Cymevene® [Ganciclovir]

Brand Hoffmann la roch

In stock 1324 Items

Available since: 2019-09-19

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Clinical Pharmacology

Cymevene® - antiviral agent. Ganciclovir is a synthetic analogue of 2'-deoxyguanosine, which suppresses the reproduction of herpes viruses both in vitro and in vivo. The viruses sensitive to ganciclovir include human cytomegalovirus (h-CMV), herpes simplex viruses -1 and -2 (Herpes simplex 1 and 2), human herpes virus types 6, 7 and 8 (HHV-6, HHV-7, HHV-8), Epstein-Barr virus (EBV), varicella-zoster virus (Varicella / zoster) and hepatitis B virus. Clinical studies were limited to evaluating the efficacy of the drug in patients infected with cytomegalovirus.
In CMV-infected cells, ganciclovir is first phosphorylated by viral protein kinase to form ganciclovir monophosphate. Further phosphorylation occurs under the action of several cell kinases, as a result of which ganciclovir triphosphate is formed, which is then subjected to slow intracellular metabolism. It is shown that this metabolism occurs in cells infected with human CMV and herpes simplex virus, while after the disappearance of ganciclovir from the extracellular fluid, the period of intracellular half-life of the drug is, respectively, 18 and 6-24 hours. Since the phosphorylation of ganciclovir is more dependent on the action of viral kinase, it occurs mainly in infected cells.
The virostatic effect of ganciclovir is due to the suppression of viral DNA synthesis by: (1) competitively inhibiting the insertion of deoxyguanosine triphosphate into DNA under the action of DNA polymerase (2) by including ganciclovir triphosphate into viral DNA, leading to the cessation of elongation of viral DNA or its very limited elongation. Typical antiviral IC₅₀ for CMV, determined in vitro, ranges from 0.14 μM (0.04 μg / ml) to 14 μM (3.5 μg / ml).

Indications

Prevention and treatment of life-threatening or impaired manifest CMV infection in individuals with immunodeficiencies; prevention of manifest CMV infection in patients after organ transplantation.

Composition

One bottle of the drug contains:
Ganciclovir 500 mg (as ganciclovir sodium salt).

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Dosage and Administration

Standard Dosing for the Treatment of Retinitis CMV
Initial therapy:IV infusion at a dose of 5 mg / kg for 1 hour, every 12 hours (10 mg / kg / day) for 14-21 days (for patients with normal renal function).
Maintenance Therapy:at 5 mg / kg by intravenous infusion for 1 hour, daily for 7 days a week, or at 6 mg / kg body weight daily for 5 days a week.

Standard dosage for prophylaxis in patients after transplantation
Initial therapy:IV infusion at a dose of 5 mg / kg for 1 hour, every 12 hours, for 7-14 days (for patients with normal renal function).
Maintenance Therapy:5 mg / kg by intravenous infusion for 1 hour, daily for 7 days a week, or 6 mg / kg body weight daily for 5 days a week.

Adverse reactions

HIV-infected patients
Clinical adverse events that occurred in 2% of patients who received intravenous ganciclovir, regardless of their causal relationship with the drug and severity:
from the blood system and lymphatic system:neutropenia, anemia, thrombocytopenia, leukopenia, lymphadenopathy;
on the part of the digestive system:diarrhea, abdominal pain, dysphagia, esophageal candidiasis;
organism as a whole:fever, candidiasis, infections at the injection site, sepsis, secondary sepsis, anorexia, mycobacteriosis (mycobacterium avium), pain of different localization, chest pain, bacteremia;
from the central and peripheral nervous system:hypoesthesia, anxiety;
from skin and its appendages:itching;
on the part of the respiratory system:cough, pneumocystic pneumonia, cough with sputum, congestion in the paranasal sinuses;
laboratory values:increased activity of alkaline phosphatase in the blood, increased levels of creatinine in the blood, neutropenia, anemia, thrombocytopenia, increased levels of creatinine;
from the musculoskeletal system:arthralgia.

