Ruconest 2100 U powder for solution for injection

1. Name Of The Medicinal Product

Ruconest 2100 U powder for solution for injection.

2. Qualitative And Quantitative Composition

One vial contains 2100 units of conestat alfa, corresponding to 2100 units per 14 ml after reconstitution, or a concentration of 150 units/ml.

Conestat alfa is the recombinant analogue of the human C1 esterase inhibitor (rhC1INH) produced by recombinant DNA technology in the milk of transgenic rabbits.

1 Unit of conestat alfa activity is defined as the equivalent of C1 esterase inhibiting activity present in 1 ml of pooled normal plasma.

For a full list of excipients, see section 6.1

3. Pharmaceutical Form

Powder for solution for injection.

White to off-white powder.

4. Clinical Particulars

4.1 Therapeutic Indications

Ruconest is indicated for treatment of acute angioedema attacks in adults with hereditary angioedema (HAE) due to C1 esterase inhibitor deficiency.

4.2 Posology And Method Of Administration

Ruconest should be initiated under the guidance and supervision of a physician experienced in the diagnosis and treatment of hereditary angioedema.

Ruconest should be administered by a healthcare professional.

Patients who have not previously received Ruconest should be tested for the presence of IgE antibodies against rabbit epithelium (dander) prior to initiation of Ruconest (see section 4.4).

Posology

- Adults up to 84 kg body weight

One intravenous injection of 50 U/kg body weight.

- Adults of 84 kg body weight or greater

One intravenous injection of 4200 U (two vials).

In the majority of cases a single dose of Ruconest is sufficient to treat an acute angioedema attack.

In case of an insufficient clinical response, an additional dose (50 U/kg body weight up to 4200 U) can be administered (see section 5.1).

Not more than two doses should be administered within 24 hours.

Dose calculation

Determine the patient's body weight.

- Adults up to 84 kg body weight

For patients up to 84 kg calculate the volume required to be administered according to the formula below:

- Adults of 84 kg body weight or greater

For patients of 84 kg or above the volume required to be administered is 28 ml, corresponding to 4200 U (2 vials).

Paediatric population

The safety and efficacy of Ruconest in children (age 0 to 12 years) has not yet been established. Currently available data on adolescents (age 13 to 17 years) are described in section 5.1, but no recommendation on a posology can be made.

Elderly (

Data in patients older than 65 years are limited.

There is no rationale for patients older than 65 years to respond differently to Ruconest.

Renal impairment

No dose adjustment is necessary in patients with renal impairment since conestat alfa does not undergo renal clearance.

Hepatic impairment

There is no clinical experience with Ruconest in patients with hepatic impairment. Hepatic impairment may prolong the plasma half-life of conestat alfa, but this is not thought to be a clinical concern. No recommendation on a dose adjustment can be made.

Method of Administration

For intravenous use.

For instructions on reconstitution of Ruconest before administration, see section 6.6.

The required volume of the reconstituted solution should be administered as a slow intravenous injection over approximately 5 minutes.

4.3 Contraindications

• Known or suspected allergy to rabbits (see section 4.4)

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

4.4 Special Warnings And Precautions For Use

Conestat alfa is derived from milk of transgenic rabbits and contains traces of rabbit protein. Before initiating treatment with Ruconest, patients should be tested for the presence of IgE antibodies against rabbit allergens using a validated test for IgE antibodies against rabbit epithelium (dander) e.g. ImmunoCap system, Phadia, Sweden. Only patients who have been shown to have negative results for such a test, should be treated with Ruconest. IgE antibody testing should be repeated once a year or after 10 treatments, whichever occurs first.

As with any intravenously administered protein product, hypersensitivity reactions cannot be excluded.

Patients must be closely monitored and carefully observed for any symptoms of hypersensitivity throughout the administration period. Patients should be informed of the early signs of hypersensitivity reactions including hives, generalised urticaria, tightness of the chest, wheezing, hypotension and anaphylaxis. If these symptoms occur after administration, they should alert their physician.

In case of anaphylactic reactions or shock, emergency medical treatment should be administered.

Although cross-reactivity between cow milk and rabbit milk is considered unlikely, the possibility of such a cross-reactivity in a patient who has evidence of clinical allergy to cow milk cannot be excluded.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

No drug-drug interaction studies have been performed.

Scientific literature indicates an interaction of tissue-type plasminogen activator (tPA) and C1INH containing medicinal products. Ruconest should not be administered simultaneously with tPA.

4.6 Pregnancy And Lactation

Pregnancy and breast-feeding

There is no experience with the use of Ruconest in pregnant and breast-feeding women.

In one animal study reproductive toxicity was observed (see section 5.3). Ruconest is not recommended for use during pregnancy or breast-feeding, unless the treating physician judges the benefits to outweigh the possible risks.

Fertility

There are no data on the effects of Ruconest on male or female fertility.

4.7 Effects On Ability To Drive And Use Machines

Based on the known pharmacology and adverse reaction profile of Ruconest, effects on the ability to drive and use machines are not expected. However headache or vertigo have been reported following the use of Ruconest, but may also occur as a result of an attack of HAE. Patients should be advised not to drive and use machines if they experience headache or vertigo.

4.8 Undesirable Effects

The clinical experience supporting safety of Ruconest consists of 300 administrations (83 administrations to healthy subjects or asymptomatic HAE patients and 217 administrations to 119 HAE patients). The table below lists all adverse reactions occurring within 7 days after treatment with Ruconest, as reported in the six treatment studies.

Adverse reactions were usually mild to moderate in severity. The incidence of adverse reactions was similar for all dose groups and did not increase upon repeated administrations.

The frequency of possible adverse reactions listed below is defined using the following convention:

Very common (

Common (

Uncommon (

Rare (

Very rare (<1/10,000),

Not known, frequency could not be estimated from the available data.

	Adverse reactions
Common	Uncommon
Nervous system disorders	Headache	Vertigo Paraesthesia
Respiratory, thoracic and mediastinal disorders		Throat irritation
Gastrointestinal disorders		Diarrhoea Nausea Abdominal discomfort Oral paraesthesia
Skin and subcutaneous tissue disorders		Urticaria
General disorders and administration site conditions		Swelling

4.9 Overdose

No clinical information on overdose is available.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group and ATC code: not yet assigned

The plasma protein C1INH is the main regulator of activation of the contact and complement systems in vivo. HAE patients have a heterozygous deficiency of the plasma protein C1INH. As a result they may suffer from uncontrolled activation of contact and complement systems, with formation of inflammatory mediators, which clinically becomes manifest as the occurrence of acute angioedema attacks.

Conestat alfa, recombinant human complement component 1 (C1) esterase inhibitor (rhC1INH), is an analogue of human C1INH and is obtained from the milk of rabbits expressing the gene encoding for human C1INH. The amino acid sequence of conestat alfa is identical to that of endogenous C1INH.

C1INH exerts an inhibitory effect on several proteases (target proteases) of the contact and complement systems. The effect of conestat alfa on the following target proteases was assessed in vitro: activated C1s, kallikrein, factor XIIa and factor XIa. Inhibition kinetics were found to be comparable with those observed for plasma-derived human C1INH.

The complement component (protein) C4, is a substrate for activated C1s. Patients with HAE have low levels of C4 in the circulation. As for plasma-derived C1INH, the pharmacodynamic effects of conestat alfa on C4 show dose-dependent restoration of complement homeostasis in HAE patients at a plasma C1INH activity level greater than 0.7 U/ml, which is the lower limit of the normal range. In HAE patients, Ruconest at a dose of 50 U/kg increases plasma C1INH activity level to greater than 0.7 U/ml for approximately 2 hours (see section 5.2).

