Qvar MDI 50 micrograms

1. Name Of The Medicinal Product

Qvar 50 Aerosol 50 micrograms per actuation pressurised inhalation solution

2. Qualitative And Quantitative Composition

Beclometasone Dipropionate 50 micrograms per metered (ex-valve) dose.

(The dose delivered from the mouthpiece is an average 37.5 micrograms).

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Pressurised inhalation, solution.

A colourless solution in a pressurised aluminium canister fitted with a metering valve and an actuator.

Qvar contains a propellant, which does not contain any chlorofluorocarbons (CFCs).

4. Clinical Particulars

4.1 Therapeutic Indications

Prophylactic management of mild, moderate or severe asthma.

4.2 Posology And Method Of Administration

Qvar is for inhalation use only.

Patients should be instructed in the proper use of their inhaler, including rinsing out their mouth with water after use. Patients should be advised that Qvar may have a different taste and feel than a CFC inhaler.

NOTE: The recommended total daily dose of Qvar is lower than that for current beclometasone dipropionate CFC containing products and should be adjusted to the needs of the individual patient.

ADULT STARTING AND MAINTENANCE DOSE:

It is important to gain control of asthma symptoms and optimise pulmonary function as soon as possible. When patients' symptoms remain under satisfactory control, the dose should be titrated to the lowest dose at which effective control of asthma is maintained.

To be effective, inhaled Qvar must be used on a regular basis even when patients are asymptomatic.

THERAPY IN NEW PATIENTS SHOULD BE INITIATED AT THE FOLLOWING DOSAGES

Mild asthma:	100 to 200 micrograms per day in two divided doses.
Moderate asthma:	200 to 400 micrograms per day in two divided doses.
Severe asthma:	400 to 800 micrograms per day in two divided doses.

TRANSFERRING PATIENTS TO QVAR FROM A CFC-CONTAINING INHALER

The general approach to switching patients to Qvar involves two steps as detailed below. Specific guidance on switching well-controlled and poorly-controlled (symptomatic) patients is given below the table.

Step 1: Consider the dose of CFC containing beclometasone dipropionate product appropriate to the patient's current condition.

Step 2: Convert the CFC containing beclometasone dipropionate dose to the Qvar dose according to the table below.

Total Daily Dose (mcg/day)
CFC-BDP*	200-250	300	400-500	600-750	800-1000	1100	1200-1500	1600-2000
QVAR	100	150	200	300	400	500	600	800

*CFC-BDP = CFC beclometasone dipropionate

1. Dosing in well-controlled patients with asthma

Patients with well-controlled asthma using beclometasone dipropionate CFC containing product should be switched to Qvar at a dose in accordance with the table above.

For example:

Patients on 2 puffs twice daily of CFC beclometasone dipropionate 100 micrograms would change to 2 puffs twice daily of Qvar 50 micrograms.

2. Dosing in poorly-controlled (symptomatic) patients with asthma

Patients with poorly-controlled asthma may be switched from CFC containing beclometasone dipropionate products to Qvar at the same microgram for microgram dose up to 800 micrograms daily. Comparative clinical studies have demonstrated that asthma patients achieve equivalent pulmonary function and control of symptoms with Qvar at lower total daily doses than with CFC containing beclometasone dipropionate products.

Alternatively the patient's current CFC containing beclometasone dipropionate dose can be doubled and this dose can be converted to the Qvar dose according to the table above.

Patients on budesonide inhalers may be transferred to Qvar as described for CFC containing beclometasone dipropionate products.

Patients on fluticasone inhalers may be transferred to the same total daily dose of Qvar up to 800 micrograms daily.

Once transferred to Qvar the dose should be adjusted to meet the needs of the individual patient.

The maximum recommended dose is 800 micrograms per day in divided doses.

The same total daily dose in micrograms from either Qvar 50 or Qvar 100 (a higher strength) aerosol provides the same clinical effect.

CHILDREN

There are no data to date on Qvar in children under 12 years of age, hence no definitive dosage recommendation can be made.

SPECIAL PATIENT GROUPS

No special dosage recommendations are made for elderly or patients with hepatic or renal impairment.

INSTRUCTIONS FOR USE

Qvar aerosol is recommended for those patients who have demonstrated consistent good technique with co-ordinating actuation and inhalation.

The patient should read the instruction leaflet before use.

Before first use of the inhaler, or if the inhaler has not been used for two weeks or more, prime the inhaler by releasing two puffs into the air.

Where a spacer is considered necessary for specific patient needs, Qvar aerosol can be used with AeroChamber Plus™ holding chamber, as the extrafine particle fraction is maintained.

Qvar delivers a consistent dose

- whether or not the canister is shaken by the patient

- without the need for the patient to wait between individual actuations

- regardless of storage orientation or periods without use of up to 14 days

- at temperatures as low as -10°C.

4.3 Contraindications

Hypersensitivity to beclometasone dipropionate or to any of the excipients.

4.4 Special Warnings And Precautions For Use

To be effective, Qvar must be used by patients on a regular basis, even when patients do not have asthma symptoms. When symptoms are controlled, maintenance Qvar therapy should be reduced in a stepwise manner to the minimum effective dose. Inhaled steroid treatment should not be stopped abruptly. Patients with asthma are at risk of acute attacks and should have regular assessments of their asthma control including pulmonary function tests.

Qvar is not indicated for the immediate relief of asthma attacks. Patients therefore need to have relief medication (inhaled short-acting bronchodilator) available for such circumstances.

Qvar is not indicated in the management of status asthmaticus.

Severe asthma exacerbations should be managed in the usual way. Subsequently, it may be necessary to increase the dose of Qvar up to the maximum daily dose. Systemic steroid treatment may be needed and/or an antibiotic, if there is an infection.

Patients should be advised to seek medical attention for review of maintenance Qvar therapy if peak flow falls, symptoms worsen or if the short-acting bronchodilator becomes less effective and increased inhalations are required. This may indicate worsening asthma.

Patients who have received systemic steroids for long periods of time or at high doses, or both, need special care and subsequent management when being transferred to inhaled steroid therapy. Patients should have stable asthma before being given inhaled steroids in addition to the usual maintenance dose of systemic steroid. Withdrawal of systemic steroids should be gradual, starting about seven days after the introduction of Qvar therapy. For daily oral doses of prednisolone of 10mg or less, dose reduction in 1mg steps, at intervals of not less than one week is recommended. For patients on daily maintenance doses of oral prednisolone greater than 10mg, larger weekly reductions in the dose might be acceptable. The dose reduction scheme should be chosen to correlate with the magnitude of the maintenance systemic steroid dose.

Most patients can be successfully transferred to inhaled steroids with maintenance of good respiratory function, but special care is necessary for the first few months after the transfer, until the hypothalamic-pituitary-adrenal (HPA) system has sufficiently recovered to enable the patient to cope with stressful emergencies such as trauma, surgery or serious infections. Patients should, therefore, carry a steroid warning card to indicate the possible need to re-instate systemic steroid therapy rapidly during periods of stress or where airways obstruction or mucus significantly compromises the inhaled route of administration. In addition, it may be advisable to provide such patients with a supply of corticosteroid tablets to use in these circumstances. The dose of inhaled steroids should be increased at this time and then gradually reduced to the maintenance level after the systemic steroid has been discontinued. As recovery from impaired adrenocortical function, caused by prolonged systemic steroid therapy is slow, adrenocortical function should be monitored regularly.

