Author: druginteractionchecker_lgaiz4

DOSAGE AND ADMINISTRATION

Bisoprolol is an effective treatment of hypertension in once-daily doses of 2.5 to 40 mg, while hydrochlorothiazide is effective in doses of 12.5 to 50 mg.

In clinical trials of bisoprolol/hydrochlorothiazide combination therapy using bisoprolol doses of 2.5 to 20 mg and hydrochlorothiazide doses of 6.25 to 25 mg, the antihypertensive effects increased with increasing doses of either component.

The adverse effects (see WARNINGS ) of bisoprolol are a mixture of dose-dependent phenomena (primarily bradycardia, diarrhea, asthenia, and fatigue) and dose-independent phenomena (eg, occasional rash); those of hydrochlorothiazide are a mixture of dose-dependent phenomena (primarily hypokalemia) and dose-independent phenomena (eg, possibly pancreatitis); the dose-dependent phenomena for each being much more common than the dose-independent phenomena.

The latter consist of those few that are truly idiosyncratic in nature or those that occur with such low frequency that a dose relationship may be difficult to discern.

Therapy with a combination of bisoprolol and hydrochlorothiazide will be associated with both sets of dose-independent adverse effects, and to minimize these, it may be appropriate to begin combination therapy only after a patient has failed to achieve the desired effect with monotherapy.

On the other hand, regimens that combine low doses of bisoprolol and hydrochlorothiazide should produce minimal dose-dependent adverse effects, eg, bradycardia, diarrhea, asthenia and fatigue, and minimal dose-dependent adverse metabolic effects, ie, decreases in serum potassium (see CLINICAL PHARMACOLOGY ).

Therapy Guided by Clinical Effect A patient whose blood pressure is not adequately controlled with 2.5-20 mg bisoprolol daily may instead be given ZIAC.

Patients whose blood pressures are adequately controlled with 50 mg of hydrochlorothiazide daily, but who experience significant potassium loss with this regimen, may achieve similar blood pressure control without electrolyte disturbance if they are switched to ZIAC.

Initial Therapy Antihypertensive therapy may be initiated with the lowest dose of ZIAC, one 2.5/6.25 mg tablet once daily.

Subsequent titration (14-day intervals) may be carried out with ZIAC tablets up to the maximum recommended dose 20/12.5 mg (two 10/6.25 mg tablets) once daily, as appropriate.

Replacement Therapy The combination may be substituted for the titrated individual components.

Cessation of Therapy If withdrawal of ZIAC therapy is planned, it should be achieved gradually over a period of about 2 weeks.

Patients should be carefully observed.

Patients with Renal or Hepatic Impairment: As noted in the WARNINGS section, caution must be used in dosing/titrating patients with hepatic impairment or renal dysfunction.

Since there is no indication that hydrochlorothiazide is dialyzable, and limited data suggest that bisoprolol is not dialyzable, drug replacement is not necessary in patients undergoing dialysis.

Geriatric Patients: Dosage adjustment on the basis of age is not usually necessary, unless there is also significant renal or hepatic dysfunction (see above and WARNINGS section).

Pediatric Patients: There is no pediatric experience with ZIAC.

DOSAGE AND ADMINISTRATION

Directions adults and children 12 years of age and over: take 3 lozenges every 6-8 hours, do not take more than 12 lozenges per day children 6 to under 12 years of age: take 1 lozenge every 4 hours, do not take more than 6 lozenges per day children 4 to under 6 years of age: ask a doctor do not use in children under 4 years of age

DOSAGE AND ADMINISTRATION

Directions find right dose on chart below mL = milliliters repeat dose every 4 hours do not give more than 6 times in 24 hours Age (yr) Dose (mL) under 4 years do not use 4 to 5 years 5 mL 6 to 11 years 10 mL Attention: use only enclosed dosing cup specifically designed for use with this product.

Do not use any other dosing device.

DOSAGE AND ADMINISTRATION

Ceftriaxone may be administered intravenously or intramuscularly.

Do not use diluents containing calcium, such as Ringer’s solution or Hartmann’s solution, to reconstitute ceftriaxone vials or to further dilute a reconstituted vial for IV administration because a precipitate can form.

Precipitation of ceftriaxone-calcium can also occur when ceftriaxone is mixed with calcium-containing solutions in the same IV administration line.

Ceftriaxone must not be administered simultaneously with calcium-containing IV solutions, including continuous calcium-containing infusions such as parenteral nutrition via a Y-site.

However, in patients other than neonates, ceftriaxone and calcium-containing solutions may be administered sequentially of one another if the infusion lines are thoroughly flushed between infusions with a compatible fluid (see WARNINGS ).

There have been no reports of an interaction between ceftriaxone and oral calcium-containing products or interaction between intramuscular ceftriaxone and calcium-containing products (IV or oral).

