Kaletra, 80 mg/ml+20 mg/ml 5 pcs.

HIV infection

Human acquired immunodeficiency syndrome (HIV infection) in adults and children from 3 years old as part of combination therapy.

Active ingredient

Composition

1 ml of oral solution contains:

the active ingredients:

lopinavir 80 mg and ritonavir 20 mg

excipients:

ethanol,

high fructose corn syrup,

How to take, the dosage

The recommended dose for adults and adolescents is 400/100 mg (5 ml oral solution) 2 times/day with meals. Oral solution may be used in patients who have difficulty swallowing.

Oral solution for children over 2 years of age is indicated at a dose of 230/57.5 mg/m2 2 times/day with meals; the maximum dose is 400/100 mg 2 times/day.
The dose of 230/57.5 mg/m2 may not be sufficient in some children who are concomitantly taking nevirapine or efavirenz. In this case, the dose should be increased to 300/75 mg/m2. Dosing should be done using a dosing syringe.

Interaction

Lopinavir/ritonavir in vitro and in vivo is an inhibitor of CYP3A isoenzyme. Concomitant use of lopinavir/ritonavir and drugs mainly metabolized by CYP3A isoenzyme (e.g. dihydropyridine “slow” calcium channel blockers, HMG-CoA reductase inhibitors, immunosuppressants and phosphodiesterase 5 (PDE-5) inhibitors) may lead to increased plasma concentrations of these drugs, therapeutic or side effects may be enhanced or prolonged. Drugs that are actively metabolized by CYP3A isoenzyme and have high presystemic metabolism, when taken simultaneously with lopinavir/ritonavir more often have a significant increase in AUC (more than 3-fold). Drugs that are contraindicated specifically because of undesirable interactions and the potential for serious side effects are listed under “Contraindications.

Lopinavir/ritonavir is metabolized by the CYP3A isoenzyme. Concomitant use of lopinavir/ritonavir and drugs that induce CYP3A isoenzyme may decrease plasma concentrations of lopinavir and reduce its therapeutic effect, although these changes have not been noted with ketoconazole.

The concomitant use of lopinavir/ritonavir and other drugs that inhibit the CYP3A isoenzyme may increase plasma concentrations of lopinavir.

HIV medications

Nucleoside reverse transcriptase inhibitors (NRTIs)

Stavudine and lamivudine

. No changes in lopinavir pharmacokinetics were observed with concomitant use of lopinavir/ritonavir with stavudine and lamivudine compared with lopinavir/ritonavir monotherapy.

Didanosine

Didanosine is recommended to be taken on an empty stomach; therefore, in combination with didanosine, lopinavir/ritonavir tablets should be taken one hour before or two hours after a meal.

Zidovudine and abacavir

Lopinavir/ritonavir induces glucuronidation, so the drug may decrease plasma concentrations of zidovudine and abacavir. The clinical significance of this potential interaction is unknown.

Tenofovir

A study has shown that lopinavir/ritonavir increases the plasma concentration of tenofovir. The mechanism of this interaction is unknown. Patients taking lopinavir/ritonavir and tenofovir should be monitored for tenofovir-related side effects.

Other NRTIs

An increase in creatine phosphokinase (CPK) activity, myalgia, myositis, and, rarely, rhabdomyolysis have been reported when taking HIV protease inhibitors, especially in combination with NRTIs.

Non-nucleoside reverse transcriptase inhibitors (NNRTIs)

Nevirapine

No changes in lopinavir pharmacokinetics were observed in healthy adult patients during concomitant use of nevirapine and lopinavir/ritonavir. Results from a study involving HIV-positive children showed decreased concentrations of lopinavir during concomitant use with nevirapine. It is believed that the effect of nevirapine on HIV-positive adult patients may be similar to that in children, which may result in decreased lopinavir concentrations. The clinical significance of the pharmacokinetic interaction is unknown.

