Beechams All-In-One Tablets

1. Name Of The Medicinal Product

Beechams All-In-One Tablets

2. Qualitative And Quantitative Composition

Each tablet contains paracetamol 250 mg, guaifenesin 100 mg and phenylephrine hydrochloride 5 mg

Contains lactose

For full list of excipients, see section 6.1

3. Pharmaceutical Form

Tablets.

White, film-coated tablets embossed with a 'B' on one side.

4. Clinical Particulars

4.1 Therapeutic Indications

Short term symptomatic relief of colds, chills and influenza including chesty coughs.

4.2 Posology And Method Of Administration

Adults and children 12 years and over

Two tablets. Repeat every four hours as necessary.

Do not take more than 8 tablets in 24 hours.

Not to be given to children under 12 years except on medical advice.

Elderly

The normal adult dose may be taken.

Do not take continuously for more than 5 days without medical advice.

4.3 Contraindications

Known hypersensitivity to any of the ingredients.

Concomitant use of other sympathomimetic decongestants.

Phaeochromocytoma.

Closed angle glaucoma.

Hepatic or severe renal impairment, hypertension, hyperthyroidism, diabetes, heart disease or those taking tricyclic antidepressants or beta-blocking drugs and those patients who are taking or have taken, within the last two weeks, monoamine oxidase inhibitors (see section 4.5).

4.4 Special Warnings And Precautions For Use

Patients suffering from chronic cough or asthma should consult a physician before taking this product.

Patients should stop using the product and consult a health care professional if cough lasts for more than 5 days or comes back, or is accompanied by a fever, rash or persistent headache.

Do not take with a cough suppressant.

Medical advice should be sought before taking this product in patients with these conditions:

An enlargement of the prostate gland

Occlusive vascular disease (e.g. Raynaud's Phenomenon)

Cardiovascular disease

This product should not be used by patients taking other sympathomimetics (such as decongestants, appetite suppressants and amphetamine-like psychostimulants)

Concomitant use of other paracetamol-containing products should be avoided. If symptoms persist consult your doctor.

Keep out of the reach and sight of children.

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

Special label warnings

Do not take with any other paracetamol-containing products. Do not take with other flu, cold or decongestant products.

Immediate medical advice should be sought in the event of an overdose, even if you feel well.

Special leaflet warnings

Immediate medical advice should be sought in the event of an overdose, even if you feel well, because of the risk of delayed, serious liver damage.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

The anticoagulant effect of warfarin and other coumarins may be enhanced by prolonged regular use of paracetamol with increased risk of bleeding. The hepato-toxicity of paracetamol may be potentiated by excessive intake of alcohol. The speed of absorption of paracetamol may be increased by metoclopramide or domperidone and absorption reduced by colestyramine. Pharmacological interactions involving paracetamol with a number of other drugs have been reported. These are considered to be of unlikely clinical significance in acute use at the dosage regimen proposed.

Phenylephrine should be used with caution in combination with the following drugs as interactions have been reported:

Monoamine oxidase inhibitors (including moclobemide)	Hypertensive interactions occur between sympathomimetic amines such as phenylephrine and monoamine oxidase inhibitors (see contraindications)..
Sympathomimetic amines	Concomitant use of phenylephrine with other sympathomimetic amines can increase the risk of cardiovascular side effects.
Beta-blockers and other antihypertensives (including debrisoquine, guanethidine, reserpine, methyldopa)	Phenylephrine may reduce the efficacy of beta-blocking drugs and antihypertensive drugs. The risk of hypertension and other cardiovascular side effects may be increased.
Tricyclic antidepressants (e.g. amitriptyline)	May increase the risk of cardiovascular side effects with phenylephrine.
Ergot alkaloids (ergotamine and methylsergide)	Increased risk of ergotism
Digoxin and cardiac glycosides	Increase the risk of irregular heartbeat or heart attack

If urine is collected within 24 hours of a dose of this product, a metabolite may cause a colour interference with laboratory determinations of 5 hydroxyindoleacetic acid (5-HIAA) and vanillymandelic acid (VMA).

4.6 Pregnancy And Lactation

This product should not be used during pregnancy without medical advice.

Epidemiological studies in human pregnancy have shown no ill effects due to paracetamol used in the recommended dosage, but patients should follow the advice of their doctor regarding its use. The safety of guaiphenesin and phenylephrine during pregnancy has not been established.

Paracetamol and phenylephrine are excreted in breast milk but not in a clinically significant amount. This product should not be used in breast feedingwithout medical advice.

4.7 Effects On Ability To Drive And Use Machines

Patients should be advised not to drive or operate machinery if affected by dizziness.

4.8 Undesirable Effects

Adverse events from historical clinical trial data are both infrequent and from small patient exposure. Events reported from extensive post-marketing experience at therapeutic/labelled dose and considered attributable are tabulated below by MedDRA System Organ Class. Due to limited clinical trial data, the frequency of these adverse events is not known (cannot be estimated from available data), but post-marketing experience indicates that adverse reactions to paracetamol are rare and serious reactions are very rare.

Body System	Undesirable effect
Blood and lymphatic system disorders	Thrombocytopenia Agranulocytosis These are not necessarily causally related to paracetamol
Immune system disorders	Anaphylaxis Cutaneous hypersensitivity reactions including skin rashes, angiodema and Stevens Johnson syndrome
Respiratory, thoracic and mediastinal disorders	Bronchospasm in patients sensitive to aspirin and other NSAIDs
Hepatobiliary disorders	Hepatic dysfunction
Gastrointestinal disorders	Acute pancreatitis

The following adverse events have been observed in clinical trials with phenylephrine and may therefore represent the most commonly occurring adverse events.

Body System	Undesirable effect
Psychiatric disorders	Nervousness, irritability, restlessness, and excitability
Nervous system disorders	Headache, dizziness, insomnia
Cardiac disorders	Increased blood pressure
Gastrointestinal disorders	Nausea, Vomiting, diarrhoea

Adverse reactions identified during post-marketing use are listed below. The frequency of these reactions is unknown but likely to be rare.

Eye disorders	Mydriasis, acute angle closure glaucoma, most likely to occur in those with closed angle glaucoma
Cardiac disorders	Tachycardia, palpitations
Skin and subcutaneous disorders	Allergic reactions (e.g. rash, urticaria, allergic dermatitis). Hypersensitivity reactions – including that cross-sensitivity may occur with other sympathomimetics.
Renal and urinary disorders	Dysuria, urinary retention. This is most likely to occur in those with bladder outlet obstruction, such as prostatic hypertrophy.

Guaifenesin

The frequency of these events is unknown but considered likely to be rare .

Body system	Undesirable effect
Immune system disorders	Allergic reactions, angioedema, anaphylactic reactions
Respiratory, thoracic and mediastinal disorders	Dyspnoea*
Gastrointestinal disorders	Nausea, vomiting, abdominal discomfort,
Skin and subcutaneous disorders	Rash, urticaria

4.9 Overdose

Paracetamol

Liver damage is possible in adults who have taken 10g or more of paracetamol. Ingestion of 5g or more of paracetamol may lead to liver damage if the patient has risk factors (see below).

Risk factors:

If the patient

a, Is on long term treatment with carbamazepine, phenobarbitone, phenytoin, primidone, rifampicin, St John's Wort or other drugs that induce liver enzymes.

Or

b, Regularly consumes ethanol in excess of recommended amounts.

Or

c, Is likely to be glutathione deplete e.g. eating disorders, cystic fibrosis, HIV infection, starvation, cachexia.

Symptoms:

Symptoms of paracetamol overdosage in the first 24 hours are pallor, nausea, vomiting, anorexia and abdominal pain. Liver damage may become apparent 12 to 48 hours after ingestion. Abnormalities of glucose metabolism and metabolic acidosis may occur. In severe poisoning, hepatic failure may progress to encephalopathy, haemorrhage, hypoglycaemia, cerebral oedema, and death. Acute renal failure with acute tubular necrosis, strongly suggested by loin pain, haematuria and proteinuria, may develop even in the absence of severe liver damage. Cardiac arrhythmias and pancreatitis have been reported.

