APREDUD

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT APUTUDE (APRETUDE)

Composition:

Active substance: cabotegravir sodium;

One tablet contains 30 mg of cabotegravir (as cabotegravir sodium);

Excipients: lactose monohydrate, microcrystalline cellulose, hypromellose, sodium starch glycolate (type A), magnesium stearate;

Film coating: Aquarius BP18237 White or Opadry OY-S-28876 White.

**Medicinal form.** Film-coated tablets.

Main physicochemical properties: White, film-coated, oval-shaped tablets with "SV CTV" debossed on one side.

Pharmacotherapeutic group. Antiviral medicinal products. Integrase inhibitors. Cabotegravir. ATC code J05A J04.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action

Cabotegravir inhibits HIV integrase by binding to the integrase active site and blocking the strand transfer step of retroviral deoxyribonucleic acid (DNA) integration, which is critical for the HIV replication cycle.

Pharmacodynamic effects

Antiviral activity in cell culture

Cabotegravir demonstrated antiviral activity against laboratory strains of wild-type HIV-1, with a mean 50% effective concentration (EC50) required to reduce viral replication by 50% of 0.22 nM in peripheral blood mononuclear cells (PBMCs), 0.74 nM in 293T cells, and 0.57 nM in MT4 cells. Cabotegravir showed antiviral activity in cell culture against a panel of 24 clinical isolates of HIV-1 (three in each of clades A, B, C, D, E, F, and G, and three in clade O), with EC50 values against HIV-1 ranging from 0.02 nM to 1.06 nM. EC50 values of cabotegravir against three clinical isolates of HIV-2 ranged from 0.10 nM to 0.14 nM. There are no clinical data available for patients with HIV-2.

Antiviral activity in combination with other antiretrovirals

In vitro combination studies showed that cabotegravir had weak synergistic antiviral activity in combination with nucleoside reverse transcriptase inhibitors (lamivudine, tenofovir disoproxil fumarate, emtricitabine) and additive activity in combination with the non-nucleoside reverse transcriptase inhibitor rilpivirine.

Effect of human serum and serum proteins

In vitro studies showed a 408-fold shift in the IC50 of cabotegravir in the presence of 100% human serum (by extrapolation method), and the protein binding-adjusted IC50 (PA-IC50) in MT4 cells was 102 nM.

Resistance in vitro

Selection from wild-type HIV-1 and activity against resistant strains: During a 112-day passage of the IIIB strain, no viruses with more than a 10-fold increase in cabotegravir EC50 were observed. Further integrase mutations emerged after passaging wild-type HIV-1 (with T124A polymorphism) in the presence of cabotegravir: Q146L (fold change range 1.3–4.6), S153Y (fold change range 2.8–8.4), and I162M (fold change = 2.8). As noted above, the detection of T124A represents selection of a pre-existing minor variant with no differential sensitivity to cabotegravir. No amino acid substitutions in the integrase region were isolated by day 56 during passage of wild-type HIV-1 NL-432 in the presence of cabotegravir at a concentration of 6.4 nM.

Among known tested integrase-resistant mutants, moderate resistance (≥ 5-fold but < 10-fold) was observed for strains E92Q/N155H, G118R, G140S/Q148H, Y143H/N155H, Q148K, Q148R, T66K/L74M, and G140S/Q148K. High resistance (≥ 10-fold) was observed for strains E138K/Q148K, V72I/E138K/Q148K, E138K/Q148R, E138K/G140S/Q148R, L74M/V75A/G140S/Q148H, G140C/Q148R, Q148R/N155H, and G140S/Q148R.

Resistance in vivo

HPTN 083

At the time of primary analysis in the HPTN 083 study, 13 cases of infection were recorded in the cabotegravir group and 39 cases in the tenofovir disoproxil fumarate (TDF)/emtricitabine (FTC) group. In the cabotegravir group, 5 infections occurred during administration of injectable cabotegravir for PrEP, with 4 participants receiving injections on schedule and 1 participant receiving one injection off-schedule. Five infections occurred ≥ 6 months after the last dose of cabotegravir administered for PrEP. Three infections occurred during the oral lead-in period.

HIV genotyping and phenotyping were performed at the first visit when HIV viral load was > 500 copies/mL. Of the 13 infection cases in the cabotegravir group, 4 participants had resistance mutations to integrase strand transfer inhibitors (INSTIs). In the TDF/FTC group, among 4 participants with resistance to nucleoside reverse transcriptase inhibitors (NRTIs) (including 3 with multiclass resistance), three had the M184V/I mutation and one had K65R.

None of the 5 participants infected after a prolonged gap in cabotegravir administration had INSTI resistance mutations. One of these 5 participants could not undergo either genotyping or phenotyping because the HIV-1 RNA level was only 770 copies/mL. One of the other 4 participants could not have integrase phenotyping determined. The remaining 3 participants retained susceptibility to all INSTIs.

Three participants became infected during the oral lead-in period prior to injectable cabotegravir administration. One participant with undetectable plasma cabotegravir levels had no INSTI resistance mutations and was susceptible to all INSTIs. Two participants with detectable plasma cabotegravir concentrations had INSTI resistance mutations. The first participant had the INSTI resistance mutations E138E/K, G140G/S, Q148R, and E157Q. Integrase phenotyping could not be determined. The second participant had the INSTI resistance mutations E138A and Q148R. This virus was resistant to cabotegravir (fold change 5.92) but susceptible to dolutegravir (fold change 1.69).

