Trovan

trovafloxacin mesylate

Dosage Form: Tablets and Injection

Trovan® HAS BEEN ASSOCIATED WITH SERIOUS LIVER INJURY LEADING TO LIVER TRANSPLANTATION AND/OR DEATH. Trovan-ASSOCIATED LIVER INJURY HAS BEEN REPORTED WITH BOTH SHORT-TERM AND LONG-TERM DRUG EXPOSURE. Trovan USE EXCEEDING 2 WEEKS IN DURATION IS ASSOCIATED WITH A SIGNIFICANTLY INCREASED RISK OF SERIOUS LIVER INJURY. LIVER INJURY HAS ALSO BEEN REPORTED FOLLOWING Trovan RE-EXPOSURE. Trovan SHOULD BE RESERVED FOR USE IN PATIENTS WITH SERIOUS, LIFE- OR LIMB-THREATENING INFECTIONS WHO RECEIVE THEIR INITIAL THERAPY IN AN IN-PATIENT HEALTH CARE FACILITY (I.E., HOSPITAL OR LONG-TERM NURSING CARE FACILITY). Trovan SHOULD NOT BE USED WHEN SAFER, ALTERNATIVE ANTIMICROBIAL THERAPY WILL BE EFFECTIVE. (SEE WARNINGS.)

Trovan is available as Trovan Tablets (trovafloxacin mesylate) for oral administration and as Trovan I.V. (alatrofloxacin mesylate injection), a prodrug of trovafloxacin, for intravenous administration.

Trovan Description

Trovan Tablets

Trovan Tablets contain trovafloxacin mesylate, a synthetic broad-spectrum antibacterial agent for oral administration. Chemically, trovafloxacin mesylate, a fluoronaphthyridone related to the fluoroquinolone antibacterials, is (1α, 5α, 6α) - 7 - (6 - amino - 3 - azabicyclo[3.1.0]hex - 3 - yl) - 1 - (2,4 - difluorophenyl) - 6 - fluoro - 1,4 - dihydro - 4 - oxo - 1,8 - naphthyridine - 3 - carboxylic acid, monomethanesulfonate. Trovafloxacin mesylate differs from other quinolone derivatives by having a 1,8-naphthyridine nucleus.

The chemical structure is:

Its empirical formula is C20H15F3N4O3•CH3SO3H and its molecular weight is 512.46.

Trovafloxacin mesylate is a white to off-white powder.

Trovafloxacin mesylate is available in 100 mg and 200 mg (trovafloxacin equivalent) blue, film-coated tablets. Trovan Tablets contain microcrystalline cellulose, cross-linked sodium carboxymethylcellulose and magnesium stearate. The tablet coating is a mixture of hydroxypropylcellulose, hydroxypropylmethylcellulose, titanium dioxide, polyethylene glycol and FD&C blue #2 aluminum lake.

Trovan I.V.

Trovan I.V. contains alatrofloxacin mesylate, the L-alanyl-L-alanyl prodrug of trovafloxacin mesylate. Chemically, alatrofloxacin mesylate is (1α, 5α, 6α) - L - alanyl - N - [3 - [6 - carboxy - 8 - (2,4 - difluorophenyl) - 3 - fluoro - 5,8 - dihydro - 5 - oxo - 1,8 - naphthyridine - 2 - yl] - 3 - azabicyclo[3.1.0]hex - 6 - yl] - L - alaninamide, monomethanesulfonate. It is intended for administration by intravenous infusion.

Following intravenous administration, the alanine substituents in alatrofloxacin are rapidly hydrolyzed in vivo to yield trovafloxacin. (See CLINICAL PHARMACOLOGY.)

The chemical structure is:

Its empirical formula is C26H25F3N6O5•CH3SO3H and its molecular weight is 654.62.

Alatrofloxacin mesylate is a white to light yellow powder.

Trovan I.V. is available in 40 mL and 60 mL single use vials as a sterile, preservative-free aqueous concentrate of 5 mg trovafloxacin/mL as alatrofloxacin mesylate intended for dilution prior to intravenous administration of doses of 200 mg or 300 mg of trovafloxacin, respectively. (See HOW SUPPLIED.)

The formulation contains Water for Injection, and may contain sodium hydroxide or hydrochloric acid for pH adjustment. The pH range for the 5 mg/mL aqueous concentrate is 3.5 to 4.3.

Trovan - Clinical Pharmacology

After intravenous administration, alatrofloxacin is rapidly converted to trovafloxacin. Plasma concentrations of alatrofloxacin are below quantifiable levels within 5 to 10 minutes of completion of a 1 hour infusion.

Absorption

Trovafloxacin is well-absorbed from the gastrointestinal tract after oral administration. The absolute bioavailability is approximately 88%. For comparable dosages, no dosage adjustment is necessary when switching from parenteral to oral administration (Figure 1). (See DOSAGE AND ADMINISTRATION.)

Figure 1. Mean trovafloxacin serum concentrations determined following 1 hour intravenous infusions of alatrofloxacin at daily doses of 200 mg (trovafloxacin equivalents) to healthy male volunteers and following daily oral administration of 200 mg trovafloxacin for 7 days to six male and six female healthy young volunteers.

Pharmacokinetics

The mean pharmacokinetic parameters (±SD) of trovafloxacin after single and multiple 100 mg and 200 mg oral doses and 1 hour intravenous infusions of alatrofloxacin in doses of 200 and 300 mg (trovafloxacin equivalents) appear in the chart below.

TROVAFLOXACIN PHARMACOKINETIC PARAMETERS
	Cmax (µg/mL)	Tmax (hrs)	AUC* (µg•h/mL)	T½ (hrs)	Vdss (L/Kg)	CL (mL/hr/Kg)	CLr (mL/hr/Kg)
Cmax=Maximum serum concentration; Tmax=Time to Cmax; AUC=Area under concentration vs. time curve; T1/2=serum half-life; Vdss=Volume of distribution; Cl=Total clearance; Clr=Renal clearance
* Single dose: AUC(0–∞), multiple dose: AUC(0–24) † trovafloxacin equivalents
Trovafloxacin 100 mg
Single dose	1.0±0.3	0.9±0.4	11.2±2.2	9.1	—	—	—
Multiple dose	1.1±0.2	1.0±0.5	11.8±1.8	10.5	—	—	—
Trovafloxacin 200 mg
Single dose	2.1±0.5	1.8±0.9	26.7±7.5	9.6	—	—	—
Multiple dose	3.1±1.0	1.2±0.5	34.4±5.7	12.2	—	—	—
Alatrofloxacin 200 mg†
Single dose	2.7±0.4	1.0±0.0	28.1±5.1	9.4	1.2±0.2	93.0±17.4	6.5±3.5
Multiple dose	3.1±0.6	1.0±0.0	32.2±7.3	11.7	1.3±0.1	81.7±17.8	8.6±2.4
Alatrofloxacin 300 mg†
Single dose	3.6±0.6	1.3±0.4	46.1±5.2	11.2	1.2±0.1	84.6±6.0	6.9±0.5
Multiple dose	4.4±0.6	1.2±0.2	46.3±3.9	12.7	1.4±0.1	84.5±11.1	8.4±1.8

Serum concentrations of trovafloxacin are dose proportional after oral administration of trovafloxacin in the dose range of 30 to 1000 mg or after intravenous administration of alatrofloxacin in the dose range of 30 to 400 mg (trovafloxacin equivalents). Steady state concentrations are achieved by the third daily oral or intravenous dose of trovafloxacin with an accumulation factor of approximately 1.3 times the single dose concentrations.

Oral absorption of trovafloxacin is not altered by concomitant food intake; therefore, it can be administered without regard to food.

The systemic exposure to trovafloxacin (AUC0–∞) administered as crushed tablets via nasogastric tube into the stomach was identical to that of orally administered intact tablets. Administration of concurrent enteral feeding solutions had no effect on the absorption of trovafloxacin given via nasogastric tube into the stomach. When trovafloxacin was administered as crushed tablets into the duodenum via nasogastric tube, the AUC0–∞ and peak serum concentration (Cmax) were reduced by 30% relative to the orally administered intact tablets. Time to peak serum level (Tmax) was also decreased from 1.7 hrs to 1.1 hrs.

Distribution

The mean plasma protein bound fraction is approximately 76%, and is concentration-independent. Trovafloxacin is widely distributed throughout the body. Rapid distribution of trovafloxacin into tissues results in significantly higher trovafloxacin concentrations in most target tissues than in plasma or serum.

Fluid or Tissue	Tissue-Fluid/Serum Ratio* (Range)
* Mean values in adults over 2–29 hours following drug administration, except individual lung tissues, which were single time points of 6 hours following drug administration † Ratio of composite AUC(0–24) in CSF/composite AUC(0–24) in serum in 22 pediatric patients aged 1 to 12 years after 1 hour I.V. infusion of single dose alatrofloxacin (equivalent trovafloxacin dose range: 4.5–9.9 mg/kg)
Respiratory
bronchial macrophages (multiple dose)	24.1 (9.6–41.8)
lung mucosa	1.1 (0.7–1.5)
lung epithelial lining fluid (multiple dose)	5.8 (1.1–17.5)
whole lung	2.1 (0.42–5.03)
Skin, Musculoskeletal
skin	1.0 (0.20–1.88)
subcutaneous tissue	0.4 (0.15–0.68)
skin blister fluid	0.7–0.9 (blister/plasma)
skeletal muscle	1.5 (0.50–2.90)
bone	1.0 (0.55–1.67)
Gastrointestinal
colonic tissue	0.7 (0.0–1.47)
peritoneal fluid	0.4 (0.0–1.25)
bile	15.4 (11.9–21.0)
Central Nervous System
cerebrospinal fluid (CSF), adults	0.25 (0.03–0.33)
cerebrospinal fluid (CSF), children	0.28†
Reproductive
prostatic tissue	1.0 (0.5–1.6)
cervix (multiple dose)	0.6 (0.5–0.7)
ovary	1.6 (0.3–2.2)
fallopian tube	0.7 (0.2–1.1)
myometrium (multiple dose)	0.6 (0.4–0.8)
uterus	0.6 (0.3–0.8)
vaginal fluid (multiple dose)	4.7 (0.8–20.8)

Presence in Breast Milk

Trovafloxacin was found in measurable concentrations in the breast milk of three lactating subjects. The average measurable breast milk concentration was 0.8 µg/mL (range: 0.3–2.1 µg/mL) after single I.V. alatrofloxacin (300 mg trovafloxacin equivalents) and repeated oral trovafloxacin (200 mg) doses.

Metabolism

Trovafloxacin is metabolized by conjugation (the role of cytochrome P450 oxidative metabolism of trovafloxacin is minimal). Thirteen percent of the administered dose appears in the urine in the form of the ester glucuronide and 9% appears in the feces as the N-acetyl metabolite (2.5% of the dose is found in the serum as the active N-acetyl metabolite). Other minor metabolites (diacid, sulfamate, hydroxycarboxylic acid) have been identified in both urine and feces in small amounts (<4% of the administered dose).

Excretion

Approximately 50% of an oral dose is excreted unchanged (43% in the feces and 6% in the urine).

After multiple 200 mg doses, to healthy subjects, mean (±SD) cumulative urinary trovafloxacin concentrations were 12.1±3.4 µg/mL. With these levels of trovafloxacin in urine, crystals of trovafloxacin have not been observed in the urine of human subjects.

