Celzentri - instructions for use, doses, side effects, contraindications

Active substanceMaravirocMaraviroc

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Pfizer Manufakchuring Deutschland GmbH Germany

Dosage form: & nbspfilm coated tablets.

Composition:

Name of substance	Quantity, mg / table
Name of substance	150 mg	300 mg
Active substance
Maraviroc	150,00	300,00
Excipients
Microcrystalline cellulose	282,00	564,00
Calcium hydrophosphate	142,50	285,00 .
Sodium carboxymethyl starch	18,00	36,00
Magnesium stearate	7,50	15,00
Fade blue (85G20583)	24,00	48,00
Composition of Fallen Blue
Polyvinyl alcohol	10,56	21,12
Talc	4,8	9,6
Titanium dioxide	4,63	9,26
Macrogol 3350	2,96	5,92
Soy lecithin	0,84	1,68
Aluminum lacquer based on indigo carmine	0,21	0,42

Description:

Dosage of 150 mg: blue capsular biconvex tablets, covered film shell, with engraving "150 MUS" on one side of the tablet. On the cross-section, two layers are visible. The core of the tablet is white.

Dosage of 300 mg: blue capsular biconvex tablets, covered film shell, with engraving "300 MUS" on one side of the tablet. On the cross-section, two layers are visible. The core of the tablet is white.

Pharmacotherapeutic group:An antiviral (HIV) agent.

ATX: & nbsp

J.05.A.X.09 Maraviroc

Pharmacodynamics:

Mechanism of action

Maraviroc belongs to the class of drugs - antagonists of chemokine receptors CCR5. Maraviroc selectively binds to chemokine receptors CCR5, preventing the entry of HIV-1, tropic to these receptors, inside the cell. Antiviral activity in cell culture

Inhibitory concentration at which the activity of the pathogen in vitro is suppressed by 90% (EU90), at 43 primary clinical isolates CCR5-TponHoro HIV-1 was 0.57 (0.06 - 10.7) ng / ml (non-cohesive fraction), with no significant changes between the various tested subtypes.

When combined with other antiretroviral drugs in cell culture maraviroc did not demonstrate antagonism with nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), HIV protease inhibitors (PIs), and HIV fusion inhibitors-enfuvirtide.

Resistance

The resistance of the virus to maraviroc can be manifested in two ways: by selecting a virus that can bind to chemokine receptors CXCR4 as a co-receptor for entry into the cell (CXCh4-tropic virus), or selection of a virus that continues to be used exclusively CCR5 receptors (CBC5-tropic virus) in the presence of maraviroc.

Resistance in cell culture

Variants of HIV-1, which have a reduced sensitivity to maraviroc, were selected in the culture of the cells by several passages of CXJ5-tropic clinical isolates of viruses. Viruses resistant to maraviroc remained CCR5-TponHbiMH, conversions CCR5-TponHoro the virus did not occur in CXSV4-tropic.

Phenotypic resistance: the curves of the inhibitory concentrations for maraviroc resistant viruses did not reach 100% oppression in the trials using the maraviroc dilution series.

Genotypic Resistance: the accumulation of mutations in the enveloped glycoprotein gpl20 (viral protein that binds to the co-receptor CCR5). Thus, the association of these mutations with sensitivity to maraviroc in other viruses is unknown. The position of these mutations in different isolates was not constant. Cross-resistance: all clinical isolates of HIV-1 resistant to NRTI, NNRTI, HIV and enfuvirtide, were sensitive to maraviroc in cell culture. Maraviroc resistant viruses in cell culture remained sensitive to the inhibitor of enfuvirtide fusion and to the HIV of saquinavir.

Resistance In vivo

Both ways of developing resistance were observed in clinical studies of maraviroc in both previously untreated patients and in patients with previous antiretroviral therapy.

The presence of CXS114-tropic virus in the failure of treatment is due to its presence in the original viral population.Conducting a test to exclude the presence of this variant of HIV before the appointment of maraviroc reduces the risk of failure of therapy associated with this pathway of resistance development. In patients with failure of therapy and having only 115-tropic viruses maraviroc can be considered as preserving activity if the maximum value of the inhibition index (MPI) > 95% (test Phenosense Entry). Residual activity in vivo for viruses with a value MPI <95% has not been determined.

Genotypic resistance: key mutations (in the loop V3) can not be indicated because of the high variability of the sequence V3 and a small number of samples analyzed.

Resistance in patients with prior antiretroviral therapy In pilot studies, 7.6% of patients who received antiretroviral therapy earlier, between the screening and the start of treatment (4-6 tropism of viruses with CCR5 on CXCR4 either double and / or mixed.

Pharmacokinetics:

Suction

Absorption of maraviroc is variable and has multiple peaks. The maximum concentration (C_max) in blood plasma is achieved on average after 2 hours with a single oral intake of 300 mg of maraviroc. When oral administration of maraviroc in a dose exceeding 1200 mg, the pharmacokinetics of the drug are non-linear.

The absolute bioavailability of the maraviroc in a dosage of 100 mg is 23% and the estimated bioavailability at a dosage of 300 mg is 33%. Maraviroc is a substrate for the transport P-glycoprotein, which ensures the release of substances from the cell.

Joint intake of 300 mg tablets with fatty foods during breakfast in healthy volunteers reduced C_max and AUC maraviroc by 33%. There were no restrictions on food intake in studies that demonstrated the effectiveness and safety of maraviroc. In this way, maraviroc can be taken at recommended doses regardless of food intake.

Distribution

Maraviroc binds (approximately 76%) to human plasma proteins and binds weakly to albumin and alpha-1-acid glycoprotein. The volume distribution of maraviroc is approximately 194 liters.

Metabolism

Research on humans and research in vitro using human liver microsomes and expressed enzymes demonstrated that maraviroc, is mainly metabolized by the cytochrome P450 system to metabolites that are not active against HIV-1. Research in vitro showed that isoenzyme CYP3A4 is the main isoenzyme responsible for the metabolism of maraviroc. At the same time, research in viti-o showed that polymorphic isozymes CYP2C9, CYP2D6 and CYP2C19 do not participate significantly in the metabolism of maraviroc.