The efficacy and safety of Ruconest as a treatment of acute angioedema attacks in patients with HAE has been evaluated in two double blind randomized placebo controlled and four open label clinical studies. The doses evaluated in the clinical studies ranged from a single vial of 2100 U (corresponding to 18-40 U/kg), to 50 and 100 U/kg. Efficacy of Ruconest as a treatment for acute angioedema attacks was demonstrated by significantly shorter time to beginning of relief of symptoms and time to minimal symptoms and few therapeutic failures. The table below shows the results (primary and secondary endpoints) of the two randomized controlled trials:

Study	Treatment	Time (minutes) to beginning of relief median (95% CI)	Time (minutes) to minimal symptoms median (95% CI)
C1-1205 RCT	100 U/kg n =13	68 (62, 132) p = 0.001	245 (125, 270) p = 0.04
50 U/kg n =12	122 (72, 136) p < 0.001	247 (243, 484)
Saline n = 13	258 (240, 720)	1101 (970, 1494)
C1-1304 RCT	100 U/kg n =16	62 (40, 75) p = 0.003	480 (243, 723) p = 0.005
Saline n = 16	508 (70, 720)	1440 (720, 2885)

The results of the open label studies were consistent with the above findings and support the repeated use of Ruconest in the treatment of subsequent attacks of angioedema.

In the randomized controlled trials 39/41 (95%) of patients treated with Ruconest reached time to beginning of relief within 4 hours. In an open label study 114/119 (95%) attacks treated with a single dose of 50 U/kg reached time to beginning of relief within 4 hours. An additional dose of 50 U/kg was administered for 13/133 (10%) attacks.

Paediatric population

Nine adolescent HAE patients (aged 13 to 17 years) were treated with 50 U/kg for 26 acute angioedema attacks, and 7 (aged 16 to 17 years) with 2100 U for 24 acute angioedema attacks.

The European Medicines Agency has deferred the obligation to submit the results of studies with Ruconest in one or more subsets of the paediatric population in treatment of acute angioedema attacks (see section 4.2 for information on paediatric use).

5.2 Pharmacokinetic Properties

Distribution

No formal distribution studies have been performed. The distribution volume of conestat alfa was approximately 3 L, comparable to plasma volume.

Biotransformation and elimination

Based on animal data, conestat alfa is cleared from the circulation by the liver via receptor-mediated endocytosis followed by complete hydrolysis/degradation.

After administration of Ruconest (50 U/kg) to asymptomatic HAE patients, a C_max of 1.36 U/ml was observed. The elimination half-life of conestat alfa was approximately 2 hours.

Excretion

There is no excretion, as conestat alfa is cleared from the circulation via receptor-mediated endocytosis followed by complete hydrolysis/degradation in the liver.

5.3 Preclinical Safety Data

Preclinical data do not indicate any safety concern for the use of conestat alfa in humans based on studies of safety pharmacology, single-dose toxicity, two-week sub-chronic toxicity and local tolerance in various animal species including rats, dogs, rabbits and cynomolgus monkeys. Genotoxic and carcinogenic potential is not expected.

Embryofetal studies in rat and rabbit; Daily single doses of vehicle or 625 U/kg/administration of rhC1INH were administered intravenously to mated rats and rabbits. In the study in rats there were no malformed fetuses in either the conestat alfa or the control group. In a rabbit embryotoxicity study an increase in the incidence of fetal cardiac vessel defects (1.12% in the treatment group versus 0.03% in historical controls) was observed for animals that were administered conestat alfa.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Sucrose

Sodium citrate (E331)

Citric acid (E330)

6.2 Incompatibilities

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.

6.3 Shelf Life

4 years.

Reconstituted solution

Chemical and physical in-use stability has been demonstrated for 48 hours between 5˚C and 25˚C. From a microbiological point of view, the medicinal product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2 to 8ºC, unless reconstitution has taken place in controlled and validated aseptic conditions.

6.4 Special Precautions For Storage

Do not store above 25°C.

Store in the original package in order to protect from light.

For storage conditions of the reconstituted medicinal product, see section 6.3.

6.5 Nature And Contents Of Container

2100 U of conestat alfa in a powder in a 25 ml vial (type 1 glass) with a stopper (siliconized chlorobutyl rubber) and a flip-off seal (aluminium and coloured plastic).

Pack size of 1.

6.6 Special Precautions For Disposal And Other Handling

Each vial of Ruconest is for single use only.

An aseptic technique should be used for reconstitution, combining and mixing the solutions.

Reconstitution

Each vial of Ruconest (2100 U) should be reconstitued with 14 ml water for injections. Water for injections should be added slowly to avoid forceful impact on the powder and mixed gently to avoid foaming of the solution. The reconstituted solution contains 150 U/ml conestat alfa and appears as a clear colourless solution.

The reconstituted solution in each vial should be visually inspected for particulate matter and discoloration. A solution exhibiting particulates or discoloration should not be used. The medicinal product should be used immediately (see section 6.3).

There are no special requirements for disposal.

7. Marketing Authorisation Holder

Pharming Group N.V.,

Darwinweg 24,

NL-2333 CR LEIDEN,

The Netherlands

8. Marketing Authorisation Number(S)

EU/1/10/641/001

9. Date Of First Authorisation/Renewal Of The Authorisation

Date of first authorisation: 28/10/2010

10. Date Of Revision Of The Text

08/2011

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

Ropinirole 0.5 mg Film-Coated Tablets (Actavis UK Ltd)

1. Name Of The Medicinal Product

Ropinirole 0.5 mg Film-Coated Tablets

2. Qualitative And Quantitative Composition

Each film-coated tablet contains ropinirole hydrochloride equivalent to 0.5 mg ropinirole base.

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Film-coated tablet.

Ropinirole 0.5 mg Film-Coated Tablets are yellow, round (7mm in diameter), biconvex, and embossed with R0.5 on one side.

4. Clinical Particulars

4.1 Therapeutic Indications

Ropinirole is indicated for the symptomatic treatment of moderate to severe idiopathic Restless Legs Syndrome (see Section 5.1).

4.2 Posology And Method Of Administration

Oral use.

Adults

Individual dose titration against efficacy and tolerability is recommended.

Ropinirole should be taken just before bedtime, however the dose can be taken up to 3 hours before retiring. Ropinirole may be taken with food, to improve gastrointestinal tolerance.

Treatment initiation (week 1)

The recommended initial dose is 0.25 mg once daily (administered as above) for 2 days. If this dose is well tolerated the dose should be increased to 0.5 mg once daily for the remainder of week 1.

Therapeutic regimen (week 2 onwards)

Following treatment initiation, the daily dose should be increased until optimal therapeutic response is achieved. The average dose in clinical trials, in patients with moderate to severe Restless Legs Syndrome, was 2.0 mg once a day.

The dose may be increased to 1.0 mg once a day at week 2. The dose may then be increased by 0.5 mg per week over the next two weeks to a dose of 2.0 mg once a day. In some patients, to achieve optimal improvement, the dose may be increased gradually up to a maximum of 4.0 mg once a day. In clinical trials the dose was increased by 0.5 mg each week to 3.0 mg once a day and then by 1.0 mg up to the maximum recommended dose of 4.0 mg once a day as shown in Table 1.

Doses above 4.0 mg once daily have not been investigated in Restless Legs Syndrome patients.

