Zoledronic Acid

Zoledronic acid injection must be administered as an intravenous infusion over no less than 15 minutes.

The recommended dose is a 5 mg infusion. The infusion time must not be less than 15 minutes given over a constant infusion rate.

Re-treatment of Paget's Disease

After a single treatment with zoledronic acid injection in Paget's disease an extended remission period is observed. Specific re-treatment data are not available. However, re-treatment with zoledronic acid injection may be considered in patients who have relapsed, based on increases in serum alkaline phosphatase, or in those patients who failed to achieve normalization of their serum alkaline phosphatase, or in those patients with symptoms, as dictated by medical practice.

The zoledronic acid injection infusion time must not be less than 15 minutes given over a constant infusion rate.

The i.v. infusion should be followed by a 10 mL normal saline flush of the intravenous line.

Zoledronic acid injection solution for infusion must not be allowed to come in contact with any calcium or other divalent cation-containing solutions, and should be administered as a single intravenous solution through a separate vented infusion line.

If refrigerated, allow the refrigerated solution to reach room temperature before administration. After opening, the solution is stable for 24 hours at 2°C to 8°C (36°F to 46°F) [see How Supplied/Storage and Handling (16)].

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

The maximum recommended dose of zoledronic acid injection in hypercalcemia of malignancy (albumin-corrected serum calcium greater than or equal to 12 mg/dL [3 mmol/L]) is 4 mg. The 4 mg dose must be given as a single-dose intravenous infusion over no less than 15 minutes. Patients who receive zoledronic acid injection should have serum creatinine assessed prior to each treatment.

Dose adjustments of zoledronic acid injection are not necessary in treating patients for hypercalcemia of malignancy presenting with mild-to-moderate renal impairment prior to initiation of therapy (serum creatinine less than 400 μmol/L or less than 4.5 mg/dL).
 
Patients should be adequately rehydrated prior to administration of zoledronic acid injection [see Warnings and Precautions (5.2)].
 
Consideration should be given to the severity of, as well as the symptoms of, tumor-induced hypercalcemia when considering use of zoledronic acid injection. Vigorous saline hydration, an integral part of hypercalcemia therapy, should be initiated promptly and an attempt should be made to restore the urine output to about 2 L/day throughout treatment. Mild or asymptomatic hypercalcemia may be treated with conservative measures (i.e., saline hydration, with or without loop diuretics). Patients should be hydrated adequately throughout the treatment, but overhydration, especially in those patients who have cardiac failure, must be avoided. Diuretic therapy should not be employed prior to correction of hypovolemia.

Retreatment with zoledronic acid injection 4 mg may be considered if serum calcium does not return to normal or remain normal after initial treatment. It is recommended that a minimum of 7 days elapse before retreatment, to allow for full response to the initial dose. Renal function must be carefully monitored in all patients receiving zoledronic acid injection and serum creatinine must be assessed prior to retreatment with zoledronic acid injection [see Warnings and Precautions (5.2)].

The recommended dose of zoledronic acid injection in patients with multiple myeloma and metastatic bone lesions from solid tumors for patients with creatinine clearance (CrCl)greater than 60 mL/min is 4 mg infused over no less than 15 minutes every 3 to 4 weeks. The optimal duration of therapy is not known.

Upon treatment initiation, the recommended zoledronic acid injection doses for patients with reduced renal function (mild and moderate renal impairment) are listed in Table 1. These doses are calculated to achieve the same area under the curve (AUC) as that achieved in patients with creatinine clearance of 75 mL/min. CrCl is calculated using the Cockcroft-Gault formula [see Warnings and Precautions (5.2)].

During treatment, serum creatinine should be measured before each zoledronic acid injection dose and treatment should be withheld for renal deterioration. In the clinical studies, renal deterioration was defined as follows:

For patients with normal baseline creatinine, increase of 0.5 mg/dL
For patients with abnormal baseline creatinine, increase of 1 mg/dL

In the clinical studies, zoledronic acid injection treatment was resumed only when the creatinine returned to within 10% of the baseline value. Zoledronic acid injection should be reinitiated at the same dose as that prior to treatment interruption.

Patients should also be administered an oral calcium supplement of 500 mg and a multiple vitamin containing 400 international units of vitamin D daily.

Zoledronic acid injection must not be mixed with calcium or other divalent cation-containing infusion solutions, such as Lactated Ringer’s solution, and should be administered as a single intravenous solution in a line separate from all other drugs.
4 mg/5 mL Single-Use Vial
Vials of zoledronic acid injection concentrate for infusion contain overfill allowing for the withdrawal of 5 mL of concentrate (equivalent to 4 mg zoledronic acid). This concentrate should immediately be diluted in 100 mL of sterile 0.9% Sodium Chloride, USP, or 5% Dextrose Injection, USP, following proper aseptic technique, and administered to the patient by infusion. Do not store undiluted concentrate in a syringe, to avoid inadvertent injection.

To prepare reduced doses for patients with baseline CrCl less than or equal to 60 mL/min, withdraw the specified volume of the zoledronic acid injection concentrate from the vial for the dose required (see Table 2).

The withdrawn concentrate must be diluted in 100 mL of sterile 0.9% Sodium Chloride, USP, or 5% Dextrose Injection, USP.

If not used immediately after dilution with infusion media, for microbiological integrity, the solution should be refrigerated at 2°C to 8°C (36°F to 46°F). The refrigerated solution should then be equilibrated to room temperature prior to administration. The total time between dilution, storage in the refrigerator, and end of administration must not exceed 24 hours.

Due to the risk of clinically significant deterioration in renal function, which may progress to renal failure, single doses of zoledronic acid injectionshould not exceed 4 mg and the duration of infusion should be no less than 15 minutes [see Warnings and Precautions (5.3)]. In the trials and in postmarketing experience, renal deterioration, progression to renal failure and dialysis, have occurred in patients, including those treated with the approved dose of 4 mg infused over 15 minutes. There have been instances of this occurring after the initial zoledronic acid injectiondose.

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

The maximum recommended dose of zoledronic acid injection in hypercalcemia of malignancy (albumin-corrected serum calcium greater than or equal 12 mg/dL [3 mmol/L]) is 4 mg. The 4-mg dose must be given as a single-dose intravenous infusion over no less than 15 minutes. Patients who receive zoledronic acid injection should have serum creatinine assessed prior to each treatment.

Dose adjustments of zoledronic acid injection are not necessary in treating patients for hypercalcemia of malignancy presenting with mild-to-moderate renal impairment prior to initiation of therapy (serum creatinine less than 400 μmol/L or less than 4.5 mg/dL).

Patients should be adequately rehydrated prior to administration of zoledronic acid injection [see Warnings And Precautions (5.2)].

Consideration should be given to the severity of, as well as the symptoms of, tumor-induced hypercalcemia when considering use of zoledronic acid injection. Vigorous saline hydration, an integral part of hypercalcemia therapy, should be initiated promptly and an attempt should be made to restore the urine output to about 2 L/day throughout treatment. Mild or asymptomatic hypercalcemia may be treated with conservative measures (i.e., saline hydration, with or without loop diuretics). Patients should be hydrated adequately throughout the treatment, but overhydration, especially in those patients who have cardiac failure, must be avoided. Diuretic therapy should not be employed prior to correction of hypovolemia.

Retreatment with zoledronic acid injection 4 mg may be considered if serum calcium does not return to normal or remain normal after initial treatment. It is recommended that a minimum of 7 days elapse before retreatment, to allow for full response to the initial dose. Renal function must be carefully monitored in all patients receiving zoledronic acid injection and serum creatinine must be assessed prior to retreatment with zoledronic acid injection [see Warnings And Precautions (5.2)].

The recommended dose of zoledronic acid injection in patients with multiple myeloma and metastatic bone lesions from solid tumors for patients with creatinine clearance greater than 60 mL/min is 4 mg infused over no less than 15 minutes every 3 to 4 weeks. The optimal duration of therapy is not known.

