Cedax

ceftibuten dihydrate

Dosage Form: capsules, oral suspension
Cedax®

(ceftibuten capsules)

and

(ceftibuten for oral suspension)

FOR ORAL USE ONLY

PRODUCT INFORMATION

Cedax Description

Cedax (ceftibuten capsules) and (ceftibuten for oral suspension) contain the active ingredient ceftibuten as ceftibuten dihydrate. Ceftibuten dihydrate is a semisynthetic cephalosporin antibiotic for oral administration. Chemically, it is (+) - (6R,7R) - 7 - [(Z) - 2 - (2 - Amino - 4 - thiazolyl) - 4 - carboxycrotonamido] - 8 - oxo - 5 - thia - 1 - azabicyclo[4.2.0]oct - 2 - ene - 2 - carboxylic acid, dihydrate. Its molecular formula is C15H14N4O6S2•2H2O. Its molecular weight is 446.43 as the dihydrate.

Ceftibuten dihydrate has the following structural formula:

Cedax Capsules contain ceftibuten dihydrate equivalent to 400 mg of ceftibuten. Inactive ingredients contained in the capsule formulation include: magnesium stearate, microcrystalline cellulose, and sodium starch glycolate. The capsule shell and/or band contains gelatin, sodium lauryl sulfate, titanium dioxide, and polysorbate 80. The capsule shell may also contain benzyl alcohol, sodium propionate, edetate calcium disodium, butylparaben, propylparaben, and methylparaben.

Cedax Oral Suspension after reconstitution contains ceftibuten dihydrate equivalent to 90 mg of ceftibuten per 5 mL or 180 mg of ceftibuten per 5 mL. Cedax Oral Suspension is cherry flavored and contains the inactive ingredients: cherry flavoring, polysorbate 80, silicon dioxide, simethicone, sodium benzoate, sucrose (approximately 1 g/5 mL), titanium dioxide, and xanthan gum.

Cedax - Clinical Pharmacology

PHARMACOKINETICS

Absorption

Cedax CAPSULES

Ceftibuten is rapidly absorbed after oral administration of Cedax Capsules. The plasma concentrations and pharmacokinetic parameters of ceftibuten after a single 400-mg dose of Cedax Capsules to 12 healthy adult male volunteers (20 to 39 years of age) are displayed in the table below. When Cedax Capsules were administered once daily for 7 days, the average Cmax was 17.9 µg/mL on day 7. Therefore, ceftibuten accumulation in plasma is about 20% at steady state.

Cedax ORAL SUSPENSION

Ceftibuten is rapidly absorbed after oral administration of Cedax Oral Suspension. The plasma concentrations and pharmacokinetic parameters of ceftibuten after a single 9-mg/kg dose of Cedax Oral Suspension to 32 fasting pediatric patients (6 months to 12 years of age) are displayed in the following table:

Parameter	Average Plasma Concentration (in µg/mL of ceftibuten after a single 400-mg dose) and Derived Pharmacokinetic Parameters (± 1 SD) (n = 12 healthy adult males)	Average Plasma Concentration (in µg/mL of ceftibuten after a single 9-mg/kg dose) and Derived Pharmacokinetic Parameters (± 1 SD) (n = 32 pediatric patients)
1.0 h	6.1 (5.1)	9.3 (6.3)
1.5 h	9.9 (5.9)	8.6 (4.4)
2.0 h	11.3 (5.2)	11.2 (4.6)
3.0 h	13.3 (3.0)	9.0 (3.4)
4.0 h	11.2 (2.9)	6.6 (3.1)
6.0 h	5.8 (1.6)	3.8 (2.5)
8.0 h	3.2 (1.0)	1.6 (1.3)
12.0 h	1.1 (0.4)	0.5 (0.4)
Cmax, µg/mL	15.0 (3.3)	13.4 (4.9)
Tmax, h	2.6 (0.9)	2.0 (1.0)
AUC, µg∙h/mL	73.7 (16.0)	56.0 (16.9)
T½, h	2.4 (0.2)	2.0 (0.6)
Total body clearance (CI/F) mL/min/kg	1.3 (0.3)	2.9 (0.7)

The absolute bioavailability of Cedax Oral Suspension has not been determined. The plasma concentrations of ceftibuten in pediatric patients are dose proportional following single doses of Cedax Capsules of 200 mg and 400 mg and of Cedax Oral Suspension between 4.5 mg/kg and 9 mg/kg.

Distribution

Cedax CAPSULES

The average apparent volume of distribution (V/F) of ceftibuten in 6 adult subjects is 0.21 L/kg (± 1 SD = 0.03 L/kg).

Cedax ORAL SUSPENSION

The average apparent volume of distribution (V/F) of ceftibuten in 32 fasting pediatric patients is 0.5 L/kg (± 1 SD = 0.2 L/kg).

Protein Binding

Ceftibuten is 65% bound to plasma proteins. The protein binding is independent of plasma ceftibuten concentration.

Tissue Penetration

Bronchial secretions

In a study of 15 adults administered a single 400-mg dose of ceftibuten and scheduled to undergo bronchoscopy, the mean concentrations in epithelial lining fluid and bronchial mucosa were 15% and 37%, respectively, of the plasma concentrations.

Sputum

Ceftibuten sputum levels average approximately 7% of the concomitant plasma ceftibuten level. In a study of 24 adults administered ceftibuten 200 mg bid or 400 mg qd, the average Cmax in sputum (1.5 µg/mL) occurred at 2 hours postdose and the average Cmax in plasma (17 µg/mL) occurred at 2 hours postdose.

Middle-ear fluid (MEF)

In a study of 12 pediatric patients administered 9 mg/kg, ceftibuten MEF area under the curve (AUC) averaged approximately 70% of the plasma AUC. In the same study, Cmax values were 14.3 ± 2.7 µg/mL in MEF at 4 hours postdose and 14.5 ± 3.7 µg/mL in plasma at 2 hours postdose.

Tonsillar tissue

Data on ceftibuten penetration into tonsillar tissue are not available.

Cerebrospinal fluid

Data on ceftibuten penetration into cerebrospinal fluid are not available.

Metabolism and Excretion

A study with radiolabeled ceftibuten administered to 6 healthy adult male volunteers demonstrated that cis-ceftibuten is the predominant component in both plasma and urine. About 10% of ceftibuten is converted to the trans-isomer. The trans-isomer is approximately ⅛ as antimicrobially potent as the cis-isomer.

Ceftibuten is excreted in the urine; 95% of the administered radioactivity was recovered either in urine or feces. In 6 healthy adult male volunteers, approximately 56% of the administered dose of ceftibuten was recovered from urine and 39% from the feces within 24 hours. Because renal excretion is a significant pathway of elimination, patients with renal dysfunction and patients undergoing hemodialysis require dosage adjustment (see DOSAGE AND ADMINISTRATION).

Food Effect on Absorption

Food affects the bioavailability of ceftibuten from Cedax Capsules and Cedax Oral Suspension.

The effect of food on the bioavailability of Cedax Capsules was evaluated in 26 healthy adult male volunteers who ingested 400 mg of Cedax Capsules after an overnight fast or immediately after a standardized breakfast. Results showed that food delays the time of Cmax by 1.75 hours, decreases the Cmax by 18%, and decreases the extent of absorption (AUC) by 8%.

