Rukobia (Tablets) Instructions for Use

Marketing Authorization Holder

ViiV Healthcare UK, Limited (United Kingdom)

Manufactured By

GlaxoSmithKline Manufacturing, S.p.A. (Italy)

ATC Code

J05AX29 (Fostemsavir)

Active Substance

Fostemsavir (Rec.INN registered by WHO)

Dosage Form

Rukobia

Extended-release film-coated tablets, 600 mg: 60 pcs.

Dosage Form, Packaging, and Composition

Extended-release film-coated tablets pale yellow-brown in color, oval, biconvex, with the inscription “SV 1V7” engraved on one side and smooth on the other side.

Excipients: hypromellose, hydroxypropyl cellulose (type 2208), colloidal anhydrous silicon dioxide, magnesium stearate; film coating Opadry^® II 85F170022 beige [polyvinyl alcohol, titanium dioxide, polyethylene glycol (macrogol) 3350, talc, iron oxide yellow dye, iron oxide red dye].

60 pcs. – high-density polyethylene bottles (1) – cardboard packs with first-opening control.

Clinical-Pharmacological Group

Antiviral drug active against HIV

Pharmacotherapeutic Group

Systemic antiviral agents; direct-acting antiviral agents; other antiviral agents

Pharmacological Action

Fostemsavir is a prodrug with no significant antiviral activity, which is hydrolyzed to the active form – temsavir – upon cleavage of the phosphonooxymethyl group in vivo. Temsavir binds directly to the gp120 subunit within the HIV-1 envelope glycoprotein gp160 and selectively inhibits the interaction between the virus and the cellular CD4 receptor, thereby preventing the virus from entering host cells and infecting them.

Pharmacokinetics

The pharmacokinetics of temsavir after fostemsavir administration are comparable in healthy volunteers and HIV-1 infected patients. In HIV-1 infected patients, the inter-subject variability (%CV) for plasma temsavir C_max and AUC ranged from 20.5 to 63%, and for C_t from 20 to 165%. The inter-subject variability of oral clearance and oral V_d in the central compartment was estimated in a population pharmacokinetic analysis in healthy volunteers from selected Phase I studies and in HIV-1 infected patients and was 43% and 48%, respectively.

Fostemsavir is a prodrug, metabolized to temsavir by alkaline phosphatase in the lumen of the small intestine and is usually not detected in plasma after oral administration. The active form – temsavir – is readily absorbed, and the mean time to reach plasma C_max (T_max) is 2 hours after drug administration (fasting). Temsavir is absorbed in the small intestine and cecum/proximal ascending colon.

After multiple oral administration of fostemsavir 600 mg twice daily in HIV-1 infected adult patients, C_max is 1.77 (39.9) µg/ml, AUC 12.90 (46.4) µg×h/ml.

The absolute bioavailability of temsavir after a single oral 600 mg dose of fostemsavir was 26.9%.

Temsavir binding to human plasma proteins is approximately 88%. Human serum albumin is the major contributor to temsavir binding to human plasma proteins. The V_d of temsavir at steady state after IV administration is estimated to be 29.5 L. The ratio of C_max of total radiolabeled carbon in blood to its C_max in plasma was approximately 0.74, indicating minimal association of temsavir or its metabolites with erythrocytes. The free fraction of temsavir in plasma was approximately 12% to 18% in healthy volunteers, 23% in patients with severe hepatic impairment, 19% in patients with severe renal impairment, and 12% in HIV-1 infected patients.

In vivo, temsavir is metabolized mainly via esterase hydrolysis (36.1% of the administered dose), as well as via a CYP3A4-mediated oxidative pathway (21.2% of the administered dose). Other metabolites not related to CYP3A4 account for 7.2% of the administered dose. Glucuronidation is a minor metabolic pathway (1% of the administered dose).

