Ichthocortin may be available in the countries listed below.
Hydrocortisone 21-acetate (a derivative of Hydrocortisone) is reported as an ingredient of Ichthocortin in the following countries:
Ichthammol sodium salt, decolorized (a derivative of Ichthammol) is reported as an ingredient of Ichthocortin in the following countries:
International Drug Name Search
To reduce the development of drug-resistant bacteria and maintain the effectiveness of TIMENTIN (ticarcillin disodium and clavulanate potassium) and other antibacterial drugs, TIMENTIN should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria.
TIMENTIN is a sterile injectable antibacterial combination consisting of the semisynthetic antibiotic ticarcillin disodium, and the β-lactamase inhibitor clavulanate potassium (the potassium salt of clavulanic acid) for intravenous administration. Ticarcillin is derived from the basic penicillin nucleus, 6-amino-penicillanic acid.
Chemically, ticarcillin disodium is N-(2-Carboxy-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-6-yl)-3-thiophenemalonamic acid disodium salt and may be represented as:
Clavulanic acid is produced by the fermentation of Streptomyces clavuligerus . It is a β-lactam structurally related to the penicillins and possesses the ability to inactivate a wide variety of β-lactamases by blocking the active sites of these enzymes. Clavulanic acid is particularly active against the clinically important plasmid-mediated β-lactamases frequently responsible for transferred drug resistance to penicillins and cephalosporins.
Chemically, clavulanate potassium is potassium (Z)-(2R ,5R)-3-(2-hydroxyethylidene)-7-oxo-4-oxa-1-azabicyclo[3.2.0]heptane-2-carboxylate and may be represented structurally as:
TIMENTIN is supplied as a white to pale yellow powder for reconstitution. TIMENTIN is very soluble in water, its solubility being greater than 600 mg/mL. The reconstituted solution is clear, colorless or pale yellow, having a pH of 5.5 to 7.5.
For the 3.1-gram dosage of TIMENTIN, the theoretical sodium content is 4.51 mEq (103.6 mg) per gram of TIMENTIN. The theoretical potassium content is 0.15 mEq (6 mg) per gram of TIMENTIN.
After an intravenous infusion (30 min.) of 3.1 grams of TIMENTIN, peak serum concentrations of both ticarcillin and clavulanic acid are attained immediately after completion of infusion. Ticarcillin serum levels are similar to those produced by the administration of equivalent amounts of ticarcillin alone with a mean peak serum level of 330 mcg/mL. The corresponding mean peak serum level for clavulanic acid was 8 mcg/mL. (See following table.)
SERUM LEVELS IN ADULTS
AFTER A 30-MINUTE IV INFUSION OF TIMENTIN®
TICARCILLIN SERUM LEVELS (mcg/mL)
Dose | 0 | 15 min. | 30 min. | 1 hr. | 1.5 hr. | 3.5 hr. | 5.5 hr. |
3.1 gram | 324 | 223 | 176 | 131 | 90 | 27 | 6 |
(293 to 388) | (184 to 293) | (135 to 235) | (102 to 195) | (65 to 119) | (19 to 37) | (5 to 7) |
CLAVULANIC ACID SERUM LEVELS (mcg/mL)
Dose | 0 | 15 min. | 30 min. | 1 hr. | 1.5 hr. | 3.5 hr. | 5.5 hr. |
3.1 gram | 8.0 | 4.6 | 2.6 | 1.8 | 1.2 | 0.3 | 0 |
(5.3 to 10.3) | (3.0 to 7.6) | (1.8 to 3.4) | (1.6 to 2.2) | (0.8 to 1.6) | (0.2 to 0.3) |
The mean area under the serum concentration curve was 485 mcg•hr/mL for ticarcillin and 8.2 mcg•hr/mL for clavulanic acid.
The mean serum half-lives of ticarcillin and clavulanic acid in healthy volunteers are 1.1 hours and 1.1 hours, respectively.
In pediatric patients receiving approximately 50 mg/kg of TIMENTIN (30:1 ratio ticarcillin to clavulanate), mean ticarcillin serum half-lives were 4.4 hours in neonates (n = 18) and 1.0 hour in infants and children (n = 41). The corresponding clavulanate serum half-lives averaged 1.9 hours in neonates (n = 14) and 0.9 hour in infants and children (n = 40). Area under the serum concentration time curves averaged 339 mcg•hr/mL in infants and children (n = 41), whereas the corresponding mean clavulanate area under the serum concentration time curves was approximately 7 mcg•hr/mL in the same population (n = 40).
Approximately 60% to 70% of ticarcillin and approximately 35% to 45% of clavulanic acid are excreted unchanged in urine during the first 6 hours after administration of a single dose of TIMENTIN to normal volunteers with normal renal function. Two hours after an intravenous injection of 3.1 grams of TIMENTIN, concentrations of ticarcillin in urine generally exceed 1,500 mcg/mL. The corresponding concentrations of clavulanic acid in urine generally exceed 40 mcg/mL. By 4 to 6 hours after injection, the urine concentrations of ticarcillin and clavulanic acid usually decline to approximately 190 mcg/mL and 2 mcg/mL, respectively. Neither component of TIMENTIN is highly protein bound; ticarcillin has been found to be approximately 45% bound to human serum protein and clavulanic acid approximately 25% bound.
Somewhat higher and more prolonged serum levels of ticarcillin can be achieved with the concurrent administration of probenecid; however, probenecid does not enhance the serum levels of clavulanic acid.
Ticarcillin can be detected in tissues and interstitial fluid following parenteral administration.
Penetration of ticarcillin into bile and pleural fluid has been demonstrated. The results of experiments involving the administration of clavulanic acid to animals suggest that this compound, like ticarcillin, is well distributed in body tissues.
An inverse relationship exists between the serum half-life of ticarcillin and creatinine clearance. The dosage of TIMENTIN need only be adjusted in cases of severe renal impairment. (See DOSAGE AND ADMINISTRATION.)
Ticarcillin may be removed from patients undergoing dialysis; the actual amount removed depends on the duration and type of dialysis.
Ticarcillin is a semisynthetic antibiotic with a broad spectrum of bactericidal activity against many gram-positive and gram-negative aerobic and anaerobic bacteria.
Ticarcillin is, however, susceptible to degradation by β-lactamases, and therefore, the spectrum of activity does not normally include organisms which produce these enzymes.
Clavulanic acid is a β-lactam, structurally related to the penicillins, which possesses the ability to inactivate a wide range of β-lactamase enzymes commonly found in microorganisms resistant to penicillins and cephalosporins. In particular, it has good activity against the clinically important plasmid-mediated β-lactamases frequently responsible for transferred drug resistance.
The formulation of ticarcillin with clavulanic acid in TIMENTIN protects ticarcillin from degradation by β-lactamase enzymes and effectively extends the antibiotic spectrum of ticarcillin to include many bacteria normally resistant to ticarcillin and other β-lactam antibiotics. Thus, TIMENTIN possesses the distinctive properties of a broad-spectrum antibiotic and a β-lactamase inhibitor. Ticarcillin/clavulanic acid 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.
Staphylococcus aureus (β-lactamase and non−β-lactamase−producing)*
Staphylococcus epidermidis (β-lactamase and non−β-lactamase−producing)*
*Staphylococci that are resistant to methicillin/oxacillin must be considered resistant to ticarcillin/clavulanic acid.
