Fosaprepitant

Fosaprepitant is a substance P/Neurokinin 1 Receptor Antagonist belonging to Antiemetic agent.

Fosaprepitant is an antiemetic drug used in combination with other antiemetic agents for the prevention of acute and delayed nausea and vomiting caused by chemotherapy.

The time to peak plasma concentration of Fosaprepitant is about 30 minutes. Aprepitant is greater than 95% bound to plasma proteins. The mean apparent volume of distribution at steady state (Vdss) was approximately 70 L in humans. Rapidly converted in hepatic and extrahepatic tissues into aprepitant which undergoes extensive metabolism via oxidation primarily by CYP3A4 enzyme and some by CYP1A2 and CYP2C19 enzymes into 7 weakly-active metabolites. Excreted Mainly via urine (57% as metabolites) and faeces (45% as metabolites).

Fosaprepitant shows side effects like Tiredness or weakness, diarrhea, redness, itching, hardness, or swelling at the injection site, weakness, numbness, tingling, or pain in arms or legs, headache, heartburn.

Fosaprepitant is available in the form of Powder for Injection.

Fosaprepitant is available in India, US, Canada, France, Japan, Germany, Malaysia, Russia, China, Spain, Australia, and Italy.

Fosaprepitant belongs to the Antiemetic agent acts as a substance P/Neurokinin 1 Receptor Antagonist.

Aprepitant has been shown in animal models to inhibit emesis induced by cytotoxic chemotherapeutic agents, such as cisplatin, via central actions. Animal and human Positron Emission Tomography (PET) studies with Aprepitant have shown that it crosses the blood brain barrier and occupies brain NK1 receptors. Animal and human studies show that Aprepitant augments the antiemetic activity of the 5-HT₃-receptor antagonist ondansetron and the corticosteroid ethasone and inhibits both the acute and delayed phases of cisplatin induced emesis. In summary, the active form of Fosaprepitant is as an NK1 antagonist which is because it blocks signals given off by NK1 receptors. This therefore decreases the likelihood of vomiting in patients experiencing.

The Data of Onset and duration of action of Fosaprepitant is not clinically established.

The Tmax of Fosaprepitant (aprepitant) is within 30 minutes after the end of infusion.

Fosaprepitant is available in the form of Powder for injection.

Fosaprepitant Powder for injection is given via intravenous route.

Fosaprepitant is an antiemetic medicine which is used along with other medications to prevent acute and delayed nausea and vomiting associated with cancer chemotherapy in adults and children above six months of age. It works by blocking the action of a natural substance that causes nausea and vomiting.

Fosaprepitant is a substance P/Neurokinin 1 Receptor Antagonist belonging to Antiemetic agent.

Fosaprepitant is a prodrug of aprepitant, a substance P/neurokinin 1 (NK1) receptor antagonist. Fosaprepitant is rapidly converted to aprepitant, which prevents acute and delayed vomiting by inhibiting the substance P/neurokinin 1 (NK1) receptor; also augments the antiemetic activity of the 5-HT₃ receptor antagonist and corticosteroid activity and inhibits chemotherapy-induced emesis.

Fosaprepitant is approved for use in the following clinical indications

• Prevention of chemotherapy-induced nausea/vomiting

Fosaprepitant is an antiemetic drug used in combination with other antiemetic agents for the prevention of acute and delayed nausea and vomiting caused by chemotherapy.

• Prevention of chemotherapy-induced nausea/vomiting

Highly emetogenic chemotherapy: IV: 150 mg on day 1 only (infusion should be completed ~30 minutes prior to chemotherapy).

Moderately emetogenic chemotherapy: IV: 150 mg on day 1 only (infusion should be completed ~30 minutes prior to chemotherapy).

Fosaprepitant is available in the form of Powder for injection.

• Dosage Adjustment in Hepatic impairment Patient

Mild or moderate impairment (Child-Pugh class A or B): No dosage adjustment necessary.

