Miranda Lambert – Profile

 

 

 

Miranda Lambert is a Grammy-nominated singer-songwriter who first made a name for herself on a nationally televised talent show, which she parlayed into a major recording career. With a delicate yet strong voice, an immense talent for writing honest heartfelt songs, and girl-next-door beauty, Lambert has quickly become one of country music’s most respected young artists.

Origins and Early Musical Drive

 

Born on November 10, 1983 in Lindale, Texas, a small town 90 miles east of Dallas, Lambert’s musical career began in earnest when she was just five years old, appearing on the Johnny High Country Music Review, the same show that helped launch LeAnn Rimes’ career. Lambert’s father, Rick, was a policeman at the time, as well as a singer-songwriter of country music, and he encouraged his talented young daughter to pursue her passion for music.

When Lambert was ten, she attended a Garth Brooks concert in Dallas, which further fanned the flames of her growing obsession with country music. During that time, her family made annual trips to Nashville to attend Fan Fair (now called the CMA Music Festival), and she became an avid autograph collector. At 14 her father purchased her a guitar, but she showed little interest in learning the instrument, an attitude that would soon change.

Lambert’s First Recording Sessions in Nashville

As a young teen, Lambert attended a music business seminar in Nashville, which resulted in her recording a demo of four pop-country singles. She was not pleased with the songs, which were chosen for her to record by others, and she quickly realized that she needed to learn the guitar so she could write her own material. So she returned to Texas and let her father teach her the instrument.

In addition to her father, Lambert’s musical influences growing up included notable singer-songwriters like Emmylou Harris and Merle Haggard. As her talent grew, so did her early successes. She landed a commercial spot for Ruffles potato chips, a bit part in the comedy film, Slap Her She’s French, and she came in second place out of over 400 hopefuls to portray Tammy Wynette in the musical Stand By Your Man.

Miranda’s High School Days

Longview, Texas is where 17-year old Lambert really honed her musical skills. Her band, Texas Pride, landed a regular gig at the Reo Palm Isle Ballroom, a landmark music venue built in the ‘30s that over the years showcased such superstars as Elvis Presley, Willie Nelson, Bob Wills, Brooks and Dunn, Glen Miller and Tommy Dorsey.

Around this time, Lambert’s family further invested in her career by funding a CD of her music, building a website to promote it, and traveling to various radio stations throughout the Lone Star State to put her music in front of as many people as possible. The family even bought a motor home with a trailer and a complete state-of-the-art sound system to enable her to perform anywhere and everywhere. Shortly after appearing in her high school’s production of Annie Get Your Gun, Lambert left school early to pursue music full-time.

Miranda Dazzles on Nashville Star

Lambert’s first really big break came in January of 2003 when she took first place in the Texas auditions for the nationally televised talent show, Nashville Star. She eventually competed on the show, placing third. This exposure led to her signing her first major recording contract with Epic Records.

In the summer of 2004, Lambert released her debut CD, Kerosene, which debuted at No. 1 on Billboard’s Top Country Album chart. She wrote or co-wrote eleven of the CD’s twelve songs. Her first single, “Me and Charlie Talking,” was co-written by her father, and it climbed to No. 27 on Billboard’s country chart. Her next three singles were all top 40 country hits, including the album’s title track, “Kerosene,” which hit No. 15 and garnered Lambert three major award nominations, including a Grammy nomination for Best Female Country Vocal Performance. Lambert was also nominated for the Country Music Association’s Horizon Award, which is given to country music’s top newcomer.

Lambert’s Successful Move to Columbia

With the closure of Lambert’s Epic label in Nashville, her contract was transferred to Columbia for her sophomore album, 2007’s Crazy Ex-Girlfriend. She wrote eight of the album’s eleven tracks, including all four of the singles. The first single fizzled on the charts, but the next three, “Famous in a Small Town,” “Gunpowder & Lead” and “More Like Her” all hit the top 20. To promote the album, she toured extensively with Keith Urban, George Strait, Dierks Bentley and Toby Keith.

Lambert released her third CD, Revolution, on September 29, 2009. She wrote all but three songs on the album

Chondrolysis Reported with Continuously Infused Local Anesthetics

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The Food and Drug Administration (FDA) has reviewed 35 reports of chondrolysis (necrosis and destruction of cartilage) in patients given continuous intra-articular infusions of local anesthetics (marketed as bupivacaine, chlorprocaine, lidocaine, mepivacaine, procaine and ropivacaine) with elastomeric infusion devices to control post-surgical pain. The significance of this injury to otherwise healthy young adults warrants notification to health care professionals.

The local anesthetics (with and without epinephrine) were infused for extended periods of time (48 to 72 hours) directly into the intra-articular space using an elastomeric pump.

Chondrolysis was diagnosed within a median of 8.5 months after the infusion.  Almost all of the reported cases of chondrolysis (97%) occurred following shoulder surgeries. Joint pain, stiffness, and loss of motion were reported as early as the second month after receiving the infusion. In more than half of these reports, the patients required additional surgery, including arthroscopy or arthroplasty (joint replacement)

 

Some New Medical Findings

Anesthesia and intraoperative neurophysiological monitoring in children

PURPOSE: Anesthesia for pediatric patients undergoing surgery where intraoperative neurophysiological monitoring (IONM) is performed is based on an understanding of the anesthetic influence on the neural pathways involved and the physiology that supplies nutrients to the neural systems. Anesthesia in pediatric patients may be different than in adults due to the specific anesthesia considerations in children, notably the propofol infusion syndrome (PRIS) and the need to monitor immature neural pathways. This review was done to determine if the anesthesia protocols used were different than those used in adults. METHODS: After reviewing the implications of anesthetic action, a survey of pediatric anesthesia practitioners in 40 North American centers was conducted to determine the anesthesia protocols used in pediatric surgery with IONM and if these were specifically modified over concerns about PRIS. RESULTS: Twenty-five centers responded with 35 different protocols used by practitioners. These protocols are similar to protocols used in adult patients. Although no centers specifically avoided propofol in all patients, several strategies were used to reduce the dosage, avoid its use in selected patients, or monitor for the onset of the syndrome. CONCLUSION: Anesthesia for pediatric patients undergoing surgery where IONM is being performed is consistent with the practice and principles of anesthesia for adults. Although PRIS has not caused major alterations in most patients, concern has modified the practice of some anesthesiologists.

Sodium valproate and the fetus: a case study and review of the literature:

Sodium valproate is a teratogen responsible for a wide range of abnormalities, including neural tube defects. It has traditionally been prescribed for epilepsy, but is increasingly used for such psychiatric conditions as bipolar disease. Women of childbearing age taking valproate should be warned of its teratogenicity and advised to plan pregnancies, take a higher dose of folate, discuss reducing the dose of valproate or changing the medication with their physician, and have antenatal screening. After birth, the infant should be examined for a wide range of reported abnormalities. Neurodevelopmental assessment should continue throughout childhood. We present a case that illustrates the need for better education of mothers taking valproate and the medical staff prescribing it.

Efficacy of dexmethylphenidate for the treatment of fatigue after cancer chemotherapy: a randomized clinical trial:

Cancer and its treatment can induce subjective and objective evidence of diminished functional capacity encompassing physical fatigue and cognitive impairment. Dexmethylphenidate (D-MPH; the D-isomer of methylphenidate) was evaluated for treatment of chemotherapy-related fatigue and cognitive impairment. A randomized, double-blind, placebo-controlled, parallel-group study evaluated the potential therapeutic effect and safety of D-MPH in the treatment of patients with chemotherapy-related fatigue. Change from baseline in the Functional Assessment of Chronic Illness Therapy-Fatigue Subscale (FACIT-F) total score at Week 8 was the primary outcome measure. One hundred fifty-four patients (predominantly with breast and ovarian cancers) were randomized and treated. Compared with placebo, D-MPH-treated subjects demonstrated a significant improvement in fatigue symptoms at Week 8 in the FACIT-F (P=0.02) and the Clinical Global Impression-Severity scores (P=0.02), without clinically relevant changes in hemoglobin levels. Cognitive function was not significantly improved. There was a higher rate of study drug-related adverse events (AEs) (48 of 76 [63%] vs. 22 of 78 [28%]) and a higher discontinuation rate because of AEs (8 of 76 [11%] vs. 1 of 78 [1.3%]) in D-MPH-treated subjects compared with placebo-treated subjects. The most commonly reported AEs independent of study drug relationship in D-MPH-treated subjects were headache, nausea, and dry mouth, and in placebo-treated subjects were headache, diarrhea, and insomnia. D-MPH produced significant improvement in fatigue in subjects previously treated with cytotoxic chemotherapy. Further studies with D-MPH or other agents to explore treatment response in chemotherapy-associated fatigue should be considered.

HIV/AIDS Update -Expanded indication for Selzentry (maraviroc)

On November 20, 2009, the Food and Drug Administration approved a supplemental NDA to expand the indication for Selzenttry (maraviroc) to include combination antiretroviral treatment of therapy naïve adults infected with CCR5-tropic HIV-1 virus.  Maraviroc was previously approved (8/6/2007) for treatment of therapy experienced adult patients infected with CCR5-tropic HIV-1 virus.  The expanded indication is based upon data collected through 96 weeks from Study A4001026, demonstrating safety and efficacy.

The new label can be found on the FDA website at Drugs@FDA. 

The following changes were made to the labeling: 
Under HIGHLIGHTS OF PRESCRIBING INFORMATION: 
RECENT MAJOR CHANGES 
Indication and Usage (1) 
Warnings and Precautions (5.1), (5.2), (5.4), (5.5)

————————INDICATIONS AND USAGE—————————- 
SELZENTRY is a CCR5 co-receptor antagonist indicated for combination antiretroviral 
treatment of adults infected with only CCR5-tropic HIV-1. 
• In treatment-naïve subjects, more subjects treated with SELZENTRY experienced virologic 
failure and developed lamivudine resistance compared to efavirenz [see Microbiology 
(12.4) Clinical Studies (14.3]. 
• Tropism testing with a highly sensitive assay is required for the appropriate use of 
SELZENTRY (1).

  
——————–DOSAGE AND ADMINISTRATION——————— 

When given with potent CYP3A  inhibitors (with or without potent  CYP3A inducers) including PIs (except  tipranavir/ritonavir), delavirdine (2,  7.1)	150 mg  twice daily
With NRTIs, tipranavir/ritonavir,  nevirapine, raltegravir, and other drugs  that are not potent CYP3A inhibitors or  CYP3A inducers (2, 7.1)	300 mg  twice daily
With potent CYP3A inducers including  efavirenz (without a potent CYP3A  inhibitor) (2, 7.1)	600 mg  twice daily

———————-WARNINGS AND PRECAUTIONS—————— 
• More cardiovascular events including myocardial ischemia and/or infarction were observed in 
treatment-experienced subjects who received SELZENTRY. Use with caution in patients at 
increased risk of cardiovascular events (5.2).

—————————ADVERSE REACTIONS————————— 
The most common adverse events in treatment-experienced subjects (>8% incidence) which 
occurred at a higher frequency compared to placebo are upper respiratory tract infections, cough, 
pyrexia, rash, and dizziness (6).

