Videx - instructions for use, dose, side effects, contraindications

granules coated with enteric coating: active substance - didanosine 125 mg, 250 mg or 400 mg, Excipients: sodium carboxymethyl starch 5.25 mg, 10.50 mg or 16.80 mg, carmellose sodium 12 1.31 mg, 2.62 mg or 4.20 mg, purified water q.s. (removed during production);

composition of the enteric membrane of granules: methacrylic acid and ethacrylate copolymer [1: 1] 25.11 mg, 50.22 mg or 80.36 mg, diethyl phthalate 3.75 mg, 7.50 mg or 12.00 mg, purified water q.s. (removed in the manufacturing process), sodium hydroxide q.s.;

Excipients: talc 0.31 mg, 0.62 mg or 1.00 mg;

composition of the capsule shell: sodium lauryl sulfate 0.1600%, titanium dioxide 2.9079% gelatin up to 100%;

ink composition:

capsules 125 mg - shellac, ethanol anhydrous (it is removed in the process of production), isopropanol (it is removed in the process of production), butanol (is removed in the manufacturing process), propylene glycol, ammonia water, potassium hydroxide, purified water, titanium dioxide (E171), iron dye oxide red (E172), iron dye oxide yellow (E172);

capsules 250 mg - shellac, ethanol anhydrous (it is removed in the production process), isopropanol (it is removed in the production process), butanol (it is removed in the production process), propylene glycol, water ammonia, indigocarmine (E132);

capsules 400 mg - shellac, iron dye red oxide (E172), isopropanol (removed during production), butanol (removed during production), propylene glycol, ammonium hydroxide, simethicone.

Description:

Hard gelatin capsules, consisting of two parts of opaque white. Contents of the capsules: white or almost white granules, covered with an enteric coating.

Capsules of 125 mg: Size 3, average capacity 0.3 ml. The inscriptions "BMS", "125 mg" and "6671" are painted in a tan color.

Capsules of 250 mg: Size No. 1, average capacity 0.5 ml. The inscriptions "BMS", "250 mg" and "6673" are marked in blue.

Capsules of 400 mg: Size # 0, average capacity of 0.68 ml. The inscriptions "BMS", "400 mg" and "6674" are marked in red.

Pharmacotherapeutic group:Antiviral (HIV) agent

ATX: & nbsp

J.05.A.F.02 Didanosine

Pharmacodynamics:

Didanosine (2 ', 3'-dideoxyinosine or ddI) is a synthetic analogue of the nucleoside of deoxyadenosine, inhibits reverse transcriptase of HIV. It is proved that didanosine suppresses the replication of HIV in cultured human cells and in cell lines in vitro.

After entering the cage didanosine under the action of cellular enzymes is converted into an active metabolite dideoxyadenosine-5'-triphosphate (ddATF). When replicating the nucleic acid of the virus, the inclusion of 2 ', 3'-dideoxynucleoside.

The active metabolite ddATF suppresses HIV-1 reverse transcriptase activity due to competition with deoxyadenosine-5'-triphosphate (dATF) for binding to active regions of the enzyme. Linking to the active site of the enzyme, it inhibits the growth of the chain and, thereby, suppresses the replication of the virus.

Pharmacokinetics:

Absorption

After oral administration didanosine quickly absorbed, the maximum concentration in the blood plasma (C_m_Oh) is dose-dependent when administered in the form of capsules with a dosage of up to 400 mg and is indicated after 30 to 90 minutes. Bioavailability is about 42%.

The area under the concentration curve is the time (AUC) in the equilibrium state averages 2.60 mg h / l for adult patients and children. When using capsules with fatty foods, the values of C_m_Oh and AUC decrease by 46% and 19%, respectively. Apparent volume of distribution - an average of about 300 liters for adults and 100 liters - for children. Binding to plasma proteins - no more than 5%.

Metabolism

The metabolism of didanosine in humans has not been studied. According to animal studies, it is assumed that in humans it occurs along the pathway of endogenous purine metabolism.

Excretion

After oral administration, the half-life of didanosine averages 1.2 hours, in urine, approximately 20% of the dose is detected. The clearance is approximately 175 l / h for adults and 90 l / h for children.