Patients after transplantation

Clinical adverse events that were observed in ≥ 5% of patients who received ganciclovir intravenously for the treatment or prevention of manifest CMV infection after bone marrow transplantation, regardless of their causal relationship with the drug and severity:
on the part of the blood-forming organs:pancytopenia, leukopenia;
organism as a whole:mucosal lesions, fever, tremors, sepsis, anorexia, swelling of the face;
on the part of the digestive system:diarrhea, dyspepsia;
laboratory values:increased creatinine, liver transaminase activity, hypomagnesemia, hypocalcemia, hypokalemia;
nervous system:headache, tremor, confusion;
from the skin and its appendages:exfoliative dermatitis;
on the part of the respiratory system:rhinitis, shortness of breath;
on the part of the cardiovascular system:tachycardia, hypotension;
from the organs of the urogenital tract:hematuria;
senses:bleeding in the eye;
musculoskeletal system:myalgia

Clinical adverse events that occurred in ≥ 5% of patients who received intravenous ganciclovir after a heart transplant, regardless of the causal relationship with the drug or the severity of:
The body as a whole:infections (18%).
Metabolism and nutrition disorders:swelling (9%).
Central and peripheral nervous system:headache (18%), confusion (5%), peripheral neuropathy (7%).
Respiratory system:pleural effusion (5%).
The cardiovascular system:arterial hypertension (20%).
Genitourinary tract:deterioration of renal function (14%), renal failure (12%).

Due to the high bioavailability of intravenously administered ganciclovir, it cannot be ruled out that the same adverse effects can be observed with intravenous administration of the drug, as in studies with oral administration of ganciclovir.

To fully characterize the safety profile of intravenously administered ganciclovir, the following are the relevant adverse events identified with greater frequency when orally taking ganciclovir in HIV-infected or patients after organ transplantation, regardless of their severity and causal relationship with the drug.Some undesirable effects when taking oral ganciclovir may be associated with this method of taking the drug.
Blood system and lymphatic system:leukocytosis.
Digestive organs:constipation, cholangitis, flatulence, vomiting.
The body as a whole:ascites, asthenia, bleeding, bacterial, fungal and viral infections, malaise.
The cardiovascular system:vasodilation (decrease in blood pressure, redness of the skin of the face).
Central and peripheral nervous system:depression, dizziness, insomnia.
Liver and biliary tract:cholestatic jaundice.
Leather:increased sweating.
Sense organs:amblyopia, taste disturbances.
Metabolism and nutrition disorders:diabetes mellitus, hyponatremia, hypoproteinemia, weight loss.

Other adverse events

The following are significant adverse events that were not mentioned above, because did not meet the inclusion criteria (less than 2%).
Blood system and lymphatic system:aplastic anemia, myelosuppression, eosinophilia.
Digestive organs:gastrointestinal bleeding, belching, fecal incontinence, ulcerative stomatitis, pancreatitis, glossitis.
Infections:episodes of infections caused by inhibition of the bone marrow and immune system (local and systemic infections and sepsis).
Bleeding:potentially life-threatening bleeding due to thrombocytopenia.
The body as a whole:cachexia, dehydration, weakness, thrombosis at the injection site, abscess at the injection site, edema at the injection site, pain at the injection site, hemorrhage at the injection site, malaise, photosensitivity reactions.
Central and peripheral nervous system:excitement, convulsions, hallucinations, psychosis, thought disorder, "nightmarish" dreams, ataxia, coma, dry mouth, euphoria, nervousness, drowsiness.
Skin and its appendages:dermatitis, acne, alopecia, herpes simplex, urticaria.
Sense organs:retinal detachment, visual impairment, blindness, hearing loss, pain in the eyeball, glaucoma, vitreous destruction.
Laboratory indicators:increased activity of creatine phosphokinase and lactate dehydrogenase in the blood, hypoglycemia.
Genitourinary tract:frequent urination.
The cardiovascular system:arrhythmias (including ventricular), deep vein thrombophlebitis, migraine, phlebitis.
Musculoskeletal system:myasthenic syndrome.

Contraindications

Hypersensitivity to Cymevene®u, valganciclovir or any other component of the drug.
Because of the similarity of the chemical structure of Cymevene® and acyclovir and valacyclovir, cross-hypersensitivity reactions are possible between these drugs.
The absolute neutrophil count is less than 500 cells in 1 mcl, or the platelet count is less than 25,000 cells in 1 mcl, or the hemoglobin level is less than 8 g / dl.
Children's age up to 12 years.

Drug interactions

Interactions with the intravenous administration of ganciclovir

The degree of binding of ganciclovir with plasma proteins is only 1-2%, therefore, interactions caused by the displacement of drugs from the sites of communication with proteins should not be expected.

Didanosine:It was found that with the simultaneous administration of didanosine and intravenous or oral administration of ganciclovir, didanosine plasma concentrations steadily increase. With intravenous administration of ganciclovir in doses of 5–10 mg / kg per day, the AUC of didanosine increased by 38–67%. This increase cannot be explained by a change in the tubular secretion of the drug, since the percentage of didanosine excretion has increased. This increase in AUC can be caused either by increased bioavailability or a decrease in metabolic rate. There were no clinically significant changes in the concentrations of ganciclovir. However, given the increased plasma concentrations of didanosine in the presence of ganciclovir, patients should be carefully monitored for the toxicity of didanosine.

