INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT ISENTRESS (ISENTRESS)

Composition:

Active substance: raltegravir;

One film-coated tablet contains 400 mg of raltegravir;

Excipients: microcrystalline cellulose, lactose monohydrate, calcium hydrogen phosphate anhydrous, hydroxypropylmethylcellulose, poloxamer, sodium stearyl fumarate, magnesium stearate;

Tablet coating: Oparay® II Pink, which contains: partially hydrolyzed polyvinyl alcohol, polyethylene glycol, talc, titanium dioxide (E 171), black iron oxide (E 172), and red iron oxide (E 172).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: pink-colored, oval, biconvex tablets with the imprint «227» on one side and smooth on the other.

Pharmacological Properties

Pharmacodynamics

Mechanism of Action

Raltegravir is an integrase strand transfer inhibitor active against human immunodeficiency virus (HIV-1). Raltegravir inhibits the catalytic activity of integrase—a virus-encoded enzyme essential for viral replication. Inhibition of integrase prevents the covalent insertion, or integration, of the HIV genome into the host cell genome. HIV genomes that cannot integrate are unable to produce new viral particles, resulting in suppression of the integration process and prevention of further spread of viral infection within the body.

Clinical Experience

Evidence of efficacy of the medicinal product Isentress is based on analysis of data up to 96 weeks from two consecutive randomized, double-blind, placebo-controlled studies (BENCHMRK 1 and BENCHMRK 2, protocols 018 and 019) involving HIV-1 infected adult patients who had previously received antiretroviral therapy, and on analysis of data up to 240 weeks from a continuous randomized, double-blind, active-controlled study (STARTMRK, protocol 021) involving HIV-1 infected adult patients who had not previously received antiretroviral therapy.

Pharmacokinetics

Absorption

In healthy volunteers, after a single oral dose administered fasting, raltegravir was rapidly absorbed, reaching maximum concentration (t_max) at approximately 3 hours. With a twice-daily dosing regimen, steady-state pharmacokinetics are achieved rapidly, within approximately 2 days after initiation of treatment.

Distribution

Approximately 83% of raltegravir is bound to plasma proteins over a concentration range of 2 to 10 μmol.

In rats, raltegravir readily crossed the placental barrier but did not penetrate the brain to any significant extent.

In two studies of HIV-1 infected patients receiving raltegravir 400 mg twice daily, the drug was rapidly detected in cerebrospinal fluid (CSF). In the first study (n=18), the mean CSF concentration was 5.8% (range: 1% to 53.5%) of the corresponding plasma concentration. In the second study (n=16), the mean CSF concentration was 3% (range: 1% to 61%) of the corresponding plasma concentration. These median ratios were 3 to 6 times lower than the free fraction of raltegravir in plasma.

Metabolism and Elimination

The apparent terminal half-life of raltegravir is approximately 9 hours, with a shorter alpha-phase half-life (approximately 1 hour), which contributes the majority of the AUC. After oral administration of radiolabeled raltegravir, approximately 51% and 32% of the total dose were excreted in feces and urine, respectively. Only raltegravir was excreted in feces, most likely derived from hydrolysis of raltegravir-glucuronide secreted into bile, as observed in preclinical studies. Two components—raltegravir and raltegravir-glucuronide—were excreted in urine, accounting for 9% and 23% of the dose, respectively. Raltegravir was the primary circulating substance, representing approximately 70% of total radioactivity; the remainder of radiolabeled drug in plasma was raltegravir-glucuronide. Studies using isoform-selective chemical inhibitors and cDNA-expressed UDP-glucuronosyltransferases (UGT) demonstrated that UGT1A1 is the primary enzyme responsible for the formation of raltegravir-glucuronide. These data indicate that the primary mechanism of raltegravir clearance in humans is UGT1A1-mediated glucuronidation.

Polymorphism of UGT1A1

When comparing data from 30 adults with the *28/*28 genotype and 27 adults with the non-mutant genotype, the geometric mean ratio (90% CI) for AUC was 1.41 (0.96, 2.09), and the geometric mean ratio for AUC_0–12h was 1.91 (1.43, 2.55). Dose adjustment is not considered necessary for patients with reduced UGT1A1 activity due to genetic polymorphism.

Special Populations

Elderly

No clinically significant effect of age on the pharmacokinetics of raltegravir was observed across the studied age range (19 to 71 years), including a small number (8) of individuals aged 65 years and older.

Sex, Race, and Body Mass Index (BMI)

In adults, no clinically significant effect of sex, race, or BMI on the pharmacokinetics of raltegravir was observed.