Management:

Immediate treatment is essential in the management of paracetamol overdose. Despite a lack of significant early symptoms, patients should be referred to hospital urgently for immediate medical attention. Symptoms may be limited to nausea or vomiting and may not reflect the severity of overdose or the risk of organ damage. Management should be in accordance with established treatment guidelines, see BNF overdose section.

Treatment with activated charcoal should be considered if the overdose has been taken within 1 hour. Plasma paracetamol concentration should be measured at 4 hours or later after ingestion (earlier concentrations are unreliable). Treatment with N-acetylcysteine may be used up to 24 hours after ingestion of paracetamol, however, the maximum protective effect is obtained up to 8 hours post-ingestion. The effectiveness of the antidote declines sharply after this time. If required the patient should be given intravenous N-acetylcysteine, in line with the established dosage schedule. If vomiting is not a problem, oral methionine may be a suitable alternative for remote areas, outside hospital. Management of patients who present with serious hepatic dysfunction beyond 24h from ingestion should be discussed with the NPIS or a liver unit.

Phenylephrine

Symptoms and signs

Phenylephrine overdosage is likely to result in effects similar to those listed under advserse reactions. Additional symptoms may include hypertension and possibly reflux bradycardia. In severe cases confusion, hallucinations, seizures and arrythmias may occir. However the amount required to produce serious phenylephrine toxicity would be greater than required to cause paracetamol-related toxicity.

Treatment

Treatment should be as clinically appropriate. Severe hypertension may need to be treated with an alpha blocking drug such as phentolamine.

Guaifenesin

Symptoms and signs

Very large doses of guaifenesin cause nausea and vomiting.

Treatment

Vomiting would be treated by fluid replacement and monitoring of electrolytes if indicated.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

ATC Code: N02BE 51 Paracetamol combinations excluding psycholeptics.

Paracetamol is an analgesic and antipyretic.

Guaifenesin is an expectorant.

Phenylephrine Hydrochloride is a sympathomimetic decongestant.

The active ingredients are not known to cause sedation.

5.2 Pharmacokinetic Properties

Paracetamol is readily absorbed from the gastrointestinal tract. It is metabolised in the liver and excreted in the urine, mainly as glucuronide and sulphate conjugates.

Guaifenesin is rapidly absorbed after oral administration. It is rapidly metabolised by oxidation to ß-(2 methoxy-phenoxy) lactic acid, which is excreted in the urine.

Phenylephrine hydrochloride is irregularly absorbed from the gastrointestinal tract and undergoes first-pass metabolism by monoamine oxidase in the gut and liver; orally administered phenylephrine has reduced bioavailability. It is excreted in the urine almost entirely as the sulphate conjugate.

5.3 Preclinical Safety Data

Preclinical safety data on these active ingredients in the literature have not revealed any pertinent and conclusive findings which are of relevance to the recommended dosage and use of the product and which have not already been mentioned elsewhere in this SPC.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Tablets

Lactose

Microcrystalline cellulose

Maize starch

Stearic acid

Colloidal anhydrous silica

Purified talc

Povidone

Potassium sorbate

Pregelatinised starch

Film coating

Hypromellose E464

Titanium dioxide E171

Polyethylene glycol 4000

Lactose monohydrate

6.2 Incompatibilities

None known.

6.3 Shelf Life

Three years.

6.4 Special Precautions For Storage

Do not store above 25°C

6.5 Nature And Contents Of Container

Blister of 250µm PVC/ 25µm LDPE/ 90gsm PVdC/ 30µm Aluminium foil containing 8, 12 or 16 tablets

6.6 Special Precautions For Disposal And Other Handling

Not applicable.

7. Marketing Authorisation Holder

Beecham Group plc

980 Great West Road

Brentford

Middlesex

TW8 9GS

United Kingdom

Trading as: GlaxoSmithKline Consumer Healthcare, Brentford, TW8 9GS

8. Marketing Authorisation Number(S)

PL 00079/0630

9. Date Of First Authorisation/Renewal Of The Authorisation

3^rd July 2008

10. Date Of Revision Of The Text

14/10/2011

Aciclovir Cream 5% w / w (Pharmacia Limited)

1. Name Of The Medicinal Product

Aciclovir Cream 5% w/w

2. Qualitative And Quantitative Composition

5% w/w (50mg per g) Aciclovir Ph Eur.

3. Pharmaceutical Form

Cream

4. Clinical Particulars

4.1 Therapeutic Indications

Aciclovir Cream 5% w/w is indicated for the treatment of recurrent herpes labialis and herpes genitalis.

4.2 Posology And Method Of Administration

Dose:

Unless otherwise instructed, apply a thin layer of cream over the site of infection every four hours, five times a day.

Length of treatment:

The cream should be applied to the lesion or developing lesion as soon as possible after the start of the infection. Treatment with Aciclovir Cream 5% w/w is normally continued for five days. If the situation deteriorates or, if after ten days there is no clinical benefit (crusted vesicles, healing of lesions), treatment should be discontinued and patients should consult their physician.

Method of administration:

A cotton bud should be used to apply a sufficient quantity of Aciclovir Cream 5% w/w to cover all lesions. The cream should be applied to visibly infected sites (vesicles, swelling, erythema) and the adjoining areas. If hands are used to apply the cream, they should be thoroughly washed before and after application to prevent further infection of the lesions by bacteria and to prevent autoinoculation of the virus to other mucous membrane and cutaneous sites not yet infected.

4.3 Contraindications

Hypersensitivity to aciclovir, polyoxyethylene fatty acid esters, cetyl alcohol, dimethicone or propylene glycol.

4.4 Special Warnings And Precautions For Use

Aciclovir Cream 5% w/w should not be used on mucous membranes (e.g. oral cavity, eyes, vagina) since local reactions may occur.

Severely immunocompromised patients should consult their physician before starting treatment with Aciclovir Cream 5% w/w. For these patients, oral administration should be considered.

Because of possible infections of partners, patients with herpes genitalis should be advised to abstain from sexual contact if any lesions are visible.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

No interactions known.

4.6 Pregnancy And Lactation

Pregnancy:

Systemic administration of aciclovir in internationally accepted studies did not produce teratogenic effects in mice, rats or rabbits.

In one other study a teratogenic effect was seen, but only at high doses and the clinical relevance of these findings is uncertain.

No evidence of malformations was observed in a group of several hundred patients exposed to aciclovir during the first trimester of pregnancy.

No foetotoxic effect was observed after aciclovir administration during the second and third trimesters of pregnancy.

Only about 0.1% of the aciclovir applied to the skin is detectable in the plasma. Concentrations are minimal so that no systemic effect should occur.

Consequently, topical administration of aciclovir for the specified indications is acceptable.

Lactation:

As there is only minimal systemic absorption of aciclovir, adverse effects on the infant during lactation are unlikely.

4.7 Effects On Ability To Drive And Use Machines

Aciclovir Cream 5% w/w is unlikely to impair a patient´s ability to drive or to use machines.

4.8 Undesirable Effects

Transient burning and itching may occur after application of Aciclovir Cream 5% w/w.

Occasionally erythema, dryness, pruritus and desquamation of cutaneous sites have been observed.

Rarely, contact dermatitis has been reported after administration of Aciclovir Cream 5% w/w. Examination showed that in most cases the contact dermatitis was caused by one of the excipients rather than by the active ingredient aciclovir. The contact dermatitis is characterized by the occurrence of the cutaneous reactions as described above, with a widespread distribution.

4.9 Overdose

As only 0.1% of the aciclovir applied to the skin is detectable in the plasma, overdose is unlikely.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

After penetrating into a cell infected by herpes simplex virus, aciclovir converts to aciclovir triphosphate. Viral replication is selectively inhibited by viral DNA polymerase.

Aciclovir does not eradicate latent virus.

5.2 Pharmacokinetic Properties

Concentrations in the plasma are minimal so that there should be no systemic effect.

5.3 Preclinical Safety Data

Local effects:

Aciclovir cream was applied to guinea pig and rabbit skin (damaged and normal) once a day for 21 days. A mild irritation occurred after repeated application.

