8.39 and 6.79ng/mL, respectively. These values of Cmax are achieved during the first day after the administration at 8, 12 and 7 hours (median values). From the peak serum levels of lanreotide, concentrations decrease slowly following first-order kinetics with a terminal elimination half-life of 23.3, 27.4 and 30.1 days, respectively. 4 weeks after the administration mean lanreotide serum levels were 0.9, 1.11 and 1.69ng/mL, respectively. Absolute bioavailability was 73.4, 69.0 and 78.4%, respectively.

After deep subcutaneous administration of Somatuline Autogel 60, 90 and 120mg to patients with acromegaly, lanreotide concentrations increase to achieve average maximum serum concentrations of 1.6, 3.5 and 3.1ng/mL, respectively. These values of Cmax are achieved during the first day after the administration at 6, 6 and 24 hours. From the peak serum levels of lanreotide, concentrations decrease slowly following first-order kinetics and 4 weeks after the administration mean lanreotide serum levels were 0.7, 1.0 and 1.4ng/mL, respectively.

Steady state serum levels of lanreotide were reached, on average, after 4 injections every 4 weeks. After repeated dose administration every 4 weeks the average values of Cmax at steady state were 3.8, 5.7 and 7.7ng/mL for 60, 90 and 120mg, respectively, the average Cmin values obtained being 1.8, 2.5 and 3.8ng/mL. The peak trough fluctuation index was moderate ranging from 81 to 108%.

Linear pharmacokinetic release profiles were observed after deep subcutaneous administration of Somatuline Autogel 60, 90 and 120mg in patients with acromegaly.

Trough lanreotide serum levels obtained after three deep subcutaneous injections of Somatuline Autogel 60, 90 or 120mg given every 28 days are similar to the steady-state trough lanreotide serum levels obtained in patients with acromegaly previously treated with intramuscular administrations of lanreotide 30mg prolonged release microparticles (Somatuline LA) every 14, 10 or 7 days, respectively.

Lanreotide serum levels of 1ng/mL are able to suppress GH to < 5ng/mL in more than 60% of patients studied. Lanreotide serum levels of 2.5ng/mL are able to suppress GH to < 5ng/mL in more than 90% of patients studied.

Renal/Hepatic impairment

Subjects with severe renal impairment show an approximately 2-fold decrease in total serum clearance of lanreotide, with a consequent increase in half-life and AUC. In subjects with moderate to severe hepatic impairment, a reduction in clearance was observed (30%). The volume of distribution and mean residence time increased in subjects with all degrees of hepatic insufficiency.

It is not necessary to alter the starting dose in patients with renal or hepatic impairment, as lanreotide serum concentrations in these populations are expected to be well within the range of serum concentrations safely tolerated in healthy subjects.

Elderly patients

Elderly subjects show an increase in half-life and mean residence time compared with healthy young subjects. It is not necessary to alter the starting dose in elderly patients, as lanreotide serum concentrations in this population are expected to be well within the range of serum concentrations safely tolerated in healthy subjects.

5.3 Preclinical Safety Data

In carcinogenic bioassay studies conducted in rats and mice, no systemic neoplastic changes were observed at doses in excess of those achieved in humans at therapeutic doses. Increased incidence of subcutaneous tumours were observed at the injection sites likely due to the increased dose frequency in animals (daily) compared to monthly dosing in humans and therefore may not be clinically relevant.

In in vitro and in vivo standard battery tests, lanreotide did not show any genotoxic potential.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Water for injections.

6.2 Incompatibilities

Not applicable.

6.3 Shelf Life

2 years.

After opening the protective laminated pack, the product should be administered immediately.

6.4 Special Precautions For Storage

Store in a refrigerator between 2°C to 8°C in the original package. Do not freeze.

6.5 Nature And Contents Of Container

Somatuline Autogel is supplied in a clear polypropylene pre-filled syringe with a stainless steel needle and a plunger stopper made from bromobutyl rubber coated with silicone.

Each pre-filled syringe is packed in a nylon/polyethylene/aluminium laminated bag.

Box of one individual 60mg dose in a 0.3mL syringe with a needle (1.2mm x 20mm).

Box of one individual 90mg dose in a 0.3mL syringe with a needle (1.2mm x 20mm).

Box of one individual 120mg dose in a 0.5mL syringe with a needle (1.4mm x 20mm).