Neonates Hyperbilirubinemic neonates, especially prematures, should not be treated with ceftriaxone for injection.

Ceftriaxone is contraindicated in premature neonates (see CONTRAINDICATIONS ).

Ceftriaxone is contraindicated in neonates (≤ 28 days) if they require (or are expected to require) treatment with calcium-containing IV solutions, including continuous calcium-containing infusions such as parenteral nutrition because of the risk of precipitation of ceftriaxone-calcium (see CONTRAINDICATIONS ).

Intravenous doses should be given over 60 minutes in neonates to reduce the risk of bilirubin encephalopathy.

Pediatric Patients For the treatment of skin and skin structure infections, the recommended total daily dose is 50 to 75 mg/kg given once a day (or in equally divided doses twice a day).

The total daily dose should not exceed 2 grams.

For the treatment of acute bacterial otitis media, a single intramuscular dose of 50 mg/kg (not to exceed 1 gram) is recommended (see INDICATIONS AND USAGE ).

For the treatment of serious miscellaneous infections other than meningitis, the recommended total daily dose is 50 to 75 mg/kg, given in divided doses every 12 hours.

The total daily dose should not exceed 2 grams.

In the treatment of meningitis, it is recommended that the initial therapeutic dose be 100 mg/kg (not to exceed 4 grams).

Thereafter, a total daily dose of 100 mg/kg/day (not to exceed 4 grams daily) is recommended.

The daily dose may be administered once a day (or in equally divided doses every 12 hours).

The usual duration of therapy is 7 to 14 days.

Adults The usual adult daily dose is 1 to 2 grams given once a day (or in equally divided doses twice a day) depending on the type and severity of infection.

The total daily dose should not exceed 4 grams.

If Chlamydia trachomatis is a suspected pathogen, appropriate antichlamydial coverage should be added, because ceftriaxone sodium has no activity against this organism.

For the treatment of uncomplicated gonococcal infections, a single intramuscular dose of 250 mg is recommended.

For preoperative use (surgical prophylaxis), a single dose of 1 gram administered intravenously 1/2 to 2 hours before surgery is recommended.

Generally, ceftriaxone therapy should be continued for at least 2 days after the signs and symptoms of infection have disappeared.

The usual duration of therapy is 4 to 14 days; in complicated infections, longer therapy may be required.

When treating infections caused by Streptococcus pyogenes , therapy should be continued for at least 10 days.

No dosage adjustment is necessary for patients with impairment of renal or hepatic function (see PRECAUTIONS ).

The dosages recommended for adults require no modification in elderly patients, up to 2 g per day, provided there is no severe renal and hepatic impairment (see PRECAUTIONS ).

Directions for Use Intramuscular Administration Reconstitute ceftriaxone sodium powder with the appropriate diluent (see : Compatibility and Stability ).

Inject diluent into vial, shake vial thoroughly to form solution.

Withdraw entire contents of vial into syringe to equal total labeled dose.

After reconstitution, each 1 mL of solution contains approximately 250 mg or 350 mg equivalent of ceftriaxone according to the amount of diluent indicated below.

If required, more dilute solutions could be utilized.

A 350 mg/mL concentration is not recommended for the 250 mg vial since it may not be possible to withdraw the entire contents.

As with all intramuscular preparations, ceftriaxone should be injected well within the body of a relatively large muscle; aspiration helps to avoid unintentional injection into a blood vessel.

Vial Dosage Size Amount of Diluent to be Added 250 mg/mL 350 mg/mL 250 mg 0.9 mL – 500 mg 1.8 mL 1 mL 1 g 3.6 mL 2.1 mL 2 g 7.2 mL 4.2 mL Intravenous Administration Ceftriaxone should be administered intravenously by infusion over a period of 30 minutes, except in neonates where administration over 60 minutes is recommended to reduce the risk of bilirubin encephalopathy.

Concentrations between 10 mg/mL and 40 mg/mL are recommended; however, lower concentrations may be used if desired.

Reconstitute vials with an appropriate IV diluent (see : Compatibility and Stability ).

Vial Dosage Size Amount of Diluent to be Added 250 mg 2.4 mL 500 mg 4.8 mL 1 g 9.6 mL 2 g 19.2 mL After reconstitution, each 1 mL of solution contains approximately 100 mg equivalent of ceftriaxone.

Withdraw entire contents and dilute to the desired concentration with the appropriate IV diluent.

Compatibility and Stability Do not use diluents containing calcium, such as Ringer’s solution or Hartmann’s solution, to reconstitute ceftriaxone for injection vials or to further dilute a reconstituted vial for IV administration.

Particulate formation can result.

Ceftriaxone has been shown to be compatible with Flagyl® IV (metronidazole hydrochloride).

