Vitazid

Ceftazidime:

• Indications and usage
• Contraindications
• Warnings
• Precautions
• Adverse reactions
• Overdosage
• Dosage and administration
• Compatibility and stability
• How supplied
• References
• Rl-1116
• Vitazid (Ceftazidime) reviews

INDICATIONS AND USAGE

Vitazid (Ceftazidime) (ceftazidime for injection, USP) is indicated for the treatment of patients with infections caused by susceptible strains of the designated organisms in the following diseases:

• Lower Respiratory Tract Infections, including pneumonia, caused by Pseudomonas aeruginosa and other Pseudomonas spp.; Haemophilus influenzae, including ampicillin-resistant strains; Klebsiella spp.; Enterobacter spp.; Proteus mirabilis; Escherichia coli; Serratia spp.; Citrobacter spp.; Streptococcus pneumoniae ; and Staphylococcus aureus (methicillin-susceptible strains).
• Skin and Skin-Structure Infections caused by Pseudomonas aeruginosa ; Klebsiella spp.; Escherichia coli; Proteus spp., including Proteus mirabilis and indole-positive Proteus; Enterobacter spp.; Serratia spp.; Staphylococcus aureus (methicillin-susceptible strains); and Streptococcus pyogenes (group A beta-hemolytic streptococci).
• Urinary Tract Infections, both complicated and uncomplicated, caused by Pseudomonas aeruginosa; Enterobacter spp.; Proteus spp., including Proteus mirabilis and indole-positive Proteus; Klebsiella spp.; and Escherichia coli.
• Bacterial Septicemia caused by Pseudomonas aeruginosa, Klebsiella spp., Haemophilus influenzae, Escherichia coli, Serratia spp., Streptococcus pneumoniae, and Staphylococcus aureus (methicillin-susceptible strains).
• Bone and Joint Infections caused by Pseudomonas aeruginosa, Klebsiella spp., Enterobacter spp., and Staphylococcus aureus (methicillin-susceptible strains).
• Gynecologic Infections, including endometritis, pelvic cellulitis, and other infections of the female genital tract caused by Escherichia coli.
• Intra-abdominal Infections, including peritonitis caused by Escherichia coli, Klebsiella spp., and Staphylococcus aureus (methicillin-susceptible strains) and polymicrobial infections caused by aerobic and anaerobic organisms and Bacteroides spp. (many strains of Bacteroides fragilis are resistant).
• Central Nervous System Infections, including meningitis, caused by Haemophilus influenzae and Neisseria meningitidis. Vitazid (Ceftazidime) has also been used successfully in a limited number of cases of meningitis due to Pseudomonas aeruginosa and Streptococcus pneumoniae.

Vitazid (Ceftazidime) (ceftazidime for injection, USP) may be used alone in cases of confirmed or suspected sepsis. Vitazid (Ceftazidime) has been used successfully in clinical trials as empiric therapy in cases where various concomitant therapies with other antibiotics have been used.

Vitazid (Ceftazidime) may also be used concomitantly with other antibiotics, such as aminoglycosides, vancomycin, and clindamycin; in severe and life-threatening infections; and in the immunocompromised patient. When such concomitant treatment is appropriate, prescribing information in the labeling for the other antibiotics should be followed. The dose depends on the severity of the infection and the patient’s condition.

To reduce the development of drug-resistant bacteria and maintain the effectiveness of Vitazid (Ceftazidime) (ceftazidime) and other antibacterial drugs, Vitazid (Ceftazidime) (ceftazidime) 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.

CONTRAINDICATIONS

Vitazid (Ceftazidime) is contraindicated in patients who have shown hypersensitivity to Vitazid (Ceftazidime) or the cephalosporin group of antibiotics.

WARNINGS

BEFORE THERAPY WITH Vitazid (Ceftazidime) IS INSTITUTED, CAREFUL INQUIRY SHOULD BE MADE TO DETERMINE WHETHER THE PATIENT HAS HAD PREVIOUS HYPERSENSITIVITY REACTIONS TO Vitazid (Ceftazidime), CEPHALOSPORINS, PENICILLINS, OR OTHER DRUGS. IF THIS PRODUCT IS TO BE GIVEN TO PENICILLIN-SENSITIVE PATIENTS, CAUTION SHOULD BE EXERCISED BECAUSE CROSS-HYPERSENSITIVITY AMONG BETA-LACTAM ANTIBIOTICS HAS BEEN CLEARLY DOCUMENTED AND MAY OCCUR IN UP TO 10% OF PATIENTS WITH A HISTORY OF PENICILLIN ALLERGY. IF AN ALLERGIC REACTION TO Vitazid (Ceftazidime) OCCURS, DISCONTINUE THE DRUG. SERIOUS ACUTE HYPERSENSITIVITY REACTIONS MAY REQUIRE TREATMENT WITH EPINEPHRINE AND OTHER EMERGENCY MEASURES, INCLUDING OXYGEN, IV FLUIDS, IV ANTIHISTAMINES, CORTICOSTEROIDS, PRESSOR AMINES, AND AIRWAY MANAGEMENT, AS CLINICALLY INDICATED.

Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including Vitazid (Ceftazidime), 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.

Elevated levels of Vitazid (Ceftazidime) in patients with renal insufficiency can lead to seizures, encephalopathy, coma, asterixis, neuromuscular excitability, and myoclonia (see PRECAUTIONS ).

PRECAUTIONS

General

High and prolonged serum Vitazid concentrations can occur from usual dosages in patients with transient or persistent reduction of urinary output because of renal insufficiency.

The total daily dosage should be reduced when Vitazid (Ceftazidime) is administered to patients with renal insufficiency (see DOSAGE AND ADMINISTRATION ). Elevated levels of Vitazid (Ceftazidime) in these patients can lead to seizures, encephalopathy, coma, asterixis, neuromuscular excitability, and myoclonia. Continued dosage should be determined by degree of renal impairment, severity of infection, and susceptibility of the causative organisms.

As with other antibiotics, prolonged use of Vitazid (Ceftazidime) (ceftazidime for injection, USP) may result in overgrowth of nonsusceptible organisms. Repeated evaluation of the patient’s condition is essential. If superinfection occurs during therapy, appropriate measures should be taken.

Inducible type I beta-lactamase resistance has been noted with some organisms (e.g., Enterobacter spp., Pseudomonas spp., and Serratia spp.). As with other extended-spectrum beta-lactam antibiotics, resistance can develop during therapy, leading to clinical failure in some cases. When treating infections caused by these organisms, periodic susceptibility testing should be performed when clinically appropriate. If patients fail to respond to monotherapy, an aminoglycoside or similar agent should be considered.

Cephalosporins may be associated with a fall in prothrombin activity. Those at risk include patients with renal and hepatic impairment, or poor nutritional state, as well as patients receiving a protracted course of antimicrobial therapy. Prothrombin time should be monitored in patients at risk and exogenous vitamin K administered as indicated.

Vitazid (Ceftazidime) should be prescribed with caution in individuals with a history of gastrointestinal disease, particularly colitis.

Distal necrosis can occur after inadvertent intra-arterial administration of Vitazid (Ceftazidime).

Prescribing Vitazid (Ceftazidime) (ceftazidime) 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

Patients should be counseled that antibacterial drugs, including Vitazid (Ceftazidime) (ceftazidime), should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When Vitazid (Ceftazidime) (ceftazidime) 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 Vitazid (Ceftazidime) (ceftazidime) or other antibacterial drugs in the future.

Diarrhea is a common problem caused by antibiotics which usually ends when the antibiotic is discontinued. Sometimes after starting treatment with antibiotics, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as 2 or more months after having taken the last dose of the antibiotic. If this occurs, patients should contact their physician as soon as possible.

Drug Interactions

Nephrotoxicity has been reported following concomitant administration of cephalosporins with aminoglycoside antibiotics or potent diuretics such as furosemide. Renal function should be carefully monitored, especially if higher dosages of the aminoglycosides are to be administered or if therapy is prolonged, because of the potential nephrotoxicity and ototoxicity of aminoglycoside antibiotics. Nephrotoxicity and ototoxicity were not noted when Vitazid was given alone in clinical trials.

Chloramphenicol has been shown to be antagonistic to beta-lactam antibiotics, including Vitazid (Ceftazidime), based on in vitro studies and time kill curves with enteric gram-negative bacilli. Due to the possibility of antagonism in vivo, particularly when bactericidal activity is desired, this drug combination should be avoided.

