Tizanidine Hydrochloride

Class: Centrally Acting Skeletal Muscle Relaxants
VA Class: MS200
Chemical Name: 5-chloro-N-(4,5-dihydro-1H-imidazol-2-yl)-2,1,3-benzothiadiazol-4-amine monohydrochloride
Molecular Formula: C₉H₈ClN₅S•HCl
CAS Number: 64461-82-1
Brands: Zanaflex

Introduction

Skeletal muscle relaxant; centrally acting α₂-adrenergic agonist.^{1 2}

Uses for Tizanidine Hydrochloride

Spasticity

Management of spasticity associated with cerebral or spinal injury, alone or in conjunction with other standard therapies (e.g., baclofen).^{1 2 5}

Tizanidine Hydrochloride Dosage and Administration

General

• 
  

  Individualize dosage according to the patient's requirements and response using the lowest dosage that produces optimum response without adverse effects.^{1 2}

  
  

Administration

Oral Administration

Clinically important differences (e.g., increased adverse effects, delayed or more rapid onset of activity) may be apparent when switching administration of capsules or tablets between fed and/or fasting states, switching between capsules and tablets in fed state, or switching between administration of intact capsule and sprinkling capsule contents on applesauce.¹ Be thoroughly familiar with possible pharmacokinetic changes associated with these conditions.¹ (See Absorption under Pharmacokinetics.)

Dosage

Available as tizanidine hydrochloride; dosage expressed in terms of tizanidine.¹

Adults

Spasticity

Oral

Initially, 4 mg; single doses <8 mg not effective in clinical trials, but 4-mg dose used to minimize the incidence of common dose-related adverse effects (e.g., orthostatic hypotension).^{1 2}

Repeat 4-mg dose every 6–8 hours as needed for a maximum of 3 doses in 24 hours.^{1 2}

Increase dosage gradually in increments of 2–4 mg daily over a period of 2–4 weeks until optimum therapeutic effects are obtained with tolerable adverse effects.^{1 2} (See Limited Experience with Long-term Use of Higher Dosages under Cautions.)

Prescribing Limits

Adults

Spasticity

Oral

Maximum 36 mg in a 24-hour period.^{1 2}

Special Populations

Renal Impairment

Initiate with caution in patients with renal impairment (Cl_cr <25 mL/minute).¹ In these patients, use smaller individual doses during dosage titration; if higher doses are needed, increase the amount of each individual dose rather than increasing the frequency of dosing.¹

Cautions for Tizanidine Hydrochloride

Contraindications

• 
  

  Concomitant therapy with ciprofloxacin or fluvoxamine.^{1 6 7 8} (See Specific Drugs under Interactions.)

  
  


• 
  

  Known hypersensitivity to tizanidine or any ingredient in the formulation.¹

  
  

Warnings/Precautions

Warnings

Limited Experience with Long-term Use of Higher Dosages

Only limited clinical experience with long-term use of tizanidine at single doses of 8–16 mg or total daily dosages of 24–36 mg.¹ Therefore, only adverse effects with a relatively high incidence were likely to be identified in clinical studies.¹ (See Dosage and Administration.)

Hypotension

Hypotension,^{1 2} occasionally associated with bradycardia, orthostatic effects, dizziness, and, rarely, syncope, reported.¹ Hypotensive effect is dose related.¹

Minimize risk of marked hypotension by careful dosage titration; observe patients for manifestations of hypotension prior to dosage adjustment.¹ Patients moving from supine to upright position may be at increased risk for hypotension and orthostatic effects.¹

Use caution in patients receiving concomitant antihypertensive therapy and avoid use with other α₂-adrenergic agonists (e.g., clonidine).¹ Because clinically important hypotension reported with concurrent use of either fluvoxamine or ciprofloxacin, these drugs are contraindicated in patients receiving tizanidine.¹ (See Interactions.)

Risk of Liver Injury

Liver injury (most often hepatocellular) reported occasionally.¹ Elevations (i.e., >3 times ULN, or 2 times ULN if baseline levels were elevated) of ALT or AST reported in about 5% of tizanidine-treated patients in controlled studies.¹ In most cases, resolved rapidly upon drug discontinuance without residual problems.¹ In patients with elevated aminotransferase concentrations, nausea, vomiting, anorexia, and jaundice occasionally reported.¹ Death associated with liver failure reported rarely.¹

Monitor serum aminotransferase concentrations prior to and during the first 6 months of treatment (e.g., at baseline and at 1, 3, and 6 months) and periodically thereafter based on clinical status.¹

Avoid tizanidine or use only with extreme caution in patients with hepatic impairment. ¹ (See Hepatic Impairment under Cautions.)

Sedation

Dose-related sedation, sometimes severe.¹ May interfere with daily activity.¹

Hallucinations/Psychotic-like Symptoms

Hallucinations (formed, visual) or delusions reported in 3% of tizanidine-treated patients in 2 controlled studies; all cases reported within first 6 weeks of therapy.¹ Psychoses associated with hallucinations reported in at least 1 patient.¹

Potential Interaction with Fluvoxamine or Ciprofloxacin

In pharmacokinetic studies, substantial increases in serum tizanidine concentrations observed during concurrent administration of fluvoxamine or ciprofloxacin^{1 6 8 10} (potent CYP1A2 inhibitors); potentiated hypotensive and sedative effects also observed.^{1 6 8 10} Concurrent administration of fluvoxamine or ciprofloxacin contraindicated.^{1 6 7 8} (See Interactions.)

Potential Interaction with Other CYP1A2 Inhibitors

Potential drug interactions with other CYP1A2 inhibitors; ordinarily should avoid concurrent use.¹ If combined use is necessary, use drugs with caution.¹ (See Interactions.)

General Precautions

Cardiovascular Effects

Potential for prolongation of the QT interval and bradycardia based on animal studies.¹

Pulse rate reduction associated with decreases in BP reported.¹

Ocular Effects

Dose-related retinal degeneration and corneal opacities observed in animal studies.¹ No reports of corneal opacities or retinal degeneration in clinical studies.¹

Use in Women Taking Oral Contraceptives

Concurrent use of tizanidine and oral contraceptives may substantially reduce the clearance of tizanidine; ordinarily should avoid concomitant use.¹ If clinically necessary, reduce initial tizanidine dosage and titration rate.¹ (See Specific Drugs under Interactions.)

Discontinuance of Therapy

Possible rebound manifestations with abrupt withdrawal of therapy, including hypertension, tachycardia, hypertonia, tremor, and anxiety.¹

If therapy is to be discontinued, decrease dosage gradually, particularly in patients who have been receiving high dosages for prolonged periods, to minimize the risk of withdrawal and rebound symptoms.¹

Specific Populations

Pregnancy

Category C.¹

Lactation

Not known whether tizanidine is distributed into milk.¹ However, because it is lipid-soluble, tizanidine might be expected to pass into milk.¹ Use caution in nursing women.¹

Pediatric Use

Safety and efficacy not established.¹

Geriatric Use

Clearance is decreased 4-fold; use with caution.¹

Hepatic Impairment

Tizanidine undergoes extensive first-pass metabolism in the liver; hepatic impairment is likely to substantially affect the drug's pharmacokinetics.¹ Avoid use or use only with extreme caution in patients with hepatic impairment.¹ (See Risk of Liver Injury under Cautions.)

