Tacrolimus

Class: Immunosuppressive Agents
VA Class: IM600
Chemical Name: [3S[3R*,[E(1S*,3S*,4S*)],4S*,5R*,8S*,9E,12R*,14R*,15S*,16R*,18S*,19S*,26aR*]] - 5,6,8,11,12,13,14,15,16,17,18,19,24,25,26,26a - hexadecahydro - 5,19 - dihydroxy - 3 - [2 - (4 - hydroxy - 3 - methoxycyclohexyl) - 1 - methylethenyl] - 14,16 - dimethoxy - 4,10,12,18 - tetramethyl - 8 - (2 - propenyl) - 15,19 - epoxy - 3H - pyrido[2,1 - c][1,4]oxaazacyclotricosine - 1,7,20,21(4H,23H) - tetrone monohydrate
Molecular Formula: C₄₄H₆₉NO₁₂•H₂O
CAS Number: 109581-93-3
Brands: Prograf

• 
  

  Use only under the supervision of a clinician experienced in immunosuppressive therapy and the management of organ transplant patients.¹

  
  


• 
  

  Patients should be managed in facilities with adequate laboratory and supportive medical resources; the clinician responsible for maintenance therapy should have complete information for patient follow-up.¹

  
  


• 
  

  Immunosuppression may result in increased susceptibility to infection^{1 2 4 7 13 20 21 22 23 24 28 29 30 32} and possible development of lymphoma¹ or other neoplasms.^{1 4 7 21}

  
  

Introduction

Immunosuppressive agent.^{1 2 3 4 7 11 12}

Uses for Tacrolimus

Hepatic Allotransplantation

Prevention of hepatic allograft rejection;^{1 2 4 9 13} should be used in conjunction with corticosteroid therapy.^{1 13}

1-year graft and patient survival rates of approximately 73–88%.¹

Efficacy is comparable to that of a cyclosporine-based regimen in terms of 1-year patient and graft survival.^{1 3 4 5 13}

Renal Allotransplantation

Prevention of renal allograft rejection;^{1 37 38 39 42 45 46 47 48 49 52 54} should be used in conjunction with corticosteroid therapy.¹

1-year graft and patient survival rates of approximately 82–100%.^{37 38 39 45 46 49 50 51 52}

Efficacy is comparable to that of a cyclosporine-based regimen in terms of 1-year patient and graft survival.^{1 37 39 42 52}

Also has been used as “rescue” therapy†^{38 40 41 43 44 46 48 50 51 53 56} for acute or chronic renal allograft rejection^{38 40 41 43 44 46 48 51 53 56} or cyclosporine toxicity;^{38 40 56} overall graft survival following such therapy ranges from 59–86%.^{40 41 43 46 48 50 51 53}

Tacrolimus Dosage and Administration

General

• Therapeutic Drug Monitoring


• 
  

  Monitoring whole blood tacrolimus concentrations may be useful in assessing organ rejection and toxicity, adjusting dosage, and determining compliance.^{1 2 3 4 6 13} Factors influencing frequency of monitoring include hepatic or renal dysfunction, addition or discontinuance of potentially interacting drugs, and time since transplant.¹

  
  


• 
  

  Monitoring of whole blood trough concentrations is recommended to assist in the clinical evaluation of toxicity.¹

  
  


• 
  

  Methods for assaying tacrolimus concentrations: microparticle enzyme immunoassay (MEIA) and an enzyme-linked immunosorbent assay (ELISA).¹

  
  


• 
  

  Whole blood is the matrix of choice; collect specimens in tubes containing ethylene diamine tetraacetic acid (EDTA) anticoagulant.¹ Do not use heparin.¹

  
  


• 
  

  Typical whole blood trough tacrolimus concentrations for hepatic transplant patients: 5–20 ng/mL (for months 1–12 posttransplant); long term, posttransplant patients are maintained at the lower end of this range.¹

  
  


• 
  

  Typical whole blood trough tacrolimus concentrations for renal transplant patients: 7–20 ng/mL (for months 1–3 posttransplant) and 5–15 ng/mL (for months 4–12 posttransplant).¹

  
  


• 
  

  Consult specialized sources for further discussion of the clinical utility of tacrolimus concentration monitoring.¹

  
  