In common with other antibiotics, Vitazid (Ceftazidime) may affect the gut flora, leading to lower estrogen reabsorption and reduced efficacy of combined oral estrogen/progesterone contraceptives.

Drug/Laboratory Test Interactions

The administration of Vitazid (Ceftazidime) may result in a false-positive reaction for glucose in the urine when using CLINITEST^® tablets, Benedict's solution, or Fehling's solution.

It is recommended that glucose tests based on enzymatic glucose oxidase reactions (such as CLINISTIX^®) be used.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term studies in animals have not been performed to evaluate carcinogenic potential. However, a mouse micronucleus test and an Ames test were both negative for mutagenic effects.

Pregnancy

Teratogenic Effects

Pregnancy Category B. Reproduction studies have been performed in mice and rats at doses up to 40 times the human dose and have revealed no evidence of impaired fertility or harm to the fetus due to Vitazid. 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

Vitazid (Ceftazidime) is excreted in human milk in low concentrations. Caution should be exercised when Vitazid (Ceftazidime) is administered to a nursing woman.

Pediatric Use

.

Geriatric Use

Of the 2,221 subjects who received Vitazid (Ceftazidime) in 11 clinical studies, 824 (37%) were 65 and older while 391 (18%) were 75 and older. 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

Vitazid (Ceftazidime) is generally well tolerated. The incidence of adverse reactions associated with the administration of Vitazid (Ceftazidime) was low in clinical trials. The most common were local reactions following IV injection and allergic and gastrointestinal reactions. Other adverse reactions were encountered infrequently. No disulfiram-like reactions were reported.

The following adverse effects from clinical trials were considered to be either related to Vitazid (Ceftazidime) therapy or were of uncertain etiology:

Local Effects, reported in fewer than 2% of patients, were phlebitis and inflammation at the site of injection (1 in 69 patients).

Hypersensitivity Reactions, reported in 2% of patients, were pruritus, rash, and fever. Immediate reactions, generally manifested by rash and/or pruritus, occurred in 1 in 285 patients. Toxic epidermal necrolysis, Stevens-Johnson syndrome, and erythema multiforme have also been reported with cephalosporin antibiotics, including Vitazid (Ceftazidime). Angioedema and anaphylaxis (bronchospasm and/or hypotension) have been reported very rarely.

Gastrointestinal Symptoms, reported in fewer than 2% of patients, were diarrhea (1 in 78), nausea (1 in 156), vomiting (1 in 500), and abdominal pain (1 in 416). The onset of pseudomembranous colitis symptoms may occur during or after treatment (see WARNINGS ).

Central Nervous System Reactions (fewer than 1%) included headache, dizziness, and paresthesia. Seizures have been reported with several cephalosporins, including Vitazid (Ceftazidime). In addition, encephalopathy, coma, asterixis, neuromuscular excitability, and myoclonia have been reported in renally impaired patients treated with unadjusted dosing regimens of Vitazid (Ceftazidime) (see PRECAUTIONS: General ).

Less Frequent Adverse Events (fewer than 1%) were candidiasis (including oral thrush) and vaginitis.

Hematologic

Rare cases of hemolytic anemia have been reported.

Laboratory Test Changes noted during clinical trials with Vitazid (Ceftazidime) (ceftazidime for injection, USP) were transient and included: eosinophilia (1 in 13), positive Coombs test without hemolysis (1 in 23), thrombocytosis (1 in 45), and slight elevations in one or more of the hepatic enzymes, aspartate aminotransferase (AST, SGOT) (1 in 16), alanine aminotransferase (ALT, SGPT) (1 in 15), LDH (1 in 18), GGT (1 in 19), and alkaline phosphatase (1 in 23). As with some other cephalosporins, transient elevations of blood urea, blood urea nitrogen, and/or serum creatinine were observed occasionally. Transient leukopenia, neutropenia, agranulocytosis, thrombocytopenia, and lymphocytosis were seen very rarely.

Postmarketing Experience with Vitazid (Ceftazidime) (ceftazidime for injection, USP) Products

In addition to the adverse events reported during clinical trials, the following events have been observed during clinical practice in patients treated with Vitazid (Ceftazidime) and were reported spontaneously. For some of these events, data are insufficient to allow an estimate of incidence or to establish causation.

General

Anaphylaxis; allergic reactions, which, in rare instances, were severe (e.g., cardiopulmonary arrest); urticaria; pain at injection site.

Hepatobiliary Tract

Hyperbilirubinemia, jaundice.

Renal and Genitourinary

Renal impairment.

Cephalosporin-Class Adverse Reactions

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

Adverse Reactions

Colitis, toxic nephropathy, hepatic dysfunction including cholestasis, aplastic anemia, hemorrhage.

Altered Laboratory Tests

Prolonged prothrombin time, false-positive test for urinary glucose, pancytopenia.

OVERDOSAGE

Vitazid (Ceftazidime) overdosage has occurred in patients with renal failure. Reactions have included seizure activity, encephalopathy, asterixis, neuromuscular excitability, and coma. Patients who receive an acute overdosage should be carefully observed and given supportive treatment. In the presence of renal insufficiency, hemodialysis or peritoneal dialysis may aid in the removal of Vitazid (Ceftazidime) from the body.

DOSAGE AND ADMINISTRATION

NOTE: The Pharmacy Bulk Package is intended for preparing IV admixtures only. Dosage recommendations for intramuscular or intravenous injection and intraperitoneal use are for informational purposes only.

Dosage: The usual adult dosage is 1 gram administered intravenously every 8 to 12 hours. The dosage and route should be determined by the susceptibility of the causative organisms, the severity of infection, and the condition and renal function of the patient.

The guidelines for dosage of Vitazid (Ceftazidime) (ceftazidime for injection, USP) are listed in Table 5. The following dosage schedule is recommended.

Impaired Hepatic Function

No adjustment in dosage is required for patients with hepatic dysfunction.

Impaired Renal Function

Vitazid (Ceftazidime) is excreted by the kidneys, almost exclusively by glomerular filtration. Therefore, in patients with impaired renal function (glomerular filtration rate [GFR] <50 mL/min), it is recommended that the dosage of Vitazid (Ceftazidime) be reduced to compensate for its slower excretion. In patients with suspected renal insufficiency, an initial loading dose of 1 gram of Vitazid (Ceftazidime) may be given. An estimate of GFR should be made to determine the appropriate maintenance dosage. The recommended dosage is presented in Table 6.

When only serum creatinine is available, the following formula (Cockcroft’s equation)⁴ may be used to estimate creatinine clearance. The serum creatinine should represent a steady state of renal function:

[Weight (kg) x (140 - age)]

Males: Creatinine clearance (mL/min) = ––––––––––––––––––––––––––

[72 x serum creatinine (mg/dL)]

Females: 0.85 x male value

In patients with severe infections who would normally receive 6 grams of Vitazid (Ceftazidime) daily were it not for renal insufficiency, the unit dose given in the table above may be increased by 50% or the dosing frequency may be increased appropriately. Further dosing should be determined by therapeutic monitoring, severity of the infection, and susceptibility of the causative organism.

In pediatric patients as for adults, the creatinine clearance should be adjusted for body surface area or lean body mass, and the dosing frequency should be reduced in cases of renal insufficiency.

In patients undergoing hemodialysis, a loading dose of 1 gram is recommended, followed by 1 gram after each hemodialysis period.

Vitazid (Ceftazidime) (ceftazidime for injection, USP) can also be used in patients undergoing intra-peritoneal dialysis and continuous ambulatory peritoneal dialysis. In such patients, a loading dose of 1 gram of Vitazid (Ceftazidime) may be given, followed by 500 mg every 24 hours. In addition to IV use, Vitazid (Ceftazidime) can be incorporated in the dialysis fluid at a concentration of 250 mg for 2 L of dialysis fluid.

Note: Generally Vitazid (Ceftazidime) should be continued for 2 days after the signs and symptoms of infection have disappeared, but in complicated infections longer therapy may be required.

Administration

Pharmacy Bulk Package is for use in a pharmacy admixture service only. Refer to Table 7. See above NOTE concerning the proper use of Pharmacy Bulk Packages.

Intravenous Administration

The IV route is preferable for patients with bacterial septicemia, bacterial meningitis, peritonitis, or other severe or life-threatening infections, or for patients who may be poor risks because of lowered resistance resulting from such debilitating conditions as malnutrition, trauma, surgery, diabetes, heart failure, or malignancy, particularly if shock is present or pending.