The effect of food on the bioavailability of Cedax Oral Suspension was evaluated in 18 healthy adult male volunteers who ingested 400 mg of Cedax Oral Suspension after an overnight fast or immediately after a standardized breakfast. Results obtained demonstrated a decrease in Cmax of 26% and an AUC of 17% when Cedax Oral Suspension was administered with a high-fat breakfast, and a decrease in Cmax of 17% and an AUC of 12% when Cedax Oral Suspension was administered with a low-calorie nonfat breakfast (see PRECAUTIONS).

Bioequivalence of Dosage Formulations

A study in 18 healthy adult male volunteers demonstrated that a 400-mg dose of Cedax Capsules produced equivalent concentrations to a 400-mg dose of Cedax Oral Suspension. Average Cmax values were 15.6 (3.1) µg/mL for the capsule and 17.0 (3.2) µg/mL for the suspension. Average AUC values were 80.1 (14.4) µg∙hr/mL for the capsule and 87.0 (12.2) µg∙hr/mL for the suspension.

Special Populations

Geriatric patients

Ceftibuten pharmacokinetics have been investigated in elderly (65 years of age and older) men (n = 8) and women (n = 4). Each volunteer received ceftibuten 200-mg capsules twice daily for 3½ days. The average Cmax was 17.5 (3.7) µg/mL after 3½ days of dosing compared to 12.9 (2.1) µg/mL after the first dose; ceftibuten accumulation in plasma was 40% at steady state. Information regarding the renal function of these volunteers was not available; therefore, the significance of this finding for clinical use of Cedax Capsules in elderly patients is not clear. Ceftibuten dosage adjustment in elderly patients may be necessary (see DOSAGE AND ADMINISTRATION).

Patients with renal insufficiency

Ceftibuten pharmacokinetics have been investigated in adult patients with renal dysfunction. The ceftibuten plasma half-life increased and apparent total clearance (CI/F) decreased proportionately with increasing degree of renal dysfunction. In 6 patients with moderate renal dysfunction (creatinine clearance 30 to 49 mL/min), the plasma half-life of ceftibuten increased to 7.1 hours and CI/F decreased to 30 mL/min. In 6 patients with severe renal dysfunction (creatinine clearance 5 to 29 mL/min), the half-life increased to 13.4 hours and CI/F decreased to 16 mL/min. In 6 functionally anephric patients (creatinine clearance <5 mL/min), the half-life increased to 22.3 hours and CI/F decreased to 11 mL/min (a 7- to 8-fold change compared to healthy volunteers). Hemodialysis removed 65% of the drug from the blood in 2 to 4 hours. These changes serve as the basis for dosage adjustment recommendations in adult patients with mild to severe renal dysfunction (see DOSAGE AND ADMINISTRATION).

Microbiology

Ceftibuten exerts its bactericidal action by binding to essential target proteins of the bacterial cell wall. This binding leads to inhibition of cell-wall synthesis.

Ceftibuten is stable in the presence of most plasmid-mediated beta-lactamases, but it is not stable in the presence of chromosomally-mediated cephalosporinases produced in organisms such as Bacteroides, Citrobacter, Enterobacter, Morganella, and Serratia. Like other beta-lactam agents, ceftibuten should not be used against strains resistant to beta-lactams due to general mechanisms such as permeability or penicillin-binding protein changes like penicillin-resistant S. pneumoniae.

Ceftibuten has been shown to be active against most strains of the following organisms both in vitro and in clinical infections (see INDICATIONS AND USAGE):

Gram-positive aerobes:

 

Streptococcus pneumoniae (penicillin-susceptible strains only)

 

Streptococcus pyogenes

Gram-negative aerobes:

 

Haemophilus influenzae (including β-lactamase-producing strains)

 

Moraxella catarrhalis (including β-lactamase-producing strains)

There are no known organisms which are potential pathogens in the indications approved for ceftibuten for which ceftibuten exhibits in vitro activity but for which the safety and efficacy of ceftibuten in treating clinical infections due to these organisms, have not been established in adequate and well-controlled trials.

NOTE: Ceftibuten is INACTIVE in vitro against Acinetobacter, Bordetella, Campylobacter, Enterobacter, Enterococcus, Flavobacterium, Hafnia, Listeria, Pseudomonas, Staphylococcus, and Streptococcus (except pneumoniae and pyogenes) species. In addition, it shows little in vitro activity against most anaerobes, including most species of Bacteroides.

Susceptibility testing

Dilution Techniques

Quantitative methods are used to determine antimicrobial minimal inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs should be determined using a standardized procedure. Standardized procedures are based on a dilution method (broth, agar, or microdilution) or equivalent with standardized inoculum concentrations and standardized concentrations of ceftibuten powder. The MIC values should be interpreted according to the following criteria when testing Haemophilus species using Haemophilus Test Media (HTM):

	MIC (µg/mL)		Interpretation
	≤2		(S) Susceptible

The current absence of resistant strains precludes defining any categories other than "Susceptible". Strains yielding results suggestive of a "Nonsusceptible" category should be submitted to a reference laboratory for further testing.

A report of "Susceptible" implies that an infection due to the strain may be appropriately treated with the dosage of antimicrobial agent recommended for that type of infection and infecting species, unless otherwise contraindicated.

Ceftibuten is indicated for penicillin-susceptible only strains of Streptococcus pneumoniae. A pneumococcal isolate that is susceptible to penicillin (MIC ≤0.06 µg/mL) can be considered susceptible to ceftibuten for approved indications. Testing of ceftibuten against penicillin-intermediate or penicillin-resistant isolates is not recommended. Reliable interpretive criteria for ceftibuten are not currently available. Physicians should be informed that clinical response rates with ceftibuten may be lower in strains that are not penicillin-susceptible.

Standardized susceptibility test procedures require the use of laboratory control microorganisms to control the technical aspect of laboratory procedures. Standard ceftibuten powder should provide the following MIC values:

		Organism		MIC range (µg/mL)
Haemophilus influenzae ATCC 49247				0.25-1.0

Diffusion Techniques

Quantitative methods that require measurement of zone diameters also provide estimates of the susceptibility of bacteria to antimicrobial compounds. One such standardized procedure requires the use of standardized inoculum concentrations. This procedure uses paper disks impregnated with 30 µg of ceftibuten to test the susceptibility of microorganisms to ceftibuten.

Reports from the laboratory providing results of the standard single-disk susceptibility test with a 30-µg ceftibuten disk should be interpreted according to the following criteria when testing Haemophilus species using Haemophilus Test Media (HTM):

	Zone diameter (mm)		Interpretation
	≥28		(S) Susceptible

The current absence of resistant strains precludes defining any categories other than "Susceptible". Strains yielding results suggestive of a "Nonsusceptible" category should be submitted to a reference laboratory for further testing.

Interpretation should be as stated above for results using dilution techniques.

Ceftibuten is indicated for penicillin-susceptible only strains of Streptococcus pneumoniae. Pneumococcal isolates with oxacillin zone sizes of ≥20 mm are susceptible to penicillin and can be considered susceptible for approved indications. Reliable disk diffusion tests for ceftibuten do not yet exist.

As with standardized dilution techniques, diffusion methods require the use of laboratory control microorganisms that are used to control the technical aspects of the laboratory procedures. For the diffusion technique, the 30-µg ceftibuten disk should provide the following zone diameters in these laboratory test quality control strains:

		Organism		Zone diameter (mm)
Haemophilus influenzae ATCC 49247				28-34

Cephalosporin-class disks should not be used to test for susceptibility to ceftibuten.

