Isentress, 100 mg 60 pcs.

Raltegravir inhibits the catalytic activity of HIV integrase, an enzyme involved in HIV virus replication. Inhibition of integrase prevents covalent insertion (integration) of the HIV genome into the host cell genome in the early stages of infection. HIV genomes not incorporated into human DNA are unable to induce the production of new viral particles, so suppression of the integration process prevents the spread of viral infection in the body. The inhibitory ability of raltegravir against human phosphotransferases, including DNA polymerases α, β and γ, is expressed insignificantly.

Microbiology

At a plasma concentration of 31±20 nmol/L, raltegravir provided 95% suppression of viral replication (95% inhibitory concentration, IR₉₅) in cell cultures of human T lymphocytes infected with cell culture-adapted variant H9IIIB HIV-1 compared with control virus-infected cell cultures. IR₉₅ was achieved at concentrations ranging from 6 to 50 nmol/L in cultures of human mitogen-activated peripheral blood mononuclear cells infected with various primary clinical strains of HIV-1, including strains of 5 non-B HIV-1 subtypes as well as strains resistant to HIV reverse transcriptase inhibitors and protease inhibitors.

In a single infection cycle assay, raltegravir suppressed infection caused by 23 strains of HIV representing 5 non-B subtypes and 5 circulating recombinant forms, with IR₅₀ – 5-12 nmol/L. Raltegravir also suppressed HIV-2 strain replication when tested on CEMx174 cells (IR₉₅ = 6 nmol/L). When raltegravir and nucleoside reverse transcriptase inhibitors (zidovudine, zalcitabine, stavudine, abacavir, tenofovir, didanosine, and lamivudine) were simultaneously introduced into a culture of human T lymphocytes infected with variant H9IIIB of HIV-1 virus, non-nucleoside reverse transcriptase inhibitors (efavirenz, nevirapine and delavirdine), HIV protease inhibitors (indinavir, saquinavir, ritonavir, amprenavir, lopinavir, nelfinavir and atazanavir) or fusion inhibitor (enfuvirtide) had additive to synergistic antiretroviral activity.

Drug resistance

. HIV-1 integrase mutations that contribute to raltegravir-resistant virus strains (developed in vitro or in patients taking raltegravir) mainly involve substitutions at positions 155 (N155 substitution for H) 148 (Q148 substitution for H, K, or R) or 143 (Y143 substitution for C, H, or R), combined with one or more additional mutations (e.g., L74M, E92Q, T97A, E138A/K, G140A/S, V151I, G163R, S230R).

The recombinant viruses with a single primary mutation (Q148H, K or R, or N155H) were characterized by reduced replication ability and reduced sensitivity to raltegravir in vitro. Secondary mutations of the virus further reduced sensitivity to raltegravir, sometimes compensating for the reduced replication ability of the virus.

Mutations associated with the development of resistance to raltegravir can also lead to the formation of resistance to another integrase chain transfer inhibitor elvitegravir. The substitution at position 143 reduces the sensitivity to raltegravir to a greater extent than the sensitivity to elvitegravir, while mutations in E92Q cause greater resistance to elvitegravir than to raltegravir. Viruses with a mutation at position 148 in combination with one or more additional mutations causing resistance to raltegravir can also show clinically significant resistance to dolutegravir.

The effect on cardiac electrophysiologic activity or ECG parameters

In a placebo-controlled clinical trial involving healthy volunteers, a single administration of 1600 mg of raltegravir had no effect on QTc interval duration despite the fact that C_max of raltegravir in plasma was 4 times greater than that of a single dose of 400 mg raltegravir.

Indications

Treatment of HIV-1 infection in combination with other antiretroviral drugs in children aged 2-11 years, both previously receiving and not receiving antiretroviral therapy.

Active ingredient

Raltegravir

How to take, the dosage

Ingestion. Isentress® chewable tablets are prescribed regardless of meals.

The treatment with Isentress® should be given by a physician who has adequate experience in treating HIV infection.

Because the dosage forms of raltegravir are not bioequivalent, chewable tablets should not be replaced with film-coated tablets of 400 mg. No studies of Isentress^® in the form of chewable tablets have been conducted in HIV-infected children aged 12 to 18 years and adults.

