APERTURA

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

Composition:

active substance: cabotegravir;

1 vial contains 600 mg of cabotegravir;

excipients: mannitol (E 421), polysorbate 20, macrogol 3350, water for injections.

Pharmaceutical form. Prolonged-release injectable suspension.

Main physicochemical properties: free-flowing suspension, white to pale pink in color.

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 active site of integrase 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 HIV-1 wild type, with a mean concentration of cabotegravir required to reduce viral replication by 50 percent (EC50) 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 the M 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. The 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 antiviral agents

In vitro combination studies showed that cabotegravir exerted weak synergistic antiviral effects in combination with nucleoside reverse transcriptase inhibitors (lamivudine, tenofovir disoproxil fumarate, emtricitabine) and additive effects 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

Isolation from HIV-1 wild type and activity against resistant strains: during a 112-day passage of the IIIB strain, no viruses with more than a 10-fold increase in the EC50 of cabotegravir were observed.

Further integrase mutations emerged after passaging HIV-1 wild type (with polymorphism T124A) in the presence of cabotegravir: Q146L (range of fold change 1.3–4.6), S153Y (range of fold change 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 HIV-1 wild type 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 primary analysis of 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 cases of infection occurred during the administration of injectable cabotegravir for PrEP, of which 4 participants received injections on time and 1 participant received one injection off-schedule. Five cases of infection occurred ≥6 months after the last dose of cabotegravir administered for PrEP. Three cases of infection occurred during the oral lead-in phase.

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 the K65R mutation.

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 RNA-1 level was only 770 copies/mL. In one of the other 4 participants, integrase phenotyping could not be determined. The remaining 3 participants retained susceptibility to all INSTIs.

Three participants were infected during the oral lead-in phase before 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 cabotegravir plasma 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 acquired HIV-1 despite receiving cabotegravir injections, with 4 participants receiving injections on time and one off-schedule. Two participants had viral loads too low for analysis. The third participant had no INSTI resistance mutations at the first viremic visit (week 17) but later developed the R263K mutation (on days 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). The 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 INSTI resistance mutations E138K and Q148K were detected 60 days later. Phenotype determination was not possible.

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 time, one was previously infected.

HPTN 084

At the primary analysis of 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 infection cases occurred during the injection phase; 3 cabotegravir injections were administered late to one participant, and both participants did not adhere to the oral cabotegravir regimen.

Two infection cases occurred after the last dose of oral cabotegravir; both participants did not adhere to the oral regimen. The first HIV-positive visit occurred approximately 11 weeks after enrollment in one participant and 57 weeks after enrollment in 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 resistant to NNRTIs due to the K103N mutation. Nine other participants were resistant to NNRTIs (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-adjusted, the maximum mean change in QTc interval, time-matched, corrected by Fridericia’s method (QTcF), with cabotegravir administration was 2.62 msec (upper limit of 1-sided 90% confidence interval [CI]: 5.26 msec). Cabotegravir did not prolong the QTc interval over 24 hours after dose administration.

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 for HIV-1 infection, and HPTN 084 in HIV-1-uninfected cisgender women at risk for infection. The efficacy of CABENUVA was compared with that of daily oral tenofovir disoproxil fumarate (TDF)/emtricitabine (FTC).

Participants randomized to the CABENUVA group initially took one oral tablet of CABENUVA 30 mg once daily and placebo for approximately 5 weeks, followed by intramuscular injections of CABENUVA (single 600 mg [3 mL] injection at 1 month, 2 months, and every 2 months thereafter), along with daily placebo tablets. 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, 4,566 cisgender men and transgender women who have sex with men were randomized 1:1 and received investigational cabotegravir (n = 2,281) or TDF/FTC (n = 2,285) in a blinded manner until week 153.