Patients should be advised that they may feel unwell in a non-specific way during systemic steroid withdrawal despite maintenance of, or even improved respiratory function. Patients should be advised to persevere with their inhaled product and to continue withdrawal of systemic steroids, even if feeling unwell, unless there is evidence of HPA axis suppression.

Discontinuation of systemic steroids may also cause exacerbation of allergic diseases such as atopic eczema and rhinitis. These should be treated as required with topical therapy, including corticosteroids and/or antihistamines.

Beclometasone dipropionate, like other inhaled steroids, is absorbed into the systemic circulation from the lungs. Beclometasone dipropionate and its metabolites may exert detectable suppression of adrenal function. Within the dose range 100-800 micrograms daily, clinical studies with Qvar have demonstrated mean values for adrenal function and responsiveness within the normal range. However, systemic effects of inhaled corticosteroids may occur, particularly at high doses prescribed for prolonged periods. These effects are much less likely to occur than with oral corticosteroids. Possible systemic effects include Cushing's syndrome, Cushingoid features, adrenal suppression, growth retardation in children and adolescents, decrease in bone mineral density, cataract, glaucoma, and more rarely, a range of psychological or behavioural effects including psychomotor hyperactivity, sleep disorders, anxiety, depression or aggression (particularly in children). It is important, therefore, that the dose of inhaled corticosteroid is titrated to the lowest dose at which effective control of asthma is maintained.

It is recommended that the height of children receiving prolonged treatment with inhaled corticosteroids is regularly monitored. If growth is slowed, therapy should be reviewed with the aim of reducing the dose of inhaled corticosteroid, if possible, to the lowest dose at which effective control of asthma is maintained. In addition, consideration should be given to referring the patient to a paediatric respiratory specialist.

Prolonged treatment with high doses of inhaled corticosteroids, particularly higher than the recommended doses, may result in clinically significant adrenal suppression. Additional systemic corticosteroid cover should be considered during periods of stress or elective surgery.

Like other corticosteroids, caution is necessary in patients with active or latent pulmonary tuberculosis.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

No interaction studies have been performed.

4.6 Pregnancy And Lactation

The potential risk of this product for humans is unknown.

Qvar

There is no experience of this product in pregnancy and lactation in humans, therefore the product should only be used if the expected benefits to the mother are thought to outweigh any potential risk to the foetus or neonate

Beclometasone dipropionate

There is inadequate evidence of safety in human pregnancy.

The use of beclometasone dipropionate in pregnancy requires that the possible benefits of the drug be weighed against the possible hazards. The drug has been in widespread use for many years without apparent ill consequence.

It is probable that beclometasone dipropionate is excreted in milk. However, given the relatively low doses used by the inhalation route, the levels are likely to be low. In mothers breast feeding their baby the therapeutic benefits of the drug should be weighed against the potential hazards to mother and baby.

4.7 Effects On Ability To Drive And Use Machines

Not relevant.

4.8 Undesirable Effects

A serious hypersensitivity reaction including oedema of the eye, face, lips and throat (angioedema) has been reported rarely.

As with other inhaled therapy, paradoxical bronchospasm may occur after dosing. Immediate treatment with a short-acting bronchodilator should be initiated, Qvar should be discontinued immediately and an alternate prophylactic treatment introduced.

Systemic effects of inhaled corticosteroids may occur, particularly with high doses prescribed for prolonged periods. These include adrenal suppression, growth retardation in children, decrease in bone mineral density and the occurrence of cataract and glaucoma.

Commonly, when taking Qvar, hoarseness and candidiasis of the throat and mouth may occur. To reduce the risk of hoarseness and candida infection, patients are advised to rinse their mouth after using their inhaler.

Based on the MedDra system organ class and frequencies, adverse events are listed in the table below according to the following frequency estimate: very common (

MedDra – system organ class	Frequency and Symptom
Infections and infestations	Common: Candidiasis in mouth and throat
Immune system disorders	Rare: Allergic reactions, angioedema in eyes, throat, lips and face
Endocrine disorders	Very rare: Adrenal suppression, growth retardation in children
Nervous system disorders	Uncommon: Headache, vertigo, tremor
Eye disorders	Very rare: Cataract, glaucoma
Respiratory, thoracic and mediastinal disorders	Common: Hoarseness, pharyngitis Uncommon: Cough, increased asthma symptoms Rare: Paradoxical bronchospasm
Gastrointestinal disorders	Common: Taste disturbances Uncommon: Nausea
Skin and subcutaneous tissue disorders	Uncommon: Urticaria, rash pruritus, erythema, purpura
Musculoskeletal and connective tissue disorders	Very rare: Decrease bone mineral density
Psychiatric Disorders	Unknown: Psychomotor hyperactivity, sleep disorders, anxiety, depression, aggression, behavioural changes (predominantly in children)

4.9 Overdose

Acute overdosage is unlikely to cause problems. The only harmful effect that follows inhalation of large amounts of the drug over a short time period is suppression of HPA function. Specific emergency action need not be taken. Treatment with Qvar should be continued at the recommended dose to control the asthma; HPA function recovers in a day or two.

If excessive doses of beclometasone dipropionate were taken over a prolonged period a degree of atrophy of the adrenal cortex could occur in addition to HPA suppression. In this event the patient should be treated as steroid dependent and transferred to a suitable maintenance dose of a systemic steroid such as prednisolone. Once the condition is stabilised, the patient should be returned to Qvar by the method described above in section 4.4.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Glucocorticoids, ATC Code: R03B A01

Qvar contains beclometasone dipropionate in solution in propellant HFA-134a resulting in an extrafine aerosol. The aerosol droplets are on average much smaller than the beclometasone dipropionate particles delivered by CFC-suspension formulations or dry powder formulations of beclometasone dipropionate. The extrafine particle fraction will be 60% ± 20% of the drug particles

Radio-labelled deposition studies in adults with mild asthma have demonstrated that the majority of drug (>55% ex-actuator) is deposited in the lung and a small amount (< 35% ex-actuator) is deposited in the oropharynx. These delivery characteristics result in equivalent therapeutic effects at lower total daily doses of Qvar, compared with CFC beclometasone dipropionate formulations.

Inhaled beclometasone dipropionate is now well established in the management of asthma. It is a synthetic glucocorticoid and exerts a topical, anti-inflammatory effect on the lungs, with fewer systemic effects than oral corticosteroids.

Comparative clinical studies have demonstrated that asthma patients achieve equivalent pulmonary function and control of symptoms with Qvar at lower total daily doses than CFC containing beclometasone dipropionate aerosol inhalers.

Pharmacodynamic studies in patients with mild asthma given Qvar for 14 days, have shown that there is a linear correlation among urinary free cortisol suppression, dose administered, and serum total-beclometasone levels obtained. At a daily dose of 800 micrograms Qvar, suppression of urinary free cortisol was comparable with that observed with the same daily dose of CFC containing beclometasone dipropionate, indicating a wider safety margin, as Qvar is administered at lower doses than the CFC product.

5.2 Pharmacokinetic Properties

The pharmacokinetic profile of Qvar shows that the peak serum concentration for total- beclometasone (BOH) (total of any beclometasone OH and beclometasone dipropionate or monopropionate hydrolysed to beclometasone OH) after single and multiple doses is achieved after 30 minutes.