Indications and Usage for Cedax

Cedax (ceftibuten) is indicated for the treatment of individuals with mild-to-moderate infections caused by susceptible strains of the designated microorganisms in the specific conditions listed below (see DOSAGE AND ADMINISTRATION and CLINICAL STUDIES sections).

Acute Bacterial Exacerbations of Chronic Bronchitis due to Haemophilus influenzae (including β-lactamase-producing strains), Moraxella catarrhalis (including β-lactamase-producing strains), or Streptococcus pneumoniae (penicillin-susceptible strains only).

NOTE: In acute bacterial exacerbations of chronic bronchitis clinical trials where Moraxella catarrhalis was isolated from infected sputum at baseline, ceftibuten clinical efficacy was 22% less than control.

Acute Bacterial Otitis Media due to Haemophilus influenzae (including β-lactamase-producing strains), Moraxella catarrhalis (including β-lactamase-producing strains), or Streptococcus pyogenes.

NOTE: Although ceftibuten used empirically was equivalent to comparators in the treatment of clinically and/or microbiologically documented acute otitis media, the efficacy against Streptococcus pneumoniae was 23% less than control. Therefore, ceftibuten should be given empirically only when adequate antimicrobial coverage against Streptococcus pneumoniae has been previously administered.

Pharyngitis and Tonsillitis due to Streptococcus pyogenes.

NOTE: Only penicillin by the intramuscular route of administration has been shown to be effective in the prophylaxis of rheumatic fever. Ceftibuten is generally effective in the eradication of Streptococcus pyogenes from the oropharynx; however, data establishing the efficacy of the Cedax product for the prophylaxis of subsequent rheumatic fever are not available.

Contraindications

Cedax (ceftibuten) is contraindicated in patients with known allergy to the cephalosporin group of antibiotics.

Warnings

BEFORE THERAPY WITH THE Cedax PRODUCT IS INSTITUTED, CAREFUL INQUIRY SHOULD BE MADE TO DETERMINE WHETHER THE PATIENT HAS HAD PREVIOUS HYPERSENSITIVITY REACTIONS TO CEFTIBUTEN, OTHER 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 THE Cedax PRODUCT OCCURS, DISCONTINUE THE DRUG. SERIOUS ACUTE HYPERSENSITIVITY REACTIONS MAY REQUIRE TREATMENT WITH EPINEPHRINE AND OTHER EMERGENCY MEASURES, INCLUDING OXYGEN, INTRAVENOUS FLUIDS, INTRAVENOUS ANTIHISTAMINES, CORTICOSTEROIDS, PRESSOR AMINES, AND AIRWAY MANAGEMENT, AS CLINICALLY INDICATED.

Pseudomembranous colitis has been reported with nearly all antibacterial agents, including ceftibuten, and may range in severity from mild to life threatening. Therefore, it is important to consider this diagnosis in patients who present with diarrhea subsequent to the administration of antibacterial agents.

Treatment with antibacterial agents alters normal flora of the colon and may permit overgrowth of clostridia. Studies indicate that a toxin produced by Clostridium difficile is one primary cause of "antibiotic-associated colitis".

After the diagnosis of pseudomembranous colitis has been established, appropriate therapeutic measures should be initiated. Mild cases of pseudomembranous colitis usually respond to drug discontinuation alone. In moderate to severe cases, consideration should be given to management with fluids and electrolytes, protein supplementation, and treatment with an antibacterial drug clinically effective against Clostridium difficile.

Precautions

General

As with other broad-spectrum antibiotics, prolonged treatment may result in the possible emergence and overgrowth of resistant organisms. Careful observation of the patient is essential. If superinfection occurs during therapy, appropriate measures should be taken.

The dose of ceftibuten may require adjustment in patients with varying degrees of renal insufficiency, particularly in patients with creatinine clearance less than 50 mL/min or undergoing hemodialysis (see DOSAGE AND ADMINISTRATION). Ceftibuten is readily dialyzable. Dialysis patients should be monitored carefully, and administration of ceftibuten should occur immediately following dialysis.

Ceftibuten should be prescribed with caution to individuals with a history of gastrointestinal disease, particularly colitis.

Information to Patients

Patients should be informed that:

• If the patient is diabetic, he/she should be informed that Cedax Oral Suspension contains 1 gram sucrose per teaspoon of suspension.


• Cedax Oral Suspension should be taken at least 2 hours before a meal or at least 1 hour after a meal (see CLINICAL PHARMACOLOGY, Food Effect on Absorption).

Drug Interactions

Theophylline

Twelve healthy male volunteers were administered one 200-mg ceftibuten capsule twice daily for 6 days. With the morning dose of ceftibuten on day 6, each volunteer received a single intravenous infusion of theophylline (4 mg/kg). The pharmacokinetics of theophylline were not altered. The effect of ceftibuten on the pharmacokinetics of theophylline administered orally has not been investigated.

Antacids or H2-receptor antagonists

The effect of increased gastric pH on the bioavailability of ceftibuten was evaluated in 18 healthy adult volunteers. Each volunteer was administered one 400-mg ceftibuten capsule. A single dose of liquid antacid did not affect the Cmax or AUC of ceftibuten; however, 150 mg of ranitidine q12h for 3 days increased the ceftibuten Cmax by 23% and ceftibuten AUC by 16%. The clinical relevance of these increases is not known.

Drug/Laboratory Test Interactions

There have been no chemical or laboratory test interactions with ceftibuten noted to date. False-positive direct Coombs' tests have been reported during treatment with other cephalosporins. Therefore, it should be recognized that a positive Coombs' test could be due to the drug. The results of assays using red cells from healthy subjects to determine whether ceftibuten would cause direct Coombs' reactions in vitro showed no positive reaction at ceftibuten concentrations as high as 40 µg/mL.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term animal studies have not been performed to evaluate the carcinogenic potential of ceftibuten. No mutagenic effects were seen in the following studies: in vitro chromosome assay in human lymphocytes, in vivo chromosome assay in mouse bone marrow cells, Chinese Hamster Ovary (CHO) cell point mutation assay at the hypoxanthine-guanine phosphoribosyl transferase (HGPRT) locus, and in a bacterial reversion point mutation test (Ames). No impairment of fertility occurred when rats were administered ceftibuten orally up to 2000 mg/kg/day (approximately 43 times the human dose based on mg/m2/day).

Pregnancy

Teratogenic effects

Pregnancy Category B

Ceftibuten was not teratogenic in the pregnant rat at oral doses up to 400 mg/kg/day (approximately 8.6 times the human dose based on mg/m2/day). Ceftibuten was not teratogenic in the pregnant rabbit at oral doses up to 40 mg/kg/day (approximately 1.5 times the human dose based on mg/m2/day) and has revealed no evidence of harm to the fetus. There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Labor and Delivery

Ceftibuten has not been studied for use during labor and delivery. Its use during such clinical situations should be weighed in terms of potential risk and benefit to both mother and fetus.

Nursing Mothers

It is not known whether ceftibuten (at recommended dosages) is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when ceftibuten is administered to a nursing woman.

Pediatric Use

The safety and efficacy of ceftibuten in infants less than 6 months of age has not been established.

Geriatric Patients

The usual adult dosage recommendation may be followed for patients in this age group. However, these patients should be monitored closely, particularly their renal function, as dosage adjustment may be required.

