Regaine for Women Regular Strength

1. Name Of The Medicinal Product

Regaine for Women Regular Strength

2. Qualitative And Quantitative Composition

Minoxidil 20 mg/ml (2% w/v).

Contains propylene glycol.

For full list of excipients see section 6.1.

3. Pharmaceutical Form

Cutaneous Solution (to be applied to the scalp).

4. Clinical Particulars

4.1 Therapeutic Indications

Regaine for Women Regular Strength is indicated for the treatment of alopecia androgenetica in women aged between 18 and 65.

Onset and degree of hair regrowth may be variable among users. Although trends in the data suggest that those users who are younger, whose hair has been thinning for a shorter period of time or who have a smaller area of thinning on the vertex are more likely to respond to Regaine for Women Regular Strength, individual responses cannot be predicted.

4.2 Posology And Method Of Administration

Women aged 18-65:

Hair and scalp should be thoroughly dry prior to topical application of Regaine for Women Regular Strength. A dose of 1 ml Regaine for Women Regular Strength cutaneous solution should be applied to the total affected areas of the scalp twice daily. The total dosage should not exceed 2 ml. If fingertips are used to facilitate drug application, hands should be washed afterwards.

It may take twice daily applications for four months or more before evidence of hair growth can be expected.

If hair re-growth occurs, twice daily applications of Regaine for Women Regular Strength are necessary for continued hair growth. Anecdotal reports indicate that re-grown hair may disappear three to four months after stopping Regaine for Women Regular Strength application and the balding process will continue.

Users should discontinue treatment if there is no improvement after one year.

The method of application varies according to the disposable applicator used:

Pump spray applicator: this is useful for large areas. Aim the pump at the centre of the bald area, press once and spread with fingertips over the entire bald area. Repeat for a total of 6 times to apply a dose of 1 ml. Avoid breathing spray mist.

Extended spray-tip applicator: this is useful for small areas, or under hair. The pump spray applicator must be in place in order to use this additional applicator. Use in the same way as the pump spray.

Rub-on applicator: squeeze the upright bottle once to fill the 1 ml chamber to the black line. Invert bottle, dab on scalp, and spread Regaine for Women Regular Strength over the entire bald area until chamber is empty.

Children and the Elderly

Not recommended. The safety and effectiveness of Regaine for Women Regular Strength in users aged under 18 or over 65 has not been established.

4.3 Contraindications

Regaine for Women Regular Strength is contra-indicated:

− in users with a history of sensitivity to minoxidil, ethanol, or propylene glycol

− in users with treated or untreated hypertension

− in users with any scalp abnormality (including psoriasis and sunburn)

− in users with a shaved scalp

− if occlusive dressings or other topical medical preparations are being used.

4.4 Special Warnings And Precautions For Use

Before using Regaine for Women Regular Strength, the user should determine that the scalp is normal and healthy.

Minoxidil is only indicated for the treatment of alopecia androgenetica and should not be used in other types of hair loss for example when there is no family history of hair loss, hair loss is sudden and/or patchy, hair loss is due to childbirth or the reason for hair loss is unknown.

The patient should stop using Regaine for Women Regular Strength and see a doctor if hypotension is detected or if the patient is experiencing chest pain, rapid heart beat, faintness or dizziness, sudden unexplained weight gain, swollen hands or feet or persistent redness.

Patients with known cardiovascular disease or cardiac arrhythmia should contact a physician before using Regaine for Women Regular Strength.

Regaine for Women Regular Strength is for external use only. Do not apply to areas of the body other than the scalp.

Hands should be washed thoroughly after applying the solution. Inhalation of the spray mist should be avoided.

Regaine for Women Regular Strength contains ethanol (alcohol), which will cause burning and irritation of the eye. In the event of accidental contact with sensitive surfaces (eye, abraded skin and mucous membranes) the area should be bathed with large amounts of cool tap water.

Regaine for Women Regular Strength contains propylene glycol, which may cause skin irritation.

Some patients have experienced changes in hair colour and/or texture with use of Regaine for Women Regular Strength.

Patients should be advised to consult their doctor or pharmacist if they are concerned at any time during treatment with Regaine for Women Regular Strength.

Some consumers reported increased hair shedding upon initiation of therapy with Regaine for Women Regular Strength. This is most likely due to minoxidil's action of shifting hairs from the resting telogen phase to the growing anagen phase (old hairs fall out as new hairs grow in their place). This temporary increase in hair shedding generally occurs two to six weeks after beginning treatment and subsides within a couple of weeks. If shedding persists (>2 weeks), users should stop using Regaine for Women Regular Strength and consult their doctor.

Users should be aware that, whilst extensive use of Regaine for Women Regular Strength has not revealed evidence that sufficient minoxidil is absorbed to have systemic effects, greater absorption because of misuse, individual variability, unusual sensitivity or decreased integrity of the epidermal barrier caused by inflammation or disease processes in the skin (e.g. excoriations of the scalp, or scalp psoriasis) could lead, at least theoretically, to systemic effects.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Topical drugs, such as corticosteroids, tretinoin, dithranol or petrolatum, which alter the stratum corneum barrier, could result in increased absorption of minoxidil if applied concurrently. Although it has not been demonstrated clinically, there exists the theoretical possibility of absorbed minoxidil potentiating orthostatic hypotension caused by peripheral vasodilators.

4.6 Pregnancy And Lactation

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

Animal studies have shown a risk to the foetus at exposure levels that are very high compared to those intended for human exposure (see section 5.3). The potential risk in humans is unknown.

Systemically absorbed minoxidil is secreted in human milk.

Regaine for Women Regular Strength should not be used during pregnancy or lactation.

4.7 Effects On Ability To Drive And Use Machines

Based on the pharmacodynamic and overall safety profile of minoxidil, it is not expected that Regaine for Women Regular Strength would interfere with the ability to drive or operate machinery.

4.8 Undesirable Effects

In placebo controlled trials, the overall frequency of adverse events in females in all body system categories was approximately five times that of males.

Several thousand patients have used topical minoxidil in clinical trials where a comparison with an inactive solution was made. Dermatological reactions (e.g. irritation, itching) occurred in patients using both solutions. This has been explained by the presence of propylene glycol in both the active and inactive solution.

Data from 7 placebo controlled trials are available with a population of 1,197 males and females treated with topical minoxidil solution (2% and 5% combined) where adverse events were assessed. Additionally, adverse events reported in post-marketing are included.

The frequency of adverse reactions to topical minoxidil solution is defined using the following convention:

Very common (

Body system	Incidence	Reported adverse event
Nervous system disorders	Common	Headache
Vascular disorders	Uncommon:	Hypotension
Respiratory, thoracic and mediastinal disorders	Uncommon:	Dyspnoea
Skin and subcutaneous tissue disorders	Common:	Hypertrichosis (unwanted non-scalp hair including facial hair growth in women), pruritus (including rash pruritic and application site, generalized and eye pruritus
Uncommon:	Temporary hair loss (see section 4.4), changes in hair texture and hair colour, skin exfoliation (including application site, exfoliative rash and dermatitis exfoliative), rash (including application site, pustular, papular, generalized vestibular and macular rash), acne (acne form rash), dermatitis (including contact, application site, allergic, atopic and seborrhoeic dermatitis) and dry skin (including application site dryness)
General disorders and administration site conditions	Uncommon:	Oedema peripheral, Application site irritation (including skin irritation), application site erythema (including erythema and rash erythematous)

Users should stop using Regaine for Women Regular Strength if they experience chest-pain, tachycardia, faintness, dizziness, sudden unexplained weight gain, swollen hands or feet or persistent redness or irritation of the scalp.

4.9 Overdose

Increased systemic absorption of minoxidil may potentially occur if higher-than-recommended doses of Regaine for Women Regular Strength are applied to larger surface areas of the body or areas other than the scalp.

Because of the concentration of minoxidil in Regaine for Women Regular Strength, accidental ingestion has the potential of producing systemic effects related to the pharmacological action of the drug (5 ml of Regaine for Women Regular Strength contains 100 mg minoxidil; the maximum recommended adult dose for oral minoxidil administration in the treatment of hypertension). Signs and symptoms of minoxidil overdosage would primarily be cardiovascular effects associated with sodium and water retention, tachycardia and hypotension.

