Australian Regulators Warn of Neuropsychiatric Side Effects Associated with Singulair

April 9, 2013 By

In the April 2013 edition of the Medicines Safety Update, the Therapeutic Goods Administration (TGA) of Australia reminded the public of potential neuropsychiatric adverse events associated with Singulair (montelukast) treatment. Neuropsychiatric events include suicidal ideation, depression, agitation, aggressive behavior, hallucinations, insomnia, and tremor, as well as other side effects.

Singulair (or generic montelukast) is indicated for prevention and chronic treatment of asthma in patients 12 months of age and older. It is indicated for prevention of exercise-induced bronchoconstriction (EIB) in patients 15 years of age and older, and for relief of symptoms of allergic rhinitis (AR): seasonal allergic rhinitis (SAR) in patients 2 years of age and older, and perennial allergic rhinitis (PAR) in patients 6 months of age and older. Manufactured by Merck, Singulair was first FDA approved on February 20, 1998.

The “Warnings and Precautions” section prescribing information for Singulair and generic montelukast include a general warning for the possibility of experiencing such side effects in children, adolescents, and adults. TGA received 58 reports of neuropsychiatric events in children and adolescents treated with Singulair or generic montelukast between the years 2000 and 2013. Their records show 5 reported cases of suicidal ideation, 5 reports of depression, and 8 reports of agitation.

The TGA warned health care providers and caregivers of children to be watchful for such adverse events in children and adolescents, especially when initiating montelukast (Singulair) treatment or increasing dose strength.

Analysis:

FAERS data (from 11/01/1997 to 08/27/2012) was aggregated and standardized by the AdverseEvent RxFilter process. We identified 31,284 serious adverse events which listed Singulair as a suspect drug, while 8,168 of these reports listed Singulair or generic montelukast as the primary suspect.

The most commonly reported side effects were suicidal ideation, allergic granulomatous angiitis, and depression. We identified 2,319 hospitalizations and 342 patient deaths where Singulair or generic montelukast was determined to be the primary suspect.

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Study Finds Emend Halts Growth of Brain Cancer

March 26, 2013 By

On March 18, 2013, researchers from the University of Adelaide in Australia presented data from a new study showing that Emend (aprepitant), a drug used to prevent nausea and vomiting caused by certain anti-cancer medications, is effective in halting the growth of brain tumors.

The researchers were analyzing the link between brain tumors and substance P, a neuropeptide associated with inflammation in the brain. They found that levels of substance P were greatly increased in brain tumor tissue. Knowing that substance P binds to the neurokinin-1 receptor, the researchers used Emend, a substance P/neurokinin-1 receptor antagonist, to substance P binding to the receptor.

Dr. Elizabeth Harford-Wright, a postdoctoral fellow in the University’s Adelaide Centre for Neuroscience Research, states:

We were successful in blocking substance P from binding to the NK1 receptor, which resulted in a reduction in brain tumor growth – and it also caused cell death in the tumor cells. So preventing the actions of substance P from carrying out its role in brain tumors actually halted the growth of brain cancer.

Analysis:

Emend (aprepitant) is a substance P/neurokinin-1 (NK1) receptor antagonist indicated in combination with other antiemetic agents for the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of highly emetogenic cancer chemotherapy (HEC) and for the prevention of postoperative nausea and vomiting. Manufactured by Merck, Emend was FDA approved on March 27, 2003. On January 25, 2008, the FDA approved fosaprepitant, an intravenous form of aprepitant, sold as Emend Injection.

FAERS data (from 11/01/1997 to 08/27/2012) was aggregated and standardized by the AdverseEvent RxFilter process. We identified 2,560 serious adverse events which listed Emend as a suspect drug, while 830 of these reports listed Emend as the primary suspect.

The most commonly reported side effects were nausea, dyspnea, and flushing. We identified 268 hospitalizations and 59 patient deaths where Emend was determined to be the primary suspect.