The concentration should not exceed 5 to 7.5 mg/mL metronidazole hydrochloride with ceftriaxone 10 mg/mL as an admixture.

The admixture is stable for 24 hours at room temperature only in 0.9% sodium chloride injection or 5% dextrose in water (D5W).

No compatibility studies have been conducted with the Flagyl® IV RTU® (metronidazole) formulation or using other diluents.

Metronidazole at concentrations greater than 8 mg/mL will precipitate.

Do not refrigerate the admixture as precipitation will occur.

Vancomycin, amsacrine, aminoglycosides, and fluconazole are incompatible with ceftriaxone in admixtures.

When any of these drugs are to be administered concomitantly with ceftriaxone by intermittent intravenous infusion, it is recommended that they be given sequentially, with thorough flushing of the intravenous lines (with one of the compatible fluids) between the administrations.

Ceftriaxone for injection solutions should not be physically mixed with or piggybacked into solutions containing other antimicrobial drugs or into diluent solutions other than those listed above, due to possible incompatibility (see WARNINGS ).

Ceftriaxone sodium sterile powder should be stored at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature] and protected from light.

After reconstitution, protection from normal light is not necessary.

The color of solutions ranges from light yellow to amber, depending on the length of storage, concentration and diluent used.

Ceftriaxone intramuscular solutions remain stable (loss of potency less than 10%) for the following time periods: Diluent Concentration Storage mg/mL Room Temperature (25°C) Refrigerated (4°C) Sterile Water for Injection 100 250, 350 2 days 24 hours 10 days 3 days 0.9% Sodium Chloride Solution 100 250, 350 2 days 24 hours 10 days 3 days 5% Dextrose Solution 100 250, 350 2 days 24 hours 10 days 3 days Bacteriostatic Water + 0.9% Benzyl Alcohol 100 250, 350 24 hours 24 hours 10 days 3 days 1% Lidocaine Solution (without epinephrine) 100 250, 350 24 hours 24 hours 10 days 3 days Ceftriaxone intravenous solutions, at concentrations of 10, 20 and 40 mg/mL, remain stable (loss of potency less than 10%) for the following time periods stored in glass or PVC containers: Diluent Storage Room Temperature (25°C) Refrigerated (4°C) Sterile Water 2 days 10 days 0.9% Sodium Chloride Solution 2 days 10 days 5% Dextrose Solution 2 days 10 days 10% Dextrose Solution 2 days 10 days 5% Dextrose + 0.9% Sodium Chloride Solution 2 days Incompatible 5% Dextrose + 0.45% Sodium Chloride Solution 2 days Incompatible * Data available for 10 to 40 mg/mL concentrations in this diluent in PVC containers only.

The following intravenous ceftriaxone solutions are stable at room temperature (25°C) for 24 hours, at concentrations between 10 mg/mL and 40 mg/mL: Sodium Lactate (PVC container), 10% Invert Sugar (glass container), 5% Sodium Bicarbonate (glass container), Freamine III (glass container), Normosol-M in 5% Dextrose (glass and PVC containers), Ionosol-B in 5% Dextrose (glass container), 5% Mannitol (glass container), 10% Mannitol (glass container).

After the indicated stability time periods, unused portions of solutions should be discarded.

NOTE: Parenteral drug products should be inspected visually for particulate matter before administration.

Ceftriaxone reconstituted with 5% Dextrose or 0.9% Sodium Chloride solution at concentrations between 10 mg/mL and 40 mg/mL, and then stored in frozen state (-20°C) in PVC or polyolefin containers, remains stable for 26 weeks.

Frozen solutions of ceftriaxone for injection should be thawed at room temperature before use.

After thawing, unused portions should be discarded.

DO NOT REFREEZE .

DOSAGE AND ADMINISTRATION

General Considerations: The steady-state peak serum theophylline concentration is a function of the dose, the dosing interval, and the rate of theophylline absorption and clearance in the individual patient.

Because of marked individual differences in the rate of theophylline clearance, the dose required to achieve a peak serum theophylline concentration in the 10-20 mcg/mL range varies fourfold among otherwise similar patients in the absence of factors known to alter theophylline clearance (e.g., 400- 1600 mg/day in adults <60 years old and 10-36 mg/kg/day in children 1-9 years old).

For a given population there is no single theophylline dose that will provide both safe and effective serum concentrations for all patients.

Administration of the median theophylline dose required to achieve a therapeutic serum theophylline concentration in a given population may result in either sub-therapeutic or potentially toxic serum theophylline concentrations in individual patients.

For example, at a dose of 900 mg/d in adults <60 years or 22 mg/kg/d in children 1-9 years, the steady state peak serum theophylline concentration will be <10 mcg/mL in about 30% of patients, 10-20 mcg/mL in about 50% and 20-30 mcg/mL in about 20% of patients.