Treatment

Treatment of minoxidil overdosage should be symptomatic and supportive.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: other dermatologicals, ATC code: D11AX

Individual responses to Regaine for Women Regular Strength are variable and unpredictable.

The effect of Regaine for Women Regular Strength has been assessed in phase III clinical trials in women conducted over a 48 week treatment period.

In these studies Regaine for Women Regular Strength was compared to the product vehicle without the minoxidil active ingredient. The primary efficacy criterion was non-vellus hair count in a 1.0 cm² reference area of affected scalp. The mean changes observed in this parameter in these studies were significantly in favour of Regaine and were as follows:

Mean change in non-vellus hair count in reference 1 cm2 area of scalp compared with baseline
	Regaine for Women Regular Strength (minoxidil 2%)	Vehicle	Pairwise comparison
Baseline	150.4	138.4
	Mean change from baseline	Mean change from baseline
16 weeks	+35.9	+20.0	2>vehicle
32 weeks	+26.7	+15.2	2>vehicle
48 weeks	+20.7	+9.4	2>vehicle

Using non-vellus hair count as an efficacy criteria, Regaine for Women Regular Strength has also been shown to stabilise hair loss (defined as re-growth or no loss) in 88% of patients compared with 69% of patients who received vehicle in one trial following 48 weeks treatment and in 87% of patients compared with 73% of patients who received vehicle in a further trial following 32 weeks treatment.

Female patients' own evaluations in clinical studies have shown that hair growth was reported by approximately 60% of females after 8 months of Regaine for Women Regular Strength usage.

Patient evaluation of visible hair growth
	% of Females reporting re-growth after 8 months Regaine for Women Regular Strength usage	% of Females reporting re-growth after 4 months Product vehicle usage
Minimal re-growth	30-40	29-33
Moderate to dense re-growth	20-25	7-12
Total	55-59	40-41

In addition, Regaine for Women Regular Strength has been shown to stabilise hair loss (shown as re-growth or no loss) in 4 out of 5 females as calculated from two clinical studies that showed stabilisation with 88 and 87% respectively while corresponding figures for vehicle were 69 and 74%.

The mechanism by which minoxidil stimulates hair growth is not fully understood, but minoxidil can reverse the hair loss process of androgenetic alopecia by the following means:

- increase the diameter of the hair shaft

- stimulate anagen growth

- prolong the anagen phase

- stimulate anagen recovery from the telogen phase

As a peripheral vasodilator minoxidil enhances microcirculation to hair follicles. The Vascular Endothelial Growth Factor (VEGF) is stimulated by minoxidil and VEGF is presumably responsible for the increased capillary fenestration, indicative of a high metabolic activity, observed during the anagen phase.

5.2 Pharmacokinetic Properties

The failure to detect evidence of systemic effects during treatment with Regaine solution reflects the poor absorption of topically applied minoxidil from normal intact skin. Systemic absorption of minoxidil from topically applied solution ranges between 1% and 2% of the total applied dose.

In a study in males, the minoxidil serum concentration time curve (AUC) for the 2% solution averaged 7.54 ng·h/ml compared to a mean AUC of 35.1 ng·h/ml for the 2.5 mg oral formulation. The mean peak plasma concentration (C_max) for the topical solution was 1.25 ng/ml, compared to 18.5 ng/ml following the 2.5 mg oral dose.

There is some evidence from in vitro studies that minoxidil reversibly binds to human plasma proteins. However, since only 1 – 2% of topically applied minoxidil is absorbed, the extent of plasma protein binding occurring in vivo after topical application would be clinically insignificant. The volume of distribution of minoxidil after intravenous administration has been estimated at 70 litres.

Approximately 60% minoxidil absorbed after topical application is metabolised to minoxidil glucuronide, primarily in the liver. Minoxidil and its metabolites are excreted almost entirely in the urine, with a very minor degree of elimination via the faeces. Following cessation of dosing, approximately 95% of topically applied minoxidil will be eliminated within four days.

5.3 Preclinical Safety Data

Preclinical data reveal no special hazards for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity or carcinogenic potential.

Cardiac effects of minoxidil in dogs are species-specific in terms of the low doses that cause profound haemodynamic effects and associated changes in the heart. Available data indicate that similar cardiac effects do not occur in humans treated topically or orally with minoxidil.

Mutagenicity

Minoxidil showed no evidence of mutagenic/genotoxic potential in a number of in vitro and in vivo assays.

Teratogenicity

Animal reproduction toxicity studies in rats and rabbits have shown signs of maternal toxicity and a risk to the foetus at exposure levels that are very high compared to those intended for human exposure (from 19 to 570-fold human exposure). A low, albeit remote, risk of foetal harm is possible in humans.

Fertility

Preclinical fertility studies in rats have shown minoxidil doses equal to or greater than 3 mg/kg/day (at least 21-fold human exposure) when administered orally and greater than 9 mg/kg/day (at least 64-fold human exposure) when administered subcutaneously were associated with reduced conception and implantation rates as well as a reduction in the number of live pups.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Propylene glycol

Ethanol

Water

6.2 Incompatibilities

Not applicable.

6.3 Shelf Life

48 months

6.4 Special Precautions For Storage

Regaine for Women Regular Strength is flammable. Do not store above 25°C.

6.5 Nature And Contents Of Container

HDPE bottle with spray-pump/dabbing applicator containing 60 ml of solution.

Pack size: 1 x 60 ml.

6.6 Special Precautions For Disposal And Other Handling

The solution is flammable. Do not use while smoking, or near any naked flame or strong heat source. Avoid exposure of the container and contents to naked flames during use, storage and disposal. Any unused product or waste material should be disposed of in accordance with local requirements.

7. Marketing Authorisation Holder

McNeil Products Limited

Foundation Park

Roxborough Way

Maidenhead

Berkshire SL6 3UG

United Kingdom

8. Marketing Authorisation Number(S)

PL 15513/0149

9. Date Of First Authorisation/Renewal Of The Authorisation

7^th March 2005/27 Feb 2009

10. Date Of Revision Of The Text

6 October 2010

Rectogesic 4 mg / g Rectal Ointment

1. Name Of The Medicinal Product

Rectogesic 4 mg/g Rectal Ointment.

2. Qualitative And Quantitative Composition

Glyceryl trinitrate: 4 mg/g.

One gram of rectal ointment contains 40 mg Glyceryl trinitrate in propylene glycol corresponding to 4 mg Glyceryl trinitrate (GTN). The delivered dose from 375 mg of this formulation is approximately 1.5 mg GTN.

The ointment also contains 36 mg Propylene Glycol, and 140 mg Lanolin, per gram rectal ointment.

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Rectal ointment.

Off-white smooth opaque ointment formulation.

4. Clinical Particulars

4.1 Therapeutic Indications

Rectogesic 4 mg/g Rectal Ointment is indicated for relief of pain associated with chronic anal fissure.

In the clinical development of the drug, a modest effect has been shown on improvements in average daily pain intensity (see Section 5.1).

4.2 Posology And Method Of Administration

Route of administration: rectal use

Adults:

A finger covering, such as cling film or a finger cot, may be placed on the finger to be used to apply the ointment. (Finger cots to be obtained separately from local pharmacy or surgical supplies retailer or cling film from local store.) The finger is placed along side a 2.5cm dosing line which is provided on the outside carton in which Rectogesic is supplied, and a strip of ointment the length of the line is expressed onto the end of the finger by gently squeezing the tube. The amount of ointment expressed is approximately 375 mg (1.5 mg GTN). The covered finger is then gently inserted into the anal canal to the distal interphalangeal joint of the finger and applied circumferentially to the anal canal.

The dose delivered from the 4 mg/g ointment is 1.5 mg glyceryl trinitrate. The dose is to be applied intra-anally every twelve hours. Treatment may be continued until the pain abates, up to a maximum of 8 weeks.

Rectogesic should be used following conservative treatment failure for acute symptoms of anal fissure.

