Approved Drug Label (PDF)
5
Warnings and Precautions
5.1 QTc Prolongation
Subsection title revised
Additions and revisions underlined:
SIRTURO prolongs the QTc interval [see Clinical
Pharmacology (12.2)]. Use with drugs that
prolong the QTc interval may cause additive QTc prolongation
[see Adverse Reactions (6)]. In
Study 4, where SIRTURO was administered with the QTc
prolonging drugs clofazimine and
levofloxacin, 5% of patients in the 40-week SIRTURO
treatment group experienced a QTc
> or =500 ms and 43% of patients experienced an increase in
QTc > or =60 ms over baseline. Of the
clofazimine- and levofloxacin-treated patients in the
40-week control arm, 7% of patients
experienced a QTc > or =500 ms and 39% experienced an increase
in QTc > or =60 ms over baseline.
Obtain an ECG before initiation of treatment, 2 weeks after initiation,
during treatment, as
clinically indicated and at the expected time of maximum
increase in the QTc interval of the
concomitantly administered QTc prolonging drugs (as
applicable). Obtain electrolytes at baseline
and during treatment and correct electrolytes as
clinically indicated.
The following may increase the risk for QTc
prolongation when patients are taking SIRTURO:
• use with other QTc prolonging drugs
• a history of Torsade de Pointes
• a history of congenital long QTc syndrome
• a history of or ongoing hypothyroidism
• a history of or ongoing bradyarrhythmias
• a history of uncompensated heart failure
• serum calcium, magnesium, or potassium levels below the
lower limits of normal
Discontinue SIRTURO if the patient develops:
• Clinically significant ventricular arrhythmia
• A QTc interval of greater than 500 ms (confirmed by
repeat ECG)
If syncope occurs, obtain an ECG to detect QTc
prolongation.
5.2 Mortality Imbalance in Clinical Trials
Subsection title revised
Additions and revisions underlined:
An increased risk of death was seen in the SIRTURO
treatment group (9/79, 11.4%)
compared to the placebo treatment
group (2/81, 2.5%) in one placebo-controlled trial in
adults (Study 1; based
on the 120 week visit window). One death occurred during the 24 weeks of administration of SIRTURO. The imbalance
in deaths is unexplained. No discernible pattern between death and sputum culture
conversion, relapse, sensitivity to other drugs
used to treat tuberculosis, HIV status,
or severity of disease could be observed. In a subsequent active-controlled
trial in adults (Study 4), deaths by Week 132 occurred in 11/211 (5.2%)
patients in the 40-week SIRTURO treatment group, 8/202 (4%) patients
in the active-control treatment group
including four of 29 patients
who received SIRTURO as part of a salvage treatment, and 2/143 (1.4%)
patients in the 28-week SIRTURO treatment group [see Adverse Reactions (6.1)].
5.3 Risk of Development of Resistance to Bedaquiline
Additions and revisions underlined:
A
potential for development of resistance to bedaquiline in M. tuberculosis exists [see
Microbiology (12.4)]. Bedaquiline must only be used in an appropriate
combination regimen for the treatment
of pulmonary TB due to M. tuberculosis resistant to at least
rifampin and isoniazid, to reduce the risk of development of resistance to
bedaquiline [see Indications and Usage
(1)].
5.4 Hepatotoxicity
Additions and revisions underlined:
Discontinue
SIRTURO if:
transaminase elevations are accompanied by total bilirubin elevation greater than two
times the upper limit of normal
transaminase elevations are greater than eight times
the upper limit of normal
transaminase elevations are greater
than five times
the upper limit
of normal and persist beyond two weeks
5.5 Drug Interactions
Additions and revisions underlined:
CYP3A4 Inducers
Coadministration of SIRTURO with a moderate
or strong CYP3A4 inducer decreases the systemic
exposure of bedaquiline and may reduce the therapeutic effect of
SIRTURO. Avoid coadministration of SIRTURO with moderate or strong
CYP3A4 inducers, such as efavirenz and rifamycins (i.e., rifampin,
rifapentine and rifabutin) [see Drug
Interactions (7.1)].
CYP3A4 Inhibitors
Coadministration
of SIRTURO with CYP3A4 inhibitors increases the systemic exposure of
bedaquiline, which may increase the risk of adverse
reactions. Closely monitor
patient safety (e.g., liver function) when SIRTURO
is coadministered with CYP3A4 inhibitors [see Drug Interactions
(7.1)].
