Robaxin-750

1. Name Of The Medicinal Product

Robaxin-750

2. Qualitative And Quantitative Composition

Each white, capsule-shaped tablet contains 750 mg methocarbamol.

3. Pharmaceutical Form

Film coated tablet.

4. Clinical Particulars

4.1 Therapeutic Indications

As a short-term adjunct to the symptomatic treatment of acute musculoskeletal disorders associated with painful muscle spasms.

4.2 Posology And Method Of Administration

For oral use.

Dosage:

Adults: The usual dose is 2 tablets four times daily but therapeutic response has been achieved with doses as low as 1 tablet three times daily.

Elderly: Half the maximum dose or less may be sufficient to produce a therapeutic response.

Children: Not recommended.

Hepatically impaired: In patients with chronic hepatic disease the elimination half-life may be prolonged. Therefore, consideration should be given to increasing the dose level.

4.3 Contraindications

Hypersensitivity to methocarbamol or any of the other excipients in Robaxin-750. Coma or pre-coma states. Known brain damage or epilepsy. Myasthenia gravis.

4.4 Special Warnings And Precautions For Use

Robaxin should be used with caution in patients with renal and hepatic insufficiency.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

This product may potentiate the effects of other central nervous system depressants and stimulants including alcohol, barbiturates, anaesthetics and appetite suppressants. The effects of anticholinergics, e.g. atropine and some psychotropic drugs may be potentiated by methocarbamol. Methocarbamol may inhibit the effect of pyridostigmine bromide. Therefore methocarbamol should be used with caution in patients with myasthenia gravis receiving anticholinesterase agents. Little is known about the possibility of interactions with other drugs.

Methocarbamol may cause colour interference in certain screening tests for 5-hydroxyindolacetic acid (5-HIAA) using nitrosoaphthol reagent and in screening tests for urinary vanillymandelic acid (VMA) using the Gitlow method.

4.6 Pregnancy And Lactation

Animal reproductive studies have not been conducted with methocarbamol. It is also not known whether methocarbamol can cause foetal harm when administered to a pregnant woman or can affect reproduction capacity.

Safe use of methocarbamol has not been established with regard to possible adverse effects upon foetal development. There have been very rare reports of foetal and congenital abnormalities following in utero exposure to methocarbamol. Therefore methocarbamol tablets should not be used in women who are or may become pregnant and particularly during early pregnancy unless in the judgement of the physician the potential benefits outweigh the possible hazards.

Methocarbamol and/or its metabolites are excreted in the milk of dogs: however, it is not known whether methocarbamol or its metabolites are excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Robaxin-750 is administered to a nursing woman.

4.7 Effects On Ability To Drive And Use Machines

This product may cause drowsiness and patients receiving it should not drive nor operate machinery unless their physical and mental capabilities remain unaffected - especially if other medication capable of causing drowsiness is also being taken.

4.8 Undesirable Effects

Adverse reactions reported coincident with the administration of methocarbamol include

Body as a whole: Angioneurotic oedema, anaphylactic reaction, fever, headache.

Cardiovascular system: Bradycardia, flushing, hypotension, syncope.

Digestive system: Dyspepsia, jaundice (including cholestatic jaundice), nausea and vomiting.

Blood and lymphatic system: Leucopenia.

Nervous system: Restlessness, anxiety, tremor, amnesia, confusion, diplopia, dizziness or light-headedness, vertigo, drowsiness, insomnia, mild muscular incoordination, nystagmus, seizures (including grand mal).

Skin and special senses: Blurred vision, conjunctivitis with nasal congestion, metallic taste, pruritus, rash, urticaria.

4.9 Overdose

Limited information is available on the acute toxicity of methocarbamol. Overdose of methocarbamol is frequently in conjunction with alcohol or other CNS depressants and includes the following symptoms: nausea, drowsiness, blurred vision, hypotension, seizures and coma. One adult survived the deliberate ingestion of 22 to 30 grams of methocarbamol without serious toxicity. Another adult survived a dose of 30 to 50 grams. The principal symptom in both cases was extreme drowsiness. Treatment was symptomatic and recovery was uneventful. However, there have been cases of fatal overdose.

Management of overdose includes symptomatic and supportive treatment. Supportive measures include maintenance of an adequate airway, monitoring urinary output and vital signs, and administration of intravenous fluids if necessary. The usefulness of haemodialysis in managing overdose is unknown.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Robaxin 750 is used as a short-term adjunct to the symptomatic treatment of acute musculoskeletal disorders associated with painful muscle spasms.

The mechanism of action of methocarbamol in humans has not been established, but may be due to general central nervous system depression. It has no direct action on the contractile mechanism of striated muscle, the motor end plate or the nerve fibre.

5.2 Pharmacokinetic Properties

Methocarbamol is absorbed from the gastro-intestinal tract and produces peak plasma concentrations after about 1-3 hours. Its activity derives from the intact molecule and only a small proportion is converted to guaiphenesin.

Renally impaired

The clearance of methocarbamol in renally-impaired patients on maintenance haemodialysis was reduced about 40% compared to a normal population, although the mean elimination half-life in these two groups was similar (1.2 versus 1.1 hours, respectively).

Hepatically impaired

In patients with cirrhosis secondary to alcohol abuse, the mean total clearance of methocarbamol was reduced approximately 70% compared to a normal population (11.9 L/hr), and the mean elimination half-life was extended to approximately 3.4 hours. The fraction of methocarbamol bound to plasma proteins was decreased to approximately 40 to 45% compared to 46 to 50% in an age- and weight-matched normal population.

5.3 Preclinical Safety Data

Nothing of note to the prescriber.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Alginic acid, maize starch, povidone, sodium lauryl sulphate, gelatin, magnesium stearate, talc, sepifilm 002, sepisperse white AP 7001, potable mains water.

6.2 Incompatibilities

Not applicable.

6.3 Shelf Life

Amber glass bottles: 60 months

Blister packs: 24 months

HDPE bottles with HDPE child resistant caps: 60 months

6.4 Special Precautions For Storage

No special storage conditions are necessary.

6.5 Nature And Contents Of Container

Amber glass bottles containing 500, 100 or 6 tablets.

Blister packs containing 56 or 8 tablets.

HDPE bottles with HDPE child resistant caps containing 100 tablets.

6.6 Special Precautions For Disposal And Other Handling

None

7. Marketing Authorisation Holder

Almirall, S.A.

Ronda General Mitre, 151

08022 Barcelona

Spain

8. Marketing Authorisation Number(S)

PL 16973/0015

9. Date Of First Authorisation/Renewal Of The Authorisation

26^th August 2003

10. Date Of Revision Of The Text

26^th March 2010

Rasilez tablets 150 mg and 300 mg

1. Name Of The Medicinal Product

2. Qualitative And Quantitative Composition

Each film-coated tablet contains 150 mg aliskiren (as hemifumarate).

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Film-coated tablet

Light-pink, biconvex, round tablet, imprinted “IL” on one side and “NVR” on the other side.

4. Clinical Particulars

4.1 Therapeutic Indications

Treatment of essential hypertension.

4.2 Posology And Method Of Administration

The recommended dose of Rasilez is 150 mg once daily. In patients whose blood pressure is not adequately controlled, the dose may be increased to 300 mg once daily.

The antihypertensive effect is substantially present within two weeks (85-90%) after initiating therapy with 150 mg once daily.

Rasilez may be used alone or in combination with other antihypertensive agents (see sections 4.4 and 5.1).

Rasilez should be taken with a light meal once a day, preferably at the same time each day. Grapefruit juice should not be taken together with Rasilez.

Renal impairment

No adjustment of the initial dose is required for patients with mild to severe renal impairment (see sections 4.4 and 5.2).

Hepatic impairment

No adjustment of the initial dose is required for patients with mild to severe hepatic impairment (see section 5.2).

Elderly patients (over 65 years)

The recommended starting dose of aliskiren in elderly patients is 150 mg. No clinically meaningful additional blood pressure reduction is observed by increasing the dose to 300 mg in the majority of elderly patients.

Paediatric patients (below 18 years)

Rasilez is not recommended for use in children and adolescents below age 18 due to a lack of data on safety and efficacy (see section 5.2).

4.3 Contraindications

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

History of angioedema with aliskiren.

Hereditary or idiopathic angioedema.

Second and third trimesters of pregnancy (see section 4.6).

The concomitant use of aliskiren with ciclosporin and itraconazole, two highly potent P-gp inhibitors, and other potent P-gp inhibitors (e.g. quinidine), is contraindicated (see section 4.5).

4.4 Special Warnings And Precautions For Use

Patients receiving other medicinal products inhibiting the renin-angiotensin system (RAS), and/or those with reduced kidney function and/or diabetes mellitus are at an increased risk of hyperkalaemia during aliskiren therapy.

Aliskiren should be used with caution in patients with serious congestive heart failure (New York Heart Association (NYHA) functional class III-IV).