Renal Impairment

Renal clearance accounts for a minor portion of the elimination of unchanged raltegravir from the body. In adults, no clinically significant differences in pharmacokinetic parameters were observed in patients with severe renal impairment compared to healthy subjects. Since the efficacy of dialysis for removing raltegravir is unknown, administration of the drug immediately before a dialysis session is not recommended.

Hepatic Impairment

Raltegravir is primarily eliminated via glucuronidation in the liver. In adults, no clinically significant differences in pharmacokinetic parameters were observed in patients with moderate hepatic impairment compared to healthy patients. The effect of severe hepatic impairment on the pharmacokinetic parameters of raltegravir has not been studied.

Clinical characteristics.

Indications.

Treatment of adults and children with body weight of at least 25 kg with HIV-1 infection in combination with other antiretroviral medicinal products.

Contraindications.

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

Interaction with other medicinal products and other forms of interaction.

In vitro studies have shown that raltegravir is not a substrate of cytochrome P450 (CYP) isoenzymes and does not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, or CYP3A, does not induce CYP3A4, and does not inhibit P-glycoprotein-mediated transport. Based on these data, raltegravir is not expected to affect the pharmacokinetics of medicinal products that are substrates of these enzymes or P-glycoprotein.

According to in vitro and in vivo studies, raltegravir is primarily eliminated from the body via metabolism through glucuronidation by UGT1A1.

Although in vitro studies indicated that raltegravir is not an inhibitor of uridine diphosphate-glucuronosyltransferases (UGT) – 1A1, 2B7, one clinical study suggests that some inhibition of UGT1A1 may occur in vivo, based on observed effects during bilirubin glucuronidation. However, the frequency and variability of this effect are unlikely to result in clinically significant drug interactions.

Significant inter- and intra-subject variability has been observed in the pharmacokinetic parameters of raltegravir. The following information on drug interactions is based on geometric mean values; the effect in any individual patient cannot be precisely predicted.

Effect of raltegravir on the pharmacokinetics of other medicinal products

In interaction studies, raltegravir did not have a clinically significant effect on the pharmacokinetics of etravirine, maraviroc, tenofovir, hormonal contraceptives, methadone, midazolam, or boceprevir.

In some studies, concomitant administration of Isentress with darunavir resulted in a moderate decrease in darunavir plasma concentrations; the mechanism of this effect is unknown. However, the effect of raltegravir on darunavir plasma concentrations is not considered clinically significant.

Effect of other medicinal products on the pharmacokinetics of raltegravir

Since raltegravir is primarily metabolized by UGT1A1, caution should be exercised when co-administering Isentress with medicinal products that are strong inducers of UDG1A1 (e.g., rifampicin). Rifampicin reduces raltegravir plasma concentrations; the impact on raltegravir efficacy is unknown. However, if concomitant use with rifampicin cannot be avoided, doubling the dose of Isentress may be considered for adults. There are no data to provide recommendations for concomitant use of Isentress with rifampicin in patients under 18 years of age. The effect of other strong enzyme inducers metabolizing the drug, such as phenytoin and phenobarbital, on UGT1A1 is unknown. Less potent inducers (e.g., efavirenz, nevirapine, etravirine, rifabutin, glucocorticoids, St. John's wort, pioglitazone) can be used concomitantly with the recommended doses of Isentress.

Concomitant administration of Isentress with strong inhibitors of UGT1A1 (e.g., atazanavir) may increase raltegravir plasma concentrations. Less potent inhibitors of UGT1A1 (e.g., indinavir, saquinavir) may also increase raltegravir plasma levels, but to a lesser extent than atazanavir. In addition, tenofovir may increase raltegravir plasma levels, although the mechanism of this effect is unknown (see Table 1 "Pharmacokinetic interaction data"). Clinical trial data show that most patients received atazanavir and/or tenofovir, both agents increasing raltegravir plasma levels, as part of optimized background regimens. The safety profile observed in patients receiving atazanavir and/or tenofovir was generally similar to that in patients not receiving these agents. Therefore, dose adjustment is not necessary.

Concomitant administration of Isentress with antacids containing divalent metal cations may reduce raltegravir absorption due to chelate formation, leading to decreased raltegravir plasma concentrations. Administration of antacids containing aluminum and magnesium within 6 hours after taking Isentress significantly reduces raltegravir plasma levels. Therefore, concomitant administration of Isentress with antacids containing aluminum and/or magnesium is not recommended. Concomitant use of Isentress with an antacid containing calcium carbonate reduces raltegravir plasma levels; however, this interaction is not clinically significant. Therefore, no dose adjustment is required when Isentress is co-administered with antacids containing calcium carbonate.

