Phosaprepitant (Lyophilisate) Instructions for Use

ATC Code

A04AD12 (Aprepitant)

Active Substance

Fosaprepitant (Rec.INN registered by WHO)

Clinical-Pharmacological Group

Antiemetic drug. NK₁ receptor antagonist

Pharmacotherapeutic Group

Antiemetic agent – neurokinin receptor blocker

Pharmacological Action

Antiemetic agent. The active metabolite of fosaprepitant is aprepitant, a selective, high-affinity antagonist of neurokinin 1 (NK₁) substance P receptors. The binding selectivity of aprepitant for NK₁ receptors is at least 3000 times higher than for other enzymes, transport proteins, ion channels, and receptors, including dopamine and serotonin receptors, which are the targets of existing drugs for preventing chemotherapy-induced nausea and vomiting.

Preclinical studies have shown that NK₁ receptor antagonists prevent vomiting induced by chemotherapeutic agents such as cisplatin through a central mechanism of action. According to data obtained from positron emission tomography (PET) studies, aprepitant penetrates the brain and binds to brain NK₁ receptors. The central action of aprepitant has a long duration, inhibiting both the acute and delayed phases of cisplatin-induced vomiting, and also enhances the antiemetic activity of 5-HT₃ receptor antagonists (e.g., ondansetron) and corticosteroids (dexamethasone).

In a randomized, double-blind, placebo-controlled QT_c interval study, a single dose of fosaprepitant 200 mg did not affect the QT_c interval value.

After a single intravenous administration of fosaprepitant 150 mg to healthy volunteers, brain NK₁ receptor binding was 100% at 24 hours, at least 97% at 48 hours, and 75% at 120 hours. The proportion of bound NK₁ receptors correlated with the plasma concentration of aprepitant.

Pharmacokinetics

After a single 20-minute intravenous infusion of 150 mg fosaprepitant to healthy volunteers, the mean AUC_0-∞ of aprepitant was 35 µg×h/ml and the mean C_max of aprepitant was 4.01 µg/ml.

Aprepitant protein binding is more than 95%. The geometric mean apparent V_d at steady state in humans is approximately 66 L. PET study data showed that aprepitant crosses the blood-brain barrier.

Fosaprepitant is rapidly metabolized to aprepitant (following intravenous administration within 30 minutes after the end of infusion). The conversion of fosaprepitant to aprepitant may occur in various tissues.

Aprepitant undergoes extensive metabolism. Seven metabolites of aprepitant have been identified in human plasma, which have weak activity. Aprepitant metabolism occurs primarily through oxidation of the morpholine ring and its side chains. In vitro studies using human liver microsomes show that aprepitant is metabolized predominantly by CYP3A4, to a minor extent by CYP1A2 and CYP2C19, while CYP2D6, CYP2C9, and CYP2E1 are not involved in its metabolism.

All metabolites identified in urine, feces, and plasma after intravenous administration of 100 mg [¹⁴C]-fosaprepitant were also identified after oral administration of [¹⁴C]-aprepitant.

After a single intravenous administration of 100 mg [¹⁴C]-fosaprepitant to healthy volunteers, 57% of the radioactivity was detected in urine and 45% in feces.

Aprepitant is eliminated mainly as metabolites; unchanged aprepitant is not excreted by the kidneys. The terminal T_1/2 of aprepitant is approximately from 9 to 13 hours.

Indications

For the prevention of acute and delayed nausea and vomiting associated with highly or moderately emetogenic anticancer chemotherapy (in combination with other antiemetic agents).

ICD codes

Dosage Regimen

Administer fosaprepitant intravenously as a single 150 mg dose.

Initiate the infusion on day 1 of the chemotherapy cycle, approximately 30 minutes before chemotherapy administration.

Infuse the reconstituted solution over a period of 20 to 30 minutes.

Use fosaprepitant exclusively as part of a combination antiemetic regimen.

Always co-administer with a corticosteroid and a 5-HT₃ receptor antagonist.

