Topiramate 25, 50, 100 and 200 mg film-coated Tablets

1. Name Of The Medicinal Product

Topiramate 25, 50, 100 and 200 mg film-coated Tablets

2. Qualitative And Quantitative Composition

Topiramate 25 mg film-coated Tablets

Each film-coated tablets contains 25 mg of topiramate.

Excipient: 17.8 mg lactose /film-coated tablet.

Topiramate 50 mg film-coated Tablets

Each film-coated tablet contains 50 mg of topiramate.

Excipient: 35.6 mg lactose /film-coated tablet.

Topiramate 100 mg film-coated Tablets

Each film-coated tablet contains 100 mg of topiramate.

Excipient: 71.1 mg lactose /film-coated tablet.

Topiramate 200 mg film-coated Tablets

Each film-coated tablet contains 200 mg of topiramate.

Excipient: 142.2 mg lactose /film-coated tablet.

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Film-coated tablet

Topiramate 25 mg film-coated tablet: White, round shaped, film-coated tablet, plain on both sides.

Topiramate 50 mg film-coated tablet: Yellow, round shaped, film-coated tablet, plain on both sides.

Topiramate 100 mg film-coated tablet: White, round shaped, film-coated tablet, plain on both sides.

Topiramate 200 mg film-coated tablet: Yellow, round shaped, film-coated tablet, plain on both sides.

4. Clinical Particulars

4.1 Therapeutic Indications

Monotherapy in adults, adolescents and children over 6 years of age with partial seizures with or without secondary generalised seizures, and primary generalised tonic-clonic seizures.

Adjunctive therapy in children aged 2 years and above, adolescents and adults with partial onset seizures with or without secondary generalization or primary generalized tonic-clonic seizures and for the treatment of seizures associated with Lennox-Gastaut syndrome

Topiramate is indicated in adults for the prophylaxis of migraine headache after careful evaluation of possible alternative treatment options. Topiramate is not intended for acute treatment.

4.2 Posology And Method Of Administration

General

It is recommended that therapy be initiated at a low dose followed by titration to an effective dose. Dose and titration rate should be guided by clinical response.

Topiramate is available in film-coated tablets and a hard capsule formulation. It is recommended that film-coated tablets not be broken.The hard capsule formulation is provided for those patients who cannot swallow tablets, e.g. paediatric and the elderly.

It is not necessary to monitor topiramate plasma concentrations to optimize therapy with Topiramate. On rare occasions, the addition of topiramate to phenytoin may require an adjustment of the dose of phenytoin to achieve optimal clinical outcome. Addition or withdrawal of phenytoin and carbamazepine to adjunctive therapy with topiramate may require adjustment of the dose of Topiramate.

Topiramate can be taken without regard to meals.

In patients with or without a history of seizures or epilepsy, antiepileptic drugs including topiramate should be gradually withdrawn to minimize the potential for seizures or increased seizure frequency. In clinical trials, daily dosages were decreased in weekly intervals by 50-100 mg in adults with epilepsy and by 25-50 mg in adults receiving topiramate at doses up to 100 mg/day for migraine prophylaxis. In paediatric clinical trials, topiramate was gradually withdrawn over a 2-8 week period.

Monotherapy epilepsy

General

When concomitant antiepileptic drugs (AEDs) are withdrawn to achieve monotherapy with topiramate, consideration should be given to the effects this may have on seizure control. Unless safety concerns require an abrupt withdrawal of the concomitant AED, a gradual discontinuation at the rate of approximately one-third of the concomitant AED dose every 2 weeks is recommended.

When enzyme inducing medicinal products are withdrawn, topiramate levels will increase. A decrease in Topiramate dosage may be required if clinically indicated.

Adults

Dose and titration should be guided by clinical response. Titration should begin at 25 mg nightly for 1 week. The dosage should then be increased at 1- or 2-week intervals by increments of 25 or 50 mg/day, administered in two divided doses. If the patient is unable to tolerate the titration regimen, smaller increments or longer intervals between increments can be used.

The recommended initial target dose for topiramate monotherapy in adults is 100 mg/day to 200 mg/day in 2 divided doses. The maximum recommended daily dose is 500 mg/day in 2 divided doses. Some patients with refractory forms of epilepsy have tolerated topiramate monotherapy at doses of 1,000 mg/day. These dosing recommendations apply to all adults including the elderly in the absence of underlying renal disease.

Paediatric population (children over 6 years of age)

Dose and titration rate in children should be guided by clinical outcome. Treatment of children over 6 years of age should begin at 0.5 to 1 mg/kg nightly for the first week. The dosage should then be increased at 1 or 2 week intervals by increments of 0.5 to 1 mg/kg/day, administered in two divided doses. If the child is unable to tolerate the titration regimen, smaller increments or longer intervals between dose increments can be used.

The recommended initial target dose range for topiramate monotherapy in children over 6 years of age is 100 mg/day depending on clinical response, (this is about 2.0mg/kg/day in children 6-16 years).

Adjunctive therapy epilepsy (partial onset seizures with or without secondary generalization, primary generalized tonic-clonic seizures, or seizures associated with Lennox-Gastaut syndrome)

Adults

Therapy should begin at 25-50 mg nightly for one week. Use of lower initial doses has been reported, but has not been studied systematically. Subsequently, at weekly or bi-weekly intervals, the dose should be increased by 25-50 mg/day and taken in two divided doses. Some patients may achieve efficacy with once-a-day dosing.

In clinical trials as adjunctive therapy, 200 mg was the lowest effective dose. The usual daily dose is 200-400 mg in two divided doses.

These dosing recommendations apply to all adults, including the elderly, in the absence of underlying renal disease (see section 4.4).

Paediatric population (children aged 2 years and above)

The recommended total daily dose of Topiramate (topiramate) as adjunctive therapy is approximately 5 to 9 mg/kg/day in two divided doses. Titration should begin at 25 mg (or less, based on a range of 1 to 3 mg/kg/day) nightly for the first week. The dosage should then be increased at 1- or 2-week intervals by increments of 1 to 3 mg/kg/day (administered in two divided doses), to achieve optimal clinical response.

Daily doses up to 30 mg/kg/day have been studied and were generally well tolerated.

Migraine

Adults

The recommended total daily dose of topiramate for prophylaxis of migraine headache is 100 mg/day administered in two divided doses. Titration should begin at 25 mg nightly for 1 week. The dosage should then be increased in increments of 25 mg/day administered at 1-week intervals. If the patient is unable to tolerate the titration regimen, longer intervals between dose adjustments can be used.

Some patients may experience a benefit at a total daily dose of 50 mg/day. . Patients have received a total daily dose up to 200 mg/day. This dose may be benefit in some patients, nevertheless, caution is advised due to an increase incidence of side effects.

Paediatric population

Topiramate (topiramate) is not recommended for treatment or prevention of migraine in children due to insufficient data on safety and efficacy.

General dosing recommendations for Topiramate in special patient populations

Renal impairment

In patients with impaired renal function (CLCR

In patients with end-stage renal failure, since topiramate is removed from plasma by haemodialysis, a supplemental dose of Topiramate equal to approximately one-half the daily dose should be administered on haemodialysis days. The supplemental dose should be administered in divided doses at the beginning and completion of the haemodialysis procedure. The supplemental dose may differ based on the characteristics of the dialysis equipment being used.

Hepatic impairment

In patients with moderate to severe hepatic impairment topiramate should be administered with caution as the clearance of topiramate is decreased.

Elderly

No dose adjustment is required in the elderly population providing renal function is intact.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients.

Migraine prophylaxis in pregnancy and in women of childbearing potential if not using effective methods of contraception.

4.4 Special Warnings And Precautions For Use

In situations where rapid withdrawal of topiramate is medically required, appropriate monitoring is recommended (see section 4.2 for further details).

As with other anti-epileptic drugs, some patients may experience an increase in seizure frequency or the onset of new types of seizures with topiramate. These phenomena may be the consequence of an overdose, a decrease in plasma concentrations of concomitantly used anti-epileptics, progress of the disease, or a paradoxical effect.

Adequate hydration while using topiramate is very important. Hydration can reduce the risk of nephrolithiasis (see below). Proper hydration prior to and during activities such as exercise or exposure to warm temperatures may reduce the risk of heat-related adverse reactions (see section 4.8).

Mood disturbances/depression

An increased incidence of mood disturbances and depression has been observed during topiramate treatment.

Suicide/suicide ideation

Suicidal ideation and behaviour have been reported in patients treated with anti-epileptic agents in several indications. A meta-analysis of randomised placebo-controlled trials of anti-epileptic drugs has shown a small increased risk of suicidal ideation and behaviour. The mechanism of this risk is not known and the available data do not exclude the possibility of an increased risk for topiramate.

In double blind clinical trials, suicide related events (SREs) (suicidal ideation, suicide attempts and suicide) occurred at a frequency of 0.5% in topiramate treated patients (46 out of 8,652 patients treated) and at a nearly 3 fold higher incidence than those treated with placebo (0.2%; 8 out of 4,045 patients treated).

Patients therefore should be monitored for signs of suicidal ideation and behaviour and appropriate treatment should be considered. Patients (and caregivers of patients) should be advised to seek medical advice should signs of suicidal ideation or behaviour emerge.