Under FULL PRESCRIBING INFORMATION: CONTENTS*: 
6 ADVERSE REACTIONS 
6.1 Clinical Trials 
6.2 Postmarketing Experience 
12 CLINICAL PHARMACOLOGY 
12.1 Mechanism of Action 
12.2 Pharmacodynamics 
12.3 Pharmacokinetics 
12.4 Microbiology 
14 CLINICAL STUDIES 
14.1 Studies in CCR5-tropic, Treatment-experienced Subjects 
14.2 Study in Dual/Mixed-tropic, Treatment-experienced Subjects 
14.3 Study in CCR5-tropic, Treatment-naïve Subjects

 The following main changes were made to the FULL PRESCRIBING INFORMATION:

1 INDICATION AND USAGE

SELZENTRY, in combination with other antiretroviral agents, is indicated for adult patients infected with only CCR5-tropic HIV-1.

 

This indication is based on analyses of plasma HIV-1 RNA levels in two controlled studies of SELZENTRY in treatment-experienced subjects and one study in treatment-naïve subjects. Both studies in treatment-experienced subjects were conducted in clinically advanced, 3-class antiretroviral-experienced (NRTI, NNRTI, PI, or enfuvirtide) adults with evidence of HIV-1 replication despite ongoing antiretroviral therapy.

The following points should be considered when initiating therapy with SELZENTRY:

• Adult patients infected with only CCR5-tropic HIV-1 should use SELZENTRY.
• Tropism testing must be conducted with a highly sensitive and specific tropism assay that has demonstrated the ability to identify patients appropriate for SELZENTRY use. Outgrowth of pre-existing low-level CXCR4- or dual/mixed-tropic HIV-1 not detected by tropism testing at screening has been associated with virologic failure on SELZENTRY [see Microbiology (12.4) Clinical Studies (14.3)].

Use of SELZENTRY is not recommended in subjects with dual/mixed or CXCR4-tropic HIV-1 as efficacy was not demonstrated in a phase 2 study of this patient group. 


• The safety and efficacy of SELZENTRY have not been established in pediatric patients.
• In treatment-naïve subjects, more subjects treated with SELZENTRY experienced virologic failure and developed lamivudine resistance compared to efavirenz [see Microbiology (12.4) Clinical Studies (14.3)].

2 DOSAGE AND ADMINISTRATION

Table 1 Recommended Dosing Regimen

Concomitant Medications	SELZENTRY Dose
Concomitant Medications  Potent CYP3A inhibitors (with or without a CYP3A inducer) including: protease inhibitors (except tipranavir/ritonavir) delavirdine ketoconazole, itraconazole, clarithromycin other potent CYP3A inhibitors (e.g., nefazodone, telithromycin)	150 mg twice daily
Other concomitant medications, including tipranavir/ritonavir, nevirapine, raltegravir all NRTIs and enfuvirtide	300 mg twice daily
Potent CYP3A inducers (without a potent CYP3A inhibitor) including: efavirenz rifampin etravirine carbamazepine, phenobarbital, and phenytoin	600 mg twice daily

5 WARNINGS and PRECAUTIONS

5.1 Hepatotoxicity 
A case of possible SELZENTRY-induced hepatotoxicity with allergic features has been 
reported in a study of healthy volunteers. Discontinuation of SELZENTRY should be considered 
in any patient with signs or symptoms of hepatitis, or with increased liver transaminases 
combined with rash or other systemic symptoms. 
The safety and efficacy of SELZENTRY have not been specifically studied in patients with 
significant underlying liver disorders. In studies of treatment-experienced HIV-infected subjects, 
approximately 6% of subjects were co-infected with hepatitis B and approximately 6% were coinfected 
with hepatitis C. Due to the small number of co-infected subjects studied, no 
conclusions can be drawn regarding whether they are at an increased risk for hepatic adverse 
events with SELZENTRY administration. However, caution should be used when administering 
SELZENTRY to patients with pre-existing liver dysfunction or who are co-infected with viral 
hepatitis B or C.

5.2 Cardiovascular Events 
Use with caution in patients at increased risk for cardiovascular events. Eleven subjects 
(1.3%) who received SELZENTRY had cardiovascular events including myocardial ischemia 
and/or infarction during the Phase 3 studies in treatment-experienced studies [total exposure 609 
patient-years (300 on once daily + 309 on twice daily SELZENTRY)], while no subjects who 
received placebo had such events (total exposure 111 patient-years). These subjects generally 
had cardiac disease or cardiac risk factors prior to SELZENTRY use, and the relative 
contribution of SELZENTRY to these events is not known. 
In the Phase 2b/3 study in treatment-naïve subjects, 3 subjects (0.8%) who received 
SELZENTRY had events related to ischemic heart diseases and 5 subjects (1.4%) who received 
efavirenz had such events (total exposure 506 and 508 patient-years for SELZENTRY and 
efavirenz, respectively).

 

5.4 Potential Risk of Infection

SELZENTRY antagonizes the CCR5 co-receptor located on some immune cells, and 
therefore could potentially increase the risk of developing infections. The overall incidence and 
severity of infection, as well as AIDS-defining category C infections, was comparable in the 
treatment groups during the Phase 3 treatment-experienced studies of SELZENTRY. While 
there was a higher rate of certain upper respiratory tract infections reported in the SELZENTRY 
arm compared to placebo (23% versus 13%), there was a lower rate of pneumonia (2% vs 5%) 
reported in subjects receiving SELZENTRY. A higher incidence of Herpes virus infections (11 
per 100 patient-years) was also reported in the SELZENTRY arm when adjusted for exposure 
compared to placebo (8 per 100 patient-years). 
In the Phase 2b/3 study in treatment-naïve subjects, the incidence of AIDS-defining Category 
C events when adjusted for exposure was 1.8 for SELZENTRY compared to 2.4 for efavirenz per 
100 patient-years of exposure. 
Patients should be monitored closely for evidence of infections while receiving 
SELZENTRY.

 

5.5 Potential Risk of Malignancy

While no increase in malignancy has been observed with SELZENTRY, due to this drug’s 
mechanism of action it could affect immune surveillance and lead to an increased risk of 
malignancy.

The exposure-adjusted rate for malignancies per 100 patient-years of exposure in treatmentexperienced 
studies was 4.6 for SELZENTRY compared to 9.3 on placebo. In treatment-naïve 
subjects, the rates were 1.0 and 2.4 per 100 patient-years of exposure for SELZENTRY and 
efavirenz, respectively.

Long-term follow-up is needed to more fully assess this risk.

6.1 Clinical Trials Experience

Study in Treatment-Naïve Subjects

Treatment-Emergent Adverse Events

Treatment-emergent adverse events, regardless of causality, from Study A4001026, a doubleblind 
comparative controlled study in which 721 treatment-naïve subjects received SELZENTRY 
300 mg BID (N=360) or efavirenz (N=361) in combination with zidovudine/lamivudine for 96 
weeks, are summarized in Table 4. Selected events occurring at = 2% of subjects and at a 
numerically higher rate in subjects treated with SELZENTRY are included; events that occurred 
at the same or higher rate on efavirenz are not displayed.

Table 4 
Percentage of Subjects with Selected Treatment-Emergent Adverse Events (All Causality) 
(>2% on SELZENTRY and at a higher rate compared to efavirenz)

	SELZENTRY  + ZDV/LMV  300 mg BID  N = 360  (%)	EFAVIRENZ  + ZDV/LMV  600 mg QD  N = 361  (%)
BLOOD AND LYMPHATIC SYSTEM DISORDERS
Anemias NEC	8	5
Neutropenias	4	3
EAR AND LABYRINTH DISORDERS
Ear disorders NEC	3	2
GASTROINTESTINAL DISORDERS
Flatulence, bloating and distention	10	7
Gastrointestinal atonic and hypomotility disorders NEC	9	5
Gastrointestinal signs and symptoms NEC	3	2
GENERAL DISORDERS AND ADMINISTRATION SITE  CONDITIONS
Body Temperature perception	3	1
INFECTIONS AND INFESTATIONS
Bronchitis	13	9
Herpes Infection	7	6
Upper Respiratory Tract Infection	32	30
Bacterial infections NEC	6	3
Herpes zoster/varicella	5	4
Lower respiratory tract and lung infections	3	2
Neisseria infections	3	0
Tinea infections	4	3
Viral infections NEC	3	2
MUSCULOSKELETAL AND CONNECTIVE TISSUE  DISORDERS
Joint related signs and symptoms	6	5
NERVOUS SYSTEM DISORDERS
Memory loss (excluding dementia)	3	1
Parasthesias and Dyesthesias	4	3
RENAL AND URINARY DISORDERS
Bladder and urethral symptoms	4	3
REPRODUCTIVE SYSTEM AND BREAST DISORDERS
Erection and ejaculation conditions and disorders	3	2
RESPIRATORY, THORACIC AND MEDIASTINAL  DISORDERS
Upper respiratory tract signs and symptoms	9	5
SKIN AND SUBCUTANEOUS TISSUE DISORDERS
Acnes	3	2
Alopecias	2	1
Lipodystrophies	4	3
Nail and nail bed conditions (excl infections and infestations)	6	2

Laboratory Abnormalities

Table 5 
Maximum Shift in Laboratory Test Values (Without Regard to Baseline) 
Incidence =2% of Grade 3-4 Abnormalities (ACTG Criteria) 
Study A4001026 (96 Weeks)

Laboratory Parameter  Preferred Term	Limit	SELZENTRY  300 Twice daily  + ZDV/LMV  N =353*  %	Efavirenz  600 mg QD  + ZDV/LMV  N =350*  %
Aspartate aminotransferase	>5.0x ULN	4.0	4.0
Alanine  aminotransferase	>5.0x ULN	3.9	4.0
Creatine kinase		3.9	4.8
Amylase	>2.0x ULN	4.3	6.0
Absolute neutrophil count	<750/mm3	5.7	4.9
Hemoglobin	<7.0 g/dL	2.9	2.3

*N = total number of subjects evaluable for laboratory abnormalities. 
Percentages based on total subjects evaluated for each laboratory parameter. If the same subject in a given treatment group had >1 occurrence of the 
same abnormality, only the most severe is counted.

Less Common Adverse Events in Clinical Trials

The following adverse events occurred in <2% of SELZENTRY-treated subjects. These events 
have been included because of their seriousness and either increased frequency on SELZENTRY 
or are potential risks due to the mechanism of action. Events attributed to the patient’s 
underlying HIV infection are not listed.

