Esbriet - instructions for use, dose, side effects, contraindications

Active substancePyrfenidonePyrfenidone

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Esbriet

capsules inwards

Hoffmann-La Roche Ltd. Switzerland

Dosage form: & nbspcapsules

Composition:

1 capsule contains:

active substance: pirfenidone - 267 mg;

Excipients: croscarmellose sodium - 26.5 mg, microcrystalline cellulose - 24.0 mg, povidone K29 / 32 - 6.0 mg, magnesium stearate - 1.5 mg;

capsule shell - 75.0 mg (lid, body - titanium dioxide E171 (2.91%), gelatin (up to 100%));

ink for inscription on the cap of the capsule: shellac, iron dye oxide black E172, iron dye oxide red E172, iron oxide dye yellow E172; commercially available inks can be used, for example, Opacode Brown identical composition.

Description:

Hard gelatin capsules, size 1. The capsule body and capsule are white or almost white in color, opaque. On the cap of the capsule there is an inscription "PFD 267 mg"Brown color.Capsule contents: powder from white to light yellow color.

Pharmacotherapeutic group:Immunosuppressive remedy

ATX: & nbsp

L.04.A.X.05 Pyrfenidone

Pharmacodynamics:

Mechanism of action

The mechanism of action of Esbriet is not fully established. However, existing data indicate that pyrfenidone exhibits antifibrotic and anti-inflammatory properties in a variety of systems in vitro and in animal models of pulmonary fibrosis (fibomycosis induced by bleomycin and transplantation).

Idiopathic pulmonary fibrosis (ILF) is a chronic fibrotic and inflammatory lung disease caused by the synthesis and release of pro-inflammatory cytokines, including tumor necrosis factor alpha (TNF-α) and interleukin-1-beta (IL-1β). It is proved that Esbriet is able to reduce the accumulation of inflammatory cells in response to various stimuli.

Esbriete drug weakens the proliferation of fibroblasts, the production of fibrosis-related proteins and cytokines, and increases the biosynthesis and accumulation of the interstitial matrix in response to cytokine growth factors, such as the transforming growth factor beta (TGFβ) and platelet growth factor (PDT).

Efficiency

The clinical efficacy of Esbriet was studied in three international multicenter, randomized, double-blind, placebo-controlled studies of the 3rd phase in patients with ILF.

In 2 studies (PIPF 004 and PIPF 006), Esbriet was administered 3 times a day (2403 mg / day) for a minimum of 72 weeks. The studies were almost identical in design with a few exceptions, including the group receiving the intermediate dose (1197 mg / day, study PIPF 004).The primary end point in both studies was a change in the forced vital capacity of the lungs (FVC) from baseline to 72 weeks in percent.

In the first study (PIPF 004), the percentage reduction in the calculated forced vital capacity (FVC) (the threshold indicative of the mortality risk with ILF) from baseline to 72 weeks of treatment was significantly less in patients receiving Esbriet (N= 174) compared with patients receiving placebo (N= 174; p = 0.001).

In the second study (PIPF 006), the percentage reduction in the calculated FVC from the baseline to the 24th week (p <0.001), before the 36th week (p = 0.011), and the 48th week (p = 0.005) decreased in the patients receiving Esbriet.

At the 72nd week, a decrease in FVC ≥10% were observed in 20% and 23% of patients receiving Esbriet and in 35% and 27% of patients receiving placebo (the first and second study, respectively). Reducing the distance in the 6-minute walk test from the baseline to the 72nd week was significantly lower compared to placebo (the distance was reduced to ≥50 m in 37% and 33% of patients receiving Esbriet (first and second study respectively), compared with 47% of patients receiving placebo (first and second studies)).

In a combined analysis of survival in two studies (PIPF 004 and PIPF 006), the death rate in the Esbriet treatment group at a dose of 2403 mg / day was 7.8% compared with 9.8% in the placebo group (0.77 [95% CI, 0.77% 1,28]) ..

