Author: druginteractionchecker_lgaiz4

DOSAGE AND ADMINISTRATION

Important Dosage and Administration Instructions Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals [see WARNINGS ].

Initiate the dosing regimen for each patient individually, taking into account the patient’s severity of pain, patient response, prior analgesic treatment experience, and risk factors for addiction, abuse, and misuse [see WARNINGS ].

Follow patients closely for respiratory depression, especially within the first 24-72 hours of initiating therapy and following dosage increases with hydrocodone bitartrate and acetaminophen tablets and adjust the dosage accordingly [see WARNINGS ].

Initial Dosage Initiating Treatment with HydrocodoneBitartrate and Acetaminophen Tablets VICODIN ® 5 mg/300 mg The usual adult dosage is one or two tablets every four to six hours as needed for pain.

The total daily dosage should not exceed 8 tablets.

VICODIN ES ® 7.5 mg/300 mg The usual adult dosage is one tablet every four to six hours as needed for pain.

The total daily dosage should not exceed 6 tablets.

VICODIN HP ® 10 mg/300 mg The usual adult dosage is one tablet every four to six hours as needed for pain.

The total daily dosage should not exceed 6 tablets.

Conversion from Other Opioids to HydrocodoneBitartrate and Acetaminophen Tablets There is inter-patient variability in the potency of opioid drugs and opioid formulations.

Therefore, a conservative approach is advised when determining the total daily dosage of hydrocodone bitartrate and acetaminophen tablets.

It is safer to underestimate a patient’s 24-hour hydrocodone bitartrate and acetaminophen tablets dosage than to overestimate the 24-hour hydrocodone bitartrate and acetaminophen tablets dosage and manage an adverse reaction due to overdose.

Conversion from HydrocodoneBitartrate and Acetaminophen Tablets to Extended-Release Hydrocodone The relative bioavailability of hydrocodone from hydrocodone bitartrate and acetaminophen tablets compared to extended-release hydrocodone products is unknown, so conversion to extended-release products must be accompanied by close observation for signs of excessive sedation and respiratory depression.

Titration and Maintenance of Therapy Individually titrate hydrocodone bitartrate and acetaminophen tablets to a dose that provides adequate analgesia and minimizes adverse reactions.

Continually reevaluate patients receiving hydrocodone bitartrate and acetaminophen tablets to assess the maintenance of pain control and the relative incidence of adverse reactions, as well as monitoring for the development of addiction, abuse, or misuse [see WARNINGS ].

Frequent communication is important among the prescriber, other members of the healthcare team, the patient, and the caregiver/family during periods of changing analgesic requirements, including initial titration.

If the level of pain increases after dosage stabilization, attempt to identify the source of increased pain before increasing the hydrocodone bitartrate and acetaminophen tablets dosage.

If unacceptable opioid-related adverse reactions are observed, consider reducing the dosage.

Adjust the dosage to obtain an appropriate balance between management of pain and opioid-related adverse reactions.

Discontinuation of Hydrocodone Bitartrate and Acetaminophen Tablets When a patient who has been taking hydrocodone bitartrate and acetaminophen tablets regularly and may be physically dependent no longer requires therapy with hydrocodone bitartrate and acetaminophen tablets, taper the dose gradually, by 25% to 50% every 2 to 4 days, while monitoring carefully for signs and symptoms of withdrawal.

If the patient develops these signs or symptoms, raise the dose to the previous level and taper more slowly, either by increasing the interval between decreases, decreasing the amount of change in dose, or both.

Do not abruptly discontinue hydrocodone bitartrate and acetaminophen tablets in a physically-dependent patient [see WARNINGS , DRUG ABUSE AND DEPENDENCE ].

DOSAGE AND ADMINISTRATION

The recommended adult and pediatric dosages and routes of administration are outlined in the following table 10.

Cefepime for injection should be administered intravenously over approximately 30 minutes.

Table 10: Recommended Dosage Schedule for Cefepime for Injection in Patients with CrCL Greater Than 60 mL/min Adjust dose in patients with CrCL less than or equal to 60 mL/min Site and Type of Infection Dose Frequency Duration (days) Adults Moderate to Severe Pneumonia due to S.

pneumoniae including cases associated with concurrent bacteremia.

, P.

aeruginosa For Pseudomonas aeruginosa, use 2 g IV every 8 hours (50 mg per kg per dose in pediatric patients 2 months up to 16 years) , K.

pneumoniae , or Enterobacter species 1 to 2 g IV Every 8 to 12 hours 10 Empiric therapy for febrile neutropenic patients (See INDICATIONS AND USAGE and CLINICAL STUDIES .) 2 g IV Every 8 hours 7 or until resolution of neutropenia.

In patients whose fever resolves but who remain neutropenic for more than 7 days, the need for continued antimicrobial therapy should be re-evaluated frequently.

Mild to Moderate Uncomplicated or Complicated Urinary Tract Infections, including pyelonephritis, due to E.

coli, K.

pneumoniae , or P.

mirabilis 0.5 to 1 g IV/IM Intramuscular route of administration is indicated only for mild to moderate, uncomplicated or complicated UTIs due to E.

coli when the intramuscular route is considered to be a more appropriate route of drug administration.

Every 12 hours 7 to 10 Severe Uncomplicated or Complicated Urinary Tract Infections, including pyelonephritis, due to E.

coli or K.

pneumoniae 2 g IV Every 12 hours 10 Moderate to Severe Uncomplicated Skin and Skin Structure Infections due to S.

aureus or S.

pyogenes 2 g IV Every 12 hours 10 Complicated Intra-abdominal Infections (used in combination with metronidazole) caused by E.

coli , viridans group streptococci, P.

aeruginosa , K.

pneumoniae , Enterobacter species, or B.

fragilis .