Special Populations

Geriatric

In adult subjects, the pharmacokinetics of trovafloxacin are not affected by age (range 19–78 years).

Pediatric

Limited information is available in the pediatric population (see Distribution). The pharmacokinetics of trovafloxacin have not been fully characterized in pediatric populations less than 18 years of age.

Gender

There are no significant differences in trovafloxacin pharmacokinetics between males and females when differences in body weight are taken into account. After single 200 mg doses, trovafloxacin Cmax and AUC(0–∞) were 60% and 32% higher, respectively, in healthy females compared to healthy males. Following repeated daily administration of 200 mg for 7 days, the Cmax for trovafloxacin was 38% higher and AUC(0–24) was 16% higher in healthy females compared to healthy males. The clinical importance of the increases in serum levels of trovafloxacin in females has not been established. (See PRECAUTIONS: Information for Patients.)

Chronic Hepatic Disease

Following repeated administration of 100 mg for 7 days to patients with mild cirrhosis (Child-Pugh Class A), the AUC(0–24) for trovafloxacin was increased ~45% compared to matched controls. Repeated administration of 200 mg for 7 days to patients with moderate cirrhosis (Child-Pugh Class B) resulted in an increase of ~50% in AUC(0–24) compared to matched controls. There appeared to be no significant effect on trovafloxacin Cmax for either group. The oral clearance of trovafloxacin was reduced ~30% in both cirrhosis groups, which corresponded to prolongation of half life by 2–2.5 hours (25–30% increase) compared to controls. There are no data in patients with severe cirrhosis (Child-Pugh Class C). Dosage adjustment is recommended in patients with mild to moderate cirrhosis. (See DOSAGE AND ADMINISTRATION.)

Renal Insufficiency

The pharmacokinetics of trovafloxacin are not affected by renal impairment. Trovafloxacin serum concentrations are not significantly altered in subjects with severe renal insufficiency (creatinine clearance <20 mL/min), including patients on hemodialysis.

Photosensitivity Potential

In a study of the skin response to ultraviolet and visible radiation conducted in 48 healthy volunteers (12 per group), the minimum erythematous dose (MED) was measured for ciprofloxacin, lomefloxacin, trovafloxacin and placebo before and after drug administration for 5 days. In this study, trovafloxacin (200 mg q.d.) was shown to have a lower potential for producing delayed photosensitivity skin reactions than ciprofloxacin (500 mg b.i.d.) or lomefloxacin (400 mg q.d.), although greater than placebo. (See PRECAUTIONS: Information for Patients.)

Drug-drug Interactions

The systemic availability of trovafloxacin following oral tablet administration is significantly reduced by the concomitant administration of antacids containing aluminum and magnesium salts, sucralfate, vitamins or minerals containing iron, and concomitant intravenous morphine administration.

Administration of trovafloxacin (300 mg p.o.) 30 minutes after administration of an antacid containing magnesium hydroxide and aluminum hydroxide resulted in reductions in systemic exposure to trovafloxacin (AUC) of 66% and peak serum concentration (Cmax) of 60%. (See PRECAUTIONS: Drug Interactions, DOSAGE AND ADMINISTRATION.)

Concomitant sucralfate administration (1g) with trovafloxacin 200 mg p.o. resulted in a 70% decrease in trovafloxacin systemic exposure (AUC) and a 77% reduction in peak serum concentration (Cmax). (See PRECAUTIONS: Drug Interactions, DOSAGE AND ADMINISTRATION.)

Concomitant administration of ferrous sulfate (120 mg elemental iron) with trovafloxacin 200 mg p.o. resulted in a 40% reduction in trovafloxacin systemic exposure (AUC) and a 48% decrease in trovafloxacin Cmax. (See PRECAUTIONS: Drug Interactions, DOSAGE AND ADMINISTRATION.)

Concomitant administration of intravenous morphine (0.15 mg/kg) with oral trovafloxacin (200 mg) resulted in a 36% reduction in trovafloxacin AUC and a 46% decrease in trovafloxacin Cmax. Trovafloxacin administration had no effect on the pharmacokinetics of morphine or its pharmacologically active metabolite, morphine-6-β-glucuronide. (See PRECAUTIONS: Drug Interactions, DOSAGE AND ADMINISTRATION.)

Minor pharmacokinetic interactions that are most likely without clinical significance include calcium carbonate, omeprazole and caffeine.

Concomitant administration of calcium carbonate (1000 mg) with trovafloxacin 200 mg p.o. resulted in a 20% reduction in trovafloxacin AUC and a 17% reduction in peak serum trovafloxacin concentration (Cmax).

A 40 mg dose of omeprazole given 2 hours prior to trovafloxacin (300 mg p.o.) resulted in a 17% reduction in trovafloxacin AUC and a 17% reduction in trovafloxacin peak serum concentration (Cmax).

Administration of trovafloxacin (200 mg) concomitantly with caffeine (200 mg) resulted in a 17% increase in caffeine AUC and a 15% increase in caffeine Cmax. These changes in caffeine exposure are not considered clinically significant.

No significant pharmacokinetic interactions were seen when Trovan was co-administered with cimetidine, theophylline, digoxin, warfarin and cyclosporine.

Cimetidine co-administration (400 mg twice daily for 5 days) with trovafloxacin (200 mg p.o. daily for 3 days) resulted in changes in trovafloxacin AUC and Cmax of less than 5%.

Trovafloxacin (200 mg p.o. daily for 7 days) co-administration with theophylline (300 mg twice daily for 14 days) resulted in no change in theophylline AUC and Cmax.

Trovafloxacin (200 mg p.o. daily for 10 days) co-administration with digoxin (0.25 mg daily for 20 days) did not significantly alter systemic exposure (AUC) to digoxin or the renal clearance of digoxin.

Trovafloxacin (200 mg p.o. daily for 7 days) did not interfere with either the pharmacokinetics or the pharmacodynamics of warfarin (daily for 21 days).

Concomitant oral administration of trovafloxacin did not affect the systemic exposure (AUC) or peak plasma concentrations (Cmax) of the S or R isomers of warfarin, nor did it influence prothrombin times. (See PRECAUTIONS: Drug Interactions.)

Trovafloxacin (200 mg p.o. daily for 7 days) co-administration with cyclosporine (daily doses from 150–450 mg for 7 days) resulted in decreases of 10% or less in systemic exposure to cyclosporine (AUC) and in the peak blood concentrations of cyclosporine.

Microbiology

Trovafloxacin is a fluoronaphthyridone related to the fluoroquinolones with in vitro activity against a wide range of gram-negative and gram-positive aerobic, and anaerobic microorganisms. The bactericidal action of trovafloxacin results from inhibition of DNA gyrase and topoisomerase IV. DNA gyrase is an essential enzyme that is involved in the replication, transcription and repair of bacterial DNA. Topoisomerase IV is an enzyme known to play a key role in the partitioning of the chromosomal DNA during bacterial cell division. Mechanism of action of fluoroquinolones including trovafloxacin is different from that of penicillins, cephalosporins, aminoglycosides, macrolides, and tetracyclines. Therefore, fluoroquinolones may be active against pathogens that are resistant to these antibiotics. There is no cross-resistance between trovafloxacin and the mentioned classes of antibiotics. The overall results obtained from in vitro synergy studies, testing combinations of trovafloxacin with beta-lactams and aminoglycosides, indicate that synergy is strain specific and not commonly encountered. This agrees with results obtained previously with other fluoroquinolones. Resistance to trovafloxacin in vitro develops slowly via multiple-step mutation in a manner similar to other fluoroquinolones. Resistance to trovafloxacin in vitro occurs at a general frequency of between 1×10-7 to 10-10. Although cross-resistance has been observed between trovafloxacin and some other fluoroquinolones, some microorganisms resistant to other fluoroquinolones may be susceptible to trovafloxacin.

Trovafloxacin has been shown to be active against most strains of the following microorganisms, both in vitro and in clinical infections as described in the INDICATIONS AND USAGE section:

Aerobic gram-positive microorganisms

Enterococcus faecalis (many strains are only moderately susceptible)

Staphylococcus aureus (methicillin-susceptible strains)

Streptococcus agalactiae

Streptococcus pneumoniae (penicillin-susceptible strains)

Viridans group streptococci

Aerobic gram-negative microorganisms

Escherichia coli

Gardnerella vaginalis

Haemophilus influenzae

Klebsiella pneumoniae

Moraxella catarrhalis

Proteus mirabilis

Pseudomonas aeruginosa

Anaerobic microorganisms

Bacteroides fragilis

Peptostreptococcus species

Prevotella species

Other microorganisms

Chlamydia pneumoniae

Legionella pneumophila

Mycoplasma pneumoniae

The following in vitro data are available, but their clinical significance is unknown.

Trovafloxacin exhibits in vitro minimum inhibitory concentrations (MICs) of ≤2 µg/mL against most (90%) strains of the following microorganisms; however, the safety and effectiveness of trovafloxacin in treating clinical infections due to these microorganisms have not been established in adequate and well-controlled clinical trials.

Aerobic gram-positive microorganisms

Streptococcus pneumoniae (penicillin resistant strains)

Aerobic gram-negative microorganisms

Citrobacter freundii

Enterobacter aerogenes

Morganella morganii

Proteus vulgaris

Anaerobic microorganisms

Bacteroides distasonis

Bacteroides ovatus

Clostridium perfringens

Other microorganisms

Mycoplasma hominis

Ureaplasma urealyticum

NOTE: Mycobacterium tuberculosis and Mycobacterium avium-intracellulare complex organisms are commonly resistant to trovafloxacin.

NOTE: The activity of trovafloxacin against Treponema pallidum has not been evaluated; however, other quinolones are not active against Treponema pallidum. (See WARNINGS.)

Susceptibility Tests

Dilution Techniques: Quantitative methods are used to determine antimicrobial minimum inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs should be determined using a standardized procedure. Standardized procedures are based on dilution methods1 (broth or agar) or equivalent with standardized inoculum concentrations and standardized concentrations of trovafloxacin mesylate powder. The MIC values should be interpreted according to the following criteria:

For testing non-fastidious aerobic organisms:

MIC (µg/mL)	Interpretation
≤2.0	Susceptible (S)
4.0	Intermediate (I)
≥8.0	Resistant (R)

For testing Haemophilus spp.1

MIC (µg/mL)	Interpretation*
* The current absence of data on resistant strains precludes defining any results other than "Susceptible". Strains yielding MIC results suggestive of a "nonsusceptible" category should be submitted to a reference laboratory for further testing.
≤1.0	Susceptible (S)

For testing Streptococcus spp. including Streptococcus pneumoniae2:

MIC (µg/mL)	Interpretation
≤1.0	Susceptible (S)
2.0	Intermediate (I)
≥4.0	Resistant (R)

A report of "Susceptible" indicates that the pathogen is likely to be inhibited if the antimicrobial compound in the blood reaches the concentration usually achievable. A report of "Intermediate" indicates that the result should be considered equivocal, and, if the microorganism is not fully susceptible to alternative, clinically feasible drugs, the test should be repeated. This category implies possible clinical applicability in body sites where the drug is physiologically concentrated or in situations where high dosage of drug can be used. This category also provides a buffer zone which prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of "Resistant" indicates that the pathogen is not likely to be inhibited if the antimicrobial compound in the blood reaches the concentration usually achievable; other therapy should be selected.