Renal Impairment

Clearance is reduced by >50% in patients with Cl_cr <25 mL/minute.¹ Use with caution in patients with renal impairment.¹ Monitor closely for onset or increased severity of adverse effects (e.g., dry mouth, somnolence, asthenia, dizziness) that may indicate potential overdosage.¹ (See Renal Impairment under Dosage and Administration.)

Common Adverse Effects

Dry mouth,^{1 2 3 4} somnolence,^{1 2 3 4} asthenia (weakness, fatigue, and/or tiredness),^{1 2 3} dizziness.^{1 2 3}

Interactions for Tizanidine Hydrochloride

Extensively metabolized, mainly by CYP1A2.¹

Drugs Affecting Hepatic Microsomal Enzymes

CYP1A2 inhibitors: Potential pharmacokinetic interaction (decreased plasma clearance of tizanidine).^{1 6 7 8 9} Ordinarily avoid concomitant use; if concomitant use is necessary, use with caution.¹ (See Specific Drugs under Interactions.)

Drugs Metabolized by Hepatic Microsomal Enzymes

Not likely to affect metabolism of CYP substrates.¹

Specific Drugs

Drug	Interaction	Comments
Acetaminophen	Peak plasma concentrations of acetaminophen may be delayed; no effect on tizanidine pharmacokinetics1
Acyclovir	Possible increased plasma tizanidine concentrations1	Ordinarily avoid concomitant use; if concomitant use is necessary, use with caution1
Alcohol	Increased AUCs and peak concentrations of tizanidine; potential additive CNS depression1 11
Antiarrhythmics (amiodarone, mexiletine, propafenone, verapamil)	Possible increased plasma tizanidine concentrations1	Ordinarily avoid concomitant use; if concomitant use is necessary, use with caution1
Antihypertensive agents	Potential additive hypotensive effects1 11	Use antihypertensive agents concomitantly with caution; avoid concurrent use with other α2-adrenergic agonists (e.g., clonidine)1
CNS depressants (e.g., baclofen, dantrolene, diazepam)	Potential additive CNS depression1
Fluoroquinolones	Ciprofloxacin: Markedly increased plasma concentrations and AUCs of tizanidine; 1 10 increased risk of adverse cardiovascular and CNS effects1 10 Other fluoroquinolones: Possible increased plasma tizanidine concentrations1	Ciprofloxacin: Concomitant use contraindicated1 Other fluoroquinolones: Ordinarily avoid concomitant use; if concomitant use is necessary, use with caution1
Fluvoxamine	Markedly increased plasma concentrations, elimination half-life, and AUCs of tizanidine1 6 8 Increased risk of adverse cardiovascular and CNS effects1 6 8	Concomitant use contraindicated1 6 7 8
Histamine H2-receptor antagonists (cimetidine, famotidine)	Possible increased plasma tizanidine concentrations1	Ordinarily avoid concomitant use; if concomitant use is necessary, use with caution1
Oral contraceptives	Potential decreased plasma clearance of tizanidine (by ≤50%)1	Avoid concurrent use, if possible1 If concomitant use is necessary, reduce initial tizanidine dosage and rate of subsequent dosage titration1
Ticlopidine	Possible increased plasma tizanidine concentrations1	Ordinarily avoid concomitant use; if concomitant use is necessary, use with caution1
Zileuton	Possible increased plasma tizanidine concentrations1	Ordinarily avoid concomitant use; if concomitant use is necessary, use with caution1

Tizanidine Hydrochloride Pharmacokinetics

Absorption

Bioavailability

Essentially completely absorbed following oral administration of capsules and tablets; peak plasma concentrations attained in about 1 hour.¹

Commercially available capsules and tablets are bioequivalent under fasting conditions, but not under nonfasting conditions.¹

Food

Tablets: Food increases the mean peak plasma concentration by about 30%, increases the median time to peak plasma concentration from about 60 minutes to 85 minutes, and increases the extent of absorption by about 30%.¹

Capsules: Food decreases the mean peak plasma concentration by 20% and increases the median time to peak plasma concentration from about 1 hour to 3 hours, and increases the extent of absorption by about 10%.¹ When given with food, the amount of tizanidine absorbed from the capsules about 80% of the amount absorbed from the tablet.¹

Administration of the capsule contents sprinkled on applesauce is not bioequivalent to intact capsule under fasting conditions and results in a 15–20% increase in peak plasma concentration and AUC and a 15-minute decrease in median lag time and time to achieve peak plasma concentration compared with administration of intact capsule while fasting.¹

Distribution

Plasma Protein Binding

About 30%.¹

Elimination

Metabolism

Undergoes extensive first-pass hepatic metabolism.¹ Metabolized mainly by CYP1A2. ¹

Elimination Route

Recovered in urine (60%) and feces (20%) following administration of single or multiple radiolabeled doses.¹

Half-life

About 2.5 hours.¹

Stability

Storage

Oral

Capsules and Tablets

25°C (may be exposed to 15–30°C).¹

Actions

• 
  

  Centrally acting α₂-adrenergic agonist with myotonolytic effects on skeletal muscle.^{1 2 3 4}

  
  


• 
  

  Exact mechanism in reducing muscle tone and spasm frequency is not clear.¹ Reportedly decreases the frequency and amplitude of muscle spasms (tonic reflexes) that arise in response to muscle stretching in patients with various spinal cord lesions.² Appears to reduce spasticity by increasing presynaptic inhibition of motor neurons, leading to reduced facilitation of spinal motor neurons and a resultant decrease in muscle tone.^{1 5}

  
  


• 
  

  Greatest effects on polysynaptic pathways, with no important effect on monosynaptic spinal reflexes.^{1 2} The drug does not have direct effects on skeletal muscle fibers or the neuromuscular junction.¹

  
  


• 
  

  Shown to have antinociceptive effects in animals,^{2 3} and some reports have suggested that it may improve pain associated with muscle spasm.²

  
  


• 
  

  Structurally and pharmacologically related to clonidine and other α₂-adrenergic agonists;¹ however, tizanidine has only one-tenth to one-fiftieth of clonidine's antihypertensive potency.¹

  
  

Advice to Patients

• 
  

  Importance of advising patients that clinical experience with long-term or high-dose tizanidine therapy is limited.¹

  
  


• 
  

  Risk of marked orthostatic hypotension; importance of exercising caution when moving from a supine to a fixed upright position.¹

  
  


• 
  

  Risk of sedation, which may be additive when taken in conjunction with alcohol or other CNS depressants; importance of exercising caution when performing activities requiring alertness, including driving a motor vehicle or operating machinery.¹

  
  


• 
  

  Importance of advising patients of potential changes in absorption profile and resulting changes in efficacy and adverse effect profile when taken with food.¹ (See Pharmacokinetics.)