Maraviroc is the main circulating substance (approximately 42 % radioactive fraction) after a single oral dose of 300 mg. The most significant circulating metabolite in humans is the secondary amine formed by N-dealkylation, and not having significant pharmacological activity. Other metabolites are products of monooxidation and are only minor components of the radioactive fraction of plasma.

Excretion

A mass balance and elimination study was performed using a single dose of 300 mg maraviroc, labeled ^,4C. About 20% is excreted by the kidneys, and 76% by the intestine within 168 hours. Maraviroc is the main substance present in the urine (an average of 8% of the dose) and feces (an average of 25% of the dose).

The rest is excreted in the form of metabolites. After intravenous administration (30 mg), the half-life of maraviroc was 13.2 hours, 22% of the dose was excreted unchanged by the kidneys, and the values of total clearance and renal clearance were 44.0 l / h and 10.2 l / h, respectively.

Pharmacokinetics in children

The pharmacokinetics of maraviroc in children under the age of 16 has not been studied.

Pharmacokinetics in the elderly

The pharmacokinetics of maraviroc in people older than 65 years is not established.

Impaired renal function

The pharmacokinetics observed in patients with severe renal insufficiency and the final stage of kidney disease were within the same range as in healthy volunteers with normal renal function, in studies on a single dose of 300 mg of maraviroc. In this regard, there is no need to adjust the dose of the drug in patients with renal insufficiency in the absence of potent inhibitors of the isoenzyme CYP3A4.

In patients with moderate renal insufficiency (and with extrapolation to patients with severe renal insufficiency), a dosing frequency exceeding 24 hours may result in inadequate pharmacokinetics in the 24-48 hour interval. Patients with renal failure receiving maraviroc together with powerful inhibitors of isoenzyme CYP3A4, a recommended dose of 150 mg every 24 hours.

Impaired liver function

Maraviroc is metabolized and excreted mainly by the liver. The study compared the pharmacokinetics of a single dose of 300 mg of maraviroc in patients with mild (Class A Child-Pugh classification, n = 8) and mean (Child-Pugh class B,n = 8) degrees of severity of liver dysfunction, in comparison with healthy patients (n = 8). The geometric mean C_max and the area under the concentration-time curve until the last measurement (AUCi_ast) were 11% and 25%, respectively, higher for patients with mild liver function impairment and 32% and 46% higher for patients with an average degree of impaired liver function compared to normal liver function. Influence of hepatic insufficiency of an average degree of gravity can be underestimated, because little data obtained from patients with reduced metabolic activity and with increased renal clearance. In patients with severe impairment of liver function, the pharmacokinetics of maraviroc were not studied.

Indications:

Treatment of HIV-infected patients who have not previously received or received antiretroviral therapy, infected with HIV-1 with tropism only to CCR5 Co-receptor in combination with other antiretroviral drugs.

Contraindications:

Hypersensitivity to maraviroc or any other component in the formulation. Simultaneous reception with preparations containing St. John's Wort. Maraviroc is not recommended for use in children under the age of 18 due to lack of data on efficacy and safety.

Carefully:

Use with caution in patients with an increased risk of developing cardiovascular disease, as well as in patients with cardiovascular disease.

In connection with the possibility of developing orthostatic hypotension, caution should be exercised when using maraviroc in patients with severe renal failure, orthostatic hypotension in anamnesis, or in patients taking medications leading to a reduction in blood pressure.

Because there is insufficient data on patients with concomitant hepatitis B or C, caution should be exercised in treating these patients with maraviroc. In the case of concomitant antiviral therapy for hepatitis B and / or C, you should also consult the relevant information on these drugs.

The experience of using the drug in patients with impaired liver function is negligible, in connection with which, maraviroc these patients should be used with caution.There are limited data on the safety and effectiveness of maraviroc in patients with impaired renal function, obtained in a comparative pharmacokinetic study. The study was conducted in patients with renal insufficiency and healthy volunteers taking maraviroc in combination with saquinavir + ritonavir. In general, the maraviroc was well tolerated, but in patients with renal insufficiency, the incidence of adverse events was higher (mostly unexpressed).

The risk of developing orthostatic hypotension is increased in patients with severe renal insufficiency, receiving boosted HIV and maraviroc. The greatest risk can be expected with the joint admission of maraviroc and HIV saquinavir, darunavir, lopinavir - all in combination with ritonavir. Patients with impaired renal function have a high risk of developing cardiovascular disease, which can be exacerbated by the presence of orthostatic hypotension.

Pregnancy and lactation:

Fertility

There is no evidence of the effect of Celzentri® on human fertility.

Pregnancy

Significant clinical data on the use of maraviroc during pregnancy are absent. Studies in animals have not revealed a direct or indirect adverse effect on pregnancy, embryo or fetal development, childbirth or postnatal development. Maraviroc should be used during pregnancy only if the potential benefit to the mother exceeds the potential risk to the fetus.

Lactation

It is not known whether maraviroc with breast milk. HIV-infected lactating women receiving maraviroc, it is recommended that breastfeeding be abandoned because of the risk of HIV transmission to the baby during breastfeeding and because of the risk of developing unwanted phenomena in children.

Dosing and Administration:

Inside, regardless of food intake.

Adults

Table 1. The dosage regimen of Celzentri® in combination with other drugs

Associated medications

The recommended dose of Celzentri®

Inhibitor inhibitors CYP3A (with isoenzyme inducer CYP3A or without it), including, but not limited to, the following drugs: delavirdine, boosted elvitegravir;

HIV (other than tipranavir + ritonavir), ketoconazole, itraconazole, clarithromycin and other potent inhibitors of isoenzyme CYP3A

150 mg twice daily

(nefazodone, telithromycin)
Inductors of isoenzyme CYP3A (without a potent inhibitor of isoenzyme CYP3A), including, but not limited to, the following drugs: efavirenz, rifampicin, carbamazepine, phenobarbital, phenytoin, etravirine	600 mg twice daily
Other concomitant medications that do not relate to potent inhibitors or potent isoenzyme inducers CYP3A, including tipranavir + ritonavir, nevirapine, raltegravir, all NRTIs and enfuvirtide	300 mg twice a day

Special patient groups

Children

The effectiveness and safety of the use of Celzentri ® in children under the age of 18 years have not been established. Therefore, use in children is not recommended.

