Plaquenil Tablets

1. Name Of The Medicinal Product

Plaquenil 200mg Tablets

2. Qualitative And Quantitative Composition

Hydroxychloroquine Sulphate BP 200mg

3. Pharmaceutical Form

Film coated tablet.

4. Clinical Particulars

4.1 Therapeutic Indications

Treatment of rheumatoid arthritis, juvenile chronic arthritis, discoid and systemic lupus erythematosus, and dermatological conditions caused or aggravated by sunlight.

4.2 Posology And Method Of Administration

Adults (including the elderly)

The minimum effective dose should be employed. This dose should not exceed 6.5mg/kg/day (calculated from ideal body weight and not actual body weight) and will be either 200mg or 400mg per day.

In patients able to receive 400mg daily:

Initially 400mg daily in divided doses. The dose can be reduced to 200mg when no further improvement is evident. The maintenance dose should be increased to 400mg daily if the response lessens.

Children

The minimum effective dose should be employed and should not exceed 6.5mg/kg/day based on ideal body weight. The 200mg tablet is therefore not suitable for use in children with an ideal body weight of less than 31kg.

Each dose should be taken with a meal or glass of milk.

Hydroxychloroquine is cumulative in action and will require several weeks to exert its beneficial effects, whereas minor side effects may occur relatively early. For rheumatic disease treatment should be discontinued if there is no improvement by 6 months. In light-sensitive diseases, treatment should only be given during periods of maximum exposure to light.

The tablets are for oral administration.

4.3 Contraindications

- known hypersensitivity to 4-aminoquinoline compounds

- pre-existing maculopathy of the eye

- pregnancy (see section 4.6 Pregnancy and lactation).

4.4 Special Warnings And Precautions For Use

General

• The occurrence of retinopathy is very uncommon if the recommended daily dose is not exceeded. The administration of doses in excess of the recommended maximum is likely to increase the risk of retinopathy, and accelerate its onset.

• All patients should have an ophthalmological examination before initiating treatment with Plaquenil. Thereafter, ophthalmological examinations must be repeated at least every 12 months.

The examination should include testing visual acuity, careful ophthalmoscopy, fundoscopy, central visual field testing with a red target, and colour vision.

This examination should be more frequent and adapted to the patient in the following situations:

- daily dosage exceeds 6.5mg/kg lean body weight. Absolute body weight used as a guide to dosage could result in an overdosage in the obese.

- renal insufficiency

- visual acuity below 6/8

- age above 65 years

- cumulative dose more than 200 g.

Plaquenil should be discontinued immediately in any patient who develops a pigmentary abnormality, visual field defect, or any other abnormality not explainable by difficulty in accommodation or presence of corneal opacities. Patients should continue to be observed for possible progression of the changes.

Patients should be advised to stop taking the drug immediately and seek the advice of their prescribing doctor if any disturbances of vision are noted, including abnormal colour vision.

Plaquenil should be used with caution in patients taking medicines which may cause adverse ocular or skin reactions. Caution should also be applied when it is used in the following:

• patients with hepatic or renal disease, and in those taking drugs known to affect those organs. Estimation of plasma hydroxychloroquine levels should be undertaken in patients with severely compromised renal or hepatic function and dosage adjusted accordingly.

• patients with severe gastrointestinal, neurological or blood disorders.

Although the risk of bone marrow depression is low, periodic blood counts are advisable as anaemia, aplastic anaemia, agranulocytosis, a decrease in white blood cells, and thrombocytopenia have been reported. Plaquenil should be discontinued if abnormalities develop.

Caution is also advised in patients with a sensitivity to quinine, those with glucose-6-phosphate dehydrogenase deficiency, those with porphyria cutanea tarda which can be exacerbated by hydroxychloroquine and in patients with psoriasis since it appears to increase the risk of skin reactions.

Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Small children are particularly sensitive to the toxic effects of 4-aminoquinolines; therefore patients should be warned to keep Plaquenil out of the reach of children.

All patients on long-term therapy should undergo periodic examination of skeletal muscle function and tendon reflexes. If weakness occurs, the drug should be withdrawn.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Hydroxychloroquine sulphate has been reported to increase plasma digoxin levels: serum digoxin levels should be closely monitored in patients receiving combined therapy.

Hydroxychloroquine sulphate may also be subject to several of the known interactions of chloroquine even though specific reports have not appeared. These include: potentiation of its direct blocking action at the neuromuscular junction by aminoglycoside antibiotics; inhibition of its metabolism by cimetidine which may increase plasma concentration of the antimalarial; antagonism of effect of neostigmine and pyridostigmine; reduction of the antibody response to primary immunisation with intradermal human diploid-cell rabies vaccine.

As with chloroquine, antacids may reduce absorption of hydroxychloroquine so it is advised that a 4 hour interval be observed between Plaquenil and antacid dosaging.

As hydroxychloroquine may enhance the effects of a hypoglycaemic treatment, a decrease in doses of insulin or antidiabetic drugs may be required.

4.6 Pregnancy And Lactation

Pregnancy:

Hydroxychloroquine crosses the placenta. Data are limited regarding the use of hydroxychloroquine during pregnancy. It should be noted that 4-aminoquinolines in therapeutic doses have been associated with central nervous system damage, including ototoxicity (auditory and vestibular toxicity, congenital deafness), retinal hemorrhages and abnormal retinal pigmentation. Therefore Plaquenil should not be used in pregnancy.

Lactation:

Careful consideration should be given to using hydroxychloroquine during lactation, since it has been shown to be excreted in small amounts in human breast milk, and it is known that infants are extremely sensitive to the toxic effects of 4-aminoquinolines.

4.7 Effects On Ability To Drive And Use Machines

Impaired visual accommodation soon after the start of treatment has been reported and patients should be warned regarding driving or operating machinery. If the condition is not self-limiting, it will resolve on reducing the dose or stopping treatment.

4.8 Undesirable Effects

• Ocular effects:

Retinopathy with changes in pigmentation and visual field defects can occur, but appears to be uncommon if the recommended daily dose is not exceeded. In its early form it appears reversible on discontinuation of Plaquenil. If allowed to develop, there may be a risk of progression even after treatment withdrawal.

Patients with retinal changes may be asymptomatic initially, or may have scotomatous vision with paracentral, pericentral ring types, temporal scotomas and abnormal colour vision.

Corneal changes including oedema and opacities have been reported. They are either symptomless or may cause disturbances such as haloes, blurring of vision or photophobia. They may be transient and are reversible on stopping treatment.

Blurring of vision due to a disturbance of accommodation which is dose dependent and reversible may also occur.

• Dermatologic effects:

Skin rashes sometimes occur; pruritus, pigmentary changes in skin and mucous membranes, bleaching of hair and alopecia have also been reported. These usually resolve readily on stopping treatment.

Bullous eruptions including very rare cases of erythema multiforme and Stevens-Johnson syndrome, photosensitivity and isolated cases of exfoliative dermatitis have been reported. Very rare cases of acute generalised exanthematous pustulosis (AGEP) has to be distinguished from psoriasis, although hydroxychloroquine may precipitate attacks of psoriasis. It may be associated with fever and hyperleukocytosis. Outcome is usually favourable after drug withdrawal.

• Gastrointestinal effects:

Gastrointestinal disturbances such as nausea, diarrhoea, anorexia, abdominal pain and, rarely, vomiting may occur. These symptoms usually resolve immediately on reducing the dose or on stopping treatment.

• CNS effects:

Less frequently, dizziness, vertigo, tinnitus, hearing loss, headache, nervousness, emotional lability, toxic psychosis and convulsions have been reported with this class of drugs.

• Neuromuscular effects:

Skeletal muscle myopathy or neuromyopathy leading to progressive weakness and atrophy of proximal muscle groups have been noted. Myopathy may be reversible after drug discontinuation, but recovery may take many months.

Associated mild sensory changes, depression of tendon reflexes and abnormal nerve conduction may be observed.

• Cardio-vascular effects:

Cardiomyopathy has been rarely reported.

Chronic toxicity should be suspected when conduction disorders (bundle branch block/atrioventricular heart block) as well as biventricular hypertrophy are found. Drug withdrawal may lead to recovery.

