Mycophenolate mofetil TEVA: prophylaxis of acute rejection in organ transplant patients
Mycophenolate mofetil is indicated in combination with ciclosporin and corticosteroids for the prevention of acute rejection in patients with allogeneic kidney, heart, or liver transplantation. Treatment should be initiated and maintained by qualified organ transplant specialists.
Each tablet: Mycophenolate mofetil 500mg.
Presentation and packaging
Film-coated tablets: Box of 3 blisters x 10 tablets.
Pharmacotherapeutic classification: Immunosuppressive drugs.
ATC code: L04A A06
Mechanism of action: Mycophenolate mofetil is the 2-morpholino ethyl ester form of mycophenolic acid (MPA). MPA is a potent, selective, non-competitive, and reversible inhibitor of inosine monophosphate dehydrogenase and thus inhibits the new pathway of guanosine nucleotide synthesis without DNA binding. Because the proliferation of T and B lymphocytes is strongly dependent on purine nucleosynthesis while other cell lines can take advantage of the mechanism of purine nuclear reuse, MPA has a cytostatic effect. lymphocytes are stronger than other cells.
Following oral administration, mycophenolate mofetil is rapidly and extensively absorbed and undergoes complete first-pass metabolism to the active metabolite MPA. The results of acute rejection inhibition after renal transplantation showed that the immunosuppressive activity of mycophenolate mofetil is related to MPA concentrations. The mean bioavailability of mycophenolate mofetil orally administered as a MPA AUC was 94% compared with intravenous administration. Food did not affect the extent of absorption (MPA AUC value) of mycophenolate mofetil when administered at a dose of 1.5 g twice daily to renal transplant patients. However, the Cmax value of MPA decreased by 40% in the presence of food. After oral administration, plasma concentrations of mycophenolate mofetil are low, undetectable.
As a result of enterohepatic circulation, secondary elevations in MPA plasma concentrations are usually noted approximately 6-12 hours after dosing. MPA AUC was reduced by approximately 40% with concomitant use of cholestyramine (4 g 3 times a day), indicating that a large amount of drug enters the enterohepatic circulation.
At clinical concentrations, 97% of MPA is bound to plasma albumin.
MPA is metabolized primarily by glycoronyl transferase to the phenolic glucuronide conjugate form of MPA (MPAG), which is pharmacologically inactive.
An insignificant amount (<1% of the dose) is excreted in the urine as MPA. The dose of radiolabeled mycophenolate mofetil administered orally was found to be adequate with 93% of the dose recovered in urine and 6% in feces. Most (approximately 87%) of the administered dose is excreted in the urine as MPAG.
At clinical concentrations, MPA and MPAG are not removed from the circulation by hemodialysis. However, at high plasma concentrations of MPAG (>100 µg/mL), small amounts of PAG are removed from the circulation by hemodialysis.
In the early stage (< 40 days) post-transplant, kidney, heart, and liver transplant patients had about 30% lower mean MPA AUC and about 40% lower Cmax than in the late stage (3- 6 months after organ transplant).
Patients with renal failure
In a single-dose study (6 patients/group) the mean MPA plasma AUC was observed in patients with severe chronic renal failure (glomerular filtration rate <25 mL/min). /1.73 m2) is 28-75% higher than in healthy people or people with milder kidney failure. However, mean MPAG AUC values for single-dose administration in patients with severe renal impairment were 3-6 times higher than in patients with mild renal impairment or in healthy subjects, consistent with the elimination profile of MPAG via the kidney. The use of multiple doses of mycophenolate mofetil in patients with severe chronic renal failure has not been studied. There are no data on the use of the drug in heart or liver transplant patients with severe renal impairment.
Kidney transplant slow to work
In patients whose transplanted kidney was slow to function after transplantation, the mean AUC values (0-12 hours) of MPA were similar to those in patients in whom the transplanted kidney did not experience delayed posttransplantation. The mean plasma MPAG AUC value (0-12 hours) in these patients was 2-3 times higher than in patients whose transplanted kidneys did not experience retardation after transplantation. The rate of free MPA and plasma MPA concentrations in patients with impaired renal function is transiently increased. No dose adjustment of mycophenolate mofetil is required in this case.