Do not administer as a bolus injection; ensure the intravenous infusion is given over the specified duration.

This regimen is indicated for the prevention of both acute and delayed nausea and vomiting associated with highly or moderately emetogenic chemotherapy.

Reconstitute the lyophilisate strictly according to the manufacturer’s instructions using only compatible solutions.

Avoid solutions containing divalent cations such as calcium or magnesium (e.g., Lactated Ringer’s) for reconstitution or dilution.

This is a three-day antiemetic regimen where fosaprepitant is administered only on day 1; the oral formulation of aprepitant may be used on subsequent days as per the prescribed schedule.

Adverse Reactions

Fosaprepitant is metabolized to aprepitant; therefore, the same adverse reactions as for aprepitant are possible with the use of fosaprepitant.

From the hematopoietic system infrequently – anemia, febrile neutropenia.

Psychiatric disorders infrequently – anxiety; rarely – euphoria, disorientation.

From the nervous system infrequently – dizziness, drowsiness; rarely – cognitive disorders, lethargy, taste perversion.

From the sensory organs rarely – conjunctivitis, tinnitus.

From the cardiovascular system infrequently – palpitations, paroxysmal sensations of heat (hot flashes), increased blood pressure; rarely – bradycardia, thrombophlebitis (predominantly, thrombophlebitis at the injection site).

From the respiratory system frequently – hiccups; rarely – sore throat, sneezing, cough, postnasal drip syndrome, pharyngeal irritation.

From the digestive system frequently – dyspepsia, decreased appetite, increased ALT activity; infrequently – belching, nausea, gastroesophageal reflux, vomiting, abdominal pain, dry mouth, flatulence, increased AST activity, ALP; rarely – hard stools, perforated duodenal ulcer, neutropenic colitis, stomatitis, abdominal distension.

From the skin and subcutaneous tissues infrequently – rash, acne, erythema; rarely – photosensitivity, increased sweating, seborrhea, increased skin oiliness, itchy rash, Stevens-Johnson syndrome.

From the musculoskeletal system rarely – muscle spasms, muscle weakness.

From the urinary system infrequently – dysuria; rarely – pollakiuria, increased diuresis, presence of red blood cells in urine, polydipsia, edema.

Infectious and parasitic diseases rarely – candidiasis, staphylococcal infection.

From metabolism rarely – hyponatremia, weight loss, glucosuria.

Allergic reactions hypersensitivity reactions, including urticaria, erythema, dyspnea, anaphylactic reactions.

Local reactions: infrequently – erythema, itching, pain at the injection site; rarely – induration at the injection site.

Other: frequently – fatigue; infrequently – asthenia, discomfort; rarely – chest discomfort, gait disturbance, decreased neutrophil count. When administered as a single 40 mg dose for the prevention of postoperative nausea and vomiting in patients (not receiving chemotherapy) after general anesthesia, increased ALT activity, upper abdominal pain, atypical bowel sounds, dysarthria, dyspnea, hypesthesia, insomnia, miosis, nausea, sensory disturbances, intestinal discomfort, decreased visual acuity, wheezing (rales) were observed. When used in doses greater than 150 mg, 1 case of constipation and 1 case of partial intestinal obstruction were observed.

Contraindications

Severe hepatic insufficiency (more than 9 points on the Child-Pugh scale); simultaneous use with pimozide, terfenadine, astemizole, and cisapride; pregnancy; childhood; hypersensitivity to fosaprepitant, aprepitant.

Use in Pregnancy and Lactation

Use during pregnancy is contraindicated.

It is not known whether Fosaprepitant is excreted in breast milk. The decision to discontinue breastfeeding or discontinue fosaprepitant should be made taking into account the necessity of treatment for the mother.

Special Precautions

The infusion of fosaprepitant should not be resumed in patients who have experienced manifestations of immediate-type allergic reactions.

When using fosaprepitant in combination with other antiemetic drugs, the instructions for use of these drugs must be followed.

