International Approvals

International Approvals: NovoRapid, Fentanyl, Atriance

Yael Waknine

September 24, 2007 — The European Commission (EC) has approved insulin aspart subcutaneous injection for use in the elderly and patients with renal or hepatic impairment; the Japanese Ministry of Health, Labor, and Welfare has approved fentanyl citrate 0.1- and 0.25-mg injections for use in pediatric patients aged 2 years and younger; and the EC has approved nelarabine intravenous infusion for the treatment of refractory and relapsed T-cell acute lymphoblastic leukemia and lymphoblastic lymphoma.

Insulin Aspart (NovoRapid) for Use in Elderly Patients in EU

On September 20, the European Commission approved an expanded indication for insulin aspart subcutaneous injection (NovoRapid, Novo Nordisk), allowing its use for the treatment of types 1 and 2 diabetes in the elderly and in patients with renal or hepatic impairment.

According to the International Diabetes Federation, approximately 20% of the world's elderly population has diabetes, and that figure is steadily rising, the company said in a news release. Insulin aspart is the only rapid-acting, modern insulin approved for use in this population.

Insulin aspart previously was approved by the EC for use in children aged 2 years and older and pregnant women. Marketed as NovoLog in the United States, it has been approved by the US Food and Drug Administration for the control of hyperglycemia in diabetic patients, with the caveats that its benefits should justify the risk to the fetus during pregnancy and that lower doses may be required in the setting of renal or hepatic impairment.

Fentanyl Injection for Use in Children Aged Less Than 2 Years in Japan

On August 28, the Japanese Ministry of Health, Labor, and Welfare (MHLW) approved an expanded indication for fentanyl citrate 0.1- and 0.25-mg injections (Daiichi Sankyo Company, Ltd), allowing use of the drug in pediatric patients aged 2 years and younger.

According to a company news release, the approval was based on data from a physician-led phase 3 trial that demonstrated the drug's safety in children and infants.

Fentanyl injection is approved by the MHLW and the US Food and Drug Administration (FDA) for use as a short-term analgesic during anesthetic periods, induction/maintenance, and immediate postoperative period; as a narcotic analgesic supplement in general/regional anesthesia; and as an anesthetic agent with oxygen in high-risk patients. It also may be used with a neuroleptic as an anesthetic premedication, for the induction of anesthesia, and as an adjunct in the maintenance of general/regional anesthesia.

Although the FDA does not contraindicate use of fentanyl injection in children aged less than 2 years, the safety labeling states that rare cases of unexplained clinically significant methemoglobinemia have occurred in premature neonates undergoing emergency anesthesia and surgery that included combined use of fentanyl, pancuronium, and atropine. A direct cause between use of these drugs and methemoglobinemia has not been established.

Nelarabine Injection (Atriance) for Refractory T-ALL and T-LBL in EU

On August 28, the European Commission approved nelarabine intravenous injection (Atriance, GlaxoSmithKline) for the treatment of T-cell acute lymphoblastic leukemia (T-ALL) and T-cell lymphoblastic lymphoma (T-LBL) in patients who have not responded to or have relapsed after treatment with at least 2 chemotherapy regimens. The approval is valid in all 27 member states of the European Union, with identical national licenses usually issued in Norway, Iceland, and Liechtenstein.

Nelarabine is a prodrug of arabinosylguanine with T-cell selectivity. The nucleoside analog is converted into arabinosylguanine nucleotide triphosphate, which inhibits DNA synthesis and induces apoptosis.

The approval was based on complete response rates induced by nelarabine therapy; randomized trials demonstrating increased survival or other clinical benefits have not been conducted.

Data from 2 multicenter, phase 2 clinical studies of single-agent therapy of nelarabine in relapsed/refractory patients (28 adults, 39 children) showed that 21% of adults and 23% of children achieved a complete response (defined as the disappearance of all detectable signs of disease) both with and without full hematologic recovery. One adult and 4 children went on to receive a stem cell transplant; median overall survival after nelarabine therapy was 21 and 13 weeks in adults and children, respectively.

These findings were supported by those of a German ALL Study Group trial (n = 57), in which 47% of patients treated with nelarabine achieved remission and 74% of those demonstrating complete response were transferred to a stem cell transplant.

