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Hemangeol(Propranolol Hydrochloride Oral Solution)

2015-03-18 15:05:04 来源: 作者: 【大中小】浏览:420次评论:0条

HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use HEMANGEOL safely and effectively. See full prescribing information for HEMANGEOL.

HEMANGEOL™ (propranolol hydrochloride oral solution)
Initial U.S. Approval: 1967

INDICATIONS AND USAGE

HEMANGEOL oral solution is a beta-adrenergic blocker indicated for the treatment of proliferating infantile hemangioma requiring systemic therapy. (1)

DOSAGE AND ADMINISTRATION

Initiate treatment at ages 5 weeks to 5 months. (2)
Starting dose is 0.15 mL/kg (0.6 mg/kg) twice daily. After 1 week, increase dose to 0.3 mL/kg (1.1 mg/kg) twice daily. After 2 weeks, increase to a maintenance dose of 0.4 mL/kg (1.7 mg/kg) twice daily. (2)
Administer doses at least 9 hours apart during or after feeding. (2)
Readjust dose for changes in the child’s weight. (2)
Monitor heart rate and blood pressure for 2 hours after the first dose or increasing dose. (2)

DOSAGE FORMS AND STRENGTHS

Oral solution: 4.28 mg/mL propranolol hydrochloride (3)

CONTRAINDICATIONS

Premature infants with corrected age <5 weeks (4 )
Infants weighing less than 2 kg (4)
Known hypersensitivity to propranolol or excipients (4)
Asthma or history of bronchospasm (4, 5.3, 6, 10, 17)
Bradycardia (<80 beats per minute), greater than first degree heart block, decompensated heart failure (4, 5.2, 5.4, 10, 17)
Blood pressure <50/30 mmHg (4, 5.2, 10, 17)
Pheochromocytoma (4)

WARNINGS AND PRECAUTIONS

Hypoglycemia: Administer during or after feeding. Do not use in patients who are not able to feed or are vomiting (4, 5.1, 6, 10, 17)
Bradycardia and hypotension (4, 5.2, 17)
Bronchospasm: Avoid use in patients with asthma or lower respiratory infection (4, 5.3, 6, 10, 17)
Increased risk of stroke in PHACE syndrome (5.5)

ADVERSE REACTIONS

The most common adverse reactions to HEMANGEOL (occurring ≥ 10% of patients) were sleep disorders, aggravated respiratory tract infections, diarrhea, and vomiting. (6)

To report SUSPECTED ADVERSE REACTIONS, contact Pierre Fabre Pharmaceuticals, Inc. at 1-855-PFPHARM (737-4276) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

See 17 for PATIENT COUNSELING INFORMATION and Medication Guide.

Revised: 3/2014

FULL PRESCRIBING INFORMATION: CONTENTS*

1 INDICATIONS AND USAGE

2 DOSAGE AND ADMINISTRATION

3 DOSAGE FORMS AND STRENGTHS

4 CONTRAINDICATIONS

5 WARNINGS AND PRECAUTIONS

5.1 Hypoglycemia

5.2 Bradycardia and Hypotension

5.3 Bronchospasm

5.4 Cardiac Failure

5.5 Increased Risk of Stroke in PHACE Syndrome

5.6 Hypersensitivity

6 ADVERSE REACTIONS

6.1 Clinical Trials Experience

6.2 Postmarketing Experience

7 DRUG INTERACTIONS

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

8.3 Nursing Mothers

8.4 Pediatric Use

8.6 Hepatic Impairment

8.7 Renal Impairment

10 OVERDOSAGE

11 DESCRIPTION

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

12.2 Pharmacodynamics

12.3 Pharmacokinetics

12.6 Drug Interactions

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis and Mutagenesis and Impairment of Fertility

13.2 Animal Toxicology and/or Pharmacology

14 CLINICAL STUDIES

16 HOW SUPPLIED/STORAGE AND HANDLING

16.1 How Supplied

16.2 Storage and Handling

17 PATIENT COUNSELING INFORMATION

*: Sections or subsections omitted from the full prescribing information are not listed.

