阿那莫林(Anamorelin)详细说明书:适应症、用法用量、副作用、注意事项

Anamorelin is a new, oral, selective ghrelin receptor agonist, non-hormonal drug. On December 11, 2020, it was approved for the first time in Japan for the treatment of cancer cachexia in patients with non-small cell lung cancer, pancreatic cancer, gastric cancer, colorectal cancer and other malignant tumors.

Indications of Anamorelin

Cancer cachexia in the following malignant tumors: non-small cell lung cancer, gastric cancer, pancreatic cancer, and colon cancer.

Notes on indications:

(1) For the treatment of patients with cancer cachexia due to unresectable, advanced or recurrent non-small cell lung cancer, gastric cancer, pancreatic cancer or colorectal cancer.

(2) Used for patients with cancer cachexia who have failed nutritional therapy and other treatments.

(3) It is used for patients who have lost more than 5% of their body weight within 6 months, developed anorexia, and have two or more of the following symptoms:

1) Fatigue or discomfort;

2) General muscle weakness;

3) One or more of the following symptoms: CRP level exceeds 0.5mg/dL, hemoglobin level is less than 12g/dL, or albumin level is less than 3.2g/dL.

The pictures are from public channels (such as the official website of the FDA, the official website of the original drug manufacturer, etc.) and are for reference only.

Usage and Dosage of Anamorelin

1. Recommended dose

The common adult dose is 100 mg of Anamorelin hydrochloride, taken orally once a day on an empty stomach.

2. Usage and medication precautions

(1) To avoid the influence of food, please take this medicine on an empty stomach and do not eat within one hour after taking the medicine.

(2) If there is no weight gain or improvement in appetite after taking this medicine, in principle, the medicine should be stopped about 3 weeks after starting to take it.

(3) This medicine should not be taken for more than 12 weeks. The need for continued use should be assessed periodically, such as through a medical interview to check weight and appetite.

3. Other important instructions

(1) This drug inhibits sodium channels and therefore inhibits the conduction system. Taking this medicine may cause electrocardiogram abnormalities (significant prolongation of the PR interval or QRS width, prolongation of the QT interval, etc.). Therefore, before starting to take this drug and during the period of taking this drug, electrocardiogram, pulse, blood pressure, cardiothoracic ratio, electrolytes, etc. should be measured regularly. If abnormalities are found, appropriate measures should be taken, such as discontinuing the drug. Particular caution should be exercised in the early stages of taking this medicine.

(2) Hyperglycemia may occur. Blood sugar and urine sugar should be measured regularly before taking this product and during taking it.

(3) This product may cause liver dysfunction, so liver function tests should be performed before starting to take this product and regularly during taking it.

4. Precautions when dispensing

Instruct patients to take the medicine out of the PTP package before taking it. If PTP tablets are accidentally swallowed, their hard and sharp edges may pierce the esophageal mucosa, leading to perforation and serious complications such as mediastinitis.

Side effects of Anamorelin

The following side effects may occur, so please observe closely and stop use or take other appropriate measures if any abnormalities are found.

1. Serious side effects

(1) Conduction system depression (10.7%)

Electrocardiogram abnormalities (significantly prolonged PR interval or QRS complex, prolonged QT interval, etc.), atrioventricular block, tachycardia, bradycardia, palpitations, decreased blood pressure, premature supraventricular contractions, etc. may occur.

(2) Hyperglycemia (4.3%), exacerbation of diabetes (4.3%)

Pay attention to the occurrence of symptoms such as dry mouth and frequent urination, and take appropriate measures if necessary, such as giving insulin or oral hypoglycemic drugs, or discontinuing this drug.

(3) Liver dysfunction (6.4%)

Liver dysfunction may occur, accompanied by increases in AST, ALT, ALP, γ-GTP, blood bilirubin, etc.

Special population use of Anamorelin

1. Patients with complications or medical history

(1) Patients with underlying heart disease (valvular disease, cardiomyopathy, etc.)

It may suppress cardiac function and worsen symptoms.

(2) Patients with a history of myocardial infarction or angina pectoris

It may suppress heart function and worsen symptoms.

(3) Patients with conduction system diseases (AV block, sinoatrial block, bundle branch block, etc.)

This drug inhibits sodium channels and may inhibit the conduction system, thereby worsening it.

(4) Patients with risk or history of QT interval prolongation

may develop QT interval prolongation.

(5) Patients with electrolyte abnormalities (hypokalemia, hypomagnesemia, hypocalcemia)

are at risk of conducting system depression.

(6) Patients with a history of anthracycline treatment

Anthracyclines have cumulative cardiotoxicity and may produce serious side effects.

(7) Diabetic patients

may experience elevated blood sugar levels.