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

Microorganism	MIC Range (µg/mL)
* This quality control range is applicable to only H. influenzae ATCC 49247 tested by a microdilution procedure using HTM1. † This quality control range is applicable to only S. pneumoniae ATCC 49619 tested by a microdilution procedure using cation-adjusted Mueller-Hinton broth with 2–5% lysed horse blood.
Escherichia coli ATCC 25922	0.004–0.016
Staphylococcus aureus ATCC 29213	0.008–0.03
Pseudomonas aeruginosa ATCC 27853	0.25–2.0
Enterococcus faecalis ATCC 29212	0.06–0.25
Haemophilus influenzae* ATCC 49247	0.004–0.016
Streptococcus pneumoniae† ATCC 49619	0.06–0.25

Diffusion Techniques: Quantitative methods that require measurement of zone diameters also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. One such standardized procedure2 requires the use of standardized inoculum concentrations. This procedure uses paper disks impregnated with trovafloxacin mesylate equivalent to 10 µg trovafloxacin to test the susceptibility of microorganisms to trovafloxacin.

Reports from the laboratory providing results of the standard single-disk susceptibility test with a trovafloxacin mesylate disk (equivalent to 10 µg trovafloxacin) should be interpreted according to the following criteria:

The following zone diameter interpretive criteria should be used for testing non-fastidious aerobic organisms:

Zone Diameter (mm)	Interpretation
≥17	Susceptible (S)
14–16	Intermediate (I)
≤13	Resistant (R)

For testing Haemophilus spp.3:

Zone Diameter (mm)	Interpretation*
* The current absence of data on resistant strains precludes defining any results other than "Susceptible". Strains yielding MIC results suggestive of a "nonsusceptible" category should be submitted to a reference laboratory for further testing.
≥22	Susceptible (S)

For testing Streptococcus spp. including Streptococcus pneumoniae4:

Zone Diameter (mm)	Interpretation
≥19	Susceptible (S)
18–16	Intermediate (I)
≤15	Resistant (R)

Interpretation should be as stated above for results using dilution techniques. Interpretation involves correlation of the diameter obtained in the disk test with the MIC for trovafloxacin.

As with standardized dilution techniques, diffusion methods require the use of laboratory control microorganisms that are used to control the technical aspects of the laboratory procedures. For the diffusion technique, the trovafloxacin mesylate equivalent to 10-µg trovafloxacin disk should provide the following zone diameters in these laboratory quality control strains:

Microorganism	Zone Diameter Range (mm)
* This quality control limit applies to tests conducted with Haemophilus influenzae ATCC 49247 using HTM2. † This quality control range is applicable only to tests performed by disk diffusion using Mueller-Hinton agar supplemented with 5% defibrinated sheep blood.
Escherichia coli ATCC 25922	29–36
Staphylococcus aureus ATCC 25923	29–35
Pseudomonas aeruginosa ATCC 27853	21–27
Haemophilus influenzae* ATCC 49247	32–39
Streptococcus pneumoniae† ATCC 49619	25–32

Anaerobic Techniques: For anaerobic bacteria, the susceptibility to trovafloxacin as MICs can be determined by standardized test methods3. The MIC values obtained should be interpreted according to the following criteria:

MIC (µg/mL)	Interpretation
≤2.0	Susceptible (S)
4.0	Intermediate (I)
≥8.0	Resistant (R)

Interpretation is identical to that stated above for results using dilution techniques.

As with other susceptibility techniques, the use of laboratory control microorganisms is required to control the technical aspects of the laboratory standardized procedures. Standardized trovafloxacin mesylate powder should provide the following MIC values:

Microorganism	MIC* (µg/mL)
* kThese quality control ranges were derived from tests performed in the broth formulation of Wilkins-Chalgren agar.
Bacteroides fragilis ATCC 25285	0.125–0.5
Bacteroides thetaiotamicron ATCC 29741	0.25–1.0
Eubacterium lentum ATCC 43055	0.25–1.0

1

This interpretive standard is applicable only to broth microdilution susceptibility tests with Haemophilus spp. using Haemophilus Test Medium (HTM)1.

2

These interpretive standards are applicable only to broth microdilution susceptibility tests using cation adjusted Mueller-Hinton broth with 2–5% lysed horse blood.

3

This zone diameter standard is applicable only to tests with Haemophilus spp. using HTM2.

4

These zone diameter standards only apply to tests performed using Mueller-Hinton agar supplemented with 5% sheep blood incubated in 5% CO2.

Indications and Usage for Trovan

Trovan is indicated for the treatment of patients initiating therapy in in-patient health care facilities (i.e., hospitals and long term nursing care facilities) with serious, life- or limb-threatening infections caused by susceptible strains of the designated microorganisms in the conditions listed below. (See DOSAGE AND ADMINISTRATION.)

Nosocomial pneumonia caused by Escherichia coli, Pseudomonas aeruginosa, Haemophilus influenzae, or Staphylococcus aureus. As with other antimicrobials, where Pseudomonas aeruginosa is a documented or presumptive pathogen, combination therapy with either an aminoglycoside or aztreonam may be clinically indicated.

Community acquired pneumonia caused by Streptococcus pneumoniae, Haemophilus influenzae, Klebsiella pneumoniae, Staphylococcus aureus, Mycoplasma pneumoniae, Moraxella catarrhalis, Legionella pneumophila, or Chlamydia pneumoniae.

Complicated intra-abdominal infections, including post-surgical infections caused by Escherichia coli, Bacteroides fragilis, viridans group streptococci, Pseudomonas aeruginosa, Klebsiella pneumoniae, Peptostreptococcus species, or Prevotella species.

Gynecologic and pelvic infections including endomyometritis, parametritis, septic abortion and post-partum infections caused by Escherichia coli, Bacteroides fragilis, viridans group streptococci, Enterococcus faecalis, Streptococcus agalactiae, Peptostreptococcus species, Prevotella species, or Gardnerella vaginalis.

Complicated skin and skin structure infections, including diabetic foot infections, caused by Staphylococcus aureus, Streptococcus agalactiae, Pseudomonas aeruginosa, Enterococcus faecalis, Escherichia coli, or Proteus mirabilis. NOTE: Trovan has not been studied in the treatment of osteomyelitis. (See WARNINGS.)

Contraindications

Trovan is contraindicated in persons with a history of hypersensitivity to trovafloxacin, alatrofloxacin, quinolone antimicrobial agents or any other components of these products.

Warnings

(See boxed WARNING.) Trovan-ASSOCIATED LIVER ENZYME ABNORMALITIES, SYMPTOMATIC HEPATITIS, JAUNDICE, AND LIVER FAILURE (INCLUDING RARE REPORTS OF ACUTE HEPATIC NECROSIS WITH EOSINOPHILIC INFILTRATION, LIVER TRANSPLANTATION AND/OR DEATH) HAVE BEEN REPORTED WITH BOTH SHORT-TERM AND LONG-TERM DRUG EXPOSURE IN MEN AND WOMEN. Trovan USE EXCEEDING 2 WEEKS IN DURATION IS ASSOCIATED WITH A SIGNIFICANTLY INCREASED RISK OF SERIOUS LIVER INJURY. LIVER INJURY HAS ALSO BEEN REPORTED FOLLOWING Trovan RE-EXPOSURE. CLINICIANS SHOULD MONITOR LIVER FUNCTION TESTS (e.g., AST, ALT, BILIRUBIN) IN Trovan RECIPIENTS WHO DEVELOP SIGNS OR SYMPTOMS CONSISTENT WITH HEPATITIS. CLINICIANS SHOULD CONSIDER DISCONTINUING Trovan IN THOSE PATIENTS WHO DEVELOP LIVER FUNCTION TEST ABNORMALITIES.

THE SAFETY AND EFFECTIVENESS OF TROVAFLOXACIN IN PEDIATRIC PATIENTS AND ADOLESCENTS LESS THAN 18 YEARS OF AGE, PREGNANT WOMEN, AND NURSING WOMEN HAVE NOT BEEN ESTABLISHED. (See PRECAUTIONS: Pediatric Use, Pregnancy, and Nursing Mothers subsections.)

As with other members of the quinolone class, trovafloxacin has caused arthropathy and/or chondrodysplasia in immature rats and dogs. The significance of these findings to humans is unknown. (See ANIMAL PHARMACOLOGY.)

Convulsions, increased intracranial pressure and psychosis have been reported in patients receiving quinolones. Quinolones may also cause central nervous system stimulation which may lead to tremors, restlessness, lightheadedness, confusion, hallucinations, paranoia, depression, nightmares and insomnia. These reactions may occur following the first dose. If these reactions occur in patients receiving trovafloxacin or alatrofloxacin, the drug should be discontinued and appropriate measures instituted. (See PRECAUTIONS: General,Information for Patients, Drug Interactions and ADVERSE REACTIONS.)

As with other quinolones, Trovan should be used with caution in patients with known or suspected CNS disorders, such as severe cerebral atherosclerosis, epilepsy, and other factors that predispose to seizures. (See ADVERSE REACTIONS.)

Serious and occasionally fatal hypersensitivity and/or anaphylactic reactions have been reported in patients receiving therapy with Trovan. These reactions may occur following the first dose. Some reactions have been accompanied by cardiovascular collapse, hypotension/shock, seizure, loss of consciousness, tingling, angioedema (including tongue, laryngeal, throat or facial edema/swelling), airway obstruction (including bronchospasm, shortness of breath and acute respiratory distress), dyspnea, urticaria, itching and other serious skin reactions, including generalized erythema.

Life-threatening hypotension has been reported with alatrofloxacin administration. This has occurred in patients receiving alatrofloxacin at either the recommended rate of infusion or if given more rapidly. Hypotension may be potentiated with the concomitant administration of anesthetic agents. Alatrofloxacin should only be administered by slow intravenous infusion over a period of 60 minutes. Blood pressure should be monitored closely during infusion.

Trovan should be discontinued at the first appearance of a skin rash or any other sign of hypersensitivity. Serious acute hypersensitivity reactions may require treatment with epinephrine and other resuscitative measures, including oxygen, intravenous fluids, antihistamines, corticosteroids, pressor amines and airway management, as clinically indicated. (See PRECAUTIONS and ADVERSE REACTIONS.)

Serious and sometimes fatal events, some due to hypersensitivity and some due to uncertain etiology, have been reported in patients receiving therapy with all antibiotics. These events may be severe and generally occur following the administration of multiple doses. Clinical manifestations may include one or more of the following: fever, rash or severe dermatologic reactions (e.g., toxic epidermal necrolysis, Stevens-Johnson Syndrome); vasculitis, arthralgia, myalgia, serum sickness; allergic pneumonitis, interstitial nephritis; acute renal insufficiency or failure; hepatitis, jaundice, acute hepatic necrosis or failure; anemia, including hemolytic and aplastic; thrombocytopenia, including thrombotic thrombocytopenic purpura; leukopenia; agranulocytosis; pancytopenia; and/or other hematologic abnormalities.

