Raltegravir

Name: Raltegravir

Pharmacology

Mechanism of Action

Inhibits catalytic activity of HIV-1 integrase, an HIV encoded enzyme required for viral replication

Absorption

Peak Plasma Time: 3 hr in fasted state

Distribution

Protein Bound: 83%

Metabolism

Liver

Elimination

Half-Life: 9 hr

Excretion: Feces 51%; urine 32%

What are the side effects of raltegravir?

The most common side effects of raltegravir include:

  • Trouble sleeping insomnia)
  • Headache
  • Dizziness
  • Nausea
  • Tiredness

Other potential side effects of raltegravir include:

  • Depression
  • Hepatitis (a type of viral infection of the liver)
  • Paranoia
  • Blood disorders
  • Kidney failure
  • Kidney stones
  • Indigestion or stomach pain
  • Muscle pain (myopathy)
  • Rhabdomyolysis (muscle destruction)
  • Increased bilirubin
  • Increased levels of liver enzymes
  • Increased blood glucose
  • Vomiting
  • Suicidal thoughts or actions
  • Weakness

Some patients taking raltegravir experience serious skin and allergic reactions. These reactions can be severe or life-threatening if not treated promptly. Patients who develop any type of skin rash with other symptoms should call their doctor right away.

What should I discuss with my health care provider before taking raltegravir?

You should not use raltegravir if you are allergic to it.

To make sure raltegravir is safe for you, tell your doctor if you have ever had:

  • a muscle disorder;

  • kidney disease (or if you are on dialysis);

  • liver disease; or

  • mental illness or depression.

It is not known whether raltegravir will harm an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant while using this medicine.

HIV can be passed to your baby if you are not properly treated during pregnancy. Take all of your HIV medicines as directed to control your infection.

If you are pregnant, your name may be listed on a pregnancy registry. This is to track the outcome of the pregnancy and to evaluate any effects of raltegravir on the baby.

Women with HIV or AIDS should not breast feed a baby. Even if your baby is born without HIV, the virus may be passed to the baby in your breast milk.

Raltegravir chewable tablets contain phenylalanine. Talk to your doctor before using this form of raltegravir if you have phenylketonuria (PKU).

Commonly used brand name(s)

In the U.S.

  • Isentress
  • Isentress HD

Available Dosage Forms:

  • Powder for Suspension
  • Tablet, Chewable
  • Tablet

Therapeutic Class: Antiretroviral Agent

Pharmacologic Class: Integrase Inhibitor

Uses For raltegravir

Raltegravir is used together with other medicines for the treatment of the infection caused by human immunodeficiency virus (HIV). HIV is the virus that causes acquired immune deficiency syndrome (AIDS). raltegravir is usually given to patients who have already received HIV medicines in the past.

Raltegravir will not cure or prevent HIV infection or AIDS. It helps keep HIV from reproducing and appears to slow down the destruction of the immune system. This may help delay problems that are usually related to AIDS or HIV disease from occurring. Raltegravir will not keep you from spreading HIV to other people. People who receive raltegravir may continue to have other problems usually related to AIDS or HIV disease.

raltegravir is available only with your doctor's prescription.

Before Using raltegravir

In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For raltegravir, the following should be considered:

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to raltegravir or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.

Pediatric

Appropriate studies performed to date have not demonstrated pediatric-specific problems that would limit the usefulness of Isentress® film-coated tablets, chewable tablets, or oral suspension in children 4 weeks of age and older. Safety and efficacy have not been established in children younger than 4 weeks of age.

Appropriate studies performed to date have not demonstrated pediatric-specific problems that would limit the usefulness of Isentress HD® film-coated tablets in children weighing 40 kilograms (kg) and over. Safety and efficacy have not been established in children weighing less than 40 kg.

Geriatric

Appropriate studies performed to date have not demonstrated geriatric-specific problems that would limit the usefulness of raltegravir in the elderly. However, elderly patients are more likely to have age-related kidney, liver, or heart problems, which may require caution and an adjustment in the dose for patients receiving raltegravir.

Pregnancy

Pregnancy Category Explanation
All Trimesters C Animal studies have shown an adverse effect and there are no adequate studies in pregnant women OR no animal studies have been conducted and there are no adequate studies in pregnant women.

Breast Feeding

There are no adequate studies in women for determining infant risk when using this medication during breastfeeding. Weigh the potential benefits against the potential risks before taking this medication while breastfeeding.

