Download CEFORAL®

2009 ‫ נובמבר‬:‫ עלון מאושר‬."‫פורמט עלון זה נקבע ע"י משרד הבריאות ותוכנו נבדק ואושר‬
“This leaflet format has been determined by the Ministry of Health and the content thereof has been
checked and approved.” Date of approval: November 2009
CEFORAL®
CAPSULES. SUSPENSION
Composition
Ceforal 250 Capsules
Active Ingredient:
Each capsule contains:
Cephalexin
250 mg
Ceforal 500 Capsules
Each capsule contains:
Active Ingredient:
Cephalexin
500 mg
Other Ingredients
Magnesium stearate.
Ceforal 250 Suspension
Active Ingredient
Each teaspoonful (5 ml) contains:
Cephalexin
250 mg
Other Ingredients
Sucrose, strawberry flavor, edetate disodium, color FDC yellow.
Mechanism of Action
Ceforal is a potent orally acting cephalosporin. It is bactericidal, acting by inhibition
of bacterial cell wall synthesis. Ceforal is stable in gastric acid, and may be
administered without regard to meals. It is rapidly and almost completely absorbed
from the upper gastrointestinal tract. Therefore, gastrointestinal side effects are of a
relatively low incidence.
Peak blood levels are reached within 1 hour of administration. They are comparable
to those attained with equivalent doses of intramuscular cephaloridine, and exceed
those obtained with equivalent doses of intramuscular cephalothin.
Ceforal is widely distributed in the tissues and high concentrations are achieved in
all organs, especially kidneys and liver.
Ceforal is excreted unchanged in the urine, in its antimicrobial- active form.
Ceforal enjoys a wide margin of safety, and may be safely administered to the
majority of penicillin-sensitive patients.
Ceforal is effective against the following microorganisms:
♦Staphylococci (including penicillinase-producing strains)
♦β-hemolytic streptoccocci
♦Streptococcus pneumoniae (formerly Diplococcus pneumoniae)
♦Corynebacterium diphtheriae
♦Escherichia coli
♦Proteus mirabilis
♦Klebsiella pneumoniae
CEFORAL,
21. 12. 2009, RH
2
♦Neisseria gonorrhoeae
♦Neisseria meningitidis
♦Salmonella species
♦Shigella species
♦Some strains of Haemophilus influenzae.
♦Moraxella (Branhamella) catarrhalis.
Most strains of enterococci (Streptococcus faecalis) and a few strains of
staphylococci are resistant to cephalexin.
Most strains of Enterobacter species, Proteus vulgaris and Morganella morganii
(formerly Proteus morganii) are resistant.
Methicillin-resistant staphylococci, Pseudomonas species and Herellea species are
resistant to cephalexin.
Susceptibility Tests
Quantitative methods that require measurement of zone diameters give the most
precise estimates of antibiotic susceptibility. One such procedure has been
recommended for use with discs to test susceptibility to cephalexin.
Organisms of intermediate susceptibility will be susceptible if high dosage is used,
or if the infection is confined to tissues and fluids (e.g. urine) in which high antibiotic
levels are attained.
Resistant organisms are not likely to respond to therapy, and other therapy should
be selected.
Indications
Ceforal is indicated for the treatment of the following infections, when caused by
susceptible organisms:
♦genitourinary tract infections and acute prostatitis
♦upper and lower respiratory tract infections
♦skin and soft tissue infections
♦bone infections
♦otitis media.
Contraindications
Known hypersensitivity to any ingredient of the product and the cephalosporin group
of antibiotics.
