What is sunitinib? A definition from the National Cancer Institute Dictionary of Cancer Terms

A drug used to treat gastrointestinal stromal tumors (GIST) that have not responded to treatment with imatinib mesylate (Gleevec). Sunitinib maleate is also used to treat advanced kidney cancer and is being studied in the treatment of other types of cancer. It is a type of tyrosine kinase inhibitor, a type of vascular endothelial growth factor (VEGF) receptor inhibitor, and a type of angiogenesis inhibitor. Also called SU011248, SU11248, sunitinib, and Sutent.

Some further details about the decision and the role of immunotherapy in the current management of renal cell cancer:

The guidance on first line use of sunitinib has been developed on the understanding that the currently available treatment for advanced and/or metastatic renal cell carcinoma is immunotherapy (namely interferon-alfa and interleukin-2). The Institute recognises that there are people who have had or who are currently receiving immunotherapy and wish to clarify the implications of the guidance for these people. Sunitinib can be considered as a treatment option for those people with advanced and/or metastatic RCC who are currently receiving immunotherapy or who have had immunotherapy before the release of our final recommendations to ensure they are not disadvantaged by our proposed guidance.

Guidance PDF: NICE recommends sunitinib for the first-line treatment of renal cancer

This excerpt from the Wikipedia article summarizes the approach to the hormonal treatment of prostate cancer affecting the GnRH pathway:

GnRH action can be interrupted in one of two ways. GnRH antagonists suppress the production of LH directly, while GnRH agonists suppress LH through the process of downregulation after an initial stimulation effect. Abarelix is an example of a GnRH antagonist, while the GnRH agonists include leuprolide (Lupron, Eligard) , goserelin (Zoladex) , triptorelin, and buserelin(Suprefact, Suprecor) . Initially, GnRH agonists increase the production of LH. However, because the constant supply of the medication does not match the body’s natural production rhythm, production of both LH and GnRH decreases after a few weeks.

Some review papers on the role of GnRH agonists and antagonists in prostate cancer and assisted conception:

GnRH agonists in the treatment of prostate cancer. Endocrine Reviews. 2005

Will GnRH antagonists improve prostate cancer treatment? Trends in Endocrinology & Metabolism. January 2009

Gonadotrophin-releasing hormone antagonists for assisted conception. Cochrane Reviews 2001

FDA Approves Drug for Patients with Advanced Prostate Cancer

The U.S. Food and Drug Administration recently approved the injectable drug degarelix, the first new drug in several years for prostate cancer.  

Degarelix is intended to treat patients with advanced prostate cancer. It belongs to a class of agents called gonadotropin releasing hormone (GnRH) receptor inhibitors. These agents slow the growth and progression of prostate cancer by suppressing testosterone, which plays an important role in the continued growth of prostate cancer.

Hormonal treatments for prostate cancer may cause an initial surge in testosterone production before lowering testosterone levels. This initial stimulation of the hormone receptors may temporarily prompt tumor growth rather than inhibiting it. Degarelix doesn’t do this.

“Prostate cancer is the second leading cause of cancer death among men in the United States and there is an ongoing need for additional treatment options for these patients,” said Richard Pazdur, M.D., director of the Office of Oncology Drug Products, Center for Drug Evaluation and Research, FDA.

Prostate cancer is one of the most commonly diagnosed cancers in the United States. In 2004, the most recent year for which statistics are currently available, nearly 190,000 men were diagnosed with prostate cancer and 29,000 men died from the cancer.

Several treatment options exist for different stages of prostate cancer including observation, prostatectomy (surgical removal of the prostate gland), radiation therapy, chemotherapy, and hormone therapy with agents that affect GnRH receptors.

The efficacy of degarelix was established in a clinical trial in which patients with prostate cancer received either degarelix or leuprolide, a drug currently used for hormone therapy in treating advanced prostate cancer. Degarelix treatment did not cause the temporary increase in testosterone that is seen with some other drugs that affect GnRH receptors.

In fact, nearly all of the patients on either drug had suppression of testosterone to levels seen with surgical removal of the testes.