Table 1 - Dose titration

Week	2	3	4	5*	6*	7*
Dose (mg) / once daily	1.0	1.5	2.0	2.5	3.0	4.0

* To achieve optimal improvement in some patients.

The patient's response to ropinirole should be evaluated after 3 months treatment (see Section 5.1). At this time the dose prescribed and the need for continued treatment should be considered. If treatment is interrupted for more than a few days it should be re-initiated by dose titration carried out as above.

Children and Adolescents

Ropinirole is not recommended for use in children below 18 years of age due to a lack of data on safety and efficacy.

Elderly

The clearance of ropinirole is decreased in patients over 65 years of age. Any increase in dosage should be gradual and titrated against the symptomatic response.

Renal impairment

No dosage adjustment is necessary in patients with mild to moderate renal impairment (creatinine clearance between 30 and 50 ml/min).

4.3 Contraindications

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

Severe renal impairment (creatinine clearance < 30ml/min).

Severe hepatic impairment.

4.4 Special Warnings And Precautions For Use

Ropinirole should not be used to treat neuroleptic akathisia, tasikinesia (neuroleptic-induced compulsive tendency to walk), or secondary Restless Legs Syndrome (e.g. caused by renal failure, iron deficiency anaemia or pregnancy).

During treatment with ropinirole, paradoxical worsening of Restless Legs Syndrome symptoms occurring with earlier onset (augmentation), and reoccurrence of symptoms in the early morning hours (early morning rebound), may be observed. If this occurs, treatment should be reviewed and dosage adjustment or discontinuation of treatment may be considered.

In Parkinson's disease, ropinirole has been associated uncommonly with somnolence and episodes of sudden sleep onset (see Section 4.8) however in Restless Legs Syndrome, this phenomenon is very rare. Nevertheless, patients must be informed of this phenomenon and advised to exercise caution while driving or operating machines during treatment with ropinirole. Patients who have experienced somnolence and/or an episode of sudden sleep onset must refrain from driving or operating machines. Furthermore, a reduction of dosage or termination of therapy may be considered.

Patients with major psychotic disorders should not be treated with dopamine agonists unless the potential benefits outweigh the risks.

Impulse control disorders including pathological gambling and hypersexuality, and increased libido, have been reported in patients treated with dopamine agonists, including ropinirole, principally for Parkinson's disease. Those disorders were reported especially at high doses and were generally reversible upon reduction of the dose or treatment discontinuation. Risk factors such as a history of compulsive behaviours were present in some cases (see section 4.8).

Ropinirole should be administered with caution to patients with moderate hepatic impairment. Undesirable effects should be closely monitored.

Due to the risk of hypotension, patients with severe cardiovascular disease (in particular coronary insufficiency) should be treated with caution.

Ropinirole Film-Coated Tablets contain lactose monohydrate. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Ropinirole is principally metabolised by the cytochrome P450 isoenzyme CYP1A2. A pharmacokinetic study (with a ropinirole dose of 2 mg, three times a day) revealed that ciprofloxacin increased the C_max and AUC of ropinirole by 60% and 84% respectively, with a potential risk of adverse events. Hence, in patients already receiving ropinirole, the dose of ropinirole may need to be adjusted when medicinal products known to inhibit CYP1A2, e.g. ciprofloxacin, enoxacin or fluvoxamine, are introduced or withdrawn.

A pharmacokinetic interaction study between ropinirole (at a dose of 2 mg, three times a day) and theophylline, a substrate of CYP1A2, revealed no change in the pharmacokinetics of either ropinirole or theophylline. Therefore, it is not expected that ropinirole will compete with the metabolism of other medicinal products which are metabolised by CYP1A2.

Based on in-vitro data, ropinirole has little potential to inhibit cytochrome P450 at therapeutic doses. Hence, ropinirole is unlikely to affect the pharmacokinetics of other medicinal products, via a cytochrome P450 mechanism.

Smoking is known to induce CYP1A2 metabolism. Therefore, if patients stop or start smoking during treatment with ropinirole, dose adjustment may be required.

Increased plasma concentrations of ropinirole have been observed in patients treated with hormone replacement therapy. In patients already receiving hormone replacement therapy, ropinirole treatment may be initiated in the usual manner. However, it may be necessary to adjust the ropinirole dose, in accordance with clinical response, if hormone replacement therapy is stopped or introduced during treatment with ropinirole.

No pharmacokinetic interaction has been seen between ropinirole and domperidone (a medicinal product used to treat nausea and vomiting) that would necessitate dosage adjustment of either medicinal product. Domperidone antagonises the dopaminergic actions of ropinirole peripherally and does not cross the blood-brain barrier. Hence its value as an anti-emetic in patients treated with centrally acting dopamine agonists

Neuroleptics and other centrally active dopamine antagonists, such as sulpiride or metoclopramide, may diminish the effectiveness of ropinirole and, therefore, concomitant use of these medicinal products with ropinirole should be avoided.

4.6 Pregnancy And Lactation

There are no adequate data from the use of ropinirole in pregnant women.

Studies in animals have shown reproductive toxicity (see section 5.3). As the potential risk for humans is unknown, it is recommended that ropinirole is not used during pregnancy unless the potential benefit to the patient outweighs the potential risk to the foetus.

Ropinirole should not be used in nursing mothers as it may inhibit lactation.

4.7 Effects On Ability To Drive And Use Machines

Patients being treated with ropinirole and presenting with somnolence and/or sudden sleep episodes must be informed to refrain from driving or engaging in activities where impaired alertness may put themselves or others at risk of serious injury or death (e.g. operating machines) until such effects have resolved (see also Section 4.4).

4.8 Undesirable Effects

Adverse drug reactions are listed below by system organ class and frequency. Frequencies from clinical trials are determined as excess incidence over placebo and are classed as Very Common (> 1/10) or Common (> 1/100 to < 1/10) or uncommon (> 1/1000 to < 1/100).

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

Use of ropinirole in Restless Legs Syndrome

In Restless Legs Syndrome clinical trials the most common adverse drug reaction was nausea (approximately 30% of patients). Undesirable effects were normally mild to moderate and experienced at the start of therapy or on increase of dose and few patients withdrew from the clinical studies due to undesirable effects.

Table 2 lists the adverse drug reactions reported for ropinirole in the 12-week clinical trials at

Table 2 - Adverse drug reactions reported in 12-week Restless Legs Syndrome clinical trials (ropinirole n=309, placebo n=307)

Psychiatric Disorders
Common:	Nervousness
Uncommon:	Confusion
Nervous System Disorders
Common:	Syncope, Somnolence, Dizziness (including vertigo)
Vascular Disorders
Uncommon:	Postural hypotension, hypotension
Gastrointestinal Disorders
Very Common:	Vomiting, Nausea
Common:	Abdominal pain
General Disorders and Administration Site Conditions
Common:	Fatigue

Hallucinations were reported uncommonly in the open label long-term studies.

Paradoxical worsening of Restless Legs Syndrome symptoms occurring with earlier onset (augmentation), and reoccurrence of symptoms in the early morning hours (early morning rebound), may be observed during treatment with ropinirole.

Management of undesirable effects

Dose reduction should be considered if patients experience significant undesirable effects. If the undesirable effect abates, gradual up-titration can be re-instituted. Anti-nausea medicinal products that are not centrally active dopamine antagonists, such as domperidone, may be used if required.

