Rivastigmine Sandoz 2 mg / ml oral solution

1. Name Of The Medicinal Product

Rivastigmine Sandoz 2 mg/ml oral solution

2. Qualitative And Quantitative Composition

Each ml contains rivastigmine hydrogen tartrate corresponding to rivastigmine base 2.0 mg.

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Oral solution

Clear, yellow solution.

4. Clinical Particulars

4.1 Therapeutic Indications

Symptomatic treatment of mild to moderately severe Alzheimer's dementia.

Symptomatic treatment of mild to moderately severe dementia in patients with idiopathic Parkinson's disease.

4.2 Posology And Method Of Administration

Treatment should be initiated and supervised by a physician experienced in the diagnosis and treatment of Alzheimer's dementia or dementia associated with Parkinson's disease. Diagnosis should be made according to current guidelines. Therapy with rivastigmine should only be started if a caregiver is available who will regularly monitor intake of the medicinal product by the patient.

Rivastigmine oral solution should be administered twice a day, with morning and evening meals. The prescribed amount of solution should be withdrawn from the container using the oral dosing syringe supplied. Rivastigmine oral solution may be swallowed directly from the syringe. Rivastigmine oral solution and rivastigmine capsules may be interchanged at equal doses.

Initial dose

1.5 mg twice a day.

Dose titration

The starting dose is 1.5 mg twice a day. If this dose is well tolerated after a minimum of two weeks of treatment, the dose may be increased to 3 mg twice a day. Subsequent increases to 4.5 mg and then 6 mg twice a day should also be based on good tolerability of the current dose and may be considered after a minimum of two weeks of treatment at that dose level.

If adverse reactions (e.g. nausea, vomiting, abdominal pain or loss of appetite), weight decrease or worsening of extrapyramidal symptoms (e.g. tremor) in patients with dementia associated with Parkinson's disease are observed during treatment, these may respond to omitting one or more doses. If adverse reactions persist, the daily dose should be temporarily reduced to the previous well-tolerated dose or the treatment may be discontinued.

Maintenance dose

The effective dose is 3 to 6 mg twice a day; to achieve maximum therapeutic benefit patients should be maintained on their highest well tolerated dose. The recommended maximum daily dose is 6 mg twice a day.

Maintenance treatment can be continued for as long as a therapeutic benefit for the patient exists. Therefore, the clinical benefit of rivastigmine should be reassessed on a regular basis, especially for patients treated at doses less than 3 mg twice a day. If after 3 months of maintenance dose treatment the patient's rate of decline in dementia symptoms is not altered favourably, the treatment should be discontinued. Discontinuation should also be considered when evidence of a therapeutic effect is no longer present.

Individual response to rivastigmine cannot be predicted. However, a greater treatment effect was seen in Parkinson's disease patients with moderate dementia. Similarly a larger effect was observed in Parkinson's disease patients with visual hallucinations (see section 5.1).

Treatment effect has not been studied in placebo-controlled trials beyond 6 months.

Re-initiation of therapy

If treatment is interrupted for more than several days, it should be re-initiated at 1.5 mg twice daily. Dose titration should then be carried out as described above.

Renal and hepatic impairment

Due to increased exposure in moderate renal and mild to moderate hepatic impairment, dosing recommendations to titrate according to individual tolerability should be closely followed (see section 5.2).

Patients with severe liver impairment have not been studied (see section 4.3).

Children

Rivastigmine is not recommended for use in children.

4.3 Contraindications

The use of this medicinal product is contraindicated in patients with

- hypersensitivity to the active substance, other carbamate derivatives or to any of the excipients used in the formulation,

- severe liver impairment, as it has not been studied in this population.

4.4 Special Warnings And Precautions For Use

The incidence and severity of adverse reactions generally increase with higher doses. If treatment is interrupted for more than several days, it should be re-initiated at 1.5 mg twice daily to reduce the possibility of adverse reactions (e.g. vomiting).

Dose titration: Adverse reactions (e.g. hypertension and hallucinations in patients with Alzheimer's dementia and worsening of extrapyramidal symptoms, in particular tremor, in patients with dementia associated with Parkinson's disease) have been observed shortly after dose increase. They may respond to a dose reduction. In other cases, rivastigmine has been discontinued (see section 4.8).

Gastrointestinal disorders such as nausea and vomiting may occur particularly when initiating treatment and/or increasing the dose. These adverse reactions occur more commonly in women. Patients with Alzheimer's disease may lose weight. Cholinesterase inhibitors, including rivastigmine, have been associated with weight loss in these patients. During therapy patient's weight should be monitored.

In case of severe vomiting associated with rivastigmine treatment, appropriate dose adjustments as recommended in section 4.2 must be made. Some cases of severe vomiting were associated with oesophageal rupture (see section 4.8). Such events appeared to occur particularly after dose increments or high doses of rivastigmine.

Care must be taken when using rivastigmine in patients with sick sinus syndrome or conduction defects (sino-atrial block, atrio-ventricular block) (see section 4.8).

Rivastigmine may cause increased gastric acid secretions. Care should be exercised in treating patients with active gastric or duodenal ulcers or patients predisposed to these conditions.

Cholinesterase inhibitors should be prescribed with care to patients with a history of asthma or obstructive pulmonary disease.

Cholinomimetics may induce or exacerbate urinary obstruction and seizures. Caution is recommended in treating patients predisposed to such diseases.

One of the excipients in Rivastigmine Sandoz oral solution is sodium benzoate. Benzoic acid is a mild irritant to the skin, eyes and mucous membrane.

The use of rivastigmine in patients with severe dementia of Alzheimer's disease or associated with Parkinson's disease, other types of dementia or other types of memory impairment (e.g. age-related cognitive decline) has not been investigated and therefore use in these patient populations is not recommended.

Like other cholinomimetics, rivastigmine may exacerbate or induce extrapyramidal symptoms. Worsening (including bradykinesia, dyskinesia, gait abnormality) and an increased incidence or severity of tremor have been observed in patients with dementia associated with Parkinson's disease (see section 4.8). These events led to the discontinuation of rivastigmine in some cases (e.g. discontinuations due to tremor 1.7% on rivastigmine vs 0% on placebo). Clinical monitoring is recommended for these adverse reactions.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

As a cholinesterase inhibitor, rivastigmine may exaggerate the effects of succinylcholine-type muscle relaxants during anaesthesia. Caution is recommended when selecting anaesthetic agents. Possible dose adjustments or temporarily stopping treatment can be considered if needed.

In view of its pharmacodynamic effects, rivastigmine should not be given concomitantly with other cholinomimetic substances and might interfere with the activity of anticholinergic medicinal products.

No pharmacokinetic interaction was observed between rivastigmine and digoxin, warfarin, diazepam or fluoxetine in studies in healthy volunteers. The increase in prothrombin time induced by warfarin is not affected by administration of rivastigmine. No untoward effects on cardiac conduction were observed following concomitant administration of digoxin and rivastigmine.

