Lakonivir (Tablets) Instructions for Use

Marketing Authorization Holder

Pharmasintez, JSC (Russia)

ATC Code

J05AG05 (Rilpivirine)

Active Substance

Rilpivirine (Rec.INN registered by WHO)

Dosage Form

Lakonivir

Film-coated tablets, 25 mg: 30 pcs.

Dosage Form, Packaging, and Composition

Film-coated tablets white, round, biconvex, with a white or almost white core on the cross-section.

Excipients : lactose monohydrate – 55.15 mg, low-substituted hypromellose – 5.1 mg, microcrystalline cellulose – 11.5 mg, croscarmellose sodium – 6.05 mg, povidone K30 – 3.25 mg, polysorbate 20 – 0.35 mg, sodium stearyl fumarate – 1.1 mg.

Film coating composition hypromellose E15 – 1.6 mg; lactose monohydrate – 0.88 mg; macrogol 6000 – 0.32 mg; triethyl citrate – 0.24 mg; titanium dioxide – 0.96 mg.

30 pcs. – polymer jars (1) – cardboard packs.
10 pcs. – blister packs (3) – cardboard packs.

Clinical-Pharmacological Group

Antiviral drug active against HIV

Pharmacotherapeutic Group

Antiviral [HIV] agent

Pharmacological Action

Antiviral agent, a diarylpyrimidine non-nucleoside inhibitor of HIV-1 reverse transcriptase. The activity of rilpivirine is mediated by non-competitive inhibition of HIV-1 reverse transcriptase. Rilpivirine does not inhibit human cellular alpha-, beta-, gamma-DNA polymerases.

Rilpivirine is active against laboratory wild-type HIV-1 strains in acutely infected T-cell lines with a mean EC₅₀ for HIV-1/IIIB of 0.73 nM (0.27 ng/ml).

Rilpivirine has antiviral activity against a wide range of HIV-1 group M representatives (subtypes A, B, C, D, E, F, G, H), for which its mean effective dose (EC₅₀) ranges from 0.07 to 1.01 nM (0.03-0.37 ng/ml), and primary group O isolates, for which its mean effective dose (EC₅₀) ranges from 2.88 to 8.45 nM (1.06-3.10 ng/ml).

Rilpivirine has additive antiviral activity in combination with nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) (abacavir, didanosine, emtricitabine, stavudine, tenofovir), with protease inhibitors (amprenavir, atazanavir, darunavir, indinavir, lopinavir, nelfinavir, ritonavir, tipranavir, saquinavir), with non-nucleoside reverse transcriptase inhibitors (NNRTIs) (efavirenz, etravirine, nevirapine), as well as in combination with the fusion inhibitor enfuvirtide and the CCR5 co-receptor antagonist maraviroc. Rilpivirine produces a synergistic or additive antiviral effect in combination with the nucleoside reverse transcriptase inhibitors lamivudine and zidovudine, as well as the integrase inhibitor raltegravir.

Pharmacokinetics

After oral administration, the C_max of rilpivirine in plasma is reached within 4-5 hours. The absolute bioavailability of rilpivirine is unknown. The bioavailability of rilpivirine was approximately 40% lower when the drug was taken on an empty stomach than when taken simultaneously with a normal-calorie meal (533 kcal) or a high-fat meal (928 kcal). When taken with a protein-enriched drink, bioavailability was 50% lower than when taken simultaneously with food.

Plasma protein binding, primarily to albumin, is 99.7%. The distribution of rilpivirine in biological fluids (cerebrospinal fluid, genital tract secretions) has not been studied.

In vitro studies have shown that Rilpivirine undergoes oxidative metabolism mediated by the CYP3A isoenzyme system.

The terminal T_1/2 of rilpivirine is approximately 45 hours. After a single oral dose of ¹⁴C-rilpivirine, approximately 85% and 6.1% of the radiolabeled dose was found in feces and urine, respectively.

The amount of rilpivirine found unchanged in feces averaged 25% of the administered dose. Only a negligible amount of unchanged rilpivirine (less than 1% of the dose) was detected in urine.

Indications

Treatment of human immunodeficiency virus type 1 (HIV-1) infection in adult patients – in combination with other antiretroviral drugs as first-line therapy.