Upon treatment initiation, the recommended zoledronic acid injection doses for patients with reduced renal function (mild and moderate renal impairment) are listed in Table 1. These doses are calculated to achieve the same AUC as that achieved in patients with creatinine clearance of 75 mL/min. Creatinine clearance (CrCl) is calculated using the Cockcroft-Gault formula [see Warnings And Precautions (5.2)].

During treatment, serum creatinine should be measured before each zoledronic acid injection dose and treatment should be withheld for renal deterioration. In the clinical studies, renal deterioration was defined as follows:

For patients with normal baseline creatinine, increase of 0.5 mg/dL

For patients with abnormal baseline creatinine, increase of 1 mg/dL

In the clinical studies, zoledronic acid injection treatment was resumed only when the creatinine returned to within 10% of the baseline value. zoledronic acid injection should be reinitiated at the same dose as that prior to treatment interruption.

Patients should also be administered an oral calcium supplement of 500 mg and a multiple vitamin containing 400 IU of Vitamin D daily.

Zoledronic acid injection must not be mixed with calcium or other divalent cation-containing infusion solutions, such as Lactated Ringer's solution, and should be administered as a single intravenous solution in a line separate from all other drugs.

4 mg per 5 mL Single-Use Vial

Vials of zoledronic acid injection concentrate for infusion contain overfill allowing for the withdrawal of 5 mL of concentrate (equivalent to 4 mg zoledronic acid). This concentrate should immediately be diluted in 100 mL of sterile 0.9% Sodium Chloride, USP, or 5% Dextrose Injection, USP, following proper aseptic technique, and administered to the patient by infusion. Do not store undiluted concentrate in a syringe, to avoid inadvertent injection.

To prepare reduced doses for patients with baseline CrCl less than or equal to 60 mL/min, withdraw the specified volume of the zoledronic acid injection concentrate from the vial for the dose required (see Table 2).

The withdrawn concentrate must be diluted in 100 mL of sterile 0.9% Sodium Chloride, USP, or 5% Dextrose Injection, USP.

If not used immediately after dilution with infusion media, for microbiological integrity, the solution should be refrigerated at 2°C to 8°C (36°F to 46°F). The refrigerated solution should then be equilibrated to room temperature prior to administration. The total time between dilution, storage in the refrigerator, and end of administration must not exceed 24 hours. 

Due to the risk of clinically significant deterioration in renal function, which may progress to renal failure, single doses of zoledronic acid injection should not exceed 4 mg and the duration of infusion should be no less than 15 minutes [see Warnings And Precautions (5.2)]. In the trials and in postmarketing experience, renal deterioration, progression to renal failure and dialysis, have occurred in patients, including those treated with the approved dose of 4 mg infused over 15 minutes. There have been instances of this occurring after the initial zoledronic acid injection dose.

The dose is one drop of dorzolamide hydrochloride ophthalmic Solution in the affected eye(s) three times daily. Dorzolamide hydrochloride may be used concomitantly with other topical ophthalmic drug products to lower intraocular pressure. If more than one topical ophthalmic drug is being used, the drugs should be administered at least five minutes apart.

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

The maximum recommended dose of zoledronic acid injection in hypercalcemia of malignancy (albumin-corrected serum calcium greater than or equal 12 mg/dL [3 mmol/L]) is 4 mg. The 4-mg dose must be given as a single-dose intravenous infusion over no less than 15 minutes. Patients who receive zoledronic acid injection should have serum creatinine assessed prior to each treatment.

Dose adjustments of zoledronic acid injection are not necessary in treating patients for hypercalcemia of malignancy presenting with mild-to-moderate renal impairment prior to initiation of therapy (serum creatinine less than 400 μmol/L or less than 4.5 mg/dL).

Patients should be adequately rehydrated prior to administration of zoledronic acid injection [see Warnings And Precautions (5.2)].

Consideration should be given to the severity of, as well as the symptoms of, tumor-induced hypercalcemia when considering use of zoledronic acid injection. Vigorous saline hydration, an integral part of hypercalcemia therapy, should be initiated promptly and an attempt should be made to restore the urine output to about 2 L/day throughout treatment. Mild or asymptomatic hypercalcemia may be treated with conservative measures (i.e., saline hydration, with or without loop diuretics). Patients should be hydrated adequately throughout the treatment, but overhydration, especially in those patients who have cardiac failure, must be avoided. Diuretic therapy should not be employed prior to correction of hypovolemia.

Retreatment with zoledronic acid injection 4 mg may be considered if serum calcium does not return to normal or remain normal after initial treatment. It is recommended that a minimum of 7 days elapse before retreatment, to allow for full response to the initial dose. Renal function must be carefully monitored in all patients receiving zoledronic acid injection and serum creatinine must be assessed prior to retreatment with zoledronic acid injection [see Warnings And Precautions (5.2)].

The recommended dose of zoledronic acid injection in patients with multiple myeloma and metastatic bone lesions from solid tumors for patients with creatinine clearance greater than 60 mL/min is 4 mg infused over no less than 15 minutes every 3 to 4 weeks. The optimal duration of therapy is not known.

Upon treatment initiation, the recommended zoledronic acid injection doses for patients with reduced renal function (mild and moderate renal impairment) are listed in Table 1. These doses are calculated to achieve the same AUC as that achieved in patients with creatinine clearance of 75 mL/min. Creatinine clearance (CrCl) is calculated using the Cockcroft-Gault formula [see Warnings And Precautions (5.2)].

Baseline Creatinine Clearance (mL/min)

Zoledronic acid injection Recommended Dose*

greater than 60

4 mg

50 to 60

3.5 mg

40 to 49

3.3 mg

30 to 39

3 mg

*Doses calculated assuming target AUC of 0.66 (mg•hr/L) (CrCl = 75 mL/min)

During treatment, serum creatinine should be measured before each zoledronic acid injection dose and treatment should be withheld for renal deterioration. In the clinical studies, renal deterioration was defined as follows:

          For patients with normal baseline creatinine, increase of 0.5 mg/dL
          For patients with abnormal baseline creatinine, increase of 1 mg/dL

In the clinical studies, zoledronic acid injection treatment was resumed only when the creatinine returned to within 10% of the baseline value. zoledronic acid injection should be reinitiated at the same dose as that prior to treatment interruption.

Patients should also be administered an oral calcium supplement of 500 mg and a multiple vitamin containing 400 IU of Vitamin D daily.

Zoledronic acid injection must not be mixed with calcium or other divalent cation-containing infusion solutions, such as Lactated Ringer’s solution, and should be administered as a single intravenous solution in a line separate from all other drugs.

4 mg per 5 mL Single-Use Vial

Vials of zoledronic acid injection concentrate for infusion contain overfill allowing for the withdrawal of 5 mL of concentrate (equivalent to 4 mg zoledronic acid). This concentrate should immediately be diluted in 100 mL of sterile 0.9% Sodium Chloride, USP, or 5% Dextrose Injection, USP, following proper aseptic technique, and administered to the patient by infusion. Do not store undiluted concentrate in a syringe, to avoid inadvertent injection.

To prepare reduced doses for patients with baseline CrCl less than or equal to 60 mL/min, withdraw the specified volume of the zoledronic acid injection concentrate from the vial for the dose required (see Table 2).

The withdrawn concentrate must be diluted in 100 mL of sterile 0.9% Sodium Chloride, USP, or 5% Dextrose Injection, USP.

If not used immediately after dilution with infusion media, for microbiological integrity, the solution should be refrigerated at 2°C to 8°C (36°F to 46°F). The refrigerated solution should then be equilibrated to room temperature prior to administration. The total time between dilution, storage in the refrigerator, and end of administration must not exceed 24 hours.

Due to the risk of clinically significant deterioration in renal function, which may progress to renal failure, single doses of zoledronic acid injection should not exceed 4 mg and the duration of infusion should be no less than 15 minutes [see Warnings And Precautions (5.2)]. In the trials and in postmarketing experience, renal deterioration, progression to renal failure and dialysis, have occurred in patients, including those treated with the approved dose of 4 mg infused over 15 minutes. There have been instances of this occurring after the initial zoledronic acid injection dose.

Escitalopram tablets should be administered once daily, in the morning or evening, with or without food.

