Meropenem

Dosage Form: injection, powder, for solution
FULL PRESCRIBING INFORMATION

Indications and Usage for Meropenem

To reduce the development of drug-resistant bacteria and maintain the effectiveness of Meropenem for injection (I.V.) and other antibacterial drugs, Meropenem for injection (I.V.) should only be used 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.

Meropenem for injection (I.V.) is useful as presumptive therapy in the indicated condition (e.g., intra-abdominal infections) prior to the identification of the causative organisms because of its broad spectrum of bactericidal activity.

Skin and Skin Structure Infections (Adult Patients and Pediatric Patients ≥ 3 Months only)

Meropenem for injection (I.V.) is indicated as a single agent therapy for the treatment of complicated skin and skin structure infections due to Staphylococcus aureus (β-lactamase- and non-β-lactamase-producing, methicillin-susceptible isolates only), Streptococcus pyogenes, Streptococcus agalactiae, viridans group streptococci, Enterococcus faecalis (excluding vancomycin-resistant isolates), Pseudomonas aeruginosa, Escherichia coli, Proteus mirabilis, Bacteroides fragilis, and Peptostreptococcus species.

Intra-abdominal Infections (Adult Patients and Pediatric Patients ≥ 3 Months only)

Meropenem for injection (I.V.) is indicated as a single agent therapy for the treatment of complicated appendicitis and peritonitis caused by viridans group streptococci, Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Bacteroides fragilis, B. thetaiotaomicron, and Peptostreptococcus species.

Bacterial Meningitis (Pediatric Patients ≥ 3 Months only)

Meropenem for injection (I.V.) is indicated as a single agent therapy for the treatment of bacterial meningitis caused by Streptococcus pneumoniae‡, Haemophilus influenzae (β-lactamase- and non-β-lactamase-producing isolates), and Neisseria meningitidis.

‡ The efficacy of Meropenem as monotherapy in the treatment of meningitis caused by penicillin nonsusceptible isolates of Streptococcus pneumoniae has not been established.

Meropenem for injection (I.V.) has been found to be effective in eliminating concurrent bacteremia in association with bacterial meningitis.

For information regarding use in pediatric patients (3 months of age and older) [see Indications and Usage (1.1), (1.2) or (1.3); Dosage and Administration (2.5), and Adverse Reactions (6.1)].

Meropenem Dosage and Administration

Adult Patients

The recommended dose of Meropenem for injection (I.V.) is 500 mg given every 8 hours for skin and skin structure infections and 1 g given every 8 hours for intra-abdominal infections. Meropenem for injection (I.V.) should be administered by intravenous infusion over approximately 15 to 30 minutes. Doses of 1 g may also be administered as an intravenous bolus injection (5 to 20 mL) over approximately 3-5 minutes.

Use in Adult Patients with Renal Impairment

Dosage should be reduced in patients with creatinine clearance of 50 mL/min or less. (See dosing table below.)

When only serum creatinine is available, the following formula (Cockcroft and Gault equation)5 may be used to estimate creatinine clearance.

Males: Creatinine Clearance (mL/min) = Weight (kg) x (140 - age)__

72 x serum creatinine (mg/dL)

Females: 0.85 x above value

Recommended Meropenem for injection (I.V.) Dosage Schedule for Adult Patients With Renal Impairment

Creatinine Clearance (mL/min)	Dose (dependent on type of infection)	Dosing Interval
> 50	Recommended dose (500 mg cSSSI and 1 g Intra-abdominal)	Every 8 hours
> 25-50	Recommended dose	Every 12 hours
10-25	One-half recommended dose	Every 12 hours
< 10	One-half recommended dose	Every 24 hours

There is inadequate information regarding the use of Meropenem for injection (I.V.) in patients on hemodialysis or peritoneal dialysis.

Use in Pediatric Patients (≥ 3 Months only)

For pediatric patients from 3 months of age and older, the Meropenem for injection (I.V.) dose is 10, 20 or 40 mg/kg every 8 hours (maximum dose is 2 g every 8 hours), depending on the type of infection (complicated skin and skin structure, intra-abdominal or meningitis). (See dosing table below.) Pediatric patients weighing over 50 kg should be administered Meropenem for injection (I.V.) at a dose of 500 mg every 8 hours for complicated skin and skin structure infections, 1 g every 8 hours for intra-abdominal infections and 2 g every 8 hours for meningitis. Meropenem for injection (I.V.) should be given as intravenous infusion over approximately 15 to 30 minutes or as an intravenous bolus injection (5 to 20 mL) over approximately 3-5 minutes.

Recommended Meropenem for injection (I.V.) Dosage Schedule for Pediatric Patients With Normal Renal Function

Type of Infection	Dose (mg/kg)	Up to a Maximum Dose	Dosing Interval
Complicated skin and skin structure	10	500 mg	Every 8 hours
Intra-abdominal	20	1 g	Every 8 hours
Meningitis	40	2 g	Every 8 hours

There is no experience in pediatric patients with renal impairment.

Preparation of Solution

For Intravenous Bolus Administration

Constitute injection vials (500 mg and 1 g) with sterile Water for Injection. (See table below.) Shake to dissolve and let stand until clear.

Vial size	Amount of Diluent Added (mL)	Approximate Withdrawable Volume (mL)	Approximate Average Concentration (mg/mL)
500 mg	10	10	50
1 g	20	20	50

For Infusion

Infusion vials (500 mg and 1 g) may be directly constituted with a compatible infusion fluid. Alternatively, an injection vial may be constituted, then the resulting solution added to an I.V. container and further diluted with an appropriate infusion fluid [see Dosage and Administration (2.8) and (2.9)].

WARNING: Do not use flexible container in series connections.

Compatibility

Compatibility of Meropenem with other drugs has not been established. Meropenem should not be mixed with or physically added to solutions containing other drugs.

Stability and Storage

Freshly prepared solutions of Meropenem should be used whenever possible. However, constituted solutions of Meropenem maintain satisfactory potency at controlled room temperature 15-25°C (59-77°F) or under refrigeration at 4°C (39°F) as described below. Solutions of intravenous Meropenem should not be frozen.

Intravenous Bolus Administration

Meropenem injection vials constituted with sterile Water for Injection for bolus administration (up to 50 mg/mL of Meropenem) may be stored for up to 2 hours at controlled room temperature 15-25°C (59-77°F) or for up to 12 hours at 4°C (39°F).

Intravenous Infusion Administration

Stability in Infusion Vials: Meropenem infusion vials constituted with Sodium Chloride Injection 0.9% (Meropenem concentrations ranging from 2.5 to 50 mg/mL) are stable for up to 2 hours at controlled room temperature 15-25°C (59-77°F) or for up to 18 hours at 4°C (39°F). Infusion vials of Meropenem constituted with Dextrose Injection 5% (Meropenem concentrations ranging from 2.5 to 50 mg/mL) are stable for up to 1 hour at controlled room temperature 15-25°C (59-77°F) or for up to 8 hours at 4°C (39°F).

Stability in Plastic I.V. Bags: Solutions prepared for infusion (Meropenem concentrations ranging from 1 to 20 mg/mL) may be stored in plastic intravenous bags with diluents as shown below:

	Number of Hours Stable at Controlled Room Temperature 15-25°C (59-77°F)	Number of Hours Stable at 4°C (39°F)
Sodium Chloride Injection 0.9%	4	24
Dextrose Injection 5%	1	4
Dextrose Injection 10%	1	2
Dextrose and Sodium Chloride Injection 5% / 0.9%	1	2
Dextrose and Sodium Chloride Injection 5% / 0.2%	1	4
Potassium Chloride in Dextrose Injection 0.15% / 5%	1	6
Sodium Bicarbonate in Dextrose Injection 0.02% / 5%	1	6
Dextrose Injection 5% in Normosol®-M†	1	8
Dextrose Injection 5% in Ringers Lactate Injection	1	4
Dextrose and Sodium Chloride Injection 2.5% / 0.45%	3	12
Mannitol Injection 2.5%	2	16
Ringers Injection	4	24
Ringers Lactate Injection	4	12
Sodium Lactate Injection 1/6 N	2	24
Sodium Bicarbonate Injection 5%	1	4

†NORMOSOL is a registered trademark of Hospira Inc.

Stability in Baxter Minibag Plus: Solutions of Meropenem (Meropenem concentrations ranging from 2.5 to 20 mg/mL) in Baxter Minibag Plus bags with Sodium Chloride Injection 0.9% may be stored for up to 4 hours at controlled room temperatures 15-25°C (59-77°F) or for up to 24 hours at 4°C (39°F). Solutions of Meropenem (Meropenem concentrations ranging from 2.5 to 20 mg/mL) in Baxter Minibag Plus bags with Dextrose Injection 5% may be stored up to 1 hour at controlled room temperatures 15-25°C (59-77°F) or for up to 6 hours at 4°C (39°F).

Stability in Plastic Syringes, Tubing and Intravenous Infusion Sets: Solutions of Meropenem (Meropenem concentrations ranging from 1 to 20 mg/mL) in Water for Injection or Sodium Chloride Injection 0.9% (for up to 4 hours) or in Dextrose Injection 5% (for up to 2 hours) at controlled room temperatures 15-25°C (59-77°F) are stable in plastic tubing and volume control devices of common intravenous infusion sets.

Solutions of Meropenem (Meropenem concentrations ranging from 1 to 20 mg/mL) in Water for Injection or Sodium Chloride Injection 0.9% (for up to 48 hours) or in Dextrose Injection 5% (for up to 6 hours) are stable at 4°C (39°F) in plastic syringes.

NOTE: Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

Dosage Forms and Strengths

Single use clear glass vials containing 500 mg or 1 g (as the trihydrate blend with anhydrous sodium carbonate for constitution) of sterile Meropenem powder.