6.6 Special Precautions For Disposal And Other Handling

The solution for injection in a pre-filled syringe is ready for use.

For immediate and single use following first opening.

7. Marketing Authorisation Holder

Ipsen Limited

190 Bath Road

Slough, Berkshire

SL1 3XE, UK

8. Marketing Authorisation Number(S)

PL 34926/0005 (Somatuline^® Autogel^® 60mg)

PL 34926/0006 (Somatuline^® Autogel^® 90mg)

PL 34926/0007 (Somatuline^® Autogel^® 120mg)

9. Date Of First Authorisation/Renewal Of The Authorisation

16^th October 2001

10. Date Of Revision Of The Text

14^th September 2011

Sporanox -Pulse

1. Name Of The Medicinal Product

Sporanox-Pulse.

2. Qualitative And Quantitative Composition

Itraconazole 100 mg.

For excipients, see 6.1.

3. Pharmaceutical Form

Capsule (Size 0): opaque blue cap and pink transparent body containing coated beads.

4. Clinical Particulars

4.1 Therapeutic Indications

Onychomycosis caused by dermatophytes and/or yeasts.

Tinea pedis and/or tinea manuum.

4.2 Posology And Method Of Administration

Sporanox-Pulse is for oral administration and must be taken immediately after a meal for maximal absorption.

Treatment schedules in adults are as follows:

Indication	Dose	Remarks
Tinea pedis and/or tinea manuum	1 pulse treatment	A pulse treatment consists of 200 mg bd. for 7 days.
Onychomycosis – fingernails	2 pulse treatments	Pulse treatments are separated by a 3-week
Onychomycosis – toenails	3 pulse treatments	drug-free interval

Impaired absorption in AIDS and neutropenic patients may lead to low itraconazole blood levels and lack of efficacy. In such cases, blood level monitoring is indicated.

Use in children

Not recommended. See 4.4 Special warnings and special precautions for use.

In Elderly

Not recommended. See 4.4 Special warnings and special precautions for use.

Use in patients with renal impairment

The oral bioavailability of itraconazole may be lower in patients with renal insufficiency, a dose adjustment may be considered. See 4.4 Special warnings and special precautions for use.

Use in patients with hepatic impairment

Itraconazole is predominantly metabolised by the liver. The terminal half-life of itraconazole in cirrhotic patients is somewhat prolonged. The oral bioavailability in cirrhotic patients is somewhat decreased. A dose adjustment may be considered. See 4.4 Special warnings and special precautions for use.

4.3 Contraindications

Sporanox-Pulse is contra-indicated in patients with known hypersensitivity to itraconazole or to any of the excipients.

Co-administration of the following drugs is contraindicated with Sporanox-Pulse capsules (see also section 4.5):

- CYP3A4 metabolised substrates that can prolong the QT-interval e.g., astemizole, bepridil, cisapride, dofetilide, levacetylmethadol (levomethadyl), mizolastine, pimozide, quinidine, sertindole and terfenadine are contraindicated with Sporanox-Pulse capsules. Co-administration may result in increased plasma concentrations of these substrates, which can lead to QTc prolongation and rare occurrences of torsades de pointes.

- CYP3A4 metabolised HMG-CoA reductase inhibitors such as atorvastatin, lovastatin and simvastatin

- Triazolam and oral midazolam

- Ergot alkaloids such as dihydroergotamine, ergometrine (ergonovine), ergotamine and methylergometrine (methylergonovine)

- Eletriptan

- Nisoldipine

- Sporanox-Pulse capsules should not be administered to patients receiving disopyramide or halofantrine

Sporanox-Pulse capsules should not be administered to patients with evidence of ventricular dysfunction such as congestive heart failure (CHF) or a history of CHF except for the treatment of life-threatening or other serious infections. See section 4.4.

Sporanox-Pulse must not be used during pregnancy. See section 4.6.

Women of childbearing potential taking Sporanox-Pulse should use contraceptive precautions. Effective contraception should be continued until the menstrual period following the end of Sporanox-Pulse therapy.

4.4 Special Warnings And Precautions For Use

Cross-hypersensitivity

There is no information regarding cross hypersensitivity between itraconazole and other azole antifungal agents. Caution should be used in prescribing Sporanox to patients with hypersensitivity to other azoles.

Cardiac effects

In a healthy volunteer study with Sporanox IV, a transient asymptomatic decrease of the left ventricular ejection fraction was observed; this resolved before the next infusion. The clinical relevance of these findings to the oral formulations is unknown.

