Aprepitant

The dosage of Aprepitant is strictly dictated by the clinical indication and the specific chemotherapy regimen being used. It is rarely used as a monotherapy (single drug).

For Chemotherapy-Induced Nausea and Vomiting (CINV)

For patients receiving highly emetogenic chemotherapy, the standard 3-day regimen is:

• Day 1: 125 mg orally, administered 1 hour prior to chemotherapy treatment.
• Day 2: 80 mg orally in the morning.
• Day 3: 80 mg orally in the morning.

Aprepitant is typically given alongside a 5-HT3 antagonist (like Ondansetron) on Day 1 and Dexamethasone on Days 1 through 4.

For Postoperative Nausea and Vomiting (PONV)

• Standard Dose: A single 40 mg oral dose.
• Timing: This should be administered within 3 hours prior to the induction of anesthesia.

Aprepitant is approved for use in pediatric patients (6 months of age and older) for the prevention of CINV. The dosing is typically weight-based:

• Weight-based Regimen: For children, the dose is often calculated as 3 mg/kg on Day 1 (max 125 mg) and 2 mg/kg on Days 2 and 3 (max 80 mg).
• Formulation: The oral suspension is generally preferred for younger children to ensure accurate dosing.

Renal Impairment

No dosage adjustment is necessary for patients with renal impairment or those with end-stage renal disease (ESRD) undergoing hemodialysis. Because Aprepitant is not significantly cleared by the kidneys, the pharmacokinetic profile remains stable.

Hepatic Impairment

• Mild to Moderate: No dosage adjustment is required for patients with Child-Pugh scores of 5 to 9.
• Severe: There is limited data regarding the use of Aprepitant in patients with severe hepatic impairment (Child-Pugh score >9). Healthcare providers will exercise extreme caution in these cases.

Elderly Patients

Clinical studies have shown that the efficacy and safety of Aprepitant in the elderly (65 years and older) are comparable to younger adults. No specific dose adjustments are required based solely on age, though overall health and other medications must be considered.

1. 1Timing is Critical: For chemotherapy, the first dose must be taken before the infusion starts. If you forget to take it, contact your oncology team immediately.
2. 2With or Without Food: Aprepitant may be taken regardless of meals.
3. 3Administration: Capsules should be swallowed whole with a full glass of water. Do not crush or chew the capsules, as this may alter the absorption rate.
4. 4Storage: Store at room temperature (68°F to 77°F or 20°C to 25°C). Keep the medication in its original packaging to protect it from moisture.

If you miss a dose, contact your doctor immediately for instructions. Because Aprepitant is part of a precisely timed regimen, a missed dose can significantly increase the risk of breakthrough nausea. Do not double the dose to catch up unless specifically instructed by your healthcare provider.

In the event of an overdose, symptoms may include extreme drowsiness or a intensified version of common side effects. There is no specific antidote for Aprepitant. If an overdose is suspected, contact a Poison Control Center (1-800-222-1222 in the US) or seek emergency medical attention immediately. Treatment is generally supportive, focusing on managing symptoms and monitoring vital signs.

> Important: Follow your healthcare provider's dosing instructions exactly. Do not adjust your dose or stop the 3-day regimen without medical guidance, even if you do not feel nauseous.

Most patients tolerate Aprepitant well, especially since it is used for a short duration. However, because it is almost always given with chemotherapy and other antiemetics, it can be difficult to distinguish which drug is causing a specific symptom. Common side effects include:

• Fatigue and Asthenia: A profound sense of tiredness or lack of energy. This is the most frequently reported side effect, affecting roughly 15-20% of patients.
• Diarrhea or Constipation: Changes in bowel habits are common. Diarrhea may occur as the body adjusts to the medication, while constipation is often a result of the combined antiemetic regimen.
• Hiccups: A unique side effect associated with NK1 receptor antagonists. While usually mild, they can be persistent for some patients.
• Dyspepsia (Indigestion): A feeling of fullness, bloating, or heartburn. This typically resolves once the 3-day treatment course is completed.

• Anorexia: A temporary loss of appetite or decreased food intake.
• Headache: Mild to moderate headaches may occur shortly after the first dose.
• Elevated Liver Enzymes: Transient increases in AST (aspartate aminotransferase) and ALT (alanine aminotransferase) have been observed in clinical trials, usually without clinical symptoms.
• Dizziness: Some patients report a sensation of spinning or lightheadedness.

