Kaletra^® (Tablets, Solution) Instructions for Use

ATC Code

J05AR10 (Lopinavir and Ritonavir)

Active Substances

Ritonavir (Rec.INN registered by WHO)

Lopinavir (Rec.INN registered by WHO)

Clinical-Pharmacological Group

Antiviral drug active against HIV

Pharmacotherapeutic Group

Antiviral [HIV] agent

Pharmacological Action

A combined antiviral drug.

Lopinavir is an inhibitor of HIV-1 and HIV-2 protease and provides the antiviral activity of this combination. Inhibition of HIV proteases prevents the synthesis of viral proteins and prevents the cleavage of the gag-pol polypeptide, leading to the formation of an immature and non-infectious virus.

Ritonavir inhibits the CYP3A4-mediated metabolism of lopinavir in the liver, leading to an increase in lopinavir plasma concentrations. Ritonavir is also an HIV protease inhibitor.

Pharmacokinetics

Lopinavir is almost completely metabolized by CYP3A isoenzymes. Ritonavir inhibits the metabolism of lopinavir and causes an increase in its plasma concentration. When lopinavir/ritonavir was administered at a dose of 400/100 mg twice daily, the mean steady-state plasma concentrations of lopinavir in HIV-infected patients were 15-20 times higher than those of ritonavir, and the plasma concentration of ritonavir was less than 7% of the concentration when ritonavir was administered at a dose of 600 mg twice daily. The in vitro EC₅₀ of lopinavir is approximately 10 times lower than that of ritonavir. Thus, the antiviral activity of the combination of lopinavir and ritonavir is determined by lopinavir.

When taking 400/100 mg of lopinavir/ritonavir twice daily with food for 3 weeks, the mean C_max was 9.8±3.7 µg/ml and was reached in approximately 4 hours. The steady-state concentration before the morning dose was 7.1±2.9 µg/ml and the minimum concentration (C_min) within the dosing interval was 5.5±2.7 µg/ml. The AUC of lopinavir over 12 hours after drug administration averaged 92.6±36.7 µg×h/ml. The absolute bioavailability of lopinavir in combination with ritonavir in humans has not been established.

At steady state, approximately 98-99% of lopinavir is bound to plasma proteins. Lopinavir binds to alpha₁-acid glycoprotein and albumin, but lopinavir has a higher affinity for alpha₁-acid glycoprotein. At steady state, the binding of lopinavir to plasma proteins remains constant at the concentrations achieved in the blood after administration of lopinavir/ritonavir at a dose of 400/100 mg twice daily.

In vitro studies have shown that Lopinavir undergoes predominantly oxidative metabolism by the cytochrome P450 system in hepatocytes, mainly under the influence of the CYP3A isoenzyme. Ritonavir is a potent inhibitor of the CYP3A isoenzyme, which inhibits the metabolism of lopinavir, leading to increased plasma concentrations of lopinavir. After a single dose of 400/100 mg lopinavir/ritonavir (with labeled ¹⁴C-lopinavir), 89% of the radioactivity was accounted for by the parent drug. At least 13 oxidative metabolites of lopinavir have been identified in humans. Ritonavir is capable of inducing cytochrome P450 isoenzymes, leading to induction of its own metabolism. During long-term use, lopinavir concentrations before the next dose decreased over time and stabilized after approximately 10-16 days.

After administration of 400/100 mg of ¹⁴C-lopinavir/ritonavir, approximately 10.4±2.3% and 82.6±2.5% of the administered dose of ¹⁴C-lopinavir is detected in urine and feces, respectively, after 8 days. Unchanged Lopinavir accounts for 2.2% and 19.8%, respectively. After long-term use, less than 3% of the lopinavir dose is excreted unchanged by the kidneys. The oral clearance of lopinavir is 5.98±5.75 L/h.

Hepatic insufficiency. Lopinavir is metabolized and eliminated primarily by the liver. Combined dosing of lopinavir/ritonavir at 400/100 mg twice daily in patients co-infected with HIV and hepatitis C virus with mild to moderate hepatic impairment resulted in a 30% increase in lopinavir AUC and a 20% increase in C_max compared to HIV-infected patients with normal liver function. The binding of lopinavir to plasma proteins was lower in mild and moderate hepatic impairment compared to control groups (99.09% vs. 99.31%, respectively).

Indications

Treatment of HIV infection in adults and children from 3 years of age as part of combination therapy.

ICD codes

Dosage Regimen

Administer Kaletra^® orally with food to enhance bioavailability.

