Celsentri 150mg film-coated tablets

1. Name Of The Medicinal Product

CELSENTRI 150 mg film-coated tablets.

2. Qualitative And Quantitative Composition

Each film-coated tablet contains 150 mg of maraviroc.

Excipients

Each 150 mg film-coated tablet contains 0.84 mg of soya lecithin.

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Film-coated tablet.

Blue, biconvex, oval film-coated tablets debossed with “Pfizer” on one side and “MVC 150” on the other

4. Clinical Particulars

4.1 Therapeutic Indications

CELSENTRI, in combination with other antiretroviral medicinal products, is indicated for treatment-experienced adult patients infected with only CCR5-tropic HIV-1 detectable (see section 4.2).

This indication is based on safety and efficacy data from two double-blind, placebo-controlled trials in treatment-experienced patients (see section 5.1).

4.2 Posology And Method Of Administration

Therapy should be initiated by a physician experienced in the management of HIV infection.

Before taking CELSENTRI it has to be confirmed that only CCR5-tropic HIV-1 is detectable (i.e. CXCR4 or dual/mixed tropic virus not detected) using an adequately validated and sensitive detection method on a newly drawn blood sample. The Monogram Trofile assay was used in the clinical studies of CELSENTRI (see sections 4.4 and 5.1). Other phenotypic and genotypic assays are currently being evaluated. The viral tropism cannot be safely predicted by treatment history and assessment of stored samples.

There are currently no data regarding the reuse of CELSENTRI in patients that currently have only CCR5-tropic HIV-1 detectable, but have a history of failure on CELSENTRI (or other CCR5 antagonists) with a CXCR4 or dual/mixed tropic virus. There are no data regarding the switch from a medicinal product of a different antiretroviral class to CELSENTRI in virologically suppressed patients. Alternative treatment options should be considered.

Adults: the recommended dose of CELSENTRI is 150 mg, 300 mg or 600 mg twice daily depending on interactions with co-administered antiretroviral therapy and other medicinal products (see Table 2 in Section 4.5). CELSENTRI can be taken with or without food.

Children: CELSENTRI is not recommended for use in children due to lack of data on safety, efficacy and pharmacokinetics (see section 5.2).

Elderly: there is limited experience in patients>65 years of age (see section 5.2), therefore CELSENTRI should be used with caution in this population.

Renal impairment: dosage adjustment is only recommended in patients with renal impairment who are receiving potent CYP3A4 inhibitors such as:

• protease inhibitors (except tipranavir/ritonavir)

• ketoconazole, itraconazole, clarithromycin, telithromycin.

CELSENTRI should be used with caution in patients with severe renal impairment (CLcr < 30mL/min) who are receiving potent CYP3A4 inhibitors (see sections 4.4 and 5.2).

The dose and dosing interval for CELSENTRI should be modified in renally impaired patients (CLcr <80 mL/min), including patients with end stage renal disease (ESRD) requiring dialysis (Table 1 below). These dosing recommendations are based on data from a renal impairment study (see section 5.2) in addition to modelling of pharmacokinetic data in subjects with varying degrees of renal impairment.

Table 1. Dose and interval adjustments for patients with renal impairment

Recommended CELSENTRI dose interval	Creatinine clearance <80 mL/min
If administered without potent CYP3A4 inhibitors or if co-administered with tipranavir/ritonavir	No dose interval adjustment required
If co-administered with fosamprenavir/ritonavir	CELSENTRI 150 mg every 12 hours
If co-administered with potent CYP3A4 inhibitors, e.g. saquinavir/ritonavir, lopinavir/ritonavir, darunavir/ritonavir, atazanavir/ritonavir, ketoconazole	CELSENTRI 150 mg every 24 hours

Hepatic impairment: limited data are available in patients with hepatic impairment, therefore CELSENTRI should be used with caution in this population (see sections 4.4 and 5.2).

4.3 Contraindications

Hypersensitivity to the active substance or to peanut or soya or to any of the excipients.