The dos e of theophylline mus t be individ ualized on the bas is of peak s erum theophylline concentration meas urements in order to achieve a dos e that will provide maximum potential benefit with minimal risk to adverse effects .

Transient caffeine-like adverse effects and excessive serum concentrations in slow metabolizers can be avoided in most patients by starting with a sufficiently low dose and slowly increasing the dose, if judged to be clinically indicated, in small increments (See Table V ).

Dose increases should only be made if the previous dosage is well tolerated and at intervals of no less than 3 days to allow serum theophylline concentrations to reach the new steady state.

Dosage adjustment should be guided by serum theophylline concentration measurement (see PRECAUTIONS, Laboratory Tests and , Table VI ).

Health care providers should instruct patients and care givers to discontinue any dosage that causes adverse effects, to withhold the medication until these symptoms are gone and to then resume therapy at a lower, previously tolerated dosage (see WARNINGS ).

If the patient’s symptoms are well controlled, there are no apparent adverse effects, and no intervening factors that might alter dosage requirements (see WARNINGS and PRECAUTIONS ), serum theophylline concentrations should be monitored at 6 month intervals for rapidly growing children and at yearly intervals for all others.

In acutely ill patients, serum theophylline concentrations should be monitored at frequent intervals, e.g., every 24 hours.

Theophylline distributes poorly into body fat, therefore, mg/kg dose should be calculated on the basis of ideal body weight.

Table V contains theophylline dosing titration schema recommended for patients in various age groups and clinical circumstances.

Table VI contains recommendations for theophylline dosage adjustment based upon serum theophylline concentrations.

Application of these general dos ing recommendat ions to individual patients mus t take into account the unique clinical characteris tics of each patient.

In general, these recommendations should serve as the upper limit for dos age adj ustments in order to decrease the risk of potentially serious adverse events ass ociated with unexpected large increases in s erum theophylline concentration.

A.

Infants <1 year old.

1.

Initial Dosage.

a.

Premature Neonates: i.

<24 days postnatal age; 1.0 mg/kg every 12 hr ii.

≥ 24 days postnatal age; 1.5 mg/kg every 12 hr b.

Full term infants and infants up to 52 weeks of age: Total daily dose (mg) = [(0.2 x age in weeks)+5.0] x (Kg body Wt).

i.

up to age 26 weeks; divide dose into 3 equal amounts administered at 8 hour intervals ii.

≥26 weeks of age; divide dose into 4 equal amounts administered at 6 hour intervals.

2.

Final Dosage.

Adjusted to maintain a peak steady state serum theophylline concentration of 5-10 mcg/ml in neonates and 10-15 mcg/mL in older infants (see Table VI ).

Since the time required to reach steady-state is a function of theophylline half-life, up to 5 days may be required to achieve steady state in a premature neonate while only 2-3 days may be required in a 6 month old infant without other risk factors for impaired clearance in the absence of a loading dose.

If a s erum theophylline concentrati on is obtained before steady s tate is achieved, the maintena nce dose s hould not be increased, even if the s erum theophylline concentration is <10 mcg/mL.

B.

Children (1-15 years ) and ad ults (16-60 years) without ris k factors for impaired clearance.

Table V.

Dosing initation and titration (as anhydrous theophylline).* Titration Step Children 45 kg and adults 1.

Starting Dosage 12-14 mg/kg/day up to a maximum of 300 mg/day divided Q4-6 hrs* 300 mg/day divided Q6-8 hrs* 2.

After 3 days, if tolerated, increase dose to: 16 mg/kg/day up to a maximum of 400 mg/day divided Q4-6 hrs* 400 mg/day divided Q6-8 hrs* 3.

After 3 more days, if tolerated , increase dose to: 20 mg/kg/day up to a maximum of 600 mg/day divided Q4-6 hrs* 600 mg/day divided Q6-8 hrs* C.

Patients With Risk Factors For Impaired Clearance, The Elderly (>60 Years), And Those In Whom It Is Not Feasible To Monitor Serum Theophylline Concentrations: In children 1-15 years of age, the final theophylline dose should not exceed 16 mg/kg/day up to a maximum of 400 mg/day in the presence of risk factors for reduced theophylline clearance (see WARNINGS ) or if it is not feasible to monitor serum theophylline concentrations.

In adolescents ≥16 years and adults, including the elderly, the final theophylline dose should not exceed 400 mg/day in the presence of risk factors for reduced theophylline clearance (see WARNINGS ) or if it is not feasible to monitor serum theophylline concentrations.

D.

Loading Dose for Acute Bronchodilatation : An inhaled beta-2 selective agonist, alone or in combination with a systemically administered corticosteroid, is the most effective treatment for acute exacerbations of reversible airways obstruction.