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Supreme Court Ruling on Generic Clinoril May Alter System for Cases Against Generic Manufacturers

March 19, 2013 By

On March 18, 2013 Reuters posted an article regarding an upcoming Supreme Court decision on whether generic pharmaceutical manufacturers can be sued by patients who suffered from adverse effects. In 2011, the Supreme Court justices stated that generic drug manufacturers were exempt from being sued by patients as long as generic product warning labels were exact replicas of the equivalent brand-name products.

After Mutual Pharmaceutical Co, Inc. was charged by the court in New Hampshire to pay $21 million to a patient who suffered from Stevens-Johnson Syndrome (SJS) after taking sulindac (generic Clinoril), the case was brought to the Supreme Court for a final decision. The labels for sulindac and brand-name Clinoril carry warnings of the potential for this rare side effect, but some argue that the risks far outweigh the benefits in the case of this drug.

Clinoril (sulindac) is a non-steroidal, anti-inflammatory drug indicated for acute or long-term use in the relief of signs and symptoms of osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, acute painful shoulder (acute subacromial bursitis/supraspinatus tendinitis), and acute gouty arthritis. Marketed by Merck, Clinoril was first approved by the FDA on September 27, 1978.

SJS is a rare skin condition that results in the deterioration of the skin, leaving those affected with large, open wounds.

The Supreme Court’s ruling could drastically change the way legal suits for generic drugs are handled, as almost all cases are not brought to court due to the right for manufacturers to avoid legal persecution as their products are exact copies of brand-name drugs. This means that at this time, only brand-name manufacturers can be sued for adverse effects that were caused by their brand-name drugs. The court’s decision has not yet been made.

Analysis:

FAERS data (from 11/01/1997 to 08/27/2012) was aggregated and standardized by the AdverseEvent RxFilter process. We identified 1,899 serious adverse events which listed Clinoril as a suspect drug, while 257 of these reports listed Clinoril as the primary suspect.

We identified 9 reports which listed Clinoril as the primary suspect associated with Stevens-Johnson Syndrome or toxic epidermal necrolysis.

 

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Study Shows Relationship between Bisphosphonates and Nonhealing Femoral Fractures

March 4, 2013 By

On February 20, 2013 a study published in the Journal of Bone and Joint Surgery stated that use of bisphosphonate therapy in the United States has been linked to a rise in atypical femoral fractures. Researchers conducted a literature review and analyzed reports from the FDA’s Adverse Events Reporting System (FAERS) to determine the extent of the association between bisphosphonates and nonhealing femoral fractures.

Bisphosphonates (Fosamax, Actonel, Atelvia, Boniva, Reclast)  are a class of drugs used for the treatment of bone loss associated with osteoporosis. Researchers stated that though the use of bisphosphonates in the U.S. has led to a 30% decrease in hip fractures, they sought to explore the known rare risk of fractures related to these treatments.

Investigators found the majority of cases (n=317) that involved nonhealing femoral fractures were linked to patient use of Fosamax (alendronate sodium). Researchers determined that the proportional reporting ratio (PRR) was 4.51 for nonhealing femoral fractures and use of bisphosphonates.

Analysis:

FAERS data (from 11/01/1997 to 08/27/2012) was aggregated and standardized by the AdverseEvent RxFilter process. We analyzed the reported adverse events involving femoral fracture for patients taking Fosamax, Actonel, Atelvia, Boniva, Reclast, or their generic equivalents.

Fosamax (alendronate sodium) is a bisphosphonate drug used to treat osteoporosis and Paget’s disease. Manufactured by Merck, Fosamax was originally approved by the FDA on September 29, 1995. Fosamax Plus D, a formulating containing vitamin D3 (cholecalciferol), was approved by the FDA on April 7, 2005. We identified 5,108 serious adverse event case reports involving femoral fracture which listed Fosamax or generic alendronate as the primary suspect.

Actonel (risedronate sodium) is a bisphosphonate medication used for the prevention and treatment of postmenopausal osteoporosis and glucocorticoid-induced osteoporosis, to increase bone mass in men with osteoporosis, and for the treatment of Paget’s disease of bone. Marketed by Warner Chilcott, Actonel was approved by the FDA on March 27, 1998. An enteric-coated delayed-release formulation of risedronate, marketed under the brand name Atelvia, was approved by the FDA on October 8, 2010. We identified 231 serious adverse event case reports involving femoral fracture which listed Actonel, Atelvia, or generic risedronate as the primary suspect.

