Generic Prograf

1. Denomination

Prograf

2. Active Substance

Tacrolimus

3. Indications for Use.

Prevention and treatment of the reaction of rejection of allotransplants of liver, kidneys and heart.

4. Action

Immunodepressant. The drug suppresses the elaboration of the cytotoxic educated cells, which mainly are responsible for rejection of grafts.
The reactions of graft rejection against immune suppressive therapy, containing Tacrolimus occur more seldom than the ones against the therapy engaging cyclosporine, also they proceed easier and easier yield to arresting.

5. Posology and Administration

Tacrolimus may be used both orally and intravenously. Water-based solutions may be introduced through Levin tube.
A dosage rate of Tacrolimus should be corrected in relation to individual requests of patient, in compliance with the results of monitoring of the levels of the drug in the patient’s blood.
It is recommended to divide a daily peroral dose into two intakes (for instance, in the morning and in the evening). In order to attain the maximum absorption the drug should be taken on an empty stomach (fasting) or, as a minimum, 1 hour before or 2—3 hours after meal, rinsing it with liquid (preferably with water).

Recommendations on Dosage Rate in Liver Transplantation
Primary immune suppression - adults. Peroral Tacrolimus therapy should be started with a dosage rate of 0,10—0,20 mg/kg/daily, this dose should be divided (for instance, in the morning and in the evening). The use of the drug should be started about 12 hour after the finish of the operation. If the condition of the patient does not allow to take the drug orally, an intravenous therapy should be started from the dose rate of 0,01—0,05 mg/kg/daily, introducing the medication in the form of an intravenous infusion during 24 hours.

Primary immune suppression - children. Initial dosage of the drug for peroral use 0,30 mg/daily should be divided into 2 intakes (for instance, in the morning and in the evening). If clinical state of the patient does not allow taking medicines orally, an intravenous therapy should be initiated from a dosage rate of 0,05 mg/daily in the form of intravenous diffusion during 24 hours.

Supporting therapy – adults and children. During a supporting therapy a dosage rate of Tacrolimus usually decreases. In some cases it is possible to cancel the drugs of a concomitant immune suppression therapy, leaving Tacrolimus in the quality of a base monotherapy. Improvement of the condition of the patient after transplantation may change the pharmokinetics of Tacrolimus, and there will be a need in dose correction of the drug. To attain similar levels of the drug in blood children usually need dose ratings 1,5—2 times as high as those of adults.

Treatment of rejection – adults and children. For the treatment of rejection episodes it is necessary to use higher dose rates of Tacrolimus in combination with additional corticosteroid therapy and short courses of introduction of mono/polyclonal antibodies. If there are noticed signs of toxicity, decrease of dosage rate of Tacrolimus may be needed.

Elderly patients. Nowadays there is no evidence of the necessity to correct a dose rate of the drug for elderly patients.

Transference from Cyclosporine therapy. Associated use of Cyclosporine and Tacrolimus may enlarge a period of excretion of Cycloporine and may enhance toxic performance. That is why it is necessary to take caution in transference of patients from Cycloporine to Tacrolimus therapy. The treatment of Tacrolimus should be started after the evaluation of Cycloporine concentrations in the patient’s blood and a clinical condition of the patient. The use of the drug should be postponed if there are elevated levels of Cycloporine in the patient’s blood. In practice the treatment of Tacrolimus starts after 12—24 hours after the cancellation of the use of Cycloporine. The therapy should be started from an initial peroral dosage rate which is recommended for an initial immune suppression in a particular allotransplantate (both in adults and in children). After the transference of the patient it is necessary to continue monitoring of the levels of Cyclosporine in the patient’s blood due to the possibility of a disorder in Cyclosporine clearance.

Recommendations on the Achievement of the Needed Level of Drug Concentration in Whole Blood
In an early post-surgery period minimal levels of Tacrolimus in whole blood should be controlled. While using perorally, for the definition of the minimal levels of the drug in blood it is necessary to obtain samples of blood 12 hours after the medicine intake, immediately before intake of the next dose. The frequency of the drug level monitoring of blood must depend on clinical requests. Since Tacrolimus is a drug with a low clearance level, it may take several days to correct a dosage regimen up to the moment when changes of the drug level in blood become evident. Minimal levels of the drug in blood should be controlled approximately twice a week during an early post-transplantation period, and then from time to time in the course of a supporting therapy. Also it is important to control minimal levels of Tacrolimus in blood after change of the drug dose rate, also after change of immune suppressive regimen or after a joint use with the drugs that may influence the concentration of Tacrolimus in whole blood.

The results of clinical studies analysis allow supposing that there is a possibility to cure most patients successfully, provided that minimal levels of Tacrolinus in blood are maintained less than 20 ng/ml.