Theophylline is a relatively weak bronchodilator, is less effective than an inhaled beta-2 selective agonist and provides no added benefit in the treatment of acute bronchospasm.

If an inhaled or parenteral beta agonist is not available, a loading dose of an oral immediate release theophylline can be used as a temporary measure.

A single 5 mg/kg dose of theophylline, in a patient who has not received any theophylline in the previous 24 hours, will produce an average peak serum theophylline concentration of 10 mcg/mL (range 5-15 mcg/mL).

If dosing with theophylline is to be continued beyond the loading dose, the guidelines in Sections A.1.b., B.3, or C., above, should be utilized and serum theophylline concentration monitored at 24 hour intervals to adjust final dosage.

* Patients with more rapid metabolism, clinically identified by higher than average dose requirements, should receive a smaller dose more frequently to prevent breakthrough symptoms resulting from low trough concentrations before the next dose.

A reliably absorbed slow-release formulation will decrease fluctuations and permit longer dosing intervals.

VI Table.

Dosage adjustment guided by serum theophylline concentration.

Peak Serum Concentration Dosage Adjustment <9.9 mcg/mL If symptoms are not controlled and current dosage is tolerated, increase dose about 25%.

Recheck serum concentration after three days for further dosage adjustment.

10 to 14.9 mcg/mL If symptoms are controlled and current dosage is tolerated, maintain dose and recheck serum concentration at 6-12 month intervals.

¶ If symptoms are not controlled and current dosage is tolerated consider adding additional medication(s) to treatment regimen.

15-19.9 mcg/mL Consider 10% decrease in dose to provide greater margin of safety even if current dosage is tolerated.¶ 20-24.9 mcg/mL Decrease dose by 25% even if no adverse effects are present.

Recheck serum concentration after 3 days to guide further dosage adjustment.

25-30 mcg/mL Skip next dose and decrease subsequent doses at least 25% even if no adverse effects are present.

Recheck serum concentration after 3 days to guide further dosage adjustment.

If symptomatic, consider whether overdose treatment is indicated (see recommendations for chronic overdosage).

>30 mcg/mL Treat overdose as indicated (see recommendations for chronic overdosage).

If theophylline is subsequently resumed, decrease dose by at least 50% and recheck serum concentration after 3 days to guide further dosage adjustment.

¶ Dose reduction and/or serum theophylline concentration measurement is indicated whenever adverse effects are present, physiologic abnormalities that can reduce theophylline clearance occur (e.g., sustained fever), or a drug that interacts with theophylline is added or discontinued (see WARNINGS ).

DOSAGE AND ADMINISTRATION

Directions Adults and children 2 years of age and older: Apply to the affected area not more than 3 to 4 times daily.

Children under 2 year of age: consult a doctor.

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

2 Evaluate iron status before and during treatment and maintain iron repletion.

Correct or exclude other causes of anemia before initiating treatment ( 2.1 ).

In pregnant women, lactating women, neonates, infants: Use only single-dose vials ( 2.1 ).

Patients with CKD: Initial dose: 50 to 100 Units/kg 3 times weekly (adults) and 50 Units/kg 3 times weekly (pediatric patients).

Individualize maintenance dose.

Intravenous route recommended for patients on hemodialysis ( 2.2 ).

Patients on Zidovudine due to HIV Infection: 100 Units/kg 3 times weekly ( 2.3 ).

Patients with Cancer on Chemotherapy: 40,000 Units weekly or 150 Units/kg 3 times weekly (adults); 600 Units/kg intravenously weekly (pediatric patients ≥ 5 years) ( 2.4 ).

Surgery Patients: 300 Units/kg per day daily for 15 days or 600 Units/kg weekly ( 2.5 ).

2.1 Important Dosing Information Evaluation of Iron Stores and Nutritional Factors Evaluate the iron status in all patients before and during treatment.

Administer supplemental iron therapy when serum ferritin is less than 100 mcg/L or when serum transferrin saturation is less than 20%.

The majority of patients with CKD will require supplemental iron during the course of ESA therapy.

Monitoring of Response to Therapy Correct or exclude other causes of anemia (e.g., vitamin deficiency, metabolic or chronic inflammatory conditions, bleeding, etc.) before initiating PROCRIT.

Following initiation of therapy and after each dose adjustment, monitor hemoglobin weekly until the hemoglobin level is stable and sufficient to minimize the need for RBC transfusion.

Selection of Formulation In pregnant women, lactating women, neonates, and infants use only single-dose vials (the benzyl alcohol-free formulation) [see Contraindications (4) and Use in Specific Populations (8.1 , 8.2 , and 8.4) ].

2.2 Patients with Chronic Kidney Disease In controlled trials, patients experienced greater risks for death, serious adverse cardiovascular reactions, and stroke when administered ESAs to target a hemoglobin level of greater than 11 g/dL.