Five participants became infected with HIV-1 despite receiving cabotegravir injections, with 4 participants receiving injections on schedule and one off-schedule. In two participants, viral load was too low for analysis. A third participant had no INSTI resistance mutations at the first visit with viremia (week 17) but later developed the R263K mutation (at day 112 and 117). Although phenotyping on day 112 could not be determined, phenotyping on day 117 showed that this virus was susceptible to both cabotegravir (fold change 2.32) and dolutegravir (fold change 2.29). A fourth participant had the INSTI resistance mutations G140A and Q148R. Phenotyping showed resistance to cabotegravir (fold change 13) but susceptibility to dolutegravir (fold change 2.09). The fifth participant had no INSTI resistance mutations.

In addition to the 13 new infection cases, one participant was already infected with HIV-1 at study entry and had no INSTI resistance mutations, but the INSTI resistance mutations E138K and Q148K were detected 60 days later. Phenotype could not be determined.

After the primary analysis, expanded retrospective virological testing was conducted to better characterize the timing of HIV infection. As a result, it was determined that among the 13 infected participants who received cabotegravir injections on schedule, one was previously infected.

HPTN 084

At the time of primary analysis in the HPTN 084 study, 4 cases of infection were recorded in the cabotegravir group and 36 cases in the tenofovir disoproxil fumarate (TDF)/emtricitabine (FTC) group.

In the cabotegravir group, 2 infections occurred during the injection period; 3 cabotegravir injections were administered late to one participant, and both participants did not adhere to the oral cabotegravir regimen.

Two infections occurred after the last dose of oral cabotegravir; both participants were non-adherent to the oral drug regimen. The first visit with an HIV-positive test occurred approximately 11 weeks after study entry for one participant and 57 weeks after study entry for the other.

HIV genotyping was performed at the first visit when HIV viral load was > 500 copies/mL (first visit with viremia). HIV genotyping results were available for 3 of the 4 participants in the cabotegravir group. No significant INSTI resistance mutations were detected.

HIV genotyping results were available for 33 of the 36 participants in the TDF/FTC group who became infected. One participant had a significant NRTI resistance mutation (M184V); this participant was also NNRTI-resistant due to the K103N mutation. Nine other participants were NNRTI-resistant (7 had the K103N mutation, alone or in combination with E138A or P225H; 1 had only the K101E mutation; 1 had only the E138K mutation).

After the primary analysis, expanded retrospective virological testing was conducted to better characterize the timing of HIV infection. As a result, it was determined that among the 4 infected participants receiving cabotegravir, one was previously infected.

Effect on electrocardiogram

In a randomized, placebo-controlled, three-period crossover study, 42 healthy volunteers were randomized into 6 sequences and received three oral doses of placebo or cabotegravir 150 mg every 12 hours (mean Cmax at steady state was approximately 2.8-fold and 5.6-fold higher than with oral cabotegravir 30 mg once daily and injectable cabotegravir 600 mg every 2 months, respectively) or a single dose of moxifloxacin 400 mg (active control). After baseline and placebo adjustment, the maximum mean change in time-matched QTc interval corrected by Fridericia’s method (QTcF) with cabotegravir administration was 2.62 msec (upper bound of one-sided 90% confidence interval [CI]: 5.26 msec). Cabotegravir did not prolong the QTc interval over 24 hours after dosing.

Clinical studies

Clinical efficacy

The efficacy of CABENUVA for reducing the risk of HIV-1 infection was evaluated in two randomized (1:1), double-blind, multicenter, two-group, controlled trials: HPTN 083 in HIV-1-uninfected men and transgender women who have sex with men and are at high risk of HIV-1 infection, and HPTN 084 in cisgender women who are HIV-1-uninfected but at risk of infection. The efficacy of CABENUVA was evaluated in comparison with daily oral tenofovir disoproxil fumarate (TDF)/emtricitabine (FTC).

Participants randomized to the CABENUVA group initially took one oral tablet of cabotegravir 30 mg once daily and placebo for approximately 5 weeks, followed by intramuscular injections of CABENUVA (single injection of 600 mg [3 mL] at 1 month, 2 months, and every 2 months thereafter), and took placebo tablets daily. Participants randomized to the TDF/FTC group initially took oral TDF 300 mg/FTC 200 mg and placebo for approximately 5 weeks, followed by daily oral TDF 300 mg/FTC 200 mg, and received intramuscular placebo injections (3 mL of 20% lipid emulsion for injection) at 1 month, 2 months, and every 2 months thereafter.

HPTN 083

In the HPTN 083 non-inferiority study, 4566 cisgender men and transgender women who have sex with men were randomized 1:1 and received investigational cabotegravir (n = 2281) or TDF/FTC (n = 2285) in a blinded manner up to week 153.

At baseline, the mean age of participants was 26 years, 12% were transgender women, 72% were non-White, and 67% were under 30 years of age.

The primary endpoint was the incidence of HIV infection among participants randomized to oral and injectable CABENUVA compared with the TDF/FTC group (adjusted for early discontinuation). The primary analysis demonstrated superior efficacy of CABENUVA compared to TDF/FTC: the risk of HIV infection was reduced by 66%; the hazard ratio (95% CI) was 0.34 (0.18–0.62). A subsequent analysis showed that one participant in the cabotegravir group was previously infected, meaning the risk reduction was 69% compared to the TDF/FTC group (see Table 1).

Table 1. Primary efficacy endpoint: comparison of HIV infection rates in the randomized phase of the HPTN 083 study (modified intent-to-treat population (mITT), expanded retrospective virological testing)

• Following the primary analysis, an expanded retrospective virological testing was conducted to better characterize the timing of HIV infection. As a result, it was determined that among the 13 infected participants who received Apretude, one participant had already been infected previously. The initial risk ratio (95% CI) in the primary analysis is 0.34 (0.18–0.62).