  
  


• 
  

  Importance of not discontinuing abruptly because of potential for rebound hypertension and tachycardia.¹

  
  


• 
  

  Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and herbal supplements, as well as any concomitant illnesses, and of informing clinicians or pharmacists whenever any drug is added or discontinued.¹ Importance of not taking tizanidine concomitantly with either ciprofloxacin or fluvoxamine.¹

  
  


• 
  

  Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.¹

  
  


• 
  

  Importance of advising patients of other important precautionary information.¹ (See Cautions.)

  
  

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Tizanidine Hydrochloride

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Oral	Capsules	2 mg (of tizanidine)	Zanaflex	Acorda
		4 mg (of tizanidine)	Zanaflex	Acorda
		6 mg (of tizanidine)	Zanaflex	Acorda
	Tablets	2 mg (of tizanidine)*	Tizanidine Hydrochloride Tablets
			Zanaflex (scored)	Acorda
		4 mg (of tizanidine)*	Tizanidine Hydrochloride Tablets
			Zanaflex (scored)	Acorda

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 09/2011. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

TiZANidine HCl 2MG Tablets (SANDOZ): 90/$20.99 or 100/$22.97

Zanaflex 2MG Capsules (ACORDA THERAPEUTICS): 150/$376.00 or 450/$1,059.99

Zanaflex 4MG Capsules (ACORDA THERAPEUTICS): 150/$470.00 or 450/$1,359.96

Zanaflex 4MG Tablets (ACORDA THERAPEUTICS): 90/$215.00 or 270/$613.95

Zanaflex 6MG Capsules (ACORDA THERAPEUTICS): 150/$680.02 or 450/$2,000.94

Disclaimer

This report on medications is for your information only, and is not considered individual patient advice. Because of the changing nature of drug information, please consult your physician or pharmacist about specific clinical use.

The American Society of Health-System Pharmacists, Inc. and Drugs.com represent that the information provided hereunder was formulated with a reasonable standard of care, and in conformity with professional standards in the field. The American Society of Health-System Pharmacists, Inc. and Drugs.com make no representations or warranties, express or implied, including, but not limited to, any implied warranty of merchantability and/or fitness for a particular purpose, with respect to such information and specifically disclaims all such warranties. Users are advised that decisions regarding drug therapy are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and the information is provided for informational purposes only. The entire monograph for a drug should be reviewed for a thorough understanding of the drug's actions, uses and side effects. The American Society of Health-System Pharmacists, Inc. and Drugs.com do not endorse or recommend the use of any drug. The information is not a substitute for medical care.

AHFS Drug Information. © Copyright, 1959-2011, Selected Revisions August 25, 2011. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

1. Acorda Therapeutics, Inc. Zanaflex (tizanidine hydrochloride) capsules and tablets prescribing information. Hawthorne, NY; 2008 Apr.

2. Wagstaff AJ, Bryson HM. Tizanidine: a review of its pharmacology, clinical efficacy, and tolerability in the management of spasticity associated with cerebral and spinal disorders. Drugs. 1997; 53:435-52. [PubMed 9074844]

3. Nance PW, Bugaresti J, Shellenberger K et al. and the North American Tizanidine Study Group. Efficacy and safety of tizanidine in the treatment of spasticity in patients with spinal cord injury. Neurology. 1994; 44:S44-52. [IDIS 339523] [PubMed 7970010]

4. United Kingdom Tizanidine Trial Group. A double-blind, placebo-controlled trial of tizanidine in the treatment of spasticity caused by multiple sclerosis. Neurology. 1994; 44:S70-8.

5. Lataste X, Emre M, Davic C et al. Comparative profile of tizanidine in the management of spasticity. Neurology. 1994; 44:S53-9.

6. Granfors MT, Backman JT, Neuvonen M et al. Fluvoxamine drastically increases concentrations and effects of tizanidine: a potentially hazardous interaction. Clin Pharmacol Ther. 2004; 75:331-41. [IDIS 514169] [PubMed 15060511]

7. Momo K, Doki K, Hosono H et al. Drug interaction of tizanidine and fluvoxamine. Clin Pharmacol Ther. 2004; 76:509-10. [PubMed 15536467]

8. Barr Laboratories, Inc. Fluvoxamine maleate tablets prescribing information. Ponoma, NY; 2005 Jan.

9. Granfors MT, Backman JT, Laitila J et al. Tizanidine is mainly metabolized by cytochrome p450 1A2 in vitro. Br J Clin Pharmacol. 2004; 57:349-53. [PubMed 14998432]

10. Granfors MT, Backman JT, Neuvonen M et al. Ciprofloxacin greatly increases concentrations and hypotensive effect of tizanidine by inhibiting its cytochrome P450 1A2-mediated presystemic metabolism. Clin Pharmacol Ther. 2004; 76:598-606. [PubMed 15592331]

11. Publow SW, Branam DL. Hypotension and bradycardia associated with concomitant tizanidine and lisinopril therapy. Am J Health Syst Pharm. 2010; 67:1606-10. [PubMed 20852161]

c. Drug interaction of tizanidine and fluvoxamine. Clin Pharmacol Ther. 2004; 76:509-10. Letter.

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Tobramycin Ophthalmic Solution

Dosage Form: ophthalmic solution
Tobramycin Ophthalmic Solution USP, 0.3%

DESCRIPTION

Tobramycin Ophthalmic Solution USP, 0.3% is a sterile topical ophthalmic antibiotic formulation prepared specifically for topical therapy of external ophthalmic infections. Each mL of Tobramycin Ophthalmic Solution USP, 0.3% contains: Active: tobramycin 0.3% (3 mg). Preservative: benzalkonium chloride 0.01% (0.1 mg). Inactives: boric acid, sodium sulfate, sodium chloride, tyloxapol, sodium hydroxide and/or sulfuric acid (to adjust pH) and purified water.

Tobramycin Ophthalmic Solution USP, 0.3% has a pH range between 7.0 and 8.0.

Tobramycin is a water-soluble aminoglycoside antibiotic active against a wide variety of gram-negative and gram-positive ophthalmic pathogens.

The chemical structure of tobramycin is:

MW=467.2

Molecular Formula

C18H37N5O9

Chemical name: 0-{3-amino-3-deoxy-α-D-gluco-pyranosyl-(1→4)} -0- {2,6-diamino-2,3,6-trideoxy-α-D-ribohexopyranosyl-(1→6) }-2-deoxystreptamine.

CLINICAL PHARMACOLOGY

In Vitro Data: In vitro studies have demonstrated tobramycin is active against susceptible strains of the following microorganisms: Staphylococci, including S. aureus and S. epidermidis (coagulase-positive and coagulase-negative), including penicillin-resistant strains. Streptococci, including some of the Group A-beta-hemolytic species, some nonhemolytic species, and some Streptococcus pneumoniae. Pseudomonas aeruginosa, Escherichia coli, Klebsiella pneumoniae, Enterobacter aerogenes, Proteus mirabilis, Morganella morganii, most Proteus vulgaris strains, Haemophilus influenzae and H. aegyptius, Moraxella lacunata, Acinetobacter calcoaceticus and some Neisseria species. Bacterial susceptibility studies demonstrate that in some cases, microorganisms resistant to gentamicin retain susceptibility to tobramycin.