Kidney clearance is 50% of the total clearance (800 ml / min), which indicates active tubular secretion when dedating dedanosine through the kidneys, along with glomerular filtration.

Pharmacokinetics in renal dysfunction

After oral administration, the half-life increases on average from 1.4 hours in patients with normal renal function to 4.1 hours in patients with severe renal dysfunction. In peritoneal dialysis fluid didanosine is not found, while during the hemodialysis after 3-4 hours the concentrations of didanosine are 0.6-7.4% of the administered dose. Absolute bioavailability does not change in patients with severe renal dysfunction, compared with patients with normal renal function, however, the clearance of didanosine decreases in proportion to the creatinine clearance.

Pharmacokinetics for violations of liver function

Mean values of C_m_Oh and AUC in patients with impaired liver function were slightly higher (13% and 19%, respectively) than in healthy patients, however, dose adjustments for this category of patients are not required, since the spread of individual indicators in patients with hepatic and non-liver function was the same.

Pharmacokinetics in children and adolescents.

During the study of pharmacokinetics in children aged 1 to 17 years, the absorption of didanosine varied over a wide range. Despite this, the values of C_m_Oh and AUC increased in proportion to the dose. The absolute bioavailability of didanosine upon oral administration of the drug was approximately 36% after the first dose and 47% in the equilibrium state.

The half-life period averages about 0.8 hours. After the first oral dose, didanosine concentrations in urine were 18% and 21% in the steady state. Renal clearance about 243 ml / m²/ min, which was 46% of the total clearance from the body. As in adults, children showed active tubular secretion. When oral intake of the drug for 26 days cumulation didanosine in children is not observed.

Indications:Treatment of HIV-1 infection (in combination with other antiretroviral drugs).

Contraindications:

- Hypersensitivity to didanosine and / or any of the excipients of the drug,

- Simultaneous application with allopurinol, ribavirin,

- The period of breastfeeding,

- Children under 3 years old and weighing up to 25 kg (for this dosage form, recommended use of the drug in the form of powder to prepare a solution for oral administration).

Carefully:The drug should be used with caution in patients with an increased risk of developing pancreatitis, with pancreatitis in the anamnesis, in patients with risk factors for lactic acidosis (obesity, long-term treatment with nucleotide analogues), with progressive HIV infection, with peripheral neuropathy in the anamnesis, in patients taking neurotoxic drugs (an increased risk of peripheral neuropathy), in elderly patients, in the treatment of patients with impaired renal function with uncorrected doses of the drug, in patients with eye diseases (due to the risk of developing neuritis and changes in the retina). With extreme caution should be used inpatients with impaired liver function due to the risk of developing severe hepatomegaly with steatosis.

Pregnancy and lactation:

Adequate and controlled studies in pregnant women have not been conducted. Use during pregnancy should only be in the presence of strict indications and only in those cases where the potential benefit to the mother outweighs the possible risk to the fetus.

During treatment with the drug, breastfeeding should be discontinued.

Dosing and Administration:

Inside. Capsules should be swallowed whole, without chewing, on an empty stomach, 1.5 hours before or 2 hours after eating.

The recommended daily dose depends on the body weight (see table).

Body mass	Dosing regimen
≥60 kg	400 mg once a day
25 - 59 kg		250 mg once a day
20 -25 kg		200 mg once a day

Children older than 3 years with a body weight of up to 25 kg are advised to take the drug in the form of a powder to prepare a solution for ingestion.

In case of impaired renal function it is recommended to reduce the dose and / or increase the intervals between doses depending on the creatinine clearance:

Ground clearance for (ml / min / 1.73 m²)	Capsules	Powder for solution for ingestion for children
Body mass >60 kg
> 60 (conventional dose)	400 mg once a day	400 mg once a day or 200 mg 2 times a day
30-59	200 mg once a day	200 mg once a day or 100 mg 2 times a day
10-29	125 mg once daily	150 mg once a day
< 10	125 mg once daily	100 mg once a day
Body weight <60 kg
> 60 (conventional dose)	250 mg once a day	250 mg once a day or 125 mg twice daily
30-59	125 mg once daily	150 mg once a day or 75 mg twice daily
10-29	125 mg once daily	100 mg once a day
< 10	- ^a	75 mg once a day

^a Patients with a body weight <60 kg and creatinine clearance <10 ml / min should be given a drug in the form of a powder to prepare a solution for oral administration ..