In the event of severe and persistent diarrhoea, Rasilez therapy should be stopped.

Angioedema

As with other agents acting on the renin-angiotensin system, angioedema or symptoms suggestive of angioedema (swelling of the face, lips, throat and/or tongue) have been reported in patients treated with aliskiren.

A number of these patients had a history of angioedema or symptoms suggestive of angioedema, which in some cases followed use of other medicines that can cause angioedema, including RAS blockers (angiotensin converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs)) (see section 4.8).

Patients with a history of angioedema may be at increased risk of experiencing angioedema during treatment with aliskiren (see sections 4.3 and 4.8). Caution should therefore be exercised when prescribing aliskiren to patients with a history of angioedema, and such patients should be closely monitored during treatment (see section 4.8) especially at the beginning of the treatment.

If angioedema occurs, Rasilez should be promptly discontinued and appropriate therapy and monitoring provided until complete and sustained resolution of signs and symptoms has occurred. Where there is involvement of the tongue, glottis or larynx adrenaline should be administered. In addition, measures necessary to maintain patent airways should be provided.

Sodium and/or volume depleted patients

In patients with marked volume- and/or salt-depletion (e.g. those receiving high doses of diuretics) symptomatic hypotension could occur after initiation of treatment with Rasilez. This condition should be corrected prior to administration of Rasilez, or the treatment should start under close medical supervision.

Renal impairment

In clinical studies Rasilez has not been investigated in hypertensive patients with severe renal impairment (serum creatinine

As for other agents acting on the renin-angiotensin system, caution should be exercised when aliskiren is given in the presence of conditions pre-disposing to kidney dysfunction such as hypovolaemia (eg. due to blood loss, severe prolonged diarrhoea, prolonged vomiting, etc.), heart disease, liver disease or kidney disease. Acute renal failure, reversible upon discontinuation of treatment, has been reported in at-risk patients receiving aliskiren in post-marketing experience. In the event that any signs of renal failure occur, aliskiren should be promptly discontinued.

Renal artery stenosis

No controlled clinical data are available on the use of Rasilez in patients with unilateral or bilateral renal artery stenosis, or stenosis to a solitary kidney. However, as with other agents acting on the renin-angiotensin system, there is an increased risk of renal insufficiency, including acute renal failure, when patients with renal artery stenosis are treated with aliskiren. Therefore, caution should be exercised in these patients. If renal failure occurs, treatment should be discontinued.

Moderate P-gp inhibitors

Co-administration of aliskiren 300 mg with ketoconazole 200 mg or verapamil 240 mg resulted in a 76% or 97% increase in aliskiren AUC, respectively. Therefore caution should be exercised when aliskiren is administered with moderate P-gp inhibitors such as ketoconazole or verapamil (see section 4.5).

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Rasilez has no known clinically relevant interactions with medicinal products commonly used to treat hypertension or diabetes.

Compounds that have been investigated in clinical pharmacokinetic studies include acenocoumarol, atenolol, celecoxib, pioglitazone, allopurinol, isosorbide-5-mononitrate, ramipril and hydrochlorothiazide. No interactions have been identified.

Co-administration of aliskiren with either valsartan (_max or AUC of Rasilez. When administered with atorvastatin, steady-state Rasilez AUC and C_max increased by 50%. Co-administration of Rasilez had no significant impact on atorvastatin, valsartan, metformin or amlodipine pharmacokinetics. As a result no dose adjustment for Rasilez or these co-administered medicinal products is necessary.

Digoxin and verapamil bioavailability may be slightly decreased by Rasilez.

Preliminary data suggest that irbesartan may decrease Rasilez AUC and C_max.

In experimental animals, it has been shown that P-gp is a major determinant of Rasilez bioavailability. Inducers of P-gp (St. John's wort, rifampicin) might therefore decrease the bioavailability of Rasilez.

CYP450 interactions

Aliskiren does not inhibit the CYP450 isoenzymes (CYP1A2, 2C8, 2C9, 2C19, 2D6, 2E1 and 3A). Aliskiren does not induce CYP3A4. Therefore aliskiren is not expected to affect the systemic exposure of substances that inhibit, induce or are metabolised by these enzymes. Aliskiren is metabolised minimally by the cytochrome P450 enzymes. Hence, interactions due to inhibition or induction of CYP450 isoenzymes are not expected. However, CYP3A4 inhibitors often also affect P-gp. Increased aliskiren exposure during co-administration of CYP3A4 inhibitors that also inhibit P-gp can therefore be expected (see P-glycoprotein interactions below).

P-glycoprotein interactions

MDR1/Mdr1a/1b (P-gp) was found to be the major efflux system involved in intestinal absorption and biliary excretion of aliskiren in preclinical studies. Rifampicin, which is an inducer of P-gp, reduced aliskiren bioavailability by approximately 50% in a clinical study. Other inducers of P-gp (St. John's wort) might decrease the bioavailability of Rasilez. Although this has not been investigated for aliskiren, it is known that P-gp also controls tissue uptake of a variety of substrates and P-gp inhibitors can increase the tissue-to-plasma concentration ratios. Therefore, P-gp inhibitors may increase tissue levels more than plasma levels. The potential for drug interactions at the P-gp site will likely depend on the degree of inhibition of this transporter.

P-gp potent inhibitors

A single dose drug interaction study in healthy subjects has shown that ciclosporin (200 and 600 mg) increases C_max of aliskiren 75 mg approximately 2.5-fold and AUC approximately 5-fold. The increase may be higher with higher aliskiren doses. In healthy subjects, itraconazole (100 mg) increases AUC and C_max of aliskiren (150 mg) by 6.5-fold and 5.8-fold, respectively. Therefore, concomitant use of aliskiren and P-gp potent inhibitors is contraindicated (see section 4.3).

Moderate P-gp inhibitors

Co-administration of ketoconazole (200 mg) or verapamil (240 mg) with aliskiren (300 mg) resulted in a 76% or 97% increase in aliskiren AUC, respectively. The change in plasma levels of aliskiren in the presence of ketoconazole or verapamil is expected to be within the range that would be achieved if the dose of aliskiren were doubled; aliskiren doses of up to 600 mg, or twice the highest recommended therapeutic dose, have been found to be well tolerated in controlled clinical trials. Preclinical studies indicate that aliskiren and ketoconazole co-administration enhances aliskiren gastrointestinal absorption and decreases biliary excretion. Therefore, caution should be exercised when aliskiren is administered with ketoconazole, verapamil or other moderate P-gp inhibitors (clarithromycin, telithromycin, erythromycin, amiodarone).

P-gp substrates or weak inhibitors

No relevant interactions with atenolol, digoxin, amlodipine or cimetidine have been observed. When administered with atorvastatin (80 mg), steady-state aliskiren (300 mg) AUC and C_max increased by 50%.

Organic anion transporting polypeptide (OATP) inhibitors

Preclinical studies indicate that aliskiren might be a substrate of organic anion transporting polypeptides. Therefore, the potential exists for interactions between OATP inhibitors and aliskiren when administered concomitantly (see interaction with Grapefruit juice).

Furosemide

When aliskiren was co-administered with furosemide, the AUC and C_max of furosemide were reduced by 28% and 49%, respectively. It is therefore recommended that the effects be monitored when initiating and adjusting furosemide therapy to avoid possible under-utilisation in clinical situations of volume overload.

Non-steroidal anti-inflammatory drugs (NSAIDs)

As with other agents acting on the renin-angiotensin system, NSAIDs may reduce the anti-hypertensive effect of aliskiren. In some patients with compromised renal function (dehydrated patients or elderly patients) aliskiren given concomitantly with NSAIDs may result in further deterioration of renal function, including possible acute renal failure, which is usually reversible. Therefore the combination of aliskiren with an NSAID requires caution, especially in elderly patients.

Potassium and potassium-sparing diuretics

Based on experience with the use of other substances that affect the renin-angiotensin system, concomitant use of potassium-sparing diuretics, potassium supplements, salt substitutes containing potassium or other substances that may increase serum potassium levels (e.g. heparin) may lead to increases in serum potassium. If co-medication is considered necessary, caution is advisable.

Grapefruit juice

Administration of grapefruit juice with aliskiren resulted in a decrease in AUC and C_max of aliskiren. Co-administration with aliskiren 150 mg resulted in a 61% decrease in aliskiren AUC and co-administration with aliskiren 300 mg resulted in a 38% decrease in aliskiren AUC. This decrease is likely due to an inhibition of organic anion transporting polypeptide-mediated uptake of aliskiren by grapefruit juice in the gastrointestinal tract. Therefore, because of the risk of therapeutic failure, grapefruit juice should not be taken together with Rasilez.

Warfarin

The effects of Rasilez on warfarin pharmacokinetics have not been evaluated.

Food intake

Meals with a high fat content have been shown to reduce the absorption of Rasilez substantially.