1 INDICATIONS AND USAGE

HEMANGEOL oral solution contains the beta-adrenergic blocker propranolol hydrochloride and is indicated for the treatment of proliferating infantile hemangioma requiring systemic therapy.

2 DOSAGE AND ADMINISTRATION

Initiate treatment at ages 5 weeks to 5 months.

The recommended starting dose of HEMANGEOL is 0.15 mL/kg (0.6 mg/kg) (see Table 1) twice daily, taken at least 9 hours apart. After 1 week, increase the daily dose to 0.3 mL/kg (1.1 mg/kg) twice daily. After 2 weeks of treatment, increase the dose to 0.4 mL/kg (1.7 mg/kg) twice daily and maintain this for 6 months. Readjust the dose periodically as the child’s weight increases.

To reduce the risk of hypoglycemia, administer HEMANGEOL orally during or right after a feeding. Skip the dose if the child is not eating or is vomiting [see Warnings and Precautions (5.1)].

Monitor heart rate and blood pressure for 2 hours after HEMANGEOL initiation or dose increases [see Warnings and Precautions (5.2)].

If hemangiomas recur, treatment may be re-initiated [see Clinical Studies (14)].

HEMANGEOL is supplied with an oral dosing syringe for administration. Administration directly into the child’s mouth is recommended. Nevertheless, if necessary, the product may be diluted in a small quantity of milk or fruit juice, given in a baby’s bottle.

Table 1. Dose Titration According to Weight

	Week 1	Week 2	Week 3 (maintenance)
Weight (kg)	Volume administered	Volume administered	Volume administered
Weight (kg)	twice a day	twice a day	twice a day
2 to <2.5	0.3 mL	0.6 mL	0.8 mL
2.5 to <3	0.4 mL	0.8 mL	1 mL
3 to <3.5	0.5 mL	0.9 mL	1.2 mL
3.5 to <4	0.5 mL	1.1 mL	1.4 mL
4 to <4.5	0.6 mL	1.2 mL	1.6 mL
4.5 to <5	0.7 mL	1.4 mL	1.8 mL
5 to <5.5	0.8 mL	1.5 mL	2 mL
5.5 to <6	0.8 mL	1.7 mL	2.2 mL
6 to <6.5	0.9 mL	1.8 mL	2.4 mL
6.5 to <7	1 mL	2 mL	2.6 mL
7 to <7.5	1.1 mL	2.1 mL	2.8 mL
7.5 to <8	1.1 mL	2.3 mL	3 mL
8 to <8.5	1.2 mL	2.4 mL	3.2 mL
8.5 to <9	1.3 mL	2.6 mL	3.4 mL
9 to <9.5	1.4 mL	2.7 mL	3.6 mL
9.5 to <10	1.4 mL	2.9 mL	3.8 mL
10 to <10.5	1.5 mL	3 mL	4 mL
10.5 to <11	1.6 mL	3.2 mL	4.2 mL
11 to <11.5	1.7 mL	3.3 mL	4.4 mL
11.5 to <12	1.7 mL	3.5 mL	4.6 mL
12 to <12.5	1.8 mL	3.6 mL	4.8 mL

3 DOSAGE FORMS AND STRENGTHS

Oral solution: 4.28 mg/mL propranolol hydrochloride.

Alcohol, paraben and sugar free.

4 CONTRAINDICATIONS

HEMANGEOL is contraindicated in the following conditions:

Premature infants with corrected age < 5 weeks
Infants weighing less than 2 kg
Known hypersensitivity to propranolol or any of the excipients [see Description (11)]
Asthma or history of bronchospasm
Heart rate <80 beats per minute, greater than first degree heart block, or decompensated heart failure
Blood pressure <50/30 mmHg
Pheochromocytoma

5 WARNINGS AND PRECAUTIONS

5.1 Hypoglycemia

HEMANGEOL prevents the response of endogenous catecholamines to correct hypoglycemia and masks the adrenergic warning signs of hypoglycemia, particularly tachycardia, palpitations and sweating. HEMANGEOL can cause hypoglycemia in children, especially when they are not feeding regularly or are vomiting; withhold the dose under these conditions. Hypoglycemia may present in the form of seizures, lethargy, or coma. If a child has clinical signs of hypoglycemia, discontinue HEMANGEOL and call their health care provider immediately or take the child to the emergency room.