Hematologic toxicity was the most common moderate-to-severe (grade 3 – 4) nelarabine-associated adverse event. As with other cytotoxic agents, nelarabine is associated with treatment-limiting neurologic adverse events; close monitoring of patients is recommended, and dosing should be discontinued if neurologic events of grade 2 or greater severity occur.

The recommended regimen for nelarabine in adults is 1500 mg/m², administered intravenously over 2 hours on days 1, 3, and 5 and repeated every 21 days. Pediatric patients should be given 650 mg/m² intravenously over 1 hour daily for 5 consecutive days, repeated every 21 days.

Nelarabine (marketed as Arranon) previously was approved for this indication by the US Food and Drug Administration in October 2005.
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Efficacy of Granisetron for Treatment of Postoperative Nausea

Patients and Methods

After obtaining approval from our institutional ethics committee and informed consent from each patient, we studied women who were American Society of Anesthesiologist physical status I (no organic, physiological, biochemical or psychiatric disturbances) and who experienced nausea lasting >10 minutes and/or vomiting within the 3 hours after recovery from general anaesthesia for breast surgery. Breast surgery included partial mastectomy, partial mastectomy with axillary dissection, modified radical mastectomy, and modified radical mastectomy with axillary dissection.

We excluded patients who had gastrointestinal disease, those who had a history of motion sickness and/or previous PONV, those who had taken antiemetics within 24 hours before surgery, and those who were pregnant, menstruating or taking hormonal therapy.

Patients were randomly assigned to study groups according to a computer-generated table of random numbers. Placebo or granisetron at four different doses (10 µg/kg, 20 µg/kg, 40 µg/kg and 80 µg/kg) was administered intravenously when patients experienced nausea lasting >10 minutes and/or vomiting within 3 hours after anaesthesia. Identical syringes containing each drug were prepared by personnel not otherwise involved in this study.

For preanaesthetic medication, patients received oral diazepam 5mg, as is routine in our institution. Anaesthesia was induced with intravenous propofol 2 mg/kg and intravenous fentanyl 2 µg/kg; intravenous vecuronium bromide 0.15 mg/kg was used to facilitate tracheal intubation. After tracheal intubation, anaesthesia was maintained with isoflurane 1.0–3.0% (inspired concentration) and nitrous oxide (N2O) 66% in oxygen, with controlled ventilation adjusted using an anaesthetic/respiratory gas analyzer to keep an end-tidal CO2 concentration of 35–40mm Hg. Neuromuscular block was achieved with vecuronium bromide and was antagonized by administering intravenous atropine 0.02 mg/kg and neostigmine 0.04 mg/kg at the end of surgery. The trachea was extubated when the patient was awake. Rectal temperature was monitored and maintained at 36.5–37.0°C using a warming pad. Postoperative analgesia was provided with indometacin 50mg administered rectally when the patient complained of pain. To maintain the integrity of our results, no patients received any intraoperative PONV prophylaxis.

The patients were observed for a 24-hour period after administration of the study drug in order to assess efficacy. All episodes of emetic symptoms (nausea, retching and vomiting) were recorded by nursing staff blinded to the study group allocation of the patient. These nurses observed the patients at intervals according to normal ward routine. Nausea was defined as a subjectively unpleasant feeling associated with an awareness of the urge to vomit; retching was defined as the labored, spasmodic, rhythmic contraction of the respiratory muscles without the expulsion of the gastric contents; and vomiting was defined as the forcing of gastric contents from the mouth.[3] Complete control of established PONV was defined as no emetic symptoms and no need for rescue antiemetic medication. If more than two episodes of vomiting occurred within the 24-hour period after study drug administration, a rescue antiemetic (e.g. domperidone rectally) was given, as is common practice in our institution. The details of any other adverse effects were recorded by the nurses who interviewed the patients.Statistical Analysis

Based on previously published data,[1,2] complete control of established PONV (which was regarded as the primary end-point) in patients receiving placebo would be 50%. An improvement from 50% to 90% with the use of granisetron would be considered clinically significant. To provide 80% power (beta = 0.2) to detect such an absolute difference using a test at a = 0.05, a sample size of 20 patients per group was required. Patient demographic data were analyzed by ANOVA with Bonferroni's correction for multiple comparison (continuous variables) and the Chi-square (χ2) test (discrete variables). The numbers of patients having complete control of established PONV (no emetic symptoms and no rescue medication), experiencing nausea, retching, vomiting or requiring a rescue antiemetic, and the incidence of adverse events were compared with Fisher's exact probability test. A p-value of <0.05 was considered to be significant.  Printer- Friendly Email This

Clin Drug Invest.  2006;26(4):203-208.  ©2006 Adis Data Information BV
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Effective Strategies for Managing Late-Stage Primary Biliary Cirrhosis?