Citrobacter species (β-lactamase and non−β-lactamase−producing)
Enterobacter species including E. cloacae (β-lactamase and non−β-lactamase−producing)
(Although most strains of Enterobacter species are resistant in vitro, clinical efficacy has been demonstrated with TIMENTIN in urinary tract infections and gynecologic infections caused by these organisms.)
Escherichia coli (β-lactamase and non−β-lactamase−producing)
Haemophilus influenzae (β-lactamase and non−β-lactamase−producing)†
Klebsiella species including K. pneumoniae (β-lactamase and non−β-lactamase−producing)
Pseudomonas species including P. aeruginosa (β-lactamase and non−β-lactamase−producing)
Serratia marcescens (β-lactamase and non−β-lactamase−producing)
†β-lactamase−negative, ampicillin-resistant (BLNAR) strains of H. influenzae must be considered resistant to ticarcillin/clavulanic acid.
Bacteroides fragilis group (β-lactamase and non−β-lactamase−producing)
Prevotella (formerly Bacteroides ) melaninogenicus (β-lactamase and non−β-lactamase−producing)
The following in vitro data are available, but their clinical significance is unknown.
The following strains exhibit an in vitro minimum inhibitory concentration (MIC) less than or equal to the susceptible breakpoint for ticarcillin/clavulanic acid. However, with the exception of organisms shown to respond to ticarcillin alone, the safety and effectiveness of ticarcillin/clavulanic acid in treating infections due to these microorganisms have not been established in adequate and well-controlled clinical trials.
Staphylococcus saprophyticus (β-lactamase and non−β-lactamase− producing)
Streptococcus agalactiae‡ (Group B)
Streptococcus bovis‡
Streptococcus pneumoniae‡ (penicillin-susceptible strains only)
Streptococcus pyogenes‡
Viridans group streptococci‡
Acinetobacter baumannii (β-lactamase and non−β-lactamase−producing)
Acinetobacter calcoaceticus (β-lactamase and non−β-lactamase−producing)
Acinetobacter haemolyticus (β-lactamase and non−β-lactamase−producing)
Acinetobacter lwoffi (β-lactamase and non−β-lactamase−producing)
Moraxella catarrhalis (β-lactamase and non−β-lactamase−producing)
Morganella morganii (β-lactamase and non−β-lactamase−producing)
Neisseria gonorrhoeae (β-lactamase and non−β-lactamase−producing)
Pasteurella multocida (β-lactamase and non−β-lactamase−producing)
Proteus mirabilis (β-lactamase and non−β-lactamase−producing)
Proteus penneri (β-lactamase and non−β-lactamase−producing)
Proteus vulgaris (β-lactamase and non−β-lactamase−producing)
Providencia rettgeri (β-lactamase and non−β-lactamase−producing)
Providencia stuartii (β-lactamase and non−β-lactamase−producing)
Stenotrophomonas maltophilia (β-lactamase and non−β-lactamase−producing)
Clostridium species including C. perfringens , C. difficile, C. sporogenes, C. ramosum, and C. bifermentans (β-lactamase and non−β-lactamase−producing)
Eubacterium species
Fusobacterium species including F. nucleatum and F. necrophorum (β-lactamase and non−β-lactamase−producing)
Peptostreptococcus species‡
Veillonella species‡
‡These are non−β-lactamase−producing strains, and therefore, are susceptible to ticarcillin.
In vitro synergism between TIMENTIN and gentamicin, tobramycin, or amikacin against multiresistant strains of Pseudomonas aeruginosa has been demonstrated.
Quantitative methods are used to determine antimicrobial 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 a dilution method1,3 (broth or agar) or equivalent with standardized inoculum concentrations and standardized concentrations of ticarcillin/clavulanate potassium powder.
The recommended dilution pattern utilizes a constant level of 2 mcg/mL clavulanic acid in all tubes with varying amounts of ticarcillin. MICs are expressed in terms of the ticarcillin concentration in the presence of clavulanic acid at a constant 2 mcg/mL. The MIC values should be interpreted according to the following criteria:
RECOMMENDED RANGES FOR TICARCILLIN/CLAVULANIC ACID SUSCEPTIBILITY TESTING*
For Pseudomonas aeruginosa:
MIC (mcg/mL) | Interpretation |
≤64 | Susceptible (S) |
≥128 | Resistant (R) |
For Enterobacteriaceae:
MIC (mcg/mL) | Interpretation |
≤16 | Susceptible (S) |
32-64 | Intermediate (I) |
≥128 | Resistant (R) |
For Staphylococci†:
MIC (mcg/mL) | Interpretation |
≤8 | Susceptible (S) |
≥16 | Resistant (R) |
* Expressed as concentration of ticarcillin in the presence of clavulanic acid at a constant 2 mcg/mL.
†Staphylococci that are susceptible to ticarcillin/clavulanic acid but resistant to methicillin/oxacillin must be considered as resistant.
A report of “Susceptible” indicates that the pathogen is likely to be inhibited if the antimicrobial compound in the blood reaches the concentrations 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 that 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 concentrations 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 ticarcillin/clavulanate potassium powder should provide the following MIC values3:
Microorganism | MIC (mcg/mL)‡ | |
Escherichia coli | ATCC 25922 | 4-16 |
Escherichia coli | ATCC 35218 | 8-32 |
Pseudomonas aeruginosa | ATCC 27853 | 8-32 |
Staphylococcus aureus | ATCC 29213 | 0.5-2 |
‡ Expressed as concentration of ticarcillin in the presence of clavulanic acid at a constant 2 mcg/mL.
Quantitative methods that require measurement of zone diameters also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. One such standardized procedure2,3 requires the use of standardized inoculum concentrations. This procedure uses paper disks impregnated with 85 mcg of ticarcillin/clavulanate potassium (75 mcg ticarcillin plus 10 mcg clavulanate potassium) to test the susceptibility of microorganisms to ticarcillin/clavulanic acid.
Reports from the laboratory providing results of the standard single-disk susceptibility test with an 85 mcg of ticarcillin/clavulanate potassium (75 mcg ticarcillin plus 10 mcg clavulanate potassium) disk should be interpreted according to the following criteria:
RECOMMENDED RANGES FOR TICARCILLIN/CLAVULANIC ACID SUSCEPTIBILITY TESTING
For Pseudomonas aeruginosa:
Zone Diameter (mm) | Interpretation |
≥15 | Susceptible (S) |
≤14 | Resistant (R) |
For Enterobacteriaceae:
Zone Diameter (mm) | Interpretation |
≥20 | Susceptible (S) |
15-19 | Intermediate (I) |
≤14 | Resistant (R) |
For Staphylococci§:
Zone Diameter (mm) | Interpretation |
≥23 | Susceptible (S) |
≤22 | Resistant (R) |
§Staphylococci that are resistant to methicillin/oxacillin must be considered as resistant to ticarcillin/clavulanic acid.
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 ticarcillin/clavulanic acid.
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 85 mcg of ticarcillin/clavulanate potassium (75 mcg ticarcillin plus 10 mcg clavulanate potassium) disk should provide the following zone diameters in these laboratory test quality control strains:
Microorganism | Zone Diameter (mm) | |
Escherichia coli | ATCC 25922 | 24-30 |
Escherichia coli | ATCC 35218 | 21-25 |
Pseudomonas aeruginosa | ATCC 27853 | 20-28 |
Staphylococcus aureus | ATCC 25923 | 29-37 |
For anaerobic bacteria, the susceptibility to ticarcillin/clavulanic acid can be determined by standardized test methods.3,4 The MIC values obtained should be interpreted according to the following criteria:
RECOMMENDED RANGES FOR TICARCILLIN/CLAVULANIC ACID SUSCEPTIBILITY TESTING||
MIC (mcg/mL) | Interpretation |
≤32 | Susceptible (S) |
64 | Intermediate (I) |
≥128 | Resistant (R) |
||Expressed as concentration of ticarcillin in the presence of clavulanic acid at a constant 2 mcg/mL.
