FDA Safety Changes: Carbatrol, DepoDur, Vectibix 

-MedScape

04/14/2008 - In November and December 2007, the US Food and Drug Administration (FDA) approved safety labeling revisions to advise of the risk for serious rash in genetically at-risk patients receiving treatment with carbamazepine, certain situations associated with an increased risk for respiratory depression after use of morphine sulfate extended-release liposome injection, and the increased risk for toxicity associated with concomitant use of panitumumab intravenous infusion and chemotherapy with or without bevacizumab.

Presence of HLA Allele Linked to Increased Risk for Serious Carbamazepine-Related Rash

On December 11, 2007, the FDA approved safety labeling revisions for carbamazepine extended-release capsules (Carbatrol; Shire, Inc) to warn of the risk for serious rash in genetically at-risk patients receiving treatment with this and other carbamazepine products.

The agency has received reports of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) in patients receiving carbamazepine therapy. Whereas the incidence of these events is approximately 1 to 6 per 10,000 new users in mainly Caucasian countries, it is 10-fold higher in some Asian countries.

An analysis of data from retrospective case-control studies has revealed a strong association between the risk for development of carbamazepine-related SJS and TEN and the presence of the human leukocyte antigen allele B*1502 (HLA-B*1502), which occurs almost exclusively in patients with Asian ancestry.

Prevalence of HLA-B*1502 is highest (15%) in individuals from Hong Kong, Thailand, Malaysia, and parts of the Philippines vs approximately 10% in Taiwan and 4% in North China. South Asians, including Indians, are at moderate risk (2% - 4%, but it may be higher in some groups), whereas patients with Japanese or Korean ancestry are at low risk (< 1%).

The FDA advises that patients with Asian ancestry undergo genetic testing for HLA-B*1502 before beginning carbamazepine therapy. Although the prevalence data provide a rough guide for screening, limitations to its use include wide-rate variability among ethnic groups, difficulty of ascertaining ethnic ancestry, and the potential for mixed ancestry.

Carbamazepine should not be used in patients who test positive for HLA-B*1502 unless the expected benefit clearly outweighs the increased risk for serious skin reactions. Limited evidence suggests that consideration also be given to avoiding other antiepileptic drugs associated with SJS and TEN in patients who test positive for HLA-B*1502 if other therapies are equally acceptable.

The majority of carbamazepine-related SJS and TEN cases (90%) occur within the first few months of treatment; therapy should be permanently discontinued at the first sight of rash, unless the rash is clearly not drug related.

The FDA notes that use of HLA-B*1502 genotyping as a screening tool should not be viewed as a substitute for appropriate clinical vigilance and patient management. Many Asian patients who test positive for HLA-B*1502 will not develop SJS and TEN, and these reactions can also occur in patients of any ethnicity who test negative for HLA-B*1502. The potential role of other factors such as antiepileptic dosing, compliance, concomitant medication, comorbidities, and dermatologic monitoring has not been studied.

Also, the HLA-B*1502 allele has not been found to predict the risk for less severe carbamazepine-related cutaneous reaction, such as anticonvulsant hypersensitivity syndrome or maculopapular eruption.

Carbamazepine extended-release tablets are indicated for the treatment of epilepsy and pain associated with trigeminal neuralgia.

FDA Warns of Settings That Increase Risk for Respiratory Depression From Morphine Sulfate Extended-Release Liposome Injection (DepoDur)

On December 14, 2007, the FDA approved safety labeling revisions for morphine sulfate extended-release liposome epidural injection (DepoDur; Skye Pharma Inc) to warn of settings associated with an increased risk for respiratory depression.

Although the formulation is intended for administration by the epidural route only, postmarketing reports have included cases of intrathecal use. In all cases, signs of prolonged respiratory depression required use of a narcotic antagonist (naloxone) or ventilatory support.

Because a breached dural membrane can lead to intrathecal leakage, particularly when the epidural drug is administered in a bolus, vigilant monitoring of respiratory function for a prolonged period (48 hours) is advised when extended-release morphine sulfate liposome injection is administered after a recent dural puncture. Provision should be made for emergency ventilation to minimize the risk for serious respiratory depression.

Subarachnoid puncture during epidural administration of the product has also been linked to cases of prolonged and serious respiratory depression or apnea, occurring within 12 hours of injection and after apparent recovery from anesthesia. Respiratory depression can be successfully treated with a naloxone bolus or, more commonly, a naloxone infusion; intubation and mechanical ventilation may be necessary in some cases.

Morphine sulfate extended-release liposome injection is indicated for single-dose epidural administration at the lumbar level to treat postoperative pain; it is given before surgery or after clamping the umbilical cord during cesarean delivery. The injection is not intended for intrathecal, intravenous, or intramuscular administration.

FDA Warns Against Concomitant Use of Panitumumab (Vectibix) With Chemotherapy

On November 6, 2007, the FDA approved safety labeling revisions for panitumumab intravenous infusion (Vectibix; Amgen, Inc) to warn of the increased risk for toxicity associated with its addition to chemotherapy with or without bevacizumab.

The warning was based on an interim analysis of data from a randomized (1:1) clinical trial of treatment-naive patients, showing that the addition of panitumumab to bevacizumab and chemotherapy decreased progression-free survival and increased the incidence of National Cancer Institute common toxicology criteria (NCI-CTC) grades 3 to 5 adverse events (87% vs 72%) vs bevacizumab plus chemotherapy alone. Oxaliplatin- and irinotecan-fluoropyrimidine–based regimens were used in 86% and 14% of patients, respectively.

NCI-CTC grade 3/4 adverse events reported at a higher rate in the panitumumab-treated patients included rash/dermatitis/acneiform (26% vs 1%), diarrhea (23% vs 12%), dehydration that primarily occurred in patients with diarrhea (16% vs 5%), hypokalemia (10% vs 4%), stomatitis/mucositis (4% vs < 1%), and hypomagnesemia (4% vs 0%). Grade 3 to 5 pulmonary embolisms also occurred more often in panitumumab-treated patients (7% vs 4%), leading to 3 deaths in that population (< 1%).

Because of these toxicities, patients randomized to receive panitumumab in addition to bevacizumab and chemotherapy received a significantly lower mean relative dose of each chemotherapeutic agent (oxaliplatin, irinotecan, bolus or infusional 5-fluorouracil [5-FU]) during the first 24 weeks of the study vs those randomized to receive bevacizumab and chemotherapy.

The FDA notes that the addition of panitumumab to other chemotherapy regimens has likewise led to an increased risk for toxicity.

In a single-group study of panitumumab in combination with irinotecan/leucovorin/5-FU, 58% of 19 patients experienced NCI-CTC grade 3/4 diarrhea; 1 patient had grade 5 symptoms.

Data from a study of panitumumab plus leucovorin/5-FU/irinotecan revealed a 25% incidence of NCI-CTC grade 3 diarrhea among 24 patients.

Panitumumab is indicated as a single agent for the treatment of epidermal growth factor receptor –expressing metastatic colorectal carcinoma in patients with disease progression while receiving or after chemotherapy regimens containing fluoropyrimidine, oxaliplatin, and irinotecan. It is not indicated for use in combination with chemotherapy.