Cefadroxil 500mg Capsules

Document: spc-doc_PL 04416-0433 change

SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Cefadroxil 500 mg Capsules

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

One capsule contains 500mg of cefadroxil (as monohydrate)

For a full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Capsules, hard

Description: white, opaque capsule containing white to slightly yellowish powder

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

Treatment of following infections caused by cefadroxil-susceptible organisms, when an oral therapy is indicated:

- Streptococcal pharyngitis and tonsillitis

- Bronchopneumonia, bacterial pneumonia

- Urinary tract infections: pyelonephritis, cystitis

- Skin and soft tissue infections: abscesses, furunculosis, impetigo, erysipelas, pyoderma, lymphadenitis

Consideration should be given to official local guidance regarding the appropriate use of antibacterial agents.

Regarding treatment of meningitis, Streptococcus pyogenes infections and prevention of rheumatic fever see (4.4. Special warnings and precautions for use)

4.2 Posology and method of administration

The dosage depends on the susceptibility of the pathogens, the severity of the disease and on the clinical status of the patient (renal and hepatic function).

Indication	Adults and adolescents > 40 kg with normal renal function	Children (< 40 kg) with normal renal function
Streptococcal pharyngitis / tonsillitis	Dosage may be decreased to 1000 mg once a day over at least 10 days	30 mg/kg/day once a day over at least 10 days
Bronchopneumonia, bacterial pneumonia	1000 mg twice a day	30-50 mg/kg/day divided into two daily doses
Urinary tract infections	1000 mg twice a day	30-50 mg/kg/day divided into two daily doses
Skin & soft tissue infections	1000 mg twice a day	30-50 mg/kg/day divided into two daily doses

Children may benefit of increased posology up to 100 mg/kg/day.

Depending on the severity of the infection, adults may require increased posology.

Chronic urinary tract infection may require a prolonged and intensive treatment with continued testing of susceptibility and clinical monitoring.

For children (< 40 kg) with normal renal function, liquid oral forms are available.

• Dosage in renal insufficiency

The dosage should be adjusted according to creatinine clearance rates to prevent accumulation of cefadroxil. In patients with creatinine clearance of 50 ml/min or less, the following reduced dosage schedule is recommended as a guideline for adults:

Creatinine clearance (ml/ min/ 1.73 2 m)	Serum Creatinine (mg/100ml)	Initial dose	Following dose	Dosage interval
50 - 25	1.4 - 2.5	1000	500 mg - 1000	every	12
		mg	mg	hours
25 - 10	2.5 - 5.6	1000	500 mg - 1000	every	24
		mg	mg	hours
10 - 0	> 5.6	1000	500 mg - 1000	every	36
		mg	mg	hours

• Children (< 40 kg) with renal insufficiency

Cefadroxil is not indicated in children suffering from renal insufficiency and children requiring haemodialysis.

Dosage for haemodialysis patients

Haemodialysis eliminates 63% of 1000 mg of cephalosporin after 6 to 8 hours of haemodialysis. Elimination half-time of cephalosporin is about 3 hours during dialysis.

Patients with haemodialysis receive one additional dose of 500 mg - 1000 mg at the end of the haemodialysis.

• Dosage in hepatic insufficiency

No adjustment of posology is necessary.

• Elderly

As cefadroxil is excreted by renal route, the dosage should be adjusted if necessary as described under impaired renal function.

Mode of administration

Bioavailability is not affected by food and cefadroxil may be taken with meals or on an empty stomach. In case of gastro-intestinal disturbances, it may be administered with food.

The capsules are taken unchewed with a liberal quantity of fluid.

Duration of therapy

Treatment should be applied for 2 to 3 further days after regression of the acute clinical symptoms or evidence of bacterial eradication has been obtained. In infections caused by Streptococcus pyogenes up to 10 days treatment may be considered.

4.3 Contraindications

- History of or suspected hypersensitivity to cephadroxil, to any other cephalosporin or to any of the excipients.

- History of severe reactions to penicillins or to any other beta-lactam drugs.

4.4 Special warnings and precautions for use

. Cefadroxil does not penetrate in the CSF and is not indicated for the treatment of meningitis (see section 5.2).