Nephrolithiasis

Some patients, especially those with a predisposition to nephrolithiasis, may be at increased risk for renal stone formation and associated signs and symptoms such as renal colic, renal pain or flank pain.

Risk factors for nephrolithiasis include prior stone formation, a family history of nephrolithiasis and hypercalciuria. None of these risk factors can reliably predict stone formation during topiramate treatment. In addition, patients taking other medicinal products associated with nephrolithiasis may be at increased risk.

Decreased hepatic function

In hepatically-impaired patients, topiramate should be administered with caution as the clearance of topiramate may be decreased.

Acute myopia and secondary angle closure glaucoma

A syndrome consisting of acute myopia associated with secondary angle closure glaucoma has been reported in patients receiving topiramate. Symptoms include acute onset of decreased visual acuity and/or ocular pain. Ophthalmologic findings can include myopia, anterior chamber shallowing, ocular hyperaemia (redness) and increased intraocular pressure. Mydriasis may or may not be present. This syndrome may be associated with supraciliary effusion resulting in anterior displacement of the lens and iris, with secondary angle closure glaucoma. Symptoms typically occur within 1 month of initiating topiramate therapy. In contrast to primary narrow angle glaucoma, which is rare under 40 years of age, secondary angle closure glaucoma associated with topiramate has been reported in paediatric patients as well as adults. Treatment includes discontinuation of topiramate, as rapidly as possible in the judgment of the treating physician, and appropriate measures to reduce intraocular pressure. These measures generally result in a decrease in intraocular pressure.

Elevated intraocular pressure of any aetiology, if left untreated, can lead to serious sequelae including permanent vision loss.

A determination should be made whether patients with history of eye disorders should be treated with topiramate.

Metabolic acidosis

Hyperchloremic, non-anion gap, metabolic acidosis (i.e. decreased serum bicarbonate below the normal reference range in the absence of respiratory alkalosis) is associated with topiramate treatment. This decrease in serum bicarbonate is due to the inhibitory effect of topiramate on renal carbonic anhydrase. Generally, the decrease in bicarbonate occurs early in treatment although it can occur at any time during treatment. These decreases are usually mild to moderate (average decrease of 4 mmol/l at doses of 100 mg/day or above in adults and at approximately 6 mg/kg/day in paediatric patients). Rarely, patients have experienced decreases to values below 10 mmol/l. Conditions or therapies that predispose to acidosis (such as renal disease, severe respiratory disorders, status epilepticus, diarrhoea, surgery, ketogenic diet, or certain medicinal products) may be additive to the bicarbonate lowering effects of topiramate.

Chronic metabolic acidosis increases the risk of renal stone formation and may potentially lead to osteopenia.

Chronic metabolic acidosis in paediatric patients can reduce growth rates. The effect of topiramate on bone-related sequelae has not been systematically investigated in paediatric or adult populations.

Depending on underlying conditions, appropriate evaluation including serum bicarbonate levels is recommended with topiramate therapy. If metabolic acidosis develops and persists, consideration should be given to reducing the dose or discontinuing topiramate (using dose tapering).

Topiramate should be used with caution in patients with conditions or treatments that represent a risk factor for the appearance of metabolic acidosis.

Nutritional supplementation

Some patients may experience weight loss whilst on treatment with topiramate. It is recommended that patients on topiramate treatment should be monitored for weight loss. A dietary supplement or increased food intake may be considered if the patient is losing weight while on topiramate.

Topiramat Sandoz contains sucrose. Patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption should not take this medication.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Effects of topiramate on other antiepileptic medicinal products

The addition of topiramate to other antiepileptic drugs (phenytoin, carbamazepine, valproic acid, phenobarbital, primidone) has no effect on their steady-state plasma concentrations, except in the occasional patient, where the addition of topiramate to phenytoin may result in an increase of plasma concentrations of phenytoin. This is possibly due to inhibition of a specific enzyme polymorphic isoform (CYP2C19). Consequently, any patient on phenytoin showing clinical signs or symptoms of toxicity should have phenytoin levels monitored.

A pharmacokinetic interaction study of patients with epilepsy indicated the addition of topiramate to lamotrigine had no effect on steady state plasma concentration of lamotrigine at topiramate doses of 100 to 400 mg/day. In addition, there was no change in steady state plasma concentration of topiramate during or after removal of lamotrigine treatment (mean dose of 327 mg/day).

Topiramate inhibits the enzyme CYP 2C19 and may interfere with other substances metabolized via this enzyme (e.g., diazepam, imipramin, moclobemide, proguanil, omeprazol).

Effects of other antiepileptic medicinal products on topiramate

Phenytoin and carbamazepine decrease the plasma concentration of topimarate. The addition or withdrawal of phenytoin or carbamazepine to topiramate therapy may require an adjustment in dosage of the latter. This should be done by titrating to clinical effect. The addition or withdrawal of valproic acid does not produce clinically significant changes in plasma concentrations of topiramate and, therefore, does not warrant dosage adjustment of Topiramate. The results of these interactions are summarized below:

AED Coadministered	AED Concentration	Topiramate Concentration
Phenytoin	↔**
Carbamazepine (CBZ)	↔
Valproic acid	↔	↔
Lamotrigine	↔	↔
Phenobarbital	↔	NS
Primidone	↔	NS
↔ = No effect on plasma concentration ( ** = Plasma concentrations increase in individual patients NS = Not studied AED = antiepileptic drug

Other medicinal product interactions

Digoxin

In a single-dose study, serum digoxin area under plasma concentration curve (AUC) decreased 12% due to concomitant administration of Topiramate. The clinical relevance of this observation has not been established. When Topiramate is added or withdrawn in patients on digoxin therapy, careful attention should be given to the routine monitoring of serum digoxin.

CNS depressants

Concomitant administration of topiramate and alcohol or other CNS depressant medicinal products has not been evaluated in clinical studies. It is recommended that topiramate not be used concomitantly with alcohol or other CNS depressant medicinal products.

St John's Wort (Hypericum perforatum).

A risk of decreased plasma concentrations resulting in a loss of efficacy could be observed with co-administration of topiramate and St John's Wort. There have been no clinical studies evaluating this potential interaction.

Oral contraceptives

In a pharmacokinetic interaction study in healthy volunteers with a concomitantly administered combination oral contraceptive product containing 1 mg norethindrone (NET) plus 35 μg ethinyl estradiol (EE), Topiramate given in the absence of other medications at doses of 50 to 200 mg/day was not associated with statistically significant changes in mean exposure (AUC) to either component of the oral contraceptive. In another study, exposure to EE was statistically significantly decreased at doses of 200, 400, and 800 mg/day (18%, 21%, and 30%, respectively) when given as adjunctive therapy in epilepsy patients taking valproic acid. In both studies, topiramate (50-200 mg/day in healthy volunteers and 200-800 mg/day in epilepsy patients) did not significantly affect exposure to NET. Although there was a dose dependent decrease in EE exposure for doses between 200-800 mg/day (in epilepsy patients), there was no significant dose dependent change in EE exposure for doses of 50-200 mg/day (in healthy volunteers). The clinical significance of the changes observed is not known. The possibility of decreased contraceptive efficacy and increased breakthrough bleeding should be considered in patients taking combination oral contraceptive products with topiramate. Patients taking estrogen containing contraceptives should be asked to report any change in their bleeding patterns. Contraceptive efficacy can be decreased even in the absence of breakthrough bleeding.

Lithium

In healthy volunteers, there was an observed reduction (18% for AUC) in systemic exposure for lithium during concomitant administration with topiramate 200 mg/day. In patients with bipolar disorder, the pharmacokinetics of lithium were unaffected during treatment with topiramate at doses of 200 mg/day; however, there was an observed increase in systemic exposure (26% for AUC) following topiramate doses of up to 600 mg/day. Lithium levels should be monitored when co-administered with topiramate.

Risperidone

Drug-drug interaction studies conducted under single dose conditions in healthy volunteers and multiple dose conditions in patients with bipolar disorder, yielded similar results. When administered concomitantly with topiramate at escalating doses of 100, 250 and 400 mg/day there was a reduction in risperidone (administered at doses ranging from 1 to 6 mg/day) systemic exposure (16% and 33% for steady-state AUC at the 250 and 400 mg/day doses, respectively). However, differences in AUC for the total active moiety between treatment with risperidone alone and combination treatment with topiramate were not statistically significant. Minimal alterations in the pharmacokinetics of the total active moiety (risperidone plus 9-hydroxyrisperidone) and no alterations for 9-hydroxyrisperidone were observed. There were no significant changes in the systemic exposure of the risperidone total active moiety or of topiramate. When topiramate was added to existing risperidone (1-6 mg/day) treatment, adverse events were reported more frequently than prior to topiramate (250-400 mg/day) introduction (90% and 54 % respectively). The most frequently reported AE's when topiramate was added to risperidone treatment were: somnolence (27% and 12%), paraesthesia (22% and 0%) and nausea (18% and 9% respectively).

