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Pharmacokinetic interaction with omeprazole (substantially increased raltegravir peak plasma concentrations and area under the concentration-time curve (AUC)).

Pharmacokinetic interaction with rifabutin (increased raltegravir peak plasma concentrations and AUC).

Pharmacokinetic interaction with rifampin (decreased raltegravir plasma concentrations and AUC); rifampin is a strong inducer of UGT 1A1. If raltegravir is used in adults receiving rifampin, dosage of raltegravir film-coated tablets should be increased ... twice daily and patients monitored closely for virologic response.

Concomitant use of raltegravir and rifapentine is not recommended. HIV-infected tuberculosis patients treated with rifapentine have a higher rate of tuberculosis relapse than those treated with other rifamycin-based tuberculosis regimens; an alternative antimycobacterial agent is recommended in HIV-infected patients.

For more Interactions (Complete) data for Raltegravir (17 total), please visit the HSDB record page.

In large clinical trials, therapy with raltegravir was associated with alanine aminotransferase (ALT) elevations in up to 10% and elevations of greater than 5 times the upper limit of normal (ULN) in 3% to 4% of patients, but these rates were similar to those in comparator groups receiving matched background optimized antiretroviral therapy without raltegravir. These elevations were not associated with clinical symptoms and generally did not require dose modification. There have been no published reports of clinically apparent cases of liver injury attributed to raltegravir. Nevertheless, the product label for raltegravir mentions hepatitis and hepatic failure as a potential adverse reactions, but without specific details. Raltegravir has also been linked to instances of Stevens Johnson syndrome and drug hypersensitivity reactions, which can be accompanied by hepatic involvement. Finally, initiation of antiretroviral therapy with raltegravir can result in the immune reconstitution syndrome which may cause a worsening or flare of an accompanying chronic hepatitis B or C in coinfected individuals.

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 95(SRC), determined from a structure estimation method(2), indicates that raltegravir is expected to have high mobility in soil(SRC). Volatilization of raltegravir from moist soil surfaces is not expected to be an important fate process(SRC) given an estimated Henry's Law constant of 9.1X10-23 atm-cu m/mole(SRC), using a fragment constant estimation method(3). Raltegravir is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 4.5X10-22 mm Hg at 25 °C(SRC), determined from a fragment constant method(2). Biodegradation data in soil were not available(SRC, 2013).

AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 95(SRC), determined from a structure estimation method(2), indicates that raltegravir is not expected to adsorb to suspended solids and sediment(SRC). Volatilization from water surfaces is not expected(3) based upon an estimated Henry's Law constant of 9.1X10-23 atm-cu m/mole(SRC), developed using a fragment constant estimation method(4). According to a classification scheme(5), an estimated BCF of 3(SRC), from an estimated log Kow of 0.40(6) and a regression-derived equation(2), suggests the potential for bioconcentration in aquatic organisms is low(SRC). Biodegradation data in water were not available(SRC, 2013).

ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), raltegravir, which has an estimated vapor pressure of 4.5X10-22 mm Hg at 25 °C(SRC), determined from a fragment constant method(2), is expected to exist solely in the particulate phase in the ambient atmosphere. Particulate-phase raltegravir may be removed from the air by wet and dry deposition(SRC). Raltegravir contains chromophores that absorb at wavelengths >290 nm(3) and, therefore, may be susceptible to direct photolysis by sunlight(SRC).

It is not known whether raltegravir is secreted in human milk. However, raltegravir is secreted in the milk of lactating rats. Mean drug concentrations in milk were approximately 3-fold greater than those in maternal plasma at a maternal dose of 600 mg/kg/day in rats.

Antiviral drugs have been recently recognized as one of the emerging contaminants in the environment. These are discharged after therapeutic use through human excretion. Effluent containing high concentration of antiviral drugs discharged from production facilities is also a cause of concern to nearby aquatic bodies. There is an increased interest in their removal because they are highly bioactive. Some antiviral drugs are resistant to conventional methods of degradation, and there is a risk of development of antiviral resistance in humans and animals if exposed repeatedly for long periods. To date, the potential human, animal, and ecological risks associated with the discharge of these antiviral compounds to the environment are not well documented. This study presents a brief summary on occurrence, ecotoxicological risks, and physicochemical properties of antiviral drugs in the environment. The needs regarding removal, disposal, and treatment of antiviral drugs are also addressed(1). /Antiviral drugs/

Using a structure estimation method based on molecular connectivity indices(1), the Koc of raltegravir can be estimated to be 95(SRC). According to a classification scheme(2), this estimated Koc value suggests that raltegravir is expected to have high mobility in soil.