Boniva (ibandronate sodium) is indicated for the treatment and prevention of postmenopausal osteoporosis. Boniva helps increase bone mass and aids in reducing the chance of having a spinal fracture. Boniva was FDA approved on May 16, 2003 and is manufactured by Genentech, Inc. We identified 463 serious adverse event case reports involving femoral fracture which listed Boniva or generic ibandronate as the primary suspect.

Reclast (zoledronic acid) is a bisphosphonate medication used for the treatment of osteoporosis in men and postmenopausal women, Paget’s disease of bone, and for the prevention and treatment of glucocorticoid-induced osteoporosis. It is administered as a once-yearly intravenous infusion containing 5 mg of zoledronic acid in 100 mL of solution. Manufactured by Novartis, Reclast was approved by the FDA on April 16, 2007. We identified 139 serious adverse event case reports involving femoral fracture which listed Reclast or generic zoledronic acid as the primary suspect.

Note: This analysis does not take into account the number of patients on each medication. In order to calculate the total number of cases involving femoral fracture, we aggregated case reports listing the following adverse events: MedDRA Preferred Terms: femur fracture and femoral neck fracture.

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Study Finds Tredaptive, Zocor Combination Therapy Increases Risk for Muscular Side Effects

March 1, 2013 By

On February 26, 2013 an article was published in European Heart Journal that found patients treated with Zocor (simvastatin) plus Tredaptive (nicotinic acid, laropiprant) experienced higher rates of side effects than those treated with Zocor alone. Included in the final analysis were 25,673 participants with occlusive arterial disease who were also identified as being at high risk of cardiovascular events.

Patients were randomly assigned to receive Zocor plus either Tredaptive or placebo, and were followed for approximately 4 years. Some patients were also treated with Zetia (ezetimibe) in order to stabilize their cholesterol levels. A total of 25% of participants given Tredaptive compared to 17% of placebo patients opted to halt treatment before the end of the study. The most commonly reported adverse effects related to Tredaptive therapy were musculoskeletal, gastrointestinal, diabetes, and skin complications.

Researchers stated that myopathy risk was higher in patients assigned to Zocor/Tredaptive combination therapy. Myopathy risk was present regardless of additional treatment with Zetia.

Merck, the manufacturer of Tredaptive, announced the worldwide withdrawal of the medication in January of this year.

Analysis:

Tredaptive (nicotinic acid, laropiprant) is an extended-release medication indicated for lowering low-density lipoprotein (LDL) cholesterol and increasing high density lipoprotein (HDL) cholesterol levels in addition to diet. Tredaptive was never approved by the FDA for use in the U. S. , though the drug was approved in Europe and elsewhere before being discontinued by the manufacturer (Merck) on January 11, 2013.

Zocor (simvastatin) is a member of the statin class of drugs and is used to control elevated cholesterol levels. It is recommended for use in individuals with unhealthy cholesterol levels and, when combined with a healthy diet and regular exercise, is effective at lowering bad cholesterol, raising good cholesterol, and lowering triglycerides. Zocor was FDA approved on December 23, 1991 and is manufactured by Merck & Co., Inc.

FAERS data (from 11/01/1997 to 08/27/2012) was aggregated and standardized by the AdverseEvent RxFilter process. We identified 131 serious adverse events which listed Zocor or Tredaptive as a suspect drug. The most commonly reported side effects were myalgia (muscle pain), rhabdomyolysis (rapid breakdown of muscle), and drug ineffective.

Zetia (ezetimibe) is indicated as an adjunct to diet to reduce the levels of LDL cholesterol in the blood in patients who cannot control their cholesterol levels by diet and exercise alone. Zetia can be used alone or with other medicines to treat high cholesterol. Approved by the FDA on October 25, 2002, Zetia is manufactured by Merck.