For treatment-naive adults and adolescents (over 12 years), the standard dose is 400 mg lopinavir/100 mg ritonavir administered twice daily.

For treatment-experienced adults and adolescents where reduced susceptibility is suspected, consider a dose of 600 mg lopinavir/150 mg ritonavir twice daily; this higher dose is not recommended for patients previously treated with non-nucleoside reverse transcriptase inhibitors (NNRTIs).

For pediatric patients (aged 6 months to 12 years), base the dose on body weight or body surface area (BSA) using the oral solution or tablets; do not use once-daily dosing in children.

For children weighing 15 to 40 kg and able to swallow tablets, the recommended dose is 200 mg lopinavir/50 mg ritonavir per square meter of BSA twice daily, not to exceed the adult dose of 400/100 mg.

For the oral solution in children aged 6 months to 12 years, administer based on weight: for 7 to less than 15 kg, give 12 mg lopinavir/3 mg ritonavir per kg twice daily; for 15 to 40 kg, give 10 mg lopinavir/2.5 mg ritonavir per kg twice daily.

Do not administer once-daily dosing to children, adolescents under 18 years, pregnant patients, or treatment-experienced patients.

In patients receiving concomitant efavirenz, nevirapine, or nelfinavir, use the increased dose of 600 mg lopinavir/150 mg ritonavir twice daily; this applies to treatment-naive and treatment-experienced adults and adolescents.

For patients with moderate hepatic impairment (Child-Pugh Class B), consider a dose reduction; the standard dose is not recommended. Contraindicated in severe hepatic impairment (Child-Pugh Class C).

No dose adjustment is required for patients with renal impairment, including those on hemodialysis.

Always use as part of a combination antiretroviral therapy regimen.

Adverse Reactions

Adults

Definition of frequency of adverse reactions: very common (≥1/10), common (≥1/100 but <1/10), uncommon (≥1/1000 but <1/100).

Immune system disorders: common – hypersensitivity reactions, including urticaria and angioedema; uncommon – immune reconstitution syndrome.

Digestive system disorders: very common – diarrhea, nausea; common – vomiting, abdominal pain (upper and lower), gastroenteritis, colitis, dyspepsia, pancreatitis, gastroesophageal reflux, hemorrhoids, flatulence, abdominal distension, hepatitis, hepatomegaly, cholangitis, hepatic steatosis; uncommon – constipation, stomatitis, oral mucosal ulcers, duodenitis, gastritis, gastrointestinal bleeding (including rectal bleeding), dry mouth, gastric and intestinal ulcers, fecal incontinence.

Nervous system disorders: common – headache, migraine, insomnia, peripheral neuropathy, dizziness, anxiety; uncommon – ageusia, seizures, tremor, cerebrovascular disorders, sleep disorders, decreased libido.

Cardiovascular system disorders common – arterial hypertension; uncommon – atherosclerosis, myocardial infarction, AV block, tricuspid valve insufficiency, deep vein thrombosis; frequency unknown – PR interval prolongation.

Skin and subcutaneous tissue disorders common – rash (including maculopapular), dermatitis, eczema, seborrhea, night sweats, pruritus; uncommon – alopecia, capillaritis, vasculitis; frequency unknown – lipodystrophy and subcutaneous fat redistribution.

Musculoskeletal system disorders common – musculoskeletal pain (including arthralgia and back pain), myalgia, muscle weakness, muscle spasms; uncommon – rhabdomyolysis, osteonecrosis.

Metabolism and nutrition disorders common – hypercholesterolemia, hypertriglyceridemia, weight loss, decreased appetite, diabetes mellitus; uncommon – weight gain, lactic acidosis, increased appetite, male hypogonadism; frequency unknown – insulin resistance.

Renal and urinary disorders common – renal failure; uncommon – hematuria, nephritis.

Reproductive system and breast disorders: common – erectile dysfunction, amenorrhea, menorrhagia.

Blood and lymphatic system disorders: common – anemia, leukopenia, neutropenia, lymphadenopathy.

Ear and labyrinth disorders: uncommon – vestibular dizziness, tinnitus, vision disorders.

Infections very common – upper respiratory tract infections; common – lower respiratory tract infections, skin and subcutaneous tissue infections, including cellulitis, folliculitis, furunculosis.

General disorders common – weakness, asthenia.

Changes in laboratory parameters increased concentration of glucose, uric acid, total cholesterol, total bilirubin, triglycerides, increased activity of AST, ALT, GGT, lipase, amylase, CPK, decreased concentration of inorganic phosphorus, hemoglobin, decreased CC.