• Conversion from One Immunosuppressive Regimen to Another


• 
  

  To avoid excessive nephrotoxicity, do not use concomitantly with cyclosporine.^{1 4}

  
  


• 
  

  Allow ≥24 hours to elapse between discontinuance of cyclosporine and initiation of tacrolimus, and vice versa.¹ Further delay the transfer to the alternative agent if blood cyclosporine or tacrolimus concentrations are elevated.¹

  
  

Administration

Administer orally or by IV infusion.^{1 4 13}

Initiate therapy with the oral capsules, whenever possible.¹ If therapy is initiated with the IV formulation, substitute oral therapy as soon as tolerated.^{1 4 13}

Concomitant corticosteroid therapy is recommended by the manufacturer during the early posttransplantation period.^{1 13}

Oral Administration

Administer orally every 12 hours.¹

Manufacturer makes no specific recommendation regarding administration with meals.¹

Avoid concomitant administration with grapefruit juice.¹

IV Administration

For solution and drug compatibility information, see Compatibility under Stability.

Prepare infusion solutions in glass or polyethylene containers; avoid use of PVC containers.^{1 8} Use PVC-free tubing for administration of more-dilute solutions (e.g., those for pediatric patients).¹ (See Storage under Stability.)

Continuously observe patient for ≥30 minutes following initiation of the IV infusion and then at frequent intervals thereafter for possible allergic manifestations.¹ (See Sensitivity Reactions under Cautions.)

Dilution

Must be diluted with 0.9% sodium chloride or 5% dextrose injection to a concentration of 4–20 mcg (0.004–0.02 mg) per mL prior to administration.¹

Rate of Administration

Administer daily dose over 24 hours by continuous IV infusion.^{1 9}

Dosage

Available as anhydrous tacrolimus; dosage expressed in terms of anhydrous drug.¹

Individualize dosage based on clinical assessments of organ rejection and patient tolerability.^{1 4 13}

Dosage requirements generally decline with continued therapy; long-term administration is necessary to prevent rejection.^{1 4 13}

Pediatric Patients

Hepatic Allotransplantation

Children generally appear to require higher dosages than adults on a weight basis to achieve comparable blood concentrations.^{1 4}

Oral

Initially, 150–200 mcg/kg (0.15–0.2 mg/kg) daily, administered in 2 divided doses every 12 hours; initiate therapy no earlier than 6 hours after liver transplantation.¹

IV

Initially, 30–50 mcg/kg (0.03–0.05 mg/kg) daily commencing after revascularization of the graft.^{1 4 9}

Continue IV therapy only until the patient can tolerate oral therapy.^{1 4 13} In most cases, therapy can be switched to the oral route within 2–4 days.^{1 4 13} Initiate oral tacrolimus 8–12 hours after IV infusion is discontinued.¹

Adults

Hepatic Allotransplantation

Oral

Initially, 100–150 mcg/kg (0.1–0.15 mg/kg) daily, administered in 2 divided doses every 12 hours; initiate therapy no earlier than 6 hours after liver transplantation.¹

IV

Initially, 30–50 mcg/kg (0.03–0.05 mg/kg) daily commencing after revascularization of the graft.^{1 4 9} Adults should receive a dosage at the lower end of this range.¹

Continue IV therapy only until the patient can tolerate oral therapy.^{1 4 13} In most cases, therapy can be switched to the oral route within 2–4 days.^{1 4 13} Initiate oral tacrolimus 8–12 hours after IV infusion is discontinued.¹

Renal Allotransplantation

Black renal transplant patients may require higher doses than patients of other races to maintain comparable whole blood trough drug concentrations.¹

Oral

Usual initial dosage: 200 mcg/kg (0.2 mg/kg) daily, administered in 2 divided doses every 12 hours.¹ Therapy may be administered within 24 hours of kidney transplantation, but should be delayed until renal function has recovered (e.g., S_cr ≤4 mg/dL).¹

IV

Initially, 30–50 mcg/kg (0.03–0.05 mg/kg) daily commencing after revascularization of the graft.^{1 4 9} Adults should receive a dosage at the lower end of this range.¹

Continue IV therapy only until the patient can tolerate oral therapy.¹

Special Populations

Hepatic Impairment

Initiate therapy with the lowest dosage in the recommended range.¹

Further dosage reduction may be required (e.g., in patients with severe hepatic impairment [Child-Pugh score ≥10]).¹