The value at the peak is approximately 2 nanograms/ml after a total daily dose of 800 micrograms and the serum levels after 100, 200 and 400 micrograms are proportional. The principal route of elimination of beclometasone dipropionate and its several metabolites is in the faeces. Between 10% and 15% of an orally administered dose is excreted in the urine, as both conjugated and free metabolites of the drug.

In both single dose and multiple dose pharmacokinetic studies, a dose of 200 micrograms of Qvar achieved comparable total-BOH levels, as a dose of 400 micrograms of CFC containing beclometasone dipropionate aerosol. This provided the scientific rationale for investigating lower total daily doses of Qvar to achieve the same clinical effect.

Pharmacokinetic studies with Qvar have not been carried out in any special populations.

5.3 Preclinical Safety Data

In animal studies, propellant HFA-134a has been shown to have no significant pharmacological effects other than at very high exposure concentrations, then narcosis and a relatively weak cardiac sensitising effect were found. The potency of the cardiac sensitisation was less than that of CFC-11 (trichlorofluoromethane).

In studies to detect toxicity, repeated high dose levels of propellant HFA-134a indicated that safety margins based on systemic exposure would be of the order 2200, 1314 and 381 for mouse, rat and dog with respect to humans.

There are no reasons to consider propellant HFA-134a as a potential mutagen, clastogen or carcinogen judged from in vitro and in vivo studies including long-term administration by inhalation in rodents.

Studies of propellant HFA-134a administered to pregnant and lactating rats and rabbits have not revealed any special hazard.

In animals, systemic administration of relatively high doses can cause abnormalities of foetal development including growth retardation and cleft palate. There may therefore be a very small risk of such effects in the human foetus. However, inhalation of beclometasone dipropionate into the lungs avoids the high level of exposure that occurs with administration by systemic routes.

Safety studies with Qvar in rat and dog showed few, if any, adverse effects other than those normally associated with general steroid exposure including lymphoid tissue alterations such as reduction in thymus, adrenal and spleen weights. An inhalation reproductive study with this product in rats did not exhibit any teratogenic effects.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Propellant HFA-134a (Norflurane)

Ethanol.

6.2 Incompatibilities

Not applicable.

6.3 Shelf Life

3 years

6.4 Special Precautions For Storage

Do not store above 25°C. Protect from frost and direct sunlight.

The canister contains a pressurised liquid. Do not expose to temperatures higher that 50°C. Do not pierce the canister.

6.5 Nature And Contents Of Container

Pressurised aluminium canister closed with a metering valve containing either 100 or 200 actuations.

6.6 Special Precautions For Disposal And Other Handling

Not applicable.

7. Marketing Authorisation Holder

Teva UK Limited

Brampton Road

Hampden Park

Eastbourne

East Sussex

BN22 9AG

United Kingdom

8. Marketing Authorisation Number(S)

PL 00289/1371

9. Date Of First Authorisation/Renewal Of The Authorisation

2^nd November 2009

10. Date Of Revision Of The Text

11/05/2011

Isordil

isosorbide dinitrate

Dosage Form: Sublingual Tablets

Rx only

Isordil Description

Isosorbide dinitrate (ISDN) is 1,4:3,6-dianhydro-D-glucitol 2,5-dinitrate, an organic nitrate whose structural formula is

and whose molecular weight is 236.14. The organic nitrates are vasodilators, active on both arteries and veins.

Isosorbide dinitrate is a white, crystalline, odorless compound which is stable in air and in solution, has a melting point of 70°C and has an optical rotation of +134° (c=1.0, alcohol, 20°C). Isosorbide dinitrate is freely soluble in organic solvents such as acetone, alcohol, and ether, but is only sparingly soluble in water.

Each Isordil® Sublingual tablet contains 2.5, 5, or 10 mg of isosorbide dinitrate. The inactive ingredients in each tablet are cellulose, lactose, magnesium stearate, and starch. The 2.5 mg dosage strength also contains D&C Yellow 10 and FD&C Yellow 6, and the 5 mg dosage strength also contains FD&C Red 40.

Isordil - Clinical Pharmacology

The principal pharmacological action of isosorbide dinitrate is relaxation of vascular smooth muscle and consequent dilatation of peripheral arteries and veins, especially the latter. Dilatation of the veins promotes peripheral pooling of blood and decreases venous return to the heart, thereby reducing left ventricular end-diastolic pressure and pulmonary capillary wedge pressure (preload). Arteriolar relaxation reduces systemic vascular resistance, systolic arterial pressure, and mean arterial pressure (afterload). Dilatation of the coronary arteries also occurs. The relative importance of preload reduction, afterload reduction, and coronary dilatation remains undefined.

Dosing regimens for most chronically used drugs are designed to provide plasma concentrations that are continuously greater than a minimally effective concentration. This strategy is inappropriate for organic nitrates. Several well-controlled clinical trials have used exercise testing to assess the anti-anginal efficacy of continuously-delivered nitrates. In the large majority of these trials, active agents were no more effective than placebo after 24 hours (or less) of continuous therapy. Attempts to overcome nitrate tolerance by dose escalation, even to doses far in excess of those used acutely, have consistently failed. Only after nitrates have been absent from the body for several hours has their anti-anginal efficacy been restored.

Pharmacokinetics

Bioavailability of ISDN after single sublingual doses is 40 to 50%.Multiple-dose studies of sublingual ISDN pharmacokinetics have not been reported; multiple-dose studies of ingested ISDN have observed progressive increases in bioavailability during chronic therapy. Serum levels of ISDN reach their maxima 10 to 15 minutes after sublingual dosing.

Once absorbed, the volume of distribution of isosorbide dinitrate is 2 to 4 L/kg, and this volume is cleared at the rate of 2 to 4 L/min, so ISDN's half-life in serum is about an hour. Since the clearance exceeds hepatic blood flow, considerable extrahepatic metabolism must also occur. Clearance is affected primarily by denitration to the 2-mononitrate (15 to 25%) and the 5-mononitrate (75 to 85%).

Both metabolites have biological activity, especially the 5-mononitrate. With an overall half-life of about 5 hours, the 5-mononitrate is cleared from the serum by denitration to isosorbide, glucuronidation to the 5-mononitrate glucuronide, and denitration/hydration to sorbitol. The 2-mononitrate has been less well studied, but it appears to participate in the same metabolic pathways, with a half-life of about 2 hours.

The daily dose-free interval sufficient to avoid tolerance to organic nitrates has not been well defined. Studies of nitroglycerin (an organic nitrate with a very short half-life) have shown that daily dose-free intervals of 10 to 12 hours are usually sufficient to minimize tolerance. Daily dose-free intervals that have succeeded in avoiding tolerance during trials of moderate doses (e.g., 30 mg) of immediate-release ISDN have generally been somewhat longer (at least 14 hours), but this is consistent with the longer half-lives of ISDN and its active metabolites.

Few well-controlled clinical trials of organic nitrates have been designed to detect rebound or withdrawal effects. In one such trial, however, subjects receiving nitroglycerin had less exercise tolerance at the end of the daily dose-free interval than the parallel group receiving placebo. The incidence, magnitude, and clinical significance of similar phenomena in patients receiving ISDN have not been studied.

Clinical trials

In a controlled trial in which 0.4 mg of sublingual nitroglycerin took 1.9 minutes to begin to produce an anti-anginal effect, 5 mg of sublingual ISDN took 3.4 minutes to begin to produce a similar effect. In the same trial, the anti-anginal effect of the sublingual nitroglycerin was evident for about an hour, while that of the sublingual ISDN lasted about 2 hours.