2. Patients with hepatic insufficiency

Patients with mild hepatic insufficiency (Child-Pugh Class A) should be particularly cautious when combined with moderate CYP3A4 inhibitors. Since the liver is primarily responsible for clearing this drug from the body, plasma concentrations may be elevated and may result in conduction system depression. In addition, concomitant use with moderate CYP3A4 inhibitors may inhibit the metabolism of the drug, thereby further increasing plasma concentrations.

3. Pregnant women

Pregnant women or women who may become pregnant should only use this product when the benefits of treatment outweigh the risks. Administration of ghrelin or ghrelin analogs to mice has been shown to delay embryonic development, reduce fetal weight, reduce pregnancy rates, and reduce the number of fetuses. Although the placental passage of this drug is unknown, it is possible that it crosses the placenta given its high lipid solubility and weak alkalinity.

4. Breastfeeding women

Consider the benefits of treatment and the benefits of breastfeeding, and consider whether to continue or stop breastfeeding. It is unknown whether this drug is excreted in breast milk, but given its high fat solubility and weak alkaline nature, it may be excreted in breast milk.

5. Children

No clinical trials have been conducted on children.

6. Elderly people

Please use with caution while observing the patient’s condition. Often, physiological functions (kidney function, liver function, immune function, etc.) are impaired.

Drug interactions of Anamorelin

This drug is mainly metabolized by CYP3A4.

1. Contraindications for simultaneous use (do not use in combination)

Clarithromycin, Clariside and other preparations containing specific ingredients, if used simultaneously with related drugs, may cause the blood concentration of the drug to increase and increase the occurrence of side effects. This is because this type of drug has a strong inhibitory effect on CYP3A4, thereby inhibiting the metabolism of this type of drug.

2. Precautions for concurrent use (pay attention when using in combination)

When antiarrhythmic drugs such as pixicanide hydrochloride hydrate are used in combination with related drugs, the antiarrhythmic effect and proarrhythmic effect may be enhanced; β-blockers such as atenolol, etc., when used in combination with other related drugs, may have excessive cardiac depressant effects, and the negative inotropic effects of the two drugs may be Mutual enhancement of cardiac depressant effects; cardiotoxic anticancer drugs such as anthracyclines, etc., may increase cardiotoxicity when used concurrently with related drugs; drugs known to prolong the QT interval, such as imipramine, etc., may cause serious side effects such as QT interval prolongation and ventricular arrhythmias (including torsade de pointes) when used concurrently with related drugs, because the inhibitory effect of this drug on the conduction system may enhance the QT interval prolonging effect of these drugs.

Moderate CYP3A4 inhibitors, such as erythromycin and diltiazem, etc., inhibit the metabolism of the drug, which may cause the blood concentration of the drug to increase and increase the occurrence of side effects. The components contained in grapefruit juice have inhibitory effects on CYP3A4 and can inhibit the metabolism of the drug. Likewise, It may lead to an increase in the blood concentration of the drug and increase the occurrence of side effects; the CYP3A4 induction effect of CYP3A4 inducers such as drugs containing carbamazepine, rifampicin and food containing St. John's wort accelerates the metabolism of the drug, which may lead to a decrease in the blood concentration of the drug and a weakening of the efficacy.

Contraindications of Anamorelin

1. Patients with a history of allergies to any component of the drug.

2. Patients with congestive heart failure.

3. Patients with myocardial infarction and angina pectoris.

4. Patients with severe conduction system diseases (such as complete atrioventricular block).

5. Patients who are receiving the following drugs: clarithromycin, itraconazole, voriconazole, ritonavir-containing preparations, cobicistat-containing preparations and encitravir fumarate.

6. Patients with moderate or severe hepatic insufficiency (Child-Pugh B and C).

7. Patients who have difficulty in taking food orally due to organic abnormalities of the digestive tract (such as gastrointestinal obstruction).

Pharmacokinetics of Anamorelin

1. Blood concentration

(1) Single dose

In the dose range of 50-125 mg, an increase in exposure greater than dose proportionality was observed.

(2) Repeated administration

The plasma concentration of anamulin reaches steady state within 7 days after administration. Of note, greater than dose proportional increases in exposure were observed in the 50-150 mg range.

2. Absorption

(1) Absolute bioavailability

When healthy adults (8 cases) received a single oral dose of 100 mg or a single intravenous injection of 10 mg, the absolute bioavailability of anamulin was 37.0%7) (foreign data).

(2) Effect of diet

Seven healthy Japanese adults took 50 mg of the drug orally on an empty stomach, one hour before meals and two hours after meals. When taken one hour before meals, the Cmax and AUC0-∞ of anamorelin were 1.09 times and 0.80 times those in the fasting state, respectively, and no significant clinical effect was observed. However, when taken two hours after a meal, the Cmax and AUC0-∞ of anamorelin were 0.31 times and 0.49 times those in the fasting state, respectively, indicating a food effect.