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

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

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

Although not seen in Trovan clinical trials, ruptures of the shoulder, hand, and Achilles tendons that required surgical repair or resulted in prolonged disability have been reported in patients receiving quinolones. Trovan should be discontinued if the patient experiences pain, inflammation or rupture of a tendon. Patients should rest and refrain from exerci

Timoptic Ocumeter

Generic Name: timolol ophthalmic (TIM oh lol off THAL mik)

Brand Names: Betimol, Istalol, Timoptic Ocudose, Timoptic Ocumeter, Timoptic Ocumeter Plus, Timoptic-XE

What is Timoptic Ocumeter (timolol ophthalmic)?

Timolol is a beta-blocker that also reduces pressure inside the eye.

Timolol ophthalmic (for the eyes) is used to treat open-angle glaucoma and other causes of high pressure inside the eye.

Timolol ophthalmic may also be used for other purposes not listed in this medication guide.

What is the most important information I should know about Timoptic Ocumeter (timolol ophthalmic)?

Do not allow the dropper to touch any surface, including the eyes or hands. If the dropper becomes contaminated it could cause an infection in your eye, which can lead to vision loss or serious damage to the eye.

Do not use any other eye medication unless your doctor has prescribed it for you. If you use another eye medication, use it at least 10 minutes before or after using timolol ophthalmic. Do not use the medications at the same time.

Timolol ophthalmic can cause blurred vision. Be careful if you drive or do anything that requires you to be able to see clearly.

What should I discuss with my healthcare provider before using Timoptic Ocumeter (timolol ophthalmic)?

Do not use this medication if you are allergic to timolol, or if you have:

• 
  

  asthma or severe chronic obstructive pulmonary disease (COPD);

  
  


• 
  

  certain serious heart conditions, especially "AV block"; or

  
  


• 
  

  severe or uncontrolled congestive heart failure.

  
  

If you have any of these other conditions, you may need a dose adjustment or special tests to safely use this medication:

• 
  

  breathing problems such as bronchitis or emphysema;

  
  


• 
  

  a history of heart disease or congestive heart failure;

  
  


• 
  

  diabetes;

  
  


• 
  

  history of stroke, blood clot, or circulation problems;

  
  


• 
  

  a thyroid disorder;

  
  


• 
  

  a muscle disorder such as myasthenia gravis;

  
  


• 
  

  kidney disease; or

  
  


• 
  

  liver disease.

  
  

FDA pregnancy category C. It is not known whether timolol ophthalmic is harmful to an unborn baby. Before using this medication, tell your doctor if you are pregnant or plan to become pregnant during treatment. Timolol ophthalmic passes into breast milk and could cause harm to a nursing baby. Do not use this medication without telling your doctor if you are breast-feeding a baby. Do not use this medicine for a child younger than 2 years old.

How should I use Timoptic Ocumeter (timolol ophthalmic)?

Use timolol ophthalmic exactly as it was prescribed for you. Do not use the medication in larger amounts, or use it for longer than recommended by your doctor. Follow the instructions on your prescription label.

Wash your hands before using the eye drops. Do not use this medication while you are wearing contact lenses. Timolol ophthalmic may contain a preservative that can be absorbed by soft contact lenses. Wait at least 15 minutes after using timolol before putting your contact lenses in.

To apply the eye drops:

• 
  

  Tilt your head back slightly and pull down your lower eyelid. Hold the dropper above the eye with the dropper tip down. Look up and away from the dropper as you squeeze out a drop, then close your eye.

  
  


• 
  

  Gently press your finger to the inside corner of the eye (near your nose) for about 1 minute to keep the liquid from draining into your tear duct. If you use more than one drop in the same eye, wait about 5 minutes before putting in the next drop.

  
  


• 
  

  Do not allow the dropper tip to touch any surface, including the eyes or hands. If the dropper becomes contaminated it could cause an infection in your eye, which can lead to vision loss or serious damage to the eye.

  
  

Do not use the eye drops if the liquid has changed colors or has particles in it. Call your doctor for a new prescription.

If you need to have any type of surgery, especially eye surgery, tell the surgeon ahead of time that you are using timolol ophthalmic. You may need to stop using the medicine for a short time.

Store this medication at room temperature away from moisture and heat. Keep the bottle tightly closed when not in use.

What happens if I miss a dose?

Use the medication as soon as you remember. If it is almost time for the next dose, skip the missed dose and use the medicine at the next regularly scheduled time. Do not use extra medicine to make up the missed dose.

What happens if I overdose?

Seek emergency medical attention if you think you have used too much of this medicine.

Overdose symptoms may include feeling dizzy or short of breath, headache, slow heart beat, chest pain, or fainting.

What should I avoid while using Timoptic Ocumeter (timolol ophthalmic)?

Timolol ophthalmic can cause blurred vision. Be careful if you drive or do anything that requires you to be able to see clearly.

Do not use any other eye medication unless your doctor has prescribed it for you. If you use another eye medication, use it at least 10 minutes before or after using timolol ophthalmic. Do not use the medications at the same time.

Timoptic Ocumeter (timolol ophthalmic) side effects

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat. Stop using this medication and call your doctor at once if you have any of these serious side effects:

• 
  

  swelling or redness of your eyelids;

  
  


• 
  

  eye redness, discomfort, or sensitivity to light;

  
  


• 
  

  drainage, crusting, or oozing of your eyes or eyelids;

  
  


• 
  

  depressed mood, confusion, hallucinations, unusual thoughts or behavior;

  
  


• 
  

  wheezing, gasping, or other breathing problems;

  
  


• 
  

  swelling, rapid weight gain;

  
  


• 
  

  chest pain, slow or uneven heart rate; or

  
  


• 
  

  feeling short of breath, even with mild exertion.

  
  

Less serious side effects may include:

• 
  

  blurred vision, double vision, drooping eyelid;

  
  


• 
  

  burning or stinging in your eye;

  
  


• 
  

  headache, weakness, drowsiness;

  
  


• 
  

  numbness, tingling, or cold feeling in your hands or feet;

  
  


• 
  

  ringing in your ears;

  
  


• 
  

  dry mouth;

  
  


• 
  

  nausea, diarrhea, loss of appetite, upset stomach;

  
  


• 
  

  skin rash or worsening psoriasis;

  
  


• 
  

  sleep problems (insomnia); or

  
  


• 
  

  cough, stuffy nose.

  
  

This is not a complete list of side effects and others may occur. Tell your doctor about any unusual or bothersome side effect. You may report side effects to FDA at 1-800-FDA-1088.

What other drugs will affect Timoptic Ocumeter (timolol ophthalmic)?

Before using timolol ophthalmic, tell your doctor if you are using any of the following drugs:

• 
  

  clonidine (Catapres);

  
  


• 
  

  quinidine (Cardioquin, Quinadex, Quinaglute);

  
  


• 
  

  reserpine;

  
  


• 
  

  digitalis (digoxin, Lanoxin, Lanoxicaps);

  
  


• 
  

  acetazolamide (Diamox), dichlorphenamide (Daranide), or methazolamide (Neptazane);

  
  


• 
  

  oral timolol (Blocadren);

  
  


• 
  

  any other beta-blocker such as atenolol (Tenormin), bisoprolol (Zebeta), labetalol (Normodyne, Trandate), metoprolol (Lopressor, Toprol), nadolol (Corgard), penbutolol (Levatol), pindolol (Visken), propranolol (Inderal, InnoPran), sotalol (Betapace), and others;

  
  


• 
  

  a calcium channel blocker such as diltiazem (Tiazac, Cartia, Cardizem), felodipine (Plendil), nifedipine (Procardia, Adalat), verapamil (Calan, Covera, Isoptin, Verelan), and others; or

  
  


• 
  

  antidepressants such as citalopram (Celexa), escitalopram (Lexapro), fluoxetine (Prozac, Sarafem), fluvoxamine (Luvox), paroxetine (Paxil), or sertraline (Zoloft).

  
  

This list is not complete and there may be other drugs that can interact with timolol ophthalmic. Tell your doctor about all the prescription and over-the-counter medications you use. This includes vitamins, minerals, herbal products, and drugs prescribed by other doctors. Do not start using a new medication without telling your doctor.

More Timoptic Ocumeter resources

• Timoptic Ocumeter Side Effects (in more detail)
• Timoptic Ocumeter Use in Pregnancy & Breastfeeding
• Timoptic Ocumeter Drug Interactions
• Timoptic Ocumeter Support Group
• 1 Review for Timoptic Ocumeter - Add your own review/rating

• Timoptic Ocumeter Advanced Consumer (Micromedex) - Includes Dosage Information


• Timolol Ophthalmic Prescribing Information (FDA)


• Betimol Prescribing Information (FDA)


• Betimol Drops MedFacts Consumer Leaflet (Wolters Kluwer)


• Istalol Prescribing Information (FDA)


• Istalol Consumer Overview


• Istalol Drops MedFacts Consumer Leaflet (Wolters Kluwer)

Compare Timoptic Ocumeter with other medications

• Glaucoma, Open Angle
• Intraocular Hypertension

Where can I get more information?

• Your pharmacist can provide more information about timolol ophthalmic.

See also: Timoptic Ocumeter side effects (in more detail)

Tramadol Tablets

Dosage Form: tablet, coated
Tramadol Hydrochloride Tablets, USP

Tramadol Tablets Description

Tramadol hydrochloride tablet, USP is a centrally acting analgesic. The chemical name for tramadol hydrochloride is (±)cis-2-[(dimethylamino)methyl]-1-(3-methoxyphenyl) cyclohexanol hydrochloride. Its structural formula is:

The molecular weight of tramadol hydrochloride is 299.8. Tramadol hydrochloride is a white, bitter, crystalline and odorless powder. It is readily soluble in water and ethanol and has a pKa of 9.41. The n-octanol/water log partition coefficient (logP) is 1.35 at pH 7. Tramadol Hydrochloride Tablets, USP, for oral administration, contain 50 mg of tramadol hydrochloride and are white to off-white in color. In addition, each tablet contains the following inactive ingredients: hydroxyethyl cellulose, magnesium stearate, microcrystalline cellulose, polyethylene glycol and titanium dioxide.

Tramadol Tablets - Clinical Pharmacology

Pharmacodynamics

Tramadol hydrochloride is a centrally acting synthetic opioid analgesic. Although its mode of action is not completely understood, from animal tests, at least two complementary mechanisms appear applicable: binding of parent and M1 metabolite to μ-opioid receptors and weak inhibition of re-uptake of norepinephrine and serotonin.

Opioid activity is due to both low affinity binding of the parent compound and higher affinity binding of the O-demethylated metabolite M1 to μ-opioid receptors. In animal models, M1 is up to 6 times more potent than tramadol in producing analgesia and 200 times more potent in μ-opioid binding. Tramadol-induced analgesia is only partially antagonized by the opiate antagonist naloxone in several animal tests. The relative contribution of both tramadol and M1 to human analgesia is dependent upon the plasma concentrations of each compound (see CLINICAL PHARMACOLOGY, Pharmacokinetics).

Tramadol has been shown to inhibit reuptake of norepinephrine and serotonin in vitro, as have some other opioid analgesics. These mechanisms may contribute independently to the overall analgesic profile of tramadol hydrochloride. Analgesia in humans begins approximately within one hour after administration and reaches a peak in approximately two to three hours.

Apart from analgesia, tramadol hydrochloride administration may produce a constellation of symptoms (including dizziness, somnolence, nausea, constipation, sweating and pruritus) similar to that of other opioids. In contrast to morphine, tramadol has not been shown to cause histamine release. At therapeutic doses, tramadol hydrochloride has no effect on heart rate, left-ventricular function or cardiac index. Orthostatic hypotension has been observed.