4.4 Special Warnings And Precautions For Use

CELSENTRI should be taken as part of an antiretroviral combination regimen. CELSENTRI should optimally be combined with other antiretrovirals to which the patient's virus is sensitive (see section 5.1).

CELSENTRI should only be used when only CCR5-tropic HIV-1 is detectable (i.e. CXCR4 or dual/mixed tropic virus not detected) as determined by an adequately validated and sensitive detection method (see sections 4.1, 4.2 and 5.1). The Monogram Trofile assay was used in the clinical studies of CELSENTRI. Other phenotypic and genotypic assays are currently being evaluated. The viral tropism cannot be predicted by treatment history or assessment of stored samples.

Changes in viral tropism occur over time in HIV-1 infected patients. Therefore there is a need to start therapy shortly after a tropism test.

Background resistance to other classes of antiretrovirals have been shown to be similar in previously undetected CXCR4-tropic virus of the minor viral population, as that found in CCR5-tropic virus.

CELSENTRI is not recommended to be used in treatment-naïve patients based on the results of a clinical study in this population (see section 5.1).

Dose adjustment: physicians should ensure that appropriate dose adjustment of CELSENTRI is made when CELSENTRI is co-administered with CYP3A4 inhibitors and/or inducers since maraviroc concentrations and its therapeutic effects may be affected (see sections 4.2 and 4.5). Please also refer to the respective Summary of Product Characteristics of the other antiretroviral medicinal products used in the combination.

Information for patients: patients should be advised that antiretroviral therapies including CELSENTRI have not been shown to prevent the risk of transmission of HIV to others through sexual contact or contamination with blood. They should continue to use appropriate precautions. Patients should also be informed that CELSENTRI is not a cure for HIV-1 infection.

Postural hypotension: when CELSENTRI was administered in studies with healthy volunteers at doses higher than the recommended dose, cases of symptomatic postural hypotension were seen at a greater frequency than with placebo. However, when CELSENTRI was given at the recommended dose in HIV infected patients in Phase 3 studies, postural hypotension was seen at a similar rate compared to placebo (approximately 0.5%). Caution should be used when administering CELSENTRI in patients with a history of postural hypotension or on concomitant medicinal products known to lower blood pressure.

Potential effect on immunity: CCR5 antagonists could potentially impair the immune response to certain infections. This should be taken into consideration when treating infections such as active tuberculosis and invasive fungal infections. The incidence of AIDS-defining infections was similar between CELSENTRI and placebo arms in the pivotal studies.

Cardiovascular safety: limited data exist with the use of CELSENTRI in patients with severe cardiovascular disease, therefore special caution should be exercised when treating these patients with CELSENTRI. In the pivotal studies of treatment-experienced patients (MOTIVATE) coronary heart disease events was more common in patients treated with CELSENTRI than with placebo (11 during 609 PY vs 0 during 111 PY of follow-up). In treatment-naïve patients (MERIT) such events occurred at a similarly low rate with CELSENTRI and control (efavirenz).

When CELSENTRI was administered to healthy volunteers at doses higher than the recommended dose, cases of symptomatic postural hypotension were seen at a greater frequency than with placebo. However, when CELSENTRI was given at the recommended dose in HIV infected patients in Phase 3 studies, postural hypotension was seen at a similar rate compared to placebo/comparator. Caution should be used when administering CELSENTRI in patients with a history of postural hypotension or on concomitant medicinal products known to lower blood pressure.

Immune reconstitution syndrome: in HIV infected patients with severe immune deficiency at the time of institution of combination antiretroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunistic pathogens may arise and cause serious clinical conditions, or aggravation of symptoms. Typically, such reactions have been observed within the first few weeks or months of initiation of CART. Relevant examples are cytomegalovirus retinitis, generalised and/or focal mycobacterial infections, and pneumonia caused by Pneumocystis jiroveci (formerly known as Pneumocystis carinii). Any inflammatory symptoms should be evaluated and treatment initiated when necessary.