Initial Treatment

Adolescents

The recommended dose of escitalopram tablets is 10 mg once daily. A flexible-dose trial of escitalopram tablets (10 to 20 mg/day) demonstrated the effectiveness of escitalopram tablets [see Clinical Studies (14.1)]. If the dose is increased to 20 mg, this should occur after a minimum of three weeks.

Adults

The recommended dose of escitalopram tablets is 10 mg once daily. A fixed-dose trial of escitalopram tablets demonstrated the effectiveness of both 10 mg and 20 mg of escitalopram tablets, but failed to demonstrate a greater benefit of 20 mg over 10 mg [see Clinical Studies (14.1)]. If the dose is increased to 20 mg, this should occur after a minimum of one week.

Maintenance Treatment

It is generally agreed that acute episodes of major depressive disorder require several months or longer of sustained pharmacological therapy beyond response to the acute episode. Systematic evaluation of continuing escitalopram tablets 10 or 20 mg/day in adult patients with major depressive disorder who responded while taking escitalopram tablets during an 8 week, acute-treatment phase demonstrated a benefit of such maintenance treatment [see Clinical Studies (14.1)]. Nevertheless, the physician who elects to use escitalopram tablets for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient. Patients should be periodically reassessed to determine the need for maintenance treatment.

Initial Treatment

Adults

The recommended starting dose of escitalopram tablets is 10 mg once daily. If the dose is increased to 20 mg, this should occur after a minimum of one week.

Maintenance Treatment

Generalized anxiety disorder is recognized as a chronic condition. The efficacy of escitalopram tablets in the treatment of GAD beyond 8 weeks has not been systematically studied. The physician who elects to use escitalopram tablets for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient.

10 mg/day is the recommended dose for most elderly patients and patients with hepatic impairment.

No dosage adjustment is necessary for patients with mild or moderate renal impairment. Escitalopram tablets should be used with caution in patients with severe renal impairment.

Symptoms associated with discontinuation of escitalopram tablets and other SSRIs and SNRIs have been reported [see Warnings and Precautions (5.3)]. Patients should be monitored for these symptoms when discontinuing treatment. A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the physician may continue decreasing the dose but at a more gradual rate.

At least 14 days should elapse between discontinuation of an MAOI intended to treat psychiatric disorders and initiation of therapy with escitalopram tablets. Conversely, at least 14 days should be allowed after stopping escitalopram tablets before starting an MAOI intended to treat psychiatric disorders [see Contraindications (4.1)].

Do not start escitalopram tablets in a patient who is being treated with linezolid or intravenous methylene blue because there is an increased risk of serotonin syndrome. In a patient who requires more urgent treatment of a psychiatric condition, other interventions, including hospitalization, should be considered [see Contraindications (4.1)].

In some cases, a patient already receiving escitalopram tablets therapy may require urgent treatment with linezolid or intravenous methylene blue. If acceptable alternatives to linezolid or intravenous methylene blue treatment are not available and the potential benefits of linezolid or intravenous methylene blue treatment are judged to outweigh the risks of serotonin syndrome in a particular patient, escitalopram tablets should be stopped promptly, and linezolid or intravenous methylene blue can be administered. The patient should be monitored for symptoms of serotonin syndrome for 2 weeks or until 24 hours after the last dose of linezolid or intravenous methylene blue, whichever comes first. Therapy with escitalopram tablets may be resumed 24 hours after the last dose of linezolid or intravenous methylene blue [see Warnings and Precautions (5.2)].

The risk of administering methylene blue by non-intravenous routes (such as oral tablets or by local injection) or in intravenous doses much lower than 1 mg/kg with escitalopram tablets is unclear. The clinician should, nevertheless, be aware of the possibility of emergent symptoms of serotonin syndrome with such use [see Warnings and Precautions (5.2)].

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

The maximum recommended dose of Zoledronic Acid Injection in hypercalcemia of malignancy (albumin-corrected serum calcium greater than or equal to 12 mg/dL [3.0 mmol/L]) is 4 mg. The 4-mg dose must be given as a single-dose intravenous infusion over no less than 15 minutes. Patients who receive Zoledronic Acid Injection should have serum creatinine assessed prior to each treatment.

Dose adjustments of Zoledronic Acid Injection are not necessary in treating patients for hypercalcemia of malignancy presenting with mild-to-moderate renal impairment prior to initiation of therapy (serum creatinine less than 400 μmol/L or less than 4.5 mg/dL).

Patients should be adequately rehydrated prior to administration of Zoledronic Acid Injection [see Warnings and Precautions (5.2)].

Consideration should be given to the severity of, as well as the symptoms of, tumor-induced hypercalcemia when considering use of Zoledronic Acid Injection. Vigorous saline hydration, an integral part of hypercalcemia therapy, should be initiated promptly and an attempt should be made to restore the urine output to about 2 L/day throughout treatment. Mild or asymptomatic hypercalcemia may be treated with conservative measures (i.e., saline hydration, with or without loop diuretics). Patients should be hydrated adequately throughout the treatment, but overhydration, especially in those patients who have cardiac failure, must be avoided. Diuretic therapy should not be employed prior to correction of hypovolemia.

Retreatment with Zoledronic Acid Injection 4 mg may be considered if serum calcium does not return to normal or remain normal after initial treatment. It is recommended that a minimum of 7 days elapse before retreatment, to allow for full response to the initial dose. Renal function must be carefully monitored in all patients receiving Zoledronic Acid Injection and serum creatinine must be assessed prior to retreatment with Zoledronic Acid Injection [see Warnings and Precautions (5.2)].

The recommended dose of Zoledronic Acid Injection in patients with multiple myeloma and metastatic bone lesions from solid tumors for patients with creatinine clearance greater than 60 mL/min is 4 mg infused over no less than 15 minutes every 3-4 weeks. The optimal duration of therapy is not known.

Upon treatment initiation, the recommended Zoledronic Acid Injection doses for patients with reduced renal function (mild and moderate renal impairment) are listed in Table 1. These doses are calculated to achieve the same AUC as that achieved in patients with creatinine clearance of 75 mL/min. Creatinine clearance (CrCl) is calculated using the Cockcroft-Gault formula [see Warnings and Precautions (5.2)].

*Doses calculated assuming target AUC of 0.66(mg•hr/L) (CrCl = 75mL/min)

During treatment, serum creatinine should be measured before each Zoledronic Acid Injection dose and treatment should be withheld for renal deterioration. In the clinical studies, renal deterioration was defined as follows:

In the clinical studies, Zoledronic Acid Injection treatment was resumed only when the creatinine returned to within 10% of the baseline value. Zoledronic Acid Injection should be reinitiated at the same dose as that prior to treatment interruption.

Patients should also be administered an oral calcium supplement of 500 mg and a multiple vitamin containing 400 IU of Vitamin D daily.

Zoledronic Acid Injection must not be mixed with calcium or other divalent cation-containing infusion solutions, such as Lactated Ringer's solution, and should be administered as a single intravenous solution in a line separate from all other drugs.

4 mg/5 mL Single-Use Vial

Vials of Zoledronic Acid Injection concentrate for infusion contain overfill allowing for the withdrawal of 5 mL of concentrate (equivalent to 4 mg zoledronic acid). This concentrate should immediately be diluted in 100 mL of sterile 0.9% Sodium Chloride, USP, or 5% Dextrose Injection, USP, following proper aseptic technique, and administered to the patient by infusion. Do not store undiluted concentrate in a syringe, to avoid inadvertent injection.

To prepare reduced doses for patients with baseline CrCl less than or equal to 60 mL/min, withdraw the specified volume of the Zoledronic Acid Injection concentrate from the vial for the dose required (see Table 2).

The withdrawn concentrate must be diluted in 100 mL of sterile 0.9% Sodium Chloride, USP, or 5% Dextrose Injection, USP.

If not used immediately after dilution with infusion media, for microbiological integrity, the solution should be refrigerated at 2°C-8°C (36°F-46°F). The refrigerated solution should then be equilibrated to room temperature prior to administration. The total time between dilution, storage in the refrigerator, and end of administration must not exceed 24 hours.