No trial has identified a hemoglobin target level, ESA dose, or dosing strategy that does not increase these risks.

Individualize dosing and use the lowest dose of PROCRIT sufficient to reduce the need for RBC transfusions [see Warnings and Precautions (5.1) ] .

Physicians and patients should weigh the possible benefits of decreasing transfusions against the increased risks of death and other serious cardiovascular adverse reactions [see Boxed Warning and Clinical Studies (14) ].

For all patients with CKD: When initiating or adjusting therapy, monitor hemoglobin levels at least weekly until stable, then monitor at least monthly.

When adjusting therapy consider hemoglobin rate of rise, rate of decline, ESA responsiveness and hemoglobin variability.

A single hemoglobin excursion may not require a dosing change.

Do not increase the dose more frequently than once every 4 weeks.

Decreases in dose can occur more frequently.

Avoid frequent dose adjustments.

If the hemoglobin rises rapidly (e.g., more than 1 g/dL in any 2-week period), reduce the dose of PROCRIT by 25% or more as needed to reduce rapid responses.

For patients who do not respond adequately, if the hemoglobin has not increased by more than 1 g/dL after 4 weeks of therapy, increase the dose by 25%.

For patients who do not respond adequately over a 12-week escalation period, increasing the PROCRIT dose further is unlikely to improve response and may increase risks.

Use the lowest dose that will maintain a hemoglobin level sufficient to reduce the need for RBC transfusions.

Evaluate other causes of anemia.

Discontinue PROCRIT if responsiveness does not improve.

For adult patients with CKD on dialysis: Initiate PROCRIT treatment when the hemoglobin level is less than 10 g/dL.

If the hemoglobin level approaches or exceeds 11 g/dL, reduce or interrupt the dose of PROCRIT.

The recommended starting dose for adult patients is 50 to 100 Units/kg 3 times weekly intravenously or subcutaneously.

The intravenous route is recommended for patients on hemodialysis.

For adult patients with CKD not on dialysis: Consider initiating PROCRIT treatment only when the hemoglobin level is less than 10 g/dL and the following considerations apply: The rate of hemoglobin decline indicates the likelihood of requiring a RBC transfusion and , Reducing the risk of alloimmunization and/or other RBC transfusion-related risks is a goal If the hemoglobin level exceeds 10 g/dL, reduce or interrupt the dose of PROCRIT, and use the lowest dose of PROCRIT sufficient to reduce the need for RBC transfusions.

The recommended starting dose for adult patients is 50 to 100 Units/kg 3 times weekly intravenously or subcutaneously.

For pediatric patients with CKD: Initiate PROCRIT treatment only when the hemoglobin level is less than 10 g/dL.

If the hemoglobin level approaches or exceeds 12 g/dL, reduce or interrupt the dose of PROCRIT.

The recommended starting dose for pediatric patients (ages 1 month or older) is 50 Units/kg 3 times weekly intravenously or subcutaneously.

When treating patients who have chronic kidney disease and cancer, physicians should refer to Warnings and Precautions (5.1 and 5.2) .

2.3 Zidovudine-treated Patients with HIV Infection Starting Dose The recommended starting dose in adults is 100 Units/kg as an intravenous or subcutaneous injection 3 times per week.

Dose Adjustment If hemoglobin does not increase after 8 weeks of therapy, increase PROCRIT dose by approximately 50 to 100 Units/kg at 4- to 8-week intervals until hemoglobin reaches a level needed to avoid RBC transfusions or 300 Units/kg.

Withhold PROCRIT if hemoglobin exceeds 12 g/dL.

Resume therapy at a dose 25% below the previous dose when hemoglobin declines to less than 11 g/dL.

Discontinue PROCRIT if an increase in hemoglobin is not achieved at a dose of 300 Units/kg for 8 weeks.

2.4 Patients on Cancer Chemotherapy Initiate PROCRIT in patients on cancer chemotherapy only if the hemoglobin is less than 10 g/dL, and if there is a minimum of two additional months of planned chemotherapy.

Use the lowest dose of PROCRIT necessary to avoid RBC transfusions.

Recommended Starting Dose Adults: 150 Units/kg subcutaneously 3 times per week until completion of a chemotherapy course or 40,000 Units subcutaneously weekly until completion of a chemotherapy course.

Pediatric Patients (5 to 18 years): 600 Units/kg intravenously weekly until completion of a chemotherapy course.

Dose Reduction Reduce dose by 25% if: Hemoglobin increases greater than 1 g/dL in any 2-week period or Hemoglobin reaches a level needed to avoid RBC transfusion.

Withhold dose if hemoglobin exceeds a level needed to avoid RBC transfusion.