 

Blood and Lymphatic System: marrow depression and hypoplastic anemia

Cardiac Disorders: unstable angina, acute cardiac failure, coronary artery disease, coronary 
artery occlusion, myocardial infarction, myocardial ischemia

Hepatobiliary Disorders: hepatic cirrhosis, hepatic failure, cholestatic jaundice, portal vein 
thrombosis, hypertransaminasemia, jaundice

Infections and Infestations: endocarditis, infective myositis, viral meningitis, pneumonia, treponema infections, septic shock, Clostridium difficile colitis, meningitis

Musculoskeletal and Connective Tissue Disorders: myositis, osteonecrosis, rhabdomyolysis, blood CK increased

Neoplasms benign, Malignant and Unspecified (including Cysts and Polyps): abdominal 
neoplasm, anal cancer, basal cell carcinoma, Bowen’s disease, cholangiocarcinoma, diffuse large 
B-cell lymphoma, lymphoma, metastases to liver, esophageal carcinoma, nasopharyngeal 
carcinoma, squamous cell carcinoma, squamous cell carcinoma of skin, tongue neoplasm 
(malignant stage unspecified), anaplastic large cell lymphomas T- and null-cell types, bile duct 
neoplasms malignant, endocrine neoplasms malignant and unspecified

Nervous System Disorders: cerebrovascular accident, convulsions and epilepsy, tremor 
(excluding congenital), facial palsy, hemianopia, loss of consciousness, visual field defect

6.2 Postmarketing Experience

The following events have been identified during post-approval use of SELZENTRY. Because 
these reactions are reported voluntarily from a population of unknown size, it is not possible to 
estimate their frequency or establish a causal relationship to SELZENTRY exposure.

Skin and Subcutaneous Tissue Disorders 
Stevens-Johnson syndrome.

8 USE IN SPECIFIC POPULATIONS

8.9 Race 
Population pharmacokinetic analysis of pooled Phase 1/2a data indicated exposure was 
26.5% higher in Asians (N=95) as compared to non-Asians (n=318). However, a study designed 
to evaluate pharmacokinetic differences between Caucasians (n=12) and Singaporeans (n=12) 
showed no difference between these two populations. No dose adjustment based on race is 
needed.

12 CLINICAL PHARMACOLOGY

12.2 Pharmacodynamics 
Exposure Response Relationship in Treatment-Experienced Subjects 
The relationship between maraviroc, modeled plasma trough concentration (Cmin) (1-9 
samples per patient taken on up to 7 visits), and virologic response was evaluated in 973 
treatment-experienced HIV-1-infected subjects with varied optimized background antiretroviral 
regimens in studies A4001027 and A4001028. The Cmin, baseline viral load, baseline CD4+ cell 
count and overall sensitivity score (OSS) were found to be important predictors of virologic 
success (defined as viral load < 400 copies/mL at 24 weeks). Table 6 illustrates the proportion of 
subjects with virologic success (%) within each Cmin quartile for 150 mg twice daily and 300 mg 
twice daily groups.

Table 6 Treatment-Experienced Subjects with Virologic Success by Cmin Quartile (Q1-Q4))

150 mg BID (with CYP3A inhibitors)				300 mg BID (without CYP3A inhibitors)
	n	Median Cmin	% subjects with virologic  success	n	Median Cmin	% subjects with virologic
Placebo	160	–	30.6	35	–	28.6
Q1	78	33	52.6	22	13	50.0
Q2	77	87	63.6	22	29	68.2
Q3	78	166	78.2	22	46	63.6
Q4	78	279	74.4	22	97	68.2

 

Exposure Response Relationship in Treatment-Naive Subjects 
The relationship between maraviroc, modeled plasma trough concentration (Cmin) (1-12 
samples per patient taken on up to 8 visits), and virologic response was evaluated in 294 
treatment-naive HIV-1-infected subjects receiving maraviroc 300 mg twice daily in combination 
with zidovudine/lamivudine in study A4001026. Table 7 illustrates the proportion of subjects 
with virologic success (%) within each Cmin quartile for the 300 mg twice daily dose.

 

Table 7 Treatment-Naïve Subjects with Virologic Success by Cmin Quartile (Q1-Q4)

300 mg BID
	n	Median Cmin	% subjects with v
Q1	75	23	57.3
Q2	72	39	72.2
Q3	73	56	74.0
Q4	74	81	83.8

Eighteen of 75 (24%) subjects in Q1 had no measurable maraviroc concentration on at least one occasion vs. 1 of 73 
and 1 of 74 in quartiles 3 and 4 respectively. 

12.3 Pharmacokinetics

Table 8 Mean Maraviroc Pharmacokinetic Parameters

	Maraviroc dose	N	AUC12  (ng.h/Ml)	Cmax  (ng/mL)	Cmin  (ng/mL)
Healthy volunteers (phase 1)	300 mg twice daily	64	2908	888	43.1
Asymptomatic HIV subjects (phase 2a)	300 mg twice daily	8	2550	618	33.6
Treatment-experienced HIV subjects (phase 3)*	300 mg twice daily	94	1513	266	37.2
	150 mg twice daily  (+ CYP3A inhibitor)	375	2463	332	101
Treatment-naïve HIV subjects (phase 2b/3)*	300 mg twice daily	344	1865	287	60

* The estimated exposure is lower compared to other studies possibly due to sparse sampling, food effect, compliance and concomitant 
medications.

Hepatic Impairment

Maraviroc is primarily metabolized and eliminated by the liver. A study compared the 
pharmacokinetics of a single 300 mg dose of SELZENTRY in subjects with mild (Child-Pugh 
Class A, n=8), and moderate (Child-Pugh Class B, n=8) hepatic impairment to pharmacokinetics 
in healthy subjects (n=8). The mean Cmax and AUC were 11% and 25% higher, respectively, for 
subjects with mild hepatic impairment, and 32% and 46% higher, respectively, for subjects with 
moderate hepatic impairment compared to subjects with normal hepatic function. These changes 
do not warrant a dose adjustment. Maraviroc concentrations are higher when SELZENTRY 150 
mg is administered with a potent CYP3A inhibitor compared to following administration of 300 
mg without a CYP3A inhibitor, so patients with moderate hepatic impairment who receive 
SELZENTRY 150 mg with a potent CYP3A inhibitor should be monitored closely for 
maraviroc-associated adverse events. The pharmacokinetics of maraviroc have not been studied 
in subjects with severe hepatic impairment [see Warnings and Precautions (5.1)].

Effect of Concomitant Drugs on the Pharmacokinetics of Maraviroc 
Maraviroc is a substrate of CYP3A and Pgp and hence its pharmacokinetics are likely to be 
modulated by inhibitors and inducers of these enzymes/transporters. The CYP3A/Pgp inhibitors 
ketoconazole, lopinavir/ritonavir, ritonavir, darunavir/ritonavir, saquinavir/ritonavir and 
atazanavir ± ritonavir all increased the Cmax and AUC of maraviroc [see Table 9]. The CYP3A 
inducers rifampin, etravirine and efavirenz decreased the Cmax and AUC of maraviroc [see Table 
9].

Tipranavir/ritonavir (net CYP3A inhibitor/Pgp inducer) did not affect the steady state 
pharmacokinetics of maraviroc (see Table 9). Co-trimoxazole and tenofovir did not affect the 
pharmacokinetics of maraviroc.

Table 9 Effect of Coadministered Agents on the Pharmacokinetics of Maraviroc

Coadministered drug  and dose	N	Maraviroc Dose	Ratio (90% CI) of maraviroc pharmacokinetic parameters  with/without coadministered drug  (no effect = 1.00)
			Cmin	AUCtau	Cmax
CYP3A and/or P-gp Inhibitors
Ketoconazole  400 mg QD	12	100 mg BID	3.75  (3.01, 4.69)	5.00  (3.98, 6.29)	3.38  (2.38, 4.78)
Ritonavir  100 mg BID	8	100 mg BID	4.55  (3.37, 6.13)	2.61  (1.92, 3.56)	1.28  (0.79, 2.09)
Saquinavir (soft gel capsules)  /ritonavir  1000 mg/100 mg BID	11	100 mg BID	11.3  (8.96, 14.1)	9.77  (7.87, 12.14)	4.78  (3.41, 6.71)
Lopinavir/ritonavir  400 mg/100 mg BID	11	300 mg BID	9.24  (7.98, 10.7)	3.95  (3.43, 4.56)	1.97  (1.66, 2.34)
Atazanavir  400 mg QD	12	300 mg BID	4.19  (3.65, 4.80)	3.57  (3.30, 3.87)	2.09  (1.72, 2.55)
Atazanavir/ritonavir  300 mg/100 mg QD	12	300 mg BID	6.67  (5.78, 7.70)	4.88  (4.40, 5.41)	2.67  (2.32, 3.08)
Darunavir/ritonavir  600 mg/100 mg BID	12	150 mg BID	8.00  (6.35, 10.1)	4.05  2.94, 5.59	2.29  (1.46, 3.59)
CYP3A and/or P-gp Inducers  Efavirenz  600 mg QD	12	100 mg BID	0.55  (0.43,0.72)	0.552  (0.492, 0.620)	0.486  (0.377, 0.626)
Efavirenz  600 mg QD	12	200 mg BID  (+efavirenz):  100 mg BID  (alone)	1.09  (0.89, 1.35)	1.15  (0.98, 1.35)	1.16  (0.87, 1.55)
Rifampicin  600 mg QD	12	100 mg BID	0.22  (0.17, 0.28)	0.368  (0.328, 0.413)	0.335  (0.260, 0.431)
Rifampicin  600 mg QD	12	200 mg BID  (+rifampicin):  100 mg BID  (alone)	0.66  (0.54, 0.82)	1.04  (0.89, 1.22)	0.97  (0.72, 1.29)
Etravirine  200 mg BID	14	300 mg BID	0.609  (0.525, 0.707)	0.468  (0.381, 0.576)	0.400  (0.282, 0.566)
Nevirapine*  200 mg BID  (+ lamivudine 150 mg BID,  tenofovir 300 mg QD)	8	300 mg SD	–	1.01  (0.65, 1.55)	1.54  (0.94, 2.51)
CYP3A and/or P-gp Inhibitors and Inducers
Lopinavir/ritonavir + efavirenz  400 mg/100 mg BID + 600 mg QD	11	300 mg BID	6.29  (4.72, 8.39)	2.53  (2.24, 2.87)	1.25  (1.01, 1.55)
Saquinavir(soft gel capsules)  /ritonavir + efavirenz  1000 mg/100 mg BID + 600 mg QD	11	100 mg BID	8.42  (6.46, 10.97)	5.00  (4.26, 5.87)	2.26  (1.64, 3.11)
Darunavir/ritonavir + etravirine  600 mg/100 mg BID + 200 mg BID	10	150 mg BID	5.27  (4.51, 6.15)	3.10  (2.57, 3.74)	1.77  (1.20, 2.60)
Tipranavir/ritonavir  500 mg/200 mg BID	12	150 mg BID	1.80  (1.55, 2.09)	1.02  (0.850, 1.23)	86  (0.61, 1.21)
Other
Raltegravir  400 mg BID	17	300 mg BID	0.90  (0.85, 0.96)	0.86  (0.80, 0.92)	0.79  (0.67, 0.94)

* Compared to historical data

Effect of Maraviroc on the Pharmacokinetics of Concomitant Drugs 
Maraviroc is unlikely to inhibit the metabolism of coadministered drugs metabolized by the following 
cytochrome P enzymes (CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, and CYP3A) because 
maraviroc did not inhibit activity of those enzymes at clinically relevant concentrations in vitro. Maraviroc 
does not induce CYP1A2 in vitro.