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

The primary endpoint was the incidence of HIV infection among participants randomized to oral and injectable CABENUVA compared with those in the oral TDF/FTC group (adjusted for early discontinuation). The primary analysis demonstrated superior efficacy of CABENUVA compared with 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 with the TDF/FTC group (see Table 1).

Table 1. Primary efficacy endpoint: comparison of HIV infection incidence in the randomized phase of the HPTN 083 study (modified intent-to-treat population [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 among the 13 infected participants who received Apretude, one participant had been previously infected. The initial risk ratio (95% CI) in the primary analysis was 0.34 (0.18–0.62).

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

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

Table 2. Incidence of HIV infection in the HPTN 083 study by subgroup (mITT, expanded retrospective virological testing)

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

HPTN 084

In the HPTN 084 trial evaluating superior efficacy, 3224 cisgender women were randomized in a 1:1 ratio to receive either the investigational agent cabotegravir (n = 1613) or TDF/FTC (n = 1610) in a double-blind manner through week 153.

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

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 was reduced by 88%; the hazard ratio (95% CI) was 0.12 (0.05–0.31). A 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 incidence during the randomized phase of the study (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 4 infected participants receiving Apretude, one participant had already been infected earlier. The initial risk ratio adjusted for early discontinuation (95% CI) in the primary analysis was 0.12 (0.05–0.31).

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

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

Results of pre-planned subgroup analyses were consistent with the overall protective effect. The incidence of HIV-1 infection in participants randomized to the CABOTEBRABE group was lower compared to that in participants randomized to the TDF/FTC group (see Table 4).

Table 4. Incidence of HIV-1 infection 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 Apretude for pre-exposure prophylaxis of HIV-1 in adolescents aged 12 years and older with body weight of at least 35 kg who are at risk are supported by data from two appropriate and well-controlled studies of Apretude for PrEP of HIV-1 in adults. These data are supplemented by safety and pharmacokinetic data from studies in HIV-1-infected adults who received CABENUVA (CABENUVA) (cabotegravir and rilpivirine, extended-release injectable suspension), as well as studies in HIV-1-infected children who received the individual components of CABENUVA in addition to ongoing antiretroviral therapy (see sections "Dosage and administration", "Side 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.

b tau – dosing interval: 24 hours for oral administration; 1 month for initial injections and 2 months for subsequent intramuscular injections of the long-acting injectable 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), the geometric mean (5th, 95th percentile) Cmax of cabotegravir (measured 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

The pharmacokinetics of injectable cabotegravir are absorption-limited, as cabotegravir is slowly absorbed into systemic circulation from the gluteal muscle, resulting in sustained plasma concentrations. After a single intramuscular injection of 600 mg, cabotegravir plasma concentrations are detectable as early as day 1, with plasma concentrations at 4 hours post-injection averaging 0.290 mg/mL (exceeding the in vitro PA-IC90 value of 0.166 mg/mL), and peak plasma concentration reached with a median Tmax of 7 days. Target concentrations are achieved after the initial IM injection (see Table 10). Cabotegravir remains detectable in plasma for 52 weeks or longer after a single injection.

After single and multiple IM doses of cabotegravir ranging from 100 to 800 mg, plasma concentrations increased proportionally or slightly less than proportionally to dose.

Distribution

In vitro data indicate that cabotegravir is highly bound (approximately >99%) to human plasma proteins. Following oral tablet administration, the mean apparent volume of distribution (Vz/F) in plasma was 12.3 L. In humans, the 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 intramuscular injection of 3 mL (600 mg), as observed in a study involving healthy volunteers (n = 15). Mean cabotegravir concentrations on day 3 (the earliest tissue PK sampling time point) 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 levels exceed the in vitro PA-IC90 value.

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 total radioactive dose in plasma after administration of radiolabeled drug. In humans, following oral administration, cabotegravir is eliminated predominantly 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 fully 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. Additionally, 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.

Pediatric patients (aged >12 to <18 years)

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

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

• Pharmacokinetic (PK) parameter values were based on population PK modeling in a virtual population of HIV-1-infected children 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 injectable 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.