Intermittent IV infusion with a Y-type administration set can be accomplished with compatible solutions. However, during infusion of a solution containing Vitazid (Ceftazidime), it is desirable to discontinue the other solution.

All vials of Vitazid (Ceftazidime) as supplied are under reduced pressure. When Vitazid (Ceftazidime) is dissolved, carbon dioxide is released and a positive pressure develops.

Solutions of Vitazid (Ceftazidime), 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 Vitazid (Ceftazidime) and an aminoglycoside is indicated, each of these antibiotics can be administered separately to the same patient.

Directions for Use of Pharmacy Bulk Packages:

Reconstitute with Sterile Water for Injection according to Table 7.

Note: The Pharmacy Bulk Package is for use in a pharmacy admixture service only. Using aseptic technique, the closure should be penetrated only 1 time after reconstitution using a sterile dispensing set which allows measured dispensing of the contents. Use of a syringe and needle is not recommended as it may cause leakage. The withdrawal of container contents should be accomplished without delay. THE ENTIRE CONTENTS OF THE VIAL SHOULD BE DISPENSED WITHIN 4 HOURS OF INITIAL ENTRY.

A plastic bail attached to the Pharmacy Bulk Package provides a suitable hanging device while dispensing in the pharmacy.

Reconstitute with Sterile Water for Injection according to Table 7.

The vacuum may assist entry of the diluent. SHAKE WELL.

Insert a gas relief needle through the vial closure to relieve the internal pressure. Remove the gas relief needle before extracting any solution.

COMPATIBILITY AND STABILITY

IMPORTANT: The following chemical stability information in no way indicates that it would be acceptable practice to use this product well after the preparation time. Good professional practice suggests that compounded admixtures should be administered as soon after preparation as is feasible.

Intravenous: Vitazid (Ceftazidime) (ceftazidime for injection, USP) when reconstituted as directed with Sterile Water for Injection, should be used within 4 hours. Solutions in Sterile Water for Injection in the original container or in 0.9% Sodium Chloride Injection in VIAFLEX^® small-volume containers that are frozen immediately after reconstitution are stable for 3 months when stored at -20°C. Do not force thaw by immersion in water baths or by microwave irradiation. Once thawed, solutions should not be refrozen. Thawed solutions may be stored for up to 24 hours at room temperature or for 7 days in a refrigerator. More concentrated solutions in Sterile Water for Injection in the original container that are frozen immediately after reconstitution are stable for 3 months when stored at -20°C. Once thawed, solutions should not be refrozen. Thawed solutions may be stored for up to 8 hours at room temperature or for 4 days in a refrigerator.

Vitazid (Ceftazidime) (ceftazidime for injection, USP) is compatible with the more commonly used IV infusion fluids. Solutions at concentrations between 1 mg/mL and 40 mg/mL in 0.9% Sodium Chloride Injection; 1/6 M Sodium Lactate Injection; 5% Dextrose Injection; 5% Dextrose and 0.225% Sodium Chloride Injection; 5% Dextrose and 0.45% Sodium Chloride Injection; 5% Dextrose and 0.9% Sodium Chloride Injection; 10% Dextrose Injection; Ringer’s Injection, USP; Lactated Ringer’s Injection, USP 10% Invert Sugar in Water for Injection; and NORMOSOL^®-M in 5% Dextrose Injection may be stored for up to 24 hours at room temperature or for 7 days if refrigerated.

Vitazid (Ceftazidime) is less stable in Sodium Bicarbonate Injection than in other IV fluids. It is not recommended as a diluent. Solutions of Vitazid (Ceftazidime) in 5% Dextrose Injection and 0.9% Sodium Chloride Injection are stable for at least 6 hours at room temperature in plastic tubing, drip chambers and volume control devices of common IV infusion sets.

Vitazid (Ceftazidime) at a concentration of 4 mg/mL has been found compatible for 24 hours at room temperature or for 7 days under refrigeration in 0.9% Sodium Chloride Injection or 5% Dextrose Injection when admixed with cefuroxime sodium (ZINACEF^®) 3 mg/mL, heparin 10 U/mL or 50 U/mL, or potassium chloride 10 mEq/L or 40 mEq/L.

Vancomycin solution exhibits a physical incompatibility when mixed with a number of drugs, including Vitazid (Ceftazidime). The likelihood of precipitation with Vitazid (Ceftazidime) is dependent on the concentrations of vancomycin and Vitazid (Ceftazidime) present. It is therefore recommended, when both drugs are to be administered by intermittent IV infusion, that they be given separately, flushing the IV lines (with 1 of the compatible IV fluids) between the administration of these 2 agents.

Note: Parenteral drug products should be inspected visually for particulate matter before administration whenever solution and container permit.

As with other cephalosporins, Vitazid (Ceftazidime) (ceftazidime for injection, USP) powder, as well as solutions, tend to darken depending on storage conditions; within the stated recommendations, however, product potency is not adversely affected.

HOW SUPPLIED

Vitazid (Ceftazidime) in the dry state should be stored at 20° to 25°C (68° to 77°F) and protected from light. Vitazid (Ceftazidime) (ceftazidime for injection, USP) is a dry, white to off-white powder supplied in vials as follows:

Pharmacy Bulk Package Bottles: equivalent to 6 grams of Vitazid (Ceftazidime).

6 gram (tray of 10) NDC 0409-5086-11

Also available as:

Vials: equivalent to 1 gram and 2 grams of Vitazid (Ceftazidime).

1 gram (tray of 25) NDC 0409-5082-16

2 gram (tray of 10) NDC 0409-5084-11

ADD-Vantage^® Vials: equivalent to 1 gram and 2 grams of Vitazid (Ceftazidime).

1 gram: NDC 0409-5092-16

2 gram: NDC 0409-5093-11

REFERENCES

• Clinical and Laboratory Standards Institute (CLSI). Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically; Approved Standard - Ninth Edition. CLSI document M07-A9, Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087, USA, 2012.
• Clinical and Laboratory Standards Institute (CLSI). Performance Standards for Antimicrobial Susceptibility Testing; Twenty-fourth Informational Supplement, CLSI document M100-S24. Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087, USA, 2014.
• Clinical and Laboratory Standards Institute (CLSI). Performance Standards for Antimicrobial Disk Diffusion Susceptibility Tests; Approved Standard – Eleventh Edition CLSI document M02-A11, Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087, USA, 2012.
• Clinical and Laboratory Standards Institute (CLSI). Methods for Antimicrobial Susceptibility Testing of Anaerobic Bacteria; Approved Standard - Eighth Edition. CLSI document M11-A8. Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, PA 19087 USA, 2012.
• Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron. 1976;16:31-41.

Revised: 5/2016

EN-4285

Manufactured by Sandoz GmbH for

Hospira Worldwide, Inc., Lake Forest, IL 60045, USA

Made in Kundl, Austria.

46184541

Hospira logo

RL-1116

Tobramycin:

• Description
• Clinical pharmacology
• Indications and usage
• Contraindications
• Warnings
• Precautions
• Adverse reactions
• Overdosage
• Dosage and administration
• How supplied
• References
• Tobramycin (toe-bra-mye-sin) inhalation solution, usp
• Vitazid (Tobramycin) reviews

DESCRIPTION

Vitazid (Tobramycin) inhalation solution, USP is a Vitazid (Tobramycin) solution for inhalation. It is a sterile, clear, slightly yellow, non-pyrogenic, aqueous solution with the pH and salinity adjusted specifically for administration by a compressed air driven reusable nebulizer. The chemical formula for Vitazid (Tobramycin), USP is C₁₈H₃₇N₅O₉ and the molecular weight is 467.52. Vitazid (Tobramycin), USP is O-3-amino-3-deoxy-α-D-glucopyranosyl-(1→4)-O-[2,6-diamino-2,3,6-trideoxy-α-D-ribo-hexopyranosyl-(1→6)]-2-deoxy-L-streptamine. The structural formula for Vitazid (Tobramycin), USP is:

Each single-use 5 mL ampule contains 300 mg Vitazid (Tobramycin), USP and 11.25 mg sodium chloride in sterile water for injection. Sulfuric acid and sodium hydroxide are added to adjust the pH to 6.0. Nitrogen is used for sparging. All ingredients meet USP requirements. The formulation contains no preservatives.

