Raltegravir: Uses, Indications, Side Effects, and Pharmacology

Overview

Raltegravir is an antiretroviral medication that belongs to a class of drugs called integrase strand transfer inhibitors (INSTIs). It is used to treat HIV-1 infection, the most common strain of the human immunodeficiency virus (HIV). HIV is responsible for causing acquired immunodeficiency syndrome (AIDS), a condition that weakens the immune system and can lead to opportunistic infections and diseases. Raltegravir received its initial approval from the U.S. (United States) Food and Drug Administration (FDA) on October 12, 2007. It was approved for treating HIV-1 infection in combination with other antiretroviral medications.

Drug Group:

Raltegravir belongs to a class of drugs known as integrase strand transfer inhibitors (INSTIs). This drug group includes other medications like Elvitegravir, Dolutegravir, and Bictegravir.

Available Doses and Dosage Forms:

• Tablets: 400 mg (milligrams) tablets are the standard strength for treating HIV infection.

• Chewable Tablets: 25 mg chewable tablets are available for pediatric patients or individuals who have difficulty swallowing regular tablets.

• Oral Suspension: 100 mg per 1 mL (milliliter) oral suspension: This form was typically used for pediatric patients or those with difficulty swallowing tablets.

For Patients

What Is HIV?

HIV is known as the human immunodeficiency virus. This virus attacks the human immune system and lowers the body's defense against infections and diseases. HIV specifically targets CD4 (clusters of differentiation 4) cells, also known as T-helper cells, which are a crucial part of the immune system's response to infections. When a person gets an infection of HIV, the virus enters their bloodstream and starts replicating within CD4 cells. Over time, the virus can significantly decrease the number of these cells in the body. As the immune system becomes compromised, the person becomes more susceptible to opportunistic infections and certain cancers that a healthy immune system typically controls.

If left untreated, HIV infection can progress to a more advanced stage called AIDS, which stands for acquired immunodeficiency syndrome. Antiretroviral therapy (ART) involves taking a combination of medications that target different aspects of the HIV lifecycle, helping to suppress viral replication and maintain a healthier immune system. While ART cannot cure HIV, it can significantly improve the quality and length of life for individuals with it.

Preventive measures such as safe sex practices, using condoms, and avoiding sharing needles for drug use are essential to reduce the risk of HIV transmission. Additionally, pre-exposure prophylaxis (PrEP) is available for individuals at high risk of HIV infection to take medication to prevent infection.

How Does Raltegravir Work?

Here's how Raltegravir works:

• Attachment and Fusion: HIV enters human cells by binding to specific receptors on the surface of CD4 cells, a type of immune cell. After attachment, the virus fuses with the host cell membrane and releases its genetic material (RNA - ribonucleic acid) into the cell.

• Reverse Transcription: Once inside the host cell, reverse transcription converts the viral RNA into DNA (deoxyribonucleic acid). This newly synthesized viral DNA is then transported into the host cell's nucleus.

• Integrase Enzyme: The viral DNA must integrate into the host cell's DNA to replicate. This is where the integrase enzyme comes into play. Integrase helps the viral DNA insert itself into the host cell's DNA at a specific location.

• Integration Inhibition: Raltegravir interferes with the integrase enzyme's function. It binds to the active site of integrase and prevents it from properly inserting the viral DNA into the h in the host cell's DNA. This inhibition prevents the virus from completing the integration process, halting its ability to replicate effectively.

What Is the Dosage of Raltegravir?

For Adults and Adolescents:

• The typical dosage of Raltegravir for adults and adolescents was 400 mg orally twice daily.

• The medication was available in tablet form (400 mg) for oral administration.

For Pediatric Patients:

• The dosage for pediatric patients depended on their weight and age. Pediatric dosages were typically lower than adult dosages.

• Raltegravir was available in chewable tablet form (25 mg) or oral suspension (100 mg per one mL) to facilitate dosing for children who had difficulty swallowing tablets.

How Effective Is Raltegravir?

Clinical studies and real-world experience have demonstrated the effectiveness of Raltegravir in suppressing the replication of the human immunodeficiency virus (HIV) and reducing the viral load in the bloodstream. When used as part of a combination antiretroviral therapy (ART) regimen, Raltegravir, like other integrase strand transfer inhibitors (INSTIs), has effectively achieved and maintained viral suppression, a key goal of HIV treatment.