6
Adverse Reactions
Additions and revisions underlined:
The following serious adverse
reactions are discussed
elsewhere in the labeling:
QTc Prolongation [see Warnings
and Precautions (5.1) and Clinical
Pharmacology (12.2)]
Mortality Imbalance
in Clinical Trials [see Warnings and Precautions (5.2)]
Hepatotoxicity [see Warnings
and Precautions (5.4)]
6.1 Clinical Studies Experience
Extensive changes; please refer to label
7
Drug Interactions
7.1 Effect of Other Drugs on SIRTURO
Newly added subsection:
Strong and Moderate CYP3A4
Inducers
Coadministration of SIRTURO with moderate or strong CYP3A4 inducers may decrease systemic exposure of bedaquiline.
Avoid coadministration of SIRTURO with strong or moderate CYP3A4 inducers [see Clinical Pharmacology (12.3)].
CYP3A4 Inhibitors
Coadministration of SIRTURO with CYP3A4
inhibitors increases the systemic exposure of bedaquiline which may increase
the risk of adverse reactions. Closely monitor patient
safety (e.g., liver function)
when SIRTURO is coadministered with CYP3A4 inhibitors. No dose adjustment of
SIRTURO is needed when coadministered with CYP3A4 inhibitors
[see Clinical Pharmacology (12.3)].
7.3 QTc Interval Prolonging Drugs
Subsection title revised
Additions and revisions underlined:
In clinical
trials of adult patients, additional QTc interval prolongation was observed
during combination treatment with SIRTURO and other QTc prolonging drugs.
In Study 3,
concurrent use of clofazimine with SIRTURO resulted in QTc prolongation: mean
increases in QTc were larger
in the 17 adult patients
who were taking
clofazimine with bedaquiline at Week 24 (mean
change from Day-1 of 32 ms) than in patients who were not taking clofazimine with bedaquiline at Week 24 (mean
change from Day-1 of 12 ms). Monitor ECGs if SIRTURO
is coadministered to patients receiving other drugs that prolong the QTc
interval, and discontinue SIRTURO if there
is evidence of serious ventricular arrhythmia or QTc interval greater than 500
ms [see Warnings and Precautions (5.1)
and Clinical Pharmacology (12.2)]. ECG monitoring should be performed prior to
initiation and at the expected time of maximum increase in the QTc interval of
the concomitantly administered QTc prolonging drugs.
8
Use in Specific Populations
8.4 Pediatric Use
Additions and revisions underlined:
The safety and effectiveness of SIRTURO
have been established in pediatric patients
5 years and older weighing at
least 15 kg. The use of SIRTURO in
this pediatric population is supported by evidence from the study of SIRTURO in
adults together with additional pharmacokinetic and safety data from the
single-arm, open-label, multi-cohort trial that enrolled 30 pediatric patients 5 years to less than 18 years of age with confirmed or probable pulmonary TB caused by M. tuberculosis
resistant to at least rifampin who were treated with SIRTURO for 24 weeks in combination with a background
regimen.
8.5 Geriatric Use
Additions and revisions underlined:
Clinical
studies of SIRTURO did not include sufficient numbers of patients 65 years
of age and older to determine whether they respond differently from younger
adult patients [see Clinical Pharmacology
(12.3)].
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
Medication Guide
What is SIRTURO?
SIRTURO is a diarylquinoline antibiotic prescription medicine
used as a part of combination therapy in adults and children (5 years of age and older and weighing at
least 33 pounds) with pulmonary tuberculosis (TB) of the lungs that
is resistant to at least rifampin and isoniazid.
It is not known
if SIRTURO is safe and effective in:
people who
have a tuberculosis (TB) infection, but do not show symptoms of TB (also known
as latent TB)
people who have TB of the lungs that is not resistant to antibiotics.
PATIENT COUNSELING INFORMATION
Additions and revisions underlined:
Advise the patient to read the FDA-approved patient
labeling (Medication Guide).
Serious Adverse
Reactions
Advise patients
that the following serious side effects can occur with SIRTURO: heart rhythm
abnormalities, death and/or hepatitis. In addition, advise
patients about other potential side effects:
nausea, vomiting, joint pain, increased transaminases, dizziness,
headache, myalgia, diarrhea, increased blood amylase, hemoptysis, chest
pain, anorexia, rash, and/or abdominal pain. Additional testing may be needed to
monitor or reduce the likelihood of adverse effects.
