ROLITRANS Capsules (Tacrolimus)

Table of Content

To be sold by retail on the prescription of a Nephrologist only.

Black Box Warning

Malignancies And Serious Infections

Increased risk for developing serious infections and malignancies with tacrolimus or other immunosuppressants that may lead to hospitalization or death .

Qualitative And Quantitative Composition

ROLITRANS 0.5 mg

Each hard gelatin capsule contains:

Tacrolimus IP…..........0.5 mg

Excipients …............. q.s.

Approved colors used in empty capsule shell.

Capsule meets IP related substance Test B.

ROLITRANS 1 mg

Each hard gelatin capsule contains:

Tacrolimus IP….........1 mg

Excipients …............. q.s.

Approved colors used in empty capsule shell.

Capsule meets IP related substance Test B.

ROLITRANS 2 mg

Each hard gelatin capsule contains:

Tacrolimus IP…..........2 mg

Excipients …............. q.s.

Approved colors used in empty capsule shell.

Capsule meets IP related substance Test B.

Dosage Form(S) And Strength(S)

Hard gelatin capsule of tacrolimus (0.5 mg, 1 mg and 2 mg) for oral use

Clinical Particulars

Therapeutic Indications

ROLITRANS Capsules is indicated for prophylaxis of organ rejection in patients receiving allogenic kidney transplant and lupus nephritis (in a case where the effect of steroids is insufficient or administration of steroids is difficult because of their adverse reactions).

Posology and Method of Administration

Important Administration Instructions

Tacrolimus should not be used without supervision by a physician with experience in immunosuppressive therapy.

Tacrolimus capsules are not interchangeable or substitutable for other tacrolimus extended-release products. This is because rate of absorption following the administration of an extended-release tacrolimus product is not equivalent to that of an immediate-release tacrolimus drug product. Under- or overexposure to tacrolimus may result in graft rejection or other serious adverse reactions. Changes between tacrolimus immediate-release and extended-release dosage forms must occur under physician supervision .

Oral Formulations (Capsules)

If patients are able to initiate oral therapy, the recommended starting doses should be initiated.

General Administration Instructions

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

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

·       Therapeutic drug monitoring (TDM) is recommended for all patients receiving tacrolimus .

Dosing for Adult Kidney Transplant Patients

The recommended starting oral dose of tacrolimus is mentioned in Table 1. The initial dose of tacrolimus may be administered within 24 hours of transplantation. Some patients may require higher doses to achieve comparable blood concentrations.

Table 1: Summary of Initial Oral ROLITRANS Capsules Dosing Recommendations and Whole Blood Trough Concentration Range in Adults

 Population

Tacrolimus Capsules *Initial Oral Dosing

Whole Blood Trough Concentration Range

Adult kidney transplant

 

With azathioprine

0.2 mg/kg/day capsules, divided in two doses, every 12 hours

Month 1-3: 7-20 ng/mL Month 4-12: 5-15 ng/mL

With MMF/IL-2 receptor antagonist

0.1 mg/kg/day capsules, divided in two doses, every 12 hours

Month 1-12: 4-11 ng/mL

MMF = mycophenolate mofetil; IL-2 = Interleukin 2

*African-American patients may require higher doses compared to Caucasians.

† In a second smaller trial, the initial dose of tacrolimus was 0.15-0.2 mg/kg/day and observed tacrolimus concentrations were 6-16 ng/mL during month 1-3 and 5-12 ng/mL during month 4-12

Dosage Adjustment in Patients with Renal and Hepatic Impairment

Due to the potential for nephrotoxicity, patients with renal or hepatic impairment should receive doses at the lowest value of the recommended oral dosing ranges. Further reductions in dose below these ranges may be required. Tacrolimus therapy, usually, should be delayed up to 48 hours or longer in patients with post-operative oliguria.

Therapeutic Drug Monitoring

Monitoring of tacrolimus blood concentrations in conjunction with other laboratory and clinical parameters is considered an essential aid to patient management for the evaluation of rejection, toxicity, dose adjustments and compliance. 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. During the first three months, 80% of the patients-maintained trough concentrations between 7-20 ng/mL, and then between 5-15 ng/mL, through 1 year.

The relative risk of toxicity is increased with higher trough concentrations. Therefore, monitoring of whole blood trough concentrations is recommended to assist in the clinical evaluation of toxicity.

Contraindications

·       Hypersensitivity to tacrolimus or other macrolides

·       Hypersensitivity to any of the excipients

Special Warnings and Precautions for Use

Lymphoma and other Malignancies

Patients receiving immunosuppressants, including tacrolimus, 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, examine patients for skin changes; exposure to sunlight and UV light should be limited by wearing protective clothing and using a broad-spectrum sunscreen with a high protection factor.

Post-transplant lymphoproliferative disorder (PTLD) 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. Monitor EBV serology during treatment.

Serious Infections

Patients receiving immunosuppressants, including tacrolimus, are at increased risk of developing bacterial, viral, fungal, and protozoal infections, including opportunistic infections. These infections may lead to serious, including fatal, outcomes. Serious viral infections reported include:

·       Polyomavirus-associated nephropathy (PVAN), mostly due to BK virus infection

·       JC virus-associated progressive multifocal leukoencephalopathy (PML)

·       Cytomegalovirus infections: CMV seronegative transplant patients who receive an organ from a CMV seropositive donor disease are at higher risk of developing CMV viremia and CMV disease.

Monitor for the development of infection and adjust the immunosuppressive regimen to balance the risk of rejection with the risk of infection .