Reinitiate at a dose 25% below the previous dose when hemoglobin approaches a level where RBC transfusions may be required.

Dose Increase After the initial 4 weeks of PROCRIT therapy, if hemoglobin increases by less than 1 g/dL and remains below 10 g/dL, increase dose to: 300 Units/kg three times per week in adults or 60,000 Units weekly in adults 900 Units/kg (maximum 60,000 Units) weekly in pediatric patients After 8 weeks of therapy, if there is no response as measured by hemoglobin levels or if RBC transfusions are still required, discontinue PROCRIT.

2.5 Surgery Patients The recommended PROCRIT regimens are: 300 Units/kg per day subcutaneously for 15 days total: administered daily for 10 days before surgery, on the day of surgery, and for 4 days after surgery.

600 Units/kg subcutaneously in 4 doses administered 21, 14, and 7 days before surgery and on the day of surgery.

Deep venous thrombosis prophylaxis is recommended during PROCRIT therapy [see Warnings and Precautions (5.1) ] .

2.6 Preparation and Administration Do not shake.

Do not use PROCRIT that has been shaken or frozen.

Protect vials from light.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration.

Do not use any vials exhibiting particulate matter or discoloration.

Discard unused portions of PROCRIT in preservative-free vials.

Do not re-enter preservative-free vials.

Store unused portions of PROCRIT in multiple-dose vials at 36°F to 46°F (2°C to 8°C).

Discard 21 days after initial entry.

Do not dilute.

Do not mix with other drug solutions except for admixing as described below: Preservative-free PROCRIT from single-dose vials may be admixed in a syringe with bacteriostatic 0.9% sodium chloride injection, USP, with benzyl alcohol 0.9% (bacteriostatic saline) in a 1:1 ratio using aseptic technique at the time of administration.

Do not mix PROCRIT with bacteriostatic saline when administering to pregnant women, lactating women, neonates, and infants [see Use in Specific Populations (8.1 , 8.2 , 8.4) ].

DOSAGE AND ADMINISTRATION

General Principles The goal of replacement therapy is to achieve and maintain a clinical and biochemical euthyroid state.

The goal of suppressive therapy is to inhibit growth and/or function of abnormal thyroid tissue.

The dose of SYNTHROID that is adequate to achieve these goals depends on a variety of factors including the patient’s age, body weight, cardiovascular status, concomitant medical conditions, including pregnancy, concomitant medications, and the specific nature of the condition being treated (see WARNINGS and PRECAUTIONS ).

Hence, the following recommendations serve only as dosing guidelines.

Dosing must be individualized and adjustments made based on periodic assessment of the patient’s clinical response and laboratory parameters (see PRECAUTIONS – Laboratory Tests ).

SYNTHROID is administered as a single daily dose, preferably one-half to one-hour before breakfast.

SYNTHROID should be taken at least 4 hours apart from drugs that are known to interfere with its absorption (see PRECAUTIONS – Drug Interactions ).

Due to the long half-life of levothyroxine, the peak therapeutic effect at a given dose of levothyroxine sodium may not be attained for 4-6 weeks.

Caution should be exercised when administering SYNTHROID to patients with underlying cardiovascular disease, to the elderly, and to those with concomitant adrenal insufficiency (see PRECAUTIONS ).

Specific Patient Populations Hypothyroidism in Adults and in Children in Whom Growth and Puberty are Complete (see WARNINGS and PRECAUTIONS – Laboratory Tests ) Therapy may begin at full replacement doses in otherwise healthy individuals less than 50 years old and in those older than 50 years who have been recently treated for hyperthyroidism or who have been hypothyroid for only a short time (such as a few months).

The average full replacement dose of levothyroxine sodium is approximately 1.7 mcg/kg/day (e.g., 100-125 mcg/day for a 70 kg adult).

Older patients may require less than 1 mcg/kg/day.

Levothyroxine sodium doses greater than 200 mcg/day are seldom required.

An inadequate response to daily doses ≥ 300 mcg/day is rare and may indicate poor compliance, malabsorption, and/or drug interactions.

For most patients older than 50 years or for patients under 50 years of age with underlying cardiac disease, an initial starting dose of 25-50 mcg/day of levothyroxine sodium is recommended, with gradual increments in dose at 6-8 week intervals, as needed.

The recommended starting dose of levothyroxine sodium in elderly patients with cardiac disease is 12.5-25 mcg/day , with gradual dose increments at 4-6 week intervals.

The levothyroxine sodium dose is generally adjusted in 12.5-25 mcg increments until the patient with primary hypothyroidism is clinically euthyroid and the serum TSH has normalized.

In patients with severe hypothyroidism, the recommended initial levothyroxine sodium dose is 12.5-25 mcg/day with increases of 25 mcg/day every 2-4 weeks, accompanied by clinical and laboratory assessment, until the TSH level is normalized.

