Raltegravir Tablet USP 600mg Taj Pharma

  1. Name of the medicinal product

Raltegravir Tablet USP 25mg Taj Pharma
Raltegravir Tablet USP 100mg Taj Pharma
Raltegravir Tablet USP 400mg Taj Pharma
Raltegravir Tablet USP 600mg Taj Pharma

  1. Qualitative and quantitative composition

a) Raltegravir Tablet USP 25mg Taj Pharma
Each chewable tablet contains:
Raltegravir Potassium USP
Equivalent to Raltegravir 25mg

b) Raltegravir Tablet USP 100mg Taj Pharma
Each chewable tablet contains:
Raltegravir Potassium USP
Equivalent to Raltegravir 100mg

c) Raltegravir Tablet USP 400mg Taj Pharma
Each chewable tablet contains:
Raltegravir Potassium USP
Equivalent to Raltegravir 400mg

d) Raltegravir Tablet USP 600mg Taj Pharma
Each chewable tablet contains:
Raltegravir Potassium USP
Equivalent to Raltegravir 600mg

For the full list of excipients, see section 6.1.

  1. Pharmaceutical form

Chewable tablet

The pale Yellow, Round, Chewable tablet

  1. Clinical particulars
  • Therapeutic indications

Raltegravir Taj Pharma is indicated in combination with other anti-retroviral medicinal products for the treatment of human immunodeficiency virus (HIV-1) infection (see sections 4.2, 4.4, 5.1 and 5.2).

  • Posology and method of administration

Therapy should be initiated by a physician experienced in the management of HIV infection.

Posology

Raltegravir Taj Pharma should be used in combination with other active anti-retroviral therapies (ARTs) (see sections 4.4 and 5.1).

The maximum dose of the chewable tablet is 300mg twice daily.

Because the formulations have different pharmacokinetic profiles neither the chewable tablets nor the granules for oral suspension should be substituted for the 400mg tablet or 600mg tablet (see section 5.2). The chewable tablets and the granules for oral suspension have not been studied in HIV-infected adolescents (12 to 18 years) or adults.

Paediatric Population

Children at least 11 kg: weight based dose of the chewable tablet to a maximum dose of 300mg, twice daily as specified in Tables 1 and 2. The chewable tablets are available in 25mg and scored 100mg strengths.

See section 5.2 regarding the limited data on which these dose recommendations are based.

Table 1

Recommended Dose* for Raltegravir Taj Pharma Chewable Tablets for Paediatric Patients Weighing at Least 25 kg

Body weight

(kg)

Dose Number of chewable tablets
25 to less than 28 150mg twice daily 1.5 x 100mg twice daily
28 to less than 40 200mg twice daily 2 x 100mg twice daily
At least 40 300mg twice daily 3 x 100mg twice daily
*The weight-based dosing recommendation for the chewable tablet is based on approximately 6mg/kg/dose twice daily (see section 5.2).

The 100mg chewable tablet can be divided into equal 50mg doses. However, breaking the tablets should be avoided whenever possible.

If at least 4 weeks of age and weighing at least 3 kg to less than 25 kg: Weight based dosing, as specified in Table 2.

For patients weighing between 11 and 20 kg, either the chewable tablet or oral suspension can be used, as specified in Table 2. Patients can remain on the oral suspension as long as their weight is below 20 kg. Refer to Table 2 for appropriate dosing (see section 5.1).

Table 2

Recommended Dose* for Raltegravir Taj Pharma Granules For Oral Suspension and Chewable Tablets in Paediatric Patients at least 4 weeks of age and weighing 3 to 25 kg

Body Weight

(kg)

Volume (Dose) of Suspension to be Administered Number of Chewable Tablets
3 to less than 4 2.5 mL (25mg) twice daily
4 to less than 6 3 mL (30mg) twice daily
6 to less than 8 4 mL (40mg) twice daily
8 to less than 11 6 mL (60mg) twice daily
11 to less than 14 8 mL (80mg) twice daily 3 x 25mg twice daily
14 to less than 20 10 mL (100mg) twice daily 1 x 100mg twice daily
20 to less than 25 1.5 x 100mg‡ twice daily
*The weight-based dosing recommendation for the chewable tablet, and oral suspension in 10mL of water is based on approximately 6mg/kg/dose twice daily (see section 5.2).

For weight between 11 and 20 kg either formulation can be used.

Note: The chewable tablets are available as 25mg and 100mg tablets.

The 100mg chewable tablet can be divided into equal halves.

No data are available in pre-term neonates. The use of Raltegravir Taj Pharma is not recommended in pre-term neonates.

  • Patients should be instructed to keep scheduled appointments because the Raltegravir Taj Pharma dosage should be adjusted as the child grows.

Additional formulations and strengths available

Raltegravir Taj Pharma is also available in a 400mg tablet and as granules for oral suspension for use. Refer to the 400mg tablet and granules for oral suspension SmPCs for additional dosing information.

The safety and efficacy of Raltegravir Taj Pharma in preterm (<37 weeks of gestation) and low birth weight (<2000 g) newborns have not been established. No data are available in this population and no dosing recommendations can be made.

Raltegravir Taj Pharma is also available for adults and paediatric patients (weighing at least 40 kg), as a 600mg tablet to be administered as 1,200mg once daily (two 600mg tablets) for treatment-naïve patients or patients who are virologically suppressed on an initial regimen of Raltegravir Taj Pharma 400mg twice daily. Refer to the 600mg tablet SmPCs for additional dosing information.

Elderly

There is limited information regarding the use of Raltegravir Taj Pharma in the elderly (see section 5.2). Therefore, Raltegravir Taj Pharma should be used with caution in this population.

Renal impairment

No dosage adjustment is required for patients with renal impairment (see section 5.2).

Hepatic impairment

No dosage adjustment is required for patients with mild to moderate hepatic impairment. The safety and efficacy of Raltegravir Taj Pharma have not been established in patients with severe underlying liver disorders. Therefore, Raltegravir Taj Pharma should be used with caution in patients with severe hepatic impairment (see sections 4.4 and 5.2).

Method of administration

Oral use.

Raltegravir Taj Pharma chewable tablets can be administered with or without food (see section 5.2).

  • Contraindications

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

  • Special warnings and precautions for use

General

Patients should be advised that current anti-retroviral therapy does not cure HIV and has not been proven to prevent the transmission of HIV to others through blood contact. 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.

Raltegravir Taj Pharma has a relatively low genetic barrier to resistance. Therefore, whenever possible, Raltegravir Taj Pharma should be administered with two other active ARTs to minimise the potential for virological failure and the development of resistance (see section 5.1).

In treatment-naïve patients, the clinical study data on use of Raltegravir Taj Pharma are limited to use in combination with two nucleotide reverse transcriptase inhibitors (NRTIs) (emtricitabine and tenofovir disoproxil fumarate).

Depression

Depression, including suicidal ideation and behaviours, has been reported, particularly in patients with a pre-existing history of depression or psychiatric illness. Caution should be used in patients with a pre-existing history of depression or psychiatric illness.

Hepatic impairment

The safety and efficacy of Raltegravir Taj Pharma have not been established in patients with severe underlying liver disorders. Therefore, Raltegravir Taj Pharma should be used with caution in patients with severe hepatic impairment (see sections 4.2 and 5.2).

Patients with pre-existing liver dysfunction including chronic hepatitis have an increased frequency of liver function abnormalities during combination anti-retroviral therapy and should be monitored according to standard practice. If there is evidence of worsening liver disease in such patients, interruption or discontinuation of treatment should be considered.

Patients with chronic hepatitis B or C and treated with combination anti-retroviral therapy are at an increased risk for severe and potentially fatal hepatic adverse reactions.

Osteonecrosis

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

Immune reactivation syndrome

In HIV-infected patients with severe immune deficiency at the time of institution of combination anti-retroviral 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 weeks or months of initiation of CART. Relevant examples are cytomegalovirus retinitis, generalised and/or focal mycobacterial infections and pneumonia caused by Pneumocystis jiroveci (formerly known as Pneumocystis carinii). Any inflammatory symptoms should be evaluated and treatment instituted when necessary.

Autoimmune disorders (such as Graves’ disease and autoimmune hepatitis) have also been reported to occur in the setting of immune reactivation: however, the reported time to onset is more variable and these events can occur many months after initiation of treatment.

Antacids

Co-administration of Raltegravir Taj Pharma with aluminium and magnesium antacids resulted in reduced Raltegravir Taj Pharma plasma levels. Co-administration of Raltegravir Taj Pharma with aluminium and/or magnesium antacids is not recommended (see section 4.5).

Rifampicin

Caution should be used when co-administering Raltegravir Taj Pharma with strong inducers of uridine diphosphate glucuronosyltransferase (UGT) 1A1 (e.g., rifampicin). Rifampicin reduces plasma levels of Raltegravir Taj Pharma; the impact on the efficacy of Raltegravir Taj Pharma is unknown. However, if co-administration with rifampicin is unavoidable, a doubling of the dose of Raltegravir Taj Pharma can be considered in adults. There are no data to guide co-administration of Raltegravir Taj Pharma with rifampicin in patients below 18 years of age (see section 4.5).

Myopathy and rhabdomyolysis

Myopathy and rhabdomyolysis have been reported. Use with caution in patients who have had myopathy or rhabdomyolysis in the past or have any predisposing issues including other medicinal products associated with these conditions (see section 4.8).

Severe skin and hypersensitivity reactions

Severe, potentially life-threatening, and fatal skin reactions have been reported in patients taking Raltegravir Taj Pharma, in most cases concomitantly with other medicinal products associated with these reactions. These include cases of Stevens-Johnson syndrome and toxic epidermal necrolysis. Hypersensitivity reactions have also been reported and were characterised by rash, constitutional findings, and sometimes, organ dysfunction, including hepatic failure. Discontinue Raltegravir Taj Pharma and other suspect agents immediately if signs or symptoms of severe skin reactions or hypersensitivity reactions develop (including, but not limited to, severe rash or rash accompanied by fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, facial oedema, hepatitis, eosinophilia, angioedema). Clinical status including liver aminotransferases should be monitored and appropriate therapy initiated. Delay in stopping Raltegravir Taj Pharma treatment or other suspect agents after the onset of severe rash may result in a life-threatening reaction.