According to its metabolism, metabolic interactions with other medicinal products appear unlikely, although rivastigmine may inhibit the butyrylcholinesterase mediated metabolism of other substances.

4.6 Pregnancy And Lactation

For rivastigmine no clinical data on exposed pregnancies are available. No effects on fertility or embryofoetal development were observed in rats and rabbits, except at doses related to maternal toxicity. In peri/postnatal studies in rats, an increased gestation time was observed. Rivastigmine should not be used during pregnancy unless clearly necessary.

In animals, rivastigmine is excreted into milk. It is not known if rivastigmine is excreted into human milk. Therefore, women on rivastigmine should not breast-feed.

4.7 Effects On Ability To Drive And Use Machines

Alzheimer's disease may cause gradual impairment of driving performance or compromise the ability to use machinery. Furthermore, rivastigmine can induce dizziness and somnolence, mainly when initiating treatment or increasing the dose. As a consequence, rivastigmine has minor or moderate influence on the ability to drive and use machines. Therefore, the ability of patients with dementia on rivastigmine to continue driving or operating complex machines should be routinely evaluated by the treating physician.

4.8 Undesirable Effects

The most commonly reported adverse reactions are gastrointestinal, including nausea (38%) and vomiting (23%), especially during titration. Female patients in clinical studies were found to be more susceptible than male patients to gastrointestinal adverse reactions and weight loss.

The following adverse reactions, listed below in Table 1, have been accumulated in patients with Alzheimer's dementia treated with rivastigmine.

Adverse reactions in Table 1 are listed according to MedDRA system organ class and frequency category. Frequency categories are defined using the following convention: very common (

Table 1

Infections and infestations Very rare	Urinary infection
Metabolism and nutritional disorders Very common	Anorexia
Psychiatric disorders Common Common Uncommon Uncommon Very rare	Agitation Confusion Insomnia Depression Hallucinations
Nervous system disorders Very common Common Common Common Uncommon Rare Very rare	Dizziness Headache Somnolence Tremor Syncope Seizures Extrapyramidal symptoms (including worsening of Parkinson's disease)
Cardiac disorders Rare Very rare	Angina pectoris Cardiac arrhythmia (e.g. bradycardia, atrio-ventricular block, atrial fibrillation and tachycardia)
Vascular disorders Very rare	Hypertension
Gastrointestinal disorders Very common Very common Very common Common Rare Very rare Very rare Not known	Nausea Vomiting Diarrhoea Abdominal pain and dyspepsia Gastric and duodenal ulcers Gastrointestinal haemorrhage Pancreatitis Some cases of severe vomiting were associated with oesophageal rupture (see section 4.4).
Hepatobiliary disorders Uncommon	Elevated liver function tests
Skin and subcutaneous tissue disorders Common Rare Not known	Sweating increased Rash Pruritus
General disorders and administration site conditions Common Common Uncommon	Fatigue and asthenia Malaise Accidental fall
Investigations Common	Weight loss

The following additional adverse reactions have been observed with rivastigmine transdermal patches: anxiety, delirium, pyrexia (common).

Table 2 shows the adverse reactions reported in patients with dementia associated with Parkinson's disease treated with rivastigmine.

Table 2

Metabolism and nutritional disorders Common Common	Anorexia Dehydration
Psychiatric disorders Common Common Common	Insomnia Anxiety Restlessness
Nervous system disorders Very common Common Common Common Common Common Common Uncommon	Tremor Dizziness Somnolence Headache Worsening of Parkinson's disease Bradykinesia Dyskinesia Dystonia
Cardiac disorders Common Uncommon Uncommon	Bradycardia Arial fibrillation Atrioventricular block
Gastrointestinal disorders Very common Very common Common Common Common	Nausea Vomiting Diarrhoea Abdominal pain and dyspepsia Salivary hypersecretion
Skin and subcutaneous tissue disorders Common	Sweating increased
Musculoskeletal and connective tissue disorders Common	Muscle rigidity
General disorders and administration site conditions Common Common	Fatigue and asthenia Gait abnormality

Table 3 lists the number and percentage of patients from the specific 24-week clinical study conducted with rivastigmine in patients with dementia associated with Parkinson's disease with pre-defined adverse events that may reflect worsening of parkinsonian symptoms.

Table 3

Pre-defined adverse events that may reflect worsening of parkinsonian symptoms in patients with dementia associated with Parkinson's disease	Rivastigmine n (%)	Placebo n (%)
Total patients studied Total patients with pre-defined AE(s)	362 (100) 99 (27.3)	179 (100) 28 (15.6)
Tremor Fall Parkinson's disease (worsening) Salivary hypersecretion Dyskinesia Parkinsonism Hypokinesia Movement disorder Bradykinesia Dystonia Gait abnormality Muscle rigidity Balance disorder Musculoskeletal stiffness Rigors Motor dysfunction	37 (10.2) 21 (5.8) 12 (3.3) 5 (1.4) 5 (1.4) 8 (2.2) 1 (0.3) 1 (0.3) 9 (2.5) 3 (0.8) 5 (1.4) 1 (0.3) 3 (0.8) 3 (0.8) 1 (0.3) 1 (0.3)	7 (3.9) 11 (6.1) 2 (1.1) 0 1 (0.6) 1 (0.6) 0 0 3 (1.7) 1 (0.6) 0 0 2 (1.1) 0 0 0

4.9 Overdose

Symptoms

Most cases of accidental overdose have not been associated with any clinical signs or symptoms and almost all of the patients concerned continued rivastigmine treatment. Where symptoms have occurred, they have included nausea, vomiting and diarrhoea, hypertension or hallucinations. Due to the known vagotonic effect of cholinesterase inhibitors on heart rate, bradycardia and/or syncope may also occur. Ingestion of 46 mg occurred in one case; following conservative management the patient fully recovered within 24 hours.

Treatment

As rivastigmine has a plasma half-life of about 1 hour and a duration of acetylcholinesterase inhibition of about 9 hours, it is recommended that in cases of asymptomatic overdose no further dose of rivastigmine should be administered for the next 24 hours. In overdose accompanied by severe nausea and vomiting, the use of antiemetics should be considered. Symptomatic treatment for other adverse reactions should be given as necessary.

In massive overdose, atropine can be used. An initial dose of 0.03 mg/kg intravenous atropine sulphate is recommended, with subsequent doses based on clinical response. Use of scopolamine as an antidote is not recommended.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: anticholinesterases, ATC code: N06DA03

Rivastigmine is an acetyl- and butyrylcholinesterase inhibitor of the carbamate type, thought to facilitate cholinergic neurotransmission by slowing the degradation of acetylcholine released by functionally intact cholinergic neurones. Thus, rivastigmine may have an ameliorative effect on cholinergic-mediated cognitive deficits in dementia associated with Alzheimer's disease and Parkinson's disease.