Due to the risk of clinically significant deterioration in renal function, which may progress to renal failure, single doses of Zoledronic Acid Injection should not exceed 4 mg and the duration of infusion should be no less than 15 minutes [see Warnings And Precautions (5.2)]. In the trials and in postmarketing experience, renal deterioration, progression to renal failure and dialysis, have occurred in patients, including those treated with the approved dose of 4 mg infused over 15 minutes. There have been instances of this occurring after the initial Zoledronic Acid Injection dose.

Zoledronic acid injection must be administered as an intravenous infusion over no less than 15 minutes. 

The recommended dose is a 5 mg infusion. The infusion time must not be less than 15 minutes given over a constant infusion rate.  

After a single treatment with zoledronic acid injection in Paget’s disease an extended remission period is observed. Specific re-treatment data are not available. However, re-treatment with zoledronic acid injection may be considered in patients who have relapsed, based on increases in serum alkaline phosphatase, or in those patients who failed to achieve normalization of their serum alkaline phosphatase, or in those patients with symptoms, as dictated by medical practice.

The zoledronic acid injection infusion time must not be less than 15 minutes given over a constant infusion rate.  

The i.v. infusion should be followed by a 10 mL normal saline flush of the intravenous line.

Zoledronic acid injection solution for infusion must not be allowed to come in contact with any calcium or other divalent cation-containing solutions, and should be administered as a single intravenous solution through a separate vented infusion line.  

If refrigerated, allow the refrigerated solution to reach room temperature before administration. After opening, the solution is stable for 24 hours at 2°C–8°C (36°F-46°F) [see How Supplied/Storage and Handling (16)].

The potency Units of XEOMIN (incobotulinumtoxinA) for injection are specific to the preparation and assay method utilized. They are not interchangeable with other preparations of botulinum toxin products and, therefore, Units of biological activity of XEOMIN cannot be compared to or converted into Units of any other botulinum toxin products assessed with any other specific assay method [see Warnings and Precautions (5.2) and Description (11)].

The recommended initial total dose of XEOMIN for cervical dystonia is 120 Units. In a placebo-controlled trial utilizing initial XEOMIN doses of 120 Units and 240 Units, no meaningful difference in effectiveness was demonstrated between the doses [see Clinical Studies (14.1)]. In previously treated patients, their past dose, response to treatment, duration of effect, and adverse event history should be taken into consideration when determining the XEOMIN dose.

In the treatment of cervical dystonia, XEOMIN is usually injected into the sternocleidomastoid, levator scapulae, splenius capitis, scalenus, and/or the trapezius muscle(s). This list is not exhaustive, as any of the muscles responsible for controlling head position may require treatment [see Clinical Studies (14.1)]. The dose and number of injection sites in each treated muscle should be individualized based on the number and location of the muscle(s) to be treated, the degree of spasticity/dystonia, muscle mass, body weight, and response to any previous botulinum toxin injections.

The frequency of XEOMIN repeat treatments should be determined by clinical response, but should generally be no more frequent than every 12 weeks [see Clinical Studies (14.1)].

The recommended initial total dose of XEOMIN should be the same dose as the patient's previous treatment of onabotulinumtoxinA (Botox), although responses to XEOMIN and onabotulinumtoxinA (Botox) may differ in individual patients. In a placebo-controlled trial in which patients were dosed with the same number of Units as they had received previously with onabotulinumtoxinA (Botox), the mean dose per eye was about 33 Units (range 10-50 Units), and the mean number of injections per eye was 6. The maximum dose per eye in the controlled trials was 50 Units, with a range of 10-50 Units. In the controlled trial, few patients received a total dose of greater than 75 Units.

If the previous dose of Botox is not known, the initial dose of XEOMIN should be between 1.25-2.5 Units/injection site.

The total initial dose of XEOMIN in both eyes should not exceed 70 Units (35 Units/eye).

The number and location of injection sites should be based on the severity of blepharospasm, and previous dose and response to onabotulinumtoxinA (Botox) injections. Subsequent dosing should be tailored to the individual patient, based on response, up to a maximum dose of 35 Units per eye [see Clinical Studies 14.2]. XEOMIN dosing has not been established in patients with blepharospasm who have not been previously treated with onabotulinumtoxinA (Botox).

The frequency of XEOMIN repeat treatments should be determined by clinical response but should generally be no more frequent than every 12 weeks [see Clinical Studies (14.2)].

The total recommended XEOMIN dose is 20 Units per treatment session divided into five equal intramuscular injections of 4 Units each. The five injection sites are: two injections in each corrugator muscle and one injection in the procerus muscle.

Retreatment with XEOMIN should be administered no more frequently than every three months.

The safety and effectiveness of XEOMIN in the treatment of cervical dystonia, blepharospasm, and glabellar lines in patients below 18 years of age have not been assessed [see Warnings and Precautions (5.1)].

Prior to injection, reconstitute each vial of XEOMIN with sterile, preservative-free 0.9% Sodium Chloride Injection, USP. Draw up an appropriate amount of preservative-free 0.9% Sodium Chloride Injection, USP into a syringe (see Table 1). Clean the exposed portion of the rubber stopper of the vial with alcohol (70%) prior to insertion of the needle. Gently inject the saline solution into the vial. If the vacuum does not pull the solvent into the vial, then XEOMIN must be discarded. Gently mix XEOMIN with the saline by rotating the vial. Reconstituted XEOMIN is a clear, colorless solution free of particulate matter. XEOMIN should not be used if the reconstituted solution has a cloudy appearance or contains floccular or particulate matter.

Diluent volumes for reconstitution of XEOMIN are indicated in Table 1.

Reconstituted XEOMIN solution should be administered within 24 hours after dilution. During this time period, reconstituted XEOMIN should be stored in a refrigerator 2-8°C (36-46°F) [see How Supplied/Storage and Handling (16.2)].

Reconstituted XEOMIN is intended for intramuscular injection only. After reconstitution, XEOMIN should be used for only one injection session and for only one patient.

If proposed injection sites are marked with a pen, the product must not be injected through the pen marks; otherwise a permanent tattooing effect may occur.

The number of injection sites is dependent upon the size of the muscle to be treated and the volume of reconstituted XEOMIN injected.

XEOMIN should be injected carefully when injected at sites close to sensitive structures, such as the carotid artery, lung apices and esophagus. Before administering XEOMIN, the physician should be familiar with the patient's anatomy and any anatomic alterations, e.g., due to prior surgical procedures.

Cervical Dystonia

A suitable sterile needle (e.g., 26-gauge (0.45 mm diameter), 37 mm length for superficial muscles; or 22-gauge (0.70 mm diameter), 75 mm length for injections into deeper muscles) should be used in the administration in the treatment of cervical dystonia.

Localization of the involved muscles with electromyographic guidance or nerve stimulation techniques may be useful.

Blepharospasm

A suitable sterile needle (e.g., 26-gauge (0.45 mm diameter), 37 mm length for superficial muscles; or 22-gauge (0.70 mm diameter), 75 mm length for injections into deeper muscles) should be used in the administration in the treatment of blepharospasm.

Glabellar Lines

A suitable sterile needle 30-33 gauge (0.3-0.2 mm diameter), 13 mm length should be used in the administration in the treatment of glabellar lines.

The median first onset of XEOMIN effect occurs within seven days after injection. The typical duration of effect of each treatment is up to 3 months; however, the effect may last significantly longer, or shorter, in individual patients.

Amphetamines should be administered at the lowest effective dosage and dosage should be individually adjusted. Late evening doses should be avoided because of the resulting insomnia.

Usual dose is 5 to 60 mg per day in divided doses, depending on the individual patient response.
Narcolepsy seldom occurs in children under 12 years of age; however, when it does, dextroamphetamine sulfate may be used. The suggested initial dose for patients aged 6 to 12 is 5 mg daily; daily dose may be raised in increments of 5 mg at weekly intervals until an optimal response is obtained. In patients 12 years of age and older, start with 10 mg daily; daily dosage may be raised in increments of 10 mg at weekly intervals until an optimal response is obtained. If bothersome adverse reactions appear (e.g., insomnia or anorexia), dosage should be reduced, extended-release capsules may be used for once-a-day dosage wherever appropriate.

