Advagraf - Instructions For Use, Indications, Doses, Analogues

2024 Author: Rachel Wainwright | [email protected]. Last modified: 2023-12-15 07:39

Advagraph

Instructions for use:

1. 1. Release form and composition
2. 2. Indications for use
3. 3. Contraindications
4. 4. Method of application and dosage
5. 5. Side effects
6. 6. Special instructions
7. 7. Drug interactions
8. 8. Analogs
9. 9. Terms and conditions of storage
10. 10. Terms of dispensing from pharmacies

Prices in online pharmacies:

from 900 rubles

Buy

Advagraf is a highly active immunosuppressive drug; a calcineurin inhibitor.

Release form and composition

Dosage form of the drug - capsules of prolonged action: gelatinous solid filled with white powder (10 pcs. In PVC / aluminum foil blisters, in an aluminum sealed bag, 5 blisters, 1 bag in a cardboard box):

• 0.5 mg: size 5, pale yellow cover with red lettering "0.5 mg", orange case with numbers "647" and the company logo;
• 1 mg: size 4, white cap with red lettering “1mg”, orange case with numbers “677” and company logo;
• 3 mg: size # 1, orange cover with red lettering “3 mg”, orange case with numbers “637” and company logo;
• 5 mg: size # 0, grayish-red cap with red lettering "5 mg", orange case with numbers "687" and the company logo.

1 capsule of prolonged action contains:

• Active ingredient: tacrolimus (in the form of tacrolimus monohydrate) - 0.5 mg, 1 mg, 3 mg or 5 mg;
• Auxiliary components: hypromellose, lactose monohydrate, ethylcellulose, magnesium stearate;
• Capsule shell: iron dyes (yellow oxide and red oxide (E 172)), gelatin, titanium dioxide (E 171), sodium lauryl sulfate;
• Ink for the inscription on the capsule (Opacode S-1-15083): pharmaceutical glaze 45% (shellac solution in ethanol), hyprolose, simethicone, lecithin (soy), iron oxide red dye.

Indications for use

Advagraf is indicated for use in adult patients to prevent renal or liver allograft rejection and to treat rejection of allograft resistant to standard immunosuppressive therapy.

Contraindications

• Lactose intolerance, lactase deficiency, glucose-galactose malabsorption;
• Children and adolescents up to 18 years of age (limited clinical experience of use);
• Increased individual sensitivity to tacrolimus, other macrolides, auxiliary components of the drug.

Since the safety of using tacrolimus during pregnancy has not been sufficiently established, drug therapy during this period is allowed only in the absence of a safer alternative treatment, and only in the case of a significant excess of the benefits to the mother over the potential risk to the fetus.

According to clinical observations, tacrolimus passes into breast milk, as a result, breastfeeding should be interrupted during Advagraf therapy.

With severe hepatic dysfunction, a dose reduction may be required.

In renal failure, there is no need to adjust tacrolimus doses, but due to its nephrotoxic potential, it is recommended to carefully monitor renal function - serum creatinine concentration, creatinine clearance (CC) and the amount of urine excreted.

Method of administration and dosage

Extended-release capsules Advagraf are taken orally immediately after being removed from the blister, whole, washed down with a liquid (preferably water). It is recommended to take the daily dose at one time, in the morning, on an empty stomach - 1 hour before meals or 2-3 hours after meals (to achieve maximum absorption of tacrolimus). A missed dose should be taken as soon as possible, preferably on the same day, and should not be doubled the next morning.

It is necessary to warn patients about the presence in the package of a sachet of silica gel for moisture absorption, which is not intended for use.

The duration of taking Advagraf is not limited, since the state of immunosuppression must be constantly maintained to prevent transplant rejection.

Recommended dosing regimen (once a day, in the morning):

• Prevention of transplanted kidney rejection: initial daily dose of 0.2-0.3 mg / kg; taking the drug must be started within 24 hours after transplantation;
• Prevention of transplanted liver rejection: initial daily dose of 0.1-0.2 mg / kg; taking the drug should be started 12-18 hours after transplantation;
• Kidney or liver transplantation: Switching to Advagraf from other immunosuppressive drugs should be started with the doses recommended to prevent rejection of the transplanted kidney or liver;
• Heart transplantation: switching to Advagraf from other immunosuppressants should be started with a dose of 0.15 mg / kg;
• Transplantation of other organs: there is no clinical experience with the use of Advagraf in the treatment of patients after transplantation of the pancreas, lung, intestines, but as part of the drug Prograf, tacrolimus is used after lung transplantation at an initial oral dose of 0.1-0.15 mg / kg, pancreas - 0, 2 mg / kg, intestines - 0.3 mg / kg.