Hydrochlorothiazide (HCTZ)

A drug-drug interaction study conducted in healthy volunteers evaluated the steady-state pharmacokinetics of HCTZ (25 mg q24h) and topiramate (96 mg q12h) when administered alone and concomitantly. The results of this study indicate that topiramate Cmax increased by 27% and AUC increased by 29% when HCTZ was added to topiramate. The clinical significance of this change is unknown. The addition of HCTZ to topiramate therapy may require an adjustment of the topiramate dose. The steady-state pharmacokinetics of HCTZ were not significantly influenced by the concomitant administration of topiramate. Clinical laboratory results indicated decreases in serum potassium after topiramate or HCTZ administration, which were greater when HCTZ and topiramate were administered in combination.

Metformin

A drug-drug interaction study conducted in healthy volunteers evaluated the steady-state pharmacokinetics of metformin and topiramate in plasma when metformin was given alone and when metformin and topiramate were given simultaneously. The results of this study indicated that metformin mean Cmax and mean AUC0-12h increased by 18% and 25%, respectively, while mean CL/F decreased 20% when metformin was co-administered with topiramate. Topiramate did not affect metformin tmax. The clinical significance of the effect of topiramate on metformin pharmacokinetics is unclear. Oral plasma clearance of topiramate appears to be reduced when administered with metformin. The extent of change in the clearance is unknown. The clinical significance of the effect of metformin on topiramate pharmacokinetics is unclear.

When Topiramate is added or withdrawn in patients on metformin therapy, careful attention should be given to the routine monitoring for adequate control of their diabetic disease state.

Pioglitazone

A drug-drug interaction study conducted in healthy volunteers evaluated the steady-state pharmacokinetics of topiramate and pioglitazone when administered alone and concomitantly. A 15% decrease in the AUC_,ss of pioglitazone with no alteration in Cmax,ss was observed. This finding was not statistically significant. In addition, a 13% and 16% decrease in Cmax,ss and AUC_,ss respectively, of the active hydroxy-metabolite was noted as well as a 60% decrease in Cmax,ss and AUC_,ss of the active keto-metabolite. The clinical significance of these findings is not known. When Topiramate is added to pioglitazone therapy or pioglitazone is added to topiramate therapy, careful attention should be given to the routine monitoring of patients for adequate control of their diabetic disease state.

Glyburide

A drug-drug interaction study conducted in patients with type 2 diabetes evaluated the steady-state pharmacokinetics of glyburide (5 mg/day) alone and concomitantly with topiramate (150 mg/day). There was a 25% reduction in glyburide AUC24 during topiramate administration. Systemic exposure of the active metabolites, 4-trans-hydroxy-glyburide (M1) and 3-cis-hydroxyglyburide (M2), were also reduced by 13% and 15%, respectively. The steady-state pharmacokinetics of topiramate were unaffected by concomitant administration of glyburide.

When topiramate is added to glyburide therapy or glyburide is added to topiramate therapy, careful attention should be given to the routine monitoring of patients for adequate control of their diabetic disease state.

Other forms of interactions

Agents predisposing to nephrolithiasis

Topiramate, when used concomitantly with other agents predisposing to nephrolithiasis, may increase the risk of nephrolithiasis. While using topiramate, agents like these should be avoided since they may create a physiological environment that increases the risk of renal stone formation.

Valproic acid

Concomitant administration of topiramate and valproic acid has been associated with hyperammonemia with or without encephalopathy in patients who have tolerated either medicinal product alone. In most cases, symptoms and signs abated with discontinuation of either medicinal product. This adverse reaction is not due to a pharmacokinetic interaction. An association of hyperammonemia with topiramate monotherapy or concomitant treatment with other anti-epileptics has not been established.

Additional pharmacokinetic drug interaction studies

Clinical studies have been conducted to assess the potential pharmacokinetic drug interaction between topiramate and other agents. The changes in Cmax or AUC as a result of the interactions are summarized below. The second column (concomitant drug concentration) describes what happens to the concentration of the concomitant drug listed in the first column when topiramate is added. The third column (topiramate concentration) describes how the coadministration of a drug listed in the first column modifies the concentration of topiramate.

Summary of Results from Additional Clinical Pharmacokinetic Drug Interaction Studies
Concomitant Drug	Concomitant Drug Concentrationa	Topiramate Concentrationa
Amitriptyline	↔ 20% increase in Cmax and AUC of nortriptyline metabolite	NS
Dihydroergotamine (Oral and Subcutaneous)	↔	↔
Haloperidol	↔ 31% increase in AUC of the reduced metabolite	NS
Propranolol	↔ 17% increase in Cmax for 4-OH propranolol (TPM 50 mg q12h)	9% and 16% increase in Cmax, 9% and17% increase in AUC (40 and 80 mg propranolol q12h respectively)
Sumatriptan (Oral and Subcutaneous)	↔	NS
Pizotifen	↔	↔
Diltiazem	25% decrease in AUC of diltiazem and 18% decrease in DEA, and ↔ for DEM*	20% increase in AUC
Venlafaxine	↔	↔
Flunarizine	16% increase in AUC (TPM 50 mg q12h)b	↔
a % values are the changes in treatment mean Cmaxor AUC with respect to monotherapy ↔ = No effect on Cmax and AUC ( NS = Not studied *DEA = des acetyl diltiazem, DEM = N-demethyl diltiazem b Flunarizine AUC increased 14% in subjects taking flunarizine alone. Increase in exposure may be attributed to accumulation during achievement of steady state.

4.6 Pregnancy And Lactation

Topiramate was teratogenic in mice, rats and rabbits. In rats, topiramate crosses the placental barrier.

There are no adequate and well-controlled studies with topiramate in pregnant women.

Pregnancy registry data suggest that there may be an association between the use of topiramate during pregnancy and congenital malformations (e.g., craniofacial defects, such as cleft lip/palate, hypospadias, and anomalies involving various body systems). This has been reported with topiramate monotherapy and topiramate as part of a polytherapy regimen. This data should be interpreted with caution, as more data is needed to identify increased risks for malformations.

In addition, data from these registries and other studies suggest that, compared with monotherapy, there may be an increased risk of teratogenic effects associated with the use of anti-epileptic drugs in combination therapy.

It is recommended that women of child bearing potential use adequate contraception.

Animal studies have shown excretion of topiramate in milk. The excretion of topiramate in human milk has not been evaluated in controlled studies. Limited observations in patients suggest an extensive excretion of topiramate into breast milk. Since many medicinal products are excreted into human milk, a decision must be made whether to suspend breast-feeding or to discontinue/ abstain from topiramate therapy taking into account the importance of the medicinal product to the mother (section 4.4).

Indication Epilepsy

During pregnancy, topiramate should be prescribed after fully informing the woman of the known risks of uncontrolled epilepsy to the pregnancy and the potential risks of the medicinal product to the foetus.

Indication Migraine Prophylaxis

Topiramate is contraindicated in pregnancy, and in women of childbearing potential if an effective method of contraception is not used (see section 4.3 and 4.5 Interactions with oral contraceptives).

4.7 Effects On Ability To Drive And Use Machines

Topiramate acts on the central nervous system and may produce drowsiness, dizziness or other related symptoms. It may also cause visual disturbances and/or blurred vision. These adverse reactions could potentially be dangerous in patients driving a vehicle or operating machinery, particularly until such time as the individual patient's experience with the medicinal products established.

No studies on the effects on the ability to drive and use machines have been performed.

4.8 Undesirable Effects

The safety of topiramate was evaluated from a clinical trial database consisting of 4,111 patients (3,182 on topiramate and 929 on placebo) who participated in 20 double-blind trials and 2,847 patients who participated in 34 open-label trials, respectively, for topiramate as adjunctive treatment of primary generalized tonic-clonic seizures, partial onset seizures, seizures associated with Lennox-Gastaut syndrome, monotherapy for newly or recently diagnosed epilepsy or migraine prophylaxis. The majority of ADRs were mild to moderate in severity. ADRs identified in clinical trials, and during post-marketing experience (as indicated by “*”) are listed by their incidence in clinical trials in Table 1. Assigned frequencies are as follows:

Very common

Common

Uncommon

Rare

Not known cannot be estimated from the available data

The most common ADRs (those with an incidence of >5% and greater than that observed in placebo in at least 1 indication in double-blind controlled studies with topiramate) include: anorexia, decreased appetite, bradyphrenia, depression, expressive language disorder, insomnia, coordination abnormal, disturbance in attention, dizziness, dysarthria, dysgeusia, hypoesthesia, lethargy, memory impairment, nystagmus, paresthesia, somnolence, tremor, diplopia, vision blurred, diarrhoea, nausea, fatigue, irritability, and weight decreased.

Paediatric population

ADRs reported more frequently (

ADRs that were reported in children but not in adults in double-blind controlled studies include: eosinophilia, psychomotor hyperactivity, vertigo, vomiting, hyperthermia, pyrexia, and learning disability.