The extended-release capsule formulation is not recommended for pediatric patients younger than 6 years of age.

In pediatric patients 6 years of age and older, start with 5 mg once or twice daily; daily dosage may be raised in increments of 5 mg at weekly intervals until optimal response is obtained.

Only in rare cases will it be necessary to exceed a total of 40 mg per day. Extended-release capsules may be used for once-a-day dosage wherever appropriate.

Where possible, drug administration should be interrupted occasionally to determine if there is a recurrence of behavioral symptoms sufficient to require continued therapy.

In the management of ACS, initiate BRILINTA treatment with a 180 mg loading dose. Administer 90 mg twice daily during the first year after an ACS event. After one year administer 60 mg twice daily.

Do not administer BRILINTA with another oral P2Y12 platelet inhibitor.

Use BRILINTA with a daily maintenance dose of aspirin of 75-100 mg [see Warnings (5.2) and Clinical Studies (14.1)]. A patient who misses a dose of BRILINTA should take one tablet (their next dose) at its scheduled time.

For patients who are unable to swallow tablets whole, BRILINTA tablets can be crushed, mixed with water and drunk. The mixture can also be administered via a nasogastric tube (CH8 or greater) [see Clinical Pharmacology (12.3)].

The recommended dose of sildenafil tablets is 20 mg three times a day. Administer sildenafil tablet doses 4 to 6 hours apart.

In the clinical trial no greater efficacy was achieved with the use of higher doses. Treatment with doses higher than 20 mg three times a day is not recommended.

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

The maximum recommended dose of zoledronic acid injection in hypercalcemia of malignancy (albumin-corrected serum calcium greater than or equal to 12 mg/dL [3.0 mmol/L]) is 4 mg. The 4-mg dose must be given as a single-dose intravenous infusion over no less than 15 minutes. Patients who receive zoledronic acid injection should have serum creatinine assessed prior to each treatment.

Dose adjustments of zoledronic acid injection are not necessary in treating patients for hypercalcemia of malignancy presenting with mild-to-moderate renal impairment prior to initiation of therapy (serum creatinine less than 400 µmol/L or less than 4.5 mg/dL).

Patients should be adequately rehydrated prior to administration of zoledronic acid injection [see Warnings and Precautions (5.2)].

Consideration should be given to the severity of, as well as the symptoms of, tumor-induced hypercalcemia when considering use of zoledronic acid injection. Vigorous saline hydration, an integral part of hypercalcemia therapy, should be initiated promptly and an attempt should be made to restore the urine output to about 2 L/day throughout treatment. Mild or asymptomatic hypercalcemia may be treated with conservative measures (i.e., saline hydration, with or without loop diuretics). Patients should be hydrated adequately throughout the treatment, but overhydration, especially in those patients who have cardiac failure, must be avoided. Diuretic therapy should not be employed prior to correction of hypovolemia.

Retreatment with zoledronic acid injection 4 mg may be considered if serum calcium does not return to normal or remain normal after initial treatment. It is recommended that a minimum of 7 days elapse before retreatment, to allow for full response to the initial dose. Renal function must be carefully monitored in all patients receiving zoledronic acid injection and serum creatinine must be assessed prior to retreatment with zoledronic acid injection [see Warnings and Precautions (5.2)].

The recommended dose of zoledronic acid injection in patients with multiple myeloma and metastatic bone lesions from solid tumors for patients with creatinine clearance (CrCl) greater than 60 mL/min is 4 mg infused over no less than 15 minutes every 3 to 4 weeks. The optimal duration of therapy is not known.

Upon treatment initiation, the recommended zoledronic acid injection doses for patients with reduced renal function (mild and moderate renal impairment) are listed in Table 1. These doses are calculated to achieve the same area under the curve (AUC) as that achieved in patients with creatinine clearance of 75 mL/min. CrCl is calculated using the Cockcroft-Gault formula [see Warnings and Precautions (5.2)].

Table 1: Reduced Doses for Patients with Baseline CrCl Less Than or Equal to 60 mL/min

During treatment, serum creatinine should be measured before each zoledronic acid injection dose and treatment should be withheld for renal deterioration. In the clinical studies, renal deterioration was defined as follows:

For patients with normal baseline creatinine, increase of 0.5 mg/dL

For patients with abnormal baseline creatinine, increase of 1.0 mg/dL

In the clinical studies, zoledronic acid injection treatment was resumed only when the creatinine returned to within 10% of the baseline value. Zoledronic acid injection should be reinitiated at the same dose as that prior to treatment interruption.

Patients should also be administered an oral calcium supplement of 500 mg and a multiple vitamin containing 400 international units of Vitamin D daily.

Zoledronic acid injection must not be mixed with calcium or other divalent cation-containing infusion solutions, such as Lactated Ringer’s solution, and should be administered as a single intravenous solution in a line separate from all other drugs.

4 mg / 5 mL Single-Use Vial

Vials of zoledronic acid injection concentrate for infusion contain overfill allowing for the withdrawal of 5 mL of concentrate (equivalent to 4 mg zoledronic acid). This concentrate should immediately be diluted in 100 mL of sterile 0.9% Sodium Chloride, USP, or 5% Dextrose Injection, USP, following proper aseptic technique, and administered to the patient by infusion. Do not store undiluted concentrate in a syringe, to avoid inadvertent injection.

To prepare reduced doses for patients with baseline CrCl less than or equal to 60 mL/min, withdraw the specified volume of the zoledronic acid injection concentrate from the vial for the dose required (see Table 3).

Table 3: Preparation of Reduced Doses - Zoledronic Acid Injection Concentrate

The withdrawn concentrate must be diluted in 100 mL of sterile 0.9% Sodium Chloride, USP, or 5% Dextrose Injection, USP.

If not used immediately after dilution with infusion media, for microbiological integrity, the solution should be refrigerated at 2°C-8°C (36°F-46°F). The refrigerated solution should then be equilibrated to room temperature prior to administration. The total time between dilution, storage in the refrigerator, and end of administration must not exceed 24 hours.

Due to the risk of clinically significant deterioration in renal function, which may progress to renal failure, single doses of zoledronic acid injection should not exceed 4 mg and the duration of infusion should be no less than 15 minutes [see Warnings and Precautions (5.3)]. In the trials and in postmarketing experience, renal deterioration, progression to renal failure and dialysis, have occurred in patients, including those treated with the approved dose of 4 mg infused over 15 minutes. There have been instances of this occurring after the initial zoledronic acid injection dose.

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

The maximum recommended dose of zoledronic acid injection in hypercalcemia of malignancy (albumin-corrected serum calcium greater than or equal to 12 mg/dL [3 mmol/L]) is 4 mg. The 4 mg dose must be given as a single-dose intravenous infusion over no less than 15 minutes. Patients who receive zoledronic acid injection should have serum creatinine assessed prior to each treatment.

Dose adjustments of zoledronic acid injection are not necessary in treating patients for hypercalcemia of malignancy presenting with mild-to-moderate renal impairment prior to initiation of therapy (serum creatinine less than 400 µmol/L or less than 4.5 mg/dL).

Patients should be adequately rehydrated prior to administration of zoledronic acid injection [see Warnings and Precautions (5.2)].

Consideration should be given to the severity of, as well as the symptoms of, tumor-induced hypercalcemia when considering use of zoledronic acid injection. Vigorous saline hydration, an integral part of hypercalcemia therapy, should be initiated promptly and an attempt should be made to restore the urine output to about 2 L/day throughout treatment. Mild or asymptomatic hypercalcemia may be treated with conservative measures (i.e., saline hydration, with or without loop diuretics). Patients should be hydrated adequately throughout the treatment, but overhydration, especially in those patients who have cardiac failure, must be avoided. Diuretic therapy should not be employed prior to correction of hypovolemia.

