Tivicay, 50 mg 30 pcs.

Pharmacodynamics

Mechanism of Action

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

In a biochemical chain transfer assay using purified HIV-1 integrase and pretreated DNA substrate, IC50 (concentration that inhibits replication by 50%) values of 2.7 nM and 12.6 nM were obtained. In vitro, dolutegravir dissociates slowly from the active center of the wild-type DNA integrase complex (t1/2 71 hours).

Pharmacodynamic effects

. In a randomized trial to determine the optimal dose in HIV-1-infected patients who received dolutegravir monotherapy (ING111521), rapid and dose-dependent antiviral effects were observed, with mean HIV-1 RNA reduction at day 11 compared with baseline of 1.5, 2.0 and 2.5 log10 for 2mg, 10mg, and 50mg of dolutegravir when taken once daily, respectively.

This antiviral response was maintained for 3-4 days from the last dose in the group of patients taking 50 mg of dolutegravir.

Antiviral activity in cell culture

In peripheral blood mononuclear cells (PBMCs) infected with HIV-1 strain Bal or HIV-1 strain NL432, IC50 0.51 nM 0.53 nM were obtained for dolutegravir, respectively. In MT-4 cells infected with strain 1MB HIV-1 and incubated with dolutegravir for 4 or 5 days, IC50 0.71 and 2.1 nM were obtained.

In a viral integrase sensitivity assay using the integrase coding site of 13 clinically distinct subtype B isolates, dolutegravir demonstrated antiviral activity similar to that against laboratory strains, with an average IC50 of 0.52 nM.

In an ICRP analysis of a panel consisting of 24 clinical HIV-1 isolates [group M (subtypes A, B. C, D, E, F, and G) and group O] and 3 clinical HIV-2 isolates, the geometric mean IC50 was 0.20 nM, and IC50 values ranged from 0.02 to 2.14 nM for HIV-1, whereas for HIV-2 isolates the geometric mean IC50 was 0.18 nM. and IC50 values ranged from 0.09 to 0.61 nM.

Antiviral activity in combination with other antiviral drugs

None of the drugs with typical antiviral activity against HIV exhibited antagonism to dolutegravir [in vivo assessments were performed in combination with stavudine, abacavir, efavirenz, nevirapine, lopinavir, amprenavir, enfuvirtide, maraviroc, adefovir and raltegravir, selected in staggered order].

In addition, antiviral drugs without typical HIV activity (ribavirin) had no apparent effect on dolutegravir activity

The effects of human serum and serum proteins

In-vitro studies confirmed a 75-fold change (CI) of IC50 of dolutegravir in the presence of 100% human serum (extrapolation method), and IC90, adjusted for protein binding (PA-IC90), in ICPC was 64 ng/mL.

The minimum concentration of dolutegravir after a single dose of 50 mg in patients who had not previously taken integrase inhibitors (INIs) was 1.20 µg/mL, 9 times the established PA-IC90.

In vitro resistance

HIV-1 wild-type isolates: no viruses with high resistance to dolutegravir were detected during the 112-day passages of strain IIIB. The maximum 4.1-fold change was observed in resistant virus groups obtained in passages with SI53Y and S153F replacements in conserved positions of the integrase gene.

Passage of wild-type HIV-1 strain HL432 in the presence of dolutegravir resulted in selection of the 92Q (crossed virus group with CI = 3.1) and G193B (crossed virus group with CI 3.2) replacements at day 56. Additional passaging of B. C and A/G subtypes of wild-type virus in the Presence of dolutegravir resulted in selection of R263K. Gl 18R and S153T.

Antiviral activity against resistant strains: strains resistant to reverse transcriptase inhibitors (RTIs) and protease inhibitors (PIs): Aolutegravir showed equal activity against 2 non-nucleoside (NN)-IOT-resistant, 3 nucleoside (H)-IOT-resistant, and 2 AI-resistant mutant HIV-1 clones (1 with triple and 1 with sixfold resistance) compared with the wild-type strain.