• Tinnitus: Ringing in the ears.
• Dysuria: Pain or difficulty during urination.
• Insomnia: Difficulty falling or staying asleep.
• Dehydration: Often secondary to other gastrointestinal symptoms.

While rare, serious reactions can occur. You must monitor your body closely during the treatment period.

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

1. 1Severe Hypersensitivity (Anaphylaxis): Symptoms include hives, rash, itching, swelling of the face, lips, or tongue, and difficulty breathing. This can be life-threatening.
2. 2Severe Skin Reactions: Although extremely rare, cases of Stevens-Johnson Syndrome (SJS) have been reported. Look for blistering, peeling skin, or painful red/purple rashes that spread.
3. 3Severe Liver Dysfunction: Symptoms include yellowing of the skin or eyes (jaundice), dark urine, or severe right-sided abdominal pain.
4. 4Significant Cognitive Changes: Confusion, extreme disorientation, or hallucinations.

Aprepitant is typically administered for very short durations (1 to 3 days per chemotherapy cycle). Consequently, long-term side effects are not well-documented in standard clinical use. However, repeated use across many cycles of chemotherapy is generally considered safe, provided liver function is monitored and drug interactions are managed.

There are currently no FDA black box warnings for Aprepitant. However, the FDA does emphasize the critical nature of its drug-drug interactions, particularly with medications metabolized by CYP3A4, which can lead to life-threatening complications if not managed correctly.

Report any unusual symptoms to your healthcare provider. Even mild side effects should be discussed, as your doctor may be able to provide supportive care to manage them.

Aprepitant is a powerful modulator of liver enzymes. The most important safety consideration is the potential for interactions with other medications. Patients must provide a complete list of all prescriptions, over-the-counter drugs, and herbal supplements to their oncology team before starting Aprepitant.

No FDA black box warnings for Aprepitant.

Allergic Reactions and Anaphylaxis

Hypersensitivity reactions, including anaphylaxis, have occurred in patients taking Aprepitant. These reactions can occur with the first dose. If you have a known allergy to Aprepitant or Fosaprepitant (the IV version), you must not take this medication. Signs of a reaction include wheezing, chest tightness, and swelling of the throat.

Severe Skin Reactions

Isolated cases of Stevens-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN) have been reported. These are medical emergencies. If you notice a blistering rash, especially one accompanied by fever or flu-like symptoms, stop the medication and seek emergency care immediately.

Hormonal Contraceptive Failure

Aprepitant reduces the effectiveness of hormonal contraceptives (birth control pills, patches, implants, and some IUDs). This effect can last for up to 28 days after the last dose of Aprepitant. Patients of childbearing potential should use a highly effective back-up method of contraception (such as condoms) during treatment and for one full month after the final dose to prevent unintended pregnancy.

Warfarin Interaction

For patients on chronic warfarin therapy, Aprepitant can cause a significant decrease in the International Normalized Ratio (INR), which increases the risk of blood clots. This effect is delayed, usually peaking 7 to 10 days after the 3-day Aprepitant regimen is completed.

Healthcare providers typically monitor the following during Aprepitant therapy:

• Liver Function Tests (LFTs): To ensure the liver is processing the drug safely, especially in patients with pre-existing liver disease.
• INR/Prothrombin Time: Specifically for patients on warfarin. Monitoring should occur in the 2-week period following each chemotherapy cycle.
• Drug Levels: For medications with a narrow therapeutic index (like certain immunosuppressants) that are metabolized by CYP3A4.

Aprepitant may cause dizziness or fatigue in some patients. You should avoid driving or operating heavy machinery until you know how the medication affects you. This is particularly important because chemotherapy itself often causes significant cognitive 'fog' and exhaustion.

There is no direct chemical interaction between Aprepitant and alcohol. However, alcohol can irritate the stomach lining and worsen nausea or vomiting, which defeats the purpose of the medication. Furthermore, alcohol can increase the risk of dizziness and liver strain. It is generally advised to avoid alcohol during the days you are taking Aprepitant.

There is no known withdrawal syndrome associated with stopping Aprepitant after a 3-day course. Because it is used for short-term prevention, tapering is not required. However, stopping the medication early during a chemotherapy cycle will likely result in a failure to prevent delayed nausea.

> Important: Discuss all your medical conditions, especially liver disease and any history of allergic reactions, with your healthcare provider before starting Aprepitant.

Certain drugs must never be used with Aprepitant because the interaction can cause dangerously high levels of the other medication in the bloodstream, potentially leading to fatal heart rhythm problems (QT prolongation).