Concomitant administration of Isentress with other medicinal products that increase gastric pH (e.g., omeprazole and famotidine) may increase the rate of raltegravir absorption and lead to elevated plasma levels of raltegravir (see Table 1 "Pharmacokinetic interaction data"). Safety profiles in subgroups of patients in Phase III studies who received proton pump inhibitors or H2-histamine receptor blockers were comparable to those not receiving these agents. Therefore, no dose adjustment is required when using proton pump inhibitors or H2-histamine receptor blockers.

All studies were conducted in adult patients.

Table 1. Pharmacokinetic interaction data

Medicinal products by therapeutic indication	Interaction (mechanism, if known)		Recommendations for concomitant use
ANTIRETROVIRAL AGENTS
Protease inhibitors
Atazanavir/ritonavir (raltegravir 400 mg twice daily)	Raltegravir AUC ↑ 41% Raltegravir C_12h ↑ 77% Raltegravir C_max ↑ 24% (inhibition of UGT1A1)		No dose adjustment of Isentress is required.
Tipranavir/ritonavir (raltegravir 400 mg twice daily)	Raltegravir AUC ↓ 24% Raltegravir C_12h ↓ 55% Raltegravir C_max ↓ 18% (induction of UGT1A1)		No dose adjustment of Isentress is required.
Non-nucleoside reverse transcriptase inhibitors (NNRTIs)
Efavirenz (raltegravir 400 mg single dose)	Raltegravir AUC ↓ 36% Raltegravir C_12h ↓ 21% Raltegravir C_max ↓ 36% (induction of UGT1A1)		No dose adjustment of Isentress is required.
Etravirine (raltegravir 400 mg twice daily)	Raltegravir AUC ↓ 10% Raltegravir C_12h ↓ 34% Raltegravir C_max ↓ 11% (induction of UGT1A1) Etravirine AUC ↑ 10% Etravirine C_12h ↑ 17% Etravirine C_max ↑ 4%		No dose adjustment of Isentress or etravirine is required.
Nucleoside reverse transcriptase inhibitors
Tenofovir (raltegravir 400 mg twice daily)	Raltegravir AUC ↑ 49% Raltegravir C_12h ↑ 3% Raltegravir C_max ↑ 64% (mechanism of interaction unknown) Tenofovir AUC ↓ 10% Tenofovir C_12h ↓ 13% Tenofovir C_max ↓ 23%		No dose adjustment of Isentress or tenofovir disoproxil fumarate is required.
C-C chemokine receptor type 5 (CCR5) inhibitors
Maraviroc (raltegravir 400 mg twice daily)	Raltegravir AUC ↓ 37% Raltegravir C_12h ↓ 28% Raltegravir C_max ↓ 33% (mechanism of interaction unknown) Maraviroc AUC ↓ 14% Maraviroc C_12h ↓ 10% Maraviroc C_max ↓ 21%		No dose adjustment of Isentress or maraviroc is required.
ANTIVIRAL AGENTS FOR HEPATITIS C VIRUS
NS3/4A protease inhibitors
Boceprevir (single dose of raltegravir 400 mg)	Raltegravir AUC ↑ 4% Raltegravir C_12h ↓ 25% Raltegravir C_max ↑ 11% (mechanism of interaction unknown)		No dose adjustment of Isentress or boceprevir is required.
ANTIMICROBIAL AGENTS
Antimycobacterial agents
Rifampicin (single dose of raltegravir 400 mg)		Raltegravir AUC ↓ 40% Raltegravir C_12h ↓ 61% Raltegravir C_max ↓ 38% (induction of UGT1A1)	Rifampicin reduces plasma concentrations of Isentress. However, if concomitant use with rifampicin cannot be avoided, doubling the dose of Isentress may be considered.
SEDATIVE AGENTS
Midazolam (raltegravir 400 mg twice daily)		Midazolam AUC ↓ 8% Midazolam C_max ↑ 3%	No dose adjustment of Isentress or midazolam is required. These results indicate that raltegravir is neither an inducer nor inhibitor of CYP3A4, and it is not expected to affect the pharmacokinetics of medicinal products that are CYP3A4 substrates.
ANTACIDS (containing metal cations)
Antacids containing aluminium/magnesium hydroxide (raltegravir 400 mg twice daily)		Raltegravir AUC ↓ 49% Raltegravir C_12h ↓ 63% Raltegravir C_max ↓ 44% 2 hours before raltegravir administration Raltegravir AUC ↓ 51% Raltegravir C_12h ↓ 56% Raltegravir C_max ↓ 51% 2 hours after raltegravir administration Raltegravir AUC ↓ 30% Raltegravir C_12h ↓ 57% Raltegravir C_max ↓ 24% 6 hours before raltegravir administration Raltegravir AUC ↓ 13% Raltegravir C_12h ↓ 50% Raltegravir C_max ↓ 10% 6 hours after raltegravir administration Raltegravir AUC ↓ 11% Raltegravir C_12h ↓ 49% Raltegravir C_max ↓ 10% (metal cation chelation)	Antacids containing aluminium/magnesium hydroxide reduce raltegravir plasma levels. Concomitant use of Isentress with antacids containing aluminium and/or magnesium is not recommended.
Antacids containing calcium carbonate (raltegravir 400 mg twice daily)		Raltegravir AUC ↓ 55% Raltegravir C_12h ↓ 32% Raltegravir C_max ↓ 52% (metal cation chelation)	No dose adjustment of Isentress is required.
OTHER AGENTS CONTAINING METAL CATIONS
Preparations containing iron salts		Probable mechanism: Raltegravir AUC ↓ (metal cation chelation)	Plasma levels of raltegravir are expected to decrease when coadministered with products containing iron salts; administration of iron salt-containing products no sooner than two hours after raltegravir may reduce this effect.
H2-RECEPTOR BLOCKERS AND PROTON PUMP INHIBITORS
Omeprazole (raltegravir 400 mg twice daily)		Raltegravir AUC ↑ 37% Raltegravir C_12h ↑ 24% Raltegravir C_max ↑ 51% (increased solubility)	No dose adjustment of Isentress is required.
Famotidine (raltegravir 400 mg twice daily)		Raltegravir AUC ↑ 44% Raltegravir C_12h ↑ 6% Raltegravir C_max ↑ 60% (increased solubility)	No dose adjustment of Isentress is required.
HORMONAL CONTRACEPTIVES
Ethinylestradiol/norelgestromin (raltegravir 400 mg twice daily)		Ethinylestradiol AUC ↓ 2% Ethinylestradiol C_max ↑ 6% Norelgestromin AUC ↑ 14% Norelgestromin C_max ↑ 29%	No dose adjustment of Isentress or hormonal contraceptives (estrogen and/or progestin-based) is required.
OPIOID ANALGESICS
Methadone (raltegravir 400 mg twice daily)		Methadone AUC ↔ Methadone C_max ↔	No dose adjustment of Isentress or methadone is required.