INDICATIONS AND USAGE

Tobramycin Ophthalmic Solution USP, 0.3% is a topical antibiotic indicated in the treatment of external infections of the eye and its adnexa caused by susceptible bacteria. Appropriate monitoring of bacterial response to topical antibiotic therapy should accompany the use of Tobramycin Ophthalmic Solution USP, 0.3%. Clinical studies have shown tobramycin to be safe and effective for use in children.

CONTRAINDICATIONS

Tobramycin Ophthalmic Solution USP, 0.3% is contraindicated in patients with known hypersensitivity to any of its components.

WARNINGS

FOR TOPICAL OPHTHALMIC USE ONLY. NOT FOR INJECTION INTO THE EYE. Sensitivity to topically applied aminoglycosides may occur in some patients. If a sensitivity reaction to Tobramycin Ophthalmic Solution USP, 0.3% occurs, discontinue use.

PRECAUTIONS

General

As with other antibiotic preparations, prolonged use may result in overgrowth of nonsusceptible organisms, including fungi. If superinfection occurs, appropriate therapy should be initiated. Cross-sensitivity to other aminoglycoside antibiotics may occur; if hypersensitivity develops with this product, discontinue use and institute appropriate therapy. Patients should be advised not to wear contact lenses if they have signs and symptoms of bacterial conjunctivitis.

Information For Patients

Do not touch dropper tip to any surface, as this may contaminate the solution.

Pregnancy Category B

Reproduction studies in three types of animals at doses up to thirty-three times the normal human systemic dose have revealed no evidence of impaired fertility or harm to the fetus due to tobramycin. There are, however, no adequate and well-controlled studies in pregnant women. Because animal studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Nursing Mothers

Because of the potential for adverse reactions in nursing infants from Tobramycin Ophthalmic Solution USP, 0.3%, a decision should be made whether to discontinue nursing the infant or discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

Safety and effectiveness in pediatric patients below the age of 2 months has not been established.

Geriatric Use

No overall differences in safety or effectiveness have been observed between elderly and other adult patients.

ADVERSE REACTIONS

The most frequent adverse reactions to Tobramycin Ophthalmic Solution USP, 0.3% are hypersensitivity and localized ocular toxicity, including lid itching and swelling, and conjunctival erythema. These reactions occur in less than three of 100 patients treated with Tobramycin Ophthalmic Solution USP, 0.3%. Similar reactions may occur with the topical use of other aminoglycoside antibiotics. Other adverse reactions have not been reported from Tobramycin Ophthalmic Solution USP, 0.3% therapy; however, if topical ocular tobramycin is administered concomitantly with systemic aminoglycoside antibiotics, care should be taken to monitor the total serum concentration.

OVERDOSAGE

Clinically apparent signs and symptoms of an overdose of Tobramycin Ophthalmic Solution USP, 0.3% (punctate keratitis, erythema, increased lacrimation, edema and lid itching) may be similar to adverse reaction effects seen in some patients.

DOSAGE AND ADMINISTRATION

In mild to moderate disease, instill one or two drops into the affected eye(s) every four hours. In severe infections, instill two drops into the eye(s) hourly until improvement, following which treatment should be reduced prior to discontinuation.

HOW SUPPLIED

5 mL sterile solution is packaged in a 5 mL white plastic DROP-TAINER* bottle with a plastic dispensing plug and white plastic closure (NDC 61314-643-05) containing tobramycin 0.3% (3 mg/mL).

Storage: Store at 2° - 25°C (36° - 77°F).

Rx Only

*DROP-TAINER is a registered trademark of Alcon Manufacturing, Ltd.

9000857-0605

Dist. by:

FALCON Pharmaceuticals, Ltd

Fort Worth, TX 76134

Mfd. by:

ALCON LABORATORIES, INC.

Fort Worth, TX 76134 USA

Revised: June 2005

Printed in USA

PRINCIPAL DISPLAY PANEL

NDC 61314-643-05       Rx Only

FALCON PHARMACEUTICALS®

Tobramycin

Ophthalmic

Solution USP

0.3%

5 mL STERILE

AFFILIATE OF

ALCON LABORATORIES, INC.

QUALITY RX

TOBRAMYCIN  tobramycin  solution

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 61314-643 Route of Administration OPHTHALMIC DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength TOBRAMYCIN (TOBRAMYCIN) TOBRAMYCIN 3 mg  in 1 mL

Inactive Ingredients Ingredient Name Strength BENZALKONIUM CHLORIDE   BORIC ACID   SODIUM SULFATE   SODIUM CHLORIDE   TYLOXAPOL   SODIUM HYDROXIDE   SULFURIC ACID   WATER

Product Characteristics Color      Score      Shape Size Flavor Imprint Code Contains

Packaging # NDC Package Description Multilevel Packaging 1 61314-643-05 5 mL In 1 BOTTLE, PLASTIC None

Marketing Information
Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
ANDA	ANDA062535	01/09/1995

Labeler - Falcon Pharmaceuticals, Ltd. (874345820)

Registrant - Alcon Laboratories, Inc. (008018525)

Establishment
Name	Address	ID/FEI	Operations
Alcon Laboratories, Inc.		008018525	MANUFACTURE

Revised: 08/2011Falcon Pharmaceuticals, Ltd.

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Tobramycin and Dexamethasone

Tobramycin and Dexamethasone Ophthalmic Suspension

Sterile

DESCRIPTION

Tobramycin and Dexamethasone Ophthalmic Suspension is a sterile, multiple dose antibiotic and steroid combination for topical ophthalmic use.

The chemical structures for Tobramycin and Dexamethasone are presented below:

Each mL of Tobramycin and Dexamethasone Ophthalmic Suspension contains: Actives: tobramycin 0.3% (3 mg) and dexamethasone 0.1% (1 mg). Preservative: benzalkonium chloride 0.01%. Inactives: tyloxapol, edetate disodium, sodium chloride, hydroxyethyl cellulose, sodium sulfate, sulfuric acid and/or sodium hydroxide (to adjust pH) and purified water.

CLINICAL PHARMACOLOGY

Corticoids suppress the inflammatory response to a variety of agents and they probably delay or slow healing. Since corticoids may inhibit the body's defense mechanism against infection, a concomitant antimicrobial drug may be used when this inhibition is considered to be clinically significant. Dexamethasone is a potent corticoid.

The antibiotic component in the combination (tobramycin) is included to provide action against susceptible organisms. In vitro studies have demonstrated that tobramycin is active against susceptible strains of the following microorganisms:

Staphylococci, including S. aureus and S. epidermidis (coagulase-positive and coagulase-negative), including penicillin-resistant strains.

Streptococci, including some of the Group A-beta-hemolytic species, some nonhemolytic species, and some Streptococcus pneumoniae.

Pseudomonas aeruginosa, Escherichia coli, Klebsiella pneumoniae, Enterobacter aerogenes, Proteus mirabilis, Morganella morganii, most Proteus vulgaris strains, Haemophilus influenzae and H. aegyptius, Moraxella lacunata, Acinetobacter calcoaceticus and some Neisseria species.

