Cromidin

Cromidin uses

• Indications and usage
• Dosage and administration
• Dosage forms and strengths
• Contraindications
• Warnings and precautions
• Adverse reactions
• Drug interactions
• Use in specific populations
• Overdosage
• Description
• Clinical pharmacology
• Nonclinical toxicology
• Clinical studies
• How supplied / storage and handling
• Patient counseling information
• Patient information
• Cromidin reviews

1 INDICATIONS AND USAGE

Cromidin Capsules USP is a calcineurin-inhibitor immunosuppressant indicated for

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  Prophylaxis of organ rejection in patients receiving allogeneic liver and kidney transplants
  

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  Use concomitantly with adrenal corticosteroids; in kidney transplant, use in conjunction with azathioprine or mycophenolate mofetil (MMF) (1.1, 1.2)
  

• Limitations of Use (1.4):
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    Do not use simultaneously with cyclosporine.
    

  • Intravenous use reserved for patients who can not tolerate capsules orally.
  • Use with sirolimus is not recommended in liver transplant; use with sirolimus in kidney transplant has not been established.

1.1 Prophylaxis of Organ Rejection in Kidney Transplant

Cromidin Capsules USP are indicated for the prophylaxis of organ rejection in patients receiving allogeneic kidney transplants. It is recommended that Cromidin be used concomitantly with azathioprine or mycophenolate mofetil (MMF) and adrenal corticosteroids . Therapeutic drug monitoring is recommended for all patients receiving Cromidin Capsules USP .

1.2 Prophylaxis of Organ Rejection in Liver Transplant

Cromidin Capsules USP are indicated for the prophylaxis of organ rejection in patients receiving allogeneic liver transplants. It is recommended that Cromidin be used concomitantly with adrenal corticosteroids . Therapeutic drug monitoring is recommended for all patients receiving Cromidin Capsules USP .

1.4 Limitations of Use

Cromidin Capsules USP should not be used simultaneously with cyclosporine.

Cromidin Injection should be reserved for patients unable to take Cromidin Capsules USP orally .

Use with sirolimus is not recommended in liver transplant. The safety and efficacy of Tacrolimus with sirolimus has not been established in kidney transplant .

2 DOSAGE AND ADMINISTRATION

Summary of Initial Oral Dosage Recommendation and Observed Whole Blood Trough Concentrations.

• Careful and frequent monitoring of Cromidin trough concentrations is recommended; Black patients may require higher doses in order to achieve comparable trough concentrations (2.1)
• Hepatic/Renal impaired patients should receive doses at the lowest value of recommended initial oral dosing range (2.3, 2.4)
• Administer capsules consistently with or without food; do not drink grapefruit juice (2.5, 7.2)

2.1 Dosage in Adult Kidney or Liver Transplant Patients

The initial oral dosage recommendations for adult patients with kidney or liver transplants along with recommendations for whole blood trough concentrations are shown in Table 1. The initial dose of Cromidin Capsules USP should be administered no sooner than 6 hours after transplantation in the liver transplant patients. In kidney transplant patients, the initial dose of Cromidin Capsules USP 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).

Dosing should be titrated based on clinical assessments of rejection and tolerability. Lower Cromidin 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).

Initial Dose - Injection

Cromidin injection should be used only as a continuous IV infusion and when the patient cannot tolerate oral administration of Cromidin Capsules USP. Cromidin injection should be discontinued as soon as the patient can tolerate oral administration of Cromidin Capsules USP, 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 Cromidin Capsules USP only; while monitoring Cromidin concentrations in patients receiving Cromidin 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 Cromidin injection is 0.03-0.05 mg/kg/day in kidney and liver 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 Cromidin injection .

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.

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 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 Cromidin Capsules USP at the lower end of the therapeutic dosing range in patients who have received a liver 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 Cromidin Capsules USP 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 may require lower doses of Cromidin. Close monitoring of blood concentrations is warranted.

The use of Cromidin Capsules USP 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 Cromidin. These patients should be monitored closely and dosage adjustments should be considered. Some evidence suggests that lower doses should be used in these patients .

2.5 Administration Instructions

It is recommended that patients initiate oral therapy with Cromidin Capsules USP if possible. Initial dosage and observed Cromidin whole blood trough concentrations for adults are shown in Table 1 and for pediatrics in Table 3 ; for blood concentration monitoring details in kidney transplant patients .

It is important to take Cromidin Capsules USP consistently every day either with or without food because the presence and composition of food decreases the bioavailability of Cromidin .

Patients should not eat grapefruit or drink grapefruit juice in combination with Cromidin .

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

In patients unable to take oral Cromidin Capsules USP, therapy may be initiated with Cromidin injection as a continuous IV infusion. If IV therapy is necessary, conversion from IV to oral Cromidin Capsules USP 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 Cromidin 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 Cromidin whole blood concentrations were most variable during the first week post-transplantation.

The relative risks of toxicity and efficacy failure are related to Cromidin 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 Cromidin 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.

3 DOSAGE FORMS AND STRENGTHS

Oblong shape, hard gelatin capsules for oral administration contains Cromidin USP as follows:

• Cromidin Capsules USP, 0.5 mg: Light yellow color, oblong shape, size “5” hard gelatin capsules printed with “PBT” and “0.5” in red ink on cap and body respectively.
• Cromidin Capsules USP, 1 mg: White color, oblong shape, size “5” hard gelatin capsules printed with “PBT” and “1.0” in red ink on cap and body respectively.
• Cromidin Capsules USP, 5 mg: Pink color, oblong shape, size “4” hard gelatin capsules printed with “PBT” and “5.0” in red ink on cap and body respectively.

Capsules: 0.5 mg, 1 mg and 5 mg (3)

4 CONTRAINDICATIONS

Cromidin capsule USP is contraindicated in patients with a hypersensitivity to Cromidin. Cromidin injection is contraindicated in patients with a hypersensitivity to HCO-60 (polyoxyl 60 hydrogenated castor oil) or any components of the formulation. Hypersensitivity symptoms reported include dyspnea, rash, pruritus, and acute respiratory distress syndrome .

Hypersensitivity to Cromidin or HCO-60 (polyoxyl 60 hydrogenated castor oil) or any components of the formulation (4)

5 WARNINGS AND PRECAUTIONS

• Lymphoma and Other Malignancies: Risk of lymphomas, including post transplant lymphoproliferative disorder ; appears related to intensity and duration of use. Avoid prolonged exposure to UV light and sunlight (5.2)
• Serious infections: Increased risk of bacterial, viral, fungal and protozoal infections, including opportunistic infections: combination immunosuppression should be used with caution (5.3)
• Polyoma Virus Infections: Serious, sometimes fatal outcomes, including polyoma virus-associated nephropathy (PVAN), mostly due to BK virus, and JC virus-associated progressive multifocal leukoencephalopathy (PML); consider reducing immunosuppression (5.4)
• Cytomegalovirus (CMV) Infections: Increased risk of CMV viremia and disease; consider reducing immunosuppression (5.5)
• New Onset Diabetes After Transplant: Monitor blood glucose (5.6)
• Nephrotoxicity: Acute and/or chronic; reduce the dose; use caution with other nephrotoxic drugs (5.7)
• Neurotoxicity: Risk of Posterior Reversible Encephalopathy Syndrome, monitor for neurologic abnormalities; reduce or discontinue Cromidin Capsules USP and other immunosuppressants (5.8)
• Hyperkalemia: Monitor serum potassium levels. Careful consideration should be given prior to use of other agents also associated with hyperkalemia (5.9)
• Hypertension: May require antihypertensive therapy. Monitor relevant drug drug interactions (5.10)
• Anaphylactic Reactions with IV formulation: Observe patients receiving Cromidin injection for signs and symptoms of anaphylaxis (5.11)
• Use with Sirolimus: Not recommended in liver transplant due to increased risk of serious adverse reactions (5.12)
• Myocardial Hypertrophy: Consider dosage reduction or discontinuation (5.15)
• Immunizations: Use of live vaccines should be avoided (5.16)
• Pure Red Cell Aplasia: Discontinuation should be considered (5.17)

5.1 Management of Immunosuppression

Only physicians experienced in immunosuppressive therapy and management of organ transplant patients should use Cromidin Capsules USP. Patients receiving the drug should be managed in facilities equipped and staffed with adequate laboratory and supportive medical resources. The physicians responsible for maintenance therapy should have complete information requisite for the follow up of the patient .

5.2 Lymphoma and Other Malignancies

Patients receiving immunosuppressants, including Cromidin Capsules USP, are at increased risk of developing lymphomas and other malignancies, particularly of the skin . The risk appears to be related to the intensity and duration of immunosuppression rather than to the use of any specific agent.

As usual for patients with increased risk for skin cancer, exposure to sunlight and UV light should be limited by wearing protective clothing and using a sunscreen with a high protection factor.

Post transplant lymphoproliferative disorder has been reported in immunosuppressed organ transplant recipients. The majority of PTLD events appear related to Epstein Barr Virus (EBV) infection. The risk of PTLD appears greatest in those individuals who are EBV seronegative, a population which includes many young children.

5.3 Serious Infections

Patients receiving immunosuppressants, including Cromidin Capsules USP, are at increased risk of developing bacterial, viral, fungal, and protozoal infections, including opportunistic infections . These infections may lead to serious, including fatal, outcomes. Because of the danger of oversuppression of the immune system which can increase susceptibility to infection, combination immunosuppressant therapy should be used with caution.

5.4 Polyoma Virus Infections

Patients receiving immunosuppressants, including Cromidin Capsules USP, are at increased risk for opportunistic infections, including polyoma virus infections. Polyoma virus infections in transplant patients may have serious, and sometimes fatal, outcomes. These include polyoma virus-associated nephropathy, mostly due to BK virus infection, and JC virus-associated progressive multifocal leukoencephalopathy (PML) which have been observed in patients receiving Cromidin .

PVAN is associated with serious outcomes, including deteriorating renal function and kidney graft loss . Patient monitoring may help detect patients at risk for PVAN.

Cases of PML have been reported in patients treated with Cromidin Capsules USP. PML, which is sometimes fatal, commonly presents with hemiparesis, apathy, confusion, cognitive deficiencies and ataxia. Risk factors for PML include treatment with immunosuppressant therapies and impairment of immune function. In immunosuppressed patients, physicians should consider PML in the differential diagnosis in patients reporting neurological symptoms and consultation with a neurologist should be considered as clinically indicated.