Special precautions for use.

Patients should be advised that current antiretroviral therapy does not cure HIV infection and does not prevent transmission of the HIV virus to others through blood.

Overall, considerable inter- and intra-subject variability in the pharmacokinetic parameters of raltegravir has been observed.

Raltegravir has a relatively low genetic barrier to resistance. Therefore, whenever possible, raltegravir should be administered with two other active antiretroviral agents (ART – antiretroviral therapy) to minimize the risk of virological failure and development of resistance.

Regarding treatment-naïve patients, there are limited clinical trial data on the use of raltegravir in combination with two nucleoside reverse transcriptase inhibitors (NRTIs) (emtricitabine and tenofovir disoproxil fumarate).

Depression. Depression, including suicidal ideation and behavior, has been reported, particularly in patients with a history of depression or psychiatric illness. Precautions should be taken when treating patients with a history of depression or psychiatric disorders.

Patients with impaired liver function. The safety and efficacy of raltegravir in patients with severe hepatic impairment have not been established. Therefore, Isentress should be used with caution in patients with severe hepatic impairment.

Patients with pre-existing liver function abnormalities, including chronic hepatitis, have a higher incidence of hepatic adverse events during combination antiretroviral therapy; their condition should be monitored according to standard practice. If signs of worsening liver disease occur in such patients, a decision should be made to temporarily discontinue or permanently discontinue the drug.

Patients with chronic hepatitis B or C who are receiving combination antiretroviral therapy are at increased risk of developing severe and potentially fatal hepatic adverse reactions.

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

Immune Reconstitution Syndrome. In HIV-infected patients with advanced immunodeficiency, initiation of combination antiretroviral therapy (cART) may result in an inflammatory response to asymptomatic or residual opportunistic pathogens, leading to serious clinical conditions or symptom exacerbation. Such reactions are generally observed within the first weeks or months after starting cART. Typical examples include cytomegalovirus retinitis, generalized and/or focal mycobacterial infections, and Pneumocystis jiroveci (previously known as Pneumocystis carinii) pneumonia. Any inflammatory symptoms should be evaluated and appropriate treatment initiated if necessary.

