Guanfacine Extended-Release (Page 3 of 7)

6.2 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of guanfacine. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Less frequent, possibly guanfacine-related events observed in the post-marketing study and/or reported spontaneously, not included in section 6.1, include:

General : edema, malaise, tremor

Cardiovascular : palpitations, tachycardia, rebound hypertension, hypertensive encephalopathy

Central Nervous System : paresthesias, vertigo

Eye Disorders : blurred vision

Musculo-Skeletal System : arthralgia, leg cramps, leg pain, myalgia

Psychiatric : confusion, hallucinations

Reproductive System, Male : erectile dysfunction

Respiratory System : dyspnea

Skin and Appendages : alopecia, dermatitis, exfoliative dermatitis, pruritus, rash

Special Senses : alterations in taste

7 DRUG INTERACTIONS

Table 14 contains clinically important drug interactions with guanfacine extended-release tablets [see Clinical Pharmacology ( 12.3) ] .

Table 14: Clinically Important Drug Interactions: Effect of other Drugs on Guanfacine Extended-Release Tablets
Concomitant Drug Name or Drug Class Clinical Rationale and Magnitude of Drug Interaction Clinical Recommendation
Strong and moderate CYP3A4 inhibitors, e.g., ketoconazole, fluconazole Guanfacine is primarily metabolized by CYP3A4 and its plasma concentrations can be significantly affected resulting in an increase in exposure Consider dose reduction [see Dosage and administration ( 2.7) ]
Strong and moderate CYP3A4 inducers, e.g., rifampin, efavirenz Guanfacine is primarily metabolized by CYP3A4 and its plasma concentrations can be significantly affected resulting in a decrease in exposure Consider dose increase [see Dosage and administration ( 2.7) ]

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category B

Risk Summary

There are no adequate and well-controlled studies of guanfacine extended-release tablets in pregnant women. No fetal harm was observed in rats and rabbits with administration of guanfacine at 4 and 2.7 times, respectively, the maximum recommended human dose. Because animal studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Animal data

Reproduction studies conducted in rats have shown that guanfacine crosses the placenta. However, administration of guanfacine to rats and rabbits at 4 and 2.7 times, respectively, the maximum recommended human dose of 0.12 mg/kg/day on a mg/m 2 basis resulted in no evidence of harm to the fetus. Higher doses (13.5 times the maximum recommended human dose in both rabbits and rats) were associated with reduced fetal survival and maternal toxicity.

8.3 Nursing Mothers

It is not known whether guanfacine is excreted in human milk; however, guanfacine is excreted in rat milk. Because many drugs are excreted in human milk, caution should be exercised when guanfacine extended-release tablets are administered to a nursing woman. Observe human milk-fed infants for sedation and somnolence.

8.4 Pediatric Use

Safety and efficacy of guanfacine extended-release tabletsin pediatric patients less than 6 years of age have not been established. The efficacy of guanfacine extended-release tablets was studied for the treatment of ADHD in five controlled monotherapy clinical trials (up to 15 weeks in duration), one randomized withdrawal study and one controlled adjunctive trial with psychostimulants (8 weeks in duration) in children and adolescents ages 6 to 17 who met DSM-IV ® criteria for ADHD [see ADVERSE REACTIONS ( 6) and CLINICAL STUDIES ( 14) ] .

Animal Data

In studies in juvenile rats, guanfacine alone produced a slight delay in sexual maturation in males and females at 2 to 3 times the maximum recommended human dose (MRHD). Guanfacine in combination with methylphenidate produced a slight delay in sexual maturation and decreased growth as measured by a decrease in bone length in males at a dose of guanfacine comparable to the MRHD and a dose of methylphenidate approximately 4 times the MRHD.

In a study where juvenile rats were treated with guanfacine alone from 7 to 59 days of age, development was delayed as indicated by a slight delay in sexual maturation and decreased body weight gain in males at 2 mg/kg/day and in females at 3 mg/kg/day. The No Adverse Effect Level (NOAEL) for delayed sexual maturation was 1 mg/kg/day, which is equivalent to the MRHD of 4 mg/day, on a mg/m 2 basis. The effects on fertility were not evaluated in this study.

In a study where juvenile rats were treated with guanfacine in combination with methylphenidate from 7 to 59 days of age, a decrease in ulna bone length and a slight delay in sexual maturation were observed in males given 1 mg/kg/day of guanfacine in combination with 50 mg/kg/day of methylphenidate. The NOAELs for these findings were 0.3 mg/kg of guanfacine in combination with 16 mg/kg/day of methylphenidate, which are equivalent to 0.3 and 1.4 times the MRHD of 4 mg/day and 54 mg/day for guanfacine and methylphenidate, respectively, on a mg/m 2 basis. These findings were not observed with guanfacine alone at 1 mg/kg/day or methylphenidate alone at 50 mg/kg/day.

8.5 Geriatric Use

The safety and efficacy of guanfacine extended-release tablets in geriatric patients have not been established.

8.6 Renal Impairment

It may be necessary to reduce the dosage in patients with significant impairment of renal function [see Clinical Pharmacology ( 12.3) ] .

8.7 Hepatic Impairment

It may be necessary to reduce the dosage in patients with significant impairment of hepatic function [see Clinical Pharmacology ( 12.3) ] .

9 DRUG ABUSE AND DEPENDENCE

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