In the third study (PIPF 016) Esbriet was used 3 times a day for 52 weeks (primary end point). The decrease in the percentage of calculated FVC from baseline to 52 weeks of therapy was significantly lower in patients receiving Esbriet (N= 278), compared with patients receiving placebo (N= 277; p = 0.000001). At the 52nd week, a decrease from baseline FVC in% ≥10% or a fatal outcome was observed in 17% of patients receiving Esbriet, compared with 32% of patients receiving placebo. The decrease in distance traveled in the 6-minute walk test from the baseline to the 52nd week was significantly less in patients receiving Esbriet than in patients receiving placebo (26% of patients receiving the Esbriet drug showed a decrease of ≥50 m in compared with 36% of patients receiving a placebo).

In a pre-determined pooled analysis of all three studies at 12 months, mortality from all causes was significantlower in the Esbriet treatment group 2403 mg / day (3.5%, 22 of 623 patients) compared with placebo (6.7%, 42 of 624 patients), i.e. the risk of death from all causes decreased by 48% during the first 12 months (RR 0.52 [95% CI, 0.31-0.87], p = 0.0107, log-rank test).

Preclinical safety data

Analysis of preclinical safety profile data, conducted on the basis of standard studies of safety pharmacology, repeated dose toxicity, genotoxicity and carcinogenic potential, did not reveal any danger to patients.

Carcinogenicity

Significant changes for patients were not detected.

Mutagenicity

Pyrfenidone showed no evidence of mutagenic or genotoxic activity in the standard test group and showed no mutagenicity in ultraviolet (UV) tests. When tested under UV pyrfenidone had a photoclastogenic effect in the lung cells of a Chinese hamster.

Impairment of fertility

In animals, the transfer of pyrfenidone and / or its metabolites is via the placenta with the possibility of accumulation in the amniotic fluid. At high doses (≥450 mg / kg / day), the estrous cycle was prolonged in rats,there was a high frequency of irregular cycles; at high doses (≥1000 mg / kg / day), gestation was prolonged, and the viability of the fetus decreased. During studies in lactating rats, it was found that pyrfenidone and its metabolites are excreted with milk and can accumulate in it.

Teratogenicity

Studies of toxicity in relation to the reproductive system did not show an undesirable effect on the fertility of males and females or the postnatal development of the offspring of rats. There is no evidence of teratogenicity in rats (1000 mg / kg / day) or rabbits (300 mg / kg / day).

Other

Phototoxicity and pruritus were noted in guinea pigs after administration of pyrfenidone into the interior and exposure to ultraviolet rays of spectrum A and B (UVA / UVB). The severity of phototoxic damage was minimized with the help of sunscreens.

Pharmacokinetics:

Suction

Taking Esbriet with food leads to a greater decrease in the maximum concentration in the plasma (C_mOh) (by 50%) and less impact on the area under the concentration-time curve (AUC) in comparison with the administration of the drug on an empty stomach. When a single dose of 801 mg was used in healthy older volunteers (50-66 years), the rate of absorption of pyrfenidone slowed down after eating, whereas the value AUC After meals, it was approximately 80-85% of AUC on an empty stomach. After eating, there was a decrease in the incidence of adverse events (nausea and dizziness) compared with the use of the drug on an empty stomach. Thus, the preparation Esbriet is recommended to be taken with food to reduce the frequency of nausea and dizziness.

Bioavailability of pyrfenidone in humans was not determined.

Distribution

Pyrfenidone binds to human plasma proteins, predominantly with serum albumin. The overall average binding level varied from 50% to 58% at concentrations observed in clinical studies (1-100 μg / ml). The average apparent volume of distribution in the equilibrium state after oral administration was approximately 70 liters, indicating a moderate distribution of pirfenidone in the tissues.

Metabolism

During the study of metabolism in vitro with hepatic microsomes, it was found that pyrfenidone metabolized mainly through isoenzyme CYP1A2 with less participation of other isoenzymes CYP, including isozymes CYP2C9, 2C19, 2D6 and 2E1. Research in vitro and in vivo To date, no activity of the main metabolite (5-carboxy-pyrphenidone) has been detected even with the use of doses and concentrations exceeding those,related to the activity of pyrphenidone itself.

Excretion

The clearance of pyrfenidone for oral administration is moderately saturated. In a study on the selection of a range of multiple doses in healthy older volunteers (doses of 267 mg to 1335 mg 3 times a day), the average clearance was reduced by about 25% when a dose greater than 801 mg was administered 3 times a day. After applying a single dose of pyrfenidone to healthy older volunteers, the average apparent terminal elimination half-life was approximately 2.4 hours. Approximately 80% of pirfenidone administered orally is excreted by the kidneys within the next 24 hours. The greatest amount of pyrfenidone is released as a metabolite of 5-carboxy-pyrphenidone (> 95% of the isolated one), less than 1% of pyrphenidone is excreted by the kidneys unchanged.