Patients with liver failure
In volunteers with alcoholic cirrhosis, MPA glucuronide conjugation in the liver was not affected by the parenchymal disease. The effect of liver disease on this process may depend on the specific disease condition. However, liver disease, primary biliary tract conditions such as primary biliary fibrosis, may have a different effect.
Children and adolescents (2 to 18 years old)
Pharmacokinetic parameters were evaluated in 49 pediatric renal transplant patients receiving mycophenolate mofetil at a dose of 600 mg/m2 orally twice daily. Using this dose level obtained MPA AUC values similar to those found in renal transplant adults receiving mycophenolate mofetil at a dose of 1 g twice daily during the early and late post-transplant period. MPA AUC values were similar between groups when comparing early and late stages.
Elderly patients (≥ 65 years old)
The pharmacokinetics of mycophenolate mofetil in elderly patients have not been formally evaluated.
The pharmacokinetics of oral contraceptives are not affected by the concomitant use of mycophenolate mofetil. A study of co-administration of mycophenolate mofetil (1g twice daily) and combined oral contraceptives containing ethinylestradiol (0.02mg to 0.04mg) and levonorgestrel (0.05mg to 0.15mg), desogestrel (0. .15mg) or gestodene (0.05mg to 0.10g) performed in 18 non-transplant women (no other immunosuppressants) for 3 consecutive menstrual cycles showed no effect of mycophenolate mofetil affect the anti-ovulatory effect of oral contraceptives. Serum levels of luteinizing hormone (LH), follicle-stimulating hormone (FSH), and progesterone were not significantly affected.
Indications and uses
Mycophenolate mofetil is indicated in combination with ciclosporin and corticosteroids for the prevention of acute rejection in patients with allogeneic kidney, heart, or liver transplantation.
Dosage and Administration
Treatment with mycophenolate mofetil should be initiated and maintained by appropriately qualified transplant specialists.
Use in kidney transplant
Adults: Mycophenolate mofetil should be started within 72 hours of a kidney transplant. The recommended dose for kidney transplant patients is 1g, twice daily (2g/day dose).
Children and adolescents (2 to 18 years): The recommended dose of mycophenolate mofetil is 600 mg/m2, orally twice daily (up to a maximum of 2 g/day). Mycophenolate mofetil tablets should only be used in patients with a body surface area greater than 1.5 m2 at a dose of 1 g twice daily (2 g/day). Because some adverse reactions occur with a higher frequency in this age group than in adults, a temporary dose reduction or discontinuation may be necessary, taking into account relevant clinical factors such as the severity of adverse reactions.
Children (< 2 years): There are insufficient data on safety and efficacy in children under 2 years of age. There is insufficient information to make dosing recommendations and therefore the use of mycophenolate mofetil is not recommended for this age group.
Use in heart transplant
Adults: Mycophenolate mofetil should be started within 5 days of a heart transplant. The recommended dose for heart transplant patients is 1.5g, twice a day (3g/day).
Children: There are no data on use in pediatric heart transplant patients.
Use in liver transplantation
Adults: Intravenous mycophenolate mofetil should be used for the first 4 days after liver transplantation with oral mycophenolate mofetil starting immediately after IV administration if the drug is tolerated. The recommended oral dose for liver transplant patients is 1.5g, twice daily (3g/day).
Children and adolescents: There are no data on the use of the drug in pediatric liver transplant patients.
Use in elderly patients (≥ 65 years old)
The recommended dose of 1g, twice daily in case of kidney transplant, and 1.5g, twice daily in case of heart or liver transplant is appropriate for elderly patients.
Use for patients with renal failure
In renal transplant patients with severe chronic renal failure (glomerular filtration rate < 25 mL/min/1.73 m2), in addition to the immediate post-transplant administration, doses greater than 1 g twice daily should be avoided. . These patients should also be carefully monitored. No dose adjustment is required in patients whose transplanted kidney is slow to function after surgery. There are no data on its use in heart or liver transplant patients with severe chronic renal failure.
Use in patients with severe liver failure
No dose adjustment is required for renal transplant patients with severe parenchymal liver disease. There are no data on the use of the drug in heart transplant patients with severe parenchymal liver disease.
Treatment in stages of rejection
Mycophenolic acid (MPA) is the active metabolite of mycophenolate mofetil. Renal rejection did not alter the pharmacokinetics of MPA; No dose reduction or discontinuation of mycophenolate mofetil is required. There is no basis for adjusting the dose of mycophenolate mofetil after cardiac transplant rejection. There are no data on the pharmacokinetics of the drug during liver transplant rejection.