Autoimmune disorders (e.g., Graves’ disease) have also been reported to occur during immune reconstitution; however, the time to onset varies widely, and these events may occur many months after initiation of therapy.

Interaction with other medicinal products.

Antacids. Concomitant administration of Isentress with antacids containing aluminum and/or magnesium results in decreased plasma levels of raltegravir. Concomitant use of Isentress with antacids containing aluminum and/or magnesium is not recommended (see section "Interaction with other medicinal products and other forms of interaction").

Rifampicin. Isentress should be administered with caution concomitantly with potent inducers of uridine diphosphate glucuronosyltransferase (UGT) 1A1 (e.g., rifampicin). Rifampicin reduces raltegravir plasma concentrations; the impact on raltegravir efficacy is unknown. However, if concomitant use with rifampicin cannot be avoided in adult patients, consideration should be given to doubling the dose of Isentress (see section "Interaction with other medicinal products and other forms of interaction"). There are no data to provide recommendations for concomitant use of Isentress and rifampicin in patients under 18 years of age.

Myopathy and rhabdomyolysis. Cases of myopathy and rhabdomyolysis have been reported. The drug should be used with caution in patients with a history of myopathy or rhabdomyolysis, or in patients with risk factors such as concomitant use of drugs that may cause these conditions.

Severe skin and allergic reactions. Severe, potentially life-threatening and fatal skin reactions have been reported in patients receiving Isentress in combination with other drugs associated with such reactions. These include cases of Stevens-Johnson syndrome and toxic epidermal necrolysis. Hypersensitivity reactions characterized by rash, systemic symptoms, and sometimes organ dysfunction, including hepatic failure, have also been reported. Isentress and other suspected drugs should be discontinued immediately upon the appearance of signs or symptoms suggestive of severe skin or allergic reactions (including severe rash or rash accompanied by fever, malaise, fatigue, muscle or joint pain, blisters, oral lesions, conjunctivitis, facial edema, hepatitis, eosinophilia, or angioedema). Clinical status, including liver aminotransferase levels, should be monitored and appropriate therapy initiated. Delay in discontinuing Isentress or other suspected drugs after the onset of severe rash may lead to life-threatening reactions.

Rash. Rash occurs more frequently in patients receiving regimens containing Isentress + darunavir compared to patients receiving Isentress without darunavir or darunavir without Isentress (see section "Adverse reactions").

Lactose. This medicinal product contains lactose. It is contraindicated in patients with rare hereditary problems of galactose intolerance, total lactase deficiency, or glucose-galactose malabsorption.

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

Use during pregnancy or breastfeeding.

Pregnancy.

Extensive data from pregnant women who received raltegravir at a dose of 400 mg twice daily during the first trimester of pregnancy (over 1000 prospective pregnancy outcomes) indicate no teratogenic effects due to toxicity. Animal studies have demonstrated reproductive toxicity. Moderate data from pregnant women who received raltegravir at a dose of 400 mg twice daily during the second and/or third trimester of pregnancy (between 300 and 1000 expected pregnancy outcomes) suggest no increased risk of fetal or neonatal toxicity. Raltegravir at a dose of 400 mg may be used during pregnancy if clinically indicated.

Antiretroviral Pregnancy Registry.

A registry has been established—the Antiretroviral Pregnancy Registry (APR)—to monitor the effects of Isentress on the mother and fetus. Physicians are encouraged to register affected patients in this registry.

In general, when making decisions about using antiretroviral agents to treat HIV infection in pregnant women and to reduce the risk of vertical transmission of HIV to the newborn, both animal study data and clinical experience in pregnant women should be considered to assess fetal safety.

Breastfeeding period.

Raltegravir/metabolites are excreted in breast milk to an extent that may have an impact on breastfed infants. Available pharmacodynamic/toxicological data from animal studies have demonstrated excretion of raltegravir/metabolites into breast milk. Therefore, a risk to newborns/infants cannot be excluded.

HIV-infected women should not breastfeed in order to prevent transmission of HIV to the infant.

Fertility.

No effects on fertility were observed in male and female rats at doses up to 600 mg/kg/day, resulting in 3-fold higher exposure compared to the recommended human dose.

Ability to influence reaction speed when driving or operating machinery.

Dizziness has been reported in some patients receiving treatment regimens containing Isentress. Dizziness may affect a patient's ability to drive or operate machinery (see section "Adverse reactions").