Rash

Rash occurred more commonly in treatment-experienced patients receiving regimens containing Raltegravir Taj Pharma and darunavir compared to patients receiving Raltegravir Taj Pharma without darunavir or darunavir without Raltegravir Taj Pharma (see section 4.8).

Fructose

Raltegravir Taj Pharma chewable tablets contain fructose and sorbitol. Patients with rare hereditary problems of fructose intolerance should not take this medicine.

  • Interaction with other medicinal products and other forms of interaction

In vitro studies indicate that Raltegravir Taj Pharma is not a substrate of cytochrome P450 (CYP) enzymes, does not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 or CYP3A, does not inhibit UDP glucuronosyltransferases (UGTs) 1A1 and 2B7, does not induce CYP3A4 and does not inhibit P-glycoprotein-mediated transport. Based on these data, Raltegravir Taj Pharma is not expected to affect the pharmacokinetics of medicinal products that are substrates of these enzymes or P-glycoprotein.

Based on in vitro and in vivo studies, Raltegravir Taj Pharma is eliminated mainly by metabolism via a UGT1A1-mediated glucuronidation pathway.

Considerable inter- and intra-individual variability was observed in the pharmacokinetics of Raltegravir Taj Pharma.

Effect of Raltegravir Taj Pharma on the pharmacokinetics of other medicinal products

In interaction studies, Raltegravir Taj Pharma did not have a clinically meaningful effect on the pharmacokinetics of etravirine, maraviroc, tenofovir disoproxil fumarate, hormonal contraceptives, methadone, midazolam or boceprevir.

In some studies, co-administration of Raltegravir Taj Pharma with darunavir resulted in a modest decrease in darunavir plasma concentrations; the mechanism for this effect is unknown. However, the effect of Raltegravir Taj Pharma on darunavir plasma concentrations does not appear to be clinically meaningful.

Effect of other medicinal products on the pharmacokinetics of Raltegravir Taj Pharma

Given that Raltegravir Taj Pharma is metabolised primarily via UGT1A1, caution should be used when co-administering Raltegravir Taj Pharma with strong inducers of UGT1A1 (e.g., rifampicin). Rifampicin reduces plasma levels of Raltegravir Taj Pharma; the impact on the efficacy of Raltegravir Taj Pharma is unknown. However, if co-administration with rifampicin is unavoidable, a doubling of the dose of Raltegravir Taj Pharma can be considered in adults. There are no data to guide co-administration of Raltegravir Taj Pharma with rifampicin in patients below 18 years of age (see section 4.4). The impact of other strong inducers of drug metabolizing enzymes, such as phenytoin and phenobarbital, on UGT1A1 is unknown. Less potent inducers (e.g., efavirenz, nevirapine, etravirine, rifabutin, glucocorticoids, St. John’s wort, pioglitazone) may be used with the recommended dose of Raltegravir Taj Pharma.

Co-administration of Raltegravir Taj Pharma with medicinal products that are known to be potent UGT1A1 inhibitors (e.g., atazanavir) may increase plasma levels of Raltegravir Taj Pharma. Less potent UGT1A1 inhibitors (e.g., indinavir, saquinavir) may also increase plasma levels of Raltegravir Taj Pharma, but to a lesser extent compared with atazanavir. In addition, tenofovir disoproxil fumarate may increase plasma levels of Raltegravir Taj Pharma, however, the mechanism for this effect is unknown (see Table 3). From the clinical trials, a large proportion of patients used atazanavir and / or tenofovir disoproxil fumarate, both agents that result in increases in Raltegravir Taj Pharma plasma levels, in the optimised background regimens. The safety profile observed in patients who used atazanavir and / or tenofovir disoproxil fumarate was generally similar to the safety profile of patients who did not use these agents. Therefore no dose adjustment is required.

Co-administration of Raltegravir Taj Pharma with antacids containing divalent metal cations may reduce Raltegravir Taj Pharma absorption by chelation, resulting in a decrease of Raltegravir Taj Pharma plasma levels. Taking an aluminium and magnesium antacid within 6 hours of Raltegravir Taj Pharma administration significantly decreased Raltegravir Taj Pharma plasma levels. Therefore, co-administration of Raltegravir Taj Pharma with aluminium and/or magnesium containing antacids is not recommended. Co-administration of Raltegravir Taj Pharma with a calcium carbonate antacid decreased Raltegravir Taj Pharma plasma levels; however, this interaction is not considered clinically meaningful. Therefore, when Raltegravir Taj Pharma is co-administered with calcium carbonate containing antacids no dose adjustment is required.

Co-administration of Raltegravir Taj Pharma with other agents that increase gastric pH (e.g., omeprazole and famotidine) may increase the rate of Raltegravir Taj Pharma absorption and result in increased plasma levels of Raltegravir Taj Pharma (see Table 3). Safety profiles in the subgroup of patients in Phase III trials taking proton pump inhibitors or H2 antagonists were comparable with those who were not taking these antacids. Therefore no dose adjustment is required with use of proton pump inhibitors or H2 antagonists.

All interaction studies have been performed in adults.

Table 3

Pharmacokinetic Interaction Data in Adults

Medicinal products by therapeutic area Interaction

(mechanism, if known)

Recommendations concerning co-administration
ANTI-RETROVIRAL
Protease inhibitors (PI)
atazanavir /ritonavir

(Raltegravir Taj Pharma 400mg Twice Daily)

Raltegravir Taj Pharma AUC ↑ 41 %

Raltegravir Taj Pharma C12hr ↑ 77 %

Raltegravir Taj Pharma Cmax ↑ 24 %

(UGT1A1 inhibition)

No dose adjustment required for Raltegravir Taj Pharma.
tipranavir /ritonavir

(Raltegravir Taj Pharma 400mg Twice Daily)

Raltegravir Taj Pharma AUC ↓ 24 %

Raltegravir Taj Pharma C12hr ↓ 55 %

Raltegravir Taj Pharma Cmax ↓ 18 %

(UGT1A1 induction)

No dose adjustment required for Raltegravir Taj Pharma.
Non-nucleoside reverse transcriptase inhibitors (NNRTIs)
efavirenz

(Raltegravir Taj Pharma 400mg Single Dose)

Raltegravir Taj Pharma AUC ↓ 36 %

Raltegravir Taj Pharma C12hr ↓ 21 %

Raltegravir Taj Pharma Cmax ↓ 36 %

(UGT1A1 induction)

No dose adjustment required for Raltegravir Taj Pharma.
etravirine

(Raltegravir Taj Pharma 400mg Twice Daily)

Raltegravir Taj Pharma AUC ↓ 10 %

Raltegravir Taj Pharma C12hr ↓ 34 %

Raltegravir Taj Pharma Cmax ↓ 11 %

(UGT1A1 induction)

etravirine AUC ↑ 10 %

etravirine C12hr ↑ 17 %

etravirine Cmax ↑ 4 %

No dose adjustment required for Raltegravir Taj Pharma or etravirine.
Nucleoside/tide reverse transcriptase inhibitors
tenofovir disoproxil fumarate

(Raltegravir Taj Pharma 400mg Twice Daily)

Raltegravir Taj Pharma AUC ↑ 49 %

Raltegravir Taj Pharma C12hr ↑ 3 %

Raltegravir Taj Pharma Cmax ↑ 64 %

(mechanism of interaction unknown)

tenofovir AUC ↓ 10 %

tenofovir C24hr ↓ 13 %

tenofovir Cmax ↓ 23 %

No dose adjustment required for Raltegravir Taj Pharma or tenofovir disoproxil fumarate.
CCR5 inhibitors
maraviroc

(Raltegravir Taj Pharma 400mg Twice Daily)

Raltegravir Taj Pharma AUC ↓ 37 %

Raltegravir Taj Pharma C12hr ↓ 28 %

Raltegravir Taj Pharma Cmax ↓ 33 %

(mechanism of interaction unknown)

maraviroc AUC ↓ 14 %

maraviroc C12hr ↓ 10 %

maraviroc Cmax ↓ 21 %

No dose adjustment required for Raltegravir Taj Pharma or maraviroc.
HCV ANTIVIRALS
NS3/4A protease inhibitors (PI)
boceprevir

(Raltegravir Taj Pharma 400mg Single Dose)

Raltegravir Taj Pharma AUC ↑ 4 %

Raltegravir Taj Pharma C12hr ↓ 25 %

Raltegravir Taj Pharma Cmax ↑ 11 %

(mechanism of interaction unknown)

No dose adjustment required for Raltegravir Taj Pharma or boceprevir.
ANTIMICROBIALS
Antimycobacterial
rifampicin

(Raltegravir Taj Pharma 400mg Single Dose)

Raltegravir Taj Pharma AUC ↓ 40 %

Raltegravir Taj Pharma C12hr ↓ 61 %

Raltegravir Taj Pharma Cmax ↓ 38 %

(UGT1A1 induction)

Rifampicin reduces plasma levels of Raltegravir Taj Pharma. If co-administration with rifampicin is unavoidable, a doubling of the dose of Raltegravir Taj Pharma can be considered (see section 4.4).
SEDATIVE
midazolam

(Raltegravir Taj Pharma 400mg Twice Daily)

midazolam AUC ↓ 8 %

midazolam Cmax ↑ 3 %

No dosage adjustment required for Raltegravir Taj Pharma or midazolam.

These results indicate that Raltegravir Taj Pharma is not an inducer or inhibitor of CYP3A4, and Raltegravir Taj Pharma is thus not anticipated to affect the pharmacokinetics of medicinal products which are CYP3A4 substrates.