Elderly patients

There is limited experience in patients older than 65 years. Therefore, care should be taken when prescribing Celzentri® in elderly patients.

Patients with impaired renal function

Patients with renal insufficiency taking potent inhibitors of isoenzyme CYP3A, such as:

- protease inhibitors, excluding tipranavir + ritonavir and fosamprenavir + ritonavir;

- delavirdine, boosted elvitegravir;

- ketoconazole, itraconazole, clarithromycin, nefazodone, telithromycin is recommended dosing regimen - once a day.

Celtzentri ® should be used with caution in patients with severe renal failure (creatinine clearance less than 30 ml / min) taking potent inhibitors of the isoenzyme CYP3A.

In patients with impaired renal function (creatinine clearance <80 ml / min), including the terminal stage of renal failure requiring hemodialysis, Use Celsentry® every 24 hours, If it is administered in combination with potent inhibitors of the isoenzyme CYP3A. In the absence of potent inhibitors of the isoenzyme CYP3A correction of the dose and the interval of reception of maraviroc is not required.

Table 2 shows recommendations for dose adjustment and intervals between doses.

Table 2. Multiplicity of correction of dosing for patients with impaired renal function.

Associated medications	Creatinine clearance < 80 ml / min *
Without powerful inhibitors of isoenzyme	There is no need to correct the interval between
CYP3A or together with	doses
tipranavir + ritonavir	300 mg every 12 hours
When combined with potent inhibitors of isoenzyme CYP3A, for example, with lopinavir + ritonavir, darunavir + ritonavir, saquinavir + ritonavir atazanavir + ritonavir, ketoconazole	150 mg once every 24 hours
When used in conjunction with	150 mg every 12 hours
fosamprenavir + ritonavir

* including patients with terminal stage of renal failure who need hemodialysis.

Patients with impaired hepatic function

Limited data in patients with mild to moderate hepatic impairment showed a slight increase in the mean C_max maraviroc, in this regard, it is assumed that dose adjustment is not required. Nevertheless, maraviroc should be used with caution in patients with hepatic insufficiency.

Side effects:

Maraviroc was studied in clinical trials of Phase III, involving 1374 HIV-1 positive patients. This included 426 patients with prior treatment experience and 360 patients without treatment experience who received 300 mg twice a day, as well as 400 patients with previous experience and 174 patients without treatment experience who received maraviroc 300 mg once a day. The maraviroc safety profile was determined on the basis of data from 786 HIV-1 infected patients who received maraviroc 300 mg twice a day.The evaluation of adverse events associated with therapy in adult patients infected with CC115 tropic HIV-1 was performed on the basis of the combined data of two Phase III studies, among previously treated patients (MOTIVATE 1 and MOTIVATE 2) and one study conducted in untreated patients (MERIT).

The adverse events presented below are listed in accordance with the damage to organs and organ systems and frequency of occurrence. Frequency of occurrence is defined as follows: very often (> 1/10), often (> 1/100 and <1/10), infrequently (> 1/1 000 and <1/100), rarely (> 1/10 000 and <1/1 000), very rarely (<1/10 000, including individual cases), is unknown (can not be estimated from available data). The following undesirable phenomena and laboratory indices are not classified depending on the duration of the drug exposure.

Patients previously treated

Table 3 and Table 4 present all the data obtained during the research MOTIVATE 1 and 2.

Table 3. Data on adverse events, all degrees of severity in patients with previous experience of treatment and who received maraviroc in a dose of 300 mg twice a day in combination with an optimized basal therapy (CBT) that occur with a frequency> 1 and a higher frequency than patients,who received placebo in combination with OBT alone (pooled data MOTIVATEl and MOTIVATE 2)

System-Organic grade		Unwanted phenomenon	Maximum frequency
Infectious	and	Pneumonia, esophageal candidiasis	Infrequently
parasitic
diseases
Benign,		Bile duct cancer, diffuse B -	Rarely
malignant	and	large cell lymphoma, disease
unspecified		Hodgkin's, metastases to the bone,
neoplasms		metastases in the liver, metastases in the
(including cysts	and	peritoneum, nasopharyngeal cancer, cancer
polyps)		esophagus

Violations of the blood and lymphatic system	Anemia	Often
Violations of the blood and lymphatic system	Pancytopenia, granulocytopenia	Rarely
Metabolic disorders	Weight loss, anorexia	Often
Disorders of the psyche	Depression, insomnia	Often
Disturbances from the nervous system	Peripheral neuropathy, dizziness, paresthesia, dysgeusia, drowsiness	Often
Disturbances from the nervous system	Epileptic seizure, epilepsy	Infrequently
Heart Disease	Angina pectoris	Rarely
Disturbances from the respiratory system, chest and mediastinal organs	Cough	Often
Infringements from gastrointestinal tract	Pain in the abdomen, bloating, constipation, indigestion	Often
Disturbances from the liver and bile ducts	Increased activity of alanine aminotransferase (ALT), aspartate aminotransferase (ACT), rise gamma glutamyl transferase (GGT)	Often
	Hyperbilirubinemia	Infrequently
	Toxic hepatitis, hepatic insufficiency, liver cirrhosis, increased alkaline phosphatase	Rarely
	Liver failure with	Rarely

	allergic manifestations
Disturbances from the skin and subcutaneous tissues	Rash, alopecia	Often
	Stevens-Johnson Syndrome	Rarely
	Toxic epidermal necrolysis	Unknown
Disturbances from musculoskeletal and connective tissue	Muscle spasms, back pain, pain in the limbs, increased activity of creatine phosphokinase in the blood	Often
Disturbances from musculoskeletal and connective tissue	Muscular atrophy	Rarely
Disorders from the kidneys and urinary tract	Renal insufficiency, proteinuria	Infrequently
General disorders and disorders at the site of administration	Asthenia, fatigue	Often