Itraconazole has been shown to have a negative inotropic effect and Sporanox-Pulse has been associated with reports of congestive heart failure. Heart failure was more frequently reported among spontaneous reports of 400 mg total daily dose than among those of lower total daily doses, suggesting that the risk of heart failure might increase with the total daily dose of itraconazole.

Sporanox-Pulse should not be used in patients with congestive heart failure or with a history of congestive heart failure unless the benefit clearly outweighs the risk. This individual benefit/risk assessment should take into consideration factors such as the severity of the indication, the dose and duration of treatment (e.g. total daily dose), and individual risk factors for congestive heart failure. These risk factors include cardiac disease, such as ischemic and valvular disease; significant pulmonary disease, such as chronic obstructive pulmonary disease; and renal failure and other edematous Such patients should be informed of the signs and symptoms of congestive heart failure, should be treated with caution, and should be monitored for signs and symptoms of congestive heart failure during treatment; if such signs or symptoms do occur during treatment, Sporanox-Pulse should be discontinued.

Calcium channel blockers can have negative inotropic effects which may be additive to those of itraconazole. In addition, itraconazole can inhibit the metabolism of calcium channel blockers. Therefore, caution should be exercised when co-administering itraconazole and calcium channel blockers (see section 4.5) due to an increased risk of congestive heart failure.

Hepatic effects

Very rare cases of serious hepatotoxicity, including some cases of fatal acute liver failure, have occurred with the use of Sporanox-Pulse capsules. Most of these cases involved patients who, had pre-existing liver disease, were treated for systemic indications, had significant other medical conditions and/or were taking other hepatotoxic drugs. Some patients had no obvious risk factors for liver disease. Some of these cases were observed within the first month of treatment, including some within the first week. Liver function monitoring should be considered in patients receiving Sporanox-Pulse capsules treatment. Patients should be instructed to promptly report to their physician signs and symptoms suggestive of hepatitis such as anorexia, nausea, vomiting, fatigue, abdominal pain or dark urine. In these patients treatment should be stopped immediately and liver function testing should be conducted. In patients with raised liver enzymes or active liver disease, or who have experienced liver toxicity with other drugs, treatment should not be started unless the expected benefit exceeds the risk of hepatic injury. In such cases liver enzyme monitoring is necessary.

Reduced gastric acidity

Absorption of itraconazole from Sporanox-Pulse is impaired when the gastric acidity is reduced. In patients also receiving acid neutralising medicines (eg aluminium hydroxide), these should be administered at least 2 hours after the intake of Sporanox-Pulse. In patients with achlorhydria such as certain AIDS patients and patients on secretion suppressors (eg H2-antagonists, proton-pump inhibitors), it is advisable to administer Sporanox-Pulse with a cola beverage.

Use in children

Clinical data on the use of Sporanox-Pulse capsules in paediatric patients is limited. Sporanox-Pulse capsules should not be used in paediatric patients unless the potential benefit outweighs the potential risks.

Use in elderly

Clinical data on the use of Sporanox-Pulse capsules in elderly patients is limited. Sporanox-Pulse capsules should not be used in these patients unless the potential benefit outweighs the potential risks.

Hepatic impairment

Limited data are available on the use of oral itraconazole in patients with hepatic impairment. Caution should be exercised when the drug is administered in this patient population. (See Section 5.2)

Renal impairment

Limited data are available on the use of oral itraconazole in patients with renal impairment. Caution should be exercised when this drug is administered in this patient population. The oral bioavailability of itraconazole may be lower in patients with renal insufficiency. Dose adaptation may be considered.

Hearing Loss

Transient or permanent hearing loss has been reported in patients receiving treatment with itraconazole. Several of these reports included concurrent administration of quinidine which is contraindicated (see 4.3 and 4.5). The hearing loss usually resolves when treatment is stopped, but can persist in some patients.

Immunocompromised patients

In some immunocompromised patients (e.g., neutropenic, AIDS or organ transplant patients), the oral bioavailability of Sporanox-Pulse capsules may be decreased.

Patients with immediately life-threatening systemic fungal infections

Due to the pharmacokinetic properties (See section 5.2), Sporanox-Pulse capsules are not recommended for initiation of treatment in patients with immediately life-threatening systemic fungal infections.