Retreatment with zoledronic acid injection 4 mg, may be considered if serum calcium does not return to normal or remain normal after initial treatment. It is recommended that a minimum of 7 days elapse before retreatment, to allow for full response to the initial dose. Renal function must be carefully monitored in all patients receiving zoledronic acid injection and serum creatinine must be assessed prior to retreatment with zoledronic acid injection [see Warnings and Precautions (5.2)].

The recommended dose of zoledronic acid injection in patients with multiple myeloma and metastatic bone lesions from solid tumors for patients with creatinine clearance (CrCl) greater than 60 mL/min is  4 mg infused over no less than15 minutes every 3 to 4 weeks. The optimal duration of therapy is not known.

Upon treatment initiation, the recommended zoledronic acid injection doses for patients with reduced renal function (mild and moderate renal impairment) are listed in Table 1. These doses are calculated to achieve the same area under the curve (AUC) as that achieved in patients with creatinine clearance of 75 mL/min. CrCl is calculated using the Cockcroft-Gault formula [see Warnings and Precautions (5.2)].

      During treatment, serum creatinine should be measured before each zoledronic acid injection dose and treatment should be withheld for renal deterioration. In the clinical studies, renal deterioration was defined as follows:

For patients with normal baseline creatinine, increase of 0.5 mg/dL

For patients with abnormal baseline creatinine, increase of 1 mg/dL

In the clinical studies, zoledronic acid injection treatment was resumed only when the creatinine returned to within 10% of the baseline value. Zoledronic acid injection should be re-initiated at the same dose as that prior to treatment interruption.

Patients should also be administered an oral calcium supplement of 500 mg and a multiple vitamin containing 400 international units of Vitamin D daily.

Zoledronic acid injection must not be mixed with calcium or other divalent cation-containing infusion solutions, such as Lactated Ringer’s solution, and should be administered as a single intravenous solution in a line separate from all other drugs.

4 mg /5 mL Single-Use Vial

Vials of zoledronic acid injection concentrate for infusion contain overfill allowing for the withdrawal of 5 mL of concentrate (equivalent to 4 mg zoledronic acid). This concentrate should immediately be diluted in 100 mL of sterile 0.9% Sodium Chloride, USP, or 5% Dextrose Injection, USP, following proper aseptic technique, and administered to the patient by infusion. Do not store undiluted concentrate in a syringe, to avoid inadvertent injection.  

To prepare reduced doses for patients with baseline CrCl less than or equal to 60 mL/min, withdraw the specified volume of the zoledronic acid injection concentrate from the vial for the dose required (see Table 2).

The withdrawn concentrate must be diluted in 100 mL of sterile 0.9% Sodium Chloride, USP, or 5% Dextrose Injection, USP.

If not used immediately after dilution with infusion media, for microbiological integrity, the solution should be refrigerated at 2°C-8°C (36°F-46°F). The refrigerated solution should then be equilibrated to room temperature prior to administration. The total time between dilution, storage in the refrigerator, and end of administration must not exceed 24 hours.

Due to the risk of clinically significant deterioration in renal function, which may progress to renal failure, single doses of zoledronic acid injection should not exceed 4 mg and the duration of infusion should be no less than 15 minutes [seeWarnings and Precautions (5.3)]. In the trials and in postmarketing experience, renal deterioration, progression to renal failure and dialysis, have occurred in patients, including those treated with the approved dose of 4 mg infused over 15 minutes. There have been instances of this occurring after the initial zoledronic acid injection dose.

The dose for UrthPet D-Wormer is 1 tsp per 10 pounds of body weight (330 mg/kg).

For maximum control of an infestation: Administer Daily for 10 Days.

For maximum prevention: Administer Every Third Day in Adult Pets.

For kittens and puppies: Administer Daily for 6-8 Weeks to Prevent and Control Infestation, or as recommended by your veterinarian.

Lactating pets: Should be treated 2 weeks after whelping or queening. Administer Every Third Day, or Daily, depending on the animals condition or as recommended by your veterinarian.

Please refer to the following dosing table for help finding the right dose for your cat, kitten, dog, or puppy.

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

The maximum recommended dose of zoledronic acid injection in hypercalcemia of malignancy (albumin-corrected serum calcium greater than or equal 12 mg/dL [3.0 mmol/L]) is 4 mg. The 4-mg dose must be given as a single-dose intravenous infusion over no less than 15 minutes. Patients who receive zoledronic acid injection should have serum creatinine assessed prior to each treatment.

Dose adjustments of zoledronic acid injection are not necessary in treating patients for hypercalcemia of malignancy presenting with mild-to-moderate renal impairment prior to initiation of therapy (serum creatinine less than 400 μmol/L or less than 4.5 mg/dL).

Patients should be adequately rehydrated prior to administration of zoledronic acid injection [see Warnings and Precautions (5.2)].

Consideration should be given to the severity of, as well as the symptoms of, tumor-induced hypercalcemia when considering use of zoledronic acid injection. Vigorous saline hydration, an integral part of hypercalcemia therapy, should be initiated promptly and an attempt should be made to restore the urine output to about 2 L/day throughout treatment. Mild or asymptomatic hypercalcemia may be treated with conservative measures (i.e., saline hydration, with or without loop diuretics). Patients should be hydrated adequately throughout the treatment, but overhydration, especially in those patients who have cardiac failure, must be avoided. Diuretic therapy should not be employed prior to correction of hypovolemia.

Retreatment with zoledronic acid injection 4 mg may be considered if serum calcium does not return to normal or remain normal after initial treatment. It is recommended that a minimum of 7 days elapse before retreatment, to allow for full response to the initial dose. Renal function must be carefully monitored in all patients receiving zoledronic acid injection and serum creatinine must be assessed prior to retreatment with zoledronic acid injection [see Warnings and Precautions (5.2)].

The recommended dose of zoledronic acid injection in patients with multiple myeloma and metastatic bone lesions from solid tumors for patients with creatinine clearance greater than 60 mL/min is 4 mg infused over no less than 15 minutes every 3 to 4 weeks. The optimal duration of therapy is not known.

Upon treatment initiation, the recommended zoledronic acid injection doses for patients with reduced renal function (mild and moderate renal impairment) are listed in Table 1. These doses are calculated to achieve the same AUC as that achieved in patients with creatinine clearance of 75 mL/min. CrCl is calculated using the Cockcroft-Gault formula [see Warnings and Precautions (5.2)].

During treatment, serum creatinine should be measured before each zoledronic acid injection dose and treatment should be withheld for renal deterioration. In the clinical studies, renal deterioration was defined as follows:

For patients with normal baseline creatinine, increase of 0.5 mg/dL

For patients with abnormal baseline creatinine, increase of 1.0 mg/dL

In the clinical studies, zoledronic acid injection treatment was resumed only when the creatinine returned to within 10% of the baseline value. Zoledronic acid injection should be reinitiated at the same dose as that prior to treatment interruption.

Patients should also be administered an oral calcium supplement of 500 mg and a multiple vitamin containing 400 international units of Vitamin D daily.

Zoledronic acid injection must not be mixed with calcium or other divalent cation-containing infusion solutions, such as Lactated Ringer's solution, and should be administered as a single intravenous solution in a line separate from all other drugs.

4 mg per 5 mL Single-Use Vial

Vials of zoledronic acid injection concentrate for infusion contain overfill allowing for the withdrawal of 5 mL of concentrate (equivalent to 4 mg zoledronic acid). This concentrate should immediately be diluted in 100 mL of sterile 0.9% Sodium Chloride, USP, or 5% Dextrose Injection, USP, following proper aseptic technique, and administered to the patient by infusion. Do not store undiluted concentrate in a syringe, to avoid inadvertent injection.

To prepare reduced doses for patients with baseline CrCl less than or equal to 60 mL/min, withdraw the specified volume of the zoledronic acid injection concentrate from the vial for the dose required (see Table 3).

The withdrawn concentrate must be diluted in 100 mL of sterile 0.9% Sodium Chloride, USP, or 5% Dextrose Injection, USP.

If not used immediately after dilution with infusion media, for microbiological integrity, the solution should be refrigerated at 2°C to 8°C (36°F to 46°F). The refrigerated solution should then be equilibrated to room temperature prior to administration. The total time between dilution, storage in the refrigerator, and end of administration must not exceed 24 hours. 