Compliance with Treatment
Advise patients
to take SIRTURO in combination with other antimycobacterial drugs as
prescribed. Emphasize compliance with the full course of therapy. Advise
patients that skipping doses or not completing the full course of therapy may
(1) decrease the effectiveness of the treatment and (2) increase
the likelihood that their mycobacterium may develop resistance and the disease will
not be treatable by SIRTURO or other antimycobacterial drugs in the
future.
. . .
Approved Drug Label (PDF)
8
Use in Specific Populations
8.2 Lactation
Additions and/or revisions underlined:
Risk Summary
Data from a published clinical lactation study
demonstrate higher bedaquiline concentrations in breast milk
compared to maternal plasma, suggesting that bedaquiline accumulates in
breast milk (see Data). Data are insufficient
to determine effects of the drug on the breastfed infants. No data are
available on the effects of the drug on milk production. Because of the
potential for serious adverse reactions in a breastfed infant, including
hepatotoxicity, advise patients that breastfeeding is not recommended
during treatment with SIRTURO and for 27.5 months (5 times the half-life)
after the last dose unless infant formula is not available.
Clinical Considerations
If an infant is exposed
to bedaquiline through breast milk, monitor for signs of
bedaquiline-related adverse reactions, such as hepatotoxicity [see Adverse Reactions (6)].
Data
A clinical lactation study was conducted in two
lactating women who were approximately 7 weeks’ postpartum. Bedaquiline and M2,
its active metabolite, levels were measured between approximately 27 and 48
hours after the last bedaquiline dose, and concentrations of bedaquiline and M2
ranged from 2.61 to 8.11 mg/L and 0.27 to 0.81 mg/L, respectively. The
milk:plasma ratios for bedaquiline and M2 at 27 to 48 hours after the last dose
of bedaquiline ranged from approximately 19 to 29 and 4 to 6, respectively.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
PATIENT COUNSELING
INFORMATION
Additions and/or revisions underlined:
…
Lactation
Advise patients not to breastfeed during
treatment with SIRTURO and for 27.5 months after the last dose unless infant
formula is not available. If an infant is exposed to bedaquiline through
breast milk, advise caregivers to monitor the infant for signs of
bedaquiline-related adverse reactions, such as hepatotoxicity (yellowing of the
eyes and changes in the color of the urine or stool) [see Adverse Reactions (6) and Use in Specific Populations (8.2)].
MEDICATION GUIDE
Additions
and/or revisions underlined:
…
Before you take
SIRTURO, tell your healthcare provider about all your medical conditions
including, if you:
…
are
breastfeeding or plan to breastfeed. Do
not breastfeed while taking SIRTURO, and for
27.5
months (2 years 3 months and 2 weeks) after your last dose, unless formula is
not available. SIRTURO passes into breast milk. Talk to your healthcare
provider about the best way to feed your baby while taking SIRTURO.
…
Approved Drug Label (PDF)
5
Warnings and Precautions
Additions and/or revisions underlined
5.1 Increased Mortality
… Only use SIRTURO
in patients aged 5 years and older when an effective treatment regimen
cannot otherwise be provided [see Adverse
Reactions (6)].
5.4
Hepatotoxicity
… Hepatic-related adverse reactions have
also been reported in pediatric patients 5 years of age and older
[see Adverse Reactions (6.1) …
6
Adverse Reactions
6.1 Clinical Trials Experience
Additions
and/or revisions underlined:
Clinical Studies Experience in Pediatric
Patients
The safety assessment of bedaquiline is
based on the Week 24 analysis from 30 pediatric patients in an ongoing,
single-arm, open-label, multi-cohort trial, (Study 4).
Pediatric
Patients (12 years to less than 18 years of age)
The first cohort was designed to
enroll patients 12 years to less than 18 years of age (fifteen patients
14 years to less than 18 years of age were enrolled) with confirmed or probable
pulmonary MDR-TB infection who received SIRTURO (400 mg once daily for the
first 2 weeks and 200 mg 3
times/week for the following 22 weeks) in combination with a background regimen
[see Clinical Studies (14.2)].
The most common adverse reactions were
arthralgia in 6/15 (40%) patients, nausea in 2/15 (13%) patients, and abdominal
pain in 2/15 (13%) patients. Among the 15 patients, no deaths occurred during
treatment with SIRTURO. Observed laboratory abnormalities were comparable to
those in adults.
