Isentress HD

Isentress HD Side Effects

raltegravir

Manufacturer:

MSD

Distributor:

Zuellig Pharma
Full Prescribing Info
Side Effects
Adults: Treatment-Experienced Adverse Experiences: The safety assessment of ISENTRESS in treatment-experienced patients is based on the pooled safety data from the randomized clinical studies, P018 and P019 reported using the recommended dose of ISENTRESS 400 mg twice daily in combination with optimized background therapy (OBT) in 462 patients, in comparison to 237 patients taking placebo in combination with OBT. During double-blind treatment, the total follow-up was 1051 patient-years in the group receiving ISENTRESS 400 mg b.i.d. and 322 patient-years in the group receiving placebo.
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.
For patients in the group receiving ISENTRESS 400 mg twice daily + OBT (mean follow-up 118.7 weeks) and the comparator group receiving placebo + OBT (mean follow-up 71.0 weeks) in the pooled analysis for studies P018 and P019, the most commonly reported clinical adverse experiences (>10% in either group), of all intensities and regardless of causality were: diarrhea in 26.6% and 24.9%, nausea in 13.6% and 16.0%, headache in 12.1% and 13.5%, nasopharyngitis in 14.3% and 8.9%, fatigue in 12.1% and 5.9%, upper respiratory tract infection in 15.8% and 10.1%, bronchitis in 12.1% and 6.8%, pyrexia in 9.7% and 13.9%, vomiting in 8.9% and 11.0% of patients, respectively. In this pooled analysis, the rates of discontinuation of therapy due to adverse experiences (clinical and laboratory) were 4.5% in patients receiving ISENTRESS + OBT and 5.5% in patients receiving placebo + OBT.
Drug Related Adverse Experiences: The clinical adverse experiences listed as follows were considered by investigators to be of moderate to severe intensity and causally related to ISENTRESS or placebo alone or in combination with OBT.
Drug-related clinical adverse experiences of moderate to severe intensity occurring in ≥2% of treatment-experienced adult patients in either treatment group are presented in Table 14. (See Table 14.)

Click on icon to see table/diagram/image

Drug related clinical adverse experiences, occurring in less than 2% of treatment-experienced patients (n=462) receiving ISENTRESS + OBT and of moderate to severe intensity are listed as follows by System Organ Class.
[Common (≥1/100, <1/10), Uncommon (≥1/1,000, <1/100)].
Cardiac Disorders: Uncommon: ventricular extrasystoles.
Ear and Labyrinth Disorders: Uncommon: vertigo.
Eye Disorders: Uncommon: visual impairment.
Gastrointestinal Disorders: Common: diarrhea, nausea.
Uncommon: abdominal pain, distension, abdominal pain upper, vomiting, constipation, abdominal discomfort, dyspepsia, flatulence, gastritis, gastroesophageal reflux disease, dry mouth, eructation.
General Disorders and Administration Site Conditions: Common: asthenia, fatigue.
Uncommon: pyrexia, chills, face edema, peripheral edema.
Hepatobiliary Disorders: Uncommon: hepatitis.
Immune System Disorders: Uncommon: drug hypersensitivity.
Infections and Infestations: Uncommon: herpes simplex, genital herpes, gastroenteritis.
Investigations: Uncommon: weight increased, weight decreased.
Metabolism and Nutrition Disorders: Uncommon: diabetes mellitus, dyslipidaemia, increased appetite, decreased appetite.
Musculoskeletal and Connective Tissue Disorders: Uncommon: arthralgia, myalgia, back pain, musculoskeletal pain, osteoporosis, polyarthritis.
Nervous System Disorders: Uncommon: dizziness, neuropathy peripheral, paraesthesia, somnolence, tension headache, tremor.
Psychiatric Disorders: Uncommon: depression, insomnia, anxiety.
Renal and Urinary Disorders: Uncommon: nephritis, nephrolithiasis, nocturia, renal failure, tubulointerstitial nephritis.
Reproductive System and Breast Disorders: Uncommon: gynaecomastia.
Respiratory, Thoracic and Mediastinal Disorders: Uncommon: epistaxis.
Skin and Subcutaneous Tissue Disorders: Uncommon: lipodystrophy acquired, rash, hyperhidrosis, dermatitis acneiform, erythema, lipohypertrophy, night sweats, rash macular, rash maculopapular, rash pruritic, xeroderma, prurigo, lipoatrophy, pruritus.
Serious Events: The following serious drug related clinical adverse experiences were reported in clinical studies gastritis, hepatitis, renal failure, genital herpes, accidental overdose.
Treatment Naïve Adverse Experiences: The safety of ISENTRESS was evaluated in HIV-infected treatment-naïve subjects in 2 Phase III studies; STARTMRK (Protocol 021) evaluated ISENTRESS 400 mg twice daily versus efavirenz, both in combination with emtricitabine (+) tenofovir disoproxil fumarate and ONCEMRK (Protocol 292) evaluated ISENTRESS 1200 mg (2 x 600 mg) once daily versus ISENTRESS 400 mg twice daily, both in combination with emtricitabine (+) tenofovir disoproxil fumarate.
STARTMRK (Protocol 021; ISENTRESS 400 mg twice daily): The following safety assessment of ISENTRESS in treatment-naïve patients is based on the randomized double-blind active controlled study of treatment-naïve patients, protocol 021 (STARTMRK) with ISENTRESS 400 mg twice daily in combination with a fixed dose of emtricitabine 200 mg (+) tenofovir disoproxil fumarate 245 mg, (N=281) versus efavirenz (EFV) 600 mg at bedtime in combination with emtricitabine (+) tenofovir disoproxil fumarate (N=282). During double-blind treatment, the total follow-up for patients with ISENTRESS 400 mg twice daily + emtricitabine (+) tenofovir disoproxil fumarate was 1104 patient-years and 1036 patient-years for patients with efavirenz 600 mg at bedtime + emtricitabine (+) tenofovir disoproxil fumarate.
Numbers (%) of patients with clinical adverse experiences and with drug-related adverse experiences in the group receiving ISENTRESS, were less frequent than in the group receiving efavirenz based on the nominal p-values (0.325 and <0.001, respectively). In this study, the rates of discontinuation of therapy due to adverse experiences (clinical and laboratory) were 5.0% in patients receiving ISENTRESS + emtricitabine (+) tenofovir disoproxil fumarate and 10.0% in patients receiving efavirenz + emtricitabine (+) tenofovir disoproxil fumarate.
For patients in the group receiving ISENTRESS 400 mg twice daily + emtricitabine (+) tenofovir disoproxil fumarate and the group receiving the comparator, efavirenz 600 mg at bedtime + emtricitabine (+) tenofovir disoproxil fumarate, the most commonly reported clinical adverse experiences (>10% in either group), of all intensities and regardless of causality are shown in Table 15. (See Table 15.)