Severe impairment (Child-Pugh class C): There is no dosage adjustment provided.

Fosaprepitant is contraindicated in patients with

• Patients who are hypersensitive to any component of the product. Hypersensitivity reactions including anaphylactic reactions, flushing, erythema, and dyspnea have been reported.
• Taking pimozide. Inhibition of CYP3A4 by aprepitant, the active moiety, could result in elevated plasma concentrations of this drug, which is a CYP3A4 substrate, potentially causing serious or life-threatening reactions, such as QT prolongation, a known adverse reaction of pimozide.

• Hypersensitivity Reactions

Serious hypersensitivity reactions, including anaphylaxis and anaphylactic shock, during or soon after infusion of Fosaprepitant have occurred. Symptoms including flushing, erythema, dyspnea, hypotension, and syncope have been reported. Monitor patients during and after infusion. If hypersensitivity reactions occur, discontinue the infusion and administer appropriate medical therapy. Do not reinitiate Fosaprepitant for Injection in patients who experience these symptoms with previous use

• Infusion Site Reactions

Infusion site reactions (ISRs) have been reported with the use of Fosaprepitant for Injection. The majority of severe ISRs, including thrombophlebitis and vasculitis, were reported with concomitant vesicant (anthracycline-based) chemotherapy administration, particularly when associated with extravasation. Necrosis was also reported in some patients with concomitant vesicant chemotherapy. Most ISRs occurred with the first, second or third exposure to single doses of Fosaprepitant for Injection and in some cases, reactions persisted for two weeks or longer. Treatment of severe ISRs consisted of medical, and in some cases surgical, intervention. Avoid infusion of Fosaprepitant for Injection into small veins or through a butterfly catheter. If a severe ISR develops during infusion, discontinue the infusion, and administer appropriate medical treatment.

• Decrease in INR with Concomitant Warfarin

Coadministration of Fosaprepitant for Injection with warfarin, a CYP2C9 substrate, may result in a clinically significant decrease in the International Normalized Ratio (INR) of prothrombin time. Monitor the INR in patients on chronic warfarin therapy in the 2-week period, particularly at 7 to 10 days, following initiation of Fosaprepitant for Injection with each chemotherapy cycle.

• Risk of Reduced Efficacy of Hormonal Contraceptives

Upon coadministration with Fosaprepitant for Injection, the efficacy of hormonal contraceptives may be reduced during administration of and for 28 days following the last dose of Fosaprepitant for Injection. Advise patients to use effective alternative or back-up methods of contraception during treatment with Fosaprepitant for Injection and for 1 month following administration of Fosaprepitant for Injection, Use in Specific Populations.

There are no data on the presence of aprepitant in human milk, the effects on the breastfed infant, or the effects on milk production. Aprepitant is present in rat milk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Fosaprepitant for Injection and any potential adverse effects on the breastfed infant from Fosaprepitant for Injection or from the underlying maternal condition.

There are no available data on use of Fosaprepitant in pregnant women to inform a drug-associated risk of adverse developmental outcomes. In animal reproduction studies, no adverse developmental effects were observed in rats or rabbits exposed during the period of organogenesis to systemic exposures (AUC) approximately equivalent to the exposure at the recommended human dose (RHD) of 150 mg. The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Common

• Fatigue, Diarrhea, Peripheral neuropathy, Dyspepsia, Urinary tract infection, Neutropenia, anemia, leukopenia Local: Infusion-site reaction (2% to 3%; includes induration at injection site, infusion-site pain, local pruritus, localized erythema), Weakness, limb pain.

Rare

• Anaphylactic shock, anaphylaxis, dyspnea, erythema, flushing, hypersensitivity reaction, hypotension, pruritus, skin rash, Stevens-Johnson syndrome, syncope, toxic epidermal necrolysis, urticaria.