(See CLINICAL STUDIES .) 2 g IV Every 8 to 12 hours 7 to 10 Pediatric Patients (2 months up to 16 years) The maximum dose for pediatric patients should not exceed the recommended adult dose.

The usual recommended dosage in pediatric patients up to 40 kg in weight for uncomplicated and complicated urinary tract infections (including pyelonephritis), uncomplicated skin and skin structure infections, and pneumonia is 50 mg per kg per dose, administered every 12 hours (50 mg per kg per dose, every 8 hours for febrile neutropenic patients), for durations as given above.

Patients with Hepatic Impairment No adjustment is necessary for patients with hepatic impairment.

Patients with Renal Impairment In patients with creatinine clearance less than or equal to 60 mL/min, the dose of cefepime for injection should be adjusted to compensate for the slower rate of renal elimination.

The recommended initial dose of cefepime for injection should be the same as in patients with normal renal function except in patients undergoing hemodialysis.

The recommended doses of cefepime for injection in patients with renal impairment are presented in Table 11.

When only serum creatinine is available, the following formula (Cockcroft and Gault equation) 4 may be used to estimate creatinine clearance.

The serum creatinine should represent a steady state of renal function: Males: Creatinine Clearance (mL/min) = Weight (kg) × (140-age) 72 × serum creatinine (mg/dL) Females: 0.85 × above value Table 11: Recommended Dosing Schedule for Cefepime for Injection in Adult Patients (Normal Renal Function, Renal Impairment, and Hemodialysis) Creatinine Clearance (mL/min) Recommended Maintenance Schedule Greater than 60 Normal recommended dosing schedule 500 mg every 12 hours 1 g every 12 hours 2 g every 12 hours 2 g every 8 hours 30 to 60 500 mg every 24 hours 1 g every 24 hours 2 g every 24 hours 2 g every 12 hours 11 to 29 500 mg every 24 hours 500 mg every 24 hours 1 g every 24 hours 2 g every 24 hours Less than 11 250 mg every 24 hours 250 mg every 24 hours 500 mg every 24 hours 1 g every 24 hours CAPD 500 mg every 48 hours 1 g every 48 hours 2 g every 48 hours 2 g every 48 hours Hemodialysis On hemodialysis days, cefepime should be administered following hemodialysis.

Whenever possible, cefepime should be administered at the same time each day.

1 g on day 1, then 500 mg every 24 hours thereafter 1 g every 24 hours In patients undergoing continuous ambulatory peritoneal dialysis, cefepime for injection may be administered at normally recommended doses at a dosage interval of every 48 hours (see Table 11).

In patients undergoing hemodialysis, approximately 68% of the total amount of cefepime present in the body at the start of dialysis will be removed during a 3-hour dialysis period.

The dosage of cefepime for injection for hemodialysis patients is 1 g on Day 1 followed by 500 mg every 24 hours for the treatment of all infections except febrile neutropenia, which is 1 g every 24 hours.

Cefepime for injection should be administered at the same time each day and following the completion of hemodialysis on hemodialysis days (see Table 11).

Data in pediatric patients with impaired renal function are not available; however, since cefepime pharmacokinetics are similar in adults and pediatric patients (see CLINICAL PHARMACOLOGY ), changes in the dosing regimen proportional to those in adults (see Tables 10 and 11) are recommended for pediatric patients.

Administration For Intravenous Infusion Dilute with a suitable parenteral vehicle prior to intravenous infusion.

Constitute the 1 g, or 2 g vial, and add an appropriate quantity of the resulting solution to an intravenous container with one of the compatible intravenous fluids listed in the Compatibility and Stability subsection.

THE RESULTING SOLUTION SHOULD BE ADMINISTERED OVER APPROXIMATELY 30 MINUTES.

Intermittent intravenous infusion with a Y-type administration set can be accomplished with compatible solutions.

However, during infusion of a solution containing cefepime, it is desirable to discontinue the other solution.

Intramuscular Administration For intramuscular administration, cefepime for injection should be constituted with one of the following diluents: Sterile Water for Injection, 0.9% Sodium Chloride, 5% Dextrose Injection, 0.5% or 1% Lidocaine Hydrochloride, or Sterile Bacteriostatic Water for Injection with Parabens or Benzyl Alcohol (refer to Table 12).

Preparation of cefepime for injection solutions is summarized in Table 12.

Table 12: Preparation of Solutions of Cefepime for Injection Single-Dose Vials for Intravenous/Intramuscular Administration Amount of Diluent to be added (mL) Approximate Available Volume (mL) Approximate Cefepime Concentration (mg/mL) cefepime vial content 1 g (IV) 10 11.3 100 1 g (IM) 2.4 3.6 280 2 g (IV) 10 12.5 160 Compatibility and Stability Intravenous Cefepime for injection is compatible at concentrations between 1 mg per mL and 40 mg per mL with the following intravenous infusion fluids: 0.9% Sodium Chloride Injection, 5% and 10% Dextrose Injection, M/6 Sodium Lactate Injection, 5% Dextrose and 0.9% Sodium Chloride Injection, Lactated Ringers and 5% Dextrose Injection, Normosol™-R, and Normosol™-M in 5% Dextrose Injection.

These solutions may be stored up to 24 hours at controlled room temperature 20° C to 25° C (68° F to 77° F) or 7 days in a refrigerator 2° C to 8° C (36° F to 46° F).

Cefepime for injection admixture compatibility information is summarized in Table 13.