Children

The profile of adverse effects in children aged 6 months to 12 years was similar to that in adults. Rash, dysgeusia, vomiting, and diarrhea were most commonly observed.

Laboratory parameters in children showed the following changes: increased total bilirubin, total cholesterol, increased amylase activity, increased AST, ALT activity, neutropenia, thrombocytopenia, increased or decreased sodium levels.

Isolated cases of hepatitis, toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme, and bradyarrhythmia have also been reported with the use of lopinavir/ritonavir.

Description of selected adverse effects

HIV-infected patients with severe immune deficiency may develop asymptomatic or residual opportunistic infections during the initiation of combination antiretroviral therapy (cART). Autoimmune disorders (such as diffuse toxic goiter) have also been reported, although the time of onset is more variable—the disease may begin long after the start of treatment.

Cases of osteonecrosis have been noted, especially in patients with a history of risk factors, advanced HIV infection, or after long-term use of antiretroviral therapy. The frequency of their occurrence is unknown.

Contraindications

Severe hepatic impairment; concomitant use of drugs whose clearance is significantly dependent on metabolism via the CYP3A isoenzyme. Such drugs include astemizole, blonanserin, terfenadine, midazolam (for oral administration), triazolam, cisapride, pimozide, salmeterol, sildenafil (only in the treatment of pulmonary hypertension), tadalafil (only in the treatment of pulmonary hypertension), vardenafil, avanafil, voriconazole, ergot alkaloids (e.g., ergotamine and dihydroergotamine, ergometrine and methylergometrine), HMG-CoA reductase inhibitors (lovastatin, simvastatin, atorvastatin), fosamprenavir, alfuzosin, fusidic acid (in the treatment of skin infections), amiodarone, quetiapine; concomitant use with St. John’s wort preparations, boceprevir, simeprevir; concomitant use with high doses of ketoconazole and itraconazole (more than 200 mg/day); concomitant use of the standard dose of the combination with rifampicin; concomitant use of the tipranavir combination with low-dose ritonavir; children under 6 months of age; children under 3 years of age (for dosage forms intended for children over 3 years of age and adults); use of the combination in combination with carbamazepine, phenobarbital or phenytoin; use of the combination in combination with efavirenz, nevirapine, amprenavir or nelfinavir; use of the combination in children and adolescents under 18 years of age; use of the combination during pregnancy; hypersensitivity to lopinavir and/or ritonavir.

With caution

Viral hepatitis B and C; liver cirrhosis; mild and moderate hepatic impairment; increased activity of liver enzymes; pancreatitis; hemophilia A and B; dyslipidemia (hypercholesterolemia, hypertriglyceridemia); elderly patients over 65 years of age; patients with organic heart disease, patients with a history of cardiac conduction disorders or patients taking drugs that prolong the PR interval (such as verapamil or atazanavir), or drugs that prolong the QT interval (pheniramine, quinidine, erythromycin, clarithromycin); concomitant use with drugs for the treatment of erectile dysfunction, namely sildenafil, tadalafil; concomitant use with fentanyl, rosuvastatin, bupropion, inhaled or intranasal corticosteroids (e.g., fluticasone, budesonide), with antiarrhythmic drugs (such as bepridil, lidocaine and quinidine), with digoxin, lamotrigine, valproic acid, bedaquiline, with trazodone.

Use in Pregnancy and Lactation

Available data show that Lopinavir/Ritonavir does not increase the risk of overall serious congenital malformations compared to the baseline incidence of congenital malformations. If necessary, Lopinavir/Ritonavir can be used during pregnancy.

Studies in rats have shown that Lopinavir is excreted in breast milk. It is not known whether the active substances of the combination are excreted in human breast milk. If use during lactation is necessary, breastfeeding should be discontinued.

Use in Hepatic Impairment

The drug should be used with caution in viral hepatitis B and C; liver cirrhosis; mild and moderate hepatic impairment; increased activity of liver enzymes.

The use of lopinavir/ritonavir is contraindicated in patients with severe hepatic impairment.

Use in Renal Impairment

The pharmacokinetics of lopinavir in patients with renal impairment have not been studied. Since the renal clearance of lopinavir and ritonavir is negligible, an increase in their plasma concentration is not expected in patients with renal impairment.

Pediatric Use

Contraindicated for use in children under 3 months of age; in children under 3 years of age (for dosage forms intended for children over 3 years of age and adults).