Other experience with Ropinirole

Ropinirole is also indicated for the treatment of Parkinson's disease. The adverse drug reactions reported in patients with Parkinson's disease on ropinirole monotherapy and adjunct therapy at doses up to 24 mg/day at excess incidence over placebo are described below.

Table 3 - Adverse drug reactions reported in Parkinson's disease clinical trials at doses up to 24 mg/day

Psychiatric Disorders
Common:	Hallucinations, Confusion
Uncommon:	Increased libido
Nervous System Disorders
Very Common:	Syncope, Dyskinesia, Somnolence
Gastrointestinal Disorders
Very Common:	Nausea
Common:	Vomiting, Abdominal pain, Heartburn
General Disorders and Administration Site Conditions
Common:	Leg oedema

Post marketing reports

Hypersensitivity reactions (including urticaria, angioedema, rash, pruritus)

Psychotic reactions (other than hallucinations) including delirium, delusion, paranoia have been reported.

Impulse control disorders including pathological gambling and hypersexuality, and increased libido, have been reported (see section 4.4).

In Parkinson's disease, ropinirole is associated with somnolence and has been associated uncommonly (>1/1,000, <1/100) with excessive daytime somnolence and sudden sleep onset episodes, however, in Restless Legs Syndrome, this phenomenon is very rare (<1/10,000).

Following ropinirole therapy, postural hypotension or hypotension has been reported uncommonly (>1/1,000, <1/100), rarely severe.

Very rare cases of hepatic reactions (<1/10,000), mainly increase of liver enzymes, have been reported.

4.9 Overdose

It is anticipated that the symptoms of ropinirole overdose will be related to its dopaminergic activity. These symptoms may be alleviated by appropriate treatment with dopamine antagonists such as neuroleptics or metoclopramide.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic Group: Dopamine agonist ATC code: N04BC04

Mechanism of action

Ropinirole is a non-ergoline D2/D3 dopamine agonist which stimulates striatal dopamine receptors.

Clinical efficacy

Ropinirole Film-coated Tablets should only be prescribed to patients with moderate to severe idiopathic Restless Legs Syndrome. Moderate to severe idiopathic Restless Legs Syndrome is typically represented by patients who suffer with insomnia or severe discomfort in the limbs.

In the four 12-week efficacy studies, patients with Restless Legs Syndrome were randomised to ropinirole or placebo, and the effects on the IRLS scale scores at week 12 were compared to baseline. The mean dose of ropinirole for the moderate to severe patients was 2.0 mg/day. In a combined analysis of moderate to severe Restless Legs Syndrome patients from the four 12-week studies, the adjusted treatment difference for the change from baseline in IRLS scale total score at week 12 Last Observation Carried Forward (LOCF) Intention To Treat population was -4.0 points (95% CI -5.6, -2.4, p<0.0001; baseline and week 12 LOCF mean IRLS points: ropinirole 28.4 and 13.5; placebo 28.2 and 17.4).

A 12-week placebo-controlled polysomnography study in Restless Legs Syndrome patients examined the effect of treatment with ropinirole on periodic leg movements of sleep. A statistically significant difference in the periodic leg movements of sleep was seen between ropinirole and placebo from baseline to week 12.

Although sufficient data is not available to adequately demonstrate the long term efficacy of ropinirole in Restless Legs Syndrome (see Section 4.2), in a 36-week study, patients who continued on ropinirole demonstrated a significantly lower relapse rate compared with patients randomised to placebo (33% versus 58%, p=0.0156).

A combined analysis of data from moderate to severe Restless Legs Syndrome patients, in the four 12-week placebo-controlled studies, indicated that ropinirole-treated patients reported significant improvements over placebo on the parameters of the Medical Outcome Study Sleep Scale (scores on 0-100 range except sleep quantity). The adjusted treatment differences between ropinirole and placebo were: sleep disturbance (-15.2, 95% CI -19.37, -10.94; p<0.0001), sleep quantity (0.7 hours, 95% CI 0.49, 0.94; p<0.0001), sleep adequacy (18.6, 95% CI 13.77, 23.45; p<0.0001) and daytime somnolence (-7.5, 95% CI -10.86, -4.23; p<0.0001).

A rebound phenomenon following discontinuation of ropinirole treatment (end of treatment rebound) cannot be excluded. In clinical trials, although the average IRLS total scores 7-10 days after withdrawal of therapy were higher in ropinirole-treated patients than in placebo-treated patients, the severity of symptoms following withdrawal of therapy generally did not exceed the baseline assessment in ropinirole-treated patients.

In clinical studies most patients were of Caucasian origin.

Study of the effect of ropinirole on cardiac repolarisation

A thorough QT study conducted in male and female healthy volunteers who received doses of 0.5, 1, 2 and 4 mg of ropinirole film-coated (immediate release) tablets once daily showed a maximum increase of the QT interval duration at the 1mg dose of 3.46 milliseconds (point estimate) as compared to placebo. The upper bound of the one sided 95% confidence interval for the largest mean effect was less than 7.5 milliseconds. The effect of ropinirole at higher doses has not been systematically evaluated.

The available clinical data from a thorough QT study do not indicate a risk of QT prolongation at doses of ropinirole up to 4 mg/day.

5.2 Pharmacokinetic Properties

Absorption

The bioavailability of ropinirole is about 50% (36% to 57%), with C_max reached on average 1.5 hours after the dose. A high fat meal decreases the rate of absorption of Ropinirole, as shown by a delay in median T_max by 2.6 hours and an average 25% decrease in C_max.

Distribution

Plasma protein binding of ropinirole is low (10 - 40%). Consistent with its high lipophilicity, ropinirole exhibits a large volume of distribution (approx. 7 l/kg).

Metabolism

Ropinirole is primarily cleared by the cytochrome P450 enzyme, CYP1A2, and its metabolites are mainly excreted in the urine. The major metabolite is at least 100 times less potent than ropinirole in animal models of dopaminergic function.

Elimination

Ropinirole is cleared from the systemic circulation with an average elimination half-life of approximately 6 hours. No change in the oral clearance of ropinirole is observed following single and repeated oral administration. Wide inter-individual variability in the pharmacokinetic parameters has been observed.

Linearity

The pharmacokinetics of ropinirole are linear overall (C_max and AUC) in the therapeutic range between 0.25 mg and 4 mg, after a single dose and after repeated dosing.

Population-related characteristics

In patients over 65 years of age, a reduction in the systemic clearance of ropinirole by about 30% is possible.

In patients with mild to moderate renal impairment (creatinine clearance between 30 and 50 ml/min), no change in the pharmacokinetics of ropinirole is observed. No data is available in patients with severe renal impairment.

Paediatric population

Limited pharmacokinetic data obtained in adolescents (12-17 years, n=9) showed that the systemic exposure following single doses of 0.125 mg and 0.25 mg was similar to that observed in adults (see also section 4.2; subparagraph “Children and adolescents).

5.3 Preclinical Safety Data

Toxicology: The toxicology profile is principally determined by the pharmacological activity of the drug: behavioural changes, hypoprolactinaemia, decrease in blood pressure and heart rate, ptosis and salivation. In the albino rat only, retinal degeneration was observed in a long term study at a high dose (50 mg/kg), probably associated with an increased exposure to light.

Genotoxicity: Genotoxicity was not observed in the usual battery of in vitro and in vivo tests.

Carcinogenicity: From two-year studies conducted in the mouse and rat at dosages up to 50 mg/kg/day there was no evidence of any carcinogenic effect in the mouse. In the rat, the only drug-related lesions were Leydig cell hyperplasia and testicular adenoma resulting from the hypoprolactinaemic effect of ropinirole. These lesions are considered to be a species specific phenomenon and do not constitute a hazard with regard to the clinical use of ropinirole.

