INSTGRA

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT INSTGRA (INSTGRA)

Composition:

Active substance: dolutegravir;

1 tablet contains dolutegravir sodium equivalent to dolutegravir 50 mg;

Excipients: mannite (E 421), microcrystalline cellulose, sodium starch glycolate (type A), povidone, sodium stearyl fumarate, Opadry II Blue 85F505121 coating: polyvinyl alcohol, titanium dioxide (E 171), macrogol, talc, indigo carmine lake (E 132).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: round, film-coated, light blue tablets, debossed with "HP" on one side and "526" on the other side.

Pharmacotherapeutic group.

Antivirals for systemic use. Direct-acting antivirals. Other antivirals. ATC code J05A X12.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action

Dolutegravir inhibits HIV integrase by binding to the active site of the integrase enzyme and blocking the integration step of retroviral deoxyribonucleic acid (DNA), which is essential for the replication cycle of human immunodeficiency virus (HIV).

Antiviral activity in combination with other antiviral agents

No antagonistic effect was observed in vitro when dolutegravir was used in combination with other investigated antiretroviral agents: stavudine, abacavir, efavirenz, nevirapine, lopinavir, amprenavir, enfuvirtide, maraviroc, and raltegravir. No antagonistic effect was observed between dolutegravir and adefovir, and ribavirin had no apparent effect on the activity of dolutegravir.

Pharmacokinetics.

The pharmacokinetics of dolutegravir are similar in healthy and HIV-infected individuals. The pharmacokinetic variability of dolutegravir is low to moderate. In Phase I studies among healthy volunteers, the coefficient of variation (CV) for area under the concentration-time curve (AUC) and maximum concentration (Cmax) ranged from ~20% to 40%, while the concentration at the end of the dosing interval (Cτ) ranged from 30% to 65% across all studies. The pharmacokinetic variability of dolutegravir was higher in HIV-infected patients compared to healthy volunteers. Intra-patient variability (CVw%) is lower than inter-patient variability.

Absorption

Dolutegravir is rapidly absorbed after oral administration, with a median time to reach maximum concentration (Tmax) of 2–3 hours after tablet intake. Food intake increased the extent and slowed the rate of dolutegravir absorption. The bioavailability of dolutegravir depends on the composition of food: low-, medium-, and high-fat meals increased the AUC(0–∞) of dolutegravir by 33%, 41%, and 66%, increased Cmax by 46%, 52%, and 67%, and prolonged Tmax to 3, 4, and 5 hours, respectively, compared to 2 hours under fasting conditions. This increase in pharmacokinetic parameters may be clinically significant in patients with existing resistance to integrase inhibitor class drugs. Therefore, dolutegravir should be administered with food in HIV-infected patients with resistance to integrase inhibitor class drugs (see section "Dosage and administration"). The absolute bioavailability of dolutegravir has not been determined.

Distribution

Dolutegravir has a high binding capacity (>99%) to plasma proteins, as determined from in vitro data. The apparent volume of distribution is 17–20 L in HIV-infected patients based on population pharmacokinetic analysis. The total blood-to-plasma ratios of radioactivity associated with the drug range from 0.441 to 0.535, indicating minimal binding of radioactivity to blood cellular components. The unbound fraction of dolutegravir in plasma increases with low serum albumin levels (<35 g/L), which may be observed in patients with moderate hepatic impairment.

Dolutegravir is detectable in cerebrospinal fluid (CSF). In 13 treatment-naïve patients currently on a stable regimen of dolutegravir in combination with abacavir/lamivudine, the concentration of dolutegravir in CSF averaged 18 ng/mL (at the level of unbound drug concentration in plasma and above IC50).

Dolutegravir is detectable in the genital tracts of men and women. AUC in cervical-vaginal secretions, cervical tissue, and vaginal tissue was 6–10% of the corresponding plasma value at steady state. AUC in semen and rectal tissue was 7% and 17% of the corresponding plasma value at steady state, respectively.