Rivastigmine interacts with its target enzymes by forming a covalently bound complex that temporarily inactivates the enzymes. In healthy young men, an oral 3 mg dose decreases acetylcholinesterase (AChE) activity in CSF by approximately 40% within the first 1.5 hours after administration. Activity of the enzyme returns to baseline levels about 9 hours after the maximum inhibitory effect has been achieved. In patients with Alzheimer's disease, inhibition of AChE in CSF by rivastigmine was dose-dependent up to 6 mg given twice daily, the highest dose tested. Inhibition of butyrylcholinesterase activity in CSF of 14 Alzheimer patients treated by rivastigmine was similar to that of AChE.

Clinical studies in Alzheimer's dementia

The efficacy of rivastigmine has been established through the use of three independent, domain specific, assessment tools which were assessed at periodic intervals during 6 month treatment periods. These include the ADAS-Cog (a performance based measure of cognition), the CIBIC-Plus (a comprehensive global assessment of the patient by the physician incorporating caregiver input), and the PDS (a caregiver-rated assessment of the activities of daily living including personal hygiene, feeding, dressing, household chores such as shopping, retention of ability to orient oneself to surroundings as well as involvement in activities relating to finances, etc.).

The patients studied had an MMSE (Mini-Mental State Examination) score of 10–24.

The results for clinically relevant responders pooled from two flexible dose studies out of the three pivotal 26-week multicentre studies in patients with mild-to-moderately severe Alzheimer's Dementia, are provided in Table 4 below. Clinically relevant improvement in these studies was defined a priori as at least 4-point improvement on the ADAS-Cog, improvement on the CIBIC-Plus, or at least a 10% improvement on the PDS.

In addition, a post-hoc definition of response is provided in the same table. The secondary definition of response required a 4-point or greater improvement on the ADAS-Cog, no worsening on the CIBIC-Plus, and no worsening on the PDS. The mean actual daily dose for responders in the 6–12 mg group, corresponding to this definition, was 9.3 mg. It is important to note that the scales used in this indication vary and direct comparisons of results for different therapeutic agents are not valid.

Table 4

	Patients with Clinically Significant Response (%)
	Intent to Treat	Last Observation Carried Forward
Response Measure	Rivastigmine 6-12 mg N=473	Placebo   N=472	Rivastigmine 6-12 mg N=379	Placebo   N=444
ADAS-Cog: improvement of at least 4 points	21***	12	25***	12
CIBIC-Plus: improvement	29***	18	32***	19
PDS: improvement of at least 10%	26***	17	30***	18
At least 4 points improvement on ADAS-Cog with no worsening on CIBIC-Plus and PDS	10*	6	12**	6

*p<0.05, **p<0.01, ***p<0.001

Clinical studies in dementia associated with Parkinson's disease

The efficacy of rivastigmine in dementia associated with Parkinson's disease has been demonstrated in a 24-week multicentre, double-blind, placebo-controlled core study and its 24-week open-label extension phase. Patients involved in this study had an MMSE (Mini-Mental State Examination) score of 10-24. Efficacy has been established by the use of two independent scales which were assessed at regular intervals during a 6-month treatment period as shown in Table 5 below: the ADAS-Cog, a measure of cognition, and the global measure ADCS-CGIC (Alzheimer's Disease Cooperative Study-Clinician's Global Impression of Change).

Table 5

Dementia associated with Parkinson's Disease	ADAS-Cog Rivastigmine	ADAS-Cog Placebo	ADCS-CGIC Rivastigmine	ADCS-CGIC Placebo
ITT + RDO population Mean baseline ± SD Mean change at 24 weeks ± SD	(n=329) 23.8 ± 10.2 2.1 ± 8.2	(n=161) 24.3 ± 10.5 -0.7 ± 7.5	(n=329) n/a 3.8 ± 1.4	(n=165) n/a 4.3 ± 1.5
Adjusted treatment difference p-value versus placebo	2.881 <0.0011	n/a 0.0072
ITT - LOCF population Mean baseline ± SD Mean change at 24 weeks ± SD	(n=287) 24.0 ± 10.3 2.5 ± 8.4	(n=154) 24.5 ± 10.6 -0.8 ± 7.5	(n=289) n/a 3.7 ± 1.4	(n=158) n/a 4.3 ± 1.5
Adjusted treatment difference p-value versus placebo	3.541 <0.0011	n/a <0.0012

¹ Based on ANCOVA with treatment and country as factors and baseline ADAS-Cog as a covariate. A positive change indicates improvement.

² Mean data shown for convenience, categorical analysis performed using van Elteren test

ITT: Intent-To-Treat; RDO: Retrieved Drop Outs; LOCF: Last Observation Carried Forward

Although a treatment effect was demonstrated in the overall study population, the data suggested that a larger treatment effect relative to placebo was seen in the subgroup of patients with moderate dementia associated with Parkinson's disease. Similarly a larger treatment effect was observed in those patients with visual hallucinations (see Table 6).

Table 6

Dementia associated with Parkinson's Disease	ADAS-Cog Rivastigmine	ADAS-Cog Placebo	ADAS-Cog Rivastigmine	ADAS-Cog Placebo
	Patients with visual hallucinations	Patients without visual hallucinations
ITT + RDO population Mean baseline ± SD Mean change at 24 weeks ± SD	(n=107) 25.4 ± 9.9 1.0 ± 9.2	(n=60) 27.4 ± 10.4 -2.1 ± 8.3	(n=220) 23.1 ± 10.4 2.6 ± 7.6	(n=101) 22.5 ± 10.1 0.1 ± 6.9
Adjusted treatment difference p-value versus placebo	4.271 0.0021	2.091 0.0151
	Patients with moderate dementia (MMSE 10-17)	Patients with mild dementia (MMSE 18-24)
ITT + RDO population Mean baseline ± SD Mean change at 24 weeks ± SD	(n=87) 32.6 ± 10.4 2.6 ± 9.4	(n=44) 33.7 ± 10.3 -1.8 ± 7.2	(n=237) 20.6 ± 7.9 1.9 ± 7.7	(n=115) 20.7 ± 7.9 -0.2 ± 7.5
Adjusted treatment difference p-value versus placebo	4.731 0.0021	2.141 0.0101

¹ Based on ANCOVA with treatment and country as factors and baseline ADAS-Cog as a covariate. A positive change indicates improvement.

ITT: Intent-To-Treat; RDO: Retrieved Drop Outs

5.2 Pharmacokinetic Properties

Absorption

Rivastigmine is rapidly and completely absorbed. Peak plasma concentrations are reached in approximately 1 hour. As a consequence of rivastigmine's interaction with its target enzyme, the increase in bioavailability is about 1.5-fold greater than that expected from the increase in dose. Absolute bioavailability after a 3 mg dose is about 36%±13%. Administration of rivastigmine oral solution with food delays absorption (t_max) by 74 min and lowers C_max by 43% and increases AUC by approximately 9%.

Distribution

Protein binding of rivastigmine is approximately 40%. It readily crosses the blood brain barrier and has an apparent volume of distribution in the range of 1.8–2.7 l/kg.