Since the amount of active ingredient absorbed from the cream does not lead to significant plasma levels (see paragraph 5.2 on pharmacokinetics) there were no further studies on this form of administration.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Glycerin monostearate/polyoxyethylen-30-stearate (Arlatone 983S), Dimeticone Ph Eur, Cetyl Alcohol Ph Eur, Liquid Paraffin Ph Eur, White Soft Paraffin USP/DAB10, Propylene Glycol Ph Eur, Purified Water Ph Eur.

6.2 Incompatibilities

None.

6.3 Shelf Life

The proposed shelf life is thirty six months.

6.4 Special Precautions For Storage

Store below 25°C. Do not refrigerate.

6.5 Nature And Contents Of Container

Aluminium tube containing 2*, 5, 10* or 15g of Aciclovir Cream 5% w/w.

One tube is packed in a carton together with a patient information leaflet.

*These tubes only are available in the UK.

6.6 Special Precautions For Disposal And Other Handling

None.

7. Marketing Authorisation Holder

TAD Pharma GmbH

Heinz-Lohmann-Strasse 5

27472 Cuxhaven

Germany

Tel: +49 (0)4721/606-0

Fax: +49 (0)4721/606-333

8. Marketing Authorisation Number(S)

United Kingdom: PL 04986/0008

9. Date Of First Authorisation/Renewal Of The Authorisation

21 November 1996

10. Date Of Revision Of The Text

November 1999

LEGAL CATEGORY

POM.

Adalat retard 10 mg modified-release tablets

1. Name Of The Medicinal Product

Adalat retard 10 mg modified-release tablets

2. Qualitative And Quantitative Composition

Each modified-release tablet contains 10 mg nifedipine.

For excipients see Section 6.1.

3. Pharmaceutical Form

Modified-release tablets.

Grey-pink, round, modified-release tablets marked with A10 on one side and a Bayer cross on the reverse.

4. Clinical Particulars

4.1 Therapeutic Indications

For the prophylaxis of chronic stable angina pectoris and the treatment of hypertension.

4.2 Posology And Method Of Administration

Method of administration

Oral use.

As a rule, tablets are swallowed whole with a little liquid, either with or without food.

Adalat retard should not be taken with grapefruit juice (see Section 4.5).

Dosage regimen

The recommended starting dose of Adalat retard is 10 mg every 12 hours swallowed with water with subsequent titration of dosage according to response. Adalat retard tablets permit titration of the initial dosage, which may be adjusted to 40 mg every 12 hours, to a maximum daily dose of 80 mg.

Co-administration with CYP 3A4 inhibitors or CYP 3A4 inducers may result in the recommendation to adapt the nifedipine dose or not to use nifedipine at all (see Section 4.5).

Duration of treatment

Treatment may be continued indefinitely.

Additional information on special populations

Children and adolescents

The safety and efficacy of Adalat retard in children below 18 years of age has not been established. Currently available data for the use of nifedipine in hypertension are described in section 5.1

Geriatric patients

The pharmacokinetics of Adalat retard are altered in the elderly so that lower maintenance doses of nifedipine may be required compared to younger patients.

Patients with hepatic impairment

Nifedipine is metabolised primarily by the liver and therefore patients with liver dysfunction should be carefully monitored and in severe cases, a dose reduction may be necessary.

Patients with renal impairment

Based on pharmacokinetic data, no dosage adjustment is required in patients with renal impairment (see Section 5.2).

4.3 Contraindications

Adalat retard must not be administered to patients with known hypersensitivity to nifedipine, or to other dihydropyridines because of the theoretical risk of cross-reactivity, or to any of the excipients.

Adalat retard is contraindicated in pregnancy before week 20 and during breastfeeding (see Sections 4.4, 4.6 and 5.3).

Adalat retard must not be used in cases of cardiogenic shock, clinically significant aortic stenosis, unstable angina, or during or within 4 weeks of a myocardial infarction.

Adalat retard should not be used for the treatment of acute attacks of angina.

The safety of Adalat retard in malignant hypertension has not been established.

Adalat retard should not be used for secondary prevention of myocardial infarction.

Adalat retard should not be administered concomitantly with rifampicin since effective plasma levels of nifedipine may not be achieved owing to enzyme induction (see section 4.5).

4.4 Special Warnings And Precautions For Use

Adalat retard is not a beta-blocker and therefore gives no protection against the dangers of abrupt beta-blocker withdrawal; any such withdrawal should be a gradual reduction of the dose of beta-blocker preferably over 8 - 10 days.

Adalat retard may be used in combination with beta-blocking drugs and other antihypertensive agents but the possibility of an additive effect resulting in postural hypotension should be borne in mind. Adalat retard will not prevent possible rebound effects after cessation of other antihypertensive therapy.

Care must be exercised in patients with very low blood pressure (severe hypotension with systolic pressure less than 90 mm Hg).

Careful monitoring of blood pressure must be exercised when administering nifedipine with I.V. magnesium sulphate, owing to the possibility of an excessive fall in blood pressure, which could harm both mother and foetus. For further information regarding use in pregnancy, refer to section 4.6.

In patients with impaired liver function, careful monitoring, and in severe cases, a dose reduction may be necessary.

Adalat retard should be used with caution in patients whose cardiac reserve is poor. Deterioration of heart failure has occasionally been observed with nifedipine.

The use of Adalat retard in diabetic patients may require adjustment of their control.

In dialysis patients with malignant hypertension and hypovolaemia, a marked decrease in blood pressure can occur.

Nifedipine is metabolised via the cytochrome P450 3A4 system. Drugs that are known to either inhibit or to induce this enzyme system may therefore alter the first pass or the clearance of nifedipine (see Section 4.5).

Drugs that are known inhibitors of the cytochrome P450 3A4 system, and which may therefore lead to increased plasma concentrations of nifedipine include, for example:

- macrolide antibiotics (e.g., erythromycin)

- anti-HIV protease inhibitors (e.g., ritonavir)

- azole antimycotics (e.g., ketoconazole)

- the antidepressants, nefazodone and fluoxetine

- quinupristin/dalfopristin

- valproic acid

- cimetidine

Upon co-administration with these drugs, the blood pressure should be monitored and, if necessary, a reduction of the nifedipine dose should be considered (see Section 4.5).

Since this medicinal product contains lactose, patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

For use in special populations see Section 4.2.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Drugs that affect nifedipine

Nifedipine is metabolised via the cytochrome P450 3A4 system, located both in the intestinal mucosa and in the liver. Drugs that are known to either inhibit or to induce this enzyme system may therefore alter the first pass (after oral administration) or the clearance of nifedipine (see Section 4.4).

The extent as well as the duration of interactions should be taken into account when administering nifedipine together with the following drugs:

Rifampicin: Rifampicin strongly induces the cytochrome P450 3A4 system. Upon co-administration with rifampicin, the bioavailability of nifedipine is distinctly reduced and thus its efficacy weakened. The use of nifedipine in combination with rifampicin is therefore contraindicated (see Section 4.3).

Upon co-administration of known inhibitors of the cytochrome P450 3A4 system, the blood pressure should be monitored and, if necessary, a reduction in the nifedipine dose considered (see Sections 4.2 and 4.4). In the majority of these cases, no formal studies to assess the potential for a drug interaction between nifedipine and the drug(s) listed have been undertaken, thus far.

Drugs increasing nifedipine exposure:

• macrolide antibiotics (e.g., erythromycin)

• anti-HIV protease inhibitors (e.g., ritonavir)

• azole anti-mycotics (e.g., ketoconazole)

• fluoxetine

• nefazodone

• quinupristin/dalfopristin

• cisapride

• valproic acid

• cimetidine

• diltiazem

Upon co-administration of inducers of the cytochrome P450 3A4 system, the clinical response to nifedipine should be monitored and, if necessary, an increase in the nifedipine dose considered. If the dose of nifedipine is increased during co-administration of both drugs, a reduction of the nifedipine dose should be considered when the treatment is discontinued.

Drugs decreasing nifedipine exposure:

• rifampicin (see above)

• phenytoin

• carbamazepine

• phenobarbital

Effects of nifedipine on other drugs

Nifedipine may increase the blood pressure lowering effect of concomitant applied antihypertensives.

