Dosage Form: tablet, film coated; tablet, chewable
FULL PRESCRIBING INFORMATION
Indications and Usage for Isentress
Adults
Isentress® is indicated in combination with other antiretroviral agents for the treatment of human immunodeficiency virus (HIV-1) infection.
This indication is based on analyses of plasma HIV-1 RNA levels through 96 weeks in three double-blind controlled studies of Isentress. Two of these studies were conducted in clinically advanced, 3-class antiretroviral (NNRTI, NRTI, PI) treatment-experienced adults and one was conducted in treatment-naïve adults.
The use of other active agents with Isentress is associated with a greater likelihood of treatment response [see Clinical Studies (14)].
Pediatrics
Isentress is indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection in children and adolescents 2 years of age and older and weighing at least 10 kg [see Use in Specific Populations (8.4)].
This indication is based on the evaluation of safety, tolerability, pharmacokinetic parameters and efficacy of Isentress through at least 24-weeks in a multi-center, open-label, noncomparative study in HIV-1 infected children and adolescents 2 to 18 years of age [see Clinical Studies (14.3)].
The safety and efficacy of Isentress have not been established in children less than 2 years of age.
Isentress Dosage and Administration
General Dosing Recommendations
- Isentress Film-Coated Tablets and Chewable Tablets can be administered with or without food [see Clinical Pharmacology (12.3)].
- Maximum dose of chewable tablets is 300 mg twice daily.
- Isentress Chewable Tablets may be chewed or swallowed whole.
- Isentress Film-Coated Tablets must be swallowed whole.
- Because the formulations are not bioequivalent, do not substitute chewable tablets for the 400 mg film-coated tablet.
- During coadministration of Isentress 400 mg film-coated tablets with rifampin, the recommended dosage of Isentress is 800 mg twice daily in adults. There are no data to guide co-administration of Isentress with rifampin in patients below 18 years of age [see Drug Interactions (7)].
Adults
For the treatment of adult patients with HIV-1 infection, the dosage of Isentress is one 400 mg film-coated tablet administered orally, twice daily.
Pediatrics
For the treatment of children and adolescents with HIV-1 infection, the dosage of Isentress is as follows:
- 12 years of age and older: One 400 mg film-coated tablet orally, twice daily
- 6 to less than 12 years of age:
If at least 25 kg in weight:- One 400 mg film-coated tablet orally, twice daily OR
- Chewable tablets: weight based to maximum dose 300 mg, twice daily as specified in Table 1
- Chewable tablets: weight based to maximum dose 300 mg, twice daily as specified in Table 1
- 2 to less than 6 years of age:
If at least 10 kg in weight:- Chewable tablets: weight based to maximum dose 300 mg, twice daily as specified in Table 1
| Body Weight (kg) | Dose | Number of Chewable Tablets |
|---|---|---|
| ||
| 10 to less than 14 | 75 mg twice daily | 3 × 25 mg twice daily |
| 14 to less than 20 | 100 mg twice daily | 1 × 100 mg twice daily |
| 20 to less than 28 | 150 mg twice daily | 1.5 × 100 mg† twice daily |
| 28 to less than 40 | 200 mg twice daily | 2 × 100 mg twice daily |
| at least 40 | 300 mg twice daily | 3 × 100 mg twice daily |
Dosage Forms and Strengths
- Film-coated Tablets
400 mg pink, oval-shaped, film-coated tablets with "227" on one side. - Chewable Tablets
100 mg are pale orange, oval-shaped, orange-banana flavored, chewable tablets scored on both sides and imprinted on one face with the Merck logo and "477" on opposite sides of the score.
25 mg pale yellow, round, orange-banana flavored, chewable tablets with the Merck logo on one side and "473" on the other side.
Contraindications
None
Warnings and Precautions
Severe Skin and Hypersensitivity Reactions
Severe, potentially life-threatening, and fatal skin reactions have been reported. These include cases of Stevens-Johnson syndrome and toxic epidermal necrolysis. Hypersensitivity reactions have also been reported and were characterized by rash, constitutional findings, and sometimes, organ dysfunction, including hepatic failure. Discontinue Isentress 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 edema, hepatitis, eosinophilia, angioedema). Clinical status including liver aminotransferases should be monitored and appropriate therapy initiated. Delay in stopping Isentress treatment or other suspect agents after the onset of severe rash may result in a life-threatening reaction.