Figure 1. Cumulative frequency of HIV infection cases in the HPTN 083 study

Results across all subgroups were consistent with the overall protective efficacy. The incidence of HIV-1 infection was lower in participants randomized to the CABOTEBRANE group compared to those randomized to the TDF/FTC group (see Table 2).

Table 2. HIV infection incidence in the HPTN 083 study by subgroups (mITT, expanded retrospective virological testing)

Cisgender men who have sex with men (Cis-MSM).
Transgender women who have sex with men (TGW).

HPTN 084

In the HPTN 084 study evaluating superior efficacy, 3224 cisgender women were randomized in a 1:1 ratio and received either the investigational drug cabotegravir (n = 1613) or TDF/FTC (n = 1610) in a blinded manner until week 153.

At baseline, the median age of participants was 25 years; > 99% were non-Caucasian, > 99% were cisgender women, and 49% were aged < 25 years.

The primary endpoint was the incidence of HIV infection among participants randomized to receive oral and injectable administration of Apretude compared to TDF/FTC oral administration (adjusted for early discontinuation). The primary analysis demonstrated superior efficacy of Apretude compared to TDF/FTC: the risk of HIV-1 infection decreased by 88%; the hazard ratio (95% CI) was 0.12 (0.05–0.31). Further analysis showed that in the Apretude group, one participant was already infected at baseline, indicating a 90% reduction in the risk of HIV-1 infection compared to the TDF/FTC group (see Table 3).

Table 3. Primary efficacy endpoint in the HPTN 084 study: comparison of HIV infection rates during the randomized phase of the study (mITT, expanded retrospective virological testing)

• After the primary analysis, an expanded retrospective virological testing was conducted to better characterize the timing of HIV infection. As a result, it was determined that out of 4 infected participants receiving Apretude, one participant had already been infected previously. The initial risk ratio adjusted for early discontinuation (95 % CI) in the primary analysis was 0.12 (0.05–0.31).

Figure 2. Cumulative frequency of HIV infection cases in the HPTN 084 study

Results of pre-specified subgroup analyses were consistent with the overall protective efficacy. In participants randomized to the CABOTEBRUTINIB group, the rate of HIV-1 infection was lower compared to that in participants randomized to the TDF/FTC group (see Table 4).

Table 4. HIV-1 infection rate in the HPTN 084 study by subgroups (mITT, expanded retrospective virological testing)

Children aged 12 years and older with body weight of at least 35 kg

The safety and efficacy of using APRETUDE for pre-exposure prophylaxis (PrEP) of HIV-1 in children aged 12 years and older with body weight of at least 35 kg who are at risk are supported by data from 2 adequate and well-controlled studies of APRETUDE for HIV-1 PrEP in adults. These data are supplemented by safety and pharmacokinetic data from studies in HIV-1-infected adults receiving CABENUVA (CABENUVA) (cabotegravir and rilpivirine, extended-release injectable suspension), as well as in HIV-1-infected children receiving the individual components of CABENUVA in addition to ongoing antiretroviral therapy (see sections "Posology and method of administration", "Undesirable effects", "Pharmacokinetics").

Pharmacokinetics

The pharmacokinetics of cabotegravir are similar in healthy and HIV-infected individuals. The pharmacokinetic variability of cabotegravir ranges from moderate to high. In phase I studies involving healthy volunteers, the between-subject coefficient of variation (CVb%) for AUC, Cmax, and Ctau values ranged from 34% to 91% across different studies. The within-subject variability (CVw%) is lower than the between-subject variability.

Table 5. Pharmacokinetic parameters of cabotegravir after once-daily oral administration and after initial and subsequent (every 2 months) intramuscular injections

• Pharmacokinetic (PK) parameter values were based on individual retrospective assessments from population PK models of participants in phase III HIV treatment trials.
  • tau – dosing interval: 24 hours for oral administration; 1 month for initial injections and 2 months for subsequent intramuscular injections of the long-acting suspension.
    • Pharmacokinetic parameter values during the oral lead-in phase correspond to steady state.
      • Cmax values during the initial injection phase primarily reflect oral administration, as the initial injection was administered on the same day as the last oral dose; however, AUC(0-tau) and Ctau values correspond to the initial injection. In HIV-infected recipients who received the initial injection without prior oral lead-in (n = 110), geometric mean (5th, 95th percentile) Cmax of cabotegravir (1 week after the initial injection) was 1.89 µg/mL (0.438–5.69), and Ctau was 1.43 µg/mL (0.403–3.90).
        • Pharmacokinetic parameter values correspond to steady state.

Absorption

Cabotegravir is rapidly absorbed after oral administration, with a median Tmax of 3 hours following tablet intake. The pharmacokinetics of cabotegravir are dose- and formulation-dependent. Following oral administration of tablet formulations, cabotegravir pharmacokinetics were proportional or slightly less than proportional to doses ranging from 5 mg to 60 mg. With once-daily dosing, steady-state pharmacokinetics are achieved by day 7.

Cabotegravir can be administered regardless of food intake. Food increases the extent of cabotegravir absorption. The bioavailability of cabotegravir is not diet-dependent: a high-fat meal increased AUC(0–∞) and Cmax of cabotegravir by 14% each compared to fasting conditions. These increases are not clinically significant.

The absolute bioavailability of cabotegravir has not been established.