When nifedipine is administered simultaneously with beta-receptor blockers the patient should be carefully monitored, since deterioration of heart failure is also known to develop in isolated cases.

Digoxin: The simultaneous administration of nifedipine and digoxin may lead to reduced digoxin clearance and, hence, an increase in the plasma digoxin level. The patient should therefore be subjected to precautionary checks for symptoms of digoxin overdosage and, if necessary, the glycoside dose should be reduced.

Quinidine: Co-administration of nifedipine with quinidine may lower plasma quinidine levels, and after discontinuation of nifedipine, a distinct increase in plasma quinidine levels may be observed in individual cases. Consequently, when nifedipine is either additionally administered or discontinued, monitoring of the quinidine plasma concentration, and if necessary, adjustment of the quinidine dose are recommended. Blood pressure should be carefully monitored and, if necessary, the dose of nifedipine should be decreased.

Tacrolimus: Tacrolimus is metabolised via the cytochrome P450 3A4 system. Published data indicate that the dose of tacrolimus administered simultaneously with nifedipine may be reduced in individual cases. Upon co-administration of both drugs, the tacrolimus plasma concentrations should be monitored and, if necessary, a reduction in the tacrolimus dose considered.

Drug food interactions

Grapefruit juice inhibits the cytochrome P450 3A4 system. Administration of nifedipine together with grapefruit juice thus results in elevated plasma concentrations and prolonged action of nifedipine due to a decreased first pass metabolism or reduced clearance. As a consequence, the blood pressure lowering effect of nifedipine may be increased. After regular intake of grapefruit juice, this effect may last for at least three days after the last ingestion of grapefruit juice. Ingestion of grapefruit/grapefruit juice is therefore to be avoided while taking nifedipine (see Section 4.2).

Other forms of interaction

Nifedipine may increase the spectrophotometric values of urinary vanillylmandelic acid falsely. However, HPLC measurements are unaffected.

4.6 Pregnancy And Lactation

Adalat retard is contra-indicated in pregnancy before week 20 (see Section 4.3).

In animal studies, nifedipine has been shown to produce embryotoxicity, foetotoxicity and teratogenicity (see Section 5.3 Preclinical safety data).

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

From the clinical evidence available a specific prenatal risk has not been identified, although an increase in perinatal asphyxia, caesarean delivery, as well as prematurity and intrauterine growth retardation have been reported. It is unclear whether these reports are due to the underlying hypertension, its treatment, or to a specific drug effect.

The available information is inadequate to rule out adverse drug effects on the unborn and newborn child. Therefore any use in pregnancy after week 20 requires a very careful individual risk benefit assessment and should only be considered if all other treatment options are either not indicated or have failed to be efficacious.

In single cases of in vitro fertilisation calcium antagonists like nifedipine have been associated with reversible biochemical changes in the spermatozoa's head section that may result in impaired sperm function. In those men who are repeatedly unsuccessful in fathering a child by in vitro fertilisation, and where no other explanation can be found, calcium antagonists like nifedipine should be considered as possible causes.

Nifedipine passes into the breast milk. As there is no experience of possible effects on infants, breastfeeding should first be stopped if nifedipine treatment becomes necessary during the breastfeeding period.

4.7 Effects On Ability To Drive And Use Machines

Reactions to the drug, which vary in intensity from individual to individual, may impair the ability to drive or to operate machinery. This applies particularly at the start of treatment, on changing the medication and in combination with alcohol.

4.8 Undesirable Effects

Adverse drug reactions (ADRs) based on placebo-controlled studies with nifedipine sorted by CIOMS III categories of frequency (clinical trial data base: nifedipine n = 2,661; placebo n = 1,486; status: 22 Feb 2006 and the ACTION study: nifedipine n = 3,825; placebo n = 3,840) are listed below: ADRs listed under "common" were observed with a frequency below 3% with the exception of oedema (9.9%) and headache (3.9%). ADRs derived from post marketing reports (status: 31 Mar 2006) are printed in bold italic.

Common >1% to <10%	Uncommon >0.1% to <1%	Rare >0.01% to <0.1%	Frequency Not Known
Immune System Disorders
	Allergic reaction Allergic oedema / angioedema (incl. larynx oedema*)	Pruritus Urticaria Rash	Anaphylactic/ anaphylactoid reaction
Psychiatric Disorders
	Anxiety reactions Sleep disorders
Nervous System Disorders
Headache	Vertigo Migraine
	Dizziness Tremor
		Par-/Dysaesthesia
Eye Disorders
	Visual disturbances
Cardiac Disorders
	Tachycardia Palpitations
Vascular Disorders
Oedema Vasodilatation	Hypotension Syncope
Respiratory, Thoracic and Mediastinal Disorders
	Nasal congestion Nosebleed		Dyspnoea
Gastrointestinal Disorders
Constipation	Gastrointestinal and abdominal pain Nausea Dyspepsia Flatulence Dry mouth	Gingival hyperplasia	Vomiting
Hepatobiliary Disorders
	Transient increase in liver enzymes
Skin and Subcutaneous Tissue Disorders
	Erythema
Musculoskeletal, Connective Tissue and Bone Disorders
	Muscle cramps Joint swelling
Renal and Urinary Disorders
	Polyuria Dysuria
Reproductive System and Breast Disorders
	Erectile dysfunction
General Disorders and Administration Site Conditions
Feeling unwell	Unspecific pain Chills

* = may result in life-threatening outcome

In dialysis patients with malignant hypertension and hypovolaemia a distinct fall in blood pressure can occur as a result of vasodilation.

4.9 Overdose

Symptoms

The following symptoms are observed in cases of severe nifedipine intoxication:

Disturbances of consciousness to the point of coma, a drop in blood pressure, tachycardia, bradycardia, hyperglycaemia, metabolic acidosis, hypoxia, cardiogenic shock with pulmonary oedema.

Treatment

As far as treatment is concerned, elimination of nifedipine and the restoration of stable cardiovascular conditions have priority. Elimination must be as complete as possible, including the small intestine, to prevent the otherwise inevitable subsequent absorption of the active substance.

The benefit of gastric decontamination is uncertain.

1. Consider activated charcoal (50 g for adults, 1 g/kg for children) if the patient presents within 1 hour of ingestion of a potentially toxic amount.

Although it may seem reasonable to assume that late administration of activated charcoal may be beneficial for sustained release (SR, MR) preparations there is no evidence to support this.

2. Alternatively consider gastric lavage in adults within 1 hour of a potentially life-threatening overdose.

3. Consider further doses of activated charcoal every 4 hours if a clinically significant amount of a sustained release preparation has been ingested with a single dose of an osmotic laxative (e.g. sorbitol, lactulose or magnesium sulphate).

4. Asymptomatic patients should be observed for at least 4 hours after ingestion and for 12 hours if a sustained release preparation has been taken.

Haemodialysis serves no purpose as nifedipine is not dialysable.

Hypotension as a result of cardiogenic shock and arterial vasodilatation can be treated with calcium (10-20 ml of a 10 % calcium gluconate solution administered intravenously over 5-10 minutes). If the effects are inadequate, the treatment can be continued, with ECG monitoring. If an insufficient increase in blood pressure is achieved with calcium, vasoconstricting sympathomimetics such as dopamine or noradrenaline should be administered. The dosage of these drugs should be determined by the patient's response.

Symptomatic bradycardia may be treated with atropine, beta-sympathomimetics or a temporary cardiac pacemaker, as required.

Additional fluids should be administered with caution to avoid cardiac overload.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

ATC code: C08CA05

Nifedipine is a specific and potent calcium antagonist of the 1, 4-dihydropyridine type. Calcium antagonists reduce the transmembranal influx of calcium ions through the slow calcium channel into the cell. Nifedipine acts particularly on the cells of the myocardium and the smooth muscle cells of the coronary arteries and the peripheral resistance vessels.

In hypertension, the main action of Adalat retard is to cause peripheral vasodilatation and thus reduce peripheral resistance.

In angina, Adalat retard reduces peripheral and coronary vascular resistance, leading to an increase in coronary blood flow, cardiac output and stroke volume, whilst decreasing after-load.

