Norvir

• Headache and Dizziness: Some patients report mild to moderate neurological symptoms.
• Rash: Allergic skin reactions can occur, ranging from mild redness to more significant eruptions.
• Increased Lipids: Ritonavir can cause significant elevations in cholesterol and triglycerides (hyperlipidemia). This often requires monitoring and sometimes treatment with lipid-lowering agents.
• Insomnia: Difficulty falling or staying asleep has been noted in clinical trials.

• Pancreatitis: Inflammation of the pancreas is a rare but life-threatening complication. Symptoms include severe upper abdominal pain that radiates to the back, accompanied by nausea and vomiting.
• PR Interval Prolongation: Ritonavir can affect the electrical activity of the heart, specifically slowing the conduction between the atria and ventricles. This is usually asymptomatic but can be dangerous in patients with underlying heart disease.
• New-Onset Diabetes: Protease inhibitors have been linked to the development of high blood sugar (hyperglycemia) and diabetes mellitus.

> Warning: Stop taking Ritonavir and call your doctor immediately if you experience any of these serious symptoms:

• Hepatotoxicity (Liver Toxicity): Symptoms include yellowing of the skin or eyes (jaundice), dark urine, pale stools, and pain in the upper right side of the stomach. Ritonavir has been associated with significant elevations in liver enzymes and, in rare cases, liver failure.
• Severe Allergic Reactions (Anaphylaxis): Look for swelling of the face, lips, or tongue; difficulty breathing; or a widespread, blistering rash (Stevens-Johnson Syndrome).
• Immune Reconstitution Inflammatory Syndrome (IRIS): In patients with HIV, the immune system may begin to recover and then react strongly to a previously hidden infection, causing a sudden onset of inflammatory symptoms.
• Cardiac Arrhythmias: If you feel your heart racing, skipping beats, or if you feel faint, seek emergency care, as Ritonavir can interact with other drugs to cause dangerous heart rhythms.

• Lipodystrophy: Prolonged use of protease inhibitors like Ritonavir can lead to changes in body fat distribution. This may include loss of fat from the legs, arms, and face, and increased fat in the abdomen, neck ("buffalo hump"), and breasts.
• Metabolic Syndrome: Long-term use is associated with insulin resistance and chronic elevations in triglycerides, which may increase the risk of cardiovascular disease over time.
• Bone Loss: Some studies suggest that long-term antiretroviral therapy may be associated with a decrease in bone mineral density (osteopenia or osteoporosis).

Ritonavir carries a significant warning regarding Drug-Drug Interactions. Because it is such a potent inhibitor of the CYP3A enzyme, co-administration with certain other drugs can lead to life-threatening toxicities. For example, taking Ritonavir with certain sedatives (like midazolam), antiarrhythmics (like amiodarone), or ergot derivatives can cause severe respiratory depression, dangerous heart rhythms, or restricted blood flow to the limbs. Always provide your doctor with a complete list of every medication, supplement, and herbal product you use.

Report any unusual symptoms to your healthcare provider. Monitoring of blood work (liver enzymes, lipids, and glucose) is a standard part of Ritonavir therapy.

Your healthcare provider will require regular blood tests to ensure Ritonavir is safe for you:

1. 1Liver Function Tests (ALT, AST, Bilirubin): Monitored closely, especially in the first few months.
2. 2Lipid Profile: Fasting triglycerides and cholesterol levels should be checked before starting and periodically during treatment.
3. 3Blood Glucose: Monitoring for signs of hyperglycemia or new-onset diabetes.
4. 4Viral Load and CD4 Count: To ensure the HIV treatment is working effectively.

Ritonavir may cause dizziness or fatigue in some patients. You should not drive or operate heavy machinery until you know how the medication affects you. If you experience dizziness or blurred vision, avoid these activities.

Patients should be cautious with alcohol. The Ritonavir oral solution contains 43.2% alcohol by volume. Consumption of alcohol while taking the oral solution can lead to a disulfiram-like reaction (nausea, vomiting, flushing, and rapid heartbeat). Furthermore, chronic alcohol use can increase the risk of liver toxicity.

Do not stop taking Ritonavir without consulting your doctor. In HIV treatment, stopping one medication in a combination regimen can lead to the virus developing resistance, making the entire treatment ineffective. If you need to stop Ritonavir due to side effects, your doctor will provide a plan to switch to an alternative medication.

> Important: Discuss all your medical conditions, including liver disease, heart disease, or diabetes, with your healthcare provider before starting Ritonavir.

• Erectile Dysfunction Drugs: Sildenafil (Viagra), Vardenafil, and Tadalafil. Ritonavir significantly increases these levels. A much lower dose is required to avoid severe low blood pressure and prolonged erections (priapism).
• Anticoagulants: Warfarin and Rivaroxaban. Ritonavir can change how these drugs work, increasing the risk of bleeding or blood clots.
• Corticosteroids: Fluticasone (found in Flonase and Advair). Ritonavir prevents the breakdown of these steroids, which can lead to Cushing's Syndrome (weight gain, moon face) and adrenal suppression.
• Anticonvulsants: Phenytoin, Carbamazepine, and Phenobarbital. These drugs can lower the levels of Ritonavir, making your HIV or COVID treatment fail.