4.6 Pregnancy And Lactation

Pregnancy

There are no data on the use of aliskiren in pregnant women. Rasilez was not teratogenic in rats or rabbits (see section 5.3). Other substances that act directly on the RAS have been associated with serious foetal malformations and neonatal death. As for any medicine that acts directly on the RAS, Rasilez should not be used during the first trimester of pregnancy or in women planning to become pregnant and is contraindicated during the second and third trimesters (see section 4.3). Healthcare professionals prescribing any agents acting on the RAS should counsel women of childbearing potential about the potential risk of these agents during pregnancy. If pregnancy is detected during therapy, Rasilez should be discontinued accordingly.

Breast-feeding

It is not known whether aliskiren is excreted in human milk. Rasilez was secreted in the milk of lactating rats. Its use is therefore not recommended in women who are breast-feeding.

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. However, when driving vehicles or operating machinery it must be borne in mind that dizziness or weariness may occasionally occur when taking any antihypertensive therapy. Rasilez has negligible influence on the ability to drive and use machines.

4.8 Undesirable Effects

Rasilez has been evaluated for safety in more than 7,800 patients, including over 2,300 treated for over 6 months, and more than 1,200 for over 1 year. The incidence of adverse reactions showed no association with gender, age, body mass index, race or ethnicity. Treatment with Rasilez resulted in an overall incidence of adverse reactions similar to placebo up to 300 mg. Adverse reactions have generally been mild and transient in nature and have only infrequently required discontinuation of therapy. The most common adverse drug reaction is diarrhoea.

The adverse drug reactions (Table 1) are ranked under heading of frequency, the most frequent first, using the following convention: very common (

Table 1

Metabolism and nutrition disorders
	Uncommon:	Hyperkalaemia
Gastrointestinal disorders
	Common:	Diarrhoea
Immune system disorders
	Rare:	Hypersensitivity reactions
Skin and subcutaneous tissue disorders
	Uncommon:	Rash
	Rare:	Angioedema
Renal and urinary disorders
	Uncommon:	Acute renal failure, renal impairment
General disorders and administration site conditions
	Uncommon:	Oedema peripheral
Investigations
	Rare:	Haemoglobin decreased, haematocrit decreased
	Rare:	Blood creatinine increased

Angioedema and hypersensitivity reactions have occurred during treatment with aliskiren. In controlled clinical trials, angioedema and hypersensitivity reactions occurred rarely during treatment with aliskiren with rates comparable to treatment with placebo or comparators.

Cases of angioedema or symptoms suggestive of angioedema (swelling of the face, lips, throat and/or tongue) have also been reported in post-marketing experience. A number of these patients had a history of angioedema or symptoms suggestive of angioedema which in some cases was associated with the administration of other medicines known to cause angioedema, including RAS blockers (ACE inhibitors or ARBs).

Hypersensitivity reactions have also been reported in post-marketing experience.

In the event of any signs suggesting a hypersensitivity reaction/angioedema (in particular difficulties in breathing or swallowing, rash, itching, hives or swelling of the face, extremities, eyes, lips and/or tongue, dizziness) patients should discontinue treatment and contact the physician (see section 4.4).

Laboratory findings

In controlled clinical trials, clinically relevant changes in standard laboratory parameters were uncommonly associated with the administration of Rasilez. In clinical studies in hypertensive patients, Rasilez had no clinically important effects on total cholesterol, high density lipoprotein cholesterol (HDL-C), fasting triglycerides, fasting glucose or uric acid.

Haemoglobin and haematocrit: Small decreases in haemoglobin and haematocrit (mean decreases of approximately 0.05 mmol/l and 0.16 volume percent, respectively) were observed. No patients discontinued therapy due to anaemia. This effect is also seen with other agents acting on the renin-angiotensin system, such as ACEI and ARBs.

Serum potassium: Increases in serum potassium were minor and infrequent in patients with essential hypertension treated with Rasilez alone (0.9% compared to 0.6% with placebo). However, in one study where Rasilez was used in combination with an ACEI in a diabetic population, increases in serum potassium were more frequent (5.5%). Therefore as with any agent acting on the RAS system, routine monitoring of electrolytes and renal function is indicated in patients with diabetes mellitus, kidney disease, or heart failure.

In post-marketing experience, renal dysfunction and cases of acute renal failure have been reported in patients at risk (see section 4.4). There have also been reports of peripheral oedema and increase in blood creatinine.

4.9 Overdose

Limited data are available related to overdose in humans. The most likely manifestations of overdosage would be hypotension, related to the antihypertensive effect of aliskiren. If symptomatic hypotension should occur, supportive treatment should be initiated.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Renin inhibitor, ATC code: C09XA02

Aliskiren is an orally active, non-peptide, potent and selective direct inhibitor of human renin.

By inhibiting the enzyme renin, aliskiren inhibits the RAS at the point of activation, blocking the conversion of angiotensinogen to angiotensin I and decreasing levels of angiotensin I and angiotensin II. Whereas other agents that inhibit the RAS (ACEI and angiotensin II receptor blockers (ARB)) cause a compensatory rise in plasma renin activity (PRA), treatment with aliskiren decreases PRA in hypertensive patients by approximately 50 to 80%. Similar reductions were found when aliskiren was combined with other antihypertensive agents. The clinical implications of the differences in effect on PRA are not known at the present time.

Hypertension

In hypertensive patients, once-daily administration of Rasilez at doses of 150 mg and 300 mg provided dose-dependent reductions in both systolic and diastolic blood pressure that were maintained over the entire 24-hour dose interval (maintaining benefit in the early morning) with a mean peak to trough ratio for diastolic response of up to 98% for the 300 mg dose. 85 to 90% of the maximal blood-pressure-lowering effect was observed after 2 weeks. The blood-pressure-lowering effect was sustained during long-term treatment, and was independent of age, gender, body mass index and ethnicity. Rasilez has been studied in 1,864 patients aged 65 years or older, and in 426 patients aged 75 years or older.

Rasilez monotherapy studies have shown blood pressure lowering effects comparable to other classes of antihypertensive agents including ACEI and ARB. Compared to a diuretic (hydrochlorothiazide - HCTZ), Rasilez 300 mg lowered systolic/diastolic blood pressure by 17.0/12.3 mmHg, compared to 14.4/10.5 mmHg for HCTZ 25 mg after 12 weeks of treatment. In diabetic hypertensive patients, Rasilez monotherapy was safe and effective.

Combination therapy studies are available for Rasilez added to the diuretic hydrochlorothiazide, the ACEI ramipril, the calcium channel blocker amlodipine, the angiotensin receptor antagonist valsartan, and the beta blocker atenolol. These combinations were well tolerated. Rasilez induced an additive blood-pressure-lowering effect when added to hydrochlorothiazide and to ramipril. In patients who did not adequately respond to 5 mg of the calcium channel blocker amlodipine, the addition of Rasilez 150 mg had a blood-pressure-lowering effect similar to that obtained by increasing amlodipine dose to 10 mg, but had a lower incidence of oedema (aliskiren 150 mg/amlodipine 5 mg 2.1% vs. amlodipine 10 mg 11.2%). Rasilez in combination with the angiotensin receptor antagonist valsartan showed an additive antihypertensive effect in the study specifically designed to investigate the effect of the combination therapy.

The efficacy and safety of aliskiren-based therapy were compared to ramipril-based therapy in a 9-month non-inferiority study in 901 elderly patients (

In a 8-week study in 754 hypertensive elderly (

In obese hypertensive patients who did not adequately respond to HCTZ 25 mg, add-on treatment with Rasilez 300 mg provided additional blood pressure reduction that was comparable to add-on treatment with irbesartan 300 mg or amlodipine 10 mg. In diabetic hypertensive patients, Rasilez provided additive blood pressure reductions when added to ramipril, while the combination of Rasilez and ramipril had a lower incidence of cough (1.8%) than ramipril (4.7%).

There has been no evidence of first-dose hypotension and no effect on pulse rate in patients treated in controlled clinical studies. Excessive hypotension was uncommonly (0.1%) seen in patients with uncomplicated hypertension treated with Rasilez alone. Hypotension was also uncommon (<1%) during combination therapy with other antihypertensive agents. With cessation of treatment, blood pressure gradually returned towards baseline levels over a period of several weeks, with no evidence of a rebound effect for blood pressure or PRA.

In a 36-week study involving 820 patients with ischaemic left ventricular dysfunction, no changes in ventricular remodelling as assessed by left ventricular end systolic volume were detected with aliskiren compared to placebo on top of background therapy.

The combined rates of cardiovascular death, hospitalisation for heart failure, recurrent heart attack, stroke and resuscitated sudden death were similar in the aliskiren group and the placebo group. However, in patients receiving aliskiren there was a significantly higher rate of hyperkalaemia, hypotension and kidney dysfunction when compared to the placebo group.