Question

When a patient with primary biliary cirrhosis (PBC) begins to exhibit markedly abnormal liver function tests and is experiencing increasing pruritis that is not relieved by an H1 blocker, hydroxyzine, or cholestyramine, what other therapies may be beneficial? The patient is unable to tolerate doxepin.

Charla Bright, PA-C

Response from  Mary P. Ettari, MPH, PA-C 
A PA in family practice with Medical Partners of Martin County, Stuart, Florida. She is immediate past-president of the Florida Academy of Physician Assistants, past secretary of the American Academy of Physician Assistants, and presently a trustee of the PA Foundation.

PBC is an autoimmune disorder characterized by pruritis and fatigue. The cause is unknown but the mechanism of the disease produces a chronic inflammatory reaction in the liver that damages the interlobular bile ducts, leading to progressive cholestasis and finally cirrhosis.[1]

The disease affects mainly middle-aged women between the ages of 35 and 60 but can affect all ages and races. At least 30% of patients are initially asymptomatic. The diagnosis is usually made during routine bloodwork.[2]

The clinical course of the disease is divided into 4 stages. Stage I is characterized by lymphocytic destruction of the interlobular ducts, and during stage II, there is bile ductular proliferation. Stages III and IV have worsening fibrosis, with cirrhosis occurring in stage IV.[3]

Most cases of PBC are diagnosed on the basis of abnormal liver function tests (LFTs), which lead to further investigation and the ultimate diagnosis of PBC. The most common symptoms are fatigue and pruritis. Additional symptoms are xanthelasma on the eyelids, xanthoma on the palms of the hands and heels, neuropathy, and asymptomatic urinary tract infections (UTIs). As the disease worsens, the patient may develop esophageal varices, osteopenia and osteoporosis, and hepatocellular carcinoma. About 50% of patients present with an enlarged nontender liver, 25% with splenomegaly, 10% with hyperpigmentation, and fewer than 10% with jaundice alone.[2]

The presence of antimitochondrial antibody (AMA) in the serum is a hallmark in the diagnosis of PBC, although not all patients test positive.[3] Additionally, elevations of alkaline phosphatase, gammaglutamyl transpeptidase, and 5'-nucleotidase may be found. These enzymes may be substantially elevated; a less dramatic elevation of the serum aminotransferase may be seen. The conjugated fraction of hyperbilirubinemia may also be elevated.[1]

Medications used in the therapy of PBC are ursodeoxycholic acid 12-15 mg/kg each day in divided doses.[1] Treatment with immunosuppressive agents such as azathioprine and cyclosporine have not improved survival. A clinical trial evaluating methotrexate is currently being evaluated. Colchicine may improve liver function in terms of prothrombin time and serum albumin, but no large-scale studies have yet been done to show improved survival.[1]

Other strategies used to control pruritus include avoiding nylon or wool next to the skin, avoiding hot showers, and not getting overheated in bed at night. Ultraviolet light helps some, but sunburn must be avoided. The old standby of bicarbonate of soda in a cool bath is soothing, as is a post shampoo rinse of bicarbonate of soda. Avoidance of perfumed soaps, bath gels, and powder may also lessen pruritis.[4]

Liver transplantation remains the only cure for PBC and has a survival rate of greater than 70%.Posted 03/13/2001

References

Heathcote J. Primary biliary cirrhosis. In: Harrison's Online. New York, NY: McGraw-Hill Companies, Inc. 2000. Available at:
http://www.medscape.com/HOL/articles/2000/11/hol52/hol52-01.htmlBerkow R, Beers MH, Fletcher AJ, Bogin RM, eds. The Merck Manual. Whitehouse Station, NJ: Merck and Co., Inc. 2000. Available at:
http://www.merckhomeedition.com/home.htmlHeathcote J. Update on Primary biliary cirrhosis. Can J Gastroenterol. 2000;14:43-48.That dreaded itch. The PBC Foundation. Available at: http://www.nhtech.demon.co.uk/pbc/itching.html

Medscape Family Medicine/Primary Care.  2001;3(1) ©2001 Medscape


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Medical Cannabis Is A Blunt Tool

IF anecdotes and ancient medicine are to be trusted, cannabis is a wonder drug. Yet results of clinical trials have been mixed and its use in modern medicine remains limited. Now it seems the reasons may be practical as much as political and cultural: there are fundamental problems with how our bodies respond to the stuff.