Viral suppression not only improves the individual's overall health and quality of life but also helps to prevent the progression of HIV infection to more advanced stages and reduces the risk of transmitting the virus to others.

What Are the Things to Inform the Doctor Before Taking the Drug?

Here are some important things to inform the doctor about before taking Raltegravir:

• Provide a detailed medical history, including pre-existing health conditions like liver or kidney disease, diabetes, or other chronic illnesses. Also, inform the doctor about any history of mental health disorders, substance abuse, or other relevant medical conditions.

• Ensure the doctor knows all patient medications, including prescription drugs, over-the-counter medications, supplements, and herbal remedies. This is important to prevent potential drug interactions.

• Inform the doctor of any known allergies, especially if a patient has had allergic reactions to any medications.

• Discuss with the doctor if the patient is pregnant, planning to become pregnant, or breastfeeding. They can guide patients on the risks and benefits of taking Raltegravir during these periods.

• Raltegravir is metabolized by the liver and excreted through the kidneys. If a patient has impaired liver or kidney function, the doctor may need to adjust the dosage or closely monitor the body's response to the medication.

• Inform the doctor about any ongoing medical treatments or procedures a patient is undergoing and any recent surgeries or hospitalizations.

• The doctor needs to know the HIV status, including whether a patient is newly diagnosed or has been on previous antiretroviral therapy. This information helps guide the selection of appropriate treatment regimens.

• Discuss any lifestyle factors affecting the treatment, such as tobacco or alcohol use, recreational drug use, or risky sexual behaviors. This information can help the doctor tailor the treatment plan to the needs.

• If a patient is of reproductive age and sexually active, discuss contraception options with the doctor. Some medications, including Raltegravir, can interact with hormonal contraceptives.

• Mention any other medications or supplements a patient is taking, as there may be potential interactions that could affect the effectiveness or safety of Raltegravir.

• If a patient has experienced adverse reactions to other medications, share this information with the doctor to help them assess Raltegravir's potential risks and benefits.

How Is Raltegravir Administered?

Here are the common ways in which Raltegravir is administered:

• Tablets (Standard Tablets): The standard dosage form of Raltegravir is a tablet that is taken orally with water. This form is suitable for individuals who can easily swallow pills. The tablets are typically available in a strength of 400 mg.

• Chewable Tablets: Raltegravir is available in chewable tablet form for individuals with difficulty swallowing tablets. These tablets can be chewed or crushed before swallowing, making them easier to take, especially for children or those who struggle with swallowing large pills. Chewable tablets often come in lower strengths, such as 25 mg.

• Oral Suspension: An oral suspension of Raltegravir is a liquid form of medication that can be taken by mouth. This form is particularly useful for pediatric patients or individuals with trouble swallowing tablets. A measuring device is typically provided to ensure accurate dosing of the suspension. Raltegravir oral suspension is available at 100 mg per one mL.

What Are the Side Effects of Raltegravir?

Common Side Effects:

• Nausea.

• Diarrhea.

• Headache.

• Fatigue.

• Insomnia (difficulty sleeping).

• Rash.

Less Common Side Effects:

• Changes in liver function tests.

• Elevated levels of creatine kinase (a muscle enzyme).

• Muscle pain or weakness.

• Increased levels of blood sugar.

• Changes in body fat distribution.

Serious Side Effects (Rare but Possible):

• Severe skin reactions, such as Stevens-Johnson syndrome or toxic epidermal necrolysis (these are very rare but can be life-threatening).

• Liver problems, including hepatotoxicity.

• Allergic reactions.

• Immune reconstitution syndrome (when the immune system improves and reacts to previously hidden infections).

Dietary Considerations:

Here are a few dietary guidelines to consider:

• Consistency: Try to take Raltegravir consistently concerning meals. Taking it with food may improve its absorption and reduce the likelihood of gastrointestinal side effects such as nausea or diarrhea.

• Grapefruit and Grapefruit Juice: Some medications can interact with grapefruit and grapefruit juice, potentially affecting how the medication is metabolized. While Raltegravir is not known to have significant interaction with grapefruit, it is always a good idea to discuss the diet, including the consumption of grapefruit products, with the healthcare provider to ensure no potential issues.