In clinical practice, during an early period after transplantation, minimal levels of the drug in whole blood usually will range from 5 to 20 ng/ml in recipients of a liver transplant, and that of from 10 to 20 ng/ml in recipients of a kidney transplant. Thus, in the course of a maintenance therapy the drug concentration in blood should be 5—15 ng/ml both in liver transplant recipients and in kidney transplant recipients.

6. Counterindications

- a known hypersensitivity to Tacrolimus or other macrolides;
- pregnancy;
- lactation.

7. Should Be Taken with Precautions, if…

The patients who receive immune suppressive therapy fall under a higher risk group of malign tumors. On application of Tacrolimus there is registered development both of benign and malign tumors. In the patients who take Tacrolimus, as well as during other immune suppressive drugs therapy a risk of development of infectious diseases (virus, bacterial, fungal and protozoan) is elevated. A course of previously detected infectious diseases is also risky.
Tacrolimus may influence on the metabolism of steroid contraceptives, that is why a special attention should be given to regulations of pregnancy protection.
As well as in the use of other immune suppressive drugs, due to a potential risk of progression of malign skin changes, exposure of the sun rays and UV-irradiation should be limited, for that purpose the skin should be protected with due clothes and creams of a high protection factor.

8. Interface with Other Medications

Prograf is highly active in relation to other medications. Do not take any other medications together with Prograf, without seeing your attending doctor as it may result in aggravation of side effects, bad assimilability and poisoning. Also patients should be on the diet prescribed by the doctor as some food products may enhance or – the opposite - arrest the action of Tacrolimus.

9. Overdosing

Tremor, headache, nausea, vomiting, infections, hives, lethargy, high level of urea nitrogen in blood and elevation of serum concentration of creatinine. See your doctor immediately if you suspect overdosage!

10. Side Effects

Many of adverse drug responses are inversive, or they decrease with the decrease of a dose rate. In peroral use the frequency of progression of adverse drug responses are lower than that of intravenous introduction.

Very often (>1/100):
- hypertension, diarrhea and nausea and/or vomiting, kidneys function failure (for instance, high level of creatinine in blood serum), hyperglycemia, diabetes, tremor, headache, insomnia, topalgia (for instance, athralgia).

Often (>1/100, - hypotonia, tachycardia, abnormal heart rhythms, conduction abnormality, thromboembolic and ischemic presentations, stenocardia, vessels diseases, dysfunction of intestinal tract (for instance, dyspepsia), deviations in levels of liver ferments, pain in stomach, constipation, changes in weight and appetite, inflammation and ulcers in intestinal tract, yellow sickness, diseases of biliary tracts and gall bladder, anemia, leucopenia, thrombocytopenia, hemorrhagic disease, leukocytosis, failures of coagulation, injury of kidney tissues, kidney failure, hypomagnesimia, hyperlipidemia, hypophosphatemia, hyperkalemia, hyperurikemia, hypocalcemia, acid intoxication, hyponatremia, hypovolemia, and other disorders of electrolyte balance, water deprivation, convulsions, sense shock (for instance, paresthesia), vision disorders, mental fog, depression, dizziness, agitation, neuropathy, convulsions, de-coordination, mental affection, anxiety, disturbance of sleep, impairment of consciousness, emotional instability, hallucinations, hearing disorders, thought disorder, encephalopathy, disorders of respiratory function (panting), pleural fluid, itching, baldness, rash, sweating, acne, photosensitivity, fever, peripheral hydrops, asthenia, acraturesis.

Not often (>1/100, 1/1000,

- deflections in ECG, infarction, cardiac failure, shock, myocardial hypertrophy, cardiac standstill, abdominal dropsy, bowel obstruction (ileums), liver tissue injury, pancreatitis, failure of hematopoietic system, including pancytopenia, thrombolytic microangiopathy, proteinuria, myasthenia, arthropathy, hypertension, illnesses of eyes, amnesia, cataract, speech disorders, paralysis, coma, deafness, atelectasia, bronchial spasm, puffiness and other genital disorders in women, liver failure.

11. Pregnancy and Lactation

Results of preclinical studies and studies on people show that Tacrolimus may excrete through placenta. Since the safety of the use of the drug in pregnant women has not been far enough determined, the drug should not be administered to pregnant women, apart from the cases when the benefit received from the treatment justifies a potential risk for the fetus.

Results of preclinical studies and studies on people show that Tacrolimus excretes into breast milk. Since there is no possibility to exclude its adverse influence on infants, the women who take the drug should not breastfeed their babies.

12. Driving

Tacrolimus may provoke the visual and neurologic disorders, which influence on the ability to drive vehicles and operate mechanisms. Interaction may be enhanced in simultaneous intake of the drug and alcohol.

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