Distribution

In vitro data indicate that cabotegravir is highly bound (approximately >99%) to human plasma proteins. After oral administration of tablets, the mean apparent volume of distribution (Vz/F) in plasma was 12.3 L. In humans, estimated Vc/F of cabotegravir in plasma was 5.27 L and Vp/F was 2.43 L. These volume estimates, together with the assumption of high F, suggest that cabotegravir distributes to some extent into the extracellular space.

Cabotegravir is present in male and female genital tracts following a single 3 mL (600 mg) intramuscular injection, as observed in a study involving healthy volunteers (n = 15). Mean cabotegravir concentrations on day 3 (the earliest tissue PK sampling time) were 0.49 mg/mL in cervical tissue, 0.29 mg/mL in cervicovaginal fluid, 0.37 mg/mL in vaginal tissue, 0.32 mg/mL in rectal tissue, and 0.69 mg/mL in rectal fluid. These concentrations exceed the in vitro PA-IC90 values.

Metabolism

Cabotegravir is primarily metabolized by the enzyme UGT1A1, with minor contribution from UGT1A9. Cabotegravir is the major circulating compound in plasma and accounts for >90% of the total dose of radiolabeled drug in plasma. In humans, following oral administration, cabotegravir is primarily eliminated via metabolism; renal excretion of unchanged cabotegravir is very low (<1% of dose). Forty-seven percent of the total oral dose is excreted in feces as unchanged cabotegravir. It is unknown whether this is entirely or partially due to unabsorbed drug or biliary excretion of the glucuronide conjugate, which may subsequently be hydrolyzed to release the parent compound in the intestinal lumen. Cabotegravir was detected in bile samples from the duodenum. The glucuronic acid metabolite was detected in some, but not all, duodenal bile samples. Twenty-seven percent of the total oral dose is excreted in urine, primarily as glucuronide (75% of total radioactivity in urine, 20% of total dose).

Elimination

The mean terminal half-life of cabotegravir is 41 hours, and the apparent clearance (CL/F) is 0.21 L/hour, as observed after oral administration in healthy volunteers.

Special patient populations

Sex

Population pharmacokinetic analyses did not identify a clinically significant effect of patient sex on cabotegravir exposure. Furthermore, in the HPTN 083 study, no clinically significant differences in plasma cabotegravir concentrations were observed based on sex, including among cisgender men and transgender women receiving cross-sex hormone therapy and those not receiving it. Therefore, dose adjustment based on patient sex is not required.

Race

Population pharmacokinetic analyses did not identify a clinically significant effect of patient race on cabotegravir exposure; therefore, dose adjustment based on race is not required.

Body mass index (BMI)

Population pharmacokinetic analyses did not identify a clinically significant effect of patient BMI on cabotegravir exposure; therefore, dose adjustment based on BMI is not required.

Children (aged >12 to <18 years)

Population pharmacokinetic analyses did not identify clinically significant differences in exposure between HIV-1-infected children and HIV-1-infected and uninfected adult participants in cabotegravir trials; therefore, dose adjustment in children weighing ≥35 kg is not required.

Table 6. Predicted pharmacokinetic parameters following once-daily oral cabotegravir and after initial intramuscular injections and subsequent injections every 2 months in children aged 12 to 18 years (≥35 kg)

• Pharmacokinetic (PK) parameter values were based on population PK modeling in a virtual pediatric population infected with HIV-1, with body weights ranging from 35 to 156 kg.
  • tau – dosing interval: 24 hours for oral administration; 1 month for initial injections and 2 months for subsequent intramuscular injections of the prolonged-release suspension.
    • Pharmacokinetic parameter values during the oral lead-in phase correspond to steady state.
      • Cmax values during the initial injection phase primarily relate to oral administration, as the initial injection was administered on the same day as the last oral dose; however, AUC(0-tau) and Ctau values correspond to the initial injection.
        • Pharmacokinetic parameter values correspond to steady state.

Elderly patients (> 65 years of age)

Population pharmacokinetic analysis did not reveal a clinically significant effect of patient age on cabotegravir exposure.

There is insufficient pharmacokinetic data on cabotegravir in individuals over 65 years of age.

Renal impairment

No clinically significant pharmacokinetic differences were observed between patients with severe renal impairment (with creatinine clearance < 30 mL/min who are not on dialysis) and healthy volunteers. Dose adjustment is not required for individuals with mild to severe renal impairment who are not on dialysis. Studies on the use of cabotegravir in patients on dialysis have not been conducted.

Hepatic impairment

No clinically significant pharmacokinetic differences were observed between patients with moderate hepatic impairment and healthy volunteers. Dose adjustment is not required for patients with mild or moderate hepatic impairment (Child–Pugh class A or B). The effect of severe hepatic impairment (Child–Pugh class C) on the pharmacokinetics of cabotegravir has not been studied.

Individuals infected with hepatitis B or C virus

There are no data on the use of cabotegravir in individuals infected with HBV or HCV from pre-exposure prophylaxis studies.

Polymorphisms of drug-metabolizing enzymes

A meta-analysis of studies involving healthy and HIV-infected individuals showed that, in HIV-infected patients with UGT1A1 genotypes associated with poor metabolism of cabotegravir, there was on average a 1.2-fold increase in steady-state AUC, Cmax, and Ctau of cabotegravir after injection compared to a 1.38-fold average increase after oral administration of cabotegravir. This is comparable to the 1.3–1.5-fold average increase in steady-state AUC, Cmax, and Ctau of cabotegravir observed after oral administration in combined healthy and HIV-infected individuals. These differences are not considered clinically significant. Polymorphisms of the UGT1A9 enzyme were not associated with differences in cabotegravir pharmacokinetics; therefore, dose adjustment is not required for individuals with UGT1A1 or UGT1A9 polymorphisms.