METAL CATION ANTACIDS
aluminium and magnesium hydroxide antacid

(Raltegravir Taj Pharma 400mg Twice Daily)

Raltegravir Taj Pharma AUC ↓ 49 %

Raltegravir Taj Pharma C12 hr ↓ 63 %

Raltegravir Taj Pharma Cmax ↓ 44 %

2 hours before Raltegravir Taj Pharma

Raltegravir Taj Pharma AUC ↓ 51 %

Raltegravir Taj Pharma C12 hr ↓ 56 %

Raltegravir Taj Pharma Cmax ↓ 51 %

2 hours after Raltegravir Taj Pharma

Raltegravir Taj Pharma AUC ↓ 30 %

Raltegravir Taj Pharma C12 hr ↓ 57 %

Raltegravir Taj Pharma Cmax ↓ 24 %

6 hours before Raltegravir Taj Pharma

Raltegravir Taj Pharma AUC ↓ 13 %

Raltegravir Taj Pharma C12 hr ↓ 50 %

Raltegravir Taj Pharma Cmax ↓ 10 %

6 hours after Raltegravir Taj Pharma

Raltegravir Taj Pharma AUC ↓ 11 %

Raltegravir Taj Pharma C12 hr ↓ 49 %

Raltegravir Taj Pharma Cmax ↓ 10 %

(chelation of metal cations)

Aluminium and magnesium containing antacids reduce Raltegravir Taj Pharma plasma levels. Co-administration of Raltegravir Taj Pharma with aluminium and/or magnesium containing antacids is not recommended.
calcium carbonate antacid

(Raltegravir Taj Pharma 400mg Twice Daily)

Raltegravir Taj Pharma AUC ↓ 55 %

Raltegravir Taj Pharma C12 hr ↓ 32 %

Raltegravir Taj Pharma Cmax ↓ 52 %

(chelation of metal cations)

No dose adjustment required for Raltegravir Taj Pharma.
H2 BLOCKERS AND PROTON PUMP INHIBITORS
omeprazole

(Raltegravir Taj Pharma 400mg Twice Daily)

Raltegravir Taj Pharma AUC ↑ 37 %

Raltegravir Taj Pharma C12 hr ↑ 24 %

Raltegravir Taj Pharma Cmax ↑ 51 %

(increased solubility)

No dose adjustment required for Raltegravir Taj Pharma.
famotidine

(Raltegravir Taj Pharma 400mg Twice Daily)

Raltegravir Taj Pharma AUC ↑ 44 %

Raltegravir Taj Pharma C12 hr ↑ 6 %

Raltegravir Taj Pharma Cmax ↑ 60 %

(increased solubility)

No dose adjustment required for Raltegravir Taj Pharma.
HORMONAL CONTRACEPTIVES
Ethinyl Estradiol

Norelgestromin

(Raltegravir Taj Pharma 400mg Twice Daily)

Ethinyl Estradiol AUC ↓ 2 %

Ethinyl Estradiol Cmax ↑ 6 %

Norelgestromin AUC ↑ 14 %

Norelgestromin Cmax ↑ 29 %

No dosage adjustment required for Raltegravir Taj Pharma or hormonal contraceptives (estrogen- and/or progesterone-based).
OPIOID ANALGESICS
methadone

(Raltegravir Taj Pharma 400mg Twice Daily)

methadone AUC ↔

methadone Cmax ↔

No dose adjustment required for Raltegravir Taj Pharma or methadone.
  • Fertility, pregnancy and lactation

Pregnancy

There are no data for the use of Raltegravir Taj Pharma chewable tablets in pregnant women. A moderate amount of data on pregnant women (between 300 – 1,000 pregnancy outcomes from first trimester exposure) indicate no malformative or feto/neonatal toxicity of Raltegravir Taj Pharma 400mg film-coated tablets twice daily. Animal studies have shown reproductive toxicity (see section 5.3). Raltegravir Taj Pharma chewable tablets should be used during pregnancy only if the expected benefit justifies the potential risk to the foetus. See section 4.2 for dosing recommendations.

Anti-retroviral Pregnancy Registry

To monitor maternal-foetal outcomes in patients inadvertently administered Raltegravir Taj Pharma while pregnant, an Anti-retroviral Pregnancy Registry has been established. Physicians are encouraged to register patients in this registry.

As a general rule, when deciding to use antiretroviral agents for the treatment of HIV infection in pregnant women and consequently for reducing the risk of HIV vertical transmission to the newborn, the animal data as well as the clinical experience in pregnant women should be taken into account in order to characterise the safety for the foetus.

Breast-feeding

It is unknown whether Raltegravir Taj Pharma/metabolites are excreted in human milk. Available pharmacodynamics/toxicological data in animals have shown excretion of Raltegravir Taj Pharma/metabolites in milk (for details see section 5.3).

A risk to the newborns/infants cannot be excluded.

Raltegravir Taj Pharma should not be used during breast-feeding. As a general rule, it is recommended that mothers infected by HIV do not breast-feed their babies in order to avoid transmission of HIV.

Fertility

No effect on fertility was seen in male and female rats at doses up to 600mg/kg/day which resulted in 3-fold exposure above the exposure at the recommended human dose.

  • Effects on ability to drive and use machines

Dizziness has been reported in some patients during treatment with regimens containing Raltegravir Taj Pharma. Dizziness may influence some patients’ ability to drive and use machines (see section 4.8).

  • Undesirable effects

Summary of the safety profile

In randomised clinical trials Raltegravir Taj Pharma 400mg twice daily was administered in combination with fixed or optimised background treatment regimens to treatment-naïve (N=547) and treatment-experienced (N=462) adults for up to 96 weeks. A further 531 treatment-naïve adults have received Raltegravir Taj Pharma 1,200mg once daily with emtricitabine and tenofovir disoproxil fumarate for up to 96 weeks. See section 5.1.

The most frequently reported adverse reactions during treatment were headache, nausea and abdominal pain. The most frequently reported serious adverse reaction was immune reconstitution syndrome and rash. The rates of discontinuation of Raltegravir Taj Pharma due to adverse reactions were 5% or less in clinical trials.

Rhabdomyolysis was an uncommonly reported serious adverse reaction in post-marketing use of Raltegravir Taj Pharma 400mg twice daily.

Tabulated summary of adverse reactions

Adverse reactions considered by investigators to be causally related to Raltegravir Taj Pharma (alone or in combination with other ART), as well as adverse reactions established in post-marketing experience, are listed below by System Organ Class. Frequencies are defined as common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), and not known (cannot be estimated from the available data).

System Organ Class Frequency Adverse reactions

Raltegravir Taj Pharma (alone or in combination with other ART)

Infections and infestations Uncommon genital herpes, folliculitis, gastroenteritis, herpes simplex, herpes virus infection, herpes zoster, influenza, lymph node abscess, molluscum contagiosum, nasopharyngitis, upper respiratory tract infection
Neoplasms benign, malignant and unspecified (including cysts and polyps) Uncommon skin papilloma
Blood and lymphatic system disorders Uncommon anaemia, iron deficiency anaemia, lymph node pain, lymphadenopathy, neutropenia, thrombocytopenia
Immune system disorders Uncommon immune reconstitution syndrome, drug hypersensitivity, hypersensitivity
Metabolism and nutrition disorders Common decreased appetite
Uncommon cachexia, diabetes mellitus, dyslipidaemia, hypercholesterolaemia, hyperglycaemia, hyperlipidaemia, hyperphagia, increased appetite, polydipsia, body fat disorder
Psychiatric disorders Common abnormal dreams, insomnia, nightmare, abnormal behaviour, depression
Uncommon mental disorder, suicide attempt, anxiety, confusional state, depressed mood, major depression, middle insomnia, mood altered, panic attack, sleep disorder, suicidal ideation, suicidal behaviour (particularly in patients with a pre-existing history of psychiatric illness)
Nervous system disorders Common dizziness, headache, psychomotor hyperactivity
Uncommon amnesia, carpal tunnel syndrome, cognitive disorder, disturbance in attention, dizziness postural, dysgeusia, hypersomnia, hypoaesthesia, lethargy, memory impairment, migraine, neuropathy peripheral, paraesthesia, somnolence, tension headache, tremor, poor quality sleep
Eye disorders Uncommon visual impairment
Ear and labyrinth disorders Common vertigo
Uncommon tinnitus
Cardiac disorders Uncommon palpitations, sinus bradycardia, ventricular extrasystoles
Vascular disorders Uncommon hot flush, hypertension
Respiratory, thoracic and mediastinal disorders Uncommon dysphonia, epistaxis, nasal congestion
Gastrointestinal disorders Common abdominal distention, abdominal pain, diarrhoea, flatulence, nausea, vomiting, dyspepsia
Uncommon gastritis, abdominal discomfort, abdominal pain upper, abdominal tenderness, anorectal discomfort, constipation, dry mouth, epigastric discomfort, erosive duodenitis, eructation, gastroesophageal reflux disease, gingivitis, glossitis, odynophagia, pancreatitis acute, peptic ulcer, rectal haemorrhage
Hepato-biliary disorders Uncommon hepatitis, hepatic steatosis, hepatitis alcoholic, hepatic failure
Skin and subcutaneous tissue disorders Common rash
Uncommon acne, alopecia, dermatitis acneiforme, dry skin, erythema, facial wasting, hyperhidrosis, lipoatrophy, lipodystrophy acquired, lipohypertrophy, night sweats, prurigo, pruritus, pruritus generalised, rash macular, rash maculo-papular, rash pruritic, skin lesion, urticaria, xeroderma, Stevens Johnson syndrome, drug rash with eosinophilia and systemic symptoms (DRESS)
Musculoskeletal and connective tissue disorders Uncommon arthralgia, arthritis, back pain, flank pain, musculoskeletal pain, myalgia, neck pain, osteopenia, pain in extremity, tendonitis, rhabdomyolysis
Renal and urinary disorders Uncommon renal failure, nephritis, nephrolithiasis, nocturia, renal cyst, renal impairment, tubulointerstitial nephritis
Reproductive system and breast disorders Uncommon erectile dysfunction, gynaecomastia, menopausal symptoms
General disorders and administration site conditions Common asthenia, fatigue, pyrexia
Uncommon chest discomfort, chills, face oedema, fat tissue increased, feeling jittery, malaise, submandibular mass, oedema peripheral, pain
Investigations Common alanine aminotransferase increased, atypical lymphocytes, aspartate aminotransferase increased, blood triglycerides increased, lipase increased, blood pancreatic amylase increased
Uncommon absolute neutrophil count decreased, alkaline phosphatase increased, blood albumin decreased, blood amylase increased, blood bilirubin increased, blood cholesterol increased, blood creatinine increased, blood glucose increased, blood urea nitrogen increased, creatine phosphokinase increased, fasting blood glucose increased, glucose urine present, high density lipoprotein increased, international normalised ratio increased, low density lipoprotein increased, platelet count decreased, red blood cells urine positive, waist circumference increased, weight increased, white blood cell count decreased
Injury, poisoning and procedural complications Uncommon accidental overdose

Description of selected adverse reactions

Cancers were reported in treatment-experienced and treatment-naïve patients who initiated Raltegravir Taj Pharma in conjunction with other antiretroviral agents. The types and rates of specific cancers were those expected in a highly immunodeficient population. The risk of developing cancer in these studies was similar in the groups receiving Raltegravir Taj Pharma and in the groups receiving comparators.