Biotransformation

Dolutegravir is primarily metabolized via glucuronidation by the UGT1A1 enzyme, with minor involvement of CYP3A. Dolutegravir circulates predominantly unchanged in plasma; renal excretion of unchanged active substance is very low (<1% of dose). 53% of the total orally administered dose is excreted unchanged in feces. It is unknown whether this is fully or partially related to unabsorbed drug or biliary excretion of the glucuronide conjugate, which may subsequently be hydrolyzed to release the parent compound in the intestinal lumen. 32% of the total orally administered dose is excreted in urine as dolutegravir glucuronide (18.9% of total dose), N-dealkylation metabolite (3.6% of total dose), and a metabolite formed by oxidation at the benzyl carbon (3% of total dose).

Interaction with medicinal products

In vitro, dolutegravir showed no direct or weak inhibition (IC50 > 50 µM) of cytochrome P450 enzymes (CYP)1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A, uridine diphosphate-glucuronosyltransferases (UGT)1A1 or UGT2B7, or transporters Pgp, BCRP, BSEP, OATP1B1, OATP1B3, OCT1, MATE2-K, MRP2, or MRP4. In vitro, dolutegravir does not induce CYP1A2, CYP2B6, or CYP3A4 enzymes. Based on these data, no effect of dolutegravir on the pharmacokinetics of medicinal products that are substrates of major enzymes or transporters is expected (see section "Interaction with other medicinal products and other forms of interaction").

In vitro, dolutegravir was not a substrate of human OATP1B1, OATP1B3, or OCT1.

Elimination

The elimination half-life of dolutegravir is ~14 hours. The apparent total clearance of the drug from plasma (CL/F) is approximately 1 L/hour in HIV-infected patients, as determined by population pharmacokinetic analysis. Linearity/non-linearity

The linearity of dolutegravir pharmacokinetics depends on dose and pharmaceutical form. After oral administration, dolutegravir exhibits non-linear pharmacokinetics with less than dose-proportional increases in plasma concentrations at doses ranging from 2 mg to 100 mg, although the increase in dolutegravir concentration is dose-proportional at doses from 25 mg to 50 mg (for tablets). When administered at 50 mg twice daily, the 24-hour concentration was approximately doubled compared to 50 mg once daily.

Pharmacokinetic/pharmacodynamic relationship

In a randomized dose-finding study, patients infected with HIV-1 received dolutegravir as monotherapy (ING111521). Rapid and dose-dependent antiviral activity was demonstrated, with a mean reduction in HIV-1 RNA of 2.5 log10 by day 11 for the 50 mg dose. This antiviral response was maintained for 3–4 days after the last dose in the group receiving 50 mg.

Special populations

Children

Pharmacokinetics of dolutegravir in 10 children aged 12 years and older infected with HIV-1 who were receiving antiretroviral therapy showed that an oral dose of dolutegravir 50 mg once daily results in dolutegravir concentrations comparable to those observed in adults receiving dolutegravir 50 mg orally once daily.

Elderly patients

Population pharmacokinetic analysis of dolutegravir using data from adults infected with HIV-1 showed no clinically significant effect of age on dolutegravir concentrations.

Pharmacokinetic data for dolutegravir in patients over 65 years of age are limited. Renal impairment

Renal clearance of unchanged active substance is a minor elimination pathway for dolutegravir. A pharmacokinetic study of dolutegravir was conducted in patients with severe renal impairment (creatinine clearance <30 mL/min) and healthy control volunteers. Dolutegravir concentrations decreased by approximately 40% in patients with severe renal impairment. The mechanism of this phenomenon is unknown. Dose adjustment is not considered necessary for patients with renal impairment. Dolutegravir has not been studied in patients on dialysis.

Hepatic impairment

Dolutegravir is primarily metabolized and eliminated by the liver. A single 50 mg dose of dolutegravir was administered to 8 patients with moderate hepatic impairment (Child-Pugh class B) and 8 healthy control volunteers. Although total plasma dolutegravir concentrations were similar, patients with moderate hepatic impairment showed a 1.5- to 2-fold increase in unbound dolutegravir concentration compared to healthy control volunteers. Dose adjustment is not considered necessary for patients with mild or moderate hepatic impairment. The effect of severe hepatic impairment on the pharmacokinetics of dolutegravir has not been studied.

Clinical characteristics.

Indications.

INSTGRA is indicated in combination with other antiretroviral medicinal products for the treatment of adults and children aged 12 years and older infected with human immunodeficiency virus (HIV).