In patients who have previously received antiretroviral therapy or who have phenotypic or genotypic signs of significant desensitization to lopinavir, increased doses of lopinavir/ritonavir to 500/125 mg twice daily may be required if lopinavir/ritonavir is used concomitantly with nevirapine. Lopinavir/ritonavir in combination with nevirapine should not be used once daily.

Efavirenz

. Increasing the dose of lopinavir/ritonavir tablets to 500/125 mg (two Caletra 200/50 mg tablets + one Caletra 100/25 mg tablet) twice daily has no effect on lopinavir plasma concentrations compared to using lopinavir/ritonavir 400/100 mg twice daily without efavirenz. Increasing the lopinavir/ritonavir tablet dose to 600/150 mg (three (3) 200/50 mg tablets) twice daily when used concomitantly with efavirenz increased plasma lopinavir concentration by approximately 36% and ritonavir concentration by approximately 56%-92% compared to the lopinavir/ritonavir 400/100 mg tablet dose (two (2) 200/50 mg tablets) when taken twice daily without efavirenz (see See “Dosage and administration”).

Efavirenz and nevirapine induce the CYP3A isoenzyme and thus may decrease plasma concentrations of other viral protease inhibitors when used in combination with lopinavir/ritonavir. Simultaneous use of lopinavir/ritonavir with both efavirenz and nevirapine once daily is contraindicated.

Delavirdine

Delavirdine is able to increase plasma concentrations of lopinavir.

HIV protease inhibitors

Amprenavir

Lopinavir/ritonavir can increase amprenavir concentrations (taking amprenavir at a dose of 750 mg twice daily plus lopinavir/ritonavir leads to increased AUC, similar to Cmax, increase in Cmin relative to amprenavir at a dose of 1200 mg twice daily). Concomitant use of lopinavir/ritonavir and amprenavir promotes reduction of lopinavir concentrations (see section “Dosage and administration”). Simultaneous use of lopinavir/ritonavir with amprenavir once daily is contraindicated.

Fosamprenavir

A study has shown that concomitant use of lopinavir/ritonavir with fosamprenavir reduces concentrations of fosamprenavir and lopinavir. Adequate safety and efficacy doses of fosamprenavir and lopinavir/ritonavir in combination have not been established.

Indinavir

Lopinavir/ritonavir may increase indinavir concentrations (when indinavir is combined at a dose of 600 mg twice daily with concomitant lopinavir/ritonavir, a decrease in Cmax, an increase in Cmin compared to taking indinavir three times daily at a dose of 800 mg, with similar AUC observed). The dose of indinavir may need to be reduced when lopinavir/ritonavir is used concomitantly at a dose of 400/100 mg twice daily. Taking lopinavir/ritonavir in combination with indinavir once daily has not been studied.

Nelfinavir

. Lopinavir/ritonavir can increase concentrations of nelfinavir and the nelfinavir metabolite M8 (taking nelfinavir 1000 mg twice daily and lopinavir/ritonavir compared to taking nelfinavir 1250 mg twice daily shows similar AUC, similar Cmax, increased Cmin). Concomitant use of lopinavir/ritonavir and nelfinavir results in decreased lopinavir concentrations (see section “Dosage and administration”). Simultaneous use of lopinavir/ritonavir with nelfinavir once daily is contraindicated.

Ritonavir

When lopinavir/ritonavir was coadministered with an additional 100 mg of ritonavir twice daily, lopinavir AUC increased by 33% and Cmin increased by 64% compared to taking lopinavir/ritonavir at 400/100 mg twice daily.

Saquinavir

. Lopinavir/ritonavir increases saquinavir concentrations (taking saquinavir 800 mg twice daily plus lopinavir/ritonavir versus taking saquinavir 1200 mg three times daily leads to increased AUC, Cmax and Cmin). The dose of saquinavir when used concomitantly with lopinavir/ritonavir 400/100 mg twice daily may need to be reduced. Taking lopinavir/ritonavir in combination with saquinavir once daily has not been studied.