To stop transplant rejection, it is recommended to increase the dose of tacrolimus, short courses of therapy with antibodies (mono- / polyclonal), and intensify therapy with glucocorticosteroids; in the event of signs of tacrolimus toxicity (pronounced unwanted side effects), a dose reduction of Advagraf may be required.

Over time, after liver or kidney transplantation, the dose of the drug is usually reduced, it is also possible to switch to monotherapy with the abolition of concomitant immunosuppressants. As the patient's condition improves, the pharmacokinetics of tacrolimus may change, which requires additional dose adjustment.

When choosing the doses of the drug, it is necessary to take into account the clinical assessment of the individual tolerance of the drug and the likelihood of transplant rejection, as well as monitoring data on the concentration of tacrolimus in the blood. In most cases, according to clinical studies, therapy is successful if this indicator is ≥ 20 ng / ml.

Initial therapeutic blood concentrations of tacrolimus:

• Kidney or heart (after transplantation) - 10-20 ng / ml;
• Liver (after transplantation) - 5-20 ng / ml;
• Liver, kidney or heart (during maintenance immunosuppressive therapy) - 5-15 ng / ml.

Dose adjustments to achieve equal minimum tacrolimus concentrations in selected patient categories:

• Race - Black patients may require higher doses than Caucasian patients;
• Gender - there is no information about the need for different doses for men and women;
• Older age - there is no information about the need for special doses.

Careful monitoring is required during Advagraph therapy by appropriately qualified medical personnel and the availability of the necessary equipment. The drug can only be prescribed by a physician experienced in immunosuppressive therapy in patients with organ transplants.

If clinical signs of rejection appear, the need to adjust the dosage of immunosuppressive therapy should be considered.

Side effects

It is difficult to establish the exact profile of adverse reactions of immunosuppressants due to the characteristics of the underlying disease and the large number of drugs used after organ transplantation.

Most often (> 10%), the following side effects are noted: renal failure, tremors, hyperglycemia, diabetes mellitus, infections, hypertension, hyperkalemia, insomnia.

When using Advagraf in therapeutic doses, the following side effects from organs and systems are possible (frequency distribution in accordance with the following gradation: very often -> 1/10, often -> 1 / 100-1 / 1000-1 / 10,000- < 1/1000, very rarely - <1/10 000, uncertain frequency - not enough data to establish):

