Usage
Ritonavir is an antiretroviral medication, specifically a protease inhibitor, primarily used in combination with other antiretroviral agents for the treatment of HIV-1 infection. It inhibits the activity of HIV-1 protease, an enzyme crucial for viral replication, thus preventing the formation of mature infectious viral particles. Although initially used as a standalone protease inhibitor, ritonavir is now more commonly used in lower doses as a pharmacokinetic booster for other protease inhibitors due to its potent inhibitory effect on CYP3A4, the enzyme responsible for metabolizing these drugs. This boosting effect increases the plasma concentrations and prolongs the half-life of other protease inhibitors, allowing for less frequent dosing and improved efficacy.
Alternate Names
Ritonavir is also known by its brand name, Norvir. There are no widely recognized international or regional variations of the name.
How It Works
Pharmacodynamics: Ritonavir exerts its antiviral effect by binding to the active site of the HIV-1 protease enzyme, thereby preventing the cleavage of viral polyprotein precursors necessary for the assembly of infectious virions. This leads to the production of immature, non-infectious viral particles. As a pharmacokinetic booster, ritonavir inhibits CYP3A4, increasing plasma concentrations of co-administered protease inhibitors.
Pharmacokinetics: Ritonavir is well absorbed orally, reaching peak plasma concentrations within 2-4 hours. Food increases the bioavailability of the drug. Ritonavir is extensively metabolized in the liver, primarily by CYP3A4 and to a lesser extent by CYP2D6. It undergoes both hepatic and renal excretion, with the majority eliminated in feces. The half-life of ritonavir when used as a booster is shorter than when used as a primary protease inhibitor.
Mode of Action: Ritonavir acts by competitive inhibition of HIV-1 protease. It binds to the active site of the enzyme, preventing the binding and subsequent cleavage of the viral polyprotein substrates.
Dosage
Standard Dosage
Adults:
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As a pharmacokinetic booster: 100 mg to 400 mg once or twice daily, co-administered with another protease inhibitor. The specific dose depends on the co-administered protease inhibitor.
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As a primary protease inhibitor: Initially 300 mg twice daily orally with food, increasing by 100 mg twice daily every 2-3 days up to a maximum of 600 mg twice daily.
Children:
Dosing in children (over 2 years of age) is based on body surface area (BSA): 350 mg/m² to 400 mg/m² twice daily orally with food, not to exceed 600 mg twice daily. The oral solution is recommended for younger children or those unable to swallow capsules. Refer to pediatric dosage guidelines based on BSA for precise dosing. Ritonavir is not recommended for children under 2 years of age.
Special Cases:
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Elderly Patients: No specific dosage adjustment is required based on age, but caution is advised due to the increased likelihood of age-related organ dysfunction.
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Patients with Renal Impairment: Caution is recommended as ritonavir may be used with caution as a pharmacokinetic enhancer in patients with renal insufficiency.
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Patients with Hepatic Dysfunction: Ritonavir should not be given as a pharmacokinetic enhancer to patients with decompensated liver disease. Caution is required in patients with stable severe hepatic impairment. Dose adjustment depends on the specific protease inhibitor co-administered.
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Patients with Comorbid Conditions: Close monitoring is recommended for patients with diabetes, hyperlipidemia, or cardiovascular disease.
Clinical Use Cases
Ritonavir is not typically used in clinical settings like intubation, surgical procedures, mechanical ventilation, ICU use, or emergency situations outside of its role in HIV treatment. It doesn’t have properties relevant to these scenarios like sedation, analgesia, or cardiovascular support.
Dosage Adjustments
Dose adjustments may be necessary based on specific patient factors such as hepatic or renal impairment, concomitant medications, and the specific protease inhibitor co-administered.
Side Effects
Common Side Effects:
Nausea, vomiting, diarrhea, abdominal pain, headache, fatigue, taste disturbances, paresthesias (numbness or tingling), dizziness.
Rare but Serious Side Effects:
Pancreatitis, cardiac arrhythmias, hepatotoxicity, severe skin reactions (Stevens-Johnson syndrome, toxic epidermal necrolysis), hypersensitivity reactions, new-onset diabetes or worsening of existing diabetes, hyperlipidemia, changes in body fat distribution, increased bleeding in hemophiliacs.
Long-Term Effects:
Chronic complications can include hyperlipidemia, insulin resistance, diabetes, changes in body fat distribution, and increased risk of cardiovascular disease.
Adverse Drug Reactions (ADR):
Clinically significant ADRs include pancreatitis, hepatic dysfunction, severe skin reactions, and cardiac arrhythmias, requiring prompt discontinuation of ritonavir and supportive care.