The most frequently reported adverse reactions in the clinical study included injection site reactions (pain, redness, and swelling), hot flashes, increased weight, fatigue, and increases in some liver enzymes.

Degarelix is manufactured for Ferring Pharmaceuticals Inc., Parsippany, N.J., by Rentschler Biotechnologie Gmbh, Laupheim, Germany.

An animation on the mechanism of action of  GnRH antagonists explains their advantages over GnRH receptor agonists.

Source. FDA newsroom. FDA Approves Drug for Patients with Advanced Prostate Cancer

Temsirolimus

Torisel (Wyeth)
vials containing 25 mg/mL concentrate
Approved indication: advanced renal cell carcinoma
Australian Medicines Handbook section 14.2.3

About 30% of patients with renal cell carcinoma have advanced or metastatic disease at the time of diagnosis. Chemotherapy is generally ineffective and nephrectomy is the mainstay of treatment for disease confined to the kidney. Treatment with drugs such as interferon alfa, interleukin-2 and the tyrosine kinase inhibitors sunitinib and sorafenib may benefit some patients.1

Temsirolimus is a kinase inhibitor derived from sirolimus (rapamycin) (see Aust Prescr 2002;25:97-9). It works by inhibiting the action of an enzyme called ‘mammalian target of rapamycin’ or mTOR. Inhibition prevents the division of cancerous cells, slowing the growth and spread of the cancer.

Following intravenous administration, temsirolimus is extensively metabolised by CYP3A4, with the main metabolite being sirolimus. The half-life is 17 hours for temsirolimus and 55 hours for sirolimus. Metabolites are primarily eliminated in the faeces.

The efficacy of temsirolimus in advanced renal cell carcinoma was first assessed in a dose escalation trial of 111 previously treated patients. After a weekly dose of 25, 75 or 250 mg (for a median of 5.6 months), 7% of the patients had a complete or partial response to temsirolimus, but this was not dose-dependent.2 In a larger trial of 626 previously untreated patients, median overall survival was longer in patients treated with temsirolimus (25 mg each week) than those treated with interferon alfa (10.9 months vs 7.3 months). Adding interferon alfa to temsirolimus did not improve the overall survival time and was associated with more serious adverse events than temsirolimus alone.3

In the trials, rash, fatigue, mucositis, nausea, oedema, anaemia and anorexia were common adverse events in patients receiving temsirolimus. The most frequent laboratory test abnormalities were hyperglycaemia, hypercholesterolaemia, hyperlipidaemia, hypophosphataemia, thrombocytopenia, leucopenia and elevated alkaline phosphatase, serum creatinine and aspartate aminotransferase.2,3

Approximately 5% of the participants in the larger trial had a hypersensitivity reaction to temsirolimus so patients should be given intravenous antihistamine approximately 30 minutes before temsirolimus is administered. If a hypersensitivity reaction develops, the temsirolimus infusion should be stopped.

Cases of interstitial lung disease have occurred in patients taking temsirolimus and patients should be advised to seek medical attention if they develop worsening respiratory symptoms. Other rare but serious adverse events that have been reported include fatal bowel perforation and renal failure. Patients with central nervous system tumours and/or taking anticoagulants may have an increased risk of intracerebral bleeding.

Immunosuppression may occur with temsirolimus, so be vigilant for infections. Also, live vaccines and contact with people who have recently had them should be avoided. Temsirolimus may delay wound healing and should not be given to patients in the peri-surgical period.

Drugs that induce or inhibit the CYP3A4 enzyme should be avoided in patients taking temsirolimus. Concomitant use of sunitinib can result in dose-limiting toxicities such as serious maculopapular rash and gout or cellulitis requiring hospitalisation. Angioneurotic oedema-type reactions have been observed in patients who were receiving temsirolimus concomitantly with an angiotensin converting enzyme inhibitor. Some patients on temsirolimus and interferon alfa have developed cataracts.

