Tivicay 50 mg film-coated tablets - Ireland[爱尔兰药品]

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Tivicay 50 mg film-coated tablets

2015-03-05 22:21:09 来源: 作者: 【大中小】浏览:414次评论:0条

1. Name of the medicinal product

Tivicay® 50 mg film-coated tablets

2. Qualitative and quantitative composition

Each film-coated tablet contains dolutegravir sodium equivalent to 50 mg dolutegravir.

For the full list of excipients, see section 6.1.

3. Pharmaceutical form

Film-coated tablet (tablet).

Yellow, round, biconvex tablets approximately 9 mm in diameter debossed with 'SV 572' on one side and '50' on the other side.

4. Clinical particulars

4.1 Therapeutic indications

Tivicay is indicated in combination with other anti-retroviral medicinal products for the treatment of Human Immunodeficiency Virus (HIV) infected adults and adolescents above 12 years of age.

4.2 Posology and method of administration

Tivicay should be prescribed by physicians experienced in the management of HIV infection.

Posology

Adults

Patients infected with HIV-1 without documented or clinically suspected resistance to the integrase class

The recommended dose of dolutegravir is 50 mg (one tablet) orally once daily.

Tivicay should be administered twice daily in this population when co-administered with some medicines (e.g. efavirenz, nevirapine, tipranavir/ritonavir, or rifampicin). Please refer to section 4.5.

Patients infected with HIV-1 with resistance to the integrase class (documented or clinically suspected)

The recommended dose of dolutegravir is 50 mg (one tablet) twice daily. The decision to use dolutegravir for such patients should be informed by the integrase resistance pattern (see section 5.1).

Co-administration of Tivicay with some medicines should be avoided in this population (e.g. efavirenz, nevirapine, tipranavir/ritonavir, or rifampicin). Please refer to section 4.4 and 4.5.

Missed doses

If the patient misses a dose of Tivicay, the patient should take Tivicay as soon as possible, providing the next dose is not due within 4 hours. If the next dose is due within 4 hours, the patient should not take the missed dose and simply resume the usual dosing schedule.

Adolescents aged 12 and above

In adolescents (aged from 12 to 17 years and weighing at least 40 kg) infected with HIV-1 without resistance to the integrase class, the recommended dose of dolutegravir is 50 mg once daily.

Elderly

There are limited data available on the use of dolutegravir in patients aged 65 years and over. There is no evidence that elderly patients require a different dose than younger adult patients (see section 5.2).

Renal impairment

No dosage adjustment is required in patients with mild, moderate or severe (CrCl <30 mL/min, not on dialysis) renal impairment. No data are available in subjects receiving dialysis although differences in pharmacokinetics are not expected in this population (see section 5.2).

Hepatic impairment

No dosage adjustment is required in patients with mild or moderate hepatic impairment (Child-Pugh grade A or B). No data are available in patients with severe hepatic impairment (Child-Pugh grade C); therefore dolutegravir should be used with caution in these patients (see section 5.2).

Paediatric population

The safety and efficacy of Tivicay in children aged less than 12 years or weighing less than 40 kg has not yet been established. In the presence of integrase inhibitor resistance, there are insufficient data to recommend a dose for Tivicay in children and adolescents. Currently available data are described in section 4.8, 5.1 and 5.2, but no recommendation on a posology can be made.

Method of administration

Oral use.

Tivicay can be taken with or without food (see section 5.2). In the presence of integrase class resistance, Tivicay should preferably be taken with food to enhance exposure (particularly in patients with Q148 mutations) (see section 5.2).

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Co-administration with dofetilide (see section 4.5).

4.4 Special warnings and precautions for use

While effective viral suppression with antiretroviral therapy has been proven to substantially reduce the risk of sexual transmission, a residual risk cannot be excluded. Precautions to prevent transmission should be taken in accordance with national guidelines.

Integrase class resistance of particular concern

The decision to use dolutegravir in the presence of integrase class resistance should take into account that the activity of dolutegravir is considerably compromised for viral strains harbouring Q148+≥2 secondary mutations from G140A/C/S, E138A/K/T, L74I (see section 5.1). To what extent dolutegravir provides added efficacy in the presence of such integrase class resistance is uncertain.

Hypersensitivity reactions

Hypersensitivity reactions have been reported with dolutegravir, and were characterized by rash, constitutional findings, and sometimes, organ dysfunction, including severe liver reactions. Dolutegravir and other suspect agents should be discontinued immediately if signs or symptoms of hypersensitivity reactions develop (including, but not limited to, severe rash or rash accompanied by raised liver enzymes, fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, facial oedema, eosinophilia, angioedema). Clinical status including liver aminotransferases and bilirubin should be monitored. Delay in stopping treatment with dolutegravir or other suspect active substances after the onset of hypersensitivity may result in a life-threatening allergic reaction.