Elderly:

No specific information concerning the usage of Rectogesic in the elderly is available

Patients with Hepatic or Renal Impairment

No specific information concerning the usage of Rectogesic in patients with hepatic or renal impairment is available

Children and Adolescents:

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

4.3 Contraindications

Hypersensitivity to the active substance “glyceryl trinitrate” or to any of the excipients or idiosyncratic reactions to other organic nitrates.

Concomitant treatment with sildenafil citrate, tadalafil, vardenafil and with nitric oxide (NO) donors, such as other long-acting GTN products, isosorbide dinitrate and amyl or butyl-nitrite.

Postural hypotension, hypotension or uncorrected hypovolaemia as the use of glyceryl trinitrate in such states could produce severe hypotension or shock.

Increased intracranial pressure (e.g. head trauma or cerebral haemorrhage) or inadequate cerebral circulation.

Migraine or recurrent headache.

Aortic or mitral stenosis.

Hypertrophic obstructive cardiomyopathy.

Constrictive pericarditis or pericardial tamponade.

Marked anaemia.

Closed-angle glaucoma.

4.4 Special Warnings And Precautions For Use

The risk/benefit ratio of Rectogesic has to be established on an individual basis. In some patients, following treatment with Rectogesic, severe headache can occur. In some cases re-evaluation of the correct dosing is suggested. In patients where the risk benefit ratio is deemed to be negative, treatment with Rectogesic should be withdrawn under the guidance of a physician and other therapeutic or surgical interventions should be initiated.

Rectogesic should be used with caution in patients who have severe hepatic or renal disease.

Excessive hypotension, especially for prolonged periods of time, must be avoided because of possible deleterious effects on the brain, heart, liver and kidney from poor perfusion and the attendant risk of ischaemia, thrombosis and altered function of these organs. Patients should be advised to change position slowly when changing from lying or sitting to upright to minimize postural hypotension. This advice is particularly important for those patients with low blood volume and under diuretic treatment. Paradoxical bradycardia and increased angina pectoris may accompany glyceryl trinitrate-induced hypotension. The elderly may be more susceptible to the development of postural hypotension, particularly on sudden rising. No specific information concerning the usage of Rectogesic in the elderly is available.

Alcohol may enhance the hypotensive effects of glyceryl trinitrate.

If the physician elects to use glyceryl trinitrate ointment for patients with acute myocardial infarction or congestive heart failure, careful clinical and haemodynamic monitoring must be used to avoid the potential hazards of hypotension and tachycardia.

If bleeding associated with haemorrhoids increases, treatment should be stopped.

This formulation contains propylene glycol and lanolin which may cause skin irritations and skin reactions (e.g. contact dermatitis).

If anal pain persists, differential diagnosis may be required to exclude other causes of the pain.

Glyceryl trinitrate can interfere with the measurement of catecholamines and vanilmandelic acid in urine as it increases the excretion of these substances.

Concomitant treatment with a number of other medicinal products should be handled with caution. Please refer to section 4.5 for specific information.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Concomitant treatment with other vasodilators, calcium channel blockers, ACE inhibitors, beta blockers, diuretics, anti-hypertensives, tricyclic anti-depressants and major tranquillisers, as well as the consumption of alcohol, may potentiate the blood pressure lowering effects of Rectogesic. Therefore, concomitant treatment with these medications should be carefully considered before treatment with Rectogesic is initiated.

The hypotensive effect of nitrates are potentiated by concurrent administration of phosphodiesterase inhibitors, e.g. sildenafil, tadalafil and vardenafil (see Section 4.3).

Rectogesic is contraindicated for concomitant treatment with, nitric oxide (NO) donors such as isosorbide dinitrate and amyl or butyl-nitrite (see Section 4.3).

Acetyl cysteine may potentiate the vasodilatory effects of glyceryl trinitrate.

Concomitant treatment with heparin leads to a decrease in heparin efficacy. Close monitoring of blood coagulation parameters is necessary and the dose of heparin has to be adapted accordingly. After withdrawal of Rectogesic there may be an abrupt increase in PTT. In this case reduction of heparin dosage may be necessary.

Concurrent administration of glyceryl trinitrate may cause a reduction of the thrombolytic activity of alteplase.

Co-administration of Rectogesic with dihydroergotamine may increase the bioavailability of dihydroergotamine and lead to coronary vasoconstriction. The possibility that the ingestion of acetylsalicylic acid and non-steroidal anti-inflammatory drugs might diminish the therapeutic response to Rectogesic cannot be excluded.

4.6 Pregnancy And Lactation

Pregnancy: There are no adequate data from the use of glyceryl trinitrate in pregnant women. Animal studies are inconclusive with respect to effects on pregnancy embryonal/foetal parturition and postnatal development (see Section 5.3). Rectogesic should not be used during pregnancy.

Lactation: It is not known whether glyceryl trinitrate is excreted in human milk. Due to the potential harmful effects on the breast fed child (see Section 5.3), the use of Rectogesic is not recommended during breast feeding.

4.7 Effects On Ability To Drive And Use Machines

No studies on the effect on the ability to drive and use machines have been performed with Rectogesic. Rectogesic may cause dizziness, light-headedness, blurred vision, headache or tiredness in some patients, especially on first use. Patients should be cautioned about driving or operating machinery while using Rectogesic.

4.8 Undesirable Effects

In patients treated with Rectogesic 4 mg/g Rectal Ointment, the most common treatment related adverse reaction was dose-related headache which occurred with an incidence of 57%.

Adverse reactions from clinical studies are displayed by system organ class in the table below. Within the system organ class, the adverse reactions are listed by frequency using the following groupings: very common (> 1/10), common (>1/100 <1/10), uncommon (>1/1000 <1/100).

System Organ Class	Frequency	Adverse Reaction
Nervous system disorder	Very common	Headache
	Common	Dizziness
Gastrointestinal disorders	Common	Nausea
	Uncommon	Diarrhoea, anal discomfort, vomiting, rectal bleeding, rectal disorder
Skin and subcutaneous tissue disorders	Uncommon	Pruritus, anal burning and itching
Cardiovascular system disorders	Uncommon	Tachycardia

Adverse reactions to glyceryl trinitrate 2% ointment (used in the prophylaxis of angina pectoris) are generally dose-related and almost all of these reactions are the result of vasodilator activity. Headache, which may be severe, is the most commonly reported side effect. In the Phase III clinical trials with Rectogesic 4 mg/g Rectal Ointment the incidence of mild, moderate and severe headache was 18%, 25% and 20%. Patients with a previous history of migraine or recurrent headache were at a higher risk of developing headache during treatment (see Section 4.3). Headache may be recurrent with each daily dose, especially at higher doses. Headache can be treated with mild analgesics e.g. paracetamol and in general is reversible on discontinuation of treatment.

Transient episodes of light-headedness, occasionally related to blood pressure changes, also may occur. Hypotension (including orthostatic hypotension) occurs infrequently, but in some patients may be severe enough to warrant discontinuation of therapy. Syncope, crescendo angina and rebound hypertension have been reported but are uncommon. Allergic reactions to glyceryl trinitrate are uncommon, and the great majority of those reported have been cases of contact dermatitis or fixed drug eruptions occurring in patients receiving glyceryl trinitrate in ointments or patches. There have been a few reports of genuine anaphylactoid reactions and these reactions can probably occur in patients receiving glyceryl trinitrate by any route. Extremely rarely, ordinary doses of organic nitrates have caused methaemoglobinaemia in normal–seeming patients. Flush has been observed as a rare adverse reaction for other products containing glyceryl trinitrate.

4.9 Overdose

Accidental overdose of Rectogesic may result in hypotension and reflex tachycardia. No specific antagonist of the vasodilator effects of nitroglycerin is known, and no intervention has been subjected to controlled study as a therapy for nitroglycerin overdose. Because the hypotension associated with nitroglycerin overdose is the result of venodilation and arterial hypovolaemia, prudent therapy in this situation should be directed toward increasing central fluid volume. Passive elevation of the patient's legs may be sufficient, but intravenous infusion of normal saline or similar fluid may also be necessary. In exceptional cases of severe hypotension or shock, resuscitation measures may be needed.