Interactions with Medicines

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are taking raltegravir, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using raltegravir with any of the following medicines is usually not recommended, but may be required in some cases. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

  • Aluminum Carbonate, Basic
  • Aluminum Hydroxide
  • Aluminum Phosphate
  • Amprenavir
  • Dihydroxyaluminum Aminoacetate
  • Dihydroxyaluminum Sodium Carbonate
  • Fosamprenavir
  • Magaldrate
  • Magnesium Carbonate
  • Magnesium Hydroxide
  • Magnesium Oxide
  • Magnesium Trisilicate
  • Orlistat

Using raltegravir with any of the following medicines may cause an increased risk of certain side effects, but using both drugs may be the best treatment for you. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

  • Etravirine
  • Omeprazole
  • Rifampin

Interactions with Food/Tobacco/Alcohol

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. Discuss with your healthcare professional the use of your medicine with food, alcohol, or tobacco.

Other Medical Problems

The presence of other medical problems may affect the use of raltegravir. Make sure you tell your doctor if you have any other medical problems, especially:

  • Liver disease, severe—Use with caution. raltegravir has not been studied in patients with severe liver problems.
  • Myopathy (muscle weakness), history of or
  • Rhabdomyolysis (muscle problem that could lead to kidney problem), history of—Use with caution. May make these conditions worse.
  • Phenylketonuria (PKU)—The chewable tablet contains phenylalanine, which can make this condition worse.

Brand Names U.S.

  • Isentress
  • Isentress HD

Dosing Pediatric

HIV-1 infection, treatment: Oral:

Note: Raltegravir film-coated tablets and chewable tablets or oral suspension are not bioequivalent and are not substitutable on a mg/mg basis

Oral suspension (20 mg/mL): Infants and Children weighing 3 to <20 kg:

Weight-directed dosing: 6 mg/kg/dose twice daily; maximum dose: 100 mg/dose

Fixed-dosing:

3 to <4 kg: 20 mg (1 mL) twice daily.

4 to <6 kg: 30 mg (1.5 mL) twice daily.

6 to <8 kg: 40 mg (2 mL) twice daily.

8 to <11 kg: 60 mg (3 mL) twice daily.

11 to <14 kg: 80 mg (4 mL) twice daily.

14 to <20 kg: 100 mg (5 mL) twice daily.

Chewable tablets: Children weighing ≥11 kg:

Weight-directed dosing: 6 mg/kg/dose twice daily; maximum dose: 300 mg/dose

Fixed-dosing:

11 to <14 kg: 75 mg (3 x 25 mg tablet) twice daily.

14 to <20 kg: 100 mg (1 x 100 mg tablet) twice daily.

20 to <28 kg: 150 mg (1.5 x 100 mg tablet) twice daily.

28 to <40 kg: 200 mg (2 x 100 mg tablet) twice daily.

≥40 kg: 300 mg (3 x 100 mg tablet) twice daily.

Film-coated tablets:

Children and Adolescents weighing ≥25 kg who are able to swallow a tablet whole: 400 mg twice daily.

Children and Adolescents weighing ≥40 kg who are treatment-naïve: 400 mg twice daily or 1,200 mg (2 x 600 mg tablet) once daily. Note: Patients virologically suppressed on an initial regimen of raltegravir 400 mg twice daily may switch to 1,200 mg (2 x 600 mg tablet) once daily.

Dosage adjustment for rifampin coadministration: There are no data to guide dose adjustment in patients <18 years.

HIV-1 nonoccupational postexposure prophylaxis (nPEP) (off-label use) (HHS [nPEP] 2016): Oral: Note: Initiate therapy within 72 hours of exposure and continue for 28 days; use in combination with other antiretroviral agents.

Infants and Children <2 years: Oral suspension: 6 mg/kg/dose twice daily

Children ≥2 years:

Chewable tablets:

11 to <14 kg: 75 mg twice daily

14 to <20 kg: 100 mg twice daily

20 to <28 kg: 150 mg twice daily

28 to <40 kg: 200 mg twice daily

≥40 kg: 300 mg twice daily

Film-coated tablet: Children ≥ 6 years weighing >25 kg who are able to swallow a tablet whole: 400 mg twice daily

Adolescents: Oral: Film-coated tablet: Refer to adult dosing.

Dietary Considerations

Some products may contain phenylalanine.