Administration and Dosage.

For oral use. Treatment with Isentress should be initiated by a physician experienced in the management of HIV infection. Isentress must be administered in combination with other antiretroviral agents.

Do not chew, crush, or split the tablets. Isentress may be taken with or without food.

The dose of Isentress is 1 tablet of 400 mg twice daily for the treatment of the following patient groups with HIV-1 infection:

Adults;
Children with body weight of at least 25 kg.

If a child cannot swallow the film-coated tablet, an alternative dosage form—chewable tablets with appropriate dosing—may be used.

Isentress is also available in the form of chewable tablets.

For additional dosing information, refer to the medical instructions for Isentress chewable tablets.

The maximum dose of chewable tablets is 300 mg twice daily. Since different dosage forms of Isentress have different pharmacokinetic profiles, chewable tablets must not be substituted with 400 mg film-coated tablets.

Chewable tablets have not been studied for the treatment of HIV infection in adolescents (12–18 years) or adults.

Elderly patients.

Limited data are available on the use of raltegravir in elderly patients. Therefore, Isentress should be used with caution in this population.

Renal impairment.

No dose adjustment is required for patients with renal impairment.

Hepatic impairment.

No dose adjustment is required for patients with mild to moderate hepatic impairment. The safety and efficacy of raltegravir have not been established in patients with severe hepatic impairment. Therefore, Isentress should be used with caution in patients with severe hepatic impairment.

Pediatric population.

Isentress may be administered to children with body weight of at least 25 kg.

The safety and efficacy of 400 mg raltegravir tablets in children weighing less than 25 kg have not been established.

Overdose.

There is no specific information on the management of Isentress overdose.

In case of overdose, standard supportive measures are recommended, such as removal of unabsorbed drug from the gastrointestinal tract, clinical monitoring (including ECG), and administration of supportive therapy as needed. It should be noted that raltegravir is formulated for clinical use as the potassium salt. There is no data on the effectiveness of dialysis in eliminating raltegravir.

Adverse Reactions

The safety profile of the drug Isentress is based on pooled safety data from two Phase III clinical trials in treatment-experienced adult patients and one Phase III clinical trial in treatment-naïve adult patients. The most commonly reported adverse reactions during treatment were headache and nausea, occurring at a frequency of 5% or higher. The most frequently reported serious adverse reaction was immune reconstitution syndrome.

In two randomized clinical trials involving treatment-experienced patients, the recommended dose of Isentress 400 mg twice daily in combination with optimized background therapy (OBT) was administered to 462 patients, compared with 237 patients receiving placebo plus OBT. During double-blind treatment, the total follow-up period was 708 patient-years in the Isentress group (400 mg twice daily) and 244 patient-years in the placebo group.

In treatment-naïve patients, a multicenter, randomized, double-blind, active-controlled clinical trial evaluated 400 mg of Isentress twice daily in combination with fixed-dose emtricitabine 200 mg (+) tenofovir disoproxil 245 mg in 281 patients, compared to 282 patients receiving 600 mg efavirenz (EFV) at bedtime in combination with emtricitabine (+) tenofovir. During double-blind treatment, the total observation period was 1104 patient-years in the group receiving 400 mg Isentress twice daily and 1036 patient-years in the group receiving 600 mg efavirenz at bedtime.

In the pooled analysis of treatment-naïve patients, the rates of discontinuation due to adverse reactions were 3.9% in patients receiving Isentress + OBT and 4.6% in patients receiving placebo + OBT.

In treatment-naïve patients, the rates of discontinuation due to adverse reactions were 5% in patients receiving Isentress + emtricitabine (+) tenofovir and 10% in patients receiving efavirenz + emtricitabine (+) tenofovir.

Adverse reactions considered by investigators to be causally related to raltegravir (monotherapy or in combination with ART), as well as adverse reactions reported during post-marketing surveillance, are listed below by system organ class. Frequency is defined as: common – ≥ 1/100 to <1/10, uncommon – ≥ 1/1000 to <1/100, unknown – cannot be estimated from available data.

Table 2. Adverse Reactions (AR).