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 ticarcillin/clavulanate potassium powder should provide the following MIC values:
Agar dilution | Broth microdilution | ||
MIC Range | MIC Range | ||
Microorganism | (mcg/mL) || | (mcg/mL) ║ | |
Bacteroides thetaiotaomicron | ATCC 29741 | 0.5-2 | 0.5-2 |
Eubacterium lentum | ATCC 43055 | 16-64 | 8-32 |
║Expressed as concentration of ticarcillin in the presence of clavulanic acid at a constant 2 mcg/mL.
TIMENTIN is indicated in the treatment of infections caused by susceptible strains of the designated microorganisms in the conditions listed below:
Septicemia (including bacteremia) caused by β-lactamase−producing strains of Klebsiella spp.*, E. coli *, S. aureus*, or P. aeruginosa * (or other Pseudomonas species*)
Lower Respiratory Infections caused by β-lactamase−producing strains of S. aureus, H. influenzae *, or Klebsiella spp.*
Bone and Joint Infections caused by β-lactamase−producing strains of S. aureus
Skin and Skin Structure Infections caused by β-lactamase−producing strains of S. aureus, Klebsiella spp.*, or E. coli*
Urinary Tract Infections (complicated and uncomplicated) caused by β-lactamase−producing strains of E. coli , Klebsiella spp., P. aeruginosa* (or other Pseudomonas spp.*), Citrobacter spp.*, Enterobacter cloacae *, S. marcescens*, or S. aureus*
Gynecologic Infections endometritis caused by β-lactamase−producing strains of P. melaninogenicus*, Enterobacter spp. (including E. cloacae*), E. coli, K. pneumoniae*, S. aureus , or S. epidermidis
Intra-abdominal Infections peritonitis caused by β-lactamase−producing strains of E. coli, K. pneumoniae, or B. fragilis* group
*Efficacy for this organism in this organ system was studied in fewer than 10 infections.
NOTE: For information on use in pediatric patients (≥3 months of age) see PRECAUTIONS-Pediatric Use and CLINICAL STUDIES sections. There are insufficient data to support the use of TIMENTIN in pediatric patients under 3 months of age or for the treatment of septicemia and/or infections in the pediatric population where the suspected or proven pathogen is H. influenzae type b.
While TIMENTIN is indicated only for the conditions listed above, infections caused by ticarcillin-susceptible organisms are also amenable to treatment with TIMENTIN due to its ticarcillin content. Therefore, mixed infections caused by ticarcillin-susceptible organisms and β-lactamase−producing organisms susceptible to ticarcillin/clavulanic acid should not require the addition of another antibiotic.
Appropriate culture and susceptibility tests should be performed before treatment in order to isolate and identify organisms causing infection and to determine their susceptibility to ticarcillin/clavulanic acid. Because of its broad spectrum of bactericidal activity against gram-positive and gram-negative bacteria, TIMENTIN is particularly useful for the treatment of mixed infections and for presumptive therapy prior to the identification of the causative organisms. TIMENTIN has been shown to be effective as single drug therapy in the treatment of some serious infections where normally combination antibiotic therapy might be employed. Therapy with TIMENTIN may be initiated before results of such tests are known when there is reason to believe the infection may involve any of the β-lactamase−producing organisms listed above.
Based on the in vitro synergism between ticarcillin/clavulanic acid and aminoglycosides against certain strains of P. aeruginosa, combined therapy has been successful, especially in patients with impaired host defenses. Both drugs should be used in full therapeutic doses.
To reduce the development of drug-resistant bacteria and maintain the effectiveness of TIMENTIN and other antibacterial drugs, TIMENTIN should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.
TIMENTIN is contraindicated in patients with a history of hypersensitivity reactions to any of the penicillins.
SERIOUS AND OCCASIONALLY FATAL HYPERSENSITIVITY (ANAPHYLACTIC) REACTIONS HAVE BEEN REPORTED IN PATIENTS ON PENICILLIN THERAPY. THESE REACTIONS ARE MORE LIKELY TO OCCUR IN INDIVIDUALS WITH A HISTORY OF PENICILLIN HYPERSENSITIVITY AND/OR A HISTORY OF SENSITIVITY TO MULTIPLE ALLERGENS. THERE HAVE BEEN REPORTS OF INDIVIDUALS WITH A HISTORY OF PENICILLIN HYPERSENSITIVITY WHO HAVE EXPERIENCED SEVERE REACTIONS WHEN TREATED WITH CEPHALOSPORINS. BEFORE INITIATING THERAPY WITH TIMENTIN CAREFUL INQUIRY SHOULD BE MADE CONCERNING PREVIOUS HYPERSENSITIVITY REACTIONS TO PENICILLINS, CEPHALOSPORINS, OR OTHER ALLERGENS. IF AN ALLERGIC REACTION OCCURS, TIMENTIN SHOULD BE DISCONTINUED AND THE APPROPRIATE THERAPY INSTITUTED. SERIOUS ANAPHYLACTIC REACTIONS REQUIRE IMMEDIATE EMERGENCY TREATMENT WITH EPINEPHRINE. OXYGEN, INTRAVENOUS STEROIDS, AND AIRWAY MANAGEMENT, INCLUDING INTUBATION, SHOULD ALSO BE PROVIDED AS INDICATED.
Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including TIMENTIN, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile.
C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents.
If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.
When very high doses of TIMENTIN are administered, especially in the presence of impaired renal function, patients may experience convulsions. (See ADVERSE REACTIONS and OVERDOSAGE.)
While TIMENTIN possesses the characteristic low toxicity of the penicillin group of antibiotics, periodic assessment of organ system functions, including renal, hepatic, and hematopoietic function, is advisable during prolonged therapy.
Bleeding manifestations have occurred in some patients receiving β-lactam antibiotics. These reactions have been associated with abnormalities of coagulation tests such as clotting time, platelet aggregation, and prothrombin time and are more likely to occur in patients with renal impairment. If bleeding manifestations appear, treatment with TIMENTIN should be discontinued and appropriate therapy instituted.
TIMENTIN has only rarely been reported to cause hypokalemia; however, the possibility of this occurring should be kept in mind particularly when treating patients with fluid and electrolyte imbalance. Periodic monitoring of serum potassium may be advisable in patients receiving prolonged therapy.
The theoretical sodium content is 4.51 mEq (103.6 mg) per gram of TIMENTIN. This should be considered when treating patients requiring restricted salt intake.
As with any penicillin, an allergic reaction, including anaphylaxis, may occur during administration of TIMENTIN, particularly in a hypersensitive individual.
The possibility of superinfections with mycotic or bacterial pathogens should be kept in mind, particularly during prolonged treatment. If superinfections occur, appropriate measures should be taken.
Prescribing TIMENTIN in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.
Patients should be counseled that antibacterial drugs, including TIMENTIN, should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When TIMENTIN is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may: (1) decrease the effectiveness of the immediate treatment, and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by TIMENTIN or other antibacterial drugs in the future.
Diarrhea is a common problem caused by antibiotics which usually ends when the antibiotic is discontinued. Sometimes after starting treatment with antibiotics, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as 2 or more months after having taken the last dose of the antibiotic. If this occurs, patients should contact their physician as soon as possible.
