CO-FLUAMPICIL CAPSULES - summary of medicine characteristics

1 NAME OF THE MEDICINAL PRODUCT

Co-fluampicil Capsules

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Ampicillin Trihydrate BP 288.71 mg (equivalent to 250 mg Ampicillin) and Flucloxacillin Sodium BP 272.00 mg (equivalent to 250 mg Flucloxacillin) per capsule.

3. PHARMACEUTICAL FORM

Co-fluampicil capsules are presented as size 0, powder blue opaque (body)/black opaque (cap) capsules printed with company logo and co-fluam.

4. CLINICAL PARTICULARS

4.1 Therapeutic Indications

Ampicillin/flu­cloxacillin is indicated for the treatment of severe infections where the causative organism is unknown and for mixed infections involving 0 Lactamase producing staphylococci. Typical indications include:

In General Practice

Chest infections, ENT infections, skin and soft tissue infections and infections in patients whose underlying pathology places them at special risk.

In hospital (prior to laboratory results being available):

Severe respiratory tract infections. Post operative chest and wound infections. Septic abortion, puerperal fever. Septicaemia prophylaxis in major surgery. Infections in patients receiving immuno suppressive therapy.

4.2 Posology and method of administrationAdults (including elderly) and children over 10 years:

One capsule to be taken four times daily.

Half the usual adult dose, using a Co-fluampicil Syrup

The above doses for adults and children may be doubled where necessary.

Co-fluampicil Capsules, should be taken at least 1 hour before or 2 hours after meals.

The capsules should be taken with a full glass of water (250 ml), to reduce the risk of oesophageal pain (see section 4.8).

Patients should not lay down immediately after Co-fluampicil Capsules, intake.

4.3 Contra-indications

Patients with a history of hypersensitivity to P-lactam antibiotics ie. penicillins, cephalosporins or to any of the excipients.

Patients with a history of flucloxacillin-associated jaundice/hepatic dysfunction.

Patients with porphyria.

4.4 Special warnings and precautions for use

Before initiating therapy with Co-fluampicil careful enquiries should be made concerning previous hypersensitivity to ß-lactam antibiotics. Serious and occasionally fatal hypersensitivity reactions (anaphylaxis) have been reported in patients receiving ß-lactam antibiotics. Although anaphylaxis is more frequent following parenteral therapy, it has occurred in patients on oral therapy. These reactions are more likely to occur in individuals with a hypersensitivity to ß-lactam antibiotics.

The occurrence at the treatment initiation of a feverish generalised erythema associated with pustula may be a symptom of acute generalised exanthematous pustulosis (AGEP) (see section 4.8). In case of AGEP diagnosis, flucloxacillin should be discontinued and any subsequent administration of flucloxacillin contra- indicated.

Co-fluampicil contains ampicillin and should be avoided if infectious mononucleosis and/or acute or chronic leukaemia of lymphoid origin are suspected. The occurrence of a skin rash has been associated with these conditions following the administration of ampicillin.

In case of severe and persistent diarrhoea, the possibility of pseudomembranous colitis should be considered; flucloxacillin therapy should be discontinued.

Care is required when treating some patients with spirochaete infections such as syphilis or leptospirosis because the Jarisch-Herxheimer reaction may occur shortly after treatment with a penicillin is started.

Co-fluampicil should be used with caution in patients with evidence of hepatic dysfunction (see section 4.8).

Care is necessary if very high doses of flucloxacillin are given, especially if renal function is poor, because of the risk of nephrotoxicity and/or neurotoxicity. Care is also necessary if large doses of sodium (salts) are given to patients with impaired renal function or heart failure. Flucloxacillin should be used with caution in patients with evidence of hepatic dysfunction (see section 4.8). Renal, hepatic and haematological status should be monitored during prolonged and high-dose therapy (e.g. osteomyelitis, endocarditis). Prolonged use may occasionally result in overgrowth of non-susceptible organisms.

Caution is advised when flucloxacillin is administered concomitantly with paracetamol due to the increased risk of high anion gap metabolic acidosis (HAGMA). Patients at high risk for HAGMA are in particular those with severe renal impairment, sepsis or malnutrition especially if the maximum daily doses of paracetamol are used.

After co-administration of flucloxacillin and paracetamol, a close monitoring is recommended in order to detect the appearance of acid-base disorders, namely HAGMA, including the search of urinary 5-oxoproline.

If flucloxacillin is continued after cessation of paracetamol, it is advisable to ensure that there are no signals of HAGMA, as there is a possibility of flucloxacillin maintaining the clinical picture of HAGMA (see section 4.5).