Metabolism

Rivastigmine is rapidly and extensively metabolised (half-life in plasma approximately 1 hour), primarily via cholinesterase-mediated hydrolysis to the decarbamylated metabolite. In vitro, this metabolite shows minimal inhibition of acetylcholinesterase (<10%). Based on evidence from in vitro and animal studies the major cytochrome P450 isoenzymes are minimally involved in rivastigmine metabolism. Total plasma clearance of rivastigmine was approximately 130 l/h after a 0.2 mg intravenous dose and decreased to 70 l/h after a 2.7 mg intravenous dose.

Excretion

Unchanged rivastigmine is not found in the urine; renal excretion of the metabolites is the major route of elimination. Following administration of ¹⁴C-rivastigmine, renal elimination was rapid and essentially complete (>90%) within 24 hours. Less than 1% of the administered dose is excreted in the faeces. There is no accumulation of rivastigmine or the decarbamylated metabolite in patients with Alzheimer's disease.

Elderly subjects

While bioavailability of rivastigmine is greater in elderly than in young healthy volunteers, studies in Alzheimer patients aged between 50 and 92 years showed no change in bioavailability with age.

Subjects with hepatic impairment

The C_max of rivastigmine was approximately 60% higher and the AUC of rivastigmine was more than twice as high in subjects with mild to moderate hepatic impairment than in healthy subjects.

Subjects with renal impairment

C_max and AUC of rivastigmine were more than twice as high in subjects with moderate renal impairment compared with healthy subjects; however there were no changes in C_max and AUC of rivastigmine in subjects with severe renal impairment.

5.3 Preclinical Safety Data

Repeated-dose toxicity studies in rats, mice and dogs revealed only effects associated with an exaggerated pharmacological action. No target organ toxicity was observed. No safety margins to human exposure were achieved in the animal studies due to the sensitivity of the animal models used.

Rivastigmine was not mutagenic in a standard battery of in vitro and in vivo tests, except in a chromosomal aberration test in human peripheral lymphocytes at a dose 10⁴ times the maximum clinical exposure. The in vivo micronucleus test was negative.

No evidence of carcinogenicity was found in studies in mice and rats at the maximum tolerated dose, although the exposure to rivastigmine and its metabolites was lower than the human exposure. When normalised to body surface area, the exposure to rivastigmine and its metabolites was approximately equivalent to the maximum recommended human dose of 12 mg/day; however, when compared to the maximum human dose, a multiple of approximately 6-fold was achieved in animals.

In animals, rivastigmine crosses the placenta and is excreted into milk. Oral studies in pregnant rats and rabbits gave no indication of teratogenic potential on the part of rivastigmine.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Sodium benzoate

Citric acid

Sodium citrate

Quinoline yellow WS dye (E104)

Purified water

6.2 Incompatibilities

Not applicable.

6.3 Shelf Li

Cefuroxime Dextrose

Generic Name: cefuroxime and dextrose

Dosage Form: injection, solution
CefUROXime for Injection USP and Dextrose Injection USP

To reduce the development of drug-resistant bacteria and maintain the effectiveness of Cefuroxime for Injection USP and Dextrose Injection USP and other antibacterial drugs, Cefuroxime for Injection USP and Dextrose Injection USP should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria.

Cefuroxime Dextrose Description

Cefuroxime for Injection USP and Dextrose Injection USP is a sterile, nonpyrogenic, single use, packaged combination of Cefuroxime Sodium USP (crystalline) and Dextrose Injection USP (diluent) in the DUPLEX® sterile container. The DUPLEX® Container is a flexible dual chamber container.

The drug chamber is filled with sterile crystalline Cefuroxime for Injection USP, a semisynthetic, broad-spectrum, cephalosporin antibiotic for parenteral administration. It is the sodium salt of (6R,7R) - 7 - [2 - (2 - furyl)glyoxylamido] - 3 - (hydroxymethyl) - 8 - oxo - 5 - thia - 1 - azabicyclo[4.2.0]oct - 2 - ene - 2 - carboxylate, 72-(Z)-(O-methyloxime), carbamate (ester).

Cefuroxime Sodium USP has the following structural formula:

The empirical formula is C16H15N4NaO8S, representing a molecular weight of 446.4.

Cefuroxime contains approximately 54.2 mg (2.4 mEq) of sodium per gram of cefuroxime activity.

The diluent chamber contains Dextrose Injection USP. The concentration of Hydrous Dextrose USP has been adjusted to render the reconstituted drug product iso-osmotic. Dextrose Injection USP is sterile, nonpyrogenic, and contains no bacteriostatic or antimicrobial agents.

Hydrous Dextrose USP has the following structural (molecular) formula:

The molecular weight of Hydrous Dextrose USP is 198.17.

Dextrose hydrous USP has been added to the diluent to adjust osmolality (approximately 2.05 g and 1.45 g to 750 mg and 1.5 g dosages, respectively).

After removing the peelable foil strip, activating the seals, and thoroughly mixing, the reconstituted drug product is intended for single intravenous use. When reconstituted, the approximate osmolality of the reconstituted solution for Cefuroxime for Injection USP and Dextrose Injection USP is 290 mOsmol/kg.

The DUPLEX® Container is Latex-free, PVC-free, and Di (2-ethylhexyl) phthalate (DEHP)-free.

The DUPLEX® dual chamber container is made from a specially formulated material. The product (diluent and drug) contact layer is a mixture of thermoplastic rubber and a polypropylene ethylene copolymer that contains no plasticizers. The safety of the container system is supported by USP biological evaluation procedures.

Cefuroxime Dextrose - Clinical Pharmacology

Following IV doses of 750 mg and 1.5 g, serum concentrations were approximately 50 and 100 mcg/mL, respectively, at 15 minutes. Therapeutic serum concentrations of approximately 2 mcg/mL or more were maintained for 5.3 hours and 8 hours or more, respectively. There was no evidence of accumulation of cefuroxime in the serum following IV administration of 1.5 g doses every 8 hours to normal volunteers. The serum half-life after IV injection is approximately 80 minutes.

Approximately 89% of a dose of cefuroxime is excreted by the kidneys over an 8 hour period, resulting in high urinary concentrations.

Intravenous doses of 750 mg and 1.5 g produced urinary levels averaging 1,150 and 2,500 mcg/mL, respectively, during the first 8 hour period.

The concomitant oral administration of probenecid with cefuroxime slows tubular secretion, decreases renal clearance by approximately 40%, increases the peak serum level by approximately 30%, and increases the serum half-life by approximately 30%. Cefuroxime is detectable in therapeutic concentrations in pleural fluid, joint fluid, bile, sputum, bone, cerebrospinal fluid (in patients with meningitis), and aqueous humor.

Cefuroxime is detectable in therapeutic concentrations in cerebrospinal fluid (CSF) of adults and pediatric patients with meningitis. The following table shows the concentrations of cefuroxime achieved in cerebrospinal fluid during multiple dosing of patients with meningitis.