Excessive dosage may also give rise to methaemoglobinaemia. This should be treated with methylene blue infusion.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Muscle relaxants

ATC Code: C05AE01

The principal pharmacologic action of glyceryl trinitrate is mediated via the release of nitric oxide. When glyceryl trinitrate ointment is applied by the intra-anal route, the internal anal sphincter becomes relaxed.

Hypertonicity of the internal but not the external anal sphincter is a predisposing factor in the formation of anal fissures. The blood vessels to the anoderm course through the internal anal sphincter (IAS). Therefore hypertonicity of the IAS may thereby decrease blood flow and cause ischaemia to this region.

Distension of the rectum results in the anorector inhibitory reflex and relaxation of the internal anal sphincter. The nerves mediating this reflex lie in the wall of the gut. Release of the neurotransmitter NO from nerves of this type play a significant role in the physiology of the internal anal sphincter. Specifically, NO mediates the anorector inhibitory reflex in man, relaxing the IAS.

The link between IAS hypertonicity and spasm and the presence of an anal fissure has been established. Patients with chronic anal fissure have a significantly higher mean maximum resting anal pressure than controls and anodermal blood flow in chronic anal fissure patients was significantly lower than in controls. In patients whose fissures healed following a sphincterotomy, a reduction in anal pressure and improvement in anodermal blood flow was demonstrated, providing further evidence for the ischaemic nature of anal fissure. Topical application of a NO donor (glyceryl trinitrate) relaxes the anal sphincter, resulting in a reduction of anal pressure and an improvement in anoderm blood flow.

Effect on pain

In three Phase III clinical trials Rectogesic 4 mg/g Rectal Ointment has been shown to improve the average daily pain intensity associated with chronic anal fissure compared with placebo, measured using a 100mm visual analogue scale. In the first study, Rectogesic 4 mg/g Rectal Ointment decreased average daily pain intensity over 21 days by 13.3mm (baseline 39.2mm) compared to 4.3mm (baseline 25.7mm) for placebo (p<0.0063) and over 56 days by 18.8mm compared to 6.9mm (p<0.0001), respectively. This corresponds to a treatment effect (difference between the percentage change for Rectogesic and placebo) of 17.2% over 21 days and 21.1% over 56 days. In the second study, Rectogesic 4 mg/g Rectal Ointment decreased average daily pain intensity over 21 days by 11.1mm (baseline 33.4mm) compared to 7.7mm (baseline 34.0mm) for placebo (p<0.0388) and over 56 days by 17.2mm compared to 13.8mm (p<0.0039), respectively. This corresponds to a treatment effect of 10.6% over 21 days and 10.9% over 56 days. In the third study, Rectogesic 4 mg/g Rectal Ointment decreased average daily pain intensity over 21 days by 28.1mm (baseline 55.0mm) compared to 24.9mm (baseline 54.1mm) for placebo (p<0.0489) and over 56 days by 35.2mm compared to 33.8mm (p<0.0447), respectively. This corresponds to a treatment effect of 5.1% over 21 days and 1.5% over 56 days.

Effect on healing

In all three studies, healing of anal fissures in patients treated with Rectogesic 4 mg/g Rectal Ointment was not statistically different from placebo. Rectogesic is not indicated for healing of chronic anal fissure.

5.2 Pharmacokinetic Properties

The volume of distribution of glyceryl trinitrate is about 3 L/kg and is cleared from this volume at extremely rapid rates, with a resulting serum half-life of about 3 minutes. The observed clearance rates (close to 1 L/kg/min) greatly exceed hepatic blood flow. The known sites of extrahepatic metabolism include red blood cells and vascular walls. The initial products in the metabolism of glyceryl trinitrate are inorganic nitrate and the 1,2 and 1,3-dinitroglycerols. The dinitrates are less effective vasodilators than glyceryl trinitrate, but they are longer lived in the serum. Their contribution to the relaxation of the internal anal sphincter is unknown. The dinitrates are further metabolised to non-vasoactive mononitrates and ultimately to glycerol and carbon dioxide. In six healthy subjects, the average bioavailability of glyceryl trinitrate applied to the anal canal as a 0.2% ointment was approximately 50% of the 0.75 mg dose.

5.3 Preclinical Safety Data

Repeat Dose Toxicity

No systemic toxicity studies have been conducted with Rectogesic. Published data suggest that high oral doses of glyceryl trinitrate may have toxic effects (methaemoglobinaemia, testicular atrophy and aspermatogenesis) in long term treatment. However, these findings represent no special hazards for humans under the conditions of therapeutic use.

Mutagenicity and carcinogenicity

Data from preclinical studies with GTN indicate genotoxic effects in the repair deficient S. typhimurium strain TA1535 only and carcinogenic effects. However, an increased carcinogenic risk under the conditions of therapeutic use is considered very unlikely.

Reproductive Toxicity

Reproductive toxicity studies, in rats and rabbits with intravenous, intraperitoneal, and dermal administration of glyceryl trinitrate did not show any adverse effects on fertility or embryonic development at dosages which did not induce parental toxicity. No teratogenicity had been observed. In rats foetotoxic effects (decreased birth weights) were seen at dosages above 1 mg/kg/d (i.p.) and 28 mg/kg/d (dermal) after in utero exposure during foetal development.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Propylene glycol

Lanolin

Sorbitan sesquioleate

Hard paraffin

White soft paraffin

6.2 Incompatibilities

Not applicable.

6.3 Shelf Life

15 months

After first opening: 8 weeks

6.4 Special Precautions For Storage

Do not store above 25°C.

Do not freeze.

Keep the tube tightly closed.

6.5 Nature And Contents Of Container

30 g

Aluminium tubes with white polyethylene non-piercing screw caps

6.6 Special Precautions For Disposal And Other Handling

No special requirements.

7. Marketing Authorisation Holder

ProStrakan Limited

Galabank Business Park

Galashiels

TD1 1QH

UK

8. Marketing Authorisation Number(S)

PL 16508/0037

9. Date Of First Authorisation/Renewal Of The Authorisation

28/08/2009

10. Date Of Revision Of The Text

28/08/2009

Wilzin 25 mg hard capsules

1. Name Of The Medicinal Product

Wilzin25 mg hard capsules

2. Qualitative And Quantitative Composition

Each hard capsule contains 25 mg of zinc (corresponding to 83.92 mg of zinc acetate dihydrate).

For excipients, see section 6.1.

3. Pharmaceutical Form

Hard capsule.

Size 1 hard capsule with aqua blue opaque cap and body, imprinted "93-376”.

4. Clinical Particulars

4.1 Therapeutic Indications

Treatment of Wilson's disease.

4.2 Posology And Method Of Administration

Wilzin treatment should be initiated under the supervision of a physician experienced in the treatment of Wilson's disease (see section 4.4). Wilzin is a life-long therapy.

There is no difference in dosage between symptomatic and presymptomatic patients.

Wilzin is available in hard capsules of 25 mg or 50 mg.

•Adults:

The usual dosage is 50 mg 3 times daily with a maximum dose of 50 mg 5 times daily.

•Children and adolescents:

Data are very limited in children under 6 years but since the disease is fully penetrant, prophylactic treatment should be considered as early as possible. The recommended dosage is as follows:

- from 1 to 6 years: 25 mg twice daily

- from 6 to 16 years if bodyweight under 57 kg: 25 mg three times daily

- from 16 years or if bodyweight above 57 kg: 50 mg three times daily.

•Pregnant women:

A dosage of 25 mg 3 times daily is usually effective but the dosage should be adjusted to copper levels (see section 4.4 and section 4.6).

In all cases, dosage should be adjusted according to therapeutic monitoring (see section 4.4.).

Wilzin must be taken on an empty stomach, at least 1 hour before or 2-3 hours after meals. In case of gastric intolerance, often occurring with the morning dose, this dose may be delayed to mid-morning, between breakfast and lunch. It is also possible to take Wilzin with a little protein, such as meat (see section 4.5).

In children who are unable to swallow capsules, these should be opened and their content suspended in a little water (possibly sugar or syrup flavoured water).