Renal Impairment

Initiate therapy with the lowest dosage in the recommended range.¹ Further dosage reduction may be required.¹

Delay initiation of therapy for ≥48 hours in patients who develop postoperative oliguria.¹

Cautions for Tacrolimus

Contraindications

• 
  

  Known hypersensitivity to tacrolimus or any ingredient in the formulation (e.g., polyoxyl 60 hydrogenated castor oil [HCO-60] in the IV formulation).¹

  
  

Warnings/Precautions

Warnings

Metabolic Effects

Increased risk of hyperglycemia^{1 2 4 7 9 13 16 21 24 29 30 31 32} or new-onset, insulin-dependent, posttransplant diabetes mellitus.^{1 4 7 9 13 22 29} Black and Hispanic renal transplant patients are most at risk for development of posttransplant diabetes mellitus.¹

Development of insulin-dependent diabetes mellitus reported in 20% of renal transplant patients receiving tacrolimus; insulin resistance was reversible in 15 and 50% of these patients at 1 and 2 years posttransplant, respectively.¹

Development of insulin-dependent diabetes mellitus also reported in 11–18% of hepatic transplant patients receiving the drug; insulin resistance was reversible in 31–45% of these patients at 1 year posttransplant.¹

Monitor fasting blood glucose concentrations regularly.¹

Nephrotoxicity

Potential for nephrotoxicity,^{1 4 6 7 9 13 21 22 23 24 31 32} especially at high doses.¹ Nephrotoxicity reported in 36–40 or 52% of patients receiving tacrolimus following hepatic or renal transplantation, respectively, in clinical trials.¹

Monitor S_cr regularly and adjust dosage as needed.¹

Consider switching to other immunosuppressive therapy (e.g., cyclosporine and corticosteroids) if BUN and S_cr remain persistently high despite dosage adjustments.¹

Avoid concomitant therapy with cyclosporine;^{1 4} use other nephrotoxic drugs with caution.¹ (See Specific Drugs and Foods under Interactions.)

Neurotoxicity

Risk of neurotoxicity (e.g., tremor, headache, other changes in motor function, mental status, or sensory function), especially at high doses.^{1 17 18 19 22}

Closely monitor neurologic function and status.³⁶

Tremor and headache may respond to dosage reduction.^{1 8}

Infectious Complications

Possible increased susceptibility to infection.^{1 2 4 7 13 20 21 22 23 24 28 29 30 32 500}

Infectious complications (e.g., pneumonia, sepsis, meningitis, and urinary tract, intra-abdominal, viral, local and systemic fungal, upper respiratory tract, skin and wound infections) reported commonly.^{1 2 4 7 13 20 21 22 23 24 28 29 30 31 32}

Latent Viral Infections

Increased risk of reactivation of latent viral infections, including BK virus-associated nephropathy (BKVN).^{484 485 486 487 488 489 490 491 492 500} Principally observed in renal transplant patients (usually within the first year posttransplantation); may result in severe allograft dysfunction and/or graft loss.^{484 485 486 487 488 489 490 491 492} Risk appears to correlate with degree of overall immunosuppression rather than use of specific immunosuppressant.^{485 486 487 488 489 490 491 492} Monitor closely for signs of BKVN (e.g., deterioration of renal function);^{484 485 486 488} if BKVN develops, institute early treatment, and consider reducing immunosuppressive therapy.^{484 485 486 487 488 490 491 492}

Progressive multifocal leukoencephalopathy (PML), an opportunistic viral infection of the brain caused by the JC virus, reported during postmarketing experience with tacrolimus.^{493 494 495 496 497 500} Use of multiple immunosuppressive agents may contribute to risk of PML.^{495 496 497} Consider possible diagnosis of PML in any immunocompromised patient who develops progressive neurologic deficits.^{495 496} If PML develops, consider decreasing total immunosuppression.^{493 494 495 496}

Lymphomas and Other Malignancies

Possible increased development of lymphoma¹ or other malignancies,^{1 4 7 21} particularly of the skin.¹

A lymphoproliferative disorder^{1 2 4 7 22 24 27 28 29} that appears to be associated with Epstein-Barr virus (EBV) infections has been reported in immunosuppressed organ transplant patients.^{1 2 4 7 24 27} Risk of this disorder appears greatest in young children who are at risk for primary EBV infections while immunosuppressed or whose immunosuppressive regimen is changed to tacrolimus following long-term immunosuppressive therapy.^{1 22 24 27}