Pediatric population

The pharmacokinetics and dosing recommendations of cabotegravir in children under 12 years of age or with body weight ≤ 35 kg have not been established.

Clinical characteristics.

Indications.

APRETUDE is indicated for adults and children aged 12 years and older with a body weight of at least 35 kg who are at risk for pre-exposure prophylaxis (PrEP) to reduce the risk of sexually acquired HIV-1 infection.

APRETUDE tablets may be used as an oral agent to assess cabotegravir tolerability prior to initiating injectable cabotegravir, or as an oral agent for short-term PrEP in individuals who miss a scheduled cabotegravir injection.

Prior to initiating APRETUDE for HIV-1 pre-exposure prophylaxis, a documented negative HIV-1 test result is required.

Contraindications.

APRETUDE is contraindicated:

• in individuals with unknown or positive HIV-1 status;
• in individuals with known hypersensitivity to cabotegravir or to any of the excipients in either the tablet or injectable formulation of the product;
• in individuals taking rifampicin, rifapentine, phenytoin, phenobarbital, carbamazepine, or oxcarbazepine.

Interaction with other medicinal products and other forms of interaction.

Effect of other medicinal products on the pharmacokinetics of cabotegravir

Cabotegravir is primarily metabolized by uridine diphosphate-glucuronosyltransferase (UGT) 1A1, with some contribution from UGT1A9. Medicinal products that are strong inducers of UGT1A1 or UGT1A9 are expected to reduce plasma concentrations of cabotegravir, leading to reduced efficacy (see section "Contraindications").

Physiologically based pharmacokinetic (PBPK) modeling studies suggest that clinically significant interactions are not expected when cabotegravir is coadministered with medicinal products that inhibit UGT enzymes.

In vitro, cabotegravir was not a substrate of organic anion transporting polypeptides (OATP) 1B1, OATP1B3, OATP2B1, or organic cation transporter (OCT) 1.

Cabotegravir is a substrate of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP); however, due to its high permeability, changes in absorption are not expected when coadministered with inhibitors of P-gp or BCRP.

Effect of cabotegravir on the pharmacokinetics of other medicinal products

In vivo, cabotegravir had no effect on midazolam, a probe substrate for cytochrome P450 (CYP) 3A4. Cabotegravir is not a clinically significant inhibitor of the following enzymes and transporters: CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A4, UGT1A1, UGT1A3, UGT1A4, UGT1A6, UGT1A9, UGT2B4, UGT2B7, UGT2B15, UGT2B17, P-gp, BCRP, bile salt export pump (BSEP), OCT1, OCT2, OATP1B1, OATP1B3, multidrug and toxin extrusion protein (MATE) 1, MATE 2-K, multidrug resistance-associated protein (MRP) 2, and MRP4.

Cabotegravir inhibited organic anion transporters (OAT) 1 (IC50 = 0.81 µM) and OAT3 (IC50 = 0.41 µM) in vitro; however, based on PBPK modeling results, no clinically significant interaction with OAT substrates is expected at clinically relevant concentrations.

In vitro, cabotegravir did not induce the enzymes CYP1A2, CYP2B6, or CYP3A4.

Based on the above data and drug interaction study results, cabotegravir is not expected to affect the pharmacokinetics of drugs that are substrates of the listed enzymes and transporters.

Considering the in vitro and clinical drug interaction profile, cabotegravir is not expected to alter the concentrations of other antiretroviral agents, including protease inhibitors, nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, integrase inhibitors, entry inhibitors, and ibalizumab.

Drug interaction studies with injectable cabotegravir and other medicinal products have not been conducted. The drug interaction data presented in Table 7 were obtained from studies with oral cabotegravir.

Table 7. Drug interactions

Special precautions for use.

General strategy for prevention of HIV-1 infection

APRETUDE is not always effective in preventing HIV-1 infection (see section "Pharmacological properties"). The time to onset of protective effect after initiation of APRETUDE has not been established.

APRETUDE is used for pre-exposure prophylaxis (PrEP) as part of a comprehensive strategy to prevent HIV-1 infection, which also includes other preventive measures (e.g., knowledge of HIV-1 status, regular testing for other sexually transmitted infections, consistent use of condoms).

APRETUDE should be used to reduce the risk of HIV-1 infection in individuals who have tested negative for HIV (see section "Contraindications"). During the period of APRETUDE use for pre-exposure prophylaxis, HIV-negative status must be confirmed periodically (in accordance with local guidelines, but no less frequently than once every 3 months).

More frequent visits and counseling may be beneficial for adolescents to ensure adherence to the dosing schedule and testing.

If clinical symptoms suggestive of acute viral infection occur and recent (<1 month) HIV-1 infection is suspected, HIV-1 status should be reconfirmed.

Potential risk of resistance

There is a potential risk of developing resistance to APRETUDE if an individual becomes infected with HIV-1 before, during, or after discontinuation of APRETUDE (see "Prolonged action of injectable APRETUDE").

To minimize this risk, it is important to conduct regular clinical assessments of HIV risk and frequent testing to confirm HIV-negative status. Individuals with suspected or confirmed HIV-1 infection must initiate antiretroviral therapy (ART) immediately.

For individuals with ongoing risk of HIV infection, alternative forms of PrEP should be considered and initiated within 2 months after the last injection of APRETUDE.