ADVERSE EVENTS

Clinical Trials

Cedax CAPSULES (adult patients)

In clinical trials, 1728 adult patients (1092 US and 636 international) were treated with the recommended dose of ceftibuten capsules (400 mg per day). There were no deaths or permanent disabilities thought due to drug toxicity in any of the patients in these studies. Thirty-six of 1728 (2%) patients discontinued medication due to adverse events thought by the investigators to be possibly, probably, or almost certainly related to drug toxicity. The discontinuations were primarily for gastrointestinal disturbances, usually diarrhea, vomiting, or nausea. Six of 1728 (0.3%) patients were discontinued due to rash or pruritus thought related to ceftibuten administration.

In the US trials, the following adverse events were thought by the investigators to be possibly, probably, or almost certainly related to ceftibuten capsules in multipledose clinical trials (n = 1092 ceftibuten-treated patients).

ADVERSE REACTIONS CEFTIBUTEN CAPSULES US CLINICAL TRIALS IN ADULT PATIENTS (n = 1092)
Incidence equal to or greater than 1%	Nausea	4%
	Headache	3%
	Diarrhea	3%
	Dyspepsia	2%
	Dizziness	1%
	Abdominal pain	1%
	Vomiting	1%
Incidence less than 1% but greater than 0.1%	Anorexia, Constipation, Dry mouth, Dyspnea, Dysuria, Eructation, Fatigue, Flatulence, Loose stools, Moniliasis, Nasal congestion, Paresthesia, Pruritus, Rash, Somnolence, Taste perversion, Urticaria, Vaginitis

LABORATORY VALUE CHANGES* CEFTIBUTEN CAPSULES US CLINICAL TRIALS IN ADULT PATIENTS
* Changes in laboratory values with possible clinical significance regardless of whether or not the investigator thought that the change was due to drug toxicity.
Incidence equal to or greater than 1%	↑ BUN	4%
	↑ Eosinophils	3%
	↓ Hemoglobin	2%
	↑ ALT (SGPT)	1%
	↑ Bilirubin	1%
Incidence less than 1% but greater than 0.1%	↑ Alk phosphatase
	↑ Creatinine
	↑ Platelets
	↓ Platelets
	↓ Leukocytes
	↑ AST (SGOT)

Cedax ORAL SUSPENSION (pediatric patients)

In clinical trials, 1152 pediatric patients (772 US and 380 international), 97% of whom were younger than 12 years of age, were treated with the recommended dose of ceftibuten (9 mg/kg once daily up to a maximum dose of 400 mg per day) for 10 days. There were no deaths, life-threatening adverse events, or permanent disabilities in any of the patients in these studies. Eight of 1152 (<1%) patients discontinued medication due to adverse events thought by the investigators to be possibly, probably, or almost certainly related to drug toxicity. The discontinuations were primarily (7 out of 8) for gastrointestinal disturbances, usually diarrhea or vomiting. One patient was discontinued due to a cutaneous rash thought possibly related to ceftibuten administration.

In the US trials, the following adverse events were thought by the investigators to be possibly, probably, or almost certainly related to ceftibuten oral suspension in multipledose clinical trials (n = 772 ceftibuten-treated patients).

ADVERSE REACTIONS CEFTIBUTEN ORAL SUSPENSION US CLINICAL TRIALS IN PEDIATRIC PATIENTS (n = 772)
* NOTE: The incidence of diarrhea in pediatric patients ≤2 years old was 8% (23/301) compared with 2% (9/471) in pediatric patients >2 years old.
Incidence equal to or greater than 1%	Diarrhea*	4%
	Vomiting	2%
	Abdominal pain	2%
	Loose stools	2%
Incidence less than 1% but greater than 0.1%	Agitation, Anorexia, Dehydration, Diaper dermatitis, Dizziness, Dyspepsia, Fever, Headache, Hematuria, Hyperkinesia, Insomnia, Irritability, Nausea, Pruritus, Rash, Rigors, Urticaria

LABORATORY VALUE CHANGES* CEFTIBUTEN ORAL SUSPENSION US CLINICAL TRIALS IN PEDIATRIC PATIENTS
* Changes in laboratory values with possible clinical significance regardless of whether or not the investigator thought that the change was due to drug toxicity.
Incidence equal to or greater than 1%	↑ Eosinophils	3%
	↑ BUN	2%
	↓ Hemoglobin	1%
	↑ Platelets	1%
Incidence less than 1% but greater than 0.1%	↑ ALT (SGPT)
	↑ AST (SGOT)
	↑ Alk phosphatase
	↑ Bilirubin
	↑ Creatinine

In Post-marketing Experience

The following adverse experiences have been reported during worldwide post-marketing surveillance: aphasia, jaundice, melena, psychosis, serum sickness-like reactions, stridor, Stevens-Johnson syndrome, and toxic epidermal necrolysis.

Cephalosporin-class Adverse Reactions

In addition to the adverse reactions listed above that have been observed in patients treated with ceftibuten capsules, the following adverse events and altered laboratory tests have been reported for cephalosporin-class antibiotics:

 

allergic reactions, anaphylaxis, drug fever, Stevens-Johnson syndrome, renal dysfunction, toxic nephropathy, hepatic cholestasis, aplastic anemia, hemolytic anemia, hemorrhage, false-positive test for urinary glucose, neutropenia, pancytopenia, and agranulocytosis. Pseudomembranous colitis; onset of symptoms may occur during or after antibiotic treatment (see WARNINGS).

Several cephalosporins have been implicated in triggering seizures, particularly in patients with renal impairment when the dosage was not reduced (see DOSAGE AND ADMINISTRATION and OVERDOSAGE). If seizures associated with drug therapy occur, the drug should be discontinued. Anticonvulsant therapy can be given if clinically indicated.

Overdosage

Overdosage of cephalosporins can cause cerebral irritation leading to convulsions. Ceftibuten is readily dialyzable and significant quantities (65% of plasma concentrations) can be removed from the circulation by a single hemodialysis session. Information does not exist with regard to removal of ceftibuten by peritoneal dialysis.

Cedax Dosage and Administration

The recommended doses of Cedax Oral Suspension are presented in the table below. Cedax Oral Suspension must be administered at least 2 hours before or 1 hour after a meal.

Type of infection (as qualified in the INDICATIONS AND USAGE section of this labeling)	Daily Maximum Dose	Dose and Frequency	Duration
ADULTS (12 years of age and older):	400 mg	400 mg QD	10 days
Acute Bacterial Exacerbations of Chronic Bronchitis due to H. influenzae (including β-lactamase-producing strains), M. catarrhalis (including β-lactamase-producing strains), or Streptococcus pneumoniae (penicillin-susceptible strains only). (See INDICATIONS AND USAGE - NOTE.) Pharyngitis and tonsillitis due to S. pyogenes. Acute Bacterial Otitis Media due to H. influenzae (including β-lactamase-producing strains), M. catarrhalis (including β-lactamase-producing strains), or S. pyogenes. (See INDICATIONS AND USAGE - NOTE.)
PEDIATRIC PATIENTS:	400 mg	9 mg/kg QD	10 days
Pharyngitis and tonsillitis due to S. pyogenes. Acute Bacterial Otitis Media due to H. influenzae (including β-lactamase-producing strains), and M. catarrhalis (including β-lactamase-producing strains), or S. pyogenes. (See INDICATIONS AND USAGE - NOTE.)

