Simponi is a recently approved human monoclonal antibody for the treatment of rheumatic diseases. Its indications include:

• Moderately to severely active Rheumatoid Arthritis (RA) in adults, in combination with methotrexate.
• Active Psoriatic Arthritis (PsA) in adults, alone or in combination with methotrexate.
• Active Ankylosing Spondylitis in adults (AS).

According to the FDA, histoplasmosis and other invasive fungal infections are not consistently recognized in patients under other TNF-α blockers such as Cimzia (certolizumab pegol), Enbrel (etanercept), Humira (adalimumab), and Remicade (infliximab). This has resulted in delays in appropriate antifungal treatment, which in some cases has lead to death. The agency also added  a Boxed Warning to this group of medications,  alerting about an increased risk of  lymphoma.

Also, the UK’s National Institute for Health and Clinical Excellence (NICE) issued in February 2009 an update of the rheumatoid arthritis clinical guidelines.

Source

MedWatch: The FDA Safety Information and Adverse Event Reporting Program. Simponi (golimumab)

In addition to the updated Boxed Warning, FDA is requiring several other changes to the prescribing information for TNF blockers to warn of and mitigate the risks associated with these drugs. These changes are based on additional safety reviews and include a(n):

Source.  FDA alert: Information for Healthcare Professionals: Tumor Necrosis Factor (TNF) Blockers (marketed as Remicade, Enbrel, Humira, Cimzia, and Simponi).

This 2008 video was an alert on possible association between TNF blockers and the development of lymphomas. At that time, the FDA was in the middle of an ongoing safety review, and did not take any regulatory action.

Further reading

Follow-up to the June 4, 2008 Early Communication about the Ongoing Safety Review of Tumor Necrosis Factor (TNF) Blockers (marketed as Remicade, Enbrel, Humira, Cimzia, and Simponi)

Early Communication About an Ongoing Safety Review of Tumor Necrosis Factor (TNF) Blockers (marketed as Remicade, Enbrel, Humira, and Cimzia)

In addition to the alert, the FDA requested the manufacturer (Roche) to conduct in vitro studies to assess the potential of precipitation of ceftriaxone and calcium  when ceftriaxone and calcium-containing products are mixed in vials and infusion lines.

The updated recommendations include the following:
Concomitant use of ceftriaxone and intravenous calcium-containing products is contraindicated in neonates (<28 days of age). Ceftriaxone should not be used in neonates (<28 days of age) if they are receiving (or are expected to receive) calcium-containing intravenous products.

In patients >28 days of age, ceftriaxone and calcium-containing products may be administered sequentially, provided the infusion lines are thoroughly flushed between infusions with a compatible fluid.

Ceftriaxone must not be administered simultaneously with intravenous calcium-containing solutions via a Y-site in any age group.

FDA now recommends that ceftriaxone and calcium-containing products may be used concomitantly in patients >28 days of age, using the precautionary steps above because the risk of precipitation is low in this population.

FDA had previously recommended, but no longer recommends, that in all age groups ceftriaxone and calcium-containing products should not be administered within 48 hours of one another.

In addition, the agency repeats three of the 2007 recommendations:

Do not reconstitute or mix ceftriaxone with a calcium-containing product, such as Ringer’s or Hartmann’s solution or parenteral nutrition containing calcium, because particulate formation can result.

There are no data on interactions between intravenous ceftriaxone and oral calcium-containing products or between intramuscular ceftriaxone and intravenous or oral calcium-containing products.

Report patients who have adverse events following ceftriaxone administration to the FDA’s MedWatch program.

The warning includes serious adverse effects such as:

Gastrointestinal perforation (with very high mortality). This risk is increased in patients receiving concomitant anti-angiogenic therapy, corticosteroids, NSAIDs, or taxane-based chemotherapy, and it is also greater in those with a history of peptic ulceration or diverticular disease. Erlotinib (Tarceva) should be permanently discontinued if the patient develops gastrointestinal perforation.