Tipranavir

The concomitant use of tipranavir (500 mg twice daily) with ritonavir (200 mg twice daily) and lopinavir/ritonavir (400/100 mg twice daily) decreases AUC and Cmin of lopinavir by 55% and 70%, respectively. Simultaneous administration of lopinavir/ritonavir and tipranavir with a low dose of ritonavir is contraindicated.

Hepatitis C virus protease inhibitors

Telaprevir

The concomitant use of lopinavir/ritonavir with telaprevir leads to a decrease in the equilibrium concentration of telaprevir without changing the equilibrium concentration of lopinavir.

Boceprevir

The concomitant use of lopinavir/ritonavir with boceprevir leads to a decrease in the equilibrium concentrations of boceprevir and lopinavir. Concomitant use of lopinavir/ritonavir with boceprevir is contraindicated.

Antiviral drugs – CCR5 chemokine receptor inhibitors

Maraviroc

The concomitant use of maraviroc with lopinavir/ritonavir leads to increased concentrations of maraviroc. When used concomitantly with lopinavir/ritonavir at a dose of 400/100 mg twice daily, the dose of maraviroc should be reduced. The dose of maraviroc should be adjusted according to its instructions for use.

Other drugs

The narcotic analgesics

Fentanyl

Because lopinavir/ritonavir inhibits the CYP3A4 isoenzyme, plasma fentanyl concentrations may increase.

When lopinavir/ritonavir and fentanyl are used concomitantly, therapeutic and side effects (including respiratory depression) should be monitored closely.

Antirhythmic agents (bepridil, lidocaine and quinidine)

Concomitant use with lopinavir/ritonavir may increase concentrations of these drugs. Caution is necessary when using these drugs and monitoring therapeutic concentrations if possible.

Digoxin

The literature review showed that concomitant use of ritonavir (300 mg every 12 hours) and digoxin resulted in a significant increase in blood digoxin concentrations. Caution should be exercised when using lopinavir/ritonavir concomitantly with digoxin with monitoring of serum digoxin concentrations.

Drugs prolonging the QT interval

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

Antineoplastic agents (e.g., dasatinib, nilotinib, vincristine, vinblastine)

Their serum concentrations may increase with lopinavir/ritonavir, which may lead to side effects usually associated with these antitumor drugs.

The dose of nilotinib and dasatinib should be adjusted according to the instructions for use of these drugs.

Anticoagulants

Possible effect on warfarin concentrations when used concomitantly with lopinavir/ritonavir. Monitoring of INR (international normalized ratio) is recommended.

Rivaroxaban

The concomitant use of rivaroxaban with lopinavir/ritonavir may cause increased concentrations of rivaroxaban, which may increase the risk of bleeding.

Antidepressants

Bupropion

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

Trazodone

The concomitant use of ritonavir and trazodone may increase trazodone concentrations. Side effects have been observed: nausea, dizziness, arterial hypotension, and fainting. Use trazodone with a CYP3A4 isoenzyme inhibitor such as lopinavir/ritonavir with caution and reducing the dose of trazodone.

Anticonvulsants (phenobarbital, phenytoin, carbamazepine)

It is known that these drugs can induce the CYP3A4 isoenzyme and thus reduce lopinavir concentrations. Simultaneous use of lopinavir/ritonavir once daily in combination with phenobarbital, phenytoin or carbamazepine is contraindicated.

In addition, concomitant use of phenytoin and lopinavir/ritonavir leads to a moderate decrease in equilibrium concentrations of phenytoin. Phenytoin concentrations should be monitored when using the drug concomitantly with lopinavir/ritonavir.