Table 1: Topiramate Adverse Drug Reactions

System Organ Class	Very common	Common	Uncommon	Rare	Not known
Investigations	Weight decreased	Weight increased*	Crystal urine present, tandem gait test abnormal, white blood cell count decreased	Blood bicarbonate decreased
Cardiac disorders			Bradycardia, sinus bradycardia, palpitations
Blood and lymphatic system disorders		Anaemia	Leucopenia, thrombocytopenia lymphadenopathy, eosinophilia	Neutropenia*
Nervous system disorders	Paraesthesia, somnolence Dizziness	Disturbance in attention, memory impairment, amnesia, cognitive disorder, mental impairment, psychomotor skills impaired, convulsion, coordination abnormal, tremor, lethargy, hypoaesthesia, nystagmus, dysgeusia, balance disorder, dysarthria, intention tremor, sedation ,	Depressed level of consciousness, grand mal convulsion, visual field defect, complex partial seizures, speech disorder, psychomotor hyperactivity, syncope, sensory disturbance, drooling, hypersomnia, aphasia, repetitive speech, hypokinesia, dyskinesia, dizziness postural, poor quality sleep, burning sensation, sensory loss, parosmia, cerebellar syndrome, dysaesthesia, hypogeusia, stupor, clumsiness, aura, ageusia, dysgraphia, dysphasia, neuropathy peripheral, presyncope, dystonia, formication	Apraxia, circadian rhythm sleep disorder, hyperaesthesia, hyposmia, anosmia, essential tremor, akinesia, unresponsive to stimuli
Eye disorders		Vision blurred, diplopia, visual disturbance	Visual acuity reduced, scotoma, myopia*, abnormal sensation in eye*, dry eye, photophobia, blepharospasm, lacrimation increased, photopsia, mydriasis, presbyopia	Blindness unilateral, blindness transient, glaucoma, accommodation disorder, altered visual depth perception, scintillating scotoma, eyelid oedema*, night blindness, amblyopia	Angle closure glaucoma*, Maculopathy*, eye movement disorder*
Ear and labyrinth disorders		Vertigo, tinnitus, ear pain	Deafness, deafness unilateral, deafness neurosensory, ear discomfort, hearing impaired
Respiratory, thoracic and mediastinal disorders		Dyspnoea, epistaxis, nasal congestion, rhinorrhoea	Dyspnoea exertional, Paranasal sinus hypersecretion, dysphonia
Gastrointestinal disorders	Nausea, diarrhoea	Vomiting, constipation, abdominal pain upper, dyspepsia, abdominal pain, dry mouth, stomach discomfort, paraesthesia oral, gastritis, abdominal discomfort	Pancreatitis, flatulence, gastrooesophageal reflux disease, abdominal pain lower, hypoaesthesia oral, gingival bleeding, abdominal distension, epigastric discomfort, abdominal tenderness, salivary hypersecretion, oral pain, breath odour, glossodynia
Renal and urinary disorders		Nephrolithiasis, pollakisuria, dysuria	Calculus urinary, urinary incontinence, haematuria, incontinence, micturition urgency, renal colic, renal pain	Calculus ureteric, renal tubular acidosis*
Skin and subcutaneous tissue disorders		Alopecia, rash, pruritus	Anhidrosis, hypoaesthesia facial, urticaria, erythema, pruritus generalised, rash macular, skin discolouration, dermatitis allergic, swelling face	Stevens-Johnson syndrome* erythema multiforme*, skin odour abnormal, periorbital oedema*, urticaria localised	Toxic epidermal necrolysis*
Musculoskeletal and connective tissue disorders		Arthralgia, muscle spasms, myalgia, muscle twitching, muscular weakness, musculoskeletal chest pain	Joint swelling*, musculoskeletal stiffness, flank pain, muscle fatigue	Limb discomfort*
Metabolism and nutrition disorders		Anorexia, decreased appetite	Metabolic acidosis, Hypokalaemia, increased appetite, polydipsia	Acidosis hyperchloraemic
Infections and infestations	Nasopharyngitis*
Vascular disorders

Timoptol 0.25% and 0.5% w / v Eye Drops Solution

1. Name Of The Medicinal Product

TIMOPTOL® 0.25% w/v Eye Drops Solution

TIMOPTOL® 0.5% w/v Eye Drops Solution

2. Qualitative And Quantitative Composition

'Timoptol' 0.25% w/v Eye Drops Solution contains timolol maleate equivalent to 0.25% w/v solution of timolol with preservative.

'Timoptol' 0.5% w/v Eye Drops Solution contains timolol maleate equivalent to 0.5% w/v solution of timolol with preservative.

3. Pharmaceutical Form

Eye drops solution.

Clear, colourless to light yellow, sterile eye drops solution.

4. Clinical Particulars

4.1 Therapeutic Indications

'Timoptol' Eye Drops Solution is a beta-adrenoreceptor blocking agent used topically in the reduction of elevated intra-ocular pressure in various conditions including the following: patients with ocular hypertension; patients with chronic open-angle glaucoma including aphakic patients; some patients with secondary glaucoma.

4.2 Posology And Method Of Administration

Recommended therapy is one drop 0.25% solution in the affected eye twice a day.

If clinical response is not adequate, dosage may be changed to one drop 0.5% solution in each affected eye twice a day. If needed, 'Timoptol' may be used with other agent(s) for lowering intra-ocular pressure. The use of two topical beta-adrenergic blocking agents is not recommended (see 4.4 'Special warnings and precautions for use').

Intra-ocular pressure should be reassessed approximately four weeks after starting treatment because response to 'Timoptol' may take a few weeks to stabilise.

Provided that the intra-ocular pressure is maintained at satisfactory levels, many patients can than be placed on once-a-day therapy.

Transfer from other agents

When another topical beta-blocking agent is being used, discontinue its use after a full day of therapy and start treatment with 'Timoptol' the next day with one drop of 0.25% 'Timoptol' in each affected eye twice a day. The dosage may be increased to one drop of 0.5% solution in each affected eye twice a day, if the response is not adequate.

When transferring a patient from a single anti-glaucoma agent other than a topical beta-blocking agent, continue the agent and add one drop of 0.25% 'Timoptol' in each affected eye twice a day. On the following day, discontinue the previous agent completely, and continue with 'Timoptol'. If a higher dosage of 'Timoptol' is required, substitute one drop of 0.5% solution in each affected eye twice a day.

'Timoptol' Eye Drops Solution is also available as 'Timoptol' Unit dose: The Unit-dose Dispenser of 'Timoptol' is free from preservative and should be used for patients who may be sensitive to the preservative benzalkonium chloride, or when use of a preservative-free topical medication is advisable.

Paediatric use: is not currently recommended.

Use in the elderly: there has been wide experience with the use of timolol maleate in elderly patients. The dosage recommendations given above reflect the clinical data derived from this experience.

4.3 Contraindications

Bronchial asthma, history of bronchial asthma or severe chronic obstructive pulmonary disease; sinus bradycardia, second- and third-degree AV block, overt cardiac failure, cardiogenic shock; and hypersensitivity to this product or other beta-blocking agents.

4.4 Special Warnings And Precautions For Use

Like other topically applied ophthalmic drugs, 'Timoptol' may be absorbed systemically and adverse reactions seen with oral beta-blockers may occur.

Cardiac failure should be adequately controlled before beginning therapy with 'Timoptol'. Patients with a history of severe cardiac disease should be watched for signs of cardiac failure and have their pulse rates checked.

Respiratory and cardiac reactions, including death due to bronchospasm in patients with asthma and, rarely, death associated with cardiac failure have been reported.

The effect on intra-ocular pressure or the known effects of systemic beta-blockade may be exaggerated when 'Timoptol' is given to the patients already receiving a systemic beta-blocking agent. The response of these patients should be closely observed. The use of two topical beta-adrenergic blocking agents is not recommended.

There have been reports of skin rashes and/or dry eyes associated with the use of beta-adrenoreceptor blocking drugs. The reported incidence is small and in most cases the symptoms have cleared when treatment was withdrawn. Discontinuation of the drug should be considered if any such reaction is not otherwise explicable. Cessation of therapy involving beta-blockade should be gradual.

Choroidal detachment has been reported with administration of aqueous suppressant therapy (e.g. timolol, acetazolamide) after filtration procedures.

'Timoptol' has been generally well tolerated in glaucoma patients wearing conventional hard contact lenses. 'Timoptol' has not been studied in patients wearing lenses made with material other than polymethylmethacrylate (PMMA), which is used to make hard contact lenses.

The Ocumeter® Dispenser of 'Timoptol' contains benzalkonium chloride as a preservative which may be deposited in soft contact lenses; therefore 'Timoptol' should not be used while wearing these lenses. The lenses should be removed before application of the drops and not reinserted earlier than 15 minutes after use.

In patients with angle-closure glaucoma, the immediate objective of treatment is to reopen the angle. This requires constricting the pupil with a miotic. 'Timoptol' has little or no effect on the pupil. When 'Timoptol' is used to reduce elevated intra-ocular pressure in angle-closure glaucoma it should be used with a miotic and not alone.

Patients should be advised that if they develop an intercurrent ocular condition (e.g. trauma, ocular surgery or infection), they should immediately seek their physician's advice concerning the continued use of the present multidose container (see 6.6 'Special precautions for disposal and other handling').

There have been reports of bacterial keratitis associated with the use of multiple dose containers of topical ophthalmic products. These containers had been inadvertently contaminated by patients who, in most cases, had a concurrent corneal disease or a disruption of the ocular epithelial surface.