• Healthy Eating: Maintaining a balanced and healthy diet is important for overall health, especially when managing a chronic condition like HIV. A well-rounded diet can help support the immune system, energy levels, and overall well-being.

• Hydration: Stay well-hydrated by drinking enough water throughout the day. Proper hydration can support overall health and help manage potential side effects.

• Vitamin and Mineral Supplements: Some people living with HIV may benefit from specific vitamin or mineral supplements to address deficiencies or support their immune system. However, before taking any supplements, it is advisable to consult the healthcare provider.

• Alcohol and Substance Use: If a patient consumes alcohol or uses recreational drugs, it is important to discuss this with the healthcare provider. Some substances can interact with medications or affect overall health and treatment.

Overdose:

If a patient suspects that a patient or someone else has overdosed on Raltegravir, it is important to seek medical attention immediately. Overdosing on any medication, including Raltegravir, can have serious health consequences. Here are some steps to take in case of an overdose:

• Call Emergency Services: If the overdose is severe or if a patient's experiencing any symptoms of an overdose, call emergency services or go to the nearest emergency room as soon as possible.

• Symptoms of Overdose: A Raltegravir overdose can include severe or unusual side effects, such as severe nausea, vomiting, dizziness, confusion, or any other unusual or severe symptoms.

• Medical Assessment: Once a patient is under medical care, healthcare professionals will assess the condition, provide appropriate treatments, and monitor the health to ensure safety.

• Bring Medication Information: Bring the medication container or information about the medication to the healthcare facility. This can help medical professionals understand the medication involved and its potential effects.

Storage

• Always follow the storage instructions provided on the medication's packaging or the prescription label.

• Raltegravir tablets can typically be stored at room temperature, which is usually around 68 to 77 degrees Fahrenheit (20 to 25 degrees Celsius). Keep the medication away from direct sunlight, heat sources, and moisture.

• If a patient is using Raltegravir oral suspension, follow the manufacturer's instructions for storage. It might need to be stored in a refrigerator, and a patient should follow specific guidelines for how long the suspension can be stored after it is mixed or opened.

• Store medications, including Raltegravir, out of reach of children and pets to prevent accidental ingestion.

• Avoid storing medications in the bathroom, as the humidity and temperature changes in bathrooms can affect the stability of the medication.

• If a patient has leftover or expired medication, dispose of it according to local regulations. Many pharmacies and healthcare facilities have medication disposal programs.

• If a patient is traveling with Raltegravir, follow the storage instructions while on the go. Keep the medication in its original packaging to provide necessary information to healthcare professionals if needed.

For Doctors

Indication:

Raltegravir is indicated for treating HIV-1 infection, specifically in combination with other antiretroviral medications. It is prescribed for individuals newly diagnosed with HIV-1 infection and those who have developed resistance to other antiretroviral drugs.

The medication is part of a comprehensive antiretroviral therapy (ART) regimen to suppress the replication of the human immunodeficiency virus (HIV) and reduce the viral load in the bloodstream. Raltegravir belongs to the class of drugs known as integrase strand transfer inhibitors (INSTIs), which target the integrase enzyme of the virus to prevent its integration into the host cell's DNA.

Pharmacodynamics

The pharmacodynamics of Raltegravir include the following key points:

• Inhibition of Integrase: Raltegravir is classified as an integrase strand transfer inhibitor (INSTI). Its primary mechanism of action is to inhibit the integrase enzyme of the human immunodeficiency virus (HIV). During viral replication, integrase inserts the viral DNA into the host cell's DNA.

• Preventing Integration: By binding to the active site of integrase, Raltegravir prevents the enzyme from effectively integrating the viral DNA into the host cell's DNA.

• Viral Replication Suppression: The inhibition of integrase by Raltegravir leads to a decrease in viral replication. The virus cannot effectively integrate its genetic material into host cell DNA, so it cannot produce new infectious viral particles.

• Reduction of Viral Load: Through suppressing viral replication, Raltegravir helps reduce the viral load in the bloodstream. Viral load is the amount of HIV RNA in the blood and is a key marker of disease progression.

• Immune System Recovery: By reducing the viral load, Raltegravir supports the recovery of the immune system. As the virus is controlled, CD4 T-cell counts can increase, helping the immune system regain strength and function.