Pharmacokinetic data in individuals over 65 years of age are limited.

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 patients 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.

Patients infected with hepatitis B or C virus

There are no data on the use of cabotegravir in patients 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 HIV-infected patients with UGT1A1 genotypes associated with poor metabolism of cabotegravir had, 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 healthy and HIV-infected individuals combined. These differences are not considered clinically significant. Polymorphisms of the UGT1A9 enzyme were not associated with differences in cabotegravir pharmacokinetics; therefore, dose adjustment based on UGT1A1 or UGT1A9 enzyme polymorphisms is not required.

Pediatric population

The pharmacokinetics and dosing recommendations for 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) weighing at least 35 kg who are at risk for HIV-1 infection, for pre-exposure prophylaxis (PrEP) to reduce the risk of sexually acquired HIV-1 infection.

Prior to initiating APRETUDE for HIV-1 PrEP, 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 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 cabotegravir pharmacokinetics

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, potentially leading to reduced efficacy (see section "Contraindications").

Physiologically based pharmacokinetic (PBPK) modeling studies indicate that clinically significant interactions are not expected when cabotegravir is co-administered 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 (OCT1).

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 co-administered with inhibitors of P-gp or BCRP.

Effect of cabotegravir on the pharmacokinetics of other medicinal products

In vivo, cabotegravir did not affect 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, drug and toxin extrusion protein (MATE) 1, MATE 2-K, multidrug resistance protein (MRP) 2, and MRP4.

In vitro, cabotegravir inhibited organic anion transporters (OAT) 1 (IC50 = 0.81 µM) and OAT3 (IC50 = 0.41 µM); however, based on physiologically based pharmacokinetic (PBPK) modeling, interactions with OAT substrates at clinically relevant concentrations are not expected.

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

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

Given 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 have not been conducted. The drug interaction data presented in Table 7 were obtained from studies using 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 reduce the risk of 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 acquiring HIV-1 in individuals confirmed to be HIV-negative (see section "Contraindications"). During the period of APRETUDE use for pre-exposure prophylaxis, HIV-negative status must be confirmed periodically (according to local guidelines, but no less frequently than once every 3 months).

More frequent visits and consultations may be beneficial for children 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 should immediately initiate antiretroviral therapy (ART).

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

Prolonged action of injectable APRETUDE

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

Importance of adherence to the schedule

Regular counseling on the importance of strict adherence to the recommended APRETUDE dosing schedule 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 at risk of hypersensitivity reactions. Although no such reactions have been observed to date with APRETUDE, clinicians should remain vigilant and discontinue APRETUDE and any other suspected medications immediately if signs or symptoms of hypersensitivity occur (such as severe rash, rash with fever, malaise, fatigue, muscle or joint pain, blistering, oral mucosal lesions, conjunctivitis, facial swelling, hepatitis, eosinophilia, or angioedema). Clinical status, including liver aminotransferase levels, should be monitored, and appropriate therapy initiated (see sections "Dosage and administration", "Contraindications", and the "Clinical studies" subsection of section "Pharmacological properties").

Hepatotoxicity

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

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

Drug interactions

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 "Dosage and administration" and subsections "Pharmacokinetics" and "Special patient populations" in section "Pharmacological properties".

Use in renal impairment

See section "Dosage and administration" and subsections "Pharmacokinetics" and "Special patient populations" in section "Pharmacological properties".

Use in elderly

See section "Dosage and administration" 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 incidence of psychiatric disorders in children compared to adults, considering the vulnerability of the pediatric population, children should be counseled prior to and periodically during APRETUDE treatment, and managed according to clinical indications.

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 men or women. 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 doses up to 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]) did not show any adverse effects on male or female reproductive organs or on spermatogenesis. In rats receiving cabotegravir up to 1000 mg/kg/day, no functional effect on mating or fertility in males or females was observed.