Hyperkalemia

Possible hyperkalemia (sometimes severe).^{1 2 4 7 9 21 22 23 24 28 31}

Monitor serum potassium concentrations regularly; avoid concomitant use of potassium-sparing diuretics or potassium supplements.¹

If hyperkalemia occurs, institute appropriate management (e.g., restriction of potassium intake, administration of potassium-binding resin or mineralocorticoid).^{2 4 7 21 22 24}

Sensitivity Reactions

Anaphylaxis

Risk of anaphylaxis associated with IV therapy; reserve for patients who cannot accommodate oral administration.¹

Have appropriate equipment and agents for the treatment of anaphylactic reactions readily available whenever tacrolimus is administered IV.¹ If anaphylaxis occurs, immediately discontinue the IV infusion and institute appropriate therapy (e.g., epinephrine, oxygen).¹

General Precautions

Laboratory Monitoring

Regularly monitor S_cr, potassium, and fasting glucose concentrations.¹

Hypertension

Development of hypertension reported commonly; generally is mild to moderate; may require antihypertensive therapy.¹

Myocardial Hypertrophy

Risk of myocardial hypertrophy; generally reversible following dosage reduction or drug discontinuance.^{1 23 25 31}

Consider performing echocardiographic evaluation if renal failure or clinical manifestations of ventricular dysfunction occur.¹

If myocardial hypertrophy is diagnosed, consider decreasing dosage or discontinuing therapy.¹

Specific Populations

Pregnancy

Category C.¹

Lactation

Distributed into milk; women should not breast-feed infants while receiving tacrolimus.¹

Pediatric Use

Limited experience in pediatric renal transplant patients.¹

Hepatic transplants have been performed successfully in pediatric patients (up to 16 years of age) receiving tacrolimus; living related-donor hepatic transplants performed successfully in a small number of pediatric patients <12 years of age receiving the drug.^{1 23 24 28}

Safety and efficacy in children appear to be similar to those in adults.^{4 23 24 28}

Children without preexisting renal or hepatic impairment generally require and tolerate higher tacrolimus dosages after hepatic transplantation than adults,^{1 4} but pediatric patients may be more susceptible to lymphoproliferative disorders associated with tacrolimus use.^{1 22 24 27}

Geriatric Use

Insufficient experience in patients ≥65 years of age to determine whether geriatric patients respond differently than younger adults; select dosage with caution.³⁶

If evidence of renal impairment exists or develops, adjust dosage.¹ (See Renal Impairment under Dosage and Administration.)

Hepatic Impairment

Decreased clearance in patients with severe hepatic impairment; adjust dosage and closely monitor blood concentrations in these patients.¹ (See Hepatic Impairment under Dosage and Administration.)

Hepatic transplant patients experiencing posttransplant hepatic impairment may be at increased risk of renal impairment secondary to high blood tacrolimus concentrations; monitor such patients closely and consider dosage adjustment.¹

Renal Impairment

Potential for nephrotoxicity; monitor patient closely. Dosage adjustments recommended.¹ (See Renal Impairment under Dosage and Administration.)

Blacks

Black renal transplant patients may require higher doses than patients of other races to maintain comparable whole blood trough drug concentrations.¹

Common Adverse Effects

Renal dysfunction,^{1 2 4 7 9 13 21 22 23 24 28 31 32} adverse nervous system effects (e.g., tremor, headache),^{1 2 4 7 9 17 18 19 24 28 30 31 32} adverse GI effects (e.g., diarrhea, nausea),^{1 9 28} hypertension,^{1 2 4 7 9 13 21 22 23 24 25 28 31} altered glucose metabolism,^{1 2 4 7 9 13 16 21 24 29 30 31 32} hyperkalemia,^{1 2 4 7 9 21 22 23 24 30 31 32} infectious complications.^{13 20 24 25 26 27 28 30 31 32}

Interactions for Tacrolimus

Metabolized by CYP isoenzymes, principally CYP3A.¹

Drugs Affecting Hepatic Microsomal Enzymes

Pharmacokinetic interactions are likely with drugs that are potent inhibitors or inducers of CYP3A, possibly resulting in increased or decreased blood concentrations of tacrolimus.¹ If such drugs are used concomitantly, monitor blood tacrolimus concentrations and adjust dosage as needed.¹