Grade 2-4 creatine kinase laboratory abnormalities were observed in patients treated with Raltegravir Taj Pharma. Myopathy and rhabdomyolysis have been reported. Use with caution in patients who have had myopathy or rhabdomyolysis in the past or have any predisposing issues including other medicinal products associated with these conditions (see section 4.4).

Cases of osteonecrosis have been reported, particularly in patients with generally acknowledged risk factors, advanced HIV disease or long-term exposure to combination antiretroviral therapy (CART). The frequency of this is unknown (see section 4.4).

In HIV-infected patients with severe immune deficiency at the time of initiation of combination antiretroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunistic infections may arise. Autoimmune disorders (such as Graves’ disease and autoimmune hepatitis) have also been reported; however, the reported time to onset is more variable and these events can occur many months after initiation of treatment (see section 4.4).

For each of the following clinical adverse reactions there was at least one serious occurrence: genital herpes, anaemia, immune reconstitution syndrome, depression, mental disorder, suicide attempt, gastritis, hepatitis, renal failure, accidental overdose.

In clinical studies of treatment-experienced patients, rash, irrespective of causality, was more commonly observed with regimens containing Raltegravir Taj Pharma and darunavir compared to those containing Raltegravir Taj Pharma without darunavir or darunavir without Raltegravir Taj Pharma. Rash considered by the investigator to be drug-related occurred at similar rates. The exposure-adjusted rates of rash (all causality) were 10.9, 4.2, and 3.8 per 100 patient-years (PYR), respectively; and for drug-related rash were 2.4, 1.1, and 2.3 per 100 PYR, respectively. The rashes observed in clinical studies were mild to moderate in severity and did not result in discontinuation of therapy (see section 4.4).

Patients co-infected with hepatitis B and/or hepatitis C virus

In clinical trials, there were 79 patients co-infected with hepatitis B, 84 co-infected with hepatitis C, and 8 patients co-infected with hepatitis B and C who were treated with Raltegravir Taj Pharma in combination with other agents for HIV-1. In general the safety profile of Raltegravir Taj Pharma in patients with hepatitis B and/or hepatitis C virus co-infection was similar to that in patients without hepatitis B and/or hepatitis C virus co-infection, although the rates of AST and ALT abnormalities were somewhat higher in the subgroup co-infected with hepatitis B and/or hepatitis C virus

At 96-weeks, in treatment-experienced patients, Grade 2 or higher laboratory abnormalities that represent a worsening Grade from baseline of AST, ALT or total bilirubin occurred in 29 %, 34 % and 13 %, respectively, of co-infected patients treated with Raltegravir Taj Pharma as compared to 11 %, 10 % and 9 % of all other patients treated with Raltegravir Taj Pharma. At 240-weeks, in treatment-naïve patients, Grade 2 or higher laboratory abnormalities that represent a worsening Grade from baseline of AST, ALT or total bilirubin occurred in 22 %, 44 % and 17 %, respectively, of co-infected patients treated with Raltegravir Taj Pharma as compared to 13 %, 13 % and 5 % of all other patients treated with Raltegravir Taj Pharma.

Paediatric population

Children and adolescents 2 to 18 years of age

Raltegravir Taj Pharma has been studied in 126 antiretroviral treatment-experienced HIV-1 infected children and adolescents 2 to 18 years of age, in combination with other antiretroviral agents in IMPAACT P1066 (see sections 5.1 and 5.2). Of the 126 patients, 96 received the recommended dose of Raltegravir Taj Pharma.

In these 96 children and adolescents, frequency, type and severity of drug related adverse reactions through Week 48 were comparable to those observed in adults.

One patient experienced drug related clinical adverse reactions of Grade 3 psychomotor hyperactivity, abnormal behaviour and insomnia; one patient experienced a Grade 2 serious drug related allergic rash.

One patient experienced drug related laboratory abnormalities, Grade 4 AST and Grade 3 ALT, which were considered serious.

Infants and toddlers 4 weeks to less than 2 years of age

Raltegravir Taj Pharma has also been studied in 26 HIV-1 infected infants and toddlers 4 weeks to less than 2 years of age, in combination with other antiretroviral agents in IMPAACT P1066 (see sections 5.1 and 5.2).

In these 26 infants and toddlers, the frequency, type and severity of drug related adverse reactions through Week 48 were comparable to those observed in adults.

One patient experienced a Grade 3 serious drug related allergic rash that resulted in treatment discontinuation.

HIV-1 Exposed Neonates

In IMPAACT P1110 (see section 5.2) eligible infants were at least 37 weeks gestation and at least 2 kg in weight. Sixteen (16) neonates received 2 doses of Raltegravir Taj Pharma in first 2 weeks of life, and 26 neonates received 6 weeks of daily dosing; all were followed for 24 weeks. There were no drug related clinical adverse experiences and three drug-related laboratory adverse experiences (one a transient Grade 4 neutropenia in a subject receiving zidovudine containing prevention of mother to child transmission (PMTCT), and two bilirubin elevations (one each, Grade 1 and Grade 2) considered non-serious and not requiring specific therapy).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product.

  • Overdose

No specific information is available on the treatment of overdose with Raltegravir Taj Pharma.

In the event of an overdose, it is reasonable to employ the standard supportive measures, e.g., remove unabsorbed material from the gastrointestinal tract, employ clinical monitoring (including obtaining an electrocardiogram), and institute supportive therapy if required. It should be taken into account that Raltegravir Taj Pharma is presented for clinical use as the potassium salt. The extent to which Raltegravir Taj Pharma may be dialysable is unknown.

  1. Pharmacological properties
    • Pharmacodynamic properties

Pharmacotherapeutic group: antivirals for systemic use, other antivirals,

Mechanism of action

Raltegravir Taj Pharma is an integrase strand transfer inhibitor active against the Human Immunodeficiency Virus (HIV-1). Raltegravir Taj Pharma inhibits the catalytic activity of integrase, an HIV-encoded enzyme that is required for viral replication. Inhibition of integrase prevents the covalent insertion, or integration, of the HIV genome into the host cell genome. HIV genomes that fail to integrate cannot direct the production of new infectious viral particles, so inhibiting integration prevents propagation of the viral infection.

Antiviral activity in vitro

Raltegravir Taj Pharma at concentrations of 31 ± 20 nM resulted in 95 % inhibition (IC95) of HIV-1 replication (relative to an untreated virus-infected culture) in human T-lymphoid cell cultures infected with the cell-line adapted HIV-1 variant H9IIIB. In addition, Raltegravir Taj Pharma inhibited viral replication in cultures of mitogen-activated human peripheral blood mononuclear cells infected with diverse, primary clinical isolates of HIV-1, including isolates from 5 non-B subtypes, and isolates resistant to reverse transcriptase inhibitors and protease inhibitors. In a single-cycle infection assay, Raltegravir Taj Pharma inhibited infection of 23 HIV isolates representing 5 non-B subtypes and 5 circulating recombinant forms with IC50 values ranging from 5 to 12 nM.

Resistance

Most viruses isolated from patients failing Raltegravir Taj Pharma had high-level Raltegravir Taj Pharma resistance resulting from the appearance of two or more mutations in integrase. Most had a signature mutation at amino acid 155 (N155 changed to H), amino acid 148 (Q148 changed to H, K, or R), or amino acid 143 (Y143 changed to H, C, or R), along with one or more additional integrase mutations (e.g., L74M, E92Q, T97A, E138A/K, G140A/S, V151I, G163R, S230R). The signature mutations decrease viral susceptibility to Raltegravir Taj Pharma and addition of other mutations results in a further decrease in Raltegravir Taj Pharma susceptibility. Factors that reduced the likelihood of developing resistance included lower baseline viral load and use of other active anti-retroviral agents. Mutations conferring resistance to Raltegravir Taj Pharma generally also confer resistance to the integrase strand transfer inhibitor elvitegravir. Mutations at amino acid 143 confer greater resistance to Raltegravir Taj Pharma than to elvitegravir, and the E92Q mutation confers greater resistance to elvitegravir than to Raltegravir Taj Pharma. Viruses harbouring a mutation at amino acid 148, along with one or more other Raltegravir Taj Pharma resistance mutations, may also have clinically significant resistance to dolutegravir.

Clinical experience

The evidence of efficacy of Raltegravir Taj Pharma was based on the analyses of 96-week data from two randomised, double-blind, placebo-controlled trials (BENCHMRK 1 and BENCHMRK 2, Protocols 018 and 019) in antiretroviral treatment-experienced HIV-1 infected adult patients and the analysis of 240-week data from a randomised, double-blind, active-control trial (STARTMRK, Protocol 021) in antiretroviral treatment-naïve HIV-1 infected adult patients.

Efficacy

Treatment-experienced adult patients

BENCHMRK 1 and BENCHMRK 2 (multi-centre, randomised, double-blind, placebo-controlled trials) evaluated the safety and anti-retroviral activity of Raltegravir Taj Pharma 400mg twice daily vs. placebo in a combination with optimised background therapy (OBT), in HIV-infected patients, 16 years or older, with documented resistance to at least 1 drug in each of 3 classes (NRTIs, NNRTIs, PIs) of anti-retroviral therapies. Prior to randomisation, OBT were selected by the investigator based on the patient’s prior treatment history, as well as baseline genotypic and phenotypic viral resistance testing.

Patient demographics (gender, age and race) and baseline characteristics were comparable between the groups receiving Raltegravir Taj Pharma 400mg twice daily and placebo. Patients had prior exposure to a median of 12 anti-retrovirals for a median of 10 years. A median of 4 ARTs was used in OBT.