Reductions in immunosuppression should be considered for patients who develop evidence of PVAN or PML. Physicians should also consider the risk that reduced immunosuppression represents to the functioning allograft.

5.5 Cytomegalovirus (CMV) Infections

Patients receiving immunosuppressants, including Cromidin Capsules USP, are at increased risk of developing CMV viremia and CMV disease. The risk of CMV disease is highest among transplant recipients seronegative for CMV at time of transplant who receive a graft from a CMV seropositive donor. Therapeutic approaches to limiting CMV disease exist and should be routinely provided. Patient monitoring may help detect patients at risk for CMV disease. Consideration should be given to reducing the amount of immunosuppression in patients who develop CMV viremia and/or CMV disease.

5.6 New Onset Diabetes After Transplant

Cromidin Capsules USP was shown to cause new onset diabetes mellitus in clinical trials of kidney and liver transplantation. New onset diabetes after transplantation may be reversible in some patients. Black and Hispanic kidney transplant patients are at an increased risk. Blood glucose concentrations should be monitored closely in patients using Cromidin .

5.7 Nephrotoxicity

Cromidin Capsules USP, like other calcineurin-inhibitors, can cause acute or chronic nephrotoxicity, particularly when used in high doses. Acute nephrotoxicity is most often related to vasoconstriction of the afferent renal arteriole, is characterized by increasing serum creatinine, hyperkalemia, and/or a decrease in urine output, and is typically reversible. Chronic calcineurin-inhibitor nephrotoxicity is associated with increased serum creatinine, decreased kidney graft life, and characteristic histologic changes observed on renal biopsy; the changes associated with chronic calcineurin-inhibitor nephrotoxicity are typically progressive. Patients with impaired renal function should be monitored closely as the dosage of Cromidin Capsules USP may need to be reduced. In patients with persistent elevations of serum creatinine who are unresponsive to dosage adjustments, consideration should be given to changing to another immunosuppressive therapy.

Based on reported adverse reactions terms related to decreased renal function, nephrotoxicity was reported in approximately 52% of kidney transplantation patients and in 40% and 36% of liver transplantation patients receiving Cromidin Capsules USP in the U.S. and European randomized trials, respectively .

Due to the potential for additive or synergistic impairment of renal function, care should be taken when administering Cromidin Capsules USP with drugs that may be associated with renal dysfunction. These include, but are not limited to, aminoglycosides, ganciclovir, amphotericin B, cisplatin, nucleotide reverse transcriptase inhibitors (e.g., tenofovir) and protease inhibitors (e.g., ritonavir, indinavir). Similarly, care should be exercised when administering with CYP3A4 inhibitors such as antifungal drugs (e.g., ketoconazole), calcium channel blockers (e.g., diltiazem, verapamil), and macrolide antibiotics (e.g., clarithromycin, erythromycin, troleandomycin) which will result in increased Cromidin whole blood concentrations due to inhibition of Cromidin metabolism .

5.8 Neurotoxicity

Cromidin Capsules USP may cause a spectrum of neurotoxicities, particularly when used in high doses. The most severe neurotoxicities include posterior reversible encephalopathy syndrome, delirium, and coma. Patients treated with Cromidin have been reported to develop PRES. Symptoms indicating PRES include headache, altered mental status, seizures, visual disturbances and hypertension. Diagnosis may be confirmed by radiological procedure. If PRES is suspected or diagnosed, blood pressure control should be maintained and immediate reduction of immunosuppression is advised. This syndrome is characterized by reversal of symptoms upon reduction or discontinuation of immunosuppression.

Coma and delirium, in the absence of PRES, have also been associated with high plasma concentrations of Cromidin. Seizures have occurred in adult and pediatric patients receiving Cromidin .

Less severe neurotoxicities, include tremors, parathesias, headache, and other changes in motor function, mental status, and sensory function . Tremor and headache have been associated with high whole-blood concentrations of Cromidin and may respond to dosage adjustment.

5.9 Hyperkalemia

Hyperkalemia has been reported with Cromidin Capsules USP use. Serum potassium levels should be monitored. Careful consideration should be given prior to use of other agents also associated with hyperkalemia (e.g., potassium-sparing diuretics, ACE inhibitors, angiotensin receptor blockers) during Cromidin therapy .

5.10 Hypertension

Hypertension is a common adverse effect of Cromidin therapy and may require antihypertensive therapy . The control of blood pressure can be accomplished with any of the common antihypertensive agents, though careful consideration should be given prior to use of antihypertensive agents associated with hyperkalemia (e.g., potassium-sparing diuretics, ACE inhibitors, angiotensin receptor blockers) . Calcium-channel blocking agents may increase Cromidin blood concentrations and therefore require dosage reduction of Cromidin .

5.11 Anaphylactic Reactions with Cromidin Injection

Anaphylactic reactions have occurred with injectables containing castor oil derivatives, including Cromidin Capsules USP, in a small percentage of patients (0.6%). The exact cause of these reactions is not known. Cromidin injection should be reserved for patients who are unable to take Cromidin Capsules USP .

Patients receiving Cromidin injection should be under continuous observation for at least the first 30 minutes following the start of the infusion and at frequent intervals thereafter. If signs or symptoms of anaphylaxis occur, the infusion should be stopped. An aqueous solution of epinephrine should be available at the bedside as well as a source of oxygen.

5.12 Use with Sirolimus

The safety and efficacy of Cromidin with sirolimus has not been established in kidney transplant patients. Use of sirolimus with Cromidin in studies of de novo liver transplant patients was associated with an excess mortality, graft loss, and hepatic artery thrombosis and is not recommended .

5.13 Use with CYP3A4 Inhibitors and Inducers

When coadministration Cromidin with strong CYP3A4-inhibitors (e.g., telaprevir, boceprevir, ritonavir, ketoconazole, itraconazole, voriconazole, clarithromycin) and strong inducers (e.g., rifampin, rifabutin) adjustments in the dosing regimen of Cromidin and subsequent frequent monitoring of Cromidin whole blood trough concentrations and tacrolimus-associated adverse reactions are recommended .

5.14 QT Prolongation

Cromidin may prolong the QT/QTc interval and may cause Torsade de Pointes. Avoid Cromidin in patients with congenital long QT syndrome. In patients with congestive heart failure, bradyarrhythmias, those taking certain antiarrhythmic medications or other medicinal products that lead to QT prolongation, and those with electrolyte disturbances such as hypokalemia, hypocalcemia, or hypomagnesemia, consider obtaining electrocardiograms and monitoring electrolytes periodically during treatment.

When coadministering Cromidin with other substrates and/or inhibitors of CYP3A4 that also have the potential to prolong the QT interval, a reduction in Cromidin dose, frequent monitoring of Cromidin whole blood concentrations, and monitoring for QT prolongation is recommended. Use of Cromidin with amiodarone has been reported to result in increased Cromidin whole blood concentrations with or without concurrent QT prolongation .

5.15 Myocardial Hypertrophy

Myocardial hypertrophy has been reported in infants, children, and adults, particularly those with high Cromidin trough concentrations, and is generally manifested by echocardiographically demonstrated concentric increases in left ventricular posterior wall and interventricular septum thickness. This condition appears reversible in most cases following dose reduction or discontinuance of therapy. In patients who develop renal failure or clinical manifestations of ventricular dysfunction while receiving Cromidin therapy, echocardiographic evaluation should be considered. If myocardial hypertrophy is diagnosed, dosage reduction or discontinuation of Cromidin Capsules USP should be considered .

5.16 Immunizations

The use of live vaccines should be avoided during treatment with Cromidin; examples include the following: intranasal influenza, measles, mumps, rubella, oral polio, BCG, yellow fever, varicella, and TY21a typhoid vaccines.

5.17 Pure Red Cell Aplasia

Cases of pure red cell aplasia (PRCA) have been reported in patients treated with Cromidin. A mechanism for tacrolimus-induced PRCA has not been elucidated. All patients reported risk factors for PRCA such as parvovirus B19 infection, underlying disease, or concomitant medications associated with PRCA. If PRCA is diagnosed, discontinuation of Cromidin Capsules USP should be considered .

5.18 Gastrointestinal Perforation

Gastrointestinal perforation has been reported in patients treated with Cromidin; all reported cases were considered to be a complication of transplant surgery or accompanied by infection, diverticulum, or malignant neoplasm. As gastrointestinal perforation may be serious or life-threatening, appropriate medical/surgical management should be instituted promptly .

6 ADVERSE REACTIONS

The following serious and otherwise important adverse drug reactions are discussed in greater detail in other sections of labeling:

• Lymphoma and Other Malignancies
• Serious Infections
• Polyoma Virus Infections
• CMV Infections
• New Onset Diabetes After Transplant
• Nephrotoxicity
• Neurotoxicity
• Hyperkalemia
• Hypertension
• Anaphylaxis with Cromidin Injection
• Myocardial Hypertrophy
• Pure Red Cell Aplasia
• Gastrointestinal Perforation

• Kidney Transplant: The most common adverse reactions ( ≥ 30%) were infection, tremor, hypertension, abnormal renal function, constipation, diarrhea, headache, abdominal pain, insomnia, nausea, hypomagnesemia, urinary tract infection, hypophosphatemia, peripheral edema, asthenia, pain, hyperlipidemia, hyperkalemia, anemia (6.1)
• Liver Transplant: The most common adverse reactions ( ≥ 40%) were tremor, headache, diarrhea, hypertension, nausea, abnormal renal function, abdominal pain, insomnia, paresthesia, anemia, pain, fever, asthenia, hyperkalemia, hypomagnesemia, and hyperglycemia (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact Panacea Biotec Global Pharmacovigilance Function at 1-877-687-4130 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Studies Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. In addition, the clinical trials were not designed to establish comparative differences across study arms with regards to the adverse reactions discussed below.

Kidney Transplant

The incidence of adverse reactions was determined in three randomized kidney transplant trials. One of the trials used azathioprine and corticosteroids and two of the trials used mycophenolate mofetil (MMF) and corticosteroids concomitantly for maintenance immunosuppression.