Patients on dialysis should take a daily dose of the drug after dialysis. There is no need for an additional dose of the drug.

Children with impaired renal function.

Precise recommendations for adjusting the dose of the drug in children are absent. It is possible to reduce the dose and / or increase the interval between doses of the drug.

For elderly patients It is necessary to carefully select the dose in view of a possible decrease in kidney function. It is necessary to monitor the function of the kidneys and, accordingly, adjust the dose of the drug.

For patients with impaired liver function no dose reduction is required. During treatment with the drug, it is necessary to examine the level of liver enzymes.With a clinically significant excess of the level of liver enzymes, it is necessary to suspend treatment with the drug. With a rapidly rising level aminotransferase may require discontinuation or suspension of treatment with any nucleoside analogues.

Dosing regimen with simultaneous use with tenofovir

For patients who take both Videx® and tenofovir, a reduction in the daily dose of Videx® is required: for adults with a body weight of at least 60 kg and creatinine clearance of at least 60 ml / min, 250 mg once a day at the same time as light meals (not more than 400 kcal, with a fat content of not more than 20 %) or on an empty stomach; for adults with a body weight of less than 60 kg and a creatinine clearance of at least 60 ml / min - 200 mg once a day. In this case, it is recommended to take the drug in the form of a powder to prepare a solution for oral administration. Recommendations for use depending on food intake are indicated in the instructions for the preparation Videx®, powder for the preparation of solution for oral administration.

Side effects:

From the digestive system and liver: anorexia, dyspepsia, nausea, vomiting, abdominal pain,diarrhea and increased gassing, hepatitis, hepatic insufficiency, portal hypertension, not associated with cirrhosis of the liver, pancreatitis, lactic acidosis / severe steatosis with hepatomegaly, parotid gland hypertrophy, sialadenitis, lipodystrophy, lipoatrophy.

From the nervous system: peripheral neuropathy, paresthesia, pain in the hands and feet, headache.

From the sense organs: dry mouth, dry eyes, optic neuritis, depigmentation of the retina.

From the musculoskeletal system: myalgia (with or without elevation of the level of creatine kinase), arthralgia, myopathy, rhabdomyolysis.

From the hematopoiesis: Anemia, granulocytopenia, leukopenia, thrombocytopenia.

Side effects with combination therapy

With the simultaneous use of didanosine and drugs with a similar toxicity profile (stavudine and / or hydroxycarbamide), side effects such as pancreatitis, hepatotoxicity (including fatal), and severe peripheral neuropathy are more frequent than in the absence of such treatment regimens.

Laboratory indicators: hypo- and hyperkalemia, hyperuricamia, increased activity of amylase and lipase, increased activity of "hepatic" transaminases and alkaline phosphatase, hyperbilirubinemia, hypo- and hyperglycemia.

Other: diabetes, alopecia, anaphylactoid / allergic reactions, asthenia, fatigue, chills / fever, pruritus, skin rash.

Children. The side effects of the drug in children and adult patients are similar. The development of pancreatitis in children is observed in 3% of cases when taken in doses not exceeding recommended and in 13% - when treated with elevated doses of the drug. Visual disturbances are observed in children in rare cases and are characterized by changes in the retina and neuritis of the optic nerve.

Overdose:Antidote for an overdose of didanosine.

The main manifestations of an overdose of the drug: pancreatitis, peripheral neuropathy, hyperuricemia, violations of the liver.

Treatment: symptomatic, control over vital vital functions is necessary.

Didanosine is not removed from the body by peritoneal dialysis and very little hemodialysis. During the 3-4 hour period of hemodilysis, approximately 25-30% of didanosine is removed from the total concentration of didanosine circulating in the blood at the beginning of hemodialysis.