As with other penicillins, the mixing of TIMENTIN with an aminoglycoside in solutions for parenteral administration can result in substantial inactivation of the aminoglycoside.
Probenecid interferes with the renal tubular secretion of ticarcillin, thereby increasing serum concentrations and prolonging serum half-life of the antibiotic.
In common with other antibiotics, ticarcillin disodium/clavulanate potassium may affect the gut flora, leading to lower estrogen reabsorption and reduced efficacy of combined oral estrogen/progesterone contraceptives.
High urine concentrations of ticarcillin may produce false-positive protein reactions (pseudoproteinuria) with the following methods: Sulfosalicylic acid and boiling test, acetic acid test, biuret reaction and nitric acid test. The bromphenol blue (MULTI-STIX®) reagent strip test has been reported to be reliable.
The presence of clavulanic acid in TIMENTIN may cause a nonspecific binding of IgG and albumin by red cell membranes, leading to a false-positive Coombs test.
Long-term studies in animals have not been performed to evaluate carcinogenic potential. However, results from assays for gene mutation in vitro using bacteria (Ames tests) and yeast, and for chromosomal effects in vitro in human lymphocytes, and in vivo in mouse bone marrow (micronucleus test) indicate that TIMENTIN is without any mutagenic potential.
Reproduction studies have been performed in rats given doses up to 1,050 mg/kg/day and have revealed no evidence of impaired fertility or harm to the fetus due to TIMENTIN. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.
It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when TIMENTIN is administered to a nursing woman.
The safety and effectiveness of TIMENTIN have been established in the age group of 3 months to 16 years. Use of TIMENTIN in these age groups is supported by evidence from adequate and well-controlled studies of TIMENTIN in adults with additional efficacy, safety, and pharmacokinetic data from both comparative and non-comparative studies in pediatric patients. There are insufficient data to support the use of TIMENTIN in pediatric patients under 3 months of age or for the treatment of septicemia and/or infections in the pediatric population where the suspected or proven pathogen is H. influenzae type b.
In those patients in whom meningeal seeding from a distant infection site or in whom meningitis is suspected or documented, or in patients who require prophylaxis against central nervous system infection, an alternate agent with demonstrated clinical efficacy in this setting should be used.
An analysis of clinical studies of TIMENTIN was conducted to determine whether subjects aged 65 and over respond differently from younger subjects. Of the 1,078 subjects treated with at least one dose of TIMENTIN, 67.5% were <65 years old, and 32.5% were ≥65 years old. No overall differences in safety or efficacy were observed between these subjects and younger subjects, and other reported clinical experience have not identified differences in responses between the elderly and younger patients, but a greater sensitivity of some older individuals cannot be ruled out.
This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function (see DOSAGE and ADMINISTRATION).
TIMENTIN contains 103.6 mg (4.51 mEq) of sodium per gram of TIMENTIN. At the usual recommended doses, patients would receive between 1,285 and 1,927 mg/day (56 and 84 mEq) of sodium. The geriatric population may respond with a blunted natriuresis to salt loading. This may be clinically important with regard to such diseases as congestive heart failure.
As with other penicillins, the following adverse reactions may occur:
Skin rash, pruritus, urticaria, arthralgia, myalgia, drug fever, chills, chest discomfort, erythema multiforme, toxic epidermal necrolysis, Stevens-Johnson syndrome, and anaphylactic reactions.
Headache, giddiness, neuromuscular hyperirritability, or convulsive seizures.
Disturbances of taste and smell, stomatitis, flatulence, nausea, vomiting and diarrhea, epigastric pain, and pseudomembranous colitis have been reported. Onset of pseudomembranous colitis symptoms may occur during or after antibiotic treatment. (See WARNINGS.)
Thrombocytopenia, leukopenia, neutropenia, eosinophilia, reduction of hemoglobin or hematocrit, and prolongation of prothrombin time and bleeding time.
Elevation of serum aspartate aminotransferase (SGOT), serum alanine aminotransferase (SGPT), serum alkaline phosphatase, serum LDH, serum bilirubin. There have been reports of transient hepatitis and cholestatic jaundice—as with some other penicillins and some cephalosporins.
Hemorrhagic cystitis, elevation of serum creatinine and/or BUN, hypernatremia, reduction in serum potassium and uric acid.
Pain, burning, swelling, and induration at the injection site and thrombophlebitis with intravenous administration.
Available safety data for pediatric patients treated with TIMENTIN demonstrate a similar adverse event profile to that observed in adult patients.
Neither abuse of nor dependence on TIMENTIN has been reported.
As with other penicillins, neurotoxic reactions may arise when very high doses of TIMENTIN are administered, especially in patients with impaired renal function. (See WARNINGS and ADVERSE REACTIONS-Central Nervous System.)
In case of overdosage, discontinue TIMENTIN, treat symptomatically, and institute supportive measures as required. Ticarcillin may be removed from circulation by hemodialysis. The molecular weight, degree of protein binding, and pharmacokinetic profile of clavulanic acid, together with information from a single patient with renal insufficiency all suggest that this compound may also be removed by hemodialysis.
TIMENTIN should be administered by intravenous infusion (30 min.).
The usual recommended dosage for systemic and urinary tract infections for average (60 kg) adults is 3.1 grams of TIMENTIN (3.1-gram vial containing 3 grams ticarcillin and 100 mg clavulanic acid) given every 4 to 6 hours. For gynecologic infections, TIMENTIN should be administered as follows: Moderate infections 200 mg/kg/day in divided doses every 6 hours and for severe infections 300 mg/kg/day in divided doses every 4 hours. For patients weighing less than 60 kg, the recommended dosage is 200 to 300 mg/kg/day, based on ticarcillin content, given in divided doses every 4 to 6 hours.
In patients <60 kg, TIMENTIN is dosed at 50 mg/kg/dose based on the ticarcillin component. TIMENTIN should be administered as
Zolpidem tartrate tablets are indicated for the short-term treatment of insomnia characterized by difficulties with sleep initiation. Zolpidem tartrate tablets have been shown to decrease sleep latency for up to 35 days in controlled clinical studies [see Clinical Studies (14)].
The clinical trials performed in support of efficacy were 4 to 5 weeks in duration with the final formal assessments of sleep latency performed at the end of treatment.
The dose of Zolpidem tartrate tablets should be individualized.
The recommended dose for adults is 10 mg once daily immediately before bedtime. The total Zolpidem tartrate tablets dose should not exceed 10 mg per day.
Elderly or debilitated patients may be especially sensitive to the effects of Zolpidem tartrate tablets. Patients with hepatic insufficiency do not clear the drug as rapidly as normal subjects. The recommended dose of Zolpidem tartrate tablets in both of these patient populations is 5 mg once daily immediately before bedtime [see Warningsand Precautions (5.6)].
Dosage adjustment may be necessary when Zolpidem tartrate tablets are combined with other CNS depressant drugs because of the potentially additive effects [see Warnings and Precautions(5.5)].
The effect of Zolpidem tartrate tablets may be slowed by ingestion with or immediately after a meal.
Zolpidem tartrate tablets are available in 5 mg and 10 mg strength tablets for oral administration. Tablets are not scored.
Zolpidem tartrate tablets, 5 mg are pink, film-coated, round tablets; debossed "TEVA" on one side and "73" on the other.
Zolpidem tartrate tablets, 10 mg are white to off-white, film-coated, round tablets; debossed "TEVA" on one side and "74" on the other.