Osteonecrosis: although the etiology is considered to be multifactorial (including corticosteroid use, alcohol consumption, severe immunosuppression, higher body mass index), cases of osteonecrosis have been reported particularly in patients with advanced HIV-disease and/or long-term exposure to combination antiretroviral therapy (CART). Patients should be advised to seek medical advice if they experience joint aches and pain, joint stiffness or difficulty in movement.

Hepatic safety: the safety and efficacy of CELSENTRI have not been specifically studied in patients with significant underlying liver disorders.

A case of possible CELSENTRI-induced hepatotoxicity with allergic features has been reported in a study in healthy volunteers. In addition, an increase in hepatic adverse reactions with CELSENTRI was observed during studies of treatment-experienced subjects with HIV infection, although there was no overall increase in ACTG Grade 3/4 liver function test abnormalities (see section 4.8). Hepatobiliary disorders reported in treatment-naïve patients were uncommon and balanced between treatment groups (see section 4.8). Patients with pre-existing liver dysfunction, including chronic active hepatitis, can have an increased frequency of liver function abnormalities during combination antiretroviral therapy and should be monitored according to standard practice.

Discontinuation of CELSENTRI should be considered in any patient with signs or symptoms of acute hepatitis, in particular if drug-related hypersensitivity is suspected or with increased liver transaminases combined with rash or other systemic symptoms of potential hypersensitivity (e.g. pruritic rash, eosinophila or elevated IgE).

Since there are very limited data in patients with hepatitis B/C co-infection, special caution should be exercised when treating these patients with CELSENTRI. In case of concomitant antiviral therapy for hepatitis B and/or C, please refer also to the relevant product information for these medicinal products.

There is limited experience in patients with reduced hepatic function, therefore CELSENTRI should be used with caution in this population (see sections 4.2 and 5.2).

Renal impairment: An increased risk of postural hypotension may occur in patients with severe renal insufficiency who are treated with boosted protease inhibitors (PIs) and CELSENTRI. This risk is due to potential increases in maraviroc maximum concentrations when CELSENTRI is co-administered with boosted PIs in these patients. The risk of postural hypotension is highest when CELSENTRI is co-administered with PIs having the most potent CYP3A4 inhibitory effect (saquinavir/ ritonavir, darunavir/ ritonavir, lopinavir/ ritonavir). Patients with impaired renal function may frequently have cardiovascular co-morbidities, and could be at increased risk of cardiovascular adverse events triggered by postural hypotension. No studies have been performed in subjects with severe renal impairment co-treated with potent CYP3A4 inhibitors. Dose adjustments are based on modelling and simulations (see sections 4.2, 4.5 and 5.2)

Soya lecithin: CELSENTRI contains soya lecithin. If a patient is hypersensitive to peanut or soya, CELSENTRI should not be used.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Maraviroc is a substrate of cytochrome P450 CYP3A4. Co-administration of CELSENTRI with medicinal products that induce CYP3A4 may decrease maraviroc concentrations and reduce its therapeutic effects. Co-administration of CELSENTRI with medicinal products that inhibit CYP3A4 may increase maraviroc plasma concentrations. Dose adjustment of CELSENTRI is recommended when CELSENTRI is co-administered with CYP3A4 inhibitors and/or inducers. Further details for concomitantly administered medicinal products are provided below (see Table 2).

Studies in human liver microsomes and recombinant enzyme systems have shown that maraviroc does not inhibit any of the major P450 enzymes at clinically relevant concentrations (CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and CYP3A4). Maraviroc had no clinically relevant effect on the pharmacokinetics of midazolam, the oral contraceptives ethinylestradiol and levonorgestrel, or urinary 6β-hydroxycortisol/cortisol ratio, suggesting no inhibition or induction of CYP3A4 in vivo. At higher exposure of maraviroc a potential inhibition of CYP2D6 cannot be excluded. Based on the in vitro and clinical data, the potential for maraviroc to affect the pharmacokinetics of co-administered medicinal products is low.