The use of the Lopinavir/Ritonavir combination once daily in children and adolescents under 18 years of age is contraindicated.

Geriatric Use

The drug should be used with caution in elderly patients (over 65 years of age).

Special Precautions

Pharmacokinetic data indicate that in HIV-positive patients with hepatitis C and mild to moderate hepatic impairment, an increase in lopinavir plasma concentration of approximately 30% is possible, as well as a decrease in its binding to plasma proteins. If the patient has hepatitis B or C or a significant increase in aminotransferase activity before starting treatment, there is an increased risk of their further increase.

Patients with pre-existing liver disorders, including chronic hepatitis, have an increased frequency of liver dysfunction during combination antiretroviral therapy. Therefore, careful monitoring should be carried out in accordance with standard clinical practice. If the patient’s condition worsens, lopinavir/ritonavir therapy should be discontinued.

HIV-infected patients with chronic hepatitis B or C receiving combination antiretroviral therapy are at increased risk of developing serious and potentially fatal adverse effects. They were usually observed in patients with advanced HIV infection and concomitant chronic hepatitis or cirrhosis of the liver receiving excessive drug therapy. A causal relationship of such cases with lopinavir/ritonavir therapy has not been established.

In the post-marketing period, cases of development and decompensation of diabetes mellitus and hyperglycemia have been reported in HIV-infected patients receiving protease inhibitors. To treat these conditions, it was necessary in some cases to prescribe insulin or oral hypoglycemic drugs, or to increase their doses. In some cases, diabetic ketoacidosis developed. In some patients, hyperglycemia persisted after discontinuation of the protease inhibitor. These cases were reported voluntarily, so it is not possible to assess their frequency and relationship with protease inhibitor therapy. When using lopinavir/ritonavir in patients with diabetes mellitus, blood glucose levels should be monitored.

Patients with advanced HIV infection have an increased risk of developing hypertriglyceridemia and pancreatitis, and patients with a history of pancreatitis have an increased risk of its recurrence during treatment with lopinavir/ritonavir. Patients who experience nausea, vomiting, abdominal pain, or abnormal laboratory parameters (e.g., increased lipase or amylase activity) should be examined, and if pancreatitis is confirmed, treatment with this combination should be discontinued.

In patients with hemophilia type A and B, cases of bleeding, including spontaneous subcutaneous hematomas and hemarthrosis, have been described during treatment with protease inhibitors. Some patients were prescribed additional doses of factor VIII. In more than half of the described cases, treatment with protease inhibitors was able to be continued or resumed.

During treatment with Lopinavir/ritonavir, some patients experienced moderate asymptomatic prolongation of the PR interval. Rare cases of second- and third-degree AV block have been reported with lopinavir/ritonavir in patients with organic heart disease and pre-existing cardiac conduction disorders or in patients taking drugs that prolong the PR interval (such as verapamil or atazanavir). Lopinavir/Ritonavir should be used with caution in such patients.

Redistribution/accumulation of adipose tissue with deposition in the central parts of the body, in the back and neck area, the appearance of a “buffalo hump”, a decrease in fat deposits on the face and limbs, breast enlargement and a cushingoid appearance have been observed during antiretroviral therapy. The mechanism and long-term consequences of these adverse events are unknown. Their relationship with Lopinavir/Ritonavir combination therapy has not been established.

A high risk of developing lipodystrophy is associated with individual characteristics, such as old age, concomitant therapy (long-term antiretroviral therapy and associated metabolic disorders). Clinical examination should include assessment of both physical signs of fat redistribution and laboratory parameters (fasting serum lipids and blood glucose levels). Treatment of lipid metabolism disorders should be carried out in accordance with standard clinical practice.

Treatment with lopinavir/ritonavir led to increased concentrations of total cholesterol and triglycerides. Triglyceride and cholesterol concentrations should be monitored before starting treatment with lopinavir/ritonavir and regularly during therapy. If lipid disorders are present, appropriate therapy is indicated. Particular caution should be exercised when prescribing lopinavir/ritonavir to patients with high baseline blood lipid levels and a history of lipid metabolism disorders. Treatment of lipid metabolism disorders should be carried out in accordance with standard clinical practice.

Immune reconstitution syndrome has been observed in patients receiving combination antiretroviral therapy, including with lopinavir/ritonavir. Against the background of immune function recovery at the start of combination antiretroviral therapy, an exacerbation of asymptomatic or residual opportunistic infections (caused by pathogens such as Mycobacterium avium , cytomegalovirus, Pneumocystis jirovecii (Pneumocystis carinii) or Mycobacterium tuberculosis) may occur, which may require additional examination and treatment.