Table 1. Concentrations of Cefuroxime Achieved in Cerebrospinal Fluid During Multiple Dosing of Patients with Meningitis

Patients	Dose	Number of Patients	Mean (Range) CFS Cefuroxime Concentrations (mcg/mL) Achieved Within 8 Hours Post Dose
Pediatric patients (4 weeks to 6.5 years)	200 mg/kg/day, divided q 6 hours	5	6.6 (0.9–17.3)
Pediatric patients (7 months to 9 years)	200 to 230 mg/kg/day, divided q 8 hours	6	8.3 (<2–22.5)
Adults	1.5 grams q 8 hours	2	5.2 (2.7–8.9)
Adults	1.5 grams q 6 hours	10	6.0 (1.5–13.5)

Cefuroxime is approximately 50% bound to serum protein.

Microbiology

Cefuroxime has in vitro activity against a wide range of gram-positive and gram-negative organisms, and it is highly stable in the presence of beta-lactamases of certain gram-negative bacteria. The bactericidal action of cefuroxime results from inhibition of cell-wall synthesis.

Cefuroxime is usually active against the following organisms in vitro.

Aerobes, Gram-positive:

Staphylococcus aureus

Staphylococcus epidermidis

Streptococcus pneumoniae, and

Streptococcus pyogenes (and other streptococci)

NOTE: Most strains of enterococci, e.g., Enterococcus faecalis (formerly Streptococcus faecalis), are resistant to cefuroxime. Methicillin-resistant staphylococci and Listeria monocytogenes are resistant to cefuroxime.

Aerobes, Gram-negative:

Citrobacter spp.

Enterobacter spp.

Escherichia coli

Haemophilus influenzae (including ampicillin-resistant strains)

Haemophilus parainfluenzae

Klebsiella spp. (including Klebsiella pneumoniae)

Moraxella (Branhamella) catarrhalis (including ampicillin- and cephalothin-resistant strains)

Morganella morganii (formerly Proteus morganii)

Neisseria gonorrhoeae (including penicillinase- and non-penicillinase-producing strains)

Neisseria meningitidis

Proteus mirabilis

Providencia rettgeri (formerly Proteus rettgeri)

Salmonella spp., and Shigella spp.

NOTE: Some strains of Morganella morganii, Enterobacter cloacae, and Citrobacter spp. have been shown by in vitro tests to be resistant to cefuroxime and other cephalosporins. Pseudomonas and Campylobacter spp., Acinetobacter calcoaceticus, and most strains of Serratia spp. and Proteus vulgaris are resistant to most first- and second-generation cephalosporins.

Anaerobes: Gram-positive and gram-negative cocci (including Peptococcus and Peptostreptococcus spp.), gram-positive bacilli (including Clostridium spp.), and gram-negative bacilli (including Bacteroides and Fusobacterium spp.).

NOTE: Clostridium difficile and most strains of Bacteroides fragilis are resistant to cefuroxime.

Susceptibility Tests

Diffusion Techniques

Quantitative methods that require measurement of zone diameters give an estimate of antibiotic susceptibility. One such standard procedure1 that has been recommended for use with disks to test susceptibility of organisms to cefuroxime uses the 30 mcg cefuroxime disk. Interpretation involves the correlation of the diameters obtained in the disk test with the minimum inhibitory concentration (MIC) for cefuroxime.

A report of "Susceptible" indicates that the pathogen is likely to be inhibited by generally achievable blood levels. A report of "Moderately Susceptible" suggests that the organism would be susceptible if high dosage is used or if the infection is confined to tissues and fluids in which high antibiotic levels are attained. A report of "Intermediate" suggests an equivocable or indeterminate result. A report of "Resistant" indicates that achievable concentrations of the antibiotic are unlikely to be inhibitory and other therapy should be selected.

Reports from the laboratory giving results of the standard single-disk susceptibility test for organisms other than Haemophilus spp. and Neisseria gonorrhoeae with a 30 mcg cefuroxime disk should be interpreted according to the following criteria:

Zone Diameter (mm)	Interpretation
≥18	(S) Susceptible
15–17	(MS) Moderately Susceptible
≤14	(R) Resistant

Results for Haemophilus spp. should be interpreted according to the following criteria:

Zone Diameter (mm)	Interpretation
≥ 24	(S) Susceptible
21–23	(I) Intermediate
≤ 20	(R) Resistant

Results for Neisseria gonorrhoeae should be interpreted according to the following criteria:

Zone Diameter (mm)	Interpretation
≥ 31	(S) Susceptible
26–30	(MS) Moderately Susceptible
≤25	(R) Resistant

Organisms should be tested with the cefuroxime disk since cefuroxime has been shown by in vitro tests to be active against certain strains found resistant when other beta-lactam disks are used. The cefuroxime disk should not be used for testing susceptibility to other cephalosporins.

Standardized procedures require the use of laboratory control organisms. The 30 mcg cefuroxime disk should give the following zone diameters.

1. Testing for organisms other than Haemophilus spp. and Neisseria gonorrhoeae:

Organism	Zone Diameter (mm)
Staphylococcus aureus ATCC® 25923	27–35
Escherichia coli ATCC® 25922	20–26

2. Testing for Haemophilus spp.:

Organism	Zone Diameter (mm)
Haemophilus influenzae ATCC® 49766	28–36

3. Testing for Neisseria gonorrhoeae:

Organism	Zone Diameter (mm)
Neisseria gonorrhoeae ATCC® 49226	33–41
Staphylococcus aureus ATCC® 25923	29–33

Dilution Techniques

Use a standardized dilution method1 (broth, agar, microdilution) or equivalent with cefuroxime powder. The MIC values obtained for bacterial isolates other than Haemophilus spp. and Neisseria gonorrhoeae should be interpreted according to the following criteria:

MIC (mcg/mL)	Interpretation
≤8	(S) Susceptible
16	(MS) Moderately Susceptible
≥32	(R) Resistant

MIC values obtained for Haemophilus spp. should be interpreted according to the following criteria:

MIC (mcg/mL)	Interpretation
≤4	(S) Susceptible
8	(I) Intermediate
≥16	(R) Resistant

MIC values obtained for Neisseria gonorrhoeae should be interpreted according to the following criteria:

MIC (mcg/mL)	Interpretation
≤1	(S) Susceptible
2	(MS) Moderately Susceptible
≥4	(R) Resistant

As with standard diffusion techniques, dilution methods require the use of laboratory control organisms. Standard cefuroxime powder should provide the following MIC values.