In a 6-month study of 599 patients with hypertension, type 2 diabetes mellitus, and nephropathy, all of whom were receiving losartan 100 mg and optimised antihypertensive background therapy, addition of Rasilez 300 mg achieved a 20% reduction versus placebo in urinary albumin:creatinine ratio (UACR), i.e. from 58 mg/mmol to 46 mg/mmol. The proportion of patients who had UACR reduced at least 50% from baseline to endpoint was 24.7% and 12.5% for Rasilez and placebo, respectively.

The clinical relevance of a reduction in UACR is not established in the absence of an effect on blood pressure. Rasilez did not affect the serum concentration of creatinine but was associated with an increased frequency (4.2% vs. 1.9% for placebo) of serum potassium concentration

Beneficial effects of Rasilez on mortality and cardiovascular morbidity and target organ damage are currently unknown.

Cardiac electrophysiology

No effect on QT interval was reported in a randomised, double-blind, placebo, and active-controlled study using standard and Holter electrocardiography.

5.2 Pharmacokinetic Properties

Absorption

Following oral absorption, peak plasma concentrations of aliskiren are reached after 1-3 hours. The absolute bioavailability of aliskiren is approximately 2-3%. Meals with a high fat content reduce C_max by 85% and AUC by 70%. Steady-state-plasma concentrations are reached within 5-7 days following once-daily administration and steady-state levels are approximately 2-fold greater than with the initial dose.

Distribution

Following intravenous administration, the mean volume of distribution at steady state is approximately 135 litres, indicating that aliskiren distributes extensively into the extravascular space. Aliskiren plasma protein binding is moderate (47-51%) and independent of the concentration.

Metabolism and elimination

The mean half-life is about 40 hours (range 34-41 hours). Aliskiren is mainly eliminated as unchanged compound in the faeces (78%). Approximately 1.4% of the total oral dose is metabolised. The enzyme responsible for this metabolism is CYP3A4. Approximately 0.6% of the dose is recovered in urine following oral administration. Following intravenous administration, the mean plasma clearance is approximately 9 l/h.

Linearity/non-linearity

Exposure to aliskiren increased more than in proportion to the increase in dose. After single dose administration in the dose range of 75 to 600 mg, a 2-fold increase in dose results in a ~2.3 and 2.6-fold increase in AUC and C_max, respectively. At steady state the non-linearity may be more pronounced. Mechanisms responsible for deviation from linearity have not been identified. A possible mechanism is saturation of transporters at the absorption site or at the hepatobiliary clearance route.

Characteristics in patients

Aliskiren is an effective once-a-day antihypertensive treatment in adult patients, regardless of gender, age, body mass index and ethnicity.

The AUC is 50% higher in elderly (>65 years) than in young subjects. Gender, weight and ethnicity have no clinically relevant influence on aliskiren pharmacokinetics.

The pharmacokinetics of aliskiren were evaluated in patients with varying degrees of renal insufficiency. Relative AUC and C_max of aliskiren in subjects with renal impairment ranged between 0.8 to 2 times the levels in healthy subjects following single dose administration and at steady state. These observed changes, however, did not correlate with the severity of renal impairment. No adjustment of the initial dosage of Rasilez is required in patients with mild to severe renal impairment, however caution should be exercised in patients with severe renal impairment.

The pharmacokinetics of aliskiren were not significantly affected in patients with mild to severe liver disease. Consequently, no adjustment of the initial dose of aliskiren is required in patients with mild to severe hepatic impairment.

5.3 Preclinical Safety Data

Carcinogenic potential was assessed in a 2-year rat study and a 6-month transgenic mouse study. No carcinogenic potential was detected. One colonic adenoma and one caecal adenocarcinoma recorded in rats at the dose of 1,500 mg/kg/day were not statistically significant. Although aliskiren has known irritation potential, safety margins obtained in humans at the dose of 300 mg during a study in healthy volunteers were considered to be appropriate at 9-11-fold based on faecal concentrations or 6-fold based on mucosa concentrations in comparison with 250 mg/kg/day in the rat carcinogenicity study.

Aliskiren was devoid of any mutagenic potential in the in vitro and in vivo mutagenicity studies. The assays included in vitro assays in bacterial and mammalian cells and in vivo assessments in rats.

Reproductive toxicity studies with aliskiren did not reveal any evidence of embryofoetal toxicity or teratogenicity at doses up to 600 mg/kg/day in rats or 100 mg/kg/day in rabbits. Fertility, pre-natal development and post-natal development were unaffected in rats at doses up to 250 mg/kg/day. The doses in rats and rabbits provided systemic exposures of 1 to 4 and 5 times higher, respectively, than the maximum recommended human dose (300 mg).

Safety pharmacology studies did not reveal any adverse effects on central nervous, respiratory or cardiovascular function. Findings during repeat-dose toxicity studies in animals were consistent with the known local irritation potential or the expected pharmacological effects of aliskiren.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Crospovidone

Magnesium stearate

Cellulose, microcrystalline

Povidone

Silica, colloidal anhydrous

Hypromellose

Macrogol

Talc

Iron oxide, black (E 172)

Iron oxide, red (E 172)

Titanium dioxide (E 171)

6.2 Incompatibilities

Not applicable

6.3 Shelf Life

2 years

6.4 Special Precautions For Storage

Do not store above 30°C. Store in the original package in order to protect from moisture.

6.5 Nature And Contents Of Container

PA/Alu/PVC – Alu blisters:

Packs containing 7, 14, 28, 30, 50, 56, 84, 90, 98 or 280 tablets.

Packs containing 84 (3x28), 98 (2x49) or 280 (20x14) tablets are multi-packs.

PVC/polychlorotrifluoroethylene (PCTFE) – Alu blisters:

Packs containing 14, 28, 30, 50, 56, 90, 98 or 280 tablets.

Packs containing 98 (2x49) or 280 (20x14) tablets are multi-packs.

Packs containing 56 and 98 (2x49) tablets are perforated unit-dose blisters.

Not all pack sizes may be marketed.

6.6 Special Precautions For Disposal And Other Handling

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

7. Marketing Authorisation Holder

Novartis Europharm Limited

Wimblehurst Road

Horsham

West Sussex, RH12 5AB

United Kingdom

8. Marketing Authorisation Number(S)

EU/1/07/405/001-010

EU/1/07/405/021-030

9. Date Of First Authorisation/Renewal Of The Authorisation

22.08.2007

10. Date Of Revision Of The Text

23.05.2011

Detailed information on this product is available on the website of the European Medicines Agency http://www.ema.europa.eu

LEGAL CATEGORY

POM

Rozex Cream

1. Name Of The Medicinal Product

Rozex Cream

2. Qualitative And Quantitative Composition

Metronidazole Ph. Eur 0.75% w/w

3. Pharmaceutical Form

Cream

4. Clinical Particulars

4.1 Therapeutic Indications

Indicated in the treatment of inflammatory papules, pustules and erythema of rosacea

4.2 Posology And Method Of Administration

For topical administration only.

The average period of treatment is three to four months. The recommended duration of treatment should not be exceeded. However, if a clear benefit has been demonstrated, continued therapy for a further three to four months period may be considered by the prescribing physician depending on the severity of the condition. In clinical studies, topical metronidazole therapy for rosacea has been continued for up to 2 years. In the absence of a clear clinical improvement, therapy should be stopped.

Adults: Rozex Cream should be applied in a thin layer to the affected areas of the skin twice daily, morning and evening. Areas to be treated should be washed with a mild cleanser before application. Patients may use non-comedogenic and non-astringent cosmetics after application of Rozex Cream.

Elderly: The dosage recommended in the elderly is the same as that recommended in adults.

Children: Not recommended. Safety and efficacy have not been established.

4.3 Contraindications

Contraindicated in individuals with a history of hypersensitivity to Metronidazole, or other ingredients of the formulation.

4.4 Special Warnings And Precautions For Use

Contact with mucous membranes should be avoided.

Rozex Cream has been reported to cause lacrimation of the eyes, therefore, contact with the eyes should be avoided. If a reaction suggesting local irritation occurs patients should be directed to use the medication less frequently or discontinue use temporarily and to seek medical advice if necessary. Metronidazole is a nitroimidazole and should be used with care in patients with evidence of, or history of, blood dyscrasia. Exposure of treated sites to ultraviolet (e.g. solarium, sun-lamp) or strong sunlight (including sun-bathing) should be avoided during use of metronidazole. Unnecessary and prolonged use of this medication should be avoided.

Evidence suggests that metronidazole is carcinogenic in certain animal species. There is no evidence to date of a carcinogenic effect in human (see section 5.3).