Prolonged action of injectable APRETUDE

Residual concentrations of injectable cabotegravir may persist in the systemic circulation for a prolonged period (up to 12 months or longer). Therefore, physicians should consider the prolonged action of APRETUDE after discontinuation of treatment (see sections "Interaction with other medicinal products and other forms of interaction", "Use during pregnancy or breastfeeding", "Overdose").

Importance of adherence to the dosing schedule

Regular counseling on the importance of strict adherence to the recommended dosing schedule of APRETUDE is necessary to reduce the risk of HIV-1 infection and potential development of resistance.

Hypersensitivity reactions

Hypersensitivity reactions have been reported with other integrase inhibitors. These reactions were characterized by rash, constitutional symptoms, and sometimes organ dysfunction, including liver involvement. Oral lead-in with APRETUDE tablets was used in clinical trials to identify individuals who may be at risk of hypersensitivity reactions. Although no such reactions have been observed to date with APRETUDE, physicians should remain vigilant and discontinue APRETUDE and any other suspected medications immediately if signs or symptoms of hypersensitivity occur (such as severe rash or rash with fever, malaise, fatigue, muscle or joint pain, blistering, oral lesions, conjunctivitis, facial swelling, hepatitis, eosinophilia, or angioedema). Clinical status, including liver aminotransferase levels, should be monitored, and appropriate therapy initiated (see sections "Method of administration and dosage", "Contraindications", and subsections "Clinical studies" and "Prolonged action of injectable APRETUDE" in section "Pharmacological properties").

Hepatotoxicity

Cases of hepatotoxicity have been reported in a limited number of individuals receiving APRETUDE, with or without pre-existing liver disease (see section "Adverse reactions").

If hepatotoxicity is confirmed, APRETUDE should be discontinued, clinical and laboratory monitoring considered, and treatment provided as clinically indicated (see subsection "Prolonged action of injectable APRETUDE").

Interaction with medicinal products

APRETUDE should be used with caution when co-administered with medicinal products that may reduce its exposure (see section "Interaction with other medicinal products and other forms of interaction").

Use in hepatic impairment

See section "Method of administration and dosage" and subsections "Pharmacokinetics" and "Special patient populations" in section "Pharmacological properties".

Use in renal impairment

See section "Method of administration and dosage" and subsections "Pharmacokinetics" and "Special patient populations" in section "Pharmacological properties".

Use in elderly

See section "Method of administration and dosage" and subsections "Pharmacokinetics" and "Special patient populations" in section "Pharmacological properties".

Children

Suicidal ideation and suicide attempts have been reported with cabotegravir, particularly in patients with pre-existing psychiatric disorders (see section "Adverse reactions"). Although clinical trials did not show an increased frequency of psychiatric disorders in children compared to adults, due to the vulnerability of the pediatric population, children should be counselled before initiating and periodically during treatment with APRETUDE, and managed appropriately based on clinical judgment.

Excipients

APRETUDE should not be administered to individuals with rare hereditary conditions of galactose intolerance, total lactase deficiency, or glucose-galactose malabsorption.

APRETUDE contains less than 1 mmol sodium (23 mg) per tablet, i.e., essentially "sodium-free".

Use during pregnancy or breastfeeding

Fertility. There are no data on the effect of cabotegravir on fertility in humans. Animal studies indicate no effect of cabotegravir on fertility in males or females.

Oral administration of cabotegravir to male and female rats for 26 weeks at a dose of 1000 mg/kg/day (more than 30 times the human exposure at the maximum recommended human dose [MRHD] of 30 mg orally or 400 mg intramuscularly [IM]) had no adverse effects on male or female reproductive organs or on spermatogenesis. In rats receiving cabotegravir at doses up to 1000 mg/kg/day, no functional effects on mating or fertility in males or females were observed.

Pregnancy (Category B1 according to fetal risk classification of drugs)

There are insufficient data on the use of cabotegravir in pregnant women. The effect of APRETUDE on pregnancy in women has not been established.

APRETUDE may be used during pregnancy only if the expected benefit outweighs the potential risk to the fetus.

Cabotegravir remains in systemic circulation for 12 months or longer after injection; therefore, potential effects on the fetus during pregnancy should be considered (see section "Special precautions for use").

In pregnant rats, cabotegravir crossed the placenta and was detected in fetal tissues. Cabotegravir was not teratogenic in rats at oral doses up to 1000 mg/kg/day (more than 30 times the human exposure at the MRHD of 30 mg orally or 400 mg IM), but caused delayed parturition associated with reduced offspring survival and viability; when offspring were delivered by cesarean section, no effect on survival at birth was observed. The exposure at the no-observed-adverse-effect level (NOAEL) was at least 11 times higher than human exposure at the MRHD of 30 mg orally or 400 mg IM. The relevance of these findings to human pregnancy is not established.

Breastfeeding period. Based on animal studies, cabotegravir is expected to be excreted in breast milk, although this has not been confirmed in clinical studies. Cabotegravir may be present in breast milk of women for 12 months or longer after the last cabotegravir injection.

Breastfeeding may be recommended only if the expected benefit outweighs the potential risk to the infant.

Ability to influence the speed of reactions when driving or operating machinery.

Studies on the effect of cabotegravir on the ability to drive or operate machinery have not been conducted. When assessing the ability to drive or operate machinery, the patient's clinical condition and the adverse effect profile of APRETUDE should be taken into account.

Method of administration and dosage.

Before initiating APRETUDE, the patient must have a documented negative test result for HIV-1 according to current guidelines.

When prescribing APRETUDE, healthcare providers should carefully select individuals who are willing to adhere to the injection schedule and counsel them on the importance of adhering to scheduled visits for administration of the drug to reduce the risk of acquiring HIV-1 (see section "Special precautions for use").