Risk from anaphylactic reaction: While taking beta-blockers, patients with a history of atopy or a history of severe anaphylactic reaction to a variety of allergens may be more reactive to repeated challenge with such allergens, either accidental, diagnostic, or therapeutic. Such patients may be unresponsive to the usual doses of epinephrine (adrenaline) used to treat anaphylactic reactions.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Although 'Timoptol' alone has little or no effect on pupil size, mydriasis has occasionally been reported when 'Timoptol' is given with epinephrine (adrenaline).

Potentiated systemic beta-blockade (e.g. decreased heart rate, depression) has been reported during combined treatment with CYP2D6 inhibitors (e.g.quinidine, SSRIs) and timolol.

Oral β-adrenergic blocking agents may exacerbate the rebound hypertension which can follow the withdrawal of clonidine.

'Timoptol' may potentially add to the effects of oral calcium antagonists, rauwolfia alkaloids or beta-blockers, to induce hypotension and/or marked bradycardia.

Close observation of the patient is recommended when a beta-blocker is administered to patients receiving catecholamine-depleting drugs such as reserpine, because of possible additive effects and the production of hypotension and/or marked bradycardia, which may produce vertigo, syncope, or postural hypotension.

Oral calcium antagonists may be used in combination with beta-adrenergic blocking agents when heart function is normal, but should be avoided in patients with impaired cardiac function.

The potential exists for hypotension, AV conduction disturbances and left ventricular failure to occur in patients receiving a beta-blocking agent when an oral calcium entry blocker is added to the treatment regimen. The nature of any cardiovascular adverse effect tends to depend on the type of calcium blocker used. Dihydropyridine derivatives, such as nifedipine, may lead to hypotension, whereas verapamil or diltiazem have a greater propensity to lead to AV conduction disturbances or left ventricular failure when used with a beta-blocker.

Intravenous calcium channel blockers should be used with caution in patients receiving beta-adrenergic blocking agents.

The concomitant use of beta-adrenergic blocking agents and digitalis with either diltiazem or verapamil may have additive effects in prolonging AV conduction time.

4.6 Pregnancy And Lactation

Use in pregnancy: 'Timoptol' has not been studied in human pregnancy. The use of 'Timoptol' requires that the anticipated benefit be weighed against possible hazards.

Breast-feeding mothers: Timolol is detectable in human milk. A decision for breast-feeding mothers, either to stop taking 'Timoptol' or stop nursing, should be based on the importance of the drug to the mother.

4.7 Effects On Ability To Drive And Use Machines

Possible side effects such as dizziness and visual disturbances may affect some patients' ability to drive or operate machinery.

4.8 Undesirable Effects

Side effects

'Timoptol' is usually well tolerated. The following adverse reactions have been reported with ocular administration of this or other timolol maleate formulations, either in clinical trials or since the drug has been marketed. Additional side effects have been reported in clinical experiences with systemic timolol maleate, and may be considered potential effects of ophthalmic timolol maleate:

Special senses:

ocular: signs and symptoms of ocular irritation, including burning and stinging, conjunctivitis, blepharitis, keratitis, dry eyes and decreased corneal sensitivity. Tinnitus, visual disturbances, including refractive changes (due to withdrawal of miotic therapy in some cases), diplopia, ptosis and choroidal detachment following filtration surgery (see 4.4 'Special warnings and precautions for use').

Cardiovascular:

ocular: bradycardia, arrhythmia, hypotension, syncope, heart block, cerebrovascular accident, cerebral ischaemia, congestive heart failure, palpitation, cardiac arrest, oedema, claudication, Raynaud's phenomenon, cold hands and feet.

systemic: AV block (second- or third-degree), sino-atrial block, pulmonary oedema, worsening of arterial insufficiency, worsening of angina pectoris, vasodilation.

Respiratory:

ocular: bronchospasm (predominantly in patients with pre-existing bronchospastic disease), respiratory failure, dyspnoea, cough.

systemic: rales

Body as a whole:

ocular: headache, asthenia, fatigue, chest pain.

systemic: extremity pain, decreased exercise tolerance.

Integumentary:

ocular: alopecia, psoriasiform rash or exacerbation of psoriasis.

systemic: pruritus, sweating, exfoliative dermatitis.

Hypersensitivity:

ocular: signs and symptoms of allergic reactions including anaphylaxis, angioedema, urticaria, localised and generalised rash.

Nervous system/psychiatric:

ocular: dizziness, depression, insomnia, nightmares, memory loss, increase in signs and symptoms of myasthenia gravis, paresthesia.

systemic: vertigo, local weakness, diminished concentration, increased dreaming.

Digestive:

ocular: nausea, diarrhoea, dyspepsia, dry mouth.

systemic: vomiting

Urogenital:

ocular: decreased libido, Peyronie's disease.

systemic: impotence, micturition difficulties.

Immunologic:

ocular: systemic lupus erythematosus

Endocrine:

systemic: hyperglycaemia, hypoglycaemia.

Musculoskeletal:

systemic: arthralgia.

Haematologic:

systemic: non-thrombocytopenic purpura.

4.9 Overdose

There have been reports of inadvertent overdosage with 'Timoptol' resulting in systemic effects similar to those seen with systemic beta-adrenergic blocking agents such as dizziness, headache, shortness of breath, bradycardia, bronchospasm, and cardiac arrest (see 'Side effects').

If overdosage occurs, the following measures should be considered:

1. Gastric lavage, if ingested. Studies have shown that timolol does not dialyse readily.

2. Symptomatic bradycardia: atropine sulphate, 0.25 to 2 mg intravenously, should be used to induce vagal blockade. If bradycardia persists, intravenous isoprenaline hydrochloride should be administered cautiously. In refractory cases, the use of a cardiac pacemaker may be considered.

3. Hypotension: a sympathomimetic pressor agent such as dopamine, dobutamine or noradrenaline should be used. In refractory cases, the use of glucagon has been reported to be useful.

4. Bronchospasm: isoprenaline hydrochloride should be used. Additional therapy with aminophylline may be considered.

5. Acute cardiac failure: conventional therapy with digitalis, diuretics, and oxygen should be instituted immediately. In refractory cases, the use of intravenous aminophylline is suggested. This may be followed, if necessary, by glucagon, which has been reported useful.

6. Heart block (second- or third-degree): isoprenaline hydrochloride or a pacemaker should be used.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Timolol maleate is a non-selective beta-adrenergic receptor blocking agent that does not have significant intrinsic sympathomimetic, direct myocardial depressant, or local anaesthetic activity. Timolol maleate combines reversibly with the beta-adrenergic receptor, and this inhibits the usual biologic response that would occur with stimulation of that receptor. This specific competitive antagonism blocks stimulation of the beta-adrenergic stimulating (agonist) activity, whether these originate from an endogenous or exogenous source. Reversal of this blockade can be accomplished by increasing the concentration of the agonist which will restore the usual biological response.

Unlike miotics, 'Timoptol' reduces IOP with little or no effect on accommodation or pupil size. In patients with cataracts, the inability to see around lenticular opacities when the pupil is constricted is avoided. When changing patients from miotics to 'Timoptol' a refraction might be necessary when the effects of the miotic have passed.

Diminished response after prolonged therapy with 'Timoptol' has been reported in some patients.

5.2 Pharmacokinetic Properties

The onset of reduction in intra-ocular pressure can be detected within one-half hour after a single dose. The maximum effect occurs in one or two hours; significant lowering of IOP can be maintained for as long as 24 hours with a single dose.

5.3 Preclinical Safety Data

No adverse ocular effects were observed in rabbits and dogs administered 'Timoptol' topically in studies lasting one and two years, respectively. The oral LD₅₀ of the drug is 1,190 and 900 mg/kg in female mice and female rats, respectively.

Carcinogenesis, mutagenesis, impairment of fertility

In a two-year oral study of timolol maleate in rats there was a statistically significant (p

In a lifetime oral study in mice, there were statistically significant (p

The increased occurrence of mammary adenocarcinoma was associated with elevations in serum prolactin which occurred in female mice administered timolol at 500 mg/kg/day, but not at doses of 5 or 50 mg/kg/day. An increased incidence of mammary adenocarcinomas in rodents has been associated with administration of several other therapeutic agents which elevate serum prolactin, but no correlation between serum prolactin levels and mammary tumours has been established in man. Furthermore, in adult human female subjects who received oral dosages of up to 60 mg of timolol maleate, the maximum recommended human oral dosage, there were no clinically meaningful changes in serum prolactin.

Timolol maleate was devoid of mutagenic potential when evaluated in vivo (mouse) in the micronucleus test and cytogenetic assay (doses up to 800 mg/kg) and in vitro in a neoplastic cell transformation assay (up to 100 mcg/ml). In Ames tests the highest concentrations of timolol employed, 5,000 or 10,000 mcg/plate, were associated with statistically significant (p

Reproduction and fertility studies in rats showed no adverse effect on male or female fertility at doses up to 150 times the maximum recommended human oral dose.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Disodium phosphate dodecahydrate (may be replaced by equivalent amounts of the dihydrate or anhydrous )

Sodium dihydrogen phosphate dihydrate (may be replaced by equivalent amounts of monohydrate)

Sodium hydroxide

Benzalkonium chloride

Water for injections

6.2 Incompatibilities

None known.

6.3 Shelf Life

24 months

Discard 'Timoptol' Eye Drops Solution 28 days after opening the bottle.