In other controlled trials, the anti-anginal efficacy of sublingual ISDN has persisted for periods ranging from 30 minutes up to 4 hours.

Multiple-dose trials of sublingual ISDN have not been reported.

Multiple-dose trials of ingested formulations of ISDN have shown that ISDN's anti-anginal efficacy is substantially attenuated by tolerance unless the daily regimen includes a dose-free interval of at least 14 hours. The daily dose-free interval necessary in any chronic regimen using sublingual ISDN is not known.

From large, well-controlled studies of other nitrates, it is reasonable to believe that the maximal achievable daily duration of anti-anginal effect from isosorbide dinitrate is about 12 hours. No dosing regimen for isosorbide dinitrate has, however, ever actually been shown to achieve this duration of effect. In the absence of data from multiple-dose trials, and considering the capacity of organic nitrates to induce tolerance, it is not reasonable to assume that multiple sublingual ISDN tablets taken during the course of a day will all have similar effects.

Indications and Usage for Isordil

Isordil (isosorbide dinitrate) Sublingual tablets are indicated for the prevention and treatment of angina pectoris due to coronary artery disease. However, because the onset of action of sublingual ISDN is significantly slower than that of sublingual nitroglycerin, sublingual ISDN is not the drug of first choice for abortion of an acute anginal episode.

Contraindications

Allergic reactions to organic nitrates are extremely rare, but they do occur. Isordil is contraindicated in patients who are allergic to isosorbide dinitrate or any of its other ingredients.

Warnings

Amplification of the vasodilatory effects of Isordil by sildenafil can result in severe hypotension. The time course and dose dependence of this interaction have not been studied. Appropriate supportive care has not been studied, but it seems reasonable to treat this as a nitrate overdose, with elevation of the extremities and with central volume expansion.

The benefits of sublingual isosorbide dinitrate in patients with acute myocardial infarction or congestive heart failure have not been established. If one elects to use isosorbide dinitrate in these conditions, careful clinical or hemodynamic monitoring must be used to avoid the hazards of hypotension and tachycardia.

Precautions

General

Severe hypotension, particularly with upright posture, may occur with even small doses of isosorbide dinitrate. This drug should therefore be used with caution in patients who may be volume depleted or who, for whatever reason, are already hypotensive. Hypotension induced by isosorbide dinitrate may be accompanied by paradoxical bradycardia and increased angina pectoris.

Nitrate therapy may aggravate the angina caused by hypertrophic cardiomyopathy.

As tolerance to isosorbide dinitrate develops, the effect of sublingual nitroglycerin on exercise tolerance, although still observable, is somewhat blunted.

Some clinical trials in angina patients have provided nitroglycerin for about 12 continuous hours of every 24-hour day. During the daily dose-free interval in some of these trials, anginal attacks have been more easily provoked than before treatment, and patients have demonstrated hemodynamic rebound and decreased exercise tolerance. The importance of these observations to the routine, clinical use of sublingual isosorbide dinitrate is not known.

In industrial workers who have had long-term exposure to unknown (presumably high) doses of organic nitrates, tolerance clearly occurs. Chest pain, acute myocardial infarction, and even sudden death have occurred during temporary withdrawal of nitrates from these workers, demonstrating the existence of true physical dependence.

Information for Patients

Patients should be told that the anti-anginal efficacy of isosorbide dinitrate is strongly related to its dosing regimen, so the prescribed schedule of dosing should be followed carefully. In particular, daily headaches sometimes accompany treatment with isosorbide dinitrate. In patients who get these headaches, the headaches are a marker of the activity of the drug. Patients should resist the temptation to avoid headaches by altering the schedule of their treatment with isosorbide dinitrate, since loss of headache may be associated with simultaneous loss of anti-anginal efficacy. Aspirin and/or acetaminophen, on the other hand, often successfully relieve isosorbide dinitrate-induced headaches with no deleterious effect on isosorbide dinitrate's anti-anginal efficacy.

Treatment with isosorbide dinitrate may be associated with lightheadedness on standing, especially just after rising from a recumbent or seated position. This effect may be more frequent in patients who have also consumed alcohol.

Drug Interactions

The vasodilating effects of isosorbide dinitrate may be additive with those of other vasodilators. Alcohol, in particular, has been found to exhibit additive effects of this variety.

Carcinogenesis, Mutagenesis, Impairment of Fertility

No long-term studies in animals have been performed to evaluate the carcinogenic potential of isosorbide dinitrate. In a modified two-litter reproduction study, there was no remarkable gross pathology and no altered fertility or gestation among rats fed isosorbide dinitrate at 25 or 100 mg/kg/day.

Pregnancy Category C

At oral doses 35 and 150 times the maximum recommended human daily dose, isosorbide dinitrate has been shown to cause a dose-related increase in embryotoxicity (increase in mummified pups) in rabbits. There are no adequate, well-controlled studies in pregnant women. Isosorbide dinitrate should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nursing Mothers

It is not known whether isosorbide dinitrate is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when isosorbide dinitrate is administered to a nursing woman.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Geriatric Use

Clinical studies of Isordil (isosorbide dinitrate) Sublingual did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Adverse Reactions

Adverse reactions to isosorbide dinitrate are generally dose-related, and almost all of these reactions are the result of isosorbide dinitrate's activity as a vasodilator. Headache, which may be severe, is the most commonly reported side effect. Headache may be recurrent with each daily dose, especially at higher doses. Transient episodes of lightheadedness, occasionally related to blood pressure changes, may also occur.

Hypotension occurs infrequently, but in some patients it may be severe enough to warrant discontinuation of therapy. Syncope, crescendo angina, and rebound hypertension have been reported but are uncommon.

Extremely rarely, ordinary doses of organic nitrates have caused methemoglobinemia in normal-seeming patients. Methemoglobinemia is so infrequent at these doses that further discussion of its diagnosis and treatment is deferred (see OVERDOSAGE).

Data are not available to allow estimation of the frequency of adverse reactions during treatment with Isordil® Sublingual tablets.

Overdosage

Hemodynamic Effects

The ill effects of isosorbide dinitrate overdose are generally the results of isosorbide dinitrate's capacity to induce vasodilatation, venous pooling, reduced cardiac output, and hypotension. These hemodynamic changes may have protean manifestations, including increased intracranial pressure, with any or all of persistent throbbing headache, confusion, and moderate fever; vertigo; palpitations; visual disturbances; nausea and vomiting (possibly with colic and even bloody diarrhea); syncope (especially in the upright posture); air hunger and dyspnea, later followed by reduced ventilatory effort; diaphoresis, with the skin either flushed or cold and clammy; heart block and bradycardia; paralysis; coma; seizures; and death.

Laboratory determinations of serum levels of isosorbide dinitrate and its metabolites are not widely available, and such determinations have, in any event, no established role in the management of isosorbide dinitrate overdose.

There are no data suggesting what dose of isosorbide dinitrate is likely to be life-threatening in humans. In rats, the median acute lethal dose (LD50) was found to be 1100 mg/kg.

No data are available to suggest physiological maneuvers (e.g., maneuvers to change the pH of the urine) that might accelerate elimination of isosorbide dinitrate and its active metabolites. Similarly, it is not known which, if any, of these substances can usefully be removed from the body by hemodialysis.

