Astellas Pharma Us, Inc.

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Astellas Pharma Us, Inc. Drugs

Mycamine

Mycamine

Do not mix or co-infuse Mycamine with other medications. Mycamine has been shown to precipitate when mixed directly with a number of other commonly used medications.The recommended doses for adult patients based on indications are shown in Table 1.

2.1 Dose and Schedule for Adults
Table 1. Mycamine Dosage in Adult Patients * In patients treated successfully for candidemia and other Candida infections, the mean duration of treatment was 15 days (range 10-47 days). † In patients treated successfully for esophageal candidiasis, the mean duration of treatment was 15 days (range 10-30 days). ‡ In hematopoietic stem cell transplant (HSCT) recipients who experienced success of prophylactic therapy, the mean duration of prophylaxis was 19 days (range 6-51 days).
Indication

Recommended Reconstituted Dose Once Daily

Treatment of Candidemia, Acute Disseminated Candidiasis, Candida Peritonitis and Abscesses*

100 mg

Treatment of Esophageal Candidiasis†

150 mg

Prophylaxis of Candida Infections in HSCT Recipients‡

50 mg

A loading dose is not required. Typically, 85% of the steady-state concentration is achieved after three daily Mycamine doses.

No dosing adjustments are required based on race, gender, or in patients with severe renal impairment or in patients with mild, moderate, or severe hepatic impairment [see Use in Specific Populations (8)].

No dose adjustment for Mycamine is required with concomitant use of mycophenolate mofetil, cyclosporine, tacrolimus, prednisolone, sirolimus, nifedipine, fluconazole, voriconazole, itraconazole, amphotericin B, ritonavir, or rifampin [see Drug Interactions (7)].

2.2 Dose and Schedule for Pediatric Patients

The recommended doses for pediatric patients based on indication and weight are shown in Table 2.
Table 2. Mycamine Dosage in Pediatric Patients 4 months or older
Indication

Pediatric Dose Given Once Daily

30 kg or less

Greater than 30 kg

Treatment of Candidemia, Acute Disseminated Candidiasis, Candida Peritonitis and Abscesses (1.1)

2 mg/kg(maximum daily dose 100 mg)

Treatment of Esophageal Candidiasis (1.2)

3 mg/kg

2.5 mg/kg (maximum daily dose 150 mg)

Prophylaxis of Candida Infections in HSCT Recipients (1.3)

1 mg/kg(maximum daily dose 50 mg)

2.3 Directions for Reconstitution, Dilution, and Preparation

Please read this entire section carefully before beginning reconstitution.

Reconstitution

Reconstitute Mycamine vials by aseptically adding 5 mL of one of the following compatible solutions:
• 0.9% Sodium Chloride Injection, USP (without a bacteriostatic agent). • 5% Dextrose Injection, USP
To minimize excessive foaming, Gently dissolve the Mycamine powder by swirling the vial. Do Not Vigorously Shake The Vial. Visually inspect the vial for particulate matter.

Mycamine 50 mg vial: after reconstitution each mL contains 10 mg of micafungin sodium. Mycamine 100 mg vial: after reconstitution each mL contains 20 mg of micafungin sodium.

As with all parenteral drug products, reconstituted Mycamine should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not use material if there is any evidence of precipitation or foreign matter. Aseptic technique must be strictly observed in all handling since no preservative or bacteriostatic agent is present in Mycamine or in the materials specified for reconstitution and dilution.

Dilution and Preparation

The diluted solution should be protected from light. It is not necessary to cover the infusion drip chamber or the tubing.

Adult Patients:
1. Add the appropriate volume of reconstituted Mycamine into 100 mL of 0.9% Sodium Chloride Injection, USP or 100 mL of 5% Dextrose Injection, USP. 2. Appropriately label the bag.
Pediatric Patients:
1. Calculate the total Mycamine dose in milligrams (mg) by multiplying the recommended pediatric dose (mg/kg) for a given indication [see Table 2] and the weight of the patient in kilograms (kg). 2. To calculate the volume (mL) of drug needed, divide the calculated dose (mg) from step 1 by the final concentration of the selected reconstituted vial(s) (either 10 mg/mL for the 50 mg vial or 20 mg/mL for the 100 mg vial), see example below:Using 50 mg vials: Divide the calculated mg dose (from step 1) by 10 mg/mL to determine the volume (mL) needed. OR Using 100 mg vials: Divide the calculated mg dose (from step 1) by 20 mg/mL to determine the volume (mL) needed. 3. Withdraw the calculated volume (mL) of drug needed from the selected concentration and size of reconstituted Mycamine vial(s) used in Step 2 (ensure the selected concentration and vial size used to calculate the dose is also used to prepare the infusion). 4. Add the withdrawn volume of drug (step 3) to a 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP intravenous infusion bag or syringe. Ensure that the final concentration of the solution is between 0.5 mg/mL to 4 mg/mL. Note: To minimize the risk of infusion reactions, concentrations of greater than 1.5 mg/mL should be administered via central catheter [see Adverse Reactions (6.1)]. 5. Appropriately label the infusion bag or syringe. For concentrations above 1.5 mg/mL, if required, label to specifically warn to administer the solution via central catheter.
Mycamine is preservative-free. Discard partially used vials.