Pharmacokinetics

The analgesic activity of tramadol hydrochloride is due to both parent drug and the M1 metabolite (see CLINICAL PHARMACOLOGY, Pharmacodynamics). Tramadol is administered as a racemate and both the [-] and [+] forms of both tramadol and M1 are detected in the circulation. Linear pharmacokinetics have been observed following multiple doses of 50 and 100 mg to steady-state.

Absorption

The mean absolute bioavailability of a 100 mg oral dose is approximately 75%. The mean peak plasma concentration of racemic tramadol and M1 occurs at two and three hours, respectively, after administration in healthy adults. In general, both enantiomers of tramadol and M1 follow a parallel time course in the body following single and multiple doses although small differences (~10%) exist in the absolute amount of each enantiomer present.

Steady-state plasma concentrations of both tramadol and M1 are achieved within two days with four times per day dosing. There is no evidence of self-induction (see Figure 1 and Table 1 below).

Figure 1:   Mean Tramadol and M1 Plasma Concentration Profiles after a Single 100 mg Oral Dose and after Twenty-Nine 100 mg Oral Doses of Tramadol HCl given four times a day.

Table 1 Mean (%CV) Pharmacokinetic Parameters for Racemic Tramadol and M1 Metabolite

Population/	Parent Drug/	Peak Conc.	Time to	Clearance/Fb	t1/2
Dosage Regimen	Metabolite	(ng/mL)	Peak (hrs)	(mL/min/Kg)	(hrs)
Healthy Adults, 100 mg qid, MD p.o	Tramadol M1	592 (30) 110 (29)	2.3 (61) 2.4 (46)	5.90 (25) c	6.7 (15) 7.0 (14)
Healthy Adults, 100 mg SD p.o	Tramadol M1	308 (25) 55.0 (36)	1.6 (63) 3.0 (51)	8.50 (31) c	5.6 (20) 6.7 (16)
Geriatric, (>75 yrs) 50 mg SD p.o.	Tramadol M1	208 (31) d	2.1 (19) d	6.89 (25) c	7.0 (23) d
Hepatic Impaired, 50 mg SD p.o.	Tramadol M1	217 (11) 19.4 (12)	1.9 (16) 9.8 (20)	4.23 (56) c	13.3 (11) 18.5 (15)
Renal Impaired, CLcr10-30 mL/min 100 mg SD i.v.	Tramadol M1	c c	c c	4.23 (54) c	10.6 (31) 11.5 (40)
Renal Impaired, CLcr<5 mL/min 100 mg SD i.v.	Tramadol M1	c  c	c  c	3.73 (17) c	11.0 (29) 16.9 (18)

a SD = Single dose, MD = Multiple dose, p.o.= Oral administration, i.v.= Intravenous administration, q.i.d. = Four times daily

b  F represents the oral bioavailability of tramadol

c  Not applicable

d  Not measured

Food Effects

Oral administration of tramadol hydrochloride tablets with food does not significantly affect its rate or extent of absorption, therefore, tramadol hydrochloride tablets can be administered without regard to food.

Distribution

The volume of distribution of tramadol was 2.6 and 2.9 liters/kg in male and female subjects, respectively, following a 100 mg intravenous dose. The binding of tramadol to human plasma proteins is approximately 20% and binding also appears to be independent of concentration up to 10 mcg/mL. Saturation of plasma protein binding occurs only at concentrations outside the clinically relevant range.

Metabolism

Tramadol is extensively metabolized after oral administration by a number of pathways, including CYP2D6 and CYP3A4, as well as by conjugation of parent and metabolites. Approximately 30% of the dose is excreted in the urine as unchanged drug, whereas 60% of the dose is excreted as metabolites. The remainder is excreted either as unidentified or as unextractable metabolites. The major metabolic pathways appear to be N- and O-demethylation and glucuronidation or sulfation in the liver. One metabolite (O-desmethyltramadol, denoted M1) is pharmacologically active in animal models. Formation of M1 is dependent on CYP2D6 and as such is subject to inhibition, which may affect the therapeutic response (see PRECAUTIONS, Drug Interaction).

Approximately 7% of the population has reduced activity of the CYP2D6 isoenzyme of cytochrome P-450. These individuals are "poor metabolizers" of debrisoquine, dextromethorphan, tricyclic antidepressants, among other drugs. Based on a population PK analysis of Phase I studies in healthy subjects, concentrations of tramadol were approximately 20% higher in "poor metabolizers" versus "extensive metabolizers", while M1 concentrations were 40% lower. Concomitant therapy with inhibitors of CYP2D6 such as fluoxetine, paroxetine and quinidine could result in significant drug interactions. In vitro drug interaction studies in human liver microsomes indicate that inhibitors of CYP2D6 such as fluoxetine and its metabolite norfluoxetine, amitriptyline and quinidine inhibit the metabolism of tramadol to various degrees, suggesting that concomitant administration of these compounds could result in increases in tramadol concentrations and decreased concentrations of M1. The full pharmacological impact of these alterations in terms of either efficacy or safety is unknown. Concomitant use of SEROTONIN re-uptake INHIBITORS and MAO INHIBITORS may enhance the risk of adverse events, including seizure (see WARNINGS) and serotonin syndrome.

Elimination

Tramadol is eliminated primarily through metabolism by the liver and the metabolites are eliminated primarily by the kidneys. The mean terminal plasma elimination half-lives of racemic tramadol and racemic M1 are 6.3 ± 1.4 and 7.4 ± 1.4 hours, respectively. The plasma elimination half-life of racemic tramadol increased from approximately six hours to seven hours upon multiple dosing.

Special Populations

Renal

Impaired renal function results in a decreased rate and extent of excretion of tramadol and its active metabolite, M1. In patients with creatinine clearances of less than 30 mL/min, adjustment of the dosing regimen is recommended (see DOSAGE AND ADMINISTRATION). The total amount of tramadol and M1 removed during a 4-hour dialysis period is less than 7% of the administered dose.

Hepatic

Metabolism of tramadol and M1 is reduced in patients with advanced cirrhosis of the liver, resulting in both a larger area under the concentration time curve for tramadol and longer tramadol and M1 elimination half-lives (13 hrs. for tramadol and 19 hrs. for M1). In cirrhotic patients, adjustment of the dosing regimen is recommended (see DOSAGE AND ADMINISTRATION).

Geriatric

Healthy elderly subjects aged 65 to 75 years have plasma tramadol concentrations and elimination half-lives comparable to those observed in healthy subjects less than 65 years of age. In subjects over 75 years, maximum serum concentrations are elevated (208 vs. 162 ng/mL) and the elimination half-life is prolonged (7 vs. 6 hours) compared to subjects 65 to 75 years of age. Adjustment of the daily dose is recommended for patients older than 75 years (see DOSAGE AND ADMINISTRATION).

Gender

The absolute bioavailability of tramadol was 73% in males and 79% in females. The plasma clearance was 6.4 mL/min/kg in males and 5.7 mL/min/kg in females following a 100 mg IV dose of tramadol. Following a single oral dose, and after adjusting for body weight, females had a 12% higher peak tramadol concentration and a 35% higher area under the concentration-time curve compared to males. The clinical significance of this difference is unknown.

CLINICAL STUDIES

Tramadol hydrochloride tablets have been given in single oral doses of 50, 75 and 100 mg to patients with pain following surgical procedures and pain following oral surgery (extraction of impacted molars).

In single-dose models of pain following oral surgery, pain relief was demonstrated in some patients at doses of 50 mg and 75 mg. A dose of 100 mg tramadol hydrochloride tended to provide analgesia superior to codeine sulfate 60 mg, but it was not as effective as the combination of aspirin 650 mg with codeine phosphate 60 mg.

Tramadol hydrochloride has been studied in three long-term controlled trials involving a total of 820 patients, with 530 patients receiving tramadol hydrochloride. Patients with a variety of chronic painful conditions were studied in double-blind trials of one to three months duration. Average daily doses of approximately 250 mg of tramadol hydrochloride in divided doses were generally comparable to five doses of acetaminophen 300 mg with codeine phosphate 30 mg (TYLENOL® with Codeine #3) daily, five doses of aspirin 325 mg with codeine phosphate 30 mg daily, or two to three doses of acetaminophen 500 mg with oxycodone hydrochloride 5 mg (TYLOX®) daily.

Titration Trials

In a randomized, blinded clinical study with 129 to 132 patients per group, a 10-day titration to a daily tramadol hydrochloride dose of 200 mg (50 mg four times per day), attained in 50 mg increments every 3 days, was found to result in fewer discontinuations due to dizziness or vertigo than titration over only 4 days or no titration. In a second study with 54 to 59 patients per group, patients who had nausea or vomiting when titrated over 4 days were randomized to re-initiate tramadol hydrochloride therapy using slower titration rates.

A 16-day titration schedule, starting with 25 mg qAM and using additional doses in 25 mg increments every third day to 100 mg/day (25 mg four times per day), followed by 50 mg increments in the total daily dose every third day to 200 mg/day (50 mg four times per day), resulted in fewer discontinuations due to nausea or vomiting and fewer discontinuations due to any cause than did a 10-day titration schedule.

Figure 2:

Indications and Usage for Tramadol Tablets

Tramadol hydrochloride tablets are indicated for the management of moderate to moderately severe pain in adults.

Contraindications

Tramadol hydrochloride tablets should not be administered to patients who have previously demonstrated hypersensitivity to tramadol, any other component of this product or opioids. Tramadol hydrochloride tablets are contraindicated in any situation where opioids are contraindicated, including acute intoxication with any of the following: alcohol, hypnotics, narcotics, centrally acting analgesics, opioids or psychotropic drugs. Tramadol hydrochloride tablets may worsen central nervous system and respiratory depression in these patients.

Warnings

Seizure Risk

Seizures have been reported in patients receiving tramadol hydrochloride within the recommended dosage range. Spontaneous post-marketing reports indicate that seizure risk is increased with doses of tramadol hydrochloride above the recommended range. Concomitant use of tramadol hydrochloride increases the seizure risk in patients taking:

• Selective serotonin re-uptake inhibitors (SSRI antidepressants or anorectics),


• Tricyclic antidepressants (TCAs), and other tricyclic compounds (e.g., cyclobenzaprine, promethazine, etc.), or


• Other opioids.

Administration of tramadol hydrochloride may enhance the seizure risk in patients taking:

• MAO inhibitors (see also WARNINGS - Use with MAO Inhibitor and Serotonin Re-Uptake Inhibitors),


• Neuroleptics, or


• Other drugs that reduce the seizure threshold.

Risk of convulsions may also increase in patients with epilepsy, those with a history of seizures, or in patients with a recognized risk for seizure (such as head trauma, metabolic disorders, alcohol and drug withdrawal, CNS infections). In tramadol hydrochloride tablets overdose, naloxone administration may increase the risk of seizure.

Suicide Risk

• Do not prescribe tramadol hydrochloride for patients who are suicidal or addiction-prone.


• Prescribe tramadol hydrochloride tablets with caution for patients who are taking tranquilizers or antidepressant drug and patients who use alcohol in excess and who suffer from emotional disturbance or depression.