Lamotrigine and valproic acid

Lamotrigine and valproic acid concentrations were decreased when these drugs were used concomitantly with lopinavir/ritonavir. The reduction in lamotrigine concentrations was up to 50%. These drug combinations should be used with caution. If these drugs are used concomitantly with lopinavir/ritonavir, especially during dose selection, it may be necessary to increase the dose of lamotrigine or valproic acid and monitor their plasma concentrations.

Antifungal agents

The serum concentrations of ketoconazole and itraconazole may be increased by lopinavir/ritonavir. It is not recommended to use ketoconazole and itraconazole in high doses (more than 200 mg/day) together with lopinavir/ritonavir.

Voriconazole

A study showed that concomitant use of ritonavir at a dose of 100 mg every 12 hours reduced the equilibrium AUC of voriconazole by an average of 39%; concomitant use of lopinavir/ritonavir and voriconazole is contraindicated.

Gout medications

Concomitant use of colchicine with lopinavir/ritonavir may increase colchicine concentrations. Prescribing and dose selection of colchicine should be done according to its instructions for use.

Antibacterials

Lopinavir/ritonavir may cause a moderate increase in the AUC of clarithromycin. In patients with impaired renal or hepatic function, the dose of clarithromycin should be reduced when used concomitantly with lopinavir/ritonavir.

Antituberculosis drugs

Rifabutin

When rifabutin and lopinavir/ritonavir are used concomitantly for ten days, Cmax and AUC of rifabutin (unchanged drug and active 25-O-desacetyl metabolite) increased 3.5-fold and 5.7-fold, respectively. Based on these data, it is recommended that the dose of rifabutin be reduced by 75% (i.e., taking 150 mg every other day or three times a week) when used with lopinavir/ritonavir. Further reductions in rifabutin dose may be necessary.

Rifampicin

The concomitant use of rifampicin with lopinavir/ritonavir is accompanied by a dose-dependent decrease in lopinavir plasma concentrations compared to lopinavir/ritonavir at the standard dose of 400/100 mg without rifampicin. Use of rifampicin with standard dose lopinavir/ritonavir may lead to loss of virologic response and possible development of resistance to lopinavir/ritonavir or to a class of HIV protease inhibitors or other concomitant antiretrovirals.

Concomitant use of rifampicin with lopinavir/ritonavir (800/200 mg twice daily) reduced plasma concentrations of lopinavir by up to 57% compared to taking lopinavir/ritonavir at a dose of 400/100 mg twice daily without concomitant administration of rifampicin. When rifampicin was used concomitantly with lopinavir/ritonavir at a dose of 400/400 mg twice daily, the corresponding decrease in plasma concentrations of lopinavir was up to 7%.

In studies with higher doses of lopinavir/ritonavir, an increase in ALT and AST activity was noted with concomitant use of rifampicin; this phenomenon may depend on the sequence of dosing.

If concomitant use of lopinavir/ritonavir and rifampicin is necessary, lopinavir/ritonavir should be started at a standard dose of 400/100 mg twice daily approximately 10 days before starting rifampicin, with the lopinavir/ritonavir dose gradually increased. Close monitoring of liver function is necessary.

Antiparasitic agents

Therapeutic concentrations of atovaquone may be reduced when used concomitantly with lopinavir/ritonavir. Increased doses of atovaquone may be necessary.

Glucocorticosteroids (GCS)

Dexamethasone may increase CYP3A4 activity and decrease lopinavir concentrations.

Fluticasone: Concomitant use of lopinavir/ritonavir and fluticasone may significantly increase plasma concentrations of fluticasone and decrease serum concentrations of cortisol. Use should be used with caution. It is recommended that alternatives to fluticasone be considered, especially with long-term use.

Systemic effects of glucocorticosteroids, including Icenko-Cushing’s syndrome and suppression of the adrenal cortex, have been reported when ritonavir is used simultaneously with intranasal and inhaled forms of fluticasone and budesonide.