Not Interchangeable with Extended-Release Tacrolimus Products - Medication Errors

Medication errors, including substitution and dispensing errors, between tacrolimus immediate-release products and tacrolimus extended-release products were reported outside the U.S. This led to serious adverse reactions, including graft rejection, or other adverse reactions due to under- or overexposure to tacrolimus. Tacrolimus is not interchangeable or substitutable for tacrolimus extended-release products. Changes between tacrolimus immediate-release and extended- release dosage forms must occur under physician supervision. Instruct patients and caregivers to recognize the appearance of tacrolimus dosage forms and to confirm with the healthcare provider if a different product is dispensed.

New Onset Diabetes after Transplant

Tacrolimus was shown to cause new onset diabetes mellitus in clinical trials of kidney, transplantation. New onset diabetes after transplantation may be reversible in some patients. African-American and Hispanic kidney transplant patients are at an increased risk. Blood glucose concentrations should be monitored closely in patients using tacrolimus .

Nephrotoxicity

Tacrolimus, like other calcineurin inhibitors, can cause acute or chronic nephrotoxicity. Nephrotoxicity was reported in clinical trials . Consider dosage reduction in patients with elevated serum creatinine and tacrolimus whole blood trough concentrations greater than the recommended range. The risk for nephrotoxicity may increase when tacrolimus is concomitantly administered with CYP3A inhibitors (by increasing tacrolimus whole blood concentrations) or drugs associated with nephrotoxicity (e.g., aminoglycosides, ganciclovir, amphotericin B, cisplatin, nucleotide reverse transcriptase inhibitors, protease inhibitors). Monitor renal function and consider dosage reduction if nephrotoxicity occurs.

Neurotoxicity

Tacrolimus may cause a spectrum of neurotoxicities. The most severe neurotoxicities include posterior reversible encephalopathy syndrome (PRES), delirium, seizure and coma; others include tremors, paresthesias, headache, mental status changes, and changes in motor and sensory functions . As symptoms may be associated with tacrolimus whole blood trough concentrations at or above the recommended range, monitor for neurologic symptoms and consider dosage reduction or discontinuation of tacrolimus if neurotoxicity occurs.

Hyperkalemia

Hyperkalemia has been reported with tacrolimus 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 tacrolimus therapy . Monitor serum potassium levels periodically during treatment.

Hypertension

Hypertension is a common adverse effect of tacrolimus 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 tacrolimus blood concentrations and therefore require dosage reduction of tacrolimus .

Not Recommended for use with Sirolimus

Tacrolimus is not recommended for use with sirolimus.

Interactions with CYP3A4 Inhibitors and Inducers

When co-administering tacrolimus 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 tacrolimus and subsequent frequent monitoring of tacrolimus whole blood trough concentrations and tacrolimus -associated adverse reactions are recommended .

QT Prolongation

Tacrolimus may prolong the QT/QTc interval and may cause torsade de pointes. Avoid tacrolimus 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 (magnesium, potassium, calcium) periodically during treatment.

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

Myocardial Hypertrophy

Myocardial hypertrophy has been reported in adults, particularly those with high tacrolimus 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 tacrolimus therapy, echocardiographic evaluation should be considered. If myocardial hypertrophy is diagnosed, dosage reduction or discontinuation of tacrolimus should be considered .

Immunizations

Whenever possible, administer the complete complement of vaccines before transplantation and treatment with tacrolimus.

The use of live vaccines should be avoided during treatment with tacrolimus; examples include (not limited to) the following: intranasal influenza, measles, mumps, rubella, oral polio, BCG, yellow fever, varicella, and TY21a typhoid vaccines.

Inactivated vaccines noted to be safe for administration after transplantation may not be sufficiently immunogenic during treatment with tacrolimus.

Pure Red Cell Aplasia

Cases of pure red cell aplasia (PRCA) have been reported in patients treated with tacrolimus. 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 tacrolimus should be considered .

Drug Interactions

Tacrolimus is extensively metabolized in the liver and intestinal mucosa by CYP3A4 isoenzymes and P-glycoprotein and thus, drugs interacting with these systems may affect the pharmacokinetic properties of tacrolimus.

Mycophenolic Acid

When tacrolimus is prescribed with a given dose of a mycophenolic acid (MPA) product, exposure to MPA is higher with tacrolimus co-administration than with cyclosporine co-administration with MPA, because cyclosporine interrupts the enterohepatic recirculation of MPA while tacrolimus does not. Monitor for MPA-associated adverse reactions and reduce the dose of concomitantly administered mycophenolic acid products as needed.

Effects of Other Drugs on Tacrolimus

Table 2. displays the effects of other drugs on tacrolimus.

Table 2. Effects of Other Drugs/Substances on Tacrolimus*

Drug/Substance Class or Name

Drug Interaction Effect

Recommendations

Grapefruit or grapefruit juice

May increase tacrolimus whole blood trough concentrations and increase the risk of serious adverse reactions (e.g., neurotoxicity, QT prolongation) supervision .

 

Avoid grapefruit or grapefruit juice.

Strong CYP3A Inducers:

Anti-mycobacterials (e.g., rifampin, rifabutin), anticonvulsants (e.g., phenytoin, carbamazepine, and phenobarbital), St John’s Wort

May decrease tacrolimus whole blood trough concentrations and increase the risk of rejection .

 

 

Increase tacrolimus dose and monitor tacrolimus whole blood trough concentrations .

 

Strong CYP3A Inhibitors:

Protease inhibitors (e.g., nelfinavir, telaprevir, boceprevir, ritonavir), azole antifungals (e.g., voriconazole, posaconazole, itraconazole, ketoconazole), antibiotics (e.g., clarithromycin, troleandomycin, chloramphenicol), nefazodone, letermovir, Schisandra sphenanthera extracts

May increase tacrolimus whole blood trough concentrations and increase the risk of serious adverse reactions (e.g., neurotoxicity, QT prolongation) .