Additionally, nifedipine dilates submaximally both clear and atherosclerotic coronary arteries, thus protecting the heart against coronary artery spasm and improving perfusion to the ischaemic myocardium.

Nifedipine reduces the frequency of painful attacks and the ischaemic ECG changes irrespective of the relative contribution from coronary artery spasm or atherosclerosis.

Adalat retard administered twice-daily provides 24-hour control of raised blood pressure. Adalat retard causes reduction in blood pressure such that the percentage lowering is directly related to its initial level. In normotensive individuals, Adalat retard has little or no effect on blood pressure.

Paediatric population:

Limited information on comparison of nifedipine with other antihypertensives is available for both acute hypertension and long-term hypertension with different formulations in different dosages. Antihypertensive effects of nifedipine have been demonstrated but dose recommendations, long term safety and effect on cardiovascular outcome remain unestablished. Pediatric dosing forms are lacking.

5.2 Pharmacokinetic Properties

Absorption

After oral administration nifedipine is rapidly and almost completely absorbed. The systemic availability of orally administered nifedipine is 45 – 56 % owing to a first pass effect. Maximum plasma and serum concentrations are reached at 1.5 to 4.2 hours with Adalat retard (20 mg tablets). Simultaneous food intake leads to delayed, but not reduced absorption.

Distribution

Nifedipine is about 95 % bound to plasma protein (albumin). The distribution half-life after intravenous administration was determined to be 5 to 6 minutes.

Biotransformation

After oral administration nifedipine is metabolized in the gut wall and in the liver, primarily by oxidative processes. These metabolites show no pharmacodynamic activity. Nifedipine is excreted in the form of its metabolites predominantly via the kidneys and about 5 – 15 % via the bile in the faeces. The unchanged substance is recovered only in traces (below 0.1 %) in the urine.

Elimination

The terminal elimination half-life is 6 - 11 hours (Adalat retard), because of delayed absorption. No accumulation of the substance after the usual dose was reported during long-term treatment. In cases of impaired kidney function no substantial changes have been detected in comparison with healthy volunteers. In cases of impaired liver function the elimination half-life is distinctly prolonged and the total clearance is reduced. A dose reduction may be necessary in severe cases.

5.3 Preclinical Safety Data

Preclinical data reveal no special hazard for humans based on conventional studies of single and repeated dose toxicity, genotoxicity and carcinogenic potential.

Reproduction toxicology

Nifedipine has been shown to produce teratogenic findings in rats, mice and rabbits, including digital anomalies, malformation of the extremities, cleft palates, cleft sternum, and malformation of the ribs. Digital anomalies and malformation of the extremities are possibly a result of compromised uterine blood flow, but have also been observed in animals treated with nifedipine solely after the end of the organogenesis period.

Nifedipine administration was associated with a variety of embryotoxic, placentotoxic and foetotoxic effects, including stunted foetuses (rats, mice, rabbits), small placentas and underdeveloped chorionic villi (monkeys), embryonic and foetal deaths (rats, mice, rabbits) and prolonged pregnancy/decreased neonatal survival (rats; not evaluated in other species). The risk to humans cannot be ruled out if a sufficiently high systemic exposure is achieved, however, all of the doses associated with the teratogenic, embryotoxic or foetotoxic effects in animals were maternally toxic and were several times the recommended maximum dose for humans (see Section 4.6).

6. Pharmaceutical Particulars

6.1 List Of Excipients

Cellulose microcrystalline

Maize starch

Lactose monohydrate

Polysorbate 80

Magnesium stearate

Hypromellose

Macrogol 4000

Ferric iron oxide (E172)

Titanium dioxide (E171).

6.2 Incompatibilities

Not applicable.

6.3 Shelf Life

PP blister packs: 48 months

6.4 Special Precautions For Storage

Store in the original container. The tablets should be protected from strong light.

6.5 Nature And Contents Of Container

Blister strips of 14 tablets in a cardboard outer container, in packs of 56 tablets.

Blister strips are composed of red polypropylene foil 0.3 mm backed with aluminium foil.

6.6 Special Precautions For Disposal And Other Handling

No additional information

7. Marketing Authorisation Holder

Bayer plc

Bayer House

Strawberry Hill

Newbury

Berkshire

RG14 1JA

United Kingdom

Trading as Bayer plc, Bayer Schering Pharma.

8. Marketing Authorisation Number(S)

PL 00010/0151

9. Date Of First Authorisation/Renewal Of The Authorisation

Date of first authorisation:	7 May 1987
Date of last renewal:	19 May 2002

10. Date Of Revision Of The Text

24 November 2011

Earex Plus Ear Drops

1. Name Of The Medicinal Product

Earex Plus Ear Drops.

2. Qualitative And Quantitative Composition

Choline Salicylate Solution BP 43.22% w/v; and Glycerol BP 12.62% w/v.

3. Pharmaceutical Form

Solution for topical administration to the ear.

4. Clinical Particulars

4.1 Therapeutic Indications

For the symptomatic relief of ear pain in acute and chronic otitis media and externa. Patients with ear pain should always seek medical advice. Softening of ear wax as an aid to ear wax removal.

4.2 Posology And Method Of Administration

Auricular Use. Adults, the elderly and children: For pain relief: With the head tilted to one side, the external ear canal is filled completely with Earex Plus Ear Drops using the dropper provided. The ear should be plugged with cotton wool soaked with the ear drops. A wick may be inserted, if preferred, using the ear drops to keep it moist. Earex Plus Ear Drops should be instilled every three to four hours. For the softening of ear wax: Apply as described above, twice daily, for four days.

4.3 Contraindications

Not to be used in children under one year of age without medical advice being sought. Salicylate sensitivity. Perforated ear drum. Hypersensitivity to any of the ingredients.

4.4 Special Warnings And Precautions For Use

None stated.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

None stated.

4.6 Pregnancy And Lactation

There is no known hazard with the use of this product during pregnancy and lactation.

4.7 Effects On Ability To Drive And Use Machines

None stated.

4.8 Undesirable Effects

None stated.

4.9 Overdose

Each bottle of Earex Plus Ear Drops contains 1.6g of choline salicylate, equivalent to 1.2g of aspirin. Accidental or deliberate ingestion of the contents of a bottle of Earex Plus Ear Drops is therefore only of concern in small infants. In such cases, signs of intoxication may include dizziness, tinnitus, sweating, vomiting, confusion and hyperventilation. Gross overdosage may lead to central nervous system depression. Management should include, as appropriate, induced vomiting, correction of fluid and electrolyte balance and measurement of plasma salicylate levels. At concentrations in excess of 300mg/litre measures such as forced alkaline diuresis and haemodialysis to enhance clearance may be appropriate.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Choline salicylate ATC code: N02BA03.

Choline salicylate has actions similar to those of aspirin, that is analgesic, anti-inflammatory and antipyretic actions considered to be due to inhibition of the biosynthesis of prostaglandins. Glycerol softens ear wax due to its water-retaining and emollient properties.

5.2 Pharmacokinetic Properties

Not applicable as Earex Plus Ear Drops are applied topically.

5.3 Preclinical Safety Data

None stated.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Ethylene Oxide Polyoxypropylene Glycol; Chlorbutol (Hemihydrate); Hydrochloric Acid; Propylene Glycol.

6.2 Incompatibilities

None stated.

6.3 Shelf Life

Three years unopened.

6.4 Special Precautions For Storage

Do not store above 25^oC.

6.5 Nature And Contents Of Container

Cartoned amber glass bottle with screw cap and integral dropper containing 10ml of product.

6.6 Special Precautions For Disposal And Other Handling

Not applicable.

7. Marketing Authorisation Holder

SSL International PLC. Venus, 1 Old Park Lane, Trafford Park, Manchester, M41 7HA.

8. Marketing Authorisation Number(S)

PL 17905/0018

9. Date Of First Authorisation/Renewal Of The Authorisation

21/08/2006

10. Date Of Revision Of The Text

21/08/2006

Asthma Medications

Definition of Asthma: Asthma is an inflammatory disorder of the airways, characterized by periodic attacks of wheezing, shortness of breath, chest tightness, and coughing.