Immune Reconstitution Syndrome
During the initial phase of treatment, patients responding to antiretroviral therapy may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium complex, cytomegalovirus, Pneumocystis jiroveci pneumonia, Mycobacterium tuberculosis, or reactivation of varicella zoster virus), which may necessitate further evaluation and treatment.
Phenylketonurics
Isentress Chewable Tablets contain phenylalanine, a component of aspartame. Each 25 mg Isentress Chewable Tablet contains approximately 0.05 mg phenylalanine. Each 100 mg Isentress Chewable Tablet contains approximately 0.10 mg phenylalanine. Phenylalanine can be harmful to patients with phenylketonuria.
Adverse Reactions
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
Clinical Trials Experience: Treatment-Naïve Adults
The following safety assessment of Isentress in treatment-naïve subjects is based on the randomized double-blind active controlled study of treatment-naïve subjects, STARTMRK (Protocol 021) with Isentress 400 mg twice daily in combination with a fixed dose of emtricitabine 200 mg (+) tenofovir 300 mg, (N=281) versus efavirenz (EFV) 600 mg at bedtime in combination with emtricitabine (+) tenofovir, (N=282). During double-blind treatment, the total follow-up for subjects receiving Isentress 400 mg twice daily + emtricitabine (+) tenofovir was 480 patient-years and 463 patient-years for subjects receiving efavirenz 600 mg at bedtime + emtricitabine (+) tenofovir.
In Protocol 021, the rate of discontinuation of therapy due to adverse reactions was 4% in subjects receiving Isentress + emtricitabine (+) tenofovir and 7% in subjects receiving efavirenz + emtricitabine (+) tenofovir.
The clinical adverse drug reactions (ADRs) listed below were considered by investigators to be causally related to Isentress + emtricitabine (+) tenofovir or efavirenz + emtricitabine (+) tenofovir. Clinical ADRs of moderate to severe intensity occurring in ≥2% of treatment-naïve subjects treated with Isentress and occurring at a higher rate than efavirenz are presented in Table 2.
| System Organ Class, Preferred Term | Randomized Study Protocol 021 | |
|---|---|---|
| Isentress 400 mg Twice Daily + Emtricitabine (+) Tenofovir (n = 281)‡ % | Efavirenz 600 mg At Bedtime + Emtricitabine (+) Tenofovir (n = 282)‡ % | |
| Psychiatric Disorders | ||
| ||
| Insomnia | 4 | 3 |
Laboratory Abnormalities
The percentages of adult subjects treated with Isentress 400 mg twice daily or efavirenz in Protocol 021 with selected Grades 2 to 4 laboratory abnormalities that represent a worsening Grade from baseline are presented in Table 3.
| Randomized Study Protocol 021 | |||
|---|---|---|---|
| Laboratory Parameter Preferred Term (Unit) | Limit | Isentress 400 mg Twice Daily + Emtricitabine (+) Tenofovir (N = 281) | Efavirenz 600 mg At Bedtime + Emtricitabine (+) Tenofovir (N = 282) |
| ULN = Upper limit of normal range | |||
| Hematology | |||
| Absolute neutrophil count (103/µL) | |||
| Grade 2 | 0.75 - 0.999 | 3% | 4% |
| Grade 3 | 0.50 - 0.749 | 2% | 1% |
| Grade 4 | <0.50 | <1% | <1% |
| Hemoglobin (gm/dL) | |||
| Grade 2 | 7.5 - 8.4 | 1% | 1% |
| Grade 3 | 6.5 - 7.4 | <1% | 1% |
| Grade 4 | <6.5 | <1% | 0% |
| Platelet count (103/µL) | |||
| Grade 2 | 50 - 99.999 | 2% | 0% |
| Grade 3 | 25 - 49.999 | <1% | <1% |
| Grade 4 | <25 | 0% | 0% |
| Blood chemistry | |||
| Fasting (non-random) serum glucose test (mg/dL) | |||
| Grade 2 | 126 - 250 | 3% | 4% |
| Grade 3 | 251 - 500 | 1% | 0% |
| Grade 4 | >500 | 0% | 0% |
| Total serum bilirubin | |||
| Grade 2 | 1.6 - 2.5 × ULN | 4% | 0% |
| Grade 3 | 2.6 - 5.0 × ULN | 1% | 0% |
| Grade 4 | >5.0 × ULN | 0% | 0% |
| Serum aspartate aminotransferase | |||
| Grade 2 | 2.6 - 5.0 × ULN | 4% | 5% |
| Grade 3 | 5.1 - 10.0 × ULN | 2% | 2% |
| Grade 4 | >10.0 × ULN | 1% | <1% |
| Serum alanine aminotransferase | |||
| Grade 2 | 2.6 - 5.0 × ULN | 6% | 9% |
| Grade 3 | 5.1 - 10.0 × ULN | 1% | 2% |
| Grade 4 | >10.0 × ULN | 1% | 1% |
| Serum alkaline phosphatase | |||
| Grade 2 | 2.6 - 5.0 × ULN | 1% | 3% |
| Grade 3 | 5.1 - 10.0 × ULN | 0% | <1% |
| Grade 4 | >10.0 × ULN | 0% | <1% |
Lipids, Change from Baseline
Changes from baseline in fasting lipids are shown in Table 4.