2.4 Infusion Volume and Duration

Mycamine should be administered by intravenous infusion only. Infuse over one hour. More rapid infusions may result in more frequent histamine mediated reactions.

An existing intravenous line should be flushed with 0.9% Sodium Chloride Injection, USP, prior to infusion of Mycamine.

Pediatric Patients Mycamine should be infused over one hour. To minimize the risk of infusion reactions, concentrations of greater than 1.5 mg/mL should be administered via central catheter [see Adverse Reactions (6.1)].
Vibativ

Vibativ

2.1 Complicated Skin and Skin Structure Infections

The recommended dosing for VIBATIV is 10 mg/kg administered over a 60-minute period in patients ≥18 years of age by intravenous infusion once every 24 hours for 7 to 14 days. The duration of therapy should be guided by the severity and site of the infection and the patient's clinical and bacteriological progress.

2.2 Patients with Renal Impairment

Because telavancin is eliminated primarily by the kidney, a dosage adjustment is required for patients whose creatinine clearance is ≤50 mL/min, as listed in Table 1 [see Clinical Pharmacology (12.3)].
Table 1: Dosage Adjustment in Adult Patients with Renal Impairment
* As calculated using the Cockcroft-Gault formula [see Clinical Pharmacology (12.3)]
Creatinine Clearance* (mL/min) VIBATIV Dosage Regimen >50 10 mg/kg every 24 hours 30 - 50 7.5 mg/kg every 24 hours 10 - <30 10 mg/kg every 48 hours
There is insufficient information to make specific dosage adjustment recommendations for patients with end-stage renal disease (CrCl <10 mL/min), including patients undergoing hemodialysis.

2.3 Preparation and Administration

250 mg vial: Reconstitute the contents of a VIBATIV 250 mg vial with 15 mL of 5% Dextrose Injection, USP; Sterile Water for Injection, USP; or 0.9% Sodium Chloride Injection, USP. The resultant solution has a concentration of 15 mg/mL (total volume of approximately 17.0 mL).

750 mg vial: Reconstitute the contents of a VIBATIV 750 mg vial with 45 mL of 5% Dextrose Injection, USP; Sterile Water for Injection, USP; or 0.9% Sodium Chloride Injection, USP, The resultant solution has a concentration of 15 mg/mL (total volume of approximately 50.0 mL).

The following formula can be used to calculate the volume of reconstituted VIBATIV solution required to prepare a dose:

Telavancin dose (mg) = 10 mg/kg or 7.5 mg/kg x patient weight (in kg) (see Table 1)

Volume of reconstituted solution (mL) = Telavancin dose (mg) 15 mg/mL

For doses of 150 to 800 mg, the appropriate volume of reconstituted solution must be further diluted in 100 to 250 mL prior to infusion. Doses less than 150 mg or greater than 800 mg should be further diluted in a volume resulting in a final concentration of 0.6 to 8 mg/mL. Appropriate infusion solutions include: 5% Dextrose Injection, USP; 0.9% Sodium Chloride Injection, USP; or Lactated Ringer's Injection, USP. The dosing solution should be administered by intravenous infusion over a period of 60 minutes.

Reconstitution time is generally under 2 minutes, but can sometimes take up to 20 minutes. Mix thoroughly to reconstitute and check to see if the contents have dissolved completely. Parenteral drug products should be inspected visually for particulate matter prior to administration. Discard the vial if the vacuum did not pull the diluent into the vial.

Since no preservative or bacteriostatic agent is present in this product, aseptic technique must be used in preparing the final intravenous solution. Studies have shown that the reconstituted solution in the vial should be used within 4 hours when stored at room temperature or within 72 hours under refrigeration at 2 to 8°C (36 to 46°F). The diluted (dosing) solution in the infusion bag should be used within 4 hours when stored at room temperature or used within 72 hours when stored under refrigeration at 2 to 8°C (36 to 46°F). However, the total time in the vial plus the time in the infusion bag should not exceed 4 hours at room temperature and 72 hours under refrigeration at 2 to 8°C (36 to 46°F).

VIBATIV is administered intravenously. Because only limited data are available on the compatibility of VIBATIV with other IV substances, additives or other medications should not be added to VIBATIV single-use vials or infused simultaneously through the same IV line. If the same intravenous line is used for sequential infusion of additional medications, the line should be flushed before and after infusion of VIBATIV with 5% Dextrose Injection, USP; 0.9% Sodium Chloride Injection, USP; or Lactated Ringer's Injection, USP.
Pravastatin Sodium