Dermatologic adverse effects: these may include Stevens-Johnson syndrome and toxic epidermal necrolysis.

Ophthalmic adverse effects: such as corneal perforation or ulceration.

Further reading

Dear Healthcare Professional Letter – OSI – Genentech

The FDA announced the approval of Avastin (bevacizumab) for the treatment of glioblastoma multiforme.

Glioblastoma multiforme (GBM) is the most frequent and most aggressive type of primary brain tumor.

This is an excerpt from the FDA’s prescribing  information:

Avastin is indicated for the treatment of glioblastoma with progressive disease following prior therapy as a single agent.

The effectiveness of Avastin in glioblastoma is based on an improvement in objective response rate.  There are no data demonstrating an improvement in disease-related symptoms or increased survival with Avastin

Download PDF full text

Mechanism of action

Bevacizumab is a monoclonal antibody that acts as a VEGF ( Vascular Endothelial Growth Factor) inhibitor, this produces an inhibition of the process of angiogenesis.

Source: Nature Reviews

This video explains in a very simple way the role VEGF plays in angiogenesis.

Other approved indications for the use of bevacizumab in oncology

Metastatic colon carcinoma (Approved in June 2006)

A first-line treatment of patients with locally advanced, metastatic or recurrent non-small cell lung cancer in combination with platinum-based chemotherapy (October  2006)

Metastatic HER2 negative breast cancer:  in combination with paclitaxel for the treatment of patients who have not received chemotherapy (February 2008).

What FDA says about Avastin (bevacizumab) adverse effects:

The most serious side effects associated with Avastin, in some cases resulting in death, are gastrointestinal perforation, wound healing complications, hemorrhage, and blood clots. Other serious side effects of Avastin are severe high blood pressure, nervous system and vision disturbances, decreased white blood cell counts, infection, stroke, myocardial infarction, and kidney problems.

The most common adverse reactions were nose bleeds, headache, high blood pressure, runny nose, excess proteins in the urine, taste alteration, dry skin, rectal bleeding, excessive tearing, and skin peeling.

Now the agency issues a patient safety warning on the same topic. This has brought about some legal implications, many law firms now offer legal representation for patients who suffered metoclopramide side effects.

This neurology video shows some more examples of patients that suffer tardive dyskinesia.

The U.S. Food and Drug Administration today issued an alert to health care professionals reminding them that single-patient insulin pens and insulin cartridges should not be used to administer medication to multiple patients due to the potential risk of transmitting blood-borne pathogens such as HIV and the hepatitis viruses.

Insulin pens are pen-shaped injector devices that contain a disposable needle and either an insulin reservoir or an insulin cartridge. The devices typically contain enough insulin for a patient to self-administer several doses of insulin before the reservoir or cartridge is empty. All insulin pens are approved only for single-patient use (one device for only one patient).

 

Amy Egan, M.D., deputy director of safety at the FDA’s Division of Metabolism and Endocrinology Products in the Center for Drug Evaluation and Research declared:

“Insulin pens are not designed, and are not safe, for one pen to be used by more than one patient, even if needles are changed between patients due to the risk of transmitting blood-borne pathogens.”

Further information on the CDER website: Information for Healthcare Professionals: Risk of Transmission of Blood-borne Pathogens from Shared Use of Insulin Pens

The U.S. Food and Drug Administration announced today that manufacturers of metoclopramide, a drug used to treat gastrointestinal disorders, must add a boxed warning to their drug labels about the risk of its long-term or high-dose use. Chronic use of metoclopramide has been linked to tardive dyskinesia, which may include involuntary and repetitive movements of the body, even after the drugs are no longer taken.

Current product labeling warns of the risk of tardive dyskinesia with chronic metoclopramide treatment. The development of this condition is directly related to the length of time a patient is taking metoclopramide and the number of doses taken. Those at greatest risk include the elderly, especially older women, and people who have been on the drug for a long time.