Ipi-resistant HIV-1 strains: 60 IP-resistant mutant HIV-1 isolates (28 with one substitution and 32 with 2 or more substitutions) were derived from wild-type BL432 virus by site-directed mutagenesis.

Dolutegravir demonstrated antiviral activity (sensitivity) against HIV with KI < 5 against 27 of 8 mutant AI-resistant viruses with one substitution, including T66A/I/K. E92Q/V, 43C/M/R. Q148H/K/R and N15511, while for raltegravir and elvitegravir, sgivability was evident against 17/28 and 11/21 mutant viruses tested with CI < 5. respectively.

In addition, of the 32 mutant viruses resistant to AI with 2 or more substitutions, 23 of 32 demonstrated CI < 5 for dolutegravir compared with CI < 5 for 4 of 32 for raltegravir and CI < 5 for 2 of 25 tested viruses for titegravir.

The HIV-2 strains resistant to AI: viruses were obtained by site-directed mutagenesis of HIV-2 isolates isolated from HIV-2-infected patients who were receiving raltegravir and who had virologic treatment failure.

In general, the CIs in HIV-2 were similar to those of HIV-1, which were observed with a similar set of mutations. The CI of dolutegravir was < 5 against 4 HIV-2 viruses (S163D, G140A/Q148R, A153G/N155H/S163G, and I292Q/T97A/N155H/S163D); for E92Q/N155II the CI of dolutegravir was 8.5, and for G140S/QI48R the CI of dolutegravir was 17.

Dolutegravir, raltegravir, and elvitegravir showed similar activity against HIV-2 with a site-directed mutation with SI63D as against the wild type, and for the remaining mutant HIV-2 viruses, the CI ranges of raltegravir were 6.4-420 and the CI ranges of elvitegravir were 22-640.

Clinical isolates in patients with virologic ineffectiveness of raltegravir treatment: 30 clinical isolates with genotypic and phenotypic resistance to raltegravir (median CI >81) were tested for sensitivity to olutegravir (median CI 1.5) by analysis with Monogram Biosciences PlienoSense.

The median CI of dolutegravir for isolates with substitutions at positions 140S-I-Q148II was 3.75: G140S + Q148R was 13.3: T97A + Y143R – 1.05 and 15511 – 1.37. 705 raltegravir-resistant isolates obtained from patients receiving raltegravir were analyzed for sensitivity to dolutegravir by analysis with Monogram Biosciences PhenoSense.

Dolutegravir exhibited KI<10 against 93.9% of 705 clinical isolates, with 16 (9%) of 184 QI48 + 1 substituted isolates with resistance to AI and 25 (27%) of 92 clinical isolates with Q148 +>2 substituted isolates with resistance to AI showing more than a 10-fold change.

In vivo resistance: Patients who did not take InI

No mutations of InI resistance or treatment-associated resistance to nucleoside reverse transcriptase inhibitors (NRTIs) basis therapy were observed in previously untreated patients who were taking 50 mg of dolutegravir once daily ( SPRING-1, SPRING-2, SINGLE and FLAMINGO studies).

In the SAILINGy study of patients receiving dolutegravir who had not previously received InI (n = 354 in the delutegravir group), treatment-related replacements in integrase were observed at 48 weeks in 4 of 17 patients with virologic ineffectiveness receiving dolutegravir.

Two of 4 patients had a unique R263K substitution in the integrase gene with a maximum FC of 1.93, 1 patient had a polymorphic V151V/I integrase substitution with a maximum FC of 0.92, and 1 patient had an initial integrase mutation and was thought to have previously received an AI or had been infected with an AI-resistant virus.

In vivo resistance: InI-resistant patients

The VIKING-3 study examined dolutegravir (plus optimized baseline therapy) in patients with existing resistance to InI. Up to 24 weeks, 36 of 183 patients had protocol-established virologic ineffectiveness (RDVF).