Reproductive Toxicity: Administration of ropinirole to pregnant rats at maternally toxic doses resulted in decreased foetal body weight at 60 mg/kg/day (approximately 15 times the AUC at the maximum dose in humans), increased foetal death at 90 mg/kg/day (approximately 25 times the AUC at the maximum dose in humans) and digit malformations at 150 mg/kg/day (approximately 40 times the AUC at the maximum dose in humans). There were no teratogenic effects in the rat at 120 mg/kg/day (approximately 30 times the AUC at the maximum dose in humans) and no indication of an effect on development in the rabbit.

Safety Pharmacology: In vitro studies have shown that ropinirole inhibits hERG-mediated currents. The IC₅₀ is 5-fold higher than the expected maximum plasma concentration in patients treated at the highest recommended dose (4 mg/day), see section 5.1.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Tablet core:

Lactose monohydrate

Microcrystalline cellulose

Pregelatinised starch

Magnesium stearate

Film coating:

Opadry II 85F32111 (Polyvinyl alcohol, Titanium dioxide, Macrogol 3350, Talc, Iron oxide yellow)

6.2 Incompatibilities

Not applicable

6.3 Shelf Life

24 months

6.4 Special Precautions For Storage

Do not store above 25°C

Store in the original package in order to protect from light

HDPE tablet containers only:

Keep the container tightly closed in order to protect from moisture

6.5 Nature And Contents Of Container

Aluminium/Aluminium blister or induction sealed HDPE tablet containers of 2, 5, 7, 10, 12, 14, 20, 21, 28, 30, 50, 56, 60, 84, 100, 126 and 210 tablets.

Not all pack sizes may be marketed.

6.6 Special Precautions For Disposal And Other Handling

No special requirements

7. Marketing Authorisation Holder

Caduceus Pharma Limited

6^th Floor, 94 Wigmore Street,

London W1U 3RF

UK

8. Marketing Authorisation Number(S)

PL 24668/0079

9. Date Of First Authorisation/Renewal Of The Authorisation

21/01/2011

10. Date Of Revision Of The Text

25/03/2011

Robinul-Neostigmine Injection

1. Name Of The Medicinal Product

Robinul-Neostigmine Injection

Glycopyrronium Bromide 0.5mg and Neostigmine Metilsulfate 2.5mg in 1ml solution for Injection

2. Qualitative And Quantitative Composition

Each 1ml of solution contains 500 micrograms (0.5mg) of glycopyrrolate (Glycopyrronium bromide) and 2.5mg of neostigmine metilsulfate.

3. Pharmaceutical Form

Clear, colourless sterile solution for injection intended for parenteral administration presented in 1ml clear, type 1, Ph. Eur. glass ampoules.

4. Clinical Particulars

4.1 Therapeutic Indications

Reversal of residual non-depolarising (competitive) neuromuscular block.

4.2 Posology And Method Of Administration

Robinul-Neostigmine Injection is for intravenous administration.

Adults and older patients: 1 - 2ml intravenously over a period of 10 - 30 seconds [equivalent to neostigmine metilsulfate 2500 micrograms (2.5mg) with glycopyrrolate 500 micrograms (0.5mg) to neostigmine metilsulfate 5000 micrograms (5mg) with glycopyrrolate 1000 micrograms (1mg)].

Alternatively 0.02ml/kg intravenously over a period of 10 - 30 seconds may be used [equivalent to neostigmine metilsulfate 50 micrograms/kg (0.05mg/kg) with glycopyrrolate 10 micrograms/kg (0.01mg/kg)].

Children: 0.02ml/kg intravenously over a period of 10 - 30 seconds [equivalent to neostigmine metilsulfate 50 micrograms/kg (0.05mg/kg) with glycopyrrolate 10 micrograms/kg (0.01mg/kg)].

These doses may be repeated if adequate reversal of neuromuscular blockade is not achieved. Total doses in excess of 2ml are not recommended as this dose of neostigmine may produce depolarising neuromuscular block.

4.3 Contraindications

Robinul-Neostigmine Injection should not be given to patients with known hypersensitivity to either of the two active ingredients. Robinul-Neostigmine Injection should not be given to patients with mechanical obstruction of the gastrointestinal or urinary tracts.

Robinul-Neostigmine Injection should not be given in conjunction with suxamethonium as neostigmine potientates the depolarising myoneural blocking effects of this agent.

4.4 Special Warnings And Precautions For Use

Administer with caution to patients with bronchospasm, severe bradycardia or glaucoma. Administration of anticholinesterase agents to patients with intestinal anastomosis may produce rupture of the anastomosis or leakage of intestinal contents. Although Robinul-Neostigmine Injection has been shown to have less impact on the cardiovascular system than atropine with neostigmine metilsulfate, use with caution in patients with coronary artery disease, congestive heart failure, cardiac dysrhythmias, hypertension or thyrotoxicosis. Use with caution in patients with epilepsy or Parkinsonism.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Neostigmine potentiates the depolarising myoneural blocking effects of suxamethonium (see contra-indications above).

4.6 Pregnancy And Lactation

Reproduction studies in rats and rabbits revealed no teratogenic effects from glycopyrrolate. Safety in human pregnancy and lactation has not been established. However, diminished rates of conception and of survival at weaning were observed in rats, in a dose-related manner. Studies in dogs suggest that this may be due to diminished seminal secretion which is evident at high doses of glycopyrrolate. The significance of this for man is not clear. The safety of neostigmine metilsulfate in pregnancy and lactation has not been established.

4.7 Effects On Ability To Drive And Use Machines

Not applicable.

4.8 Undesirable Effects

The glycopyrrolate component of Robinul-Neostigmine Injection can give rise to dry mouth, difficulty in micturition, cardiac dysrhythmias, disturbances of visual accommodation and inhibition of sweating. The neostigmine component of Robinul-Neostigmine Injection can give rise to bradycardia, increased oropharyngeal secretions, cardiac dysrhythmias and increased gastrointestinal activity. If severe neostigmine-induced muscarinic side effects occur (bradycardia, increased oropharyngeal secretions, decreased cardiac conduction rate, bronchospasm or increased gastrointestinal activity etc), these may be treated by the intravenous administration of Robinul Injection (glycopyrrolate) 200 - 600 micrograms (0.2 - 0.6mg) or atropine 400 - 1200 micrograms (0.4 - 1.2mg).

4.9 Overdose

The treatment of overdosage depends upon whether signs of anticholinesterase or anticholinergic overdosage are predominant presenting features. Signs of neostigmine overdosage (bradycardia, increased oropharyngeal secretions, bronchospasm etc) may be treated by the administration of Robinul Injection (glycopyrrolate) 200 - 600 micrograms (0.2 - 0.6mg) or atropine 400 - 1200 micrograms (0.4 - 1.2mg). In severe cases, respiratory depression may occur and artificial ventilation may be necessary in such patients. Signs of glycopyrrolate overdosage (tachycardia, venticular irritability etc) may be treated by the administration of neostigmine metilsulfate 1000 micrograms (1.0mg) for each 1000 micrograms (1.0mg) of glycopyrrolate known to have been administered. As glycopyrrolate is a quaternary ammonium agent, symptoms of overdosage are peripheral rather than central in nature; centrally acting anticholinesterase drugs such as physostigmine are therefore unnecessary to treat glycopyrrolate overdosage.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Robinul (glycopyrrolate) is a quaternary ammonium anticholinergic agent. The quaternary ammonium moiety renders Robinul highly ionised at physiological pH and it thus penetrates the blood brain and placental barriers poorly. Robinul has a more gradual onset and longer duration of action than atropine. Neostigmine metilsulfate is a quaternary ammonium anticholinesterase. Robinul-Neostigmine Injection is associated with less initial tachycardia and better protection against the subsequent cholinergic effects of neostigmine than a mixture of atropine and neostigmine. In addition, residual central anticholinergic effects are minimised due to the limited penetration of Robinul into the central nervous system. Administration of glycopyrrolate with neostigmine is associated with greater cardiostability than administration of glycopyrrolate and neostigmine metilsulfate separately.