• Hematologic effects:

Rarely, there have been reports of bone-marrow depression. Blood disorders such as anaemia, aplastic anaemia, agranulocytosis, a decrease in white blood cells and thrombocytopenia have been reported.

Hydroxychloroquine may precipitate or exacerbate porphyria.

• Liver effects:

Isolated cases of abnormal liver function tests have been reported; rare cases of fulminant hepatic failure have also been reported.

• Allergic reactions:

Urticaria, angioedema and bronchospasm have been reported.

4.9 Overdose

Overdosage with the 4-aminoquinolines is dangerous particularly in infants, as little as 1-2g having proved fatal.

The symptoms of overdosage may include headache, visual disturbances, cardiovascular collapse, convulsions, hypokalaemia, and rhythm and conduction disorders, followed by sudden and early respiratory and cardiac arrest. Since these effects may appear soon after taking a massive dose, treatment should be prompt and symptomatic. The stomach should be immediately evacuated, either by emesis or by gastric lavage. Activated charcoal in a dose at least five times of the overdose may inhibit further absorption if introduced into the stomach by tube following lavage and within 30 minutes of ingestion of the overdose.

Consideration should be given to administration of parenteral diazepam in cases of overdosage; it has been shown to be beneficial in reversing chloroquine cardiotoxicity.

Respiratory support and shock management should be instituted as necessary.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Antimalarial agents like chloroquine and hydroxychloroquine have several pharmacological actions which may be involved in their therapeutic effect in the treatment of rheumatic disease, but the role of each is not known. These include interaction with sulphydryl groups, interference with enzyme activity (including phospholipase, NADH - cytochrome C reductase, cholinesterase, proteases and hydrolases), DNA binding, stabilisation of lysosomal membranes, inhibition of prostaglandin formation, inhibition of polymorphonuclear cell chemotaxis and phagocytosis, possible interference with interleukin 1 production from monocytes and inhibition of neutrophil superoxide release.

5.2 Pharmacokinetic Properties

Hydroxychloroquine has actions, pharmacokinetics and metabolism similar to those of chloroquine. Following oral administration, hydroxychloroquine is rapidly and almost completely absorbed. In one study, mean peak plasma hydroxychloroquine concentrations following a single dose of 400mg in healthy subjects ranged from 53-208ng/ml with a mean of 105ng/ml. The mean time to peak plasma concentration was 1.83 hours. The mean plasma elimination half-life varied, depending on the post-administration period, as follows: 5.9 hours at C_max-10 hours), 26.1 hours (at 10-48 hours) and 299 hours (at 48-504 hours). The parent compound and metabolites are widely distributed in the body and elimination is mainly via the urine, where 3% of the administered dose was recovered over 24 hours in one study.

5.3 Preclinical Safety Data

There are no preclinical safety data of relevance to the prescriber, which are additional to that already included in other sections of the SPC.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Lactose monohydrate, maize starch, magnesium stearate, polyvidone, Opadry OY-L-28900 (containing hypromellose, macrogol 4000, titanium dioxide (E171), lactose.)

6.2 Incompatibilities

No incompatibilities are known.

6.3 Shelf Life

3 years

6.4 Special Precautions For Storage

Store below 25°C.

6.5 Nature And Contents Of Container

250µm clear PVC/20µm aluminium foil blister pack containing 60 tablets.

6.6 Special Precautions For Disposal And Other Handling

None.

7. Marketing Authorisation Holder

sanofi-aventis

One Onslow Street

Guildford

Surrey

GU1 4YS

United Kingdom

8. Marketing Authorisation Number(S)

PL 04425/0621

9. Date Of First Authorisation/Renewal Of The Authorisation

27 August 1997

10. Date Of Revision Of The Text

22 July 2010

LEGAL CLASSIFICATION

POM

Pinewood Cold Sore Cream

1. Name Of The Medicinal Product

Pinewood Cold Sore Cream

Galpharm Cold Sore Cream

Superdrug Cold Sore Cream

Numark Cold Sore Cream

Lypsyl Aciclovir 5% Cold Sore Cream

Lloyds Pharmacy Cold Sore Cream

Asda Cold Sore Cream

Morrisons Cold Sore Cream

2. Qualitative And Quantitative Composition

Each g contains 50 mg of Aciclovir

Excipients:

Cetyl alcohol	15mg/g
Propylene Glycol	150mg/g

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Cream.

White to off-white cream.

4. Clinical Particulars

4.1 Therapeutic Indications

For the treatment of Herpes Simplex virus infections of the lips and face (Herpes labialis).

4.2 Posology And Method Of Administration

Adults and children

Treatment should be initiated as soon as possible after the start of the infection, ideally during the prodromal period or when the lesions first appear.

A thin film of cream should be applied to the infected and immediately adjacent skin areas 5 times daily at 4-hour intervals during the day.

Treatment should be continued for 5 days, following by a further 5 days treatment if healing has not occurred.

Patients should wash their hands before and after applying the cream and avoid unnecessary rubbing of the lesions or touching with a towel, to avoid aggravating or transferring the infection.

Elderly

No special requirements

4.3 Contraindications

Hypersensitivity to Aciclovir or any other ingredients of the preparation.

4.4 Special Warnings And Precautions For Use

Only recommended for use on cold sores on the lips and face.

People with particularly severe Herpes labialis should be encouraged to seek medical advice.

Not to be applied to mucous membranes such as inside the mouth or vagina, or on the eye. Particular care should be taken to avoid contact with the eye.

Not for use for the treatment of genital herpes or ocular herpes infections.

Not recommended for use by patients who know they are immunocompromised e.g. by HIV infection, bone marrow transplant or cancer treatment, except on the advice of a doctor.

Cold sore sufferers should be advised to avoid transmitting the virus, particularly when active lesions are present.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Probenecid increases the mean half-life and area under the plasma concentration curve of systemically administered Aciclovir. Other drugs affecting renal physiology could potentially influence the pharmacokinetics of Aciclovir. However this is likely to be of little relevance to the cutaneous application of Aciclovir.

No interactions with other drugs have been described for topical Acyclovir.

4.6 Pregnancy And Lactation

No specific studies of topical Aciclovir have been carried out in pregnant women or nursing mothers.

So far, no relevant plasma levels have been measured and no systemic effects have been observed.

However, use of the cream should be considered only when the potential benefit outweighs the possibility of unknown risks.

In internationally accepted standard tests the systemic administration of Aciclovir did not produce embryotoxic or teratogenic effects in rabbits, rats or mice.

Foetal abnormalities were observed in non-standard tests in rats, but only following such high subcutaneous doses that maternal toxicity was produced. The clinical relevance of these findings is uncertain.

Largely reversible adverse effects on spermatogenesis in association with overall toxicity in rats and dogs have been reported only at doses greatly in excess of those employed therapeutically. Two generation studies in mice did not reveal any effect of orally administered Aciclovir on fertility.

There is no experience of the effect of Aciclovir tablets on human female fertility. Aciclovir tablets have been shown to have no definite effect upon sperm count, morphology or motility in man.

Following oral administration of 200 mg Aciclovir five times a day, Aciclovir has been detected in breast milk at concentrations ranging from 0.6 to 4.1 times the corresponding plasma levels. These levels would potentially expose breast fed infants to Aciclovir doses of up to 0.3 mg/kg/day.

4.7 Effects On Ability To Drive And Use Machines

The medicinal product has no influence on the ability to drive or operate machinery.

4.8 Undesirable Effects

The following convention has been used for the classification of undesirable effects in terms of frequency:-

Very common

Skin and subcutaneous tissue disorders

Common

- Mild drying or flaking of the skin

Uncommon

- Itching

Rare

- Erythema

- Contact dermatitis following application. Where sensitivity tests have been conducted, the reactive substances have most often been shown to be components of the cream base rather than aciclovir.

Immune system disorders

Very rare

- Immediate hypersensitivity reactions including angioedema.

After application of the cream, transient burning or stinging of the treated skin areas may occur.

4.9 Overdose

Overdose is unlikely to occur, if the cream is applied locally and as indicated. There are no reports concerning an overdose of Aciclovir cream.