The concomitant use of lopinavir/ritonavir and fluticasone and other GKS that are metabolized by CYP3A4, such as budesonide, is not recommended unless the potential benefit of such therapy outweighs the risk of systemic corticosteroid effects, including Cushing’s syndrome and inhibition of adrenal cortical function.

Particular caution should be exercised when using lopinavir/ritonavir and any of the inhaled or nasally administered glucocorticosteroids concomitantly.

Dose reduction of glucocorticosteroid should be considered with careful monitoring of local and general reactions or switching to a glucocorticosteroid that is not a substrate for CYP3A4 (e.g., beclomethasone). Also, if glucocorticosteroid therapy is discontinued, the dose should be gradually reduced over an extended period of time.

Slow calcium channel blockers (e.g., felodipine, nifedipine, nicardipine).

Inhibitors with lopinavir/ritonavir may increase serum concentrations.

FDE-5 inhibitors

. Particular caution should be exercised when using sildenafil and tadalafil to treat erectile dysfunction in patients taking lopinavir/ritonavir, as a significant increase in their concentrations and the development of side effects such as hypotension and prolonged erections can be expected when these drugs are taken concurrently.

Sildenafil

The use of sildenafil to treat erectile dysfunction should be cautious at lower doses (25 mg every 48 hours) and side effects should be monitored more frequently.

The use of sildenafil to treat pulmonary arterial hypertension while taking lopinavir/ritonavir is contraindicated.

Tadalafil

Tadalafil should be used cautiously at lower doses (no more than 10 mg every 72 hours) and side effects should be monitored more frequently.

The use of tadalafil to treat pulmonary arterial hypertension while taking lopinavir/ritonavir is not recommended.

Vardenafil

The concomitant use of vardenafil with lopinavir/ritonavir is contraindicated.

Pharmaceuticals of herbal origin

Patients treated with lopinavir/ritonavir should not take preparations containing St. John’s wort at the same time, since this combination may reduce plasma concentrations of lopinavir/ritonavir. This effect may occur due to induction of CYP3A4 isoenzyme and may lead to loss of therapeutic effect and development of resistance.

HMG-CoA reductase inhibitors

Lopinavir/ritonavir can cause significant increases in plasma concentrations of HMG-CoA reductase inhibitors that are metabolized by CYP3A4, such as lovastatin and simvastatin. Increased concentrations of these statins may lead to myopathy, including rhabdomyolysis, so their combination with lopinavir/ritonavir is contraindicated. Rosuvastatin and atorvastatin, whose metabolism is less dependent on CYP3A4 enzyme, should be used with caution in minimal doses together with ritonavir/ lopinavir. When taken in combination with lopinavir/ritonavir, a 4.7-fold and 5.9-fold increase in Cmax and AUC of atorvastatin was observed, respectively, which increases the risk of serious adverse reactions of myopathy and rhabdomyolysis.

There is no evidence of clinically significant interaction of lopinavir/ritonavir with pravastatin. Pravastatin and fluvastatin metabolism is independent of CYP3A4, so they should not interact with lopinavir/ritonavir. If treatment with HMG-CoA reductase inhibitors is indicated while lopinavir/ritonavir is in use, pravastatin or fluvastatin are recommended.

Special Instructions

Hepatic impairment

Lopinavir/ritonavir is mainly metabolized in the liver. Therefore, caution should be exercised when prescribing this drug in patients with mild to moderate hepatic impairment. The use of lopinavir/ritonavir has not been studied in patients with severe hepatic impairment. Pharmacokinetic data suggest that in HIV-positive patients with HCV infection and mild to moderate hepatic impairment, lopinavir plasma concentrations may be increased by about 30% and its binding to plasma proteins decreased. In the presence of hepatitis B or C or a significant increase in aminotransferase activity before initiation of treatment, there is an increased risk of further increases. Cases of liver dysfunction, including lethal outcome, have been reported in clinical practice. They were usually observed in patients with advanced HIV infection and concomitant chronic hepatitis or cirrhosis who received excessive drug therapy. The association of these cases with lopinavir/ritonavir therapy has not been established.