Pravastatin Sodium

2.1 Important Instructions for Intravenous Administration
• Intravenous formulation must be administered via an infusion set with an in-line filter (pore size 0.2 to 1.2 micron). • Infuse the intravenous formulation over a minimum of 1 hour in 250 mL of a compatible diluent, to reduce the risk for infusion-related reactions. Do not administer as an intravenous bolus injection. • Do not infuse CRESEMBA with other intravenous medications. • Flush intravenous lines with 0.9% sodium chloride injection, USP or 5% dextrose injection, USP prior to and after infusion of CRESEMBA. • After dilution of the intravenous formulation, avoid unnecessary vibration or vigorous shaking of the solution. Do not use a pneumatic transport system.
2.2 Dosage Regimen

CRESEMBA (isavuconazonium sulfate) is the prodrug of isavuconazole, an azole antifungal drug. Prescribe CRESEMBA as shown in Table 1 below.
Table 1. Dosage Regimen for CRESEMBA a 372 mg of isavuconazonium sulfate is equivalent to 200 mg of isavuconazoleb 186 mg of isavuconazonium sulfate is equivalent to 100 mg of isavuconazolec Start maintenance doses 12 to 24 hours after the last loading dose
Loading Dose

Maintenance Dosec

CRESEMBA for Injection

372 mga of isavuconazonium sulfate per vial

1 reconstituted vial (372 mga)

intravenously

every 8 hours for 6 doses (48 hours)

1 reconstituted vial (372 mga)

intravenously

once daily

CRESEMBA Capsules

186 mgb of isavuconazonium sulfate per capsule

2 capsules (372 mga)

orally

every 8 hours for 6 doses (48 hours)

2 capsules (372 mga)

orally

once daily

Switching between the intravenous and oral formulations of CRESEMBA is acceptable as bioequivalence has been demonstrated. Loading dose is not required when switching between formulations.

With oral administration, swallow capsules whole. Do not chew, crush, dissolve, or open the capsules. CRESEMBA capsules can be taken with or without food.

2.3 Reconstitution Instructions for the Injection Formulation

Aseptic technique must be strictly observed in all handling since no preservative or bacteriostatic agent is present in CRESEMBA or in the materials specified for reconstitution. CRESEMBA is water soluble, preservative-free, sterile, and nonpyrogenic.
• Reconstitute one vial of CRESEMBA by adding 5 mL water for injection, USP to the vial. • Gently shake to dissolve the powder completely. • Visually inspect the reconstituted solution for particulate matter and discoloration. Reconstituted CRESEMBA should be clear and free of visible particulate. • The reconstituted solution may be stored below 25°C for maximum 1 hour prior to preparation of the patient infusion solution.
2.4 Dilution and Preparation Instructions for the Injection Formulation
• Remove 5 mL of the reconstituted solution from the vial and add it to an infusion bag containing 250 mL (approximately 1.5 mg isavuconazonium sulfate per mL) of compatible diluent. The diluted solution may show visible translucent to white particulates of isavuconazole (which will be removed by in-line filtration). • Use gentle mixing or roll bag to minimize the formation of particulates. Avoid unnecessary vibration or vigorous shaking of the solution. • Apply in-line filter with a microporous membrane pore size of 0.2 to 1.2 micron and in-line filter reminder sticker to the infusion bag. • Do not use a pneumatic transport system. • The intravenous administration should be completed within 6 hours of dilution at room temperature. If this is not possible, immediately refrigerate (2° to 8°C / 36° to 46°F) the infusion solution after dilution and complete the infusion within 24 hours. Do not freeze the infusion solution.
2.5 Compatibility for the Injection Formulation

CRESEMBA for injection should only be administered with the following diluents:
• 0.9% sodium chloride injection, USP • 5% dextrose injection, USP
Ambisome

Ambisome

AmBisome should be administered by intravenous infusion, using a controlled infusion device, over a period of approximately 120 minutes.

An in-line membrane filter may be used for the intravenous infusion of AmBisome; provided THE MEAN PORE DIAMETER OF THE FILTER IS NOT LESS THAN 1.0 MICRON.

NOTE: An existing intravenous line must be flushed with 5% Dextrose Injection prior to infusion of AmBisome. If this is not feasible, AmBisome must be administered through a separate line.

Infusion time may be reduced to approximately 60 minutes in patients in whom the treatment is well-tolerated. If the patient experiences discomfort during infusion, the duration of infusion may be increased.

The recommended initial dose of AmBisome for each indication for adult and pediatric patients is as follows:
Indication Dose (mg/kg/day) Empirical therapy 3
Systemic fungal infections:

Aspergillus

Candida

Cryptococcus
3-5 Cryptococcal meningitis in HIV infected patients (see DESCRIPTION OF CLINICAL STUDIES) 6

Dosing and rate of infusion should be individualized to the needs of the specific patient to ensure maximum efficacy while minimizing systemic toxicities or adverse events.

Doses recommended for visceral leishmaniasis are presented below:
Visceral Leishmaniasis Dose (mg/kg/day) Immunocompetent patients
3 (days 1-5) and
3 on days 14, 21 Immunocompromised patients
4 (days 1-5) and
4 on days 10, 17, 24, 31, 38
For immunocompetent patients who do not achieve parasitic clearance with the recommended dose, a repeat course of therapy may be useful.

