Aminosyn

Dosage Form: injection, solution
Aminosyn®-HBC 7%

Sulfite-Free

AN AMINO ACID INJECTION  — HIGH BRANCHED CHAIN

Flexible Plastic Container

Rx only

Aminosyn Description

Aminosyn®-HBC 7%, Sulfite-Free, (an amino acid injection high branched chain) is a sterile, nonpyrogenic, hypertonic solution for intravenous infusion. Aminosyn-HBC 7% is oxygen sensitive. The solution contains the following crystalline amino acids:

Essential Amino Acids (mg/100 mL)
Isoleucine	789
Leucine	1576
Lysine (acetate)*	265
Methionine	206
Phenylalanine	228
Threonine	272
Tryptophan	88
Valine	789
Nonessential Amino Acids (mg/100 mL)
Alanine	660
Arginine	507
Histidine**	154
Proline	448
Serine	221
Tyrosine	33
Glycine	660
*Amount cited is for lysine alone and does not include the acetate salt.
**Histidine is considered essential for patients in renal failure.

Crystalline Amino Acids (g/100 mL)	7
Branched Chain Amino Acids (g/100 mL)	3.2
Nitrogen (approx. g/100 mL)	1.12
Acetate (C2H3O2-)a (mEq/Liter)	71a
Osmolarity (mOsmol/liter)	623
pHb (Range)	5.2 (4.5 to 6.0)
aIncludes acetate from acetic acid used in processing and from lysine acetate.
bMay contain hydrochloric acid for pH adjustment.

The formulas for the individual amino acids present in Aminosyn-HBC 7% are as follows:

Essential Amino Acids
Isoleucine, USP	C6H13NO2
Leucine, USP	C6H13NO2
Lysine Acetate, USP	C6H14N2O2 • CH3COOH
Methionine, USP	C5H11NO2S
Phenylalanine, USP	C9H11NO2
Threonine, USP	C4H9NO3
Tryptophan, USP	C11H12N2O2
Valine, USP	C5H11NO2

Nonessential Amino Acids
Alanine, USP	C3H7NO2
Arginine, USP	C6H14N4O2
Histidine, USP	C6H9N3O2
Proline, USP	C5H9NO2
Serine, USP	C3H7NO3
Tyrosine, USP	C9H11NO3
Glycine, USP	C2H5NO2

The flexible plastic container is fabricated from a specially formulated polyvinylchloride. Water can permeate from inside the container into the overwrap but not in amounts sufficient to affect the solution significantly.

Solutions in contact with the plastic container may leach out certain chemical components from the plastic in very small amounts; however, biological testing was supportive of the safety of the plastic container materials.

Exposure to temperatures above 25°C/77°F during transport and storage will lead to minor losses in moisture content. Higher temperatures lead to greater losses. It is unlikely that these minor losses will lead to clinically significant changes within the expiration period.

Aminosyn - Clinical Pharmacology

Aminosyn-HBC 7%, Sulfite-Free, (an amino acid injection — high branched chain) provides a mixture of biologically utilizable essential and nonessential crystalline amino acids in concentrated form for protein synthesis. The solution contains a high (45%) concentration of the branched chain amino acids (isoleucine, leucine and valine) relative to other general purpose amino acid injections. Aminosyn-HBC 7%, when mixed with a concentrated source of calories such as hypertonic dextrose, supplemented with appropriate electrolytes, vitamins and trace metals and infused by central vein with or without fat emulsion, provides total parenteral nutrition (TPN) for the severely compromised patient.

Aminosyn-HBC 7% may also be administered peripherally with minimal caloric supplementation in order to conserve lean body mass in the well-nourished, mildly catabolic patient.

A high concentration of the branched chain amino acids is present in Aminosyn-HBC 7% because these amino acids have been reported to be metabolically active in the compromised patient.

The acetate content of the solution, under conditions of parenteral nutrition, would not be expected to affect acid-base status adversely when renal and respiratory functions are normal; confirmatory clinical/experimental evidence is not available. The amount of sodium present is not clinically significant. The concentration of chloride present is typical for TPN regimens.

Indications and Usage for Aminosyn

Parenteral nutrition with Aminosyn-HBC 7%, Sulfite-Free, (an amino acid injection — high branched chain) is indicated to prevent nitrogen loss or treat negative nitrogen balance in adults where (1) the alimentary tract, by the oral, gastrostomy, or jejunostomy route, cannot or should not be used, or adequate protein intake is not feasible by these routes; (2) gastrointestinal absorption of protein is impaired; or (3) nitrogen homeostasis is substantially impaired as with severe trauma or sepsis. Dosage, route of administration and concomitant infusion of nonprotein calories are dependent on various factors, such as nutritional and metabolic status of the patient, anticipated duration of parenteral nutrition support, and vein tolerance. See DOSAGE AND ADMINISTRATION for additional information.

Central Venous Nutrition: Central venous infusion should be considered when amino acid solutions are to be admixed with hypertonic dextrose to promote protein synthesis in hypercatabolic or severely depleted patients, or those requiring long-term parenteral nutrition. See SPECIAL PRECAUTIONS FOR CENTRAL INFUSIONS.

Peripheral Parenteral Nutrition: For moderately catabolic or depleted patients in whom the central venous route is not indicated, diluted amino acid solutions with minimal caloric supplementation may be infused by peripheral vein, supplemented, if desired, with fat emulsion.

Contraindications

Aminosyn-HBC 7%, Sulfite-Free, (an amino acid injection — high branched chain) is contraindicated in patients with anuria, hepatic coma, inborn errors of amino acid metabolism (especially those involving branched chain amino acid metabolism such as Maple Syrup Urine Disease and Isovaleric Acidemia), severe or uncorrected electrolyte or acid-base imbalance, hyperammonemia or other disorders involving impaired nitrogen utilization, or hypersensitivity to one or more amino acids present in the solution.

Warnings

Safe, effective use of parenteral nutrition requires a knowledge of nutrition as well as clinical expertise in recognition and treatment of the complications which can occur. Frequent evaluation and laboratory determinations are necessary for proper monitoring of parenteral nutrition. Studies should include blood sugar, serum proteins, kidney and liver function tests, electrolytes, hemogram, carbon dioxide content, serum osmolarities, blood cultures, and blood ammonia levels.

Administration of amino acids in the presence of impaired renal function or gastrointestinal bleeding may augment an already elevated blood urea nitrogen. Patients with azotemia from any cause should not be infused with amino acids without regard to total nitrogen intake.

Administration of amino acid solutions that have not been specifically formulated to treat patients with hepatic insufficiency may result in plasma amino acid imbalances, hyperammonemia, prerenal azotemia, stupor and coma.

Conservative doses of amino acids should be given, dictated by the nutritional status of the patient. Should symptoms of hyperammonemia develop, amino acid administration should be discontinued and the patient's clinical status re-evaluated.