Tacrolimus-based immunosuppression in conjunction with azathioprine and corticosteroids following kidney transplantation was assessed in trial where 205 patients received Cromidin based immunosuppression and 207 patients received cyclosporine based immunosuppression. The trial population had a mean age of 43 years (mean±sd was 43±13 years on Cromidin and 44±12 years on cyclosporine arm), the distribution was 61% male, and the composition was White (58%), Black (25%), Hispanic (12%) and Other (5%). The 12 month post-transplant information from this trial is presented below.

The most common adverse reactions (≥ 30%) observed in tacrolimus-treated kidney transplant patients are: infection, tremor, hypertension, abnormal renal function, constipation, diarrhea, headache, abdominal pain, insomnia, nausea, hypomagnesemia, urinary tract infection, hypophosphatemia, peripheral edema, asthenia, pain, hyperlipidemia, hyperkalemia and anemia.

Adverse reactions that occurred in ≥ 15% of kidney transplant patients treated with Cromidin in conjunction with azathioprine are presented below:

Two trials were conducted for tacrolimus-based immunosuppression in conjunction with MMF and corticosteroids. In the non-US trial (Study 1), the incidence of adverse reactions was based on 1195 kidney transplant patients that received Cromidin (Group C, n=403), or one of two cyclosporine (CsA) regimens (Group A, n=384 and Group B, n=408) in combination with MMF and corticosteroids; all patients, except those in one of the two cyclosporine groups, also received induction with daclizumab. The trial population had a mean age of 46 years (range 17 to 76), the distribution was 65% male, and the composition was 93% Caucasian. The 12 month post-transplant information from this trial is presented below.

Adverse reactions that occurred in ≥ 10% of kidney transplant patients treated with Cromidin in conjunction with MMF in Study 1 [Note: This trial was conducted entirely outside of the United States. Such trials often report a lower incidence of adverse reactions in comparison to U.S. trials] are presented below:

In the U.S. trial (Study 2) with tacrolimus-based immunosuppression in conjunction with MMF and corticosteroids, 424 kidney transplant patients received Cromidin (n=212) or cyclosporine (n=212) in combination with MMF 1 gram twice daily, basiliximab induction, and corticosteroids. The trial population had a mean age of 48 years (range 17 to 77), the distribution was 63% male, and the composition was White (74%), Black (20%), Asian (3%) and other (3%). The 12 month post-transplant information from this trial is presented below.

Adverse reactions that occurred in ≥15% of kidney transplant patients treated with Cromidin in conjunction with MMF in Study 2 are presented below:

Less frequently observed adverse reactions in both liver transplantation and kidney transplantation patients are described under the subsection Less Frequently Reported Adverse Reactions .

Liver Transplantation

There were two randomized comparative liver transplant trials. In the U.S. trial, 263 adult and pediatric patients received Cromidin and steroids and 266 patients received cyclosporine-based immunosuppressive regimen (CsA/AZA). The trial population had a mean age of 44 years (range 0.4 to70), the distribution was 52% male, and the composition was White (78%), Black (5%), Asian (2%), Hispanic (13%) and Other (2%). In the European trial, 270 patients received Cromidin and steroids and 275 patients received CsA/AZA. The trial population had a mean age of 46 years (range 15 to 68), the distribution was 59% male, and the composition was White (95.4%), Black (1%), Asian (2%) and Other (2%).

The proportion of patients reporting more than one adverse event was > 99% in both the Cromidin group and the CsA/AZA group. Precautions must be taken when comparing the incidence of adverse reactions in the U.S. trial to that in the European trial. The 12-month post-transplant information from the U.S. trial and from the European trial is presented below. The two trials also included different patient populations and patients were treated with immunosuppressive regimens of differing intensities. Adverse reactions reported in ≥15% in Cromidin patients (combined trial results) are presented below for the two controlled trials in liver transplantation.

The most common adverse reactions (≥40%) observed in Tacrolimus-treated liver transplant patients are: tremor, headache, diarrhea, hypertension, nausea, abnormal renal function, abdominal pain, insomnia, paresthesia, anemia, pain, fever, asthenia, hyperkalemia, hypomagnesemia, and hyperglycemia. These all occur with oral and IV administration of Cromidin and some may respond to a reduction in dosing (e.g., tremor, headache, paresthesia, hypertension). Diarrhea was sometimes associated with other gastrointestinal complaints such as nausea and vomiting.

Less frequently observed adverse reactions in both liver transplantation and kidney transplantation patients are described under the subsection Less Frequently Reported Adverse Reactions .

Other targeted treatment-emergent adverse reactions in tacrolimus-treated patients occurred at a rate of less than 15%, and include the following: Cushingoid features, impaired wound healing, hyperkalemia, Candida infection, and CMV infection/syndrome.

New Onset Diabetes After Transplant

Kidney Transplant

New Onset Diabetes After Transplant is defined as a composite of fasting plasma glucose ≥126 mg/dL, HbA1C ≥ 6%, insulin use ≥ 30 days or oral hypoglycemic use. In a trial in kidney transplant patients (Study 2), NODAT was observed in 75% in the tacrolimus-treated and 61% in the Neoral-treated patients without pre-transplant history of diabetes mellitus (Table 8) .

In early trials of Cromidin, Post-Transplant Diabetes Mellitus (PTDM) was evaluated with a more limited criteria of “use of insulin for 30 or more consecutive days with < 5 day gap” in patients without a prior history of insulin-dependent diabetes mellitus or non-insulin dependent diabetes mellitus. Data are presented in Tables 9 to 11. PTDM was reported in 20% of Tacrolimus/Azathioprine (AZA)-treated kidney transplant patients without pre-transplant history of diabetes mellitus in a Phase 3 trial (Table 9). The median time to onset of PTDM was 68 days. Insulin dependence was reversible in 15% of these PTDM patients at one year and in 50% at 2 years post-transplant. Black and Hispanic kidney transplant patients were at an increased risk of development of PTDM (Table 10).

Liver Transplant

Insulin-dependent PTDM was reported in 18% and 11% of tacrolimus-treated liver transplant patients and was reversible in 45% and 31% of these patients at 1 year post-transplant, in the U.S. and European randomized trials, respectively, (Table 11). Hyperglycemia was associated with the use of Cromidin Capsules USP in 47% and 33% of liver transplant recipients in the U.S. and European randomized trials, respectively, and may require treatment .

Less Frequently Reported Adverse Reactions

The following adverse reactions were reported in either liver and/or kidney transplant recipients who were treated with Cromidin in clinical trials.

Nervous System

Abnormal dreams, agitation, amnesia, anxiety, confusion, convulsion, crying, depression, elevated mood, emotional lability, encephalopathy, haemorrhagic stroke, hallucinations, hypertonia, incoordination, monoparesis, myoclonus, nerve compression, nervousness, neuralgia, neuropathy, paralysis flaccid, psychomotor skills impaired, psychosis, quadriparesis, somnolence, thinking abnormal, vertigo, writing impaired

Special Senses

Abnormal vision, amblyopia, ear pain, otitis media, tinnitus

Gastrointestinal

Cholangitis, cholestatic jaundice, duodenitis, dysphagia, esophagitis, flatulence, gastritis, gastroesophagitis, gastrointestinal hemorrhage, GGT increase, GI disorder, GI perforation, hepatitis, hepatitis granulomatous, ileus, increased appetite, jaundice, liver damage, oesophagitis ulcerative, oral moniliasis, pancreatic pseudocyst, rectal disorder, stomatitis

Cardiovascular

Abnormal ECG, angina pectoris, arrhythmia, atrial fibrillation, atrial flutter, bradycardia, cardiac fibrillation, cardiopulmonary failure, cardiovascular disorder, congestive heart failure, deep thrombophlebitis, echocardiogram abnormal, electrocardiogram QRS complex abnormal, electrocardiogram ST segment abnormal, heart failure, heart rate decreased, hemorrhage, hypotension, peripheral vascular disorder, phlebitis, postural hypotension, syncope, tachycardia, thrombosis, vasodilatation

Urogenital

Acute kidney failure, albuminuria, BK nephropathy, bladder spasm, cystitis, dysuria, hematuria, hydronephrosis, kidney failure, kidney tubular necrosis, nocturia, pyuria, toxic nephropathy, urge incontinence, urinary frequency, urinary incontinence, urinary retention, vaginitis

Metabolic/Nutritional

Acidosis, alkaline phosphatase increased, alkalosis, ALT (SGPT) increased, AST (SGOT) increased, bicarbonate decreased, bilirubinemia, dehydration, GGT increased, gout, healing abnormal, hypercalcemia, hypercholesterolemia, hyperphosphatemia, hyperuricemia, hypervolemia, hypocalcemia, hypoglycemia, hyponatremia, hypoproteinemia, lactic dehydrogenase increase, weight gain

Endocrine

Cushing’s syndrome

Hemic/Lymphatic

Coagulation disorder, ecchymosis, haematocrit increased, haemoglobin abnormal, hypochromic anemia, leukocytosis, polycythemia, prothrombin decreased, serum iron decreased

Miscellaneous

Abdomen enlarged, abscess, accidental injury, allergic reaction, cellulitis, chills, fall, feeling abnormal, flu syndrome, generalized edema, hernia, mobility decreased, peritonitis, photosensitivity reaction, sepsis, temperature intolerance, ulcer

Musculoskeletal

Arthralgia, cramps, generalized spasm, joint disorder, leg cramps, myalgia, myasthenia, osteoporosis

Respiratory

Asthma, emphysema, hiccups, lung disorder, lung function decreased, pharyngitis, pneumonia, pneumothorax, pulmonary edema, respiratory disorder, rhinitis, sinusitis, voice alteration

Skin

Acne, alopecia, exfoliative dermatitis, fungal dermatitis, herpes simplex, herpes zoster, hirsutism, neoplasm skin benign, skin discoloration, skin disorder, skin ulcer, sweating

6.2 Postmarketing Adverse Reactions

The following adverse reactions have been reported from worldwide marketing experience with Cromidin. Because these reactions are reported voluntarily from a population of uncertain size it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Decisions to include these reactions in labeling are typically based on one or more of the following factors: seriousness of the reaction, (2) frequency of the reporting, or (3) strength of causal connection to the drug.

Other reactions include:

Cardiovascular

Atrial fibrillation, atrial flutter, cardiac arrhythmia, cardiac arrest, electrocardiogram T wave abnormal, flushing, myocardial infarction, myocardial ischaemia, pericardial effusion, QT prolongation, Torsade de Pointes, venous thrombosis deep limb, ventricular extrasystoles, ventricular fibrillation, myocardial hypertrophy .