In vitro results indicate that maraviroc could inhibit P-glycoprotein in the gut and may thus affect 
bioavailability of certain drugs.

Drug interaction studies were performed with maraviroc and other drugs likely to be coadministered or 
commonly used as probes for pharmacokinetic interactions [see Table 6]. Maraviroc had no effect on the 
pharmacokinetics of zidovudine or lamivudine. Maraviroc decreased the Cmin and AUC of raltegravir by 
27% and 37%, respectively, which is not clinically significant. Maraviroc had no clinically relevant effect 
on the pharmacokinetics of midazolam, the oral contraceptives ethinylestradiol and levonorgestrel, no 
effect on the urinary 6ß-hydroxycortisol/cortisol ratio, suggesting no induction of CYP3A in vivo. 
Maraviroc had no effect on the debrisoquine metabolic ratio (MR) at 300 mg twice daily or less in vivo 
and did not cause inhibition of CYP2D6 in vitro until concentrations >100µM. However, there was 234% 
increase in debrisoquine MR on treatment compared to baseline at 600 mg once daily, suggesting potential 
inhibition of CYP2D6 at higher dose.

12.4 Microbiology

Cross-resistance in Cell Culture 
Maraviroc had antiviral activity against HIV-1 clinical isolates resistant to NNRTIs, PIs and 
the fusion inhibitor enfuvirtide in cell culture (EC50 values ranged from 0.7 to 8.9 nM (0.36 to 
4.57 ng/mL)). Maraviroc-resistant viruses that emerged in cell culture remained susceptible to 
the enfuvirtide and the protease inhibitor saquinavir.

Clinical Resistance 
Virologic failure on maraviroc can result from genotypic and phenotypic resistance to 
maraviroc,through outgrowth of undetected CXCR4-using virus present before maraviroc 
treatment (see Tropism below), through resistance to background therapy drugs (Table 10), or 
due to low exposure to maraviroc [see Clinical Pharmacology (12.2)].

Antiretroviral treatment-experienced subjects (Studies A4001027 and A4001028)

Week 48 data from treatment-experienced subjects failing maraviroc-containing regimens 
with CCR5-tropic virus (n=58) have identified 22 viruses that had decreased susceptibility to 
maraviroc characterized in phenotypic drug assays by concentration response curves that did not 
reach 100% inhibition. Additionally, CCR5-tropic virus from 2 of these treatment failure 
subjects had =3-fold shifts in EC50 values for maraviroc at the time of failure.

Fifteen of these viruses were sequenced in the gp120 encoding region and multiple amino 
acid substitutions with unique patterns in the heterogeneous V3 loop region were detected. 
Changes at either amino acid position 308 or 323 (HXB2 numbering) were seen in the V3 loop in 
7 of the subjects with decreased maraviroc susceptibility. Substitutions outside the V3 loop of 
gp120 may also contribute to reduced susceptibility to maraviroc.

Antiretroviral treatment-naïve subjects (Study A4001026)

Treatment-naïve subjects receiving SELZENTRY had more virologic failures and more 
treatment emergent resistance to the background regimen drugs compared to those receiving 
efavirenz (Table 10).

 

Table 10 Development of Resistance to MVC or EFV and Background Drugs in Antiretroviral Treatment-Naïve 
Trial A4001026 for Patients with CCR5-tropic Virus at Screening using Enhanced Sensitivity Trofile® Assay

	MVC	EFV
Total N in Dataset  (As-Treated)	273	241
Total Virologic Failures (As-Treated)	85(31%)	56 (23%)
Evaluable Virologic Failures with Post Baseline Genotypic and  Phenotypic Data	73	43
Lamivudine Resistance	39 (53%)	13 (30%)
Zidovudine Resistance	2 (3%)	0
Efavirenz Resistance	—	23 (53%)
Phenotypic Resistance to MVC*	19 (26 % )

*Includes subjects failing with CXCR4- or dual/mixed-tropism because these viruses are not intrinsically susceptible to maraviroc.

In an as-treated analysis of treatment-naïve subjects at 96 weeks, 32 subjects failed a 
maraviroc-containing regimen with CCR5-tropic virus and had a tropism result at failure; 7 of 
these subjects had evidence of maraviroc phenotypic resistance defined as concentration response 
curves that did not reach 95% inhibition. One additional subject had a =3-fold shift in the EC50 
value for maraviroc at the time of failure. A clonal analysis of the V3 loop amino acid envelope 
sequences was performed from 6 of the 7 subjects. Changes in V3 loop amino acid sequence 
differed between each of these different subjects, even for those infected with the same virus 
clade suggesting that that there are multiple diverse pathways to maraviroc resistance. The 
subjects who failed with CCR5-tropic virus and without a detectable maraviroc shift in 
susceptibility were not evaluated for genotypic resistance.

Of the 32 maraviroc virologic failures failing with CCR5-tropic virus, 20(63%) also had 
genotypic and/or phenotypic resistance to background drugs in the regimen (lamivudine, 
zidovudine).

Tropism 
In both treatment-experienced and treatment-naive subjects, detection of CXCR4-using virus 
prior to initiation of therapy has been associated with a reduced virologic response to maraviroc.

Antiretroviral treatment-experienced subjects 
In the majority of cases, treatment failure on maraviroc was associated with detection of 
CXCR4-using virus (i.e., CXCR4-or dual/mixed-tropic) which was not detected by the tropism 
assay prior to treatment. CXCR4-using virus was detected at failure in approximately 55% of 
subjects who failed treatment on maraviroc by week 48, as compared to 9% of subjects who 
experienced treatment failure in the placebo arm. To investigate the likely origin of the ontreatment 
CXCR4-using virus, a detailed clonal analysis was conducted on virus from 20 
representative subjects (16 subjects from the maraviroc arms and 4 subjects from the placebo 
arm) in whom CXCR4-using virus was detected at treatment failure. From analysis of amino 
acid sequence differences and phylogenetic data, it was determined that CXCR4-using virus in 
these subjects emerged from a low level of pre-existing CXCR4-using virus not detected by the 
tropism assay (which is population-based) prior to treatment rather than from a co-receptor 
switch from CCR5-tropic virus to CXCR4-using virus resulting from mutation in the virus.

Detection of CXCR4-using virus prior to initiation of therapy has been associated with a 
reduced virological response to maraviroc. Furthermore, subjects failing maraviroc BID at week 
48 with CXCR4-using virus had a lower median increase in CD4+ cell counts from baseline (+41 
cells/mm3) than those subjects failing with CCR5-tropic virus (+162 cells/mm3). The median 
increase in CD4+ cell count in subjects failing in the placebo arm was +7 cells/mm3.

Antiretroviral treatment-naïve subjects 
In a 96-week study of antiretroviral treatment-naïve subjects, 14% (12 
/85) who had CCR5-tropic virus at screening with an enhanced sensitivity tropism assay 
(Trofile®) and failed therapy on maraviroc had CXCR4-using virus at the time of treatment 
failure. A detailed clonal analysis was conducted in two previously antiretroviral treatment-naïve 
subjects enrolled in a Phase 2a monotherapy study who had CXCR4-using virus detected after 10 
days treatment with maraviroc. Consistent with the detailed clonal analysis conducted in 
treatment-experienced subjects, the CXCR4-using variants appear to emerge from outgrowth of a 
pre-existing undetected CXCR4-using virus. Screening with an enhanced sensitivity tropism 
assay reduced the number of maraviroc virologic failures with CXCR4- or dual/mixed-tropic 
virus at failure to 12 compared to 24 when screening with the original tropism assay. All but 
one (11/12; 92%) of the maraviroc failures failing with CXCR4 or dual/mixed-tropic virus also 
had genotypic and phenotypic resistance to the background drug lamivudine at failure and 33% 
(4 /12) developed zidovudine-associated resistance substitutions.

Subjects who had CCR5-tropic virus at baseline and failed maraviroc therapy with 
CXCR4-using virus had a median increase in CD4+ cell counts from baseline of +113 cells/mm3 
while those subjects failing with CCR5-tropic virus had an increase of +135 cells/mm3. The 
median increase in CD4+ cell count in subjects failing in the efavirenz arm was + 95 cells/mm3.

14 CLINICAL STUDIES 
The clinical efficacy and safety of SELZENTRY is derived from analyses of data from three 
ongoing studies in adult subjects infected with CCR5-tropic HIV-1: A4001027 and A4001028, 
in antiretroviral treatment-experienced adult subjects and A4001026 in treatment-naïve subjects. 
These studies are supported by a 48-week study in antiretroviral treatment-experienced adult 
subjects infected with dual/mixed-tropic HIV-1, A4001029

• Table 7 was renumbered Table 11
• Table 8 was renumbered Table 12

14.3 Study in Treatment-Naïve Subjects 
Study A4001026 is an ongoing, randomized, double-blind, multicenter study in subjects 
infected with CCR5-tropic HIV-1 classified by the original Monogram Biosciences Trofile™ 
tropism assay. Subjects were required to have plasma HIV-1 RNA =2000 copies/mL and could 
not have: 1) previously received any antiretroviral therapy for >14 days, 2) an active or recent 
opportunistic infection or a suspected primary HIV-1 infection, or 3) phenotypic or genotypic 
resistance to zidovudine, lamivudine, or efavirenz. Subjects were randomized in a 1:1:1 ratio to 
maraviroc 300 mg once daily, maraviroc 300 mg twice daily, or efavirenz 600 mg once daily, 
each in combination with zidovudine/lamivudine. The efficacy and safety of SELZENTRY are 
based on the comparison of SELZENTRY twice daily versus efavirenz. In a pre-planned interim 
analysis at 16 weeks, the maraviroc 300mg once per day treatment arm failed to meet the prespecified 
criteria for demonstrating non-inferiority and was discontinued.

The demographic and baseline characteristics of the maraviroc and efavirenz treatment groups 
were comparable (Table 13). Subjects were stratified by screening HIV-1 RNA levels and by 
geographic region. The median CD4 cell counts and mean HIV-1 RNA at baseline were similar 
for both treatment groups.

Table 13 Demographic and Baseline Characteristics of Subjects in Study A4001026

	SELZENTRY 300 mg BID  + zidovudine/lamivudine  (N=360)	Efavirenz 600 mg QD  + zidovudine/lamivudine  (N=361)
Age (years)
Mean	36.7	37.4
Range	20-69	18-77
Female n (%)	104 (29)	102 (28)
Race, n (%)
White	204 (57)	198 (55)
Black	123 (34)	133 (37)
Asian	6 (2)	5 (1)
Other	27 (8)	25 (7)
Median (Range) CD4 cell count (cells/µL)	241 (5-1422)	254 (8-1053)
Median (Range) HIV-1 RNA (log 10  copies/mL)	4.9 (3 -7)	4.9 (3 –7)

The treatment outcomes at 96 weeks for study A4001026 are shown in Table 14. Treatment 
outcomes are based on reanalysis of the screening samples using a more sensitive tropism assay, 
Enhanced sensitivity Trofile® HIV tropism assay, which became available after the week 48 
analysis, approximately 15% of the subjects identified as CCR5-tropic in the original analysis 
had Dual/Mixed- or CXCR4-tropic virus. Screening with enhanced sensitivity version of the 
Trofile® tropism assay reduced the number of maraviroc virologic failures with CXCR4- or 
Dual/Mixed-tropic virus at failure to 12 compared to 24 when screening with the original 
Trofile® HIV tropism assay.