Patients receiving combination immunosuppressive regimens with drugs such as mycophenolate mofetil are at increased risk of developing lymphomas and other malignancies, especially of the skin. This risk is related to the intensity and duration of immunosuppressive therapy rather than to the use of a particular drug. The general recommendation to reduce the risk of skin cancer is to limit exposure to the sun and UV rays by wearing protective clothing and using sunscreen with a high protection factor.
Patients taking mycophenolate mofetil should be instructed to immediately report any signs of infection, bruising, unusual bleeding, or other signs of bone marrow failure to their physician.
Patients treated with immunosuppressants such as mycophenolate mofetil are at increased risk of opportunistic infections (bacterial, fungal, viral, and protozoan), fatal infections, and bacteremia. Microbial infections include latent viral reactivation such as hepatitis B or C virus reactivation and polyomavirus infection (BK virus-associated with nephropathy, JC virus associated with progressive multifocal leukoencephalopathy). . Cases of hepatitis due to hepatitis B or C virus reactivation have been reported in carrier patients treated with immunosuppressive agents. These infections are often associated with high doses of immunosuppressive drugs and can lead to serious conditions or death; This should be considered by clinicians in the differential diagnosis of immunosuppressed patients with poor renal function or neurological symptoms.
Neutropenia should be monitored in patients receiving mycophenolate mofetil as this may be related to mycophenolate mofetil itself, concomitant medications, viral infections, or multiple causes. Patients receiving mycophenolate mofetil should have a complete blood count weekly for the first month of treatment, twice a month for the second and third months, and monthly thereafter for the first year. If neutropenia develops (absolute neutrophil count < 1.3 x 103/µL), mycophenolate mofetil may need to be discontinued.
Cases of pure red cell aplasia (PRCA) have been reported in patients treated with mycophenolate mofetil in combination with other immunosuppressants. The mechanism of PRCA-induced PRCA by mycophenolate mofetil is unknown. PRCA may disappear with dose reduction or discontinuation of mycophenolate mofetil. Mycophenolate mofetil therapy should only be changed in transplant patients under appropriate supervision to minimize the risk of transplant rejection.
Patients should be informed that during treatment with mycophenolate mofetil, vaccines may be reduced in potency and that vaccines containing live attenuated organisms should be avoided. The flu vaccine can be effective. Physicians should refer to national guidelines for influenza vaccine use.
Because mycophenolate mofetil has been associated with an increased incidence of gastrointestinal adverse events such as ulceration, bleeding, and infrequently gastrointestinal perforation, caution should be exercised when mycophenolate mofetil is administered to patients with severe gastrointestinal tract, active phase.
Mycophenolate mofetil is an inosine monophosphate dehydrogenase (IMPDH) inhibitor. Therefore, in theory, its use should be avoided in patients with rare hereditary problems of hypoxanthine-guanine phosphoribosyltransferase (HGPRT) deficiency such as Lesch-Nyhan and Kelley-Seegmiller syndromes.
The co-administration of mycophenolate mofetil with azathioprine is not recommended because the concomitant use of these two agents has not been studied.
Because the area under the curve (AUC) of MPA is significantly reduced by cholestyramine, caution should be exercised when mycophenolate mofetil is coadministered with drugs affecting enterohepatic circulation due to the risk of decreased potency of mycophenolate mofetil.
The benefit-risk of combining mycophenolate mofetil with tacrolimus or sirolimus has not been established.
Effects on ability to drive and use machines
Studies on the effects of the drug on the ability to drive and use machines have not been conducted. The pharmacokinetics of the drug and the observed adverse reactions indicate that the drug has little effect on the ability to drive and use machines.
Overdosage with mycophenolate mofetil has been reported in clinical trials and during post-marketing follow-up. In many of these cases, no adverse events were recorded. In the cases of Overdosage with reported adverse events, the events were all among the known adverse events of the drug.
An overdose of mycophenolate mofetil is expected to lead to over suppression of the immune system as well as increased susceptibility to infections and bone marrow suppression. If neutropenia develops, the use of mycophenolate mofetil should be discontinued or the dose reduced.