Contraindications.

Hypersensitivity to the active substance or to any of the excipients of the medicinal product. Concomitant use with medicinal products having a narrow therapeutic window that are substrates of organic cation transporter 2 (OCT2), including but not limited to fampridine (also known as dalfampridine) (see section "Interaction with other medicinal products and other types of interactions").

Interaction with other medicinal products and other types of interactions.

Effect of other medicinal products on the pharmacokinetics of dolutegravir

If resistance to integrase inhibitor class drugs exists, factors reducing dolutegravir concentrations should be avoided.

Dolutegravir is primarily eliminated via metabolism mediated by the UGT1A1 enzyme. Dolutegravir is also a substrate of UGT1A3, UGT1A9, CYP3A4, P-gp, and BCRP (breast cancer resistance protein). Therefore, medicinal products that induce these enzymes may reduce plasma concentrations of dolutegravir and diminish its therapeutic effect (see Table 1). Concomitant administration of dolutegravir with other medicinal products that inhibit these enzymes may increase plasma concentrations of dolutegravir (see Table 1).

Absorption of dolutegravir is reduced by certain antacid agents (see Table 1).

Effect of dolutegravir on the pharmacokinetics of other medicinal products

In vivo, dolutegravir does not affect midazolam—a CYP3A4 probe. Based on in vivo and in vitro data, no effect of dolutegravir on the pharmacokinetics of medicinal products that are substrates of major enzymes or transporters such as CYP3A4, CYP2C9, or P-gp is expected.

In vitro, dolutegravir inhibits the renal transporter organic cation transporter 2 (OCT2) and multidrug and toxin extrusion protein 1 (MATE-1). In vivo, a 10–14% reduction in creatinine clearance has been observed in patients (the secretory component is dependent on OCT2 and MATE-1 transporters). In vivo, dolutegravir may increase plasma concentrations of medicinal products whose elimination depends on OCT2 or MATE-1, such as dofetilide and metformin (see Table 1 and section "Contraindications").

In vitro, dolutegravir inhibits renal uptake transporters organic anion transporters (OAT1 and OAT3). Given the minimal effect of tenofovir substrate on OAT pharmacokinetics in vivo, inhibition of OAT1 in vivo is unlikely. Inhibition of OAT3 has not been studied in vivo. Dolutegravir may increase plasma concentrations of medicinal products whose elimination depends on OAT3.

Established and potential interactions with specific antiretroviral and other medicinal products are listed in Table 1, where increases are denoted by the symbol ↑, decreases by ↓, and no change by ↔. AUC denotes area under the concentration-time curve, Cmax denotes maximum observed concentration, and Cτ denotes concentration at the end of the dosing interval.

Table 1

Drug interaction table

Children

Interaction studies have been conducted only in adults.

Special precautions for use.

Although effective viral suppression by antiretroviral agents has been proven to substantially reduce the risk of sexual transmission, residual risk cannot be excluded. Preventive measures to prevent virus transmission should be taken in accordance with national recommendations.

Resistance to integrase inhibitor class drugs, which is of particular concern

When considering the use of dolutegravir in the presence of resistance to integrase inhibitor class drugs, it should be noted that the activity of dolutegravir is significantly reduced in patients infected with viral strains harboring secondary mutations Q148+ ≥ 2 from G140A/C/S, E138A/K/T, L74I (see section "Pharmacodynamics"). It is unclear whether dolutegravir provides additional efficacy in the presence of such resistance to integrase inhibitors.

Hypersensitivity reactions

Hypersensitivity reactions characterized by rash, structural changes, and sometimes organ dysfunction, including severe liver reactions, have been reported with the use of dolutegravir. Dolutegravir and other medicinal products suspected of causing hypersensitivity reactions must be discontinued immediately if signs or symptoms of hypersensitivity reactions occur (including severe rash or rash accompanied by elevated liver enzymes, fever, malaise, fatigue, muscle or joint pain, blistering, oral mucosal lesions, conjunctivitis, facial swelling, eosinophilia, angioedema, but not limited to these). Clinical status, including monitoring of liver aminotransferase and bilirubin levels, should be closely monitored. Delay in discontinuing dolutegravir or other suspected active substances after hypersensitivity reactions occur may lead to the development of life-threatening allergic reactions.