Warnings/Precautions

Concerns related to adverse effects:

• Immune reconstitution syndrome: Patients may develop immune reconstitution syndrome resulting in the occurrence of an inflammatory response to an indolent or residual opportunistic infection during initial HIV treatment or activation of autoimmune disorders (eg, Graves’ disease, polymyositis, Guillain-Barré syndrome) later in therapy; further evaluation and treatment may be required.

• Myopathy: Grade 2 to 4 creatine kinase (CK) increases have been observed and myopathy and rhabdomyolysis have been reported; use caution in patients with a history of rhabdomyolysis, myopathy, or increased serum creatine kinase or who have risk factors for CK elevations and/or skeletal muscle abnormalities, including taking other drugs known to cause myopathy or rhabdomyolysis.

• Skin and hypersensitivity reactions: Severe, life-threatening or fatal cases of Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported. Hypersensitivity reactions (rash, constitutional symptoms, organ dysfunction) have also been reported. Discontinue immediately if a severe skin reaction or hypersensitivity symptoms develop. Monitor clinical status, including liver transaminases.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Dosage form specific issues:

• Chewable tablet: Contains phenylalanine.

• Tablets and oral suspension: Raltegravir film-coated tablets and chewable tablets or oral suspension are not bioequivalent and are not substitutable on a mg/mg basis.

Other warnings/precautions:

• Appropriate use: Raltegravir plus darunavir/ritonavir should not be used in adolescent and adult HIV-1 patients with a pre-ART CD4 count <200 cells/mm3 and/or HIV RNA >100,000 copies/mL (HHS [adult] 2016).

For Healthcare Professionals

Applies to raltegravir: oral granule for reconstitution, oral tablet, oral tablet chewable

General

The safety report of this drug is based on 281 therapy-naive and 462 therapy-experienced HIV-infected patients receiving the indicated twice daily dosing regimen in combination with emtricitabine plus tenofovir and optimized background therapy, respectively. The most common side effects of moderate to severe intensity which occurred in therapy-naive patients at a higher rate compared to efavirenz were insomnia, headache, nausea, dizziness, and fatigue. The most common side effect of moderate to severe intensity which occurred in therapy-experienced patients at a higher rate compared to placebo was headache. The rates of discontinuation due to side effects were 5% and 10% in therapy-naive subjects receiving this drug and efavirenz, respectively, and 4% and 5% in therapy-experienced subjects receiving this drug and placebo, respectively.[Ref]

Hepatic

Very common (10% or more): Elevated ALT (up to 11%)
Common (1% to 10%): Elevated AST, elevated total bilirubin
Uncommon (0.1% to 1%): Hepatitis, hepatic steatosis, alcoholic hepatitis, hepatic failure
Frequency not reported: AST and ALT abnormalities[Ref]

Grade 2, 3, and 4 elevations in ALT have been reported in up to 11%, up to 4.8%, and up to 2% of patients, respectively. Grade 2, 3, and 4 elevations in AST have been reported in up to 9.5%, up to 5%, and up to 1.1% of patients, respectively. Grade 2, 3, and 4 elevations in total bilirubin have been reported in up to 6%, up to 3%, and up to 1% of patients, respectively.

The rates of AST and ALT abnormalities were higher in patients with hepatitis B and/or hepatitis C virus coinfection. In therapy-naive patients, grade 2 or higher laboratory abnormalities indicating a worsening grade from baseline of AST, ALT, or total bilirubin occurred in 22%, 44%, and 17%, respectively, of coinfected patients using this drug as compared to 13%, 13%, and 5% of all other patients using this drug. In therapy-experienced patients, grade 2 or higher laboratory abnormalities indicating a worsening grade from baseline of AST, ALT, or total bilirubin occurred in 29%, 34%, and 13%, respectively, of coinfected patients using this drug as compared to 11%, 10%, and 9% of all other patients using this drug.