Imipenem / Cilastatin:convulsions were observed in patients simultaneously receiving ganciclovir and imipenem / cilastatin. These drugs should be prescribed in combination with Cymevene only if the possible benefits exceed the risk.

Mycophenolate mofetil:co-administration of these drugs, potentially competing with tubular secretion, may lead to an increase in the concentration of ganciclovir and mfcc (phenolic glucuronide mycophenolic acid). Significant changes in the pharmacokinetics of mycophenolic acid (MPA) are not expected, adjusting the dose of mycophenolate mycophenolate is not required. In patients with impaired renal function, who simultaneously receive ganciclovir and MMF, it is necessary to follow the recommendations for dosing ganciclovir and conduct careful monitoring.

Other possible drug interactions
Perhaps increased toxicity in the appointment of ganciclovir concurrently with other drugs with myelosuppressive effects or impaired renal function (such as dapsone, pentamidine, flucytosine, vincristine, vinblastine, adriamycin, amphotericin B, nucleoside analogues and hydroxyurea). Therefore, these drugs should be prescribed simultaneously with ganciclovir only if the potential benefits outweigh the potential risks.

Pregnancy and Lactation

During treatment with ganciclovir, women of childbearing age should be advised to use reliable methods of contraception. Men are advised to use a barrier method of contraception during treatment and for at least 90 days after its termination.
In animal studies revealed the teratogenicity of the drug. Safety of ganciclovir during pregnancy in humans has not been established. Administration of the drug to pregnant women should be avoided, unless the potential positive effect for the mother does not exceed the possible risk to the fetus.
Peri- and postnatal development after exposure to ganciclovir has not been studied, but it cannot be ruled out that ganciclovir can be eliminated with milk and cause serious adverse reactions in an infant. Therefore, the decision to discontinue the drug or to discontinue breastfeeding should be made taking into account the potential positive effect of ganciclovir on a nursing mother.

Special instructions

Ganciclovir has a potential teratogenic and carcinogenic effect can cause congenital malformations and malignant neoplasms. Ganciclovir may temporarily or firmly inhibit spermatogenesis (see "Pregnancy" and "Side Effects").
Cases of severe leukopenia, neutropenia, anemia, thrombocytopenia, pancytopenia, myelosuppression and aplastic anemia were observed in patients taking ganciclovir. Do not start treatment with ganciclovir if the absolute number of neutrophils is less than 500 cells in 1 μl, or the number of platelets is less than 25,000 cells in 1 μl, or the hemoglobin level is less than 8 g / dl (see "Dosing Special Instructions" and "Side Effects" ).
During treatment, it is recommended to monitor the unfolded blood count, including platelet count. In patients with severe leukopenia, neutropenia, anemia and / or thrombocytopenia, treatment with hematopoietic growth factors is recommended and / or temporary interruption of drug therapy.
In case of impaired renal function, it is recommended to adjust the dose of the drug depending on creatinine clearance.
In patients taking imipenem / cilastatin and ganciclovir, the development of seizures has been described, so ganciclovir should not be administered concomitantly with imipenem / cilastatin, unless the potential benefits of therapy exceed the potential risk (see "Drug Interactions").
Both ganciclovir and zidovudine can cause neutropenia and anemia, so some patients may not tolerate the simultaneous use of these drugs in full doses (see"Drug Interactions").
While taking ganciclovir, didanosine plasma concentrations can increase, so these patients should be carefully monitored for the toxicity of didanosine (see "Drug Interactions"). The simultaneous intake of ganciclovir and drugs with myelosuppressive or nephrotoxic effects can lead to the development of additive toxicity.

Overdosage

With an overdose in some cases, no adverse events have occurred. Most patients had one or more of the following adverse events:
Hematologic toxicity:pancytopenia, myelosuppression, bone marrow aplasia, leukopenia, neutropenia, granulocytopenia.
Hepatotoxicity:hepatitis, abnormal liver function.
Nephrotoxicity:hematuria increase in a patient with already existing kidney damage, acute renal failure, increased creatinine level.
Gastrointestinal toxicity:abdominal pain, diarrhea, vomiting.
Neurotoxicity:generalized tremor, convulsions.

In addition, an excess volume of intravenous ganciclovir solution was injected intravitally into one adult, after which he developed a temporary loss of vision and occlusion of the central retinal artery due to an increase in intraocular pressure caused by the injected fluid volume.

Hemodialysis and hydration can be used to reduce the plasma level of ganciclovir in oral overdose of Cymeven.