Bacterial susceptibility studies demonstrate that in some cases microorganisms resistant to gentamicin remain susceptible to tobramycin.

No data are available on the extent of systemic absorption from Tobramycin and Dexamethasone Ophthalmic Suspension; however, it is known that some systemic absorption can occur with ocularly applied drugs. If the maximum dose of Tobramycin and Dexamethasone Ophthalmic Suspension is given for the first 48 hours (two drops in each eye every 2 hours) and complete systemic absorption occurs, which is highly unlikely, the daily dose of dexamethasone would be 2.4 mg. The usual physiologic replacement dose is 0.75 mg daily. If Tobramycin and Dexamethasone Ophthalmic Suspension is given after the first 48 hours as two drops in each eye every 4 hours, the administered dose of dexamethasone would be 1.2 mg daily.

INDICATIONS AND USAGE

Tobramycin and Dexamethasone Ophthalmic Suspension is indicated for steroid-responsive inflammatory ocular conditions for which a corticosteroid is indicated and where superficial bacterial ocular infection or a risk of bacterial ocular infection exists.

Ocular steroids are indicated in inflammatory conditions of the palpebral and bulbar conjunctiva, cornea and anterior segment of the globe where the inherent risk of steroid use in certain infective conjunctivitides is accepted to obtain a diminution in edema and inflammation. They are also indicated in chronic anterior uveitis and corneal injury from chemical, radiation or thermal burns, or penetration of foreign bodies.

The use of a combination drug with an anti-infective component is indicated where the risk of superficial ocular infection is high or where there is an expectation that potentially dangerous numbers of bacteria will be present in the eye.

The particular anti-infective drug in this product is active against the following common bacterial eye pathogens:

Staphylococci, including S. aureus and S. epidermidis (coagulase-positive and coagulase-negative), including penicillin-resistant strains.

Streptococci, including some of the Group A-beta-hemolytic species, some nonhemolytic species, and some Streptococcus pneumoniae.

Pseudomonas aeruginosa, Escherichia coli, Klebsiella pneumoniae, Enterobacter aerogenes, Proteus mirabilis, Morganella morganii, most Proteus vulgaris strains, Haemophilus influenzae and H. aegyptius, Moraxella lacunata, Acinetobacter calcoaceticus and some Neisseria species.

CONTRAINDICATIONS

Epithelial herpes simplex keratitis (dendritic keratitis), vaccinia, varicella, and many other viral diseases of the cornea and conjunctiva. Mycobacterial infection of the eye. Fungal diseases of ocular structures. Hypersensitivity to a component of the medication.

WARNINGS

NOT FOR INJECTION INTO THE EYE. Sensitivity to topically applied aminoglycosides may occur in some patients. If a sensitivity reaction does occur, discontinue use.

Prolonged use of steroids may result in glaucoma, with damage to the optic nerve, defects in visual acuity and fields of vision, and posterior subcapsular cataract formation. Intraocular pressure should be routinely monitored even though it may be difficult in pediatric patients and uncooperative patients. Prolonged use may suppress the host response and thus increase the hazard of secondary ocular infections. In those diseases causing thinning of the cornea or sclera, perforations have been known to occur with the use of topical steroids. In acute purulent conditions of the eye, steroids may mask infection or enhance existing infection.

PRECAUTIONS

General

The possibility of fungal infections of the cornea should be considered after long-term steroid dosing. As with other antibiotic preparations, prolonged use may result in overgrowth of nonsusceptible organisms, including fungi. If superinfection occurs, appropriate therapy should be initiated. When multiple prescriptions are required, or whenever clinical judgement dictates, the patient should be examined with the aid of magnification, such as slit lamp biomicroscopy and, where appropriate, fluorescein staining.

Cross-sensitivity to other aminoglycoside antibiotics may occur; if hypersensitivity develops with this product, discontinue use and institute appropriate therapy.

Information for Patients

Do not touch dropper tip to any surface, as this may contaminate the contents. Contact lenses should not be worn during the use of this product.

Carcinogenesis, Mutagenesis, Impairment of Fertility

No studies have been conducted to evaluate the carcinogenic or mutagenic potential. No impairment of fertility was noted in studies of subcutaneous tobramycin in rats at doses of 50 and 100 mg/kg/day.

Pregnancy

Category C

Corticosteroids have been found to be teratogenic in animal studies. Ocular administration of 0.1% dexamethasone resulted in 15.6% and 32.3% incidence of fetal anomalies in two groups of pregnant rabbits. Fetal growth retardation and increased mortality rates have been observed in rats with chronic dexamethasone therapy. Reproduction studies have been performed in rats and rabbits with tobramycin at doses up to 100 mg/kg/day parenterally and have revealed no evidence of impaired fertility or harm to the fetus. There are no adequate and well controlled studies in pregnant women. Tobramycin and Dexamethasone Ophthalmic Suspension should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nursing Mothers

Systemically administered corticosteroids appear in human milk and could suppress growth, interfere with endogenous corticosteroid production, or cause other untoward effects. It is not known whether topical administration of corticosteroids could result in sufficient systemic absorption to produce detectable quantities in human milk. Because many drugs are excreted in human milk, caution should be exercised when Tobramycin and Dexamethasone Ophthalmic Suspension is administered to a nursing woman.

Pediatric Use

Safety and effectiveness in pediatric patients below the age of 2 years have not been established.

Geriatric Use

No overall differences in safety or effectiveness have been observed between elderly and younger patients.

ADVERSE REACTIONS

Adverse reactions have occurred with steroid/anti-infective combination drugs which can be attributed to the steroid component, the anti-infective component, or the combination. Exact incidence figures are not available. The most frequent adverse reactions to topical ocular tobramycin [TOBREX®* (tobramycin ophthalmic solution)] are hypersensitivity and localized ocular toxicity, including lid itching and swelling, and conjunctival erythema. These reactions occur in less than 4% of patients. Similar reactions may occur with the topical use of other aminoglycoside antibiotics. Other adverse reactions have not been reported; however, if topical ocular tobramycin is administered concomitantly with systemic aminoglycoside antibiotics, care should be taken to monitor the total serum concentration. The reactions due to the steroid component are: elevation of intraocular pressure (IOP) with possible development of glaucoma, and infrequent optic nerve damage; posterior subcapsular cataract formation; and delayed wound healing.

Secondary Infection

The development of secondary infection has occurred after use of combinations containing steroids and antimicrobials. Fungal infections of the cornea are particularly prone to develop coincidentally with long term applications of steroids. The possibility of fungal invasion must be considered in any persistent corneal ulceration where steroid treatment has been used. Secondary bacterial ocular infection following suppression of host responses also occurs.

OVERDOSAGE

Clinically apparent signs and symptoms of an overdosage of Tobramycin and Dexamethasone Ophthalmic Suspension (punctate keratitis, erythema, increased lacrimation, edema and lid itching) may be similar to adverse reaction effects seen in some patients.

DOSAGE AND ADMINISTRATION

One or two drops instilled into the conjunctival sac(s) every four to six hours. During the initial 24 to 48 hours, the dosage may be increased to one or two drops every two (2) hours. Frequency should be decreased gradually as warranted by improvement in clinical signs. Care should be taken not to discontinue therapy prematurely.

