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

Clinical and pharmacological group: & nbsp

Means for the treatment of HIV infection

Included in the formulation

Tivicay®

pills inwards

VeeV Helsker United Kingdom Limited United Kingdom

АТХ:

J.05.A.X.12 Dolutegravir

Pharmacodynamics:

Dolutegravir inhibits HIV integration by binding to the active region of integrase and blocking the chain transfer during integration of retroviral deoxyribonucleic acid (DNA), which is necessary for the HIV replication cycle. In vitro dolutegravir is slowly separated from the active site of the wild-type DNA integrase complex (half-life 71 hours).

Pharmacokinetics:

Suction. Dolutegravir quickly absorbed after ingestion, median TC_maxis achieved 2-3 hours after taking the dose in the form of tablets coated with a film membrane. The linearity of the pharmacokinetics of dolutegravir depends on the dose and dosage form.

Bioavailability of dolutegravir depends on the food content: when eating with low, moderate and high fat AUC _(0-∞) dolutegravir increased by 33%, 41% and 66%, C_maxdecreased by 46%, 52% and 67%, TC_max lengthened to 3, 4 and 5 hours compared with 2 hours when taken on an empty stomach, respectively. These increases are not clinically significant. Absolute bioavailability of dolutegravir is not established.

Distribution. According to the data received in vitro, dolutegravir to a considerable extent (approximately 99.3%) binds to human plasma proteins. Apparent volume of distribution (V_d/ F) after ingestion of the suspension is approximately 12.5 liters. The binding of dolutegravir to plasma proteins did not depend on concentration. The free fraction of dolutegravir in blood plasma is approximately 0.5% in patients infected with HIV-1.

Dolutegravir penetrates into the cerebrospinal fluid. Dolutegravir is found in the male and female genital tract. AUC in cervico-vaginal fluid, cervical and vaginal tissues was 6-10% of that in blood plasma in equilibrium. AUC in the seminal fluid was 7%, and in the rectal tissues - 17% of that in plasma at equilibrium concentration.

Metabolism. Dolutegravir is mainly metabolized uridine diphosphate-glucuronyltransferase (UDF-HT) 1A1 with an insignificant component of the isoenzyme CYP3A (9.7% of the total accepted dose in the study of mass balance in humans). Dolutegravir is the main compound circulating in the blood plasma. Dolutegravir is slightly excreted through the kidneys in an unchanged form (<1% dose).53% of the total dose taken orally is excreted unchanged through the intestine.

Excretion. The final half-life of dolutegravir is about 14 hours, and the apparent clearance (CL / F) is 0.56 l / h.

Indications:

Treatment of HIV-1 infection in adults and children from the age of 12 and weighing 40 kg or more in combination antiretroviral therapy (APT).

ICD-10

I.B20-B24.B24 Disease caused by human immunodeficiency virus [HIV], unspecified

Contraindications:

Hypersensitivity to doltegravir or any other component of the drug; simultaneous reception with dofetilide; children under 12 years of age and body weight less than 40 kg.

Carefully:

Insufficient safety and efficacy data are available to recommend a dose to children younger than 12 years of age or weighing less than 40 kg.

With caution: hepatic impairment of severe degree (class C on the Child-Pugh scale); with simultaneous use with drugs (prescription and over-the-counter), which can change the effect of the drug, or drugs that may change under the action of the drug.

Pregnancy and lactation:

Appropriate and well-controlled studies involving pregnant women have not been conducted. The effect on pregnancy in women is unknown. In studies on reproductive toxicity in animals, it was shown that dolutegravir penetrates the placenta. The drug can be used during pregnancy only if the expected benefit for the mother exceeds the potential risk to the fetus.

HIV-infected patients are recommended not to breast-feed children to avoid vertical transmission of HIV infection. Based on the data obtained from animals, it is expected that dolutegravir will be excreted in women with breast milk, although this has not been confirmed in humans.

Dosing and Administration:

Therapy should be conducted by a doctor with experience in the treatment of HIV infection. The drug can be taken regardless of food intake.

Adults.

- Patients infected with HIV-1, without resistance to integrase inhibitors. The recommended dose is 50 mg once a day. With simultaneous use with efavirenz, nevirapine, rifampicin and tipranavir in combination with ritonavir, the recommended dose of the drug in this category of patients should be 50 mg 2 times a day.

- Patients infected with HIV-1, with resistance to integrase inhibitors (documented or suspected clinically). The recommended dose of the drug is 50 mg 2 times a day. The decision to use the drug in such patients should be made taking into account the drug resistance to integrase inhibitors. In this category of patients, simultaneous use with efavirenz, nevirapine, rifampicin and tipranavir in combination with ritonavir should be avoided.

Skipping the drug

If the patient misses the drug, he should take the missed dose as soon as possible, if at least 4 hours remain before the next dose. If there are less than 4 hours remaining before the next dose, the patient should not take the missed dose, and the drug should be resumed according to the schedule.

Children aged 12 to 18 years and weighing 40 kg and more

The recommended dose of the drug for patients who had not previously received treatment with integrase inhibitors (age 12 to 18 years, body weight 40 kg and more) is 50 mg once a day.

There is insufficient data to recommend a dose to children aged 12 to 18 years with resistance to integrase inhibitors.