Warnings
BEFORE THERAPY WITH CEPHALEXIN IS INSTITUTED, CAREFUL INQUIRY
SHOULD BE MADE TO DETERMINE WHETHER THE PATIENT HAS HAD
PREVIOUS
HYPERSENSITIVITY
REACTIONS
TO
CEPHALEXIN,
CEPHALOSPORINS, PENICILLINS OR OTHER DRUGS. IF THIS PRODUCT IS TO
BE GIVEN TO PENICILLIN-SENSITIVE PATIENTS, CAUTION SHOULD BE
EXERCISED BECAUSE CROSS-HYPERSENSITIVITY AMONG BETA-LACTAM
ANTIBIOTICS HAS BEEN CLEARLY DOCUMENTED AND MAY OCCUR IN UP TO
10% OF PATIENTS WITH A HISTORY OF PENICILLIN ALLERGY. IF AN ALLERGIC
REACTION TO CEPHALEXIN OCCURS, DISCONTINUE THE DRUG. SERIOUS
ACUTE HYPERSENSITIVITY REACTIONS MAY REQUIRE TREATMENT WITH
EMERGENCY MEASURES INCLUDING OXYGEN, INTRAVENOUS FLUIDS,
INTRAVENOUS ANTIHISTAMINES, CORTICOSTEROIDS, PRESSOR AMINES
(E.G. EPINEPHRINE) AND AIRWAY MANAGEMENT, AS CLINICALLY INDICATED.
Cephalosporin C derivatives should be administered with caution to penicillinsensitive patients.
CEFORAL,
21. 12. 2009, RH
3
There is some clinical and laboratory evidence of partial cross- allergenicity of the
penicillins and the cephalosporins. Patients have been reported to have had severe
reactions (including anaphylaxis) to both drugs.
Any patient who has demonstrated some form of allergy, particularly to drugs,
should receive antibiotics cautiously.
Clostridium difficile associated diarrhea (CDAD) has been reported with use of
nearly all antibacterial agents, including cephalexin, and may range in severity from
mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora
of the colon leading to overgrowth of C. difficile.
C. difficile produces toxins A and B which contribute to the development of CDAD.
Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as
these infections can be refractory to antimicrobial therapy and may require colectomy.
CDAD must be considered in all patients who present with diarrhea following antibiotic
use. Careful medical history is necessary since CDAD has been reported to occur
over two months after the administration of antibacterial agents.
If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C.
difficile may need to be discontinued. Appropriate fluid and electrolyte management,
protein supplementation, antibiotic treatment of C. difficile, and surgical evaluation
should be instituted as clinically indicated.
Cephalosporins may be associated with a fall in prothrombin activity. Those at risk
include patients with renal or hepatic impairment, or poor nutritional state, as well as
patients receiving a protracted course of antimicrobial therapy, and patients previously
stabilized on anticoagulant therapy. Prothrombin time should be monitored in patients
at risk and exogenous vitamin K administered as indicated.
Use in Pregnancy
Safety of use in pregnancy has not been established.
The daily oral administration of cephalexin to rats in doses of 250 or 500 mg/kg prior
to and during pregnancy, or to rats and mice during the period of organogenesis only,
had no adverse effect on fertility, fetal viability, fetal weight, or litter size. Cephalexin
showed no enhanced toxicity in weanling and newborn rats as compared with adult
animals. Nevertheless, because the studies in humans cannot rule out the possibility
of harm, cephalexin should be used during pregnancy only if clearly needed.
Use in Breastfeeding
Safety of use in breastfeeding has not been established.
The excretion of cephalexin in the milk increased up to 4 hours after a 500 mg dose;
the medicine reached a maximum level of 4 mg/L, then decreased gradually, and had
disappeared 8 hours after administration. Caution should be exercised when
cephalexin is administered to a nursing woman.
Use in Patients with Impairment of Hepatic Function
It is recom mended that patients with both severe liver disease and significant renal
disease receive a reduced dosage.
Use in Patients with Impairment of Renal Function
Cephalexin should be administered with caution in the presence of markedly
impaired renal function. Under such conditions, careful clinical observation and
laboratory studies should be made because safe dosage may be lower than that
usually recommended.
Use in the Elderly
Of the 701 subjects in 3 published clinical studies of cephalexin, 433 (62%) were 65
and over. No overall differences in safety or effectiveness were observed between
these subjects and younger subjects, and other reported clinical experience has not
identified differences in responses between the elderly and younger patients, but
greater sensitivity of some older individuals cannot be ruled out.