Pregnancy (Category B1 according to fetal risk classification)

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 potential benefit justifies the potential risk to the fetus.

Cabotegravir is detectable in systemic circulation for up to 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 human exposure at MRHD of 30 mg orally or 400 mg IM), but caused delayed parturition associated with reduced offspring survival and viability; when delivery was 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 MRHD (30 mg orally or 400 mg IM). The relevance of these findings to human pregnancy is not established.

Period of breastfeeding. 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 human breast milk for 12 months or longer after the last cabotegravir injection.

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

Ability to influence the ability to drive and use machines.

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 attending scheduled visits for drug administration in order to reduce the risk of acquiring HIV-1 (see section "Special Warnings and Precautions for Use").

Adults and children with body weight of at least 35 kg

After discussion with the patient, the physician may immediately administer an injection of APRETUDE (see administration recommendations in Table 8).

Alternatively, APRETUDE tablets may be used as an oral lead-in to assess tolerability to cabotegravir prior to initiating injectable APRETUDE.

Initial Injections

The recommended initial dose of APRETUDE is a single intramuscular injection of 3 mL (600 mg). If oral lead-in was used, the first injection should be scheduled on the last day of oral dosing or within the following 3 days.

One month later, a second intramuscular injection of 3 mL (600 mg) should be administered. The second initial injection of 3 mL (600 mg) may be given up to 7 days before or up to 7 days after the scheduled administration date.

Maintenance Injections

After the second initial injection, the recommended dose of APRETUDE is 3 mL (600 mg) as a single intramuscular injection every 2 months. The injection may be administered up to 7 days before or up to 7 days after the scheduled administration date.

Table 8. Recommended Schedule for Intramuscular Administration

Missed dose

Missed administration of the long-acting injectable suspension of APRETUDE

Strict adherence to the injection schedule is strongly recommended.

Individuals who miss a scheduled injection visit should undergo repeat clinical evaluation and HIV testing to confirm that continuation of PrEP remains appropriate. Guidance on dosing after a missed injection is provided in Table 9.

If a deviation of more than 7 days from the scheduled injection visit cannot be avoided, APRETUDE tablets (30 mg) may be taken orally once daily instead of one scheduled injection.

If oral APRETUDE for PrEP is continued for more than two months, an alternative regimen is recommended.

The first oral dose for PrEP should be taken approximately two months (±7 days) after the last APRETUDE injection. Resumption of injectable dosing should be scheduled on the last day of oral PrEP or within the following 3 days, as outlined in Table 9.

Table 9. Recommendations for injectable dosing after missed injections or after taking APRETUDE tablets instead of an injection

Children

The safety and efficacy of APRETUDE in children under 12 years of age and weighing less than 35 kg have not been established.

Special patient groups

Elderly patients

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

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 "Pharmacological properties" section).

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 APRETUDE in patients with severe hepatic impairment (Child–Pugh class C) has not been studied (see sections "Pharmacokinetics" and "Special patient groups" in the "Pharmacological properties" section).

Method of administration

For intramuscular (IM) injection only, administered in the gluteal area. Must not be administered intravenously.

Administration of APRETUDE should be performed by a healthcare professional. Instructions for use of the medicine are provided in the annex "Instructions for use".

When administering APRETUDE by injection, healthcare professionals should consider the patient's body mass index (BMI) to ensure that the needle is of sufficient length to reach the gluteal muscle.

Children

The safety and efficacy of APRETUDE in children under 12 years of age and weighing less than 35 kg have not been established.

Overdose

Symptoms and signs

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

Treatment

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

APRETUDE is highly protein-bound in plasma; therefore, dialysis is unlikely to aid in drug elimination. When managing overdose with injectable APRETUDE, the prolonged duration of action following 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 study 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 patient-years. In the HPTN 084 study, the median duration of blinded study 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 patient-years.