The maximum daily dose of chewable tablets is 300 mg twice daily.

The treatment with Isentress^® is in combination with other antiretroviral drugs.

The recommended doses of Isentress^® in the dosage form of chewable tablets for treatment of HIV-1 infection in children aged 2-11 years are calculated by body weight so that the maximum daily dose of raltegravir does not exceed 300 mg twice daily (see Table 1).

Table 1. Recommended doses* of Isentress^® in the dosage form of chewable tablets for children aged 2-11 years.

*Body weight dose recommendations are based tentatively on taking 6 mg/kg/dose 2 times/day.

¹ chewable tablets of 100 mg – can be divided into two halves. However, splitting the tablets into two halves should be avoided if possible.

The dosing schedule must be strictly followed, because the dose of Isentress^® must be adjusted as the child grows.

In adults and children 12 years of age and weighing at least 25 kg, Isentress® Coated tablets 400 mg should be used.

In patients with impaired renal function no dose adjustment is required.

In patients with mild to moderate hepatic impairment no dosage adjustment is required. The safety and efficacy of raltegravir in patients with severe hepatic impairment have not been established. Therefore, caution should be exercised when using Isentress® in patients with severe hepatic dysfunction (see sections “Pharmacological action”, “Pharmacokinetics”, “Cautions”). If there are signs of worsening liver disease in such patients, discontinuation or discontinuation of treatment should be considered.

Interaction

In in vitro studies it was shown that raltegravir is not a substrate of cytochrome P450 isoenzymes and does not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 or CYP3A. In addition, in vitro raltegravir induces CYP3A4 and is not an inhibitor of P-glycoprotein-mediated transport. Based on these data it can be concluded that Isentress^® does not affect pharmacokinetic parameters of drugs that are substrates of the above enzymes or P-glycoprotein.

In vitro and in vivo studies have shown that raltegravir is eliminated primarily by metabolism (glucuronidation) through the UDF-GT1A1-mediated pathway. Although in vitro studies have shown that raltegravir is not an inhibitor of UDP-GT1A1 and 2B7, one clinical study showed some evidence of UDP-GT1A1 inhibition in vivo based on the observed effects on bilirubin glucuronidation. However, it is unlikely that this effect leads to a clinically significant drug interaction.

There has been significant inter- and intraindividual variability in the pharmacokinetics of raltegravir. The following information on drug interactions is based on geometric averages; the effect in an individual patient cannot be accurately predicted.

The effect of raltegravir on the pharmacokinetics of other drugs

In drug interaction studies, raltegravir had no clinically significant effect on the pharmacokinetics of etravirine, maraviroc, tenofovir, hormonal contraceptives, methadone and midazolam.

In some studies, a slight decrease in plasma concentrations of darunavir was observed when Isentress® was used concomitantly with darunavir. The mechanism of this phenomenon is unknown. However, the effect of raltegravir on plasma concentrations of darunavir is not considered clinically significant.

The effect of other drugs on the pharmacokinetics of raltegravir

Caution should be exercised when using Isentress concomitantly^® with strong inducers of UDF-GT1A1 (e.g., rifampicin), given that raltegravir is metabolized primarily by UDF-GT1A1. Rifampicin reduces plasma concentrations of raltegravir. The effect on the efficacy of raltegravir is unknown. Nevertheless, if concomitant use with rifampicin cannot be avoided, the dose of Isentress^® in adults may be doubled. There are no data on concomitant use of Isentress^® and rifampicin in patients under 18 years of age.

The effect of other strong inducers of drug metabolizing isoenzymes, such as phenytoin and phenobarbital, on the UDF-GT1A1 system is unknown. Less potent inducers (e.g., efavirenz, nevirapine, etravirine, rifabutin, GCS, St. John’s wort, pioglitazone) can be used concomitantly with Isentress^® at the recommended dose.

The concomitant use of Isentress^® with strong UDF-GT1A1 inhibitors (e.g., atazanavir) may increase plasma concentrations of raltegravir. Less strong UDF-GT1A1 inhibitors (e.g., indinavir and saquinavir) can also increase plasma concentrations of raltegravir, but to a lesser extent than atazanavir. In addition, tenofovir can increase plasma concentrations of raltegravir, but the mechanism of this effect is unknown.