When switching a patient on chelating treatment to Wilzin for maintenance therapy, the chelating treatment should be maintained and co-administered for 2 to 3 weeks since this is the time it takes for the zinc treatment to induce maximum metallothionein induction and full blockade of copper absorption. The administration of the chelating treatment and Wilzin should be separated by at least 1 hour.

4.3 Contraindications

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

4.4 Special Warnings And Precautions For Use

Zinc acetate dihydrate is not recommended for the initial therapy of symptomatic patients because of its slow onset of action. Symptomatic patients must be initially treated with a chelating agent; once copper levels are below toxic thresholds and patients are clinically stable, maintenance treatment with Wilzin can be considered.

Nevertheless, while awaiting zinc induced duodenal metallothionein production and consequential effective inhibition of copper absorption, zinc acetate dihydrate could be administered initially in symptomatic patients in combination with a chelating agent.

Although rare, clinical deterioration may occur at the beginning of the treatment, as has also been reported with chelating agents. Whether this is related to mobilisation of copper stores or to natural history of the disease remains unclear. A change of therapy is recommended in this situation.

Caution should be exercised when switching patients with portal hypertension from a chelating agent to Wilzin, when such patients are doing well and the treatment is tolerated. Two patients of a series of 16 died from hepatic decompensation and advanced portal hypertension after being changed from penicillamine to zinc therapy.

Therapeutic monitoring

The aim of the treatment is to maintain the plasma free copper (also known as non-ceruloplasmin plasma copper) below 250 microgram/l (normal: 100-150 microgram/l) and the urinary copper excretion below 125 microgram/24 h (normal: < 50 microgram/24 h). The non-ceruloplasmin plasma copper is calculated by subtracting the ceruloplasmin-bound copper from the total plasma copper, given that each milligram of ceruloplasmin contains 3 micrograms of copper.

The urinary excretion of copper is an accurate reflection of body loading with excess copper only when patients are not on chelation therapy. Urinary copper levels are usually increased with chelation therapy such as penicillamine or trientine.

The level of hepatic copper cannot be used to manage therapy since it does not differentiate between potentially toxic free copper and metallothionein bound copper.

In treated patients, assays of urinary and/or plasma zinc may be a useful measure of treatment compliance. Values of urinary zinc above 2 mg/24 h and of plasma zinc above 1250 microgram/l generally indicate adequate compliance.

Like with all anti-copper agents overtreatment carries the risk of copper deficiency, which is especially harmful for children and pregnant women since copper is required for proper growth and mental development. In these patient groups, urinary copper levels should be kept a little above the upper limit of normal or in the high normal range (i.e. 40 – 50 microgram/24 h).

Laboratory follow-up including haematological surveillance and lipoproteins determination should also be performed in order to detect early manifestations of copper deficiency, such as anaemia and/or leukopenia resulting from bone marrow depression, and decrease in HDL cholesterol and HDL/total cholesterol ratio.

In case of gastric intolerance, often occurring with the morning dose, this dose may be delayed to mid-morning, between breakfast and lunch. It is also possible to take Wilzin with a little protein, such as meat (see section 4.5).

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Other anti-copper agents

Pharmacodynamic studies were conducted in Wilson's disease patients on the combination of Wilzin (50 mg three times daily) with ascorbic acid (1 g once daily), penicillamine (250 mg four times daily), and trientine (250 mg four times daily). They showed no significant overall effect on copper balance although mild interaction of zinc with chelators (penicillamine and trientine) could be detected with decreased faecal but increased urinary copper excretion as compared with zinc alone. This is probably due to some extent of complexion of zinc by the chelator, thus reducing the effect of both active substances.

When switching a patient on chelating treatment to Wilzin for maintenance therapy, the chelating treatment should be maintained and co-administered for 2 to 3 weeks since this is the time it takes for the zinc treatment to induce maximum metallothionein induction and full blockade of copper absorption. The administration of the chelating treatment and Wilzin should be separated by at least 1 hour.

Other medicinal products

The absorption of zinc may be reduced by iron and calcium supplements, tetracyclines and phosphorus-containing compounds, while zinc may reduce the absorption of iron, tetracyclines, fluoroquinolones.

Food

Studies of the co-administration of zinc with food performed in healthy volunteers showed that the absorption of zinc was significantly delayed by many foods (including bread, hard boiled eggs, coffee and milk). Substances in food, especially phytates and fibres, bind zinc and prevent it from entering the intestinal cells. However, protein appears to interfere the least.

4.6 Pregnancy And Lactation

Pregnancy:

Data on a limited number of exposed pregnancies in patients with Wilson's disease give no indication of harmful effects of zinc on embryo/foetus and mother. Five miscarriages and 2 birth defects (microcephaly and correctable heart defect) were reported in 42 pregnancies.

Animal studies conducted with different zinc salts do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development (see section 5.3).

It is extremely important that pregnant Wilson's disease patients continue their therapy during pregnancy. Which treatment should be used, zinc or chelating agent should be decided by the physician. Dose adjustments to guarantee that the foetus will not become copper deficient must be done and close monitoring of the patient is mandatory (see section 4.4).

Lactation:

Zinc is excreted in human breast milk and zinc-induced copper deficiency in the breast-fed baby may occur. Therefore, breast-feeding should be avoided during Wilzin therapy.

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.

4.8 Undesirable Effects

Clinical experience of more than 1 000 patient-years with zinc (more than 500 with zinc acetate dihydrate) as well as post-marketing surveillance with zinc acetate dihydrate of more than 1 000 patient-years showed that the most common undesirable effect is gastric irritation. This is usually worst with the first morning dose and disappears after the first days of treatment. Delaying the first dose to mid-morning or taking the dose with a little protein may usually relieve the symptoms.

Reported adverse reactions are listed below, by system organ class and by frequency. Frequencies are defined as: very common (> 1/10), common (>1/100, <1/10) and uncommon (>1/1,000, <1/100):

Blood and lymphatic system disorders	uncommon:	sideroblastic anaemia; leukopenia
Gastrointestinal disorders	common:	gastric irritation
Laboratory investigations	common:	blood amylase, lipase and alkaline phosphatase increased

Anaemia may be micro-, normo- or macrocytic and is often associated with leukopenia. Bone marrow examination usually reveals characteristic "ringed sideroblasts" (i.e. developing red blood cells containing iron-engorged paranuclear mitochondria). They may be early manifestations of copper deficiency and may recover rapidly following reduction of zinc dosage. However, they must be distinguished from haemolytic anaemia which commonly occurs where there is elevated serum free copper in uncontrolled Wilson's disease.

Elevations of serum alkaline phosphatase, amylase and lipase may occur after a few weeks of treatment, with levels usually returning to high normal within the first one or two years of treatment.

4.9 Overdose

Three cases of acute oral overdosage with zinc salts (sulphate or gluconate) have been reported in the literature. Death occurred in a 35 year-old woman on the fifth day after ingestion of 6 g of zinc (40 times the proposed therapeutic dose) and was attributed to renal failure and haemorrhagic pancreatitis with hyperglycaemic coma. The same dose did not produce any symptoms except for vomiting in an adolescent who was treated by whole-bowel irrigation. Another adolescent who ingested 4 g of zinc had serum zinc level of about 50 mg/l 5 hours later and only experienced severe nausea, vomiting and dizziness.

Treatment of overdose should be with gastric lavage or induced emesis as quickly as possible to remove unabsorbed zinc. Heavy metal chelation therapy should be considered if plasma zinc levels are markedly elevated (> 10 mg/l).

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: various alimentary tract and metabolism product, ATC code: A16AX05.

Wilson's disease (hepatolenticular degeneration) is an autosomal recessive metabolic defect in hepatic excretion of copper in the bile. Copper accumulation in the liver leads to hepatocellular injury and eventual cirrhosis. When the liver capacity of storing copper is exceeded copper is released into the blood and is taken up in extra hepatic sites, such as the brain, resulting in motor disorders and psychiatric manifestations. Patients may present clinically with predominantly hepatic, neurologic, or psychiatric symptoms.

The active moiety in zinc acetate dihydrate is zinc cation, which blocks the intestinal absorption of copper from the diet and the reabsorption of endogenously secreted copper. Zinc induces the production of metallothionein in the enterocyte, a protein that binds copper thereby preventing its transfer into the blood. The bound copper is then eliminated in the stool following desquamation of the intestinal cells.