Reduce tacrolimus dose (for voriconazole and posaconazole, give one-third of the original dose) and adjust dose based on tacrolimus whole blood trough concentrations .

 

Mild or Moderate CYP3A

Inhibitors:

Clotrimazole, antibiotics (e.g., erythromycin, fluconazole), calcium

channel blockers (e.g., verapamil, diltiazem, nifedipine, nicardipine), amiodarone, danazol, ethinyl estradiol, cimetidine, lansoprazole and omeprazole

 

May increase tacrolimus whole blood trough concentrations and increase the risk of serious adverse reactions (e.g., neurotoxicity, QT prolongation) .

Monitor tacrolimus whole blood trough concentrations and reduce tacrolimus dose if needed .

 

Other drugs, such as:

Magnesium and aluminum hydroxide antacids, prokinetic agents (cisapride and Metoclopramide), Bromocriptine

 

 

 

May increase tacrolimus whole blood trough concentrations and increase the risk of serious adverse reactions (e.g., neurotoxicity, QT prolongation) .

 

Monitor tacrolimus whole blood trough concentrations and reduce tacrolimus dose if needed see Posology and Method of Administration and Pharmacological Properties].

 

Mild or Moderate CYP3A Inducers:

Methylprednisolone, prednisone

May decrease tacrolimus concentrations.

Monitor tacrolimus whole blood trough concentrations and adjust tacrolimus dose if needed see Posology and Method of Administration and Pharmacological Properties].

 

 

* Tacrolimus dosage adjustment recommendation based on observed effect of co-administered drug on tacrolimus exposures, literature reports of altered tacrolimus exposures, or the other drug’s known CYP3A inhibitor/inducer status.

High dose or double strength grapefruit juice is a strong CYP3A inhibitor; low dose or single strength grapefruit juice is a moderate CYP3A inhibitor.

Strong CYP3A inhibitor/inducer, based on reported effect on exposures to tacrolimus along with supporting in vitro CYP3A inhibitor/inducer data, or based on drug-drug interaction studies with midazolam (sensitive CYP3A probe substrate).

 Use in Special Populations

Pregnant Women

There is a pregnancy registry that monitors pregnancy outcomes in women exposed to tacrolimus during pregnancy. The Transplantation Pregnancy Registry International (TPRI) is a voluntary pregnancy exposure registry that monitors outcomes of pregnancy in female transplant recipients and those fathered by male transplant recipients exposed to immunosuppressants including tacrolimus.

Risk Summary

Tacrolimus can cause fetal harm when administered to a pregnant woman. Data from post marketing surveillance and the TPRI suggest that infants exposed to tacrolimus in utero are at a risk of prematurity, birth defects/congenital anomalies, low birth weight, and fetal distress . Advise pregnant women of the potential risk to the fetus.

Administration of oral tacrolimus to pregnant rabbits and rats throughout the period of organogenesis was associated with maternal toxicity/lethality, and an increased incidence of abortion, malformation and embryofetal death at clinically relevant doses (0.5 to 6.9 times the recommended clinical dose range , on a mg/m2 basis). Administration of oral tacrolimus to pregnant rats after organogenesis and throughout lactation produced maternal toxicity, effects on parturition, reduced pup viability and reduced pup weight at clinically relevant doses (0.8 to 6.9 times the recommended clinical dose range, on a mg/m2 basis). Administration of oral tacrolimus to rats prior to mating, and throughout gestation and lactation produced maternal toxicity/lethality, marked effects on parturition, embryofetal loss, malformations, and reduced pup viability at clinically relevant doses (0.8 to 6.9 times the recommended clinical dose range, on a mg/m2 basis). Interventricular septal defects, hydronephrosis, craniofacial malformations and skeletal effects were observed in offspring that died .

The background risk of major birth defects and miscarriage in the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Clinical Considerations

Disease-Associated Maternal and/or Embryo-Fetal Risk

Risks during pregnancy are increased in organ transplant recipients.

The risk of premature delivery following transplantation is increased. Pre-existing hypertension and diabetes confer additional risk to the pregnancy of an organ transplant recipient. Pre-gestational and gestational diabetes are associated with birth defects/congenital anomalies, hypertension, low birth weight and fetal death.

Cholestasis of pregnancy (COP) was reported in 7% of liver-kidney (LK) transplant recipients, compared with approximately 1% of pregnancies in the general population. However, COP symptoms resolved postpartum and no long­ term effects on the offspring were reported.

Maternal Adverse Reactions

Tacrolimus may increase hyperglycemia in pregnant women with diabetes (including gestational diabetes). Monitor maternal blood glucose levels regularly .

Tacrolimus may exacerbate hypertension in pregnant women and increase pre-eclampsia. Monitor and control blood pressure regularly .

Fetal/Neonatal Adverse Reactions

Renal dysfunction, transient neonatal hyperkalemia and low birth weight have been reported at the time of delivery in infants of mothers taking tacrolimus.

Labor or Delivery

There is an increased risk for premature delivery (< 37 weeks) following transplantation and maternal exposure to tacrolimus.

Data

  HUMAN DATA

There are no adequate and well controlled studies on the effects of tacrolimus in human pregnancy. Safety data from the TPRI and post marketing surveillance suggest infants exposed to tacrolimus in utero have an increased risk for miscarriage, pre-term delivery (< 37 weeks), low birth weight (< 2500 g), birth defects/congenital anomalies and fetal distress.

TPRI reported 450 total pregnancies in kidney transplant recipients exposed to tacrolimus. The TPRI pregnancy outcomes are summarized in Table 3. In the table below, the number of recipients exposed to tacrolimus concomitantly with mycophenolic acid (MPA) products during the preconception and first trimester periods is high (27% for renal transplant recipients). Because MPA products may also cause birth defects, the birth defect rate may be confounded and this should be taken into consideration when reviewing the data, particularly for birth defects. Birth defects observed include cardiac malformations, craniofacial malformations, renal/urogenital disorders, skeletal abnormalities, neurological abnormalities and multiple malformations.