For immunocompromised patients who do not clear parasites or who experience relapses, expert advice regarding further treatment is recommended. For additional information see DESCRIPTION OF CLINICAL STUDIES.

Directions for Reconstitution, Filtration and Dilution

Read This Entire Section Carefully Before Beginning Reconstitution

AmBisome must be reconstituted using Sterile Water for Injection, USP (without a bacteriostatic agent). Vials of AmBisome containing 50 mg of amphotericin B are prepared as follows:

Reconstitution

1. Aseptically add 12 mL of Sterile Water for Injection, USP to each AmBisome vial to yield a preparation containing 4 mg amphotericin B/mL.

CAUTION: DO NOT RECONSTITUTE WITH SALINE OR ADD SALINE TO THE RECONSTITUTED CONCENTRATION, OR MIX WITH OTHER DRUGS. The use of any solution other than those recommended, or the presence of a bacteriostatic agent in the solution, may cause precipitation of AmBisome.

2. Immediately after the addition of water, SHAKE THE VIAL VIGOROUSLY for 30 seconds to completely disperse the AmBisome. AmBisome forms a yellow, translucent suspension. Visually inspect the vial for particulate matter and continue shaking until completely dispersed.

Filtration and Dilution

3. Calculate the amount of reconstituted (4 mg/mL) AmBisome to be further diluted.

4. Withdraw this amount of reconstituted AmBisome into a sterile syringe.

5. Attach the 5-micron filter, provided, to the syringe. Inject the syringe contents through the filter, into the appropriate amount of 5% Dextrose Injection. (Use only one filter per vial of AmBisome.)

6. AmBisome must be diluted with 5% Dextrose Injection to a final concentration of 1 to 2 mg/mL prior to administration. Lower concentrations (0.2 to 0.5 mg/mL) may be appropriate for infants and small children to provide sufficient volume for infusion. DISCARD PARTIALLY USED VIALS.
Protopic

Protopic

Adult

PROTOPIC Ointment 0.03% and 0.1%
Apply a thin layer of PROTOPIC (tacrolimus) Ointment to the affected skin twice daily. The minimum amount should be rubbed in gently and completely to control signs and symptoms of atopic dermatitis. Stop using when signs and symptoms of atopic dermatitis resolve. If signs and symptoms (e.g. itch, rash, and redness) do not improve within 6 weeks, patients should be re-examined by their healthcare provider to confirm the diagnosis of atopic dermatitis. Continuous long-term use of topical calcineurin inhibitors, including PROTOPIC Ointment should be avoided, and application should be limited to areas of involvement with atopic dermatitis.
The safety of PROTOPIC Ointment under occlusion, which may promote systemic exposure, has not been evaluated. PROTOPIC Ointment should not be used with occlusive dressings.

PEDIATRIC – FOR CHILDREN 2-15 YEARS

PROTOPIC Ointment 0.03%
Apply a thin layer of PROTOPIC (tacrolimus) Ointment, 0.03% to the affected skin twice daily. The minimum amount should be rubbed in gently and completely to control signs and symptoms of atopic dermatitis. Stop using when signs and symptoms of atopic dermatitis resolve. If signs and symptoms (e.g. itch, rash, and redness) do not improve within 6 weeks, patients should be re-examined by their healthcare provider to confirm the diagnosis of atopic dermatitis. Continuous long-term use of topical calcineurin inhibitors, including PROTOPIC Ointment should be avoided, and application should be limited to areas of involvement with atopic dermatitis.
The safety of PROTOPIC Ointment under occlusion, which may promote systemic exposure, has not been evaluated. PROTOPIC Ointment should not be used with occlusive dressings.
Adenocard

Adenocard

For rapid bolus intravenous use only.

Adenocard (adenosine injection) should be given as a rapid bolus by the peripheral intravenous route. To be certain the solution reaches the systemic circulation, it should be administered either directly into a vein or, if given into an IV line, it should be given as close to the patient as possible and followed by a rapid saline flush.

Adult Patients

The dose recommendation is based on clinical studies with peripheral venous bolus dosing. Central venous (CVP or other) administration of Adenocard has not been systematically studied.

The recommended intravenous doses for adults are as follows:

Initial dose: 6 mg given as a rapid intravenous bolus (administered over a 1-2 second period).

Repeat administration: If the first dose does not result in elimination of the supraventricular tachycardia within 1-2 minutes, 12 mg should be given as a rapid intravenous bolus. This 12 mg dose may be repeated a second time if required.

Pediatric Patients

The dosages used in neonates, infants, children and adolescents were equivalent to those administered to adults on a weight basis.

Pediatric Patients with a Body Weight < 50 kg:

Initial dose: Give 0.05 to 0.1 mg/kg as a rapid IV bolus given either centrally or peripherally. A saline flush should follow.

Repeat administration: If conversion of PSVT does not occur within 1-2 minutes, additional bolus injections of adenosine can be administered at incrementally higher doses, increasing the amount given by 0.05 to 0.1 mg/kg. Follow each bolus with a saline flush. This process should continue until sinus rhythm is established or a maximum single dose of 0.3 mg/kg is used.