Administration of intravenous solutions can cause fluid and/or solute overload resulting in dilution of serum electrolyte concentrations, overhydration, congested states, or pulmonary edema. The risk of dilutional states is inversely proportional to the electrolyte concentrations of the solutions. The risk of solute overload causing congested states with peripheral and pulmonary edema is directly proportional to the electrolyte concentrations of the solutions.

WARNING: This product contains aluminum that may be toxic. Aluminum may reach toxic levels with prolonged parenteral administration if kidney function is impaired. Premature neonates are particularly at risk because their kidneys are immature, and they require large amounts of calcium and phosphate solutions, which contain aluminum.

Research indicates that patients with impaired kidney function, including premature neonates, who receive parenteral levels of aluminum at greater than 4 to 5 mcg/kg/day accumulate aluminum at levels associated with central nervous system and bone toxicity. Tissue loading may occur at even lower rates of administration.

Precautions

Special care must be taken when administering hypertonic glucose to provide calories in diabetic or prediabetic patients.

Do not withdraw venous blood for blood chemistries through the peripheral infusion site, as interference with estimations of nitrogen-containing substances may occur.

Intravenously administered amino acids should be used with caution in patients with history of renal disease, pulmonary disease, or with cardiac insufficiency so as to avoid excessive fluid accumulation.

The effect of infusion of amino acids, without dextrose, upon carbohydrate metabolism of children is not known at this time.

Nitrogen intake should be carefully monitored in patients with impaired renal function.

Aminosyn-HBC 7%, Sulfite -Free, (an amino acid injection — high branched chain) contains no added phosphorus. Patients, especially those with hypophosphatemia, may require the addition of phosphate. To prevent hypocalcemia, calcium supplementation should always accompany phosphate administration. To assure adequate intake, serum levels should be monitored frequently.

For long-term total nutrition, or if a patient has inadequate fat stores, it is essential to provide adequate exogenous calories concurrently with the amino acids. Concentrated dextrose solutions are an effective source of such calories. Such strongly hypertonic nutrient solutions should be administered through an indwelling intravenous catheter with the tip located in the superior vena cava.

Aminosyn-HBC contains no more than 25 mcg/L of aluminum.

SPECIAL PRECAUTIONS FOR

CENTRAL INFUSIONS

ADMINISTRATION BY CENTRAL VENOUS CATHETER SHOULD BE USED ONLY BY THOSE FAMILIAR WITH THIS TECHNIQUE AND ITS COMPLICATIONS.

Central vein infusion (with added concentrated carbohydrate solutions) of amino acid solutions requires a knowledge of nutrition as well as clinical expertise in recognition and treatment of complications. Attention must be given to solution preparation, administration and patient monitoring. IT IS ESSENTIAL THAT A CAREFULLY PREPARED PROTOCOL, BASED ON CURRENT MEDICAL PRACTICES, BE FOLLOWED, PREFERABLY BY AN EXPERIENCED TEAM.

SUMMARY HIGHLIGHTS OF COMPLICATIONS (See also Current Medical Literature).

1. Technical

The placement of a central venous catheter should be regarded as a surgical procedure. One should be fully acquainted with various techniques of catheter insertion. For details of technique and placement sites, consult the medical literature. X-ray is the best means of verifying catheter placement. Complications known to occur from the placement of central venous catheters are pneumothorax, hemothorax, hydrothorax, artery puncture and transection, injury to the brachial plexus, malposition of the catheter, formation of arteriovenous fistula, phlebitis, thrombosis and air and catheter emboli.

2. Septic

The constant risk of sepsis is present during administration of total parenteral nutrition. It is imperative that the preparation of the solution and the placement and care of catheters be accomplished under strict aseptic conditions.

Solutions should ideally be prepared in the hospital pharmacy under a laminar flow hood using careful aseptic technique to avoid inadvertent touch contamination. Solutions should be used promptly after mixing.

Storage should be under refrigeration and limited to a brief period of time, preferably less than 24 hours.

Administration time for a single bottle and set should never exceed 24 hours.

3. Metabolic

The following metabolic complications have been reported with TPN administration: Metabolic acidosis and alkalosis, hypophosphatemia, hypocalcemia, osteoporosis, hyperglycemia, and glycosuria, rebound hypoglycemia, osmotic diuresis and dehydration, elevated liver enzymes, hypo- and hypervitaminosis, electrolyte imbalances and hyperammonemia in children. Frequent evaluations are necessary especially during the first few days of therapy to prevent or minimize these complications.

Administration of glucose at a rate exceeding the patient’s utilization rate may lead to hyperglycemia, coma and death.

Pregnancy: Teratogenic effects.

Pregnancy Category C: Animal reproduction studies have not been performed with Aminosyn-HBC 7%. It is not known whether Aminosyn-HBC 7% can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Aminosyn-HBC 7% should be given to a pregnant woman only if clearly needed.

Pediatric Use: Safety and effectiveness in children have not been established.

Geriatric Use: Clinical studies of Aminosyn-HBC 7% 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 dosage range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Drug Interactions

Because of its antianabolic activity, concurrent administration of tetracycline may reduce the potential anabolic effects of amino acids infused with dextrose as part of a parenteral feeding regimen.

Additives may be incompatible. Consult with pharmacist if available. When introducing additives, use aseptic technique, mix thoroughly and do not store.

Adverse Reactions

See WARNINGS and SPECIAL PRECAUTIONS FOR CENTRAL VENOUS NUTRITION.

Reactions secondary to the administration technique or the solution include febrile response, infection at the injection site, venous thrombosis or phlebitis extending from the site of injection, extravasation, and hypervolemia.

Local reactions at the infusion site, consisting of a warm sensation, erythema, phlebitis and thrombosis have been reported with peripherally administered amino acid solutions, especially if other substances are also administered through the same site.

Generalized flushing, fever and nausea have been reported during peripheral administration of amino acids.

Symptoms may result from an excess or deficit of one or more of the ions present in the solution; therefore, frequent monitoring of electrolyte levels is essential.

If electrolyte supplements are required during peripheral infusions, it is recommended that additives be administered throughout the day in order to avoid possible vein irritation. Irritating additive medications may require injection at another site and should not be added directly to the amino acid infusate.

Phosphorus deficiency may lead to impaired tissue oxygenation and acute hemolytic anemia. Relative to calcium, excessive phosphorus intake can precipitate hypocalcemia with cramps, tetany and muscular hyperexcitability.

If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate therapeutic countermeasures, and save the remainder of the fluid for examination if deemed necessary.

Overdosage

In the event of fluid, electrolyte or metabolic imbalances re-evaluate the patient and institute appropriate corrective measures; see WARNINGS and PRECAUTIONS.

Aminosyn Dosage and Administration

Aminosyn-HBC 7%, Sulfite-Free, (an amino acid injection — high branched chain) is administered intravenously. The total dose depends upon daily protein requirements and the patient's metabolic and clinical response. The determination of nitrogen balance and accurate daily body weights, corrected for fluid balance, is probably the best means of assessing individual protein requirements.