Immune Reconstitution Syndrome

In HIV-infected patients with advanced immunodeficiency at the start of combination antiretroviral therapy (cART), an inflammatory response to asymptomatic or residual opportunistic pathogens may occur, leading to severe clinical manifestations or worsening of symptoms. Such reactions are typically observed within the first few weeks or months after initiating cART. Relevant examples include cytomegalovirus retinitis, generalized and/or focal mycobacterial infections, and Pneumocystis jirovecii pneumonia. Any inflammatory symptoms should be evaluated and appropriate treatment initiated if necessary. Autoimmune disorders (such as Graves' disease) have also been reported to occur during immune reconstitution. However, the reported onset of these conditions is more variable, and such events may occur many months after initiation of treatment.

In some patients co-infected with hepatitis B and/or C virus, increased biochemical markers of liver function have been observed at the beginning of dolutegravir treatment. Monitoring of liver function tests is recommended in patients co-infected with hepatitis B and/or C virus. Particular caution is required when initiating or maintaining effective hepatitis B therapy if dolutegravir-based treatment is started in patients co-infected with hepatitis B virus (see section "Adverse reactions").

Opportunistic infections

Patients should be informed that dolutegravir or any other antiretroviral agent does not cure HIV infection and that they may still develop opportunistic infections and other complications of HIV infection. Therefore, patients should remain under careful clinical monitoring by physicians experienced in managing HIV-associated diseases.

Drug interactions

In patients with resistance to integrase inhibitor class drugs, factors that reduce the effect of dolutegravir must be avoided. Such factors include concomitant use of medicinal products that decrease dolutegravir concentration (such as magnesium/aluminum-containing antacids, iron and calcium supplements, multivitamins, stimulants, etravirine (without boosted protease inhibitors), tipranavir/ritonavir, rifampicin, St. John's wort, and certain antiepileptic drugs) (see section "Interaction with other medicinal products and other forms of interaction"). Dolutegravir increases metformin concentrations. Dose adjustment of metformin may be required at the initiation and upon discontinuation of concomitant treatment with dolutegravir and metformin to maintain glycemic control (see section "Interaction with other medicinal products and other forms of interaction"). Since metformin is eliminated via the kidneys, renal function should be monitored during concomitant therapy with dolutegravir. This combination may increase the risk of lactic acidosis in patients with moderate renal impairment (stage 3a, creatinine clearance 45–59 mL/min), so particular attention is recommended. The physician should consider reducing the metformin dose.

Osteonecrosis

Although the etiology of osteonecrosis is considered multifactorial (including corticosteroid use, bisphosphonates, alcohol consumption, severe immunosuppression, and high body mass index), cases of this condition have been reported in patients with advanced HIV disease and/or long-term exposure to cART. Patients should be advised to consult a physician if they experience joint pain, stiffness, or difficulty in movement.

Body weight and metabolic parameters

During antiretroviral therapy, increases in body weight and elevations in blood lipid and glucose levels may occur. These changes may be partly attributable to improved disease control and lifestyle changes. Regarding lipid elevations, treatment effects have been demonstrated in some cases, whereas there is no strong evidence linking weight gain to treatment. Monitoring of lipid and glucose levels should be performed in accordance with HIV treatment guidelines. Lipid disorders should be managed according to clinical requirements.

Lamivudine and dolutegravir

In two large randomized, double-blind studies, GEMINI 1 and GEMINI 2 (see section "Pharmacological properties"), a two-drug regimen of dolutegravir 50 mg once daily and lamivudine 300 mg once daily was evaluated. This regimen is indicated only for the treatment of HIV-1 infection in the absence of known or suspected resistance to integrase inhibitors or lamivudine.

Important information about excipients

This medicinal product contains less than 1 mmol sodium (23 mg) per tablet, i.e., essentially "sodium-free".

Use during pregnancy or breastfeeding.

Females of reproductive potential

Females of reproductive potential should be counselled about the potential risk of neural tube defects (see below) prior to initiating dolutegravir and advised to use effective contraception.

If a woman is planning pregnancy, the benefits and risks of dolutegravir treatment should be evaluated.