• Pimozide: Used for Tourette's syndrome. Aprepitant increases pimozide levels, which can cause severe cardiac arrhythmias.
• Terfenadine and Astemizole: (Though largely withdrawn from many markets) These antihistamines pose a severe heart risk when combined with Aprepitant.
• Cisapride: Used for gastric motility; the combination can lead to life-threatening heart rhythm disturbances.

• Corticosteroids (Dexamethasone/Methylprednisolone): Aprepitant significantly increases the blood levels of these steroids. When used together, the dose of oral dexamethasone should be reduced by approximately 50%.
• Chemotherapeutic Agents: Many chemo drugs (like Docetaxel, Paclitaxel, Etoposide, Irinotecan, Ifosfamide, Vinblastine, and Vincristine) are metabolized by CYP3A4. Aprepitant can increase the toxicity of these agents. Your oncologist will adjust doses as necessary.
• Warfarin: As an inducer of CYP2C9, Aprepitant can decrease the effectiveness of warfarin. Close INR monitoring is mandatory for 2 weeks following treatment.

• Benzodiazepines: Aprepitant can increase the sedative effects of midazolam, alprazolam, and triazolam. Patients may experience extreme drowsiness.
• Immunosuppressants: Drugs like cyclosporine, tacrolimus, and sirolimus may reach toxic levels if taken with Aprepitant. Blood level monitoring is required.
• Hormonal Contraceptives: As noted, the efficacy of birth control is reduced. Back-up methods are essential.

• Grapefruit Juice: Grapefruit is a potent inhibitor of CYP3A4. Consuming grapefruit juice while taking Aprepitant can lead to higher-than-intended levels of the drug, increasing the risk of side effects. It is best avoided during the 3-day treatment window.
• High-Fat Meals: While Aprepitant can be taken with food, extremely high-fat meals might slightly delay the time it takes to reach peak concentration, though this is rarely clinically significant.

• St. John’s Wort: This herbal supplement is a potent inducer of CYP3A4. It can significantly lower the levels of Aprepitant in the blood, making the antiemetic treatment less effective. Do not use St. John's Wort during your treatment cycles.
• Kava/Valerian: These may enhance the sedative effects (drowsiness) caused by Aprepitant.

Aprepitant does not have many known interactions with common laboratory tests, but its effect on liver enzymes (ALT/AST) can cause transient elevations that may be misinterpreted if the healthcare provider is unaware of the medication use.

> Important: Tell your doctor about ALL medications, supplements, and herbal products you are taking. Even 'natural' products can interfere with how Aprepitant works or cause dangerous side effects.

Absolute contraindications are conditions where the risk of using the drug clearly outweighs any potential benefit. Aprepitant must NEVER be used in the following scenarios:

1. 1Hypersensitivity: Any patient with a known, documented allergy to Aprepitant or Fosaprepitant. The risk of anaphylaxis or severe skin reactions (SJS/TEN) makes re-exposure dangerous.
2. 2Concurrent use of CYP3A4 Substrates with Narrow Therapeutic Indices: Specifically, medications like Pimozide, Cisapride, Terfenadine, or Astemizole. The mechanism involves Aprepitant's inhibition of the CYP3A4 enzyme, which prevents the breakdown of these drugs. This leads to toxic accumulation and a high risk of 'Torsades de Pointes,' a life-threatening heart rhythm.

These are conditions where the drug should be used with extreme caution and only after a thorough risk-benefit analysis by a specialist:

• Severe Hepatic Impairment (Child-Pugh Score >9): Because the liver is the primary site of metabolism, severe dysfunction can lead to unpredictable drug levels. There is insufficient clinical data to guarantee safety in this population.
• Chronic Warfarin Therapy: While not an absolute contraindication, the risk of sub-therapeutic INR (and subsequent blood clots) requires a high level of patient compliance with blood testing.
• Pregnancy: Unless the benefit of preventing severe vomiting outweighs the unknown risks to the fetus, healthcare providers may look for alternative treatments.

Patients who have had an allergic reaction to Fosaprepitant (the intravenous form) are highly likely to be allergic to Aprepitant, as Fosaprepitant is a prodrug that converts directly into Aprepitant within minutes of injection. There is no known cross-sensitivity between Aprepitant and other classes of antiemetics, such as 5-HT3 antagonists (Ondansetron) or Dopamine antagonists (Metoclopramide).