Effect on ability to drive vehicles and operate machinery

However, some side effects associated with the use of aprepitant may affect the ability to drive vehicles and perform other activities requiring increased concentration and speed of psychomotor reactions.

Drug Interactions

Since Fosaprepitant is rapidly metabolized to aprepitant (which is a weak or moderate inhibitor of the CYP3A4 isoenzyme), it should be used with caution in patients simultaneously receiving drugs that are metabolized mainly by CYP3A4; some chemotherapeutic agents are metabolized by the CYP3A4 isoenzyme. The weak inhibitory effect of fosaprepitant 150 mg on the CYP3A4 isoenzyme may lead to increased concentrations of these concomitantly administered oral drugs.

Drug interactions after fosaprepitant administration are most likely to occur with drugs that interact with aprepitant. Further information is obtained from studies conducted with oral aprepitant and studies of the combined use of fosaprepitant with dexamethasone, midazolam, or diltiazem.

Since aprepitant is a weak or moderate inhibitor of the CYP3A4 isoenzyme, and Fosaprepitant is a weak inhibitor of CYP3A4, the plasma concentrations of drugs whose metabolism involves CYP3A4 may increase when used concomitantly.

Fosaprepitant should not be used concomitantly with pimozide, terfenadine, astemizole, or cisapride. Inhibition of CYP3A4 by aprepitant may lead to increased plasma concentrations of these drugs and potentially serious or life-threatening reactions.

Aprepitant has been found to induce the metabolism of S(-) warfarin and tolbutamide, which are metabolized by CYP2C9. Concomitant use of fosaprepitant with these or other drugs that are also metabolized by the CYP2C9 isoenzyme (e.g., phenytoin) may lead to a decrease in the plasma concentration of these drugs.

When fosaprepitant 150 mg and oral dexamethasone 8 mg were administered concomitantly on days 1, 2, and 3, the administration of fosaprepitant on day 1 caused an approximately 2-fold increase in the AUC of dexamethasone on days 1 and 2. The standard dose of dexamethasone (when administered orally) in combination with fosaprepitant 150 mg (IV on day 1) should be reduced by approximately 50% to achieve dexamethasone exposure similar to that when administered without fosaprepitant 150 mg IV on day 1.

When oral aprepitant 125 mg on day 1 and 80 mg/day on days 2 and 3 were used concomitantly, a 1.3-fold increase in the AUC of methylprednisolone, a CYP3A4 substrate, was noted on day 1 and a 2.5-fold increase on day 3, with intravenous methylprednisolone 125 mg on day 1 and oral administration of 40 mg on days 2 and 3.

In clinical studies, chemotherapeutic agents whose metabolism is mainly or partially mediated by the CYP3A4 isoenzyme were administered after oral aprepitant: etoposide, vinorelbine, docetaxel, ifosfamide, cyclophosphamide, irinotecan, and paclitaxel. The doses of these drugs were not adjusted for potential drug interactions. In post-marketing studies, cases of neurotoxicity have been recorded as a possible adverse effect of ifosfamide used concomitantly with aprepitant.

Aprepitant was administered to healthy volunteers receiving long-term warfarin therapy as a single 125 mg oral dose on day 1 and 80 mg/day on days 2 and 3. Despite the absence of any effect on the AUC of R(+) or S(-) warfarin on day 3 with oral aprepitant, a 34% decrease in the minimum concentration of S(-) warfarin (a CYP2C9 substrate) was observed, accompanied by a 14% decrease in prothrombin time (INR) 5 days after the end of oral aprepitant administration. In patients receiving long-term warfarin therapy, prothrombin time (INR) should be carefully monitored for 2 weeks during each chemotherapy cycle and especially 7-10 days after the start of fosaprepitant use.

Oral aprepitant 125 mg on day 1 and 80 mg on days 2 and 3 causes a 23% decrease in the AUC of tolbutamide (a CYP2C9 substrate) on day 4, a 28% decrease on day 8, and a 15% decrease on day 15, when tolbutamide in a single 500 mg dose was administered before the start of the three-day regimen of oral aprepitant and on days 4, 8, and 15.