System organ classes	Frequency of adverse reactions	Adverse reactions of Isentress (monotherapy or in combination with 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
Benign, malignant and unspecified neoplasms (including cysts and polyps)	uncommon	skin papillomas
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
Metabolism and nutrition disorders	uncommon	cachexia, diabetes mellitus, dyslipidaemia, hypercholesterolaemia, hyperglycaemia, hyperlipidaemia, hyperphagia, increased appetite, polydipsia, fat metabolism disorder
Psychiatric disorders	common	abnormal dreams, insomnia, nightmares, unusual behaviour, depression
Psychiatric disorders	uncommon	mental disorder, suicide attempt, fear, confusion, depressed mood, severe depression, intrasomnia disorder, mood alteration, panic attack, sleep disorder, suicidal thoughts, suicidal behaviour (particularly in patients with pre-existing psychiatric illness)
Nervous system disorders	common	dizziness, headache, psychomotor hyperactivity
Nervous system disorders	uncommon	amnesia, carpal tunnel syndrome, cognitive disorder, attention disturbance, postural dizziness, dysgeusia, hypersomnia, hypoesthesia, lethargic state, memory impairment, migraine, peripheral neuropathy, paraesthesia, somnolence, tension headache, tremor, poor quality of sleep
Eye disorders	uncommon	vision blurred
Ear and labyrinth disorders	common uncommon	vertigo tinnitus
Cardiac disorders	uncommon	tachycardia, sinus bradycardia, ventricular extrasystoles
Vascular disorders	uncommon	flushing, hypertension
Respiratory, thoracic and mediastinal disorders	uncommon	dysphonia, epistaxis, nasal congestion
Gastrointestinal disorders	common	abdominal distension, abdominal pain, diarrhoea, flatulence, nausea, vomiting, dyspepsia
Gastrointestinal disorders	uncommon	gastritis, abdominal discomfort, upper abdominal pain, abdominal tenderness, anorectal discomfort, constipation, dry mouth, epigastric discomfort, erosive duodenitis, eructation, gastroesophageal reflux disease, gingivitis, glossitis, odynophagia, acute pancreatitis, peptic ulcer, rectal haemorrhage
Hepatobiliary disorders	uncommon	hepatitis, steatohepatitis, alcoholic hepatitis, hepatic failure
Skin and subcutaneous tissue disorders	common	rash
Skin and subcutaneous tissue disorders	uncommon	acne, alopecia, acneiform dermatitis, dry skin, erythema, facial atrophy, hyperhidrosis, lipoatrophy, acquired lipodystrophy, lipohypertrophy, night sweats, prurigo, pruritus, generalized pruritus, macular rash, maculopapular rash, pruritic rash, skin lesions, 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 and bone pain, myalgia, neck pain, osteopenia, limb pain, tendonitis, rhabdomyolysis
Renal and urinary disorders	uncommon	renal failure, nephritis, nephrolithiasis, nocturia, renal cyst, renal function abnormalities, tubulointerstitial nephritis
Reproductive system and breast disorders	uncommon	erectile dysfunction, gynaecomastia, menopausal symptoms
General disorders and administration site conditions	common	asthenia, fatigue, increased body temperature
General disorders and administration site conditions	uncommon	chest discomfort, chills, facial swelling, increased fat tissue, feeling of nervousness, malaise, submandibular swelling, peripheral oedema, pain
Investigations	common	elevated alanine aminotransferase level, atypical lymphocyte count, elevated aspartate aminotransferase level, elevated blood triglycerides, elevated lipase level, elevated pancreatic amylase level in blood
Investigations	uncommon	decreased absolute neutrophil count, increased alkaline phosphatase, decreased blood albumin, elevated blood amylase, elevated blood bilirubin, elevated blood cholesterol, elevated blood creatinine, elevated blood glucose, elevated blood urea nitrogen, elevated creatine phosphokinase, elevated fasting blood glucose, glucosuria, elevated high-density lipoprotein level, elevated international normalized ratio, elevated low-density lipoprotein level, decreased platelet count, erythrocyturia, increased waist size, increased body weight, decreased white blood cell count
Injury, poisoning and procedural complications	uncommon	accidental overdose

Description of individual adverse reactions

Cancer has been observed in patients with prior treatment experience and in patients without prior treatment experience who received Isentress in combination with other antiretroviral agents. The types and frequency of specific malignancies were consistent with those expected in a population with advanced immunodeficiency. The risk of cancer development in these studies was similar in the Isentress treatment groups and in the comparator treatment groups.

Grade II–IV increases in creatine kinase levels have been observed in patients receiving Isentress. Cases of myopathy and rhabdomyolysis have been reported. The drug should be used with caution in patients with a history of myopathy or rhabdomyolysis, or in those with any risk factors, including concomitant use of other medicinal products known to cause such conditions (see section "Special warnings and precautions for use").

Cases of osteonecrosis have been reported, particularly in individuals with well-known risk factors, advanced HIV disease, or long-term exposure to combination antiretroviral therapy. The frequency of this adverse reaction is unknown (see section "Special warnings and precautions for use").