Against the background of the development of immune reconstitution syndrome, the development of autoimmune diseases such as Graves’ disease, polymyositis, and Guillain-Barré syndrome has been observed; however, the time of onset of these phenomena can vary significantly and be several months after the initiation of therapy.

It is known that many factors play a role in the etiology of osteonecrosis (corticosteroid use, alcohol abuse, high BMI, severe immunosuppression, and others). In particular, cases of osteonecrosis have been reported in patients with progressive HIV infection and/or long-term use of combined antiretroviral therapy. Therefore, such patients should be advised to consult a doctor if they experience pain, joint stiffness, and impaired motor function.

Use in elderly patients

The number of patients aged 65 years and older was insufficient to assess possible differences in their response to lopinavir/ritonavir treatment compared to younger patients. Caution should be exercised when using lopinavir/ritonavir in elderly patients, considering the increased frequency of decreased liver, kidney, or heart function, concomitant diseases, and concomitant therapy.

Use in children

The safety and pharmacokinetic profile of lopinavir/ritonavir in children under 6 months of age have not been established. In HIV-infected children aged 6 months to 18 years, the adverse event profile in clinical studies was similar to that in adults.

The use of lopinavir/ritonavir once daily in children is contraindicated.

Interactions

Drugs contraindicated for concomitant use with lopinavir/ritonavir astemizole, blonanserin, terfenadine, midazolam (for oral administration), triazolam, cisapride, pimozide, salmeterol, sildenafil (only when used for the treatment of pulmonary hypertension, see the “Drug Interactions” section), tadalafil (only when used for the treatment of pulmonary hypertension, see the “Drug Interactions” section), vardenafil, avanafil, voriconazole, ergot alkaloids (e.g., ergotamine and dihydroergotamine, ergometrine and methylergometrine), HMG-CoA reductase inhibitors (lovastatin, simvastatin), fosamprenavir, alfuzosin, fusidic acid, amiodarone, quetiapine, St. John’s wort preparations, boceprevir, ketoconazole and itraconazole in high doses (more than 200 mg/day), use of the standard dose of Kaletra^® with rifampicin, use of Kaletra^® and tipranavir with low-dose ritonavir, use of Kaletra^® once daily in combination with carbamazepine, phenobarbital, or phenytoin, use of Kaletra^® once daily in combination with efavirenz, nevirapine, amprenavir, or nelfinavir, simeprevir.

Drugs not recommended for concomitant use with lopinavir/ritonavir concomitant use of lopinavir/ritonavir and fluticasone, as well as other corticosteroids that are metabolized by the CYP3A4 isoenzyme, such as budesonide, except when the potential benefit of such therapy outweighs the risk of systemic corticosteroid effects, including Cushing’s syndrome and adrenal suppression. Concomitant use of rivaroxaban and Kaletra^® may increase the risk of bleeding. Concomitant use of Kaletra^® and colchicine is not recommended due to the potential increase in the neuromuscular toxicity of colchicine (including rhabdomyolysis), especially in patients with renal or hepatic impairment.

Drugs requiring caution during concomitant use with lopinavir/ritonavir verapamil, atazanavir, pheniramine, quinidine, erythromycin, clarithromycin, concomitant use with drugs for the treatment of erectile dysfunction, namely – sildenafil, tadalafil, concomitant use with fentanyl, rosuvastatin, bupropion, concomitant use with antiarrhythmic drugs, such as bepridil, lidocaine and quinidine, concomitant use with digoxin, lamotrigine, valproic acid, trazodone.

Effect on ability to drive vehicles and operate machinery

Caution should be exercised when driving vehicles and engaging in other potentially hazardous activities that require increased concentration and speed of psychomotor reactions during the treatment period. If side effects develop that may affect these abilities (e.g., dizziness), it is recommended to refrain from driving vehicles and operating machinery. Studies on the ability to drive vehicles and operate machinery have not been conducted.

Drug Interactions

Concomitant use of the Lopinavir/Ritonavir combination and drugs that are predominantly metabolized by CYP3A may lead to an increase in the plasma concentration of the other drug, which could enhance its therapeutic and adverse reactions.

The Lopinavir/Ritonavir combination in vivo induces its own metabolism and increases the biotransformation of some drugs metabolized by cytochrome P450 (including the CYP2C9 and CYP2C19 isoenzymes) and glucuronidation. This may lead to a decrease in plasma concentrations and a reduction in the effectiveness of concomitantly used drugs.