Zolpidem tartrate tablets are contraindicated in patients with known hypersensitivity to Zolpidem tartrate or to any of the inactive ingredients in the formulation. Observed reactions include anaphylaxis and angioedema [see Warnings and Precautions (5.2)].
Because sleep disturbances may be the presenting manifestation of a physical and/or psychiatric disorder, symptomatic treatment of insomnia should be initiated only after a careful evaluation of the patient. The failure of insomnia to remit after 7 to 10 days of treatment may indicate the presence of a primary psychiatric and/or medical illness that should be evaluated. Worsening of insomnia or the emergence of new thinking or behavior abnormalities may be the consequence of an unrecognized psychiatric or physical disorder. Such findings have emerged during the course of treatment with sedative/hypnotic drugs, including Zolpidem.
Rare cases of angioedema involving the tongue, glottis or larynx have been reported in patients after taking the first or subsequent doses of sedative-hypnotics, including Zolpidem. Some patients have had additional symptoms such as dyspnea, throat closing or nausea and vomiting that suggest anaphylaxis. Some patients have required medical therapy in the emergency department. If angioedema involves the throat, glottis or larynx, airway obstruction may occur and be fatal. Patients who develop angioedema after treatment with Zolpidem should not be rechallenged with the drug.
A variety of abnormal thinking and behavior changes have been reported to occur in association with the use of sedative/hypnotics. Some of these changes may be characterized by decreased inhibition (e.g., aggressiveness and extroversion that seemed out of character), similar to effects produced by alcohol and other CNS depressants. Visual and auditory hallucinations have been reported as well as behavioral changes such as bizarre behavior, agitation and depersonalization. In controlled trials, < 1% of adults with insomnia who received Zolpidem reported hallucinations. In a clinical trial, 7.4% of pediatric patients with insomnia associated with attention-deficit/hyperactivity disorder (ADHD), who received Zolpidem reported hallucinations [see Use in Specific Populations (8.4)].
Complex behaviors such as “sleep-driving” (i.e., driving while not fully awake after ingestion of a sedative-hypnotic, with amnesia for the event) have been reported with sedative-hypnotics, including Zolpidem. These events can occur in sedative-hypnotic-naive as well as in sedative-hypnotic-experienced persons. Although behaviors such as “sleep-driving” may occur with Zolpidem tartrate tablets alone at therapeutic doses, the use of alcohol and other CNS depressants with Zolpidem tartrate tablets appears to increase the risk of such behaviors, as does the use of Zolpidem tartrate tablets at doses exceeding the maximum recommended dose. Due to the risk to the patient and the community, discontinuation of Zolpidem tartrate tablets should be strongly considered for patients who report a “sleep-driving” episode. Other complex behaviors (e.g., preparing and eating food, making phone calls, or having sex) have been reported in patients who are not fully awake after taking a sedative-hypnotic. As with “sleep-driving”, patients usually do not remember these events. Amnesia, anxiety and other neuro-psychiatric symptoms may occur unpredictably.
In primarily depressed patients, worsening of depression, including suicidal thoughts and actions (including completed suicides), has been reported in association with the use of sedative/hypnotics.
It can rarely be determined with certainty whether a particular instance of the abnormal behaviors listed above is drug induced, spontaneous in origin, or a result of an underlying psychiatric or physical disorder. Nonetheless, the emergence of any new behavioral sign or symptom of concern requires careful and immediate evaluation.
Following the rapid dose decrease or abrupt discontinuation of sedative/hypnotics, there have been reports of signs and symptoms similar to those associated with withdrawal from other CNS-depressant drugs [see Drug Abuse and Dependence (9)].
Zolpidem tartrate tablets, like other sedative/hypnotic drugs, have CNS-depressant effects. Due to the rapid onset of action, Zolpidem tartrate tablets should only be taken immediately prior to going to bed. Patients should be cautioned against engaging in hazardous occupations requiring complete mental alertness or motor coordination such as operating machinery or driving a motor vehicle after ingesting the drug, including potential impairment of the performance of such activities that may occur the day following ingestion of Zolpidem tartrate tablets. Zolpidem tartrate tablets showed additive effects when combined with alcohol and should not be taken with alcohol. Patients should also be cautioned about possible combined effects with other CNS-depressant drugs. Dosage adjustments may be necessary when Zolpidem tartrate tablets are administered with such agents because of the potentially additive effects.
Use in the elderly and/or debilitated patients: Impaired motor and/or cognitive performance after repeated exposure or unusual sensitivity to sedative/hypnotic drugs is a concern in the treatment of elderly and/or debilitated patients. Therefore, the recommended Zolpidem tartrate tablets dosage is 5 mg in such patients to decrease the possibility of side effects [see Dosage andAdministration (2.2)]. These patients should be closely monitored.
Use in patients with concomitant illness: Clinical experience with Zolpidem tartrate tablets in patients with concomitant systemic illness is limited. Caution is advisable in using Zolpidem tartrate tablets in patients with diseases or conditions that could affect metabolism or hemodynamic responses.
Although studies did not reveal respiratory depressant effects at hypnotic doses of Zolpidem in normal subjects or in patients with mild to moderate chronic obstructive pulmonary disease (COPD), a reduction in the Total Arousal Index together with a reduction in lowest oxygen saturation and increase in the times of oxygen desaturation below 80% and 90% was observed in patients with mild-to-moderate sleep apnea when treated with Zolpidem tartrate tablets (10 mg) when compared to placebo. Since sedative/hypnotics have the capacity to depress respiratory drive, precautions should be taken if Zolpidem tartrate tablets are prescribed to patients with compromised respiratory function. Postmarketing reports of respiratory insufficiency, most of which involved patients with preexisting respiratory impairment, have been received. Zolpidem tartrate tablets should be used with caution in patients with sleep apnea syndrome or myasthenia gravis.
Data in end-stage renal failure patients repeatedly treated with Zolpidem tartrate tablets did not demonstrate drug accumulation or alterations in pharmacokinetic parameters. No dosage adjustment in renally impaired patients is required; however, these patients should be closely monitored [see Clinical Pharmacology (12.3)].
A study in subjects with hepatic impairment did reveal prolonged elimination in this group; therefore, treatment should be initiated with 5 mg in patients with hepatic compromise, and they should be closely monitored [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3)].
Use in patients with depression: As with other sedative/hypnotic drugs, Zolpidem tartrate tablets should be administered with caution to patients exhibiting signs or symptoms of depression. Suicidal tendencies may be present in such patients and protective measures may be required. Intentional over-dosage is more common in this group of patients; therefore, the least amount of drug that is feasible should be prescribed for the patient at any one time.
Use in pediatric patients: Safety and effectiveness of Zolpidem have not been established in pediatric patients. In an 8 week study in pediatric patients (aged 6 to 17 years) with insomnia associated with ADHD, Zolpidem did not decrease sleep latency compared to placebo. Hallucinations were reported in 7.4% of the pediatric patients who received Zolpidem; none of the pediatric patients who received placebo reported hallucinations [see Use in Specific Populations (8.4)].
The following serious adverse reactions are discussed in greater detail in other sections of the labeling:
Associated with discontinuation of treatment: Approximately 4% of 1,701 patients who received Zolpidem at all doses (1.25 to 90 mg) in U.S. premarketing clinical trials discontinued treatment because of an adverse reaction. Reactions most commonly associated with discontinuation from U.S. trials were daytime drowsiness (0.5%), dizziness (0.4%), headache (0.5%), nausea (0.6%), and vomiting (0.5%).