No unwanted effects would be expected if the entire contents of a 2.0g tube of the cream were ingested. Doses of 800 mg five times daily (4 g per day), have administered without adverse effects. Single intravenous doses of up to 80 mg/kg have been inadvertently administered without adverse effects. Aciclovir is dialysable.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Aciclovir is a pharmacologically inactive substance. After penetration into cells which are infected with herpes simplex virus types I and (HSV I & HSV II) or varicella-zoster virus (VSV), Aciclovir is converted into a virostatic agent. The conversion of Aciclovir is catalysed by viral HSV- or VZV- thymidine kinase. Human thymidine kinase does not use Aciclovir effectively as a substrate, hence the toxicity to mammalian host cells is low.

In the infected cell, Aciclovir is phosphorylated by viral thymidine kinase to Aciclovir monophosphate, which is further converted by cellular enzymes to Aciclovir triphosphate. Aciclovir triphosphate has a greater affinity for viral DNA polymerase than host cell DNA polymerase and therefore selectively interferes with the viral enzyme causing inhibition of viral DNA replication. Aciclovir is also incorporated into viral DNA by viral DNA polymerase, which results in chain termination, as Aciclovir lacks a 3'-hydroxyl group, preventing addition of nucleotides by 3',5'-linkage.

In severely immunocompromised patients a longer or repeated treatment with Aciclovir can lead to a selection of viral strains with reduced sensitivity. As a result, these patients no longer respond to treatment with Aciclovir. Most of the clinical isolates with reduced sensitivity showed a relative lack of virus thymidine kinase. However, strains with changed/different virus thymidine kinase or DNS polymerase were also reported. The in vitro exposition of HSV-isolates can also lead to the development of less sensitive strains. The connection between the in vitro determined sensitivity of HSV-isolates and the clinical response to the treatment with Aciclovir is not clear.

5.2 Pharmacokinetic Properties

Absorption and plasma concentrations

Aciclovir penetrates into the skin. The intracutaneous concentration levels are higher than the minimal inhibitory concentration (MIC) in tissue at steady state.

After topical application of Aciclovir, no Aciclovir plasma concentration could be determined.

As the Aciclovir plasma concentrations following topical application are below the limit of detection, no pharmacokinetic studies are available on topical Aciclovir. Therefore, the following data is based on the data after oral or intravenous administration.

Plasma protein binding is reported to range between 9 and 33% as a function of dose. The volume of distribution at steady state in adults is 50± 8.7ν1.73 m², or 0.7 I/kg.

Two metabolites could be identified in the urine of patients with normal renal function after single dosing with ¹⁴C-Aciclovir: 9-carboxymethoxymethylguanine (2-14% of an administered dose) and 8-hydroxy-9-(2-hydroxyethoxymethyl)guanine(<0.2% of a dose). Subjects with normal renal function eliminate 62-91% of an Aciclovir dose unchanged and 9-14% as 9-carboxymethoxymethylguanine via the kidneys.

Aciclovir is predominantly eliminated via the kidneys, primarily by glomerular filtration and to a lesser extent by tubular secretion.

In vitro and in vivo studies of Aciclovir cream and Aciclovir ointment versus oral Aciclovir were carried out to determine the bioavailability of Aciclovir in human skin. The in vitro studies used human skin biopsates, whilst the bioassays either used human skin grafts on mice or were carried out in the human eye (3 patients).

The following dermal drug concentration gradient emerged for both topical and oral Aciclovir: stratum corneum> epidermis>dermis. There was no difference in concentration between cream and ointment.

The upper layer of the epidermis on average showed a 48-fold higher concentration following topical application of Aciclovir ointment or cream 5% than after oral dosing, but the drug concentration in the basal epidermis – the site of herpes virus infection – was 2 to 3 times lower following topical application than after oral dosing.

On the basis of continuous absorption the concentration increased as a function of time (higher drug concentrations being found 48 hours post-topical dose than 24 hours post-topical dose). Thus short dosing intervals appear rational for the special treatment of herpes simplex virus (HSV) infections.

5.3 Preclinical Safety Data

For 24 days, PEG-based Aciclovir Cream 5 or 10% was applied to the shaved (intact and grazed) skin of guinea-pigs. The treated area corresponded to 10% of the body surface. There were neither systemic nor local toxic symptoms. This is also confirmed by histologic studies and autopsy. According to the test carried out by Draize, who evaluated the allergic sensitising potential of a substance, there were no pathogenic findings.

Studies carried out in swine showed that 5% Aciclovir cream in a PEG vehicle caused an only minimal (quantitative) delay in epidermal wound healing.

Rabbits had 1, 3 or 6% Aciclovir cream in a white petrolatum vehicle introduced directly into both eyes 5 times daily at 90-minute intervals for 3 weeks. Neither autopsy nor inspection nor histological examination revealed any pathological changes in the rabbit eyes.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Arlatone 983S

Dimeticone

Cetyl alcohol

Liquid paraffin

White soft paraffin

Propylene glycol

Purified water

6.2 Incompatibilities

Not applicable

6.3 Shelf Life

3 years (unopened)

6 weeks (open)

6.4 Special Precautions For Storage

Do not store above 25°C. Do not refrigerate.

6.5 Nature And Contents Of Container

Aluminium tube with polyethylene screw cap.

Pack size: 2g

6.6 Special Precautions For Disposal And Other Handling

No special requirements

7. Marketing Authorisation Holder

Pinewood Laboratories Limited

Ballymacarbry

Clonmel

Co Tipperary

Ireland

8. Marketing Authorisation Number(S)

PL 04917/0066

9. Date Of First Authorisation/Renewal Of The Authorisation

22^nd December 2004

10. Date Of Revision Of The Text

24/04/2010

Pioglitazone 15mg Tablets

1. Name Of The Medicinal Product

Pioglitazone Sandoz 15 mg, Tablets

2. Qualitative And Quantitative Composition

Pioglitazone 15 mg

Each tablet contains 15 mg pioglitazone (as pioglitazone hydrochloride).

Excipient(s): Lactose monohydrate 77 mg

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Tablet

Pioglitazone 15 mg

white, round tablet, with imprint “PGT 15” on one side and with score line on both sides

The score line is only to facilitate breaking for ease of swallowing and not to divide into equal doses.

4. Clinical Particulars

4.1 Therapeutic Indications

Pioglitazone is indicated in the treatment of type 2 diabetes mellitus:

as monotherapy

- in adult patients (particularly overweight patients) inadequately controlled by diet and exercise for whom metformin is inappropriate because of contraindications or intolerance

Pioglitazone is also indicated for combination with insulin in type 2 diabetes mellitus adult patients with insufficient glycaemic control on insulin for whom metformin is inappropriate because of contraindications or intolerance (see section 4.4).

After initiation of therapy with pioglitazone, patients should be reviewed after 3 to 6 months to assess adequacy of response to treatment (e.g. reduction in HbA1c). In patients who fail to show an adequate response, pioglitazone should be discontinued. In light of potential risks with prolonged therapy, prescribers should confirm at subsequent routine reviews that the benefit of pioglitazone is maintained (see section 4.4).

4.2 Posology And Method Of Administration

Posology

Pioglitazone treatment may be initiated at 15 mg or 30 mg once daily. The dose may be increased in increments up to 45 mg once daily.

In combination with insulin, the current insulin dose can be continued upon initiation of pioglitazone therapy. If patients report hypoglycaemia, the dose of insulin should be decreased.

Special population

Elderly

No dosage adjustment is necessary for elderly patients (see section 5.2). Physicians should start treatment with the lowest available dose and increase the dose gradually, particularly when pioglitazone is used in combination with insulin (see section 4.4 Fluid retention and cardiac failure).

Renal impairment

No dosage adjustment is necessary in patients with impaired renal function (creatinine clearance> 4 ml/min) (see section 5.2). No information is available from dialysed patients therefore pioglitazone should not be used in such patients.

Hepatic impairment

Pioglitazone should not be used in patients with hepatic impairment (see section 4.3 and 4.4).

Paediatric population

The safety and efficacy of Pioglitazone in children and adolescents under 18 years of age have not been established. No data are available.

Method of administration

Pioglitazone tablets are taken orally once daily with or without food. Tablets should be swallowed with a glass of water.