Adults and children with body weight of at least 35 kg

After discussing with the patient, the physician may administer an immediate injection of APRETUDE (see Table 8 **"**Recommended regimen for intramuscular administration" in the package leaflet of APRETUDE prolonged-release injectable suspension).

Alternatively, APRETUDE tablets may be used as an oral lead-in to assess tolerability of cabotegravir before initiating injectable APRETUDE (see Table 8).

Oral lead-in (film-coated tablets)

If APRETUDE tablets are used as an oral lead-in, it is recommended to take them for approximately one month (at least 28 days) prior to initiating injectable APRETUDE to assess tolerability of cabotegravir.

Table 8. Oral lead-in regimen

Missed Dose

Missed dose of Aprelude film-coated tablets

If a dose of Aprelude tablet is missed, the missed dose should be taken as soon as possible.

Children

The safety and efficacy of Aprelude in children under 12 years of age with body weight less than 35 kg have not been established.

Special patient groups

Elderly patients

Dose adjustment is not required for elderly patients. Data on the use of Aprelude in patients aged ≥ 65 years are limited (see sections "Pharmacokinetics" and "Special patient groups" in the section "Pharmacological properties").

Patients with renal impairment

Dose adjustment is not required in patients with mild to severe renal impairment who are not on dialysis (see sections "Pharmacokinetics" and "Special patient groups" in the section "Pharmacological properties").

Patients with hepatic impairment

Dose adjustment is not required in patients with mild or moderate hepatic impairment (Child-Pugh class A or B). The use of Aprelude in patients with severe hepatic impairment (Child-Pugh class C) has not been studied (see sections "Pharmacokinetics" and "Special patient groups" in the section "Pharmacological properties").

Method of administration

Oral use. Aprelude tablets can be taken independently of food intake.

Children

The safety and efficacy of Aprelude in children under 12 years of age with body weight less than 35 kg have not been established.

Overdose

Symptoms and signs

There have been no reported cases of Aprelude overdose to date.

Treatment

There is no specific antidote for Aprelude overdose. In case of overdose, supportive therapy with appropriate monitoring should be initiated, if necessary. Further management should be provided according to clinical indications or recommendations from the national toxicology center, if available.

Aprelude is highly protein-bound in plasma; therefore, dialysis is unlikely to be beneficial in removing the drug from the body. When treating overdose with injectable Aprelude, the prolonged effect of the drug after injection should be taken into account (see section "Special precautions for use").

Adverse reactions

Clinical trial data

The safety assessment of APRETUDE is based on two phase III clinical trials: HPTN 083 and HPTN 084. In the HPTN 083 study, the median duration of blinded investigational product use was 65 weeks and 2 days (ranging from 1 day to 156 weeks and 1 day), with a total cabotegravir exposure of 3270 person-years. In the HPTN 084 study, the median duration of blinded investigational product use was 64 weeks and 1 day (ranging from 1 day to 153 weeks and 1 day), with a total cabotegravir exposure of 1920 person-years.

Adverse Reactions

The most common adverse reactions reported in more than 10% of participants in each of the experimental groups in studies HPTN 083 and HPTN 084 are presented in Table 9.

Table 9. Most common adverse reactions (reported in ≥ 10% of participants in any experimental group in studies HPTN 083 and HPTN 084)1 by preferred term

• During the phase of study using oral and injectable formulations under blinded conditions.

Adverse reactions are listed in decreasing order of frequency based on data from the cabotegravir group in the HPTN 083 study.

The adverse reactions listed below include those that may be attributed to the use of either oral or injectable formulations of Apretude. In cases where there were differences in the frequency of occurrence between the HPTN 083 and HPTN 084 studies, the highest frequency category is reported.

The most common adverse reactions in the HPTN 083 study were injection site reactions (ISR) (82%), headache (17%), and diarrhea (14%).

The most common adverse reactions in the HPTN 084 study were injection site reactions (38%), headache (23%), and increased transaminase levels (19%).

Adverse reactions identified in these studies are listed below, categorized by MedDRA system organ class and frequency of occurrence.

The frequency of adverse reactions was defined as follows:

very common (≥ 1/10);

common (≥ 1/100, < 1/10);

uncommon (≥ 1/1,000, < 1/100);

rare (≥ 1/10,000, < 1/1,000);

very rare (< 1/10,000);

not known (cannot be estimated from available data).

Table 10. Adverse Reactions¹

• The frequency of reported adverse reactions is based on all recorded events and is not limited to those considered by the investigator to be related to the study drug.
  • Abdominal pain is a MedDRA preferred term encompassing upper abdominal pain and abdominal pain.
    • Rash is a MedDRA high-level term that includes rash, erythematous rash, macular rash, maculopapular rash, morbilliform rash, papular rash, pruritic rash.
      • Pyrexia is a MedDRA high-level term that includes fever and feeling hot. In most cases, pyrexia occurred within one week after injection.
        • Injection site reactions (ISRs) listed in the table were observed in 2 or more participants.

* This adverse reaction was identified from post-marketing reports. The frequency category is based on adverse reactions in individuals who received cabotegravir in randomized clinical trials.

Injection site reactions

In study HPTN 083, 2% of participants discontinued APUTUDE due to injection site reactions (ISRs).

A total of 8900 ISRs were reported following 20,286 injections.

Overall, 2117 participants received at least one injection. Among the 1740 (82%) participants who experienced at least one ISR, the maximum severity of ISRs was mild (Grade 1, 34% of participants), moderate (Grade 2, 46% of participants), or severe (Grade 3, 3% of participants). No participant experienced Grade 4 ISRs. The median duration of all ISRs combined was 4 days. The proportion of participants experiencing ISRs at each visit and the severity of ISRs decreased over time.

