Included as part of the PRECAUTIONS section.
Use Of QUALAQUIN For Treatment Or Prevention Of Nocturnal
QUALAQUIN may cause unpredictable serious and
life-threatening hematologic reactions including thrombocytopenia and
hemolytic-uremic syndrome/thrombotic thrombocytopenic purpura (HUS/TTP) in
addition to hypersensitivity reactions, QT prolongation, serious cardiac
arrhythmias including torsades de pointes, and other serious adverse events
requiring medical intervention and hospitalization. Chronic renal impairment
associated with the development of TTP, and fatalities have also been reported.
The risk associated with the use of QUALAQUIN in the absence of evidence of its
effectiveness for treatment or prevention of nocturnal leg cramps, outweighs
any potential benefit in treating and/or preventing this benign, self-limiting
condition [see BOXED WARNING and CONTRAINDICATIONS].
Quinine-induced thrombocytopenia is an immune-mediated
disorder. Severe cases of thrombocytopenia that are fatal or life threatening
have been reported, including cases of HUS/TTP. Chronic renal impairment
associated with the development of TTP has also been reported. Thrombocytopenia
usually resolves within a week upon discontinuation of quinine. If quinine is
not stopped, a patient is at risk for fatal hemorrhage. Upon re-exposure to
quinine from any source, a patient with quinine-dependent antibodies could
develop thrombocytopenia that is more rapid in onset and more severe than the
QT Prolongation And Ventricular Arrhythmias
QT interval prolongation has been a consistent finding in
studies which evaluated electrocardiographic changes with oral or parenteral
quinine administration, regardless of age, clinical status, or severity of
disease. The maximum increase in QT interval has been shown to correspond with
peak quinine plasma concentration [see CLINICAL PHARMACOLOGY]. Quinine
sulfate has been rarely associated with potentially fatal cardiac arrhythmias,
including torsades de pointes, and ventricular fibrillation.
QUALAQUIN has been shown to cause concentration-dependent
prolongation of the PR and QRS interval. At particular risk are patients with
underlying structural heart disease and preexisting conduction system
abnormalities, elderly patients with sick sinus syndrome, patients with atrial
fibrillation with slow ventricular response, patients with myocardial ischemia
or patients receiving drugs known to prolong the PR interval (e.g. verapamil)
or QRS interval (e.g. flecainide or quinidine) [see CLINICAL PHARMACOLOGY].
QUALAQUIN is not recommended for use with other drugs
known to cause QT prolongation, including Class IA antiarrhythmic agents (e.g.,
quinidine, procainamide, disopyramide), and Class III antiarrhythmic agents
(e.g., amiodarone, sotalol, dofetilide).
The use of macrolide antibiotics such as erythromycin
should be avoided in patients receiving QUALAQUIN. Fatal torsades de pointes
was reported in an elderly patient who received concomitant quinine,
erythromycin, and dopamine. Although a causal relationship between a specific
drug and the arrhythmia was not established in this case, erythromycin is a
CYP3A4 inhibitor and has been shown to increase quinine plasma levels when used
concomitantly. A related macrolide antibiotic, troleandomycin, has also been
shown to increase quinine exposure in a pharmacokinetic study [see DRUG
Quinine may inhibit the metabolism of certain drugs that
are CYP3A4 substrates and are known to cause QT prolongation, e.g., astemizole,
cisapride, terfenadine, pimozide, halofantrine and quinidine. Torsades de
pointes has been reported in patients who received concomitant quinine and
astemizole. Therefore, concurrent use of QUALAQUIN with these medications, or
drugs with similar properties, should be avoided [see DRUG INTERACTIONS].
Concomitant administration of QUALAQUIN with the
antimalarial drugs, mefloquine or halofantrine, may result in
electrocardiographic abnormalities, including QT prolongation, and increase the
risk for torsades de pointes or other serious ventricular arrhythmias.
Concurrent use of QUALAQUIN and mefloquine may also increase the risk of
seizures [see DRUG INTERACTIONS].
QUALAQUIN should also be avoided in patients with known
prolongation of QT interval and in patients with clinical conditions known to
prolong the QT interval, such as uncorrected hypokalemia, bradycardia, and
certain cardiac conditions [see CONTRAINDICATIONS].
Concomitant Use Of Rifampin
Treatment failures may result from the concurrent use of
rifampin with QUALAQUIN, due to decreased plasma concentrations of quinine, and
concomitant use of these medications should be avoided [see DRUG
Concomitant Use Of Neuromuscular Blocking Agents
The use of neuromuscular blocking agents should be
avoided in patients receiving QUALAQUIN. In one patient who received
pancuronium during an operative procedure, subsequent administration of quinine
resulted in respiratory depression and apnea. Although there are no clinical
reports with succinylcholine or tubocurarine, quinine may also potentiate
neuromuscular blockade when used with these drugs [see DRUG INTERACTIONS].