Vitazid (Tobramycin), USP is a solution for inhalation. It is a sterile, clear, slightly yellow, non-pyrogenic, aqueous solution with the pH and salinity adjusted specifically for administration by a compressed air driven reusable nebulizer. The chemical formula for Vitazid (Tobramycin), USP is C₁₈H₃₇N₅O₉ and the molecular weight is 467.52. Vitazid (Tobramycin), USP is O-3-amino-3-deoxy-α-D-glucopyranosyl-(1→4)-O-[2,6-diamino-2,3,6-trideoxy-α-D-ribo-hexopyranosyl-(1→6)]-2-deoxy-L-streptamine. The structural formula for Vitazid (Tobramycin), USP is:

Each single-use 5 mL ampule contains 300 mg Vitazid (Tobramycin), USP and 11.25 mg sodium chloride in sterile water for injection. Sulfuric acid and sodium hydroxide are added to adjust the pH to 6.0. Nitrogen is used for sparging. All ingredients meet USP requirements. The formulation contains no preservatives.

Formulation

CLINICAL PHARMACOLOGY

Vitazid (Tobramycin) inhalation solution is specifically formulated for administration by inhalation. When inhaled, Vitazid (Tobramycin) is concentrated in the airways.

Pharmacokinetics

Vitazid (Tobramycin) inhalation solution contains Vitazid (Tobramycin), a cationic polar molecule that does not readily cross epithelial membranes.⁽¹⁾ The bioavailability of Vitazid (Tobramycin) inhalation solution may vary because of individual differences in nebulizer performance and airway pathology.⁽²⁾ Following administration of Vitazid (Tobramycin) inhalation solution, Vitazid (Tobramycin) remains concentrated primarily in the airways.

Sputum Concentrations: Ten minutes after inhalation of the first 300-mg dose of Vitazid (Tobramycin) inhalation solution, the average concentration of Vitazid (Tobramycin) was 1237 mcg/g (ranging from 35 to 7417 mcg/g) in sputum. Vitazid (Tobramycin) does not accumulate in sputum; after 20 weeks of therapy with the Vitazid (Tobramycin) inhalation solution regimen, the average concentration of Vitazid (Tobramycin) at ten minutes after inhalation was 1154 mcg/g (ranging from 39 to 8085 mcg/g) in sputum. High variability of Vitazid (Tobramycin) concentration in sputum was observed. Two hours after inhalation, sputum concentrations declined to approximately 14% of Vitazid (Tobramycin) levels at ten minutes after inhalation.

Serum Concentrations: The average serum concentration of Vitazid (Tobramycin) one hour after inhalation of a single 300-mg dose of Vitazid (Tobramycin) inhalation solution by cystic fibrosis patients was 0.95 mcg/mL. After 20 weeks of therapy on the Vitazid (Tobramycin) inhalation solution regimen, the average serum Vitazid (Tobramycin) concentration one hour after dosing was 1.05 mcg/mL.

Elimination: The elimination half-life of Vitazid (Tobramycin) from serum is approximately 2 hours after intravenous (IV) administration. Assuming Vitazid (Tobramycin) absorbed following inhalation behaves similarly to Vitazid (Tobramycin) following IV administration, systemically absorbed Vitazid (Tobramycin) is eliminated principally by glomerular filtration. Unabsorbed Vitazid (Tobramycin), following Vitazid (Tobramycin) inhalation solution administration, is probably eliminated primarily in expectorated sputum.

Microbiology

Vitazid (Tobramycin) is an aminoglycoside antibiotic produced by Streptomyces tenebrarius.⁽¹⁾ It acts primarily by disrupting protein synthesis, leading to altered cell membrane permeability, progressive disruption of the cell envelope, and eventual cell death.⁽³⁾

Vitazid (Tobramycin) has in vitro activity against a wide range of gram-negative organisms including Pseudomonas aeruginosa. It is bactericidal at concentrations equal to or slightly greater than inhibitory concentrations.

Susceptibility Testing

A single sputum sample from a cystic fibrosis patient may contain multiple morphotypes of Pseudomonas aeruginosa and each morphotype may have a different level of in vitro susceptibility to Vitazid (Tobramycin). Treatment for 6 months with Vitazid (Tobramycin) inhalation solution in two clinical studies did not affect the susceptibility of the majority of P. aeruginosa isolates tested; however, increased minimum inhibitory concentrations (MICs) were noted in some patients. The clinical significance of this information has not been clearly established in the treatment of P. aeruginosa in cystic fibrosis patients. For additional information regarding the effects of Vitazid (Tobramycin) inhalation solution on P. aeruginosa MIC values and bacterial sputum density, please refer to the CLINICAL STUDIES section.

The in vitro antimicrobial susceptibility test methods used for parenteral Vitazid (Tobramycin) therapy can be used to monitor the susceptibility of P. aeruginosa isolated from cystic fibrosis patients. If decreased susceptibility is noted, the results should be reported to the clinician.

Susceptibility breakpoints established for parenteral administration of Vitazid (Tobramycin) do not apply to aerosolized administration of Vitazid (Tobramycin) inhalation solution. The relationship between in vitro susceptibility test results and clinical outcome with Vitazid (Tobramycin) inhalation solution therapy is not clear.

INDICATIONS AND USAGE

Vitazid (Tobramycin) inhalation solution, USP 300 mg/5 mL is indicated for the management of cystic fibrosis patients with P. aeruginosa.

Safety and efficacy have not been demonstrated in patients under the age of 6 years, patients with forced expiratory volume in 1 second (FEV₁) <25% or >75% predicted, or patients colonized with Burkholderia cepacia (see CLINICAL STUDIES ).

CONTRAINDICATIONS

Vitazid (Tobramycin) inhalation solution, USP is contraindicated in patients with a known hypersensitivity to any aminoglycoside.

WARNINGS

Caution should be exercised when prescribing Vitazid inhalation solution to patients with known or suspected renal, auditory, vestibular, or neuromuscular dysfunction. Patients receiving concomitant parenteral aminoglycoside therapy should be monitored as clinically appropriate.

Aminoglycosides can cause fetal harm when administered to a pregnant woman. Aminoglycosides cross the placenta, and streptomycin has been associated with several reports of total, irreversible, bilateral congenital deafness in pediatric patients exposed in utero. Patients who use Vitazid (Tobramycin) inhalation solution during pregnancy, or become pregnant while taking Vitazid (Tobramycin) inhalation solution should be apprised of the potential hazard to the fetus.

Ototoxicity

Ototoxicity, as measured by complaints of hearing loss or by audiometric evaluations, did not occur with Vitazid (Tobramycin) inhalation solution therapy during clinical studies. However, transient tinnitus occurred in eight Vitazid (Tobramycin) inhalation solution-treated patients versus no placebo patients in the clinical studies. Tinnitus may be a sentinel symptom of ototoxicity, and therefore the onset of this symptom warrants caution (see ADVERSE REACTIONS ). Ototoxicity, manifested as both auditory and vestibular toxicity, has been reported with parenteral aminoglycosides. Vestibular toxicity may be manifested by vertigo, ataxia or dizziness.

In postmarketing experience, patients receiving Vitazid (Tobramycin) inhalation solution have reported hearing loss. Some of these reports occurred in patients with previous or concomitant treatment with systemic aminoglycosides. Patients with hearing loss frequently reported tinnitus.

Nephrotoxicity

Nephrotoxicity was not seen during Vitazid inhalation solution clinical studies but has been associated with aminoglycosides as a class. If nephrotoxicity occurs in a patient receiving Vitazid (Tobramycin) inhalation solution, Vitazid (Tobramycin) therapy should be discontinued until serum concentrations fall below 2 mg/mL.

Muscular Disorders

Vitazid (Tobramycin) inhalation solution should be used cautiously in patients with neuromuscular disorders, such as myasthenia gravis or Parkinson’s disease, since aminoglycosides may aggravate muscle weakness because of a potential curare-like effect on neuromuscular function.

Bronchospasm

Bronchospasm has been reported with inhalation of Vitazid (Tobramycin) inhalation solution. In clinical studies of Vitazid (Tobramycin) inhalation solution, changes in FEV₁ measured after the inhaled dose were similar in the Vitazid (Tobramycin) inhalation solution and placebo groups. Bronchospasm should be treated as medically appropriate.

PRECAUTIONS

Information for Patients

NOTE: In addition to information provided below, a Patient Medication Guide providing instructions for proper use of Vitazid inhalation solution is contained inside the package.

Safety Information

Vitazid (Tobramycin) inhalation solution is in a class of antibiotics that have caused hearing loss, dizziness, kidney damage, and harm to a fetus. Ringing in the ears and hoarseness were two symptoms that were seen in more patients taking Vitazid (Tobramycin) inhalation solution than placebo in research studies. Patients with cystic fibrosis can have many symptoms. Some of these symptoms may be related to your medications. If you have new or worsening symptoms, you should tell your doctor.