Approximately 4% of 1,959 patients who received Zolpidem at all doses (1 to 50 mg) in similar foreign trials discontinued treatment because of an adverse reaction. Reactions most commonly associated with discontinuation from these trials were daytime drowsiness (1.1%), dizziness/vertigo (0.8%), amnesia (0.5%), nausea (0.5%), headache (0.4%), and falls (0.4%).
Data from a clinical study in which selective serotonin reuptake inhibitor (SSRI)-treated patients were given Zolpidem revealed that four of the seven discontinuations during double-blind treatment with Zolpidem (n = 95) were associated with impaired concentration, continuing or aggravated depression, and manic reaction; one patient treated with placebo (n = 97) was discontinued after an attempted suicide.
Most commonly observed adverse reactions in controlled trials: During short-term treatment (up to 10 nights) with Zolpidem tartrate tablets at doses up to 10 mg, the most commonly observed adverse reactions associated with the use of Zolpidem and seen at statistically significant differences from placebo-treated patients were drowsiness (reported by 2% of Zolpidem patients), dizziness (1%), and diarrhea (1%). During longer-term treatment (28 to 35 nights) with Zolpidem at doses up to 10 mg, the most commonly observed adverse reactions associated with the use of Zolpidem and seen at statistically significant differences from placebo-treated patients were dizziness (5%) and drugged feelings (3%).
Adverse reactions observed at an incidence of ≥ 1% in controlled trials: The following tables enumerate treatment-emergent adverse reactions frequencies that were observed at an incidence equal to 1% or greater among patients with insomnia who received Zolpidem tartrate and at a greater incidence than placebo in U.S. placebo-controlled trials. Events reported by investigators were classified utilizing a modified World Health Organization (WHO) dictionary of preferred terms for the purpose of establishing event frequencies. The prescriber should be aware that these figures cannot be used to predict the incidence of side effects in the course of usual medical practice, in which patient characteristics and other factors differ from those that prevailed in these clinical trials. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigators involving related drug products and uses, since each group of drug trials is conducted under a different set of conditions. However, the cited figures provide the physician with a basis for estimating the relative contribution of drug and nondrug factors to the incidence of side effects in the population studied.
The following table was derived from results of 11 placebo-controlled short-term U.S. efficacy trials involving Zolpidem in doses ranging from 1.25 to 20 mg. The table is limited to data from doses up to and including 10 mg, the highest dose recommended for use.
| Body System/ Adverse Event* | Zolpidem (≤ 10 mg) (N = 685) | Placebo (N = 473) |
| ||
| Central and Peripheral Nervous System | ||
| Headache | 7 | 6 |
| Drowsiness | 2 | – |
| Dizziness | 1 | – |
| Gastrointestinal System | ||
| Diarrhea | 1 | - |
The following table was derived from results of three placebo-controlled long-term efficacy trials involving Zolpidem tartrate tablets. These trials involved patients with chronic insomnia who were treated for 28 to 35 nights with Zolpidem at doses of 5, 10, or 15 mg. The table is limited to data from doses up to and including 10 mg, the highest dose recommended for use. The table includes only adverse events occurring at an incidence of at least 1% for Zolpidem patients.
| Body System/ Adverse Event* | Zolpidem (≤ 10 mg) (N = 152) | Placebo (N = 161) |
| ||
| Autonomic Nervous System | ||
| Dry mouth | 3 | 1 |
| Body as a Whole | ||
| Allergy | 4 | 1 |
| Back Pain | 3 | 2 |
| Influenza-like symptoms | 2 | - |
| Chest pain | 1 | - |
| Cardiovascular System | ||
| Palpitation | 2 | - |
| Central and Peripheral Nervous System | ||
| Drowsiness | 8 | 5 |
| Dizziness | 5 | 1 |
| Lethargy | 3 | 1 |
| Drugged feeling | 3 | - |
| Lightheadedness | 2 | 1 |
| Depression | 2 | 1 |
| Abnormal dreams | 1 | - |
| Amnesia | 1 | - |
| Sleep disorder | 1 | - |
| Gastrointestinal System | ||
| Diarrhea | 3 | 2 |
| Abdominal pain | 2 | 2 |
| Constipation | 2 | 1 |
| Respiratory System | ||
| Sinusitis | 4 | 2 |
| Pharyngitis | 3 | 1 |
| Skin and Appendages | ||
| Rash | 2 | 1 |
Dose relationship for adverse reactions: There is evidence from dose comparison trials suggesting a dose relationship for many of the adverse reactions associated with Zolpidem use, particularly for certain CNS and gastrointestinal adverse events.
Adverse event incidence across the entire preapproval database: Zolpidem tartrate tablets were administered to 3,660 subjects in clinical trials throughout the U.S., Canada, and Europe. Treatment-emergent adverse events associated with clinical trial participation were recorded by clinical investigators using terminology of their own choosing. To provide a meaningful estimate of the proportion of individuals experiencing treatment-emergent adverse events, similar types of untoward events were grouped into a smaller number of standardized event categories and classified utilizing a modified World Health Organization (WHO) dictionary of preferred terms.
The frequencies presented, therefore, represent the proportions of the 3,660 individuals exposed to Zolpidem, at all doses, who experienced an event of the type cited on at least one occasion while receiving Zolpidem. All reported treatment-emergent adverse events are included, except those already listed in the table above of adverse events in placebo-controlled studies, those coding terms that are so general as to be uninformative, and those events where a drug cause was remote. It is important to emphasize that, although the events reported did occur during treatment with Zolpidem tartrate tablets, they were not necessarily caused by it.
Adverse events are further classified within body system categories and enumerated in order of decreasing frequency using the following definitions: frequent adverse events are defined as those occurring in greater than 1/100 subjects; infrequent adverse events are those occurring in 1/100 to 1/1,000 patients; rare events are those occurring in less than 1/1,000 patients.
Autonomic nervous system: Infrequent: increased sweating, pallor, postural hypotension, syncope. Rare: abnormal accommodation, altered saliva, flushing, glaucoma, hypotension, impotence, increased saliva, tenesmus.
Body as a whole: Frequent: asthenia. Infrequent: edema, falling, fatigue, fever, malaise, trauma. Rare: allergic reaction, allergy aggravated, anaphylactic shock, face edema, hot flashes, increased ESR, pain, restless legs, rigors, tolerance increased, weight decrease.
Cardiovascular system: Infrequent: cerebrovascular disorder, hypertension, tachycardia. Rare: angina pectoris, arrhythmia, arteritis, circulatory failure, extrasystoles, hypertension aggravated, myocardial infarction, phlebitis, pulmonary embolism, pulmonary edema, varicose veins, ventricular tachycardia.
Central and peripheral nervous system: Frequent: ataxia, confusion, euphoria, headache, insomnia, vertigo. Infrequent: agitation, anxiety, decreased cognition, detached, difficulty concentrating, dysarthria, emotional lability, hallucination, hypoesthesia, illusion, leg cramps, migraine, nervousness, paresthesia, sleeping (after daytime dosing), speech disorder, stupor, tremor. Rare: abnormal gait, abnormal thinking, aggressive reaction, apathy, appetite increased, decreased libido, delusion, dementia, depersonalization, dysphasia, feeling strange, hypokinesia, hypotonia, hysteria, intoxicated feeling, manic reaction, neuralgia, neuritis, neuropathy, neurosis, panic attacks, paresis, personality disorder, somnambulism, suicide attempts, tetany, yawning.