Pediatric Patients with a Body Weight ≥ 50 kg: Administer the adult dose.

Doses greater than 12 mg are not recommended for adult and pediatric patients.

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

Mycamine

Do not mix or co-infuse Mycamine with other medications. Mycamine has been shown to precipitate when mixed directly with a number of other commonly used medications.The recommended doses for adult patients based on indications are shown in Table 1.

2.1 Dose and Schedule for Adults
Table 1. Mycamine Dosage in Adult Patients * In patients treated successfully for candidemia and other Candida infections, the mean duration of treatment was 15 days (range 10-47 days). † In patients treated successfully for esophageal candidiasis, the mean duration of treatment was 15 days (range 10-30 days). ‡ In hematopoietic stem cell transplant (HSCT) recipients who experienced success of prophylactic therapy, the mean duration of prophylaxis was 19 days (range 6-51 days).
Indication

Recommended Reconstituted Dose Once Daily

Treatment of Candidemia, Acute Disseminated Candidiasis, Candida Peritonitis and Abscesses*

100 mg

Treatment of Esophageal Candidiasis†

150 mg

Prophylaxis of Candida Infections in HSCT Recipients‡

50 mg

A loading dose is not required. Typically, 85% of the steady-state concentration is achieved after three daily Mycamine doses.

No dosing adjustments are required based on race, gender, or in patients with severe renal impairment or in patients with mild, moderate, or severe hepatic impairment [see Use in Specific Populations (8)].

No dose adjustment for Mycamine is required with concomitant use of mycophenolate mofetil, cyclosporine, tacrolimus, prednisolone, sirolimus, nifedipine, fluconazole, voriconazole, itraconazole, amphotericin B, ritonavir, or rifampin [see Drug Interactions (7)].

2.2 Dose and Schedule for Pediatric Patients

The recommended doses for pediatric patients based on indication and weight are shown in Table 2.
Table 2. Mycamine Dosage in Pediatric Patients 4 months or older
Indication

Pediatric Dose Given Once Daily

30 kg or less

Greater than 30 kg

Treatment of Candidemia, Acute Disseminated Candidiasis, Candida Peritonitis and Abscesses (1.1)

2 mg/kg(maximum daily dose 100 mg)

Treatment of Esophageal Candidiasis (1.2)

3 mg/kg

2.5 mg/kg (maximum daily dose 150 mg)

Prophylaxis of Candida Infections in HSCT Recipients (1.3)

1 mg/kg(maximum daily dose 50 mg)

2.3 Directions for Reconstitution, Dilution, and Preparation

Please read this entire section carefully before beginning reconstitution.

Reconstitution

Reconstitute Mycamine vials by aseptically adding 5 mL of one of the following compatible solutions:
• 0.9% Sodium Chloride Injection, USP (without a bacteriostatic agent). • 5% Dextrose Injection, USP
To minimize excessive foaming, Gently dissolve the Mycamine powder by swirling the vial. Do Not Vigorously Shake The Vial. Visually inspect the vial for particulate matter.

Mycamine 50 mg vial: after reconstitution each mL contains 10 mg of micafungin sodium. Mycamine 100 mg vial: after reconstitution each mL contains 20 mg of micafungin sodium.

As with all parenteral drug products, reconstituted Mycamine should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not use material if there is any evidence of precipitation or foreign matter. Aseptic technique must be strictly observed in all handling since no preservative or bacteriostatic agent is present in Mycamine or in the materials specified for reconstitution and dilution.

Dilution and Preparation

The diluted solution should be protected from light. It is not necessary to cover the infusion drip chamber or the tubing.

Adult Patients:
1. Add the appropriate volume of reconstituted Mycamine into 100 mL of 0.9% Sodium Chloride Injection, USP or 100 mL of 5% Dextrose Injection, USP. 2. Appropriately label the bag.
Pediatric Patients:
1. Calculate the total Mycamine dose in milligrams (mg) by multiplying the recommended pediatric dose (mg/kg) for a given indication [see Table 2] and the weight of the patient in kilograms (kg). 2. To calculate the volume (mL) of drug needed, divide the calculated dose (mg) from step 1 by the final concentration of the selected reconstituted vial(s) (either 10 mg/mL for the 50 mg vial or 20 mg/mL for the 100 mg vial), see example below: Using 50 mg vials: Divide the calculated mg dose (from step 1) by 10 mg/mL to determine the volume (mL) needed. OR Using 100 mg vials: Divide the calculated mg dose (from step 1) by 20 mg/mL to determine the volume (mL) needed. 3. Withdraw the calculated volume (mL) of drug needed from the selected concentration and size of reconstituted Mycamine vial(s) used in Step 2 (ensure the selected concentration and vial size used to calculate the dose is also used to prepare the infusion). 4. Add the withdrawn volume of drug (step 3) to a 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP intravenous infusion bag or syringe. Ensure that the final concentration of the solution is between 0.5 mg/mL to 4 mg/mL. Note: To minimize the risk of infusion reactions, concentrations of greater than 1.5 mg/mL should be administered via central catheter [see Adverse Reactions (6.1)]. 5. Appropriately label the infusion bag or syringe. For concentrations above 1.5 mg/mL, if required, label to specifically warn to administer the solution via central catheter.
Mycamine is preservative-free. Discard partially used vials.