Of these, 32 patients had paired baseline and PDVF resistance for analysis. and 17/32 (53%) had treatment-associated mutations, the following treatment-associated mutations or mutation combinations were observed: L74L/M (n = 1), E92Q (n = 2), T97A (n = 9), E138K/A/T (n = 8), G140S (n = 2), Y143H (n = 1). S147G (n=l), Q148H/K/R (n = 4). N155II (n=1) and E157E/Q (n=1).

14 of 17 patients with treatment-associated viral mutations had a C 148 mutation at baseline or in the history. Five other patients had PDVF between weeks 24 and 48 and 2 of these 5 patients had mutations that occurred during treatment. The observed mutations that occurred during treatment or combinations of mutations were L74I (n = 1), M55H(n = 2).

The VIKING-4 study examined dolutegravir (plus optimized baseline therapy) in 30 patients with primary genotypic resistance to Ini identified at screening. The mutations arising during treatment were consistent with those observed in the VIKING-3 study.

Effects on electrocardiogram (ECG)

In a randomized, crossover, placebo-controlled clinical trial, 42 healthy volunteers received a single dose of placebo, dolutegravir 250 mg suspension (approximately 3 times the exposure to 50 mg once daily in equilibrium) and moxifloxacin (400 mg, active control) in a randomized order.

Dolutegravir did not cause prolongation of the corrected interval (QTc) within 24 hours of drug administration. After correction by baseline ECG readings and placebo administration, the maximum mean change in QTc based on correction by the Frederick formula (QTcF) was 1.99 msec (upper limit of the 1-way 95% confidence interval, 4.53 msec).

Impact on renal function

. The effects of dolutegravir on serum creatinine clearance (CK), cystic filtration rate (CFR) in the yogxsol assay and effective renal plasma flow (EPP) in the para-aminogipiurate assay were evaluated in an open randomized, placebo-controlled, 3-group study involving 37 healthy volunteers, who took 50 mg of dolutegravir once daily (n = 12), 50 mg twice daily (n = 13), or placebo once daily (n = 12) for 14 days.

There was a moderate decrease in CK with dolutegravir during the first week of treatment, consistent with the decrease seen in clinical trials.

In both doses, dolutegravir had no significant effect on GFR or EPP these findings are supported by in vitro studies, which suggest that the small increases in creatinine seen in clinical trials are due to nonpathological inhibition of the organic cation transporter (OCT2) in proximal renal tubules, which accounts for the tubular secretion of creatinine.

Pharmacokinetics

The pharmacokinetics of dolutegravir are similar in healthy volunteers and HIV-infected patients. The variability in the pharmacokinetics of dolutegravir was low to moderate.

In Phase 1 studies involving healthy volunteers, the coefficient of variation (KB) among participants for the area under the pharmacokinetic concentration-time curve (AUC) and for maximum concentration (C mah) ranged from 20 to 40%, and the end-of-dosing interval concentration (Cmax) ranged from 30 to 65%. Individual variability in dolutegravir pharmacokinetics between participants was higher in HIV-infected patients than in healthy volunteers. Individual variability in pharmacokinetics was lower than variability between individuals.

Introduction

Dolutegravir is rapidly absorbed after oral administration, with a median time to reach maximum concentration (Tmax) after a dose in tablet form of 2-3 hours. The linearity of the pharmacokinetics of dolutegravir depends on the dose and the dosage form.

After oral administration, dolutegravir in tablet form generally exhibited nonlinear pharmacokinetics, with a less than dose-dependent increase in plasma exposure from 2 to 100 mg, but the increase in dolutegravir exposure was proportional to the dose from 25 mg to 50 mg.