Temsirolimus provides another option for patients with advanced renal cell carcinoma. However, its relative efficacy compared to tyrosine kinase inhibitors is not known.

manufacturer provided clinical evaluation

References*†

1. Pavlakis N. Drug treatment of renal cancer. Aust Prescr 2006;29:151-3.

2. Atkins MB, Hidalgo M, Stadler WM, Logan TF, Dutcher JP, Hudes GR, et al. Randomized phase II study of multiple dose levels of CCI-779, a novel mammalian target of rapamycin kinase inhibitor, in patients with advanced refractory renal cell carcinoma. J Clin Oncol 2004;22:909-18.

3. Hudes G, Carducci M, Tomczak P, Dutcher J, Figlin R, Kapoor A, et al. Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med 2007;356:2271-81.

Source: Australian Prescriber. New drugs: temsirolimus. Volume 31 Number 4- August 2008

Alpha-Blocker Does Not Ease Symptoms of Chronic Prostatitis

Alfuzosin, an alpha-adrenergic–receptor blocker, does not improve symptoms in men with chronic prostatitis–chronic pelvic pain syndrome, according to a New England Journal of Medicine study.

Some 270 men who were diagnosed with the condition within the preceding 2 years and had never used an alpha-blocker were randomized to receive alfuzosin or a placebo daily for 12 weeks. By the end of treatment, approximately half of the men in each group had achieved clinically significant reductions in a symptom score measuring pain, voiding problems, and quality of life. Similarly, there were no significant differences between the groups in secondary outcomes, such as anxiety and depression.

The authors note that several meta-analyses have led some researchers to recommend alpha-blockers for chronic prostatitis. They conclude: “Our trial does not support these recommendations and should prompt reconsideration of the choice of initial therapy for these patients.”

Original study: NEJM. Alfuzosin and Symptoms of Chronic Prostatitis–Chronic Pelvic Pain Syndrome

COMMITTEE FOR MEDICINAL PRODUCTS FOR HUMAN USE SUMMARY OF POSITIVE OPINION
for
FIRMAGON

International Nonproprietary Name (INN): degarelix (as acetate)

On 18 December 2008 the Committee for Medicinal Products for Human Use (CHMP) adopted a positive opinion, recommending to grant a marketing authorisation for the medicinal product Firmagon, 80 mg and 120 mg, powder and solvent for solution for injection, intended for the treatment of prostate cancer. The applicant for this medicinal product is Ferring Pharmaceuticals A/S.

The active substance of Firmagon is degarelix, a gonadotropin-releasing hormone receptor antagonist medicinal product (ATC code: L02BX02). Degarelix binds to receptors in the anterior pituitary gland and this results in a decreased secretion of luteinizing hormone and follicle-stimulating hormone and subsequently decreased production of the steroid hormone testosterone, which is necessary for growth and spread of prostate cancer cells.

The benefits with Firmagon are its achievement and maintenance of very low levels of testosterone (≤ 0.5 ng/ml) throughout the 12-month treatment period without an initial surge in testosterone, as observed in a randomised clinical trial comparing two different degarelix dosing regimens to
leuprorelin in patients with prostate cancer requiring androgen deprivation therapy. The most common side effects are hot flushes, injection site pain, injection site erythema, increased weight, nasopharyngitis, fatigue, and back pain.

A pharmacovigilance plan for Firmagon, as for all medicinal products, will be implemented as part of the marketing authorisation.

The approved indication is: “Firmagon is a gonadotrophin releasing hormone (GnRH) antagonist indicated for treatment of adult male patients with advanced hormone-dependent prostate cancer”.

Detailed recommendations for the use of this product will be described in the Summary of Product Characteristics (SPC) which will be published in the European Public Assessment Report (EPAR) and will be available in all official European Union languages after the marketing authorisation has been
granted by the European Commission.

The CHMP, on the basis of quality, safety and efficacy data submitted, considers that there is a favourable benefit to risk balance for Firmagon and therefore recommends the granting of the marketing authorisation.

An animation on the mechanism of action of  GnRH antagonists explains their advantages over GnRH receptor agonists.