• Infections and invasions: the likelihood of local and generalized infectious lesions (bacterial, protozoal, viral, fungal) is increased; possible worsening of the course of previously diagnosed infections; there have been cases of BK virus-associated nephropathy and JC-virus-associated progressive multifocal leukoencephalopathy;
• Tumors (unspecified, benign and malignant) incl. cysts and polyps: increased risk of malignant neoplasms; noted the occurrence of both malignant and benign tumors, including associated with the Epstein-Barr virus lymphoproliferative diseases and skin cancer;
• Blood and lymphatic system: often - thrombocytopenia, anemia, leukopenia, leukocytosis, abnormalities in the results of the analysis of erythrocytes; infrequently - neutropenia, pancytopenia, coagulopathy, abnormalities in the coagulogram data; rarely - hypoprothrombinemia, thrombotic thrombocytopenic purpura; uncertain frequency - agranulocytosis, partial red cell aplasia, hemolytic anemia;
• Immune system: anaphylactic and allergic reactions;
• Endocrine system: rarely - hirsutism;
• Metabolism and nutrition: very often - hyperglycemia, diabetes mellitus, hyperkalemia; often - metabolic acidosis, decreased appetite, anorexia, electrolyte disturbances, hypophosphatemia, hypervolemia, hyponatremia, hyperuricemia, hypokalemia, hypomagnesemia, hypocalcemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia; infrequently - hyperphosphatemia, hypoglycemia, dehydration, hypoproteinemia;
• Mental disorders: very often - insomnia; often - depression, anxiety, confusion and disorientation, hallucinations, mood disorders, depressed mood, nightmares; infrequently - psychotic disorders;
• Nervous system: very often - tremor, headache; often - convulsions, impaired consciousness, dizziness, peripheral neuropathy, dysesthesia and paresthesia, impaired writing, disorders of the nervous system; infrequently - hemorrhages in the central nervous system and cerebrovascular accident, encephalopathy, articulation and speech disorders, amnesia, paralysis and paresis, coma; rarely - hypertonicity; very rarely - myasthenia gravis;
• Organ of vision: often - photophobia, blurred vision and visual impairment; infrequently - cataract; rarely - complete loss of vision;
• Hearing organ and vestibular disorders: often - ringing and tinnitus; infrequently - hearing loss; rarely - sensorineural deafness; very rarely - hearing impairment;
• Heart: often - tachycardia, ischemic coronary disorders; infrequently - palpitations, ventricular arrhythmias (up to cardiac arrest), heart failure, cardiomyopathies, supraventricular arrhythmias, pathological changes on the electrocardiogram (ECG), ventricular hypertrophy, impaired pulse and heart rate (HR); rarely, pericardial effusion; very rarely - ventricular tachysystolic arrhythmia of the "pirouette" type, prolongation of the QT interval on the ECG, pathological changes on the echocardiogram;
• Vessels: very often - arterial hypertension; often - vascular hypotension, ischemic and thromboembolic complications, impaired peripheral circulation, bleeding; infrequently - deep vein thrombosis of the extremities, heart attack, shock;
• Respiratory system, chest and mediastinal organs: often - shortness of breath, cough, pulmonary parenchymal disorders, pleural effusion, nasal congestion, rhinitis, pharyngitis; infrequently - asthma, respiratory disorders, respiratory failure; rarely - ARDS (acute respiratory distress syndrome);
• Gastrointestinal tract (GIT): very often - nausea, diarrhea; often - abdominal and gastrointestinal pain, vomiting, inflammation, bleeding, ulcers and perforation, ascites, stomatitis and ulceration of the oral mucosa, constipation, loose stools, flatulence, dyspepsia, a feeling of bloating and distention in the abdomen; infrequently - chronic and acute pancreatitis, increased blood amylase activity, peritonitis, paralytic ileus (intestinal obstruction), gastroesophageal reflux, impaired gastric evacuation function; rarely - subileus, pancreatic pseudocysts;
• Kidneys and urinary tract: very often - impaired renal function; often - acute and chronic renal failure, acute tubular necrosis, toxic nephropathy, urinary tract damage, disorders of the bladder and urethra, oliguria; infrequently - anuria, hemolytic uremic syndrome; very rarely - hemorrhagic cystitis, nephropathy;
• Hepatobiliary system: very often - pathological changes in the results of functional liver tests; often - cholestasis, biliary tract pathology, liver cell damage, hepatitis, jaundice; rarely - hepatic artery thrombosis, obliterating endophlebitis of the hepatic veins; very rarely - liver failure;
• Skin and subcutaneous tissues: often - rash, alopecia, hyperhidrosis, itching, acne; infrequently - photosensitivity, dermatitis; rarely - Lyell's syndrome (toxic epidermal necrolysis); very rarely - Stevens-Johnson syndrome;
• Musculoskeletal and connective tissue: often - back and limb pain, arthralgia, muscle cramps; infrequently - joint disorders;
• Genitals and mammary gland: infrequently - uterine bleeding, dysmenorrhea;
• General disorders: often - fever, asthenia, pain and discomfort, impaired perception of body temperature, edema, weight gain, increased activity of alkaline phosphatase in the blood; infrequently - flu-like syndrome, weight loss, increased activity of lactate dehydrogenase in the blood, feeling unwell, anxiety, chest tightness, multiple organ failure, impaired perception of ambient temperature; rarely - a feeling of stiffness in the chest, thirst, falling due to loss of balance, difficulty in movement; very rarely - an increase in the mass of lipid tissue;
• Injuries, complications of manipulations, intoxication: often - primary graft dysfunction.

Many adverse reactions are reversible and / or decrease with tacrolimus dose reduction.

Errors in prescribing and dispensing tacrolimus preparations were noted, incl. accidental, unreasonable or uncontrolled substitutions of one dosage form for another, as well as cases of transplant rejection associated with them (there are not enough data to estimate the frequency).

special instructions

Transferring patients from one tacrolimus drug to another (including extended-release capsules from conventional capsules) is not safe without proper supervision. This may result in graft rejection or an increased incidence of side effects (including hypo- or hyperimmunosuppression) due to clinically significant differences in tacrolimus exposure. Changing the dosage regimen or dosage form is carried out only under the supervision of a transplant doctor. After the transfer, the concentration of tacrolimus in the blood is closely monitored and the dose of the drug is adjusted to maintain the systemic exposure of the substance at an adequate level.

The first time after transplantation, regular monitoring of the following parameters is required: ECG, blood pressure, neurological status, visual status, electrolyte concentration (especially potassium), fasting glucose concentration, renal and liver function indicators, hematological parameters, coagulogram, the presence of proteins in plasma. In the case of clinically significant changes, it is recommended to correct the immunosuppressive therapy.

With diarrhea, a significant change in the concentration of tacrolimus in the blood is possible, therefore, with frequent bowel movements, this indicator should be carefully monitored.

Because soy lecithin is contained in Advagraf capsule ink, it is important for patients with hypersensitivity to soy or peanuts to balance the risk of allergy with the benefits of tacrolimus.

Tacrolimus, especially in combination with ethanol, can cause neurological and visual disorders, which should be taken into account when performing types of work that require increased concentration of attention and speed of psychomotor reactions.