Table 3. TPRI Reported Pregnancy Outcomes in Transplant Recipients with Exposure to Tacrolimus

 

Kidney

Pregnancy Outcomes*

462

Miscarriage

24.5%

Live births

331

Pre-term delivery (< 37 weeks)

49%

Low birth weight (< 2500 g)

42%

Birth defects

8%

* Includes multiple births and terminations.

Birth defect rate confounded by concomitant MPA products exposure in over half of offspring with birth defects.

Additional information reported by the TPRI in pregnant transplant patients receiving tacrolimus included diabetes during pregnancy in 9% of kidney recipients, and hypertension during pregnancy in 53% of kidney recipients.

ANIMAL DATA

Administration of oral tacrolimus to pregnant rabbits throughout organogenesis produced maternal toxicity and abortion at 0.32 mg/kg (0.5 to 1.4 times the recommended clinical dose range , on a mg/m2 basis). At 1 mg/kg (1.6 to 4.3 times the recommended clinical dose range), embryofetal lethality and fetal malformations (ventricular hypoplasia, interventricular septal defect, bulbous aortic arch, stenosis of ductus arteriosus, omphalocele, gallbladder agenesis, skeletal anomalies) were observed. Administration of 3.2 mg/kg oral tacrolimus (2.6 to 6.9 times the recommended clinical dose range) to pregnant rats throughout organogenesis produced maternal toxicity/lethality, embryofetal lethality and decreased fetal body weight in the offspring of C-sectioned dams; and decreased pup viability and interventricular septal defect in offspring of dams that delivered.

In a peri-/postnatal development study, oral administration of tacrolimus to pregnant rats during late gestation (after organogenesis) and throughout lactation produced maternal toxicity, effects on parturition, and reduced pup viability at 3.2 mg/kg (2.6 to 6.9 times the recommended clinical dose range); among these pups that died early, an increased incidence of kidney hydronephrosis was observed. Reduced pup weight was observed at 1.0 mg/kg (0.8 to 2.2 times the recommended clinical dose range).

Administration of oral tacrolimus to rats prior to mating, and throughout gestation and lactation, produced maternal toxicity/lethality, embryofetal loss and reduced pup viability at 3.2 mg/kg (2.6 to 6.9 times the recommended clinical dose range). Interventricular septal defects, hydronephrosis, craniofacial malformations and skeletal effects were observed in offspring that died. Effects on parturition (incomplete delivery of nonviable pups) were observed at 1 mg/kg (0.8 to 2.2 times the recommended clinical dose range) .

Lactating Women

Risk Summary

Controlled lactation studies have not been conducted in humans; however, tacrolimus has been reported to be present in human milk. The effects of tacrolimus on the breastfed infant, or on milk production have not been assessed. Tacrolimus is excreted in rat milk and in peri-/postnatal rat studies; exposure to tacrolimus during the postnatal period was associated with developmental toxicity in the offspring at clinically relevant doses .

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for tacrolimus and any potential adverse effects on the breastfed child from tacrolimus or from the underlying maternal condition.

Females and Males of Reproductive Potential

Contraception

Tacrolimus can cause fetal harm when administered to pregnant women. Advise female and male patients of reproductive potential to speak to their healthcare provider on family planning options including appropriate contraception prior to starting treatment with tacrolimus .

Infertility

Based on findings in animals, male and female fertility may be compromised by treatment with tacrolimus .

Pediatric Patients

Safety and effectiveness ROLITRANS Capsules have not been established in the pediatric population.

Geriatric Patients

Clinical trials of tacrolimus 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, renal, or cardiac function, and of concomitant disease or other drug therapy.

Patients with Renal Impairment

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

Patients with Hepatic Impairment

The mean clearance of tacrolimus 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 tacrolimus trough concentrations is warranted in patients with hepatic impairment .

Race or Ethnicity

African-American patients may need to be titrated to higher dosages to attain comparable trough concentrations compared to Caucasian patients .

African-American and Hispanic patients are at increased risk for new onset diabetes after transplant. Monitor blood glucose concentrations and treat appropriately .

Effects on Ability to Drive and Use Machines

Tacrolimus may cause visual and neurological disturbances. This effect may be enhanced if ROLITRANS Capsules are administered in association with alcohol.

Undesirable Effects

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 .

·        New Onset Diabetes after Transplant .

·        Nephrotoxicity .

·        Neurotoxicity .

·        Hyperkalemia .

·        Hypertension .

·        Myocardial Hypertrophy .

·        Pure Red Cell Aplasia .

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 with 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 Transplantation

The incidence of adverse reactions was determined in three randomized kidney transplant trials. One of the trials used azathioprine (AZA) 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 a trial where 205 patients received tacrolimus-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 tacrolimus arm and 44 ± 12 years on cyclosporine arm), the distribution was 61% male, and the composition was White (58%), African-American (25%), Hispanic (12%), and others (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 as follows: 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. Based on reported adverse reaction terms related to decreased renal function, nephrotoxicity was reported in approximately 52% of kidney transplantation patients.