| Laboratory Parameter Preferred Term | Isentress 400 mg Twice Daily + Emtricitabine (+) Tenofovir N = 281 | Efavirenz 600 mg At Bedtime + Emtricitabine (+) Tenofovir N = 282 | ||||
|---|---|---|---|---|---|---|
| Change from Baseline at Week 96 | Change from Baseline at Week 96 | |||||
| Baseline Mean (mg/dL) | Week 96 Mean (mg/dL) | Mean Change (mg/dL) | Baseline Mean (mg/dL) | Week 96 Mean (mg/dL) | Mean Change (mg/dL) | |
| Notes: | ||||||
| N = Number of subjects in the treatment group. The analysis is based on all available data. | ||||||
| If subjects initiated or increased serum lipid-reducing agents, the last available lipid values prior to the change in therapy were used in the analysis. If the missing data was due to other reasons, subjects were censored thereafter for the analysis. At baseline, serum lipid-reducing agents were used in 5% of subjects in the group receiving Isentress and 3% in the efavirenz group. Through Week 96, serum lipid-reducing agents were used in 7% of subjects in the group receiving Isentress and 9% in the efavirenz group. | ||||||
| ||||||
| LDL-Cholesterol* | 96 | 103 | 7 | 93 | 115 | 21 |
| HDL-Cholesterol* | 39 | 42 | 3 | 38 | 48 | 10 |
| Total Cholesterol* | 159 | 169 | 10 | 156 | 194 | 38 |
| Triglyceride* | 125 | 121 | -4 | 137 | 177 | 40 |
Clinical Trials Experience: Treatment-Experienced Adults
The safety assessment of Isentress in treatment-experienced subjects is based on the pooled safety data from the randomized, double-blind, placebo-controlled trials, BENCHMRK 1 and BENCHMRK 2 (Protocols 018 and 019) in antiretroviral treatment-experienced HIV-1 infected adult subjects. A total of 462 subjects received the recommended dose of Isentress 400 mg twice daily in combination with optimized background therapy (OBT) compared to 237 subjects taking placebo in combination with OBT. The median duration of therapy in these trials was 96 weeks for subjects receiving Isentress and 38 weeks for subjects receiving placebo. The total exposure to Isentress was 708 patient-years versus 244 patient-years on placebo. The rates of discontinuation due to adverse events were 4% in subjects receiving Isentress and 5% in subjects receiving placebo.
Clinical ADRs were considered by investigators to be causally related to Isentress + OBT or placebo + OBT. Clinical ADRs of moderate to severe intensity occurring in ≥2% of subjects treated with Isentress and occurring at a higher rate compared to placebo are presented in Table 5.
| System Organ Class, Adverse Reactions | Randomized Studies Protocol 018 and 019 | |
|---|---|---|
| Isentress 400 mg Twice Daily + OBT (n = 462)‡ | Placebo + OBT (n = 237)‡ | |
| ||
| Nervous System Disorders | ||
| Headache | 2 | <1 |
Laboratory Abnormalities
The percentages of adult subjects treated with Isentress 400 mg twice daily or placebo in Protocols 018 and 019 with selected Grade 2 to 4 laboratory abnormalities representing a worsening Grade from baseline are presented in Table 6.