Table 13: Cefepime Admixture Stability Stability Time for Cefepime for Injection Concentration Admixture and Concentration IV Infusion Solutions RT/L (20° to 25° C) Refrigeration (2° to 8° C) 40 mg/mL Amikacin 6 mg/mL NS or D5W 24 hours 7 days 40 mg/mL Ampicillin 1 mg/mL D5W 8 hours 8 hours 40 mg/mL Ampicillin 10 mg/mL D5W 2 hours 8 hours 40 mg/mL Ampicillin 1 mg/mL NS 24 hours 48 hours 40 mg/mL Ampicillin 10 mg/mL NS 8 hours 48 hours 4 mg/mL Ampicillin 40 mg/mL NS 8 hours 8 hours 4 to 40 mg/mL Clindamycin Phosphate 0.25 to 6 mg/mL NS or D5W 24 hours 7 days 4 mg/mL Heparin 10 to 50 units/mL NS or D5W 24 hours 7 days 4 mg/mL Potassium Chloride 10 to 40 mEq/L NS or D5W 24 hours 7 days 4 mg/mL Theophylline 0.8 mg/mL D5W 24 hours 7 days 1 to 4 mg/mL na Aminosyn™ II 4.25% with electrolytes and calcium 8 hours 3 days 0.125 to 0.25 mg/mL na Inpersol™ with 4.25% dextrose 24 hours 7 days NS = 0.9% Sodium Chloride Injection D5W = 5% Dextrose Injection na = not applicable RT/L = Ambient room temperature and light Solutions of cefepime for injection, like those of most beta-lactam antibiotics, should not be added to solutions of ampicillin at a concentration greater than 40 mg per mL, and should not be added to metronidazole, vancomycin, gentamicin, tobramycin, netilmicin sulfate, or aminophylline because of potential interaction.

However, if concurrent therapy with cefepime for injection is indicated, each of these antibiotics can be administered separately.

Intramuscular Cefepime for injection constituted as directed is stable for 24 hours at controlled room temperature 20° C to 25° C (68° F to 77° F) or for 7 days in a refrigerator 2° C to 8° C (36° F to 46° F) with the following diluents: Sterile Water for Injection, 0.9% Sodium Chloride Injection, 5% Dextrose Injection, Sterile Bacteriostatic Water for Injection with Parabens or Benzyl Alcohol, or 0.5% or 1% Lidocaine Hydrochloride.

NOTE: PARENTERAL DRUGS SHOULD BE INSPECTED VISUALLY FOR PARTICULATE MATTER BEFORE ADMINISTRATION.

IF PARTICULATE MATTER IS EVIDENT IN RECONSTITUTED FLUIDS, THE DRUG SOLUTION SHOULD BE DISCARDED.

As with other cephalosporins, the color of cefepime for injection powder, as well as its solutions, tend to darken depending on storage conditions; however, when stored as recommended, the product potency is not adversely affected.

DOSAGE AND ADMINISTRATION

2 Administration (by indications): Asthma ( 2.1 ): Once daily in the evening for patients 12 months and older.

Acute prevention of EIB ( 2.2 ): 10 mg tablet at least 2 hours before exercise for patients 15 years of age and older.

Seasonal allergic rhinitis ( 2.3 ): Once daily for patients 2 years and older.

Perennial allergic rhinitis ( 2.3 ): Once daily for patients 6 months and older.

Dosage (by age) ( 2 ): 15 years and older: one 10 mg tablet.

6 to 14 years: one 5 mg chewable tablet.

2 to 5 years: one 4 mg chewable tablet.

Patients with both asthma and allergic rhinitis should take only one dose daily in the evening ( 2.4 ).

2.1 Asthma Montelukast sodium should be taken once daily in the evening.

The following doses are recommended: For adults and adolescents 15 years of age and older: one 10 mg tablet.

For pediatric patients 6 to 14 years of age: one 5 mg chewable tablet.

For pediatric patients 2 to 5 years of age: one 4 mg chewable tablet.

Safety and effectiveness in pediatric patients less than 12 months of age with asthma have not been established.

There have been no clinical trials in patients with asthma to evaluate the relative efficacy of morning versus evening dosing.

The pharmacokinetics of montelukast are similar whether dosed in the morning or evening.

Efficacy has been demonstrated for asthma when montelukast was administered in the evening without regard to time of food ingestion.

2.2 Exercise-Induced Bronchoconstriction (EIB) in Patients 15 Years of Age and Older For prevention of EIB, a single 10 mg dose of montelukast should be taken at least 2 hours before exercise.

An additional dose of montelukast should not be taken within 24 hours of a previous dose.

Patients already taking montelukast sodium daily for another indication (including chronic asthma) should not take an additional dose to prevent EIB.

All patients should have available for rescue a short-acting β-agonist.

Safety and effectiveness in patients younger than 15 years of age have not been established.

Daily administration of montelukast sodium for the chronic treatment of asthma has not been established to prevent acute episodes of EIB.

Pediatric use information for patients ages 6 to 14 years of age for acute prevention of exercise-induced bronchoconstriction (EIB) is approved for Merck Sharp & Dohme Corp’s montelukast tablet products.

However, due to Merck Sharp & Dohme Corp’s marketing exclusivity rights, this drug product is not labeled with that pediatric information.

2.3 Allergic Rhinitis For allergic rhinitis, montelukast sodium should be taken once daily.

Efficacy was demonstrated for seasonal allergic rhinitis when montelukast was administered in the morning or the evening without regard to time of food ingestion.

The time of administration may be individualized to suit patient needs.

The following doses for the treatment of symptoms of seasonal allergic rhinitis are recommended: For adults and adolescents 15 years of age and older: one 10 mg tablet.

For pediatric patients 6 to 14 years of age: one 5 mg chewable tablet.