CEFTIBUTEN ORAL SUSPENSION PEDIATRIC DOSAGE CHART
CHILD'S WEIGHT	90 mg/5 mL	180 mg/5 mL
Pediatric patients weighing more than 45 kg should receive the maximum daily dose of 400 mg.
10 kg 22 lbs	1 tsp QD	1/2 tsp QD
20 kg 44 lbs	2 tsp QD	1 tsp QD
40 kg 88 lbs	4 tsp QD	2 tsp QD

Renal Impairment

Cedax Capsules and Cedax Oral Suspension may be administered at normal doses in the presence of impaired renal function with creatinine clearance of 50 mL/min or greater. The recommendations for dosing in patients with varying degrees of renal insufficiency are presented in the following table.

Creatinine Clearance	Recommended Dosing Schedules
(mL/min)
>50	9 mg/kg or 400 mg Q24h
	(normal dosing schedule)
30-49	4.5 mg/kg or 200 mg Q24h
5-29	2.25 mg/kg or 100 mg Q24h

Hemodialysis Patients

In patients undergoing hemodialysis two or three times weekly, a single 400-mg dose of ceftibuten capsules or a single dose of 9 mg/kg (maximum of 400 mg of ceftibuten) oral suspension may be administered at the end of each hemodialysis session.

Directions for Mixing Cedax Oral Suspension

DIRECTIONS FOR MIXING Cedax ORAL SUSPENSION

Final Concentration	Bottle Size	Amount of Water	Directions
After mixing, the suspension may be kept for 14 days and must be stored in the refrigerator. Keep tightly closed. Shake well before each use. Discard any unused portion after 14 days.
90 mg per 5 mL	60 mL	Suspend in 53 mL of water	First tap the bottle to loosen powder. Then add water in two portions, shaking well after each aliquot.
	90 mL	Suspend in 78 mL of water
	120 mL	Suspend in 103 mL of water
180 mg per 5 mL	30 mL	Suspend in 2

Hexalen

Generic Name: altretamine (all TREH tah mean)

Brand Names: Hexalen

What is Hexalen (altretamine)?

Altretamine is a cancer (antineoplastic) medication. Altretamine interferes with the growth of cancer cells and slows their growth and spread in the body.

Altretamine is used to treat cancer of the ovaries.

Altretamine may also be used for purposes other than those listed in this medication guide.

What is the most important information I should know about Hexalen (altretamine)?

Altretamine should only be administered under the supervision of a qualified healthcare provider experienced in the use of cancer chemotherapeutic agents.

Serious side effects have been reported with the use of altretamine including: allergic reactions (difficulty breathing; closing of the throat; swelling of the lips, tongue, or face; or hives); decreased bone marrow function and blood problems (extreme fatigue; easy bruising or bleeding; black, bloody or tarry stools; fever or chills; or signs of infection such as fever; chills, or sore throat); neurologic problems (mood disorders, altered consciousness, weakness, dizziness, vertigo); and others. Talk to your doctor about the possible side effects from treatment with altretamine.

What should I discuss with my healthcare provider before taking Hexalen (altretamine)?

Before taking altretamine, tell your doctor if you have:

• 
  

  any nervous system (brain and nerves) problems; or

  
  


• 
  

  bone marrow problems.

  
  

You may not be able to take altretamine, or you may require a dosage adjustment or special monitoring during treatment if you have any of the conditions listed above.

Altretamine is in the FDA pregnancy category D. This means that altretamine is known to cause birth defects in an unborn baby. Do not take altretamine without first talking to your doctor if you are pregnant or could become pregnant during treatment. Contraceptive measures are recommended during treatment with altretamine. It is not known whether altretamine passes into breast milk. Do not take altretamine without first talking to your doctor if you are breast feeding a baby.

How should I take Hexalen (altretamine)?

Take altretamine exactly as directed by your doctor. If you do not understand these instructions, as your doctor, nurse or pharmacist to explain them to you.

Your doctor will determine the correct amount and frequency of treatment with altretamine depending upon the cancer being treated and other factors. Talk to your doctor if you have any questions or concerns regarding the treatment schedule.

Altretamine is usually taken four times a day, after meals and at bedtime.

Take each oral dose with a large glass of water.

Your doctor will probably want you to have regularly scheduled blood tests and other medical evaluations during treatment with altretamine to monitor progress and side effects.

Store altretamine capsules at room temperature away from heat and moisture. Keep this product out of the reach of children.

See also: Hexalen dosage (in more detail)

What happens if I miss a dose?

Contact your doctor if you miss a dose of altretamine.

What happens if I overdose?

If for any reason an overdose of altretamine is suspected, seek emergency medical attention or contact your healthcare provider immediately.

Symptoms of an altretamine overdose tend to be similar to side effects caused by the medication, although often more severe.

What should I avoid while taking Hexalen (altretamine)?

Altretamine can lower the activity of your immune system making you susceptible to infections. Avoid contact with people who have colds, the flu, or other contagious illnesses and do not receive vaccines that contain live strains of a virus (e.g., live oral polio vaccine) during treatment with altretamine. In addition, avoid contact with individuals who have recently been vaccinated with a live vaccine. There is a chance that the virus can be passed on to you.

Hexalen (altretamine) side effects

If you experience any of the following serious side effects, seek emergency medical attention or contact your doctor immediately:

• 
  

  an allergic reaction (shortness of breath; closing of your throat; difficulty breathing; swelling of your lips, face, or tongue; or hives);

  
  


• 
  

  decreased bone marrow function and blood problems (extreme fatigue; easy bruising or bleeding; black, bloody or tarry stools; or fever, chills, or signs of infection);

  
  


• 
  

  pain, tremors, tingling, burning, or prickling in hands or feet;

  
  


• 
  

  mood changes;

  
  


• 
  

  severe drowsiness or loss of consciousness;

  
  


• 
  

  loss of coordination, weakness, dizziness, unsteadiness or falling; or

  
  


• 
  

  severe nausea or vomiting.

  
  

Other less serious side effects may be more likely to occur. Talk to your doctor if you experience:

• 
  

  temporary hair loss;

  
  


• 
  

  itching or rash; or

  
  


• 
  

  mild to moderate nausea or vomiting.

  
  

Side effects other than those listed here may also occur. Talk to your doctor about any side effect that seems unusual or that is especially bothersome. You may report side effects to FDA at 1-800-FDA-1088.

What other drugs will affect Hexalen (altretamine)?

Before taking altretamine, tell your doctor if you are taking a monoamine oxidase inhibitor (MAOI) such as isocarboxazid (Marplan), phenelzine (Nardil), or tranylcypromine (Parnate). You may require a dosage adjustment or special monitoring during treatment if you are taking one of these medicines.

Before taking altretamine, tell your doctor if you are taking cimetidine (Tagamet, Tagamet HB). You may require a dosage adjustment or special monitoring during treatment.

Do not receive "live" vaccines during treatment with altretamine. Administration of a live vaccine may be dangerous during treatment with altretamine.

Drugs other than those listed here may also interact with altretamine. Talk to your doctor and pharmacist before taking any other prescription or over-the-counter medicines, including herbal products, during treatment with altretamine.

More Hexalen resources

• Hexalen Side Effects (in more detail)
• Hexalen Dosage
• Hexalen Use in Pregnancy & Breastfeeding
• Drug Images
• Hexalen Drug Interactions
• Hexalen Support Group
• 0 Reviews for Hexalen - Add your own review/rating

• Hexalen Prescribing Information (FDA)


• Hexalen MedFacts Consumer Leaflet (Wolters Kluwer)


• Hexalen Monograph (AHFS DI)


• Hexalen Advanced Consumer (Micromedex) - Includes Dosage Information


• Altretamine Professional Patient Advice (Wolters Kluwer)

Compare Hexalen with other medications

• Ovarian Cancer

Where can I get more information?