Hemodialysis does not remove clinically significant amounts of MPA or MPAG from the circulation. Bile acid-binding agents such as cholestyramine can eliminate MPA by decreasing the enterohepatic circulation of the drug.
Hypersensitivity reactions to mycophenolate mofetil have been reported. Therefore, mycophenolate mofetil is contraindicated in patients with known hypersensitivity to mycophenolate mofetil or mycophenolic acid.
Mycophenolate mofetil is contraindicated in lactating women.
For more information on drug use during pregnancy and contraceptive requirements.
Use in pregnant and lactating women
It is not recommended to start using mycophenolate mofetil until a negative pregnancy test result has been obtained. Effective contraception must be used before starting, during, and for 6 weeks after stopping mycophenolate mofetil. Patients should be instructed to consult a doctor as soon as pregnancy is detected.
The use of mycophenolate mofetil during pregnancy is not recommended and mycophenolate mofetil should only be used in the absence of more appropriate alternative therapy. Mycophenolate mofetil should be used during pregnancy only if the potential benefit outweighs the potential risk to the fetus. There are insufficient data on the use of mycophenolate mofetil in pregnant women. However, congenital malformations such as ear malformations, i.e. abnormality or absence of the outer/middle ear, have been reported in infants whose mothers received mycophenolate mofetil in combination with other immunosuppressive agents for pregnancy. Cases of spontaneous abortion have been reported in patients receiving mycophenolate mofetil. Animal studies have shown reproductive toxicity.
Mycophenolate mofetil is secreted into milk in rats. It is not known whether the drug is excreted in human milk. Due to the risk of serious adverse reactions in nursing infants, mycophenolate mofetil is contraindicated in nursing women.
Drug interaction studies have only been conducted in adults.
Aciclovir: Higher concentrations of aciclovir have been observed when mycophenolate mofetil is coadministered with aciclovir compared with aciclovir alone. The change in the pharmacokinetics of MPAG (the glucuronide conjugate of MPA) (MPAG increased by 8%) was small and not considered clinically significant. Because MPAG plasma concentrations are increased in renal failure, similar to those of aciclovir, there may be a risk of competitive tubular secretion between mycophenolate mofetil and aciclovir or the aciclovir prodrug valaciclovir, increasing Add concentrations of both drugs.
Antacids and proton pump inhibitors (PPIs): Decreased levels of mycophenolic acid (MPA) have been reported when antacids such as magnesium and aluminum hydroxide as well as PPIs such as lansoprazole and pantoprazol are co-administered with mycophenolate mofetil. When comparing rejection rates or graft loss rates between mycophenolate mofetil-treated patients receiving PPIs versus patients not taking PPIs, no significant difference was found. These data allow extrapolation for all antacids since the reduction in drug concentrations when mycophenolate mofetil is coadministered with magnesium and aluminum hydroxide is less than when co-administered with PPIs.
Cholestyramine: When a single dose of 1.5 g of mycophenolate mofetil was administered to healthy volunteers pre-administered with 4 g of cholestyramine 3 times a day for 4 days, MPA AUC was reduced by 40%. Caution should be exercised when these two drugs are used concurrently due to the risk of reducing the therapeutic effect of mycophenolate mofetil.
Drugs affecting enterohepatic circulation: Caution should be exercised when drugs affecting enterohepatic circulation are co-administered with mycophenolate mofetil due to the risk of reducing the therapeutic efficacy of mycophenolate mofetil.
Ciclosporin A: The pharmacokinetics of ciclosporin A (CsA) was not affected by mycophenolate mofetil. In contrast, if concomitant use with ciclosporin is discontinued, MPA AUC values may increase by approximately 30%.
Ganciclovir: Based on the results of a single-dose study, the recommended dose levels of oral mycophenolate mofetil and intravenous ganciclovir as well as the known effects of renal impairment on the pharmacokinetics of mycophenolate mofetil and ganciclovir, it can be predicted that co-administration of these drugs (competing for tubular secretion) will increase concentrations of MPAG and ganciclovir. The pharmacokinetics of MPA were not significantly altered and no dose adjustment of mycophenolate mofetil was required. In patients with renal impairment in whom mycophenolate mofetil and ganciclovir or ganciclovir prodrugs such as valganciclovir are co-administered, the dosing recommendations for ganciclovir should be consulted and the patient monitored carefully.
