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CO-FLUAMPICIL CAPSULES

Active substance(s): AMPICILLIN TRIHYDRATE COMPACTED / FLUCLOXACILLIN SODIUM COMPACTED

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SUMMARY OF PRODUCT 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 β 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 administration
Adults (including elderly) and children over 10 years:
One capsule to be taken four times daily.
Children under 10 years:
Half the usual adult dose, using a Co-fluampicil Syrup
The above doses for adults and children may be doubled where necessary.
Oral doses should be administered ½ - 1 hour before meals

Route of administration: Oral

4.3

Contra-indications
Patients with a history of hypersensitivity to β-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 β-lactam antibiotics. Serious and occasionally fatal
hypersensitivity reactions (anaphylaxis) have been reported in patients receiving β-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 β-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).
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 effects
Blood 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.
Immune system disorders:
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.
Metabolism and nutrition disorders:
Electrolyte disturbances, such as hypokalaemia, 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.).
Psychiatric disorders:
There is a potential for hallucinations to occur rarely with flucloxacillin.
Nervous system disorders:
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.
Respiratory, thoracic and mediastinal disorders:
Bronchospasm may occur as a result of penicillin allergy.
There is a potential for acute, severe dyspnoea to occur with flucloxacillin.
Gastrointestinal disorders:
Minor gastrointestinal disturbances, including occasionally nausea, vomiting and diarrhoea
may occur during treatment.
Pseudomembranous colitis has been reported rarely.
Hepatobiliary disorders:

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 and subcutaneous tissue disorders
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.
Renal and urinary disorders:
Interstitial nephritis may occur but it is reversible when treatment is discontinued.
Congenital, familial and genetic disorders:
Potential for acute attacks of porphyria to occur with flucloxacillin.
General disorders and administration site conditions:
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 of suspected adverse reactions:
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 penicillinbinding 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 onehalf 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 onehalf 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 tamperevident 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.

6.6

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

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

DATE OF REVISION OF THE TEXT
05/01/2018

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Source: Medicines and Healthcare Products Regulatory Agency

Disclaimer: Every effort has been made to ensure that the information provided here is accurate, up-to-date and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. This information has been compiled for use by healthcare practitioners and consumers in the United States. The absence of a warning for a given drug or combination thereof in no way should be construed to indicate that the drug or combination is safe, effective or appropriate for any given patient. If you have questions about the substances you are taking, check with your doctor, nurse or pharmacist.

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