2.4 Infusion Volume and Duration

Mycamine should be administered by intravenous infusion only. Infuse over one hour. More rapid infusions may result in more frequent histamine mediated reactions.

An existing intravenous line should be flushed with 0.9% Sodium Chloride Injection, USP, prior to infusion of Mycamine.

Pediatric Patients Mycamine should be infused over one hour. To minimize the risk of infusion reactions, concentrations of greater than 1.5 mg/mL should be administered via central catheter [see Adverse Reactions (6.1)].
Metronidazole

Metronidazole

2.1 Dosing Information

The recommended dose of XTANDI is 160 mg (four 40 mg capsules) administered orally once daily. XTANDI can be taken with or without food [see Clinical Pharmacology (12.3)]. Swallow capsules whole. Do not chew, dissolve, or open the capsules.

2.2 Dose Modifications

If a patient experiences a ≥ Grade 3 toxicity or an intolerable side effect, withhold dosing for one week or until symptoms improve to ≤ Grade 2, then resume at the same or a reduced dose (120 mg or 80 mg), if warranted.

Concomitant Strong CYP2C8 Inhibitors

The concomitant use of strong CYP2C8 inhibitors should be avoided if possible. If patients must be co-administered a strong CYP2C8 inhibitor, reduce the XTANDI dose to 80 mg once daily. If co-administration of the strong inhibitor is discontinued, the XTANDI dose should be returned to the dose used prior to initiation of the strong CYP2C8 inhibitor [see Drug Interactions (7.1) and Clinical Pharmacology (12.3)].

Concomitant Strong CYP3A4 Inducers

The concomitant use of strong CYP3A4 inducers should be avoided if possible. If patients must be co-administered a strong CYP3A4 inducer, increase the XTANDI dose from 160 mg to 240 mg once daily. If co-administration of the strong CYP3A4 inducer is discontinued, the XTANDI dose should be returned to the dose used prior to initiation of the strong CYP3A4 inducer [see Drug Interactions (7.2) and Clinical Pharmacology (12.3)].
Prograf

Prograf

2.1 Dosage in Adult Kidney, Liver, or Heart Transplant Patients

The initial oral dosage recommendations for adult patients with kidney, liver, or heart transplants along with recommendations for whole blood trough concentrations are shown in Table 1. The initial dose of Prograf should be administered no sooner than 6 hours after transplantation in the liver and heart transplant patients. In kidney transplant patients, the initial dose of Prograf may be administered within 24 hours of transplantation, but should be delayed until renal function has recovered. For blood concentration monitoring details see Dosage and Administration (2.6).
Table 1. Summary of Initial Oral Dosage Recommendations and Observed Whole Blood Trough Concentrations in Adults * In a second smaller trial, the initial dose of tacrolimus was 0.15-0.2 mg/kg/day and observed tacrolimus concentrations were 6-16 ng/mL during month 1-3 and 5-12 ng/mL during month 4-12 [see Clinical Studies (14.1)].
Patient Population

Recommended Prograf Initial

Oral Dosage

Note: daily doses should be administered as two divided doses, every 12 hours

Observed Tacrolimus Whole Blood Trough Concentrations

Adult kidney transplant patients

In combination with azathioprine

0.2 mg/kg/day

month 1-3: 7-20 ng/mL

month 4-12: 5-15 ng/mL

In combination with MMF/IL-2 receptor antagonist*

0.1 mg/kg/day

month 1-12: 4-11 ng/mL

Adult liver transplant patients

0.10-0.15 mg/kg/day

month 1-12: 5-20 ng/mL

Adult heart transplant patients

0.075 mg/kg/day

month 1-3: 10-20 ng/mL

month ≥4: 5-15 ng/mL

Dosing should be titrated based on clinical assessments of rejection and tolerability. Lower Prograf dosages than the recommended initial dosage may be sufficient as maintenance therapy. Adjunct therapy with adrenal corticosteroids is recommended early post-transplant.

The data in kidney transplant patients indicate that the Black patients required a higher dose to attain comparable trough concentrations compared to Caucasian patients (Table 2).
Table 2. Comparative Dose and Trough Concentrations Based on Race
Time After Transplant

Caucasian

n=114

Black

n=56

Dose

(mg/kg)

Trough Concentrations

(ng/mL)

Dose

(mg/kg)

Trough Concentrations (ng/mL)

Day 7

0.18

12.0

0.23

10.9

Month 1

0.17

12.8

0.26

12.9

Month 6

0.14

11.8

0.24

11.5

Month 12

0.13

10.1

0.19

11.0

Initial Dose – Injection

Prograf injection should be used only as a continuous IV infusion and when the patient cannot tolerate oral administration of Prograf capsules. Prograf injection should be discontinued as soon as the patient can tolerate oral administration of Prograf capsules, usually within 2-3 days. In a patient receiving an IV infusion, the first dose of oral therapy should be given 8-12 hours after discontinuing the IV infusion.