Serious hypersensitivity reactions reported with quinine
sulfate include anaphylactic shock, anaphylactoid reactions, urticaria, serious
skin rashes, including Stevens-Johnson syndrome and toxic epidermal necrolysis,
angioedema, facial edema, bronchospasm, and pruritus.
A number of other serious adverse reactions reported with
quinine, including thrombotic thrombocytopenic purpura (TTP) and hemolytic
uremic syndrome (HUS), thrombocytopenia, immune thrombocytopenic purpura (ITP),
blackwater fever, disseminated intravascular coagulation, leukopenia,
neutropenia, granulomatous hepatitis, and acute interstitial nephritis may also
be due to hypersensitivity reactions.
QUALAQUIN should be discontinued in case of any signs or
symptoms of hypersensitivity [see CONTRAINDICATIONS].
Atrial Fibrillation And Flutter
QUALAQUIN should be used with caution in patients with
atrial fibrillation or atrial flutter. A paradoxical increase in ventricular
response rate may occur with quinine, similar to that observed with quinidine.
If digoxin is used to prevent a rapid ventricular response, serum digoxin levels
should be closely monitored, because digoxin levels may be increased with use
of quinine [see DRUG INTERACTIONS].
Quinine stimulates release of insulin from the pancreas,
and patients, especially pregnant women, may experience clinically significant
Patient Counseling Information
See FDA-approved patient labeling (Medication Guide)
Patients should be instructed to:
- Take all of the medication as directed.
- Take no more of the medication than the amount
- Take with food to minimize possible gastrointestinal
If a dose is missed, patients should also be instructed
not to double the next dose. If more than 4 hours has elapsed since the missed
dose, the patient should wait and take the next dose as previously scheduled.
Carcinogenesis, Mutagenesis, Impairment Of Fertility
Carcinogenicity studies of quinine have not been
Genotoxicity studies of quinine were positive in the Ames
bacterial mutation assay with metabolic activation and in the sister chromatid
exchange assay in mice. The sex-linked recessive lethal test performed in Drosophila,
the in vivo mouse micronucleus assay, and the chromosomal aberration assay in
mice and Chinese hamsters were negative.
Impairment of Fertility
Published studies indicate that quinine produces
testicular toxicity in mice at a single intraperitoneal dose of 300 mg/kg
corresponding to a dose of approximately 0.75 times the maximum recommended
human dose (MRHD; 32 mg/kg/day) and in rats at an intramuscular dose of 10
mg/kg/day, 5 days/week, for 8 weeks corresponding to a daily dose of
approximately 0.05 times the MRHD based on body surface area (BSA) comparisons.
The findings include atrophy or degeneration of the seminiferous tubules,
decreased sperm count and motility, and decreased testosterone levels in the
serum and testes. There was no effect on testes weight in studies of oral doses
of up to 500 mg/kg/day in mice and 700 mg/kg/day in rats (approximately 1.2 and
3.5 times the MRHD respectively based on BSA comparisons). In a published study
in 5 men receiving 600 mg of quinine TID for one week, sperm motility was
decreased and percent sperm with abnormal morphology was increased; sperm count
and serum testosterone were unaffected.
Use In Specific Populations
Pregnancy Category C
There are extensive published data but few
well-controlled studies of QUALAQUIN in pregnant women. Published data on over
1,000 pregnancy exposures to quinine did not show an increase in teratogenic
effects over the background rate in the general population; however, the
majority of these exposures were not in the first trimester. In developmental
and reproductive toxicity studies, central nervous system (CNS) and ear
abnormalities and increased fetal deaths occurred in some species when pregnant
animals received quinine at doses about 1 to 4 times the human clinical dose.
Quinine should be used during pregnancy only if the potential benefit justifies
the potential risk to the fetus.
P. falciparum malaria carries a higher risk of
morbidity and mortality in pregnant women than in the general population.
Pregnant women with P. falciparum malaria have an increased incidence of
fetal loss (including spontaneous abortion and stillbirth), preterm labor and
delivery, intrauterine growth retardation, low birth weight, and maternal
death. Therefore, treatment of malaria in pregnancy is important.
Hypoglycemia, due to increased pancreatic secretion of
insulin, has been associated with quinine use, particularly in pregnant women.
Quinine crosses the placenta with measurable blood
concentrations in the fetus. In 8 women who delivered live infants 1 to 6 days
after starting quinine therapy, umbilical cord plasma quinine concentrations
were between 1.0 and 4.6 mg/L (mean 2.4 mg/L) and the mean (±SD) ratio of cord
plasma to maternal plasma quinine concentrations was 0.32 ± 0.14. Quinine
levels in the fetus may not be therapeutic. If congenital malaria is suspected
after delivery, the infant should be evaluated and treated appropriately.