The safety profile observed in patients who received atazanavir and/or tenofovir is generally identical to that of patients who did not take these drugs, so no dose adjustments are necessary.

The concomitant use of Isentress^® with antacids containing bivalent metal ions may decrease the absorption of raltegravir by chelation, resulting in lower plasma concentrations of raltegravir. Since taking antacids containing aluminum or magnesium 6 hours after taking Isentress® leads to a significant decrease of plasma concentration of raltegravir, concomitant use of Isentress® and antacids containing aluminum or magnesium is not recommended.

The concomitant use of the drug Isentress^® with antacids containing calcium carbonate decreases the plasma concentration of raltegravir, but this interaction is not considered to be clinically significant. Because of this, in concomitant administration of Isentress® with antacids containing calcium carbonate no dose adjustment is required.

The concomitant use of Isentress^® with other drugs that increase the pH values of gastric juice (e.g., omeprazole or famotidine) may increase the absorption rate of raltegravir and, accordingly, the concentration of raltegravir in blood plasma. In a clinical trial, the safety profile in a subgroup of patients taking proton pump inhibitors or histamine H₂-receptor blockers was comparable with the safety profile in a subgroup of patients not taking these drugs. Dose adjustment of Isentress® is not required when concomitantly used with proton pump inhibitors or histamine H₂-receptor blockers.

All drug interaction studies have been performed with adult patients.

Table 2. Pharmacokinetic drug interaction data in adult patients.

Special Instructions

Patients should be informed that current antiretroviral drugs do not cure HIV infection or prevent transmission of HIV to others through blood or sexual contact. During treatment with Isentress^®, patients should continue to observe appropriate safety precautions. Patients should also be informed that they may still develop infections or other conditions common among HIV-infected patients (opportunistic infections). During therapy with Isentress^® it is very important to remain under the care of a physician.

Raltegravir has a relatively low genetic barrier to resistance, so raltegravir should be prescribed in combination with two other active antiretroviral agents, if possible, to increase treatment efficacy and reduce the risk of drug resistance. It is important to explain to patients the need to read the instructions for use before starting therapy with Isentress® and to reread them each time they receive another prescription from their doctor. Patients should be informed to tell their physician if any unusual symptoms occur, and if any known symptom persists or worsens.

Immune reconstitution syndrome

In the initial stages of combination ART, HIV-infected patients with severe immunodeficiency may develop what is known as immune reconstitution syndrome, i.e. an inflammatory response to asymptomatic ongoing or residual opportunistic infections (including cytomegalovirus retinitis, Pneumocystis jiroveci pneumonia, disseminated or focal mycobacterial infections). This may contribute to a worsening of the clinical condition and exacerbation of existing symptoms. Usually such a reaction can be observed in the first weeks or months after the start of combination therapy. Any inflammatory symptoms should be evaluated, and treatment prescribed if necessary.

In the development of immune reconstitution syndrome, autoimmune disorders such as Graves’ disease have been described. The development of these disorders may be seen many months after starting treatment.

Osteonecrosis

While the etiology of this complication is considered to be multifactorial (including GCS therapy, alcohol use, severe immunodeficiency, high body mass index), cases of osteonecrosis have been described, particularly in late stages of HIV infection and/or with long-term use of combination ARV therapy. Patients who have symptoms such as joint pain, stiffness, or limited mobility should see a specialist right away.

Serious skin reactions and hypersensitivity reactions

There have been reports of severe (potentially life-threatening) and fatal adverse skin reactions in patients who have taken Isentress

sup>® as part of combination therapy with other drugs associated with these adverse reactions, such as Stevens-Johnson syndrome and toxic epidermal necrolysis. Hypersensitivity reactions have also been reported, which have manifested as a generalized rash, and occasionally organ dysfunction, including hepatic failure. The use of Isentress^® should be stopped immediately and other drugs suspected of causing such reactions if signs or symptoms of severe skin reactions or hypersensitivity reactions (including but not limited to severe skin rash or rash accompanied by fever, general malaise, weakness, muscle or joint pain, skin blisters, oral lesions, conjunctivitis, facial edema, hepatitis, eosinophilia, angioedema) appear. In these cases, it is necessary to monitor the clinical status, including hepatic aminotransferase activity, and initiate appropriate therapy. Failure to discontinue therapy with Isentress^® or other drugs associated with these adverse reactions in a timely manner after the onset of a severe rash may result in life-threatening reactions.