In HIV-infected patients with severe immune deficiency at the initiation of combination antiretroviral therapy (cART), an inflammatory reaction to asymptomatic or residual opportunistic infections may occur. Autoimmune disorders (e.g., Graves’ disease) have also been reported; however, the reported time to onset is variable, and these events may occur many months after initiation of treatment (see section "Special warnings and precautions for use").

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

In clinical trials involving treatment-experienced patients, rash, regardless of cause, occurred more frequently in patients receiving Isentress + darunavir compared to patients receiving Isentress without darunavir or darunavir without Isentress. The incidence of rash considered by the investigator to be treatment-related was similar across both groups. Exposure-adjusted incidence rates of rash (all causes) were 10.9, 4.2, and 3.8 per 100 patient-years, respectively; for treatment-related rash, the rates were 2.4, 1.1, and 2.3 per 100 patient-years, respectively. In clinical trials, the intensity of rash was mild to moderate and did not lead to discontinuation of therapy (see section "Special warnings and precautions for use").

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

In Phase III trials, inclusion of patients with (N = 114/699 or 16 %; HBV=6 %, HCV=9 %, HBV+HCV=1 %) and without (N = 34/563 or 6 %; HBV=4 %, HCV=2 %, HBV+HCV=0.2 %) prior treatment experience and with concomitant chronic (but not acute) active hepatitis B and/or hepatitis C was permitted provided liver function tests at screening did not exceed five times the upper limit of normal. Overall, the safety profile of Isentress was similar in patients without and with concomitant hepatitis B and/or C infection, although elevations in AST and ALT were somewhat higher in the subgroup of patients with concomitant hepatitis B and/or C infection in both treatment groups. At Week 96, in treatment-experienced patients, laboratory abnormalities of Grade II or higher representing a worsening from baseline in AST, ALT, or total bilirubin occurred in 29 %, 34 %, and 13 % of patients with concomitant infection receiving Isentress, compared to 11 %, 10 %, and 9 % of all other patients receiving Isentress. Over 240 weeks of treatment in treatment-naïve patients, laboratory abnormalities of Grade II or higher representing a worsening from baseline in AST, ALT, or total bilirubin occurred in 22 %, 44 %, and 17 % of patients with concomitant infection receiving Isentress, compared to 13 %, 13 %, and 5 % of all other patients receiving Isentress.

The following adverse reactions have been identified during post-marketing surveillance but were not reported as treatment-related in randomized, controlled Phase III clinical trials (protocols 018, 019, and 021): thrombocytopenia, suicidal ideation, suicidal behaviour (particularly in patients with pre-existing psychiatric illness), hepatic failure, Stevens-Johnson syndrome, drug rash with eosinophilia and systemic symptoms (DRESS), rhabdomyolysis.

Paediatric population

Raltegravir was studied in 126 treatment-experienced HIV-1 infected children and adolescents aged 2 to 18 years, in combination with other antiretroviral agents in the IMPAACT P1066 study. Of the 126 patients, 96 received the recommended dose of Isentress. In these 96 children and adolescents, the frequency, type, and severity of drug-related adverse reactions at Week 48 were similar to those observed in adults.

One patient experienced Grade III psychomotor hyperactivity, abnormal behaviour, and insomnia related to study drug; one patient had Grade II allergic rash considered related to study drug. One patient experienced treatment-related laboratory abnormalities – Grade IV AST and Grade III ALT, which were considered serious.

Infants and children from 4 weeks to 2 years of age

Raltegravir was also studied in 26 HIV-1 infected infants and children aged 4 weeks to 2 years, in combination with other antiretroviral agents in the IMPAACT P1066 study. In these 26 infants and children, the frequency, type, and severity of drug-related adverse reactions at Week 48 were similar to those observed in adults. One patient experienced a Grade III allergic rash related to study drug, which led to premature discontinuation of therapy.

Shelf life. 2.5 years.

Do not use after the expiry date stated on the packaging.

Storage conditions.

Store in the original packaging at temperatures not exceeding 30 °C.

Keep out of the reach and sight of children.

Packaging.

60 film-coated tablets in a high-density polyethylene bottle, sealed with a protective membrane and closed with a child-resistant plastic cap. 1 bottle in a cardboard box with the package leaflet.

Prescription status.

Prescription only.

Manufacturer.

Merck Sharp & Dohme B.V., Netherlands.

Manufacturer's address and location of activity.

Waarderweg 39, 2031 BN Haarlem, Netherlands.