Not more than 20 mL should be prescribed initially and the prescription should not be refilled without further evaluation as outlined in PRECAUTIONS above.

HOW SUPPLIED

Sterile ophthalmic suspension in 2.5 mL (NDC 61314-647-25), 5 mL (NDC 61314-647-05) and 10 mL (NDC 61314-647-10) DROP-TAINER®* dispensers.

STORAGE

Store at 8° to 27°C (46° to 80°F).

Store suspension upright and shake well before using.

Rx Only

*TOBREX and DROP-TAINER are registered trademarks of Alcon Research, Ltd.

340032-0608

Distributed by:

FALCON Pharmaceutical, Ltd.

Fort Worth, Texas 76134 USA

Manufactured by:

ALCON LABORATORIES, INC.

Fort Worth, Texas 76134 USA

Printed in USA

Revised: June 2008

PRINCIPAL DISPLAY PANEL

NDC 61314-647-05            Rx Only

FALCON

PHARMACEUTICALS®

Tobramycin and

Dexamethasone

Ophthalmic

Suspension

FOR TOPICAL OPHTHALMIC

USE ONLY

5 mL           STERILE

AFFILIATE OF                     QUALITY RX

ALCON

LABORATORIES, INC.

Tobramycin and Dexamethasone  Tobramycin and Dexamethasone  suspension

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 61314-647 Route of Administration OPHTHALMIC DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength TOBRAMYCIN (TOBRAMYCIN) TOBRAMYCIN 3 mg  in 1 mL DEXAMETHASONE (DEXAMETHASONE) DEXAMETHASONE 1 mg  in 1 mL

Inactive Ingredients Ingredient Name Strength TYLOXAPOL   EDETATE DISODIUM   SODIUM CHLORIDE   SODIUM SULFATE   SULFURIC ACID   SODIUM HYDROXIDE   WATER   BENZALKONIUM CHLORIDE   HYDROXYETHYL CELLULOSE (2000 CPS AT 1%)

Product Characteristics Color      Score      Shape Size Flavor Imprint Code Contains

Packaging # NDC Package Description Multilevel Packaging 1 61314-647-25 2.5 mL In 1 BOTTLE None 2 61314-647-05 5 mL In 1 BOTTLE None 3 61314-647-10 10 mL In 1 BOTTLE None

Marketing Information
Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
NDA authorized generic	NDA050592	01/02/2009

Labeler - Falcon Pharmaceuticals (874345820)

Registrant - Alcon Laboratories, Inc. (008018525)

Establishment
Name	Address	ID/FEI	Operations
Alcon Laboratories, Inc.		008018525	manufacture

Revised: 07/2011Falcon Pharmaceuticals

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• Tobramycin and Dexamethasone Dosage
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• Conjunctivitis, Bacterial
• Keratitis
• Uveitis

Tirofiban

Pronunciation: tye-roe-FYE-ban
Generic Name: Tirofiban
Brand Name: Aggrastat

Tirofiban is used for:

Treating unstable angina or certain types of heart attacks in combination with heparin. It may also be used for other conditions as determined by your doctor.

Tirofiban is a platelet aggregation inhibitor. It works by blocking platelets from sticking together to form blood clots.

Do NOT use Tirofiban if:

• you are allergic to any ingredient in Tirofiban


• you have a history of stroke, major surgery, physical trauma, or bleeding conditions within the last 30 days


• you have an aneurysm, bleeding or clotting condition, malformation of the arteries or veins, or bleeding or tumors of the brain


• you have a tear of the aorta, severe high blood pressure, or inflammation around the heart


• you are taking another medicine of the same class (a platelet aggregation inhibitor)


• you have had clotting problems when using Tirofiban in the past

Contact your doctor or health care provider right away if any of these apply to you.

Before using Tirofiban:

Some medical conditions may interact with Tirofiban. Tell your doctor or pharmacist if you have any medical conditions, especially if any of the following apply to you:

• if you are pregnant, planning to become pregnant, or are breast-feeding


• if you are taking any prescription or nonprescription medicine, herbal preparation, or dietary supplement


• if you have allergies to medicines, foods, or other substances


• if you have decreased blood platelets, high blood volume, kidney problems (eg, dialysis), or bleeding or blood vessel problems in the eye


• if you have recently had a spinal (epidural) procedure

Some MEDICINES MAY INTERACT with Tirofiban. However, no specific interactions with Tirofiban are known at this time.

This may not be a complete list of all interactions that may occur. Ask your health care provider if Tirofiban may interact with other medicines that you take. Check with your health care provider before you start, stop, or change the dose of any medicine.

How to use Tirofiban:

Use Tirofiban as directed by your doctor. Check the label on the medicine for exact dosing instructions.

• Tirofiban is usually administered as an injection at your doctor's office, hospital, or clinic. If you are using Tirofiban at home, carefully follow the injection procedures taught to you by your health care provider.


• If Tirofiban contains particles or is discolored, or if the vial is cracked or damaged in any way, do not use it.


• Tirofiban is only to be injected into the vein or artery.


• Keep this product, as well as syringes and needles, out of the reach of children and away from pets. Do not reuse needles, syringes, or other materials. Dispose of properly after use. Ask your doctor or pharmacist to explain local regulations for proper disposal.


• If you miss a dose of Tirofiban, contact your doctor immediately.

Ask your health care provider any questions you may have about how to use Tirofiban.

Important safety information:

• Tirofiban may cause dizziness. Do not drive, operate machinery, or do anything else that could be dangerous until you know how you react to Tirofiban. Using Tirofiban alone, with certain other medicines, or with alcohol may lessen your ability to drive or perform other potentially dangerous tasks.


• Tirofiban may reduce the number of clot-forming cells (platelets) in your blood. To prevent bleeding, avoid situations in which bruising or injury may occur. Report any unusual bleeding, bruising, blood in stools, or dark, tarry stools to your doctor.


• Before you have any medical or dental treatments, emergency care, or surgery, tell the doctor or dentist that you are using Tirofiban.


• LAB TESTS, including complete blood cell counts, may be performed to monitor your progress or to check for side effects. Be sure to keep all doctor and lab appointments.


• Use Tirofiban with caution in the ELDERLY because they may be more sensitive to its effects.


• Tirofiban is not recommended for use in CHILDREN younger than 18 years of age. Safety and effectiveness in this age group have not been confirmed.


• PREGNANCY and BREAST-FEEDING: If you become pregnant, discuss with your doctor the benefits and risks of using Tirofiban during pregnancy. It is unknown if Tirofiban is excreted in breast milk. Do not breast-feed while taking Tirofiban.

Possible side effects of Tirofiban:

All medicines may cause side effects, but many people have no, or minor, side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome:

Dizziness; headache; leg pain; nausea; pelvic pain; sweating.

Seek medical attention right away if any of these SEVERE side effects occur:

Severe allergic reactions (rash; hives; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); bruising, pain, redness, or swelling at the injection site; changes in heart rhythm; chills; difficulty urinating; fainting; fever; numbness; tingling or weakness in the arms or legs; unusual bruising or bleeding (eg, bleeding gums, nosebleeds, bleeding in the eye, blood in the urine, black or tarry stools, coughing up blood, vomiting blood or material that looks like coffee ground).