Immune Reactivation Syndrome

In HIV-infected patients with severe immune deficiency at the time of institution of combination antiretroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunistic pathogens may arise and cause serious clinical conditions, or aggravation of symptoms. Typically, such reactions have been observed within the first few weeks or months of initiation of CART. Relevant examples are cytomegalovirus retinitis, generalised and/or focal mycobacterial infections, and Pneumocystis jirovecii pneumonia. Any inflammatory symptoms should be eva luated and treatment instituted when necessary. Autoimmune disorders (such as Graves' disease) have also been reported to occur in the setting of immune reconstitution, however, the reported time to onset is more variable and these events can occur many months after initiation of treatment.

Liver biochemistry elevations consistent with immune reconstitution syndrome were observed in some hepatitis B and/or C co-infected patients at the start of dolutegravir therapy. Monitoring of liver biochemistries is recommended in patients with hepatitis B and/or C co-infection. Particular diligence should be applied in initiating or maintaining effective hepatitis B therapy (referring to treatment guidelines) when starting dolutegravir-based therapy in hepatitis B co-infected patients (see section 4.8).

Opportunistic infections

Patients should be advised that dolutegravir or any other antiretroviral therapy does not cure HIV infection and that they may still develop opportunistic infections and other complications of HIV infection. Therefore, patients should remain under close clinical observation by physicians experienced in the treatment of these associated HIV diseases.

Drug interactions

Factors that decrease dolutegravir exposure should be avoided in the presence of integrase class resistance. This includes co-administration with medicinal products that reduce dolutegravir exposure (e.g. magnesium/ aluminium-containing antacid, iron and calcium supplements, multivitamins and inducing agents, tipranavir/ritonavir, rifampicin and certain anti-epileptic drugs) (see section 4.5).

Metformin concentrations may be increased by dolutegravir. Patients should be monitored during therapy and a dose adjustment of metformin may be required (see section 4.5).

Osteonecrosis

Although the aetiology is considered to be multifactorial (including corticosteroid use, biphosphonates, alcohol consumption, severe immunosuppression, higher body mass index), cases of osteonecrosis have been reported in patients with advanced HIV-disease and/or long-term exposure to CART. Patients should be advised to seek medical advice if they experience joint aches and pain, joint stiffness or difficulty in movement.

4.5 Interaction with other medicinal products and other forms of interaction

Effect of other agents on the pharmacokinetics of dolutegravir

All factors that decrease dolutegravir exposure should be avoided in the presence of integrase class resistance.

Dolutegravir is eliminated mainly through metabolism by UGT1A1. Dolutegravir is also a substrate of UGT1A3, UGT1A9, CYP3A4, Pgp, and BCRP; therefore medicinal products that induce those enzymes may decrease dolutegravir plasma concentration and reduce the therapeutic effect of dolutegravir (see Table 1). Co-administration of dolutegravir and other medicinal products that inhibit these enzymes may increase dolutegravir plasma concentration (see Table 1).

The absorption of dolutegravir is reduced by certain anti-acid agents (see Table 1).

Effect of dolutegravir on the pharmacokinetics of other agents

In vivo, dolutegravir did not have an effect on midazolam, a CYP3A4 probe. Based on in vivo and/or in vitro data, dolutegravir is not expected to affect the pharmacokinetics of medicinal products that are substrates of any major enzyme or transporter such as CYP3A4, CYP2C9 and P-gp (for more information see section 5.2).

In vitro, dolutegravir inhibited the renal organic cation transporter 2 (OCT2) and multidrug and toxin extrusion transporter (MATE) 1. In vivo, a 10-14% decrease of creatinine clearance (secretory fraction is dependent on OCT2 and MATE-1 transport) was observed in patients. In vivo, dolutegravir may increase plasma concentrations of medicinal products in which excretion is dependent upon OCT2 or MATE-1 (e.g. dofetilide, metformin) (see Table 1 and section 4.3).

In vitro, dolutegravir inhibited the renal uptake transporters, organic anion transporters (OAT1) and OAT3. Based on the lack of effect on the in vivo pharmacokinetics of the OAT substrate tenofovir, in vivo inhibition of OAT1 is unlikely. Inhibition of OAT3 has not been studied in vivo. Dolutegravir may increase plasma concentrations of medical products in which excretion is dependent upon OAT3.