Interaction:When didanosine is used in combination with other drugs with similar toxicity (for example, with stavudine), the risk of the described side effects effects is significantly increased. The risk of developing pancreatitis may increase in proportion to the increase in didanosine concentration caused by the joint use of Videx® and allopurinol. In this regard, the combined use of allopurinol and Videx® is contraindicated.

Methadone. With the use of didanosine powder in patients with opioid dependence on the background of prolonged treatment with methadone, a decrease in the value AUC didanosine by 57%. With simultaneous use of drugs, the dose of Videx® should be increased. There have been no studies to study the possible interaction of methadone and Videx® capsules.

Tenofovir. When combined, there is an increase in the concentration of didanosine in the plasma, so the dose of the drug should be adjusted: for adults with a body weight of at least 60 kg and creatinine clearance of at least 60 ml / min - 250 mg once a day at the same time with light food (no more than 400 kcal , with a fat content of not more than 20%) or on an empty stomach; for adults with a body weight of less than 60 kg and a creatinine clearance of at least 60 ml / min - 200 mg once a day.In this case, it is recommended to take the drug in the form of a powder to prepare a solution for oral administration. Recommendations for use depending on food intake are indicated in the instructions for the preparation Videx®, powder for the preparation of solution for oral administration.

Delavirdine or indinavir should be taken 1 hour before receiving didanosine powder. In the presence of didanosine, the AUC delavirdine or indinavir is significantly increased. The drug interaction between indinavir and didanosine in capsules is not revealed.

In special studies of repeated application of the dose of the drug simultaneously with the drugs dapsone, nevirapine, rifabutin, foscarnet, ritonavir, stavudine and zidovudine and a single dose of the drug concomitantly with the preparations loperamide, metoclopramide, ranitidine, sulfamethoxazole, trimethoprim no drug interactions were detected.

Ketoconazole or itraconazole the absorption of which, when administered orally, is affected by the acidity of the gastric juice, should be taken 2 hours before taking didanosine powder. Capsules Videx® do not contain antacids,so there is no risk of interaction between these drugs.

When taking Videx® (powder) 2 hours before admission ganciclovir or at the same time the indicator AUC In the equilibrium state didanosine increases to an average of 111%. Slight decrease AUC in the equilibrium state (by 21%) of ganciclovir was noted in those cases when patients took Videx® 2 hours before ganciclovir. No changes in renal clearance were observed for either of these two drugs. It is not known whether these changes are related to changes in the safety of Videx® or the effectiveness of ganciclovir. No data confirming the increase in didanosine myelosuppressive effects of ganciclovir.

In the absence of a suitable alternative to ganciclovir, it is advisable to use it with caution when concomitantly administered with Videx® in capsules. It is necessary to control the appearance of toxic effects associated with didanosine.

Concentrations antibiotics tetracycline and some fluoroquinolone antibiotics (eg, ciprofloxacin), in the blood plasma are reduced in the presence of antacids, since they form chelate compounds. In this regard, the powder dissolved in the antacid suspension should be taken at least 6 hours before or 2 hours after taking ciprofloxacin. Capsules Videx® do not contain antacids, therefore there is no risk of interaction with antibiotics of tetracycline and fluoroquinolone series.

Ribavirin can increase the content of intracellular didanosine triphosphates and potentially increase the risk of side effects. With the combined use of didanosine with ribavirin in combination with stavudine or without it, cases of hepatic insufficiency with a lethal outcome, as well as cases of pancreatitis, peripheral neuropathy and symptomatic hyperlactatemia / lactic acidosis, have been reported. In this regard, the combined use of didanosine and ribavirin is contraindicated.

Drugs that have a neurotoxic effect.

When joint use with didanosine should be used carefully because of the increased risk of developing neuropathy. There were no clinically significant changes in pharmacokinetic parameters nelfinavir when taken together with light food 1 hour after didanosine in the form of a powder. Less than 5% didanosine is in a bound state with blood plasma proteins, indicating a low probability of drug interactions involving the mechanism of displacement from the binding sites.