Patients with AIDS

In patients with AIDS having received treatment for a systemic fungal infection such as sporotrichosis, blastomycosis, histoplasmosis or cryptococcosis (meningeal or non-meningeal) and who are considered at risk for relapse, the treating physician should evaluate the need for a maintenance treatment.

Neuropathy

If neuropathy occurs which may be attributable to Sporanox-Pulse, treatment should be discontinued.

Disorders of Carbohydrate Metabolism

Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine.

Cross-resistance

In systemic candidosis, if fluconazole-resistant strains of Candida species are suspected, it cannot be assumed that these are sensitive to itraconazole, hence their sensitivity should be tested before the start of Sporanox-Pulse therapy.

Interaction potential

Sporanox-Pulse has a potential for clinically important drug interactions. (See section 4.5). Itraconazole should not be used within 2 weeks after discontinuation of treatment with CYP 3A4 inducing agents (rifampicin, rifabutin, phenobarbital, phenytoin, carbamazepine, Hypericum perforatum (St. John´s wort). The use of itraconazole with these drugs may lead to subtherapeutic plasma levels of itraconazole and thus treatment failure.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

1. Drugs affecting the absorption of itraconazole

Drugs that reduce the gastric acidity impair the absorption of itraconazole from Sporanox-Pulse capsules (See section 4.4).

2. Drugs affecting the metabolism of itraconazole:

Itraconazole is mainly metabolised through the cytochrome CYP3A4. Interaction studies have been performed with rifampicin, rifabutin and phenytoin, which are potent inducers of CYP3A4. Since the bioavailability of itraconazole and hydroxy-itraconazole was decreased in these studies to such an extent that efficacy may be largely reduced, the combination of itraconazole with these potent enzyme inducers is not recommended. No formal study data are available for other enzyme inducers, such as carbamazepine, Hypericum perforatum (St John's Wort), phenobarbital and isoniazid, but similar effects should be anticipated.

Potent inhibitors of this enzyme such as ritonavir, indinavir, clarithromycin and erythromycin may increase the bioavailability of itraconazole.

3. Effects of itraconazole on the metabolism of other drugs:

3.1 Itraconazole can inhibit the metabolism of drugs metabolised by the cytochrome 3A family. This can result in an increase and/or a prolongation of their effects, including side effects. When using concomitant medication, the corresponding label should be consulted for information on the route of administration. After stopping treatment, itraconazole plasma concentrations decline gradually, depending on the dose and duration of treatment (see section 5.2). This should be taken into account when the inhibitory effect of itraconazole on co-administered drugs is considered.

Examples are:

The following drugs are contraindicated with itraconazole:

- Astemizole, bepridil, cisapride, dofetilide, levacetylmethadol (levomethadyl), mizolastine, pimozide, quinidine, sertindole or terfenadine are contraindicated with Sporanox-Pulse since co-administration may result in increased plasma concentrations of these substrates, which can lead to QT prolongation and rare occurrences of Torsades de pointes.

- CYP3A4 metabolised HMG-CoA reductase inhibitors such as atorvastatin, lovastatin and simvastatin.

- Triazolam and oral midazolam.

- Ergot alkaloids such as dihydroergotamine, ergometrine (ergonovine), ergotamine and methylergometrine (methylergonovine).

- Nisoldipine

- Eletriptan

Caution should be exercised when co-administering itraconazole with calcium channel blockers due to an increased risk of congestive heart failure. In addition to possible pharmacokinetic interactions involving the drug metabolising enzyme CYP3A4, calcium channel blockers can have negative inotropic effects which may be additive to those of itraconazole.

The following drugs should be used with caution, and their plasma concentrations, effects or side effects should be monitored. Their dosage, if co-administered with itraconazole, should be reduced if necessary:

• Oral anticoagulants

• HIV protease inhibitors such as ritonavir, indinavir, saquinavir

• Certain antineoplastic agents such as vinca alkaloids, busulfan, docetaxel and trimetrexate

• CYP3A4 metabolised calcium channel blockers such as dihydropyridines and verapamil

• Certain immunosuppressive agents: ciclosporin, tacrolimus, rapamycin (also known as sirolimus)

• Certain glucocorticoids such as budesonide, dexamethasone, fluticasone and methylprednisolone

• Digoxin(via inhibition of P-glycoprotein)

• Others: carbamazepine, cilostazol, buspirone, disopyramide, alfentanil, alprazolam, brotizolam, midazolam IV, rifabutin, ebastine, fentanyl, halofantrine, repaglinide and reboxetine. The importance of the concentration increase and the clinical relevance of these changes during co-administration remain to be established.