Gastrointestinal

Bile duct stenosis, colitis, enterocolitis, gastroenteritis, gastrooesophageal reflux disease, hepatic cytolysis, hepatic necrosis, hepatotoxicity, impaired gastric emptying, liver fatty, mouth ulceration, pancreatitis haemorrhagic, pancreatitis necrotizing, stomach ulcer, venoocclusive liver disease

Hemic/Lymphatic

Agranulocytosis, disseminated intravascular coagulation, hemolytic anemia, neutropenia, pancytopenia, thrombocytopenic purpura, thrombotic thrombocytopenic purpura, pure red cell aplasia

Infections

Cases of progressive multifocal leukoencephalopathy (PML), sometimes fatal; -polyoma virus-associated nephropathy, (PVAN) including graft loss

Metabolic/Nutritional

Glycosuria, increased amylase including pancreatitis, weight decreased

Miscellaneous

Feeling hot and cold, feeling jittery, hot flushes, multi-organ failure, primary graft dysfunction

Nervous System

Carpal tunnel syndrome, cerebral infarction, hemiparesis, leukoencephalopathy, mental disorder, mutism, posterior reversible encephalopathy syndrome , progressive multifocal leukoencephalopathy (PML) , quadriplegia, speech disorder, syncope

Respiratory

Acute respiratory distress syndrome, interstitial lung disease, lung infiltration, respiratory distress, respiratory failure

Skin

Stevens-Johnson syndrome, toxic epidermal necrolysis

Special Senses

Blindness, blindness cortical, hearing loss including deafness, photophobia

Urogenital

Acute renal failure, cystitis haemorrhagic, hemolytic-uremic syndrome, micturition disorder

7 DRUG INTERACTIONS

Since Cromidin is metabolized mainly by CYP3A enzymes, drugs or substances known to inhibit these enzymes may increase Cromidin whole blood concentrations. Drugs known to induce CYP3A enzymes may decrease Cromidin whole blood concentrations . Dose adjustments may be needed along with frequent monitoring of Cromidin whole blood trough concentrations when Cromidin is administered with CYP3A inhibitors or inducers. In addition, patients should be monitored for adverse reactions including changes in renal function and QT prolongation .

• Mycophenolic Acid Products: Can increase MPA exposure after crossover from cyclosporine to Cromidin; monitor for MPA-related adverse reactions and adjust MMF or MPA-dose as needed (7.1)
• Nelfinavir and Grapefruit Juice: Increased Cromidin concentrations via CYP3A inhibition; avoid concomitant use (7.2, 7.3)
• CYP3A Inhibitors: Increased Cromidin concentrations; monitor concentrations and adjust Cromidin dose as needed with concomitant use (5.13, 7.3, 7.4, 7.5, 7.6)
• CYP3A4 inducers: Decreased Cromidin concentrations ; monitor concentrations and adjust Cromidin dose as needed with concomitant use (5.13, 7.7, 7.8, 7.9)

7.1 Mycophenolic Acid Products

With a given dose of mycophenolic acid (MPA) products, exposure to MPA is higher with Cromidin Capsules USP co-administration than with cyclosporine co-administration because cyclosporine interrupts the enterohepatic recirculation of MPA while Cromidin does not. Clinicians should be aware that there is also a potential for increased MPA exposure after crossover from cyclosporine to Cromidin in patients concomitantly receiving MPA-containing products.

7.2 Grapefruit Juice

Grapefruit juice inhibits CYP3A-enzymes resulting in increased Cromidin whole blood trough concentrations, and patients should avoid eating grapefruit or drinking grapefruit juice with Cromidin .

7.3 Protease Inhibitors

Most protease inhibitors inhibit CYP3A enzymes and may increase Cromidin whole blood concentrations. It is recommended to avoid concomitant use of Cromidin with nelfinavir unless the benefits outweigh the risks . Whole blood concentrations of Cromidin are markedly increased when co-administered with telaprevir or with boceprevir . Monitoring of Cromidin whole blood concentrations and tacrolimus-associated adverse reactions, and appropriate adjustments in the dosing regimen are recommended when Cromidin and other protease inhibitors (e.g., ritonavir, telaprevir, boceprevir) are used concomitantly.

7.4 Antifungal Agents

Frequent monitoring of whole blood concentrations and appropriate dosage adjustments of Cromidin are recommended when concomitant use of the following antifungal drugs with Cromidin is initiated or discontinued .

Azoles: Voriconazole, posaconazole, itraconazole, ketoconazole, fluconazole and clotrimazole inhibit CYP3A metabolism of Cromidin and increase Cromidin whole blood concentrations. When initiating therapy with voriconazole or posaconazole in patients already receiving Cromidin, it is recommended that the Cromidin dose be initially reduced to one-third of the original dose and the subsequent Cromidin doses be adjusted based on the Cromidin whole blood concentrations.

Caspofungin is an inducer of CYP3A and decreases whole blood concentrations of Cromidin.

7.5 Calcium Channel Blockers

Verapamil, diltiazem, nifedipine, and nicardipine inhibit CYP3A metabolism of Cromidin and may increase Cromidin whole blood concentrations. Monitoring of whole blood concentrations and appropriate dosage adjustments of Cromidin are recommended when these calcium channel blocking drugs and Cromidin are used concomitantly.

7.6 Antibacterials

Erythromycin, clarithromycin, troleandomycin and chloramphenicol inhibit CYP3A metabolism of Cromidin and may increase Cromidin whole blood concentrations. Monitoring of blood concentrations and appropriate dosage adjustments of Cromidin are recommended when these drugs and Cromidin are used concomitantly.

7.7 Antimycobacterials

Rifampin and rifabutin are inducers of CYP3A enzymes and may decrease Cromidin whole blood concentrations. Monitoring of whole blood concentrations and appropriate dosage adjustments of Cromidin are recommended when these antimycobacterial drugs and Cromidin are used concomitantly.

7.8 Anticonvulsants

Phenytoin, carbamazepine and phenobarbital induce CYP3A enzymes and may decrease Cromidin whole blood concentrations. Monitoring of whole blood concentrations and appropriate dosage adjustments of Cromidin are recommended when these drugs and Cromidin are used concomitantly. Concomitant administration of phenytoin with Cromidin may also increase phenytoin plasma concentrations. Thus, frequent monitoring phenytoin plasma concentrations and adjusting the phenytoin dose as needed are recommended when Cromidin and phenytoin are administered concomitantly.

7.9 St. John’s Wort

St. John’s Wort induces CYP3A enzymes and may decrease Cromidin whole blood concentrations. Monitoring of whole blood concentrations and appropriate dosage adjustments of Cromidin are recommended when St. John’s Wort and Cromidin are co-administered.

7.10 Gastric Acid Suppressors/Neutralizers

Lansoprazole and omeprazole, as CYP2C19 and CYP3A4 substrates, may potentially inhibit the CYP3A4 metabolism of Cromidin and thereby substantially increase Cromidin whole blood concentrations, especially in transplant patients who are intermediate or poor CYP2C19 metabolizers, as compared to those patients who are efficient CYP2C19 metabolizers. Cimetidine may also inhibit the CYP3A4 metabolism of Cromidin and thereby substantially increase Cromidin whole blood concentrations.

Coadministration with magnesium and aluminum hydroxide antacids increase Cromidin whole blood concentrations . Monitoring of whole blood concentrations and appropriate dosage adjustments of Cromidin are recommended when these drugs and Cromidin are used concomitantly.

7.11 Others

Bromocriptine, nefazodone, metoclopramide, danazol, ethinyl estradiol, amiodarone and methylprednisolone may inhibit CYP3A metabolism of Cromidin and increase Cromidin whole blood concentrations. Monitoring of blood concentrations and appropriate dosage adjustments of Cromidin are recommended when these drugs and Cromidin are co-administered.

8 USE IN SPECIFIC POPULATIONS

• 
  

  Pregnancy: Based on animal data may cause fetal harm. Use only if the potential benefit justifies the risk
  

• 
  

  Nursing Mothers: Discontinue nursing taking into consideration importance of drug to mother (8.3)
  

• 
  

  Hepatic/Renal impaired patients: Administer at the lower end of the recommended starting dose. Monitor renal function in patients with impaired renal function (2.3, 2.4, 8.6, 8.7)
  

See 17 for PATIENT COUNSELING INFORMATION

8.1 Pregnancy

Pregnancy Category C - There are no adequate and well-controlled studies in pregnant women. Cromidin is transferred across the placenta. The use of Cromidin during pregnancy in humans has been associated with neonatal hyperkalemia and renal dysfunction. Cromidin given orally to pregnant rabbits at 0.5 to 4.3 times the clinical dose and pregnant rats at 0.8 to 6.9 times the clinical dose was associated with an increased incidence of fetal death in utero, fetal malformations (cardiovascular, skeletal, omphalocele, and gallbladder agenesis) and maternal toxicity. Cromidin Capsules USP should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus.

In pregnant rabbits, Cromidin at oral doses of 0.32 and 1.0 mg/kg, 0.5 to 4.3 times the clinical dose range (0.075 – 0.2 mg/kg) based on body surface area, was associated with maternal toxicity as well as an increased incidence of abortions. At the 1 mg/kg dose, fetal rabbits showed an increased incidence of malformations (ventricular hypoplasia, interventricular septal defect, bulbous aortic arch, stenosis of ductus arteriosis, interrupted ossification of vertebral arch, vertebral and rib malformations, omphalocele, and gallbladder agenesis) and developmental variations. In pregnant rats, Cromidin at oral doses of 3.2 mg/kg, 2.6 to 6.9 times the clinical dose range was associated with maternal toxicity, an increase in late resorptions, decreased numbers of live births, and decreased pup weight and viability. Cromidin, given orally to pregnant rats after organogenesis and during lactation at 1.0 and 3.2 mg/kg, 0.8 to 6.9 times the recommended clinical dose range was associated with reduced pup weights and pup viability (3.2 mg/kg only); among the high dose pups that died early, an increased incidence of kidney hydronephrosis was observed.

8.3 Nursing Mothers

Cromidin is excreted in human milk. As the effect of chronic exposure to Cromidin in healthy infants is not established, patients maintained on Cromidin should discontinue nursing taking into consideration importance of drug to the mother.

