OREANDA-NEWS. July 22, 2015. Merck (NYSE:MRK), known as MSD outside the United States and Canada, announced today that the company's commitment to HIV and AIDS, which started with a research and development program initiated in the mid-1980s during the early years of the epidemic, is now entering its fourth decade. To commemorate Merck's 30 years of commitment in this area, the company is launching a new effort, “Positively Committed.” The campaign highlights the company’s contributions, including the development of innovative therapies to address the unmet medical needs of people infected with HIV-1.

“The global health community has made significant progress in the fight against HIV and Merck is proud of our role in this fight, starting at the outset of the epidemic, and continuing to this day,” said Daria J. Hazuda, vice president and therapeutic area head, infectious disease and vaccines. “Although antiretroviral therapy has advanced the management of HIV-1, much work remains to be done. We will continue to collaborate with scientists, clinicians, patient advocates and the global health community as we work together towards a common goal of eradicating this disease.”

Legacy of Commitment

  • In the mid-1980s, soon after the public health community first coined the term “AIDS” to describe this emerging epidemic, Merck began its HIV/AIDS research. Merck researchers were the first to describe the chemical structure of the protease enzyme, and published the findings immediately to encourage further research efforts. Merck researchers then developed CRIXIVAN® (indinavir sulfate), an HIV protease inhibitor, which was approved by the European Medicines Agency and the U.S. Food and Drug Administration (FDA) in 1996. At the time, the FDA's approval of CRIXIVAN (indinavir sulfate) was the fastest approval in FDA history.
  • In 1997, Merck's clinical study of CRIXIVAN was the first to show that a combination of antiretroviral medicines could provide prolonged suppression of HIV RNA. Today, CRIXIVAN in combination with antiretroviral agents is indicated for the treatment of HIV infection.
  • In 1999, Merck introduced efavirenz, a non-nucleoside reverse-transcriptase inhibitor (NNRTI), which was developed by Merck and DuPont Pharmaceuticals. Merck retained the rights to market efavirenz in select markets outside the U.S. Today, efavirenz is one of the most commonly prescribed antiretroviral therapies worldwide.
  • In the early 1990s, Merck was the first to demonstrate that inhibition of the HIV-1 integrase enzyme—which is required for HIV replication—was possible, and that inhibiting the integrase protein reduced replication and spread of the virus. This research advancement led to the development of ISENTRESS® (raltegravir). In 2007, the approval of ISENTRESS introduced a new class of treatments, HIV-1 integrase strand transfer inhibitors. Today, ISENTRESS is indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection in patients four weeks of age and older. The use of other active agents with ISENTRESS is associated with a greater likelihood of treatment response.

In addition, since the mid-1980s shortly after the HIV virus was identified, Merck pursued one of the largest HIV vaccine research programs, culminating in a large-scale trial that illustrated the difficulty of developing a successful HIV vaccine.

Merck's research efforts today include programs to develop novel HIV treatment and prevention technologies, and collaborations on approaches to address HIV latency and eradication.

Research is only one part of our comprehensive strategy to address unmet needs in HIV. Merck also has sought to increase access to our HIV medicines, particularly in resource limited settings.

“Effective treatments for HIV-1 infection were a distant hope in the 1980s, but collaborative scientific discovery and effective advocacy have made them possible today," said Dr. Julie Gerberding, executive vice president, strategic communications, global public policy, and population health at Merck. “I'm proud that Merck is committed to sustaining our contributions to the treatment of this infection around the world.”

Addressing the Challenge of HIV/AIDS through Collaboration

Since the inception of its HIV/AIDS research program 30 years ago, Merck has recognized the global impact of HIV/AIDS in developing countries where economic, social and political factors impede access to education, care and treatment. The Merck Foundation has partnered with governments, non-governmental organizations and various other stakeholders, contributing more than \\$122 million over the past 15 years to support intervention programs, strengthen healthcare capacity and improve access to treatment. In addition, Merck has provided access strategies, such as differential pricing and voluntary licensing, to enhance access to treatment in these communities.

This year, Merck partnered with the Medicines Patent Pool to provide access to raltegravir for infants and children from four weeks to under 12 years of age in low- and middle-income developing countries.

Ongoing Commitment Continues

Merck's steadfast dedication to patients living with HIV continues, and is a part of our broader, sustained commitment to developing medicines and vaccines to fight a broad range of infectious diseases.