Lopinavir/Ritonavir in vitro and in vivo inhibits the CYP3A isoenzyme. Concomitant use of the Lopinavir/Ritonavir combination and drugs metabolized by the CYP3A isoenzymes (including dihydropyridine calcium channel blockers, HMG-CoA reductase inhibitors, immunosuppressants, and PDE-5 inhibitors may lead to an increase in their plasma concentrations and an enhancement or prolongation of the therapeutic effect and side effects.

A significant increase in AUC (≥3 times) during treatment with lopinavir/ritonavir is observed with the concomitant use of drugs that are actively metabolized by the CYP3A isoenzymes and undergo first-pass metabolism in the liver.

Lopinavir/Ritonavir is metabolized by the CYP3A isoenzymes. Concomitant use of lopinavir/ritonavir with inducers of this isoenzyme may lead to a decrease in lopinavir plasma concentrations and its therapeutic effect. Other drugs that inhibit the CYP3A isoenzymes may cause an increase in lopinavir plasma concentrations, although these changes were not noted with concomitant use of ketoconazole.

Lopinavir/Ritonavir has been shown to cause an increase in tenofovir concentrations. The mechanism of interaction is unknown. In patients receiving Lopinavir/Ritonavir concomitantly with tenofovir, monitoring for the possibility of tenofovir-related adverse effects should be conducted.

Cases of increased CPK activity, myalgia, myositis, and rhabdomyolysis (rarely) have been reported with the use of HIV protease inhibitors, especially in combination with NRTIs.

Efavirenz and nevirapine induce the CYP3A isoenzyme and thus may reduce the plasma concentrations of other HIV protease inhibitors when used in combination with lopinavir/ritonavir.

Delavirdine may cause an increase in lopinavir plasma concentrations.

Concomitant therapy with lopinavir/ritonavir and amprenavir causes a decrease in lopinavir concentration.

A study showed that concomitant use of lopinavir/ritonavir with fosamprenavir reduces the concentrations of fosamprenavir and lopinavir. Adequate doses of fosamprenavir and lopinavir/ritonavir in combination with respect to safety and efficacy have not been established. Concomitant use of fosamprenavir and lopinavir/ritonavir is not recommended.

When using lopinavir/ritonavir at a dose of 400/100 mg twice daily, a dose reduction of indinavir may be required. The use of lopinavir/ritonavir in combination with indinavir once daily has not been studied.

Concomitant use of lopinavir/ritonavir with nelfinavir leads to a decrease in lopinavir concentration.

When lopinavir/ritonavir was used concomitantly with an additional dose of ritonavir (100 mg twice daily), an increase in lopinavir AUC by 33% and C_min by 64% was observed compared to those with lopinavir/ritonavir alone at a dose of 400/100 mg twice daily.

Lopinavir/Ritonavir increases the concentration of saquinavir (use of saquinavir at a dose of 800 mg twice daily in combination with lopinavir/ritonavir leads to an increase in AUC, C_max and C_min compared to taking saquinavir at a dose of 1200 mg three times daily). When using lopinavir/ritonavir at a dose of 400/100 mg twice daily, a dose reduction of saquinavir may be required. The use of lopinavir/ritonavir in combination with saquinavir once daily has not been studied.

When tipranavir (500 mg twice daily) is used concomitantly with ritonavir (200 mg twice daily) and lopinavir/ritonavir (400/100 mg twice daily), a decrease in AUC and C_min by 55% and 70%, respectively, occurs. Concomitant use of lopinavir/ritonavir and tipranavir with low-dose ritonavir is contraindicated.

Concomitant use of lopinavir/ritonavir with telaprevir leads to a decrease in C_ss of telaprevir without changing the C_ss of lopinavir. Concomitant use is not recommended.

Concomitant use of lopinavir/ritonavir with boceprevir leads to a decrease in C_ss of boceprevir and lopinavir in plasma. Concomitant use of lopinavir/ritonavir with boceprevir is contraindicated.

Concomitant use of simeprevir with lopinavir/ritonavir may cause an increase in simeprevir plasma concentrations. Concomitant use of lopinavir/ritonavir and simeprevir is contraindicated.

Concomitant use of maraviroc with lopinavir/ritonavir leads to an increase in maraviroc plasma concentrations. When used concomitantly with lopinavir/ritonavir at a dose of 400/100 mg twice daily, the dose of maraviroc should be reduced.