While Recommended Dietary Allowances for oral protein are approximately 0.8 g/kg of body weight for the healthy adult, protein and caloric requirements in traumatized or malnourished patients may be substantially increased. To satisfy protein needs and promote positive nitrogen balance, the daily dosage level of amino acids for adult patients with adequate caloric intake is approximately 1.5 g/kg of body weight. Severely catabolic states may require higher dosage levels. Such higher doses must be accompanied by frequent laboratory evaluation. Fat emulsion may be administered to help meet energy requirements. Fat emulsion coadministration should be considered when prolonged parenteral nutrition is required in order to prevent essential fatty acid deficiency (E.F.A.D.). Serum lipids should be monitored for evidence of E.F.A.D. in patients maintained on fat-free total parenteral nutrition.

For optimum amino acid utilization, sufficient intracellular electrolytes (sodium, magnesium, and phosphate) should be provided. Approximately 60 to 180 mEq of potassium, 10 to 30 mEq of magnesium, and 10 to 40 mM of phosphate/day appear necessary to achieve optimum metabolic response. In addition, sufficient quantities of the major extracellular electrolytes (sodium, calcium and chloride) must be given. In patients with hyperchloremic or other metabolic acidoses, sodium and potassium may be added as the acetate or lactate salts to provide bicarbonate precursors. The electrolyte content of Aminosyn-HBC 7% must be considered when calculating daily electrolyte intake. Serum electrolytes, including magnesium and phosphorus, should be monitored frequently. If a patient's nutritional intake is primarily parenteral, trace metals and vitamins, especially the water-soluble vitamins, should also be provided.

Central Venous Nutrition: For severely catabolic, depleted patients or those who require long-term parenteral nutrition, central venous nutrition should be considered. Total parenteral nutrition may be started with admixtures containing lower concentrations of dextrose; dextrose concentrations may be gradually increased to approximate estimated energy requirements as the patient’s glucose tolerance increases.

In adults, strongly hypertonic admixtures of amino acids and dextrose may be safely administered only by continuous infusion through a central venous catheter with the tip located in the superior vena cava. A mixture containing 500 mL of Aminosyn-HBC 7% with 500 mL of concentrated dextrose supplemented with electrolytes, trace metals and vitamins may be administered over a period of approximately 8 hours. If prescribed administration rates should fall behind schedule, no attempt to “catch up” to planned intake should be made. In addition to meeting protein requirements, the administration is also governed by the patient’s glucose tolerance, especially during the first few days of therapy. The daily intake of the amino acid/dextrose admixture should be increased gradually to the maximum required dose, based on serial determinations of urine and blood sugar levels. To prevent hyperglycemia and glycosuria, certain patients may require exogenous insulin in order to receive adequate calories from hypertonic dextrose. To prevent rebound hypoglycemia, a solution containing 5% dextrose should be administered when hypertonic dextrose infusions are abruptly discontinued.

Peripheral Parenteral Nutrition: For the moderately catabolic, depleted patient in whom aggressive central venous nutrition is not necessary, Aminosyn-HBC 7% may be given by peripheral vein with hypocaloric energy supplements. Dextrose in a final concentration of up to 10% and/or lipid emulsion may be administered.

Fat provides approximately 9 kcal/gram and in long-term therapy (more than 5-7 days) will prevent essential fatty acid deficiency. Parenteral fat emulsion may be administered simultaneously with amino acid-dextrose admixtures via a Y-type administration set to supplement caloric intake. Fat, however, should not provide more than 60% of the total caloric intake.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. COLOR VARIATION FROM PALE YELLOW TO YELLOW IS NORMAL AND DOES NOT ALTER EFFICACY.

WARNING: Do not use flexible container in series connections.

How is Aminosyn Supplied

Aminosyn-HBC 7%, Sulfite-Free, (an amino acid injection — high branched chain) is supplied in 500 mL single-dose container (NDC No. 0409-4168-03) and 1000 mL single-dose container (NDC No. 0409-4168-05).

Store at 20 to 25°C (68 to 77°F). [See USP Controlled Room Temperature.]Protect from freezing.

Avoid exposure to light.

Revised: June, 2008

Printed in USA	EN-1814
Hospira, Inc., Lake Forest, IL 60045 USA

IM-1002

WR-0306

Aminosyn  isoleucine, leucine, lysine acetate, methionine, phenylalanine, threonine, tryptophan, valine, alanine, arginine, histidine, proline, serine, tyrosine, and glycine  injection, solution

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 0409-4168 Route of Administration INTRAVENOUS DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength ISOLEUCINE (ISOLEUCINE) ISOLEUCINE 789 mg  in 100 mL LEUCINE (LEUCINE) LEUCINE 1576 mg  in 100 mL LYSINE ACETATE (LYSINE) LYSINE 265 mg  in 100 mL METHIONINE (METHIONINE) METHIONINE 206 mg  in 100 mL PHENYLALANINE (PHENYLALANINE) PHENYLALANINE 228 mg  in 100 mL THREONINE (THREONINE) THREONINE 272 mg  in 100 mL TRYPTOPHAN (TRYPTOPHAN) TRYPTOPHAN 88 mg  in 100 mL VALINE (VALINE) VALINE 789 mg  in 100 mL ALANINE (ALANINE) ALANINE 660 mg  in 100 mL ARGININE (ARGININE) ARGININE 507 mg  in 100 mL HISTIDINE (HISTIDINE) HISTIDINE 154 mg  in 100 mL PROLINE (PROLINE) PROLINE 448 mg  in 100 mL SERINE (SERINE) SERINE 221 mg  in 100 mL TYROSINE (TYROSINE) TYROSINE 33 mg  in 100 mL GLYCINE (GLYCINE) GLYCINE 660 mg  in 100 mL

Inactive Ingredients Ingredient Name Strength ACETIC ACID   HYDROCHLORIC ACID

Product Characteristics Color      Score      Shape Size Flavor Imprint Code Contains

Packaging # NDC Package Description Multilevel Packaging 1 0409-4168-03 12 POUCH In 1 CASE contains a POUCH 1 1 BAG In 1 POUCH This package is contained within the CASE (0409-4168-03) and contains a BAG 1 500 mL In 1 BAG This package is contained within a POUCH and a CASE (0409-4168-03) 2 0409-4168-05 6 POUCH In 1 CASE contains a POUCH 2 1 BAG In 1 POUCH This package is contained within the CASE (0409-4168-05) and contains a BAG 2 1000 mL In 1 BAG This package is contained within a POUCH and a CASE (0409-4168-05)

Marketing Information
Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
NDA	NDA019374	08/19/2010

Labeler - Hospira, Inc. (141588017)

Revised: 03/2011Hospira, Inc.