• Your pharmacist has additional information about altretamine written for health professionals that you may read.

See also: Hexalen side effects (in more detail)

Oxaliplatin Hospira 5 mg / ml Concentrate for Solution for Infusion

1. Name Of The Medicinal Product

Oxaliplatin Hospira 5 mg/ml Concentrate for Solution for Infusion

2. Qualitative And Quantitative Composition

One ml of concentrate for solution for infusion contains 5 mg oxaliplatin.

10 ml of concentrate for solution for infusion contains 50 mg of oxaliplatin.

20 ml of concentrate for solution for infusion contains 100 mg of oxaliplatin.

40 ml of concentrate for solution for infusion contains 200 mg of oxaliplatin.

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Concentrate for solution for infusion.

Clear, colourless solution.

4. Clinical Particulars

4.1 Therapeutic Indications

Oxaliplatin in combination with 5-fluorouracil (5-FU) and folinic acid (FA) is indicated for:

• Adjuvant treatment of stage III (Duke's C) colon cancer after complete resection of primary tumour

• Treatment of metastatic colorectal cancer.

4.2 Posology And Method Of Administration

The preparation of injectable solutions of cytotoxic agents must be carried out by trained specialist personnel with knowledge of the medicinal product used, in conditions that guarantee the integrity of the medicinal product, the protection of the environment and in particular the protection of the personnel handling the medicinal products, in accordance with hospital policy. It requires a preparation area reserved for this purpose. It is forbidden to smoke, eat or drink in this area (see section 6.6).

Posology

FOR ADULTS ONLY

The recommended dose for oxaliplatin in adjuvant setting is 85 mg/m² intravenously repeated every 2 weeks for 12 cycles (6 months).

The recommended dose for oxaliplatin in treatment of metastatic colorectal cancer is 85 mg/m² intravenously repeated every 2 weeks.

Dosage given should be adjusted according to tolerability (see section 4.4).

Oxaliplatin should always be administered before fluoropyrimidines – i.e. 5-fluorouracil.

Oxaliplatin is administered as a 2- to 6-hour intravenous infusion in 250 to 500 ml of glucose 5% solution (50 mg/ml) to give a concentration between 0.2 mg/ml and 0.70 mg/ml; 0.70 mg/ml is the highest concentration in clinical practice for an oxaliplatin dose of 85 mg/m².

Oxaliplatin was mainly used in combination with continuous infusion 5-fluorouracil based regimens. For the two-weekly treatment schedule 5-fluorouracil regimens combining bolus and continuous infusion were used.

Special Populations

- Renal impairment:

Oxaliplatin has not been studied in patients with severe renal impairment (See section 4.3).

In patients with moderate renal impairment, treatment may be initiated at the normally recommended dose (see section 4.4). There is no need for dose adjustment in patients with mild renal dysfunction.

- Hepatic impairment:

In a phase I study including patients with several levels of hepatic impairment, frequency and severity of hepatobiliary disorders appeared to be related to progressive disease and impaired liver function tests at baseline. No specific dose adjustment for patients with abnormal liver function tests was performed during clinical development.

- Elderly patients:

No increase in severe toxicities was observed when oxaliplatin was used as a single agent or in combination with 5-fluorouracil in patients over the age of 65. In consequence no specific dose adaptation is required for elderly patients.

Method of administration

Oxaliplatin is administered by intravenous infusion.

The administration of oxaliplatin does not require hyperhydration.

Oxaliplatin diluted in 250 to 500 ml of glucose 5% solution (50 mg/ml) to give a concentration not less than 0.2 mg/ml must be infused either via a peripheral vein or central venous line over 2 to 6 hours. Oxaliplatin infusion must always precede that of 5-fluorouracil.

In the event of extravasation, administration must be discontinued immediately.

Instructions for use:

Oxaliplatin must be diluted before use. Only 5% glucose diluent is to be used to dilute the concentrate for solution for infusion product. (See section 6.6).

4.3 Contraindications

Oxaliplatin is contraindicated in patients who

- have hypersensitivity to oxaliplatin or to the excipient.

- are breast feeding.

- have myelosuppression prior to starting first course, as evidenced by baseline neutrophils <2x10⁹/l and/or platelet count of <100x10⁹l.

- have a peripheral sensory neuropathy with functional impairment prior to first course.

- have a severely impaired renal function (creatinine clearance less than 30 ml/min).

4.4 Special Warnings And Precautions For Use

Oxaliplatin should only be used in specialised departments of oncology and should be administered under the supervision of an experienced oncologist.

Due to limited information on safety in patients with moderately impaired renal function, administration should only be considered after suitable appraisal of the benefit/risk for the patient. In this situation, renal function should be closely monitored and dose adjusted according to toxicity.

Patients with a history of allergic reaction to platinum compounds should be monitored for allergic symptoms. In case of an anaphylactic-like reaction to oxaliplatin, the infusion should be immediately discontinued and appropriate symptomatic treatment initiated. Oxaliplatin rechallenge is contra-indicated.

In case of oxaliplatin extravasation, the infusion must be stopped immediately and usual local symptomatic treatment initiated.

Neurological toxicity of oxaliplatin should be carefully monitored, especially if co-administered with other medicinal products with specific neurological toxicity. A neurological examination should be performed before each administration and periodically thereafter.

For patients who develop acute laryngopharyngeal dysaesthesia (see section 4.8), during or within the hours following the 2-hour infusion, the next oxaliplatin infusion should be administered over 6 hours.

If neurological symptoms (paraesthesia, dysaesthesia) occur, the following recommended oxaliplatin dosage adjustment should be based on the duration and severity of these symptoms:

- If symptoms last longer than seven days and are troublesome, the subsequent oxaliplatin dose should be reduced from 85 to 65 mg/m² (metastatic setting) or 75 mg/m² (adjuvant setting).

- If paraesthesia without functional impairment persists until the next cycle, the subsequent oxaliplatin dose should be reduced from 85 to 65 mg/m²(metastatic setting) or 75 mg/m² (adjuvant setting).

- If paraesthesia with functional impairment persists until the next cycle, oxaliplatin should be discontinued.

- If these symptoms improve following discontinuation of oxaliplatin therapy, resumption of therapy may be considered.

Patients should be informed of the possibilities of persistent symptoms of peripheral sensory neuropathy after the end of the treatment. Localised moderate parasthesias or parasthesias that may interfere with functional activities can persist after up to 3 years following treatment cessation in the adjuvant setting.

Gastrointestinal toxicity, which manifests as nausea and vomiting, warrants prophylactic and/or therapeutic anti-emetic therapy (see section 4.8).

Dehydration, paralytic ileus, intestinal obstruction, hypokalemia, metabolic acidosis and renal impairment may be caused by severe diarrhoea/emesis particularly when combining oxaliplatin with 5-fluorouracil.

If haematological toxicity occurs (neutrophils < 1.5x10⁹/l or platelets < 50x10⁹/l), administration of the next course of therapy should be postponed until haematological values return to acceptable levels. A full blood count with white cell differential should be performed prior to start of therapy and before each subsequent course.

Patients must be adequately informed of the risk of diarrhoea/emesis, mucositis/stomatitis and neutropenia after oxaliplatin and /5-fluorouracil administration so that they can urgently contact their treating physician for appropriate management. If mucositis/stomatitis occurs with or without neutropenia, the next treatment should be delayed until recovery from mucositis/stomatitis to grade 1 or less and/or until the neutrophil count is ⁹/l.

