Prograf Concentrate for Infusion

Update section 4.8:

Musculoskeletal and connective tissue disorders

common:              arthralgia, back pain, muscle spasms, pain in limb extremity

Description of selected adverse reactions

Pain in extremity has been described in a number of published case reports as part of Calcineurin-Inhibitor Induced Pain Syndrome (CIPS). This typically presents as a bilateral and symmetrical, severe, ascending pain in the lower extremities and may be associated with supra-therapeutic levels of tacrolimus. The syndrome may respond to tacrolimus dose reduction. In some cases, it was necessary to switch to alternative immunosuppression

Section 4.4 & 4.5:

Addition of further information on the risk of interaction with herbal preparations including the Chinese herb Schisandra sphenanthera.

Section 4.8:

This section has been revised and now includes a section on “Investigations” which lists the side effects relating to investigations in a single section rather than throughout section 4.8.

The date of revision is updated to June 2015

 

4.4     Special warnings and precautions for use

Section reformatted & the following text added:

 

High potassium intake or potassium-sparing diuretics should be avoided (see section 4.5).

 

Certain combinations of tacrolimus with drugs known to have nephrotoxic or neurotoxic effects may increase the risk of these effects (see section 4.5).

 

Vaccination

Immunosuppressants may affect the response to vaccination and vaccination during treatment with tacrolimus may be less effective. The use of live attenuated vaccines should be avoided.

 

Gastrointestinal disorders

Gastrointestinal perforation has been reported in patients treated with tacrolimus. As gastrointestinal perforation is a medically important event that may lead to a life-threatening or serious condition, adequate treatments should be considered immediately after suspected symptoms or signs occur.

 

Underlined text added:

Tacrolimus may prolong the QT interval and may cause Torsades de Pointes. Caution should be exercised in patients with risk factors for QT prolongation, including patients with a personal or family history of QT prolongation, congestive heart failure, bradyarrhythmias and electrolyte abnormalities. Caution should also be exercised in patients diagnosed or suspected to have Congenital Long QT Syndrome or acquired QT prolongation or patients on concomitant medications known to prolong the QT interval, induce electrolyte abnormalities or known to increase tacrolimus exposure (see section 4.5).

 

Excipients

Patients should be closely observed during the first 30 minutes of infusion for possible anaphylactoid reaction.

 

 

4.5       Interaction with other medicinal products and other forms of interaction

Underlined text added

Systemically available tacrolimus is metabolised by hepatic CYP3A4. There is also evidence of gastrointestinal metabolism by CYP3A4 in the intestinal wall. Concomitant use of medicinal products or herbal remedies known to inhibit or induce CYP3A4 may affect the metabolism of tacrolimus and thereby increase or decrease tacrolimus blood levels. It is therefore strongly recommended to closely monitor tacrolimus blood levels, as well as QT prolongation (with ECG),

 

Other interactions potentially leading to increased tacrolimus blood levels

Tacrolimus is extensively bound to plasma proteins. Possible interactions with other medicinal products known to have high affinity for plasma proteins should be considered (e.g., NSAIDs, oral anticoagulants, or oral antidiabetics).

Other potential interactions that may increase systemic exposure of tacrolimus include the prokinetic agent metoclopramide, cimetidine and magnesium-aluminium-hydroxide.

 

Section 4.8 is updated throughout with the following added;

very rare:          echocardiogram abnormal, electrocardiogram QT prolonged, Torsades de Pointes

The information on reporting suspected adverse drug reactions hás also been added

5.3     Preclinical safety data, the following text is added:

 

When tacrolimus is administered intravenously as rapid infusion/bolus injection at a dose of 0.1 to 1.0 mg/kg, QTc prolongation has been observed in some animal species. Peak blood concentrations achieved with these doses were above 150 ng/mL which is more than 6-fold higher than mean peak concentrations observed with Prograf in clinical transplantation.

 

 

10. Date of Revision

Updated to January 2015

2.       Qualitative and quantitative composition

 

1 ml concentrate for solution for infusion contains 5 mg of tacrolimus.

Excipients with known effect: 200 mg of polyoxyethylene hydrogenated castor oil and 638 mg of dehydrated alcohol.

 

For the a full list of excipients, see section 6.1.

 

4.2     Posology and method of administration

 

Elderly patients Older people

There is no evidence currently available to indicate that dosing should be adjusted in elderly patients older people.

 

 

4.3     Contraindications

 

Hypersensitivity to tacrolimus or other macrolides.

Hypersensitivity to any of the excipients listed in section 6.1 - in particular polyoxyethylene hydrogenated castor oil or structurally related compounds.