FAERS data (from 11/01/1997 to 08/27/2012) was aggregated and standardized by the AdverseEvent RxFilter process. We identified 21,126 serious adverse events which listed Zetia as a suspect drug, while 7,696 of these reports listed Zetia as the primary suspect.

The most commonly reported side effects were myalgia, blood creatine phosphokinase increased, and fatigue. We identified 1,178 hospitalizations and 122 patient deaths where Zetia was determined to be the primary suspect.

Note: This analysis does not take into account the number of patients taking each medication.

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Oxytrol Approved by FDA as OTC Treatment for Women with Overactive Bladder

January 29, 2013 By

On January 25, 2013 the FDA announced its approval of Oxytrol (oxybutynin) as an over-the-counter (OTC) treatment for women with overactive bladder (OAB). The safety and effectiveness of Oxytrol as an OTC medication was exemplified through clinical trials that showed female consumers were able to independently adhere to medication guidelines while weighing whether Oxytrol was the correct treatment for their condition. Side effects experienced by participants included skin irritation at patch application site, constipation, and dry mouth.

Oxytrol will be the first over-the-counter medication indicated for the treatment of OAB. Merck obtained rights to market, distribute, and sell OTC Oxytrol as a treatment for women with OAB. Merck announced that Oxytrol as an OTC treatment should be available in fall of 2013.

Analysis:

Oxytrol (oxybutynin) is a transdermal muscarinic antagonist indicated for the treatment of overactive bladder with symptoms of urge urinary incontinence, urgency, and frequency. Oxytrol is available as an over-the-counter product for women, but remains a prescription medication for men. Manufactured by Actavis (formerly known as Watson Pharmaceuticals), Oxytrol was approved by the FDA on February 26, 2003. The FDA approved Oxytrol as an over-the-counter medication for women on January 25, 2013.

FAERS data (from 11/01/1997 to 06/30/2012) was aggregated and standardized by the AdverseEvent RxFilter process. We identified 290 serious adverse events which listed Oxytrol as a suspect drug, while 95 of these reports listed Oxytrol as the primary suspect.

The most commonly reported side effects were product quality issue, agitation, and confusional state. We identified 45 hospitalizations and 9 patient deaths where Oxytrol was determined to be the primary suspect.

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Merck Withdraws Cholesterol Drug Tredaptive Worldwide

January 14, 2013 By

On January 11, 2013 Merck announced its withdrawal of the cholesterol medication Tredaptive (niacin, laropiprant) due to negative trial outcomes that were released last month. The study did not manage to reduce the occurrence of vascular events in patients, and actually increased the chance of certain non-fatal serious adverse events. The European Medicines Agency recommended that marketing and distribution for Tredaptive be halted after the agency evaluated study outcomes. Merck began the process of suspending the drug in all countries, and recommended that physicians do not prescribe Tredaptive.

The clinical trial, funded by Merck, included 25,673 patients at high risk for cardiovascular events. Patients were assigned to receive either treatment with Tredaptive plus a statin or solely statin treatment. Though detailed analyses are not available at this time, Merck disclosed that combination therapy did not significantly decrease the occurrence of coronary deaths, nonfatal heart attacks, strokes, or revascularizations when compared to treatment with a statin alone. An increased risk of serious non-fatal adverse events was also reported with combination therapy.

Analysis:

Tredaptive (nicotinic acid, laropiprant) is an extended-release medication indicated for lowering low-density lipoprotein (LDL) cholesterol and increasing high density lipoprotein (HDL) cholesterol levels in addition to diet. Tredaptive was never approved by the FDA for use in the U. S., though the drug was approved in Europe and elsewhere before being discontinued by the manufacturer (Merck) on January 11, 2013.

FAERS data (from 11/01/1997 to 06/30/2012) was aggregated and standardized by the AdverseEvent RxFilter process. We identified 624 serious adverse events which listed Tredaptive as a suspect drug, while 26 of these reports listed Tredaptive as the primary suspect.