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Diprosone Cream

1. Name Of The Medicinal Product

Diprosone Cream

2. Qualitative And Quantitative Composition

Betamethasone Dipropionate 0.064% w/w*

(* equivalent to 0.05% Betamethasone)

3. Pharmaceutical Form

Cream

4. Clinical Particulars

4.1 Therapeutic Indications

Betamethasone Dipropionate is a synthetic fluorinated corticosteroid. It is active topically and produces a rapid and sustained response in eczema and dermatitis of all types, including atopic eczema, photodermatitis., lichen planus, lichen simplex, prurigo nodularis, discoid lupus erythematosus, necrobiosis lipoidica, pretibial myxodemea and erythroderma. It is also effective in the less responsive conditions such as psoriasis of the scalp and chronic plaque psoriasis of the hands and feet, but excluding widespread plaque psoriasis.

4.2 Posology And Method Of Administration

Adults and Children :

Once to twice daily. In most cases a thin film of Diprosone Cream should be applied to cover the affected area twice daily. For some patients adequate maintenance therapy may be achieved with less frequent application.

Diprosone Cream is especially appropriate for moist or weeping surfaces and the ointment for dry, lichenifield or scaly lesions but this is not invariably so.

Control over the dosage regimen may be achieved during intermittent and maintenance therapy by using Diprobase Cream or Ointment, (PL 0201/0076 and 0201/0075), the base vehicles of Diprosone Cream and Ointment. Such control may be necessary in mild and improving dry skin conditions requiring low dose steroid treatment.

4.3 Contraindications

Rosacea, acne, perioral dermatitis, perianal and genital pruritus. Hypersensitivity to any of the ingredients of the Diprosone presentations contra-indicates their use as does tuberculous and most viral lesions of the skin, particularly herpes simplex, vacinia, varicella. Diprosone should not be used in napkin eruptions, fungal or bacterial skin infections without suitable concomitant anti-infective therapy.

4.4 Special Warnings And Precautions For Use

Local and systemic toxicity is common, especially following long continuous use on large areas of damaged skin, in flexures or with polythene occlusion. If used in children or on the face courses should be limited to 5 days. Long term continuous therapy should be avoided in all patients irrespective of age.

Occlusion must not be used.

Topical corticosteroids may be hazardous in psoriasis for a number of reasons, including rebound relapses following development of tolerance, risk of generalised pustular psoriasis and local systemic toxicity due to impaired barrier function of the skin. Careful patient supervision is important.

General: Systemic absorption of topical corticosteroids can produce reversible HPA axis suppression with the potential for glucocorticosteroid insufficiency after withdrawal of treatment. Manifestations of Cushing's syndrome also can be produced in some patients by systemic absorption of topical corticosteroids while on treatment. Patients receiving a large dose of a potent topical steroid applied to a large surface area should be evaluated periodically for evidence of HPA axis suppression is noted, an attempt should be made to withdraw the drug, to reduce the frequency of application, or to substitute a less potent corticosteroid.

Recovery of HPA axis function is genrally prompt and complete upon discontinuation of the drug. Infrequently, signs and symptoms of steroid withdrawal may occur, requiring supplemental systemic corticosteroids.

Paediatric patients may be more susceptible to systemic toxicity from equivalent doses due to their larger skin surface to body mass ratios.

If irritation develops, treatment should be discontinued and appropriate therapy instituted.

Diprosone is not for ophthalmic use.

Paediatric Use:

Paediatric patients may demonstrate greater susceptibility to topical corticosteroid-induced HPA axis suppression and to exogenous corticosteroid-induced HPA axis suppression and to exogenous corticosteroid effects than adult patients because of greater absortion due to a larger skin surface area to body weight ratio. HPA axis suppression, Cushing's syndrome and tracranial hypertension have been reported in paediatric patients receiving topical corticosteroids. Manifestations of adrenal suppression in paediatric patients include linear growth retardation, delayed weight gain, low plasma cortisol levels and an absence of response to ACTH stimulation. Manifestations of intracranial hypertension include a bulging fontanelle, headaches and bilateral papilledema.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

None stated

4.6 Pregnancy And Lactation

There are no adequate and well controlled studies of the teratogenic potential of topically applied corticosteroids in pregnant women. Therefore topical steroids should be used during pregnancy only if the potential benefit justifies the potential risk to the foetus.

It is not known whether topical administration of corticosteroids would result in sufficient systemic absorption to produce detectable quantities in breast milk. Systemically administered corticosteroids are secreted into breast milk in quantities not likely to have a deleterious effect on the infant. Nevertheless, a decision should be made whether to discontinue the drug, taking into account the importance of the drug to the mother.

4.7 Effects On Ability To Drive And Use Machines

None stated.

4.8 Undesirable Effects

Diprosone skin preparations are generally well tolerated and side-effects are rare. The systemic absorption of betamethasone dipropionate may be increased if extensive body surface areas or skin folds are treated for prolonged periods or with excessive amounts of steroids. Suitable precautions should be taken in these circumstances, particularly with infants and children.

The following local adverse reactions that have been reported with the use of Diprosone include: burning, itching, irritation, dryness, folliculitis, hypertrichosis, acneiform eruptions, hypopigmentation, perioral dermatitis, allergic contact dermatitis, maceration of the skin, secondary infection, striae and miliaria.

Continuous application without interruption may result in local atrophy of the skin, striae and superficial vascular dilation, particularly on the face.

4.9 Overdose

Excessive prolonged use of topical corticosteroids can suppress pituitary-adrenal functions resulting in secondary adrenal insufficiency which is usually reversible. In such cases appropriate symptomatic treatment is indicated. If HPA axis suppression is noted, an attempt should be made to withdraw the drug, reduce the frequency of application, or to substitute a less potent steroid.

The steroid content of each tube is so low as to have little or no toxic effect in the unlikely event of accidental oral ingestion.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Diprosone preparations contain the dipropionate ester of betamethasone which is a glucocorticoid exhibiting the general properties of corticosteroids.

In pharmacological doses, corticosteroids are used primarily for their anti-inflammatory and/or immune suppressive effects.

Topical corticosteroids such as betamethasone dipropionate are effective in the treatment of a range of dermatoses because of their anti-inflammatory, anti-pruritic and vasoconstrictive actions. However, while the physiologic, pharmacologic and clinical effects of the corticosteroids are well known, the exact mechanisms of their action in each disease are uncertain.

5.2 Pharmacokinetic Properties

The extent of percutaneous absorption of topical corticosteroids is determined by many factors including vehicle, integrity of the epidermal barrier and the use of occlusive dressings.

Topical corticosteroids can be absorbed through intact, normal skin. Inflammation and/or other disease processes in the skin may increase percutaneous absorption.

Occlusive dressings substantially increase the percutaneous absorption of topical corticosteroids.