1. For organisms other than Haemophilus spp. and Neisseria gonorrhoeae:

Organism	MIC (mcg/mL)
Staphylococcus aureus ATCC® 29213	0.5–2.0
Escherichia coli ATCC® 25922	2.0–8.0

2. For Haemophilus spp.:

Organism	MIC (mcg/mL)
Haemophilus influenzae ATCC® 49766	0.25–1.0

3. For Neisseria gonorrhoeae:

Organism	MIC (mcg/mL)
Neisseria gonorrhoeae ATCC® 49226	0.25–1.0
Staphylococcus aureus ATCC® 29213	0.25–1.0

Indications and Usage for Cefuroxime Dextrose

Cefuroxime for Injection USP and Dextrose Injection USP is indicated for the treatment of patients with infections caused by susceptible strains of the designated organisms in the following diseases:

1. Lower Respiratory Tract Infections, including pneumonia, caused by Streptococcus pneumoniae, Haemophilus influenzae (including ampicillin-resistant strains), Klebsiella spp., Staphylococcus aureus (penicillinase- and non-penicillinase-producing strains), Streptococcus pyogenes, and Escherichia coli.


2. Urinary Tract Infections caused by Escherichia coli and Klebsiella spp.


3. Skin and Skin-Structure Infections caused by Staphylococcus aureus (penicillinase- and non-penicillinase-producing strains), Streptococcus pyogenes, Escherichia coli, Klebsiella spp., and Enterobacter spp.


4. Septicemia caused by Staphylococcus aureus (penicillinase- and non-penicillinase-producing strains), Streptococcus pneumoniae, Escherichia coli, Haemophilus influenzae (including ampicillin-resistant strains), and Klebsiella spp.


5. Meningitis caused by Streptococcus pneumoniae, Haemophilus influenzae (including ampicillin-resistant strains), Neisseria meningitidis, and Staphylococcus aureus (penicillinase- and non-penicillinase-producing strains).


6. Gonorrhea: Uncomplicated and disseminated gonococcal infections due to Neisseria gonorrhoeae (penicillinase- and non-penicillinase-producing strains) in both males and females.


7. Bone and Joint Infections caused by Staphylococcus aureus (penicillinase- and non-penicillinase producing strains).

Clinical microbiological studies in skin and skin-structure infections frequently reveal the growth of susceptible strains of both aerobic and anaerobic organisms. Cefuroxime has been used successfully in these mixed infections in which several organisms have been isolated.

In certain cases of confirmed or suspected gram-positive or gram-negative sepsis or in patients with other serious infections in which the causative organism has not been identified, cefuroxime may be used concomitantly with an aminoglycoside (see PRECAUTIONS). The recommended doses of both antibiotics may be given depending on the severity of the infection and the patient's condition.

To reduce the development of drug-resistant bacteria and maintain the effectiveness of Cefuroxime for Injection USP and Dextrose Injection USP and other antibacterial drugs, Cefuroxime for Injection USP and Dextrose Injection USP should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.

Prevention

The preoperative prophylactic administration of Cefuroxime for Injection USP and Dextrose Injection USP may prevent the growth of susceptible disease-causing bacteria and thereby may reduce the incidence of certain postoperative infections in patients undergoing surgical procedures (e.g., vaginal hysterectomy) that are classified as clean-contaminated or potentially contaminated procedures. Effective prophylactic use of antibiotics in surgery depends on the time of administration. Cefuroxime for Injection USP and Dextrose Injection USP should usually be given one-half to 1 hour before the operation to allow sufficient time to achieve effective antibiotic concentrations in the wound tissues during the procedure. The dose should be repeated intraoperatively if the surgical procedure is lengthy.

Prophylactic administration is usually not required after the surgical procedure ends and should be stopped within 24 hours. In the majority of surgical procedures, continuing prophylactic administration of any antibiotic does not reduce the incidence of subsequent infections but will increase the possibility of adverse reactions and the development of bacterial resistance.

The perioperative use of Cefuroxime for Injection USP and Dextrose Injection USP has also been effective during open heart surgery for surgical patients in whom infections at the operative site would present a serious risk. For these patients it is recommended that cefuroxime therapy be continued for at least 48 hours after the surgical procedure ends. If an infection is present, specimens for culture should be obtained for the identification of the causative organism, and appropriate antimicrobial therapy should be instituted.

Contraindications

Cefuroxime for Injection USP and Dextrose Injection USP is contraindicated in patients with known allergy to the cephalosporin group of antibiotics.

Solutions containing dextrose may be contraindicated in patients with hypersensitivity to corn products.

Warnings

BEFORE THERAPY WITH CEFUROXIME FOR INJECTION USP AND DEXTROSE INJECTION USP IS INSTITUTED, CAREFUL INQUIRY SHOULD BE MADE TO DETERMINE WHETHER THE PATIENT HAS HAD PREVIOUS HYPERSENSITIVITY REACTIONS TO CEPHALOSPORINS, PENICILLINS OR OTHER DRUGS. THIS PRODUCT SHOULD BE GIVEN CAUTIOUSLY TO PENICILLIN-SENSITIVE PATIENTS. ANTIBIOTICS SHOULD BE ADMINISTERED WITH CAUTION TO ANY PATIENT WHO HAS DEMONSTRATED SOME FORM OF ALLERGY, PARTICULARLY TO DRUGS. IF AN ALLERGIC REACTION TO CEFUROXIME OCCURS, DISCONTINUE THE DRUG. SERIOUS ACUTE HYPERSENSITIVITY REACTIONS MAY REQUIRE EPINEPHRINE AND OTHER EMERGENCY MEASURES.

Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including Cefuroxime for Injection USP and Dextrose Injection USP, 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.

Precautions

General

Although Cefuroxime for Injection USP and Dextrose Injection USP rarely produces alterations in kidney function, evaluation of renal status during therapy is recommended, especially in seriously ill patients receiving the maximum doses. Cephalosporins should be given with caution to patients receiving concurrent treatment with potent diuretics as these regimens are suspected of adversely affecting renal function.

The total daily dose of cefuroxime should be reduced in patients with transient or persistent renal insufficiency (see DOSAGE AND ADMINISTRATION), because high and prolonged serum antibiotic concentrations can occur in such individuals from usual doses.

As with other antibiotics, prolonged use of cefuroxime may result in overgrowth of nonsusceptible organisms. Careful observation of the patient is essential. If superinfection occurs during therapy, appropriate measures should be taken.

Broad-spectrum antibiotics should be prescribed with caution in individuals with a history of gastrointestinal disease, particularly colitis.

Nephrotoxicity has been reported following concomitant administration of aminoglycoside antibiotics and cephalosporins.

As with other therapeutic regimens used in the treatment of meningitis, mild-to-moderate hearing loss has been reported in a few pediatric patients treated with cefuroxime. Persistence of positive CSF (cerebrospinal fluid) cultures at 18 to 36 hours has also been noted with cefuroxime injection, as well as with other antibiotic therapies; however, the clinical relevance of this is unknown.

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.

As with other dextrose-containing solutions, Cefuroxime for Injection USP and Dextrose Injection USP should be prescribed with caution in patients with overt or known subclinical diabetes mellitus or carbohydrate intolerance for any reason.

Prescribing Cefuroxime for Injection USP and Dextrose Injection USP 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.

Information for Patients

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.

