Additions and/or
revisions underlined:
5.1 Hypocalcemia
Sensipar lowers serum calcium and can
lead to hypocalcemia. Significant lowering of serum calcium can cause
paresthesias, myalgias, muscle spasms, tetany, seizures, QT interval
prolongation and ventricular arrhythmia. Life threatening events and fatal
outcomes associated with hypocalcemia have been reported in patients treated
with Sensipar, including in pediatric patients. The safety and effectiveness
of Sensipar have not been established in pediatric patients …
QT Interval Prolongation and Ventricular
Arrhythmia
Decreases in serum calcium can also
prolong the QT interval, potentially resulting in ventricular arrhythmia. Cases
of QT prolongation and ventricular arrhythmia have been reported in patients
treated with Sensipar. Patients with congenital long QT syndrome, history of QT
interval prolongation, family history of long QT syndrome or sudden cardiac
death, and other conditions that predispose to QT interval prolongation and
ventricular arrhythmia may be at increased risk for QT interval prolongation
and ventricular arrhythmias if they develop hypocalcemia due to Sensipar.
Closely monitor corrected serum calcium and QT interval in patients at risk
receiving Sensipar.
Seizures
… the threshold for seizures is lowered
by significant reductions in serum calcium levels. Monitor serum calcium
levels in patients with seizure disorders receiving Sensipar...
… Concurrent administration of Sensipar
with calcium-lowering drugs including other calcium-sensing receptor agonists
could result in severe hypocalcemia. Closely monitor serum calcium in patients
receiving Sensipar and concomitant therapies known to lower serum calcium
levels.
Educate patients on the symptoms of
hypocalcemia and advise them to contact a healthcare provider if they occur.
If corrected serum calcium falls below
the lower limit of normal or symptoms of hypocalcemia develop, start or
increase calcium supplementation (including calcium, calcium-containing
phosphate binders, and/or vitamin D sterols or increases in dialysate calcium
concentration). Sensipar dose reduction or discontinuation of Sensipar may be
necessary.
5.3 Hypotension,
Worsening Heart Failure and/or Arrhythmias Newly titled section with previous
information)
In postmarketing safety surveillance …
PLLR conversion;
revised as below:
Risk Summary
Limited case reports of Sensipar use in
pregnant women are insufficient to inform a drug associated risk of adverse
developmental outcomes. In animal reproduction studies, when female rats were
exposed to cinacalcet during the period of organogenesis through to weaning at
2-3 times the systemic drug levels (based on AUC) at the maximum recommended
human dose (MRHD) of 180 mg/day, peripartum and early postnatal pup loss and
reduced pup body weight gain were observed in the presence of maternal
hypocalcemia..
The estimated background risk of major
birth defects and miscarriage for the indicated populations is unknown. In the
U.S. general population, the estimated background risk of major birth defects
and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%,
respectively.
Data
Animal Data
Pregnant female rats given oral gavage
doses of 2, 25, 50 mg/kg/day cinacalcet during gestation, no teratogenicity was
observed at doses up to 50 mg/kg/day (exposure 4 times those resulting with a
human oral dose of 180 mg/day based on AUC comparison). Decreased fetal body
weights were observed at all doses (less than 1 to 4 times a human oral dose of
180 mg/day based on AUC comparison) in conjunction with maternal toxicity
(decreased food consumption and body weight gain).
In pregnant female rabbits given oral
gavage doses of 2, 12, 25 mg/kg/day cinacalcet during gestation, no adverse
fetal effects were observed (exposures less than with a human oral dose of 180
mg/day based on AUC comparisons). Reductions in maternal food consumption and
body weight gain were seen at doses of 12 and 25 mg/kg/day. Cinacalcet has been shown
to cross the placental barrier in rabbits.
In pregnant rats given oral gavage doses
of 5, 15, 25 mg/kg/day cinacalcet during gestation through lactation, no
adverse fetal or pup (post-weaning) effects were observed at 5 mg/kg/day (exposures
less than with a human therapeutic dose of 180 mg/day based on AUC
comparisons). Higher doses of 15 and 25 mg/kg/day cinacalcet (exposures 2 to 3
times a human oral dose of 180 mg/day based on AUC comparisons) were
accompanied by maternal signs of hypocalcemia (periparturient mortality and
early postnatal pup loss), and reductions in postnatal maternal and pup
body-weight gain.
PLLR conversion;
revised as below:
Risk Summary
There are no data regarding the presence
of Sensipar in human milk or effects on the breastfed infant or on milk
production. Studies in rats showed that cinacalcet was excreted in the milk.
The developmental and health benefits of breastfeeding should be considered
along with the mother’s clinical need for Sensipar and any potential adverse
effects on the breastfed infant from Sensipar or from the underlying maternal
condition.
Additions and/or revisions underlined:
The safety and efficacy of Sensipar have
not been established in pediatric patients.
The use of Sensipar for the
treatment of secondary HPT in pediatric patients with CKD on dialysis
was evaluated in two randomized, controlled studies (Pediatric Study 1 and
Study 2) where 47 pediatric patients aged 6 years to less than 18 years
received at least one dose of Sensipar and in one single-arm study (Pediatric
Study 3) where 17 pediatric patients aged 28 days to less than 6 years received
at least one dose of Sensipar. Dosing with Sensipar in Pediatric Study 1 was
stopped because of a fatality in a Sensipar-treated individual. The individual
was noted to be severely hypocalcemic at the time of death. The cause of death
was multifactorial and a contribution of Sensipar to the death could not be
excluded. Study 1 was terminated
and changes to Sensipar dosing after the fatality were implemented in Pediatric
Study 2 and Study 3 to minimize the risk of severe hypocalcemia. The data in
Pediatric Studies 2 and 3 were insufficient to establish the safety and
efficacy of Sensipar for the treatment of secondary HPT in pediatric patients
with CKD on dialysis. In aggregate, the pediatric studies did not establish a
safe and effective Sensipar dosing regimen for the pediatric population.
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