Contraindications

Meropenem for injection (I.V.) is contraindicated in patients with known hypersensitivity to any component of this product or to other drugs in the same class or in patients who have demonstrated anaphylactic reactions to β-lactams.

Warnings and Precautions

Hypersensitivity Reactions

Serious and occasionally fatal hypersensitivity (anaphylactic) reactions have been reported in patients receiving therapy with β-lactams. These reactions are more likely to occur in individuals with a history of sensitivity to multiple allergens.

There have been reports of individuals with a history of penicillin hypersensitivity who have experienced severe hypersensitivity reactions when treated with another β-lactam. Before initiating therapy with Meropenem for injection (I.V.), careful inquiry should be made concerning previous hypersensitivity reactions to penicillins, cephalosporins, other β-lactams, and other allergens. If an allergic reaction to Meropenem for injection (I.V.) occurs, discontinue the drug immediately. Serious anaphylactic reactions require immediate emergency treatment with epinephrine, oxygen, intravenous steroids, and airway management, including intubation. Other therapy may also be administered as indicated.

Seizure Potential

Seizures and other adverse CNS experiences have been reported during treatment with Meropenem for injection (I.V.) These experiences have occurred most commonly in patients with CNS disorders (e.g., brain lesions or history of seizures) or with bacterial meningitis and/or compromised renal function [see Adverse Reactions (6.1) and Drug Interactions (7.2)].

During clinical investigations, 2904 immunocompetent adult patients were treated for non-CNS infections with the overall seizure rate being 0.7% (based on 20 patients with this adverse event). All Meropenem-treated patients with seizures had pre-existing contributing factors. Among these are included prior history of seizures or CNS abnormality and concomitant medications with seizure potential. Dosage adjustment is recommended in patients with advanced age and/or reduced renal function. [see Dosage and Administration (2.2)].

Close adherence to the recommended dosage regimens is urged, especially in patients with known factors that predispose to convulsive activity. Anti-convulsant therapy should be continued in patients with known seizure disorders. If focal tremors, myoclonus, or seizures occur, patients should be evaluated neurologically, placed on anti-convulsant therapy if not already instituted, and the dosage of Meropenem for injection (I.V.) re-examined to determine whether it should be decreased or the antibiotic discontinued.

Interaction with Valproic Acid

Case reports in the literature have shown that co-administration of carbapenems, including Meropenem, to patients receiving valproic acid or divalproex sodium results in a reduction in valproic acid concentrations. The valproic acid concentrations may drop below the therapeutic range as a result of this interaction, therefore increasing the risk of breakthrough seizures. Increasing the dose of valproic acid or divalproex sodium may not be sufficient to overcome this interaction. The concomitant use of Meropenem and valproic acid or divalproex sodium is generally not recommended. Antibacterials other than carbapenems should be considered to treat infections in patients whose seizures are well controlled on valproic acid or divalproex sodium. If administration of Meropenem for injection (I.V.) is necessary, supplemental anti-convulsant therapy should be considered [see Drug Interactions (7.2)].

Clostridium difficile–Associated Diarrhea

Clostridium difficile-associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including Meropenem for injection (I.V.), 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 isolates 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.

Development of Drug-Resistant Bacteria

Prescribing Meropenem for injection (I.V.) 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.

Overgrowth of Nonsusceptible Organisms

As with other broad-spectrum antibiotics, prolonged use of Meropenem may result in overgrowth of nonsusceptible organisms. Repeated evaluation of the patient is essential. If superinfection does occur during therapy, appropriate measures should be taken.

Laboratory Tests

While Meropenem for injection (I.V.) possesses the characteristic low toxicity of the beta-lactam group of antibiotics, periodic assessment of organ system functions, including renal, hepatic, and hematopoietic, is advisable during prolonged therapy.

Patients with Renal Impairment

In patients with renal impairment, thrombocytopenia has been observed but no clinical bleeding reported [see Dosage and Administration (2.2), Adverse Reactions (6.1), Use In Specific Populations (8.5) and (8.6), and Clinical Pharmacology (12.3)].

Dialysis

There is inadequate information regarding the use of Meropenem for injection (I.V.) in patients on hemodialysis or peritoneal dialysis.

Adverse Reactions

The following are discussed in greater detail in other sections of labeling:

• Hypersensitivity Reactions [see Warnings and Precautions (5.1)]


• Seizure Potential [see Warnings and Precautions (5.2)]


• Interaction with Valproic Acid [see Warnings and Precautions (5.3)]


• Clostridium difficile – Associated Diarrhea [see Warnings and Precautions (5.4)]


• Development of Drug-Resistant Bacteria [see Warnings and Precautions (5.5)]


• Overgrowth of Nonsusceptible Organisms [see Warnings and Precautions (5.6)]


• Laboratory Tests [see Warnings and Precautions (5.7)]


• Patients with Renal Impairment [see Warnings and Precautions (5.8)]


• Dialysis [see Warnings and Precautions (5.9)]

Adverse Reactions from Clinical Trials

Because clinical trials are conducted under widely varying conditions, adverse reactions rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Adult Patients:

During clinical investigations, 2904 immunocompetent adult patients were treated for non-CNS infections with Meropenem for injection (I.V.) (500 mg or 1000 mg every 8 hours). Deaths in 5 patients were assessed as possibly related to Meropenem; 36 (1.2%) patients had Meropenem discontinued because of adverse events. Many patients in these trials were severely ill and had multiple background diseases, physiological impairments and were receiving multiple other drug therapies. In the seriously ill patient population, it was not possible to determine the relationship between observed adverse events and therapy with Meropenem for injection (I.V.).

The following adverse reaction frequencies were derived from the clinical trials in the 2904 patients treated with Meropenem for injection (I.V.)

Local Adverse Reactions

Local adverse reactions that were reported irrespective of the relationship to therapy with Meropenem for injection (I.V.) were as follows:

Inflammation at the injection site 2.4%

Injection site reaction 0.9%

Phlebitis/thrombophlebitis 0.8%

Pain at the injection site 0.4%

Edema at the injection site 0.2%

Systemic Adverse Reactions

Systemic adverse reactions that were reported irrespective of the relationship to Meropenem for injection (I.V.) occurring in greater than 1% of the patients were diarrhea (4.8%), nausea/vomiting (3.6%), headache (2.3%), rash (1.9%), sepsis (1.6%), constipation (1.4%), apnea (1.3%), shock (1.2%), and pruritus (1.2%).

Additional systemic adverse reactions that were reported irrespective of relationship to therapy with Meropenem for injection (I.V.) and occurring in less than or equal to 1% but greater than 0.1% of the patients are listed below within each body system in order of decreasing frequency:

Bleeding events were seen as follows: gastrointestinal hemorrhage (0.5%), melena (0.3%), epistaxis (0.2%), hemoperitoneum (0.2%), summing to 1.2%.

Body as a Whole: pain, abdominal pain, chest pain, fever, back pain, abdominal enlargement, chills, pelvic pain

Cardiovascular: heart failure, heart arrest, tachycardia, hypertension, myocardial infarction, pulmonary embolus, bradycardia, hypotension, syncope

Digestive System: oral moniliasis, anorexia, cholestatic jaundice/jaundice, flatulence, ileus, hepatic failure, dyspepsia, intestinal obstruction

Hemic/Lymphatic: anemia, hypochromic anemia, hypervolemia

Metabolic/Nutritional: peripheral edema, hypoxia

Nervous System: insomnia, agitation/delirium, confusion, dizziness, seizure, nervousness, paresthesia, hallucinations, somnolence, anxiety, depression, asthenia [see Warnings and Precautions (5.2)]

Respiratory: respiratory disorder, dyspnea, pleural effusion, asthma, cough increased, lung edema

Skin and Appendages: urticaria, sweating, skin ulcer

Urogenital System: dysuria, kidney failure, vaginal moniliasis, urinary incontinence

Adverse Laboratory Changes

Adverse laboratory changes that were reported irrespective of relationship to Meropenem for injection (I.V.) and occurring in greater than 0.2% of the patients were as follows:

Hepatic: increased SGPT (ALT), SGOT (AST), alkaline phosphatase, LDH, and bilirubin

Hematologic: increased platelets, increased eosinophils, decreased platelets, decreased hemoglobin, decreased hematocrit, decreased WBC, shortened prothrombin time and shortened partial thromboplastin time, leukocytosis, hypokalemia

Renal: increased creatinine and increased BUN

NOTE: For patients with varying degrees of renal impairment, the incidence of heart failure, kidney failure, seizure and shock reported irrespective of relationship to Meropenem for injection (I.V.), increased in patients with moderately severe renal impairment (creatinine clearance > 10 to 26 mL/min) [see Dosage and Administration (2.2), Warnings and Precautions (5.8), Use In Specific Populations (8.5) and (8.6), and Clinical Pharmacology (12.3)].

Urinalysis: presence of red blood cells

Complicated Skin and Skin Structure Infections

In a study of complicated skin and skin structure infections, the adverse reactions were similar to those listed above. The most common adverse events occurring in > 5% of the patients were: headache (7.8%), nausea (7.8%), constipation (7%), diarrhea (7%), anemia (5.5%), and pain (5.1%). Adverse events with an incidence of > 1%, and not listed above, include: pharyngitis, accidental injury, gastrointestinal disorder, hypoglycemia, peripheral vascular disorder, and pneumonia.