No specific antagonist to the vasodilator effects of isosorbide dinitrate is known, and no intervention has been subject to controlled studies as a therapy for isosorbide dinitrate overdose. Because the hypotension associated with isosorbide dinitrate overdose is the result of venodilatation and arterial hypovolemia, prudent therapy in this situation should be directed toward increase in 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.

The use of epinephrine or other arterial vasoconstrictors in this setting is likely to do more harm than good.

In patients with renal disease or congestive heart failure, therapy resulting in central volume expansion is not without hazard. Treatment of isosorbide dinitrate overdose in these patients may be subtle and difficult, and invasive monitoring may be required.

Methemoglobinemia

Nitrate ions liberated during metabolism of isosorbide dinitrate can oxidize hemoglobin into methemoglobin. Even in patients totally without cytochrome b5 reductase activity, however, and even assuming that the nitrate moieties of isosorbide dinitrate are quantitatively applied to oxidation of hemoglobin, about 1 mg/kg of isosorbide dinitrate should be required before any of these patients manifests clinically significant (≥10%) methemoglobinemia. In patients with normal reductase function, significant production of methemoglobin should require even larger doses of isosorbide dinitrate. In one study in which 36 patients received 2 to 4 weeks of continuous nitroglycerin therapy at 3.1 to 4.4 mg/hr (equivalent, in total administered dose of nitrate ions, to 4.8 to 6.9 mg of bioavailable isosorbide dinitrate per hour), the average methemoglobin level measured was 0.2%; this was comparable to that observed in parallel patients who received placebo.

Notwithstanding these observations, there are case reports of significant methemoglobinemia in association with moderate overdoses of organic nitrates. None of the affected patients had been thought to be unusually susceptible.

Methemoglobin levels are available from most clinical laboratories. The diagnosis should be suspected in patients who exhibit signs of impaired oxygen delivery despite adequate cardiac output and adequate arterial pO2. Classically, methemoglobinemic blood is described as chocolate brown, without color change on exposure to air.

When methemoglobinemia is diagnosed, the treatment of choice is methylene blue, 1 to 2 mg/kg intravenously.

Isordil Dosage and Administration

As noted under Clinical Pharmacology, multiple-dose studies with ISDN and other nitrates have shown that maintenance of continuous 24-hour plasma levels results in refractory tolerance. Every dosing regimen for ISDN must provide a daily dose-free interval to minimize the development of this tolerance. In the case of sublingual tablets, it is probably true that one of the daily dose-free intervals must be somewhat longer than 14 hours.

As also noted under CLINICAL PHARMACOLOGY, the efficacy of daily doses after the first has never been demonstrated.

Large controlled studies with other nitrates suggest that no dosing regimen with Isordil Sublingual tablets should be expected to provide more than about 12 hours of continuous anti-anginal efficacy per day.

A patient anticipating activity likely to cause angina should take one Isordil Sublingual tablet (2.5 to 5 mg) about 15 minutes before the activity is expected to begin. Isordil Sublingual tablets may be used to abort an acute anginal episode, but its use is recommended only in patients who fail to respond to sublingual nitroglycerin.

How is Isordil Supplied

Isordil® (isosorbide dinitrate) Sublingual Tablets are available as follows:

2.5 mg, round, yellow tablets imprinted "2.5" on one side and "W" on reverse side:

NDC 0008-4139-01, bottles of 100.

5 mg, round, pink tablets imprinted "5" on one side and "W" on reverse side:

NDC 0008-4126-01, bottles of 100.

Store at room temperature, approximately 25° C (77° F)

Protect from light

Keep bottles tightly closed

Dispense in a light-resistant, tight container

Use carton to protect blisters from light

10 mg, round, white tablets imprinted "10" on one side and "Wyeth" on reverse side:

NDC 0008-4161-01, bottles of 100.

Store at room temperature, approximately 25° C (77° F)

Keep tightly closed

Dispense in a tight container

ALSO AVAILABLE

Oral Titradose® Tablets in the following dosage strengths:

5 mg, NDC 0008-4152, in bottles of 100 or 1,000.

10 mg, NDC 0008-4153, in bottles of 100 or 1,000.

20 mg, NDC 0008-4154, in bottles of 100 or 500.

30 mg, NDC 0008-4159, in bottles of 100.

40 mg, NDC 0008-4192, in bottles of 100.

Wyeth Laboratories

A Wyeth-Ayerst Company

Philadelphia, PA 19101

CI 4370-3

Isordil  isosorbide dinitrate  tablet

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 0008-4139 Route of Administration ORAL DEA Schedule

INGREDIENTS Name (Active Moiety) Type Strength isosorbide dinitrate (isosorbide) Active 2.5 MILLIGRAM  In 1 TABLET cellulose Inactive   lactose Inactive   magnesium stearate Inactive   starch Inactive   D&C Yellow 10 Inactive   FD&C Yellow 6 Inactive

Product Characteristics Color YELLOW (YELLOW) Score no score Shape ROUND (ROUND) Size 4mm Flavor Imprint Code 2.5;W Contains          Coating false Symbol false

Packaging # NDC Package Description Multilevel Packaging 1 0008-4139-01 100 TABLET In 1 BOTTLE None

Isordil  isosorbide dinitrate  tablet

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 0008-4126 Route of Administration ORAL DEA Schedule

INGREDIENTS Name (Active Moiety) Type Strength isosorbide dinitrate (isosorbide) Active 5 MILLIGRAM  In 1 TABLET cellulose Inactive   lactose Inactive   magnesium stearate Inactive   starch Inactive   FD&C Red 40 Inactive

Product Characteristics Color PINK (PINK) Score no score Shape ROUND (ROUND) Size 4mm Flavor Imprint Code 5;W Contains          Coating false Symbol false

Packaging # NDC Package Description Multilevel Packaging 1 0008-4126-01 100 TABLET In 1 BOTTLE None

Isordil  isosorbide dinitrate  tablet

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 0008-4161 Route of Administration ORAL DEA Schedule

INGREDIENTS Name (Active Moiety) Type Strength isosorbide dinitrate (isosorbide) Active 10 MILLIGRAM  In 1 TABLET cellulose Inactive   lactose Inactive   magnesium stearate Inactive   starch Inactive

Product Characteristics Color WHITE (WHITE) Score no score Shape ROUND (ROUND) Size 4mm Flavor Imprint Code 10;Wyeth Contains          Coating false Symbol false

Packaging # NDC Package Description Multilevel Packaging 1 0008-4161-01 100 TABLET In 1 BOTTLE None

Revised: 03/2006Wyeth Laboratories

More Isordil resources

• Isordil Side Effects (in more detail)
• Isordil Dosage
• Isordil Use in Pregnancy & Breastfeeding
• Drug Images
• Isordil Drug Interactions
• Isordil Support Group
• 0 Reviews for Isordil - Add your own review/rating

• Isordil Advanced Consumer (Micromedex) - Includes Dosage Information


• Isosorbide Dinitrate Professional Patient Advice (Wolters Kluwer)


• Dilatrate-SR Concise Consumer Information (Cerner Multum)


• Dilatrate-SR MedFacts Consumer Leaflet (Wolters Kluwer)


• Isordil Titradose MedFacts Consumer Leaflet (Wolters Kluwer)


• Isosorbide Dinitrate/Mononitrate Monograph (AHFS DI)

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licorice

Generic Name: licorice (LIH koe rish)

Brand Names:

What is licorice?