Pharmacokinetics the special patient groups

Impaired liver function

In the study of the pharmacokinetics of pyrphenidone and the metabolite of 5-carboxy-pyrphenidone in patients with moderate impaired liver function (class B on the Child-Pugh scale) and without disturbing the liver, an average increase in exposure of pyrphenidone by 60% after a single dose of 801 mg of pyrfenidone 3x267 mg) in patients with moderate impairment of liver function. Pyrfenidone should be used with caution in patients with mild and moderate impairment of liver function and carefully observe signs of toxicity in patients, especially when concurrently taking inhibitors of the isoenzyme CYP1A2 (see the sections "Dosage and administration" and "Special instructions").

Impaired renal function

In patients with impaired renal function from mild to severe, no clinically significant differences in the pharmacokinetics of pyrfenidone were found (compared to patients with normal renal function). The starting drug was predominantly metabolized to 5-carboxy-pyrphenidone, and the pharmacokinetics of this metabolite changed in patients with impaired renal function of moderate severity or with severe renal dysfunction. However, the estimated amount of accumulated metabolite in the equilibrium state did not affect pharmacodynamics, since the terminal half-life in these patients is only 1-2 hours. In patients with impaired renal function from mild to severe severity, pyrfenidone, dose adjustment is not required. Pyrfenidone Do not use in patients with severe renal insufficiency (creatinine clearance (CK) <30 mL / min) or with terminal stage of kidney disease requiring dialysis.

Population pharmacokinetic analysis in healthy volunteers, patients with renal insufficiency and patients with ILF showed no clinically significant effect of age, sex or body surface area on the pharmacokinetics of pyrfenidone.

Indications:

Idiopathic pulmonary fibrosis in adults.

Contraindications:

- Hypersensitivity to pirfenidone or any component of the drug;

- aboutsimultaneous use of fluvoxamine (see section "Interaction with other drugs");

- tsevere renal failure (CK <30 mL / min);

- tthe terminal stage of kidney disease requiring dialysis;

- tsevere hepatic impairment;

- tterminal stage of liver disease;

- tosuction;

- aboutsimultaneous application of powerful isoenzyme inducers CYP1A2;

- bPregnancy and the period of breastfeeding.

Carefully:

Mild or moderate impairment of liver function (class A and B on the Child-Pugh scale).

Simultaneous use of ciprofloxacin in a dose of 250 mg or 500 mg 1 or 2 times a day.

Simultaneous use of moderate isoenzyme inhibitors CYP1A2.

Pregnancy and lactation:

There are no data on the use of Esbriet in pregnant women.

Animals transmit pyrphenidone and / or its metabolites through the placenta with possible accumulation of pyrfenidone and / or its metabolites in the amniotic fluid. When high doses of the drug are administered (> 1000 mg / kg / day), the gestation is prolonged in the rats and the viability of the fetus decreases. It is necessary to avoid the use of the drug during pregnancy.

Fertility

During preclinical studies, undesirable effects on fertility were not observed (see section "Pharmacological properties").

Breastfeeding period

It is not known whether pyrfenidone or its metabolites with breast milk. Available pharmacokinetic data in animals showed the excretion of pyrphenidone and / or its metabolites with breast milk and the possibility of accumulating pyrfenidone and / or metabolites in milk (see section "Pharmacological properties"). It is impossible to exclude the risk for infants.

The decision to terminate breastfeeding or prescribe Esbriet should be made taking into account the benefits of breastfeedingfeeding for the child and the benefit of therapy with the drug for the mother.

Dosing and Administration:

Capsules of Esbriet should be taken with food (to reduce the feeling of nausea and dizziness), swallowing whole and with water (see the sections "Side effect" and "Pharmacological properties").

Standard dosing regimen

Adults

At the beginning of therapy, the dose of the drug should be gradually increased to the recommended daily dose of 9 capsules per day for 14 days as follows:

- Days 1-7: one capsule 3 times a day (801 mg / day)

- Days 8-14: two capsules 3 times a day (1602 mg / day)

- Day 15 and further: three capsules 3 times a day (2403 mg / day)

The recommended daily dose of Esbriet for patients with ILF is three capsules of 267 mg three times daily with food, totaling 2403 mg / day.