Pediatric Patients

Clinical Adverse Reactions

Meropenem for injection (I.V.) was studied in 515 pediatric patients (≥ 3 months to < 13 years of age) with serious bacterial infections (excluding meningitis. See next section.) at dosages of 10 to 20 mg/kg every 8 hours. The types of clinical adverse events seen in these patients are similar to the adults, with the most common adverse events reported as possibly, probably, or definitely related to Meropenem for injection (I.V.) and their rates of occurrence as follows:

Diarrhea 3.5%

Rash 1.6%

Nausea and Vomiting 0.8%

Meropenem for injection (I.V.) was studied in 321 pediatric patients (≥ 3 months to < 17 years of age) with meningitis at a dosage of 40 mg/kg every 8 hours. The types of clinical adverse events seen in these patients are similar to the adults, with the most common adverse events reported as possibly, probably, or definitely related to Meropenem for injection (I.V.) and their rates of occurrence as follows:

Diarrhea 4.7%

Rash (mostly diaper area moniliasis) 3.1%

Oral Moniliasis 1.9%

Glossitis 1%

In the meningitis studies, the rates of seizure activity during therapy were comparable between patients with no CNS abnormalities who received Meropenem and those who received comparator agents (either cefotaxime or ceftriaxone). In the Meropenem for injection (I.V.) treated group, 12/15 patients with seizures had late onset seizures (defined as occurring on day 3 or later) versus 7/20 in the comparator arm.

Adverse Laboratory Changes

Laboratory changes seen in the pediatric studies, including the meningitis studies, were similar to those reported in the adult studies.

There is no experience in pediatric patients with renal impairment.

Post-Marketing Experience

The following adverse reactions have been identified during post-approval use of Meropenem for injection (I.V.). Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Worldwide post-marketing adverse reactions not otherwise listed in the Adverse Reactions section of this product label and reported as possibly, probably, or definitely drug related are listed within each body system in order of decreasing severity. Hematologic - agranulocytosis, neutropenia, and leukopenia; a positive direct or indirect Coombs test, and hemolytic anemia. Skin – toxic epidermal necrolysis, Stevens-Johnson Syndrome, angioedema, and erythema multiforme.

Drug Interactions

Probenecid

Probenecid competes with Meropenem for active tubular secretion, resulting in increased plasma concentrations of Meropenem. Co-administration of probenecid with Meropenem is not recommended.

Valproic Acid

Case reports in the literature have shown that co-administration of carbapenems, including Meropenem, to patients receiving valproic acid or divalproex sodium results in a reduction in valproic acid concentrations. The valproic acid concentrations may drop below the therapeutic range as a result of this interaction, therefore increasing the risk of breakthrough seizures. Although the mechanism of this interaction is unknown, data from in vitro and animal studies suggest that carbapenems may inhibit the hydrolysis of valproic acid’s glucuronide metabolite (VPA-g) back to valproic acid, thus decreasing the serum concentrations of valproic acid. If administration of Meropenem for injection (I.V.) is necessary, then supplemental anti-convulsant therapy should be considered [see Warnings and Precautions (5.3)].

USE IN SPECIFIC POPULATIONS

Pregnancy

Pregnancy Category B. Reproductive studies have been performed with Meropenem in rats at doses of up to 1000 mg/kg/day, and cynomolgus monkeys at doses of up to 360 mg/kg/day (on the basis of AUC comparisons, approximately 1.8 times and 3.7 times, respectively, to the human exposure at the usual dose of 1 g every 8 hours). These studies revealed no evidence of impaired fertility or harm to the fetus due to Meropenem, although there were slight changes in fetal body weight at doses of 250 mg/kg/day (on the basis of AUC comparisons, 0.4 times the human exposure at a dose of 1 g every 8 hours) and above in rats. 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

It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Meropenem for injection (I.V.) is administered to a nursing woman.

Pediatric Use

The safety and effectiveness of Meropenem for injection (I.V.) have been established for pediatric patients ≥ 3 months of age. Use of Meropenem for injection (I.V.) in pediatric patients with bacterial meningitis is supported by evidence from adequate and well-controlled studies in the pediatric population. Use of Meropenem for injection (I.V.) in pediatric patients with intra-abdominal infections is supported by evidence from adequate and well-controlled studies with adults with additional data from pediatric pharmacokinetics studies and controlled clinical trials in pediatric patients. Use of Meropenem for injection (I.V.) in pediatric patients with complicated skin and skin structure infections is supported by evidence from an adequate and well-controlled study with adults and additional data from pediatric pharmacokinetics studies [see Indications and Usage (1.3), Dosage and Administration (2.3)  and  (2.4), Adverse Reactions (6.1), Clinical Pharmacology (12.3) and Clinical Studies (14.3)].

Geriatric Use

Of the total number of subjects in clinical studies of Meropenem for injection (I.V.), approximately 1100 (30%) were 65 years of age and older, while 400 (11%) were 75 years and older. Additionally, in a study of 511 patients with complicated skin and skin structure infections, 93 (18%) were 65 years of age and older, while 38 (7%) were 75 years and older. No overall differences in safety or effectiveness were observed between these subjects and younger subjects; spontaneous reports and other reported clinical experience have not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

Meropenem is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with renal impairment. 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.

A pharmacokinetic study with Meropenem for injection (I.V.) in elderly patients has shown a reduction in the plasma clearance of Meropenem that correlates with age-associated reduction in creatinine clearance [see Clinical Pharmacology (12.3)].

Patients with Renal Impairment

Dosage adjustment is necessary in patients with creatinine clearance 50 mL/min or less [see Dosage and Administration (2.2), Warnings and Precautions (5.6), and Clinical Pharmacology (12.3)].

Overdosage

In mice and rats, large intravenous doses of Meropenem (2200-4000 mg/kg) have been associated with ataxia, dyspnea, convulsions, and mortalities.

Intentional overdosing of Meropenem for injection (I.V.) is unlikely, although accidental overdosing might occur if large doses are given to patients with reduced renal function. The largest dose of Meropenem administered in clinical trials has been 2 g given intravenously every 8 hours. At this dosage, no adverse pharmacological effects or increased safety risks have been observed.

Limited post-marketing experience indicates that if adverse events occur following overdosage, they are consistent with the adverse event profile described in the Adverse Reactions section and are generally mild in severity and resolve on withdrawal or dose reduction. Symptomatic treatments should be considered. In individuals with normal renal function, rapid renal elimination takes place. Meropenem and its metabolite are readily dialyzable and effectively removed by hemodialysis; however, no information is available on the use of hemodialysis to treat overdosage.

Meropenem Description

Meropenem for Injection, USP (I.V.) is a sterile, pyrogen-free, synthetic, broad-spectrum, carbapenem antibiotic for intravenous administration. It is (4R,5S,6S) - 3 - [[(3S,5S) - 5 - (Dimethylcarbamoyl) - 3 - pyrrolidinyl]thio] - 6 - [(1R) - 1 - hydroxyethyl] - 4 - methyl - 7 - oxo - 1 - azabicyclo[3.2.0]hept - 2 - ene - 2 - carboxylic acid trihydrate. Its empirical formula is C17H25N3O5S•3H2O with a molecular weight of 437.52. Its structural formula is:

Meropenem for Injection, USP (I.V.) is a white to pale yellow crystalline powder. The solution varies from colorless to yellow depending on the concentration. The pH of freshly constituted solutions is between 7.3 and 8.3. Meropenem is soluble in 5% monobasic potassium phosphate solution, sparingly soluble in water, very slightly soluble in hydrated ethanol, and practically insoluble in acetone or ether.

When constituted as instructed, each 500 mg Meropenem for Injection, USP (I.V.) vial will deliver 500 mg Meropenem and 45.1 mg of sodium as sodium carbonate (1.96 mEq). Each 1 g Meropenem for Injection, USP (I.V.) vial will deliver 1 g of Meropenem and 90.2 mg of sodium as sodium carbonate (3.92 mEq). [see Dosage and Administration (2.4)].

Meropenem - Clinical Pharmacology

Mechanism of Action

Meropenem is an antibacterial drug [see Clinical Pharmacology (12.4)]

Pharmacokinetics

Plasma Concentrations

At the end of a 30-minute intravenous infusion of a single dose of Meropenem for injection (I.V.) in healthy volunteers, mean peak plasma concentrations of Meropenem are approximately 23 mcg/mL (range 14-26) for the 500 mg dose and 49 mcg/mL (range 39-58) for the 1 g dose. A 5-minute intravenous bolus injection of Meropenem for injection (I.V.) in healthy volunteers results in mean peak plasma concentrations of approximately 45 mcg/mL (range 18-65) for the 500 mg dose and 112 mcg/mL (range 83-140) for the 1 g dose.

Following intravenous doses of 500 mg, mean plasma concentrations of Meropenem usually decline to approximately 1 mcg/mL at 6 hours after administration.

No accumulation of Meropenem in plasma was observed with regimens using 500 mg administered every 8 hours or 1 g administered every 6 hours in healthy volunteers with normal renal function.

Distribution

The plasma protein binding of Meropenem is approximately 2%.

Meropenem penetrates well into most body fluids and tissues including cerebrospinal fluid, achieving concentrations matching or exceeding those required to inhibit most susceptible bacteria. After a single intravenous dose of Meropenem for injection (I.V.), the highest mean concentrations of Meropenem were found in tissues and fluids at 1 hour (0.5 to 1.5 hours) after the start of infusion, except where indicated in the tissues and fluids listed in the table below.

Table 1: Meropenem Concentrations in Selected Tissues (Highest Concentrations Reported)

* at 1 hour unless otherwise noted † obtained from blister fluid ‡ in pediatric patients of age 5 months to 8 years § in pediatric patients of age 1 month to 15 years
Tissue	I.V. Dose (g)	Number of Samples	Mean [mcg/mL or mcg/(g)]*	Range [mcg/mL or mcg/(g)]
Endometrium	0.5	7	4.2	1.7-10.2
Myometrium	0.5	15	3.8	0.4-8.1
Ovary	0.5	8	2.8	0.8-4.8
Cervix	0.5	2	7	5.4-8.5
Fallopian tube	0.5	9	1.7	0.3-3.4
Skin	0.5	22	3.3	0.5-12.6
Interstitial fluid†	0.5	9	5.5	3.2-8.6
Skin	1	10	5.3	1.3-16.7
Interstitial fluid†	1	5	26.3	20.9-37.4
Colon	1	2

EpiPen

epinephrine

Dosage Form: injection
EpiPen®

(epinephrine) Auto-Injector 0.3 mg

EpiPen® = one dose of 0.30 mg epinephrine (USP, 1:1000, 0.3 mL)

EpiPen® JR

(epinephrine) Auto-Injector 0.15 mg

EpiPen® Jr = one dose of 0.15 mg epinephrine (USP, 1:2000, 0.3 mL)

DESCRIPTION

Each EpiPen® Auto-Injector delivers a single dose of 0.3 mg epinephrine injection, USP, 1:1000 (0.3 mL) in a sterile solution.