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CNS Events: In treatment-naïve patients (P021) central nervous system (CNS) adverse experiences, as measured by proportion of patients with 1 or more CNS symptoms (described as follows), were reported significantly less frequently in the group receiving ISENTRESS + emtricitabine (+) tenofovir disoproxil fumarate as compared with the group receiving efavirenz + emtricitabine (+) tenofovir disoproxil fumarate, p <0.001, p<0.001 and <0.001 for cumulative events through Weeks 8, 48 and 96, respectively. In the group receiving ISENTRESS, the percentage of patients with 1 or more CNS symptoms was 20.3% compared to 52.1% in the group receiving efavirenz by Week 8, 26.3% compared to 58.5% by Week 48 and 28.8% compared to 60.6% by Week 96. CNS adverse experiences for this analysis were dizziness, insomnia, concentration impaired, somnolence, depression, nightmare, confusional state, suicidal ideation, nervous system disorder, psychotic disorder, abnormal dreams, suicide attempt, acute psychosis, delirium, depressed level of consciousness, hallucination, auditory hallucination, completed suicide and major depression.
Drug Related Adverse Experiences: The clinical adverse reactions listed as follows were considered by investigators to be of moderate to severe intensity and causally related to ISENTRESS or efavirenz alone or in combination with emtricitabine (+) tenofovir disoproxil fumarate.
Drug-related clinical adverse reactions of moderate to severe intensity occurring in ≥2% of treatment-naïve adult patients in either treatment group are presented in Table 16. (See Table 16.)