Deviations of laboratory parameters in patients who received previous treatment

Table 4. Clinically significant deviations in the laboratory values of grades 3 and 4 (criteria of the group of specialists in clinical AIDS research), detected in patients previously treated, with a frequency> 1%

Laboratory

index

Range

deviations

Power

Maraviroc twice a day + CBT N = 421¹ (%)

Monotherapy

OBT

N = 207 (%)

Lipase

> 2 х ВГН - 5 х ВГН

10/171 (5,8)

9/93 (9,7)

> 5 x VGN

3/173 (1,7)

0/93 (0)

Absolute number of neutrophils	0,5-0,75 x 10^j/ mm³	3	13/420 (3,1)	6/207 (2,9)
Absolute number of neutrophils	< 0,5 x 10³/ mm^j	4	5/420 (1,2)	0/207 (0)
Bilirubin	> 2 x VGN - 5 x VGN	3	24/421 (5,7)	10/207 (4,8)
	> 5 x VGN	4	4/421 (1,0)	3/207 (1,4)
ACT	>'5 x VGN - 10 x VGN	3	19/421 (4,5)	7/207 (3,4)
	> 10 x VGN	4	6/421 (1,4)	1/207 (0,5)

¹ % based on the total number of patients for each laboratory indicator. VGN - the upper limit of the norm.

OBT is an optimized basal therapy.

Research data MOTIVATE 1 and MOTIVATE 2 were disclosed after the visit of the 48th week of the last included patient, and suitable patients could go into the open phase with a maraviroc twice daily, continuing until the 96th week. The subsequent monitoring phase, lasting 5 years, was completed to assess the level of the ratio of long-term safety and selected endpoints (LTS / SE), AIDS, AIDS, hepatic failure, myocardial infarction, cardiac ischemia, malignant neoplasms, rhabdomyolysis and other serious infectious events associated with maraviroc therapy.The data level of the selected endpoints was comparable to the data of the 96th week.

Patients who were not previously treated

Table 5. Undesirable effects of moderate or more severe in patients who have not been treated before, with a frequency> 1%

System-Organ Class	Unwanted phenomenon	Frequency
Violations from the blood and	Anemia	Often
lymphatic system
Violations from the exchange	Anorexia	Often
substances

Disorders of the psyche	Depression, unusual dreams, insomnia	Often
Disturbances from the nervous system	Dizziness, headache, drowsiness	Often
Disorders from the gastrointestinal tract	Abdominal pain, constipation, dyspepsia, flatulence, nausea, diarrhea, vomiting	Often
Disturbances from the liver and bile ducts	Increased ALT activity, ACT	Often
Disturbances from musculoskeletal and connective tissue	Pain in the neck	Often
General disorders and disorders at the site of administration	Fatigue, asthenia	Often

Table 6. Clinically significant abnormalities in laboratory grade 3 or 4 (criteria for the team of specialists in clinical AIDS studies), detected in patients who had not previously received treatment, with a frequency> 1% (MERIT)

Laboratory indicator	Range of deviations	Ste stump	Maraviroc 300 mg twice daily N = 360¹ (%)	Efavirenz 600 mg once daily N = 361¹(%)
	> 5.0 x VGN - 10.0 x VGN			12/350 (3,4)
ALT	> 5.0 x VGN - 10.0 x VGN	3	11/353 (3,1)	12/350 (3,4)
	> 10.0 x VGN	4	3/353 (0,8)	2/350 (0,6)
ACT	> 5.0 x VGN - 10.0 x VGN	3	8/353 (2,3)	12/350 (3,4)

	> 10,0 x VGN	4	6/353 (1,7)	2/350 (0,6)
Creatine- nazi	> 10,0 x vgn- 20,0 x VGN	3	10/353 (2,8)	11/350 (3,1)
Creatine- nazi	> 10,0 x vgn- 20,0 x VGN	4	4/353 (1,1)	6/350 (1,7)
Serum amylase	> 2,0 x VGN-5,0 x VGN	3	14/352 (4,0)	20/350 (5,7)
Serum amylase	> 5,0 x VGN	4	1/352 (0,3)	1/350 (0,3)
Hemoglobin	6.5 - 6.9 g / dL	3	2/352 (0,6)	2/350 (0,6)
Hemoglobin	<6.5 g / dL	4	8/352 (2,3)	6/350 (1,7)
Absolute number of neutrophils	500-749 / mm³	3	15/352 (4,3)	14/349 (4,0)
Absolute number of neutrophils	<500 / mm³ D	4	5/352 (1,4)	3/349 (0,9)

'% based on the total number of patients for each laboratory indicator. VGN - the upper limit of the norm.

Other clinically significant adverse events of moderate or more severe severity occurring in less than 1% of adult patients taking maraviroc in the course of research, included the Stevens-Johnson syndrome.
In HIV-infected patients with severe immunodeficiency at the time of the introduction of combined antiretroviral therapy (CART), it is possible to develop an inflammatory response to asymptomatic or residual opportunistic infections (see section "Special instructions and precautions for use"). The safety results at week 240 corresponded to the results observed in week 96.

Post-registration data action against any of the major cytochrome P450 isoenzymes at clinically significant concentrations (CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and CYP3A4). Maraviroc does not have a clinically significant effect on the pharmacokinetics of midazolam, oral contraceptives (ethinyl estradiol and levonorgestrel), or to a ratio of 6 [3-hydroxy cortisol + cortisol in urine, suggesting no inhibition or induction of the isoenzyme CYP3A4 in vivo. At a higher exposure of maraviroc, it is impossible to exclude possible oppression of the isoenzyme CYP2D6. Based on the data obtained in vitro and in clinical studies, the likelihood of maraviroc's influence on the pharmacokinetics of concomitant drugs is low. When using maraviroc without isoenzyme inhibitors CYP3A, its renal clearance is approximately 23%. Since both passive and active mechanisms are involved, there is a likelihood of competition for excretion with other active substances that are excreted by the kidneys.