Since Lopinavir/Ritonavir inhibits the CYP3A4 isoenzyme, an increase in fentanyl plasma concentrations is possible. When lopinavir/ritonavir and fentanyl are used concomitantly, therapeutic and adverse effects (including respiratory depression) should be carefully monitored.

When co-administered with lopinavir/ritonavir, concentrations of bepridil, lidocaine, and quinidine may increase. Caution is required when using these drugs; their therapeutic plasma concentrations should be monitored, if possible.

Literature data indicate that concomitant use of ritonavir (300 mg every 12 hours) and digoxin led to a significant increase in digoxin blood concentration. Caution should be exercised when using lopinavir/ritonavir concomitantly with digoxin and digoxin serum concentrations should be monitored.

Under the influence of lopinavir/ritonavir, concentrations of pheniramine, quinidine, erythromycin, clarithromycin may increase with subsequent QT interval prolongation and the development of cardiac adverse events. Particular caution should be exercised when using lopinavir/ritonavir concomitantly with drugs that prolong the QT interval.

An increase in serum concentrations of dasatinib, nilotinib, vincristine, vinblastine may occur when used concomitantly with lopinavir/ritonavir, which may lead to the occurrence of adverse effects characteristic of these anticancer drugs. The dose of nilotinib and dasatinib should be selected in accordance with the instructions for use of these drugs.

An effect on warfarin concentration is possible when used concomitantly with lopinavir/ritonavir.

Concomitant use of rivaroxaban with lopinavir/ritonavir may cause an increase in rivaroxaban plasma concentration, which may lead to an increased risk of bleeding. Concomitant use is not recommended.

In addition, concomitant use of phenytoin and lopinavir/ritonavir leads to a moderate decrease in C_ss of phenytoin. When phenytoin and lopinavir/ritonavir are used concomitantly, phenytoin plasma concentrations should be monitored.

A decrease in concentrations of lamotrigine and valproic acid was observed when used concomitantly with lopinavir/ritonavir; the decrease in lamotrigine concentration reached 50%. These drug combinations should be used with caution. When these drugs are used concomitantly with lopinavir/ritonavir, especially during dose titration, an increase in the dose of lamotrigine or valproic acid may be required, as well as monitoring of their plasma concentrations.

Concomitant use of bupropion with lopinavir/ritonavir decreases the plasma concentrations of bupropion and its active metabolite (hydroxybupropion). If concomitant use of lopinavir/ritonavir with bupropion is necessary, it should be carried out under careful clinical monitoring of the effectiveness of bupropion without exceeding the recommended dose, despite the observed increase in metabolism.

Concomitant use of ritonavir and trazodone may lead to an increase in trazodone concentration. Adverse effects such as nausea, dizziness, decreased blood pressure, and syncope have been observed. Trazodone should be used with caution with a CYP3A4 inhibitor such as Lopinavir/Ritonavir, reducing the dose of trazodone if necessary.

This combination and parenteral midazolam should be used with caution. Midazolam therapy should be conducted in an intensive care unit or similar setting that can provide clinical monitoring and appropriate medical equipment in case of respiratory depression and/or prolonged sedation. Dose adjustment of midazolam is necessary if more than one injection is administered.

When colchicine is used concomitantly with lopinavir/ritonavir, an increase in colchicine plasma concentration is possible. The prescription and dose selection of colchicine should be carried out in accordance with its instructions for use. Concomitant use is not recommended due to the adverse effects of colchicine associated with neuromuscular toxicity (including rhabdomyolysis), especially in patients with renal and hepatic impairment.

Lopinavir/Ritonavir may cause a moderate increase in the AUC of clarithromycin. In patients with impaired renal function (with CrCl <30 ml/min) or hepatic function, the possibility of reducing the dose of clarithromycin when used concomitantly with lopinavir/ritonavir should be considered.

When rifabutin and lopinavir/ritonavir were used concomitantly for 10 days, the C_max and AUC of rifabutin (unchanged drug and active 25-O-desacetyl metabolite) increased by 3.5 and 5.7 times, respectively.

In studies with higher doses of lopinavir/ritonavir when used concomitantly with rifampicin, an increase in ALT and AST activity was noted; this phenomenon may depend on the sequence of dose administration.

A study in healthy volunteers used a single dose of 400 mg of bedaquiline and lopinavir/ritonavir 400/100 mg twice daily for 24 days, which led to a 22% increase in the AUC of bedaquiline.