This is not a complete list of all side effects that may occur. If you have questions about side effects, contact your health care provider. Call your doctor for medical advice about side effects. To report side effects to the appropriate agency, please read the Guide to Reporting Problems to FDA.

See also: Tirofiban side effects (in more detail)

If OVERDOSE is suspected:

Contact 1-800-222-1222 (the American Association of Poison Control Centers), your local poison control center, or emergency room immediately. Symptoms may include major and minor bleeding events.

Proper storage of Tirofiban:

Tirofiban is usually handled and stored by a health care provider. If you are using Tirofiban at home, store Tirofiban as directed by your pharmacist or health care provider. Keep Tirofiban out of the reach of children and away from pets.

General information:

• If you have any questions about Tirofiban, please talk with your doctor, pharmacist, or other health care provider.


• Tirofiban is to be used only by the patient for whom it is prescribed. Do not share it with other people.


• If your symptoms do not improve or if they become worse, check with your doctor.


• Check with your pharmacist about how to dispose of unused medicine.

This information is a summary only. It does not contain all information about Tirofiban. If you have questions about the medicine you are taking or would like more information, check with your doctor, pharmacist, or other health care provider.

Issue Date: February 1, 2012

Database Edition 12.1.1.002

Copyright © 2012 Wolters Kluwer Health, Inc.

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• Tirofiban Monograph (AHFS DI)


• tirofiban Concise Consumer Information (Cerner Multum)


• Aggrastat Prescribing Information (FDA)

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• Acute Coronary Syndrome

Tobi

tobramycin

Dosage Form: nebulizer solution
Nebulizer Solution – For Inhalation Use Only

Rx only

Prescribing Information

DESCRIPTION

Tobi® is a 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 tobramycin is C18H37N5O9 and the molecular weight is 467.52. Tobramycin 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 tobramycin is:

Each single-use 5 mL ampule contains 300 mg tobramycin 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.

CLINICAL PHARMACOLOGY

Tobi® is specifically formulated for administration by inhalation. When inhaled, tobramycin is concentrated in the airways.

Pharmacokinetics

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

Sputum Concentrations: Ten minutes after inhalation of the first 300-mg dose of Tobi®, the average concentration of tobramycin was 1237 µg/g (ranging from 35 to 7414 µg/g) in sputum. Tobramycin does not accumulate in sputum; after 20 weeks of therapy with the Tobi® regimen, the average concentration of tobramycin at ten minutes after inhalation was 1154 µg/g (ranging from 39 to 8085 µg/g) in sputum. High variability of tobramycin concentration in sputum was observed. Two hours after inhalation, sputum concentrations declined to approximately 14% of tobramycin levels at ten minutes after inhalation.

Serum Concentrations: The average serum concentration of tobramycin one hour after inhalation of a single 300-mg dose of Tobi® by cystic fibrosis patients was 0.95 µg/mL. After 20 weeks of therapy on the Tobi® regimen, the average serum tobramycin concentration one hour after dosing was 1.05 µg/mL.

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

Microbiology

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)

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 tobramycin. Treatment for 6 months with Tobi® 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 Tobi® 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 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 tobramycin do not apply to aerosolized administration of Tobi®. The relationship between in-vitro susceptibility test results and clinical outcome with Tobi® therapy is not clear.

INDICATIONS AND USAGE

Tobi® 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 FEV1 <25% or >75% predicted, or patients colonized with Burkholderia cepacia (see CLINICAL STUDIES).

CONTRAINDICATIONS

Tobi® is contraindicated in patients with a known hypersensitivity to any aminoglycoside.

WARNINGS

Caution should be exercised when prescribing Tobi® 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 Tobi® during pregnancy, or become pregnant while taking Tobi® 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 Tobi® therapy during clinical studies. However, transient tinnitus occurred in eight Tobi®-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 Tobi® 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 Tobi® clinical studies but has been associated with aminoglycosides as a class. If nephrotoxicity occurs in a patient receiving Tobi®, tobramycin therapy should be discontinued until serum concentrations fall below 2 μg/mL.

Muscular Disorders

Tobi® should be used cautiously in patients with muscular 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 can occur with inhalation of Tobi®. In clinical studies of Tobi®, changes in FEV1 measured after the inhaled dose were similar in the Tobi® 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 Tobi® is contained inside the package.

Safety Information

Tobi® 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 Tobi® 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 Tobi®, you should talk with your doctor about the possibility of Tobi® causing any harm.

Nursing Mothers: If you are nursing a baby, you should talk with your doctor before using Tobi®.

Tobi® Packaging

Tobi® comes in a single dose, ready-to-use ampule containing 300 mg tobramycin. Each foil pouch contains 4 ampules, for 2 days of Tobi® therapy.

Dosage

The 300 mg dose of Tobi® is the same for patients regardless of age or weight. Tobi® 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 Tobi® 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, Tobi®.

Treatment Schedule

You should take Tobi® in repeated cycles of 28 days on drug followed by 28 days off drug. You should take Tobi® twice a day during the 28-day period on drug.

How To Administer Tobi®

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

Tobi® is specifically formulated for inhalation using a PARI LC PLUS™ Reusable Nebulizer and a DeVilbiss® Pulmo-Aide® air compressor. Tobi® 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 Tobi®.

You will need the following supplies:

• Tobi® 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 Tobi® therapy.

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

Preparing Your Tobi® for Inhalation

1. Wash your hands thoroughly with soap and water.

2a. Tobi® 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 Tobi® 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 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.

Tobi® 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 Tobi® 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 Tobi® treatment should take approximately 15 minutes to complete. Note: if you are interrupted, need to cough or rest during your Tobi® 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 Tobi® ampules in a refrigerator (2-8°C or 36-46°F). However, when you don’t have a refrigerator available (e.g., transporting your Tobi®), 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 Tobi® ampules to intense light.

Unrefrigerated Tobi®, 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 Tobi® 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 Tobi® beyond the expiration date stamped on the ampule.

Additional Information

Nebulizer: 1-800-327-8632

Compressor: 1-800-338-1988

Tobi®: 1-888-NOW-NOVA (1-888-669-6682)

Laboratory Tests

Audiograms

Clinical studies of Tobi® 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 Tobi®, serum tobramycin concentrations are approximately 1 µg/mL 1 hour after dose administration and do not require routine monitoring. Serum concentrations of tobramycin in patients with renal dysfunction or patients treated with concomitant parenteral tobramycin should be monitored at the discretion of the treating physician.

Renal Function

The clinical studies of Tobi® did not reveal any imbalance in the percentage of patients in the Tobi® 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 Tobi®, patients taking Tobi® 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 Tobi® with other drugs with neurotoxic or ototoxic potential should be avoided. Some diuretics can enhance aminoglycoside toxicity by altering antibiotic concentrations in serum and tissue. Tobi® should not be administered concomitantly with ethacrynic acid, furosemide, urea, or mannitol.