8.4 Pediatric Use

The safety and efficacy of Cromidin Capsules USP in pediatric kidney transplant patients have not been established. Successful liver transplants have been performed in pediatric patients using Cromidin Capsules USP. Two randomized active controlled trials of Cromidin Capsules USP in primary liver transplantation included 56 pediatric patients. Thirty-one patients were randomized to tacrolimus-based and 25 to cyclosporine-based therapies. Additionally, a minimum of 122 pediatric patients were studied in an uncontrolled trial of Cromidin in living related donor liver transplantation. Pediatric patients generally required higher doses of Cromidin Capsules USP to maintain blood trough concentrations of Cromidin similar to adult patients .

8.5 Geriatric Use

Clinical trials of Cromidin Capsules USP did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic and renal function, and of concomitant disease or other drug therapy.

8.6 Use in Renal Impairment

The pharmacokinetics of Cromidin in patients with renal impairment was similar to that in healthy volunteers with normal renal function. However, consideration should be given to dosing Cromidin Capsules USP at the lower end of the therapeutic dosing range in patients who have received a liver transplant and have pre-existing renal impairment. Further reductions in dose below the targeted range may be required .

8.7 Use in Hepatic Impairment

The mean clearance of Cromidin was substantially lower in patients with severe hepatic impairment (mean Child-Pugh score: >10) compared to healthy volunteers with normal hepatic function. Close monitoring of Cromidin trough concentrations is warranted in patients with hepatic impairment .

The use of Cromidin Capsules USP in liver transplant recipients experiencing post-transplant hepatic impairment may be associated with increased risk of developing renal insufficiency related to high whole-blood trough concentrations of Cromidin. These patients should be monitored closely and dosage adjustments should be considered. Some evidence suggests that lower doses should be used in these patients .

10 OVERDOSAGE

Limited overdosage experience is available. Acute overdosages of up to 30 times the intended dose have been reported. Almost all cases have been asymptomatic and all patients recovered with no sequelae. Acute overdosage was sometimes followed by adverse reactions consistent with those listed in Adverse Reactions (6) (including tremors, abnormal renal function, hypertension, and peripheral edema); in one case of acute overdosage, transient urticaria and lethargy were observed. Based on the poor aqueous solubility and extensive erythrocyte and plasma protein binding, it is anticipated that Cromidin is not dialyzable to any significant extent; there is no experience with charcoal hemoperfusion. The oral use of activated charcoal has been reported in treating acute overdoses, but experience has not been sufficient to warrant recommending its use. General supportive measures and treatment of specific symptoms should be followed in all cases of overdosage.

In acute oral studies, mortalities were seen at or above the following doses: in adult rats, 52 times the recommended human oral dose; in immature rats, 16 times the recommended oral dose; (all based on body surface area corrections).

11 DESCRIPTION

Cromidin is available for oral administration as capsules (Tacrolimus Capsules USP) containing the equivalent of 0.5 mg, 1 mg or 5 mg of Cromidin USP. Inactive ingredients include anhydrous lactose, hypromellose 2910, croscarmellose sodium, and magnesium stearate. The 0.5 mg capsule shell contains gelatin, titanium dioxide and ferric oxide, the 1 mg capsule shell contains gelatin and titanium dioxide, and the 5 mg capsule shell contains gelatin, titanium dioxide and ferric oxide.

Cromidin, previously known as FK506, is the active ingredient in Cromidin Capsules USP. Cromidin is a macrolide immunosuppressant produced by Streptomyces tsukubaensis. Chemically, Cromidin is designated as [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.

The chemical structure of Cromidin USP is:

Cromidin USP has a molecular formula of C₄₄H₆₉NO₁₂-H₂O and a formula weight of 822.03. Cromidin appears as white to off white powder. It is soluble in acetone, chloroform, ethyl acetate and insoluble in water.

The Dissolution Test criteria of Cromidin Capsules USP as outlined below:

Cromidin Capsules USP comply with USP Organic Impurities test criteria as outlined below:

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Cromidin inhibits T-lymphocyte activation, although the exact mechanism of action is not known. Experimental evidence suggests that Cromidin binds to an intracellular protein, FKBP-12.A complex of tacrolimus-FKBP-12, calcium, calmodulin, and calcineurin is then formed and the phosphatase activity of calcineurin inhibited. This effect may prevent the dephosphorylation and translocation of nuclear factor of activated T-cells, a nuclear component thought to initiate gene transcription for the formation of lymphokines (such as interleukin-2, gamma interferon). The net result is the inhibition of T-lymphocyte activation (i.e., immunosuppression).

Cromidin prolongs the survival of the host and transplanted graft in animal transplant models of liver, kidney, bone marrow, small bowel and pancreas, lung and trachea, skin, cornea, and limb.

In animals, Cromidin has been demonstrated to suppress some humoral immunity and, to a greater extent, cell-mediated reactions such as allograft rejection, delayed type hypersensitivity, collagen-induced arthritis, experimental allergic encephalomyelitis, and graft versus host disease.

12.3 Pharmacokinetics

Cromidin activity is primarily due to the parent drug. The pharmacokinetic parameters (mean±S.D.) of Cromidin have been determined following oral (PO) administration in healthy volunteers, and in kidney transplant and liver transplant patients (Table 12).

Due to intersubject variability in Cromidin pharmacokinetics, individualization of dosing regimen is necessary for optimal therapy . Pharmacokinetic data indicate that whole blood concentrations rather than plasma concentrations serve as the more appropriate sampling compartment to describe Cromidin pharmacokinetics.

Absorption

Absorption of Cromidin from the gastrointestinal tract after oral administration is incomplete and variable. The absolute bioavailability of Cromidin was 17±10% in adult kidney transplant patients, 22±6% in adult liver transplant patients (N=17), and 18±5% in healthy volunteers (N=16).

A single dose trial conducted in 32 healthy volunteers established the bioequivalence of the 1 mg and 5 mg capsules. Another single dose trial in 32 healthy volunteers established the bioequivalence of the 0.5 mg and 1 mg capsules. Cromidin maximum blood concentrations (C_max) and area under the curve (AUC) appeared to increase in a doseproportional fashion in 18 fasted healthy volunteers receiving a single oral dose of 3, 7, and 10 mg.

In 18 kidney transplant patients, Cromidin trough concentrations from 3 to 30 ng/mL measured at 10-12 hours post-dose (C_min) correlated well with the AUC (correlation coefficient 0.93). In 24 liver transplant patients over a concentration range of 10 to 60 ng/mL, the correlation coefficient was 0.94.

Food Effects

The rate and extent of Cromidin absorption were greatest under fasted conditions. The presence and composition of food decreased both the rate and extent of Cromidin absorption when administered to 15 healthy volunteers.

The effect was most pronounced with a high-fat meal (848 kcal, 46% fat): mean AUC and C_max were decreased 37% and 77%, respectively; T_max was lengthened 5-fold. A high-carbohydrate meal (668 kcal, 85% carbohydrate) decreased mean AUC and mean C_max by 28% and 65%, respectively.

In healthy volunteers (N=16), the time of the meal also affected Cromidin bioavailability. When given immediately following the meal, mean C_max was reduced 71%, and mean AUC was reduced 39%, relative to the fasted condition. When administered 1.5 hours following the meal, mean C_max was reduced 63%, and mean AUC was reduced 39%, relative to the fasted condition.

In 11 liver transplant patients, Cromidin Capsules USP administered 15 minutes after a high fat (400 kcal, 34% fat) breakfast, resulted in decreased AUC (27±18%) and C_max (50±19%), as compared to a fasted state.

Cromidin Capsules USP should be taken consistently every day either with or without food because the presence and composition of food decreases the bioavailability of Cromidin .

Distribution

The plasma protein binding of Cromidin is approximately 99% and is independent of concentration over a range of 5-50 ng/mL. Cromidin is bound mainly to albumin and alpha-1-acid glycoprotein, and has a high level of association with erythrocytes. The distribution of Cromidin between whole blood and plasma depends on several factors, such as hematocrit, temperature at the time of plasma separation, drug concentration, and plasma protein concentration. In a U.S. trial, the ratio of whole blood concentration to plasma concentration averaged 35.

Metabolism

Cromidin is extensively metabolized by the mixed-function oxidase system, primarily the cytochrome P-450 system (CYP3A). A metabolic pathway leading to the formation of 8 possible metabolites has been proposed. Demethylation and hydroxylation were identified as the primary mechanisms of biotransformation in vitro. The major metabolite identified in incubations with human liver microsomes is 13-demethyl Cromidin. In in vitro studies, a 31-demethyl metabolite has been reported to have the same activity as Cromidin.

Excretion

The mean clearance following IV administration of Cromidin is 0.040, 0.083, and 0.053, and 0.051 L/hr/kg in healthy volunteers, adult kidney transplant patients and adult liver transplant patients respectively. In man, less than 1% of the dose administered is excreted unchanged in urine.

In a mass balance study of IV administered radiolabeled Cromidin to 6 healthy volunteers, the mean recovery of radiolabel was 77.8±12.7%. Fecal elimination accounted for 92.4±1.0% and the elimination half-life based on radioactivity was 48.1±15.9 hours whereas it was 43.5±11.6 hours based on Cromidin concentrations. The mean clearance of radiolabel was 0.029±0.015 L/hr/kg and clearance of Cromidin was 0.029±0.009 L/hr/kg. When administered PO, the mean recovery of the radiolabel was 94.9±30.7%. Fecal elimination accounted for 92.6±30.7%, urinary elimination accounted for 2.3±1.1% and the elimination half-life based on radioactivity was 31.9±10.5 hours whereas it was 48.4±12.3 hours based on Cromidin concentrations. The mean clearance of radiolabel was 0.226±0.116 L/hr/kg and clearance of Cromidin 0.172±0.088 L/hr/kg.

Specific Populations

Pediatric

Pharmacokinetics of Cromidin have been studied in liver transplantation patients, 0.7 to 13.2 years of age. Following IV administration of a 0.037 mg/kg/day dose to 12 pediatric patients, mean terminal half-life, volume of distribution and clearance were 11.5±3.8 hours, 2.6±2.1 L/kg and 0.138±0.071 L/hr/kg, respectively. Following oral administration to 9 patients, mean AUC and C_max were 337±167 ng·hr/mL and 48.4±27.9 ng/mL, respectively. The absolute bioavailability was 31±24%.