- Penicillin is the first drug of choice for the treatment of the Streptococcus pyogenes and for the prevention of rheumatic fever. Data for cefadroxil are not sufficiently substantial for prophylaxis therapy.

- Special caution should be exercised in patients with history of severe allergies or asthma.

- In patients with a history of non severe hypersensitivity to penicillins, or other noncephalosporin beta -lactam drugs, cefadroxil should be used with special caution as cross allergies occur (incidence 5-10%).

- Renal impairment. Caution is necessary in patients with renal impairment; the dosage must be adjusted according to the grade of renal impairment (see Posology).

- History of gastro-intestinal disturbances. Cefadroxil should be used with caution patients with a history of gastro-intestinal disturbances, particularly colitis.

. Allergic reactions. Treatment must be discontinued at once if allergic reactions occur (urticaria, exanthema, pruritus, fall of blood pressure and increased heart rate, respiratory disturbances, collapse, etc.) and suitable countermeasures should be taken (sympathomimetics, corticosteroids and/or antihistaminics).

- Prolonged use. Particularly on prolonged use frequent checks on the blood count and regular hepatic and renal function tests are advisable. Superinfections with fungi (e.g. candida) can occur on prolonged treatment with cefadroxil.

- In case of severe and persistent diarrhea, an antibiotic-associated pseudomembranous colitis should be considered. In that case Cefadroxil must be discontinued immediately and a suitable therapy should be started (e.g. oral vancomycin, 250 mg q.i.d.). Antiperistaltics are contraindicated.

- Severe life-threatening infections or those which require higher posology or repetitive administrations per day may benefit of parenteral cephalosporins.

- The result of the Coombs' test can be transiently positive during or after treatment with cefadroxil.

4.5 Interactions with other medicaments and other forms of interaction

Contraindication of concomitant use

- Cefadroxil should not be combined with bacteriostatic antibiotics (e.g. tetracycline, erythromycin, sulfonamides, chloramphenicol) since an antagonistic effect is possible.

- Treatment with Cefadroxil in combination with aminoglycoside antibiotics, polymyxin B, colistin or high-dose loop diuretics should be avoided since such combinations can potentiate nephrotoxic effects.

Concomitant use not recommended

- Frequent checks on coagulation parameters are necessary during concomitant long term use of anticoagulants or thrombocyte aggregation inhibitors to avoid haemorrhagic complications.

Precautions

- The concomitant administration of probenicid can produce higher and sustained concentrations of cefadroxil in the serum and in the bile.

- The occurrence of diarrhoea may impair the resorption of other medicaments and therefore lead to an impairment of their efficacy.

- Forced diuresis leads to a decrease of cefadroxil blood levels.

- Cefadroxil may attenuate the effect of oral contraceptives.

- Cefadroxil binds to cholestyramine which may lead to reduced bioavailability of cefadroxil.

- The result of the direct Coombs' test can be transiently positive during or after treatment with cefadroxil. This also applies to Coombs' tests carried out in newborns whose mother received treatment with cephalosporins before delivery.

- Urinary sugar should be determined enzymatically (e.g. with test strips) during treatment with cefadroxil since reduction tests can furnish falsely elevated values.

4.6 Pregnancy and lactation

Although animal studies and clinical experience have not shown any evidence of teratogenicity, the safe use during pregnancy has not been established. Cefadroxil is present in low concentrations in breast milk; sensitization, diarrhoea or colonisation of the infants' mucosa with fungi are possible.

The use of cefadroxil during pregnancy and in lactating mothers should therefore be handled very strictly.

4.7 Effects on ability to drive and use machines

Cefadroxil may cause headache, dizziness, nervousness, sleeplessness and fatigue, therefore the ability to drive and use machines may be influenced (see 4.8 Undesirable effects).

4.8 Undesirable effects

The adverse events are ranked under headings of frequency, using the following convention:

very common (> 1/10); common (> 1/100 to < 1/10); uncommon (> 1/1,000 to < 1/100); rare (> 1/10,000 to < 1/1,000); very rare (< 1/10,000), not known (cannot be estimated from the available data).