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Interaction with systemic medication is unlikely because absorption of metronidazole following cutaneous application of Rozex Cream is low. Nevertheless, it should be mentioned that disulfiram-like reactions have been reported in a small number of patients taking metronidazole and alcohol concomitantly. Oral metronidazole has been reported to potentiate the effect of warfarin and other coumarin anticoagulants, resulting in a prolongation of prothrombin time. The effect of topical metronidazole on prothrombin is not known. However, very rare cases of modification of the INR values have been reported with concomitant use of Rozex and coumarin anticoagulants.

4.6 Pregnancy And Lactation

There is no experience to date with the use of Rozex Cream in pregnancy. In case of oral administration, metronidazole crosses the placental barrier and rapidly enters the foetal circulation. No foetotoxicity was observed after oral metronidazole in either rats or mice. However because animal reproduction studies are not always predictive of human response and since oral metronidazole has been shown to be a carcinogen in some rodents this drug should be used in pregnancy only if clearly needed.

After oral administration, Metronidazole is excreted in breast milk in concentrations similar to those found in the plasma. Even though Metronidazole blood levels from topical administration are significantly lower than those achieved after oral administration, in nursing mothers a decision should be made to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

4.7 Effects On Ability To Drive And Use Machines

Based upon the pharmacodynamic profile and clinical experience performance related to driving and using machines should not be affected.

4.8 Undesirable Effects

Because of the minimal absorption of metronidazole and consequently its insignificant plasma concentration after topical administration, the adverse experiences reported with the oral form of the drug have not been reported with Rozex Cream. Adverse reactions reported with Rozex Cream have been only local and mild.

The following spontaneous adverse experiences have been reported, and within each system organ class, are ranked by frequency, using the following convention:

Very common (

Common (

Uncommon (

Rare (

Very rare (<1/10,000), including isolated reports

Skin and subcutaneous tissue disorders:

Common: dry skin, erythema, pruritus, skin discomfort (burning, pain of skin/stinging), skin irritation, worsening of rosacea.

Unknown frequency: contact dermatitis

Nervous System disorders:

Uncommon: hypothesia, paraesthesia, dysgeusia (metallic taste)

Gastrointestinal disorders:

Uncommon: nausea

Watery eyes have been reported if applied too closely to this area.

4.9 Overdose

No data exists about overdosage in humans. Acute oral toxicity studies with a topical gel formulation containing 0.75% w/w metronidazole in rats have shown no toxic action with doses of up to 5 g of finished product per kilogram body weight, the highest dose used. This dose is equivalent to the oral intake of 12 tubes of 30g packaging Rozex Cream for an adult weighing 72 kg, and 2 tubes of Cream for a child weighing 12 kg.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Metronidazole is an antiprotozoal and antibacterial agent which is active against a wide range of pathogenic micro-organisms. The mechanisms of action of metronidazole in rosacea are unknown but available evidence suggests that the effects may be antibacterial and/or anti-inflammatory.

5.2 Pharmacokinetic Properties

Metronidazole is rapidly and nearly totally absorbed after oral administration. The drug is not significantly bound to serum proteins and distributes well to all body compartments with the lowest concentration found in the fat. Metronidazole is excreted primarily in the urine as parent drug, oxidative metabolites and conjugates.

Bioavailability studies with a topical 1g application of Rozex Cream to the face of normal subjects resulted in mean maximum serum concentrations of 32.9ng/ml (range 14.8 to 54.4ng/ml) which is approximately 100 times less than those attained after a single oral dose of 250 mg (mean Cmax = 7248ng/ml; range 4270 – 13970ng/ml). The peak concentration occurred between 0.25 – 4 hours after oral dosing, and 6 to 24 hours after cutaneous application of Rozex Cream.

Following topical application of Rozex Cream, serum concentrations of the major metabolite (the hydroxymetabolite 2-hydroxymethylmetronidazole) were below the quantifiable limit of the assay (<9.6ng/ml) at most of the time points, ranging to a maximum of 17.5ng/ml peak concentration between 8 and 24 hours after application. In comparison, the peak concentration following a 250mg oral dose ranged from 626 to 1788ng/ml between 4 and 12 hours after dosing.

The extent of exposure (Area under the curve, AUC) from a 1g application of metronidazole administered topically was 1.36% of the AUC of a single oral 250mg metronidazole dose (mean + 912.7ng.hr/ml and approximately 67207ng.ml/hr respectively).

5.3 Preclinical Safety Data

No evidence for a primary dermal irritation was observed in rabbits following a single 24-hour cutaneous application of Rozex Cream to abraded and non-abraded skin, under occlusion.

Metronidazole has shown mutagenic activity in several in vitro bacterial assay systems. In addition, a dose-response increase in the frequency of micronuclei was observed in mice after intraperitoneal injection and an increase in chromosome aberrations have been reported in patients with Crohn's disease who were treated with 200 to 1200mg/day of oral metronidazole for 1 to 24 months. However, the preponderance of evidence from these studies suggests that although metronidazole has a potential for producing mutations, this should not occur in well oxygenated mammalian cells, i.e., under normal aerobic conditions.

The carcinogenicity of metronidazole by the oral route of administration has been evaluated in rats, mice and hamsters. These studies showed that oral metronidazole caused an increased incidence of pulmonary tumours in mice and possibly other tumours, including liver tumours, in the rat. Conversely, two lifetime studies in hamsters produced negative results. Moreover, one study showed a significant enhancement of UV-induced skin tumours in hairless mice treated with metronidazole intraperitoneally (15μg per g body weight and per day for 28 weeks).

Although the significance of these results to the cutaneous use of metronidazole for the treatment of rosacea is unclear, patients should be advised to avoid or minimise exposure of metronidazole cream-treated sites to sun. After several decades of systemic use, no evidence has been published to suggest that metronidazole is associated with carcinogenic potential in humans.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Emulsifying Wax, Benzyl alcohol, Isopropyl palmitate, Glycerol, Sorbitol 70% (non-crystallising), lactic acid and/or Sodium Hydroxide, Purified Water.

6.2 Incompatibilities

None known

6.3 Shelf Life

Rozex Cream has a shelf life when unopened of 36 months

6.4 Special Precautions For Storage

Store at a temperature not exceeding 25°C. Do not refrigerate.

6.5 Nature And Contents Of Container

Aluminium tubes with epoxy phenolic lining, fitted with white polypropylene screw caps; pack sizes: 30g, 40g & 50g

6.6 Special Precautions For Disposal And Other Handling

Replace cap tightly after use.

7. Marketing Authorisation Holder

Galderma (UK.) Limited

Meridien House

69-71 Clarendon Road

Watford

Herts.

WD17 1DS

UK

8. Marketing Authorisation Number(S)

PL 10590/0028

9. Date Of First Authorisation/Renewal Of The Authorisation

18^th June 1997

10. Date Of Revision Of The Text

December 2010

Rhinolast Nasal Spray

1. Name Of The Medicinal Product

Rhinolast® Nasal Spray

2. Qualitative And Quantitative Composition

Azelastine Hydrochloride 0.1% w/v

3. Pharmaceutical Form

Nasal spray

4. Clinical Particulars

4.1 Therapeutic Indications

For the treatment of both seasonal allergic rhinitis (e.g. hayfever)

and perennial allergic rhinitis.

4.2 Posology And Method Of Administration

Route of application is topical - nasal mucosa.

Adults

One application (0.14 ml) in each nostril twice daily (0.56 mg of azelastine hydrochloride).

Elderly

There have been no specific studies in the elderly.

Children

For children aged 5 years and older, one application (0.14 ml) in each nostril twice daily (0.56 mg of azelastine hydrochloride).

4.3 Contraindications

Proven allergy against azelastine hydrochloride.

4.4 Special Warnings And Precautions For Use

None.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

No specific interactions have been studied.

4.6 Pregnancy And Lactation

At high oral doses in animals, 500 times the proposed oral human daily dose, foetal death, growth retardation and an increased incidence of skeletal abnormalities occurred during reproduction toxicity testing. Due to the nasal route of administration and the low dose administered, minimal systemic exposure can be expected. However as with all medicines caution should be exercised with use during pregnancy and lactation.

4.7 Effects On Ability To Drive And Use Machines

None.

4.8 Undesirable Effects

In rare cases, a mild, transient irritation of the inflamed nasal mucosa may occur, with symptoms such as stinging, itching, sneezing and epistaxis.

More frequently a substance-specific bitter taste may be experienced after administration (often due to incorrect method of application, namely tilting the head too far backwards during administration) which, in rare cases, may lead to nausea.

4.9 Overdose

The results of animal studies show that toxic doses can produce CNS symptoms, e.g. excitation, tremor, convulsions. Should these occur in humans, symptomatic and supportive treatment should be instigated as there is no specific antidote. Gastric lavage is recommended if the overdose is recent.

With the nasal route of administration overdosage reactions are not anticipated.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Azelastine, a phthalazinone derivative of novel structure, is classified as a potent long acting anti-allergic compound with particularly strong H1 antagonist properties.