> Important: Your healthcare provider will evaluate your complete medical history, including all allergies and current heart health, before prescribing Aprepitant.

FDA Pregnancy Category: Not Assigned (The old ABCDE system has been replaced by the Pregnancy and Lactation Labeling Rule).

There are no adequate and well-controlled studies of Aprepitant in pregnant women. Animal studies using doses much higher than the human clinical dose did not show evidence of direct harm to the fetus. However, because animal studies are not always predictive of human response, Aprepitant should be used during pregnancy only if clearly needed. It is especially important to note that Aprepitant can interfere with hormonal birth control, which may lead to unintended pregnancy if back-up methods are not used.

It is not known whether Aprepitant is excreted in human breast milk. However, animal studies have shown that the drug is present in the milk of lactating rats. Because of the potential for serious adverse reactions in a nursing infant, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Most oncology protocols suggest pausing breastfeeding during the 3-day treatment window and for a short period afterward.

Aprepitant is approved for the prevention of CINV in pediatric patients as young as 6 months of age.

• Efficacy: Studies have shown it is effective in reducing both acute and delayed vomiting in children receiving emetogenic chemotherapy.
• Safety: The side effect profile in children is generally similar to that in adults, though younger children should be monitored closely for dehydration and electrolyte imbalances if they experience any diarrhea.
• Dosing: Dosing must be calculated precisely by a pediatric oncologist based on the child's weight.

In clinical trials, no overall differences in safety or effectiveness were observed between subjects 65 years of age and older and younger subjects. However, elderly patients are more likely to have decreased hepatic or cardiac function and are often taking multiple other medications (polypharmacy). Therefore, the risk of drug interactions is significantly higher in this population. Healthcare providers should perform a comprehensive 'brown bag' medication review before prescribing.

Aprepitant is not cleared by the kidneys. Therefore, no dosage adjustment is necessary for patients with any degree of renal impairment, including those on hemodialysis. The drug is not dialyzable, so it can be administered without regard to the timing of dialysis sessions.

• Mild to Moderate: No dose adjustment is needed. The liver's ability to metabolize the drug remains sufficient.
• Severe: Caution is advised. There is a lack of data for patients with severe cirrhosis or liver failure. In these patients, the half-life of the drug may be significantly prolonged, leading to increased systemic exposure.

> Important: Special populations require individualized medical assessment. Always inform your specialist about your pregnancy status or any history of organ dysfunction.

Aprepitant is a selective, high-affinity antagonist at the Neurokinin-1 (NK1) receptor. Its primary target is the Substance P neurotransmitter, a member of the tachykinin family. Substance P is found in the vagus nerve afferent fibers and the nucleus tractus solitarius (NTS), which are key components of the brain's emetic center. By binding to the NK1 receptor, Aprepitant prevents Substance P from initiating the signaling cascade that leads to the physical act of vomiting. It has little to no affinity for other receptors involved in emesis, such as 5-HT3, dopamine D2, or muscarinic receptors.

The pharmacodynamics of Aprepitant are characterized by its ability to cross the blood-brain barrier and occupy NK1 receptors in the brain. Positron Emission Tomography (PET) studies in humans have shown that Aprepitant achieves greater than 90% receptor occupancy in the brain at clinical doses. The duration of effect is long enough to support once-daily dosing, which is critical for managing the 'delayed phase' of nausea that occurs days after chemotherapy.

| Parameter | Value |

|---|---|

| Bioavailability | ~60% to 67% |

| Protein Binding | >95% (primarily Albumin) |

| Half-life | 9 to 13 hours |

| Tmax | ~4 hours |

| Metabolism | Hepatic (Primarily CYP3A4; minor CYP1A2, CYP2C19) |

| Excretion | Fecal 86%, Renal 5% |

• Molecular Formula: C23H21F7N4O3
• Molecular Weight: 534.43 g/mol
• Solubility: Practically insoluble in water; sparingly soluble in ethanol; soluble in isopropyl acetate.
• Structure: A substituted morpholine derivative containing several fluorine atoms, which contribute to its lipophilicity and ability to cross the blood-brain barrier.

Aprepitant is the prototypical member of the Substance P/Neurokinin-1 (NK1) Receptor Antagonist class. Related medications include Fosaprepitant (the IV prodrug), Rolapitant, and Netupitant (often sold in combination with palonosetron as Akynzeo). These drugs have transformed oncology by specifically targeting the delayed phase of emesis that was previously difficult to control.