Patients should be counseled that antibacterial drugs including Cefuroxime for Injection USP and Dextrose Injection USP should only be used to treat bacterial infections. They do not treat viral infections ( e.g., the common cold). When Cefuroxime for Injection USP and Dextrose Injection USP 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 Cefuroxime for Injection USP and Dextrose Injection USP or other antibacterial drugs in the future.

Drug/Laboratory Test Interactions

A false-positive reaction for glucose in the urine may occur with copper reduction tests (Benedict's or Fehling's solution or with Clinitest® tablets) but not with enzyme-based tests for glycosuria. As a false-negative result may occur in the ferricyanide test, it is recommended that either the glucose oxidase or hexokinase method be used to determine blood plasma glucose levels in patients receiving cefuroxime.

Cefuroxime does not interfere with the assay of serum and urine creatinine by the alkaline picrate method.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Although lifetime studies in animals have not been performed to evaluate carcinogenic potential, no mutagenic activity was found for cefuroxime in the mouse lymphoma assay and a battery of bacterial mutation tests. Positive results were obtained in an in vitro chromosome aberration assay, however, negative results were found in an in vivo micronucleus test at doses up to 10 g/kg. Reproduction studies in mice at doses up to 3,200 mg/kg/day (3.1 times the recommended maximum human dose based on mg/m2) have revealed no impairment of fertility.

Reproductive studies revealed no impairment of fertility in animals.

Pregnancy

Teratogenic Effects

Pregnancy Category B

Reproduction studies have been performed in mice at doses up to 6,400 mg/kg/day (6.3 times the recommended maximum human dose based on mg/m2), and rabbits at doses up to 400 mg/kg/day (2.1 times the recommended maximum human dose based on mg/m2) and have revealed no evidence of impaired fertility or harm to the fetus due to cefuroxime. There are, however, 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.

Nursing Mothers

Since cefuroxime is excreted in human milk, caution should be exercised when cefuroxime is administered to a nursing woman.

Pediatric Use

Safety and effectiveness in pediatric patients below 3 months of age have not been established. Accumulation of other members of the cephalosporin class in newborn infants (with resulting prolongation of drug half-life) has been reported.

Cefuroxime for Injection USP and Dextrose Injection USP in the DUPLEX® Container is designed to deliver a 750 mg or 1.5 g dose of cefuroxime. To prevent unintentional overdose, this product should not be used in pediatric patients who require less than the full adult dose of cefuroxime.

Geriatric Use

Of the 1,914 subjects who received cefuroxime in 24 clinical studies of cefuroxime, 901 (47%) were 65 and over while 421 (22%) were 75 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 susceptibility of some older individuals to drug effects cannot be ruled out. 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 (see DOSAGE AND ADMINISTRATION).

Adverse Reactions

Cefuroxime is generally well tolerated. The most common adverse effects have been local reactions following IV administration. Other adverse reactions have been encountered only rarely.

Local Reactions

Thrombophlebitis has occurred with IV administration in 1 in 60 patients.

Gastrointestinal

Gastrointestinal symptoms occurred in 1 in 150 patients and included diarrhea (1 in 220 patients) and nausea (1 in 440 patients). The onset of pseudomembranous colitis may occur during or after antibacterial treatment (see WARNINGS).

Hypersensitivity Reactions

Hypersensitivity reactions have been reported in fewer than 1% of the patients treated with cefuroxime and include rash (1 in 125). Pruritus, urticaria, and positive Coombs' test each occurred in fewer than 1 in 250 patients, and, as with other cephalosporins, rare cases of anaphylaxis, drug fever, erythema multiforme, interstitial nephritis, toxic epidermal necrolysis, and Stevens-Johnson syndrome have occurred.

Blood

A decrease in hemoglobin and hematocrit has been observed in 1 in 10 patients and transient eosinophilia in 1 in 14 patients. Less common reactions seen were transient neutropenia (fewer than 1 in 100 patients) and leukopenia (1 in 750 patients). A similar pattern and incidence were seen with other cephalosporins used in controlled studies. As with other cephalosporins, there have been rare reports of thrombocytopenia.

Hepatic

Transient rise in SGOT and SGPT (1 in 25 patients), alkaline phosphatase (1 in 50 patients), LDH (1 in 75 patients), and bilirubin (1 in 500 patients) levels has been noted.

Kidney

Elevations in serum creatinine and/or blood urea nitrogen and a decreased creatinine clearance have been observed, but their relationship to cefuroxime is unknown.

Postmarketing Experience with Cefuroxime

In addition to the adverse events reported during clinical trials, the following events have been observed during clinical practice in patients treated with cefuroxime and were reported spontaneously. Data are generally insufficient to allow an estimate of incidence or to establish causation.

•  Neurologic: Seizure.


•  Non-site specific: Angioedema.

Cephalosporin-class Adverse Reactions

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

Adverse Reactions

Vomiting, abdominal pain, colitis, vaginitis including vaginal candidiasis, toxic nephropathy, hepatic dysfunction including cholestasis, aplastic anemia, hemolytic anemia, and hemorrhage.

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

Altered Laboratory Tests

Prolonged prothrombin time, pancytopenia, agranulocytosis.

Overdosage

Overdosage of cephalosporins can cause cerebral irritation leading to convulsions. Serum levels of cefuroxime can be reduced by hemodialysis and peritoneal dialysis.

Cefuroxime Dextrose Dosage and Administration

This product is intended for intravenous administration only.

Dosage

Adults

The usual adult dosage range for cefuroxime is 750 mg to 1.5 grams every 8 hours, usually for 5 to 10 days. In uncomplicated urinary tract infections, skin and skin-structure infections, disseminated gonococcal infections, and uncomplicated pneumonia, a 750 mg dose every 8 hours is recommended. In severe or complicated infections, a 1.5 gram dose every 8 hours is recommended.

In bone and joint infections, a 1.5 gram dose every 8 hours is recommended. In clinical trials, surgical intervention was performed when indicated as an adjunct to cefuroxime therapy. A course of oral antibiotics was administered when appropriate following the completion of parenteral administration of cefuroxime.

In life-threatening infections or infections due to less susceptible organisms, 1.5 grams every 6 hours may be required. In bacterial meningitis, the dosage should not exceed 3 grams every 8 hours. For preventive use for clean-contaminated or potentially contaminated surgical procedures, a 1.5 gram dose administered intravenously just before surgery (approximately one-half to 1 hour before the initial incision) is recommended. Thereafter, give 750 mg intravenously every 8 hours when the procedure is prolonged.

For preventive use during open heart surgery, a 1.5 gram dose administered intravenously at the induction of anesthesia and every 12 hours thereafter for a total of 6 grams is recommended.

Impaired Renal Function

A reduced dosage must be employed when renal function is impaired. Dosage should be determined by the degree of renal impairment and the susceptibility of the causative organism (see Table 2).

Table 2: Dosage of Cefuroxime in Adults with Reduced Renal Function

Creatinine Clearance (mL/min)	Dose	Frequency
* Since cefuroxime is dialyzable, patients on hemodialysis should be given a further dose at the end of the dialysis.
>20	750 mg–1.5 grams	q8h
10–20	750 mg	q12h
<10	750 mg	q24h*

When only serum creatinine is available, the following formula2 (based on sex, weight, and age of the patient) may be used to convert this value into creatinine clearance. The serum creatinine should represent a steady state of renal function.