Gastrointestinal system: Frequent: dyspepsia, hiccup, nausea. Infrequent: anorexia, constipation, dysphagia, flatulence, gastroenteritis, vomiting. Rare: enteritis, eructation, esophagospasm, gastritis, hemorrhoids, intestinal obstruction, rectal hemorrhage, tooth caries.
Hematologic and lymphatic system: Rare: anemia, hyperhemoglobinemia, leukopenia, lymphadenopathy, macrocytic anemia, purpura, thrombosis.
Immunologic system: Infrequent: infection. Rare: abscess herpes simplex herpes zoster, otitis externa, otitis media.
Liver and biliary system: Infrequent: abnormal hepatic function, increased SGPT. Rare: bilirubinemia, increased SGOT.
Metabolic and nutritional: Infrequent: hyperglycemia, thirst. Rare: gout, hypercholesteremia, hyperlipidemia, increased alkaline phosphatase, increased BUN, periorbital edema.
Musculoskeletal system: Frequent: arthralgia, myalgia. Infrequent: arthritis. Rare: arthrosis, muscle weakness, sciatica, tendinitis.
Reproductive system: Infrequent: menstrual disorder, vaginitis. Rare: breast fibroadenosis, breast neoplasm, breast pain.
Respiratory system: Frequent: upper respiratory infection. Infrequent: bronchitis, coughing, dyspnea, rhinitis. Rare: bronchospasm, epistaxis, hypoxia, laryngitis, pneumonia.
Skin and appendages: Infrequent: pruritus. Rare: acne, bullous eruption, dermatitis, furunculosis, injection-site inflammation, photosensitivity reaction, urticaria.
Special senses: Frequent: diplopia, vision abnormal. Infrequent: eye irritation, eye pain, scleritis, taste perversion, tinnitus. Rare: conjunctivitis, corneal ulceration, lacrimation abnormal, parosmia, photopsia.
Urogenital system: Frequent: urinary tract infection. Infrequent: cystitis, urinary incontinence. Rare: acute renal failure, dysuria, micturition frequency, nocturia, polyuria, pyelonephritis, renal pain, urinary retention.
Since the systematic evaluations of Zolpidem in combination with other CNS-active drugs have been limited, careful consideration should be given to the pharmacology of any CNS-active drug to be used with Zolpidem. Any drug with CNS-depressant effects could potentially enhance the CNS-depressant effects of Zolpidem.
Zolpidem tartrate tablets were evaluated in healthy subjects in single-dose interaction studies for several CNS drugs. Imipramine in combination with Zolpidem produced no pharmacokinetic interaction other than a 20% decrease in peak levels of imipramine, but there was an additive effect of decreased alertness. Similarly, chlorpromazine in combination with Zolpidem produced no pharmacokinetic interaction, but there was an additive effect of decreased alertness and psychomotor performance. A study involving haloperidol and Zolpidem revealed no effect of haloperidol on the pharmacokinetics or pharmacodynamics of Zolpidem. The lack of a drug interaction following single-dose administration does not predict a lack following chronic administration.
An additive effect on psychomotor performance between alcohol and Zolpidem was demonstrated [see Warnings and Precautions (5.5)].
A single-dose interaction study with Zolpidem 10 mg and fluoxetine 20 mg at steady-state levels in male volunteers did not demonstrate any clinically significant pharmacokinetic or pharmacodynamic interactions. When multiple doses of Zolpidem and fluoxetine at steady-state concentrations were evaluated in healthy females, the only significant change was a 17% increase in the Zolpidem half-life. There was no evidence of an additive effect in psychomotor performance.
Following five consecutive nightly doses of Zolpidem 10 mg in the presence of sertraline 50 mg (17 consecutive daily doses, at 7:00 am, in healthy female volunteers), Zolpidem Cmax was significantly higher (43%) and Tmax was significantly decreased (53%). Pharmacokinetics of sertraline and N-desmethylsertraline were unaffected by Zolpidem.
Some compounds known to inhibit CYP3A may increase exposure to Zolpidem. The effect of inhibitors of other P450 enzymes has not been carefully evaluated.
A randomized, double-blind, crossover interaction study in ten healthy volunteers between itraconazole (200 mg once daily for 4 days) and a single dose of Zolpidem (10 mg) given 5 hours after the last dose of itraconazole resulted in a 34% increase in AUC0-∞ of Zolpidem. There were no significant pharmacodynamic effects of Zolpidem on subjective drowsiness, postural sway, or psychomotor performance.
A randomized, placebo-controlled, crossover interaction study in eight healthy female subjects between five consecutive daily doses of rifampin (600 mg) and a single dose of Zolpidem (20 mg) given 17 hours after the last dose of rifampin showed significant reductions of the AUC (–73%), Cmax (–58%), and T½ (–36%) of Zolpidem together with significant reductions in the pharmacodynamic effects of Zolpidem.
A randomized double-blind crossover interaction study in twelve healthy subjects showed that coadministration of a single 5 mg dose of Zolpidem tartrate with ketoconazole, a potent CYP3A4 inhibitor, given as 200 mg twice daily for 2 days increased Cmax of Zolpidem by a factor of 1.3 and increased the total AUC of Zolpidem by a factor of 1.7 compared to Zolpidem alone and prolonged the elimination half-life by approximately 30% along with an increase in the pharmacodynamic effects of Zolpidem. Caution should be used when ketoconazole is given with Zolpidem and consideration should be given to using a lower dose of Zolpidem when ketoconazole and Zolpidem are given together. Patients should be advised that use of Zolpidem tartrate tablets with ketoconazole may enhance the sedative effects.
A study involving cimetidine/Zolpidem and ranitidine/Zolpidem combinations revealed no effect of either drug on the pharmacokinetics or pharmacodynamics of Zolpidem.
Zolpidem had no effect on digoxin pharmacokinetics and did not affect prothrombin time when given with warfarin in normal subjects.
Zolpidem is not known to interfere with commonly employed clinical laboratory tests. In addition, clinical data indicate that Zolpidem does not cross-react with benzodiazepines, opiates, barbiturates, cocaine, cannabinoids, or amphetamines in two standard urine drug screens.
There are no adequate and well-controlled studies of Zolpidem tartrate in pregnant women. Zolpidem tartrate tablets should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Administration of Zolpidem to pregnant rats and rabbits resulted in adverse effects on offspring development at doses greater than the Zolpidem tartrate maximum recommended human dose (MRHD) of 10 mg/day (approximately 8 mg/day Zolpidem base); however, teratogenicity was not observed.
When Zolpidem was administered at oral doses of 4, 20, and 100 mg base/kg (approximately 5, 24 and 120 times the MRHD on a mg/m2 basis) to pregnant rats during the period of organogenesis, dose-related decreases in fetal skull ossification occurred at all but the lowest dose, which is approximately 5 times the MRHD on a mg/m2 basis. In rabbits treated during organogenesis with Zolpidem at oral doses of 1, 4, and 16 mg base/kg (approximately 2.5, 10 and 40 times the MRHD on a mg/m2 basis), increased embryo-fetal death and incomplete fetal skeletal ossification occurred at the highest dose. The no-effect dose for embryo-fetal toxicity in rabbits is approximately 10 times the MRHD on a mg/m2 basis. Administration of Zolpidem to rats at oral doses of 4, 20, and 100 mg base/kg (approximately 5, 24 and 120 times the MRHD on a mg/m2 basis) during the latter part of pregnancy and throughout lactation produced decreased offspring growth and survival at all but the lowest dose, which is approximately 5 times the MRHD on a mg/m2 basis.