Established and theoretical interactions with selected antiretrovirals and non-antiretroviral medicinal products are listed in Table 1.

Interaction table

Interactions between dolutegravir and co-administered medicinal products are listed in Table 1 (increase is indicated as “↑”, decrease as “↓”, no change as “↔”, area under the concentration versus time curve as “AUC”, maximum observed concentration as “Cmax”, concentration at end of dosing interval as “C”).

Table 1: Drug Interactions

Medicinal products by therapeutic areas	Interaction Geometric mean change (%)	Recommendations concerning co-administration
HIV-1 Antiviral Agents
Non-nucleoside Reverse Transcriptase Inhibitors
Etravirine	Dolutegravir ↓ AUC ↓ 71% C_max↓ 52% C ↓ 88% Etravirine ↔ (induction of UGT1A1 and CYP3A enzymes)	Etravirine decreased plasma dolutegravir concentration, which may result in loss of virologic response and possible resistance to dolutegravir. Dolutegravir should not be used with etravirine without co-administration of atazanavir/ritonavir, darunavir/ritonavir or lopinavir/ritonavir (see further below in table).
Efavirenz	Dolutegravir ↓ AUC ↓ 57% C_max↓ 39% C ↓ 75% Efavirenz ↔ (historical controls) (induction of UGT1A1 and CYP3A enzymes)	The recommended dose of dolutegravir is 50 mg twice daily when co-administered with efavirenz. In the presence of integrase class resistance alternative combinations that do not include efavirenz should be considered (see section 4.4).
Nevirapine	Dolutegravir ↓ (Not studied, a similar reduction in exposure as observed with efavirenz is expected, due to induction)	The recommended dose of dolutegravir is 50 mg twice daily when co-administered with nevirapine. In the presence of integrase class resistance alternative combinations that do not include nevirapine should be considered (see section 4.4).
Rilpivirine	Dolutegravir ↔ AUC ↑ 12% C_max↑ 13% C ↑ 22% Rilpivirine ↔	No dose adjustment is necessary.
Nucleoside Reverse Transcriptase Inhibitors
Tenofovir	Dolutegravir ↔ AUC ↑ 1% C_max↓ 3% C ↓ 8% Tenofovir ↔	No dose adjustment is necessary.
Protease Inhibitors
Atazanavir	Dolutegravir ↑ AUC ↑ 91% C_max↑ 50% C ↑ 180% Atazanavir ↔ (historical controls) (inhibition of UGT1A1 and CYP3A enzymes)	No dose adjustment is necessary.
Atazanavir/ritonavir	Dolutegravir ↑ AUC ↑ 62% C_max↑ 34% C ↑ 121% Atazanavir ↔ Ritonavir ↔ (inhibition of UGT1A1 and CYP3A enzymes)	No dose adjustment is necessary.
Tipranavir/ritonavir (TPV+RTV)	Dolutegravir ↓ AUC ↓ 59% C_max↓ 47% C ↓ 76% (induction of UGT1A1 and CYP3A enzymes)	The recommended dose of dolutegravir is 50 mg twice daily when co-administered with tipranavir/ritonavir the absence of integrase class resistance. In the presence of integrase class resistance this combination should be avoided (see section 4.4).
Fosamprenavir/ ritonavir (FPV+RTV)	Dolutegravir ↓ AUC ↓ 35% C_max↓ 24% C ↓ 49% (induction of UGT1A1 and CYP3A enzymes)	No dose adjustment is necessary in the absence of integrase class resistance. In the presence of integrase class resistance alternative combinations that do not include fosamprenavir/ritonavir should be considered.
Nelfinavir	Dolutegravir ↔ (Not studied)	No dose adjustment is necessary.
Darunavir/ritonavir	Dolutegravir ↓ AUC ↓ 32% C_max↓ 11% C₂₄↓ 38% (induction of UGT1A1 and CYP3A enzymes)	No dose adjustment is necessary.
Lopinavir/ritonavir	Dolutegravir ↔ AUC ↓ 3% C_max↔ 0% C₂₄↓ 6%	No dose adjustment is necessary.
Protease Inhibitors and Non-nucleoside Reverse Transcriptase Inhibitors combinations
Lopinavir/ritonavir + etravirine	Dolutegravir ↔ AUC ↑ 10% C_max↑ 7% C ↑ 28% LPV ↔ RTV ↔	No dose adjustment is necessary.
Darunavir/ritonavir + etravirine	Dolutegravir ↓ AUC ↓ 25% C_max↓ 12% C ↓ 37% DRV ↔ RTV ↔	No dose adjustment is necessary.
Other Antiviral agents