Dolutegravir can be taken regardless of food intake. Food increases the degree and decreases the rate of absorption of dolutegravir. The bioavailability of dolutegravir is dependent on the lean content: low-, moderate- and high-fat AUQ0-∞) dolutegravir was increased by 33 %, 41 % and 66 %, Cmax was increased by 46 %, 52 % and 67 %, Tmax was prolonged to 3, 4 and 5 hours compared to 2 hours when taken on an empty stomach, respectively. These increases have no clinical significance. The absolute bioavailability of dolutegravir has not been established.

Distribution

According to the data obtained in vitro, dolutegravir is significantly (99.3%) bound to human plasma proteins.

The apparent volume of distribution (after oral administration in the form of suspension, Vd/F) is approximately 12.5 l. The binding of dolutegravir to plasma proteins was independent of the concentration. The ratios of the total concentration of the radioactively labeled drug in blood to plasma were 0.441-0.535, indicating minimal binding of the radioactively labeled drug to cellular components of the blood.

The free plasma fraction of dolutegravir was approximately 0.2-1.1% in healthy volunteers, approximately 0.4-0.5% in patients with moderate hepatic impairment, 0.8-1.0% in patients with severe renal impairment, and 0.5% in patients infected with HIV-1.

Dolutegravir penetrates cerebrospinal fluid (CSF). In 12 previously untreated patients who received dolutegravir and abacavir/lamivudine II for 16 weeks, the mean concentration of dolutegravir in CSF was 15.4 ng/mL at week 2 and 12.6 ng/mL at week 16, with a range of 3.7 to 23.2 ng/mL (comparable to the pretreatment plasma concentration).

The ratio of dolutegravir concentration in CSF to plasma concentration ranged from 0.11 to 2.04%. Concentrations of dolutegravir in CSF exceeded IC50, confirming a median decrease in HIV-1 RNA concentration in CSF compared with baseline concentration at 2.2 log tcl 2 weeks of therapy and 3.4 log after 16 weeks of therapy (see subsection Pharmacodynamics).

Delutegravir is detectable in the male and female genital tracts. The AUC in cervico-vaginal fluid, cervical and vaginal tissues was 6-10% of that in plasma in equilibrium. AUC in seminal fluid was 7% and in rectal tissues 17% of that in blood plasma at equilibrium concentration.

Metabolism

Dolutegravir is primarily metabolized by uridine diphosphate-glucoronosyltransferase UDF-GT1A1 with a minor component of the CYP3A isoenzyme (9.7% of total dose taken in a mass balance study in humans).

Dolutegravir is the major compound circulating in plasma, and is slightly excreted unchanged through the uterus (<1% of the dose). 53% of the total dose taken internally is excreted unchanged through the intestine.

It is unknown whether this is due to incomplete absorption of the drug or to excretion with the bile of the glucuronide conjugate, which may further break down to form related compounds in the intestinal lumen. 31% of the total dose taken orally is excreted through the kidneys in the form of doluguegravir glucuronide ester (18.9% of the total dose). N-dealkylated metabolite (3.6% of total dose) and metabolite formed by benzyl carbon acidification (3.0% of total dose).

Elimination

The final half-life of doluguegravir is approximately 14 hours and apparent clearance (CL/F) is 0.56 L/h.

Indications

Treatment of HIV-1 infection in adults and children from 12 years old and weighing 40 kg or more as part of combination antiretroviral therapy (APT).

Active ingredient

Dolutegravir

Composition

1 tablet contains:

The active ingredient:

dolutegravir sodium – 52.6 mg, which corresponds to the content of dolutegravir – 50 mg;

Excipients:

mannitol – q.s. to 145.4 mg,

microcrystalline cellulose – 60 mg,

povidone K29/32 – 15 mg,

Sodium carboxymethyl starch – 21 mg,

Sodium stearyl fumarate – 6 mg;

Contents of the film coating: Opadray II Yellow 85A92461 – 9 mg (hydrolyzed polyvinyl alcohol 40%, titanium dioxide 23.45%, macrogol (polyethylene glycol) 20.2%, talc 14.8%, iron oxide yellow 1.55%).

