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« on: May 11, 2007, 07:28:29 pm » |
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May 2, 2007 — The US Food and Drug Administration (FDA) has approved safety labeling revisions to advise of drug interactions and the potential risk for macular edema associated with the pioglitazone HCl component of pioglitazone/glimepiride tablets and contraindications to somatropin (rDNA origin) replacement therapy.
Pioglitazone Component of Duetact Linked to Drug Interactions, Risk for Macular Edema
On February 6, the FDA approved safety labeling revisions for pioglitazone HCl plus glimepiride tablets (Duetact; Takeda Pharmaceutical Co Ltd) to warn of interactions associated with concomitant use of the pioglitazone component and drugs known to induce or inhibit the cytochrome P (CYP) 450 isoenzyme 2C8 (CYP 2C8).
The metabolism of pioglitazone involves multiple cytochrome P450 (CYP) isoforms, of which CYP 2C8 (and to lesser degrees, CYP 3A4 and CYP 1A1) have the highest activity. Use of a CYP 2C8 inhibitor (eg, gemfibrozil) may therefore significantly increase the area under the curve (AUC) of pioglitazone; use of a CYP 2C8 inducer (eg, rifampin) may cause a significant decrease.
In a clinical study of 10 healthy volunteers, the addition of oral gemfibrozil (600 mg twice daily) to pioglitazone (30 mg) yielded a 226% increase in pioglitazone exposure (AUC0-24) compared with pioglitazone alone.
A similar study (n = 10) showed that concomitant administration of oral rifampin (600 mg once daily) and pioglitazone (30 mg) resulted in a decrease in the AUC of pioglitazone by 54%. The FDA notes that if an inhibitor or inducer of CYP 2C8 is started or stopped during treatment with pioglitazone, changes in diabetes treatment may be required based on clinical response.
The FDA also advised healthcare professionals regarding postmarketing reports of macular edema, sometimes accompanied by peripheral edema, in patients receiving pioglitazone or other thiazolidinediones. Some patients presented with blurred vision or decreased visual acuity, whereas others appear to have been diagnosed during routine ophthalmic examinations. Although the causal role of thiazolidinediones remains unclear, some patients had amelioration of their macular edema following discontinuation of therapy.
In addition to the regular ophthalmic examinations recommended by the American Diabetes Association, the FDA advised prompt referral to an ophthalmologist for diabetic patients who report any type of visual symptom, regardless of medication use or other physical findings.
Pioglitazone plus glimepiride once-daily tablets are indicated for use with diet and exercise to improve glycemic control in patients with type 2 diabetes who are already receiving a combination of the 2 components or whose diabetes is not adequately controlled with a sulfonylurea alone.
Somatropin Recombinant Injections Contraindicated in Acute Critical Illness
On February 12 and 15, the FDA approved safety labeling revisions for somatropin (rDNA origin) subcutaneous injection (Norditropin cartridges, Novo Nordisk Inc; Nutropin and Nutropin AQ, Genentech Inc; and Tev-Tropin, Savient Pharmaceuticals Inc) to advise of contraindications.
Because somatropin is generally contraindicated in the presence of active malignancy, preexisting disease should be inactive and its treatment completed prior to initiation of therapy; in the event of recurrent activity, somatropin use should be discontinued.
In particular, somatropin should not be used in patients with any evidence of progression or recurrence of an underlying intracranial tumor. Although the clinical literature has revealed no relationship between the replacement therapy and central nervous system tumor recurrence or new extracranial tumors, an increased risk for a second neoplasm in children receiving somatropin after their first neoplasm has been reported. These most often involved intracranial tumors, particularly meningiomas, in patients who had received radiation to the head for their first neoplasm. Whether this risk also applies to adults remains unclear.
The FDA also warned that somatropin is contraindicated in patients with acute critical illness caused by complications stemming from open-heart surgery, abdominal surgery, or multiple accidental trauma, and those with acute respiratory failure. Data from 2 placebo-controlled clinical trials of patients without growth hormone deficiency has revealed an increased risk for mortality associated with use of somatropin (5.3 - 8 mg/day) in these settings (41.9% vs 19.3%). The FDA notes that the safety of continuing therapy in patients who concurrently develop these conditions has not been established; in such cases, the potential benefit should be weighed against the risk of continued treatment.
Somatropin also should not be used in patients with Prader-Willi syndrome who are severely obese or who have severe upper respiratory impairment. The contraindication is based on reports of fatalities in children with 1 or more risk factors, including severe obesity; history of upper airway obstruction or sleep apnea; or unidentified respiratory tract infection. Male sex may confer added risk to those with 1 or more of these risk factors.
The FDA notes that somatropin may only be used in the long-term treatment of pediatric patients with genetically confirmed Prader-Willi syndrome when the diagnosis includes that of growth hormone deficiency.
According to the FDA, patients with Prader-Willi syndrome should be evaluated for signs of upper airway obstruction and sleep apnea prior to initiation of somatropin therapy. During treatment, patients should be treated effectively for weight control and monitored for signs of respiratory tract infections with an emphasis on their early diagnosis and aggressive treatment. Treatment should be interrupted in patients showing signs of upper airway obstruction (including onset of increased snoring) and/or sleep apnea.
Norditropin (5-, 10-, or 15-mg cartridges) and Tev-Tropin (5-mg vial) are indicated for the long-term treatment of children with growth failure resulting from an inadequate secretion of normal endogenous growth hormone. Norditropin may also be used to replace endogenous growth hormone in deficient adults who meet criteria for therapy.
In children, Nutropin (5- or 10-mg vials) and Nutropin AQ (10-mg vial/cartridge) are indicated for the long-term treatment of growth failure resulting from lack of adequate endogenous growth hormone secretion, the treatment of growth failure associated with chronic renal insufficiency up to the time of transplantation, the long-term treatment of short stature associated with Turner syndrome, and the long-term treatment of idiopathic short stature. They may also be used to replace endogenous growth hormone in deficient adults who meet treatment criteria.
http://www.fda.gov/medwatch/SAFETY/2007/Feb_PI/Duetact_PI.pdf
http://www.fda.gov/cder/foi/label/2007/019676s030,020522s033lbl.pdf
http://www.fda.gov/medwatch/SAFETY/2007/Feb_PI/NutropinAQ_PI.pdf
http://www.fda.gov/cder/foi/label/2007/019774s014lbl.pdf
http://www.fda.gov/cder/foi/label/2007/021148s015lbl.pdf
Source: http://www.medscape.com/viewarticle/555924?src=mp
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