In study HPTN 084, no participant discontinued APUTUDE due to ISRs. A total of 1171 ISRs were reported following 13,068 injections.

Overall, 1519 participants received at least one injection. Among the 3578 (38%) participants who experienced at least one ISR, the maximum severity of ISRs was mild (Grade 1, 25% of participants), moderate (Grade 2, 13% of participants), or severe (Grade 3, <1% of participants). No participant experienced Grade 4 ISRs. The median duration of all ISRs combined was 8 days. The proportion of participants experiencing ISRs at each visit and the severity of ISRs decreased over time.

Weight gain

By week 41 and week 97 of study HPTN 083, participants receiving APUTUDE gained a mean of 1.2 kg (interquartile range [IQR] –1.0 to 3.5; n = 1623) and 2.1 kg (IQR –0.9 to 5.9; n = 601), respectively, from baseline; participants in the tenofovir disoproxil fumarate (TDF)/emtricitabine (FTC) group gained a mean of 0.0 kg (IQR –2.1 to 2.4; n = 1611) and 1.0 kg (IQR –1.9 to 4.0; n = 598) from baseline, respectively.

By week 41 and week 97 of study HPTN 084, participants receiving APUTUDE gained a mean of 2.0 kg (IQR 0.0 to 5.0; n = 1151) and 4.0 kg (IQR 0.0 to 8.0; n = 216), respectively, from baseline; participants in the tenofovir disoproxil fumarate (TDF)/emtricitabine (FTC) group gained a mean of 1.0 kg (IQR –1.0 to 4.0; n = 1131) and 3.0 kg (IQR –1.0 to 6.0; n = 218) from baseline, respectively.

Impact on laboratory test results

In studies HPTN 083 and HPTN 084, a similar proportion of patients in the cabotegravir and tenofovir disoproxil fumarate (TDF)/emtricitabine (FTC) groups had elevated liver transaminases (ALT/AST), with maximum increases from baseline predominantly Grade 1 or Grade 2. In study HPTN 083, the number of participants with maximum ALT increases (Grade 3 or 4) from baseline was 40 (2%) versus 44 (2%) in the cabotegravir and TDF/FTC groups, respectively, and Grade 3 or 4 increases in AST were observed in 68 (3%) and 79 (3%) participants, respectively. In study HPTN 084, the number of participants with maximum ALT increases (Grade 3 or 4) from baseline was 12 (<1%) versus 18 (1%) in the cabotegravir and TDF/FTC groups, respectively, and Grade 3 or 4 increases in AST were observed in 15 (<1%) and 14 (<1%) participants, respectively.

In several participants in both the cabotegravir and TDF/FTC groups, adverse events of elevated AST or ALT led to discontinuation of the study drug. In study HPTN 083, the number of participants in the cabotegravir and TDF/FTC groups who discontinued due to elevated ALT was 29 (1%) and 31 (1%), respectively, and due to elevated AST was 7 (<1%) and 8 (<1%), respectively. In study HPTN 084, the number of participants in the cabotegravir and TDF/FTC groups who discontinued due to elevated ALT was 12 (<1%) versus 15 (<1%). There were no cases of discontinuation due to elevated AST.

Children

In children receiving APUTUDE for HIV-1 pre-exposure prophylaxis, safety data were consistent with safety data in adults receiving APUTUDE for HIV-1 PrEP (see sections "Pharmacodynamics" and "Clinical studies" in the "Pharmacological properties" section).

Based on data from two open-label, multicenter clinical studies involving 64 HIV-uninfected adolescents at risk (aged up to 18 years with body weight ≥35 kg at enrollment) who received cabotegravir, no new safety concerns were identified compared to the safety profile established in adults receiving cabotegravir for HIV-1 PrEP in HPTN 083 and HPTN 084.

Based on week 16 data from the MOCHA study involving 23 HIV-infected children (aged ≥12 years with body weight ≥35 kg) receiving background combination antiretroviral therapy, no new safety concerns were identified with the addition of oral cabotegravir followed by injectable cabotegravir (n = 8) compared to the safety profile established in adults receiving cabotegravir (see section "Pharmacodynamics" in the "Pharmacological properties" section).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after medicine authorization is important. It allows continued monitoring of the benefit-risk balance of the medicine. Healthcare professionals and patients, as well as their legal representatives, should report all suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life: 5 years.

Storage conditions: Store at temperatures not exceeding 30 °C. Keep out of the reach of children.

Packaging: Opaque white high-density polyethylene bottle closed with a child-resistant polypropylene cap and a polyethylene protective film. 30 tablets per bottle, 1 bottle per cardboard box.

Prescription status: Prescription only.

Manufacturer: Glaxo Wellcome S.A. / Glaxo Wellcome S.A.

Manufacturer’s address and place of business:

Avda. de Extremadura, 3, Pol. Ind. Allendeduero, 09400 Aranda de Duero, Burgos, Spain

Marketing authorization holder and/or its representative:

LLC "GlaxoSmithKline Pharmaceuticals Ukraine"

Address of the marketing authorization holder and/or its representative:

1-V Pavla Tychyny Avenue, Kyiv, 02152, Ukraine. Tel: (044) 585-51-85, Fax: (044) 585-51-92.

All suspected adverse reactions and lack of efficacy may also be reported to LLC "GlaxoSmithKline Pharmaceuticals Ukraine" via the 24-hour hotline (044) 585-51-85 or by email at [email protected].