The judicious prescribing of tramadol is essential to the safe use of this drug. With patients who are depressed or suicidal, consideration should be given to the use of non­narcotic analgesics.

Tramadol-related deaths have occurred in patients with previous histories of emotional disturbances or suicidal ideation or attempts as well as histories of misuse of tranquilizers, alcohol, and other CNS-active drugs (see WARNINGS, Risk of Overdosage).

Serotonin Syndrome Risk

The development of a potentially life-threatening serotonin syndrome may occur with the use of tramadol products, including tramadol hydrochloride, particularly with concomitant use of serotonergic drugs such as SSRIs, SNRIs, TCAs, MAOIs, and triptans, with drugs which impair metabolism of serotonin (including MAOIs), and with drugs which impair metabolism of tramadol (CYP2D6 and CYP3A4 inhibitors). This may occur within the recommended dose (see CLINICAL PHARMACOLOGY, Pharmacokinetics).

Serotonin syndrome may include mental-status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination) and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea).

Anaphylactoid Reactions

Serious and rarely fatal anaphylactoid reactions have been reported in patients receiving therapy with tramadol hydrochloride. When these events do occur it is often following the first dose. Other reported allergic reactions include pruritus, hives, bronchospasm, angioedema, toxic epidermal necrolysis and Stevens-Johnson syndrome. Patients with a history of anaphylactoid reactions to codeine and other opioids may be at increased risk and therefore should not receive tramadol hydrochloride (see CONTRAINDICATIONS).

Respiratory Depression

Administer tramadol hydrochloride cautiously in patients at risk for respiratory depression. In these patients alternative non-opioid analgesics should be considered. When large doses of tramadol hydrochloride are administered with anesthetic medications or alcohol, respiratory depression may result. Respiratory depression should be treated as an overdose. If naloxone is to be administered, use cautiously because it may precipitate seizures (see WARNINGS, Seizure Risk and OVERDOSAGE).

Interaction with Central Nervous System (CNS) Depressants

Tramadol hydrochloride should be used with caution and in reduced dosages when administered to patients receiving CNS depressants such as alcohol, opioids, anesthetic agents, narcotics, phenothiazines, tranquilizers or sedative hypnotics. Tramadol hydrochloride increases the risk of CNS and respiratory depression in these patients.

Interactions with Alcohol and Drugs of Abuse

Tramadol may be expected to have additive effects when used in conjunction with alcohol, other opioids, or illicit drugs that cause central nervous system depression.

Increased Intracranial Pressure or Head Trauma

Tramadol hydrochloride should be used with caution in patients with increased intracranial pressure or head injury. The respiratory depressant effects of opioids include carbon dioxide retention and secondary elevation of cerebrospinal fluid pressure, and may be markedly exaggerated in these patients. Additionally, pupillary changes (miosis) from tramadol may obscure the existence, extent, or course of intracranial pathology. Clinicians should also maintain a high index of suspicion for adverse drug reaction when evaluating altered mental status in these patients if they are receiving tramadol hydrochloride (see WARNINGS, Respiratory Depression).

Use in Ambulatory Patients

Tramadol hydrochloride may impair the mental and or physical abilities required for the performance of potentially hazardous tasks such as driving a car or operating machinery. The patient using this drug should be cautioned accordingly.

Use with MAO Inhibitors and Serotonin Re-uptake Inhibitors

Use tramadol hydrochloride with great caution in patients taking monoamine oxidase inhibitors. Animal studies have shown increased deaths with combined administration. Concomitant use of tramadol hydrochloride with MAO inhibitors or SSRI's increases the risk of adverse events, including seizure and serotonin syndrome.

Misuse, Abuse and Diversion

Tramadol has mu-opioid agonist activity. Tramadol hydrochloride can be sought by drug abusers and people with addiction disorders and may be subject to criminal diversion. The possibility of illegal or illicit use should be considered when prescribing or dispensing tramadol hydrochloride in situations where the physician or pharmacist is concerned about an increased risk of misuse, abuse, or diversion. Misuse or abuse poses a significant risk to the abuser that could result in overdose and death (see DRUG ABUSE AND DEPENDENCE and OVERDOSAGE).

Concerns about abuse, addiction, and diversion should not prevent the proper management of pain. The development of addiction to opioid analgesics in properly managed patients with pain has been reported to be rare. However, data are not available to establish the true incidence of addiction in chronic pain patients.

Risk of Overdosage

Patients taking tramadol should be warned not to exceed the dose recommended by their physician. Tramadol products in excessive doses, either alone or in combination with other CNS depressants, including alcohol, are a cause of drug-related deaths. Patients should be cautioned about the concomitant use of tramadol products and alcohol because of potentially serious CNS additive effects of these agents. Because of its added depressant effects, tramadol should be prescribed with caution for those patients whose medical condition requires the concomitant administration of sedatives, tranquilizers, muscle relaxants, antidepressants, or other CNS depressant drugs. Patients should be advised of the additive depressant effects of these combinations.

Serious potential consequences of overdosage with tramadol hydrochloride tablets are central nervous system depression, respiratory depression and death. Some deaths have occurred as a consequence of the accidental ingestion of excessive quantities of tramadol alone or in combination with other drugs. In treating an overdose, primary attention should be given to maintaining adequate ventilation along with general supportive treatment (see OVERDOSAGE).

Withdrawal

Withdrawal symptoms may occur if tramadol hydrochloride is discontinued abruptly (see DRUG ABUSE AND DEPENDENCE). Reported symptoms have included anxiety, sweating, insomnia, rigors, pain, nausea, tremors, diarrhea, upper respiratory symptoms, piloerection, and rarely hallucinations. Other symptoms that have been seen less frequently with tramadol hydrochloride discontinuation include: panic attacks, severe anxiety, and paresthesias. Clinical experience suggests that withdrawal symptoms may be avoided by tapering tramadol hydrochloride at the time of discontinuation.

Precautions

Acute Abdominal Conditions

The administration of tramadol hydrochloride may complicate the clinical assessment of patients with acute abdominal conditions.

Use in Renal and Hepatic Disease

Impaired renal function results in a decreased rate and extent of excretion of tramadol and its active metabolite, M1. In patients with creatinine clearances of less than 30 mL/min, dosing reduction is recommended (see DOSAGE AND ADMINISTRATION). Metabolism of tramadol and M1 is reduced in patients with advanced cirrhosis of the liver. In cirrhotic patients, dosing reduction is recommended (see DOSAGE AND ADMINISTRATION).

With the prolonged half-life in these conditions, achievement of steady-state is delayed, so that it may take several days for elevated plasma concentrations to develop.

Information for Patients

• Patients should be informed that tramadol hydrochloride may cause seizures and/or serotonin syndrome with concomitant use of serotonergic agents (including SSRIs, SNRIs, and triptans) or drugs that significantly reduce the metabolic clearance of tramadol.


• Tramadol hydrochloride tablets may impair mental or physical abilities required for the performance of potentially hazardous tasks such as driving a car or operating machinery.


• Tramadol hydrochloride tablets should not be taken with alcohol containing beverages.


• Tramadol hydrochloride tablets should be used with caution when taking medications such as tranquilizers, hypnotics or other opiate containing analgesics.


• The patient should be instructed to inform the physician if they are pregnant, think they might become pregnant, or are trying to become pregnant (see PRECAUTIONS, Labor and Delivery).


• The patient should understand the single-dose and 24-hour dose limit and the time interval between doses, since exceeding these recommendations can result in respiratory depression, seizures and death.

Drug Interactions

CYP2D6 and CYP3A4 Inhibitors

Concomitant administration of CYP2D6 and/or CYP3A4 inhibitors (see CLINICAL PHARMACOLOGY, Pharmacokinetics), such as quinidine, fluoxetine, paroxetine and amitriptyline (CYP2D6 inhibitors), and ketoconazole and erythromycin (CYP3A4 inhibitors), may reduce metabolic clearance of tramadol increasing the risk for serious adverse events including seizures and serotonin syndrome.

Serotonergic Drugs

There have been postmarketing reports of serotonin syndrome with use of tramadol and SSRIs/SNRIs or MAOIs and α2-adrenergic blockers. Caution is advised when tramadol hydrochloride is coadministered with other drugs that may affect the serotonergic neurotransmitter systems, such as SSRIs, MAOIs, triptans, linezolid (an antibiotic which is a reversible non-selective MAOI), lithium, or St. John’s Wort. If concomitant treatment of tramadol hydrochloride with a drug affecting the serotonergic neurotransmitter system is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases (see WARNINGS, Serotonin Syndrome).

Triptans

Based on the mechanism of action of tramadol and the potential for serotonin syndrome, caution is advised when tramadol hydrochloride is coadministered with a triptan. If concomitant treatment of tramadol hydrochloride with a triptan is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases (see WARNINGS, Serotonin Syndrome).

Use with Carbamazepine

Patients taking carbamazepine may have a significantly reduced analgesic effect of tramadol hydrochloride. Because carbamazepine increases tramadol metabolism and because of the seizure risk associated with tramadol, concomitant administration of tramadol hydrochloride and carbamazepine is not recommended.

Use with Quinidine

Tramadol is metabolized to M1 by CYP2D6. Quinidine is a selective inhibitor of that isoenzyme, so that concomitant administration of quinidine and tramadol hydrochloride results in increased concentrations of tramadol and reduced concentrations of M1. The clinical consequences of these findings are unknown. In vitro drug interaction studies in human liver microsomes indicate that tramadol has no effect on quinidine metabolism.

Potential for Other Drugs to Affect Tramadol

In vitro drug interaction studies in human liver microsomes indicate that concomitant administration with inhibitors of CYP2D6 such as fluoxetine, paroxetine, and amitriptyline could result in some inhibition of the metabolism of tramadol. Administration of CYP3A4 inhibitors, such as ketoconazole and erythromycin, or inducers, such as rifampin and St. John’s Wort, with tramadol hydrochloride may affect the metabolism of tramadol leading to alteted tramadol exposure.

Potential for Tramadol to Affect Other Drugs

In vitro studies indicate that tramadol is unlikely to inhibit the CYP3A4-mediated metabolism of other drugs when tramadol is administered concomitantly at therapeutic doses. Tramadol does not appear to induce its own metabolism in humans, since observed maximal plasma concentrations after multiple oral doses are higher than expected based on single-dose data. Tramadol is a mild inducer of selected drug metabolism pathways measured in animals.

Use with Cimetidine

Concomitant administration of tramadol hydrochloride with cimetidine does not result in clinically significant changes in tramadol pharmacokinetics. Therefore, no alteration of the tramadol hydrochloride dosage regimen is recommended.

Use with Digoxin and Warfarin

Post-marketing surveillance has revealed rare reports of digoxin toxicity and alteration of warfarin effect, including elevation of prothrombin times.

Carcinogenesis, Mutagenesis, Impairment of Fertility

A slight, but statistically significant, increase in two common murine tumors, pulmonary and hepatic, was observed in a mouse carcinogenicity study, particularly in aged mice. Mice were dosed orally up to 30 mg/kg (90 mg/m2 or 0.36 times the maximum daily human dosage of 246 mg/m2) for approximately two years, although the study was not done with the Maximum Tolerated Dose. This finding is not believed to suggest risk in humans. No such finding occurred in a rat carcinogenicity study (dosing orally up to 30 mg/kg, 180 mg/m2, or 0.73 times the maximum daily human dosage).