Pediatric
Patients (5 years to less than 12 years of age)
The second cohort was designed to enroll
patients 5 years to less than 12 years of age (fifteen patients aged 5 years to
less than 11 years of age were enrolled) with confirmed or probable pulmonary
MDR-TB infection who received SIRTURO (200 mg once daily for the first 2 weeks
and 100 mg 3 times/week for the following 22 weeks) in combination with a
background regimen [see Clinical Studies
(14.2)].
The most common adverse reactions were
related to elevations in liver enzymes (5/15, 33%), and led to discontinuation
of SIRTURO in three patients. Elevations in liver enzymes were reversible upon
discontinuation of SIRTURO and some of the background regimen drugs. Among
these 15 pediatric patients, no deaths occurred during treatment with SIRTURO.
8
Use in Specific Populations
8.4 Pediatric Use
Additions
and/or revisions underlined:
The safety and effectiveness of SIRTURO
have been established in pediatric patients 5 years and older
weighing at least 15 kg. The use of SIRTURO in this pediatric population is
supported by evidence from the study of SIRTURO in adults together with
additional pharmacokinetic and safety data from the single-arm, open-label, multi-cohort
trial that enrolled 30 pediatric patients 5 years to less than 18
years of age with confirmed or probable MDR-TB infection who were to be
treated with SIRTURO for 24 weeks in combination with a background regimen.
The safety, effectiveness and dosage
of SIRTURO in pediatric patients less than 5 years of age and/or
weighing less than 15 kg have not been established.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
MEDICATION GUIDE
Additions
and/or revisions underlined:
What
is SIRTURO?
It is not known if SIRTURO is safe and
effective in:
How
should I take SIRTURO?
Week
1 and Week 2:
Take your prescribed dose 1 time each day.
Week
3 to Week 24:
If you miss your SIRTURO dose during Week 3
to Week 24:
Take
the missed dose as soon as possible and continue taking SIRTURO on the 3 times
a week schedule.
Make sure that there is at least 24 hours between
taking the missed dose and the next scheduled dose.
Do not take more than the prescribed weekly dose in a
7-day period.
SIRTURO 20 mg tablet
or
Crush
tablets and mix with soft food. Soft food such as yogurt, apple sauce, mashed
bananas or porridge may be used. Swallow mixture immediately. Make sure no
remaining medicine is left in container, add more soft food and swallow mixture
immediately.
SIRTURO
20 mg tablets may also be given through certain nasogastric tubes by your
healthcare provider.
SIRTURO 100 mg tablet
What
are the possible side effects of SIRTURO?
SIRTURO
may cause serious side effects, including:
The most common side effects of SIRTURO in
adults include nausea,
joint pain, headache, coughing up blood, or chest pain.
The most common side effects of
SIRTURO in children 12 years to less than 18 years of age
include joint pain, nausea
and stomach pain.
The most common side effect in children 5
years to less than 12 years of age is increased level of liver enzymes in the
blood.
How should I store SIRTURO?
PATIENT COUNSELING INFORMATION
Compliance with Treatment
Additions
and/or revisions underlined:
If a dose is missed during the first 2
weeks of treatment, advise patients not to make up the missed dose but to
continue the usual dosing schedule. From Week 3 onwards, if a dose is missed,
advise patients to take the missed dose as soon as possible, and then resume
the 3 times a week regimen. Ensure that the total dose of SIRTURO during a
7-day period does not exceed the recommended weekly dose (with at least 24
hours between each intake).
Administration Instructions
Advise patients to take SIRTURO with food.
Advise patients who have difficulty
swallowing tablets that SIRTURO 20 mg tablet can be administered by the
following methods:
- Dispersed in water and the
mixture administered immediately. To aid with administration, the
dispersed mixture in water can be further mixed with a beverage (e.g.,
water, milk products, apple juice, orange juice, cranberry juice or
carbonated beverage) or soft food (e.g., yogurt, apple sauce, mashed
banana or porridge) and then administered immediately,
- Crushed and mixed with soft
food and the mixture administered immediately,
- Administered through a
nasogastric tube [see Dosage and
Administration (2.6)].
Use with Alcohol and other Medications
Instruct patients to abstain from alcohol,
hepatotoxic medications or herbal products.
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