.

How to take, the dosage

Tivicay therapy should be given by a physician experienced in treating HIV infection

Tivicay can be taken regardless of food intake.

Adults

Patients infected with HIV-1 without resistance to AIs

The recommended dose of Tivicay is 50 mg once daily.

When used concomitantly with efavirenz, nevirapine, rifampicin or tmpranavir in combination with ritonavir, the recommended dose of Tivicay in this patient population should be 50 mg twice daily.

Patients infected with HIV-1 with resistance to AIs (documented or suspected clinically)

The recommended dose of Tivicay* is 50 mg twice daily. The decision to use Tivicai in such patients should be made taking into account drug resistance to InI.

In this category of patients, concomitant use with efavirenz, nevirapine, rifampicin, or tipranavir in combination with ritonavir should be avoided.

If a patient misses a dose of Tivicay*, they should take the missed dose as soon as possible if there is at least 4 hours before the next dose. If the next dose is less than 4 hours away, the patient should not take the missed dose and should resume taking the medication according to the schedule.

Children 12 to 18 years of age and 40 kg or more in weight

The recommended dose of Tivicay for patients who have not previously been treated with InI (age 12 to 18 years and body weight 40 kg or more) is 50 mg once daily.

There is insufficient data to recommend a dose of Tivicay for children aged 12 to 18 years with resistance to InI.

Particular patient groups

Children under 12 years of age and with a body weight less than 40 kg

There are insufficient safety and effectiveness data to recommend a dose of Tivicai for children under 12 years of age or with a body weight less than 40 kg.

Patients in the Elderly

There are limited data on the use of Tivicay in patients aged 65 years and older. However, there are no data on the need for dose adjustment in elderly patients (see section “Pharmacokinetics” – “Special patient groups”).

Patients with impaired renal function

Patients with mild, moderate or severe impaired renal function (CK <30 ml/min, not on dialysis) do not require dose adjustment. No data are available for patients on dialysis, but no differences in pharmacokinetics are expected in this population (see section “Pharmacokinetics” – “Special patient groups”).

Patients with hepatic impairment

Patients with mild to moderate hepatic impairment (Child-Pugh class A or B) do not require dose adjustments.

Special Instructions

Hypersensitivity reactions

Hypersensitivity reactions characterized by rash, abnormal systemic signs, and occasionally organ dysfunction, including liver damage, have been reported with InI, including Tivikai.

In the event of signs or symptoms of hypersensitivity (including, but not limited to, severe rash or rash accompanied by elevated body temperature, general malaise, fatigue, muscle or joint pain.

Bullous lesions, oral mucosal lesions, conjunctivitis, facial edema, hepatitis, eosinophilia, angioedema) the use of Tivicay and other medications that could cause these reactions must be stopped immediately.

The clinical condition, including hepatic aminotransferase values, should be monitored and appropriate therapy should be given.

A delay in discontinuing treatment with Tivicay* or other drugs that could cause these reactions after a hypersensitivity reaction has developed can lead to life-threatening reactions.

Immune reconstitution syndrome

In HIV-infected patients with severe immunodeficiency, an inflammatory response to asymptomatic or residual opportunistic infections may occur during initiation of APT and may cause serious clinical conditions or exacerbation of symptoms.

In general, such reactions have been observed within the first few weeks or months after initiation of APT. Typical examples of such standoffs include cytomegalovirus retinitis, generalized and/or focal mycobacterial infections, and pneumonia caused by Pneumocystis jiroveci (P. carinii).

Any inflammatory symptoms should be evaluated without delay and, if necessary, treatment should be started. Autoimmune diseases (such as Graves’ disease, polymyositis and Guillain-Barré syndrome) have been observed against the background of immune reconstitution, but the timing of initial manifestations varied, and the disease could occur many months after therapy and have an atypical course.