Pharmacodynamic investigations of copper metabolism in patients with Wilson's disease included determinations of net copper balance and radiolabelled copper uptake. A daily regimen of 150 mg of Wilzin in three administrations was shown to be effective in significantly reducing copper absorption and inducing a negative copper balance.

5.2 Pharmacokinetic Properties

Since the mechanism of action of zinc is an effect on copper uptake at the level of the intestinal cell, pharmacokinetic evaluations based on blood levels of zinc do not provide useful information on zinc bioavailability at the site of action.

Zinc is absorbed in the small intestine and its absorption kinetics suggest a tendency to saturation at increasing doses. Fractional zinc absorption is negatively correlated with zinc intake. It ranges from 30 to 60% with usual dietary intake (7-15 mg/d) and decreases to 7% with pharmacological doses of 100 mg/d.

In the blood, about 80% of absorbed zinc is distributed to erythrocytes, with most of the remainder being bound to albumin and other plasma proteins. The liver is the main storage for zinc and hepatic zinc levels are increased during maintenance therapy with zinc.

The plasma elimination half-life of zinc in healthy subjects is around 1 hour after a dose of 45 mg. The elimination of zinc results primarily from faecal excretion with relatively little from urine and sweat. The faecal excretion is in the greatest part due to the passage of unabsorbed zinc but it is also due to endogenous intestinal secretion.

5.3 Preclinical Safety Data

Preclinical studies have been conducted with zinc acetate and with other zinc salts. Pharmacological and toxicological data available showed large similarities between zinc salts and among animal species.

The oral LD50 is approximately 300 mg zinc/kg body weight (about 100 to 150 times the human therapeutic dose). Repeat-dose toxicity studies have established that the NOEL (No Observed Effect Level) is about 95 mg zinc/kg body weight (about 48 times the human therapeutic dose).

The weight of evidence, from in vitro and in vivo tests, suggests that zinc has no clinically relevant genotoxic activity.

Reproduction toxicology studies performed with different zinc salts showed no clinically relevant evidence of embryotoxicity, foetotoxicity or teratogenicity.

No conventional carcinogenicity study has been conducted with zinc acetate dihydrate.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Capsule content:

maize starch

magnesium stearate

Capsule shell:

gelatin

titanium dioxide (E171)

brilliant blue FCF (E133)

Printing ink:

black iron oxide (E172)

shellac

6.2 Incompatibilities

Not applicable

6.3 Shelf Life

2 years

6.4 Special Precautions For Storage

Do not store above 25°C.

6.5 Nature And Contents Of Container

White HDPE bottle which is equipped with a polypropylene and HDPE closure and contains a filler (cotton coil). Each bottle contains 250 capsules.

6.6 Special Precautions For Disposal And Other Handling

No special requirements

7. Marketing Authorisation Holder

Orphan Europe SARL

Immeuble “Le Wilson”

F-92058 Paris-La-Défense - France

8. Marketing Authorisation Number(S)

EU/1/04/286/001

9. Date Of First Authorisation/Renewal Of The Authorisation

13 October 2004

10. Date Of Revision Of The Text

Reductil 10mg & 15mg (Abbott Laboratories Limited)

1. Name Of The Medicinal Product

Reductil 10 mg capsules, hard

Reductil 15 mg capsules, hard

2. Qualitative And Quantitative Composition

One capsule of Reductil 10 mg contains 10 mg of sibutramine hydrochloride monohydrate (equivalent to 8.37 mg of sibutramine).

One capsule of Reductil 10 mg contains 201.4 mg of lactose

One capsule of Reductil 15 mg contains 15 mg of sibutramine hydrochloride monohydrate (equivalent to 12.55 mg of sibutramine).

One capsule of Reductil 15 mg contains 196.7 mg of lactose

For a full list of excipients, see 6.1

3. Pharmaceutical Form

10 mg Hard capsule with a blue cap and yellow body

15 mg Hard capsule with a blue cap and white body

4. Clinical Particulars

4.1 Therapeutic Indications

Reductil 10 mg / 15 mg is indicated as adjunctive therapy within a weight management programme for:

- Patients with nutritional obesity and a body mass index (BMI) of 30 kg/m² or higher

- Patients with nutritional excess weight and a BMI of 27 kg/m² or higher, if other obesity-related risk factors such as type 2 diabetes or dyslipidaemia are present.

Note:

Reductil may only be prescribed to patients who have not adequately responded to an appropriate weight-reducing regimen alone, ie patients who have difficulty achieving or maintaining>5% weight loss within 3 months.

Treatment with Reductil 10 mg / 15 mg should only be given as part of a long-term integrated therapeutic approach for weight reduction under the care of a physician experienced in the treatment of obesity. An appropriate approach to obesity management should include dietary and behavioural modification as well as increased physical activity. This integrated approach is essential for a lasting change in eating habits and behaviour which is fundamental to the long-term maintenance of the reduced weight level once Reductil is stopped. Patients should change their lifestyle while on Reductil so that they are able to maintain their weight once drug treatment has ceased. They should be informed that, if they fail to do so, they may regain weight. Even after cessation of Reductil continued monitoring of the patient by the physician should be encouraged.

4.2 Posology And Method Of Administration

Adults: The initial dose is one (1) capsule of Reductil 10 mg swallowed whole, once daily, in the morning, with liquid (eg a glass of water). The capsule can be taken with or without food.

In those patients with an inadequate response to Reductil 10 mg (defined as less than 2 kg weight loss after four (4) weeks treatment), the dose may be increased to one (1) capsule of Reductil 15 mg once daily, provided that Reductil 10 mg was well tolerated.

Treatment must be discontinued in patients who have responded inadequately to Reductil 15 mg (defined as less than 2 kg weight loss after four (4) weeks treatment). Non-responders are at a higher risk of undesirable effects (see section 4.8 “Undesirable Effects”).

Duration of treatment:

Treatment must be discontinued in patients who have not responded adequately, ie whose weight loss stabilises at less than 5% of their initial bodyweight or whose weight loss within three (3) months after starting therapy has been less than 5% of their initial bodyweight. Treatment should not be continued in patients who regain 3 kg or more after previously achieved weight loss.

In patients with associated co-morbid conditions, it is recommended that treatment with Reductil 10 mg / 15 mg should only be continued if it can be shown that the weight loss induced is associated with other clinical benefits, such as improvements in lipid profile in patients with dyslipidaemia or glycaemic control of type 2 diabetes.

Reductil 10 mg / 15 mg should only be given for periods up to one year. Data on use over one year is limited.

4.3 Contraindications

- Known hypersensitivity to sibutramine hydrochloride monohydrate or to any of the excipients

- Organic causes of obesity

- History of major eating disorders

- Psychiatric illness. Sibutramine has shown potential antidepressant activity in animal studies and, therefore it cannot be excluded that sibutramine could induce a manic episode in bipolar patients.

- Gilles de la Tourette's syndrome

- Concomitant use, or use during the past two weeks, of monoamine oxidase inhibitors or of other centrally-acting drugs for the treatment of psychiatric disorders (such as antidepressants, antipsychotics) or for weight reduction, or tryptophan for sleep disturbances.

- History of coronary artery disease, congestive heart failure, tachycardia, peripheral arterial occlusive disease, arrhythmia or cerebrovascular disease (stroke or TIA)

- Inadequately controlled hypertension >145/90 mmHg; see section 4.4 “Special warnings and special precautions”)

- Hyperthyroidism

- Severe hepatic impairment

- Severe renal impairment and in patients with end stage renal disease on dialysis

- Benign prostatic hyperplasia with urinary retention

- Phaeochromocytoma

- Narrow angle glaucoma

- History of drug, medication or alcohol abuse

- Pregnancy and lactation (see section 4.6 “Pregnancy and lactation”)

- Children and young adults up to the age of 18 years, owing to insufficient data

- Patients above 65 years of age, owing to insufficient data.