Data from animal studies show that where high levels of azelastine are achieved both inhibition and release of chemical mediators (e.g. leukotriene, histamine, serotonin) involved in allergic reaction occurs.

5.2 Pharmacokinetic Properties

After repeated nasal application (0.14 mg) into each nostril twice daily, the plasma levels of azelastine were about 0.26 ng/ml. The levels of the active metabolite desmethylazelastine were detected at or below the lower limit of quantification (0.12 ng/ml).

After repeated oral administration, the mean C_max steady state plasma levels were determined giving 3.9 ng/ml for azelastine and 1.86 ng/ml for desmethylazelastine after 2.2 mg b.i.d. azelastine which represents the therapeutic oral dose for the treatment of allergic rhinitis.

Following oral administration azelastine is rapidly absorbed showing an absolute bioavailability of 81%. Food has no influence on absorption. The volume of distribution is high indicating distribution predominantly to the peripheral tissues. The level of protein binding is low (80-95%, a level too low to give concern over drug displacement reactions).

Plasma elimination half lives after a single dose of azelastine are approximately 20 hours for azelastine and about 45 hours for N-desmethylazelastine (a therapeutically active metabolite). Excretion occurs mainly via the faeces. The sustained excretion of small amounts of the dose in the faeces suggest that some enterohepatic circulation may take place.

5.3 Preclinical Safety Data

Nothing relevant.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Hypromellose, disodium edetate, , citric acid anhydrous, disodium phosphate dodecahydrate, sodium chloride, purified water.

6.2 Incompatibilities

None.

6.3 Shelf Life

Three years unopened.

6.4 Special Precautions For Storage

Do not store below 8°C. Do not refrigerate.

6.5 Nature And Contents Of Container

Polyethylene bottle with polypropylene cap and polyethylene seal containing either 10 ml or 20 ml.

Glass bottle with screw closure and polypropylene seal containing 10 ml, 20 ml or 22 ml.

Glass bottle with pump attached containing 10 ml, 20 ml or 22 ml.

10 ml glass bottle with pump attached, containing 5 ml aqueous solution.

10 ml polyethylene bottle with polypropylene cap and polyethylene seal, containing 5 ml aqueous solution.

6.6 Special Precautions For Disposal And Other Handling

For separate bottle and pump

Open the bottle by unscrewing the cap. Place the spray pump nozzle in the bottle and screw the pump onto the bottle. Remove the protective cap. Before first using, squeeze down the collar several times until an even spray emerges. The Rhinolast spray is now ready to use.

For attached pump and bottle

Remove the protective cap. Before first using, squeeze down the collar several times until an even spray emerges. The Rhinolast spray is now ready to use.

Discard product six months after first opening.

7. Marketing Authorisation Holder

Meda Pharmaceuticals Ltd

249 West George Street

Glasgow

G2 4RB

Trading as:

Meda Pharmaceuticals Ltd

Skyway House

Parsonage Road

Takeley

Bishop's Stortford

CM22 6PU

UK

8. Marketing Authorisation Number(S)

PL 15142/0037

9. Date Of First Authorisation/Renewal Of The Authorisation

14^th August 2009

10. Date Of Revision Of The Text

Rivastigmine Sandoz 4.5 mg hard capsules

1. Name Of The Medicinal Product

Rivastigmine Sandoz 4.5 mg hard capsules

2. Qualitative And Quantitative Composition

Each capsule contains rivastigmine hydrogen tartrate corresponding to rivastigmine 4.5 mg.

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Hard capsule

Off-white to slightly yellow powder in a capsule with red cap and red body, with white imprint “RIV 4.5 mg” on the body.

4. Clinical Particulars

4.1 Therapeutic Indications

Symptomatic treatment of mild to moderately severe Alzheimer's dementia.

Symptomatic treatment of mild to moderately severe dementia in patients with idiopathic Parkinson's disease.

4.2 Posology And Method Of Administration

Treatment should be initiated and supervised by a physician experienced in the diagnosis and treatment of Alzheimer's dementia or dementia associated with Parkinson's disease. Diagnosis should be made according to current guidelines. Therapy with rivastigmine should only be started if a caregiver is available who will regularly monitor intake of the medicinal product by the patient.

Rivastigmine should be administered twice a day, with morning and evening meals. The capsules should be swallowed whole.

Initial dose

1.5 mg twice a day.

Dose titration

The starting dose is 1.5 mg twice a day. If this dose is well tolerated after a minimum of two weeks of treatment, the dose may be increased to 3 mg twice a day. Subsequent increases to 4.5 mg and then 6 mg twice a day should also be based on good tolerability of the current dose and may be considered after a minimum of two weeks of treatment at that dose level.

If adverse reactions (e.g. nausea, vomiting, abdominal pain or loss of appetite), weight decrease or worsening of extrapyramidal symptoms (e.g. tremor) in patients with dementia associated with Parkinson's disease are observed during treatment, these may respond to omitting one or more doses. If adverse reactions persist, the daily dose should be temporarily reduced to the previous well-tolerated dose or the treatment may be discontinued.

Maintenance dose

The effective dose is 3 to 6 mg twice a day; to achieve maximum therapeutic benefit patients should be maintained on their highest well tolerated dose. The recommended maximum daily dose is 6 mg twice a day.

Maintenance treatment can be continued for as long as a therapeutic benefit for the patient exists. Therefore, the clinical benefit of rivastigmine should be reassessed on a regular basis, especially for patients treated at doses less than 3 mg twice a day. If after 3 months of maintenance dose treatment the patient's rate of decline in dementia symptoms is not altered favourably, the treatment should be discontinued. Discontinuation should also be considered when evidence of a therapeutic effect is no longer present.

Individual response to rivastigmine cannot be predicted. However, a greater treatment effect was seen in Parkinson's disease patients with moderate dementia. Similarly a larger effect was observed in Parkinson's disease patients with visual hallucinations (see section 5.1).

Treatment effect has not been studied in placebo-controlled trials beyond 6 months.

Re-initiation of therapy

If treatment is interrupted for more than several days, it should be re-initiated at 1.5 mg twice daily. Dose titration should then be carried out as described above.

Renal and hepatic impairment

Due to increased exposure in moderate renal and mild to moderate hepatic impairment, dosing recommendations to titrate according to individual tolerability should be closely followed (see section 5.2).

Patients with severe liver impairment have not been studied (see section 4.3).

Children

Rivastigmine is not recommended for use in children.

4.3 Contraindications

The use of this medicinal product is contraindicated in patients with

- hypersensitivity to the active substance, other carbamate derivatives or to any of the excipients used in the formulation,

- severe liver impairment, as it has not been studied in this population.

4.4 Special Warnings And Precautions For Use

The incidence and severity of adverse reactions generally increase with higher doses. If treatment is interrupted for more than several days, it should be re-initiated at 1.5 mg twice daily to reduce the possibility of adverse reactions (e.g. vomiting).

Dose titration: Adverse reactions (e.g. hypertension and hallucinations in patients with Alzheimer's dementia and worsening of extrapyramidal symptoms, in particular tremor, in patients with dementia associated with Parkinson's disease) have been observed shortly after dose increase. They may respond to a dose reduction. In other cases, rivastigmine has been discontinued (see section 4.8).

Gastrointestinal disorders such as nausea and vomiting may occur particularly when initiating treatment and/or increasing the dose. These adverse reactions occur more commonly in women. Patients with Alzheimer's disease may lose weight. Cholinesterase inhibitors, including rivastigmine, have been associated with weight loss in these patients. During therapy patient's weight should be monitored.

In case of severe vomiting associated with rivastigmine treatment, appropriate dose adjustments as recommended in section 4.2 must be made. Some cases of severe vomiting were associated with oesophageal rupture (see section 4.8). Such events appeared to occur particularly after dose increments or high doses of rivastigmine.

Care must be taken when using rivastigmine in patients with sick sinus syndrome or conduction defects (sino-atrial block, atrio-ventricular block) (see section 4.8).

Rivastigmine may cause increased gastric acid secretions. Care should be exercised in treating patients with active gastric or duodenal ulcers or patients predisposed to these conditions.

Cholinesterase inhibitors should be prescribed with care to patients with a history of asthma or obstructive pulmonary disease.

Cholinomimetics may induce or exacerbate urinary obstruction and seizures. Caution is recommended in treating patients predisposed to such diseases.

The use of rivastigmine in patients with severe dementia of Alzheimer's disease or associated with Parkinson's disease, other types of dementia or other types of memory impairment (e.g. age-related cognitive decline) has not been investigated and therefore use in these patient populations is not recommended.