Each EpiPen® Jr Auto-Injector delivers a single dose of 0.15 mg epinephrine injection, USP, 1:2000 (0.3 mL) in a sterile solution.

The EpiPen® and EpiPen® Jr Auto-Injectors each contain 2 mL epinephrine solution. Approximately 1.7 mL remains in the auto-injector after activation and cannot be used.

Each 0.3 mL in the EpiPen® Auto-Injector contains 0.3 mg epinephrine, 1.8 mg sodium chloride, 0.5 mg sodium metabisulfite, hydrochloric acid to adjust pH, and Water for Injection.

The pH range is 2.2-5.0. Each 0.3 mL in the EpiPen® Jr Auto-Injector contains 0.15 mg epinephrine, 1.8 mg sodium chloride, 0.5 mg sodium metabisulfite, hydrochloric acid to adjust pH, and Water for Injection. The pH range is 2.2-5.0.

Epinephrine is a sympathomimetic catecholamine. Chemically, epinephrine is B-(3, 4-dihydroxyphenyl)-a-methyl-aminoethanol, with the following structure:

Epinephrine solution deteriorates rapidly on exposure to air or light, turning pink from oxidation to adrenochrome and brown from the formation of melanin. Replace EpiPen® and EpiPen® Jr Auto-Injectors if the epinephrine solution appears discolored.

EpiPen® and EpiPen® Jr Auto-Injectors do not contain latex.

CLINICAL PHARMACOLOGY

Epinephrine is the drug of choice for the emergency treatment of severe allergic reactions (Type I) to insect stings or bites, foods, drugs, and other allergens. It can also be used in the treatment of anaphylaxis of unknown cause (idiopathic anaphylaxis) or exercise-induced anaphylaxis. When given intramuscularly or subcutaneously it has a rapid onset and short duration of action. Epinephrine acts on both alpha and beta adrenergic receptors. Through its action on alpha adrenergic receptors, epinephrine lessens the vasodilation and increased vascular permeability that occurs during anaphylaxis, which can lead to loss of intravascular fluid volume and hypotension. Through its action on beta-adrenergic receptors, epinephrine causes bronchial smooth muscle relaxation that helps alleviate bronchospasm, wheezing and dyspnea that may occur during anaphylaxis. Epinephrine also alleviates pruritus, urticaria, and angioedema and may be effective in relieving gastrointestinal and genitourinary symptoms associated with anaphylaxis because of its relaxer effects on the smooth muscle of the stomach, intestine, uterus, and urinary bladder.

INDICATIONS AND USAGE

EpiPen® and EpiPen® Jr Auto-Injectors are indicated in the emergency treatment of allergic reactions (Type I) including anaphylaxis to stinging insects (e.g., order Hymenoptera, which include bees, wasps, hornets, yellow jackets and fire ants) and biting insects (e.g., triatoma, mosquitos), allergen immunotherapy, foods, drugs, diagnostic testing substances (e.g., radiocontrast media) and other allergens, as well as idiopathic anaphylaxis or exercise-induced anaphylaxis. EpiPen® and EpiPen® Jr Auto-Injectors are intended for immediate administration in patients, who are determined to be at increased risk for anaphylaxis, including individuals with a history of anaphylactic reactions. Selection of the appropriate dosage strength is determined according to patient body weight (see DOSAGE AND ADMINISTRATION section).

Such reactions may occur within minutes after exposure and consist of flushing, apprehension, syncope, tachycardia, thready or unobtainable pulse associated with a fall in blood pressure, convulsions, vomiting, diarrhea and abdominal cramps, involuntary voiding, wheezing, dyspnea due to laryngeal spasm, pruritus, rashes, urticaria or angioedema.

EpiPen® and EpiPen® Jr Auto-Injectors are intended for immediate self-administration as emergency supportive therapy only and are not a substitute for immediate medical care.

CONTRAINDICATIONS

There are no absolute contraindications to the use of epinephrine in a life-threatening situation.

WARNINGS

EpiPen® and EpiPen® Jr Auto-Injectors should only be injected into the anterolateral aspect of the thigh. DO NOT INJECT INTO BUTTOCK. Injection into the buttock may not provide effective treatment of anaphylaxis. Advise the patient to go immediately to the nearest emergency room for further treatment of anaphylaxis.

Since epinephrine is a strong vasoconstrictor, accidental injection into the digits, hands or feet may result in loss of blood flow to the affected area. Treatment should be directed at vasodilation in addition to further treatment of anaphylaxis (see ADVERSE REACTIONS). Advise the patient to go immediately to the nearest emergency room and to inform the healthcare provider in the emergency room of the location of the accidental injection.

DO NOT INJECT INTRAVENOUSLY. Large doses or accidental intravenous injection of epinephrine may result in cerebral hemorrhage due to sharp rise in blood pressure. Rapidly acting vasodilators can counteract the marked pressor effects of epinephrine if there is such inadvertent administration.

Epinephrine is the preferred treatment for serious allergic reactions or other emergency situations even though this product contains sodium metabisulfite, a sulfite that may, in other products, cause allergic-type reactions including anaphylactic symptoms or life-threatening or less severe asthmatic episodes in certain susceptible persons. The alternatives to using epinephrine in a life-threatening situation may not be satisfactory. The presence of a sulfite in this product should not deter administration of the drug for treatment of serious allergic or other emergency situations even if the patient is sulfite-sensitive.

Epinephrine should be administered with caution in patients who have heart disease, including patients with cardiac arrhythmias, coronary artery or organic heart disease, or hypertension. In such patients, or in patients who are on drugs that may sensitize the heart to arrhythmias, e.g., digitalis, diuretics, or anti-arrhythmics, epinephrine may precipitate or aggravate angina pectoris as well as produce ventricular arrhythmias. It should be recognized that the presence of these conditions is not a contraindication to epinephrine administration in an acute, life-threatening situation.

Epinephrine is light sensitive and should be stored in the carrier tube provided. Store at 25°C (77°F); excursions permitted to 15°C-30°C (59°F-86°F) (See USP Controlled Room Temperature). Do not refrigerate. Before using, check to make sure the solution in the auto-injector is not discolored. Replace the auto-injector if the solution is discolored or contains a precipitate.

PRECAUTIONS

(1) General

EpiPen® and EpiPen® Jr Auto-Injectors are not intended as a substitute for immediate medical care. In conjunction with the administration of epinephrine, the patient should seek immediate medical or hospital care. More than two sequential doses of epinephrine should only be administered under direct medical supervision.

Epinephrine is essential for the treatment of anaphylaxis. Patients with a history of severe allergic reactions (anaphylaxis) to insect stings or bites, foods, drugs, and other allergens as well as idiopathic and exercise-induced anaphylaxis should be carefully instructed about the circumstances under which epinephrine should be used. It must be clearly determined that the patient is at risk of future anaphylaxis, since the following risks may be associated with epinephrine administration (see DOSAGE and ADMINISTRATION).

Epinephrine should be used with caution in patients who have cardiac arrhythmias, coronary artery or organic heart disease, hypertension, or in patients who are on drugs that may sensitize the heart to arrhythmias, e.g., digitalis, diuretics, quinidine, or other antiarrhythmics. In such patients, epinephrine may precipitate or aggravate angina pectoris as well as produce ventricular arrhythmias.

The effects of epinephrine may be potentiated by tricyclic antidepressants and monoamine oxidase inhibitors.

Some patients may be at greater risk of developing adverse reactions after epinephrine administration. These include: hyperthyroid individuals, individuals with cardiovascular disease, hypertension, or diabetes, elderly individuals, pregnant women, pediatric patients under 30 kg (66 lbs.) body weight using EpiPen® Auto-Injector, and pediatric patients under 15 kg (33 lbs.) body weight using EpiPen® J r Auto-Injector.

Despite these concerns, epinephrine is essential for the treatment of anaphylaxis. Therefore, patients with these conditions, and/or any other person who might be in a position to administer EpiPen® or EpiPen® Jr Auto-Injector to a patient experiencing anaphylaxis should be carefully instructed in regard to the circumstances under which epinephrine should be used.

(2) Information for Patients

Complete patient information, including dosage, direction for proper administration and precautions can be found inside each EpiPen®/EpiPen® Jr Auto-Injector carton.

Epinephrine may produce symptoms and signs that include an increase in heart rate, the sensation of a more forceful heartbeat, palpitations, sweating, nausea and vomiting, difficulty breathing, pallor, dizziness, weakness or shakiness, headache, apprehension, nervousness, or anxiety. These symptoms and signs usually subside rapidly, especially with rest, quiet and recumbency. Patients with hypertension or hyperthyroidism may develop more severe or persistent effects, and patients with coronary artery disease could experience angina. Patients with diabetes may develop increased blood glucose levels following epinephrine administration. Patients with Parkinson's disease may notice a temporary worsening of symptoms.

In case of accidental injection, the patient should be advised to immediately go to the emergency room for treatment. Since the epinephrine in the EpiPen® Auto-Injector is a strong vasoconstrictor when injected into the digits, hands or feet, treatment should be directed at vasodilation if there is such an inadvertent administration to these areas (see ADVERSE REACTIONS).

(3) Drug Interactions

Patients who receive epinephrine while concomitantly taking cardiac glycosides or diuretics should be observed carefully for the development of cardiac arrhythmias.