Selected Safety Information for ISENTRESS (raltegravir)

Severe, potentially life-threatening and fatal skin reactions have been reported. This includes cases of Stevens-Johnson syndrome, hypersensitivity reaction and toxic epidermal necrolysis. Immediately discontinue treatment with ISENTRESS and other suspect agents if severe hypersensitivity, severe rash, or rash with systemic symptoms or liver aminotransferase elevations develops and monitor clinical status, including liver aminotransferases closely.

Immune reconstitution syndrome can occur, including the occurrence of autoimmune disorders with variable time to onset, which may necessitate further evaluation and treatment.

ISENTRESS chewable tablets contain phenylalanine, a component of aspartame, which may be harmful to patients with phenylketonuria.

Coadministration of ISENTRESS with drugs that are strong inducers of uridine diphosphate glucuronosyltransferase (UGT) 1A1 may result in reduced plasma concentrations of raltegravir. Coadministration of ISENTRESS (raltegravir) with drugs that inhibit UGT1A1 may increase plasma levels of raltegravir.

Coadministration of ISENTRESS and other drugs may alter the plasma concentration of raltegravir. The potential for drug-drug interactions must be considered prior to and during therapy. Coadministration or staggered administration of aluminum and/or magnesium hydroxide-containing antacids and ISENTRESS is not recommended.

Rifampin, a strong inducer of UGT1A1, reduces plasma concentrations of ISENTRESS. Therefore, the dose of ISENTRESS for adults should be increased to 800 mg twice daily during coadministration with rifampin.There are no data to guide coadministration of ISENTRESS with rifampin in patients below 18 years of age.

The most commonly reported (?2%) drug-related clinical adverse reactions of moderate to severe intensity in treatment-na?ve adult patients receiving ISENTRESS compared with efavirenz were insomnia (4% vs 4%), headache (4% vs 5%), nausea (3% vs 4%), fatigue (2% vs 3%), and dizziness (2% vs 6%) respectively. In treatment-experienced adult patients receiving ISENTRESS, the most commonly reported (?2%) drug-related clinical adverse reactions of moderate to severe intensity and at a higher incidence compared with placebo was headache (2% vs <1%). In both studies, intensities were defined as: Moderate (discomfort enough to cause interference with usual activity); or Severe (incapacitating with inability to work or do usual activity).In treatment-experienced pediatric patients 4 weeks through 18 years of age receiving ISENTRESS, the frequency, type and severity of drug-related adverse reactions were comparable to those observed in adults.

Grade 2-4 creatine kinase laboratory abnormalities were observed in subjects treated with ISENTRESS. Myopathy and rhabdomyolysis have been reported. Use with caution in patients at increased risk of myopathy or rhabdomyolysis, such as patients receiving concomitant medications known to cause these conditions and patients with a history of rhabdomyolysis, myopathy or increased serum creatine kinase.

Rash occurred more commonly in treatment-experienced subjects receiving regimens containing ISENTRESS + darunavir/ritonavir compared to subjects receiving ISENTRESS without darunavir/ritonavir or darunavir/ritonavir without ISENTRESS. However, rash that was considered drug related occurred at similar rates for all 3 groups. These rashes were mild to moderate in severity and did not limit therapy; there were no discontinuations due to rash.

ISENTRESS should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.There are no adequate and well-controlled studies in pregnant women. In addition, there have been no pharmacokinetic studies conducted in pregnant patients.

To monitor maternal-fetal outcomes of pregnant patients exposed to ISENTRESS, an Antiretroviral Pregnancy Registry has been established. Physicians are encouraged to register patients by calling 1-800-258-4263.

About ISENTRESS (raltegravir)

ISENTRESS is Merck's integrase inhibitor for the treatment of HIV-1 infection in adult and pediatric patients ages four weeks and older and weighing at least 3 kg as part of combination HIV therapy. ISENTRESS works by inhibiting the insertion of HIV-1 DNA into human DNA by the integrase enzyme and has demonstrated rapid antiviral activity. Inhibiting integrase from performing this essential function limits the ability of the virus to replicate and infect new cells. ISENTRESS is now approved as part of combination therapy in more than 76 countries for use in treatment-na?ve adult patients with HIV-1 and in more than 115 countries for use in treatment-experienced adult patients with HIV-1. ISENTRESS, in combination therapy, for use in children and adolescents with HIV-1 ages two years and older has also been approved for use in 46 countries, and ISENTRESS oral suspension for infants at least four weeks of age is approved for use in 31 countries. Merck is continuing to move forward with filings of ISENTRESS for oral suspension in additional countries around the world. Please refer to the Prescribing Information for ISENTRESS for information about dosage and administration for each formulation.