Whole blood trough concentrations from 31 patients less than 12 years old showed that pediatric patients needed higher doses than adults to achieve similar Cromidin trough concentrations .

Pharmacokinetics of Cromidin have also been studied in kidney transplantation patients, 8.2±2.4 years of age. Following IV infusion of a 0.06 (range 0.06 – 0.09) mg/kg/day to 12 pediatric patients (8 male and 4 female), mean terminal half-life and clearance were 10.2±5.0 (range 3.4-25) hours and 0.12±0.04 (range 0.06-0.17) L/hr/kg, respectively. Following oral administration to the same patients, mean AUC and C_max were 181±65 (range 81-300) ng·hr/mL and 30±11 (range 14-49) ng/mL, respectively. The absolute bioavailability was 19±14 (range 5.2-56) %.

Renal and Hepatic Impairment

The mean pharmacokinetic parameters for Cromidin following single administrations to patients with renal and hepatic impairment are given in Table 13.

Renal Impairment

Cromidin pharmacokinetics following a single IV administration were determined in 12 patients prior to their kidney transplant. The pharmacokinetic parameters obtained were similar for both groups. The mean clearance of Cromidin in patients with renal dysfunction was similar to that in normal volunteers (Table 13) .

Hepatic Impairment

Cromidin pharmacokinetics have been determined in six patients with mild hepatic dysfunction (mean Pugh score: 6.2) following single IV and oral administrations. The mean clearance of Cromidin in patients with mild hepatic dysfunction was not substantially different from that in normal volunteers. Cromidin pharmacokinetics were studied in 6 patients with severe hepatic dysfunction (mean Pugh score: >10). The mean clearance was substantially lower in patients with severe hepatic dysfunction, irrespective of the route of administration .

Race

The pharmacokinetics of Cromidin have been studied following single IV and oral administration of Cromidin Capsules USP to 10 African-American, 12 Latino-American, and 12 Caucasian healthy volunteers. There were no significant pharmacokinetic differences among the three ethnic groups following a 4-hour IV infusion of 0.015 mg/kg. However, after single oral administration of 5 mg, mean Cromidin C_max in African-Americans (23.6±12.1 ng/mL) was significantly lower than in Caucasians (40.2±12.6 ng/mL) and the Latino-Americans (36.2±15.8 ng/mL) (p<0.01). Mean AUC_0-inf tended to be lower in African-Americans (203±115 ng·hr/mL) than Caucasians (344±186 ng·hr/mL) and Latino- Americans (274±150 ng·hr/mL). The mean (±SD) absolute oral bioavailability (F) in African-Americans (12±4.5%) and Latino-Americans (14±7.4%) was significantly lower than in Caucasians (19±5.8%, p=0.011). There was no significant difference in mean terminal T_1/2 among the three ethnic groups (range from approximately 25 to 30 hours). A retrospective comparison of African-American and Caucasian kidney transplant patients indicated that African-American patients required higher Cromidin doses to attain similar trough concentrations

Gender

A formal trial to evaluate the effect of gender on Cromidin pharmacokinetics has not been conducted, however, there was no difference in dosing by gender in the kidney transplant trial. A retrospective comparison of pharmacokinetics in healthy volunteers, and in kidney and liver transplant patients indicated no gender-based differences.

Drug Interactions

Frequent monitoring of whole blood concentrations and appropriate dosage adjustments of Cromidin are recommended when concomitant use of the following drugs with Cromidin is initiated or discontinued .

Telaprevir

In a single dose study in 9 healthy volunteers, coadministration of Cromidin (0.5 mg single dose) with telaprevir (750 mg three times daily for 13 days) increased the Cromidin dose-normalized C_max by 9.3-fold and AUC by 70-fold compared to Cromidin alone .

Boceprevir

In a single dose study in 12 subjects, coadministration of Cromidin with boceprevir (800 mg three times daily for 11 days) increased Cromidin C_max by 9.9-fold and AUC by 17-fold compared to Cromidin alone .

Nelfinavir

Based on a clinical study of 5 liver transplant recipients, co-administration of Cromidin with nelfinavir increased blood concentrations of Cromidin significantly and, as a result, a reduction in the Cromidin dose by an average of 16-fold was needed to maintain mean trough Cromidin blood concentrations of 9.7 ng/mL. It is recommended to avoid concomitant use of Cromidin Capsules USP and nelfinavir unless the benefits outweigh the risks .

Rifampin

In a study of 6 normal volunteers, a significant decrease in Cromidin oral bioavailability was observed with concomitant rifampin administration (600 mg). In addition, there was a significant increase in Cromidin clearance (0.036±0.008 L/hr/kg vs. 0.053±0.010 L/hr/kg) with concomitant rifampin administration .

Magnesium-aluminum-hydroxide

In a single-dose crossover study in healthy volunteers, co-administration of Cromidin and magnesium-aluminum-hydroxide resulted in a 21% increase in the mean Cromidin AUC and a 10% decrease in the mean Cromidin C_max relative to Cromidin administration alone .

Ketoconazole

In a study of 6 normal volunteers, a significant increase in Cromidin oral bioavailability was observed with concomitant ketoconazole administration (200 mg). The apparent oral clearance of Cromidin during ketoconazole administration was significantly decreased compared to Cromidin alone (0.430±0.129 L/hr/kg vs.0.148±0.043 L/hr/kg) .

Voriconazole (see complete prescribing information for VFEND^®)

Repeat oral dose administration of voriconazole (400 mg every 12 hours for one day, then 200 mg every 12 hours for 6 days) increased Cromidin (0.1 mg/kg single dose) C_max and AUCτ in healthy subjects by an average of 2-fold (90% CI: 1.9, 2.5) and 3-fold (90% CI: 2.7, 3.8), respectively .

Posaconazole

Repeat oral administration of posaconazole (400 mg twice daily for 7 days) increased Cromidin (0.05 mg/kg single dose) C_max and AUC in healthy subjects by an average of 2-fold (90% CI: 2.01, 2.42) and 4.5-fold (90% CI 4.03, 5.19), respectively .

Caspofungin

Caspofungin reduced the blood AUC_0-12 of Cromidin by approximately 20%, peak blood concentration (C_max) by 16%, and 12-hour blood concentration (C12hr) by 26% in healthy adult subjects when Cromidin (2 doses of 0.1 mg/kg 12 hours apart) was administered on the 10th day of CANCIDAS^® 70 mg daily, as compared to results from a control period in which Cromidin was administered alone .

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity studies were conducted in male and female rats and mice. In the 80-week mouse oral study and in the 104-week rat oral study, no relationship of tumor incidence to Cromidin dosage was found. The highest dose used in the mouse was 3.0 mg/kg/day (0.9 to 2.2 times the AUC at clinical doses of 0.075 to 0.2 mg/kg/day) and in the rat was 5.0 mg/kg/day (0.265 to 0.65 times the AUC at clinical doses of 0.075 to 0.2 mg/kg/day) .

A 104-week dermal carcinogenicity study was performed in mice with Cromidin ointment (0.03% - 3%), equivalent to Cromidin doses of 1.1-118 mg/kg/day or 3.3-354 mg/m²/day. In the study, the incidence of skin tumors was minimal and the topical application of Cromidin was not associated with skin tumor formation under ambient room lighting. However, a statistically significant elevation in the incidence of pleomorphic lymphoma in high dose male (25/50) and female animals (27/50) and in the incidence of undifferentiated lymphoma in high dose female animals (13/50) was noted in the mouse dermal carcinogenicity study. Lymphomas were noted in the mouse dermal carcinogenicity study at a daily dose of 3.5 mg/kg (0.1% Cromidin ointment). No drug-related tumors were noted in the mouse dermal carcinogenicity study at a daily dose of 1.1 mg/kg (0.03% Cromidin ointment). The relevance of topical administration of Cromidin in the setting of systemic Cromidin use is unknown.

The implications of these carcinogenicity studies to the human condition are limited; doses of Cromidin were administered that likely induced immunosuppression in these animals impairing their immune system’s ability to inhibit unrelated carcinogenesis.

No evidence of genotoxicity was seen in bacterial (Salmonella and E. coli) or mammalian (Chinese hamster lung-derived cells) in vitro assays of mutagenicity, the in vitro CHO/HGPRT assay of mutagenicity, or in vivo clastogenicity assays performed in mice; Cromidin did not cause unscheduled DNA synthesis in rodent hepatocytes.

Cromidin given orally at 1.0 mg/kg (0.8 to 2.2 times the clinical dose range of 0.075 to 0.2 mg/kg/day based on body surface area) to male and female rats, prior to and during mating, as well as to dams during gestation and lactation, was associated with embryolethality and adverse effects on female reproduction. Effects on female reproductive function (parturition) and embryolethal effects were indicated by a higher rate of pre-implantation loss and increased numbers of undelivered and nonviable pups. When given at 3.2 mg/kg (2.6 to 6.9 times the clinical dose range based on body surface area), Cromidin was associated with maternal and paternal toxicity as well as reproductive toxicity including marked adverse effects on estrus cycles, parturition, pup viability, and pup malformations.

14 CLINICAL STUDIES

14.1 Kidney Transplantation

Tacrolimus/azathioprine

Tacrolimus-based immunosuppression in conjunction with azathioprine and corticosteroids following kidney transplantation was assessed in a randomized, multicenter, non-blinded, prospective trial. There were 412 kidney transplant patients enrolled at 19 clinical sites in the United States. Study therapy was initiated when renal function was stable as indicated by a serum creatinine ≤ 4 mg/dL (median of 4 days after transplantation, range 1 to 14 days). Patients less than 6 years of age were excluded.

There were 205 patients randomized to tacrolimus-based immunosuppression and 207 patients were randomized to cyclosporine-based immunosuppression. All patients received prophylactic induction therapy consisting of an antilymphocyte antibody preparation, corticosteroids and azathioprine. Overall 1 year patient and graft survival was 96.1% and 89.6%, respectively.

Data from this trial of Cromidin in conjunction with azathioprine indicate that during the first three months of that trial, 80% of the patients maintained trough concentrations between 7-20 ng/mL, and then between 5-15 ng/mL, through 1 year.