Hearing: You should tell your doctor if you have ringing in the ears, dizziness, or any changes in hearing.

Kidney Damage: Inform your doctor if you have any history of kidney problems.

Pregnancy: If you want to become pregnant or are pregnant while on Vitazid (Tobramycin) inhalation solution, you should talk with your doctor about the possibility of Vitazid (Tobramycin) inhalation solution causing any harm.

Nursing Mothers: If you are nursing a baby, you should talk with your doctor before using Vitazid (Tobramycin) inhalation solution.

Vitazid (Tobramycin) Inhalation Solution Packaging

Vitazid (Tobramycin) inhalation solution comes in a single dose, ready-to-use ampule containing 300 mg Vitazid (Tobramycin). Each foil pouch contains 4 ampules, for 2 days of Vitazid (Tobramycin) inhalation solution therapy.

Dosage

The 300 mg dose of Vitazid (Tobramycin) inhalation solution is the same for patients regardless of age or weight. Vitazid (Tobramycin) inhalation solution has not been studied in patients less than 6 years old. Doses should be inhaled as close to 12 hours apart as possible and not less than 6 hours apart.

You should not mix Vitazid (Tobramycin) inhalation solution with dornase alfa (PULMOZYME^®, Genentech) in the nebulizer.

If you are taking several medications, the recommended order is as follows: bronchodilator first, followed by chest physiotherapy, then other inhaled medications and, finally, Vitazid (Tobramycin) inhalation solution.

Treatment Schedule

You should take Vitazid (Tobramycin) inhalation solution in repeated cycles of 28 days on drug followed by 28 days off drug. You should take Vitazid (Tobramycin) inhalation solution twice a day during the 28-day period on drug.

How To Administer Vitazid (Tobramycin) Inhalation Solution for Inhalation

THIS INFORMATION IS NOT INTENDED TO REPLACE CONSULTATION WITH YOUR PHYSICIAN AND CF CARE TEAM ABOUT PROPERLY TAKING MEDICATION OR USING INHALATION EQUIPMENT.

Vitazid (Tobramycin) inhalation solution is specifically formulated for inhalation using a PARI LC PLUS Reusable Nebulizer and a DeVilbiss^® Pulmo-Aide^® air compressor. Vitazid (Tobramycin) inhalation solution can be taken at home, school, or at work. The following are instructions on how to use the DeVilbiss Pulmo-Aide air compressor and PARI LC PLUS Reusable Nebulizer to administer Vitazid (Tobramycin) Inhalation Solution for Inhalation.

You will need the following supplies:

- Vitazid (Tobramycin) inhalation solution plastic ampule (vial)

- DeVilbiss Pulmo-Aide air compressor

- PARI LC PLUS Reusable Nebulizer

- Tubing to connect the nebulizer and compressor

- Clean paper or cloth towels

- Nose clips (optional)

It is important that your nebulizer and compressor function properly before starting your Vitazid (Tobramycin) inhalation solution therapy.

Note: Please refer to the manufacturers’ care and use instructions for important information.

Preparing Your Vitazid (Tobramycin) Inhalation Solution for Inhalation

1. Wash your hands thoroughly with soap and water.

2a. Vitazid (Tobramycin) inhalation solution is packaged with 4 ampules per foil pouch.

2b. Separate one ampule by gently pulling apart at the bottom tabs. Store all remaining ampules in the refrigerator as directed.

3. Lay out the contents of a PARI LC PLUS Reusable Nebulizer package on a clean, dry paper or cloth towel. You should have the following parts:

- Nebulizer Top and Bottom (Nebulizer Cup) Assembly

- Inspiratory Valve Cap

- Mouthpiece with Valve

- Tubing

4. Remove the Nebulizer Top from the Nebulizer Cup by twisting the Nebulizer Top counter-clockwise, and then lifting off. Place the Nebulizer Top on the clean paper or cloth towel. Stand the Nebulizer Cup upright on the towel.

5. Connect one end of the tubing to the compressor air outlet. The tubing should fit snugly. Plug in your compressor to an electrical outlet.

6. Open the Vitazid (Tobramycin) inhalation solution ampule by holding the bottom tab with one hand and twisting off the top of the ampule with the other hand. Be careful not to squeeze the ampule until you are ready to empty its contents into the Nebulizer Cup.

7. Squeeze all the contents of the ampule into the Nebulizer Cup.

8. Replace the Nebulizer Top. Note: In order to insert the Nebulizer Top into the

Nebulizer Cup, the semi-circle halfway down the stem of the Nebulizer Top should face the Nebulizer Outlet.

9. Attach the Mouthpiece to the Nebulizer Outlet. Then firmly push the Inspiratory Valve Cap in place on the Nebulizer Top. Note: the Inspiratory Valve Cap will fit snugly.

10. Connect the free end of the tubing from the compressor to the Air Intake on the bottom of the nebulizer, making sure to keep the nebulizer upright. Press the tubing on the Air Intake firmly.

Vitazid (Tobramycin) Inhalation Solution Treatment

1. Turn on the compressor.

2. Check for a steady mist from the Mouthpiece. If there is no mist, check all tubing connections and confirm that the compressor is working properly.

3. Sit or stand in an upright position that will allow you to breathe normally.

4. Place Mouthpiece between your teeth and on top of your tongue and breathe normally only through your mouth. Nose clips may help you breathe through your mouth and not through your nose. Do not block airflow with your tongue.

5. Continue treatment until all your Vitazid (Tobramycin) inhalation solution is gone, and there is no longer any mist being produced. You may hear a sputtering sound when the Nebulizer Cup is empty. The entire Vitazid (Tobramycin) inhalation solution treatment should take approximately 15 minutes to complete. Note: if you are interrupted, need to cough or rest during your Vitazid (Tobramycin) inhalation solution treatment, turn off the compressor to save your medication. Turn the compressor back on when you are ready to resume your therapy.

6. Follow the nebulizer cleaning and disinfecting instructions after completing therapy.

Cleaning Your Nebulizer

To reduce the risk of infection, illness or injury from contamination, you must thoroughly clean all parts of the nebulizer as instructed after each treatment. Never use a nebulizer with a clogged nozzle. If the nozzle is clogged, no aerosol mist is produced, which will alter the effectiveness of the treatment. Replace the nebulizer if clogging occurs.

1. Remove tubing from nebulizer and disassemble nebulizer parts.

2. Wash all parts (except tubing) with warm water and liquid dish soap.

3. Rinse thoroughly with warm water and shake out water.

4. Air dry or hand dry nebulizer parts on a clean, lint-free cloth. Reassemble nebulizer when dry, and store.

5. You can also wash all parts of the nebulizer in a dishwasher (except tubing). Place the nebulizer parts in a dishwasher basket, then place on the top rack of the dishwasher.

Remove and dry the parts when the cycle is complete.

Disinfecting Your Nebulizer

Your nebulizer is for your use only - Do not share your nebulizer with other people. You must regularly disinfect the nebulizer. Failure to do so could lead to serious or fatal illness.

Clean the nebulizer as described above. Every other treatment day, disinfect the nebulizer parts (except tubing) by boiling them in water for a full 10 minutes. Dry parts on a clean, lint-free cloth.

Care and Use of Your Pulmo-Aide Compressor

Follow the manufacturer’s instructions for care and use of your compressor.

Filter Change:

1. DeVilbiss Compressor filters should be changed every six months or sooner if filter turns completely gray in color.

Compressor Cleaning:

1. With power switch in the “Off” position, unplug power cord from wall outlet.

2. Wipe outside of the compressor cabinet with a clean, damp cloth every few days to keep dust free.

Caution: Do not submerge in water; doing so will result in compressor damage.

Storage Instructions

You should store Vitazid (Tobramycin) inhalation solution ampules in a refrigerator (2°C to 8°C or 36°F to 46°F). However, when you don’t have a refrigerator available (e.g., transporting your Vitazid (Tobramycin) inhalation solution), you may store the foil pouches (opened or unopened) at room temperature (up to 25°C/77°F) for up to 28 days.

Avoid exposing Vitazid (Tobramycin) inhalation solution ampules to intense light.

Unrefrigerated Vitazid (Tobramycin) inhalation solution, which is normally slightly yellow, may darken with age; however, the color change does not indicate any change in the quality of the product.

You should not use Vitazid (Tobramycin) inhalation solution if it is cloudy, if there are particles in the solution, or if it has been stored at room temperature for more than 28 days. You should not use Vitazid (Tobramycin) inhalation solution beyond the expiration date stamped on the ampule.