Temsavir undergoes extensive metabolism, so only 3% of the administered dose is excreted in urine and via the intestine. Temsavir undergoes biotransformation to form two predominant circulating inactive metabolites – BMS-646915 (hydrolysis product) and BMS-930644 (N-dealkylation product).

Indications

For the treatment of HIV-1 infection with multidrug resistance, in combination with other antiretroviral drugs in situations where it is not possible to select another suppressive antiviral therapy regimen due to resistance, intolerance, or safety considerations.

ICD codes

Dosage Regimen

Administer Rukobia orally.

The recommended adult dose is 600 mg twice daily.

Swallow the extended-release tablet whole; do not crush, split, or chew.

Take with or without food.

If a dose is missed by more than 6 hours, skip the missed dose and take the next dose at the regular time.

If vomiting occurs within 1 hour after taking a dose, take another 600 mg tablet.

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

This medication is indicated for heavily treatment-experienced adults with multidrug-resistant HIV-1 infection.

Always use Rukobia in combination with other antiretroviral drugs.

Do not co-administer with strong CYP3A inducers, such as rifampicin or St. John’s wort.

Adverse Reactions

Immune system disorders common – immune reconstitution syndrome.

Psychiatric disorders common – insomnia.

Nervous system disorders very common – headache; common – dizziness, peripheral neuropathy, somnolence, dysgeusia.

Cardiac disorders common – QT interval prolongation.

Gastrointestinal disorders very common – diarrhea, nausea, abdominal pain, vomiting; common – dyspepsia, flatulence.

Hepatobiliary disorders common – increased transaminase activity.

Skin and subcutaneous tissue disorders very common – rash; common – pruritus.

Musculoskeletal and connective tissue disorders common – myalgia.

General disorders and administration site conditions common – fatigue.

Investigations common – increased blood creatinine, increased CPK activity.

Contraindications

Hypersensitivity to fostemsavir; use in combination with strong CYP3A inducers, including, but not limited to, carbamazepine, phenytoin, mitotane, enzalutamide, rifampicin, and St. John’s wort (Hypericum perforatum).

Use in Pregnancy and Lactation

Fostemsavir should be used during pregnancy only if the expected benefit to the mother outweighs the potential risk to the fetus.

Women with HIV infection should not breastfeed to avoid transmitting HIV to the child.

Use in Hepatic Impairment

No dose adjustment is required for patients with hepatic impairment.

Use in Renal Impairment

No dose adjustment is required for patients with renal impairment or patients on hemodialysis.

Pediatric Use

Contraindicated in children and adolescents under 18 years of age.

Geriatric Use

There is no information on the need for dose adjustment in elderly patients compared to younger patients.

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Special Precautions

HIV-infected patients with severe immunodeficiency at the time of initiation of antiretroviral therapy (ART) may develop an inflammatory reaction to asymptomatic opportunistic infections or their residual manifestations, which may cause serious clinical deterioration or exacerbation of symptoms. These reactions usually occur within the first few weeks or months after starting ART.

Typical examples are cytomegalovirus retinitis, generalized and/or focal mycobacterial infection, and Pneumocystis jiroveci pneumonia. The appearance of any symptoms of inflammation requires immediate examination and, if necessary, treatment.

Autoimmune diseases (such as Graves’ disease, autoimmune hepatitis, polymyositis, and Guillain-Barré syndrome) have also been observed in the context of immune reconstitution; however, the time of initial manifestation varied, and the disease could occur many months after starting therapy and sometimes had an atypical course.

It has been demonstrated that Fostemsavir at a dose exceeding the therapeutic dose (with C_max approximately 4.2 times the therapeutic dose) significantly prolongs the QTc interval on the ECG. Fostemsavir should be used with caution in patients with a history of QT prolongation, concurrently with drugs with a known risk of torsades de pointes (e.g., amiodarone, disopyramide, ibutilide, procainamide, quinidine, or sotalol), and in patients with pre-existing heart disease. Elderly patients may be more susceptible to drug-induced QT interval prolongation.