Some compounds in cannabis, including THC and cannabidiol, interfere with a natural signalling system throughout our brains, nerves and immune system. This system, which produces its own cannabis-like compounds called endocannabinoids, plays a role in many medical conditions including pain, epilepsy, multiple sclerosis, Parkinson's disease, depression and schizophrenia.

Because the system is so widespread, smoking or ingesting cannabis is bound to have varied effects, including its influence on the mind. Now it seems that even with purified cannabis extracts, changing the amount, time or place of a dose could produce completely opposite effects on the body, according to evidence presented at the Federation of European Neuroscience Societies (FENS) meeting in Vienna earlier this month. This could explain why the medical benefits have proved so difficult to harness.

In one study, Vincenzo Di Marzo of the National Research Council in Pozzuoli, Italy, boosted levels of an endocannabinoid called andandamide in rats engineered to develop an Alzheimer's-like disease. This appeared to protect the rats from memory loss and nerve degeneration. But if the rise was prolonged, cannabinoids became ineffective or even damaging.

Beat Lutz of the University of Mainz in Germany found a similar paradox in models of epilepsy in mice. Anandamide is synthesised during epileptic fits, providing a natural calming effect. "If we apply cannabinoids we should protect from seizures," says Lutz. "But no, we actually get worsening of seizures in mice."

He believes he has found the reason. The main class of cannabinoid receptor, called CB1 receptors, occurs in two distinct populations of neurons, those that excite neighbouring neurons and those that inhibit them - so cannabinoids can have opposite effects depending on which neurons they hit. David Baker, a multiple sclerosis expert at University College London has found the same problem in MS. Mice that have been engineered to have a condition like MS and no CB1 receptors suffer much worse nerve damage than those with normal CB1 receptors, suggesting that cannabinoids are involved in protecting against the nerve damage seen in MS. But other experiments in mice have shown that cannabinoid signalling also prompts release of stress hormones called glucocorticoids that can kill neurons.

The greatest anecdotal evidence for the medical benefits of cannabis comes from its painkilling properties, and animal models have produced promising results. Yet even here new evidence suggests that an endocannabinoid called NADA binds not only to cannabinoid receptors but to a completely different class of receptor as well, where it mimicks the effect of a pain-producing chemical called capsaicin, says J. Michael Walker of Indiana University in Bloomington, who also presented his research at FENS. This may explain why human trials of cannabis for the treatment of pain have produced mixed results.

"The problem with cannabis is that there's no way of targeting the drug to any particular place," says Baker.

The answer will be to manipulate the system from within, he says. New ways of amplifying natural cannabinoid release include reuptake inhibitors that prolong this release just as Prozac does for serotonin. Such methods look promising for a range of conditions from pain and cancer to nerve degeneration and MS.

Other methods now being tried in the lab include the manipulation of enzymes that make and deliver endocannabinoids, as well as compounds that stimulate and block them. Drugs that bind to CB1 receptors and alter their efficiency are also being discovered, says Roger Pertwee, director of pharmacology at GW Pharmaceuticals, based in Porton Down Science Park, Wiltshire, UK. His company developed Sativex, the first pharmaceutical cannabis extract to gain clinical approval.

Ironically, the first offshoot of endocannabinoid research to gain clinical approval, last month, has the opposite effect to cannabis: Acomplia (rimonabant), an appetite suppressant, works by blocking CB1 receptors (New Scientist, 8 July, p 5).