Source. EMEA website. Human Medicines – CHMP Summaries of Opinion. Degarelix

Additional information about alpha 1 blocking drugs.  Source: Bertram G. Katzung, Basic & Clinical Pharmacology (Mc Graw-Hill Medical, 2007)

” Phentolamine, an imidazoline derivative, is a potent competitive antagonist at both alpha 1 and alpha 2 receptors . Phentolamine causes a reduction in peripheral resistance through blockade of alpha 1 receptors and possibly alpha 2 receptors on vascular smooth muscle. The cardiac stimulation induced by phentolamine is due to sympathetic stimulation of the heart resulting from baroreflex mechanisms. Furthermore, since phentolamine potently blocks alpha 2  receptors, antagonism of presynaptic alpha 2 receptors may lead to enhanced release of norepinephrine from sympathetic nerves. In addition to being an alpha 1- and alpha 1-receptor antagonist, phentolamine also has minor inhibitory effects at serotonin receptors and agonist effects at muscarinic and H₁ and H₂ histamine receptors.

Phentolamine has limited absorption after oral administration. Its pharmacokinetic properties are not well known; it may reach peak concentrations within an hour after oral administration and has a half life of 5-7 hours. The principal adverse effects are related to cardiac stimulation, which may cause severe tachycardia, arrhythmias, and myocardial ischemia, especially after intravenous administration. With oral administration, adverse effects include tachycardia, nasal congestion, and headache.

Phentolamine has been used in the treatment of pheochromocytoma -especially intraoperatively- as well as for male erectile dysfunction by injection intracavernosally and when taken orally (see below).

Phenoxybenzamine binds covalently to alpha receptors, causing irreversible blockade of long duration (14-48 hours or longer). It is somewhat selective for a₁ receptors but less so than prazosin . The drug also inhibits reuptake of released norepinephrine by presynaptic adrenergic nerve terminals. Phenoxybenzamine blocks histamine (H₁), acetylcholine, and serotonin receptors as well as a receptors .

The pharmacologic actions of phenoxybenzamine are primarily related to antagonism of alpha-receptor-mediated events. Most significant is that phenoxybenzamine attenuates catecholamine-induced vasoconstriction. While phenoxybenzamine causes relatively little fall in blood pressure in normal supine individuals, it reduces blood pressure when sympathetic tone is high, eg, as a result of upright posture or because of reduced blood volume. Cardiac output may be increased because of reflex effects and because of some blockade of presynaptic a₂ receptors in cardiac sympathetic nerves.

Phenoxybenzamine is absorbed after oral administration, although bioavailability is low and its kinetic properties are not well known. The drug is usually given orally, starting with low doses of 10-20 mg/d and progressively increasing the dose until the desired effect is achieved. A dosage of less than 100 mg/d is usually sufficient to achieve adequate a-receptor blockade. The major use of phenoxybenzamine is in the treatment of pheochromocytoma (see below).

Many of the adverse effects of phenoxybenzamine derive from its a-receptor-blocking action; the most important are postural hypotension and tachycardia. Nasal stuffiness and inhibition of ejaculation also occur. Since phenoxybenzamine enters the central nervous system, it may cause less specific effects, including fatigue, sedation, and nausea. Because phenoxybenzamine is an alkylating agent, it may have other adverse effects that have not yet been characterized. Phenoxybenzamine causes tumors in animals, but the clinical implications of this observation are unknown.

Tolazoline is an obsolete agent similar to phentolamine. Ergot derivatives, eg, ergotamine, dihydroergotamine, cause reversible a-receptor blockade, probably via a partial agonist action .

Prazosin is a piperazinyl quinazoline effective in the management of hypertension . It is highly selective for a₁ receptors and typically 1000-fold less potent at a₂ receptors. This may partially explain the relative absence of tachycardia seen with prazosin compared with that reported with phentolamine and phenoxybenzamine. Prazosin leads to relaxation of both arterial and venous vascular smooth muscle, as well as smooth muscle in the prostate, due to blockade of a₁ receptors. Prazosin is extensively metabolized in humans; because of metabolic degradation by the liver, only about 50% of the drug is available after oral administration. The half-life is normally about 3 hours.