Selected Safety Information for CRIXIVAN (indinavir sulfate)

CRIXIVAN is contraindicated in patients with clinically significant hypersensitivity to any of its components. CRIXIVAN, a CYP3A4 inhibitor, also is contraindicated with the following drugs due to the potential for elevated plasma concentrations of these drugs, which may lead to serious and/or life-threatening reactions: alfuzosin, amiodarone, dihydroergotamine, ergonovine, ergotamine, methylergonovine, cisapride, lovastatin, simvastatin, pimozide, Revatio (sildenafil, for treatment of pulmonary arterial hypertension), oral midazolam, triazolam, alprazolam.

ALERT: Find out about medicines that should NOT be taken with CRIXIVAN.

Nephrolithiasis/urolithiasis has occurred with therapy with CRIXIVAN. The cumulative frequency of nephrolithiasis is substantially higher in pediatric patients (29%) than in adult patients (12.4%; range across individual trials: 4.7%–34.4%). The cumulative frequency of nephrolithiasis events increases with increasing exposure to CRIXIVAN; however, the risk over time remains relatively constant. In some cases, nephrolithiasis/urolithiasis has been associated with renal insufficiency or acute renal failure, pyelonephritis with or without bacteremia. If signs or symptoms of nephrolithiasis/urolithiasis occur (including flank pain, with or without hematuria or microscopic hematuria), temporary interruption (e.g., 1–3 days) or discontinuation of therapy may be considered. Adequate hydration is recommended in all patients treated with CRIXIVAN (indinavir sulfate).

Acute hemolytic anemia, including cases resulting in death, has been reported in patients treated with CRIXIVAN. Once a diagnosis is apparent, appropriate measures for the treatment of hemolytic anemia should be instituted, including discontinuation of CRIXIVAN.

Hepatitis including cases resulting in hepatic failure and death has been reported in patients treated with CRIXIVAN. Because the majority of these patients had confounding medical conditions and/or were receiving concomitant therapy(ies), a causal relationship between CRIXIVAN and these events has not been established.

New onset diabetes mellitus, exacerbation of pre-existing diabetes mellitus and hyperglycemia have been reported during post-marketing surveillance in HIV-infected patients receiving protease inhibitor therapy. Some patients required either initiation or dose adjustments of insulin or oral hypoglycemic agents for treatment of these events. In some cases, diabetic ketoacidosis has occurred. In those patients who discontinued protease inhibitor therapy, hyperglycemia persisted in some cases.

Initiation of CRIXIVAN, a CYP3A inhibitor, in patients receiving medications metabolized by CYP3A or initiation of medications metabolized by CYP3A in patients already receiving CRIXIVAN, may increase plasma concentrations of medications metabolized by CYP3A. Initiation of medications that inhibit or induce CYP3A may increase or decrease concentrations of CRIXIVAN, respectively. These interactions may lead to:

  • Clinically significant adverse reactions, potentially leading to severe, life-threatening, or fatal events from greater exposures of concomitant medications.
  • Clinically significant adverse reactions from greater exposures of CRIXIVAN.
  • Loss of therapeutic effect of CRIXIVAN and possible development of resistance.

Consider the potential for drug interactions prior to and during CRIXIVAN therapy; review concomitant medications during CRIXIVAN therapy; and monitor for the adverse reactions associated with the concomitant medications.

Caution should be exercised if CRIXIVAN is used concurrently with atorvastatin or rosuvastatin. Titrate the atorvastatin and rosuvastatin doses carefully and use the lowest necessary dose with CRIXIVAN. Caution should be used with coadministration of CRIXIVAN and parenteral midazolam. Particular caution should be used when prescribing sildenafil, tadalafil, or vardenafil in patients receiving indinavir. Coadministration of CRIXIVAN with these medications is expected to substantially increase plasma concentrations of sildenafil, tadalafil, and vardenafil and may result in an increase in adverse events, including hypotension, visual changes, and priapism, which have been associated with sildenafil, tadalafil, and vardenafil.

Concomitant use of CRIXIVAN (indinavir sulfate) and St. John’s Wort (Hypericum perforatum) or products containing St. John’s Wort is not recommended. Coadministration of CRIXIVAN and St. John’s Wort has been shown to substantially decrease indinavir concentrations and may lead to loss of virologic response and possible resistance to CRIXIVAN or to the class of protease inhibitors.