Myopathy and rhabdomyolysis

The development of myopathy and rhabdomyolysis has been reported. Caution should be exercised when prescribing the drug in patients with a history of myopathy and rhabdomyolysis or with any factors predisposing to their development, particularly in concomitant therapy with drugs that may cause these adverse reactions.

Hepatic impairment

The safety and effectiveness of Isentress^® in patients with severe concomitant liver disease has not been established. Caution should be exercised when prescribing Isentress^® in patients with severe hepatic impairment.

Patients with existing liver dysfunction, including chronic hepatitis, have an increased incidence of hepatic dysfunction on combination ART and should be monitored as standard practice. If such patients show signs of worsening liver disease, discontinuation or discontinuation of treatment should be considered.

Patients with chronic hepatitis B or C who are also receiving combination ART are at risk for severe and potentially fatal liver adverse events.

Skin rash

In patients who have previously received ARV therapy, skin rash is more common with Isentress^® concomitantly with darunavir than with patients using the drugs alone (see section “Side effects”).

Depression

Depression, including suicidal ideation and behavior, has been observed mainly in patients with a history of depression or psychiatric illness. Caution should be exercised when prescribing Isentress^® to patients with a history of depression or psychiatric illness.

Simultaneous use with other medicinal products

Powerful inducers of UDF-GT1A1. Caution should be exercised when prescribing Isentress^® concomitantly with strong inducers of UDF-HT1A1, such as rifampicin, due to the decrease in plasma concentration of raltegravir they cause. If combined therapy with rifampicin and Isentress^® is necessary, the dose of Isentress^® should be doubled in adult patients. There are no data to adjust the doses of the drugs when Isentress^® and rifampicin are used concomitantly in patients under 18 years of age (see section “Drug Interactions”).

Antacids. Concomitant use of Isentress® with antacids containing aluminum or magnesium leads to decreased plasma concentrations of raltegravir.

The concomitant use of Isentress^® with antacids containing aluminum or magnesium is not recommended (see section “Drug Interactions”).

Fructose and sorbitol

The drug Isentress^® in the dosage form of chewable tablets contains fructose and sorbitol. Patients with rare hereditary disorders as fructose intolerance should not take Isentress^®.

Phenylketonuria

The drug Isentress^® in the dosage form of chewable tablets contains phenylalanine as an aspartame flavoring component. Each 25 mg chewable tablet of Isentress^® contains approximately 0.05 mg of phenylalanine and each 100 mg chewable tablet contains approximately 0.10 mg of phenylalanine. Phenylalanine can be harmful to patients with phenylketonuria.

The effect on driving and operating machinery

There have been no studies to study the effect on driving and operating machinery. Taking into account the possibility of dizziness, weakness, drowsiness and blurred vision during treatment with Isentress®

reme caution should be exercised while driving and operating machinery.

Contraindications

With caution:

• myopathy and rhabdomyolysis (including.
• Hepatic impairment
• Severe hepatic impairment
• Simultaneous use with strong inducers of UDF-GT1A1 (rifampicin);
® with antacids containing aluminum or magnesium;
• depression, including suicidal ideation and behavior (observed mainly in patients with a history of depression or psychiatric illness). Caution should be exercised when prescribing Isentress^® in patients with a history of depression or psychiatric illness.

Side effects

The safety profile of Isentress^® is based on pooled safety data from clinical trials involving patients previously treated with antiretroviral therapy (ART) and patients not previously treated with ART. ® and optimized complementary therapy (OCT) and 4.6% in the group of patients receiving placebo and OCT. The rate of therapy withdrawal due to adverse reactions in adult patients not previously receiving ART was 5.0% in the group of patients taking Isentress^® concurrently with emtricitabine and tenofovir and 10.0% in the group of patients taking efavirenz, emtricitabine and tenofovir concurrently.