| Randomized Studies Protocol 018 and 019 | |||
|---|---|---|---|
| Laboratory Parameter Preferred Term (Unit) | Limit | Isentress 400 mg Twice Daily + OBT (N = 462) | Placebo + OBT (N = 237) |
| ULN = Upper limit of normal range | |||
| Hematology | |||
| Absolute neutrophil count (103/µL) | |||
| Grade 2 | 0.75 - 0.999 | 4% | 5% |
| Grade 3 | 0.50 - 0.749 | 3% | 3% |
| Grade 4 | <0.50 | 1% | <1% |
| Hemoglobin (gm/dL) | |||
| Grade 2 | 7.5 - 8.4 | 1% | 3% |
| Grade 3 | 6.5 - 7.4 | 1% | 1% |
| Grade 4 | <6.5 | <1% | 0% |
| Platelet count (103/µL) | |||
| Grade 2 | 50 - 99.999 | 3% | 5% |
| Grade 3 | 25 - 49.999 | 1% | <1% |
| Grade 4 | <25 | 1% | <1% |
| Blood chemistry | |||
| Fasting (non-random) serum glucose test (mg/dL) | |||
| Grade 2 | 126 - 250 | 10% | 7% |
| Grade 3 | 251 - 500 | 3% | 1% |
| Grade 4 | >500 | 0% | 0% |
| Total serum bilirubin | |||
| Grade 2 | 1.6 - 2.5 × ULN | 6% | 3% |
| Grade 3 | 2.6 - 5.0 × ULN | 3% | 3% |
| Grade 4 | >5.0 × ULN | 1% | 0% |
| Serum aspartate aminotransferase | |||
| Grade 2 | 2.6 - 5.0 × ULN | 9% | 7% |
| Grade 3 | 5.1 - 10.0 × ULN | 4% | 3% |
| Grade 4 | >10.0 × ULN | 1% | 1% |
| Serum alanine aminotransferase | |||
| Grade 2 | 2.6 - 5.0 × ULN | 9% | 9% |
| Grade 3 | 5.1 - 10.0 × ULN | 4% | 2% |
| Grade 4 | >10.0 × ULN | 1% | 2% |
| Serum alkaline phosphatase | |||
| Grade 2 | 2.6 - 5.0 × ULN | 2% | <1% |
| Grade 3 | 5.1 - 10.0 × ULN | <1% | 1% |
| Grade 4 | >10.0 × ULN | 1% | <1% |
| Serum pancreatic amylase test | |||
| Grade 2 | 1.6 - 2.0 × ULN | 2% | 1% |
| Grade 3 | 2.1 - 5.0 × ULN | 4% | 3% |
| Grade 4 | >5.0 × ULN | <1% | <1% |
| Serum lipase test | |||
| Grade 2 | 1.6 - 3.0 × ULN | 5% | 4% |
| Grade 3 | 3.1 - 5.0 × ULN | 2% | 1% |
| Grade 4 | >5.0 × ULN | 0% | 0% |
| Serum creatine kinase | |||
| Grade 2 | 6.0 - 9.9 × ULN | 2% | 2% |
| Grade 3 | 10.0 - 19.9 × ULN | 4% | 3% |
| Grade 4 | ≥20.0 × ULN | 3% | 1% |
Less Common Adverse Reactions Observed in Treatment-Naïve and Treatment-Experienced Studies
The following ADRs occurred in <2% of treatment-naïve or treatment-experienced subjects receiving Isentress in a combination regimen. These events have been included because of their seriousness, increased frequency on Isentress compared with efavirenz or placebo, or investigator's assessment of potential causal relationship.
Gastrointestinal Disorders: abdominal pain, gastritis, dyspepsia, vomiting, nausea
General Disorders and Administration Site Conditions: fatigue, asthenia
Hepatobiliary Disorders: hepatitis
Immune System Disorders: hypersensitivity
Infections and Infestations: genital herpes, herpes zoster
Nervous System Disorders: dizziness
Psychiatric Disorders: depression (particularly in subjects with a pre-existing history of psychiatric illness), including suicidal ideation and behaviors
Renal and Urinary Disorders: nephrolithiasis, renal failure
Selected Adverse Events
Cancers were reported in treatment-experienced subjects who initiated Isentress or placebo, both with OBT, and in treatment-naïve subjects who initiated Isentress or efavirenz, both with emtricitabine (+) tenofovir; several were recurrent. The types and rates of specific cancers were those expected in a highly immunodeficient population (many had CD4+ counts below 50 cells/mm3 and most had prior AIDS diagnoses). The risk of developing cancer in these studies was similar in the group receiving Isentress and the group receiving the comparator.