Males: Creatinine clearance (mL/min) =	Weight (kg) × (140 - age)     72 × serum creatinine (mg/dL)
Females: 0.85 × male value

Note: As with antibiotic therapy in general, administration of Cefuroxime for Injection USP and Dextrose Injection USP should be continued for a minimum of 48 to 72 hours after the patient becomes asymptomatic or after evidence of bacterial eradication has been obtained; a minimum of 10 days of treatment is recommended in infections caused by Streptococcus pyogenes in order to guard against the risk of rheumatic fever or glomerulonephritis; frequent bacteriologic and clinical appraisal is necessary during therapy of chronic urinary tract infection and may be required for several months after therapy has been completed; persistent infections may require treatment for several weeks; and doses smaller than those indicated above should not be used. In staphylococcal and other infections involving a collection of pus, surgical drainage should be carried out where indicated.

Pediatric Patients Above 3 Months of Age

Administration of 50 to 100 mg/kg/day in equally divided doses every 6 to 8 hours has been successful for most infections susceptible to cefuroxime. The higher dosage of 100 mg/kg/day (not to exceed the maximum adult dosage) should be used for the more severe or serious infections.

In bone and joint infections, 150 mg/kg/day (not to exceed the maximum adult dosage) is recommended in equally divided doses every 8 hours. In clinical trials, a course of oral antibiotics was administered to pediatric patients following the completion of parenteral administration of cefuroxime.

In cases of bacterial meningitis, a larger dosage of cefuroxime is recommended, 200 to 240 mg/kg/day intravenously in divided doses every 6 to 8 hours.

In pediatric patients with renal insufficiency, the frequency of dosing should be modified consistent with the recommendations for adults.

Cefuroxime for Injection USP and Dextrose for Injection USP in the DUPLEX® Container is designed to deliver a 750 mg or 1.5 g dose of cefuroxime. To prevent unintentional overdose, this product should not be used in pediatric patients who require less than the full adult dose.

For intermittent IV infusion with a Y-type administration set, dosing can be accomplished through the tubing system by which the patient may be receiving other IV solutions. However, during infusion of the solution containing Cefuroxime, it is advisable to temporarily discontinue administration of any other solutions at the same site.

Solutions of cefuroxime, like those of most beta-lactam antibiotics, should not be added to solutions of aminoglycoside antibiotics because of potential interaction.

However, if concurrent therapy with cefuroxime and an aminoglycoside is indicated, each of these antibiotics can be administered separately to the same patient.

Use sterile equipment.

Caution: Do not use plastic containers in series connections. Such use could result in air embolism due to residual air being drawn from the primary container before administration of the fluid from the secondary container is complete.

DUPLEX® Drug Delivery System Directions for Use

• To avoid inadvertent activation, DUPLEX® Container should remain in the folded position until activation is intended.

Patient Labeling and Drug Powder/Diluent Inspection

• Apply patient-specific label on foil side of container. USE CARE to avoid activation. Do not cover any portion of foil strip with patient label.


• Unlatch side tab and unfold DUPLEX® Container. (See Diagram 1.)

• Visually inspect diluent chamber for particulate matter.


• Use only if container and seals are intact.


• To inspect the drug powder for foreign matter or discoloration, peel foil strip from drug chamber. (See Diagram 2.)

• Protect from light after removal of foil strip.
  
  

  Note: If foil strip is removed, product must be used within 7 days, but not beyond the labeled expiration date.

  
  
  


• The product should be re-folded and the side tab latched until ready to activate.

Reconstitution (Activation)

• Do not use directly after storage by refrigeration, allow the product to equilibrate to room temperature before patient use.


• Unfold the DUPLEX® Container and point the set port in a downward direction. Starting at the hanger tab end, fold the DUPLEX® Container just below the diluent meniscus trapping all air above the fold. To activate, squeeze the folded diluent chamber until the seal between the diluent and powder opens, releasing diluent into the drug powder chamber. (See Diagram 3.)

• Agitate the liquid-powder mixture until the drug powder is completely dissolved.
  

  Note: Following reconstitution (activation), product must be used within 24 hours if stored at room temperature or within 7 days if stored under refrigeration.

  
  

Administration

• Visually inspect the reconstituted solution for particulate matter.


• Point the set port in a downwards direction. Starting at the hanger tab end, fold the DUPLEX® Container just below the solution meniscus trapping all air above the fold. Squeeze the folded DUPLEX® Container until the seal between reconstituted drug solution and set port opens, releasing liquid to set port. (See Diagram 4.)

• Prior to attaching the IV set, check for minute leaks by squeezing container firmly. If leaks are found, discard container and solution as sterility may be impaired.


• Using aseptic technique, peel foil cover from the set port and attach sterile administration set. (See Diagram 5.)

• Refer to Directions for Use accompanying the administration set.

Precautions

• As with other cephalosporins, reconstituted Cefuroxime for Injection USP and Dextrose Injection USP tends to darken depending on storage conditions, within the stated recommendations. However, product potency is not adversely affected.


• Use only if prepared solution is clear and free from particulate matter.


• Do not use in series connection.


• Do not introduce additives into the DUPLEX® Container.


• Do not freeze.

How is Cefuroxime Dextrose Supplied

Cefuroxime for Injection USP and Dextrose Injection USP in the DUPLEX® Drug Delivery System is a flexible dual chamber container supplied in two concentrations. After reconstitution, the concentrations are equivalent to 750 mg and 1.5 g cefuroxime. The diluent chamber contains approximately 50 mL of Dextrose Injection USP. Dextrose Injection USP has been adjusted to 4.1% and 2.9% for the 750 mg and 1.5 g doses, respectively, such that the reconstituted solution is iso-osmotic.

Cefuroxime for Injection USP and Dextrose Injection USP is supplied sterile and nonpyrogenic in the DUPLEX® Drug Delivery System containers packaged 24 units per case.

NDC	Cat. No.	Dose	Volume
Cefuroxime for Injection USP and Dextrose Injection USP
0264-3112-11	3112-11	750 mg	50 mL
Cefuroxime for Injection USP and Dextrose Injection USP
0264-3114-11	3114-11	1.5 g	50 mL

Store the unactivated unit at 20–25°C (68–77°F). Excursions permitted to 15–30°C (59–86°F).

Rx only

Revised: October 2009

REFERENCES

1. National Committee for Clinical Laboratory Standards. Performance Standards for Antimicrobial Susceptibility Testing. Third Informational Supplement. NCCLS Document M100-S3, Vol. 11, No. 17, Villanova, PA: NCCLS; 1991.


2. Cockcroft, DW., and Gault MH.: Prediction of creatinine clearance from serum creatinine. Nephron. 16:31–41, 1976.

DUPLEX is a registe