Special patient groups

Children under 12 years of age and weighing less than 40 kg. Insufficient safety and efficacy data are available to recommend a dose to children younger than 12 years of age or weighing less than 40 kg.

Patients of advanced age. Data on the use of the drug in patients aged 65 years and older are limited. However, there is no data on the need for dose adjustment in elderly patients.

Patients with impaired renal function. Patients with renal insufficiency of mild, moderate or severe severity (creatinine clearance <30 ml / min, not on dialysis) do not require dose adjustment. There are no data available for patients on dialysis, but no differences in pharmacokinetics are expected in this population.

Patients with impaired liver function. Patients with mild to moderate hepatic insufficiency (class A or B on the Child-Pugh scale) do not require a dose adjustment. There are no data on patients with severe hepatic impairment (class C on the Child-Pugh scale).

Side effects:

Impaired immune system. Infrequently: a hypersensitivity reaction, a syndrome of restoration of immunity.

Disorders from the psyche. Often: insomnia.

Violations from the nervous system. Very often: headache. Often: dizziness, unusual dreams.

Disorders from the digestive tract. Very often: nausea, diarrhea. Often: vomiting, flatulence, pain in the upper abdomen. Infrequent: pain in the abdomen, discomfort in the abdomen.

Disorders from the liver and biliary tract. Infrequently: hepatitis.

Disturbances from the skin and subcutaneous tissues. Often: rash, itching.

General disorders and disorders at the site of administration. Often: fatigue.

Overdose:Data on overdose are limited. Further treatment should be carried out in accordance with clinical indications or recommendations of national toxicology centers, where applicable. There is no specific drug overdose treatment. In case of an overdose, supportive therapy and appropriate follow-up should be performed. Due to the high binding of dolutegravir to plasma proteins, it is unlikely that a significant amount of it can be excreted by dialysis.

Interaction:

The simultaneous use of dolutegravir and other drugs that inhibit UDP-HT 1A1, UDF-GT1A3, UDF-HT1A9, CYP3A4 and / or Pgp, may increase the concentration of dolutegravir in blood plasma.

Contraindicated concomitant reception with dofetilide.

The simultaneous use of dolutegravir and etravirine is not recommended unless the patient receives simultaneously atazanavir / ritonavir, lopinavir / ritonavir or darunavir / ritonavir.

The drug should not be administered together with antacids containing polyvalent cations. It is recommended that dolutegravir 2 hours before or 6 hours after the application of these funds.

Dolutegravir can increase the concentrations of metformin. It is necessary to monitor patients during therapy, and metformin dosages may need to be adjusted.

Special instructions:

Hypersensitivity reactions. With the use of integrase inhibitors, including dolutegravir, hypersensitivity reactions were recorded that were characterized by a rash, a violation of systemic indices, and sometimes a violation of organ function, including liver damage.If there are signs or symptoms of hypersensitivity (including but not limited to a severe rash or rash accompanied by fever, malaise, fatigue, muscle or joint pain, bullous lesions, mucous membrane damage to the mouth, conjunctivitis, face swelling, hepatitis, eosinophilia, angioedema), it is necessary to immediately discontinue the use of the drug and other medications that could cause such reactions. It is necessary to monitor the clinical state, including the parameters of hepatic aminotransferases and conduct appropriate therapy. The delay in stopping treatment with doltegravir or other medications that could trigger such reactions, after developing hypersensitivity reactions, can lead to life-threatening conditions.

Syndrome of restoration of immunity. In HIV-infected patients with severe immunodeficiency during the onset antiretroviral therapy There may be an inflammatory response to asymptomatic or residual opportunistic infections that can cause severe clinical conditions or worsen symptoms.As a rule, such reactions were observed during the first few weeks or months after the onset antiretroviral therapy. Typical examples of such conditions are cytomegalovirus retinitis, generalized and / or focal mycobacterial infections and pneumonia caused by Pneumocystis jiroveci (P. carinii). It is necessary to immediately evaluate any inflammatory symptoms and, if necessary, begin treatment. Autoimmune diseases (such as Graves' disease, polymyositis and Guillain-Barre syndrome) were observed against the background of restoration of immunity, but the time of primary manifestations varied, and the disease could occur many months after the initiation of therapy and have an atypical course. At the beginning of therapy with dolutegravir in some patients with co-infection of hepatitis B and / or C, an increase in the activity of liver enzymes, reflecting the immune reconstitution syndrome, was observed. It is recommended to monitor the activity of liver enzymes in patients with co-infection with hepatitis B and / or C. Special control is needed for the initiation or continuation of hepatitis B therapy (according to current guidelines) in patients who are treated with doltegravir.

Opportunistic infections. In patients receiving dolutegravir or other antiretroviral therapy, opportunistic infections or other complications of HIV infection may develop. Thus, patients should be under careful clinical supervision of a physician, with experience in the treatment of HIV-related diseases.

Transmission of infection. Patients should be informed that the prevention of the risk of transmission of HIV to others by sexual transmission or through the blood is not proven when receiving the currently available antiretroviral therapy, including dolutegravir. It is necessary to continue to take the necessary precautions.

It is necessary to take into account the clinical condition of the patient and the profile of undesirable phenomena of dolutegravir when considering the patient's ability to drive or control mechanisms.

Instructions

Dolutegravir (Dolutegravirum)