6.4 Special Precautions For Storage

Do not store above 25°C. Store the bottle in the outer carton.

6.5 Nature And Contents Of Container

The OCUMETER Plus ophthalmic dispenser consists of a translucent high-density polyethylene container with a sealed dropper tip, a flexible fluted side area, which is depressed to dispense the drops, and a two-piece cap assembly. The two-piece cap mechanism punctures the sealed dropper tip upon initial use, then locks together to provide a single cap during the usage period. Tamper evidence is provided by two perforated tabs on the container label extending on to the cap. The OCUMETER Plus ophthalmic dispenser contains 5 ml of solution.

6.6 Special Precautions For Disposal And Other Handling

Patients should be instructed to avoid allowing the tip of the dispensing container to contact the eye or surrounding structures.

Patients should also be instructed that ocular solutions, if handled improperly, can become contaminated by common bacteria known to cause ocular infections. Serious damage to the eye and subsequent loss of vision may result from using contaminated solutions.

7. Marketing Authorisation Holder

Merck Sharp & Dohme Limited

Hertford Road, Hoddesdon, Hertfordshire EN11 9BU, UK

8. Marketing Authorisation Number(S)

0.25% w/v Eye Drops Solution PL0025/0134

0.5% w/v Eye Drops Solution PL0025/0135

9. Date Of First Authorisation/Renewal Of The Authorisation

Granted: 5 January 1979

Last renewed: 12 February 2002

10. Date Of Revision Of The Text

February 2008

LEGAL CATEGORY

POM

® denotes registered trademark of Merck & Co., Inc., Whitehouse Station, NJ, USA.

© Merck Sharp & Dohme Limited 2008 All rights reserved

SPC.TOTOS.06.UK.2345 F.T. 020608

TORISEL 25 mg / ml concentrate and diluent for solution for infusion

1. Name Of The Medicinal Product

TORISEL

2. Qualitative And Quantitative Composition

Each vial of TORISEL concentrate contains 30 mg temsirolimus.

After first dilution of TORISEL 30 mg concentrate with 1.8 ml of withdrawn diluent, the concentration of temsirolimus is 10 mg/ml (see section 4.2).

Excipients:

1 vial TORISEL 30 mg concentrate contains 474 mg anhydrous ethanol.

1.8 ml of the diluent, provided contains 358 mg anhydrous ethanol.

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Concentrate and diluent for solution for infusion (sterile concentrate).

The concentrate is a clear, colourless to light-yellow solution, essentially free from visible particulates.

The diluent is a clear to slightly turbid, light-yellow to yellow solution, essentially free from visible particulates.

4. Clinical Particulars

4.1 Therapeutic Indications

Renal cell carcinoma

TORISEL is indicated for the first-line treatment of patients with advanced renal cell carcinoma (RCC) who have at least three of six prognostic risk factors (see section 5.1).

Mantle cell lymphoma

TORISEL is indicated for the treatment of adult patients with relapsed and/or refractory mantle cell lymphoma [MCL] (see section 5.1).

4.2 Posology And Method Of Administration

TORISEL must be administered under the supervision of a physician experienced in the use of antineoplastic medicinal products.

The vial of TORISEL concentrate must first be diluted with 1.8 ml of diluent withdrawn from the supplied vial to achieve a concentration of temsirolimus of 10 mg/ml. Withdraw the required amount of the temsirolimus-diluent mixture ( 10 mg/ml) and then inject rapidly into sodium chloride 9 mg/ml (0.9%) solution for injection.

For instructions on preparation and to help ensure correct dosing, see section 6.6.

Posology

Patients should be given intravenous diphenhydramine 25 to 50 mg (or similar antihistamine) approximately 30 minutes before the start of each dose of temsirolimus.

Treatment with TORISEL should continue until the patient is no longer clinically benefiting from therapy or until unacceptable toxicity occurs. No special dose modification is required for any of the populations that have been studied (gender, elderly).

Renal cell carcinoma

The recommended dose of temsirolimus for advanced renal cell carcinoma administered intravenously is 25 mg infused over a 30- to 60-minute period once weekly (see section 6.6 for instructions on dilution, administration and disposal).

Management of suspected adverse reactions may require temporary interruption and/or dose reduction of temsirolimus therapy. If a suspected reaction is not manageable with dose delays, then temsirolimus may be reduced by 5 mg/week decrements.

Mantle cell lymphoma

The recommended dosing regimen of temsirolimus for mantle cell lymphoma is 175 mg, infused over a 30-60 minute period once weekly for 3 weeks followed by weekly doses of 75 mg, infused over a 30-60 minute period. The starting dose of 175 mg was associated with a significant incidence of adverse events and required dose reductions/delays in the majority of patients. The contribution of the initial 175 mg doses to the efficacy outcome is currently not known.

Management of suspected adverse reactions may require temporary interruption and/or dose reduction of temsirolimus therapy according to the guidelines in the following tables. If a suspected reaction is not manageable with dose delays and/or optimal medical therapy, then the dose of temsirolimus should be reduced according to the dose reduction table below.

Dose Reduction Levels

Dose Reduction Level	Starting Dose 175 mg	Continuing Dosea 75 mg
-1	75 mg	50 mg
-2	50 mg	25 mg

^a In the MCL Clinical Trial, up to two dose level reductions were allowed per patient.

Temsirolimus Dose Modifications Based on Weekly ANC and Platelet Counts

ANC	Platelets	Dose of Temsirolimus
9/l	9/l	100% of planned dose
<1.0 x 109/l	<50 x 109/l	Holda

^a Upon recovery to ANC ⁹/l (1000 cells/mm³) and platelets to ⁹/l (50,000 cells/mm³), the doses should be modified to the next lower dose level according to the table above. If the patient cannot maintain ANC >1.0 x 10⁹/l and platelets >50 x 10⁹/l on the new dose reduction level, then the next lower dose should be given once the counts have recovered.

Abbreviation: ANC = absolute neutrophil count.

Paediatric population

There is no relevant use of temsirolimus in the paediatric population in the indication: treatment of renal cell carcinoma and mantle cell lymphoma.

Temsirolimus should not be used in the paediatric population for the treatment of neuroblastoma, rhabdomyosarcoma or high-grade glioma, because of efficacy concerns based on the available data (see section 5.1).

Elderly population

No specific dose adjustment is necessary.

Renal impairment

No dose adjustment of temsirolimus is recommended in patients with renal impairment. Temsirolimus should be used with caution in patients with severe renal impairment (see section 4.4).

Hepatic impairment

Temsirolimus should be used with caution in patients with hepatic impairment (see section 4.4).

No dose adjustment of temsirolimus is recommended for patients with advanced renal cell carcinoma (RCC) and mild to moderate hepatic impairment. For patients with RCC and severe hepatic impairment, the recommended dose for patients who have baseline platelets ⁹/l is 10 mg IV once a week infused over a 30-60 minute period (see section 5.2).

Method of administration

TORISEL must be administered by intravenous (IV) infusion. For instructions on dilution and preparation of the medicinal product before administration, see section 6.6.

4.3 Contraindications

Hypersensitivity to temsirolimus, its metabolites (including sirolimus), polysorbate 80, or to any of the excipients of TORISEL.

Use of temsirolimus in patients with mantle cell lymphoma with moderate or severe hepatic impairment is not recommended (see section 4.4).

4.4 Special Warnings And Precautions For Use

The incidence and severity of adverse events is dose-dependent. Patients receiving the starting dose of 175 mg weekly for the treatment of MCL must be followed closely to decide on dose reductions/delays.

Paediatric population

Temsirolimus is not recommended for use in paediatric patients (see sections 4.2, 4.8 and 5.1).

Elderly population

Based on the results of a phase 3 study in renal cell carcinoma, elderly patients (

Renal impairment

Temsirolimus elimination by the kidneys is negligible; studies in patients with varying renal impairment have not been conducted (see sections 4.2 and 5.2). TORISEL has not been studied in patients undergoing haemodialysis.

Renal failure

Renal failure (including fatal outcomes) has been observed in patients receiving TORISEL for advanced renal cell cancer and/or with pre-existing renal insufficiency (see section 4.8).

Hepatic impairment

Use caution when treating patients with hepatic impairment.

Temsirolimus is cleared predominantly by the liver. In an open-label, dose-escalation phase I study in 110 subjects with advanced malignancies and either normal or impaired hepatic function, concentrations of temsirolimus and its metabolite sirolimus were increased in patients with elevated AST or bilirubin levels. Assessment of AST and bilirubin levels is recommended before initiation of temsirolimus and periodically after.

An increased rate of fatal events was observed in patients with moderate and severe hepatic impairment. The fatal events included those due to progression of disease; however a causal relationship cannot be excluded.

Based on the phase I study, no dose adjustment of temsirolimus is recommended for RCC patients with baseline platelet counts ⁹/l and mild to moderate hepatic impairment (total bilirubin up to 3 times upper limit of normal [ULN] with any abnormality of AST, or as defined by Child-Pugh Class A or B). For patients with RCC and severe hepatic impairment (total bilirubin > 3 times ULN with any abnormality of AST, or as defined by Child-Pugh Class C), the recommended dose for patients who have baseline platelets ⁹/l is 10 mg IV once a week infused over a 30-60 minute period (see section 4.2).