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

Table 4. Kidney Transplantation: Adverse Reactions Occurring in ≥ 15% of Patients Treated with Tacrolimus in Conjunction with Azathioprine (AZA)

 

Tacrolimus/AZA (N = 205)

Cyclosporine/AZA (N = 207)

Nervous System

Tremor

54%

34%

Headache

44%

38%

Insomnia

32%

30%

Paresthesia

23%

16%

Dizziness

19%

16%

Gastrointestinal

Diarrhea

44%

41%

Nausea

38%

36%

Constipation

35%

43%

Vomiting

29%

23%

Dyspepsia

28%

20%

Cardiovascular

Hypertension

50%

52%

Chest Pain

19%

13%

Urogenital

Creatinine Increased

45%

42%

Urinary Tract Infection

34%

35%

Metabolic and Nutritional

Hypophosphatemia

49%

53%

Hypomagnesemia

34%

17%

Hyperlipemia

31%

38%

Hyperkalemia

31%

32%

Diabetes Mellitus

24%

9%

Hypokalemia

22%

25%

Hyperglycemia

22%

16%

Edema

18%

19%

Hemic and Lymphatic

Anemia

30%

24%

Leukopenia

15%

17%

Miscellaneous

Infection

45%

49%

Peripheral Edema

36%

48%

Asthenia

34%

30%

Abdominal Pain

33%

31%

Pain

32%

30%

Fever

29%

29%

Back Pain

24%

20%

Respiratory System

Dyspnea

22%

18%

Cough Increased

18%

15%

Musculoskeletal

Arthralgia

25%

24%

Skin

Rash

17%

12%

Pruritus

15%

7%

Two trials were conducted for tacrolimus-based immunosuppression in conjunction with MMF and corticosteroids. In the non-U.S. trial (Study 1), the incidence of adverse reactions was based on 1195 kidney transplant patients who received tacrolimus (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 tacrolimus in conjunction with MMF in Study 1 are presented below:

Table 5. Kidney Transplantation: Adverse Reactions Occurring in ≥ 10% of Patients Treated with Tacrolimus in Conjunction with MMF (Study 1)

 

Tacrolimus

(Group C)

(N = 403)

Cyclosporine

(Group A)

(N = 384)

Cyclosporine (Group B)

(N = 408)

Diarrhea

25%

16%

13%

Urinary Tract Infection

24%

28%

24%

Anemia

17%

19%

17%

Hypertension

13%

14%

12%

Leukopenia

13%

10%

10%

Edema Peripheral

11%

12%

13%

Hyperlipidemia

10%

15%

13%

Key: Group A = CsA/MMF/CS, B = CsA/MMF/CS/Daclizumab, C = Tac/MMF/CS/Daclizumab CsA = Cyclosporine, CS = Corticosteroids, Tac = Tacrolimus, MMF = mycophenolate mofetil

In the U.S. trial (Study 2) with tacrolimus-based immunosuppression in conjunction with MMF and corticosteroids, 424 kidney transplant patients received tacrolimus (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%), African-American (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 tacrolimus in conjunction with MMF in Study 2 are presented below:

Table 6. Kidney Transplantation: Adverse Reactions Occurring in ≥ 15% of Patients Treated with Tacrolimus in Conjunction with MMF (Study 2)

 

Tacrolimus/MMF

(N = 212)

Cyclosporine/MMF

(N = 212)

Gastrointestinal Disorders

Diarrhea

44%

26%

Nausea

39%

47%

Constipation

36%

41%

Vomiting

26%

25%

Dyspepsia

18%

15%

Injury, Poisoning, and Procedural Complications

Post-Procedural Pain

29%

27%

Incision Site Complication

28%

23%

Graft Dysfunction

24%

18%

Metabolism and Nutrition Disorders

Hypomagnesemia

28%

22%

Hypophosphatemia

28%

21%

Hyperkalemia

26%

19%

Hyperglycemia

21%

15%

Hyperlipidemia

18%

25%

Hypokalemia

16%

18%

Nervous System Disorders

Tremor

34%

20%

Headache

24%

25%

Blood and Lymphatic System Disorders

Anemia

30%

28%

Leukopenia

16%

12%

Miscellaneous

Edema Peripheral

35%

46%

Hypertension

32%

35%

Insomnia

30%

21%

Urinary Tract Infection

26%

22%

Blood Creatinine Increased

23%

23%

Less frequent:

Cardiomyopathy, chest pain, cramps, hyperhidrosis, hyperlipidemia, hypertension, hypertriglyceridemia, neuropathy, osteoporosis, tinnitus, visual changes

Rare:

Acute pancreatitis, conduction disorder of the heart, drug-induced hepatitis, gastric ulcer, gastroenteritis, glycosuria, hearing loss, hemolytic uremic syndrome, idiopathic thrombocytopenic purpura, left ventricular hypertrophy, leukoencephalopathy, post-transplant lymphoproliferative disease, prolonged QT interval, renal failure, Stevens-Johnson syndrome, torsades de pointes.

Post marketing Adverse Reactions

The following adverse reactions have been reported from worldwide marketing experience with tacrolimus. 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: (1) 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 ischemia, pericardial effusion, QT prolongation, torsade de pointes, venous thrombosis deep limb, ventricular extrasystoles, ventricular fibrillation, myocardial hypertrophy.

·       Gastrointestinal: Bile duct stenosis, colitis, enterocolitis, gastroenteritis, gastroesophageal reflux disease, hepatic cytolysis, hepatic necrosis, hepatotoxicity, impaired gastric emptying, liver fatty, mouth ulceration, pancreatitis hemorrhagic, pancreatitis necrotizing, stomach ulcer, veno-occlusive liver disease

·       Hemic/Lymphatic: Agranulocytosis, disseminated intravascular coagulation, hemolytic anemia, neutropenia, febrile 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

·       Musculoskeletal and Connective Tissue Disorders: Pain in extremity including Calcineurin-Inhibitor Induced Pain Syndrome (CIPS)

·       Nervous System: Carpal tunnel syndrome, cerebral infarction, hemiparesis, leukoencephalopathy, mental disorder, mutism, posterior reversible encephalopathy syndrome (PRES), 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, optic neuropathy, blindness cortical, hearing loss including deafness, photophobia.