The observed trough concentrations described above pertain to oral administration of Prograf only; while monitoring Prograf concentrations in patients receiving Prograf injection as a continuous IV infusion may have some utility, the observed concentrations will not represent comparable exposures to those estimated by the trough concentrations observed in patients on oral therapy.

The recommended starting dose of Prograf injection is 0.03-0.05 mg/kg/day in kidney and liver transplant and 0.01 mg/kg/day in heart transplant given as a continuous IV infusion. Adult patients should receive doses at the lower end of the dosing range. Concomitant adrenal corticosteroid therapy is recommended early post-transplantation.

Anaphylactic reactions have occurred with injectables containing castor oil derivatives, such as Prograf injection [see Warnings and Precautions (5.11)].

2.2 Dosage in Pediatric Liver Transplant Patients

The initial oral dosage recommendations for pediatric patients with liver transplants along with recommendations for whole blood trough concentrations are shown in Table 3. For blood concentration monitoring details see Dosage and Administration (2.6). If necessary, pediatric patients may start on an IV dose of 0.03-0.05 mg/kg/day.
Table 3. Summary of Initial Oral Dosage Recommendations and Observed Whole Blood Trough Concentrations in Children
Patient Population

Recommended Prograf Initial Oral Dosage

Note: daily doses should be administered as two divided doses, every 12 hours

Observed Tacrolimus Whole Blood Trough Concentrations

Pediatric liver transplant patients

0.15-0.20 mg/kg/day

Month 1-12: 5-20 ng/mL

Pediatric liver transplantation patients without pre-existing renal or hepatic dysfunction have required and tolerated higher doses than adults to achieve similar blood concentrations.

Experience in pediatric kidney and heart transplantation patients is limited.

2.3 Dosage Adjustment in Patients with Renal Impairment

Due to its potential for nephrotoxicity, consideration should be given to dosing Prograf at the lower end of the therapeutic dosing range in patients who have received a liver or heart transplant and have pre-existing renal impairment. Further reductions in dose below the targeted range may be required.

In kidney transplant patients with post-operative oliguria, the initial dose of Prograf should be administered no sooner than 6 hours and within 24 hours of transplantation, but may be delayed until renal function shows evidence of recovery.

2.4 Dosage Adjustments in Patients with Hepatic Impairment

Due to the reduced clearance and prolonged half-life, patients with severe hepatic impairment (Child Pugh ≥ 10) may require lower doses of Prograf. Close monitoring of blood concentrations is warranted.

The use of Prograf in liver transplant recipients experiencing post-transplant hepatic impairment may be associated with increased risk of developing renal insufficiency related to high whole-blood concentrations of tacrolimus. These patients should be monitored closely and dosage adjustments should be considered. Some evidence suggests that lower doses should be used in these patients [see Dosage and Administration (2.1), Use in Specific Populations (8.7) and Clinical Pharmacology (12.3)].

2.5 Administration Instructions

It is recommended that patients initiate oral therapy with Prograf capsules if possible.

Initial dosage and observed tacrolimus whole blood trough concentrations for adults are shown in Table 1 and for pediatrics in Table 3 [see Dosage and Administration (2.1, 2.2)]; for blood concentration monitoring details in kidney transplant patients [see Dosage and Administration (2.1)].

It is important to take Prograf capsules consistently every day either with or without food because the presence and composition of food decreases the bioavailability of Prograf [see Clinical Pharmacology (12.3)].

Patients should not eat grapefruit or drink grapefruit juice in combination with Prograf [see Drug Interactions (7.2)].

Prograf should not be used simultaneously with cyclosporine. Prograf or cyclosporine should be discontinued at least 24 hours before initiating the other. In the presence of elevated Prograf or cyclosporine concentrations, dosing with the other drug usually should be further delayed.

In patients unable to take oral Prograf capsules, therapy may be initiated with Prograf injection as a continuous IV infusion. If IV therapy is necessary, conversion from IV to oral Prograf is recommended as soon as oral therapy can be tolerated. This usually occurs within 2-3 days. In patients receiving an IV infusion, the first dose of oral therapy should be given 8-12 hours after discontinuing the IV infusion.

2.6 Therapeutic Drug Monitoring

Monitoring of tacrolimus blood concentrations in conjunction with other laboratory and clinical parameters is considered an essential aid to patient management for the evaluation of rejection, toxicity, dose adjustments and compliance. Observed whole blood trough concentrations can be found in Table 1. Factors influencing frequency of monitoring include but are not limited to hepatic or renal dysfunction, the addition or discontinuation of potentially interacting drugs and the post-transplant time. Blood concentration monitoring is not a replacement for renal and liver function monitoring and tissue biopsies. Data from clinical trials show that tacrolimus whole blood concentrations were most variable during the first week post-transplantation.