4.4 Special Warnings And Precautions For Use

Warnings:

Blood pressure and pulse rate should be monitored in all patients on Reductil 10 mg / 15mg, as sibutramine has caused clinically relevant increases in blood pressure in some patients. In the first three months of treatment, these parameters should be checked every 2 weeks; between month 4 and 6 these parameters should be checked once monthly and regularly thereafter, at maximum intervals of three months. Treatment should be discontinued in patients who have an increase, at two consecutive visits, in resting heart rate of > 10 bpm or systolic/diastolic blood pressure of > 10 mmHg. In previously well-controlled hypertensive patients, if blood pressure exceeds 145/90 mmHg at two consecutive readings, treatment should be discontinued (see section 4.8 “Undesirable effects, cardiovascular system”). In patients with sleep apnoea syndrome particular care should be taken in monitoring blood pressure.

- For use of sibutramine concomitantly with sympathomimetics, please refer to section 4.5.

- Although sibutramine has not been associated with primary pulmonary hypertension, it is important, in view of general concerns with anti-obesity drugs, to be on the look out for symptoms such as progressive dyspnoea, chest pain and ankle oedema in the course of routine check-ups. The patient should be advised to consult a doctor immediately if these symptoms occur.

- Reductil 10 mg / 15 mg should be given with caution to patients with epilepsy.

- Increased plasma levels have been observed in the assessment of sibutramine in patients with mild to moderate hepatic impairment. Although no adverse effects have been reported, Reductil 10 mg / 15 mg should be used with caution in these patients.

- Although only inactive metabolites are excreted by the renal route, Reductil 10 mg / 15 mg should be used with caution in patients with mild to moderate renal impairment.

- Reductil 10 mg / 15 mg should be given with caution to patients who have a family history of motor or verbal tics.

- Women of child-bearing potential should employ adequate contraception whilst taking Reductil 10 mg / 15 mg.

- There is the possibility of drug abuse with CNS-active drugs. However, available clinical data have shown no evidence of drug abuse with sibutramine.

- There are general concerns that certain anti-obesity drugs are associated with an increased risk of cardiac valvulopathy. However, clinical data show no evidence of an increased incidence with sibutramine.

- Patients with a history of major eating disorders, such as anorexia nervosa and bulimia nervosa, are contraindicated. No data are available for sibutramine in the treatment of patients with binge (compulsive) eating disorder.

- Sibutramine should be given with caution to patients with open angle glaucoma and those who are at risk of raised intraocular pressure, e.g. family history.

- In common with other agents that inhibit serotonin reuptake, there is a potential for an increased risk of bleeding (including gynaecological, gastrointestinal and other cutaneous or mucous bleeding) in patients taking sibutramine. Sibutramine should, therefore, be used with caution in patients predisposed to bleeding events and those taking concomitant medications known to affect haemostasis or platelet function.

- Cases of depression, psychosis, mania, suicidal ideation and suicide have been reported rarely in patients on sibutramine treatment. If any of these events should occur during treatment with sibutramine, discontinuation should be considered.

- Reductil 10 mg / 15 mg contains lactose and therefore should not be used in patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Sibutramine and its active metabolites are eliminated by hepatic metabolism; the main enzyme involved is CYP3A4, and CYP2C9 and CYP1A2 can also contribute.Caution should be exercised on concomitant administration of Reductil 10 mg / 15 mg with drugs which affect CYP3A4 enzyme activity (see section 5.2 “Pharmacokinetic properties”). CYP3A4 inhibitors include ketoconazole, itraconazole, erythromycin, clarithromycin, troleandomycin and cyclosporin. Co-administration of ketoconazole or erythromycin with sibutramine increased plasma concentrations (AUC) of sibutramine active metabolites (23% or 10% respectively) in an interaction study. Mean heart rate increased by up to 2.5 beats per minute more than on sibutramine alone.

Rifampicin, phenytoin, carbamazepine, phenobarbital and dexamethasone are CYP3A4 enzyme inducers and may accelerate sibutramine metabolism, although this has not been studied experimentally.

The simultaneous use of several drugs, each of which increases levels of serotonin in the brain, may give rise to serious interactions. This phenomenon is called serotonin syndrome and may occur in rare cases in connection with the simultaneous use of a selective serotonin reuptake inhibitor [SSRI] together with certain antimigraine drugs (such as sumatriptan, dihydroergotamine), or along with certain opioids (such as pentazocine, pethidine, fentanyl, dextromethorphan), or in the case of simultaneous use of two SSRIs.

As sibutramine inhibits serotonin reuptake (among other effects), Reductil 10 mg / 15mg should not be used concomitantly with other drugs which also raise serotonin levels in the brain.

Concomitant use of Reductil 10 mg / 15 mg with other drugs which may raise the blood pressure or heart rate (e.g. sympathomimetics) has not been systematically evaluated. Drugs of this type include certain cough, cold and allergy medications (eg ephedrine, pseudoephedrine), and certain decongestants (eg xylometazoline). Caution should be used when prescribing Reductil 10 mg / 15 mg to patients who use these medicines.

Reductil 10 mg / 15 mg does not impair the efficacy of oral contraceptives.

At single doses, there was no additional impairment of cognitive or psychomotor performance when sibutramine was administered concomitantly with alcohol. However, the consumption of alcohol is not compatible with the recommended dietary measures as a general rule.

No data on the concomitant use of Reductil 10 mg / 15 mg with orlistat are available.

Two weeks should elapse between stopping sibutramine and starting monoamine oxidase inhibitors.

4.6 Pregnancy And Lactation

Use in pregnancy: Sibutramine is contraindicated in pregnancy (see Section 4.3). Women of childbearing potential have to use effective contraception during and for 5 weeks after treatment with sibutramine. No controlled studies with Reductil have been conducted in pregnant women. Studies in pregnant rabbits have shown effects on reproduction at maternally toxic doses (see section 5.3 “Preclinical safety data”). The relevance of these findings to humans is unknown.

Use in lactation: It is not known whether sibutramine is excreted in human breast milk and therefore administration of Reductil 10 mg / 15 mg is contraindicated during lactation.

4.7 Effects On Ability To Drive And Use Machines

Although sibutramine did not affect psychomotor or cognitive performance in healthy volunteers, any centrally-acting drug may impair judgement, thinking or motor skills. Therefore, patients should be cautioned that their ability to drive a vehicle, operate machinery or work in a hazardous environment may be impaired when taking Reductil 10 mg / 15 mg.

4.8 Undesirable Effects

Most side effects reported with sibutramine occurred at the start of treatment (during the first 4 weeks). Their severity and frequency diminished over time. They were generally not serious, did not entail discontinuation of treatment, and were reversible.

The side effects observed in phase II/III clinical trials are listed below by body system (very common >1/10), (common >1/100 to <1/10):

Body system	Frequency	Undesirable effects
Cardiovascular system (see detailed information below)	Common	Tachycardia Palpitations Raised blood pressure/hypertension Vasodilation (hot flush)
Gastrointestinal system	Very common	Constipation
	Common	Nausea Haemorrhoid aggravation
Central nervous system	Very common	Dry mouth Insomnia
	Common	Light-headedness Paraesthesia Headache Anxiety
Skin	Common	Sweating
Sensory functions		Taste perversion

Cardiovascular system

A mean increase in resting systolic and diastolic blood pressure of 2-3 mmHg, and a mean increase in heart rate of 3-7 beats per minute have been observed. Higher increases in blood pressure and heart rate cannot be excluded in isolated cases.

Any clinically significant increase in blood pressure and pulse rate tends to occur early on in treatment (first 4-12 weeks). Therapy should be discontinued in such cases (see Section 4.4 “Special warnings and special precautions.”).

For use of Reductil 10 mg / 15 mg in patients with hypertension, see section 4.3 “Contraindications” and 4.4 “Special warnings and special precautions”.

Clinically significant adverse events seen in clinical studies and during postmarketing surveillance are listed below by body system:

Blood and lymphatic system disorders:

Thrombocytopenia, Henoch-Schonlein purpura

Cardiovascular disorders:

Atrial fibrillation, paroxysmal supraventricular tachycardia

Immune system disorders:

Allergic hypersensitivity reactions ranging from mild skin eruptions and urticaria to angioedema and anaphylaxis have been reported

Psychiatric disorders:

Agitation, mania, psychosis, suicidal ideation and suicide.