For oxaliplatin combined with 5-fluorouracil (with or without folinic acid), the usual dose adjustments for 5-fluorouracil associated toxicities should apply.

If grade 4 diarrhoea, grade 3-4 neutropenia (neutrophils < 1.0x10⁹/l), grade 3-4 thrombocytopenia (platelets < 50x10⁹/l) occur, the dose of oxaliplatin should be reduced from 85 to 65 mg/m² (metastatic setting) or 75 mg/m² (adjuvant setting), in addition to any 5-fluorouracil dose reductions required.

In the case of unexplained respiratory symptoms such as non-productive cough, dyspnoea, crackles or radiological pulmonary infiltrates, oxaliplatin should be discontinued until further pulmonary investigations exclude an interstitial lung disease or pulmonary fibrosis (see section 4.8).

In cases of abnormal test results of liver function or portal hypertension, which does not obviously result from liver metastases, very rare cases of drug induced hepatic vascular disorder should be considered.

For use in pregnant women see section 4.6.

Genotoxic effects were observed with oxaliplatin in the preclinical studies. Therefore male patients treated with oxaliplatin are advised not to father a child during and up to 6 months after treatment and to seek advice on conservation of sperm prior to treatment, because oxaliplatin may have an anti-fertility effect which could be irreversible.

Women should not become pregnant during treatment with oxaliplatin and should use an effective method of contraception (see section 4.6).

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

In patients who have received a single dose of 85 mg/m² of oxaliplatin, immediately before administration of 5-fluorouracil, no change in the level of exposure to 5-fluorouracil has been observed.

In vitro, no significant displacement of oxaliplatin binding to plasma proteins has been observed with the following agents: erythromycin, salicylates, granisetron, paclitaxel, and sodium valproate.

4.6 Pregnancy And Lactation

To date there is no available information on safety of use in pregnant women. In animal studies, reproductive toxicity was observed. Consequently oxaliplatin is not recommended during pregnancy and in women of childbearing potential not using contraceptive measures.

The use of oxaliplatin should only be considered after suitably appraising the patient of the risk to the foetus and with the patient's consent.

Appropriate contraceptive measures must be taken during and after cessation of therapy during 4 months for women and 6 months for men.

Excretion in breast milk has not been studied. Breast-feeding is contra-indicated during oxaliplatin therapy.

Oxaliplatin may have an anti-fertility effect (see section 4.4).

4.7 Effects On Ability To Drive And Use Machines

No studies on the effects on the ability to drive and use machinery have been preformed. However, oxaliplatin treatment resulting in an increased risk of dizziness, nausea and vomiting, and other neurological symptoms that affect gait and balance may lead to a minor or moderate influence on the ability to drive and use machines.

4.8 Undesirable Effects

The most frequent adverse events of oxaliplatin in combination with 5-fluorouracil/folinic acid (5-FU/FA) were gastrointestinal (diarrhoea, nausea, vomiting and mucositis), haematological (neutropenia, thrombocytopenia) and neurological (acute and dose cumulative peripheral sensory neuropathy). Overall these adverse events were more frequent and severe with oxaliplatin and 5-FU/FA combination than with 5-FU/FA alone.

The frequencies reported in the table below are derived from clinical trials in the metastatic and adjuvant settings (having included 416 and 1108 patients respectively in the oxaliplatin + 5-FU/FA treatment arms) and from post marketing experience.

Frequencies in this table are defined using the following convention: very common (

Further details are given after the table.

MedDRA Organ System Class	Very common	Common	Uncommon	Rare
Infections and infestations*	Infection	Rhinitis Upper respiratory tract infection Neutropenic sepsis Febrile neutropenia
Blood and lymphatic system disorders*	Anaemia Neutropenia Thrombocytopenia Leukopenia Lymphopenia			- Autoimmune thrombocytopenia Haemolytic anaemia
Immune system disorders*	Allergy/allergic reaction+
Metabolism and nutrition disorders	Anorexia Glycaemia alterations Hypokalaemia Natremia alterations	Dehydration	Metabolic acidosis
Psychiatric disorders		Depression Insomnia	Nervousness
Nervous system disorders*	Peripheral sensory neuropathy Sensory disturbance Dysgeusia Headache	Dizziness Motor neuritis Meningism		Dysarthria
Eye disorders		Conjunctivitis Visual disturbances		Visual acuity reduced transiently Visual field disturbance Optic neuritis
Ear and labyrinth disorders			Ototoxicity	Deafness
Vascular disorders	Epistaxis	Haemorrhage Flushing Deep vein thrombosis Pulmonary embolism
Respiratory, thoracic and medistinal disorders	Dyspnoea Coughing	Hiccups		Interstitial lung disease Pulmonary fibrosis**
Gastointestinal disorders*	Nausea Diarrhoea Vomiting Stomatitis/mucositis Abdominal pain Constipation	Dyspepsia Gastroesophageal reflux Rectal haemorrhage	Ileus Intestinal obstruction	Colitis including Clostridium difficile diarrhoea
Skin and subcutaneous tissue disorders	Skin disorder Alopecia	Skin exfolation (i.e Hand and Foot syndrome) Rash erythematous Rash Hyperhidrosis Nail disorder
Musculo-skeletal, connective tissue disorders	Back pain	Arthralgia Bone pain
Renal and urinary disorders		Dysuria Micturition frequency abnormal Haematuria
General disorders and administration site conditions	Fatigue Fever++ Asthenia Pain Injection site reaction+++
Investigations	Hepatic enzyme increase Blood alkaline phosphatase increase Blood bilirubin increase Blood lactate dehydrogenase increase Weight increase (adjuvant setting)	Blood Creatinine increase Weight decrease (metastatic setting)

* See detailed section below

** See section 4.4

+ Common allergic reactions such as skin rash (particularly urticaria), conjunctivitis, rhinitis. Common anaphylactic reactions, including bronchospasm, sensation of chest pain, angioedema, hypotension and anaphylactic shock.

++ Very common fever, rigors (tremors), either from infection (with or without febrile neutropenia) or possibly from immunological mechanism.

+++ Injection site reaction including local pain, redness, swelling and thrombosis have been reported. Extravasation may result in local pain and inflammation which may be severe and lead to complications, including necrosis, especially when oxaliplatin is infused through a peripheral vein (see 4.4).

Hepatobiliary disorders

Very rare (<1/10,000):

Liver sinusoidal obstruction syndrome, also known as veno-occlusive liver disease or pathological manifestations related to such liver disorders, including peliosis hepatis, nodular regenerative hyperplasia, perisinusoidal fibrosis. Clinical manifestations may be portal hypertension and/or elevation of transaminases.

Renal and urinary disorders

Very rare (:

Acute tubulo-interstitial nephropathy leading to acute renal failure.

