LANOXIN (Page 7 of 8)

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Digoxin showed no genotoxic potential in in vitro studies (Ames test and mouse lymphoma). No data are available on the carcinogenic potential of digoxin, nor have studies been conducted to assess its potential to affect fertility.

14 CLINICAL STUDIES

14.1 Chronic Heart Failure

Two 12-week, double-blind, placebo-controlled studies enrolled 178 (RADIANCE trial) and 88 (PROVED trial) adult patients with NYHA Class II or III heart failure previously treated with oral digoxin, a diuretic, and an ACE inhibitor (RADIANCE only) and randomized them to placebo or treatment with LANOXIN Tablets. Both trials demonstrated better preservation of exercise capacity in patients randomized to LANOXIN. Continued treatment with LANOXIN reduced the risk of developing worsening heart failure, as evidenced by heart failure-related hospitalizations and emergency care and the need for concomitant heart failure therapy.

DIG Trial of LANOXIN in Patients with Heart Failure

The Digitalis Investigation Group (DIG) main trial was a 37-week, multicenter, randomized, double-blind mortality study comparing digoxin to placebo in 6800 adult patients with heart failure and left ventricular ejection fraction less than or equal to 0.45. At randomization, 67% were NYHA class I or II, 71% had heart failure of ischemic etiology, 44% had been receiving digoxin, and most were receiving a concomitant ACE inhibitor (94%) and diuretics (82%). As in the smaller trials described above, patients who had been receiving open-label digoxin were withdrawn from this treatment before randomization. Randomization to digoxin was again associated with a significant reduction in the incidence of hospitalization, whether scored as number of hospitalizations for heart failure (relative risk 75%), risk of having at least one such hospitalization during the trial (RR 72%), or number of hospitalizations for any cause (RR 94%). On the other hand, randomization to digoxin had no apparent effect on mortality (RR 99%, with confidence limits of 91-107%).

14.2 Chronic Atrial Fibrillation

Digoxin has also been studied as a means of controlling the ventricular response to chronic atrial fibrillation in adults. Digoxin reduced the resting heart rate, but not the heart rate during exercise.

In 3 different randomized, double-blind trials that included a total of 315 adult patients, digoxin was compared to placebo for the conversion of recent-onset atrial fibrillation to sinus rhythm. Conversion was equally likely, and equally rapid, in the digoxin and placebo groups. In a randomized 120-patient trial comparing digoxin, sotalol, and amiodarone, patients randomized to digoxin had the lowest incidence of conversion to sinus rhythm, and the least satisfactory rate control when conversion did not occur.

In at least one study, digoxin was studied as a means of delaying reversion to atrial fibrillation in adult patients with frequent recurrence of this arrhythmia. This was a randomized, double-blind, 43-patient crossover study. Digoxin increased the mean time between symptomatic recurrent episodes by 54%, but had no effect on the frequency of fibrillatory episodes seen during continuous electrocardiographic monitoring.

16 HOW SUPPLIED/STORAGE AND HANDLING

LANOXIN (digoxin) Injection, 500 mcg (0.5 mg) in 2 mL (250 mcg [0.25 mg] per mL); box of 10 ampules (NDC 70515 260 10)

LANOXIN (digoxin) Injection, 500 mcg (0.5 mg) in 2 mL (250 mcg [0.25 mg] per mL); box of 10 vials (NDC 70515 261 10)

LANOXIN (digoxin) Injection Pediatric, 100 mcg (0.1 mg) in 1 mL; box of 10 ampules (NDC 70515 262 10)

LANOXIN (digoxin) Injection Pediatric, 100 mcg (0.1 mg) in 1 mL; box of 10 vials (NDC 70515 263 10)

Store at 25 °C (77 °F); excursions permitted to 15 °C to 30 °C (59 °F to 86 °F) [see USP Controlled Room Temperature] and protect from light.

17 PATIENT COUNSELING INFORMATION

Advise patients to contact their doctor or a health care professional if they experience nausea, vomiting, persistent diarrhea, confusion, weakness, or visual disturbances (including blurred vision, green-yellow color disturbances, halo effect) as these could be signs that the dose of LANOXIN may be too high.
Advise parents or caregivers that the symptoms of having too high LANOXIN doses may be difficult to recognize in infants and pediatric patients. Symptoms such as weight loss, failure to thrive in infants, abdominal pain, and behavioral disturbances may be indications of digoxin toxicity.
Instruct the patient to monitor and record their heart rate and blood pressure daily.

LANOXIN is registered trademark of GlaxoSmithKline.

Covis Logo

Manufactured for
Covis PharmaZug, 6300 Switzerland

2019, Covis Pharma. All rights reserved.

PRINCIPAL DISPLAY PANEL — Adult Carton Label — Ampule

Principal Display Panel -- Adult Carton Label -- Ampule
(click image for full-size original)

Adult Carton Label — Ampule

C O V I S

10 ampuls 2 mL each NDC 70515-260-10

LANOXIN® (digoxin) Injection

500 mcg (0.5 mg) in 2 mL
(250 mcg [0.25 mg] per mL)

A sterile solution for intravenous or intramuscular injection. Dilution not required.

In a vehicle of 40% propylene glycol and 10% alcohol. Dibasic sodium phosphate
0.17%, citric acid anhydrous 0.08%.

See prescribing information for dosage information.

Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP
Controlled Room Temperature] and protect from light.

Rx only

Manufactured for
Covis Pharma
Zug, 6300 Switzerland
Made in Germany©2017, Covis Pharma

PRINCIPAL DISPLAY PANEL — Adult Carton Label — Vial

Principal Display Panel -- Adult Carton Label -- Vial
(click image for full-size original)

Adult Carton Label — Vial

C O V I S

NDC 70515-261-10 10 vials 2 mL each

LANOXIN® (digoxin) Injection

500 mcg (0.5 mg) in 2 mL
(250 mcg [0.25 mg] per mL).

Rx only

NDC 70515-261-10
LANOXIN® (digoxin) Injection 500 mcg (0.5 mg) in 2 mL (250 mcg [0.25 mg] per mL)

A sterile solution for intravenous or intramuscular injection. Dilution
not required.

In a vehicle of 40% propylene glycol and 10% alcohol. Dibasic sodium
phosphate 0.17%, citric acid anhydrous 0.08%.

See prescribing information for dosage information.

Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F)
[see USP Controlled Room Temperature] and protect from light.

GTIN XXXXXXXXXXXXXX
S/N XXXXXXXXXXXX

Lot XXXXXX
Exp MMM YYYY

Manufactured for
Covis Pharma
Zug, 6300 Switzerland

Made in Germany©2019, Covis Pharma

PRINCIPAL DISPLAY PANEL — Pediatric Carton Label — Ampule

Principal Display Panel -- Pediatric Carton Label -- Ampule
(click image for full-size original)

Pediatric Carton Label — Ampule

NDC 70515-262-10 10 ampuls 1 mL each

LANOXIN® (digoxin) Injection
Pediatric

100 mcg (0.1 mg) in 1 mL

A sterile solution for intravenous or intramuscular injection. Dilution not required. In a vehicle of
40% propylene glycol and 10% alcohol. Sodium phosphate 0.17%. Citric acid anhydrous 0.08%.

See prescribing information for dosage information.

Store at 25°C (77°F); excursions permitted to 15 to 30°C (59 to 86°F) [see USP Controlled Room Temperature] and protect from light.

Rx only C O V I S

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