Carcinogenesis, Mutagenesis, Impairment of Fertility

A two-year rat inhalation toxicology study to assess carcinogenic potential of Tobi® has been completed. Rats were exposed to Tobi® 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 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, Tobi® 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. 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 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 Tobi®. However, subcutaneous administration of tobramycin at doses of 100 or 20 mg/kg/day during organogenesis was not teratogenic in rats or rabbits, respectively. Doses of 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 tobramycin. If Tobi® is used during pregnancy, or if the patient becomes pregnant while taking Tobi®, the patient should be apprised of the potential hazard to the fetus.

Nursing Mothers

It is not known if Tobi® 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 Tobi®.

Pediatric Use

The safety and efficacy of Tobi® have not been studied in pediatric patients under 6 years of age.

ADVERSE REACTIONS

Tobi® was generally well tolerated during two clinical studies in 258 cystic fibrosis patients ranging in age from 6 to 48 years. Patients received Tobi® 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 Tobi®-treated patients. Thirty-three patients (13%) treated with Tobi® complained of voice alteration compared to 17 (7%) placebo patients. Voice alteration was more common in the on-drug periods.

Eight patients from the Tobi® group (3%) reported tinnitus compared to no placebo patients. All episodes were transient, resolved without discontinuation of the Tobi® 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 Tobi® and placebo groups.

Nine (3%) patients in the Tobi® 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 Tobi® 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 Tobi® patients during the two Phase III studies.

Table 1: Percent of Patients With Treatment Emergent Adverse Experiences Occurring in >5% of Tobi® Patients

Adverse Event	Tobi® (n=258) %	Placebo (n=262) %
Cough Increased	46.1	47.3
Pharyngitis	38.0	39.3
Sputum Increased	37.6	39.7
Asthenia	35.7	39.3
Rhinitis	34.5	33.6
Dyspnea	33.7	38.5
Fever1	32.9	43.5
Lung Disorder	31.4	31.3
Headache	26.7	32.1
Chest Pain	26.0	29.8
Sputum Discoloration	21.3	19.8
Hemoptysis	19.4	23.7
Anorexia	18.6	27.9
Lung Function Decreased2	16.3	15.3
Asthma	15.9	20.2
Vomiting	14.0	22.1
Abdominal Pain	12.8	23.7
Voice Alteration	12.8	6.5
Nausea	11.2	16.0
Weight Loss	10.1	15.3
Pain	8.1	12.6
Sinusitis	8.1	9.2
Ear Pain	7.4	8.8
Back Pain	7.0	8.0
Epistaxis	7.0	6.5
Taste Perversion	6.6	6.9
Diarrhea	6.2	10.3
Malaise	6.2	5.3
Lower Respiratory Tract Infection	5.8	8.0
Dizziness	5.8	7.6
Hyperventilation	5.4	9.9
Rash	5.4	6.1
1 Includes subjective complaints of fever.
2 Includes reported decreases in pulmonary function tests or decreased lung volume on chest radiograph associated with intercurrent illness or study drug administration.

OVERDOSAGE

Signs and symptoms of acute toxicity from overdosage of IV tobramycin might include dizziness, tinnitus, vertigo, loss of high-tone hearing acuity, respiratory failure, and neuromuscular blockade. Administration by inhalation results in low systemic bioavailability of tobramycin. Tobramycin is not significantly absorbed following oral administration. 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.

Tobi® 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.

Tobi® is administered BID in alternating periods of 28 days. After 28 days of therapy, patients should stop Tobi® therapy for the next 28 days, and then resume therapy for the next 28 day on/28 day off cycle.

Tobi® 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. Tobi® is not for subcutaneous, intravenous or intrathecal administration.

Usage

Tobi® 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. Tobi® should not be diluted or mixed with dornase alfa (PULMOZYME®, Genentech) in the nebulizer.

During clinical studies, patients on multiple therapies were instructed to take them first, followed by Tobi®.

HOW SUPPLIED

Tobi® 300 mg is available as follows:

NDC 0078-0494-71

5 mL single-dose ampule (carton of 56)

Storage

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

Tobi® 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 Tobi® therapy on an outpatient basis (see Table 2) using a hand-held PARI LC PLUS™ Reusable Nebulizer with a DeVilbiss® Pulmo-Aide® compressor.

Table 2: Dosing Regimens in Clinical Studies

	Cycle 1		Cycle 2		Cycle 3
	28 days	28 days	28 days	28 days	28 days	28 days
Tobi® regimen n=258	Tobi® 300 mg BID	No drug	Tobi® 300 mg BID	No drug	Tobi® 300 mg BID	No drug
Placebo regimen n=262	placebo BID	No drug	placebo BID	No drug	placebo BID	No drug

All patients received either Tobi® 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, Tobi®-treated patients experienced significant improvement in pulmonary function. Improvement was demonstrated in the Tobi® 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, Tobi®-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, Tobi® 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. (see Figure 2).

Figure 2: Absolute Change From Baseline in Log10 CFUs

Patients treated with Tobi® were hospitalized for an average of 5.1 days compared to 8.1 days for placebo patients. Patients treated with Tobi® 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 Tobi® 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 Tobi® therapy is not clear. However, 4 Tobi® patients who began the clinical trial with P. aeruginosa isolates having MIC values ≥128 µg/mL did not experience an improvement in FEV1 or a decrease in sputum bacterial density.

Treatment with Tobi® 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 tobramycin MICs. The percentage of patients with P. aeruginosa isolates with tobramycin MICs ≥16 µg/mL was 13% at the beginning, and 23% at the end of 6 months of the Tobi® regimen.

REFERENCES

1. Neu HC. 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 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.

U.S. Patent 5,508,269; other patents pending.

Distributed by:

Novartis Pharmaceuticals Corporation

East Hanover, New Jersey 07936

REV: NOVEMBER 2009       T2009-119

© Novartis

PRINCIPAL DISPLAY PANEL

Package Label – 300 mg / 5 mL Ampules

Rx Only             NDC 0078-0494-71

Tobi®

Tobramycin Inhalation Solution, USP

300 mg / 5 mL Ampules

56 Single-Use Ampules (28-Day Supply)

Store In Refrigerator

Tobi  tobramycin  solution

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 0078-0494 Route of Administration ORAL DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength TOBRAMYCIN (TOBRAMYCIN) TOBRAMYCIN 300 mg  in 5 mL

Inactive Ingredients Ingredient Name Strength SODIUM CHLORIDE 11.25 mg  in 5 mL SODIUM HYDROXIDE   WATER   SULFURIC ACID

Product Characteristics Color      Score      Shape Size Flavor Imprint Code Contains

Packaging # NDC Package Description Multilevel Packaging 1 0078-0494-71 56 AMPULE In 1 CARTON contains a AMPULE (0078-0494-61) 1 0078-0494-61 5 mL In 1 AMPULE This package is contained within the CARTON (0078-0494-71)

Marketing Information
Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
NDA	NDA050753	12/22/1997

Labeler - Novartis Pharmaceuticals Corporation (002147023)

Revised: 01/2009Novartis Pharmaceuticals Corporation

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