Terazosin is another reversible a₁-selective antagonist that is effective in hypertension; it is also approved for use in men with urinary symptoms due to benign prostatic hyperplasia (BPH). Terazosin has high bioavailability but is extensively metabolized in the liver, with only a small fraction of unchanged drug excreted in the urine. The half-life of terazosin is 9-12 hours.

Doxazosin is efficacious in the treatment of hypertension and BPH. It differs from prazosin and terazosin in having a longer half-life of about 22 hours. It has moderate bioavailability and is extensively metabolized, with very little parent drug excreted in urine or feces. Doxazosin has active metabolites, although their contribution to the drug’s effects is probably small.

Tamsulosin is a competitive a₁ antagonist with a structure quite different from that of most other a₁-receptor blockers. It has high bioavailability and a long half-life of 9-15 hours. It is metabolized extensively in the liver. Tamsulosin has higher affinity for a_1A and a_1D receptors than for the a_1B subtype. Evidence suggests that tamsulosin has relatively greater potency in inhibiting contraction in prostate smooth muscle versus vascular smooth muscle compared with other a₁-selective antagonists. The drug’s efficacy in BPH suggests that the a_1A subtype may be the most important a subtype mediating prostate smooth muscle contraction. Furthermore, compared with other antagonists, tamsulosin has less effect on standing blood pressure in patients. Nevertheless, caution is appropriate in using any a antagonist in patients with diminished sympathetic nervous system function”.

Source of animation: Medmovie

EMEA recommends restricted use of oral norfloxacin-containing medicines in urinary infections

The European Medicines Agency has recommended restricting the use of oral norfloxacin-containing medicines in urinary infections. The Agency’s Committee for Medicinal Products for Human Use (CHMP) has concluded that the marketing authorisations for oral norfloxacin-containing medicines, when used in the treatment of acute or chronic complicated pyelonephritis (kidney infection), should be withdrawn because the benefits of these medicines do not outweigh their risks in this indication.
This is based on the fact that the efficacy has not  been adequately demonstrated for this type of infection.

Norfloxacin is a fluoroquinolone antibiotic. Medicines containing norfloxacin are authorised in all European Union (EU) Member States under various  trade names for the treatment of infections, including simple or complicated urinary tract infections, infection of the prostate, uncomplicated gonorrhoea, several types of gastroenteritis and conjunctivitis.

The CHMP review of norfloxacin medicines was initiated on the request of the Belgian medicines regulatory agency. They questioned the efficacy of oral formulations of the medicine for complicated pyelonephritis, in comparison with other fluoroquinolones. In current practice, this disease is usually treated using either injectable antibiotics, or  other fluoroquinolones taken by mouth or given by injection.

Following evaluation of information provided by the companies, the CHMP, at its July 2008 meeting, noted that there was not enough clinical data to demonstrate the efficacy of oral treatment with norfloxacin-containing medicines in complicated pyelonephritis. Therefore, the CHMP concluded that the use of oral norfloxacin-containing medicines in the treatment of acute or chronic complicated pyelonephritis could no longer be supported.

The recommendation of the CHMP does not have an impact on the use of oral norfloxacin-containing medicines in other types of infection.

Doctors should not prescribe oral norfloxacin for complicated pyelonephritis and should consider switching patients already taking oral norfloxacin for this type of infection to an alternative antibiotic.
Patients who are taking oral formulations of norfloxacin-containing medicines to treat complicated pyelonephritis should discuss their treatment with their doctor if they continue to have symptoms or at their next scheduled visit.