Special instructions:The relationship between the sensitivity of HIV to didanosine in vitro and the clinical response to treatment has not been established. The results of determining the sensitivity in vitro vary over a wide range. A positive in vivo correlation was established between the results of measurements of viral activity (for example, polymerase chain reaction of HIV RNA) and clinical progression of the disease. The administration of the drug to children under 3 years is recommended only in the form of a suspension. With the simultaneous use of the drug Videx® with drugs with toxic effect on peripheral nervous system or pancreas The risk of these toxic effects increases significantly.

With the simultaneous use of pentamidine intravenously or drugs that increase the activity of didanosine (hydroxycarbamide, allopurinol), therapy with Videx® is recommended to be suspended.

Visual disturbances

It is necessary to periodically check the vision and note any visual impairment, such as altered perception of color or a vague vision of objects. Children should conduct a retina scan every 6 months or if there is any change in vision. The decision to change therapy can be made on the basis of the patient's examination and the evaluation of the benefit / risk relationship.

Diseases of the liver

Hepatotoxicity and hepatic insufficiency with a fatal outcome were observed in post-marketing studies in HIV-infected patients during combined antiretroviral therapy in conjunction with hydroxycarbamide. Cases of liver dysfunction with a fatal outcome were observed in such patients with the application of a combination hydroxycarbamide, didanosine and stavudine, in connection with which the joint use of these drugs should be avoided. The efficacy and safety of Videx® in patients with severe hepatic impairment have not been established in history. During combined antiretroviral therapy in these patients,including in patients with active chronic hepatitis, the frequency of violations of the liver, including severe and potentially life-threatening, increases. Observation of the condition of such patients should be carried out in accordance with standard practice. In the case of worsening of such patients, as well as an increase in the activity of "hepatic" enzymes above the clinically significant level, Videx® therapy should be suspended or canceled.

Immunodeficiency Syndrome

In HIV-infected patients with severe immunodeficiency during the combined antiretroviral therapy, there may be signs of an inflammatory response to asymptomatic or residual opportunistic infections. This syndrome was observed during the first few weeks or months after initiation of antiretroviral therapy. There may be signs of cytomegalovirus retinitis, generalized or focal mycobacterial infections and pneumonia caused by Pneumocystis jiroveci. If necessary, appropriate therapy is prescribed. There have been cases of autoimmune diseases (eg, Graves' disease),the time of the onset of the development of such diseases varied in different patients and could occur many months after the initiation of therapy.

Redistribution / accumulation of fatty tissue (lipodystrophy / lipoatrophy)

In patients receiving antiretroviral therapy, there have been cases of redistribution / accumulation of fatty tissue (lipodystrophy / lipoatrophy) that manifested obesity by the central type, an increase in the amount of fat in the dorso-cervical zone ("buffalo hump"), a reduction in the amount of fatty tissue of the limbs and face, breast augmentation, "cushingoid face."

Pancreatitis

Pancreatitis is severe toxic effect of the drug. Pancreatitis of varying severity, often fatal, can develop in the patient at different stages of treatment and does not depend on whether the drug is administered as monotherapy or in combination with other drugs, or on the degree of immunosuppression. Pancreatitis is a dose-related complication. Patients taking Videx® in combination with stavudine, hydroxycarbamide, are at a higher risk of developing this side effect. The risk of developing pancreatitis increases in elderly patients, in patients with pancreatitis in history, with renal dysfunction in the absence of appropriate adjustment of the dose of the drug, as well as in patients with progressive HIV infection.

In patients with risk factors for pancreatitis, Videx® should be used with caution. When symptoms appear pancreatitis treatment with the drug should be suspended, and when the diagnosis is confirmed, treatment should be discontinued. With clinically significant excess of biochemical markers, even in the absence of symptoms of pancreatitis, treatment should also be stopped.