Grade 2-4 creatine kinase laboratory abnormalities were observed in subjects treated with Isentress (see Table 6). Myopathy and rhabdomyolysis have been reported. Use with caution in patients at increased risk of myopathy or rhabdomyolysis, such as patients receiving concomitant medications known to cause these conditions.
Rash occurred more commonly in treatment-experienced subjects receiving regimens containing Isentress + darunavir/ritonavir compared to subjects receiving Isentress without darunavir/ritonavir or darunavir/ritonavir without Isentress. However, rash that was considered drug related occurred at similar rates for all three groups. These rashes were mild to moderate in severity and did not limit therapy; there were no discontinuations due to rash.
Patients with Co-existing Conditions
Patients Co-infected with Hepatitis B and/or Hepatitis C Virus
In the randomized, double-blind, placebo-controlled trials, treatment-experienced subjects (N = 114/699 or 16%) and treatment-naïve subjects (N = 34/563 or 6%) with chronic (but not acute) active hepatitis B and/or hepatitis C virus co-infection were permitted to enroll provided that baseline liver function tests did not exceed 5 times the upper limit of normal (ULN). In general the safety profile of Isentress in subjects with hepatitis B and/or hepatitis C virus co-infection was similar to that in subjects without hepatitis B and/or hepatitis C virus co-infection, although the rates of AST and ALT abnormalities were higher in the subgroup with hepatitis B and/or hepatitis C virus co-infection for all treatment groups. In treatment-experienced subjects, 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 subjects treated with Isentress as compared to 11%, 10% and 9% of all other subjects treated with Isentress. In treatment-naïve subjects, Grade 2 or higher laboratory abnormalities that represent a worsening Grade from baseline of AST, ALT or total bilirubin occurred in 17%, 28% and 17%, respectively, of co-infected subjects treated with Isentress as compared to 6%, 6% and 3% of all other subjects treated with Isentress.
Clinical Trials Experience: Pediatrics
Isentress has been studied in 126 antiretroviral treatment-experienced HIV-1 infected children and adolescents 2 through 18 years of age, in combination with other antiretroviral agents in IMPAACT P1066 [see Use in Specific Populations (8.4) and Clinical Studies (14.3)]. Of the 126 patients, 96 received the recommended dose of Isentress.
In these 96 children and adolescents, frequency, type and severity of drug related adverse reactions through Week 24 were comparable to those observed in adults.
One patient experienced drug related clinical adverse reactions of Grade 3 psychomotor hyperactivity, abnormal behavior 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.
Postmarketing Experience
The following adverse reactions have been identified during postapproval use of Isentress. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Blood and Lymphatic System Disorders: thrombocytopenia
Gastrointestinal Disorders: diarrhea
Hepatobiliary Disorders: hepatic failure (with and without associated hypersensitivity) in patients with underlying liver disease and/or concomitant medications
Musculoskeletal and Connective Tissue Disorders: rhabdomyolysis
Nervous System Disorders: cerebellar ataxia
Psychiatric Disorders: anxiety, paranoia
Drug Interactions
Effect of Raltegravir on the Pharmacokinetics of Other Agents
Raltegravir does not inhibit (IC50>100 µM) CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 or CYP3A in vitro. Moreover, in vitro, raltegravir did not induce CYP1A2, CYP2B6 or CYP3A4. A midazolam drug interaction study confirmed the low propensity of raltegravir to alter the pharmacokinetics of agents metabolized by CYP3A4 in vivo by demonstrating a lack of effect of raltegravir on the pharmacokinetics of midazolam, a sensitive CYP3A4 substrate. Similarly, raltegravir is not an inhibitor (IC50>50 µM) of the UDP-glucuronosyltransferases (UGT) tested (UGT1A1, UGT2B7), and raltegravir does not inhibit P-glycoprotein-mediated transport. Based on these data, Isentress is not expected to affect the pharmacokinetics of drugs that are substrates of these enzymes or P-glycoprotein (e.g., protease inhibitors, NNRTIs, opioid analgesics, statins, azole antifungals, proton pump inhibitors and anti-erectile dysfunction agents).
In drug interaction studies, raltegravir did not have a clinically meaningful effect on the pharmacokinetics of the following: hormonal contraceptives, methadone, lamivudine, tenofovir, etravirine, darunavir/ritonavir.
Effect of Other Agents on the Pharmacokinetics of Raltegravir
Raltegravir is not a substrate of cytochrome P450 (CYP) enzymes. Based on in vivo and in vitro studies, raltegravir is eliminated mainly by metabolism via a UGT1A1-mediated glucuronidation pathway.