Monitoring of liver function biochemical parameters is recommended in patients co-infected with hepatitis B and/or C virus. Patients with chronic hepatitis B or C receiving combined antiretroviral therapy are at increased risk of developing severe and potentially fatal liver adverse reactions. If concomitant antiviral therapy for hepatitis B or C is administered, the prescribing information for these drugs should be consulted.

Although the etiology of this condition is multifactorial (including corticosteroid use, bisphosphonate use, alcohol consumption, severe immunosuppression, high body mass index), cases of osteonecrosis have been most frequently observed in patients with advanced HIV disease and/or on long-term combined ART. Patients should be advised to consult their physician if they experience joint pain and stiffness or difficulty moving.

Data obtained in vitro demonstrate that the antiviral activity of temsavir is limited to HIV-1 group M strains. Fostemsavir should not be used to treat infections caused by HIV-1 strains other than group M strains.

Among HIV-1 group M strains, the antiviral activity of the drug is significantly reduced against the CRF01_AE subtype virus. Available data indicate that this subtype has natural resistance to temsavir. It is not recommended to use Fostemsavir for the treatment of infections caused by HIV-1 strains of the CRF01_AE subtype of group M.

Patients should be informed that the use of fostemsavir or any other antiretroviral therapy does not cure HIV infection, and they may still develop opportunistic infections and other complications of HIV infection. Therefore, patients should remain under the close clinical supervision of a physician experienced in the treatment of these HIV-associated diseases.

Drug Interactions

In vitro, temsavir inhibited organic anion transporting polypeptide (OATP) 1B1 and OATP1B3 (IC₅₀ = 32 and 16 µM, respectively). In addition, temsavir and its two metabolites (BMS-646915 and BMS-930644) inhibited breast cancer resistance protein (BCRP) (IC₅₀ = 12, 35, and 3.5 to 6.3 µM, respectively). Based on these data, an effect of temsavir on the pharmacokinetics of drugs that are substrates of OATP1B1/3 or BCRP (e.g., rosuvastatin, atorvastatin, simvastatin, pitavastatin, and fluvastatin) is expected. Therefore, for some statins, dose adjustment and/or careful dose titration is recommended.

Temsavir is a substrate of P-glycoprotein (P-gp) and BCRP, but is not a substrate of OATP1B1 or OATP1B3. Its biotransformation into two circulating metabolites – BMS-646915 and BMS-930644 – is mediated by unidentified esterases (36.1%) and the CYP3A4 substrate enzyme (21.2%), respectively. When fostemsavir was co-administered with rifampicin, a strong CYP3A inducer, a significant decrease in plasma temsavir concentration was observed.

A significant decrease in plasma temsavir concentration may also occur when fostemsavir is co-administered with other strong CYP3A inducers and may lead to loss of virological response.

Fostemsavir should be used with caution when co-administered with a drug with a known risk of torsades de pointes.

Co-administration of fostemsavir with elbasvir/grazoprevir is not recommended, as increased grazoprevir concentrations may increase the risk of elevated ALT.

For some statins that are substrates of organic anion transporting polypeptides OATP1B1/3 or BCRP (rosuvastatin, atorvastatin, pitavastatin, simvastatin, and fluvastatin), dose adjustment and/or careful dose titration is recommended when co-administered with fostemsavir.

When fostemsavir was co-administered with oral contraceptives, temsavir increased the concentration of ethinyl estradiol. In patients receiving fostemsavir treatment, an estrogen-based therapy regimen, including oral contraceptives, should not contain more than 30 µg of ethinyl estradiol per day. In addition, caution is recommended, especially in patients with additional risk factors for thromboembolic events.

When fostemsavir and tenofovir alafenamide (TAF) are co-administered, temsavir is expected to increase plasma TAF concentrations due to inhibition of OATP1B1/3 and/or BCRP. When co-administered with fostemsavir, the recommended dose of TAF is 10 mg.

Storage Conditions

Store at 2°C (36°F) to 30°C (86°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

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