4.3 Contraindications

Pioglitazone is contraindicated in patients with:

- hypersensitivity to the active substance or to any of the excipients

- cardiac failure or history of cardiac failure (NYHA stages I to IV)

- hepatic impairment

- diabetic ketoacidosis

- current bladder cancer or a history of bladder cancer

- uninvestigated macroscopic haematuria

4.4 Special Warnings And Precautions For Use

Fluid retention and cardiac failure:

Pioglitazone can cause fluid retention, which may exacerbate or precipitate heart failure. When treating patients who have at least one risk factor for development of congestive heart failure (e.g. prior myocardial infarction or symptomatic coronary artery disease or the elderly), physicians should start with the lowest available dose and increase the dose gradually. Patients should be observed for signs and symptoms of heart failure, weight gain or oedema; particularly those with reduced cardiac reserve. There have been post-marketing cases of cardiac failure reported when pioglitazone was used in combination with insulin or in patients with a history of cardiac failure. Patients should be observed for signs and symptoms of heart failure, weight gain and oedema when pioglitazone is used in combination with insulin. Since insulin and pioglitazone are both associated with fluid retention, concomitant administration may increase the risk of oedema. Pioglitazone should be discontinued if any deterioration in cardiac status occurs.

A cardiovascular outcome study of pioglitazone has been performed in patients under 75 years with type 2 diabetes mellitus and pre-existing major macrovascular disease. Pioglitazone or placebo was added to existing antidiabetic and cardiovascular therapy for up to 3.5 years. This study showed an increase in reports of heart failure, however this did not lead to an increase in mortality in this study.

Elderly

Combination use with insulin should be considered with caution in the elderly because of increased risk of serious heart failure.

In light of age- related risks (especially bladder cancer, fractures and heart failure), the balance of benefits and risks should be considered carefully both before and during treatment in the elderly.

Bladder Cancer

Cases of bladder cancer were reported more frequently in a meta-analysis of controlled clinical trials with pioglitazone (19 cases from 12506 patients, 0.15%) than in control groups (7 cases from 10212 patients, 0.07%) HR=2.64 (95% CI 1.11-6.31, P=0.029). After excluding patients in whom exposure to study drug was less than one year at the time of diagnosis of bladder cancer, there were 7 cases (0.06%) on pioglitazone and 2 cases (0.02%) in control groups. Available epidemiological data also suggest a small increased risk of bladder cancer in diabetic patients treated with pioglitazone in particular in patients treated for the longest durations and with the highest cumulative doses. A possible risk after short term treatment cannot be excluded.

Risk factors for bladder cancer should be assessed before initiating pioglitazone treatment (risks include age, smoking history, exposure to some occupational or chemotherapy agents e.g. cyclophosphamide or prior radiation treatment in the pelvic region). Any macroscopic haematuria should be investigated before starting pioglitazone therapy.

Patients should be advised to promptly seek the attention of their physician if macroscopic haematuria or other symptoms such as dysuria or urinary urgency develop during treatment.

Monitoring of liver function:

There have been rare reports of hepatocellular dysfunction during post-marketing experience (see section 4.8). It is recommended, therefore, that patients treated with pioglitazone undergo periodic monitoring of liver enzymes. Liver enzymes should be checked prior to the initiation of therapy with pioglitazone in all patients. Therapy with pioglitazone should not be initiated in patients with increased baseline liver enzyme levels (ALT> 2.5 X upper limit of normal) or with any other evidence of liver disease.

Following initiation of therapy with pioglitazone, it is recommended that liver enzymes be monitored periodically based on clinical judgement. If ALT levels are increased to 3 X upper limit of normal during pioglitazone therapy, liver enzyme levels should be reassessed as soon as possible. If ALT levels remain> 3 X the upper limit of normal, therapy should be discontinued. If any patient develops symptoms suggesting hepatic dysfunction, which may include unexplained nausea, vomiting, abdominal pain, fatigue, anorexia and/or dark urine, liver enzymes should be checked. The decision whether to continue the patient on therapy with pioglitazone should be guided by clinical judgement pending laboratory evaluations. If jaundice is observed, the medicinal product should be discontinued.

Weight gain:

In clinical trials with pioglitazone there was evidence of dose related weight gain, which may be due to fat accumulation and in some cases associated with fluid retention. In some cases weight increase may be a symptom of cardiac failure, therefore weight should be closely monitored. Part of the treatment of diabetes is dietary control. Patients should be advised to adhere strictly to a calorie-controlled diet.

Haematology:

There was a small reduction in mean haemoglobin (4 % relative reduction) and haematocrit (4.1 % relative reduction) during therapy with pioglitazone, consistent with haemodilution. Similar changes were seen in metformin (haemoglobin 3 - 4 % and haematocrit 3.6 – 4.1 % relative reductions) and to a lesser extent sulphonylurea and insulin (haemoglobin 1 – 2 % and haematocrit 1 – 3.2 % relative reductions) treated patients in comparative controlled trials with pioglitazone.

Hypoglycaemia:

As a consequence of increased insulin sensitivity, patients receiving pioglitazone in dual or triple oral therapy with a sulphonylurea or in dual therapy with insulin may be at risk for dose-related hypoglycaemia, and a reduction in the dose of the sulphonylurea or insulin may be necessary.

Eye disorders:

Post-marketing reports of new-onset or worsening diabetic macular oedema with decreased visual acuity have been reported with thiazolidinediones, including pioglitazone. Many of these patients reported concurrent peripheral oedema. It is unclear whether or not there is a direct association between pioglitazone and macular oedema but prescribers should be alert to the possibility of macular oedema if patients report disturbances in visual acuity; an appropriate ophthalmological referral should be considered.

Others:

An increased incidence in bone fractures in women was seen in a pooled analysis of adverse reactions of bone fracture from randomised, controlled, double blind clinical trials in over 8100 pioglitazone and 7400 comparator treated patients, on treatment for up to 3.5 years.

Fractures were observed in 2.6% of women taking pioglitazone compared to 1.7% of women treated with a comparator. No increase in fracture rates was observed in men treated with pioglitazone (1.3%) versus comparator (1.5%).

The fracture incidence calculated was 1.9 fractures per 100 patient years in women treated with pioglitazone and 1.1 fractures per 100 patient years in women treated with a comparator. The observed excess risk of fractures for women in this dataset on pioglitazone is therefore 0.8 fractures per 100 patient years of use.

In the 3.5 year cardiovascular risk PROactive study, 44/870 (5.1%; 1.0 fractures per 100 patient years) of pioglitazone-treated female patients experienced fractures compared to 23/905 (2.5%; 0.5 fractures per 100 patient years) of female patients treated with comparator. No increase in fracture rates was observed in men treated with pioglitazone (1.7%) versus comparator (2.1%).

The risk of fractures should be considered in the long term care of women treated with pioglitazone.

As a consequence of enhancing insulin action, pioglitazone treatment in patients with polycystic ovarian syndrome may result in resumption of ovulation. These patients may be at risk of pregnancy. Patients should be aware of the risk of pregnancy and if a patient wishes to become pregnant or if pregnancy occurs, the treatment should be discontinued (see section 4.6).

Pioglitazone should be used with caution during concomitant administration of cytochrome P450 2C8 inhibitors (e.g. gemfibrozil) or inducers (e.g. rifampicin). Glycaemic control should be monitored closely. Pioglitazone dose adjustment within the recommended posology or changes in diabetic treatment should be considered (see section 4.5).

Pioglitazone tablets contain lactose monohydrate and therefore should not be administered to patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Interaction studies have shown that pioglitazone has no relevant effect on either the pharmacokinetics or pharmacodynamics of digoxin, warfarin, phenprocoumon and metformin. Co-administration of pioglitazone with sulphonylureas does not appear to affect the pharmacokinetics of the sulphonylurea. Studies in man suggest no induction of the main inducible cytochrome P450, 1A, 2C8/9 and 3A4. In vitro studies have shown no inhibition of any subtype of cytochrome P450. Interactions with substances metabolised by these enzymes, e.g. oral contraceptives, cyclosporin, calcium channel blockers, and HMGCoA reductase inhibitors are not to be expected.