Haematological toxicity:

Incidence by patient (%), by grade

Oxaliplatin and 5FU/FA 85 mg/m2 every 2 weeks	Metastatic Setting	Adjuvant Setting
All grades	Gr 3	Gr 4	All grades	Gr 3	Gr 4
Anaemia	82.2	3	<1	75.6	0.7	0.1
Neutropenia	71.4	28	14	78.9	28.8	12.3
Thrombocytopenia	71.6	4	<1	77.4	1.5	0.2
Febrile neutropenia	5.0	3.6	1.4	0.7	0.7	0.0
Neutropenic sepsis	1.1	0.7	0.4	1.1	0.6	0.4

Digestive toxicity:

Incidence by patient (%), by grade

Oxaliplatin and 5FU/FA 85 mg/m 2	Metastatic Setting	Adjuvant Setting
Every 2 weeks	All grades	Gr 3	Gr 4	All grades	Gr 3	Gr 4
Nausea	69.9	8	<1	73.7	4.8	0.3
Diarrhoea	60.8	9	2	56.3	8.3	2.5
Vomiting	49.0	6	1	47.2	5.3	0.5
Mucositis / Stomatitis	39.9	4	<1	42.1	2.8	0.1

Prophylaxis and/or treatment with potent antiemetic agents is indicated.

Dehydration, paralytic ileus, intestinal obstruction, hypokalemia, metabolic acidosis and renal impairment may be caused by severe diarrhoea/emesis particularly when combining oxaliplatin with 5-fluorouracil (see section 4.4).

Nervous system:

The dose limiting toxicity of oxaliplatin is neurological. It involves a sensory peripheral neuropathy characterised by dysaesthesia and/or parasthesia of the extremities with or without cramps, often triggered by the cold. These symptoms occur in up to 95% of patients treated. The duration of these symptoms, which usually regress between courses of treatment, increases with the number of treatment cycles.

The onset of pain and/or a functional disorder are indications, depending on the duration of the symptoms, for dose adjustment, or even treatment discontinuation (see section 4.4).

This functional disorder includes difficulties in executing delicate movements and is a possible consequence of sensory impairment. The risk of occurrence of persistent symptoms for a cumulative dose of 850 mg/m² (10 cycles) is approximately 10% and 20% for a cumulative dose of 1020 mg/m² (12 cycles).

In the majority of cases, the neurological signs and symptoms improve or totally recover when treatment is discontinued. In the adjuvant setting of colon cancer, 6 months after treatment cessation, 87% of patients had no or mild symptoms. After up to 3 years of follow up, about 3% of patients presented either with persisting localised paraesthesias of moderate intesity (2.3%) or with paraesthesias that may interfere with functional activities (0.5%).

Acute neurosensory manifestations (see section 5.3) have been reported. They start within hours of administration and often occur on exposure to cold. They usually present as transient paresthesia, dysesthesia and hypoesthesia. An acute syndrome of pharyngolaryngeal dysesthesia occurs in 1% and 2% of patients and is characterised by subjective sensations of dysphagia or dyspnoea/feeling of suffocation, without any objective evidence of respiratory distress (no cyanosis or hypoxia) or of laryngospasm or bronchospasm (no stridor or wheezing). Although antihistamines and bronchodilators have been administered in such cases, the symptoms are rapidly reversible even in the absence of treatment. Prolongation of the infusion helps to reduce the incidence of this syndrome (see section 4.4). Occasionally other symptoms that have been observed include jaw spasm/muscle spasm/muscle contractions-involuntary/muscle twitching/myoclonus, coordination abnormal/gait abnormal/ataxia/balance disorders, throat or chest tightness/pressure/discomfort /pain. In addition, cranial nerve dysfunction may be associated, or also occur as an isolated event such as ptosis, diplopia, aphonia/dysphonia, hoarseness, sometimes described as vocal cord paralysis, abnormal tongue sensation or dysarthria, sometimes described as aphasia, trigeminal neuralgia/facial pain/eye pain, decrease in visual acuity, visual field disorders.

Other neurological symptoms such as dysarthria, loss of deep tendon reflex and Lhermitte's sign were reported during treatment with oxaliplatin. Isolated cases of optic neuritis have been reported.

Allergic reactions:

Incidence by patient (%), by grade

Oxaliplatin and 5FU/FA 85 mg/m 2 every 2 weeks	Metastatic Setting	Adjuvant Setting
All grades	Gr 3	Gr 4	All grades	Gr 3	Gr 4
Allergic reactions / Allergy	9.1	1	<1	10.3	2.3	0.6

4.9 Overdose

There is no known antidote to oxaliplatin. In cases of overdose, exacerbation of adverse events can be expected. Monitoring of haematological parameters should be initiated and symptomatic treatment given.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Other antineoplastic agents, platinum compounds.

ATC code : L01XA 03

Oxaliplatin is an antineoplastic drug belonging to a new class of platinum-based compounds in which the platinum atom is complexed with 1,2-diaminocyclohexane (“DACH” ) and an oxalate group.

Oxaliplatin is a single enantiomer, the Cis -[oxalato ( trans-l-1,2- DACH ) platinum].

Oxaliplatin exhibits a wide spectrum of both in vitro cytotoxicity and in vivo antitumour activity in a variety of tumour model systems including human colorectal cancer models. Oxaliplatin also demonstrates in vitro and in vivo activity in various cisplatin resistant models.

A synergistic cytotoxic action has been observed in combination with 5-fluorouracil both in vitro and in vivo.

Studies on the mechanism of action of oxaliplatin, although not completely elucidated, show that the aqua-derivatives resulting from the biotransformation of oxaliplatin, interact with DNA to form both inter and intra-strand cross-links, resulting in the disruption of DNA synthesis leading to cytotoxic and antitumour effects.

In patients with metastatic colorectal cancer, the efficacy of oxaliplatin (85mg/m² repeated every two weeks) combined with 5-fluorouracil/folinic acid is reported in three clinical studies:

- In front-line treatment, the 2-arm comparative phase III EFC2962 study randomized patients either to 5-fluorouracil/folinic acid alone (LV5FU2, N=210) or the combination of oxaliplatin with 5-fluorouracil/folinic (FOLFOX4, N=210)

- In pretreated patients the comparative 3-arm EFC4584 study randomized patients refractory to an irinotecan (CPT-11) + 5-fluorouracil/folinic combination either to 5-fluorouracil/folinic acid alone (LV5FU2, N=275), oxaliplatin single agent (N=275), or combination of oxaliplatin with 5-fluorouracil/folinic (FOLFOX4, N=271)

- Finally, the uncontrolled phase II EFC2964 study included patients refractory to 5-fluorouracil/folinic acid alone, that were treated with the oxaliplatin and 5-fluorouracil/folinic acid combination (FOLFOX4, N=57)

The two randomized clinical trials, EFC2962 in front-line therapy and EFC4584 in pretreated patients, demonstrated a significantly higher response rate and a prolonged progression free survival (PFS)/time to progression (TTP) as compared to treatment with 5-fluorouracil/folinic acid alone. IN EFC 4584 performed in refractory pretreated patients, the difference in median overall survival (OS) between the combination of oxaliplatin and 5-FU/FA did not reach statistical significance.

Response rate under FOLFOX4 versus LV5FU2

Response rate % (95% CI) Independent radiological review ITT analysis	LV5FU2	FOLFOX4	Oxaliplatin Single agent
Front-line treatment EFC2962 Response assessment every 8 weeks	22 (16-27)	49 (42-46)	NA*
P value = 0.0001
Pretreated patients EFC4584 (refractory to CPT-11 + 5FU/FA) Response assessment every 6 weeks	0.7 (0.0-2.7)	11.1 (7.6-15.5)	1.1 (0.2-3.2)
P value < 0.0001
Pretreated patients EFC2964 (refractory to 5-FU/FA) Response assessment every 12 weeks	NA*	23 (13-36)	NA*

NA: Not Applicable

Median Progression Free Survival (PFS) / Median Time to Progression (TTP) FOLFOX4 versus LV5FU2

Median PFS/TTP, Months (95% CI)