Concomitant treatment with corticosteroids may increase the risk of hypoglycemia [see Drug Interactions (7)].

5.2 Bradycardia and Hypotension

HEMANGEOL may cause or worsen bradycardia or hypotension. In the studies of HEMANGEOL for infantile hemangioma the mean decrease in heart rate was about 7 bpm with little effect on blood pressure. Monitor heart rate and blood pressure after treatment initiation or increase in dose. Discontinue treatment if severe (<80 beats per minute) or symptomatic bradycardia or hypotension (systolic blood pressure <50 mmHg) occurs.

5.3 Bronchospasm

HEMANGEOL can cause bronchospasm; do not use in patients with asthma or a history of bronchospasm. Interrupt treatment in the event of a lower respiratory tract infection associated with dyspnea and wheezing.

5.4 Cardiac Failure

Sympathetic stimulation supports circulatory function in patients with congestive heart failure, beta blockade may precipitate more severe failure.

5.5 Increased Risk of Stroke in PHACE Syndrome

By dropping blood pressure, HEMANGEOL may increase the risk of stroke in PHACE syndrome patients with severe cerebrovascular anomalies.

Investigate infants with large facial infantile hemangioma for potential arteriopathy associated with PHACE syndrome prior to HEMANGEOL therapy.

5.6 Hypersensitivity

Beta-blockers will interfere with epinephrine used to treat serious anaphylaxis.

6 ADVERSE REACTIONS

The following serious adverse reactions are discussed in greater detail in other sections of the labeling:

Hypoglycemia and related events, like hypoglycemic seizure [see Warnings and Precautions (5.1)].
Bronchospasm [see Warnings and Precautions (5.3)].

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical
trials of a drug may not reflect the rates observed in clinical practice.

Clinical Trials Experience with HEMANGEOL in Infants with proliferating infantile hemangioma
In clinical trials for proliferating infantile hemangioma, the most frequently reported adverse reactions (>10%) in infants treated with HEMANGEOL were sleep disorders, aggravated respiratory tract infections such as bronchitis and bronchiolitis associated with cough and fever, diarrhea, and vomiting. Adverse reactions led to treatment discontinuation in fewer than 2% of treated patients.

Overall, 479 patients in the pooled safety population were exposed to study drug in the clinical study program (456 in placebo-controlled trials). A total of 424 patients were treated with HEMANGEOL at doses 1.2 mg/kg/day or 3.4 mg/kg/day for 3 or 6 months. Of these, 63% of patients were aged 91-150 days and 37% were aged 35-90 days at randomization.

The following table lists according to the dosage the most common adverse reactions (treatment-emergent adverse events with an incidence at least 3% greater on one of the two doses than on placebo).

Table 2. Treatment-emergent adverse events occurring at least 3% more often on HEMANGEOL than on placebo

Reaction	Placebo N=236	HEMANGEOL 1.2 mg/kg/day N=200	HEMANGEOL 3.4 mg/kg/day N=224
Sleep disorder	5.9%	17.5%	16.1%
Bronchitis	4.7	8.0	13.4
Peripheral coldness	0.4	8.0	6.7
Agitation	2.1	8.5	4.5
Diarrhea	1.3	4.5	6.3
Somnolence	0.4	5.0	0.9
Nightmare	1.7	2.0	6.3
Irritability	1.3	5.5	1.3
Decreased appetite	0.4	2.5	3.6
Abdominal pain	0.4	3.5	0.4

The following adverse events have been observed during clinical studies, with an incidence of less than 1%:

Cardiac disorders: Second degree atrioventricular heart block, in a patient with underlying conduction disorder, required definitive treatment discontinuation [see Warnings and Precautions(5.4

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