The most commonly reported side effects were hepatitis, flushing, and vomiting. We identified 15 hospitalizations and 1 patient death where Tredaptive was determined to be the primary suspect.

Note: Cases listed above were aggregated from the U.S. as well as other countries. Tredaptive was never approved by the FDA.

 

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FDA Approves Autoinjector Formulation of Rebif

January 4, 2013 By

On January 3, 2013 EMD Serono and Pfizer announced the FDA’s approval of Rebif Rebidose (interferon beta-1a), which is an auto-injector formulation intended for ease of patient use. Rebif and Rebif Rebidose are prescription medication indicated for the treatment of multiple sclerosis (MS). These compounds are intended to slow the accumulation of physical disability and decrease the frequency of clinical exacerbation due to MS. The original formulation of Rebif was approved by the FDA on March 7, 2002 for relapsing forms of MS.

The Phase III trial for the self-administration of Rebif was based on patient ratings of ease of use, patient satisfaction and acceptability, and functional reliability. Rebif Rebidose was found to be easy to use by many of the clinical trial participants during the 12 week study.

Rebif Rebidose will be available later this year in 22 and 44 microgram doses.

Analysis:

FAERS data (from 11/01/1997 to 06/30/2012) was aggregated and standardized by the AdverseEvent RxFilter process. We identified 19,522 serious adverse events which listed Rebif as a suspect drug, while 18,215 of these reports listed Rebif as the primary suspect.

The most commonly reported side effects were multiple sclerosis relapse, injection site erythema, and influenza like illness. We identified 8,581 hospitalizations and 815 patient deaths where Rebif was determined to be the primary suspect.

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Incivek Receives Black Box Warning for Potentially Fatal Skin Rash

December 21, 2012 By

On December 19, 2012 the FDA announced that the hepatitis C drug, Incivek (telaprevir), is now required to carry a black box warning on the drug label which states combination therapy with Incivek should be halted abruptly and the affected patient should receive medical care if a skin rash develops. The FDA recently received adverse event information from Japan, where two patients experienced extreme cases of toxic epidermal necrolysis (TEN) after taking Incivek in combination with peginterferon alfa and ribavirin. One patient continued treatment after the development of symptoms, and died from the severity of the skin reaction.

The label for Incivek previously outlined the risk for severe skin reactions in patients who take combination therapy with ribavirin and peginterferon alfa, which include Stevens-Johnson Syndrome (SJS) and drug rash with eosinophilia and systemic symptoms (DRESS). Though the preceding FDA-approved label for Incivek stated that these conditions may require hospitalization or become fatal, the newly approved label underlines: 1) the serious risk of these skin reactions; 2) that all drugs used in combination therapy be stopped immediately if such a reaction occurs; and, 3) that patients who experience such reactions seek urgent medical assistance. Health care providers should also keep in mind any other medication a patient may be taking that could potentially contribute to serious skin reactions.

Hepatitis C patients who take Incivek combination therapy are urged to pursue medical care if any of the following symptoms appear: rash (with or without itching), severe rash, blisters, ulcerations, fever, nausea, diarrhea, mouth sores or ulcers, swelling of the face, red or inflamed eyes, rash that does not improve after 2-3 days, or any rash that gets worse with time.

Analysis:

Incivek (telaprevir) is approved, in combination with peginterferon alfa (Peg-Intron, Pegasys) and ribavirin, for the treatment of chronic hepatitis C (CHC) genotype 1 infection in adult patients with compensated liver disease, including cirrhosis, who have not been treated before or who have failed previous treatment. Incivek was FDA approved on May 23, 2011 and is marketed by Vertex Pharmaceuticals Incorporated. Peg-Intron (peginterferon alfa-2b) is indicated for the treatment of adult patients who have chronic hepatitis C infection with certain types of liver disease. Pegasys (peginterferon alfa-2a) is used alone or in combination with ribavirin for the treatment of chronic hepatitis C, and chronic hepatitis B in patients with liver damage.