Table 14: Study Outcome (Snapshot) at Week 96 Using Enhanced Sensitivity Assay †

Outcome at week 96*	SELZENTRY 300 mg BID +  zidovudine/lamivudine  N = 311  n (%)	Efavirenz 600 mg QD +  zidovudine/lamivudine  N = 303  n (%)
Virologic Responders:  (HIV-1 RNA <400 copies/mL)	199 (64)	195 (64)
Virologic Failure:
Non-sustained HIV-1 RNA Suppression	39 (13)	22 (7)
HIV-1 RNA Never Suppressed	9(3)	1(<1)
Virologic Responders:  (HIV-1 RNA <50 copies/mL)	183 (59)	190 (63)
Virologic Failure:
Non-sustained HIV-1 RNA Suppression	43 (14)	25 (8)
HIV-1 RNA Never Suppressed	21 (7)	3 (1)
Discontinuations due to:
Adverse Events	19 (6)	47 (16)
Death	2 (1)	2 (1)
Other	43 (14)	36 (12)

*Week 48 results: Virologic responders (<400): 228/311 (73%) in SELZENTRY, 219/303 (72%) in Efavirenz 
Virologic responders (<50): 213/311 (69 %) in SELZENTRY, 207/303 (68%) in Efavirenz

†The total number of subjects (Ns) in Table 14 represents the subjects who had a CCR5-tropic virus in the reanalysis of screening 
samples using the more sensitive tropism assay. This reanalysis reclassified approximately 15% of subjects shown in Table 13 as 
having Dual/Mixed- or CXCR4-tropic virus. These numbers are different than those presented in table 13 because the numbers 
in Table 13 reflect the subjects with CCR5-tropic virus according to the original tropism assay. 
1 Other reasons for discontinuation include lost to follow-up, withdrawn, protocol violation, and other.

The median increase from baseline in CD4+ cell counts at week 96 was 184 cells/mm3 for the 
SELZENTRY arm compared to 155 cells/mm3 for the efavirenz arm.

The following statement was added to the end of the PI:

Trofile® is a registered trademark of Monogram Biosciences, Inc.

The following changes were made to the Medication Guide:

 

What is SELZENTRY?

 

SELZENTRY is an anti-HIV medicine called a CCR5 antagonist. HIV (Human 
Immunodeficiency Virus) is the virus that causes AIDS (Acquired Immune Deficiency 
Syndrome).

In a study of patients taking HIV medicines for the first time, the number of patients who 
achieved treatment success was similar in those taking either SELZENTRY or efavirenz with 
zidovudine and lamivudine (Combivir®). Nevertheless, in the same study, patients taking 
SELZENTRY along with zidovudine and lamivudine (Combivir®) failed treatment (had virus 
detected in their blood) and developed resistance to zidovudine (Retrovir®) or lamivudine 
(Epivir®) more often than patients taking efavirenz (Sustiva®) in combination with zidovudine 
and lamivudine (Combivir®).

SELZENTRY is used with other anti-HIV medicines in adults with CCR5-tropic HIV-1 
infection. 
Use of SELZENTRY is not recommended in patients with dual/mixed or CXCR4-tropic HIV-1.

How does SELZENTRY work?

When used with other anti-HIV medicines, SELZENTRY may:

• reduce the amount of HIV in your blood. This is called “viral load”.
• increase the number of white blood cells called T (CD4) cells.

Tell your doctor about all of your medical conditions, including if you:

• are breastfeeding or planning to breastfeed. It is recommended that HIV-positive women 
  should not breastfeed their babies. This is because of the chance of passing HIV to your 
  baby. You should not breastfeed if you are taking SELZENTRY because the risk to your 
  baby is unknown. Talk with your doctor about the best way to feed your baby.

Tell your doctor about all the medicines you take, including prescription and non-prescription 
medicines, vitamins and herbal supplements. Certain other medicines may affect the levels of 
SELZENTRY in your blood. Your doctor may need to change your dose of SELZENTRY when 
you take it with certain medicines.

The levels of SELZENTRY in your blood may be changed and your healthcare provider may 
need to adjust your dose of SELZENTRY when taking any of the following medications together 
with SELZENTRY:

– darunavir (Prezista®)/ritonavir (Norvir®) 
– delavirdine (Rescriptor®) 
– lopinavir/ritonavir (Kaletra®) 
– ketoconazole (Nizoral®) 
– atazanavir (Reyataz®) ± ritonavir 
– itraconazole (Sporanox®) 
– saquinavir (Invirase®) ± ritonavir 
– clarithromycin (Biaxin®) 
– nelfinavir (Viracept®) 
– nefazodone (Serzone®) 
– indinavir (Crixivan®) 
– telithromycin (Ketek®) 
– fosamprenavir (Lexiva®)/ritonavir 
– efavirenz (Sustiva®) 
– etravirine (Intelence®) 
– rifampin (Rifadin®) 
– carbamezepine (Tegretol®) 
– phenobarbital (Luminal®) 
– phenytoin (Dilantin®)

The most common side effects of SELZENTRY include colds, cough, fever, rash, 
gastrointestinal side effects including gas and bloating, and dizziness. Tell your doctor about any 
side effect that bothers you or does not go away.

These are not all of the side effects with SELZENTRY. For more information, ask your doctor 
or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 
1-800-FDA-1088.

How should I store SELZENTRY?

• Store SELZENTRY tablets at room temperature from 59 F ? to 86F? (15?C to 30?C).

Selzentry is a CCR5 co-receptor antagonist made by Pfizer.

Richard Klein 
Office of Special Health Issues 
Food and Drug Administration

Kimberly Struble 
Division of Antiviral Drug Products 
Food and Drug Administration

New FDA Apporovals

On November 24, 2009, the Food and Drug Administration granted tentative approval for generic efavirenz tablets, 50 mg, 100 mg, and 200 mg under expedited review procedures for thePresident’s Emergency Plan for AIDS Relief (PEPFAR).

This generic formulation, made by Matrix Laboratories Limited of Hyberdad, India, is indicated in combination with other antiretrovirals for the treatment of HIV-1 infection. This tablet formulation is especially suited to pediatric treatment.

“Tentative approval” means that FDA has concluded that a drug has met all of the required quality, safety and efficacy standards, but that it cannot be marketed in the United States because of existing patent restrictions, and so cannot be granted a “full marketing approval.”  However, tentative approval makes the product eligible to be considered for purchase under the PEPFAR program.

Effective patent dates for all approved drugs can be found in the agency’s publication titled Approved Drug Products with Therapeutic Equivalence Evaluations, also known as the “Orange Book”

FDA conducts an on-site inspection of each manufacturing facility, as well as the facilities that perform the bioequivalance studies prior to granting approval or tentative approval to evaluate the ability of the manufacturer to produce a quality product, and to assess the quality of bioequivalence data supporting the application.

Efavirenz is generic version of the Nonnucleoside Reverse Transcriptate Inhibitor (NNRTI), Sustiva, marketed by Bristol Myers-Squibb.

A list of all Approved and Tentatively Approved Antiretrovirals in Association with the President’s Emergency Plan is available on the FDA website.

Richard Klein 
Office of Special Health Issues 
Food and Drug Administration

Kimberly Struble 
Division of Antiviral Drug Products 
Food and Drug Administration

 

On November 24, 2009, FDA approved revisions to the INTELENCE (etravirine) labeling to include updated results through 48 weeks of dosing for the two Phase 3 trials TMC125-C206 and TMC125-C216 in treatment-experienced patients. This constitutes the required confirmatory data for Traditional approval.

The section below includes the major changes to the labeling. 

HIGHLIGHTS:

The following text depicted in bold type was added to DRUG INTERACTIONS

Co-administration of INTELENCE™ with drugs that are substrates of CYP3A, CYP2C9, and/or CYP2C19 or are transported by P-glycoprotein may alter the therapeutic effect or adverse reaction profile of the co-administered drug(s). (7)

FULL PRESCRIBING INFORMATION

Section 1: INDICATIONS AND USAGE was updated to include the indication is based on Week 48 analyses.

Section 5: WARNINGS AND PRECAUTIONS subsection 5.1 Severe Skin and Hypersensitivity Reactions was further revised since the September 15, 2009 action. Angioedema was added to the description of hypersensitivity reaction.

Section 6: ADVERSE REACTION was revised.  Clinical adverse drug reactions (ADRs) of moderate intensity or greater (≥ Grade 2) and reported in ≥ 2% of subjects treated with INTELENCE™ and occurring at a higher rate compared to placebo (excess of 1%) are peripheral neuropathy and rash. The “Less common Adverse Reactions” subsection was updated and now includes hepatic failure, and acute renal failure.

Table 3: Selected Grade 2 to 4 Laboratory Abnormalities Observed in Treatment-Experienced Subjects was updated to reflect the changes through Week 48

Section 7: DRUG INTERACTIONS was updated to include information on digoxin, maraviroc and provide further clarification to the atazanavir/ritonavir and lopinavir/ritonavir interaction as follows.

Etravirine is an inducer of CYP3A and inhibitor of CYP2C9, CYP2C19and P-glycoprotein.Therefore, co-administration of drugs that are substrates of CYP3A, CYP2C9 and CYP2C19 or are transported by P-glycoprotein with INTELENCE™ may alter the therapeutic effect or adverse reaction profile of the co-administered drug(s) (see Table 3). [See also Clinical Pharmacology (12.3).

Table 3: Established and Other Potentially Significant Drug Interactions: Alterations in Dose or Regimen May Be Recommended Based on Drug Interaction Studies or Predicted Interaction  [See Clinical Pharmacology (12.3)]
Concomitant Drug Class: Drug Name	Effect on Concentration of Etravirine or Concomitant Drug	Clinical Comment
atazanavir/ritonavir*†	↓ atazanavir  ↑ etravirine	Concomitant use of INTELENCE® with atazanavir/ritonavir may cause a significant decrease in atazanavir Cmin by about 38% and loss of therapeutic effect of atazanavir. In addition, the mean systemic exposure (AUC) of etravirine after co-administration of INTELENCE® with atazanavir/ritonavir is anticipated to be about 100% higher than the mean systemic exposure of etravirine observed in the Phase 3 trialsafter co-administration of INTELENCE® and darunavir/ritonavir (as part of the background regimen). INTELENCE® and atazanavir/ritonavir should not be co-administered.
lopinavir/ritonavir*†	↑ etravirine	The mean systemic exposure (AUC) of etravirine after co-administration of INTELENCE® with lopinavir/ritonavir is anticipated to be about 85% higher than the mean systemic exposure of etravirine observed in the Phase 3 trials after co-administration of  INTELENCE® and darunavir/ritonavir (as part of the background regimen). The amount of safety data at these increased etravirine exposures is limited, therefore, INTELENCE® and lopinavir/ritonavir should be co-administered with caution.
CCR5 Antagonists
maraviroc*	↔ etravirine ↓ maraviroc	When INTELENCE® is co-administered with maraviroc in the absence of a potent CYP3A inhibitor (e.g., ritonavir boosted protease inhibitor), the recommended dose of maraviroc is 600 mg b.i.d. No dose adjustment of INTELENCE® is needed
maraviroc/darunavir/ritonavir*‡	↔ etravirine ↑ maraviroc	When INTELENCE® is co-administered with maraviroc in the presence of a potent CYP3A inhibitor (e.g., ritonavir boosted protease inhibitor), the recommended dose of maraviroc is 150 mg b.i.d. No dose adjustment of INTELENCE® is needed.
Other Agents
Antiarrhythmics: digoxin*	↔ etravirine ↑ digoxin	For patients who are initiating a combination of INTELENCE® and digoxin, the lowest dose of digoxin should initially be prescribed. For patients on a stable digoxin regimen and initiating INTELENCE®, no dose adjustment of either INTELENCE® or digoxin is needed.The serum digoxin concentrations should be monitored and used for titration of the digoxin dose to obtain the desired clinical effect.
↑ = increase, ↓ = decrease, ↔ = no change

* The interaction between INTELENCE^® and the drug was evaluated in a clinical study. All other drug interactions shown are predicted.