Hypokalaemia (potentially life threatening) can occur with the use of flucloxacillin, especially in high doses. Hypokalaemia caused by flucloxacillin can be resistant to potassium supplementation. Regular measurements of potassium levels are recommended during the therapy with higher doses of flucloxacillin. Attention for this risk is warranted also when combining flucloxacillin with hypokalemia-inducing diuretics or when other risk factors for the development of hypokalemia are present (e.g. malnutrition, renal tubule disfunction).

Sodium content: Each capsule contains 13mg of sodium. To be taken into consideration by patients on a controlled sodium diet.

4.5 Interaction with other medicinal products and other forms of interaction

Food may interfere with the absorption of ampicillin/flu­cloxacillin, doses should therefore be taken thirty minutes to one hour before meals.

The efficacy of oral contraceptives may be reduced and patients should be warned accordingly.

Other antibacterials: There may be antagonism between penicillins, including ampicillin, and bacteriostatic agents such as chloramphenicol, erythromycins or tetracyclines. This may reduce the effectiveness of penicillins particularly in the treatment of infections such as pneumococcal meningitis and scarlet fever.

Probenecid decreases renal tubular secretion when administered concurrently resulting in increased and prolonged blood levels of both flucloxacillin and ampicillin.

Concurrent administration of allopurinol during treatment with ampicillin can increase the likelihood of allergic skin reactions.

Cytotoxics: Penicillins reduce the excretion of methotrexate. (increased risk of toxicity).

Interference with diagnostic tests: Penicillins may produce false-positive results with the direct antiglobulin (Coombs’) test, falsely high urinary glucose results with the copper sulphate test and falsely high urinary protein results, but glucose enzymatic tests (e.g. Clinistix) and bromophenol blue tests (e.g. Multistix or Albustix) are not affected.

Caution should be taken when flucloxacillin is used concomitantly with paracetamol as concurrent intake has been associated with high anion gap metabolic acidosis, especially in patients with risk factors. (see section 4.4.).

4.6 Use during pregnancy and lactation

Pregnancy: The safety of ampicillin/flu­cloxacillin combination product in human pregnancy has not been fully established. Animal studies have shown no teratogenic effects. The product may be used in pregnancy only if considered essential by the physician.

Lactation: Trace quantities of ampicillin and flucloxacillin can be detected in breast milk and hence the possibility of hypersensitivity reactions including skin rashes and diarrhoea in breast-fed infants must be considered. Therefore Co-fluampicil should only be administered to a breast-feeding mother when the potential benefit outweighs the potential risk.

4.7 Effects on Ability to Drive and Use Machines

None reported

4.8 Undesirable effectsBlood and lymphatic system disorders:

Haematological effects including reversible leucopenia, reversible thrombocytopenia and haemolytical anaemia have been reported rarely. Prolongation of bleeding time and prothrombin time have been reported rarely.

Anaphylaxis has been reported rarely (see 4.4 Special warnings and precautions).

If any hypersensitivity reactions occur, treatment should be discontinued.

Late sensitivity reactions may include serum sickness-like reactions (featuring symptoms such as arthralgia, rash, urticaria, fever, angioedema, lymphadenopathy), haemolytic anaemia and acute interstitial nephritis.

Electrolyte disturbances, such as hypokalaemia (frequency not known – cannot be estimated from the available data), due to administration of large amounts of sodium.

Post marketing experience: very rare cases of high anion gap metabolic acidosis, when flucloxacillin is used concomitantly with paracetamol, generaly in the presence of risk factors (see section 4.4.).

There is a potential for hallucinations to occur rarely with flucloxacillin.

Convulsions and other signs of CNS toxicity to the CNS may occur with high doses, particularly in infants and the elderly.

Coma may develop with high doses of flucloxacillin.

Bronchospasm may occur as a result of penicillin allergy.

There is a potential for acute, severe dyspnoea to occur with flucloxacillin.

Minor gastrointestinal disturbances, including occasionally nausea, vomiting and diarrhoea may occur during treatment.

Pseudomembranous colitis has been reported rarely.

Not known frequency (cannot be estimated from available data):

*Oesophageal pain and related events

Oesophagitis, burn oesophageal, throat irritation, oropharyngeal pain or oral pain.

Hepatitis and cholestatic jaundice have been reported rarely. These may be delayed for up to two months after withdrawal of treatment. In some cases the course of these conditions has been protracted and lasted for several months.

Very rarely deaths have been reported from hepatic effects but are mostly limited to patients with serious underlying disease.

As with most other antibiotics, a moderate transient increase in transaminases has been reported.

Skin rash, pruritis and urticaria have been reported. The incidence of rash is higher in patients suffering from infectious mononucleosis and acute or chronic leukaemia of lymphoid origin. Purpura, fever and eosinophilia and sometimes angioneurotic oedema have also been reported. Rarely, skin

reactions such as erythema multiforme, Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported. Reactions such as fever, arthralgia and myalgia can develop more than 48 hours after the start of the treatment.