Results 48 week and 96 week analyses

Durable outcomes (Week 48 and Week 96) for patients on the recommended dose Raltegravir Taj Pharma 400mg twice daily from the pooled studies BENCHMRK 1 and BENCHMRK 2 are shown in Table 4.

Table 4

Efficacy Outcome at Weeks 48 and 96

BENCHMRK 1 and 2 Pooled

Parameter

48 Weeks 96 Weeks
Raltegravir Taj Pharma 400mg twice daily + OBT

(N = 462)

Placebo + OBT

(N = 237)

Raltegravir Taj Pharma 400mg twice daily + OBT

(N = 462)

Placebo + OBT

(N = 237)

Percent HIV-RNA < 400 copies/mL (95 % CI)
All patients 72 (68, 76) 37 (31, 44) 62 (57, 66) 28 (23, 34)
Baseline Characteristic
HIV-RNA > 100,000 copies/mL 62 (53, 69) 17 (9, 27) 53 (45, 61) 15 (8, 25)
≤ 100,000 copies/mL 82 (77, 86) 49 (41, 58) 74 (69, 79) 39 (31, 47)
CD4-count ≤ 50 cells/mm3 61 (53, 69) 21 (13, 32) 51 (42, 60) 14 (7, 24)
> 50 and ≤ 200 cells/mm3 80 (73, 85) 44 (33, 55) 70 (62, 77) 36 (25, 48)
> 200 cells/mm3 83 (76, 89) 51 (39, 63) 78 (70, 85) 42 (30, 55)
Sensitivity score (GSS) §
0 52 (42, 61) 8 (3, 17) 46 (36, 56) 5 (1, 13)
1 81 (75, 87) 40 (30, 51) 76 (69, 83) 31 (22, 42)
2 and above 84 (77, 89) 65 (52, 76) 71 (63, 78) 56 (43, 69)
Percent HIV-RNA < 50 copies/mL (95 % CI)
All patients 62 (57, 67) 33 (27, 39) 57 (52, 62) 26 (21, 32)
Baseline Characteristic
HIV-RNA > 100,000 copies/mL 48 (40, 56) 16 (8, 26) 47 (39, 55) 13 (7, 23)
≤ 100,000 copies/mL 73 (68, 78) 43 (35, 52) 70 (64, 75) 36 (28, 45)
CD4-count ≤ 50 cells/mm3 50 (41, 58) 20 (12, 31) 50 (41, 58) 13 (6, 22)
> 50 and ≤ 200 cells/mm3 67 (59, 74) 39 (28, 50) 65 (57, 72) 32 (22, 44)
> 200 cells/mm3 76 (68, 83) 44 (32, 56) 71 (62, 78) 41 (29, 53)
Sensitivity score (GSS) §
0 45 (35, 54) 3 (0, 11) 41 (32, 51) 5 (1, 13)
1 67 (59, 74) 37 (27, 48) 72 (64, 79) 28 (19, 39)
2 and above 75 (68, 82) 59 (46, 71) 65 (56, 72) 53 (40, 66)
Mean CD4 Cell Change (95 % CI), cells/mm3
All patients 109 (98, 121) 45 (32, 57) 123 (110, 137) 49 (35, 63)
Baseline Characteristic
HIV-RNA > 100,000 copies/mL 126 (107, 144) 36 (17, 55) 140 (115, 165) 40 (16, 65)
≤ 100,000 copies/mL 100 (86, 115) 49 (33, 65) 114 (98, 131) 53 (36, 70)
CD4-count ≤ 50 cells/mm3 121 (100, 142) 33 (18, 48) 130 (104, 156) 42 (17, 67)
> 50 and ≤ 200 cells/mm3 104 (88, 119) 47 (28, 66) 123 (103, 144) 56 (34, 79)
> 200 cells/mm3 104 (80, 129) 54 (24, 84) 117 (90, 143) 48 (23, 73)
Sensitivity score (GSS) §
0 81 (55, 106) 11 (4, 26) 97 (70, 124) 15 (-0, 31)
1 113 (96, 130) 44 (24, 63) 132 (111, 154) 45 (24, 66)
2 and above 125 (105, 144) 76 (48, 103) 134 (108, 159) 90 (57, 123)
 Non-completer is failure imputation: patients who discontinued prematurely are imputed as failure thereafter. Percent of patients with response and associated 95 % confidence interval (CI) are reported.

 For analysis by prognostic factors, virologic failures were carried forward for percent < 400 and 50 copies/mL. For mean CD4 changes, baseline-carry-forward was used for virologic failures.

§ The Genotypic Sensitivity Score (GSS) was defined as the total oral ARTs in the optimised background therapy (OBT) to which a patient’s viral isolate showed genotypic sensitivity based upon genotypic resistance test. Enfuvirtide use in OBT in enfuvirtide-naïve patients was counted as one active drug in OBT. Similarly, darunavir use in OBT in darunavir-naïve patients was counted as one active drug in OBT.

Raltegravir Taj Pharma achieved virologic responses (using Not Completer=Failure approach) of HIV RNA < 50 copies/mL in 61.7 % of patients at Week 16, in 62.1 % at Week 48 and in 57.0 % at Week 96. Some patients experienced viral rebound between Week 16 and Week 96. Factors associated with failure include high baseline viral load and OBT that did not include at least one potent active agent.

Switch to Raltegravir Taj Pharma

The SWITCHMRK 1 & 2 (Protocols 032 & 033) studies evaluated HIV-infected patients receiving suppressive (screening HIV RNA < 50 copies/mL; stable regimen > 3 months) therapy with lopinavir 200mg (+) ritonavir 50mg 2 tablets twice daily plus at least 2 nucleoside reverse transcriptase inhibitors and randomised them 1:1 to continue lopinavir (+) ritonavir 2 tablets twice daily (n=174 and n=178, respectively) or replace lopinavir (+) ritonavir with Raltegravir Taj Pharma 400mg twice daily (n=174 and n=176, respectively). Patients with a prior history of virological failure were not excluded and the number of previous antiretroviral therapies was not limited.

These studies were terminated after the primary efficacy analysis at Week 24 because they failed to demonstrate non-inferiority of Raltegravir Taj Pharma versus lopinavir (+) ritonavir. In both studies at Week 24, suppression of HIV RNA to less than 50 copies/mL was maintained in 84.4 % of the Raltegravir Taj Pharma group versus 90.6 % of the lopinavir (+) ritonavir group, (Non-completers = Failure). See section 4.4 regarding the need to administer Raltegravir Taj Pharma with two other active agents.

Treatment-naïve adult patients

STARTMRK (multi-centre, randomised, double-blind, active-control trial) evaluated the safety and anti-retroviral activity of Raltegravir Taj Pharma 400mg twice daily vs. efavirenz 600mg at bedtime, in a combination with emtricitabine (+) tenofovir disoproxil fumarate, in treatment-naïve HIV-infected patients with HIV RNA > 5,000 copies/mL. Randomisation was stratified by screening HIV RNA level (≤ 50,000 copies/mL; and > 50,000 copies/mL) and by hepatitis B or C status (positive or negative).

Patient demographics (gender, age and race) and baseline characteristics were comparable between the group receiving Raltegravir Taj Pharma 400mg twice daily and the group receiving efavirenz 600mg at bedtime.

Results 48-week and 240-week analyses

With respect to the primary efficacy endpoint, the proportion of patients achieving HIV RNA < 50 copies/mL at Week 48 was 241/280 (86.1 %) in the group receiving Raltegravir Taj Pharma and 230/281 (81.9 %) in the group receiving efavirenz. The treatment difference (Raltegravir Taj Pharma – efavirenz) was 4.2 % with an associated 95 % CI of (-1.9, 10.3) establishing that Raltegravir Taj Pharma is non-inferior to efavirenz (p-value for non-inferiority < 0.001). At Week 240, the treatment difference (Raltegravir Taj Pharma – efavirenz) was 9.5 % with an associated 95 % CI of (1.7, 17.3). Week 48 and Week 240 outcomes for patients on the recommended dose of Raltegravir Taj Pharma 400mg twice daily from STARTMRK are shown in Table 5.

Table 5

Efficacy Outcome at Weeks 48 and 240

STARTMRK Study

Parameter

48 Weeks 240 Weeks
Raltegravir Taj Pharma 400mg twice daily

(N = 281)

Efavirenz 600mg at bedtime

(N = 282)

Raltegravir Taj Pharma 400mg twice daily

(N = 281)

Efavirenz 600mg at bedtime

(N = 282)

Percent HIV-RNA < 50 copies/mL (95 % CI)
All patients 86 (81, 90) 82 (77, 86) 71 (65, 76) 61 (55, 67)
Baseline Characteristic
HIV-RNA > 100,000 copies/mL 91 (85, 95) 89 (83, 94) 70 (62, 77) 65 (56, 72)
≤ 100,000 copies/mL 93 (86, 97) 89 (82, 94) 72 (64, 80) 58 (49, 66)
CD4-count ≤ 50 cells/mm3 84 (64, 95) 86 (67, 96) 58 (37, 77) 77 (58, 90)
> 50 and ≤ 200 cells/mm3 89 (81, 95) 86 (77, 92) 67 (57, 76) 60 (50, 69)
> 200 cells/mm3 94 (89, 98) 92 (87, 96) 76 (68, 82) 60 (51, 68)
Viral Subtype Clade B 90 (85, 94) 89 (83, 93) 71 (65, 77) 59 (52, 65)
Non-Clade B 96 (87, 100) 91 (78, 97) 68 (54, 79) 70 (54, 82)
Mean CD4 Cell Change (95 % CI), cells/mm3
All patients 189 (174, 204) 163 (148, 178) 374 (345, 403) 312 (284, 339)
Baseline Characteristic
HIV-RNA > 100,000 copies/mL 196 (174, 219) 192 (169, 214) 392 (350, 435) 329 (293, 364)
≤ 100,000 copies/mL 180 (160, 200) 134 (115, 153) 350 (312, 388) 294 (251, 337)
CD4-count ≤ 50 cells/mm3 170 (122, 218) 152 (123, 180) 304 (209, 399) 314 (242, 386)
> 50 and ≤ 200 cells/mm3 193 (169, 217) 175 (151, 198) 413 (360, 465) 306 (264, 348)
> 200 cells/mm3 190 (168, 212) 157 (134, 181) 358 (321, 395) 316 (272, 359)
Viral Subtype Clade B 187 (170, 204) 164 (147, 181) 380 (346, 414) 303 (272, 333)
Non-Clade B 189 (153, 225) 156 (121, 190) 332 (275, 388) 329 (260, 398)
† Non-completer is failure imputation: patients who discontinued prematurely are imputed as failure thereafter. Percent of patients with response and associated 95 % confidence interval (CI) are reported.