3.2. No interaction of itraconazole with zidovudine (AZT) and fluvastatin has been observed.

No inducing effects of itraconazole on the metabolism of ethinyloestradiol and norethisterone were observed.

4. Effect on protein binding:

In vitro studies have shown that there are no interactions on the plasma protein binding between itraconazole and imipramine, propranolol, diazepam, cimetidine, indometacin, tolbutamide or sulfamethazine.

4.6 Pregnancy And Lactation

Pregnancy

Sporanox-Pulse is contra-indicated in pregnancy.

In animal studies itraconazole has shown reproduction toxicity (see section 5.3).

There is limited information on the use of Itraconazole during pregnancy. During post-marketing experience, cases of congenital abnormalities have been reported. These cases included skeletal, genitourinary tract, cardiovascular and ophthalmic malformations as well as chromosomal and multiple malformations. A causal relationship with Itraconazole has not been established.

Epidemiological data on exposure to Sporanox-Pulse during the first trimester of pregnancy-mostly in patients receiving short-term treatment for vulvovaginal candidosis did not show an increased risk for malformations as compared to control subjects not exposed to any known teratogens.

Women of child bearing potential

Women of childbearing potential taking Sporanox-Pulse capsules should use contraceptive precautions. Effective contraception should be continued until the next menstrual period following the end of Sporanox-Pulse therapy.

Lactation

A very small amount of itraconazole is excreted in human milk. Sporanox-Pulse capsules must not be used during lactation.

4.7 Effects On Ability To Drive And Use Machines

No studies on the effects on the ability to drive and use machines have been performed. When driving vehicles and operating machinery the possibility of adverse reactions such as dizziness, visual disturbances and hearing loss (see Section 4.8), which may occur in some instances, must be taken into account.

4.8 Undesirable Effects

Undesirable effects listed below have been reported in clinical trials with Sporanox-Pulse and/or from spontaneous reports from post-marketing experience for all Sporanox formulations.

In open-label and double-blind clinical trials involving 8499 itraconazole-treated patients in the treatment of dermatomycoses or onychomycosis, the most frequently reported adverse experiences in clinical trials were of gastrointestinal, dermatological , and hepatic origin.

The table below presents adverse drug reactions by System Organ Class. Within each System Organ Class, the adverse drug reactions are presented by incidence, using the following convention:

Very common (

Adverse Drug Reactions
Blood and lymphatic system disorders
Rare	Leukopenia,
Not Known	Neutropenia, Thrombocytopenia
Immune system disorders
Uncommon	Hypersensitivity*
Not Known	Anaphylactic Reaction, Anaphylactoid Reaction, Angioneurotic Oedema, Serum Sickness
Metabolism and nutrition disorders
Not Known	Hypokalemia, Hypertriglyceridemia
Nervous system disorders
Uncommon	Headache, Dizziness, Paraesthesia
Rare	Hypoaesthesia
Not Known	Peripheral Neuropathy*
Eye disorders
Rare	Visual Disturbance
Not Known	Vision Blurred and Diplopia
Ear and labyrinth disorder
Rare	Tinnitus
Not Known	Transient or permanent Hearing Loss*
Cardiac disorders
Not Known	Congestive Heart Failure*
Respiratory, thoracic and mediastinal disorders
Rare	Dyspnoea
Not Known	Pulmonary Oedema
Gastrointestinal disorders
Common	Abdominal Pain, Nausea
Uncommon	Vomiting, Diarrhoea, Constipation, Dyspepsia, Dysgeusia; Flatulence
Not Known	Pancreatitis
Hepatobiliary disorders
Uncommon	Hyperbilirubinaemia, Alanine Aminotransferase Increased, Aspartate Aminotransferase Increased
Rare	Hepatic Enzyme Increased
Not Known	Acute Hepatic Failure*, Hepatitis, Hepatotoxicity*
Skin and subcutaneous tissue disorders
Common	Rash
Uncommon	Urticaria, Alopecia, Pruritus
Not Known	Toxic Epidermal Necrolysis, Stevens-Johnson Syndrome, Acute generalised exanthematous pustulosis, Erythema Multiforme, Exfoliative Dermatitis, Leukocytoclastic Vasculitis, Photosensitivity
Musculoskeletal and connective tissue disorders
Not Known	Myalgia, Arthralgia
Renal and urinary disorders
Rare	Pollakiuria,
Unknown	Urinary Incontinence
Reproductive system and breast disorders
Uncommon	Menstrual disorder
Unknown	Erectile Dysfunction
General disorders and administration site conditions
Uncommon	Oedema
Rare	Pyrexia

*see section 4.4

4.9 Overdose

No data are available.