Due to the risk of clinically significant deterioration in renal function, which may progress to renal failure, single doses of zoledronic acid injection should not exceed 4 mg and the duration of infusion should be no less than 15 minutes [see Warnings and Precautions (5.3)]. In the trials and in postmarketing experience, renal deterioration, progression to renal failure and dialysis, have occurred in patients, including those treated with the approved dose of 4 mg infused over 15 minutes. There have been instances of this occurring after the initial zoledronic acid injection dose.

MPA tablets may be given in dosages of 5 or 10 mg daily for 5 to 10 days. A dose for inducing an optimum secretory transformation of an endometrium that has been adequately primed with either endogenous or exogenous estrogen is 10 mg of MPA daily for 10 days. In cases of secondary amenorrhea, therapy may be started at any time. Progestin withdrawal bleeding usually occurs within three to seven days after discontinuing MPA therapy.

Beginning on the calculated 16th or 21st day of the menstrual cycle, 5 or 10 mg of medroxyprogesterone acetate may be given daily for 5 to 10 days. To produce an optimum secretory transformation of an endometrium that has been adequately primed with either endogenous or exogenous estrogen, 10 mg of medroxyprogesterone acetate daily for 10 days beginning on the 16th day of the cycle is suggested. Progestin withdrawal bleeding usually occurs within three to seven days after discontinuing therapy with MPA tablets. Patients with a past history of recurrent episodes of abnormal uterine bleeding may benefit from planned menstrual cycling with MPA tablets.

When estrogen is prescribed for a postmenopausal woman with a uterus, a progestin should also be initiated to reduce the risk of endometrial cancer. A woman without a uterus does not need progestin. Use of estrogen, alone or in combination with a progestin, should be with the lowest effective dose and for the shortest duration consistent with treatment goals and risks for the individual woman. Patients should be re-evaluated periodically as clinically appropriate (for example, 3 to 6 month intervals) to determine if treatment is still necessary (see WARNINGS). For women who have a uterus, adequate diagnostic measures, such as endometrial sampling, when indicated, should be undertaken to rule out malignancy in cases of undiagnosed persistent or recurring abnormal vaginal bleeding.

MPA tablets may be given in dosages of 5 or 10 mg daily for 12 to 14 consecutive days per month, in postmenopausal women receiving daily 0.625 mg conjugated estrogens, either beginning on the 1st day of the cycle or the 16th day of the cycle.

Patients should be started at the lowest dose.

The lowest effective dose of MPA has not been determined.

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

The maximum recommended dose of Zoledronic Acid Injection in hypercalcemia of malignancy (albumin-corrected serum calcium greater than or equal to 12 mg/dL [3 mmol/L]) is 4 mg. The 4 mg dose must be given as a single-dose intravenous infusion over no less than 15 minutes. Patients who receive Zoledronic Acid Injection should have serum creatinine assessed prior to each treatment.

Dose adjustments of Zoledronic Acid Injection are not necessary in treating patients for hypercalcemia of malignancy presenting with mild-to-moderate renal impairment prior to initiation of therapy (serum creatinine less than 400 μmol/L or less than 4.5 mg/dL).

Patients should be adequately rehydrated prior to administration of Zoledronic Acid Injection [see Warnings and Precautions (5.2)].

Consideration should be given to the severity of, as well as the symptoms of, tumor-induced hypercalcemia when considering use of Zoledronic Acid Injection. Vigorous saline hydration, an integral part of hypercalcemia therapy, should be initiated promptly and an attempt should be made to restore the urine output to about 2 L/day throughout treatment. Mild or asymptomatic hypercalcemia may be treated with conservative measures (i.e., saline hydration, with or without loop diuretics). Patients should be hydrated adequately throughout the treatment, but overhydration, especially in those patients who have cardiac failure, must be avoided. Diuretic therapy should not be employed prior to correction of hypovolemia.

Retreatment with Zoledronic Acid Injection 4 mg may be considered if serum calcium does not return to normal or remain normal after initial treatment. It is recommended that a minimum of 7 days elapse before retreatment, to allow for full response to the initial dose. Renal function must be carefully monitored in all patients receiving Zoledronic Acid Injection and serum creatinine must be assessed prior to retreatment with Zoledronic Acid Injection [see Warnings and Precautions (5.2)].

The recommended dose of Zoledronic Acid Injection in patients with multiple myeloma and metastatic bone lesions from solid tumors for patients with creatinine clearance (CrCl) greater than 60 mL/min is 4 mg infused over no less than 15 minutes every 3 to 4 weeks. The optimal duration of therapy is not known.

This product is not intended for use with patients with reduced renal function (CrCl 60 mL/min or less).

During treatment, serum creatinine should be measured before each Zoledronic Acid Injection dose and treatment should be withheld for renal deterioration. In the clinical studies, renal deterioration was defined as follows:

In the clinical studies, Zoledronic Acid Injection treatment was resumed only when the creatinine returned to within 10% of the baseline value. Zoledronic Acid Injection should be reinitiated at the same dose as that prior to treatment interruption.

Patients should also be administered an oral calcium supplement of 500 mg and a multiple vitamin containing 400 international units of vitamin D daily.

Zoledronic Acid Injection must not be mixed with calcium or other divalent cation-containing infusion solutions, such as Lactated Ringer's solution, and should be administered as a single intravenous solution in a line separate from all other drugs.

4 mg per 100 mL Single-Use Ready-to-Use Bag

Bags of Zoledronic Acid Injection ready-to-use solution for infusion contain overfill allowing for the administration of 100 mL of solution (equivalent to 4 mg zoledronic acid). This solution is ready to use and may be administered directly to the patient without further preparation. For single use only.

Caution:  After removing the overwrap check for minute leaks by squeezing the inner bag firmly. If leaks are found, discard container as sterility may be compromised. Use only if solution is clear and the container is undamaged.

Due to the risk of clinically significant deterioration in renal function, which may progress to renal failure, single doses of Zoledronic Acid Injection should not exceed 4 mg and the duration of infusion should be no less than 15 minutes [see Warnings and Precautions (5.3)]. In the trials and in postmarketing experience, renal deterioration, progression to renal failure and dialysis, have occurred in patients, including those treated with the approved dose of 4 mg infused over 15 minutes. There have been instances of this occurring after the initial Zoledronic Acid Injection dose.

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

The maximum recommended dose of zoledronic acid injection in hypercalcemia of malignancy (albumin-corrected serum calcium greater than or equal to12 mg/dL [3.0 mmol/L]) is 4 mg. The 4-mg dose must be given as a single-dose intravenous infusion over no less than 15 minutes. Patients who receive zoledronic acid injection should have serum creatinine assessed prior to each treatment.

Dose adjustments of zoledronic acid injection are not necessary in treating patients for hypercalcemia of malignancy presenting with mild-to-moderate renal impairment prior to initiation of therapy (serum creatinine less than 400 μmol/L or less than 4.5 mg/dL).

Patients should be adequately rehydrated prior to administration of zoledronic acid injection [see Warnings and Precautions (5.2)].

Consideration should be given to the severity of, as well as the symptoms of, tumor-induced hypercalcemia when considering use of zoledronic acid injection. Vigorous saline hydration, an integral part of hypercalcemia therapy, should be initiated promptly and an attempt should be made to restore the urine output to about 2 L/day throughout treatment. Mild or asymptomatic hypercalcemia may be treated with conservative measures (i.e., saline hydration, with or without loop diuretics). Patients should be hydrated adequately throughout the treatment, but overhydration, especially in those patients who have cardiac failure, must be avoided. Diuretic therapy should not be employed prior to correction of hypovolemia.

Retreatment with zoledronic acid injection 4 mg may be considered if serum calcium does not return to normal or remain normal after initial treatment. It is recommended that a minimum of 7 days elapse before retreatment, to allow for full response to the initial dose. Renal function must be carefully monitored in all patients receiving zoledronic acid injection and serum creatinine must be assessed prior to retreatment with zoledronic acid injection [see Warnings and Precautions (5.2)].