FAERS data (from 11/01/1997 to 06/30/2012) was aggregated and standardized by the AdverseEvent RxFilter process. We identified 1,928 cases reporting a serious skin reaction which listed Incivek as a suspect drug. In 1,638 of these cases, Incivek was prescribed with peginterferon alfa (Peg-Intron, Pegasys) and ribavirin (Rebetol, Copegus). Of the cases where Incivek was co-prescribed with peginterferon alfa and ribavirin, we identified 297 hospitalizations and 6 patient deaths.

Note: In order to calculate the total number of cases associated with serious skin reactions, we aggregated cases reporting the following adverse events: MedDRA High-Level Terms: Bullous conditions; Pruritus NEC; Rashes, eruptions, and exanthems NEC.

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NSAIDs May Affect Gastrointestinal Mucosa of Athletes, According to Study

December 14, 2012 By

In the December issue of Medicine & Science in Sports & Exercise, the relationship between nonsteroidal anti-inflammatory drugs (NSAIDs) and exercise-induced small intestinal injury was examined. The research question was based on how NSAIDs are commonly used by athletes prior to physical exercise in order to prevent associated pain. Researchers believed that these drugs could have negative effects on patients’ gastrointestinal (GI) mucosa during exercise.

The study included nine men who were in good health and who were adept at cycling. Participants were put through four different trials: two 400mg doses of ibuprofen prior to cycling; cycling with no administration of ibuprofen; two 400mg doses of ibuprofen with no physical exercise; and no administration of ibuprofen paired with physical rest. Researchers found that taking ibuprofen before cycling lead to higher rates of exercise-induced small intestinal injury and dysfunction of the gut barrier in study participants. Investigators concluded that intake of NSAIDs by athletes may lead to negative adverse events, and that administration of these drugs to active athletes should be avoided.

Analysis:

Nonsteroidal anti-inflammatory drugs, or NSAIDs, (Acular, Acular LS, Acuvail, Advil, Advil Childrens, Advil Infants, Aggrenox, Aleve, Arthrotec, Caldolor, Cambia, Cataflam, Celebrex, Clinoril, Daypro, Feldene, Fiorinal, Flector, Indocin, Lodine, Midol, Mobic, Motrin, Nalfon, Naprelan, Neoprofen, Nevanac, Ocufen, Orudis, Pennsaid, Ponstel, Profen, Relafen, Solaraze, Sprix, Toradol, Treximet, Vimovo, Voltaren, Voltaren Xr, Bromday, Xibrom, Zipsor, Bextra, Duract, Vioxx) are used for their antipyretic (fever-reducing), anti-inflammatory, and analgesic properties. Common generic compounds of these pain killers include naproxen, ibuprofen, and aspirin. These medications are available by over the counter, though some may be prescribed due to higher dose strengths.

FAERS data (from 11/01/1997 to 06/30/2012) was aggregated and standardized by the AdverseEvent RxFilter process. We identified 2,710 serious adverse events which listed NSAIDs as the primary suspect associated with gastrointestinal or abdominal injury. We identified 1,201 hospitalizations and 203 patient deaths where NSAIDs were determined to be the primary suspect.

Note: This analysis does not take into account the number of patients taking each medication. In order to calculate the number of cases involving NSAIDs, we aggregated cases reporting the following drugs as the primary suspect at the time of the adverse event: Acular, Acular LS, Acuvail, Advil, Advil Children’s, Advil Infants, Aggrenox, Aleve, Arthrotec, Caldolor, Cambia, Cataflam Celebrex, Clinoril, Daypro, Feldene, Fiorinal, Flector, Indocin, Lodine, Midol, Mobic, Motrin, Nalfon, Naprelan, Neoprofen, Nevanac, Ocufen, Orudis, Pennsaid, Ponstel, Profen, Relafen, Solaraze, Sprix, Toradol, Treximet, Vimovo, Voltaren, Voltaren Xr, Bromday, Xibrom, Zipsor, Bextra, Duract, Vioxx. In order to calculate the number of cases involving gastrointestinal or abdominal injury, we aggregated cases reporting the following adverse events: MedDRA High-Level Terms: Abdominal injuries NEC, gastrointestinal disorders.

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