The adverse events observed in clinical trials, with varying degrees of probability associated with Isentress^® or its combination with another ARV, are presented below.

The adverse events are listed according to system-organ classes and frequency classification: frequent (≥1/100 and < 1/10), infrequent (≥1/1000 and < 1/100).

Infectious and parasitic diseases: infrequent: genital herpes, folliculitis, gastroenteritis, herpes simplex, herpetic infection, shingles, influenza, lymph node abscess, contagious molluscs, nasopharyngitis, upper respiratory tract infection.

Benign, malignant and unspecified neoplasms (including cysts and polyps): infrequent – skin papillomatosis.

Hematopoietic and lymphatic system disorders: infrequent anemia, iron deficiency anemia, lymph node pain, lymphadenopathy, neutropenia, thrombocytopenia¹.

Immune system disorders: infrequent immune reconstitution syndrome, hypersensitivity to the drug, hypersensitivity reactions.

Metabolic disorders: frequent – decreased appetite; infrequent – cachexia, diabetes, dyslipidemia, hypercholesterolemia, hyperglycemia, hyperlipidemia, hyperphagia, increased appetite, polydipsia, fat metabolism disorders.

Psychiatric disorders: Frequent – unusual dreams, insomnia, nightmares, conduct disorder², depression; infrequent – psychiatric disorders, suicide attempts, anxiety, confusion, depressed mood, major depressive disorder, midnight insomnia, mood changes, panic attacks, sleep disorders, suicidal ideas¹, suicidal behavior¹ (especially in patients with a history of psychiatric illness).

Nervous system disorders: Frequent – dizziness, headache, psychomotor hyperreactivity², infrequent – amnesia, carpal tunnel syndrome, cognitive disorders, attention disorders, postural vertigo, dysgeusia, hypersomnia, hypoesthesia, lethargy, memory disorders, migraine, peripheral neuropathy, paresthesias, somnolence, tension headache, tremor, reduced sleep quality.

VIight: infrequent – decrease in visual acuity.

Hearing organ and labyrinth disorders: frequent – vertigo; infrequent – tinnitus.

Cardiovascular system disorders: infrequent – palpitations, sinus bradycardia, ventricular extrasystoles, blood rushes to the face with a feeling of heat, arterial hypertension.

Respiratory system, thorax and mediastinum disorders: infrequently – dysphonia, nasal bleeding, nasal congestion.

Digestive system disorders: frequent – feeling of distention in the abdomen, abdominal pain, diarrhea, flatulence, nausea, vomiting, dyspepsia; infrequent – gastritis, abdominal discomfort, upper abdominal pain, abdominal pain, discomfort in the anus, constipation, dry mouth, discomfort in the epigastric region, erosive duodenitis, belching, gastroesophageal reflux, gingivitis, glossitis, painful swallowing, acute pancreatitis, peptic ulcer, rectal bleeding.

Hepatic and biliary tract disorders: infrequent – hepatitis, hepatitis steatosis, alcoholic hepatitis, liver failure¹.

Skin and subcutaneous tissue disorders: common – skin rash; infrequent – acne, alopecia, acne-like rash, dry skin, erythema, facial lipoatrophy, hyperhidrosis, lipoatrophy, acquired lipodystrophy, lipohypertrophy, night sweats, Prurigo, itching (localized and generalized), macular rash, maculopapular rash, pruritus rash, urticaria, xeroderma, other skin lesions, Stevens-Johnson syndrome¹, drug rash with eosinophilia and systemic symptoms (DRESS syndrome)¹.

Muscular system disorders: infrequent – arthralgia, arthritis, back pain, side pain, myalgia, neck pain, osteopenia, pain in the extremities, osteoporosis, polyarthritis, tendinitis, myopathy, rhabdomyolysis¹.

Renal and urinary tract disorders: infrequent – renal failure, nephritis, nephrolithiasis, nycturia, renal cysts, renal dysfunction, tubulointerstitial nephritis.

Gender and breast disorders: infrequent – erectile dysfunction, gynecomastia, menopausal symptoms.