Indirect hyperbilirubinemia has occurred frequently during treatment with CRIXIVAN and has infrequently been associated with increases in serum transaminases.

Reports of tubulointerstitial nephritis with medullary calcification and cortical atrophy have been observed in patients with asymptomatic severe leukocyturia (>100 cells/high-power field). Patients with asymptomatic severe leukocyturia should be followed closely and monitored frequently with urinalyses. Further diagnostic evaluation may be warranted, and discontinuation of CRIXIVAN should be considered in all patients with severe leukocyturia.

Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including CRIXIVAN. During the initial phase of combination antiretroviral treatment, patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jiroveci pneumonia (PCP), or tuberculosis), which may necessitate further evaluation and treatment. Autoimmune disorders (such as Graves' disease, polymyositis, and Guillain-Barr? syndrome) have also been reported to occur in the setting of immune reconstitution; however, the time of onset is more variable, and can occur many months after initiation of treatment.

There have been reports of spontaneous bleeding in patients with hemophilia A and B treated with protease inhibitors.

In patients with hepatic insufficiency due to cirrhosis, the dosage of CRIXIVAN should be lowered because of decreased metabolism of CRIXIVAN. Patients with renal insufficiency have not been studied.

Redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and "cushingoid appearance" have been observed in patients receiving antiretroviral therapy. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established.

CRIXIVAN should not be coadministered with rifampin. Coadministration of CRIXIVAN with rifampin may lead to loss of virologic response and possible resistance to CRIXIVAN or to the class of protease inhibitors or other coadministered antiretroviral agents.

Coadministration of CRIXIVAN with atazanavir is not recommended. Both drugs are associated with indirect (unconjugated) hyperbilirubinemia. Combinations of these drugs have not been studied.

Alteration in dose or regimen with various HIV antiviral agents or other agents may be recommended based on drug interaction studies or predicted interaction. See Table 9 of the Precautions, Drug Interactions Section of the Prescribing Information for details.

There are no adequate and well-controlled studies in pregnant patients. CRIXIVAN should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. To monitor maternal-fetal outcomes of pregnant patients exposed to CRIXIVAN, an Antiretroviral Pregnancy Registry has been established. Physicians are encouraged to register patients by calling 1-800-258-4263.

Selected adverse reactions of severe or life-threatening intensity and of unknown drug relationship reported by patients treated with CRIXIVAN/AZT/3TC in ACTG 320 were: fever (3.8%), nausea (2.8%), nephrolithiasis/urolithiasis (2.6%), headache (2.4%), asthenia/fatigue (2.4%), anemia (2.4%), abdominal pain (1.9%), difficulty breathing/dyspnea/shortness of breath (1.8%), cough (1.6%), vomiting (1.4%), rash (1.1%), back pain (0.9%), and diarrhea (0.9%).

About CRIXIVAN (indinavir sulfate)

CRIXIVAN 200 mg and 400 mg capsules in combination with antiretroviral agents are indicated for the treatment of HIV infection. This indication is based on two clinical trials of approximately one year duration that demonstrated: 1) a reduction in the risk of AIDS-defining illnesses or death; 2) a prolonged suppression of HIV RNA. CRIXIVAN does not cure HIV infection, does not reduce the transmission of HIV, and should only be taken in combination with other drugs for HIV. Please refer to the Prescribing Information for CRIXIVAN for information about dosage and administration.

About Merck

Today's Merck is a global healthcare leader working to help the world be well. Merck is known as MSD outside the United States and Canada. Through our prescription medicines, vaccines, biologic therapies and animal health products, we work with customers and operate in more than 140 countries to deliver innovative health solutions. We also demonstrate our commitment to increasing access to healthcare through far-reaching policies, programs and partnerships. For more information, visit www.merck.com and connect with us on Twitter, Facebook and YouTube.

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This news release of Merck & Co., Inc., Kenilworth, NJ, USA (the “company”) includes “forward-looking statements” within the meaning of the safe harbor provisions of the United States Private Securities Litigation Reform Act of 1995. These statements are based upon the current beliefs and expectations of the company’s management and are subject to significant risks and uncertainties. If underlying assumptions prove inaccurate or risks or uncertainties materialize, actual results may differ materially from those set forth in the forward-looking statements.

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The company undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events or otherwise. Additional factors that could cause results to differ materially from those described in the forward-looking statements can be found in the company’s 2014 Annual Report on Form 10-K and the company’s other filings with the Securities and Exchange Commission (SEC) available at the SEC’s Internet site (www.sec.gov).