·       Urogenital: Acute renal failure, cystitis hemorrhagic, hemolytic-uremic syndrome

Reporting of Serious Adverse Events

If you experience any side effects, talk to your doctor or pharmacist or write to drugsafety@cipla.com. You can also report side effects directly via the national pharmacovigilance program of India by calling on 1800 180 3024 or you can report to Cipla ltd. on 18002677779. By reporting side effects, you can help provide more information on the safety of this product.

Overdose

Limited overdosage experience is available. Acute overdosages of up to 30 times the intended dose has been reported. Almost all cases have been asymptomatic, and all patients recovered with no sequelae. Occasionally, acute overdosage has been followed by adverse reactions consistent with those listed in the Undesirable Effects except in one case where transient urticaria and lethargy were observed. Based on the poor aqueous solubility and extensive erythrocyte and plasma protein binding, it is anticipated that tacrolimus 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 over dosage.

Pharmacological Properties

Mechanism of Action

Tacrolimus binds to an intracellular protein, FKBP-12. A complex of tacrolimus-FKBP-12, calcium, calmodulin, and calcineurin (a ubiquitous mammalian intracellular enzyme) is then formed, after which the phosphatase activity of calcineurin is inhibited. Such inhibition prevents the dephosphorylation and translocation of various factors such as the nuclear factor of activated T-cells (NF-AT), and nuclear factor kappa-light-chain enhancer of activated B-cells (NF-κB).

Tacrolimus inhibits the expression and/or production of several cytokines that include interleukin (IL)-1 beta, IL-2, IL-3, IL-4, IL-5, IL-6, IL-8, IL-10, gamma interferon, tumor necrosis factor-alfa, and granulocyte macrophage colony- stimulating factor.

Tacrolimus also inhibits IL-2 receptor expression and nitric oxide release and, induces apoptosis and production of transforming growth factor beta that can lead to immunosuppressive activity. The net result is the inhibition of T-lymphocyte activation and proliferation, as well as T-helper-cell-dependent B-cell response (i.e., immunosuppression).

Pharmacokinetic Properties

Tacrolimus activity is primarily due to the parent drug.

Absorption

Tacrolimus is rapidly, albeit incompletely, absorbed in the gastrointestinal tract, with peak tacrolimus concentrations in whole blood (Cmax) attained approximately 1-2 hours after oral administration. In renal transplant recipients receiving oral tacrolimus 0.3 mg/kg/day, respective Cmax was 24.2 ng/mL, with corresponding AUC values of 288 ng*hr/mL.

The oral bioavailability of tacrolimus is poor, with an average bioavailability of 25% (range 4–93%). The relatively low bioavailability of the drug most likely reflects incomplete absorption in the gastrointestinal tract and/ or gut metabolism of tacrolimus.

The rate and extent of absorption of tacrolimus is reduced in the presence of food.  The effect was most pronounced with a high-fat meal.

Distribution

The plasma protein binding of tacrolimus is approximately 99% and is independent of concentration over a range of 5–50 ng/mL. Tacrolimus is bound mainly to albumin and alpha-1-acid glycoprotein and has a high level of association with erythrocytes. The distribution of tacrolimus 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 (range 12 to 67).

Elimination

Metabolism

Tacrolimus 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 tacrolimus. In in vitro studies, a 31-demethyl metabolite has been reported to have the same activity as tacrolimus.

Excretion

When orally administered, 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 tacrolimus concentrations. The mean clearance of the radiolabel was 0.226 ± 0.116 L/hr/kg and clearance of tacrolimus was 0.172 ± 0.088 L/hr/kg.

Special Populations

Patients with Renal Impairment

The mean clearance of tacrolimus in patients with renal dysfunction was similar to that in normal volunteers .

Patients with Hepatic Impairment

Tacrolimus pharmacokinetics have been determined in six patients with mild hepatic dysfunction (mean Pugh score: 6.2) following oral administrations. The mean clearance of tacrolimus in patients with mild hepatic dysfunction was not substantially different from that in normal volunteers Tacrolimus 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 .

Racial or Ethnic Groups

The pharmacokinetics of tacrolimus have been studied following oral administration of tacrolimus to 10 African-American, 12 Latino-American, and 12 Caucasian healthy volunteers. After single oral administration of 5 mg, mean (± SD) tacrolimus Cmax in African-Americans (23.6 ± 12.1 ng/mL) was significantly lower than in Caucasians (40.2 ± 12.6 ng/mL) and Latino-Americans (36.2 ± 15.8 ng/mL) (p < 0.01). Mean AUC0-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 t1/2 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 tacrolimus doses to attain similar trough concentrations .

Male and Female Patients

A formal trial to evaluate the effect of gender on tacrolimus 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 transplant patients indicated no gender-based differences.

Nonclinical Properties

Animal Toxicology or Pharmacology

Carcinogenesis

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 tacrolimus 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).

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

Mutagenesis

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; tacrolimus did not cause unscheduled DNA synthesis in rodent hepatocytes.

Impairment of Fertility

Tacrolimus, subcutaneously administered to male rats at paternally toxic doses of 2 mg/kg/day (1.6 to 4.3 times the recommended clinical dose range on a mg/m2 basis) or 3 mg/kg/day (2.4 to 6.4 times the recommended clinical dose range), resulted in a dose-related decrease in sperm count. Tacrolimus administered orally at 1.0 mg/kg (0.8 to 2.2 times the clinical dose range) to male and female rats, prior to and during mating, as well as to dams during gestation and lactation, was associated with embryo lethality and adverse effects on female reproduction. Effects on female reproductive function (parturition) and embryo lethal effects were indicated by a higher rate of pre- and post- implantation loss and increased numbers of undelivered and nonviable pups. When administered at 3.2 mg/kg (2.6 to 6.9 times the clinical dose range based on body surface area), tacrolimus 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.