The effects of epinephrine may be potentiated by tricyclic antidepressants, monoamine oxidase inhibitors, levothyroxine sodium, and certain antihistamines, notably chlorpheniramine, tripe-lennamine and diphenhydramine.

The cardiostimulating and bronchodilating effects of epinephrine are antagonized by beta-adrenergic blocking drugs, such as propranolol. The vasoconstricting and hypertensive effects of epinephrine are antagonized by alpha-adrenergic blocking drugs, such as phentoloamine. Ergot alkaloids may also reverse the pressor effects of epinephrine.

(4) Carcinogenesis, Mutagenesis, Impairment of Fertility

Epinephrine and other catecholamines have been shown to have mutagenic potential in vitro and to be an oxidative mutagen in a WP2 bacterial reverse mutation assay. Epinephrine had a moderate degree of mutagenicity, and was positive in the DNA Repair test with B. subtilis (REC) assay, but was not mutagenic in the Salmonella bacterial reverse mutation assay.

Studies of epinephrine after repeated exposure in animals to evaluate the carcinogenic and mutagenic potential or the effect on fertility have not been conducted. This should not prevent the use of epinephrine under the conditions noted under INDICATIONS AND USAGE.

(5) Usage in Pregnancy

Pregnancy Category C: There is no study on the acute effect of epinephrine on pregnancy. Epinephrine has been shown to have developmental effects when administered subcutaneously in rabbits at a dose of 1.2 mg/kg daily for two to three days (approximately 30 times the maximum recommended daily subcutaneous or intramuscular dose on a mg/m2 basis), in mice at a subcutaneous dose of 1 mg/kg daily for 10 days (approximately 7 times the maximum daily subcutaneous or intramuscular dose on a mg/m2 basis) and in hamsters at a subcutaneous dose of 0.5 mg/kg daily for 4 days (approximately 5 times the maximum recommended daily subcutaneous or intramuscular dose on a mg/m2 basis). These effects were not seen in mice at a subcutaneous dose of 0.5 mg/kg daily for 10 days (approximately 3 times the maximum recommended daily subcutaneous or intramuscular dose on a mg/m2 basis). Although, there are no adequate and well-controlled studies in pregnant women, epinephrine should be used in pregnancy only if the potential benefit justifies the potential risk to the fetus.

Adverse Reactions

Adverse reactions to epinephrine include transient, moderate anxiety; apprehensiveness; restlessness; tremor; weakness; dizziness; sweating; palpitations; pallor; nausea and vomiting; headache; and/or respiratory difficulties. These symptoms occur in some persons receiving therapeutic doses of epinephrine, but are more likely to occur in patients with hypertension or hyperthyroidism. Arrhythmias, including fatal ventricular fibrillation, have been reported in patients with underlying cardiac disease or certain drugs (see PRECAUTIONS, Drug Interactions). Rapid rises in blood pressure have produced cerebral hemorrhage, particularly in elderly patients with cardiovascular disease. Angina may occur in patients with coronary artery disease. The potential for epinephrine to produce these types of adverse reactions does not contraindicate its use in an acute life-threatening allergic reaction.

Accidental injection into the digits, hands or feet may result in loss of blood flow to the affected area (see WARNINGS). Adverse events experienced as a result of accidental injections may include increased heart rate, local reactions including injection site pallor, coldness and hypoaesthesia or injury at the injection site resulting in bruising, bleeding, discoloration, erythema or skeletal injury.

OVERDOSAGE

Epinephrine is rapidly inactivated in the body and treatment following overdose with epinephrine is primarily supportive. If necessary, pressor effects may be counteracted by rapidly acting vasodilators or alpha-adrenergic blocking drugs. If prolonged hypotension follows such measure, it may be necessary to administer another pressor drug.

Overdosage of epinephrine may produce extremely elevated arterial pressure, which may result in cerebrovascular hemorrhage, particularly in elderly patients.

Overdosage may also result in pulmonary edema because of peripheral vascular constriction together with cardiac stimulation. Treatment consists of a rapidly acting alpha-adrenergic blocking drug and/or respiratory support.

Epinephrine overdosage can also cause transient bradycardia followed by tachycardia and these may be accompanied by potentially fatal cardiac arrhythmias. Premature ventricular contractions may appear within one minute after injection and may be followed by multifocal ventricular tachycardia (prefibrillation rhythm). Subsidence of the ventricular effects may be followed by atrial tachycardia and occasionally by atrioventricular block. Treatment of arrhythmias consists of administration of a beta-blocking drug such as propranolol.

Overdosage sometimes results in extreme pallor and coldness of the skin, metabolic acidosis and kidney failure. Suitable corrective measures must be taken in such situations.

DOSAGE AND ADMINISTRATION

EpiPen® or EpiPen® Jr Auto-Injector prescribers should ensure that the patient or caregiver understands the indications and use of this product. A health care provider should review the patient instructions and operation of the EpiPen® or EpiPen® Jr Auto-Injector, in detail, with the patient or caregiver. Inject EpiPen® or EpiPen® Jr intramuscularly or subcutaneously into the anterolateral aspect of the thigh, through clothing if necessary. See detailed Directions for Use on the accompanying Patient Instructions.

Selection of the appropriate dosage strength is determined according to patient body weight.

EpiPen® Auto-Injector delivers 0.3 mg epinephrine injection (0.3 mL, 1:1000) and is intended for patients who weigh 30 kg or more (approximately 66 pounds or more).

EpiPen® Jr Auto-Injector delivers 0.15 mg epinephrine injection (0.3 mL, 1:2000) and is intended for patients who weigh 15 to 30 kg (33 - 66 pounds).

Each EpiPen® or EpiPen® Jr Auto-Injector contains a single dose of epinephrine. Since the doses of epinephrine delivered from EpiPen® or EpiPen® Jr Auto-Injector are fixed, consider using other forms of injectable epinephrine if doses lower than 0.15 mg are deemed necessary. The prescriber should carefully assess each patient to determine the most appropriate dose of epinephrine, recognizing the life-threatening nature of the reactions for which this drug is indicated. With severe persistent anaphylaxis, repeat injections with an additional EpiPen® Auto-Injector may be necessary.

Patients should be instructed to periodically visually inspect the epinephrine solution for particulate matter and discoloration. If the solution contains particulate matter or develops a pinkish color or becomes darker than slightly yellow, the patient should immediately contact their physician for a replacement, since these changes indicate that the effectiveness of the drug product may be decreased.

HOW SUPPLIED

EpiPen® Auto-Injectors (epinephrine injections, USR 1:1000, 0.3 mL) are available in individual cartons, NDC 49502-500-01, and as EpiPen 2-Pak®, NDC 49502-500-02, a pack that contains two EpiPen® Auto-Injectors (epinephrine injections, USP, 1:1000, 0.3 mL) and one EpiPen® Auto-Injector trainer device.

EpiPen® Jr Auto-Injectors (epinephrine injection, USP, 1:2000, 0.3 mL) are available in individual cartons, NDC 49502-501-01, and as EpiPen Jr 2-Pak®, NDC 49502-501-02, a pack that contains two EpiPen® Jr Auto-Injectors (epinephrine injections, USP, 1:2000, 0.3 mL) and one EpiPen® Auto-Injector trainer device.

EpiPen 2-Pak® and EpiPen Jr 2-Pak® also includes a S-clip to clip two cases together.

Store at 25°C (77°F); excursions permitted to 15°C-30°C (59°F-86°F) (See USP Controlled Room Temperature).

Contains no latex. Protect from light.

Rx only.

MANUFACTURED FOR Dey, LP.,

NAPA, CALIFORNIA 94558, U.S.A.

by Meridian Medical Technologies, Inc.,

a subsidiary of King Pharmaceuticals®, Inc.,

Columbia, MD 21046, U.S.A.

EpiPen®, EpiPen® Jr, EpiPen 2-Pak®, and EpiPen Jr 2-Pak® are registered trademarks of Mylan, Inc. licensed exclusively to its wholly-owned affiliate, Dey, LP. of Napa California, USA.

09/08

0001497

03-914-00

PATIENT INSERT

EpiPen®

(epinephrine) Auto-Injector 0.3 mg

EpiPen® = one dose of 0.30 mg epinephrine (USP, 1:1000, 0.3 mL)

EpiPen® JR

(epinephrine) Auto-Injector 0.15 mg

EpiPen® Jr = one dose of 0.15 mg epinephrine (USP, 1:2000, 0.3 mL)

Pharmacist - Please Dispense this Leaflet with Product

IMPORTANT INFORMATION

The patient and caregiver should read this information carefully before using EpiPen®or EpiPen® Jr Auto-Injector. Please be prepared! Read the entire insert before an emergency occurs! EpiPen® and EpiPen® Jr Auto-Injectors are disposable, prefilled automatic injection devices for use during allergic emergencies. They contain a single dose of epinephrine which you inject into your outer thigh. EpiPen® and EpiPen® Jr Auto-Injector contain no latex. The EpiPen® and EpiPen®Jr Auto-Injectors are intended for people who have been prescribed this medication by their physician.

It's important that you have this emergency medicine with you at all times. If you need additional units to keep at work, school, etc, please talk to your doctor. This information does not take the place of talking with your doctor about your medical condition or your treatment.

What is the most important information I should know about EpiPen® and EpiPen® Jr Auto-Injector?

When you have allergic reaction (anaphylaxis) use the EpiPen® or EpiPen® Jr Auto-Injector right away and immediately go to your doctor or emergency room for more medical treatment.

• It is important not to be afraid to use the EpiPen® or EpiPen® Jr Auto-Injector for emergency treatment of allergic reactions (anaphylaxis). For most people, injection of the EpiPen® or EpiPen® Jr Auto-Injector in the thigh does not hurt, and use of the EpiPen® or EpiPen® Jr Auto-Injector early at the start of such allergic reactions is important to help prevent the allergic reaction from becoming worse.