• Aprepitant is a CYP3A4 substrate

Coadministration of Fosaprepitant for Injection with drugs that are inhibitors or inducers of CYP3A4 may result in increased or decreased plasma concentrations of aprepitant.

• Moderate to Strong CYP3A4 Inhibitors

Significantly increased exposure of aprepitant may increase the risk of adverse reactions associated with Fosaprepitant for Injection. Avoid concomitant use of Fosaprepitant for Injection

Examples Moderate inhibitor: diltiazem Strong inhibitors: ketoconazole, itraconazole, nefazodone, troleandomycin, clarithromycin, ritonavir, nelfinavir

• Strong CYP3A4 Inducers

Substantially decreased exposure of aprepitant in patients chronically taking a strong CYP3A4 inducer may decrease the efficacy of Fosaprepitant for Injection. Intervention Avoid concomitant use of Fosaprepitant for Injection Examples rifampin, carbamazepine, phenytoin

The common side effects of Fosaprepitant include the following

• Common side effects

Tiredness or weakness, diarrhea, redness, itching, hardness, or swelling at the injection site, weakness, numbness, tingling, or pain in arms or legs, headache, heartburn.

• Rare side effects

Peeling or blistering of the skin, frequent or painful urination, sudden need to urinate right away.

• Pregnancy

There are no available data on use of Fosaprepitant in pregnant women to inform a drug-associated risk of adverse developmental outcomes. In animal reproduction studies, no adverse developmental effects were observed in rats or rabbits exposed during the period of organogenesis to systemic exposures (AUC) approximately equivalent to the exposure at the recommended human dose (RHD) of 150 mg. The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

• Nursing Mothers

There are no data on the presence of aprepitant in human milk, the effects on the breastfed infant, or the effects on milk production. Aprepitant is present in rat milk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Fosaprepitant for Injection and any potential adverse effects on the breastfed infant from Fosaprepitant for Injection or from the underlying maternal condition.

• Pediatric Use

This Fosaprepitant for Injection product is not approved for use in pediatric patients.

• Geriatric Use

Of the 1649 adult cancer patients treated with intravenous Fosaprepitant in HEC and MEC clinical studies, 27% were aged 65 and over, while 5% were aged 75 and over. Other reported clinical experience has not identified differences in responses between elderly and younger patients. In general, use caution when dosing elderly patients as they have a greater frequency of decreased hepatic, renal or cardiac function and concomitant disease or other drug therapy.

In the event of overdose, Fosaprepitant for Injection should be discontinued, and general supportive treatment and monitoring should be provided. Because of the antiemetic activity of Fosaprepitant for Injection, drug induced emesis may not be effective in cases of Fosaprepitant for Injection overdosage.

Pharmacodynamic

Fosaprepitant is a prodrug of Aprepitant. Once biologically activated, the drug acts as a substance P/neurokinin 1 (NK1) receptor antagonist which, in combination with other antiemetic agents, is indicated for the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of highly emetogenic cancer chemotherapy. Aprepitant is a selective high-affinity antagonist of human substance P/neurokinin 1 (NK1) receptors. Aprepitant has little or no affinity for serotonin (5-HT₃), dopamine, and corticosteroid receptors, the targets of existing therapies for chemotherapy-induced nausea and vomiting (CI NV).

Pharmacokinetics

• Absorption

The time to peak plasma concentration of Fosaprepitant is about 30 minutes.

• Distribution

Aprepitant is greater than 95% bound to plasma proteins. The mean apparent volume of distribution at steady state (Vdss) was approximately 70 L in humans.

• Metabolism and Excretion

Rapidly converted in hepatic and extrahepatic tissues into aprepitant which undergoes extensive metabolism via oxidation primarily by CYP3A4 enzyme and some by CYP1A2 and CYP2C19 enzymes into 7 weakly-active metabolites. Excreted Mainly via urine (57% as metabolites) and faeces (45% as metabolites).

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