General disorders: frequent – asthenia, weakness, fever; infrequent – chest discomfort, chills, facial edema, increased adipose tissue, restlessness, malaise, submandibular neoplasm, peripheral edema, pain.

Laboratory and instrumental findings: frequent – increased plasma ALT, AST, pancreatic lipase and amylase activity, increased triglyceride concentration and atypical lymphocyte count; infrequent – decreased absolute plasma neutrophil count; increased plasma ALT, CPK activity, decreased albumin concentration; increased bilirubin, cholesterol, creatinine, glucose concentrations (incl.including fasting), urea nitrogen, HDL cholesterol, LDL cholesterol; increase of INR value; decrease of platelet and leukocyte count in blood; presence of glucose in urine, presence of red blood cells in urine; increase of waist circumference; increase or decrease of body weight.

Injuries, intoxications and complications of manipulation: infrequent – unintentional overdose.

11 Adverse events not related to the use of Isentress^® that were observed in the post-registration period and were not observed in clinical trials.

² One pediatric patient had adverse reactions associated with the drug: Grade 3 psychomotor hyperresponsiveness and conduct disorder; this patient also had insomnia.

In clinical studies, there have been cases of malignancies in patients who have and have not received antiretroviral therapy, when combining Isentress^® with other antiretroviral agents. Characteristics and frequency of malignant neoplasms were consistent with those of patients with severe immunodeficiency. The risk of malignancies in the clinical trials was similar in both the patient groups taking Isentress^® and the patient groups taking the comparison drugs.

In patients taking Isentress^® there was an increase of CPK activity of the 2nd-4th grade. Cases of myopathy and rhabdomyolysis have been observed. In patients with a history of myopathy or rhabdomyolysis or with other risk factors (including concomitant therapy), the drug should be administered with caution.

The development of osteonecrosis has been reported, particularly in patients with established risk factors, late-stage HIV disease, or long-term exposure to combination ART. The frequency of its development is unknown.

In clinical trials in patients previously receiving ART, cutaneous rash, regardless of etiology, was observed more frequently when Isentress^® was used concomitantly with darunavir than when the drugs were used alone. However, the incidence of drug-related skin rash was comparable in these treatment groups. The skin rash was mild to moderate in severity and did not affect continuation of ART. Patients who had not previously received ART were less likely to develop a rash when treated with Isentress^® in combination with emtricitabine and tenofovir than when treated with efavirenz in combination with emtricitabine and tenofovir.

Patients with hepatitis B and/or hepatitis C co-infection

In general, the safety profile of Isentress^® in patients both previously receiving and not receiving ART who were co-infected with chronic (but not acute) active hepatitis B and/or hepatitis C was similar to the safety profile in patients without hepatitis B and/or hepatitis C co-infection, although the rate of ALT and ACT activity deviation was sometimes higher in the hepatitis B and/or hepatitis C co-infected groups.

Children

In clinical studies of the use of raltegravir at recommended doses in combination with other antiretroviral medications in HIV-1-infected children and adolescents 2 to 18 years of age, the frequency, type, and severity of adverse reactions associated with the drug were found to be comparable to those in adult patients. One patient experienced drug-related adverse reactions: grade 3 psychomotor hyperactivity, conduct disorder, and insomnia. Another patient had a grade 2 serious adverse reaction – an allergic rash. Another patient had a grade 4 ACT and grade 3 ALT elevation that was considered serious.

Overdose

No specific symptoms of Isentress® overdose have been identified. Raltegravir was well tolerated in healthy volunteers at 1600 mg once daily and 800 mg twice daily, without any manifestation of toxicity. A single dose of 1800 mg/day in phase II/III studies had no toxic effects. Based on the available data, it can be concluded that raltegravir is well tolerated in doses up to 800 mg 2 times/day, as well as when taken with drugs that increase its exposure by 50-70% (such as tenofovir and atazanavir). Raltegravir has a wide therapeutic range, so the potential for toxic effects from overdose is limited.

Treatment: in case of overdose, standard recommendations should be followed, such as removal of unabsorbed drug from the gastrointestinal tract, monitoring of vital signs, including ECG, prescription of symptomatic therapy. There are no data on the effectiveness of dialysis in Isentress^® overdose.