There have been reported cases of increased transaminase activity with or without a concomitant increase in bilirubin concentrations within seven days of starting lopinavir/ritonavir in combination with other antiviral agents. In some cases, liver function abnormalities have been serious, but a causal relationship of such cases to lopinavir/ritonavir therapy has not been established.

In such situations, it is advisable to monitor AST/ALT activity more frequently, especially in the first months after lopinavir/ritonavir administration.

Diabetes mellitus/hyperglycemia

In post-marketing surveillance in HIV-infected patients receiving protease inhibitors, cases of development and decompensation of diabetes mellitus and hyperglycemia have been reported. In some cases, insulin or oral antidiabetic agents had to be prescribed or their doses increased. Sometimes diabetic ketoacidosis developed. In some patients, hyperglycemia persisted after withdrawal of the protease inhibitor. These cases were reported voluntarily, so it was not possible to assess their frequency and relationship to protease inhibitor therapy.

Pancreatitis

The development of pancreatitis has been observed in patients receiving lopinavir/ritonavir, including the occurrence of marked hypertriglyceridemia. Fatal cases have been reported. Although no association of this side effect with lopinavir/ritonavir has been established, a significant increase in triglyceride concentration is a risk factor for pancreatitis. Patients with advanced HIV infection have an increased risk of hypertriglyceridemia and pancreatitis, and patients with a history of pancreatitis have an increased risk of exacerbation during treatment with lopinavir/ritonavir.

Resistance/cross-resistance

Cross-resistance of varying severity has been observed in studies of protease inhibitors. The effect of lopinavir/ritonavir on the efficacy of subsequent therapy with other protease inhibitors is currently being studied.

Hemophilia

In patients with type A and type B hemophilia, cases of bleeding, including spontaneous formation of subcutaneous hematomas and development of hemarthrosis, have been described when treated with protease inhibitors. Additional doses of factor VIII have been administered to some patients. In more than half of the cases described, treatment with protease inhibitors could be continued or resumed. The cause and effect or mechanism of these adverse events during treatment with protease inhibitors has not been established.

Pr interval prolongation

Moderate asymptomatic PR interval prolongation has been reported in some patients while taking lopinavir/ritonavir. Rare cases of grade II and III atrioventricular block have been reported while taking lopinavir/ritonavir in patients with organic heart disease and pre-existing conduction system disorders or in patients taking drugs that prolong PR interval (such as verapamil or atazanavir). In these patients, lopinavir/ritonavir should be used with caution.

The electrocardiogram

The QTcF interval (corrected by Fridericia) was evaluated in a randomized, placebo-controlled crossover study with an active control (moxifloxacin 400 mg once daily) involving 39 healthy adult volunteers. Ten measurements were taken over 12 hours on day 3 of the study. The mean maximum difference in QTcF compared with placebo was 3.6 (6.3) ms and 13.1 (15.8) ms for the 400/100 mg twice daily and 800/200 mg twice daily doses of lopinavir/ritonavir, respectively. The changes observed with the above two dosing regimens were approximately 1.5 and 3 times higher than those observed with the recommended once-daily or twice-daily lopinavir/ritonavir doses in equilibrium. No patients reported an increase in the QTcF >60 ms interval from baseline; the QTcF interval did not exceed a potentially clinically meaningful threshold of 500 ms.

In the same study, patients taking lopinavir/ritonavir also showed a moderate increase in the PR interval on day 3. The maximum PR interval was 286 ms and no development of grade II or III atrial-ventricular block was observed.

The redistribution of fat

With antiretroviral therapy, redistribution/accumulation of fat with deposition in the central parts of the body, back, neck, appearance of “buffalo hump”, reduction of fat deposits in the face and extremities, increase in mammary glands and cushingoid was observed. The mechanism and long-term effects of these adverse events are not known. Their relationship to therapy has not been established.