Lactate acidosis / Severe form of steatosis with hepatomegaly

Lactate acidosis / Severe form of steatosis with hepatomegaly, including fatal cases, are noted with the use of nucleoside reverse transcriptase inhibitors in monotherapy or in combination with other antiretroviral drugs, including didanosine. In general, this side effect was observed in women.Obesity and long-term administration of nucleoside reverse transcriptase inhibitors may be a risk factor for this side effect. In pregnant women, the risk of developing lactic acidosis with a fatal outcome increases with the intake of didanosine in combination with stavudine or other antiretroviral drugs. In this regard, the combination of these drugs in pregnant women can be used with extreme caution. When clinically appears confirmed symptoms of hepatotoxicity or lactate acidosis (which may include hepatomegaly and steatosis, even if there are no obvious signs of an increase in the activity of "liver" transaminases), drug treatment should be stopped. With a significant excess of the activity of "liver enzymes" and bilirubin (increase of 3-4 degrees: 5 times higher than normal for "liver" transaminases and alkaline phosphatase, 2 times higher than normal for lipase, 2.6 times higher than normal for bilirubin) should be discontinued.

Portal hypertension, unrelated to cirrhosis of the liver

In postmarketing studies, cases of portal hypertension unrelated to cirrhosis of the liver, including cases leading to liver transplantation, as well as to fatal outcomes, were noted.Unrelated to cirrhosis of the portal portal hypertension caused by didanosine was confirmed in patients with unconfirmed viral hepatitis. The first signs and symptoms of portal hypertension appeared in the period from several months to several years after initiation of didanosine therapy. Common signs of development of portal hypertension included: increased activity of liver enzymes, varicose veins of the esophagus, bloody vomiting, ascites, splenomegaly. Patients receiving didanosine, should be regularly monitored for early signs of portal hypertension (eg, thrombocytopenia and splenomegaly) during scheduled visits to the doctor. Appropriate laboratory studies involving the study of the activity of the enzyme, the concentration of bilirubin, albumin in the serum, an expanded blood test, an international normalized attitudes (MHO) and ultrasonography, should be prescribed to such patients. The use of Videx® should be discontinued when the patient develops symptoms of portal hypertension, not associated with cirrhosis of the liver.

Peripheral Neuropathy

Peripheral neuropathy is usually accompanied by a bilateral symmetrical sense of numbness of the limbs: tingling and pain in the feet and, less often, in the hands. In the early stages of the disease, these phenomena are less common.

There is information that the course of peripheral neuropathy can be aggravated by the joint administration of antiretroviral drugs, including didanosine, stavudine, and hydroxycarbamide. When the appearance of the phenomena of peripheral neuropathy should be suspended therapy with didanosine until they are eliminated. After eliminating these symptoms, the patient may take a reduced dose of the drug.

Didanosine is rapidly destroyed in the acidic content of gastric juice. In capsules didanosine is contained in the form of granules coated with an enteric-soluble coat, as a result of which the absorption of didanosine in the intestine increases. Absorption of Didanosine regardless of the dosage form in food decreases by an average of 50%. When the drug is administered to patients on diet with a restriction of salt intake, it should be borne in mind that 100 mg of the contents of the capsules contain not less than 0.424 mg of sodium.

Does not contain sucrose, so the restrictions for the use of the drug patients with diabetes mellitus no.

Effect on the ability to drive transp. cf. and fur:Special studies that study the effect of Videx® on the ability to drive vehicles and mechanisms have not been carried out.

Form release / dosage:

Capsules intestine soluble 125 mg, 250 mg and 400 mg.

Packaging:For 10 capsules in a blister of PVC / aluminum foil. 3 blisters together with instructions for use in a cardboard box.

Storage conditions:

At a temperature of no higher than 25 ° C.

KEEP OUT OF THE REACH OF CHILDREN.

Shelf life:

2 years.

Do not take it after the expiration date.

Terms of leave from pharmacies:On prescription

Registration number:П N011537 / 02

Date of registration:12.05.2011 / 14.04.2016

Expiration Date:Unlimited

The owner of the registration certificate:Bristol-Myers Squibb CompanyBristol-Myers Squibb Company USA

Manufacturer: & nbsp

ASTRAZENECA Pharmaceuticals LP USA

Representation: & nbspBRISTOL-Majers SKVIBB, LLCBRISTOL-Majers SKVIBB, LLCRussia

Information update date: & nbsp11.01.2017

Illustrated instructions

Instructions

Videx® (Videx®)