ICD codes

Dosage Regimen

Take Lakonivir orally.

Use only in combination with other antiretroviral agents.

The recommended dose is 25 mg once daily.

Administer the tablet with a meal to ensure adequate absorption.

Do not take with a protein-enriched nutritional drink alone, as this significantly reduces bioavailability.

Swallow the tablet whole with water; do not crush or chew.

If a dose is missed and it is less than 12 hours until the next scheduled dose, skip the missed dose.

If a dose is missed and it is more than 12 hours until the next dose, take the missed dose immediately and then resume the normal schedule.

Do not take a double dose to make up for a missed one.

For patients switching from another NNRTI-based regimen, initiate Lakonivir immediately after discontinuing the previous therapy.

Monitor patients for depressive disorders and immune reconstitution inflammatory syndrome (IRIS).

Adverse Reactions

Digestive system: common – decreased appetite, abdominal pain, vomiting, nausea; uncommon – abdominal discomfort.

Central nervous system: common – depression, insomnia, abnormal dreams, sleep disorder, dizziness, headache; uncommon – depressed mood, drowsiness.

Skin and subcutaneous tissue: common – rash; with combined antiretroviral therapy, lipodystrophy may occur in HIV-infected patients, characterized by loss of subcutaneous fat in the periphery (upper and lower limbs) and facial area, accumulation of adipose tissue in the intraperitoneal and visceral areas, breast hypertrophy, and accumulation of subcutaneous fat in the dorsocervical area (“buffalo hump”).

Immune system: in HIV-infected patients with severe immunodeficiency who have just started combined antiretroviral therapy, an inflammatory response to the presence of opportunistic agents may develop against the background of immune system recovery, with the appearance or exacerbation of symptoms of a previously asymptomatic disease (immune reconstitution syndrome).

Laboratory parameters: common – increased transaminase activity. Cases of decreased hemoglobin, platelet, leukocyte concentration, increased AST, ALT, pancreatic amylase, lipase activity, increased bilirubin, total cholesterol, LDL and triglyceride levels have also been observed. The mean change in fasting total cholesterol concentration was 2 mg/dL, fasting HDL – 4 mg/dL, fasting LDL – 1 mg/dL, and fasting triglycerides – 7 mg/dL. An increase in serum creatinine was observed during the first four weeks of therapy and remained stable up to week 48; the mean change after 48 weeks of therapy was 0.09 mg/dL (range: -0.20 mg/dL to 0.62 mg/dL); in patients with mild or moderate renal impairment, the observed increase in serum creatinine was comparable to the increase in serum creatinine in patients with normal renal function (these changes were considered clinically insignificant).

General reactions: common – fatigue.

Patients co-infected with hepatitis B and/or hepatitis C virus: the frequency of elevated liver enzymes was higher than in patients with HIV infection only. The pharmacokinetic effect of rilpivirine in co-infected patients is comparable to that in patients without co-infection.

Contraindications

Severe hepatic impairment (Child-Pugh class C); children and adolescents under 18 years of age; concomitant use with drugs that significantly reduce the plasma concentration of rilpivirine (as this may lead to loss of virological response or development of resistance to rilpivirine or to the entire class of non-nucleoside reverse transcriptase inhibitors) – anticonvulsants (carbamazepine, oxcarbazepine, phenobarbital, phenytoin), antituberculosis drugs (rifabutin, rifampicin, rifapentine); proton pump inhibitors (esomeprazole, lansoprazole, omeprazole, pantoprazole, rabeprazole), systemic corticosteroids (dexamethasone when taken more than once), St. John’s wort (Hypericum perforatum) preparations; hypersensitivity to rilpivirine.

Use in Pregnancy and Lactation

No adequate and well-controlled clinical or pharmacokinetic studies on the use of rilpivirine during pregnancy have been conducted. Use is only possible in cases where the expected benefit to the mother outweighs the potential risk to the fetus.

Women of childbearing age are advised to use effective contraception during treatment.

It is not known whether Rilpivirine is excreted in human breast milk. Due to the risk of HIV transmission and the possible development of adverse events in breastfed infants, breastfeeding is not recommended during therapy.