Neonatal Complications
Studies in children to assess the effects of prenatal exposure to Zolpidem have not been conducted; however, cases of severe neonatal respiratory depression have been reported when Zolpidem was used at the end of pregnancy, especially when taken with other CNS depressants.
Children born to mothers taking sedative-hypnotic drugs may be at some risk for withdrawal symptoms during the postnatal period. Neonatal flaccidity has also been reported in infants born to mothers who received sedative-hypnotic drugs during pregnancy.
Zolpidem tartrate tablets have no established use in labor and delivery [see Pregnancy (8.1)].
Zolpidem is excreted in human milk. Studies in lactating mothers indicate that the half-life of Zolpidem is similar to that in non-lactating women (2.6 ± 0.3 hr). The effect of Zolpidem on the nursing infant is not known. Caution should be exercised when Zolpidem tartrate is administered to a nursing woman.
Safety and effectiveness of Zolpidem have not been established in pediatric patients.
In an 8 week controlled study, 201 pediatric patients (aged 6 to 17 years) with insomnia associated with attention-deficit/hyperactivity disorder (90% of the patients were using psychoanaleptics) were treated with an oral solution of Zolpidem (n = 136), or placebo (n = 65). Zolpidem did not significantly decrease latency to persistent sleep, compared to placebo, as measured by polysomnography after 4 weeks of treatment. Psychiatric and nervous system disorders comprised the most frequent (> 5%) treatment emergent adverse reactions observed with Zolpidem versus placebo and included dizziness (23.5% vs. 1.5%), headache (12.5% vs. 9.2%), and hallucinations (7.4% vs. 0%) [see Warnings and Precautions (5.6)]. Ten patients on Zolpidem (7.4%) discontinued treatment due to an adverse reaction.
A total of 154 patients in U.S. controlled clinical trials and 897 patients in non-U.S. clinical trials who received Zolpidem were ≥ 60 years of age. For a pool of U.S. patients receiving Zolpidem at doses of ≤ 10 mg or placebo, there were three adverse reactions occurring at an incidence of at least 3% for Zolpidem and for which the Zolpidem incidence was at least twice the placebo incidence (i.e., they could be considered drug related).
| Adverse Event | Zolpidem | Placebo |
| Dizziness | 3% | 0% |
| Drowsiness | 5% | 2% |
| Diarrhea | 3% | 1% |
A total of 30/1,959 (1.5%) non-U.S. patients receiving Zolpidem reported falls, including 28/30 (93%) who were ≥ 70 years of age. Of these 28 patients, 23 (82%) were receiving Zolpidem doses > 10 mg. A total of 24/1,959 (1.2%) non-U.S. patients receiving Zolpidem reported confusion, including 18/24 (75%) who were ≥ 70 years of age. Of these 18 patients, 14 (78%) were receiving Zolpidem doses > 10 mg.
The dose of Zolpidem tartrate tablets in elderly patients is 5 mg to minimize adverse effects related to impaired motor and/or cognitive performance and unusual sensitivity to sedative/hypnotic drugs [see Warnings and Precautions (5.6)].
Zolpidem tartrate is classified as a Schedule IV controlled substance by federal regulation.
Abuse and addiction are separate and distinct from physical dependence and tolerance. Abuse is characterized by misuse of the drug for non-medical purposes, often in combination with other psychoactive substances. Tolerance is a state of adaptation in which exposure to a drug induces changes that result in a diminution of one or more of the drug effects over time. Tolerance may occur to both desired and undesired effects of drugs and may develop at different rates for different effects.
Addiction is a primary, chronic, neurobiological disease with genetic, psychosocial, and environmental factors influencing its development and manifestations. It is characterized by behaviors that include one or more of the following: impaired control over drug use, compulsive use, continued use despite harm, and craving. Drug addiction is a treatable disease, using a multidisciplinary approach, but relapse is common.
Studies of abuse potential in former drug abusers found that the effects of single doses of Zolpidem tartrate 40 mg were similar, but not identical, to diazepam 20 mg, while Zolpidem tartrate 10 mg was difficult to distinguish from placebo.
Because persons with a history of addiction to, or abuse of, drugs or alcohol are at increased risk for misuse, abuse and addiction of Zolpidem, they should be monitored carefully when receiving Zolpidem or any other hypnotic.
Physical dependence is a state of adaptation that is manifested by a specific withdrawal syndrome that can be produced by abrupt cessation, rapid dose reduction, decreasing blood level of the drug, and/or administration of an antagonist.
Sedative/hypnotics have produced withdrawal signs and symptoms following abrupt discontinuation. These reported symptoms range from mild dysphoria and insomnia to a withdrawal syndrome that may include abdominal and muscle cramps, vomiting, sweating, tremors, and convulsions. The following adverse events which are considered to meet the DSM-III-R criteria for uncomplicated sedative/hypnotic withdrawal were reported during U.S. clinical trials following placebo substitution occurring within 48 hours following last Zolpidem treatment: fatigue, nausea, flushing, lightheadedness, uncontrolled crying, emesis, stomach cramps, panic attack, nervousness, and abdominal discomfort. These reported adverse events occurred at an incidence of 1% or less. However, available data cannot provide a reliable estimate of the incidence, if any, of dependence during treatment at recommended doses. Postmarketing reports of abuse, dependence and withdrawal have been received.
In postmarketing experience of overdose with Zolpidem tartrate alone, or in combination with CNS-depressant agents, impairment of consciousness ranging from somnolence to coma, cardiovascular and/or respiratory compromise, and fatal outcomes have been reported.
General symptomatic and supportive measures should be used along with immediate gastric lavage where appropriate. Intravenous fluids should be administered as needed. Zolpidem’s sedative hypnotic effect was shown to be reduced by flumazenil and therefore may be useful; however, flumazenil administration may contribute to the appearance of neurological symptoms (convulsions). As in all cases of drug overdose, respiration, pulse, blood pressure, and other appropriate signs should be monitored and general supportive measures employed. Hypotension and CNS depression should be monitored and treated by appropriate medical intervention. Sedating drugs should be withheld following Zolpidem overdosage, even if excitation occurs. The value of dialysis in the treatment of overdosage has not been determined, although hemodialysis studies in patients with renal failure receiving therapeutic doses have demonstrated that Zolpidem is not dialyzable.
As with the management of all overdosage, the possibility of multiple drug ingestion should be considered. The physician may wish to consider contacting a poison control center for up-to-date information on the management of hypnotic drug product overdosage.
Zolpidem tartrate is a non-benzodiazepine hypnotic of the imidazopyridine class and is available in 5 mg and 10 mg strength tablets for oral administration.
Chemically, Zolpidem is N,N,6-trimethyl-2-p-tolylimidazo[1,2-α]pyridine-3-acetamide L-(+)-tartrate (2:1). It has the following structure:
(C19H21N3O)2•C4H6O6 M.W. 764.88
Zolpidem tartrate is a white to off-white crystalline powder that is sparingly soluble in water, alcohol, and propylene glycol.
Each Zolpidem tartrate tablet includes the following inactive ingredients: hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polysorbate 80, sodium starch glycolate, and titanium dioxide; the 5 mg tablet also contains iron oxide red.
Zolpidem, the active moiety of Zolpidem tartrate, is a hypnotic agent with a chemical structure unrelated to benzodiazepines, barbiturates, or other drugs with known hypnotic properties. It interacts with a GABA-BZ receptor complex and shares some of the pharmacological properties of the benzodiazepines. In