However, the concomitant use of maraviroc with tenofovir (a substrate excreted by the kidneys) and co-trimoxazole (contains trimethoprim, an inhibitor of renal cationic transport) does not affect the pharmacokinetics of maraviroc.

In addition, the combined use of maraviroc with lamivudine + zidovudine did not show the effect of maraviroc on the pharmacokinetics of lamivudine (excreted mainly by the kidneys) or zidovudine (non-cytochrome P450 metabolism and renal clearance). Maraviroc inhibits in vitro P-glycoprotein (EC50 is 183 μmol / l). but maraviroc has no significant effect on the pharmacokinetics of digoxin in vivo, suggesting that maraviroc is neither an inhibitor nor an inducer of P-glycoprotein activity.

Interaction:

Table 7. Interaction with other drugs and recommendations for their dosing.

Medicinal products	Change in influence on the level	Recommendations for
drugs	medication, mean	joint application
(dose	geometric ratio (90%
maraviroc,	confidence interval CI),
using	unless otherwise specified;
in	AUC12 (μg x hour / ml) and
research)	Stach (μg / ml) BY RELATION TO initial value: - does not change f - increases 1 - decreases

ANTIRETROVIRAL PREPARATIONS YOU

NRTI

Lamivudine, 150 mg 2 times per day

(maraviroc, 300 mg twice daily)

AUCn lamivudine: <-> 1.13 (0.98, 1.32)

FROM_tOh lamivudine: 1.16 (0,88; 1.54) Maraviroc concentration was not determined, no effect expected

300 mg maraviroc twice daily¹.

There is no clinically significant interaction (observed or expected) from interaction with NRTIs.

Tenofovir, 300 mg once daily

(maraviroc, 300 mg twice daily)

AUC12 maraviroc: <-> 1.03 (0.98, 1.09)

Stach maraviroc: <-> 1.03 (0.90, 1.19) Tenofovir concentration was not determined, no effect is expected.

Zidovudine,

300 mg twice a day

(maraviroc, 300 mg twice daily)

AUCn zidovudine: <-> 0.98 (0.79; 1,22)

Stach zidovudine: <-> 0.92 (0,68; 1.24) The concentration of maraviroc was not determined, no effect is expected.

INHIBITORS

INTEGRATION

Elvitegravir + ritonavir 150 mg + 100 m g

1 once a day (maraviroc, 150 mg 2 times a day)

Maraviroc AUCi₂: |2,86 (2,33-3,51) Maraviroc FROM_max: |2,15 (1,71-2,69) Maraviroc C ^: | 4.23 (3.47-5.16)

Elvitegravir AUC24: <->1,07 (0,96-18)

Elvitergravir S_max: <->1,01 (0,89-1,15)

Elvtegravir S24: <->1,09 (0,95-1,26)

150 mg maraviroc 2 once a day with concomitant use with boosted elvitergraver.

Raltegravir 400 mg twice daily

(maraviroc,

Maraviroc AUCi₂: 1 0,86 (0,80; 0,92) Maraviroc C_max: | 0,79 (0,67; 0,94) Raltegravir AUC12: | 0,63 (0,44; 0,90)

300 mg maraviroc twice daily¹.

There is no clinically significant interaction (observed

300 mg twice a day)	Raltegravir C_max: 0,67 (0,41; 1,08) Raltegravir C \ r. 4 0,72 (0,58; 0,90)		or expected).
Nniot
Efavirenz, 600 mg once a day (maraviroc, 100 mg twice daily)		AUC12 maraviroc: 4 0.55 (0.49, 0.62) Maraviroc Stach: 4 0.49 (0.38, 0.63) Efavirenz concentration was not measured, no effect is expected.	The dose of maraviroc should be increased to 600 mg twice a day with concomitant use with efavirenz and in the absence of potent inhibitors of the isoenzyme CYP3A4. For combination with efavirenzem and HIV, see below.
Etravirine 200 mg twice daily (maraviroc, 300 mg twice daily)		Maraviroc AUC) ?: 4 0,47 (0,38; 0,58) Maraviroc C_max: 4 0,40 (0,28; 0,57) Etravirine AUCi₂: "->- 1,06 (0,99; 1,14) Etravirin C_max: <-" 1,05 (0,95; 1,17) Etravirine FROM]₂: <-*- 1,08 (0,98; 1,19)	The dose of maraviroc should be increased to 600 mg 2 times a day when combined with etravirine and in the absence of potent inhibitors of the isoenzyme CYP3A4. For combination with etravirine and HIV, see below.
Nevirapine 200 mg 2 times a day (single dose maraviroc, 300 mg)		AUC12 maraviroc: <- "is comparable to the control. The Maraviroc Stach: t in comparison with the control. The concentration of nevirapine was not measured, no effect is expected.	300 mg maraviroc twice daily¹.
Delavirdine		There are limited data on the joint use of delavirdine and maraviroc. Population pharmacokinetic analysis of phase III showed that a decrease in the dose of maraviroc when combined with delavirdine	150 mg maraviroc twice daily.

	shows the same exposure as the application of maraviroc without delavirdine in a usual dose.
iptvich
Atazanavir,	AUC12 maraviroc: f 3,57 (3,30;	150 mg maraviroc 2 times in
400 mg 1 time per	3,87)	day with a joint admission with
day	The Maraviroc Stach: f 2,09 (1,31; 4,19)	or
(maraviroc,	Concentration of atazanavir is not	unprotected HIV
300 mg 2 times in	determined, the impact is not	the exclusion of
day)	expected.	applications from
Nelfinavir	Data on the joint	tipranavir + ritonavir.
	with nelfinavir	when should I use
	are limited. Nelfinavir is	a dose of 300 mg 2 times a day.
	powerful inhibitor of isoenzyme	Maraviroc does not render
	CYP3A4, and it is expected that it will	significant impact on
	increase the concentration of maraviroc.	concentration of HIV.
Indinavir	Data on sharing with indinavir is limited. Indinavir is
	powerful inhibitor of isoenzyme CYP3A4. Data from population pharmacokinetic analysis during phase III studies suggest that when combined with indinavir, a dose reduction of maraviroc is required.	D
Atazanavir + ri	AUCj2 maraviroc: \| 4.88 (3.28;
tonavir,	6,49)
300 mg + 100 mg	FROM_thatx maraviroc: f 2,67 (1,72; 2,55)
1 time per day	Concentrations
(maraviroc,	atazanavir + ritonavir is not
300 mg twice a day)	measured, no effect is expected.