At the beginning of therapy with Tivicay, some patients with hepatitis B and or C co-infection showed increased liver enzyme activity reflecting immune reconstitution syndrome. It is recommended to monitor liver enzyme activity in patients with hepatitis B and/or C co-infection.

Particular monitoring of initiation or continuation of hepatitis B therapy (according to current guidelines) in patients treated with dolutegravir is necessary (see section “Side effects”).

Opportunistic infections

Patients receiving Tivicay or other APT may develop opportunistic infections or other complications of HIV infection. Therefore, patients must be closely monitored clinically by a physician experienced in the management of HIV-associated diseases.

Transmission

Patients should be advised that there is no proven prevention of the risk of sexual or blood-borne transmission of HIV to others when taking currently available APT, including Tivicay. You should continue to take the necessary precautions.

Interaction with other medications

Cautions should be taken when using concomitantly with medications (prescription and over-the-counter) that may alter exposure to dolutegravir or medications whose exposure may be altered by dolutegravir (see section “Interaction with other medications”).

The recommended dose of Tivicay is 50 mg twice daily when concomitantly used with etravirine (without protease inhibitors), efavirenz, nevirapine, tipranavir/ritonavir. rifampicin, carbamazepine, phenytoin, phenobarbital and St. John’s wort (see section “Interaction with other medicinal products”).

Tivicay should not be administered together with antacids containing pelyvalent cations. It is recommended to use Tivicay 2 hours before or 6 hours after administration of these drugs (see section “Interaction with other medicinal products”).

Tivicay is recommended 2 hours before or 6 hours after taking calcium or iron supplements, or alternatively, with food (see “Interaction with other medicines”).

The drug Tivicay increases mstformin concentrations. Consideration should be given to adjusting the dose of metformin at initiation and at discontinuation of co-administration of dolutegravir with metformin, to maintain glycemic control (see section “Interaction with other medicinal products”).

Resistance to integrase inhibitors of particular importance

. When deciding whether to use dolutegravir in the presence of resistance to I&I, it should be kept in mind that dolutegravir activity against viral strains carrying Q148 + >2 secondary mutations at the G140A/C/S, E138A/K/T, L74I sites is significantly reduced.

The extent to which dolutegravir provides additional efficacy in the presence of such resistance to AI remains unclear.

Osteonecrosis

While the etiology of this disease is multifactorial (including corticosteroids, diphosphonates, alcohol use, severe immunosuppression, and high body mass index), cases of osteonecrosis were most common in patients with advanced HIV infection and/or long-term combined APT.

Patients should see their doctor if they experience pain and stiffness in their joints or difficulty moving.

Impact on the ability to operate vehicles, machinery

Tivicay has not been studied for its effect on the ability to operate vehicles and machinery. The clinical condition of the patient and the profile of adverse events of the drug Tivicay® should be considered when considering the patient’s ability to drive or operate machinery.

Contraindications

Hypersensitivity to dolutegravir or any other drug ingredient. Simultaneous use with dofetilide or pelsicainide, children under 12 years of age and body weight less than 40 kg.

WARNING

Severe hepatic impairment (Child-Pugh class C);

. When used concomitantly with drugs (prescription and over-the-counter) which may modify the effects of Tivicay®, or with drugs the effects of which may be modified by Tivicay®.

Side effects

The adverse reactions presented below are established through analysis of aggregate data from Phase IIb and III clinical trials and are listed according to organ and organ system involvement and frequency of occurrence. The frequency of occurrence is defined as follows: very common (≥1/10), common (≥1/100 and < 1/10), infrequent (≥1/1,000 and < 1/100), rare (≥1/10,000 and < 1/1,000) and very rare (< 1/10,000, including individual cases).

Frequency of adverse reactions

Immune system disorders

Infrequent: hypersensitivity reaction, immune reconstitution syndrome.

Mental disorders

Often: insomnia, unusual dreams, depression.