CEFORAL,
21. 12. 2009, RH
4
This drug is known to be substantially excreted by the kidney, and the risk of toxic
reactions to this drug may be greater in patients with impaired renal function. Because
elderly patients are more likely to have decreased renal function, care should be taken
in dose selection, and it may be useful to monitor renal function
Special Populations
Patients with History of Bleeding Disorders: All cephalosporins may cause
hypoprothrombinaemia and, potentially bleeding.
Patients with Carnitine Deficiency: Some cephalosporins increase renal excretion of
carnitine.
Dental Therapy: long-term therapy with cephalosporins m ay allow for the overgrowth
of Candida albicans, resulting in oral candidiasis.
Adverse Reactions
Gastrointestinal System
Symptoms of pseudomembranous colitis may appear either during or after antibiotic
treatment. Nausea and vomiting have been reported rarely. The most frequent sideeffect has been diarrhea. It was very rarely severe enough to warrant cessation of
therapy. Dyspepsia and abdominal pain have also occurred. As with some penicillins
and some other cephalosporins, transient hepatitis and cholestatic jaundice have
been reported rarely.
Other Gastrointestinal Disorders: gastritis, oral candidiasis, flatulence.
Immune System
Hypersensitivity Reactions
Allergic reactions have been observed in the form of rash, urticaria, angioedema,
and, rarely, erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal
necrolysis. These reactions usually subsided upon discontinuation of the drug,
although in some cases supportive therapy may be necessary. Anaphylaxis has also
been reported.
Blood and Lymphatic System
Eosinophilia, neutropenia, thrombocytopenia, and haemolytic anaemia have been
reported.
Hepatobiliary
Hepatic dysfunction, including cholestatic jaundice, slight elevations in AST and
ALT.
Musculoskeletal, Connective Tissue
Arthralgia, arthritis and joint disorders, toxic epidermal necrolysis; erythema
multifomre or Stevens-Johnson syndrome.
Nervous System
Dizziness,headache,agitation,confusion,hallucinations,seizures.
Renal and urinary disorders
Rare:renal dysfunction,toxic nephropathy.
Reproductive system
Vaginal candidiasis,vaginitis,genital and anal pruritus,genital m onoliasis.
CEFORAL,
21. 12. 2009, RH
5
Precautions
Prescribing cephalexin in the absence of a proven or strongly suspected bacterial
infection or a prophylactic indication is unlikely to provide benefit to the patient and
increases the risk of the development of drug-resistant bacteria.
If an allergic reaction to Ceforal occurs, the drug should be discontinued and the
patient treated with the usual agents (e.g. epinephrine or other pressor amines,
antihistamines, or corticosteroids).
Cephalexin should be administered with caution in the presence of impaired renal
function.
The possibility of the emergence of resistant organisms which might result in
overgrowth should be kept in mind, particularly during prolonged treatment. In such
use careful observation of the patient is essential. If superinfection occurs during
therapy, appropriate measures should be taken.
Antibiotics (including cephalosporins) should be prescribed with caution in
individuals with a history of gastrointestinal disease, particularly colitis.
Pseudomembranous colitis has been reported with virtually all antibiotics (including
cephalosporins). Therefore, it is important to consider its diagnosis in patients who
develop diarrhea in association with antibiotic use.
Mild cases of pseudomembranous colitis may respond to drug discontinuation
alone. Moderate to severe cases should be managed with fluid electrolyte and protein
supplementation, as indicated.
Caution should be exercised in patients with a history of bleeding disorders, since
some cephalosporins including cefazolin, ceftizoxime, ceftriaxone, cefoperazone and
cefamandole may inhibit the production of vitamin K by the intestinal flora, thus
leading to symptoms of vitamin K deficiency (such as hypoprothrombinemia or
bleeding tendency). The tendency to develop vitamin K deficiency is higher in the
elderly population.
Each 5 ml of Ceforal 250 mg Suspension contains about 3 g. sucrose. Therefore
caution should be exercised when this drug is administered to diabetics.