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Aptivus(R) (tipranavir) Capsules Granted Full Approval By The U.S. FDA

Boehringer Ingelheim Pharmaceuticals, Inc. announced that the U.S. Food and Drug Administration (FDA) granted full (traditional) approval of Aptivus(R) (tipranavir) capsules. The FDA granted accelerated approval to APTIVUS in June 2005; accelerated approval is a regulatory process that expedites the approval of therapies for serious or life-threatening illnesses. The full approval of APTIVUS is based largely on 48-week analyses of the Phase 3 pivotal clinical studies known as the RESIST (Randomized Evaluation of Strategic Intervention in Multi-Drug ReSistant Patients with Tipranavir) trials. These trials comprise one of the largest study programs conducted in treatment-experienced HIV patients.

"Data show that APTIVUS/r may provide treatment-experienced HIV patients with an effective treatment option through nearly one year of therapy. Furthermore, longer-term safety data are now available for physician and patient consideration," said Dr. Daniel Kuritzkes, associate professor of medicine, Harvard Medical School; director of AIDS research, Brigham and Women's Hospital, Boston, MA.

APTIVUS, a protease inhibitor, co-administered with 200 mg of ritonavir (APTIVUS/r), is indicated for combination antiretroviral treatment of HIV-1 infected adult patients who are treatment-experienced and infected with HIV-1 strains resistant to more than one protease inhibitor.

This indication is based on analyses of plasma HIV-1 RNA levels in two controlled studies of APTIVUS/r of 48 weeks duration. Both studies were conducted in clinically advanced, 3-class antiretroviral (NRTI, NNRTI, PI) treatment-experienced adults with evidence of HIV-1 replication despite ongoing antiretroviral therapy.

The following points should be considered when initiating therapy with APTIVUS/r:

— The use of APTIVUS/r in treatment-naïve patients is not recommended.

— The use of other active agents with APTIVUS/r is associated with a greater likelihood of treatment response.

— Genotypic or phenotypic testing and/or treatment history should guide the use of APTIVUS/r. The number of baseline primary protease inhibitor mutations affects the virologic response to APTIVUS/r.

— Use caution when prescribing APTIVUS/r to patients with elevated transaminases, hepatitis B or C co-infection or patients with mild hepatic impairment.

— Liver function tests should be performed at initiation of therapy with APTIVUS/r and monitored frequently throughout the duration of treatment.

— The drug-drug interaction potential of APTIVUS/r when co-administered with other drugs must be considered prior to and during APTIVUS/r use.

— Use caution when prescribing APTIVUS/r in patients who may be at risk for increased bleeding or who are receiving medications known to increase the risk of bleeding.

— The risk-benefit of APTIVUS/r has not been established in pediatric patients.

There are no study results demonstrating the effect of APTIVUS/r on clinical progression of HIV-1.

APTIVUS/r does not cure HIV or help prevent passing HIV to others.

About RESIST

The RESIST clinical trial program consists of two ongoing Phase 3 pivotal trials, RESIST-1 and RESIST-2. Comprising one of the largest study programs conducted in treatment-experienced HIV patients, RESIST-1 includes 620 patients in the U.S., Canada and Australia, and RESIST-2 includes 863 patients in Europe and Latin America. The trial design and baseline patient characteristics are similar across studies. Patients enrolled in the RESIST studies were failing their current PI-based regimen, had received at least two previous PI-based regimens, had received prior treatment from at least three classes of antiretroviral agents and had documented PI resistance.

At the time of full approval, the studies examined treatment response, defined as a confirmed 1 log10 or greater decrease in the amount of HIV in the blood, or viral load, at 48 weeks versus a comparator group in which patients received one of several marketed ritonavir-boosted PIs. Investigators selected a comparator PI (CPI/r) that offered patients the best opportunity for treatment response based on resistance testing. The comparator PIs were lopinavir, indinavir, saquinavir and amprenavir. In addition, patients in both arms received an optimized background regimen of other antiretroviral drugs. Patients were treatment-experienced and the majority (85.1%) were at least possibly resistant to the comparator PI chosen.

Analysis of the primary endpoint at week 48 demonstrated that more than twice the percentage of patients (33.8%) treated with APTIVUS/r achieved a treatment response compared to those patients treated with a CPI/r (14.9%). The median change from baseline in HIV-1 viral load at the last measurement up to week 48 was -0.64 log10 copies/mL in APTIVUS/r patients versus -0.22 log10 copies/mL in CPI/r patients.