Additional Information

Nebulizer: 1-800-327-8632

Compressor: 1-800-338-1988

Vitazid (Tobramycin) Inhalation Solution: 1-877-835-5472

Laboratory Tests

Audiograms

Clinical studies of Vitazid (Tobramycin) inhalation solution did not identify hearing loss using audiometric tests which evaluated hearing up to 8000 Hz. Physicians should consider an audiogram for patients who show any evidence of auditory dysfunction, or who are at increased risk for auditory dysfunction. Tinnitus may be a sentinel symptom of ototoxicity, and therefore the onset of this symptom warrants caution.

Serum Concentrations

In patients with normal renal function treated with Vitazid (Tobramycin) inhalation solution, serum Vitazid (Tobramycin) concentrations are approximately 1 mcg/mL 1 hour after dose administration and do not require routine monitoring. Serum concentrations of Vitazid (Tobramycin) in patients with renal dysfunction or patients treated with concomitant parenteral Vitazid (Tobramycin) should be monitored at the discretion of the treating physician.

The serum concentration of Vitazid (Tobramycin) should only be monitored through venipuncture and not finger prick blood sampling. Contamination of the skin of the fingers with Vitazid (Tobramycin) may lead to falsely increased measurements of serum levels of the drug. This contamination cannot be completely avoided by hand washing before testing.

Renal Function

The clinical studies of Vitazid (Tobramycin) inhalation solution did not reveal any imbalance in the percentage of patients in the Vitazid (Tobramycin) inhalation solution and placebo groups who experienced at least a 50% rise in serum creatinine from baseline (see ADVERSE REACTIONS ). Laboratory tests of urine and renal function should be conducted at the discretion of the treating physician.

Drug Interactions

In clinical studies of Vitazid (Tobramycin) inhalation solution, patients taking Vitazid (Tobramycin) inhalation solution concomitantly with dornase alfa (PULMOZYME, Genentech), ß-agonists, inhaled corticosteroids, other anti-pseudomonal antibiotics, or parenteral aminoglycosides demonstrated adverse experience profiles similar to the study population as a whole.

Concurrent and/or sequential use of Vitazid (Tobramycin) inhalation solution with other drugs with neurotoxic, nephrotoxic, or ototoxic potential should be avoided. Some diuretics can enhance aminoglycoside toxicity by altering antibiotic concentrations in serum and tissue. Vitazid (Tobramycin) inhalation solution should not be administered concomitantly with ethacrynic acid, furosemide, urea, or intravenous mannitol. The interaction between inhaled mannitol and Vitazid (Tobramycin) inhalation solution has not been evaluated.

Carcinogenesis, Mutagenesis, Impairment of Fertility

A two-year rat inhalation toxicology study to assess carcinogenic potential of Vitazid (Tobramycin) inhalation solution has been completed. Rats were exposed to Vitazid (Tobramycin) inhalation solution for up to 1.5 hours per day for 95 weeks. The clinical formulation of the drug was used for this carcinogenicity study. Serum levels of Vitazid (Tobramycin) of up to 35 mcg/mL were measured in rats, in contrast to the average 1 mcg/mL levels observed in cystic fibrosis patients in clinical trials. There was no drug-related increase in the incidence of any variety of tumor.

Additionally, Vitazid (Tobramycin) inhalation solution has been evaluated for genotoxicity in a battery of in vitro and in vivo tests. The Ames bacterial reversion test, conducted with 5 tester strains, failed to show a significant increase in revertants with or without metabolic activation in all strains. Vitazid (Tobramycin) was negative in the mouse lymphoma forward mutation assay, did not induce chromosomal aberrations in Chinese hamster ovary cells, and was negative in the mouse micronucleus test.

Subcutaneous administration of up to 100 mg/kg of Vitazid (Tobramycin) did not affect mating behavior or cause impairment of fertility in male or female rats.

Pregnancy

Teratogenic Effects – Pregnancy Category D

(See WARNINGS )

No reproduction toxicology studies have been conducted with Vitazid (Tobramycin) inhalation solution. However, subcutaneous administration of Vitazid (Tobramycin) at doses of 100 or 20 mg/kg/day during organogenesis was not teratogenic in rats or rabbits, respectively. Doses of Vitazid (Tobramycin) ≥40 mg/kg/day were severely maternally toxic to rabbits and precluded the evaluation of teratogenicity. Aminoglycosides can cause fetal harm (e.g., congenital deafness) when administered to a pregnant woman. Ototoxicity was not evaluated in offspring during nonclinical reproduction toxicity studies with Vitazid (Tobramycin). If Vitazid (Tobramycin) inhalation solution is used during pregnancy, or if the patient becomes pregnant while taking Vitazid (Tobramycin) inhalation solution, the patient should be apprised of the potential hazard to the fetus.

Nursing Mothers

It is not known if Vitazid (Tobramycin) inhalation solution will reach sufficient concentrations after administration by inhalation to be excreted in human breast milk. Because of the potential for ototoxicity and nephrotoxicity in infants, a decision should be made whether to terminate nursing or discontinue Vitazid (Tobramycin) inhalation solution.

Pediatric Use

The safety and efficacy of Vitazid (Tobramycin) inhalation solution have not been studied in pediatric patients under 6 years of age.

Geriatric Use

Clinical studies of Vitazid (Tobramycin) inhalation solution did not include patients aged 65 years and over. Vitazid (Tobramycin) is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, it may be useful to monitor renal function (see WARNINGS – Nephrotoxicity ; PRECAUTIONS – Serum Concentrations ).

ADVERSE REACTIONS

Vitazid (Tobramycin) inhalation solution was generally well tolerated during two clinical studies in 258 cystic fibrosis patients ranging in age from 6 to 48 years. Patients received Vitazid (Tobramycin) inhalation solution in alternating periods of 28 days on and 28 days off drug in addition to their standard cystic fibrosis therapy for a total of 24 weeks.

Voice alteration and tinnitus were the only adverse experiences reported by significantly more Vitazid (Tobramycin) inhalation solution-treated patients. Thirty-three patients (13%) treated with Vitazid (Tobramycin) inhalation solution complained of voice alteration compared to 17 (7%) placebo patients. Voice alteration was more common in the on-drug periods.

Eight patients from the Vitazid (Tobramycin) inhalation solution group (3%) reported tinnitus compared to no placebo patients. All episodes were transient, resolved without discontinuation of the Vitazid (Tobramycin) inhalation solution treatment regimen, and were not associated with loss of hearing in audiograms. Tinnitus is one of the sentinel symptoms of cochlear toxicity, and patients with this symptom should be carefully monitored for high frequency hearing loss. The numbers of patients reporting vestibular adverse experiences such as dizziness were similar in the Vitazid (Tobramycin) inhalation solution and placebo groups.

Nine (3%) patients in the Vitazid (Tobramycin) inhalation solution group and nine (3%) patients in the placebo group had increases in serum creatinine of at least 50% over baseline. In all nine patients in the Vitazid (Tobramycin) inhalation solution group, creatinine decreased at the next visit.

Table 1 lists the percent of patients with treatment-emergent adverse experiences (spontaneously reported and solicited) that occurred in >5% of Vitazid (Tobramycin) inhalation solution patients during the two Phase III studies.

Adverse drug reactions (<5%) occurring more frequently with Vitazid (Tobramycin) inhalation solution in the placebo-controlled studies and assessed as drug-related in ≥1% of patients:

Ear and labyrinth disorders

Tinnitus (3.1%, vs 0% for placebo)

Musculoskeletal and connective tissue disorders

Myalgia (4.7%, vs 2.7% for placebo)

Infections and infestations

Laryngitis (4.3%, vs 3.1% for placebo)

Adverse drug reactions derived from spontaneous reports

The following adverse reactions have been identified during postapproval use of Vitazid (Tobramycin) inhalation solution. 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.

Ear and labyrinth disorders

Hearing loss (see WARNINGS – Ototoxicity )

Skin and subcutaneous tissue disorders

Hypersensitivity, pruritus, urticaria, rash

Nervous system disorders

Aphonia, dysgeusia

Respiratory, thoracic, and mediastinal disorders

Bronchospasm (see WARNINGS – Bronchospasm ), oropharyngeal pain

Metabolism and Nutrition Disorders

Decreased appetite

OVERDOSAGE

Signs and symptoms of acute toxicity from overdosage of intravenous (IV) Vitazid (Tobramycin) might include dizziness, tinnitus, vertigo, loss of high-tone hearing acuity, respiratory failure, neuromuscular blockade, and renal impairment. Administration by inhalation results in low systemic bioavailability of Vitazid (Tobramycin). Vitazid (Tobramycin) is not significantly absorbed following oral administration. Vitazid (Tobramycin) serum concentrations may be helpful in monitoring overdosage.