Adverse drug reactions occur in about 6% to 7%* of treated patients.

System Organ Class

Common 1/100 to <1/10

Uncommon 1/1,000 to <1/100

Rare

1/10,000 to <1/1,000

Very rare <1/10,000

Infections and infestations

Clinical pictures due to a growth

System Organ Class	Common 1/100 to <1/10	Uncommon 1/1,000 to <1/100	Rare 1/10,000 to <1/1,000	Very rare <1/10,000
		of opportunistic organisms (fungi), such as vaginal mycoses, thrush (see section 4.4).
Blood and lymphatic system disorders			Eosinophilia, thrombocytopenia, leucopenia, neutropenia, agranulocytosis: rare cases during prolonged use, which subside upon discontinuation of therapy.	Haemolytic anemia of immunologic origin.
Immune system disorders			Serum sickness-like reactions.	Immediate allergic reaction (anaphylactic shock) (see section 4.4).
Nervous system disorders				Headache, sleeplessness, dizziness, nervousness.
Gastrointestinal disorders	Nausea, vomiting, diarrhoea, dyspepsia, abdominal pain, glossitis (see section 4.4).			Pseudomembranous colitis has been reported (may range in severity from mild to life threatening) (see section 4.4).
Hepatobiliary disorders			Cholestase and idiosyncratic hepatic failure have been reported. Minor elevation of serum transaminases (ASAT, ALAT) and alkaline phosphatases.
Skin and subcutaneous tissue disorders	Pruritus, rash, allergic exanthema, urticaria.		Angioneurotic edema.	Stevens Johnson syndrome and erythema multiforme have been reported.
Musculoskeletal and connective tissue disorders			Arthralgia.
Renal and urinary			Interstitial nephritis (see section 4.4).

System Organ Class	Common 1/100 to <1/10	Uncommon 1/1,000 to <1/100	Rare 1/10,000 to <1/1,000	Very rare <1/10,000
disorders
General disorders and administration site conditions			Drug fever.	Fatigue.
Investigations				Direct and indirect positive Coombs tests (see section 4.4).

*incidence of suspected adverse reactions in an observational post-marketing study in 904 patients.

4.9 Overdose

No clinical reports are as yet available on cefadroxil in this respect. However in view of experience gained with other cephalosporins the following symptoms are possible: nausea, hallucinations, hyperreflexia, extrapyramidal symptoms, clouded consciousness, or even coma and renal functional impairment. First aid after intake of toxic doses: induce vomiting at once or gastric lavage, if necessary haemodialysis. Monitor and if necessary correct the water and electrolyte balance, monitor renal function.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

ATC classification ATC-Code: J01DB05

Pharmacotherapeutic group: Other beta-lactam antibacterials. First generation cephalosporins.

Mode of action

Cefadroxil is a cephalosporin for oral administration which inhibits bacterial wall synthesis of actively dividing cells by binding to one or more penicillinbinding proteins. The result is formation of a defective cell wall that is osmotically unstable, and bacterial cell lysis.

Mechanisms of resistance

Cefadroxil may be active against organisms producing some types of beta-lactamase, for example TEM-1, in low to moderate quantities. However, it is inactivated by beta-lactamases that can efficiently hydrolyse cephalosporins, such as many of the extended-spectrum beta-lactamases and chromosomal cephalosporinases, such as AmpC type enzymes.

Cefadroxil cannot be expected to be active against bacteria with penicillinbinding proteins that have reduced affinity for beta-lactam drugs. Resistance may also be mediated by bacterial impermeability or by bacterial drug efflux pumps. More than one of these four means of resistance may be present in the same organism.

In vitro, oral first generation cephalosporins are less active than penicillins G and V on Gram-positive microorganisms and are less active than aminopenicillins on H. influenzae.