Tardive dyskinesia is characterized by involuntary, repetitive movements of the extremities, or lip smacking, grimacing, tongue protrusion, rapid eye movements or blinking, puckering and pursing of the lips, or impaired movement of the fingers. These symptoms are rarely reversible and there is no known treatment. However, in some patients, symptoms may lessen or resolve after metoclopramide treatment is stopped.

Recently published analyses suggest that metoclopramide is the most common cause of drug-induced movement disorders. Another analysis of study data by the FDA showed that about 20 percent of patients in that study who used metoclopramide took it for longer than three months. The FDA has also become aware of continued spontaneous reports of tardive dyskinesia in patients who used metoclopramide, the majority of whom had taken the drug for more than three months.

In 2004, an interesting article was published in the Journal of the American Pharmacists Association: Tardive dyskinesia risks and metoclopramide use before and after US market withdrawal of cisapride. The conclusions of the retrospective and observational analysis were:

Well-described TD risk factors were common in metoclopramide-associated TD reports. Given the cisapride market withdrawal and associated increased metoclopramide utilization, the incidence of TD may increase accordingly. TD risk factors relative to the intended benefit and duration of use should be considered in metoclopramide prescribing.

Following a review of updated clinical data,  the FDA has determined that treatment with zonisamide can cause metabolic acidosis in some patients.  Zonisamide is indicated as adjunctive therapy in the treatment of partial seizures in adults with epilepsy.

The FDA recommends that healthcare professionals measure serum bicarbonate before starting treatment and periodically during treatment with zonisamide, even in the absence of symptoms.  If metabolic acidosis develops and persists, consideration should be given to reducing the dose or discontinuing zonisamide (using dose tapering), and modifying the patient’s antiepileptic treatment as appropriate.  If the decision is made to continue patients with metabolic acidosis on zonisamide, then alkali treatment should be considered. 

Other recent FDA alerts on anticonvulsants:

Antiepileptic drugs (AEDs): FDA requires warnings about suicidal thoughts and behaviors (suicidality)

EMEA has made clear their verdict: they recommend suspension of the marketing authorization of Raptiva (efalizumab). The CHMP concluded :

• • Raptiva’s benefits are modest;
  • in addition to PML, Raptiva is associated with other serious side effects, including Guillain-Barré and Miller-Fisher syndromes, encephalitis, encephalopathy, meningitis, sepsis and opportunistic infections (infections occurring in people with compromised immune systems);
  • there is not enough evidence to identify a group of patients in which the benefits of Raptiva outweigh its risks, in particular there is a lack of data on effectiveness and safety in patients who have no other treatment options and who may already have a weakened immune system as result of previous treatments.

They recommend that:

Prescribers should not issue any new prescriptions for Raptiva and should review the treatment of patients currently receiving the medicine to assess  the most appropriate alternatives. They should make sure that patients who have been treated with Raptiva are closely monitored for neurological symptoms and symptoms of infection. Patients  who are currently taking Raptiva should not stop treatment abruptly, but should make an appointment with their doctor to discuss the most appropriate replacement treatment.

On the other hand, the FDA issued the following public health advisory with recommendations for prescribers :

• • Raptiva increases the risk of PML.  Longer, continuous use may further increase this risk.
  • Inform patients using Raptiva of the potential risk of developing PML.
  • There are no known screening tests that can reliably predict PML or medical interventions that can prevent or treat this disease.
  • Monitor patients being treated with Raptiva for the onset of neurologic symptoms.  Discontinue Raptiva if PML is suspected.
  • Patients treated with Raptiva should be periodically re-evaluated to ensure that the benefit of treatment continues to outweigh the risks.  Consideration should be given to use of other approved therapies to control the patients’ psoriasis.
  • The effects of periodic or intermittent use of Raptiva, or the concomitant use of other immunosuppressant drugs on the risk for PML is not known.

You can also check the letter from EMD Serono Canada Inc to health care professionals