• Oral Contraceptives: Ritonavir can decrease the levels of ethinyl estradiol. This makes birth control pills less effective. Patients should use an alternative or backup method of contraception (like condoms).
• Antidepressants: Levels of Trazodone or Desipramine may increase, requiring dose adjustments to avoid excessive sedation.

• High-Fat Meals: Taking Ritonavir with a high-fat meal increases its absorption. This is generally beneficial and recommended to improve the drug's efficacy and reduce stomach upset.
• Grapefruit and Grapefruit Juice: Grapefruit is a natural inhibitor of CYP3A4. Combining it with Ritonavir (the most potent chemical inhibitor) can lead to unpredictably high drug levels. It is best to avoid grapefruit products.

• St. John's Wort: This herbal supplement is a potent inducer of liver enzymes. It will cause Ritonavir levels to drop significantly, leading to treatment failure and viral resistance. It is strictly contraindicated.
• Garlic Supplements: Large amounts of garlic may decrease Ritonavir concentrations.

Ritonavir can cause elevations in several laboratory parameters, including:

• Triglycerides and Cholesterol: Often significantly increased.
• CPK (Creatine Phosphokinase): May be elevated, especially if taken with certain other drugs.
• GGT (Gamma-glutamyl transpeptidase): Often elevated, reflecting the drug's effect on the liver.

For each major interaction, the mechanism is usually CYP3A4 inhibition. Because Ritonavir "clogs" the enzyme, the other drug cannot be cleared, leading to toxicity. Conversely, "inducers" like St. John's Wort speed up the enzyme, clearing Ritonavir too fast and leading to reduced efficacy.

> Important: Tell your doctor about ALL medications, supplements, and herbal products you are taking. Do not start any new over-the-counter medicine without checking with your pharmacist.

Relative Contraindications

These are conditions where the doctor must carefully weigh the risks versus the benefits:

• Chronic Hepatitis B or C: These patients have an increased risk for severe hepatic adverse events. Treatment is possible but requires very frequent monitoring of liver enzymes.
• Cardiac Conduction Abnormalities: Patients with a history of PR interval prolongation or those taking other drugs that prolong the PR interval (like calcium channel blockers) should be monitored with ECGs.
• Diabetes Mellitus: Because Ritonavir can cause hyperglycemia, patients with pre-existing diabetes may experience a loss of blood sugar control.
• Hemophilia: There is an increased risk of spontaneous bleeding; patients should be warned and monitored for hematomas.

There is no documented cross-sensitivity between Ritonavir and other classes of antiretrovirals (like NRTIs or NNRTIs). However, patients who have had severe skin reactions to other protease inhibitors (like Darunavir) should use Ritonavir with extreme caution, as the underlying mechanism of the reaction may be similar.

> Important: Your healthcare provider will evaluate your complete medical history, including any history of liver disease or heart rhythm problems, before prescribing Ritonavir.

Ritonavir is approved for pediatric patients aged 1 month and older.

• Dosing: Dosing must be calculated carefully based on Body Surface Area (BSA).
• Toxicity Warning: The oral solution contains high levels of alcohol and propylene glycol. This is particularly dangerous for preterm neonates or very young infants, as their kidneys and livers cannot clear these excipients, potentially leading to seizures, heart failure, or kidney failure.

Clinical trials of Ritonavir did not include enough subjects aged 65 and over to determine whether they respond differently.

• Pharmacokinetics: Older adults often have reduced hepatic and renal function.
• Polypharmacy: The biggest concern in the elderly is the high likelihood of drug-drug interactions, as older patients are often on multiple medications for blood pressure, cholesterol, or heart disease.

Ritonavir pharmacokinetics have not been specifically studied in patients with renal impairment. However, since only 11% of the drug is cleared by the kidneys, no dose adjustment is typically required. It is not significantly removed by hemodialysis or peritoneal dialysis.

• Mild to Moderate (Child-Pugh A/B): No dose adjustment is usually necessary when used as a booster.
• Severe (Child-Pugh C): Ritonavir is contraindicated. The risk of hepatotoxicity is significantly elevated, and drug levels may become toxic.

> Important: Special populations require individualized medical assessment. Always inform your specialist if you are pregnant, planning to become pregnant, or breastfeeding.

|---|---|

| Bioavailability | 60-80% (Increased with food) |

| Protein Binding | 98% to 99% (Albumin and AAG) |

| Half-life | 3 to 5 hours |

| Tmax | 2 to 4 hours |

| Metabolism | Hepatic (Primarily CYP3A4, secondary CYP2D6) |

| Excretion | Fecal (86%), Renal (11%) |

• Molecular Formula: C37H48N6O5S2
• Molecular Weight: 720.95 g/mol
• Solubility: Practically insoluble in water; soluble in ethanol and methanol.
• Structure: It is a thiazolyl-methyl-carbamate derivative. Its structure mimics the transition state of the polyprotein cleavage site.

Ritonavir is classified as an HIV Protease Inhibitor (PI) and a Pharmacokinetic Enhancer. Within the PI class, it is grouped with medications like Darunavir, Lopinavir, and Atazanavir. It is unique within the class for its unparalleled potency as a CYP3A4 inhibitor.