Co-administration of pioglitazone with gemfibrozil (an inhibitor of cytochrome P450 2C8) is reported to result in a 3-fold increase in AUC of pioglitazone. Since there is a potential for an increase in dose-related adverse events, a decrease in the dose of pioglitazone may be needed when gemfibrozil is concomitantly administered. Close monitoring of glycaemic control should be considered (see section 4.4). Co-administration of pioglitazone with rifampicin (an inducer of cytochrome P450 2C8) is reported to result in a 54% decrease in AUC of pioglitazone. The pioglitazone dose may need to be increased when rifampicin is concomitantly administered. Close monitoring of glycaemic control should be considered (see section 4.4).

4.6 Pregnancy And Lactation

Pregnancy

There are no adequate human data to determine the safety of pioglitazone during pregnancy. Foetal growth restriction was apparent in animal studies with pioglitazone. This was attributable to the action of pioglitazone in diminishing the maternal hyperinsulinaemia and increased insulin resistance that occurs during pregnancy thereby reducing the availability of metabolic substrates for foetal growth. The relevance of such a mechanism in humans is unclear and pioglitazone should not be used in pregnancy.

Breastfeeding

Pioglitazone has been shown to be present in the milk of lactating rats. It is not known whether pioglitazone is secreted in human milk. Therefore, pioglitazone should not be administered to breast-feeding women.

Fertility

In animal fertility studies there was no effect on copulation, impregnation or fertility index.

4.7 Effects On Ability To Drive And Use Machines

Pioglitazone has no or negligible effect on the ability to drive and use machines. However patients who experience visual disturbance should be cautious when driving or using machines.

4.8 Undesirable Effects

Adverse reactions reported in excess (> 0.5 %) of placebo and as more than an isolated case in patients receiving pioglitazone in double-blind studies are listed below as MedDRA preferred term by system organ class and absolute frequency. Frequencies are defined as: very common (

Adverse reaction	Frequency of adverse reactions of pioglitazone by treatment regimen
Monotherapy	Combination
with metformin	with sulphonylurea	with metformin and sulphonylurea	with insulin
Infections and infestations
upper respiratory tract infection	common	common	common	common	common
bronchitis					common
sinusitis	uncommon	uncommon	uncommon	uncommon	uncommon
Blood and lymphatic system disorders
anaemia		common
Metabolism and nutrition disorders
hypo-glycaemia			uncommon	very common	common
appetite increased			uncommon
Nervous system disorders
hypo-aesthesia	common	common	common	common	common
headache		common	uncommon
dizziness			common
insomnia	uncommon	uncommon	uncommon	uncommon	uncommon
Eye disorders
visual disturbance1	common	common	uncommon
macular oedema2	not known	not known	not known	not known	not known
Ear and labyrinth disorders
vertigo			uncommon
Cardiac disorders
heart failure3					common
Neoplasms benign, malignant and unspecified (including cysts and polyps)
bladder cancer	uncommon	uncommon	uncommon	uncommon	uncommon
Respiratory, thoracic and mediastinal disorders
dyspnoea					common
Gastrointestinal disorders
flatulence		uncommon	common
Skin and subcutaneous tissue disorders
sweating			uncommon
Musculoskeletal and connective tissue disorders
fracture bone4	common	common	common	common	common
arthralgia		common		common	common
back pain					common
Renal and urinary disorders
haematuria		common
glycosuria			uncommon
proteinuria			uncommon
Reproductive system and breast disorders
erectile dysfunction		common
General disorders and administration site conditions
oedema					very common
fatigue			uncommon
Investigations
weight increased5	common	common	common	common	common
blood creatine phospho-kinase increased				common
increased lactic dehydro-genase			uncommon
alanine aminotransferase increased6	not known	not known	not known	not known	not known

¹ Visual disturbance has been reported mainly early in treatment and is related to changes in blood glucose due to temporary alteration in the turgidity and refractive index of the lens as seen with other hypoglycaemic treatments.

²Oedema was reported in 6 – 9 % of patients treated with pioglitazone over one year in controlled clinical trials. The oedema rates for comparator groups (sulphonylurea, metformin) were 2 – 5 %. The reports of oedema were generally mild to moderate and usually did not require discontinuation of treatment.

³ In controlled clinical trials the incidence of reports of heart failure with pioglitazone treatment was the same as in placebo, metformin and sulphonylurea treatment groups, but was increased when used in combination therapy with insulin. In an outcome study of patients with pre-existing major macrovascular disease, the incidence of serious heart failure was 1.6 % higher with pioglitazone than with placebo, when added to therapy that included insulin. However, this did not lead to an increase in mortality in this study. Heart failure has been reported rarely with marketing use of pioglitazone, but more frequently when pioglitazone was used in combination with insulin or in patients with a history of cardiac failure.

⁴ A pooled analysis was conducted of adverse reactions of bone fractures from randomised, comparator controlled, double blind clinical trials in over 8100 patients in the pioglitazone-treated groups and 7400 in the comparator-treated groups of up to 3.5 years duration. A higher rate of fractures was observed in women taking pioglitazone (2.6%) versus comparator (1.7%). No increase in fracture rates was observed in men treated with pioglitazone (1.3%) versus comparator (1.5%).

In the 3.5 year PROactive study, 44/870 (5.1%) of pioglitazone-treated female patients experienced fractures compared to 23/905 (2.5%) of female patients treated with comparator. No increase in fracture rates was observed in men treated with pioglitazone (1.7%) versus comparator (2.1%).

⁵In active comparator controlled trials mean weight increase with pioglitazone given as monotherapy was 2 – 3 kg over one year. This is similar to that seen in a sulphonylurea active comparator group. In combination trials pioglitazone added to metformin resulted in mean weight increase over one year of 1.5 kg and added to a sulphonylurea of 2.8 kg. In comparator groups addition of sulphonylurea to metformin resulted in a mean weight gain of 1.3 kg and addition of metformin to a sulphonylurea a mean weight loss of 1.0 kg.

⁶ In clinical trials with pioglitazone the incidence of elevations of ALT greater than three times the upper limit of normal was equal to placebo but less than that seen in metformin or sulphonylurea comparator groups. Mean levels of liver enzymes decreased with treatment with pioglitazone. Rare cases of elevated liver enzymes and hepatocellular dysfunction have occurred in post-marketing experience. Although in very rare cases fatal outcome has been reported, causal relationship has not been established.

4.9 Overdose

In clinical studies, patients have taken pioglitazone at higher than the recommended highest dose of 45 mg daily. The maximum reported dose of 120 mg/day for four days, then 180 mg/day for seven days was not associated with any symptoms.

Hypoglycaemia may occur in combination with sulphonylureas or insulin. Symptomatic and general supportive measures should be taken in case of overdose.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Drugs used in diabetes, blood glucose lowering drugs, excl. insulins; ATC code: A10 BG 03.

Pioglitazone effects may be mediated by a reduction of insulin resistance. Pioglitazone appears to act via activation of specific nuclear receptors (peroxisome proliferator activated receptor gamma) leading to increased insulin sensitivity of liver, fat and skeletal muscle cells in animals. Treatment with pioglitazone has been shown to reduce hepatic glucose output and to increase peripheral glucose disposal in the case of insulin resistance.

Fasting and postprandial glycaemic control is improved in patients with type 2 diabetes mellitus. The improved glycaemic control is associated with a reduction in both fasting and postprandial plasma insulin concentrations. A clinical trial of pioglitazone vs. gliclazide as monotherapy was extended to two years in order to assess time to treatment failure (defined as appearance of HbA_1c1c < 8.0 %) was sustained in 69 % of patients treated with pioglitazone, compared with 50 % of patients on gliclazide. In a two-year study of combination therapy comparing pioglitazone with gliclazide when added to metformin, glycaemic control measured as mean change from baseline in HbA_1c was similar between treatment groups after one year. The rate of deterioration of HbA_1c during the second year was less with pioglitazone than with gliclazide.

In a placebo controlled trial, patients with inadequate glycaemic control despite a three month insulin optimisation period were randomised to pioglitazone or placebo for 12 months. Patients receiving pioglitazone had a mean reduction in HbA_1c of 0.45 % compared with those continuing on insulin alone, and a reduction of insulin dose in the pioglitazone treated group.