 

4.4     Special warnings and precautions for use

 

When substances with a potential for interaction (see section 4.5) - particularly strong inhibitors of

CYP3A4 (such as telaprevir, boceprevir, ritonavir, ketoconazole, voriconazole, itraconazole,

telithromycin or clarithromycin) or inducers of CYP3A4 (such as rifampicin, rifabutin) – are being

combined with tacrolimus, tacrolimus blood levels should be monitored to adjust the tacrolimus dose

as appropriate in order to maintain similar tacrolimus exposure.

 

 

4.5       Interaction with other medicinal products and other forms of interaction

 

Metabolic interactions

Systemically available tacrolimus is metabolised by hepatic CYP3A4. There is also evidence of gastrointestinal metabolism by CYP3A4 in the intestinal wall. Concomitant use of medicinal products or herbal remedies known to inhibit or induce CYP3A4 may affect the metabolism of tacrolimus and thereby increase or decrease tacrolimus blood levels. It is therefore strongly recommended to closely monitor tacrolimus blood levels, as well as renal function and other side effects, whenever substances which have the potential to alter CYP3A4 metabolism are used concomitantly and to interrupt or adjust the tacrolimus dose as appropriate in order to maintain similar tacrolimus exposure (see sections 4.2 and 4.4).

 

Inhibitors of metabolism

Clinically the following substances have been shown to increase tacrolimus blood levels:

Strong interactions have been observed with antifungal agents such as ketoconazole, fluconazole, itraconazole and voriconazole, the macrolide antibiotic erythromycin,  or HIV protease inhibitors (e.g. ritonavir, nelfinavir, saquinavir) or HCV protease inhibitors (e.g. telaprevir, boceprevir). Concomitant use of these substances may require decreased tacrolimus doses in nearly all patients.

Weaker interactions have been observed with clotrimazole, clarithromycin, josamycin, nifedipine, nicardipine, diltiazem, verapamil, amiodarone, danazol, ethinylestradiol, omeprazole and nefazodone.

 

 

4.6     Fertility, Ppregnancy and lactation

 

In rats and rabbits, tacrolimus caused embryofoetal toxicity at doses which demonstrated maternal toxicity (see section 5.3). Tacrolimus affected male fertility in rats (see section 5.3).

 

Lactation

Human data demonstrate that tacrolimus is excreted into breast milk. As detrimental effects on the newborn cannot be excluded, women should not breast-feed whilst receiving Prograf.

 

Fertility

A negative effect of tacrolimus on male fertility in the form of reduced sperm counts and motility was observed in rats (see section 5.3).

 

 

4.8     Undesirable effects

 

 

Reporting of suspected adverse reactions

 

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions preferably through the online reporting option accessible from the IMB homepage. A

downloadable report form is also accessible from the IMB website, which may be completed manually and submitted to the IMB via ‘freepost’. Alternatively, the traditional post-paid ‘yellow card’ option may also continue to be used.

 

 

FREEPOST

Pharmacovigilance Section

 

Irish Medicines Board

Irish Medicines Board

Kevin O’Malley House

Earlsfort Centre

Earlsfort Terrace

Dublin 2

Tel: +353 1 6764971

Fax: +353 1 6762517

Website: www.imb.ie

e-mail: imbpharmacovigilance@imb.ie

 

 

6.4     Special precautions for storage

 

Store ampoule in the original package in order to protect from light.

Do not store above 25 °C.

 

For storage conditions afterof the dilutioned of the medicinal product, see section 6.3.

 

 

6.6     Special precautions for disposal and other handling

 

 

Any Uunused concentrate in an opened ampoule or unused reconstituted solution should be disposed of immediately in accordance with local requirements to avoid contamination.

correction of spacing errors

4.       CLINICAL PARTICULARS

 

4.6     Pregnancy and lactation

 

Human data show that tacrolimus is able to cross the placenta. Limited data from organ transplant recipients show no evidence of an increased risk of adverse effects on the course and outcome of pregnancy under tacrolimus treatment compared with other immunosuppressive medicinal products. However, cases of spontaneous abortion have been reported. To date, no other relevant epidemiological data are available. Due to the need of treatment, tacrolimus can be considered in pregnant women when there is no safer alternative and when the perceived benefit justifies the potential risk to the foetus. In case of in utero exposure, monitoring of the newborn for the potential adverse effects of tacrolimus is recommended (in particular the effects on the kidneys). There is a risk for premature delivery (<37 week) as well as for hyperkalaemia in the newborn, which, however, normalizes spontaneously.