Breakpoints

The following breakpoint recommendations for cefadroxil according to the European Committee on Antimicrobial Susceptibly Testing (EUCAST) have been defined (Breakpoint tables for interpretation of MICs and zone diameters, Version 1.0, December 2009):

Cefadroxil (EUCAST Clinical Breakpoint Table)	MIC breakpoints
	S <	R >
Enterobacteriaceae (uncomplicated UTI only)	16	16
Staphylococcus spp.	Note¹	Note¹
Streptococcus groups A, B, C, and G	Note²	Note²
Non-species related breakpoints	IE	IE

Note¹: Susceptibility of staphylococci to cephalosporins is inferred from the methicillin susceptibility except for ceftazidime and cefixime and ceftibuten, which do not have breakpoints and should not be used for staphylococcal

infections.

Note : The beta-lactam susceptibility of beta-haemolytic streptococci groups A, B, C and G is inferred from the penicillin susceptibility.

IE: indicates that there is insufficient evidence that the species in question is a good target for therapy with the drug.

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.

Species_

Commonly susceptible species

Gram-positive aerobes Streptococci Group B, C and G Streptococcus pyogenes *

Gram-negative aerobes Moraxella catarrhalis *

Species for which acquired resistance may be a problem

Gram-positive aerobes

Staphylococcus aureus (methicillin-susceptible) *

Staphylococcus epidermidis Streptococcus pneumoniae *

Gram-negative aerobes

Citrobacter diversus^$Escherichia coli ^$Haemophilus influenzae ^$Klebsiellapneumoniae^$Klebsiella oxytoca^$Proteus mirabilis* ^$

Inherently resistant species

Gram-positive aerobes Enterococcus spp.

Staphylococcus aureus (Methicillin-resistant)

Staphylococcus epidermidis (Methicillin-resistant)

Streptococcus pneumoniae (penicillin-resistant)

Gram-negative aerobes Acinetobacter spp.

Citrobacter freundii Enterobacter spp.

Morganella morganii Proteus vulgaris Providencia rettgeri Providencia stuartii Pseudomonas aeruginosa Serratia marcescens

Other species

Chlamydia spp Mykoplasma spp Legionella spp

* Clinical efficacy has been demonstrated for susceptible isolates in approved clinical indications $ Species with natural intermediate susceptibility

5.2 Pharmacokinetic properties

Absorption

After oral administration cefadroxil is practically completely absorbed. Simultaneous intake of food has practically no effect on absorption (AUC).

Distribution

After oral doses of 500 mg (1000 mg) peak plasma concentrations of about 16 (30) g/ml are obtained after 1-1,3 hours. Between 18 and 20% of cefadroxil is

bound to plasma proteins. Cephalosporins do not penetrate in the CSF and should not be used for treatment of meningitis (see section 4.1)

Metabolism

Cefadroxil is not metabolised.

Elimination

Cefadroxil is eliminated far more slowly than comparable oral cephalosporins (half life: about 1,4 h to 2,6 h) so that intervals between doses can be prolonged to 12-24 hours. Roughly 90% of the substance is eliminated in unchanged form through the kidneys within 24 hours. Cefadroxil may be eliminated from the organism through haemodialysis.

Characteristics in patients with highgrade renal functional impairment

Elimination is retarded, so that interval between doses must be prolonged (see section 4.2).

5.3 Preclinical safety data

Pre-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity and reproductive toxicology.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Content: Magnesium stearate

Sodium lauryl sulfate Cellulose, microcrystalline Shell: Titanium dioxide (E171)

Gelatine

6.2 Incompatibilities

None known

3 years

6.4 Special precautions for storage

Store in the original package

6.5 Nature and Contents of Container

Single packs of 10, 12, 14, 16, 20, 30, 40 and 100 (100 x 1) capsules. Hospital packs of 100 (10x10) and 1000 (100x10) capsules in polyvinylchloride/polyvinylidene (PVC/PVDC)-Alu-blister strips

Not all pack sizes may be marketed.

6.6 Instructions for Use, Handling and Disposal

No special requirements.

7 MARKETING AUTHORISATION HOLDER

Sandoz Ltd

Frimley Business Park

Frimley

Camberley

Surrey

GU16 7 SR

8. MARKETING AUTHORISATION NUMBER(S)

PL 04416/0433

DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

DATE OF REVISION OF THE TEXT

29/12/2011