Mechanism

The mechanism of Raltegravir involves its action as an integrase strand transfer inhibitor (INSTI) in the treatment of HIV-1 infection. Raltegravir targets an enzyme called integrase, produced by the human immunodeficiency virus (HIV). Integrase is essential for the virus to integrate its genetic material into the DNA of the host cell.

Pharmacokinetics

Pharmacokinetics involves how a medication is absorbed, distributed, metabolized, and eliminated by the body. Understanding the pharmacokinetics of a medication like Raltegravir is important for optimizing its use and ensuring its effectiveness. Here are the key aspects of the pharmacokinetics of Raltegravir:

• Absorption: Raltegravir is well absorbed from the gastrointestinal tract after oral administration. The rate and extent of absorption is influenced by factors such as food intake. Taking Raltegravir with food, especially a meal containing some fat, can increase its bioavailability. However, Raltegravir can also be taken without regard to meals.

• Distribution: Raltegravir is distributed throughout the body, including various tissues and cells. It crosses the blood-brain barrier to some extent, which is important for suppressing HIV replication in the central nervous system.

• Metabolism: Raltegravir undergoes minimal metabolism in the liver. The primary metabolism pathway involves glucuronidation, where the drug is conjugated with glucuronic acid to form inactive metabolites. The cytochrome P450 enzyme system does not significantly affect the metabolism of Raltegravir, which can reduce the potential for drug interactions.

• Elimination: The elimination of Raltegravir and its metabolites occurs primarily through the kidneys, with a small portion excreted in feces. Renal function can affect the clearance of Raltegravir, and dose adjustments may be necessary for individuals with impaired kidney function.

• Half-Life: The elimination half-life of Raltegravir is relatively short, averaging around nine hours in adults. This means it takes about nine hours for half of the drug to be eliminated from the body. The short half-life often requires Raltegravir to be taken twice daily to maintain consistent drug levels.

Toxicity:

Raltegravir is generally well-tolerated when used as prescribed in HIV treatment regimens. However, like any medication, it can potentially cause adverse effects, some of which may be considered toxic or harmful. It is important to be aware of possible toxicities associated with Raltegravir and promptly report any concerning symptoms to the healthcare provider. Here are some potential areas of toxicity:

• Liver Function: Raltegravir can affect liver function in some individuals. Elevated liver enzymes (transaminases) may occur, indicating potential liver inflammation. In rare cases, severe hepatotoxicity (liver toxicity) can occur.

• Skin Reactions: These are severe skin conditions that require immediate medical attention.

• Immune Reconstitution Syndrome: As the immune system improves with antiretroviral treatment, there is a risk of immune reconstitution syndrome (IRIS). This condition occurs when the immune response to pre-existing infections becomes exaggerated, worsening symptoms. IRIS may present as inflammatory reactions, swelling, or other complications.

• Creatine Kinase Levels: Raltegravir may lead to elevated creatine kinase levels, an enzyme in muscle tissue. While this is generally not harmful, very high levels could indicate muscle-related issues.

• Gastrointestinal Effects: Common side effects of Raltegravir may include nausea, diarrhea, and abdominal discomfort. While these are not typically considered toxic, severe or persistent gastrointestinal symptoms should be reported to the healthcare provider.

What Are the Contraindications of Raltegravir?

Contraindications for Raltegravir include:

• Hypersensitivity: Do not use if there is a known hypersensitivity or allergic reaction to Raltegravir.

• Concurrent Use of Rifampin: Avoid concurrent use with rifampin, as it may significantly reduce the effectiveness of Raltegravir.

• Severe Hepatic Impairment: Raltegravir should be used cautiously in individuals with severe hepatic impairment.

Warnings and Precautions:

Here are some general warnings and precautions associated with Raltegravir:

• Hypersensitivity Reactions: Hypersensitivity reactions, including rash and other allergic reactions, have been reported with Raltegravir. If a patient experiences signs of a severe rash, blistering, or hypersensitivity, seek medical attention promptly.

• Liver Function: Raltegravir can affect liver function. Monitor liver enzymes regularly, especially during the early stages of treatment. Severe hepatotoxicity (liver toxicity) is rare but has been reported. Use with caution in individuals with pre-existing liver disease.

• Immune Reconstitution Syndrome: During the initial phase of HIV treatment, immune reconstitution syndrome (IRIS) can occur, where the immune system responds to previously hidden infections. This can lead to increased inflammation and clinical symptoms.