• Inject EpiPen® or EpiPen® Jr Auto-Injector into the middle of the outer side of the thigh (upper leg).


• Epinephrine, the active ingredient in EpiPen® and EpiPen® Jr Auto-Injectors is used to treat life-threatening allergic reactions (anaphylaxis). You should use this medication only if your doctor has prescribed it for allergic emergencies. Such emergencies may occur from insect stings or bites, foods, drugs, latex, other allergens, exercise induced anaphylaxis, or unknown causes.


• Make sure to tell your doctor about all your medical conditions and allergies.


• Always get medical treatment immediately after using EpiPen® or EpiPen® Jr Auto-Injector.

Since you cannot predict when a life-threatening allergic reaction may occur, carry the EpiPen® or EpiPen® Jr Auto-Injector with you at all times.

What is EpiPen®/EpiPen® Jr Auto-Injector?

The EpiPen® and EpiPen® Jr Auto-Injectors are products used for the emergency injection of epinephrine. Epinephrine is a medicine used for life-threatening allergic reactions such as severe swelling, breathing problems, or loss of blood pressure. Allergic reactions can be caused by stinging and biting insects, allergy injections, food, medicines, exercise, or unknown causes.

Life-threatening allergic reactions may show up as closing of your breathing airways, wheezing, sneezing, hoarseness, hives, itching, swelling, skin redness, fast heartbeat, weak pulse, feeling very anxious, confusion, stomach pain, losing control of urine or bowel movements (incontinence), faintness, or "passing out" (unconsciousness).

The EpiPen® Auto-Injector (0.3 mg) is generally intended for patients who weigh 66 pounds or more (30 kilograms or more).

The EpiPen® Jr Auto-Injector (0.15 mg) is generally intended for patients who weigh approximately 33 to 66 pounds (15 to 30 kilograms).

Who should not use EpiPen®/EpiPen® Jr Auto-Injector?

There are no absolute contraindications to the use of EpiPen® and EpiPen® Jr Auto-Injector in a life-threatening allergic reaction. People with certain medical conditions have a higher chance of having serious side effects from EpiPen® or EpiPen® Jr Auto-Injector.

Tell your doctor and pharmacist about all your medical conditions, but especially if you:

• Have heart disease or high blood pressure


• Have diabetes


• Have thyroid conditions


• Are pregnant

Tell your doctor about all the medicines you take, including prescription and non-prescription medicines, vitamins and herbal supplements. Inform your doctor of all known allergies. Some medicines may cause serious side effects if taken while you use EpiPen®/EpiPen® Jr Auto-Injector. Some medicines may affect how EpiPen®/EpiPen® Jr Auto-Injector works.

EpiPen® or EpiPen" Jr Auto-Injector may affect how your other medicines work.

What should I avoid while using EpiPen®/EpiPen® Jr Auto-Injector?

• NEVER PUT THUMB, FINGERS OR HAND OVER ORANGE TIP. NEVER PRESS OR PUSH ORANGE TIP WITH THUMB, FINGERS OR HAND. The needle comes out of orange tip. Accidental injection into finger, hands or feet may result in loss of blood flow to these areas. If this happens, go immediately to the nearest emergency room.


• Do not inject EpiPen® or EpiPen® Jr Auto-Injector into the buttock or any other part of the body, other than the middle of the outer side of your thigh (upper leg).


• Do not inject EpiPen® or EpiPen® Jr Auto-Injector into a vein.


• Do not drop carrier tube or auto-injector. If carrier tube or auto-injector is dropped, inspect for damage and leakage. Discard auto-injector and carrier tube, and replace if damage or leakage is noticed or suspected.

What are the possible side effects of EpiPen®/ EpiPen® Jr Auto-Injector?

Too much epinephrine can cause dangerous high blood pressure or stroke.

If you take certain medicines, you may develop serious life-threatening side effects from the epinephrine in EpiPen®/ EpiPen® Jr Auto-Injector. Be sure to tell your doctor all the medicines you take, especially medicines for asthma.

Patients with certain medical conditions, or who take certain medicines, may get more side effects from EpiPen®/ EpiPen® Jr Auto-Injector or the side effects may last longer. This includes patients who take certain types of medicines for asthma, allergies, depression, low thyroid, high blood pressure, and heart disease. Patients with heart disease may feel chest pain (angina).

EpiPen®/EpiPen® Jr Auto-Injector (epinephrine) can cause the following reactions. Some reactions can be serious. They usually go away with rest. Please notify your doctor if you experience any of these.

Common side effects of EpiPen®/EpiPen® Jr Auto-Injector include:

• Faster, irregular (wrong) or "pounding" heartbeat


• Sweating


• Nausea and vomiting


• Breathing problems


• Paleness


• Dizziness


• Weakness or shakiness


• Headache


• Feelings of over excitement, nervousness or anxiety

These are not all the possible side effects of

EpiPen®/EpiPen® Jr Auto-Injector.

For more information, ask your doctor or pharmacist.

Call your doctor for medical advice about side effects.

You may report side effects to FDA at 1-800-FDA-1088.

How should I store EpiPen® /EpiPen® Jr Auto-Injector?

• Keep the EpiPen® and EpiPen® Jr Auto-Injector nearby and ready for use at all times.


• Store at 25°C (77°F); excursions permitted to 15°C-30°C (59°F-86°F) (See USP Controlled Room Temperature). Contains no latex. Protect from light.


• Do NOT store in refrigerator.


• Do NOT expose to extreme cold or heat. For example, do NOT store in your vehicle's glove box.


• Examine contents in clear window of auto-injector periodically. If the solution is discolored or contains solid particles (precipitate), replace the unit. Solution should be clear.


• Always keep your EpiPen ® or EpiPen ®Jr Auto- Injector in the carrier tube with the blue safety release on until you need to use it.
  
  Your auto-injector has an expiration date


• Example:"DEC 08" = December 31, 2008


• Replace it before the expiration date.

SEE OTHER SIDE FOR "DIRECTIONS FOR USE" AND FOR EpiPen® CENTER FOR ANAPHYLACTIC SUPPORT™

FREE ENROLLMENT FORM.

DIRECTIONS FOR USE

• REMOVE AUTO-INJECTOR FROM CARRIER TUBE BEFORE USE.


• NEVER PUT THUMB, FINGERS OR HAND OVER ORANGE TIP.


• NEVER PRESS OR PUSH ORANGE TIP WITH THUMB, FINGERS OR HAND.


• THE NEEDLE COMES OUT OF ORANGE TIP.


• DO NOT REMOVE BLUE SAFETY RELEASE UNTIL READY TO USE.


• DO NOT USE IF SOLUTION IS DISCOLORED.


• DO NOT PLACE PATIENT INSERT OR ANY OTHER FOREIGN OBJECTS IN CARRIER WITH AUTO-INJECTOR, AS THIS MAY PREVENT YOU FROM REMOVING THE AUTO-INJECTOR FOR USE.
  
  
  

TO REMOVE AUTO-INJECTOR FROM THE CARRIER TUBE:

1. Flip open the yellow cap of the EpiPen® or the green cap of theEpiPen® Jr Auto-Injector carrier tube.
   
   
   


2. Remove the EpiPen® or EpiPen® Jr Auto-Injector by tipping and sliding it out of the carrier tube.

TO USE AUTO-INJECTOR:

1. Grasp unit with the orange tip pointing downward.


2. Form fist around the unit (orange tip down).
   
   
   


3. With your other hand, pull off the blue safety release.
   
   
   


4. Hold orange tip near outer thigh.
   
   DO NOT INJECT INTO BUTTOCK.
   
   
   


5. Swing and firmly push against outer thigh until it clicks so that unit is perpendicular (at 90° angle) to the thigh.
   
   (Auto-injector is designed to work through clothing.)


6. Hold firmly against thigh for approximately 10 seconds to deliver drug. (The injection is now complete. The window on auto-injector will be obscured.)
   
   
   


7. Remove unit from thigh (the orange needle cover will extend to cover needle) and massage injection area for 10 seconds.


8. Call 911 and seek immediate medical attention.


9. Take the used auto-injector with you to the hospital emergency room.

Note: Most of the liquid (about 85%) stays in the auto-injector and cannot be reused. However, you have received the correct dose of the medication if the orange needle tip is extended and the window is obscured. Trainer label has blue background color. Blue background labeled trainer contains no needle and no drug.

! WARNING !

• NEVER put thumb, fingers or hand over orange tip. NEVER press or push orange tip with thumb, fingers or hand. The needle comes out of orange tip. Accidental injection into hands or feet may result in loss of blood flow to these areas. If this happens, go immediately to the nearest emergency room.


• EpiPen® and EpiPen® Jr Auto-Injector should be injected only into the outer thigh (see "Directions for Use"). DO NOT INJECT INTO BUTTOCK.


• Do NOT remove blue safety release until ready to use.

To dispose of expired units

• Expired auto-injectors must be disposed of properly.


• To dispose of an expired auto-injector and carrier tube, take them to your doctor's office or to a hospital for proper disposal.


• Used auto-injector with extended needle cover will not fit in carrier tube.

IMMEDIATELY AFTER USE

• Go immediately to the nearest hospital emergency room or call 911.
  
  You may need further medical attention. Take your used auto-injector with you.


• Tell the doctor that you have received an injection of epinephrine in your thigh.


• Give your used EpiPen®/EpiPen® Jr Auto-Injector to the doctor for inspection and proper disposal.

Do not attempt to take the auto-injector apart.

Manufactured for Dey, L.P., Napa, CA 94558 USA.

by Meridian Medical Technologies™, Inc.

Columbia, MD 21046 USA.

A subsidiary of King Pharmaceuticals® Inc.

EpiPen® is a registered trademark of Mylan, Inc. licensed exclusively to its wholly-owned affiliate, Dey, LP. of Napa California, USA

Design and Utility patents applied for Carrier Tube and Auto-Injector design platform.