Click on icon to see table/diagram/image

Drug related clinical adverse experiences, occurring in less than 2% of treatment-naïve patients (n=281) receiving ISENTRESS + emtricitabine (+) tenofovir disoproxil fumarate and of moderate to severe intensity are listed as follows by System Organ Class.
[Common (≥1/100, <1/10), Uncommon (≥1/1,000, <1/100)].
Blood and Lymphatic System Disorders: Uncommon: lymph node pain, neutropenia, anemia, lymphadenopathy.
Ear and Labyrinth Disorders: Uncommon: tinnitus, vertigo.
Gastrointestinal Disorders: Common: diarrhea, abdominal pain.
Uncommon: vomiting, abdominal pain upper, dyspepsia, erosive duodenitis, gastroesophageal reflux disease, abdominal distension.
General Disorders and Administration Site Conditions: Common: fatigue, asthenia.
Uncommon: submandibular mass.
Hepatobiliary Disorders: Uncommon: hepatitis alcoholic.
Immune System Disorders: Uncommon: immune reconstitution syndrome.
Infections and Infestations: Uncommon: herpes zoster, gastroenteritis, folliculitis, lymph node abscess.
Metabolism and Nutrition Disorders: Uncommon: decreased appetite, hypercholesterolemia, body fat disorder.
Musculoskeletal and Connective Tissue Disorders: Uncommon: arthritis, neck pain.
Nervous System Disorders: Common: dizziness.
Uncommon: hypersomnia, somnolence, memory impairment.
Psychiatric Disorders: Common: abnormal dreams, nightmare, depression.
Uncommon: anxiety, mental disorder, confusional state, major depression, suicide attempt.
Renal and Urinary Disorders: Common: nephrolithiasis.
Reproductive System and Breast Disorders: Uncommon: erectile dysfunction.
Skin and Subcutaneous Tissue Disorders: Uncommon: Acne, alopecia, skin lesion, lipoatrophy.
Serious Events: The following serious drug-related adverse experiences were reported in the clinical study, P021 in treatment-naïve patients receiving ISENTRESS + emtricitabine (+) tenofovir disoproxil fumarate: anemia, immune reconstitution syndrome, mental disorder, suicide attempt, depression.
ONCEMRK (Protocol 292; ISENTRESS 1200 mg [2 x 600 mg] once daily): The safety of ISENTRESS 1200 mg (2 x 600 mg) once daily was assessed in one randomized double-blind active controlled study in 797 treatment-naïve HIV-1 infected patients, comparing 531 patients receiving ISENTRESS 1200 mg (2 x 600 mg) once daily with 266 patients receiving ISENTRESS 400 mg twice daily, each in combination with emtricitabine (+) tenofovir disoproxil fumarate. The total follow-up for patients on ISENTRESS 1200 mg (2 x 600 mg) once daily was 913.3 patient-years and for ISENTRESS 400 mg twice daily was 450.1 patient-years.
The proportion of patients with drug-related clinical and laboratory adverse experiences in the group receiving ISENTRESS 1200 mg (2 x 600 mg) once daily, and the group receiving ISENTRESS 400 mg twice daily were generally similar (26.0%, 1.3% versus 26.7%, 2.3%, respectively).
The rates of discontinuation of therapy due to clinical and laboratory adverse experiences were 0.9% and 0.4% in patients receiving ISENTRESS 1200 mg (2 x 600 mg) once daily and 2.3% and 0% in patients receiving ISENTRESS 400 mg twice daily.
The most commonly reported clinical adverse experiences (>10% in either treatment group), of all intensities and regardless of causality, respectively, were headache (16.0% versus 13.9%), nausea (13.6% versus 12.8%), diarrhea (13.4% versus 12.8%), upper respiratory tract infection (12.6% versus 10.2%), and nasopharyngitis (12.2% versus 9.8%).
There were no drug-related clinical adverse reactions of moderate to severe intensity occurring in ≥2% of patients reported in either treatment group.
The rates of serious clinical adverse experiences were similar between patients receiving ISENTRESS 1200 mg (2 x 600 mg) once daily and in patients receiving ISENTRESS 400 mg twice daily (9.2% versus 15.8%, respectively). The rates of serious drug related clinical adverse experiences were also similar between the treatment groups (0.2% versus 0.8%, respectively).
Selected Adverse Experiences - Adults: In studies of ISENTRESS 400 mg twice daily, cancers were observed in treatment-experienced patients who initiated ISENTRESS or placebo, both with OBT, and in treatment-naïve patients who initiated ISENTRESS or efavirenz, both with emtricitabine (+) tenofovir disoproxil fumarate; 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 14). 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 patients receiving regimens containing ISENTRESS + darunavir compared to patients receiving ISENTRESS without darunavir or darunavir 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 Phase III studies of ISENTRESS patients with chronic (but not acute) active hepatitis B and/or hepatitis C co-infection were permitted to enroll provided that baseline liver function tests did not exceed 5 times the upper limit of normal. In the treatment experienced studies, BENCHMRK 1 and BENCHMRK 2 (Protocol 018 and Protocol 019), 16% of all patients (114/699) were co-infected; in the treatment-naïve studies, STARTMRK (Protocol 021) and ONCEMRK (Protocol 292), 6% (34/563) and 2.9% (23/797), respectively, were co-infected. In general, the safety profile of ISENTRESS in patients with hepatitis B and/or hepatitis C co-infection was similar to that in patients without hepatitis B and/or hepatitis C co-infection, although the rates of AST and ALT abnormalities were somewhat higher in the subgroup with hepatitis B and/or hepatitis C coinfection for both treatment groups.
Pediatric Adverse Experiences: 2-18 Years of Age: ISENTRESS 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 Use in Children under Precautions and Pharmacology: Pharmacodynamics: Clinical Studies under Actions). 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 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 additional adverse experiences have been reported in postmarketed experience without regard to causality: Blood and Lymphatic System Disorders: thrombocytopenia.
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: depression (particularly in patients with a pre-existing history of psychiatric illness), including suicidal ideation and behaviors.
Skin and Subcutaneous Tissue Disorders: Stevens-Johnson syndrome, drug rash with eosinophilia and systemic symptoms (DRESS).
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