In the event of overdosage, supportive measures should be employed. Within the first hour after ingestion, gastric lavage may be performed. Activated charcoal may be given if considered appropriate. Itraconazole cannot be removed by haemodialysis. No specific antidote is available.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic classification: (Antimycotics for systemic use, triazole derivatives).

ATC code: J02A C02

Itraconazole, a triazole derivative, has a broad spectrum of activity.

In vitro studies have demonstrated that itraconazole impairs the synthesis of ergosterol in fungal cells. Ergosterol is a vital cell membrane component in fungi. Impairment of its synthesis ultimately results in an antifungal effect.

For itraconazole, breakpoints have only been established for Candida spp. From superficial mycotic infections (CLSI M27-A2, breakpoints have not been established for EUCAST methodology). The CLSI breakpoints are as follows: susceptible

In vitro studies demonstrate that itraconazole inhibits the growth of a broad range of fungi pathogenic for humans at concentrations usually

dermatophytes (Trichophyton spp., Epidermophyton floccosum); yeasts (Candida spp., including C. albicans and C. glabrata) , Malassezia (formerly Pityrosporum) spp., Trichosporon spp., Geotrichum spp.); Aspergillus spp.; Blastomyces dermatitidis; and various other yeasts and fungi.

Candida glabrata and Candida tropicalis are generally the least susceptible Candida species, with some isolates showing unequivocal resistance to itraconazole in vitro.

The principal fungus types that are not inhibited by itraconazole are Zygomycetes (e.g. Rhizopus spp., Rhizomucor spp., Mucor spp. and Absidia spp.), Fusarium spp., Scedosporium proliferans and Scopulariopsis spp.

Azole resistance appears to develop slowly and is often the result of several genetic mutations. Mechanisms that have been described are overexpression of ERG11, which encodes the target enzyme 14α-demethylase, point mutations in ERG11 that lead to decreased target affinity and/or transporter overexpression resulting in increased efflux. Cross resistance between members of the azole class has been observed within Candida spp., although resistance to one member of the class does not necessarily confer resistance to other azoles. Itraconazole-resistant strains of Aspergillus fumigatus have been reported.

5.2 Pharmacokinetic Properties

General pharmacokinetic characteristics

The pharmacokinetics of itraconazole has been investigated in healthy subjects, special populations and patients after single and multiple dosing.

Absorption

Itraconazole is rapidly absorbed after oral administration. Peak plasma concentrations of the unchanged drug are reached within 2 to 5 hours following an oral dose. The observed absolute bioavailability of itraconazole is about 55%. Oral bioavailability is maximal when the capsules are taken immediately after a full meal.

Distribution

Most of the itraconazole in plasma is bound to protein (99.8%) with albumin being the main binding component (99.6% for the hydroxy- metabolite). It has also a marked affinity for lipids. Only 0.2% of the itraconazole in plasma is present as free drug. Itraconazole is distributed in a large apparent volume in the body (> 700 L), suggesting its extensive distribution into tissues: Concentrations in lung, kidney, liver, bone, stomach, spleen and muscle were found to be two to three times higher than corresponding concentrations in plasma. Brain to plasma ratios were about 1 as measured in beagle dogs. The uptake into keratinous tissues, skin in particular, is up to four times higher than in plasma.

Biotransformation

Itraconazole is extensively metabolised by the liver into a large number of metabolites. One of the main metabolites is hydroxy-itraconazole, which has in vitro antifungal activity comparable to itraconazole. Plasma concentrations of the hydroxy-itraconazole are about twice those of itraconazole.

As shown in in vitro studies, CYP 3A4 is the major enzyme that is involved in the metabolism of itraconazole.

Elimination

Itraconazole is excreted as inactive metabolites to about 35% in urine within one week and to about 54% with feces. Renal excretion of the parent drug accounts for less than 0.03% of the dose, whereas fecal excretion of unchanged drug varies between 3 – 18% of the dose. Itraconazole clearance decreases at higher doses due to saturable hepatic metabolism.