The relative risks of toxicity and efficacy failure are related to tacrolimus whole blood trough concentrations. Therefore, monitoring of whole blood trough concentrations is recommended to assist in the clinical evaluation of toxicity and efficacy failure.

Methods commonly used for the assay of tacrolimus include high performance liquid chromatography with tandem mass spectrometric detection (HPLC/MS/MS) and immunoassays. Immunoassays may react with metabolites as well as parent compound. Therefore assay results obtained with immunoassays may have a positive bias relative to results of HPLC/MS. The bias may depend upon the specific assay and laboratory. Comparison of the concentrations in published literature to patient concentrations using the current assays must be made with detailed knowledge of the assay methods and biological matrices employed. Whole blood is the matrix of choice and specimens should be collected into tubes containing ethylene diamine tetraacetic acid (EDTA) anti-coagulant. Heparin anti-coagulation is not recommended because of the tendency to form clots on storage. Samples which are not analyzed immediately should be stored at room temperature or in a refrigerator and assayed within 7 days; see assay instructions for specifics. If samples are to be kept longer they should be deep frozen at -20° C. One study showed drug recovery >90% for samples stored at -20° C for 6 months, with reduced recovery observed after 6 months.

2.7 Preparation for Intravenous Product

Prograf injection must be diluted with 0.9% Sodium Chloride Injection or 5% Dextrose Injection to a concentration between 0.004 mg/mL and 0.02 mg/mL prior to use. Diluted infusion solution should be stored in glass or polyethylene containers and should be discarded after 24 hours. The diluted infusion solution should not be stored in a PVC container due to decreased stability and the potential for extraction of phthalates. In situations where more dilute solutions are utilized (e.g., pediatric dosing, etc.), PVC-free tubing should likewise be used to minimize the potential for significant drug adsorption onto the tubing.

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

Due to the chemical instability of tacrolimus in alkaline media, Prograf injection should not be mixed or co-infused with solutions of pH 9 or greater (e.g., ganciclovir or acyclovir).
Myrbetriq

Myrbetriq

2.1 Dosing Information

The recommended starting dose of MYRBETRIQ® is 25 mg once daily with or without food. MYRBETRIQ® 25 mg is effective within 8 weeks. Based on individual patient efficacy and tolerability the dose may be increased to 50 mg once daily [see Clinical Studies (14)].

MYRBETRIQ® should be taken with water, swallowed whole and should not be chewed, divided, or crushed.

2.2 Dose Adjustments in Specific Populations

The daily dose of MYRBETRIQ® should not exceed 25 mg once daily in the following populations:
• Patients with severe renal impairment (CL cr 15 to 29 mL/min or eGFR 15 to 29 mL/min/1.73 m 2) [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)]. • Patients with moderate hepatic impairment (Child-Pugh Class B) [see Use in Specific Populations (8.7) and Clinical Pharmacology (12.3)].
MYRBETRIQ® is not recommended for use in patients with end stage renal disease (ESRD), or in patients with severe hepatic impairment (Child-Pugh Class C) [see Use in Specific Populations (8.6, 8.7) and Clinical Pharmacology (12.3)].
Adenoscan

Adenoscan

The recommended Adenoscan dose is 0.14 mg/kg/min infused over six minutes (total dose of 0.84 mg/kg) (Table 1).
• Administer Adenoscan only as a continuous peripheral intravenous infusion • Inject Thallium-201 at the midpoint of the Adenoscan infusion (i.e., after the first three minutes of Adenoscan) • Thallium-201 is physically compatible with Adenoscan and may be injected directly into the Adenoscan infusion set • Inject Thallium-201 as close to the venous access as possible to prevent an inadvertent increase in the dose of Adenoscan (the contents of the intravenous tubing) being administered
Visually inspect Adenoscan for particulate matter and discoloration prior to administration. Do not administer Adenoscan if it contains particulate matter or is discolored.

There are no data on the safety or efficacy of alternative Adenoscan infusion protocols. The safety and efficacy of Adenoscan administered by the intracoronary route have not been established.
Table 1. Dosage Chart for Adenoscan
Patient Weight

(kilograms)

Infusion Rate

(mL per minute over 6 minutes for total dose of 0.84 mg/kg)

45

2.1

50

2.3

55

2.6

60

2.8

65

3

70

3.3

75

3.5

80

3.8

85

4

90

4.2

The nomogram displayed in Table 1 was derived from the following general formula:

0.14 (mg/kg/min) x total body weight (kg) = Infusion rate Adenoscan concentration (mL/min) (3 mg/mL)
Lexiscan

Lexiscan

The recommended intravenous dose of Lexiscan is 5 mL (0.4 mg regadenoson)
• Administer Lexiscan as a rapid (approximately 10 seconds) injection into a peripheral vein using a 22 gauge or larger catheter or needle. • Administer a 5 mL saline flush immediately after the injection of Lexiscan. • Administer the radionuclide myocardial perfusion imaging agent 10–20 seconds after the saline flush. The radionuclide may be injected directly into the same catheter as Lexiscan.
NOTE: Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not administer Lexiscan if it contains particulate matter or is discolored.

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