Robinul-Neostigmine Injection can be used when atropine has been used as a pre-operative anticholinergic.

5.2 Pharmacokinetic Properties

Glycopyrrolate and Neostigmine Metilsulfate are routinely administered simultaneously to reverse residual non-depolarising (competitive) neuromuscular block. Numerous clinical studies which demonstrate this to be a safe and effective combination have been published. A number or pertinent clinical studies were included in the product licence application for Robinul Injection, approved in March 1981.

In the PL Application for Robinul Injection it was demonstrated that over 90% of the glycopyrrolate disappeared from serum within 5 minutes following intravenous administration. The drug was rapidly excreted into bile with highest concentrations being found 30 to 60 minutes after dosing with some product being detected up to 48 hours after administration. Glycopyrrolate is also rapidly excreted into urine 85% of product was excreted within 48 hours. It has subsequently been confirmed in a single dose pharmacokinetic study using radioimmunological assay procedures that glycopyrrolate was rapidly distributed and/or excreted after intravenous administration. The terminal elimination phase was relatively slow with quantifiable plasma levels remaining up to 8 hours after administration. The elimination half-life was 1.7 hours.

The pharmacokinetics of neostigmine metilsulfate are described in Martindale. In one study, following intravenous administration, the plasma concentration declined to about 8% of its initial value after 5 minutes with a distribution half-life of less than one minute. Elimination half-life ranged from about 15 - 30 minutes. Trace amounts of neostigmine metilsulfate could be detected in the plasma after one hour.

In a study in non-myasthenic patients, the plasma half-life was 0.89 hours.

5.3 Preclinical Safety Data

No further relevant information other than that which is included in other sections of the Summary of Product Characteristics.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Disodium Hydrogen Phosphate Dodecahydrate

Citric Acid

Sodium Hydroxide

Water for Injections

6.2 Incompatibilities

Do not mix Robinul-Neostigmine Injection with any other product.

6.3 Shelf Life

2 years.

6.4 Special Precautions For Storage

Do not store above 25°C.

Keep in outer carton.

6.5 Nature And Contents Of Container

Robinul-Neostigmine Injection is presented in clear one point cut glass ampoules packed in cardboard cartons to contain 10 ampoules.

6.6 Special Precautions For Disposal And Other Handling

Keep out of reach of children.

If only part of an ampoule is used, discard the remaining solution.

7. Marketing Authorisation Holder

Anpharm Limited

Roscrea

County Tipperary

Ireland

8. Marketing Authorisation Number(S)

PL 15372/0006

9. Date Of First Authorisation/Renewal Of The Authorisation

1st July, 1997.

10. Date Of Revision Of The Text

May 2009

Rozex Gel

Rozex

metronidazole

GEL

Rozex 0.75% w/w Gel

Metronidazole

Read all of this leaflet carefully before you start using this medicine.

• Keep this leaflet. You may need to read it again.


• If you have any further questions, ask your doctor or pharmacist.


• This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even if their symptoms are the same as yours.


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

In this leaflet:

• 1. What Rozex is and what it is used for


• 2. Before you use Rozex


• 3. How to use Rozex


• 4. Possible side effects


• 5. How to store Rozex


• 6. Further information

What Rozex is and what it is used for

• Your doctor has prescribed this gel for your skin condition, rosacea.


• It helps to treat the pimples, pustules (spots) and redness found with this condition.


• Rozex contains the active substance metronidazole. Metronidazole belongs to a group of medicines called antiprotozoal and antibacterial agents and has been shown to help to control infection and inflammation in certain skin problems, such as rosacea.

Before you use Rozex

Do not use Rozex

• If you are allergic (hypersensitive) to metronidazole or any of the other ingredients of Rozex (see section 6 for other ingredients). An allergic reaction may include a rash or itching.

Take special care with Rozex

• Do not get the gel in your eyes. If you do so, rinse thoroughly with large amounts of warm water or eye wash.


• If you suffer from any blood disorders do not use Rozex unless your doctor says you can.


• This product should not be used in children.


• Do not go out into strong sunlight, or use UV lamps while you are using this product.


• Avoid prolonged and unnecessary use of this medicine.

Using other medicines

• Using Rozex could interfere with drugs used to thin the blood (anticoagulants) such as warfarin and dicoumarin. Contact your doctor for advice if you are taking medicines to thin your blood, or if you suffer from any other blood disorders.

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

Pregnancy and breast-feeding

• If you are pregnant or breast-feeding, it may not be advisable to use this product, unless your doctor considers it essential.

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

Important information about some of the ingredients of Rozex

Rozex contains methyl parahydroxybenzoate and propyl parahydroxybenzoate which may cause allergic reactions (possibly
delayed), and propylene glycol which can cause skin irritation.

How to use Rozex

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

Adults and the elderly

• First wash and dry the affected areas of your skin.


• Apply a thin layer of the gel to all the affected areas - be careful also not to get it in your eyes.


• Rub the gel in well.


• Always replace the cap and wash your hands after use.


• Your gel should be used in this way twice a day, (morning and evening), or as advised by your doctor.


• Your doctor will decide how long you need to use Rozex to keep your rosacea under control.

If you use more Rozex than you should or accidentally swallow the gel

• This product is for use on the skin only. Do not swallow it. If you accidentally do so, seek medical advice.

If you forget to use Rozex

• Although this gel works best if you use it regularly as directed, don’t worry if you forget to use your gel at the right time. When you do remember, start using it again in the same way as before.

If you stop taking Rozex

Rosacea may respond slowly to antibiotics. It is important that you continue using Rozex until your doctor tells you to stop.

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

Rozex Gel Side Effects

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

Effects on the skin

• Rozex can cause some temporary redness, slight dryness, itching, mild stinging or burning of the skin. If this should happen, you must either use the gel a little less often, or even stop using it until the irritation settles down or until your doctor tells you to start using this gel again.


• Rarely, worsening of the rosacea can occur.

Effects on the eyes

• If used too closely to the eyes, it has been known to cause watering of the eyes. If this should happen or you accidentally get some of the gel in your eyes, immediately bathe them thoroughly with an eye-wash or clean water.

Effects on the rest of the body

• Occasionally, a metallic taste, feeling sick (nausea) or numbness and tingling in the fingers or toes may be experienced.

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

How to store Rozex

• Keep out of the reach and sight of children.


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


• Do not store above 25ºC. Do not freeze.

Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines
no longer required. These measures will help to protect the environment.

Further information

What Rozex contains

• Rozex contains 0.75% w/w of the active substance metronidazole.


• The other ingredients are carbomer 940, disodium edetate, methyl parahydroxybenzoate, propyl parahydroxybenzoate,
  propylene glycol, sodium hydroxide and purified water.

What Rozex looks like and contents of the pack

• Rozex is a clear to light yellow gel.