‡ For analysis by prognostic factors, virologic failures were carried forward for percent < 50 and 400 copies/mL. For mean CD4 changes, baseline-carry-forward was used for virologic failures.

Notes: The analysis is based on all available data.

Raltegravir Taj Pharma and efavirenz were administered with emtricitabine (+) tenofovir disoproxil fumarate.

Paediatric population

Children and adolescents 2 to 18 years of age

IMPAACT P1066 is a Phase I/II open label multicenter trial to evaluate the pharmacokinetic profile, safety, tolerability, and efficacy of Raltegravir Taj Pharma in HIV infected children. This study enrolled 126 treatment experienced children and adolescents 2 to 18 years of age. Patients were stratified by age, enrolling adolescents first and then successively younger children. Patients received either the 400mg tablet formulation (6 to 18 years of age) or the chewable tablet formulation (2 to less than 12 years of age). Raltegravir Taj Pharma was administered with an optimised background regimen.

The initial dose finding stage included intensive pharmacokinetic evaluation. Dose selection was based upon achieving similar Raltegravir Taj Pharma plasma exposure and trough concentration as seen in adults, and acceptable short term safety. After dose selection, additional patients were enrolled for evaluation of long term safety, tolerability and efficacy. Of the 126 patients, 96 received the recommended dose of Raltegravir Taj Pharma (see section 4.2).

Table 6

Baseline Characteristics and Efficacy Outcomes at Weeks 24 and 48 from IMPAACT P1066

(2 to 18 years of age)

Parameter Final dose population
N=96
Demographics
Age (years), median [range] 13 [2 – 18]
Male Gender 49 %
Race
Caucasian 34 %
Black 59 %
Baseline Characteristics
Plasma HIV-1 RNA (log10 copies/mL), mean [range] 4.3 [2.7 – 6]
CD4 cell count (cells/mm), median [range] 481 [0 – 2361]
CD4 percent, median [range] 23.3 % [0 – 44]
HIV-1 RNA >100,000 copies/mL 8 %
CDC HIV category B or C 59 %
Prior ART Use by Class
NNRTI 78 %
PI 83 %
Response Week 24 Week 48
Achieved ≥1 log10 HIV RNA drop from baseline or <400 copies/mL 72 % 79 %
Achieved HIV RNA <50 copies/mL 54 % 57 %
Mean CD4 cell count (%) increase from baseline 119 cells/mm3 (3.8 %) 156 cells/mm(4.6 %)

Infants and toddlers 4 weeks to less than 2 years of age

IMPAACT P1066 also enrolled HIV-infected, infants and toddlers 4 weeks to less than 2 years of age who had received prior antiretroviral therapy either as prophylaxis for prevention of mother to child transmission (PMTCT) and/or as combination antiretroviral therapy for treatment of HIV infection. Raltegravir Taj Pharma was administered as granules for oral suspension formulation without regard to food in combination with an optimised background regimen that included lopinavir plus ritonavir in two-thirds of patients.

Table 7

Baseline Characteristics and Efficacy Outcomes at Weeks 24 and 48 from IMPAACT P1066

(4 weeks to less than 2 years of age)

Parameter N=26
Demographics
Age (weeks), median [range] 28 [4 -100]
Male Gender 65 %
Race
Caucasian 8 %
Black 85 %
Baseline Characteristics
Plasma HIV-1 RNA (log10 copies/mL), mean [range] 5.7 [3.1 – 7]
CD4 cell count (cells/mm), median [range] 1,400 [131 -3,648]
CD4 percent, median [range] 18.6 % [3.3 – 39.3]
HIV-1 RNA >100,000 copies/mL 69 %
CDC HIV category B or C 23 %
Prior ART Use by Class
NNRTI 73 %
NRTI 46%
PI 19 %
Response Week 24 Week 48
Achieved ≥1 log10 HIV RNA drop from baseline or <400 copies/mL 91 % 85 %
Achieved HIV RNA <50 copies/mL 43 % 53 %
Mean CD4 cell count (%) increase from baseline 500 cells/mm3 (7.5 %) 492 cells/mm(7.8 %)
Virologic failure Week 24 Week 48
Non-responder 0 0
Rebounder 0 4
Number with genotype available* 0 2

*One patient had a mutation at the 155 position.

5.2 Pharmacokinetic properties

Absorption

As demonstrated in healthy volunteers administered single oral doses of Raltegravir Taj Pharma in the fasted state, Raltegravir Taj Pharma is rapidly absorbed with a tmax of approximately 3 hours postdose. Raltegravir Taj Pharma AUC and Cmax increase dose proportionally over the dose range 100mg to 1,600mg. Raltegravir Taj Pharma C12 hr increases dose proportionally over the dose range of 100 to 800mg and increases slightly less than dose proportionally over the dose range 100mg to 1,600mg. Dose proportionality has not been established in patients.

With twice-daily dosing, pharmacokinetic steady state is achieved rapidly, within approximately the first 2 days of dosing. There is little to no accumulation in AUC and Cmax and evidence of slight accumulation in C12 hr. The absolute bioavailability of Raltegravir Taj Pharma has not been established.

Raltegravir Taj Pharma may be administered with or without food. Raltegravir Taj Pharma was administered without regard to food in the pivotal safety and efficacy studies in HIV-infected patients. Administration of multiple doses of Raltegravir Taj Pharma following a moderate-fat meal did not affect Raltegravir Taj Pharma AUC to a clinically meaningful degree with an increase of 13 % relative to fasting. Raltegravir Taj Pharma C12 hr was 66 % higher and Cmax was 5 % higher following a moderate-fat meal compared to fasting. Administration of Raltegravir Taj Pharma following a high-fat meal increased AUC and Cmax by approximately 2-fold and increased C12 hr by 4.1-fold. Administration of Raltegravir Taj Pharma following a low-fat meal decreased AUC and Cmax by 46 % and 52 %, respectively; C12 hr was essentially unchanged. Food appears to increase pharmacokinetic variability relative to fasting.

Overall, considerable variability was observed in the pharmacokinetics of Raltegravir Taj Pharma. For observed C12 hr in BENCHMRK 1 and 2 the coefficient of variation (CV) for inter-subject variability = 212 % and the CV for intra-subject variability = 122 %. Sources of variability may include differences in co-administration with food and concomitant medicines.

Distribution

Raltegravir Taj Pharma is approximately 83 % bound to human plasma protein over the concentration range of 2 to 10 µM.

Raltegravir Taj Pharma readily crossed the placenta in rats, but did not penetrate the brain to any appreciable extent.

In two studies of HIV-1 infected patients who received Raltegravir Taj Pharma 400mg twice daily, Raltegravir Taj Pharma was readily detected in the cerebrospinal fluid. In the first study (n=18), the median cerebrospinal fluid concentration was 5.8 % (range 1 to 53.5 %) of the corresponding plasma concentration. In the second study (n=16), the median cerebrospinal fluid concentration was 3 % (range 1 to 61 %) of the corresponding plasma concentration. These median proportions are approximately 3- to 6-fold lower than the free fraction of Raltegravir Taj Pharma in plasma.

Biotransformation and excretion

The apparent terminal half-life of Raltegravir Taj Pharma is approximately 9 hours, with a shorter α-phase half-life (~1 hour) accounting for much of the AUC. Following administration of an oral dose of radiolabeled Raltegravir Taj Pharma, approximately 51 and 32 % of the dose was excreted in faeces and urine, respectively. In faeces, only Raltegravir Taj Pharma was present, most of which is likely to be derived from hydrolysis of Raltegravir Taj Pharma-glucuronide secreted in bile as observed in preclinical species. Two components, namely Raltegravir Taj Pharma and Raltegravir Taj Pharma-glucuronide, were detected in urine and accounted for approximately 9 and 23 % of the dose, respectively. The major circulating entity was Raltegravir Taj Pharma and represented approximately 70 % of the total radioactivity; the remaining radioactivity in plasma was accounted for by Raltegravir Taj Pharma-glucuronide. Studies using isoform-selective chemical inhibitors and cDNA-expressed UDP-glucuronosyltransferases (UGT) show that UGT1A1 is the main enzyme responsible for the formation of Raltegravir Taj Pharma-glucuronide. Thus the data indicate that the major mechanism of clearance of Raltegravir Taj Pharma in humans is UGT1A1-mediated glucuronidation.

UGT1A1 Polymorphism

In a comparison of 30 subjects with *28/*28 genotype to 27 subjects with wild-type genotype, the geometric mean ratio (90 % CI) of AUC was 1.41 (0.96, 2.09) and the geometric mean ratio of C12 hr was 1.91 (1.43, 2.55). Dose adjustment is not considered necessary in subjects with reduced UGT1A1 activity due to genetic polymorphism.

Special populations

Paediatric population

Based on a formulation comparison study in healthy adult volunteers, the chewable tablet and granules for oral suspension have higher oral bioavailability compared to the 400mg tablet. In this study, administration of the chewable tablet with a high fat meal led to an average 6 % decrease in AUC, 62 % decrease in Cmax, and 188 % increase in C12hr compared to administration in the fasted state. Administration of the chewable tablet with a high fat meal does not affect Raltegravir Taj Pharma pharmacokinetics to a clinically meaningful degree and the chewable tablet can be administered without regard to food. The effect of food on the granules for oral suspension formulation was not studied.

Table 8 displays pharmacokinetic parameters in the 400mg tablet, the chewable tablet), and the granules for oral suspension, by body weight.