Telaprevir	Dolutegravir ↑ AUC ↑ 25% C_max↑ 19% C ↑ 37% Telaprevir ↔ (historical controls) (inhibition of CYP3A enzyme)	No dose adjustment is necessary.
Boceprevir	Dolutegravir ↔ AUC ↑ 7% C_max↑ 5% C ↑ 8% Boceprevir ↔ (historical controls)	No dose adjustment is necessary.
Other agents
Antiarrhythmics
Dofetilide	Dofetilide ↑ (Not studied, potential increase via inhibition of OCT2 transporter)	Dolutegravir and dofetilide co-administration is contraindicated due to potential life-threatening toxicity caused by high dofetilide concentration (see section 4.3).
Anticonvulsants
Oxcarbamazepine Phenytoin Phenobarbital Carbamazepine	Dolutegravir ↓ (Not studied, decrease expected due to induction of UGT1A1 and CYP3A enzymes)	Co-administration with these enzyme inducers should be avoided.
Azole anti-fungal agents
Ketoconazole Fluconazole Itraconazole Posaconazole Voriconazole	Dolutegravir ↔ (Not studied)	No dose adjustment is necessary. Based on data from other CYP3A4 inhibitors, a marked increase is not expected.
Herbal products
St. John's wort	Dolutegravir ↓ (Not studied, decrease expected due to induction of UGT1A1 and CYP3A enzymes)	Co-administration with St. John's wort is strongly discouraged.
Antacids and supplements
Magnesium/ aluminium-containing antacid	Dolutegravir ↓ AUC ↓ 74% C_max↓ 72% (Complex binding to polyvalent ions)	Magnesium/ aluminium-containing antacid should be taken well separated in time from the administration of dolutegravir (minimum 2 hours after or 6 hours before).
Calcium supplements	Dolutegravir ↓ AUC ↓ 39% C_max↓ 37% C₂₄↓ 39% (Complex binding to polyvalent ions)	Calcium supplements, iron supplements or multivitamins should be taken well separated in time from the administration of dolutegravir (minimum 2 hours after or 6 hours before).
Iron supplements	Dolutegravir ↓ AUC ↓ 54% C_max↓ 57% C₂₄↓ 56% (Complex binding to polyvalent ions)
Multivitamin	Dolutegravir ↓ AUC ↓ 33% C_max↓ 35% C₂₄↓ 32% (Complex binding to polyvalent ions)
Corticosteroids
Prednisone	Dolutegravir ↔ AUC ↑ 11% C_max↑ 6% C ↑ 17%	No dose adjustment is necessary.
Antidiabetics
Metformin	Metformin ↑ Dolutegravir ↔ (Not studied. Increase of metformin expected, due to inhibition of OCT-2 transporter)	Close monitoring of metformin efficacy and safety is recommended when starting or stopping dolutegravir in patients receiving metformin. A dose adjustment of metformin may be necessary.
Antimycobacterials
Rifampicin	Dolutegravir ↓ AUC ↓ 54% C_max↓ 43% C ↓72% (induction of UGT1A1 and CYP3A enzymes)	The recommended dose of dolutegravir is 50 mg twice daily when co-administered with rifampicin in the absence of integrase class resistance. In the presence of integrase class resistance this combination should be avoided (see section 4.4).
Rifabutin	Dolutegravir ↔ AUC ↓ 5% C_max↑ 16% C ↓ 30% (induction of UGT1A1 and CYP3A enzymes)	No dose adjustment is necessary.
Oral contraceptives
Ethinyl estradiol (EE) and Norelgestromin (NGMN)	Dolutegravir ↔ EE ↔ AUC ↑ 3% C_max↓ 1% NGMN ↔ AUC ↓ 2% C_max↓ 11%	Dolutegravir had no pharmacodynamic effect on Luteinizing Hormone (LH), Follicle Stimulating Hormone (FSH) and progesterone. No dose adjustment of oral contraceptives is necessary when co-administered with dolutegravir.
Analgesics
Methadone	Dolutegravir ↔ Methadone ↔ AUC ↓ 2% C_max↔ 0% C ↓ 1%	No dose adjustment is necessary of either agent.

Paediatric population

Interaction studies have only been performed in adults.

4.6 Fertility, pregnancy and lactation

Pregnancy

There are limited amount of data from the use of dolutegravir in pregnant women. The effect of dolutegravir on human pregnancy is unknown. In reproductive toxicity studies in animals, dolutegravir was shown to cross the placenta. Animal studies do not indicate direct or indirect harmful effects with respect t