Renal clearance accounts for approximately 23% of total clearance of maraviroc when maraviroc is administered without CYP3A4 inhibitors. As both passive and active processes are involved, there is the potential for competition for elimination with other renally eliminated active substances. However, co-administration of CELSENTRI with tenofovir (substrate for renal elimination) and Cotrimoxazole (contains trimethoprim, a renal cation transport inhibitor), showed no effect on the pharmacokinetics of maraviroc. In addition, co-administration of CELSENTRI with lamivudine/zidovudine showed no effect of maraviroc on lamivudine (primarily renally cleared) or zidovudine (non-P450 metabolism and renal clearance) pharmacokinetics. In vitro results indicate that maraviroc could inhibit P-glycoprotein in the gut and may thus affect bioavailability of certain drugs.

Table 2. Interactions and dose recommendations with other medical products

Medicinal product by therapeutic areas (dose of CELSENTRI used in study)	Effects on drug levels Geometric mean change if not stated otherwise	Recommendations concerning co-administration
ANTI-INFECTIVES
Antiretrovirals
NRTIs
Lamivudine 150 mg BID (maraviroc 300 mg BID)	Lamivudine AUC12: ↔ 1.13 Lamivudine Cmax: ↔ 1.16 Maraviroc concentrations not measured, no effect is expected.	No significant interaction seen/expected. CELSENTRI 300 mg twice daily and NRTIs can be co-administered without dose adjustment.
Tenofovir 300 mg QD (maraviroc 300 mg BID)	Maraviroc AUC12: ↔ 1.03 Maraviroc Cmax: ↔ 1.03 Tenofovir concentrations not measured, no effect is expected.
Zidovudine 300 mg BID (maraviroc 300 mg BID)	Zidovudine AUC12: ↔ 0.98 Zidovudine Cmax: ↔ 0.92 Maraviroc concentrations not measured, no effect is expected.
Integrase Inhibitors
Raltegravir 400 mg BID (maraviroc 300 mg BID)	Maraviroc AUC12: Maraviroc Cmax: Raltegravir AUC12: Raltegravir Cmax: Raltegravir C12:	No clinically significant interaction seen. CELSENTRI 300 mg twice daily and raltegravir can be co-administered without dose adjustment.
NNRTIs
Efavirenz 600 mg QD (maraviroc 100 mg BID)	Maraviroc AUC12: Maraviroc Cmax: Efavirenz concentrations not measured, no effect is expected.	CELSENTRI dose should be increased to 600 mg twice daily when co-administered with efavirenz in the absence of a potent CYP3A4 inhibitor. For combination with efavirenz + PI, see separate recommendations below.
Etravirine 200 mg BID (maraviroc 300 mg BID)	Maraviroc AUC12: Maraviroc Cmax: Etravirine AUC12: ↔ 1.06 Etravirine Cmax: ↔ 1.05 Etravirine C12: ↔ 1.08	Etravirine is only approved for use with boosted protease inhibitors. For combination with etravirine + PI, see below.
Nevirapine 200 mg BID (maraviroc 300 mg Single Dose)	Maraviroc AUC12: ↔ compared to historical controls Maraviroc Cmax: ↑ compared to historical controls Nevirapine concentrations not measured, no effect is expected.	Comparison to exposure in historical controls suggests that CELSENTRI 300 mg twice daily and nevirapine can be co-administered without dose adjustment.
PIs
Atazanavir 400 mg QD (maraviroc 300 mg BID)	Maraviroc AUC12↑ 3.57 Maraviroc Cmax: ↑ 2.09 Atazanavir concentrations not measured, no effect is expected.	CELSENTRI dose should be decreased to 150 mg twice daily when co-administered with a PI; except in combination with tipranavir/ritonavir or fosamprenavir/ritonavir where the CELSENTRI dose should be 300 mg BID. Maraviroc does not significantly affect PI drug levels.
Atazanavir/ritonavir 300 mg/100 mg QD (maraviroc 300 mg BID)	Maraviroc AUC12↑ 4.88 Maraviroc Cmax: ↑ 2.67 Atazanavir/ritonavir concentrations not measured, no effect is expected.