The effectiveness of hormonal contraceptives during the use and for 28 days after the end of fosaprepitant administration may be reduced. During treatment with fosaprepitant and for 1 month after the end of fosaprepitant use, alternative or additional methods of contraception should be used.

When fosaprepitant 150 mg IV and midazolam 2 mg orally as a single dose were administered concomitantly on day 1, an approximately 1.8-fold increase in the AUC_0-∞ of midazolam was observed. With a similar dosing regimen on day 4, there was no effect on AUC. Fosaprepitant for intravenous use at a dose of 150 mg is a weak inhibitor of CYP3A4, since its single administration on day 1 did not lead to inhibition or induction of CYP3A4, unlike the results obtained on day 4.

Aprepitant is a substrate of CYP3A4; therefore, concomitant use of fosaprepitant with drugs that inhibit CYP3A4 activity may lead to an increase in the plasma concentration of aprepitant. Consequently, Fosaprepitant should be prescribed with caution in combination with strong CYP3A4 inhibitors (e.g., ketoconazole), but concomitant use of aprepitant with moderate CYP3A4 inhibitors (e.g., diltiazem) does not cause clinically significant changes in aprepitant plasma concentration. Aprepitant is a substrate of CYP3A4; therefore, concomitant use of fosaprepitant with drugs that are strong inducers of CYP3A4 (e.g., rifampicin) may lead to a decrease in its plasma concentration and a reduction in efficacy.

When oral aprepitant was administered as a single 125 mg dose on day 5 of a 10-day regimen of ketoconazole (400 mg/day), a strong CYP3A4 inhibitor, the AUC of aprepitant increased approximately 5-fold, and the terminal T_1/2 of aprepitant increased approximately 3-fold. Fosaprepitant should be prescribed with caution in combination with strong CYP3A4 inhibitors.

When oral aprepitant was administered as a single 375 mg dose on day 9 of a 14-day regimen of rifampicin, a strong CYP3A4 inducer, the AUC of aprepitant decreased approximately 11-fold, and the terminal T_1/2 of aprepitant decreased approximately 3-fold. Concomitant use of fosaprepitant with drugs that are strong inducers of CYP3A4 may lead to a decrease in plasma concentration and a reduction in efficacy.

In patients with mild to moderate arterial hypertension, infusion of fosaprepitant 100 mg over 15 minutes in combination with diltiazem 120 mg 3 times/day led to a 1.5-fold increase in the AUC of aprepitant and a 1.4-fold increase in the AUC of diltiazem. The pharmacokinetic effects led to a small but clinically significant decrease in diastolic BP (a decrease of 16.8 mm Hg with fosaprepitant and 10.5 mm Hg without fosaprepitant) and a small but clinically significant decrease in systolic BP (a decrease of 24.4 mm Hg with fosaprepitant and 18.8 mm Hg without fosaprepitant), but did not cause clinically significant changes in heart rate, PR interval compared to changes in these parameters when using diltiazem alone. In the same study, aprepitant was administered once daily as a tablet at a dose comparable to 230 mg of the drug in capsules, and diltiazem 120 mg 3 times/day for 5 days, which led to a 2-fold increase in the AUC of aprepitant and a simultaneous 1.7-fold increase in the AUC of diltiazem. These pharmacokinetic effects did not lead to clinically significant changes in ECG, heart rate, or BP compared to changes in these parameters when using diltiazem alone.

Concomitant use of aprepitant once daily in tablet form at a dose comparable to 85 mg or 170 mg of the drug in capsules, and paroxetine 20 mg once daily led to a decrease in AUC of approximately 25% and C_max of approximately 20% for both aprepitant and paroxetine.

Fosaprepitant is incompatible with solutions containing divalent cations (e.g., Ca, Mg), including Hartmann’s solution and Ringer’s lactate solution.

Storage Conditions

Store at 2°C (36°F) to 8°C (46°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.