HOMA analysis shows that pioglitazone improves beta cell function as well as increasing insulin sensitivity. Two-year clinical studies have shown maintenance of this effect.

In one year clinical trials, pioglitazone consistently gave a statistically significant reduction in the albumin/creatinine ratio compared to baseline.

The effect of pioglitazone (45 mg monotherapy vs. placebo) was studied in a small 18-week trial in type 2 diabetics. Pioglitazone was associated with significant weight gain. Visceral fat was significantly decreased, while there was an increase in extra-abdominal fat mass. Similar changes in body fat distribution on pioglitazone have been accompanied by an improvement in insulin sensitivity. In most clinical trials, reduced total plasma triglycerides and free fatty acids, and increased HDL-cholesterol levels were observed as compared to placebo, with small, but not clinically significant increases in LDL-cholesterol levels.

In clinical trials of up to two years duration, pioglitazone reduced total plasma triglycerides and free fatty acids, and increased HDL cholesterol levels, compared with placebo, metformin or gliclazide. Pioglitazone did not cause statistically significant increases in LDL cholesterol levels compared with placebo, whilst reductions were observed with metformin and gliclazide. In a 20-week study, as well as reducing fasting triglycerides, pioglitazone reduced post prandial hypertriglyceridaemia through an effect on both absorbed and hepatically synthesised triglycerides. These effects were independent of pioglitazone's effects on glycaemia and were statistically significant different to glibenclamide.

In PROactive, a cardiovascular outcome study, 5238 patients with type 2 diabetes mellitus and pre-existing major macrovascular disease were randomised to pioglitazone or placebo in addition to existing antidiabetic and cardiovascular therapy, for up to 3.5 years. The study population had an average age of 62 years; the average duration of diabetes was 9.5 years. Approximately one third of patients were receiving insulin in combination with metformin and/or a sulphonylurea. To be eligible patients had to have had one or more of the following: myocardial infarction, stroke, percutaneous cardiac intervention or coronary artery bypass graft, acute coronary syndrome, coronary artery disease, or peripheral arterial obstructive disease. Almost half of the patients had a previous myocardial infarction and approximately 20% had had a stroke. Approximately half of the study population had at least two of the cardiovascular history entry criteria. Almost all subjects (95%) were receiving cardiovascular medications (beta blockers, ACE inhibitors, angiotensin II antagonists, calcium channel blockers, nitrates, diuretics, aspirin, statins, fibrates).

Although the study failed regarding its primary endpoint, which was a composite of all-cause mortality, non-fatal myocardial infarction, stroke, acute coronary syndrome, major leg amputation, coronary revascularisation and leg revascularisation, the results suggest that there are no long-term cardiovascular concerns regarding use of pioglitazone. However, the incidences of oedema, weight gain and heart failure were increased. No increase in mortality from heart failure was observed.

5.2 Pharmacokinetic Properties

Absorption:

Following oral administration, pioglitazone is rapidly absorbed, and peak plasma concentrations of unchanged pioglitazone are usually achieved 2 hours after administration. Proportional increases of the plasma concentration were observed for doses from 2 – 60 mg. Steady state is achieved after 4–7 days of dosing. Repeated dosing does not result in accumulation of the compound or metabolites. Absorption is not influenced by food intake. Absolute bioavailability is greater than 80 %.

Distribution:

The estimated volume of distribution in humans is 0.25 l/kg.

Pioglitazone and all active metabolites are extensively bound to plasma protein (> 99 %).

Biotransformation:

Pioglitazone undergoes extensive hepatic metabolism by hydroxylation of aliphatic methylene groups. This is predominantly via cytochrome P450 2C8 although other isoforms may be involved to a lesser degree. Three of the six identified metabolites are active (M-II, M-III, and M-IV). When activity, concentrations and protein binding are taken into account, pioglitazone and metabolite M-III contribute equally to efficacy. On this basis M-IV contribution to efficacy is approximately three-fold that of pioglitazone, whilst the relative efficacy of M-II is minimal.

In vitro studies have shown no evidence that pioglitazone inhibits any subtype of cytochrome P450. There is no induction of the main inducible P450 isoenzymes 1A, 2C8/9, and 3A4 in man.

Interaction studies have shown that pioglitazone has no relevant effect on either the pharmacokinetics or pharmacodynamics of digoxin, warfarin, phenprocoumon and metformin. Concomitant administration of pioglitazone with gemfibrozil (an inhibitor of cytochrome P450 2C8) or with rifampicin (an inducer of cytochrome P450 2C8) is reported to increase or decrease, respectively, the plasma concentration of pioglitazone (see section 4.5).

Elimination:

Following oral administration of radiolabelled pioglitazone to man, recovered label was mainly in faeces (55%) and a lesser amount in urine (45 %). In animals, only a small amount of unchanged pioglitazone can be detected in either urine or faeces. The mean plasma elimination half-life of unchanged pioglitazone in man is 5 to 6 hours and for its total active metabolites 16 to 23 hours.

Elderly:

Steady state pharmacokinetics are similar in patients age 65 and over and young subjects.

Patients with renal impairment:

In patients with renal impairment, plasma concentrations of pioglitazone

Prednisolone Tablet (Wockhardt UK Ltd)

1. Name Of The Medicinal Product

Prednisolone 1mg Tablets

Prednisolone 5mg Tablets

2. Qualitative And Quantitative Composition

Prednisolone 1.0mg

Prednisolone 5.0mg

Excipients: Lactose.

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Tablet

White circular, flat faced tablets with break line and PL1 on one face and CP on the reverse.

White circular, flat faced tablets with break line and PL5 on one face and CP on the reverse.

4. Clinical Particulars

4.1 Therapeutic Indications

Suppression of inflammatory and allergic disorders

4.2 Posology And Method Of Administration

Route of administration - Oral

Adults including the elderly

The lowest effective dose should be used for the minimum period in order to minimise side effects (see 4.4 Special Warnings and Precautions for use).

Initially:

5mg to 60mg daily in divided doses, as a single dose in the morning after breakfast, or as a double dose on alternate days. They should be taken with or after food. The dose can often be reduced within a few days but may need to be continued for several weeks or months.

Maintenance:

2.5 to 15mg daily, but higher doses may be needed. Cushingoid side-effects more likely above 7.5mg daily.

Children

Prednisolone should be used only when specifically indicated, in a minimal dosage and for the shortest possible time (see other special warnings and precautions)

4.3 Contraindications

Systemic infection unless specific anti-infective therapy is employed. Hypersensitivity to any ingredient.

4.4 Special Warnings And Precautions For Use

A patient information leaflet should be supplied with this product.

Undesirable effects may be minimised by using the lowest effective dose for the minimum period, and by administering the daily requirement as a single morning dose or whenever possible as a single morning dose on alternate days. Frequent patient review is required to appropriately titrate the dose against disease activity (see dosage section)

Adrenal suppression.

Adrenal cortical atrophy develops during prolonged therapy and may persist for years after stopping treatment. Withdrawal of corticosteroids after prolonged therapy must therefore always be gradual to avoid acute adrenal insufficiency, being tapered off over weeks or months according to the dose and duration of treatment.

In patients who have received more than physiological doses of systemic corticosteroids (approximately 7.5mg prednisolone or equivalent) for longer than three weeks, withdrawal should not be abrupt. How dose reduction should be carried out depends largely on whether the disease is likely to relapse as the dose of systemic corticosteroids is reduced. Recommendations for initial reduction have varied from as little as steps of 1mg monthly to 2.5mg to 5mg every three to seven days. Adrenal function should be monitored throughout. Clinical assessment of disease activity may be needed during withdrawal. If the disease is unlikely to relapse on withdrawal of systemic corticosteroids but there is uncertainty about hypothalamic-pituitary-adrenal (HPA) suppression, the dose of systemic corticosteroid may be reduced rapidly to physiological doses. Once a daily dose equivalent to 7.5mg of prednisolone is reached, dose reduction should be slower to allow the HPA-axis to recover.