Lopinavir/ritonavir 400 mg/100 mg BID (maraviroc 300 mg BID)	Maraviroc AUC12↑ 3.95 Maraviroc Cmax: ↑ 1.97 Lopinavir/ritonavir concentrations not measured, no effect is expected.
Saquinavir/ritonavir 1000 mg/100 mg BID (maraviroc 100 mg BID)	Maraviroc AUC12↑ 9.77 Maraviroc Cmax: ↑ 4.78 Saquinavir/ritonavir concentrations not measured, no effect is expected.
Darunavir/ritonavir 600 mg/100 mg BID (maraviroc 150 mg BID)	Maraviroc AUC12↑ 4.05 Maraviroc Cmax: ↑ 2.29 Darunavir/ritonavir concentrations were consistent with historical data.
Nelfinavir	Limited data are available for co-administration with nelfinavir. Nelfinavir is a potent CYP3A4 inhibitor and would be expected to increase maraviroc concentrations.
Indinavir	Limited data are available for co-administration with indinavir. Indinavir is a potent CYP3A4 inhibitor. Population PK analysis in phase 3 studies suggests dose reduction of maraviroc when coadministered with indinavir gives appropriate maraviroc exposure.
Fosamprenavir/ritonavir	Fosamprenavir is considered to be a moderate CYP3A4 inhibitor. Population PK studies suggest that a dose adjustment of maraviroc is not required.	CELSENTRI 300 mg twice daily and tipranavir/ritonavir or fosamprenavir/ritonavir can be co-administered without dose adjustment.
Tipranavir/ritonavir 500 mg/200 mg BID (maraviroc 150 mg BID)	Maraviroc AUC12↔ 1.02 Maraviroc Cmax: ↔ 0.86 Tipranavir/ritonavir concentrations were consistent with historical data.
NNRTI + PI
Efavirenz 600 mg QD + lopinavir/ritonavir 400mg/100 mg BID (maraviroc 300 mg BID)	Maraviroc AUC12:↑ 2.53 Maraviroc Cmax: ↑ 1.25 Efavirenz, lopinavir/ritonavir concentrations not measured, no effect expected.	CELSENTRI dose should be decreased to 150 mg twice daily when co-administered with efavirenz and a PI (except fosamprenavir/ritonavir where the dose should be 300 mg twice daily or tipranavir/ritonavir where the dose should be 600 mg twice daily).
Efavirenz 600 mg QD + saquinavir/ritonavir 1000 mg/100 mg BID (maraviroc 100 mg BID)	Maraviroc AUC12:↑ 5.00 Maraviroc Cmax: ↑ 2.26 Efavirenz, saquinavir/ritonavir concentrations not measured, no effect expected.
Efavirenz and atazanavir/ritonavir or darunavir/ritonavir	Not studied. Based on the extent of inhibition by atazanavir/ritonavir or darunavir/ritonavir in the absence of efavirenz, an increased exposure is expected.
Etravirine and darunavir/ritonavir (maraviroc 150 mg BID)	Maraviroc AUC12:↑ 3.10 Maraviroc Cmax: ↑ 1.77 Etravirine AUC12: ↔ 1.00 Etravirine Cmax: ↔ 1.08 Etravirine C12: Darunavir AUC12: Darunavir Cmax: ↔ 0.96 Darunavir C12: Ritonavir AUC12: ↔ 0.93 Ritonavir Cmax: ↔ 1.02 Ritonavir C12:	CELSENTRI dose should be decreased to 150 mg twice daily when co-administered with etravirine and a PI (except fosamprenavir/ritonavir where the dose should be 300 mg twice daily).
Etravirine and lopinavir/ritonavir, saquinavir/ritonavir or atazanavir/ritonavir	Not studied. Based on the extent of inhibition by lopinavir/ritonavir, saquinavir/ritonavir or atazanavir/ritonavir in the absence of etravirine, an increased exposure is expected.
Antibiotics
Sulphamethoxazole/ Trimethoprim 800 mg/160 mg BID (maraviroc 300 mg BID)	Maraviroc AUC12: ↔ 1.11 Maraviroc Cmax: ↔ 1.19 Sulphamethoxazole/trimethoprim concentrations not measured, no effect expected.	CELSENTRI 300 mg twice daily and sulphamethoxazole/trimethoprim can be co-administered without dose adjustment.
Rifampicin 600 mg QD (maraviroc 100 mg BID)	Maraviroc AUC: Maraviroc Cmax: Rifampicin concentrations not measured, no effect expected.	CELSENTRI dose should be increased to 600 mg twice daily when co-administered with rifampicin in the absence of a potent CYP3A4 inhibitor. This dose adjustment has not been studied in HIV patients. See also section 4.4.