For pediatric patients 2 to 5 years of age: one 4 mg chewable tablet.

Safety and effectiveness in pediatric patients younger than 2 years of age with seasonal allergic rhinitis have not been established.

The following doses for the treatment of symptoms of perennial allergic rhinitis are recommended: For adults and adolescents 15 years of age and older: one 10 mg tablet.

For pediatric patients 6 to 14 years of age: one 5 mg chewable tablet.

For pediatric patients 2 to 5 years of age: one 4 mg chewable tablet.

Safety and effectiveness in pediatric patients younger than 6 months of age with perennial allergic rhinitis have not been established.

2.4 Asthma and Allergic Rhinitis Patients with both asthma and allergic rhinitis should take only one montelukast sodium dose daily in the evening.

DOSAGE AND ADMINISTRATION

Dosage should be individualized with careful monitoring of patient response.

Oral Administration The usual total daily dosage of bumetanide is 0.5 to 2 mg and in most patients is given as a single dose.

If the diuretic response to an initial dose of bumetanide is not adequate, in view of its rapid onset and short duration of action, a second or third dose may be given at 4- to 5-hour intervals up to a maximum daily dose of 10 mg.

An intermittent dose schedule, whereby bumetanide is given on alternate days or for 3 to 4 days with rest periods of 1 to 2 days in between, is recommended as the safest and most effective method for the continued control of edema.

In patients with hepatic failure, the dosage should be kept to a minimum, and if necessary, dosage increased very carefully.

Because cross-sensitivity with furosemide has rarely been observed, bumetanide can be substituted at approximately a 1:40 ratio of bumetanide to furosemide in patients allergic to furosemide.

Parenteral Administration Bumetanide Injection may be administered parenterally (IV or IM) to patients in whom gastrointestinal absorption may be impaired or in whom oral administration is not practical.

Parenteral treatment should be terminated and oral treatment instituted as soon as possible.

DOSAGE AND ADMINISTRATION

The initial dosage of hydrocortisone tablets may vary from 20 mg to 240 mg of hydrocortisone per day depending on the specific disease entity being treated.

In situations of less severity lower doses will generally suffice while in selected patients higher initial doses may be required.

The initial dosage should be maintained or adjusted until a satisfactory response is noted.

If after a reasonable period of time there is a lack of satisfactory clinical response, hydrocortisone should be discontinued and the patient transferred to other appropriate therapy.

IT SHOULD BE EMPHASIZED THAT DOSAGE REQUIREMENTS ARE VARIABLE AND MUST BE INDIVIDUALIZED ON THE BASIS OF THE DISEASE UNDER TREATMENT AND THE RESPONSE OF THE PATIENT.

After a favorable response is noted, the proper maintenance dosage should be determined by decreasing the initial drug dosage in small decrements at appropriate time intervals until the lowest dosage which will maintain an adequate clinical response is reached.

It should be kept in mind that constant monitoring is needed in regard to drug dosage.

Included in the situations which may make dosage adjustments necessary are changes in clinical status secondary to remissions or exacerbations in the disease process, the patient’s individual drug responsiveness, and the effect of patient exposure to stressful situations not directly related to the disease entity under treatment; in this latter situation it may be necessary to increase the dosage of hydrocortisone for a period of time consistent with the patient’s condition.

If after long-term therapy the drug is to be stopped, it is recommended that it be withdrawn gradually, rather than abruptly.

Multiple Sclerosis In treatment of acute exacerbations of multiple sclerosis, daily doses of 200 mg of prednisolone for a week followed by 80 mg every other day for 1 month have been shown to be effective (20 mg of hydrocortisone is equivalent to 5 mg of prednisolone).

DOSAGE AND ADMINISTRATION

These solutions are for intravenous use only.

Dosage is to be directed by a physician and is dependent upon age, weight, clinical condition of the patient and laboratory determinations.

Frequent laboratory determinations and clinical evaluation are essential to monitor changes in blood glucose and electrolyte concentrations, and fluid and electrolyte balance during prolonged parenteral therapy.

When a hypertonic solution is to be administered peripherally, it should be slowly infused through a small bore needle, placed well within the lumen of a large vein to minimize venous irritation.

Carefully avoid infiltration.

Fluid administration should be based on calculated maintenance or replacement fluid requirements for each patient.

Some additives may be incompatible.

Consult with pharmacist.

When introducing additives, use aseptic techniques.

Mix thoroughly.

Do not store.

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

DOSAGE AND ADMINISTRATION

2 ZOSYN should be administered by intravenous infusion over 30 minutes.

The usual daily dose of ZOSYN for adults is 3.375 g every six hours totaling 13.5 g (12.0 g piperacillin/1.5 g tazobactam).

( 2.1 ) Initial presumptive treatment of patients with nosocomial pneumonia should start with ZOSYN at a dosage of 4.5 g every six hours plus an aminoglycoside, totaling 18.0 g (16.0 g piperacillin/2.0 g tazobactam).

( 2.2 ) Dosage in patients with renal impairment (≤40 mL/min of CRCL) and dialysis patients should be reduced, based on the degree of actual renal function impairment.

( 2.3 ) For children with appendicitis and/or peritonitis the recommended ZOSYN dosage is 100 mg piperacillin/12.5 mg tazobactam per kilogram of body weight, every 8 hours in pediatric patients 9 months of age and older.

For pediatric patients 2 to 9 months of age, the recommended dosage is 80 mg piperacillin/10 mg tazobactam per kilogram of body weight, every 8 hours.

( 2.4 ) ZOSYN and aminoglycosides should be reconstituted, diluted, and administered separately.