Drugs associated with Asthma

The following drugs and medications are in some way related to, or used in the treatment of Asthma. This service should be used as a supplement to, and NOT a substitute for, the expertise, skill, knowledge and judgment of healthcare practitioners.

See sub-topics

Topics under Asthma

• Allergic Asthma (0 drugs)

• Asthma, acute (88 drugs)

• Asthma, Maintenance (65 drugs)

• Reversible Airways Disease (0 drugs in 2 topics)

Learn more about Asthma

Micromedex Care Notes:

• Asthma
• Asthma In Children
• Reactive Airways Disease

Medical Encyclopedia:

• Asthma

Harvard Health Guide:

• Symptoms and treatment for Asthma

Drugs.com Health Center:

• Asthma

Drug List:

A-Methapred-Solution

Aerobid-Aerosol-Inhaler

Aerobid-M-Aerosol-Inhaler

Aerospan-Hfa-Inhaler

Alvesco

Aristocort

Atrovent

Atrovent-Hfa-Aerosol-Suspension

Azmacort

Baycadron

Broncodur-Liquid

Bronkometer

Bronkosol

Clinacort-Injection

Clinalog-Injection

Copd

De-Sone-La-Injection

Decadron

Deltasone

Depo-Medrol-Suspension

Dexacen-4-Injection

Dexacort-Phosphate-In-Turbinaire

Dexamethasone-Intensol

Dexasone-Injection

Dexasone-La-Injection

Dexpak-Tablets-Dose-Pack

Difil-G

Difil-G-Forte

Dilex-G-Liquid

Dilex-G-200

Dilex-G-400-Tablets

Dilor

Dilor-400

Dulera

Dy-G

Dyfilin-Gg

Dyflex-G

Dylix-Elixir

Dyphyllin-Gg

Dyphylline-Gg

Dyphylline-Gg-Es

Ed-Bron-G-Liquid

Elixophyllin-Gg-Liquid

Evening-Primrose-Oil

Jay-Phyl

Ken-Jec-40-Injection

Kenalog-40-Suspension

Lufyllin

Lufyllin-400

Lufyllin-Gg

Medrol

Medrol-Dosepak

Methylprednisolone-Dose-Pack

Meticorten

Neothylline

Panfil-G

Primrose-Oil

Quibron

Quibron-300

Singulair

Solu-Medrol-Solution

Solurex-Injection

Solurex-La-Injection

Sterapred

Sterapred-Ds

Tac-3-Injection

Theomar-Gg-Liquid

Triam-Forte

Triamcot-Injection

Triamonide-40-Injection

U-Tri-Lone-Injection

Zema-Pak-10-Day

Insuman Rapid (100 IU / ml) (sanofi-aventis)

1. Name Of The Medicinal Product

Insuman® Rapid 100 IU/ml solution for injection in a cartridge

Insuman® Rapid 100 IU/ml OptiSet® solution for injection

2. Qualitative And Quantitative Composition

Insuman Rapid is a neutral insulin solution (regular insulin).

Each ml of Insuman Rapid contains 100 IU of the active substance insulin human.

Each cartridge contains 3 ml, equivalent to 300 IU insulin.

Insuman Rapid OptiSet is a pre-filled disposable pen. Each pen contains 3 ml, equivalent to 300 IU insulin.

One IU (International Unit) corresponds to 0.035 mg of anhydrous human insulin.

The human insulin in Insuman Rapid is produced by recombinant DNA technology using K 12 strains of Escherichia coli.

For excipients, see section 6.1.

3. Pharmaceutical Form

Solution for injection in a cartridge or pre-filled pen.

4. Clinical Particulars

4.1 Therapeutic Indications

Diabetes mellitus where treatment with insulin is required.

Insuman Rapid cartridges are also suitable for the treatment of hyperglycaemic coma and ketoacidosis, as well as for achieving pre-, intra- and post-operative stabilisation in patients with diabetes mellitus

4.2 Posology And Method Of Administration

The desired blood glucose levels, the insulin preparations to be used and the insulin dosage (doses and timings) must be determined individually and adjusted to suit the patient's diet, physical activity and life-style.

Daily doses and timing of administration

There are no fixed rules for insulin dosage. However, the average insulin requirement is often 0.5 to 1.0 IU per kg body weight per day. The basal metabolic requirement is 40% to 60% of the total daily requirement. Insuman Rapid is injected subcutaneously 15 to 20 minutes before a meal.

Insuman Rapid OptiSet delivers insulin in increments of 2 IU up to a maximum single dose of 40 IU.

Insuman Rapid cartridges: In the treatment of severe hyperglycaemia or ketoacidosis in particular, insulin administration is part of a complex therapeutic regimen which includes measures to protect patients from possible severe complications of a relatively rapid lowering of blood glucose. This regimen requires close monitoring (metabolic status, acid-base and electrolyte status, vital parameters etc.) in an intensive care unit or similar setting.

Transfer to Insuman Rapid

Dosage adjustment may be necessary when transferring patients from one insulin preparation to another. This applies, for example, when transferring from:

- an animal insulin (especially a bovine insulin) to human insulin,

- one human insulin preparation to another,

- a regimen with only regular insulin to one with a longer-acting insulin.

The need to adjust (e.g. reduce) the dose may become evident immediately after transfer. Alternatively, it may emerge gradually over a period of several weeks.

Following transfer from an animal insulin to human insulin, dosage reduction may be required in particular in patients who

- were previously already controlled on rather low blood glucose levels,

- have a tendency to hypoglycaemia,

- previously required high insulin doses due to the presence of insulin antibodies.

Close metabolic monitoring is recommended during the transition and in the initial weeks thereafter. In patients who require high insulin doses because of the presence of insulin antibodies, transfer under medical supervision in a hospital or similar setting must be considered.

Secondary dose adjustment

Improved metabolic control may result in increased insulin sensitivity, leading to a reduced insulin requirement. Dose adjustment may also be required, for example, if

- the patient's weight changes,

- the patient's life-style changes,

- other circumstances arise that may promote an increased susceptibility to hypo- or hyperglycaemia (see section 4.4).

Use in specific patient groups

In patients with hepatic or renal impairment as well as in the elderly, insulin requirements may be diminished (see section 4.4).

Administration

Cartridges: Insuman Rapid in cartridges has been developed for use in the OptiPen^® series. For further details on handling, see section 6.6.

OptiSet: Before using the OptiSet, the Instructions for Use included in the package leaflet must be read carefully (see 6.6).

Insuman Rapid is administered subcutaneously.

Insulin absorption and hence the blood glucose lowering effect of a dose may vary from one injection area to another (e.g. the abdominal wall compared with the thigh). Injection sites within an injection area must be rotated from one injection to the next.

Insuman Rapid cartridges may also be administered intravenously. Intravenous insulin therapy must generally take place in an intensive care unit or under comparable monitoring and treatment conditions (see "Daily doses and timing of administration").

Mixing of insulins

Insuman Rapid cartridges may be mixed with all Sanofi-Aventis human insulins, but NOT with those designed specifically for use in insulin pumps. Insuman Rapid must also NOT be mixed with insulins of animal origin or with insulin analogues.

Insuman Rapid OptiSet must not be mixed with any other insulin or with insulin analogues.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients (see section 6.1).

Insuman Rapid cartridges must not be used in external or implanted insulin pumps or in peristaltic pumps with silicone tubing.

4.4 Special Warnings And Precautions For Use

Patients hypersensitive to Insuman Rapid for whom no better tolerated preparation is available must only continue treatment under close medical supervision and – where necessary – in conjunction with anti-allergic treatment.

In patients with an allergy to animal insulin intradermal skin testing is recommended prior to a transfer to Insuman Rapid, since they may experience immunological cross-reactions.

In patients with renal impairment, insulin requirements may be diminished due to reduced insulin metabolism. In the elderly, progressive deterioration of renal function may lead to a steady decrease in insulin requirements.

In patients with severe hepatic impairment, insulin requirements may be diminished due to reduced capacity for gluconeogenesis and reduced insulin metabolism.

In case of insufficient glucose control or a tendency to hyper- or hypoglycaemic episodes, the patient's adherence to the prescribed treatment regimen, injection sites and proper injection technique and all other relevant factors must be reviewed before dose adjustment is considered.