 

4.8     Undesirable effects

 

The adverse drug reaction profile associated with immunosuppressive agents is often difficult to establish owing to the underlying disease and the concurrent use of multiple medications.

 

Many of the adverse drug reactions stated below are reversible and/or respond to dose reduction. Oral administration appears to be associated with a lower incidence of adverse drug reactions compared with intravenous use. Adverse drug reactions are listed below in descending order by frequency of occurrence: very common (≥1/10); common (≥1/100, <1/10); uncommon (≥1/1,000, <1/100); rare (≥1/10,000, <1/1,000); very rare (<1/10,000); not known (cannot be estimated from the available data).

 

Cardiac disorders

common:         ischaemic coronary artery disorders, tachycardia

uncommon:     ventricular arrhythmias and cardiac arrest, heart failures, cardiomyopathies, ventricular hypertrophy, supraventricular arrhythmias, palpitations, ECG investigations abnormal, heart rate and pulse investigations abnormal

rare:                             pericardial effusion

very rare:         echocardiogram abnormal

 

Blood and lymphatic system disorders

common:         anaemia, leukopenia, thrombocytopenia, leukocytosis, red blood cell analyses abnormal

uncommon:     coagulopathies, coagulation and bleeding analyses abnormal, pancytopenia, neutropenia

rare:                             thrombotic thrombocytopenic purpura, hypoprothrombinaemia

not known:      pure red cell aplasia, agranulocytosis, haemolytic anaemia

 

4.4     Special warnings and precautions for use

Cases of pure red cell aplasia (PRCA) have been reported in patients treated with tacrolimus. All patients reported risk factors for PRCA such as parvovirus B19 infection, underlying disease or concomitant medications associated with PRCA.

 

4.8     Undesirable effects

 

Blood and lymphatic system disorders

common:         anaemia, leukopenia, thrombocytopenia, leukocytosis, red blood cell analyses abnormal

uncommon:     coagulopathies, coagulation and bleeding analyses abnormal, pancytopenia, neutropenia

rare:                             thrombotic thrombocytopenic purpura, hypoprothrombinaemia

not known:      pure red cell aplasia

Change detail

 

Prograf 5mg/ml Concentrate for solution for Infusion

                                                     July 2010

 

Changes in Red

 

 

4.5     Interaction with other medicinal products and other forms of interaction

Inhibitors of metabolism

Clinically the following substances have been shown to increase tacrolimus blood levels:

Strong interactions have been observed with antifungal agents such as ketoconazole, fluconazole, itraconazole and voriconazole, the macrolide antibiotic erythromycin or HIV protease inhibitors (e.g. ritonavir). Concomitant use of these substances may require decreased tacrolimus doses in nearly all patients.

Weaker interactions have been observed with clotrimazole, clarithromycin, josamycin, nifedipine, nicardipine, diltiazem, verapamil, danazol, ethinylestradiol, omeprazole and nefazodone.

In vitro the following substances have been shown to be potential inhibitors of tacrolimus metabolism: bromocriptine, cortisone, dapsone, ergotamine, gestodene, lidocaine, mephenytoin, miconazole, midazolam, nilvadipine, norethisterone, quinidine, tamoxifen, troleandomycin.

Grapefruit juice has been reported to increase the blood level of tacrolimus and should therefore be avoided.

Lansoprazole and ciclosporin may potentially inhibit CYP3A4-mediated metabolism of tacrolimus and thereby increase tacrolimus whole blood concentrations.

 

 

6.5     Nature and contents of container

 

PVC/PVDC/Aluminium blisters or perforated unit-dose blisters. Ten capsules per blister. Two, three, five, six, nine or ten blisters with a desiccant in an aluminium wrapper.

 

Packs of 20, 30, 50, 60 and 100 hard capsules in blisters.

Packs of 20×1, 30×1, 50×1, 60×1 and 100×1 hard capsules in perforated unit-dose blisters.

 

 

Not all pack sizes may be marketed.

 

10.   Date of revision of the text

 

July 2010

 

 

 

Section 4.4      Special warnings and precautions for use

Inserted

Patients treated with tacrolimus have been reported to develop posterior reversible encephalopathy syndrome (PRES). If patients taking tacrolimus present with symptoms indicating PRES such as headache, altered mental status, seizures, and visual disturbances, a radiological procedure (e.g. MRI) should be performed. If PRES is diagnosed, adequate blood pressure control and immediate discontinuation of systemic tacrolimus is advised. Most patients completely recover after appropriate measures are taken.