Lopinavir + ri	AUCn maraviroc: \| 3.95 (3.43;	150 mg maraviroc 2 times in
tonavir,	4,56)	day with a joint admission with
400 mg + 100 mg	FROM_tah maraviroc: f 1,97 (1,66; 2,34)	HIV IP, except for
2 times a day	Concentration	joint application with
(maraviroc,	lopinavir + ritonavir is not	tipranavir + ritonavir.
100 mg twice a day)	measured, no effect is expected.	when you should use a dose of 300 mg 2 times a day. Maraviroc does not have a significant effect on HIV-specific HIV concentrations.
Saquinavir + ri tonavir, 1000 mg + 100 mg	AUCn maraviroc: \| 9.77 (7.87, 12.1) FROM_max maraviroc: \| 4.78 (3.41, 6.71)
2 times a day	Concentrations
(maraviroc,	saquinavir + ritonavir is not
100 mg twice a day)	measured, no effect is expected.
Darunavir + rhythm	AUCn maraviroc: f 4,05 (2,94;
onavir,	5,59)
600 mg + 100 mg	The Maraviroc Stach: \| 2.29 (1.46, 3.59)
2 times a day	Concentrations
(maraviroc,	darunavir + ritonavir
150 mg 2 times in	corresponded to historical
day)	data.	g
Fosamprenavir	AUC12 maraviroc: \| 2.49
+ ritonavir 700	(2,19-2,82)
mg + 100 mg	The Maraviroc Stach: j 1,52 (1,27-1,82)
2 times a day	FROM12 maraviroc: \ 4,74 (4,03-5,57)
(maraviroc 300 mg 2 times in	AUCn amprenavir: J, 0,65
day)	(0,59-0,71) The stance of amprenavir: j. 0.66 (0.59-0.75) C amprenavir: 1 0,64 (0,57-0,73)
	AUC12 ritonavir: \| 0.66 (0.58-0.76) The rate of ritonavir: 1 0.61 (0.50-0.73)

	St of ritonavir: <-> 0.86 (0.14-5.28)	-
Fosamprenavir + ritonavir 1400 mg + 100 mg once daily (maraviroc 300 mg once a day)	AUC₂4 maraviroc: f 2,26 (1,99-2,58) C_max maraviroc: T 1.45 (1.20-1.74) C₂₄ maraviroc: f 1,80 (1,53-2,13) AUC₂4 amprenavir: 4 0,70 (0,64-0,77) C_max amprenavir: 4 0.71 (0.62-0.80) C₂4 amprenavir: 4 0,85 (0,75-0,97) AUC₂4 ritonavir: 4 0.70 (0.61-0.80) The ritonavir stan: 4 0.69 (0.57-0.84) C₂4 ritonavir: <-> - 2.66 (0.41-17.23)	-
Tipranavir + ri	AUCi₂ maraviroc: 1.02 (0.85;	300 mg maraviroc twice daily
tonavir	1,23)	day¹.
500 mg + 200 mg	FROM_tah maraviroc: 0.86 (0.61, 1.21)
2 times a day	Concentrations
(maraviroc,	tipranavir + ritonavir
150 mg 2 times in	corresponded to previous
day)	data.
nniot + ipvich
Efavirenz,	AUCi₂ maraviroc: \| 2.53 (2.24;	150 mg maraviroc 2 times in
600 mg 1 time per	2,87)	day with simultaneous
day +	The Maraviroc Stach: \| 1.25 (1.01, 1.55)	with or with
lopinavir + ri-	Concentrations of efavirenz and	efavirenzem or etravirine and
tonavir,	lopinavir / ritonavir is not	a protease inhibitor (for
400 mg + 100 mg	measured, no effect is expected.	exclusion
2 times a day		fosamprenavir + ritonavir,
(maraviroc,		the dose must be
300 mg 2 times in		300 mg twice a day
day)		or tipranavir + ritonavir,

Efavirenz,	AUC12 maraviroc: \| 5.00 (4.26;	the dose must be
600 mg 1 time per	5,87)	600 mg 2 times in
day +	FROM_thatx maraviroc: \| 2.26 (1.64, 3.11)	day).
saquinavir + ri	Concentrations of efavirenz and
tonavir,	saquinavir + ritonavir is not
1000 mg + 100 mg twice daily	measured, no effect is expected.
(maraviroc, 100 mg twice daily)
Efavirenz and	Not studied. Based on the data
atazanavir + rhythm	on the degree of oppression
onavir or	atazanavir + ritonavir or
darunavir + rhythm	darunavir + ritonavir in
onavir	absence of efavirenz, the concentration of maraviroc is expected to increase.
Etravirine and	AUCi? maraviroc_: T 3,10 (2,57;
darunavir + rhythm	3,74)
onavir	FROM_tah maraviroc: T 1.77
(maraviroc	AUCn Etravirine: <- * - 1.00 (0.86;
150mg 2 times in	1,15)
day)	Eta etavirine: 1.08 (0.98, 1.20) C etravirine: \| 0.81 (0.65, 1.01) AuC ^ darunavir: 1 0,86 (0,76; 0,96) FROM_thatdarunavir: <-> 0.96 (0.84, 1.10) Spdarunavir: \| 0.77 (0.69, 0.85) AUC12 ritonavir: <-> 0.93 (0.75, 1.16) The ritonavir stan: <- "- 1.02 (0.80, 1.30) C12 ritonavir: \| 0.74 (0.63, 0.86)