Linearity/non-linearity

As a consequence of non-linear pharmacokinetics, itraconazole accumulates in plasma during multiple dosing. Steady-state concentrations are generally reached within about 15 days, with Cmax and AUC values 4 to 7-fold higher than those seen after a single dose. The mean elimination half-life of itraconazole is about 40 hours after repeated dosing.

Special Populations

Hepatic Insufficiency: A pharmacokinetic study using a single 100 mg dose of itraconazole (one 100 mg capsule) was conducted in 6 healthy and 12 cirrhotic subjects. No statistically significant differences in AUC were seen between these two groups. A statistically significant reduction in average C_max (47%) and a two fold increase in the elimination half-life (37 ± 17 versus 16 ±5 hours) of itraconazole were noted in cirrhotic subjects compared with healthy subjects.

Data are not available in cirrhotic patients during long-term use of itraconazole.

Renal Insufficiency: Limited data are available on the use of oral itraconazole in patients with renal impairment. Caution should be exercised when the drug is administered in this patient population.

5.3 Preclinical Safety Data

Nonclinical data on itraconazole revealed no indications for gene toxicity, primary carcinogenicity or impairment of fertility. At high doses, effects were observed in the adrenal cortex, liver and the mononuclear phagocyte system but appear to have a low relevance for the proposed clinical use. Itraconazole was found to cause a dose-related increase in maternal toxicity, embryotoxicity and teratogenicity in rats and mice at high doses. A global lower bone mineral density was observed in juvenile dogs after chronic itraconazole administration, and in rats, a decreased bone plate activity, thinning of the zona compacta of the large bones, and an increased bone fragility was observed.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Sugar spheres Ph.Eur

Hypromellose 2910 5mPa.s PhEur.

Macrogol 20000 NF

Capsule shell:

Titanium dioxide E171

Indigotin carmine E132

Gelatin PhEur.

Erythrosine E127

6.2 Incompatibilities

None known.

6.3 Shelf Life

36 months.

6.4 Special Precautions For Storage

Do not store above 30°C.

Store in the original container.

6.5 Nature And Contents Of Container

Tristar blister - plastic foil consisting of 3 layers

• polyvinylchloride on the outside

• low density polyethylene in the middle

• polyvinylidene chloride on the inside

Aluminium foil (thickness 20 µm) coated on the inner side with colourless heatseal lacquer: PVC mixed polymers with acrylates 6 g/m²

or:

PVC blister consisting of:-

Polyvinylchloride "genotherm" glass clear, thickness 250 µm

Aluminium foil (thickness 20 µm) coated on the inner side with a colourless heatseal lacquer: PVC mixed polymers with acrylates 6 g/m²

Pack size: 28 capsules.

6.6 Special Precautions For Disposal And Other Handling

Not applicable.

Administrative Data

7. Marketing Authorisation Holder

Janssen-Cilag Ltd

50-100 Holmers Farm Way

High Wycombe

Buckinghamshire

HP12 4EG

UK

8. Marketing Authorisation Number(S)

00242/0334

9. Date Of First Authorisation/Renewal Of The Authorisation

26 March 1997

10. Date Of Revision Of The Text

18 October 2011

LEGAL CATEGORY

POM.

Sotacor Injection 10mg / ml

1. Name Of The Medicinal Product

SOTACOR INJECTION 10MG/ML

2. Qualitative And Quantitative Composition

Ampoules containing sotalol hydrochloride 40mg in each 4 ml of solution.

3. Pharmaceutical Form

Intravenous injection

4. Clinical Particulars

4.1 Therapeutic Indications

Termination of acute and life-threatening arrhythmias, including life-threatening ventricular tachyarrhythmias, symptomatic non-sustained ventricular arrhythmias;

Testing of drug efficacy during programmed electrical stimulation in patients with inducible ventricular and supraventricular tachyarrhythmias;

Transitory substitution for oral SOTACOR in patients temporarily unable to take oral medications.

4.2 Posology And Method Of Administration

The initiation of treatment or changes in dosage with SOTACOR 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 SOTACOR be initiated and doses increased in a facility capable of monitoring and assessing cardiac rhythm. The dosage must be individualized 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 SOTACOR 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:

For the management of acute arrhythmias, dosage range is from 20-120 mg intravenously (0.5 mg to 1.5 mg/kg). The total calculated dose has been safely administered over a 10-minute period and can be repeated at 6-hour intervals if necessary. For high risk patients with acute myocardial infarction and/or congestive heart failure, careful monitoring for haemodynamic or electrocardiographic changes is recommended.