Frequency not known: AGEP – acute generalized exanthematous pustulosis (see section 4.4)

Erythema nodosum may occur rarely with flucloxacillin.

Potential for pemphigoid reactions to occur rarely with flucloxacillin.

There is potential for non-thrombocytopenic purpura to occur rarely with flucloxacillin.

Vasculitis may occur rarely with flucloxacillin.

Interstitial nephritis may occur but it is reversible when treatment is discontinued.

Potential for acute attacks of porphyria to occur with flucloxacillin.

Some patients with spirochaete infections such as syphilis or leptospirosis may experience a Jarisch-Herxheimer reaction shortly after treatment with a penicillin is started. Symptoms include fever, chills, headache and reaction at the site of lesions. The reaction can be dangerous in cardiovascular syphilis or where there is a serious risk of increased local damage such as with optic atrophy.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

4.9 Overdose

Gastrointestinal effects such as nausea, vomiting and diarrhoea may be evident and should be treated symptomatically.

Co-fluampicil contains flucloxacillin – haemodialysis does not lower the serum levels of flucloxacillin.

Co-fluampicil contains ampicillin, which may be removed from the circulation by haemodialysis.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic Properties

Ampicillin

Ampicillin is a broad spectrum penicillin for the treatment of a wide range of infections caused by ampicillin-sensitive organisms.

Ampicillin is bactericidal. This action depends on the ability to reach and bind penicillin-binding proteins located in bacterial cytoplasmic membranes. It inhibits bacterial septum and cell wall synthesis, probably by acylation of the transpeptidase enzyme. Transpeptidase is a membrane bound bacterial enzyme responsible for cross-linking of peptidoglycan during the final stage of synthesis of bacterial cell wall hence, cross-linkage of peptidoglycan chains is prevented which is necessary for bacterial cell wall strength and rigidity.

Therefore bacterial cell division and growth are inhibited and lysis and elongation of susceptible bacterial frequently occur. Rapidly dividing bacteria are those growth produce an enzyme penicillinase which inhibits the action of ampicillin.

Minimum inhibitory concentrations for gram-positive organisms have been reported to range from 0.2 to 5 microgram per ml and for gram-negative organisms from 0.02 to 8 microgram per ml. It is inactive against most strains of pseudomonas aeruginosa. Ampicillin is acid stable and may be administered orally. An oral dose of 500 mg produces a peak blood level in one to three hours of about 4 mcg/ml and detectable amounts persist for about six hours. It is widely distributed in the tissues. Within six hours of administration about 30 % of the dose is excreted, for the most part unchanged in the urine, while a concentration at least ten times in excess of plasma levels may be obtained in bile.

Ampicillin crosses the intact meninges in only minute amounts. In bacterial meningitis, higher concentrations are found in the cerebrospinal fluid. Pregnant women given ampicillin may have therapeutic levels of the drug in the amniotic fluid in the later stages of pregnancy.

Flucloxacillin

Flucloxacillin sodium is a bactericidal antibiotic. Chemically, it is similar to dicloxacillin, one of the chlorine atoms replaced by fluorine. It has virtually the same antibacterial spectrum as cloxacillin and its analogues. The main advantage of flucloxacillin is its better absorption after oral administration, peak serum levels being almost double those obtained with cloxacillin after similar doses.

It is a penicillinase – resistant penicillin and is effective only in the treatment of infections caused by pneumococci, group a beta-haemolytic streptococci, and penicillin G-resistant and penicillin G-sensitive staphylococci.

The mechanism of action depends on ability to reach and bind penicillin binding proteins located in bacterial cytoplasmic membranes. This inhibits bacterial septum and cell wall synthesis probably by acylation of membrane bound transpeptidase enzymes. This prevents cross-linkage of peptidoglycan chains which is necessary for bacterial cell wall strength and rigidity. Cell division and growth are also inhibited and lysis and elongation of susceptible bacterial frequently occur.

5.2 Pharmacokinetic Properties

Ampicillin

Ampicillin is incompletely absorbed from the gastrointestinal tract after oral administration. About 32–53 percent is absorbed. It is stable in acid gastric secretion. Whereas absorption efficiency appears to be independent of dose up to 1000 mg, food appears to delay the onset and reduce the total amount absorbed. Ampicillin should therefore be administered ~ – 1 hour before meals. Peak serum concentration is attained in about two hours and following an oral dose of 500 mg it may range between 2 – 6 mcg/ml.

Protein binding of ampicillin is low. About 20 percent is bound to plasma proteins in circulation and plasma half-life is 1 – 2 hours.