©2008 by Meridian Medical Technologies™, Inc.

04/2008

03-855-00

0001496

SEE OTHER SIDE FOR MORE INFORMATION.

PACKAGE LABEL – PRINCIPAL DISPLAY PANEL – EpiPen 0.3 mg AUTO-INJECTOR LABEL

NDC 49502-500-01

See other side for instructions

Rx only

After use, most of liquid stays in auto-injector and can't be reused.

Delivers 0.3 mg intramuscular dose of epinephrine from epinephrine injection 1:1000 USP (0.3 mL).

Each 0.3 mL also contains 1.8 mg sodium chloride and 0.5 mg sodium metabisulfite.

EpiPen ® 0.3 mg Epinephrine Auto-Injector for Allergic Emergencies (Anaphylaxis)

REPLACE

IF SOLUTION IS DISCOLORED

STORE AT 25°C (77°F); EXCURSIONS PERMITTED TO 15-30°C (59-86°F)

DO NOT REFRIGERATE. PROTECT FROM LIGHT. CONTAINS NO LATEX.

Dey ® Mfd. For Dey, L.P., Napa, CA 94558 USA by Meridian Medical Technologies ™ , Inc.

Columbia, MD 21046 USA

A subsidiary of King Pharmaceuticals ® , Inc.

EpiPen ® 0.3 mg Epinephrine Auto-Injector

1. Pull off blue safety release.


2. Swing and firmly push orange tip against outer thigh so it ‘clicks’ AND HOLD on thigh approx. 10 seconds to deliver drug.


3. Seek emergency medical attention.
   
   
   

PACKAGE LABEL – PRINICPAL DISPLAY PANEL – EpiPen Jr 0.15 mg AUTO-INJECTOR LABEL

NDC 49502-501-01

See other side for instructions

Rx only

After use, most of liquid stays in auto-injector and can't be reused.

Delivers 0.15 mg intramuscular dose of epinephrine from epinephrine injection 1:2000 USP (0.3 mL).

Each 0.3 mL also contains 1.8 mg sodium chloride and 0.5 mg sodium metabisulfite.

EpiPen ® Jr

0.15 mg Epinephrine Auto-Injector for Allergic Emergencies (Anaphylaxis)

REPLACE

IF SOLUTION IS DISCOLORED

STORE AT 25°C (77°F); EXCURSIONS PERMITTED TO 15-30°C (59-86°F)

DO NOT REFRIGERATE. PROTECT FROM LIGHT. CONTAINS NO LATEX.

Dey ® Mfd. For Dey, L.P., Napa, CA 94558 USA by Meridian Medical Technologies ™ , Inc.

Columbia, MD 21046 USA

A subsidiary of King Pharmaceuticals ® , Inc.

EpiPen® Jr 0.15 mg Epinephrine Auto-Injector

1. Pull off blue safety release.


2. Swing and firmly push orange tip against outer thigh so it ‘clicks’ AND HOLD on thigh approx. 10 seconds to deliver drug.


3. Seek emergency medical attention.
   
   
   

PACKAGE LABEL – PRINCIPAL DISPLAY PANEL – EpiPen 0.3 mg CARTON

NDC 49502-500-01

Rx only

New Product Appearance!

For Allergic Emergencies (Anaphylaxis) 0.3 mg each

EpiPen ® (Epinephrine) Auto-Injector 0.3 mg

OPEN IMMEDIATELY

EpiPen ® Center for Anaphylactic Support ™

FREE MEMBERSHIP – Details Inside

Dey ®

PACKAGE LABEL – PRINCIPAL DISPLAY PANEL – EpiPen Jr 0.15 mg CARTON

NDC 49502-501-01

Rx only

New Product Appearance!

For Allergic Emergencies (Anaphylaxis) 0.15 mg each

EpiPen ® Jr (Epinephrine) Auto-Injector 0.15 mg

OPEN IMMEDIATELY

EpiPen ® Center for Anaphylactic Support ™

FREE MEMBERSHIP – Details Inside

Dey ®

PACKAGE LABEL – PRINCIPAL DISPLAY PANEL – EpiPen 2-Pak 0.3 mg CARTON

NDC 49502-500-02

Rx only.

New Product Appearance!

For Allergic Emergencies (Anaphylaxis) 0.3 mg each

EpiPen 2-Pak ® (Epinephrine) Auto-Injectors 0.3 mg

OPEN IMMEDIATELY

EpiPen ® Center for Anaphylactic Support ™

FREE MEMBERSHIP – Details Inside

Each carton contains 2 EpiPen ® Auto-Injectors and 1 Trainer.

Dey ®

PACKAGE LABEL – PRINCIPAL DISPLAY PANEL – EpiPen Jr 2-Pak 0.15 mg CARTON

NDC 49502-501-02

Rx only.

New Product Appearance!

For Allergic Emergencies (Anaphylaxis) 0.15 mg each

EpiPen Jr 2-Pak ® (Epinephrine) Auto-Injectors 0.15 mg

OPEN IMMEDIATELY

EpiPen ® Center for Anaphylactic Support ™

FREE MEMBERSHIP – Details Inside

Each carton contains 2 EpiPen ® Jr Auto-Injectors and 1 Trainer.

Dey ®

EpiPen  epinephrine  injection

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 49502-500 Route of Administration INTRAMUSCULAR DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength Epinephrine (Epinephrine) Epinephrine 0.3 mg  in 0.3 mL

Inactive Ingredients Ingredient Name Strength Sodium Chloride   Sodium Metabisulfite   Water   Hydrochloric Acid   Nitrogen

Product Characteristics Color      Score      Shape Size Flavor Imprint Code Contains

Packaging # NDC Package Description Multilevel Packaging 1 49502-500-01 1 CONTAINER In 1 CARTON contains a CONTAINER 1 1 SYRINGE In 1 CONTAINER This package is contained within the CARTON (49502-500-01) and contains a SYRINGE, GLASS 1 0.3 mL In 1 SYRINGE, GLASS This package is contained within a CONTAINER and a CARTON (49502-500-01) 2 49502-500-02 1 CONTAINER In 1 CARTON contains a CONTAINER 2 1 SYRINGE In 1 CONTAINER This package is contained within the CARTON (49502-500-02) and contains a SYRINGE, GLASS 2 0.3 mL In 1 SYRINGE, GLASS This package is contained within a CONTAINER and a CARTON (49502-500-02)

Marketing Information
Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
NDA	NDA019430	12/22/1987

EpiPen JR  epinephrine  injection

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 49502-501 Route of Administration INTRAMUSCULAR DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength Epinephrine (Epinephrine) Epinephrine 0.15 mg  in 0.3 mL

Inactive Ingredients Ingredient Name Strength Sodium Chloride   Sodium Metabisulfite   Water   Hydrochloric Acid   Nitrogen

Product Characteristics Color      Score      Shape Size Flavor Imprint Code Contains

Packaging # NDC Package Description Multilevel Packaging 1 49502-501-01 2 CONTAINER In 1 CARTON contains a CONTAINER 1 1 SYRINGE In 1 CONTAINER This package is contained within the CARTON (49502-501-01) and contains a SYRINGE, GLASS 1 0.3 mL In 1 SYRINGE, GLASS This package is contained within a CONTAINER and a CARTON (49502-501-01) 2 49502-501-02 2 CONTAINER In 1 CARTON contains a CONTAINER 2 1 SYRINGE In 1 CONTAINER This package is contained within the CARTON (49502-501-02) and contains a SYRINGE, GLASS 2 0.3 mL In 1 SYRINGE, GLASS This package is contained within a CONTAINER and a CARTON (49502-501-02)

Marketing Information
Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
NDA	NDA019430	12/22/1987

Labeler - Dey Pharma L.P. (194775557)

Registrant - Meridian Medical Technologies, Inc. (167671341)

Establishment
Name	Address	ID/FEI	Operations
Meridian Medical Technologies, Inc.		038889234	MANUFACTURE, ANALYSIS, STERILIZE

Establishment
Name	Address	ID/FEI	Operations
Meridian Medical Technologies, Inc.		167671341	MANUFACTURE, LABEL, PACK

Revised: 06/2010Dey Pharma L.P.

More EpiPen resources

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

Compare EpiPen with other medications

• Adams-Stokes Syndrome
• Allergic Reactions
• Asthma, acute

tocilizumab Intravenous

toe-si-LIZ-oo-mab

Intravenous route(Solution)

Patients treated with tocilizumab are at increased risk for infections, some progressing to serious infections leading to hospitalization or death. These infections have included bacterial sepsis, tuberculosis, and invasive fungal and other opportunistic infections. Evaluate for latent tuberculosis and treat if necessary prior to initiation of therapy. Monitor patients receiving tocilizumab for signs and symptoms of infection, including tuberculosis, even if initial latent tuberculosis test is negative .

Commonly used brand name(s)

In the U.S.

• Actemra

Available Dosage Forms:

• Solution

Therapeutic Class: Immunological Agent

Pharmacologic Class: Monoclonal Antibody

Uses For tocilizumab

Tocilizumab injection is a monoclonal antibody. It is used alone or together with other medicines to reduce the signs and symptoms of moderate to severe rheumatoid arthritis. Tocilizumab helps keep joint damage from getting worse after other medicines (e.g., adalimumab, etanercept, infliximab) have been used and did not work well.

Tocilizumab injection is also used to treat systemic juvenile idiopathic arthritis (SJIA) in children 2 years of age and older.

tocilizumab is available only with your doctor's prescription.

Before Using tocilizumab

In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For tocilizumab, the following should be considered:

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to tocilizumab or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.

Pediatric

Appropriate studies performed to date have not demonstrated pediatric-specific problems that would limit the usefulness of tocilizumab injection in children with SJIA. However, safety and efficacy have not been established in children younger than 2 years of age.