Drug Interactions
Cephalosporins/Aminoglycosides (e.g. Gentamicin, Neomycin)/Other Nephrotoxic
Agents (e.g. Tetracyclines, Sulfonamides): Nephrotoxicity of the aminoglycosides may
be potentiated upon the concurrent administration of some cephalosporins
(specifically cefalothin). Therefore renal function should be monitored.
The potential for increased nephrotoxicity exists when cephalosporins are used with
other nephrotoxic agents, especially in patients with pre-existing renal function
impairment.
Cephalosporins/Probenecid: Probenecid may increase and prolong cephalosporins
plasma levels by competitively inhibiting renal tubular secretion. Therefore caution
should be exercised upon concomitant administration of this combination.
Cephalosporins/ Anticoagulants, Warfarin, Coumarin-or indandione-derivative, or
Heparin or Thrombolytic agents: Because all cephalosporins can inhibit vitamin K
synthesis by suppressing gut flora, prophylactic vitam in K therapy is recommended
when any of these medications is used for prolonged periods in malnourished or
seriously ill patients.
Concomitant administration of warfarin (which exhibits inhibitory effects on the
metabolism of vitamin K) with cephalosphorins may lead to a potentiation of the
anticoagulant effects of warfarin
Cephalosporins/ Platelet Aggregation Inhibitors: Hypoprothrombinaemia induced by
large doses of salicylates and/or cephalosporins, and the gastrointestinal ulcerative or
haemorrhagic potential of nonsteriodal anti-inflammatory drugs [NSAIDS], salicylates,
or sulfinpyrazine may increase the risk of haemorrhage.
Cephalosporins/ Antacids or Ranitidine or Histamine H2-Receptor Antagonists
Concurrent use of high doses of antacids or H2-receptor antagonists or ranitidine may
have effects on peak plasma levels of cephalosporins.
CEFORAL,
21. 12. 2009, RH
6
Cephalosporins/Meformin:
In a single study of 12 healthy subjects given single
500mg doses of cephalexin and metformin, plasma metformin Cmax and AUC
increased by an average of 34% and 24%, respectively, and metformin renal
clearance decreased by an average of 14%. No side-effects were reported in the
12 healthy subjects in this study. No information is available about the interaction of
cephalexin and metformin following multiple dose administration. The clinical
significance of this study is unclear, particularly as no cases of “lactic acidosis” have
been reported in association with concomitant metformin and cephalexin treatment.
Although not observed in this study, adverse effects could potentially arise from coadministration of cephalexin and metformin by inhibition of tubular secretion via
organic cationic transporter systems. Accordingly, careful patient monitoring and
dose adjustment of metformin is recommended in patients concomitantly taking
cephalexin and metformin.
Diagnostic Interference
A false-positive reaction for glucose in the urine may occur with Benedict's solution,
Fehling's solution, or with Clinitest tablets. This has not been observed with enzymebased tests such as Clinistix and Tes-tape.
A false-positive direct Coombs' test has occurred in some patients receiving
cephalosporins, particularly those with azotemia, in hematologic studies, in
transfusion cross-matching procedures when antiglobulin tests are performed on the
minor side or in Coombs' testing of newborns of mothers receiving cephalosporins
before parturition. This reaction is non-immunological.
Prolonged prothrombin time has been rarely reported with cephalosporins.
Cephalosporins may falsely elevate urinary 17-ketosteroid values.
Information for Patients
Patients should be counseled that antibacterial drugs including cephalexin should
only be used to treat bacterial infections. They do not treat viral infections (e.g., the
common cold). When cephalexin is prescribed to treat a bacterial infection, patients
should be told that although it is common to feel better early in the course of therapy,
the medication should be taken exactly as directed. Skipping doses or not completing
the full course of therapy may (1) decrease the effectiveness of the immediate
treatment and (2) increase the likelihood that bacteria will develop resistance and will
not be treatable by cephalexin or other antibacterial drugs in the future.