Once absorbed through the skin, topical corticosteroids enter pharmacokinetic pathways similar to systemically administered corticosteroids. Corticosteroids are bound to plasma proteins in varying degrees, are metabolised primarily in the liver and excreted by the kidneys. Some of the topical corticosteroids and their metabolites are also excreted in the bile.

5.3 Preclinical Safety Data

There are no pre-clinical data of relevance to the prescriber which are additional to that already included in other sections of the SPC.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Chlorocresol

Sodium dihydrogen phosphate dihydrate

Phosphoric Acid

White Soft Paraffin

Liquid Paraffin

Cetomacrogol 1000

Cetostearyl Alcohol

Sodium hydroxide

Purified Water

6.2 Incompatibilities

None Known

6.3 Shelf Life

60 months

6.4 Special Precautions For Storage

Do not store above 25°C.

6.5 Nature And Contents Of Container

5, 30 or 100g expoxy-lined aluminium tubes with polypropylene caps.

6.6 Special Precautions For Disposal And Other Handling

Not applicable

7. Marketing Authorisation Holder

Schering-Plough Ltd

Shire Park

Welwyn Garden City

Hertfordshire AL7 1TW

England

8. Marketing Authorisation Number(S)

PL 0201/0072

9. Date Of First Authorisation/Renewal Of The Authorisation

25 July 1997 / 20 October 2008

10. Date Of Revision Of The Text

28 April 2009

11. Legal Category

Prescription Only Medicine

Diprosone Cream/UK/06-09/2

Amoxicillin 500mg Capsules (Sandoz Limited )

1. Name Of The Medicinal Product

Amoxicillin 500 mg capsules

2. Qualitative And Quantitative Composition

1 capsule contains 500 mg amoxicillin (as trihydrate)

For a full list of excipients, see section 6.1

3. Pharmaceutical Form

Capsule, hard

Yellow, opaque capsules with black imprints “Amox 500” axially

4. Clinical Particulars

4.1 Therapeutic Indications

Amoxicillin 500mg capsules are indicated for the oral treatment of the following bacterial infections caused by amoxicillin-sensitive gram-positive and gram-negative pathogens (see section 5.1):

• Infections of the upper respiratory tract, including infections of the ears, nose and throat: Acute otitis media, acute sinusitis and bacterial pharyngitis

• Infections of the lower respiratory tract: Acute exacerbation of chronic bronchitis, community-acquired pneumonia

• Infections of the lower urinary tract: Cystitis

• Endocarditis: Prophylaxis of endocarditis in patients at risk i.e. surgery in the oral cavity or upper airways

Consideration should be given to official local guidance (e.g. national recommendations) on the appropriate use of antibacterial agents.

Susceptibility of the causative organism to the treatment should be tested (if possible), although therapy may be initiated before the results are available.

4.2 Posology And Method Of Administration

Posology

The dosage of amoxicillin is dependent on age, bodyweight and renal function of the patient, on the seriousness and localisation of the infection and on the expected or proved causative agent.

Standard dosage:

Adults and adolescents (> 40 kg body weight):

The usual dosage covers a range from 750 mg to 3g amoxicillin daily in three divided doses. In some areas 1500 mg amoxicillin daily in three divided doses are recommended as the upper usual dose.

Special dosage recommendation

Acute exacerbation of chronic bronchitis in adults: 2 x 1 g per day

Children (under 12 years):

For infants and children oral suspensions containing amoxicillin are recommended.

Dosage for the prevention of endocarditis

For the prevention of endocarditis, in patients not having general anaesthetic, 3 g amoxicillin are given in the hour preceding the surgical procedure, followed by (6 hours later) a further 3 g dose, if considered necessary.

For further details and description of risk patients local official guidelines for the prevention of endocarditis should be consulted.

Dosage in impaired renal function:

The dose should be reduced in patients with severe renal function impairment. In patients with a renal clearance of less than 30 ml/min an increase in the dosage interval or a reduction in the subsequent doses is recommended (see section 4.4). Short course treatments with a single dose of 3 g cannot be given in case of renal failure.

Adults (including elderly patients):
Creatinine clearance ml/min	Dose	Interval between administration
>30	No adjustment necessary
10 – 30	500 mg	12 h
<10	500 mg	24 h
In case of haemodialysis: 500 mg should be administered at the end of the procedure.

Dosage in impaired hepatic function:

No dose reduction is necessary as long as the renal function is not impaired.

Duration of therapy

In general the therapy should be continued for 2 to 3 days following the disappearance of symptoms. In β-haemolytic streptococcal infections the duration of therapy should be at least 10 days in order to achieve eradication of the organism.

Parenteral therapy is indicated if the oral route is considered impracticable or unsuitable, and particularly for the urgent treatment of severe infection.

Method of administration

The preparations are administered orally.

Amoxicillin capsules should be taken, unchewed, with liquid (e.g. a glass of water).

The absorption of amoxicillin is not reduced by food intake.

4.3 Contraindications

Amoxicillin is contraindicated in patients with:

• Hypersensitivity to penicillin; a cross-allergy to other beta-lactams such as cephalosporins should be taken into account.

• Hypersensitivity to any of the other ingredients in the product

4.4 Special Warnings And Precautions For Use

Before initiating therapy with amoxicillin, careful enquiry should be made concerning previous hypersensitivity reactions to penicillins and cephalosporins. The possibility of cross-hypersensitivity (10 % - 15 %) with cephalosporins should be taken into account.

Serious and occasionally fatal hypersensitivity (anaphylactoid) reactions have been reported in patients on penicillin therapy. These reactions are more likely to occur in individuals with a history of hypersensitivity to beta-lactam antibiotics.

Patients suffering from severe gastrointestinal disturbances with diarrhoea and vomiting should not be treated with Amoxicillin , due to the risk of reduced absorption. In these cases a parenteral treatment with amoxicillin is advisable.

Amoxicillin should be used with caution in patients with allergic diathesis and asthma.

In patients with renal function impairment the excretion of amoxicillin will be delayed and, depending on the degree of the impairment, it may be necessary to reduce the total daily dosage (see section 4.2.).

The prolonged use of amoxicillin may occasionally result in an overgrowth of non-susceptible organisms or yeasts. Patients should therefore carefully be watched for superinfections.

The occurrence of anaphylactic shock and other severe allergic reactions is rare following the oral administration of amoxicillin. However, if such reactions occur, appropriate emergency treatment measures must be taken: I.V. administration of epinephrine, followed by antihistaminic drugs, volume substitution and administration of glucocorticoids. Patients should be kept under close observation, and further therapeutic measures (artificial respiration, oxygen) should be administered as required.

The presence of high urinary concentrations of amoxicillin can cause precipitation of the product in urinary catheters. Therefore, catheters should be visually inspected at intervals.

At high doses, adequate fluid intake and urinary output must be maintained to minimise the possibility of amoxicillin crystalluria.

Amoxicillin should be used with caution in patients with viral infections, acute lymphatic leukaemia, or infectious mononucleosis (due to an increased risk of erythematous skin rashes).