The recommended dose of zoledronic acid injection in patients with multiple myeloma and metastatic bone lesions from solid tumors for patients with creatinine clearance (CrCl) greater than 60 mL/min is 4 mg infused over no less than 15 minutes every 3 to 4 weeks. The optimal duration of therapy is not known.

Upon treatment initiation, the recommended zoledronic acid injection doses for patients with reduced renal function (mild and moderate renal impairment) are listed in Table 1. These doses are calculated to achieve the same area under curve (AUC) as that achieved in patients with creatinine clearance of 75 mL/min. CrCl is calculated using the Cockcroft-Gault formula [see Warnings and Precautions (5.2)].

During treatment, serum creatinine should be measured before each zoledronic acid injection dose and treatment should be withheld for renal deterioration. In the clinical studies, renal deterioration was defined as follows:
For patients with normal baseline creatinine, increase of 0.5 mg/dL
For patients with abnormal baseline creatinine, increase of 1.0 mg/dL
In the clinical studies, zoledronic acid injection treatment was resumed only when the creatinine returned to within 10% of the baseline value. Zoledronic acid injection should be reinitiated at the same dose as that prior to treatment interruption.

Patients should also be administered an oral calcium supplement of 500 mg and a multiple vitamin containing 400 international units of Vitamin D daily.

Zoledronic acid injection must not be mixed with calcium or other divalent cation-containing infusion solutions, such as Lactated Ringer’s solution, and should be administered as a single intravenous solution in a line separate from all other drugs.

4 mg/5 mL Single-Use Vial
Vials of zoledronic acid injection concentrate for infusion contain overfill allowing for the withdrawal of 5 mL of concentrate (equivalent to 4 mg zoledronic acid). This concentrate should immediately be diluted in 100 mL of sterile 0.9% Sodium Chloride, USP, or 5% Dextrose Injection, USP, following proper aseptic technique, and administered to the patient by infusion. Do not store undiluted concentrate in a syringe, to avoid inadvertent injection.

To prepare reduced doses for patients with baseline CrCl less than or equal to 60 mL/min, withdraw the specified volume of the zoledronic acid injection concentrate from the vial for the dose required (see Table 2).

The withdrawn concentrate must be diluted in 100 mL of sterile 0.9% Sodium Chloride, USP, or 5% Dextrose Injection, USP.

If not used immediately after dilution with infusion media, for microbiological integrity, the solution should be refrigerated at 2°C-8°C (36°F-46°F). The refrigerated solution should then be equilibrated to room temperature prior to administration. The total time between dilution, storage in the refrigerator, and end of administration must not exceed 24 hours.

Due to the risk of clinically significant deterioration in renal function, which may progress to renal failure, single doses of zoledronic acid injection should not exceed 4 mg and the duration of infusion should be no less than 15 minutes [see Warnings and Precautions (5.3)]. In the trials and in postmarketing experience, renal deterioration, progression to renal failure and dialysis, have occurred in patients, including those treated with the approved dose of 4 mg infused over 15 minutes. There have been instances of this occurring after the initial zoledronic acid injection dose.

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 or one packet of 4 mg oral granules.

For pediatric patients 12 to 23 months of age: one packet of 4 mg oral granules.

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.

For prevention of EIB, a single dose of montelukast should be taken at least 2 hours before exercise. 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.

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 efficacy in patients younger than 6 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.

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 or one packet of 4 mg oral granules.

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 or one packet of 4 mg oral granules.

For pediatric patients 6 to 23 months of age: one packet of 4 mg oral granules.

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

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

Montelukast sodium 4 mg oral granules can be administered either directly in the mouth, dissolved in one teaspoonful (5 mL) of cold or room temperature baby formula or breast milk, or mixed with a spoonful of cold or room temperature soft foods; based on stability studies, only applesauce, carrots, rice, or ice cream should be used. The packet should not be opened until ready to use. After opening the packet, the full dose (with or without mixing with baby formula, breast milk, or food) must be administered within 15 minutes. If mixed with baby formula, breast milk, or food, montelukast sodium oral granules must not be stored for future use. Discard any unused portion. Montelukast sodium oral granules are not intended to be dissolved in any liquid other than baby formula or breast milk for administration. However, liquids may be taken subsequent to administration. Montelukast sodium oral granules can be administered without regard to the time of meals.

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

The maximum recommended dose of Zoledronic Acid Injection in hypercalcemia of malignancy (albumin-corrected serum calcium greater than or equal to 12 mg/dL [3 mmol/L]) is 4 mg. The 4 mg dose must be given as a single-dose intravenous infusion over no less than 15 minutes. Patients who receive Zoledronic Acid Injection should have serum creatinine assessed prior to each treatment.

Dose adjustments of Zoledronic Acid Injection are not necessary in treating patients for hypercalcemia of malignancy presenting with mild-to-moderate renal impairment prior to initiation of therapy (serum creatinine less than 400 μmol/L or less than 4.5 mg/dL).

Patients should be adequately rehydrated prior to administration of Zoledronic Acid Injection [see Warnings and Precautions (5.2)].

Consideration should be given to the severity of, as well as the symptoms of, tumor-induced hypercalcemia when considering use of Zoledronic Acid Injection. Vigorous saline hydration, an integral part of hypercalcemia therapy, should be initiated promptly and an attempt should be made to restore the urine output to about 2 L/day throughout treatment. Mild or asymptomatic hypercalcemia may be treated with conservative measures (i.e., saline hydration, with or without loop diuretics). Patients should be hydrated adequately throughout the treatment, but overhydration, especially in those patients who have cardiac failure, must be avoided. Diuretic therapy should not be employed prior to correction of hypovolemia.

Retreatment with Zoledronic Acid Injection 4 mg may be considered if serum calcium does not return to normal or remain normal after initial treatment. It is recommended that a minimum of 7 days elapse before retreatment, to allow for full response to the initial dose. Renal function must be carefully monitored in all patients receiving Zoledronic Acid Injection and serum creatinine must be assessed prior to retreatment with Zoledronic Acid Injection [see Warnings and Precautions (5.2)].

The recommended dose of Zoledronic Acid Injection in patients with multiple myeloma and metastatic bone lesions from solid tumors for patients with creatinine clearance (CrCl) greater than 60 mL/min is 4 mg infused over no less than 15 minutes every 3 to 4 weeks. The optimal duration of therapy is not known.

This product is not intended for use with patients with reduced renal function (CrCl 60 mL/min or less).

During treatment, serum creatinine should be measured before each Zoledronic Acid Injection dose and treatment should be withheld for renal deterioration. In the clinical studies, renal deterioration was defined as follows:

In the clinical studies, Zoledronic Acid Injection treatment was resumed only when the creatinine returned to within 10% of the baseline value. Zoledronic Acid Injection should be reinitiated at the same dose as that prior to treatment interruption.

Patients should also be administered an oral calcium supplement of 500 mg and a multiple vitamin containing 400 international units of vitamin D daily.

Zoledronic Acid Injection must not be mixed with calcium or other divalent cation-containing infusion solutions, such as Lactated Ringer's solution, and should be administered as a single intravenous solution in a line separate from all other drugs.

4 mg per 100 mL Single-Use Ready-to-Use Bag

Bags of Zoledronic Acid Injection ready-to-use solution for infusion contain overfill allowing for the administration of 100 mL of solution (equivalent to 4 mg zoledronic acid). This solution is ready to use and may be administered directly to the patient without further preparation. For single use only.

Caution:  After removing the overwrap check for minute leaks by squeezing the inner bag firmly.  If leaks are found, discard container as sterility may be compromised.  Use only if solution is clear and the container is undamaged.

Due to the risk of clinically significant deterioration in renal function, which may progress to renal failure, single doses of Zoledronic Acid Injection should not exceed 4 mg and the duration of infusion should be no less than 15 minutes [see Warnings and Precautions (5.3)]. In the trials and in postmarketing experience, renal deterioration, progression to renal failure and dialysis, have occurred in patients, including those treated with the approved dose of 4 mg infused over 15 minutes. There have been instances of this occurring after the initial Zoledronic Acid Injection dose.