Rifampin, a strong inducer of UGT1A1, reduces plasma concentrations of Isentress. Therefore, in adults the dose of Isentress should be increased during coadministration with rifampin. There are no data to guide co-administration of Isentress with rifampin in patients below 18 years of age [see Dosage and Administration (2)]. The impact of other inducers of drug metabolizing enzymes, such as phenytoin and phenobarbital, on UGT1A1 is unknown.
Coadministration of Isentress with drugs that inhibit UGT1A1 may increase plasma levels of raltegravir.
All interaction studies were performed in adults.
Selected drug interactions are presented in Table 7 [see Clinical Pharmacology (12.3)].
| Concomitant Drug Class: Drug Name | Effect on Concentration of Raltegravir | Clinical Comment |
|---|---|---|
| HIV-1-Antiviral Agents | ||
| atazanavir | ↑ | Atazanavir, a strong inhibitor of UGT1A1, increases plasma concentrations of raltegravir. However, since concomitant use of Isentress with atazanavir/ritonavir did not result in a unique safety signal in Phase 3 studies, no dose adjustment is recommended. |
| atazanavir/ritonavir | ↑ | Atazanavir/ritonavir increases plasma concentrations of raltegravir. However, since concomitant use of Isentress with atazanavir/ritonavir did not result in a unique safety signal in Phase 3 studies, no dose adjustment is recommended. |
| efavirenz | ↓ | Efavirenz reduces plasma concentrations of raltegravir. The clinical significance of this interaction has not been directly assessed. |
| etravirine | ↓ | Etravirine reduces plasma concentrations of raltegravir. The clinical significance of this interaction has not been directly assessed. |
| tipranavir/ritonavir | ↓ | Tipranavir/ritonavir reduces plasma concentrations of raltegravir. However, since comparable efficacy was observed for this combination relative to other Isentress-containing regimens in Phase 3 studies 018 and 019, no dose adjustment is recommended. |
| Other Agents | ||
| omeprazole | ↑ | Coadministration of medicinal products that increase gastric pH (e.g., omeprazole) may increase raltegravir levels based on increased raltegravir solubility at higher pH. However, since concomitant use of Isentress with proton pump inhibitors and H2 blockers did not result in a unique safety signal in Phase 3 studies, no dose adjustment is recommended. |
| rifampin | ↓ | Rifampin, a strong inducer of UGT1A1, reduces plasma concentrations of raltegravir. The recommended dosage of Isentress is 800 mg twice daily during coadministration with rifampin. |
USE IN SPECIFIC POPULATIONS
Pregnancy
Pregnancy Category C
Isentress should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. There are no adequate and well-controlled studies in pregnant women. In addition, there have been no pharmacokinetic studies conducted in pregnant patients.
Developmental toxicity studies were performed in rabbits (at oral doses up to 1000 mg/kg/day) and rats (at oral doses up to 600 mg/kg/day). The reproductive toxicity study in rats was performed with pre-, peri-, and postnatal evaluation. The highest doses in these studies produced systemic exposures in these species approximately 3- to 4-fold the exposure at the recommended human dose. In both rabbits and rats, no treatment-related effects on embryonic/fetal survival or fetal weights were observed. In addition, no treatment-related external, visceral, or skeletal changes were observed in rabbits. However, treatment-related increases over controls in the incidence of supernumerary ribs were seen in rats at 600 mg/kg/day (exposures 3-fold the exposure at the recommended human dose).
Placenta transfer of drug was demonstrated in both rats and rabbits. At a maternal dose of 600 mg/kg/day in rats, mean drug concentrations in fetal plasma were approximately 1.5-to 2.5-fold greater than in maternal plasma at 1 hour and 24 hours postdose, respectively. Mean drug concentrations in fetal plasma were approximately 2% of the mean maternal concentration at both 1 and 24 hours postdose at a maternal dose of 1000 mg/kg/day in rabbits.
Antiretroviral Pregnancy Registry
To monitor maternal-fetal outcomes of pregnant patients exposed to Isentress, an Antiretroviral Pregnancy Registry has been established. Physicians are encouraged to register patients by calling 1-800-258-4263.
Nursing Mothers
Breastfeeding is not recommended while taking Isentress. In addition, it is recommended that HIV-1-infected mothers not breastfeed their infants to avoid risking postnatal transmission of HIV-1.
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 approximate
No comments:
Post a Comment