Co-administration via Y-site can be done under certain conditions.

( 2.7 ) 2.1 Adult Patients The usual total daily dose of ZOSYN for adults is 3.375 g every six hours totaling 13.5 g (12.0 g piperacillin/1.5 g tazobactam).

The usual duration of ZOSYN treatment is from 7 to 10 days.

ZOSYN should be administered by intravenous infusion over 30 minutes.

2.2 Nosocomial Pneumonia Initial presumptive treatment of patients with nosocomial pneumonia should start with ZOSYN at a dosage of 4.5 g every six hours plus an aminoglycoside, totaling 18.0 g (16.0 g piperacillin/2.0 g tazobactam).

The recommended duration of ZOSYN treatment for nosocomial pneumonia is 7 to 14 days.

Treatment with the aminoglycoside should be continued in patients from whom P.

aeruginosa is isolated.

2.3 Renal Impairment In patients with renal impairment (creatinine clearance ≤ 40 mL/min) and dialysis patients (hemodialysis and CAPD), the intravenous dose of ZOSYN should be reduced to the degree of actual renal function impairment.

The recommended daily doses of ZOSYN for patients with renal impairment are as follows: Table 1: Recommended Dosing of ZOSYN in Patients with Normal Renal Function and Renal-Impairment (As total grams piperacillin/tazobactam) Renal Function (creatinine clearance, mL/min) All Indications (except nosocomial pneumonia) Nosocomial Pneumonia >40 mL/min 3.375 q 6 h 4.5 q 6 h 20–40 mL/min Creatinine clearance for patients not receiving hemodialysis 2.25 q 6 h 3.375 q 6 h <20 mL/min 2.25 q 8 h 2.25 q 6 h Hemodialysis 0.75 g (0.67 g piperacillin/0.08 g tazobactam) should be administered following each hemodialysis session on hemodialysis days 2.25 q 12 h 2.25 q 8 h CAPD 2.25 q 12 h 2.25 q 8 h For patients on hemodialysis, the maximum dose is 2.25 g every twelve hours for all indications other than nosocomial pneumonia and 2.25 g every eight hours for nosocomial pneumonia.

Since hemodialysis removes 30% to 40% of the administered dose, an additional dose of 0.75 g ZOSYN (0.67 g piperacillin/0.08 g tazobactam) should be administered following each dialysis period on hemodialysis days.

No additional dosage of ZOSYN is necessary for CAPD patients.

2.4 Pediatric Patients For children with appendicitis and/or peritonitis 9 months of age or older, weighing up to 40 kg, and with normal renal function, the recommended ZOSYN dosage is 100 mg piperacillin/12.5 mg tazobactam per kilogram of body weight, every 8 hours.

For pediatric patients between 2 months and 9 months of age, the recommended ZOSYN dosage based on pharmacokinetic modeling, is 80 mg piperacillin/10 mg tazobactam per kilogram of body weight, every 8 hours [ see Use in Specific Populations (8.4) and Clinical Pharmacology (12.3) ].

Pediatric patients weighing over 40 kg and with normal renal function should receive the adult dose.

It has not been determined how to adjust ZOSYN dosage in pediatric patients with renal impairment.

2.5 Reconstitution and Dilution of Powder Formulations Pharmacy bulk vials Reconstituted stock solution must be transferred and further diluted for intravenous infusion.

The pharmacy bulk vial is for use in a hospital pharmacy admixture service only under a laminar flow hood.

After reconstitution, entry into the vial must be made with a sterile transfer set or other sterile dispensing device, and contents should be dispensed as aliquots into intravenous solution using aseptic technique.

Use entire contents of pharmacy bulk vial promptly.

Discard unused portion after 24 hours if stored at room temperature (20°C to 25°C [68°F to 77°F]), or after 48 hours if stored at refrigerated temperature (2°C to 8°C [36°F to 46°F]).

Reconstitute the pharmacy bulk vial with exactly 152 mL of a compatible reconstitution diluent, listed below, to a concentration of 200 mg/mL of piperacillin and 25 mg/mL of tazobactam.

Shake well until dissolved.

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

Single dose vials Reconstitute ZOSYN vials with a compatible reconstitution diluent from the list provided below.

2.25 g, 3.375 g, and 4.5 g ZOSYN should be reconstituted with 10 mL, 15 mL, and 20 mL, respectively.

Swirl until dissolved.

Compatible Reconstitution Diluents for Pharmacy and Single Dose Vials 0.9% sodium chloride for injection Sterile water for injection Dextrose 5% Bacteriostatic saline/parabens Bacteriostatic water/parabens Bacteriostatic saline/benzyl alcohol Bacteriostatic water/benzyl alcohol Reconstituted ZOSYN solutions for both bulk and single dose vials should be further diluted (recommended volume per dose of 50 mL to 150 mL) in a compatible intravenous solution listed below.

Administer by infusion over a period of at least 30 minutes.

During the infusion it is desirable to discontinue the primary infusion solution.

Compatible Intravenous Solutions for Pharmacy and Single Dose Vials 0.9% sodium chloride for injection sterile water for injection Maximum recommended volume per dose of sterile water for injection is 50 mL.

Dextran 6% in saline Dextrose 5% Lactated Ringer’s Solution (compatible only with reformulated ZOSYN containing EDTA and is compatible for co-administration via a Y-site) ZOSYN should not be mixed with other drugs in a syringe or infusion bottle since compatibility has not been established.

ZOSYN is not chemically stable in solutions that contain only sodium bicarbonate and solutions that significantly alter the pH.

ZOSYN should not be added to blood products or albumin hydrolysates.