Contraindications
Ritonavir is contraindicated in patients with known hypersensitivity to ritonavir or any of its components, decompensated liver disease, and concomitant use with medications highly dependent on CYP3A for clearance where elevated concentrations are associated with serious or life-threatening events (e.g., alfuzosin, ranolazine, amiodarone, triazolam, midazolam (oral), lovastatin, simvastatin, etc.). It is also contraindicated with potent CYP3A inducers that could significantly reduce ritonavir concentrations, leading to loss of virologic response.
Drug Interactions
Ritonavir has numerous drug interactions. It inhibits CYP3A, CYP2D6, CYP2C9, CYP2C19, and P-glycoprotein, increasing concentrations of drugs metabolized by these pathways. It can also induce certain enzymes, leading to decreased concentrations of other drugs. Clinically significant interactions can occur with numerous medications, including antiarrhythmics, sedative-hypnotics, HMG-CoA reductase inhibitors, anticonvulsants, certain antidepressants, and some immunosuppressants. Refer to a comprehensive drug interaction resource for detailed information before co-prescribing. Concomitant use with certain herbal products (e.g., St. John’s wort) and food (e.g., grapefruit juice) should also be avoided.
Pregnancy and Breastfeeding
Ritonavir is generally considered safe to use during pregnancy when the benefits outweigh the risks. The oral solution should be avoided due to its ethanol content. While ritonavir is excreted in breast milk, it is present in low amounts. The WHO recommends shared decision-making about breastfeeding in mothers living with HIV. However, the CDC, American Academy of Pediatrics, and the manufacturer advise against breastfeeding.
Drug Profile Summary
- Mechanism of Action: HIV-1 protease inhibitor; pharmacokinetic booster.
- Side Effects: Nausea, vomiting, diarrhea, hepatotoxicity, pancreatitis, cardiac arrhythmias, skin reactions, hyperlipidemia.
- Contraindications: Hypersensitivity, decompensated liver disease, co-administration with certain medications.
- Drug Interactions: Numerous drug interactions, primarily via CYP3A4 inhibition.
- Pregnancy & Breastfeeding: Generally safe in pregnancy; breastfeeding not recommended.
- Dosage: Varies depending on indication and co-administered drugs. See dosage section for details.
- Monitoring Parameters: Viral load, CD4 cell count, liver function tests, lipid profile, blood glucose.
Popular Combinations
Ritonavir is commonly used in combination with other protease inhibitors such as lopinavir, atazanavir, and darunavir, to boost their plasma concentrations.
Precautions
- General Precautions: Pre-screening for liver and renal function is recommended. Monitor for signs of pancreatitis and other adverse effects.
- Specific Populations: See Dosage section.
- Lifestyle Considerations: Alcohol should be avoided or limited due to potential additive hepatotoxicity.
FAQs (Frequently Asked Questions)
Q1: What is the recommended dosage for Ritonavir?
A: The dosage varies depending on the indication and co-administered drugs. As a booster, the dose is 100 mg to 400 mg once or twice daily. As a primary protease inhibitor, the dose is 600 mg twice daily. Pediatric and special population dosing should be individualized.
Q2: How does Ritonavir boost other protease inhibitors?
A: Ritonavir inhibits CYP3A4, the enzyme primarily responsible for metabolizing other protease inhibitors. This inhibition increases and maintains therapeutic levels of the co-administered drug.
Q3: What are the most serious side effects of Ritonavir?
A: Pancreatitis, hepatotoxicity, serious skin reactions (Stevens-Johnson syndrome, toxic epidermal necrolysis), cardiac arrhythmias, and new-onset or worsening diabetes.
Q4: Can Ritonavir be used during pregnancy?
A: Yes, but the oral solution should be avoided due to its ethanol content. The potential benefits should be weighed against the potential risks to the fetus.
Q5: What are the key drug interactions with Ritonavir?
A: Ritonavir interacts with numerous drugs, primarily via CYP3A4 inhibition. Important interactions can occur with antiarrhythmics, sedative-hypnotics, HMG-CoA reductase inhibitors, and other drugs metabolized by CYP3A4.
Q6: How should Ritonavir be administered?
A: Ritonavir tablets and oral solution should be taken orally with food to enhance absorption. The oral powder should be mixed with a small amount of food.
Q7: How often should patients on Ritonavir be monitored?
A: Patients should be monitored regularly for viral load, CD4 cell counts, liver function tests, lipid profile, and blood glucose. The frequency of monitoring depends on individual patient factors.
Q8: What patient counseling points are essential for Ritonavir?
A: Inform patients about the importance of adherence, potential side effects, drug interactions, and the need for regular monitoring. Advise patients to report any new or worsening symptoms promptly. Advise against breastfeeding and to avoid grapefruit juice and St John’s Wort.
Q9: Can Ritonavir cure HIV?
A: No, Ritonavir does not cure HIV. It is used to suppress viral replication and slow disease progression.