Specific Drugs and Foods

Drug or Food	Interaction	Comments
Antacids (aluminum- and magnesium-containing)	Possible increased blood tacrolimus concentrations500	Monitor blood tacrolimus concentrations and adjust dosage as needed500
Anticonvulsants (carbamazepine, phenobarbital, phenytoin)	Possible decreased blood tacrolimus concentrations;1 500 possible increased serum phenytoin concentrations500	Monitor blood tacrolimus concentrations and adjust dosage as needed500
Antimycobacterials (rifabutin, rifampin)	Possible decreased blood tacrolimus concentrations1 500	Monitor blood tacrolimus concentrations and adjust dosage as needed500
Antifungals, azoles (clotrimazole, fluconazole, itraconazole, ketoconazole, voriconazole)	Possible increased blood tacrolimus concentrations1 500 Ketoconazole: Concomitant oral use substantially decreases apparent clearance of oral tacrolimus; clearance of IV tacrolimus not substantially altered500	Monitor blood tacrolimus concentrations and adjust dosage as needed500
Bromocriptine	Possible increased blood tacrolimus concentrations1 500	Monitor blood tacrolimus concentrations and adjust dosage as needed500
Calcium-channel blocking agents (diltiazem, nicardipine, nifedipine, verapamil)	Possible increased blood tacrolimus concentrations1 500	Monitor blood tacrolimus concentrations and adjust dosage as needed500
Caspofungin	Possible decreased blood tacrolimus concentrations500	Monitor blood tacrolimus concentrations and adjust dosage as needed500
Chloramphenicol	Possible increased blood tacrolimus concentrations500	Monitor blood tacrolimus concentrations and adjust dosage as needed500
Cimetidine	Possible increased blood tacrolimus concentrations1 500	Monitor blood tacrolimus concentrations and adjust dosage as needed500
Cisapride	Possible increased blood tacrolimus concentrations500	Monitor blood tacrolimus concentrations and adjust dosage as needed500
Cyclosporine	Possible increased blood tacrolimus concentrations;1 500 additive/synergistic nephrotoxicity1 500	Avoid concomitant use1 500 Allow ≥24 hours to elapse between discontinuance of cyclosporine and initiation of tacrolimus, and vice versa;1 500 further delay the transfer to the alternative agent if blood concentrations of cyclosporine or tacrolimus are elevated1 500
Danazol	Possible increased blood tacrolimus concentrations1 500	Monitor blood tacrolimus concentrations and adjust dosage as needed500
Diuretics, potassium-sparing	Risk of hyperkalemia500	Avoid concomitant use500
Estrogens (ethinyl estradiol)	Possible increased blood tacrolimus concentrations1 500	Monitor blood tacrolimus concentrations and adjust dosage as needed500
Grapefruit juice	Possible increased blood tacrolimus concentrations500	Avoid concomitant use500
HIV protease inhibitors (e.g., nelfinavir, ritonavir)	Possible increased blood tacrolimus concentrations1 500	Monitor blood tacrolimus concentrations and adjust dosage as needed500
Immunosuppressive agents	Risk of oversuppression of the immune system and associated susceptibility to infection and risk of lymphoma1	Use with caution1
Macrolide antibiotics (clarithromycin, erythromycin, troleandomycin)	Possible increased blood tacrolimus concentrations1 500	Monitor blood tacrolimus concentrations and adjust dosage as needed500
Methylprednisolone	Possible increased blood tacrolimus concentrations1 500	Monitor blood tacrolimus concentrations and adjust dosage as needed500
Metoclopramide	Possible increased blood tacrolimus concentrations1 500	Monitor blood tacrolimus concentrations and adjust dosage as needed500
Nefazodone	Possible increased blood tacrolimus concentrations1 500	Monitor blood tacrolimus concentrations and adjust dosage as needed500
Nephrotoxic drugs (e.g., aminoglycosides, amphotericin B, cisplatin, ganciclovir)	Possible increased risk of nephrotoxicity500	Use with caution500
Proton-pump inhibitors (lansoprazole, omeprazole)	Possible increased blood tacrolimus concentrations1 500 Lansoprazole: Concomitant use may inhibit tacrolimus metabolism and substantially increase whole blood concentrations of the drug, particularly in poor CYP2C19 metabolizers500	Monitor blood tacrolimus concentrations and adjust dosage as needed500
Sirolimus	Possible decreased exposure to tacrolimus.500 Increased risk of hepatic artery thrombosis, graft loss, and death in de novo liver transplant recipients59 Increased risk of impaired renal function in heart transplant recipients500	Concomitant use not recommended500
St. John’s wort	Possible decreased blood tacrolimus concentrations500	Monitor blood tacrolimus concentrations and adjust dosage as needed500
Vaccines	Possible decreased response to vaccination500	Avoid use of live vaccines500