Like other cholinomimetics, rivastigmine may exacerbate or induce extrapyramidal symptoms. Worsening (including bradykinesia, dyskinesia, gait abnormality) and an increased incidence or severity of tremor have been observed in patients with dementia associated with Parkinson's disease (see section 4.8). These events led to the discontinuation of rivastigmine in some cases (e.g. discontinuations due to tremor 1.7% on rivastigmine vs 0% on placebo). Clinical monitoring is recommended for these adverse reactions.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

As a cholinesterase inhibitor, rivastigmine may exaggerate the effects of succinylcholine-type muscle relaxants during anaesthesia. Caution is recommended when selecting anaesthetic agents. Possible dose adjustments or temporarily stopping treatment can be considered if needed.

In view of its pharmacodynamic effects, rivastigmine should not be given concomitantly with other cholinomimetic substances and might interfere with the activity of anticholinergic medicinal products.

No pharmacokinetic interaction was observed between rivastigmine and digoxin, warfarin, diazepam or fluoxetine in studies in healthy volunteers. The increase in prothrombin time induced by warfarin is not affected by administration of rivastigmine. No untoward effects on cardiac conduction were observed following concomitant administration of digoxin and rivastigmine.

According to its metabolism, metabolic interactions with other medicinal products appear unlikely, although rivastigmine may inhibit the butyrylcholinesterase mediated metabolism of other substances.

4.6 Pregnancy And Lactation

For rivastigmine no clinical data on exposed pregnancies are available. No effects on fertility or embryofoetal development were observed in rats and rabbits, except at doses related to maternal toxicity. In peri/postnatal studies in rats, an increased gestation time was observed. Rivastigmine should not be used during pregnancy unless clearly necessary.

In animals, rivastigmine is excreted into milk. It is not known if rivastigmine is excreted into human milk. Therefore, women on rivastigmine should not breast-feed.

4.7 Effects On Ability To Drive And Use Machines

Alzheimer's disease may cause gradual impairment of driving performance or compromise the ability to use machinery. Furthermore, rivastigmine can induce dizziness and somnolence, mainly when initiating treatment or increasing the dose. As a consequence, rivastigmine has minor or moderate influence on the ability to drive and use machines. Therefore, the ability of patients with dementia on rivastigmine to continue driving or operating complex machines should be routinely evaluated by the treating physician.

4.8 Undesirable Effects

The most commonly reported adverse reactions are gastrointestinal, including nausea (38%) and vomiting (23%), especially during titration. Female patients in clinical studies were found to be more susceptible than male patients to gastrointestinal adverse reactions and weight loss.

The following adverse reactions, listed below in Table 1, have been accumulated in patients with Alzheimer's dementia treated with rivastigmine.

Adverse reactions in Table 1 are listed according to MedDRA system organ class and frequency category. Frequency categories are defined using the following convention: very common (

Table 1

Infections and infestations Very rare	Urinary infection
Metabolism and nutritional disorders Very common	Anorexia
Psychiatric disorders Common Common Uncommon Uncommon Very rare	Agitation Confusion Insomnia Depression Hallucinations
Nervous system disorders Very common Common Common Common Uncommon Rare Very rare	Dizziness Headache Somnolence Tremor Syncope Seizures Extrapyramidal symptoms (including worsening of Parkinson's disease)
Cardiac disorders Rare Very rare	Angina pectoris Cardiac arrhythmia (e.g. bradycardia, atrio-ventricular block, atrial fibrillation and tachycardia)
Vascular disorders Very rare	Hypertension
Gastrointestinal disorders Very common Very common Very common Common Rare Very rare Very rare Not known	Nausea Vomiting Diarrhoea Abdominal pain and dyspepsia Gastric and duodenal ulcers Gastrointestinal haemorrhage Pancreatitis Some cases of severe vomiting were associated with oesophageal rupture (see section 4.4).
Hepatobiliary disorders Uncommon	Elevated liver function tests
Skin and subcutaneous tissue disorders Common Rare Not known	Sweating increased Rash Pruritus
General disorders and administration site conditions Common Common Uncommon	Fatigue and asthenia Malaise Accidental fall
Investigations Common	Weight loss

The following additional adverse reactions have been observed with rivastigmine transdermal patches: anxiety, delirium, pyrexia (common).

Table 2 shows the adverse reactions reported in patients with dementia associated with Parkinson's disease treated with rivastigmine.

Table 2

Metabolism and nutritional disorders Common Common	Anorexia Dehydration
Psychiatric disorders Common Common Common	Insomnia Anxiety Restlessness
Nervous system disorders Very common Common Common Common Common Common Common Uncommon	Tremor Dizziness Somnolence Headache Worsening of Parkinson's disease Bradykinesia Dyskinesia Dystonia
Cardiac disorders Common Uncommon Uncommon	Bradycardia Arial fibrillation Atrioventricular block
Gastrointestinal disorders Very common Very common Common Common Common	Nausea Vomiting Diarrhoea Abdominal pain and dyspepsia Salivary hypersecretion
Skin and subcutaneous tissue disorders Common	Sweating increased
Musculoskeletal and connective tissue disorders Common	Muscle rigidity
General disorders and administration site conditions Common Common	Fatigue and asthenia Gait abnormality

Table 3 lists the number and percentage of patients from the specific 24-week clinical study conducted with rivastigmine in patients with dementia associated with Parkinson's disease with pre-defined adverse events that may reflect worsening of parkinsonian symptoms.

Table 3

Pre-defined adverse events that may reflect worsening of parkinsonian symptoms in patients with dementia associated with Parkinson's disease	Rivastigmine n (%)	Placebo n (%)
Total patients studied Total patients with pre-defined AE(s)	362 (100) 99 (27.3)	179 (100) 28 (15.6)
Tremor Fall Parkinson's disease (worsening) Salivary hypersecretion Dyskinesia Parkinsonism Hypokinesia Movement disorder Bradykinesia Dystonia Gait abnormality Muscle rigidity Balance disorder Musculoskeletal stiffness Rigors Motor dysfunction	37 (10.2) 21 (5.8) 12 (3.3) 5 (1.4) 5 (1.4) 8 (2.2) 1 (0.3) 1 (0.3) 9 (2.5) 3 (0.8) 5 (1.4) 1 (0.3) 3 (0.8) 3 (0.8) 1 (0.3) 1 (0.3)	7 (3.9) 11 (6.1) 2 (1.1) 0 1 (0.6) 1 (0.6) 0 0 3 (1.7) 1 (0.6) 0 0 2 (1.1) 0 0 0

4.9 Overdose

Symptoms

Most cases of accidental overdose have not been associated with any clinical signs or symptoms and almost all of the patients concerned continued rivastigmine treatment. Where symptoms have occurred, they have included nausea, vomiting and diarrhoea, hypertension or hallucinations. Due to the known vagotonic effect of cholinesterase inhibitors on heart rate, bradycardia and/or syncope may also occur. Ingestion of 46 mg occurred in one case; following conservative management the patient fully recovered within 24 hours.

Treatment

As rivastigmine has a plasma half-life of about 1 hour and a duration of acetylcholinesterase inhibition of about 9 hours, it is recommended that in cases of asymptomatic overdose no further dose of rivastigmine should be administered for the next 24 hours. In overdose accompanied by severe nausea and vomiting, the use of antiemetics should be considered. Symptomatic treatment for other adverse reactions should be given as necessary.

In massive overdose, atropine can be used. An initial dose of 0.03 mg/kg intravenous atropine sulphate is recommended, with subsequent doses based on clinical response. Use of scopolamine as an antidote is not recommended.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: anticholinesterases, ATC code: N06DA03

Rivastigmine is an acetyl- and butyrylcholinesterase inhibitor of the carbamate type, thought to facilitate cholinergic neurotransmission by slowing the degradation of acetylcholine released by functionally intact cholinergic neurones. Thus, rivastigmine may have an ameliorative effect on cholinergic-mediated cognitive deficits in dementia associated with Alzheimer's disease and Parkinson's disease.

Rivastigmine interacts with its target enzymes by forming a covalently bound complex that temporarily inactivates the enzymes. In healthy young men, an oral 3 mg dose decreases acetylcholinesterase (AChE) activity in CSF by approximately 40% within the first 1.5 hours after administration. Activity of the enzyme returns to baseline levels about 9 hours after the maximum inhibitory effect has been achieved. In patients with Alzheimer's disease, inhibition of AChE in CSF by rivastigmine was dose-dependent up to 6 mg given twice daily, the highest dose tested. Inhibition of butyrylcholinesterase activity in CSF of 14 Alzheimer patients treated by rivastigmine was similar to that of AChE.

Clinical studies in Alzheimer's dementia

The efficacy of rivastigmine has been established through the use of three independent, domain specific, assessment tools which were assessed at periodic intervals during 6 month treatment periods. These include the ADAS-Cog (a performance based measure of cognition), the CIBIC-Plus (a comprehensive global assessment of the patient by the physician incorporating caregiver input), and the PDS (a caregiver-rated assessment of the activities of daily living including personal hygiene, feeding, dressing, household chores such as shopping, retention of ability to orient oneself to surroundings as well as involvement in activities relating to finances, etc.).