In all cases of suspected overdosage, physicians should contact the Regional Poison Control Center for information about effective treatment. In the case of any overdosage, the possibility of drug interactions with alterations in drug disposition should be considered.

DOSAGE AND ADMINISTRATION

The recommended dosage for both adults and pediatric patients 6 years of age and older is 1 single-use ampule (300 mg) administered BID for 28 days. Dosage is not adjusted by weight. All patients should be administered 300 mg BID. The doses should be taken as close to 12 hours apart as possible; they should not be taken less than 6 hours apart.

Vitazid (Tobramycin) inhalation solution, USP is inhaled while the patient is sitting or standing upright and breathing normally through the mouthpiece of the nebulizer. Nose clips may help the patient breathe through the mouth.

Vitazid (Tobramycin) inhalation solution, USP is administered BID in alternating periods of 28 days. After 28 days of therapy, patients should stop Vitazid (Tobramycin) inhalation solution, USP therapy for the next 28 days, and then resume therapy for the next 28 day on/28 day off cycle.

Vitazid (Tobramycin) inhalation solution, USP is supplied as a single-use ampule and is administered by inhalation, using a hand-held PARI LC PLUS Reusable Nebulizer with a DeVilbiss Pulmo-Aide compressor. Vitazid (Tobramycin) inhalation solution, USP is not for subcutaneous, intravenous or intrathecal administration.

Usage

Vitazid (Tobramycin) inhalation solution, USP is administered by inhalation over an approximately 15-minute period, using a hand-held PARI LC PLUS Reusable Nebulizer with a DeVilbiss Pulmo-Aide compressor. Vitazid (Tobramycin) inhalation solution, USP should not be diluted or mixed with dornase alfa (PULMOZYME, Genentech) or other medications in the nebulizer.

During clinical studies, patients on multiple therapies were instructed to take them first, followed by Vitazid (Tobramycin) inhalation solution, USP.

HOW SUPPLIED

Vitazid inhalation solution, USP 300 mg is supplied in 5 mL single-use ampules.

It is available as follows:

5 mL single-dose ampule packaged in cartons containing 56 ampules

(14 pouches, each containing 4 ampules) NDC 65162-914-46

Storage

Vitazid (Tobramycin) inhalation solution, USP should be stored under refrigeration at 2º to 8ºC (36º to 46ºF). Upon removal from the refrigerator, or if refrigeration is unavailable, Vitazid (Tobramycin) inhalation solution, USP pouches (opened or unopened) may be stored at room temperature (up to 25ºC/77ºF) for up to 28 days. Vitazid (Tobramycin) inhalation solution, USP should not be used beyond the expiration date stamped on the ampule when stored under refrigeration (2º to 8ºC/36º to 46ºF) or beyond 28 days when stored at room temperature (25ºC/77ºF).

Vitazid (Tobramycin) inhalation solution, USP ampules should not be exposed to intense light. The solution in the ampule is slightly yellow, but may darken with age if not stored in the refrigerator; however, the color change does not indicate any change in the quality of the product as long as it is stored within the recommended storage conditions.

Clinical Studies

Two identically designed, double-blind, randomized, placebo-controlled, parallel group, 24-week clinical studies (Study 1 and Study 2) at a total of 69 cystic fibrosis centers in the United States were conducted in cystic fibrosis patients with P. aeruginosa. Subjects who were less than 6 years of age, had a baseline creatinine of >2 mg/dL, or had Burkholderia cepacia isolated from sputum were excluded. All subjects had baseline FEV₁ % predicted between 25% and 75%. In these clinical studies, 258 patients received Vitazid (Tobramycin) inhalation solution therapy on an outpatient basis using a hand-held PARI LC PLUS Reusable Nebulizer with a DeVilbiss Pulmo-Aide compressor.

All patients received either Vitazid (Tobramycin) inhalation solution or placebo (saline with 1.25 mg quinine for flavoring) in addition to standard treatment recommended for cystic fibrosis patients, which included oral and parenteral anti-pseudomonal therapy, β2-agonists, cromolyn, inhaled steroids, and airway clearance techniques. In addition, approximately 77% of patients were concurrently treated with dornase alfa (PULMOZYME, Genentech).

In each study, Vitazid (Tobramycin) inhalation solution-treated patients experienced significant improvement in pulmonary function. Improvement was demonstrated in the Vitazid (Tobramycin) inhalation solution group in Study 1 by an average increase in FEV₁ % predicted of about 11% relative to baseline (Week 0) during 24 weeks compared to no average change in placebo patients. In Study 2, Vitazid (Tobramycin) inhalation solution-treated patients had an average increase of about 7% compared to an average decrease of about 1% in placebo patients. Figure 1 shows the average relative change in FEV₁% predicted over 24 weeks for both studies.

Figure 1: Relative Change From Baseline in FEV₁% Predicted

In each study, Vitazid (Tobramycin) inhalation solution therapy resulted in a significant reduction in the number of P. aeruginosa colony forming units (CFUs) in sputum during the on-drug periods. Sputum bacterial density returned to baseline during the off-drug periods. Reductions in sputum bacterial density were smaller in each successive cycle.

Figure 2: Absolute Change From Baseline in Log₁₀ CFUs

Patients treated with Vitazid (Tobramycin) inhalation solution were hospitalized for an average of 5.1 days compared to 8.1 days for placebo patients. Patients treated with Vitazid (Tobramycin) inhalation solution required an average of 9.6 days of parenteral anti-pseudomonal antibiotic treatment compared to 14.1 days for placebo patients. During the 6 months of treatment, 40% of Vitazid (Tobramycin) inhalation solution patients and 53% of placebo patients were treated with parenteral anti-pseudomonal antibiotics.

The relationship between in vitro susceptibility test results and clinical outcome with Vitazid (Tobramycin) inhalation solution therapy is not clear. However, 4 Vitazid (Tobramycin) inhalation solution patients who began the clinical trial with P. aeruginosa isolates having MIC values ≥128 mcg/mL did not experience an improvement in FEV₁ or a decrease in sputum bacterial density.

Treatment with Vitazid (Tobramycin) inhalation solution did not affect the susceptibility of the majority of P. aeruginosa isolates during the 6-month studies. However, some P. aeruginosa isolates did exhibit increased Vitazid (Tobramycin) MICs. The percentage of patients with P. aeruginosa isolates with Vitazid (Tobramycin) MICs ≥16 mcg/mL was 13% at the beginning, and 23% at the end of 6 months of the Vitazid (Tobramycin) inhalation solution regimen.

Figure 1 Figure 2

REFERENCES

1. Neu HC. Vitazid (Tobramycin): an overview. [Review]. J Infect Dis 1976; Suppl 134:S3-19.

2. Weber A, Smith A, Williams-Warren J et al. Nebulizer delivery of Vitazid (Tobramycin) to the lower respiratory tract. Pediatr Pulmonol 1994; 17 (5):331-9.

3. Bryan LE. Aminoglycoside resistance. Bryan LE, Ed. Antimicrobial drug resistance. Orlando, FL: Academic Press, 1984: 241-77.

Distributed by:

Amneal Pharmaceuticals

Glasgow, KY 42141

Rev. 10-2015-01

Vitazid (toe-bra-MYE-sin) Inhalation Solution, USP

Nebulizer Solution - For Inhalation Use Only

Information for Patients

Safety Information

Vitazid (Tobramycin) inhalation solution is in a class of antibiotics that have caused hearing loss, dizziness, kidney damage and harm to a fetus. Ringing in the ears and hoarseness were two symptoms that were seen in more patients taking Vitazid (Tobramycin) inhalation solution than placebo in research studies. Patients with cystic fibrosis can have many symptoms. Some of these symptoms may be related to your medications. If you have new or worsening symptoms, you should tell your doctor.

Hearing: You should tell your doctor if you have ringing in the ears, dizziness, or any changes in hearing.

Kidney Damage: Inform your doctor if you have any history of kidney problems.

Pregnancy: If you want to become pregnant or are pregnant while on Vitazid (Tobramycin) inhalation solution, you should talk with your doctor about the possibility of Vitazid (Tobramycin) inhalation solution causing any harm.