Secondary endpoints included reduction in viral load to less than 400 copies/mL or 50 copies/mL and increase in CD4+ cell count. Through 48 weeks of treatment, more than twice the percentage of patients in the APTIVUS/r arm achieved a viral load of less than 400 copies/mL (30.3%) compared to the CPI/r arm (13.6%). Regarding a viral load of less than 50 copies/mL, 22.7% of APTIVUS/r patients achieved this level compared to 10.2% of CPI/r patients. The median change from baseline in CD4+ cell count at the last measurement up to week 48 was +23 cells/mm3 in APTIVUS/r patients (n=740) versus +4 cells/mm3 in CPI/r patients (n=727).

According to HIV treatment guidelines, achieving and maintaining an undetectable viral load — less than 50 copies/mL of blood — is the goal of HIV therapy.(1)

The APTIVUS labeling includes boxed warnings for reports of:

— Clinical hepatitis and hepatic decompensation including some fatalities. Extra vigilance is warranted in patients with chronic hepatitis B or hepatitis C co-infection, as these patients have an increased risk of hepatotoxicity.

— Both fatal and non-fatal intracranial hemorrhage (ICH).

The most commonly reported adverse events in patients taking APTIVUS/r are diarrhea, nausea, fever, vomiting, fatigue, headache and abdominal pain. The most common laboratory abnormalities are elevated liver enzymes (AST/ALT) and triglycerides.

"For more than a decade, Boehringer Ingelheim has been at the forefront of developing innovative therapies for HIV patients. The full approval of APTIVUS further demonstrates our commitment to HIV/AIDS," said Dr. Thor Voigt, Senior Vice President, Medicine and Drug Regulatory Affairs, Boehringer Ingelheim Pharmaceuticals, Inc. "We have developed a robust clinical trial program around APTIVUS. In addition to RESIST, clinical trials for treating HIV are in progress in racially, ethnically and gender diverse patients and hepatitis co-infected patients. A trial comparing the efficacy and safety of APTIVUS/r versus darunavir/r, both as part of combination antiretroviral therapy, is also planned."

Important Safety Information for APTIVUS

— APTIVUS/r has been associated with reports of clinical hepatitis and hepatic decompensation, including some fatalities. Extra vigilance is warranted in patients with chronic hepatitis B or hepatitis C co- infection, as these patients have an increased risk of hepatotoxicity. Patients with signs or symptoms of clinical hepatitis should discontinue APTIVUS/r treatment and seek medical evaluation.

— APTIVUS/r has been associated with reports of both fatal and non-fatal intracranial hemorrhage (ICH).

— All patients should be followed closely with clinical and laboratory monitoring, especially those with chronic hepatitis B or C co- infection, as these patients have an increased risk of hepatotoxicity. Liver function tests should be performed prior to initiating therapy with APTIVUS/r, and frequently throughout the duration of treatment.

— Treatment-experienced patients with chronic hepatitis B or hepatitis C co-infection or elevations in transaminases are at approximately 2-fold risk for developing Grade 3 or 4 transaminase elevations or hepatic decompensation. In the RESIST trials, Grade 3 and 4 increases in hepatic transaminases were observed in 10.3% (10.9/100 PEY) of patients receiving APTIVUS/r through week 48. In a study of treatment-naïve patients, 20.3% (21/100 PEY) experienced Grade 3 or 4 hepatic transaminase elevations while receiving APTIVUS/r through week 48.

— APTIVUS/r is contraindicated in patients with moderate or severe (Child-Pugh Class B or C, respectively) hepatic impairment.

— The drug-drug interaction potential of APTIVUS/r when co-administered with multiple classes of drugs must be considered prior to and during APTIVUS/r use.

— APTIVUS/r is contraindicated with amiodarone, bepridil, flecainide, propafenone, quinidine, rifampin, dihydroergotamine, ergonovine, ergotamine, methylergonovine, cisapride, St. John's wort, lovastatin, simvastatin, pimozide, midazolam and triazolam due to the potential for serious and/or life-threatening events or loss of efficacy.

— A drug interaction study in healthy subjects has shown that ritonavir significantly increases plasma fluticasone propionate exposures. Concomitant use of APTIVUS/r and fluticasone propionate may produce systemic corticosteroid side effects, including Cushing's syndrome and adrenal suppression. APTIVUS/r should not be taken with fluticasone propionate, inhaled or intranasally administered, unless the potential benefit to the patient outweighs the risk.