Description

Tacrolimus, previously known as FK506, is the active ingredient in ROLITRANS Capsules. Tacrolimus is a calcineurin-inhibitor immunosuppressant produced by Streptomyces tsukubaensis. Chemically, Tacrolimus is designated as , 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--14,16-dimethoxy-4,10,12,18-tetramethyl-8-(2-propenyl)-15,19-epoxy-3H-pyrido oxaazacyclotricosine-1,7,20,21(4H,23H)-tetrone, monohydrate.

The chemical structure of tacrolimus is:

Tacrolimus has an empirical formula of C44H69NO12•H2O and a molecular weight of 822.03.

ROLITRANS Capsules 0.5 mg, size "4" hard gelatin capsule                 

ROLITRANS Capsules 1 mg, size "4" hard gelatin capsule          

ROLITRANS Capsules 2 mg, size "4" hard gelatin capsule

The inactive ingredients in ROLITRANS Capsules 0.5 mg, 1 mg and 2 mg includes lactose I.P, croscarmellose sodium USP-NF, hydroxy propyl methyl cellulose IP, ethyl alcohol IP, magnesium stearate IP.

Pharmaceutical Particulars

Incompatibilities

Not applicable

Shelf-life

As on the pack.

Packaging Information

ROLITRANS Capsules 0.5 mg: Available as 10 capsules per strip

ROLITRANS Capsules 1 mg: Available as 10 capsules per strip

ROLITRANS Capsules 2 mg: Available as 10 capsules per strip

Storage and Handling Instructions

Store protected from light and moisture at a temperature not exceeding 30°C. Keep out of the reach of children.

Handling and Disposal

ROLITRANS Capsules can cause fetal harm. ROLITRANS Capsules should not be opened or crushed. Avoid inhalation or direct contact with skin or mucous membranes of the powder or granules contained in ROLITRANS Capsules. If such contact occurs, wash the skin thoroughly with soap and water; if ocular contact occurs, rinse eyes with water. In case a spill occurs, wipe the surface with a wet paper towel. Follow applicable special handling and disposal procedures.

Patient Counseling Information

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

Tacrolimus can cause serious side effects, including the following:

·       Increased risk of cancer. People who take tacrolimus have an increased risk of getting some kinds of cancer, including skin and lymph gland cancer (lymphoma).

·       Increased risk of infection. Tacrolimus is a medicine that affects your immune system. Tacrolimus can lower the ability of your immune system to fight infections. Serious infections can happen in people receiving tacrolimus that can cause death. Call your healthcare provider right away if you have any symptoms of an infection, including:

o    fever;                                                    

o    sweats or chills;                                     

o    cough or flu-like symptoms;

o    muscle aches;

o    warm, red, or painful areas on your skin.

What is ROLITRANS Capsules?

·       ROLITRANS Capsules is a prescription medicine used with other medicines to help prevent organ rejection in people who have had a kidney transplantation and for treatment in lupus nephritis.

Who should not take ROLITRANS Capsules?

Do not take ROLITRANS Capsules if you are allergic to ROLITRANS Capsules or any of the ingredients in ROLITRANS Capsules.

What should I tell my healthcare provider before taking ROLITRANS Capsules?

Before you take ROLITRANS Capsules, tell your healthcare provider about all of your medical conditions, including the following:

·       You plan to receive any live vaccines. People taking ROLITRANS Capsules should not receive live vaccines.

·       You have or have had liver, kidney, or heart problems.

·       You are pregnant or plan to become pregnant. ROLITRANS Capsules can harm your unborn baby.

o   If you are able to become pregnant, you should use effective birth control before and during treatment with ROLITRANS Capsules. Talk to your healthcare provider before starting treatment with ROLITRANS Capsules about birth control methods that may be right for you.

o   Males who have female partners who are able to become pregnant should also use effective birth control before and during treatment with ROLITRANS Capsules. Talk to your healthcare provider before starting treatment with ROLITRANS Capsules about birth control methods that may be right for you.

o   There is a pregnancy registry for females who become pregnant and males whose partners have become pregnanty during treatment with ROLITRANS Capsules. The purpose of this registry is to collect information about the health of you and your baby.

·       You are breastfeeding or plan to breastfeed. ROLITRANS Capsules passes into your breast milk.

You and your healthcare provider should decide if you will breastfeed while taking ROLITRANS Capsules.

Tell your healthcare provider about all the medicines you take, and when you start a new medicine or stop taking a medicine, including prescription and over-the-counter medicines, vitamins, natural, herbal or nutritional supplements.

Especially tell your healthcare provider if you take the following:

·        Sirolimus

·        Cyclosporine

·        Medicines called aminoglycosides that are used to treat bacterial infections.

·        Ganciclovir

·        Amphotericin B

·        Cisplatin

·        Antiviral medicines called nucleoside reverse transcriptase inhibitors.

·        Antiviral medicines called protease inhibitors.

·        Water pill (diuretic)

·        Medicine to treat high blood pressure.

·        Nelfinavir

·        Telaprevir

·        Boceprevir

·        Ritonavir

·        Letermovir

·        Ketoconazole

·        Itraconazole

·        Voriconazole

·        Clarithromycin

·        Rifampin

·        Rifabutin

·        Amiodarone

Ask your healthcare provider or pharmacist if you are not sure if you take any of the medicines listed above. ROLITRANS Capsules may affect the way other medicines work, and other medicines may affect how ROLITRANS Capsules works. Know the medicines you take. Keep a list of your medicines and show it to your healthcare provider and pharmacist when you get a new medicine.

How should I take ROLITRANS Capsules?

·       Take ROLITRANS Capsules exactly as your healthcare provider tells you to take it.