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

Stability of ZOSYN Powder Formulations Following Reconstitution ZOSYN reconstituted from bulk and single vials is stable in glass and plastic containers (plastic syringes, I.V.

bags and tubing) when used with compatible diluents.

The pharmacy bulk vial should NOT be frozen after reconstitution.

Discard unused portions after storage for 24 hours at room temperature or after storage for 48 hours at refrigerated temperature (2°C to 8°C [36°F to 46°F]).

Single dose or pharmacy vials should be used immediately after reconstitution.

Discard any unused portion after 24 hours if stored at room temperature (20°C to 25°C [68°F to 77°F]), or after 48 hours if stored at refrigerated temperature (2°C to 8°C [36°F to 46°F]).

Vials should not be frozen after reconstitution.

Stability studies in the I.V.

bags have demonstrated chemical stability (potency, pH of reconstituted solution and clarity of solution) for up to 24 hours at room temperature and up to one week at refrigerated temperature.

ZOSYN contains no preservatives.

Appropriate consideration of aseptic technique should be used.

ZOSYN reconstituted from bulk and single vials can be used in ambulatory intravenous infusion pumps.

Stability of ZOSYN in an ambulatory intravenous infusion pump has been demonstrated for a period of 12 hours at room temperature.

Each dose was reconstituted and diluted to a volume of 37.5 mL or 25 mL.

One-day supplies of dosing solution were aseptically transferred into the medication reservoir (I.V.

bags or cartridge).

The reservoir was fitted to a preprogrammed ambulatory intravenous infusion pump per the manufacturer’s instructions.

Stability of ZOSYN is not affected when administered using an ambulatory intravenous infusion pump.

2.6 Directions for Use of ZOSYN in GALAXY Containers ZOSYN Injection is to be administered using sterile equipment, after thawing to room temperature.

ZOSYN containing EDTA is compatible for co-administration via a Y-site intravenous tube with Lactated Ringer’s injection, USP.

Do not add supplementary medication.

Unused portions of ZOSYN should be discarded.

CAUTION: Do not use plastic containers in series connections.

Such use could result in air embolism due to residual air being drawn from the primary container before administration of the fluid from the secondary container is complete.

Thawing of Plastic Container Thaw frozen container at room temperature 20°C to 25°C [68°F to 77°F] or under refrigeration (2°C to 8°C [36°F to 46°F]).

Do not force thaw by immersion in water baths or by microwave irradiation.

Check for minute leaks by squeezing container firmly.

If leaks are detected, discard solution as sterility may be impaired.

The container should be visually inspected.

Components of the solution may precipitate in the frozen state and will dissolve upon reaching room temperature with little or no agitation.

Potency is not affected.

Agitate after solution has reached room temperature.

If after visual inspection, the solution remains cloudy or if an insoluble precipitate is noted or if any seals or outlet ports are not intact, the container should be discarded.

Administer by infusion over a period of at least 30 minutes.

During the infusion it is desirable to discontinue the primary infusion solution.

Storage Store in a freezer capable of maintaining a temperature of -20°C (-4°F).

For GALAXY containers, the thawed solution is stable for 14 days under refrigeration (2°C to 8°C [36°F to 46°F]) or 24 hours at room temperature 20°C to 25°C [68°F to 77°F].

Do not refreeze thawed ZOSYN.

2.7 Compatibility with Aminoglycosides Due to the in vitro inactivation of aminoglycosides by piperacillin, ZOSYN and aminoglycosides are recommended for separate administration.

ZOSYN and aminoglycosides should be reconstituted, diluted, and administered separately when concomitant therapy with aminoglycosides is indicated [ see Drug Interactions (7.1) ].

In circumstances where co-administration via Y-site is necessary, ZOSYN formulations containing EDTA are compatible for simultaneous co-administration via Y-site infusion only with the following aminoglycosides under the following conditions: Table 2: Compatibility with Aminoglycosides Aminoglycoside ZOSYN Dose (grams) ZOSYN Diluent Volume Diluent volumes apply only to single vials and bulk pharmacy containers (mL) Aminoglycoside Concentration Range The concentration ranges in Table 2 are based on administration of the aminoglycoside in divided doses (10–15 mg/kg/day in two daily doses for amikacin and 3–5 mg/kg/day in three daily doses for gentamicin).

Administration of amikacin or gentamicin in a single daily dose or in doses exceeding those stated above via Y-site with ZOSYN containing EDTA has not been evaluated.

See package insert for each aminoglycoside for complete Dosage and Administration instructions.

(mg/mL) Acceptable Diluents Amikacin 2.25 50 1.75 – 7.5 0.9% sodium chloride or 5% dextrose 3.375 100 4.5 150 Gentamicin 2.25 50 0.7 – 3.32 0.9% sodium chloride or 5% dextrose 3.375 ZOSYN 3.375 g per 50 mL GALAXY containers are NOT compatible with gentamicin for co-administration via a Y-site due to the higher concentrations of piperacillin and tazobactam.

100 4.5 150 Only the concentration and diluents for amikacin or gentamicin with the dosages of ZOSYN listed above have been established as compatible for co-administration via Y-site infusion.

Simultaneous co-administration via Y-site infusion in any manner other than listed above may result in inactivation of the aminoglycoside by ZOSYN.

ZOSYN is not compatible with tobramycin for simultaneous co-administration via Y-site infusion.

Compatibility of ZOSYN with other aminoglycosides has not been established.

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

DOSAGE AND ADMINISTRATION

Appetite Stimulation Initially, 2.5 mg Dronabinol Capsules should be administered orally twice daily (b.i.d.), before lunch and supper.

For patients unable to tolerate this 5 mg/day dosage of Dronabinol Capsules, the dosage can be reduced to 2.5 mg/day, administered as a single dose in the evening or at bedtime.