— Caution should be used when prescribing sildenafil, tadalafil, and vardenafil with APTIVUS/r because concentrations of these drugs may increase.

— Caution should be used when prescribing carbamazepine, phenobarbital and/or phenytoin. APTIVUS may be less effective due to decreased tipranavir plasma concentrations.

— Caution should be used when prescribing valproic acid. Valproic acid may be less effective due to decreased valproic acid plasma concentrations.

— Use caution when prescribing APTIVUS/r in patients who may be at risk of increased bleeding from trauma, surgery or other medical conditions, or who are receiving medications known to increase the risk of bleeding such as antiplatelet agents and anticoagulants, or who are taking supplemental high doses of vitamin E. In in vitro experiments, tipranavir was observed to inhibit human platelet aggregation at levels consistent with exposures observed in patients receiving APTIVUS/r. In rats, co-administration with vitamin E increased the bleeding effects of tipranavir.

— Rash, including urticarial rash, maculopapular rash, and possible photosensitivity, has been reported in patients receiving APTIVUS/r. In some, rash was accompanied by joint pain or stiffness, throat tightness, or generalized pruritus. In controlled clinical trials, rash (all grades, all causality) was observed in 10% of females and in 8% of males receiving APTIVUS/r through 48 weeks of treatment. The median time to onset of rash was 53 days and the median duration of rash was 22 days. The discontinuation rate for rash in clinical trials was 0.5%. In an uncontrolled compassionate use program (n=3,920), cases of rash, some of which were severe, accompanied by myalgia, fever, erythema, desquamation, and mucosal erosions were reported. Discontinue and initiate appropriate treatment if severe skin rash develops.

— APTIVUS should be used with caution in patients with a known sulfonamide allergy.

— New onset diabetes mellitus, exacerbation of pre-existing diabetes mellitus, hyperglycemia and increased bleeding (in patients with hemophilia) have been reported in patients taking protease inhibitors. A causal relationship between protease inhibitors and these events has not been established.

— Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including APTIVUS/r.

— Redistribution and/or accumulation of body fat have been observed in patients receiving antiretroviral therapy. A causal relationship has not been established.

— Treatment with APTIVUS/r has resulted in large increases in total cholesterol and triglycerides, which should be monitored prior to and during APTIVUS/r therapy.

— Because the potential for HIV cross-resistance among protease inhibitors has not been fully explored in APTIVUS/r-treated patients, it is unknown what effect therapy with APTIVUS will have on the activity of subsequently administered protease inhibitors.

— APTIVUS must be co-administered with 200 mg of ritonavir to exert its therapeutic effect. Failure to correctly co-administer APTIVUS with ritonavir will result in reduced plasma levels of tipranavir that will be insufficient to achieve the desired antiviral effect and will alter some drug interactions.

— Please refer to the complete ritonavir prescribing information for a description of ritonavir contraindications and additional information on precautionary measures.

— In clinical trials, the most frequently reported adverse events associated with APTIVUS/r were diarrhea, nausea, fever, vomiting, fatigue, headache and abdominal pain.

Please see full Prescribing Information (PI), including boxed WARNINGS, for APTIVUS at http://www.APTIVUS.com. The PI is in the new Physicians Labeling Rule (PLR) format required by the U.S. FDA.

Additional Information about APTIVUS

APTIVUS, a non-peptidic protease inhibitor, works by inhibiting protease, an enzyme needed to complete the HIV replication process. The approved dose of APTIVUS is 500 mg taken with 200 mg of ritonavir, twice daily.

APTIVUS is also approved in Argentina, Australia, Canada, Switzerland, Mexico, Iceland, Taiwan and the European Union.

Boehringer Ingelheim is actively conducting a clinical trial program to further evaluate APTIVUS for the treatment of HIV-1 infection. The program is comprised of ongoing and planned studies in more than 1,000 HIV-infected patients.

About Boehringer Ingelheim

Boehringer Ingelheim is committed to improving HIV therapy by providing physicians and patients with innovative antiretroviral agents.

For more information on Boehringer Ingelheim Pharmaceuticals, Inc., please visit http://us.boehringer-ingelheim.com.

(1) Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents. DHHS Panel on Antiretroviral Guidelines for Adults and Adolescents, October 10, 2006; Treatment for Adult HIV Infection. 2006 Recommendations of the International AIDS Society - - USA Panel. JAMA. 296(7): 837. August 16, 2006.