The patients studied had an MMSE (Mini-Mental State Examination) score of 10–24.

The results for clinically relevant responders pooled from two flexible dose studies out of the three pivotal 26-week multicentre studies in patients with mild-to-moderately severe Alzheimer's Dementia, are provided in Table 4 below. Clinically relevant improvement in these studies was defined a priori as at least 4-point improvement on the ADAS-Cog, improvement on the CIBIC-Plus, or at least a 10% improvement on the PDS.

In addition, a post-hoc definition of response is provided in the same table. The secondary definition of response required a 4-point or greater improvement on the ADAS-Cog, no worsening on the CIBIC-Plus, and no worsening on the PDS. The mean actual daily dose for responders in the 6-12 mg group, corresponding to this definition, was 9.3 mg. It is important to note that the scales used in this indication vary and direct comparisons of results for different therapeutic agents are not valid.

Table 4

	Patients with Clinically Significant Response (%)
	Intent to Treat	Last Observation Carried Forward
Response Measure	Rivastigmine 6–12 mg N=473	Placebo N=472	Rivastigmine 6–12 mg N=379	Placebo N=444
ADAS-Cog: improvement of at least 4 points	21***	12	25***	12
CIBIC-Plus: improvement	29***	18	32***	19
PDS: improvement of at least 10%	26***	17	30***	18
At least 4 points improvement on ADAS-Cog with no worsening on CIBIC-Plus and PDS	10*	6	12**	6

*p<0.05, **p<0.01, ***p<0.001

Clinical studies in dementia associated with Parkinson's disease

The efficacy of rivastigmine in dementia associated with Parkinson's disease has been demonstrated in a 24-week multicentre, double-blind, placebo-controlled core study and its 24-week open-label extension phase. Patients involved in this study had an MMSE (Mini-Mental State Examination) score of 10–24. Efficacy has been established by the use of two independent scales which were assessed at regular intervals during a 6-month treatment period as shown in Table 5 below: the ADAS-Cog, a measure of cognition, and the global measure ADCS-CGIC (Alzheimer's Disease Cooperative Study-Clinician's Global Impression of Change).

Table 5

Dementia associated with Parkinson's Disease	ADAS-Cog Rivastigmine	ADAS-Cog Placebo	ADCS-CGIC Rivastigmine	ADCS-CGIC Placebo
ITT + RDO population Mean baseline ± SD Mean change at 24 weeks ± SD	(n=329) 23.8 ± 10.2 2.1 ± 8.2	(n=161) 24.3 ± 10.5 -0.7 ± 7.5	(n=329) n/a 3.8 ± 1.4	(n=165) n/a 4.3 ± 1.5
Adjusted treatment difference p-value versus placebo	2.881 <0.0011	n/a 0.0072
ITT - LOCF population Mean baseline ± SD Mean change at 24 weeks ± SD	(n=287) 24.0 ± 10.3 2.5 ± 8.4	(n=154) 24.5 ± 10.6 -0.8 ± 7.5	(n=289) n/a 3.7 ± 1.4	(n=158) n/a 4.3 ± 1.5
Adjusted treatment difference p-value versus placebo	3.541 <0.0011	n/a <0.0012

¹ Based on ANCOVA with treatment and country as factors and baseline ADAS-Cog as a covariate. A positive change indicates improvement.

² Mean data shown for convenience, categorical analysis performed using van Elteren test

ITT: Intent-To-Treat; RDO: Retrieved Drop Outs; LOCF: Last Observation Carried Forward

Although a treatment effect was demonstrated in the overall study population, the data suggested that a larger treatment effect relative to placebo was seen in the subgroup of patients with moderate dementia associated with Parkinson's disease. Similarly a larger treatment effect was observed in those patients with visual hallucinations (see Table 6).

Table 6

Dementia associated with Parkinson's Disease	ADAS-Cog Rivastigmine	ADAS-Cog Placebo	ADAS-Cog Rivastigmine	ADAS-Cog Placebo
	Patients with visual hallucinations	Patients without visual hallucinations
ITT + RDO population Mean baseline ± SD Mean change at 24 weeks ± SD	(n=107) 25.4 ± 9.9 1.0 ± 9.2	(n=60) 27.4 ± 10.4 -2.1 ± 8.3	(n=220) 23.1 ± 10.4 2.6 ± 7.6	(n=101) 22.5 ± 10.1 0.1 ± 6.9
Adjusted treatment difference p-value versus placebo	4.271 0.0021	2.091 0.0151
	Patients with moderate dementia (MMSE 10-17)	Patients with mild dementia (MMSE 18-24)
ITT + RDO population Mean baseline ± SD Mean change at 24 weeks ± SD	(n=87) 32.6 ± 10.4 2.6 ± 9.4	(n=44) 33.7 ± 10.3 -1.8 ± 7.2	(n=237) 20.6 ± 7.9 1.9 ± 7.7	(n=115) 20.7 ± 7.9 -0.2 ± 7.5
Adjusted treatment difference p-value versus placebo	4.731 0.0021	2.141 0.0101

¹ Based on ANCOVA with treatment and country as factors and baseline ADAS-Cog as a covariate. A positive change indicates improvement.

ITT: Intent-To-Treat; RDO: Retrieved Drop Outs

5.2 Pharmacokinetic Properties

Absorption

Rivastigmine is rapidly and completely absorbed. Peak plasma concentrations are reached in approximately 1 hour. As a consequence of rivastigmine's interaction with its target enzyme, the increase in bioavailability is about 1.5-fold greater than that expected from the increase in dose. Absolute bioavailability after a 3 mg dose is about 36%±13%. Administration of rivastigmine with food delays absorption (t_max) by 90 min and lowers C_max and increases AUC by approximately 30%.

Distribution

Protein binding of rivastigmine is approximately 40%. It readily crosses the blood brain barrier and has an apparent volume of distribution in the range of 1.8–2.7 l/kg.

Metabolism

Rivastigmine is rapidly and extensively metabolised (half-life in plasma approximately 1 hour), primarily via cholinesterase-mediated hydrolysis to the decarbamylated metabolite. In vitro, this metabolite shows minimal inhibition of acetylcholinesterase (<10%). Based on evidence from in vitro and animal studies the major cytochrome P450 isoenzymes are minimally involved in rivastigmine metabolism. Total plasma clearance of rivastigmine was approximately 130 l/h after a 0.2 mg intravenous dose and decreased to 70 l/h after a 2.7 mg intravenous dose.

Excretion

Unchanged rivastigmine is not found in the urine; renal excretion of the metabolites is the major route of elimination. Following administration of ¹⁴C-rivastigmine, renal elimination was rapid and essentially complete (>90%) within 24 hours. Less than 1% of the administered dose is excreted in the faeces. There is no accumulation of rivastigmine or the decarbamylated metabolite in patients with Alzheimer's disease.

Elderly subjects

While bioavailability of rivastigmine is greater in elderly than in young healthy volunteers, studies in Alzheimer patients aged between 50 and 92 years showed no change in bioavailability with age.

Subjects with hepatic impairment

The C_max of rivastigmine was approximately 60% higher and the AUC of rivastigmine was more than twice as high in subjects with mild to moderate hepatic impairment than in healthy subjects.

Subjects with renal impairment

C_max and AUC of rivastigmine were more than twice as high in subjects with moderate renal impairment compared with healthy subjects; however there were no changes in C_max and AUC of rivastigmine in subjects with severe renal impairment.

5.3 Preclinical Safety Data

Repeated-dose toxicity studies in rats, mice and dogs revealed only effects associated with an exaggerated pharmacological action. No target organ toxicity was observed. No safety margins to human exposure were achieved in the animal studies due to the sensitivity of the animal models used.

Rivastigmine was not mutagenic in a standard battery of in vitro and in vivo tests, except in a chromosomal aberration test in human peripheral lymphocytes at a dose 10⁴ times the maximum clinical exposure. The in vivo micronucleus test was negative.

No evidence of carcinogenicity was found in studies in mice and rats at the maximum tolerated dose, although the exposure to rivastigmine and its metabolites was lower than the human exposure. When normalised to body surface area, the exposure to rivastigmine and its metabolites was approximately equivalent to the maximum recommended human dose of 12 mg/day; however, when compared to the maximum human dose, a multiple of approximately 6-fold was achieved in animals.

In animals, rivastigmine crosses the placenta and is excreted into milk. Oral studies in pregnant rats and rabbits gave no indication of teratogenic potential on the part of rivastigmine.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Gelatin

Magnesium stearate

Hypromellose

Microcrystalline cellulose

Silica, colloidal anhydrous

Yellow iron oxide (E172)

Red iron oxide (E172)

Titanium dioxide (E171)

6.2 Incompatibilities

Not applicable.

6.3 Shelf Life

5 years

6.4 Special Precautions For Storage

Do not store above 30°C.

6.5 Nature And Contents