Oral contraceptives: The pharmacokinetics and pharmacodynamics of oral contraceptives are not affected by the concomitant use of mycophenolate mofetil.
Rifampicin: In patients not receiving ciclosporin, co-administration of mycophenolate mofetil and rifampicin reduced MPA concentrations (AUC0-12 hours) by 18% to 70%. Monitoring of MPA levels is recommended to adjust the dose of mycophenolate mofetil accordingly to maintain the clinical efficacy of mycophenolate mofetil when co-administered with rifampicin.
Sirolimus: In renal transplant patients, co-administration of mycophenolate mofetil with CsA reduced MPA concentrations by 30-50% compared with patients receiving a combination of sirolimus and an equivalent dose of mycophenolate mofetil.
Sevelamer: A decrease in Cmax and AUC0-12 of MPA by 30% and 25%, respectively, has been observed with concomitant administration of mycophenolate mofetil and sevelamer without any clinical consequences (eg, organ rejection). ). However, mycophenolate mofetil should be administered at least 1 hour before and 3 hours after sevelamer to minimize effects on MPA absorption. There are no data on interactions between mycophenolate mofetil and phosphate-binding agents other than sevelamer.
Trimethoprim/sulfamethoxazole: No effect of these drugs on the bioavailability of MPA has been observed.
Norfloxacin and metronidazole: In healthy volunteers, no significant interactions were observed when mycophenolate mofetil was co-administered with either norfloxacin and metronidazole. However, the combination of norfloxacin and metronidazole reduced MPA concentrations by about 30% with a single dose of mycophenolate mofetil.
Ciprofloxacin and amoxicillin plus clavulanic acid: A decrease in pre-dose MPA concentrations (trough levels) of approximately 50% has been observed in renal transplant patients during the first days immediately after initiation of ciprofloxacin or amoxicillin. with clavulanic acid orally. This effect tends to lessen with continued antibiotic use or disappear within a few days of stopping antibiotics. Changes in MPA concentrations before each dose may not be representative of changes in overall MPA concentrations. Therefore, a change in the dose of mycophenolate mofetil is not usually necessary in the absence of clinical graft dysfunction. However, it is necessary to closely monitor the patient's clinical condition during the combination of drugs and immediately after antibiotic therapy.
Tacrolimus: In liver transplant patients initiated on mycophenolate mofetil and tacrolimus, the AUC and Cmax values of MPA, the active metabolite of mycophenolate mofetil, were not significantly affected by co-administration of tacrolimus. In contrast, tacrolimus AUC was increased by approximately 20% when multiple doses of mycophenolate mofetil (1.5 g twice daily in the morning and evening) were administered to patients receiving tacrolimus. However, in renal transplant patients, tacrolimus concentrations were not altered by mycophenolate mofetil.
Other interactions: Co-administration of probenecid with mycophenolate mofetil in monkeys increased MPAG AUC by 3-fold. Therefore, other drugs known to be tubularly excreted may compete for elimination with MPAG and thereby increase plasma concentrations of MPAG or drugs that are excreted by the tubules.
Vaccines containing live microorganisms: Vaccines containing live microorganisms should not be used in patients with reduced immune response. Antibody response to other vaccines may be reduced.
The following adverse reactions include those observed in clinical trials
The major adverse reactions associated with the co-administration of mycophenolate mofetil with ciclosporin and corticosteroids included diarrhea, leukopenia, sepsis, vomiting, and signs of increased frequency of certain types of infections.
Malignancies: Patients receiving combination immunosuppressive regimens, including mycophenolate mofetil, are at increased risk of developing lymphomas and other malignancies, especially of the skin. Progressive lymphoproliferative disorder or lymphoma in 0.6% of patients receiving mycophenolate mofetil (2g or 3g daily) in combination with other immunosuppressive agents in controlled clinical trials in patients kidney transplant (2g dose), heart and liver for at least 1 year. Non-melanoma skin cancers occurred in 3.6% of patients, other malignancies were reported in 1.1% of patients. Safety data at 3 years in kidney and heart transplant patients showed no unusual change in the incidence of malignancies compared with a 1-year follow-up. Liver transplant patients were followed for at least 1 year, but less than 3 years.