Depression in patients both with and without a prior history of depression (see section 4.4).

Nervous system disorders:

Seizures

Serotonin syndrome in combination with other agents affecting serotonin release (section 4.5).

Transient short-term memory disturbance

Eye disorders:

Blurred vision

Gastrointestinal disorders:

Diarrhoea, vomiting, gastrointestinal haemorrhage

Skin and subcutaneous tissue disorders:

Alopecia, rash, urticaria, cutaneous bleeding reactions (ecchmosis, petechiae)

Renal and urinary disorders:

Acute interstitial nephritis, mesangiocapillary glomerulonephritis, urinary retention

Reproductive system and breast disorders:

Abnormal ejaculation/orgasm, impotence, menstrual cycle disorders, metrorrhagia

Investigations:

Reversible increases in liver enzymes

Other:

Withdrawal symptoms such as headache and increased appetite have rarely been observed.

4.9 Overdose

There is limited experience of overdosing with sibutramine. The most frequently noted adverse events associated with overdose are tachycardia, hypertension, headache and dizziness. Treatment should consist of the general measures employed in the management of overdosing, such as keeping airways unobstructed as needed, monitoring of cardiovascular functions and general symptomatic and supportive measures. Early administration of activated charcoal may delay the absorption of sibutramine. Gastric lavage may also be of benefit. Cautious use of beta-blockers may be indicated in patients with elevated blood pressure or tachycardia.The results from a study in patients with end-stage renal disease on dialysis showed that sibutramine metabolites were not eliminated to a significant degree with hemodialysis.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: anti-obesity drug, ATC code A08A A10.

Sibutramine produces its therapeutic effects predominantly via its active secondary and primary amine metabolites (metabolite 1 and metabolite 2) which are inhibitors of noradrenaline, serotonin (5-hydroxytryptamine; 5₁, 5_1A, 5-HT_1B, 5-HT_2A, 5_2C), adrenergic (β₁, β₂, β₃, α₁, α₂), dopaminergic (D₁-like, D₂-like), muscarinic, histaminergic (H₁), benzodiazepine and NMDA receptors.

In animal models using lean growing and obese rats, sibutramine produces a reduction in bodyweight gain. This is believed to result from its impact on food intake, ie by enhancing satiety, but enhanced thermogenesis also contributes to weight loss. These effects have been shown to be mediated by the inhibition of serotonin and noradrenaline re-uptake.

In clinical trials in man, Reductil was shown to effect weight loss by enhancing satiety. Data are also available which demonstrate a thermogenic effect of Reductil by attenuating the adaptive decline in resting metabolic rate during weight loss. Weight loss induced by Reductil is accompanied by beneficial changes in serum lipids and glycaemic control in patients with dyslipidaemia and type 2 diabetes, respectively.

In obese patients with type 2 diabetes mellitus weight loss with sibutramine was associated with mean reductions of 0.6% (unit) in HbA_1c. Similarly, in obese patients with dyslipidaemia, weight loss was associated with increases in HDL cholesterol of 12-22% and reductions in triglycerides of 9-21%.

5.2 Pharmacokinetic Properties

Sibutramine is well absorbed and undergoes extensive first-pass metabolism. Peak plasma levels (C_max) were achieved 1.2 hours after a single oral dose of 20 mg of sibutramine hydrochloride monohydrate. The half-life of the parent compound is 1.1 hours. The pharmacologically active metabolites 1 and 2 reach C_max in three hours with elimination half-lives of 14 and 16 hours, respectively. Linear kinetics have been demonstrated over the dose range of 10 to 30 mg, with no dose-related change in the elimination half-lives but a dose-proportionate increase in plasma concentrations. On repeated dosing, steady-state concentrations of metabolites 1 and 2 are achieved within 4 days, with an approximately 2-fold accumulation. The pharmacokinetics of sibutramine and its metabolites in obese subjects are similar to those in normal weight subjects. The relatively limited data available so far provide no evidence of a clinically relevant difference in the pharmacokinetics of males and females. The pharmacokinetic profile observed in elderly healthy subjects (mean age 70 years) was similar to that seen in young healthy subjects.

Renal Impairment

The disposition of sibutramine metabolites 1, 2, 5 and 6 was studied in patients with varying degrees of renal function. Sibutramine itself was not measurable.

The AUCs of active metabolites 1 and 2 were generally not affected by renal impairment, except that the AUC of metabolite 2 in end-stage renal disease patients on dialysis was approximately half of that measured in normal subjects (CLcr

Sibutramine should not be used in patients with severe renal impairment, including end-stage renal disease patients on dialysis.

Hepatic impairment

In subjects with moderate hepatic impairment, bioavailability of the active metabolites was 24% higher after a single dose of sibutramine. Plasma protein binding of sibutramine and its metabolites 1 and 2 amounts to approximately 97%, 94% and 94%, respectively. Hepatic metabolism is the major route of elimination of sibutramine and its active metabolites 1 and 2. Other (inactive) metabolites are excreted primarily via the urine, at a urine: faeces ratio of 10 : 1.

In vitro hepatic microsome studies indicated that CYP3A4 is the major cytochrome P450 isoenzyme responsible for sibutramine metabolism. In vitro, there was no indication of an affinity with CYP2D6, a low capacity enzyme involved in pharmacokinetic interactions with various drugs. Further in vitro studies have revealed that sibutramine has no significant effect on the activity of the major P450 isoenzymes, including CYP3A4. The CYP450s involved in the further metabolism of metabolite 2 were shown (in vitro) to be CYP3A4 and CYP2C9. Although there are no data at present, it is likely that CYP3A4 is also involved in further metabolism of metabolite 1.

5.3 Preclinical Safety Data

The toxicity of sibutramine seen after single doses in experimental animals has generally been a result of exaggerated pharmacodynamic effects. Longer-term treatment was associated with only mild pathological changes and secondary or species-related findings. It follows that they are unlikely to present concerns during the proper clinical use of sibutramine. Reproduction studies were conducted in rats and rabbits. In rabbits, one study showed a slightly higher incidence of fetal cardiovascular anomalies in the treatment groups than in the control group, while another study showed a lower incidence than in controls. In addition, in the latter study but not in the former, the treatment group had slightly more fetuses with two minor anomalies (a tiny thread-like ossified connection between the maxilla and jugal bones, and very slight differences in the spacing of the roots of some small arteries from the aortic arch). The relevance of these findings to humans is unknown. Sibutramine's use in human pregnancy has not been investigated. Extensive genetic toxicity tests disclosed no evidence of sibutramine-induced mutagenicity. Studies in rodents have shown that sibutramine has no carcinogenic potential relevant to man.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Capsule content: lactose monohydrate, magnesium stearate, microcrystalline cellulose, colloidal anhydrous silica.

Capsule shell (10 mg): indigo carmine (E 132), titanium dioxide (E 171), gelatin, sodium lauryl sulphate, quinoline yellow (E 104).

Capsule shell (15 mg): indigo carmine (E 132), titanium dioxide (E 171), gelatin, sodium lauryl sulphate.

Printing ink: dimethicone, propylene glycol, iron oxide black (E 172), shellac glaze, lecithin (E 322), titanium dioxide (E 171).

6.2 Incompatibilities

Not applicable

6.3 Shelf Life

3 years

6.4 Special Precautions For Storage

Do not store above 25°C. Store in the original package in order to protect from light and moisture.

6.5 Nature And Contents Of Container

Reductil 10 mg / 15 mg, capsules in a PVC/PVDC blister strip pack.

Calendar pack containing 28 capsules (4 weeks)

6.6 Special Precautions For Disposal And Other Handling

No special requirements

7. Marketing Authorisation Holder

Abbott Laboratories Limited

Queenborough

Kent ME11 5EL

United Kingdom

8. Marketing Authorisation Number(S)

Reductil 10 mg: PL 0037/0326

Reductil 15 mg: PL 0037/0327

9. Date Of First Authorisation/Renewal Of The Authorisation

14 January 2004

10. Date Of Revision Of The Text

31 December 2009