Tacrolimus Pharmacokinetics

Absorption

Bioavailability

Incomplete and variable absorption following oral administration.¹

Absolute bioavailability of oral tacrolimus is approximately 17% in adult renal transplant patients, 22% in adult hepatic transplant patients, and 31% in pediatric hepatic transplant patients 0.7–13.2 years of age.¹

Food

Food can reduce both the rate and extent of oral absorption of tacrolimus capsules; effect is most pronounced with high-fat meals (e.g., 400 kcal, 34% fat).^{1 4}

Plasma Concentrations

Lack of direct correlation between blood tacrolimus concentrations and efficacy; however, high trough blood concentrations are possibly associated with increasing incidence of adverse effects.¹

Typical whole blood trough tacrolimus concentrations for hepatic transplant patients: 5–20 ng/mL (for months 1–12 posttransplant); long term, posttransplant patients are maintained at the lower end of this range.¹

Typical whole blood trough tacrolimus concentrations for renal transplant patients: 7–20 ng/mL (for months 1–3 posttransplant) and 5–15 ng/mL (for months 4–12 posttransplant).¹

Distribution

Extent

Crosses the placenta and is distributed into milk.¹

Average whole blood-to-plasma concentration ratio is 35 (range: 12–67).¹

Plasma Protein Binding

Approximately 99% (principally albumin and α-1-acid glycoprotein).¹

Elimination

Metabolism

Extensively metabolized by CYP enzymes (principally CYP3A) to several metabolites.¹ Activity of tacrolimus is related principally to the parent drug.¹

Elimination Route

Eliminated principally in feces (92%).¹

Half-life

Following IV administration, elimination half-life of approximately 34 hours in healthy individuals, 19 hours in renal transplant patients, and 12 hours in hepatic transplant patients (including those 0.7–13.2 years of age).¹ In healthy individuals, half-life values are similar after IV and oral administration.¹

Special Populations

In patients with severe hepatic impairment (mean Child-Pugh score >10), mean clearance is substantially decreased;^b clearance is not substantially altered in those with mild hepatic impairment.^b

In patients with renal impairment, clearance is similar to that in healthy individuals.¹

Stability

Storage

Oral

Capsules

25°C (may be exposed to 15–30°C).¹

Parenteral

Concentrate

5–25°C.¹

Store diluted infusion solutions in glass or polyethylene containers; discard 24 hours after dilution.¹

Do not store diluted infusion solutions in PVC containers (decreased stability and potential for extraction of phthalates).¹

Therapeutic Blood Monitoring Samples

Analyze samples immediately or store at room temperature or in a refrigerator for up to 7 days;¹ alternatively, -20°C for up to 12 months.¹

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Parenteral

Unstable in alkaline media; manufacturer recommends that tacrolimus injection not be mixed or co-infused with solutions of pH ≥9 (e.g., acyclovir sodium, ganciclovir sodium).¹

Solution Compatibility^HID

Compatible
Dextrose 5% in water
Sodium chloride 0.9%

Drug Compatibility

Admixture CompatibilityHID

Compatible
Cimetidine HCl

Y-Site CompatibilityHID

Compatible
Aminophylline
Amphotericin B
Ampicillin sodium
Ampicillin sodium–sulbactam sodium
Benztropine mesylate
Calcium gluconate
Cefazolin sodium
Cefotetan disodium
Ceftazidime
Ceftriaxone sodium
Cefuroxime sodium
Chloramphenicol sodium succinate
Cimetidine HCl
Ciprofloxacin
Clindamycin phosphate
Co-trimoxazole
Dexamethasone sodium phosphate
Digoxin
Diphenhydramine HCl
Dobutamine HCl