A study from Thailand (1999) of women with P.
falciparum malaria who were treated with oral quinine sulfate 10 mg/kg 3
times daily for 7 days at anytime in pregnancy reported no significant
difference in the rate of stillbirths at > 28 weeks of gestation in women
treated with quinine (10 of 633 women [1.6%]) as compared with a control group
without malaria or exposure to antimalarial drugs during pregnancy (40 of 2201
women [1.8%]). The overall rate of congenital malformations (9 of 633 offspring
[1.4%]) was not different for women who were treated with quinine sulfate
compared with the control group (38 of 2201 offspring [1.7%]). The spontaneous
abortion rate was higher in the control group (10.9%) than in women treated
with quinine sulfate (3.5%) [OR = 3.1; 95% CI 2.1-4.7]. An epidemiologic survey
that included 104 mother-child pairs exposed to quinine during the first 4
months of pregnancy, found no increased risk of structural birth defects was
seen (2 fetal malformations [1.9%]). Rare and isolated case reports describe
deafness and optic nerve hypoplasia in children exposed in utero due to
maternal ingestion of high doses of quinine.
In animal developmental studies conducted in multiple
animal species, pregnant animals received quinine by the subcutaneous or
intramuscular route at dose levels similar to the maximum recommended human
dose (MRHD; 32 mg/kg/day) based on body surface area (BSA) comparisons. There
were increases in fetal death in utero in rabbits at maternal doses ≥ 100
mg/kg/day and in dogs at ≥ 15 mg/kg/day corresponding to dose levels
approximately 0.5 and 0.25 times the MRHD respectively based on BSA
comparisons. Rabbit offspring had increased rates of degenerated auditory nerve
and spiral ganglion and increased rates of CNS anomalies such as anencephaly
and microcephaly at a dose of 130 mg/kg/day corresponding to a maternal dose
approximately 1.3 times the MRHD based on BSA comparison. Guinea pig offspring
had increased rates of hemorrhage and mitochondrial change in the cochlea at
maternal doses of 200 mg/kg corresponding to a dose level of approximately 1.4
times the MRHD based on BSA comparison. There were no teratogenic findings in
rats at maternal doses up to 300 mg/kg/day and in monkeys at doses up to 200
mg/kg/day corresponding to doses approximately 1 and 2 times the MRHD
respectively based on BSA comparisons.
In a pre-postnatal study in rats, an estimated oral dose
of quinine sulfate of 20 mg/kg/day corresponding to approximately 0.1 times the
MRHD based on BSA comparison resulted in offspring with impaired growth, lower
body weights at birth and during the lactation period, and delayed physical
development of teeth eruption and eye opening during the lactation period.
Labor And Delivery
There is no evidence that quinine causes uterine
contractions at the doses recommended for the treatment of malaria. In doses
several-times higher than those used to treat malaria, quinine may stimulate
the pregnant uterus.
There is limited information on the safety of quinine in
breastfed infants. No toxicity was reported in infants in a single study where
oral quinine sulfate (10 mg/kg every 8 hours for 1 to 10 days) was administered
to 25 lactating women. It is estimated from this study that breastfed infants
would receive less than 2 to 3 mg per day of quinine base ( < 0.4% of the
maternal dose) via breast milk [see CLINICAL PHARMACOLOGY].
Although quinine is generally considered compatible with
breastfeeding, the risks and benefits to infant and mother should be assessed.
Caution should be exercised when administered to a nursing woman.
If malaria is suspected in the infant, appropriate
evaluation and treatment should be provided. Plasma quinine levels may not be
therapeutic in infants of nursing mothers receiving QUALAQUIN.
The safety and efficacy of QUALAQUIN in pediatric
patients under the age of 16 has not been established.
Clinical studies of quinine sulfate did not include
sufficient numbers of subjects aged 65 and over to determine whether they
respond to treatment differently from younger subjects. Other reported clinical
experience has not identified differences in responses between the elderly and
Clearance of quinine is decreased in patients with severe
chronic renal failure. The dosage and dosing frequency should be reduced [see DOSAGE
AND ADMINISTRATION, CLINICAL PHARMACOLOGY].
In patients with severe hepatic impairment (Child-Pugh
C), quinine oral clearance (CL/F) is decreased, volume of distribution (Vd/F)
is increased, and half-life is prolonged, relative to subjects with normal
liver function. Therefore, quinine is not indicated in patients with severe
hepatic impairment and alternate therapy should be administered [see DOSAGE
AND ADMINISTRATION and CLINICAL PHARMACOLOGY].
Close monitoring is recommended for patients with mild
(Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment, as exposure to
quinine may be increased relative to subjects with normal liver function [see