Medicines containing norfloxacin include: Alenbit; Amicrobin; Baccidal; Bactracid; Barazan; Besflox; Constilax; Diperflox; Docnorfloxa; Esclebin; Firin; Flossac; Floxacin; Floxolone; Fluseminal; Grenis; Gyrablock; Lexinor; Lorcamin; Nalion; Nolicin; Norbactin; Norflocux; Norflohexal; Norflok; Norflosal; Norflox; Norfloxa; Norfloxacin; Norfloxacina; Norfloxacine; Norfloxacino; Norfluxx; Norocin; Noroxin; Noroxine; Norquin; Norsept; Pistofil; Renoxacin; Sebercim; Senro; Setanol; Sinobid; Sofasin; Steinaclox; Trizolin; Urobacid; Uroctal; Uroflox; Urospes; Uticina; Utinor; Vetamol; Xasmun; Zoroxin.

Source: EMEA recommends restricted use of oral norfloxacin-containing medicines in urinary infections (PDF)

The following is a list of drugs related to the animation:

Adrenoceptor-Activating & Other Sympathomimetic Drugs

Dobutamine, Ephedrine, Epinephrine, Hydroxyamphetamine, Isoproterenol, Methylphenidate, Naphazoline, Norepinephrine.

Adrenoceptor Antagonist Drugs

Acebutolol, Atenolol, Betaxolol, Bisoprolol, Carteolol, Carvedilo,l Carvedilol, Esmolol, Labetalol, Metoprolol, Nadolol, Pindolol, Propranolol, Sotalol, Timolol.

Cholinoceptor-Activating (Acetylcholine receptor stimulants)

Acetylcholine, Bethanechol, Carbachol, Cevimeline, Pilocarpine.

Cholinoceptor-Blocking Drugs (Cholinoceptor antagonists)

Atropine, Belladonna alkaloids, Clidinium, Cyclopentolate, Darifenacin, Dicyclomine, Homatropine,  l-Hyoscyamine, Mepenzolate, Methantheline, Methscopolamine, Oxybutynin, Propantheline, Scopolamine, Solifenacin, Tridihexethyl, Tropicamide, Trospium.

The U.S. Food and Drug Administration has approved a new drug to help patients suffering from overactive bladder (OAB). Toviaz (fesoterodine fumarate) works by relaxing the smooth muscle tissue of the bladder, thus reducing the urinary frequency, urge to urinate, and sudden urinary incontinence (leakage of urine), that are characteristic symptoms of OAB.

“Patients who suffer from overactive bladder face quality of life issues that can hamper their ability to enjoy life to its fullest,” said George Benson, M.D., deputy director, Division of Reproductive and Urologic Products at the FDA’s Center for Drug Evaluation and Research. “This new drug will provide an additional treatment option to help them manage problems with an overactive bladder.”

Toviaz will be available by prescription only, as an extended release tablet in either 4 mg or 8 mg dosage strengths. It is to be administered once daily. The recommended starting dose is 4 mg, which can be increased to 8 mg if needed, based upon individual response and tolerability. Toviaz is only approved for adults.

The safety and effectiveness of Toviaz were studied in two, 12-week, randomized controlled studies of the 4 mg and 8 mg doses. For the combined studies, a total of 554 patients received placebo, 554 patients received Toviaz 4 mg daily, and 566 patients received the drug 8 mg daily. The majority of patients were female with a mean age of 58 years. Toviaz is not approved for pediatric use.

In each of those two studies, the product showed a statistically significant and clinically meaningful improvement in decreasing the number of times patients needed to urinate per day, as well as the number of urine leaking episodes they experienced per day, as compared to placebo.

Common side effects associated with Toviaz included dry mouth and constipation. Less frequently reported side effects included dry eyes and trouble emptying the bladder.

Toviaz is not recommended in doses above 4 mg in those patients with severe reduction in kidney function or in those patients taking medications, such as ketoconazole, that block the metabolism of the drug. It should not be used in patients who suffer from urinary or gastric retention or in patients with uncontrolled, narrow-angle glaucoma. It should also not be used in patients with severe liver impairment. The product should be used with caution in patients who suffer from decreased gastrointestinal motility, such as those with severe constipation.

Health care professionals and consumers may report serious adverse events (side effects) or product quality problems with the use of this product to the FDA’s MedWatch Adverse Event Reporting program either online, by regular mail, fax or phone.

Source: FDA Approves Toviaz, a New Drug to Treat Overactive Bladder. FDA website