Rifampicin + efavirenz	Combination with two inducers has not been studied. There may be a risk of suboptimal levels with risk of loss of virologic response and resistance development.	Concomitant use of CELSENTRI and rifampicin + efavirenz is not recommended.
Rifabutin + PI	Not studied. Rifabutin is considered to be a weaker inducer than rifampicin. When combining rifabutin with protease inhibitors that are potent inhibitors of CYP3A4 a net inhibitory effect on maraviroc is expected.	CELSENTRI dose should be decreased to 150 mg twice daily when co-administered with rifabutin and a PI (except tipranavir/ritonavir or fosamprenavir/ritonavir where the dose should be 300 mg twice daily) . See also section 4.4.
Clarithromycin, Telithromycin	Not studied, but both are potent CYP3A4 inhibitors and would be expected to increase maraviroc concentrations.	CELSENTRI dose should be decreased to 150 mg twice daily when co-administered with clarithromycin and telithromycin.
Antifungals
Ketoconazole 400 mg QD (maraviroc 100 mg BID)	Maraviroc AUCtau: ↑ 5.00 Maraviroc Cmax: ↑ 3.38 Ketoconazole concentrations not measured, no effect is expected.	CELSENTRI dose should be decreased to 150 mg twice daily when co-administered with ketoconazole.
Itraconazole	Not studied. Itraconazole, is a potent CYP3A4 inhibitor and would be expected to increase the exposure of maraviroc.	CELSENTRI dose should be decreased to 150 mg twice daily when co-administered with itraconazole.
Fluconazole	Fluconazole is considered to be a moderate CYP3A4 inhibitor. Population PK studies suggest that a dose adjustment of maraviroc is not required.	CELSENTRI 300 mg twice daily should be administered with caution when co-administered with fluconazole.
Antivirals
HCV agents	Pegylated interferon and ribavirin have not been studied, no interaction is expected.	CELSENTRI 300 mg twice daily and pegylated interferon or ribavirin can be co-administered without dose adjustment.
DRUG ABUSE
Methadone	Not studied, no interaction expected.	CELSENTRI 300 mg twice daily and methadone can be coadministered without dose adjustment.
Buprenorphine	Not studied, no interaction expected.	CELSENTRI 300 mg twice daily and buprenorphine can be co-administered without dose adjustment.
LIPID LOWERING MEDICINAL PRODUCTS
Statins	Not studied, no interaction expected.	CELSENTRI 300 mg twice daily and statins can be co-administered without dose adjustment.
ORAL CONTRACEPTIVES
Ethinylestradiol 30 mcg QD (maraviroc 100 mg BID)	Ethinylestradiol. AUCt:↔ 1.00 Ethinylestradiol. Cmax: ↔ 0.99 Maraviroc concentrations not measured, no interaction expected.	CELSENTRI 300 mg twice daily. and ethinylestradiol can be co-administered without dose adjustment.
Levonorgestrel 150 mcg QD (maraviroc 100 mg BID)	Levonorgestrel. AUC12:↔ 0.98 Levonorgestrel. Cmax: ↔ 1.01 Maraviroc concentrations not measured, no interaction expected.	CELSENTRI 300 mg twice daily and levonorgestrel can be co-administered without dose adjustment.
SEDATIVES
Benzodiazepines
Midazolam 7.5 mg Single Dose (maraviroc 300 mg BID)	Midazolam. AUC: ↔ 1.18 Midazolam. Cmax: ↔ 1.21 Maraviroc concentrations not measured, no interaction expected.	CELSENTRI 300 mg twice daily and midazolam can be co-administered without dose adjustment.
HERBAL PRODUCTS
St John's Wort	Co-administration of maraviroc with St. John's wort is expected to substantially decrease maraviroc concentrations and may result in suboptimal levels and lead to loss of virologic response and possible resistance to maraviroc.	Concomitant use of maraviroc and St. John's wort (Hypericum Perforatum) or products containing St. John's wort is not recommended.