^† The expected increase in the systemic exposure of etravirine when co-administered with either atazanavir/ritonavir (~100%) or lopinavir/ritonavir (~85%) is theoretical and is based on comparing exposures of etravirine from drug-drug interaction studies with exposures in the pivotal Phase 3 trials (in which darunavir/ritonavir was co-administered as part of the background regimen).

^‡  The reference for etravirine exposure is the pharmacokinetic parameters of etravirine in the presence of darunavir/ritonavir

 

Section 12: CLINICAL PHARMACOLOGY was updated to include the results of the drug interaction trials with maraviroc. The same footnote in Table 4 was added to Table 6.

Pharmacokinetics in Adults

Table 5: Population Pharmacokinetic Estimates of Etravirine 200 mg b.i.d. in HIV-1-Infected Subjects (Integrated Data from Phase 3 Trials at Week 48)*
Parameter	Etravirine 200 mg b.i.d.  N= 575
AUC12h (ng•h/mL)
Geometric Mean ± Standard Deviation	4522 ± 4710
Median (Range)	4380 (458 – 59084)
C0h (ng/mL)
Geometric Mean ± Standard Deviation	297 ± 391
Median (Range)	298 (2 – 4852)

* All HIV-1-infected subjects enrolled in Phase 3 clinical trials received darunavir/ritonavir 600/100 mg b.i.d. as part of their background regimen. Therefore, the pharmacokinetic parameter estimates shown in Table 5 account for reductions in the pharmacokinetic parameters of etravirine due to co-administration of INTELENCE™ with darunavir/ritonavir.

Drug Interactions

Table 5: Drug Interactions: Pharmacokinetic Parameters for Etravirine in the Presence of Co-administered Drugs
Co-administered Drug	Dose/Schedule of Co-administered Drug	N	Exposure	Mean Ratio of Etravirine Pharmacokinetic Parameters 90% CI;  No Effect = 1.00
				Cmax	AUC	Cmin
Co-Administration wtih CCR5 Antagonists
Atazanavir/ritonavir*	300/100 mg q.d.	14	↑	1.30  (1.17-1.44)	1.30  (1.18-1.44)	1.26  (1.2-1.42)
Lopinavir/ritonavir  (soft gel capsule)	400/100 mg b.i.d.	13	↑	1.15  (0.94-1.41)	1.15  (0.94-1.41)	1.23  (0.98-1.53)
Maraviroc	300 mg b.i.d	14	↔	1.05  (0.95-1.17)	1.06  (0.99-1.14)	1.08  (0.9-1.9)
Maraviroc (when co-administered with darunavir/ritonavir) †	150/600/100 mg b.i.d	10	↔	1.08  (0.98-1.20)	1.00  (0.86-1.15)	0.81  (0.65-1.01))
CI = Confidence Interval; N = number of subjects with data; N.A. = not available; ↑ = increase; ↓ = decrease; ↔ = no change; q.d. = once daily; b.i.d. = twice daily *:  The expected increase in the systemic exposure of etravirine when co-administered with either atazanavir/ritonavir (~100 %) or lopinavir/ritonavir (~85 %) is theoretical and is based on comparing exposures of etravirine from drug-drug interaction studies with exposures in the pivotal phase 3 trials (in which darunavir/ritonavir was co-administered as part of the background regimen). †#160;  The reference for etravirine exposures is the pharmacokinetic parameters of etravirine in the presence of darunavir/ritonavir

 

Table 6:Drug Interactions: Pharmacokinetic Parameters for Co-administered Drugs in the Presence of INTELENCE™
Co-administered Drug	Dose/Schedule of Co-administered Drug	N	Exposure	Mean Ratio of Etravirine Pharmacokinetic Parameters 90% CI;  No Effect = 1.00
				Cmax	AUC	Cmin
Co-Administration wtih CCR5 Antagonists
Maraviroc	300 mg b.i.d.	14	↓	0.40  (0.28-0.57)	0.47  (0.38-0.58)	0.61  (0.53-0.71)
Maraviroc (when co-administered with darunavir/ritonavir)*	150/600/100 mg b.i.d.	10	↑	1.77  (1.20-2.60)	3.10  (2.57-3.74)	5.27  (4.516.15)
Digoxin	0.5 mg single dose	16	↑	1.19  (0.96-1.49)	1.18  (0.90-1.56)	NA
CI = Confidence Interval; N = number of subjects with data; N.A. = not available; ↑ = increase; ↓ = decrease; ↔ = no change; q.d. = once daily; b.i.d. = twice daily * compared to maraviroc 150 mg b.i.d..

Section 12.4 Microbiology was updated to include the results of trials C206 and C216 through Week 48. Additionally virologic response by baseline number of IAS-USA Defined NNRTI substitutions, by baseline phenotype and Enfuvirtide use, and by PSS (phenotypic susceptibility score) were updated with the Week 48 results

Section 13: NONCLINICAL TOXICOLOGY was updated to include the results of the carcinogenicity findings in mice and rats as follows:

Etravirine was evaluated for carcinogenic potential by oral gavage administration to mice and rats for up to approximately 104 weeks. Daily doses of 50, 200 and 400 mg/kg were administered to mice and doses of 70, 200 and 600 mg/kg were administered to rats in the initial period of approximately 41-52 weeks. The high and middle doses were subsequently adjusted due to tolerability and reduced by 50% in mice and by 50-66% in rats to allow for completion of the studies. In the mouse study, statistically significant increases in the incidences of hepatocellular carcinoma and incidences of hepatocellular adenomas or carcinomas combined were observed in treated females. In the rat study, no statistically significant increases in tumor findings were observed in either sex. The relevance of these liver tumor findings in mice to humans is not known. Because of tolerability of the formulation in these rodent studies, maximum systemic drug exposures achieved at the doses tested were lower than those in humans at the clinical dose (400 mg/day), with animal vs. human AUC ratios being 0.6-fold (mice) and 0.2-0.7-fold (rats).

 

Section 14: CLINICAL STUDIES was updated to include the 48 week results. Highlights include the following:

Table 12: Outcomes of Treatment at Week 48 of the TMC125-C206 and TMC125-C216 Trials (Pooled Analysis)
	Pooled TMC125-C206 and TMC125-C216 Trials
	INTELLENCE™ + BR  N=599	Placebo + BR  N=604
Virologic Responders at Week 48 Viral Load < 50 HIV-1 RNA copies/mL	359 (60%)	232 (38%)
Virologic Failures (VF) at Week 48 Viral Load ≥ 50 HIV-1 RNA copies/mL	123 (21%)	201 (33%)
Death	11 (2%)	19 (3%)
Discontinuations before Week 48:
due to VF	58 (10%)	110 (18%)
due to Adverse Events	31 (5%)	14 (2%)
due to other reasons	17 (3%)	28 (5%)
BR=background regimen

At Week 48, 70.8% of INTELENCE™-treated subjects achieved HIV-1 RNA < 400 copies/mL as compared to 46.4% of placebo-treated subjects. The mean decrease in plasma HIV-1 RNA from baseline to Week 48 was –2.23 log₁₀ copies/mL for INTELENCE™-treated subjects and –1.46 log₁₀ copies/mL for placebo-treated subjects. The mean CD4+ cell count increase from baseline for INTELENCE™-treated subjects was 96 cells/mm³ and 68 cells/mm³ for placebo-treated subjects.

Of the study population who either re-used or did not use ENF, 57.4% of INTELENCE™-treated subjects and 31.7% of placebo-treated subjects achieved HIV-1 RNA < 50 copies/mL. Of the study population using ENF de novo, 67.3% of INTELENCE™-treated subjects and 57.2% of placebo-treated subjects achieved HIV-1 RNA < 50 copies/mL.

Treatment-emergent CDC category C events occurred in 4% of INTELENCE-treated subjects and 8.4% of placebo-treated subjects.

 

Richard Klein 
Office of Special Health Issues 
Food and Drug Administration

Kimberly Struble 
Division of Antiviral Drug Products 
Food and Drug Administration

Rebecca’s Hollywood Movies Blog

The red carpet at the LA premiere of the Warner Bros Pictures R-rated action pic Ninja Assassin was littered with ninjas… Littered doesn’t sound right. A handful of guys dressed in ninja attire hung out – literally – on scaffolds surrounding the red carpet, which should have made the film’s cast and crew feel right at home. Korean pop singer Rain, who tackles his first leading role in a major feature film, was totally unaffected by the ninjas as he hit the red carpet to talk about Ninja Assassin along with his co-stars Rick Yune and Stephen Marcus, producer Joel Silver, and director James McTeigue (V for Vendetta).

Producer Silver said that Rain’s move from singer to leading man wasn’t that difficult of a leap. “He was a great dancer, but he was able to learn how to do all the fights and understand how to do all the martial arts, and really had great skill at it,” said Silver. “He just took it and ran with it. I mean it was very impressive to see him learn how to do it and watch him do it. He’s very good in the movie and he pulls it off really well.” What else did he have to say about his Ninja Assassinstar? Check out these exclusive interviews for more Ninja news:

• Rain, Stephen Marcus and Producer Joel Silver on Ninja Assassin and Action Scenes
• Rick Yune Talks Ninja Assassin and Director James McTeigue Says He’s Preparing The Raven Next

More on Ninja Assassin:

• Exclusive Ninja Assassin Premiere Photos
• Ninja Assassin Trailer and Clips
• Photos from Ninja Assassin
• 
  

 The preview audience I saw Old Dogs with was either a) in training to provide laugh tracks for TV sitcoms or b) amped up on caffeine or c) the easiest audience ever to sit through a comedy movie. Based on their reaction, Old Dogs is the funniest film of the decade. But I just don’t get what’s so funny. Old Dogsdoesn’t try any new tricks, relying instead on the same old overused gags and tried and true – and tired – topics for jokes. That reliance on old material means the humor of Old Dogs gets old quickly. Read the Old Dogs Review…

Zac Efron Talks About ‘Me and Orson Welles’

Feature film newcomer Christian McKay stars as a 22 year old Orson Welles in Me and Orson Welles, a fictionalized account of Welles’ 1937 staging of Julius Caesar at the Mercury Theatre.High School Musical standout Zac Efron plays a 17 year old actor who is unexpectedly asked to join the play as Lucius just weeks before it opens. Directed by Richard Linklater (Dazed and Confused, The School of Rock, A Scanner Darkly) and adapted for the screen by Holly Gent Palmo and Vincent Palmo Jr, Me and Orson Welles brings the fiery filmmaker’s work to life on the big screen, introducing Welles to a new generation of moviegoers.