Hypoglycaemia

Hypoglycaemia may occur if the insulin dose is too high in relation to the insulin requirement.

Particular caution should be exercised, and intensified blood glucose monitoring is advisable in patients in whom hypoglycaemic episodes might be of particular clinical relevance, such as in patients with significant stenoses of the coronary arteries or of the blood vessels supplying the brain (risk of cardiac or cerebral complications of hypoglycaemia) as well as in patients with proliferative retinopathy, particularly if not treated with photocoagulation (risk of transient amaurosis following hypoglycaemia).

Patients should be aware of circumstances where warning symptoms of hypoglycaemia are diminished. The warning symptoms of hypoglycaemia may be changed, be less pronounced or be absent in certain risk groups. These include patients:

- in whom glycaemic control is markedly improved,

- in whom hypoglycaemia develops gradually,

- who are elderly,

- in whom an autonomic neuropathy is present,

- with a long history of diabetes,

- suffering from a psychiatric illness,

- receiving concurrent treatment with certain other medicinal products (see section 4.5).

Such situations may result in severe hypoglycaemia (and possibly loss of consciousness) prior to the patient's awareness of hypoglycaemia.

If normal or decreased values for glycated haemoglobin are noted, the possibility of recurrent, unrecognised (especially nocturnal) episodes of hypoglycaemia must be considered.

Adherence of the patient to the dosage and dietary regimen, correct insulin administration and awareness of hypoglycaemia symptoms are essential to reduce the risk of hypoglycaemia. Factors increasing the susceptibility to hypoglycaemia require particularly close monitoring and may necessitate dose adjustment. These include:

- change in the injection area,

- improved insulin sensitivity (by, e.g., removal of stress factors),

- unaccustomed, increased or prolonged physical activity,

- intercurrent illness (e.g. vomiting, diarrhoea),

- inadequate food intake,

- missed meals,

- alcohol consumption,

- certain uncompensated endocrine disorders (e.g. in hypothyroidism and in anterior pituitary or adrenocortical insufficiency),

- concomitant treatment with certain other medicinal products.

Intercurrent illness

Intercurrent illness requires intensified metabolic monitoring. In many cases, urine tests for ketones are indicated, and often it is necessary to adjust the insulin dose. The insulin requirement is often increased. Patients with type 1 diabetes must continue to consume at least a small amount of carbohydrates on a regular basis, even if they are able to eat only little or no food, or are vomiting etc. and they must never omit insulin entirely.

Handling of the OptiSet pen

Before using OptiSet, the Instructions for Use included in the Package Leaflet must be read carefully. OptiSet has to be used as recommended in these Instructions for Use (see 6.6)

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

A number of substances affect glucose metabolism and may require dose adjustment of human insulin.

Substances that may enhance the blood-glucose-lowering effect and increase susceptibility to hypoglycaemia include oral antidiabetic agents, ACE inhibitors, disopyramide, fibrates, fluoxetine, MAO inhibitors, pentoxifylline, propoxyphene, salicylates and sulphonamide antibiotics.

Substances that may reduce the blood-glucose-lowering effect include corticosteroids, danazol, diazoxide, diuretics, glucagon, isoniazid, oestrogens and progestogens, phenothiazine derivatives, somatropin, sympathomimetic agents (e.g. epinephrine [adrenaline], salbutamol, terbutaline) and thyroid hormones.

Beta-blockers, clonidine, lithium salts or alcohol may either potentiate or weaken the blood-glucose-lowering effect of insulin. Pentamidine may cause hypoglycaemia which may sometimes be followed by hyperglycaemia.

In addition, under the influence of sympatholytic medicinal products such as beta-blockers, clonidine, guanethidine and reserpine, the signs of adrenergic counter-regulation may be reduced or absent.

4.6 Pregnancy And Lactation

There is no experience with the use of Insuman Rapid in pregnant women. Insulin does not cross the placental barrier.

It is essential for patients with pre-existing or gestational diabetes to maintain good metabolic control throughout pregnancy. Insulin requirements may decrease during the first trimester and generally increase during the second and third trimesters. Immediately after delivery, insulin requirements decline rapidly (increased risk of hypoglycaemia). Careful monitoring of glucose control is essential.

There are no restrictions on the use of Insuman Rapid in breast-feeding women. Lactating women may require adjustments in insulin dose and diet.

4.7 Effects On Ability To Drive And Use Machines

The patient's ability to concentrate and react may be impaired as a result of hypoglycaemia or hyperglycaemia or, for example, as a result of visual impairment. This may constitute a risk in situations where these abilities are of special importance (e.g. driving a car or operating machinery).

Patients should be advised to take precautions to avoid hypoglycaemia whilst driving. This is particularly important in those who have reduced or absent awareness of the warning symptoms of hypoglycaemia or have frequent episodes of hypoglycaemia. It should be considered whether it is advisable to drive or operate machinery in these circumstances.

4.8 Undesirable Effects

Hypoglycaemia

Hypoglycaemia, in general the most frequent undesirable effect of insulin therapy, may occur if the insulin dose is too high in relation to the insulin requirement. Severe hypoglycaemic attacks, especially if recurrent, may lead to neurological damage. Prolonged or severe hypoglycaemic episodes may be life-threatening.

In many patients, the signs and symptoms of neuroglycopenia are preceded by signs of adrenergic counter-regulation. Generally, the greater and more rapid the decline in blood glucose, the more marked is the phenomenon of counter-regulation and its symptoms.

Eyes

A marked change in glycaemic control may cause temporary visual impairment, due to temporary alteration in the turgidity and refractive index of the lens.

Long-term improved glycaemic control decreases the risk of progression of diabetic retinopathy. However, intensification of insulin therapy with abrupt improvement in glycaemic control may be associated with temporary worsening of diabetic retinopathy. In patients with proliferative retinopathy, particularly if not treated with photocoagulation, severe hypoglycaemic episodes may result in transient amaurosis.

Lipodystrophy

As with any insulin therapy, lipodystrophy may occur at the injection site and delay local insulin absorption. Continuous rotation of the injection site within the given injection area may help to reduce or prevent these reactions.

Injection site and allergic reactions

In rare cases mild reactions at the injection site may occur. Such reactions include redness, pain, itching, hives, swelling, or inflammation. Most minor reactions to insulins at the injection site usually resolve in a few days to a few weeks.

Immediate-type allergic reactions to insulin are very rare. Such reactions to insulin or the excipients may, for example, be associated with generalised skin reactions, angio-oedema, bronchospasm, hypotension and shock, and may be life-threatening.

Other reactions

Insulin administration may cause insulin antibodies to form. In rare cases, the presence of such insulin antibodies may necessitate adjustment of the insulin dose in order to correct a tendency to hyper- or hypoglycaemia.

Insulin may cause sodium retention and oedema, particularly if previously poor metabolic control is improved by intensified insulin therapy.

4.9 Overdose

Symptoms

Insulin overdose may lead to severe and sometimes long-term and life-threatening hypoglycaemia.

Management

Mild episodes of hypoglycaemia can usually be treated with oral carbohydrates. Adjustments in dosage of the medicinal product, meal patterns, or physical activity may be needed.

More severe episodes with coma, seizure, or neurologic impairment may be treated with intramuscular/subcutaneous glucagon or concentrated intravenous glucose. Sustained carbohydrate intake and observation may be necessary because hypoglycaemia may recur after apparent clinical recovery.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmaco-therapeutic group: Antidiabetic agent. Insulins and analogues, fast-acting.

ATC Code: A10AB01,

Mode of action

Insulin:

• lowers blood glucose and promotes anabolic effects as well as decreasing catabolic effects.

• increases the transport of glucose into cells as well as the formation of glycogen in the muscles and the liver, and improves pyruvate utilisation. It inhibits glycogenolysis and gluconeogenesis.

• increases lipogenesis in the liver and adipose tissue and inhibits lipolysis.

• promotes the uptake of amino acids into cells and promotes protein synthesis.

• enhances the uptake of potassium into cells.