Opportunistic infections: All organ transplant patients are at increased risk of opportunistic infections; This risk is increased with loading doses that cause complete immunosuppression. The most common opportunistic infections in patients receiving mycophenolate mofetil (2g or 3g daily) with other immunosuppressants in controlled clinical trials in kidney transplant patients (2g dose) , heart, and liver disease for at least 1 year are mucosal candidiasis, cytomegalovirus (CMV) infection/symptom in blood, and herpes simplex infection. The percentage of patients infected/with CMV virus syndrome in the blood was 13.5%.
Children and adolescents (2 to 18 years): Type and frequency of adverse reactions in a clinical study of 92 pediatric patients 2 to 18 years of age receiving an oral dose of 600 mg mycophenolate mofetil/m2. , twice daily is similar to that in adults receiving a dose of 1g mycophenolate mofetil, twice daily. However, the following drug-related adverse reactions were more common in pediatric patients than in adults, especially in children under 6 years of age: Diarrhea, bacteremia, leukopenia, anemia, and infection.
Elderly patients (≥ 65 years): Elderly patients (≥ 65 years of age) are at increased risk of adverse reactions due to immunosuppression. Elderly patients receiving mycophenolate mofetil as part of a combination immunosuppressive regimen may be at increased risk of certain types of infections (such as cytomegalovirus tissue invasive disease), gastrointestinal bleeding, and pulmonary edema compared with younger patients.
Other Adverse Reactions: Adverse reactions, possibly or possibly related to mycophenolate mofetil, have been reported in ≥ 1/10 and in ≥ 1/100 to < 1/10 of treated patients. with mycophenolate mofetil in controlled clinical trials in renal (dose 2g), heart, and liver transplant patients.
Within each organ system, undesirable effects are listed in the following frequency ranges: Very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1000); very rare (< 1/10,000) and of unknown frequency (frequency cannot be estimated from the available data). Within each frequency group, adverse events are ranked in descending order of severity.
The following undesirable effects include adverse reactions observed during post-marketing follow-up:
The types of adverse reactions observed in patients receiving mycophenolate mofetil during post-marketing follow-up were similar to those observed in renal, cardiac, and liver transplantation studies. witness. Additional adverse reactions reported during postmarketing surveillance are described below with frequency levels in parentheses, if applicable.
Gastrointestinal: gingival hyperplasia (≥ 1/100 to < 1/10), colitis, including cytomegalovirus colitis (≥ 1/100 to < 1/10), pancreatitis (≥ 1/100 to < 1/10), pancreatitis (≥ 1/100 to < 1/10), 1/10) and atrophy of small intestinal villi.
Immunosuppression-associated disorders: Serious life-threatening infections including meningitis, endocarditis, tuberculosis, and atypical mycobacterial infections. Cases of BK virus nephropathy, as well as JC virus multifocal leukoencephalopathy (PML), have been reported in patients treated with immunosuppressants such as mycophenolate mofetil. Agranulocytosis (≥1/1,000 to <1/100) and neutropenia have been reported; therefore, patients receiving mycophenolate mofetil should be regularly monitored. Aplastic anemia and bone marrow failure have been reported in patients treated with mycophenolate mofetil, in some cases leading to death.
Blood and Lymphatic System Disorders: Cases of pure red cell aplasia (PRCA) have been reported in patients treated with mycophenolate mofetil. Isolated cases of neutrophil morphology, including acquired Pelger-Huet malformation, have been reported in patients treated with mycophenolate mofetil. These changes were not associated with decreased neutrophil function. These changes may suggest a "left shift" in the development of neutrophils on hematological tests, which may be misinterpreted as a sign of infection in immunosuppressed patients such as: in subjects receiving mycophenolate mofetil.
Hypersensitivity: Hypersensitivity reactions such as angioedema and anaphylaxis have been reported.
Congenital disorders: For details, see Use in pregnancy and lactation.
Respiratory, thoracic, and mediastinal disorders: There have been isolated reports of interstitial pneumonia and pulmonary fibrosis in patients treated with mycophenolate mofetil in combination with other immunosuppressants, some of to death.
Reporting Suspected Adverse Reactions: It is important to report suspected adverse reactions after a drug is approved for marketing. This helps to continuously monitor the benefit/risk balance of the drug. Healthcare professionals are encouraged to report any suspected adverse reactions through the national reporting system outlined in Annex V.
Store below 30oC, in a cool and dry place.