Infrequent: suicidal ideation or suicide attempt (especially in patients with a history of depression or mental illness).

Nervous system disorders

Very common: headache, often: dizziness.

Gastrointestinal disorders

Very common: nausea, diarrhea,

Often: vomiting, flatulence, pain in the upper abdomen, abdominal pain, abdominal discomfort.

Liver and biliary tract disorders

Infrequent: hepatitis.

Skin and subcutaneous tissue disorders

Often: rash, itching.

General disorders and disorders at the site of administration

Often: fatigue.

Laboratory and instrumental data

Often: increased alanine aminotransferase (ALT) and/or aspartate aminotransferase (ACT) activity, creatine phosphokinase (CPK).

The safety profile was similar in populations of previously untreated patients, patients treated (and not taking integrase inhibitors), and patients with resistance to integrase inhibitors.

Description of selected side effects

Changes in laboratory parameters

In the first week of treatment with Tivicay® there was an increase in serum creatinine concentration, which persisted for 48 weeks. The mean change in creatinine concentration at week 48 of therapy was 9.96 μmol/l.

The increase in creatinine concentration was comparable for the different background regimens of therapy. These changes are not considered clinically significant because they do not reflect changes in glomerular filtration rate.

Immune reconstitution syndrome

At the time of initiation of combination antiretroviral therapy (cART), HIV-infected patients with severe immunodeficiency may develop an inflammatory response with asymptomatic opportunistic infections or their residual effects.

In cases of autoimmune diseases (e.g., Graves’ disease) developing against the background of immune reconstitution have also been reported, but the time of initial manifestations varied, and the disease could arise many months after initiation of therapy.

Performance in children

Based on limited data on use in children and adolescents aged 12 to 18 years, it can be concluded that there are no additional types of adverse reactions beyond those seen in adults.

HIV and hepatitis B or C virus co-infection

In Phase III studies, patients with hepatitis B and/or C virus co-infection were allowed to be included as long as baseline laboratory liver function results did not exceed the upper limit of normal (ULN) by more than 5-fold.

In general, the safety profile of patients with hepatitis B and/or C virus coinfection was similar to that of patients without hepatitis B or C virus coinfection, although the incidence of ACT and ALT activity abnormalities was higher in the subgroup of patients with hepatitis B and/or C virus coinfection in all treatment groups.

Elevated liver enzyme activity, consistent with immune reconstitution syndrome, was observed in some patients with hepatitis B and/or C virus coinfection at the start of therapy with Tivicay®, especially in those in whom hepatitis B treatment had been discontinued.

Post-registration data

Muscular and connective tissue disorders

Infrequent: arthralgia, myalgia.

Overdose

Symptoms

Tivicaine overdose data are limited.

Limited experience with higher single doses (up to 250 mg in healthy volunteers) has shown no specific symptoms or signs other than those described in the “Adverse Effects” section.

Treatment

The further treatment should be in accordance with clinical indications or the recommendations of the national poison center, where applicable. There is no specific treatment for overdose with Tivicay.

In case of overdose, supportive therapy and appropriate monitoring are necessary. Due to the high binding of dolutegravir to plasma proteins, it is unlikely that a significant amount can be excreted by dialysis.

Pregnancy use

Fertility

Tivicay has not been shown to affect fertility in males or females. Animal studies have shown no effect of dolutegravir on fertility in males or females.

Pregnancy

Tivicay has not been adequately and well controlled in pregnant women.

The effect of Tivicay on pregnancy in women is unknown. In animal studies of reproductive toxicity, dolutegravir has been shown to penetrate the placenta. The drug Tivicay® may be used during pregnancy only if the expected benefit to the mother exceeds the potential risk to the fetus.

Breastfeeding period

If HIV-infected patients are advised not to breastfeed their children to avoid vertical transmission of HIV infection.

Based on data in animals, dolutegravir is expected to be excreted in women with breast milk, although this has not been confirmed in humans.