Zac Efron read the Robert Kaplow novel the film’s based on, and he was familiar with Orson Welles’ work before taking on the part of Richard Samuels. “I pretty much had the standard, for my age, [knowledge]. I studied him in high school and a little bit before that. I was familiar with a lot of his work, and War of the Worlds.”

Efron quickly discovered that although he knew the basics about Orson Welles, there was a lot left to learn. “Coming into this I thought I was pretty well read on Orson, and then immediately found out that I hadn’t even scratched the surface on this guy. Rick [Linklater, writer/director] really was the one who filled us in and supplied us with endless amounts of literature and articles and the old photos. I think I’ve seen every picture of Orson,” said Efron, laughing.

At the LA press day for the Freestyle Releasing production, Efron recalled his first experience with Welles’ work. “I was probably 16 and I’ve worked with a director who said that his favorite movie of all time was Citizen Kane. And as a wrap gift, he gave me the DVD. I was definitely fascinated by it and I thought that it was an incredible movie. but I was probably too young to fully appreciate it at that point.”

Because Efron’s so popular with a younger audience due to his appearance in the High School Musical franchise, his participation in Me and Orson Welles may encourage teens to check out the film, even though it’s vastly different than Efron’s prior work. “People keep saying, ‘What about Orson Welles is going to attract the young audience?’ What I’m hoping is that the audience that does come is able to enjoy this experience with such an iconic guy, and hopefully it will spark their interest, and they’ll be able to learn more and go and find out about Welles more in depth, his amazing, very interesting, roller coaster career.”

The fact that Me and Orson Welles is so different from his past films is one of the main reasons Efron was eager to become involved in the movie. “[…]It was a very unique opportunity for me at the time, and it still is. I think it was something that just didn’t seem so cut and dry. It wasn’t an obvious decision and even I was a bit surprised, and that’s very cool. I hope I can continue to maintain that, and have those options. I mean, that’s why we do this. To grow, and try new things, and that was exactly what this movie represented for me. So thank god it came at the perfect time,” explained Efron.

 

Zac Efron’s Next Project

Efron will next be seen in theaters in The Death and Life of Charlie St. Cloud which reunites him with his 17 Again director Burr Steers. Asked who he plays, Efron had a difficult time describing what the film’s about. “I play a character named Charlie who is a kind of a golden boy in his high school, and then his life sort of takes a turn, with the death of his little brother, his little brother dies, and it’s a story about how he copes with that. And it’s sort of a love story from that point on. It’s kind of hard to explain. It always comes across like I’m digging graves…”

Viggo Mortensen Talks About ‘The Road’

I’ve always believed Viggo Mortensen is the man, and quite literally he is The Man in The Road. Cormac McCarthy never gave his characters names in the book, and the film adaptation of his work stays true to that, never mentioning any character by name. Set in a post-apocalyptic world, The Road tells the story of a father (Mortensen) who is left alone to care for his young son (newcomer Kodi Smit-McPhee) in a bleak world with few human survivors. Those who have survived get by by traveling from place to place, scrounging for meager scraps of food, or by turning into cannibals. The Man must protect, teach, and comfort The Boy while preparing him for a time when he’s no longer able to educate and guide him.

At the LA press day for the Weinstein Company film, Mortensen recalled his introduction to McCarthy’s book. “I read it the same day that I read the script because I thought, ‘This is a really good script, a tough story but beautiful, and strangely kind of uplifting at the end.’ I went through a lot of things reading the script. I couldn’t believe how much my emotion was condensed into it, and visually what it could be, you know? And so I ran out to the book store and I was happy to see that this was a very faithful adaptation of the book.”

Joe Penhall’s adaptation of McCarthy’s novel could quite possibly be the most faithful adaptation of a book to screen in recent history, and Mortensen felt drained after reading both the book and script in the same day. “Yeah, I was worthless that day,” admitted Mortensen. “I was at my mother’s house, actually, visiting her and she said, ‘So, what do you want to do for dinner?’ ‘Dinner?’ I said, ‘How can I eat now?'”

 

The Skinny on Viggo Mortensen’s Weight Loss

Mortensen had to lose weight in order to play a man who’s existing on just a few scraps of food every couple of days. Asked how he accomplished the weight loss, Mortensen replied, “It took a certain amount of discipline and fortunately I had enough time to get there. I don’t know [how much time]. I mean you can always use more. It was as I was traveling and doing other things, promoting Eastern Promises, actually. It was that period. Even at the Oscar’s for example, that was like a day before shooting our first day. It was bizarre to go to this ceremony when we’d been already preparing, seeing this world and thinking that way, and suddenly I leave the winter of Pittsburgh and this weird area of town that we’re in and I’m suddenly on the red carpet in Hollywood. It was really weird, you know? I felt strangely calm because I said, ‘How bad can it be? It’s fine. It’s nothing compared to what I’m going to be doing the next couple of months. I can handle these photographers. They’re not cannibals, as far as I can tell.’ Maybe they are…”

Since he had to stay as thin as possible, Mortensen couldn’t really enjoy the Oscar parties. “I also had to leave. I had to be on a plane, so no,” said Mortensen. “There was a chocolate shaped Oscar at the Governor’s Ball with gold wrapping and I remember I ate the hat off of that.”

There are flashbacks scenes in The Road that show Mortensen, Smit-McPhee and Charlize Theron (who plays Mortensen’s wife and Smit-McPhee’s mother) in slightly less dire times. Those scenes required Mortensen to look a little more fit, however there just wasn’t time for Mortensen to really put on any weight. “The last few days of the shoot Charlize showed up to do all those flashback scenes, and I was saying, ‘It would be great if I had a week where I could eat and gain some weight,’ because I’m supposed to look healthier and then gradually less as you see the evolution of our relationship and her eventual disappearance. They said, ‘I’m sorry…,’ and so I started cheating. Like a couple days before I started [to cheat] – and I couldn’t eat. My stomach didn’t want that much food. But I started for a couple days before she showed up, and then the day she showed up I was just wolfing down huge amounts of food and really was like, ‘Wow, that’s what that is!’ Not that I wasn’t eating before, but I wasn’t overeating.”

His food of choice? “Lots of Italian food, sweets, lot of sweets. Most of the movie what I ate was dark chocolate and drank a lot of mate, but I indulged myself tremendously to the point where I had to lie down. My body couldn’t take it. It did work. I see I can it in some of the scenes with her.”

 

Bonding with His Young Co-Star

In addition to getting prepared physically for the role, Mortensen had to develop a relationship with the actor who played his son. The two are in nearly every single scene and if we don’t buy their relationship the film does not work. Smit-McPhee may have very few acting credits to his name, but he now can list Mortensen as a fan.

“My first worry when I said yes, which is always what happens to some degree, you say yes when you’re offered this role and then you think, ‘Oh no, now I’ve got to do this. How am I going to do this?’ And in this case more than usual because in talking to the director I knew that he was going to, in principle, do things right as far as the look, shooting in real places and not green screen,” said Mortensen. “The places we were going to shoot in were going to look right. The people he hired, as far as other actors and crew, were all really good. So if we had some luck with the weather, we might have a chance to make this look right.”

 

 

 

“I felt like I had a burden that I hadn’t had before on an emotional level to constantly have this sort of turbulence under the surface, you know, and regret and all these things mixed together,” explained The Road star Viggo Mortensen. How am I going to do that believably against the landscapes? I thought, ‘Well, if this is so raw and so real, and you can look at it as a measuring stick, we can’t be any less real in our feelings and how we do things.’ So I was worried about that. But then as worried, maybe even more worried because I was so dependent – going to be – on whoever played the boy. I said to the director, ‘You know, if we don’t find a genius kid to do this part, we can only do so much. The movie can only reach a certain level. It doesn’t matter how well it’s done, how well designed, or how hard I work or am able to be honest and emotional. We’re limited.’ It really has to work, that relationship, and we’re lucky we found him because he was able to give as good as he got.”

Mortensen added, “One great thing about him is that he’s kind of a prankster. He’s a kid. He’s a well-adjusted kid so as much as he can channel, I don’t know where from, this intense emotion and sadness and presence that he has, that melancholy, he’s a goofball. He’s running around all the time, making fun of people, pulling jokes on people, and that helped us a lot.”

The film was both emotionally and physically challenging, but the relationship he developed with Smit-McPhee helped immensely. “The fact that I was a lot thinner, you know, that I had not much body fat at all meant that I got tired more quickly in the cold weather, I guess, just like Kodi who’s naturally skinny. So that was just trying to stay focused and get through the day, basically. But it wasn’t as hard as the emotional thing sometimes was, although that became easier as my relationship with him became stronger, because I trusted him more and he trusted me more. By the end we really felt like we could do anything together. It was a great feeling to have an acting partner like that.”

If he had to face the same situation as his character in The Road Mortensen’s not at all sure what he would do. “Well, you never know. That’s what makes it dramatically interesting, a story like this. And what makes life interesting, you know? I think it’s something that reaffirmed my belief in the preciousness of life and the value of making the most of life. And, I don’t know. I just think the extra physical and emotional tests that our characters go through in this story forced us to, not just as characters but ourselves too in some cases, to come face to face with and acknowledge our personal weaknesses and strengths. And by the end of the story, I think, to recognize that potential that everybody has, no matter how dire the circumstances might be, to be loving. Just because it’s the right thing, not because it’s useful. When everything is taken away, which is why the wife says, ‘What’s the point?,’ she’s right,” said Mortensen.

“But then it’s a learning thing, this is what the movie teaches I think in a way, if anything, that it’s worthwhile just for its own sake to treat other people and yourself kindly. Sounds silly in a way if you hear that – not silly, it sounds like, ‘Why, yeah, sure, it’s a simple, nice idea, concept,’ but you see the movie and you know what that means. It’s something that’s hard to do, to earn that journey, but when you get that at the end – that’s why it’s strangely uplifting, because you believe that potentially. Not saying you all do, but I did anyway. In a profound way you understand that no matter what, no matter what, it’s always better to be nice. It just is. It’s not always the easy thing and sometimes it’s like, ‘I’ve got a lot of reasons to be annoyed here,’ but still it’s better not to be if you can avoid it, or to recognize when you do things wrong. Which is also what it’s about and what the kid teaches the man, which is done really well, I think.”