Nursing Mothers: If you are nursing a baby, you should talk with your doctor before using Vitazid (Tobramycin) inhalation solution.

Vitazid (Tobramycin) Inhalation Solution Packaging

Vitazid (Tobramycin) inhalation solution comes in a single dose, ready-to-use ampule containing 300 mg Vitazid (Tobramycin). Each foil pouch contains 4 ampules, for 2 days of Vitazid (Tobramycin) inhalation solution therapy.

Dosage

The 300 mg dose of Vitazid (Tobramycin) inhalation solution is the same for patients regardless of age or weight. Vitazid (Tobramycin) inhalation solution has not been studied in patients less than 6 years old. Doses should be inhaled as close to 12 hours apart as possible and not less than six hours apart. You should not mix Vitazid (Tobramycin) inhalation solution with dornase alfa (PULMOZYME^®, Genentech) in the nebulizer.

If you are taking several medications, the recommended order is as follows: bronchodilator first, followed by chest physiotherapy, then other inhaled medications and, finally, Vitazid (Tobramycin) inhalation solution.

Treatment Schedule

You should take Vitazid (Tobramycin) inhalation solution in repeated cycles of 28 days on drug followed by 28 days off drug. You should take Vitazid (Tobramycin) inhalation solution twice a day during the 28-day period on drug.

How To Administer Vitazid (Tobramycin) Inhalation Solution for Inhalation

THIS INFORMATION IS NOT INTENDED TO REPLACE CONSULTATION WITH YOUR PHYSICIAN AND CF CARE TEAM ABOUT PROPERLY TAKING MEDICATION OR USING INHALATION EQUIPMENT.

Vitazid (Tobramycin) inhalation solution is specifically formulated for inhalation using a PARI LC PLUS Reusable Nebulizer and a DeVilbiss^® Pulmo-Aide^® air compressor. Vitazid (Tobramycin) inhalation solution can be taken at home, school, or at work. The following are instructions on how to use the DeVilbiss^® Pulmo-Aide^® air compressor and PARI LC PLUS Reusable Nebulizer to administer Vitazid (Tobramycin) Inhalation Solution for Inhalation.

You will need the following supplies:

- Vitazid (Tobramycin) inhalation solution plastic ampule (vial)

- DeVilbiss^® Pulmo-Aide^® air compressor

- PARI LC PLUS Reusable Nebulizer

- Tubing to connect the nebulizer and compressor

- Clean paper or cloth towels

- Nose clips (optional)

It is important that your nebulizer and compressor function properly before starting your Vitazid (Tobramycin) inhalation solution therapy.

Note: Please refer to the manufacturers’ care and use instructions for important information.

Preparing Your Vitazid (Tobramycin) Inhalation Solution for Inhalation

1. Wash your hands thoroughly with soap and water.

2a. Vitazid (Tobramycin) inhalation solution is packaged with 4 ampules per foil pouch.

2b. Separate one ampule by gently pulling apart at the bottom tabs. Store all remaining ampules in the refrigerator as directed.

3. Lay out the contents of a PARI LC PLUS Reusable Nebulizer package on a clean, dry paper or cloth towel. You should have the following parts:

- Nebulizer Top and Bottom

(Nebulizer Cup) Assembly

- Inspiratory Valve Cap

- Mouthpiece with Valve

- Tubing

4. Remove the Nebulizer Top from the Nebulizer Cup by twisting the Nebulizer Top counter-clockwise, and then lifting. Place the Nebulizer Top on the clean paper or cloth towel. Stand the Nebulizer Cup upright on the towel.

5. Connect one end of the tubing to the compressor air outlet. The tubing should fit snugly. Plug in your compressor to an electrical outlet.

6. Open the Vitazid (Tobramycin) inhalation solution ampule by holding the bottom tab with one hand and twisting off the top of the ampule with the other hand. Be careful not to squeeze the ampule until you are ready to empty its contents into the Nebulizer Cup.

7. Squeeze all the contents of the ampule into the Nebulizer Cup.

8. Replace the Nebulizer Top. Note: In order to insert the Nebulizer Top into the Nebulizer Cup, the semi-circle halfway down the stem of the Nebulizer Top should face the Nebulizer Outlet. Turn the Nebulizer Top clockwise until securely fastened to the Nebulizer Cup.

9. Attach the Mouthpiece to the Nebulizer Outlet. Then firmly push the Inspiratory Valve Cap in place on the Nebulizer Top. Note: The Inspiratory Valve Cap will fit snugly.

10. Connect the free end of the tubing to the Air Intake on the bottom of the nebulizer, making sure to keep the nebulizer upright. Press the tubing on the Air Intake firmly.

Vitazid (Tobramycin) Inhalation Solution Treatment

1. Turn on the compressor.

2. Check for a steady mist from the Mouthpiece. If there is no mist, check all tubing connections and confirm that the compressor is working properly.

3. Sit or stand in an upright position that will allow you to breathe normally.

4. Place Mouthpiece between your teeth and on top of your tongue and breathe normally only through your mouth. Nose clips may help you breathe through your mouth and not through your nose. Do not block airflow with your tongue.

5. Continue treatment until all of your Vitazid (Tobramycin) inhalation solution is gone, and there is no longer any mist being produced. You may hear a sputtering sound when the Nebulizer Cup is empty. The entire Vitazid (Tobramycin) inhalation solution treatment should take approximately 15 minutes to complete. Note: If you are interrupted, need to cough or rest during your Vitazid (Tobramycin) inhalation solution treatment, turn off the compressor to save your medication. Turn the compressor back on when you are ready to resume your therapy.

6. Follow the nebulizer cleaning and disinfecting instructions after completing therapy.

Cleaning Your Nebulizer

To reduce the risk of infection, illness or injury from contamination, you must thoroughly clean all parts of the nebulizer as instructed after each treatment. Never use a nebulizer with a clogged nozzle. If the nozzle is clogged, no aerosol mist is produced which will alter the effectiveness of the treatment. Replace the nebulizer if clogging occurs.

1. Remove tubing from nebulizer and disassemble nebulizer parts.

2. Wash all parts (except tubing) with warm water and liquid dish soap.

3. Rinse thoroughly with warm water and shake out water.

4. Air dry or hand dry nebulizer parts on a clean, lint-free cloth. Reassemble nebulizer when dry, and store.

5. You can also wash all parts of the nebulizer in a dishwasher (except tubing). Place the nebulizer parts in a dishwasher basket, then place on the top rack of the dishwasher. Remove and dry the parts when the cycle is complete.

Disinfecting Your Nebulizer

Your nebulizer is for your use only - Do not share your nebulizer with other people. You must regularly disinfect the nebulizer. Failure to do so could lead to serious or fatal illness.

Clean the nebulizer as described above. Every other treatment day, disinfect the nebulizer parts (except tubing) by boiling them in water for a full 10 minutes. Dry parts on a clean, lint-free cloth.

Care and Use of Your Pulmo-Aide^® Compressor

Follow the manufacturer’s instructions for care and use of your compressor.

Filter Change:

1. DeVilbiss^® Compressor filters should be changed every six months or sooner if filter turns completely gray in color.

Compressor Cleaning:

1. With power switch in the “Off” position, unplug power cord from wall outlet.

2. Wipe outside of the compressor cabinet with a clean, damp cloth every few days to keep dust free.

Caution: Do not submerge in water; doing so will result in compressor damage.

Storage Instructions

You should store Vitazid (Tobramycin) inhalation solution ampules in a refrigerator (2° to 8°C or 36° to 46°F). However, when you don’t have a refrigerator available (e.g., transporting your Vitazid (Tobramycin) inhalation solution), you may store the foil pouches (opened or unopened) at room temperature (up to 25°C/77°F) for up to 28 days.

Avoid exposing Vitazid (Tobramycin) inhalation solution ampules to intense light.

Unrefrigerated Vitazid (Tobramycin) inhalation solution, which is normally slightly yellow, may darken with age; however, the color change does not indicate any change in the quality of the product.

You should not use Vitazid (Tobramycin) inhalation solution if it is cloudy, if there are particles in the solution, or if it has been stored at room temperature for more than 28 days. You should not use Vitazid (Tobramycin) inhalation solution beyond the expiration date stamped on the ampule.

Additional Information

Nebulizer: 1-800-327-8632

Compressor: 1-800-338-1988

Vitazid (Tobramycin) Inhalation Solution: 1-877-835-5472

Distributed by:

Amneal Pharmaceuticals

Glasgow, KY 42141

Rev. 03-2015-00

Printed in USA

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