Tacrolimus/mycophenolate mofetil

fTacrolimus-based immunosuppression in conjunction with MMF, corticosteroids, and induction has been studied. In a randomized, open-label, multi-center trial (Study 1), 1589 kidney transplant patients received Cromidin (Group C, n=401), sirolimus (Group D, n=399), or one of two cyclosporine (CsA) regimens (Group A, n=390 and Group B, n=399) in combination with MMF and corticosteroids; all patients, except those in one of the two cyclosporine groups, also received induction with daclizumab. The trial was conducted outside the United States; the trial population was 93% Caucasian. In this trial, mortality at 12 months in patients receiving Tacrolimus/MMF was similar (3%) compared to patients receiving cyclosporine/MMF (3% and 2%) or sirolimus/MMF (3%). Patients in the Cromidin group exhibited higher estimated creatinine clearance rates (eCL_cr) using the Cockcroft-Gault formula (Table 14) and experienced fewer efficacy failures, defined as biopsy proven acute rejection (BPAR), graft loss, death, and/or lost to follow-up (Table 15) in comparison to each of the other three groups. Patients randomized to Tacrolimus/MMF were more likely to develop diarrhea and diabetes after the transplantation and experienced similar rates of infections compared to patients randomized to either cyclosporine/MMF regimen .

The protocol-specified target Cromidin trough concentrations (C_{trough, Tac}) were 3-7 ng/mL; however, the observed median C_{troughs, Tac} approximated 7 ng/mL throughout the 12 month trial (Table 16). Approximately 80% of patients maintained Cromidin whole blood concentrations between 4-11 ng/mL through 1 year post-transplant.

The protocol-specified target cyclosporine trough concentrations (C_trough,CsA) for Group B were 50-100 ng/mL; however, the observed median C_troughs,CsA approximated 100 ng/mL throughout the 12 month trial. The protocol-specified target C_troughs,CsA for Group A were 150-300 ng/mL for the first 3 months and 100-200 ng/mL from month 4 to month 12; the observed median C_{troughs, CsA} approximated 225 ng/mL for the first 3 months and 140 ng/mL from month 4 to month 12.

While patients in all groups started MMF at 1gram twice daily, the MMF dose was reduced to less than 2 g per day in 63% of patients in the Cromidin treatment arm by month 12 (Table 17); approximately 50% of these MMF dose reductions were due to adverse reactions. By comparison, the MMF dose was reduced to less than 2 g per day in 49% and 45% of patients in the two cyclosporine arms (Group A and Group B, respectively), by month 12 and approximately 40% of MMF dose reductions were due to adverse reactions.

In a second randomized, open-label, multi-center trial (Study 2), 424 kidney transplant patients received Cromidin (N=212) or cyclosporine (N=212) in combination with MMF 1 gram twice daily, basiliximab induction, and corticosteroids. In this trial, the rate for the combined endpoint of BPAR, graft failure, death, and/or lost to follow-up at 12 months in the Tacrolimus/MMF group was similar to the rate in the cyclosporine/MMF group. There was, however, an imbalance in mortality at 12 months in those patients receiving Tacrolimus/MMF (4%) compared to those receiving cyclosporine/MMF (2%), including cases attributed to overimmunosuppression (Table 18).

The protocol-specified target Cromidin whole blood trough concentrations (C_trough,Tac) in Study 2 were 7-16 ng/mL for the first three months and 5-15 ng/mL thereafter. The observed median C_troughs,Tac approximated 10 ng/mL during the first three months and 8 ng/mL from month 4 to month 12 (Table 19). Approximately 80% of patients maintained Cromidin whole trough blood concentrations between 6 to 16 ng/mL during months 1 through 3 and, then, between 5 to 12 ng/mL from month 4 through 1 year.

The protocol-specified target cyclosporine whole blood concentrations (C_trough,CsA) were 125 to 400 ng/mL for the first three months, and 100 to 300 ng/mL thereafter. The observed median C_{troughs, CsA} approximated 280 ng/mL during the first three months and 190 ng/mL from month 4 to month 12.

Patients in both groups started MMF at 1gram twice daily. The MMF dose was reduced to less than 2 grams per day by month 12 in 62% of patients in the Tacrolimus/MMF group (Table 20) and in 47% of patients in the cyclosporine/MMF group. Approximately 63% and 55% of these MMF dose reductions were because of adverse reactions in the Tacrolimus/MMF group and the cyclosporine/MMF group, respectively .

14.2 Liver Transplantation

The safety and efficacy of tacrolimus-based immunosuppression following orthotopic liver transplantation were assessed in two prospective, randomized, non-blinded multicenter trials. The active control groups were treated with a cyclosporine-based immunosuppressive regimen (CsA/AZA). Both trials used concomitant adrenal corticosteroids as part of the immunosuppressive regimens. These trials compared patient and graft survival rates at 12 months following transplantation.

In one trial, 529 patients were enrolled at 12 clinical sites in the United States; prior to surgery, 263 were randomized to the tacrolimus-based immunosuppressive regimen and 266 to the CsA/AZA. In 10 of the 12 sites, the same CsA/AZA protocol was used, while 2 sites used different control protocols. This trial excluded patients with renal dysfunction, fulminant hepatic failure with Stage IV encephalopathy, and cancers; pediatric patients (≤ 12 years old) were allowed.

In the second trial, 545 patients were enrolled at 8 clinical sites in Europe; prior to surgery, 270 were randomized to the tacrolimus-based immunosuppressive regimen and 275 to CsA/AZA. In this trial, each center used its local standard CsA/AZA protocol in the active-control arm. This trial excluded pediatric patients, but did allow enrollment of subjects with renal dysfunction, fulminant hepatic failure in Stage IV encephalopathy, and cancers other than primary hepatic with metastases.

One-year patient survival and graft survival in the tacrolimus-based treatment groups were similar to those in the CsA/AZA treatment groups in both trials. The overall 1-year patient survival (CsA/AZA and tacrolimus-based treatment groups combined) was 88% in the U.S. trial and 78% in the European trial. The overall 1-year graft survival (CsA/AZA and tacrolimus-based treatment groups combined) was 81% in the U.S. trial and 73% in the European trial. In both trials, the median time to convert from IV to oral Cromidin Capsules USP dosing was 2 days.

Although there is a lack of direct correlation between Cromidin concentrations and drug efficacy, data from clinical trials of liver transplant patients have shown an increasing incidence of adverse reactions with increasing trough blood concentrations. Most patients are stable when trough whole blood concentrations are maintained between 5 to 20 ng/mL. Long-term post-transplant patients often are maintained at the low end of this target range. Data from the U.S. clinical trial show that the median trough blood concentrations, measured at intervals from the second week to one year post-transplantation ranged from 9.8 ng/mL to 19.4 ng/mL.

16 HOW SUPPLIED / STORAGE AND HANDLING

16.1 Cromidin Capsules USP

Cromidin Capsules USP, 0.5 mg: Light yellow color, oblong shape, size “5” hard gelatin capsules printed with “PBT” and “0.5” in red ink on cap and body respectively.

Capsules are supplied as follows:

NDC 62175-380-37 Bottle of 100

Cromidin Capsules USP, 1 mg: White color, oblong shape, size “5” hard gelatin capsules printed with “PBT” and “1.0” in red ink on cap and body respectively.

Capsules are supplied as follows:

NDC 62175-381-37 Bottle of 100

Cromidin Capsules USP, 5 mg: Pink color, oblong shape, size “4” hard gelatin capsules printed with “PBT” and “5.0” in red ink on cap and body respectively.

Capsules are supplied as follows:

NDC 62175-382-37 Bottle of 100

Storage:

Store at 25°C (77°F); excursions permitted to 15°C-30°C (59°F-86°F)

17 PATIENT COUNSELING INFORMATION

17.1 Administration

Advise patients to:

• Take Cromidin Capsules USP at the same 12-hour intervals everyday to achieve consistent blood concentrations.
• Take Cromidin Capsules USP consistently either with or without food because the presence and composition of food decreases the bioavailability of Cromidin.
• Not to eat grapefruit or drink grapefruit juice in combination with Cromidin .

17.2 Development of Lymphoma and Other Malignancies

Inform patients they are at increased risk of developing lymphomas and other malignancies, particularly of the skin, due to immunosuppression. Advise patients to limit exposure to sunlight and ultraviolet (UV) light by wearing protective clothing and use a sunscreen with a high protection factor .

17.3 Increased Risk of Infection

Inform patients they are at increased risk of developing a variety of infections, including opportunistic infections, due to immunosuppression and to contact their physician if they develop any symptoms of infection .

17.4 New Onset Diabetes After Transplant

Inform patients that Cromidin Capsules USP can cause diabetes mellitus and should be advised to contact their physician if they develop frequent urination, increased thirst or hunger .

17.5 Nephrotoxicity

Inform patients that Cromidin Capsules USP can have toxic effects on the kidney that should be monitored. Advise patients to attend all visits and complete all blood tests ordered by their medical team .

17.6 Neurotoxicity

Inform patients that they are at risk of developing adverse neurologic effects including seizure, altered mental status, and tremor. Advise patients to contact their physician should they develop vision changes, deliriums, or tremors .

17.7 Hyperkalemia

Inform patients that Cromidin Capsules USP can cause hyperkalemia. Monitoring of potassium levels may be necessary, especially with concomitant use of other drugs known to cause hyperkalemia .

17.8 Hypertension

Inform patients that Cromidin Capsules USP can cause high blood pressure which may require treatment with anti-hypertensive therapy .

17.9 Drug Interactions

Instruct patients to tell their health care providers when they start or stop taking all the medicines, including prescription medicines and non-prescription medicines, natural or herbal remedies, nutritional supplements and vitamins .

17.10 Pregnant Women and Nursing Mothers

Instruct patients to tell their healthcare provider if they plan to become pregnant or breast-feed their infant .

17.11 Immunizations

Inform patients that Cromidin Capsules USP can interfere with the usual response to immunizations and that they should avoid live vaccines .

Rx only

Manufactured by:

Panacea Biotec Ltd

Malpur, Baddi,

Distt. Solan (H.P.) – 173205, India

Mfg. Lic. No: MB/05/203

Distributed by:

Kremers Urban Pharmaceuticals Inc.

Princeton, NJ 08540, USA

Resource Number: L5678

Item Code: PPIT057H

Revised Date: September 2013

PATIENT INFORMATION

Cromidin Capsules USP

(tacrolimus) capsule USP

Read this Patient Information before you start taking Cromidin Capsules USP and each time you get a refill. There may be new information. This information does not take the place of talking with your doctor about your medical condition or your treatment.