If clinically indicated and in the absence of significant adverse effects, the dosage may be gradually increased to a maximum of 20 mg/day Dronabinol Capsules, administered in divided oral doses.

Caution should be exercised in escalating the dosage of Dronabinol Capsules because of the increased frequency of dose-related adverse experiences at higher dosages.

(See PRECAUTIONS .

) Antiemetic Dronabinol Capsules are best administered at an initial dose of 5 mg/m 2 , given 1 to 3 hours prior to the administration of chemotherapy, then every 2 to 4 hours after chemotherapy is given, for a total of 4 to 6 doses/day.

Should the 5 mg/m 2 dose prove to be ineffective, and in the absence of significant side effects, the dose may be escalated by 2.5 mg/m 2 increments to a maximum of 15 mg/m 2 per dose.

Caution should be exercised in dose escalation, however, as the incidence of disturbing psychiatric symptoms increases significantly at maximum dose.

(See PRECAUTIONS .

)

DOSAGE AND ADMINISTRATION

Captopril tablets should be taken one hour before meals.

Dosage must be individualized.

Hypertension : Initiation of therapy requires consideration of recent antihypertensive drug treatment, the extent of blood pressure elevation, salt restriction, and other clinical circumstances.

If possible, discontinue the patient’s previous antihypertensive drug regimen for one week before starting captopril.

The initial dose of captopril tablets, USP is 25 mg b.i.d.

or t.i.d.

If satisfactory reduction of blood pressure has not been achieved after one or two weeks, the dose may be increased to 50 mg b.i.d.

or t.i.d.

Concomitant sodium restriction may be beneficial when captopril is used alone.

The dose of captopril in hypertension usually does not exceed 50 mg t.i.d.

Therefore, if the blood pressure has not been satisfactorily controlled after one to two weeks at this dose, (and the patient is not already receiving a diuretic), a modest dose of a thiazide-type diuretic (e.g., hydrochlorothiazide, 25 mg daily), should be added.

The diuretic dose may be increased at one- to two-week intervals until its highest usual antihypertensive dose is reached.

If captopril is being started in a patient already receiving a diuretic, captopril therapy should be initiated under close medical supervision (see WARNINGS and PRECAUTIONS: Drug Interactions regarding hypotension ), with dosage and titration of captopril as noted above.

If further blood pressure reduction is required, the dose of captopril may be increased to 100 mg b.i.d.

or t.i.d.

and then, if necessary, to 150 mg b.i.d.

or t.i.d.

(while continuing the diuretic).

The usual dose range is 25 to 150 mg b.i.d.

or t.i.d.

A maximum daily dose of 450 mg captopril should not be exceeded.

For patients with severe hypertension (e.g., accelerated or malignant hypertension), when temporary discontinuation of current antihypertensive therapy is not practical or desirable, or when prompt titration to more normotensive blood pressure levels is indicated, diuretic should be continued but other current antihypertensive medication stopped and captopril dosage promptly initiated at 25 mg b.i.d.

or t.i.d., under close medical supervision.

When necessitated by the patient’s clinical condition, the daily dose of captopril may be increased every 24 hours or less under continuous medical supervision until a satisfactory blood pressure response is obtained or the maximum dose of captopril is reached.

In this regimen, addition of a more potent diuretic, e.g., furosemide, may also be indicated.

Beta-blockers may also be used in conjunction with captopril therapy (see PRECAUTIONS: Drug Interactions ), but the effects of the two drugs are less than additive.

Heart Failure : Initiation of therapy requires consideration of recent diuretic therapy and the possibility of severe salt/volume depletion.

In patients with either normal or low blood pressure, who have been vigorously treated with diuretics and who may be hyponatremic and/or hypovolemic, a starting dose of 6.25 or 12.5 mg t.i.d.

may minimize the magnitude or duration of the hypotensive effect (see WARNINGS: Hypotension ); for these patients, titration to the usual daily dosage can then occur within the next several days.

For most patients the usual initial daily dosage is 25 mg t.i.d.

After a dose of 50 mg t.i.d.

is reached, further increases in dosage should be delayed, where possible, for at least two weeks to determine if a satisfactory response occurs.

Most patients studied have had a satisfactory clinical improvement at 50 or 100 mg t.i.d.

A maximum daily dose of 450 mg of captopril should not be exceeded.

Captopril should generally be used in conjunction with a diuretic and digitalis.

Captopril therapy must be initiated under very close medical supervision.

Left Ventricular Dysfunction After Myocardial Infarction : The recommended dose for long-term use in patients following a myocardial infarction is a target maintenance dose of 50 mg t.i.d.

Therapy may be initiated as early as three days following a myocardial infarction.

After a single dose of 6.25 mg, captopril tablets therapy should be initiated at 12.5 mg t.i.d.

Captopril tablets should then be increased to 25 mg t.i.d.

during the next several days and to a target dose of 50 mg t.i.d.

over the next several weeks as tolerated (see CLINICAL PHARMACOLOGY ).

Captopril tablets may be used in patients treated with other post-myocardial infarction therapies, e.g.

thrombolytics, aspirin, beta blockers.

Diabetic Nephropathy: The recommended dose of captopril tablets for long term use to treat diabetic nephropathy is 25 mg t.i.d.

Other antihypertensives such as diuretics, beta blockers, centrally acting agents or vasodilators may be used in conjuction with captopril tablets if additional therapy is required to further lower blood pressure.

Dosage Adjustment in Renal Impairment : Because captopril is excreted primarily by the kidneys, excretion rates are reduced in patients with impaired renal function.