 

Patients treated with immunosuppressants, including Prograf are at increased risk of opportunistic infections (bacterial, fungal, viral and protozoal). Among these conditions are BK virus associated nephropathy and JC virus associated progressive multifocal leukoencephalopathy (PML). These infections are often related to a high total immunosuppressive burden and may lead to serious or fatal conditions that physicians should consider in patients with deteriorating renal function or neurological symptoms.

 

 

 

Section 4.8      Undesirable effects

 

Inserted

Infections and infestations

Cases of BK virus associated nephropathy, as well as cases of JC virus associated progressive multifocal leukoencephalopathy (PML), have been reported in patients treated with immunosuppressants, including Prograf.

 

 

Injury, poisoning and procedural complications

Medication errors, including inadvertent, unintentional or unsupervised substitution of immediate- or prolonged-release tacrolimus formulations, have been observed. A number of associated cases of transplant rejection have been reported (frequency cannot be estimated from available data).

 

Section 5.1      Pharmacodynamic properties

 

Pharmacotherapeutic group: Macrolide immunosuppressant, ATC code: L04A A05

 

Changed to read:

Pharmacotherapeutic group: Calcineurin inhibitors, ATC code: L04AD02

 

 

section 10. Date of revision of the text

 

February 2008 updated to April 2009

 

 

 

Section 2: ¡°Tacrolimus 5 mg per 1 ml¡± was removed and replaced with the following ¡°1 ml concentrate for solution for infusion contains 5 mg of tacrolimus.

Excipients: 200 mg of polyoxyethylene hydrogenated castor oil and 638 mg of dehydrated alcohol.¡±

 

Section 3, comma removed

 

Section 4.2: Dosage recommendations - Kidney transplantation, Rejection therapy ¨C adults and children: ¡°For conversion to Prograf Concentrate for Infusion¡± has been changed to read ¡°For conversion to Prograf¡±

 

Section 4.2: ¡°(HCO-60)¡± has been removed.

 

Section 4.4: the last sentence ¡°The ethanol content (638 mg per ml) of Prograf 5mg/ml Concentrate for Solution for Infusion should be taken into account¡± is no longer underlined.

 

Section 4.5:

 

Inhibitors of metabolism: ¡°(triacetyl)oleandomycin¡± has been changed to ¡°troleandomycin¡±and ¡°norethindrone¡± has been changed to ¡°norethisterone¡±

 

Effect of tacrolimus on the metabolism of other medicinal products         :

¡°antipyrine¡± changed to ¡°phenazone¡±

 

Other interactions which have led to clinically detrimental effects:

¡°cotrimoxazole¡± changed to ¡°sulfamethoxazole + trimethoprim¡±

 

Section 4.8: Undersirable effects:

Frequency of occurrence ¡°>¡± has been changed to read ¡°¡Ý¡±, ¡°including isolated reports¡± has been removed. ¡°not known (cannot be estimated form the available data¡± has been inserted.

 

The order of undesirable effects has been changed.

 

Neoplasms benign, malignant and unspecified inclusion of ¡°(incl. cysts and polyps)¡±

 

Section 6.2: The following sentence was inserted: ¡°When diluting, this medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.¡±

 

Section 6.3: ¡°unless reconstitution has¡± has been changed to read ¡°unless the dilution¡±

 

Section 6.5 ¡°type 1¡± has been changed to ¡°type I¡±

 

Section 6.6 ¡°of¡± has been changed to ¡°or¡±

 

 

 

 

Section 9: (DATE OF FIRST AUTHORISATION/RENEWAL OF AUTHORISATION) Updated to read

Date of first authorisation: 16^th February 1996

 

Date of last renewal:         27^th November 2007

 

Section 10: (DATE OF REVISION OF THE TEXT) updated to February 2008.

 

 

Prograf Ampoules SPC

Changes from April 2006 v April 2007

 

4.2     Posology and method of administration

Method of administration

New text added: “The concentration of a solution for infusion should be within the range 0.004-0.100 mg/ml. The total volume of infusion during a 24-hour period should be in the range 20-500ml. The diluted solution should not be given as a bolus.”

 

6.4         Special precautions for storage

New text added: “Store ampoule in the original package in order to protect from light. For storage conditions of the diluted medicinal product, see section 6.3.”

Text deleted: “Keep container in the outer carton.”

 

6.5     Nature and contents of container

Text slightly reworded but meaning unchanged.

 

6.6     Instructions for Use and Handling (standard heading reworded)

Text slightly reworded. Also text added that PVC containers should not be used, and only transparent and colourless solutions should be used.

 

9.       Date of first authorisation/RENEWAL OF THE AUTHORISATION

Updated to: “15^th February 2011”

 

10.       Date of revision of the text

Updated to: “April 2007”