 

About That “Viggo’s Retiring From Acting” Story…

News24.com did an interview with Mortensen which made it seem as though Mortensen was throwing in the towel as far as acting was concerned. But, thankfully, that is not what Mortensen meant at all. “[…]Somebody wrote that because they asked me and I just gave them an honest answer. ‘What do you have lined up for the next movie?’ And I said, ‘I don’t. There isn’t anything right now.’ I could have said, ‘Oh, there’s a bunch of things I’m not at liberty to discuss at this time,’ or something like that, like people say. But it was the truth. I didn’t have something lined up. They’re like, ‘Awww, he’s quit.’ And, no, the next thing I’m going to do is a play which is as terrifying to do as The Road to me because I haven’t done a play in over 20 years. And then I think I’m going to do a movie, a very small movie, in Spanish in Argentina about a year from now.”

Top 10 Traditional Christian Christmas Songs

Christmas music is an important part of the whole holiday season. The music and sounds of Christmas come from all styles and genres, providing something for every musical taste. Some carols are totally secular, focusing on the fun of the holiday. Others are much more religious, bringing the reason for the season front and center.Here you will find the Top Traditional Christian Christmas Songs; their history, their lyrics and the Top 10 versions of each one that has been released by a Christian artist or band.

 

1. “O Holy Night”

Sony

The carol has been covered by artists of from just about every style of music. Point of Grace, BarlowGirl, David Phelps, and Smokie Norful are only some of the Christian artists that have released wonderful versions. From Martina McBride, *Nsync and Jewel to Placido Domingo, Johnny Mathis and Joan Baez — secular artists have also done the song justice for years. The Top Christian versions of the carol are found in the following list …

• Top 10 Versions of “O Holy Night” by Christian Artists

2. “What Child Is This?”

Northern Records

Written in 1865, “What Child Is This?” has been covered by artists of from just about every style of music. Kevin Max, Yolanda Adams, ZOEgirl, and Point of Grace are only some of the Christian artists that have released wonderful versions. From Sarah McLachlan, Josh Groban and Jessica Simpson to Johnny Mathis, Joan Baez and Burl Ives — secular artists have also done beautiful versions of the carol. The Top Christian versions of the carol are found in the following list …

• Top 10 Versions of “What Child Is This?” by Christian Artists

3. “Hark! The Herald Angels Sing”

Courtesy of: Blackmore’s Night

“Hark! The Herald Angels Sing” was written in 1739 by Charles Wesley, the brother of the founder of the Methodist church, John Wesley. The carol has been covered by artists of from just about every style of music. Blackmore’s Night, Mahalia Jackson, Charlotte Church, and Diamond Rio are only some of the Christian artists that have released wonderful versions. From Frank Sinatra, Steve Martin and Nat King Cole to Martina McBride, Mariah Carey and Shedaisy — secular artists have also released some wonderful renditions. The Top Christian versions of the carol are found in the following list …

• Top 10 Versions of “Hark! The Herald Angels Sing” by Christian Artists

4. “The First Noel”

Word

“The First Noel” was first published in 1833 when it appeared in Christmas Carols Ancient and Modern, a collection of seasonal carols put together by William B. Sandys. The carol has been covered by artists from just about every style of music. Bebe Winans, Newsong, Third Day, and John P. Kee & The New Life Community Choir are only some of the Christian artists that have released wonderful versions. From Josh Groban, Sarah McLachlan and Vanessa Williams to Emmylou Harris, Joan Baez and Kenny Rogers — secular artists have also done enchanting versions. The Top Christian versions of the carol are found in the following list …

• Top 10 Versions of “The First Noel” by Christian Artists

5. “Angels We Have Heard on High”

Sparrow Records

This popular carol was translated from French to English in 1862. The music and lyrics combined were first published together in a carol collection dated 1855. The carol has been covered by artists from just about every style of music. Sandi Patty, John Michael Talbot, Point Of Grace, and Steven Curtis Chapman are only some of the Christian artists that have released wonderful versions. From Josh Groban, Billy Gilman and Brian Culbertson to Bing Crosby, Joan Baez and Olivia Newton-John — secular artists have sung of the angels as well, in many beautiful and moving ways. The Top Christian versions of the carol are found in the following list …

• Top 10 Versions of “Angels We Have Heard on High” by Christian Artists

6. “Silent Night”

Word

“Silent Night” has been translated into over 300 languages and dialects. It is the song that was sung simultaneously in English and German by troops fighting in WWI during the Christmas truce of 1914.The carol has been covered by artists from just about every style of music. Third Day, MercyMe, Yolanda Adams, and Amy Grant are only some of the Christian artists that have released wonderful versions. From Sinead O’Connor, Josh Groban and Kenny Chesney to Dean Martin, Johnny Cash and Emmylou Harris — secular artists have done the song justice for years. The Top Christian versions of the carol are found in the following list …

 

• Top 10 Versions of “Silent Night” by Christian Artists

7. “Away in a Manger”

Sparrow

The author of the first 2 verses of “Away in a Manger” is unknown, but the 3rd verse was composed by John T. Mc­Far­land. The music was composed by William J. Kirkpatrick in 1895. The carol has been covered by artists from several styles of music. Jim Brickman, Twila Paris, Michael W. Smith, and Steven Curtis Chapman are only some of the Christian artists that have released wonderful versions. From Martina McBride, Dwight Yoakam and Sufjan Stevens to Julie Andrews, Linda Ronstadt and Nat King Cole — secular artists have covered even more versions, making this a carol done in every style you can imagine. The Top Christian versions of the carol are found in the following list …

• Top 10 Versions of “Away in a Manger” by Christian Artists

8. “O Little Town of Bethlehem”

San Juan Music Group

The words to the popular traditional religious Christmas carol “O Little Town of Bethlehem” were written by an Episcopal priest named Phillips Brooks in 1867. The music, titled “St. Louis,” was written by Lewis H. Redner in 1868.The carol has been covered by artists from several styles of music. Sandi Patty, Kathy Troccoli, Steven Curtis Chapman, and Bebe Winans are some of the Christian artists that have released wonderful versions. From Kenny Chesney, Sarah McLachlan and Alabama to Elvis Presley, Emmylou Harris and Frank Sinatra — secular artists have released many moving versions as well. The Top Christian versions of the carol are found in the following list …

 

• Top 10 Versions of “O Little Town of Bethlehem” by Christian Artists

9. “O Come, All Ye Faithful”

Forefront

The words to “O Come, All Ye Faithful” were written by John Francis Wade in 1743. Verses 1-3 and 6 were translated from Latin to English by Frederick Oakeley in 1841, while verses 4 & 5 were translated by William Thomas Brooke.The carol has been covered by artists from just about every style of music. Third Day, Amy Grant, Mahalia Jackson, and Stacie Orrico are only some of the Christian artists that have released wonderful versions. From Josh Groban, Clay Aiken and Martina McBride to Nat King Cole, Elvis Presley and Johnny Cash — secular artists have released some beautiful renditions as well. The Top Christian versions of the carol are found in the following list …

 

• Top 10 Versions of “O Come, All Ye Faithful” by Christian Artists

10. “God Rest Ye Merry, Gentlemen”

Benson Records

The traditional religious carol “God Rest Ye Merry, Gentlemen” was sung for centuries before being first published in Britain in 1833. The story goes that the carol was sung to the gentry by town watchmen who earned extra money during Christmas.The carol has been covered by artists from several styles of music. Jars Of Clay, Steven Curtis Chapman, and MercyMe are some of the Christian artists that have released wonderful versions. From Julie Andrews, Perry Como and Neil Diamond to Mariah Carey, Chicago and Barenaked Ladies — secular artists have also gotten in to the festivities. The Top Christian versions of the carol are found in the following list …

 

Yerba Mate Benefits – Yerba Mate and Weight Loss

What Is Yerba Mate?

Yerba mate (Ilex paraguayenis) is a tree native to the rainforests of South America. A member of the holly family, the tree produces leaves and stems that have long been used to make tea in Brazil, Paraguay, and Argentina. Consumed as a beverage, yerba mate tea (often simply called “yerba mate”) is also used in traditional medicine to treat various health problems.

Uses for Yerba Mate

Yerba mate proponents claim that the tea can help with these health concerns:

weight loss

pain

headaches

fatigue

bad breath

Benefits of Yerba Mate

To date, research on yerba mate’s health effects is very limited. Existing studies suggest that the tea and/or yerba mate extract may be useful for the following:

1) Weight Loss

In a 2001 study of 47 healthy overweight adults, researchers found that taking a mixed herbal preparation (containing yerba mate, guarana, and damiana) three times daily for 45 days induced significant weight loss. The herbal blend also helped participants feel full more quickly while eating.

A more recent study on mice (published in 2009) found that yerba mate may modulate the expression of several obesity-related genes and, in turn, produce a potent anti-obesity effect.

2) Cardiovascular Problems

Yerba mate extract may help attenuate heart-muscle dysfunction resulting from ischemia (a condition that occurs when blockage in a coronary artery reduces blood flow to the heart), according to a 2005 study on rats.

3) DNA Repair

A study published in 2008 found that yerba mate helped neutralize free radicals and protect mice from DNA damage, a hallmark of cancer and other diseases.

Yerba Mate and Cancer

A number of studies have linked chronic consumption of yerba mate with increased risk of bladder, esophageal, lung, and head and neck cancers. Although researchers have yet to determine how or why yerba mate might raise cancer risk, there’s evidence that steeping the tea at high temperatures may promote the absorption of certain carcinogenic compounds found in the plant.

Safety Concerns for Yerba Mate

In some cases, consumption of yerba mate may trigger adverse effects such as anxiety, insomnia, nausea, and headache.

Due to yerba mate’s caffeine content, people with high blood pressure, heart disease, and anxiety should avoid the tea or extract. Women who are pregnant or breastfeeding should also avoid yerba mate.

_Sources:

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_{De Stefani E, Correa P, Fierro L, Fontham E, Chen V, Zavala D. “Black tobacco, maté, and bladder cancer. A case-control study from Uruguay.” Cancer. 1991 15;67(2):536-40.}

_{De Stefani E, Fierro L, Correa P, Fontham E, Ronco A, Larrinaga M, Balbi J, Mendilaharsu M. “Mate drinking and risk of lung cancer in males: a case-control study from Uruguay.” Cancer Epidemiol Biomarkers Prev. 1996 (7):515-9.}

_{Goldenberg D, Lee J, Koch WM, Kim MM, Trink B, Sidransky D, Moon CS. “Habitual risk factors for head and neck cancer.” Otolaryngol Head Neck Surg. 2004 131(6):986-93.}

_{Miranda DD, Arçari DP, Pedrazzoli J Jr, Carvalho Pde O, Cerutti SM, Bastos DH, Ribeiro ML. “Protective effects of mate tea (Ilex paraguariensis) on H2O2-induced DNA damage and DNA repair in mice.” Mutagenesis. 2008 23(4):261-5.}

_{Pintos J, Franco EL, Oliveira BV, Kowalski LP, Curado MP, Dewar R. “Maté, coffee, and tea consumption and risk of cancers of the upper aerodigestive tract in southern Brazil.” Epidemiology. 1994 5(6):583-90.}

_{Schinella G, Fantinelli JC, Mosca SM. “Cardioprotective effects of Ilex paraguariensis extract: evidence for a nitric oxide-dependent mechanism.” Clin Nutr. 2005 24(3):360-6.}