It is not recommended to apply the drug at a dose of more than 2403 mg / day.

Patients who missed 14 or more days of Esbriet therapy should be re-started with initial 2-week titration to the recommended daily dose.

If interrupted for less than 14 consecutive days, therapy can be resumed at the previous recommended daily dose.

Correction of dose

Disorders from the gastrointestinal tract

Patients with intolerance of therapy due to adverse events from the gastrointestinal tract need to be reminded of the need to take the drug with food.

If these symptoms persist, the dose of Esbriet can be reduced to 1-2 capsules (267 mg - 534 mg) 2-3 times a day with food with a second increase to the recommended daily dose, depending on the tolerability.

If these symptoms persist, it is recommended that the treatment be discontinued for 1-2 weeks before the symptoms resolve.

Photosensitivity reactions or rash

Patients with mild or moderate photosensitivity reactions or with a rash should be reminded of the need to use sunscreen products and avoid exposure to sunlight (see section "Special instructions"). The dose of Esbriet can be reduced to 3 capsules / day (1 capsule 3 times a day). If the rash persists for more than 7 days, Esbriet therapy should be discontinued for 15 days with a second dose increase up to the recommended daily dose, guided by the above recommendations.

Patients with severe photosensitivity reactions or rash should stop taking the drug and seek medical help (see section "Special instructions").After resolving the rash, Esbriet can be used again with a second dose increase up to the recommended daily dose as decided by the doctor.

Disorders from the side of the liver

In the case of a significant increase in the activity of alanine aminotransferase and / or aspartate aminotransferase (ALT / AST) with an increase in the concentration of bilirubin or without it, the dose of Esbriet should be adjusted or discontinued.

Recommendations in case of increased ALT activity, ACT and serum bilirubin concentrations.

When the activity of aminotransferases increases from> 3 to ≤5xVGN (upper limit of the norm) after the beginning of therapy with Esbriet, it is necessary to cancel the concomitant medications that could cause the development of this disorder, exclude other causes and carefully observe the patient. In case of clinical necessity, the dose of Esbriet should be reduced or interrupted. Once the "hepatic" tests are normalized, the dose of Esbriet can be re-raised to the recommended daily dose with tolerability.

When the activity of aminotransferases increases to ≤5xVGN (upper limit of the norm) in combination with clinical symptoms or hyperbilirubinemia,and also when the activity of aminotransferases> 5xVGN is increased, Esbriet therapy should be abolished and not restarted again.

Dosing in special cases

Patients of elderly and senile age

Patients aged 65 years and older are not required to adjust the dose (see section "Pharmacological properties").

Impaired liver function

Patients with mild and moderate impairment of liver function (ie, class A and B on the Child-Pugh scale) do not need dose adjustment. However, since in some patients with mild or moderate impairment of liver function, the concentration of pyrfenidone in the plasma may increase, caution should be exercised when treating Esbriet in this population. Patients should be carefully monitored for signs of toxicity, especially when combined intake of inhibitors of isoenzyme CYP1A2 (see the sections "Interaction with other drugs" and "Pharmacological properties").

The use of Esbriet in patients with severe impairment of liver function or terminal liver failure has not been studied, and the drug should not be used in such conditions (see section "Special instructions" and "Pharmacological properties").

During treatment it is necessary to monitor liver function, if the activity of "liver" enzymes is increased, a dose adjustment may be required (see section "Special instructions" and subsection "Pharmacokinetics in special patient groups").

Impaired renal function

Patients with mild to moderate renal insufficiency do not need dose adjustment. Esbriet therapy should not be given to patients with severe renal impairment (creatinine clearance <30 mL / min) or terminal stage of kidney disease requiring dialysis (see subsection "Pharmacokinetics in special patient groups").

Side effects:

The most frequent adverse events in the clinical trials of Esbriet at a dose of 2403 mg / day compared with placebo were nausea (32.4% and 12.2%, respectively), rashes (26.2% and 7.7%), Diarrhea (18.8% and 14.4%), fatigue (18.5% and 10.4%), dyspepsia (16.1% and 5.0%), anorexia (11.4% and 3.5% ), headache (10.1% and 7.7%) and photosensitivity reactions (9.3% and 1.1%).