These patients will take longer to reach steady-state captopril levels and will reach higher steady-state levels for a given daily dose than patients with normal renal function.

Therefore, these patients may respond to smaller or less frequent doses.

Accordingly, for patients with significant renal impairment, initial daily dosage of captopril should be reduced, and smaller increments utilized for titration, which should be quite slow (one- to two-week intervals).

After the desired therapeutic effect has been achieved, the dose should be slowly back-titrated to determine the minimal effective dose.

When concomitant diuretic therapy is required, a loop diuretic (e.g., furosemide), rather than a thiazide diuretic, is preferred in patients with severe renal impairment.

(See WARNINGS: Anaphylactoid reactions during membrane exposure and PRECAUTIONS: Hemodialysis .)

DOSAGE AND ADMINISTRATION

If diarrhea occurs during therapy, this antibiotic should be discontinued.

(See WARNING box).

Adults: Parenteral (I.M.

or I.V.

Administration): Serious infections due to aerobic gram-positive cocci and the more susceptible anaerobes (NOT generally including Bacteroides fragilis , Peptococcus species and Clostridium species other than Clostridium perfringens ): 600 to 1200 mg/day in 2, 3 or 4 equal doses.

More severe infections, particularly those due to proven or suspected Bacteroides fragilis , Peptococcus species, or Clostridium species other than Clostridium perfringens : 1200 to 2700 mg/day in 2, 3 or 4 equal doses.

For more serious infections, these doses may have to be increased.

In life-threatening situations due to either aerobes or anaerobes, these doses may be increased.

Doses of as much as 4800 mg daily have been given intravenously to adults.

See Dilution and Infusion Rates section below.

Single I.M.

injections of greater than 600 mg are not recommended.

Alternatively, drug may be administered in the form of a single rapid infusion of the first dose followed by continuous I.V.

infusion as follows: To maintain serum clindamycin levels Above 4 mcg/mL Above 5 mcg/mL Above 6 mcg/mL Rapid infusion rate 10 mg/min for 30 min 15 mg/min for 30 min 20 mg/min for 30 min Maintenance infusion rate 0.75 mg/min 1 mg/min 1.25 mg/min Neonates (less than 1 month): 15 to 20 mg/kg/day in three to four equal doses.

The lower dosage may be adequate for small prematures.

Pediatric patients (1 month of age to 16 years): Parenteral (I.M.

or I.V.) administration: 20 to 40 mg/kg/day in 3 or 4 equal doses.

The higher doses would be used for more severe infections.

As an alternative to dosing on a body weight basis, pediatric patients may be dosed on the basis of square meters body surface: 350 mg/m 2 /day for serious infections and 450 mg/m 2 /day for more severe infections.

Parenteral therapy may be changed to clindamycin palmitate hydrochloride for oral solution or clindamycin hydrochloride capsules when the condition warrants and at the discretion of the physician.

In cases of β-hemolytic streptococcal infections, treatment should be continued for at least 10 days.

Dilution and Infusion Rates: Clindamycin phosphate must be diluted prior to I.V.

administration.

The concentration of clindamycin in diluent for infusion should not exceed 18 mg per mL.

Infusion rates should not exceed 30 mg per minute.

The usual infusion dilutions and rates are as follows: Dose Diluent Time 300 mg 600 mg 900 mg 1200 mg 50 mL 50 mL 50-100 mL 100 mL 10 min 20 min 30 min 40 min Administration of more than 1200 mg in a single 1-hour infusion is not recommended.

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

Dilution and Compatibility: Physical and biological compatibility studies monitored for 24 hours at room temperature have demonstrated no inactivation or incompatibility with the use of clindamycin phosphate in I.V.

solutions containing sodium chloride, glucose, calcium or potassium, and solutions containing vitamin B complex in concentrations usually used clinically.

No incompatibility has been demonstrated with the antibiotics cephalothin, kanamycin, gentamicin, penicillin or carbenicillin.

The following drugs are physically incompatible with clindamycin phosphate: ampicillin sodium, phenytoin sodium, barbiturates, aminophylline, calcium gluconate, and magnesium sulfate.

The compatibility and duration of stability of drug admixtures will vary depending on concentration and other conditions.

Physico-Chemical Stability of Diluted Solutions of Clindamycin: Room temperature: 6, 9, and 12 mg/mL (equivalent to clindamycin base) in 5% Dextrose Injection, 0.9% Sodium Chloride Injection, or Lactated Ringer’s Injection in glass bottles or minibags, demonstrated physical and chemical stability for at least 16 days at 25°C.

Also, 18 mg/mL (equivalent to clindamycin base) in 5% Dextrose Injection, in minibags, demonstrated physical and chemical stability for at least 16 days at 25°C.

Refrigeration: 6, 9 and 12 mg/mL (equivalent to clindamycin base) in 5% Dextrose Injection, 0.9% Sodium Chloride Injection, or Lactated Ringer’s Injection in glass bottles or minibags, demonstrated physical and chemical stability for at least 32 days at 4°C.

IMPORTANT: This chemical stability information in no way indicates that it would be acceptable practice to use this product well after the preparation time.

Good professional practice suggests that compounded admixtures should be administered as soon after preparation as is feasible.

Frozen: 6, 9 and 12 mg/mL (equivalent to clindamycin base) in 5% Dextrose Injection, 0.9% Sodium Chloride Injection, or Lactated Ringer’s Injection in minibags demonstrated physical and chemical stability for at least eight weeks at -10°C.

Frozen solutions should be thawed at room temperature and not refrozen.

Caution: Do not use plastic containers in series connections.

Such use could result in air embolism due to residual air being drawn from the primary container before administration of the fluid from the secondary container is complete.