Tramadol was not mutagenic in the following assays: Ames Salmonella microsomal activation test, CHO/HPRT mammalian cell assay, mouse lymphoma assay (in the absence of metabolic activation), dominant lethal mutation tests in mice, chromosome aberration test in Chinese hamsters, and bone marrow micronucleus tests in mice and Chinese hamsters. Weakly mutagenic results occurred in the presence of metabolic activation in the mouse lymphoma assay and micronucleus test in rats. Overall, the weight of evidence from these tests indicates that tramadol does not pose a genotoxic risk to humans.

No effects on fertility were observed for tramadol at oral dose levels up to 50 mg/kg (300 mg/m2) in male rats and 75 mg/kg (450 mg/m2) in female rats. These dosages are 1.2 and 1.8 times the maximum daily human dosage of 246 mg/m2, respectively.

Pregnancy

Teratogenic Effects

Pregnancy Category C

Tramadol has been shown to be embryotoxic and fetotoxic in mice, (120 mg/kg or 360 mg/m2), rats (≥ 25 mg/kg or 150 mg/m2) and rabbits (≥ 75 mg/kg or 900 mg/m2) at maternally toxic dosages, but was not teratogenic at these dose levels. These dosages on a mg/m2 basis are 1.4, ≥ 0.6, and ≥ 3.6 times the maximum daily human dosage (246 mg/m2) for mouse, rat and rabbit, respectively.

No drug-related teratogenic effects were observed in progeny of mice (up to 140 mg/kg or 420 mg/m2), rats (up to 80 mg/kg or 480 mg/m2) or rabbits (up to 300 mg/kg or 3600 mg/m2) treated with tramadol by various routes. Embryo and fetal toxicity consisted primarily of decreased fetal weights, skeletal ossification and increased supernumerary ribs at maternally toxic dose levels. Transient delays in developmental or behavioral parameters were also seen in pups from rat dams allowed to deliver. Embryo and fetal lethality were reported only in one rabbit study at 300 mg/kg (3600 mg/m2), a dose that would cause extreme maternal toxicity in the rabbit. The dosages listed for mouse, rat and rabbit are 1.7, 1.9 and 14.6 times the maximum daily human dosage (246 mg/m2), respectively.

Non-teratogenic Effects

Tramadol was evaluated in peri- and post-natal studies in rats. Progeny of dams receiving oral (gavage) dose levels of 50 mg/kg (300 mg/m2 or 1.2 times the maximum daily human tramadol dosage) or greater had decreased weights, and pup survival was decreased early in lactation at 80 mg/kg (480 mg/m2 or 1.9 and higher the maximum daily human dose).

There are no adequate and well-controlled studies in pregnant women. Tramadol hydrochloride should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Neonatal seizures, neonatal withdrawal syndrome, fetal death and still birth have been reported during post-marketing.

Labor and Delivery

Tramadol hydrochloride should not be used in pregnant women prior to or during labor unless the potential benefits outweigh the risks. Safe use in pregnancy has not been established. Chronic use during pregnancy may lead to physical dependence and post-partum withdrawal symptoms in the newborn (see DRUG ABUSE AND DEPENDENCE). Tramadol has been shown to cross the placenta. The mean ratio of serum tramadol in the umbilical veins compared to maternal veins was 0.83 for 40 women given tramadol during labor.

The effect of tramadol hydrochloride, if any, on the later growth, development, and functional maturation of the child is unknown.

Nursing Mothers

Tramadol hydrochloride tablets are not recommended for obstetrical preoperative medication or for post-delivery analgesia in nursing mothers because its safety in infants and newborns has not been studied. Following a single IV 100 mg dose of tramadol, the cumulative excretion in breast milk within 16 hours postdose was 100 mcg of tramadol (0.1% of the maternal dose) and 27 mcg of M1.

Pediatric Use

The safety and efficacy of tramadol hydrochloride tablets in patients under 16 years of age have not been established. The use of tramadol hydrochloride tablets in the pediatric population is not recommended.

Geriatric Use

In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac function and of concomitant disease or other drug therapy. In patients over 75 years of age, daily doses in excess of 300 mg are not recommended (see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION).

A total of 455 elderly (65 years of age or older) subjects were exposed to tramadol hydrochloride in controlled clinical trials. Of those, 145 subjects were 75 years of age and older.

In studies including geriatric patients, treatment-limiting adverse events were higher in subjects over 75 years of age compared to those under 65 years of age. Specifically, 30% of those over 75 years of age had gastrointestinal treatment-limiting adverse events compared to 17% of those under 65 years of age. Constipation resulted in discontinuation of treatment in 10% of those over 75.

Adverse Reactions

Tramadol hydrochloride was administered to 550 patients during the double-blind or open-label extension periods in U.S. studies of chronic nonmalignant pain. Of these patients, 375 were 65 years old or older. Table 2 reports the cumulative incidence rate of adverse reactions by 7, 30 and 90 days for the most frequent reactions (5% or more by 7 days). The most frequently reported events were in the central nervous system and gastrointestinal system. Although the reactions listed in the table are felt to be probably related to tramadol hydrochloride administration, the reported rates also include some events that may have been due to underlying disease or concomitant medication. The overall incidence rates of adverse experiences in these trials were similar for tramadol hydrochloride and the active control groups, TYLENOL® with Codeine #3 (acetaminophen 300 mg with codeine phosphate 30 mg), and aspirin 325 mg with codeine phosphate 30 mg, however, the rates of withdrawals due to adverse events appeared to be higher in the tramadol hydrochloride groups.

Table 2: Cumulative Incidence of Adverse Reactions for Tramadol Hydrochloride Tablets in Chronic Trials of Nonmalignant Pain (N=427)

	Up to 7 Days	Up to 30 Days	Up to 90 Days
Dizziness/Vertigo	26%	31%	33%
Nausea	24%	34%	40%
Constipation	24%	38%	46%
Headache	18%	26%	32%
Somnolence	16%	23%	25%
Vomiting	9%	13%	17%
Pruritus	8%	10%	11%
"CNS Stimulation"1	7%	11%	14%
Asthenia	6%	11%	12%
Sweating	6%	7%	9%
Dyspepsia	5%	9%	13%
Dry Mouth	5%	9%	10%
Diarrhea	5%	6%	10%

1“CNS Stimulation” is a composite of nervousness, anxiety, agitation, tremor, spasticity, euphoria, emotional lability and hallucinations.

Incidence 1% to less than 5%, possibly causally related

The following lists adverse reactions that occurred with an incidence of 1% to less than 5% in clinical trials, and for which the possibility of a causal relationship with tramadol hydrochloride exists.

Body as a Whole

Malaise.

Cardiovascular

Vasodilation.

Central Nervous System

Anxiety, Confusion, Coordination disturbance, Euphoria, Miosis, Nervousness, Sleep disorder.

Gastrointestinal

Abdominal pain, Anorexia, Flatulence.

Musculoskeletal

Hypertonia.

Skin

Rash.

Special Senses

Visual disturbance.

Urogenital

Menopausal symptoms, Urinary frequency, Urinary retention.

Incidence less than 1%, possibly causally related

The following lists adverse reactions that occurred with an incidence of less than 1% in clinical trials and/or reported in post-marketing experience.

Body as a Whole

Accidental injury, Allergic reaction, Anaphylaxis, Death, Suicidal tendency, Weight loss, Serotonin syndrome (mental status change, hyperreflexia, fever, shivering, tremor, agitation, diaphoresis, seizures and coma).

Cardiovascular

Orthostatic hypotension, Syncope, Tachycardia.

Central Nervous System

Abnormal gait, Amnesia, Cognitive dysfunction, Depression, Difficulty in concentration, Hallucinations, Paresthesia, Seizure (see WARNINGS), Tremor.

Respiratory

Dyspnea.

Skin

Stevens-Johnson syndrome/Toxic epidermal necrolysis, Urticaria, Vesicles.

Special Senses

Dysgeusia.

Urogenital

Dysuria, Menstrual disorder.

Other adverse experiences, causal relationship unknown

A variety of other adverse events were reported infrequently in patients taking tramadol hydrochloride during clinical trials and/or reported in post-marketing experience. A causal relationship between tramadol hydrochloride and these events has not been determined. However, the most significant events are listed below as alerting information to the physician.

Cardiovascular

Abnormal ECG, Hypertension, Hypotension, Myocardial ischemia, Palpitations, Pulmonary edema, Pulmonary embolism.

Central Nervous System

Migraine, Speech disorders.

Gastrointestinal

Gastrointestinal bleeding, Hepatitis, Stomatitis, Liver failure.

Laboratory Abnormalities

Creatinine increase, Elevated liver enzymes, Hemoglobin decrease, Proteinuria.

Sensory

Cataracts, Deafness, Tinnitus.

Drug Abuse and Dependence

Abuse

Tramadol has mu-opioid agonist activity. Tramadol hydrochloride can be abused and may be subject to criminal diversion.

Addiction is a primary, chronic, neurobiologic disease, with genetic, psychosocial, and environmental factors influencing its development and manifestations. Drug addiction is characterized by behaviors that include one or more of the following: impaired control over drug use, compulsive use, use for non-medical purposes, and continued use despite harm or risk of harm, and craving. Drug addiction is a treatable disease, utilizing a multi­disciplinary approach, but relapse is common.

“Drug-seeking” behavior is very common in a

Selsun Blue Conditioner

Pronunciation: PIR-i-THYE-one zink
Generic Name: Pyrithione Zinc
Brand Name: Selsun Blue Conditioner

Selsun Blue Conditioner is used for:

Treating and preventing flaking, itching, and scaling of the scalp caused by dandruff or seborrhea (crusting, oily, or scaling skin). It also moisturizes dry hair.

Selsun Blue Conditioner is an antiseborrheic. It works by slowing the production of skin cells, which helps to reduce flakiness.

Do NOT use Selsun Blue Conditioner if:

• you are allergic to any ingredient in Selsun Blue Conditioner

Contact your doctor or health care provider right away if this applies to you.

Before using Selsun Blue Conditioner:

Some medical conditions may interact with Selsun Blue Conditioner. 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 a condition that covers a large area of the body

Some MEDICINES MAY INTERACT with Selsun Blue Conditioner. Because little, if any, of Selsun Blue Conditioner is absorbed into the blood, the risk of it interacting with another medicine is low.

Ask your health care provider if Selsun Blue Conditioner 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 Selsun Blue Conditioner:

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

• Apply Selsun Blue Conditioner to wet hair as directed after you shampoo. Rinse well.


• For best results, use Selsun Blue Conditioner at least 2 times per week or as directed by your doctor. Do not use more often than once daily.


• If you miss a dose of Selsun Blue Conditioner, use it as soon as you remember. Continue to use it as directed by your doctor or on the package label.

Ask your health care provider any questions you may have about how to use Selsun Blue Conditioner.

Important safety information:

• Selsun Blue Conditioner is for external use only. Do not get Selsun Blue Conditioner in your eyes, nose, or mouth. If you get Selsun Blue Conditioner in your eyes, rinse immediately with cool water.


• If your symptoms do not get better with regular use or if they get worse, check with your doctor.


• Use of Selsun Blue Conditioner is not recommended in CHILDREN younger than 2 years old without checking with your doctor.