It is widely distributed in most body fluids and bone. Penetration into cells, the eyes and across normal menninges is poor. Inflammation increases the amount which crosses the blood brain barrier. Ampicillin crosses the placenta and appears in cord blood and amniotic fluid. It does not penetrate and is not bound to human erythrocyte.

Ampicillin serum levels in pregnant women are approximately one-half those in non-pregnant women after a comparable dose but urinary recoveries appear similar. Therefore renal clearance rate is doubled during pregnancy. Ampicillin levels in the placenta and umbilical blood are the same as those in maternal serum. Serum clearance in the newborn is about one-half to two-third that of an adult with normal kidney function. Serum half-life is about 2.2 H in infants 2–5 days old, 3.4 H in those under one day and 1.1 H in those older than four months.

About 12–50 per cent is metabolised by the liver. Ampicillin is excreted by the kidneys both as a result of tubular secretion and glomerular filtration. The amount excreted by glomerular filtration depends on the extent of protein binding. Renal concentration range between one-half and twice those in serum and appears to be uniformly distributed among the cortex, medulla and papilla. Within six hours of administration about thirty percent of the dose is excreted for most part unchanged in the urine, about twenty percent of oral dose is excreted in the urine as penicilloic acid. Small amount of ampicillin is excreted in bile and milk.

Concomitant probenecid administration effectively reduces the renal clearance of ampicillin to that of glomerular filtration rate, the net effect is to increase mean serum concentrations by a factor of two and to decrease urinary recovery by 18 percent. Concomitant administration of oxacillin or cimetidine has no effect on ampicillin absorption, biotransformation or excretion.

Flucloxacillin

Flucloxacillin is rapidly but incompletely absorbed from the gastro-intestinal tract.

Flucloxacillin is better absorbed from the gastro-intestinal tract than cloxacillin. Its absorption is reduced by food both in stomach and the small intestine.

After an oral dose of 250 to 500 mg, peak serum concentrations are attained within an hour and range between 3 – 27 micrograms per ml with mean peak concentration being 11–15 micrograms per ml. Therapeutic concentration persists for 4 hours. About 95 per cent is bound to plasma proteins. About 50 per cent of the oral dose is excreted in the urine within 6 hours. There is also significant hepatic elimination of flucloxacillin in the bile.

The half life is between 30 and 60 minutes.

5.3

Preclinical safety data

Not applicable

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Sodium Starch Glycolate

Magnesium Stearate

Capsule Body

Erythrosine (El27)

Patent Blue V (E131)

Titanium Dioxide (El71)

Water

Sodium Laurilsulfate

Gelatin

Capsule Cap

Black Iron Oxide (E172)

Titanium Dioxide (E171)

Water

Sodium Laurilsulfate

Gelatin

Printing Ink

Titanium Dioxide (E171)

Polyoxyethylene 20 Sorbitan Mono-oleate

Shellac

6.2 Incompati­bilities

Incompatibilities with colistin sulphomethate sodium, gentamicin, kanamycin and polymyxin

B sulphate. Loss of potency after mixing with streptomycin has also been reported.

6.3 Shelf Life

3 years

6.4 Special Precautions for Storage

Protect from heat, light and moisture.

Keep out of the reach of children.

6.5 Nature and Contents of Container

1. Opaque plastic containers with plastic caps in pack sizes of 9, 10, 14, 15, 20, 21, 28, 30, 50, 56, 84, 100, 250, 500, 1000 and bulk capsules.

2. Opaque plastic containers composed of either high density polypropylene or high density polyethylene with a tamper-evident or child-resistant tamper-evident closure composed of high density polyethylene with a packing inclusion of polyether foam or polyethylene or polypropylene filler in pack sizes of 9, 10, 14, 15, 20, 21, 28, 30, 50, 56, 84, 100, 250, 500, 1000 and bulk capsules.

3. Opaque plastic containers composed of either high density polypropylene or high density polyethylene with a silica gel sachet inclusion, a laminated aluminium foil seal and a tamper-evident or child-resistant tamper-evident screw-cap composed of high density polyethylene in pack sizes of 9, 10, 14, 15, 20, 21, 28, 30, 50, 56, 84, 100, 250, 500, 1000 and bulk capsules.

4. Blister packs of aluminium/opaque PVC in pack sizes of 9, 10, 14, 15, 20, 21, 28, 30, 56 and 84 capsules.

6.6 Special precautions for disposal

No special instructions for use/handling.

7 MARKETING AUTHORISATION HOLDER

Crescent Pharma Limited

Units 3 and 4, Quidhampton Business Units

Polhampton Lane

Overton

Hampshire

RG25 3ED

8. MARKETING AUTHORISATION NUMBER

PL 20416/0051

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

30/01/2009

10