• It is available in a 5 g, 30 g, 40 g or 50 g tube, only on prescription from your doctor. Not all pack sizes may be marketed.

Marketing Authorisation Holder and Manufacturer

Marketing Authorisation Holder:

Galderma (UK) Limited

Meridien House

69-71 Clarendon Road

Watford

Herts

WD17 1DS

UK

(PL 10590/0016)

Manufacturer:

Laboratoires Galderma

Z.I. - Montdésir

74540, Alby-sur-Chéran

France

This leaflet was last approved in 12/2007.

P22770-5

Robinul Powder

1. Name Of The Medicinal Product

Robinul Powder

2. Qualitative And Quantitative Composition

Robinul Powder consists of Glycopyrrolate (glycopyrronium bromide) 100% w/w.

3. Pharmaceutical Form

White, crystalline powder.

4. Clinical Particulars

4.1 Therapeutic Indications

Iontophoretic treatment of the plantar and palmar skin for idiopathic hyperhidrosis.

4.2 Posology And Method Of Administration

Route of Administration: Iontophoresis

Dosage and Administration:

A 0.05% solution in distilled water of Glycopyrrolate USP is applied to palmar or plantar skin. When treating the foot or hand, sufficient solution to cover the palm or sole is placed in a non-metallic container and the anode, of sheet metal larger in area than the part being treated, is placed in the solution. The sole or palm is separated from the anode by 5mm of plastic foam or a layer of lint or sponge sheet.

In all cases an electrical circuit is completed by placing another limb in lukewarm tap water containing the cathode, similarly shielded from direct contact with the skin.

Recommended average conditions are 90 volts DC at 10-20 mA for adults (including older patients) and 2-10 mA for children, for 12 minutes at each site, depending on the patient's skin tolerance, body weight and size. Only one site should be treated at a time and only two sites in any one day. Treatments should not be repeated within seven days, but may be repeated later varying the precise conditions according to the recurrence and severity of hyperhidrosis. See also 'Special warnings and special precautions for use' below.

4.3 Contraindications

Glaucoma. Do not use during pregnancy.

4.4 Special Warnings And Precautions For Use

Glycopyrrolate may cause tachycardia.

This product should be used with great caution in patients with cardiovascular disease, thyrotoxicosis and obstructive disorders of the lower urinary tract. Patients with mycotic or other skin infections should not be treated.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Not applicable.

4.6 Pregnancy And Lactation

Do not use during pregnancy, as safety in this condition has not been established. Reproduction studies in rats and rabbits revealed no teratogenic effects from glycopyrrolate. However, diminished rates of conception and of survival at weaning were observed in rats, in a dose related manner. Studies in dogs suggest that this may be due to diminished seminal secretion, which is evident at high doses of glycopyrrolate. The significance of this for man is not clear.

4.7 Effects On Ability To Drive And Use Machines

Since this drug may cause drowsiness, patients receiving glycopyrrolate should not drive or operate machinery immediately after treatment unless it has been shown not to affect their physical or mental ability.

4.8 Undesirable Effects

Dryness of the mouth, blurred vision and mild abdominal discomfort may occur. Exercise care in patients with prostatic hypertrophy. Due to the effect of anticholinergics on mucous secretions, it is advisable not to treat people with chronic bronchitis. Occasionally difficulty in eating may occur and micturition may be temporarily affected for some hours after treatment. A mild tingling feeling may occur in the immersed areas during treatment and any recent cuts or cracks in the skin may smart when the current is increased at the start of iontophoresis. The latter can be avoided by covering the lesion with a thin smear of petroleum jelly. Avoid over-exertion especially in hot weather, until any side effects have disappeared.

4.9 Overdose

Not appropriate for the product.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Glycopyrrolate is an anticholinergic agent. The pharmacological particulars of anticholinergic drugs are well documented in the scientific literature.

5.2 Pharmacokinetic Properties

This product is indicated for use by Topical Iontophoresis for hyperhidrosis. Glycopyrrolate is a Quaternary Ammonium Compound and as such is absorbed through the skin in negligible amounts only.

5.3 Preclinical Safety Data

Nothing of relevance to the prescriber.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Not applicable - no other constituents present.

6.2 Incompatibilities

None.

6.3 Shelf Life

48 months unopened. 14 days after reconstitution.

6.4 Special Precautions For Storage

There are no special storage precautions for this product.

6.5 Nature And Contents Of Container

The product is presented in a screw cap amber bottle containing 3, 5 or 10g of glycopyrrolate USP.

6.6 Special Precautions For Disposal And Other Handling

The product should only be used by specialist units experienced in IONTOPHORETIC technique. The electrodes and treated skin areas must be placed in non-metallic containers and separated carefully by layers of, for example, sponge or lint. Direct contact between electrodes and skin must be avoided otherwise burns may result. The current must be very slowly increased from zero mA and decreased to zero mA at the beginning and end of the treatment period respectively to avoid any Faradic discharge between the electrode and skin on removal of the patient's limb from the container of solution. Instruct patient that contact must not be broken during treatment. Prior to use in iontophoresis a stock solution of Robinul powder (glycopyrrolate) may be made up with freshly boiled and cooled distilled or deionised water. Glycopyrrolate does hydrolyse slowly at pH 7 and it is recommended that stock solutions be discarded after not more than 14 days.

The solution must not be alkaline otherwise glycopyrrolate will hydrolyse more rapidly.

ADMINISTRATION DETAILS

7. Marketing Authorisation Holder

Anpharm Limited

Roscrea

Co. Tipperary

Ireland

8. Marketing Authorisation Number(S)

PL 15372/0003

9. Date Of First Authorisation/Renewal Of The Authorisation

1^st July, 1997.

10. Date Of Revision Of The Text

May, 2003.

Robinul Injection

1. Name Of The Medicinal Product

Robinul Injection

Glycopyrronium Bromide 200 micrograms in 1ml Solution for Injection.

2. Qualitative And Quantitative Composition

Each 1ml of injection contains 200 micrograms (0.2mg) of glycopyrronium bromide (glycopyrrolate).

3. Pharmaceutical Form

Solution for injection.

Clear, colourless, sterile solution.

4. Clinical Particulars

4.1 Therapeutic Indications

.

1.	To protect against the peripheral muscarinic actions of anticholinesterases such as neostigmine and pyridostigmine, used to reverse residual neuromuscular blockade produced by non-depolarising muscle relaxants.
2.	As a pre-operative antimuscarinic agent to reduce salivary tracheobronchial and pharyngeal secretions and to reduce the acidity of the gastric contents.
3.	As a pre-operative or intra-operative antimuscarinic to attenuate or prevent intra-operative bradycardia associated with the use of suxamethonium or due to cardiac vagal reflexes.

4.2 Posology And Method Of Administration

Robinul Injection is for intravenous or intramuscular injection.

Premedication: Adults and older patients: 200 to 400 micrograms (0.2mg to 0.4mg) intravenously or intramuscularly before the induction of anaesthesia. Alternatively, a dose of 4 to 5 micrograms/kg (0.004 to 0.005mg/kg) up to a maximum of 400 micrograms (0.4mg) may be used. Larger doses may result in profound and prolonged antisialagogue effect which may be unpleasant for the patient.

Children: 4 to 8 micrograms/kg (0.004 to 0.008mg/kg) up to a maximum of 200 micrograms (0.2mg) intravenously or intramuscularly before the induction of anaesthesia. Larger doses may result in profound and prolonged antisialagogue effect which may be unpleasant for the patient.