The use of licorice in cultural and traditional settings may differ from concepts accepted by current Western medicine. When considering the use of herbal supplements, consultation with a primary health care professional is advisable. Additionally, consultation with a practitioner trained in the uses of herbal/health supplements may be beneficial, and coordination of treatment among all health care providers involved may be advantageous.

Licorice is also known as liquorice, American licorice, Spanish licorice, Russian licorice, sweet root, and Glycyrrhiza glabra.

Licorice is a commonly used flavoring agent and food product. Licorice is also available as an herbal supplement. The information contained in this leaflet refers to the use of licorice as an herbal supplement. When used as a food product, the benefits and potential side effects of licorice may be less pronounced than when it is used as an herbal supplement.

Licorice has been used to loosen congestion that may occur due to a cough or cold, and to treat and prevent inflammation and/or ulceration of the stomach. Licorice has been used topically to suppress the production of oil on the scalp.

Licorice has not been evaluated by the FDA for safety, effectiveness, or purity. All potential risks and/or advantages of licorice may not be known. Additionally, there are no regulated manufacturing standards in place for these compounds. There have been instances where herbal/health supplements have been sold which were contaminated with toxic metals or other drugs. Herbal/health supplements should be purchased from a reliable source to minimize the risk of contamination.

Licorice may also have uses other than those listed in this product guide.

What is the most important information I should know about licorice?

Licorice is a commonly used flavoring agent and food product. Licorice is also available as an herbal supplement. The information contained in this leaflet refers to the use of licorice as an herbal supplement. When used as a food product, the benefits and potential side effects of licorice may be less pronounced than when it is used as an herbal supplement.

Do not take more of this medication than is directed. Too much licorice could be dangerous. Also, do not take licorice for longer than 6 weeks. The use of licorice at high doses (over 50 g per day) and/or for longer than 6 weeks may cause low blood levels of potassium, high blood levels of sodium, water retention, increased blood pressure, heart problems, and blood problems.

Licorice has not been evaluated by the FDA for safety, effectiveness, or purity. All potential risks and/or advantages of licorice may not be known. Additionally, there are no regulated manufacturing standards in place for these compounds. There have been instances where herbal/health supplements have been sold which were contaminated with toxic metals or other drugs. Herbal/health supplements should be purchased from a reliable source to minimize the risk of contamination.

Who should not take licorice?

Do not take licorice without first talking to your doctor if you have

• 
  

  heart disease,

  
  


• 
  

  high blood pressure, or

  
  


• 
  

  diabetes.

  
  

You may not be able to take licorice, or you may require a dosage adjustment or special monitoring during your treatment if you have any of the conditions listed above.

Talk to your doctor before taking licorice if you have any other medical conditions, allergies (especially to plants), or if you take other medicines or herbal/health supplements. Licorice may not be recommended in some situations.

Do not take licorice without first talking to your doctor if you are pregnant or could become pregnant. It is not known whether licorice will harm an unborn baby. Do not take licorice without first talking to your doctor if you are breast-feeding a baby. It is also not known whether licorice will harm a nursing infant. There is no information available regarding the use of licorice by children. Do not give any herbal/health supplement to a child without first talking to the child's doctor.

How should I take licorice?

The use of licorice in cultural and traditional settings may differ from concepts accepted by current Western medicine. When considering the use of herbal supplements, consultation with a primary health care professional is advisable. Additionally, consultation with a practitioner trained in the uses of herbal/health supplements may be beneficial, and coordination of treatment among all health care providers involved may be advantageous.

If you choose to take licorice, use it as directed on the package or as directed by your doctor, pharmacist, or other health care provider.

Standardized extracts, tinctures, and solid formulations of herbal/health supplements may provide a more reliable dose of the product.

Licorice is available in pill formulations, powered or crushed forms, liquid drops, and tea formulations.

Do not take more of this product than is directed. Too much licorice could be dangerous. Also, do not take licorice for longer than 6 weeks. The use of licorice at high doses (over 50 g per day) and/or for longer than 6 weeks may cause low blood levels of potassium, high blood levels of sodium, water retention, increased blood pressure, heart problems, and blood problems. Do not use different formulations (e.g., tablets, topical formulations, teas, tinctures, and others) of licorice at the same time, unless specifically directed to do so by a health care professional. Using different formulations together increases the risk of an overdose of licorice.

Store licorice as directed on the package. In general, licorice should be protected from light and moisture.

What happens if I miss a dose?

Skip the missed dose if it is almost time for your next scheduled dose. Do not use extra licorice to make up the missed dose.

What happens if I overdose?

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

Symptoms of a licorice overdose may include low blood levels of potassium, high blood levels of sodium, water retention, increased blood pressure, heart problems, decreased or stopped menstrual periods, weakness, dulled reflexes, lethargy, and blood problems.

What should I avoid while taking licorice?

Follow your healthcare provider's instructions about any restrictions on food, beverages, or activity.

Licorice side effects

Although uncommon, allergic reactions to licorice have been reported. Stop taking licorice and seek emergency medical attention if you experience symptoms of a serious allergic reaction including difficulty breathing; closing of your throat; swelling of your lips, tongue, or face; or hives.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

What other drugs will affect licorice?

Do not take licorice without first talking to your doctor if you are taking any of the following medicines:

• 
  

  a heart or blood pressure medicine;

  
  


• 
  

  spironolactone (Aldactone);

  
  


• 
  

  isocarboxazid (Marplan), tranylcypromine (Parnate), or phenelzine (Nardil);

  
  


• 
  

  cyclosporine (Neoral, Sandimmune);

  
  


• 
  

  a diabetes medicine such as insulin, glipizide (Glucotrol), glyburide (Micronase, Diabeta, Glynase), metformin (Glucophage), troglitazone (Rezulin), rosiglitazone (Avandia), pioglitazone (Actos), and others;

  
  


• 
  

  a steroid medicine such as cortisone (Cortone), hydrocortisone (Cortef, Hydrocortone, others), prednisone (Deltasone, others), prednisolone (Prelone, Pediapred, others), methylprednisolone (Medrol, Solu-Medrol, others), triamcinolone (Aristocort, others), and others;

  
  


• 
  

  birth control pills such as Triphasil, Ovral, Lo-Ovral, Nordette, Alesse, Demulen, Ortho-Novum, and many others;

  
  


• 
  

  estrogen replacement products such as Premarin, Cenestin, Vivelle, Climara, Fempatch, and many others; or

  
  


• 
  

  tamoxifen (Nolvadex) or toremifene (Fareston).

  
  

You may not be able to take licorice, or you may require a dosage adjustment or special monitoring during treatment if you are taking any of the medicines listed above.

Drugs other than those listed here may also interact with licorice or affect your condition. Talk to your doctor, pharmacist, or health care provider before taking any prescription or over-the-counter medicines or other herbal/health supplements.

More licorice resources

• Licorice Side Effects (in more detail)
• Licorice Use in Pregnancy & Breastfeeding
• Licorice Drug Interactions
• Licorice Support Group
• 0 Reviews for Licorice - Add your own review/rating

• Licorice Natural MedFacts for Professionals (Wolters Kluwer)


• Licorice Natural MedFacts for Consumers (Wolters Kluwer)


• Licorice MedFacts Consumer Leaflet (Wolters Kluwer)

Compare licorice with other medications

• Cough
• Herbal Supplementation
• Stomach Ulcer
• Upper Respiratory Tract Infection

Where can I get more information?

