Product Information
Registration Status: ActiveJULUCA FILM-COATED TABLET 50MG/25MG is approved to be sold in Singapore with effective from 2019-03-22. It is marketed by GLAXOSMITHKLINE PTE LTD, with the registration number of SIN15649P.
This product contains Dolutegravir 50mg, and Rilpivirine 25mg in the form of TABLET, FILM COATED. It is approved for ORAL use.
This product is manufactured by Glaxo Operations UK Ltd (trading as Glaxo Wellcome Operations) in SPAIN, andGlaxo Wellcome S.A. (Primary and secondary packager) in UNITED KINGDOM.
It is a Prescription Only Medicine that can only be obtained from a doctor or a dentist, or a pharmacist with a prescription from a Singapore-registered doctor or dentist.
Description
Dolutegravir is a HIV-1 intergrase inhibitor that blocks the strand transfer step of the integration of the viral genome into the host cell (INSTI).[A7514] The effect of this drug has no homology in human host cells which gives it an excellent tolerability and minimal toxicity.[A31342] Dolutegravir was developed by ViiV Healthcare and FDA approved on August 12, 2013.[L1035] On November 21, 2017, dolutegravir, in combination with rilpivirine, was approved as part of the first complete treatment regimen with only two drugs for the treatment of adults with HIV-1 named Juluca.[L1031]
Indication
Dolutegravir is indicated in combination with other antiretroviral agents for the treatment of patients with HIV-1 infection that comply with the characteristics of being adults or children aged 12 years and older and present at least a weight of 40 kg.[A7520] The FDA combination therapy approval of dolutegravir and rilpivirine is indicated for adults with HIV-1 infections whose virus is currently suppressed (< 50 copies/ml) on a stable regimen for at least six months, without history of treatment failure and no known substitutions associated to resistance to any of the two components of the therapy.[L1031]
Mechanism of Action
Dolutegravir is an HIV-1 antiviral agent. It inhibits HIV integrase by binding to the active site and blocking the strand transfer step of retroviral DNA integration in the host cell. The strand transfer step is essential in the HIV replication cycle and results in the inhibition of viral activity. Dolutegravir has a mean EC50 value of 0.5 nM (0.21 ng/mL) to 2.1 nM (0.85 ng/mL) in peripheral blood mononuclear cells (PBMCs) and MT-4 cells.[A7517]
Pharmacokinetics
- Absorption
- When 50 mg of dolutegravir once daily was orally administered to HIV-1 infected adults, the AUC, Cmax, and Cmin is 53.6 mcg h/mL, 3.67 mcg/mL, and 1.11 mcg/mL, respectively. The peak plasma concentration was observed 2 to 3 hours post-dose. Steady state is achieved within approximately 5 days with average accumulation ratios for AUC, Cmax, and C24h ranging from 1.2 to 1.5. When 50 mg once daily is given to pediatric patients (12 to < 18 years and weighing ≥40 kg) the Cmax, AUC, and C24 is 3.49 mcg/mL, 46 mcg.h/mL, and 0.90 mcg/mL respectively.[A7514]
- Distribution
- The administration of a dose of 50 mg of dolutegravir presents an apparent volume of distribution of 17.4 L. The median dolutegravir concentration in CSF was 18 ng/mL after 2 weeks of treatment.[A7514]
- Metabolism
- Dolutegravir is highly metabolized through three main pathways and it forms no long-lived metabolites. The first pathway is defined by the glucuronidation by UGT1A1, the second pathway by carbon oxidation by CYP3A4 and the third pathway is what appears to be a sequential oxidative defluorination and glutathione conjugation. The main metabolite found in blood plasma is the ether glucuronide form (M2) and its chemical properties disrupt its ability to bind metal ions, therefore, it is inactive.[A31344]
- Elimination
Clearance
The apparent clearance rate of dultegravir is 1.0 L/h.[FDA label]
Toxicity
There was no significant increases in drug-related neoplasms or in genotoxic effects or in mating or fertility effects.[A31345]
Active Ingredient/Synonyms
Dolutegravir | Dolutegravir |
Source of information: Drugbank (External Link). Last updated on: 3rd July 18. *Trade Name used in the content below may not be the same as the HSA-registered product.
Description
Rilpivirine is non-nucleoside reverse transcriptase inhibitor (NNRTI) which is used for the treatment of HIV-1 infections in treatment-naive patients.[A31328] It is a diarylpyrimidine derivative, a class of molecules that resemble pyrimidine nucleotides found in DNA.[A31329] The internal conformational flexibility of rilpivirine and the plasticity of it interacting binding site gives it a very high potency and an unlikely generation of resistance compared to other NNRTI's.[A31331] Rilpivirine was developed by Tilbotec, Inc. and FDA approved on May 20, 2011.[L1030] On November 21, 2017, Rilpivirine, in combination with dolutegravir, was approved as part of the first complete treatment regimen with only two drugs for the treatment of adults with HIV-1 named Juluca.[L1031]
Indication
Rilpivirine, in combination with other agents, is indicated for the treatment of HIV-1 infections in antiretroviral treatment-naive patients with HIV-1 RNA ≤100,000 copies/mL and CD4+ cell count >200 cells/mm3.[L1030] The FDA combination therapy approval of rilpivirine and dolutegravir is indicated for adults with HIV-1 infections whose virus is currently suppressed (< 50 copies/ml) on a stable regimen for at least six months, without history of treatment failure and no known substitutions associated to resistance to any of the two components of the therapy.[L1031]
Mechanism of Action
Rilpivirine is a non-competitive NNRTI that binds to reverse transcriptase. Its binding results in the blockage of RNA and DNA- dependent DNA polymerase activities, like HIV-1 replication. It does not present activity against human DNA polymerases α, β and γ.[L1032] Rilpivirine binds to the HIV-1 reverse transcriptase (RT) and its flexible structure around the aromatic rings allows the adaptation to changes in the non-nucleoside RT binding pocket.[A31335]
Pharmacokinetics
- Absorption
- Absorption of rilpivirine is characterized by a lag time followed by a linear increase in plasma concentration. Under fasting conditions, the Cmax of rilpivirine can be decreased even by 46% while its AUC can be reduced by 43%. When given with a protein-rich drink the Cmax and AUC of rilpivirine is decreased by 50%. Therefore, it is recommended to consume rilpiviridine with a non-protein-rich meal. The average Tmax of various rilpivirine concentrations is 3-4 h.[A31331] The reported AUC in patients from clinical studies is 2235 ng h/ml.[FDA label]
- Distribution
- In VIH-1 patients, the apparent volume of distribution in the central compartment was determined to be 152-173 L.[L1032]
- Metabolism
- Mainly hepatically metabolized by CYP3A. Because it is highly protein bound, its free plasma concentration is very small thus is unlikely to inhibit cytochrome proteins to a clinically relevant degree despite being an inhibitor of CYP3A4, CYP2C19, and CYP2B6.[A7414]
- Elimination
Clearance
In HIV-1 patients, the apparent oral clearance is estimated to be 10.5-11.8 L/h.[L1032]
Toxicity
Rilpivirine did not induce chromosomal damage in vivo. It did not show any effect on mating or fertility in animal studies. On the other hand, mice studies have result positive for the formation of hepatocellular neoplasms which can be rodent-specific.[FDA label]
Active Ingredient/Synonyms
4-{[4-({4-[(E)-2-cyanovinyl]-2,6-dimethylphenyl}amino)pyrimidin-2-yl]amino}benzonitrile | Rilpivirine |
Source of information: Drugbank (External Link). Last updated on: 3rd July 18. *Trade Name used in the content below may not be the same as the HSA-registered product.