Pharmacodynamic characteristics

Insuman Rapid is an insulin with rapid onset and short duration of action. Following subcutaneous injection, onset of action is within 30 minutes, the phase of maximum action is between 1 and 4 hours after injection and the duration of action is 7 to 9 hours.

5.2 Pharmacokinetic Properties

In healthy subjects, the serum half-life of insulin is approximately 4 to 6 minutes. It is longer in patients with severe renal insufficiency. However, it must be noted that the pharmacokinetics of insulin do not reflect its metabolic action.

5.3 Preclinical Safety Data

The acute toxicity was studied following subcutaneous administration in rats. No evidence of toxic effects was found. Local tolerability studies following subcutaneous and intramuscular administration in rabbits gave no remarkable findings. Studies of pharmacodynamic effects following subcutaneous administration in rabbits and dogs revealed the expected hypoglycaemic reactions.

6. Pharmaceutical Particulars

6.1 List Of Excipients

M-cresol, sodium dihydrogen phosphate dihydrate, glycerol, sodium hydroxide, hydrochloric acid, water for injections.

6.2 Incompatibilities

As with all insulin preparations, Insuman Rapid must not be mixed with solutions containing reducing agents such as thioles and sulfites. It must also be remembered that neutral regular insulin precipitates out at a pH of approximately 4.5 to 6.5.

Concerning mixing and incompatibility with other insulins see section 4.2. Care must be taken to ensure that no alcohol or other disinfectants enter the insulin solution.

6.3 Shelf Life

2 years.

Cartridges: Once in use, the cartridges may be kept for up to four weeks. This applies irrespective of whether the cartridges are immediately put into the pen or are first carried as a spare for a while.

OptiSet: Once in use the pens may be kept for up to four weeks. This applies irrespective of whether the pens are immediately used or are first carried as a spare for a while.

6.4 Special Precautions For Storage

Store at 2°C to 8°C. Keep the container in the outer carton. Do not freeze. Ensure that the container is not directly touching the freezer compartment or freezer packs.

Cartridges: Once in use, do not store above 25°C, and protect from direct heat and light. When in use (in the pen) , do not store in a refrigerator.

OptiSet pens: Before first use, Insuman Rapid OptiSet must be kept at room temperature for 1 to 2 hours. Once in use, do not store above 25°C, and protect from direct heat and light. When in use, do not store in a refrigerator.

6.5 Nature And Contents Of Container

Cartridges

3 ml, type 1 colourless glass cartridge with bromobutyl rubber (type 1) plunger and flanged aluminium cap with bromobutyl rubber (type 1) stopper.

Each cartridge contains 3 ml solution (300 IU insulin human). Pack of 5 cartridges are available.

OptiSet

Disposable pen filled with a 3 ml, type 1 colourless glass cartridge with bromobutyl rubber (type 1) plunger and flanged aluminium cap with bromobutyl rubber (type 1) stopper.

Each cartridge contains 3 ml solution (300 IU insulin human). The cartridges are sealed in a disposable pen injector. Needles are not included in the pack. Pack of 5 pens are available.

6.6 Special Precautions For Disposal And Other Handling

Insulin pen

The cartridges are to be used in conjunction with an insulin pen such as OptiPen and other pens suitable for Insuman cartridges and as recommended in the information provided by the device manufacturer

The manufacturer's instructions for using the pen must be followed carefully for loading the partridge, attaching the needle and administering the insulin injection.

If the insulin pen is damaged or not working properly (due to mechanical defects) is has to be discarded and a new insulin pen has to be used.

If the pen malfunctions (see instructions of using the pen), the solution may be drawn from the cartridge into a syringe (suitable for an insulin with 100 IU/ml) and injected.

Cartridges

Before insertion into the pen, Insuman Rapid must be stored at room temperature for 1 to 2 hours. Inspect the cartridge before use. Insuman Rapid must only be used if the solution is clear, colourless, with no solid particles visible, and if it is of a water-like consistency.

Air bubbles must be removed from the cartridge before injection (see instructions for using the pen).

Insuman Rapid cartridges are not designed to allow any other insulin to be mixed in the cartridge.

OptiSet

Insuman Rapid must only be used if the solution is clear, colourless, with no solid particles visible, and if it is of a water-like consistency.

Empty pens must never be reused and must be properly discarded.

To prevent the possible transmission of disease, each pen must be used by one patient only.

Handling of the pen

The Instructions for Use included in the Package Leaflet must be read carefully before using OptiSet.

Schematic diagram of the pen

Important information for use of OptiSet:

• Before each use, a new needle must be attached and a safety test must be performed.

• The dosage selector must never be turned after the injection button has been pulled out.

• If a problem occurs with OptiSet, the section “Troubleshooting” in the Instructions for Use should be referred to.

• If OptiSet is damaged, or not working properly (due to mechanical defects) it has to be discarded and a new OptiSet has to be used.

 General Notes

- The injection button allows checking the actual loaded dose. The button should be pulled out. While holding it out, the last thick bar visible (only the top part can be seen) shows the amount of insulin loaded. If it is difficult to see, the pen may be held at an angle.

- The insulin pen must not be dropped or subjected to impact; otherwise, the insulin cartridge in the transparent insulin reservoir may break and the pen will not work. If this happens, a new pen must be used.

Step 1. Check the Insulin

After removing the pen cap, the label on the insulin reservoir should be checked to make sure it contains the correct insulin. The appearance of insulin should also be checked: the insulin solution must be clear, colourless, with no solid particles visible, and must have a water-like consistency.

Step 2. Attaching the needle

Only needles that have been approved for use with OptiSet should be used.

The needle should be carefully attached straight onto the pen.

Step 3. Safety test

Prior to each injection a safety test has to be performed.

For a new and unused OptiSet, the dose arrow should point to the number 8, as preset by the manufacturer.

Otherwise, the dosage selector should be turned until the dose arrow points to 2.

Then the injection button should be pulled out as far as it will go.

The outer and inner needle caps should be removed.

While holding the pen with the needle pointing upwards, the insulin reservoir should be tapped gently with the finger so that any air bubbles rise up towards the needle

Then the injection button should be pressed in completely.

If insulin has been expelled through the needle tip, then the pen and the needle are working properly.

If no insulin appears at the needle tip, step 3 should be repeated until insulin appears at the needle tip.

Step 4. Setting and loading the insulin dose

The dose can be set in steps of 2 units, from a minimum of 2 units to a maximum of 40 units. If a dose greater than 40 units is required, it should be given as two or more injections.

The dosage selector should be turned in either direction until the dose arrow points to the required dose.

The injection button should be pulled out as far as it will go in order to load the pen.

Step 5. Injecting the insulin dose

The patient should be informed on the injection technique by his health care professional.

The needle should be inserted into the skin.

The injection button should be pressed in completely. Then the injection button should be held down 10 seconds before withdrawing the needle. This ensures that the full dose of insulin has been injected.

Step 6. Removing the needle

The needle should be removed after each injection and discarded. This will prevent contamination as well as leakage, re-entry of air and potential needle blocks. Needles must not be reused.

The pen cap should be replaced on the pen.

Checking the reservoir for remaining insulin

The residual insulin scale on the transparent insulin reservoir shows approximately how much insulin remains in the OptiSet. This scale must not be used to set the insulin dose.

The actual loaded dose should be checked as per “General notes”. In case, the patient is not sure whether enough insulin remains in the reservoir, the OptiSet should be discarded.

Example:If the dose arrow has been set to 30 units and injection button can only be pulled out to as far as 12 units, then only 12 units insulin can be injected with this pen. In this example, either the other 18 units will have to be injected using a new pen, or the entire 30 units dose will have to be injected using a new pen.

7. Marketing Authorisation Holder

Sanofi-Aventis Deutschland GmbH

D-65926 Frankfurt am Main

Germany

8. Marketing Authorisation Number(S)

5 cartridges of 3 ml: EU/1/97/030/030

5 OptiSet pens of 3 ml: EU/1/97/030/067

9. Date Of First Authorisation/Renewal Of The Authorisation

Cartridge: 11 November 1998

OptiSet: 20 March 2000

10. Date Of Revision Of The Text

June 2006

11. Legal Category

POM