Pseudomembranous colitis should be borne in mind if severe persistent diarrhoea occurs (in most cases caused by Clostridium difficile). In this case Amoxicillin should be discontinued and an adequate therapy has to be started. The use of antiperistaltics is contraindicated.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Concomitant use not recommended with:

Allopurinol

Concomitant administration of allopurinol may promote the occurrence of allergic cutaneous reactions and is therefore not advised.

Digoxin

An increase in the absorption of digoxin is possible on concurrent administration with amoxicillin. A dose adjustment of digoxin may be necessary.

Disulfiram

Simultaneous administration of disulfiram is not recommended.

Anticoagulants

Concomitant administration of amoxicillin and anticoagulants from the coumarin class, may prolong the bleeding time. A dose adjustment of anticoagulants may be necessary.

Probenecid

By inhibiting the renal elimination of amoxicillin the concomitant administration of probenecid leads to an increase in the concentrations of amoxicillin in serum and bile.

Other antibiotics

In general amoxicillin should not be combined with bacteriostatic chemotherapeutics/antibiotics (like tetracyclines, macrolids, sulfonamids or chloramphenicol), because in vitro antagonism is observed. When used simultaneously with aminoglycosides a synergistic effect may occur.

Methotrexate

Interaction between amoxicillin and methotrexate leading to methotrexate toxicity has been reported. Serum methotrexate levels should be closely monitored in patients who receive amoxicillin and methotrexate simultaneously. Amoxicillin decreases the renal clearance of methotrexate, probably by competition at the common tubular secretion system.

Caution is recommended when amoxicillin is given concomitantly with:

Oral hormonal contraceptives

Administration of amoxicillin can transiently decrease the plasma level of estrogens and progesterone, and may reduce the efficacy of oral contraceptives. It is therefore recommended to take supplemental non-hormonal contraceptive measures.

Other forms of interactions:

− Forced diuresis leads to a reduction in blood concentrations by increased elimination of amoxicillin.

− The occurrence of diarrhoea may impair the absorption of other medicaments and consequently adversely affect the efficacy.

− It is recommended that when testing for the presence of glucose in urine during amoxicillin treatment, enzymatic glucose oxidase methods should be used. Due to the high urinary concentrations of amoxicillin, false positive readings are common with chemical methods.

− Amoxicillin may decrease the amount of urinary estriol in pregnant women.

− At high concentrations, amoxicillin may diminish the results of serum glycemia levels

− Amoxicillin may interfere with protein testing when colormetric methods are used.

4.6 Pregnancy And Lactation

Amoxicillin passes the placenta and foetal plasma concentrations are approximately 25-30% of the maternal plasma concentrations.

Data on a limited number of exposed pregnancies indicate no adverse effects of amoxicillin on pregnancy or on the health of the foetus/new-born child. To date, no other relevant epidemiological data are available. Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development. Caution should be exercised when prescribing to pregnant women.

Amoxicillin diffuses into the breast milk (approx. 10% of the corresponding serum concentration) and in rare cases this can lead to diarrhoea and/or fungal colonisation of the mucosa in the infant. The possibility of sensitisation of the infant to beta-lactam drugs should also be considered.

4.7 Effects On Ability To Drive And Use Machines

No effects on the ability to drive and use machines have been observed.

4.8 Undesirable Effects

In this section undesirable effects are defined as follows:

Very common
Common
Uncommon
Rare
Very rare	<1/10,000, not known (cannot be estimated from the available data)

Infections and infestations

Uncommon

Superinfections and colonization with resistant organisms or yeasts such as oral and vaginal candidiasis after prolonged and repeated use of amoxicillin.

Blood and the lymphatic system disorders

Rare

Eosinophilia and haemolytic anaemia.

Very rare

Leucopenia, granulocytopenia, thrombocytopenia, pancytopenia, anaemia, myelosuppression, agranulocytosis, prolongation of bleeding time, and prolongation of prothrombin time. All were reversible on discontinuation of therapy.

Immune system disorders

Rare

Laryngeal oedema, serum sickness, allergic vasculitis, anaphylaxis and anaphylactic.

Nervous system disorders

Rare

CNS effects including hyperkinesia, dizziness and convulsions. Convulsions may occur in patients with impaired renal function or in those receiving high doses.

Gastrointestinal disorders:

Common

Gastric complaints, nausea, loss of appetite, vomiting, flatulence, soft stools, diarrhoea, enanthemas (particularly in the region of the mouth), dry mouth, taste disturbances. These effects on the gastrointestinal system are mostly mild and frequently disappear either during the treatment or very soon after completion of therapy. The occurrence of these side effects can generally be reduced by taking amoxicillin during meals.

Rare

Superficial discoloration of the teeth (especially with the suspension). Usually the discoloration can be removed by teeth brushing.

Very rare

If severe and persistent diarrhoea occurs, the very rare possibility of pseudomembranous colitis should be considered. The administration of anti-peristaltic drug is contraindicated.

Development of a black tongue.

Hepato-biliary disorders:

Uncommon

Moderate and transient increase of liver enzymes.

Rare

Hepatitis and cholestatic jaundice.

Skin and subcutaneous tissue disorders:

Common

Cutaneous reactions such as exanthema, pruritus, urticaria; the typical morbilliform exanthema occurs 5 - 11 days after start of therapy. Immediate appearance of urticaria indicates an allergic reaction to amoxicillin and therapy should therefore be discontinued.

Rare (see also section 4.4)

Angioneurotic oedema (Quincke's oedema),erythema multiforme exsudativum, acute generalized pustulosis, Stevens-Johnson syndrome, toxic epidermal necrolysis, bullous and exfoliative dermatitis.

Renal disorders

Rare

Acute interstitial nephritis.

General disorders and administration site conditions

Rare

Drug fever.

4.9 Overdose

Symptoms of overdose:

Amoxicillin is not generally associated with acute toxic effects, even when accidentally consumed in high doses. Overdosage can lead to symptoms such as gastrointestinal disturbances and fluid and electrolyte imbalance. In patients with severely impaired renal function, large overdoses can result in signs of renal toxicity; crystalluria is possible.

Management of overdose:

There is no specific antidote for an overdose of amoxicillin.

Treatment consists primarily of administration of activated charcoal (a gastric lavage is usually not necessary) or symptomatic measures. Particular attention should be paid to the water and electrolyte balance of the patients.

Amoxicillin can be eliminated via haemodialysis.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

General Properties

ATC-Code: J01CA04

Pharmacotherapeutic group: Beta-lactam antibacterials

Mode of action

Amoxicillin is an aminobenzyl penicillin that has a bactericidal action due to its inhibition of the synthesis of the bacterial cell wall.