Hepatic failure (with and without associated hypersensitivity) has been reported during postmarketing experience in patients with underlying liver disease and/or concomitant medications.[Ref]

Metabolic

Very common (10% or more): Elevated serum glucose (up to 11.3%)
Common (1% to 10%): Elevated alkaline phosphatase, decreased appetite, elevated blood triglycerides
Uncommon (0.1% to 1%): Cachexia, diabetes mellitus, dyslipidemia, hypercholesterolemia, hyperglycemia, hyperlipidemia, hyperphagia, increased appetite, polydipsia, body fat disorder, decreased blood albumin, elevated blood cholesterol, elevated fasting blood glucose, elevated high-density lipoprotein, elevated low-density lipoprotein cholesterol
Frequency not reported: Elevated fasting cholesterol[Ref]

Grade 2 and 3 elevations in fasting (nonrandom) serum glucose test have been reported in up to 11.3% and up to 3% of patients, respectively. Grade 2, 3, and 4 elevations in alkaline phosphatase have been reported in up to 2.2%, less than 1%, and up to 1% of patients, respectively.[Ref]

Gastrointestinal

Very common (10% or more): Diarrhea (up to 26.6%), nausea (up to 16.7%), vomiting (up to 11%)
Common (1% to 10%): Elevated lipase, elevated blood pancreatic amylase, abdominal pain, dyspepsia, abdominal distention, flatulence
Uncommon (0.1% to 1%): Gastroenteritis, 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 hemorrhage, elevated blood amylase
Frequency not reported: Mouth ulceration, peritonitis (including perihepatitis)[Ref]

Grade 2 and 3 elevations in lipase have been reported in 5% and 2% of patients, respectively. Grade 2, 3, and 4 elevations in pancreatic amylase have been reported in 2%, 4%, and less than 1% of patients, respectively.

Diarrhea has also been reported during postmarketing experience.[Ref]

Nervous system

Very common (10% or more): Central nervous system (CNS) side effects/symptoms (up to 28.8%), headache (up to 26%), dizziness (up to 16.4%)
Common (1% to 10%): Psychomotor hyperactivity, vertigo
Uncommon (0.1% to 1%): Amnesia, carpal tunnel syndrome, cognitive disorder, disturbance in attention/concentration impaired, postural dizziness, dysgeusia, hypersomnia, hypoesthesia, lethargy, memory impairment, migraine, peripheral neuropathy, paresthesia, somnolence, tension headache, tremor, poor quality sleep, tinnitus
Frequency not reported: Nervous system disorder, depressed level of consciousness
Postmarketing reports: Cerebellar ataxia[Ref]

CNS side effects were reported less often in therapy-naive patients using this drug (with emtricitabine and tenofovir) than those using efavirenz (with emtricitabine and tenofovir). By weeks 8, 48, and 96, at least 1 CNS symptom was reported in 20.3%, 26.3%, and 28.8% of patients using this drug, respectively, compared with 52.1%, 58.5%, and 60.6% of patients using efavirenz, respectively. CNS side effects included 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.[Ref]

Psychiatric

Very common (10% or more): Insomnia (up to 15.7%), depression (up to 10.3%)
Common (1% to 10%): Abnormal dreams, nightmare, abnormal behavior, anxiety
Uncommon (0.1% to 1%): Mental disorder, suicide attempt, confusional state, depressed mood, major depression, middle insomnia, mood altered, panic attack, sleep disorder, suicidal ideation, suicidal behavior
Frequency not reported: Exacerbation of depression, psychotic disorder, acute psychosis, delirium, hallucination, auditory hallucination, completed suicide
Postmarketing reports: Paranoia[Ref]

Depression (including suicidal ideation and behaviors) has been reported in clinical studies and during postmarketing experience, particularly in patients with history of psychiatric illness or depression.

Anxiety, suicidal ideation, and suicidal behavior (particularly in patients with history of psychiatric illness) have also been reported during postmarketing experience.[Ref]

Hematologic

Grade 2, 3, and 4 decreases in absolute neutrophil count have been reported in up to 4%, 3%, and 1% of patients, respectively. Grade 2, 3, and 4 decreases in platelet count have been reported in up to 3%, up to 1%, and up to 1% of patients, respectively. Grade 2, 3, and 4 decreases in hemoglobin have been reported in 1%, 1%, and less than 1% of patients, respectively.

Thrombocytopenia has also been reported during postmarketing experience.[Ref]

Common (1% to 10%): Decreased absolute neutrophil count, decreased platelet count, decreased hemoglobin, atypical lymphocytes
Uncommon (0.1% to 1%): Anemia, iron deficiency anemia, lymph node abscess, lymph node pain, lymphadenopathy, neutropenia, thrombocytopenia, elevated INR, decreased WBC count[Ref]

Other

Very common (10% or more): Pyrexia (up to 15.7%), fatigue (up to 12.1%)
Common (1% to 10%): Asthenia
Uncommon (0.1% to 1%): Herpes virus infection, hot flush, menopausal symptoms, chest discomfort, chills, face edema, increased fat tissue, feeling jittery, malaise, submandibular mass, peripheral edema, pain, increased waist circumference, increased weight, accidental overdose
Frequency not reported: Decreased weight[Ref]

Musculoskeletal

Grade 2, 3, and 4 elevations in creatine phosphokinase have been reported in 2.6%, 4.1%, and 3% of patients, respectively.