Abrupt withdrawal of systemic corticosteroid treatment which has continued up to three weeks is appropriate if it is considered that the disease is unlikely to relapse. Abrupt withdrawal of doses of up to 40mg daily of prednisolone, or equivalent, for three weeks, is unlikely to lead to clinically relevant HPA-axis suppression, in the majority of patients. In the following patient groups, gradual withdrawal of systemic corticosteroid therapy should be considered even after courses lasting three weeks or less:

• Patients who have had repeated courses of systemic corticosteroids, particularly if taken for longer than three weeks.

• When a short course has been prescribed within one year of cessation of long term therapy (months or years).

• Patients who may have reasons for adrenocortical insufficiency other than exogenous corticosteroid therapy.

• Patients receiving doses of systemic corticosteroid greater than 40mg daily of prednisolone (or equivalent),

• Patients repeatedly taking doses in the evening.

Patients should carry 'steroid treatment' cards which give clear guidance on the precautions to be taken to minimise risk and which provide details of prescriber, drug, dosage and the duration of treatment.

Anti-inflammatory/ immunosuppressive effects and infection.

Suppression of the inflammatory response and immune function increases the susceptibility to infections and their severity. The clinical presentation may often be atypical and serious infections such as septicaemia and tuberculosis may be masked and may reach an advanced stage before being recognised. The immunosuppressive effects of corticosteroids, including prednisolone, may result in the activation or exacerbation of strongyloidiasis or fungal infection, or the activation of latent infection, or exacerbation of intercurrent infection involving other pathogens such as pneumocystis carinii. During prolonged therapy any intercurrent illness, trauma or surgical procedures will require a temporary increase in dosage, if corticosteroids have been stopped following prolonged therapy they may need to be temporarily re-introduced.

Chickenpox is of particular concern since this normally minor illness may be fatal in immunosuppressed patients. Patients (or parents of children) without a definite history of chickenpox should be advised to avoid close personal contact with chickenpox or herpes zoster and if exposed they should seek urgent medical attention. Passive immunisation with varicella zoster immunoglobulin (vzig) is needed by exposed non-immune patients who are receiving systemic corticosteroids or who have used them within the previous 3 months; this should be given within 10 days of exposure to chickenpox. If a diagnosis of chickenpox is confirmed, the illness warrants specialist care and urgent treatment. Corticosteroids should not be stopped and the dose may need to be increased.

Patients taking corticosteroids should be advised to take particular care to avoid exposure to measles and to seek immediate medical advice if exposure occurs.

Live vaccines should not be given to individuals with impaired immune responsiveness. The antibody response to other vaccines may be diminished.

Particular care is required when considering the use of systemic corticosteroids in patients with the following conditions and frequent patient monitoring is necessary.

a) osteoporosis (post menopausal females are particularly at risk)

b) hypertension or congestive heart failure

c) diabetes mellitus (or a family history of diabetes)

d) history of, or active tuberculosis

e) glaucoma (or a family history of glaucoma)

f) previous corticosteroid-induced myopathy

g) liver failure

h) renal insufficiency

i) epilepsy

j) peptic ulceration

k) hypothyroidism

l) recent myocardial infarction

Patients and/or carers should be warned that potentially severe psychiatric adverse reactions may occur with systemic steroids (see section 4.8). Symptoms typically emerge within a few days or weeks of starting the treatment. Risks may be higher with high doses/systemic exposure (see also section 4.5 pharmacokinetic interactions that can increase the risk of side effects), although dose levels do not allow prediction of the onset, type, severity or duration of reactions. Most reactions recover after either dose reduction or withdrawal, although specific treatment may be necessary. Patients/carers should be encouraged to seek medical advice if worrying psychological symptoms develop, especially if depressed mood or suicidal ideation is suspected. Patients/carers should also be alert to possible psychiatric disturbances that may occur either during or immediately after dose tampering/withdrawal of systemic steroids, although such reactions have been reported infrequently.

Particular care is required when considering the use of systemic corticosteroids in patients with existing or previous history of severe affective disorders in themselves or in their first degree relatives. These would include depressive or manic-depressive illness and previous steroid psychosis.

Use in children - corticosteroids cause dose-related growth retardation in infancy, childhood and adolescence, which may be irreversible.

Use in the elderly - the common adverse effects of systemic corticosteroids may be associated with more serious consequences in old age, especially osteoporosis, hypertension, hypokalaemia, diabetes, susceptibility to infection and thinning of the skin. Close clinical supervision is required to avoid life-threatening reactions.

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

Hepatic microsomal enzyme inducers: Rifampicin, rifabutin, carbamazepine, phenobarbitone, phenytoin, primidone and aminoglutethimide enhance the metabolism of prednisolone and its therapeutic effects may be reduced.

Anticoagulants: The efficacy of coumarin anticoagulants may be enhanced or reduced by concomitant corticosteroid therapy and close monitoring of the INR or prothrombin time is required to avoid spontaneous bleeding.

Non-steroidal anti-inflammatory drugs (NSAIDs): There is an increased risk of gastro-intestinal bleeding and ulceration when corticosteroids are used concomitantly with NSAIDs, including aspirin. The renal clearance of salicylates is increased by corticosteroids and steroid withdrawal may result in salicylate intoxication.

Hormones: Oestrogens may enhance the effects of corticosteroids and dosage adjustments may be required in some cases.

Prednisolone can inhibit the growth stimulating effect of somatropin.

Antibacterials: Corticosteroids can lower plasma concentrations of isoniazid and enhance its renal clearance.

Antifungals: Concomitant use with ketoconazole may inhibit the metabolism of prednisolone and enhance its adrenal suppressive effects. There is the potential for an increased risk of hypokalaemia when corticosteroids are used concomitantly with amphotericin.

Antineoplastics and immunosuppressants: Mutual inhibition of metabolism may occur between ciclosporin and prednisolone, and may increase the plasma concentration of either drug.

Antivirals: Plasma concentrations of prednisolone may be increased with antiviral drugs such as ritonavir and indinavir.

Vaccines: Concomitant use of high dose corticosteroids and live vaccines should be avoided. Corticosteroids may impair the immune response to other vaccines.

Neuromuscular blockers: Neuromuscular blocking effects may be antagonised by prednisolone in patients with adrenocortical insufficiency.

Cardiac glycosides: There is the potential for an increased risk of digitalis toxicity associated with hypokalaemia, when corticosteroids and cardiac glycosides are used concomitantly.

Sympathomimetics: There is an increased risk of hypokalaemia if high doses of corticosteroids are given with high doses of bambuterol, fenoterol, formoterol, reproterol, ritodrine, salbutamol, salmeterol, terbutaline and tulobuterol.

Thalidomide: The dosage of prednisolone needs to be reduced considerably when used with thalidomide. It has been suggested that prednisolone should not be given with thalidomide.

Intra-uterine devices (IUDs) –There is the potential for contraceptive failure in women using intra-uterine devices and receiving corticosteroid therapy.

Other: The desired effects of hypoglycaemic agents (including insulin), antihypertensives and diuretics are antagonised by corticosteroids and the hypokalaemic effects of acetazolamide loop diuretics, and thiazide diuretics are enhanced. The effect of corticosteroids may be reduced for 3 to 4 days after the use of mifepristone. There is the potential for an increased risk of hypokalaemia when corticosteroids and theophylline are used concomitantly.

4.6 Pregnancy And Lactation

Pregnancy

The ability of corticosteroids to cross the placenta varies between individual drugs, however, 88% of prednisolone is inactivated as it crosses the placenta.

Administration of corticosteroids to pregnant animals can cause abnormalities of foetal development including cleft palate, intra-uterine growth retardation and effects on brain growth and development. There is no evidence that corticosteroids result in an increased incidence of congenital abnormalities, such as cleft palate/lip in man. However, when administered for prolonged periods or repeatedly during pregnancy, corticosteroids may increase the risk of intra-uterine growth retardation. The use of corticosteroids, including prednisolone, during pregnancy may also result in stillbirth. Hypoadrenalism may, in theory, occur in the neonate following prenatal exposure to corticosteroids but usually resolves spontaneously following birth and is rarely clinically important. As with all drugs, corticosteroids should only be prescribed when the benefits to the mother and child outweigh the risks. When corticosteroids are essential however, patients with normal pregnancies may be treated as though they were in the non-gravid state. Patients with pre-eclampsia or fluid retention require dose monitoring

Lactation

Corticosteroids are excreted in small amounts in breast milk. However, doses of up to 40mg daily of prednisolone are unlikely to cause systemic effects in the infant. Infants of mothers receiving 40mg or more daily should be monitored for signs of adrenal suppression but the benefits of breast- feeding are likely to outweigh any theoretical risk.