Mechanism of resistance

Bacteria may be resistant to amoxicillin (and, thus, ampicillin) due to production of beta-lactamases which hydrolyse aminopenicillins (hydrolysis which can be inhibited by clavulanic acid), due to alteration in penicillin-binding proteins, due to impermeability to the drug, or due to drug efflux pumps. One or more of these mechanisms may co-exist in the same organism, leading to a variable and unpredictable cross-resistance to other beta-lactams and to antibacterial drugs of other classes.

Breakpoints (CLSI)

Enterobacteriaceae:	S
Staphylococcus spp.:	S
Haemophilus spp.:	S
Str. pneumoniae:	S

Susceptibility:

The prevalence of resistance may vary geographically and with time for selected species and local information on resistance is desirable, particularly when treating severe infections. As necessary, expert advice should be sought when the local prevalence of resistance is such that the utility of the agent in at least some types of infections is questionable.

Commonly susceptible species

Aerobic Gram-positive Bacillus anthracis Listeria monocytogenes Staphylococcus aureus (beta-lactamase negative, methicillin susceptible) Streptococcus agalactiae Streptococcus bovis Streptococcus pyogenes * Aerobic Gram-negative Neisseria meningitidis Anaerobes Peptostreptococci

Species for which acquired resistance may be a problem

Aerobic Gram-positive Corynebacterium spp Enterococcus faecalis Streptococcus pneumoniae * + Streptococcus viridans Aerobic Gram-negative Haemophilus influenzae * Haemophilus para-influenzae * Neisseria gonorrhoea Proteus mirabilis Anaerobes Bacteroides melaninogenicus Fusobacterium spp

Inherently resistant organisms

Aerobic Gram-positive Staphylococcus (β-lactamase producing strains) Aerobic Gram-negative Acinetobacter spp Citrobacter spp Enterobacter spp Escherichia coli Klebsiella spp Moraxella catarrhalis * Proteus spp (indol positive) Proteus vulgaris Providencia spp Pseudomonas spp Serratia spp Anaerobes Bacteroides fragilis Others Chlamydia Mycoplasma Rickettsia

* Clinical efficacy has been demonstrated for susceptible isolates in approved clinical indications

+ Rates of resistance vary within Europe

5.2 Pharmacokinetic Properties

Absorption:

The absolute bioavailability of amoxicillin depends on the dose and ranges between 75 and 90%. In the dose range between 250 mg and 750 mg the bioavailability (parameters: AUC and/or recovery in urine) is linearly proportional to the dose. At higher doses the extent of absorption decreases. The absorption is not affected by concomitant food intake. Oral administration of a single dose of 500 mg amoxicillin results in plasma concentrations of 6 - 11 mg/l. After administration of a single dose of 3 g amoxicillin, the plasmaconcentrations reach 27 mg/l. Peak plasma concentrations are present about 1-2 hours after administration.

Distribution:

Protein binding for amoxicillin is approximately 17%. Therapeutic drug levels are rapidly achieved in serum, lung tissue, bronchial secretions, middle ear fluid, bile and urine. In healthy meninges amoxicillin diffuses badly in liquor cerebrospinalisis. In inflamed meninges the concentration can reach approximately 20% of the concentration in blood. Amoxicillin crosses the placenta and a small percentage is excreted into the breast milk.

Biotransformation and elimination:

The main route of excretion of amoxicillin is the kidney. About 60-80% of an oral dose of amoxicillin are excreted in unchanged active form in the urine within 6 hours of administration, and a small fraction is excreted in the bile. Approximately 7 - 25% of the administered dose is metabolised to inactive penicilloic acid. The serum half-life in patients with normal renal function is approximately 1 – 1,5 hour. In patients with end-stage renal failure the half-life ranges between 5 to 20 hours. The substance is haemodialysable.

5.3 Preclinical Safety Data

Preclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity and toxicity to reproduction.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Content:	Magnesium stearate
	Cellulose, microcrystalline
Shell:	Yellow iron oxide (E172)
	Titanium dioxide (E171)
	Gelatin
Black printing ink:
	Propylene Glycol
	Shellac
	Black iron oxide (E172)

6.2 Incompatibilities

Not applicable.

6.3 Shelf Life

4 years

6.4 Special Precautions For Storage

Do not store above 25 °C.

6.5 Nature And Contents Of Container

Nature:	Blister consisting of a clear polyvinyl chloride foil with a coating of polyvinylidene chloride (PVC/PVDC) 236 µm and aluminium foil 20 µm.
Contents:	Amoxicillin 500 mg Capsules:

single packs for 10, 12, 16, 20, 21, 24, 30 and 100 capsules

hospital packs for 500 and 1000 capsules

Not all pack sizes may be marketed.

6.6 Special Precautions For Disposal And Other Handling

No special requirements.

7. Marketing Authorisation Holder

Sandoz Ltd

Frimley Business Park,

Frimley,

Camberley,

Surrey,

GU16 7SR.

United Kingdom

8. Marketing Authorisation Number(S)

PL 04416/0577

9. Date Of First Authorisation/Renewal Of The Authorisation

18.02.1998 / 14.09.2005

10. Date Of Revision Of The Text

November 2010

InfectoBicillin

InfectoBicillin may be available in the countries listed below.

Ingredient matches for InfectoBicillin

Phenoxymethylpenicillin

Phenoxymethylpenicillin benzathine (a derivative of Phenoxymethylpenicillin) is reported as an ingredient of InfectoBicillin in the following countries:

• Germany

International Drug Name Search

Cefalexin 500mg Capsules

1. Name Of The Medicinal Product

Cefalexin Capsules BP 500mg

2. Qualitative And Quantitative Composition

500 mg Cefalexin (as monohydrate)

For excipients, see 6.1

3. Pharmaceutical Form

Capsules, hard

Size 0 grey/orange capsule containing white powder printed CHX 500.

4. Clinical Particulars

4.1 Therapeutic Indications

Cefalexin is indicated in the treatment of the following infections due to susceptible micro-organisms: respiratory tract infections; otitis media; skin and soft tissue infections; bone and joint infections; genito-urinary infections, including acute prostatitis; dental infections.

Cefalexin is active against the following organisms in vitro: beta-haemolytic streptococci; staphylococci, including coagulase-positive, coagulase-negative and penicillinase-producing strains; streptococcus pneumoniae; escherichia coli; proteus mirabilis; klebsiella species, haemophilus influenzae; branhamella catarrhalis.

Most strains of enterococci (streptococcus faecalis) and a few strains of staphylococci are resistant to cefalexin. It is not active against most strains of enterobacter species, morganella morganii and pr. Vulgaris. It has no activity against pseudomonas or herellea species. When tested by in vitro methods, staphylococci exhibit cross-resistance between cefalexin and methicillin-type antibiotics.