Pregnancy

In a birth outcomes surveillance study in Botswana, a slightly increased incidence of neural tube defects was observed: 7 cases of neural tube defects were reported among 3591 births (0.19%; 95% CI 0.09%, 0.40%) in mothers who received dolutegravir-containing regimens from conception, compared with 21 cases among 19,361 births (0.11%; 95% CI 0.07%, 0.17%) in mothers who received regimens without dolutegravir from conception.

In the same study, two newborns whose mothers received dolutegravir during pregnancy had neural tube defects among 4448 births (0.04%), compared with 5 cases among 6748 births (0.07%) in mothers who received regimens without dolutegravir.

The background incidence of neural tube defects in the general population ranges from 0.5–1 case per 1000 live births (0.05–0.1%). Most neural tube defects occur within the first 4 weeks of embryonic development after conception (approximately 6 weeks after the last menstrual period). If pregnancy is confirmed during the first trimester while on dolutegravir, the benefits and risks of continuing dolutegravir should be evaluated, and switching to another antiretroviral regimen should be considered, taking into account gestational age and the critical period of neural tube development. Data analyzed from the Antiretroviral Pregnancy Registry do not indicate an increased risk of major birth defects in over 600 women who received dolutegravir during pregnancy. However, these data are insufficient to resolve concerns regarding the risk of neural tube defects. Reproductive toxicity studies of dolutegravir in animals did not show adverse effects on fetal development, including neural tube defects. Dolutegravir crosses the placenta in animals.

Data from over 1000 outcomes of dolutegravir exposure in women during the second and third trimesters indicate no increased risk of fetal/neonatal toxicity. Dolutegravir may be used during the second and third trimesters of pregnancy only if the expected benefit to the woman outweighs the potential risk to the fetus.

Breastfeeding period

Dolutegravir is excreted in human breast milk in small amounts. Information on the effects of dolutegravir on neonates/infants is limited. HIV-infected women should not breastfeed under any circumstances to avoid transmission of HIV.

Reproductive function

There are no data on the effect of dolutegravir on reproductive function in men and women. Animal studies did not show any effect of dolutegravir on reproductive function in males or females.

Ability to influence the speed of reactions while driving or operating machinery.

Studies evaluating the ability of dolutegravir to affect reaction speed while driving or operating machinery have not been conducted. However, patients should be informed about the possibility of dizziness during treatment with dolutegravir. The patient's clinical status and adverse reaction profile should be considered when assessing the patient's ability to drive or operate machinery.

Dosage and Administration

INSTGRA must be prescribed by a physician experienced in the management of HIV infection.

Dosage

Adults

HIV-1-infected patients without documented or clinically suspected resistance to integrase inhibitors

The recommended dose of dolutegravir is 50 mg (1 tablet) orally once daily.

The drug may be administered twice daily when co-administered with certain medications such as efavirenz, nevirapine, tipranavir/ritonavir, or rifampicin (see section "Interaction with other medicinal products and other forms of interaction").

HIV-1-infected patients with resistance to integrase inhibitor class drugs (documented or clinically suspected)

The recommended dose of dolutegravir is 50 mg (1 tablet) twice daily. When considering the use of dolutegravir in such patients, resistance to integrase inhibitors should be taken into account (see subsection "Pharmacodynamics").

Missed dose

If a patient misses a dose of the medication, they should take it as soon as possible, provided that the next dose is not due within the following 4 hours. If the next dose is due within 4 hours, the patient should not take the missed dose and should return to their regular dosing schedule.

Children aged 12 years and older

For children (aged 12 to 17 years, with body weight at least 40 kg) infected with HIV-1 without resistance to integrase inhibitors, the recommended dose of dolutegravir is 50 mg once daily.

Elderly patients

There is limited data on the use of dolutegravir in patients aged 65 years and older. There is no evidence that elderly patients require a different dosage than younger adults (see section "Pharmacokinetics").

Renal impairment

No dose adjustment is necessary for patients with mild, moderate, or severe renal impairment (creatinine clearance < 30 mL/min, not on dialysis). Data in patients on dialysis are lacking, although no differences in pharmacokinetics are expected in this population (see section "Pharmacokinetics").