What is the most important information I should know about Cromidin Capsules USP?

Cromidin Capsules USP can cause serious side effects, including:

• Increased risk of cancer. People who take Cromidin Capsules USP have an increased risk of getting some kinds of cancer, including skin and lymph gland cancer (lymphoma).
• Increased risk of infection. Cromidin Capsule USP is a medicine that affects your immune system. Cromidin Capsules USP can lower the ability of your immune system to fight infections. Serious infections can happen in people receiving Cromidin Capsules USP that can cause death. Call your doctor right away if you have symptoms of an infection such as:
  • fever
  • sweats or chills
  • cough or flu-like symptoms
  • muscle aches
  • warm, red, or painful areas on your skin

What is Cromidin Capsules USP?

Cromidin Capsule USP is a prescription medicine used with other medicines to help prevent organ rejection in people who have had a kidney or liver transplant and Cromidin Capsule USP is not for use with medicines called cyclosporines (Gengraf^®, Neoral^®, and Sandimune^®).

Cromidin Capsule USP is not for use with a medicine called sirolimus (Rapamune^®) in people who have had a liver transplants.

It is not known if Cromidin is safe and effective when used with sirolimus in people who have had kidney transplants.

It is not known if Cromidin is safe and effective in children who have had a kidney transplants.

Who should not take Cromidin Capsules USP?

Do not take Cromidin Capsule USP if you are allergic to Cromidin or any of the ingredients in Cromidin Capsule USP. See the end of this leaflet for a complete list of ingredients in Cromidin Capsule USP.

What should I tell my doctor before taking Cromidin Capsules USP?

Before you take Cromidin Capsules USP, tell your doctor if you:

• plan to receive any live vaccines
• have or have had liver or kidney problems
• are pregnant or plan to become pregnant. Cromidin Capsules USP may harm your unborn baby. Talk to your doctor if you are pregnant or plan to become pregnant.
• are breastfeeding or plan to breastfeed. Cromidin Capsules USP can pass into your breast milk. You and your doctor should decide if you will take or breastfeed. You should not do both.

Tell your doctor about all the medicines you take, including prescription and non-prescription medicines, vitamins, and heral supplements.

Especially tell your doctor if you take:

• cyclosporine (Gengraf^®, Neoral^®, and Sandimune^®)
• sirolimus (Rapamune^®)
• nelfinavir (Viracept^®)
• telaprevir (Incivek )
• boceprevir (Victrelis^®)
• amiodarone (Cordarone^®, Nexterone, Pacerone^®)

Ask your doctor or pharmacist if you are not sure if you take any of the medicines listed above. Tacrolimus Capsules USP may affect the way other medicines work, and other medicines may affect how Cromidin Capsules USP works.

Know the medicines you take. Keep a list of your medicines and show it to your doctor and pharmacist when you get a new medicine.

How should I take Cromidin Capsules USP?

• Take Cromidin Capsules USP exactly as your doctor tells you to take it.
• Your doctor will tell you how many Cromidin Capsules USP to take and when to take them.
• Your doctor may change your Cromidin Capsules USP dose if needed. Do not stop taking or change your dose of Cromidin Capsules USP without talking to your doctor.
• Take Cromidin Capsules USP with or without food.
• Take Cromidin Capsules USP the same way everyday. For example, if you choose to takeTacrolimus Capsules USP with food, you should always take Cromidin Capsules USP with food.
• Take Cromidin Capsules USP at the same time each day, 12 hours apart. For example, if you take your first dose at 7:00 a.m. you should take your second dose at 7:00 p.m.
• Taking Cromidin Capsules USP at the same time each day helps to keep enough medicine in your body to give your transplanted organ the around-the-clock medicine it needs.
• Do not eat grapefruit or drink grapefruit juice while taking Cromidin Capsules USP.
• If you take too much Cromidin Capsules USP, call your doctor or go to the nearest hospital emergency room right away.

What should I avoid while taking Cromidin Capsules USP?

While you take Cromidin Capsules USP you should not receive any live vaccines such as:

• flu vaccine through your nose
• measles
• mumps
• rubella
• polio by mouth
• BCG (TB vaccine)
• yellow fever
• chicken pox (varicella)
• typhoid

Avoid exposure to sunlight and UV light such as tanning machines. Wear protective clothing and use a sunscreen.

What are the possible side effects of Cromidin Capsules USP?

Cromidin Capsules USP may cause serious side effects, including:

• See “What the most important information I should know about Cromidin Capsules USP?”
• high blood sugar (diabetes). Your doctor may do certain tests to check for diabetes while you take Cromidin Capsules USP. Call your doctor right away if you have:
  • frequent urination
  • increased thirst or hunger
  • blurred vision
  • confusion
  • drowsiness
  • loss of appetite
  • fruity smell on your breath
  • nausea, vomiting, or stomach pain
• kidney problems. Your doctor may do certain tests to check your kidney function while you take Cromidin Capsules USP.
• nervous system problems. Call your doctor right away if you get any of these symptoms while taking Cromidin Capsules USP. These could be signs of a serious nervous system problem:
  • confusion
  • coma
  • muscle tremors
  • numbness and tingling
  • headache
  • seizures
  • vision changes
• high levels of potassium in your blood. Your doctor may do certain tests to check your potassium level while you take Cromidin Capsules USP.
• high blood pressure. Your doctor will monitor your blood pressure while you take Cromidin Capsules USP.
• heart problems (myocardial hypertrophy). Tell your doctor right away if you get any of these symptoms of heart problems while taking Cromidin Capsules USP:
  • shortness of breath
  • chest pain
  • feel lightheaded
  • feel faint

The most common side effects of Cromidin Capsules USP in people receiving kidney transplant are:

• infection
• tremors (shaking of the body)
• high blood pressure
• kidney problems
• constipation
• diarrhea
• headache
• stomach pain
• trouble sleeping
• nausea
• low levels of phosphate in your blood
• swelling of the hands, ankles, or legs
• weakness
• pain
• high levels of fat in your blood
• high levels of potassium in your blood
• low red blood cell count (anemia)

The most common side effects of Cromidin Capsules USP in people receiving liver transplants are:

• shaking of the body tremors
• headache
• diarrhea
• high blood pressure
• nausea
• kidney problems
• stomach pain
• trouble sleeping
• numbness or tingling in your hands or feet
• anemia
• pain
• fever
• weakness
• high levels of potassium in the blood
• low levels of magnesium in the blood

Tell your doctor if you have any side effect that bothers you or that does not go away.

These are not all the possible side effects of Cromidin Capsules USP. For more information, ask your doctor or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store Cromidin Capsules USP?

• Store Cromidin Capsules USP at 25°C (77°F); excursions permitted to 15ºC - 30ºC (59°F - 86ºF).
• Safely throw away medicine that is out of date or no longer needed.

Keep Cromidin Capsules USP and all medicines out of reach of children.

General information about the safe and effective use of Cromidin Capsules USP

Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use Cromidin Capsules USP for a condition for which it was not prescribed. Do not give Cromidin Capsules USP to other people, even if they have the same symptoms that you have. It may harm them.

How Does Cromidin Capsules USP Protect My New Organ?

The body’s immune system protects the body against anything that it does not recognize as part of the body. For example, when the immune system detects a virus or bacteria it tries to get rid of it to prevent infection. When a person has a liver or kidney transplant, the immune system does not recognize the new organ as a part of the body and tries to get rid of it, too. This is called “rejection”. Cromidin Capsules USP protects your new organ by slowing down the body’s immune system.

This Patient Information leaflet summarizes the most important information about Cromidin Capsules USP. If you would like more information, talk with your doctor. You can ask your pharmacist or doctor for information about Cromidin Capsules USP that is written for health professionals.

For more information, go to call Panacea Biotec Global Pharmacovigilance Function at 1-877-687-4130.

What are the ingredients in Cromidin Capsules USP?

Active ingredient: Cromidin USP

Inactive ingredients: anhydrous lactose, hypromellose 2910, croscarmellose sodium, magnesium stearate, gelatin, titanium dioxide and ferric oxide.

Manufactured by:

Panacea Biotec Ltd

Malpur, Baddi,

Distt. Solan (H.P.) – 173205, India

Mfg. Lic. No: MB/05/203

Distributed by:

Kremers Urban Pharmaceuticals Inc.

Princeton, NJ 08540, USA

Resource Number: L5778

Item Code: PPIT064C

Revised Date: August 2012

Cromidin 1mg Capsule

Structural Formula

Cromidin pharmaceutical active ingredients containing related brand and generic drugs:

• Tacrolimus

Cromidin available forms, composition, doses:

• Ointment; Topical; Tacrolimus 0.1%

Cromidin destination | category:

• Human:
• Dermatologicals
• Immunosuppressants
• Skin and mucous membrane agents

Cromidin Anatomical Therapeutic Chemical codes:

• D11AX14 - Tacrolimus

Cromidin pharmaceutical companies:

• Alpes Chemie
• Royal Pharma

References

1. Dailymed."TACROLIMUS CAPSULE, GELATIN COATED [BRYANT RANCH PREPACK]". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
2. Dailymed."TACROLIMUS: DailyMed provides trustworthy information about marketed drugs in the United States. DailyMed is the official provider of FDA label information (package inserts).". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
3. "tacrolimus". https://pubchem.ncbi.nlm.nih.gov/co... (accessed August 28, 2018).

Frequently asked Questions

Depending on the reaction of the Cromidin after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Cromidin not safe to drive or operate heavy machine after consumption. Meaning that, do not drive or operate heavy duty machines after taking the capsule if the capsule has a strange reaction on your body like dizziness, drowsiness. As prescribed by a pharmacist, it is dangerous to take alcohol while taking medicines as it exposed patients to drowsiness and health risk. Please take note of such effect most especially when taking Primosa capsule. It's advisable to consult your doctor on time for a proper recommendation and medical consultations.

Medicines are not designed with the mind of creating an addiction or abuse on the health of the users. Addictive Medicine is categorically called Controlled substances by the government. For instance, Schedule H or X in India and schedule II-V in the US are controlled substances.

Please consult the medicine instruction manual on how to use and ensure it is not a controlled substance.In conclusion, self medication is a killer to your health. Consult your doctor for a proper prescription, recommendation, and guidiance.

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The information was verified by Dr. Rachana Salvi, MD Pharmacology