Etravirine and lopinavir + rhytavir, saquinavir + ri tonavir or atazanavir + rhytavir	Not studied. Based on data on the degree of oppression lopinavir + ritonavir, saquinavir + ritonavir or atazanavir + ritonavir in the absence of etravirine, an increase in the concentration of maraviroc is expected.
ANTIBACTERIAL PREPARATIONS
Sulfamethoxa-	AUC12 Maraviroc: <-> ■ 1.11 (1.01;	300 mg maraviroc twice daily
ashes + trimethop-	1,21)	day
Rome,	The Maraviroc Stach: 1.19 (1.04, 1.37)
800 mg + 160 mg	Concentrations of sulfamethoxazole
2 times a day	+ trimethoprim were not measured, so
(maraviroc, 300 mg twice daily)	as influence is not expected.
Rifampicin,	AUC maraviroc: \| 0.37 (0.33, 0.41)	600 mg maraviroc twice daily
600 mg 1 time per	Cmdx maraviroc: J, 0,34 (0,26; 0,43)	day When joint
day	Rifampicin concentrations are not	use with rifampicin
(maraviroc,	measured effects are not expected.	in the absence of a powerful
100 mg 2 times in		inhibitor of isoenzyme
day)		CYP3A4. This dose adjustment has not been studied in patients with HIV.
Rifabutin + FE	The combination was not studied.	150 mg maraviroc 2 times in
HIV	Rifabutin is weaker	day with a joint
	inducer of microsomal	with rifabutin and
	liver enzymes than	IP (excluding
	rifampicin. When combining	tipranavir + ritonavir, with
	rifabutin with HIV-1, which	this dose should be 300 mg
	are potent inhibitors of the isoenzyme CYP3A4, An inhibitory effect against maraviroc is expected.	2 times a day)

Clarithromycin, telithromycin	The combination has not been studied, but both are potent inhibitors of the isoenzyme CYP3A4, and an increase in the concentration of maraviroc is expected.	150 mg maraviroc twice daily
ANTI-GRIB1	YOUNG PREPARATIONS
Ketoconazole, 400 mg once daily (maraviroc, 100 mg twice daily)	AUC_tau maraviroc: ] 5,00 (3,98; 6,29) The Maraviroc Stach: \| 3.38 (2.38, 4.78) Ketoconazole concentration was not measured, since no effect is expected.	150 mg maraviroc twice daily.
Itraconazole	The combination was not studied. Itraconazole is a potent inhibitor of isoenzyme CYP3A4 and it is expected that it will increase the concentration of maraviroc.	150 mg maraviroc twice daily.
Fluconazole	Fluconazole is a mild isoenzyme inhibitor CYP3A4. Population pharmacokinetic studies suggest that correction of the dose of maraviroc is not required.	300 mg maraviroc 2 times a day clinically significant interaction with fluconazole is not expected
ANTI-VIRUS PRECAUTIONS OF YOU
Means for treatment of viral hepatitis C	Combination with pegylated interferon and ribavirin has not been studied, no interaction is expected.	300 mg maraviroc twice daily¹.
PREPARATIONS, IN	CONTRACTING DEPENDENCE
Methadone	The combination was not studied, no interaction is expected.	300 mg maraviroc twice daily¹.
Buprenorphine	The combination was not studied,	300 mg maraviroc twice daily

	interaction is not expected.	day.
HYPOLI PIDEA	YOUR PRECAUTIONS
Statins	The combination of drugs has not been studied, no interaction is expected.	300 mg maraviroc twice daily¹.
ANTIARITHMICH	YOUR PREPARATIONS YOU
Digoxin 0.25 mg single dose (maraviroc, 300 mg twice a day)	AUC_t digoxin: <-> 1.00 The digoxin stag: <-+1.04 The concentration of maraviroc was not measured, since no effect is expected.	300 mg maraviroc twice daily¹.
ORAL CONTRACEPTIVES
Ethinyl estradiol l, 30 mcg once a day (maraviroc, 100 mg twice a day)	AUC12 ethinylestradiol:_: <-" 1,00 (0,95; 1,05) The ethylene estradiol ethanol: <-> 0.99 (0.91, 1.06) Concentrations of maraviroc were not determined, no interaction is expected.	300 mg maraviroc twice daily¹.
Levonorgestrel, 150 mcg once a day (maraviroc, 100 mg twice a day)	AUC12 levonorgestrel:_: <-> 0,98 (0,92; 1,04) FROM_gaah levonorgestrel: 1.01 (0.93, 1.08) Concentrations of maraviroc were not determined, no interaction is expected.	300 mg maraviroc twice daily¹.
BENZODIAZESH	pennies
Midazolam, 7.5 mg, single reception (maraviroc, 300 mg 2 times in	AUC midazolam: <-> 1.18 (1.04, 1.34) The midazolam stan: <-> 1.21 (0.92, 1.60) Maraviroc concentrations were not determined, no interaction is expected.	300 mg maraviroc twice daily¹.

day)

PREPARATIONS ON THE VEGETABLE BASIS

St. John's Wort

perforated

the

(Hypericum

perforatum)

It is suggested that the combined use of maraviroc and St. John's wort can partially reduce the concentration of maraviroc to a suboptimal level, which can lead to the loss of virologic control and possible resistance to maraviroc.

It is not recommended joint use of maraviroc and St. John's wort perfumed or products containing it.

¹ When combined with powerful inhibitors and / or inducers of isoenzyme CYP3A4, the dosage regimen should be observed according to Table 1 of the "Method of administration and dose".

Special instructions:Therapy should be performed by a physician with experience in the treatment of HIV infection.

The Celtzentri ® drug should be used only when the HIV-1 CC115-tropic HIV-1 is determined by an adequately validated and sensitive method (ie, a virus with tropism is not detected CXCR4 or having a double and / or mixed tropism). Tropism of the virus can not be determined on the basis of anamnesis of treatment or testing of stored blood samples of the patient. ^gTo estimate tropism, only the newly obtained patient blood sample can be used.

In HIV-1-infected patients, changes in the tropism of the virus occur over time. Therefore, it is necessary to begin treatment soon after the definition of tropism.