For programmed electrical stimulation, an initial bolus of 1.5 mg/kg should be given over 10 to 20 minutes, followed by maintenance infusion at a rate of between 0.2 and 0.5 mg/kg/hour.

For substitution in place of oral therapy, infusion of between 0.2 and 0.5 mg/kg/hour should be used with the total daily dose not exceeding 640 mg.

Children

SOTACOR is not intended for administration to children.

Dosage in renally impaired patients

Because SOTACOR 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 SOTACOR Dose
30-6 0	½ recommended SOTACOR Dose
10-30	¼ recommended SOTACOR Dose
< 10	Avoid

The creatinine clearance can be estimated from serum creatinine by the Cockroft and Gault formula:

Men:
Women:	idem x 0.85

When serum creatinine is given in µmol/l, divide the value by 88.4 (1mg/dl = 88.4 µmol/l).

Dosage in hepatically impaired patients

No dosage adjustment is required in hepatically impaired patients.

4.3 Contraindications

SOTACOR 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).

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 SOTACOR, 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 I and 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, reduction of the 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.

The incidence of torsades de pointes is dose dependent. Torsades de pointes usually occurs within 7 days of 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.

Other risk factors for torsades de pointes were excessive prolongation of the QT_C and history of cardiomegaly or congestive heart failure. 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 SOTACOR caution should be used if the QT_C exceeds 500 msec whilst on therapy, and serious consideration should be given to reducing the dose or discontinuing therapy when the QT_C-interval exceeds 550 msec. Due to the multiple risk factors associated with torsades de pointes, however, caution should be exercised regardless of the QT_C-interval.

Electrolyte Disturbances SOTACOR 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. SOTACOR 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, SOTACOR 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 SOTACOR 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).

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

Antiarrhythmics 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 SOTACOR, because of their potential to prolong refractoriness (see 4.4 Special Warnings and Precautions). The concomitant use of other beta-blocking agents with SOTACOR may result in additive Class II effects.

Other drugs prolonging the QT-interval SOTACOR 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.

Potassium-Depleting Diuretics Hypokalaemia or hypomagnesaemia may occur, increasing the potential for torsades 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 SOTACOR.

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 SOTACOR 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 SOTACOR. 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 utilizing 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, SOTACOR 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 SOTACOR 2-3 days before the birthdate.

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, occuring in 1% or more of patients treated with SOTACOR.

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, paresthesia, 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 SOTACOR 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 SOTACOR 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 SOTACOR 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 SOTACOR 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

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

SOTACOR 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 QT_C (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, SOTACOR 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 SOTACOR 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

Glacial acetic acid, sodium chloride, sodium hydroxide, water.

6.2 Incompatibilities

There are no known incompatibilities.

6.3 Shelf Life

Three years.

6.4 Special Precautions For Storage

Store between 15 and 30^oC in a dry place, protected from light.

6.5 Nature And Contents Of Container

SOTACOR injection is supplied as 40 mg sotalol hydrochloride in 4 ml ampoules, with 5 ampoules per box.

6.6 Special Precautions For Disposal And Other Handling

SOTACOR injection fluid can be administered as an intravenous infusion with 5% glucose intravenous infusion or 0.9% sodium chloride intravenous infusion. The final concentration should be between 0.01-2 mg/ml.

In concentrations of 0.01-2 mg/ml, dilution of SOTACOR injection fluid with 5% glucose intravenous infusion or 0.9% sodium chloride intravenous infusion, is chemically and physically stable during at least 4 days at room temperature (15-25 ^oC) and 3 weeks under refrigeration (2-8 ^oC) .

As the formulation does not contain a preservative, the solutions of SOTACOR should be prepared in an aseptic manner. Prompt use of the solution is recommended.

7. Marketing Authorisation Holder

Bristol-Myers Squibb Holdings Limited

t/a Bristol-Myers Pharmaceuticals

Uxbridge Business Park

Sanderson Road

Uxbridge

Middlesex UB8 1DH

8. Marketing Authorisation Number(S)

0125/0123

9. Date Of First Authorisation/Renewal Of The Authorisation

25 January 1990

10. Date Of Revision Of The Text

February 2006