Intracerebral bleeding

Patients with central nervous system (CNS) tumours (primary CNS tumours or metastases) and/or receiving anticoagulation therapy may be at an increased risk of developing intracerebral bleeding (including fatal outcomes) while receiving therapy with temsirolimus.

Thrombocytopaenia and neutropaenia

Grades 3 and 4 thrombocytopaenia and/or neutropaenia have been observed in the MCL Clinical Trial (see section 4.8). Patients on temsirolimus who develop thrombocytopaenia may be at increased risk of bleeding events, including epistaxis (see section 4.8). Patients on temsirolimus with baseline neutropaenia may be at risk of developing febrile neutropaenia.

Infections

Patients may be immunosuppressed and should be carefully observed for the occurrence of infections, including opportunistic infections. Among patients receiving 175 mg/week for the treatment of MCL, infections (including grade 3 and 4 infections) were substantially increased compared to lower doses and compared to conventional chemotherapy.

Cataracts

Cataracts have been observed in some patients who received the combination of temsirolimus and interferon-α.

Hypersensitivity/infusion reactions

Hypersensitivity/infusion reactions (including some life-threatening and rare fatal reactions), including and not limited to flushing, chest pain, dyspnoea, hypotension, apnoea, loss of consciousness, hypersensitivity and anaphylaxis, have been associated with the administration of temsirolimus (see section 4.8). These reactions can occur very early in the first infusion, but may also occur with subsequent infusions. Patients should be monitored early during the infusion and appropriate supportive care should be available. Temsirolimus infusion should be interrupted in all patients with severe infusion reactions and appropriate medical therapy administered. A benefit-risk assessment should be done prior to the continuation of temsirolimus therapy in patients with severe or life-threatening reactions.

If a patient develops a hypersensitivity reaction during the TORISEL infusion, despite the premedication, the infusion must be stopped and the patient observed for at least 30 to 60 minutes (depending on the severity of the reaction). At the discretion of the physician, treatment may be resumed after the administration of an H₁-receptor antagonist (diphenhydramine or similar antihistamine) and a H₂-receptor antagonist (intravenous famotidine 20 mg or intravenous ranitidine 50 mg) approximately 30 minutes before restarting the TORISEL infusion. Administration of corticosteroids may be considered; however, the efficacy of corticosteroid treatment in this setting has not been established. The infusion may then be resumed at a slower rate (up to 60 minutes) and should be completed within six hours from the time that TORISEL is first added to sodium chloride 9 mg/ml (0.9%) solution for injection.

Because it is recommended that an H₁ antihistamine be administered to patients before the start of the intravenous temsirolimus infusion, temsirolimus should be used with caution in patients with known hypersensitivity to the antihistamine or in patients who cannot receive the antihistamine for other medical reasons.

Hypersensitivity reactions, including anaphylactic/anaphylactoid reactions, angioedema, exfoliative dermatitis and hypersensitivity vasculitis, have been associated with the oral administration of sirolimus.

Hyperglycaemia/glucose intolerance/diabetes mellitus

Patients should be advised that treatment with TORISEL may be associated with an increase in blood glucose levels in diabetic and non-diabetic patients. In the RCC Clinical Trial, a phase 3 clinical trial for renal cell carcinoma, 26% of patients reported hyperglycaemia as an adverse event. In the MCL Clinical Trial, a phase 3 clinical trial for mantle cell lymphoma, 11% of patients reported hyperglycaemia as an adverse event. This may result in the need for an increase in the dose of, or initiation of, insulin and/or hypoglycaemic agent therapy. Patients should be advised to report excessive thirst or any increase in the volume or frequency of urination.

Interstitial lung disease

There have been cases of non-specific interstitial pneumonitis, including fatal reports, occurring in patients who received weekly intravenous TORISEL. Some patients were asymptomatic or had minimal symptoms with pneumonitis detected on computed tomography scan or chest radiograph. Others presented with symptoms such as dyspnoea, cough, and fever. Some patients required discontinuation of TORISEL or treatment with corticosteroids and/or antibiotics, while some patients continued treatment without additional intervention. It is recommended that patients undergo baseline radiographic assessment by lung computed tomography scan or chest radiograph prior to the initiation of TORISEL therapy. Periodical follow-up assessments may be considered. It is recommended that patients be followed closely for occurrence of clinical respiratory symptoms and patients should be advised to report promptly any new or worsening respiratory symptoms. If clinically significant respiratory symptoms develop, consider withholding TORISEL administration until after recovery of symptoms and improvement of radiographic findings related to pneumonitis. Empiric treatment with corticosteroids and/or antibiotics may be considered.

Hyperlipaemia

The use of TORISEL was associated with increases in serum triglycerides and cholesterol. In the RCC Clinical Trial 1, hyperlipaemia was reported as an adverse event in 27% of patients. In the MCL Clinical Trial, hyperlipaemia was reported as an adverse event in 9.3% of patients. This may require initiation, or increase, in the dose of lipid-lowering agents. Serum cholesterol and triglycerides should be tested before and during treatment with TORISEL.

Wound healing complications

The use of TORISEL has been associated with abnormal wound healing; therefore, caution should be exercised with the use of TORISEL in the peri-surgical period.

Concomitant use of temsirolimus with sunitinib

The combination of temsirolimus and sunitinib resulted in dose-limiting toxicity. Dose-limiting toxicities (grade 3/4 erythematous maculopapular rash, gout/cellulitis requiring hospitalisation) were observed in two out of three patients treated in the first cohort of a phase 1 study at doses of temsirolimus 15 mg intravenous per week and sunitinib 25 mg oral per day (days 1-28 followed by a 2-week rest).

Concomitant use of angiotensin-converting enzyme (ACE) inhibitors

Angioneurotic oedema-type reactions (including delayed reactions occurring two months following initiation of therapy) have been observed in some patients who received temsirolimus and ACE inhibitors concomitantly (see section 4.5).

Agents inducing CYP3A metabolism

Agents such as carbamazepine, phenobarbital, phenytoin, rifampicin, and St. John's Wort are strong inducers of CYP3A4/5 and may decrease composite exposure of the active moieties, temsirolimus and its metabolite, sirolimus. Therefore, for patients with renal cell carcinoma, continuous administration beyond 5-7 days with agents that have CYP3A4/5 induction potential should be avoided. For patients with mantle cell lymphoma, it is recommended that coadministration of CYP3A4/5 inducers should be avoided due to the higher dose of temsirolimus (see section 4.5).

Agents inhibiting CYP3A metabolism

Agents such as protease inhibitors (nelfinavir, ritonavir), antifungals (e.g., itraconazole, ketoconazole, voriconazole), and nefazodone are strong CYP3A4 inhibitors and may increase blood concentrations of the active moieties, temsirolimus and its metabolite, sirolimus. Therefore, concomitant treatment with agents that have strong CYP3A4 inhibition potential should be avoided. Concomitant treatment with moderate CYP3A4 inhibitors (e.g., aprepitant, erythromycin, fluconazole, verapamil, grapefruit juice) should only be administered with caution in patients receiving 25 mg and should be avoided in patients receiving temsirolimus doses higher than 25 mg (see section 4.5). Alternative treatments with agents that do not have CYP3A4 inhibition potential should be considered (see section 4.5).

Vaccinations

Immunosuppressants may affect responses to vaccination. During treatment with TORISEL, vaccination may be less effective. The use of live vaccines should be avoided during treatment with TORISEL. Examples of live vaccines are: measles, mumps, rubella, oral polio, BCG, yellow fever, varicella, and TY21a typhoid vaccines.

Excipients

After first dilution of TORISEL 30 mg concentrate with 1.8 ml of withdrawn diluent, the concentrate-diluent mixture contains 35% volume ethanol (alcohol); i.e., up to 0.693 g per 25 mg dose of TORISEL, equivalent to 17.6 ml beer, 7.3 ml wine per dose. Patients administered the higher dose of 175 mg of TORISEL for the initial treatment of MCL may receive up to 4.85 g of ethanol (equivalent to 123 ml beer, 51 ml wine per dose).

Harmful for those suffering from alcoholism.

To be taken into account in pregnant or breast-feeding women, children and high-risk groups, such as patients with liver disease or epilepsy. The amount of alcohol in this medicinal product may alter the effects of other medicines. The amount of alcohol in this medicinal product may impair your ability to drive or use machines.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Interaction studies have only been performed in adults.

Concomitant use of angiotensin-converting enzyme (ACE) inhibitors

Angioneurotic oedema-type reactions (including delayed reactions occurring two months following initiation of therapy) have been observed in some patients who received temsirolimus and ACE inhibitors concomitantly (see section 4.4).

Agents inducing CYP3A metabolism

Co-administration of TORISEL with rifampicin, a potent CYP3A4/5 inducer, had no significant effect on temsirolimus C_max (maximum concentration) and AUC (area under the concentration vs. time curve) after intravenous administration, but decreased sirolimus C_max by 65% and AUC by 56%, compared to TORISEL treatment alone. Therefore, concomitant treatment with agents that have CYP3A4/5 induction potential should be avoided [e.g., carbamazepine, phenobarbital, phenytoin, rifampicin, and St. John's Wort] (see section 4.4).