The drug Celzentri ® should be used as part of the combined antiretroviral therapy regimen. The drug Celzentri ® should be optimally combined with other antiretroviral drugs, to which the patient's virus is susceptible. Information for patients

Patients should be informed that antiretroviral therapy, including the use of Celzentri®, does not prevent the transmission of HIV to other people by sexual contact or through contact with blood. Patients should continue to observe all precautions. Maraviroc does not lead to eradication of HIV-1.

Correction of dose

Doctors should ensure that the dose of Celzentri® is correctly adjusted when combined with inhibitors and / or isoenzyme inducers CYP3A4, since they can influence the concentration and therapeutic efficacy of Celzentri®.

Immunodeficiency Syndrome

In HIV-infected patients with severe immunodeficiency, in the first few weeks or months of the onset of highly active antiretroviral therapy (HAART), symptoms of inflammatory reactions may occur as a result of exacerbation of secondary infections that have occurred in asymptomatic form. Usually, such reactions can lead to a worsening of the patient's condition. Examples of such reactions are cytomegalovirus retinitis, generalized and / or focal mycobacterial infections and pneumonia caused by Pneumocystis jiroveci (formerly known as Pneumocystis carinii). Any symptoms of inflammation should be identified and, if necessary, appropriate treatment should be started.

Influence on immunity

Chemokine receptor antagonists CCR5 can adversely affect the immune response in certain infections. This must be taken into account when treating infections such as active tuberculosis and invasive fungal infections.

Osteonecrosis

Despite the fact that the nature of osteonecrosis is considered multifactorial (corticosteroids, alcohol abuse, severe immunosuppression, high body mass index), cases of osteonecrosis are more common in patients with HIV and / or with prolonged use of HAART.Patients should be advised to consult a doctor if they are concerned about pain in the joints or joint movement is difficult. Dysfunction of the liver

The safety and effectiveness of maraviroc in patients with severe liver disease has not been studied.

In a study on healthy volunteers, there were cases of hepatotoxicity with signs of an allergic reaction, possibly associated with the administration of maraviroc. In addition, during studies involving patients with previous experience of therapy against the background of taking Celzentri®, there was an increase in the incidence of adverse reactions from the liver, while at the same time there was generally no increase in the incidence of abnormalities in functional hepatic tests to levels of 3-4 degrees of severity on a scale ACTG (AIDS Clinical Trial Group - a group that conducts clinical research in the field of AIDS treatment, USA).

Even fewer cases of damage to the hepatobiliary system were observed in patients who had not previously received therapy. The frequency of side effects from the liver and the deviation of hepatic functional tests of grade 3-4 on a scale ACTG were comparable between the groups receiving maraviroc and efavirenz.

In patients with liver disease, including chronic active hepatitis during combined antiretroviral therapy, the incidence of hepatic impairment may increase, so these patients should be monitored in accordance with standard practice of managing patients with liver disease.

In all patients with signs or symptoms of acute hepatitis, especially if there is a suspicion of hypersensitivity to the drug or an increase in the activity of "hepatic" transaminases in combination with a rash or other symptoms of possible hypersensitivity (itching rash, eosinophilia or increased concentration IgE in plasma), the use of Celzentri® should be discontinued.

Severe skin reactions and hypersensitivity reactions

Hypersensitivity reactions, including severe and potentially life-threatening, have been observed in patients taking maraviroc, in most cases simultaneously with other drugs that can cause similar reactions. These reactions included a rash, constitutional symptoms and, in some cases, liver failure and impaired function of other organs.Stevens-Johnson syndrome, toxic epidermal necrolysis, and a rash with eosinophilia and systemic symptoms were also observed. It should immediately stop taking Celzentri® and other medications in case of signs and symptoms of severe hypersensitivity reaction.

The delay in stopping treatment with Celzentri® and other suspected drugs after the appearance of the rash may lead to a life-threatening reaction. It is necessary to monitor the clinical condition, including the activity of aminotransferases, and if necessary start the appropriate treatment. Disorders of the cardiovascular system

Caulzentri® should be given with caution in patients with an increased risk of developing cardiovascular conditions.

Renal impairment

In patients with severe renal failure who are receiving HIV therapy and a drug maraviroc, the risk of orthostatic hypotension may increase.

This risk is associated with an increase in the maximum concentration of maraviroc.

Orthostatic hypotension

Caution should be exercised when administering maraviroc to patients with severe renal failure who have risk factors or episodes of orthostatic hypotension in the history or patients taking concomitant therapy with hypotensive drugs.

Patients with concomitant cardiovascular diseases are at increased risk of cardiovascular adverse events that may be caused by orthostatic hypotension.

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

Studies of the effect on the ability to drive a car or work with mechanisms have not been carried out. Patients should be warned about the possible development of symptoms associated with orthostatic hypotension, such as dizziness while taking maraviroc. When these symptoms occur, patients should avoid potentially dangerous activities, such as driving or working with machinery.

Form release / dosage:

Tablets, film-coated, 150 mg, 300 mg.

Packaging:

For 10 tablets in PVC / aluminum blister. For 180 tablets in a bottle of high-density polyethylene with a protective liner made of aluminum foil and polyethylene with a screw cap,protected from opening by children.

For 3, 6, 9 blisters together with the instruction for use are placed in a cardboard box. One bottle together with the instruction for use is placed in a cardboard box.

Storage conditions:

Store at a temperature not exceeding 25 ° C.

Keep out of the reach of children.

Shelf life:

3 years.

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

Terms of leave from pharmacies:On prescription

Registration number:LP-000565

Date of registration:14.07.2011 / 24.09.2012

Expiration Date:14.07.2016

The owner of the registration certificate:Pfizer Manufakchuring Deutschland GmbH Pfizer Manufakchuring Deutschland GmbH Germany

Manufacturer: & nbsp

PFIZER MANUFACTURING DEUTSCHLAND, GmbH Germany

Information update date: & nbsp14.07.2016

Illustrated instructions

Instructions

Celzentry® (Celsentri® )