Rhabdomyolysis has also been reported during postmarketing experience.[Ref]

Very common (10% or more): Back pain (up to 12.1%)
Common (1% to 10%): Elevated creatine phosphokinase, arthralgia
Uncommon (0.1% to 1%): Arthritis, flank pain, musculoskeletal pain, myalgia, neck pain, osteopenia, pain in extremity, tendonitis, rhabdomyolysis
Frequency not reported: Myopathy, osteonecrosis, osteoporosis, polyarthritis[Ref]

Cardiovascular

Uncommon (0.1% to 1%): Palpitations, sinus bradycardia, ventricular extrasystoles, hypertension
Frequency not reported: Myocardial infarction[Ref]

Renal

Uncommon (0.1% to 1%): Nephrolithiasis, renal failure, nephritis, renal cyst, renal impairment, tubulointerstitial nephritis, elevated blood creatinine, elevated BUN
Frequency not reported: Toxic nephropathy, chronic renal failure, renal tubular necrosis[Ref]

Hypersensitivity

Common (1% to 10%): Hypersensitivity (less than 2%)
Uncommon (0.1% to 1%): Drug hypersensitivity
Frequency not reported: Hypersensitivity reactions (characterized by rash, constitutional findings, and sometimes, organ dysfunction, including hepatic failure)[Ref]

Dermatologic

Rashes considered drug related were mild to moderate in severity and did not limit treatment. In clinical trials of therapy-experienced patients, rash occurred more often with regimens containing this drug and darunavir compared to those containing this drug without darunavir or darunavir without this drug.

Severe, potentially life-threatening, and fatal skin reactions (including Stevens-Johnson syndrome, toxic epidermal necrolysis) have been reported.

Stevens-Johnson syndrome and DRESS have also been reported during postmarketing experience.[Ref]

Common (1% to 10%): Rash
Uncommon (0.1% to 1%): Pruritus, acne, alopecia, dermatitis acneiform, dry skin, erythema, facial wasting, hyperhidrosis, lipoatrophy, acquired lipodystrophy, lipohypertrophy, night sweats, prurigo, generalized pruritus, macular rash, maculopapular rash, pruritic rash, skin lesion, urticaria, xeroderma, Stevens-Johnson syndrome, drug rash with eosinophilia and systemic symptoms (DRESS), folliculitis, herpes simplex, herpes zoster, molluscum contagiosum
Frequency not reported: Severe skin reactions, toxic epidermal necrolysis, diaphoresis[Ref]

Oncologic

Uncommon (0.1% to 1%): Skin papilloma
Frequency not reported: Kaposi's sarcoma, lymphoma, squamous cell carcinoma, skin cancer, hepatocellular carcinoma, rectal adenocarcinoma, anal cancer[Ref]

The types and rates of specified cancers were expected in a highly immunodeficient population and most patients had other risk factors for cancer, including tobacco use, papillomavirus, and active hepatitis B virus infection. It is unknown if these cancer diagnoses were related to use of this drug.[Ref]

Immunologic

Uncommon (0.1% to 1%): Immune reconstitution syndrome
Frequency not reported: Autoimmune disorders in the setting of immune reconstitution (e.g., Graves' disease, polymyositis, Guillain-Barre syndrome)[Ref]

Endocrine

Uncommon (0.1% to 1%): Gynecomastia

Genitourinary

Uncommon (0.1% to 1%): Genital herpes, nocturia, erectile dysfunction, glucose present in urine, positive for RBCs in urine[Ref]

Ocular

Uncommon (0.1% to 1%): Visual impairment[Ref]

Respiratory

Very common (10% or more): Nasopharyngitis (up to 26.7%), upper respiratory tract infection (up to 21.4%), cough (up to 16.7%), influenza (up to 11.7%)
Uncommon (0.1% to 1%): Dysphonia, epistaxis, nasal congestion[Ref]

Some side effects of raltegravir may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.

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