Diarrhea is a common problem caused by antibiotics which usually ends when the
antibiotic is discontinued. Sometimes after starting treatment with antibiotics, patients
can develop watery and bloody stools (with or without stomach cramps and fever)
even as late as two or more months after having taken the last dose of the antibiotic. If
this occurs, patients should contact their physician as soon as possible.
Dosage and Administration
Susceptibility tests should be initiated prior to and during therapy.
Renal function studies should be performed when indicated.
Adults
The dosage ranges from 1-4 g daily, in divided doses. The usual dosage is 250
mg, every 6 hours.
For the following infections, a dosage of 500 mg may be administered every 12
hours: streptococcal pharyngitis, skin and skin-structure infections, uncomplicated
cystitis in patients over 15 years of age. Cystitis therapy should be continued for 714 days.
For more severe infections or those caused by less susceptible organisms, larger
doses may be required. If daily doses greater than 4 g are needed, parenteral
cephalosporins, in appropriate doses, should be considered.
CEFORAL,
21. 12. 2009, RH
7
Children
The recommended daily dosage for children is 25-50 mg/kg body weight, divided
into 4 doses.
10 kg body weight
1/4 teaspoonful (1.25 ml)- 1/2 teaspoonful (2.5 ml)
of Ceforal 250 mg Suspension 4 times daily
20 kg body weight
1/2-1 teaspoonful of Ceforal 250 Suspension
4 times daily
40 kg body weight
1-2 teaspoonful of Ceforal 250 Suspension 4 times
daily
For streptococcal pharyngitis in patients over 1 year of age and for skin and skinstructure infections, the total daily dose may be divided and administered every 12
hours.
In severe infections, the dosage may be doubled.
In the treatment of otitis media, a dosage of 75-100 mg/kg body weight/day, in
4 divided doses, is required.
In the treatment of β-hemolytic streptococcal infections, a therapeutic dosage of
Ceforal should be administered for at least 10 days.
Overdosage
Manifestations
Symptoms of overdosage may include nausea, vomiting, epigastric distress,
diarrhea, and hematuria. If other symptoms are present, it is probably secondary to an
underlying disease state, an allergic reaction, or toxicity due to ingestion of a second
medication.
Treatment
In managing overdosage, consider the possibility of multiple medicine overdoses,
interaction among medicines, and unusual medicine kinetics in your patient.
Unless 5 to 10 times the normal dose of cephalexin has been ingested,
gastrointestinal decontamination should not be necessary.
Protect the patient's airway and support ventilation and perfusion. Meticulously
monitor and maintain, within acceptable limits, the patient's vital signs, blood gases,
serum electrolytes, etc. Absorption of drugs from the gastrointestinal tract may be
decreased by giving activated charcoal, which, in many cases, is more effective than
emesis or lavage; consider charcoal instead of or in addition to gastric emptying.
Repeated doses of charcoal over time may hasten elimination of some drugs that
have been absorbed. Safeguard the patient's airway when employing gastric emptying
or charcoal.
Forced diuresis, peritoneal dialysis, hemodialysis, or charcoal hemoperfusion have
not been established as beneficial for an overdose of cephalexin; however, it would be
extremely unlikely that one of these procedures would be indicated. The oral median
lethal dose of cephalexin in rats is 5,000 mg/kg.
There have been reports of haematuria, without impairment of renal function, in
children accidentally ingesting more than 3.5g of cephalexin in a day. Treatment has
been supportive (fluids) and no sequelae have been reported
CEFORAL,
21. 12. 2009, RH
8
Pharmaceutical Precautions
Ceforal Capsules
Ceforal Powder for the preparation of suspension:
Store in a dry place below 25°C.
Ceforal Suspension (following reconstitution):
Reconstituted Ceforal 250 mg Suspension should be kept in the refrigerator and
used within 7 days from reconstitution.
Registration Numbers:
Capsules
250 mg : 049 62 23334 00
500 mg : 045 95 24027 00
Suspension 250 mg/5 ml
043 93 23336 00
Manufacturer
Teva Pharmaceutical Industries Ltd
P.O.Box 3190, Petach Tikva .
CEFORAL,
21. 12. 2009, RH