4.6 Pregnancy And Lactation

No meaningful clinical data on exposure during pregnancy are available. Studies in rats and rabbits showed reproductive toxicity at high exposures. Primary pharmacological activity (CCR5 receptor affinity) was limited in these species (see section 5.3). CELSENTRI should be used during pregnancy only if the potential benefit justifies the potential risk to the foetus.

Studies in lactating rats indicate that maraviroc is extensively secreted into rat milk. Primary pharmacological activity (CCR5 receptor affinity) was limited in these species. It is not known whether maraviroc is secreted into human milk. Mothers should be instructed not to breast-feed if they are receiving CELSENTRI because of the potential for HIV transmission as well as any possible undesirable effects in breast-fed infants.

4.7 Effects On Ability To Drive And Use Machines

No studies on the effects on the ability to drive and use machines have been performed. CELSENTRI may cause dizziness. Patients should be instructed that if they experience dizziness they should avoid potentially hazardous tasks such as driving or operating machinery.

4.8 Undesirable Effects

The safety profile of CELSENTRI is based on 1,374 HIV-1 infected patients who received at least one dose of CELSENTRI during Phase 2b/3 clinical studies. This includes 426 treatment-experienced patients and 360 treatment-naïve patients who received the recommended dose 300 mg twice daily and a further 588 treatment-experienced and treatment-naïve patients who received 300 mg once daily. Assessment of treatment related adverse reactions is based on pooled data from two Phase 2b/3 studies in treatment-experienced adult patients (MOTIVATE 1 and MOTIVATE 2) and one study in treatment-naïve adult patients (MERIT) infected with CCR5-tropic HIV-1 (see section 4.4 and 5.1)..

The most frequently reported adverse reactions occurring in the Phase 2b/3 studies were nausea, diarrhoea, fatigue and headache. These adverse reactions were common (

The adverse reactions are listed by system organ class (SOC) and frequency. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. Frequencies are defined as very common (

The following table presents clinically important adverse reactions of moderate intensity or more occurring among patients receiving CELSENTRI in Phase 2b/3 studies at rates greater than rates in the comparator.

Table 3. Clinically important adverse reactions of moderate intensity or more among patients receiving CELSENTRI at rates greater than rates in the comparator

System Organ Class	Adverse Reaction	Frequency
Infections and infestations	Pneumonia, oesophageal candidiasis	uncommon
Neoplasm benign, malignant and unspecified (incl. cysts and polyps)	Bile duct cancer, diffuse large B-cell lymphoma, Hodgkin's disease, metastases to bone, metastases to liver, metastases to peritoneum, nasopharyngeal cancer, oesophageal carcinoma	rare
Blood and lymphatic system disorders	Anaemia	common
Pancytopenia, granulocytopenia	rare
Metabolism and nutrition disorders