Elevated lipid concentrations

Lopinavir/ritonavir treatment resulted in increased concentrations of total cholesterol and triglycerides. Triglyceride and cholesterol concentrations should be monitored before starting lopinavir/ritonavir treatment and regularly during therapy. If lipid abnormalities are present, appropriate therapy is indicated.

Contraindications

Cautions

Side effects

Adults

The most common side effects associated with lopinavir/ritonavir administration were diarrhea, nausea, vomiting, hypertriglyceridemia, and hypercholesterolemia. Diarrhea, nausea, and vomiting may occur early in therapy, whereas hypertriglyceridemia and hypercholesterolemia may develop later.

Immune system disorders

Often: hypersensitivity reactions, including urticaria and angioedema; infrequent: 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, bloating, hepatitis, hepatomegaly, cholangitis, liver steatosis; infrequent: constipation, stomatitis, oral mucous membrane ulcers, duodenitis, gastritis, gastrointestinal bleeding, including rectal bleeding, dry mouth, gastric and intestinal ulcers, fecal incontinence.

Nervous system disorders

Frequently: headache, migraine, insomnia, neuropathy, peripheral neuropathy, dizziness, anxiety; infrequently: aguevnia, seizures, tremors, cerebrovascular disorders, sleep disturbance, decreased libido.

Systemic diseases

Often: arterial hypertension; infrequent: atherosclerosis, myocardial infarction, atrioventricular block, tricuspid valve failure, deep vein thrombosis.

Skin and subcutaneous fat disorders

Often: rash, including maculopapular, lipodystrophy, including facial subcutaneous fat depletion, dermatitis, eczema, seborrhea, increased night sweats, itching; infrequent: alopecia, capillaritis, vasculitis.

Musculoskeletal system disorders

Often: musculoskeletal pain, including arthralgia and back pain, myalgia, muscle weakness, muscle spasms; infrequent: rhabdomyolysis, osteonecrosis.

Metabolic and endocrine disorders

Often: hypercholesterolemia, hypertriglyceridemia, weight loss, decreased appetite, diabetes; infrequent: weight gain, lactacidosis, increased appetite, male hypogonadism.

Renal and urinary tract disorders

Often: renal failure; infrequent: hematuria, nephritis.

Reproductive system disorders

Often: erectile dysfunction, amenorrhea, menorrhagia.

Blood and hematopoietic system disorders

Often: anemia, leukopenia, neutropenia, lymphadenopathy.

Sensory organs

Infrequent: vestibular dizziness, tinnitus, visual impairment.

Infections

Very common: upper respiratory tract infections; common: lower respiratory tract infections, skin and subcutaneous fatty tissue infections, including cellulitis, folliculitis and furunculosis.

General

Often: weakness, asthenia.

Changes in laboratory values: increased concentration of glucose, uric acid, total cholesterol, total bilirubin, triglycerides, increased activity of serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma glutamyl transpeptidase (GGTP), lipase, amylase, creatine phosphokinase, decrease inorganic phosphorus concentration, hemoglobin, decrease creatinine clearance.

Children

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

From the laboratory parameters in children the following changes were registered: increase in total bilirubin, total cholesterol, increased amylase activity, increased activity of AST, ALT, neutropenia, thrombocytopenia, increase or decrease in sodium. Individual cases of hepatitis, toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme exudative and bradyarrhythmia have also been reported with lopinavir/ritonavir.

Overdose

There is currently limited clinical experience with acute lopinavir/ritonavir overdose in humans. There is no specific antidote.

The treatment consists of measures aimed at maintaining the body’s life support, including control of vital systems and monitoring the clinical condition of the patient.

If necessary, unabsorbed medications are removed by gastric lavage, for which administration of activated charcoal may be helpful. Since lopinavir/ritonavir is highly bound to plasma proteins, the use of dialysis is not appropriate.