Drug interactions

• Preparations or medicinal herbs with an inducing or inhibitory effect on CYP3A4 - can accordingly increase or decrease the concentration of tacrolimus (to maintain its stable adequate exposure, it is recommended to control the concentration and, if necessary, adjust the dose or stop taking it; it is also necessary to monitor kidney function and possible side effects);
• Antifungal agents (fluconazole, ketoconazole, voriconazole, itraconazole), HIV protease inhibitors (ritonavir, saquinavir, nelfinavir), macrolide antibiotics (erythromycin), hepatitis C virus protease inhibitors (boceprevir, telaprevirvir can significantly increase their concentration if necessary) simultaneous use may require a reduction in doses of Advagraf in almost all patients);
• Clotrimazole, clarithromycin, josamycin, nifedipine, nicardipine, diltiazem, verapamil, amiodarone, danazol, ethinyl estradiol, omeprazole and nefazodone - drug interactions with tacrolimus are less pronounced;
• Cortisone, bromocriptine, dapsone, ergotamine, lidocaine, mefenytoin, gestodene, miconazole, midazolam, norethisterone, quinidine, tamoxifen, triacetyl (oleandomycin) - potential inhibitors of tacrolimus metabolism (in vitro studies);
• Grapefruit juice - may increase the concentration of tacrolimus;
• Lansoprazole and cyclosporine - potentially capable of inhibiting CYPZA4, indirectly increasing tacrolimus levels;
• Drugs with high affinity for blood plasma proteins (oral anticoagulants, non-steroidal anti-inflammatory drugs (NSAIDs), oral antidiabetic drugs) - it is required to take into account their possible competitive interaction with tacrolimus;
• Phenytoin, rifampicin, St. John's wort (Hypericum perforatum) - can significantly reduce the concentration of tacrolimus (clinical data) (if used together, it is likely that the dose of Advagraf should be increased);
• Phenobarbital - clinically significant interactions have been observed;
• Corticosteroids (maintenance doses) - usually decrease the concentration of tacrolimus;
• Prednisolone or methylprednisolone (in high doses) - can decrease or increase tacrolimus levels;
• Carbamazepine, metamizole and isoniazid - may reduce the concentration of tacrolimus;
• Cyclosporine - increases its half-life period T ¹ / ₂, are possible nephrotoxic synergistic / additive effects (not recommended for simultaneous reception and tacrolimus when assigning patients receiving cyclosporin previously, caution);
• Phenytoin - tacrolimus increases its concentration in the blood;
• Hormonal contraceptives - due to the ability of tacrolimus to reduce their clearance, it is important to choose contraceptives carefully;
• Statins - their pharmacokinetics does not change (clinical observation data);
• Phenobarbital and antipyrine - potentially may reduce clearance and increase T ¹ / ₂ (data from experiments on animals);
• Prokinetics (cisapride, metoclopramide), magnesium and aluminum hydroxide, cimetidine - can increase the systemic exposure of tacrolimus;
• Aminoglycosides, vancomycin, gyrase inhibitors, co-trimoxazole, NSAIDs, acyclovir, ganciclovir - may increase nephrotoxicity or neurotoxicity;
• Amphotericin B and ibuprofen - their nephrotoxicity increases;
• Potassium or potassium-sparing diuretics (triamterene, amiloride, spironolactone) - development or intensification of hyperkalemia is possible (their use in high doses should be avoided);
• Vaccines, especially live attenuated vaccines - tacrolimus can alter the body's response to vaccination, reducing its effectiveness (vaccination should be avoided).

Tubes, syringes and other equipment used to prepare a suspension from the powder contained in Advagraph capsules should not contain polyvinyl chloride (PVC), since tacrolimus is incompatible with it.

Analogs

Analogs of Advagraf are: Tacrolimus-Acri, Tacrolimus-Teva, Tacrolimus Stada, Prograf.

Terms and conditions of storage

Store at temperatures up to 25 ° C in original packaging. Keep out of the reach of children.

The shelf life is 3 years. After opening the aluminum bag, the preparation is stored for 1 year.

Terms of dispensing from pharmacies

Dispensed by prescription.

Advagraf: prices in online pharmacies

Drug name Price Pharmacy

Advagraf 0.5 mg capsules of prolonged action 50 pcs. RUB 900 Buy

Advagraf 0.5 mg capsules of prolonged action 50 pcs. 1700 RUB Buy

Advagraf 1 mg sustained-release capsules 50 pcs. 1900 RUB Buy

Advagraf 5 mg sustained-release capsules 50 pcs. 5700 RUB Buy

Advagraf 5 mg sustained-release capsules 50 pcs. 16500 rub. Buy

Information about the drug is generalized, provided for informational purposes only and does not replace the official instructions. Self-medication is hazardous to health!