Intra-operative use: Adults and older patients: A single dose of 200 to 400 micrograms (0.2 to 0.4mg) by intravenous injection should be used. Alternatively, a single dose of 4 to 5 micrograms/kg (0.004 to 0.005mg/kg) up to a maximum of 400 micrograms (0.4mg) may be used. This dose may be repeated if necessary.

Children: A single dose of 200 micrograms (0.2mg) by intravenous injection should be used. Alternatively, a single dose of 4 to 8 micrograms/kg (0.004 to 0.008mg/kg) up to a maximum of 200 micrograms (0.2mg) may be used. This dose may be repeated if necessary.

Reversal of residual non-depolarising neuromuscular block:

Adults and older patients: 200 micrograms (0.2mg) intravenously per 1000 micrograms (1mg) neostigmine or the equivalent dose of pyridostigmine. Alternatively, a dose of 10 to 15 micrograms/kg (0.01 to 0.015mg/kg) intravenously with 50 micrograms/kg (0.05mg/kg) neostigmine or equivalent dose of pyridostigmine. Robinul may be administered simultaneously from the same syringe with the anticholinesterase; greater cardiovascular stability results from this method of administration.

Children: 10 micrograms/kg (0.01mg/kg) intravenously with 50 micrograms/kg (0.05mg/kg) neostigmine or the equivalent dose of pyridostigmine. Robinul may be administered simultaneously from the same syringe with the anticholinesterase; greater cardiovascular stability results from this method of administration.

4.3 Contraindications

Apart from established hypersensitivity to glycopyrrolate, there are no absolute contra-indications to Robinul.

4.4 Special Warnings And Precautions For Use

Because of the increase in heart rate produced by the administration of anticholinergics, use with caution in patients with coronary artery disease; congestive heart failure; cardiac arrhythmias; hypertension; thyrotoxicosis. This product should be used very cautiously in pyrexial patients due to inhibition of sweating.

Large doses of quaternary ammonium anticholinergic compounds have been shown to block end plate nicotinic receptors. This should be considered before using glycopyrrolate in patients with myasthenia gravis.

It is known that the administration of anticholinergic agents during inhalation anaesthesia can result in ventricular arrhythmias.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Anticholinergic agents may delay absorption of other medicaments given concomitantly.

Excessive cholinergic blockade can occur if Robinul Injection is given concomitantly with belladonna alkaloids or other synthetic anticholinergic agents (such as antiparkinsonism agents), phenothiazines, tricyclic antidepressants, disopyramide, procainamide, quinidine, antihistamines, or narcotic analgesics such as meperidine.

Concurrent administration of anticholinergics and corticosteroids may result in increased intraocular pressure.

Concurrent use of anticholinergic agents with slow-dissolving tablets of digoxin may cause increased serum digoxin levels.

4.6 Pregnancy And Lactation

Although reproduction studies in rats and rabbits revealed no teratogenic effects from glycopyrrolate, safety in human pregnancy and lactation has not been established. Diminished rates of conception and of survival at weaning were observed in rats, in a dose-related manner. Studies in dogs suggest that this may be due to diminished seminal secretion which is evident at high doses of glycopyrrolate. The significance of this for man is not clear.

4.7 Effects On Ability To Drive And Use Machines

Do not operate or drive heavy machinery unless the drug has been shown not to interfere with mental or physical ability.

4.8 Undesirable Effects

Robinul may produce the following effects which are extensions of its fundamental pharmacological actions: dry mouth, difficulty in micturition, disturbances in visual accommodation, tachycardia, palpitation, inhibition of sweating. However the use of Robinul Injection as a preoperative anticholinergic is associated with less effect on the cardiovascular system compared to atropine.

4.9 Overdose

Since glycopyrrolate is a quaternary ammonium agent, symptoms of overdosage are peripheral rather than central in nature. To combat peripheral anticholinergic effects, a quaternary ammonium anticholinesterase such as neostigmine methylsulphate may be given in a dose of 1000 micrograms (1.0mg) for each 1000 micrograms (1.0mg) of glycopyrrolate known to have been administered by the parenteral route.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Glycopyrrolate is a quaternary ammonium antimuscarinic agent and like other anticholinergic agents, it inhibits the action of acetylcholine on structures innervated by postganglionic cholinergic nerves and on smooth muscles that respond to acetylcholine but lack cholinergic innervation. These peripheral cholinergic receptors are present in the autonomic effector cells of smooth muscle, cardiac muscle, the sinoatrial node, the atrioventricular node, exocrine glands and to a limited degree in the autonomic ganglia. Thus it diminishes the volume and free acidity of gastric secretions and controls excessive pharyngeal, tracheal and bronchial secretions. Glycopyrrolate antagonizes muscarinic symptoms (e.g. bronchorrhea, bronchospasm, bradycardia and intestinal hypermotility) induced by cholinergic drugs such as the anticholinesterases.

The highly polar quaternary ammonium group of glycopyrrolate limits its passage across lipid membranes, such as the blood-brain barrier, in contrast to atropine sulphate and scopolamine hydrobromide, which are non-polar tertiary amines which penetrate lipid barriers easily.

Robinul Injection has been used successfully as an adjunct to reversal by neostigmine when atropine has been used as the preoperative anticholinergic. The use of Robinul Injection as an adjunct to reversal by neostigmine of non-depolarising muscle relaxants is associated with less initial tachycardia and better protection against the cholinergic effects of neostigmine compared to reversal with a mixture of neostigmine and atropine.

5.2 Pharmacokinetic Properties

Glycopyrrolate is rapidly diminished and/or excreted after intravenous administration. The terminal elimination phase is relatively slow with quantifiable levels remaining up to 8 hours after administration. Peak effects occur approximately 30 to 45 minutes after intramuscular administration. The vagal blocking effects persist for 2 to 3 hours and the antisialagogue effects persist up to 7 hours, periods longer than for atropine. With intravenous injection, the onset of action is generally evident within one minute.

5.3 Preclinical Safety Data

No further relevant information other than that which is included in other sections of the Summary of Product Characteristics.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Sodium Chloride

Dilute Hydrochloric Acid

Water for Injections

6.2 Incompatibilities

Robinul Injection has been shown to be physically compatible with the following agents commonly used in anaesthetic practice: Butorphanol, Lorazepam, Droperidol and Fentanyl Citrate, Levorphanol Tartrate, Pethidine Hydrochloride, Morphine Sulphate, Neostigmine, Promethazine and Pyridostigmine.

Robinul Injection has been shown to be physically incompatible with the following agents commonly used in anaesthetic practice: Diazepam, Dimenhydrinate, Methohexitone Sodium, Pentazocine, Pentobarbitone Sodium, Thiopentone Sodium.

6.3 Shelf Life

5 years.

6.4 Special Precautions For Storage

Do not store above 25°C.

6.5 Nature And Contents Of Container

Robinul Injection 1ml and 3ml is presented in clear One point cut (OPC) glass ampoules, packed in cardboard cartons to contain 10 x 1ml; 10 x 3ml and 3 x 3ml ampoules.

6.6 Special Precautions For Disposal And Other Handling

Keep out of reach and sight of children.

If only part of an ampoule is used, discard the remaining solution.

7. Marketing Authorisation Holder

Anpharm Ltd.

Roscrea

Co. Tipperary

Ireland.

8. Marketing Authorisation Number(S)

PL 15372/0004

9. Date Of First Authorisation/Renewal Of The Authorisation

1 July 1997

10. Date Of Revision Of The Text

March 2009