In preclinical studies in animals, no signs of embryotoxicity or effects on reproductive function were identified.

Special Precautions

Rilpivirine should be used with caution in combination with drugs that can cause torsades de pointes ventricular tachycardia. Data on the potential interaction between rilpivirine and drugs that prolong the QT interval are limited. A study in healthy volunteers found that Rilpivirine at high doses (75 mg once daily and 300 mg once daily) prolongs the QT interval on the ECG.

Patients should be informed that current antiretroviral therapy cannot cure HIV infection, nor can it prevent the transmission of HIV through blood or sexual contact. Necessary precautions should be taken to prevent HIV infection.

Cases of depressive disorders (mood swings, depression, dysphoria, major depression, behavioral disturbances, negative thoughts, suicidal ideation, suicide attempts) have been reported during the use of rilpivirine. If a connection with rilpivirine intake is proven, the risk versus benefit of continuing therapy should be assessed.

Combined antiretroviral therapy may cause redistribution of subcutaneous adipose tissue (lipodystrophy) in HIV-infected patients. The exact mechanism of occurrence and long-term consequences of this phenomenon are currently unknown. It is assumed that there is a connection between the development of visceral lipomatosis and the use of protease inhibitors, as well as between lipoatrophy and NRTIs. An increased risk of developing lipodystrophy is associated with individual factors such as older age, as well as drug-related factors, such as a longer course of antiretroviral therapy and associated metabolic disorders. Clinical examination of patients should include an assessment of physical signs of subcutaneous fat redistribution.

At the start of antiretroviral therapy, HIV-infected patients with severe immunodeficiency may develop an inflammatory response to the presence of asymptomatic opportunistic agents with the appearance or exacerbation of symptoms of a previously asymptomatic disease (immune reconstitution syndrome), which may require further careful monitoring and treatment. Such reactions are usually observed within the first few weeks after starting treatment. Similar examples include cytomegalovirus retinitis, generalized and/or focal mycobacterial infections, and Pneumocystis pneumonia. Any symptoms of inflammation should be assessed and, if necessary, treatment prescribed.

Effect on ability to drive vehicles and operate machinery

Rilpivirine has a minor effect on the ability to drive vehicles and operate machinery.

Drug Interactions

Rilpivirine is metabolized by CYP3A isoenzymes, so drugs that induce or inhibit CYP3A affect the elimination of rilpivirine.

Concomitant use of rilpivirine and drugs that can induce CYP3A may lead to a decrease in rilpivirine plasma concentration and a reduction in the therapeutic efficacy of rilpivirine.

Concomitant use of rilpivirine and drugs that inhibit CYP3A may lead to an increase in rilpivirine plasma concentration.

Concomitant use of rilpivirine and drugs that increase gastric pH may lead to a decrease in rilpivirine plasma concentration and a possible reduction in the therapeutic efficacy of rilpivirine.

It is not recommended to use Rilpivirine with other NNRTIs, including delavirdine, efavirenz, etravirine, nevirapine.

When rilpivirine is used concomitantly with darunavir/ritonavir, an increase in rilpivirine plasma concentration may be observed due to inhibition of the CYP3A isoenzyme (dose adjustment is not required).

When rilpivirine is used concomitantly with lopinavir/ritonavir, an increase in rilpivirine plasma concentrations may be observed due to inhibition of CYP3A isoenzymes (dose adjustment is not required).

When rilpivirine is used concomitantly with ketoconazole, an increase in rilpivirine plasma concentrations may be observed due to inhibition of CYP3A isoenzymes (dose adjustment is not required).

Rilpivirine should be used with caution concomitantly with histamine H₂-receptor blockers, as this may lead to a significant decrease in rilpivirine plasma concentration due to an increase in gastric pH. Histamine H₂-receptor blockers should be taken at least 12 hours before or 4 hours after taking rilpivirine.

Data on the potential interaction between rilpivirine and drugs that prolong the QT interval are limited. Rilpivirine at high doses (75 mg once daily and 300 mg once daily) has been shown to prolong the QT interval on the ECG. Therefore, Rilpivirine should be used with caution in combination with drugs that can cause torsades de pointes ventricular tachycardia.

Storage Conditions

Store at 2°C (36°F) to 30°C (86°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.