Interaction studies of delamanid with ritonavir alone have not been conducted. In studies on healthy volunteers, delamanid 100 mg twice daily and Lopinavir/Ritonavir 400/100 mg twice daily were used for 14 days, with a small increase in concentrations of delamanid and the delamanid metabolite (DM-6705) observed. If the use of delamanid and ritonavir is indeed necessary, ECG monitoring should be performed throughout the treatment period with delamanid due to the risk of QTc interval prolongation associated with the DM-6705 metabolite.

A decrease in the therapeutic concentration of atovaquone is possible when used concomitantly with lopinavir/ritonavir. An increase in the dose of atovaquone may be required.

Dexamethasone may cause an increase in CYP3A isoenzyme activity and a decrease in lopinavir concentration. Antiviral activity monitoring should be conducted.

Concomitant use of lopinavir/ritonavir and fluticasone may significantly increase fluticasone plasma concentrations and reduce serum cortisol concentrations. Should be used with caution. Consideration should be given to alternatives to fluticasone, especially if long-term use is necessary.

When ritonavir was used concomitantly with intranasal and inhaled forms of fluticasone and budesonide, systemic effects of corticosteroids have been reported, including Cushing’s syndrome and adrenal suppression. Concomitant use of lopinavir/ritonavir and fluticasone, as well as other corticosteroids that are metabolized by the CYP3A4 isoenzyme, such as budesonide, is not recommended, except when the potential benefit of such therapy outweighs the risk of systemic corticosteroid effects, including Cushing’s syndrome and adrenal suppression.

Particular caution should be exercised when lopinavir/ritonavir and any corticosteroid for inhaled and intranasal use are used concomitantly.

The possibility of reducing the corticosteroid dose with careful monitoring of local and systemic reactions or switching to a corticosteroid that is not a substrate for the CYP3A4 isoenzyme (e.g., beclomethasone) should be considered. In case of discontinuation of corticosteroid therapy, a gradual dose reduction over a long period should be carried out.

An increase in serum concentrations of felodipine, nifedipine, nicardipine may be observed when taking lopinavir/ritonavir. Clinical monitoring should be conducted when used concomitantly with lopinavir/ritonavir.

Particular caution should be exercised when using sildenafil and tadalafil for the treatment of erectile dysfunction in patients taking Lopinavir/Ritonavir. Concomitant use of lopinavir/ritonavir with these drugs may significantly increase their concentrations, which may lead to an increased frequency of adverse effects such as arterial hypotension and prolonged erection.

Concomitant use of preparations containing St. John’s wort is contraindicated in patients receiving treatment with lopinavir/ritonavir, as this combination may contribute to a decrease in lopinavir/ritonavir plasma concentrations. This effect may occur due to induction of the CYP3A4 isoenzyme and may lead to loss of therapeutic effect and development of resistance.

If a patient is already taking St. John’s wort preparations and is prescribed Lopinavir/Ritonavir, then St. John’s wort preparations should be discontinued and the viral load level should be checked. Upon discontinuation of preparations containing St. John’s wort, the plasma concentration of lopinavir/ritonavir may increase. A change in the dose of lopinavir/ritonavir may be required. The inducing effect may persist for at least 2 weeks after cessation of treatment with St. John’s wort preparations. Lopinavir/Ritonavir is recommended to be prescribed 2 weeks after discontinuation of St. John’s wort preparations.

No signs of clinically significant interaction between lopinavir/ritonavir and pravastatin have been identified. The metabolism of pravastatin and fluvastatin does not depend on the CYP3A4 isoenzyme, so no interaction with lopinavir/ritonavir is expected. If treatment with HMG-CoA reductase inhibitors is indicated during the use of lopinavir/ritonavir, then pravastatin or fluvastatin is recommended.

Concentrations of these drugs (e.g., cyclosporine, tacrolimus, and sirolimus) may increase when used concomitantly with lopinavir/ritonavir. More frequent monitoring of therapeutic concentrations is recommended until the blood concentrations of these drugs are stabilized.

It is known that Lopinavir/Ritonavir reduces the plasma concentrations of methadone. Monitoring of methadone plasma concentrations is recommended.

Since the plasma concentrations of ethinyl estradiol may be decreased with the concomitant use of lopinavir/ritonavir and estrogen-containing oral contraceptives or contraceptive patches, alternative or additional contraceptive methods should be used.

When bosentan was used concomitantly with lopinavir/ritonavir, an increase in the C_max and AUC of bosentan by 6 and 5 times, respectively, was observed.

Storage Conditions

Store at 15°C (59°F) to 25°C (77°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.