Table 8

Raltegravir Taj Pharma Pharmacokinetic Parameters IMPAACT P1066 Following Administration of Doses in Section 4.2 (excluding neonates)

Body weight Formulation Dose N* Geometric mean

(%CV)

AUC0-12hr (μM●hr)

Geometric mean

(%CV)

C12hr (nM)

≥ 25 kg Film-coated tablet 400mg twice daily 18 14.1 (121 %) 233 (157 %)
≥ 25 kg Chewable tablet Weight based dosing, see dosing Table 1 9 22.1 (36 %) 113 (80 %)
11 to less than 25 kg Chewable tablet Weight based dosing, see dosing Table 2 13 18.6 (68 %) 82 (123 %)
3 to less than 20 kg Oral suspension Weight based dosing, see dosing table for granules for oral suspension 19 24.5 (43 %) 113 (69 %)
*Number of patients with intensive pharmacokinetic (PK) results at the final recommended dose.

Geometric coefficient of variation.

Elderly

There was no clinically meaningful effect of age on Raltegravir Taj Pharma pharmacokinetics in healthy subjects and patients with HIV-1 infection over the age range studied (19 to 84 years, with few individuals over the age of 65).

Gender, race and BMI

There were no clinically important pharmacokinetic differences due to gender, race or body mass index (BMI) in adults.

Renal impairment

Renal clearance of unchanged medicinal product is a minor pathway of elimination. In adults, there were no clinically important pharmacokinetic differences between patients with severe renal insufficiency and healthy subjects (see section 4.2). Because the extent to which Raltegravir Taj Pharma may be dialysable is unknown, dosing before a dialysis session should be avoided.

Hepatic impairment

Raltegravir Taj Pharma is eliminated primarily by glucuronidation in the liver. In adults, there were no clinically important pharmacokinetic differences between patients with moderate hepatic insufficiency and healthy subjects. The effect of severe hepatic insufficiency on the pharmacokinetics of Raltegravir Taj Pharma has not been studied (see sections 4.2 and 4.4).

5.3 Preclinical safety data

Non-clinical toxicology studies, including conventional studies of safety pharmacology, repeated-dose toxicity, genotoxicity, developmental toxicity and juvenile toxicity, have been conducted with Raltegravir Taj Pharma in mice, rats, dogs and rabbits. Effects at exposure levels sufficiently in excess of clinical exposure levels indicate no special hazard for humans.

Mutagenicity

No evidence of mutagenicity or genotoxicity was observed in in vitro microbial mutagenesis (Ames) tests, in vitro alkaline elution assays for DNA breakage and in vitro and in vivo chromosomal aberration studies.

Carcinogenicity

A carcinogenicity study of Raltegravir Taj Pharma in mice did not show any carcinogenic potential. At the highest dose levels, 400mg/kg/day in females and 250mg/kg/day in males, systemic exposure was similar to that at the clinical dose of 400mg twice daily. In rats, tumours (squamous cell carcinoma) of the nose/nasopharynx were identified at 300 and 600mg/kg/day in females and at 300mg/kg/day in males. This neoplasia could result from local deposition and/or aspiration of drug on the mucosa of the nose/nasopharynx during oral gavage dosing and subsequent chronic irritation and inflammation; it is likely that it is of limited relevance for the intended clinical use. At the NOAEL, systemic exposure was similar to that at the clinical dose of 400mg twice daily. Standard genotoxicity studies to evaluate mutagenicity and clastogenicity were negative.

Developmental toxicity

Raltegravir Taj Pharma was not teratogenic in developmental toxicity studies in rats and rabbits. A slight increase in incidence of supernumerary ribs, a variant in the normal developmental process, was observed in rat foetuses of dams exposed to Raltegravir Taj Pharma at approximately 4.4-fold human exposure at 400mg twice daily based on AUC0-24 hr. No development effects were seen at 3.4-fold human exposure at 400mg twice daily based on AUC0-24 hr. Similar findings were not observed in rabbits.

  1. Pharmaceutical particulars
  • List of excipients

Chewable tablet 25mg/100mg/400mg/600mg

  • Hydroxypropyl cellulose
  • Sucralose
  • Saccharin sodium
  • Sodium citrate dihydrate
  • Mannitol
  • Monoammonium glycyrrhizinate
  • Sorbitol
  • Fructose
  • Banana flavour
  • Orange flavour
  • Masking flavour
  • Aspartame
  • Crospovidone, Type A
  • Sodium stearyl fumarate
  • Magnesium stearate
  • Hypromellose 2910/6cP
  • Macrogol/PEG 400
  • Ethylcellulose 20 cP
  • Ammonium hydroxide
  • Medium chain triglycerides
  • Oleic acid
  • Yellow iron oxide

Incompatibilities

Not applicable.

Shelf life

2 years

Special precautions for storage

Keep the bottle tightly closed, with the desiccant in order to protect from moisture.

Nature and contents of container

High density polyethylene (HDPE) bottle with a child-resistant polypropylene closure, induction seal and silica gel desiccant:

Pack Size:

Each pack contains 10, 15, 20, 25, 30, 60, 80, 100, 120 chewable tablets.

Maximum pack size is 120, 240, 360, and 500 chewable tablets.

Not all pack size may be marketed

  • Special precautions for disposal and other handling

No special requirements for disposal.

Manufactured in India by:
TAJ PHARMACEUTICALS LTD.
Mumbai, India
Unit No. 214.Old Bake House,
Maharashtra chambers of  Commerce Lane,
Fort, Mumbai – 400001
at: Gujarat, INDIA.
Customer Service and Product Inquiries:
1-800-TRY-FIRST (1-800-222-434 & 1-800-222-825)
Monday through Saturday 9:00 a.m. to 7:00 p.m. EST
E-mail: tajgroup@tajpharma.com

Raltegravir Tablet USP 600mg Taj Pharma

Package leaflet: Information for the user

Raltegravir Taj Pharma

Read all of this leaflet carefully before you start taking this medicine because it contains important information for you.

If you are the parent of a child taking Raltegravir Taj Pharma, please read this information carefully with your child.

  • Keep this leaflet. You may need to read it again.
  • If you have any further questions, ask your doctor, pharmacist or nurse.
  • This medicine has been prescribed for you or your child only. Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours.
  • If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. See section 4.

What is in this leaflet

  1. What Raltegravir Taj Pharma is and what it is used for
  2. What you need to know before you take Raltegravir Taj Pharma
  3. How to take Raltegravir Taj Pharma
  4. Possible side effects
  5. How to store Raltegravir Taj Pharma
  6. Contents of the pack and other information

1. What Raltegravir Taj Pharma is and what it is used for

What Raltegravir Taj Pharma is

Raltegravir Taj Pharma contains the active substance Raltegravir Taj Pharma. Raltegravir Taj Pharma is an antiviral medicine that works against the Human Immunodeficiency Virus (HIV). This is the virus that causes Acquired Immune Deficiency Syndrome (AIDS).

How Raltegravir Taj Pharma works

The virus produces an enzyme called HIV integrase. This helps the virus to multiply in the cells in your body. Raltegravir Taj Pharma stops this enzyme from working. When used with other medicines, Raltegravir Taj Pharma may reduce the amount of HIV in your blood (this is called your “viral load”) and increase your CD4-cell count (a type of white blood cells that plays an important role in maintaining a healthy immune system to help fight infection). Reducing the amount of HIV in the blood may improve the functioning of your immune system. This means your body may fight infection better.

When Raltegravir Taj Pharma should be used

Raltegravir Taj Pharma is used to treat those who are infected by HIV. Your doctor has prescribed Raltegravir Taj Pharma to help control your HIV infection.

  1. What you need to know before you take Raltegravir Taj Pharma

Do not take Raltegravir Taj Pharma

  • If you are allergic to Raltegravir Taj Pharma or to any of the other ingredients in this medicine (listed in section 6).

Warnings and precautions

Talk to your doctor, pharmacist or nurse before taking Raltegravir Taj Pharma.

Remember that Raltegravir Taj Pharma is not a cure for HIV infection. This means that you may keep getting infections or other illnesses associated with HIV. You should keep seeing your doctor regularly while taking this medicine.

Mental health problems

Tell your doctor if you have a history of depression or psychiatric illness. Depression, including suicidal thoughts and behaviours, has been reported in some patients taking this medicine, particularly in patients with a prior history of depression or psychiatric illness.

Bone problems

Some patients taking combination anti-retroviral therapy may develop a bone disease called osteonecrosis (death of bone tissue caused by loss of blood supply to the bone). The length of combination anti-retroviral therapy, corticosteroid use, alcohol consumption, severe reduction of the activity of the immune system, higher body mass index, among others, may be some of the many risk factors for developing this disease. Signs of osteonecrosis are joint stiffness, aches and pains (especially of the hip, knee and shoulder) and difficulty in movement. If you notice any of these symptoms please inform your doctor.

Liver problems

Tell your doctor, pharmacist or nurse if you have had problems with your liver before, including hepatitis B or C. Your doctor may evaluate how severe your liver disease is before deciding if you can take this medicine.

Passing HIV to others

HIV infection is spread by contact with blood or sexual contact with a person with HIV. You can still pass on HIV when taking this medicine, although the risk is lowered by effective antiretroviral therapy. Discuss with your doctor the precautions needed to avoid infecting other people.

Infections

Tell your doctor, pharmacist or nurse immediately if you notice any symptoms of infection, such as fever, and/or feeling unwell. In some patients with advanced HIV infection and a history of opportunistic infection, signs and symptoms of inflammation from previous infections may occur soon after anti-HIV treatment is started. It is believed that these symptoms are due to an improvement in the body’s immune response, enabling the body to fight infections that may have been present with no obvious symptoms.

In addition to the opportunistic infections, autoimmune disorders (a condition that occurs when the immune system attacks healthy body tissue) may also occur after you start taking medicines for the treatment of your HIV infection. Autoimmune disorders may occur many months after the start of treatment. If you notice any symptoms of infection or other symptoms such as muscle weakness, weakness beginning in the hands and feet and moving up towards the trunk of the body, palpitations, tremor or hyperactivity, please inform your doctor immediately to seek necessary treatment.

Muscle problems

Contact your doctor, pharmacist or nurse immediately if you experience unexplained muscle pain, tenderness, or weakness while taking this medicine.