• Risk of Resistance: Incomplete viral suppression can lead to the development of drug-resistant HIV strains. Raltegravir should be combined with other antiretroviral drugs to reduce the risk of resistance.

• Pediatric Use: The safety and effectiveness of Raltegravir in pediatric patients may differ from that of adult patients. Pediatric dosing should be based on age and weight; specific guidance from healthcare providers is recommended.

• Geriatric Use: Clinical experience in older adults is limited. Consider age-related factors, coexisting conditions, and potential drug interactions in geriatric patients.

• Pregnancy and Breastfeeding: Raltegravir's safety during pregnancy and breastfeeding is not fully established.

• Drug Interactions: Raltegravir's interactions with other medications can affect its effectiveness and safety. Inform the healthcare provider about all medications, supplements, and over-the-counter drugs a patient is taking.

• Renal Impairment: Raltegravir is primarily excreted through the kidneys. Dosage adjustments may be necessary for individuals with impaired kidney function.

• Potential for Myopathy: While rare, some individuals using Raltegravir have experienced myopathy (muscle-related side effects). Contact the healthcare provider if a patient experiences muscle pain or weakness.

What Are the Drug Interactions of Raltegravir?

Here are some notable drug interactions associated with Raltegravir:

• Antacids and Buffering Agents: Some antacids and buffering agents containing aluminum and magnesium hydroxides may decrease the absorption of Raltegravir. If a patient needs to take an antacid, try to space it at least two hours before or six hours after taking Raltegravir.

• Polyvalent Cations: Drugs or supplements containing polyvalent cations (e.g., calcium, iron, zinc) can interact with Raltegravir and reduce its absorption. Administer Raltegravir at least two hours before or six hours after these substances.

• Rifampin: Rifampin, a medication used to treat tuberculosis and other bacterial infections, can significantly decrease Raltegravir levels. Only co-administration of Raltegravir and Rifampin, if there are suitable alternatives and the benefits outweigh the risks.

• Etravirine: Etravirine, another antiretroviral medication, can decrease Raltegravir levels. Dose adjustments may be needed if used together, and monitoring is essential.

• Atazanavir or Ritonavir and Darunavir or Ritonavir: Boosted protease inhibitors like Atazanavir or Ritonavir and Darunavir or Ritonavir can increase Raltegravir levels. While the combination can be used, adjustments to Raltegravir dosage may be required.

• Efavirenz: Efavirenz, an antiretroviral medication, can decrease Raltegravir levels. If used together, healthcare providers may consider increasing the Raltegravir dosage.

• Enzyme Inducers and Inhibitors: Medications that induce or inhibit enzymes involved in drug metabolism can impact Raltegravir levels. Inform the healthcare provider about any medications a patient takes that may fall into these categories.

• Statins: Raltegravir increases exposure to certain Statins, which are used to lower cholesterol levels.

Specific Considerations:

• Pregnancy: Raltegravir is pregnancy category B by the FDA, which means animal studies have not shown a risk to the fetus, but there are no adequate and well-controlled studies in pregnant women. The potential benefits and risks should be discussed with the healthcare provider. Pregnant individuals with HIV should receive antiretroviral therapy to reduce the risk of mother-to-child transmission. Raltegravir can be considered part of the treatment regimen if determined appropriate by the healthcare provider.

• Breastfeeding: Raltegravir is excreted in human milk. Because of the potential for HIV transmission through breast milk, it is generally recommended that HIV-infected individuals not breastfeed their infants. Breastfeeding is not advised for individuals with HIV due to the risk of transmitting the virus to the baby. Suppose an alternative feeding method is not feasible, and the mother's viral load is well-suppressed. In that case, the decision to breastfeed should be made in consultation with healthcare providers specializing in HIV treatment.

• Pediatric Use: Raltegravir has been studied and approved for use in pediatric patients as part of HIV treatment. Pediatric patients should be monitored regularly for safety and effectiveness, and their growth and development should be carefully tracked.

• Geriatric Use: Clinical experience with Raltegravir in older adults (geriatric population) is limited. The pharmacokinetics and response to treatment may differ from younger adults. Geriatric patients often have other medical conditions and take multiple medications, increasing the potential for drug interactions and complications. Close monitoring and individualized treatment plans are important.