4.7 Effects On Ability To Drive And Use Machines

None

4.8 Undesirable Effects

The incidence of predictable undesirable effects, including hypothalamic-pituitary-adrenal suppression correlates with the relative potency of the drug, dosage, timing of administration and the duration of treatment (see 4.4 Special Warnings and Precautions for use)

Endocrine/metabolic - suppression of the hypothalamic-pituitary-adrenal axis, growth suppression in infancy, childhood and adolescence, menstrual irregularity and amenorrhoea. Hirsutism, weight gain, impaired carbohydrate tolerance, hyperglycaemia, precipitation of diabetes mellitus or increased requirement for anti-diabetic therapy in pre-existing diabetes. Negative nitrogen and calcium balance. Increased appetite. Hypercholesterolaemia and hypertriglyceridaemia. High doses or prolonged administration of corticosteroids may cause Cushing's syndrome.

Anti-inflammatory and immunosuppressive effects - increased susceptibility and severity of infections with suppression of clinical symptoms and signs, opportunistic infections, recurrence of dormant tuberculosis (see other special warnings and precautions).

Musculoskeletal - osteoporosis, vertebral and long bone fractures, tendon rupture. Proximal myopathy, muscular weakness, musclular atrophy and buffalo hump. Avascular osteonecrosis has been associated with long term or high dose corticosteroid therapy.

Fluid and electrolyte disturbance - sodium and water retention, potassium loss, hypokalaemic alkalosis, oedema.

Blood and lymphatic system disorders-corticosteroids have the potential to increase the coagulability of blood.

Vascular disorders - hypertension.

Neuropsychiatric - A wide range of psychiatric reactions including affective disorders (such as irritable, euphoric, depressed and labile mood, and suicidal thoughts), psychotic reactions (including mania, delusions, hallucinations, and aggravation of schizophrenia), behavioural disturbances, irritability, anxiety, sleep disturbances, and cognitive dysfunction including confusion and amnesia have been reported. Reactions are common and may occur in both adults and children. In adults, the frequency of severe reactions has been estimated to be 5 – 6 %. Psychological effects have been reported on withdrawal of corticosteroids; the frequency is unknown. Psychological dependence, depression, insomnia, psychosis, delirium, and nervousness and/or restlessness have also been reported.

Increased intra-cranial pressure with papilloedema in children (pseudotumour cerebri), usually after treatment withdrawal. Aggravation of epilepsy.

Ophthalmic - increased intra-ocular pressure, glaucoma, papilloedema, posterior subcapsular cataracts, corneal or scleral thinning, serious retinal detachment, exacerbation of ophthalmic viral of fungal diseases and sudden blindness. Potential for exophthalmos to occur with long-term administration of corticosteroids.

Gastrointestinal - dyspepsia, peptic ulceration with perforation and haemorrhage, acute pancreatitis, candidiasis, hiccups and nausea.

Dermatological - impaired healing, skin atrophy, bruising, telangiectasia, striae, acne, skin thinning, flushing, hyperhidrosis.

General - hypersensitivity including anaphylaxis, has been reported. Leucocytosis. Thromboembolism, myocardial rupture following recent myocardial infarction, increased risk of Stevens-Johnson syndrome or toxic epidermal necrolysis, tumour lysis syndrome.

Withdrawal symptoms and signs - too rapid a reduction of corticosteroid dosage following prolonged treatment can lead to acute adrenal insufficiency, hypotension and death (see Special Warnings and Precautions for Use). A 'withdrawal syndrome' may also occur including, fever, myalgia, weakness, arthralgia, rhinitis, conjunctivitis, painful itchy skin nodules, loss of weight, mental changes, emotional changes, nausea, vomiting, hypotension, benign intracranial hypertension, dizziness, headache, and reappearance of disease symptoms.

4.9 Overdose

Treatment is unlikely to be needed; serum electrolytes should be monitored.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

The major therapeutic use of prednisolone is based on the anti-inflammatory and immunosuppressive activities of glucocorticoids. The suppression of inflammatory response is independent of the initiating stimulus and the action is mainly local. Some important components of the mechanism underlying the anti-inflammatory effects of corticosteroids are:

(i) inhibition of the adherence of neutrophils and monocyte-macrophages to the capillary endothelial cells of the inflamed area,

(ii) blocking of the effect of macrophage migration inhibitory factor,

(iii) decreased activation of plasminogen to plasmin, and

(iv) inhibition of phospholipase A₂ activity thereby lowering the formation of prostaglandins, leukotrienes and related compounds.

This suppression of inflammatory response by corticoids may also be a key feature of the way they counteract complications that arise from cell-mediated immune reactions. An acute effect of such steroids is sequestration of lymphocytes from blood although lysis of tissues also occurs, e.g. in lymphatic malignancies. At therapeutic dose levels corticoids do not seem to have any significant effect on circulating antibodies or on the metabolism of complement.

The two major targets of glucocorticoids, such as prednisolone, would be the liver (induction of enzymes, e.g. those involved in gluconeogenesis and amino acid degradation) and the lymphatic system (growth inhibitory actions which ultimately may result in cell death). The central feature of these hormonal actions is the combination of the steroid with an intracellular receptor, producing conformational changes that expose the DNA-binding domain on the receptor. The binding of the steroid receptor complex to specific sequences, known as hormone response elements, brings about transcriptional activation or repression of specific genes.

5.2 Pharmacokinetic Properties

Prednisolone is readily absorbed from the gastrointestinal tract and already exists in a metabolically active form.

Peak plasma concentrations of prednisolone are obtained one or two hours after administration by mouth, and it has a usual plasma half-life of two to four hours. Its initial absorption, but not its overall bioavailability, is affected by food.

Prednisolone is extensively bound to plasma proteins, although less so than hydrocortisone (cortisol).

Prednisolone is excreted in the urine as free and conjugated metabolites, together with an appreciable proportion of unchanged prednisolone. Prednisolone crosses the placenta and small amounts are excreted in breast milk.

Prednisolone has a biological half-life lasting several hours, intermediate between those of hydrocortisone (cortisol) and the longer acting glucocorticoids, such as dexamethasone. It is this intermediate duration of action that makes it suitable for the alternate day administration regimens that have been found to reduce the risk of adrenocortical insufficiency, yet provide adequate corticosteroid coverage in some disorders.

5.3 Preclinical Safety Data

Teratogenic effects of glucocorticoids have not been demonstrated in the human. Although malignancies are known to arise in patients undergoing immunosuppression with corticosteroids, any role of these compounds in the induction of tumours remain uncertain. The classic toxic effects of prednisolone like drugs are given under adverse reactions.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Lactose

Maize starch

Stearic acid

Purified talc

Magnesium stearate

6.2 Incompatibilities

None

6.3 Shelf Life

Three years

6.4 Special Precautions For Storage

Do not store above 25^oC

6.5 Nature And Contents Of Container

50 tablets in amber glass bottles or 100, 500 and 1000 tablets in polypropylene or polyethylene containers.

28 or 56 tablets in blister pack strips of 250 micron white rigid PVC and 20 micron hard tempered aluminium foil coated with PVC compatible heat seal lacquer on the reverse side.

28 or 56 tablets in polypropylene or polyethylene containers in cartons.

6.6 Special Precautions For Disposal And Other Handling

Not applicable.

7. Marketing Authorisation Holder

Wockhardt UK Ltd

Ash Road North

Wrexham Industrial Estate

Wrexham LL13 9UF

United Kingdom

8. Marketing Authorisation Number(S)

Prednisolone 1mg Tablets - PL 29831/0177

Prednisolone 5mg Tablets – PL 29831/0178

9. Date Of First Authorisation/Renewal Of The Authorisation

20/06/2007

10. Date Of Revision Of The Text

05/03/2008