Boehringer Ingelheim Pharmaceuticals, Inc.
http://us.boehringer-ingelheim.com
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Rimonabant: Endocannabinoid Inhibition for the Metabolic Syndrome

Comparison With Other Agents

Rimonabant is a new agent and thus long-term safety data applicable to rare side effects is not yet available. However, it is possible to compare rimonabant with the other drugs used to treat obesity[15,17] ( Table 2 ). Orlistat is well established as a weight loss agent and is considered pharmacologically safe enough that in the USA it may become available over-the-counter. However, in clinical practice a meta-analysis of 29 orlistat studies showed a 2.89 kg (2.27-3.51) weight loss in patients with an initial BMI of 36.7 kg/m2.[15] Orlistat therapy was associated with a 3.4-fold increase in diarrhoea, 3.1-fold in flatulence and 1.48-fold in dyspepsia.[15] Clinical trial data from the XENDOS and other studies shows that therapy over 2 years with % losing >5% of body weight and % losing >10%. In parallel to these changes in weight orlistat reduces triglycerides by 15-20% though it has a little effect on HDL-C or blood pressure. Only 70% of patients comply either because of poor adherence to trial protocols, which is a common problem in obesity trials or because of side effects. The main side effects of orlistat are explosive diarrhoea and bloating on consumption of fat (especially saturated fat). Thus this agent has low patient acceptance. In addition, many obese patients especially from ethnic minorities do not consume diets rich in saturated fat but vast quantities of carbohydrates. In these groups orlistat has limited efficacy.

Sibutramine has less end-point data than orlistat though 2 year studies recruiting on the basis of BMI have been performed of sibutramine added to −500 kCal/day[18] and −1200 kCal/day diets.[64] In weight loss studies it induces an average 4.45 kg (3.62-5.29) weight loss with 19-34% achieving >5% and 12-31% achieving >10% weight loss respectively.[17] In a meta-analysis, sibutramine reduced triglycerides by 0.04 mmol/l HbA1c by 0.3%, and raised HDL-C by 0.05 mmol/l.[17] Its blood pressure effects were variable with long-term trials showing a 4.6/2.8 mmHg increase. There are no data on its effectiveness in preventing diabetes or cardiovascular disease as yet though the Sibutramine Cardiovascular OUTcome study is underway.[65] The tolerability of sibutramine is 70% in obesity trials with the majority of discontinuations being caused by poor compliance or adrenergic side effects (headache, dry mouth, tachycardia and tachypnoea). It has no additive effect when combined with orlistat and seems to act as a general appetite suppressant to reduce snacks in particular but anecdotally not to affect meal habits or portion sizes.

The clinical trial data for rimonabant shows superior weight loss (5.4 kg) compared with orlistat (2.85 kg) and sibutramine (4.85 kg) in clinical trials allied with a wider degree of benefit on cardiovascular risk factors. Compliance in all the obesity trials is about 70% and side effects are generally seen in 10-30%. The side effect profile of rimonabant is better than that of orlistat where gastrointestinal side effects occur in 20-30% and similar to sibutramine where compliance and side effect rates are similar but the drug is contraindicated in significant groups of patients (secondary prevention and hypertension). No data exists as yet for rimonabant in combination with other obesity medications. Given the profoundly different mechanism of action of rimonabant it is a good alternative where other anti-obesity medications have not been tolerated or are contraindicated. As it has beneficial action on lipid profiles that are not seen with orlistat, it may be superior to this agent in patients with notable dyslipidaemia as well as obesity and insulin resistance and also has beneficial effects in helping increase rates of cessation of smoking. The long-term benefits of rimonabant will be confirmed in studies looking directly at its effects on the progression of atherosclerosis by intravascular ultrasound and in a cardiovascular end-point trial (the Comprehensive Rimonabant Evaluation Study of Cardiovascular ENDpoints and Outcomes[66] trial) where rate of progression to diabetes is a secondary end-point.  Printer- Friendly Email This

Int J Clin Pract.  2006;60(12):1697-1706.  ©2006 Blackwell Publishing
This is a part of article Rimonabant: Endocannabinoid Inhibition for the Metabolic Syndrome Taken from "Buy Acomplia Tablet" Information Blog

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