• Consult with a licensed healthcare professional before using any herbal/health supplement. Whether you are treated by a medical doctor or a practitioner trained in the use of natural medicines/supplements, make sure all your healthcare providers know about all of your medical conditions and treatments.

See also: licorice side effects (in more detail)

Soluble Prednisolone Tablets 5mg

1. Name Of The Medicinal Product

Prednesol Tablets 5mg

Soluble Prednisolone Tablets 5mg

2. Qualitative And Quantitative Composition

Small, pink, soluble tablets engraved 'Pred 5 Sov' on one side and scored on the reverse. Each tablet contains 5mg prednisolone as the sodium phosphate ester.

3. Pharmaceutical Form

Tablet.

4. Clinical Particulars

4.1 Therapeutic Indications

A wide variety of diseases may sometimes require corticosteroid therapy. Some of the principal indications are:

• bronchial asthma, severe hypersensitivity reactions, anaphylaxis; rheumatoid arthritis, systemic lupus erythematosus, dermatomyositis, mixed connective tissue disease (excluding systemic sclerosis), polyarteritis nodosa; • inflammatory skin disorders, including pemphigus vulgaris, bullous pemphigoid and pyoderma gangrenosurn; • minimal change nephrotic syndrome, acute interstitial nephritis; • ulcerative colitis, Crohn's disease; sarcoidosis; • rheumatic carditis; • haemolytic anaemia (autoimmune), acute lymphoblastic and chronic lymphocytic leukaemia, malignant lymphoma, multiple myeloma, idiopathic thrombocytopenic purpura; • immunosuppression in transplantation.

4.2 Posology And Method Of Administration

Prednesol / Soluble Prednisolone Tablets are best taken dissolved in water, but they can be swallowed whole without difficulty.

The lowest dosage that will produce an acceptable result should be used (See precautions section); when it is possible to reduce the dosage, this must be accomplished by stages. During prolonged therapy any intercurrent illness, trauma or surgical procedure will require a temporary increase in dosage; if corticosteroids have been stopped following prolonged therapy they may need to be temporarily re-introduced.

Adults: The dose used will depend upon the disease, its severity, and the clinical response obtained. The following regimens are for guidance only. Divided dosage is usually employed.

Short-term treatment: 20 to 30 mg daily for the first few days, subsequently reducing the daily dosage by 2.5 or 5 mg every two to five days, depending upon the response.

Rheumatoid arthritis: 7.5 to 10 mg daily. For maintenance therapy the lowest effective dosage is used.

Most other conditions: 10 to 100 mg daily for one to three weeks, then reducing to the minimum effective dosage.

Children: Fractions of the adult dosage may be used (e.g. 75% at 12 years, 50% at 7 years and 25% at 1 year) but clinical factors must be given due weight.

Soluble Prednisolone Tablets may be given early in the treatment of acute asthma attacks in children. For children over 5 years use a dose of 30-40 mg prednisolone. For children aged 2-5 years use a dose of 20 mg prednisolone. Those already receiving maintenance steroid tablets should receive 2 mg/kg prednisolone up to a maximum dose of 60 mg. The dose of prednisolone may be repeated for children who vomit; but intravenous steroids should be considered in children who are unable to retain orally ingested medication. Treatment for up to three days is usually sufficient, but the length of course should be tailored to the number of days necessary to bring about recovery. There is no need to taper the dose at the end of treatment.

For children under 2 years, Soluble Prednisolone Tablets can be used early in the management of moderate to severe episodes of acute asthma in the hospital setting, at a dose of 10 mg for up to three days.

4.3 Contraindications

Systemic infections, unless specific anti-infective therapy is employed. Live virus immunisation. Hypersensitivity to any component of the tablets.

4.4 Special Warnings And Precautions For Use

In patients who have received more than physiological doses of systemic corticosteroids (approximately 7.5 mg prednisolone or equivalent) for greater than 3 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. 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 HPA suppression, the dose of systemic corticosteroid may be reduced rapidly to physiological doses. Once a daily dose equivalent to 7.5 mg 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 3 weeks is appropriate if it is considered that the disease is unlikely to relapse. Abrupt withdrawal of doses of up to 40 mg daily of prednisolone, or equivalent for 3 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 3 weeks or less:

• Patients who have had repeated courses of systemic corticosteroids, particularly if taken for greater than 3 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, been stopped following prolonged therapy they may need to be temporarily reintroduced. • 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.

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. During prolonged therapy any intercurrent illness, trauma or surgical procedure will require a temporary increase in dosage; if corticosteroids have been stopped following prolonged therapy they may need to be temporarily re-introduced.

Suppression of the HPA axis and other 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).

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.

Chickenpox is of particular concern since this normally minor illness may be fatal in immunosuppressed patients. Patients 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. If the patient is a child parents must be given the above advice. 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 should be advised to take particular care to avoid exposure to measles and to seek immediate advice if exposure occurs. Prophylaxis with intramuscular normal immunoglobulin may be needed.

Live vaccines should not be given to individuals with impaired immune responsiveness caused by high doses of corticosteroids. The antibody response to other vaccines may be diminished.

Kaposi's sarcoma has been reported to occur in patients receiving corticosteroid therapy. Discontinuation of corticosteroids may result in clinical remission. .

Because of the possibility of fluid retention, care must be taken when corticosteroids are administered to patients with renal insufficiency or hypertension or congestive heart failure.

Corticosteroids may worsen diabetes mellitus, osteoporosis, hypertension, glaucoma and epilepsy and therefore patients with these conditions or a family history of them should be monitored frequently.

Care is required and frequent patient monitoring necessary where there is a history of severe affective disorders (especially a previous history of steroid psychosis), previous steroid myopathy, peptic ulceration, hypothyroidism, recent myocardial infarction or patients with a history of tuberculosis.

In patients with liver failure, blood levels of corticosteroid may be increased, as with other drugs which are metabolised in the liver. Frequent patient monitoring is therefore necessary.

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/and or carers should be warned that potentially severe psychiatric adverse reactions may occur with systemic steroids (see Section 4.8 Undesirable effects). 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 Interaction with other medicinal products and other forms of interaction), although dose levels do not allow prediction of the onset, type, severity or duration of reactions. Most adverse reactions resolve after either dose reduction or withdrawal of the medicine, 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 tapering/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 a 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.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Rifampicin, rifabutin, carbamazepine, phenobarbitone, phenytoin, primidone, ephedrine and aminoglutethimide enhance the metabolism of corticosteroids and its therapeutic effects may be reduced.

Mifepristone may reduce the effect of corticosteroids for 3-4 days.

Erythromycin and ketoconazole may inhibit the metabolism of some corticosteroids.

Ciclosporin increases plasma concentration of prednisolone. The same effect is possible with ritonavir.

Oestrogens and other oral contraceptives may potentiate the effects of glucocorticoids and dosage adjustments may be required if oral contraceptives are added to or withdrawn from a stable dosage regimen.

The desired effects of hypoglycaemic agents (including insulin), anti-hypertensives and diuretics are antagonised by corticosteroids.

The growth promoting effect of somatotropin may be inhibited by the concomittant use of corticosteroids.

Steroids may reduce the effects of anticholinesterases in myasthenia gravis and cholecystographic x-ray media.

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

Concomitant use of aspirin and Non Steroidal Anti-Inflammatory Drugs (NSAIDs) with corticosteroids increases the risk of gastro-intestinal bleeding and ulceration.