/HUMAN EXPOSURE STUDIES/ In a randomized, placebo-controlled, crossover study, 31 healthy subjects were administered a single oral supratherapeutic dose of raltegravir 1600 mg and placebo. Peak raltegravir plasma concentrations were approximately 4-fold higher than the peak concentrations following a 400 mg dose. ISENTRESS did not appear to prolong the QTc interval for 12 hours postdose. After baseline and placebo adjustment, the maximum mean QTc change was -0.4 msec (1-sided 95% upper Cl: 3.1 msec).

/SIGNS AND SYMPTOMS/ No specific information is available on the treatment of overdosage with ISENTRESS. Doses as high as 1600-mg single dose and 800-mg twice-daily multiple doses were studied in healthy volunteers without evidence of toxicity. Occasional doses of up to 1800 mg per day were taken in the clinical studies of HIV-1 infected subjects without evidence of toxicity.

/SIGNS AND SYMPTOMS/ Severe, potentially life-threatening skin reactions have been reported, including some fatalities. Stevens-Johnson syndrome, toxic epidermal necrolysis, and hypersensitivity reactions characterized by rash, constitutional findings, and organ dysfunction (including hepatic failure) have occurred.

/CASE REPORTS/ DRESS syndrome (drug reaction with eosinophilia and systemic symptoms) is a life-threatening adverse drug reaction. Raltegravir is an integrase inhibitor used in HIV-1 infection. /the authors/ report on a patient who developed a DRESS syndrome under raltegravir treatment, which was identified as a probable case of DRESS on the basis of Kardaun and Naranjo scores. ...

For more Human Toxicity Excerpts (Complete) data for Raltegravir (6 total), please visit the HSDB record page.

Drug-Induced Liver Injury Severity and Toxicity (DILIst)

raltegravir

DILI Positive

Oral

DOI:10.1016/j.drudis.2019.09.022

An estimated BCF of 3 was calculated in fish for raltegravir(SRC), using an estimated log Kow of 0.40(1) and a regression-derived equation(2). According to a classification scheme(3), this BCF suggests the potential for bioconcentration in aquatic organisms is low(SRC).

The Henry's Law constant for raltegravir is estimated as 9.1X10-23 atm-cu m/mole(SRC) using a fragment constant estimation method(1). This Henry's Law constant indicates that raltegravir is expected to be essentially nonvolatile from water surfaces and moist soil surfaces(2). Raltegravir is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 4.5X10-22 mm Hg(SRC), determined from a fragment constant method(3).

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including raltegravir potassium, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. /Raltegravir potassium/

MEDICATION

Use (kg; approx.) in Germany (2009): >500

Each 400 mg film-coated tablet of ISENTRESS for oral administration contains 434.4 mg of raltegravir (as potassium salt), equivalent to 400 mg of raltegravir free phenol and the following inactive ingredients: microcrystalline cellulose, lactose monohydrate, calcium phosphate dibasic anhydrous, hypromellose 2208, poloxamer 407 (contains 0.01% butylated hydroxytoluene as antioxidant), sodium stearyl fumarate, magnesium stearate.

Each 100 mg chewable tablet of ISENTRESS for oral administration contains 108.6 mg of raltegravir (as potassium salt), equivalent to 100 mg of raltegravir free phenol and the following inactive ingredients: hydroxypropyl cellulose, sucralose, saccharin sodium, sodium citrate dihydrate, mannitol, red iron oxide, yellow iron oxide, monoammonium glycyrrhizinate, sorbitol, fructose, natural and artificial flavors (orange, banana, and masking that contains aspartame), crospovidone, magnesium stearate, sodium stearyl fumarate, ethylcellulose 20 cP, ammonium hydroxide, medium chain triglycerides, oleic acid, hypromellose 2910/6cP, PEG 400.

Each 25 mg chewable tablet of ISENTRESS for oral administration contains 27.16 mg of raltegravir (as potassium salt), equivalent to 25 mg of raltegravir free phenol and the following inactive ingredients: hydroxypropyl cellulose, sucralose, saccharin sodium, sodium citrate dihydrate, mannitol, yellow iron oxide, monoammonium glycyrrhizinate, sorbitol, fructose, natural and artificial flavors (orange, banana, and masking that contains aspartame), crospovidone, magnesium stearate, sodium stearyl fumarate, ethylcellulose 20 cP, ammonium hydroxide, medium chain triglycerides, oleic acid, hypromellose 2910/6cP, PEG 400.