Hepatic impairment

No dose adjustment is necessary for patients with mild or moderate hepatic impairment (Child-Pugh class A or B). Data in patients with severe hepatic impairment (Child-Pugh class C) are lacking; therefore, dolutegravir should be used with caution in these patients (see section "Pharmacokinetics").

Administration method

Oral administration. The drug can be taken regardless of food intake (see section "Pharmacokinetics"). If resistance to integrase inhibitors is present, the drug should be taken with food to enhance its effect, particularly in patients with Q148 mutations (see section "Pharmacokinetics").

Children

The drug is administered to children aged 12 years and older. The safety and efficacy of dolutegravir in children under 12 years of age or with body weight less than 40 kg have not been established. In cases of resistance to integrase inhibitors, there are insufficient data to recommend the use of dolutegravir in children.

Overdose

Experience with dolutegravir overdose is currently limited.

Symptoms
Based on limited experience with single high doses (up to 250 mg in healthy volunteers), no additional specific symptoms or signs were observed beyond those listed as adverse reactions.

Treatment
There is no specific treatment for dolutegravir overdose. In case of overdose, patients should receive symptomatic treatment with appropriate monitoring, if necessary. Since dolutegravir is highly plasma protein-bound, significant removal by hemodialysis is unlikely.

Adverse reactions.

Safety profile overview

The most serious adverse reaction observed in individual patients was hypersensitivity reaction, including rash and severe hepatic effects (see section "Special precautions"). The most commonly occurring adverse reactions during treatment were nausea (13%), diarrhea (18%), and headache (13%).

Adverse reactions are listed by system organ classes. Frequency of occurrence is defined as follows: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100), rare (≥ 1/10,000 to < 1/1000), very rare (< 1/10,000).

Table 2

*See below in the section "Some adverse reactions".

Some adverse reactions

Changes in laboratory biochemical parameters

Increased serum creatinine levels occurred during the first week of treatment with dolutegravir and persisted for 48 weeks. After 48 weeks of treatment, the mean change from baseline was 9.96 µmol/L. The increase in creatinine levels was similar across different background regimens. These changes are not considered clinically significant, as they do not reflect changes in glomerular filtration rate.

Concomitant hepatitis B or C virus infection

In Phase III studies, patients with concomitant hepatitis B and/or C virus infection were allowed to participate provided that baseline liver function tests did not exceed five times the upper limit of normal (ULN). Overall, the safety profile in patients with concomitant hepatitis B and/or C virus infection was similar to that in patients without concomitant hepatitis B or C virus infection, although abnormal ALT and AST levels were higher in the subgroup with concomitant hepatitis B and/or C virus infection across all treatment groups. Biochemical liver function test elevations consistent with immune reconstitution syndrome were observed in some patients with concomitant hepatitis B and/or C virus infection at the start of dolutegravir treatment, particularly in those who discontinued hepatitis B treatment (see section "Special warnings and precautions").

Immune reconstitution syndrome

In HIV-infected patients with severe immunodeficiency at the start of combination antiretroviral therapy (CART), an inflammatory response to asymptomatic or residual opportunistic infections may occur. Autoimmune disorders such as Graves' disease have also been reported; however, the reported time to onset is more variable, and these events may occur many months after initiation of treatment (see section "Special warnings and precautions").

Metabolic parameters

During antiretroviral therapy, increases in body weight and levels of lipids and blood glucose may occur (see section "Special warnings and precautions").

Children

Based on limited data in children aged 12 years and older with body weight of at least 40 kg, no additional types of adverse reactions were observed beyond those identified in adults.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after drug authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua

Shelf life. 2 years.

Storage conditions.

Store at temperatures not exceeding 25 °C in the original packaging.

Keep out of reach of children.

Packaging.

30, 90, or 180 tablets in a plastic container.

30, 90, or 180 tablets in a plastic container, with 1 plastic container in a cardboard package.

Prescription status. Prescription only.

Manufacturer.

Emcure Pharmaceuticals Ltd.

Manufacturer's address and location of operations.

Plot No. P-1 and P-2, IT/ITES Park, Phase II, MIDC, Hinjewadi, Pune - 411 057, Maharashtra, India.