Adverse Reactions

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

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

• During the phase of the study using oral and injectable drug in a blinded manner.

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 include those that may be attributed to the use of oral or injectable forms of Apretude. In cases of differences in the frequency of occurrence between the HPTN 083 and HPTN 084 studies, the highest frequency category is indicated.

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, classified by MedDRA system organ class and frequency of occurrence.

Frequency of adverse reactions was defined as follows:

very common (≥ 1/10);

common (≥ 1/100, < 1/10);

uncommon (≥ 1/1000, < 1/100);

rare (≥ 1/10000, < 1/1000);

very rare (< 1/10000);

not known (cannot be estimated from available data).

Table 11. 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 preferred term encompassing rash, erythematous rash, macular rash, maculopapular rash, morbilliform rash, papular rash, pruritic rash.
      • Pyrexia is a MedDRA preferred term encompassing fever and feeling hot. In most cases, pyrexia was observed within one week after injection.
        • Injection site reactions (ISRs) listed in the table were reported 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 8,900 ISRs were reported following 20,286 injections.

Overall, 2,117 participants received at least one injection. Among the 1,740 (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 had 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 1,171 ISRs were reported following 13,068 injections.

Overall, 1,519 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 had 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 experienced a mean weight increase of 1.2 kg (interquartile range [IQR] from –1.0 to 3.5; n = 1,623) and 2.1 kg (IQR from –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 from –2.1 to 2.4; n = 1,611) and 1.0 kg (IQR from –1.9 to 4.0; n = 598), respectively, from baseline.

By Week 41 and Week 97 of study HPTN 084, participants receiving APUTUDE experienced a mean weight increase of 2.0 kg (IQR from 0.0 to 5.0; n = 1,151) and 4.0 kg (IQR from 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 from –1.0 to 4.0; n = 1,131) and 3.0 kg (IQR from –1.0 to 6.0; n = 218), respectively, from baseline.

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 the maximum increase from baseline predominantly Grade 1 and Grade 2. In study HPTN 083, the number of participants with maximum increase in ALT (Grade 3 or 4) from baseline was 40 (2%) vs. 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 increase in ALT (Grade 3 or 4) from baseline was 12 (<1%) vs. 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 increased AST or ALT levels 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 increased ALT levels was 29 (1%) and 31 (1%), respectively, and due to increased AST levels 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 increased ALT levels was 12 (<1%) vs. 15 (<1%). There were no cases of discontinuation due to increased AST levels.

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 section "Pharmacological properties").

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

Based on data from the Week 16 analysis of the MOCHA study involving 23 HIV-infected children (aged 12 years and older 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 section "Pharmacological properties").

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, pharmacists, patients, or their legal representatives should report all suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua.

Shelf life. 3 years.

Storage conditions. Store below 30°C. Do not freeze. Keep out of reach of children. After drawing into a syringe, the product must be administered within 2 hours.

Incompatibilities. Since compatibility studies have not been conducted, cabotegravir for injection must not be mixed with other medicinal products.

Packaging. Clear glass vial stoppered with a bromobutyl rubber stopper and sealed with an aluminum cap with a removable plastic flip-off cap. Each vial contains 3 mL; 1 or 25 vials per cardboard box.

Prescription status. Prescription only.

Manufacturer. Glaxo Operations UK Ltd, trading as Glaxo Wellcome Operations / Glaxo Operations UK Ltd (trading as Glaxo Wellcome Operations).

Manufacturer's address.
Harmire Road, Barnard Castle, DL12 8DT, United Kingdom /
Harmire Road, Barnard Castle, DL12 8DT, United Kingdom

Marketing authorization holder and/or applicant.
LLC "GlaxoSmithKline Pharmaceuticals Ukraine".

Address of the marketing authorization holder and/or applicant.
1-V Pavla Tychyny Avenue, Kyiv, 02152, Ukraine. Tel: (044) 585-51-85, Fax: (044) 585-51-92.

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].