The renal clearance of salicylates is increased by corticosteroids and steroid withdrawal may result in salicylate intoxication.

The hypokalaemic effects of acetazolamide, loop diuretics, thiazide diuretics, and carbenoxolone, are enhanced by corticosteroids. The risk of hypokalaemia is increased with theophylline and amphotericin. Corticosteroids should not be given concomitantly with amphotericin, unless required to control reactions.

The risk of hypokalaemia also increases if high doses of corticosteroids are given with high doses of bambuterol, fenoterol, formoterol, ritodrine, salbutamol, salmeterol and terbutaline. The toxicity of cardiac glycosides is increased if hypokalaemia occurs with corticosteroids.

Concomitant use with methotrexate may increase the risk of haematological toxicity.

High doses of corticosteroids impair the immune response and so live vaccines should be avoided (see also warnings).

4.6 Pregnancy And Lactation

The ability of corticosteroids to cross 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 intrauterine growth retardation.

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 close monitoring.

Depression of hormone levels has been described in pregnancy but the significance of this finding is not clear.

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 taking higher doses than this may have a degree 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 known.

4.8 Undesirable Effects

The incidence of predictable undesirable effects, including hypothalamo-pituitary-adrenal (HPA) suppression, correlates with the relative potency of the drug, dosage, timing of administration and the duration of treatment (see Section 4.4).

The following side effects may be associated with the long-term systemic use of corticosteroids.

Infections and Infestations

Increased susceptibility and severity of infections with suppression of clinical symptoms and signs, opportunistic infections, recurrence of dormant tuberculosis (see section 4.4).

Neoplasms benign, malignant and unspecified (incl cysts and polyps)

Kaposi's sarcoma has been reported to occur in patients receiving corticosteroid therapy. Discontinuation of corticosteroids may result in clinical remission.

Blood and lymphatic system disorders

Leukocytosis.

Immune system disorders

Hypersensitivity including anaphylaxis has been reported.

Endocrine disorders

Suppression of the HPA axis.

Cushingoid.

Impaired carbohydrate intolerance with increased requirement for anti-diabetic therapy, manifestation of latent diabetes mellitus.

Metabolism and nutrition disorders

Sodium and water retention, hypokalaemia, hypokalaemic alkalosis, increased appetite, negative protein and calcium balance.

Psychiatric disorders

Euphoric mood, psychological dependence, depressed mood, insomnia, aggravation of schizophrenia.

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.

Nervous system disorders

Dizziness, headache.

Increased intracranial pressure with papilloedema in children (pseudotumour cerebri) -usually after treatment withdrawal.

Aggravation of epilepsy.

Eye disorders

Glaucoma, papilloedema, posterior subcapsular cataracts, central serous chorioretinopathy, exophthalmos, corneal or scleral thinning, exacerbation of ophthalmic viral or fungal diseases.

Ear and labyrinth disorders

Vertigo

Cardiac disorders

Myocardial rupture following recent myocardial infarction.

Congestive cardiac failure (in susceptible patients).

Vascular disorders

Hypertension, embolism.

Respiratory, thoracic and mediastinal disorders

Hiccups.

Gastrointestinal disorders

Dyspepsia, nausea, vomiting, abdominal distension, abdominal pain, diarrhoea, oesophageal ulceration, candidiasis, pancreatitis acute.

Peptic ulceration with perforation and haemorrhage.

Skin and subcutaneous tissue disorders

Skin Atrophy, skin striae, acne, telangiectasia, hyperhidrosis, rash, pruritus, urticaria, hirsutism.

Musculoskeletal and connective tissue disorders

Myopathy, osteoporosis, vertebral and long bone fractures, avascular osteonecrosis, myalgia.

Growth retardation in infancy, childhood and adolescence.

Reproductive system and breast disorders

Menstruation irregular, amenorrhoea.

General disorders and administration site conditions

Impaired healing, malaise.

Investigations

Weight increased.

Injury, poisoning and procedural complications

Tendon rupture, contusion (bruising).

Withdrawal Symptoms

Too rapid a reduction of corticosteroid dosage following prolonged treatment can lead to acute adrenal insufficiency, hypotension and death (See Section 4.4)

A 'withdrawal syndrome' may also occur including fever, myalgia, arthralgia, rhinitis, conjunctivitis, painful itchy skin nodules and loss of weight.

In some instances, withdrawal symptoms may involve or resemble a clinical relapse of the disease for which the patient has been undergoing treatment.

Other effects that may occur during withdrawal or change of corticosteroid therapy include benign intracranial hypertension with headache and vomiting and papilloedema caused by cerebral oedema.

Latent rhinitis or eczema may be unmasked.

4.9 Overdose

Treatment is unlikely to be needed in cases of acute overdosage.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Prednesol / Soluble Prednisolone tablets contain the equivalent of 5mg of prednisolone in the form of the 21-disodium phosphate ester. Prednisolone sodium phosphate is a synthetic glucocorticoid with the same general properties as prednisolone itself and other compounds classified as corticosteroids. Prednisolone is four times as active as hydrocortisone on a weight for weight basis.

Prednisolone sodium phosphate is very soluble in water, and is therefore less likely to cause local gastric irritation than prednisolone alcohol, which is only slightly soluble. This is important when high dosages are required, as in immunosuppressive therapy.

5.2 Pharmacokinetic Properties

Absorption

Prednisolone is readily absorbed from the gastrointestinal tract with peak plasma concentrations achieved by 1-2 hours after an oral dose. Plasma prednisolone is mainly protein bound (70-90%), with binding to albumin and corticosteroid-binding globulin. The plasma half-life of prednisolone, after a single dose, is between 2.5-3.5 hours.

Distribution

The volume of distribution and clearance of total and unbound prednisolone are concentration dependent, and this has been attributed to saturable protein binding over the therapeutic plasma concentration range.

Metabolism

Prednisolone is extensively metabolised, mainly in the liver, but the metabolic pathways are not clearly defined.

Excretion

Over 90% of the prednisolone dose is excreted in the urine, with 7-30% as free prednisolone, and the remainder being recovered as a variety of metabolites.

5.3 Preclinical Safety Data

No additional data of relevance.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Sodium Acid Citrate	BP
Sodium Bicarbonate	Ph.Eur
Saccharin Sodium	BP
Povidone	BP
Erythrosine El27	HSE
Sodium Benzoate	Ph.Eur

6.2 Incompatibilities

None known.

6.3 Shelf Life

2 years.

6.4 Special Precautions For Storage

Store below 25°C.

Protect from light.

6.5 Nature And Contents Of Container

The tablets are foil strip packed and supplied in cartons of 30 or 100 tablets.

6.6 Special Precautions For Disposal And Other Handling

For detailed instructions for use refer to the Patient Information Leaflet in every pack.

ADMINISTRATIVE DATA

7. Marketing Authorisation Holder

Waymade PLC trading as Sovereign Medical

Sovereign House

Miles Gray Road

Basildon

Essex

SS14 3FR

8. Marketing Authorisation Number(S)

PL 06464/0914

9. Date Of First Authorisation/Renewal Of The Authorisation

16 December 1999

10. Date Of Revision Of The Text

March 2010

Jacutin Pedicul Fluid

Jacutin Pedicul Fluid may be available in the countries listed below.

Ingredient matches for Jacutin Pedicul Fluid

Dimeticone

Dimeticone is reported as an ingredient of Jacutin Pedicul Fluid in the following countries:

• Germany

International Drug Name Search