·       Your healthcare provider will tell you how much ROLITRANS Capsules to take and when to take it. Your healthcare provider may change your ROLITRANS Capsules dose if needed. Do not stop taking or change your dose of ROLITRANS Capsules without talking to your healthcare provider.

·       Take ROLITRANS Capsules with or without food.

·       Take ROLITRANS Capsules the same way every day. For example, if you choose to take ROLITRANS Capsules with food, you should always take ROLITRANS Capsules with food.

·       Take ROLITRANS Capsules 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 ROLITRANS Capsules at the same time each day helps to keep the amount of medicine in your body at a steady level.

·       Do not eat grapefruit or drink grapefruit juice while taking ROLITRANS.

·       If you take too much ROLITRANS Capsules, call your healthcare provider or go to the nearest hospital emergency room right away.

·       Do not open or crush ROLITRANS Capsules.

What should I avoid while taking ROLITRANS Capsules?

·       While taking ROLITRANS Capsules you should not receive any live vaccines.

·       Limit the amount of time you spend in sunlight and avoid exposure to ultraviolet (UV) light, such as tanning machines. Wear protective clothing and use a sunscreen with a high sun protection factor (SPF).

What are the possible side effects of ROLITRANS Capsules?

ROLITRANS Capsules may cause serious side effects, including the following:

·       Problems from medicine errors. People who take tacrolimus have sometimes been given the wrong type of tacrolimus product. Tacrolimus extended-release medicines are not the same as tacrolimus capsules and cannot be substituted for each other, unless specifically prescribed by your healthcare provider, who recommend checking of tacrolimus levels in your blood at a lab. Check your ROLITRANS Capsules when you get a new prescription and before you take it to make sure you have received ROLITRANS Capsules.

·       Check with the pharmacist and call your healthcare provider if you think you were given the wrong medicine.

·       High blood sugar (diabetes). Your healthcare provider may recommend to do blood tests to check for diabetes while you take ROLITRANS Capsules. Call your healthcare provider right away if you have any symptoms of high blood sugar, including:

o    frequent urination;                                        

o    increased thirst or hunger;                             

o    blurred vision;                                               

o    confusion;

o    drowsiness;

o    loss of appetite;

o    fruity smell on your breath;

o    nausea, vomiting, or stomach pain.               

·       Kidney problems. Kidney problems are a serious and common side effect of tacrolimus. Your healthcare provider may do blood tests to check your kidney function while you take ROLITRANS Capsules.

·       Nervous system problems. Nervous system problems are a serious and common side effect of tacrolimus. Call your healthcare provider right away if you get any of these symptoms while taking ROLITRANS Capsules. These could be signs of a serious nervous system problem:

o    headache                                                     

o    changes in behavior

o    confusion                                                     

o    coma

o    seizures                                                       

o    tremors

o    changes in your vision

o    numbness and tingling

·       High levels of potassium in your blood. Your healthcare provider may do blood tests to check your potassium level while you take ROLITRANS Capsules.

·       High blood pressure. High blood pressure is a serious and common side effect of tacrolimus. Your healthcare provider will monitor your blood pressure while you take ROLITRANS Capsules and may prescribe blood pressure medicine for you, if needed. Your healthcare provider may instruct you to check your blood pressure at home.

·       Changes in the electrical activity of your heart (QT prolongation).

·       Heart problems (myocardial hypertrophy). Tell your healthcare provider right away if you get any of these symptoms of heart problems while taking ROLITRANS Capsules:

o    shortness of breath                                       

o    feel lightheaded.

o    chest pain                                                    

o    feel faint.

·       Severe low red blood cell count (anemia).

The most common side effects of tacrolimus in people who have received a kidney are as follows:

o   infections in general, including cytomegalovirus.

o   swelling of the hands, legs, ankles, or feet (CMV) infection

o   weakness

o   tremors (shaking of the body)

o   pain

o   constipation      

o   high levels of fat in your blood

o   diarrhea  

o   high levels of potassium in your blood

o   headache

o   low red blood cell count (anemia)

o   stomach pain    

o   low white blood cell count

o   trouble sleeping

o   fever

o   nausea   

o   numbness or tingling in your hands and feet.

o   high blood sugar (diabetes)    

o   inflammation of your airway (bronchitis)

o   low levels of magnesium in your blood        

o   fluid around your heart

o   low levels of phosphate in your blood

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

These are not all the possible side effects of tacrolimus. For more information, ask your healthcare provider or pharmacist.

Reporting of Serious Adverse Events:

If you experience any side effects, talk to your doctor or pharmacist or write to drugsafety@cipla.com.  You can also report side effects directly via the national pharmacovigilance program of India by calling on 1800 180 3024 or you can report to Cipla ltd. on 18002677779.  By reporting side effects, you can help provide more information on the safety of this product.

How should I store ROLITRANS Capsules?

Store protected from light and moisture at a temperature not exceeding 30°C. Keep out of the reach of children.

General information about the safe and effective use of ROLITRANS Capsules.

·       Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use ROLITRANS Capsules for a condition for which it was not prescribed. Do not give ROLITRANS Capsules to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about ROLITRANS Capsules that is written for healthcare professionals.

·       This Patient Information leaflet summarizes the most important information about ROLITRANS Capsules. If you would like more information, talk to your healthcare provider.

Details of the Manufacturer

Manufactured. by: The Madras Pharmaceuticals

137-B, Old Mahabalipuram Road, Karapakkam, Chennai-600096

Marketed by: Cipla Ltd.

Regd. Office: Cipla House, Peninsula Business Park, Ganpatrao Kadam Marg, Lower Parel, Mumbai – 400013, India.

Details of Permission or Licence Number with Date

Mfg. Lic. No.: 247/13.11.1989

Date Of Revision

Last Updated: 17/05/2021