• PREGNANCY and BREAST-FEEDING: If you become pregnant, contact your doctor. You will need to discuss the benefits and risks of using Selsun Blue Conditioner while you are pregnant. It is not known if Selsun Blue Conditioner is found in breast milk. If you are or will be breast-feeding while you use Selsun Blue Conditioner, check with your doctor. Discuss any possible risks to your baby.

Possible side effects of Selsun Blue Conditioner:

All medicines may cause side effects, but many people have no, or minor side effects. No COMMON side effects have been reported with Selsun Blue Conditioner. Seek medical attention right away if any of these SEVERE side effects occur:

Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); skin irritation.

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: Selsun Blue 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. Selsun Blue Conditioner may be harmful if swallowed.

Proper storage of Selsun Blue Conditioner:

Store Selsun Blue Conditioner at room temperature, between 68 and 77 degrees F (20 and 25 degrees C). Store away from heat, moisture, and light. Do not store in the bathroom. Keep Selsun Blue Conditioner out of the reach of children and away from pets.

General information:

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


• Selsun Blue Conditioner 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 Selsun Blue Conditioner. 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.

More Selsun Blue resources

• Selsun Blue Side Effects (in more detail)
• Selsun Blue Use in Pregnancy & Breastfeeding
• 0 Reviews for Selsun Blue - Add your own review/rating

Compare Selsun Blue with other medications

• Dandruff
• Seborrheic Dermatitis

Noxafil

Generic Name: posaconazole (Oral route)

poe-sa-KON-a-zole

Commonly used brand name(s)

In the U.S.

• Noxafil

Available Dosage Forms:

• Suspension

Therapeutic Class: Antifungal

Chemical Class: Triazole

Uses For Noxafil

Posaconazole is used to prevent certain fungus infections in patients 13 years of age and older, who have a weakened immune system (e.g., hematopoietic stem cell transplant or HSCT recipients, or patients with blood cancers). Posaconazole is also used to treat a fungus infection of the mouth or throat called oral thrush (candidiasis). This medicine may be used as an initial treatment or after treatment with other antifungal medicines (e.g., itraconazole or fluconazole) have failed.

This medicine is available only with your doctor's prescription.

Before Using Noxafil

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

Allergies

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

Pediatric

Appropriate studies performed to date have not demonstrated pediatric-specific problems that would limit the usefulness of posaconazole in children and teenagers 13 to 17 years of age. However, safety and efficacy have not been established in children younger than 13 years of age.

Geriatric

Appropriate studies performed to date have not demonstrated geriatric-specific problems that would limit the usefulness of posaconazole in the elderly.

Pregnancy

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

Breast Feeding

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

Interactions with Medicines

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

Using this medicine with any of the following medicines is not recommended. Your doctor may decide not to treat you with this medication or change some of the other medicines you take.

• Alfuzosin


• Amiodarone


• Astemizole


• Cisapride


• Clarithromycin


• Clozapine


• Crizotinib


• Dasatinib


• Dihydroergotamine


• Disopyramide


• Dofetilide


• Dronedarone


• Ergoloid Mesylates


• Ergonovine


• Ergotamine


• Erythromycin


• Halofantrine


• Iloperidone


• Lapatinib


• Lopinavir


• Lumefantrine


• Mefloquine


• Mesoridazine


• Methadone


• Methylergonovine


• Methysergide


• Nilotinib


• Ondansetron


• Pazopanib


• Pimozide


• Propafenone


• Quetiapine


• Quinidine


• Quinine


• Ranolazine


• Salmeterol


• Saquinavir


• Simvastatin


• Sirolimus


• Solifenacin


• Sorafenib


• Sparfloxacin


• Sunitinib


• Telithromycin


• Terfenadine


• Thioridazine


• Toremifene


• Trazodone


• Vardenafil


• Vemurafenib


• Voriconazole


• Ziprasidone

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

• Amitriptyline


• Amoxapine


• Apomorphine


• Arsenic Trioxide


• Asenapine


• Atorvastatin


• Azithromycin


• Boceprevir


• Chloroquine


• Chlorpromazine


• Cimetidine


• Ciprofloxacin


• Citalopram


• Clomipramine


• Cyclosporine


• Desipramine


• Dolasetron


• Droperidol


• Efavirenz


• Etravirine


• Everolimus


• Flecainide


• Fluconazole


• Gatifloxacin


• Gemifloxacin


• Granisetron


• Haloperidol


• Ibutilide


• Imipramine


• Levofloxacin


• Lovastatin


• Midazolam


• Moxifloxacin


• Norfloxacin


• Nortriptyline


• Octreotide


• Ofloxacin


• Paliperidone


• Perflutren Lipid Microsphere


• Phenytoin


• Procainamide


• Prochlorperazine


• Promethazine


• Protriptyline


• Rifabutin


• Rifampin


• Rivaroxaban


• Ruxolitinib


• Sodium Phosphate


• Sodium Phosphate, Dibasic


• Sodium Phosphate, Monobasic


• Sotalol


• Tacrolimus


• Telavancin


• Tetrabenazine


• Trifluoperazine


• Trimipramine


• Vandetanib


• Vinblastine


• Vincristine


• Vincristine Liposome


• Vinorelbine

Using this medicine with any of the following medicines may cause an increased risk of certain side effects, but using both drugs may be the best treatment for you. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Atazanavir


• Digoxin


• Esomeprazole


• Metoclopramide


• Ritonavir


• Topiramate

Interactions with Food/Tobacco/Alcohol

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Other Medical Problems

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

• Heart disease, history of or


• Heart rhythm problems (e.g., arrhythmia, QT prolongation) or


• Liver disease or


• Mineral imbalance (low potassium, magnesium, or calcium in the blood)—These conditions may cause side effects to become worse.

• Kidney disease, severe—May cause the medicine to not work as well.

Proper Use of Noxafil

This medicine comes with a patient information leaflet. Read and follow these instructions carefully. Talk to your doctor if you have any questions.

Shake the oral suspension well before measuring the dose. Use the dosing spoon in the package to measure the dose. The average household teaspoon may not hold the right amount of liquid. Rinse the measuring spoon with water after using and before storage.

Take this medicine during or right after (within 20 minutes) a full meal or liquid nutritional supplement. This medicine may also be taken with an acidic beverage (e.g., ginger ale).

This medicine works best when there is a constant amount in the blood. To help keep the amount constant, do not miss any doses. Also, it is best to take each dose at the same time every day. If you need help in planning the best time to take your medicine, check with your doctor.

Dosing

The dose of this medicine will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of this medicine. If your dose is different, do not change it unless your doctor tells you to do so.

The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.

• For oral dosage form (suspension):
  
  • For prevention of fungus infections:
    
    • Adults and teenagers—200 milligrams (mg) or 5 milliliters (mL) three times a day.
    
    
    • Children younger than 13 years of age—Use and dose must be determined by your doctor.
    
    
  
  
  • For initial treatment of oral candidiasis:
    
    • Adults and teenagers—100 milligrams (mg) or 2.5 milliliters (mL) two times a day on the first day, then 100 mg or 2.5 mL once a day for 13 days.
    
    
    • Children younger than 13 years of age—Use and dose must be determined by your doctor.
    
    
  
  
  • For treatment of oral candidiasis after failed treatment with itraconazole or fluconazole:
    
    • Adults and teenagers—400 milligrams (mg) or 10 milliliters (mL) two times a day.
    
    
    • Children younger than 13 years of age—Use and dose must be determined by your doctor.
    
    
  
  

Missed Dose

If you miss a dose of this medicine, take it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not double doses.

Storage

Store the medicine in a closed container at room temperature, away from heat, moisture, and direct light. Keep from freezing.

Keep out of the reach of children.

Do not keep outdated medicine or medicine no longer needed.

Ask your healthcare professional how you should dispose of any medicine you do not use.

Precautions While Using Noxafil

It is very important that your doctor check your progress at regular visits. This will allow your doctor to see if the medicine is working properly and to decide if you should continue to take it. Blood tests will be needed to check for unwanted effects.

You should not use ergotamine medicines (e.g., bromocriptine, dihydroergotamine, ergonovine, ergotamine, methylergonovine, methysergide, Ergomar®, Ergotrate®, Methergine®, Migranal®, Parlodel®, or Sansert®), pimozide (Orap®), quinidine (Quinaglute®), simvastatin (Zocor®), or sirolimus (Rapamune®). Using any of them together with this medicine may increase the chance of unwanted effects.

This medicine can cause changes in heart rhythms, such as a condition called QT prolongation. It may change the way your heart beats and cause fainting or serious side effects in some patients. Contact your doctor right away if you have any symptoms of heart rhythm problems, such as fast, pounding, or irregular heartbeats.

Stop using this medicine and check with your doctor right away if you have pain or tenderness in the upper stomach; pale stools; dark urine; loss of appetite; nausea; unusual tiredness or weakness; or yellow eyes or skin. These could be symptoms of a serious liver problem.

Check with your doctor right away if you have severe diarrhea or vomiting while using this medicine.

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

Noxafil Side Effects

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

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

More common

• abdominal or stomach pain


• black, tarry stools


• bleeding gums


• bloody nose


• blurred vision


• body aches or pain


• burning or stinging of the skin


• chills


• confusion


• cough


• cracked lips


• decreased urine


• diarrhea


• difficult or labored breathing


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


• drowsiness


• dry mouth


• dry or sore throat


• ear congestion


• feeling unusually cold


• fever


• flushed, dry skin


• fruit-like breath odor


• headache


• heavy non-menstrual vaginal bleeding


• increased hunger


• increased thirst


• increased urination


• irregular heartbeats


• loss of appetite


• loss of voice


• mood changes


• muscle pain


• muscle spasms or twitching


• nasal congestion


• nausea or vomiting


• numbness or tingling in the hands, feet, lips, mouth, or fingertips


• painful cold sores or blisters on the lips, nose, eyes, or genitals


• painful or difficult urination


• pale skin


• pounding in the ears


• runny nose


• shivering


• slow or fast heartbeat


• small red or purple spots on the skin


• sneezing


• sores, ulcers, or white spots on the lips, tongue, or inside mouth


• sweating


• tender, swollen glands in the neck


• tightness in the chest


• trembling


• trouble with swallowing


• unexplained weight loss


• yellow eyes or skin

Less common

• Fainting


• irregular heartbeat, recurrent

Incidence not known

• Anxiety


• change in mental status


• chest pain or discomfort


• darkening of the skin


• difficulty speaking


• itching


• mental depression


• seizures


• skin rash


• sudden shortness of breath or troubled breathing


• swelling of the eyes or eyelids


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


• weakness

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

More common

• Acid or sour stomach


• back pain


• belching


• bone pain


• difficulty having a bowel movement (stool)


• difficulty with moving


• heartburn


• indigestion


• muscle stiffness


• pain in the joints


• sleeplessness


• stomach discomfort or upset


• trouble sleeping


• unable to sleep


• weight loss

Less common

• Bad, unusual, or unpleasant (after) taste


• change in taste

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

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

See also: Noxafil side effects (in more detail)

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More Noxafil resources

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

• Noxafil Prescribing Information (FDA)


• Noxafil Consumer Overview


• Noxafil Monograph (AHFS DI)


• Noxafil Suspension MedFacts Consumer Leaflet (Wolters Kluwer)


• Posaconazole Professional Patient Advice (Wolters Kluwer)

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