4.2 Posology And Method Of Administration

Adults

The adult dosage ranges from 1-4 g daily in divided doses; most infections will respond to a dosage of 500 mg every 8 hours. For skin and soft tissue infections, streptococcal pharyngitis and mild, uncomplicated urinary tract infections, the usual dosage is 250 mg every 6 hours, or 500 mg every 12 hours. For more severe infections or those caused by less susceptible organisms, larger doses may be needed. If daily doses of cefalexin greater than 4g are required parenteral cephalosporins, in appropriate doses, should be considered.

Elderly

As for adults. Reduce dosage if renal function is markedly impaired.

Children

The usual recommended daily dosage for children is 25-50mg/kg (10-20mg/lb) in divided doses. For skin and soft tissue infections, streptococcal pharyngitis and mild, uncomplicated urinary tract infections, the total daily dose may be divided and administered every 12 hours. For most infections the following schedule is suggested:

Children under 5 years:	125mg every 8 hours.
Children 5 years and over:	250mg every 8 hours.

In severe infections, the dosage may be doubled. In the therapy of otitis media, clinical studies have shown that a dosage of 75-100mg/kg/day in 4 divided doses is required: In the treatment of beta-haemolytic streptococcal infections, a therapeutic dose should be administered for at least 10 days.

Route of administration

Oral

4.3 Contraindications

Cefalexin is contraindicated in patients with known allergy to the cephalosporins group of antibiotics.

Cefalexin should be given cautiously to patients who have shown hypersensitivity to other drugs. Cephalosporins should be given with caution to penicillin

Cefalexin is contraindicated in patients with porphyria.

4.4 Special Warnings And Precautions For Use

If an allergic reaction to cefalexin occurs the drug should be discontinued and the patient treated with the appropriate agents. Prolonged use of cefalexin may result in the overgrowth of non

Cefalexin should be administered with caution in the presence of markedly impaired renal function. Careful clinical and laboratory studies should be made because safe dosage may be lower than that usually recommended.

A false positive reaction for glucose in the urine may occur with Benedict's or Fehling's solutions or with copper sulphate test tablets.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Probenecid causes reduced excretion of cefalexin, leading to increased plasma concentration.

4.6 Pregnancy And Lactation

Although laboratory and clinical studies have shown no evidence of teratogenicity, caution should be exercised when prescribing for the pregnant patient.

Usage in nursing mothers: The excretion of cefalexin in human breast milk increased up to 4 hours following a 500mg dose. The drug reached a maximum level of 4 micrograms/ml then decreased gradually and had disappeared 8 hours after administration. Caution should be exercised when cefalexin is administered to a nursing woman.

4.7 Effects On Ability To Drive And Use Machines

Not applicable.

4.8 Undesirable Effects

Gastro-intestinal-nausea, vomiting, dyspepsia, and abdominal pain have occurred. Diarrhoea has been reported infrequently. It is rarely severe enough to warrant cessation of therapy. Colitis, including rare instances of pseudomembranous colitis, has been reported.

Hypersensitivity - Allergies (in the form of rash, urticaria and angio-oedema), and rarely erythema multiforme, Stevens-Johnson syndrome and toxic epidermal necrolysis have been observed. These reactions usually subside upon discontinuation of the drug. Anaphylaxis has also been reported.

Haematological - eosinophilia, neutropenia, thrombocytopenia and positive Coombe's test have been reported.

Hepatic - slight elevations of AST and ALT have been observed. As with some penicillins and some other cephalosporins, transient hepatitis and cholestatic jaundice have been reported rarely.

Miscellaneous - other reactions have included genital and anal pruritus, genital moniliasis, vaginitis and vaginal discharge, dizziness, fatigue, headache, agitation, confusion, hallucinations, arthralgia, arthritis and joint disorder. Reversible interstitial nephritis has been reported rarely.

4.9 Overdose

Symptoms of overdosage may include nausea, vomiting, epigastric distress, diarrhoea and haematuria.

Treatment of overdosage

In the event of severe overdosage, general supportive care is recommended including close clinical and laboratory monitoring of haematological, renal and hepatic functions and coagulation status until the patient is stable.

Unless 5 - 10 times the normal total daily dose has been ingested, gastro-intestinal decontamination should not be necessary.

There have been reports of haematuria without impairment of renal function in children accidentally ingesting more than 3.5g of cefalexin in a day. Treatment has been supportive (fluids) and no sequence have been reported.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Cefalexin is bactericidal and has antimicrobial activity similar to that of cephaloridine or cephalothin against both gram-positive and gram-negative organisms.

5.2 Pharmacokinetic Properties

Cefalexin is almost completely absorbed from the gastro-intestinal tract and produces peak plasma concentrations about 1 hour after administration. A dose of 500 mg produces a mean peak plasma concentration of about 18 micrograms per ml, about the same as the concentration produced by an equal dose of cephaloridine given intramuscularly and greater than that produced by cephalothin. If cefalexin is taken with food there is delayed and slightly reduced absorption and there may be delayed elimination from the plasma. About 10 to 15% of a dose is bound to plasma proteins.

The biological half-life has been reported to range from 0.6 to at least 1.2 hours and this increases with reduced renal function. About 80% or more of a dose is excreted unchanged in the urine in the first 6 hours by glomerular filtration and tubular secretion; urinary concentrations greater than 1 mg per ml have been achieved after a dose of 500 mg. Probenecid delays urinary excretion and has been reported to increase biliary excretion. Cefalexin is widely distributed in the body but does not enter the cerebrospinal fluid in significant quantities unless the meninges are inflamed. It diffuses across the placenta and small quantities are found in the milk of nursing mothers. Therapeutically effective concentrations may be found in the bile.

5.3 Preclinical Safety Data

Not applicable

6. Pharmaceutical Particulars

6.1 List Of Excipients

Lactose

Magnesium stearate

Capsule shell

Black iron oxide (E172)

Titanium dioxide (E171)

Erythrosin (E127)

Quinoline yellow (E104)

Gelatin

6.2 Incompatibilities

None known.

6.3 Shelf Life

36 months.

6.4 Special Precautions For Storage

Do not store above 25^°C.

Keep the container tightly closed (for bottles).

Store in the original package (for blisters).

6.5 Nature And Contents Of Container

Each container consists of a polypropylene tubular container with an open end equipped to accept a polyethylene closure, with a tamper-evident tear strip, or PVC/aluminium blisters, or PVDC coated PVC/ Aluminium blisters (60g/m² PVDC on 250μm PVC/20μm Al) of an appropriate size to accomodate 7, 14, 20, 21, 28, 30, 50, 56, 60, 100, or 500 capsules. Not all pack sizes may be marketed.

6.6 Special Precautions For Disposal And Other Handling

No special instructions

7. Marketing Authorisation Holder

Milpharm Limited,

Ares,

Odyssey Business Park,

West End Road,

South Ruislip HA4 6QD,

United Kingdom

8. Marketing Authorisation Number(S)

PL 16363/0119

9. Date Of First Authorisation/Renewal Of The Authorisation

04/03/2009

10. Date Of Revision Of The Text

04/03/2009