Skin problems

Contact your doctor promptly if you develop a rash. Severe and life-threatening skin reactions and allergic reactions have been reported in some patients taking this medicine.

Other medicines and Raltegravir Taj Pharma

Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines with or without a prescription.

Raltegravir Taj Pharma might interact with other medicines.

Tell your doctor, pharmacist or nurse if you are taking, have recently taken or might take:

  • antacids (an agent that counteracts or neutralises the acid in the stomach to relieve indigestion and heartburn). It is not recommended to take Raltegravir Taj Pharma with certain antacids (those containing aluminium and/or magnesium). Talk to your doctor about other antacids you can take.
  • rifampicin (a medicine used to treat some infections such as tuberculosis), as it may decrease your levels of Raltegravir Taj Pharma. Your doctor may consider increasing your dose of Raltegravir Taj Pharma if you are taking rifampicin.

Taking Raltegravir Taj Pharma with food and drink

See section 3.

Pregnancy and breast-feeding

If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before taking this medicine.

  • Raltegravir Taj Pharma chewable tablets are not recommended in pregnancy because they have not been studied in pregnant women.
  • Women with HIV should not breast-feed their infants because babies can be infected with HIV through their breast milk. Talk with your doctor about the best way to feed your baby.

Ask your doctor, pharmacist or nurse for advice before taking any medicine if you are pregnant or breast-feeding.

Driving and using machines

Do not operate machines, drive or cycle if you feel dizzy after taking this medicine.

Raltegravir Taj Pharma chewable tablets contain fructose and sorbitol

If you have been told by your doctor that you have an intolerance to some sugars, talk to your doctor before taking this medicine.

Sweeteners contained in this medicine may be harmful to teeth.

Raltegravir Taj Pharma chewable tablets contain aspartame

Raltegravir Taj Pharma contains aspartame, a source of phenylalanine, which may be harmful to people with phenylketonuria.

  1. How to take Raltegravir Taj Pharma

Always take this medicine exactly as your doctor, pharmacist or nurse has told you. You should check with your doctor, pharmacist or nurse if you are not sure. Raltegravir Taj Pharma must be used in combination with other medicines for HIV.

The 100mg chewable tablet can be split into equal halves if necessary; however, breaking the tablets should be avoided.

How much to take

Dose for children of 2 through 11 years of age

The doctor will work out the right dose of the chewable tablet based on the age and weight of the child. This dose must not exceed 300mg twice a day. The doctor will tell you how many chewable tablets the child must take.

Raltegravir Taj Pharma is also available in a 400mg tablet, a 600mg tablet and in granules for oral suspension.

Do not switch between the chewable tablet, granules for oral suspension, 600mg tablet or 400mg tablet without first talking with your doctor, pharmacist or nurse.

Children should keep scheduled doctor’s visits because their Raltegravir Taj Pharma dosage should be adjusted as they get older, grow or gain weight. Their doctor may also want to prescribe the 400mg tablet when they are able to swallow a tablet.

You can take this medicine with or without food or drink.

If you take more Raltegravir Taj Pharma than you should

Do not take more tablets than the doctor recommends. If you do take too many tablets, contact your doctor.

If you forget to take Raltegravir Taj Pharma

  • If you forget to take a dose, take it as soon as you remember it.
  • However, if it is time for your next dose, skip the missed dose and go back to your regular schedule.
  • Do not take a double dose to make up for a forgotten dose.

If you stop taking Raltegravir Taj Pharma

It is important that you take Raltegravir Taj Pharma exactly as your doctor has instructed. Do not change the dose or stop taking this medicine without first talking with your doctor, pharmacist or nurse. Do not stop taking it because:

  • It is very important to take all your HIV medicines as prescribed and at the right times of day. This can help your medicines work better. It also lowers the chance that your medicines will stop being able to fight HIV (also called “drug resistance”).
  • When your supply of Raltegravir Taj Pharma starts to run low, get more from your doctor or pharmacy. This is because it is very important not to be without the medicine, even for a short time. During a short break in taking the medicine the amount of virus in your blood may increase. This may mean that the HIV virus will develop resistance to Raltegravir Taj Pharma and become harder to treat.

If you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse.

  1. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.

Serious side effects – these are uncommon (may affect up to 1 in 100 people)

See a doctor immediately, if you notice any of the following:

  • herpes infections including shingles
  • anaemia including due to low iron
  • signs and symptoms of infection or inflammation
  • mental disorder
  • suicide intention or attempt
  • stomach inflammation
  • inflammation of liver
  • liver failure
  • allergic rash
  • certain kinds of kidney problems
  • drug ingestion in quantities greater than recommended

See a doctor immediately, if you notice any of the side effects above.

Common: the following may affect up to 1 in 10 people

  • decreased appetite
  • trouble sleeping; abnormal dreams; nightmare; abnormal behaviour; feelings of deep sadness and unworthiness
  • feeling dizzy; headache
  • spinning sensation
  • bloating; abdominal pain; diarrhoea; excessive gas in the stomach or bowel; feeling sick; vomiting; indigestion; belching
  • certain kinds of rash (more often when used in combination with darunavir)
  • tiredness, unusual tiredness or weakness; fever
  • increased liver blood tests; abnormal white blood cells; increased fat levels in blood; increased level of enzyme from salivary glands or pancreas

Uncommon: the following may affect up to 1 in 100 people

  • infection of the hair roots; influenza; skin infection due to virus; vomiting or diarrhoea due to an infectious agent; upper respiratory tract infection; lymph node abscess
  • wart
  • lymph node pain; low count of white blood cells that fight infection; swollen glands in the neck, armpit and groin
  • allergic reaction
  • increased appetite; diabetes; increased blood cholesterol and lipids; high sugar levels in the blood; excessive thirst; severe weight loss; high levels of fat (such as cholesterol and triglycerides) in the blood; body fat disorder
  • feeling anxious; feeling of confusion; depressed mood; mood changes; panic attack
  • loss of memory; pain in the hand due to nerve compression; disturbance in attention; dizziness with rapid changes in posture; abnormal taste; increased sleepiness; lack of energy; forgetfulness; migraine headache; loss of feeling, numbness or weakness of the arms and/or legs; tingling; sleepiness; tension headache; tremors; poor quality sleep
  • visual disturbance
  • buzzing, hissing, whistling, ringing or other persistent noise in the ears
  • palpitations; slow heart rates; fast or irregular heart beats
  • hot flush; high blood pressure
  • harsh, raspy, or strained voice; nosebleed; nasal congestion
  • abdominal pain upper; rectal discomfort; constipation; dry mouth; heartburn; pain when swallowing; inflammation of the pancreas; ulcer or sore in stomach or upper intestine; bleeding at anus; stomach discomfort; inflammation of the gums; swollen, red sore tongue
  • accumulation of fat in the liver
  • acne; unusual hair loss or thinning; redness of skin; unusual distribution of fat on the body, this may include loss of fat from legs, arms, and face, and increase in abdomen fat; excessive sweating; night sweats; thickening and itching of the skin due to repeated scratching; skin lesion; dry skin
  • joint pain; painful joint disease; back pain; pain in bone/muscle; muscle tenderness or weakness; neck pain; pain in arms or legs; inflammation of the tendons; decrease in the amount of minerals in the bone
  • kidney stones; urination at night; kidney cyst
  • erectile dysfunction; breast enlargement in men; menopausal symptoms
  • chest discomfort; chills; swelling of face; feeling jittery; generally feeling unwell; neck mass; swelling of hands, ankles or feet; pain
  • decreased white blood cell count; decreased count of platelets in blood (a kind of cell that helps blood clot); blood test showing reduced kidney function; high blood sugar level; increased muscle enzyme in blood; sugar present in urine; red blood cells present in urine; weight gain; increase in waist size; decreased blood protein (albumin); increase in time for blood to clot

Additional side effects in children and adolescents

  • hyperactivity

Reporting of side effects

If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. By reporting side effects you can help provide more information on the safety of this medicine.

  1. How to store Raltegravir Taj Pharma
  • Keep this medicine out of the sight and reach of children.
  • Do not use this medicine after the expiry date which is stated on the bottle after EXP. The expiry date refers to the last day of that month.
  • Store in the original package with the bottle tightly closed. Keep the drying agent in the bottle to protect from moisture.
  • Prior to breaking the seal, this product does not require any special storage conditions.

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment.

  1. Contents of the pack and other information

What Raltegravir Taj Pharma contains

The active substance is Raltegravir Taj Pharma.

Each chewable tablet contains 25mg/100mg/400mg/600mg of Raltegravir Taj Pharma (as potassium).

The other ingredients are: Hydroxypropyl Cellulose, Sucralose, Saccharin Sodium, Sodium Citrate Dihydrate, Mannitol, Yellow Iron Oxide, Monoammonium Glycyrrhizinate, Sorbitol, Fructose, Natural And Artificial Flavours (Orange, Banana, And Masking), Aspartame, Crospovidone Type A, Magnesium Stearate, Sodium Stearyl Fumarate, Ethylcellulose 20cp, Ammonium Hydroxide, Medium Chain Triglycerides, Oleic Acid, Hypromellose 2910/6cp And Macrogol/PEG 400.

What Raltegravir Taj Pharma looks like and contents of the pack

Raltegravir Tablet USP 25mg Taj Pharma
Raltegravir Tablet USP 100mg Taj Pharma
Raltegravir Tablet USP 400mg Taj Pharma
Raltegravir Tablet USP 600mg Taj Pharma

The above strength Raltegravir Taj Pharma are orange-banana flavoured chewable tablet is round and pale yellow,

Pack Size:

Each pack contains 10, 15, 20, 25, 30, 60, 80, 100, 120 chewable tablets.

Maximum pack size is 120, 240, 360, and 500 chewable tablets.

Not all pack size may be marketed

Manufactured in India by:
TAJ PHARMACEUTICALS LTD.
Mumbai, India
Unit No. 214.Old Bake House,
Maharashtra chambers of  Commerce Lane,
Fort, Mumbai – 400001
at: Gujarat, INDIA.
Customer Service and Product Inquiries:
1-800-TRY-FIRST (1-800-222-434 & 1-800-222-825)
Monday through Saturday 9:00 a.m. to 7:00 p.m. EST
E-mail: tajgroup@tajpharma.com