In clinical trials, serious adverse events were recorded at the same frequency in patients receiving Esbriet at a dose of 2403 mg / day and patients in the placebo group.

The following categories are used to describe the frequency of unwanted reactions: very often (≥1/10), often (≥1 / 100 and <1/10), infrequently (≥1 / 1000 and <1/100), rarely (≥1 / 10000 and <1/1000), very rarely (<1/10000, including individual cases).

Infectious and parasitic diseases: often - infections of the upper respiratory tract; urinary tract infection.

Violations from the blood and lymphatic system: rarely - agranulocytosis *.

Immune system disorders: infrequently - angioedema.

Disorders from the metabolism and nutrition: very often - anorexia; often - weight loss, loss of appetite.

Disorders of the psyche: often - insomnia.

Impaired nervous system: very often - headache; often - dizziness, drowsiness, dysgeusia (a taste disorder), apathy.

Disorders from the cardiovascular system: often - hot flushes.

Disturbances from the respiratory system, chest and mediastinal organs: often - shortness of breath, cough, productive cough.

Disorders from the gastrointestinal tract: very often - dyspepsia, nausea, diarrhea; often vomiting, gastroesophageal reflux disease, abdominal pain (including pain in the upper abdomen), abdominal pain, bloating, flatulence, discomfort, gastritis, constipation.

Disturbances from the liver and bile ducts: often - increased activity of ALT, ACT, gammaglutamintransferase; rarely - an increase in the concentration of bilirubin together with an increase in the concentration of ALT and ACT * activity.

Disturbances from the skin and subcutaneous tissues: very often - rashes, photosensitivity reactions; often erythema, itching, dry skin, erythematous rash, macular rash, itching rash.

Disturbances from musculoskeletal and connective tissue: often - arthralgia, myalgia.

General disorders and disorders at the site of administration: very often fatigue; often - extracardiac pain in the chest, asthenia.

Trauma, intoxication and complications of manipulation: often - sunburn.

* Adverse events identified during post-marketing surveillance.

Overdose:

Clinical experience associated with overdose is limited.

When multiple doses of Esbriet were used in healthy adult volunteers (12-day period of dose increase, maximum dose of 4806 mg / day), the adverse events observed were of mild severity, transient in nature, and corresponded to the most frequent adverse reactions to Esbriet.

In the event of an alleged overdose, symptomatic care should be provided, including monitoring vital signs, and careful monitoring of the clinical condition of the patient.

Interaction:

Pirfenidone is primarily metabolized by isoenzyme CYP1A2 with a small participation of other CYP isoenzymes, including CYP2C9, 2C19, 2D6 and 2E1.

Fluvoxamine and inhibitors of isoenzyme CYP1A2

The combined use of Esbriet and fluvoxamine (a potent inhibitor of the isoenzyme CYP1A2 with a depressing effect on other isoenzymes CYP [CYP2C9, 2C19 and 2D6]) led to a 4-fold increase in the exposure of pyrfenidone in non-smoking patients.

Esbriet is contraindicated in patients with the concomitant use of fluvoxamine (see "Contraindications"), treatment with fluvoxamine should be discontinued before the beginning of Esbriet therapy and do not take fluvoxamine during therapy with Esbriet due to decreased clearance of pyrfenidone.

Powerful and selective inhibitors of isoenzyme CYP1A2 can increase the exposure of pyrfenidone by about 2-4 times (data obtained by extrapolating the results of the study in vitro in conditions in vivo). If it is not possible to avoid the combined use of Esbriet with powerful and selective inhibitors of the isoenzyme CYP1A2, the dose of Esbriet should be reduced to 801 mg / day (one capsule three times a day). Careful observation of patients should be carried out to identify unwanted reactions associated with Esbriet therapy. If necessary, therapy with Esbriet should be discontinued (see the section "Dosing and Administration" and "Special instructions").

Simultaneous use of Esbriet and ciprofloxacin (a moderate and selective inhibitor of isoenzyme CYP1A2) in a dose of 750 mg resulted in an increase in the exposure of pyrfenidone by 81%. If it is impossible to avoid the use of ciprofloxacin 750 mg twice a day, the dose of Esbriet should be reduced to 1602 mg per day (two capsules three times a day).