In patients with secondary (pituitary) or tertiary (hypothalamic) hypothyroidism, the levothyroxine sodium dose should be titrated until the patient is clinically euthyroid and the serum free- T 4 level is restored to the upper half of the normal range.

Pediatric Dosage – Congenital or Acquired Hypothyroidism (see PRECAUTIONS – Laboratory Tests ) General Principles In general, levothyroxine therapy should be instituted at full replacement doses as soon as possible.

Delays in diagnosis and institution of therapy may have deleterious effects on the child’s intellectual and physical growth and development.

Undertreatment and overtreatment should be avoided (see PRECAUTIONS – Pediatric Use ).

SYNTHROID may be administered to infants and children who cannot swallow intact tablets by crushing the tablet and suspending the freshly crushed tablet in a small amount (5-10 mL or 1-2 teaspoons) of water.

This suspension can be administered by spoon or by dropper.

DO NOT STORE THE SUSPENSION .

Foods that decrease absorption of levothyroxine, such as soybean infant formula, should not be used for administering levothyroxine sodium tablets (see PRECAUTIONS – Drug-Food Interactions ).

Newborns The recommended starting dose of levothyroxine sodium in newborn infants is 10-15 mcg/kg/day .

A lower starting dose (e.g., 25 mcg/day) should be considered in infants at risk for cardiac failure, and the dose should be increased in 4-6 weeks as needed based on clinical and laboratory response to treatment.

In infants with very low (< 5 mcg/dL) or undetectable serum T 4 concentrations, the recommended initial starting dose is 50 mcg/day of levothyroxine sodium.

Infants and Children Levothyroxine therapy is usually initiated at full replacement doses, with the recommended dose per body weight decreasing with age (see Table 3 ).

However, in children with chronic or severe hypothyroidism, an initial dose of 25 mcg/day of levothyroxine sodium is recommended with increments of 25 mcg every 2-4 weeks until the desired effect is achieved.

Hyperactivity in an older child can be minimized if the starting dose is one-fourth of the recommended full replacement dose, and the dose is then increased on a weekly basis by an amount equal to one-fourth the full-recommended replacement dose until the full recommended replacement dose is reached.

Table 3.

Levothyroxine Sodium Dosing Guidelines for Pediatric Hypothyroidism AGE Daily Dose Per Kg Body Weight a 0-3 months 10-15 mcg/kg/day 3-6 months 8-10 mcg/kg/day 6-12 months 6-8 mcg/kg/day 1-5 years 5-6 mcg/kg/day 6-12 years 4-5 mcg/kg/day > 12 years but growth and puberty incomplete 2-3 mcg/kg/day Growth and puberty complete 1.7 mcg/kg/day a The dose should be adjusted based on clinical response and laboratory parameters (see PRECAUTIONS – Laboratory Tests and Pediatric Use ).

Pregnancy Pregnancy may increase levothyroxine requirements (see PREGNANCY ).

Subclinical Hypothyroidism If this condition is treated, a lower levothyroxine sodium dose (e.g., 1 mcg/kg/day ) than that used for full replacement may be adequate to normalize the serum TSH level.

Patients who are not treated should be monitored yearly for changes in clinical status and thyroid laboratory parameters.

TSH Suppression in Well-differentiated Thyroid Cancer and Thyroid Nodules The target level for TSH suppression in these conditions has not been established with controlled studies.

In addition, the efficacy of TSH suppression for benign nodular disease is controversial.

Therefore, the dose of SYNTHROID used for TSH suppression should be individualized based on the specific disease and the patient being treated.

In the treatment of well-differentiated (papillary and follicular) thyroid cancer, levothyroxine is used as an adjunct to surgery and radioiodine therapy.

Generally, TSH is suppressed to < 0.1 mU/L, and this usually requires a levothyroxine sodium dose of greater than 2 mcg/kg/day .

However, in patients with high-risk tumors, the target level for TSH suppression may be < 0.01 mU/L.

In the treatment of benign nodules and nontoxic multinodular goiter, TSH is generally suppressed to a higher target (e.g., 0.1 to either 0.5 or 1.0 mU/L) than that used for the treatment of thyroid cancer.

Levothyroxine sodium is contraindicated if the serum TSH is already suppressed due to the risk of precipitating overt thyrotoxicosis (see CONTRAINDICATIONS , WARNINGS and PRECAUTIONS ).

Myxedema Coma Myxedema coma is a life-threatening emergency characterized by poor circulation and hypometabolism, and may result in unpredictable absorption of levothyroxine sodium from the gastrointestinal tract.

Therefore, oral thyroid hormone drug products are not recommended to treat this condition.

Thyroid hormone products formulated for intravenous administration should be administered.