(3) Distribution

The protein binding rate of this drug in human plasma is 97.3~98.3%, and the main binding protein is α1-acid glycoprotein (AGP) (in vitro).

(4) Metabolism

The main metabolizing enzyme of this drug is CYP3A4.

(5) Excretion

When 25 mg of 14C-anamorelin hydrochloride was given orally as a single oral dose to 8 healthy adults, 92-93% of the administered radioactive material was excreted in the feces, and the remaining 7-8% was excreted in the urine. 1% of administered radioactive material is excreted unchanged in the urine. The liver is thought to be the main factor in eliminating this drug from the body (data from foreign subjects).

3. Drug interactions

(1) Rifampicin

When healthy adults (16 cases) took 100 mg of this product orally and combined it with 600 mg of rifampicin (a strong inducer of CYP3A4) (once a day for 7 days), the Cmax and AUC0-∞ of anamorelin were reduced by 0.43 times and 0.32 times respectively compared with when used alone (foreign subject data).

(2) Simulation using a physiologically based pharmacokinetic model

The exposure of cancer cachectic patients with a typical background who had liver impairment and were treated with a moderate CYP3A4 inhibitor was predicted based on the severity of liver impairment and the increased plasma anamorelin exposure resulting from concomitant use of a moderate CYP3A4 inhibitor (estimated using a physiological pharmacokinetic model).

Cmax and AUCtau in patients with moderate or severe hepatic impairment may exceed the Cmax and AUCtau ranges experienced to date (3,670 ng/mL and 14,100 ng·h/mL, respectively, both predicted values ​​based on Bayesian estimation).

Since body weight and AGP concentration are used as covariates in the PPK analysis, for patients from a representative background, a weight of 38.6kg (5% of the population weight used in the PPK analysis) and an AGP concentration of 242m g/dL (95% of AGP concentration) as a background, and predicted steady-state Cmax and AUCtau values (2,300ng/mL and 6,820ngh/mL, respectively) for patients with cancer cachexia were used as exposure levels.

4. Others

(1) In vitro test results

This drug inhibits and induces CYP3A413.

This drug is a substrate of P-gp and OATP1B315.

This drug inhibits MATE115.

(2) Ketoconazole

When healthy adults (12 cases) took 25 mg of this product orally, combined with 200 mg of ketoconazole (a strong inhibitor of CYP3A4), three times with an interval of 12 hours, the Cmax and AUC0-∞ of anamulin increased 3.12 times and 3.22 times respectively compared with the drug alone (foreign subject data).

(3) Midazolam (oral preparation, not approved in Japan)

Administer 75 mg of this drug orally once a day to healthy adults (8 subjects) for 6 days, combined with the CYP3A4 substrate midazolam ( When taking 6 mg alone and 3 mg in combination with this drug, compared with taking this drug alone, the Cmax and AUC0-∞ corrected by the dose of midazolam were 1.28 times and 0.98 times respectively 17) (data from foreign subjects).

(4) Paroxetine

Healthy adults (16 subjects) took 20 mg of paroxetine (a strong inhibitor of CYP2D6) orally once a day for 11 days. When combined with 100 mg of this drug, the Cmax and AUC0-∞ of anamorelin were 1.28 times and 0.87 times that of single drug administration, respectively. No clinically significant effect of paroxetine was observed.

(5) Pantoprazole

When healthy adults (12 cases) took 25 mg of this product orally and two intravenous injections of 40 mg of pantoprazole in combination, the Cmax and AUC0-∞ of anamorelin were 1.21 times and 1.06 times higher than when the drug was administered alone, and the increase in gastric juice pH caused by the concurrent use of pantoprazole did not affect the pharmacokinetics of anamorelin.

Pharmacology of Anamorelin

1. Mechanism of action

This drug has an agonistic effect on the ghrelin receptor GHS-R1a (growth hormone releasing factor receptor type 1a). By activating GHS-R1a, the drug promotes the secretion of growth hormone (GH) and increases appetite, leading to weight gain.

2. Pharmacological effects

This drug combines with recombinant human GHS-R1a, acts on rat pituitary cells, and promotes GH secretion (in vitro).

After a single oral administration of this drug to rats, the plasma GH concentration increased.

Repeated oral administration of this drug can increase food intake and body weight in rats.

Active ingredients of Anamorelin

Chemical name: (3R)-3-benzyl-N,N',N'-trimethyl-1-(2-methylalanyl-D-tryptophanyl)piperidine-3-carbohydrazide hydrochloride.

Molecular formula: C31H42N6O3·HCl

Molecular weight: 583.16

Properties: This product is a white to off-white solid, easily soluble in water, methanol, ethanol or N-methylpyrrolidone.

Storage method and validity period of Anamorelin

Store at room temperature, the validity period is 4 years.