Caution should be exercised when concomitant use of Esbriet and ciprofloxacin 250 mg or 500 mg once or twice a day, as well as simultaneous use of Esbriet and moderate isoenzyme inhibitors CYP1A2.

Do not use Esbriet with drugs / combinations of drugs that are mild or potent inhibitors of both isoenzyme CYP1A2, and one or more other isoenzymes CYP, involved in the metabolism of pyrfenidone (i.e. CYP2C9, 2C19, 2D6 and 2E1).

Smoking and inducers of isoenzyme CYP1A2

Exposure of pyrfenidone in smokers (isoenzyme inducer CYP1A2) was 50% of that for non-smokers.

Smoking can increase the production of "liver" enzymes, thereby increasing the clearance and reducing the exposure of the drug Esbriet. It should avoid the concomitant use of powerful isoenzyme inducers CYP1A2, including smoking, during therapy with Esbriet, based on the reported interaction with smoking and its potential to induce isoenzyme CYP1A2. Patients should be advised to stop taking powerful isoenzyme inducers CYP1A2 and stop smoking before and during treatment with pyrphenidone.

Concomitant therapy with mild isoenzyme inducers CYP1A2 (eg, omeprazole) can theoretically lead to a decrease in the concentration of pyrfenidone in the blood plasma.

Simultaneous application of powerful isoenzyme inducers CYP1A2 and other isoenzymes CYP, involved in the metabolism of pyrfenidone (eg, rifampicin), can lead to a significant decrease in the concentration of pyrfenidone in the blood plasma.The simultaneous use of these medicines should be avoided.

Special instructions:

Liver function

In patients receiving Esbriet therapy, there was an increase in ALT activity and ACT > 3хВГН, rarely accompanied by an increase in the concentration of bilirubin. Functional "liver" tests (ALT, ACT and bilirubin) should be performed before the beginning of Esbriet therapy, then at intervals of once a month for the first 6 months and then at intervals of once every three months. In the case of a significant increase in the activity of "hepatic" transaminases, the dose of Esbriet should be adjusted or canceled. Patients with confirmed increases in ALT, ACT, or bilirubin during treatment may require a dose change (see the section "Dosing and Administration").

Photosensitivity reactions and rash

Avoid or minimize exposure to direct sunlight (including sunlight) during Esbriet therapy. Patients should be informed of the need to use effective sunscreens in the daytime, the use of clothing that protects against sun exposure and avoid other drugs that cause photosensitivity.Patients should be informed of the need to inform the attending physician about the symptoms of photosensitivity reactions or rashes. If photosensitivity reactions or rashes occur, you may need a dose adjustment or a temporary discontinuation of therapy (see the "Application and dosage" section).

Effect on the ability to drive transp. cf. and fur:

Studies of the effect of the drug on the ability to drive and work with mechanisms have not been conducted. The drug Esbriet can cause dizziness and fatigue, which can affect the ability to drive vehicles and work with mechanisms.

Form release / dosage:

Capsules, 267 mg.

Packaging:

270 capsules per bottle of high-density polyethylene (HDPE) white with a screw cap made of polypropylene, which opens when pressed. The method of opening the vial is shown on the lid in the form of a diagram with explanatory inscriptions.

The neck of the bottle to ensure the control of the opening is hermetically sealed with a two-layer membrane of polyester film and aluminum foil.

Each vial with the instruction for use is placed in a cardboard box.

Storage conditions:

Store at a temperature not exceeding 30 ° C.

Keep out of the reach of children.

Shelf life:

3 years.

Do not use after the expiration date printed on the package.

Terms of leave from pharmacies:On prescription

Registration number:LP-004030

Date of registration:22.12.2016

Expiration Date:22.12.2021

The owner of the registration certificate:Hoffmann-La Roche Ltd.Hoffmann-La Roche Ltd. Switzerland

Manufacturer: & nbsp

F.Hoffmann-La Roche, Ltd. Switzerland

Representation: & nbspF.Hoffmann-La Roche Ltd. F.Hoffmann-La Roche Ltd. Switzerland

Information update date: & nbsp20.01.2017

Illustrated instructions

Instructions

Esbriet (Esbriet®)