Geriatric

Appropriate studies performed to date have not demonstrated geriatric-specific problems that would limit the usefulness of tocilizumab injection in the elderly. However, elderly patients are more likely to have serious infections, which may require caution in patients receiving tocilizumab injection.

Pregnancy

	Pregnancy Category	Explanation
All Trimesters	C	Animal studies have shown an adverse effect and there are no adequate studies in pregnant women OR no animal studies have been conducted and there are no adequate studies in pregnant women.

Breast Feeding

There are no adequate studies in women for determining infant risk when using this medication during breastfeeding. Weigh the potential benefits against the potential risks before taking this medication while breastfeeding.

Interactions with Medicines

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are receiving tocilizumab, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using tocilizumab with any of the following medicines is usually not recommended, but may be required in some cases. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Infliximab

Interactions with Food/Tobacco/Alcohol

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. Discuss with your healthcare professional the use of your medicine with food, alcohol, or tobacco.

Other Medical Problems

The presence of other medical problems may affect the use of tocilizumab. Make sure you tell your doctor if you have any other medical problems, especially:

• Hyperlipidemia (high fats in the blood) or


• Liver disease, history of or


• Multiple sclerosis, history of or


• Neutropenia (low level of white blood cells) or


• Stomach or bowel problems (e.g., diverticulosis, perforations, or ulcers) or


• Thrombocytopenia (low level of platelets in the blood) or


• Weak immune system (e.g., cancer history or steroid use)—Use with caution. May make these conditions worse.

• Infection, active or recurring or


• Liver disease, active—Should not be used in patients with this condition.

• Tuberculosis, history of—Use with caution. May cause infection to come back (reactivate).

Proper Use of tocilizumab

A nurse or other trained health professional will give you tocilizumab. tocilizumab is given through a needle placed in one of your veins. tocilizumab must be given slowly, so the needle will remain in place for at least one hour.

tocilizumab should come with a Medication Guide. It is very important that you read and understand this information. Be sure to ask your doctor about anything you do not understand.

Precautions While Using tocilizumab

It is very important that your doctor check your or your child's progress at regular visits to make sure that tocilizumab is working properly. Blood tests may be needed to check for unwanted effects.

Tell your doctor if you are pregnant or if you plan to become pregnant. If you become pregnant while receiving tocilizumab, your doctor may want you to join a registry for pregnant patients.

You will need to have a skin test for tuberculosis before you or your child start using tocilizumab. Tell your doctor if you or anyone in your home has ever had a positive reaction to a tuberculosis skin test.

tocilizumab may increase your risk of developing infections. Avoid being near people who are sick or have infections while you or your child are using tocilizumab. Wash your hands often. Tell your doctor if you have any kind of infection before you start using tocilizumab. Also tell your doctor if you have ever had an infection that would not go away or an infection that kept coming back.

Using tocilizumab may increase your risk of having certain cancers. Talk to your doctor if you or your child have concerns about this risk.

Call your doctor right away if you or your child start to have a cough that won't go away, weight loss, night sweats, fever, chills, or flu-like symptoms, such as a runny or stuffy nose, headache, blurred vision, or feeling generally ill. These may be signs that you have an infection.

Tocilizumab may cause headaches and skin reactions, such as a rash or itching, while you are receiving the injection or within 24 hours after you receive it. Check with your doctor or nurse right away if you or your child have any of these symptoms.

tocilizumab may cause a serious type of allergic reaction called anaphylaxis. Anaphylaxis can be life-threatening and requires immediate medical attention. Tell your doctor right away if you or your child have a rash; hives; itching; swelling of the face, tongue, and throat; trouble breathing; or chest pain after you receive the medicine.

tocilizumab may cause serious stomach and bowel problems, especially if you have a history of ulcers or diverticulosis. Check with your doctor right away if you or your child start having severe stomach cramps or pain; black, tarry stools; diarrhea; fever; or vomiting that is severe and sometimes bloody while being treated with tocilizumab.

While you or your child are being treated with tocilizumab, and after you stop treatment, do not have any immunizations (vaccines) without your doctor's approval. Tocilizumab may lower your body's resistance, and there is a chance you might get the infection the immunization is meant to prevent. In addition, other persons living in your household should not get live vaccines (e.g., nasal flu virus vaccine). Try to avoid being around persons who have received live vaccines. Do not get close to them and do not stay in the same room with them for very long. If you or your child cannot take these precautions, you should wear a protective face mask that covers the nose and mouth. Talk to your doctor if you have questions about this.

Your child's vaccines need to be current before he or she begins using tocilizumab injection. Be sure to ask your child's doctor if you have any questions about this.

tocilizumab may increase the level of cholesterol and fats in your blood. If this condition occurs, your doctor may give you a medicine to lower the cholesterol and fats. Talk to your doctor if you or your child have concerns.

Do not take other medicines unless they have been discussed with your doctor. This includes prescription or nonprescription (over-the-counter [OTC]) medicines and herbal or vitamin supplements.

tocilizumab Side Effects

Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor or nurse immediately if any of the following side effects occur:

More common

• Abdominal or stomach pain


• black, tarry stools


• bloody or cloudy urine


• blurred vision


• body aches or pain


• chest pain


• cough


• cough producing mucus


• diarrhea


• difficult, burning, or painful urination


• difficulty with breathing


• difficulty with swallowing


• dizziness


• ear congestion


• fast heartbeat


• feeling of warmth


• fever or chills


• frequent urge to urinate


• headache


• hives


• itching


• loss of appetite


• loss of consciousness


• loss of voice


• lower back or side pain


• nasal congestion


• nausea


• nervousness


• pain or tenderness around the eyes and cheekbones


• painful blisters on the trunk of the body


• pale skin


• pounding in the ears


• puffiness or swelling of the eyelids or around the eyes, face, lips, or tongue


• redness of the face, neck, arms, and occasionally, upper chest


• shortness of breath or troubled breathing


• skin rash


• slow or fast heartbeat


• sneezing


• sore throat


• stuffy or runny nose


• sudden sweating


• tightness of the chest or wheezing


• troubled breathing


• ulcers, sores, or white spots in the mouth


• unusual bleeding or bruising


• unusual tiredness or weakness


• weakness

Less common

• Bladder pain


• blurred vision


• burning feeling in the chest or stomach


• confusion


• dark urine


• decrease in height


• difficulty with moving


• dizziness, faintness, or lightheadedness when getting up suddenly from a lying or sitting position


• fast, irregular, pounding, or racing heartbeat or pulse


• feeling hot


• frequent urge to urinate


• general feeling of discomfort or illness


• heartburn


• indigestion


• itching, pain, redness, swelling, tenderness, or warmth on the skin at the injection site


• joint pain


• light-colored stools


• muscle aches and pains


• muscle cramps or stiffness


• pain in the back, ribs, arms, or legs


• pain in the groin or genitals


• pale skin


• severe stomach pain


• sharp back pain just below the ribs


• shivering


• stomach upset


• sweating


• swelling


• swollen joints


• swollen, painful, or tender lymph glands in the face, neck, armpit, or groin


• tenderness in the stomach area


• trouble with sleeping


• troubled breathing with exertion


• unexplained runny nose or sneezing


• upper right abdominal or stomach pain


• vomiting


• yellow eyes and skin

Rare

• Acid or sour stomach


• belching


• changes in skin color


• confusion


• coughing or spitting up blood


• fainting


• gaseous abdominal or stomach pain


• lightheadedness


• neck pain


• night sweats


• noisy breathing


• pain


• pain, swelling, or redness in the joints


• rapid, shallow breathing


• recurrent fever


• red, tender, or oozing skin at incision


• stomach bloating, burning, cramping, or pain


• sudden high fever or low-grade fever for months


• swelling of the foot or leg


• swollen lymph nodes


• weight loss

Incidence not known

• Dilated neck veins


• extreme fatigue


• severe abdominal or stomach pain, cramping, or burning


• swelling of the face, fingers, feet, or lower legs


• vomiting of material that looks like coffee grounds, severe and continuing


• weight gain

Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

More common

• Burning, dry, or itching eyes


• constipation


• discharge, excessive tearing


• redness, pain, or swelling of the eye, eyelid, or inner lining of the eyelid


• skin rash, encrusted, scaly and oozing


• swelling or inflammation of the mouth


• warmth on the skin

Less common

• Abnormal or decreased touch sensation


• accumulation of pus


• back pain


• bleeding gums


• blemishes on the skin


• bloody eye


• chapped, red, or swollen lips


• earache


• feeling of constant movement of self or surroundings


• hives or welts


• irritation in the mouth


• loose teeth


• persistent breath odor or bad taste in your mouth


• pimples


• redness and swelling of the gums


• redness of the eye


• redness of the skin


• redness or swelling in the ear


• scaling, redness, burning, pain, or other signs of inflammation of the lips


• sensation of spinning


• sleeplessness


• sore mouth or tongue


• sores on the skin


• stomach soreness or discomfort


• swollen, red, or tender area of infection


• unable to sleep


• white patches in the mouth or on the tongue

Rare

• Bleeding after defecation


• blindness


• bloody nose


• burning, numbness, tingling, or painful sensations


• change in hearing


• continuing ringing or buzzing or other unexplained noise in the ears


• coughing or spitting up blood


• decreased vision or other changes in vision


• dry mouth


• ear drainage


• earache


• flushed, dry skin


• fruit-like breath odor


• hearing loss


• increased hunger


• increased thirst


• increased urination


• itching ears


• loss of consciousness


• redness, swelling, or soreness of the tongue


• thirst


• uncomfortable swelling around the anus


• unexplained weight loss


• unsteadiness or awkwardness


• weakness in the arms, hands, legs, or feet

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

See also: tocilizumab Intravenous side effects (in more detail)

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More tocilizumab Intravenous resources

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

Compare tocilizumab Intravenous with other medications

• Juvenile Idiopathic Arthritis
• Rheumatoid Arthritis