Agents inhibiting CYP3A metabolism

Co-administration of TORISEL 5 mg with ketoconazole, a potent CYP3A4 inhibitor, had no significant effect on temsirolimus C_max or AUC; however, sirolimus AUC increased 3.1-fold, and AUC_sum (temsirolimus + sirolimus) increased 2.3-fold compared to TORISEL alone. The effect on the unbound concentrations of sirolimus has not been determined, but is expected to be larger than the effect on whole-blood concentrations due to the saturable binding to red blood cells. The effect may also be more pronounced at a 25 mg dose. Therefore, substances that are potent inhibitors of CYP3A4 activity (e.g., nelfinavir, ritonavir, itraconazole, ketoconazole, voriconazole, nefazodone) increase sirolimus blood concentrations. Concomitant treatment of TORISEL with these agents should be avoided see section 4.4).

Concomitant treatment with moderate CYP3A4 inhibitors (e.g., diltiazem, verapamil, clarithromycin, erythromycin, aprepitant, amiodarone) should only be administered with caution in patients receiving 25 mg and should be avoided in patients receiving temsirolimus doses higher than 25 mg.

Interaction with medicinal products metabolised by CYP2D6 or CYP3A4

In 23 healthy subjects, the concentration of desipramine, a CYP2D6 substrate, was unaffected when 25 mg of temsirolimus was co-administered. No clinically significant effect is anticipated when TORISEL is co-administered with agents that are metabolised by CYP2D6 in patients with renal cell carcinoma. For patients with mantle cell lymphoma, the effect of a 175 or 75 mg temsirolimus dose on CYP2D6 or 3A4 substrates has not been studied. However, based on in vitro studies in human liver microsomes, the plasma concentrations achieved after a 175 mg dose of temsirolimus might possibly lead to inhibition of CYP3A4/5 and CYP2D6 (see section 5.2). Therefore, caution is advised during concomitant administration of temsirolimus at a dose of 175 mg with medicinal products that are metabolised via CYP3A4/5 or CYP2D6 and that have a narrow therapeutic index.

Interactions with drugs that are P-glycoprotein substrates

In an in vitro study, temsirolimus inhibited the transport of P-glycoprotein (P-gp) substrates with an IC₅₀ value of 2 µM. In vivo, the effect of P-gp inhibition has not been investigated, but mean C_max concentrations of temsirolimus are 2.6 µM in MCL patients receiving the 175 mg IV dose of temsirolimus. Therefore, when temsirolimus is co-administered with medications which are P-gp substrates (e.g. digoxin, vincristine, colchicine, and paclitaxel) close monitoring for adverse events related to the co-administered drugs should be observed.

Amphiphilic agents

Temsirolimus has been associated with phospholipidosis in rats. Phospholipidosis has not been observed in mice or monkeys treated with temsirolimus, nor has it been documented in patients treated with temsirolimus. Although phospholipidosis has not been shown to be a risk for patients administered temsirolimus, it is possible that combined administration of temsirolimus with other amphiphilic agents such as amiodarone or statins could result in an increased risk of amphiphilic pulmonary toxicity.

4.6 Pregnancy And Lactation

Women of childbearing potential/ Contraception in males and females

Due to the unknown risk related to potential exposure during early pregnancy, women of childbearing potential must be advised not to become pregnant while using TORISEL.

Men with partners of childbearing potential should use medically acceptable contraception while receiving TORISEL (see section 5.3).

Pregnancy

There are no adequate data from the use of temsirolimus in pregnant women. Studies in animals have shown reproductive toxicity. In reproduction studies in animals, temsirolimus caused embryo/foetotoxicity that was manifested as mortality and reduced foetal weights (with associated delays in skeletal ossification) in rats and rabbits. Teratogenic effects (omphalocele) were seen in rabbits (see section 5.3).

The potential risk for humans is unknown. TORISEL must not be used during pregnancy, unless the risk for the embryo is justified by the expected benefit for the mother.

Breastfeeding

It is unknown whether temsirolimus is excreted in human breast milk. The excretion of temsirolimus in milk has not been studied in animals. However, sirolimus, the main metabolite of temsirolimus, is excreted in milk of lactating rats. Because of the potential for adverse reactions in breast-fed infants from temsirolimus, breast-feeding should be discontinued during therapy.

Fertility

In male rats, decreased fertility and partly reversible reductions in sperm counts were reported (see section 5.3).

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.

For patients receiving the higher dose of 175 mg IV of TORISEL for the treatment of MCL, the amount of ethanol in this medicinal product may impair your ability to drive or use machines (see section 4.4).

4.8 Undesirable Effects

Due to the different approved posology for RCC and MCL and the dose-dependency of the frequency and severity of undesirable effects, adverse drug reactions are listed separately.

Renal cell carcinoma

A total of 626 patients were randomly assigned in a phase 3, three-arm, randomised, open-label study of Interferon alfa (IFN-α) alone, TORISEL alone, and TORISEL and IFN-α. A total of 616 patients received treatment: 200 patients received IFN-α weekly; 208 received TORISEL 25 mg weekly, and 208 patients received a combination of IFN-α and TORISEL weekly. Based on the results of the phase 3 study, elderly patients may be more likely to experience certain adverse reactions, including face oedema and pneumonia.

The most serious reactions observed with TORISEL are hypersensitivity/infusion reactions (including some life-threatening and rare fatal reactions), hyperglycaemia/glucose intolerance, infections, interstitial lung disease (pneumonitis), hyperlipaemia, intracerebral bleeding, renal failure, bowel perforation, and wound healing complication.

The most common (

Cataracts have been observed in some patients who received the combination of temsirolimus and interferon-α.

See section 4.4 for additional information concerning serious adverse reactions, including appropriate actions to be taken if specific reactions occur.

The following list contains adverse reactions seen in RCC Clinical Trial 1. Only events for which there is at least reasonable suspicion of a causal relationship to intravenous treatment with TORISEL are listed.

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

Adverse reactions are listed according to the following categories:

Very common:

Common:

Uncommon:

Adverse Reactions in RCC Clinical Trial 1
System Organ Class	Frequency	Adverse Reactions	All Grades n (%)	Grade 3 & 4 n (%)
Infections and infestations	Very common	Bacterial and viral infections (including infection, cellulitis, herpes zoster, herpes simplex, bronchitis, sinusitis, abscess)*	42 (20)	6 (3)
Very common	Urinary tract infection (including dysuria, haematuria, cystitis, urinary frequency, urinary tract infection)*	31 (15)	4 (2)
Very common	Pharyngitis	25 (12)	0 (0)
Very common	Rhinitis	20 (10)	0 (0)
Common	Pneumonia	17 (8)	5 (2)
Common	Upper respiratory tract infection	14 (7)	0 (0)
Common	Folliculitis	4 (2)	0 (0)
Blood and lymphatic system disorders	Very common	Thrombocytopaenia	28 (14)	3 (1)
Very common	Anaemia	94 (45)	41 (20)
Common	Neutropaenia	15 (7)	6 (3)
Common	Leukopoenia	13 (6)	1 (1)
Common	Lymphopaenia	11 (5)	9 (4)
Immune system disorders	Common	Allergic/hypersensitivity reactions	18 (9)	0 (0)
Metabolism and nutrition disorders	Very common	Hypokalaemia	20 (10)	7 (3)
Very common	Anorexia	66 (32)	6 (3)
Very common	Hyperglycaemia/diabetes mellitus**	53 (26)	22 (11)
Very common	Hypercholesterolaemia	51 (24)	1 (1)
Very common	Hyperlipaemia	57 (27)	8 (4)
Common	Hypophosphataemia	17 (8)	11 (5)
Psychiatric disorders	Very common	Insomnia	24 (12)	1 (1)
Common	Anxiety	16 (8)	0 (0)
Common	Depression	9 (4)	0 (0)
Nervous system disorders	Very common	Dysgeusia	31 (15)	0 (0)
Common	Somnolence	14 (7)	3 (1)
Common	Paresthaesia	13 (6)	1 (1)
Common	Dizziness	19 (9)	1 (1)
Common	Ageusia	11 (5)	0 (0)
Uncommon	Intracerebral bleeding	1 (0.5)	1 (0.5)
Eye disorders	Common	Conjunctivitis (including conjunctivitis, lacrimation disorders)*	15 (7)	1 (1)
Cardiac disorders	Uncommon	Pericardial effusion (including haemodynamically significant pericardial effusions requiring intervention)	2 (1)	1 (1)
Vascular disorders	Common	Venous thromboembolism (including deep vein thrombosis, pulmonary embolus [including fatal outcomes], thrombosis)*	6 (3)	3 (1)
Common	Hypertension	14 (7)	3 (1)
Common	Thrombophlebitis	2 (1)	0 (0)
Respiratory, thoracic and mediastinal disorders	Very common	Dyspnoea	58 (28)	18 (9)
Very common	Epistaxis	25 (12)	0 (0)
Very common	Cough	54 (26)	2 (1)
Common	Pneumonitis [including fatal pneumonitis] (see section 4.4)	4 (2)	1 (1)
Common	Pleural effusion	8 (4)	5 (2)
Gastrointestinal disorders	Very common